Glucocorticoid receptor agonist and conjugate thereof

Abstract

The present application relates to a glucocorticoid receptor agonist and a conjugate thereof. Specifically, the present application relates to a glucocorticoid receptor agonist, which is a compound as represented by formula I, or a pharmaceutically acceptable salt, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug thereof, exhibits a good agonistic activity, and has excellent therapeutic effects on inflammatory diseases such as rheumatoid arthritis.

Description

Glucocorticoid receptor agonists and conjugates thereof TECHNICAL FIELD

[0001] The present application relates to the field of medicine, in particular to a glucocorticoid receptor agonist and an antibody-drug conjugate thereof. Specifically, the present application provides a class of glucocorticoid receptor agonists, which have excellent agonistic activity. The present application also provides a drug-linker compound for conjugation, the drug being a glucocorticoid receptor agonist. The present application further provides an antibody-drug conjugate prepared by conjugating the drug-linker compound with an antibody, which has good drug conjugation uniformity and excellent therapeutic effect on inflammatory diseases such as rheumatoid arthritis. The present application further provides a preparation method of the glucocorticoid receptor agonist and the antibody-drug conjugate thereof and application thereof in the field of medicine. BACKGROUND

[0002] Steroid glucocorticoid receptor agonists are a class of therapeutic drugs widely used for the treatment of inflammatory and immune diseases. This class of drugs exerts anti-inflammatory effect by activating glucocorticoid receptors in cells, interfering with the recruitment of leukocytes to the inflammatory site, and inhibiting the formation and release of inflammatory mediators from leukocytes and tissue cells. Long-term and large-dose use of steroid glucocorticoid receptor agonist drugs may cause side effects such as infection, gastrointestinal reactions, endocrine disorders (such as moon face, buffalo hump, weight gain, hypokalemia, abnormal blood sugar and blood pressure, etc.), osteoporosis, etc. In order to reduce the above-mentioned side effects of steroid glucocorticoid receptor agonist drugs, inhalation preparations or preparations for topical application to the skin have made progress; in addition, the introduction of metabolically unstable groups into the steroid structure to accelerate inactivation and reduce systemic exposure is also one of the measures to reduce adverse reactions.

[0003] In recent years, in order to improve the effectiveness and safety of steroid glucocorticoid receptor agonist drugs, it is necessary to develop new drug structures, and in addition, conjugation with antibodies is also a new direction for the research and development of this class of drugs.

[0004] SUMMARY

[0005] The present application relates to a glucocorticoid receptor agonist and a linker conjugate and an antibody conjugate thereof, which have excellent agonistic activity and good drugability (including physicochemical properties, pharmacodynamic activity, pharmacokinetic properties, and safety), and are expected to be used for the treatment of inflammatory and immune diseases.

[0006] One object of the present application is to provide a glucocorticoid receptor agonist, which is a compound represented by Formula I, a pharmaceutically acceptable salt, a stereoisomer, a tautomer, a polymorph, a solvate, an N-oxide, an isotopically labeled compound, a metabolite or a prodrug thereof:

[0007] wherein,

[0008] Q1and Q2are each independently selected from hydrogen, halogen;

[0009] Q3is selected from hydrogen, C 1-6 alkyl;

[0010] Ring A and Ring B are each independently selected from aryl, heteroaryl, saturated carbocyclic ring, heterocyclyl;

[0011] Q4is each independently selected from hydrogen, C 1-6 alkyl, haloC 1-6 alkyl, halogen;

[0012] Q5and Q6are each independently selected from hydrogen, deuterium, C 1-6 alkyl, fluorine, or Q5and Q6are linked to adjacent carbons to form a ring;

[0013] Q7is each independently selected from hydrogen, C 1-6 alkyl, haloC 1-6 alkyl, halogen, C 1-6 alkoxy, hydroxy, hydroxyalkylene;

[0014] X is selected from HOCH2-, (HO)2P(=O)OCH2-, glycosyl-O-CH2-, HO-S(=O)2-OCH2-, FCH2S-, ClCH2S-, CNCH2S-, HO(CH2)2S-, FCH2O-, ClCH2O-, CNCH2O-;

[0015] Y is selected from a single bond, C 1-6 alkylene, carbonyl, -(CR a R b ) n -O-, -(CR a R b ) n -NR a -, -(CR a R b ) n -O-(CR a R b ) n -, -(CR a R b ) n -NR a -(CR a R b ) n -;

[0016] Z is selected from oxygen or nitrogen;

[0017] R1is selected from hydrogen, HO-(CRa R b ) n -、H2N-(CR a R b ) n -、HO-(CR a R b ) n -C(=O)-、H2N-(CR a R b ) n -C(=O)-、HO-(CR a R b ) n -OC(=O)-、H2N-(CR a R b ) n -OC(=O)-、HO-(CR a R b ) n -NR a -C(=O)-、H2N-(CR a R b ) n -NR a -C(=O)-;

[0018] when Z is oxygen, R2 is absent;

[0019] when Z is nitrogen, R2 is selected from hydrogen, C 1-6 alkyl; or R1 and R2 are linked to adjacent nitrogen atoms to form a ring, which is optionally substituted with one or more substituents selected from hydrogen, hydroxy, amino, hydroxyalkylene, aminoalkylene, C 1-6 alkyl, C 1-6 alkoxy, halogen, oxo; R a and R b are each independently selected from hydrogen, C 1-6 alkyl, haloC 1-6 alkyl, halogen, cycloalkyl, or R a and R b are linked to adjacent carbon atoms to form a ring;

[0020] m = 0, 1, 2, 3, or 4;

[0021] n is, at each occurrence, independently 1, 2, 3, 4, or 5.

[0022] It is another object of the present application to provide a pharmaceutical composition containing a compound of the present application, a pharmaceutically acceptable salt, stereoisomer, tautomer, polymorph, solvate, isotopically-labeled compound, metabolite, or prodrug thereof, and one or more pharmaceutically acceptable carriers.

[0023] Another object of the present application is to provide a use of the compound of the present application, a pharmaceutically acceptable salt, a stereoisomer, a tautomer, a polymorph, a solvate, an isotopically labeled compound, a metabolite or a prodrug thereof, or a pharmaceutical composition of the present application in the manufacture of a medicament for treating an inflammatory or immune disease.

[0024] Another object of the present application is to provide a use of the compound of the present application, a pharmaceutically acceptable salt, a stereoisomer, a tautomer, a polymorph, a solvate, an isotopically labeled compound, a metabolite or a prodrug thereof, or a pharmaceutical composition of the present application in the manufacture of a medicament for treating an inflammatory or immune disease.

[0025] Another object of the present application is to provide a method of treating an inflammatory or immune disease, comprising administering to a subject in need thereof an effective amount of the compound of the present application, a pharmaceutically acceptable salt, a stereoisomer, a tautomer, a polymorph, a solvate, an isotopically labeled compound, a metabolite or a prodrug thereof, or a pharmaceutical composition of the present application.

[0026] DETAILED DESCRIPTION

[0027] Compound

[0028] In one aspect, the present application provides a glucocorticoid receptor agonist, which is a compound of Formula I, a pharmaceutically acceptable salt, a stereoisomer, a tautomer, a polymorph, a solvate, an N-oxide, an isotopically labeled compound, a metabolite or a prodrug thereof:

[0029] wherein,

[0030] Q1and Q2are each independently selected from hydrogen, halogen;

[0031] Q3is selected from hydrogen, C 1-6 alkyl;

[0032] Ring A and Ring B are each independently selected from aryl, heteroaryl, saturated carbocyclic ring, heterocyclyl;

[0033] Q4is each independently selected from hydrogen, C 1-6 alkyl, haloC 1-6 alkyl, halogen;

[0034] Q5and Q6are each independently selected from hydrogen, deuterium, C 1-6 alkyl, fluorine, or Q5and Q6are linked to form a ring with the adjacent carbon;

[0035] Q7is each independently selected from hydrogen, C 1-6 alkyl, haloC 1-6 alkyl, halogen, C 1-6 alkoxy, hydroxy, hydroxyalkylene;

[0036] X is selected from the group consisting of HOCH2-, (HO)2P(=O)OCH2-, glycosyl-O-CH2-, HO-S(=O)2-OCH2-, FCH2S-, ClCH2S-, CNCH2S-, HO(CH2)2S-, FCH2O-, ClCH2O-, CNCH2O-;

[0037] Y is selected from the group consisting of a single bond, C 1-6 alkylene, carbonyl, -(CR a R b ) n -O-, -(CR a R b ) n -NR a -(CR a R b ) n -O-(CR a R b ) n -(CR a R b ) n -NR a -(CR a R b ) n -;

[0038] Z is selected from oxygen or nitrogen;

[0039] R1is selected from the group consisting of hydrogen, HO-(CR a R b ) n -, H2N-(CR a R b ) n -, HO-(CR a R b ) n -C(=O)-, H2N-(CR a R b ) n -C(=O)-, HO-(CR a R b ) n -OC(=O)-, H2N-(CR a R b ) n -OC(=O)-, HO-(CR a R b ) n -NR a -C(=O)-, H2N-(CR a R b ) n -NRa -C(=O)-;

[0040] when Z is oxygen, R2is absent;

[0041] when Z is nitrogen, R2is selected from hydrogen, C 1-6 alkyl; or R1and R2are linked to the adjacent nitrogen atom to form a ring, which is optionally substituted with one or more substituents selected from hydrogen, hydroxyl, amino, hydroxyalkylene, aminoalkylene, C 1-6 alkyl, C 1-6 alkoxy, halo, oxo; a and R b are each independently selected from hydrogen, C 1-6 alkyl, haloC 1-6 alkyl, halo, cycloalkyl, or R a and R b are linked to the adjacent carbon atom to form a ring;

[0042] m = 0, 1, 2, 3, or 4;

[0043] n, at each occurrence, is independently 1, 2, 3, 4, or 5.

[0044] In some embodiments, the compound has the structure of Formula I-A:

[0045] wherein, ring A, ring B, Q1-Q7, R1-R2, X, Y, Z, and m are as described in any one of the above.

[0046] In some embodiments, when Z is nitrogen, R1and R2are not both hydrogen; and, when Z is nitrogen, R1is hydrogen, R2is not methyl.

[0047] In some embodiments, when Z is nitrogen, R1and R2are not both hydrogen; and, when Z is nitrogen, R1is hydrogen, R2is not C 1-6 alkyl.

[0048] In some embodiments, ring A and ring B are each independently selected from C 6-10 aryl, 5-10 membered heteroaryl, C 3-12 saturated carbocyclic, 3-10 membered heterocyclyl.

[0049] In some embodiments, ring A and ring B are each independently selected from phenyl, 5-6 membered heteroaryl, C 3-6 saturated carbocyclic, 3-6 membered heterocyclyl.

[0050] In some embodiments, ring A and ring B are each independently selected from phenyl and 5-6 membered heteroaryl.

[0051] In some embodiments, ring A and ring B are phenyl.

[0052] In some embodiments, Q1and Q2are each independently selected from hydrogen, F, and Cl.

[0053] In some embodiments, Q1and Q2are each independently selected from hydrogen and F.

[0054] In some embodiments, Q3is hydrogen.

[0055] In some embodiments, Q4is hydrogen.

[0056] In some embodiments, Q5and Q6are each independently selected from hydrogen, deuterium, C 1-6 alkyl, fluoro, or Q5and Q6are taken together with the adjacent carbon atoms to form a C 3-12 saturated carbocyclic or 3-10 membered heterocyclic ring.

[0057] In some embodiments, Q5and Q6are each hydrogen.

[0058] In some embodiments, Q7is each independently selected from hydrogen, C 1-6 alkyl, haloC 1-6 alkyl, halo, C 1-6 alkoxy, hydroxy, hydroxyC 1-6 alkyl.

[0059] In some embodiments, Q7is hydrogen.

[0060] In some embodiments, X is selected from HOCH2-, FCH2S-, ClCH2S-, CNCH2S-, HO(CH2)2S-, FCH2O-, ClCH2O-, CNCH2O-.

[0061] In some embodiments, X is selected from HOCH2- and FCH2S-.

[0062] In some embodiments, Y is a single bond.

[0063] In some embodiments, R1is selected from hydrogen, HO-(CR a R b ) n -, H2N-(CR a R b ) n -, HO-(CR a R b ) n -C(=O)-, H2N-(CR a R b ) n -C(=O)-, HO-(CR a R b) n -OC(=O)-, H2N-(CR a R b ) n -OC(=O)-, HO-(CR a R b ) n -NR a -C(=O)-, H2N-(CR a R b ) n -NR a -C(=O)-;

[0064] R a and R b are each independently selected from hydrogen, C 1-6 alkyl, haloC 1-6 alkyl, halo, C 3-6 cycloalkyl, or R a and R b are joined to form a C 3-6 cycloalkyl or 3-6 membered heterocyclyl.

[0065] In some embodiments, R1is selected from hydrogen, HO-(CHR a ) n -, H2N-(CHR a ) n -, HO-(CHR a ) n -C(=O)-, H2N-(CHR a ) n -C(=O)-, HO-(CHR a ) n -OC(=O)-, H2N-(CHR a ) n -OC(=O)-, HO-(CHR a ) n -NR a -C(=O)-, H2N-(CHR a ) n -NR a -C(=O)-;

[0066] R a and R b are each independently selected from hydrogen, C 1-6 alkyl and C 3-6 cycloalkyl.

[0067] In some embodiments, when Z is nitrogen, R2is selected from hydrogen, C 1-6alkyl; or R1and R2are linked to the adjacent nitrogen atom to form a 3-12 membered heterocyclic ring, which is optionally substituted with one or more substituents selected from hydrogen, hydroxy, amino, hydroxyC 1-6 alkylene, aminoC 1-6 alkylene, C 1-6 alkyl, C 1-6 alkoxy, halo, oxo; R1and R2are not both hydrogen; and when R1is hydrogen, R2is not methyl.

[0068] In some embodiments, when Z is nitrogen, R2is selected from hydrogen, C 1-6 alkyl; or R1and R2are linked to the adjacent nitrogen atom to form a 3-12 membered heterocyclic ring, which is optionally substituted with one or more substituents selected from hydrogen, hydroxy, amino, hydroxyC 1-6 alkylene, aminoC 1-6 alkylene, C 1-6 alkyl, C 1-6 alkoxy, halo, oxo; R1and R2are not both hydrogen; and when R1is hydrogen, R2is not C 1-6 alkyl.

[0069] In some embodiments, Z is nitrogen.

[0070] In some embodiments, R a and R b are each independently selected from hydrogen, C 1-6 alkyl, haloC 1-6 alkyl, halo, C 3- 6cycloalkyl, or R a and R b are linked to form a C 3-6 saturated carbocyclic or 3-8 membered heterocyclic ring.

[0071] In another aspect, the present application provides a glucocorticoid receptor agonist, which is a compound of Formula II, a pharmaceutically acceptable salt, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotopically-labeled compound, metabolite, or prodrug thereof:

[0072] wherein,

[0073] Q1and Q2are each independently selected from hydrogen, fluoro, chloro;

[0074] Q3is selected from hydrogen, methyl;

[0075] Ring A and Ring B are each independently selected from phenyl or heteroaryl;

[0076] Q4is each independently selected from hydrogen, methyl, fluoro, or chloro;

[0077] Q5and Q6are each independently selected from hydrogen, deuterium, or fluorine;

[0078] Q7is each independently selected from hydrogen, C 1-6 alkyl, halogen, C 1-6 alkoxy, hydroxyl, hydroxyalkylene;

[0079] X is selected from HOCH2-, (HO)2P(=O)OCH2-, glycosyl-O-CH2-, HO-S(=O)2-OCH2-, FCH2S-, ClCH2S-, CNCH2S-, HO(CH2)2S-, FCH2O-, ClCH2O-, CNCH2O-;

[0080] Y is selected from a single bond, C 1-6 alkylene, carbonyl, -(CR a R b ) n -O-, -(CR a R b ) n -NR a -, -(CR a R b ) n -O-(CR a R b ) n -, -(CR a R b ) n -NR a -(CR a R b ) n -;

[0081] Z is selected from oxygen or nitrogen;

[0082] R1is selected from hydrogen, HO-(CR a R b ) n -, H2N-(CR a R b ) n -, HO-(CR a R b ) n -C(=O)-, H2N-(CR a R b ) n -C(=O)-, HO-(CR a R b ) n -OC(=O)-, H2N-(CR a R b ) n -OC(=O)-, HO-(CRa R b ) n -NR a -C(=O)-, H2N-(CR a R b ) n -NR a -C(=O)-;

[0083] when Z is oxygen, R2 is absent;

[0084] when Z is nitrogen, R2 is selected from hydrogen, C 1-6 alkyl; or R1 and R2 are linked to adjacent nitrogen atoms to form a ring, which is optionally substituted with one or more substituents selected from hydrogen, hydroxy, amino, hydroxyalkylene, aminoalkylene, C 1-6 alkyl, C 1-6 alkoxy, halo, oxo;

[0085] R a and R b are each independently selected from hydrogen, C 1-6 alkyl, haloC 1-6 alkyl, halo, cycloalkyl, or R a and R b are linked to adjacent carbon atoms to form a ring;

[0086] m = 0, 1, 2, 3, or 4;

[0087] n, at each occurrence, is independently 1, 2, 3, 4, or 5.

[0088] In some embodiments, when Z is nitrogen, R1 and R2 are not both hydrogen; and, when Z is nitrogen, R1 is hydrogen, R2 is not methyl.

[0089] In some embodiments, when Z is nitrogen, R1 and R2 are not both hydrogen; and, when Z is nitrogen, R1 is hydrogen, R2 is not C 1-6 alkyl.

[0090] In some embodiments, ring A and ring B are each independently selected from phenyl or 5-10 membered heteroaryl.

[0091] In some embodiments, Q7 is independently selected from hydrogen, C 1-6 alkyl, halo, C 1-6 alkoxy, hydroxy, hydroxyC 1-6 alkyl.

[0092] In some embodiments, when Z is nitrogen, R2 is selected from hydrogen, C 1-6alkyl; or R1and R2, together with the adjacent nitrogen atom, join to form a 3-12 membered heterocyclic ring, optionally substituted with one or more substituents selected from the group consisting of hydrogen, hydroxyl, amino, hydroxyC 1-6 alkylene, aminoC 1-6 alkylene, C 1-6 alkyl, C 1-6 alkoxy, halo, oxo; R1and R2are not both hydrogen; and when R1is hydrogen, R2is not methyl.

[0093] In some embodiments, when Z is nitrogen, R2is selected from the group consisting of hydrogen, C 1-6 alkyl; or R1and R2, together with the adjacent nitrogen atom, join to form a 3-12 membered heterocyclic ring, optionally substituted with one or more substituents selected from the group consisting of hydrogen, hydroxyl, amino, hydroxyC 1-6 alkylene, aminoC 1-6 alkylene, C 1-6 alkyl, C 1-6 alkoxy, halo, oxo; R1and R2are not both hydrogen; and when R1is hydrogen, R2is not C 1-6 alkyl.

[0094] In some embodiments, R a and R b are each independently selected from the group consisting of hydrogen, C 1-6 alkyl, haloC 1-6 alkyl, halo, C 3- 6cycloalkyl, or R a and R b join to form a C 3-6 saturated carbocyclic ring or a 3-8 membered heterocyclic ring.

[0095] In another aspect, the present application provides a glucocorticoid receptor agonist, which is a compound represented by Formula III, a pharmaceutically acceptable salt, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotopically-labeled compound, metabolite, or prodrug thereof:

[0096] wherein,

[0097] Q1and Q2are each independently selected from hydrogen or fluorine;

[0098] Q4is each independently selected from hydrogen, methyl;

[0099] Q5and Q6are each independently selected from hydrogen, deuterium, or fluorine;

[0100] Q7is each independently selected from hydrogen, C 1-6 alkyl, halo, C 1-6 alkoxy, hydroxyl, hydroxyalkylene;

[0101] X is selected from the group consisting of HOCH2-, (HO)2P(=O)OCH2-, glycosyl-O-CH2-, HO-S(=O)2-OCH2-, FCH2S-, ClCH2S-, CNCH2S-, HO(CH2)2S-, FCH2O-, ClCH2O-, CNCH2O-;

[0102] Y is selected from the group consisting of a single bond, C 1-6 alkylene, carbonyl, -(CR a R b ) n -O-, -(CR a R b ) n -NR a -(CR a R b ) n -O-(CR a R b ) n -, a R b ) n -NR a -(CR a R b ) n -;

[0103] Z is selected from oxygen or nitrogen;

[0104] R1is selected from the group consisting of hydrogen, HO-(CR a R b ) n -, H2N-(CR a R b ) n -, HO-(CR a R b ) n -C(=O)-, H2N-(CR a R b ) n -C(=O)-, HO-(CR a R b ) n -OC(=O)-, H2N-(CR a R b ) n -OC(=O)-, HO-(CR a R b ) n -NR a -C(=O)-, H2N-(CR a R b ) n -NRa -C(=O)-;

[0105] when Z is oxygen, R2is absent;

[0106] when Z is nitrogen, R2is selected from hydrogen, C 1-6 alkyl; or R1and R2are linked to the adjacent nitrogen atom to form a ring, which is optionally substituted with one or more substituents selected from hydrogen, hydroxy, amino, hydroxyalkylene, aminoalkylene, C 1-6 alkyl, C 1-6 alkoxy, halo, oxo;

[0107] R a and R b are each independently selected from hydrogen, C 1-6 alkyl, haloC 1-6 alkyl, halo, cycloalkyl, or R a and R b are linked to the adjacent carbon atom to form a ring;

[0108] m = 0, 1, 2, 3, or 4;

[0109] n, at each occurrence, is independently 1, 2, 3, 4, or 5.

[0110] In some embodiments, the compound is of the structure of Formula III-A:

[0111] wherein Q1, Q2, Q4-Q7, R1-R2, X, Y, Z, and m are as described in any one of the above.

[0112] In some embodiments, when Z is nitrogen, R1and R2are not both hydrogen; and, when Z is nitrogen, R1is hydrogen, R2is not methyl.

[0113] In some embodiments, when Z is nitrogen, R1and R2are not both hydrogen; and, when Z is nitrogen, R1is hydrogen, R2is not C 1-6 alkyl.

[0114] In some embodiments, Q7is each independently selected from hydrogen, C 1-6 alkyl, halo, C 1-6 alkoxy, hydroxy, hydroxyC 1-6 alkyl.

[0115] In some embodiments, when Z is nitrogen, R2is selected from hydrogen, C 1-6 alkyl; or R1and R2are linked to the adjacent nitrogen atom to form a 3-12 membered heterocyclic ring, which is optionally substituted with one or more substituents selected from hydrogen, hydroxy, amino, hydroxyC 1-6 alkylene, aminoC 1-6alkylene, C 1-6 alkyl, C 1-6 alkoxy, halo, oxo; R1and R2are not both hydrogen; and when R1is hydrogen, R2is not methyl.

[0116] In some embodiments, when Z is nitrogen, R2is selected from hydrogen, C 1-6 alkyl; or R1and R2are joined with the adjacent nitrogen atom to form a 3-12 membered heterocyclic ring, which is optionally substituted with one or more substituents selected from hydrogen, hydroxy, amino, hydroxyC 1-6 alkylene, aminoC 1-6 alkylene, C 1-6 alkyl, C 1-6 alkoxy, halo, oxo; R1and R2are not both hydrogen; and when R1is hydrogen, R2is not C 1-6 alkyl.

[0117] In some embodiments, R a and R b are each independently selected from hydrogen, C 1-6 alkyl, haloC 1-6 alkyl, halo, C 3- 6cycloalkyl, or R a and R b are joined with the adjacent carbon atom to form a C 3-6 saturated carbocyclic ring or a 3-8 membered heterocyclic ring.

[0118] In another aspect, the present application provides a glucocorticoid receptor agonist, which is a compound represented by Formula IV, a pharmaceutically acceptable salt, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotopically-labeled compound, metabolite, or prodrug thereof:

[0119] wherein,

[0120] Q1and Q2are each independently selected from hydrogen or fluoro;

[0121] X is selected from HOCH2-, (HO)2P(=O)OCH2-, glycosyl-O-CH2-, HO-S(=O)2-OCH2-, FCH2S-, ClCH2S-, CNCH2S-, HO(CH2)2S-, FCH2O-, ClCH2O-, CNCH2O-;

[0122] Y is selected from a single bond, C 1-6 alkylene, carbonyl, -(CR a R b ) n -O-, -(CR a R b )n -NR a -, -(CR a R b ) n -O-(CR a R b ) n -, -(CR a R b ) n -NR a -(CR a R b ) n - ;

[0123] Z is selected from oxygen or nitrogen;

[0124] R1is selected from hydrogen, HO-(CR a R b ) n -, H2N-(CR a R b ) n -, HO-(CR a R b ) n -C(=O)-, H2N-(CR a R b ) n -C(=O)-, HO-(CR a R b ) n -OC(=O)-, H2N-(CR a R b ) n -OC(=O)-, HO-(CR a R b ) n -NR a -C(=O)-, H2N-(CR a R b ) n -NR a -C(=O)-;

[0125] when Z is oxygen, R2is absent;

[0126] when Z is nitrogen, R2is selected from hydrogen, C 1-6 alkyl; or R1and R2are linked to the adjacent nitrogen atom to form a ring, said ring being optionally substituted with one or more substituents selected from hydrogen, hydroxy, amino, hydroxyalkylene, aminoalkylene, C 1-6 alkyl, C 1-6 alkoxy, halogen, oxo;

[0127] R a and Rb each independently selected from hydrogen, C 1-6 alkyl, haloC 1-6 alkyl, halo, cycloalkyl, or R a and R b together with the adjacent carbon atom form a ring;

[0128] n at each occurrence is independently 1, 2, 3, 4, or 5.

[0129] In some embodiments, the compound is of the structure of Formula IV-A:

[0130] wherein Q1, Q2, R1-R2, X, Y, and Z are as described in any one of the above.

[0131] In some embodiments, when Z is nitrogen, R1and R2are not both hydrogen; and when Z is nitrogen and R1is hydrogen, R2is not methyl.

[0132] In some embodiments, when Z is nitrogen, R1and R2are not both hydrogen; and when Z is nitrogen and R1is hydrogen, R2is not C 1-6 alkyl.

[0133] In some embodiments, when Z is nitrogen, R2is selected from hydrogen, C 1-6 alkyl; or R1and R2are joined to the adjacent nitrogen atom to form a 3-12 membered heterocyclic ring, which 3-12 membered heterocyclic ring is optionally substituted with one or more substituents selected from hydrogen, hydroxyl, amino, hydroxylC 1-6 alkylene, aminoC 1-6 alkylene, C 1-6 alkyl, C 1-6 alkoxy, halo, oxo; R1and R2are not both hydrogen; and when R1is hydrogen, R2is not methyl.

[0134] In some embodiments, when Z is nitrogen, R2is selected from hydrogen, C 1-6 alkyl; or R1and R2are joined to the adjacent nitrogen atom to form a 3-12 membered heterocyclic ring, which 3-12 membered heterocyclic ring is optionally substituted with one or more substituents selected from hydrogen, hydroxyl, amino, hydroxylC 1-6 alkylene, aminoC 1-6 alkylene, C 1-6 alkyl, C 1-6 alkoxy, halo, oxo; R1and R2are not both hydrogen; and when R1is hydrogen, R2is not C 1-6 alkyl.

[0135] In some embodiments, R a and R b each independently selected from hydrogen, C1-6 Alkyl, Halogenated C 1-6 Alkyl, halogen, C 3- 6-cycloalkyl, or R a and R b Connected to adjacent carbon atoms to form C 3-6 Saturated carbon rings or 3-8 membered heterocycles.

[0136] On the other hand, this application provides a glucocorticoid receptor agonist, which is a compound of formula V, a pharmaceutically acceptable salt thereof, a stereoisomer, a tautomer, a polymorph, a solvate, an N-oxide, an isotopically labeled compound, a metabolite, or a prodrug:

[0137] in,

[0138] Q1 and Q2 are each independently selected from hydrogen or fluorine;

[0139] X is selected from HOCH2-, (HO)2P(=O)OCH2-, glycosyl-O-CH2-, HO-S(=O)2-OCH2-, FCH2S-, ClCH2S-, CNCH2S-, HO(CH2)2S-, FCH2O-, ClCH2O-, CNCH2O-;

[0140] Y is selected from single bond, C 1-6 Alkylene, carbonyl, -(CR) a R b ) n -O-、-(CR a R b ) n -NR a -、-(CR a R b ) n -O-(CR a R b ) n -、-(CR a R b ) n -NR a -(CR a R b ) n -;

[0141] Z is selected from oxygen or nitrogen;

[0142] R1 is selected from hydrogen, HO-(CR) a R b ) n -、H2N-(CR a R b ) n -、HO-(CRa R b ) n -C(=O)-, H2N-(CR a R b ) n -C(=O)-, HO-(CR a R b ) n -OC(=O)-, H2N-(CR a R b ) n -OC(=O)-, HO-(CR a R b ) n -NR a -C(=O)-, H2N-(CR a R b ) n -NR a -C(=O)-;

[0143] when Z is oxygen, R2 is absent;

[0144] when Z is nitrogen, R2 is selected from hydrogen, C 1-6 alkyl; or R1 and R2 are linked to adjacent nitrogen atoms to form a ring, which is optionally substituted with one or more substituents selected from hydrogen, hydroxy, amino, hydroxyalkylene, aminoalkylene, C 1-6 alkyl, C 1-6 alkoxy, halogen, carbonyl;

[0145] R a and R b are each independently selected from hydrogen, C 1-6 alkyl, haloC 1-6 alkyl, halogen, cycloalkyl, or R a and R b are linked to adjacent carbon atoms to form a ring;

[0146] n is, at each occurrence, independently 1, 2, 3, 4, or 5.

[0147] In some embodiments, when Z is nitrogen, R1 and R2 are not both hydrogen; and, when Z is nitrogen, R1 is hydrogen, R2 is not methyl.

[0148] In some embodiments, when Z is nitrogen, R1 and R2 are not both hydrogen; and, when Z is nitrogen, R1 is hydrogen, R2 is not C 1-6 alkyl.

[0149] In some embodiments, when Z is nitrogen, R2 is selected from hydrogen, C 1-6alkyl; or R1and R2, together with the adjacent nitrogen atom, join to form a 3-12 membered heterocyclic ring, said 3-12 membered heterocyclic ring being optionally substituted with one or more substituents selected from the group consisting of hydrogen, hydroxy, amino, hydroxyC 1-6 alkylene, aminoC 1-6 alkylene, C 1-6 alkyl, C 1-6 alkoxy, halo, oxo; R1and R2are not both hydrogen; and when R1is hydrogen, R2is not methyl.

[0150] In some embodiments, when Z is nitrogen, R2is selected from the group consisting of hydrogen, C 1-6 alkyl; or R1and R2, together with the adjacent nitrogen atom, join to form a 3-12 membered heterocyclic ring, said 3-12 membered heterocyclic ring being optionally substituted with one or more substituents selected from the group consisting of hydrogen, hydroxy, amino, hydroxyC 1-6 alkylene, aminoC 1-6 alkylene, C 1-6 alkyl, C 1-6 alkoxy, halo, oxo; R1and R2are not both hydrogen; and when R1is hydrogen, R2is not C 1-6 alkyl.

[0151] In some embodiments, R a and R b are each independently selected from the group consisting of hydrogen, C 1-6 alkyl, haloC 1-6 alkyl, halo, C 3- 6cycloalkyl, or R a and R b , together with the adjacent carbon atom, join to form a C 3-6 saturated carbocyclic or 3-8 membered heterocyclic ring.

[0152] In another aspect, the present application provides a glucocorticoid receptor agonist, which is a compound of Formula VI, a pharmaceutically acceptable salt, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotopically-labeled compound, metabolite, or prodrug thereof:

[0153] wherein,

[0154] Q1and Q2are each independently selected from hydrogen or fluoro;

[0155] X is selected from HOCH2-, (HO)2P(=O)OCH2-, FCH2S-;

[0156] Y is selected from a single bond, C 1-6 alkylene, carbonyl, -(CR a R b ) n -O-, -(CR a Rb ) n -NR a -、-(CR a R b ) n -O-(CR a R b ) n -、-(CR a R b ) n -NR a -(CR a R b ) n -;

[0157] Z is selected from oxygen or nitrogen;

[0158] R1is selected from hydrogen, HO-(CR a R b ) n -, H2N-(CR a R b ) n -, HO-(CR a R b ) n -C(=O)-, H2N-(CR a R b ) n -C(=O)-, HO-(CR a R b ) n -OC(=O)-, H2N-(CR a R b ) n -OC(=O)-, HO-(CR a R b ) n -NR a -C(=O)-, H2N-(CR a R b ) n -NR a -C(=O)-;

[0159] when Z is oxygen, R2is absent;

[0160] when Z is nitrogen, R2is selected from hydrogen, C 1-6 alkyl; or R1and R2are linked to the adjacent nitrogen atom to form a ring, said ring being optionally substituted with one or more substituents selected from hydrogen, hydroxy, amino, hydroxyalkylene, aminoalkylene, C 1-6 alkyl, C 1-6 alkoxy, halogen, oxo;

[0161] Ra and R b Each is independently selected from hydrogen and C. 1-6 Alkyl, Halogenated C 1-6 Alkyl, halogen, cycloalkyl, or R a and R b It connects with adjacent carbon atoms to form a ring;

[0162] Each time n appears, it is independently 1, 2, 3, 4 or 5.

[0163] In some embodiments, when Z is nitrogen, R1 and R2 are not both hydrogen; and when Z is nitrogen and R1 is hydrogen, R2 is not methyl.

[0164] In some embodiments, when Z is nitrogen, R1 and R2 are not both hydrogen; and when Z is nitrogen and R1 is hydrogen, R2 is not C. 1-6 alkyl.

[0165] In some implementation schemes, when Z is nitrogen, R2 is selected from hydrogen, C 1-6 Alkyl group; or R1 and R2 are attached to adjacent nitrogen atoms to form a 3-12 membered heterocycle, wherein the 3-12 membered heterocycle is optionally surrounded by one or more atoms selected from hydrogen, hydroxyl, amino, or hydroxyl C. 1-6 Alkylene, amino C 1-6 Alkylene, C 1-6 Alkyl, C 1-6 The alkoxy, halogen, or oxo groups are substituted; R1 and R2 are not both hydrogen; and when R1 is hydrogen, R2 is not methyl.

[0166] In some implementation schemes, when Z is nitrogen, R2 is selected from hydrogen, C 1-6 Alkyl group; or R1 and R2 are attached to an adjacent nitrogen atom to form a 3-12 membered heterocycle, said 3-12 membered heterocycle optionally being bonded by one or more atoms selected from hydrogen, hydroxyl, amino, hydroxyl C 1-6 Alkylene, amino C 1-6 Alkylene, C 1-6 Alkyl, C 1-6 Substituents include alkoxy, halogen, and oxo groups; R1 and R2 are not both hydrogen; and when R1 is hydrogen, R2 is not C. 1-6 alkyl.

[0167] In some implementation schemes, R a and R b Each is independently selected from hydrogen and C. 1-6 Alkyl, Halogenated C 1-6 Alkyl, halogen, C 3- 6-cycloalkyl, or R a and R b Connected to adjacent carbon atoms to form C 3-6saturated carbocyclic or 3-8 membered heterocyclic ring.

[0168] In another aspect, the present application provides a glucocorticoid receptor agonist which is a compound of Formula VII, a pharmaceutically acceptable salt, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotopically-labeled compound, metabolite, or prodrug thereof:

[0169] wherein,

[0170] Q1and Q2are each independently selected from hydrogen or fluoro;

[0171] X is selected from HOCH2-, (HO)2P(=O)OCH2-, FCH2S-;

[0172] Z is selected from oxygen or nitrogen;

[0173] R1is selected from hydrogen, HO-(CR a R b ) n -OC(=O)-, H2N-(CR a R b ) n -OC(=O)-, HO-(CR a R b ) n -C(=O)-, H2N-(CR a R b ) n -C(=O)-, HO-(CR a R b ) n -OC(=O)-, H2N-(CR a R b ) n -OC(=O)-, HO-(CR a R b ) n -NR a -C(=O)-, H2N-(CR a R b ) n -NR a -C(=O)-;

[0174] when Z is oxygen, R2is absent;

[0175] when Z is nitrogen, R2is selected from hydrogen, C 1-6 alkyl; or R1and R2are linked to the adjacent nitrogen atom to form a ring, which is optionally substituted with one or more substituents selected from hydrogen, hydroxy, amino, hydroxyalkylene, aminoalkylene, C 1-6 alkyl, C 1-6 alkoxy, halo, oxo;

[0176] R a and R b are each independently selected from hydrogen, C 1-6 alkyl, haloC 1-6 alkyl, halo, cycloalkyl, or R a and R b are connected to adjacent carbon atoms to form a ring;

[0177] n is, at each occurrence, independently 1, 2, 3, 4, or 5.

[0178] In some embodiments, the compound is of the structure of Formula VII-A:

[0179] wherein Q1, Q2, R1-R2, X, and Z are as described in any one of the above.

[0180] In some embodiments, in any one of Formulas I-V, when R1and R2are selected from hydrogen, and Z is nitrogen, X is not HOCH2-, (HO)2P(=O)OCH2-, FCH2S-.

[0181] In some embodiments, when Z is nitrogen, R1and R2are not both hydrogen; and, when Z is nitrogen, R1is hydrogen, R2is not methyl.

[0182] In some embodiments, when Z is nitrogen, R1and R2are not both hydrogen; and, when Z is nitrogen, R1is hydrogen, R2is not C 1-6 alkyl.

[0183] In some embodiments, when Z is nitrogen, R2is selected from hydrogen, C 1-6 alkyl; or R1and R2are connected to adjacent nitrogen atoms to form a 3-12 membered heterocyclic ring, which 3-12 membered heterocyclic ring is optionally substituted with one or more substituents selected from hydrogen, hydroxyl, amino, hydroxylC 1-6 alkylene, aminoC 1-6 alkylene, C 1-6 alkyl, C 1-6 alkoxy, halo, oxo; R1and R2are not both hydrogen; and, when R1is hydrogen, R2is not methyl.

[0184] In some embodiments, when Z is nitrogen, R2is selected from hydrogen, C 1-6 alkyl; or R1and R2are connected to adjacent nitrogen atoms to form a 3-12 membered heterocyclic ring, which 3-12 membered heterocyclic ring is optionally substituted with one or more substituents selected from hydrogen, hydroxyl, amino, hydroxylC 1-6 alkylene, aminoC 1-6 alkylene, C 1-6 alkyl, C 1-6substituted with alkyl, halo, alkoxy, haloalkyl, haloalkoxy, oxo, or -OH; R1and R2are not both hydrogen; and when R1is hydrogen, R2is not C 1-6 alkyl.

[0185] In some embodiments, R a and R b are each independently selected from hydrogen, C 1-6 alkyl, haloC 1-6 alkyl, halo, C 3- 6 cycloalkyl, or R a and R b are taken together with the adjacent carbon atom to form a C 3-6 saturated carbocyclic or 3-8 membered heterocyclic ring.

[0186] In some embodiments, Z is nitrogen; R1is selected from HO-(CR a R b ) n -, H2N-(CR a R b ) n -, HO-(CR a R b ) n -C(=O)-, H2N-(CR a R b ) n -C(=O)-, HO-(CR a R b ) n -OC(=O)-, H2N-(CR a R b ) n -OC(=O)-, HO-(CR a R b ) n -NR a -C(=O)-, H2N-(CR a R b ) n -NR a -C(=O)-; and R2is selected from hydrogen or C 1-6 alkyl.

[0187] In another aspect, the present application provides a glucocorticoid receptor agonist that is a compound of Formula VIII, a pharmaceutically acceptable salt, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotopically-labeled compound, metabolite, or prodrug thereof:

[0188] wherein,

[0189] Q1and Q2are each independently selected from hydrogen or fluoro;

[0190] X is selected from HOCH2-, (HO)2P(=O)OCH2-, FCH2S-;

[0191] R1is selected from HO-(CR a R b ) n -OC(=O)-, H2N-(CR a R b ) n -OC(=O)-, HO-(CR a R b ) n -C(=O)-, H2N-(CR a R b ) n -C(=O)-, HO-(CR a R b ) n -OC(=O)-, H2N-(CR a R b ) n -OC(=O)-, HO-(CR a R b ) n -NR a -C(=O)-, H2N-(CR a R b ) n -NR a -C(=O)-;

[0192] R a and R b are each independently selected from hydrogen, C 1-6 alkyl, haloC 1-6 alkyl, halogen, cycloalkyl, or R a and R b are joined to form a ring with the adjacent carbon atom;

[0193] n is, at each occurrence, independently 1, 2, 3, 4, or 5.

[0194] In some embodiments, the compound has a structure according to Formula VIII-A:

[0195] wherein Q1, Q2, R1, X are as described in any one of the preceding items.

[0196] In some embodiments, R a and R b are each independently selected from hydrogen, C 1-6 alkyl, haloC 1-6 alkyl, halogen, C 3-6cycloalkyl, or R a and R b with the adjacent carbon atom to form a C 3-6 saturated carbocycle or 3-8 membered heterocycle.

[0197] In another aspect, the present application provides a glucocorticoid receptor agonist that is a compound of Formula IX, a pharmaceutically acceptable salt, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotopically-labeled compound, metabolite, or prodrug thereof:

[0198] wherein,

[0199] Q1and Q2are each independently selected from hydrogen or fluoro;

[0200] R1is selected from HO-(CR a R b ) n -, H2N-(CR a R b ) n -, HO-(CR a R b ) n -C(=O)-, H2N-(CR a R b ) n -C(=O)-, HO-(CR a R b ) n -OC(=O)-, H2N-(CR a R b ) n -OC(=O)-, HO-(CR a R b ) n -NR a -C(=O)-, H2N-(CR a R b ) n -NR a -C(=O)-;

[0201] R2is selected from hydrogen, C 1-6 alkyl;

[0202] R a and R b are each independently selected from hydrogen, C 1-6 alkyl, C 3-6 cycloalkyl;

[0203] n is, at each occurrence, independently 1, 2, or 3.

[0204] In some embodiments, the compound has the structure of Formula IX-A:

[0205] wherein Q1, Q2, R1, R2 are as described in any one of the above.

[0206] In another aspect, the present application provides a glucocorticoid receptor agonist, which is a compound of Formula X, a pharmaceutically acceptable salt, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotopically-labeled compound, metabolite, or prodrug thereof:

[0207] wherein,

[0208] Q1and Q2are each independently selected from hydrogen or fluoro;

[0209] R1is selected from HO-(CR a R b ) n -OC(=O)-, H2N-(CR a R b ) n -OC(=O)-, HO-(CR a R b ) n -C(=O)-, H2N-(CR a R b ) n -C(=O)-, HO-(CR a R b ) n -OC(=O)-, H2N-(CR a R b ) n -OC(=O)-, HO-(CR a R b ) n -NR a -C(=O)-, H2N-(CR a R b ) n -NR a -C(=O)-;

[0210] R2is selected from hydrogen, C 1-6 alkyl;

[0211] R a and R b are each independently selected from hydrogen, C 1-6 alkyl, C 3-6 cycloalkyl;

[0212] n is, at each occurrence, independently 1, 2, or 3.

[0213] In some embodiments, the compound has a structure according to Formula X-A:

[0214] wherein Q1, Q2, R1, R2 are as described in any one of the above.

[0215] In another aspect, the present application provides a glucocorticoid receptor agonist, which is a compound represented by the following formula or a pharmaceutically acceptable salt, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotopically-labeled compound, metabolite, or prodrug thereof:

[0216] In another aspect, the present application provides a glucocorticoid receptor agonist, which is a compound represented by the following formula or a pharmaceutically acceptable salt, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotopically-labeled compound, metabolite, or prodrug thereof:

[0217] Antibody-drug conjugate

[0218] In another aspect, the present application provides an antibody-drug conjugate having a structure according to Formula Ab-[M-L-E-D] x wherein:

[0219] Ab is an antibody or antigen binding fragment thereof that specifically binds to an antigen;

[0220] M is a linker that is attached to the antibody or antigen binding fragment thereof;

[0221] L is a moiety that links the linker M to E;

[0222] E is a moiety that links L to D;

[0223] D is a glucocorticoid drug moiety that is a monovalent structure resulting from the loss of one H from -OH, -NH2, or a secondary amino group on a glucocorticoid receptor agonist as described in any one of the above;

[0224] x is an integer selected from 1 to 10.

[0225] In some embodiments, the antibody-drug conjugate has the structure: x y wherein:

[0226] Ab is an antibody or antigen binding fragment thereof that specifically binds to an antigen;

[0227] M is a linker that is attached to the antibody or antigen binding fragment thereof;

[0228] L is a moiety that links the linker M to E;

[0229] E is a moiety that links L to D;

[0230] D is a glucocorticoid drug moiety that is a monovalent structure resulting from the loss of one H from -OH, -NH2, or a secondary amino group on a glucocorticoid receptor agonist as described in any one of the above;

[0231] x and y are each independently an integer selected from 1 to 10.

[0232] In some embodiments, the antigen bound to the antibody in the antibody-drug conjugate includes, but is not limited to, TNFa, IL6R, BDCA2, NR3C1, MSR1, PRLR, CD19, CD25, CD40, CD70, CD74, CD163, and the like.

[0233] In another aspect, the application provides a drug-linker compound having the structure: x wherein:

[0234] G is a functional group or leaving group that reacts with a specific amino acid or glycosyl group in an antibody or antigen binding fragment and derivatives thereof;

[0235] ​M is a linker attached to the antibody or antigen-binding fragment thereof;

[0236] L is a moiety connecting M and E;

[0237] E is a moiety connecting L and D;

[0238] D is a glucocorticoid drug moiety which is a monovalent structure obtained by losing one H from -OH, -NH2, or a secondary amino group on the glucocorticoid receptor agonist of any one of the above;

[0239] x is an integer selected from 1 to 10.

[0240] In some embodiments, the drug-linker compound has a structure represented by the formula G-M-L-E-D, wherein G, M, L, E, D are each independently as described in any one of the above.

[0241] In some embodiments, the present application provides use of a compound for the preparation of an antibody-drug conjugate, the compound being as described in any one of the above.

[0242] Pharmaceutical composition

[0243] In another aspect, the present application provides a pharmaceutical composition comprising the glucocorticoid receptor agonist of the present application, the antibody-drug conjugate of the present application, or the drug-linker compound of the present application, and one or more pharmaceutically acceptable carriers.

[0244] The selection of the pharmaceutically acceptable carrier depends on the dosage form of the pharmaceutical composition, first on the route of administration of the dosage form, and second on the formulation of the dosage form. For example, the pharmaceutically acceptable carrier can include water (e.g., water for injection), a buffer, an isotonic saline solution such as PBS (phosphate buffered saline), glucose, mannitol, dextrose, lactose, starch, magnesium stearate, cellulose, magnesium carbonate, 0.3% glycerol, hyaluronic acid, ascorbic acid, lactic acid, ethanol, polyalkylene glycol such as polyethylene glycol (e.g., polyethylene glycol 4000) or polypropylene glycol, triglyceride, and the like.

[0245] The glucocorticoid receptor agonist, the antibody-drug conjugate, or the drug-linker compound described herein is generally formulated in a unit injectable form with a pharmaceutically acceptable parenteral vehicle for parenteral use, e.g., subcutaneous injection, intramuscular injection, intravenous bolus injection, intravenous drip infusion, local injection into a diseased tissue, intratumoral injection, and the like. Optionally, the glucocorticoid receptor agonist, the antibody-drug conjugate, or the drug-linker compound having a desired purity is mixed with a pharmaceutically acceptable diluent, carrier, excipient, or stabilizer in the form of a lyophilized agent or a solution agent (Remington's Pharmaceutical Sciences (1980) 16th Ed., Mack Publishing Company, Easton, PA).th edition, Osol, A. Ed.). The glucocorticoid receptor agonists, antibody-drug conjugates, drug-linker compounds described herein, or the pharmaceutical compositions described herein can be administered by any route suitable for the

[0246] Methods of treatment

[0247] In another aspect, the application provides use of a glucocorticoid receptor agonist of the application, an antibody-drug conjugate of the application, a drug-linker compound of the application, or a pharmaceutical composition of the application in the manufacture of a medicament for treating an inflammatory or immune disease.

[0248] In another aspect, the application provides a glucocorticoid receptor agonist of the application, an antibody-drug conjugate of the application, a drug-linker compound of the application, or a pharmaceutical composition of the application for use in treating an inflammatory or immune disease.

[0249] In another aspect, the application provides a method of treating an inflammatory or immune disease, comprising administering to an individual in need thereof a therapeutically effective amount of a glucocorticoid receptor agonist of the application, an antibody-drug conjugate of the application, a drug-linker compound of the application, or a pharmaceutical composition of the application.

[0250] In some embodiments, the inflammatory or immune disease described herein includes, but is not limited to, rheumatoid arthritis, idiopathic arthritis, systemic lupus erythematosus, asthma, ulcerative colitis, neuromyelitis optica, and autoimmune liver disease.

[0251] Definitions

[0252] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this application belongs. References to technical terms used herein are intended to refer to the technical field as commonly understood by those of ordinary skill in the art, including variations or replacements of techniques or equivalents of techniques that would be apparent to those of ordinary skill in the art. Also, the laboratory operations procedures of genomics, nucleic acid chemistry, molecular biology, etc. used herein are all conventional procedures widely used in the corresponding fields. Although the following terms are believed to be well understood by those of ordinary skill in the art, the following definitions are set forth to better explain the present application.

[0253] The term "antibody" refers to an immunoglobulin molecule that is generally composed of two pairs of polypeptide chains (each pair having one light (LC) and one heavy (HC) chain). Antibody light chains can be classified as kappa (kappa) and lambda (lambda) light chains. Heavy chains can be classified as mu, delta, gamma, alpha, or epsilon, and define a different class of antibodies, IgM, IgD, IgG, IgA, and IgE, respectively. Within light chains and heavy chains, the variable and constant regions are joined by a "J" region of about 12 or more amino acids. The heavy chains also contain a "D" region of about 3 or more amino acids. Each heavy chain is composed of a heavy chain variable region (VH) and a heavy chain constant region (CH). The heavy chain constant region is comprised of three domains, CH1, CH2 and CH3. Each light chain is composed of a light chain variable region (VL) and a light chain constant region (CL). The light chain constant region is comprised of one domain, CL. The constant domains are not involved directly in binding of an antibody to an antigen, but exhibit various effector functions, such as mediating immunoglobulin- host tissue or factor, including various cells of the immune system (e.g., effector cells) and the first component (Clq) of the classical complement system. The VH and VL regions can be further subdivided into regions of hypervariability, termed complementarity determining regions (CDR), interspersed with regions that are more conserved, termed framework regions (FR). Each VH and VL is composed of three CDRs and four FRs, arranged from amino-terminus to carboxy-terminus in the following order: FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4. The variable regions of the heavy chain / light chain pair (VH and VL) form the antigen binding site. Assignment of amino acids to each region or domain can follow various numbering systems known in the art.

[0254] The term "complementarity determining region" or "CDR" refers to amino acid residues within the variable region of an antibody that are responsible for antigen binding. There are three CDRs in each of the variable regions of the heavy and light chains, designated CDR1, CDR2, and CDR3. The precise boundaries of these CDRs can be defined according to various numbering systems known in the art, e.g., as defined by the Rabat numbering system (Rabat et al., Sequences of Proteins of Immunological Interest, 5th Ed. Public Health Service, National Institutes of Health, Bethesda, Md., 1991), the Chothia numbering system (Chothia & Lesk (1987) J. Mol. Biol. 196:901-917; Chothia et al. (1989) Nature 342:878-883), the IMGT numbering system (Lefranc et al., Dev. Comparat. Immunol. 27:55-77, 2003), or the AbM numbering system (Martin ACR, Cheetham JC, Rees AR (1989) Modelling antibody hypervariable loops: A combined algorithm. Proc Natl Acad Sci USA 86:9268-9272). For a given antibody, one of skill in the art will readily be able to identify the CDRs defined by each numbering system. Moreover, the correspondence between different numbering systems is well known to those skilled in the art (e.g., see Lefranc et al., Dev. Comparat. Immunol. 27:55-77, 2003).

[0255] In the present application, the CDRs contained by an antibody or antigen-binding fragment thereof can be determined according to various numbering systems known in the art, e.g., by the Rabat, Chothia, IMGT, or AbM numbering system. In certain embodiments, the CDRs contained by an antibody or antigen-binding fragment thereof are defined by the Chothia numbering system.

[0256] The term "framework region" or "FR" residues refer to those amino acid residues in the variable region of an antibody other than the CDR residues as defined above.

[0257] The term "antigen binding fragment" of an antibody refers to a polypeptide of a fragment of an antibody, e.g., a polypeptide of a fragment of a full-length antibody, that retains the ability to specifically bind to the same antigen bound by the full-length antibody, and / or competes with the full-length antibody for specific binding to the antigen, which is also referred to as an "antigen binding portion". See generally, Fundamental Immunology, Ch. 7 (Paul, W., ed., 2nded. Raven Press, N.Y. (1989)), which is incorporated herein by reference in its entirety for all purposes. Antigen binding fragments of an antibody can be produced by recombinant DNA techniques or by enzymatic or chemical cleavage of intact antibodies. Non-limiting examples of antigen binding fragments include Fab fragments, Fab' fragments, F(ab)'2 fragments, F(ab)'3 fragments, Fd, Fv, scFv, di-scFv, (scFv)2, disulfide stabilized Fv proteins ("dsFv"), single domain antibodies (sdAb, nanobodies), and polypeptides comprising at least a portion of an antibody that is sufficient to confer specific antigen binding ability to the polypeptide. Engineered antibody variants are reviewed in Holliger et al., 2005; Nat Biotechnol, 23: 1126-1136.

[0258] The term "Fd" means an antibody fragment consisting of a VH and CHI domain; the term "dAb fragment" means an antibody fragment that consists of a VH domain (Ward et al., Nature 341:544 546 (1989)); the term "Fab fragment" means an antibody fragment consisting of a VL, VH, CL and CHI domain; the term "F(ab')2 fragment" means an antibody fragment that comprises two Fab fragments linked by disulfide bridges on the hinge region; the term "Fab' fragment" means the fragment obtained by reducing the disulfide bonds of a F(ab')2 fragment, consisting of an intact light chain and a Fd fragment of a heavy chain (consisting of a VH and CHI domain).

[0259] The term "Fv" means an antibody fragment consisting of the VL and VH domains of a single arm of an antibody. The Fv fragment is commonly considered the smallest fragment of an antibody that is capable of forming a complete antigen binding site. It is generally considered that the six CDRs confer antigen binding specificity to an antibody. However, even a single variable domain (e.g., a Fd fragment, which contains only three CDRs specific for an antigen) is capable of recognizing and binding antigen, although it may do so at a lower affinity than the entire binding site.

[0260] The term "Fc" means an antibody fragment formed by disulfide bonds between the second, third constant regions of the first heavy chain and the second, third constant regions of the second heavy chain of an antibody. The Fc fragment of an antibody has various diverse functions, but is not involved in antigen binding.

[0261] The term "scFv" refers to a single polypeptide chain comprising a VL and a VH domain, wherein the VL and VH are connected by a linker (see, e.g., Bird et al., Science 242:423-426 (1988); Huston et al., Proc. Natl. Acad. Sci. USA 85:5879-5883 (1988); and Pluckthun, in The Pharmacology of Monoclonal Antibodies, vol. 113, Rosenburg and Moore eds., Springer-Verlag, New York, pp. 269-315 (1994)). Such scFv molecules can have the general structure: NH2-VL-linker-VH-COOH or NH2-VH-linker-VL-COOH. Suitable prior art linkers consist of repeating GGGGS amino acid sequences or variants thereof. For example, a linker having the amino acid sequence (GGGGS)4 can be used, but variants thereof can also be used (Holliger et al. (1993), Proc. Natl. Acad. Sci. USA 90:6444-6448). Other linkers useful in the present application are described by Alfthan et al. (1995), Protein Eng. 8:725-731, Choi et al. (2001), Eur. J. Immunol. 31:94-106, Hu et al. (1996), Cancer Res. 56:3055-3061, Kipriyanov et al. (1999), J. Mol. Biol. 293:41-56, and Roovers et al. (2001), Cancer Immunol. In some cases, a disulfide bond can also exist between the VHand VLof an scFv. In certain embodiments, the VHand VLdomains can be positioned relative to each other in any suitable arrangement. For example, scFv comprising NH2-VH-VH-COOH, NH2-VH-VL-COOH, NH2-VL-VH-COOH, or NH2-VL-VL-COOH are contemplated. 2- scFv comprising NH2-VL-VL-COOH.

[0262] The term "single-domain antibody (sdAb)" has the meaning generally understood by those skilled in the art and refers to an antibody fragment consisting of a single monomeric variable antibody domain, such as a single heavy chain variable region, that retains the ability to specifically bind the same antigen to which a full-length antibody binds (Holt, L. et al., Trends in Biotechnology, 21(11):484-490, 2003). Single-domain antibodies are also known as nanobodies.

[0263] Each of the above-described antibody fragments is capable of specifically binding to the same antigen bound by the full-length antibody from which it is derived, and / or competing for specific binding to the antigen with the full-length antibody.

[0264] In the present context, the term "antibody" when used in reference to a term "antibody" includes not only intact antibodies, but also antigen binding fragments of antibodies, unless otherwise clearly indicated by context.

[0265] Antigen binding fragments of antibodies (e.g., the above-described antibody fragments) can be obtained using conventional techniques known to those of skill in the art (e.g., recombinant DNA technology or enzymatic or chemical cleavage methods) from a given antibody (e.g., an antibody provided herein) and screened for specificity in the same manner as is done for intact antibodies.

[0266] The term "murine antibody" refers to an antibody obtained by fusing B cells from an immunized mouse with myeloma cells, screening for murine hybridoma cells that both proliferate indefinitely and secrete antibody, followed by screening, antibody production, and antibody purification, or refers to an antibody secreted by a plasma cell that developed from a B cell that proliferated in response to an antigen invading a mouse.

[0267] The term "humanized antibody" refers to a non-human antibody that has been genetically engineered to have an amino acid sequence that is modified to increase homology to the sequence of a human antibody. Typically, all or a portion of the CDR regions of a humanized antibody are derived from a non-human antibody (donor antibody), and all or a portion of the non-CDR regions (e.g., variable region FR and / or constant region) are derived from a human immunoglobulin (recipient antibody). A humanized antibody typically retains the desired properties of the donor antibody, including but not limited to, antigen specificity, affinity, reactivity, ability to increase immune cell activity, ability to enhance an immune response, and the like. The donor antibody can be a mouse, rat, rabbit, or non-human primate (e.g., cynomolgus monkey) antibody that has the desired properties (e.g., antigen specificity, affinity, reactivity, ability to increase immune cell activity, and / or ability to enhance an immune response).

[0268] The term "identity" is used in reference to the matching of sequences between two polypeptides or between two nucleic acids. When a position in each sequence that is being compared is occupied by the same base or amino acid monomer subunit (e.g., a position in each of two DNA molecules that is occupied by adenine, or a position in each of two polypeptides that is occupied by lysine), then the molecules are identical at that position. The "percentage of identity" between two sequences is the function of the number of matching positions shared by the two sequences divided by the number of positions compared x 100. For example, if 6 of 10 positions in two sequences are matched then the two sequences have 60% identity. For example, the DNA sequences CTGACT and CAGGTT share 50% identity (3 of 6 positions are matched). Typically, the comparison is made over the full length of the two sequences. Such a comparison can be conveniently accomplished by use of the method of Needleman et al. (1970) J. Mol. Biol. 48:443-453, as implemented in the computer program Align (DNAstar, Inc.), or by using the algorithm of E. Meyers and W. Miller (Comput. Appl. Biosci., 4:11-17 (1988)) as integrated into the ALIGN program (version 2.0) using a PAM120 weight residue table, a gap length penalty of 12, and a gap penalty of 4. In addition, the percentage of identity between two amino acid sequences can be determined using the algorithm of Needleman and Wunsch (J MoI Biol. 48:444-453 (1970)) as implemented in the GAP program, using either a Blossum 62 matrix or a PAM250 matrix, and a gap weight of 16, 14, 12, 10, 8, 6, or 4 and a gap length weight of 1, 2, 3, 4, 5, or 6, as incorporated into the GCG software package (available at www.gcg.com).

[0269] The term "conservative substitution" means an amino acid substitution that does not adversely affect or alter the intended properties of a protein / polypeptide comprising the amino acid sequence. For example, conservative substitutions can be introduced by standard techniques known in the art, such as site-directed mutagenesis and PCR-mediated mutagenesis. Conservative amino acid substitutions include substitutions of an amino acid residue with an amino acid residue having a similar side chain, e.g., substitutions that take place within a family of amino acid residues that are physicochemically or functionally similar, e.g., have similar size, shape, charge, chemical properties, including ability to form covalent or hydrogen bonds, etc. Families of amino acid residues having similar side chains have been defined in the art. These families include amino acids with basic side chains (e.g., lysine, arginine, and histidine), acidic side chains (e.g., aspartic acid, glutamic acid), uncharged polar side chains (e.g., glycine, asparagine, glutamine, serine, threonine, tyrosine, cysteine, tryptophan), nonpolar side chains (e.g., alanine, valine, leucine, isoleucine, proline, phenylalanine, methionine), beta-branched side chains (e.g., threonine, valine, isoleucine), and aromatic side chains (e.g., tyrosine, phenylalanine, tryptophan, histidine). Thus, a conservative substitution is one in which the replacement amino acid residue is of the same family as the original. Methods of identifying amino acid conservative substitutions are well known in the art (see, e.g., Brummell et al., Biochem. 32:1180-1187 (1993); Kobayashi et al. Protein Eng. 12(10):879-884 (1999); and Burks et al. Proc. Natl Acad. Set USA 94:412-417 (1997), which are incorporated herein by reference).

[0270] The nomenclature used herein for the twenty conventional amino acids follows the conventional usage. See, e.g., Immunology - A Synthesis (2nd Edition, E.S. Golub and D.R. Gren, Eds., Sinauer Associates, Sunderland, Mass. (1991)), which is incorporated herein by reference. In the present application, the amino acids are generally represented by the one-letter and three-letter abbreviations well known in the art. For example, alanine can be represented by A or Ala.

[0271] The terms "comprising", "including", "having" "containing" or "involving" and

[0272] The term "alkyl" denotes a straight or branched chain alkane radical, for example "C 1-20"alkyl", "C 1-10 "alkyl", "C 1-6 "alkyl", "C 1-4 "alkyl", "C 1-3 "alkyl", "C Specific examples include, but are not limited to, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, n-pentyl, i-pentyl, 2-methylbutyl, neopentyl, 1-ethylpropyl, n-hexyl, i-hexyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,3-dimethylbutyl, 2-ethylbutyl, 1,2-dimethylpropyl, and the like.

[0273] The term "alkylene" denotes a straight-chain or branched alkane group less two hydrogen atoms, for example "C 1-20 "alkylene", "C 1-10 "alkylene", "C 3-10 "alkylene", "C 5-8 "alkylene", "C 1-6 "alkylene", "C 1-4 "alkylene", "C 1-3 "alkylene", "C Specific examples include, but are not limited to, methylene, ethylene, 1,3- propylene, 1,4-butylene, 1,5-pentylene, or 1,6-hexylene, and the like.

[0274] The term "cycloalkyl" refers to a saturated or unsaturated non-aromatic monocyclic or polycyclic (such as bicyclic) hydrocarbon ring (e.g., monocyclic, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, or bicyclic, including spiro, fused, or bridged systems (such as bicyclo[l.l.l]pentyl, bicyclo[2.2.1]heptyl, bicyclo[3.2.1]octyl, or bicyclo[5.2.0]nonyl, decahydronaphthyl, and the like), which is optionally substituted with one or more (e.g., 1, 2, 3, or 4) suitable substituents. The cycloalkyl group has 3 to 15, for example 3 to 6, carbon atoms. For example, the term "C 3-6 "Cycloalkyl" refers to a saturated or unsaturated non-aromatic monocyclic or polycyclic (such as bicyclic) hydrocarbon ring containing 3 to 6 ring-forming carbon atoms (e.g., cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl).

[0275] The term "alkoxy" means an "alkyl" group as defined above attached to the parent molecular moiety through an oxygen atom, for example C1-C6alkoxy, C1-C3alkoxy, specific examples include, but are not limited to, methoxy, ethoxy, propyloxy, isopropoxy, butoxy, isobutoxy, pentoxy, isopentoxy, hexyloxy, and the like.

[0276] The term "halo" or "halogen" refers to fluorine (F), chlorine (CI), bromine (Br), and iodine (I).

[0277] The term "haloalkyl" refers to an alkyl group substituted with one or more (such as 1 to 3) same or different halogen atoms. For example, the term "Ci-C6haloalkyl" as used herein refers to a haloalkyl group having 1 to 6 carbon atoms, including but not limited to -CH2F, -CHF2, -CF3, -CH2CF3, -CF2CF3, -CH2CH2CF3, -CH2CI, and the like.

[0278] The term "aromatic ring" or "aryl" refers to an all-carbon monocyclic or fused-ring polycyclic aromatic hydrocarbon having a conjugated pi-electron system. Common aromatic rings include, but are not limited to, benzene, naphthalene, anthracene, phenanthrene, acenaphthene, azulene, fluorene, indene, pyrene, and the like. For example, the term "C6-Ci0aryl" refers to an aromatic ring containing 6 to 10 carbon atoms, such as benzene or naphthalene. 10 The term "aromatic ring" or "aryl" refers to an all-carbon monocyclic or fused-ring polycyclic aromatic hydrocarbon having a conjugated pi-electron system. Common aromatic rings include, but are not limited to, benzene, naphthalene, anthracene, phenanthrene, acenaphthene, azulene, fluorene, indene, pyrene, and the like. For example, the term "C6-Ci0aryl" refers to an aromatic ring containing 6 to 10 carbon atoms, such as benzene or naphthalene.

[0279] The term "carbocycle" refers to a saturated or partially saturated non-aromatic ring structure in which all ring members are carbon atoms, including but not limited to C 3-10 The term "carbocycle" refers to a saturated or partially saturated non-aromatic ring structure in which all ring members are carbon atoms, including but not limited to C 3-8 The term "carbocycle" refers to a saturated or partially saturated non-aromatic ring structure in which all ring members are carbon atoms, including but not limited to C

[0280] The term "heterocycle" or "heterocyclyl" refers to a saturated or partially saturated non-aromatic ring structure containing at least one ring member selected from N, O, and S, including but not limited to 5-10 membered heterocycle, 5-6 membered heterocycle, and the like, such as 5-6 membered nitrogen-containing heterocycle, 5-6 membered oxygen-containing heterocycle, and the like. Specific examples include, but are not limited to, tetrahydrofuran, pyrrolidine, piperidine, tetrahydropyran, and the like.

[0281] The term "heteroaromatic ring" or "heteroaryl" refers to an aromatic ring structure containing at least one ring member selected from N, O, and S, including but not limited to 5-10 membered aromatic heterocycle, 5-6 membered aromatic heterocycle, and the like, such as 5-6 membered nitrogen-containing aromatic heterocycle, 5-6 membered oxygen-containing aromatic heterocycle, and the like. Specific examples include, but are not limited to, furan, thiophene, pyrrole, thiazole, isothiazole, thiadiazole, oxazole, isoxazole, oxadiazole, imidazole, pyrazole, 1,2,3-triazole, 1,2,4-triazole, 1,2,3-oxadiazole, 1,2,4-oxadiazole, 1,2,5-oxadiazole, 1,3,4-oxadiazole, pyridine, pyrimidine, pyridazine, pyrazine, 1,2,3-triazine, 1,3,5-triazine, 1,2,4,5-tetrazine, and the like.

[0282] The term "aromatic ring system" refers to a monocyclic or polycyclic system comprising at least one aromatic ring (e.g., benzene ring, etc.) or heteroaromatic ring (e.g., pyrimidine ring, etc.), two or more aromatic and / or heteroaromatic rings can form a fused ring or be connected by a single bond (e.g., dipyrimidinylphenyl, etc.), the aromatic ring system can be divalent or higher valent (e.g., trivalent or tetravalent), e.g., 5-20 membered aromatic ring system.

[0283] If a substituent is described as "optionally substituted," the substituent can be (1) unsubstituted or (2) substituted. If a carbon of a substituent is described as being optionally substituted with one or more of a list of substituents, then one or more hydrogens on the carbon (to the extent there are any hydrogens present) can be replaced, singly and / or collectively, with a substituent independently selected from the list of substituents or none. If a nitrogen of a substituent is described as being optionally substituted with one or more of a list of substituents, then one or more hydrogens on the nitrogen (to the extent there are any hydrogens present) can each be replaced with a substituent independently selected from the list of substituents or none.

[0284] If a substituent is described as "independently selected from" a group of substituents, then each substituent is selected independently of the other(s). Thus, each substituent can be the same or different from the other substituent(s).

[0285] Unless otherwise indicated, as used herein, the point of attachment of a substituent can be from any suitable position on the substituent.

[0286] When a bond to a substituent is shown as passing through a ring, then such substituent can be bonded to any atom in the ring which can be substituted.

[0287] Pharmaceutically acceptable salts of the compounds of the present application include acid addition salts and base addition salts. Suitable acid addition salts are formed from acids which form pharmaceutically acceptable salts. Suitable base addition salts are formed from bases which form pharmaceutically acceptable salts. A review of suitable salts can be found in "Handbook of Pharmaceutical Salts: Properties, Selection, and Use" by Stahl and Wermuth (Wiley-VCH, 2002). Methods for preparing pharmaceutical acceptable salts of compounds of the present application are known to those skilled in the art.

[0288] The term "stereoisomers" (or "optical isomers") refers to stable isomers having a fixed orientation of atoms in space, resulting from the presence of at least one chiral element (including chiral centers, chiral axes, chiral planes, etc.) that is capable of producing an asymmetry plane perpendicular to which the plane polarized light can be rotated. Since the compounds of the present application can have asymmetric centers that potentially lead to stereoisomers and other chemical structures, the present application also includes these stereoisomers and mixtures thereof. Since the compounds of the present application (or their pharmaceutically acceptable salts) include asymmetric carbon atoms, they can exist in single stereoisomer form, racemates, mixtures of enantiomers, and mixtures of diastereomers. Generally, these compounds can be prepared in racemic form. However, if desired, pure stereoisomers, i.e., single enantiomers or diastereomers, or mixtures that are enriched in single stereoisomers (purity > 98%, > 95%, > 93%, > 90%, > 88%, > 85%, or > 80%) can be prepared from such compounds after their preparation or isolation. As described below, single stereoisomers of the compounds are prepared either synthetically from optically pure starting materials that contain the requisite chiral centers, or by resolution of a mixture of enantiomers, for example, by separation of a mixture of diastereoisomers via separation of a mixture of diastereoisomers followed by separation or recrystallization, chromatographic techniques, the use of chiral resolving agents, or direct separation of the enantiomers on a chiral chromatographic column. The starting compounds having the specified stereochemistry can be obtained commercially or prepared by the methods described below and resolved by techniques well known in the art. The term "enantiomers" refers to a pair of stereoisomers that are non-superimposable mirror images of one another. The term "diastereoisomers" or "diastereomers" refers to a pair of stereoisomers that are not mirror images of each other. The term "racemic mixture" or "racemate" refers to a mixture of equal amounts of single enantiomers (i.e., an equimolar mixture of two R and S enantiomers). The term "non-racemic mixture" refers to a mixture of unequal amounts of single enantiomers. Unless otherwise indicated, all stereoisomer forms of the compounds of the present application are within the scope of the present application.

[0289] The term "tautomers" (or "tautomeric forms") refers to structural isomers that have different energy states and can interconvert through low energy barriers. If tautomerization is possible (e.g., in solution), a chemical equilibrium of tautomers can be achieved. For example, prototropic tautomers (or proton-shift tautomers) include, but are not limited to, interconversions by proton migration, such as keto-enol isomerization, imine-enamine isomerization, amide-imidol isomerization, etc. Unless otherwise indicated, all tautomeric forms of the compounds of the present application are within the scope of the present application.

[0290] The term "polymorph" (or "polymorphic form") refers to a solid crystalline form of a compound or complex. Polymorphs can be detected, classified, and characterized using well-known techniques, including, but not limited to, differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), X-ray powder diffraction (XRPD), single crystal X-ray diffraction (SCXRD), solid state nuclear magnetic resonance (NMR), infrared spectroscopy (IR), Raman spectroscopy, and scanning electron microscopy (SEM).

[0291] The term "solvate" refers to a molecular complex of a compound of the present application (or a pharmaceutically acceptable salt thereof) with one or more solvent molecules, typically water or ethanol.

[0292] The term "nitroxide" refers to a compound formed by oxidation of a tertiary amine or a nitrogen-containing (hetero)aromatic ring in the structure of a compound.

[0293] The term "oxo" refers to a =0 structure.

[0294] The term "amino" refers to an -NR2group, where each R is independently selected from hydrogen, C 1-6 alkyl, or haloC 1-6 alkyl.

[0295] The term "carbonyl" refers to a -C(=0)- structure.

[0296] The term "sugar group" refers to a substituent formed by removal of the hemiacetal hydroxyl group from a monosaccharide or an oligosaccharide. The monosaccharides include aldoses and ketoses. The oligosaccharides, also known as oligosaccharides, refer to compounds containing 2-11 monosaccharides, and each monosaccharide is polymerized by a glycosidic bond. Examples of the monosaccharides or polysaccharides include, but are not limited to, erythrose, threose, arabinose, ribose, xylose, lyxose, glucose, glucuronic acid, galactose, galacturonic acid, mannose, fructose, lactose, sucrose, maltose, a-cyclodextrin, b-cyclodextrin, g-cyclodextrin.

[0297] The present application also includes all pharmaceutically acceptable isotopically-labeled compounds, which are identical to those of the present application, but for the fact that one or more atoms are replaced by an atom having the same atomic number but an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes suitable for inclusion in the compounds of the present application include, but are not limited to, isotopes of hydrogen (e.g., 2H, 3H, deuterium, tritium), carbon (e.g., 11C, 13C, and 14C), chlorine (e.g., 37CI), fluorine (e.g., 18F), iodine (e.g., 123I and 125I), nitrogen (e.g., 13N and 15N), oxygen (e.g., 15O, 17O, and 18O), and sulfur (e.g., 35S).

[0298] Also included within the scope of the application are metabolites of the compounds of the application, i.e., substances produced within the body that result from the metabolism of a compound of the application. Such products can result for example from the oxidation, reduction, hydrolysis, amidation, deamidation, esterification, enzymatic cleavage, and the like, of the administered compound. Accordingly, the application includes metabolites of compounds of the application, including those produced by the in vivo conversion of a compound of the application into a metabolic product.

[0299] The application further includes within its scope prodrugs of the compounds of the application, which are certain derivatives of the compounds of the application that have less or no pharmacological activity themselves but are converted into the active compounds of the application after administration to the body, for example, by hydrolytic cleavage. Generally, such prodrugs will be functional derivatives of the compounds that are readily convertible in vivo into the desired therapeutically active compound. For examples of prodrugs see "Pro-drugs as Novel Delivery Systems", Vol. 14 of the A.C.S. Symposium Series (T. Higuchi and W. Stella) and "Bioreversible Carriers in Drug Design," Pergamon Press, 1987 (ed. E. B. Roche, American Pharmaceutical Association). Prodrugs of the application can be prepared by replacing appropriate functionalities present in the compounds of the application with certain moieties known to those skilled in the art as "pro-moieties" (for example, as described in "Design of Prodrugs", H. Bundgaard (Elsevier, 1985).

[0300] Preparation of compounds

[0301] In another aspect, the application provides a method for preparing a compound of Formula VIII.

[0302] In some embodiments, the compounds of Formula VIII of the application can be synthesized by the following synthetic route:

[0303] wherein R1, X, Q1and Q2are as defined above.

[0304] In some embodiments, the above steps are carried out in the presence of the following reactants:

[0305] wherein X, Q1and Q2are as defined above.

[0306] In some embodiments, the above step is carried out in the presence of a suitable condensing reagent, which can be selected from HATU, HBTU, EDCI, DCC, T3P, POCl3and HOBT, preferably HATU.

[0307] In some embodiments, the above step is carried out at a suitable temperature, which is in the range of 0-140 °C, such as 0 °C, 20 °C, 25 °C, 40 °C, 50 °C, 60 °C, 100 °C, 140 °C, preferably in the range of 0-35 °C;

[0308] In some embodiments, the above step is carried out in a suitable organic solvent, which can be selected from halogenated hydrocarbons (such as dichloromethane (DCM), chloroform (TCM), 1,2-dichloroethane (1,2-DCE), and the like), nitriles (such as acetonitrile (AN) and the like), N-methylpyrrolidone (NMP), N,N-dimethylformamide (DMF), N,N-dimethylacetamide (DMA), tetrahydrofuran (THF), 1,4-dioxane (Dioxane), dimethylsulfoxide (DMSO), and any combination thereof, preferably N,N-dimethylformamide (DMF).

[0309] In some embodiments, the above step is carried out in the presence of a suitable base, which includes an organic base or an inorganic base, the organic base can be selected from N,N-diisopropylethylamine (DIPEA), triethylamine (TEA), potassium tert-butoxide (t-BuOK), and pyridine (Py), the inorganic base can be selected from potassium phosphate (K3PO4), sodium hydride (NaH), potassium carbonate (K2CO3), sodium carbonate (Na2CO3), sodium bicarbonate (NaHCO3), cesium carbonate (Cs2CO3), and NaOH, preferably N,N-diisopropylethylamine (DIPEA).

[0310] Synthetic intermediates

[0311] In another aspect, the present application provides a synthetic intermediate or its acceptable pharmaceutically acceptable salt, the structure of which is shown as follows:

[0312] wherein PG is a hydroxyl protecting group, preferably triphenylmethyl (Trt), trimethylsilyl ether (TMS), triethylsilyl ether (TES), tert-butyldimethylsilyl ether (TBS / TBDMS), tert-butyldiphenylsilyl ether (TBDPS), benzyl ether (Bn), p-methoxybenzyl ether (PMB), further preferably triphenylmethyl (Trt); PG’ is an amino protecting group, preferably carbobenzyloxy (Cbz), tert-butyloxycarbonyl (Boc), fluorenylmethoxycarbonyl (Fmoc), allyloxycarbonyl (Alloc), further preferably tert-butyloxycarbonyl (Boc).

[0313] In some implementations, the intermediate structure is as follows: Example

[0314] The present invention will be further described below through specific embodiments, but this is not intended to limit the invention. Those skilled in the art can make various modifications or improvements based on the teachings of the present invention without departing from the basic spirit and scope of the invention.

[0315] The abbreviations used in this article have the following meanings:

[0316] The structures of the compounds described in the following examples were determined by nuclear magnetic resonance (NMR). 1 It can be determined by 1H NMR or mass spectrometry (MS).

[0317] Nuclear magnetic resonance (NMR) 1 The H NMR measurements were performed using a Bruker 400MHz NMR spectrometer; the deuterated reagent was hexadeuterated dimethyl sulfoxide (DMSO-d6); and the internal standard was tetramethylsilane (TMS).

[0318] The abbreviations used in the nuclear magnetic resonance (NMR) spectra in the embodiments are shown below.

[0319] s: singlet, d: doublet, t: triplet, q: quartet, m: multiplet, br: broad, J: coupling constant, Hz: Hertz, DMSO-d6: dimethyl sulfoxide deuterated. δ values ​​are expressed in ppm.

[0320] Mass spectrometry (MS) measurements were performed using an Agilent (ESI) mass spectrometer, model Agilent 6120B.

[0321] Preparation Example 1: Preparation of N-(3-(4-((2S,6aS,6bR,7S,8aS,8bS,10R,11aR,12aS,12bS)-2,6b-difluoro-7-hydroxy-8b-(2-hydroxyacetyl)-6a,8a-dimethyl-4-oxo-2,4,6a,6b,7,8,8a,8b,11a,12,12a,12b-dodecylhydro-1H-naphtho[2',1':4,5]indeno[1,2-d][1,3]dioxacyclopenten-10-yl)benzyl)phenyl)-2-hydroxyacetamide (A-1)

[0322] (2S,6aS,6bR,7S,8aS,8bS,10R,11aR,12aS,12bS)-10-(4-(3-aminobenzyl)phenyl)- 2,6b-difluoro-7-hydroxy-8b-(2-hydroxyacetyl)-6a,8a-dimethyl-1,2,6a,6b,7,8,8a,8b,11a, 12,12a,12b-dodecahydro-4H-naphtho[2',1':4,5]indeno[1,2-d][1,3]dioxol-4-one (30 mg, 49.5 μmol) was dissolved in DMF (1.0 mL), after the addition of HATU (37.6 mg, 99.0 μmol) and DIPEA (19.2 mg, 148.3 μmol), it was stirred at 25 °C for 1 h. The reaction solution was directly purified by high performance liquid chromatography to give the title compound (5.57 mg, 8.24 μmol) after freeze-drying.

[0323] Column: Waters SunFire Prep C18 OBD 19mm x 150mm x 5μm

[0324] Mobile Phase A: Acetonitrile; Mobile Phase B: Water (0.05% trifluoroacetic acid)

[0325] Its structure was characterized as follows:

[0326] ESI-MS (m / z): 665.3 [M+H] + .

[0327] 1 H NMR (400 MHz, DMSO) δ 9.56 (s, 1H), 7.58 - 7.48 (m, 2H), 7.35 (d, J = 7.8 Hz, 2H), 7.26 (t, J = 7.0 Hz, 3H), 7.19 (t, J = 7.8 Hz, 1H), 6.92 (d, J = 7.6 Hz, 1H), 6.30 (d, J = 9.6 Hz, 1H), 6.13 (s, 1H), 5.77 - 5.50 (m, 3H), 5.45 (s, 1H), 5.12 (s, 1H), 4.94 (d, J = 4.6 Hz, 1H), 4.51 (dd, J = 19.4, 5.6 Hz, 1H), 4.29 - 4.15 (m, 2H), 3.94 (d, J = 4.8 Hz, 2H), 3.88 (s, 2H), 2.78 - 2.58 (m, 2H), 2.35 - 2.20 (m, 2H), 2.04 (d, J = 13.4 Hz, 1H), 1.69 (d, J = 13.4 Hz, 3H), 1.50 (s, 3H), 0.86 (s, 3H).

[0328] Preparation Example Two: Preparation of (S)-N-(3-(4-((2S,6aS,6bR,7S,8aS,8bS,10R,11aR,12aS,12bS)-2,6b-difluoro-7-hydroxy-8b-(2-hydroxyacetyl)-6a,8a-dimethyl-4-oxo-2,4,6a,6b,7,8,8a,8b,11a,12,12a,12b-dodecahydro-lH-naphtho[2',l':4,5]indeno[l,2-d][l,3]dioxol-10-yl)benzyl)phenyl)-2-hydroxypropanamide (A-4)

[0329] (2S,6aS,6bR,7S,8aS,8bS,10R,11aR,12aS,12bS)-10-(4-(3-aminobenzyl)phenyl)-2,6b-difluoro-7-hydroxy-8b-(2-hydroxyacetyl)-6a,8a-dimethyl-l,2,6a,6b,7,8,8a,8b,11a,12,12a,12b-dodecahydro-4H-naphtho[2',l':4,5]indeno[l,2-d][l,3]dioxol-4-one (55 mg, 90.81 μmol, FR) was dissolved in DMF (2 mL), after adding (S)-2-hydroxypropanoic acid (55 mg, 90.81 μmol), HATU (34.53 mg, 90.81 μmol) and DIPEA (35.21 mg, 272.43 μmol), the reaction was carried out at 25 °C for 2 hours. The reaction solution was concentrated to obtain a crude product directly, which was purified by high performance liquid chromatography preparation and freeze-dried to obtain the title compound (20 mg, 28.63 μmol).

[0330] Column: Phenomenex Luna C18 200mm x 40mm x 10μm

[0331] Mobile Phase A: Acetonitrile; Mobile Phase B: Water (0.05% Formic Acid)

[0332] Its structure was characterized as follows:

[0333] ESI-MS (m / z): 678.7 [M+H] + .

[0334] 1H NMR (400 MHz, DMSO) δ 9.52 (s, 1H), 7.54 (d, J = 7.9 Hz, 2H), 7.35 (d, J = 8.1 Hz, 2H), 7.26 (dd, J = 9.7, 3.9 Hz, 3H), 7.18 (t, J = 7.7 Hz, 1H), 6.92 (d, J = 7.6 Hz, 1H), 6.30 (dd, J = 10.2, 1.8 Hz, 1H), 6.13 (s, 1H), 5.78 - 5.54 (m, 3H), 5.52 (d, J = 3.0 Hz, 1H), 5.45 (s, 1H), 5.10 (t, J = 6.0 Hz, 1H), 4.94 (d, J = 4.9 Hz, 1H), 4.51 (dd, J = 19.4, 6.4 Hz, 1H), 4.24 - 4.17 (m, 2H), 4.09 (dd, J = 6.7, 5.3 Hz, 1H), 3.87 (s, 2H), 2.59 (d, J = 12.2 Hz, 1H), 2.30 - 2.19 (m, 2H), 2.04 (d, J = 13.8 Hz, 1H), 1.71 (dd, J = 16.1, 10.1 Hz, 2H), 1.50 (s, 3H), 1.27 (d, J = 6.8 Hz, 3H), 0.86 (s, 3H).

[0335] Preparation of (R)-N-(3-(4-((2S,6aS,6bR,7S,8aS,8bS,10R,11aR,12aS,12bS)- 2,6b-difluoro-7-hydroxy-8b-(2-hydroxyacetyl)-6a,8a-dimethyl-4-oxo-2,4,6a,6b,7,8,8a,8b,11a,12,12a,12b-dodecahydro-lH-naphtho[2',l':4,5]indeno[l,2- d][l,3]dioxol-10-yl)benzyl)phenyl)-2-hydroxypropanamide (A-7)

[0336] (2S,6aS,6bR,7S,8aS,8bS,10R,11aR,12aS,12bS)-10-(4-(3-aminobenzyl)phenyl)- 2,6b-difluoro-7-hydroxy-8b-(2-hydroxyacetyl)-6a,8a-dimethyl-1,2,6a,6b,7,8,8a,8b,11a, 12,12a,12b-dodecahydro-4H-naphtho[2',1':4,5]indeno[1,2-d][1,3]dioxepin-4-one (55 mg, 90.81 μmol, FR) was dissolved in DMF (2 mL), after adding (R)-2-hydroxypropanoic acid (55 mg, 90.81 μmol), HATU (34.53 mg, 90.81 μmol) and DIPEA (35.21 mg, 272.43 μmol), the reaction was carried out at 25 °C for 2 hours. The reaction was concentrated to get the crude product directly, which was purified by high performance liquid chromatography preparation and freeze-dried to obtain the title compound (12 mg, 17.54 μmol).

[0337] Column: Phenomenex Luna C18 200mm x 40mm x 10μm

[0338] Mobile Phase A: Acetonitrile; Mobile Phase B: Water (0.05% Formic Acid)

[0339] The structure is characterized as follows:

[0340] ESI-MS (m / z): 678.3 [M+H] + .

[0341] 1H NMR (400 MHz, DMSO) δ 9.53 (s, 1H), 7.53 (d, J = 7.9 Hz, 2H), 7.35 (d, J = 8.1 Hz, 2H), 7.26 (dd, J = 9.7, 3.9 Hz, 3H), 7.19 (t, J = 7.7 Hz, 1H), 6.92 (d, J = 7.6 Hz, 1H), 6.30 (d, J = 10.2 Hz, 1H), 6.13 (s, 1H), 5.78 - 5.54 (m, 2H), 5.53 (d, J = 3.0 Hz, 1H), 5.45 (s, 1H), 5.11 (t, J = 6.0 Hz, 1H), 4.94 (d, J = 4.9 Hz, 1H), 4.51 (dd, J = 19.4, 6.4 Hz, 1H), 4.26 - 4.13 (m, 2H), 4.12-4.05 (m, 5.3 Hz, 1H), 3.87 (s, 2H), 2.73-2.57 (m, 1H), 2.33 - 2.17 (m, 2H), 2.07-1.98 (m, 1H), 1.77-1.62 (m, 3H), 1.57-1.43 (m, 1H), 1.50 (s, 3H), 1.27 (d, J = 6.8 Hz, 3H), 0.86 (s, 3H).

[0342] Preparation of (S)-2-cyclopropyl-N-(3-(4-((2S,6aS,6bR,7S,8aS,8bS,10R,11aR,12aS,12bS)- 2,6b-difluoro-7-hydroxy-8b-(2-hydroxyacetyl)-6a,8a-dimethyl-4-oxo-2,4,6a,6b,7,8,8a,8b,11a,12,12a,12b-dodecahydro-lH-naphtho[2',l':4,5]indeno[l,2-d][l,3]dioxol-10-yl)benzyl)phenyl)-2-hydroxyacetamide (A-10)

[0343] (S)-2-cyclopropyl-2-hydroxyacetic acid (6 mg, 51.67 μmol) and (2S,6aS,6bR,7S,8aS,8bS,10R,11aR,12aS,12bS)-10-(4-(3-aminobenzyl)phenyl)-2,6b-difluoro-7-hydroxy-8b-(2-hydroxyacetyl)-6a,8a-dimethyl-1,2,6a,6b,7,8,8a,8b,11a,12,12a,12b-dodecahydro-4H-naphtho[2',1':4,5]indeno[1,2-d][1,3]dioxol-4-one (31.30 mg, 51.67 μmol) were dissolved in DMF (1 mL), DIPEA (16.69 mg, 129.15 μmol) was added, then HATU (19.64 mg, 51.67 μmol) was added, and the reaction was stirred at room temperature for 1 hour. After the reaction was completed, the reaction solution was directly purified by high performance liquid chromatography to obtain the title compound (18 mg, 24.30 μmol) after freeze-drying.

[0344] Column: Waters Sunfire Prep C18 OBD 150mm×19mm×5μm

[0345] Mobile phase A: acetonitrile; mobile phase B: water (0.05% formic acid)

[0346] The structure thereof is characterized as follows:

[0347] ESI-MS (m / z): 704.3 [M+H] + .

[0348] 1H NMR (400 MHz, DMSO-d6) δ 9.51 (s, 1H), 7.55 - 7.53 (m, 2H), 7.37 - 7.35 (m, 2H), 7.28 - 7.25 (m, 3H), 7.21 - 7.17 (m, 1H), 6.92 (d, J = 7.6 Hz, 1H), 6.30 (dd, J = 10.0, 2.0 Hz, 1H), 6.13 (s, 1H), 5.73 - 5.57 (m, 1H), 5.53 - 5.51 (m, 1H), 5.45 (s, 1H), 4.94 (d, J = 4.8 Hz, 1H), 4.53 - 4.17 (m, 3H), 3.88 (s, 3H), 3.60 (d, J = 6.4 Hz, 1H), 2.71 - 2.58 (m, 1H), 2.33 - 2.20 (m, 2H), 2.07 - 2.06 (m, 1H), 1.76 - 1.63 (m, 3H), 1.56 - 1.52 (m, 1H), 1.49 (s, 3H), 1.15 - 1.07 (m, 1H), 0.86 (s, 3H), 0.44 - 0.32 (m, 4H).

[0349] Preparation Example Five: Preparation of (R)-2-cyclopropyl-N-(3-(4-((2S,6aS,6bR,7S,8aS,8bS,10R,11aR,12aS,12bS)- 2,6b-difluoro-7-hydroxy-8b-(2-hydroxyacetyl)-6a,8a-dimethyl-4-oxo-2,4,6a,6b,7,8,8a,8b,11a,12,12a,12b-dodecahydro-1H-naphtho[2',1':4,5]indeno[1,2-d][1,3]dioxol-10-yl)benzyl)phenyl)-2-hydroxyacetamide (A-13)

[0350] (2S,6aS,6bR,7S,8aS,8bS,10R,11aR,12aS,12bS)-10-(4-(3-aminobenzyl)phenyl)- 2,6b-difluoro-7-hydroxy-8b-(2-hydroxyacetyl)-6a,8a-dimethyl-1,2,6a,6b,7,8,8a,8b,11a, 12,12a,12b-dodecahydro-4H-naphtho[2',1':4,5]indeno[1,2-d][1,3]dioxol-4-one (50 mg, 82.55 μmol) was dissolved in DMF (2 mL), after adding (R)-2-cyclopropyl-2- hydroxyacetic acid (9.59 mg, 82.55 μmol), HATU (47.08 mg, 123.83 μmol) and DIPEA (32.01 mg, 247.66 μmol), the reaction was carried out at 25 °C for 2 hours. The reaction solution was concentrated to get the crude product directly, which was purified by high performance liquid chromatography preparation and freeze-dried to obtain the title compound (14.25 mg, 19.24 μmol).

[0351] Column: Phenomenex Luna C18 200mm x 40mm x 10μm

[0352] Mobile Phase A: Acetonitrile; Mobile Phase B: Water (0.05% Formic Acid)

[0353] The structure was characterized as follows:

[0354] ESI-MS (m / z): 704.3 [M+H] + .

[0355] 1H NMR (400 MHz, DMSO) δ 9.52 (s, 1H), 7.52 (dd, J = 3.6, 1.8 Hz, 2H), 7.35 (d, J = 8.2 Hz, 2H), 7.27 (dd, J = 9.3, 3.8 Hz, 3H), 7.20 (dd, J = 8.6, 7.7 Hz, 1H), 6.94 (d, J = 7.7 Hz, 1H), 6.31 (dd, J = 10.1, 1.9 Hz, 1H), 6.14 (s, 1H), 5.75 - 5.55 (m, 2H), 5.44 (s, 1H), 4.94 (d, J = 3.9 Hz, 1H), 4.50 (d, J = 19.4 Hz, 1H), 4.23 - 4.15 (m, 2H), 3.89 (s, 2H), 3.60 (s, 4H), 2.67 - 2.57 (m, 1H), 2.24 (dd, J = 19.4, 11.8 Hz, 2H), 2.04 (d, J = 13.8 Hz, 1H), 1.70 (t, J = 9.4 Hz, 2H), 1.52 (d, J = 15.9 Hz, 4H), 1.10 (m, 1H), 0.86 (s, 3H), 0.44 - 0.32 (m, 4H).

[0356] Preparation Example Six: Preparation of N-(3-(4-((2S,6aS,6bR,7S,8aS,8bS,10R,11aR,12aS,12bS)- 2,6b-difluoro-7-hydroxy-8b-(2-hydroxyacetyl)-6a,8a-dimethyl-4-oxo-2,4,6a,6b,7,8,8a,8b,11a,12,12a,12b-dodecahydro-lH-naphtho[2',l':4,5]indeno[l,2-d][l,3]dioxol-10-yl)benzyl)phenyl)-3-hydroxypropanamide (B-l)

[0357] (2S,6aS,6bR,7S,8aS,8bS,10R,11aR,12aS,12bS)-10-(4-(3-aminobenzyl)phenyl)- 2,6b-difluoro-7-hydroxy-8b-(2-hydroxyacetyl)-6a,8a-dimethyl-1,2,6a,6b,7,8,8a,8b,11a, 12,12a,12b-dodecahydro-4H-naphtho[2',1':4,5]indeno[1,2-d][1,3]dioxepin-4-one (127.08 mg, 209.82 μmol) was dissolved in DMF (2 mL), after adding (R)-2-cyclopropyl-2- hydroxyacetic acid (63 mg, 209.82 μmol), HATU (209.82 μmol) and DIPEA (135.58 mg, 1.05 mmol), the reaction was carried out at 25 °C for 2 hours. The reaction solution was concentrated to obtain the crude product directly, which was purified by high performance liquid chromatography preparation and freeze-dried to obtain the title compound (44.11 mg, 61.83 μmol).

[0358] Column: Phenomenex Luna C18 200mm x 40mm x 10μm

[0359] Mobile Phase A: Acetonitrile; Mobile Phase B: Water (0.05% Formic Acid)

[0360] Its structural characterization is as follows:

[0361] ESI-MS (m / z): 678.3 [M+H] + .

[0362] 1H NMR (400 MHz, DMSO) δ 9.79 (s, 1H), 7.45 (d, J = 7.9 Hz, 1H), 7.42 - 7.31 (m, 3H), 7.25 (t, J = 9.5 Hz, 3H), 7.17 (t, J = 7.8 Hz, 1H), 6.89 (d, J = 7.6 Hz, 1H), 6.30 (dd, J = 10.2, 1.8 Hz, 1H), 6.13 (s, 1H), 5.58 (d, J = 10.1 Hz, 1H), 5.52 (d, J = 2.9 Hz, 1H), 5.45 (s, 1H), 4.94 (d, J = 5.0 Hz, 1H), 4.51 (d, J = 19.5 Hz, 1H), 4.19 (d, J = 19.3 Hz, 2H), 3.88 (s, 2H), 3.67 (t, J = 6.4 Hz, 2H), 2.41 (t, J = 6.4 Hz, 2H), 2.24 (dd, J = 18.9, 12.7 Hz, 2H), 2.04 (d, J = 13.6 Hz, 1H), 1.71 (dd, J = 16.1, 10.1 Hz, 3H), 1.52 (d, J = 19.9 Hz, 4H), 0.86 (s, 3H).

[0363] Preparation Example Seven: Preparation of 2-hydroxyethyl (3-(4-((2S,6aS,6bR,7S,8aS,8bS,10R,11aR,12aS,12bS)-2,6b-difluoro-7-hydroxy-8b-(2-hydroxyacetyl)-6a,8a-dimethyl-4-oxo-2,4,6a,6b,7,8,8a,8b,11a,12,12a,12b-dodecahydro-1H-naphtho[2',1':4,5]indeno[1,2-d][1,3]dioxol-10-yl)benzyl)phenyl)carbamate (D-1)

[0364] Step One: Preparation of 2-(trityloxy)ethan-1-ol (D-1-2)

[0365] Ethylene glycol (500 mg, 8.06 mmol) was dissolved in DMF (5.0 mL), pyridine (2 mL) was added, and triphenylmethyl chloride (2.25 g, 8.06 mmol), 4-dimethylaminopyridine (196.83 mg, 1.61 mmol) were added, and stirred at 25 °C for 16 hours. Water (50 mL) was added to the reaction solution, extracted with 30 mL of ethyl acetate, the organic phase was washed with saturated brine 3 times, dried over anhydrous sodium sulfate, filtered and concentrated to give the crude product, which was purified by silica gel column (ethyl acetate / petroleum ether = 0-70%) and concentrated again to give the title compound (998.0 mg, 3.28 mmol).

[0366] Its structure was characterized as follows:

[0367] 1 H NMR (400 MHz, DMSO) d 7.47-7.39 (m, 6H), 7.37-7.29 (m, 6H), 7.28-7.20 (m, 3H), 3.63-3.52 (m, 2H), 3.02-2.93 (m, 2H).

[0368] Step two: Preparation of 4-nitrophenyl (2-(trityloxy)ethyl) carbonate (D-1-3)

[0369] 2-(trityloxy)ethan-1-ol (50 mg, 0.16 mmol) was dissolved in DMF (1.0 mL), DIPEA (42.46 mg, 0.32 mmol), bis(4-nitrophenyl) carbonate (59.9 mg, 0.20 mmol) was added, stirred at 25 °C for 3 hours. The reaction solution was directly used for the next step.

[0370] The structure was characterized as follows:

[0371] ESI-MS (m / z): 492.2 (M+Na) + .

[0372] Step three: Preparation of 2-(trityloxy)ethyl (3-(4-((2S,6aS,6bR,7S,8aS,8bS,10R,11aR,12aS,12bS)- 2,6b-difluoro-7-hydroxy-8b-(2-hydroxyacetyl)-6a,8a-dimethyl-4-oxo-2,4,6a,6b,7,8,8a,8b,11a,12,12a,12b-dodecahydro-1H-naphtho[2',1':4,5]indeno[1,2-d][1,3]dioxol-10-yl)benzyl)phenyl)carbamate (D-1-4)

[0373] (2S,6aS,6bR,7S,8aS,8bS,10R,11aR,12aS,12bS)-10-(4-(3-aminobenzyl)phenyl)- 2,6b-difluoro-7-hydroxy-8b-(2-hydroxyacetyl)-6a,8a-dimethyl-l,2,6a,6b,7,8,8a,8b, 11a, 12, 12a, 12b-dodecahydro-4H-naphtho[2',l':4,5]indeno[l,2-d][l,3]dioxol-4-one (60.0 mg, 0.1 mmol) was dissolved in DMF (1.5 mL), after the addition of DIPEA (38.4 mg, 0.3 mmol), HOBT (26.8 mg, 0.30 mmol), 4-nitrophenyl (2- (triphenylmethoxy)ethyl) carbonate (46.5 mg, 0.1 mmol) was added, and stirred at 25 °C for 2 hours. The reaction solution was purified by C18 column (acetonitrile / 0.05% formic acid aqueous solution = 0-90%) and freeze-dried to obtain the title compound (40.0 mg, 0.04 mmol).

[0374] The structure is characterized as follows:

[0375] ESI-MS (m / z): 959.1 (M+Na) + .

[0376] Step four: Preparation of 2-hydroxyethyl (3-(4-((2S,6aS,6bR,7S,8aS,8bS,10R,11aR,12aS,12bS)-2,6b-difluoro-7-hydroxy-8b-(2-hydroxyacetyl)-6a,8a-dimethyl-4-oxo-2,4,6a,6b,7,8,8a,8b,11a,12,12a,12b-dodecahydro-lH-naphtho[2',l':4,5]indeno[l,2-d][l,3]dioxol-10-yl)benzyl)phenyl)carbamate (D-1)

[0377] (3-(4-((2S,6aS,6bR,7S,8aS,8bS,10R,11aR,12aS,12bS)-2,6b-difluoro-7-hydroxy-8b-(2- hydroxyacetyl)-6a,8a-dimethyl-4-oxo-2,4,6a,6b,7,8,8a,8b,11a,12,12a,12b-dodecahydro- 1H-naphtho[2',1':4,5]indeno[1,2-d][1,3]dioxol-10-yl)benzyl)phenyl)carbamate (40.0 mg, 0.04 mmol) was dissolved in DCM (2.0 mL), formic acid (0.4 mL) was added, and stirred at 25 °C for 1 h. The reaction was concentrated to get crude, which was purified by preparative HPLC and freeze-dried to give the title compound (5.01 mg, 6.96 μmol).

[0378] Column: Waters SunFire Prep C18 OBD 19mm x 150mm x 5um

[0379] Mobile Phase A: Acetonitrile; Mobile Phase B: Water (0.05% Formic Acid)

[0380] The structure was characterized as follows:

[0381] ESI-MS (m / z): 694.1 [M+H] + .

[0382] 1 H NMR (400 MHz, DMSO) δ 9.58 (s, 1H), 7.34 (t, J = 7.0 Hz, 3H), 7.30 - 7.20 (m, 4H), 7.15 (t, J = 7.8 Hz, 1H), 6.83 (d, J = 7.6 Hz, 1H), 6.30 (dd, J = 10.2, 1.8 Hz, 1H), 6.13 (s, 1H), 5.76 - 5.56 (m, 1H), 5.52 (d, J = 2.9 Hz, 1H), 5.45 (s, 1H), 5.10 (t, J = 6.0 Hz, 1H), 4.94 (d, J = 5.0 Hz, 1H), 4.79 (t, J = 5.2 Hz, 1H), 4.51 (dd, J = 19.6, 6.4 Hz, 1H), 4.26 - 4.13 (m, 2H), 4.10 - 4.00 (m, 2H), 3.86 (s, 2H), 3.59 (q, J = 16.0, 2H), 2.36 - 2.17 (m, 3H), 2.09 - 1.99 (m, 2H), 1.77 - 1.63 (m, 3H), 1.50 (s, 3H), 0.86 (s, 3H).

[0383] Preparation Example Eight: Preparation of N-(3-(4-((6aS,6bR,7S,8aS,8bS,10R,11aR,12aS,12bS)-6b-fluoro-7-hydroxy-8b-(2-hydroxyacetyl)-6a,8a-dimethyl-4-oxo-2,4,6a,6b,7,8,8a,8b,11a,12,12a,12b-dodecahydro-1H-naphtho[2',1':4,5]indeno[1,2-d][1,3]dioxol-10-yl)benzyl)phenyl)-2-hydroxyacetamide (A-2)

[0384] (6aS,6bR,7S,8aS,8bS,10R,11aR,12aS,12bS)-10-(4-(3-aminobenzyl)phenyl)-6b-fluoro-7-hydroxy-8b-(2-hydroxyacetyl)-6a,8a-dimethyl-1,2,6a,6b,7,8,8a,8b,11a,12,12a,12b-dodecahydro-4H-naphtho[2',1':4,5]indeno[1,2-d][1,3]dioxol-4-one (80 mg, 136.1 µmol) and 2-hydroxyacetic acid (10.5 mg, 136.1 µmol) were dissolved in DMF (1.5 mL), after adding HATU (62.1 mg, 163.4 µmol) and DIPEA (52.8 mg, 408.3 µmol), stirring at 25 °C for 1 hour. The reaction solution was directly purified by high performance liquid chromatography preparation and freeze-dried to obtain the title compound (23.23 mg, 35.83 µmol).

[0385] Column: Waters SunFire Prep C18 OBD 19mmx150mmx5µm

[0386] Mobile Phase A: Acetonitrile; Mobile Phase B: Water (0.05% trifluoroacetic acid)

[0387] The structure is characterized as follows:

[0388] ESI-MS (m / z): 646.3 [M+H] + .

[0389] 1H NMR (400 MHz, DMSO) δ 9.56 (s, 1H), 7.63 - 7.46 (m, 2H), 7.37 - 7.33 (m, 3H), 7.32 - 7.16 (m, 4H), 6.92 (d, J = 7.8 Hz, 1H), 6.24 (dd, J = 10.2, 1.8 Hz, 1H), 6.04 (s, 1H), 5.59 (t, J = 6.0 Hz, 1H), 5.51 - 5.37 (m, 2H), 5.11 (t, J = 5.8 Hz, 1H), 4.92 (d, J = 4.0 Hz, 1H), 4.50 (dd, J = 19.6, 6.4 Hz, 1H), 4.26 - 4.08 (m, 2H), 3.94 (d, J = 6.0 Hz, 2H), 3.90 - 3.85 (m, 2H), 2.70 - 2.54 (m, 2H), 2.40 - 2.31 (m, 1H), 2.25 - 1.99 (m, 2H), 1.90 - 1.79 (m, 1H), 1.73 - 1.61 (m, 3H), 1.50 (s, 3H), 0.86 (s, 3H).

[0390] Preparation Example Nine: Preparation of 2-hydroxy-N-(3-(4-((6aR,6bS,7S,8aS,8bS,10R,11aR,12aS,12bS)-7-hydroxy-8b-(2-hydroxyacetyl)-6a,8a-dimethyl-4-oxo-2,4,6a,6b,7,8,8a,8b,11a,12,12a,12b-dodecahydro-1H-naphtho[2',1':4,5]indeno[1,2-d][1,3]dioxol-10-yl)benzyl)phenyl)acetamide (A-3)

[0391] (6aR,6bS,7S,8aS,8bS,10R,11aR,12aS,12bS)-10-(4-(3-aminobenzyl)phenyl)-7-hydroxy-8b-(2-hydroxyacetyl)-6a,8a-dimethyl-1,2,6a,6b,7,8,8a,8b,11a,12,12a,12b-dodecahydro-4H-naphtho[2',1':4,5]indeno[1,2-d][1,3]dioxol-4-one (80 mg, 136.1 μmol) and 2-hydroxyacetic acid (10.3 mg, 136.1 μmol) were dissolved in DMF (1.5 mL), after adding HATU (62.1 mg, 163.4 μmol) and DIPEA (52.8 mg, 408.3 μmol), stirring at 25 °C for 1 hour. The reaction solution was directly purified by high performance liquid chromatography preparation, and freeze-dried to obtain the title compound (23.58 mg, 37.37 μmol).

[0392] Column: Waters SunFire Prep C18 OBD 19mm x 150mm x 5pm

[0393] Mobile Phase A: Acetonitrile; Mobile Phase B: Water (0.05% Formic Acid)

[0394] Its structural characterization is as follows:

[0395] ESI-MS (m / z): 628.3 [M+H] + .

[0396] 1 H NMR (400 MHz, DMSO) δ 9.56 (s, 1H), 7.53 - 7.49 (m, 2H), 7.38 (d, J = 8.0 Hz, 2H), 7.31 (d, J = 10.0 Hz, 1H), 7.27 - 7.16 (m, 3H), 6.92 (d, J = 7.6 Hz, 1H), 6.16 (dd, J = 10.2, 1.8 Hz, 1H), 5.93 (s, 1H), 5.60 (s, 1H), 5.40 (s, 1H), 5.09 (t, J = 5.8 Hz, 1H), 4.91 (d, J = 5.0 Hz, 1H), 4.79 (d, J = 3.0 Hz, 1H), 4.49 (dd, J = 19.6, 6.0 Hz, 1H), 4.29 (s, 1H), 4.24 - 4.11 (m, 1H), 3.94 (d, J = 5.2 Hz, 2H), 3.88 (s, 2H), 2.38 - 2.27 (m, 1H), 2.17 - 1.97 (m, 2H), 1.81 - 1.56 (m, 5H), 1.39 (s, 3H), 1.11 - 0.93 (m, 2H), 0.86 (s, 3H).

[0397] Preparation Example Ten: Preparation of (S)-N-(3-(4-((6aS,6bR,7S,8aS,8bS,10R,11aR,12aS,12bS)-6b-fluoro-7-hydroxy-8b-(2-hydroxyacetyl)-6a,8a-dimethyl-4-oxo-2,4,6a,6b,7,8,8a,8b,11a,12,12a,12b-dodecahydro-1H-naphtho[2',1':4,5]indeno[1,2-d][1,3]dioxol-10-yl)benzyl)phenyl)-2-hydroxypropanamide (A-5)

[0398] (6aS,6bR,7S,8aS,8bS,10R,11aR,12aS,12bS)-10-(4-(3-aminobenzyl)phenyl)-6b-fluoro-7-hydroxy-8b-(2-hydroxyacetyl)-6a,8a-dimethyl-1,2,6a,6b,7,8,8a,8b,11a,12,12a,12b-dodecahydro-4H-naphtho[2',1':4,5]indeno[1,2-d][1,3]dioxol-4-one (60 mg, 81.23 pmol, TF) was dissolved in DMF (2 mL), after adding (S)-2-hydroxypropanoic acid (7.32 mg, 81.23 pmol, FR), HATU (30.89 mg, 81.23 pmol) and DIPEA (31.50 mg, 243.69 pmol), the reaction was carried out at 25 °C for 2 hours. The reaction solution was concentrated to obtain the crude product directly, which was purified by high performance liquid chromatography preparation and freeze-dried to obtain the title compound (9.13 mg, 13.42 pmol).

[0399] Column: Phenomenex Luna C18 200mm x 40mm x 10pm

[0400] Mobile phase A: acetonitrile; mobile phase B: water (0.05% formic acid)

[0401] The structure is characterized as follows:

[0402] ESI-MS (m / z): 660.3 [M+H] + .

[0403] 1H NMR (400 MHz, DMSO) δ 9.54 (s, 1H), 7.54 (d, J = 8.5 Hz, 2H), 7.35 (d, J = 8.1 Hz, 2H), 7.31 - 7.16 (m, 4H), 6.92 (d, J = 7.6 Hz, 1H), 6.23 (dd, J = 10.1, 1.8 Hz, 1H), 6.04 (s, 1H), 5.47 (d, J = 22.8 Hz, 2H), 4.92 (d, J = 4.1 Hz, 1H), 4.50 (d, J = 19.5 Hz, 1H), 4.19 (d, J = 19.4 Hz, 2H), 4.09 (q, J = 6.7 Hz, 1H), 3.86 (d, J = 9.3 Hz, 2H), 3.38 (s, 3H), 2.66 - 2.54 (m, 1H), 2.35 (dd, J = 13.6, 3.6 Hz, 1H), 2.16 (dd, J = 11.6, 7.4 Hz, 1H), 2.08 - 2.01 (m, 1H), 1.88 - 1.80 (m, 1H), 1.73 - 1.56 (m, 3H), 1.50 (s, 3H), 1.43 - 1.34 (m, 1H), 1.27 (d, J = 6.8 Hz, 3H), 0.87 (s, 3H).

[0404] Preparation Example XI: Preparation of (S)-2-hydroxy-N-(3-(4-((6aR,6bS,7S,8aS,8bS,10R,11aR,12aS,12bS)-7-hydroxy-8b-(2-hydroxyacetyl)-6a,8a-dimethyl-4-oxo-2,4,6a,6b,7,8,8a,8b,11a,12,12a,12b-dodecahydro-1H-naphtho[2',1':4,5]indeno[1,2-d][1,3]dioxol-10-yl)benzyl)phenyl)propanamide (A-6)

[0405] (6aR,6bS,7S,8aS,8bS,10R,11aR,12aS,12bS)-10-(4-(3-aminobenzyl)phenyl)-7- hydroxy-8b-(2-hydroxyacetyl)-6a,8a-dimethyl-1,2,6a,6b,7,8,8a,8b,11a,12,12a,12b- dodecahydro-4H-naphtho[2',1':4,5]indeno[1,2-d][1,3]dioxepin-4-one (77.55 mg, 129.32 μmol, FR) was dissolved in DMF (2 mL), after adding (S)-2-hydroxypropanoic acid (11.65 mg, 129.32 μmol, FR), HATU (49.17 mg, 129.32 μmol) and DIPEA (50.14 mg, 387.97 μmol), the reaction was carried out at 25 °C for 2 hours. The reaction was concentrated to get the crude product directly, which was purified by high performance liquid chromatography and freeze-dried to obtain the title compound (19.66 mg, 29.72 μmol, FR).

[0406] Column: Phenomenex Luna C18 200mm x 40mm x 10μm

[0407] Mobile Phase A: Acetonitrile; Mobile Phase B: Water (0.05% Formic Acid)

[0408] Its structural characterization is as follows:

[0409] ESI-MS (m / z): 642.3 [M+H] + .

[0410] 1H NMR (400 MHz, DMSO) δ 9.55 (s, 1H), 7.61 - 7.49 (m, 2H), 7.38 (d, J = 8.1 Hz, 2H), 7.31 (d, J = 10.1 Hz, 1H), 7.26 - 7.14 (m, 3H), 6.91 (d, J = 7.6 Hz, 1H), 6.16 (dd, J = 10.1, 1.8 Hz, 1H), 5.93 (s, 1H), 5.40 (s, 1H), 4.92 (d, J = 5.1 Hz, 1H), 4.79 (s, 1H), 4.50 (d, J = 19.5 Hz, 1H), 4.29 (s, 1H), 4.17 (d, J = 19.5 Hz, 1H), 4.10 (q, J = 6.7 Hz, 1H), 3.88 (s, 2H), 3.58 (s, 2H), 2.58 - 2.51 (m, 1H), 2.31 (d, J = 11.3 Hz, 1H), 2.15 - 1.97 (m, 2H), 1.82 - 1.57 (m, 5H), 1.39 (s, 3H), 1.27 (d, J = 6.8 Hz, 3H), 1.09 - 0.98 (m, 2H), 0.86 (s, 3H).

[0411] Preparation Example Twelve: Preparation of (R)-N-(3-(4-((6aS,6bR,7S,8aS,8bS,10R,11aR,12aS,12bS)-6b-fluoro-7-hydroxy-8b-(2-hydroxyacetyl)- 6a,8a-dimethyl-4-oxo-2,4,6a,6b,7,8,8a,8b,11a,12,12a,12b-dodecahydro-1H- naphtho[2',1':4,5]indeno[1,2-d][1,3]dioxol-10-yl)benzyl)phenyl)-2-hydroxypropanamide (A-8)

[0412] (6aS,6bR,7S,8aS,8bS,10R,11aR,12aS,12bS)-10-(4-(3-aminobenzyl)phenyl)-6b-fluoro-7-hydroxy-8b-(2-hydroxyacetyl)-6a,8a-dimethyl-1,2,6a,6b,7,8,8a,8b,11a,12,12a,12b-dodecahydro-4H-naphtho[2',1':4,5]indeno[1,2-d][1,3]dioxol-4-one (50 mg, 85.08 μmol, FR) was dissolved in DMF (2 mL), after adding (R)-2-hydroxypropanoic acid (7.66 mg, 85.08 μmol), HATU (35.56 mg, 93.59 μmol) and DIPEA (32.99 mg, 255.24 μmol), the reaction was carried out at 25 °C for 2 hours. The reaction solution was concentrated to obtain the crude product directly, which was purified by high performance liquid chromatography and freeze-dried to obtain the title compound (9.8 mg, 14.71 μmol).

[0413] Column: Phenomenex Luna C18 200mm x 40mm x 10μm

[0414] Mobile Phase A: Acetonitrile; Mobile Phase B: Water (0.05% Formic Acid)

[0415] The structure was characterized as follows:

[0416] ESI-MS (m / z): 660.3 [M+H] + .

[0417] 1H NMR (400 MHz, DMSO) δ 9.53 (s, 1H), 7.55 (s, 1H), 7.53 (s, 1H), 7.34 (s, 1H), 7.33 (s, 1H), 7.32-7.19 (m, 3H), 7.19-7.16 (m, 1H), 6.92 (d, J = 7.6 Hz, 1H), 6.23 (dd, J = 10.2, 2.0 Hz, 1H), 6.04 (s, 1H), 5.66 (d, J = 5.2 Hz, 1H), 5.44 (s, 2H), 5.10 (t, J = 6.0 Hz, 1H), 4.92 (d, J = 4.0 Hz, 1H), 4.50 (dd, J = 19.6 Hz, 6.4 Hz, 1H), 4.23-4.14 (m, 2H), 4.11-4.05 (m, 2H), 3.87 (s, 2H), 2.66-2.58 (m, 1H), 2.38-2.35 (m, 1H), 2.23-2.13 (m, 1H), 2.08-2.02 (m, 1H), 1.89-1.80 (m, 1H), 1.71 - 1.62 (m, 3H), 1.50 (s, 3H), 1.45-1.31 (2, 2H), 1.27 (d, J = 6.8 Hz, 3H), 0.86 (s, 3H).

[0418] Preparation of (R)-2-hydroxy-N-(3-(4-((6aR,6bS,7S,8aS,8bS,10R,11aR,12aS,12bS)- 7-hydroxy-8b-(2-hydroxyacetyl)-6a,8a-dimethyl-4-oxo-2,4,6a,6b,7,8,8a,8b,11a,12,12a,12b- dodecahydro-lH-naphtho[2',l':4,5]indeno[l,2-d][l,3]dioxol-10-yl)benzyl)phenyl)propanamide (A-9)

[0419] (6aR,6bS,7S,8aS,8bS,10R,11aR,12aS,12bS)-10-(4-(3-aminobenzyl)phenyl)-7- hydroxy-8b-(2-hydroxyacetyl)-6a,8a-dimethyl-1,2,6a,6b,7,8,8a,8b,11a,12,12a,12b- dodecahydro-4H-naphtho[2',1':4,5]indeno[1,2-d][1,3]dioxepin-4-one (50 mg, 87.77 pmol, FR) was dissolved in DMF (2 mL), after adding (R)-2-hydroxypropanoic acid (7.91 mg, 87.77 pmol), HATU (33.35 mg, 87.77 pmol) and DIPEA (33.97 mg, 263.31 pmol), it was reacted at 25 °C for 2 hours. The reaction solution was concentrated to obtain a crude product directly, which was purified by high performance liquid chromatography preparation and freeze-dried to obtain the title compound (14.82 mg, 22.86 pmol).

[0420] Column: Phenomenex Luna C18 200mm x 40mm x 10pm

[0421] Mobile Phase A: Acetonitrile; Mobile Phase B: Water (0.05% Formic Acid)

[0422] Its structure was characterized as follows:

[0423] ESI-MS (m / z): 643.3 [M+H] + .

[0424] 1 H NMR (400 MHz, DMSO) d 9.55 (s, 1H), 7.60 - 7.50 (m, 2H), 7.40 (s, 1H), 7.38 (s, 1H), 7.32 (d, J = 10.0 Hz, 1H), 7.29 - 7.16 (m, 3H), 6.93 (d, J = 7.8 Hz, 1H), 6.18 (dd, J = 10.0, 1.8 Hz, 1H), 5.95 (s, 1H), 5.41 (s, 1H), 4.93 (d, J = 5.1 Hz, 1H), 4.80 (s, 1H), 4.51 (d, J = 19.6 Hz, 1H), 4.30 (s, 1H), 4.19 (d, J = 19.6 Hz, 1H), 4.11 (q, J = 6.8 Hz, 1H), 3.90 (s, 2H), 2.18 - 2.06 (m, 1H), 2.04 - 1.98 (m, 1H), 1.83 - 1.60 (m, 5H), 1.41 (s, 3H), 1.29 (d, J = 6.8 Hz, 3H), 1.09 - 1.00 (m, 2H), 0.87 (s, 3H).

[0425] Preparation Example Fourteen: Preparation of (S)-2-cyclopropyl-N-(3-(4-((6aS,6bR,7S,8aS,8bS,10R,11aR,12aS,12bS)-6b-fluoro-7-hydroxy-8b-(2-hydroxyacetyl)-6a,8a-dimethyl-4-oxo-2,4,6a,6b,7,8,8a,8b,11a,12,12a,12b-dodecahydro-1H-naphtho[2',1':4,5]indeno[1,2-d][1,3]dioxol-10-yl)benzyl)phenyl)-2-hydroxyacetamide (A-11)

[0426] A salt of (6aS,6bR,7S,8aS,8bS,10R,11aR,12aS,12bS)-10-(4-(3-aminobenzyl)phenyl)-6b-fluoro-7-hydroxy-8b-(2-hydroxyacetyl)-6a,8a-dimethyl-1,2,6a,6b,7,8,8a,8b,11a,12,12a,12b-dodecahydro-4H-naphtho[2',1':4,5]indeno[1,2-d][1,3]dioxol-4-one trifluoroacetate (35 mg, 49.88 µmol) and (S)-2-cyclopropyl-2-hydroxyacetic acid (5.79 mg, 49.88 µmol) were dissolved in DMF (1 mL), DIPEA (16.00 mg, 123.80 µmol) was added, then HATU (18.95 mg, 49.88 µmol) was added, and the reaction was stirred at room temperature for 1 hour. After the reaction was completed, the reaction solution was directly purified by high performance liquid chromatography to obtain the title compound (6.51 mg, 23.59 µmol) after freeze-drying.

[0427] Column: Waters Sunfire Prep C18 OBD 150mm×19mm×5µm

[0428] Mobile phase A: acetonitrile; mobile phase B: water (0.05% formic acid)

[0429] The structure thereof is characterized as follows:

[0430] ESI-MS (m / z): 686.3 [M+H] + .

[0431] 1H NMR (400 MHz, DMSO-d6) δ 9.51 (s, 1H), 7.56 - 7.53 (m, 2H), 7.35 - 7.34 (m, 2H), 7.30 - 7.24 (m, 3H), 7.21 - 7.17 (m, 1H), 7.48 - 7.46 (m, 1H), 6.93 - 6.90 (m, 1H), 6.23 (dd, J = 9.2, 2.0 Hz, 1H), 6.03 (br s, 1H), 5.56 (d, J = 5.6 Hz, 1H), 5.44 (br s, 1H), 5.10 (t, J = 6.0 Hz, 1H), 4.92 (d, J = 4.0 Hz, 1H), 4.53 - 4.47 (m, 1H), 4.21 - 4.15 (m, 2H), 3.88 (s, 2H), 3.60 (t, J = 6.0 Hz, 1H), 2.67 - 2.44 (m, 2H), 2.37 - 2.32 (m, 1H), 2.21 - 2.14 (m, 1H), 2.07 - 2.03 (m, 1H), 1.86 - 1.83 (m, 1H), 1.69 - 1.60 (m, 3H), 1.50 (s, 3H), 1.44 - 1.33 (m, 1H), 1.15 - 1.06 (m, 1H), 0.86 (s, 3H), 0.44 - 0.32 (m, 4H).

[0432] Preparation Example Fifteen: Preparation of (S)-2-cyclopropyl-2-hydroxy-N-(3-(4-((6aR,6bS,7S,8aS,8bS,10R,11aR,12aS,12bS)-7-hydroxy-8b-(2-hydroxyacetyl)-6a,8a-dimethyl-4-oxo-2,4,6a,6b,7,8,8a,8b,11a,12,12a,12b-dodecahydro-1H-naphtho[2',1':4,5]indeno[1,2-d][1,3]dioxol-10-yl)benzyl)phenyl)acetamide (A-12)

[0433] (6aR,6bS,7S,8aS,8bS,10R,11aR,12aS,12bS)-10-(4-(3-aminobenzyl)phenyl)-7- hydroxy-8b-(2-hydroxyacetyl)-6a,8a-dimethyl-1,2,6a,6b,7,8,8a,8b,11a,12,12a,12b- dodecahydro-4H-naphtho[2',1':4,5]indeno[1,2-d][1,3]dioxepin-4-one trifluoroacetate (35 mg, 49.88 μmol) and (S)-2-cyclopropyl-2-hydroxyacetic acid (5.79 mg, 49.88 μmol) were dissolved in DMF (1 mL), DIPEA (16.00 mg, 123.80 μmol) was added, then HATU (18.95 mg, 49.88 μmol) was added, the reaction was stirred at room temperature for 1 hour. After the reaction was completed, the reaction solution was directly purified by high performance liquid chromatography to give the title compound (20.56 mg, 30.17 μmol, 98% purity) after freeze-drying.

[0434] Column: Waters Sunfire Prep C18 OBD 150mm x 19mm x 5μm

[0435] Mobile Phase A: Acetonitrile; Mobile Phase B: Water (0.05% Formic Acid)

[0436] The structure is characterized as follows:

[0437] ESI-MS (m / z): 669.3 [M+H] + .

[0438] 1H NMR (400 MHz, DMSO-d6) δ 9.53 (s, 1H), 7.57 - 7.51 (m, 2H), 7.39 - 7.37 (m, 2H), 7.30 (d, J = 10.0 Hz, 1H), 7.25 - 7.22 (m, 2H), 7.19 (t, J = 8.0 Hz, 1H), 6.92 - 6.90 (m, 1H), 6.15 (dd, J = 1.6, 10.0 Hz, 1H), 5.92 (br s, 1H), 5.59 (d, J = 5.2 Hz, 1H), 5.40 (s, 1H), 5.10 (t, J = 6.0 Hz, 1H), 4.91 (d, J = 5.2 Hz, 1H), 4.79 (d, J = 3.6 Hz, 1H), 4.53 - 4.46 (m, 1H), 4.30 - 4.27 (m, 1H), 4.20 - 4.14 (m, 1H), 3.88 (s, 1H), 3.60 (t, J = 5.6 Hz, 1H), 2.58 - 2.53 (m, 1H), 2.33 - 2.28 (m, 1H), 2.13 - 2.06 (m, 1H), 2.03 - 1.99 (m, 1H), 1.81 - 1.61 (m, 5H), 1.39 (s, 1H), 1.13 - 0.99 (m, 3H), 0.85 (s, 1H), 0.44 - 0.32 (m, 4H).

[0439] Preparation Example Sixteen: Preparation of (R)-2-cyclopropyl-N-(3-(4-((6aS,6bR,7S,8aS,8bS,10R,11aR,12aS,12bS)-6b-fluoro-7-hydroxy-8b-(2-hydroxyacetyl)-6a,8a-dimethyl-4-oxo-2,4,6a,6b,7,8,8a,8b,11a,12,12a,12b-dodecahydro-1H-naphtho[2',1':4,5]indeno[1,2-d][1,3]dioxol-10-yl)benzyl)phenyl)-2-hydroxyacetamide (A-14)

[0440] (6aS,6bR,7S,8aS,8bS,10R,11aR,12aS,12bS)-10-(4-(3-aminobenzyl)phenyl)- 6b-fluoro-7-hydroxy-8b-(2-hydroxyacetyl)-6a,8a-dimethyl-1,2,6a,6b,7,8,8a,8b,11a, 12,12a,12b-dodecahydro-4H-naphtho[2',1':4,5]indeno[1,2-d][1,3]dioxepin-4-one (45 mg, 64.13 μmol, TF) was dissolved in DMF (2 mL), after adding 3-hydroxypropanoic acid (7.45 mg, 64.13 μmol, FR), HATU (24.38 mg, 64.13 μmol) and DIPEA (20.72 mg, 160.33 μmol, 22.52 μL), the reaction was carried out at 25 °C for 2 hours. The reaction solution was concentrated to obtain the crude product directly, which was purified by high performance liquid chromatography preparation and freeze-dried to obtain A-14 (18.67 mg, 25.86 μmol, FR).

[0441] Column: Phenomenex Luna C18 200mm x 40mm x 10μm

[0442] Mobile Phase A: Acetonitrile; Mobile Phase B: Water (0.05% Formic Acid)

[0443] The structure is characterized as follows:

[0444] ESI-MS (m / z): 686.3 [M+H] + .

[0445] 1H NMR (400 MHz, DMSO) δ 9.51 (s, 1H), 7.54 (d, J = 7.2 Hz, 2H), 7.37 - 7.16 (m, 6H), 6.92 (d, J = 7.7 Hz, 1H), 6.23 (dd, J = 10.1, 1.9 Hz, 1H), 6.03 (s, 1H), 5.56 (d, J = 5.4 Hz, 1H), 5.46 (d, J = 17.9 Hz, 2H), 5.10 (t, J = 6.0 Hz, 1H), 4.92 (d, J = 4.2 Hz, 1H), 4.50 (dd, J = 19.5, 6.4 Hz, 1H), 4.18 (dd, J = 19.4, 5.4 Hz, 2H), 3.88 (s, 2H), 3.63 - 3.58 (m, 1H), 2.72 - 2.54 (m, 1H), 2.36 (s, 1H), 2.18 (d, J = 7.3 Hz, 1H), 2.05 (d, J = 14.0 Hz, 1H), 1.88 - 1.82 (m, 1H), 1.73 - 1.60 (m, 3H), 1.50 (s, 3H), 1.39 (dd, J = 12.8, 5.0 Hz, 1H), 1.23 (s, 1H), 1.10 (dd, J = 12.6, 6.5 Hz, 1H), 0.86 (s, 3H), 0.45 - 0.31 (m, 4H).

[0446] Preparation Example Seventeen: Preparation of (R)-2-cyclopropyl-2-hydroxy-N-(3-(4-((6aR,6bS,7S,8aS,8bS,10R,11aR,12aS,12bS)-7-hydroxy-8b-(2-hydroxyacetyl)-6a,8a-dimethyl-4-oxo-2,4,6a,6b,7,8,8a,8b,11a,12,12a,12b-dodecahydro-1H-naphtho[2',1':4,5]indeno[1,2-d][1,3]dioxol-10-yl)benzyl)phenyl)acetamide (A-15)

[0447] (6aR,6bS,7S,8aS,8bS,10R,11aR,12aS,12bS)-10-(4-(3-aminobenzyl)phenyl)-7- hydroxy-8b-(2-hydroxyacetyl)-6a,8a-dimethyl-1,2,6a,6b,7,8,8a,8b,11a,12,12a,12b- dodecahydro-4H-naphtho[2',1':4,5]indeno[1,2-d][1,3]dioxepin-4-one (80 mg, 133.41 μmol, FR) was dissolved in DMF (2 mL), after adding 3-hydroxypropanoic acid (16.31 mg, 140.43 μmol, FR), HATU (80.09 mg, 210.64 μmol) and DIPEA (45.37 mg, 351.07 μmol), the reaction was carried out at 25 °C for 2 hours. The reaction solution was concentrated to get the crude product directly, after high performance liquid chromatography preparation purification, freeze-drying to get A-15 (24 mg, 34.86 μmol, FR).

[0448] Column: Phenomenex Luna C18 200mm x 40mm x 10μm

[0449] Mobile Phase A: Acetonitrile; Mobile Phase B: Water (0.05% Formic Acid)

[0450] The structure was characterized as follows:

[0451] ESI-MS (m / z): 668.3 [M+H] + .

[0452] 1H NMR (400 MHz, DMSO) δ 9.52 (s, 1H), 7.57 - 7.50 (m, 2H), 7.38 (d, J = 8.1 Hz, 2H), 7.30 (d, J = 10.1 Hz, 1H), 7.26 - 7.17 (m, 3H), 6.91 (d, J = 7.6 Hz, 1H), 6.16 (dd, J = 10.1, 1.8 Hz, 1H), 5.93 (s, 1H), 5.40 (s, 1H), 4.91 (d, J = 5.1 Hz, 1H), 4.78 (d, J = 3.0 Hz, 1H), 4.50 (d, J = 19.4 Hz, 1H), 4.28 (s, 1H), 4.17 (d, J = 19.4 Hz, 1H), 3.88 (s, 2H), 3.60 (d, J = 6.3 Hz, 1H), 2.59 - 2.52 (m, 1H), 2.34 - 2.29 (m, 1H), 2.11 - 1.97 (m, 2H), 1.88 - 1.52 (m, 6H), 1.39 (s, 3H), 1.24 - 0.98 (m, 4H), 0.86 (s, 3H), 0.44 - 0.32 (m, 4H).

[0453] Preparation Example Eighteen: Preparation of N-(3-(4-((6aS,6bR,7S,8aS,8bS,10R,11aR,12aS,12bS)-6b-fluoro-7-hydroxy-8b-(2-hydroxyacetyl)-6a,8a-dimethyl-4-oxo-2,4,6a,6b,7,8,8a,8b,11a,12,12a,12b-dodecahydro-1H-naphtho[2',1':4,5]indeno[1,2-d][1,3]dioxol-10-yl)benzyl)phenyl)-3-hydroxypropanamide (B-2)

[0454] (6aS,6bR,7S,8aS,8bS,10R,11aR,12aS,12bS)-10-(4-(3-aminobenzyl)phenyl)-6b-fluoro-7-hydroxy-8b-(2-hydroxyacetyl)-6a,8a-dimethyl-1,2,6a,6b,7,8,8a,8b,11a,12,12a,12b-dodecahydro-4H-naphtho[2',1':4,5]indeno[1,2-d][1,3]dioxepin-4-one (80 mg, 108.31 pmol, TF) was dissolved in DMF (2 mL), after adding 3-hydroxypropanoic acid (32.52 mg, 108.31 pmol, FR), HATU (41.18 mg, 108.31 pmol) and DIPEA (41.99 mg, 324.93 pmol), it was reacted at 25 °C for 2 hours. The reaction solution was concentrated to obtain a crude product directly, which was purified by high performance liquid chromatography preparation and freeze-dried to obtain B-2 (23.61 mg, 35.07 pmol, FR).

[0455] Column: Phenomenex Luna C18 200mm x 40mm x 10pm

[0456] Mobile Phase A: Acetonitrile; Mobile Phase B: Water (0.05% Formic Acid)

[0457] The structure was characterized as follows:

[0458] ESI-MS (m / z): 660.3 [M+H] + .

[0459] 1 H NMR (400 MHz, DMSO) d 9.80 (s, 1H), 7.46 (d, J = 8.2 Hz, 1H), 7.39 - 7.15 (m, 7H), 6.89 (d, J = 7.5 Hz, 1H), 6.23 (dd, J = 10.1, 1.9 Hz, 1H), 6.04 (s, 1H), 5.44 (s, 2H), 5.13 - 5.06 (m, 1H), 4.92 (d, J = 4.1 Hz, 1H), 4.48 (s, 1H), 4.19 (d, J = 18.2 Hz, 2H), 3.88 (s, 2H), 3.67 (t, J = 6.3 Hz, 2H), 2.67 - 2.55 (m, 2H), 2.41 (t, J = 6.4 Hz, 4H), 2.17 (d, J = 7.2 Hz, 1H), 2.05 (d, J = 13.5 Hz, 1H), 1.85 (d, J = 12.6 Hz, 1H), 1.66 (dd, J = 14.8, 8.2 Hz, 3H), 1.50 (s, 3H), 1.42 - 1.36 (m, 1H), 0.87 (s, 3H).

[0460] Preparation Example Nineteen: Preparation of 3-hydroxy-N-(3-(4-((6aR,6bS,7S,8aS,8bS,10R,11aR,12aS,12bS)-7-hydroxy-8b-(2-hydroxyacetyl)-6a,8a-dimethyl-4-oxo-2,4,6a,6b,7,8,8a,8b,11a,12,12a,12b-dodecahydro-1H-naphtho[2',1':4,5]indeno[1,2-d][1,3]dioxol-10-yl)benzyl)phenyl)propanamide (B-3)

[0461] (6aR,6bS,7S,8aS,8bS,10R,11aR,12aS,12bS)-10-(4-(3-aminobenzyl)phenyl)-7-hydroxy-8b-(2-hydroxyacetyl)-6a,8a-dimethyl-1,2,6a,6b,7,8,8a,8b,11a,12,12a,12b-dodecahydro-4H-naphtho[2',1':4,5]indeno[1,2-d][1,3]dioxol-4-one (80 mg, 133.41 µmol, FR) was dissolved in DMF (2 mL), after adding 3-hydroxypropanoic acid (40.06 mg, 133.41 µmol, FR), HATU (50.73 mg, 133.41 µmol) and DIPEA (51.72 mg, 400.22 µmol), the reaction was carried out at 25 °C for 2 hours. The reaction solution was concentrated to obtain the crude product directly, which was purified by high performance liquid chromatography preparation and freeze-dried to obtain B-3 (45.45 mg, 67.99 µmol, FR).

[0462] Column: Phenomenex Luna C18 200mm×40mm×10µm

[0463] Mobile phase A: acetonitrile; mobile phase B: water (0.05% formic acid)

[0464] Its structure is characterized as follows:

[0465] ESI-MS (m / z): 642.3 [M+H] + .

[0466] 1H NMR (400 MHz, DMSO) δ 9.82 (s, 1H), 7.41 (dd, J = 21.6, 7.9 Hz, 4H), 7.31 (d, J = 10.1 Hz, 1H), 7.24 - 7.16 (m, 3H), 6.89 (d, J = 7.6 Hz, 1H), 6.16 (dd, J = 10.1, 1.9 Hz, 1H), 5.93 (s, 1H), 5.40 (s, 1H), 4.92 (d, J = 5.1 Hz, 1H), 4.79 (s, 1H), 4.50 (d, J = 19.5 Hz, 1H), 4.29 (s, 1H), 4.18 (d, J = 19.5 Hz, 1H), 3.88 (s, 2H), 3.67 (d, J = 6.3 Hz, 2H), 2.56 (dd, J = 13.5, 5.0 Hz, 1H), 2.41 (t, J = 6.4 Hz, 2H), 2.34 - 2.27 (m, 1H), 2.15 - 1.97 (m, 2H), 1.83 - 1.59 (m, 5H), 1.39 (s, 3H), 1.11 - 0.98 (m, 2H), 0.86 (s, 3H).

[0467] Preparation Example Twenty: Preparation of N-(3-(4-((2S,6aS,6bR,7S,8aS,8bS,10R,11aR,12aS,12bS)- 2,6b-difluoro-7-hydroxy-8b-(2-hydroxyacetyl)-6a,8a-dimethyl-4-oxo-2,4,6a,6b,7,8,8a,8b,11a,12,12a,12b-dodecahydro-1H-naphtho[2',1':4,5]indeno[1,2-d][1,3]dioxol-10-yl)benzyl)phenyl)-4-hydroxybutanamide (C-1)

[0468] Step One: Preparation of 4-hydroxybutanoic acid (C-1-2)

[0469] Benzyl 4-hydroxybutanoate (1.2 g, 6.18 mmol) was dissolved in methanol (5.0 mL), 10% palladium on carbon (100 mg) was added, and the mixture was stirred at 25 °C for 5 hours after hydrogen replacement for 3 times. The mixture was filtered and concentrated to give the title compound (998.0 mg, 3.28 mmol) as a crude product, which was used in the next step without purification.

[0470] Step two: Preparation of N-(3-(4-((2S,6aS,6bR,7S,8aS,8bS,10R,11aR,12aS,12bS)- 2,6b-difluoro-7-hydroxy-8b-(2-hydroxyacetyl)-6a,8a-dimethyl-4-oxo-2,4,6a,6b,7,8,8a,8b,11a,12,12a,12b-dodecahydro-lH-naphtho[2',l':4,5]indeno[l,2- d][l,3]dioxol-10-yl)benzyl)phenyl)-4-hydroxybutanamide (C-l)

[0471] (2S,6aS,6bR,7S,8aS,8bS,10R,11aR,12aS,12bS)-10-(4-(3-aminobenzyl)phenyl)-2,6b- difluoro-7-hydroxy-8b-(2-hydroxyacetyl)-6a,8a-dimethyl-l,2,6a,6b,7,8,8a,8b,11a,12,12a,12b- dodecahydro-4H-naphtho[2',l':4,5]indeno[l,2-d][l,3]dioxol-4-one (80 mg, 132.1 μmol) and 4-hydroxybutanoic acid (13.7 mg, 132.1 μmol) were dissolved in DMF (1.5 mL), after adding HATU (75.2 mg, 198.1 μmol) and DIPEA (51.2 mg, 396.3 μmol), stirred at 25 °C for 1 hour. The reaction solution was directly purified by high performance liquid chromatography preparation, and then freeze-dried to obtain the title compound (25.75 mg, 35.4 μmol).

[0472] Column: Waters SunFire Prep C18 OBD 19mmx150mmx5μm

[0473] Mobile phase A: acetonitrile; mobile phase B: water (0.05% formic acid)

[0474] Its structure is characterized as follows:

[0475] ESI-MS (m / z): 692.3 [M+H] + .

[0476] 1H NMR (400 MHz, DMSO) δ 9.79 (s, 1H), 7.45 (d, J = 8.2 Hz, 1H), 7.36 (d, J = 8.2 Hz, 3H), 7.25 (t, J = 9.2 Hz, 3H), 7.17 (t, J = 7.8 Hz, 1H), 6.88 (d, J = 7.6 Hz, 1H), 6.30 (dd, J = 10.2, 1.8 Hz, 1H), 6.13 (s, 1H), 5.76 - 5.56 (m, 1H), 5.53 (s, 1H), 5.45 (s, 1H), 5.11 (t, J = 5.8 Hz, 1H), 4.94 (d, J = 4.8 Hz, 1H), 4.58 - 4.44 (m, 2H), 4.25 - 4.10 (m, 2H), 3.87 (s, 2H), 3.48 - 3.45 (m, 2H), 2.73 - 2.56 (m, 1H), 2.35 - 2.23 (m, 4H), 2.10 - 2.0 (m, 1H), 1.75 - 1.62 (m, 5H), 1.50 (s, 3H), 0.86 (s, 3H).

[0477] Preparation Example Twenty-one: Preparation of N-(3-(4-((6aS,6bR,7S,8aS,8bS,10R,11aR,12aS,12bS)-6b-fluoro-7-hydroxy-8b-(2-hydroxyacetyl)-6a,8a-dimethyl-4-oxo-2,4,6a,6b,7,8,8a,8b,11a,12,12a,12b-dodecahydro-1H-naphtho[2',1':4,5]indeno[1,2-d][1,3]dioxol-10-yl)benzyl)phenyl)-4-hydroxybutanamide (C-2)

[0478] (6aS,6bR,7S,8aS,8bS,10R,11aR,12aS,12bS)-10-(4-(3-aminobenzyl)phenyl)-6b-fluoro-7-hydroxy-8b-(2-hydroxyacetyl)-6a,8a-dimethyl-1,2,6a,6b,7,8,8a,8b,11a,12,12a,12b-dodecahydro-4H-naphtho[2',1':4,5]indeno[1,2-d][1,3]dioxin-4-one (100 mg, 170.1 μmol) and 4-hydroxybutanoic acid (13.7 mg, 132.1 μmol) were dissolved in DMF (1.5 mL), after adding HATU (75.2 mg, 198.1 μmol) and DIPEA (51.2 mg, 396.3 μmol), stirred at 25 °C for 1 hour. The reaction solution was directly purified by high performance liquid chromatography preparation, and freeze-dried to obtain the title compound (25.75 mg, 35.4 μmol).

[0479] Column: Waters SunFire Prep C18 OBD 19mm x 150mm x 5pm

[0480] Mobile Phase A: Acetonitrile; Mobile Phase B: Water (0.05% Formic Acid)

[0481] Its structure characterization is as follows:

[0482] ESI-MS (m / z): 692.3 [M+H] + .

[0483] 1 H NMR (400 MHz, DMSO) δ 9.79 (s, 1H), 7.45 (d, J = 8.2 Hz, 1H), 7.38 - 7.33 (m, 3H), 7.29 (d, J = 10.2 Hz, 1H), 7.24 (d, J = 8.2 Hz, 2H), 7.20 - 7.13 (m, 1H), 6.88 (d, J = 7.6 Hz, 1H), 6.24 (dd, J = 10.2, 2.0 Hz, 1H), 6.04 (s, 1H), 5.44 (s, 2H), 4.92 (d, J = 4.0 Hz, 1H), 4.50 (d, J = 19.6 Hz, 1H), 4.23 - 4.13 (m, 2H), 3.87 (s, 2H), 3.60 - 3.48 (m, 4H), 2.70 - 2.59 (m, 1H), 2.39 - 2.26 (m, 3H), 2.23 - 2.12 (m, 1H), 2.09 - 1.99 (m, 1H), 1.90 - 1.79 (m, 1H), 1.74 - 1.60 (m, 5H), 1.50 (s, 3H), 1.43 - 1.32 (m, 1H), 0.87 (s, 3H).

[0484] Preparation Example Twenty-two: Preparation of 4-hydroxy-N-(3-(4-((6aR,6bS,7S,8aS,8bS,10R,11aR,12aS,12bS)-7-hydroxy-8b-(2-hydroxyacetyl)-6a,8a-dimethyl-4-oxo-2,4,6a,6b,7,8,8a,8b,11a,12,12a,12b-dodecahydro-1H-naphtho[2',1':4,5]indeno[1,2-d][1,3]dioxol-10-yl)benzyl)phenyl)butanamide (C-3)

[0485] (6aR,6bS,7S,8aS,8bS,10R,11aR,12aS,12bS)-10-(4-(3-aminobenzyl)phenyl)-7- hydroxy-8b-(2-hydroxyacetyl)-6a,8a-dimethyl-1,2,6a,6b,7,8,8a,8b,11a,12,12a,12b- dodecahydro-4H-naphtho[2',1':4,5]indeno[1,2-d][1,3]dioxepin-4-one (80.0 mg, 140.4 μmol) and 4-hydroxybutanoic acid (14.7 mg, 140.4 μmol) were dissolved in DMF (1.5 mL), after adding HATU (80.2 mg, 210.6 μmol) and DIPEA (54.5 mg, 421.3 μmol), stirred at 25 °C for 1 h. The reaction solution was directly purified by high performance liquid chromatography preparation and freeze-dried to obtain the title compound (6.98 mg, 10.4 μmol).

[0486] Column: Waters SunFire Prep C18 OBD 19mm x 150mm x 5um

[0487] Mobile Phase A: Acetonitrile; Mobile Phase B: Water (0.05% trifluoroacetic acid)

[0488] The structure was characterized as follows:

[0489] ESI-MS (m / z): 656.3 [M+H] + .

[0490] 1 H NMR (400 MHz, DMSO) δ 9.80 (s, 1H), 7.45 - 7.35 (m, 4H), 7.31 (d, J = 10.2 Hz, 1H), 7.22 (d, J = 8.2 Hz, 2H), 7.17 (t, J = 7.8 Hz, 1H), 6.88 (d, J = 7.6 Hz, 1H), 6.16 (dd, J = 10.0 1.8 Hz, 1H), 5.93 (s, 1H), 5.40 (s, 1H), 5.09 (s, 1H), 4.91 (d, J = 5.2 Hz, 1H), 4.79 (d, J = 3.0 Hz, 1H), 4.49 (d, J = 19.6 Hz, 1H), 4.29 (s, 1H), 4.17 (d, J = 19.6 Hz, 1H), 3.88 (s, 2H), 3.50 - 3.38 (m, 4H), 2.36 - 2.27 (m, 3H), 2.18 - 2.06 (m, 1H), 2.06 - 1.97 (m, 1H), 1.81 - 1.60 (m, 7H), 1.39 (s, 3H), 1.07 - 0.98 (m, 2H), 0.86 (s, 3H).

[0491] Preparation Example Twenty-Three: Preparation of 2-hydroxyethyl (3-(4-((6aS,6bR,7S,8aS,8bS,10R,11aR,12aS,12bS)-6b-fluoro-7-hydroxy-8b-(2-hydroxyacetyl)-6a,8a-dimethyl-4-oxo-2,4,6a,6b,7,8,8a,8b,11a,12,12a,12b-dodecahydro-1H-naphtho[2',1':4,5]indeno[1,2-d][1,3]dioxol-10-yl)benzyl)phenyl)carbamate (D-2)

[0492] Step One: Preparation of 2-(trityloxy)ethyl (3-(4-((6aS,6bR,7S,8aS,8bS,10R,11aR,12aS,12bS)-6b-fluoro-7-hydroxy-8b-(2-hydroxyacetyl)-6a,8a-dimethyl-4-oxo-2,4,6a,6b,7,8,8a,8b,11a,12,12a,12b-dodecahydro-1H-naphtho[2',1':4,5]indeno[1,2-d][1,3]dioxol-10-yl)benzyl)phenyl)carbamate (D-2-1)

[0493] (6aS,6bR,7S,8aS,8bS,10R,11aR,12aS,12bS)-10-(4-(3-aminobenzyl)phenyl)-6b-fluoro-7-hydroxy-8b-(2-hydroxyacetyl)-6a,8a-dimethyl-1,2,6a,6b,7,8,8a,8b,11a,12,12a,12b-dodecahydro-4H-naphtho[2',1':4,5]indeno[1,2-d][1,3]dioxol-4-one (100.0 mg, 0.21 mmol) was dissolved in DMF (2.0 mL), after the addition of DIPEA (82.4 mg, 0.64 mmol), HOBT (28.8 mg, 0.21 mmol), 4-nitrophenyl (2-(trityloxy)ethyl) carbonate (125.5 mg, 0.21 mmol) was added, and stirring was performed at 45°C for 16 hours. The reaction solution was purified by a C18 column (acetonitrile / 0.05% aqueous formic acid solution = 0-90%) and freeze-dried to obtain the title compound (45.0 mg, 0.05 mmol).

[0494] The structure thereof was characterized as follows:

[0495] ESI-MS (m / z): 941.1 (M+Na) + .

[0496] Step two: Preparation of 2-hydroxyethyl (3-(4-((6aS,6bR,7S,8aS,8bS,10R,11aR,12aS,12bS)-6b-fluoro-7-hydroxy-8b-(2-hydroxyacetyl)-6a,8a-dimethyl-4-oxo-2,4,6a,6b,7,8,8a,8b,11a,12,12a,12b-dodecahydro-1H-naphtho[2',1':4,5]indeno[1,2-d][1,3]dioxol-10-yl)benzyl)phenyl)carbamate (D-2)

[0497] A solution of 2-(trityloxy)ethyl (3-(4-((6aS,6bR,7S,8aS,8bS,10R,11aR,12aS,12bS)-6b-fluoro-7-hydroxy-8b-(2-hydroxyacetyl)-6a,8a-dimethyl-4-oxo-2,4,6a,6b,7,8,8a,8b,11a,12,12a,12b-dodecahydro-1H-naphtho[2',1':4,5]indeno[1,2-d][1,3]dioxol-10-yl)benzyl)phenyl)carbamate (45.0 mg, 0.05 mmol) in DCM (2.0 mL) was added formic acid 0.5 mL and stirred at 25 °C for 2 hours. The reaction was concentrated to get the crude product, which was purified by preparative HPLC and freeze-dried to give the title compound (6.85 mg, 9.76 μmol).

[0498] Column: Waters SunFire Prep C18 OBD 19mmx150mmx5μm

[0499] Mobile Phase A: Acetonitrile; Mobile Phase B: Water (0.05% Formic Acid)

[0500] The structure was characterized as follows:

[0501] ESI-MS (m / z): 676.3 [M+H] + .

[0502] 1H NMR (400 MHz, DMSO) δ 9.59 (s, 1H), 7.34 (d, J = 8.2 Hz, 3H), 7.31 - 7.25 (m, 2H), 7.23 (d, J = 8.0 Hz, 2H), 7.16 (t, J = 7.8 Hz, 1H), 6.84 (d, J = 7.5 Hz, 1H), 6.23 (dd, J = 10.0, 1.6 Hz, 1H), 6.04 (s, 1H), 5.44 (s, 2H), 5.10 (t, J = 5.8 Hz, 1H), 4.92 (d, J = 4.0 Hz, 1H), 4.79 (t, J = 5.4 Hz, 1H), 4.50 (dd, J = 19.6, 6.4 Hz, 1H), 4.23 - 4.13 (m, 2H), 4.10 - 4.01 (m, 2H), 3.86 (s, 2H), 3.63 - 3.55 (m, 2H), 2.71 - 2.57 (m, 1H), 2.40 - 2.31 (m, 1H), 2.24 - 2.01 (m, 2H), 1.90 - 1.77 (m, 1H), 1.71 - 1.60 (m, 3H), 1.50 (s, 3H), 0.87 (s, 3H).

[0503] Preparation Example Twenty-Four: Preparation of 2-hydroxyethyl (3-(4-((6aR,6bS,7S,8aS,8bS,10R,11aR,12aS,12bS)-7-hydroxy-8b-(2-hydroxyacetyl)-6a,8a-dimethyl-4-oxo-2,4,6a,6b,7,8,8a,8b,11a,12,12a,12b-dodecahydro-1H-naphtho[2',1':4,5]indeno[1,2-d][1,3]dioxol-10-yl)benzyl)phenyl)carbamate (D-3)

[0504] Step One: Preparation of 2-(trityloxy)ethyl (3-(4-((2S,6aS,6bR,7S,8aS,8bS,10R,11aR,12aS,12bS)-2,6b-difluoro-7-hydroxy-8b-(2-hydroxyacetyl)-6a,8a-dimethyl-4-oxo-2,4,6a,6b,7,8,8a,8b,11a,12,12a,12b-dodecahydro-1H-naphtho[2',1':4,5]indeno[1,2-d][1,3]dioxol-10-yl)benzyl)phenyl)carbamate (D-3-1)

[0505] (6aR,6bS,7S,8aS,8bS,10R,11aR,12aS,12bS)-10-(4-(3-aminobenzyl)phenyl)-7- hydroxy-8b-(2-hydroxyacetyl)-6a,8a-dimethyl-l,2,6a,6b,7,8,8a,8b,11a,12,12a,12b- dodecahydro-4H-naphtho[2',l':4,5]indeno[l,2-d][l,3]dioxol-4-one (150.0 mg, 0.26 mmol) was dissolved in DMF (3.0 mL), after adding DIPEA (100.6 mg, 0.78 mmol), HOBT (43.2 mg, 0.32 mmol), 4-nitrophenyl (2-(triphenylmethoxy)ethyl) carbonate (141.5 mg, 0.30 mmol) was added, and stirring was performed at 45 °C for 16 hours. After the reaction solution was purified by C18 column (acetonitrile / 0.05% formic acid aqueous solution = 0-90%), freeze-drying was performed to obtain the title compound (60.0 mg, 0.06 mmol).

[0506] The structure thereof was characterized as follows:

[0507] ESI-MS (m / z): 958.1 (M+Na) + .

[0508] Step two: Preparation of 2-hydroxyethyl (3-(4-((6aR,6bS,7S,8aS,8bS,10R,11aR,12aS,12bS)-7-hydroxy-8b-(2-hydroxyacetyl)-6a,8a-dimethyl-4-oxo-2,4,6a,6b,7,8,8a,8b,11a,12,12a,12b-dodecahydro-lH-naphtho[2',l':4,5]indeno[l,2-d][l,3]dioxol-10-yl)benzyl)phenyl)carbamate (D-3)

[0509] 2-(triphenylmethyl oxy)ethyl (3-(4-((2S,6aS,6bR,7S,8aS,8bS,10R,11aR,12aS,12bS)-2,6b-difluoro-7-hydroxy-8b-(2-hydroxyacetyl)-6a,8a-dimethyl-4-oxo-2,4,6a,6b,7,8,8a,8b,11a,12,12a,12b-dodecahydro-lH-naphtho[2',l':4,5]indeno[l,2-d][l,3]dioxol-10-yl)benzyl)phenyl)carbamate (60.0 mg, 0.06 mmol) was dissolved in DCM (3.0 mL), formic acid 0.8 mL was added, and stirring was performed at 25 °C for 2 hours. The reaction solution was concentrated to obtain a crude product, which was purified by high performance liquid chromatography preparation and freeze-dried to obtain the title compound (7.22 mg, 10.82 μmol).

[0510] Column: Waters SunFire Prep C18 OBD 19mm x 150mm x 5pm

[0511] Mobile Phase A: Acetonitrile; Mobile Phase B: Water (0.05% Formic Acid)

[0512] Its structure was characterized as follows:

[0513] ESI-MS (m / z): 658.2 [M+H] + .

[0514] 1 H NMR (400 MHz, DMSO) δ 9.59 (s, 1H), 7.39 - 7.29 (m, 4H), 7.26 (d, J = 8.4 Hz, 1H), 7.21 (d, J = 8.2 Hz, 2H), 7.16 (t, J = 7.8 Hz, 1H), 6.83 (d, J = 7.6 Hz, 1H), 6.16 (dd, J = 10.2, 1.8 Hz, 1H), 5.93 (s, 1H), 5.39 (s, 1H), 5.07 (t, J = 5.8 Hz, 1H), 4.91 (d, J = 5.2 Hz, 1H), 4.81 - 4.75 (m, 2H), 4.49 (dd, J = 19.6, 6.4 Hz, 1H), 4.29 (s, 1H), 4.17 (dd, J = 19.6, 5.6 Hz, 1H), 4.11 - 4.02 (m, 2H), 3.87 (s, 2H), 3.60 (q, J = 4.0, 2H), 2.59 - 2.53 (m, 1H), 2.36 - 2.24 (m, 1H), 2.17 - 2.08 (m, 1H), 2.06 - 1.96 (m, 1H), 1.82 - 1.58 (m, 5H), 1.39 (s, 3H), 1.11 - 0.95 (m, 2H), 0.86 (s, 3H).

[0515] Preparation Example Twenty-Five: Preparation of 2-hydroxyethyl (3-(4-((2S,6aS,6bR,7S,8aS,8bS,10R,11aR,12aS,12bS)- 2,6b-difluoro-7-hydroxy-8b-(2-hydroxyacetyl)-6a,8a-dimethyl-4-oxo-2,4,6a,6b,7,8,8a,8b,11a,12,12a,12b-dodecahydro-1H-naphtho[2',1':4,5]indeno[1,2-d][1,3]dioxol-10-yl)benzyl)phenyl)(methyl)carbamate (D-4)

[0516] Step one: Preparation of tert-butyl N-methyl-(3-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)phenyl)carbamate (D-4-2)

[0517] Into a single-neck flask were placed tert-butyl (3-bromophenyl)(methyl)carbamate (600.0 mg, 2.1 mmol), bis(pinacolato)diboron (1.33 g, 5.24 mmol), dichlorobis(triphenylphosphine)palladium (441.5 mg, 0.63 mmol), potassium acetate (616.5 mg, 6.29 mmol), 1,4-dioxane (10.0 mL), and the mixture was stirred at 101 °C for 4 h after being replaced with nitrogen for 3 times. The reaction mixture was diluted with water (100 mL) and extracted with ethyl acetate (80 mL). The organic phase was washed with saturated brine (50 mL x 2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a crude product. The crude product was purified by column chromatography (petroleum ether / ethyl acetate = 0-90%) to give the title compound (460.2 mg, 1.38 mmol).

[0518] The structure thereof was characterized as follows:

[0519] 1 H NMR (400 MHz, DMSO) d 7.55-7.53 (m, 1H), 7.49-7.46 (m, 1H), 7.41-7.36 (m, 2H), 3.18 (s, 3H), 1.40 (s, 9H), 1.29 (s, 12H).

[0520] Step two: Preparation of tert-butyl (3-(4-formylbenzyl)phenyl)(methyl)carbamate (D-4-3)

[0521] Into a single-neck flask were placed tert-butyl N-methyl-(3-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)phenyl)carbamate (460.2 mg, 1.38 mmol), 4-bromomethylbenzaldehyde (302.1 mg, 1.52 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (201.7 mg, 0.28 mmol), potassium carbonate (380.9 mg, 2.76 mmol), tetrahydrofuran (10.0 mL), and water (2.0 mL), and the mixture was stirred at 75 °C for 2 h after being replaced with nitrogen for 3 times. The reaction mixture was diluted with water (60 mL) and extracted with ethyl acetate (50 mL). The organic phase was washed with saturated brine (50 mL x 2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a crude product. The crude product was purified by column chromatography (petroleum ether / ethyl acetate = 0-90%) to give the title compound (267.2 mg, 0.82 mmol).

[0522] The structure thereof was characterized as follows:

[0523] ESI-MS (m / z): 326.2 [M+H] + .

[0524] Step three: Preparation of (2S,6aS,6bR,7S,8aS,8bS,10R,11aR,12aS,12bS)-2,6b-difluoro-7-hydroxy-8b-(2-hydroxyacetyl)-6a,8a-dimethyl-10-(4-(3-(methylamino)benzyl)phenyl)-1,2,6a,6b,7,8,8a,8b,11a,12,12a,12b-dodecahydro-4H-naphtho[2',1':4,5]indeno[1,2-d][1,3]dioxol-4-one (D-4-4)

[0525] tert-Butyl (3-(4-formylbenzyl)phenyl)(methyl)carbamate (267.2 mg, 0.82 mmol), (6S,8S,9R,10S,11S,13S,14S,16R,17S)-6,9-difluoro-11,16,17-trihydroxy-17-(2-hydroxyacetyl)-10,13-dimethyl-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-3-one (350.1 mg, 0.82 mmol) were added into a single neck flask, after adding dichloromethane (5.0 mL), acetonitrile (5.0 mL), perchloric acid (2.0 mL) was added, stirred at 25 °C for 16 hours. Concentrated at room temperature under reduced pressure to get the crude product, purified by C18 column (0.05% formic acid water / acetonitrile = 0-90%) to get the title compound (270.0 mg, 0.43 mmol) after freeze-drying.

[0526] The structure was characterized as follows:

[0527] ESI-MS (m / z): 620.2 [M+H] + .

[0528] Step four: Preparation of 2-(trityloxy)ethyl (3-(4-((2S,6aS,6bR,7S,8aS,8bS,10R,11aR,12aS,12bS)-2,6b-difluoro-7-hydroxy-8b-(2-hydroxyacetyl)-6a,8a-dimethyl-4-oxo-2,4,6a,6b,7,8,8a,8b,11a,12,12a,12b-dodecahydro-1H-naphtho[2',1':4,5]indeno[1,2-d][1,3]dioxol-10-yl)benzyl)phenyl)(methyl)carbamate (D-4-5)

[0529] (2S,6aS,6bR,7S,8aS,8bS,10R,11aR,12aS,12bS)-2,6b-difluoro-7-hydroxy-8b-(2- hydroxyacetyl)-6a,8a-dimethyl-10-(4-(3-(methylamino)benzyl)phenyl)-1,2,6a,6b,7,8,8a,8b,11a,12,12a,12b-dodecahydro-4H-naphtho[2',1':4,5]indeno[1,2- d][1,3]dioxol-4-one (50.0 mg, 0.08 mmol) was dissolved in DMF (1.5 mL), after the addition of DIPEA (31.3 mg, 0.24 mmol), HOBT (9.8 mg, 0.08 mmol), 4-nitrophenyl (2-(triphenylmethoxy)ethyl) carbonate (45.6 mg, 0.09 mmol) was added, and stirring was performed at 45 °C for 16 hours. The reaction solution was purified by a C18 column (acetonitrile / 0.05% aqueous formic acid solution = 0-90%) and freeze-dried to obtain the title compound (18.2 mg, 0.02 mmol).

[0530] The structure thereof was characterized as follows:

[0531] ESI-MS (m / z): 972.1 (M+Na) + .

[0532] Step five: Preparation of 2-hydroxyethyl (3-(4-((2S,6aS,6bR,7S,8aS,8bS,10R,11aR,12aS,12bS)-2,6b-difluoro-7-hydroxy-8b-(2-hydroxyacetyl)-6a,8a-dimethyl-4-oxo-2,4,6a,6b,7,8,8a,8b,11a,12,12a,12b-dodecahydro-1H-naphtho[2',1':4,5]indeno[1,2-d][1,3]dioxol-10-yl)benzyl)phenyl)(methyl)carbamate (D-4)

[0533] (2S,6aS,6bR,7S,8aS,8bS,10R,11aR,12aS,12bS)-2,6b-difluoro-7-hydroxy-8b-(2- hydroxyacetyl)-6a,8a-dimethyl-4-oxo-2,4,6a,6b,7,8,8a,8b,11a,12,12a,12b- dodecahydro-1H-naphtho[2',1':4,5]indeno[1,2-d][1,3]dioxol-10-yl)benzyl)phenyl)(methyl)carbamate (18.2 mg, 0.02 mmol) was dissolved in DCM (2.0 mL), formic acid 0.5 mL was added, stirred at 25 °C for 2 hours. The reaction was concentrated to get the crude, purified by preparative high performance liquid chromatography, then freeze-dried to get the title compound (0.51 mg, 0.72 μmol).

[0534] Column: Waters SunFire Prep C18 OBD 19mmx150mmx5um

[0535] Mobile Phase A: Acetonitrile; Mobile Phase B: Water (0.05% Formic Acid)

[0536] Its structure was characterized as follows:

[0537] ESI-MS (m / z): 708.3 [M+H] + .

[0538] 1 H NMR (400 MHz, DMSO) δ 7.35 (d, J = 8.2 Hz, 1H), 7.31 - 7.21 (m, 5H), 7.12 (d, J = 9.0 Hz, 1H), 7.04 (d, J = 7.8 Hz, 1H), 6.30 (dd, J = 10.2, 1.8 Hz, 1H), 6.12 (s, 1H), 5.75 - 5.51 (m, 2H), 5.45 (s, 1H), 5.15 - 5.08 (m, 1H), 4.94 (d, J = 4.8 Hz, 1H), 4.75 (s, 1H), 4.55 - 4.56 (m, 1H), 4.23 - 4.14 (m, 2H), 4.05 - 3.97 (m, 2H), 3.90 (s, 2H), 3.55 - 3.49 (m, 2H), 3.19 (s, 3H), 2.70 - 2.65 (m, 1H), 2.36 - 2.26 (m, 2H), 2.08 - 1.99 (m, 1H), 1.77 - 1.65 (m, 3H), 1.49 (s, 3H), 0.86 (s, 3H).

[0539] Preparation Example Twenty-Six: Preparation of 2-aminoethyl (3-(4-((2S,6aS,6bR,7S,8aS,8bS,10R,11aR,12aS,12bS)-2,6b-difluoro-7-hydroxy-8b-(2-hydroxyacetyl)-6a,8a-dimethyl-4-oxo-2,4,6a,6b,7,8,8a,8b,11a,12,12a,12b-dodecahydro-1H-naphtho[2',1':4,5]indeno[1,2-d][1,3]dioxol-10-yl)benzyl)phenyl)carbamate (E-1)

[0540] Step One: Preparation of 2-(tert-butoxycarbonyl)amino)ethyl (3-(4-((2S,6aS,6bR,7S,8aS,8bS,10R,11aR,12aS,12bS)-2,6b-difluoro-7-hydroxy-8b-(2-hydroxyacetyl)-6a,8a-dimethyl-4-oxo-2,4,6a,6b,7,8,8a,8b,11a,12,12a,12b-dodecahydro-1H-naphtho[2',1':4,5]indeno[1,2-d][1,3]dioxol-10-yl)benzyl)phenyl)carbamate (E-1-2)

[0541] tert-Butyl (2-hydroxyethyl)carbamate (79.85 mg, 495.32 μmol) was dissolved in DCM (3.0 mL), DIPEA (64.02 mg, 495.33 μmol) was added, and then triphosgene (73.49 mg, 247.66 μmol) was added. The reaction was stirred at 25 °C for 30 min under nitrogen, and then (2S,6aS,6bR,7S,8aS,8bS,10R,11aR,12aS,12bS)-10-(4-(3-aminobenzyl)phenyl)-2,6b-difluoro-7-hydroxy-8b-(2-hydroxyacetyl)-6a,8a-dimethyl-1,2,6a,6b,7,8,8a,8b,11a,12,12a,12b-dodecahydro-4H-naphtho[2',1':4,5]indeno[1,2-d][1,3]dioxol-4-one (100 mg, 165.11 μmol) was added. The reaction was stirred at 25 °C for 1 h. The reaction was concentrated to give a crude product, which was purified by preparative high performance liquid chromatography and then freeze-dried to give the title compound (20 mg, 25.23 μmol).

[0542] The structure thereof was characterized as follows:

[0543] ESI-MS (m / z): 793.3 [M+H] + .

[0544] Step two: Preparation of 2-aminoethyl (3-(4-((2S,6aS,6bR,7S,8aS,8bS,10R,11aR,12aS,12bS)- 2,6b-difluoro-7-hydroxy-8b-(2-hydroxyacetyl)-6a,8a-dimethyl-4-oxo-2,4,6a,6b,7,8,8a,8b,11a,12,12a,12b-dodecahydro-1H-naphtho[2',1':4,5]indeno[1,2-d][1,3]dioxol-10-yl)benzyl)phenyl)carbamate (E-1)

[0545] 2-(tert-Butoxycarbonyl)amino)ethyl (3-(4-((2S,6aS,6bR,7S,8aS,8bS,10R,11aR,12aS,12bS)- 2,6b-difluoro-7-hydroxy-8b-(2-hydroxyacetyl)-6a,8a-dimethyl-4-oxo-2,4,6a,6b,7,8,8a,8b,11a,12,12a,12b-dodecahydro-1H-naphtho[2',1':4,5]indeno[1,2-d][1,3]dioxol-10-yl)benzyl)phenyl)carbamate (20 mg, 25.23 μmol) was dissolved in DCM (2.0 mL), TFA (1.0 mL) was added, and the mixture was stirred at 25 °C for 1 h. The reaction was concentrated to give a crude product, which was purified by preparative HPLC and freeze-dried to give the title compound (10.5 mg, 12.88 μmol).

[0546] Column: Waters SunFire Prep C18 OBD 19mm x 150mm x 5μm

[0547] Mobile Phase A: Acetonitrile; Mobile Phase B: Water (0.05% Formic Acid)

[0548] Its structure was characterized as follows:

[0549] ESI-MS (m / z): 693.3 [M+H] + .

[0550] 1H NMR (400 MHz, DMSO) δ 9.59 (s, 1H), 7.85 (s, 3H), 7.36 - 7.17 (m, 7H), 6.88 (d, J = 7.5 Hz, 1H), 6.30 (dd, J = 10.2, 1.8 Hz, 1H), 6.13 (s, 1H), 5.76 - 5.57 (m, 1H), 5.53 (d, J = 2.9 Hz, 1H), 5.45 (s, 1H), 5.12 (t, J = 6.0 Hz, 1H), 4.94 (d, J = 4.5 Hz, 1H), 4.50 (dd, J = 19.5, 6.5 Hz, 1H), 4.28 - 4.14 (m, 4H), 3.14 - 3.06 (m, 2H), 3.10 (s, 2H), 2.66 - 2.56 (m, 1H), 2.31 - 2.19 (m, 2H), 2.03 (d, J = 13.5 Hz, 1H), 1.76 - 1.65 (m, 3H), 1.58 - 1.44 (m, 1H), 1.5 (s, 3H), 0.86 (s, 3H).

[0551] Preparation Example Twenty-seven: Preparation of 3-amino-N-(3-(4-((2S,6aS,6bR,7S,8aS,8bS,10R,11aR,12aS,12bS)-2,6b-difluoro-7-hydroxy-8b-(2-hydroxyacetyl)-6a,8a-dimethyl-4-oxo-2,4,6a,6b,7,8,8a,8b,11a,12,12a,12b-dodecahydro-1H-naphtho[2',1':4,5]indeno[1,2-d][1,3]dioxol-10-yl)benzyl)phenyl)propanamide (F-1)

[0552] Step one: Preparation of tert-butyl (3-((3-(4-((2S,6aS,6bR,7S,8aS,8bS,10R,11aR,12aS,12bS)-2,6b-difluoro-7-hydroxy-8b-(2-hydroxyacetyl)-6a,8a-dimethyl-4-oxo-2,4,6a,6b,7,8,8a,8b,11a,12,12a,12b-dodecahydro-1H-naphtho[2',1':4,5]indeno[1,2-d][1,3]dioxol-10-yl)benzyl)phenyl)amino)-3-oxopropyl)carbamate (F-1-1)

[0553] (2S,6aS,6bR,7S,8aS,8bS,10R,11aR,12aS,12bS)-10-(4-(3-aminobenzyl)phenyl)- 2,6b-difluoro-7-hydroxy-8b-(2-hydroxyacetyl)-6a,8a-dimethyl-l,2,6a,6b,7,8,8a,8b, 11a, 12, 12a, 12b-dodecahydro-4H-naphtho[2',l':4,5]indeno[l,2-d][l,3]dioxepin-4- one (40 mg, 66.04 μmol, FR) was dissolved in DMF (2 mL), after adding 3-((tert- butoxycarbonyl)amino)propanoic acid (10.76 mg, 119.40 μmol, FR), HATU (25.11 mg, 66.04 μmol) and DIPEA (25.61 mg, 198.13 μmol), the reaction was carried out at 25 °C for 2 hours. The reaction solution was concentrated to obtain a crude product directly, which was purified by high performance liquid chromatography preparation and freeze-dried to obtain F-l-l (34 mg, 43.77 μmol, FR).

[0554] Column: Phenomenex Luna C18 200mm x 40mm x 10μm

[0555] Mobile Phase A: Acetonitrile; Mobile Phase B: Water (0.05% Formic Acid)

[0556] The structure is characterized as follows:

[0557] ESI-MS (m / z): 777.3 [M+H] + .

[0558] Step two: Preparation of 3-amino-N-(3-(4-((2S,6aS,6bR,7S,8aS,8bS,10R,11aR,12aS,12bS)- 2,6b-difluoro-7-hydroxy-8b-(2-hydroxyacetyl)-6a,8a-dimethyl-4-oxo-2,4,6a,6b,7,8,8a,8b, 11a, 12, 12a, 12b-dodecahydro-lH-naphtho[2',l':4,5]indeno[l,2-d][l,3]dioxepin-10-yl)benzyl)phenyl) propanamide (F-l)

[0559] tert-Butyl (3-((3-(4-((2S,6aS,6bR,7S,8aS,8bS,10R,11aR,12aS,12bS)-2,6b-difluoro-7-hydroxy-8b-(2-hydroxyacetyl)-6a,8a-dimethyl-4-oxo-2,4,6a,6b,7,8,8a,8b,11a,12,12a,12b-dodecahydro-1H-naphtho[2',1':4,5]indeno[1,2-d][1,3]dioxol-10-yl)benzyl)phenyl)amino)-3-oxopropyl)carbamate (F-1-1) (34 mg, 43.77 µmol, FR) was dissolved in DCM (2 mL), then HCl (4 M, 547.07 µL) was added, and the reaction was stirred at room temperature for 1 h. The reaction was concentrated directly to give the crude product, which was purified by preparative high performance liquid chromatography and then lyophilized to give the title compound (4.35 mg, 6.23 µmol, FR).

[0560] Column: Phenomenex Luna C18 200mm x 40mm x 10µm

[0561] Mobile Phase A: Acetonitrile; Mobile Phase B: Water (0.05% Formic Acid)

[0562] The structure was characterized as follows:

[0563] ESI-MS (m / z): 677.3 [M+H] + .

[0564] 1 H NMR (400 MHz, DMSO) δ 8.41 (s, 1H), 7.39 (d, J = 5.5 Hz, 2H), 7.33 (d, J = 8.1 Hz, 2H), 7.26 (d, J = 10.3 Hz, 1H), 7.25 – 7.17 (m, 3H), 6.94 (d, J = 7.6 Hz, 1H), 6.30 (dd, J = 10.2, 1.8 Hz, 1H), 6.14 (s, 1H), 5.72 – 5.52 (m, 1H), 5.42 (s, 1H), 4.92 (d, J = 3.0 Hz, 1H), 4.48 (d, J = 19.4 Hz, 1H), 4.21 – 4.15 (m, 2H), 3.87 (s, 2H), 3.74 (s, 3H), 2.98 (t, J = 6.5 Hz, 2H), 2.58 (t, J = 6.6 Hz, 2H), 2.31 (s, 1H), 2.21 (d, J = 10.8 Hz, 1H), 2.00 (d, J = 13.5 Hz, 1H), 1.67 (d, J = 12.1 Hz, 3H), 1.48 (s, 5H), 1.21 (s, 1H), 0.84 (s, 3H).

[0565] Preparation Example Twenty-eight: Preparation of 2-amino-N-(3-(4-((2S,6aS,6bR,7S,8aS,8bS,10R,11aR,12aS,12bS)-2,6b-difluoro-7-hydroxy-8b-(2-hydroxyacetyl)-6a,8a-dimethyl-4-oxo-2,4,6a,6b,7,8,8a,8b,11a,12,12a,12b-dodecahydro-1H-naphtho[2',1':4,5]indeno[1,2-d][1,3]dioxol-10-yl)benzyl)phenyl)acetamide (G-1)

[0566] Step one: Preparation of tert-butyl (2-((3-(4-((2S,6aS,6bR,7S,8aS,8bS,10R,11aR,12aS,12bS)-2,6b-difluoro-7-hydroxy-8b-(2-hydroxyacetyl)-6a,8a-dimethyl-4-oxo-2,4,6a,6b,7,8,8a,8b,11a,12,12a,12b-dodecahydro-1H-naphtho[2',1':4,5]indeno[1,2-d][1,3]dioxol-10-yl)benzyl)phenyl)amino)-2-oxoethyl)carbamate (G-1-1)

[0567] (2S,6aS,6bR,7S,8aS,8bS,10R,11aR,12aS,12bS)-10-(4-(3-aminobenzyl)phenyl)-2,6b-difluoro-7-hydroxy-8b-(2-hydroxyacetyl)-6a,8a-dimethyl-1,2,6a,6b,7,8,8a,8b,11a,12,12a,12b-dodecahydro-4H-naphtho[2',1':4,5]indeno[1,2-d][1,3]dioxin-4-one (45 mg, 74.30 μmol) and (tert-butoxycarbonyl)glycine (13.02 mg, 74.30 μmol) were dissolved in DMF (1 mL), DIPEA (16 mg, 123.80 μmol) was added, then HATU (19.64 mg, 51.67 μmol) was added, and the reaction was stirred at room temperature for 1 hour. After the reaction was completed, the reaction solution was extracted with water and ethyl acetate, the organic phase was washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product of the title compound (56 mg, 73.41 μmol), which was directly used in the next step reaction without purification.

[0568] The structure thereof was characterized as follows:

[0569] ESI-MS (m / z): 763.3 [M+H] + .

[0570] Step two: Preparation of 2-amino-N-(3-(4-((2S,6aS,6bR,7S,8aS,8bS,10R,11aR,12aS,12bS)- 2,6b-difluoro-7-hydroxy-8b-(2-hydroxyacetyl)-6a,8a-dimethyl-4-oxo-2,4,6a,6b,7,8,8a,8b,11a,12,12a,12b-dodecahydro-1H-naphtho[2',1':4,5]indeno[1,2-d][1,3]dioxol-10-yl)benzyl)phenyl)acetamide (G-1)

[0571] To tert-butyl (2-((3-(4-((2S,6aS,6bR,7S,8aS,8bS,10R,11aR,12aS,12bS)-2,6b-difluoro-7-hydroxy-8b-(2- hydroxyacetyl)-6a,8a-dimethyl-4-oxo-2,4,6a,6b,7,8,8a,8b,11a,12,12a,12b-dodecahydro-1H- naphtho[2',1':4,5]indeno[1,2-d][1,3]dioxol-10-yl)benzyl)phenyl)amino)-2-oxoethyl)carbamate (56 mg, 73.41 µmol) was added dichloromethane (2 mL), hydrochloric acid-dioxane (4 M, 1 mL) was added dropwise, there was a large amount of insoluble, after stirring for 0.5 hours, it was not completely reacted. Added methanol (0.5 mL), the solid was dissolved, and stirring at room temperature was continued for 0.5 hours. After the reaction was completed, the reaction solution was directly concentrated under reduced pressure, and the crude product was freeze-dried after preparative purification by high performance liquid chromatography to obtain the hydrochloride salt of the title compound (7.11 mg, 9.70 µmol, 95.4% purity).

[0572] Column: Waters Sunfire Prep C18 OBD 150mm×19mm×5µm

[0573] Mobile phase A: acetonitrile; mobile phase B: water (0.05% formic acid)

[0574] The structure is characterized as follows:

[0575] ESI-MS (m / z): 663.3 [M+H] + .

[0576] 1H NMR (400 MHz, DMSO-d6) δ 7.49 - 7.47 (m, 1H), 7.41 - 7.40 (m, 1H), 7.36 - 7.34 (m, 2H), 7.28 - 7.24 (m, 3H), 7.21 - 7.17 (m, 1H), 6.91 (d, J = 7.6 Hz, 1H), 6.29 (dd, J = 10.4, 2.0 Hz, 1H), 6.13 (s, 1H), 5.73 - 5.56 (m, 2H), 5.52-5.51 (m, 1H), 5.45 (s, 1H), 5.07 (br s, 1H), 4.94 (d, J = 4.4 Hz, 1H), 4.53 - 4.17 (m, 4H), 3.88 (s, 2H), 3.24 (s, 2H), 2.67 - 2.57 (m, 1H), 2.52 - 2.51 (m, 1H), 2.30 - 2.21 (m, 2H), 2.07 - 2.03 (m, 1H), 1.75 - 1.68 (m, 3H), 1.54 - 1.45 (m, 4H), 0.86 (s, 1H).

[0577] Preparation Example Twenty-Nine: Preparation of (2S,6aS,6bR,7S,8aS,8bS,10R,11aR,12aS,12bS)-2,6b-Difluoro-7-hydroxy-8b-(2-hydroxyacetyl)-10-(4-(3-((2-hydroxyethyl)amino)benzyl)phenyl)-6a,8a-dimethyl-1,2,6a,6b,7,8,8a,8b,11a,12,12a,12b-dodecahydro-4H-naphtho[2',1':4,5]indeno[1,2-d][1,3]dioxepin-4-one (J-1)

[0578] (2S,6aS,6bR,7S,8aS,8bS,10R,11aR,12aS,12bS)-10-(4-(3-aminobenzyl)phenyl)-2,6b-difluoro-7-hydroxy-8b-(2-hydroxyacetyl)-6a,8a-dimethyl-1,2,6a,6b,7,8,8a,8b,11a,12,12a,12b-dodecahydro-4H-naphtho[2',1':4,5]indeno[1,2-d][1,3]dioxepin-4-one (50 mg, 82.55 µmol, FR) was dissolved in DMF (2 mL), after adding iodoethanol (70.96 mg, 412.77 µmol), potassium carbonate (68.46 mg, 495.32 µmol), it was reacted at 25 °C for 2 hours. The reaction solution was concentrated to obtain a crude product directly, which was purified by high performance liquid chromatography preparation and freeze-dried to obtain the title compound (3.87 mg, 5.84 µmol).

[0579] Column: Waters SunFire Prep C18 OBD (5 pm x 19 mm x 150 mm)

[0580] Mobile phase A: Acetonitrile; Mobile phase B: Water (0.05% formic acid)

[0581] Its structural characterization is as follows:

[0582] ESI-MS (m / z): 650.3 [M+H] + .

[0583] 1 H NMR (400 MHz, DMSO) d 7.31 - 7.21 (m, 5H), 6.96 (t, J = 8.0 Hz, 1H), 6.45 - 6.41 (m, 1H), 6.40 - 6.36 (m, 2H), 6.33 - 6.32 (m, 1H), 6.30 - 6.29 (m, 1H), 5.70 - 5.53 (m, 1H), 5.41 (m, 1H), 4.92 - 4.91 (m, 1H), 4.51 - 4.46 (m, 1H), 4.21 - 4.16 (m, 2H), 4.07 - 4.05 (m, 2H), 3.74 (s, 2H), 3.50 (t, J = 6.0 Hz, 2H), 3.03 (t, J = 6.0 Hz, 2H), 2.73 - 2.56 (m, 1H), 2.38 - 2.29 (m, 1H), 2.24 - 2.16 (m, 1H), 2.04 - 1.96 (m, 1H), 1.71 - 1.60 (m, 3H), 1.52 - 1.40 (m, 4H), 0.83 (s, 3H).

[0584] Preparation Example Thirty: Preparation of N-(4-(4-((2S,6aS,6bR,7S,8aS,8bS,10R,11aR,12aS,12bS)- 2,6b-difluoro-7-hydroxy-8b-(2-hydroxyacetyl)-6a,8a-dimethyl-4-oxo-2,4,6a,6b,7,8,8a,8b,11a,12,12a,12b-dodecahydro-1H-naphtho[2',1':4,5]indeno[1,2-d][1,3]dioxol-10-yl)benzyl)phenyl)-2-hydroxyacetamide (M-1)

[0585] (2S,6aS,6bR,7S,8aS,8bS,10R,11aR,12aS,12bS)-10-(4-(4-aminobenzyl)phenyl)- 2,6b-difluoro-7-hydroxy-8b-(2-hydroxyacetyl)-6a,8a-dimethyl-1,2,6a,6b,7,8,8a,8b,11a, 12,12a,12b-dodecahydro-4H-naphtho[2',1':4,5]indeno[1,2-d][1,3]dioxepin-4-one (15 mg, 24.77 pmol, FR) was dissolved in DMF (2 mL), after adding 2-hydroxyacetic acid (2.83 mg, 37.15 pmol), HATU (18.83 mg, 49.53 pmol) and DIPEA (16.00 mg, 123.83 pmol), it was reacted at 25 °C for 2 hours. The reaction solution was concentrated to obtain a crude product directly, which was purified by high performance liquid chromatography to obtain the title compound (6.3 mg, 9.11 pmol) after freeze-drying.

[0586] Column: Phenomenex Luna C18 200mm x 40mm x 10pm

[0587] Mobile Phase A: Acetonitrile; Mobile Phase B: Water (0.05% Formic Acid)

[0588] The structure is characterized as follows:

[0589] ESI-MS (m / z): 664.3 [M+H] + .

[0590] 1 H NMR (400 MHz, DMSO) d 9.54 (s, 1H), 7.57 (d, J = 8.4 Hz, 2H), 7.34 (d, J = 8.4 Hz, 2H), 7.27 - 7.23 (m, 3H), 7.13 (d, J = 8.4 Hz, 2H), 6.29 (dd, J = 10.0, 2.4 Hz, 1H), 6.13 (s, 1H), 5.72 - 5.63 (m, 2H), 5.51 - 5.50 (m, 1H), 5.44 (s, 1H), 5.08 (t, J = 6.0 Hz, 1H), 4.94 (d, J = 4.8 Hz, 1H), 4.51 (dd, J = 20.8, 6.4 Hz 1H), 4.22 - 4.14 (m, 2H), 3.94 (d, J = 6.0 Hz, 2H), 3.86 (s, 2H), 2.67 - 2.57 (m, 1H), 2.32 - 2.20 (m, 2H), 2.06 - 2.02 (m, 1H), 1.75 - 1.63 (m, 3H), 1.54 - 1.49 (s, 4H), 0.86 (s, 3H).

[0591] Preparation Example Thirty-one: Preparation of (R)-N-(4-(4-((2S,6aS,6bR,7S,8aS,8bS,10R,11aR,12aS,12bS)-2,6b-difluoro-7-hydroxy-8b-(2-hydroxyacetyl)-6a,8a-dimethyl-4-oxo-2,4,6a,6b,7,8,8a,8b,11a,12,12a,12b-dodecahydro-lH-naphtho[2',l':4,5]indeno[l,2-d][l,3]dioxol-10-yl)benzyl)phenyl)-2-hydroxypropanamide (N-l)

[0592] (2S,6aS,6bR,7S,8aS,8bS,10R,11aR,12aS,12bS)-10-(4-(4-aminobenzyl)phenyl)-2,6b-difluoro-7-hydroxy-8b-(2-hydroxyacetyl)-6a,8a-dimethyl-l,2,6a,6b,7,8,8a,8b,11a,12,12a,12b-dodecahydro-4H-naphtho[2',l':4,5]indeno[l,2-d][l,3]dioxol-4-one (20 mg, 33.02 μmol, FR) was dissolved in DMF (2 mL), after adding (R)-2-hydroxypropanoic acid (5.95 mg, 66.04 μmol), HATU (18.83 mg, 49.53 μmol) and DIPEA (17.07 mg, 132.09 μmol), the reaction was carried out at 25 °C for 2 hours. The reaction solution was concentrated to obtain a crude product directly, which was purified by high performance liquid chromatography preparation and freeze-dried to obtain the title compound (6.69 mg, 9.58 μmol).

[0593] Column: Waters SunFire Prep C18 OBD (5 μm X 19 mm X 150 mm)

[0594] Mobile phase A: acetonitrile; mobile phase B: water (0.05% formic acid)

[0595] Its structure was characterized as follows:

[0596] ESI-MS (m / z): 678.3 [M+H] + .

[0597] 1H NMR (400 MHz, DMSO) δ 9.54 (s, 1H), 7.58 (d, J = 8.4 Hz, 2H), 7.34 (d, J = 8.0 Hz, 2H), 7.28-7.23 (m, 3H), 7.13 (d, J = 8.0 Hz, 2H), 6.31-6.28 (m, 1H), 6.13 (s, 1H), 5.73-5.67 (m, 2H), 5.63-5.50 (m, 2H), 5.44 (s, 1H), 5.12-5.09 (m, 1H), 4.94 (d, J = 5.2 Hz, 1H), 4.54-4.48 (m 1H), 4.22-4.16 (m, 2H), 4.13-4.07 (m, 1H), 3.86 (s, 2H), 2.33-2.20 (m, 3H), 2.06-2.02 (m, 1H), 1.75-1.65 (m, 3H), 1.50 (s, 3H), 1.28 (d, J = 6.8 Hz, 3H).

[0598] Preparation Example Thirty-two: Preparation of (S)-N-(4-(4-((2S,6aS,6bR,7S,8aS,8bS)- 2,6b-difluoro-7-hydroxy-8b-(2-hydroxyacetyl)-6a,8a-dimethyl-4-oxo-2,4,6a,6b,7,8,8a,8b,11a,12,12a,12b-dodecahydro-lH-naphtho[2',l':4,5]indeno[l,2- d][l,3]dioxol-10-yl)benzyl)phenyl)-2-hydroxypropanamide (O-l)

[0599] To DMF (2 mL) was added (2S,6aS,6bR,7S,8aS,8bS,10R,11aR,12aS,12bS)-10-(4-(4- aminobenzyl)phenyl)-2,6b-difluoro-7-hydroxy-8b-(2-hydroxyacetyl)-6a,8a-dimethyl-l,2,6a,6b,7,8,8a,8b,11a,12,12a,12b-dodecahydro-4H-naphtho[2',l':4,5]indeno[l,2- d][l,3]dioxol-4-one (20 mg, 33.02 μmol), (S)-2-hydroxypropanoic acid (9.95 mg, 66.04 μmol), DIPEA (17.07 mg, 132.09 μmol), and HATU (18.83 mg, 49.53 μmol), and after addition, the reaction was stirred at 25 °C for 3 hours. The reaction solution was purified by preparative high performance liquid chromatography and lyophilized to give the title compound (8.12 mg, 14.33 μmol).

[0600] Column: Phenomenex Luna C18 200mm x 40mm x 10pm

[0601] Mobile Phase A: Acetonitrile; Mobile Phase B: Water (0.05% Formic Acid)

[0602] Its structure characterization is as follows:

[0603] ESI-MS (m / z): 678.3 [M+H] + .

[0604] 1H NMR (400 MHz, DMSO) δ 9.53 (s, 1H), 7.59 - 7.56 (m, 2H), 7.35 - 7.33 (d, J = 8.2 Hz, 2H), 7.26 - 7.23 (m, 3H), 7.16 - 7.12 (m, 2H), 6.29 (dd, J = 10.1, 1.8 Hz, 1H), 6.13 (s, 1H), 5.69 (d, J = 5.3 Hz, 1H), 5.60 - 5.56 (m, 1H), 5.52 (dd, J = 4.4, 1.7 Hz, 1H), 5.45 (s, 1H), 5.10 (t, J = 6.0 Hz, 1H), 4.94 (d, J = 4.9 Hz, 1H), 4.51 (m, 1H), 4.19 (m, 1H), 4.10 (m, 1H), 3.86 (s, 2H), 2.73 - 2.57 (1H), 2.34 - 2.18 (m, 1H), 2.07 - 2.02 (1H), 1.75 - 1.63 (m, 3H), 1.50 (s, 3H), 1.30 - 1.27 (d, J = 6.8 Hz, 3H), 0.86 (s, 3H).

[0605] Preparation Example Thirty-three: Preparation of (R)-2-cyclopropyl-N-(4-(4-((2S,6aS,6bR,7S,8aS,8bS,10R,11aR,12aS,12bS)-2,6b-difluoro-7-hydroxy-8b-(2-hydroxyacetyl)-6a,8a-dimethyl-4-oxo-2,4,6a,6b,7,8,8a,8b,11a,12,12a,12b-dodecahydro-1H-naphtho[2',1':4,5]indeno[1,2-d][1,3]dioxol-10-yl)benzyl)phenyl)-2-hydroxyacetamide (P-1)

[0606] (2S,6aS,6bR,7S,8aS,8bS,10R,11aR,12aS,12bS)-10-(4-(4-aminobenzyl)phenyl)- 2,6b-difluoro-7-hydroxy-8b-(2-hydroxyacetyl)-6a,8a-dimethyl-1,2,6a,6b,7,8,8a,8b,11a, 12,12a,12b-dodecahydro-4H-naphtho[2',1':4,5]indeno[1,2-d][1,3]dioxol-4-one (17 mg, 28.07 μmol, FR) was dissolved in DMF (2 mL), after adding (R)-2-cyclopropyl-2- hydroxyacetic acid (4.89 mg, 42.10 μmol), HATU (21.34 mg, 56.14 μmol) and DIPEA (10.88 mg, 84.20 μmol), the reaction was carried out at 25 °C for 2 hours. The reaction was concentrated to get the crude product directly, which was purified by high performance liquid chromatography and freeze-dried to obtain the title compound (8.6 mg, 11.73 μmol).

[0607] Column: Phenomenex Luna C18 200mm x 40mm x 10μm

[0608] Mobile Phase A: Acetonitrile; Mobile Phase B: Water (0.05% Formic Acid)

[0609] The structure was characterized as follows:

[0610] ESI-MS (m / z): 704.3 [M+H] + .

[0611] 1H NMR (400 MHz, DMSO) δ 9.52 (s, 1H), 7.58 (d, J = 8.4 Hz, 2H), 7.34 (d, J = 8.4 Hz, 2H), 7.27 - 7.23 (m, 3H), 7.13 (d, J = 6.4 Hz, 2H), 6.29 (dd, J = 10.4, 2.4 Hz, 1H), 6.12 (s, 1H), 5.73 - 5.57 (m, 1H), 5.54 - 5.52 (m, 1H), 5.44 (s, 1H), 5.08 (s, 1H), 4.93 (d, J = 4.8 Hz, 1H), 4.51 (d, J = 19.6, 1H), 4.22 - 4.16 (m, 2H), 3.86 (s, 2H), 3.62 (d, J = 4.8 Hz, 1H), 2.67 - 2.57 (m, 1H), 2.30 - 2.20 (m, 2H), 2.07 - 2.02 (m, 1H), 1.75 - 1.67 (m, 3H), 1.57 - 1.45 (m, 4H), 1.16 - 1.07 (m, 1H), 0.86 (s, 3H), 0.45 - 0.32 (m, 4H).

[0612] Preparation Example Thirty-Four: Preparation of (S)-2-cyclopropyl-N-(4-(4-((2S,6aS,6bR,7S,8aS,8bS,10R,11aR,12aS,12bS)- 2,6b-difluoro-7-hydroxy-8b-(2-hydroxyacetyl)-6a,8a-dimethyl-4-oxo-2,4,6a,6b,7,8,8a,8b,11a,12,12a,12b-dodecahydro-lH-naphtho[2',l':4,5]indeno[l,2-d][l,3]dioxol-10-yl)benzyl)phenyl)-2-hydroxyacetamide (Q-1)

[0613] (2S,6aS,6bR,7S,8aS,8bS,10R,11aR,12aS,12bS)-10-(4-(4-aminobenzyl)phenyl)- 2,6b-difluoro-7-hydroxy-8b-(2-hydroxyacetyl)-6a,8a-dimethyl-1,2,6a,6b,7,8,8a,8b,11a, 12,12a,12b-dodecahydro-4H-naphtho[2',1':4,5]indeno[1,2-d][1,3]dioxol-4-one (20 mg, 33.02 μmol, FR) was dissolved in DMF (4 mL), after adding (S)-2-cyclopropyl-2- hydroxyacetic acid (7.67 mg, 66.04 μmol), HATU (25.11 mg, 66.04 μmol) and DIPEA (21.34 mg, 165.11 μmol), the reaction was carried out at 25 °C for 2 hours. The reaction was concentrated to get the crude product directly, which was purified by high performance liquid chromatography preparation and freeze-dried to obtain the title compound (9 mg, 12.66 μmol).

[0614] Column: Phenomenex Luna C18 200mm x 40mm x 10μm

[0615] Mobile Phase A: Acetonitrile; Mobile Phase B: Water (0.05% Formic Acid)

[0616] The structure is characterized as follows:

[0617] ESI-MS (m / z): 704.3 [M+H] + .

[0618] 1H NMR (400 MHz, DMSO) δ 9.51 (s, 1H), 7.58 (d, J = 8.4 Hz, 2H), 7.34 (d, J = 8.0 Hz, 2H), 7.29 - 7.21 (m, 3H), 7.13 (d, J = 8.4 Hz, 2H), 6.29 (dd, Ji = 10.4 Hz, J2 = 2.4 Hz, 1H), 6.13 (s, 1H), 5.75 - 5.55 (m, 2H), 5.55 - 5.50 (m, 1H), 5.45 (s, 1H), 5.10 (t, J = 6.0 Hz, 1H), 4.94 (d, J = 4.8 Hz, 1H), 4.51 (dd, Ji = 19.6 Hz, J2 = 6.4 Hz, 1H), 4.25 - 4.13 (m, 2H), 3.86 (s, 2H), 3.62 (t, J = 6.0 Hz, 1H), 2.67 - 2.57 (m, 1H), 2.32 - 2.18 (m, 2H), 2.09 - 1.99 (m, 1H), 1.79 - 1.63 (m, 3H), 1.58 - 1.40 (m, 4H), 1.17 - 1.03 (m, 1H), 0.86 (s, 3H), 0.46 - 0.31 (m, 4H).

[0619] Preparation Example Thirty-Five: Preparation of 2-hydroxyethyl (4-(4-((2S,6aS,6bR,7S,8aS,8bS,10R,11aR,12aS,12bS)-2,6b-difluoro-7-hydroxy-8b-(2-hydroxyacetyl)-6a,8a-dimethyl-4-oxo-2,4,6a,6b,7,8,8a,8b,11a,12,12a,12b-dodecahydro-1H-naphtho[2',1':4,5]indeno[1,2-d][1,3]dioxol-10-yl)benzyl)phenyl)carbamate (R-1)

[0620] Step One: Preparation of 2-(trityloxy)ethyl (4-(4-((2S,6aS,6bR,7S,8aS,8bS,10R,11aR,12aS,12bS)-2,6b-difluoro-7-hydroxy-8b-(2-hydroxyacetyl)-6a,8a-dimethyl-4-oxo-2,4,6a,6b,7,8,8a,8b,11a,12,12a,12b-dodecahydro-1H-naphtho[2',1':4,5]indeno[1,2-d][1,3]dioxol-10-yl)benzyl)phenyl)carbamate (R-1-1)

[0621] (2S,6aS,6bR,7S,8aS,8bS,10R,11aR,12aS,12bS)-10-(4-(4-aminobenzyl)phenyl)-2,6b-difluoro-7-hydroxy-8b-(2-hydroxyacetyl)-6a,8a-dimethyl-1,2,6a,6b,7,8,8a,8b,11a,12,12a,12b-dodecylhydro-4H-naphtho[2',1':4,5]indeno[1,2-d][1,3]dioxane-4-one (50.00 mg) 0.082 mmol) was dissolved in DMF (1 mL), and 4-nitrophenyl (2-(triphenylmethoxy)ethyl) carbonate (45 mg, 0.091 mmol), 2,6-dimethylpyridine (44 mg, 0.413 mmol) and HOBT (11 mg, 0.082 mmol) were added. The mixture was heated to 50 °C and stirred for 6 hours. The reaction solution was purified by C18 reverse column chromatography (acetonitrile / 0.05% formic acid aqueous solution = 20-95%) and lyophilized to give the title compound (69.0 mg, 0.074 mmol).

[0622] Its structural characterization is as follows:

[0623] ESI-MS (m / z): 959.3 (M+Na) + .

[0624] Step 2: Preparation of 2-hydroxyethyl (4-(4-((2S,6aS,6bR,7S,8aS,8bS,10R,11aR,12aS,12bS)-2,6b-difluoro-7-hydroxy-8b-(2-hydroxyacetyl)-6a,8a-dimethyl-4-oxo-2,4,6a,6b,7,8,8a,8b,11a,12,12a,12b-dodecylhydro-1H-naphtho[2',1':4,5]indeno[1,2-d][1,3]dioxacyclopenten-10-yl)benzyl)phenyl)carbamate (R-1) R,11aR,12aS,12bS)-2,6b-difluoro-7-hydroxy-8b-(2-hydroxyacetyl)-6a,8a-dimethyl-4-oxo-2,4,6a,6b,7,8,8a,8b,11a,12,12a,12b-dodecylhydro-1H-naphtho[2',1':4,5]indo[1,2-d][1,3]dioxacyclopenten-10-yl)benzyl)phenyl)carbamate (69.0 mg, 0.074 mmol) was dissolved in methanol (2.0 mL) and formic acid (1.0 mL), heated to 60 °C and reacted for 4 hours. The mixture was concentrated to obtain a crude product, which was then purified by high performance liquid chromatography and lyophilized to obtain the title compound (28 mg, 0.040 mmol).

[0625] Column: Waters SunFire Prep C18 OBD 19mm x 150mm x 5pm

[0626] Mobile Phase A: Acetonitrile; Mobile Phase B: Water (0.05% Formic Acid)

[0627] Its structural characterization is as follows:

[0628] ESI-MS (m / z): 694.1 [M+H] + .

[0629] 1 H NMR (400 MHz, DMSO) δ 9.58 (s, 1H), 7.36 - 7.33 (m, 4H), 7.28 - 7.22 (m, 3H), 7.12 - 7.10 (d, J = 8.4 Hz, 2H), 6.30 (dd, J = 10.2, 1.8 Hz, 1H), 6.13 (s, 1H), 5.73 - 5.57 (m, 1H), 5.53 (d, J = 2.8 Hz, 1H), 5.44 (s, 1H), 5.11 (t, J = 5.8 Hz, 1H), 4.94 (d, J = 5.2 Hz, 1H), 4.80 (t, J = 5.2 Hz, 1H), 4.51 (dd, J = 19.6, 6.4 Hz, 1H), 4.22 - 4.16 (m, 2H), 4.07 (t, J = 5.2 Hz, 2H), 3.84 (s, 2H), 3.60 (dd, J = 10.4, 5.2 Hz, 2H), 2.71 - 2.57 (m, 1H), 2.33 - 2.19 (m, 2H), 2.06 - 2.02 (m, 1H), 1.77 - 1.63 (m, 3H), 1.57 - 1.44 (m, 4H), 0.86 (s, 3H).

[0630] Preparation Example Thirty-six: Preparation of N-(4-(4-((2S,6aS,6bR,7S,8aS,8bS,10R,11aR,12aS,12bS)- 2,6b-difluoro-7-hydroxy-8b-(2-hydroxyacetyl)-6a,8a-dimethyl-4-oxo-2,4,6a,6b,7,8,8a,8b,11a,12,12a,12b-dodecahydro-1H-naphtho[2',1':4,5]indeno[1,2-d][1,3]dioxol-10-yl)benzyl)phenyl)-3-hydroxypropanamide (S-1):

[0631] To DMF (2 mL) was added (2S,6aS,6bR,7S,8aS,8bS,10R,11aR,12aS,12bS)-10-(4-(4- aminobenzyl)phenyl)-2,6b-difluoro-7-hydroxy-8b-(2-hydroxyacetyl)-6a,8a-dimethyl- 1,2,6a,6b,7,8,8a,8b,11a,12,12a,12b-dodecahydro-4H-naphtho[2',1':4,5]indeno[1,2- d][1,3]dioxol-4-one (20 mg, 33.02 μmol), 30% 3-hydroxypropionic acid aqueous solution (19.83 mg, 66.04 μmol), DIPEA (12.80 mg, 99.06 μmol), and HATU (15.07 mg, 39.63 μmol), and after addition, the reaction was stirred at 25 °C for 3 hours. The reaction solution was purified by high performance liquid chromatography preparation and freeze-dried to obtain the title compound (10.46 mg, 16.82 μmol).

[0632] Column: Phenomenex Luna C18 200mm x 40mm x 10μm

[0633] Mobile phase A: acetonitrile; mobile phase B: water (0.05% formic acid)

[0634] The structure is characterized as follows:

[0635] ESI-MS (m / z): 678.3 [M+H] + .

[0636] 1H NMR (400 MHz, DMSO) δ 9.82 (s, 1H), 7.52 - 7.46 (m, 2H), 7.34 (d, J = 8.2 Hz, 2H), 7.29 - 7.21 (m, 3H), 7.12 (d, J = 8.6 Hz, 2H), 6.30 (dd, J = 10.1, 2.0 Hz, 1H), 6.13 (s, 1H), 5.76 - 5.56 (m, 1H), 5.56 - 5.50 (m, 1H), 5.45 (s, 1H), 5.13 (s, 1H), 4.95 (d, J = 4.9 Hz, 1H), 4.67 (s, 1H), 4.49 - 4.53 (m, 1H), 4.22 - 4.17 (m, 2H), 3.85 (s, 2H), 3.69 - 3.66 (t, J = 6.5 Hz, 2H), 2.75 - 2.56 (m, 1H), 2.43 - 2.40 (t, J = 6.4 Hz, 2H), 2.34 - 2.20 (m, 2H), 2.08 - 1.99 (m, 1H), 1.75 - 1.63 (m, 3H), 1.50 (s, 3H), 0.86 (s, 3H).

[0637] Preparation Example Thirty-seven: Preparation of N-(4-(4-((2S,6aS,6bR,7S,8aS,8bS,10R,11aR,12aS,12bS)-2,6b-difluoro-7-hydroxy-8b-(2-hydroxyacetyl)-6a,8a-dimethyl-4-oxo-2,4,6a,6b,7,8,8a,8b,11a,12,12a,12b-dodecahydro-1H-naphtho[2',1':4,5]indeno[1,2-d][1,3]dioxol-10-yl)benzyl)phenyl)-4-hydroxybutanamide (T-1)

[0638] (2S,6aS,6bR,7S,8aS,8bS,10R,11aR,12aS,12bS)-10-(4-(4-aminobenzyl)phenyl)-2,6b-difluoro-7-hydroxy-8b-(2-hydroxyacetyl)-6a,8a-dimethyl-1,2,6a,6b,7,8,8a,8b,11a,12,12a,12b-dodecahydro-4H-naphtho[2',1':4,5]indeno[1,2-d][1,3]dioxol-4-one (25 mg, 41.28 µmol, FR) was dissolved in DMF (3 mL), after adding 4-hydroxybutanoic acid (6.45 mg, 61.92 µmol), HATU (31.39 mg, 82.55 µmol) and DIPEA (26.67 mg, 206.38 µmol), the reaction was carried out at 25 °C for 2 hours. The reaction solution was concentrated to obtain the crude product directly, which was purified by high performance liquid chromatography preparation and freeze-dried to obtain the title compound (4 mg, 5.72 µmol).

[0639] Column: Phenomenex Luna C18 200mm x 40mm x 10µm

[0640] Mobile Phase A: Acetonitrile; Mobile Phase B: Water (0.05% Formic Acid)

[0641] Its structure was characterized as follows:

[0642] ESI-MS (m / z): 692.3 [M+H] + .

[0643] 1H NMR (400 MHz, DMSO) δ 9.79 (s, 1H), 7.47 (d, J = 8.4 Hz, 2H), 7.34 (d, J = 8.0 Hz, 2H), 7.29 - 7.21 (m, 3H), 7.11 (d, J = 8.4 Hz, 2H), 6.30 (dd, Ji = 10.4, J2 = 2.0 Hz, 1H), 6.13 (s, 1H), 5.75 - 5.55 (m, 1H), 5.55 - 5.49 (m, 1H), 5.44 (s, 1H), 5.10 (t, J = 6.0 Hz, 1H), 4.94 (d, J = 5.2 Hz, 1H), 4.55 - 4.45 (m, 2H), 4.24 - 4.14 (m, 2H), 3.85 (s, 2H), 3.45 - 3.38 (m, 2H), 2.67 - 2.53 (m, 1H), 2.35 - 2.18 (m, 4H), 2.08 - 1.99 (m, 1H), 1.77 - 1.62 (m, 5H), 1.56 - 1.46 (m, 4H), 0.86 (s, 3H).

[0644] Preparation Example Thirty-Eight: Preparation of (2S,6aS,6bR,7S,8aS,8bS,10R,11aR,12aS,12bS)-2,6b-Difluoro-7-hydroxy-8b-(2-hydroxyacetyl)-10-(4-(4-((2-hydroxyethyl)amino)benzyl)phenyl)-6a,8a-dimethyl-1,2,6a,6b,7,8,8a,8b,11a,12,12a,12b-dodecahydro-4H-naphtho[2',1':4,5]indeno[1,2-d][1,3]dioxepin-4-one (U-1)

[0645] (2S,6aS,6bR,7S,8aS,8bS,10R,11aR,12aS,12bS)-10-(4-(4-aminobenzyl)phenyl)-2,6b-difluoro-7-hydroxy-8b-(2-hydroxyacetyl)-6a,8a-dimethyl-1,2,6a,6b,7,8,8a,8b,11a,12,12a,12b-dodecahydro-4H-naphtho[2',1':4,5]indeno[1,2-d][1,3]dioxepin-4-one (30 mg, 49.53 μmol, FR) was dissolved in DMF (2 mL), after adding 2-iodoethan-1-ol (170.36 mg, 990.64 μmol), potassium carbonate (40.48 mg, 297.19 μmol), the reaction was carried out at 25 °C for 16 hours. The reaction solution was concentrated to obtain the crude product directly, which was purified by high performance liquid chromatography preparation and freeze-dried to obtain the title compound (4.81 mg, 7.11 μmol).

[0646] Column: Phenomenex Luna C18 200mm x 40mm x 10pm

[0647] Mobile Phase A: Acetonitrile; Mobile Phase B: Water (0.05% ammonium bicarbonate)

[0648] Its structure characterization is as follows:

[0649] ESI-MS (m / z): 650.3 [M+H] + .

[0650] 1 H NMR (400 MHz, DMSO) 7.32 (d, J = 8.0 Hz, 2H), 7.26 (d, J = 10.0 Hz, 1H), 7.20 (d, J = 8.0 Hz, 2H), 6.90 (d, J = 8.4 Hz, 2H), 6.47 (d, J = 8.8 Hz, 2H), 6.30 (dd, J = 10.0, 2.0 Hz, 1H), 6.13 (s, 1H), 5.73 - 5.57 (m, 1H), 5.52-5.51 (m, 1H), 5.44 (m, 1H), 5.29 (t, J = 6.4 Hz, 1H), 5.10 (t, J = 6.4 Hz, 1H), 4.94 (d, J = 4.8 Hz, 1H), 4.62 (t, J = 6.4 Hz, 1H), 4.50 (dd, J = 19.6, 4.8 Hz, 1H), 4.22 - 4.16 (m, 2H), 3.73 (s, 2H), 3.51 (q, 6.0 Hz, 2H), 3.02 (q, 6.0 Hz, 2H), 2.67 - 2.57 (m, 1H), 2.30 - 2.20 (m, 2H), 2.06 - 2.02 (m, 1H), 1.75 - 1.67 (m, 3H), 1.55 - 1.49 (m, 4H), 0.86 (s, 3H).

[0651] Preparation Example Thirty-Nine: Preparation of S-(fluoromethyl) (2S,6aS,6bR,7S,8aS,8bS,10R,11aR,12aS,12bS)-2,6b-difluoro-7-hydroxy-10-(4-(3-(2-hydroxyacetamido)benzyl)phenyl)-6a,8a-dimethyl-4-oxo-1,2,4,6a,6b,7,8,8a,11a,12,12a,12b-dodecahydro-8bH-naphtho[2',1':4,5]indeno[1,2-d][1,3]dioxole-8b-carbthioate (A'-1)

[0652] S-(fluoromethyl)(2S,6aS,6bR,7S,8aS,8bS,10R,11aR,12aS,12bS)-10-(4-(3- aminobenzyl)phenyl)-2,6b-difluoro-7-hydroxy-6a,8a-dimethyl-4-oxo-1,2,4,6a,6b,7,8,8a,11a,12,12a,12b-dodecahydro-8bH-naphtho[2',1':4,5]indeno[1,2- d][1,3]dioxole-8b-carbthioate (80 mg, 125.1 μmol) and 2-hydroxyacetic acid (9.5 mg, 125.1 μmol) were dissolved in DMF (1.5 mL), after adding HATU (57.1 mg, 150.1 μmol) and DIPEA (48.5 mg, 375.2 μmol), stirred at 25 °C for 1 hour. The reaction solution was directly purified by high performance liquid chromatography preparation and freeze-dried to obtain the title compound (16.98 mg, 22.68 μmol).

[0653] Column: Waters SunFire Prep C18 OBD 19mm x 150mm x 5μm

[0654] Mobile Phase A: Acetonitrile; Mobile Phase B: Water (0.05% Formic Acid)

[0655] The structure is characterized as follows:

[0656] ESI-MS (m / z): 699.2 [M+H] + .

[0657] 1 H NMR (400 MHz, DMSO) δ 9.56 (s, 1H), 7.57 - 7.48 (m, 2H), 7.35 (d, J = 8.2 Hz, 2H), 7.29 (d, J = 8.2 Hz, 2H), 7.25 - 7.16 (m, 2H), 6.94 (d, J = 8.2 Hz, 1H), 6.30 (dd, J = 10.2, 1.8 Hz, 1H), 6.13 (s, 1H), 6.07 - 5.79 (m, 2H), 5.77 - 5.56 (m, 2H), 5.52 (s, 1H), 4.93 (t, J = 8.0 Hz, 1H), 4.25 - 4.15 (m, 1H), 3.94 (s, 2H), 3.89 (s, 2H), 2.79 - 2.58 (m, 1H), 2.36 - 2.18 (m, 2H), 2.05 - 1.98 (m, 1H), 1.81 - 1.68 (m, 3H), 1.50 (s, 3H), 0.96 (s, 3H).

[0658] Preparation 40: Preparation of S-(fluoromethyl)(2S,6aS,6bR,7S,8aS,8bS,10R,11aR,12aS,12bS)-2,6b-difluoro-7-hydroxy-10-(4-(3-(3-hydroxypropanamido)benzyl)phenyl)-6a,8a-dimethyl-4-oxo-1,2,4,6a,6b,7,8,8a,11a,12,12a,12b-dodecahydro-8bH-naphtho[2',1':4,5]indeno[1,2-d][1,3]dioxol-8b-carbthioate (A'-4)

[0659] S-(fluoromethyl)(2S,6aS,6bR,7S,8aS,8bS,10R,11aR,12aS,12bS)-10-(4-(3- aminobenzyl)phenyl)-2,6b-difluoro-7-hydroxy-6a,8a-dimethyl-4-oxo-1,2,4,6a,6b,7,8,8a,11a,12,12a,12b-dodecahydro-8bH-naphtho[2',1':4,5]indeno[1,2-d][1,3]dioxol-8b-carbthioate (60 mg, 79.60 pmol, TF) was dissolved in DMF (2 mL), after adding (S)-2-hydroxypropanoic acid (10.76 mg, 119.40 pmol, FR), HATU (45.40 mg, 119.40 pmol) and DIPEA (30.86 mg, 238.81 pmol), the reaction was carried out at 25 °C for 2 hours. The reaction solution was concentrated to obtain the crude product directly, which was purified by high performance liquid chromatography preparation and freeze-dried to obtain the title compound (15.36 mg, 21.15 pmol, FR).

[0660] Column: Phenomenex Luna C18 200mm x 40mm x 10pm

[0661] Mobile phase A: acetonitrile; mobile phase B: water (0.05% formic acid)

[0662] Its structure was characterized as follows:

[0663] ESI-MS (m / z): 712.3 [M+H] +. .

[0664] 1H NMR (400 MHz, DMSO) δ 9.53 (s, 1H), 7.54 (t, J = 5.4 Hz, 2H), 7.39 - 7.16 (m, 6H), 6.92 (d, J = 7.6 Hz, 1H), 6.30 (dd, J = 10.2, 1.9 Hz, 1H), 6.13 (s, 1H), 5.93 (dd, J = 12.7, 9.5 Hz, 2H), 5.72 - 5.57 (m, 2H), 5.52 (s, 1H), 4.94 (d, J = 3.3 Hz, 1H), 4.19 (s, 1H), 4.09 (q, J = 6.7 Hz, 1H), 3.89 (s, 2H), 2.68 - 2.59 (m, 1H), 2.24 (dd, J = 19.7, 11.5 Hz, 2H), 2.01 (d, J = 13.7 Hz, 1H), 1.81 - 1.69 (m, 3H), 1.59 - 1.45 (m, 4H), 1.30 - 1.20 (m, 4H), 0.97 (d, J = 8.4 Hz, 3H).

[0665] Preparation Example Forty-one: Preparation of S-(fluoromethyl)(2S,6aS,6bR,7S,8aS,8bS,10R,11aR,12aS,12bS)-2,6b-difluoro-7-hydroxy-10-(4-(3-((R)-2-hydroxypropanamido)benzyl)phenyl)-6a,8a-dimethyl-4-oxo-1,2,4,6a,6b,7,8,8a,11a,12,12a,12b-dodecahydro-8bH-naphtho[2',1':4,5]indeno[1,2-d][1,3]dioxole-8b-carbthioate (A'-7)

[0666] S-(fluoromethyl)(2S,6aS,6bR,7S,8aS,8bS,10R,11aR,12aS,12bS)-10-(4-(3-aminobenzyl)phenyl)-2,6b-difluoro-7-hydroxy-6a,8a-dimethyl-4-oxo-1,2,4,6a,6b,7,8,8a,11a,12,12a,12b-dodecahydro-8bH-naphtho[2',1':4,5]indeno[1,2-d][1,3]dioxole-8b-carbthioate (50 mg, 78.16 μmol, FR) was dissolved in DMF (2 mL), after adding (R)-2-hydroxypropanoic acid (7.04 mg, 78.16 μmol), HATU (35.64 mg, 93.79 μmol) and DIPEA (30.30 mg, 234.48 μmol), the reaction was carried out at 25 °C for 2 hours. The reaction solution was concentrated directly to obtain the crude product, which was purified by high performance liquid chromatography preparation and freeze-dried to obtain the title compound (7.5 mg, 10.43 μmol).

[0667] Column: Phenomenex Luna C18 200mm x 40mm x 10pm

[0668] Mobile Phase A: Acetonitrile; Mobile Phase B: Water (0.05% Formic Acid)

[0669] Its structure characterization is as follows:

[0670] ESI-MS (m / z): 712.3 [M+H] + .

[0671] 1 H NMR (400 MHz, DMSO) δ 9.53 (s, 1H), 7.55 (s, 1H), 7.53 (s, 1H), 7.39 - 7.16 (m, 6H), 6.92 (d, J = 7.5 Hz, 1H), 6.30 (d, J = 10.2, 1H), 6.13 (s, 1H), 6.06 - 5.95 (m, 1H), 5.95 - 5.84 (m, 1H), 5.82 - 5.55 (m, 3H), 5.52 (s, 1H), 4.94 (s, 1H), 4.24-4.16 (m, 1H), 4.09 (dd, J = 13.4, 6.7 Hz, 1H), 3.89 (s, 2H), 2.73-2.58 (m, 1H), 2.33-2.17 (m, 2H), 2.01 (d, J = 14.0 Hz, 1H), 1.82-1.68 (m, 3H), 1.60 - 1.45 (m, 1H), 1.50 (s, 3H) 1.26 (d, J = 7.2 Hz, 3H), 0.96 (s, 3H).

[0672] Preparation Example Forty-Two: Preparation of S-(fluoromethyl)(2S,6aS,6bR,7S,8aS,10R,11aR,12aS,12bS)-10-(4-(3-((S)-2-cyclopropyl-2-hydroxyacetamido)benzyl)phenyl)-2,6b-difluoro-7-hydroxy-6a,8a-dimethyl-4-oxo-1,2,4,6a,6b,7,8,8a,11a,12,12a,12b-dodecahydro-8bH-naphtho[2',1':4,5]indeno[1,2-d][1,3]dioxole-8b-thiocarboxylate (A'-10)

[0673] (S)-2-cyclopropyl-2-hydroxyacetic acid (7.26 mg, 62.53 μmol) and the trifluoroacetate salt of S-(fluoromethyl)(2S,6aS,6bR,7S,8aS,10R,11aR,12aS,12bS)-10-(4-(3- aminobenzyl)phenyl)-2,6b-difluoro-7-hydroxy-6a,8a-dimethyl-4-oxo-1,2,4,6a,6b,7,8,8a,11a,12,12a,12b-dodecahydro-8bH-naphtho[2',1':4,5]indeno[1,2-d][1,3]dioxole-8b-thiocarboxylate (40 mg, 62.53 μmol) were dissolved in DMF (1 mL), DIPEA (37.70 mg, 291.73 μmol) was added, followed by HATU (28.51 mg, 75.03 μmol), and the reaction was stirred at room temperature for 1 hour. After the reaction was completed, the reaction solution was directly purified by high performance liquid chromatography to give the title compound (15.11 mg, 19.46 μmol) after lyophilization.

[0674] Column: Waters Sunfire Prep C18 OBD 150mm x 19mm x 5um

[0675] Mobile Phase A: Acetonitrile; Mobile Phase B: Water (0.05% Formic Acid)

[0676] The structure was characterized as follows:

[0677] ESI-MS (m / z): 738.3 [M+H] + .

[0678] 1H NMR (400 MHz, DMSO-d6) δ 9.51 (s, 1H), 7.56 - 7.54 (m, 2H), 7.37 - 7.35 (m, 2H), 7.31 - 7.23 (m, 3H), 7.22 - 7.17 (m, 1H), 6.94 - 6.91 (m, 1H), 6.30 (dd, J = 10.4, 2.0 Hz, 1H), 6.12 (br s, 1H), 6.05 - 5.81 (m, 2H), 5.74 - 5.61 (m, 1H), 5.58 - 5.57 (m, 1H), 5.52 (s, 1H), 4.94 - 4.93 (m, 1H), 4.23 - 4.17 (m, 1H), 3.89 (s, 2H), 3.60 (d, J = 6.4 Hz, 1H), 2.74 - 2.61 (m, 1H), 2.34 - 2.28 (m, 1H), 2.25 - 2.20 (m, 1H), 2.03 - 2.00 (m, 1H), 1.79 - 1.70 (m, 3H), 1.59 - 1.53 (m, 1H), 1.50 (s, 3H), 1.15 - 1.07 (m, 1H), 0.96 (s, 3H), 0.44 - 0.32 (m, 4H).

[0679] Preparation Example Forty-Three: Preparation of S-(fluoromethyl)(2S,6aS,6bR,7S,8aS,8bS,10R,11aR,12aS,12bS)-10-(4-(3-((R)-2-cyclopropyl-2-hydroxyacetamido)benzyl)phenyl)-2,6b-difluoro-7-hydroxy-6a,8a-dimethyl-4-oxo-1,2,4,6a,6b,7,8,8a,11a,12,12a,12b-dodecahydro-8bH-naphtho[2',1':4,5]indeno[1,2-d][1,3]dioxole-8b-carbthioate (A'-13)

[0680] S-(fluoromethyl)(2S,6aS,6bR,7S,8aS,8bS,10R,11aR,12aS,12bS)-10-(4-(3- aminobenzyl)phenyl)-2,6b-difluoro-7-hydroxy-6a,8a-dimethyl-4-oxo-1,2,4,6a,6b,7,8,8a,11a,12,12a,12b-dodecahydro-8bH-naphtho[2',1':4,5]indeno[1,2- d][1,3]dioxole-8b-carbthioate (50 mg, 66.34 μmol, TF) was dissolved in DMF (2 mL), after adding (R)-2-cyclopropyl-2-hydroxyacetic acid (8.47 mg, 72.97 μmol, FR), HATU (27.74 mg, 72.97 μmol) and DIPEA (25.72 mg, 199.01 μmol), the reaction was carried out at 25 °C for 2 hours. The reaction solution was concentrated to obtain the crude product directly, which was purified by high performance liquid chromatography preparation and freeze-dried to obtain the title compound (13.39 mg, 17.24 μmol, FR).

[0681] Column: Phenomenex Luna C18 200mm x 40mm x 10μm

[0682] Mobile Phase A: Acetonitrile; Mobile Phase B: Water (0.05% Formic Acid)

[0683] The structure is characterized as follows:

[0684] ESI-MS (m / z): 738.3 [M+H] + .

[0685] 1H NMR (400 MHz, DMSO) δ 9.51 (s, 1H), 7.55 (d, J = 8.4 Hz, 2H), 7.37 - 7.17 (m, 6H), 6.92 (d, J = 7.6 Hz, 1H), 6.30 (dd, J = 10.2, 1.8 Hz, 1H), 6.13 (s, 1H), 6.05 - 5.81 (m, 2H), 5.72 - 5.56 (m, 2H), 5.52 (s, 1H), 4.97 - 4.89 (m, 1H), 4.21 (d, J = 6.5 Hz, 1H), 3.89 (s, 2H), 3.60 (d, J = 6.4 Hz, 1H), 2.72 - 2.60 (m, 1H), 2.28 (ddd, J = 31.5, 14.5, 6.7 Hz, 2H), 2.06 - 1.99 (m, 1H), 1.75 (dd, J = 21.1, 10.5 Hz, 3H), 1.59 - 1.45 (m, 4H), 1.12 (dt, J = 18.8, 6.5 Hz, 1H), 0.97 (d, J = 8.6 Hz, 3H), 0.45 - 0.32 (m, 4H).

[0686] Preparation Example Forty-Four: Preparation of S-(fluoromethyl)(2S,6aS,6bR,7S,8aS,8bS,10R,11aR,12aS,12bS)-2,6b-difluoro-7-hydroxy-10-(4-(3-(3-hydroxypropanamido)benzyl)phenyl)-6a,8a-dimethyl-4-oxo-1,2,4,6a,6b,7,8,8a,11a,12,12a,12b-dodecahydro-8bH-naphtho[2',1':4,5]indeno[1,2-d][1,3]dioxole-8b-carbthioate (B'-1)

[0687] S-(fluoromethyl)(2S,6aS,6bR,7S,8aS,8bS,10R,11aR,12aS,12bS)-10-(4-(3- aminobenzyl)phenyl)-2,6b-difluoro-7-hydroxy-6a,8a-dimethyl-4-oxo-1,2,4,6a,6b,7,8,8a,11a,12,12a,12b-dodecahydro-8bH-naphtho[2',1':4,5]indeno[1,2- d][1,3]dioxole-8b-carbthioate (60 mg, 79.60 pmol, TF) was dissolved in DMF (2 mL), after adding 3-hydroxypropanoic acid (35.85 mg, 119.40 pmol, FR), HATU (45.40 mg, 119.40 pmol) and DIPEA (30.86 mg, 238.81 pmol), the reaction was carried out at 25 °C for 2 hours. The reaction solution was concentrated to obtain the crude product directly, which was purified by high performance liquid chromatography preparation and freeze-dried to obtain the title compound (20.45 mg, 27.29 pmol, FR).

[0688] Column: Phenomenex Luna C18 200mm x 40mm x 10pm

[0689] Mobile Phase A: Acetonitrile; Mobile Phase B: Water (0.05% Formic Acid)

[0690] The structure is characterized as follows:

[0691] ESI-MS (m / z): 712.3 [M+H] + .

[0692] 1H NMR (400 MHz, DMSO) δ 9.80 (s, 1H), 7.47 (d, J = 8.1 Hz, 1H), 7.31 (dt, J = 15.9, 7.1 Hz, 6H), 7.18 (t, J = 7.8 Hz, 1H), 6.90 (d, J = 7.6 Hz, 1H), 6.30 (dd, J = 10.2, 1.8 Hz, 1H), 6.13 (s, 1H), 6.07 - 5.94 (m, 1H), 5.93 - 5.81 (m, 1H), 5.73 - 5.57 (m, 2H), 5.52 (s, 1H), 4.94 (d, J = 3.2 Hz, 1H), 4.20 (s, 1H), 3.89 (s, 2H), 3.67 (t, J = 6.3 Hz, 2H), 3.35 (s, 1H), 2.74 - 2.60 (m, 1H), 2.41 (t, J = 6.4 Hz, 2H), 2.32 - 2.19 (m, 2H), 2.02 (d, J = 13.8 Hz, 1H), 1.80 - 1.69 (m, 3H), 1.57 - 1.46 (m, 4H), 1.02 - 0.93 (m, 3H).

[0693] Preparation Example Forty-Five: Preparation of S-(fluoromethyl)(2S,6aS,6bR,7S,8aS,8bS,10R,11aR,12aS,12bS)-2,6b-difluoro-7-hydroxy-10-(4-(3-(((2-hydroxyethoxy)carbonyl)amino)benzyl)phenyl)-6a,8a-dimethyl-4-oxo-1,2,4,6a,6b,7,8,8a,11a,12,12a,12b-dodecahydro-8bH-naphtho[2',1':4,5]indeno[1,2-d][1,3]dioxole-8b-thiocarboxylate (D'-1)

[0694] Step One: Preparation of S-(fluoromethyl)(2S,6aS,6bR,7S,8aS,8bS,10R,11aR,12aS,12bS)-2,6b-difluoro-7-hydroxy-6a,8a-dimethyl-4-oxo-10-(4-(3-(((2-(triphenylmethyl oxy)ethoxy)carbonyl)amino)benzyl)phenyl)-1,2,4,6a,6b,7,8,8a,11a,12,12a,12b-dodecahydro-8bH-naphtho[2',1':4,5]indeno[1,2-d][1,3]dioxole-8b-thiocarboxylate (D'-1-1)

[0695] S-(fluoromethyl)(2S,6aS,6bR,7S,8aS,8bS,10R,11aR,12aS,12bS)-10-(4-(3- aminobenzyl)phenyl)-2,6b-difluoro-7-hydroxy-6a,8a-dimethyl-4-oxo- 1,2,4,6a,6b,7,8,8a,11a,12,12a,12b-dodecahydro-8bH-naphtho[2',1':4,5]indeno[1,2- d][1,3]dioxol-8b-carbthioate (80.0 mg, 0.13 mmol) was dissolved in DMF (2.0 mL), after the addition of DIPEA (50.3 mg, 0.39 mmol), HOBT (17.8 mg, 0.13 mmol), 4-nitrophenyl (2-(trityloxy)ethyl) carbonate (73.5 mg, 0.16 mmol) was added, and stirring was performed at 45 °C for 16 hours. The reaction solution was purified by a C18 column (acetonitrile / 0.05% formic acid aqueous solution = 0-90%) and freeze-dried to obtain the title compound (28.2 mg, 0.06 mmol).

[0696] The structure thereof was characterized as follows:

[0697] ESI-MS (m / z): 958.1 (M+Na) + .

[0698] Step two: Preparation of S-(fluoromethyl)(2S,6aS,6bR,7S,8aS,8bS,10R,11aR,12aS,12bS)-2,6b-difluoro-7-hydroxy-10-(4-(3-(((2-hydroxyethoxy)carbonyl)amino)benzyl)phenyl)-6a,8a-dimethyl-4-oxo-1,2,4,6a,6b,7,8,8a,11a,12,12a,12b-dodecahydro-8bH-naphtho[2',1':4,5]indeno[1,2-d][1,3]dioxol-8b-carbthioate (D'-1)

[0699] S-(fluoromethyl)(2S,6aS,6bR,7S,8aS,8bS,10R,11aR,12aS,12bS)-2,6b-difluoro-7- hydroxy-6a,8a-dimethyl-4-oxo-10-(4-(3-(((2-(trityloxy)ethoxy)carbonyl)amino) benzyl)phenyl)-1,2,4,6a,6b,7,8,8a,11a,12,12a,12b-dodecahydro-8bH-naphtho[2',1':4,5]indeno[1,2- d][1,3]dioxol-8b-thioate (28.2 mg, 0.06 mmol) was dissolved in DCM (2.0 mL), formic acid 0.5 mL was added, stirred at 25 °C for 2 hours. The reaction was concentrated to get the crude, purified by preparative high performance liquid chromatography, then freeze-dried to get the title compound (3.39 mg, 4.56 pmol).

[0700] Column: Waters SunFire Prep C18 OBD 19mm x 150mm x 5pm

[0701] Mobile Phase A: Acetonitrile; Mobile Phase B: Water (0.05% Formic Acid)

[0702] Its structure was characterized as follows:

[0703] ESI-MS (m / z): 728.2 [M+H] + .

[0704] 1 H NMR (400 MHz, DMSO) d 9.59 (s, 1H), 7.40 - 7.32 (m, 3H), 7.30 - 7.22 (m, 4H), 7.17 (q, J = 7.6 Hz, 1H), 6.86 (d, J = 8.2 Hz, 1H), 6.30 (dd, J = 10.2, 1.8 Hz, 1H), 6.13 (s, 1H), 6.09 - 5.79 (m, 2H), 5.78 - 5.56 (m, 2H), 5.52 (s, 1H), 4.94 (d, J = 3.0 Hz, 1H), 4.79 (t, J = 5.4 Hz, 1H), 4.25 - 4.16 (m, 1H), 4.16 ((t, J = 5.4 Hz, 2H), 3.87 (s, 2H), 3.59 (q, 5.2 Hz, 2H), 2.79 - 2.59 (m, 1H), 2.35 - 2.17 (m, 2H), 2.02 (d, J = 13.6 Hz, 1H), 1.83 - 1.66 (m, 3H), 1.50 (s, 3H), 0.96 (s, 3H).

[0705] Preparation Example Forty-Six: Preparation of S-(fluoromethyl)(2S,6aS,6bR,7S,8aS,8bS,10R,11aR,12aS,12bS)-10-(4-(3-(((2-aminoethoxy)carbonyl)amino)benzyl)phenyl)-2,6b-difluoro-7-hydroxy-6a,8a-dimethyl-4-oxo-1,2,4,6a,6b,7,8,8a,11a,12,12a,12b-dodecahydro-8bH-naphtho[2',1':4,5]indeno[1,2-d][1,3]dioxole-8b-carbthioate (E'-1)

[0706] Step One: Preparation of S-(fluoromethyl)(2S,6aS,6bR,7S,8aS,8bS,10R,11aR,12aS,12bS)-10-(4-(3-(((2-((tert-butoxycarbonyl)amino)ethoxy)carbonyl)amino)benzyl)phenyl)-2,6b-difluoro-7-hydroxy-6a,8a-dimethyl-4-oxo-1,2,4,6a,6b,7,8,8a,11a,12,12a,12b-dodecahydro-8bH-naphtho[2',1':4,5]indeno[1,2-d][1,3]dioxole-8b-carbthioate (E'-1-2)

[0707] tert-Butyl (2-hydroxyethyl)carbamate (25.20 mg, 156.32 μmol) was dissolved in DCM (3.0 mL), DIPEA (50.5 mg, 391.47 μmol) was added, and then triphosgene (34.78 mg, 117.20 μmol) was added. The reaction was stirred at 25 °C under nitrogen for 30 min, and then S-(fluoromethyl)(2S,6aS,6bR,7S,8aS,8bS,10R,11aR,12aS,12bS)-10-(4-(3-aminobenzyl)phenyl)-2,6b-difluoro-7-hydroxy-6a,8a-dimethyl-4-oxo-1,2,4,6a,6b,7,8,8a,11a,12,12a,12b-dodecahydro-8bH-naphtho[2',1':4,5]indeno[1,2-d][1,3]dioxole-8b-carbthioate (50 mg, 78.16 μmol) was added. The reaction was stirred at 25 °C for 1 h. The reaction was concentrated to give a crude product, which was purified by preparative HPLC and then lyophilized to give the title compound (20 mg, 24.19 μmol).

[0708] The structure thereof was characterized as follows:

[0709] ESI-MS (m / z): 827.5 [M+H] + .

[0710] Step two: Preparation of S-(fluoromethyl)(2S,6aS,6bR,7S,8aS,8bS,10R,11aR,12aS,12bS)-10-(4-(3-(((2- aminoethoxy)carbonyl)amino)benzyl)phenyl)-2,6b-difluoro-7-hydroxy-6a,8a- dimethyl-4-oxo-1,2,4,6a,6b,7,8,8a,11a,12,12a,12b-dodecahydro-8bH- naphtho[2',1':4,5]indeno[1,2-d][1,3]dioxol-8b-carbothioate (E'-1)

[0711] S-(fluoromethyl)(2S,6aS,6bR,7S,8aS,8bS,10R,11aR,12aS,12bS)-10-(4-(3-(((2-((tert- butoxycarbonyl)amino)ethoxy)carbonyl)amino)benzyl)phenyl)-2,6b-difluoro-7- hydroxy-6a,8a-dimethyl-4-oxo-1,2,4,6a,6b,7,8,8a,11a,12,12a,12b-dodecahydro-8bH- naphtho[2',1':4,5]indeno[1,2-d][1,3]dioxol-8b-carbothioate (20 mg, 24.19 μmol) was dissolved in DCM (2.0 mL), TFA (1.0 mL) was added and stirred at 25 °C for 1 h. The reaction was concentrated to get the crude product, which was purified by preparative high performance liquid chromatography and freeze-dried to give the title compound (9.6 mg, 11.07 μmol).

[0712] Column: Waters SunFire Prep C18 OBD 19mmx150mmx5μm

[0713] Mobile Phase A: Acetonitrile; Mobile Phase B: Water (0.05% Formic Acid)

[0714] Its structure was characterized as follows:

[0715] ESI-MS (m / z): 727.3 [M+H] + .

[0716] 1H NMR (400 MHz, DMSO) δ 9.60 (s, 1H), 8.30 (d, J = 9.4 Hz, 1H), 7.36 (d, J = 8.1 Hz, 2H), 7.33 - 7.20 (m, 5H), 7.17 (t, J = 7.8 Hz, 1H), 6.85 (d, J = 7.5 Hz, 1H), 6.30 (dd, J = 10.2, 1.8 Hz, 1H), 6.13 (s, 1H), 6.07 - 6.04 (d, J = 9.5 Hz, 1H), 5.98 - 5.88 (m, 2H), 5.76 - 5.67 (m, 1H), 5.60 (s, 1H), 5.62 - 5.56 (m, 1H), 4.94 (t, J = 2.9 Hz, 1H), 4.23 - 4.17 (m, 1H), 4.08 - 4.02 (m, 2H), 3.88 (s, 2H), 2.89 - 2.79 (m, 2H), 2.75 - 2.66 (m, 1H), 2.30 - 2.20 (m, 2H), 1.99 (d, J = 14.0 Hz, 1H), 1.80 - 1.69 (m, 3H), 1.56 - 1.44 (m, 1H), 1.50 (s, 3H), 0.96 (s, 3H).

[0717] Preparation Example Forty-Seven: Preparation of S-(fluoromethyl)(2S,6aS,6bR,7S,8aS,8bS,10R,11aR,12aS,12bS)-10-(4-(3-(3-aminopropionamido)benzyl)phenyl)-2,6b-difluoro-7-hydroxy-6a,8a-dimethyl-4-oxo-1,2,4,6a,6b,7,8,8a,11a,12,12a,12b-dodecahydro-8bH-naphtho[2',1':4,5]indeno[1,2-d][1,3]dioxole-8b-thiocarboxylate (F'-1)

[0718] Step One: Preparation of S-(fluoromethyl)(2S,6aS,6bR,7S,8aS,8bS,10R,11aR,12aS,12bS)-10-(4-(3-(3-((tert-butoxycarbonyl)amino)propionamido)benzyl)phenyl)-2,6b-difluoro-7-hydroxy-6a,8a-dimethyl-4-oxo-1,2,4,6a,6b,7,8,8a,11a,12,12a,12b-dodecahydro-8bH-naphtho[2',1':4,5]indeno[1,2-d][1,3]dioxole-8b-thiocarboxylate (F'-1-1)

[0719] S-(fluoromethyl)(2S,6aS,6bR,7S,8aS,8bS,10R,11aR,12aS,12bS)-10-(4-(3- aminobenzyl)phenyl)-2,6b-difluoro-7-hydroxy-6a,8a-dimethyl-4-oxo- 1,2,4,6a,6b,7,8,8a,11a,12,12a,12b-dodecahydro-8bH-naphtho[2',1':4,5]indeno[1,2- d][1,3]dioxol-8b-thiocarboxylate (50 mg, 66.34 μmol, TF) was dissolved in DMF (2 mL), 3-(tert-butoxycarbonylamino)propanoic acid (15.06 mg, 79.60 μmol, FR), HATU (30.27 mg, 79.60 μmol) and DIPEA (25.72 mg, 199.01 μmol) were added and the reaction was stirred at 25 °C for 2 h. The reaction was concentrated directly to give the crude product which was used directly in the next step without purification.

[0720] Step two: Preparation of S-(fluoromethyl)(2S,6aS,6bR,7S,8aS,8bS,10R,11aR,12aS,12bS)-10-(4-(3-(3-aminopropionamido)benzyl)phenyl)-2,6b-difluoro-7-hydroxy-6a,8a-dimethyl-4-oxo-1,2,4,6a,6b,7,8,8a,11a,12,12a,12b-dodecahydro-8bH-naphtho[2',1':4,5]indeno[1,2-d][1,3]dioxol-8b-thiocarboxylate (F'-1)

[0721] S-(fluoromethyl)(2S,6aS,6bR,7S,8aS,8bS,10R,11aR,12aS,12bS)-10-(4-(3-(3-((tert-butoxycarbonyl)amino)propionamido)benzyl)phenyl)-2,6b-difluoro-7-hydroxy-6a,8a-dimethyl-4-oxo-1,2,4,6a,6b,7,8,8a,11a,12,12a,12b-dodecahydro-8bH-naphtho[2',1':4,5]indeno[1,2-d][1,3]dioxol-8b-thiocarboxylate (53 mg, 65.36 μmol, FR) was dissolved in DCM (2 mL) and TFA (7.45 mg, 65.36 μmol, 0.5 mL) was added. The reaction was stirred at room temperature for 1 h. The reaction was concentrated and purified by preparative HPLC to give the title compound (22.36 mg, 25.75 μmol, TF) after lyophilization.

[0722] Column: Phenomenex Luna C18 200mm x 40mm x 10μm

[0723] Mobile phase A: Acetonitrile; Mobile phase B: Water (0.05% formic acid)

[0724] The structure is characterized as follows:

[0725] ESI-MS (m / z): 711.3 [M+H] + .

[0726] 1 H NMR (400 MHz, DMSO) δ 10.05 (s, 1H), 7.71 (s, 1H), 7.47 - 7.15 (m, 9H), 6.95 (d, J = 7.6 Hz, 1H), 6.30 (dd, J = 10.2, 1.8 Hz, 1H), 6.18 - 6.02 (m, 2H), 5.90 (ddd, J = 34.6, 12.5, 7.5 Hz, 2H), 5.62 (t, J = 24.1 Hz, 2H), 5.52 (s, 1H), 4.97 - 4.92 (m, 1H), 4.19 (s, 1H), 3.90 (s, 2H), 3.43 (s, 1H), 3.06 (dd, J = 12.1, 6.1 Hz, 2H), 2.65 (t, J = 6.6 Hz, 2H), 2.31 - 2.19 (m, 2H), 2.00 (d, J = 13.8 Hz, 1H), 1.75 (dd, J = 17.1, 12.0 Hz, 3H), 1.49 (d, J = 10.2 Hz, 4H), 0.94 (d, J = 15.1 Hz, 3H).

[0727] Preparation Example Forty-Eight: Preparation of S-(fluoromethyl)(2S,6aS,6bR,7S,8aS,10R,11aR,12aS,12bS)-10-(4-(3-(2-aminoacetylamino)benzyl)phenyl)-2,6b-difluoro-7-hydroxy-6a,8a-dimethyl-4-oxo-1,2,4,6a,6b,7,8,8a,11a,12,12a,12b-dodecahydro-8bH-naphtho[2',1':4,5]indeno[1,2-d][1,3]dioxol-8b-thioate (G'-1)

[0728] Step one: Preparation of S-(fluoromethyl) (2S,6aS,6bR,7S,8aS,10R,11aR,12aS,12bS)-10-(4-(3-(2-((tert-butoxycarbonyl)amino)acetamido)benzyl)phenyl)-2,6b-difluoro-7-hydroxy-6a,8a-dimethyl-4-oxo-1,2,4,6a,6b,7,8,8a,11a,12,12a,12b-dodecahydro-8bH-naphtho[2',1':4,5]indeno[1,2-d][1,3]dioxol-8b-thioate (G'-1-1)

[0729] (tert-butoxycarbonyl)glycine (13.94 mg, 79.60 μmol) and the trifluoroacetate salt of S-(fluoromethyl) (2S,6aS,6bR,7S,8aS,10R,11aR,12aS,12bS)-10-(4-(3-aminobenzyl)phenyl)-2,6b-difluoro-7-hydroxy-6a,8a-dimethyl-4-oxo-1,2,4,6a,6b,7,8,8a,11a,12,12a,12b-dodecahydro-8bH-naphtho[2',1':4,5]indeno[1,2-d][1,3]dioxole-8b-thioate (60 mg, 79.60 μmol) were dissolved in DMF (1 mL), DIPEA (32 mg, 247.60 μmol) was added, followed by the addition of HATU (36.30 mg, 95.52 μmol), and the reaction was stirred at room temperature for 1 hour. After the reaction was completed, the reaction solution was extracted with water and ethyl acetate, the organic phase was washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product of the title compound (63 mg, 79.06 μmol), which was used directly in the next step without purification.

[0730] The structure thereof was characterized as follows:

[0731] ESI-MS (m / z): 798.3 [M+H] + .

[0732] Step two: Preparation of S-(fluoromethyl)(2S,6aS,6bR,7S,8aS,10R,11aR,12aS,12bS)-10-(4-(3-(2-aminoacetylamino)benzyl)phenyl)-2,6b-difluoro-7-hydroxy-6a,8a-dimethyl-4-oxo-1,2,4,6a,6b,7,8,8a,11a,12,12a,12b-dodecahydro-8bH-naphtho[2',1':4,5]indeno[1,2-d][1,3]dioxol-8b-thioate (G'-1) S-(fluoromethyl)(2S,6aS,6bR,7S,8aS,10R,11aR,12aS,12bS)-10-(4-(3-(2-((tert-butoxycarbonyl)amino)acetylamino)benzyl)phenyl)-2,6b-difluoro-7-hydroxy-6a,8a-dimethyl-4-oxo-1,2,4,6a,6b,7,8,8a,11a,12,12a,12b-dodecahydro-8bH-naphtho[2',1':4,5]indeno[1,2-d][1,3]dioxole-8b-thioate (63 mg, 79.06 μmol) was dissolved in dichloromethane (1 mL), hydrochloric acid-dioxane (4 M, 3 mL) was added dropwise, and the reaction was stirred at room temperature for 1 hour. After the reaction was completed, the reaction solution was directly purified by high performance liquid chromatography to obtain the title compound (27.85 mg, 38.77 μmol, 97% purity) after freeze-drying.

[0733] Column: Waters Sunfire Prep C18 OBD 150mm x 19mm x 5μm

[0734] Mobile Phase A: Acetonitrile; Mobile Phase B: Water (0.05% Formic Acid)

[0735] Its structure was characterized as follows:

[0736] ESI-MS (m / z): 697.3 [M+H] + .

[0737] 1H NMR (400 MHz, DMSO-d6 + D2O) δ 8.37 (s, 1H), 7.48 - 7.46 (m, 1H), 7.40 - 7.35 (m, 3H), 7.29 - 7.21 (m, 4H), 6.95 (d, J = 7.6 Hz, 1H), 6.32 - 6.29 (m, 1H), 6.14 (br s, 1H), 6.05 - 5.81 (m, 2H), 5.74 - 5.57 (m, 2H), 5.52 (s, 1H), 4.95 - 4.93 (m, 1H), 4.21 - 4.19 (m, 1H), 3.91 (s, 2H), 3.38 (s, 2H), 2.75 - 2.61 (m, 1H), 2.35 - 2.31 (m, 1H), 2.28 - 2.20 (m, 1H), 2.04 - 1.97 (m, 1H), 1.81 - 1.71 (m, 3H), 1.50 (s, 3H), 0.96 (s, 3H).

[0738] Biological data

[0739] Experimental Example 1: GRE reporter gene assay

[0740] Hela-MMTV cells were constructed by the following steps: pGL4.36[luc2P / MMTV / Hygro] plasmid was extracted, transfected into Hela cells, and pressure-selected and sorted into a stable monoclonal cell line, marked as Hela-MMTV, which can be used to study the activation response of glucocorticoid receptor. The luciferase reporter gene system of Hela-MMTV cells was used to test the activation activity of the compounds of the present application on glucocorticoid receptor.

[0741] After the adherently growing Hela-MMTV cells were digested with Trypsin-EDTA (0.25%) solution, they were resuspended with complete culture medium (1640 + 10% FBS) and plated at 10000 cells / 100 μl per well in a cell culture 96-well plate. The compounds of the present application were diluted in DMSO in a 4-fold gradient, 10 concentration points to prepare a 100X stock solution, which was diluted with complete culture medium to a 2X stock solution, and then 100 μl per well was added to the plated cells, so that the final concentration of DMSO was 1%, and the final concentration of the compound was 0.0004-100 nM.

[0742] Incubate in a 37°C cell culture incubator for 48 hours. After incubation, add 20 μl Bio-Lite luciferase assay reagent (Novozyme DD1201-03) per well to the cells, shake well for 10 minutes, and use a microplate reader to detect Luminescence readings. Use four-parameter curve fitting to analyze the data and calculate EC 50 .

[0743] Table 1. Activity of compounds to activate glucocorticoid receptor in cells

[0744] Table 2. Activity of compounds to activate glucocorticoid receptor in cells

[0745] In addition to the compounds shown in Table 1 and Table 2, other compounds also show significant activation of glucocorticoid receptor: for example, compound D-4 activates glucocorticoid receptor in cells with an EC 50 of 0.22 nM. In summary, the compounds of the present application show excellent activity to activate glucocorticoid receptor in cells in vitro.

[0746] Experimental Example 2: B cell killing assay (OCI-LY19 cells)

[0747] OCI-LY19 cells were resuspended in complete medium (1640 + 10% FBS) and plated at 20000 cells / 90 μl per well in a cell culture 96 well plate. Compounds of the present application were diluted in DMSO to make 100X stock solutions at 10-fold gradient, 9 concentration points, and then diluted to 10X stock solutions in complete medium, and 10 μl per well was added to the plated cells to give a final DMSO concentration of 1% and a final compound concentration of 0.0000001-10 nM.

[0748] The cells were incubated in a cell culture incubator at 37°C for 5 days. After incubation, 50 μl of CellTiter-Glo luciferase assay reagent (Promega, DD1101-03) was added to each well, mixed by shaking for 10 minutes, and the luminescence reading was detected by a microplate reader. The data was analyzed using a four-parameter curve fitting, and the IC 50 .

[0749] Table 3. Activity of compounds to kill B cells (OCL-LY19)

[0750] The results show that the compounds of the present application (for example, the compounds listed in Table 3) have significant killing activity on B cells (OCL-LY19).

[0751] Experimental Example 3: B cell killing assay (RS4; 11 cells)

[0752] Resuspend RS4;11 cells with complete medium (1640 + 10% FBS) and plate 20000 cells / 90ul per well in a 96-well cell culture plate. Prepare 100X stock of the compounds of the application in DMSO with 5-fold gradient, 9 concentration points, dilute to 10X stock with complete medium, then add 10ul per well to the plated cells, so that the final concentration of DMSO is 1%, and the final concentration of the compounds is 0.000256-100nM.

[0753] Incubate in a 37°C cell culture incubator for 5 days. After incubation, add 50ul CellTiter-Glo Luciferase Assay Reagent (Promega, DD1101-03) per well, shake to mix for 10 minutes, then detect Luminescence reading in a microplate reader. Analyze the data using a four-parameter curve fit, and calculate IC 50 .

[0754] Table 4 Killing activity of compounds on B cells (RS4;11)

[0755] Table 5 Killing activity of compounds on B cells (RS4;11)

[0756] The results show that the compounds of the application (for example the compounds listed in Tables 4 and 5) have significant killing activity on B cells (RS4;11).

[0757] While the specific embodiments of the application have been described in detail, those skilled in the art will appreciate that various modifications and substitutions can be made thereto without departing from the spirit and scope of the application as set forth in the following claims. The scope of the application is defined by the appended claims and their equivalents.

Claims

1. Compounds represented by Formula I, their pharmaceutically acceptable salts, stereoisomers, tautomers, polymorphs, solvates, isotopically labeled compounds, metabolites, or prodrugs: in, Q1 and Q2 are each independently selected from hydrogen and halogen; Q3 is selected from hydrogen, C 1-6 alkyl; Ring A and ring B are each independently selected from aryl, heteroaryl, saturated carbocyclic, and heterocyclic groups; Q4 is independently selected from hydrogen and C. 1-6 Alkyl, Halogenated C 1-6 Alkyl groups, halogens; Q5 and Q6 are each independently selected from hydrogen, deuterium, and carbon. 1-6 Alkyl groups, fluorine, or Q5 and Q6 are linked to adjacent carbons to form a ring; Q7 is independently selected from hydrogen and C. 1-6 Alkyl, Halogenated C 1-6 Alkyl, halogen, C 1-6 Alkoxy, hydroxy, hydroxyalkylene; X is selected from HOCH2-, (HO)2P(=O)OCH2-, glycosyl-O-CH2-, HO-S(=O)2-OCH2-, FCH2S-, ClCH2S-, CNCH2S-, HO(CH2)2S-, FCH2O-, ClCH2O-, CNCH2O-; Y is selected from single bond, C 1-6 Alkylene, carbonyl, -(CR) a R b ) n -O-、-(CR a R b ) n -NR a -、-(CR a R b ) n -O-(CR a R b ) n -、-(CR a R b ) n -NR a -(CR a R b ) n -; Z is selected from oxygen or nitrogen; R1 is selected from hydrogen, HO-(CR a R b ) n -, H2N-(CR a R b ) n -, HO-(CR a R b ) n -C(=O)-, H2N-(CR a [[ID=2)) b ) n -C(=O)-, HO-(CR a R b ) n -OC(=O)-, H2N-(CR a R b ) n -OC(=O)-, HO-(CR a R b ) n -NR a -C(=O)-, H2N-(CR a R b ) n -NR a -C(=O)-; When Z is oxygen, R2 does not exist; When Z is nitrogen, R2 is selected from hydrogen and C. 1-6 Alkyl group; or R1 and R2 are linked to an adjacent nitrogen atom to form a ring, said ring optionally being bounded by one or more atoms selected from hydrogen, hydroxyl, amino, hydroxyalkylene, aminoalkylene, C 1-6 Alkyl, C 1-6 Substituents of alkoxy, halogen, and oxo groups; R a and R b Each is independently selected from hydrogen and C. 1-6 Alkyl, Halogenated C 1-6 Alkyl, halogen, cycloalkyl, or R a and R b It connects with adjacent carbon atoms to form a ring; R a and R b Each is independently selected from hydrogen and C. 1-6 Alkyl, Halogenated C 1-6 Alkyl, halogen, cycloalkyl, or R a and R b It forms a ring with adjacent carbon atoms; m = 0, 1, 2, 3 or 4; Each time n appears, it is independently 1, 2, 3, 4 or 5.

2. The compound of claim 1, its pharmaceutically acceptable salt, stereoisomer, tautomer, polymorph, solvate, isotopically labeled compound, metabolite, or prodrug, wherein the compound is a compound represented by formula II: in, Q1 and Q2 are each independently selected from hydrogen, fluorine, and chlorine; Q3 is selected from hydrogen and methyl; Ring A and ring B are each independently selected from phenyl or heteroaryl groups; Q4 is selected independently from hydrogen, methyl, fluorine or chlorine; Q5 and Q6 are each independently selected from hydrogen, deuterium, or fluorine; Q7 is independently selected from hydrogen and C. 1-6 Alkyl, halogen, C 1-6 Alkoxy, hydroxy, hydroxyalkylene; X is selected from HOCH2-, (HO)2P(=O)OCH2-, glycosyl-O-CH2-, HO-S(=O)2-OCH2-, FCH2S-, ClCH2S-, CNCH2S-, HO(CH2)2S-, FCH2O-, ClCH2O-, CNCH2O-; Y is selected from single bond, C 1-6 Alkylene, carbonyl, -(CR) a R b ) n -O-、-(CR a R b ) n -NR a -、-(CR a R b ) n -O-(CR a R b ) n -、-(CR a R b ) n -NR a -(CR a R b ) n -; Z is selected from oxygen or nitrogen; R1 is selected from hydrogen, HO-(CR a R b ) n -, H2N-(CR a R b ) n -, HO-(CR a R b ) n -C(=O)-, H2N-(CR a R b ) n -C(=O)-, HO-(CR a R b ) n -OC(=O)-, H2N-(CR a R b ) n -OC(=O)-, HO-(CR a R b ) n -NR a -C(=O)-, H2N-(CR a R b ) n -NR a -C(=O)-; When Z is oxygen, R2 does not exist; When Z is nitrogen, R2 is selected from hydrogen and C. 1-6 Alkyl group; or R1 and R2 are linked to an adjacent nitrogen atom to form a ring, said ring optionally being bounded by one or more atoms selected from hydrogen, hydroxyl, amino, hydroxyalkylene, aminoalkylene, C 1-6 Alkyl, C 1-6 Substituted by alkoxy, halogen, or oxo groups; R a and R b Each is independently selected from hydrogen and C. 1-6 Alkyl, Halogenated C 1-6 Alkyl, halogen, cycloalkyl, or R a and R b It connects with adjacent carbon atoms to form a ring; m = 0, 1, 2, 3 or 4; Each time n appears, it is independently 1, 2, 3, 4 or 5.

3. The compound of claim 2, its pharmaceutically acceptable salt, stereoisomer, tautomer, polymorph, solvate, isotopically labeled compound, metabolite, or prodrug, wherein the compound is a compound represented by Formula III: in, Q1 and Q2 are each independently selected from hydrogen or fluorine; Q4 is independently selected from hydrogen and methyl; Q5 and Q6 are each independently selected from hydrogen, deuterium, or fluorine; Q7 is independently selected from hydrogen and C. 1-6 Alkyl, halogen, C 1-6 Alkoxy, hydroxy, hydroxyalkylene; X is selected from HOCH2-, (HO)2P(=O)OCH2-, glycosyl-O-CH2-, HO-S(=O)2-OCH2-, FCH2S-, ClCH2S-, CNCH2S-, HO(CH2)2S-, FCH2O-, ClCH2O-, CNCH2O-; Y is selected from single bond, C 1-6 Alkylene, carbonyl, -(CR) a R b ) n -O-、-(CR a R b ) n -NR a -、-(CR a R b ) n -O-(CR a R b ) n -、-(CR a R b ) n -NR a -(CR a R b ) n -; Z is selected from oxygen or nitrogen; R1 is selected from hydrogen, HO-(CR a R b ) n -, H2N-(CR a R b ) n -, HO-(CR a R b ) n -C(=O)-, H2N-(CR a R b ) n -C(=O)-, HO-(CR a R b ) n -OC(=O)-, H2N-(CR a R b ) n -OC(=O)-, HO-(CR a R b ) n -NR a -C(=O)-, H2N-(CR a R b ) n -NR a -C(=O)-; When Z is oxygen, R2 does not exist; When Z is nitrogen, R2 is selected from hydrogen and C. 1-6 Alkyl group; or R1 and R2 are linked to an adjacent nitrogen atom to form a ring, said ring optionally being bounded by one or more atoms selected from hydrogen, hydroxyl, amino, hydroxyalkylene, aminoalkylene, C 1-6 Alkyl, C 1-6 Substituted by alkoxy, halogen, or oxo groups; R a and R b Each is independently selected from hydrogen and C. 1-6 Alkyl, Halogenated C 1-6 Alkyl, halogen, cycloalkyl, or R a and R b It connects with adjacent carbon atoms to form a ring; m = 0, 1, 2, 3 or 4; Each time n appears, it is independently 1, 2, 3, 4 or 5.

4. The compound of claim 3, its pharmaceutically acceptable salt, stereoisomer, tautomer, polymorph, solvate, isotopically labeled compound, metabolite, or prodrug, wherein the compound is a compound represented by formula IV: in, Q1 and Q2 are each independently selected from hydrogen or fluorine; X is selected from HOCH2-, (HO)2P(=O)OCH2-, glycosyl-O-CH2-, HO-S(=O)2-OCH2-, FCH2S-, ClCH2S-, CNCH2S-, HO(CH2)2S-, FCH2O-, ClCH2O-, CNCH2O-; Y is selected from single bond, C 1-6 Alkylene, carbonyl, -(CR) a R b ) n -O-、-(CR a R b ) n -NR a -、-(CR a R b ) n -O-(CR a R b ) n -、-(CR a R b ) n -NR a -(CR a R b ) n -; Z is selected from oxygen or nitrogen; R1 is selected from hydrogen, HO-(CR a R b ) n -, H2N-(CR a R b ) n -, HO-(CR a R b ) n -C(=O)-, H2N-(CR a R b ) n -C(=O)-, HO-(CR a R b ) n -OC(=O)-, H2N-(CR a R b ) n -OC(=O)-, HO-(CR a R b ) n -NR a -C(=O)-, H2N-(CR a R b ) n -NR a -C(=O)-; When Z is oxygen, R2 does not exist; When Z is nitrogen, R2 is selected from hydrogen and C. 1-6 Alkyl group; or R1 and R2 are linked to an adjacent nitrogen atom to form a ring, said ring optionally being bounded by one or more atoms selected from hydrogen, hydroxyl, amino, hydroxyalkylene, aminoalkylene, C 1-6 Alkyl, C 1-6 Substituted by alkoxy, halogen, or oxo groups; R a and R b Each is independently selected from hydrogen and C. 1-6 Alkyl, Halogenated C 1-6 Alkyl, halogen, cycloalkyl, or R a and R b It connects with adjacent carbon atoms to form a ring; Each time n appears, it is independently 1, 2, 3, 4 or 5.

5. The compound of claim 4, its pharmaceutically acceptable salt, stereoisomer, tautomer, polymorph, solvate, isotopically labeled compound, metabolite, or prodrug, in, Q1 and Q2 are each independently selected from hydrogen or fluorine; X is selected from HOCH2-, (HO)2P(=O)OCH2-, and FCH2S-; Y is selected from single bond, C 1-6 Alkylene, carbonyl, -(CR) a R b ) n -O-、-(CR a R b ) n -NR a -、-(CR a R b ) n -O-(CR a R b ) n -、-(CR a R b ) n -NR a -(CR a R b ) n -; Z is selected from oxygen or nitrogen; R1 is selected from hydrogen, HO-(CR a R b ) n -, H2N-(CR a R b ) n -, HO-(CR a R b ) n -C(=O)-, H2N-(CR a R b ) n -C(=O)-, HO-(CR a R b ) n -OC(=O)-, H2N-(CR a R b ) n -OC(=O)-, HO-(CR a R b ) n -NR a -C(=O)-, H2N-(CR a R b ) n -NR a -C(=O)-; When Z is oxygen, R2 does not exist; When Z is nitrogen, R2 is selected from hydrogen and C. 1-6 Alkyl group; or R1 and R2 are linked to an adjacent nitrogen atom to form a ring, said ring optionally being bounded by one or more atoms selected from hydrogen, hydroxyl, amino, hydroxyalkylene, aminoalkylene, C 1-6 Alkyl, C 1-6 Substituted by alkoxy, halogen, or oxo groups; R a and R b Each is independently selected from hydrogen and C. 1-6 Alkyl, Halogenated C 1-6 Alkyl, halogen, cycloalkyl, or R a and R b It connects with adjacent carbon atoms to form a ring; Each time n appears, it is independently 1, 2, 3, 4 or 5.

6. The compound of claim 5, its pharmaceutically acceptable salt, stereoisomer, tautomer, polymorph, solvate, isotopically labeled compound, metabolite, or prodrug, wherein the compound is a compound represented by formula VII: in, Q1 and Q2 are each independently selected from hydrogen or fluorine; X is selected from HOCH2-, (HO)2P(=O)OCH2-, and FCH2S-; Z is selected from oxygen or nitrogen; R1 is selected from hydrogen, HO-(CR a R b ) n -, H2N-(CR a R b ) n -, HO-(CR a R b ) n -C(=O)-, H2N-(CR a R b ) n -C(=O)-, HO-(CR a R b ) n -OC(=O)-, H2N-(CR a R b ) n -OC(=O)-, HO-(CR a R b ) n -NR a -C(=O)-, H2N-(CR a R b ) n -NR a -C(=O)-; When Z is oxygen, R2 does not exist; When Z is nitrogen, R2 is selected from hydrogen and C. 1-6 Alkyl group; or R1 and R2 are linked to an adjacent nitrogen atom to form a ring, said ring optionally being bounded by one or more atoms selected from hydrogen, hydroxyl, amino, hydroxyalkylene, aminoalkylene, C 1-6 Alkyl, C 1-6 Substituted by alkoxy, halogen, or oxo groups; R a and R b Each is independently selected from hydrogen and C. 1-6 Alkyl, Halogenated C 1-6 Alkyl, halogen, cycloalkyl, or R a and R b It connects with adjacent carbon atoms to form a ring; Each time n appears, it is independently 1, 2, 3, 4 or 5.

7. The compound of claim 6, its pharmaceutically acceptable salt, stereoisomer, tautomer, polymorph, solvate, isotopically labeled compound, metabolite, or prodrug, wherein the compound is a compound represented by formula VIII: in, Q1 and Q2 are each independently selected from hydrogen or fluorine; X is selected from HOCH2-, (HO)2P(=O)OCH2-, and FCH2S-; R1 is selected from HO-(CR a R b ) n -, H2N-(CR a R b )<00003...​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​ R a and R b Each is independently selected from hydrogen and C. 1-6 Alkyl, Halogenated C 1-6 Alkyl, halogen, cycloalkyl, or R a and R b It connects with adjacent carbon atoms to form a ring; Each time n appears, it is independently 1, 2, 3, 4 or 5.

8. The compound of any one of claims 1-7, its pharmaceutically acceptable salt, stereoisomer, tautomer, polymorph, solvate, isotopically labeled compound, metabolite, or prodrug, The cycloalkyl group is C 3-6 Cycloalkyl.

9. The compound of claim 8, its pharmaceutically acceptable salt, stereoisomer, tautomer, polymorph, solvate, isotopically labeled compound, metabolite, or prodrug, wherein the compound is a compound represented by formula IX or X: in, Q1 and Q2 are each independently selected from hydrogen or fluorine; R1 is selected from HO-(CR a R b ) n -, H2N-(CR a R b ) n -, HO-(CR a R b ) n -C(=O)-, H2N-(CR a R b ) n -C(=O)-, HO-(CR a R b ) n -OC(=O)-, H(CR a R b ) n -OC(=O)-, HO-(CR a R b ) n -NR a -C(=O)-, H2N-(CR a R b ) n -NR a -C(=O)-; R2 is selected from hydrogen, C 1-6 alkyl; R a and R b Each is independently selected from hydrogen and C. 1-6 Alkyl, C 3-6 cycloalkyl; Each time n appears, it is independently 1, 2, or 3.

10. The compound of any one of claims 1-9, its pharmaceutically acceptable salt, stereoisomer, tautomer, polymorph, solvate, isotopically labeled compound, metabolite, or prodrug, wherein the compound is selected from:

11. A method for preparing a compound, said method being carried out according to the following synthetic route: in, R1, X, Q1, and Q2 are as described in any one of claims 1-10.

12. A pharmaceutical composition comprising the compound of any one of claims 1-10, a pharmaceutically acceptable salt thereof, a stereoisomer, a tautomer, a polymorph thereof, a solvate, an isotopically labeled compound, a metabolite or a prodrug, and one or more pharmaceutically acceptable carriers.

13. Use of any compound of claims 1-10, its pharmaceutically acceptable salt, stereoisomer, tautomer, polymorph, solvate, isotopically labeled compound, metabolite or prodrug, or pharmaceutical composition of claim 12 in the preparation of a medicament for treating inflammatory or immune diseases; Preferably, the inflammatory or immune disease is selected from rheumatoid arthritis, idiopathic arthritis, systemic lupus erythematosus, asthma, ulcerative colitis, neuromyelitis optica, and autoimmune liver disease.

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