Novel glucocorticoid as well as preparation method and application thereof

Abstract

The invention belongs to the technical field of medicinal chemistry, and particularly relates to a novel glucocorticoid and a preparation method and application thereof, the novel glucocorticoid comprises a compound of a formula I, an optical isomer of the compound, a medicinal salt of the compound or a solvate of the compound, and the structural formula of the compound of the formula I is shown in the description. The compound provided by the invention has the advantages of high plasma removal rate, short half-life period, low systemic drug exposure and higher target selectivity to a glucocorticoid receptor (GR), and can obviously reduce side effects caused by systemic absorption of a glucocorticoid drug. The compound has remarkable anti-inflammatory activity on animal asthma, uveitis, xerophthalmia, inflammatory bowel disease, psoriasis and the like. The compound provided by the invention has good safety, no abnormal intraocular pressure is detected when the compound is continuously administered to the eyes of guinea pigs, and no obvious abnormal epidermal layer thickness occurs after the compound is continuously administered to the skin of rats.

Description

Novel glucocorticoid, preparation method and use thereof Technical Field

[0001] The present invention relates to the field of pharmaceutical chemistry technology, and in particular to a novel glucocorticoid, a preparation method thereof, and its use in preparing a medicament for treating glucocorticoid receptor-mediated diseases, including but not limited to various eye diseases, respiratory diseases, autoimmune diseases, skin diseases, kidney diseases, etc. Background Art

[0002] Glucocorticoids, with their anti-inflammatory properties, are widely used to treat inflammatory disorders or diseases, such as respiratory diseases, rheumatic autoimmune diseases, renal diseases, and skin diseases. They can control symptoms and slow disease progression, with significant clinical efficacy. The primary mechanisms of action of glucocorticoids in treating various inflammatory diseases include inhibiting the migration and activation of inflammatory cells such as eosinophils and neutrophils; inhibiting the production of cytokines such as prostaglandins and leukotrienes; inhibiting the release of inflammatory mediators; and enhancing β2 receptor responsiveness in bronchial smooth muscle cells. Because glucocorticoid receptors are widely distributed within effector cells, the effects of glucocorticoids are closely dose-dependent. At supraphysiological doses, glucocorticoids exhibit a wide range of pharmacological effects, particularly important ones such as anti-inflammatory, immunosuppressive, and anti-shock effects. However, they can also be associated with numerous adverse reactions, such as obesity, moon facies, buffalo hump, edema, spontaneous fractures, osteoporosis and femoral head necrosis, ulcers, acute gastrointestinal bleeding, insomnia, hirsutism, and decreased immunity, which limit their clinical application. For example, topical glucocorticoids are primarily applied topically. However, long-term, high-dose use can lead to various side effects, including weakened skin barrier function. This can significantly increase systemic exposure, leading to systemic absorption side effects. Glucocorticoid-induced osteoporosis, in particular, affects 30% to 50% of patients receiving long-term glucocorticoid therapy. Currently, there is no effective treatment, and once discovered, glucocorticoid use is the only option.

[0003] Although topical administration of glucocorticoids is the preferred treatment modality, systemic drug levels remain a concern. Commonly used glucocorticoids have a long plasma half-life in the human body after entering the systemic circulation. For example, fluticasone propionate has a half-life of 180 minutes, while dexamethasone and betamethasone have half-lives of 100-300 minutes. Topical administration of glucocorticoids for respiratory diseases via inhalation carries the risk of systemic exposure because some of the drug enters the systemic circulation through the lungs. Topical administration for ocular diseases also carries the risk of some drug entering the systemic circulation due to the low permeability and efficient drainage of the cornea and the presence of eyelid blood vessels. Furthermore, for dermal administration, local injections, and implantable medical devices, there is a significant risk of drug leakage into the systemic circulation. Therefore, when applied topically, glucocorticoids should ideally possess properties that significantly minimize systemic exposure.

[0004] In summary, there is an urgent need to develop a class of glucocorticoids with high anti-inflammatory activity and low side effects. The compounds described in the present invention (including the compounds themselves, their optical isomers, their pharmaceutically acceptable salts or solvates) and pharmaceutically acceptable compositions thereof can be used to treat or alleviate various glucocorticoid receptor-mediated conditions. More specifically, the compounds of the present invention are preferably used to treat at least one glucocorticoid receptor-mediated disease. For example, the compounds of the present invention can be used to treat the following diseases:

[0005] Eye diseases: including but not limited to external eye diseases such as blepharitis, conjunctivitis, keratitis, allergic conjunctivitis, epidemic keratoconjunctivitis, scleritis, episcleritis, etc.; anterior eye diseases such as iritis, iridocyclitis, uveitis, etc.; posterior eye diseases such as dry eye, diabetic retinopathy, wet age-related macular degeneration, choroidal neovascularization, posterior uveitis, etc.; postoperative inflammation such as cataract, glaucoma, retinal detachment, strabismus correction, etc.; abnormal corneal wound healing and eye pain.

[0006] Airway diseases; including but not limited to pulmonary fibrosis, emphysema, chronic bronchitis, asthma, pneumonia, cystic fibrosis, chronic obstructive pulmonary disease (COPD), bronchiolitis, and respiratory distress syndrome.

[0007] Throat, nose and ear disorders: including but not limited to sinus problems, hearing problems, toothache, tonsillitis, ulcers and rhinitis.

[0008] Skin disorders: including but not limited to hyperkeratosis, parakeratosis, stratum granulosum hyperplasia, stratum acanthosum, dyskeratosis, edema of the spinous layer, and ulcers.

[0009] Intestinal diseases: including but not limited to inflammatory bowel disease (IBD), enteritis, gastroenteritis, intestinal obstruction, ileitis, appendicitis, ulcerative colitis and Crohn's disease.

[0010] Inflammatory diseases: including but not limited to contact dermatitis, atopic dermatitis, psoriasis, rheumatoid arthritis, juvenile rheumatoid arthritis, ankylosing spondylitis, and psoriatic arthritis.

[0011] Neurological diseases: including but not limited to neuropathic pain, used to prevent nerve degeneration and stimulate nerve regeneration in various neurological diseases.

[0012] Kidney diseases: including but not limited to renal fibrosis, renal insufficiency and chronic glomerulonephritis.

[0013] Bone diseases: including but not limited to osteoarthritis.

[0014] Summary of the Invention

[0015] The main purpose of the present invention is to provide a novel glucocorticoid, a preparation method thereof and use thereof, in order to at least partially solve at least one of the above-mentioned technical problems.

[0016] The compound of formula I provided by the present invention has the ability to interact with the glucocorticoid receptor and thus has a wide range of therapeutic uses as described below, which is due to the main reason that the glucocorticoid receptor plays a role in the physiology of all mammals. Therefore, the present invention relates to a compound of formula I, an optical isomer thereof, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate of the compound or salt, which is used to treat or prevent diseases mediated by glucocorticoid receptors. The present invention also relates to the use of a compound of formula I, an optical isomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate of the compound or salt in the preparation of a drug for treating a disease mediated by glucocorticoid receptors. The present invention also relates to a method for treating mammals including humans using a glucocorticoid receptor agonist, the method comprising treating the mammal with an effective amount of a compound of formula I, an optical isomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate of the compound or salt. In addition, it also relates to a method for preparing the compound and a pharmaceutical composition comprising the compound.

[0017] This application provides the following technical solutions:

[0018] In a first aspect, embodiment 1 is provided:

[0019] The compound of formula I has the following structural formula:

[0020] its optical isomer, its pharmaceutically acceptable salt or its solvate,

[0021] Wherein, A, B, R1, R2, and R3 shown in the structural formula of the compound of formula I are selected independently of each other, and:

[0022] A is selected from substituted or unsubstituted aryl containing 6-10 carbon atoms, substituted or unsubstituted heteroaryl or heterocyclic group containing 4-10 carbon atoms, substituted or unsubstituted cycloalkyl containing 3-10 carbon atoms, wherein the substituent is selected from one or more, or one, of the following: halogen, hydroxyl, carbonyl, amino, cyano, carboxyl, aryl containing 6-10 carbon atoms, heteroaryl containing 4-10 carbon atoms, cycloalkyl containing 3-6 carbon atoms, alkoxy containing 1-10 carbon atoms, alkylamino containing 1-10 carbon atoms, or alkyl ester containing 1-10 carbon atoms;

[0023] Preferably, A is selected from substituted or unsubstituted phenyl, substituted or unsubstituted piperidinyl, substituted or unsubstituted cyclohexyl, substituted or unsubstituted pyridinyl, substituted or unsubstituted pyrimidinyl, and the substituent is selected from one or more, or one, of the following: halogen or cyano;

[0024] More preferably, A is selected from substituted or unsubstituted phenyl, substituted or unsubstituted cyclohexyl, substituted or unsubstituted pyridyl, substituted or unsubstituted pyrimidinyl, and the substituent is selected from one or more, or one, of the following: halogen or cyano;

[0025] Further preferably, A is selected from substituted or unsubstituted phenyl, substituted or unsubstituted cyclohexyl, substituted or unsubstituted pyridyl, and the substituent is selected from one or more, or one of the following: halogen;

[0026] More preferably, A is selected from substituted or unsubstituted phenyl, substituted or unsubstituted pyridyl, and the substituent is selected from one or more of the following, or 1): halogen;

[0027] B is selected from no group, O, S, NH, CH2, OCH2, SCH2, NHCH2, CHO, CH2S, CH2SO, CH2SO2, CH2NH, C=O or NH(CO);

[0028] Preferably, B is selected from O, S, NH, CH2, OCH2, SCH2, NHCH2, CHO, CH2S, CH2SO, CH2SO2, CH2NH, C=O or NH(CO);

[0029] More preferably, B is selected from S, CH2, OCH2, SCH2, NHCH2, CHO, CH2S, CH2SO, CH2SO2, CH2NH or NH(CO);

[0030] Further preferably, B is selected from S, CH2O, CH2S, CH2SO or CH2NH;

[0031] More preferably, B is selected from CH2O, CH2S or CH2NH;

[0032] B and ring 2-, 3- or 4-position connections;

[0033] Preferably, B and ring 2- or 3-position connection;

[0034] R1 is selected from H or halogen;

[0035] Preferably, R1 is selected from halogen;

[0036] R2 is selected from H, CH3 or halogen;

[0037] Preferably, R2 is selected from H or halogen;

[0038] R3 is selected from CH2R4, R4 is selected from OH, halogen, OR5 or OCOR5, or, R3 is selected from SCH2R6 or OCH2R6;

[0039] wherein R5 is selected from an alkyl group containing 1 to 6 carbon atoms, an alkenyl group containing 2 to 6 carbon atoms, an alkynyl group containing 2 to 6 carbon atoms, an aryl group containing 6 to 10 carbon atoms, a heteroaryl group containing 4 to 10 carbon atoms, or a heterocyclic group; and R6 is selected from a halogen or CN.

[0040] Preferably, R3 is selected from CH2R4, R4 is selected from OH or halogen, or, R3 is selected from SCH2R6 or OCH2R6, R6 is selected from halogen or CN;

[0041] More preferably, R3 is selected from CH2R4, R4 is selected from OH, or, R3 is selected from SCH2R6 or OCH2R6, R6 is selected from halogen or CN;

[0042] Preferably, the halogen is selected from F or Cl;

[0043] is a single bond or a double bond, preferably a double bond.

[0044] Embodiment 2: The compound according to embodiment 1, characterized in that, wherein the compound of formula I is the following structural formula I':

[0045] Among them, the variables A, B, R1, R2, R3 and B are related to the ring The attachment position of is as defined in Embodiment 1.

[0046] Embodiment 3: The compound according to embodiment 1 or 2, characterized in that, wherein the compound of formula I is selected from the following structural formula I-1 or I-2, and the compound of formula I' is selected from the following structural formula I'-1 or I'-2:

[0047] Wherein, A, B, R1, R2, and R3 shown in the structural formula of the compound of formula I-1 and I'-1 are selected independently of each other, and:

[0048] A is selected from substituted or unsubstituted cyclohexyl, substituted or unsubstituted piperidinyl, substituted or unsubstituted phenyl, substituted or unsubstituted pyridinyl, substituted or unsubstituted pyrimidinyl, wherein the substituent is one or more, or one of the following: halogen, preferably F or Cl;

[0049] Preferably, A is selected from:

[0050] B is selected from O, S, NH, CH2, OCH2, SCH2, NHCH2, CH2O, CH2S, CH2SO, CH2SO2, CH2NH;

[0051] R1 is selected from H or halogen; preferably, R1 is selected from H, F or Cl;

[0052] R2 is selected from H or halogen; preferably, R2 is selected from H or F;

[0053] R3 is selected from the following: CH2R4, R4 is selected from OH or halogen; SCH2R6 or OCH2R6, R6 is selected from halogen or CN;

[0054] Preferably, R3 is selected from the following: CH2R4, R4 is selected from OH or Cl; SCH2R6 or OCH2R6, R6 is selected from F or CN;

[0055] is a single bond or a double bond, preferably a double bond;

[0056] Wherein, A, B, R1, R2, and R3 shown in the structural formula of the compound of formula I-2 and I'-2 are selected independently of each other, and:

[0057] A is selected from substituted or unsubstituted cyclohexyl, substituted or unsubstituted piperidinyl, substituted or unsubstituted phenyl, wherein the substituent is one or more, or one of the following: halogen, preferably F or Cl, or cyano;

[0058] Preferably, A is selected from:

[0059] B is selected from C=O, NH(CO), CH2O, CH2S, CH2NH;

[0060] R1 is selected from H or halogen; preferably, R1 is selected from H, F or Cl;

[0061] R2 is selected from H or halogen; preferably, R2 is selected from H or F;

[0062] R3 is selected from the following: CH2R4, R4 is selected from OH or halogen; SCH2R6, R6 is selected from halogen;

[0063] Preferably, R3 is selected from the following: CH2R4, R4 is selected from OH or Cl; SCH2R6, R6 is selected from F;

[0064] is a single bond or a double bond, preferably a double bond.

[0065] Embodiment 4: The compound according to embodiment 1 or 2, characterized in that,

[0066] A, B, R1, R2, R3 are selected independently of each other, and:

[0067] A is selected from substituted or unsubstituted cyclohexyl, substituted or unsubstituted phenyl, substituted or unsubstituted pyridyl, substituted or unsubstituted pyrimidinyl, wherein the substituent is one or more, or one of the following: halogen, preferably F or Cl, or cyano;

[0068] Preferably, A is selected from:

[0069] B is selected from S, CH2, OCH2, SCH2, NHCH2, CH2O, CH2S, CH2SO, CH2SO2, CH2NH, NH(CO);

[0070] R1 is selected from H or halogen; preferably, R1 is selected from H, F or Cl;

[0071] R2 is selected from H or halogen; preferably, R2 is selected from H or F;

[0072] R3 is selected from the following: CH2R4, R4 is selected from OH or halogen; SCH2R6 or OCH2R6, R6 is selected from halogen or CN;

[0073] Preferably, R3 is selected from the following: CH2R4, R4 is selected from OH or Cl; SCH2R6 or OCH2R6, R6 is selected from F or CN;

[0074] is a single bond or a double bond, preferably a double bond.

[0075] Embodiment 5: The compound according to any one of embodiments 1, 2, and 4, wherein

[0076] The compound of formula I is selected from the following structural formula I-1 or I-2, and the compound of formula I' is selected from the following structural formula I'-1 or I'-2:

[0077] Wherein, A, B, R1, R2, and R3 shown in the structural formula of the compound of formula I-1 and I'-1 are selected independently of each other, and:

[0078] A is selected from substituted or unsubstituted cyclohexyl, substituted or unsubstituted phenyl, substituted or unsubstituted pyridyl, substituted or unsubstituted pyrimidinyl, and the substituent is one or more, or one of the following: halogen, preferably F or Cl;

[0079] Preferably, A is selected from:

[0080] B is selected from S, CH2, OCH2, SCH2, NHCH2, CH2O, CH2S, CH2SO, CH2SO2, CH2NH;

[0081] R1 is selected from H or halogen; preferably, R1 is selected from H, F or Cl;

[0082] R2 is selected from H or halogen; preferably, R2 is selected from H or F;

[0083] R3 is selected from the following: CH2R4, R4 is selected from OH or halogen; SCH2R6 or OCH2R6, R6 is selected from halogen or CN;

[0084] Preferably, R3 is selected from the following: CH2R4, R4 is selected from OH or Cl; SCH2R6 or OCH2R6, R6 is selected from F or CN;

[0085] is a single bond or a double bond, preferably a double bond;

[0086] Wherein, A, B, R1, R2, and R3 shown in the structural formula of the compound of formula I-2 and I'-2 are selected independently of each other, and:

[0087] A is selected from substituted or unsubstituted phenyl, wherein the substituent is one or more, or one of the following: halogen, preferably F or Cl, or cyano;

[0088] Preferably, A is selected from:

[0089] B is selected from NH(CO), CH2O, CH2S, CH2NH;

[0090] R1 is selected from H or halogen; preferably, R1 is selected from H, F or Cl;

[0091] R2 is selected from H or halogen; preferably, R2 is selected from H or F;

[0092] R3 is selected from the following: CH2R4, R4 is selected from OH or halogen; SCH2R6, R6 is selected from halogen;

[0093] Preferably, R3 is selected from the following: CH2R4, R4 is selected from OH or Cl; SCH2R6, R6 is selected from F;

[0094] is a single bond or a double bond, preferably a double bond.

[0095] Embodiment 6: The compound according to embodiment 1 or 2, characterized in that,

[0096] A, B, R1, R2, R3 are selected independently of each other, and:

[0097] A is selected from substituted or unsubstituted cyclohexyl, substituted or unsubstituted phenyl, substituted or unsubstituted pyridyl, and the substituents are one or more, or one of the following: halogen, preferably F or Cl;

[0098] Preferably, A is selected from

[0099] B is selected from S, CH2O, CH2S, CH2SO, CH2NH;

[0100] R1 is selected from halogen; preferably, R1 is selected from F or Cl;

[0101] R2 is selected from H or halogen; preferably, R2 is selected from H or F;

[0102] R3 is selected from the following: CH2R4, R4 is selected from OH or halogen; SCH2R6 or OCH2R6, R6 is selected from halogen or CN;

[0103] Preferably, R3 is selected from the following: CH2R4, R4 is selected from OH or Cl; SCH2R6 or OCH2R6, R6 is selected from F or CN;

[0104] is a single bond or a double bond, preferably a double bond.

[0105] Embodiment 7: The compound according to any one of Embodiments 1, 2, and 6, wherein

[0106] The compound of formula I is selected from the following structural formula I-1 or I-2, and the compound of formula I' is selected from the following structural formula I'-1 or I'-2:

[0107] Wherein, A, B, R1, R2, and R3 shown in the structural formula of the compound of formula I-1 and I'-1 are selected independently of each other, and:

[0108] A is selected from substituted or unsubstituted cyclohexyl, substituted or unsubstituted phenyl, substituted or unsubstituted pyridyl, and the substituents are one or more, or one of the following: halogen, preferably F or Cl;

[0109] Preferably, A is selected from:

[0110] B is selected from S, CH2O, CH2S, CH2SO, CH2NH;

[0111] R1 is selected from halogen; preferably, R1 is selected from F or Cl;

[0112] R2 is selected from H or halogen; preferably, R2 is selected from H or F;

[0113] R3 is selected from the following: CH2R4, R4 is selected from OH or halogen; SCH2R6 or OCH2R6, R6 is selected from halogen or CN;

[0114] Preferably, R3 is selected from the following: CH2R4, R4 is selected from OH or Cl; SCH2R6 or OCH2R6, R6 is selected from F or CN;

[0115] is a single bond or a double bond, preferably a double bond;

[0116] Wherein, A, B, R1, R2, and R3 shown in the structural formula of the compound of formula I-2 and I'-2 are selected independently of each other, and:

[0117] A is selected from substituted or unsubstituted phenyl, and the substituents are one or more, or one of the following: halogen, preferably Cl;

[0118] Preferably, A is selected from:

[0119] B is selected from CH2O, CH2S, CH2NH;

[0120] R1 is selected from halogen; preferably, R1 is selected from F or Cl;

[0121] R2 is selected from H or halogen; preferably, R2 is selected from H or F;

[0122] R3 is selected from the following: CH2R4, R4 is selected from OH;

[0123] is a single bond or a double bond, preferably a double bond.

[0124] Embodiment 8.: A compound according to embodiment 1 or 2, characterized in that,

[0125] A, B, R1, R2, R3 are selected independently of each other, and:

[0126] A is selected from substituted or unsubstituted phenyl, substituted or unsubstituted pyridyl, and the substituents are one or more, or one of the following: halogen, preferably F or Cl;

[0127] Preferably, A is selected from:

[0128] B is selected from CH2O, CH2S, CH2NH;

[0129] R1 is selected from halogen; preferably, R1 is selected from F or Cl;

[0130] R2 is selected from H or halogen; preferably, R2 is selected from H or F;

[0131] R3 is selected from the following: CH2R4, R4 is selected from OH; SCH2R6 or OCH2R6, R6 is selected from halogen or CN;

[0132] Preferably, R3 is selected from the following: CH2R4, R4 is selected from OH; SCH2R6 or OCH2R6, R6 is selected from F or CN;

[0133] is a single bond or a double bond, preferably a double bond.

[0134] Embodiment 9: The compound according to any one of embodiments 1, 2, and 8, wherein

[0135] The compound of formula I is selected from the following structural formula I-1 or I-2, and the compound of formula I' is selected from the following structural formula I'-1 or I'-2:

[0136] Wherein, A, B, R1, R2, and R3 shown in the structural formula of the compound of formula I-1 and I'-1 are selected independently of each other, and:

[0137] A is selected from substituted or unsubstituted phenyl, substituted or unsubstituted pyridyl, and the substituents are one or more, or one of the following: halogen, preferably F or Cl;

[0138] Preferably, A is selected from:

[0139] B is selected from CH2O, CH2S;

[0140] R1 is selected from halogen; preferably, R1 is selected from F or Cl;

[0141] R2 is selected from H or halogen; preferably, R2 is selected from H or F;

[0142] R3 is selected from the following: CH2R4, R4 is selected from OH; SCH2R6 or OCH2R6, R6 is selected from halogen or CN;

[0143] Preferably, R3 is selected from the following: CH2R4, R4 is selected from OH; SCH2R6 or OCH2R6, R6 is selected from F or CN;

[0144] is a single bond or a double bond, preferably a double bond;

[0145] Wherein, A, B, R1, R2, and R3 shown in the structural formula of the compound of formula I-1 and I'-1 are selected independently of each other, and:

[0146] A is selected from substituted or unsubstituted phenyl, and the substituents are one or more, or one of the following: halogen, preferably Cl;

[0147] Preferably, A is selected from:

[0148] B is selected from CH2S, CH2NH;

[0149] R1 is selected from halogen; preferably, R1 is selected from F or Cl;

[0150] R2 is selected from H;

[0151] R3 is selected from the following: CH2R4, R4 is selected from OH;

[0152] is a single bond or a double bond, preferably a double bond.

[0153] Embodiment 10: The compound according to any one of embodiments 1-3, characterized in that the compound of formula I is selected from compounds 1-60;

[0154] Preferably, compound 5, compound 7, compound 8, compound 9, compound 10, compound 11, compound 12, compound 13, compound 14, compound 15, compound 16, compound 17, compound 18, compound 19, compound 20, compound 21, compound 22, compound 23, compound 24, compound 25, compound 26, compound 27, compound 28, compound 29, compound 30, compound 32, compound 33, compound 34, compound 35, compound 36, compound 37, compound 38, compound 39, compound 41, compound 43, compound 45, compound 46, compound 47, compound 48, compound 49, compound 50, compound 51, compound 52, compound 54, compound 55, compound 56, compound 57, compound 58, compound 59, and compound 60;

[0155] More preferably, compound 7, compound 8, compound 10, compound 11, compound 16, compound 17, compound 18, compound 19, compound 20, compound 21, compound 22, compound 23, compound 24, compound 25, compound 26, compound 27, compound 34, compound 35, compound 36, compound 37, compound 38, compound 45, compound 46, compound 47, compound 48, compound 49, compound 50, compound 51, and compound 57;

[0156] More preferably, compound 16, compound 17, compound 20, compound 21, compound 22, compound 23, compound 26, compound 34, compound 35, compound 36, compound 37, compound 46, compound 47, compound 48, and compound 51.

[0157] In a second aspect, embodiment 12 is provided: a method for preparing the compound according to any one of embodiments 1 to 11, characterized in that the preparation is performed using method 1 or method 2:

[0158] Method 1:

[0159] The compound of formula II reacts with the compound of formula III under acidic conditions to obtain the compound of formula I:

[0160] Wherein, A, B, R1, R2, and R3 in the compound of formula I are as defined in any one of embodiments 1-11;

[0161] In the compound of formula II, R1, R2, and R3 are defined the same as those in the compound of formula I, and R7 and R8 are selected from OH, or R7 and R8 together form C 16 , C 17 The sites are connected by oxygen bridges, R9, R 10 Each is independently selected from H or an alkyl group containing 1-6 carbons;

[0162] In the compound of formula III, A and B are the same as those in the compound of formula I;

[0163] or,

[0164] The compound of formula II' reacts with the compound of formula III under acidic conditions to prepare the compound of formula I':

[0165] Wherein, A, B, R1, R2, and R3 in the compound of formula I' are as defined in any one of embodiments 1-11;

[0166] In the compound of formula II', R1, R2, and R3 are defined the same as those in the compound of formula I', and R7 and R8 are selected from OH, or R7 and R8 together form C 16 , C 17 The sites are connected by oxygen bridges, R9, R 10 Each is independently selected from H or an alkyl group containing 1-6 carbons;

[0167] In the compound of formula III, A and B are the same as those in the compound of formula I';

[0168] Alternatively, method 2: To obtain a compound of formula I wherein B is selected from CH2NH, the following method may also be used:

[0169] (a) The compound of formula II reacts with the compound of formula V under acidic conditions to obtain the compound of formula IV:

[0170] (b) reacting a compound of formula IV with a compound of formula VI or a compound of formula VII to obtain a compound of formula I:

[0171] Wherein, in the compound of formula I, A, R1, R2, and R3 are as defined in any one of embodiments 1-11, and B is selected from CH2NH;

[0172] In the compound of formula II, R1, R2, and R3 are defined the same as those in the compound of formula I, and R7 and R8 are selected from OH, or R7 and R8 together form C 16 , C 17 The sites are connected by oxygen bridges, R9, R 10 Each is independently selected from H or an alkyl group containing 1-6 carbons;

[0173] In the compound of formula IV, A, B, R1, R2, and R3 are the same as those in the compound of formula I;

[0174] In the compound of formula V, A is defined the same as in the compound of formula I, B is selected from CH2NH, and Z is selected from a Boc protecting group;

[0175] The compound of formula VI is selected from Wherein, Q is a leaving group selected from Cl or Br;

[0176] Formula VII is selected from

[0177] or,

[0178] (a) The compound of formula II' is reacted with the compound of formula V under acidic conditions to obtain the compound of formula IV':

[0179] (b) reacting a compound of formula IV' with a compound of formula VI or a compound of formula VII to obtain a compound of formula I':

[0180] Wherein, in the compound of formula I', A, R1, R2, and R3 are as defined in any one of embodiments 1-11, and B is selected from CH2NH;

[0181] In the compound of formula II', R1, R2, and R3 are defined the same as those in the compound of formula I', and R7 and R8 are selected from OH, or R7 and R8 together form C 16 , C 17 The sites are connected by oxygen bridges, R9, R 10 Each is independently selected from H or an alkyl group containing 1-6 carbons;

[0182] In the compound of formula IV', A, B, R1, R2, and R3 are the same as those in the compound of formula I';

[0183] In the compound of formula V, A is defined the same as in the compound of formula I', B is selected from CH2NH, and Z is selected from a Boc protecting group;

[0184] The compound of formula VI is selected from Wherein, Q is a leaving group selected from Cl or Br;

[0185] Formula VII is selected from

[0186] In a third aspect, embodiment 13 is provided: a pharmaceutical composition, characterized in that it comprises the compound described in any one of embodiments 1-11 or the compound prepared by the preparation method described in embodiment 12.

[0187] Embodiment 14: The composition according to Embodiment 13 is characterized in that the dosage form of the pharmaceutical composition is selected from creams, ointments, gels, transdermal patches, intradermal injections, eye drops, intraocular injections, ophthalmic implants, nasal sprays, inhalation powders, inhalation aerosols, inhalation sprays, inhalation liquid preparations, vaginal suppositories, vaginal tablets, vaginal gels, and preparations that are administered orally or rectally and act locally in the digestive tract.

[0188] Embodiment 15: Use of the compound according to any one of Embodiments 1-11, the compound prepared by the preparation method according to Embodiment 12, or the pharmaceutical composition according to Embodiment 13 or 14 in the preparation of a medicament for treating a glucocorticoid receptor-mediated disease;

[0189] Preferably, the disease is selected from blepharitis, conjunctivitis, keratitis, iritis, iridocyclitis, uveitis, dry eye, diabetic retinopathy, wet age-related macular degeneration, choroidal neovascularization, posterior uveitis, cataract, glaucoma, retinal detachment, inflammation after strabismus correction surgery, eczema, psoriasis, atopic dermatitis, allergic dermatitis, pruritus, hypersensitivity reaction, rheumatoid arthritis, multiple sclerosis and disseminated lupus erythematosus, rhinitis, sinusitis, asthma, nasal polyps, asthma, chronic obstructive pulmonary disease, inflammatory bowel disease, Crohn's disease, ulcerative colitis or chronic glomerulonephritis;

[0190] More preferably, the disease is selected from conjunctivitis, keratitis, uveitis, dry eye, asthma, chronic obstructive pulmonary disease, allergic rhinitis, nasal polyps, Crohn's disease, eczema and psoriasis.

[0191] Embodiment 16: A method for treating a glucocorticoid receptor-mediated disease, comprising providing a subject in need thereof with the compound of any one of Embodiments 1-11, the compound prepared by the preparation method of Embodiment 12, or the pharmaceutical composition of Embodiment 13 or 14;

[0192] Preferably, the disease is selected from blepharitis, conjunctivitis, keratitis, iritis, iridocyclitis, uveitis, dry eye, diabetic retinopathy, wet age-related macular degeneration, choroidal neovascularization, posterior uveitis, cataract, glaucoma, retinal detachment, inflammation after strabismus correction surgery, eczema, psoriasis, atopic dermatitis, allergic dermatitis, pruritus, hypersensitivity reaction, rheumatoid arthritis, multiple sclerosis and disseminated lupus erythematosus, rhinitis, sinusitis, asthma, nasal polyps, asthma, chronic obstructive pulmonary disease, inflammatory bowel disease, Crohn's disease, ulcerative colitis or chronic glomerulonephritis;

[0193] More preferably, the disease is selected from conjunctivitis, keratitis, uveitis, dry eye, asthma, chronic obstructive pulmonary disease, allergic rhinitis, nasal polyps, Crohn's disease, eczema and psoriasis.

[0194] Embodiment 17: The compound according to any one of Embodiments 1-11, the compound prepared by the preparation method according to Embodiment 12, or the pharmaceutical composition according to Embodiment 13 or 14, for treating a glucocorticoid receptor-mediated disease;

[0195] Preferably, the disease is selected from blepharitis, conjunctivitis, keratitis, iritis, iridocyclitis, uveitis, dry eye, diabetic retinopathy, wet age-related macular degeneration, choroidal neovascularization, posterior uveitis, cataract, glaucoma, retinal detachment, inflammation after strabismus correction surgery, eczema, psoriasis, atopic dermatitis, allergic dermatitis, pruritus, hypersensitivity reaction, rheumatoid arthritis, multiple sclerosis and disseminated lupus erythematosus, rhinitis, sinusitis, asthma, nasal polyps, asthma, chronic obstructive pulmonary disease, inflammatory bowel disease, Crohn's disease, ulcerative colitis or chronic glomerulonephritis;

[0196] More preferably, the disease is selected from conjunctivitis, keratitis, uveitis, dry eye, asthma, chronic obstructive pulmonary disease, allergic rhinitis, nasal polyps, Crohn's disease, eczema and psoriasis.

[0197] In addition, this application also relates to the following implementation schemes:

[0198] As the first aspect of the present invention, the present invention provides a compound of formula I, the structural formula of which is as follows:

[0199] its optical isomer, its pharmaceutically acceptable salt or its solvate,

[0200] Wherein, A, B, R1, R2, and R3 shown in the structural formula of the compound of formula I are selected independently of each other, and:

[0201] A is selected from substituted or unsubstituted aryl containing 6-10 carbon atoms, substituted or unsubstituted heteroaryl or heterocyclic group containing 4-10 carbon atoms, substituted or unsubstituted cycloalkyl containing 3-10 carbon atoms, wherein the substituent is selected from halogen, hydroxyl, carbonyl, amino, cyano, carboxyl, aryl containing 6-10 carbon atoms, heteroaryl containing 4-10 carbon atoms, cycloalkyl containing 3-6 carbon atoms, alkoxy containing 1-10 carbon atoms, alkylamino containing 1-10 carbon atoms, or alkyl ester containing 1-10 carbon atoms;

[0202] B is selected from no group, O, S, NH, CH2, OCH2, SCH2, NHCH2, CHO, CH2S, CH2SO, CH2SO2, CH2NH, C=O or NH(CO);

[0203] R1 is selected from H or halogen;

[0204] R2 is selected from H, CH3 or halogen;

[0205] R3 is selected from CH2R4, R4 is selected from OH, halogen, OR5 or OCOR5, or, R3 is selected from SCH2R6 or OCH2R6;

[0206] wherein R5 is selected from an alkyl group containing 1 to 6 carbon atoms, an alkenyl group containing 2 to 6 carbon atoms, an alkynyl group containing 2 to 6 carbon atoms, an aryl group containing 6 to 10 carbon atoms, a heteroaryl group containing 4 to 10 carbon atoms, or a heterocyclic group; and R6 is selected from a halogen or CN.

[0207] Halogen is selected from F or Cl;

[0208] It is a single bond or a double bond.

[0209] It should be noted that in the structural formula of the compound of formula I, the B group is connected to the α, β or γ carbon atom of the lactone ring.

[0210] Furthermore, A is selected from substituted or unsubstituted phenyl, substituted or unsubstituted piperidinyl, substituted or unsubstituted cyclohexyl, substituted or unsubstituted pyridinyl, substituted or unsubstituted pyrimidinyl, and the substituent is selected from halogen or cyano.

[0211] Furthermore, A is selected from substituted or unsubstituted phenyl, substituted or unsubstituted cyclohexyl, substituted or unsubstituted pyridyl, substituted or unsubstituted pyrimidinyl, and the substituent is selected from halogen or cyano.

[0212] Furthermore, A is selected from substituted or unsubstituted phenyl, substituted or unsubstituted cyclohexyl, substituted or unsubstituted pyridyl, and the substituent is selected from halogen.

[0213] Furthermore, A is selected from substituted or unsubstituted phenyl, substituted or unsubstituted pyridyl, and the substituent is selected from halogen.

[0214] Further, B is selected from O, S, NH, CH2, OCH2, SCH2, NHCH2, CH2O, CH2S, CH2SO, CH2SO2, CH2NH, C=O or NH(CO).

[0215] Furthermore, B is selected from S, CH2, OCH2, SCH2, NHCH2, CH2O, CH2S, CH2SO, CH2SO2, CH2NH or NH(CO).

[0216] Furthermore, B is selected from S, CH2O, CH2S, CH2SO or CH2NH.

[0217] Furthermore, B is selected from CH2O, CH2S or CH2NH.

[0218] Furthermore, B is selected from CH2O or CH2S.

[0219] Furthermore, R1 is selected from H or halogen, and halogen is selected from F or Cl.

[0220] Furthermore, R1 is selected from halogen, and halogen is selected from F or Cl.

[0221] Furthermore, R2 is selected from H or halogen, and halogen is selected from F or Cl.

[0222] Further, R3 is selected from CH2R4, R4 is selected from OH or halogen, or R3 is selected from SCH2R6 or OCH2R6, R6 is halogen or CN, and halogen is selected from F or Cl.

[0223] Further, R3 is selected from CH2R4, R4 is selected from OH, or R3 is selected from SCH2R6 or OCH2R6, R6 is halogen or CN, and halogen is selected from F or Cl.

[0224] Further, For double bonds.

[0225] Furthermore, A, B, R1, R2, and R3 shown in the structural formula of the compound of Formula I are selected independently of each other, and:

[0226] A is selected from substituted or unsubstituted phenyl, substituted or unsubstituted piperidinyl, substituted or unsubstituted cyclohexyl, substituted or unsubstituted pyridinyl, substituted or unsubstituted pyrimidinyl, and the substituent is selected from halogen or cyano;

[0227] B is selected from O, S, NH, CH2, OCH2, SCH2, NHCH2, CHO, CH2S, CH2SO, CH2SO2, CH2NH, C=O or NH(CO);

[0228] R1 is selected from H or halogen;

[0229] R2 is selected from H or halogen;

[0230] R3 is selected from CH2R4, R4 is selected from OH or halogen, or, R3 is selected from SCH2R6 or OCH2R6, R6 is selected from halogen or CN;

[0231] Halogen is selected from F or Cl;

[0232] For double bonds.

[0233] Furthermore, A, B, R1, R2, and R3 shown in the structural formula of the compound of Formula I are selected independently of each other, and:

[0234] A is selected from substituted or unsubstituted phenyl, substituted or unsubstituted cyclohexyl, substituted or unsubstituted pyridyl, substituted or unsubstituted pyrimidinyl, and the substituent is selected from halogen or cyano;

[0235] B is selected from S, CH2, OCH2, SCH2, NHCH2, CHO, CH2S, CH2SO, CH2SO2, CH2NH or NH(CO);

[0236] R1 is selected from H or halogen;

[0237] R2 is selected from H or halogen;

[0238] R3 is selected from CH2R4, R4 is selected from OH or halogen, or, R3 is selected from SCH2R6 or OCH2R6, R6 is selected from halogen or CN;

[0239] Halogen is selected from F or Cl;

[0240] For double bonds.

[0241] Furthermore, A, B, R1, R2, and R3 shown in the structural formula of the compound of Formula I are selected independently of each other, and:

[0242] A is selected from substituted or unsubstituted phenyl, substituted or unsubstituted cyclohexyl, substituted or unsubstituted pyridyl, and the substituent is selected from halogen;

[0243] B is selected from S, CH2O, CH2S, CH2SO or CH2NH;

[0244] R1 is selected from halogen;

[0245] R2 is selected from H or halogen;

[0246] R3 is selected from CH2R4, R4 is selected from OH or halogen, or, R3 is selected from SCH2R6 or OCH2R6, R6 is selected from halogen or CN;

[0247] Halogen is selected from F or Cl;

[0248] For double bonds.

[0249] Furthermore, A, B, R1, R2, and R3 shown in the structural formula of the compound of Formula I are selected independently of each other, and:

[0250] A is selected from substituted or unsubstituted phenyl, substituted or unsubstituted pyridyl, and the substituent is selected from halogen;

[0251] B is selected from CH2O, CH2S or CH2NH;

[0252] R1 is selected from halogen;

[0253] R2 is selected from H or halogen;

[0254] R3 is selected from CH2R4, R4 is selected from OH, or, R3 is selected from SCH2R6 or OCH2R6, R6 is selected from halogen or CN;

[0255] Halogen is selected from F or Cl;

[0256] For double bonds.

[0257] Furthermore, the compound of formula I is selected from the following compounds:

[0258] Further, the compound of formula I is selected from the following compounds: compound 5, compound 7, compound 8, compound 9, compound 10, compound 11, compound 12, compound 13, compound 14, compound 15, compound 16, compound 17, compound 18, compound 19, compound 20, compound 21, compound 22, compound 23, compound 24, compound 25, compound 26, compound 27, compound 28, compound 29, compound 30, compound 32, compound 33, compound 34, compound 35, compound 36, compound 37, compound 38, compound 39, compound 41, compound 43, compound 45, compound 46, compound 47, compound 48, compound 49, compound 50, compound 51, compound 52, compound 54, compound 55, compound 56, compound 57, compound 58, compound 59, and compound 60.

[0259] Further, the compound of formula I is selected from the following compounds: compound 7, compound 8, compound 10, compound 11, compound 16, compound 17, compound 18, compound 19, compound 20, compound 21, compound 22, compound 23, compound 24, compound 25, compound 26, compound 27, compound 34, compound 35, compound 36, compound 37, compound 38, compound 45, compound 46, compound 47, compound 48, compound 49, compound 50, compound 51, and compound 57.

[0260] Furthermore, the compound of formula I is selected from the following compounds: Compound 16, Compound 17, Compound 20, Compound 21, Compound 22, Compound 23, Compound 26, Compound 34, Compound 35, Compound 36, Compound 37, Compound 46, Compound 47, Compound 48, and Compound 51.

[0261] Further, the pharmaceutically acceptable salts of the compounds of Formula I are conventional non-toxic salts formed from, for example, inorganic or organic acids, including, but not limited to, acetate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, citrate, camphorate, camphorsulfonate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, fumarate, gluconoheptate, glycerophosphate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate, methanesulfonate, 2-naphthalene-sulfonate, nicotinate, oxalate, palmitate, pectinate, persulfate, 3-phenylpropionate, picrate, pivalate, propionate, succinate, tartrate, thiocyanate, toluenesulfonate or undecanoate.

[0262] As the second aspect of the present invention, the present invention provides a method for preparing the above-mentioned compound, which is prepared by method one or method two:

[0263] Method 1:

[0264] The compound of formula II reacts with the compound of formula III under acidic conditions to obtain the compound of formula I:

[0265] Wherein, A, B, R1, R2, and R3 in the compound of formula I are as defined in the first aspect above;

[0266] In the compound of formula II, R1, R2, and R3 are defined the same as those in the compound of formula I, and R7 and R8 are selected from OH, or R7 and R8 together form C 16 , C 17 The sites are connected by oxygen bridges, R9, R 10 Each is independently selected from H or an alkyl group containing 1-6 carbons;

[0267] In the compound of formula III, A and B are the same as those in the compound of formula I.

[0268] It should be noted that the compound of formula III represents an aldehyde containing an A fragment and a B fragment.

[0269] Alternatively, method 2: To obtain a compound of formula I wherein B is selected from CH2NH, the following method may also be used:

[0270] (a) The compound of formula II reacts with the compound of formula V under acidic conditions to obtain the compound of formula IV:

[0271] (b) reacting a compound of formula IV with a compound of formula VI or a compound of formula VII to obtain a compound of formula I:

[0272] Wherein, in the compound of formula I, A, R1, R2, and R3 are as defined in the first aspect above, and B is selected from CH2NH;

[0273] In the compound of formula II, R1, R2, and R3 are defined the same as those in the compound of formula I, and R7 and R8 are selected from OH, or R7 and R8 together form C 16 , C 17 The sites are connected by oxygen bridges, R9, R 10 are independently selected from H or an alkyl group containing 1-6 carbon atoms; A, B, R1, R2, and R3 in the compound of formula IV are the same as those in the compound of formula I;

[0274] In the compound of formula V, A is defined the same as in the compound of formula I, B is selected from CH2NH, and Z is selected from a Boc protecting group;

[0275] The compound of formula VI is selected from Wherein, Q is a leaving group selected from Cl or Br;

[0276] Formula VII is selected from

[0277] As the third aspect of the present invention, the present invention provides a pharmaceutical composition comprising the above compound or the compound prepared by the above preparation method.

[0278] Furthermore, the dosage forms of the compositions of the present invention include, but are not limited to, tablets, pills, granules, powders, lozenges, suspensions, emulsions, solutions, syrups, aerosols, ointments, creams, gels, lotions, soft and hard gelatin capsules, suppositories, eye drops, transdermal patches, injections, implants, sprays, inhalants, and preparations for oral or rectal administration that act locally in the digestive tract.

[0279] Furthermore, the dosage form of the pharmaceutical composition is selected from creams, ointments, gels, transdermal patches, intradermal injections, eye drops, intraocular injections, ophthalmic implants, nasal sprays, inhalation powders, inhalation aerosols, inhalation sprays, inhalation liquid preparations, vaginal suppositories, vaginal tablets, vaginal gels, and preparations that are administered orally or rectally and act locally in the digestive tract.

[0280] The compositions of the present invention may optionally contain other pharmaceutically active substances (which may or may not produce synergistic effects with the compounds of the present invention) and suitable carriers, excipients and diluents for formulation, such as lubricants, wetting agents, emulsifiers and suspending agents, dispersants, disintegrants, extenders, fillers, preservatives, sweeteners, flavorings, flow regulators, release agents, etc. For example, lactose, glucose, sucrose, sorbitol, mannitol, starch, acacia gum, calcium phosphate, alginates, tragacanth gum, gelatin, calcium silicate, microcrystalline cellulose, polyvinyl pyrrolidone, polyethylene glycol, cellulose, (sterile) water, methylcellulose, talc, magnesium stearate, edible oils, vegetable oils and mineral oils or suitable mixtures thereof. The release of the active compound can also be regulated by adding other substances, for example, using liposomes or hydrophilic polymer matrices based on natural gels or synthetic polymers. In order to enhance the solubility and / or stability of the compound, α-, β- or γ-cyclodextrin or their derivatives can be used. When preparing aqueous compositions, the use of co-solvents such as alcohols can also improve the solubility and / or stability of the compounds.

[0281] For the treatment of dermatological conditions, the compounds of the invention may be applied topically, for example, as a spray, cream, ointment, gel, transdermal patch or other form of the compound suitable for topical, transdermal and / or intradermal administration may be beneficial.

[0282] For the treatment of ophthalmic diseases, the compounds of the present invention can be in the form of eye drops, gels or implants, etc., usually using physiological saline solution or excipients as the main vehicle. Ophthalmic preparations are preferably prepared at a comfortable pH using an appropriate buffer system.

[0283] Furthermore, the administration of the pharmaceutical composition includes, but is not limited to, topical administration to the skin, topical administration to the eyes, administration to the ears, administration to the nasal cavity, administration by inhalation, administration into the vagina, and oral or rectal administration to act locally in the digestive tract.

[0284] The above-mentioned administration forms may be solid, semi-solid or liquid depending on the mode of administration, and the methods and carriers, diluents and excipients used in their preparation are clear to those skilled in the art.

[0285] For oral administration, the compositions of the present invention may be mixed with suitable additives, such as excipients, stabilizers or inert carriers, and converted into suitable administration forms, such as tablets, capsules, aqueous or alcoholic solutions, etc., in a conventional manner. Suitable inert carriers may be gum arabic, magnesium oxide, magnesium carbonate, potassium phosphate, lactose, glucose or starch, particularly corn starch. Suitable excipients or solvents may be vegetable or animal oils, such as sunflower oil or cod liver oil. Suitable solvents for aqueous or alcoholic solutions are water, ethanol, sugar solutions or mixtures thereof.

[0286] When administered via nasal spray or inhalation, the compositions of the present invention can be prepared according to techniques known in the art. For example, liquid formulations can employ benzyl alcohol or other suitable preservatives or absorption enhancers to enhance bioavailability. Fluorocarbons and / or other solubilizing agents or dispersants known in the art can also be employed. Suitable pharmaceutical formulations administered as aerosols or sprays can be solutions, suspensions, or emulsions. The solvent employed can include ethanol, water, or mixtures thereof. Other adjuvants, such as surfactants, emulsifiers, stabilizers, and propellants, can also be included, if desired.

[0287] For subcutaneous injection, the composition of the present invention can be formulated into a solution, suspension or emulsion using conventional substances (such as solubilizers, emulsifiers or other adjuvants). For example, suitable solvents are water, physiological saline solutions or alcoholic solvents (such as ethanol, propanol or glycerol), in addition to sugar solutions such as glucose solutions or mannitol solutions, or mixtures of the various solvents mentioned above. The above-mentioned formulations can be prepared according to techniques known in the art, for example, using suitable non-toxic, parenterally acceptable diluents or solvents, such as mannitol, 1,3-butanediol, water, Ringer's solution or isotonic sodium chloride solution, or using suitable dispersants or wetting agents and suspending agents, such as sterile, non-irritating, fixed oils, including synthetic monoglycerides or diglycerides and fatty acids (such as oleic acid).

[0288] When administered rectally via suppository, the compositions of the present invention can be prepared by mixing the compounds of the present invention with a suitable non-irritating excipient, such as cocoa butter, synthetic glycerides or polyethylene glycols, which are solid at ordinary temperatures but will liquefy and / or dissolve in the rectal cavity to release the drug.

[0289] As the fourth aspect of the present invention, the present invention provides use of the above-mentioned compound, the compound prepared by the above-mentioned preparation method or the above-mentioned pharmaceutical composition in the preparation of a drug for treating glucocorticoid receptor-mediated diseases.

[0290] Preferably, the disease is selected from blepharitis, conjunctivitis, keratitis, iritis, iridocyclitis, uveitis, dry eye, diabetic retinopathy, wet age-related macular degeneration, choroidal neovascularization, posterior uveitis, cataract, glaucoma, retinal detachment, inflammation after strabismus correction surgery, eczema, psoriasis, atopic dermatitis, allergic dermatitis, pruritus, hypersensitivity reaction, rheumatoid arthritis, multiple sclerosis and disseminated lupus erythematosus, rhinitis, sinusitis, asthma, nasal polyps, asthma, chronic obstructive pulmonary disease, inflammatory bowel disease, Crohn's disease, ulcerative colitis or chronic glomerulonephritis;

[0291] More preferably, the disease is selected from conjunctivitis, keratitis, uveitis, dry eye, asthma, chronic obstructive pulmonary disease, allergic rhinitis, nasal polyps, Crohn's disease, eczema and psoriasis.

[0292] Furthermore, the diseases include but are not limited to skin diseases, respiratory diseases, intestinal inflammatory diseases, autoimmune diseases, eye diseases or kidney diseases.

[0293] Furthermore, the skin diseases include but are not limited to eczema, psoriasis, atopic dermatitis, allergic dermatitis, pruritus and hypersensitivity reaction.

[0294] Furthermore, the respiratory diseases include but are not limited to rhinitis, sinusitis, asthma, nasal polyps, and chronic obstructive pulmonary disease;

[0295] More specifically, rhinitis of any type, etiology or pathogenesis, in particular rhinitis selected from the group consisting of seasonal allergic rhinitis or perennial allergic rhinitis;

[0296] Sinusitis of any type, etiology or pathogenesis, in particular sinusitis selected from the group consisting of suppurative or non-suppurative sinusitis, acute or chronic sinusitis and ethmoid, frontal, maxillary or sphenoid sinusitis;

[0297] Asthma of whatever type, etiology or pathogenesis, in particular asthma selected from the group consisting of atopic asthma, non-atopic asthma, allergic asthma, atopic bronchial IgGE-mediated asthma, bronchial asthma, intrinsic asthma due to pathophysiological disorders, extrinsic asthma due to environmental factors, idiopathic asthma of unknown or occult cause, exercise-induced asthma, allergen-induced asthma, cold air-induced asthma, occupational asthma, infectious asthma due to bacterial, fungal, protozoal or viral infection, non-allergic asthma, incipient asthma, wheezing infant syndrome and bronchitis;

[0298] Obstructive or inflammatory airways diseases of whatever type, etiology or pathogenesis, in particular obstructive or inflammatory airways diseases selected from the group consisting of chronic eosinophilic pneumonia, chronic obstructive pulmonary disease (COPD), COPD including chronic bronchitis, emphysema with or without dyspnea associated with COPD, COPD characterized by irreversible progressive airway obstruction, adult respiratory distress syndrome (ARDS), exacerbation of airway hyperresponsiveness following other drug therapies and airway diseases associated with pulmonary hypertension;

[0299] Furthermore, the intestinal inflammatory disease includes but is not limited to inflammatory bowel disease, Crohn's disease and ulcerative colitis.

[0300] Furthermore, the autoimmune disease includes but is not limited to rheumatoid arthritis, multiple sclerosis and disseminated lupus erythematosus.

[0301] Furthermore, the eye diseases include but are not limited to external eye diseases such as blepharitis, conjunctivitis, keratitis, anterior eye diseases such as iritis, iridocyclitis, uveitis, dry eye, diabetic retinopathy, age-related wet macular degeneration, choroidal neovascularization, posterior uveitis, and postoperative inflammation such as cataracts, glaucoma, retinal detachment, and strabismus correction.

[0302] Furthermore, the kidney disease includes but is not limited to chronic glomerulonephritis, etc.

[0303] The compounds of the present invention also have utility in the treatment of cancer (e.g., glioma and prostate cancer), acquired immune deficiency syndrome, osteoarthritis, septic shock, transplant rejection, emphysema (particularly in patients with COPD), post-ischemic damage, pulmonary hypertension, pulmonary fibrosis, interstitial lung disease, acute respiratory distress syndrome, prevention of restenosis after coronary angioplasty, Stevens-Johnson syndrome, HELLP syndrome (a variant of severe pre-eclampsia), chronic active hepatitis, blood disorders, and acute spinal cord injury.

[0304] Furthermore, the disease is selected from conjunctivitis, keratitis, uveitis, dry eye, asthma, COPD, allergic rhinitis, nasal polyps, Crohn's disease, eczema and psoriasis.

[0305] Compared with the prior art, the present invention has the following beneficial effects:

[0306] The compound provided by the present invention is a glucocorticoid based on a lactone ring modification, with a high plasma clearance rate and a short half-life (Cl_obs is greater than 400mL / min / kg, T1 / 2 is less than 0.5h), and low systemic drug exposure. Relative to the mineralocorticoid receptor (MR) and the progesterone receptor (PR), the compound provided by the present invention has a higher target selectivity for the glucocorticoid receptor (GR) (MR / GR or PR / GR is more than 1000 times), which can significantly reduce the side effects caused by the systemic absorption of glucocorticoid drugs. In the anti-asthma efficacy experiment, after administration of the compound of the present invention, the mouse expiratory interval (Penh) value can be significantly or extremely significantly reduced; and the high airway responsiveness of asthma model mice can be significantly suppressed, and the inflammatory factors in the alveolar lavage fluid can be suppressed, with significant anti-inflammatory activity. It has significant anti-inflammatory activity for animal uveitis, dry eye, inflammatory bowel disease and psoriasis. The compound of the present invention has good safety. No abnormal intraocular pressure was detected after continuous administration in the guinea pig eye, and no obvious abnormality occurred in the epidermal thickness after continuous administration in rat skin. DETAILED DESCRIPTION

[0307] In the present invention, unless otherwise explicitly stated, the description method "...selected independently of each other" used throughout this document can mean that in different groups, the specific options expressed by the same or different symbols do not affect each other, and can also mean that in the same group, the specific options expressed by the same or different symbols do not affect each other.

[0308] The substituents of the compounds of the present invention are disclosed by group class or range. It is specifically noted that the present invention includes each independent subcombination of the individual members of these group classes and ranges. For example, the term "alkyl containing 1-6 carbon atoms" specifically refers to the independently disclosed methyl, ethyl, C3 alkyl, C4 alkyl, C5 alkyl, and C6 alkyl.

[0309] Unless otherwise specified, the above groups and substituents have the common meanings in the field of medicinal chemistry.

[0310] The term "alkyl group containing 1-6 carbon atoms" refers to any straight-chain or branched group containing 1-6 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, tert-pentyl, n-hexyl, etc. Similarly, "C1-C4 alkyl group" refers to any straight-chain or branched group containing 1-4 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, etc.

[0311] As used herein, the term "alkenyl containing 2-6 carbon atoms" refers to a straight chain or branched unsaturated hydrocarbon group containing at least one carbon-carbon double bond and having 2-6 carbon atoms (such as 2, 3, 4, 5 or 6). Specific examples include but are not limited to ethenyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, 1,3-butadienyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 1,3-pentadienyl, 1,4-pentadienyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, and 1,4-hexadienyl.

[0312] As used herein, the term "alkynyl containing 2-6 carbon atoms" refers to a straight-chain or branched unsaturated hydrocarbon group containing at least one triple bond and having 2-6 carbon atoms, specific examples of which include but are not limited to ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 1,3-butadiynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 1,3-pentadiynyl, 1,4-pentadiynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, and 1,4-hexadiynyl.

[0313] The term "alkoxy containing 1-10 carbon atoms" refers to any of the above alkyl groups (e.g., alkyl containing 1-10 carbon atoms, etc.) connected to the rest of the molecule through an oxygen atom -O-, such as alkoxy containing 1-10 carbon atoms, specifically methoxy, ethoxy, propoxy, butoxy, etc.

[0314] The term "alkylamino group containing 1-10 carbon atoms" refers to any of the above alkyl groups (e.g., an alkyl group containing 1-10 carbon atoms, etc.) connected to the rest of the molecule via a nitrogen atom -NR- (wherein R can be H or an alkyl group containing 1-10 carbon atoms), such as methylamino ((CH3)NH-), ethylmethylamino ((C2H5)N(CH3)-), propylamino ((C3H7)NH-), butylethylamino ((C4H9)N(C2H5)-), etc.

[0315] As used herein, the term "alkyl ester containing 1-10 carbon atoms" refers to -COO (alkyl containing 1-10 carbon atoms). Suitable ester groups include, but are not limited to, -COO(CH3), -COO(C2H5), -COO(C3H7), -COO(C4H9), and the like.

[0316] The term "cycloalkyl containing 3-10 carbon atoms" refers to a saturated hydrocarbon monovalent ring containing 3-10 ring carbon atoms. The cycloalkyl group may be in the form of a single ring, a fused ring, a bridged ring, etc. Exemplary cycloalkyl groups include, but are not limited to, the following:

[0317] Examples include wait.

[0318] Halogen refers to fluorine, chlorine, bromine or iodine.

[0319] The term "aryl group containing 6 to 10 carbon atoms" refers to an aromatic monocyclic or bicyclic group containing 6 to 10 carbon atoms, and specific examples include phenyl and naphthyl, with phenyl being preferred.

[0320] The term "heteroaryl containing 4-10 carbon atoms" refers to an unsaturated group having a conjugated π electron system and containing 4-10 carbon atoms and at least one (e.g., 1, 2, 3, or 4) ring atom being a heteroatom, wherein the heteroatom is selected from N, O, and S, wherein the nitrogen atom is optionally quaternized, and the nitrogen and sulfur heteroatoms are optionally oxidized. For example, a heteroaryl consisting of 4 to 12 (e.g., 4, 5, 6, 7, 8, 9, 10, 11, or 12) ring atoms includes a 4-10-membered, 4-9-membered, 6-9-membered, or 5-6-membered heteroaryl group. The heteroaryl groups include monocyclic and polycyclic groups, and specific examples include but are not limited to furyl, pyrrolyl, thienyl, pyrazolyl, imidazolyl, thiazolyl, isothiazolyl, thiadiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, benzofuranyl, benzothienyl, benzoxazolyl, benzisoxazolyl, benzimidazolyl, benzotriazolyl, indazolyl, indolyl, quinolyl, isoquinolyl, and the like.

[0321] As used herein, the term "heterocyclyl containing 4-10 carbon atoms" refers to a saturated or partially unsaturated cyclic group containing 4-10 carbon atoms and at least one (e.g., 1, 2, 3, 4, or 5 heteroatoms) ring atom being a heteroatom, wherein the heteroatom is selected from N, O, and S, wherein the nitrogen atom is optionally quaternized, the nitrogen and sulfur heteroatoms are optionally oxidized, and the carbon atoms are optionally oxoed. For example, it is composed of 4, 5, 6, 7, 8, 9, 10, 11, or 12 ring atoms, including 4-10 membered heterocyclyl, 4-9 membered heterocyclyl, 6-9 membered heterocyclyl, etc. The heterocyclic group includes a monocyclic, bicyclic or polycyclic ring, including a spirocyclic, paracyclic or bridged ring. Specific examples include but are not limited to: pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, imidazolinyl, 2,3-dihydrobenzofuranyl, 1,2,3,4-tetrahydroquinolinyl, 3,4-dihydro-1H-benzopyranyl, 1,4-benzodioxanyl, benzomorpholinyl, 1,2,3,4-tetrahydroquinoxaline, etc.

[0322] The term "substituted" means optionally substituted by one or more (e.g., 2-9, such as 2, 3, 4, 5, 6, 7, 8, 9) substituents selected from the following: halogen, hydroxy, carbonyl, amino, cyano, carboxyl, aryl containing 6-10 carbon atoms, heteroaryl containing 4-10 carbon atoms, cycloalkyl containing 3-6 carbon atoms, alkoxy containing 1-10 carbon atoms, alkylamino containing 1-10 carbon atoms, or alkyl ester containing 1-10 carbon atoms, and the like.

[0323] As used herein, "treat" generally refers to obtaining a desired pharmacological and / or physiological effect. This effect can be prophylactic, in terms of completely or partially preventing a disease or its symptoms; and / or therapeutic, in terms of partially or completely stabilizing or curing a disease and / or causing side effects due to the disease. As used herein, "treat" encompasses any treatment of a disease in a patient, including: (a) preventing the onset of a disease or symptom in a patient who is susceptible to the disease or symptom but has not yet been diagnosed with the disease; (b) suppressing the symptoms of a disease, i.e., arresting its development; or (c) alleviating the symptoms of a disease, i.e., causing the disease or symptom to regress.

[0324] In the present invention, an "effective amount" refers to an amount that is effective at the necessary dosage and time to achieve the desired therapeutic or preventive effect. The "therapeutically effective amount" of the substance / molecule of the present invention may vary according to factors such as the individual's disease state, age, sex and weight, and the ability of the substance / molecule to elicit the desired response in the individual. A therapeutically effective amount also encompasses an amount in which the therapeutically beneficial effects of the substance / molecule outweigh any toxic or deleterious consequences. A "prophylactically effective amount" refers to an amount that is effective at the necessary dosage and time to achieve the desired preventive effect. Usually, but not necessarily, since a prophylactic dose is used for a subject before the onset of the disease or in the early stages of the disease, the prophylactic effective amount will be lower than the therapeutically effective amount. In the case of cancer, a therapeutically effective amount of a drug can reduce the number of cancer cells; reduce the size of the tumor; inhibit (i.e., slow down to a certain extent, preferably stop) the infiltration of cancer cells into surrounding organs; inhibit (i.e., slow down to a certain extent, preferably stop) tumor metastasis; inhibit tumor growth to a certain extent; and / or alleviate one or more symptoms associated with cancer to a certain extent.

[0325] In the present invention, "subject" refers to a vertebrate. In certain embodiments, the vertebrate refers to a mammal. Mammals include, but are not limited to, livestock (such as cattle), pets (such as cats, dogs, and horses), primates, mice, and rats. In certain embodiments, the mammal refers to a human.

[0326] The compounds of the present invention may optionally be used in combination with one or more other active ingredients, and the dosage and ratio of each can be adjusted by those skilled in the art according to the specific disease and patient conditions and clinical needs.

[0327] As used herein, the term "optical isomer" refers to a substance with a structure that can rotate the polarization plane of polarized light by a certain angle, and is therefore called an optically active substance. These structures are mutually called optical isomers, including enantiomers and diastereomers.

[0328] As used herein, the term "solvate" refers to a compound that exists in combination with certain solvent molecules. The combination may include a stoichiometric amount of a certain solvent, for example, when the solvent is water, a "hydrate" such as a monohydrate or a dihydrate is formed, or may include any amount of water; for example, when the solvent is an alcohol such as methanol or ethanol, an "alcoholate" may be formed, which may also be stoichiometric or non-stoichiometric.

[0329] The embodiments of the present invention will be described in detail below with reference to the examples, but those skilled in the art will appreciate that the following examples are intended only to illustrate the present invention and should not be construed as limiting the scope of the invention. Where specific conditions are not specified in the examples, conventional conditions were used. Where the manufacturers of the reagents or instruments are not specified, they are all conventional products that can be purchased commercially.

[0330] The liquid chromatography-mass spectrometry (LC-MS) of the present invention uses an AB Sciex TripleTOF 4600 mass spectrometer; the nuclear magnetic resonance uses a BRUKER AVANCE NEO 400 MHz nuclear magnetic resonance spectrometer; the liquid chromatography uses a Shimadzu LC-20AD XR high performance liquid chromatograph, and the chromatographic column is: Agela Venusil MP C18 (2.1x50, 3um).

[0331] Synthesis Example 1

[0332] (2S,6aS,6bR,7S,8aS,8bS,11aR,12aS,12bS)-2,6b-difluoro-7-hydroxy-8b-(2-hydroxyacetyl)-6a,8a-dimethyl-10-(1-(5-acyltetrahydrofuran-3-carbonyl)piperidin-4-yl)-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]dioxolane-4-one (1)

[0333] 1-(5-Acyltetrahydrofuran-3-carbonyl)piperidine-4-carbaldehyde

[0334] Piperidine-4-carboxaldehyde (0.5 g, 4.42 mmol), 5-acyltetrahydrofuran-3-carboxylic acid (0.63 g, 4.86 mmol), 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (1.85 g, 4.86 mmol), N,N-diisopropylethylamine (1.54 mL, 8.84 mmol), and 30 mL of dichloromethane were added to a reaction flask and reacted at room temperature for 5 hours. After completion of the reaction, the mixture was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 4 / 1) and concentrated under reduced pressure to obtain 0.55 g of 1-(5-acyltrahydrofuran-3-carbonyl)piperidine-4-carboxaldehyde in a yield of 55%. MS m / z (ESI): 226.22 [M+H] +

[0335] (6α,9α,11β,16α)-6,9-difluoro-11,16,17,21-tetrahydroxy-pregna-1,4-diene-3,20-dione (0.5 g, 1.21 mmol), 1-(5-acyltetrahydrofuran-3-carbonyl)piperidine-4-carbaldehyde (0.33 g, 1.45 mmol), and 30 mL of acetonitrile were added to a reaction flask. Perchloric acid (0.3 mL, 3.64 mmol) was slowly added dropwise. The reaction was allowed to proceed at room temperature. TLC monitoring was performed until the (6α,9α,11β,16α)-6,9-difluoro-11,16,17,21-tetrahydroxy-pregna-1,4-diene-3,20-dione was removed. After completion of the reaction, the mixture was concentrated under reduced pressure. Water and dichloromethane were added to extract the separated liquids. The organic phases were combined, washed with saturated brine, and concentrated under reduced pressure. The crude product was separated and purified by silica gel column chromatography (dichloromethane / acetone = 4 / 1) and concentrated under reduced pressure to obtain 0.35 g of compound 1. Yield: 46%. 1 H NMR (400MHz, d6-DMSO): δ7.27(m,1H),6.32(m,1H),6.15(s,1H),5.55-5.53 (m,1H),5.52(s,1H),5.50(s,1H),5.22-5.15(m,2H),5.02-4.85(m,2H),4. 35-4.18(m,3H),3.94-3.44(m,4H),3.12-3.05(m,1H),2.62-2.58(m,2H),2 .12-2.01(m,5H),1.83-1.45(m,7H),1.40-1.33(m,4H),0.90-0.86(m,3H). MS m / z(ESI):620.28[M+H] +

[0336] Synthesis Example 2

[0337] N-(4-((2S,6aS,6bR,7S,8aS,8bS,11aR,12aS,12bS)-2,6b-difluoro-7-hydroxy-8b-(2-hydroxyacetyl)-6a,8a-dimethyl-4-acyl-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]dioxolan-10-yl)phenyl)-5-acyltetrahydrofuran-3-carboxamide (2)

[0338] N-(4-Formylphenyl)-5-acyltetrahydroxyfuran-3-amide

[0339] 4-Aminobenzaldehyde (0.5 g, 4.13 mmol), 5-acyltetrahydrofuran-3-carboxylic acid (0.6 g, 4.54 mmol), 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (1.73 g, 4.54 mmol), N,N-diisopropylethylamine (1.44 mL, 8.25 mmol), and 30 mL of dichloromethane were added to a reaction flask and allowed to react at room temperature for 5 hours. After completion of the reaction, the mixture was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 4 / 1) and concentrated under reduced pressure to obtain 0.6 g of N-(4-formylphenyl)-5-acyltrahydrofuran-3-amide in a yield of 62%. MS m / z (ESI): 234.10 [M+H] +

[0340] (6α,9α,11β,16α)-6,9-difluoro-11,16,17,21-tetrahydroxy-pregna-1,4-diene-3,20-dione (0.5 g, 1.21 mmol), N-(4-formylphenyl)-5-acyltetrahydrofuran-3-amide (0.34 g, 1.45 mmol), and 30 mL of acetonitrile were added to a reaction flask. Perchloric acid (0.3 mL, 3.64 mmol) was slowly added dropwise. The reaction was allowed to proceed at room temperature. TLC monitoring was performed until the (6α,9α,11β,16α)-6,9-difluoro-11,16,17,21-tetrahydroxy-pregna-1,4-diene-3,20-dione was removed. After completion of the reaction, the mixture was concentrated under reduced pressure, and water and dichloromethane were added. The separated liquids were extracted and the organic phases were combined, washed with saturated brine, and concentrated under reduced pressure. The crude product was separated and purified by silica gel column chromatography (dichloromethane / acetone = 4 / 1) and concentrated under reduced pressure to obtain 0.33 g of compound 2, with a yield of 43%. 1H NMR (400MHz, d6-DMSO): δ8.33(s,1H),7.45-7.37(m,4H),7.26(m,1H),6.44(m,1H) ,6.22(s,1H),5.55-5.53(m,1H),5.48(s,1H),5.45(s,1H),5.08-4.95(m,2H),4.65 -4.59(m,2H),4.22-3.94(m,3H),3.43-3.22(m,1H),2.82-2.73(m,2H),2.42-2.29( m,6H),2.05-1.96(m,1H),1.70-1.65(m,3H),1.60-1.55(m,1H),0.88-0.86(s,3H). MS m / z(ESI): 628.25[M+H] +

[0341] Synthesis Example 3

[0342] N-(4-((2S,6aS,6bR,7S,8aS,8bS,11aR,12aS,12bS)-2,6b-difluoro-7-hydroxy-8b-(2-hydroxyacetyl)-6a,8a-dimethyl-4-acyl-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]dioxolan-10-yl)cyclohexyl)-5-acyltetrahydrofuran-3-carboxamide (3)

[0343] N-(4-Formylcyclohexyl)-5-acyltetrahydrofuran-3-amide

[0344] 4-Aminocyclohexane-1-carboxaldehyde (0.5 g, 3.93 mmol), 5-acyltetrahydrofuran-3-carboxylic acid (0.56 g, 4.32 mmol), 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (1.64 g, 4.32 mmol), N,N-diisopropylethylamine (1.37 mL, 7.86 mmol), and 30 mL of dichloromethane were added to a reaction flask and allowed to react at room temperature for 5 hours. After completion of the reaction, the mixture was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 4 / 1) and concentrated under reduced pressure to obtain 0.45 g of N-(4-formylcyclohexyl)-5-acyltrahydrofuran-3-amide in a yield of 48%. MS m / z (ESI): 240.23 [M+H] +

[0345] (6α,9α,11β,16α)-6,9-difluoro-11,16,17,21-tetrahydroxy-pregna-1,4-diene-3,20-dione (0.5 g, 1.21 mmol), N-(4-formylcyclohexyl)-5-acyltetrahydrofuran-3-amide (0.35 g, 1.45 mmol), and 30 mL of acetonitrile were added to a reaction flask. Perchloric acid (0.3 mL, 3.64 mmol) was slowly added dropwise. The reaction was allowed to proceed at room temperature. TLC monitoring was performed until the (6α,9α,11β,16α)-6,9-difluoro-11,16,17,21-tetrahydroxy-pregna-1,4-diene-3,20-dione was removed. After completion of the reaction, the mixture was concentrated under reduced pressure, and water and dichloromethane were added. The separated liquids were extracted and the organic phases were combined, washed with saturated brine, and concentrated under reduced pressure. The crude product was separated and purified by silica gel column chromatography (dichloromethane / acetone = 4 / 1) and concentrated under reduced pressure to obtain 0.4 g of compound 3, yield: 54%. 1 H NMR (400MHz, d6-DMSO): δ8.35(s,1H),7.26(m,1H),6.33(m,1H),6.11(s,1H), 5.57-5.53(m,1H),5.50(s,1H),5.48(s,1H),5.32-5.20(m,2H),4.92-4.85(m, 2H),4.32-4.20(m,3H),3.54-3.47(m,1H),3.04-2.98(m,1H),2.67-2.58(m,2H ),2.15-2.01(m,9H),1.86-1.48(m,7H),1.38-1.30(m,4H),0.86-0.83(m,3H). MS m / z(ESI):634.25[M+H] +

[0346] Synthesis Example 4

[0347] S-(Fluoromethyl)(2S,6aS,6bR,7S,8aS,8bS,11aR,12aS,12bS)-2,6b-difluoro-7-hydroxy-6a,8a-dimethyl-4-acyl-10-(1-(5-acyltetrahydrofuran-3-carbonyl)piperidin-4-yl)-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]dioxolane-8b-carboxythioester (4)

[0348] first step

[0349] Fluocinolone acetonide (10 g, 0.022 mol) and 100 mL of tetrahydrofuran were added to a reaction flask, and sodium periodate (5.1 g, 0.024 mol) was added portionwise. The reaction was allowed to react at room temperature and monitored by TLC until no fluocinolone acetonide was present. After completion of the reaction, the mixture was concentrated under reduced pressure, water was added, and the mixture was concentrated until no solvent was removed. The pH of the system was adjusted to 9-10 with 1% sodium hydroxide solution, and all solids dissolved. The aqueous phase was washed with ethyl acetate, and the pH of the aqueous phase was adjusted to 1-2 with concentrated hydrochloric acid, resulting in the precipitation of solids. The mixture was filtered under reduced pressure, the filter cake was washed with water until neutral, and the filter cake was dried to obtain 8.4 g of compound 4aa in an 87% yield.

[0350] Step 2

[0351] Compound 4aa (8 g, 0.018 mol), triethylamine (2.8 mL, 0.02 mol), sodium iodide (3 g, 0.02 mol), and 80 mL of tetrahydrofuran were added to a reaction flask. Dimethylthiocarbamoyl chloride (11.1 g, 0.09 mol) was slowly added and allowed to react at room temperature. TLC monitoring was performed until compound 4aa disappeared. After completion of the reaction, the mixture was concentrated under reduced pressure, water was added, and the mixture was evaporated until no solvent was removed. Filtration under reduced pressure and the filter cake was dried to obtain 7.6 g of compound 4ab in an 80% yield.

[0352] Step 3

[0353] Compound 4ab (7.5 g, 0.014 mol), potassium carbonate (2.9 g, 0.021 mol), and 80 mL of methanol were added to a reaction flask and heated to reflux. TLC monitoring was performed until compound 4ab disappeared. After completion of the reaction, the mixture was concentrated under reduced pressure, water was added, and the mixture was evaporated until no solvent was removed. Filtration under reduced pressure and the filter cake was dried to obtain 5.4 g of compound 4ac in an 85% yield.

[0354] Step 4

[0355] Compound 4ac (5 g, 0.011 mol), sodium sulfite (2.1 g, 0.017 mol), and 20 mL of N,N-dimethylacetamide were added to a reaction flask. Iodofluoromethane (2.7 g, 0.017 mol) was slowly added and allowed to react at room temperature. TLC monitoring was performed until compound 4ac disappeared. After completion of the reaction, the reaction mixture was poured into water and stirred for 30 minutes. The mixture was filtered under reduced pressure, the filter cake dried, and the crude product was purified by silica gel column chromatography (dichloromethane / acetone = 4 / 1). The mixture was concentrated under reduced pressure to afford 1.9 g of compound 4a in a 35% yield. MS m / z (ESI): 487.20 [M+H] +

[0356] Compound 4a (0.5 g, 1 mmol), 1-(5-acyltetrahydrofuran-3-carbonyl)piperidine-4-carboxaldehyde (0.28 g, 1.23 mmol), and 30 mL of acetonitrile were added to a reaction flask. Perchloric acid (0.26 mL, 3.1 mmol) was slowly added dropwise and allowed to react at room temperature. TLC monitoring was performed until compound 4a disappeared. After completion of the reaction, the mixture was concentrated under reduced pressure. Water and dichloromethane were added, and the separated liquids were extracted. The organic phases were combined, washed with saturated brine, and concentrated under reduced pressure. The crude product was separated and purified by silica gel column chromatography (dichloromethane / acetone = 4 / 1) and concentrated under reduced pressure to obtain 0.32 g of compound 4, with a yield of 48%. 1 H NMR (400MHz, d6-DMSO): δ7.28(m,1H),6.30(m,1H),6.15(s,1H),5.76(s, 2H),5.52-5.49(m,1H),5.42(s,1H),5.35(s,1H),5.15-4.95(m,2H),4.34-4.14(m,3H),3.94-3.42(m,4H),3.0 4-2.95(m,1H),2.82-2.78(m,2H),2.05-1.94(m,5H),1.73-1.40(m,7H),1.30-1.23(m,3H),0.86-0.83(m,3H). MS m / z(ESI):654.24[M+H] +

[0357] Synthesis Example 5

[0358] S-(Fluoromethyl)(2S,6aS,6bR,7S,8aS,8bS,11aR,12aS,12bS)-2,6b-difluoro-7-hydroxy-6a,8a-dimethyl-4-acyl-10-(4-(5-acyltetrahydrofuran-3-carboxamide)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]dioxolane-8b-carboxythioester (5)

[0359] Compound 4a (0.5 g, 1 mmol), N-(4-formylphenyl)-5-acyltetrahydrofuran-3-amide (0.29 g, 1.23 mmol), and 30 mL of acetonitrile were added to a reaction flask. Perchloric acid (0.26 mL, 3.1 mmol) was slowly added dropwise and allowed to react at room temperature. TLC monitoring was performed until compound 4a disappeared. After completion of the reaction, the mixture was concentrated under reduced pressure. Water and dichloromethane were added, and the separated liquids were extracted. The organic phases were combined, washed with saturated brine, and concentrated under reduced pressure. The crude product was separated and purified by silica gel column chromatography (dichloromethane / acetone = 4 / 1) and concentrated under reduced pressure to obtain 0.35 g of compound 5, with a yield of 52%. 1 H NMR (400MHz, d6-DMSO): δ8.35(s,1H),7.47-7.38(m,4H),7.28(m,1H),6.44(m,1H ),6.16(s,1H),5.80(s,1H),5.54-5.52(m,1H),5.50(s,1H),5.48(s,1H),5.05-4. 88(m,2H),4.33-3.98(m,3H),3.53-3.26(m,1H),2.80-2.73(m,2H),2.40-2.25(m ,6H),2.03-1.95(m,1H),1.72-1.65(m,3H),1.62-1.57(m,1H),0.90-0.86(s,3H). MS m / z(ESI): 662.32[M+H] +

[0360] Synthesis Example 6

[0361] S-(Fluoromethyl)(2S,6aS,6bR,7S,8aS,8bS,11aR,12aS,12bS)-2,6b-difluoro-7-hydroxy-6a,8a-dimethyl-4-acyl-10-(4-(5-acyltetrahydrofuran-3-carboxamide)cyclohexyl)-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]dioxolane-8b-carboxythioester (6)

[0362] Compound 4a (0.5 g, 1 mmol), N-(4-formylcyclohexyl)-5-acyltetrahydrofuran-3-amide (0.3 g, 1.23 mmol), and 30 mL of acetonitrile were added to a reaction flask. Perchloric acid (0.26 mL, 3.1 mmol) was slowly added dropwise and allowed to react at room temperature. TLC monitoring was performed until compound 4a disappeared. After completion of the reaction, the mixture was concentrated under reduced pressure. Water and dichloromethane were added, and the separated liquids were extracted. The organic phases were combined, washed with saturated brine, and concentrated under reduced pressure. The crude product was separated and purified by silica gel column chromatography (dichloromethane / acetone = 4 / 1) and concentrated under reduced pressure to obtain 0.38 g of compound 6, with a yield of 55%. 1 H NMR (400MHz, d6-DMSO): δ8.36(s,1H),7.28(m,1H),6.35(m,1H),6.15(s,1H) ,5.78(s,1H),5.55-5.53(m,1H),5.50(s,1H),5.47(s,1H),5.20-4.90(m,2H) ,4.52-4.40(m,3H),3.74-3.58(m,1H),3.10-3.01(m,1H),2.88-2.68(m,2H) ,2.20-2.11(m,9H),1.86-1.48(m,7H),1.40-1.32(m,4H),0.87-0.83(m,3H). MS m / z(ESI):668.35[M+H] +

[0363] Synthesis Example 7

[0364] (2S,6aS,6bR,7S,8aS,8bS,11aR,12aS,12bS)-2,6b-difluoro-10-(2-fluoro-4-(((2-acyltetrahydrofuran-3-yl)oxy)methyl)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]dioxolane-4-one (7)

[0365] 2-Fluoro-4-((2-acyltetrahydrofuran-3-oxy)methyl)benzaldehyde

[0366] Sodium hydride (60%) (0.54 g, 13.5 mmol), 3-hydroxydihydrofuran-2(3H)-one (1.25 g, 12.3 mmol), and 50 mL of anhydrous tetrahydrofuran were added to a reaction flask, cooled to 0°C, and reacted for 30 minutes. 4-(Bromomethyl)-2-fluorobenzaldehyde (3.3 g, 15.3 mmol) and tetrabutylammonium iodide (0.45 g, 1.2 mmol) were added and reacted at room temperature for 3 hours. After completion of the reaction, water was slowly added, the aqueous phase was extracted with dichloromethane, and the organic phases were combined and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 6 / 4) and concentrated under reduced pressure to obtain 1.4 g of 2-fluoro-4-((2-acyltetrahydrofuran-3-oxy)methyl)benzaldehyde, in a yield of 49%. MS m / z (ESI): 239.12 [M+H] +

[0367] (6α,9α,11β,16α)-6,9-difluoro-11,16,17,21-tetrahydroxy-pregna-1,4-diene-3,20-dione (0.5 g, 1.21 mmol), 2-fluoro-4-((2-acyltetrahydrofuran-3-oxy)methyl)benzaldehyde (0.35 g, 1.45 mmol), and 30 mL of acetonitrile were added to a reaction flask. Perchloric acid (0.3 mL, 3.64 mmol) was slowly added dropwise. The reaction was allowed to proceed at room temperature. TLC monitoring was performed until the (6α,9α,11β,16α)-6,9-difluoro-11,16,17,21-tetrahydroxy-pregna-1,4-diene-3,20-dione was removed. After completion of the reaction, the mixture was concentrated under reduced pressure, and water and dichloromethane were added. The separated liquids were extracted and the organic phases were combined, washed with saturated brine, and concentrated under reduced pressure. The crude product was separated and purified by silica gel column chromatography (dichloromethane / acetone = 4 / 1) and concentrated under reduced pressure to obtain 0.44 g of compound 7. Yield: 57%. 1 H NMR (400MHz, d6-DMSO): δ7.44-7.37(m,3H),7.26(d,J=4.4Hz,1H),6.32(d,J=8.0Hz,1 H),6.10(s,1H),5.67-5.54(m,1H),5.50(s,2H),5.45(s,1H),5.40(s,1H),5.15-4.98( m,2H),4.57-4.52(m,1H),4.30-4.18(m,4H),3.67-3.59(m,1H),2.78-2.68(m,2H),2. 30-2.26(m,2H),2.09-1.95(m,2H),1.75-1.71(m,3H),1.68-1.51(m,4H),0.88(s,3H). MS m / z(ESI): 633.25[M+H] +

[0368] Synthesis Example 8

[0369] (2S,6aS,6bR,7S,8aS,8bS,11aR,12aS,12bS)-2,6b-difluoro-7-hydroxy-8b-(2-hydroxyacetyl)-6a,8a-dimethyl-10-(4-(((2-acyltetrahydrofuran-3-yl)mercapto)methyl)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]dioxolane-4-one (8)

[0370] 4-((2-Acyltetrahydrofuran-3-mercapto)methyl)benzaldehyde

[0371] first step

[0372] 3-Bromodihydrofuran-2(3H)-one (20 g, 0.12 mol), potassium thioacetate (16 g, 0.14 mol), and 200 mL of acetone were added to a reaction flask and reacted at room temperature for 3 hours. After completion of the reaction, the mixture was filtered under reduced pressure and the filtrate was concentrated under reduced pressure. Dichloromethane was added, and the organic phase was washed sequentially with water and saturated brine, and concentrated under reduced pressure to obtain 15.4 g of S-(2-acyltetrahydrofuran-3-yl)thioacetate, with a yield of 82%.

[0373] Step 2

[0374] S-(2-Acyltetrahydrofuran-3-yl)thioacetate (15 g, 0.09 mol), hydrazine hydrate (80%) (7 mL, 0.11 mol), and 100 mL of acetonitrile were added to a reaction flask and allowed to react at room temperature for 4 hours. After completion of the reaction, the reaction solution was concentrated under reduced pressure, and dichloromethane was added. The organic phases were combined and concentrated under reduced pressure. The crude product was separated and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 2 / 1) to obtain 8 g of 3-mercaptodihydrofuran-2(3H)-one, with a yield of 75%.

[0375] Step 3

[0376] 3-Mercaptodihydrofuran-2(3H)-one (8 g, 0.07 mol), 4-(bromomethyl)benzaldehyde (15.3 g, 0.077 mol), potassium carbonate (11 g, 0.08 mol), and 60 mL of N,N-dimethylformamide were added to a reaction flask and allowed to react at room temperature for 6 hours. After completion of the reaction, water and dichloromethane were added, the separated liquids were extracted, and the organic phase was washed sequentially with water and saturated brine, and concentrated under reduced pressure. The crude product was separated and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 4 / 1) and concentrated under reduced pressure to obtain 10.8 g of 4-((2-acyltetrahydrofuran-3-mercapto)methyl)benzaldehyde, with a yield of 65%. MS m / z (ESI): 237.14 [M+H] +

[0377] (6α,9α,11β,16α)-6,9-difluoro-11,16,17,21-tetrahydroxy-pregna-1,4-diene-3,20-dione (0.5 g, 1.21 mmol), 4-((2-acyltetrahydrofuran-3-mercapto)methyl)benzaldehyde (0.34 g, 1.45 mmol), and 30 mL of acetonitrile were added to a reaction flask. Perchloric acid (0.3 mL, 3.64 mmol) was slowly added dropwise. The reaction was allowed to proceed at room temperature. TLC monitoring was performed until the (6α,9α,11β,16α)-6,9-difluoro-11,16,17,21-tetrahydroxy-pregna-1,4-diene-3,20-dione was removed. After completion of the reaction, the mixture was concentrated under reduced pressure, and water and dichloromethane were added. The separated liquids were extracted and the organic phases were combined, washed with saturated brine, and concentrated under reduced pressure. The crude product was separated and purified by silica gel column chromatography (dichloromethane / acetone = 4 / 1) and concentrated under reduced pressure to obtain 0.41 g of compound 8. Yield: 54%. 1 H NMR (400MHz, d6-DMSO): δ7.41-7.34(m,4H),7.26(d,J=4.4Hz,1H),6.30(d,J=8.0Hz,1H), 6.12(s,1H),5.52-5.51(m,1H),5.50(s,1H),5.48(s,1H),5.11-4.95(m,2H),4.55-4.49( m,1H),4.28-4.18(m,4H),4.02-3.94(m,2H),3.56-3.53(m,1H),2.62-2.58(m,2H),2.32- 2.29(m,2H),2.05-1.96(m,2H),1.74-1.71(m,3H),1.68-1.49(m,4H),0.87-0.86(m,3H). MS m / z(ESI): 631.31[M+H] +

[0378] Synthesis Example 9

[0379] (2S,6aS,6bR,7S,8aS,8bS,11aR,12aS,12bS)-2,6b-difluoro-7-hydroxy-8b-(2-hydroxyacetyl)-6a,8a-dimethyl-10-(4-(((2-acyltetrahydrofuran-3-yl)amino)methyl)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]dioxolane-4-one (9)

[0380] first step

[0381] (6α,9α,11β,16α)-6,9-difluoro-11,16,17,21-tetrahydroxy-pregna-1,4-diene-3,20-dione (0.8 g, 1.94 mmol), tert-butyl (4-formylbenzyl) carbamate (0.68 g, 2.91 mmol), and 30 mL of acetonitrile were added to a reaction flask. Perchloric acid (0.5 mL, 5.82 mmol) was slowly added dropwise. The reaction was allowed to proceed at room temperature. TLC monitoring was performed until the (6α,9α,11β,16α)-6,9-difluoro-11,16,17,21-tetrahydroxy-pregna-1,4-diene-3,20-dione was removed. After completion of the reaction, the mixture was concentrated under reduced pressure, and water and dichloromethane were added. The separated liquids were extracted and the organic phases were combined, washed with saturated brine, and concentrated under reduced pressure. The crude product was separated and purified by silica gel column chromatography (dichloromethane / acetone = 4 / 1) and concentrated under reduced pressure to obtain 0.65 g of compound 9a in a yield of 63%.

[0382] Step 2

[0383] 3-Bromodihydrofuran-2(3H)-one (0.15 g, 0.94 mmol), compound 9a (0.5 g, 0.94 mmol), potassium phosphate (0.6 g, 2.82 mmol), and 50 mL of acetonitrile were added to a reaction flask and reacted at room temperature. TLC monitoring was performed until compound 9a disappeared. After completion of the reaction, the mixture was filtered under reduced pressure and the filtrate was concentrated under reduced pressure. Dichloromethane was added, and the organic phase was washed sequentially with water and saturated brine, and then concentrated under reduced pressure. The crude product was separated and purified by silica gel column chromatography (dichloromethane / acetone = 3 / 1) and concentrated under reduced pressure to obtain 0.18 g of compound 9, with a yield of 32%. 1H NMR (400MHz, d6-DMSO): δ7.40-7.34(m,4H),7.26(d,J=4.4Hz,1H),6.29(d,J=8.0H z,1H),6.10(s,1H),5.55-5.53(m,1H),5.50(s,1H),5.46(s,1H),5.10-4.95(m,2H) ,4.66-4.52(m,2H),4.28-4.18(m,4H),3.98-3.85(m,2H),3.43-3.38(m,1H),2.32- 2.24(m,2H),2.12-1.86(m,7H),1.78-1.71(m,3H),1.64-1.50(m,1H),0.89(m,3H). MS m / z(ESI): 614.33[M+H] +

[0384] Synthesis Example 10

[0385] (2S,6aS,6bR,7S,8aS,8bS,11aR,12aS,12bS)-2,6b-difluoro-7-hydroxy-8b-(2-hydroxyacetyl)-6a,8a-dimethyl-10-(4-(((5-acyltetrahydrofuran-3-yl)oxy)methyl)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]dioxolane-4-one (10)

[0386] 4-((5-Acyltetrahydrofuran-3-oxy)methyl)benzaldehyde

[0387] Sodium hydride (60%) (0.4 g, 10 mmol), 4-hydroxydihydrofuran-2(3H)-one (0.93 g, 9.11 mmol), and 50 mL of anhydrous tetrahydrofuran were added to a reaction flask, cooled to 0°C, and reacted for 30 minutes. 4-(Bromomethyl)benzaldehyde (2.2 g, 11.1 mmol) and tetrabutylammonium iodide (0.3 g, 0.81 mmol) were added, and the mixture was allowed to react at room temperature for 3 hours. After completion of the reaction, water was slowly added, the aqueous phase was extracted with dichloromethane, and the organic phases were combined and concentrated under reduced pressure. The crude product was separated and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 6 / 4) and concentrated under reduced pressure to obtain 1.24 g of 4-((5-acyltetrahydrofuran-3-oxy)methyl)benzaldehyde in a yield of 62%. MS m / z (ESI): 221.10 [M+H] +

[0388] (6α,9α,11β,16α)-6,9-difluoro-11,16,17,21-tetrahydroxy-pregna-1,4-diene-3,20-dione (0.5 g, 1.21 mmol), 4-((5-acyltetrahydrofuran-3-oxy)methyl)benzaldehyde (0.32 g, 1.45 mmol), and 30 mL of acetonitrile were added to a reaction flask. Perchloric acid (0.3 mL, 3.64 mmol) was slowly added dropwise. The reaction was allowed to proceed at room temperature. TLC monitoring was performed until the (6α,9α,11β,16α)-6,9-difluoro-11,16,17,21-tetrahydroxy-pregna-1,4-diene-3,20-dione was removed. After completion of the reaction, the mixture was concentrated under reduced pressure. Water and dichloromethane were added, and the separated liquids were extracted. The organic phases were combined, washed with saturated brine, and concentrated under reduced pressure. The crude product was separated and purified by silica gel column chromatography (dichloromethane / acetone = 4 / 1) and concentrated under reduced pressure to obtain 0.36 g of compound 10. Yield: 48%. 1 H NMR (400MHz, d6-DMSO): δ7.39-7.35(m,4H),7.27(d,J=4.4Hz,1H),6.30(d,J=8.0Hz,1H ),6.15(s,1H),5.60-5.56(m,1H),5.52(s,2H),5.48(s,1H),4.98-4.85(m,2H),4.78-4. 66(m,2H),4.53-4.47(m,3H),4.18-4.10(m,1H),3.95-3.88(m,2H),2.66-2.56(m,2H),2 .22-2.10(m,2H),2.01-1.92(m,2H),1.88-1.75(m,3H),1.69-1.53(m,3H),0.90(s,3H). MS m / z(ESI): 615.34[M+H] +

[0389] Synthesis Example 11

[0390] (2S,6aS,6bR,7S,8aS,8bS,11aR,12aS,12bS)-2,6b-difluoro-7-hydroxy-8b-(2-hydroxyacetyl)-6a,8a-dimethyl-10-(4-(((5-acyltetrahydrofuran-3-yl)mercapto)methyl)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]dioxolane-4-one (11)

[0391] 4-((5-Acyltetrahydrofuran-3-mercapto)methyl)benzaldehyde

[0392] first step

[0393] Furan-2(5H)-one (5g, 60mmol), thioacetic acid (4.5g, 60mmol), and 100mL of dichloromethane were added to a reaction flask, followed by triethylamine (0.8mL, 6mmol). The mixture was allowed to react at room temperature for 20 hours. After completion of the reaction, the organic phase was washed sequentially with water and saturated brine, and concentrated under reduced pressure to obtain 8.2g of S-(5-acyltetrahydrofuran-3-yl)thioacetate in an 85% yield.

[0394] Step 2

[0395] S-(5-Acyltetrahydrofuran-3-yl)thioacetate (8g, 0.05mol), hydrazine hydrate (80%) (3.73mL, 0.06mol), and 150mL of acetonitrile were added to a reaction flask and allowed to react at room temperature for 4 hours. After completion of the reaction, the reaction solution was concentrated under reduced pressure, and dichloromethane was added. The organic phases were combined and concentrated under reduced pressure. The crude product was separated and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 2 / 1) to obtain 3.84g of 4-mercaptodihydrofuran-2(3H)-one, with a yield of 65%.

[0396] Step 3

[0397] 4-Mercaptodihydrofuran-2(3H)-one (3.5 g, 0.03 mol), 4-(bromomethyl)benzaldehyde (6.7 g, 0.033 mol), potassium carbonate (4.8 g, 0.035 mol), and 60 mL of N,N-dimethylformamide were added to a reaction flask and allowed to react at room temperature for 6 hours. After completion of the reaction, water and dichloromethane were added, the separated liquids were extracted, and the organic phase was washed sequentially with water and saturated brine, and concentrated under reduced pressure. The crude product was separated and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 4 / 1) and concentrated under reduced pressure to obtain 5 g of 4-((5-acyltetrahydrofuran-3-mercapto)methyl)benzaldehyde in a yield of 71%. MS m / z (ESI): 237.11 [M+H] +

[0398] (6α,9α,11β,16α)-6,9-difluoro-11,16,17,21-tetrahydroxy-pregna-1,4-diene-3,20-dione (0.5 g, 1.21 mmol), 4-((5-acyltetrahydrofuran-3-mercapto)methyl)benzaldehyde (0.34 g, 1.45 mmol), and 30 mL of acetonitrile were added to a reaction flask. Perchloric acid (0.3 mL, 3.64 mmol) was slowly added dropwise. The reaction was allowed to proceed at room temperature. TLC monitoring was performed until the (6α,9α,11β,16α)-6,9-difluoro-11,16,17,21-tetrahydroxy-pregna-1,4-diene-3,20-dione was absent. After completion of the reaction, the mixture was concentrated under reduced pressure, and water and dichloromethane were added. The separated liquids were extracted and the organic phases were combined, washed with saturated brine, and concentrated under reduced pressure. The crude product was separated and purified by silica gel column chromatography (dichloromethane / acetone = 4 / 1) and concentrated under reduced pressure to obtain 0.47 g of compound 11. Yield: 62%. 1 H NMR (400MHz, d6-DMSO): δ7.43-7.36(m,4H),7.26(d,J=4.4Hz,1H),6.29(d,J=8.0Hz,1 H),6.10(s,1H),5.49-5.45(m,1H),5.42(s,1H),5.40(s,1H),5.08-4.93(m,2H),4.77- 4.69(m,2H),4.20-3.98(m,3H),3.75(s,2H),3.22(m,1H),2.75-2.52(m,2H),2.21-2. 03(m,4H),2.01-1.88(m,2H),1.72-1.68(m,4H),1.58-1.43(m,1H),0.87-0.86(m,3H). MS m / z(ESI): 631.21[M+H] +

[0399] Synthesis Example 12

[0400] (2S,6aS,6bR,7S,8aS,8bS,11aR,12aS,12bS)-2,6b-difluoro-10-(2-fluoro-4-(((5-acyltetrahydrofuran-3-yl)amino)methyl)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]dioxolane-4-one (12)

[0401] first step

[0402] (6α,9α,11β,16α)-6,9-difluoro-11,16,17,21-tetrahydroxy-pregna-1,4-diene-3,20-dione (0.8 g, 1.94 mol), tert-butyl (3-fluoro-4-formylbenzyl) carbamate (0.74 g, 2.91 mmol), and 30 mL of acetonitrile were added to a reaction flask. Perchloric acid (0.5 mL, 5.82 mmol) was slowly added dropwise. The reaction was allowed to proceed at room temperature. TLC monitoring was performed until the (6α,9α,11β,16α)-6,9-difluoro-11,16,17,21-tetrahydroxy-pregna-1,4-diene-3,20-dione was absent. After completion of the reaction, the mixture was concentrated under reduced pressure, and water and dichloromethane were added. The separated liquids were extracted and the organic phases were combined, washed with saturated brine, and concentrated under reduced pressure. The crude product was separated and purified by silica gel column chromatography (dichloromethane / acetone = 4 / 1) to obtain 0.65 g of compound 12a, yield: 61%.

[0403] Step 2

[0404] Furan-2(5H)-one (0.12 g, 1.42 mmol), compound 12a (0.5 g, 0.94 mmol), and 30 mL of methanol were added to a reaction flask and reacted at room temperature. TLC monitoring was performed until compound 12a disappeared. After completion of the reaction, the product was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (dichloromethane / acetone = 3 / 1) to obtain 0.21 g of compound 12, in a yield of 35%. 1 H NMR (400MHz, d6-DMSO): δ7.42-7.34(m,3H),7.27(d,J=4.4Hz,1H),6.28(d,J=8.0H z,1H),6.12(s,1H),5.54-5.52(m,1H),5.48(s,1H),5.45(s,1H),5.02-4.99(m,2H) ,4.65-4.50(m,2H),4.25-4.16(m,3H),3.82-3.77(m,2H),3.23-3.18(m,1H),2.50- 2.25(m,3H),2.10-1.83(m,7H),1.78-1.68(m,3H),1.62-1.50(m,1H),0.92(m,3H). MS m / z(ESI): 632.33[M+H] +

[0405] Synthesis Example 13

[0406] (2S,6aS,6bR,7S,8aS,8bS,11aR,12aS,12bS)-2,6b-difluoro-7-hydroxy-8b-(2-hydroxyacetyl)-6a,8a-dimethyl-10-(4-((5-acyltetrahydrofuran-3-yl)methoxy)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]dioxolane-4-one (13)

[0407] 4-((2-Acyltetrahydrofuran-3-yl)methoxy)benzaldehyde

[0408] 3-(Bromomethyl)dihydrofuran-2(3H)-one (7.88 g, 0.044 mol), 4-hydroxybenzaldehyde (5 g, 0.04 mol), potassium carbonate (6.9 g, 0.05 mol), and 150 mL of acetonitrile were added to a reaction flask and reacted at room temperature for 6 hours. After the reaction was completed, water and dichloromethane were added, the liquid was extracted, and the organic phase was washed with water and saturated brine in sequence and concentrated under reduced pressure. The crude product was separated and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 4 / 1) to obtain 4 g of 4-((2-acyltetrahydrofuran-3-yl)methoxy)benzaldehyde in a yield of 45%. MS m / z (ESI): 221.10 [M+H] +

[0409] (6α,9α,11β,16α)-6,9-difluoro-11,16,17,21-tetrahydroxy-pregna-1,4-diene-3,20-dione (0.5 g, 1.21 mmol), compound (0.32 g, 1.45 mmol), and 30 mL of acetonitrile were added to a reaction flask. Perchloric acid (0.3 mL, 3.64 mmol) was slowly added dropwise. The reaction was allowed to proceed at room temperature. TLC monitoring was performed until the (6α,9α,11β,16α)-6,9-difluoro-11,16,17,21-tetrahydroxy-pregna-1,4-diene-3,20-dione was absent. After completion of the reaction, the mixture was concentrated under reduced pressure, and water and dichloromethane were added. The separated liquids were extracted and the organic phases were combined, washed with saturated brine, and concentrated under reduced pressure. The crude product was separated and purified by silica gel column chromatography (dichloromethane / acetone = 4 / 1) and concentrated under reduced pressure to obtain 0.45 g of compound 13. Yield: 60%. 1H NMR (400MHz, d6-DMSO): δ7.43(m,2H),7.07(d,J=4.4Hz,1H),6.89(m,2H),6.40(d,J=8.0 Hz,1H),6.33(s,1H),5.79-5.75(m,1H),5.22(s,1H),5.15(s,1H),4.92-4.85(m,2H),4. 56-4.44(m,2H),4.27-3.96(m,3H),3.77-3,69(m,2H),2.60(m,1H),2.37-2.12(m,2H),2 .02-1.92(m,4H),1.90-1.78(m,3H),1.74-1.58(m,3H),1.55-1.48(m,1H),0.91(s,3H). MS m / z (ESI): 615.35[M+H] +

[0410] Synthesis Example 14

[0411] (2S,6aS,6bR,7S,8aS,8bS,11aR,12aS,12bS)-2,6b-difluoro-7-hydroxy-8b-(2-hydroxyacetyl)-6a,8a-dimethyl-10-(4-(((5-acyltetrahydrofuran-3-yl)methyl)mercapto)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]dioxolane-4-one (14)

[0412] 4-(((2-Acyltetrahydrofuran-3-yl)methyl)mercapto)benzaldehyde

[0413] first step

[0414] 4-Hydroxybenzaldehyde (5 g, 40.94 mmol), 1,4-diazabicyclo[2.2.2]octane (9.2 g, 81.88 mmol), and 50 mL of N,N-dimethylformamide were added to a reaction flask. N,N-dimethylthiocarbamoyl chloride (10.1 g, 81.88 mmol) was slowly added and allowed to react at room temperature for 12 hours. After completion of the reaction, the reaction mixture was poured into ice water and stirred for 30 minutes. Filter under reduced pressure, wash the filter cake with water, and dry it to obtain 5.2 g of O-(4-formylphenyl)dimethylthiocarbamate, with a yield of 60.6%.

[0415] Step 2

[0416] O-(4-Formylphenyl)dimethylthiocarbamate (5 g, 23.9 mmol) was added to a reaction flask and heated to 200°C for 3 hours. After completion of the reaction, the crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 3 / 1) to obtain 4.2 g of S-(4-formylphenyl)dimethylthiocarbamate in an 84% yield.

[0417] Step 3

[0418] S-(4-Formylphenyl)dimethylthiocarbamate (2 g, 9.6 mmol), potassium hydroxide (5 g, 89.1 mmol), and 60 mL of methanol were added to a reaction flask, heated to reflux, and reacted for 3 hours. After completion of the reaction, the mixture was concentrated under reduced pressure, and hydrochloric acid solution was added to adjust the pH to 6-7. Ethyl acetate was added, and the liquids were separated and extracted. The organic phases were combined and concentrated under reduced pressure. The crude product was separated and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 3 / 1) to obtain 1.1 g of 4-mercaptobenzaldehyde in a yield of 83.3%.

[0419] Step 4

[0420] 3-(Bromomethyl)dihydrofuran-2(3H)-one (1.43 g, 8 mmol), 4-mercaptobenzaldehyde (1 g, 7.24 mmol), potassium carbonate (1.2 g, 8.69 mmol), and 60 mL of acetonitrile were added to a reaction flask and allowed to react at room temperature for 6 hours. After completion of the reaction, water and dichloromethane were added, the separated liquids were extracted, and the organic phase was washed sequentially with water and saturated brine, and concentrated under reduced pressure. The crude product was separated and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 4 / 1) to obtain 1.1 g of 4-(((2-acyltetrahydrofuran-3-yl)methyl)mercapto)benzaldehyde in a yield of 65%. MS m / z (ESI): 237.10 [M+H] +

[0421] (6α,9α,11β,16α)-6,9-difluoro-11,16,17,21-tetrahydroxy-pregna-1,4-diene-3,20-dione (0.5 g, 1.21 mmol), 4-(((2-acyltetrahydrofuran-3-yl)methyl)mercapto)benzaldehyde (0.34 g, 1.45 mmol), and 30 mL of acetonitrile were added to a reaction flask. Perchloric acid (0.3 mL, 3.64 mmol) was slowly added dropwise. The reaction was allowed to proceed at room temperature. TLC monitoring was performed until the (6α,9α,11β,16α)-6,9-difluoro-11,16,17,21-tetrahydroxy-pregna-1,4-diene-3,20-dione was absent. After completion of the reaction, the mixture was concentrated under reduced pressure, and water and dichloromethane were added. The separated liquids were extracted and the organic phases were combined, washed with saturated brine, and concentrated under reduced pressure. The crude product was separated and purified by silica gel column chromatography (dichloromethane / acetone = 4 / 1) and concentrated under reduced pressure to obtain 0.49 g of compound 14. Yield: 64%. 1 H NMR (400MHz, d6-DMSO): δ7.33-7.31(m,4H),7.06(m,1H),6.40(m,1H),6.33 (s,1H),5.79-5.75(m,1H),5.25(s,1H),5.17(s,1H),4.85-4.69(m,2H),4. 47-4.22(m,2H),4.07-3.83(m,3H),2.84-2.53(s,2H),2.40-2.12(m,3H),2 .01-1.76(m,6H),1.62-1.58(m,1H),1.55-1.43(m,4H),0.87-0.86(m,3H). MS m / z(ESI):631.31[M+H] +

[0422] Synthesis Example 15

[0423] (2S,6aS,6bR,7S,8aS,8bS,11aR,12aS,12bS)-2,6b-difluoro-7-hydroxy-8b-(2-hydroxyacetyl)-6a,8a-dimethyl-10-(4-(((5-acyltetrahydrofuran-3-yl)methyl)amino)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]dioxolane-4-one (15)

[0424] 4-(((2-Acyltetrahydrofuran-3-yl)methyl)amino)benzaldehyde

[0425] 4-Aminobenzaldehyde (5 g, 0.04 mol), 3-methylenedihydrofuran-2(3H)-one (5 g, 0.05 mol), lithium tetrafluoroborate (0.75 g, 8 mmol), and 60 mL of methanol were added to a reaction flask, heated to reflux, and reacted for 12 hours. After completion of the reaction, the mixture was concentrated under reduced pressure, and water and dichloromethane were added. The separated liquids were extracted, and the organic phases were combined, washed with saturated brine, and concentrated under reduced pressure. The crude product was separated and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 4 / 1) and concentrated under reduced pressure to obtain 2.8 g of 4-(((2-acyltetrahydrofuran-3-yl)methyl)amino)benzaldehyde, with a yield of 32%. MS m / z (ESI): 220.11 [M+H] +

[0426] (6α,9α,11β,16α)-6,9-difluoro-11,16,17,21-tetrahydroxy-pregna-1,4-diene-3,20-dione (0.5 g, 1.21 mmol), 4-(((2-acyltetrahydrofuran-3-yl)methyl)amino)benzaldehyde (0.32 g, 1.45 mmol), and 30 mL of acetonitrile were added to a reaction flask. Perchloric acid (0.3 mL, 3.64 mmol) was slowly added dropwise. The reaction was allowed to proceed at room temperature. TLC monitoring was performed until the (6α,9α,11β,16α)-6,9-difluoro-11,16,17,21-tetrahydroxy-pregna-1,4-diene-3,20-dione was absent. After completion of the reaction, the mixture was concentrated under reduced pressure, and water and dichloromethane were added. The separated liquids were extracted and the organic phases were combined, washed with saturated brine, and concentrated under reduced pressure. The crude product was separated and purified by silica gel column chromatography (dichloromethane / acetone = 4 / 1) to obtain 0.36 g of compound 15, with a yield of 48%. 1 H NMR (400MHz, d6-DMSO): δ7.33(m,2H),7.30(s,1H),7.03(m,1H),6.45(m,2H),6.4 0(m,1H),6.30(s,1H),5.57-5.54(m,1H),5.22(s,1H),5.14(s,1H),4.88-4.72(m, 2H),4.66-4.12(m,5H),3.22-3.10(m,2H),2.47(m,2H),2.22(m,1H),2.02-1.88(m ,4H),1.85-1.73(m,3H),1.70-1.62(m,3H),1.58-1.49(m,1H),0.89-0.87(m,3H). MS m / z(ESI): 614.32[M+H] +

[0427] Synthesis Example 16

[0428] (6aS,6bR,7S,8aS,8bS,11aR,12aS,12bS)-6b-fluoro-7-hydroxy-8b-(2-hydroxyacetyl)-6a,8a-dimethyl-10-(4-(((2-acyltetrahydrofuran-3-yl)oxy)methyl)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]dioxolane-4-one (16)

[0429] 4-((2-Acyltetrahydrofuran-3-oxy)methyl)benzaldehyde

[0430] Sodium hydride (60%) (0.54 g, 13.5 mmol), 3-hydroxydihydrofuran-2(3H)-one (1.25 g, 12.3 mmol), and 50 mL of anhydrous tetrahydrofuran were added to a reaction flask, cooled to 0°C, and reacted for 30 minutes. 4-(Bromomethyl)benzaldehyde (3 g, 15.3 mmol) and tetrabutylammonium iodide (0.45 g, 1.2 mmol) were added, and the reaction was allowed to proceed at room temperature for 3 hours. After completion of the reaction, water was slowly added, the aqueous phase was extracted with dichloromethane, and the organic phases were combined and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 6 / 4) and concentrated under reduced pressure to obtain 1.5 g of 4-((2-acyltetrahydrofuran-3-oxy)methyl)benzaldehyde in a yield of 55.3%. MS m / z (ESI): 221.18 [M+H] +

[0431] (9α,11β,16α)-9-fluoro-11,16,17,21-tetrahydroxy-pregna-1,4-diene-3,20-dione (0.5 g, 1.27 mmol), 4-((2-acyltetrahydrofuran-3-oxy)methyl)benzaldehyde (0.33 g, 1.52 mmol), and 30 mL of acetonitrile were added to a reaction flask. Perchloric acid (0.32 mL, 3.8 mmol) was slowly added dropwise. The reaction was allowed to proceed at room temperature. TLC monitoring was performed until the (9α,11β,16α)-9-fluoro-11,16,17,21-tetrahydroxy-pregna-1,4-diene-3,20-dione was removed. After completion of the reaction, the mixture was concentrated under reduced pressure. Water and dichloromethane were added, and the separated liquids were extracted. The organic phases were combined, washed with saturated brine, and concentrated under reduced pressure. The crude product was separated and purified by silica gel column chromatography (dichloromethane / acetone = 4 / 1) and concentrated under reduced pressure to obtain 0.42 g of compound 16. Yield: 55%. 1H NMR (400MHz, d6-DMSO): δ7.45-7.21(m,4H),7.25(m 1H),6.25-6.22(m,1H),6.05(s,1H),5.48-5.43(m,1H),5.12-5.09(m,1H),4.95-4.93(m,1H),4.69(m,2H),4.63(m,2H),4.35-4.2 5(m,3H),4.14-4.10(m,2H),2.42-2.11(m,4H),2.08-1.72(m,6H),1.65(m,1H),1.55-1.40(m,3H),1.38-1.33(m,1H),0.87(m,3H). MS m / z(ESI):597.35[M+H] +

[0432] Synthesis Example 17

[0433] (6aS,6bR,7S,8aS,8bS,11aR,12aS,12bS)-6b-fluoro-7-hydroxy-8b-(2-hydroxyacetyl)-6a,8a-dimethyl-10-(4-(((2-acyltetrahydrofuran-3-yl)mercapto)methyl)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]dioxolane-4-one (17)

[0434] (9α,11β,16α)-9-fluoro-11,16,17,21-tetrahydroxy-pregna-1,4-diene-3,20-dione (0.5 g, 1.27 mmol), 4-((2-acyltetrahydrofuran-3-mercapto)methyl)benzaldehyde (0.36 g, 1.52 mmol), and 30 mL of acetonitrile were added to a reaction flask. Perchloric acid (0.32 mL, 3.8 mmol) was slowly added dropwise. The reaction was allowed to proceed at room temperature. TLC monitoring was performed until the (9α,11β,16α)-9-fluoro-11,16,17,21-tetrahydroxy-pregna-1,4-diene-3,20-dione was absent. After completion of the reaction, the mixture was concentrated under reduced pressure, and water and dichloromethane were added. The separated liquids were extracted and the organic phases were combined, washed with saturated brine, and concentrated under reduced pressure. The crude product was separated and purified by silica gel column chromatography (dichloromethane / acetone = 4 / 1) and concentrated under reduced pressure to obtain 0.45 g of compound 17. Yield: 58%. 1H NMR (400MHz, d6-DMSO): δ7.41-7.35(m,4H),7.28(d,J=10.0Hz,1H),6.24-6.21(m,1H),6.02(s,1H ),5.47-5.43(m,2H),5.10-5.07(m,1H),4.94-4.93(m,1H),4.55-4.48(m,1H),4.17-4.16(m,4H),4 .03-3.84(m,2H),3.56-3.53(m,1H),2.65-2.56(m,2H),2.50-2.49(m,1H),2.34-2.32(m,1H),2.1 8-1.96(m,3H),1.83(m,1H),1.69-1.64(m,3H),1.49-1.40(m,3H),1.37-1.36(m,1H),0.86(m,3H). MS m / z(ESI): 613.32[M+H] +

[0435] Synthesis Example 18

[0436] (6aS,6bR,7S,8aS,8bS,11aR,12aS,12bS)-6b-fluoro-7-hydroxy-8b-(2-hydroxyacetyl)-6a,8a-dimethyl-10-(4-(((2-acyltetrahydrofuran-3-yl)amino)methyl)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]dioxolane-4-one (18)

[0437] first step

[0438] (9α,11β,16α)-9-fluoro-11,16,17,21-tetrahydroxy-pregna-1,4-diene-3,20-dione (0.8 g, 2.03 mmol), tert-butyl (4-formylbenzyl) carbamate (0.72 g, 3.04 mmol), and 30 mL of acetonitrile were added to a reaction flask. Perchloric acid (0.5 mL, 6.08 mmol) was slowly added dropwise. The reaction was allowed to proceed at room temperature. TLC monitoring was performed until the (9α,11β,16α)-9-fluoro-11,16,17,21-tetrahydroxy-pregna-1,4-diene-3,20-dione was eliminated. After completion of the reaction, the mixture was concentrated under reduced pressure, and water and dichloromethane were added. The separated liquids were extracted and the organic phases were combined, washed with saturated brine, and concentrated under reduced pressure. The crude product was separated and purified by silica gel column chromatography (dichloromethane / acetone = 4 / 1) and concentrated under reduced pressure to obtain 0.6 g of compound 18a in a yield of 58%.

[0439] Step 2

[0440] 3-Bromodihydrofuran-2(3H)-one (0.15 g, 0.94 mmol), compound 18a (0.48 g, 0.94 mmol), potassium phosphate (0.6 g, 2.82 mmol), and 50 mL of acetonitrile were added to a reaction flask and reacted at room temperature. TLC monitoring was performed until compound 18a disappeared. After completion of the reaction, the mixture was filtered under reduced pressure and the filtrate was concentrated under reduced pressure. Dichloromethane was added, and the organic phase was washed sequentially with water and saturated brine, and then concentrated under reduced pressure. The crude product was separated and purified by silica gel column chromatography (dichloromethane / acetone = 3 / 1) and concentrated under reduced pressure to obtain 0.14 g of compound 18, with a yield of 25%. 1 H NMR (400MHz, d6-DMSO): δ7.45-7.27(m,4H),7.23(m 1H),6.30-6.25(m,1H),6.10(s,1H),5.50-5.48(m,1H),5.15-5.10(m,1H),4.98-4.95(m,1H),4.72(m,2H),4 .23(m,1H),4.17-4.05(m,4H),3.82(m,2H),3.52(m,1H),2.32-2.11(m,4H),2.06-1.72(m,6H),1.70(m,1H), 1.65-1.56(m,3H),1.45-1.38(m,1H),0.95(m,3H). MS m / z(ESI): 596.37[M+H] +

[0441] Synthesis Example 19

[0442] (6aS,6bR,7S,8aS,8bS,11aR,12aS,12bS)-6b-fluoro-7-hydroxy-8b-(2-hydroxyacetyl)-6a,8a-dimethyl-10-(4-(((5-acyltetrahydrofuran-3-yl)oxy)methyl)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]dioxolane-4-one (19)

[0443] (9α,11β,16α)-9-fluoro-11,16,17,21-tetrahydroxy-pregna-1,4-diene-3,20-dione (0.5 g, 1.27 mmol), 4-((5-acyltetrahydrofuran-3-oxy)methyl)benzaldehyde (0.33 g, 1.52 mmol), and 30 mL of acetonitrile were added to a reaction flask. Perchloric acid (0.32 mL, 3.8 mmol) was slowly added dropwise. The reaction was allowed to proceed at room temperature. TLC monitoring was performed until the (9α,11β,16α)-9-fluoro-11,16,17,21-tetrahydroxy-pregna-1,4-diene-3,20-dione was absent. After completion of the reaction, the mixture was concentrated under reduced pressure, and water and dichloromethane were added. The separated liquids were extracted and the organic phases were combined, washed with saturated brine, and concentrated under reduced pressure. The crude product was separated and purified by silica gel column chromatography (dichloromethane / acetone = 4 / 1) and concentrated under reduced pressure to obtain 0.46 g of compound 19. Yield: 61%. 1 H NMR (400MHz, d6-DMSO): δ7.44-7.21(m,4H),7.27(m 1H),6.27-6.25(m,1H),6.07(s,1H),5.50-5.45(m,1H),5.11-5.08(m,1H),4.95-4.93(m,1H),4.69(m,2H),4.63(m,2H),4.55-4.3 0(m,3H),4.14-3.95(m,2H),2.56-2.32(m,4H),2.05-1.72(m,6H),1.69(m,1H),1.60-1.53(m,3H),1.47-1.39(m,1H),092(m,3H). MS m / z(ESI):597.33[M+H] +

[0444] Synthesis Example 20

[0445] (6aS,6bR,7S,8aS,8bS,11aR,12aS,12bS)-10-(2-chloro-4-(((5-acyltetrahydrofuran-3-yl)mercapto)methyl)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]dioxolane-4-one (20)

[0446] 2-Chloro-4-((5-acyltethrahydrofuran-3-mercapto)methyl)benzaldehyde

[0447] 4-Mercaptodihydrofuran-2(3H)-one (3.5 g, 0.03 mol), 4-(bromomethyl)-2-chlorobenzaldehyde (7.7 g, 0.033 mol), potassium carbonate (4.8 g, 0.035 mol), and 60 mL of N,N-dimethylformamide were added to a reaction flask and allowed to react at room temperature for 6 hours. After completion of the reaction, water and dichloromethane were added, the separated liquids were extracted, and the organic phase was washed sequentially with water and saturated brine, and concentrated under reduced pressure. The crude product was separated and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 4 / 1) and concentrated under reduced pressure to obtain 5.3 g of 2-chloro-4-((5-acyltethrahydrofuran-3-mercapto)methyl)benzaldehyde, with a yield of 65%. MS m / z (ESI): 271.08 [M+H] +

[0448] (9α,11β,16α)-9-fluoro-11,16,17,21-tetrahydroxy-pregna-1,4-diene-3,20-dione (0.5 g, 1.27 mmol), 2-chloro-4-((5-acyltetrahydrofuran-3-mercapto)methyl)benzaldehyde (0.41 g, 1.52 mmol), and 30 mL of acetonitrile were added to a reaction flask. Perchloric acid (0.32 mL, 3.8 mmol) was slowly added dropwise. The reaction was allowed to proceed at room temperature. TLC monitoring was performed until the (9α,11β,16α)-9-fluoro-11,16,17,21-tetrahydroxy-pregna-1,4-diene-3,20-dione was removed. After completion of the reaction, the mixture was concentrated under reduced pressure. Water and dichloromethane were added, and the separated layers were extracted. The organic phases were combined, washed with saturated brine, and concentrated under reduced pressure. The crude product was separated and purified by silica gel column chromatography (dichloromethane / acetone = 4 / 1) and concentrated under reduced pressure to obtain 0.47 g of compound 20. Yield: 57%. 1 H NMR (400MHz, d6-DMSO): δ7.44-7.37(m,3H),7.26(m,1H),6.30-6.27(m,1H),6.05(s,1H),5. 50-5.47(m,1H),5.12-5.09(m,1H),4.95-4.93(m,1H),4.75-4.50(m,2H),4.48-4.41(m,2H), 4.32-4.14(m,2H),3.70(s,2H),3.14(m,1H),2.75-2.52(m,2H),2.42-2.32(m,2H),2.19-1.9 6(m,2H),1.85(m,2H),1.70-1.66(m,3H),1.52-1.44(m,3H),1.39-1.37(m,1H),0.87(m,3H). MS m / z(ESI): 647.22[M+H] +

[0449] Synthesis Example 21

[0450] (6aS,6bR,7S,8aS,8bS,11aR,12aS,12bS)-6b-fluoro-7-hydroxy-8b-(2-hydroxyacetyl)-6a,8a-dimethyl-10-(4-(((5-acyltetrahydrofuran-3-yl)amino)methyl)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]dioxolane-4-one (21)

[0451] first step

[0452] (9α,11β,16α)-9-fluoro-11,16,17,21-tetrahydroxy-pregna-1,4-diene-3,20-dione (0.8 g, 2.03 mmol), tert-butyl (4-formylbenzyl) carbamate (0.72 g, 3.04 mmol), and 30 mL of acetonitrile were added to a reaction flask. Perchloric acid (0.5 mL, 6.08 mmol) was slowly added dropwise. The reaction was allowed to proceed at room temperature. TLC monitoring was performed until the (9α,11β,16α)-9-fluoro-11,16,17,21-tetrahydroxy-pregna-1,4-diene-3,20-dione was eliminated. After completion of the reaction, the mixture was concentrated under reduced pressure, and water and dichloromethane were added. The separated liquids were extracted and the organic phases were combined, washed with saturated brine, and concentrated under reduced pressure. The crude product was separated and purified by silica gel column chromatography (dichloromethane / acetone = 4 / 1) and concentrated under reduced pressure to obtain 0.64 g of compound 21a in a yield of 62%.

[0453] Step 2

[0454] Furan-2(5H)-one (0.12 g, 1.42 mmol), compound 21a (0.48 g, 0.94 mmol), and 30 mL of methanol were added to a reaction flask and reacted at room temperature. TLC monitoring was performed until compound 21a disappeared. After completion of the reaction, the mixture was concentrated under reduced pressure. The crude product was separated and purified by silica gel column chromatography (dichloromethane / acetone = 3 / 1) and concentrated under reduced pressure to obtain 0.20 g of compound 21, a yield of 35%. 1H NMR (400MHz, d6-DMSO): δ7.43-7.27(m,4H),7.22(m 1H),6.32-6.25(m,2H),6.12(s,1H),5.51-5.49(m,1H),5.15-5.12(m,1H),4.98-4.96(m,1H),4.75(m,2H),4.50-4.35(m,2H),4.32-4.15 (m,2H),3.85(m,2H),3.23(m,1H),2.52-2.22(m,4H),2.06-1.75(m,6H),1.68(m,1H),1.63-1.54(m,3H),1.48-1.40(m,1H),0.98(m,3H). MS m / z(ESI): 596.32[M+H] +

[0455] Synthesis Example 22

[0456] (6aS,6bR,7S,8aS,8bS,11aR,12aS,12bS)-6b-chloro-7-hydroxy-8b-(2-hydroxyacetyl)-6a,8a-dimethyl-10-(4-(((2-acyltetrahydrofuran-3-yl)oxy)methyl)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]dioxolane-4-one (22)

[0457] (9α,11β,16α)-9-chloro-11,16,17,21-tetrahydroxy-pregna-1,4-diene-3,20-dione (0.5 g, 1.22 mmol), 4-((2-acyltetrahydrofuran-3-oxy)methyl)benzaldehyde (0.32 g, 1.46 mmol), and 30 mL of acetonitrile were added to a reaction flask. Perchloric acid (0.31 mL, 3.65 mmol) was slowly added dropwise. The reaction was allowed to proceed at room temperature. TLC monitoring was performed until the (9α,11β,16α)-9-chloro-11,16,17,21-tetrahydroxy-pregna-1,4-diene-3,20-dione was removed. After completion of the reaction, the mixture was concentrated under reduced pressure. Water and dichloromethane were added, and the separated layers were extracted. The organic phases were combined, washed with saturated brine, and concentrated under reduced pressure. The crude product was separated and purified by silica gel column chromatography (dichloromethane / acetone = 4 / 1) and concentrated under reduced pressure to obtain 0.42 g of compound 22. Yield: 56%. 1H NMR (400MHz, d6-DMSO): δ7.48(m,2H),7.38-7.33(m,2H),7.27(m,1H),6.26-6.24(m, 1H),6.01(s,1H),5.60-5.58(m,1H),5.50(s,1H),5.10-5.03(m,1H),4.93-4.92(m,1 H),4.47-4.39(m,2H),4.30-4.26(m,2H),4.21-4.12(m,3H),3.55-3.52(m,1H),2.79 -2.32(m,5H),2.01-1.95(m,2H),1.84-1.79(m,1H),1.78-1.56(m,7H),0.85(s,3H). MS m / z(ESI): 613.25[M+H] +

[0458] Synthesis Example 23

[0459] (6aS,6bR,7S,8aS,8bS,11aR,12aS,12bS)-6b-chloro-7-hydroxy-8b-(2-hydroxyacetyl)-6a,8a-dimethyl-10-(4-(((2-acyltetrahydrofuran-3-yl)mercapto)methyl)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]dioxolane-4-one (23)

[0460] (9α,11β,16α)-9-chloro-11,16,17,21-tetrahydroxy-pregna-1,4-diene-3,20-dione (0.5 g, 1.22 mmol), 4-((2-acyltetrahydrofuran-3-mercapto)methyl)benzaldehyde (0.35 g, 1.46 mmol), and 30 mL of acetonitrile were added to a reaction flask. Perchloric acid (0.31 mL, 3.65 mmol) was slowly added dropwise. The reaction was allowed to proceed at room temperature. TLC monitoring was performed until the (9α,11β,16α)-9-chloro-11,16,17,21-tetrahydroxy-pregna-1,4-diene-3,20-dione was removed. After completion of the reaction, the mixture was concentrated under reduced pressure. Water and dichloromethane were added, and the separated layers were extracted. The organic phases were combined, washed with saturated brine, and concentrated under reduced pressure. The crude product was separated and purified by silica gel column chromatography (dichloromethane / acetone = 4 / 1) and concentrated under reduced pressure to obtain 0.52 g of compound 23. Yield: 68%. 1H NMR (400MHz, d6-DMSO): δ7.46 (d, J = 8.4Hz, 2H), 7.36-7.31 (m, 2H), 7.28 (m, 1H), 6.25-6 .21(m,1H),5.99(s,1H),5.61-5.60(m,1H),5.49(s,1H),5.09-5.01(m,1H),4.93-4.92 (m,1H),4.47-4.39(m,2H),4.28-4.16(m,3H),4.00-3.84(m,2H),3.56-3.53(m,1H),2. 75-2.33(m,5H),2.01-1.96(m,2H),1.81-1.79(m,1H),1.76-1.56(m,7H),0.82(s,3H). MS m / z(ESI): 629.22[M+H] +

[0461] Synthesis Example 24

[0462] (6aS,6bR,7S,8aS,8bS,11aR,12aS,12bS)-6b-chloro-7-hydroxy-8b-(2-hydroxyacetyl)-6a,8a-dimethyl-10-(4-(((2-acyltetrahydrofuran-3-yl)amino)methyl)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]dioxolane-4-one (24)

[0463] first step

[0464] (9α,11β,16α)-9-chloro-11,16,17,21-tetrahydroxy-pregna-1,4-diene-3,20-dione (0.8 g, 1.95 mmol), tert-butyl (4-formylbenzyl) carbamate (0.69 g, 2.92 mmol), and 30 mL of acetonitrile were added to a reaction flask. Perchloric acid (0.5 mL, 5.84 mmol) was slowly added dropwise. The reaction was allowed to proceed at room temperature. TLC monitoring was performed until the (9α,11β,16α)-9-chloro-11,16,17,21-tetrahydroxy-pregna-1,4-diene-3,20-dione was removed. After completion of the reaction, the mixture was concentrated under reduced pressure, and water and dichloromethane were added. The separated liquids were extracted and the organic phases were combined, washed with saturated brine, and concentrated under reduced pressure. The crude product was separated and purified by silica gel column chromatography (dichloromethane / acetone = 4 / 1) and concentrated under reduced pressure to obtain 0.65 g of compound 24a in a yield of 63%.

[0465] Step 2

[0466] 3-Bromodihydrofuran-2(3H)-one (0.15 g, 0.94 mmol), compound 24a (0.5 g, 0.94 mmol), potassium phosphate (0.6 g, 2.82 mmol), and 50 mL of acetonitrile were added to a reaction flask and reacted at room temperature. TLC monitoring was performed until compound 24a disappeared. After completion of the reaction, the mixture was filtered under reduced pressure and the filtrate was concentrated under reduced pressure. Dichloromethane was added, and the organic phase was washed sequentially with water and saturated brine, and then concentrated under reduced pressure. The crude product was separated and purified by silica gel column chromatography (dichloromethane / acetone = 3 / 1) to obtain 0.16 g of compound 24, in a yield of 28%. 1 H NMR (400MHz, d6-DMSO): δ7.45 (d, J = 8.4Hz, 2H), 7.36-7.30 (m, 2H), 7.26 (m, 1H), 6.27-6 .23(m,1H),6.00(s,1H),5.62-5.60(m,1H),5.51(s,1H),5.10-5.03(m,1H),4.92-4.90 (m,1H),4.45-4.39(m,2H),4.28-4.15(m,4H),3.84-3.64(m,2H),3.52-3.48(m,1H),2. 73-2.37(m,5H),2.00-1.96(m,2H),1.82-1.79(m,1H),1.77-1.56(m,7H),0.86(s,3H). MS m / z(ESI): 612.34[M+H] +

[0467] Synthesis Example 25

[0468] (6aS,6bR,7S,8aS,8bS,11aR,12aS,12bS)-6b-chloro-7-hydroxy-8b-(2-hydroxyacetyl)-6a,8a-dimethyl-10-(4-(((5-acyltetrahydrofuran-3-yl)oxy)methyl)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]dioxolane-4-one (25)

[0469] (9α,11β,16α)-9-chloro-11,16,17,21-tetrahydroxy-pregna-1,4-diene-3,20-dione (0.5 g, 1.22 mmol), 4-((5-acyltetrahydrofuran-3-oxy)methyl)benzaldehyde (0.32 g, 1.46 mmol), and 30 mL of acetonitrile were added to a reaction flask. Perchloric acid (0.31 mL, 3.65 mmol) was slowly added dropwise. The reaction was allowed to proceed at room temperature. TLC monitoring was performed until the (9α,11β,16α)-9-chloro-11,16,17,21-tetrahydroxy-pregna-1,4-diene-3,20-dione was removed. After completion of the reaction, the mixture was concentrated under reduced pressure. Water and dichloromethane were added, and the separated liquids were extracted. The organic phases were combined, washed with saturated brine, and concentrated under reduced pressure. The crude product was separated and purified by silica gel column chromatography (dichloromethane / acetone = 4 / 1) and concentrated under reduced pressure to obtain 0.35 g of compound 25. Yield: 47%. 1 H NMR (400MHz, d6-DMSO): δ7.45(m,2H),7.35-7.30(m,2H),7.26(m,1H),6.28-6.2 4(m,1H),6.00(s,1H),5.59-5.57(m,1H),5.52(s,1H),5.15-5.09(m,1H),4.73- 4.55(m,2H),4.52-4.30(m,3H),4.27-4.15(m,2H),4.11-4.05(m,2H),2.56-2.3 1(m,4H),2.01-1.96(m,2H),1.84-1.73(m,5H),1.62-1.43(m,4H),0.87(s,3H). MS m / z(ESI):613.33[M+H] +

[0470] Synthesis Example 26

[0471] (6aS,6bR,7S,8aS,8bS,11aR,12aS,12bS)-6b-chloro-7-hydroxy-8b-(2-hydroxyacetyl)-6a,8a-dimethyl-10-(4-(((5-acyltetrahydrofuran-3-yl)mercapto)methyl)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]dioxolane-4-one (26)

[0472] (9α,11β,16α)-9-chloro-11,16,17,21-tetrahydroxy-pregna-1,4-diene-3,20-dione (0.5 g, 1.22 mmol), 4-((5-acyltetrahydrofuran-3-mercapto)methyl)benzaldehyde (0.35 g, 1.46 mmol), and 30 mL of acetonitrile were added to a reaction flask. Perchloric acid (0.31 mL, 3.65 mmol) was slowly added dropwise. The reaction was allowed to proceed at room temperature. TLC monitoring was performed until the (9α,11β,16α)-9-chloro-11,16,17,21-tetrahydroxy-pregna-1,4-diene-3,20-dione was removed. After completion of the reaction, the mixture was concentrated under reduced pressure. Water and dichloromethane were added, and the separated layers were extracted. The organic phases were combined, washed with saturated brine, and concentrated under reduced pressure. The crude product was separated and purified by silica gel column chromatography (dichloromethane / acetone = 4 / 1) and concentrated under reduced pressure to obtain 0.42 g of compound 26. Yield: 55%. 1 H NMR (400MHz, d6-DMSO): δ7.45 (d, J = 8.4Hz, 2H), 7.36-7.33 (m, 2H), 7.27 (m, 1H), 6.23-6.25 (m, 1H),6.02(s,1H),5.60-5.58(m,1H),5.50(s,1H),5.12-5.05(m,1H),4.72(s,2H),4.70-4.50(m ,2H),4.32-4,21(m,1H),3.85-3.70(m,3H),3.24-3.14(m,1H),2.75-2.50(m,2H),2.42-2.30(m ,2H),1.97-1.72(m,2H),1.70-1.46(m,4H),1.43-1.39(m,4H),1.07-1.04(m,1H),0.89(s,3H). MS m / z(ESI): 629.23[M+H] +

[0473] Synthesis Example 27

[0474] (6aS,6bR,7S,8aS,8bS,11aR,12aS,12bS)-6b-chloro-7-hydroxy-8b-(2-hydroxyacetyl)-6a,8a-dimethyl-10-(4-(((5-acyltetrahydrofuran-3-yl)amino)methyl)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]dioxolane-4-one (27)

[0475] first step

[0476] (9α,11β,16α)-9-chloro-11,16,17,21-tetrahydroxy-pregna-1,4-diene-3,20-dione (0.8 g, 1.95 mmol), tert-butyl (4-formylbenzyl) carbamate (0.69 g, 2.92 mmol), and 30 mL of acetonitrile were added to a reaction flask. Perchloric acid (0.5 mL, 5.84 mmol) was slowly added dropwise. The reaction was allowed to proceed at room temperature. TLC monitoring was performed until the (9α,11β,16α)-9-chloro-11,16,17,21-tetrahydroxy-pregna-1,4-diene-3,20-dione was removed. After completion of the reaction, the mixture was concentrated under reduced pressure, and water and dichloromethane were added. The separated liquids were extracted and the organic phases were combined, washed with saturated brine, and concentrated under reduced pressure. The crude product was separated and purified by silica gel column chromatography (dichloromethane / acetone = 4 / 1) and concentrated under reduced pressure to obtain 0.64 g of compound 27a in a yield of 62%.

[0477] Step 2

[0478] Furan-2(5H)-one (0.12 g, 1.42 mmol), compound 27a (0.5 g, 0.94 mmol), and 30 mL of methanol were added to a reaction flask and reacted at room temperature. TLC monitoring was performed until compound 27a disappeared. After completion of the reaction, the mixture was concentrated under reduced pressure. The crude product was separated and purified by silica gel column chromatography (dichloromethane / acetone = 3 / 1) and concentrated under reduced pressure to obtain 0.2 g of compound 27 in a yield of 34%. 1 H NMR (400MHz, d6-DMSO): δ7.44 (d, J = 8.4Hz, 2H), 7.35-7.30 (m, 2H), 7.28 (m, 1H), 6. 36(m,1H),6.25-6.23(m,1H),6.02(s,1H),5.60-5.58(m,1H),5.51(s,1H),5.10-5 .03(m,1H),4.72-4.70(m,2H),4.47-4.39(m,3H),3.82-3.65(m,3H),3.25(m,1H), 2.53-2.27(m,4H),1.97-1.76(m,2H),1.70-1.45(m,5H),1.43(m,3H),1.04(m,1H), 0.86(s,3H). MS m / z(ESI): 612.35[M+H] +

[0479] Synthesis Example 28

[0480] (6aR,6bS,7S,8aS,8bS,11aR,12aS,12bS)-7-Hydroxy-8b-(2-hydroxyacetyl)-6a,8a-dimethyl-10-(4-(((2-acyltetrahydrofuran-3-yl)oxy)methyl)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]dioxolane-4-one (28)

[0481] (11β,16α)-11,16,17,21-tetrahydroxy-pregna-1,4-diene-3,20-dione (0.5 g, 1.33 mmol), 4-((2-acyltetrahydrofuran-3-oxy)methyl)benzaldehyde (0.35 g, 1.59 mmol), and 30 mL of acetonitrile were added to a reaction flask. Perchloric acid (0.34 mL, 4 mmol) was slowly added dropwise. The reaction was allowed to proceed at room temperature. TLC monitoring was performed until the (11β,16α)-11,16,17,21-tetrahydroxy-pregna-1,4-diene-3,20-dione was absent. After completion of the reaction, the mixture was concentrated under reduced pressure. Water and dichloromethane were added, and the separated liquids were extracted. The organic phases were combined, washed with saturated brine, and concentrated under reduced pressure. The crude product was separated and purified by silica gel column chromatography (dichloromethane / acetone = 4 / 1) and concentrated under reduced pressure to obtain 0.37 g of compound 28. Yield: 48%. 1 H NMR (400MHz, d6-DMSO): δ7.45(m,2H),7.40-7.36(m,2H),7.27(m,1H),6.25(m,1H),6 .02(s,1H),5.58-5.56(m,1H),5.50(s,1H),5.15(m,1H),4.72-4.69(m,2H),4.63(s, 2H),4.35-4.25(m,3H),4.18-4.12(m,1H),3.44-3.42(m,1H),2.42-2.12(m,4H),2.0 0-1.96(m,2H),1.88-1.79(m,4H),1.78-1.56(m,4H),1.38-1.14(m.2H),0.83(s,3H). MS m / z(ESI): 579.34[M+H] +

[0482] Synthesis Example 29

[0483] (6aR,6bS,7S,8aS,8bS,11aR,12aS,12bS)-7-Hydroxy-8b-(2-hydroxyacetyl)-6a,8a-dimethyl-10-(4-(((2-acyltetrahydrofuran-3-yl)mercapto)methyl)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]dioxolane-4-one (29)

[0484] (11β,16α)-11,16,17,21-tetrahydroxy-pregna-1,4-diene-3,20-dione (0.5 g, 1.33 mmol), 4-((2-acyltetrahydrofuran-3-mercapto)methyl)benzaldehyde (0.38 g, 1.59 mmol), and 30 mL of acetonitrile were added to a reaction flask. Perchloric acid (0.34 mL, 4 mmol) was slowly added dropwise. The reaction was allowed to proceed at room temperature. TLC monitoring was performed until the (11β,16α)-11,16,17,21-tetrahydroxy-pregna-1,4-diene-3,20-dione was absent. After completion of the reaction, the mixture was concentrated under reduced pressure. Water and dichloromethane were added, and the separated liquids were extracted. The organic phases were combined, washed with saturated brine, and concentrated under reduced pressure. The crude product was separated and purified by silica gel column chromatography (dichloromethane / acetone = 4 / 1) and concentrated under reduced pressure to obtain 0.4 g of compound 29. Yield: 51%. 1 H NMR (400MHz, d6-DMSO): δ7.45(d,J=8.4Hz,2H),7.36-7.30(m,2H),7.27(m,1H),6.25-6.22(m,1H),6.01(s,1H),5.60-5.59(m,1H),5.52(s,1H),5 .10-5.01(m,1H),4.45-4.24(m,4H),3.56-3.34(m,4H),2.75-2.32(m,4H ),2.01-1.79(m,7H),1.70-1.56(m,4H),1.32-1.04(m,2H),0.85(s,3H). MS m / z(ESI): 595.35[M+H] +

[0485] Synthesis Example 30

[0486] (6aR,6bS,7S,8aS,8bS,11aR,12aS,12bS)-7-Hydroxy-8b-(2-hydroxyacetyl)-6a,8a-dimethyl-10-(4-(((2-acyltetrahydrofuran-3-yl)amino)methyl)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]dioxolane-4-one (30)

[0487] first step

[0488] (11β,16α)-11,16,17,21-tetrahydroxy-pregna-1,4-diene-3,20-dione (0.8 g, 2.13 mmol), tert-butyl (4-formylbenzyl) carbamate (0.75 g, 3.19 mmol), and 30 mL of acetonitrile were added to a reaction flask. Perchloric acid (0.54 mL, 6.38 mmol) was slowly added dropwise. The reaction was allowed to proceed at room temperature. TLC monitoring was performed until the (11β,16α)-11,16,17,21-tetrahydroxy-pregna-1,4-diene-3,20-dione was eliminated. After completion of the reaction, the mixture was concentrated under reduced pressure. Water and dichloromethane were added, and the separated liquids were extracted. The organic phases were combined, washed with saturated brine, and concentrated under reduced pressure. The crude product was separated and purified by silica gel column chromatography (dichloromethane / acetone = 4 / 1) and concentrated under reduced pressure to obtain 0.71 g of compound 30a in a yield of 68%.

[0489] Step 2

[0490] 3-Bromodihydrofuran-2(3H)-one (0.15 g, 0.94 mmol), compound 30a (0.46 g, 0.94 mmol), potassium phosphate (0.6 g, 2.82 mmol), and 50 mL of acetonitrile were added to a reaction flask and reacted at room temperature. TLC monitoring was performed until compound 30a disappeared. After completion of the reaction, the mixture was filtered under reduced pressure and the filtrate was concentrated under reduced pressure. Dichloromethane was added, and the organic phase was washed sequentially with water and saturated brine, and then concentrated under reduced pressure. The crude product was separated and purified by silica gel column chromatography (dichloromethane / acetone = 3 / 1) and concentrated under reduced pressure to obtain 0.19 g of compound 30, a yield of 35%. 1H NMR (400MHz, d6-DMSO): δ7.46 (d, J = 8.4Hz, 2H), 7.36-7.32 (m, 2H), 7.26 (m, 1H), 6.25-6.21 ( m,1H),6.00(s,1H),5.61-5.99(m,1H),5.50(s,1H),5.10-5.02(m,1H),4.75-4.69(m,2H),4 .35-4.21(m,3H),4.16-4.12(m,1H),3.84-3.82(m,2H),3.44-3.43(m,2H),2.43-2.07(m,4H ),2.00-1.97(m,2H),1.82-1.78(m,5H),1.75-1.35(m,3H),1.12-1.04(m,2H),0.86(s,3H). MS m / z(ESI): 578.34[M+H] +

[0491] Synthesis Example 31

[0492] (6aR,6bS,7S,8aS,8bS,11aR,12aS,12bS)-7-Hydroxy-8b-(2-hydroxyacetyl)-6a,8a-dimethyl-10-(4-(((5-acyltetrahydrofuran-3-yl)oxy)methyl)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]dioxolane-4-one (31)

[0493] (11β,16α)-11,16,17,21-tetrahydroxy-pregna-1,4-diene-3,20-dione (0.5 g, 1.33 mmol), 4-((5-acyltetrahydrofuran-3-oxy)methyl)benzaldehyde (0.35 g, 1.59 mmol), and 30 mL of acetonitrile were added to a reaction flask. Perchloric acid (0.34 mL, 4 mmol) was slowly added dropwise. The reaction was allowed to proceed at room temperature. TLC monitoring was performed until the (11β,16α)-11,16,17,21-tetrahydroxy-pregna-1,4-diene-3,20-dione was absent. After completion of the reaction, the mixture was concentrated under reduced pressure. Water and dichloromethane were added, and the separated liquids were extracted. The organic phases were combined, washed with saturated brine, and concentrated under reduced pressure. The crude product was separated and purified by silica gel column chromatography (dichloromethane / acetone = 4 / 1) and concentrated under reduced pressure to obtain 0.48 g of compound 31. Yield: 62%. 1H NMR (400MHz, d6-DMSO): δ7.45(m,2H),7.38-7.36(m,2H),7.26(m,1H),6.27(m,1H),6.00( s,1H),5.60-5.58(m,1H),5.51(s,1H),5.15(m,1H),4.70-4.67(m,2H),4.63-4.60(s,2H) ,4.55-4.30(m,3H),4.14-4.12(m,1H),3.90(m,1H),3.44-3.42(m,1H),2.40-2.11(m,4H) ,2.00-1.95(m,2H),1.89-1.78(m,4H),1.76-1.58(m,3H),1.42-1.16(m.2H),0.86(s,3H). MS m / z(ESI): 579.33[M+H] +

[0494] Synthesis Example 32

[0495] 2-((6aR,6bS,7S,8aS,8bS,11aR,12aS,12bS)-7-hydroxy-8b-(2-hydroxyacetyl)-6a,8a-dimethyl-4-acyl-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]dioxolane-10-yl)-5-(((5-acyltetrahydrofuran-3-yl)mercapto)methyl)benzonitrile (32)

[0496] 2-Formyl-5-((5-acyltethrahydrofuran-3-mercapto)methyl)benzonitrile

[0497] 4-Mercaptodihydrofuran-2(3H)-one (3.5 g, 0.03 mol), 5-(bromomethyl)-2-formylbenzonitrile (7.4 g, 0.033 mol), potassium carbonate (4.8 g, 0.035 mol), and 60 mL of N,N-dimethylformamide were added to a reaction flask and allowed to react at room temperature for 6 hours. After completion of the reaction, water and dichloromethane were added, the separated liquids were extracted, and the organic phase was washed sequentially with water and saturated brine, and concentrated under reduced pressure. The crude product was separated and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 4 / 1) and concentrated under reduced pressure to obtain 4.3 g of 2-formyl-5-((5-acyltethrahydrofuran-3-mercapto)methyl)benzonitrile, in a yield of 55%. MS m / z (ESI): 262.12 [M+H] +

[0498] (11β,16α)-11,16,17,21-tetrahydroxy-pregna-1,4-diene-3,20-dione (0.5 g, 1.33 mmol), 2-formyl-5-((5-acyltethrahydrofuran-3-mercapto)methyl)benzonitrile (0.42 g, 1.59 mmol), and 30 mL of acetonitrile were added to a reaction flask. Perchloric acid (0.34 mL, 4 mmol) was slowly added dropwise. The reaction was allowed to proceed at room temperature. TLC monitoring was performed until the (11β,16α)-11,16,17,21-tetrahydroxy-pregna-1,4-diene-3,20-dione was eliminated. After completion of the reaction, the mixture was concentrated under reduced pressure. Water and dichloromethane were added, and the separated liquids were extracted. The organic phases were combined, washed with saturated brine, and concentrated under reduced pressure. The crude product was separated and purified by silica gel column chromatography (dichloromethane / acetone = 4 / 1) and concentrated under reduced pressure to obtain 0.49 g of compound 32. Yield: 60%. 1 H NMR (400MHz, d6-DMSO): δ7.46(s,1H),7.36-7.32(m,2H),7.27(m,1H),6.25-6. 21(m,1H),6.00(s,1H),5.62-5.60(m,1H),5.53(s,1H),5.10-5.00(m,1H),4.7 5-4.50(m,4H),4.32(m,1H),3.70(s,2H),3.44(m,1H),3.14(s,1H),2.74-2.30 (m,4H),1.98-1.75(m,7H),1.67-1.56(m,3H),1.30-1.05(m,2H),0.87(s,3H). MS m / z(ESI):620.33[M+H] +

[0499] Synthesis Example 33

[0500] (6aR,6bS,7S,8aS,8bS,11aR,12aS,12bS)-7-Hydroxy-8b-(2-hydroxyacetyl)-6a,8a-dimethyl-10-(4-(((5-acyltetrahydrofuran-3-yl)amino)methyl)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]dioxolane-4-one (33)

[0501] first step

[0502] (11β,16α)-11,16,17,21-tetrahydroxy-pregna-1,4-diene-3,20-dione (0.8 g, 2.13 mmol), tert-butyl (4-formylbenzyl) carbamate (0.75 g, 3.19 mmol), and 30 mL of acetonitrile were added to a reaction flask. Perchloric acid (0.54 mL, 6.38 mmol) was slowly added dropwise. The reaction was allowed to proceed at room temperature. TLC monitoring was performed until the (11β,16α)-11,16,17,21-tetrahydroxy-pregna-1,4-diene-3,20-dione was eliminated. After completion of the reaction, the mixture was concentrated under reduced pressure. Water and dichloromethane were added, and the separated liquids were extracted. The organic phases were combined, washed with saturated brine, and concentrated under reduced pressure. The crude product was separated and purified by silica gel column chromatography (dichloromethane / acetone = 4 / 1) and concentrated under reduced pressure to obtain 0.61 g of compound 33a in a yield of 58%.

[0503] Step 2

[0504] Furan-2(5H)-one (0.12 g, 1.42 mmol), compound 33a (0.46 g, 0.94 mmol), and 30 mL of methanol were added to a reaction flask and reacted at room temperature. TLC monitoring was performed until compound 33a disappeared. After completion of the reaction, the mixture was concentrated under reduced pressure. The crude product was separated and purified by silica gel column chromatography (dichloromethane / acetone = 3 / 1) and concentrated under reduced pressure to obtain 0.17 g of compound 33, a yield of 32%. 1 H NMR (400MHz, d6-DMSO): δ7.47(d,J=8.4Hz,2H),7.35-7.32(m,2H),7.28(m,1H),6.36(m,1H) ,6.25-6.22(m,1H),6.02(s,1H),5.60-5.98(m,1H),5.52(s,1H),5.13-5.05(m,1H),4.74-4 .69(m,2H),4.50-4.25(m,3H),4.06-3.98(m,2H),3.44(m,1H),3.23(m,1H),2.43-2.06(m,4 H),1.99-172(m,2H),1.72-1.35(m,4H),1.35-1.15(m,4H),1.07-1.02(m,2H),0.86(s,3H). MS m / z(ESI): 578.33[M+H] +

[0505] Synthesis Example 34

[0506] S-(Fluoromethyl)(2S,6aS,6bR,7S,8aS,8bS,11aR,12aS,12bS)-2,6b-difluoro-7-hydroxy-6a,8a-dimethyl-4-acyl-10-(4-(((2-acyltetrahydrofuran-3-yl)mercapto)methyl)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]dioxolane-8b-carboxylic acid thioester (34)

[0507] Compound 4a (0.5 g, 1 mmol), 4-((2-acyltethrahydrofuran-3-mercapto)methyl)benzaldehyde (0.3 g, 1.23 mmol), and 30 mL of acetonitrile were added to a reaction flask. Perchloric acid (0.26 mL, 3.1 mmol) was slowly added dropwise and allowed to react at room temperature. TLC monitoring was performed until compound 4a disappeared. After completion of the reaction, the mixture was concentrated under reduced pressure. Water and dichloromethane were added, and the separated liquids were extracted. The organic phases were combined, washed with saturated brine, and concentrated under reduced pressure. The crude product was separated and purified by silica gel column chromatography (dichloromethane / acetone = 4 / 1) and concentrated under reduced pressure to obtain 0.31 g of compound 34, a yield of 45%. 1 H NMR (400MHz, d6-DMSO): δ7.43-7.35(m,4H),7.27(d,J=4.4Hz,1H),6.31(d,J=8.0Hz,1H),6.11(s,1H),5.72-5.67(m,1H),5.62-5.58(s,2H),5 .52(s,1H),5.49(s,1H),4.35-4.25(m,4H),3.94-3.91(m,1H),3.70(s ,2H),3.34(m,1H),2.56-2.31(m,2H),2.22-1.29(m,10H),0.89(m,3H). MS m / z(ESI): 665.22[M+H] +

[0508] Synthesis Example 35

[0509] S-(Cyanomethyl)(2S,6aS,6bR,7S,8aS,8bS,11aR,12aS,12bS)-2,6b-difluoro-7-hydroxy-6a,8a-dimethyl-4-acyl-10-(4-(((2-acyltetrahydrofuran-3-yl)mercapto)methyl)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]dioxolane-8b-carboxylic acid thioester (35)

[0510] first step

[0511] Compound 4ac (2 g, 4.4 mmol), sodium sulfite (0.84 g, 6.8 mmol), and 10 mL of N,N-dimethylacetamide were added to a reaction flask. 2-iodoacetonitrile (1.1 g, 6.8 mmol) was slowly added and allowed to react at room temperature. TLC monitoring was performed until compound 4ac disappeared. After completion of the reaction, the reaction mixture was poured into water and stirred for 30 minutes. The mixture was filtered under reduced pressure, the filter cake was dried, and the crude product was purified by silica gel column chromatography (dichloromethane / acetone = 4 / 1) and concentrated under reduced pressure to afford 0.9 g of compound 35a in a 42% yield.

[0512] Step 2

[0513] Compound 35a (0.5 g, 1 mmol), 4-((2-acyltethrahydrofuran-3-mercapto)methyl)benzaldehyde (0.29 g, 1.22 mmol), and 30 mL of acetonitrile were added to a reaction flask. Perchloric acid (0.26 mL, 3 mmol) was slowly added dropwise and allowed to react at room temperature. TLC monitoring was performed until compound 35a disappeared. After completion of the reaction, the mixture was concentrated under reduced pressure. Water and dichloromethane were added, and the separated liquids were extracted. The organic phases were combined, washed with saturated brine, and concentrated under reduced pressure. The crude product was separated and purified by silica gel column chromatography (dichloromethane / acetone = 4 / 1) and concentrated under reduced pressure to obtain 0.38 g of compound 35 (yield: 56%). 1 H NMR (400MHz, d6-DMSO): δ7.44-7.37(m,4H),7.27(d,J=4.4Hz,1H),6.30(d,J=8.0Hz,1H),6.10(s,1H),5.60-5.58(m,1H),5.52(s,1H),5 .50(s,1H),4.37-4.25(m,4H),3.99(s,2H),3.91(m,1H),3.72(s,2H),3.36(m,1H),2.55-2.31(m,2H),2.11-1.24(m,10H),0.87(m,3H). MS m / z(ESI): 672.28[M+H] +

[0514] Synthesis Example 36

[0515] Fluoromethyl (2S,6aS,6bR,7S,8aS,8bS,11aR,12aS,12bS)-2,6b-difluoro-7-hydroxy-6a,8a-dimethyl-4-acyl-10-(4-(((2-acyltetrahydrofuran-3-yl)mercapto)methyl)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]dioxolane-8b-carboxylate (36)

[0516] first step

[0517] Compound 4aa (1.9 g, 4.4 mmol), sodium sulfite (0.84 g, 6.8 mmol), and 10 mL of N,N-dimethylacetamide were added to a reaction flask. Iodofluoromethane (1.1 g, 6.8 mmol) was slowly added and allowed to react at room temperature. TLC monitoring was performed until compound 4aa disappeared. After completion of the reaction, the reaction mixture was poured into water and stirred for 30 minutes. The mixture was filtered under reduced pressure, the filter cake dried, and the crude product was purified by silica gel column chromatography (dichloromethane / acetone = 4 / 1) and concentrated under reduced pressure to afford 0.9 g of compound 36a in a 45% yield.

[0518] Step 2

[0519] Compound 36a (0.5 g, 1 mmol), 4-((2-acyltethrahydrofuran-3-mercapto)methyl)benzaldehyde (0.3 g, 1.28 mmol), and 30 mL of acetonitrile were added to a reaction flask. Perchloric acid (0.27 mL, 3.2 mmol) was slowly added dropwise and allowed to react at room temperature. TLC monitoring was performed until compound 36a disappeared. After completion of the reaction, the mixture was concentrated under reduced pressure. Water and dichloromethane were added, and the separated liquids were extracted. The organic phases were combined, washed with saturated brine, and concentrated under reduced pressure. The crude product was separated and purified by silica gel column chromatography (dichloromethane / acetone = 4 / 1) and concentrated under reduced pressure to obtain 0.38 g of compound 36 (yield: 55%). 1 H NMR (400MHz, d6-DMSO): δ7.45-7.37 (m, 4H), 7.26 (d, J = 4.4Hz, 1H), 6.88 (s, 2H), 6.32(d,J=8.0Hz,1H),6.13(s,1H),5.65-5.63(m,1H),5.50(s,1H),5.46(s,1H),4.37-4.27(m, 3H),3.91(m,1H),3.70(s,2H),3.35(m,2H),2.57-2.35(m,2H),2.03-1.18(m,10H),0.85(m,3H). MS m / z(ESI): 649.31[M+H] +

[0520] Synthesis Example 37

[0521] Cyanomethyl (2S,6aS,6bR,7S,8aS,8bS,11aR,12aS,12bS)-2,6b-difluoro-7-hydroxy-6a,8a-dimethyl-4-acyl-10-(4-(((2-acyltetrahydrofuran-3-yl)mercapto)methyl)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]dioxolane-8b-carboxylate (37)

[0522] first step

[0523] Compound 4aa (1.9 g, 4.4 mmol), sodium sulfite (0.84 g, 6.8 mmol), and 10 mL of N,N-dimethylacetamide were added to a reaction flask. 2-iodoacetonitrile (1.1 g, 6.8 mmol) was slowly added and allowed to react at room temperature. TLC monitoring was performed until compound 4aa disappeared. After completion of the reaction, the reaction mixture was poured into water and stirred for 30 minutes. The mixture was filtered under reduced pressure, the filter cake was dried, and the crude product was purified by silica gel column chromatography (dichloromethane / acetone = 4 / 1) and concentrated under reduced pressure to afford 0.8 g of compound 37a in a yield of 38%.

[0524] Step 2

[0525] Compound 37a (0.5 g, 1 mmol), 4-((2-acyltethrahydrofuran-3-mercapto)methyl)benzaldehyde (0.3 g, 1.26 mmol), and 30 mL of acetonitrile were added to a reaction flask. Perchloric acid (0.27 mL, 3.14 mmol) was slowly added dropwise and allowed to react at room temperature. TLC monitoring was performed until compound 37a disappeared. After completion of the reaction, the mixture was concentrated under reduced pressure. Water and dichloromethane were added, and the separated liquids were extracted. The organic phases were combined, washed with saturated brine, and concentrated under reduced pressure. The crude product was separated and purified by silica gel column chromatography (dichloromethane / acetone = 4 / 1) and concentrated under reduced pressure to obtain 0.42 g of compound 37, a yield of 61%. 1H NMR (400MHz, d6-DMSO): δ7.45-7.38(m,4H),7.27(d,J=4.4Hz,1H),6.35(d,J=8.0Hz,1H),6.15(s,1H),5.63-5.60(m,1H),5.55(s,1H),5.53(s ,1H),5.20(s,2H),4.73(m,1H),4.35-4.25(m,3H),3.91(m,1H),3.70(s ,2H),3.37(m,1H),2.57-2.33(m,2H),2.04-1.11(m,10H),0.88(m,3H). MS m / z(ESI): 656.32[M+H] +

[0526] Synthesis Example 38

[0527] (6aS,6bR,7S,8aS,8bS,11aR,12aS,12bS)-6b-chloro-8b-(2-chloroacetyl)-7-hydroxy-6a,8a-dimethyl-10-(4-(((2-acyltetrahydrofuran-3-yl)mercapto)methyl)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]dioxolane-4-one (38)

[0528] first step

[0529] (9α,11β,16α)-9-chloro-11,16,17,21-tetrahydroxy-pregna-1,4-diene-3,20-dione (5 g, 0.012 mol) and 50 mL of acetone were added to a reaction flask. Perchloric acid (5 mL, 0.06 mol) was slowly added dropwise. The reaction was allowed to proceed at room temperature. TLC monitoring was performed until the (9α,11β,16α)-9-chloro-11,16,17,21-tetrahydroxy-pregna-1,4-diene-3,20-dione was removed. After completion of the reaction, the mixture was concentrated under reduced pressure, water was added, and the mixture was evaporated until no solvent was removed. The mixture was stirred for 30 minutes. Filtration under reduced pressure and the filter cake was dried to obtain 3.8 g of compound 38aa in a yield of 71%.

[0530] Step 2

[0531] Compound 38aa (3.5 g, 7.76 mmol) and 30 mL of pyridine were added to a reaction flask, cooled to 0°C, and methanesulfonyl chloride (1.2 mL, 15.5 mmol) was slowly added dropwise. The reaction was allowed to react at room temperature. TLC monitoring indicated the disappearance of compound 38aa. After completion of the reaction, the reaction mixture was poured into 1N dilute hydrochloric acid and stirred for 30 minutes. The mixture was filtered under reduced pressure, and the filter cake was washed with water until neutral. The filter cake was then dried to obtain 2.7 g of compound 38ab in a 65% yield.

[0532] Step 3

[0533] Compound 38ab (2.5 g, 4.73 mmol), lithium chloride (0.4 g, 9.46 mmol), and 25 mL of N,N-dimethylformamide were added to a reaction flask and reacted at room temperature. TLC monitoring was performed until compound 38ab disappeared. After completion of the reaction, the reaction mixture was poured into water and stirred for 30 minutes. The mixture was filtered under reduced pressure, the filter cake was dried, and the crude product was purified by silica gel column chromatography (dichloromethane / acetone = 4 / 1) to obtain 0.93 g of compound 38a in a yield of 42%. MS m / z (ESI): 469.21 [M+H] +

[0534] Compound 38a (0.5 g, 1.16 mmol), 4-((2-acyltethrahydrofuran-3-mercapto)methyl)benzaldehyde (0.33 g, 1.4 mmol), and 30 mL of acetonitrile were added to a reaction flask. Perchloric acid (0.3 mL, 3.5 mmol) was slowly added dropwise and allowed to react at room temperature. TLC monitoring was performed until compound 38a disappeared. After completion of the reaction, the mixture was concentrated under reduced pressure. Water and dichloromethane were added, and the separated liquids were extracted. The organic phases were combined, washed with saturated brine, and concentrated under reduced pressure. The crude product was separated and purified by silica gel column chromatography (dichloromethane / acetone = 4 / 1) and concentrated under reduced pressure to obtain 0.49 g of compound 38, a yield of 65%. 1 H NMR (400MHz, d6-DMSO): δ7.45(m,2H),7.36-7.32(m,2H),7.26(m,1H),6. 24-6.22(m,1H),6.00(s,1H),5.60-5.58(m,1H),5.52(s,1H),4.54(s,2H) ,4.35-4.25(m,3H),3.75-3.70(m,3H),3.40-3.34(m,1H),2.55-2.38(m,4 H),2.01-1.96(m,2H),1.85-1.82(m,2H),1.79-1.58(m,7H),0.85(s,3H). MS m / z(ESI):647.22[M+H] +

[0535] Synthesis Example 39

[0536] (6aS,6bR,7S,8aS,8bS,11aR,12aS,12bS)-6b-chloro-8b-(2-chloroacetyl)-7-hydroxy-6a,8a-dimethyl-10-(4-(((5-acyltetrahydrofuran-3-yl)mercapto)methyl)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]dioxolane-4-one (39)

[0537] Compound 38a (0.5 g, 1.16 mmol), 4-((5-acyltethrahydrofuran-3-mercapto)methyl)benzaldehyde (0.33 g, 1.4 mmol), and 30 mL of acetonitrile were added to a reaction flask. Perchloric acid (0.3 mL, 3.5 mmol) was slowly added dropwise and allowed to react at room temperature. TLC monitoring was performed until compound 38a disappeared. After completion of the reaction, the mixture was concentrated under reduced pressure. Water and dichloromethane were added, and the separated liquids were extracted. The organic phases were combined, washed with saturated brine, and concentrated under reduced pressure. The crude product was separated and purified by silica gel column chromatography (dichloromethane / acetone = 4 / 1) and concentrated under reduced pressure to obtain 0.44 g of compound 39, a yield of 58%. 1 H NMR (400MHz, d6-DMSO): δ7.47(m,2H),7.38-7.34(m,2H),7.26(m,1H),6.25-6.2 2(m,1H),6.01(s,1H),5.61-5.59(m,1H),5.51(s,1H),4.75-4.55(m,2H),4.51( s,2H),4.32(m,1H),3.75-3.70(m,3H),3.14(m,1H),2.75-2.41(m,4H),2.00-1. 96(m,2H),1.72-1.45(m,5H),1.44-1.42(m,3H),1.06-1.04(m,1H),0.86(s,3H). MS m / z(ESI):647.24[M+H] +

[0538] Synthesis Example 40

[0539] (6aS,6bR,7S,8aS,8bS,11aR,12aS,12bS)-6b-fluoro-7-hydroxy-8b-(2-hydroxyacetyl)-6a,8a-dimethyl-1-10-(4-((2-acyltetrahydrofuran-3-yl)oxy)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]dioxolane-4-one (40)

[0540] 4-(2-Acyltetrahydrofuran-3-oxy)benzaldehyde

[0541] 3-Bromodihydrofuran-2(3H)-one (7.26 g, 0.044 mol), 4-hydroxybenzaldehyde (5 g, 0.04 mol), potassium carbonate (6.9 g, 0.05 mol), and 150 mL of acetonitrile were added to a reaction flask and allowed to react at room temperature for 6 hours. After completion of the reaction, water and dichloromethane were added, and the separated liquids were extracted. The organic phase was washed sequentially with water and saturated brine, and concentrated under reduced pressure. The crude product was separated and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 4 / 1) and concentrated under reduced pressure to obtain 3.5 g of 4-(2-acyltetrahydrofuran-3-oxy)benzaldehyde, with a yield of 43%. MS m / z (ESI): 207.12 [M+H] +

[0542] (9α,11β,16α)-9-fluoro-11,16,17,21-tetrahydroxy-pregna-1,4-diene-3,20-dione (0.5 g, 1.27 mmol), 4-(2-acyltetrahydrofuran-3-oxy)benzaldehyde (0.31 g, 1.52 mmol), and 30 mL of acetonitrile were added to a reaction flask. Perchloric acid (0.32 mL, 3.8 mmol) was slowly added dropwise. The reaction was allowed to proceed at room temperature. TLC monitoring was performed until the (9α,11β,16α)-9-fluoro-11,16,17,21-tetrahydroxy-pregna-1,4-diene-3,20-dione was eliminated. After completion of the reaction, the mixture was concentrated under reduced pressure, and water and dichloromethane were added. The separated liquids were extracted and the organic phases were combined, washed with saturated brine, and concentrated under reduced pressure. The crude product was separated and purified by silica gel column chromatography (dichloromethane / acetone = 4 / 1) and concentrated under reduced pressure to obtain 0.32 g of compound 40. Yield: 43%. 1H NMR (400MHz, d6-DMSO): δ7.42-7.37(m,4H),7.28(m,1H),6.25-6.21(m,1H) ,6.00(s,1H),5.50-5.47(m,1H),5.10(m,1H),4.94(m,1H),4.58-4.49(m,2 H),4.45(m,1H),4.37-4.16(m,4H),2.65-2.39(m,2H),2.10-1.83(m,2H),1 .80-1.46(m,3H),1.44-1.02(m,4H),0.98(m,1H),0.93(m,3H),0.86(m,3H). MS m / z(ESI):583.31[M+H] +

[0543] Synthesis Example 41

[0544] (6aS,6bR,7S,8aS,8bS,11aR,12aS,12bS)-6b-fluoro-7-hydroxy-8b-(2-hydroxyacetyl)-6a,8a-dimethyl-1-10-(4-((2-acyltetrahydrofuran-3-yl)mercapto)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]dioxolane-4-one (41)

[0545] 4-((2-Acyltetrahydrofuran-3-mercapto)benzaldehyde

[0546] 3-Bromodihydrofuran-2(3H)-one (7.26 g, 0.044 mol), 4-mercaptobenzaldehyde (5.5 g, 0.04 mol), potassium carbonate (6.9 g, 0.05 mol), and 150 mL of acetonitrile were added to a reaction flask and allowed to react at room temperature for 6 hours. After completion of the reaction, water and dichloromethane were added, and the separated liquids were extracted. The organic phase was washed sequentially with water and saturated brine, and concentrated under reduced pressure. The crude product was separated and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 4 / 1) and concentrated under reduced pressure to obtain 3.6 g of 4-((2-acyltetrahydrofuran-3-mercapto)benzaldehyde, with a yield of 40%. MS m / z (ESI): 223.15 [M+H] +

[0547] (9α,11β,16α)-9-fluoro-11,16,17,21-tetrahydroxy-pregna-1,4-diene-3,20-dione (0.5 g, 1.27 mmol), 4-((2-acyltetrahydrofuran-3-mercapto)benzaldehyde (0.34 g, 1.52 mmol), and 30 mL of acetonitrile were added to the reaction flask, and perchloric acid (0.32 mL, 3.8 mmol) was slowly added dropwise and reacted at room temperature. The reaction was complete, and TLC monitoring confirmed the absence of (9α,11β,16α)-9-fluoro-11,16,17,21-tetrahydroxy-pregna-1,4-diene-3,20-dione. After completion of the reaction, the mixture was concentrated under reduced pressure, and water and dichloromethane were added. The separated liquids were extracted, and the organic phases were combined, washed with saturated brine, and concentrated under reduced pressure. The crude product was separated and purified by silica gel column chromatography (dichloromethane / acetone = 4 / 1) and concentrated under reduced pressure to obtain 0.34 g of compound 41, with a yield of 45%. 1 H NMR (400MHz, d6-DMSO): δ7.45-7.37(m,4H),7.26(m,1H),6.27-6.23(m,1H),6.02(s,1H),5.52-5.49(m,1H),5.07(m,1H),4.93(m,1H),4.69-4.6 5(m,2H),4.35-4.15(m,4H),3.69(m,1H),2.59-2.32(m,4H),2.07-1.85 (m,3H),1.80-1.46(m,4H),1.42-1.02(m,3H),0.98(m,1H),0.87(m,3H). MS m / z(ESI): 599.30[M+H] +

[0548] Synthesis Example 42

[0549] (6aS,6bR,7S,8aS,8bS,11aR,12aS,12bS)-6b-fluoro-7-hydroxy-8b-(2-hydroxyacetyl)-6a,8a-dimethyl-1-10-(4-((2-acyltetrahydrofuran-3-yl)amino)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]dioxolane-4-one (42)

[0550] first step

[0551] (9α,11β,16α)-9-fluoro-11,16,17,21-tetrahydroxy-pregna-1,4-diene-3,20-dione (0.8 g, 2.03 mmol), tert-butyl (4-formylphenyl) carbamate (0.67 g, 3.04 mmol), and 30 mL of acetonitrile were added to a reaction flask. Perchloric acid (0.5 mL, 6.08 mmol) was slowly added dropwise. The reaction was allowed to proceed at room temperature. TLC monitoring was performed until the (9α,11β,16α)-9-fluoro-11,16,17,21-tetrahydroxy-pregna-1,4-diene-3,20-dione was eliminated. After completion of the reaction, the mixture was concentrated under reduced pressure, and water and dichloromethane were added. The separated liquids were extracted and the organic phases were combined, washed with saturated brine, and concentrated under reduced pressure. The crude product was separated and purified by silica gel column chromatography (dichloromethane / acetone = 4 / 1) and concentrated under reduced pressure to obtain 0.7 g of compound 42a in a yield of 68%.

[0552] Step 2

[0553] Compound 42a (0.5 g, 1 mmol), 3-bromodihydrofuran-2(3H)-one (0.18 g, 1.1 mmol), potassium carbonate (0.17 g, 1.2 mmol), and 10 mL of N,N-dimethylformamide were added to a reaction flask and heated to 80°C. TLC monitoring was performed until the absence of compound 42a was achieved. After completion of the reaction, the reaction mixture was poured into water and stirred for 30 minutes. The mixture was filtered under reduced pressure, the filter cake was washed with water, and dried. The crude product was separated and purified by silica gel column chromatography (dichloromethane / acetone = 4 / 1) and concentrated under reduced pressure to obtain 0.15 g of compound 42 (yield: 25%). 1 H NMR (400MHz, d6-DMSO): δ10.01(m,1H),7.46-7.37(m,4H),7.27(m,1H),6.27-6.23(m,1H),6.00(s,1H),5.50-5.48(m,1H),5.05(m,1H),4.95( m,1H),4.69-4.64(m,2H),4.37-4.12(m,4H),3.52(m,1H),2.61-2.35( m,4H),2.09-1.66(m,5H),1.58-1.22(m,5H),1.03(m,1H),0.86(m,3H). MS m / z(ESI): 582.31[M+H] +

[0554] Synthesis Example 43

[0555] (6aS,6bR,7S,8aS,8bS,11aR,12aS,12bS)-6b-fluoro-7-hydroxy-8b-(2-hydroxyacetyl)-6a,8a-dimethyl-10-(4-((2-acyltetrahydrofuran-3-yl)methyl)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]dioxolane-4-one (43)

[0556] 4-((2-Acyltetrahydrofuran-3-yl)methyl)benzaldehyde

[0557] first step

[0558] 4-Bromomethylformaldehyde (5 g, 0.025 mol), triethyl orthoformate (4.6 mL, 0.028 mol), p-toluenesulfonic acid monohydrate (0.5 g, 2.5 mmol), and 20 mL of ethanol were added to a reaction flask and allowed to react overnight at room temperature. After completion, the reaction was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1) and concentrated under reduced pressure to obtain 2.87 g of 1-bromomethyl-4-(diethoxymethyl)benzene, in a yield of 42%.

[0559] Step 2

[0560] Diisopropylamine (1.3 mL, 9 mmol) and 20 mL of dry tetrahydrofuran were added to a reaction flask, cooled to -78°C, and a 2.5 M n-butyllithium solution in n-hexane (3.6 mL, 9 mmol) was slowly added dropwise. Dihydrofuran-2(3H)-one (0.77 g, 9 mmol) was added and stirred for 30 minutes. 1-Bromomethyl-4-(diethoxymethyl)benzene (2.7 g, 10 mmol) was added and the mixture was slowly warmed to room temperature. The reaction was allowed to react for 20 hours. After completion, the reaction was quenched by saturated ammonium chloride solution. Dichloromethane was added, the separated liquids were extracted, and the organic phases were combined, washed with saturated brine, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5 / 1) and concentrated under reduced pressure to obtain 1.4 g of 3-(4-(diethoxymethylphenyl)dihydrofuran-2(3H)-one, with a yield of 55%.

[0561] Step 3

[0562] 3-(4-(diethoxymethylphenyl)dihydrofuran-2(3H)-one (1 g, 3.6 mmol), 5 mL of tetrahydrofuran, and 10 mL of 2M HCl solution were added to a reaction flask and reacted at room temperature for 2 hours. After the reaction, water and ethyl acetate were added, the separated liquids were extracted, and the organic phases were combined, washed with saturated brine, and concentrated under reduced pressure. The crude product was separated and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 4 / 1) and concentrated under reduced pressure to obtain 0.55 g of 4-((2-acyltetrahydrofuran-3-yl)methyl)benzaldehyde, with a yield of 75%. MS m / z (ESI): 205.15 [M+H] +

[0563] (9α,11β,16α)-9-fluoro-11,16,17,21-tetrahydroxy-pregna-1,4-diene-3,20-dione (0.5 g, 1.27 mmol), 4-((2-acyltetrahydrofuran-3-yl)methyl)benzaldehyde (0.31 g, 1.52 mmol), and 30 mL of acetonitrile were added to a reaction flask. Perchloric acid (0.32 mL, 3.8 mmol) was slowly added dropwise. The reaction was allowed to proceed at room temperature. TLC monitoring was performed until the (9α,11β,16α)-9-fluoro-11,16,17,21-tetrahydroxy-pregna-1,4-diene-3,20-dione was absent. After completion of the reaction, the mixture was concentrated under reduced pressure, and water and dichloromethane were added. The separated liquids were extracted and the organic phases were combined, washed with saturated brine, and concentrated under reduced pressure. The crude product was separated and purified by silica gel column chromatography (dichloromethane / acetone = 4 / 1) and concentrated under reduced pressure to obtain 0.47 g of compound 43. Yield: 64%. 1 H NMR (400MHz, d6-DMSO): δ7.46-7.38(m,4H),7.27(m,1H),6.25-6.23(m,1H), 6.00(s,1H),5.55-5.53(m,1H),5.10(m,1H),4.98(m,1H),4.75-4.72(m,2H), 4.44-4.21(m,4H),3.23-3.02(m,2H),2.70(m,1H),2.41-2.32(m,2H),2.17- 1.85(m,6H),1.80-1.45(m,3H),1.22-1.03(m,3H),0.99(m,1H),0.85(m,3H). MS m / z(ESI):581.37[M+H] +

[0564] Synthesis Example 44

[0565] (6aS,6bR,7S,8aS,8bS,11aR,12aS,12bS)-6b-fluoro-7-hydroxy-8b-(2-hydroxyacetyl)-6a,8a-dimethyl-10-(1-((2-acyltetrahydrofuran-3-yl)methyl)piperidin-4-yl)-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]dioxolane-4-one (44)

[0566] 1-((2-Acyltetrahydrofuran-3-yl)methyl)piperidine-4-carbaldehyde

[0567] Piperidine-4-carboxaldehyde (5 g, 0.04 mol), 3-bromomethyldihydrofuran-2(3H)-one (9 g, 0.05 mol), and 60 mL of dichloromethane were added to a reaction flask and allowed to react at room temperature for 12 hours. After completion of the reaction, the mixture was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 4 / 1) and concentrated under reduced pressure to obtain 3 g of 1-((2-acyltetrahydrofuran-3-yl)methyl)piperidine-4-carboxaldehyde in a yield of 35%. MS m / z (ESI): 212.23 [M+H] +

[0568] (9α,11β,16α)-9-fluoro-11,16,17,21-tetrahydroxy-pregna-1,4-diene-3,20-dione (0.5 g, 1.27 mmol), 1-((2-acyltetrahydrofuran-3-yl)methyl)piperidine-4-carboxaldehyde (0.32 g, 1.52 mmol), and 20 mL of acetonitrile were added to a reaction flask. Perchloric acid (0.32 mL, 3.8 mmol) was slowly added dropwise. The reaction was allowed to proceed at room temperature. TLC monitoring was performed until the (9α,11β,16α)-9-fluoro-11,16,17,21-tetrahydroxy-pregna-1,4-diene-3,20-dione was absent. After completion of the reaction, the mixture was concentrated under reduced pressure, and water and dichloromethane were added. The separated liquids were extracted and the organic phases were combined, washed with saturated brine, and concentrated under reduced pressure. The crude product was separated and purified by silica gel column chromatography (dichloromethane / acetone = 4 / 1) and concentrated under reduced pressure to obtain 0.31 g of compound 44 in a yield of 43%. 1H NMR (400MHz, d6-DMSO): δ7.27(m,1H),6.23-6.20(m,1H),6.02(s,1H),5.39-5.36(m,1H),5.12(m,1H),4.97(m,1H),4.69-4.67(m,2H),4.35-4.1 4(m,3H),3.94(m,1H),2.81-2.78(m,2H),2.51-1.98(m,9H),2.17-1.85 (m,6H),1.80-1.45(m,4H),1.25-1.05(m,5H),0.99(m,1H),0.86(m,3H). MS m / z(ESI): 588.32[M+H] +

[0569] Synthesis Example 45

[0570] (6aS,6bR,7S,8aS,8bS,11aR,12aS,12bS)-6b-fluoro-7-hydroxy-8b-(2-hydroxyacetyl)-6a,8a-dimethyl-10-(4-((2-acyltetrahydrofuran-3-yl)mercapto)cyclohexyl)-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]dioxolane-4-one (45)

[0571] 4-(2-Acyltetrahydrofuran-3-mercapto)cyclohexane-1-carbaldehyde

[0572] 3-Mercaptotetrahydrofuran-2(3H)-one (0.68 g, 5.75 mmol), 4-bromo-1-carbaldehyde (1 g, 5.23 mmol), potassium carbonate (0.87 g, 6.28 mmol), and 10 mL of N,N-dimethylformamide were added to a reaction flask and allowed to react at room temperature for 6 hours. After completion of the reaction, water and dichloromethane were added, the separated liquids were extracted, and the organic phase was washed sequentially with water and saturated brine, and concentrated under reduced pressure. The crude product was separated and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 4 / 1) and concentrated under reduced pressure to obtain 0.72 g of 4-(2-acyltetrahydrofuran-3-mercapto)cyclohexane-1-carbaldehyde, with a yield of 60%. MS m / z (ESI): 229.11 [M+H] +

[0573] (9α,11β,16α)-9-fluoro-11,16,17,21-tetrahydroxy-pregna-1,4-diene-3,20-dione (0.5 g, 1.27 mmol), 4-(2-acyltetrahydrofuran-3-mercapto)cyclohexane-1-carbaldehyde (0.34 g, 1.52 mmol), and 30 mL of acetonitrile were added to a reaction flask. Perchloric acid (0.32 mL, 3.8 mmol) was slowly added dropwise. The reaction was allowed to proceed at room temperature. TLC monitoring was performed until the (9α,11β,16α)-9-fluoro-11,16,17,21-tetrahydroxy-pregna-1,4-diene-3,20-dione was absent. After completion of the reaction, the mixture was concentrated under reduced pressure, and water and dichloromethane were added. The separated liquids were extracted and the organic phases were combined, washed with saturated brine, and concentrated under reduced pressure. The crude product was separated and purified by silica gel column chromatography (dichloromethane / acetone = 4 / 1) and concentrated under reduced pressure to obtain 0.42 g of compound 45. Yield: 55%. 1 H NMR (400MHz, d6-DMSO): δ7.27(m,1H),6.22-6.20(m,1H),6.00(s,1H),5.55-5.52(m,1H),5.10(m,1H),4.97(m,1H),4.72-4.69(m,2H ),4.37-4.15(m,3H),3.97(m,1H),3.34(m,1H),2.56-2.31(m,5H),1.93-1.35(m,15H),1.22-1.05(m,4H),1.02(m,1H),0.85(m,3H). MS m / z(ESI): 605.37[M+H] +

[0574] Synthesis Example 46

[0575] (2S,6aS,6bR,7S,8aS,8bS,11aR,12aS,12bS)-2,6b-difluoro-7-hydroxy-8b-(2-hydroxyacetyl)-6a,8a-dimethyl-10-(6-(((2-acyltetrahydrofuran-3-yl)mercapto)methyl)pyridin-3-yl)-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]dioxolane-4-one (46)

[0576] 6-((2-Acyltetrahydrofuran-3-mercapto)methyl)picolinaldehyde

[0577] 3-Mercaptodihydrofuran-2(3H)-one (1 g, 8.46 mmol), 6-(bromomethyl)picolinaldehyde (1.86 g, 9.31 mmol), potassium carbonate (1.4 g, 10.1 mmol), and 20 mL of N,N-dimethylformamide were added to a reaction flask and allowed to react at room temperature for 6 hours. After completion of the reaction, water and dichloromethane were added, the separated liquids were extracted, and the organic phase was washed sequentially with water and saturated brine, and concentrated under reduced pressure. The crude product was separated and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 2 / 1) and concentrated under reduced pressure to obtain 0.7 g of 6-((2-acyltetrahydrofuran-3-mercapto)methyl)picolinaldehyde, with a yield of 35%. MS m / z (ESI): 238.15 [M+H] +

[0578] (6α,9α,11β,16α)-6,9-difluoro-11,16,17,21-tetrahydroxy-pregna-1,4-diene-3,20-dione (0.5 g, 1.21 mmol), 6-((2-acyltetrahydrofuran-3-mercapto)methyl)pyridinecarboxaldehyde (0.35 g, 1.45 mmol), and 30 mL of acetonitrile were added to a reaction flask. Perchloric acid (0.3 mL, 3.64 mmol) was slowly added dropwise. The reaction was allowed to proceed at room temperature. TLC monitoring was performed until the (6α,9α,11β,16α)-6,9-difluoro-11,16,17,21-tetrahydroxy-pregna-1,4-diene-3,20-dione was absent. After completion of the reaction, the mixture was concentrated under reduced pressure, and water and dichloromethane were added. The separated liquids were extracted and the organic phases were combined, washed with saturated brine, and concentrated under reduced pressure. The crude product was separated and purified by silica gel column chromatography (dichloromethane / acetone = 4 / 1) and concentrated under reduced pressure to obtain 0.48 g of compound 46. Yield: 62%. 1 H NMR (400MHz, d6-DMSO): δ8.40(m,1H),7.70(m,1H),7.34(m,1H),7.15(m,1H),6 .45(m,1H),6.33(s,1H),6.07(m,1H),5.10(s,1H),4.95(s,1H),4.85(m,2H),4 .44-4.32(m,3H),4.28-4.20(m,2H),4.02-3.94(m,2H),3.34(m,1H),2.62-2.4 8(m,2H),2.32-1.96(m,4H),1.75-1.65(m,3H),1.55-1.42(m,4H),0.86(m,3H). MS m / z(ESI):632.32[M+H] +

[0579] Synthesis Example 47

[0580] (6aS,6bR,7S,8aS,8bS,11aR,12aS,12bS)-6b-fluoro-7-hydroxy-8b-(2-hydroxyacetyl)-6a,8a-dimethyl-10-(6-(((2-acyltetrahydrofuran-3-yl)mercapto)methyl)pyridin-3-yl)-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]dioxolane-4-one (47)

[0581] (9α,11β,16α)-9-fluoro-11,16,17,21-tetrahydroxy-pregna-1,4-diene-3,20-dione (0.5 g, 1.27 mmol), 6-((2-acyltetrahydrofuran-3-mercapto)methyl)pyridinecarboxaldehyde (0.36 g, 1.52 mmol), and 30 mL of acetonitrile were added to a reaction flask. Perchloric acid (0.3 mL, 3.8 mmol) was slowly added dropwise. The reaction was allowed to proceed at room temperature. TLC monitoring was performed until the (9α,11β,16α)-9-fluoro-11,16,17,21-tetrahydroxy-pregna-1,4-diene-3,20-dione was absent. After completion of the reaction, the mixture was concentrated under reduced pressure, and water and dichloromethane were added. The separated liquids were extracted and the organic phases were combined, washed with saturated brine, and concentrated under reduced pressure. The crude product was separated and purified by silica gel column chromatography (dichloromethane / acetone = 4 / 1) and concentrated under reduced pressure to obtain 0.53 g of compound 47. Yield: 68%. 1 H NMR (400MHz, d6-DMSO): δ8.42(m,1H),7.75(m,1H),7.36(m,1H),7.10(m,1H),6 .47(m,1H),6.30(s,1H),6.05(m,1H),5.13(s,1H),4.96(s,1H),4.90(m,2H),4 .45-4.32(m,3H),4.30-4.22(m,2H),4.00-3.95(m,2H),3.35(m,1H),2.62-2.4 8(m,2H),2.32-1.95(m,5H),1.77-1.68(m,3H),1.58-1.42(m,4H),0.89(m,3H). MS m / z(ESI):614.32[M+H] +

[0582] Synthesis Example 48

[0583] (6aS,6bR,7S,8aS,8bS,11aR,12aS,12bS)-6b-chloro-7-hydroxy-8b-(2-hydroxyacetyl)-6a,8a-dimethyl-10-(6-(((2-acyltetrahydrofuran-3-yl)mercapto)methyl)pyridin-3-yl)-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]dioxolane-4-one (48)

[0584] (9α,11β,16α)-9-chloro-11,16,17,21-tetrahydroxy-pregna-1,4-diene-3,20-dione (0.5 g, 1.22 mmol), 6-((2-acyltetrahydrofuran-3-mercapto)methyl)pyridinecarboxaldehyde (0.35 g, 1.46 mmol), and 30 mL of acetonitrile were added to a reaction flask. Perchloric acid (0.3 mL, 3.65 mmol) was slowly added dropwise. The reaction was allowed to proceed at room temperature. TLC monitoring was performed until the (9α,11β,16α)-9-chloro-11,16,17,21-tetrahydroxy-pregna-1,4-diene-3,20-dione was removed. After completion of the reaction, the mixture was concentrated under reduced pressure. Water and dichloromethane were added, and the separated liquids were extracted. The organic phases were combined, washed with saturated brine, and concentrated under reduced pressure. The crude product was separated and purified by silica gel column chromatography (dichloromethane / acetone = 4 / 1) and concentrated under reduced pressure to obtain 0.50 g of compound 48. Yield: 65%. 1 H NMR (400MHz, d6-DMSO): δ8.40(m,1H),7.76(m,1H),7.40(m,1H), 7.12(m,1H),6.45(m,1H),6.32(s,1H),6.10(m,1H),5.12(s,1H),4.96(s,1H),4.88(m,2H),4.35-4.25(m,2H),4.30(s,2H),3.96 -3.90(m,2H),3.34(m,1H),2.58-2.31(m,4H),2.32-2.02(m,3H),1.78-1.68(m,4H),1.48-1.35(m,3H),1.10(m,1H),0.87(m,3H). MS m / z(ESI): 630.25[M+H] +

[0585] Synthesis Example 49

[0586] (2S,6aS,6bR,7S,8aS,8bS,11aR,12aS,12bS)-2,6b-difluoro-7-hydroxy-8b-(2-hydroxyacetyl)-6a,8a-dimethyl-10-(5-(((2-acyltetrahydrofuran-3-yl)mercapto)methyl)pyridin-2-yl)-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]dioxolane-4-one (49)

[0587] 5-((2-Acyltetrahydrofuran-3-mercapto)methyl)picolinaldehyde

[0588] 3-Mercaptodihydrofuran-2(3H)-one (1 g, 8.46 mmol), 5-(bromomethyl)picolinaldehyde (1.86 g, 9.31 mmol), potassium carbonate (1.4 g, 10.1 mmol), and 20 mL of N,N-dimethylformamide were added to a reaction flask and allowed to react at room temperature for 6 hours. After completion of the reaction, water and dichloromethane were added, the separated liquids were extracted, and the organic phase was washed sequentially with water and saturated brine, and concentrated under reduced pressure. The crude product was separated and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 2 / 1) and concentrated under reduced pressure to obtain 0.64 g of 5-((2-acyltetrahydrofuran-3-mercapto)methyl)picolinaldehyde, with a yield of 32%. MS m / z (ESI): 238.17 [M+H] +

[0589] (6α,9α,11β,16α)-6,9-difluoro-11,16,17,21-tetrahydroxy-pregna-1,4-diene-3,20-dione (0.5 g, 1.21 mmol), 5-((2-acyltetrahydrofuran-3-mercapto)methyl)picolinaldehyde (0.35 g, 1.45 mmol), and 30 mL of acetonitrile were added to a reaction flask. Perchloric acid (0.3 mL, 3.64 mmol) was slowly added dropwise. The reaction was allowed to proceed at room temperature. TLC monitoring was performed until the (6α,9α,11β,16α)-6,9-difluoro-11,16,17,21-tetrahydroxy-pregna-1,4-diene-3,20-dione was removed. After completion of the reaction, the mixture was concentrated under reduced pressure. Water and dichloromethane were added, and the separated layers were extracted. The organic phases were combined, washed with saturated brine, and concentrated under reduced pressure. The crude product was separated and purified by silica gel column chromatography (dichloromethane / acetone = 4 / 1) and concentrated under reduced pressure to obtain 0.44 g of compound 49. Yield: 58%. 1H NMR (400MHz, d6-DMSO): δ8.40(m,1H),7.78(m,1H),7.54(m,1H),7.01(m,1H ),6.44(m,1H),6.35(s,1H),6.05(m,1H),5.15(s,1H),4.96(s,1H),4.87(m, 2H),4.45-4.32(m,3H),4.31-4.25(m,2H),3.70(m,2H),3.35(m,1H),2.56-2 .31(m,2H),2.30-1.65(m,7H),1.44-1.35(m,3H),1.11(m,1H),0.90(m,3H). MS m / z(ESI):632.35[M+H] +

[0590] Synthesis Example 50

[0591] (6aS,6bR,7S,8aS,8bS,11aR,12aS,12bS)-6b-fluoro-7-hydroxy-8b-(2-hydroxyacetyl)-6a,8a-dimethyl-10-(5-(((2-acyltetrahydrofuran-3-yl)mercapto)methyl)pyridin-2-yl)-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]dioxolane-4-one (50)

[0592] (9α,11β,16α)-9-fluoro-11,16,17,21-tetrahydroxy-pregna-1,4-diene-3,20-dione (0.5 g, 1.27 mmol), 5-((2-acyltetrahydrofuran-3-mercapto)methyl)pyridinecarboxaldehyde (0.36 g, 1.52 mmol), and 30 mL of acetonitrile were added to a reaction flask. Perchloric acid (0.3 mL, 3.8 mmol) was slowly added dropwise. The reaction was allowed to proceed at room temperature. TLC monitoring was performed until the (9α,11β,16α)-9-fluoro-11,16,17,21-tetrahydroxy-pregna-1,4-diene-3,20-dione was absent. After completion of the reaction, the mixture was concentrated under reduced pressure, and water and dichloromethane were added. The separated liquids were extracted and the organic phases were combined, washed with saturated brine, and concentrated under reduced pressure. The crude product was separated and purified by silica gel column chromatography (dichloromethane / acetone = 4 / 1) and concentrated under reduced pressure to obtain 0.47 g of compound 50, 61%. 1H NMR (400MHz, d6-DMSO): δ8.40(m,1H),7.87(m,1H),7.55(m,1H),7.11(m,1H),6 .52(m,1H),6.12(s,1H),6.07(m,1H),5.12(s,1H),4.98(s,1H),4.86(m,2H),4. 45-4.15(m,3H),4.30-4.22(m,2H),4.00(m,1H),3.70(m,2H),3.34(m,1H),2.4 6-2.31(m,4H),2.26-1.92(m,4H),1.77-1.42(m,4H),1.22(m,1H),0.89(m,3H). MS m / z(ESI):614.35[M+H] +

[0593] Synthesis Example 51

[0594] (6aS,6bR,7S,8aS,8bS,11aR,12aS,12bS)-6b-chloro-7-hydroxy-8b-(2-hydroxyacetyl)-6a,8a-dimethyl-10-(5-(((2-acyltetrahydrofuran-3-yl)mercapto)methyl)pyridin-2-yl)-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]dioxolane-4-one (51)

[0595] (9α,11β,16α)-9-chloro-11,16,17,21-tetrahydroxy-pregna-1,4-diene-3,20-dione (0.5 g, 1.22 mmol), 5-((2-acyltetrahydrofuran-3-mercapto)methyl)pyridinecarboxaldehyde (0.35 g, 1.46 mmol), and 30 mL of acetonitrile were added to a reaction flask. Perchloric acid (0.3 mL, 3.65 mmol) was slowly added dropwise. The reaction was allowed to proceed at room temperature. TLC monitoring was performed until the (9α,11β,16α)-9-chloro-11,16,17,21-tetrahydroxy-pregna-1,4-diene-3,20-dione was removed. After completion of the reaction, the mixture was concentrated under reduced pressure. Water and dichloromethane were added, and the separated liquids were extracted. The organic phases were combined, washed with saturated brine, and concentrated under reduced pressure. The crude product was separated and purified by silica gel column chromatography (dichloromethane / acetone = 4 / 1) and concentrated under reduced pressure to obtain 0.45 g of compound 51. Yield: 59%. 1H NMR (400MHz, d6-DMSO): δ8.39(m,1H),7.77(m,1H),7.43(m,1H),7.02(m,1H),6. 42(m,1H),6.33(s,1H),6.11(m,1H),5.10(s,1H),4.96(s,1H),4.70(m,2H),4.37 -4.26(m,2H),3.94-3.92(m,1H),3.70(s,2H),3.35(m,1H),2.55-2.30(m,4H),2. 33-1.89(m,6H),1.79-1.68(m,2H),1.50-1.38(m,3H),1.15(m,1H),0.87(m,3H). MS m / z(ESI):630.28[M+H] +

[0596] Synthesis Example 52

[0597] (2S,6aS,6bR,7S,8aS,8bS,11aR,12aS,12bS)-2,6b-difluoro-7-hydroxy-8b-(2-hydroxyacetyl)-6a,8a-dimethyl-10-(2-(((2-acyltetrahydrofuran-3-yl)mercapto)methyl)pyrimidin-5-yl)-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]dioxolane-4-one (52)

[0598] 2-((2-Acyltetrahydrofuran-3-mercapto)methyl)pyrimidine-5-carbaldehyde

[0599] 3-Mercaptodihydrofuran-2(3H)-one (1 g, 8.46 mmol), 2-(chloromethyl)pyrimidine-5-carboxaldehyde (1.46 g, 9.31 mmol), potassium carbonate (1.4 g, 10.1 mmol), and 20 mL of N,N-dimethylformamide were added to a reaction flask and allowed to react at room temperature for 6 hours. After completion of the reaction, water and dichloromethane were added, the separated liquids were extracted, and the organic phase was washed sequentially with water and saturated brine, and concentrated under reduced pressure. The crude product was separated and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 2 / 1) and concentrated under reduced pressure to obtain 0.83 g of 2-((2-acyltetrahydrofuran-3-mercapto)methyl)pyrimidine-5-carboxaldehyde, with a yield of 41%. MS m / z (ESI): 239.15 [M+H] +

[0600] (6α,9α,11β,16α)-6,9-difluoro-11,16,17,21-tetrahydroxy-pregna-1,4-diene-3,20-dione (0.5 g, 1.21 mmol), 2-((2-acyltetrahydrofuran-3-mercapto)methyl)pyrimidine-5-carboxaldehyde (0.35 g, 1.45 mmol), and 30 mL of acetonitrile were added to a reaction flask. Perchloric acid (0.3 mL, 3.64 mmol) was slowly added dropwise. The reaction was allowed to proceed at room temperature. TLC monitoring was performed until the (6α,9α,11β,16α)-6,9-difluoro-11,16,17,21-tetrahydroxy-pregna-1,4-diene-3,20-dione was removed. After completion of the reaction, the mixture was concentrated under reduced pressure, and water and dichloromethane were added. The separated liquids were extracted and the organic phases were combined, washed with saturated brine, and concentrated under reduced pressure. The crude product was separated and purified by silica gel column chromatography (dichloromethane / acetone = 4 / 1) and concentrated under reduced pressure to obtain 0.44 g of compound 52. Yield: 57%. 1 H NMR (400MHz, d6-DMSO): δ8.83(m,2H),7.01(m,1H),6.41(m,1H),6.33(s,1H),6.05(m,1H),5.01(s,1H),4.88(s,1H),4.79(m,2H),4.35-4. 25(m,3H),4.02-3.98(m,2H),3.72(m,2H),3.34(m,1H),2.54-2.31(m ,2H),2.35-1.65(m,7H),1.48-1.35(m,3H),1.08(m,1H),0.87(m,3H). MS m / z(ESI): 633.33[M+H] +

[0601] Synthesis Example 53

[0602] (6aS,6bR,7S,8aS,8bS,11aR,12aS,12bS)-6b-fluoro-7-hydroxy-8b-(2-hydroxyacetyl)-6a,8a-dimethyl-10-(2-(((2-acyltetrahydrofuran-3-yl)mercapto)methyl)pyrimidin-5-yl)-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]dioxolane-4-one (53)

[0603] (9α,11β,16α)-9-fluoro-11,16,17,21-tetrahydroxy-pregna-1,4-diene-3,20-dione (0.5 g, 1.27 mmol), 2-((2-acyltetrahydrofuran-3-mercapto)methyl)pyrimidine-5-carboxaldehyde (0.36 g, 1.52 mmol), and 30 mL of acetonitrile were added to a reaction flask. Perchloric acid (0.3 mL, 3.8 mmol) was slowly added dropwise. The reaction was allowed to proceed at room temperature. TLC monitoring was performed until the (9α,11β,16α)-9-fluoro-11,16,17,21-tetrahydroxy-pregna-1,4-diene-3,20-dione was absent. After completion of the reaction, the mixture was concentrated under reduced pressure, and water and dichloromethane were added. The separated liquids were extracted and the organic phases were combined, washed with saturated brine, and concentrated under reduced pressure. The crude product was separated and purified by silica gel column chromatography (dichloromethane / acetone = 4 / 1) and concentrated under reduced pressure to obtain 0.39 g of compound 53. Yield: 50%. 1 H NMR (400MHz, d6-DMSO): δ8.85(m,2H),6.99(m,1H),6.38(m,1H), 6.28(s,1H),6.03(m,1H),5.10(s,1H),4.98(s,1H),4.67(m,2H),4.37-4.25(m,2H),3.96(m,1H),3.75(s,2H),3. 35(m,1H),2.56-2.37(m,4H),2.31-1.85(m,6H),1.79-1.69(m,2H),1.58-1.38(m,3H),1.02(m,1H),0.85(m,3H). MS m / z(ESI): 615.38[M+H] +

[0604] Synthesis Example 54

[0605] (6aS,6bR,7S,8aS,8bS,11aR,12aS,12bS)-6b-chloro-7-hydroxy-8b-(2-hydroxyacetyl)-6a,8a-dimethyl-10-(2-(((2-acyltetrahydrofuran-3-yl)mercapto)methyl)pyrimidin-5-yl)-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]dioxolane-4-one (54)

[0606] (9α,11β,16α)-9-chloro-11,16,17,21-tetrahydroxy-pregna-1,4-diene-3,20-dione (0.5 g, 1.22 mmol), 2-((2-acyltetrahydrofuran-3-mercapto)methyl)pyrimidine-5-carboxaldehyde (0.35 g, 1.46 mmol), and 30 mL of acetonitrile were added to a reaction flask. Perchloric acid (0.3 mL, 3.65 mmol) was slowly added dropwise. The reaction was allowed to proceed at room temperature. TLC monitoring was performed until the (9α,11β,16α)-9-chloro-11,16,17,21-tetrahydroxy-pregna-1,4-diene-3,20-dione was removed. After completion of the reaction, the mixture was concentrated under reduced pressure. Water and dichloromethane were added, and the separated liquids were extracted. The organic phases were combined, washed with saturated brine, and concentrated under reduced pressure. The crude product was separated and purified by silica gel column chromatography (dichloromethane / acetone = 4 / 1) and concentrated under reduced pressure to obtain 0.41 g of compound 54. Yield: 53%. 1 H NMR (400MHz, d6-DMSO): δ8.79(m,2H),7.02(m,1H),6.35(m,1H),6.31(s, 1H),6.02(m,1H),5.04(s,1H),4.94(s,1H),4.69(m,2H),4.35-4.24(m,2 H),3.94(m,1H),3.68(s,2H),3.33(m,1H),2.56-2.37(m,4H),2.33-1.87 (m,6H),1.74-1.68(m,2H),1.55-1.42(m,3H),1.22(m,1H),0.97(m,3H). MS m / z(ESI): 631.25[M+H] +

[0607] Synthesis Example 55

[0608] (2S,6aS,6bR,7S,8aS,8bS,11aR,12aS,12bS)-2,6b-difluoro-7-hydroxy-8b-(2-hydroxyacetyl)-6a,8a-dimethyl-10-(4-(((2-acyltetrahydrofuran-3-yl)sulfinyl)methyl)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]dioxolane-4-one (55)

[0609] 4-(((2-Acyltetrahydrofuran-3-yl)sulfinyl)methyl)benzaldehyde

[0610] 4-(((2-acyltetrahydrofuran-3-yl)thioyl)methyl)benzaldehyde (1 g, 4.23 mmol), 10 mL of 30% hydrogen peroxide, and 20 mL of acetonitrile were added to a reaction flask and allowed to react at room temperature for 24 hours. After completion of the reaction, water and ethyl acetate were added, the separated liquids were extracted, and the organic phase was washed sequentially with water and saturated brine, and concentrated under reduced pressure. The crude product was separated and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 2 / 1) and concentrated under reduced pressure to obtain 0.9 g of 4-(((2-acyltetrahydrofuran-3-yl)sulfinyl)methyl)benzaldehyde, in a yield of 83%. MS m / z (ESI): 253.11 [M+H] +

[0611] (6α,9α,11β,16α)-6,9-difluoro-11,16,17,21-tetrahydroxy-pregna-1,4-diene-3,20-dione (0.5 g, 1.21 mmol), 4-(((2-acyltetrahydrofuran-3-yl)sulfinyl)methyl)benzaldehyde (0.37 g, 1.45 mmol), and 30 mL of acetonitrile were added to a reaction flask. Perchloric acid (0.3 mL, 3.64 mmol) was slowly added dropwise. The reaction was allowed to proceed at room temperature. TLC monitoring was performed until the (6α,9α,11β,16α)-6,9-difluoro-11,16,17,21-tetrahydroxy-pregna-1,4-diene-3,20-dione was removed. After completion of the reaction, the mixture was concentrated under reduced pressure, and water and dichloromethane were added. The separated liquids were extracted and the organic phases were combined, washed with saturated brine, and concentrated under reduced pressure. The crude product was separated and purified by silica gel column chromatography (dichloromethane / acetone = 4 / 1) and concentrated under reduced pressure to obtain 0.43 g of compound 55. Yield: 55%. 1 H NMR (400MHz, d6-DMSO): δ8.83(m,2H),7.01(m,1H),6.41(m,1H),6.33(s,1H),6.05(m,1H),5.01(s,1H),4.88(s,1H),4.79(m,2H) ,4.35-4.08(m,5H),3.72(m,2H),3.52(m,1H),2.54-2.31(m,4H),2.35-1.65(m,7H),1.48-1.35(m,3H),1.08(m,1H),0.85(m,3H). MS m / z(ESI): 647.31[M+H] +

[0612] Synthesis Example 56

[0613] (6aS,6bR,7S,8aS,8bS,11aR,12aS,12bS)-6b-fluoro-7-hydroxy-8b-(2-hydroxyacetyl)-6a,8a-dimethyl-10-(4-(((2-acyltetrahydrofuran-3-yl)sulfinyl)methyl)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]dioxolane-4-one (56)

[0614] (9α,11β,16α)-9-fluoro-11,16,17,21-tetrahydroxy-pregna-1,4-diene-3,20-dione (0.5 g, 1.27 mmol), 4-(((2-acyltetrahydrofuran-3-yl)sulfinyl)methyl)benzaldehyde (0.38 g, 1.52 mmol), and 30 mL of acetonitrile were added to a reaction flask. Perchloric acid (0.32 mL, 3.8 mmol) was slowly added dropwise. The reaction was allowed to proceed at room temperature. TLC monitoring was performed until the (9α,11β,16α)-9-fluoro-11,16,17,21-tetrahydroxy-pregna-1,4-diene-3,20-dione was absent. After completion of the reaction, the mixture was concentrated under reduced pressure, and water and dichloromethane were added. The separated liquids were extracted and the organic phases were combined, washed with saturated brine, and concentrated under reduced pressure. The crude product was separated and purified by silica gel column chromatography (dichloromethane / acetone = 4 / 1) and concentrated under reduced pressure to obtain 0.38 g of compound 56. Yield: 48%. 1 H NMR (400MHz, d6-DMSO): δ8.85(m,2H),6.99(m,1H),6.38(m,1H),6.28(s,1H),6.03(m,1H),5.10(s,1H),4.98(s,1H),4.67-4.35(m,4H),4. 05(m,1H),3.75(s,2H),3.35(m,1H),2.56-2.37(m,4H),2.31-1.85(m ,6H),1.79-1.69(m,4H),1.58-1.38(m,3H),1.02(m,1H),0.87(m,3H). MS m / z(ESI): 629.32[M+H] +

[0615] Synthesis Example 57

[0616] (6aS,6bR,7S,8aS,8bS,11aR,12aS,12bS)-6b-chloro-7-hydroxy-8b-(2-hydroxyacetyl)-6a,8a-dimethyl-10-(4-(((2-acyltetrahydrofuran-3-yl)sulfinyl)methyl)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]dioxolane-4-one (57)

[0617] (9α,11β,16α)-9-chloro-11,16,17,21-tetrahydroxy-pregna-1,4-diene-3,20-dione (0.5 g, 1.22 mmol), 4-(((2-acyltetrahydrofuran-3-yl)sulfinyl)methyl)benzaldehyde (0.37 g, 1.46 mmol), and 30 mL of acetonitrile were added to a reaction flask. Perchloric acid (0.3 mL, 3.65 mmol) was slowly added dropwise. The reaction was allowed to proceed at room temperature. TLC monitoring was performed until the (9α,11β,16α)-9-chloro-11,16,17,21-tetrahydroxy-pregna-1,4-diene-3,20-dione was removed. After completion of the reaction, the mixture was concentrated under reduced pressure. Water and dichloromethane were added, and the separated liquids were extracted. The organic phases were combined, washed with saturated brine, and concentrated under reduced pressure. The crude product was separated and purified by silica gel column chromatography (dichloromethane / acetone = 4 / 1) and concentrated under reduced pressure to obtain 0.43 g of compound 57. Yield: 55%. 1 H NMR (400MHz, d6-DMSO): δ8.79(m,2H),7.02(m,1H),6.35(m,1H),6.31(s,1H),6.02(m,1H),5.04(s,1H),4.94(s,1H),4.69-4.36(m,4H),4.0 54(m,1H),3.68(s,2H),3.33(m,1H),2.56-2.37(m,4H),2.33-1.87(m ,6H),1.74-1.68(m,4H),1.55-1.42(m,3H),1.22(m,1H),0.86(m,3H). MS m / z(ESI): 645.32[M+H] +

[0618] Synthesis Example 58

[0619] (2S,6aS,6bR,7S,8aS,8bS,11aR,12aS,12bS)-2,6b-difluoro-7-hydroxy-8b-(2-hydroxyacetyl)-6a,8a-dimethyl-10-(4-(((2-acyltetrahydrofuran-3-yl)sulfonyl)methyl)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]dioxolane-4-one (58)

[0620] 4-(((2-Acyltetrahydrofuran-3-yl)sulfonyl)methyl)benzaldehyde

[0621] 4-(((2-acyltetrahydrofuran-3-yl)thioyl)methyl)benzaldehyde (1 g, 4.23 mmol), m-chloroperbenzoic acid (3.6 g, 0.02 mol), and 30 mL of acetonitrile were added to a reaction flask and reacted at room temperature for 8 hours. After the reaction was completed, water and ethyl acetate were added, the liquid was extracted, and the organic phase was washed with water and saturated brine in sequence and concentrated under reduced pressure. The crude product was separated and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 2 / 1) and concentrated under reduced pressure to obtain 0.84 g of 4-(((2-acyltetrahydrofuran-3-yl)sulfonyl)methyl)benzaldehyde, with a yield of 74%. MS m / z (ESI): 269.15 [M+H] +

[0622] (6α,9α,11β,16α)-6,9-difluoro-11,16,17,21-tetrahydroxy-pregna-1,4-diene-3,20-dione (0.5 g, 1.21 mmol), 4-(((2-acyltetrahydrofuran-3-yl)sulfonyl)methyl)benzaldehyde (0.39 g, 1.45 mmol), and 30 mL of acetonitrile were added to a reaction flask. Perchloric acid (0.3 mL, 3.64 mmol) was slowly added dropwise. The reaction was allowed to proceed at room temperature. TLC monitoring was performed until the (6α,9α,11β,16α)-6,9-difluoro-11,16,17,21-tetrahydroxy-pregna-1,4-diene-3,20-dione was absent. After completion of the reaction, the mixture was concentrated under reduced pressure, and water and dichloromethane were added. The separated liquids were extracted and the organic phases were combined, washed with saturated brine, and concentrated under reduced pressure. The crude product was separated and purified by silica gel column chromatography (dichloromethane / acetone = 4 / 1) and concentrated under reduced pressure to obtain 0.42 g of compound 58. Yield: 52%. 1H NMR (400MHz, d6-DMSO): δ8.83(m,2H),7.01(m,1H),6.41(m,1H),6.33(s,1H),6.05(m,1H),5.01(s,1H),4.88(s,1H),4.79(m,2H) ,4.42-4.12(m,5H),3.86(m,2H),3.52(m,1H),2.54-2.31(m,4H),2.35-1.65(m,7H),1.48-1.35(m,3H),1.08(m,1H),0.85(m,3H). MS m / z(ESI): 663.32[M+H] +

[0623] Synthesis Example 59

[0624] (6aS,6bR,7S,8aS,8bS,11aR,12aS,12bS)-6b-fluoro-7-hydroxy-8b-(2-hydroxyacetyl)-6a,8a-dimethyl-10-(4-(((2-acyltetrahydrofuran-3-yl)sulfonyl)methyl)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]dioxolane-4-one (59)

[0625] (9α,11β,16α)-9-fluoro-11,16,17,21-tetrahydroxy-pregna-1,4-diene-3,20-dione (0.5 g, 1.27 mmol), 4-(((2-acyltetrahydrofuran-3-yl)sulfonyl)methyl)benzaldehyde (0.4 g, 1.52 mmol), and 30 mL of acetonitrile were added to a reaction flask. Perchloric acid (0.32 mL, 3.8 mmol) was slowly added dropwise. The reaction was allowed to proceed at room temperature. TLC monitoring was performed until the (9α,11β,16α)-9-fluoro-11,16,17,21-tetrahydroxy-pregna-1,4-diene-3,20-dione was eliminated. After completion of the reaction, the mixture was concentrated under reduced pressure. Water and dichloromethane were added, and the separated layers were extracted. The organic phases were combined, washed with saturated brine, and concentrated under reduced pressure. The crude product was separated and purified by silica gel column chromatography (dichloromethane / acetone = 4 / 1) and concentrated under reduced pressure to obtain 0.44 g of compound 59. Yield: 52%. 1H NMR (400MHz, d6-DMSO): δ8.85(m,2H),6.99(m,1H),6.38(m,1H),6.28(s,1H),6.03(m,1H),5.10(s,1H),4.98(s,1H),4.78-4.42(m,4H),4. 21(m,1H),3.75(s,2H),3.35(m,1H),2.56-2.37(m,4H),2.31-1.85(m ,6H),1.79-1.69(m,4H),1.58-1.38(m,3H),1.02(m,1H),0.87(m,3H). MS m / z(ESI): 645.23[M+H] +

[0626] Synthesis Example 60

[0627] (6aS,6bR,7S,8aS,8bS,11aR,12aS,12bS)-6b-chloro-7-hydroxy-8b-(2-hydroxyacetyl)-6a,8a-dimethyl-10-(4-(((2-acyltetrahydrofuran-3-yl)sulfonyl)methyl)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]dioxolane-4-one (60)

[0628] (9α,11β,16α)-9-chloro-11,16,17,21-tetrahydroxy-pregna-1,4-diene-3,20-dione (0.5 g, 1.22 mmol), 4-(((2-acyltetrahydrofuran-3-yl)sulfonyl)methyl)benzaldehyde (0.39 g, 1.46 mmol), and 30 mL of acetonitrile were added to a reaction flask. Perchloric acid (0.3 mL, 3.65 mmol) was slowly added dropwise. The reaction was allowed to proceed at room temperature. TLC monitoring was performed until the (9α,11β,16α)-9-chloro-11,16,17,21-tetrahydroxy-pregna-1,4-diene-3,20-dione was absent. After completion of the reaction, the mixture was concentrated under reduced pressure, and water and dichloromethane were added. The separated liquids were extracted and the organic phases were combined, washed with saturated brine, and concentrated under reduced pressure. The crude product was separated and purified by silica gel column chromatography (dichloromethane / acetone = 4 / 1) and concentrated under reduced pressure to obtain 0.43 g of compound 60. Yield: 54%. 1H NMR (400MHz, d6-DMSO): δ8.79(m,2H),7.02(m,1H),6.35(m,1H),6.31(s,1H),6.02(m,1H),5.04(s,1H),4.94(s,1H),4.72-4.44(m,4H),4. 21(m,1H),3.68(s,2H),3.33(m,1H),2.56-2.37(m,4H),2.33-1.87(m ,6H),1.74-1.68(m,4H),1.55-1.42(m,3H),1.22(m,1H),0.86(m,3H). MS m / z(ESI): 661.32[M+H] +

[0629] Pharmacological Example 1 Determination of agonist activity of glucocorticoid receptor (GR)

[0630] 1.1 Preparation of stock solution

[0631] Test compound stock solution: Accurately weigh the test compound (Compound 1-60), dissolve it in DMSO to prepare a stock solution with a concentration of 20 mM, and store it at -20°C.

[0632] 1.2 Preparation of test solution

[0633] The test substance was diluted 4-fold starting at 10 μM, and serially diluted to 10 concentrations with replicates. The blank control was 0.1% DMSO.

[0634] 1.3 Cell culture

[0635] HEK293 cells (Beijing Aisiyipu Biotechnology Co., Ltd., batch number TYP-20220519) transiently transfected with glucocorticoid receptor (GR) were cultured in Dulbecco's Modified Eagle Medium (DMEM) + 10% fetal bovine serum (FBS) + 200 μg / ml Hygromycin B in a 37°C incubator with 5% CO2. The old medium was removed and the cells were washed once with phosphate-buffered saline (PBS), and then 1 mL of TrypLE was added. TM Incubate the cells in Express solution at 37°C for approximately 2 minutes. Once the cells have detached from the bottom of the dish, add approximately 5 mL of complete culture medium preheated at 37°C. Gently pipette the cell suspension to dissociate any aggregated cells. Transfer the cell suspension to a sterile centrifuge tube and centrifuge at 1000 rpm for 5 minutes to collect the cells for use in experiments or subculture.

[0636] 1.4 Determination of GR receptor agonist activity of compounds

[0637] HEK293 cells were digested and seeded into 6 cm dishes. The pBIND-GR plasmid was transfected into HEK293 cells using a transfection reagent to obtain HEK293 cells successfully transfected with the pBIND-GR plasmid. The cells were resuspended in phenol red-free DMEM medium containing 5% carbon-adsorbed serum, counted, and seeded into 96-well plates. The test substances were added and then incubated in an incubator. The luminescence signal value was read using a multi-function microplate reader according to the instructions of the luciferase assay kit. The EC of each test substance was calculated using the nonlinear fitting formula of GraphPad Prism 8.0 software. 50 value.

[0638] 1.5 Results

[0639] Table 1 Agonist activity of glucocorticoid receptor

[0640] The results showed that the compounds provided by the present invention all had agonist activity on the glucocorticoid receptor (GR), among which compounds 7, 8, 10, 11, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 34, 35, 36, 37, 38, 45, 46, 47, 48, 49, 50, 51, 55, 56, and 57 showed an EC lower than 3 nM. 50 Further compounds 8, 11, 16, 17, 19, 20, 21, 22, 23, 26, 34, 35, 36, 37, 38, 46, 47, 48, 50, 51, and 57 showed EC values ​​below 1 nM. 50 value.

[0641] Pharmacological Example 2 Determination of agonist activity of mineralocorticoid receptor (MR) and progesterone receptor (PR)

[0642] 2.1 Preparation of stock solution

[0643] Test substance stock solution: Accurately weigh each test compound (compounds 4, 5, 7, 8, 9, 11, 13, 16, 17, 18, 22, 23, 24, 34, 35, 36, 38, 41, 45, 47, 53, 55, 59), dissolve in DMSO to prepare a stock solution with a concentration of 20 mM, and store at -20°C.

[0644] 2.2 Preparation of test solution

[0645] The test substance was diluted 4-fold starting at 50 μM, and serially diluted to 12 concentrations with replicate wells. The blank control was 0.1% DMSO.

[0646] 2.3 Cell culture

[0647] HEK293 stably transfected cells expressing mineralocorticoid receptor (MR) and progesterone receptor (PR) (Beijing Aisiyipu Biotechnology Co., Ltd., batch numbers TYP-20220819 and TPJ-20220812) were cultured in Dulbecco's Modified Eagle Medium (DMEM) supplemented with 10% fetal bovine serum (FBS) and 200 μg / ml Hygromycin B at 37°C in a 5% CO2 incubator. The old medium was removed and the cells were washed once with phosphate-buffered saline (PBS), followed by the addition of 1 mL of TrypLE TM Incubate the cells in Express solution at 37°C for approximately 2 minutes. Once the cells have detached from the bottom of the dish, add approximately 5 mL of complete culture medium preheated at 37°C. Gently pipette the cell suspension to dissociate any aggregated cells. Transfer the cell suspension to a sterile centrifuge tube and centrifuge at 1000 rpm for 5 minutes to collect the cells for use in experiments or subculture.

[0648] 2.4 Determination of the agonist activity of compounds on MR and PR

[0649] HEK293 cells were digested and inoculated into 6 cm dishes. The pBIND-MR and pBIND-PR plasmids were transfected into HEK293 cells using transfection reagents, respectively, to obtain HEK293 cells successfully transfected with pBIND-MR and pBIND-PR plasmids. The cells were resuspended in phenol red-free DMEM medium containing 5% carbon-adsorbed serum, counted, and inoculated into 96-well plates. The test substances were added and then incubated in an incubator. The luminescence signal value was read using a multi-function microplate reader according to the instructions of the luciferase assay kit, and the EC of each test substance was calculated using the nonlinear fitting formula of GraphPad Prism 8.0 software. 50 value.

[0650] 2.5 Results

[0651] Table 2 Agonist activity of mineralocorticoid receptor and progesterone receptor

[0652] The results showed that the compounds provided by the present invention had no agonist activity on either the mineralocorticoid receptor (MR) or the progesterone receptor (PR). Compared with the MR receptor and the PR receptor, the compounds provided by the present invention had higher target selectivity for the glucocorticoid receptor (GR).

[0653] Under the same experimental conditions, the target selectivity of compounds 20, 21, 26, 37, 46, 48, 51 and the like of the present invention is similar to that of compound 23, and will not be further elaborated here.

[0654] Pharmacological Example 3 In vitro plasma stability determination

[0655] 3.1 Preparation of working solution

[0656] Accurately weigh the test compound 8 and dissolve it in DMSO to prepare a 10 mM stock solution. Dilute the stock solution with acetonitrile to a 100 μM working solution. Prepare immediately before use and use at room temperature.

[0657] 3.2 Plasma incubation

[0658] Table 3 Plasma incubation experimental conditions

[0659] 990 μL of human and mouse plasma (N=2) were pre-incubated at 37°C for 5 min, and 10 μL of the test compound working solution was added and vortexed to mix thoroughly (final concentration of the test compound was 1 μM). Immediately, 50 μL of the plasma sample was added to 150 μL of ice precipitant containing the internal standard and vortexed to mix thoroughly as the time 0 sample. The remaining plasma sample was incubated at 37°C. At the predetermined sampling time point, 50 μL of the plasma sample was aspirated and added to 150 μL of ice precipitant containing the internal standard and vortexed to mix thoroughly. The collected samples were stored in a refrigerator at -60 to -90°C until testing.

[0660] 3.3 Sample analysis

[0661] The LC-MS / MS method was used for analysis to determine the concentration of the test compound and observe its reduction (semi-quantitative determination was performed by the ratio of the peak area of ​​the test compound to the peak area of ​​the internal standard).

[0662] 3.4 Results

[0663] Table 4 Half-life T in plasma of different species 1 / 2 (min)

[0664] The results show that the half-life of compound 8 provided by the present invention in human and mouse plasma is less than 30 minutes, and it is unstable in plasma.

[0665] In addition, the compound 8 provided by the present invention is relatively stable in animal lung tissue homogenate, skin tissue homogenate and aqueous humor.

[0666] Under the same experimental conditions, compounds 16, 17, 20, 21, 22, 23, 26, 34, 35, 36, 37, 46, 47, 48, and 51 of the present invention all have the characteristics of plasma instability and are relatively stable in animal lung tissue homogenates, skin tissue homogenates, and aqueous humor.

[0667] Pharmacological Example 4 Anti-asthma pharmacodynamics experiment

[0668] 4.1 Test sample preparation method

[0669] Test sample: Accurately weigh the jet-pulverized compounds 8, 11, and 23, and prepare a suspension with a concentration of 0.3 mg / ml using citric acid-sodium citrate buffer (pH 5.4) containing 2% Tween 80 as the test sample. Store at room temperature in the dark for later use.

[0670] Positive control drug: Budesonide suspension for inhalation (specification 2 ml: 1 mg; AstraZeneca; batch number 327392) was diluted with sodium chloride solution for injection to 0.3 mg / ml as a positive control drug and stored in the dark at room temperature for later use.

[0671] 4.2 Model preparation

[0672] Sixty female BALB / c mice were adaptively fed. After one week, 10 mice were randomly selected as a blank control group, and 50 mice were used to establish an asthma model. All 50 model mice were sensitized with 0.2 mL of a sensitizing solution containing 50 μg OVA and 2 mg Al(OH)3 via intraperitoneal injection on days 0, 7, and 14. A control group received an equal volume of saline.

[0673] On days 21-23 after sensitization, mice in the model group and the drug-treated group were challenged with 5% OVA by aerosol for 30 min, and mice in the normal group were challenged with physiological saline by aerosol for the same period of time.

[0674] 4.3 Grouping and Dosing

[0675] 30 minutes before daily stimulation, mice in the blank group and model group were intratracheally administered with 50 μl of normal saline, and mice in the compound 8, 11, 23 and positive drug budesonide groups were intratracheally administered with 50 μl of corresponding drugs, once a day for 3 consecutive days.

[0676] Table 5 Animal grouping and dosage

[0677] 4.4 Airway hyperresponsiveness measurement

[0678] Airway reactivity was measured in each group of mice after the final challenge. Mice were placed in a body scan chamber, and after measuring the baseline expiratory pause (Penh) value, they were challenged with nebulized methacholine. The concentrations of methacholine ranged from 0, 6.25, and 12.5 mg / mL, with a nebulized dose of 100 μL per session for 60 seconds. After each concentration, the mice were observed for signs of hypoxia, such as shortness of breath, head scratching, and irritability. The Penh values ​​were then recorded for 3 minutes, and the average values ​​were taken to compare airway reactivity among the groups.

[0679] 4.5 Sample Collection and Detection of Inflammatory Factors in Bronchoalveolar Lavage Fluid

[0680] After the mouse airway hyperresponsiveness test was completed, the mice were killed by dislocating the cervical vertebrae and fixed on a dissecting dish. The abdomen and chest cavity of the mice were opened, the skin and excess tissue on the neck were cut off, the mouse trachea was exposed, and a small incision was made on the transverse axis of the trachea with small scissors. A 1ml syringe needle that had been processed in advance was inserted and the needle was fixed with surgical thread. 0.5ml of pre-cooled phosphate buffered saline (PBS) was drawn with a 1ml syringe and slowly injected into the mouse lungs, and then slowly aspirated. Each mouse was lavaged once, and a total of about 0.4ml of lavage fluid was collected. The alveolar lavage fluid was centrifuged at 3000rpm for 5min. After centrifugation, the supernatant was packaged and the content of inflammatory factors IL-6 and IL-12 in the alveolar lavage fluid was determined using an ELISA kit.

[0681] 4.6 Statistics

[0682] SPSS software was used for statistical analysis. The measurement data were expressed as mean ± standard deviation. One-way ANOVA was used for comparison between groups. LSD test was used for homogeneous variances, and Dunnett-t test was used for unequal variances. P < 0.05 was considered statistically significant.

[0683] 4.7 Results

[0684] 4.7.1 Effects on Airway Hyperresponsiveness in Mice

[0685] Table 6 Effects on the expiratory interval (Penh) value of mice Note: Compared with the blank group, ## P<0.01, ### P<0.001; compared with the model group, * P<0.05, ** P<0.01, *** P<0.001.

[0686] Mice were sensitized with OVA+Al(OH)3 for 3 weeks and then stimulated with 5% OVA for 3 consecutive days. After stimulation with 6.25 mg / ml and 12.5 mg / ml methacholine, the Penh value was significantly increased compared with the blank control group (P<0.001), proving that the mouse asthma model was successfully established.

[0687] Compared with the model group, the nebulized administration of the positive drug budesonide before provocation significantly reduced the expiratory pause (Penh) value of the mice (P<0.01); the nebulized administration of compounds 8, 11, and 23 before provocation significantly reduced the expiratory pause (Penh) value of the mice, among which compounds 11 and 23 showed extremely significant differences (P<0.001).

[0688] Under the same experimental conditions, the pharmacological effects of compounds 16, 17, 20, 21, 22, 26, 34, 35, 36, 37, 46, 47, 48, and 51 of the present invention are similar to those of compound 23, and all can significantly reduce the expiratory interval (Penh) value of mice, and compared with the model group, all have extremely significant differences (P<0.001).

[0689] 4.7.2 Effects on Inflammatory Factors in Mouse Bronchoalveolar Lavage Fluid

[0690] Table 7 Effects on inflammatory factors in mouse bronchoalveolar lavage fluid Note: Compared with the blank group: ###P<0.001; compared with the model group: ***P<0.001.

[0691] After mice were sensitized with OVA+Al(OH)3 for 3 weeks and then stimulated with 5% OVA for 3 consecutive days, the levels of IL-6 and IL-12 in the alveolar lavage fluid increased significantly (P<0.001), proving that the mouse asthma model was successfully established.

[0692] Compared with the model group, the IL-6 and IL-12 levels of mice were significantly reduced after aerosol administration of the positive drug budesonide, compounds 8, 11, and 23 before provocation (P<0.001), indicating that compounds 8, 11, and 23 can significantly inhibit the high airway responsiveness of asthma model mice and inhibit inflammatory factors in alveolar lavage fluid, and have significant anti-inflammatory activity.

[0693] Under the same experimental conditions, compounds 16, 17, 20, 21, 22, 26, 34, 35, 36, 37, 46, 47, 48, and 51 of the present invention had similar efficacy to compound 23, and could significantly inhibit the high airway responsiveness of asthma model mice, and had extremely significant differences compared with the model group (P<0.001).

[0694] Pharmacological Example 5 Anti-uveitis Pharmacodynamics Experiment

[0695] 5.1 Test sample preparation method

[0696] Test sample: Compounds 23 and 26 were prepared as 5 mg / 5 mL suspension eye drops according to the formulation of fluorometholone eye drops. They were stored at room temperature in the dark and ready for use.

[0697] Positive control drug: Fluorometholone eye drops (specification 5 ml / 5 mg; Santen Pharmaceutical (China) Co., Ltd.; batch number J20180068) were used as positive control drug and stored in the dark at room temperature for later use.

[0698] 5.2 Model preparation

[0699] Fifty male SD rats were fed adaptively for one week and then randomly divided into five groups: group 1 was a blank group, and groups 2-5 were model, fluorometholone, compound 23, and compound 26, respectively. Groups 2-5 were given a single subcutaneous injection of 1 mg / kg LPS (Salmonella; Sigma; batch number: 0000164114) at the sole of the rat to establish a rat uveitis model. Salmonella endotoxin was dissolved in saline and prepared into an injection solution with a concentration of 2 mg / mL. 1 mg / kg was injected into the subcutaneous tissue of one sole of the rat. Group 1 was injected with an equal amount of saline.

[0700] 5.3 Grouping and Dosing

[0701] After modeling, 40 μl of normal saline was administered to the eyes (bilaterally) of mice in the blank group and model group, and 40 μl of the corresponding drugs were administered to the eyes (bilaterally) of mice in the compound 23, 26 group and the positive drug fluorometholone group, 3 times a day for 2 days.

[0702] Table 8 Animal grouping and dosage

[0703] 5.4 Record of eye injuries

[0704] At the end of the experiment, photos of the rats' eyes were taken using a slit lamp microscope, and the differences in eye lesions among the rats in each group were compared and analyzed.

[0705] 5.5 Sample Collection and Detection of Aqueous Humor Inflammatory Factors

[0706] After 30 hours of modeling, the aqueous humor of both eyes of the rats was collected, and part of the eyeballs of the rats were retained to detect the content of inflammatory factors (TNF-α) using a rat ELISA detection kit.

[0707] 5.6 Statistics

[0708] SPSS software was used for statistical analysis. The measurement data were expressed as mean ± standard deviation. One-way ANOVA was used for comparison between groups. LSD test was used for homogeneous variances, and Dunnett-t test was used for unequal variances. P < 0.05 was considered statistically significant.

[0709] 5.7 Results

[0710] 5.7.1 Ocular pathology scoring

[0711] Table 9 Rat eye symptom scores Note: Compared with the blank group, ## P<0.01, ### P<0.001; compared with the model group, *P<0.05, ** P<0.01, *** P<0.001.

[0712] After LPS was injected into the subcutaneous tissue of the rat's sole, the model group showed obvious abnormalities in the eyes compared with the blank group, proving that the rat uveitis model was successfully established.

[0713] Compared with the model group, the eye abnormalities of rats were significantly improved after administration of the positive drugs fluorometholone, compounds 23 and 26, and the eye pathology scores were significantly reduced.

[0714] In addition, compounds 23 and 26 provided by the present invention can also significantly inhibit the ocular inflammatory response of uveitis model rats, inhibit inflammatory factors in the aqueous humor, and have significant anti-inflammatory activity.

[0715] Under the same experimental conditions, Compound 16, Compound 17, Compound 20, Compound 21, Compound 22, Compound 34, Compound 35, Compound 36, Compound 37, Compound 46, Compound 47, Compound 48, Compound 51 and the like of the present invention have similar efficacy to Compound 23, and can significantly improve ocular abnormalities and inhibit inflammatory factors in aqueous humor, showing significant anti-inflammatory activity. Pharmacological Example 6 Pharmacodynamic Experiment on the Treatment of Dry Eye in New Zealand Rabbits

[0716] 6.1 Test sample preparation method

[0717] Test sample: Compounds 20 and 23 were prepared as 5 mg / 5 mL suspension eye drops, according to the formulation of fluorometholone eye drops, and stored at room temperature in the dark for later use.

[0718] Positive control drug: Fluorometholone eye drops (specification 5 ml / 5 mg; Santen Pharmaceutical (China) Co., Ltd.; batch number 1FM6625) were used as positive control drug and stored in the dark at room temperature for future use.

[0719] 6.2 Model preparation

[0720] Thirty standard male New Zealand rabbits were randomly selected as the blank control group. Six rabbits were treated with 0.1% benzalkonium chloride instillations in the left eye twice daily, morning and evening, at a rate of 10 μL per rabbit. On the sixth day of modeling, tear secretion was measured using a phenol red cotton thread to determine if the model was successfully established. After the model was established, the rabbits were randomly divided into four groups based on the length of the phenol red cotton thread: the model group, the fluorometholone group, the compound 20 group, and the compound 23 group, with six rabbits in each group. During the treatment period, 10 μL of 0.1% benzalkonium chloride was administered to the left eye of each New Zealand rabbit once daily, except for the blank control group, to maintain dry eye symptoms.

[0721] 6.3 Grouping and Dosing

[0722] The New Zealand rabbits in the blank group and the model group were given 50 μL of normal saline in the eyes (bilaterally), and the compound 20, 23 group and the positive drug fluorometholone group were given 50 μL of the corresponding drugs in the eyes (bilaterally), 3 times a day for 14 consecutive days.

[0723] Table 10 Animal grouping and dosage

[0724] 6.4 Tear secretion detection

[0725] Detection time: D3, D7, D 15 ;

[0726] Testing animals: All animals were tested before grouping; all surviving animals were tested after drug administration;

[0727] Test method: Tear secretion is measured using a phenol red cotton thread. A tear secretion test strip is folded back and placed approximately at the middle and outer thirds of the rabbit's conjunctival sac. Time for 1 minute, remove the strip, and observe and record the wet length of the filter paper. Repeat the measurement three times and take the average value.

[0728] 6.5 Tear film breakup time

[0729] Detection time: D3, D7, D 15 ;

[0730] Testing animals: All animals were tested before grouping; all surviving animals were tested after drug administration;

[0731] Test method: 1% sodium fluorescein is dripped onto the inner side of the rabbit's lower eyelid at a rate of 10 μL per rabbit. The rabbit's eyes are then closed and gently rubbed to evenly distribute the sodium fluorescein over the ocular surface. Both rabbits are then placed under a slit lamp. The tear film breakup time (TBT) is the time from eye opening to the appearance of the first dark spot. The time without the appearance of a dark spot is calculated as 60 seconds.

[0732] 6.6 Corneal fluorescein sodium staining

[0733] Detection time: D3, D7, D 15 ;

[0734] Testing animals: All animals were tested before grouping; all surviving animals were tested after drug administration;

[0735] Detection method: Drop 2 μL of 1% sodium fluorescein into the conjunctival sac, rinse the excess fluorescein with 0.9% saline after 5 seconds, and observe the conjunctival staining under cobalt blue diffuse light of a slit lamp.

[0736] 6.7 Statistics

[0737] Normality and homogeneity of variance were tested using the Leven's test. If the results were not statistically significant (P>0.05), statistical analysis was performed using one-way analysis of variance (ANOVA). If the ANOVA results were statistically significant (P≤0.05), comparative analysis was performed using the LSD test (parametric method). If the variances were not homogeneous (P≤0.05), the Kruskal-Wallis test was used. If the Kruskal-Wallis test was statistically significant (P≤0.05), comparative analysis was performed using the Dunnett's test (nonparametric method).

[0738] 6.8 Results

[0739] 6.8.1 Tear secretion detection

[0740] Table 11 Tear secretion detection Note: Compared with the blank group, ## P<0.01, ### P<0.001; compared with the model group, * P<0.05, ** P<0.01, *** P<0.001.

[0741] After benzalkonium chloride was added to the eyes of New Zealand rabbits, the tear secretion of the model group was significantly reduced compared with the blank group, proving that the New Zealand rabbit dry eye model was successfully established.

[0742] Compared with the model group, the tear secretion of New Zealand rabbits was significantly increased on the 15th day after administration of the positive drug fluorometholone, compounds 20 and 23.

[0743] Under the same experimental conditions, compounds 16, 17, 21, 22, 26, 34, 35, 36, 37, 46, 47, 48, and 51 of the present invention have similar pharmacological effects to compound 23 and can significantly increase tear secretion.

[0744] 6.8.2 Tear film breakup time detection

[0745] Table 12 Tear film breakup time detection Note: Compared with the blank group, ## P<0.01, ### P<0.001; compared with the model group, * P<0.05, ** P<0.01, *** P<0.001.

[0746] After benzalkonium chloride was added to the eyes of New Zealand rabbits, the tear film breakup time of the model group was significantly reduced compared with the blank group, proving that the New Zealand rabbit dry eye model was successfully established.

[0747] Compared with the model group, the tear film breakup time of New Zealand rabbits was significantly increased on the 15th day after administration of the positive drug fluorometholone, compounds 20 and 23.

[0748] Under the same experimental conditions, compounds 16, 17, 21, 22, 26, 34, 35, 36, 37, 46, 47, 48, and 51 of the present invention have similar efficacy to compound 23 and can significantly increase the tear film breakup time.

[0749] 6.8.3 Corneal fluorescein sodium staining scoring

[0750] Table 13 Corneal fluorescein sodium staining scores Note: Compared with the blank group, ## P<0.01, ### P<0.001; compared with the model group, * P<0.05, ** P<0.01, *** P<0.001.

[0751] After benzalkonium chloride was added to the eyes of New Zealand rabbits, the corneal fluorescein sodium staining scores of the model group were significantly increased compared with the blank group, proving that the New Zealand rabbit dry eye model was successfully established.

[0752] Compared with the model group, the New Zealand rabbits' eyes could significantly inhibit the ocular surface inflammatory response on the 15th day after being administered the positive drug fluorometholone, compounds 20, and 23, indicating that compounds 20 and 23 can significantly alleviate the ocular symptoms of New Zealand rabbits with dry eye model, inhibit the inflammatory response of the ocular surface, and have significant anti-inflammatory activity.

[0753] Under the same experimental conditions, compounds 16, 17, 21, 22, 26, 34, 35, 36, 37, 46, 47, 48, and 51 of the present invention have similar efficacy to compound 23 and can significantly alleviate the ocular symptoms of New Zealand rabbits with dry eye model.

[0754] Pharmacological Example 7 Pharmacodynamics Experiment on Inflammatory Bowel Disease in Rats

[0755] 7.1 Test sample preparation method

[0756] Test sample: Accurately weigh the airflow-pulverized compounds 23 and 34, first prepare a 2 mg / mL clear solution with anhydrous ethanol, then add double-distilled water to dilute to a 0.2 mg / mL solution as the test sample, store at room temperature in the dark, and set aside.

[0757] Positive control drug: Dexamethasone was prepared into a 0.2 mg / mL suspension solution with 0.5% sodium carboxymethyl cellulose and stored in the dark at room temperature for later use.

[0758] 7.2 Model preparation

[0759] 38 rats that passed the quarantine were randomly divided into 5 groups. Group 1 was a blank group, and groups 2-5 were model group, dexamethasone group, compound 23 group, and compound 34 group, respectively. Animals in groups 2-5 were subjected to trinitrobenzenesulfonic acid (TNBS) modeling as follows: 5% TNBS aqueous solution was adjusted to 20mg / mL TNBS (50% ethanol solution) by alcohol and water; after the rats were fasted for 24 hours, they were anesthetized using an inhalation anesthesia machine, and a silicone hose was inserted from the anus. After the hose entered about 8cm, TNBS was injected at a dose of 50mg / kg TNBS. After the injection was completed, the rats were placed vertically for 1min to prevent reflux of TNBS liquid, and then placed in a cage and observed until the animals recovered.

[0760] 7.3 Grouping and Dosing

[0761] Drug administration began the day before modeling, with a single dose 1 hour before modeling and then daily for 5 consecutive days. Rats in the blank and model groups were intragastrically administered with 20% ethanol solution, the dexamethasone group was intragastrically administered with 2 mg / kg of the drug, and the compound 23 and 34 groups were intragastrically administered with 2 mg / kg of the corresponding drug.

[0762] Table 14 Animal grouping and dosage

[0763] 7.4 Systematic (or gross) anatomy and histopathological examination

[0764] The experiment was terminated on the 5th day after TNBS modeling. After isoflurane anesthesia, blood was taken from the heart and euthanasia was performed. The abdominal cavity was quickly opened, and the rat colon macroscopic injury score was performed based on adhesion, obstruction, colon wall thickening, colon congestion and necrosis in the colon; the colon contents were cleaned, the colon samples were cut longitudinally, and the proximal 2 / 3 of the colon were taken and prepared into Swiss rolls, which were then stored in 4% neutral formalin buffer for histopathological analysis. The tissue was trimmed, dehydrated, paraffin-embedded and sliced ​​(about 5 μm thick), stained with hematoxylin-eosin (HE), and observed for pathological changes. A pathologist scored the colon lesions blindly.

[0765] 7.5 Statistics

[0766] Quantitative indicators were first tested for homogeneity of variance using the Bartlett's test. When homogeneity of variance was achieved (P>0.05), one-way analysis of variance (ANOVA) was used for statistical analysis. If statistically significant (P≤0.05), Dunnett's t test (Dunnett method) was used to compare differences between groups. If statistically insignificant (P>0.05), statistical analysis was terminated. If heterogeneity of variance was achieved (P≤0.05), the Kruskal-Wallis H rank sum test (KW method) was used for statistical analysis. If statistically significant (P≤0.05), Mann-Whitney U test (MW method) was used to compare differences between groups. If statistically insignificant (P>0.05), statistical analysis was terminated.

[0767] 7.6 Results

[0768] 7.6.1 Macroscopic injury score of rat colon

[0769] Table 15 Macroscopic injury scores of rat colon Note: Compared with the blank group, ## P<0.01, ### P<0.001; compared with the model group, * P<0.05, ** P<0.01, *** P<0.001.

[0770] After rats were given TNBS through the rectum, the colon surface of the model group showed significant abnormalities compared with the blank group, proving that the rat inflammatory bowel disease model was successfully established.

[0771] Compared with the model group, the rat colon can significantly inhibit the inflammatory response on the intestinal surface after administration of the positive drug dexamethasone, compounds 23 and 34, indicating that compounds 23 and 34 can significantly alleviate the intestinal symptoms of inflammatory bowel disease model rats, inhibit the inflammatory response on the intestinal surface, and have significant anti-inflammatory activity.

[0772] Under the same experimental conditions, compounds 16, 17, 20, 21, 22, 26, 35, 36, 37, 46, 47, 48, and 51 of the present invention have similar efficacy to compound 23 and can significantly alleviate the intestinal symptoms of rats with inflammatory bowel disease models.

[0773] Pharmacological Example 8 Pharmacodynamics Experiment on Psoriasis in Mice

[0774] 8.1 Test sample preparation method

[0775] Test sample: Compounds 8, 17, and 23 were prepared as 0.1% creams according to the formulation of fluticasone propionate cream, stored at room temperature in the dark, and set aside.

[0776] Positive control drug: fluticasone propionate cream (specification 0.05% × 15g, Zhejiang Xianjun Pharmaceutical Co., Ltd., batch number: 211106), stored at room temperature in the dark for later use.

[0777] 8.2 Model preparation

[0778] Adult mice were selected, and a 2cm×3cm area of ​​the mouse back skin was locally depilated. The model group and the treatment group mice were smeared with 5% imiquimod cream 62.5mg on the back to establish the model. The blank group mice were smeared with medical vaseline on the back every day. The above process was repeated once a day for 7 consecutive days.

[0779] 8.3 Grouping and Dosing

[0780] Forty-eight mice were randomly divided into six groups, including a blank group, a model group, a fluticasone propionate cream group, a compound 8 group, a compound 17 group, and a compound 23 group, with eight animals in each group. Mice in the drug-treated groups received a daily 0.2g application of the corresponding drug matrix to their backs. The control and model groups received only 0.2g of the test drug matrix. One hour after drug administration, the drug was wiped clean with a sterile cotton swab, and imiquimod was then applied. This process was repeated once daily for seven consecutive days.

[0781] Table 16 Animal grouping and dosage

[0782] 8.4 Index detection

[0783] 8.4.1 Skin Lesion Scoring

[0784] With reference to the clinical Psoriasis Area and Severity Index (PASI) scoring standard, the erythema, scaling, and thickness of the lesions were scored from 0 to 4 on the 8th day of modeling, and the total score was obtained by adding the three scores.

[0785] PASI scoring criteria: (1) Erythema: 0 means no erythema, 1 means light red erythema, 2 means red erythema, 3 means dark red erythema, and 4 means very dark erythema; (2) Squama: 0 means no scales on the surface, 1 means scales covering part of the lesion surface, 2 means scales covering most of the lesion surface, 3 means almost all of the lesion is covered with scales in layers, and 4 means all of the lesion is covered with scales; (3) Thickness: 0 means the lesion is flush with the normal skin, 1 means the lesion is slightly higher than the normal skin surface, 2 means the lesion is moderately raised, 3 means the lesion is thickened and obviously raised, and 4 means the lesion is highly thickened and obviously raised.

[0786] 8.4.2 Determination of serum inflammatory factors

[0787] After PASI scoring on the 8th day of modeling, blood was collected from the mouse orbits and centrifuged at 3000 rpm for 10 min. The supernatant was taken to detect IL-17 content according to the instructions of the ELISA kit.

[0788] 8.5 Statistics

[0789] SPSS software was used for statistical analysis. The data were expressed as mean ± standard deviation. One-way ANOVA was used for comparison between groups. LSD test was used for homogeneous variances, and Dunnett-t test was used for unequal variances. P < 0.05 was considered statistically significant.

[0790] 8.6 Results

[0791] 8.6.1 Effects on PASI Scores in Mice

[0792] Table 17 PASI scores of mice Note: Compared with the control group: ### P<0.001; compared with the model group: *** P<0.001.

[0793] After the back of mice was treated with imiquimod, the skin of the model group was significantly thickened compared with the blank group, and scales and erythema appeared. The PASI score increased significantly, proving that the mouse psoriasis model was successfully established.

[0794] Compared with the model group, the PASI scores of mice on the back were significantly decreased on the 7th day after administration of the positive drugs fluticasone propionate, compounds 8, 17, and 23.

[0795] Under the same experimental conditions, compound 16, compound 20, compound 21, compound 22, compound 26, compound 34, compound 35, compound 36, compound 37, compound 46, compound 47, compound 48, compound 51, etc. had similar efficacy to compound 23, and the PASI scores on day 7 were significantly decreased.

[0796] 8.6.2 Effects on Serum Inflammatory Factors

[0797] Table 18 Effects on IL-17 levels in mouse serum Note: Compared with the blank control group: ##P<0.01; compared with the model group: *P<0.05, **P<0.01.

[0798] After mice were treated with imiquimod for 7 days, the IL-17 content in the serum increased significantly, proving that the mouse psoriasis model was successfully established.

[0799] Compared with the model group, the IL-17 content was significantly reduced after the positive drug fluticasone propionate, compounds 8, 17, and 23 were administered to the mouse skin, indicating that compounds 8, 17, and 23 can significantly inhibit the inflammatory factors in the skin of psoriasis model mice and have significant anti-inflammatory activity.

[0800] Under the same experimental conditions, compounds 16, 20, 21, 22, 26, 34, 35, 36, 37, 46, 47, 48, and 51 had similar efficacy to compound 23 and could significantly inhibit inflammatory factors in the skin of psoriasis model mice.

[0801] Pharmacological Example 9 Adverse reaction experiment of continuous administration to guinea pig eyes

[0802] 9.1 Experimental Methods

[0803] Test sample: Compounds 17 and 23 were prepared as 5 mg / 5 mL suspension eye drops, according to the formulation of fluorometholone eye drops, stored at room temperature in the dark, and ready for use.

[0804] Positive control drugs: fluorometholone eye drops (specification 5 ml / 5 mg; Santen Pharmaceutical (China) Co., Ltd.; batch number: 1FM6545), loteprednol eye drops (specification 0.5% (5 mg / mL); Shandong Bausch and Lomb Freda Pharmaceutical Co., Ltd.; batch number: 386521), kept in the dark at room temperature for later use.

[0805] Experimental animals: 50 guinea pigs, ordinary grade, half male and half female, 300-350g.

[0806] Animal grouping: After 5 days of adaptive feeding, the guinea pigs were randomly divided into 5 groups according to their body weight. Group 1 was a blank group, and 50 μl of normal saline was dripped into the eyes (bilaterally) of the guinea pigs. Groups 2-5 were fluorometholone group, loteprednol group, compound 17 group and compound 23 group, and the corresponding drugs were dripped into the eyes (bilaterally) of the guinea pigs.

[0807] Table 19 Grouping and dosing regimen of experimental animals for adverse reactions to continuous drug administration in guinea pig eyes

[0808] IOP testing time: The IOP of each group of animals was measured before administration and on the 7th, 14th, 21st and 28th day after administration.

[0809] 9.2 Results

[0810] Table 20 Changes in intraocular pressure in guinea pigs Note: Compared with the blank group, ** P<0.01, *** P<0.001.

[0811] The results showed that compared with pre-dose, elevated intraocular pressure was detected in guinea pigs 7 days after administration of the positive drugs fluorometholone and loteprednol, while no abnormal intraocular pressure was detected after administration of compounds 17 and 23. This indicates that the safety of continuous ocular administration of compounds 17 and 23 is significantly better than that of the positive drugs fluorometholone and loteprednol.

[0812] Under the same experimental conditions, compounds 16, 20, 21, 22, 26, 34, 35, 36, 37, 46, 47, 48, and 51 of the present invention had similar safety profiles to compounds 17 and 23, and no abnormal intraocular pressure was detected.

[0813] Pharmacological Example 10 Adverse reaction experiment of continuous administration to rat skin

[0814] 10.1 Experimental Methods

[0815] Test sample: Compounds 17 and 23 were prepared as 0.1% cream according to the formulation of compound dexamethasone acetate cream, stored at room temperature in the dark, and set aside.

[0816] Positive control drug: compound dexamethasone acetate cream (specification 0.75 mg / g; China Resources Sanjiu Pharmaceutical; batch number: 2112002X), stored at room temperature in the dark, ready for use.

[0817] Experimental animals: SD rats, SPF grade, half male and half female, 230-250 g.

[0818] Animal Grouping: After acclimation, rats were randomly divided into four groups: Group 1 was a blank group, and Groups 2-4 were treated with the compound dexamethasone acetate cream, compound 17, and compound 23, respectively. One day before administration, the rats' backs were shaved, covering an area of ​​5×6 cm. The corresponding drugs (100 mg each time) were applied to the backs of the rats in the compound dexamethasone acetate cream, compound 17, and compound 23 groups, respectively, twice daily. The blank group received a corresponding amount of blank matrix applied to the backs of rats twice daily for one week.

[0819] Table 21 Animal groups and dosing regimens for adverse reactions to continuous drug administration to rat skin

[0820] 10.2 Measurement of rat epidermal thickness

[0821] To examine the effects of continuous administration of the test article on the epidermis, dorsal skin tissues were stained with hematoxylin and eosin (H&E) (magnification ×40), and the thickness of the epidermis was quantitatively measured based on the H&E-stained sections.

[0822] 10.3 Results

[0823] Table 22 Rat epidermal thickness Note: Compared with the blank group, *** P<0.001.

[0824] The results showed that compared with the blank group, the epidermal thickness of rats was significantly thinner after administration of the positive drug compound dexamethasone acetate, while there was no significant abnormality in epidermal thickness after administration of compounds 17 and 23. This indicates that the continuous skin administration of compounds 17 and 23 is safer than the positive drug compound dexamethasone acetate.

[0825] Under the same experimental conditions, compounds 16, 20, 21, 22, 26, 34, 35, 36, 37, 46, 47, 48, and 51 of the present invention had similar safety profiles to compounds 17 and 23, and showed no significant abnormalities in epidermal thickness.

[0826] Pharmacological Example 11 Pharmacokinetic (PK) Experiment in Rats

[0827] 11.1 Experimental Methods

[0828] Preparation method of test sample: accurately weigh compound 8, dissolve it in 10% DMSO + 25% PEG400 + 65% saline, and prepare a 1 mg / ml solution as the test sample, which is prepared before administration.

[0829] Experimental animals: 6 male SD rats, SPF grade (Beijing Weitonglihua Laboratory Animal Technology Co., Ltd.).

[0830] Animal grouping: Weigh animals before administration and calculate the dosage based on body weight. Animals in the oral administration group were fasted overnight (10-14 hours) before administration and fed 4 hours after administration.

[0831] Table 23 Animal groups and dosing regimens for rat pharmacokinetic (PK) experiments

[0832] Blood collection time points: 2 min, 5 min, 15 min, 30 min, 1 h, 2 h, 4 h, 8 h, and 24 h after administration, with approximately 0.25 mL of blood collected for each sample. The samples were anticoagulated with sodium heparin and placed on wet ice after collection.

[0833] Plasma sample processing: After blood collection, place the blood samples on ice and centrifuge them within 1 hour to separate the plasma (centrifugation conditions: 6000 rpm, 3 minutes, 2-8°C). Plasma samples were stored in a -80°C freezer before analysis.

[0834] Data processing: Phoenix WinNonlin8.2.0 was used to calculate the pharmacokinetic parameters based on the plasma drug concentration data at different time points.

[0835] 11.2 Results

[0836] Table 24 Pharmacokinetic parameters in rats

[0837] Pharmacokinetic parameters showed that compound 8 provided by the present invention had a high plasma clearance rate and a short half-life after intravenous administration in rats, with a Cl_obs greater than 400 mL / min / kg and a T1 / 2 less than 0.5 h. Following oral administration in rats, compound 8 exhibited low drug exposure and low bioavailability, with an AUC less than 70 h*ng / mL and a bioavailability F of approximately 10%. These results suggest that the compound provided by the present invention has a rapid plasma clearance rate and low systemic drug exposure, effectively reducing the systemic adverse reactions associated with high exposure to glucocorticoids.

[0838] Under the same experimental conditions, compounds 16, 17, 20, 21, 22, 23, 26, 34, 35, 36, 37, 46, 47, 48, and 51 of the present invention have similar pharmacokinetic properties to compound 8, have fast plasma clearance rates, and low systemic drug exposure, and can effectively reduce the systemic adverse reactions caused by high exposure to glucocorticoids.

[0839] Finally, it should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention, rather than to limit it. Although the present invention has been described in detail with reference to the above embodiments, those skilled in the art should understand that they can still modify the technical solutions described in the above embodiments, or replace some or all of the technical features therein with equivalents. However, these modifications or replacements do not cause the essence of the corresponding technical solutions to deviate from the scope of the technical solutions of the embodiments of the present invention.

Claims

1. The compound of formula I has the following structural formula: its optical isomer, its pharmaceutically acceptable salt or its solvate, in, A, B, R1, R2, and R3 shown in the structural formula of the compound of formula I are selected independently of each other, and: A is selected from substituted or unsubstituted aryl containing 6-10 carbon atoms, substituted or unsubstituted heteroaryl or heterocyclic group containing 4-10 carbon atoms, substituted or unsubstituted cycloalkyl containing 3-10 carbon atoms, wherein the substituent is selected from one or more, or one, of the following: halogen, hydroxyl, carbonyl, amino, cyano, carboxyl, aryl containing 6-10 carbon atoms, heteroaryl containing 4-10 carbon atoms, cycloalkyl containing 3-6 carbon atoms, alkoxy containing 1-10 carbon atoms, alkylamino containing 1-10 carbon atoms, or alkyl ester containing 1-10 carbon atoms; Preferably, A is selected from substituted or unsubstituted phenyl, substituted or unsubstituted piperidinyl, substituted or unsubstituted cyclohexyl, substituted or unsubstituted pyridinyl, substituted or unsubstituted pyrimidinyl, and the substituent is selected from one or more, or one, of the following: halogen or cyano; More preferably, A is selected from substituted or unsubstituted phenyl, substituted or unsubstituted cyclohexyl, substituted or unsubstituted pyridyl, substituted or unsubstituted pyrimidinyl, and the substituent is selected from one or more, or one, of the following: halogen or cyano; Further preferably, A is selected from substituted or unsubstituted phenyl, substituted or unsubstituted cyclohexyl, substituted or unsubstituted pyridyl, and the substituent is selected from one or more, or one of the following: halogen; More preferably, A is selected from substituted or unsubstituted phenyl, substituted or unsubstituted pyridyl, and the substituent is selected from one or more, or one of the following: halogen; B is selected from no group, O, S, NH, CH2, OCH2, SCH2, NHCH2, CHO, CH2S, CH2SO, CH2SO2, CH2NH, C=O or NH(CO); Preferably, B is selected from O, S, NH, CH2, OCH2, SCH2, NHCH2, CHO, CH2S, CH2SO, CH2SO2, CH2NH, C=O or NH(CO); More preferably, B is selected from S, CH2, OCH2, SCH2, NHCH2, CHO, CH2S, CH2SO, CH2SO2, CH2NH or NH(CO); Further preferably, B is selected from S, CH2O, CH2S, CH2SO or CH2NH; More preferably, B is selected from CH2O, CH2S or CH2NH; B and ring 2-, 3- or 4-position connections; Preferably, B and ring 2- or 3-position connection; R1 is selected from H or halogen; Preferably, R1 is selected from halogen; R2 is selected from H, CH3 or halogen; Preferably, R2 is selected from H or halogen; R3 is selected from CH2R4, R4 is selected from OH, halogen, OR5 or OCOR5, or, R3 is selected from SCH2R6 or OCH2R6; wherein R5 is selected from an alkyl group containing 1 to 6 carbon atoms, an alkenyl group containing 2 to 6 carbon atoms, an alkynyl group containing 2 to 6 carbon atoms, an aryl group containing 6 to 10 carbon atoms, a heteroaryl group containing 4 to 10 carbon atoms, or a heterocyclic group; and R6 is selected from a halogen or CN. Preferably, R3 is selected from CH2R4, R4 is selected from OH or halogen, or, R3 is selected from SCH2R6 or OCH2R6, R6 is selected from halogen or CN; More preferably, R3 is selected from CH2R4, R4 is selected from OH, or, R3 is selected from SCH2R6 or OCH2R6, R6 is selected from halogen or CN; Preferably, the halogen is selected from F or Cl; is a single bond or a double bond, preferably a double bond.

2. The compound according to claim 1, characterized in that in, The compound of formula I is represented by the following structural formula I': Among them, the variables A, B, R1, R2, R3 and B are related to the ring The connection position is as defined in claim 1.

3. The compound according to claim 1 or 2, characterized in that in, The compound of formula I is selected from the following structural formula I-1 or I-2, and the compound of formula I' is selected from the following structural formula I'-1 or I'-2: Wherein, A, B, R1, R2, and R3 shown in the structural formula of the compound of formula I-1 and I'-1 are selected independently of each other, and: A is selected from substituted or unsubstituted cyclohexyl, substituted or unsubstituted piperidinyl, substituted or unsubstituted phenyl, substituted or unsubstituted pyridinyl, substituted or unsubstituted pyrimidinyl, wherein the substituent is one or more, or one of the following: halogen, preferably F or Cl; Preferably, A is selected from: B is selected from O, S, NH, CH2, OCH2, SCH2, NHCH2, CH2O, CH2S, CH2SO, CH2SO2, CH2NH; R1 is selected from H or halogen; preferably, R1 is selected from H, F or Cl; R2 is selected from H or halogen; preferably, R2 is selected from H or F; R3 is selected from the following: CH2R4, R4 is selected from OH or halogen; SCH2R6 or OCH2R6, R6 is selected from halogen or CN; Preferably, R3 is selected from the following: CH2R4, R4 is selected from OH or Cl; SCH2R6 or OCH2R6, R6 is selected from F or CN; is a single bond or a double bond, preferably a double bond; Wherein, A, B, R1, R2, and R3 shown in the structural formula of the compound of formula I-2 and I'-2 are selected independently of each other, and: A is selected from substituted or unsubstituted cyclohexyl, substituted or unsubstituted piperidinyl, substituted or unsubstituted phenyl, wherein the substituent is one or more, or one of the following: halogen, preferably F or Cl, or cyano; Preferably, A is selected from: B is selected from C=O, NH(CO), CH2O, CH2S, CH2NH; R1 is selected from H or halogen; preferably, R1 is selected from H, F or Cl; R2 is selected from H or halogen; preferably, R2 is selected from H or F; R3 is selected from the following: CH2R4, R4 is selected from OH or halogen; SCH2R6, R6 is selected from halogen; Preferably, R3 is selected from the following: CH2R4, R4 is selected from OH or Cl; SCH2R6, R6 is selected from F; is a single bond or a double bond, preferably a double bond.

4. The compound according to claim 1 or 2, characterized in that in, A, B, R1, R2, R3 are selected independently of each other, and: A is selected from substituted or unsubstituted cyclohexyl, substituted or unsubstituted phenyl, substituted or unsubstituted pyridyl, substituted or unsubstituted pyrimidinyl, wherein the substituent is one or more, or one of the following: halogen, preferably F or Cl, or cyano; Preferably, A is selected from: B is selected from S, CH2, OCH2, SCH2, NHCH2, CH2O, CH2S, CH2SO, CH2SO2, CH2NH, NH(CO); R1 is selected from H or halogen; preferably, R1 is selected from H, F or Cl; R2 is selected from H or halogen; preferably, R2 is selected from H or F; R3 is selected from the following: CH2R4, R4 is selected from OH or halogen; SCH2R6 or OCH2R6, R6 is selected from halogen or CN; Preferably, R3 is selected from the following: CH2R4, R4 is selected from OH or Cl; SCH2R6 or OCH2R6, R6 is selected from F or CN; is a single bond or a double bond, preferably a double bond.

5. The compound according to any one of claims 1, 2 and 4, characterized in that in, The compound of formula I is selected from the following structural formula I-1 or I-2, and the compound of formula I' is selected from the following structural formula I'-1 or I'-2: Wherein, A, B, R1, R2, and R3 shown in the structural formula of the compound of formula I-1 and I'-1 are selected independently of each other, and: A is selected from substituted or unsubstituted cyclohexyl, substituted or unsubstituted phenyl, substituted or unsubstituted pyridyl, substituted or unsubstituted pyrimidinyl, and the substituents are one or more, or one of the following: halogen, preferably F or Cl; Preferably, A is selected from: B is selected from S, CH2, OCH2, SCH2, NHCH2, CH2O, CH2S, CH2SO, CH2SO2, CH2NH; R1 is selected from H or halogen; preferably, R1 is selected from H, F or Cl; R2 is selected from H or halogen; preferably, R2 is selected from H or F; R3 is selected from the following: CH2R4, R4 is selected from OH or halogen; SCH2R6 or OCH2R6, R6 is selected from halogen or CN; Preferably, R3 is selected from the following: CH2R4, R4 is selected from OH or Cl; SCH2R6 or OCH2R6, R6 is selected from F or CN; is a single bond or a double bond, preferably a double bond; Wherein, A, B, R1, R2, and R3 shown in the structural formula of the compound of formula I-2 and I'-2 are selected independently of each other, and: A is selected from substituted or unsubstituted phenyl, wherein the substituent is one or more, or one of the following: halogen, preferably F or Cl, or cyano; Preferably, A is selected from: B is selected from NH(CO), CH2O, CH2S, CH2NH; R1 is selected from H or halogen; preferably, R1 is selected from H, F or Cl; R2 is selected from H or halogen; preferably, R2 is selected from H or F; R3 is selected from the following: CH2R4, R4 is selected from OH or halogen; SCH2R6, R6 is selected from halogen; Preferably, R3 is selected from the following: CH2R4, R4 is selected from OH or Cl; SCH2R6, R6 is selected from F; is a single bond or a double bond, preferably a double bond.

6. The compound according to claim 1 or 2, characterized in that in, A, B, R1, R2, R3 are selected independently of each other, and: A is selected from substituted or unsubstituted cyclohexyl, substituted or unsubstituted phenyl, substituted or unsubstituted pyridyl, and the substituents are one or more, or one of the following: halogen, preferably F or Cl; Preferably, A is selected from: B is selected from S, CH2O, CH2S, CH2SO, CH2NH; R1 is selected from halogen; preferably, R1 is selected from F or Cl; R2 is selected from H or halogen; preferably, R2 is selected from H or F; R3 is selected from the following: CH2R4, R4 is selected from OH or halogen; SCH2R6 or OCH2R6, R6 is selected from halogen or CN; Preferably, R3 is selected from the following: CH2R4, R4 is selected from OH or Cl; SCH2R6 or OCH2R6, R6 is selected from F or CN; is a single bond or a double bond, preferably a double bond.

7. The compound according to any one of claims 1, 2 and 6, characterized in that in, The compound of formula I is selected from the following structural formula I-1 or I-2, and the compound of formula I' is selected from the following structural formula I'-1 or I'-2: Wherein, A, B, R1, R2, and R3 shown in the structural formula of the compound of formula I-1 and I'-1 are selected independently of each other, and: A is selected from substituted or unsubstituted cyclohexyl, substituted or unsubstituted phenyl, substituted or unsubstituted pyridyl, and the substituents are one or more, or one of the following: halogen, preferably F or Cl; Preferably, A is selected from: B is selected from S, CH2O, CH2S, CH2SO, CH2NH; R1 is selected from halogen; preferably, R1 is selected from F or Cl; R2 is selected from H or halogen; preferably, R2 is selected from H or F; R3 is selected from the following: CH2R4, R4 is selected from OH or halogen; SCH2R6 or OCH2R6, R6 is selected from halogen or CN; Preferably, R3 is selected from the following: CH2R4, R4 is selected from OH or Cl; SCH2R6 or OCH2R6, R6 is selected from F or CN; is a single bond or a double bond, preferably a double bond; Wherein, A, B, R1, R2, and R3 shown in the structural formula of the compound of formula I-2 and I'-2 are selected independently of each other, and: A is selected from substituted or unsubstituted phenyl, and the substituents are one or more, or one of the following: halogen, preferably Cl; Preferably, A is selected from: B is selected from CH2O, CH2S, CH2NH; R1 is selected from halogen; preferably, R1 is selected from F or Cl; R2 is selected from H or halogen; preferably, R2 is selected from H or F; R3 is selected from the following: CH2R4, R4 is selected from OH; is a single bond or a double bond, preferably a double bond.

8. The compound according to claim 1 or 2, characterized in that in, A, B, R1, R2, R3 are selected independently of each other, and: A is selected from substituted or unsubstituted phenyl, substituted or unsubstituted pyridyl, and the substituents are one or more, or one of the following: halogen, preferably F or Cl; Preferably, A is selected from: B is selected from CH2O, CH2S, CH2NH; R1 is selected from halogen; preferably, R1 is selected from F or Cl; R2 is selected from H or halogen; preferably, R2 is selected from H or F; R3 is selected from the following: CH2R4, R4 is selected from OH; SCH2R6 or OCH2R6, R6 is selected from halogen or CN; Preferably, R3 is selected from the following: CH2R4, R4 is selected from OH; SCH2R6 or OCH2R6, R6 is selected from F or CN; is a single bond or a double bond, preferably a double bond.

9. The compound according to any one of claims 1, 2 and 8, characterized in that in, The compound of formula I is selected from the following structural formula I-1 or I-2, and the compound of formula I' is selected from the following structural formula I'-1 or I'-2: Wherein, A, B, R1, R2, and R3 shown in the structural formula of the compound of formula I-1 and I'-1 are selected independently of each other, and: A is selected from substituted or unsubstituted phenyl, substituted or unsubstituted pyridyl, and the substituents are one or more, or one of the following: halogen, preferably F or Cl; Preferably, A is selected from: B is selected from CH2O, CH2S; R1 is selected from halogen; preferably, R1 is selected from F or Cl; R2 is selected from H or halogen; preferably, R2 is selected from H or F; R3 is selected from the following: CH2R4, R4 is selected from OH; SCH2R6 or OCH2R6, R6 is selected from halogen or CN; Preferably, R3 is selected from the following: CH2R4, R4 is selected from OH; SCH2R6 or OCH2R6, R6 is selected from F or CN; is a single bond or a double bond, preferably a double bond; Wherein, A, B, R1, R2, and R3 shown in the structural formula of the compound of formula I-1 and I'-1 are selected independently of each other, and: A is selected from substituted or unsubstituted phenyl, and the substituents are one or more, or one of the following: halogen, preferably Cl; Preferably, A is selected from: B is selected from CH2S, CH2NH; R1 is selected from halogen; preferably, R1 is selected from F or Cl; R2 is selected from H; R3 is selected from the following: CH2R4, R4 is selected from OH; is a single bond or a double bond, preferably a double bond.

10. The compound according to any one of claims 1 to 3, characterized in that The compound of formula I is selected from the following compounds: Preferably, compound 5, compound 7, compound 8, compound 9, compound 10, compound 11, compound 12, compound 13, compound 14, compound 15, compound 16, compound 17, compound 18, compound 19, compound 20, compound 21, compound 22, compound 23, compound 24, compound 25, compound 26, compound 27, compound 28, compound 29, compound 30, compound 32, compound 33, compound 34, compound 35, compound 36, compound 37, compound 38, compound 39, compound 41, compound 43, compound 45, compound 46, compound 47, compound 48, compound 49, compound 50, compound 51, compound 52, compound 54, compound 55, compound 56, compound 57, compound 58, compound 59, and compound 60; More preferably, compound 7, compound 8, compound 10, compound 11, compound 16, compound 17, compound 18, compound 19, compound 20, compound 21, compound 22, compound 23, compound 24, compound 25, compound 26, compound 27, compound 34, compound 35, compound 36, compound 37, compound 38, compound 45, compound 46, compound 47, compound 48, compound 49, compound 50, compound 51, and compound 57; More preferably, compound 16, compound 17, compound 20, compound 21, compound 22, compound 23, compound 26, compound 34, compound 35, compound 36, compound 37, compound 46, compound 47, compound 48, and compound 51.

11. A method for preparing the compound according to any one of claims 1 to 10, characterized in that: Prepared using method 1 or method 2: Method 1: The compound of formula II reacts with the compound of formula III under acidic conditions to obtain the compound of formula I: Wherein, A, B, R1, R2, and R3 in the compound of formula I are as defined in any one of claims 1 to 10; In the compound of formula II, R1, R2, and R3 are defined the same as those in the compound of formula I, and R7 and R8 are selected from OH, or R7 and R8 together form C 16 , C 17 The sites are connected by oxygen bridges, R9, R 10 Each is independently selected from H or an alkyl group containing 1-6 carbons; In the compound of formula III, A and B are the same as those in the compound of formula I; or, The compound of formula II' reacts with the compound of formula III under acidic conditions to prepare the compound of formula I': Wherein, A, B, R1, R2, and R3 in the compound of formula I' are as defined in any one of claims 1 to 10; In the compound of formula II', R1, R2, and R3 are defined the same as those in the compound of formula I', and R7 and R8 are selected from OH, or R7 and R8 together form C 16 , C 17 The sites are connected by oxygen bridges, R9, R 10 Each is independently selected from H or an alkyl group containing 1-6 carbons; In the compound of formula III, A and B are the same as those in the compound of formula I'; Alternatively, method 2: To obtain a compound of formula I wherein B is selected from CH2NH, the following method may also be used: (a) The compound of formula II reacts with the compound of formula V under acidic conditions to obtain the compound of formula IV: (b) reacting a compound of formula IV with a compound of formula VI or a compound of formula VII to obtain a compound of formula I: Wherein, in the compound of formula I, A, R1, R2, and R3 are as defined in any one of claims 1 to 10, and B is selected from CH2NH; In the compound of formula II, R1, R2, and R3 are defined the same as those in the compound of formula I, and R7 and R8 are selected from OH, or R7 and R8 together form C 16 , C 17 The sites are connected by oxygen bridges, R9, R 10 Each is independently selected from H or an alkyl group containing 1-6 carbons; In the compound of formula IV, A, B, R1, R2, and R3 are the same as those in the compound of formula I; In the compound of formula V, A is defined the same as in the compound of formula I, B is selected from CH2NH, and Z is selected from a Boc protecting group; The compound of formula VI is selected from Wherein, Q is a leaving group selected from Cl or Br; Formula VII is selected from or, (a) The compound of formula II' reacts with the compound of formula V under acidic conditions to obtain the compound of formula IV': (b) reacting a compound of formula IV' with a compound of formula VI or a compound of formula VII to obtain a compound of formula I': Wherein, in the compound of formula I', A, R1, R2, and R3 are as defined in any one of claims 1 to 10, and B is selected from CH2NH; In the compound of formula II', R1, R2, and R3 are defined the same as those in the compound of formula I', and R7 and R8 are selected from OH, or R7 and R8 together form C 16 , C 17 The sites are connected by oxygen bridges, R9, R 10 Each is independently selected from H or an alkyl group containing 1-6 carbons; In the compound of formula IV', A, B, R1, R2, and R3 are the same as those in the compound of formula I'; In the compound of formula V, A is defined the same as in the compound of formula I', B is selected from CH2NH, and Z is selected from a Boc protecting group; The compound of formula VI is selected from Wherein, Q is a leaving group selected from Cl or Br; Formula VII is selected from 12. A pharmaceutical composition, characterized in that The invention relates to a compound comprising the compound according to any one of claims 1 to 10 or a compound prepared by the preparation method according to claim 11.

13. The composition according to claim 12, characterized in that The dosage form of the pharmaceutical composition is selected from creams, ointments, gels, transdermal patches, intradermal injections, eye drops, intraocular injections, ophthalmic implants, nasal sprays, inhalation powders, inhalation aerosols, inhalation sprays, inhalation liquid preparations, vaginal suppositories, vaginal tablets, vaginal gels, and preparations that are administered orally or rectally and act locally in the digestive tract.

14. Use of the compound according to any one of claims 1 to 10, the compound prepared by the preparation method according to claim 11, or the pharmaceutical composition according to claim 12 or 13 in the preparation of a medicament for treating glucocorticoid receptor-mediated diseases; Preferably, the disease is selected from blepharitis, conjunctivitis, keratitis, iritis, iridocyclitis, uveitis, dry eye, diabetic retinopathy, wet age-related macular degeneration, choroidal neovascularization, posterior uveitis, cataract, glaucoma, retinal detachment, inflammation after strabismus correction, eczema, psoriasis, atopic dermatitis, allergic dermatitis, pruritus, hypersensitivity reaction, rheumatoid arthritis, Arthritis, multiple sclerosis and disseminated lupus erythematosus, rhinitis, sinusitis, asthma, nasal polyps, asthma, chronic obstructive pulmonary disease, inflammatory bowel disease, Crohn's disease, ulcerative colitis, or chronic glomerulonephritis; More preferably, the disease is selected from conjunctivitis, keratitis, uveitis, dry eye, asthma, chronic obstructive pulmonary disease, allergic rhinitis, nasal polyps, Crohn's disease, eczema and psoriasis.