Glucocorticoid prodrug, preparation method therefor, and use thereof

Abstract

The present invention belongs to the field of medicinal chemistry, and particularly relates to a glucocorticoid prodrug, a preparation method therefor, and use thereof. The glucocorticoid prodrug has relatively low solubility and is suitable for preparing a long-acting sustained-release formulation. Compared to existing dexamethasone palmitate formulations on the market, the compound of the present invention provides a better long-acting sustained-release effect, and also effectively reduces systemic drug exposure, thereby minimizing or avoiding systemic side effects that may be caused by glucocorticoids.

Description

A glucocorticoid prodrug, its preparation method and application Technical Field

[0001] This invention belongs to the field of medicinal chemistry, specifically relating to a glucocorticoid prodrug, its preparation method, and its application. Background Technology

[0002] Glucocorticoids, as a crucial class of regulatory molecules in the body, play a key role in regulating growth, development, metabolism, and immune function. In 1948, Hench first used glucocorticoids to treat acute rheumatic diseases, and its remarkable efficacy shocked the medical community. This discovery not only greatly promoted the widespread use of glucocorticoids in various diseases but also earned Hench the Nobel Prize in Physiology or Medicine in 1950. Since then, glucocorticoids, due to their powerful anti-inflammatory, antitoxin, anti-shock, and immunosuppressive effects, have occupied an indispensable position in clinical treatment, boasting an application history of over seventy years.

[0003] However, the use of glucocorticoids is not without risks. Inappropriate or excessive reliance on glucocorticoids can lead to a range of serious side effects, including but not limited to Cushing's syndrome, osteoporosis, elevated blood sugar levels, and increased susceptibility to infections. For eye diseases, topical application of glucocorticoids may also trigger complications such as glaucoma and cataracts. Therefore, glucocorticoids are considered a double-edged sword, with therapeutic benefits and potential risks coexisting. To ensure patients achieve optimal treatment outcomes while minimizing the incidence of side effects, physicians must comprehensively assess each patient's individual condition before deciding to use glucocorticoids, carefully select appropriate dosages and durations, and regularly monitor treatment response.

[0004] Currently, various glucocorticoid preparations are available on the market, with oral tablets and intravenous injections being the most commonly used dosage forms. While these two forms are popular due to their ease of administration, they are also major sources of potential side effects because they can rapidly affect the whole body. Therefore, in clinical practice, the rational selection of the route of administration, dosage, and treatment duration is crucial for optimizing treatment regimens.

[0005] To minimize systemic side effects, various sustained-release formulations for local application have been introduced to the market, such as triamcinolone microspheres for intra-articular injection and dexamethasone implants for intravitreal administration. These sustained-release formulations enable the slow release of glucocorticoids, maintaining an effective drug concentration at the local treatment site while significantly reducing the drug's systemic effects.

[0006] Existing glucocorticoid sustained-release technologies encompass prodrug technology, polylactic-co-glycolic acid (PLGA) microsphere technology, microcrystal technology, and both non-biodegradable and biodegradable implant technologies. In recent years, prodrug design has garnered significant attention due to its unique advantages in new drug development. In the field of glucocorticoid research, prodrug technology is primarily used to improve drug solubility, converting poorly soluble drugs into hydrophilic prodrugs for formulation into injectable formulations, thereby achieving rapid onset of action. Examples include dexamethasone sodium phosphate, betamethasone sodium phosphate, and methylprednisolone sodium succinate, all prepared using this method.

[0007] However, there are relatively few marketed sustained-release glucocorticoid prodrugs. It is worth mentioning that dexamethasone palmitate (DXP) injection (trade name: [not specified]) is used to treat rheumatoid arthritis. This is a long-acting prodrug formulation, recommended for intravenous injection every two weeks. This product enhances the lipophilicity of dexamethasone by synthesizing a palmitate prodrug, which is then formulated into a fat emulsion, allowing for the slow release of the active ingredient, dexamethasone, in vivo via esterase action. Research on dexamethasone palmitate formulations is extensive, encompassing various forms such as emulsions, liposomes, lipid nanoparticles, and microparticles. Furthermore, budesonide palmitate, a lipophilic prodrug of budesonide, has also been investigated for use in the preparation of nanoparticles.

[0008] Besides palmitic acid, other fatty acids, such as linoleic acid and linolenic acid, have also been used to construct prodrug structures for glucocorticoids. Simultaneously, fatty alcohols have also been used to synthesize glucocorticoid prodrugs; for example, studies have reported stearyl ketal dexamethasone, a prodrug that responsively releases dexamethasone under specific pH conditions. These technological innovations not only improve the therapeutic efficacy of glucocorticoids but also significantly reduce their potential side effects, demonstrating the broad prospects of glucocorticoid therapy.

[0009] Existing technologies for glucocorticoid prodrugs demonstrate the ongoing technological innovation in this field.

[0010] US4427649A discloses a liposomal formulation containing an anti-inflammatory corticosteroid, wherein the corticosteroid is designed as a prodrug form linked to a long-chain fatty acid (such as palmitic acid), specific examples including cortisone palmitate, fluocinolone palmitate, dexamethasone palmitate, and prednisolone palmitate.

[0011] CN108350022B discloses a polyethylene glycol (PEG) modified glucocorticoid prodrug. Due to its amphiphilic nature, this prodrug can self-assemble into micelles, making it suitable for the treatment of inflammatory and autoimmune diseases.

[0012] CN113661170A discloses a polymorph of a dexamethasone prodrug dimer linked by a carbonate-triethylene glycol-carbonate linker, the design of which enables delayed or controlled release of dexamethasone.

[0013] CN115003308A discloses a glucocorticoid compound that achieves specific targeting of macrophages by linking a folic acid group, an anti-folic acid group, or a folic acid analog group.

[0014] CN113967264A discloses a steroidal macromolecular prodrug nanocarrier for the treatment of atherosclerosis and its preparation method. The nanocarrier is self-assembled from a macromolecular polymer prodrug, wherein the anti-inflammatory drug is linked to the polymer backbone via dicarbonyl bonds.

[0015] CN118027128A discloses a dexamethasone-linolenic acid prodrug self-assembled nanoparticle for synergistic treatment of inflammation. The unique feature of this prodrug is that dexamethasone and linolenic acid are linked by sensitive disulfide or thioether bonds within the inflammatory microenvironment.

[0016] In summary, research on glucocorticoid prodrugs covers a wide range, including polymers, carbohydrates, dendritic polymers, antibodies, peptides, and other small molecule-based prodrugs. Although some small molecule prodrugs have been successfully marketed or are in clinical trials, clinical research on polymeric prodrugs and prodrug-based nano-self-assembled drugs remains relatively limited, mainly due to their complex manufacturing processes and potential safety concerns.

[0017] To improve the drug-likeness of prodrugs, the following aspects need to be considered comprehensively: (1) Pharmacokinetics: For prodrugs that rely on enzyme activation, individual differences in enzyme activity must be considered to ensure effective activation of the drug in the target tissue. (2) Safety and toxicity: Prodrugs and their metabolites may trigger immune responses, so materials with high biocompatibility should be selected. The safety of linkers and functional groups in prodrugs is particularly important. Whether it is a polymer, antibody, amino acid, carbohydrate, or other material, its safety to the human body must be ensured. (3) Stability: Prodrugs should have good stability to ensure reliability and consistency during storage and use. (4) Targeting: Through specific design, prodrugs can be specifically delivered to target tissues or cells, reducing systemic exposure and thus reducing side effects.

[0018] This invention aims to develop novel glucocorticoid prodrugs for local administration at the disease site. These novel prodrugs exhibit low solubility and, after local administration, can serve as a drug reservoir, slowly releasing the drug and reducing systemic exposure to glucocorticoids, thus minimizing side effects. Furthermore, the fragments used in the synthesis of the prodrug all possess good biocompatibility and safety. Summary of the Invention

[0019] This invention provides a compound of Formula I or a pharmaceutically acceptable salt thereof:

[0020] in, Indicates the formation of prodrugs by glucocorticoids residues;

[0021] A is selected from:

[0022] C 1-6 Alkylene;

[0023] -L-CHR 1A -;

[0024] or -L-CR 1A R 2A -;

[0025] R 1A R 2A Selected independently from hydrogen and -LC 1-6 Alkyl, -LC 3-8 Cycloalkyl, -L-3-7-membered heterocycloalkyl, -L-6-12-membered aryl, or -L-5-10-membered heteroaryl; wherein, the C 1-6 Alkyl, C 3-8 Cycloalkyl, 3-7-membered heterocycloalkyl, 6-12-membered aryl, 5-10-membered heteroaryl can be optionally selected by one or more independently chosen from R 1B Substituents of the substituents;

[0026] R 1B Selected from hydrogen, halogen, hydroxyl, methimazole, -LC 1-6 Alkyl, -LC 1-6 Alkoxy, -LC 3-8 Cycloalkyl, -L-3-7 heterocycloalkyl, -L-6-12 aryl or -LC 5-10 Mixed aromatics;

[0027] R 3A Selected from bonds, hydrogen, or C 1-6 alkyl;

[0028] R 4A Selected from C 7-21 Straight-chain or branched alkyl groups, -C 1-6 Alkylene-C 3-8 cycloalkyl, -C 1-6 Alkylene-3-7-membered heterocyclic alkyl, -C 1-6 alkylene-6-12-membered aryl or -C 1-6 alkylene-5-10-membered heteroaryl;

[0029] L is selected from either a key or C.1-6 Alkylene;

[0030] R 1A and R 2A It can form 3-8 membered carbon rings together with the C atoms it is bonded to;

[0031] When R 3A When selected from the key, R 1A The CH atoms it bonds with, together with the adjacent N atoms, form 3-7 membered nitrogen heterocycles.

[0032] In some embodiments of the present invention Selected from the following glucocorticoids:

[0033] Preferably, A prodrug is formed by selecting one, two, or three OH groups from primary (with two hydrogen atoms on the carbon atom to which the hydroxyl group is attached), secondary (with one hydrogen atom on the carbon atom to which the hydroxyl group is attached), or tertiary (with no hydrogen atoms on the carbon atom to which the hydroxyl group is attached) of a glucocorticoid.

[0034] Preferably, A prodrug is formed by selecting one of the primary alcohol (with two hydrogen atoms on the carbon atom to which the hydroxyl group is attached), secondary alcohol (with one hydrogen atom on the carbon atom to which the hydroxyl group is attached), or tertiary alcohol (with no hydrogen atom on the carbon atom to which the hydroxyl group is attached) from the glucocorticoid.

[0035] Preferably, Through the OH group in the primary alcohol of glucocorticoids, i.e. The OH group on the surface forms a prodrug.

[0036] In some embodiments of the present invention, Formula I Represented as amino acids residues, Selected from natural amino acids or pharmaceutically acceptable synthetic amino acids.

[0037] Preferably, Selected from amino acids with hydrophobic side chains.

[0038] Preferably, The amino acids selected are those shown below:

[0039] Preferably, Chiral amino acids are selected from D- or L-type amino acids.

[0040] Preferably, Chiral amino acids are selected from L-type amino acids.

[0041] Preferably, The amino acids selected are those shown below:

[0042] Preferably, Chiral amino acids are selected from D-type amino acids.

[0043] Preferably, The amino acids selected are those shown below:

[0044] In some embodiments of the present invention, when R 4A Selected from C 7-21 For straight-chain or branched alkyl groups, C 7-21 The straight-chain or branched alkyl group is selected from straight-chain or branched alkyl groups having 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, or 21 carbon atoms.

[0045] In some embodiments of the present invention, R 1A and R 2A It can form 3, 4, 5, 6, 7 or 8-membered carbon rings together with the C atoms it is bonded to.

[0046] Preferably, Selected from Or its D- or L- type.

[0047] In some embodiments of the present invention, R 1A The CH atoms bonded to it can form 3, 4, 5, 6 or 7-membered nitrogen heterocycles together with the adjacent N atoms.

[0048] Preferably, Selected from Or its D- or L- type.

[0049] A compound or a pharmaceutically acceptable salt thereof, wherein the compound is selected from:

[0050] Terminology definition:

[0051] In this invention, the term "C" 1-6 "Alkyl" refers to a straight-chain or branched alkyl group comprising 1 to 6 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, neopentyl, pterpentyl, or similar groups.

[0052] In this invention, the term "C" 1-6 "Alkylene" refers to the removal of C 1-6The alkyl group is a divalent group formed by another hydrogen atom, and can be substituted or unsubstituted. In some embodiments, C 1-4 Alkylene, C 2-4 Alkylene and C 1-3 Alkylenes are preferred. Unsubstituted alkylenes include, but are not limited to, methylene, ethylene, propylene, butylene, pentylene, hexylene, etc.

[0053] In this invention, the term "C" 1-6 "Alkoxy" refers to a straight-chain or branched alkoxy group having 1-6 carbon atoms, and includes, without limitation, methoxy, ethoxy, propoxy, isopropoxy, and butoxy groups. Preferably, it is C16. 1-4 Alkyl group.

[0054] In this invention, the term "C" 7-21 "Straight-chain or branched alkyl" refers to straight-chain or branched alkyl groups having 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, or 21 carbon atoms.

[0055] In this invention, the term "C" 1-6 "Alkoxy" refers to a straight-chain or branched alkoxy group having 1-6 carbon atoms, and includes, without limitation, methoxy, ethoxy, propoxy, isopropoxy, and butoxy groups. Preferably, it is C16. 1-4 Alkyl group.

[0056] In this invention, the term "C" 3-8 "Cycloalkyl" or "3-8 membered carbon ring" refers to a cyclic alkyl group having 3-8 carbon atoms on the ring, including, without limitation, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.

[0057] In this invention, the term "3-7 membered heterocyclic alkyl" refers to a 3-7 membered (e.g., 3, 4, 5, 6, 7 membered) heterocyclic group containing 1, 2, or 3 heteroatoms selected from N, O, and S, including but not limited to the following groups: wait.

[0058] 3-7 membered nitrogen heterocycles are 3-7 membered (e.g., 3, 4, 5, 6, 7 membered) heterocyclic groups containing one nitrogen atom, including but not limited to the following groups:

[0059] In this invention, the term "6-12 aryl" refers to an aromatic cyclic group with 6-12 carbon atoms that does not contain heteroatoms on the ring, such as phenyl, naphthyl, etc.

[0060] In this invention, the term "5-10-membered heteroaryl" refers to a heteroaromatic group containing one or more heteroatoms. For example, "heteroaryl" refers to an aromatic heterocycle containing 1 to 4 (1, 2, 3, 4) heteroatoms selected from oxygen, sulfur, and nitrogen, and 3 to 10 (3, 4, 5, 6, 7, 8, 9, 10) carbon atoms. "Heteroaryl" can be selected from 5-10-membered, 5-6-membered, and 9-10-membered heteroaryl groups. Non-limiting examples include: indolyl, imidazolyl, pyridinyl, furanyl, thiophene, pyrazolyl, pyrroleyl, N-alkylpyrroleyl, pyrimidinyl, pyrazinyl, tetrazolyl, etc.

[0061] In this invention, the term "halogen" includes fluorine, chlorine, bromine, and iodine.

[0062] In this invention, the term "substituted by one or more" means that one or more hydrogen atoms on a specific group are substituted by a specific substituent. The specific substituent is the substituent described accordingly above, or the substituent appearing in the various embodiments. Unless otherwise specified, a substituted group may have a substituent selected from a specific group at any substituted site of that group, and the substituents may be the same or different at each position. "A plurality of" includes two or more, for example, 2, 3, 4, 5, or 6.

[0063] The term "1-6" refers to 1, 2, 3, 4, 5, or 6 items. Other similar terms each have a similar meaning independently.

[0064] Independent substitution means that (two or more) substituents can be the same or different.

[0065] In another aspect, the present invention discloses a pharmaceutical composition comprising any of the compounds described above or a pharmaceutically acceptable salt thereof.

[0066] In another aspect, the present invention discloses a suspension containing any of the compounds described above or a pharmaceutically acceptable salt thereof.

[0067] Another aspect of the invention relates to the use of a compound or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition or suspension as a medicine, preferably, the use being in the preparation of a medicine for the treatment, prevention or control of a condition, symptom or disease in response to glucocorticoids in mammals in need.

[0068] The present invention also relates to the use of a compound or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition or suspension, in the preparation of a medicament for treating, preventing or controlling inflammatory diseases, painful diseases, immune-related diseases, endocrine diseases, allergic diseases, tumor-related diseases, skin diseases or ophthalmic diseases;

[0069] Preferably, the subject is treated with one or more additional therapeutic agents simultaneously, before, or after treatment with the compound or its pharmaceutically acceptable salt or pharmaceutical composition. Beneficial effects

[0070] The compounds of this invention exhibit significantly lower solubility than the parent drug, making them suitable for preparing long-acting sustained-release formulations. Taking dexamethasone prodrug as an example, these compounds can not only be formulated into suspensions—something dexamethasone palmitate cannot do—but also demonstrate superior ability to degrade and convert to the parent drug compared to dexamethasone palmitate. This is in contrast to existing dexamethasone palmitate formulations on the market. In comparison, the compounds of this invention provide superior long-acting sustained-release effects while effectively reducing systemic drug exposure, thereby minimizing or avoiding the systemic side effects that glucocorticoids may cause. Attached Figure Description

[0071] Figure 1 shows the appearance of different compound suspensions and dexamethasone palmitate (DXP) suspension in Test Example 3.

[0072] Figure 2 shows the in vitro release curves of different compound suspensions in Test Example 5.

[0073] Figure 3 shows the drug concentration-time curves of prodrugs in plasma for different compound suspensions in Test Example 6.

[0074] Figure 4 shows the time-concentration curves of dexamethasone in plasma for different compound suspensions in Test Example 6.

[0075] Figure 5 shows the drug concentration data of the prodrug in the different compound suspensions SF in Test Example 6.

[0076] Figure 6 shows the drug concentration data of dexamethasone in different compound suspensions SF in Test Example 6.

[0077] Figure 7 shows the drug concentration data of the prodrug in the different compound suspension ST in Test Example 6.

[0078] Figure 8 shows the drug concentration data of dexamethasone in different compound suspensions ST in Test Example 6. Detailed Implementation

[0079] The technical solution of the present invention will be further described in detail below with reference to specific embodiments. It should be understood that the following embodiments are merely illustrative and explanatory of the present invention, and should not be construed as limiting the scope of protection of the present invention. All technologies implemented based on the above content of the present invention are covered within the scope of protection intended by the present invention.

[0080] Unless otherwise specified, the raw materials, reagents, and methods used in the examples are all conventional raw materials, reagents, and methods in the art, and the experimental materials and reagents used can be obtained from commercially available channels.

[0081] Experimental materials and analytical instruments:

[0082] 1 H-NMR / 19 F-NMR was recorded using a Varian 400MHz NMR spectrometer with tetramethylsilane (TMS) as the internal standard; chemical shifts were (ppm, δ:), and proton coupling was labeled as singlet (s), doublet (d), triplet (t), quartet (q), and multiplet (m).

[0083] Low-resolution mass spectrometry was recorded using a Shimadzu LCMS2020 mass spectrometer.

[0084] Abbreviations and Notes:

[0085] DCM: N,N-Dimethylformamide; MeOH: Methanol; THF: Tetrahydrofuran; EDCI: Carbodiimide hydrochloride; DMAP: 4-Dimethylaminopyridine; NaOH: Sodium hydroxide; HCl: Hydrogen chloride; Na2SO4: Sodium sulfate; BSA: Bovine serum albumin; DSC: Differential scanning calorimetry; PVDF: Polyvinylidene fluoride; K2EDTA: Dipotassium ethylenediaminetetraacetate; LC-MS / MS: Liquid chromatography-tandem mass spectrometry.

[0086] Example 1: Preparation of Compound 1

[0087] The synthetic route for compound 1 is as follows:

[0088] EDCI (458.6 mg, 2.39 mmol) and DMAP (536.7 mg, 4.78 mmol) were added to a DCM (30 mL) solution of palmitoylglycine (500.0 mg, 1.59 mmol) and dexamethasone (626.0 mg, 1.59 mmol). The reaction mixture was stirred at room temperature for 16 hours, quenched with water (30 mL), and extracted with DCM (200 mL × 2). The organic phase was washed successively with 1 N HCl solution (30 mL × 3) and saturated brine (30 mL), then dried over anhydrous Na₂SO₄ and concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (DCM / MeOH = 200 / 1-50 / 1) to give a white solid compound (800 mg, yield: 72%). MS m / z 688.4 [M+H] + .

[0089] 1H NMR (400MHz, CDCl3) δ7.20 (d, J=10.1Hz, 1H), 6.33 (dd, J=10.2, 1.8Hz, 1H), 6.11 (s, 1H) ,5.95(d,J=5.7Hz,1H),4.37(d,J=9.1Hz,1H),4.28–4.08(m,2H),3.15–3.04(m,1H),2. 61(d,J=5.8Hz,1H),2.48–2.27(m,4H),2.23(t,J=7.6Hz,2H),2.14(d,J=8.2Hz,1H),1. 88–1.70(m,3H),1.62(d,J=8.4Hz,10H),1.24(s,24H),1.03(s,3H),0.93–0.84(m,6H).

[0090] 19 F NMR (376MHz, CDCl3) -166.1.

[0091] Example 2 Preparation of Compound 2

[0092] The synthetic route for compound 2 is as follows:

[0093] Step 1: Preparation of N-palmitoyl-L-alanine

[0094] At 0 °C, 20 mL of 1 N NaOH solution and 2.9 g of palmitoyl chloride (10.66 mmol) were added to a 50 mL THF solution of L-alanine (1.0 g, 11.22 mmol). The reaction mixture was stirred at room temperature for 3 hours. The pH of the reaction mixture was adjusted to 1 with 2 N HCl solution, and then extracted with DCM (80 mL × 3). The organic phase was washed with saturated brine (80 mL), dried over anhydrous Na₂SO₄, and concentrated under reduced pressure to obtain crude N-palmitoyl-L-alanine (3.2 g, white solid, yield: 87%). MS m / z 328.3 [M+H] + .

[0095] Step 2: Preparation of 2-((8S,9R,10S,11S,13S,14S,16R,17R)-9-fluoro-11,17-dihydroxy-10,13,16-trimethyl-3-oxo-6,7,8,9,10,11,12,13,14,15,16,17-dodecylhydro-3H-cyclopentan[a]phenanthrene-17-yl)-2-oxoethylpalmitoyl-L-alanine ester

[0096] To a DCM (30 mL) solution of N-palmitoyl-L-alanine (0.6 g, 1.83 mmol) and dexamethasone (719.0 mg, 1.83 mmol), EDCI (526.8 mg, 2.75 mmol) and DMAP (616.5 mg, 5.50 mmol) were added. The reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was quenched with water (30 mL) and extracted with DCM (30 mL × 3). The organic phase was washed successively with 1 N HCl solution (30 mL × 2) and saturated brine (30 mL), then dried over anhydrous Na₂SO₄ and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (DCM / MeOH = 200 / 1-60 / 1) to give a white solid compound (900 mg, yield: 70%). MS m / z 702.4 [M+H] + .

[0097] 1 H NMR(400MHz, CDCl3) δ7.20(d,J=10.1Hz,1H),6.33(dd,J=10.2,1.8Hz,1H),6.11(d,J=1.7Hz,1H),5.95 (d,J=4.3Hz,1H),5.01(d,J=17.3Hz,1H),4.87(dd,J=17.3,7.0Hz,1H),4.67(t,J=7.2Hz,1H),4.36(d, J=9.8Hz,1H),3.09(td,J=7.3,3.7Hz,1H),2.66–2.56(m,1H),2.48–2.31(m,4H),2.17(dt,J=22.9,7.1 Hz, 4H), 1.84–1.59 (m, 10H), 1.53–1.46 (m, 3H), 1.24 (s, 24H), 1.03 (d, J = 9.1Hz, 3H), 0.93–0.85 (m, 6H).

[0098] 19 F NMR (376MHz, CDCl3) -166.1.

[0099] Example 3 Preparation of Compound 3

[0100] The synthetic route for compound 3 is as follows:

[0101] Step 1: Preparation of N-lauroyl-L-phenylalanine

[0102] At 0°C, 60 mL of 1N NaOH solution and 12.6 g of lauroyl chloride (57.5 mmol) were added to a 150 mL THF solution of L-phenylalanine (10.0 g, 60.5 mmol). The reaction mixture was stirred at room temperature for 3 hours, and the pH of the reaction mixture was adjusted to 1 with 1N HCl solution. The mixture was then extracted with DCM (250 mL × 3). The organic phase was washed with saturated brine (400 mL), dried over anhydrous Na₂SO₄, and concentrated under reduced pressure to obtain crude N-lauroyl-L-phenylalanine (18 g, white solid, yield: 85%). 1 H NMR (400MHz, CDCl3) δ7.33–7.26(m,3H),7.19–7.13(m,2H),5.90(d,J=7.4Hz,1H),4.87(q,J=6.4Hz,1H),3.25(dd,J=14.1,5.6Hz ,1H),3.13(dd,J=14.1,6.4Hz,1H),2.17(td,J=7.3,1.7Hz,2H),1.56(t,J=7.2Hz,2H),1.31–1.21(m,16H),0.88(t,J=6.8Hz,3H).

[0103] Step 2: Preparation of 2-((8S,9R,10S,11S,13S,14S,16R,17R)-9-fluoro-11,17-dihydroxy-10,13,16-trimethyl-3-oxo-6,7,8,9,10,11,12,13,14,15,16,17-dodecylhydro-3H-cyclopentan[a]phenanthrene-17-yl)-2-oxoethyllauroyl-L-phenylalanine ester

[0104] EDCI (12.4 g, 64.7 mmol) and DMAP (15.8 g, 129.5 mmol) were added to a DCM (300 mL) solution of N-lauroyl-L-phenylalanine (15.0 g, 34.5 mmol) and dexamethasone (14.4 g, 36.7 mmol). The reaction solution was stirred at room temperature for 16 hours. The reaction solution was quenched with water (400 mL) and extracted with DCM (500 mL × 2). The organic phase was washed successively with 1N HCl solution (300 mL × 2) and saturated brine (200 mL), then dried over anhydrous Na2SO4 and concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (DCM / MeOH = 500 / 1-60 / 1) to give a white solid compound (22 g, yield: 70%).

[0105] 1H NMR (400MHz, DMSO-d6) δ8.29–8.19(m,1H),7.33–7.16(m,6H),6.22(d,J=9.9Hz,1H),6.00(s,1H ),5.40(d,J=15.3Hz,1H),5.24–5.02(m,2H),4.82(dd,J=41.0,17.6Hz,1H),4.66–4.55(m,1H),4 .15(s,1H),2.98–2.81(m,2H),2.68–2.56(m,1H),2.39–2.25(m,2H),2.16(t,J=16.0Hz,2H),2.0 6–1.93(m,2H),1.76(d,J=8.3Hz,1H),1.69–1.43(m,5H),1.39–1.05(m,21H),0.93–0.76(m,9H).

[0106] 19 F NMR (376MHz, DMSO-d6)-164.40.

[0107] Example 4: Preparation of Compound 4

[0108] The synthetic route for compound 4 is as follows:

[0109] Step 1: Preparation of N-palmitoyl-L-phenylalanine

[0110] At 0 °C, 20 mL of 1 N NaOH solution and 3.2 g of palmitoyl chloride (11.50 mmol) were added to a 50 mL THF solution of L-phenylalanine (2.0 g, 12.11 mmol). The reaction mixture was stirred at room temperature for 3 hours, and the pH of the reaction mixture was adjusted to 1 with 2 N HCl solution. The mixture was then extracted with DCM (80 mL × 3). The organic phase was washed with saturated brine (80 mL), dried over anhydrous Na₂SO₄, and concentrated under reduced pressure to obtain crude N-palmitoyl-L-phenylalanine (4.2 g, white solid, yield: 85%). MS m / z 404.1 [M+H] + .

[0111] Step 2: Preparation of 2-((8S,9R,10S,11S,13S,14S,16R,17R)-9-fluoro-11,17-dihydroxy-10,13,16-trimethyl-3-oxo-6,7,8,9,10,11,12,13,14,15,16,17-dodecylhydro-3H-cyclopentan[a]phenanthrene-17-yl)-2-oxoethylpalmitoyl-L-phenylalanine ester

[0112] To a DCM (30 mL) solution of N-palmitoyl-L-phenylalanine (0.6 g, 1.49 mmol) and dexamethasone (583.4 mg, 1.83 mmol), EDCI (427.5 mg, 2.23 mmol) and DMAP (500.3 mg, 4.46 mmol) were added. The reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was quenched with water (30 mL) and extracted with DCM (30 mL × 3). The organic phase was washed successively with 1 N HCl solution (30 mL × 2) and saturated brine (30 mL), then dried over anhydrous Na₂SO₄ and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (DCM / MeOH = 200 / 1-80 / 1) to give a white solid compound (850 mg, yield: 73%). MS m / z 778.5 [M+H] + .

[0113] 1 H NMR(400MHz, CDCl3)δ7.29(q,J=6.3Hz,3H),7.25–7.15(m,4H),6.33(dd,J=10.1,1.8Hz,1 H),6.11(s,1H),5.75(dd,J=30.8,7.6Hz,1H),5.06–4.87(m,3H),4.36(d,J=10.0Hz,1H),3 .40–3.24(m,1H),3.12(dd,J=14.2,7.0Hz,2H),2.67–2.54(m,1H),2.49–2.26(m,4H),2.18 –2.08(m,3H),1.84–1.56(m,10H),1.24(d,J=6.9Hz,24H),1.04(s,3H),0.93–0.85(m,6H).

[0114] 19 F NMR (376MHz, CDCl3) -166.1.

[0115] Example 5: Preparation of Compound 5

[0116] The synthetic route for compound 5 is as follows:

[0117] Step 1: Preparation of N-palmitoyl-D-phenylalanine

[0118] At 0 °C, 20 mL of 1 N NaOH solution and 3.2 g of palmitoyl chloride (11.50 mmol) were added to a 50 mL THF solution of D-phenylalanine (2.0 g, 12.11 mmol). The reaction mixture was stirred at room temperature for 3 hours, and the pH of the reaction mixture was adjusted to 1 with 2 N HCl solution. The mixture was then extracted with DCM (80 mL × 3). The organic phase was washed with saturated brine (80 mL), dried over anhydrous Na₂SO₄, and concentrated under reduced pressure to obtain crude N-palmitoyl-D-phenylalanine (4.4 g, white solid, yield: 91%). MS m / z 404.1 [M+H] + .

[0119] Step 2: Preparation of 2-((8S,9R,10S,11S,13S,14S,16R,17R)-9-fluoro-11,17-dihydroxy-10,13,16-trimethyl-3-oxo-6,7,8,9,10,11,12,13,14,15,16,17-dodecylhydro-3H-cyclopentan[a]phenanthrene-17-yl)-2-oxoethylpalmitoyl-D-phenylalanine ester

[0120] To a DCM (30 mL) solution of N-palmitoyl-D-phenylalanine (0.6 g, 1.49 mmol) and dexamethasone (600 mg, 1.49 mmol), EDCI (427.5 mg, 2.23 mmol) and DMAP (500.3 mg, 4.46 mmol) were added. The reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was quenched with water (30 mL) and extracted with DCM (30 mL × 3). The organic phase was washed successively with 1 N HCl solution (30 mL × 2) and saturated brine (30 mL), then dried over anhydrous Na₂SO₄ and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (DCM / MeOH = 200 / 1-80 / 1) to give a white solid compound (960 mg, yield: 87%). MS m / z 778.5 [M+H] + .

[0121] 1H NMR(400MHz, CDCl3) δ7.32(d,J=7.1Hz,2H),7.26–7.18(m,3H),6.36(dd,J=10.2,1.8Hz,1H),6.1 4(s,1H),5.83(dd,J=35.7,7.6Hz,1H),5.12–4.89(m,3H),4.38(d,J=9.8Hz,1H),3.33(dd,J=28.9 ,5.7Hz,1H),3.15(dd,J=14.0,7.1Hz,2H),2.64(d,J=6.0Hz,1H),2.40(dd,J=13.1,5.5Hz,3H),2. 25–2.09(m,3H),1.78(d,J=43.7Hz,12H),1.27(d,J=7.4Hz,25H),1.07(s,3H),0.96–0.87(m,6H).

[0122] 19 F NMR (376MHz, CDCl3) -166.1.

[0123] Example 6: Preparation of Compound 6

[0124] The synthetic route for compound 6 is as follows:

[0125] Step 1: Preparation of N-palmitoyl-L-tryptophan

[0126] At 0 °C, 1 N NaOH solution (12 mL) and palmitoyl chloride (2.6 g, 8.81 mmol) were added to a THF (30 mL) solution of L-tryptophan (2.0 g, 9.79 mmol). The reaction mixture was stirred at room temperature for 3 hours. The pH of the reaction mixture was adjusted to 1 with 1 N HCl solution, and then extracted with DCM / MeOH = 10 / 1 (100 mL × 2). The organic phase was washed with saturated brine (100 mL), dried over anhydrous Na₂SO₄, and concentrated under reduced pressure to obtain crude N-palmitoyl-L-tryptophan (3 g, white solid, yield: 72%). MS m / z 443.30 [M+H] + .

[0127] 1H NMR (400MHz, DMSO-d6) δ10.79(d,J=2.5Hz,1H),8.00(d,J=7.9Hz,1H),7.50( d,J=7.8Hz,1H),7.29(d,J=8.0Hz,1H),7.16–6.85(m,3H),4.44(td,J=8.4,5 .0Hz,1H),3.13(dd,J=14.6,5.0Hz,1H),2.96(dd,J=14.6,8.9Hz,1H),2.02( t,J=7.3Hz,2H),1.37(t,J=7.2Hz,2H),1.21(s,24H),0.83(t,J=6.6Hz,3H).

[0128] Step 2: Preparation of 2-((8S,9R,10S,11S,13S,14S,16R,17R)-9-fluoro-11,17-dihydroxy-10,13,16-trimethyl-3-oxo-6,7,8,9,10,11,12,13,14,15,16,17-dodecylhydro-3H-cyclopentan[a]phenanthrene-17-yl)-2-oxoethylpalmitoyl-L-tryptophan ester

[0129] To a DCM (40 mL) solution of N-palmitoyl-L-tryptophan (2.0 g, 4.52 mmol) and dexamethasone (1.5 g, 3.84 mmol), EDCI (1.3 g, 6.78 mmol) and DMAP (1.7 g, 13.56 mmol) were added. The reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was quenched with water (100 mL) and extracted with DCM (200 mL × 2). The organic phase was washed successively with 1 N HCl solution (50 mL × 2) and saturated brine (100 mL), then dried over anhydrous Na₂SO₄ and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (DCM / MeOH = 500 / 1-100 / 1) to give a white solid compound (2.1 g, yield: 67%). MS m / z 817.55 [M+H] + .

[0130] 1H NMR (400MHz, DMSO-d6) δ10.83(s,1H),8.20(dd,J=8.0,4.6Hz,1H),7.49(dd,J=7.9,3.9Hz,1H),7.34–7.23(m,2H),7.14(dd,J=6.0,2.3Hz ,1H),7.04(t,J=7.5Hz,1H),6.96(t,J=7.4Hz,1H),6.25–6.13(m,1H),5.99(s,1H),5.39(dd,J=13.2,4.7Hz,1H),5.22–5.01(m,2H),4.80( dd,J=41.1,17.6Hz,1H),4.60(tt,J=8.8,4.3Hz,1H),4.14(s,1H),3.10–2.97(m,1H),2.89(s,1H),2.59(td,J=13.8,6.1Hz,1H),2.44–2. 24(m,2H),2.23–1.93(m,4H),1.82–1.69(m,1H),1.69–1.50(m,2H),1.47(s,3H),1.18(d,J=23.3Hz,29H),0.89(s,3H),0.86–0.73(m,6H).

[0131] 19 F NMR (376MHz, DMSO-d6)-164.40.

[0132] Example 7 Preparation of compounds 7-1 and 7-2

[0133] The synthetic routes for compounds 7-1 and 7-2 are as follows:

[0134] Step 1: Preparation of N-palmitoyl-L-histidine

[0135] At 0 °C, 25 mL of 1 N NaOH solution and 2.6 g of palmitoyl chloride (11.63 mmol) were added to a 75 mL THF solution of L-histidine (2.0 g, 12.89 mmol). The reaction mixture was stirred at room temperature for 3 hours. The pH of the reaction mixture was adjusted to 7 with 1 N HCl solution. Extraction was then performed using a DCM / MeOH ratio of 10 / 1 (100 mL × 3). The organic phase was washed with saturated brine (100 mL), dried over anhydrous Na₂SO₄, and concentrated under reduced pressure to obtain crude N-palmitoyl-L-histidine (1.8 g, white solid, yield: 56%). MS m / z 394.35 [M+H] + .

[0136] Step 2: 2-((8S,9R,10S,11S,13S,14S,16R,17R)-9-fluoro-11,17-dihydroxy-10,13,16-trimethyl-3-oxo-6,7,8,9,10,11,12,13,14,15,16,17-dodecylhydro-3H-cyclopentan[a]phenanthrene-17-yl)-2-oxoethylpalmitoyl-L-histidine ester Preparation of 2-((8S,9R,10S,11S,13S,14S,16R,17R)-9-fluoro-11,17-dihydroxy-10,13,16-trimethyl-3-oxo-6,7,8,9,10,11,12,13,14,15,16,17-dodecylhydro-3H-cyclopentan[a]phenanthrene-17-yl)-2-oxoethylpalmitoyl-D-histidine ester

[0137] To a DCM (60 mL) solution of N-palmitoyl-L-histidine (1.8 g, 4.57 mmol) and dexamethasone (1.6 g, 4.12 mmol), EDCI (1.3 g, 6.86 mmol) and DMAP (1.7 g, 13.72 mmol) were added, and the reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was quenched with water (100 mL), extracted with DCM (200 mL × 2), and the organic phase was washed successively with 1N HCl solution (100 mL × 2) and saturated brine (100 mL). The mixture was then dried over anhydrous Na₂SO₄ and concentrated under reduced pressure to obtain the crude product. The crude product was purified successively by silica gel column chromatography (DCM / MeOH = 500 / 1-20 / 1) and thin-layer chromatography (DCM / MeOH = 15 / 1) to give a white solid L-histidine ester compound (250 mg, yield: 7.1%). MS m / z 768.50 [M+H] + .

[0138] 1H NMR (400MHz, DMSO-d6) δ11.81(s,1H),8.15(d,J=7.7Hz,1H),7.51(d,J=1.0Hz,1H),7.27(d,J=10.2Hz,1H),6.79(s,1H),6.20(dd,J=10 .1,1.9Hz,1H),5.98(d,J=1.6Hz,1H),5.43(d,J=4.8Hz,1H),5.17(s,1H),5.01(d,J=17.5Hz,1H),4.83(d,J=17.6Hz,1H),4.54(d,J=2.2 Hz,1H),4.18–4.09(m,1H),3.06(s,1H),2.86(dd,J=9.0,5.8Hz,2H),2.59(td,J=13.5,13.0,5.7Hz,1H),2.28(s,2H),2.18–2.00(m,4H) ,1.80–1.70(m,1H),1.55(d,J=12.9Hz,2H),1.46(s,3H),1.39(t,J=7.2Hz,3H),1.20(d,J=8.4Hz,25H),1.05(s,1H),0.86–0.75(m,9H).

[0139] 19 F NMR (376MHz, DMSO-d6)-164.40.

[0140] White D-histidine ester compound (150 mg, yield: 4.3%). MS m / z 768.50 [M+H] + .

[0141] 1H NMR (400MHz, DMSO-d6) δ11.79(s,1H),8.15(d,J=7.9Hz,1H),7.50(s,1H),7.27(d,J=10.1Hz,1H),6.79(s,1H),6.20(dd,J=10.1, 1.9Hz,1H),5.98(s,1H),5.38(d,J=4.5Hz,1H),5.17(s,1H),5.10(d,J=17.6Hz,1H),4.73(d,J=17.6Hz,1H),4.56(td,J=8.7,4.7H z,1H),4.18–4.07(m,1H),3.01(d,J=12.4Hz,1H),2.93–2.80(m,2H),2.59(td,J=13.6,5.8Hz,1H),2.31(ddt,J=24.2,11.3,5.3Hz ,2H),2.20–2.00(m,4H),1.75(dd,J=12.5,5.5Hz,1H),1.66–1.34(m,8H),1.19(d,J=9.2Hz,25H),1.05(s,1H),0.89–0.74(m,9H).

[0142] 19 F NMR (376MHz, DMSO-d6)-164.40.

[0143] Example 8: Preparation of Compound 8

[0144] The synthetic route for compound 8 is as follows:

[0145] Step 1: Preparation of 3-palmitoylaminopropionic acid

[0146] At 0 °C, 20 mL of 1 N NaOH solution and 2.8 g of palmitoyl chloride (10.10 mmol) were added to a THF (50 mL) solution of 1.0 g (11.22 mmol). The reaction mixture was stirred at room temperature for 3 hours. The pH of the reaction mixture was adjusted to 1 with 2 N HCl solution, and then extracted with DCM (80 mL × 3). The organic phase was washed with saturated brine (80 mL), dried over anhydrous Na₂SO₄, and concentrated under reduced pressure to obtain crude 3-palmitoylaminopropionic acid (0.7 g, white solid, yield: 19%). MS m / z 328.3 [M+H] + .

[0147] Step 2: Preparation of 2-((8S,9R,10S,11S,13S,14S,16R,17R)-9-fluoro-11,17-dihydroxy-10,13,16-trimethyl-3-oxo-6,7,8,9,10,11,12,13,14,15,16,17-dodecylhydro-3H-cyclopentan[a]phenanthrene-17-yl)-2-oxoethyl 3-palmitoylaminopropionate

[0148] To a DCM (30 mL) solution of 3-palmitoylaminopropionic acid (700.0 mg, 2.14 mmol) and dexamethasone (838.8 mg, 2.14 mmol), EDCI (614.6 mg, 3.21 mmol) and DMAP (783.3 mg, 6.41 mmol) were added. The reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was quenched with water (30 mL) and extracted with DCM (30 mL × 3). The organic phase was washed successively with 1 N HCl solution (30 mL × 2) and saturated brine (30 mL), then dried over anhydrous Na₂SO₄ and concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (DCM / MeOH = 200 / 1-50 / 1) to give a white solid compound (850 mg, yield: 56%). MS m / z 702.4 [M+H] + .

[0149] 1 H NMR (400MHz, CD3OD) δ7.40(d,J=10.1Hz,1H),6.28(dd,J=10.1,1.9Hz,1H),6.07(t,J=1.7Hz,1H) ,4.99(d,J=10.6Hz,2H),4.56(s,2H),4.26(dd,J=6.9,4.8Hz,1H),3.48(td,J=6.6,2.7Hz,2H),3 .02(ddd,J=11.2,7.3,4.1Hz,1H),2.63(td,J=6.5,2.1Hz,3H),2.18(t,J=7.6Hz,6H),1.93–1.83 (m,1H),1.58(s,8H),1.29(d,J=9.5Hz,25H),1.22–1.17(m,1H),1.01(s,3H),0.93–0.82(m,6H).

[0150] 19 F NMR (376MHz, CD3OD) -166.3.

[0151] Example 9: Preparation of Compound 9

[0152] The synthetic route for compound 9 is as follows:

[0153] Step 1: Preparation of 4-(3-cyclopentylpropionylamino)butyric acid

[0154] At 0 °C, 12 mL of 1 N NaOH solution and 2.8 g of 3-cyclopentylpropionyl chloride (2.8 g, 17.45 mmol) were added to a THF (30 mL) solution of 4-aminobutyric acid (2.0 g, 19.39 mmol). The reaction mixture was stirred at room temperature for 3 hours. The pH of the reaction mixture was adjusted to 1 with 1 N HCl solution, and then extracted with DCM (150 mL × 2). The organic phase was washed with saturated brine (100 mL), dried over anhydrous Na₂SO₄, and concentrated under reduced pressure to obtain crude 4-(3-cyclopentylpropionamido)butyric acid (3 g, white solid, yield: 75%). MS m / z 228.15 [M+H] + .

[0155] Step 2: Preparation of 2-((8S,9R,10S,11S,13S,14S,16R,17R)-9-fluoro-11,17-dihydroxy-10,13,16-trimethyl-3-oxo-6,7,8,9,10,11,12,13,14,15,16,17-dodecylhydro-3H-cyclopentan[a]phenanthrene-17-yl)-2-oxoethyl 4-(3-cyclopentylpropionylamino)butyrate

[0156] To a solution of 4-(3-cyclopentylpropionamide)butyric acid (1.0 g, 4.40 mmol) and dexamethasone (1.7 g, 4.40 mmol) in DCM (40 mL), EDCI (1.3 g, 6.60 mmol) and DMAP (1.6 g, 13.20 mmol) were added. The reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was quenched with water (100 mL), extracted with DCM (200 mL × 2), and the organic phase was washed successively with 1N HCl solution (50 mL × 2) and saturated brine (100 mL). The solution was then dried over anhydrous Na₂SO₄ and concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (DCM / MeOH = 500 / 1-60 / 1) to give a white solid compound (1 g, yield: 38%). MS m / z 602.35 [M+H] + .

[0157] 1H NMR (400MHz, DMSO-d6) δ7.80(t,J=5.6Hz,1H),7.27(d,J=10.1Hz,1H),6.20(dd,J=10.1,1.8Hz,1H),5.98(d,J=1.6Hz,1H ),5.43–5.31(m,1H),5.14(s,1H),5.00(d,J=17.7Hz,1H),4.77(d,J=17.6Hz,1H),4.19–4.04(m,1H),3.04(q,J=6.6Hz,2 H),2.85(ddd,J=11.2,7.3,4.1Hz,1H),2.59(td,J=13.5,6.0Hz,1H),2.33(dt,J=23.3,7.3Hz,4H),2.20–1.99(m,4H),1. 80–1.42(m,17H),1.32(dd,J=13.0,4.8Hz,1H),1.04(ddt,J=14.5,10.4,5.3Hz,3H),0.85(s,3H),0.76(d,J=7.2Hz,3H).

[0158] 19 F NMR (376MHz, DMSO-d6)-164.4.

[0159] Example 10: Preparation of Compound 10

[0160] The synthetic route for compound 10 is as follows:

[0161] Step 1: Preparation of 4-(3-phenylpropionylamino)butyric acid

[0162] At 0 °C, 1 N NaOH solution (6 mL) and phenylpropionyl chloride (1.5 g, 8.7 mmol) were added to a THF (15 mL) solution of 4-aminobutyric acid (1.0 g, 9.70 mmol). The reaction mixture was stirred at room temperature for 3 hours. The pH of the reaction mixture was adjusted to 1 with 1 N HCl solution, and then extracted with DCM (80 mL × 3). The organic phase was washed with saturated brine (100 mL), dried over anhydrous Na₂SO₄, and concentrated under reduced pressure to obtain crude 4-(3-phenylpropionylamino)butyric acid (1.8 g, white solid). MS m / z 236.10 [M+H] + .

[0163] Step 2: Preparation of 2-((8S,9R,10S,11S,13S,14S,16R,17R)-9-fluoro-11,17-dihydroxy-10,13,16-trimethyl-3-oxo-6,7,8,9,10,11,12,13,14,15,16,17-dodecylhydro-3H-cyclopentan[a]phenanthrene-17-yl)-2-oxoethyl 4-(3-phenylpropionylamino)butyrate

[0164] To a DCM (40 mL) solution of 4-(3-phenylpropionylamino)butyric acid (1.8 g, crude) and dexamethasone (2.4 g, 6.12 mmol), EDCI (2.2 g, 11.5 mmol) and DMAP (2.8 g, 23.0 mmol) were added, and the reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was quenched with water (100 mL), extracted with DCM (200 mL × 2), and the organic phase was washed successively with 1 N HCl solution (50 mL × 2) and saturated brine (100 mL). The solution was then dried over anhydrous Na₂SO₄ and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (DCM / MeOH = 500 / 1-60 / 1) to give a white solid compound (1.9 g, 2-step yield: 32%). MS m / z 610.00 [M+H] + .

[0165] 1 H NMR (400MHz, DMSO-d6) δ7.84(t,J=5.6Hz,1H),7.33–7.08(m,6H),6.22(dd,J=10.1,1.8Hz,1H),6.00(s,1H),5.40(d,J =4.8Hz,1H),5.15(s,1H),5.02(d,J=17.6Hz,1H),4.79(d,J=17.6Hz,1H),4.20–4.08(m,1H),3.06(q,J=6.6Hz,2H),2. 92–2.76(m,3H),2.60(dt,J=13.6,6.8Hz,1H),2.33(dq,J=11.3,6.7,5.5Hz,6H),2.21–2.08(m,2H),1.82–1.71(m,1H) ,1.71–1.54(m,4H),1.48(s,3H),1.35(dt,J=12.8,6.6Hz,1H),1.11–1.01(m,1H),0.88(s,3H),0.78(d,J=7.2Hz,3H).

[0166] 19 F NMR (376MHz, DMSO-d6)-164.40.

[0167] Example 11 Preparation of Compound 11

[0168] The synthetic route for compound 11 is as follows:

[0169] Step 1: Preparation of 4-Octaaminobutyric acid

[0170] At 0 °C, 20 mL of 1 N NaOH solution and 2.8 g of octanoyl chloride (17.45 mmol) were added to a 50 mL THF solution of 2.0 g (19.39 mmol) of 4-aminobutyric acid (GABA). The reaction mixture was stirred at room temperature for 3 hours, and the pH of the reaction mixture was adjusted to 1 with 2 N HCl solution. The mixture was then extracted with DCM (80 mL × 3). The organic phase was washed with saturated brine (80 mL), dried over anhydrous Na₂SO₄, and concentrated under reduced pressure to obtain crude 4-octanoylaminobutyric acid (4 g, white solid, yield: 90%). MS m / z 230.00 [M+H] + .

[0171] Step 2: Preparation of ethyl 2-((8S,9R,10S,11S,13S,14S,16R,17R)-9-fluoro-11,17-dihydroxy-10,13,16-trimethyl-3-oxo-6,7,8,9,10,11,12,13,14,15,16,17-dodecylhydro-3H-cyclopentan[a]phenanthrene-17-yl)-2-oxoethyl 4-octanoaminobutyrate

[0172] To a DCM (30 mL) solution of 4-octanoaminobutyric acid (876 mg, 2.55 mmol) and dexamethasone (1.5 g, 2.55 mmol), EDCI (1.09 g, 3.82 mmol) and DMAP (1.40 g, 7.64 mmol) were added, and the reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was quenched with water (50 mL), extracted with DCM (50 mL × 3), and the organic phase was washed successively with 1 N HCl solution (50 mL × 2) and saturated brine (50 mL). The solution was then dried over anhydrous Na₂SO₄ and concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (DCM / MeOH = 200 / 1-80 / 1) to give a white solid compound (1.3 g, yield: 84%). MS m / z 1207.2 [2M+H] + .

[0173] 1H NMR (400MHz, CDCl3) δ7.40 (d, J=10.1Hz, 1H), 6.28 (dd, J=10.1, 1.9Hz, 1H), 6 .07(d,J=1.8Hz,1H),4.96(d,J=7.5Hz,2H),4.28–4.23(m,1H),3.23(d,J=6. 9Hz,2H),3.02(s,1H),2.71(d,J=5.9Hz,1H),2.49–2.15(m,8H),1.89–1.49( m,12H),1.31(q,J=5.1Hz,8H),1.19(s,1H),1.00(s,3H),0.91–0.83(m,6H).

[0174] 19 F NMR (376MHz, CD3OD) -166.3.

[0175] Example 12 Preparation of Compound 12

[0176] The synthetic route for compound 12 is as follows:

[0177] Step 1: Preparation of 4-Lauroylaminobutyric acid

[0178] At 0 °C, 20 mL of 1 N NaOH solution and 1.9 g of lauroyl chloride (8.73 mmol) were added to a THF (50 mL) solution of 4-aminobutyric acid (1.0 g, 9.70 mmol). The reaction solution was stirred at room temperature for 3 hours. The pH of the reaction solution was adjusted to 1 with 2 N HCl solution. The solution was then extracted with DCM (80 mL × 3). The organic phase was washed with saturated brine (80 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure to obtain crude 4-lauroylaminobutyric acid (2.2 g, white solid, yield: 79%).

[0179] Step 2: Preparation of 2-((8S,9R,10S,11S,13S,14S,16R,17R)-9-fluoro-11,17-dihydroxy-10,13,16-trimethyl-3-oxo-6,7,8,9,10,11,12,13,14,15,16,17-dodecano-3H-cyclopentan[a]phenanthrene-17-yl)-2-oxoethyl 4-dodecanoylaminobutyrate

[0180] To a DCM (30 mL) solution of dexamethasone (600.0 mg, 2.10 mmol) and 4-lauroylaminobutyric acid (825.0 mg, 2.10 mmol), EDCI (604.4 mg, 3.15 mmol) and DMAP (764.1 mg, 6.31 mmol) were added. The reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was quenched with water (30 mL) and extracted with DCM (30 mL × 3). The organic phase was washed successively with 1 N HCl solution (30 mL × 2) and saturated brine (50 mL), then dried over anhydrous Na₂SO₄ and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (DCM / MeOH = 200 / 1-80 / 1) to give a white solid compound (700 mg, yield: 52%). MS m / z 660.20 [M+H] + .

[0181] 1 H NMR (400MHz, CDCl3) δ7.23 (d, J=10.2Hz, 1H), 6.32 (dd, J=10.0, 1.8Hz, 1H), 6.09 (s, 1H),5.93(t,J=5.6Hz,1H),4.90(d,J=1.7Hz,2H),4.39–4.32(m,1H),3.31(qd,J=6. 8,3.0Hz,2H),3.08(td,J=7.3,3.8Hz,1H),2.62–2.33(m,7H),2.14(q,J=5.9,4.2Hz ,3H),1.88–1.51(m,11H),1.26(d,J=12.1Hz,18H),1.03(s,3H),0.92–0.84(m,6H).

[0182] 19 F NMR (376MHz, CDCl3) -166.02.

[0183] Example 13 Preparation of Compound 13

[0184] The synthetic route for compound 13 is as follows:

[0185] Step 1: Preparation of 4-palmitoylaminobutyric acid

[0186] At 0 °C, 20 mL of 1 N NaOH solution and 2.9 g of palmitoyl chloride (10.67 mmol) were added to a 50 mL THF solution of 1.0 g (9.70 mmol). The reaction mixture was stirred at room temperature for 3 hours. The pH of the reaction mixture was adjusted to 1 with 2 N HCl solution, and then filtered. The resulting solid was washed with 20 mL of water and dried under vacuum to obtain a 2.5 g sample of 4-palmitoylaminobutyric acid (white solid, yield: 75%). MS m / z 342.30 [M+H] + .

[0187] Step 2: Preparation of 2-((8S,9R,10S,11S,13S,14S,16R,17R)-9-fluoro-11,17-dihydroxy-10,13,16-trimethyl-3-oxo-6,7,8,9,10,11,12,13,14,15,16,17-dodecylhydro-3H-cyclopentan[a]phenanthrene-17-yl)-2-oxoethyl 4-palmitoylaminobutyrate

[0188] To a DCM (30 mL) solution of 4-palmitoylaminobutyric acid (0.5 g, 1.46 mmol) and dexamethasone (574.6 mg, 1.46 mmol), EDCI (421.0 mg, 2.20 mmol) and DMAP (492.6 mg, 4.39 mmol) were added. The reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was quenched with water (30 mL) and extracted with DCM (30 mL × 3). The organic phase was washed successively with 1 N HCl solution (30 mL × 2) and saturated brine (30 mL), then dried over anhydrous Na₂SO₄ and concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (DCM / MeOH = 200 / 1-40 / 1) to give a white solid compound (0.9 g, yield: 64%). MS m / z 716.35 [M+H] + .

[0189] 1H NMR (400MHz, DMSO-d6) δ7.76(t,J=5.5Hz,1H),7.27(d,J=10.2Hz,1H),6.20(dd,J=10.2,1.9Hz,1H),5.99(t,J=1.6Hz,1H),5.37(dd,J= 5.0,1.4Hz,1H),5.12(s,1H),5.01(d,J=17.6Hz,1H),4.77(d,J=17.6Hz,1H),4.13(d,J=10.5Hz,1H),3.05(q,J=6.6Hz,2H),2.86(td,J =7.1,3.7Hz,1H),2.65–2.54(m,1H),2.40–2.27(m,4H),2.18–2.07(m,2H),2.02(t,J=7.4Hz,2H),1.80–1.72(m,1H),1.61(ddd,J=35.5 ,14.1,9.7Hz,4H),1.47(s,4H),1.39–1.31(m,1H),1.22(s,25H),1.06(td,J=8.0,4.1Hz,1H),0.89–0.81(m,6H),0.77(d,J=7.2Hz,3H).

[0190] 19 F NMR (376MHz, DMSO-d6)-164.4.

[0191] Example 14 Preparation of Compound 14

[0192] The synthetic route for compound 14 is as follows:

[0193] Step 1: Preparation of 4-stearoylaminobutyric acid

[0194] At 0 °C, 6 mL of 1 N NaOH solution and 0.7 g of 4-aminobutyric acid (GABA) were added to a 15 mL THF solution of stearoyl chloride (2.1 g, 6.93 mmol). The reaction mixture was stirred at room temperature for 3 hours. The pH of the reaction mixture was adjusted to 1 with 1 N HCl solution, and then extracted with DCM (200 mL × 2). The organic phase was washed with saturated brine (100 mL), dried over anhydrous Na₂SO₄, and concentrated under reduced pressure to obtain crude 4-stearoylaminobutyric acid (2 g, white solid). MS m / z 370.3 [M+H] + .

[0195] Step 2: Preparation of 2-((8S,9R,10S,11S,13S,14S,16R,17R)-9-fluoro-11,17-dihydroxy-10,13,16-trimethyl-3-oxo-6,7,8,9,10,11,12,13,14,15,16,17-dodecylhydro-3H-cyclopentan[a]phenanthrene-17-yl)-2-oxoethyl 4-stearoylaminobutyrate

[0196] To a DCM (40 mL) solution of 4-stearoylaminobutyric acid (2 g, 5.41 mmol) and dexamethasone (2.1 g, 5.41 mmol), EDCI (1.6 g, 8.11 mmol) and DMAP (2.0 g, 16.22 mmol) were added. The reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was quenched with water (100 mL) and extracted with DCM (200 mL × 2). The organic phase was washed successively with 1 N HCl solution (50 mL × 2) and saturated brine (50 mL), then dried over anhydrous Na₂SO₄ and concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (DCM / MeOH = 500 / 1-60 / 1) to give a white solid compound (1.5 g, two-step yield: 29%). MS m / z 744.15 [M+H] + .

[0197] 1 H NMR (400MHz, DMSO-d6) δ7.78(t,J=5.6Hz,1H),7.27(d,J=10.1Hz,1H),6.20(dd,J=10.2,1.8Hz,1H),5.98(d,J=1.9Hz,1H),5.3 9(d,J=4.8Hz,1H),5.13(s,1H),5.00(d,J=17.6Hz,1H),4.77(d,J=17.6Hz,1H),4.11(dd,J=10.7,5.3Hz,1H),3.04(q,J=6.6Hz ,2H),2.85(ddd,J=11.5,7.6,4.2Hz,1H),2.59(td,J=13.6,5.9Hz,1H),2.44–2.22(m,4H),2.23–1.97(m,4H),1.78–1.70(m,1H) ),1.67–1.50(m,4H),1.46(s,4H),1.34(q,J=7.9Hz,1H),1.20(s,29H),1.04(ddd,J=12.4,8.4,4.1Hz,1H),0.91–0.68(m,9H).

[0198] 19 F NMR (376MHz, DMSO-d6)-164.40.

[0199] Example 15 Preparation of Compound 15

[0200] The synthetic route for compound 15 is as follows:

[0201] Step 1: Preparation of 4-Eocodecanylaminobutyric acid

[0202] At 0 °C, 8 mL of 1 N NaOH solution and 129 mg of 4-aminobutyric acid (1.25 mmol) were added to a 20 mL THF solution of docosanoyl chloride (500 mg, 1.39 mmol). The reaction mixture was stirred at room temperature for 3 hours. The pH of the reaction mixture was adjusted to 1 with 1 N HCl solution, and then extracted with DCM (80 mL × 2). The organic phase was washed with saturated brine (80 mL), dried over anhydrous Na₂SO₄, and concentrated under reduced pressure to obtain crude 4-docosanoylaminobutyric acid (590 mg, white solid). MS m / z 426.25 [M+H] + .

[0203] Step 2: Preparation of 2-((8S,9R,10S,11S,13S,14S,16R,17R)-9-fluoro-11,17-dihydroxy-10,13,16-trimethyl-3-oxo-6,7,8,9,10,11,12,13,14,15,16,17-dodecano-3H-cyclopentan[a]phenanthrene-17-yl)-2-oxoethyl 4-eicosanoylaminobutyrate

[0204] To a DCM (20 mL) solution of 4-docosahexaenoic acid (590 mg, 1.39 mmol) and dexamethasone (543 mg, 1.39 mmol), EDCI (399 mg, 2.08 mmol) and DMAP (508 mg, 4.16 mmol) were added. The reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was quenched with water (30 mL) and extracted with DCM (50 mL × 2). The organic phase was washed successively with 1 N HCl solution (30 mL × 2) and saturated brine (30 mL), then dried over anhydrous Na₂SO₄ and concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (DCM / MeOH = 500 / 1-60 / 1) to give a white solid compound (500 mg, 2-step yield: 44%). MS m / z 800.15 [M+H] + .

[0205] 1H NMR (400MHz, DMSO-d6) δ7.77(t,J=5.7Hz,1H),7.27(d,J=10.2Hz,1H),6.20(dd,J=10.1,1.9Hz,1H),5.98(s,1H),5.39(d,J= 4.8Hz,1H),5.13(s,1H),5.00(d,J=17.6Hz,1H),4.77(d,J=17.6Hz,1H),4.12(d,J=10.5Hz,1H),3.04(q,J=6.3Hz,2H),2.85( s,1H),2.58(dt,J=13.4,7.0Hz,1H),2.39–2.23(m,4H),2.11(dt,J=20.0,11.9Hz,2H),2.01(t,J=7.4Hz,2H),1.80–1.71(m, 1H),1.70–1.51(m,4H),1.46(s,4H),1.35–1.30(m,1H),1.20(s,37H),1.04(s,1H),0.87–0.79(m,6H),0.76(d,J=7.2Hz,3H).

[0206] 19 F NMR (376MHz, DMSO-d6)-164.4.

[0207] Example 16 Preparation of Compound 16

[0208] The synthetic route for compound 16 is as follows:

[0209] To a DCM solution of 4-palmitoylaminobutyric acid (700 mg, 2.05 mmol) and methylprednisolone (689 mg, 1.84 mmol) in 30 mL of DCM, EDCI (588 mg, 3.07 mmol) and DMAP (751 mg, 6.15 mmol) were added. The reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was quenched with water (100 mL) and extracted with DCM (150 mL × 2). The organic phase was washed successively with 1 N HCl solution (50 mL × 2) and saturated brine (100 mL), then dried over anhydrous Na₂SO₄ and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (DCM / MeOH = 500 / 1-50 / 1) to give a white solid compound (875 mg, yield: 61%). MS m / z 698.25 [M+H] + .

[0210] 1H NMR(400MHz, DMSO-d6)δ7.78(t,J=5.6Hz,1H),7.30(d,J=10.0Hz,1H),6.15(dd,J=10.0,1.7Hz,1H), 5.79(s,1H),5.38(s,1H),5.03(d,J=17.5Hz,1H),4.72(d,J=17.3Hz,2H),4.25(s,1H),3.04(q,J=6.6 Hz,2H),2.69–2.56(m,1H),2.36(t,J=7.5Hz,2H),2.15–1.94(m,4H),1.85(d,J=12.1Hz,1H),1.63(dq ,J=14.6,7.5Hz,5H),1.40(d,J=32.9Hz,7H),1.20(s,26H),1.02(d,J=6.3Hz,3H),0.90–0.63(m,8H).

[0211] Example 17 Preparation of Compound 17

[0212] The synthetic route for compound 17 is as follows:

[0213] To a DCM solution of 4-palmitoylaminobutyric acid (800 mg, 3.31 mmol) and hydrocortisone (900 mg, 2.48 mmol) in 30 mL, EDCI (950 mg, 4.96 mmol) and DMAP (1.2 g, 9.93 mmol) were added. The reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was quenched with water (30 mL) and extracted with DCM (30 mL × 2). The organic phase was washed successively with 1 N HCl solution (30 mL × 2) and saturated brine (30 mL), then dried over anhydrous Na₂SO₄ and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (DCM / MeOH = 200 / 1-40 / 1) to give a white solid (600 mg, yield: 35%). MS m / z 686.40 [M+H] + .

[0214] 1H NMR(400MHz,DMSO-d6)δ7.76(s,1H),5.52(d,J=1.4Hz,1H),5.37(s,1H),5.04(d,J=17.5Hz,1H) ,4.72(d,J=17.5Hz,1H),4.33(d,J=3.9Hz,1H),4.23(d,J=3.3Hz,1H),3.03(d,J=6.2Hz,2H),2.3 5(t,J=7.5Hz,4H),2.18–2.12(m,2H),1.99(t,J=7.4Hz,3H),1.87(s,3H),1.63(t,J=7.3Hz,7H) ,1.46–1.39(m,3H),1.19(s,28H),0.95(dd,J=13.4,4.2Hz,1H),0.84–0.79(m,4H),0.72(s,3H).

[0215] Example 18 Preparation of Compound 18

[0216] The synthetic route for compound 18 is as follows:

[0217] To a DCM (30 mL) solution of 4-palmitoylaminobutyric acid (1.2 g, 3.60 mmol) and prednisolone (1.0 g, 2.77 mmol), EDCI (904 mg, 4.71 mmol) and DMAP (1.01 g, 8.31 mmol) were added. The reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was quenched with water (30 mL) and extracted with DCM (80 mL × 2). The organic phase was washed successively with 1 N HCl solution (80 mL × 2) and saturated brine (150 mL), then dried over anhydrous Na₂SO₄ and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (DCM / MeOH = 150 / 1-50 / 1) to give a white solid (591 mg, yield: 31%). MS m / z 684.20 [M+H] + .

[0218] 1H NMR (400MHz, CDCl3) δ7.28(s,1H),6.27(dd,J=10.1,1.9Hz,1H),6.01(t,J=1.6Hz,1H),5.81(s,1H),5.00(d,J=17.4H z,1H),4.88(d,J=17.4Hz,1H),4.50(d,J=3.3Hz,1H),3.33(q,J=6.6Hz,2H),2.85–2.70(m,1H),2.63–2.52(m,1H),2. 48(td,J=7.0,4.5Hz,2H),2.33(dd,J=13.9,4.5Hz,2H),2.19–2.05(m,5H),1.97–1.78(m,3H),1.75–1.70(m,1H),1.6 1(s,6H),1.53–1.46(m,2H),1.29–1.23(m,25H),1.11(ddd,J=19.9,11.9,4.0Hz,2H),0.97(s,3H),0.91–0.85(m,3H).

[0219] Example 19 Preparation of Compound 19

[0220] The synthetic route for compound 19 is as follows:

[0221] Step 1: Preparation of 6-palmitoylaminohexanoic acid

[0222] 6-Aminohexanoic acid (1.0 g, 7.6 mmol) was dissolved in THF (16 mL), and 1N NaOH (6 mL) and palmitoyl chloride (2.0 g, 7.2 mmol) were added at 0 °C. The reaction mixture was stirred at room temperature for 16 hours. The pH of the reaction mixture was adjusted to 1 with 1N HCl solution, and then extracted with DCM (200 mL × 2). The organic phase was washed with saturated brine (100 mL), dried over anhydrous Na₂SO₄, and concentrated under reduced pressure to give 1.2 g of white solid. MS m / z 370.15 [M+H] + .

[0223] Step 2: Preparation of 2-[[8S,9R,10S,11S,13S,14S,16R,17R]-9-fluoro-11,17-dihydroxy-10,13,16-trimethyl-3-oxo-6,7,8,9,10,11,12,13,14,15,16,17-dodecano-3H-cyclopentano[a]phenanthrene-17-yl]-2-oxoethyl 6-hexadecanoylaminohexanoate

[0224] To a DCM (20 mL) solution of 6-palmitoylaminocaproic acid (1.2 g, 3.2 mmol) and dexamethasone (957 mg, 2.4 mmol), EDCI (920 mg, 8.11 mmol) and DMAP (1.2 g, 9.6 mmol) were added. The reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was quenched with water (100 mL) and extracted with DCM (200 mL × 2). The organic phase was washed successively with 1 N HCl solution (50 mL × 2) and saturated brine (50 mL), then dried over anhydrous Na₂SO₄ and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (DCM / MeOH = 500 / 1-60 / 1) to give a white solid (700 mg, 2-step yield: 29%). MS m / z 744.10 [M+H] + .

[0225] 1 H NMR (400MHz, DMSO-d6) δ7.67(t,J=5.6Hz,1H),7.26(d,J=10.2Hz,1H),6.19(dd,J=10.1,1.9Hz,1H),5.97(d,J=1.6Hz,1H),5.43–5.30(m,1 H),5.11(s,1H),4.98(d,J=17.6Hz,1H),4.75(d,J=17.6Hz,1H),4.17–4.06(m,1H),2.97(q,J=6.5Hz,2H),2.84(dq,J=7.2,4.6,4.1Hz,1H) ,2.58(d,J=6.0Hz,1H),2.40–2.21(m,4H),2.20–2.04(m,2H),1.98(t,J=7.4Hz,2H),1.81–1.68(m,1H),1.64–1.48(m,4H),1.45(s,5H),1. 37–1.32(m,2H),1.29–1.24(m,2H),1.20(s,26H),1.03(ddd,J=12.2,8.3,4.1Hz,1H),0.82(dd,J=12.7,6.3Hz,6H),0.75(d,J=7.2Hz,3H).

[0226] Example 20 Preparation of Compound 20

[0227] The synthetic route for compound 20 is as follows:

[0228] To a DCM (20 mL) solution of 4-acetaminophen (481 mg, 3.32 mmol) and dexamethasone (1.0 g, 2.55 mmol), EDCI (841 mg, 4.25 mmol) and DMAP (843 mg, 6.9 mmol) were added. The reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was quenched with water (100 mL) and extracted with DCM (200 mL × 2). The organic phase was washed successively with 1 N HCl solution (50 mL × 2) and saturated brine (50 mL), then dried over anhydrous Na₂SO₄ and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (DCM / MeOH = 200 / 1-60 / 1) to give a white solid (560 mg, yield: 42%). MS m / z 519.90 [M+H] + .

[0229] 1 H NMR (400MHz, DMSO-d6) δ7.83(s,1H),7.26(d,J=10.1Hz,1H),6.19(dd,J=10.1,1.9Hz,1H),5.97(d,J=2.1Hz,1H),5 .37(d,J=4.8Hz,1H),5.12(s,1H),5.00(d,J=17.6Hz,1H),4.76(d,J=17.6Hz,1H),4.12(d,J=7.6Hz,1H),3.03(q,J =6.6Hz,2H),2.84(s,1H),2.58(td,J=14.1,13.5,6.4Hz,1H),2.40–2.25(m,4H),2.17–2.04(m,2H),1.76(s,3H),1 .67–1.50(m,4H),1.45(s,3H),1.31(dd,J=13.0,4.9Hz,1H),1.10–0.97(m,1H),0.85(s,3H),0.75(d,J=7.2Hz,3H).

[0230] Example 21 Preparation of Compound 21

[0231] The synthetic route for compound 21 is as follows:

[0232] To a DCM (30 mL) solution of 4-propionylaminobutyric acid (810 mg, 5.09 mmol) and dexamethasone (1.0 g, 2.55 mmol), EDCI (1.46 g, 7.63 mmol) and DMAP (1.86 g, 15.27 mmol) were added. The reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was quenched with water (100 mL) and extracted with DCM (200 mL × 2). The organic phase was washed successively with 1 N HCl solution (50 mL × 2) and saturated brine (50 mL), then dried over anhydrous Na₂SO₄ and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (DCM / MeOH = 200 / 1-40 / 1) to give a white solid (717 mg, yield: 52%). MS m / z 534.25 [M+H] + .

[0233] 1 H NMR (400MHz, DMSO-d6) δ7.74(s,1H),7.26(d,J=10.1Hz,1H),6.19(dd,J=10.1,1.9Hz,1H),5.97(t,J=1.6Hz,1H),5.37(dd ,J=4.9,1.4Hz,1H),5.12(s,1H),4.99(d,J=17.6Hz,1H),4.76(d,J=17.6Hz,1H),4.15–4.08(m,1H),3.03(d,J=6.3Hz,2H) ,2.69(s,0H),2.56(dd,J=13.4,5.9Hz,1H),2.35(t,J=7.5Hz,4H),2.02(q,J=7.6Hz,4H),1.78–1.70(m,1H),1.64(t,J=7. 2Hz, 4H), 1.45 (s, 3H), 1.20 (s, 2H), 1.03 (td, J = 8.0, 4.0Hz, 1H), 0.95 (t, J = 7.6Hz, 3H), 0.85 (s, 3H), 0.75 (d, J = 7.2Hz, 3H).

[0234] Example 22 Preparation of Compound 22

[0235] The synthetic route for compound 22 is as follows:

[0236] To a DCM solution of 4-benzoylaminobutyric acid (1.0 g, 4.83 mmol) and dexamethasone (1.46 g, 3.7 mmol) in 30 mL of DCM, EDCI (1.2 g, 6.29 mmol) and DMAP (1.36 g, 11.1 mmol) were added. The reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was quenched with water (100 mL) and extracted with DCM (200 mL × 2). The organic phase was washed successively with 1 N HCl solution (50 mL × 2) and saturated brine (50 mL), then dried over anhydrous Na₂SO₄ and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (PE / EA = 1 / 1-0 / 1) to give a white solid (753 mg, yield: 34%). MS m / z 581.90 [M+H] + .

[0237] 1 H NMR(400MHz, DMSO-d6)δ8.50(t,J=5.6Hz,1H),7.88–7.81(m,2H),7.55–7.49(m,1H),7.50–7.42(m,2H),7.29(d,J=10.1Hz,1H),6.23(dd,J=1 0.1,1.9Hz,1H),6.01(t,J=1.6Hz,1H),5.40(d,J=4.8Hz,1H),5.15(s,1H),5.03(d,J=17.6Hz,1H),4.80(d,J=17.6Hz,1H),4.18–4.11(m,1H) ,2.88(ddd,J=11.2,7.3,4.0Hz,1H),2.68–2.54(m,2H),2.45(d,J=7.4Hz,2H),2.41–2.27(m,2H),2.21–2.10(m,2H),1.81(tt,J=14.3,6.4Hz ,3H),1.61(dt,J=25.1,12.7Hz,2H),1.49(s,3H),1.44–1.27(m,1H),1.07(ddd,J=11.9,8.0,4.1Hz,1H),0.89(s,3H),0.79(d,J=7.2Hz,3H).

[0238] Test experiment:

[0239] Test Example 1: Determination of Compound Solubility

[0240] Method for determining solubility of compound in pH 7.4 phosphate buffer: Take an excess of the compound and place it in pH 7.4 phosphate buffer. Shake at 37℃ and 100 rpm for 24 h. Take a sample, filter it through a 0.22 μm filter membrane, and take the filtrate to determine the concentration.

[0241] Method for determining the solubility of the compound in pH 7.4 phosphate buffer containing 10% BSA: Take an excess of the compound and place it in pH 7.4 phosphate buffer containing 10% BSA. Shake at 37℃ and 100 rpm for 24 h. Take a sample, filter it through a 0.22 μm filter membrane, take the filtrate, add 5 times the amount of acetonitrile to precipitate the protein, centrifuge and take the supernatant to determine the concentration.

[0242] The solubility of the compounds in Table 1 in pH 7.4 phosphate buffer and pH 7.4 phosphate buffer containing 10% BSA was determined using the methods described above.

[0243] Table 1 Results of compound solubility determination

[0244] The results showed that the prodrug compounds of this invention all had solubility below 0.1 μg / mL in phosphate buffer at pH 7.4, significantly lower than the original drug. This characteristic makes them particularly suitable for developing long-acting sustained-release formulations based on solubility control. However, in 10% BSA pH 7.4 phosphate buffer simulating in vivo conditions, the solubility of different compounds showed some differences. Specifically, compounds 3, 4, 5, 6, 11, 12, 13, 16, and 19 showed even lower solubility, all lower than the solubility of compounds 20, 21, and 22 in phosphate buffer at pH 7.4. In the prodrug series of this invention, comparing compounds 3 and 4, and compounds 11, 12, and 13, a decreasing trend in solubility was observed with increasing carbon chain length.

[0245] Test Example 2: Determination of the melting point of the compound

[0246] The melting points were determined using a differential scanning calorimeter (TA, Q2000). 5 mg of each sample was placed in a dry aluminum crucible, and the heating rate was set to 5 °C / min. The test temperature range was 30 °C–300 °C under a nitrogen atmosphere, and the DSC curves were recorded. The melting points of each compound are shown in Table 2.

[0247] Table 2 Results of compound melting point determination

[0248] When developing suspension formulations, choosing compounds with higher melting points may be more advantageous. High-melting-point prodrugs help improve the stability and efficacy of the suspension. Given that such formulations are best subjected to high-temperature sterilization, and that lower-melting-point prodrugs may deteriorate under these conditions, higher-melting-point prodrugs are preferred. However, the ability to withstand high-temperature sterilization is not the only criterion for selecting a prodrug; for lower-melting-point prodrugs, aseptic manufacturing processes can also be considered to mitigate the risks associated with high-temperature sterilization.

[0249] Test Example 3: Preparation of Prodrug Suspension

[0250] Preparation method of prodrug suspension: First, dissolve mannitol and Tween 80 in ultrapure water to prepare an aqueous solution containing 5 mg / mL Tween 80 and 50 mg / mL mannitol. Then, add 5 mg / mL of the prodrug and ball mill for 5 min to obtain the solution. Figure 1 shows the appearance of suspensions with different prodrugs and dexamethasone palmitate (DXP) suspension.

[0251] The results showed that although DXP is also a long-chain dexamethasone derivative, DXP ​​has poor dispersibility and cannot be prepared into a suspension; however, the dexamethasone prodrug compounds 1-15, 19, the methylprednisolone prodrug compound 16, the hydrocortisone prodrug compound 17, and the prednisolone prodrug compound 18 of the present invention can all be prepared into suspensions.

[0252] Test Example 4: In vitro degradation study of the prodrug

[0253] Prodrugs need to be degraded into the original drug to exert their efficacy. This test case investigated the degradation and transformation of prodrugs through an in vitro simulation experiment. Each prodrug was prepared into a 1 mg / mL DMSO solution. 10 μL of the solution was mixed with 2 mL of fetal bovine serum and incubated at 37℃ and 100 r / min. At 0 h, 6 h, and 24 h, 200 μL of the incubated sample was taken, 1 mL of acetonitrile was added to precipitate the protein, and the mixture was centrifuged at 10000 r / min for 10 min. The supernatant was collected to determine the concentrations of the prodrug and the original drug. The molar concentrations of the remaining prodrug and the original drug produced at each time point were calculated to the molar concentration of the prodrug at time 0. The results are shown in Table 3.

[0254] Table 3. Results of in vitro degradation of compounds

[0255] The sustained-release process of prodrug particles in vivo can be divided into two steps: first, the prodrug particles dissolve to generate free molecular prodrugs; second, these molecular prodrugs degrade and are converted into the original drug. According to the solubility data in the test examples, the prodrug compounds of the present invention exhibit extremely low solubility, which means that the first step, namely the dissolution of the prodrug particles, is the rate-limiting step in the entire release process, and thus meets the requirements for sustained release.

[0256] In this experiment, we used compounds already in a dissolved state for our study, thus directly proceeding to the second step to evaluate the rate at which different compounds were converted into active ingredients after release. In this way, we can focus on examining the efficiency of each compound's conversion from a molecular prodrug to the drug substance, unaffected by the dissolution process.

[0257] The results showed that the degradation process of DXP in fetal bovine serum was relatively slow, with 93% remaining undegraded within 24 hours, and no original dexamethasone was detected during this period. However, existing technologies have confirmed that DXP can achieve a long-lasting effect of up to one month. If a compound can degrade and produce a certain amount of dexamethasone after 24 hours, it means that its ability to be converted into the active drug is superior to that of DXP.

[0258] Test Example 5: In vitro release of prodrug suspension

[0259] Preparation of Compound 3 suspension: Weigh 0.5 g of Compound 3, add 8 mL of ethanol, dissolve, and filter through a 0.22 μm nylon membrane to obtain the filtrate. Evaporate to dryness in a 40 °C water bath to obtain the solid, and then vacuum dry to obtain recrystallized Compound 3. Dissolve Tween 80 and mannitol in ultrapure water to prepare an aqueous solution containing 0.5 mg / mL Tween 80 and 50 mg / mL mannitol. Filter through a 0.22 μm PVDF membrane to obtain the aqueous phase. Add the recrystallized Compound 3 to the aqueous phase and ball mill to obtain a 5 mg / mL suspension of Compound 3.

[0260] Preparation of Compound 4 suspension: Weigh 0.5 g of Compound 4, add 8 mL of ethanol, dissolve, and filter through a 0.22 μm nylon membrane to obtain the filtrate. Evaporate to dryness in a 40 °C water bath to obtain the solid, and then vacuum dry to obtain recrystallized Compound 4. Dissolve Tween 80 and mannitol in ultrapure water to prepare an aqueous solution containing 5 mg / mL Tween 80 and 50 mg / mL mannitol. Filter through a 0.22 μm PVDF membrane to obtain the aqueous phase. Add the recrystallized Compound 4 to the aqueous phase and ball mill to obtain a 5 mg / mL suspension of Compound 4.

[0261] Preparation of Compound 12 suspension: Weigh 0.5 g of Compound 12, add 10 mL of dichloromethane and 3 mL of ethanol, dissolve, and filter through a 0.22 μm nylon membrane to obtain the filtrate. After natural evaporation, add 5 mL of methyl tert-butyl ether for ultrasonic dispersion, filter under reduced pressure to obtain the solid, and dry under vacuum to obtain recrystallized Compound 12. Dissolve Tween 80 and mannitol in ultrapure water to prepare an aqueous solution containing 0.5 mg / mL Tween 80 and 50 mg / mL mannitol. Filter through a 0.22 μm PVDF membrane to obtain the aqueous phase. Add the recrystallized Compound 12 to the aqueous phase and ball mill to obtain a 5 mg / mL Compound 12 suspension.

[0262] Preparation of Compound 13 suspension: Weigh 1 g of Compound 13, add 12 mL of dichloromethane, dissolve, and filter through a 0.22 μm nylon membrane to obtain the filtrate. After natural evaporation, add 30 mL of acetonitrile for ultrasonic dispersion, filter under reduced pressure to obtain the solid, and dry under vacuum to obtain recrystallized Compound 13. Dissolve Tween 80 and mannitol in ultrapure water to prepare an aqueous solution containing 0.5 mg / mL Tween 80 and 50 mg / mL mannitol. Filter through a 0.22 μm PVDF membrane to obtain the aqueous phase. Add the recrystallized Compound 13 to the aqueous phase and ball mill to obtain a 5 mg / mL Compound 13 suspension.

[0263] The particle size of the suspension was determined using a laser particle size analyzer (OMEC, Topsizer). The results are shown in Table 4.

[0264] The in vitro release of the prodrug suspension was determined using 10 mL of 2% Tween 20 pH 3.0 aqueous solution under release conditions of 37℃ and 100 r / min. A certain amount of the prodrug suspension (containing 50 μg of prodrug) was placed in the release medium for the experiment. 1 mL samples were collected at 3 h, 6 h, 24 h, 48 h, 72 h, 96 h, 120 h, and 144 h, filtered, and the drug concentration was determined by HPLC to calculate the release rate. The experimental results are shown in Figure 2.

[0265] Table 4 shows the particle size data of the suspensions prepared in Test Example 5.

[0266] In vitro release results showed that compound 3 was released significantly faster than compound 4, and compound 12 was released significantly faster than compound 13. These results were consistent with the solubility test results, indicating that the longer the carbon chain, the better the sustained-release effect.

[0267] Test Example 6: In vivo pharmacokinetic experiment of prodrug suspension

[0268] Following a single intra-articular injection of different test formulations into New Zealand rabbits, the concentrations of prodrugs and dexamethasone in plasma, synovial fluid (SF), and synovial tissue (ST) were measured. The experimental groups consisted of suspensions of compounds 3, 4, 12, and 13 from Test Example 5, while the control group consisted of commercially available drugs.

[0269] New Zealand rabbits weighing approximately 3 kg had free access to food and water throughout the experiment. Propofol (1–2 mL / kg) was used for administration; the drug was injected via puncture at the hind leg knee joint after flexion, and administration was completed within 1 minute. Both joints were administered the drug at a dose of 0.5 mg / joint (calculated as dexamethasone). Blood samples of approximately 0.8 mL were collected from each group at 0 h before administration and at 15 min, 30 min, 1 h, 2 h, 4 h, 8 h, 24 h, 48 h, 72 h, 120 h, 168 h, and 336 h after administration, and placed into K2EDTA anticoagulant tubes. Plasma samples were collected by centrifugation at 8000 rpm for 5 min at 2–8 °C. The concentrations of prodrug and dexamethasone in the plasma samples were determined by LC-MS / MS.

[0270] Animals in each group were sacrificed 7 days and 14 days after drug administration (2 animals / time point / group). Synovial fluid (SF) and synovial tissue (ST) were collected from the bilateral hind leg knee joints of each animal. The concentrations of prodrug and dexamethasone in the samples were detected by LC-MS / MS.

[0271] The results of prodrug detection in plasma are shown in Figure 3. Compounds 3, 12, and 13 were not detected in plasma (limit of detection 0.1 ng / mL). The C of compound 4... max The concentration was 0.89 ng / ml, and it fell below the detection limit after 48 hours. C in DXP max The concentration was 2.53 ng / ml, and it fell below the detection limit after 120 hours.

[0272] The results of dexamethasone detection in plasma are shown in Figure 4. Pharmacokinetic parameters were calculated using WinNonlin 8.3 software, and the results are shown in Table 5.

[0273] Table 5. Pharmacokinetic parameters of dexamethasone in plasma

[0274] NR: The software cannot calculate.

[0275] The results show:

[0276] (1) Dexamethasone was detected in plasma after administration of compounds 3, 4, 12 and 13, indicating that the prodrug of the present invention can be converted into the original drug dexamethasone in vivo, and the results are consistent with the in vitro experiments.

[0277] (2) The results in Table 5 show that the C values ​​of each experimental group max (Maximum blood drug concentration) was significantly lower than that of the control group. This indicates that the compounds of the present invention have a low tendency for burst release. Furthermore, the data confirm that with increasing carbon chain length, solubility decreases, release slows, and burst release decreases.

[0278] (3) Table 5 shows the AUC of each experimental group. 0-t All were significantly lower than the control group. This indicates that the compounds of the present invention have low systemic exposure, which can reduce or eliminate systemic side effects caused by glucocorticoids;

[0279] (4) Figure 3 shows that the concentration of the prodrug of the present invention in plasma is lower than that in the control group. Figure 4 further shows that the concentration of dexamethasone converted from the prodrug of this invention in plasma is also lower than that of other drugs. This result suggests that this product is more suitable for local administration, indicating that the drug is mainly confined to the site of action, reducing diffusion into the bloodstream. Therefore, this not only reduces the risk of potential side effects but also demonstrates better sustained-release performance and higher safety.

[0280] (5) The results in Figures 5 and 6 show that the concentrations of prodrug and dexamethasone in the synovial fluid (SF) of each experimental group were significantly higher than those in the control group 14 days after drug administration. Figures 7 and 8 show that the concentrations of prodrug and dexamethasone in the synovial tissue (ST) of each experimental group were significantly higher than those in the control group 14 days after drug administration. Drug concentration data in SF and ST indicate that compounds 3, 4, 12, and 13 form a drug reservoir at the administration site, slowly releasing and converting to dexamethasone to exert a long-lasting effect, and all showed better performance than the control group. Better long-lasting and sustained-release effect.

[0281] The exemplary embodiments of the present invention have been described above. However, the scope of protection of the present invention is not limited to the above embodiments. Any modifications, equivalent substitutions, improvements, etc., made within the spirit and principles of the present invention should be included within the scope of protection of the present invention.

Claims

1. The compound represented by Formula I or a pharmaceutically acceptable salt thereof: in, Indicates the formation of prodrugs by glucocorticoids residues; A is selected from: C 1-6 Alkylene; -L-CHR 1A -; or -L-CR 1A R 2A -; R 1A R 2A Selected independently from hydrogen and -LC 1-6 Alkyl, -LC 3-8 Cycloalkyl, -L-3-7-membered heterocycloalkyl, -L-6-12-membered aryl, or -L-5-10-membered heteroaryl; wherein, the C 1-6 Alkyl, C 3-8 Cycloalkyl, 3-7-membered heterocycloalkyl, 6-12-membered aryl, 5-10-membered heteroaryl can be optionally selected by one or more independently chosen from R 1B Substituents of the substituents; R 1B Selected from hydrogen, halogen, hydroxyl, methimazole, -LC 1-6 Alkyl, -LC 1-6 Alkoxy, -LC 3-8 Cycloalkyl, -L-3-7 heterocycloalkyl, -L-6-12 aryl or -LC 5-10 Mixed aromatics; R 3A Selected from bonds, hydrogen, or C 1-6 alkyl; R 4A Selected from C 7-21 Straight-chain or branched alkyl groups, -C 1-6 Alkylene-C 3-8 cycloalkyl, -C 1-6 Alkylene-3-7-membered heterocyclic alkyl, -C 1-6 alkylene-6-12-membered aryl or -C 1-6 alkylene-5-10-membered heteroaryl; L is selected from either a key or C. 1-6 Alkylene; R 1A and R 2A It can form 3-8 membered carbon rings together with the C atoms it is bonded to; When R 3A When selected from the key, R 1A The CH atoms it bonds with, together with the adjacent N atoms, form 3-7 membered nitrogen heterocycles.

2. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein, glucocorticoids that form prodrugs Selected from the following glucocorticoids: Preferably, Prodrugs are formed by selecting one, two, or three OH groups from primary, secondary, or tertiary alcohols on glucocorticoids; Preferably, Prodrugs are formed by selecting one of the primary, secondary, or tertiary OH groups on glucocorticoids; Preferably, Through the OH group in the primary alcohol of glucocorticoids, i.e. The OH group on the surface forms a prodrug.

3. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein in formula I... Represented as amino acids residues, Selected from natural amino acids or pharmaceutically acceptable synthetic amino acids; preferably, Selected from amino acids with hydrophobic side chains.

4. The compound according to claim 3 or a pharmaceutically acceptable salt thereof, wherein... The amino acids selected are those shown below:

5. The compound according to claim 3 or a pharmaceutically acceptable salt thereof, wherein, Chiral amino acids, selected from D- or L-type amino acids; preferably, Chiral, selected from L-type amino acids; preferably, The amino acids selected are those shown below: Preferably, Chiral amino acids are selected from D-type amino acids; Preferably, The amino acids selected are those shown below:

6. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein, When R 4A Selected from C 7-21 For straight-chain or branched alkyl groups, C 7-21 The straight-chain or branched alkyl group is selected from straight-chain or branched alkyl groups having 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, or 21 carbon atoms.

7. A compound or a pharmaceutically acceptable salt thereof, wherein the compound is selected from:

8. A pharmaceutical composition comprising any one of claims 1-7 or a pharmaceutically acceptable salt thereof.

9. A suspension comprising any one of claims 1-7 or a pharmaceutically acceptable salt thereof.

10. Use as a medicament of any compound or pharmaceutically acceptable salt thereof according to any one of claims 1-7, or the pharmaceutical composition of claim 8, or the suspension of claim 9, preferably, said use is for the preparation of a medicament for the treatment, prevention or control of symptoms or diseases responsive to glucocorticoids in mammals in need.

11. Use of the compound or a pharmaceutically acceptable salt thereof according to any one of claims 1-7, or the pharmaceutical composition of claim 8, or the suspension of claim 9 in the preparation of a medicament for treating, preventing or controlling inflammatory diseases, painful diseases, immune-related diseases, endocrine diseases, allergic diseases, tumor-related diseases, skin diseases or ophthalmic diseases; Preferably, the subject is treated with one or more additional therapeutic agents simultaneously, before, or after treatment with the compound or its pharmaceutically acceptable salt or pharmaceutical composition.

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