Use of pde4b inhibitor in treatment of psoriasis and atopic dermatitis

Abstract

The present invention relates to use of a compound of formula (I), or a stereoisomer thereof, a tautomer thereof, a pharmaceutically acceptable salt thereof, or a composition thereof in the preparation of a medicament for treating psoriasis and atopic dermatitis. The present invention also relates to a method for treating psoriasis and atopic dermatitis. The method comprises administering an effective dose of the compound of formula (I), or the stereoisomer thereof, the tautomer thereof, the pharmaceutically acceptable salt thereof, or the composition thereof.

Description

Use of a PDE4B inhibitor in the treatment of psoriasis and atopic dermatitis

[0001] Cross-reference to related applications

[0002] This application claims priority to Chinese Patent Application No. 202510200009.5, filed on February 24, 2025, and Chinese Patent Application No. 202511843033.7, filed on December 9, 2025, the entire contents of which are incorporated herein by reference. Technical Field

[0003] This invention relates to the use of a compound of formula (I) or its stereoisomers, tautomers, pharmaceutically acceptable salts or combinations thereof in the preparation of a medicament for treating psoriasis and atopic dermatitis. Background Technology

[0004] Psoriasis is a chronic, relapsing, inflammatory, systemic disease mediated by the immune system and induced by both genetic and environmental factors. Clinically, it manifests as scaly erythematous plaques or patches, localized or widespread. The exact cause of psoriasis is not fully understood, but genetic, immune, and environmental factors play important roles in its development. Psoriasis can be complicated by other systemic diseases, such as cardiovascular diseases, metabolic diseases, liver and kidney diseases, autoimmune diseases, and psychological disorders, severely impacting patients' quality of life. Based on clinical manifestations, psoriasis can be classified into vulgaris psoriasis, pustular psoriasis, erythrodermic psoriasis, psoriatic arthritis (PsA), and other special types. Vulgaris psoriasis is the most common type of psoriasis, and based on the characteristics of the skin lesions, it can be divided into guttate psoriasis and plaque psoriasis, with plaque psoriasis accounting for approximately 80%–90% of all psoriasis cases.

[0005] There is currently no cure for psoriasis. The goals of treatment are to control and stabilize the condition, slow the disease progression, inhibit the worsening of skin lesions and itching, prevent disease recurrence and exacerbation, reduce short-term and long-term adverse drug reactions, control psoriasis-related complications, reduce comorbidities, improve the patient's physical, psychological, and social functions, and improve their quality of life.

[0006] Current treatments for psoriasis include topical therapies, systemic therapies, and physical therapies. While most existing topical medications offer some efficacy, their effectiveness is limited, they have adverse reactions, and the disease is prone to relapse, leading to poor patient adherence with long-term use. Traditional systemic therapies have limitations in efficacy and safety, restricting their long-term use in psoriasis patients. Biologics offer superior efficacy and safety compared to traditional systemic therapies and have become one of the main treatment methods for psoriasis; however, they still suffer from drawbacks such as inconvenient administration, poor treatment adherence, potential risks of serious infections and malignancies, and high cost. Compared to biologics, small molecule targeted therapies have certain advantages, such as definite efficacy, less interference with systemic immune function, convenient oral administration, and relatively well-defined targets. However, currently marketed small molecule targeted therapies still have some safety concerns; for example, JAK inhibitors (tofacitinib, utpatinib) may cause serious infections, death, and malignancies. Apremilast, a phosphodiesterase-4 (PDE4) inhibitor, has adverse reactions such as diarrhea, nausea, vomiting, and headache. The product information leaflet warns and precautions mention that apremilast may cause depression. Furthermore, to reduce gastrointestinal symptoms, dose titration is required at the beginning of apremilast administration, which significantly impacts its ease of clinical use. Therefore, there is an urgent clinical need for effective, safer, and more convenient small-molecule targeted therapies to provide psoriasis patients with more treatment options.

[0007] Atopic dermatitis (AD) is a chronic, relapsing, inflammatory skin disease. Because patients often have co-existing atopic conditions such as allergic rhinitis and asthma, it is considered a systemic disease. The global prevalence of AD has gradually increased over the past 30 years, and the prevalence in my country has also increased rapidly in the last 10 years. The pathogenesis of AD is closely related to genetic and environmental factors. Although the exact pathogenesis is still unclear, current research suggests that immune abnormalities, skin barrier dysfunction, and skin flora imbalance are important factors in the development of this disease. AD usually begins in infancy, with about 50% of patients developing the disease before the age of one. However, recent findings indicate that late-onset cases are also not uncommon. The disease has a chronic course and diverse clinical manifestations. The most basic characteristics are dry skin, chronic eczematous lesions, and significant itching. AD patients also have other characteristic manifestations that aid in diagnosis, including ichthyosis, keratosis pilaris, and palmar erythema.

[0008] The goal of Alzheimer's disease (AD) treatment is to relieve or eliminate clinical symptoms, eliminate triggering and / or aggravating factors, reduce and prevent relapses, reduce or alleviate comorbidities, and improve the patient's quality of life. Drug treatment for AD includes topical medications and systemic therapies. Topical medications mainly include topical corticosteroids (TCS), topical calcineurin inhibitors (TCIs), and PDE4 inhibitors. When topical treatment is ineffective or the patient cannot tolerate it, systemic anti-inflammatory therapy should be considered. Systemic therapies mainly include oral antihistamines, traditional immunosuppressants, corticosteroids, biologics, and JAK inhibitors. However, these systemic therapies still have problems such as some patients not achieving treatment goals and numerous adverse reactions. Currently, more effective and safe drugs are still needed for approval and market launch.

[0009] PDE4 is widely expressed on inflammatory and immune cells (eosinophils, neutrophils, monocytes, macrophages, T lymphocytes, and B lymphocytes), blocking its activation of PKA (protein kinase A) by hydrolyzing cAMP (cyclic adenosine monophosphate). Activated PKA activates downstream transcription factors such as CREB and inhibits transcription factors such as NF-κB and Bcl-6, promoting the production of anti-inflammatory cytokines like IL-10 while inhibiting the production of various inflammatory cytokines such as TNF-α, IFN-γ, and IL-12. Therefore, inhibiting PDE4 activity can promote the production of anti-inflammatory factors, reduce the production of pro-inflammatory factors, and reduce the activation and recruitment of inflammatory cells, thereby producing a therapeutic effect on inflammatory diseases such as psoriasis and atopic dermatitis. PDE4 inhibitors have been used to treat psoriasis, including apremilast and roflumilast. These drugs exert their therapeutic effect by regulating the function of immune cells and reducing the expression of psoriasis-related inflammatory cytokines. Currently, all approved PDE4 pan-target inhibitors for atopic dermatitis are topical formulations: Crizoborone ointment can effectively improve the severity of skin lesions and symptoms such as itching, and is the first approved topical PDE4 inhibitor for the treatment of AD; Roflumilast cream was approved by the FDA in July 2024 for mild to moderate AD in people aged 6 years and older.

[0010] The PDE4 family comprises four members: PDE4A, PDE4B, PDE4C, and PDE4D. Studies have found that selective inhibition of PDE4B may retain more beneficial anti-inflammatory effects and reduce side effects such as vomiting associated with PDE4D inhibition, with a projected better safety profile than pan-targeted PDE4 drugs. WO2024032673 describes a compound of formula (I) exhibiting good PDE4B inhibitory activity. Summary of the Invention

[0011] This invention provides the use of a compound of formula (I) or its stereoisomers, tautomers, pharmaceutically acceptable salts, or combinations thereof in the preparation of a medicament for treating psoriasis and atopic dermatitis.

[0012] Among them, L4 is The product comprises 1-3 5-6-membered heteroaryl groups selected from N, S, and O heteroatoms; 1-3 5-membered monoheterocyclic alkyl groups selected from N, S, and O heteroatoms; 1-3 7-8-membered monoheterocyclic alkyl groups selected from N, S, and O heteroatoms; 1-3 5-6-membered heterocyclic alkyl groups with 5-6-membered heterocyclic alkyl groups selected from N, S, and O heteroatoms; 1-3 5-6-membered heterocyclic alkyl groups with 5-6-membered heterocyclic alkyl groups with 5-6-membered heterocyclic alkyl groups with 5-6-membered heterocyclic alkyl groups with 1-3 7-12-membered spirocyclic heterocyclic alkyl groups selected from N, S, and O heteroatoms; wherein the monoheterocyclic alkyl, 5-6-membered heterocyclic alkyl groups with 5-6-membered heterocyclic alkyl groups, 5-6-membered heterocyclic alkyl groups with 5-6-membered heterocyclic alkyl groups, and spirocyclic heterocyclic alkyl groups are optionally surrounded by 1-3 groups selected from halogens, =O, CN, and C. 1- 4-alkyl, C 1-4 Substitution of alkoxy, OH, and NH2 groups;

[0013] A is -S(O)-, -C(O)-, -B(OH)-, -S-, -S(=N)-CN or -C(=N)-CN;

[0014] X1 and X2 are CR independently X1 S or N;

[0015] R L2 For H, C 1-4 Alkyl or C 3-6 cycloalkyl;

[0016] R6 represents H, halogens, =O, CN, and C. 1-4 Alkyl or C 1-4 Alkoxy;

[0017] Each R X1 R can be independently H, halogen, or C. 1-4 Alkyl, C 1-4 Alkoxy, -N(CH3)2, -NH(CH3), C 2-6 Alkyne group, NHSO2NH2, NHCONH2, NHCOC 1-4 Alkyl, CONHC 1-4 Alkyl, NHSO2C 1-4 Alkyl, SO2NHC 1-4 Alkyl, SO2C 1-4 Alkyl, SCF3, SF5, 3-5 membered cycloalkyl, C1-4 Haloalkyl or 5-10 membered heterocyclic alkyl groups containing 1-3 heteroatoms selected from N, S, O, and Si, or two R, R and R on adjacent ring atoms. X1 Or R X1 Together with R6 and the atoms it is attached to, they form C. 3-8 The cycloalkyl group, a 5-10 membered heterocycloalkyl group containing 1-3 heteroatoms selected from N, S, O, and Si, a phenyl group, or a 5-6 membered heteroaryl group containing 1-3 heteroatoms selected from N, S, and O, wherein the cycloalkyl group, heterocycloalkyl group, phenyl group, and heteroaryl group are optionally surrounded by 1-3 heteroatoms selected from halogen, =O, CN, and C. 1-4 Alkyl, C 1-4 Substitution of alkoxy, OH, and NH2 groups;

[0018] R1 and R2, together with the atoms they are attached to, form a 5-10 membered heterocyclic alkyl group or a 5-6 membered heteroaryl group containing 1-3 heteroatoms selected from N, S, B, and O, wherein the cycloalkyl, heterocyclic alkyl, and heteroaryl group are optionally surrounded by 1-3 atoms selected from halogen, =O, CN, and C. 1-4 Alkyl, C 1-4 Substitution of alkoxy, OH, and NH2 groups;

[0019] R 12 Selected from 4-10-membered heterocyclic alkylene, 3-10-membered heterocyclic alkylene, 6-10-membered arylene, 5-10-membered heterocyclic arylene, hydroxy-C 1-6 Alkyl, C 1- 4-alkyl-CN, -CRaRb=NOC 1-4 Alkyl group, -C(NRaRb)=N-CN, -C(C 1-4 Alkyl group = N-CN, -C (NRaRb = CRa-NO) 2、 -C(CH3)2-CH2-OC(O)NH2, -C(CH3)2-CH2-NH-C(O)O(C 1-4 Alkyl groups, -C(CH3)2-CH2-OC(O)NHCH3, -CH(CH3)-CH2-OC(O)NH2, -CH(CH3)-CH2-NH-C(O)O(C 1-4 Alkyl group, -CH(CH3)-CH2-OC(O)NHCH3, -C(O)-Ra or -C(O)- (4-6 membered heterocyclic alkyl group), wherein the heterocyclic alkyl group, alkylene group, arylene group, or heteroarylene group may optionally be further surrounded by 1-3 halogens, CN, =O, OH, -SF5, C 1-4 Alkyl, C 1-4 Alkyl-CN, Hydroxyl-C 1-4 Alkyl, C 1-4 Haloalkyl, -(CH2) t-OC(O)NH2、-(CH2) t -NRa-C(O)NH2、-(CH2) t -NRa-C(=NH)NH2、-(CH2) t -NRa-C(O)-O-(C 1-4 Alkyl group), -(CH2) t -NRa-C(C 1-4 Alkyl group = N-CN, -(CH2) t -NRa-C(NRaRb)=N-CN、-(CH2) t -NRa-C(NRaRb)=CRa-NO2, -(CH2) t -C(NRaRb)=N-CN、-(CH2) t -C(C 1-4 Alkyl group = N-CN, -(CH2) t -C(C 1-4 Alkyl group) = NO-(C 1-4 Alkyl), =NOC 1-4 Alkyl, 5-6 membered heteroaryl, -(CH2) t -OC 1-4 Alkyl group, -(CH2) t -OC(O)NHCH3、-(CH2) t -OC 1-2 Haloalkyl, -(CH2) t -OC 3-6 Cycloalkyl, -(CH2) t -OC 1-4 Alkyl-OC 3-6 Cycloalkyl, -(CH2) t -COOH, -(CH2) t -NRaRb、-(CH2) t -C(O)NRaRb、-(CH2) t Substitution of the -NRa-C(O)CH3 group;

[0020] Ra and Rb are each independently selected from H, halogens, and C. 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkyl groups or alkyl groups containing 1-2 4-6 membered heterocyclic alkyl groups selected from N and O heteroatoms;

[0021] t is selected from 0, 1, 2, 3, or 4;

[0022] p is selected from 0 or 1.

[0023] Furthermore, in equation (I),

[0024] L4 is

[0025] R 12 Selected from -C(CH3)2-CH2-OC(O)NH2, -C(CH3)2-CH2-NH-C(O)O(C 1-4 Alkyl groups, -C(CH3)2-CH2-OC(O)NHCH3, -CH(CH3)-CH2-OC(O)NH2, -CH(CH3)-CH2-NH-C(O)O(C 1-4 Alkyl group), -CH(CH3)-CH2-OC(O)NHCH3.

[0026] Furthermore, the compound of formula (I) is selected from one of the following structures:

[0027] or

[0028] Furthermore, the compound of formula (I) is selected from the following structures:

[0029] In some embodiments, the use described is to administer an effective dose of a compound of formula (A) or its stereoisomers, tautomers, pharmaceutically acceptable salts or combinations thereof to mammals.

[0030] In some embodiments, the pharmaceutically acceptable salt of formula (A) is selected from maleate, 2-naphthalenesulfonic acid, 1,5-naphthalenedisulfonate, fumarate, hydrohalate, sulfate, phosphate, L-tartrate, citrate, L-malate, hippurate, D-glucuronate, glycolate, mucilage, succinate, lactate, orotate, pamoate, glycine, alanine, arginine, cinnamate, benzoate, benzenesulfonate, p-toluenesulfonate, acetate, propionate, valerate, triphenylethyl acetate, etc. Salts, L-proline salts, ferulic acid salts, 2-hydroxyethanesulfonate salts, mandelic acid salts, nitrates, methanesulfonate salts, malonate salts, gentianate salts, salicylates, oxalates, or glutarate salts; preferably from benzenesulfonate salts, L-malate salts, phosphates, sulfates, p-toluenesulfonate salts, hydrochloride salts, maleate salts, 2-naphthalenesulfonate salts, hydrobromide salts, methanesulfonate salts, citrate salts, mandelic acid salts, lactobionate salts, succinate salts, salicylates, 1,5-naphthalenedisulfonate salts, fumarate salts, nicotinate salts, hippurate salts, and oxalates; more preferably from hydrochloride salts.

[0031] In some embodiments, the described use, wherein the effective dose is calculated as 1-1500 mg / day of the free base of formula (A), preferably 10-1500 mg / day, 20-1500 mg / day, 25-1500 mg / day, 50-1500 mg / day, 75-1500 mg / day, 100-1500 mg / day, 200-1500 mg / day, 10-1000 mg / day, 20-1000 mg / day, 25-1000 mg / day, 50-1000 mg / day, 75-1000 mg / day, 100-1000 mg / day, 200-1000 mg / day, or 25-800 mg / day. / day, 50-800mg / day, 100-800mg / day, 200-800mg / day, 25-400mg / day, 50-400mg / day, 100-400mg / day, 200-400mg / day, or selected from 1mg / day, 5mg / day, 10mg / day, 20mg / day, 25mg / day, 50mg / day, 75mg / day, 100mg / day, 125mg / day, 150mg / day, 200mg / day, 400mg / day, 600mg / day, 800mg / day, 1000mg / day, 1200mg / day, 1400mg / day, 1500mg / day.

[0032] In some embodiments, the route of administration of the compound of formula (A) or its stereoisomers, tautomers, pharmaceutically acceptable salts or combinations thereof is selected from oral or topical application.

[0033] This invention also provides a method for treating psoriasis and atopic dermatitis, comprising administering to mammals an effective dose of a compound of formula (I) or formula (A), or its stereoisomers, tautomers, pharmaceutically acceptable salts, or combinations thereof, wherein the effective dose, calculated as free base, is 1-1500 mg / day, preferably 10-1500 mg / day, 20-1500 mg / day, 25-1500 mg / day, 50-1500 mg / day, 75-1500 mg / day, 100-1500 mg / day, 200-1500 mg / day, 10-1000 mg / day, 20-1000 mg / day, 25-1000 mg / day, 50-1000 mg / day, 75-1000 mg / day, or 100-1000 mg / day. The dosage is 200-1000 mg / day, 25-800 mg / day, 50-800 mg / day, 100-800 mg / day, 200-800 mg / day, 25-400 mg / day, 50-400 mg / day, 100-400 mg / day, 200-400 mg / day, or selected from 1 mg / day, 5 mg / day, 10 mg / day, 20 mg / day, 25 mg / day, 50 mg / day, 75 mg / day, 100 mg / day, 125 mg / day, 150 mg / day, 200 mg / day, 400 mg / day, 600 mg / day, 800 mg / day, 1000 mg / day, 1200 mg / day, 1400 mg / day, 1500 mg / day; the route of administration is selected from oral or topical application.

[0034] In some embodiments, the method of administration of the compound of formula (A) or its stereoisomers, tautomers, pharmaceutically acceptable salts or combinations thereof is selected from oral or topical administration. Attached Figure Description

[0035] Figure 1: Inhibition curves of positive control BI 1015550 and compound (A) on LPS-induced TNF-α secretion in human PBMCs.

[0036] Figure 2: Inhibition curves of Apremilast and compound (A) on PHA-induced IL-2 secretion by human PBMCs.

[0037] Figure 3: Inhibition curves of Apremilast and compound (A) on PHA-induced IFN-γ secretion by human PBMCs.

[0038] Figure 4: Thickness change curve of the right ear in an imiquimod-induced mouse psoriasis model.

[0039] Figure 5: Curve showing changes in skin thickness on the back of mice in the MC903 atopic dermatitis model.

[0040] Figure 6: Clinical score change curve of imiquimod-induced mouse psoriasis model

[0041] Figure 7: Clinical score AUC in psoriasis model mice

[0042] Figure 8: Ear thickness change curve in a mouse atopic dermatitis model induced by MC903. Detailed Implementation

[0043] The technical solution of the present invention will be described in detail below with reference to the accompanying drawings and embodiments, but the scope of protection of the present invention includes, but is not limited to, these.

[0044] Synthesis Example:

[0045] Compound (A): Prepared according to the method described in WO2024032673.

[0046] Biological test examples

[0047] Example 1: Study on the inhibitory effect of compound (A) on LPS-induced secretion of TNF-α by human PBMCs

[0048] In this test, under different concentrations of the positive control BI 1015550 or compound (A), PBMCs were stimulated to secrete TNF-α by LPS, and the inhibitory activity of the test substance was determined by ELISA. The specific procedure is as follows:

[0049] 1) Resuscitate frozen human PBMCs with 1640 medium containing 10% inactivated FBS and 1% P / S, adjust the density to 10^6 / mL, transfer to cell culture flasks, and incubate at 37℃ and 5% CO2 for 30 minutes.

[0050] 2) Collect revived PBMCs and prepare cell suspensions with 1640 medium containing 10% inactivated FBS and 1% P / S. Seed the suspensions in 96-well plates at a ratio of 10^5 cells / well / 200 μL.

[0051] 3) Positive control BI 1015550 dilution: Add 2 μL of 10 mM positive control stock solution to 18 μL of DMSO to dilute to 1 mM. Then, take 5 μL of the dilution and add it to 15 μL of DMSO for a 4-fold serial dilution (1000,000, 250,000, 62,500, 15,625, 3906, 0.976, 244, 61, 15 nM, DMSO). Dilute the 2 μL serial dilutions again 25-fold with 48 μL of 1640 medium to prepare a 40× working solution. Final concentrations: 1000, 250, 62.5, 15.625, 3.906, 0.977, 0.244, 0.061, 0.0153 nM, DMSO;

[0052] 4) Dilution of Compound (A): Add 0.160 μL of DMSO to 10 μL of 10.160 mM compound (A) stock solution to obtain a 10 mM stock solution. Add 3 μL of the solution to 7 μL of DMSO to obtain a 3 mM stock solution. Add 2 μL of the solution to 18 μL of DMSO to obtain a 0.3 mM stock solution. Perform a 3-fold serial dilution (300,000, 100,000, 33,333.33, 11,111.11, 3703.703, 1234.568, 4115.23, 137.174, 45.725 nM, DMSO) using 48 μL of DMSO. 2 μL of the 1640 medium solution was diluted 25-fold again to prepare a 40× working solution for later use; final concentrations: 300, 100, 33.33, 11.11, 37.04, 12.35, 4.12, 1.37, 0.46 nM, DMSO).

[0053] 5) Add 5 μL of the compound 40× working solution diluted with culture medium to each well of the PBMC plate, for a final volume of 200 μL. Incubate the plate at 37°C and 5% CO2 for 1 hour.

[0054] 6) LPS dilution: Add 100 mL of ultrapure water to 100 mg of LPS powder to prepare an LPS stock solution with a concentration of 1 mg / mL. Take 2 μL of the stock solution with a concentration of 1 mg / mL LPS and add it to 498 μL of 1640 medium containing 10% inactivated FBS and 1% P / S. The concentration will then be 4 μg / mL. Take 2 μL of the diluted solution and add it to 1998 μL of 1640 medium containing 10% inactivated FBS and 1% P / S. Mix thoroughly. The concentration at this point is 4 ng / mL.

[0055] 7) Add 5 μL of diluted LPS to a final volume of 200 μL, resulting in a final concentration of 100 pg / mL. Incubate at 37°C in a 5% CO2 incubator for 6 hours.

[0056] 8) Centrifuge at 1000 rpm at room temperature for 1 minute, collect the supernatant, and detect TNF-α by ELISA as follows:

[0057] 9) Add the prepared standard and diluted sample to each well of a 96-well ELISA plate at a volume of 100 μL, cover with a sealing film, and incubate at 37°C for 90 minutes.

[0058] 10) Wash the plate three times with washing solution at a volume of 300 μL per well.

[0059] 11) Add 100 μL of biotinylated antibody diluted 100 times to each well of a 96-well ELISA plate, cover with a sealing film, and incubate at 37°C for 60 minutes.

[0060] 12) Wash the plate three times with washing solution at a volume of 300 μL per well.

[0061] 13) Add 100 μL of the 100-fold diluted enzyme conjugate to each well of a 96-well ELISA plate, cover with a sealing film, and incubate at 37°C for 30 minutes.

[0062] 14) Wash the plate three times with washing solution at a volume of 300 μL per well.

[0063] 15) Add 100 μL of the colorimetric reagent to each well of a 96-well ELISA plate, attach the sealing film, and incubate at 37°C for 15 minutes.

[0064] 16) Add the stop solution to the 96-well ELISA plate at a volume of 100 μL per well and gently tap the side of the plate to mix.

[0065] 17) Immediately read the OD450 value on the BMG instrument.

[0066] 18) Fit the standard curve of ELISA using a nonlinear fitting formula, as follows:

[0067] Y = Minimum value + (Maximum value - Minimum value) / [1 + 10^((LogEC50 - X) × HillSlope)]

[0068] X: Logarithm of the concentration of the standard

[0069] Y: OD450 signal value

[0070] 19) The concentrations of IL-2 / IFN-γ after compound treatment were calculated by regression analysis using a standard curve.

[0071] 20) Inhibition rate calculation:

[0072] 21) Inhibition rate (%) = (AVE_H - sample) / (AVE_H - AVE_L) × 100

[0073] 22) Among them, the DMSO control well (H) is used as the High Control; the well without PHA stimulation (L) is used as the Low Control.

[0074] 23) Calculate the IC50 value of the compound using a nonlinear fitting formula:

[0075] Y = minimum value + (maximum value - minimum value) / (1 + 10^((LogIC50 - X) × HillSlope))

[0076] X: Logarithm of compound concentration; Y: Inhibition rate (%)

[0077] (The IC50 obtained from the formula fitting is the relative IC50, also known as R_IC50, while the absolute IC50, also known as A_IC50, is the reading of X when Y = 50.)

[0078] In this test, the relative IC50 of compound (A) on TNF-α secretion was... 50 It's 6.46nm, absolute IC 50 It is 9.55 nM; the relative IC50 of the positive control BI 1015550 against TNF-α secretion is 9.55 nM. 50 It is 80.97nM, absolute IC 50 The concentration was 115.79 nM. The results indicate that the test compound (A) has a good inhibitory effect on TNF-α secretion. (See Figure 1 for details)

[0079] Example 2: Evaluation of the inhibitory effect of compound (A) on the secretion of the cytokine IL-2 by human PBMCs

[0080] In this test, under different concentrations of the test substance Apremilast or compound (A), PBMCs were stimulated to secrete IL-2 by phytohemagglutinin (PHA), and the inhibitory activity of the test substance was determined by ELISA. The specific procedure is as follows:

[0081] 1) Resuscitate frozen human peripheral blood mononuclear cells with RPMI 1640 complete medium containing 10% inactivated FBS and 1% P / S, and incubate in an incubator for 30 minutes.

[0082] 2) Collect cells and prepare a cell suspension using RPMI 1640 complete growth medium containing 10% inactivated FBS and 1% P / S. Seed 10^5 cells / well / 200μL into 96-well plates.

[0083] 3) Diluting the positive control drug Apremilast and compound (A): Add 2 μL of 10 mM positive control drug and test substance stock solution to 18 μL of DMSO and dilute to 1 mM. Take 5 μL of the diluent and add it to 10 μL of DMSO for a 3-fold serial dilution (1,000,000.000 nM, 333,333.333 nM, 111,111.111 nM, 370,37.037 nM, 123,45.679 nM, 41,15.226 nM, 1371.742 nM, 457.247 nM, 152.416 nM, DMSO). Dilute the 2 μL serial dilution with 48 μL of 1640 medium for a 25-fold further dilution to prepare a 40× working solution for later use.

[0084] 4) Add 5 μL of the compound diluted in 40× working solution to each well of the PBMC cell plate, with a final volume of 200 μL. The final concentrations of the test substances are 1000.000 nM, 333.333 nM, 111.111 nM, 37.037 nM, 12.346 nM, 4.115 nM, 1.372 nM, 0.457 nM, 0.152 nM, and DMSO. Incubate at 37℃ in a 5% CO2 incubator for 1 hour.

[0085] 5) PHA dilution: Take 96 μL of PHA stock solution with a concentration of 2.5 mg / mL and add it to 504 μL of 1640 medium containing 10% inactivated FBS and 1% P / S to change the concentration to 400 μg / mL.

[0086] 6) Add 5 μL of diluted PHA to each well of the PBMC cell plate to a final concentration of 10 μg / mL, and incubate at 37℃ in a 5% CO2 incubator for 20 hours.

[0087] 7) Centrifuge the cell plate at 1000 rpm for 1 minute, transfer the supernatant to a new 96-well plate, and store at -80°C.

[0088] 8) According to the instructions of ELISA KIT (Sizhengbai, CHE0003), the content of IL-2 in the supernatant was detected, and the IC50 value of the compound was calculated using a nonlinear fitting formula.

[0089] In this test, Apremilast and compound (A) effectively inhibited IL-2 secretion induced by 10 μg / mL PHA in human PBMCs, with a relative IC50 value of [missing value]. 50 The absolute IC50 values ​​were 43.45 nM and 6.07 nM, respectively, with values ​​of 34.13 nM and 5.18 nM. Compound (A) exhibited better inhibitory activity than the positive control drug Apremilast. (See Figure 2)

[0090] Example 3: Evaluation of the inhibitory effect of compound (A) on the secretion of the human PBMC cytokine IFN-γ

[0091] In this test, under different concentrations of the test substance (Apremilast) or compound (A), PBMCs were stimulated to secrete IFN-γ by phytohemagglutinin (PHA), and the inhibitory activity of the test substance was determined by ELISA. The specific procedure is as follows:

[0092] 1) Resuscitate frozen human peripheral blood mononuclear cells with RPMI 1640 complete growth medium containing 10% inactivated FBS and 1% P / S, and incubate in an incubator for 30 minutes.

[0093] 2) Prepare a cell suspension using RPMI 1640 complete growth medium containing 10% inactivated FBS and 1% P / S, and seed 10^5 cells / well / 200μL into a 96-well plate.

[0094] 3) Diluting the positive control drug Apremilast and compound (A): Add 2 μL of 10 mM positive control drug and test substance stock solution to 18 μL of DMSO and dilute to 1 mM. Take 5 μL of the diluent and add it to 10 μL of DMSO for a 3-fold serial dilution (1,000,000.000 nM, 333,333.333 nM, 111,111.111 nM, 370,37.037 nM, 123,45.679 nM, 41,15.226 nM, 1371.742 nM, 457.247 nM, 152.416 nM, DMSO). Dilute the 2 μL serial dilution with 48 μL of 1640 medium for a 25-fold further dilution to prepare a 40× working solution for later use.

[0095] 4) Add 5 μL of the compound diluted in 40× working solution to each well of the PBMC cell plate, with a final volume of 200 μL. The final concentrations of the test substances are 1000.000 nM, 333.333 nM, 111.111 nM, 37.037 nM, 12.346 nM, 4.115 nM, 1.372 nM, 0.457 nM, 0.152 nM, and DMSO. Incubate at 37℃ in a 5% CO2 incubator for 1 hour.

[0096] 5) PHA dilution: Take 6 μL of PHA stock solution with a concentration of 2.5 mg / mL and add it to 619 μL of 1640 medium containing 10% inactivated FBS and 1% P / S to change the concentration to 24 μg / mL.

[0097] 6) Add 5 μL of diluted PHA to each well of the PBMC cell plate to a final concentration of 600 ng / mL, and incubate at 37°C in a 5% CO2 incubator for 20 hours.

[0098] 7) Centrifuge the cell plate at 1000 rpm for 1 minute, transfer the supernatant to a new 96-well plate, and store at -80°C.

[0099] 8) According to the instructions of ELISA KIT (Sizhengbai, CHE0017), the content of IFN-γ in the supernatant was detected, and the IC50 value of the compound was calculated using a nonlinear fitting formula.

[0100] In this test, Apremilast and compound (A) effectively inhibited PHA-induced IFN-γ secretion by human PBMCs, with a relative IC50 value of [missing value]. 50 The absolute IC50 values ​​were 17.54 nM and 2.39 nM, respectively, with 22.53 nM and 2.30 nM, respectively. Compound (A) showed better inhibitory activity than the positive control drug Apremilast. (See Figure 3)

[0101] Example 4: In vivo pharmacodynamic study of compound (A) in an imiquimod-induced mouse model of psoriasis.

[0102] This study induced a psoriasis model in mice by applying imiquimod cream to the skin of the back and right ear, and evaluated the pharmacodynamic effects of compound (A) in this model. The main assay was the change in ear thickness (Δear thickness) curve.

[0103] Experimental Methods: To induce psoriasis symptoms in model mice, from Day 0 to Day 6, starting at 13:30 each day, mice in the modeling group (G2-G8) were sensitized by applying 17.6 mg of imiquimod cream to the skin of their right ear for 7 days; mice in the blank control group (G1) were sensitized by applying 17.6 mg of petrolatum to the skin of their right ear for 7 days. At 10:00 AM each day, G1-G2 mice were given the oral solvent, G4-G8 mice were given the oral compound, and G3 mice were given 22 mg of dexamethasone cream to the skin of their right ear each morning. G4-G8 mice received a second dose at 10:00 PM each evening. The administration was continued for 8 days. Mouse weight was recorded each morning, right ear thickness was measured, and Δear thickness (Δear thickness = ear thickness measured on the day of measurement – ​​ear thickness on day 0) was calculated.

[0104] The ear thickness curve is shown in Figure 4. It can be seen that after the initial application of imiquimod, ear thickness continuously increased from Day 3 until the experimental endpoint, indicating the successful establishment of the ear psoriasis model. The overall statistical analysis results are shown in Table 1 below. Compared with the solvent control group (G2), the positive control Dexamethasone topical administration group (G3) and the Apremilast group (G4) significantly inhibited ear thickening in mice (p<0.0001). The oral administration of compound (A) at doses of 1 mg / kg, 10 mg / kg, and 30 mg / kg (G5, G7, G8) all significantly inhibited the increase in ear thickness and showed good dose-dependency (p<0.05 or p<0.0001), indicating that compound (A) has the potential to treat psoriasis.

[0105] Table 1. Statistical analysis of imiquimod-induced changes in right ear thickness in psoriatic mice. Note: *p<0.05, ***p<0.001, ****p<0.0001 vs. G2 Vehicle group, Two-way ANOVA.

[0106] Example 5: In vivo pharmacodynamic study of compound (A) in an MC903-induced mouse atopic dermatitis model

[0107] This study established a mouse dermatitis model by applying MC903 (calcipotriol) to the back skin of mice and explored the in vivo efficacy of compound (A). The main indicator of the experiment was the change curve of mouse back skin thickness.

[0108] Experimental Methods: This experiment used 80 7-9 week old female BALB / c mice. On Day 1, each mouse was ear-tagged on its left ear, and its weight was recorded. After anesthetizing the mice with isoflurane, the hair was shaved in a 2×3 cm area on the back of the mice, and the skin thickness on the back of the mice was measured using a digital micrometer. 56 mice with uniform back skin thickness and weight were selected and randomly divided into groups of 8 mice each according to back thickness and weight. The groups were as follows: G1 Normal group (8 mice), G2 Vehicle control group (8 mice), G3 Dexamethasone 2 mpk (8 mice), G4 Apremilast 25 mpk (8 mice), G5 Compound (A) 1 mpk (8 mice), G6 Compound (A) 3 mpk (8 mice), and G7 Compound (A) 10 mpk (8 mice). The G1 normal group did not undergo modeling treatment. The remaining G2-G7 groups were stimulated continuously for 4 days starting from Day 1, with a 1-day pause in between, for 2 cycles. Day 12 was the experimental endpoint. During the experiment, the mice were administered drugs by gavage daily according to their body weight. The G2 group received the solvent, while the G3-G7 groups received the corresponding drugs. During the modeling period (Day 1-Day 11), the skin thickness on the back of the mice was measured every other day.

[0109] Figure 5 shows the curve of skin thickness changes on the back of mice during the experiment, and Table 2 shows the statistical analysis of the back thickness data. The results showed that there was no significant change in the back skin thickness of the normal group mice, while the back skin thickness of the model control group mice gradually increased with the stimulation of MC903 application, indicating that the MC903-induced atopic dermatitis model of the back skin was successfully established. Compared with the model control group, the positive control dexamethasone topical administration group (G3) and the apremilast oral administration group (G4) significantly improved the swelling thickness of the back skin in mice (p<0.0001 and p<0.05, respectively). Oral administration of compound (A) at different doses of 1 mg / kg, 3 mg / kg, and 10 mg / kg (G5, G6, G7) dose-dependently reduced the back skin thickness of mice, with the medium and high dose groups showing a significant reduction (p<0.0001), indicating that compound (A) has the potential to treat atopic dermatitis.

[0110] Table 2. Multiple statistical analysis of dorsal thickness in mice of different groups in the MC903 atopic dermatitis model. Note: ns: P>0.05, *: P<0.05, ****: P<0.0001, Two-way ANOVA.

[0111] Example 6: In vivo pharmacodynamic study of compound (A) topical formulation in an imiquimod-induced mouse psoriasis model

[0112] This study induced psoriasis in mice by applying imiquimod (IMQ) cream to the skin on the back of the mouse, and evaluated the pharmacodynamic activity of compound (A) when applied topically to the mouse.

[0113] Experimental Methods: This experiment used 80 female C57BL / 6J mice aged 7-9 weeks. On Day 1, each mouse was ear-tagged on its left ear, and its weight was recorded. After anesthetizing the mice with isoflurane, a 2cm*3cm area on the back of each animal was shaved using a mold to ensure uniform coverage. 56 mice with uniform back skin condition and weight were selected and randomly divided into groups according to weight: G1 Normal control group (n=8), G2 Vehicle control group (n=8), G3 0.3% roflumilast cream group (n=8), G4 0% compound (A) blank cream group (n=8), G5 0.1% compound (A) cream group (n=8), G6 0.3% compound (A) cream group (n=8), and G7 1% compound (A) cream group (n=8). The G1 normal group did not undergo modeling treatment; starting from Day 0, imiquimod was applied to the dorsal skin of mice in groups G2–G7 to sensitize them for 7 days to induce a psoriasis skin model. During the experiment, the clinical scores of the dorsal skin of mice were performed before administration each morning, and the test compound was administered at 10:30 am and imiquimod was applied at 1:30 pm; Day 7 was the experimental endpoint.

[0114] The clinical score changes of the dorsal skin phenotype of each group of animals during the experiment are shown in Figure 6. The statistical analysis of the clinical scores is shown in Table 3. The area under the curve (AUC) of the clinical scores is shown in Figure 7.

[0115] The results showed that, compared with the G1 normal control mice, the psoriasis phenotype on the back of the G2 model control mice gradually became more pronounced with the increase of IMQ application days, manifested in increased clinical scores for skin redness, crusting, and thickening. Significant differences appeared from Day 2 onwards (p<0.0001), indicating that the IMQ-induced mouse psoriasis model was successfully established. Compared with the G2 model control group, the low-dose (0.1%) group (G5), medium-dose (0.3%) group (G6), and high-dose (1.0%) group (G7) of compound (A) cream all showed significant differences in ear thickness at Day 5 (p<0.01, p<0.0001, and p<0.0001, respectively). The area under the clinical score curve (AUC) can reflect the overall disease severity of the animals throughout the modeling period. Compared with the clinical score AUC of the G2 model control group, the AUC inhibition rates of low (0.1%), medium (0.3%), and high (1.0%) of compound (A) cream were 17.68%, 24.42%, and 30.53%, respectively, showing significant differences. These data indicate that compound (A) cream significantly inhibited the increase in clinical scores of back skin at all tested concentrations (0.1%–1%), exhibiting a dose-dependent effect, with high doses showing superior efficacy compared to medium and low doses.

[0116] Conclusion: Under the conditions of this experiment, the clinical score of the severity of skin disease on the back of psoriasis model mice showed that topical application of compound (A) could alleviate the psoriasis symptoms in mice, specifically by alleviating the clinical manifestations of redness, swelling, crusting, and thickening on the back, and this effect was dose-dependent, with higher doses being superior to medium and low doses.

[0117] Table 3 Clinical score data of mice in each group during the experiment (mean ± SEM) Note: Statistical analysis was performed between each treatment group (G3-G7) and the model control group (G2) using two-way ANOVA. *p<0.05, **p<0.01, ***p<0.001, ****p<0.0001; Statistical analysis was also performed between the G2 group and the G1 group. # p<0.05, ## p<0.01, ### p<0.001, #### p<0.0001.

[0118] Example 7: In vivo pharmacodynamic study of compound (A) topical formulation in an MC903-induced mouse atopic dermatitis model.

[0119] This study used MC903 (calcipotriol) applied to the ear skin of mice to establish an atopic dermatitis model and to explore the in vivo efficacy of compound (A) applied topically.

[0120] Experimental Methods: Eighty male Balb / c mice were divided into nine groups based on the thickness of their right ear. Groups G1 (Sham group) and G2 (Model group) each contained five mice; Groups G3-G5 (0.1% / 0.3% / 1% Compound (A) solution group), G6-G7 (0.1% / 1% Compound (A) cream group), and G8-G9 (0.1% / 1% Compound (A) ointment group) each contained ten mice. The day of grouping was designated Day 0. Right ear modeling was initiated for 10 days (Day 1 to Day 10) after grouping. Modeling Method: After anesthesia with isoflurane, 15 μL (30 μL total) of 0.067 mM MC903 solution was applied to the inner and outer sides of the right ear in groups G2-G9. Group G1 received the same volume of anhydrous ethanol solution in the same manner. Drug administration: Groups G1-G5 were administered the drug 30±5 min after modeling. Animals in groups G1 and G2 had 10 μL (20 μL total) of 70% ethanol solution applied to the inner and outer sides of their right ears. Animals in groups G3-G5 had 10 μL (20 μL total) of a solution containing the corresponding concentration of compound (A) applied to the inner and outer sides of their right ears for 10 consecutive days (Day 1-Day 10). Groups G6-G9 were administered the drug 4±0.25 h after modeling. Animals in groups G6-G9 had a total of 15 mg of a topical preparation containing the corresponding concentration of compound (A) applied to the inner and outer sides of their right ears for 10 consecutive days (Day 1-Day 10). During the experiment, the ear thickness of the right ears of the participating animals was measured using a digital micrometer on Days 3, 5, 7, 9, and 11.

[0121] Experimental Results: The change curve of right ear thickness in mice during the experiment is shown in Figure 8, and the statistical analysis of ear thickness is shown in Table 4. The results showed that there was no significant change in ear thickness in the Sham group. Compared with the Sham group, the ear thickness of the Model group mice gradually increased with the application of MC903, indicating that the MC903-induced atopic dermatitis model was successfully established and the data were reliable. Compared with the Model group, the topical solutions containing 0.1%, 0.3%, and 1% of compound (A) showed dose-dependent inhibition rates of 40.9%, 53.4%, and 74.2% on ear thickness growth in mice, respectively; the creams containing 0.1% and 1% of compound (A) showed dose-dependent inhibition rates of 54.0% and 60.3% on ear thickness growth in mice, respectively; and the ointment formulations containing 0.1% and 1% of compound (A) also showed significant inhibitory effects on ear thickness growth in mice, with inhibition rates of 65.0% and 65.0%, respectively.

[0122] Conclusion: Under the conditions of this experiment, different concentrations of compound (A) solution and different concentrations of compound (A) cream and ointment formulations all significantly inhibited MC903-induced ear thickening in mice.

[0123] Table 4. Statistical analysis of ear thickness in mice of different groups in the MC903-induced atopic dermatitis model using compound (A) topical formulation. Note: G1-G2, n=5, G3-G9, n=10. ****P<0.0001 vs. Model, Two-way ANOVA analysis was used, and Dunnett's multiple comparisons test was used for inter-group comparisons.

[0124] Example 8: Phase I clinical study of compound (A)

[0125] (1) This embodiment is a phase I clinical study of the safety, tolerability, pharmacokinetics and food effects on pharmacokinetics of compound (A) tablets (prepared according to the method disclosed in WO2025162431A1) in healthy subjects.

[0126] The study employed a single-center, randomized, double-blind, placebo-controlled trial design. Healthy subjects were administered the compound (A) at doses ranging from 1 mg to 24 mg, either before or after meals, once or multiple times over 7 consecutive days, according to different endpoints. The study was divided into two phases: Phase A (Single-Dose Elevation Trial) assessed the safety, tolerability, pharmacokinetic (PK) characteristics, and effects of food on PK of a single dose of compound (A), and conducted exploratory studies on metabolite identification and excretion pathways and amounts. Phase B (Multiple-Dose Elevation Trial) assessed the safety, tolerability, and PK characteristics of compound (A) with multiple doses. A total of 82 healthy subjects were included in Parts A and B. Part A consisted of 5 dose groups: 8 subjects in each dose group (excluding the 6 mg group with 14 subjects), totaling 46 subjects. Part B consisted of 3 dose groups: 12 subjects in each dose group, totaling 36 subjects.

[0127] Evaluation indicators

[0128] Safety indicators:

[0129] From the time healthy subjects sign the informed consent form until the end of follow-up, subjects are required to undergo safety checks at specified times, including vital signs, physical examination, 12-lead electrocardiogram (ECG), and laboratory tests (complete blood count, urinalysis, blood biochemistry, coagulation function, and stool routine examination). The clinical characteristics, severity, time of occurrence, time of termination, duration, treatment, and outcome of any adverse events must be recorded, and their relevance to the investigational drug must be determined. Adverse events (AEs) should be graded according to the NCI CTCAE 5.0 standard.

[0130] Pharmacokinetic parameters:

[0131] Single-dose pharmacokinetic parameters: AUC 0-24 AUC 0-t AUC0-inf C max T max t 1 / 2 CL / F, Vd / F, λ z MRT 0-inf AUC _％Extrap Etc.; The Power model was used to evaluate the main PK parameters (AUC). 0-24 AUC 0-t AUC 0-inf C max Linear relationship between dose and p-value. Multiple-dose p-values: D1: AUC 0-t AUC 0-inf C max T max t 1 / 2 CL / F, Vd / F, λ z MRT 0-inf etc. D7: AUC 0-t AUC 0- inf AUC 0-tau C max T max t 1 / 2 CL / F, Vd / F, λ z MRT 0-inf C min C avg R AUC R Cmax DF, etc.; the Power model was used to evaluate the main PK parameters (AUC, AUC, etc.). 0-inf AUC 0-tau C max The linear relationship between PK and dose was established. WinNonlin version 8.4 was used to calculate the above PK parameters using a non-compartmental model.

[0132] Effects of food on pharmacokinetics: Investigating the effects of postprandial administration on the main PK parameters (AUC) of the investigational drug. 0-t AUC 0-inf and C max The influence of PK parameters was investigated. After logarithmic transformation of the main PK parameters, analysis of variance was performed to calculate the AUC for fasting and postprandial dosing. 0-t AUC 0-inf and C max Geometric mean ratio and its 90% confidence interval.

[0133] Metabolite identification and exploratory study of excretion pathways: Determine the concentrations of the parent drug and metabolites in plasma, urine, and feces after a single dose, and in plasma after multiple doses; identify the metabolites in plasma, urine, and feces after a single dose, and in plasma after multiple doses (please refer to a separate metabolite identification analysis plan and report for metabolite identification analysis). After identifying the metabolites of compound (A), determine the PK detection of the metabolites based on the identification results. Calculate the cumulative excretion in urine and feces (Ae), cumulative excretion rate (Ae%), and renal clearance (CLr).

[0134] Pharmacokinetic parameters: After whole blood samples were stimulated with LPS, the plasma TNF-α content was measured and the rate of change from baseline was calculated.

[0135] Results of a pharmacokinetic study of healthy subjects: After a single oral administration of compound (A) on an empty stomach, compound (A) was absorbed more rapidly, and T... max The median ranges from 1.00 to 3.50 h, t 1 / 2 The mean exposure time was 5.09 h to 7.17 h; drug exposure C was within the dose range of 1 mg to 24 mg. max Both T and AUC increase linearly with increasing dose. Compared to fasting administration, administration after a high-fat meal results in higher T values. max The duration was extended from 1.75h to 3.50h, C max A decrease of 47.30%, AUC 0-inf A 26.69% reduction. On day 7 after oral administration of compound (A) following a standard meal, compound (A) was absorbed rapidly, with a median Tmax of 2.00–3.00 h and a mean t1 / 2 of approximately 7.28 h–8.72 h; drug exposure C in the 2 mg–8 mg dose range... max AUC increases with increasing dose, and the exposure ratio is slightly higher than the dose ratio; C max and AUC 0-tau The accumulation indices were 1.35–1.63 and 1.42–1.55, respectively.

[0136] PD results in healthy subjects: The mean maximum inhibition rate of TNF-α after a single dose of 1 mg to 24 mg increased with increasing dose, ranging from approximately 43.9% to 87.2%. With continuous administration of 2 mg to 8 mg, no significant inhibition was observed at 2 mg, while significant inhibition was observed at 4 mg and 8 mg. The mean maximum inhibition on day 7 was 45.8% at 4 mg and 63.0% at 8 mg.

[0137] Safety results in healthy subjects: Compound (A) was well-tolerated and safe in healthy subjects after single or multiple administrations over 7 consecutive days. No treatment-emergent adverse events (TEAEs) of grade ≥3 occurred, and no subjects withdrew from the trial due to adverse events. No serious adverse events or serious adverse reactions occurred. The vast majority of adverse events were mild and reversible without treatment. After a single dose of 1 mg–24 mg of the study drug in healthy subjects, the overall incidence of adverse events was 97.1% in the compound (A) group and 100% in the placebo group (all 8 subjects experienced AEs). The incidence of treatment-related adverse events (TRAEs) was 85.7% (compound (A) group) and 70.0% (placebo group). The most common adverse events associated with the study drug (TRAE) in the compound (A) group were increased fecal calprotectin (65.7%), positive occult blood (34.3%), and nausea (22.9%). Except for nausea and dizziness, no significant dose-related trend was observed in the incidence of other study drug-related adverse events. The most common TRAE in the placebo group was increased fecal calprotectin (50.0%). After multiple administrations of the study drug (2-8 mg) following standard meals for 7 consecutive days in healthy subjects, the overall safety and tolerability were good. The most common treatment-related adverse events associated with the study drug in the compound (A) group were increased fecal calprotectin (51.9%), positive occult blood (22.2%), and elevated C-reactive protein (14.8%). Most TRAEs did not show a significant dose-related trend. The most common treatment-related adverse events associated with the study drug in the placebo group were increased fecal calprotectin (88.9%), elevated C-reactive protein (22.2%), and positive occult blood (11.1%).

[0138] (2) This embodiment is a Phase I clinical study of the safety, tolerability, and pharmacokinetics of compound (A) tablets (prepared according to the method disclosed in WO2025162431A1) in healthy subjects. The study adopted a single-center, randomized, double-blind, placebo-controlled trial design. A total of 13 subjects were enrolled in the study, and 12 completed the trial. Among them, 9 subjects took compound (A) tablets and 3 subjects took placebo. The dosage was 12 mg twice daily for 7 consecutive days.

[0139] Pharmacokinetic results: After oral administration of compound (A) tablets twice daily at a dose of 12 mg after a standard meal, on day 7, the T of compound (A) was... max The median is 4.00h, t 1 / 2 The mean was 15.69 h; the exposure time of compound (A) was C. max The geometric mean was 200 ng / ml, and the AUC was... 0-tau The geometric mean is 1360 h*ng / ml; Cmax and AUC 0-tau The accumulation indices were 1.66 and 1.65, respectively.

[0140] Pharmacokinetic results: After oral administration of compound (A) 12 mg twice daily following a standard meal, the mean maximum inhibition rate of TNF-α release on day 1 was 63.6% in the compound (A) group and -8.61% in the placebo group; on day 7, the mean maximum inhibition rate of TNF-α release was 77.9% in the compound (A) group and 12.0% in the placebo group. Compound (A) showed a significant inhibitory effect on TNF-α, which was significantly different from that of placebo.

[0141] Safety Results: In the compound (A)-12mg group, 8 out of 9 subjects (88.9%) experienced a total of 19 TEAEs, of which 8 TEAEs in 5 subjects (55.6%) were related to the study drug. In the placebo group, 3 out of 100% of subjects experienced a total of 8 TEAEs, of which 6 TEAEs in 2 subjects (66.7%) were related to the study drug. No grade 2 or higher TEAEs occurred in the compound (A) group; all TEAEs were CTCAE grade 1. Follow-up outcomes for TEAEs were generally positive. No serious adverse events (SAEs) occurred in this study, and no TEAEs led to subject withdrawal, dose reduction, permanent discontinuation, or death. TEAEs related to the study drug in the compound (A)-12mg group (vs. placebo) included positive fecal occult blood (22.2% vs. 33.3%), shortened PR on ECG (22.2% vs. 33.3%), increased fecal calprotectin (11.1% vs. 66.7%), elevated C-reactive protein (11.1% vs. 33.3%), abnormal T-wave on ECG (11.1% vs. 0%), and elevated serum thyroid-stimulating hormone (11.1% vs. 0%). Regarding clinical laboratory assessments, the incidence of laboratory abnormalities in the compound (A)-12mg group was comparable to that in the placebo group. No vital signs, physical examination abnormalities, or ECG abnormalities requiring special attention were observed during this phase. The magnitude of weight loss after administration was low, comparable between the compound (A)-12mg and placebo groups.

[0142] Example 9: A multicenter, randomized, double-blind, placebo-controlled phase II clinical study evaluating the efficacy and safety of compound (A) tablets in subjects with moderate to severe plaque psoriasis.

[0143] This example describes the preparation of compound (A) tablets according to the method disclosed in WO2025162431A1, with a specification of 4 mg (as per C). 23 H 29 (N7O3S calculation).

[0144] (I) Research Objectives

[0145] Primary objective: To preliminarily evaluate the efficacy of compound (A) tablets in adult subjects with moderate to severe plaque psoriasis.

[0146] Secondary objective:

[0147] 1) To evaluate the safety of compound (A) tablets in adult subjects with moderate to severe plaque psoriasis;

[0148] 2) To evaluate the pharmacokinetic (PK) characteristics of compound (A) tablets in adult subjects with moderate to severe plaque psoriasis.

[0149] (II) Research Design

[0150] This study was a multicenter, randomized, double-blind, placebo-controlled phase II clinical trial. 150 human subjects with moderate to severe plaque psoriasis were enrolled and randomly assigned in a 1:1:1 stratification manner to the compound (A)-8 mg BID group (n=50), the compound (A)-12 mg BID group (n=50), and the placebo group (n=50). Stratification factor was "whether or not they had used biologics (yes or no)".

[0151] This study was divided into three phases: screening, treatment, and follow-up.

[0152] Screening period: D-28~D-1

[0153] Patients with plaque psoriasis who meet the diagnostic criteria signed the informed consent form for this study, completed the screening period examination according to the trial procedure, and had their baseline information collected before treatment.

[0154] Treatment period: W1D1~W17D1+3 days

[0155] Inclusion / exclusion criteria were reviewed after baseline assessment on Day 1 or W1D1, and randomization numbers were assigned to subjects who met all inclusion criteria but not any exclusion criteria. The day of first administration of the investigational drug was designated W1D1. Successfully randomized subjects received the investigational drug on the morning of W1D1, twice daily for 16 weeks.

[0156] During the treatment period, subjects are required to complete the relevant scales according to the research procedure and return to the research center on W3D1±2 days, W5D1±2 days, W9D1±3 days, W13D1±3 days, and W17D1+3 days to complete the procedures and examinations at each visit point according to the flowchart.

[0157] Follow-up period: within 28 days after the last study medication (W17D1+3 days to W20D7±3 days)

[0158] During this period, adverse events and concomitant medications of the subjects were collected, and relevant procedures and examinations were completed according to the flowchart during the safety visit (W20D7±3 days).

[0159] (III) Selection Criteria

[0160] Subjects who meet all of the following criteria are eligible to be included in this study:

[0161] Demography:

[0162] 1) Fully understand and voluntarily participate in this research and sign an informed consent form;

[0163] 2) Age ≥ 18 years old, gender not limited;

[0164] 3) Able to understand and complete the research-related scales, agree to have photos taken of the skin lesions, and able to comply with the follow-up schedule and other protocol requirements.

[0165] Disease related:

[0166] 4) Diagnosed with plaque psoriasis for ≥6 months (up to randomization);

[0167] 5) Plaque psoriasis is stable within the past 4 weeks, defined as: no morphological changes or severe disease exacerbation (as assessed by the investigator).

[0168] 6) Both the screening visit and baseline assessment meet the criteria for moderate to severe psoriasis, and the following requirements must be met simultaneously:

[0169] Psoriasis skin lesions with a body surface area (BSA) ≥ 10%;

[0170] Psoriasis Skin Area and Severity Index (PASI) ≥ 12 points;

[0171] Investigator Overall Assessment (IGA) score ≥ 3.

[0172] 7) The investigator assesses that the patient is suitable for systemic treatment.

[0173] Contraception requirements:

[0174] 8) Throughout the study period, from the signing of the informed consent form to 3 months after the last dose, female subjects of childbearing potential and male subjects who have not undergone vasectomy must use effective contraception [effective contraception includes: vasectomy, abstinence, intrauterine device (IUD), hormones (oral, patch, ring, injection, implant) and barrier methods (diaphragm, cervical cap, sponge, condom)].

[0175] (iv) Exclusion criteria

[0176] Subjects meeting any of the following criteria are not eligible for inclusion in this study:

[0177] Previous / comorbid treatments:

[0178] 1) Those who have used topical anti-psoriasis treatment within 7 days prior to randomization, including but not limited to: emollients containing medicated ingredients, corticosteroids (such as fluocinolone acetonide, betamethasone valerate, mometasone furoate, hydrocortisone butyrate, desonide, etc.), vitamin D3 derivatives (such as calcipotriol, tacalcitol, etc.), retinoids (such as tazarotene, etc.), calcineurin inhibitors (such as tacrolimus, pimecrolimus, etc.), benvitimod, anti-human IL-8 monoclonal antibodies, keratolytic agents (such as tar, salicylic acid, etc.), keratolytic agents (such as sulfur, lactic acid, etc.), and anthraquinol;

[0179] 2) Those who have received systemic anti-psoriasis medication with non-biologic agents within the four weeks prior to randomization, including but not limited to:

[0180] Traditional drugs: methotrexate, cyclosporine, retinoids (such as acitretin, adapalene, tazarotene, etc.), glucocorticoids (such as prednisone, dexamethasone, betamethasone, etc.), azathioprine, leflunomide, mycophenolate mofetil.

[0181] Small molecule targeted drugs: PDE4 inhibitors (such as apramisitol), JAK inhibitors (such as tofacitinib and utpatinib), TYK inhibitors (such as deuterocelexitinib).

[0182] Traditional Chinese medicine preparations for the treatment of psoriasis (based on the indications in the instructions) and Chinese herbal medicines (based on the intended use in the medical documents).

[0183] 3) Those who have received systemic anti-psoriasis treatment with biologics within the 12 weeks prior to randomization, including but not limited to: TNF-α inhibitors (such as etanercept, infliximab, adalimumab, etc.), IL-12 / 23 inhibitors (such as ustekinumab, etc.), IL-17A inhibitors (such as secukinumab, ixekizumab, etc.), IL-23 inhibitors (such as gusekinumab, tirekizumab, etc.), and IL-36 inhibitors (such as pesolimab, etc.);

[0184] 4) Those who have received phototherapy (such as NB-UVB, PUVA, etc.) within the previous 4 weeks;

[0185] 5) Previous treatment with PDE4 inhibitors and / or PDE4B inhibitors;

[0186] 6) Patients who have used strong inhibitors or inducers of CYP3A4 within 14 days or 5 half-lives prior to randomization (whichever is longer) or patients who will need to take such agents during the study period;

[0187] 7) Patients who have used any clinical trial drug within 4 weeks or 5 half-lives (whichever is longer, at least 12 weeks for biologics) prior to randomization.

[0188] Medical history and general condition:

[0189] 8) The screening visit and / or baseline assessment laboratory tests (with a maximum of one repeat test allowed) meet any of the following criteria:

[0190] a. Hemoglobin ≤ 90g / L;

[0191] b. White blood cell count <3.0×10⁹ / L or white blood cell count >14×10⁹ / L;

[0192] c. Platelet count <100×10⁹ / L;

[0193] d. Estimated glomerular filtration rate (eGFR) calculated using the modified MDRD formula for the Chinese population is ≤45 ml / min / 1.73 m2;

[0194] e. Total bilirubin > 1.5 × ULN;

[0195] f. Aspartate aminotransferase or alanine aminotransferase >1.5×ULN.

[0196] 9) Other types of psoriasis besides plaque psoriasis (such as pustular psoriasis, erythrodermic psoriasis, guttate psoriasis, drug-induced psoriasis, etc.);

[0197] 10) In addition to psoriasis, there may be other skin diseases or skin infections that could affect the evaluation of the study;

[0198] 11) In addition to psoriasis, there may be other autoimmune diseases that could affect the evaluation of the study;

[0199] 12) Screening visits for abnormal chest X-ray or CT scans are clinically significant and the investigators judge that there is a safety risk;

[0200] 13) History of invasive opportunistic infections (such as histoplasmosis, coccidioidomycosis, etc.); or chronic active or acute infection within the four weeks prior to randomization, requiring systemic treatment with antibiotics, antiviral or antifungal drugs;

[0201] 14) Suffering from asthma or respiratory disease and requiring treatment with biologics or high-dose inhaled corticosteroids;

[0202] 15) Had or planned to undergo major surgery within the three months prior to randomization during the study period (subject to investigator assessment);

[0203] 16) Screening visits showed systolic blood pressure ≥160 mmHg and / or diastolic blood pressure ≥100 mmHg after receiving drug treatment;

[0204] 17) Cardiovascular or cerebrovascular events (such as cerebral infarction, cerebral hemorrhage, transient ischemic attack, deep vein thrombosis, pulmonary embolism, etc.) occurred within the six months prior to randomization. Lacunar infarction must be confirmed by the investigator to determine whether it is eligible for inclusion in the study.

[0205] 18) Subjects with any clinically significant heart disease (such as unstable ischemic heart disease, NYHA class III / IV, myocardial infarction, etc.) within the six months prior to randomization are deemed unsuitable for participation in the study by the investigator;

[0206] 19) Screening visits for 12-lead electrocardiogram abnormalities are clinically significant and, as assessed by the investigator, pose a safety risk or may affect the study evaluation.

[0207] 20) A history of suicide attempt within the two years prior to randomization, or a history of a major mental illness requiring hospitalization within the three years prior to randomization;

[0208] 21) History of malignant tumors within 5 years prior to randomization (excluding malignant tumors that have been cured by the investigator and have not recurred within 3 years prior to randomization);

[0209] 22) A history of gastrointestinal surgery or severe gastrointestinal disease (excluding appendectomy and simple hernia repair) that may affect the pharmacokinetic assessment of the study within 1 month prior to randomization;

[0210] 23) Screening visits showing positive HIV or HCV antibodies; or presence of active HBV, syphilis, or tuberculosis infection, defined as:

[0211] Active HBV infection: If the hepatitis B surface antigen is positive, HBV DNA testing is required. If HBV DNA > ULN, it is considered to be active HBV infection.

[0212] Active syphilis infection: If the Treponema pallidum antibody is positive (such as TPPA, etc.), then a non-specific syphilis antibody test (such as RPR, TRUST, etc.) is required. A positive non-specific syphilis antibody test is considered to be an active syphilis infection.

[0213] Active tuberculosis infection: If the interferon-gamma release assay (IGRA) is positive (such as TSPOT), researchers can combine symptoms, signs, chest imaging examinations (such as X-ray, CT, etc.) and other laboratory tests (such as smear, mycobacterial nucleic acid test, etc.) to comprehensively assess whether the subject has an active tuberculosis infection.

[0214] 24) A history of drug abuse, drug use, or alcoholism within the three months prior to the randomization; alcoholism is defined as an average daily intake of more than 2 units of alcohol (1 unit = 360 mL of 5% alcohol beer or 45 mL of 40% alcohol spirits or 150 mL of wine).

[0215] 25) Individuals with a history of severe drug allergies or allergies to compound (A) tablets;

[0216] 26) Pregnant and lactating women, or women who plan to become pregnant or lactating during the study period;

[0217] 27) Researchers assessed that any other factors made participants unsuitable for participation in this study.

[0218] (V) Dosing regimen (Compound (A) tablets - 8 mg, Compound (A) tablets - 12 mg, Placebo)

[0219] Successful randomized participants began medication on W1D1 and continued until the day before the V8 (EOT) visit; no medication was required on the day of the V8 (EOT) visit. The medication was administered twice daily, once in the morning and once in the evening within 30 minutes of the start of meals, with warm water, for 16 weeks. The interval between the two doses was 12 hours ± 2 hours, and efforts were made to ensure that the morning and evening dose times were identical (± 60 minutes). If a dose was missed, it could be taken if the missed dose was more than 8 hours from the next scheduled dose; otherwise, it was not. Regardless of whether a missed dose was taken, the next scheduled dose should be taken.

[0220] Several research centers were selected to enroll 24 subjects (8 subjects in each of the following groups: Compound (A) tablet-8mg BID group, Compound (A) tablet-12mg BID group, and placebo group) for an intensive blood collection PK study (PK subgroup). Subjects requiring intensive PK collection were to take the medication within 30 minutes after breakfast on the morning of their follow-up visit on W1D1 and W3D1±2 days later, with approximately 240mL of warm water. They were to fast for 2 hours and refrain from drinking water for 1 hour after taking the medication, and PK blood samples were collected according to the PK collection time points.

[0221] For subjects who experience intolerance during the trial, medication may be temporarily discontinued at the investigator's discretion. Subjects whose symptoms disappear or return to baseline levels within one week may resume the original dose at the investigator's discretion.

[0222] In this study, intolerance was defined as: according to the CTCAE 6.0 criteria, when the investigator determined that the subject experienced a grade 2 or higher adverse event (TRAE) related to the investigational drug, which the subject could not tolerate, and the investigator determined that there was a risk to continue treatment.

[0223] (vi) Research endpoint

[0224] Primary therapeutic endpoint:

[0225] The proportion of subjects who achieved PASI-75 (PASI score ≥75% reduction from baseline) at week 16 of treatment.

[0226] Secondary efficacy endpoints

[0227] The proportion of subjects with an IGA score of 0 (complete clearance) or 1 (basic clearance) at weeks 2, 4, 8, 12 and 16 of treatment, and a decrease of ≥2 points from baseline;

[0228] The percentage of subjects who achieved PASI-75 at weeks 2, 4, 8, and 12 of treatment;

[0229] The proportion of subjects who achieved PASI-50 (PASI score ≥50% reduction from baseline) at weeks 2, 4, 8, 12 and 16 of treatment;

[0230] The proportion of subjects who achieved PASI-90 (PASI score ≥90% reduction from baseline) at weeks 2, 4, 8, 12 and 16 of treatment;

[0231] Percentage change in BSA from baseline at weeks 2, 4, 8, 12, and 16 of treatment;

[0232] Percentage change in PASI score from baseline at weeks 2, 4, 8, 12, and 16 of treatment;

[0233] Percentage change in DLQI score from baseline at weeks 2, 4, 8, 12, and 16 of treatment;

[0234] The proportion of subjects whose pruritus NRS score decreased by ≥4 points from baseline at week 16 of treatment;

[0235] Percentage change from baseline in pruritus NRS score at weeks 2, 4, 8, 12, and 16 of treatment;

[0236] The proportion of subjects who achieved PASI-75 at week 16 of treatment and whose IGA score was 0 or 1 and decreased by ≥2 points from baseline.

[0237] Safety endpoint

[0238] Incidence and severity of adverse events;

[0239] Vital signs, 12-ECG, physical examination, weight, and laboratory tests, etc.

[0240] Pharmacokinetic endpoints

[0241] Pharmacokinetic characteristics of compound (A) and its metabolites in subjects (PK-intensive subjects), and plasma concentrations of compound (A) and its metabolites at predetermined time points (all subjects).

[0242] (vii) Statistical Methods

[0243] Statistical analysis software used is SAS EG8.3 or later. For continuous variables, the number of subjects (including missing subjects), mean, standard deviation, median, minimum, and maximum values ​​are used for summarization; for categorical data, frequency and percentage are used for summarization; for pharmacokinetic (PK) data (concentration), in addition to using statistics for continuous data, statistics including coefficient of variation, geometric mean, geometric standard deviation, and geometric coefficient of variation can also be used according to the data distribution.

[0244] Analyzing the population

[0245] Full Analysis Set (FAS): All subjects who were randomized, received the investigational drug, and had at least one primary efficacy evaluation.

[0246] The Per-Protocol Set (PPS) includes subjects who have good adherence to the FAS and have not committed any major protocol deviations that would affect the primary efficacy assessment. Subjects with major protocol deviations excluded from the PPS must be identified before the database is locked.

[0247] Safe Set (SS): Includes all subjects who have been randomized and have received at least one investigational drug.

[0248] Pharmacokinetic concentration set (PKCS): All subjects who were randomized, received the investigational drug, and had at least one PK concentration observation.

[0249] Sample size estimation

[0250] Referring to the Phase III studies of similar products, PSOR-008 or PSOR-009, the response rate in the placebo group was 5.5%. At week 16, the PASI-75 (PASI total score improvement of at least 75% relative to baseline) difference between the Apramisarti tablet and placebo groups, with a 95% confidence interval of 26.2% (22.4%, 30.0%). Using conservative estimates, we assumed a 10% response rate in the placebo group and a 22% difference between compound (A) and placebo at week 16. At a significance level of 0.1 (two-sided), with a power of at least 80%, and considering a 15% dropout rate, subjects were randomly assigned 1:1:1 to the compound (A) tablet-8mg BID group, the compound (A) tablet-12mg BID group, and the placebo group, with 50 subjects in each group; a total of 150 subjects.

[0251] Validity analysis

[0252] Primary therapeutic endpoint

[0253] Logistic regression was used to analyze the proportion of subjects who achieved PASI-75 (PASI score ≥75% reduction from baseline) at week 16. The independent variables included the stratification factor "whether or not a biologic was used (yes or no)", baseline PASI score, and group information. The odds ratio (OR), 90% confidence interval, and corresponding p-values ​​between each investigational drug group and the placebo group are presented.

[0254] Secondary therapeutic endpoint:

[0255] The proportion of subjects with an IGA score of 0 (complete clearance) or 1 (basic clearance) at weeks 2, 4, 8, 12 and 16 of treatment, and a decrease of ≥2 points from baseline;

[0256] The percentage of subjects who achieved PASI-75 at weeks 2, 4, 8, and 12 of treatment;

[0257] The proportion of subjects who achieved PASI-50 (PASI score ≥50% reduction from baseline) at weeks 2, 4, 8, 12 and 16 of treatment;

[0258] The proportion of subjects who achieved PASI-90 (PASI score ≥90% reduction from baseline) at weeks 2, 4, 8, 12 and 16 of treatment;

[0259] The proportion of subjects whose pruritus NRS score decreased by ≥4 points from baseline at week 16 of treatment;

[0260] The proportion of subjects who achieved PASI-75 at week 16 of treatment and whose IGA score was 0 or 1 and decreased by ≥2 points from baseline.

[0261] All secondary indicators were statistically analyzed using the same methods as the primary efficacy indicators.

[0262] Percentage change in BSA from baseline at weeks 2, 4, 8, 12, and 16 of treatment;

[0263] Percentage change in PASI score from baseline at weeks 2, 4, 8, 12, and 16 of treatment;

[0264] Percentage change in DLQI score from baseline at weeks 2, 4, 8, 12, and 16 of treatment;

[0265] Percentage change from baseline in pruritus NRS score at weeks 2, 4, 8, 12, and 16 of treatment;

[0266] Repeated measures mixed-effects (MMRM) models were used to analyze the percentage change in scores relative to baseline at weeks 2, 4, 8, 12, and 16 post-baseline. The model used stratification factors, group, analytical visits, and the interaction between group and analytical visits as fixed effects, and subjects as random effects. Baseline scores were used as covariates. The least squares mean and 90% confidence intervals of the percentage change relative to baseline were calculated for inter-group comparisons. Line graphs were plotted for each experimental group, showing the baseline and post-baseline means of the analytical visit scales, the change in scores from baseline, the percentage change, and the least squares mean of the percentage change relative to baseline.

[0267] Security Analysis:

[0268] Safety analysis is based on a safety analysis set, which is summarized and listed according to trial groups. It includes, but is not limited to, statistical descriptions and lists of adverse events, laboratory test data, vital sign test data, physical examination data, electrocardiogram test data, etc.

[0269] Pharmacokinetic analysis:

[0270] Based on PKCS, descriptive statistical analyses were performed on the blood drug concentrations of compound (A) and its metabolites at different time points according to different dosing groups. For subjects with intensive PK blood collection, a non-compartmental model was used to estimate pharmacokinetic parameters, calculating the main pharmacokinetic parameters of the drug (including but not limited to AUC0-tau, Tmax, Cmax, t1 / 2, CL / F, Vd / F, etc.). Blood drug concentration data and PK parameters from this study were combined with clinical trial data of other compounds (A) to establish a population pharmacokinetic model. This model was used to assess the influence of covariates on the pharmacokinetic characteristics of compound (A). In addition, exposure-response analyses were performed for specific efficacy and safety endpoints. The results of the above population pharmacokinetic and exposure-response analyses were included in separate reports.

[0271] Clinical trial conclusions:

[0272] The aforementioned Phase II clinical study demonstrated that compound (A) tablets exhibited good safety and efficacy in subjects with moderate to severe plaque psoriasis.

[0273] Example 10: A multicenter, randomized, double-blind, placebo-controlled phase II clinical study evaluating the efficacy and safety of compound (A) tablets in patients with atopic dermatitis.

[0274] This example describes the preparation of compound (A) tablets according to the method disclosed in WO2025162431A1, with a specification of 4 mg (as per C). 23 H 29 (N7O3S calculation).

[0275] (I) Research Topic

[0276] Main objective: To preliminarily evaluate the efficacy of compound (A) tablets in adult patients with moderate to severe atopic dermatitis;

[0277] Secondary objective:

[0278] To evaluate the safety of compound (A) tablets in adult patients with moderate to severe atopic dermatitis;

[0279] To evaluate the pharmacokinetic (PK) characteristics of compound (A) tablets in adult patients with moderate to severe atopic dermatitis.

[0280] (II) Study population

[0281] Selection criteria (all of the following criteria must be met to be selected):

[0282] Demography:

[0283] 1. Fully understand and voluntarily participate in this research and sign an informed consent form;

[0284] 2. Age 18 ≤ age ≤ 75, gender not limited;

[0285] 3. Able to understand and complete the research-related scales, agree to have photos taken of the skin lesions, and able to comply with the follow-up schedule and other protocol requirements.

[0286] Disease related:

[0287] 4. Suffering from atopic dermatitis (AD) according to the Hanifin and Rajka criteria, and having a history of atopic dermatitis or eczema for at least 1 year prior to screening;

[0288] 5. At screening and baseline visit, the Eczema Area and Severity Index (EASI) score is ≥16;

[0289] 6. During screening and baseline visits, the Investigator Global Assessment (IGA) score is ≥3;

[0290] 7. At screening and baseline visit, the body surface area (BSA) affected by AD is ≥10%;

[0291] 8. The weekly mean of the baseline daily most severe pruritus numerical score (WI-NRS) is ≥4 (calculated based on the first 7 days of randomization, with at least 4 days assessed within those 7 days);

[0292] 9. As determined by the investigators, candidates who received topical AD treatment within the 6 months prior to screening but had an inadequate clinical response and / or intolerance, or who received systemic therapy to control the disease. An inadequate clinical response is defined as: failure to achieve and maintain remission or low disease activity (equivalent to IGA = 0–2) after receiving ≥4 weeks of intermediate / high potency topical corticosteroids (TCS) or ≥2 weeks of high potency TCS (whichever is shorter, depending on the longest recommended duration in the drug's package insert) ± topical calcineurin inhibitors (TCI).

[0293] 10. Before the baseline visit, a stable dose of a topical moisturizer containing no added drugs or active ingredients (ceramides, urea, filaggrin degradation products or hyaluronic acid) was applied twice daily for at least 7 consecutive days and continued during the trial period;

[0294] Requirements for contraception:

[0295] 11. Throughout the study period, from the signing of the informed consent form to 3 months after the last dose, female subjects of childbearing potential and male subjects who have not undergone vasectomy must use effective contraception [effective contraception includes: vasectomy, abstinence, intrauterine device (IUD), hormones (oral, patch, ring, injection, implant) and barrier methods (diaphragm, cervical cap, sponge, condom)].

[0296] Exclusion criteria (applicants meeting any of the following criteria are excluded):

[0297] Previous / comorbid treatments:

[0298] 1. Patients who received the following treatments prior to the baseline visit, including:

[0299] a) Received excessive plinuma or sepcitabine within 6 weeks;

[0300] b) Received other known or potentially influential biologics within 12 weeks, including but not limited to monoclonal antibodies targeting IL-2, IL-4, IL-5, IL-12, IL-13, IL-22, IL-23, IL-31, IL-33, OX40, TSLP, CD20, TNF-α and IgE;

[0301] c) Received systemic drug treatment for atopic dermatitis within 4 weeks, including but not limited to systemic glucocorticoids, immunosuppressants (cyclosporine, methotrexate, azathioprine, mycophenolate mofetil, IFN-γ, etc.), JAK inhibitors, traditional Chinese medicine treatment, etc.

[0302] d) Received topical treatment for atopic dermatitis within 7 days, including but not limited to TCS, TCIs, topical JAK inhibitors, topical PDE4 inhibitors, topical traditional Chinese medicine, topical antihistamines, and topical emollients with added drugs or active ingredients;

[0303] e) Have received phototherapy for AD (including but not limited to narrowband UVB, PUVA, etc.) within 4 weeks;

[0304] 2. Patients who have previously received systemic therapy with phosphodiesterase 4 (PDE4) inhibitors;

[0305] 3. Patients who have used strong inhibitors or inducers of CYP3A4 within 14 days or 5 half-lives prior to randomization (whichever is longer) or patients who will need to take such agents during the study period;

[0306] 4. Patients who have used any clinical trial drug within the four weeks prior to randomization or within five half-lives (whichever is longer, at least 12 weeks for biologics);

[0307] Note: Subjects who have participated in studies related to compound (A) are not eligible to participate in this clinical trial.

[0308] Medical history and general condition:

[0309] 5. Screening period laboratory tests (including baseline visit):

[0310] a) Hemoglobin ≤ 90g / L;

[0311] b) White blood cell count <3.0×10⁹ / L or white blood cell count >14×10⁹ / L;

[0312] c) Platelet count <100×10⁹ / L;

[0313] d) The estimated glomerular filtration rate (eGFR) calculated using the modified MDRD formula for the Chinese population is ≤45 ml / min / 1.73 m2;

[0314] e) Total bilirubin > 1.5 × ULN;

[0315] f) Both aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels were >1.5 × ULN;

[0316] Note: The above results can be repeated up to once during the screening period. If the researcher believes, based on clinical judgment, that a repeat test may not meet the exclusion criteria, the laboratory test may be repeated once.

[0317] 6. Individuals assessed by the investigator to have other active skin diseases or skin infections that may affect the assessment of the treatment response to atopic dermatitis;

[0318] 7. Individuals with clinically significant abnormalities on chest X-ray or CT scans during screening, and in the investigator's opinion, who may place the subjects at a safety risk;

[0319] 8. Known history of invasive opportunistic infections (such as histoplasmosis, coccidioidomycosis, etc.); or those who have had chronic active or acute infections requiring systemic treatment with antibiotics, antiviral or antifungal drugs within 4 weeks prior to screening;

[0320] 9. Patients with rheumatic fever, rheumatoid arthritis, systemic lupus erythematosus, dermatomyositis, multiple sclerosis, Sjögren's syndrome, inflammatory bowel disease, or other autoimmune diseases that investigators have assessed as affecting efficacy and safety assessments at the time of screening;

[0321] 10. Asthma requiring high-dose inhaled corticosteroids, systemic corticosteroids, or biologics;

[0322] 11. Those who have undergone or plan to undergo major surgery within the three months prior to screening (as assessed by the investigator);

[0323] 12. Blood pressure that has not been controlled by antihypertensive drugs within 3 months prior to screening, with systolic blood pressure ≥160 mmHg or diastolic blood pressure ≥100 mmHg at screening visit or baseline visit;

[0324] 13. Screening candidates must have experienced a thrombotic event (including stroke, transient ischemic attack, deep vein thrombosis, pulmonary embolism, etc.) within the 6 months prior to screening.

[0325] 14. Any subject with clinically significant heart disease (e.g., but not limited to unstable ischemic heart disease, NYHA class III / IV or myocardial infarction) or clinically significant 12-lead electrocardiogram abnormalities discovered in the six months prior to screening, and in the investigator's opinion, may put the subject at safety risk or may interfere with the study evaluation.

[0326] 15. Subjects who have a history of suicide attempt within 2 years prior to screening, or a history of major mental illness requiring hospitalization within 3 years prior to screening;

[0327] 16. Screening criteria include a history of malignant tumors within the past 5 years (excluding patients with treated basal cell carcinoma of the skin, squamous cell carcinoma in situ of the skin, or cervical carcinoma in situ);

[0328] 17. History of gastrointestinal surgery or severe gastrointestinal disease (excluding appendectomy or simple hernia repair) that may interfere with the pharmacokinetics (PK) of the investigational drug;

[0329] 18. During the screening period, individuals with active hepatitis B [positive for hepatitis B surface antigen (HBsAg) and hepatitis B virus DNA (HBV-DNA) above the upper limit of the normal range], positive for hepatitis C antibody, syphilis infection [positive for anti-TP test (but those who have undergone standard treatment and have a negative non-treponemal antigen serological test can be included)], or human immunodeficiency virus (HIV) infection (positive for anti-HIV) are eligible to be included.

[0330] 19. Those with a history of drug abuse, drug use, or alcoholism within the three months prior to screening. Alcoholism is defined as an average daily intake of more than 2 units of alcohol (1 unit = 360 mL of 5% alcohol beer, 45 mL of 40% alcohol spirits, or 150 mL of wine).

[0331] 20. Individuals with a history of severe drug allergies or who are allergic to the investigational drugs specified in the protocol;

[0332] 21. Pregnant and lactating women, or women who plan to become pregnant or lactating during the study period;

[0333] 22. Subjects who, in the researchers' opinion, have any other factors that would preclude them from participating in this clinical study.

[0334] Early withdrawal of subjects

[0335] Participants may withdraw from the study voluntarily at any time, or at the request of the researcher or sponsor for safety or compliance reasons. Participants may withdraw from the study treatment early if they meet the following conditions:

[0336] 1. The subject voluntarily requested to terminate the treatment;

[0337] 2. Pregnancy occurred in a participant during the study;

[0338] 3. If any adverse event, abnormal laboratory test result, or other medical condition occurs, and the investigator assesses that continued medication would no longer benefit the subject;

[0339] 4. If atopic dermatitis symptoms worsen or become unacceptable, the individual is not suitable to continue participating in the study;

[0340] 5. Received systemic drug rescue therapy during the treatment period;

[0341] 6. The researchers believe that the participants' compliance is poor and they are not suitable to continue participating in this study;

[0342] 7. Loss to follow-up of participants;

[0343] 8. The subject died;

[0344] 9. Other reasons why the researcher feels unable to continue participating in the research;

[0345] 10. The sponsor terminates the research prematurely.

[0346] (III) Research Design

[0347] This study was a multicenter, randomized, double-blind, placebo-controlled phase II clinical trial. Approximately 150 subjects with moderate to severe atopic dermatitis were enrolled and randomly assigned in a 1:1:1 stratified manner to the compound (A)-8 mg BID group (n=50), the compound (A)-12 mg BID group (n=50), and the placebo group (n=50). Stratification was based on baseline disease severity [moderate (IGA=3) or severe (IGA=4)]. Dosage adjustments were determined based on safety results at a Special Responsible Registry (SRC) meeting.

[0348] Research Process

[0349] This study was divided into three phases: screening, treatment, and follow-up.

[0350] Screening period: D-42 to before the first dose

[0351] Alzheimer's disease (AD) patients who meet the diagnostic criteria sign the informed consent form for this study, complete the screening according to the trial flowchart, and collect baseline information on efficacy and safety indicators before treatment.

[0352] Treatment period: Week 1 to the end of week 12.

[0353] Subjects who meet all inclusion criteria but not any exclusion criteria will be assigned a random number on the day of their first dose of the investigational drug (or the day before after completing baseline assessment). The day of the first dose of the investigational drug will be designated as D1.

[0354] Successful randomized subjects received the investigational drug on the morning of day 1, twice daily for 12 weeks.

[0355] During the treatment period, subjects are required to complete the relevant scales according to the research procedure and return to the research center on D8±2 (W2D1±D2), D15±3 (W3D1±D2), D29±3 (W5D1±D3), D57±3 (W9D1±D3), and D85+3 (W13D1+D3) to complete the procedures and examinations at each visit point according to the research procedure.

[0356] Follow-up period: 28 days after the end of the treatment period (W16D7±D3)

[0357] During this period, adverse events and concomitant medications of the subjects were collected, and relevant procedures and examinations were completed in accordance with the research process during the EOS visit.

[0358] (iv) Dosing regimen

[0359] Compound (A)-8mg BID;

[0360] Compound (A) - 12 mg BID;

[0361] Placebo.

[0362] Successful randomized participants received the investigational drug twice daily from day 1 to day 84 (week 12-7), either compound (A) or placebo, administered with warm water within 30 minutes of the start of each morning and evening meal. The interval between doses was 12 hours ± 2 hours, with efforts made to ensure that the morning and evening dose times were identical (± 60 minutes). If a dose was missed, it could be taken if the interval was >8 hours before the next scheduled dose; otherwise, it was not. Regardless of whether a missed dose was taken, the next scheduled dose should be taken.

[0363] Several research centers were selected to enroll 24 subjects (8 in each group: placebo group, compound (A) tablet 8mg BID group, and compound (A) tablet 12mg BID group) for an intensive blood collection PK study (PK subgroup). Subjects requiring intensive PK collection were to take the medication within 30 minutes after breakfast on the morning of the PK blood collection days D1 (W1D1) and D15 (W3D1±D2), with approximately 240ml of warm water. They were to fast for 2 hours and refrain from drinking water for 1 hour after taking the medication, and PK blood samples were collected according to the PK collection time points.

[0364] For subjects who experience intolerance during the trial, medication may be temporarily discontinued at the investigator's discretion. Subjects whose symptoms disappear or return to baseline levels within one week may resume the original dose at the investigator's discretion.

[0365] In this study, intolerance was defined as: according to the CTCAE 5.0 criteria, when the investigator determined that the subject experienced a grade 2 or higher adverse event related to the study drug, and the subject could not tolerate it, and the investigator determined that there was a risk to continue treatment.

[0366] (V) Research Endpoints

[0367] Primary therapeutic endpoint:

[0368] The percentage change in EASI from baseline at week 12;

[0369] Secondary therapeutic endpoint:

[0370] The proportion of subjects who reached EASI-75 (EASI at least 75% lower than baseline) by week 12;

[0371] The proportion of subjects whose IGA score was 0 or 1 at week 12 and had decreased by ≥2 points from baseline;

[0372] The proportion of participants whose weekly mean score of most severe pruritus (WI-NRS) improved by ≥3 and ≥4 points from baseline at week 12;

[0373] Other therapeutic endpoints:

[0374] The percentage change in EASI from baseline at other visit time points;

[0375] The proportion of subjects who reached EASI-75 at other visit time points;

[0376] The proportion of subjects whose IGA scores were 0 or 1 at other visit time points and decreased by ≥2 points from baseline;

[0377] The proportion of subjects whose weekly mean of most severe pruritus score (WI-NRS) improved by ≥3 and ≥4 points from baseline at other time points;

[0378] The proportion of subjects who reached EASI-50 (EASI decreased by at least 50% from baseline) at each visit time point;

[0379] The proportion of subjects who achieved EASI-90 (EASI at least 90% lower than baseline) at each visit time point;

[0380] The proportion of subjects who reached EASI-100 (EASI decreased by 100% from baseline) at each visit time point;

[0381] The percentage of skin lesions (BSA%) involved in AD at each visit time point compared to baseline.

[0382] Changes in the weekly mean of the most severe pruritus numerical score (WI-NRS) at each visit time point from baseline;

[0383] Changes in atopic dermatitis score (SCORAD) at each visit time point compared to baseline;

[0384] Changes in the Dermatology Quality of Life (DLQI) index at each visit time point compared to baseline;

[0385] Changes in the Short Form Health Survey (SF-36) at each visit time point compared to baseline;

[0386] Changes in the Patient Self-Eczema Scale (POEM) at each visit time point compared to baseline.

[0387] Safety endpoint:

[0388] Incidence and severity of adverse events;

[0389] Vital signs, 12-ECG, physical examination and laboratory tests.

[0390] Pharmacokinetic endpoints:

[0391] Pharmacokinetic characteristics of compound (A) and its metabolites in patients (PK-intensive subjects), and plasma concentrations of compound (A) and its metabolites at predetermined time points (all subjects).

[0392] (vi) Sample size

[0393] The sample size in this study was not based on statistical considerations. A total of 150 subjects with moderate to severe atopic dermatitis were enrolled and randomly assigned in a 1:1:1 ratio to the compound (A)-8mg BID group (N=50), the compound (A)-12mg BID group (N=50), and the placebo group (N=50).

[0394] (vii) Statistical Analysis

[0395] The statistical analysis software used is SAS EG 8.3 or later.

[0396] For continuous variables, list the number of cases, number of missing cases, mean, standard deviation, median, quartiles (Q1 and Q3), minimum, and maximum. For categorical variables, describe their frequency and percentage. In this study, unless otherwise specified, "baseline" is defined as the last non-missing observation before the first administration of the investigational drug.

[0397] All analyses were performed according to the treatment group unless otherwise specified.

[0398] Analyze the dataset:

[0399] The ITT (Intention to Treat Anaysis Set) analysis set includes all subjects who were randomized and received the investigational drug at least once.

[0400] The Per-Protocol Set (PPS) comprises subjects from the ITT analysis who maintained good adherence throughout all studies, had complete primary efficacy endpoint data, and were unaffected by significant protocol deviations. Subjects with significant protocol deviations excluded from the PPS set were identified before the database was locked. Significant protocol deviations refer to deviations from the protocol that impacted the primary efficacy endpoint.

[0401] Safety Set (SS): Includes all subjects who were randomized and received the investigational drug at least once and have post-treatment safety evaluation data.

[0402] Pharmacokinetics analysis set (PKS): This includes all subjects who were randomized, received the investigational drug at least once, had at least one measurable concentration, and did not experience any protocol deviations that would affect the PK data.

[0403] Validity analysis

[0404] Primary therapeutic endpoint:

[0405] The percentage change in EASI from baseline at week 12;

[0406] ITT was used as the primary analysis set, with PPS used as a supplementary analysis.

[0407] Descriptive statistics were performed on the percentage change of EASI from baseline at week 12, categorized by group.

[0408] An ANCOVA model was used with the percentage change in EASI from baseline at week 12 as the dependent variable, and treatment group and baseline disease severity [moderate (IGA=3) or severe (IGA=4)] as fixed effects, and baseline EASI values ​​as covariates. The adjusted least-squares mean and standard error of the percentage change in EASI from baseline at week 12 for each group were listed. The percentage difference in EASI from baseline at week 12 between each dose group of compound (A) and the placebo group and its 95% confidence interval were calculated, and the p-value was calculated. If the basic assumptions of normality or homogeneity of variance were not met, nonparametric tests were used for intergroup comparisons.

[0409] Secondary therapeutic endpoint:

[0410] The proportion of subjects who reached EASI-75 (EASI at least 75% lower than baseline) by week 12;

[0411] The proportion of subjects whose IGA score was 0 or 1 at week 12 and had decreased by ≥2 points from baseline;

[0412] The proportion of participants whose weekly mean score of most severe pruritus (WI-NRS) improved by ≥3 and ≥4 points from baseline at week 12;

[0413] Based on the ITT, descriptive statistics were performed on the proportion of subjects who achieved EASI-75 (EASI at least 75% reduction from baseline) at week 12, categorized by group. Using the proportion of subjects achieving EASI-75 (EASI at least 75% reduction from baseline) at week 12 as the dependent variable, a logistic regression model was established with treatment group and baseline disease severity [moderate (IGA=3) or severe (IGA=4)] as fixed effects, and baseline EASI value as a covariate. With the placebo group as the control, the odds ratio and its 95% confidence interval for the proportion of subjects achieving EASI-75 (EASI at least 75% reduction from baseline) at week 12 were calculated for each dosage group of compound (A), and p-values ​​were calculated. The proportion of subjects who achieved an IGA of 0 or 1 at week 12 with a decrease of ≥2 points from baseline, and the proportion of subjects whose weekly mean of the most severe pruritus numerical score (WI-NRS) improved by ≥3 and ≥4 points from baseline at week 12 were analyzed using the same method as the proportion of subjects who achieved EASI-75 (EASI decreased by at least 75% from baseline) at week 12.

[0414] Security Analysis

[0415] Adverse events:

[0416] Based on the Standards of Medical Action (SS), adverse events (AEs) were coded using the ICH Dictionary of Medical Actions for Regulatory Activities (MedDRA 28.0 or later) and categorized by Systemic Organ Classification (SOC) and Preferred Terminology (PT). Unless otherwise specified, the severity of adverse events was graded according to the Common Terminology Standard for Adverse Events (CTCAE) [version 5.0]. The number, incidence, and frequency of all treatment-related adverse events (TEAEs), grade 3 or higher TEAEs, adverse events of particular concern (AESIs), investigational drug-related TEAEs, serious adverse events (SAEs), investigational drug-related SAEs, and TEAEs leading to early withdrawal from treatment were calculated, and the number and percentage were summarized separately by systemic organ classification, preferred terminology, and treatment group.

[0417] The list provides detailed information on adverse events (AEs). It details AEs that occurred during treatment following drug administration.

[0418] Various checks:

[0419] Based on SS (Statistical Score), the laboratory test indicators were statistically described. Descriptive statistics were performed on the results of laboratory test indicators based on baseline, post-treatment measurement time points, and changes from baseline. Cross-tabulations were created based on baseline, post-treatment measurement time points, and clinical interpretations of laboratory test indicators for each group, and the results of all and clinically significant abnormalities were presented in a table.

[0420] Descriptive statistics were performed on the results of 12-ECG, vital signs, and physical examination. Cross-tabulations were created based on baseline, post-treatment measurement time points, and results for each group, and all clinically significant abnormalities were presented in a table.

[0421] Pharmacokinetic parameters:

[0422] Based on PKS, descriptive statistical analysis was performed on the blood drug concentrations of compound (A) and its metabolites at different time points according to different dosing groups. For subjects with intensive PK blood collection, a non-compartmental model was used to estimate and analyze pharmacokinetic parameters, and the main pharmacokinetic parameters of the drug and metabolites (including but not limited to AUC0-tau, Tmax, Cmax, t1 / 2, CL / F, Vd / F, etc.) were calculated.

[0423] The pharmacokinetic parameters and plasma concentration data from this study were combined with clinical trial data from other compounds (A) to establish a population pharmacokinetic model. This model was used to assess the influence of covariates on the pharmacokinetic characteristics of compound (A). Additionally, exposure-response analyses may be performed for specific efficacy and safety endpoints. The results of the aforementioned population pharmacokinetic and exposure-response analyses will be included in separate reports.

[0424] Clinical trial conclusions:

[0425] The aforementioned Phase II clinical study demonstrated that compound (A) tablets have good safety and efficacy in patients with atopic dermatitis.

[0426] Abbreviations

Claims

1. The use of a compound of formula (I) or its stereoisomers, tautomers, pharmaceutically acceptable salts or combinations thereof in the preparation of a medicament for treating psoriasis and atopic dermatitis, characterized in that... A compound of formula (I) or its stereoisomers, tautomers, pharmaceutically acceptable salts or combinations thereof, administered in effective doses to mammals. Among them, L4 is The product comprises 1-3 5-6-membered heteroaryl groups selected from N, S, and O heteroatoms; 1-3 5-membered monoheterocyclic alkyl groups selected from N, S, and O heteroatoms; 1-3 7-8-membered monoheterocyclic alkyl groups selected from N, S, and O heteroatoms; 1-3 5-6-membered heterocyclic alkyl groups with 5-6-membered heterocyclic alkyl groups selected from N, S, and O heteroatoms; 1-3 5-6-membered heterocyclic alkyl groups with 5-6-membered heterocyclic alkyl groups with 5-6-membered heterocyclic alkyl groups with 5-6-membered heterocyclic alkyl groups with 1-3 7-12-membered spirocyclic heterocyclic alkyl groups selected from N, S, and O heteroatoms; wherein the monoheterocyclic alkyl, 5-6-membered heterocyclic alkyl groups with 5-6-membered heterocyclic alkyl groups, 5-6-membered heterocyclic alkyl groups with 5-6-membered heterocyclic alkyl groups, and spirocyclic heterocyclic alkyl groups are optionally surrounded by 1-3 groups selected from halogens, =O, CN, and C. 1- 4-alkyl, C 1-4 Substitution of alkoxy, OH, and NH2 groups; A is -S(O)-, -C(O)-, -B(OH)-, -S-, -S(=N)-CN or -C(=N)-CN; X1 and X2 are CR independently X1 S or N; R L2 For H, C 1-4 Alkyl or C 3-6 cycloalkyl; R6 represents H, halogens, =O, CN, and C. 1-4 Alkyl or C 1-4 Alkoxy; Each R X1 R can be independently H, halogen, or C. 1-4 Alkyl, C 1-4 Alkoxy, -N(CH3)2, -NH(CH3), C 2-6 Alkyne group, NHSO2NH2, NHCONH2, NHCOC 1-4 Alkyl, CONHC 1-4 Alkyl, NHSO2C 1-4 Alkyl, SO2NHC 1-4 Alkyl, SO2C 1-4 Alkyl, SCF3, SF5, 3-5 membered cycloalkyl, C 1-4 Haloalkyl or 5-10 membered heterocyclic alkyl groups containing 1-3 heteroatoms selected from N, S, O, and Si, or two R, R and R on adjacent ring atoms. X1 Or R X1 Together with R6 and the atoms it is attached to, they form C. 3-8 The cycloalkyl group, a 5-10 membered heterocycloalkyl group containing 1-3 heteroatoms selected from N, S, O, and Si, a phenyl group, or a 5-6 membered heteroaryl group containing 1-3 heteroatoms selected from N, S, and O, wherein the cycloalkyl group, heterocycloalkyl group, phenyl group, and heteroaryl group are optionally surrounded by 1-3 heteroatoms selected from halogen, =O, CN, and C. 1-4 Alkyl, C 1-4 Substitution of alkoxy, OH, and NH2 groups; R1 and R2, together with the atoms they are attached to, form a 5-10 membered heterocyclic alkyl group or a 5-6 membered heteroaryl group containing 1-3 heteroatoms selected from N, S, B, and O, wherein the cycloalkyl, heterocyclic alkyl, and heteroaryl group are optionally surrounded by 1-3 atoms selected from halogen, =O, CN, and C. 1-4 Alkyl, C 1-4 Substitution of alkoxy, OH, and NH2 groups; R 12 Selected from 4-10-membered heterocyclic alkylene, 3-10-membered heterocyclic alkylene, 6-10-membered arylene, 5-10-membered heterocyclic arylene, hydroxy-C 1-6 Alkyl, C 1- 4-alkyl-CN, -CRaRb=NOC 1-4 Alkyl group, -C(NRaRb)=N-CN, -C(C 1-4 Alkyl group = N-CN, -C (NRaRb = CRa-NO) 2、 -C(CH3)2-CH2-OC(O)NH2, -C(CH3)2-CH2-NH-C(O)O(C 1-4 Alkyl groups, -C(CH3)2-CH2-OC(O)NHCH3, -CH(CH3)-CH2-OC(O)NH2, -CH(CH3)-CH2-NH-C(O)O(C 1-4 Alkyl group, -CH(CH3)-CH2-OC(O)NHCH3, -C(O)-Ra or -C(O)- (4-6 membered heterocyclic alkyl group), wherein the heterocyclic alkyl group, alkylene group, arylene group, or heteroarylene group may optionally be further surrounded by 1-3 halogens, CN, =O, OH, -SF5, C 1-4 Alkyl, C 1-4 Alkyl-CN, Hydroxyl-C 1-4 Alkyl, C 1-4 Haloalkyl, -(CH2) t -OC(O)NH2、-(CH2) t -NRa-C(O)NH2、-(CH2) t -NRa-C(=NH)NH2、-(CH2) t -NRa-C(O)-O-(C 1-4 Alkyl group), -(CH2) t -NRa-C(C 1-4 Alkyl group = N-CN, -(CH2) t -NRa-C(NRaRb)=N-CN、-(CH2) t -NRa-C(NRaRb)=CRa-NO2, -(CH2) t -C(NRaRb)=N-CN、-(CH2) t -C(C 1-4 Alkyl group = N-CN, -(CH2) t -C(C 1-4 Alkyl group) = NO-(C 1-4 Alkyl), =NOC 1-4 Alkyl, 5-6 membered heteroaryl, -(CH2) t -OC 1-4 Alkyl group, -(CH2) t -OC(O)NHCH3、-(CH2) t -OC 1-2 Haloalkyl, -(CH2) t -OC 3-6 Cycloalkyl, -(CH2) t -OC 1-4 Alkyl-OC 3-6 Cycloalkyl, -(CH2) t -COOH, -(CH2) t -NRaRb、-(CH2) t -C(O)NRaRb、-(CH2) t Substitution of the -NRa-C(O)CH3 group; Ra and Rb are each independently selected from H, halogens, and C. 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkyl groups or alkyl groups containing 1-2 4-6 membered heterocyclic alkyl groups selected from N and O heteroatoms; t is selected from 0, 1, 2, 3, or 4; p is selected from 0 or 1.

2. The use according to claim 1, in, L4 is R 12 Selected from -C(CH3)2-CH2-OC(O)NH2, -C(CH3)2-CH2-NH-C(O)O(C 1-4 Alkyl groups, -C(CH3)2-CH2-OC(O)NHCH3, -CH(CH3)-CH2-OC(O)NH2, -CH(CH3)-CH2-NH-C(O)O(C 1-4 Alkyl group), -CH(CH3)-CH2-OC(O)NHCH3.

3. The use according to claim 1 or 2, wherein the compound of formula (I) is selected from one of the following structures: or 4. The use according to claim 3, wherein, Compounds of formula (I) are selected from the following structures:

5. The use according to claim 4, characterized in that... A compound of formula (A) or its stereoisomers, tautomers, pharmaceutically acceptable salts or combinations thereof, administered in an effective dose to mammals.

6. The use according to claim 5, wherein the pharmaceutically acceptable salt is selected from maleate, 2-naphthalenesulfonic acid, 1,5-naphthalenedisulfonate, fumarate, hydrohalate, sulfate, phosphate, L-tartrate, citrate, L-malate, hippurate, D-glucuronate, glycolate, mucilage, succinate, lactate, orotate, pamoate, glycine, alanine, arginine, cinnamate, benzoate, benzenesulfonate, p-toluenesulfonate, acetate, propionate, valerate, triphenyl Acetate, L-proline, ferulic acid salt, 2-hydroxyethanesulfonate, mandelic acid salt, nitrate, methanesulfonate, malonate, gentianate, salicylate, oxalate, or glutarate; preferably from benzenesulfonate, L-malate, phosphate, sulfate, p-toluenesulfonate, hydrochloride, maleate, 2-naphthalenesulfonate, hydrobromide, methanesulfonate, citrate, mandelic acid salt, lactobionate, succinate, salicylate, 1,5-naphthalenedisulfonate, fumarate, nicotinate, hippurate, and oxalate; more preferably from hydrochloride.

7. The use according to any one of claims 4 to 6, wherein the effective dose is calculated as the free base of formula (A), said effective dose being 1-1500 mg / day, preferably 10-1500 mg / day, 20-1500 mg / day, 25-1500 mg / day, 50-1500 mg / day, 75-1500 mg / day, 100-1500 mg / day, 200-1500 mg / day, 10-1000 mg / day, 20-1000 mg / day, 25-1000 mg / day, 50-1000 mg / day, 75-1000 mg / day, 100-1000 mg / day, 200-1000 mg / day, 25 -800mg / day, 50-800mg / day, 100-800mg / day, 200-800mg / day, 25-400mg / day, 50-400mg / day, 100-400mg / day, 200-400mg / day, or selected from 1mg / day, 5mg / day, 10mg / day, 20mg / day, 25mg / day, 50mg / day, 75mg / day, 100mg / day, 125mg / day, 150mg / day, 200mg / day, 400mg / day, 600mg / day, 800mg / day, 1000mg / day, 1200mg / day, 1400mg / day, 1500mg / day.

8. The use according to any one of claims 4-7, wherein the route of administration of the compound of formula (A) or its stereoisomers, tautomers, pharmaceutically acceptable salts or combinations thereof is selected from oral or topical administration.

9. A method for treating psoriasis and atopic dermatitis, the method comprising administering to a mammal an effective dose of a compound of formula (I) or formula (A) of any one of claims 1-6, or a stereoisomer, tautomer, pharmaceutically acceptable salt thereof, or a combination thereof, wherein the effective dose, calculated as free base, is 1-1500 mg / day, preferably 10-1500 mg / day, 20-1500 mg / day, 25-1500 mg / day, 50-1500 mg / day, 75-1500 mg / day, 100-1500 mg / day, 200-1500 mg / day, 10-1000 mg / day, 20-1000 mg / day, 25-1000 mg / day, 50-1000 mg / day, 75-1000 mg / day, 100- 1000mg / day, 200-1000mg / day, 25-800mg / day, 50-800mg / day, 100-800mg / day, 200-800mg / day, 25-400mg / day, 50-400mg / day, 100-400mg / day, 200-400mg / day, or selected from 1mg / day, 5mg / day, 10mg / day, 20mg / day, 25mg / day, 50mg / day, 75mg / day, 100mg / day, 125mg / day, 150mg / day, 200mg / day, 400mg / day, 600mg / day, 800mg / day, 1000mg / day, 1200mg / day, 1400mg / day, 1500mg / day; the route of administration is selected from oral or topical application.

10. The method according to claim 9, wherein the route of administration of the compound of formula (A) or its stereoisomers, tautomers, pharmaceutically acceptable salts or combinations thereof is selected from oral or topical application.

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