Application of tri-fused ring compound in preparation of medicine for preventing and / or treating inflammatory diseases

Abstract

The invention relates to application of a tri-fused ring compound in preparation of drugs for preventing and / or treating inflammatory diseases. Specifically, the invention relates to an application of at least one of a compound I, a pharmaceutically acceptable salt thereof, a deuterated substance thereof, a solvate thereof and a solvate of the pharmaceutically acceptable salt thereof in preparation of drugs for preventing and / or treating inflammatory diseases, the inflammatory diseases are one or more of moderate and severe active rheumatoid arthritis, moderate and severe atopic dermatitis and active ankylosing spondylitis. The compound can be used for effectively treating one or more of moderate-severe rheumatoid arthritis, moderate-severe atopic dermatitis and active ankylosing spondylitis.

Description

Application of tri-fused ring compounds in the preparation of drugs for preventing and / or treating inflammatory diseases

[0001] This application claims priority to the following Chinese patent applications: priority to Chinese patent application 2024101777798, filed on February 8, 2024; priority to Chinese patent application 202510084888X, filed on January 17, 2025.

[0002] This application cites the full text of the above-mentioned Chinese patent application. Technical Field

[0003] The present invention relates to the use of a tri-fused ring compound in preparing medicines for preventing and / or treating inflammatory diseases. Background Art

[0004] Rheumatoid arthritis (RA) is an autoimmune disease characterized by erosive joint inflammation that can occur at any age. The pathogenesis of RA remains unclear. The pathogenesis of RA includes abnormal B cell activation, T cell co-stimulation, osteoclast differentiation, and cytokine release.

[0005] The condition and course of RA are heterogeneous and can manifest as monoarthritis to polyarthritis. Furthermore, RA can affect internal organs beyond the joints, inducing complications such as cardiovascular disease, fractures, and malignant tumors, posing a significant challenge to the prevention, treatment, and long-term prognosis of RA. For patients, RA not only reduces their physical function, quality of life, and social participation, but also places a significant economic burden on their families and society. The overall goal of RA treatment is to improve symptoms of joint swelling and pain, control disease progression, reduce disability, and improve patient prognosis and quality of life.

[0006] According to the "Rheumatoid Arthritis Diagnosis and Treatment Guidelines" issued by the Chinese Medical Association in 2022, the current primary goal of RA treatment is clinical remission. For patients with long-term disease, low disease activity can be selected as an alternative treatment goal. RA treatment mainly relies on drugs. Current therapeutic drugs include small molecule therapeutic drugs, such as non-steroidal anti-inflammatory drugs (NSAIDs); glucocorticoids (GCs) and disease-modifying anti-rheumatic drugs (DMARDs); biological macromolecule therapeutic drugs, such as tumor necrosis factor α inhibitors, B cell inhibitors, cytokine receptor inhibitors, nuclear factor KB ligand receptor activators, etc.

[0007] Atopic dermatitis (AD) is a chronic, recurrent, inflammatory skin disease characterized by dry skin, chronic eczema-like lesions and obvious itching, which seriously affects the patient's mental health and quality of life, thereby increasing socioeconomic costs. The pathogenesis of AD is complex, mainly involving genetics, immune abnormalities, neuroimmune factors, skin barrier dysfunction and other aspects. The severe and stubborn itching of AD is the most unbearable symptom, which can lead to extensive scratching and damage the skin barrier function, causing viral or bacterial skin infections. AD will cause a considerable disease burden, and patients with moderate to severe AD will experience sleep disorders, physical pain and psychological suffering.

[0008] AD is a chronic, relapsing disease with no complete cure. Its treatment goals are to alleviate or eliminate clinical symptoms, eliminate predisposing and / or exacerbating factors, reduce and prevent relapses, and improve patients' quality of life. Treatments for AD primarily include topical medications and systemic medications. Topical medications for AD include topical corticosteroids (TCSs), topical calcineurin inhibitors (TCIs) such as tacrolimus and pimecrolimus, and topical phosphodiesterase 4 (PDE-4) inhibitors.

[0009] Ankylosing spondylitis (AS) is a chronic inflammatory disease that primarily affects the sacroiliac joints, spine, paraspinal soft tissues, and peripheral joints. It can be accompanied by extra-articular manifestations, and in severe cases, spinal deformity and ankylosis can occur. Sacroiliitis is a characteristic hallmark and early manifestation of AS, while enthesitis is a hallmark pathological change. In the late stages of spinal involvement, "bamboo joints" are a typical manifestation. AS has an insidious onset, with patients gradually experiencing low back pain or sacroiliac pain and / or stiffness. In the middle and late stages, it can be accompanied by spinal stiffness, deformity, and severe mobility limitations. AS reduces patients' quality of life and imposes a significant economic burden on patients, their families, and society.

[0010] There is currently no cure for AS. The clinical treatment goals are to relieve pain and stiffness, reduce inflammation, achieve or maintain remission or reduced activity, maintain good posture, prevent spinal and joint deformities, and correct joint deformities when necessary, ultimately improving and enhancing the patient's quality of life. Commonly used treatments include nonsteroidal anti-inflammatory drugs (NSAIDs), disease-modifying antirheumatic drugs (DMARDs), glucocorticoids, biologics, JAK inhibitors, and other medications.

[0011] However, existing drugs for treating rheumatoid arthritis, atopic dermatitis or ankylosing spondylitis have more or less safety or tolerability issues and cannot meet clinical needs.

[0012] In summary, in order to meet the clinical needs for the prevention and / or treatment of rheumatoid arthritis, atopic dermatitis and ankylosing spondylitis, it is necessary to provide more different types of drugs. Summary of the Invention

[0013] The technical problem to be solved by the present invention is to overcome the deficiency of the existing art in the variety of drugs for preventing and / or treating inflammatory diseases and to provide a tri-fused ring compound for use in the preparation of a drug for preventing and / or treating rheumatoid inflammatory diseases. The compound of the present invention is effective in treating one or more of moderate to severe rheumatoid arthritis, moderate to severe atopic dermatitis, and active ankylosing spondylitis. In particular, it is effective in treating moderate to severe active rheumatoid arthritis, moderate to severe atopic dermatitis, or active ankylosing spondylitis that has a poor response to or intolerance to csDMARDs.

[0014] The present invention solves the above technical problems through the following technical solutions.

[0015] The present invention provides a use of at least one of Compound I, its pharmaceutically acceptable salt, its deuterated form, its solvate, and its pharmaceutically acceptable salt solvate in the preparation of a medicament for preventing and / or treating an inflammatory disease, wherein the inflammatory disease is one or more of moderately to severely active rheumatoid arthritis, moderately to severely active atopic dermatitis, and active ankylosing spondylitis.

[0016] In one embodiment of the present invention, the active ingredient in the drug includes at least one of Compound I, its deuterated substance, its pharmaceutically acceptable salt, its solvate and its pharmaceutically acceptable salt solvate.

[0017] In one embodiment of the present invention, the active ingredient in the drug is at least one of Compound I, its deuterated substance, its pharmaceutically acceptable salt, its solvate and its pharmaceutically acceptable salt solvate.

[0018] There are currently two international classification standards for diagnosing RA: the 1987 ACR classification standard and the 2010 ACR / EULAR classification standard. This protocol uses the 2010 ACR / EULAR classification standard for rheumatoid arthritis, which is as follows:

[0019] Notes: 1. The new criteria are intended to categorize patients with new disease. Additionally, patients with a history of erosive disease, such as that typical of rheumatoid arthritis, who meet the 2010 criteria should be classified as having rheumatoid arthritis. Patients with long-standing disease, including those in an inactive phase (with or without treatment), who previously met the 2010 criteria based on retrospectively available data, should also be classified as having rheumatoid arthritis.

[0020] 2. The differential diagnosis varies with patient presentation, but systemic lupus erythematosus, psoriatic arthritis, and gout should be considered. If it is unclear which differential diagnoses should be considered, a rheumatologist should be consulted.

[0021] 3. Although patients with a score of less than 6 points cannot be classified as having rheumatoid arthritis, their status can be reassessed and may meet the criteria over time.

[0022] 4. Any joint swelling or tenderness detected during physical examination, confirmed by radiographic evidence of synovitis. The distal interphalangeal joints, first carpometacarpal joint, and first metatarsophalangeal joint are excluded from the assessment. Joint distribution is categorized based on the location and number of affected joints, with the joint most likely to be affected.

[0023] 5. Large joints refer to the shoulder, elbow, hip, knee and ankle joints.

[0024] 6. Small joints refer to the metacarpophalangeal joints, proximal interphalangeal joints, metatarsophalangeal joints 2-5, thumb interphalangeal joints and wrist joints.

[0025] 7. In this category, at least one affected joint must be a small joint; other joints may include any combination of large or additional small joints, such as joints not specifically listed elsewhere (temporomandibular joint, acromioclavicular joint, sternoclavicular joint, etc.).

[0026] 8. Negative means less than or equal to the upper limit of normal for the local laboratory. A low-titer positive refers to an IU value above the upper limit of normal but less than three times the upper limit of normal. A high-titer positive refers to an IU value greater than three times the upper limit of normal. When the RF value can only be positive or negative, a positive result should be classified as a low-titer positive.

[0027] 9. Normal or abnormal is determined according to local laboratory standards.

[0028] 10. Symptom duration refers to the duration of signs or symptoms of synovitis (such as pain, swelling, tenderness) in the affected joints as reported by the patient at the time of evaluation, regardless of whether treatment has been received.

[0029] The goal of RA treatment is to achieve disease remission or low disease activity, known as targeted therapy. The ultimate goal is to control the disease, reduce disability, and improve patients' quality of life. According to the 2010 European Union for the Advancement of Research (EULAR) recommendations, targeted therapy includes both clinical remission and low disease activity, as measured by the RA28 joint disease activity score (DAS28). Clinical remission is defined as DAS28 ≤ 2.6, low disease activity is 2.6 < DAS28 ≤ 3.2, moderate disease activity is 3.2 < DAS28 ≤ 5.1, and severe disease activity is DAS28 > 5.1.

[0030] In one embodiment of the present invention, the diagnostic criteria for moderate to severe active rheumatoid arthritis meet the following A1 and A2:

[0031] A1: According to the 2010 American College of Rheumatology (ACR) / European League Against Rheumatism (EULAR) classification criteria for rheumatoid arthritis (RA), the patient was diagnosed with RA and the disease duration was at least 3 months at the screening visit;

[0032] A2: In addition to A1, the following criteria are met: ≥6 swollen joints (SJC) (based on a 66-joint count) and ≥6 tender joints (TJC) (based on a 68-tender joint count) at screening and baseline visits; and erythrocyte sedimentation rate (ESR) ≥28 mm / h or central laboratory high-sensitivity C-reactive protein (hsCRP) ≥upper limit of normal at screening.

[0033] In a certain embodiment of the present invention, the moderately to severely active rheumatoid arthritis is moderately to severely active rheumatoid arthritis that responds poorly to or is intolerant to traditional synthetic disease-modifying antirheumatic drugs (csDMARDs).

[0034] The traditional synthetic disease-modifying antirheumatic drug is a conventional disease-modifying antirheumatic drug in the art, for example, one or more selected from methotrexate, sulfasalazine, leflunomide, chloroquine and hydroxychloroquine.

[0035] In one embodiment of the present invention, the patient is allowed to have used nonsteroidal anti-inflammatory drugs (such as aspirin) or glucocorticoids (such as corticosteroids, further such as prednisone) before using the drug.

[0036] In one embodiment of the present invention, the clinical diagnostic criteria for moderate to severe atopic dermatitis are as follows: atopic dermatitis is confirmed using validated diagnostic criteria, such as the Hanifin & Rajka criteria or the Williams criteria, and is diagnosed using severity assessment criteria. The severity is evaluated using four parameters: EASI score, IGA score, body surface area BSA, and pruritus NRS score. For moderate to severe patients, EASI score ≥16, IGA score ≥3, body surface BSA ≥10%, and pruritus NRS score ≥4 can be considered as criteria.

[0037] In one embodiment of the present invention, the clinical diagnostic criteria for moderate to severe atopic dermatitis are as follows: meeting 3 or more of the basic characteristics of the Hanifin & Rajka criteria, plus 3 or more of the secondary characteristics, and an EASI score ≥16, an IGA score ≥3, a body surface BSA ≥10%, and an itch NRS score ≥4.

[0038] Hanifin & Rajka standards are as follows:

[0039] Basic Features

[0040] 1. Itching;

[0041] 2. Typical rash morphology and distribution: lichenification or strip-like appearance on the flexural side in adults, and involvement of the face and extensor side in infants and children;

[0042] 3. Chronic or chronic recurrent dermatitis;

[0043] 4. Personal or family history of atopic diseases (asthma, allergic rhinitis and AD).

[0044] Secondary features

[0045] 1. Xeroderma;

[0046] 2. Ichthyosis / palmarism / keratosis pilaris;

[0047] 3. Immediate (type I) skin test reaction;

[0048] 4. Increased serum IgE;

[0049] 5. Early onset;

[0050] 6. Prone to skin infections (especially Staphylococcus aureus and herpes simplex) / impaired cell-mediated immunity;

[0051] 7. Tendency to nonspecific hand and foot dermatitis;

[0052] 8. Nipple eczema;

[0053] 9. Cheilitis;

[0054] 10. Recurrent conjunctivitis;

[0055] 11.Dennie-Morgan infraorbital crease;

[0056] 12. Keratoconus;

[0057] 13. Anterior subcapsular cataract;

[0058] 14. Periorbital dark circles;

[0059] 15. Pale face / facial erythema;

[0060] 16. Pityriasis alba;

[0061] 17. Anterior neck wrinkles;

[0062] 18. Itching when sweating;

[0063] 19. Wool is intolerant to lipid solvents;

[0064] 20. Peripapillary bulge;

[0065] 21. Food intolerance;

[0066] 22. The course of the disease is affected by environmental / emotional factors;

[0067] 23. White scratch sign / delayed blanching.

[0068] In one embodiment of the present invention, the patient with moderate to severe atopic dermatitis satisfies the following conditions B1 and B2:

[0069] B1: Patients with a history of atopic dermatitis for at least 1 year and who meet the diagnostic criteria for atopic dermatitis defined by Hanifin and Rajka at screening

[0070] B2: EASI ≥ 16, IGA score ≥ 3, and BSA involvement ≥ 10% at screening and baseline visits.

[0071] The 1984 revised New York criteria for AS are commonly used. For those who do not currently meet these criteria, reference can be made to the diagnostic criteria for spondyloarthropathies (SpA), primarily including the classification criteria for axial SpA recommended by Amor, the European Spondyloarthropathies Study Group (ESSG), and the 2009 ASAS. The 1984 revised New York criteria for ankylosing spondylitis used in this study are as follows:

[0072] Clinical criteria:

[0073] ① Lower back pain and stiffness persist for at least 3 months, and the pain improves with exercise but cannot be relieved by rest;

[0074] ② The lumbar spine is limited in its front-back and lateral flexion movements;

[0075] ③ The chest expansion range is smaller than the normal range related to age and gender.

[0076] Radiological criteria:

[0077] ④ Bilateral sacroiliitis grade II to IV, or unilateral sacroiliitis grade III to IV.

[0078] If the subject has ④ and any one of ① to ③, AS can be diagnosed.

[0079] Article 4: The usual grading standards for the severity of sacroiliitis based on X-rays are:

[0080] Level 0: Normal;

[0081] Level I: Suspicious;

[0082] Grade II: mild sacroiliitis;

[0083] Grade III: moderate sacroiliitis;

[0084] Grade IV: Ankylosis of the joints.

[0085] The Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) is the most widely used tool for assessing AS disease activity. Other assessment methods include the Ankylosing Spondylitis Disease Activity Score (ASDAS) and the Rapid Assessment of Daily Patients Index (RAPID3). When using the BASDAI to assess disease activity, patients are divided into a low-activity group (BASDAI <4) and a high-activity group (BASDAI ≥4).

[0086] In one embodiment of the present invention, the active ankylosing spondylitis satisfies the following criteria C1 and C2:

[0087] C1: According to the 1984 revised New York criteria for ankylosing spondylitis, the patient is diagnosed with AS (item 4 is present and any one of items 1) to 3) is additionally diagnosed with AS):

[0088] 1) Low back pain persists for at least 3 months, and the pain improves with activity but does not subside with rest;

[0089] 2) Limited lumbar spine movement in the anterior-posterior and lateral flexion directions;

[0090] 3) The chest expansion range is less than the normal value for the same age and gender;

[0091] 4) Bilateral sacroiliitis grade II to IV, or unilateral sacroiliitis grade III to IV

[0092] C2: Subjects had active disease at baseline, defined as follows: BASDAI score ≥ 4 and spinal pain score ≥ 4.

[0093] In one embodiment of the present invention, the active ankylosing spondylitis is active ankylosing spondylitis that is poorly responsive to, intolerant of, or contraindicated with nonsteroidal anti-inflammatory drugs.

[0094] The nonsteroidal anti-inflammatory drug can be a conventional nonsteroidal anti-inflammatory drug in the art, such as aspirin.

[0095] The administration route of the drug can be a conventional administration route in the art.

[0096] In one embodiment of the present invention, the drug is administered orally, parenterally or transdermally, preferably orally.

[0097] The dosage form of the drug can be a conventional drug dosage form in the art.

[0098] In one embodiment of the present invention, the dosage form of the drug is tablets, capsules, granules, pills, granules, syrups, solutions, suspensions, injections, emulsions or dispersions, such as capsules.

[0099] In the medicine, the content of the compound I can be a therapeutically effective amount.

[0100] In one embodiment of the present invention, the content of the compound I in the drug is 12×a mg or 12 / a mg, where a is any positive integer, such as 1, 2, 3, 4, 5 or 6, and further such as 1, 2 or 3.

[0101] In one embodiment of the present invention, the content of the compound I in the medicine is 1 to 84 mg.

[0102] In one embodiment of the present invention, the daily dosage of the compound I in the medicine is 1 to 84 mg.

[0103] In one embodiment of the present invention, the daily dose of Compound I in the drug is 24 mg, 48 mg or 72 mg, preferably 24 mg or 48 mg.

[0104] In one embodiment of the present invention, in the medicine, each dose of the compound I is 12 mg, 24 mg or 36 mg, preferably 12 mg or 24 mg.

[0105] In one embodiment of the present invention, the drug is administered once a day, twice a day, or three times a day, for example, twice a day.

[0106] In a certain embodiment of the present invention, in the drug, the daily dose of the compound I is 24 mg or 48 mg, the drug is administered twice a day, and each dose of the compound I is the same or different.

[0107] In one embodiment of the present invention, the drug is administered twice a day, and each dose of Compound I in the drug is 12 mg or 24 mg.

[0108] In one embodiment of the present invention, the drug is administered after a meal.

[0109] The present invention also provides a method for preventing and / or treating an inflammatory disease, comprising administering a therapeutically effective amount of a substance X to an individual in need thereof, wherein the substance X is at least one of Compound I, a deuterated substance thereof, a pharmaceutically acceptable salt thereof, a solvate thereof, and a solvate of a pharmaceutically acceptable salt thereof, wherein the disease is one or more of moderately to severely active rheumatoid arthritis, moderately to severely active atopic dermatitis, and active ankylosing spondylitis.

[0110] In one embodiment of the present invention, the patient with moderate to severe active rheumatoid arthritis meets the following criteria A1 and A2:

[0111] A1: According to the 2010 American College of Rheumatology (ACR) / European League Against Rheumatism (EULAR) classification criteria for rheumatoid arthritis (RA), the patient was diagnosed with RA and the disease duration was at least 3 months at the screening visit;

[0112] A2: In addition to A1, the following criteria are met: ≥6 swollen joints (SJC) (based on a 66-joint count) and ≥6 tender joints (TJC) (based on a 68-tender joint count) at screening and baseline visits; and erythrocyte sedimentation rate (ESR) ≥28 mm / h or central laboratory high-sensitivity C-reactive protein (hsCRP) ≥upper limit of normal at screening.

[0113] In a certain embodiment of the present invention, the moderately to severely active rheumatoid arthritis is moderately to severely active rheumatoid arthritis that is inadequately responsive to or intolerant to traditional synthetic disease-modifying antirheumatic drugs (csDMARDs).

[0114] The traditional synthetic disease-modifying antirheumatic drug is a conventional disease-modifying antirheumatic drug in the art, for example, one or more selected from methotrexate, sulfasalazine, leflunomide, chloroquine and hydroxychloroquine.

[0115] In one embodiment of the present invention, the patient is allowed to have used nonsteroidal anti-inflammatory drugs (such as aspirin) or glucocorticoids (such as corticosteroids, further such as prednisone) before using the drug.

[0116] In one embodiment of the present invention, the clinical diagnostic criteria for moderate to severe atopic dermatitis are as follows: diagnosis is made using validated diagnostic criteria, such as the Hanifin & Rajka criteria or the Williams criteria, and severity assessment criteria. The severity is evaluated by four parameters: EASI score, IGA score, body surface area BSA, and pruritus NRS score. For moderate to severe patients, EASI score ≥16, IGA score ≥3, body surface BSA ≥10%, and pruritus NRS score ≥4 can be considered as criteria.

[0117] In one embodiment of the present invention, the clinical diagnostic criteria for moderate to severe atopic dermatitis are as follows: meeting 3 or more of the basic characteristics of the Hanifin & Rajka criteria, plus 3 or more of the secondary characteristics, and an EASI score ≥16, an IGA score ≥3, a body surface BSA ≥10%, and an itch NRS score ≥4.

[0118] In one embodiment of the present invention, the patient with moderate to severe atopic dermatitis satisfies the following (1) and (2):

[0119] (1) Have a history of atopic dermatitis for at least 1 year and meet the diagnostic criteria for atopic dermatitis defined by Hanifin and Rajka at the time of screening

[0120] (2) EASI ≥ 16, IGA score ≥ 3, and BSA involvement ≥ 10% at screening and baseline visits.

[0121] In one embodiment of the present invention, the active ankylosing spondylitis meets the following criteria:

[0122] A: According to the 1984 revised New York criteria for ankylosing spondylitis, AS is diagnosed if the patient meets item 4 and any one of items 1) to 3) is present.

[0123] 1) Low back pain persists for at least 3 months, and the pain improves with activity but does not subside with rest;

[0124] 2) Limited lumbar spine movement in the anterior-posterior and lateral flexion directions;

[0125] 3) The chest expansion range is less than the normal value for the same age and gender;

[0126] 4) Bilateral sacroiliitis grade II-IV, or unilateral sacroiliitis grade III-IV;

[0127] B: Subjects had active disease at baseline, defined as follows: BASDAI score ≥ 4 and spinal pain score ≥ 4.

[0128] In one embodiment of the present invention, the active ankylosing spondylitis is active ankylosing spondylitis that is poorly responsive to, intolerant of, or contraindicated with nonsteroidal anti-inflammatory drugs.

[0129] The nonsteroidal anti-inflammatory drug can be a conventional nonsteroidal anti-inflammatory drug in the art, such as aspirin.

[0130] The administration method of the substance X can be a conventional administration method in the art.

[0131] In one embodiment of the present invention, the substance X is administered orally, parenterally or transdermally, preferably orally.

[0132] In one embodiment of the present invention, the substance X is administered in the form of tablets, capsules, granules, pills, granules, syrups, solutions, suspensions, injections, emulsions or dispersions, preferably in the form of capsules.

[0133] In one embodiment of the present invention, the substance X is administered at a dose of 12×a mg / day or 12 / a mg / day, based on the content of compound I, where a is any positive integer, such as 1, 2, 3, 4, 5 or 6, and further such as 1, 2 or 3.

[0134] In one embodiment of the present invention, the substance X is administered at a dosage of 1 to 84 mg / day based on the content of compound I.

[0135] In one embodiment of the present invention, based on the content of Compound I, the substance X is administered at a dose of 24 mg / day, 48 mg / day or 72 mg / day, preferably 24 mg / day or 48 mg / day.

[0136] In one embodiment of the present invention, the substance X is administered once a day, twice a day, or three times a day, for example, twice a day.

[0137] In one embodiment of the present invention, the substance X is administered at a dose of 24 mg / day or 48 mg / day based on the content of compound I. The dose is administered in two divided doses, and the doses each time are the same or different, preferably the same.

[0138] In one embodiment of the present invention, based on the content of Compound I, the substance X is administered at 12 mg / time, twice / day, or at 24 mg / time, twice / day.

[0139] In one embodiment of the present invention, the substance X is administered after a meal.

[0140] On the basis of conforming to the common sense in this field, the above-mentioned preferred conditions can be arbitrarily combined to obtain the preferred embodiments of the present invention.

[0141] The reagents and raw materials used in the present invention are commercially available.

[0142] The positive progress of the present invention is that the compounds of the present invention can effectively treat one or more of moderate to severe rheumatoid arthritis, moderate to severe atopic dermatitis and active ankylosing spondylitis, and are highly safe. In particular, they can effectively treat moderate to severe rheumatoid arthritis that has an inadequate response to or is intolerant to csDMARDs, or active ankylosing spondylitis that has a poor response to, is intolerant to, or is contraindicated with nonsteroidal anti-inflammatory drugs. DETAILED DESCRIPTION

[0143] The present invention is further illustrated by way of examples below, but the present invention is not limited to the scope of the examples. Experimental methods in the following examples where specific conditions are not specified were performed according to conventional methods and conditions, or selected according to the product specifications.

[0144] Clinical trials of compound I

[0145] Test drug: Compound I capsules, with a specification of 12 mg (content of Compound I).

[0146] The capsules can be prepared using conventional capsule preparation methods in the art, and the excipients used are also conventional excipients used in the art.

[0147] Part I: Indications: Moderately to severely active rheumatoid arthritis

[0148] 1. Evaluate the efficacy of compounds in the adjuvant-induced arthritis model of Lewis rats

[0149] 1.1 Specific experimental plan

[0150] Rheumatoid arthritis is a common autoimmune disease caused by an autoimmune response, leading to inflammation, damage, and deformity in the joints. In severe cases, it can cause a systemic inflammatory response. The adjuvant-induced arthritis rat model is a commonly used animal model in rheumatoid arthritis research and drug development. Its pathogenesis and clinical symptoms are similar to those of human rheumatoid arthritis. This model uses footpad injection of Mycobacterium tuberculosis to induce immune cells and antibodies with bone and joint damage, triggering a systemic response manifested by joint swelling, osteolysis, synovial damage, and other symptoms similar to those of human rheumatoid arthritis.

[0151] This experiment is intended to evaluate the therapeutic effect of Compound I on adjuvant-induced arthritis. This experiment is a total of 7 groups, namely normal group (Normal group), solvent control group (Vehicle group), compound 1mg / kg, 3mg / kg, 5mg / kg, 15mg / kg dosage group, positive drug tofacitinib group. Except the normal group, all rats were injected with adjuvant-induced arthritis subcutaneously in the left foot on the 0th day. On the 6th day, some rats began to show arthritis symptoms such as foot erythema or redness. According to the experimental protocol, on the 14th day, they were divided into groups according to body weight and score, and began to be administered for 14 days. The body weight, foot volume and clinical score of rats were monitored during the experiment. PK blood sampling was carried out at the experimental endpoint, and the right hind foot of rats was collected for H&E staining pathological analysis.

[0152] 1.2 Experimental Results

[0153] This study aims to evaluate the therapeutic effect of Compound I on adjuvant-induced arthritis and the relationship between the efficacy and pharmacokinetics of Compound I.

[0154] The results showed that the 3mg / kg, 5mg / kg, and 15mg / kg groups of Compound I had a certain effect on alleviating the weight loss trend caused by the onset of the disease in the animals, and significant differences were observed compared to the solvent control group from the 24th and 20th days, respectively. Compound I inhibited the increase in arthritis clinical scores and paw volume, and this inhibitory effect was dose-dependent. The 1mg / kg, 3mg / kg, 5mg / kg, and 15mg / kg groups of Compound I had an inhibitory effect on the increase in clinical scores and paw volume from the 20th, 18th, 16th, and 16th days, respectively, with significant differences compared to the solvent control group. The effect of 15mg / kg was the most obvious. The average arthritis clinical score of this group decreased from a peak of 4.9 points on the 14th day to 1.8 points at the end of the experiment on the 27th day. The average pathology score of this group was 3.9 points, which was significantly improved compared to the solvent control group, with an inhibition rate of 75.63%.

[0155] Area under the plasma concentration-time curve (AUC) of each compound I group 0-last They are 114, 306, 805, and 2790 h*ng / ml, respectively, showing a good linear relationship with the efficacy results.

[0156] 2. A Phase Ib clinical study to evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamics of a compound of Formula I in subjects with rheumatoid arthritis (RA) using a multiple-dose, randomized, double-blind, dose-escalation, placebo-controlled regimen.

[0157] 2.1 Enrolled Population

[0158] Subjects must be between 18 and 70 years old, diagnosed with rheumatoid arthritis and meet the ACR / EULAR 2010 classification criteria, have C-reactive protein or high-sensitivity C-reactive protein (CRP / hsCRP) ≥ the upper limit of normal at screening, and have ≥4 swollen and / or painful joints (based on a 66-joint count) at screening and baseline visits.

[0159] Major exclusion criteria included use of a JAK inhibitor within 4 weeks before the first dose; any systemic inflammatory disease other than RA; intraarticular, intramuscular, intravenous, trigger point or tender point, intracapsular, or intratendonal glucocorticoid therapy within 8 weeks before the first dose; and active TB, a history of TB, or occult TB without appropriate prophylaxis.

[0160] 2.2 Dosage regimen

[0161] The study included three dose groups of Compound I: 7 subjects in the 12 mg group, 12 subjects in the 24 mg group, and 7 subjects in the 36 mg group. Twelve subjects also received a placebo. Dosing was twice daily for 28 consecutive days, with a single dose on day 28. The study evaluated the safety, tolerability, pharmacokinetics, and pharmacodynamics of the compound of Formula I capsule after multiple doses, and also explored its efficacy.

[0162] 2.3 Test results

[0163] Tolerability and safety conclusions

[0164] This trial demonstrated good safety and tolerability across all dose groups after repeated dosing. Compound I (12 mg to 36 mg) was well tolerated in Chinese subjects. No severe or fatal TEAEs occurred. No subjects withdrew prematurely from the study due to AEs.

[0165] Pharmacokinetic conclusions

[0166] After multiple oral administration of 12mg-36mg of Compound I to Chinese subjects, it was rapidly absorbed, with a median T max The average t of plasma compound I was 2h-3h. 1 / 2 After multiple administrations, steady state was achieved after Day 2, with little accumulation. The plasma exposure of compound I (C max The AUC and AUC increased in a dose-proportional manner with increasing doses.

[0167] Pharmacodynamics and effectiveness conclusions

[0168] After administration of Compound I to the 12-36 mg dose group and placebo, the placebo group showed no inhibitory effect on the pSTAT3 (pharmacodynamic) marker, while the 12-36 mg dose group achieved maximum pSTAT3 inhibition between 2 and 4 hours. The pSTAT3 inhibition rate increased with increasing Compound I plasma concentrations and then plateaued. CRP and ESR decreased to varying degrees compared to the placebo group, with the magnitude of decrease increasing with increasing dose. Compound I doses of 12-36 mg also showed varying degrees of improvement in ACR20 response rates, as well as DAS28 (CRP) and DAS28 (ESR). This suggests that Compound I exerted its efficacy, improving rheumatoid arthritis activity in subjects, with a dose-dependent trend. The 24 and 36 mg doses showed greater efficacy over a short treatment period, and the efficacy of Compound I at 24 and 36 mg reached saturation.

[0169] 3. A randomized, double-blind, placebo-controlled, multicenter Phase II clinical study to evaluate the efficacy and safety of Compound I as shown in Formula I in subjects with moderate to severe active rheumatoid arthritis who have poor efficacy or intolerance to csDMARDs

[0170] 3.1 Enrolled Population

[0171] Participants must be between 18 and 70 years of age, have been diagnosed with RA for ≥3 months, and meet the ACR / EULAR 2010 criteria for moderately to severely active RA. Moderately to severely active RA is defined as: a C-reactive protein (CRP) level greater than the upper limit of normal (ULN) or an erythrocyte sedimentation rate (ESR) ≥28 mm / h, ≥6 swollen joints (based on a 66-joint count) and ≥6 tender joints (based on a 68-joint count) at screening and baseline.

[0172] Eligible subjects must have had an inadequate response to at least one of the following conventional synthetic disease-modifying antirheumatic drugs (csDMARDs): methotrexate, sulfasalazine, and leflunomide, and had received at least 3 months of background therapy with up to two csDMARD combinations (excluding the combination of MTX and leflunomide) at least 4 weeks prior to the first dose of study drug. Subjects on stable doses of nonsteroidal anti-inflammatory drugs (NSAIDs) or oral or inhaled corticosteroids (≤10 mg / day of prednisone equivalents) were permitted. Major exclusion criteria included prior use of JAK inhibitors; a current diagnosis of a systemic inflammatory disease other than rheumatoid arthritis; receipt of intra-articular, intramuscular, intravenous, trigger point or tender point, intracapsular, or intratendinous corticosteroids within 8 weeks prior to randomization; active TB; or occult but inadequately treated TB.

[0173] 3.2 Experimental plan

[0174] This study is a multicenter, randomized, double-blind, placebo-controlled Phase II clinical trial evaluating the efficacy and safety of Compound I in the treatment of moderately to severely active rheumatoid arthritis (RA) in subjects with an inadequate response or intolerance to csDMARDs. A total of 150 subjects are planned to be enrolled. The study will be divided into three phases:

[0175] Screening period: Day 35 to Day 1: Screen the subjects and verify the inclusion and exclusion criteria. Those who meet the requirements can enter the treatment period.

[0176] Treatment period: Week 0 to Week 24:

[0177] Phase I: The inclusion and exclusion criteria were reassessed on D1, and all subjects who met the inclusion criteria were randomly assigned to Compound I capsule 12 mg (low-dose group), Compound I capsule 24 mg (high-dose group), and placebo group in a ratio of 1:1:1. The subjects took the corresponding dose of Compound I capsule and / or placebo orally twice a day for 12 consecutive weeks.

[0178] The primary endpoint analysis for the Phase 1 study is planned to be conducted when all subjects have completed 12 weeks of follow-up.

[0179] Phase II: At week 13, subjects in the placebo group were randomly redistributed in a 1:1 ratio to receive Compound I low-dose or Compound I high-dose twice daily for 12 consecutive weeks, up to week 24. Subjects in the original experimental groups (low-dose and high-dose groups) will continue to maintain their original dose treatment until week 24.

[0180] Follow-up period: Subjects who completed the study treatment or withdrew from the study early entered the safety follow-up period. Subjects who completed the study treatment were required to come to the hospital for follow-up within 4 weeks after the last dose of the drug. Subjects who withdrew from the study early were required to come to the hospital for follow-up within 7 days after deciding to withdraw from the study.

[0181] 3.3 Data Analysis

[0182] Efficacy analyses were based on data sets that included all randomized subjects who received at least one dose of study drug. Safety analyses were based on data sets that included subjects who received at least one dose of study drug.

[0183] For the first-stage binary efficacy endpoints, 95% confidence intervals (95% CIs) were calculated using the Clopper-Pearson method. Nonresponder imputation (NRI) was used for missing data on the binary efficacy endpoints. Binary efficacy endpoints were compared between treatment groups using the Cochran-Mantel-Haenszel (CMH) method, and P values ​​were calculated. For the first-stage continuous efficacy endpoints, repeated-measures mixed linear models (MMRMs) were used. The models included treatment group, visit, randomization stratification factor, and the interaction term between visit and treatment group as fixed effects, with baseline score as a covariate. The least-squares means (LSMs) of the differences between treatment groups and their corresponding 95% CIs were calculated.

[0184] The efficacy analysis in the second stage was mainly based on descriptive statistics. For binary efficacy endpoints, the 95% CI of the percentage of responding subjects was calculated based on the Clopper Pearson method.

[0185] 3.4 Test results

[0186] 3.4.1 Patient distribution

[0187] All 156 randomized participants were included in the analysis. The mean age of the 156 participants was 52.4 years, 76.9% were female, and the mean time from RA diagnosis to randomization was 6.6 years. Most participants had RA functional status II (71.2%), were positive for rheumatoid factor (RF) (87.8%), and were positive for anti-cyclic citrullinated peptide antibodies (ACPA) (85.9%). The mean DAS28-CRP score was 5.9, the mean TJC68 count was 22.3, the mean SJC66 count was 13.3, and the mean hsCRP was 27.3 mg / L. Baseline characteristics were similar across treatment groups.

[0188] 3.4.2 Efficacy

[0189] 3.4.2.1 Phase II Clinical Trial Efficacy of Compound I

[0190] At week 1, compared with the placebo group, the proportion of subjects achieving ACR20 remission in the 12 mg and 24 mg groups of Compound I was significantly higher than that in the placebo group; at week 12, compared with the placebo group, the proportion of subjects achieving the primary endpoint ACR20 in the 12 mg and 24 mg groups of Compound I was significantly higher than that in the placebo group, and the number of subjects achieving ACR50 and ACR70 remission in the Compound I group (12 mg or 24 mg) was significantly higher than that in the placebo group. The proportion of subjects with DAS28 (CRP) ≤ 3.2 and DAS28 (CRP) < 2.6 in the 12 mg and 24 mg groups of Compound I at week 12 was significantly higher than that in the placebo group. The details are shown in Table 1 below:

[0191] Table 1

[0192] Compared with the placebo group, * p<0.05, ** p<0.01, *** p<0.001, **** p<0.0001.

[0193] At week 24, the ACR20 response rates in the 12 mg and 24 mg groups of Compound I were 91.1% and 90.7%, respectively.

[0194] 3.4.2.2 Comparison of Compound I with other marketed drugs

[0195] After 12 weeks of continuous treatment, indirect comparison with clinical trial data from other marketed RA treatments of the same phase (comparing placebo-adjusted ACR20 / ACR50 / ACR70 response rates) showed that the overall efficacy of the 12 mg group of Compound I was similar to that of upadacitinib, while the efficacy of the 24 mg group of Compound I was slightly superior to that of other marketed RA treatments. This is shown in Table 2 below:

[0196] Table 2

[0197] Phase II efficacy results from the 24-week study showed that Compound I 12mg and 24mg demonstrated stable improvements in ACR20 and disease activity, with ACR20 response rates exceeding 90%. Response rates for the efficacy indicators of partial deep remission (ACR50 and ACR70) reached as high as 74.4% and 42.4%, respectively, and the response rates continued to rise. Compared with approved JAK inhibitors, the ACR20 response rate at 12mg, as well as the ACR20 and ACR50 response rates at 24mg, were slightly superior to those of upadacitinib 15mg QD and other approved JAK inhibitors. Other efficacy indicators were similar to those of upadacitinib.

[0198] 3.4.3 Security

[0199] Treatment-emergent adverse events (TEAEs) were low grade after 12 weeks of treatment (as detailed in Table 3), with hyperlipidemia being the most frequently reported TEAE in subjects receiving Compound I. However, the HDL / LDL ratio did not change during the study.

[0200] Table 3

[0201] No venous thromboembolism, major adverse cardiovascular events, serious infections, malignancies, or deaths were reported within 24 weeks.

[0202] Part II: Indications for moderate to severe atopic dermatitis

[0203] 1. Pharmacodynamics of Compound I in a mouse atopic dermatitis model

[0204] In this study, oxazolone (OXA) was topically applied to BALB / c mice to establish an atopic dermatitis animal model, and the in vivo efficacy of Compound I in this model was evaluated.

[0205] Sixty-five animals were randomly divided into seven groups based on body weight. Except for the G1 non-modeling group, which consisted of five animals, the remaining six groups each included ten animals. All sensitized animals were subjected to continuous OXA challenge to induce dermatitis-like lesions. Group G2 served as a vehicle-treated model (negative) control group; G3 served as a dexamethasone (DXM, 0.09%) positive control group; Groups G4 to G6 received low (3 mg / kg), medium (10 mg / kg), and high (30 mg / kg) doses of Compound I, respectively; and Group G7 received upadacitinib (10 mg / kg). The experimental results showed that the animals tolerated the treatment with Compound I well during the experiment. Compound I at medium (10 mg / kg) and high (30 mg / kg) doses exhibited significant pharmacodynamic inhibition of AD-like symptoms, comparable to the positive small molecule DXM.

[0206] 2. Phase Ib data for atopic dermatitis subjects

[0207] 2.1 Enrolled Population

[0208] Subjects must be between 18 and 65 years old, meet the Hanifin & Rajka diagnostic criteria for atopic dermatitis (AD), and have a history of AD for ≥ 6 months before screening.

[0209] The main exclusion criteria included the use of JAK inhibitors within 6 months before dosing; any systemic inflammatory disease other than RA; any systemic disease or other active skin disease (such as psoriasis, seborrheic dermatitis, lupus erythematosus) that may affect the evaluation of trial results; receiving systemic treatment for AD within 4 weeks before dosing; and active TB.

[0210] 2.2 Clinical trial plan

[0211] The study enrolled three dose groups of Compound I: seven subjects in the 12 mg group, seven in the 24 mg group, and seven in the 36 mg group. Nine subjects also received a placebo. Dosing was twice daily for 14 consecutive days, with a single dose at breakfast on the 14th day. The study evaluated the safety, tolerability, pharmacokinetics, and pharmacodynamics of Compound I capsules (as represented by Formula I) after multiple doses, and also explored their efficacy.

[0212] 2.3 Test results

[0213] After continuous administration of Compound I to subjects in each dose group (12 mg, 24 mg, 36 mg BID), the trough concentrations from Day 2 to Day 14 remained within a small range. PK parameter T after the first dose and multiple doses max 、C max , AUC 0-inf , CL / F were basically the same. Compound I did not accumulate in the body after multiple administrations. In the dose range of 12mg-36mg, the PK exposure parameters of Compound I (C max , AUC 0-t and AUC 0-inf ) increased in a dose-proportional manner.

[0214] Using E max The model explored and constructed a dose-effect relationship between the plasma concentration of compound I and the pSTAT3 inhibition rate. The pSTAT3 inhibition rate increased with the increase of the plasma concentration of compound I and then tended to be flat. EC 50 It is 37.7094ng / mL.

[0215] Within the dosage range of 12 mg-36 mg, compound I administered twice daily for 14 consecutive days had a significant improvement effect on multiple atopic dermatitis disease activity indicators (including EASI score, pruritus NRS score, IGA score, etc.), and showed a certain dose-related effect.

[0216] 3. Phase II data for atopic dermatitis subjects

[0217] 3.1 Enrolled Population

[0218] Subjects must be between 18 and 75 years old, have a history of AD for at least 1 year at screening and meet the Hanifin-Rajka diagnostic criteria at screening; at screening and baseline, according to the investigator's assessment, meet the criteria for moderate to severe AD: EASI > 16 points; IGA score ≥ 3 points; BSA (body surface area) ≥ 10%.

[0219] Eligible subjects were required to have recently (within 6 months prior to screening) received topical AD treatment with an inadequate clinical response or received systemic AD treatment, as determined by the investigator; and be able and willing to use only a stable dose of topical mild emollients starting at least 7 days prior to baseline and continuing during the study. Major exclusion criteria included the presence of other skin comorbidities other than AD that could interfere with study assessments; previous systemic use of JAK inhibitors; active TB; or occult TB that was not adequately treated.

[0220] 3.2 Clinical trial plan

[0221] This trial includes a screening period, a dosing observation period, and a follow-up period:

[0222] All subjects who met the inclusion criteria were randomly divided into three dose groups (12 mg, 24 mg and placebo group) at a ratio of 1:1:1, with 50 subjects in each dose group, for a total of 150 subjects.

[0223] All dose groups received oral administration of the study drug or placebo twice a day (BID) for 12 consecutive weeks. The study dosing schedule is as follows:

[0224] Abbreviation: BID = twice a day

[0225] The subjects signed an informed consent form (ICF) and completed the screening examination. Those who were evaluated and determined to meet the criteria entered the 12-week dosing observation period. After completing the dosing observation period, the subjects entered a 4-week safety follow-up period.

[0226] 3.3 Data Analysis

[0227] Efficacy analyses were based on data sets that included all randomized subjects who received at least one dose of study drug. Safety analyses were based on data sets that included all randomized subjects who received at least one dose of study drug and had at least one safety assessment.

[0228] For continuous efficacy endpoints, an ANCOVA model was used with baseline score as a covariate to calculate the difference in LSM between treatment groups and its 95% confidence interval (CI). P values ​​for between-group comparisons were reported. The last observation carried forward (LOCF) method was used for missing data on continuous efficacy endpoints. For binary efficacy endpoints, 95% confidence intervals (95% CIs) were calculated based on the Clopper-Pearson method, and P values ​​for between-group comparisons were reported using the Pearson chi-square method. Non-responder imputation (NRI) was used for missing data on binary efficacy endpoints.

[0229] 3.4 Experimental Results

[0230] In a Phase II clinical study of Compound I, 150 subjects with moderate to severe AD were enrolled and randomly assigned to the 12 mg, 24 mg, and placebo groups in a 1:1:1 ratio. All subjects received Compound I capsules or placebo orally twice daily for 12 weeks. The primary efficacy endpoint of the study was the percentage change in EASI score from baseline at Week 12.

[0231] The results showed that after 12 weeks of continuous treatment with Compound I capsules in AD patients (N=150), the LSM (standard error [SEM]) of the percentage change from baseline in the EASI score of the subjects in the 12mg, 24mg and placebo groups were -74.6% (4.32%), -82.6% (4.26%) and -51.2% (4.27%), respectively. The differences between the 12mg and 24mg groups compared with the placebo group were statistically significant (p values ​​< 0.001), and the percentage change from baseline in the EASI score in the 24mg group was higher than that in the 12mg group. In other efficacy indicators, including IGA response, EASI-50 / 75 response, itching NRS response, etc., the overall efficacy of the two dose groups of Compound I was significantly better than that of placebo.

[0232] 4. Summary safety data of subjects with atopic dermatitis

[0233] Compound I has completed two studies in AD patients: a Phase Ib study and a Phase II study conducted in China. A total of 121 AD patients received Compound I treatment.

[0234] The majority of TEAEs were Grade 1-2. Seven subjects (5.8%) experienced CTCAE Grade 3 TEAEs, and no subjects experienced Grade 3 or higher TEAEs. Three subjects (2.5%) experienced SAEs, of which only one (herpes zoster) was judged by the investigator to be related to the study drug. Two subjects experienced TEAEs leading to discontinuation of treatment, both of which were judged by the investigator to be related to the study drug. No major adverse cardiovascular events, thrombosis, gastrointestinal perforation, or malignancy were reported during this study, and no deaths occurred.

[0235] Part III: Indications for active ankylosing spondylitis

[0236] 1. Phase I clinical trial

[0237] 1.1 Enrolled Population

[0238] Participants were required to be between 18 and 75 years of age, diagnosed with AS according to the 1984 revised New York criteria for ankylosing spondylitis, and to have active AS. Participants had active disease at baseline, defined as a BASDAI score ≥ 4 and a spinal pain score ≥ 4. Participants had received nonsteroidal anti-inflammatory drugs (NSAIDs) but still had active AS, or had a poor response to, intolerance to, or contraindications to NSAIDs. Participants could be biologic-naive or had previously received up to one biologic. Participants who had previously received biologics must be resistant or intolerant to the biologic and must have undergone a washout period. Major exclusion criteria included prior use of JAK inhibitors; active fibromyalgia or panspondyloarthritis ("bamboo spine"); or any other inflammatory arthritis, such as rheumatoid arthritis, systemic lupus erythematosus, or sarcoidosis. Participants also had active TB or inadequately treated TB.

[0239] 1.2 Clinical Trial Plan

[0240] This study is divided into two phases, with each treatment phase lasting 12 weeks, for a total of 24 weeks. The first phase is a placebo-controlled, double-blind trial with three experimental groups: two high-dose and low-dose Compound I treatment groups (12 mg and 24 mg) and a placebo group for comparison. Eligible subjects with active AS will be randomly assigned to one of the three treatment groups to observe the preliminary efficacy and safety of Compound I at different doses. The second phase will be a double-blind trial with only two high-dose and low-dose treatment groups (12 mg and 24 mg). Following the efficacy evaluation in the first phase, the efficacy and safety of Compound I will continue to be observed.

[0241] Phase I study of treatment

[0242] Phase I will enroll approximately 174 subjects across three trial groups: Compound I 12 mg, Compound I 24 mg, and placebo, with approximately 58 subjects in each group. Qualified subjects will be randomly assigned to one of the three groups in a 1:1:1 ratio. All subjects will receive the trial drug or placebo twice daily (BID) for up to 12 weeks. The treatment schedule for Phase I is shown in the table below:

[0243] *BID = twice daily dosing.

[0244] After all Phase 1 subjects complete the 12-week visit, an independent, open-label statistical team will conduct an analysis of the Phase 1 study. The analysis will include efficacy and safety data collected from Visit 1 through the 12-week dosing visit. A detailed protocol will be developed to describe the relevant processes and content.

[0245] Phase II study of treatment

[0246] In the second phase, only two Compound I treatment groups (12 mg and 24 mg) will be retained. In the previous phase, subjects who received Compound I will be reallocated to different dose treatment groups based on the ASAS40 response [For subjects who received trial drug treatment: subjects who achieved an ASAS40 response compared to baseline (defined as responders) will start receiving 12 mg of trial drug treatment at week 13. Subjects who did not achieve an ASAS40 response compared to baseline (defined as non-responders) will start receiving 24 mg of trial drug treatment at week 13]. The placebo group will be randomly assigned 1:1 to Compound I 12 mg and 24 mg treatment groups to receive Compound I treatment. All subjects will receive oral administration, BID, and continue to receive treatment for 12 weeks, or withdraw if they meet the withdrawal criteria.

[0247] A 4-week follow-up period was conducted after the completion of Phase 2.

[0248] 1.3 Data Analysis

[0249] Efficacy analyses were based on data sets that included all randomized subjects who received at least one dose of study drug. Safety analyses were based on data sets that included all randomized subjects who received at least one dose of study drug and had at least one safety assessment.

[0250] For binary efficacy endpoints in the first phase, 95% confidence intervals (95% CIs) were calculated using the Clopper-Pearson method, and P values ​​for between-group comparisons were reported using Pearson chi-square. Nonresponder imputation (NRI) was used for missing data for binary efficacy endpoints. For continuous efficacy endpoints in the first phase, repeated measures mixed linear models (MMRMs) were used, with group, visit, and the interaction term between visit and group as fixed effects and baseline score as a covariate. The least-squares means (LSMs) between treatment groups were calculated, along with their corresponding 95% CIs.

[0251] The efficacy analysis in the second stage was mainly based on descriptive statistics. For binary efficacy endpoints, the 95% CI of the percentage of responding subjects was calculated based on the Clopper Pearson method.

[0252] 1.4 Summary Safety Data of Ankylosing Spondylitis Subjects

[0253] Compound I completed a Phase II study in patients with AS. In the pooled analysis, data from the entire study period (i.e., Week 0-Week 24) were included in the analysis. However, for subjects who switched from placebo to the Compound I group in Phase 2, only data after the first dose of Compound I were included. The Compound I 12 mg group included subjects who received Compound I 12 mg in both Phase 1 and Phase 2, as well as subjects who switched from placebo to Compound I 12 mg in Phase 2. The same logic was used for the Compound I 24 mg group. In addition, subjects who received Compound I 12 mg in Phase 1 but did not enter Phase 2 were included in the Compound I 12 mg-12 mg group and the Compound I 12 mg group for analysis. The same logic was used for subjects who received Compound I 24 mg in Phase 1 but did not enter Phase 2. A total of 170 patients with AS received Compound I.

[0254] The majority of TEAEs were Grade 1-2. Six subjects (3.5%) experienced TEAEs of CTCAE Grade 3 or higher. Four subjects (2.4%) experienced SAEs, of which only one (infectious pneumonia) was judged by the investigator to be related to the study drug. Only one subject (0.6%) discontinued the drug due to infectious pneumonia, which was judged by the investigator to be related to the study drug. No major adverse cardiovascular events, thrombosis, gastrointestinal perforation, malignant tumors, or other safety events were reported during this study, and no deaths occurred.

[0255] 1.5 Summary of effectiveness data for ankylosing spondylitis

[0256] The Phase II study in patients with active AS was a multicenter, randomized, double-blind, placebo-controlled study (N=177). The study was divided into two phases. The first phase was a placebo-controlled, double-blind trial with three experimental groups: two treatment groups (12 mg and 24 mg) of Compound I and a placebo group. Eligible active AS subjects were randomly assigned to one of the three treatment groups and received the corresponding study treatment for 12 weeks. In the second phase, all subjects received either 12 mg BID or 24 mg BID of Compound I.

[0257] A total of 163 subjects (92.1%) completed the first phase of treatment and all received the second phase of treatment, and 162 subjects (91.5%) completed the second phase of study treatment. The results showed that at 12 weeks of treatment, the ASAS40 response rate (primary endpoint) and 95% CI were 27.6% (16.7%, 40.9%) in the 12 mg group, 35.6% (23.6%, 49.1%) in the 24 mg group, and 11.7% (4.8%, 22.6%) in the placebo group. Both the 12 mg group and the 24 mg group were significantly higher than the placebo group. The inter-group ratio differences (95% CI) between the 12 mg group and the 24 mg group and the placebo group were 15.9% (1.8%, 30.0%) and 23.9% (9.3%, 38.6%), respectively, with p values ​​of 0.0291 and 0.0021, respectively. The response rate of the 24 mg group was numerically higher than that of the 12 mg group (p = 0.3517). In other efficacy indicators, including ASAS20, ASAS 5 / 6 response rate, ASDAS-CRP, ASDASESR, BASDAI, CRP, ESR, etc., compound I also showed significant improvement effects. The quality of life of subjects treated with compound I was significantly improved. In the second phase, all subjects received compound I treatment for 24 weeks, and clinical responses, disease activity and quality of life were continuously controlled and improved.

[0258] Although the above describes specific embodiments of the present invention, it should be understood by those skilled in the art that these are merely illustrative and that various changes or modifications may be made to these embodiments without departing from the principles and essence of the present invention. Therefore, the scope of protection of the present invention is defined by the appended claims.

Claims

1. Use of at least one of Compound I, its pharmaceutically acceptable salt, its deuterated form, its solvate, and its pharmaceutically acceptable salt solvate in the preparation of a medicament for preventing and / or treating an inflammatory disease, wherein the inflammatory disease is one or more of moderately to severely active rheumatoid arthritis, moderately to severely active atopic dermatitis, and active ankylosing spondylitis.

2. The use according to claim 1, characterized in that It meets one or more of the following conditions: (1) The drug wherein the active ingredient comprises at least one of Compound I, a deuterated form thereof, a pharmaceutically acceptable salt thereof, a solvate thereof, and a solvate of a pharmaceutically acceptable salt thereof; (2) The corresponding patient diagnostic criteria for moderate to severe active rheumatoid arthritis meet A1 and A2: A1: According to the 2010 American College of Rheumatology (ACR) / European League Against Rheumatism (EULAR) classification criteria for rheumatoid arthritis (RA), the patient was diagnosed with RA and the disease duration was at least 3 months at the screening visit; A2: In addition to A1, the following criteria are met: ≥6 swollen joints (SJC) (based on a 66-joint count) and ≥6 tender joints (TJC) (based on a 68-tender joint count) at screening and baseline visits; and erythrocyte sedimentation rate (ESR) ≥28 mm / h or central laboratory high-sensitivity C-reactive protein (hsCRP) ≥upper limit of normal at screening; (3) The moderate to severe active rheumatoid arthritis is moderate to severe rheumatoid arthritis that responds poorly or is intolerant to traditional synthetic disease-modifying antirheumatic drugs; (4) The diagnostic criteria for moderate to severe atopic dermatitis are as follows: meeting 3 or more of the basic features and 3 or more of the minor features of the Hanifin & Rajka criteria, and EASI score ≥ 16, IGA score ≥ 3, body surface BSA ≥ 10%, and pruritus NRS score ≥ 4; (5) The active ankylosing spondylitis meets the following criteria C1 and C2: C1: According to the 1984 revised New York criteria for ankylosing spondylitis, the patient is diagnosed with AS (item 4 is present and any one of items 1) to 3) is additionally diagnosed with AS): 1) Low back pain persists for at least 3 months, and the pain improves with activity but does not subside with rest; 2) Limited lumbar spine movement in the anterior-posterior and lateral flexion directions; 3) The chest expansion range is less than the normal value for the same age and gender; 4) Bilateral sacroiliitis grade II to IV, or unilateral sacroiliitis grade III to IV; Among them, the grading standards for the degree of sacroiliitis on X-ray films are: Level 0: Normal; Level I: Suspicious; Grade II: mild sacroiliitis; Grade III: moderate sacroiliitis; Grade IV: Ankylosis of joint fusion; C2: Subjects had active disease at baseline, defined as follows: BASDAI score ≥ 4 and spinal pain score ≥ 4.

3. The use according to claim 1, characterized in that It meets one or more of the following conditions: (1) The active ingredient of the drug is at least one of Compound I, its deuterated form, its pharmaceutically acceptable salt, its solvate, and its pharmaceutically acceptable salt solvate; (2) The moderate to severe active rheumatoid arthritis is moderate to severe rheumatoid arthritis that responds poorly or is intolerant to traditional synthetic disease-modifying antirheumatic drugs, wherein the traditional synthetic disease-modifying antirheumatic drugs are selected from one or more of methotrexate, sulfasalazine, leflunomide, chloroquine and hydroxychloroquine; (3) The diagnostic criteria for moderate to severe atopic dermatitis meet the following B1 and B2: B1: Patients have a history of atopic dermatitis for at least 1 year and meet the diagnostic criteria for atopic dermatitis defined by Hanifin and Rajka criteria at screening; B2: EASI ≥16, IGA score ≥3, and BSA involvement ≥10% at screening and baseline visits; (4) The active ankylosing spondylitis is active ankylosing spondylitis that is poorly responsive to, intolerant of, or contraindicated for nonsteroidal anti-inflammatory drugs, such as aspirin.

4. The use according to at least one of claims 1 to 3, characterized in that It meets one or more of the following conditions: (1) The drug is administered orally, parenterally or transdermally, preferably orally; (2) The drug is in the form of tablets, capsules, granules, pills, granules, syrups, solutions, suspensions, injections, emulsions or dispersions, such as capsules; (3) In the drug, for example, the content of the compound I is 1 to 84 mg; (4) In the drug, the daily dose of Compound I is 1 to 84 mg; for example, the daily dose of Compound I is 24 mg, 48 mg, or 72 mg, preferably 24 mg or 48 mg; (5) In the drug, each dose of Compound I is 12 mg, 24 mg or 36 mg, preferably 12 mg or 24 mg; (6) The drug is administered once a day, twice a day, or three times a day, for example, twice a day.

5. The use according to at least one of claims 1 to 3, characterized in that It meets one or more of the following conditions: (1) In the drug, the content of Compound I is 12×a mg or 12 / a mg, where a is any positive integer, such as 1, 2, 3, 4, 5 or 6, further such as 1, 2 or 3; (2) In the drug, the daily dose of Compound I is 24 mg or 48 mg, the drug is administered twice daily, and the doses of Compound I are the same or different; preferably, the drug is administered twice daily, and the dose of Compound I is 12 mg or 24 mg; (3) The drug is administered after meals.

6. A method for preventing and / or treating an inflammatory disease, comprising administering to a subject in need thereof a therapeutically effective amount of a substance X, wherein the substance X is at least one of Compound I, a deuterated substance thereof, a pharmaceutically acceptable salt thereof, a solvate thereof, and a solvate of a pharmaceutically acceptable salt thereof, wherein: The disease is one or more of moderate to severe active rheumatoid arthritis, moderate to severe atopic dermatitis and active ankylosing spondylitis.

7. The method according to claim 6, wherein It meets one or more of the following conditions: (1) The patient with moderate to severe active rheumatoid arthritis meets the following criteria A1 and A2: A1: According to the 2010 American College of Rheumatology (ACR) / European League Against Rheumatism (EULAR) classification criteria for rheumatoid arthritis (RA), the patient was diagnosed with RA and the disease duration was at least 3 months at the screening visit; A2: In addition to A1, the following criteria are met: ≥6 swollen joints (SJC) (based on a 66-joint count) and ≥6 tender joints (TJC) (based on a 68-tender joint count) at screening and baseline visits; and erythrocyte sedimentation rate (ESR) ≥28 mm / h or central laboratory high-sensitivity C-reactive protein (hsCRP) ≥upper limit of normal at screening; (2) The moderate to severe active rheumatoid arthritis is moderate to severe rheumatoid arthritis that is inadequately responsive to or intolerant to traditional synthetic disease-modifying antirheumatic drugs; (3) The clinical diagnostic criteria for moderate to severe atopic dermatitis are as follows: meeting 3 or more of the basic features and 3 or more of the minor features of the Hanifin & Rajka criteria, and EASI score ≥ 16, IGA score ≥ 3, body surface BSA ≥ 10%, and pruritus NRS score ≥ 4; (4) The active ankylosing spondylitis meets the following criteria C1 and C2: C1: According to the 1984 revised New York criteria for ankylosing spondylitis, the patient is diagnosed with AS (item 4 is present and any one of items 1) to 3) is additionally diagnosed with AS): 1) Low back pain persists for at least 3 months, and the pain improves with activity but does not subside with rest; 2) Limited lumbar spine movement in the anterior-posterior and lateral flexion directions; 3) The chest expansion range is less than the normal value for the same age and gender; 4) Bilateral sacroiliitis grade II to IV, or unilateral sacroiliitis grade III to IV; Among them, the grading standards for the degree of sacroiliitis on X-ray films are: Level 0: Normal; Level I: Suspicious; Grade II: mild sacroiliitis; Grade III: moderate sacroiliitis; Grade IV: Ankylosis of joint fusion; C2: Subjects had active disease at baseline, defined as follows: BASDAI score ≥ 4 and spinal pain score ≥ 4.

8. The method according to claim 6, wherein It meets one or more of the following conditions: (1) The moderate to severe active rheumatoid arthritis is moderate to severe rheumatoid arthritis that responds poorly or is intolerant to traditional synthetic disease-modifying antirheumatic drugs, wherein the traditional synthetic disease-modifying antirheumatic drugs are selected from one or more of methotrexate, sulfasalazine, leflunomide, chloroquine and hydroxychloroquine; (2) The corresponding patients with moderate to severe atopic dermatitis meet the following B1 and B2: B1: Patients with a history of atopic dermatitis for at least 1 year and who meet the diagnostic criteria for atopic dermatitis defined by Hanifin and Rajka at screening B2: EASI ≥16, IGA score ≥3, and BSA involvement ≥10% at screening and baseline visits; (3) The active ankylosing spondylitis is active ankylosing spondylitis that is poorly responsive to, intolerant of, or contraindicated for nonsteroidal anti-inflammatory drugs, such as aspirin.

9. The method according to at least one of claims 6 to 8, characterized in that It meets one or more of the following conditions: (1) The substance X is administered orally, parenterally or transdermally, preferably orally; (2) The substance X is administered in the form of tablets, capsules, granules, pills, granules, syrups, solutions, suspensions, injections, emulsions or dispersions, preferably in the form of capsules; (3) The substance X is administered at a dose of 1 to 84 mg / day, based on the content of compound I, for example, 24 mg / day, 48 mg / day, or 72 mg / day, preferably 24 mg / day or 48 mg / day; Alternatively, the substance X is administered at a dose of 12×a mg / day or 12 / a mg / day, based on the content of compound I, where a is any positive integer, such as 1, 2, 3, 4, 5 or 6, further such as 1, 2 or 3; (4) The substance X is administered once a day, twice a day, or three times a day, for example, twice a day; (5) The substance X is administered after a meal.

10. The method according to at least one of claims 6 to 8, characterized in that Based on the content of Compound I, the substance X is administered at a dose of 24 mg / day or 48 mg / day, and the dose is administered twice, with each dose being the same or different, preferably the same; Preferably, based on the content of Compound I, the substance X is administered at 12 mg / time, twice / day, or at 24 mg / time, twice / day.

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