Use of benzazepine derivatives in the treatment of complement factor b mediated diseases

Abstract

Use of a compound of formula (I) or its stereoisomer, tautomer, pharmaceutically acceptable salt, co-crystal or composition thereof, in the manufacture of a medicament for the treatment of complement factor B mediated diseases. And a method for treating complement factor B mediated diseases, which comprises administering an effective dose of a compound of formula (I) or its stereoisomer, tautomer, pharmaceutically acceptable salt, co-crystal or composition thereof.

Description

Use of benzazepine aromatic ring derivatives in treating diseases mediated by complement factor B Technical Field

[0001] The present invention relates to use of a compound of formula (I) or its stereoisomers, tautomers, pharmaceutically acceptable salts, cocrystals or compositions thereof in the preparation of drugs for treating diseases mediated by complement factor B. Background Art

[0002] Imbalance in complement system homeostasis is associated with a series of kidney diseases and hemolytic diseases, including atypical hemolytic uremic syndrome (aHUS), antineutrophil cytoplasmic antibody-mediated vasculitis (ANCA), paroxysmal nocturnal hemoglobinuria (PNH), C3 glomerulopathy (C3G), IgA nephropathy (IgAN), immune complex membranoproliferative glomerulonephritis, lupus nephritis, membranous nephropathy and chronic transplant-mediated glomerulopathy.

[0003] Primary IgA nephropathy is the most common primary glomerulonephritis. my country has a high incidence of IgA nephropathy, accounting for approximately 45% to 50% of primary glomerular diseases. 80% of IgA nephropathy patients are young and middle-aged, and the vast majority of patients present with a chronic, progressive course. Approximately 30% to 40% of IgAN patients develop end-stage renal disease within 10 to 20 years of diagnosis. The pathogenesis of IgAN remains incompletely elucidated, but it is currently believed to involve a combination of autoimmunity, inflammatory activation, genetics, and environmental factors. Its pathological hallmark is the deposition of immunoglobulin A (IgA) in the glomerular mesangium, with or without C3 deposition. C3 nephropathy is a rare and severe kidney disease that has only recently been recognized. Approximately 60% of C3G patients develop end-stage renal disease within 10 years of diagnosis. The pathological hallmark of C3G is the deposition of complement C3 along the glomerular capillary loops, as detected by immunofluorescence staining, without the presence of other immunoglobulin deposits. Electron microscopy reveals electron-dense deposits in the subendothelial and / or mesangial regions of the glomerular capillary loops. Medical treatment for primary glomerular diseases primarily involves immunosuppression and angiotensin-converting enzyme inhibitors (ACEIs) or angiotensin II receptor blockers (ARBs). Secondary glomerular diseases are caused by systemic diseases, such as lupus nephritis, systemic vasculitis, and diabetic nephropathy. Treatment of lupus nephritis requires individualized treatment based on clinical and pathological findings. Medical treatments primarily include steroids, immunosuppressants, ACEIs / ARBs, and biomarker monoclonal antibodies. Overall, current treatment options are limited and can only partially delay the onset of end-stage renal disease, failing to meet current clinical needs.

[0004] Paroxysmal nocturnal hemoglobinuria (PNH) is a complement-driven hemolytic anemia caused by a mutation in the phosphatidylinositol glycan-A (PIG-A) gene on the X chromosome of hematopoietic stem cells, resulting in impaired glycophosphatidylinositol (GPI) synthesis. This leads to a loss of GPI-anchored proteins, including CD55 and CD59, on the surfaces of hematopoietic stem cells and their progeny (erythrocytes, granulocytes, monocytes, and lymphocytes). The former inhibits the formation of complement C3 convertase, while the latter prevents the conversion of fluid-phase complement C9 into the membrane attack complex. The loss of CD55 and CD59 on the erythrocyte membrane triggers intravascular hemolysis. PNH patients may present with hemolytic anemia, thrombophilia, and bone marrow failure. PNH is a rare disease characterized by chronic intravascular hemolysis and bone marrow failure, with an incidence of approximately 1.3 per 1 million and a prevalence of approximately 15.9 per 1 million.

[0005] Atypical hemolytic uremic syndrome (aHUS) is a thrombotic microangiopathy caused by complement dysregulation, characterized by microangiopathic hemolytic anemia, thrombocytopenia, and end-organ damage (primarily the kidneys). It mostly develops in infancy, with an annual incidence of 3.3 / 100,000 children. Among children with hemolytic uremic syndrome, the proportion of typical HUS is 85% to 90%, and aHUS is 5% to 10%.

[0006] Complement inhibitors targeting terminal complement are the preferred treatment for PNH and aHUS. In 2007, eculizumab (a monoclonal antibody that blocks terminal complement C5) was introduced, which changed the natural history of PNH and aHUS. Several new complement inhibitors are now available that inhibit C5 and complement upstream of C5, but to date, only eculizumab and ravulizumab have been approved by the US Food and Drug Administration (FDA) and the European Medicines Agency for the treatment of PNH and aHUS.

[0007] Eculizumab and ravolumab are currently the only FDA-approved treatments for PNH and aHUS. Thrombosis, severe anemia, or symptoms of PNH (chronic fatigue, pain, dyspnea) are strong indications for initiating treatment. Terminal complement inhibition increases the risk of Neisseria infection; therefore, all patients taking eculizumab are recommended to receive Neisseria vaccination. Even with vaccination, the risk of Neisseria infection is >1000-fold higher than in healthy controls, with an absolute annual risk of up to 0.5%. Gupta et al. found that women with aHUS associated with a first pregnancy who received eculizumab had significantly better outcomes compared with women who did not receive eculizumab.

[0008] Eculizumab and ravolumab prevent intravascular hemolysis and thrombosis in the natural history of PNH; however, there is room for improvement. More than 50% of PNH patients treated with C5 inhibitors develop mild to moderate PNH symptoms, and up to 20% still require occasional blood transfusions. The most common cause of persistent anemia is extravascular hemolysis. New complement inhibitors are in development for the treatment of PNH, some of which may receive FDA approval in the next year or two. Pegcetacoplan, a C3 inhibitor, is administered subcutaneously twice weekly and blocks both intravascular and extravascular hemolysis. It is being compared head-to-head with eculizumab in a phase 3 clinical trial. Danicopan is another promising agent that blocks the alternative complement pathway by inhibiting complement factor D.51. Danicopan, administered orally, improves hemoglobin levels and eliminates the need for transfusions in patients with transfusion-dependent PNH. In December 2023, the FDA approved iptacopan, a small molecule inhibitor of complement factor B, for the treatment of paroxysmal nocturnal hemoglobinuria (PNH). This was based on the fact that iptacopan achieved two primary endpoints in a pivotal Phase 3 clinical trial for the treatment of paroxysmal nocturnal hemoglobinuria (PNH): an increase in hemoglobin level by ≥2 g / dL from baseline and the proportion of subjects who achieved a stable hemoglobin level of 12 g / dL or higher after 24 weeks. Furthermore, in adult patients with PNH who have previously received complement inhibitor therapy but still experience anemia, iptacopan was superior to anti-C5 therapies (eculizumab or long-acting ravulizumab), providing a safer and more effective treatment option for PNH patients. Therefore, the development of novel small molecule complement factor B inhibitors to better control intravascular and extravascular hemolysis addresses the shortcomings of anti-C5 antibodies and provides an oral single-agent option for patients with PHN and aHUS. This is expected to address the unmet clinical needs of complement-related diseases and has significant clinical value and social significance.

[0009] WO2023020566 describes a compound of formula (I) having good complement factor B inhibitory activity and a high inhibition rate of C3a levels in vivo. Summary of the Invention

[0010] The present invention provides a compound of formula (I) or its stereoisomers, tautomers, pharmaceutically acceptable salts, cocrystals or compositions thereof, for use in the preparation of a medicament for preventing or treating diseases or conditions mediated by complement factor B.

[0011] Selected from

[0012] R 1Selected from -OCH3 or -OCD3;

[0013] R 2 Selected from -CH3 or -CD3;

[0014] n is selected from 1, 2 or 3.

[0015] Furthermore, the structure of the compound described by general formula (I) is selected from one of the structures shown in Table S-1:

[0016] Table S-1 Compound Structure

[0017] Furthermore, the compound of formula (I) is selected from the following compounds:

[0018] In some embodiments, the use is to administer an effective dose of the compound of formula (A) or its stereoisomers, tautomers, pharmaceutically acceptable salts, cocrystals or compositions thereof to a mammal.

[0019] Furthermore, the pharmaceutically acceptable salt is selected from hydrochloride, succinate, sulfate, maleate, phosphate, tartrate, fumarate, citrate, naphthalene disulfonate, p-toluenesulfonate, methanesulfonate, benzenesulfonate, oxalate, gentisate, succinate or hydrobromide.

[0020] The present invention relates to a disease or disorder mediated by complement factor B selected from at least one of the following: paroxysmal nocturnal hemoglobinuria, primary glomerulonephritis, membranous nephropathy, C3 glomerulonephritis, and atypical hemolytic uremic syndrome.

[0021] The present invention relates to uses in drugs for preventing or treating diseases mediated by complement factor B and in some embodiments of the treatment methods, an effective dose of a compound of formula (A) or its stereoisomers, tautomers, pharmaceutically acceptable salts, cocrystals or compositions thereof is administered to a mammal. When the amount is calculated based on the compound of structural formula (A), the amount of the compound is 1-2400 mg / day.

[0022] In some embodiments of the present invention, the use of the drug for preventing or treating diseases mediated by complement factor B and the method of treatment are as follows: when the amount is calculated based on the compound of formula (A), the amount of the compound is 1-2400 mg / day, 1-1000 mg / day, 1-900 mg / day, 1-800 mg / day, 1-700 mg / day, 1-600 mg / day, 1-500 mg / day, 1-400 mg / day, 1-300 mg / day, 1-200 mg / day, 1-100 mg / day, 10-1000 mg / day, 10-900 mg / day, 10-800 mg / day, 10-700 mg / day, 10-600 mg / day, 10-500 mg / day , 10-400mg / day, 10-300mg / day, 10-200mg / day, 10-100mg / day, 20-500mg / day, 20-400mg / day, 20-300mg / day, 20-250mg / day, 20-200mg / day, 20-150mg / day, 30-100mg / day, 30-150mg / day, 30-250mg / day, 30-300mg / day, 30-400mg / day, 40-400mg / day, 50-100mg / day, 50-200mg / day, 50-300mg / day, 50-400mg / day, 50-500mg / day, 50-600mg / day.

[0023] The present invention relates to the use of a drug for preventing or treating diseases mediated by complement factor B and some embodiments of the method for treating diseases mediated by complement factor B. In some embodiments, when calculated based on the compound of formula (A), the amount of the compound is 0.5 mg / kg-20 mg / kg, and is administered orally.

[0024] The present invention relates to the use of a drug for preventing or treating complement factor B-mediated diseases and some embodiments of the method for treating complement factor B-mediated diseases, when calculated based on the compound of formula (A), the amount of the compound is 0.5-1 mg / kg, 2-4 mg / kg, 5-10 mg / kg, 11-20 mg / kg, 1-2 mg / kg, 4-8 mg / kg, 8-16 mg / kg, and is administered orally.

[0025] The present invention relates to the use of a drug for preventing or treating diseases mediated by complement factor B and some embodiments of the method for treating diseases mediated by complement factor B. In some embodiments, when calculated based on the compound of formula (A), the amount of the compound is 20 mg-800 mg / day, administered orally.

[0026] The present invention relates to the use of a drug for preventing or treating complement factor B-mediated diseases and some embodiments of the method for treating complement factor B-mediated diseases, when the amount is calculated based on the compound of formula (A), the amount of the compound is 20 mg-50 mg / day, 60 mg-150 mg / day, 120 mg-300 mg / day, 240 mg-600 mg / day, 320 mg-800 mg / day, 40 mg-100 mg / day, 120 mg-300 mg / day, 240 mg-600 mg / day, 60 mg-150 mg / day, 180 mg-450 mg / day, 360 mg-800 mg / day, and is administered orally.

[0027] In some embodiments of the present invention, the use of the compound of formula (A) or its stereoisomer, tautomer, pharmaceutically acceptable salt, cocrystal or composition thereof in a medicament for preventing or treating complement factor B-mediated diseases is selected from once a day, twice a day, three times a day, once a week, twice a week, three times a week or once every other day.

[0028] The present invention relates to the use of a compound of formula (A) in a drug for preventing or treating a disease mediated by complement factor B and in some embodiments of a method for treating a disease mediated by complement factor B, the compound or its stereoisomer, tautomer, pharmaceutically acceptable salt, cocrystal or composition thereof is administered by a route selected from oral administration, injection, instillation, transdermal absorption, buccal absorption, parenteral intraperitoneal, rectal, transbuccal, nasal spray, nasal drops, inhalation, topical delivery, subcutaneous, intrafatty, intraarticular, intraperitoneal or intrathecal. Preferably, the administration route is oral administration, injection or nasal spray.

[0029] The present invention relates to the use of a drug for preventing or treating a disease mediated by complement factor B and in some embodiments of a method for treating a disease mediated by complement factor B, the route of administration of the compound of formula (A) or its stereoisomers, tautomers, pharmaceutically acceptable salts, cocrystals or compositions thereof is selected from oral administration, intravenous injection, intravenous drip, arterial injection, intramuscular injection, subcutaneous injection, intraarticular injection, intraperitoneal injection, intrathecal injection or nasal drops. Preferably, the route of administration is oral administration, injection or nasal spray.

[0030] Unless otherwise stated, the terms used in the specification and claims have the following meanings:

[0031] "Pharmaceutical composition" means a mixture of one or more compounds described herein or their physiologically / pharmaceutically acceptable salts or stereoisomers, solvates, pharmaceutically acceptable salts or cocrystals, and other ingredients, wherein the other ingredients include physiologically / pharmaceutically acceptable carriers and excipients.

[0032] "Stereoisomers" refer to isomers resulting from different spatial arrangements of atoms in a molecule, including cis-trans isomers, enantiomers, and conformational isomers.

[0033] An "effective amount" refers to that amount of a compound that will elicit the physiological or medical response of a tissue, system, or subject that is being sought, and includes an amount of the compound that, when administered to a subject, is sufficient to prevent or alleviate to some extent one or more symptoms of the disorder or condition being treated. BRIEF DESCRIPTION OF THE DRAWINGS

[0034] FIG1 shows the effect of compound A in Test Example 3 of the present invention on the rabbit erythrocyte hemolysis rate mediated by PNH patient serum.

[0035] FIG2 shows the effect of compound A in Test Example 4 of the present invention on the urine protein to creatinine ratio UPCR in rats in a passive Heymann nephropathy model.

[0036] FIG3 shows the effect of compound A in Test Example 4 of the present invention on AP deposition in rat serum in a passive Heymann nephropathy model.

[0037] FIG4 shows the effect of compound A in Test Example 4 of the present invention on renal pathology in rats in a passive Heymann nephropathy model.

[0038] FIG5 shows the effect of compound A in Test Example 5 of the present invention on the urine protein to creatinine ratio UPCR in rats in an IgA nephropathy model.

[0039] FIG6 shows the effect of Compound A in Test Example 5 of the present invention on C5b-9 deposition in rat serum in an IgA nephropathy model.

[0040] FIG7 shows the effect of compound A in Test Example 5 of the present invention on the serum IgA level of rats in an IgA nephropathy model.

[0041] FIG8 shows the effect of Compound A in Test Example 5 of the present invention on C3 deposition in rat kidneys in an IgA nephropathy model. DETAILED DESCRIPTION

[0042] The technical solutions of the present invention are described in detail below with reference to the accompanying drawings and embodiments, but the protection scope of the present invention includes but is not limited to them.

[0043] Synthesis Example:

[0044] The following compounds were prepared according to the method described in WO2023020566:

[0045] Compound A: 4-((2S,4R)-4-cyclopropyl-1-((5-(methoxy-d3)-7-methyl-1H-indol-4-yl)methyl)piperidin-2-yl)benzoic acid (CAS No. 2910876-03-6)

[0046] Biological test cases

[0047] Test Example 1:

[0048] In vitro complement factor B enzyme activity test of compound A

[0049] 1 μM CVF protein (Quidel Corp, Cat#: A600), 1 μM FB protein (Quidel Corp, Cat#: A408), and 300 nM FD protein (Quidel Corp, Cat#: A409) were incubated in assay buffer (PBS, pH 7.4, 10 mM MgCl2, 0.05% (m / v) CHAPS) at room temperature for 3 hours to generate the CVFBb complex (C3 convertase). Using an Echo 555, 25 nL of compound was transferred to a Greiner-784075 reaction plate. Compounds were diluted to a maximum concentration of 600 μM and then diluted three-fold to 10 concentration points in duplicate. The generated CVFBb complex was diluted to 1.67 nM, and 3 μL was added to each well of the plate and incubated with the compounds for 1 hour at room temperature. The enzymatic reaction was initiated by adding 2 μL of C3 protein to each well of the plate, diluted to 2.5 μM in assay buffer. After incubation at room temperature for 1 hour, the enzymatic reaction was terminated by adding a phosphatase inhibitor cocktail. C3a in the sample was quantified using an ELISA kit (HycultBiotech, Cat#: HK354). IC was calculated using a log(dose)-inhibition curve fit using GraphPad Prism. 50 , to evaluate the inhibitory effect of the compounds on the enzymatic activity of FB.

[0050] The results are shown in Table 1. Compound A can inhibit the enzymatic activity of human complement FB in a dose-dependent manner. IC 50 The maximum concentration of complement B was 19.57 nM, indicating that compound A could significantly inhibit the enzymatic activity of complement B.

[0051] Table 1

[0052] Test Example 2:

[0053] Detection of the inhibitory activity of compound A on AP (Alternative pathway) deposition in human serum

[0054] Test Example 2: 10mL of whole blood was collected from healthy volunteers at Shanghai Liquan Hospital and placed in anticoagulant-free blood collection tubes. The blood was allowed to clot in serum tubes at room temperature (20-25°C) for 30 minutes. The blood sample was centrifuged at 3000 rpm for 10 minutes, and the cell-free serum was transferred to a clean tube. The serum was directly diluted 30-fold using AP diluent from the WIESLAB Complement System Alternative Pathway Kit (WIESLAB, Cat#: COMPL AP330 RUO). Compounds were diluted in DMSO starting at 5μM and serially diluted 4-fold to eight concentrations. Separately, a 96-well plate was prepared, and 150μL of serum was added to designated wells. Then, 1.5μL of compound was added to corresponding wells. The plates were incubated at 37°C for 60 minutes. 100μL of the reaction product was transferred to the assay wells of the WIESLAB Complement System Alternative Pathway Kit to measure C5b-9 production and evaluate the compound's inhibitory effect on AP activity of the human serum alternative pathway.

[0055] The results are shown in Table 2. Compound A can inhibit the deposition of AP in the alternative complement pathway of human serum in a dose-dependent manner. 50 The concentration of compound A was 21.81 nM, indicating that compound A could significantly inhibit the activation of the alternative pathway in human serum.

[0056] Table 2

[0057] Test Example 3:

[0058] Study on the efficacy of compound A in inhibiting serum hemolysis rate in PNH patients

[0059] Take 1 mL of 6% rabbit red blood cells (Solyb, Cat: S9453) in a 2 mL EP tube, centrifuge at 9500g for 1 min at room temperature, remove the supernatant, and add 1 mL of EGTA-Mg 2+ -GVB buffer (CompTech, Cat: CPT-B103), gently pipette to mix, and use a cell counter to count the living cells. Take an appropriate amount of rabbit red blood cells and use EGTA-Mg 2+ - Adjust the rabbit red blood cell concentration to 6 x 10 7 The drug to be tested was diluted with physiological saline to concentrations of 1000 μM and 60 μM.

[0060] Then, the following components were added to the 96-well plate; 1) Test well: 88 μL EGTA-Mg 2+ -GVB buffer, 2 μL PNH serum, 10 μL test substance diluent. 2) Background well: 100 μL EGTA-Mg 2+-GVB buffer. 3) 100% hemolysis well: 88 μL EGTA-Mg 2+ -GVB buffer, 2 μL PHN serum, and 10 μL normal saline. Mix well and incubate at 37°C, 200 rpm for 30 min. Duplicate wells are prepared for each sample. 100 μL of a 6 x 10 7 The 96-well plate was placed on a constant temperature microplate shaker at 200 rpm and incubated at 37°C for 30 minutes. Then, it was centrifuged at 1000 x g for 2 minutes at room temperature. 100 μL of supernatant was taken from each well and placed in a new 96-well plate. The OD value of the supernatant was measured at 415 nm using a microplate reader (Flexstation3, Molecular Devices). The hemolysis rate of each sample was calculated using the following formula: Hemolysis rate % = 100 x (OD 受试物孔平均 值 -OD 背景孔平均值 ) / (OD 100％溶血孔平均值 -OD 背景孔平均值 ).

[0061] The results are shown in Figure 1. Compound A can dose-dependently inhibit erythrocyte hemolysis mediated by PNH patient serum. IC 50 The IC value of the positive control (LNP023) for inhibiting PNH-mediated erythrocyte hemolysis was 12.71 μM. 50 The inhibitory effect of compound A on complement-mediated erythrocyte hemolysis was better than that of the positive control (LNP023).

[0062] Test Example 4:

[0063] Pharmacological effect of compound A against serum Fx1A-induced passive Heymann nephropathy in rats

[0064] This study investigated the protective effect of compound A in the Fx1A-induced Heymann nephropathy model in rats.

[0065] On Day 1, 60 male Sprague-Dawley rats were divided equally into 6 groups of 10 rats each based on body weight. On Day 0, except for the normal group (which received blank serum), all rats received a slow tail vein injection of Anti-Rat Fx1A serum at a dose of 0.8 mL / 100 g. Four hours after injection, the corresponding compound or vehicle was administered. The rats were observed for any signs of discomfort or reaction to the injection within 4 hours. Days 0-14: All animals were administered the corresponding compound or vehicle based on body weight at a volume of 5 mL / kg twice daily. On Day 13, the animals were placed in metabolic cages after dosing. On Day 14, a 24-hour urine collection was performed, and the volume was recorded for the measurement of TP (total protein) and creatinine. Rats were euthanized by CO2 1 hour after dosing and blood was collected from the heart. Serum was collected for the measurement of creatinine, urea, and AP activity. The kidneys were perfused with pre-chilled 0.9% saline. After complete perfusion, both kidneys were harvested and weights were recorded. The midsection of the left kidney was formalin-fixed and pathologically examined.

[0066] The results are shown in Figure 2 . Compound A reduced UPCR at doses of 20, 60, and 120 mg / kg, demonstrating a good protective effect on the kidneys.

[0067] As shown in Figure 3 , compound A inhibited the activity of complement marker AP in rat serum in a dose-dependent manner at 20, 60, and 120 mg / kg, indicating that compound A exerted its renal protective effect by inhibiting AP activity;

[0068] As shown in Figure 4, the effect of compound A on renal pathology in rats with Heymann nephropathy was detected. The results showed that compound A at 20, 60, and 120 mg / kg doses reduced renal tubular injury, renal fibrosis, renal interstitial inflammation, and the overall renal score.

[0069] Test Example 5:

[0070] This study investigated the protective effect of compound A in the BSA-induced IgA nephritis model in rats.

[0071] Before the experiment began, 95 Wistar rats were pre-screened using urine protein test strips, animals with abnormal values ​​were removed, and 55 rats were retained for the experiment. Five animals with normal urine protein values ​​were randomly selected as the G1 normal group. Then the remaining animals with normal urine protein were modeled. All model rats received tail vein injection of BSA solution starting on Day 0, with an injection volume of 0.5 mg / rat, three times a week, 1 mL each time, for 5-7 weeks. After tail vein injection of BSA, the model animals were grouped according to the changes in the total protein content in urine measured by a biochemical analyzer. There were 5 groups of model rats, 10 rats in each group, plus 5 rats in the normal group, a total of 55 rats. Drug administration began after grouping. On Day 49, 24-hour urine was collected using a rat metabolic cage. Total urine volume was recorded, and total protein and creatinine concentrations were measured using a biochemical analyzer. Total 24-hour urine protein and UPCR were calculated based on volume. At the end of the experiment on Day 54, blood was collected from the abdominal aorta of all experimental animals after anesthesia. C5b-9 and IgA levels were measured using an ELISA kit. After blood collection, the animals were perfused with normal saline, and the right kidney was harvested for renal pathology testing, including renal C3 deposition testing.

[0072] The results are shown in FIG5 . On Day 49, compared with the model group, compound A at 20 and 60 mg / kg could dose-dependently reduce the UPCR of rats, showing a good protective effect on the kidneys, which was better than the positive control (LNP023) group at the same dose.

[0073] As shown in Figure 6, the serum complement marker C5b-9 level was detected at the end point of the experiment. The results showed that Compound A inhibited the deposition of C5b-9 in rat serum in a dose-dependent manner at 20 and 60 mg / kg, and the degree of inhibition increased with the increase of administration time, indicating that Compound A exerts a renal protective effect by inhibiting the activity of the entire complement pathway.

[0074] As shown in FIG7 , compound A at 20 and 60 mg / kg significantly reduced the content of serum marker IgA in the IgA nephritis model, which was superior to the positive control (LNP023) group at the same dose.

[0075] As shown in FIG8 , compound A at 60 mg / kg dose-dependently inhibited the deposition of C3 in rat kidneys, which was superior to the positive control (LNP023) group at the same dose.

[0076] Clinical Research:

[0077] Clinical Study 1: A multicenter, randomized, open-label Phase II clinical study to evaluate the efficacy and safety of Compound A tablets in patients with paroxysmal nocturnal hemoglobinuria

[0078] 1. Overall Research Design

[0079] This study is a Phase II, multicenter, randomized, open-label trial that plans to enroll approximately 45 patients with paroxysmal nocturnal hemoglobinuria who have not received complement inhibitor treatment. Eligible subjects will be randomly assigned to Compound A tablets in a 1:1:1 ratio to receive treatment in dose groups A, B, and C. An interim data analysis will be conducted after all subjects complete 12 weeks of study treatment. During the interim analysis, enrolled subjects will continue to receive study treatment in their assigned dose group for 24 weeks. After the treatment observation period, subjects who are determined by the investigator to have no treatment benefit will enter a dose-reduction period and safety follow-up period. The remaining subjects will enter a separate extended-dose study after providing informed consent.

[0080] The trial period consists of a screening period (up to 8 weeks), a treatment observation period (24 weeks), a dose reduction period (1 week), and a safety follow-up period (3 weeks).

[0081] Screening period:

[0082] After signing the informed consent form, participants will complete screening visits and vaccinations between Days 56 and 2. Participants who have not previously received meningococcal and pneumococcal vaccines must complete vaccinations at least 2 weeks prior to the first dose. Participants will undergo additional laboratory tests and assessments one day prior to the first dose (Day 1).

[0083] Treatment observation period:

[0084] Subjects who meet all inclusion criteria and do not meet any exclusion criteria as assessed by the investigator will be randomized on Day 1. If the first dose of Compound A tablets is initiated before 2 weeks after vaccination, the subject will receive antibiotic prophylaxis for at least 2 weeks after vaccination.

[0085] During the treatment observation period, subjects in Group A received Compound A tablets 75 mg BID for 4 weeks starting on D1, followed by 125 mg BID for 20 weeks. If the LDH level on D15 decreased by less than 40% compared to baseline, the dose was increased to 125 mg BID. Subjects in Group B received Compound A tablets 100 mg BID at a fixed dose starting on D1. Subjects in Group C received Compound A tablets 200 mg QD at a fixed dose starting on D1. The treatment observation period was 24 weeks. During treatment, for safety or tolerability reasons, the dose could be adjusted after consultation between the investigator and the sponsor (e.g., 125 mg BID dose reduced to 100 mg BID, 100 mg BID dose reduced to 75 mg BID).

[0086] Extended Dosing Studies:

[0087] After the 24-week treatment observation period, if there are no safety and tolerability issues, the subjects will enter a separate extended-dose study after informed consent. Subjects participating in the extended-dose study must continue taking the drug according to the study protocol.

[0088] Dose reduction phase:

[0089] After the 24-week treatment observation period, subjects who were judged by the researchers to have no treatment benefit entered a 1-week dose reduction period, with the dose reduced to 50 mg QD for 4 days, and then to 25 mg QD for 3 days before discontinuation.

[0090] Safety follow-up period:

[0091] After the dose reduction period, subjects entered a 3-week safety follow-up period. At the final visit, subjects were discharged after completing the collection and assessment of safety indicators as specified in the protocol.

[0092] 2. Study Population

[0093] 2.1 Inclusion Criteria

[0094] Subjects who meet all of the following criteria can be included in this study:

[0095] (1) Age ≥18 years at screening, regardless of gender;

[0096] (2) PNH was confirmed by flow cytometry (granulocyte clone size >10%) within 6 months before screening, and the flow cytometry results of the V1 test during the screening period were acceptable;

[0097] (3) no previous treatment with complement inhibitors;

[0098] (4) blood LDH > 1.5 times the upper limit of normal (ULN) during V1 and V2 of the screening period;

[0099] (5) Laboratory hemoglobin test meets one of the following conditions: (1) Hemoglobin (local laboratory) <100 g / L at V1 and V2 during the screening period; (2) If the subject receives red blood cell transfusion for PNH-related anemia during the screening period, hemoglobin (local laboratory) <100 g / L at V1;

[0100] (6) Vaccination with Neisseria meningitidis and Streptococcus pneumoniae vaccine at least 2 weeks before the first dose, and in compliance with the vaccination requirements of the protocol; if the study drug treatment must be started less than 2 weeks after vaccination, prophylactic antibiotic treatment must be started for at least 2 weeks after vaccination;

[0101] (7) Female subjects of fertile potential must have a negative pregnancy test during the screening period and must agree not to attempt pregnancy or donate eggs for at least 30 days from the signing of the informed consent form to the last dose of the study drug, and must use effective contraceptive measures; male subjects of fertile potential must agree not to donate sperm for at least 90 days from the signing of the informed consent form to the last dose of the study drug, and must use effective contraceptive measures with their female partners;

[0102] (8) Those who understand the research procedures and methods, voluntarily participate in this trial, and sign the informed consent form.

[0103] 2.2 Exclusion criteria

[0104] Subjects who meet any of the following criteria are not eligible for inclusion in this study:

[0105] (1) Participated in other interventional clinical trials within 3 months before screening, or was still in the follow-up period of a clinical study or within 5 half-lives of the investigational drug (whichever is longer) at the time of screening;

[0106] (2) known or suspected hereditary or acquired complement deficiency;

[0107] (3) history of currently active primary or secondary immunodeficiency;

[0108] (4) history of splenectomy;

[0109] (5) history of bone marrow / hematopoietic stem cell or solid organ transplantation (e.g., heart, lung, kidney, liver);

[0110] (6) History of malignant tumor within 5 years before screening (except for cured basal cell carcinoma of the skin or cervical cancer in situ);

[0111] (7) A history of recurrent invasive infection with encapsulated bacteria (such as Neisseria meningitidis, Streptococcus pneumoniae, etc.) or Mycobacterium tuberculosis;

[0112] (8) Patients with a history of or suspected systemic active bacterial, viral, or fungal infection within 2 weeks before the first administration of the study drug and deemed unsuitable for study participation by the investigator;

[0113] (9) Those with laboratory evidence of bone marrow failure (reticulocytes <100×109 / L, or platelets <30×109 / L, or neutrophils <0.5×109 / L) during the screening period V1 or V2 (local laboratory);

[0114] (10) Those who tested positive for hepatitis B virus surface antigen (HBsAg), hepatitis C virus antibody (HCV-Ab), human immunodeficiency virus antibody (HIV-Ab), or Treponema pallidum antibody (TP-Ab) during the screening period;

[0115] (11) Before screening, the subject was receiving the following medications, and the duration of treatment at a stable dose of the drug:

[0116] (a) Erythropoietin for less than 8 weeks;

[0117] (b) Immunosuppressants (including but not limited to cyclosporine, tacrolimus, mycophenolate mofetil or mycophenolic acid, cyclophosphamide, methotrexate, etc.) for less than 8 weeks;

[0118] (c) hypoxia-inducible factor prolyl hydroxylase inhibitor (HIF-PHI) for less than 8 weeks;

[0119] (d) systemic glucocorticoids for less than 4 weeks;

[0120] (e) Vitamin K antagonists (e.g., warfarin) with stable international normalized ratio for less than 4 weeks;

[0121] (f) Low molecular weight heparin or oral anticoagulants (such as rivaroxaban) for less than 4 weeks;

[0122] (g) iron, vitamin B12, and folic acid supplements for less than 4 weeks;

[0123] (h) Androgens for less than 4 weeks.

[0124] (12) The patient has severe comorbidities, including but not limited to severe liver damage, severe kidney disease (e.g., eGFR < 30 mL / min / 1.73 m2), unstable angina, or other blood system diseases (e.g., chronic anemia unrelated to PNH), and is deemed unsuitable for participation in the study by the investigator;

[0125] (13) Those suspected of being allergic to any component of the study drug or similar drugs;

[0126] (14) Pregnant or lactating women;

[0127] (15) There are risks that may interfere with the conduct of the study, increase the number of subjects, or other situations that are assessed by the researcher as unsuitable for participation in the study.

[0128] 2.3 Completion of the study

[0129] The study is considered complete after the subject has signed the informed consent form and completed the last visit or trial process planned in the trial protocol. The study is considered complete after the last subject completes the last visit or trial process planned in the trial protocol.

[0130] 3. Research medication

[0131] 3.1 Investigational Drugs

[0132] Compound A tablets were produced and provided by Sichuan Hisike Pharmaceutical Co., Ltd. and prepared according to the method described in WO2024175028A1.

[0133] Specifications: 25mg and 100mg (both in C 26 H 27 D3N2O3);

[0134] Dosage: Oral, can be taken on an empty stomach or after meals, frequency of use is BID (once in the morning and evening) or QD (once in the morning);

[0135] Storage conditions: Store at room temperature, sealed.

[0136] 3.2 Study medication methods

[0137] 3.2.1 Planned medication method

[0138] All qualified subjects will receive the trial medication on the first day of treatment (D1). Investigators must inform subjects of medication requirements and precautions during the study treatment period, including but not limited to: swallowing medication without chewing, taking the medication at the prescribed frequency and number of tablets per day, and taking medication at the same time as possible.

[0139] The dosing regimens and methods of administration for different treatment groups during the observation period are as follows:

[0140] Group A: Subjects received Compound A tablets 75 mg BID for 4 weeks starting on D1, followed by 125 mg BID for 20 weeks; if the LDH level on D15 decreased by <40% compared with baseline, the dose was increased to 125 mg BID.

[0141] Group B: subjects received Compound A 100 mg BID fixed-dose treatment starting on D1 for 24 weeks.

[0142] Group C: subjects received Compound A 200 mg QD fixed-dose treatment starting on D1 for 24 weeks.

[0143] The treatment observation period is 24 weeks. During treatment, the dose may be adjusted (e.g., 125 mg BID to 100 mg BID, 100 mg BID to 75 mg BID) for safety or tolerability reasons, after consultation between the investigator and the sponsor.

[0144] Dose reduction phase:

[0145] The dose was gradually reduced to 50 mg QD for 4 days and then to 25 mg QD for 3 days before discontinuation.

[0146] 3.2.2 Extended treatment

[0147] After the 24-week treatment observation period, if there are no safety and tolerability issues and the investigator determines that the subject has benefited from the treatment, they will enter a separate extended-dose study after obtaining informed consent. Subjects participating in the extended-dose study must continue taking the drug according to the study protocol.

[0148] 4. Clinical trial process

[0149] Subjects should go to the research center for the visit according to the visit time notified in advance by the investigator. If any of the following requirements are not met, the visit should be rescheduled:

[0150] ● Subjects should be fasting (at least 8 hours) for all routinely scheduled clinical visits.

[0151] ● Subjects should refrain from high-fat, high-calorie diets the day before the study visit;

[0152] ● Subjects should refrain from smoking, drinking alcohol, or consuming caffeine within 8 hours prior to the study visit.

[0153] In this study, blood samples for hemoglobin and reticulocyte counts (including V2, treatment observation, and early withdrawal visits), free hemoglobin, C3 fragment deposition, and PNH clone size were sent to a central laboratory for testing for efficacy assessment. Given the stability of central laboratory samples, complete blood counts and reticulocyte counts from all visits were sent to a local laboratory for simultaneous testing.

[0154] 5. Evaluation indicators

[0155] 5.1 Effectiveness Evaluation

[0156] 5.1.1 Primary Endpoint

[0157] The proportion of subjects whose hemoglobin (Hb) concentration increased by ≥20 g / L compared to baseline after 24 weeks of treatment among subjects who did not receive red blood cell transfusion after 4 weeks of dosing.

[0158] 5.1.2 Secondary End Points

[0159] The proportion of participants with an Hb level ≥120 g / L at week 24 who had not received a red blood cell transfusion four weeks after dosing;

[0160] The proportion of subjects whose lactate dehydrogenase (LDH) decreased by 60% or more from baseline or whose LDH was below the upper limit of normal after 24 weeks of treatment;

[0161] Changes from baseline in Hb and reticulocyte counts at week 24 in subjects who did not receive a red blood cell transfusion after week 4 of treatment;

[0162] ● Changes from baseline in LDH, indirect bilirubin, and free hemoglobin at week 24 of treatment;

[0163] The proportion of subjects who did not receive a red blood cell transfusion between weeks 4 and 24 of treatment;

[0164] The change in the average number of red blood cell units transfused per week from pre-dose to treatment week 4 through week 24;

[0165] Change from baseline in PNH red blood cell clone size at week 24 in subjects who did not receive a red blood cell transfusion after week 4 of treatment;

[0166] ●Changes in C3 complement protein fragment deposition on PNH red blood cells compared to baseline after 24 weeks of treatment.

[0167] ●Change in the Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) scale score compared to baseline after 24 weeks of treatment.

[0168] 5.2 Safety Assessment

[0169] Safety indicators include:

[0170] The incidence and severity of adverse events;

[0171] The incidence of thromboembolic events;

[0172] ●Laboratory tests, electrocardiogram, vital signs and physical examination, etc.

[0173] 5.3 Pharmacokinetic / pharmacodynamic evaluation

[0174] Pharmacokinetic parameters include:

[0175] ●Concentration of Compound A in plasma;

[0176] ●Changes from baseline in complement alternative pathway (AP) activity, Bb concentration, and plasma sC5b-9 concentration.

[0177] 6. Adverse events

[0178] Adverse events (AEs) are any untoward medical occurrences in subjects in a clinical study. AEs can manifest as symptoms, signs, illnesses, or laboratory abnormalities, but they do not necessarily have a causal relationship with the investigational drug. Therefore, an AE can be any unfavorable, unexpected symptom, sign, test value, or illness (new onset or exacerbation of a pre-existing condition).

[0179] All adverse events that occurred after the subjects used the investigational drug were defined as TEAEs.

[0180] AE does not include:

[0181] ● Chronic diseases that existed but were not aggravated before participating in this clinical study;

[0182] ●Elective medical examinations or surgical procedures before entering the clinical study;

[0183] ● Overdose of investigational drugs or concomitant medications without any symptoms or signs.

[0184] 7. Indicator Analysis

[0185] 7.1 Analysis of Main Efficacy Indicators

[0186] The primary endpoint of this study was the proportion of subjects whose hemoglobin (Hb) concentration increased by ≥20g / L compared with baseline after 24 weeks of treatment among subjects who did not receive red blood cell transfusions 4 weeks after dosing; the study used a historical control design to analyze whether the primary endpoint was significantly higher than the target value (15%) of the historical control.

[0187] For the primary efficacy endpoint, the following statistical assumptions were made:

[0188] Null hypothesis:

[0189] π T -π0≤0

[0190] Alternative hypothesis:

[0191] π T -π0>0

[0192] where π T The proportion of subjects whose hemoglobin (Hb) concentration increased by ≥20 g / L compared with baseline after 24 weeks of treatment among subjects who did not receive red blood cell transfusion after 4 weeks of dosing; π0 was 0.15. The proportion of subjects whose hemoglobin (Hb) concentration increased by ≥20 g / L compared with baseline after 4 weeks of dosing among subjects who did not receive red blood cell transfusion after 24 weeks of treatment, along with the 95% confidence interval and the corresponding P value using the binomial distribution test with a threshold of 15%, was calculated.

[0193] The FAS was used as the primary analysis set, and the PPS was used for sensitivity analysis.

[0194] For other sensitivity analysis methods, please refer to SAP.

[0195] 7.2 Analysis of Secondary Efficacy Indicators

[0196] Statistical analysis is generally performed based on the FAS set.

[0197] The proportion of participants who achieved an Hb level of ≥120 g / L at week 24, among those who had not received a red blood cell transfusion four weeks after dosing;

[0198] A similar method was used to calculate the primary efficacy indicator: the proportion of subjects whose Hb levels reached ≥120 g / L and its corresponding 95% confidence interval among subjects who did not receive red blood cell transfusion 4 weeks after treatment for 24 weeks.

[0199] The proportion of subjects whose LDH decreased by ≥60% from baseline or whose LDH was below the upper limit of normal at week 24;

[0200] The proportion of subjects whose LDH decreased by ≥60% compared with baseline or whose LDH was below the upper limit of normal after 24 weeks of treatment and its corresponding 95% confidence interval were calculated according to the group using a similar method for the primary efficacy indicator.

[0201] Changes from baseline in Hb and reticulocyte counts at week 24 in subjects who did not receive a red blood cell transfusion after week 4 of treatment;

[0202] A repeated measures mixed-effects model (MMRM) was used to analyze the changes in Hb and reticulocyte counts compared to baseline at each analysis visit after baseline. The model used analysis visit and treatment group as fixed effects, subject as a random effect, and baseline values ​​of Hb and reticulocyte count as covariates. The least squares mean (LSMean), standard error (SE), and corresponding 95% CI were calculated. The model was established using an unstructured (UN) covariance structure. If the model did not converge, the Toeplitz matrix (TOEP), first-order autoregressive (AR(1)), or compound symmetric (CS) covariance structure were considered in turn until the non-convergence problem was resolved. Line graphs of the least squares means of the changes in Hb and reticulocyte counts compared to baseline at baseline and each analysis visit after baseline were plotted, with week as the horizontal axis.

[0203] Changes from baseline in LDH, indirect bilirubin, and free hemoglobin at week 24;

[0204] Similar to the changes in Hb and reticulocyte count compared with baseline, the repeated measures mixed effects model (MMRM) was used to analyze the changes in LDH, indirect bilirubin, and free hemoglobin compared with baseline by treatment group, and the corresponding least squares means and their 95% confidence intervals were calculated.

[0205] The proportion of subjects who did not receive a red blood cell transfusion between weeks 4 and 24 of treatment;

[0206] The proportion of subjects who did not receive red blood cell transfusion during treatment weeks 4 to 24 and its 95% confidence interval were calculated using a similar method to the primary efficacy indicator.

[0207] The change in the average number of red blood cell units transfused per week from pre-dose treatment between Weeks 4 and 24;

[0208] Similar to the changes in Hb and reticulocyte counts compared with baseline, the repeated measures mixed effects model (MMRM) was used to analyze the changes in the average weekly number of red blood cell transfusion units compared with pre-dose treatment during weeks 4 to 24 of treatment by group, and the corresponding least squares means and their 95% confidence intervals were calculated.

[0209] Change from baseline in PNH red blood cell clone size at week 24 in subjects who did not receive a red blood cell transfusion after week 4 of treatment;

[0210] Similar to the changes in Hb and reticulocyte counts from baseline, the changes in PNH red cell clone size from baseline in subjects who did not receive red cell transfusions after 4 weeks of dosing were analyzed separately by group using a repeated measures mixed-effects model (MMRM) and the corresponding least squares means and 95% confidence intervals were calculated.

[0211] Change in C3 complement protein fragment deposition on PNH red blood cells compared to baseline at week 24 of treatment;

[0212] Similar to the changes in Hb and reticulocyte counts compared with baseline, the repeated measures mixed effects model (MMRM) was used to analyze the changes in C3 complement protein fragment deposition on PNH erythrocytes compared with baseline, and the corresponding least squares means and their 95% confidence intervals were calculated.

[0213] Change from baseline in the Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) scale score after 24 weeks of treatment.

[0214] Similar to the changes in Hb and reticulocyte counts compared with baseline, the repeated measures mixed-effects model (MMRM) was used to analyze the changes in the Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) scale scores compared with baseline, and the corresponding least squares means and their 95% confidence intervals were calculated.

[0215] 7.3 Security Analysis

[0216] Unless otherwise specified, descriptive statistics were used to analyze safety data in SS.

[0217] Adverse events were coded using MedDRA version 27.0 and above, summarized by preferred term (PT) and system organ class (SOC), and the number, frequency, and percentage of subjects experiencing adverse events were reported. Adverse events were summarized and tabulated according to their relationship to the investigational drug and severity. Adverse events related to the investigational drug, those leading to drug suspension, those leading to dose reduction, those leading to permanent drug discontinuation, those leading to trial withdrawal, serious adverse events, and deaths were summarized and tabulated separately.

[0218] Results of laboratory tests such as routine blood tests, routine urine tests, blood biochemistry tests, coagulation function tests, electrocardiograms, and vital signs at the planned evaluation time points were summarized by group. Cross-tabulations were used to describe the clinical judgment of changes in the post-dose visit results for each indicator relative to baseline. All test results and abnormal test results were tabulated by subject.

[0219] Physical examination data were tabulated by subject, and abnormal results were summarized.

[0220] Descriptive statistics were used to describe the incidence of thromboembolic events by group and the data on thrombosis were tabulated by subject.

[0221] 7.4 Pharmacokinetic / pharmacodynamic analysis

[0222] Pharmacokinetic analysis

[0223] Pharmacokinetic Concentration Analysis: PK concentration data were statistically summarized and tabulated by dose group at each planned sampling time point defined in the protocol. Mean drug concentration-time curves (linear and semi-logarithmic) were plotted for each dose group for V5 and V8. PK concentration data for individual subjects in V5 and V8 were plotted against time (linear and semi-logarithmic) according to the actual sampling time and dose group.

[0224] Pharmacokinetic parameter analysis: The non-compartmental model was used to calculate the pharmacokinetic parameters. The Power model was used to evaluate the main PK parameters (AUC 0-tau 、C max ) and dose.

[0225] Pharmacodynamic analysis

[0226] AP, Bb, and sC5b-9 measurements and their changes from baseline were statistically summarized and tabulated by dose group at each planned sampling time point defined in the protocol. Individual and mean plots of the rate of change relative to baseline over time were also drawn by dose group.

[0227] 8. Research Conclusions

[0228] The results of the study showed that Compound A tablets have good efficacy and safety in the treatment of paroxysmal nocturnal hemoglobinuria.

[0229] Clinical Study 2: A randomized, double-blind, placebo-controlled Phase II clinical trial to evaluate the efficacy and safety of Compound A tablets in the treatment of primary IgA nephropathy

[0230] 1. Study objectives and endpoints

[0231] Table 6 Study objectives and study endpoints

[0232] 2. Overall design

[0233] This Phase II, multicenter, randomized, double-blind, placebo-controlled clinical trial is planned to enroll 80 patients with primary IgA nephropathy. The study will include a screening phase (up to 2 weeks), a run-in phase (at least 4 weeks), a 12-week core treatment phase, a 12-week extension phase, and a 4-week safety follow-up period.

[0234] Screening period:

[0235] Screening will begin after the subjects sign the informed consent form. The screening period is up to 2 weeks. Subjects who complete the screening examination and are assessed by the researchers to meet the lead-in period criteria will enter the lead-in period.

[0236] ●Introduction period:

[0237] After entering the lead-in period, subjects must complete vaccination against Neisseria meningitidis and Streptococcus pneumoniae 2 weeks before the first dose.

[0238] For subjects who have not previously received optimized RAS blocker therapy: Optimized RAS blocker therapy will begin immediately after the run-in period. This treatment regimen will be determined by the investigator based on clinical practice (see Appendix 3). After reaching the maximum recommended dose or maximum tolerated dose, the dose must be maintained stable for at least 4 weeks. Optimized RAS blocker therapy should last for at least 12 weeks. Subjects who meet the randomization criteria at the end of the run-in period may begin randomization.

[0239] Subjects who have previously started RAS blocker optimization treatment but have not reached the maximum recommended dose or maximum tolerated dose: For subjects who have not reached the maximum recommended dose or maximum tolerated dose of RAS blockers before entering the run-in period (with a traceable treatment plan), the investigator will continue to adjust the RAS blocker dose to the maximum recommended dose or maximum tolerated dose based on clinical practice, and then maintain the current dose stable for 4 weeks. Subjects who meet the randomization criteria at the end of the run-in period can start randomization.

[0240] For subjects who have previously received optimized RAS blocker therapy and have reached the maximum recommended dose or maximum tolerated dose: the subjects should maintain the current dose stable for 4 weeks after entering the lead-in period. Those who meet the randomization criteria at the end of the lead-in period can start randomization.

[0241] Core treatment period:

[0242] Subjects who met the randomization criteria were randomly assigned to Compound A 50 mg BID, 100 mg BID, 200 mg QD and placebo groups in a ratio of 1:1:1:1, with 20 subjects in each group.

[0243] The core treatment period totaled 12 weeks, with participants returning to the center for clinical visits every four weeks. Data were cleaned, frozen, and analyzed after the last enrolled participant completed their 12-week clinical visit.

[0244] Extended treatment period:

[0245] The extended treatment period totaled 12 weeks, and patients returned to the center for clinical visits every 4 weeks during the treatment period.

[0246] Safety follow-up period:

[0247] Subjects returned to the center for safety follow-up 4 weeks after the last dose. Subjects were discharged from the study group after completing the protocol-specified safety assessments and evaluations. Any adverse events (AEs) were followed up according to Section 7 of the protocol.

[0248] 3. Study Population

[0249] The inclusion of qualified subjects is an important guarantee for achieving the intended objectives of this study. All medical and non-medical conditions of each subject are considered in determining whether they meet the trial criteria.

[0250] Introduction Period Selection Criteria (You can enter the introduction period only if you meet all of the following criteria)

[0251] 1) Before any study-related activities, participants must understand the nature, purpose, procedures, requirements, and possible risks of the study, voluntarily participate in the study, and sign a written informed consent form;

[0252] 2) Aged ≥ 18 years (based on the signing of the informed consent form), regardless of gender;

[0253] 3) Weight ≥ 35 kg, BMI < 35 kg / m 2 ;

[0254] 4) Primary IgA nephropathy confirmed by renal biopsy within 5 years before screening, with no known secondary causes (including but not limited to Henoch-Schonlein purpura, systemic lupus erythematosus, etc.);

[0255] 5) 24h-UPE ≥ 0.75g / 24h, or FMV UPCR ≥ 0.8g / g at screening;

[0256] 6) eGFR ≥ 30 ml / min / 1.73 m at screening 2 ; (calculated according to the CKD-EPI2021 formula)

[0257] 7) Laboratory tests during screening meet the following criteria:

[0258] a) AST and ALT ≤ 3.0 × ULN; total bilirubin ≤ 2.0 × ULN;

[0259] b) Hemoglobin ≥90 g / L;

[0260] c) Platelet count ≥80×10 9 / L;

[0261] d) Female subjects must meet the following requirements:

[0262] a) Not of childbearing potential, i.e., surgically sterilized (hysterectomy, bilateral salpingectomy, bilateral oophorectomy at least 6 weeks prior to screening) or postmenopausal (postmenopausal is defined as no menstruation for 12 months without other medical reasons), or

[0263] b) If you are a female of childbearing age, you must have a negative pregnancy test at screening. You must agree not to attempt pregnancy, not to donate eggs, and to use effective contraception from the time you sign the informed consent form until at least 30 days after the last dose of the investigational drug.

[0264] 8) Male subjects, if not surgically sterilized, must agree not to donate sperm from the time they sign the informed consent form until at least 90 days after the last dose of the study drug. If they have sexual intercourse with a female partner who may become pregnant, in addition to having the female partner use an effective contraceptive method, they must also voluntarily use condoms.

[0265] Randomization inclusion criteria (randomization can only be performed if all the following criteria are met)

[0266] 9) Received optimized RAS blocker (ACEI or ARB) treatment for ≥12 weeks before randomization, and the dose has been stable for ≥4 weeks after reaching the maximum recommended dose or maximum tolerated dose; subjects who are intolerant to RAS blockers as determined by the investigator may be enrolled;

[0267] 10) Subjects receiving SGLT2 inhibitors, endothelin receptor antagonists, or hydroxychloroquine must have been receiving stable treatment for ≥12 weeks before randomization and are expected to maintain a stable prescription during the study;

[0268] 11) 24h-UPE ≥ 0.75g / 24h before randomization;

[0269] 12) eGFR ≥ 30 ml / min / 1.73 m before randomization 2 ; (calculated according to the CKD-EPI2021 formula)

[0270] 13) Vaccination against Neisseria meningitidis and Streptococcus pneumoniae must be performed at least 2 weeks before the first dose of Compound A. If Compound A treatment must be started less than 2 weeks after vaccination, prophylactic antibiotic treatment must be started for at least 2 weeks after vaccination.

[0271] Subjects who meet any of the following criteria are not eligible for inclusion in this study:

[0272] 1) Participants who have participated in any clinical trial of drugs or medical devices within 3 months before screening and are expected to have residual effects of the trial treatment (judged by the investigator), or are still in the follow-up period of a clinical trial or within 5 half-lives of the trial drug (whichever is longer) before screening;

[0273] 2) Known or suspected (judgment by the investigator) immunodeficiency disease or hereditary complement deficiency;

[0274] 3) As assessed by the investigator, blood pressure was uncontrolled at screening (e.g., systolic blood pressure ≥160 mmHg or diastolic blood pressure ≥100 mmHg);

[0275] 4) As assessed by the investigator, blood sugar levels were uncontrolled at screening (e.g., fasting blood sugar ≥ 11.1 mmol / L);

[0276] 5) Rapidly progressive glomerulonephritis (eGFR decreases by more than 50% within 3 months, or less than 50% but with a risk of rapid decline in renal function as assessed by the investigator); renal pathology showing crescents in more than 50% of the glomeruli (referring to large crescents, i.e., crescents occupying more than 50% of the renal capsule); tubular atrophy and interstitial fibrosis exceeding 50%;

[0277] 6) History of bone marrow / hematopoietic stem cell or solid organ transplantation;

[0278] 7) Patients diagnosed with malignant tumors within the past 5 years (excluding radically resected basal cell carcinoma of the skin, papillary thyroid cancer, squamous cell carcinoma of the skin, or cervical cancer in situ);

[0279] 8) History of infection with encapsulated bacteria (such as Neisseria meningitidis, Streptococcus pneumoniae, Haemophilus influenzae, etc.);

[0280] 9) Patients with active tuberculosis who have been or are currently diagnosed, or patients with untreated latent tuberculosis;

[0281] 10) Any history or signs of significant chronic active or recurrent infection within 6 months prior to screening, or laboratory evidence of significant chronic active or recurrent infection requiring treatment with antibacterial, antiviral or antifungal drugs at screening;

[0282] 11) Human immunodeficiency virus (HIV) infection (known history of HIV or positive HIV antibody screening), active syphilis infection; active hepatitis B virus infection (positive hepatitis B surface antigen and HBV DNA ≥ 1×ULN), hepatitis C virus infection (positive HCV antibody and HCV RNA ≥ 1×ULN);

[0283] 12) Patients who have received systemic glucocorticoids (prednisone or equivalent drugs, including budesonide enteric-coated capsules), immunosuppressants / modulators (such as mycophenolic acid, cyclosporine, calcineurin inhibitors, etc.), or traditional Chinese medicines with immunosuppressive effects (such as tripterygium wilfordii preparations and Sinomene sinomenine preparations) within 12 weeks before administration, or who are assessed by the investigator to be likely to use the above treatments during the study;

[0284] 13) Patients who have received aldosterone receptor antagonists, renin inhibitors, or drugs that significantly affect creatinine levels (such as Urea Clearance Granules, Shenshuaining, fibrate lipid-lowering drugs, and medicinal charcoal tablets) within 4 weeks prior to administration; or patients who may need to use the above treatments during the study as assessed by the investigator;

[0285] 14) Patients who have received biological treatment within 6 months before administration, such as CD20 monoclonal antibody, CD38 monoclonal antibody, or cytokine inhibitors; or other complement pathway inhibitors other than the experimental drugs in this study;

[0286] 15) Major comorbidities, as judged by the investigator, including but not limited to advanced heart disease (such as New York Heart Association (NYHA) class III and IV), severe lung disease (such as severe pulmonary hypertension (World Health Organization (WHO) class III and IV), or severe liver disease;

[0287] 16) Subjects who have undergone gastrointestinal surgery that may significantly affect drug absorption, distribution, metabolism, and excretion, or have a history of severe gastrointestinal diseases, or have difficulty swallowing or taking medication due to dysphagia or repeated vomiting;

[0288] 17) Allergic to any ingredient in the experimental drug;

[0289] 18) Those who have donated blood within 12 weeks before screening or have a history of severe blood loss (blood volume ≥ 400 mL), or have received blood transfusion within 12 weeks before screening;

[0290] 19) Patients with a history of severe trauma or major surgery within 12 weeks prior to screening, or those planning to undergo major surgery during the trial;

[0291] 20) Women who are pregnant or breastfeeding, or women who plan to become pregnant during the study and follow-up period;

[0292] 21) Any medical condition that the researcher determines may affect the patient's participation in the study, may increase the significant risk to the subject's safety, poor compliance, or other conditions that the researcher determines are unsuitable for study participation.

[0293] 4. Study Intervention

[0294] According to the definition of investigational drugs in the current "Good Clinical Practice for Drugs" (referring to investigational drugs and control drugs used in clinical trials), the investigational drugs in this study include: Compound A tablets and placebo.

[0295] 4.1 Information on investigational drugs

[0296] Experimental drug: Compound A tablets, provided by Sichuan Hisike Pharmaceutical Co., Ltd., prepared according to the method described in WO2024175028A1; dosage form: tablets; specifications: 25 mg and 100 mg; storage conditions: sealed; shelf life: tentatively 24 months.

[0297] The control drug (placebo) is a Compound A tablet sham. The packaging, administration method, labeling, appearance, taste, and smell are identical to those of Compound A tablets, concealing the true nature of the therapeutic drug. All shams are manufactured by Sichuan Hisike Pharmaceutical Co., Ltd. according to the specifications and appearance of Compound A tablets and stored under the same conditions as the study drug, Compound A tablets.

[0298] 4.2 Dosage Regimen

[0299] Dosage and Administration:

[0300] Subjects who passed the screening and met the randomization criteria were randomly assigned to each trial drug group and placebo group in a ratio of 1:1:1:1. The specific dosing regimen is as follows:

[0301] Take once a day, morning and evening, on an empty stomach or after a meal, with appropriate amount of water. The treatment time shall be as per the requirements in the following section.

[0302] The treatment period of this study is 24 weeks in total, including a 12-week core treatment period and a 12-week extension treatment period.

[0303] Table 7 Dosage

[0304] 5. Research steps

[0305] Before any study procedures begin, subjects will need to read and sign the ICF approved by the ethics committee. Investigators will confirm subject eligibility before enrollment. Detailed study procedures and assessment schedules are provided in the trial flow chart (Tables 8 and 9). All study steps must be performed within the time window indicated in the trial flow chart (Tables 8 and 9). Visit times and time windows are calculated based on the first dose date as Day 1 (D1).

[0306] The study process includes screening period, lead-in period, core treatment period, extended treatment period and safety follow-up period.

[0307] End of study

[0308] This is defined as the last subject completing the final safety follow-up.

[0309] 6. Research Evaluation

[0310] Every effort should be made to ensure that the tests and procedures required by the protocol are completed as planned. When a protocol-required test cannot be performed, the investigator should document the reasons, state the corrective and preventive measures taken to ensure the clinical trial proceeds according to the protocol, and promptly inform the research team of such unexpected circumstances.

[0311] 6.1 Effectiveness Evaluation

[0312] At the scheduled visit time points, laboratory parameters assessing renal function, including 24-hour UPCR, 24-hour UPE, FMV UPCR, UACR, eGFR, and serum creatinine, were collected for efficacy evaluation. All of these parameters were sent to the central laboratory for testing at baseline and during the dosing period.

[0313] 6.2 Safety evaluation

[0314] Safety will be monitored by vital signs, physical examination, 12-lead ECG, laboratory tests, pregnancy testing, and concomitant treatment, as well as collection of all AEs (including serious adverse events, SAEs, surveillance events).

[0315] Adverse events

[0316] The evaluation includes type, severity, onset and end time, whether it is a serious adverse event, relevance to the investigational drug, and outcome, etc. AEs occurring during the study, including screening signs and symptoms, will be recorded in the original medical records.

[0317] 6.3 Pharmacokinetic Evaluation

[0318] PK blood samples were collected on D1, the first dose, and at V4, V5, V6, V8, and V9. Detailed collection schedules are provided in the experimental flow chart (Tables 8 and 9). PK blood samples were sent to the bioanalytical laboratory for testing of Compound A plasma concentrations.

[0319] 6.4 Pharmacodynamic Evaluation

[0320] Collect PD blood and / or urine samples on Day 1 (d1) at the time of first administration, and on Days 3, 4, 5, 6, 8, and 9. Detailed collection schedules are provided in the study flow chart (Tables 8 and 9). PD blood and urine samples were sent to the bioanalytical laboratory for testing.

[0321] 7. Definition of Adverse Events

[0322] Adverse events (AEs) refer to all adverse medical events that occur to subjects in clinical studies. They may manifest as symptoms, signs, diseases, or laboratory abnormalities, but are not necessarily causally related to the investigational drug. AEs include but are not limited to:

[0323] 1) Exacerbation of existing medical conditions / diseases (before entering the clinical trial) (including aggravation of symptoms, signs, and laboratory abnormalities);

[0324] 2) Any new AE: any new adverse medical condition (including symptoms, signs, and newly diagnosed diseases);

[0325] 3) Abnormal laboratory test results with clinical significance.

[0326] 4) If the investigator believes that a significantly abnormal laboratory value is of no clinical significance, the reason should be clearly recorded in the original documentation (e.g., normal fluctuations of the disease).

[0327] 8. Indicator Analysis

[0328] 8.1 Effectiveness Analysis

[0329] 8.1.1 Five Attributes of the Main Estimation Target

[0330] Treatment: Compound A 50 mg BID, 100 mg BID, 200 mg QD or placebo was administered on top of optimized supportive care.

[0331] ● Population: Patients with primary IgA nephropathy confirmed by renal biopsy, who meet the inclusion criteria and do not meet the exclusion criteria and undergo randomization;

[0332] ●Variable: Ratio of 24h-UPCR after 12 weeks of treatment to baseline;

[0333] Concomitant events and management strategies: Concomitant events include premature withdrawal from treatment, adjustment of the basic treatment prescription during treatment, and receipt of prohibited treatments during treatment. Data collected after all concomitant events, based on the treatment strategy, will be included in the statistical analysis;

[0334] ●Group-level summary: least squares geometric mean ratio between groups.

[0335] 8.1.2 Primary Efficacy Endpoint Analysis

[0336] The primary analysis of the study's primary objective will be based on the FAS, using a repeated measures mixed-effects model (MMRM) to estimate the least squares mean and 95% CI of the ratio of 24h-UPCR to baseline after 12 weeks of treatment in each treatment group, as well as the least squares geometric mean ratio and 95% CI between each treatment group and the placebo group. The MMRM model will include data from baseline to all planned visits (natural log-transformed) from week 12 of the treatment period, with randomization factors, treatment group, visit, and visit-treatment group interaction as fixed effects, log-baseline 24h-UPCR as a covariate, and subject as a random effect. The model uses an unstructured (UN) covariance matrix to fit the correlations between repeated measurements of subjects (if the model does not converge, a covariance matrix structure such as TOEPH, ARH(1) or CS can be used in sequence); the covariance matrix parameters will be estimated using the restricted maximum likelihood method (REML); and the degrees of freedom will be calculated using the Kenward-Roger method.

[0337] At the same time, the dose-effect relationship was explored for the main estimation targets, and analysis was performed based on monotonic dose-effect models including linear models and Emax models.

[0338] 8.1.3 Secondary Endpoint Analysis

[0339] Secondary efficacy measures will be analyzed based on the FAS. For secondary efficacy endpoints (ratios of 24-hour UPCR to baseline at other clinical visits during the treatment period, ratios of 24-hour UPE to baseline at each clinical visit during the treatment period, and ratios of FMV UPCR and UACR to baseline at each clinical visit during the treatment period), after natural logarithm transformation, the MMRM model will be used for analysis. Data from baseline to week 24 of the treatment period will be included. The randomization stratification factor, treatment group, visit, and visit-treatment group interaction term will be used as fixed effects, the log-baseline variable will be used as a covariate, and the subject will be used as a random effect. The change in estimated glomerular filtration rate from baseline at each clinical visit during the treatment period and the change in serum creatinine from baseline at each clinical visit during the treatment period will be analyzed using the MMRM model. The model will include the randomization stratification factor, treatment group visit, and visit-treatment group interaction term as fixed effects, the log-baseline variable will be used as a covariate, and the subject will be used as a random effect.

[0340] 8.2 Security Analysis

[0341] The safety analysis will be summarized and tabulated based on the safety analysis set, according to the stage and the treatment group actually received by the subject, including but not limited to statistical descriptions and tabulations of the subject's adverse events, laboratory data, vital signs data, electrocardiogram data, etc.

[0342] 8.3 Pharmacokinetic Analysis

[0343] Statistical analysis of PK parameters will be descriptively summarized based on the PK parameter analysis data set. Non-compartmental models will be used to estimate and analyze pharmacokinetic parameters. Key pharmacokinetic parameters include but are not limited to AUC0-τ, Tmax, Cmax, t1 / 2, CL / F, Vd / F, etc.

[0344] Compound A plasma concentrations will be statistically described at scheduled blood sampling times. Data from this study will be combined with data from other Compound A clinical trials to develop a population pharmacokinetic model to assess the impact of internal and external covariates on the pharmacokinetic properties of Compound A. Additionally, exposure-response analyses will be conducted for specific efficacy and safety endpoints. The results of these population pharmacokinetic and exposure-response analyses will be included in separate reports.

[0345] 8.4 Pharmacodynamic Analysis

[0346] Based on the PDS, changes from baseline in AP activity, plasma Bb fragment levels, and plasma and urine sC5b-9 levels were summarized and tabulated descriptively.

[0347] 9. Research Conclusions

[0348] The results of a randomized, double-blind, placebo-controlled Phase II clinical study showed that Compound A tablets have good efficacy and safety in the treatment of primary IgA nephropathy.

Claims

1. Use of a compound of formula (I) or a stereoisomer, tautomer, pharmaceutically acceptable salt, cocrystal or a combination thereof in the preparation of a medicament for preventing or treating a disease or condition mediated by complement factor B, wherein: administering an effective dose of a compound of formula (I) or a stereoisomer, tautomer, pharmaceutically acceptable salt, co-crystal or a combination thereof to a mammal, Selected from R 1 Selected from -OCH3 or -OCD3; R 2 Selected from -CH3 or -CD3; n is selected from 1, 2 or 3; The complement factor B-mediated disease or condition is selected from at least one of the following: paroxysmal nocturnal hemoglobinuria, primary glomerulonephritis, membranous nephropathy, C3 glomerulonephritis, and atypical hemolytic uremic syndrome.

2. The use according to claim 1, wherein The compound of formula (I) is selected from the following structures: or 3. The use according to claim 2, wherein An effective dose of the compound of formula (A) or its stereoisomer, tautomer, pharmaceutically acceptable salt, co-crystal or combination thereof is administered to a mammal.

4. The use according to claim 3, wherein The pharmaceutically acceptable salt is selected from hydrochloride, succinate, sulfate, maleate, phosphate, tartrate, fumarate, citrate, naphthalene disulfonate, p-toluenesulfonate, methanesulfonate, benzenesulfonate, oxalate, gentisate, succinate or hydrobromide.

5. The use according to any one of claims 1 to 4, wherein The effective dose is based on the free base of formula (A), and the effective dose is 1-2400 mg / day.

6. The use according to claim 5, wherein The administration interval of the compound of formula (A) or its stereoisomer, tautomer, pharmaceutically acceptable salt, cocrystal or composition thereof is selected from once a day, twice a day, three times a day, once a week, twice a week, three times a week or once every other day.

7. The use according to claim 6, wherein The administration route of the compound of formula (A) or its stereoisomer, tautomer, pharmaceutically acceptable salt, cocrystal or composition thereof is selected from oral, injection, instillation, transdermal absorption, buccal absorption, parenteral intraperitoneal, rectal, transbuccal, nasal spray, nasal drops, inhalation, local delivery, subcutaneous, intrafatty, intraarticular, intraperitoneal or intrathecal, preferably oral, injection and nasal spray.

8. The use according to claim 7, wherein The administration route of the compound of formula (A) or its stereoisomer, tautomer, pharmaceutically acceptable salt, cocrystal or composition thereof is selected from oral administration, intravenous injection, intravenous drip, arterial injection, intramuscular injection, subcutaneous injection, intraarticular injection, intraperitoneal injection, intrathecal injection or nasal drops.

9. A method for treating a disease or condition mediated by complement factor B, the method comprising administering to a mammal an effective dose of a compound of formula (I) or (A) according to any one of claims 1 to 4, or a stereoisomer, tautomer, pharmaceutically acceptable salt, cocrystal or a combination thereof, wherein the effective dose is 1-2400 mg / day, preferably 20 mg-50 mg / day, 60 mg-150 mg / day, 120 mg-300 mg / day, 240 mg-600mg / day, 320mg-800mg / day, 40mg-100mg / day, 120mg-300mg / day, 240mg-600mg / day, 480mg-1200mg / day, 640-1600mg / day, 60mg-150mg / day, 180mg-450mg / day, 360mg-9000mg / day, 720mg-1800mg / day or 96-2400mg / day; The complement factor B-mediated disease or condition is selected from at least one of the following: paroxysmal nocturnal hemoglobinuria, primary glomerulonephritis, membranous nephropathy, C3 glomerulonephritis, and atypical hemolytic uremic syndrome.

10. The method according to claim 9, wherein: The administration interval of the compound of structural formula (A) or its stereoisomer, tautomer, pharmaceutically acceptable salt, cocrystal or composition thereof is selected from once a day, twice a day, three times a day, once a week, twice a week, three times a week or once every other day.

11. The method according to claim 9 or 10, wherein: The administration route of the compound of formula (A) or its stereoisomer, tautomer, pharmaceutically acceptable salt, co-crystal or composition is selected from oral, injection, instillation, transdermal absorption, buccal absorption, parenteral intraperitoneal, rectal, transbuccal, nasal drops, inhalation, topical delivery, subcutaneous, intrafatty, intraarticular, intraperitoneal or intrathecal.

12. The method according to claim 11, wherein: The administration route of the compound of formula (A) or its stereoisomer, tautomer, pharmaceutically acceptable salt, cocrystal or composition thereof is selected from oral administration, intravenous injection, intravenous drip, arterial injection, intramuscular injection, subcutaneous injection, intraarticular injection, intraperitoneal injection, intrathecal injection or nasal drops.

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