Use of complement factor b inhibitor in preparation of drug for treating or preventing pnh

Abstract

The present invention belongs to the field of biotechnology. Disclosed is use of a complement factor B inhibitor in the preparation of a drug for treating or preventing a disease or condition related to paroxysmal nocturnal hemoglobinuria. Specifically, the present invention provides use of a compound represented by formula A or a pharmaceutically acceptable salt thereof or a hydrate thereof in the preparation of a drug for treating or preventing a disease or condition related to paroxysmal nocturnal hemoglobinuria. The present invention can effectively inhibit the incidence of hemolysis in paroxysmal nocturnal hemoglobinuria, providing an effective and safe new option for the treatment of paroxysmal nocturnal hemoglobinuria.

Description

Use of complement factor B inhibitors in the manufacture of a medicament for treating or preventing PNH

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims the benefit of Chinese Patent Application No. CN202410898436.0, filed July 5, 2024; the entire contents of which are incorporated herein by reference. TECHNICAL FIELD

[0003] The present application belongs to the field of biological medicine, and relates to the use of a complement factor B inhibitor in the manufacture of a medicament for treating or preventing PNH, in particular, the use of a complement factor B inhibitor in the manufacture of a medicament for treating or preventing a disease or disorder associated with paroxysmal nocturnal hemoglobinuria (PNH). BACKGROUND

[0004] The complement system is part of the host innate immune system that participates in the lysis of foreign cells, enhances antigen phagocytosis, agglutinates antigen carriers, and attracts macrophages and neutrophils, and is an important part of the body's innate immunity against infections of exogenous pathogens, bacteria, and parasites, etc. The complement system is also an important component of the connection between innate immunity and adaptive immunity. The complement system includes complement intrinsic components and various regulatory proteins. The complement intrinsic components include C1-C9, among which C3 has the highest content. The complement system is mainly activated through three pathways: the classical pathway (CP), the lectin pathway (LP), and the alternative pathway (AP).

[0005] Under normal physiological conditions in healthy individuals, the AP pathway is always in a low-level activated state to monitor the invasion of foreign pathogens at any time. Complement proteins are distributed on the surface of apoptotic cells, and complement activation is strictly regulated, only for the clearance of apoptotic cells, without further activation of other innate immune or adaptive immune responses. In the case of infection of foreign pathogens, the complement system is fully activated, producing inflammatory reactions, opsonization or phagocytosis, etc., to destroy pathogens and ultimately activate adaptive immune responses. Both the inefficiency and the excessive stimulation of complement can be harmful to the human body and are associated with increased susceptibility to infections or non-infectious diseases. Complement dysfunction or overactivation has been associated with certain autoimmune, inflammatory, and neurodegenerative diseases, as well as ischemia-reperfusion injury and cancer. For example, paroxysmal nocturnal hemoglobinuria (PNH).

[0006] Paroxysmal nocturnal hemoglobinuria (PNH) is a clonal disease of acquired genetic mutation of hematopoietic stem cells, with thrombosis, hemolytic anemia and bone marrow failure as the main clinical features. Continuous intravascular hemolysis can be triggered by various stress factors, such as infection or physical exertion, thereby causing smooth muscle contraction (free hemoglobin), chronic anemia and increased risk of severe thromboembolism. Thromboembolism is the most common cause of death in PNH patients, which can lead to pulmonary hypertension and end-organ damage of important organs such as liver, kidney, brain and intestine. Since PNH patients have a high risk of morbidity and mortality, medical personnel in the field have been committed to finding strategies to treat PNH.

[0007] Current treatment strategies for PNH include terminal complement blockade and allogeneic hematopoietic stem cell transplantation. Allogeneic hematopoietic stem cell transplantation is the only radical method, but the high treatment cost makes poor patients hesitate, and the treatment-related death caused by large-dose chemotherapy during pretreatment and rejection after transplantation is also a problem that cannot be ignored. Since 2007, the successful application of complement inhibitors represented by eculizumab has brought hope to PNH patients, but the high price, lifelong medication and regular medication have brought a great burden to patients. Therefore, it is of great clinical significance to develop a new drug for treating PNH.

[0008] PCT / CN2024 / 071419 provides a class of complement factor B inhibitors, complement factor B (Complement Factor B, FB) is a key protein involved in AP activation, inhibiting FB activity can prevent AP pathway activation, and does not interfere with CP and LP pathways, which can avoid increasing the risk of infection due to complement system inhibition. SUMMARY

[0009] All the contents involved in the patent PCT / CN2024 / 071419 are added to the present application by reference.

[0010] The purpose of the present application is to provide a complement factor B inhibitor or a pharmaceutically acceptable salt thereof or a hydrate thereof for use in the preparation of a medicament or a pharmaceutical composition for treating or preventing a disease or a disorder associated with paroxysmal nocturnal hemoglobinuria.

[0011] In one aspect, the present application provides a use of a compound of formula A or a pharmaceutically acceptable salt thereof or a hydrate thereof in the preparation of a medicament for treating and / or preventing a disease or a disorder associated with paroxysmal nocturnal hemoglobinuria,

[0012] The structure of formula A is as follows:

[0013] wherein X is selected from H or glucuronyl group;

[0014] Preferably, X is selected from H or D-glucuronide.

[0015] In another aspect, the present application provides use of a compound of Formula A, or a pharmaceutically acceptable salt thereof, or a hydrate thereof, in the manufacture of a medicament for reducing the incidence of paroxysmal nocturnal hemoglobinuria (PNH)-related hemolysis in a population of subjects,

[0016] The structure of Formula A is as follows:

[0017] wherein X is selected from H or glucuronide;

[0018] Preferably, X is selected from H or D-glucuronide.

[0019] In some embodiments of the present application, the medicament or pharmaceutical composition further comprises one or more pharmaceutically acceptable carriers or other therapeutic agents.

[0020] In one embodiment of the present application, X is H, and the compound of Formula A is further represented by Formula I:

[0021] In one embodiment of the present application, X is D-glucuronide, and the compound of Formula A is further represented by Formula II-M:

[0022] In one embodiment of the present application, X is D-glucuronide, and the compound of Formula A is further represented by Formula II:

[0023] In one embodiment of the present application, the present application provides use of a compound of Formula I, or a pharmaceutically acceptable salt thereof, or a hydrate thereof, in the manufacture of a medicament or a pharmaceutical composition for treating or preventing a disease or a disorder associated with paroxysmal nocturnal hemoglobinuria (PNH).

[0024] In one embodiment of the present application, the present application provides use of a compound of Formula II-M, or a pharmaceutically acceptable salt thereof, or a hydrate thereof, in the manufacture of a medicament or a pharmaceutical composition for treating or preventing a disease or a disorder associated with paroxysmal nocturnal hemoglobinuria (PNH).

[0025] In one embodiment of the present application, the present application provides use of a compound of Formula II, or a pharmaceutically acceptable salt thereof, or a hydrate thereof, in the manufacture of a medicament or a pharmaceutical composition for treating or preventing a disease or a disorder associated with paroxysmal nocturnal hemoglobinuria (PNH).

[0026] In one embodiment of the present application, the present application provides use of a compound of Formula I or a pharmaceutically acceptable salt thereof or a hydrate thereof in the manufacture of a medicament or a pharmaceutical composition for reducing the incidence of paroxysmal nocturnal hemoglobinuria-associated hemolysis in a population of subjects.

[0027] In one embodiment of the present application, the present application provides use of a compound of Formula II-M or a pharmaceutically acceptable salt thereof or a hydrate thereof in the manufacture of a medicament or a pharmaceutical composition for reducing the incidence of paroxysmal nocturnal hemoglobinuria-associated hemolysis in a population of subjects.

[0028] In one embodiment of the present application, the present application provides use of a compound of Formula II or a pharmaceutically acceptable salt thereof or a hydrate thereof in the manufacture of a medicament or a pharmaceutical composition for reducing the incidence of paroxysmal nocturnal hemoglobinuria-associated hemolysis in a population of subjects.

[0029] In one embodiment of the present application, the compound of formula A is administered in a dose of 0.1 to 2000 mg per dose, in particular 1 mg per dose, 2.5 mg per dose, 5 mg per dose, 7.5 mg per dose, 10 mg per dose, 12.5 mg per dose, 15 mg per dose, 17.5 mg per dose, 20 mg per dose, 22.5 mg per dose, 25 mg per dose, 27.5 mg per dose, 30 mg per dose, 32.5 mg per dose, 35 mg per dose, 37.5 mg per dose, 40 mg per dose, 42.5 mg per dose, 45 mg per dose, 47.5 mg per dose, 50 mg per dose, 52.5 mg per dose, 55 mg per dose, 60 mg per dose, 65 mg per dose, 70 mg per dose, 75 mg per dose, 80 mg per dose, 85 mg per dose, 90 mg per dose, 95 mg per dose, 100 mg per dose, 105 mg per dose, 110 mg per dose, 120 mg per dose, 130 mg per dose, 140 mg per dose, 150 mg per dose, 160 mg per dose, 170 mg per dose, 180 mg per dose, 190 mg per dose, 200 mg per dose, 210 mg per dose, 220 mg per dose, 230 mg per dose, 240 mg per dose, 250 mg per dose, 260 mg per dose, 270 mg per dose, 280 mg per dose, 290 mg per dose, 300 mg per dose, 350 mg per dose, 400 mg per dose, 450 mg per dose, 500 mg per dose, 550 mg per dose, 600 mg per dose, 700 mg per dose, 750 mg per dose, 800 mg per dose, 900 mg per dose, 1000 mg per dose, 1200 mg per dose, 1500 mg per dose, 1800 mg per dose, 2000 mg per dose and values in between any of the above-mentioned values (although not listed, are considered to be explicitly mentioned); preferably 10 to 1000 mg per dose; more preferably 50 to 700 mg per dose; further preferably 75 to 600 mg per dose; even further preferably 100 to 600 mg per dose; even further preferably 100 mg per dose, 200 mg per dose, 300 mg per dose or 400 mg per dose.

[0030] In one embodiment of the present application, the compound of formula A is administered in a dose of 100 mg per dose, 200 mg per dose, 300 mg per dose or 400 mg per dose.

[0031] In one embodiment of the present application, the compound of formula A is administered in a dose of 100 mg per dose or 200 mg per dose.

[0032] In one embodiment of the present application, the compound of formula A is administered in a dose of 100 mg per dose.

[0033] In one embodiment of the present application, the compound of formula A is administered in a dose of 200 mg per dose.

[0034] In one embodiment of the present application, the compound of formula A is administered at a dose of 300 mg per administration.

[0035] In one embodiment of the present application, the compound of formula A is administered at a dose of 400 mg per administration.

[0036] In one embodiment of the present application, the compound of formula A is administered once a day, twice a day, three times a day, once a week, three times a week, once in two weeks, once in three weeks or once in a month; preferably once a day, twice a day or three times a day.

[0037] In one embodiment of the present application, the compound of formula A is administered once a day.

[0038] In one embodiment of the present application, the compound of formula A is administered at a dose of 100 mg per administration, 200 mg per administration, 300 mg per administration or 400 mg per administration, and the administration is once a day.

[0039] In one embodiment of the present application, the compound of formula A is administered at a dose of 100 mg per administration or 200 mg per administration, and the administration is once a day.

[0040] In one embodiment of the present application, the compound of formula A is administered at a dose of 100 mg per administration, and the administration is once a day.

[0041] In one embodiment of the present application, the compound of formula A is administered at a dose of 200 mg per administration, and the administration is once a day.

[0042] In one embodiment of the application, the compound of formula I is administered in a dose of 0.1 to 2000 mg, in particular 1 mg, 2.5 mg, 5 mg, 7.5 mg, 10 mg, 12.5 mg, 15 mg, 17.5 mg, 20 mg, 22.5 mg, 25 mg, 27.5 mg, 30 mg, 32.5 mg, 35 mg, 37.5 mg, 40 mg, 42.5 mg, 45 mg, 47.5 mg, 50 mg, 52.5 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 105 mg, 110 mg, 120 mg, 130 mg, 140 mg, 150 mg, 160 mg, 170 mg, 180 mg, 190 mg, 200 mg, 210 mg, 220 mg, 230 mg, 240 mg, 250 mg, 260 mg, 270 mg, 280 mg, 290 mg, 300 mg, 350 mg, 400 mg, 450 mg, 500 mg, 550 mg, 600 mg, 700 mg, 750 mg, 800 mg, 900 mg, 1000 mg, 1200 mg, 1500 mg, 1800 mg, 2000 mg, or a value between any of the above-mentioned values (although not listed, this is considered to be explicitly mentioned); preferably 10 to 1000 mg; more preferably 50 to 700 mg; further preferably 75 to 600 mg; even further preferably 100 to 600 mg; even further preferably 100 mg, 200 mg, 300 mg or 400 mg.

[0043] In one embodiment of the application, the compound of formula I is administered in a dose of 100 mg, 200 mg, 300 mg or 400 mg.

[0044] In one embodiment of the application, the compound of formula I is administered in a dose of 100 mg or 200 mg.

[0045] In one embodiment of the application, the compound of formula I is administered in a dose of 100 mg.

[0046] In one embodiment of the application, the compound of formula I is administered in a dose of 200 mg.

[0047] In one embodiment of the application, the compound of formula I is administered at a dose of 300 mg per administration.

[0048] In one embodiment of the application, the compound of formula I is administered at a dose of 400 mg per administration.

[0049] In one embodiment of the application, the compound of formula I is administered once a day, twice a day, three times a day, once a week, three times a week, once in two weeks, once in three weeks or once in a month; preferably once a day, twice a day or three times a day.

[0050] In one embodiment of the application, the compound of formula I is administered once a day.

[0051] In one embodiment of the application, the compound of formula I is administered at a dose of 100 mg per administration, 200 mg per administration, 300 mg per administration or 400 mg per administration, and the administration is once a day.

[0052] In one embodiment of the application, the compound of formula I is administered at a dose of 100 mg per administration or 200 mg per administration, and the administration is once a day.

[0053] In one embodiment of the application, the compound of formula I is administered at a dose of 100 mg per administration, and the administration is once a day.

[0054] In one embodiment of the application, the compound of formula I is administered at a dose of 200 mg per administration, and the administration is once a day.

[0055] In one embodiment of the application, the compound of formula I is administered at a dose of 300 mg per administration, and the administration is twice a day.

[0056] In one embodiment of the application, the compound of formula I is administered at a dose of 400 mg per administration, and the administration is twice a day.

[0057] In one embodiment of the present application, the compound of formula II-M or the compound of formula II is administered in a dose of 0.1 to 2000 mg per time, in particular 1 mg per time, 2.5 mg per time, 5 mg per time, 7.5 mg per time, 10 mg per time, 12.5 mg per time, 15 mg per time, 17.5 mg per time, 20 mg per time, 22.5 mg per time, 25 mg per time, 27.5 mg per time, 30 mg per time, 32.5 mg per time, 35 mg per time, 37.5 mg per time, 40 mg per time, 42.5 mg per time, 45 mg per time, 47.5 mg per time, 50 mg per time, 52.5 mg per time, 55 mg per time, 60 mg per time, 65 mg per time, 70 mg per time, 75 mg per time, 80 mg per time, 85 mg per time, 90 mg per time, 95 mg per time, 100 mg per time, 105 mg per time, 110 mg per time, 120 mg per time, 130 mg per time, 140 mg per time, 150 mg per time, 160 mg per time, 170 mg per time, 180 mg per time, 190 mg per time, 200 mg per time, 210 mg per time, 220 mg per time, 230 mg per time, 240 mg per time, 250 mg per time, 260 mg per time, 270 mg per time, 280 mg per time, 290 mg per time, 300 mg per time, 350 mg per time, 400 mg per time, 450 mg per time, 500 mg per time, 550 mg per time, 600 mg per time, 700 mg per time, 750 mg per time, 800 mg per time, 900 mg per time, 1000 mg per time, 1200 mg per time, 1500 mg per time, 1800 mg per time, 2000 mg per time and values between any two of the above-mentioned values (although not listed one by one, but considered to be explicitly mentioned); preferably 10 to 1000 mg per time; more preferably 50 to 700 mg per time; further preferably 75 to 600 mg per time; further more preferably 100 to 600 mg per time; further more preferably 100 mg per time, 200 mg per time, 300 mg per time or 400 mg per time.

[0058] In one embodiment of the present application, the compound of formula II-M or the compound of formula II is administered in a dose of 100 mg per time, 200 mg per time, 300 mg per time or 400 mg per time.

[0059] In one embodiment of the present application, the compound of formula II-M or the compound of formula II is administered in a dose of 100 mg per time or 200 mg per time.

[0060] In one embodiment of the present application, the compound of formula II-M or the compound of formula II is administered in a dose of 100 mg per time.

[0061] In one embodiment of the present application, the compound of Formula II-M or the compound of Formula II is administered at a dose of 200 mg per dose.

[0062] In one embodiment of the present application, the compound of Formula II-M or the compound of Formula II is administered at a dose of 300 mg per dose.

[0063] In one embodiment of the present application, the compound of Formula II-M or the compound of Formula II is administered at a dose of 400 mg per dose.

[0064] In one embodiment of the present application, the compound of Formula II-M or the compound of Formula II is administered at a dose of 400 mg per dose.

[0065] In one embodiment of the present application, the compound of Formula II-M or the compound of Formula II is administered at a dose of 400 mg per dose.

[0066] In one embodiment of the present application, the compound of Formula II-M or the compound of Formula II is administered at a dose of 400 mg per dose.

[0067] In one embodiment of the present application, the compound of Formula II-M or the compound of Formula II is administered at a dose of 400 mg per dose.

[0068] In one embodiment of the present application, the compound of Formula II-M or the compound of Formula II is administered at a dose of 400 mg per dose.

[0069] In one embodiment of the present application, the compound of Formula II-M or the compound of Formula II is administered at a dose of 400 mg per dose.

[0070] In one embodiment of the present application, the compound of Formula II-M or the compound of Formula II is administered at a dose of 400 mg per dose.

[0071] In one embodiment of the present application, the compound of Formula II-M or the compound of Formula II is administered at a dose of 400 mg per dose.

[0072] In one embodiment of the present application, the compound of Formula I can be used alone, but can also be used in combination with other therapeutic agents or treatment methods for treating or preventing a disease or condition associated with paroxysmal nocturnal hemoglobinuria, for example, in combination with other C5 antibody inhibitors, such as eculizumab.

[0073] In one embodiment of the present application, the compound of Formula II-M or the compound of Formula II can be used alone, and can also be used in combination with other therapeutic agents or therapeutic methods for treating or preventing a disease or disorder associated with paroxysmal nocturnal hemoglobinuria, for example, in combination with other C5 antibody inhibitors, such as Eculizumab.

[0074] In one embodiment of the present application, the compound of Formula I or the compound of Formula II-M or the compound of Formula II can be administered to a subject in need thereof in the form of a free base, or in the form of a pharmaceutically acceptable salt, hydrate, and prodrug (which will be converted to the free base form in vivo).

[0075] In another aspect, the present application also provides a method for preventing and / or treating a disease or disorder associated with paroxysmal nocturnal hemoglobinuria, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of Formula A, or a pharmaceutically acceptable salt thereof, or a hydrate thereof.

[0076] In another aspect, the present application also provides a method for preventing and / or treating a disease or disorder associated with paroxysmal nocturnal hemoglobinuria, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof, or a hydrate thereof.

[0077] In another aspect, the present application also provides a method for preventing and / or treating a disease or disorder associated with paroxysmal nocturnal hemoglobinuria, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of Formula II-M or a compound of Formula II, or a pharmaceutically acceptable salt thereof, or a hydrate thereof.

[0078] In another aspect, the present application also provides a method for reducing the incidence of paroxysmal nocturnal hemoglobinuria associated hemolysis in a population of subjects, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of Formula A, or a pharmaceutically acceptable salt thereof, or a hydrate thereof.

[0079] In another aspect, the present application also provides a method for reducing the incidence of paroxysmal nocturnal hemoglobinuria associated hemolysis in a population of subjects, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof, or a hydrate thereof.

[0080] In another aspect, the present application also provides a method for reducing the incidence of paroxysmal nocturnal hemoglobinuria associated hemolysis in a population of subjects, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of Formula II-M or a compound of Formula II, or a pharmaceutically acceptable salt thereof, or a hydrate thereof.

[0081] The present application also provides a compound of Formula A, or a pharmaceutically acceptable salt thereof, or a hydrate thereof, for use in preventing and / or treating a disease or disorder associated with paroxysmal nocturnal hemoglobinuria. The present application also provides a compound of Formula A, or a pharmaceutically acceptable salt thereof, or a hydrate thereof, for use in preventing and / or treating a disease or disorder associated with paroxysmal nocturnal hemoglobinuria.

[0082] The present application also provides a compound of Formula I or a pharmaceutically acceptable salt thereof or a hydrate thereof for use in the prevention and / or treatment of a disease or disorder associated with paroxysmal nocturnal hemoglobinuria.

[0083] In another aspect, the present application also provides a compound of Formula II-M or a compound of Formula II or a pharmaceutically acceptable salt thereof or a hydrate thereof for use in the prevention and / or treatment of a disease or disorder associated with paroxysmal nocturnal hemoglobinuria.

[0084] In another aspect, the present application also provides a compound of Formula A or a pharmaceutically acceptable salt thereof or a hydrate thereof for use in reducing the incidence of paroxysmal nocturnal hemoglobinuria-associated hemolysis in a population of subjects.

[0085] In another aspect, the present application also provides a compound of Formula I or a pharmaceutically acceptable salt thereof or a hydrate thereof for use in reducing the incidence of paroxysmal nocturnal hemoglobinuria-associated hemolysis in a population of subjects.

[0086] In another aspect, the present application also provides a compound of Formula II-M or a compound of Formula II or a pharmaceutically acceptable salt thereof or a hydrate thereof for use in reducing the incidence of paroxysmal nocturnal hemoglobinuria-associated hemolysis in a population of subjects.

[0087] In another aspect, the present application also provides a medicament or a pharmaceutical composition for use in the prevention and / or treatment of a disease or disorder associated with paroxysmal nocturnal hemoglobinuria, the medicament or the pharmaceutical composition containing a compound of Formula A or a pharmaceutically acceptable salt thereof or a hydrate thereof.

[0088] In another aspect, the present application also provides a medicament or a pharmaceutical composition for use in the prevention and / or treatment of a disease or disorder associated with paroxysmal nocturnal hemoglobinuria, the medicament or the pharmaceutical composition containing a compound of Formula I or a pharmaceutically acceptable salt thereof or a hydrate thereof.

[0089] In another aspect, the present application also provides a medicament or a pharmaceutical composition for use in the prevention and / or treatment of a disease or disorder associated with paroxysmal nocturnal hemoglobinuria, the medicament or the pharmaceutical composition containing a compound of Formula II-M or a compound of Formula II or a pharmaceutically acceptable salt thereof or a hydrate thereof.

[0090] In another aspect, the present application also provides a medicament or a pharmaceutical composition for use in reducing the incidence of paroxysmal nocturnal hemoglobinuria-associated hemolysis in a population of subjects in need thereof, the medicament or the pharmaceutical composition containing a compound of Formula A or a pharmaceutically acceptable salt thereof or a hydrate thereof.

[0091] In another aspect, the present application also provides a medicament or a pharmaceutical composition for use in reducing the incidence of paroxysmal nocturnal hemoglobinuria-associated hemolysis in a population of subjects in need thereof, the medicament or the pharmaceutical composition containing a compound of Formula I or a pharmaceutically acceptable salt thereof or a hydrate thereof.

[0092] In another aspect, the present application also provides a pharmaceutical or pharmaceutical composition for reducing the incidence of paroxysmal nocturnal hemoglobinuria (PNH)-related hemolysis in a subject in need thereof, the pharmaceutical or pharmaceutical composition comprising a compound of Formula II-M or Formula II, or a pharmaceutically acceptable salt thereof, or a hydrate thereof.

[0093] In another aspect, the present application also provides a pharmaceutical or pharmaceutical composition for preventing and / or treating a PNH-related disease or disorder, the pharmaceutical or pharmaceutical composition comprising a compound of Formula A, or a pharmaceutically acceptable salt thereof, or a hydrate thereof, and one or more pharmaceutically acceptable carriers or other therapeutic agents.

[0094] In another aspect, the present application also provides a pharmaceutical or pharmaceutical composition for preventing and / or treating a PNH-related disease or disorder, the pharmaceutical or pharmaceutical composition comprising a compound of Formula I, or a pharmaceutically acceptable salt thereof, or a hydrate thereof, and one or more pharmaceutically acceptable carriers or other therapeutic agents.

[0095] In another aspect, the present application also provides a pharmaceutical or pharmaceutical composition for preventing and / or treating a PNH-related disease or disorder, the pharmaceutical or pharmaceutical composition comprising a compound of Formula II-M or Formula II, or a pharmaceutically acceptable salt thereof, or a hydrate thereof, and one or more pharmaceutically acceptable carriers or other therapeutic agents.

[0096] In another aspect, the present application also provides a pharmaceutical or pharmaceutical composition for reducing the incidence of paroxysmal nocturnal hemoglobinuria (PNH)-related hemolysis in a subject, the pharmaceutical or pharmaceutical composition comprising a compound of Formula A, or a pharmaceutically acceptable salt thereof, or a hydrate thereof, and one or more pharmaceutically acceptable carriers or other therapeutic agents.

[0097] In another aspect, the present application also provides a pharmaceutical or pharmaceutical composition for reducing the incidence of paroxysmal nocturnal hemoglobinuria (PNH)-related hemolysis in a subject, the pharmaceutical or pharmaceutical composition comprising a compound of Formula I, or a pharmaceutically acceptable salt thereof, or a hydrate thereof, and one or more pharmaceutically acceptable carriers or other therapeutic agents.

[0098] In another aspect, the present application also provides a pharmaceutical or pharmaceutical composition for reducing the incidence of paroxysmal nocturnal hemoglobinuria (PNH)-related hemolysis in a subject, the pharmaceutical or pharmaceutical composition comprising a compound of Formula II-M or Formula II, or a pharmaceutically acceptable salt thereof, or a hydrate thereof, and one or more pharmaceutically acceptable carriers or other therapeutic agents.

[0099] In another aspect, the present application also provides a compound of Formula II-M:

[0100] In preferred embodiments of the present application, the compound of Formula II-M is The retention time is 28.7 min, and the specific detection method is as follows:

[0101] Chromatographic column: Inertsil ODS-3, 4.6 mm x 250 mm, 5 μm;

[0102] Mobile phase A: 0.1% phosphoric acid solution; mobile phase B: acetonitrile;

[0103] Flow rate: 1 mL / min;

[0104] Column temperature: 40°C;

[0105] Detection wavelength: 236 nm;

[0106] Gradient condition:

[0107] In another aspect, the present application also provides a compound represented by formula II:

[0108] The compound of formula I or formula II-M or formula II or its pharmaceutically acceptable salt or hydrate thereof of the present application can also be administered to a subject in need thereof in any suitable administration manner, such as oral, parenteral, rectal, pulmonary or topical administration, etc.

[0109] In some specific embodiments, 0.1-2000 mg of the compound of formula A or its pharmaceutically acceptable salt or hydrate thereof is administered to a subject in need thereof.

[0110] In some specific embodiments, 10-1000 mg of the compound of formula A or its pharmaceutically acceptable salt or hydrate thereof is administered to a subject in need thereof.

[0111] In some specific embodiments, 50-700 mg of the compound of formula A or its pharmaceutically acceptable salt or hydrate thereof is administered to a subject in need thereof.

[0112] In some specific embodiments, 75-600 mg of the compound of formula A or its pharmaceutically acceptable salt or hydrate thereof is administered to a subject in need thereof.

[0113] In some specific embodiments, 100-600 mg of the compound of formula A or its pharmaceutically acceptable salt or hydrate thereof is administered to a subject in need thereof.

[0114] In some specific embodiments, 100 mg, 200 mg, 300 mg or 400 mg of the compound of formula A or its pharmaceutically acceptable salt or hydrate thereof is administered to a subject in need thereof.

[0115] In some preferred embodiments of the application, 100 or 200 mg of the compound of Formula A, or a pharmaceutically acceptable salt thereof, or a hydrate thereof, is administered to a subject in need thereof.

[0116] In some preferred embodiments of the application, 100 mg of the compound of Formula A, or a pharmaceutically acceptable salt thereof, or a hydrate thereof, is administered to a subject in need thereof.

[0117] In some preferred embodiments of the application, 200 mg of the compound of Formula A, or a pharmaceutically acceptable salt thereof, or a hydrate thereof, is administered to a subject in need thereof.

[0118] In some specific embodiments, 10-1000 mg of the compound of Formula I, or a pharmaceutically acceptable salt thereof, or a hydrate thereof, is administered to a subject in need thereof.

[0119] In some specific embodiments, 50-700 mg of the compound of Formula I, or a pharmaceutically acceptable salt thereof, or a hydrate thereof, is administered to a subject in need thereof.

[0120] In some specific embodiments, 75-600 mg of the compound of Formula I, or a pharmaceutically acceptable salt thereof, or a hydrate thereof, is administered to a subject in need thereof.

[0121] In some specific embodiments, 100-600 mg of the compound of Formula I, or a pharmaceutically acceptable salt thereof, or a hydrate thereof, is administered to a subject in need thereof.

[0122] In some specific embodiments, 100 mg, 200 mg, 300 mg, or 400 mg of the compound of Formula I, or a pharmaceutically acceptable salt thereof, or a hydrate thereof, is administered to a subject in need thereof.

[0123] In some preferred embodiments of the application, 100 or 200 mg of the compound of Formula I, or a pharmaceutically acceptable salt thereof, or a hydrate thereof, is administered to a subject in need thereof.

[0124] In some preferred embodiments of the application, 100 mg of the compound of Formula I, or a pharmaceutically acceptable salt thereof, or a hydrate thereof, is administered to a subject in need thereof.

[0125] In some preferred embodiments of the application, 200 mg of the compound of Formula I, or a pharmaceutically acceptable salt thereof, or a hydrate thereof, is administered to a subject in need thereof.

[0126] In some specific embodiments, 10-1000 mg of the compound of Formula II-M or Formula II, or a pharmaceutically acceptable salt thereof, or a hydrate thereof, is administered to a subject in need thereof.

[0127] In some embodiments, 50-700 mg of a compound of Formula II-M or Formula II, or a pharmaceutically acceptable salt thereof, or a hydrate thereof, is administered to a subject in need thereof.

[0128] In some embodiments, 75-600 mg of a compound of Formula II-M or Formula II, or a pharmaceutically acceptable salt thereof, or a hydrate thereof, is administered to a subject in need thereof.

[0129] In some embodiments, 100-600 mg of a compound of Formula II-M or Formula II, or a pharmaceutically acceptable salt thereof, or a hydrate thereof, is administered to a subject in need thereof.

[0130] In some embodiments, 100 mg, 200 mg, 300 mg, or 400 mg of a compound of Formula II-M or Formula II, or a pharmaceutically acceptable salt thereof, or a hydrate thereof, is administered to a subject in need thereof.

[0131] In some preferred embodiments of the application, 100 or 200 mg of a compound of Formula II-M or Formula II, or a pharmaceutically acceptable salt thereof, or a hydrate thereof, is administered to a subject in need thereof.

[0132] In some preferred embodiments of the application, 100 mg of a compound of Formula II-M or Formula II, or a pharmaceutically acceptable salt thereof, or a hydrate thereof, is administered to a subject in need thereof.

[0133] In some preferred embodiments of the application, 200 mg of a compound of Formula II-M or Formula II, or a pharmaceutically acceptable salt thereof, or a hydrate thereof, is administered to a subject in need thereof.

[0134] In some embodiments, the compound of Formula A, or a pharmaceutically acceptable salt thereof, or a hydrate thereof, is administered to a subject in need thereof once a day, twice a day, three times a day, once a week, three times a week, once every two weeks, once every three weeks, or once a month; preferably once a day, twice a day, or three times a day.

[0135] In some preferred embodiments of the application, the compound of Formula A, or a pharmaceutically acceptable salt thereof, or a hydrate thereof, is administered to a subject in need thereof once a day.

[0136] In some preferred embodiments of the application, 100 or 200 mg of the compound of Formula A, or a pharmaceutically acceptable salt thereof, or a hydrate thereof, is administered to a subject in need thereof once a day.

[0137] In some preferred embodiments of the application, 100 mg of the compound of Formula A, or a pharmaceutically acceptable salt thereof, or a hydrate thereof, is administered to a subject in need thereof once a day.

[0138] In some preferred embodiments of the application, 100 mg of the compound of Formula I, or a pharmaceutically acceptable salt thereof, or a hydrate thereof, is administered to a subject in need thereof once a day.

[0139] In some preferred embodiments of the application, 100 mg of the compound of Formula I, or a pharmaceutically acceptable salt thereof, or a hydrate thereof, is administered to a subject in need thereof once a day.

[0140] In some preferred embodiments of the application, 100 mg of the compound of Formula I, or a pharmaceutically acceptable salt thereof, or a hydrate thereof, is administered to a subject in need thereof once a day.

[0141] In some preferred embodiments of the application, 200 mg of the compound of Formula I, or a pharmaceutically acceptable salt thereof, or a hydrate thereof, is administered to a subject in need thereof once a day.

[0142] In some preferred embodiments of the application, 100 mg of the compound of Formula II-M or Formula II, or a pharmaceutically acceptable salt thereof, or a hydrate thereof, is administered to a subject in need thereof once a day.

[0143] In some preferred embodiments of the application, 100 mg of the compound of Formula II-M or Formula II, or a pharmaceutically acceptable salt thereof, or a hydrate thereof, is administered to a subject in need thereof once a day.

[0144] In some preferred embodiments of the application, 200 mg of the compound of Formula II-M or Formula II, or a pharmaceutically acceptable salt thereof, or a hydrate thereof, is administered to a subject in need thereof once a day.

[0145] Related Definitions

[0146] Unless otherwise specifically indicated, the following terms used in the specification and claims have the following meanings:

[0147] As used herein, "dosing amount" refers to the amount of active compound (free base) referred to. It is understood that when it is in the form of a pharmaceutically acceptable salt or hydrate, the amount is in terms of the active compound (free base). For example, when a 2 mg dose of the compound of Formula I is administered and the compound of Formula I is administered in a tablet containing a salt form of the compound of Formula I, the tablet will contain the salt form of the compound of Formula I equivalent to 2 mg of the compound of Formula I.

[0148] The "salt" described herein can exist alone or in a mixture with the free compound of the present application, and is preferably a pharmaceutically acceptable salt. The "pharmaceutically acceptable salt" described herein refers to an acid or base salt commonly used in pharmacy, wherein the acid salt includes a conventional organic acid salt or inorganic acid salt, wherein the organic acid salt includes, but is not limited to, a p-toluenesulfonate, maleate, citrate or tartrate; wherein the inorganic acid salt includes, but is not limited to, a hydrobromide, hydrochloride, sulfate or phosphate, preferably a hydrochloride, sulfate or phosphate; wherein the base salt includes, but is not limited to, a sodium salt, potassium salt, calcium salt, choline salt or diethylamine salt, preferably a sodium salt or calcium salt.

[0149] The "oral administration" described herein refers to the intake of a drug into the body by the oral route, and the drug is absorbed into the blood circulation through the gastrointestinal tract and then distributed to the whole body or acts on a specific organ.

[0150] The "parenteral administration" described herein refers to a drug administration method that does not pass through the gastrointestinal tract, including subcutaneous injection, intramuscular injection, intravenous injection, etc.

[0151] The "rectal administration" described herein refers to a method of administering a drug into the rectum through the anus, and the drug is absorbed into the blood circulation through the rectal mucosa.

[0152] The "pulmonary administration" described herein refers to a method of directly administering a drug into the lung by inhalation, and the drug is absorbed into the blood circulation through the alveoli.

[0153] The "topical administration" described herein refers to a method of administering a drug by directly coating or applying the drug on the epidermal tissue, including the skin or mucosa of the oral cavity or vagina.

[0154] The "effective amount" or "therapeutically effective amount" described herein refers to a sufficient amount of a drug or agent that is non-toxic but can achieve the desired effect.

[0155] The "treatment" described herein includes inhibition, alleviation, prevention or elimination of one or more symptoms or side effects associated with the disease, disorder or disorder to be treated.

[0156] The "subject" described herein refers to an animal, including but not limited to primates (e.g., humans), cattle, pigs, sheep, goats, horses, dogs, cats, rabbits, rats or mice. In this context, the terms "subject" and "patient" are used interchangeably, for example, to refer to a mammal or human; the "patient" described herein generally refers to a human.

[0157] A "pharmaceutical composition" as described herein means a composition comprising a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable ingredient selected from the group consisting of carriers, diluents, adjuvants, excipients, preservatives, fillers, disintegrants, wetting agents, emulsifiers, suspending agents, sweetening agents, flavoring agents, flavorants, antibacterial agents, antifungal agents, lubricants, dispersing agents, temperature-sensitive materials, temperature-regulating agents, adhesion agents, stabilizing agents, suspending agents, and the like, as appropriate to the mode of administration and the nature of the dosage form.

[0158] A "pharmaceutically acceptable carrier" as described herein includes, but is not limited to, diluents, binders, disintegrants, lubricants.

[0159] An "additional therapeutic agent" as described herein includes, but is not limited to, a C5 complement inhibitor (such as Eculizumab, Ravulizumab, Crovalimab, Cemdisiran), a C3 complement inhibitor (such as Pegcetacoplan, ARO-C3), a CFD inhibitor (such as Danicopan, Pelecopan), a Properdin inhibitor (such as NM5072), or a C3b inhibitor (such as QY-F11).

[0160] DMSO: dimethyl sulfoxide.

[0161] DMSO-d6: deuterated dimethyl sulfoxide.

[0162] PBS: phosphate buffered solution.

[0163] MgCl2: magnesium chloride.

[0164] HCl: hydrochloric acid.

[0165] BSA: bovine serum albumin.

[0166] 1 H NMR: proton nuclear magnetic resonance.

[0167] HPLC: high-performance liquid chromatography.

[0168] m / z: mass-to-charge ratio.

[0169] SFC: supercritical fluid chromatography.

[0170] V / V: volume / volume.

[0171] PK: pharmacokinetics.

[0172] PD: pharmacodynamics.

[0173] LDH: lactate dehydrogenase. One of the important enzymes of anaerobic glycolysis and gluconeogenesis, catalyzes the reduction and oxidation between pyruvic acid and L-lactic acid, and also catalyzes related α-keto acids. LDH is widely present in human tissues, with the highest content in heart, kidney, skeletal muscle, followed by liver, spleen, pancreas and lung tissues.

[0174] Bid (bid): twice a day. BRIEF DESCRIPTION OF DRAWINGS

[0175] FIG. 1 is a crystal structure of compound 1a-2 in Experimental Example 1;

[0176] FIG. 2 is a compound dose-response curve in Experimental Example 6. DETAILED DESCRIPTION

[0177] The preparation method of the compound of the present application is described in more detail below, but these specific preparation methods do not constitute any limitation on the scope of the present application. In addition, the reaction conditions such as the reactants, solvents, bases, the amount of the compound used, the reaction temperature, the reaction time, etc. are not limited to the following examples.

[0178] The compound of the present application can also be optionally prepared by combining various synthesis methods described in the present specification or known in the art, and such combination can be easily performed by those skilled in the art.

[0179] Unless otherwise specified, the raw materials and equipment used in the detailed description of the present application are known products, which can be obtained by purchasing commercially available products.

[0180] Example 1: Preparation of 4-((3S,4S)-4-((5-methoxy-7-methyl-1H-indol-4-yl)oxy)-1-(2,2,2- trifluoroethyl)piperidin-3-yl)benzoic acid and 4-((3R,4R)-4-((5-methoxy-7-methyl-1H-indol-4- yl)oxy)-1-(2,2,2-trifluoroethyl)piperidin-3-yl)benzoic acid and 4-((3S,4R)-4-((5-methoxy-7- methyl-1H-indol-4-yl)oxy)-1-(2,2,2-trifluoroethyl)piperidin-3-yl)benzoic acid and 4-((3R,4S)-4- ((5-methoxy-7-methyl-1H-indol-4-yl)oxy)-1-(2,2,2-trifluoroethyl)piperidin-3-yl)benzoic acid

[0181] a) Preparation of (±) tert-butyl 3-(4-(methoxycarbonyl)phenyl)-4-oxopiperidine-1-carboxylate

[0182] Into a reaction flask was placed 3-bromo-4-oxopiperidine-l-carboxylic acid tert-butyl ester (50 g), (4-(methoxycarbonyl)phenyl)boronic acid (48.52 g), nickel(II) trifluoromethanesulfonate (3.21 g), 1,10-phenanthroline (1.62 g), potassium carbonate (49.62 g), 1,4-dioxane (500 mL), and the reaction was protected by nitrogen replacement. The mixture was stirred at 80 °C for 16 h. The reaction solution was diluted with water (500 mL) and extracted with ethyl acetate (3 x 500 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give a sand. The sand was purified by column chromatography (mobile phase: petroleum ether / ethyl acetate = 5 / 1 (V / V)) to give the title compound 32 g.

[0183] b) Preparation of (±)-rel-(3S,4R)-4-hydroxy-3-(4-(methoxycarbonyl)phenyl)piperidine-l- carboxylic acid tert-butyl ester and (±)-rel-(3S,4S)-4-hydroxy-3-(4-(methoxycarbonyl)phenyl)piperidine-l-carboxylic acid tert-butyl ester

[0184] Into a reaction flask was placed (±) 3-(4-(methoxycarbonyl)phenyl)-4-oxopiperidine-l- carboxylic acid tert-butyl ester (30 g) and methanol (300 mL). The reaction was protected by nitrogen replacement. Sodium borohydride (10.21 g) was added portionwise at 0 °C. The mixture was stirred at room temperature for 1 h. The reaction was quenched by the addition of water (500 mL) in an ice bath. The mixture was extracted with ethyl acetate (3 x 500 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give a sand. The sand was purified by column chromatography (mobile phase: petroleum ether / ethyl acetate = 3 / 1 (V / V)) to give the title compounds 8.9 g and 21.3 g, respectively.

[0185] (±)-rel-(3S,4R)-4-hydroxy-3-(4-(methoxycarbonyl)phenyl)piperidine-l-carboxylic acid tert-butyl ester

[0186] 1 HNMR (400 MHz, DMSO-d6) δ 7.88 (d, J = 8.4 Hz, 2H), 7.43 (d, J = 8.4 Hz, 2H), 4.75 (d, J = 4.2 Hz, 1H), 3.99 (d, J = 7.8 Hz, 1H), 3.84 (s, 3H), 3.77 (d, J = 12.4 Hz, 2H), 3.49 (d, J = 14.2 Hz, 1H), 3.16 (s, 1H), 2.83 (d, J = 11.2 Hz, 1H), 1.71 - 1.64 (m, 2H), 1.39 (s, 9H).

[0187] (±)-rel-(3S,4S)-4-hydroxy-3-(4-(methoxycarbonyl)phenyl)piperidine-l-carboxylic acid tert-butyl ester

[0188] 1 HNMR (400MHz, DMSO-d6) δ7.90(d,J=8.3Hz,2H),7.42(d,J=8.3Hz,2H),4.71(d,J=6.0Hz,1H),4.03(q,J=7.1Hz,1H),3.97 (d,J=11.8Hz,1H),3.85(s,3H),3.83–3.72(m,2H),2.89(s,2H),1.99(s,1H),1.89(dd,J=12.4,3.8Hz,1H),1.40(s,9H).

[0189] Example 1a: 4-((3S,4S)-4-((5-methoxy-7-methyl-1H-indol-4-yl)oxy)-1-(2,2,2-trifluoroethyl)piperidin-3-yl)benzoic acid and 4-((3R,4R)-4-((5-methoxy-7-methyl-1H-indol-4-yl)oxy)-1-(2,2,2-trifluoroethyl)piperidin-3-yl)benzoic acid

[0190] Preparation of tert-butyl ester of a)(±)-rel-(3S,4S)-4-((1-(tert-butoxycarbonyl)-3-(4-(methoxycarbonyl)phenyl)piperidin-4-yl)oxy)-5-methoxy-7-methyl-1H-indole-1-carboxylic acid

[0191] 10.06 g of tert-butyl 4-hydroxy-5-methoxy-7-methyl-1H-indole-1-carboxylic acid, 8.4 g of (±)-rel-(3S,4R)-4-hydroxy-3-(4-(methoxycarbonyl)phenyl)piperidine-1-carboxylic acid tert-butyl ester, 23.82 g of triphenylphosphine, and 200 mL of anhydrous tetrahydrofuran were added to a three-necked flask under nitrogen purging protection. Diisopropyl azodicarbonate (18.33 g) was added dropwise at 0 °C. The reaction system was heated to room temperature and reacted for 16 hours. The reaction was diluted with water (500 mL), extracted with ethyl acetate (3 × 200 mL), separated, and the combined organic phases were dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated under reduced pressure to prepare slurry. The slurry was purified by column chromatography (mobile phase: petroleum ether ethyl acetate = 5 / 1 (V / V)) to give 22 g of the title compound.

[0192] b)(±)-rel-(3S,4S)-5-methoxy-4-((3-(4-(methoxycarbonyl)phenyl)piperidin-4-yl)oxy)-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester preparation

[0193] (±)-rel-(3S,4S)-4-((1-(tert-butoxycarbonyl)-3-(4-(methoxycarbonyl)phenyl)piperidin-4-yl)oxy)-5-methoxy-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester (10 g) was dissolved in 4 M hydrochloric acid in 1,4-dioxane (70 mL) and stirred at room temperature for 4 hours. The reaction solution was concentrated under reduced pressure to give a residue, which was the title compound 16 g.

[0194] LCMS m / z = 495.4 [M+1] + .

[0195] c) Preparation of (±)-rel-(3S,4S)-5-methoxy-4-((3-(4-(methoxycarbonyl)phenyl)-1-(2,2,2-trifluoroethyl)piperidin-4-yl)oxy)-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester

[0196] (±)-rel-(3S,4S)-5-methoxy-4-((3-(4-(methoxycarbonyl)phenyl)piperidin-4-yl)oxy)-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester (6.3 g) and N,N-diisopropylethylamine (6.6 mL) were added to a reaction flask, tetrahydrofuran (80 mL) was added, and then 2,2,2-trifluoroethyl trifluoromethanesulfonate (8.9 g) was added. The reaction was protected by nitrogen replacement, stirred at 70°C for 2 hours, and then the reaction solution was diluted with water (500 mL) and extracted with ethyl acetate (3 x 200 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give a residue, which was purified by column chromatography (mobile phase: petroleum ether / ethyl acetate = 5 / 1 (V / V)) to give the title compound 5 g.

[0197] LCMS m / z = 577.1 [M+H] + .

[0198] d) Preparation of 4-((3S,4S)-4-((5-methoxy-7-methyl-1H-indol-4-yl)oxy)-1-(2,2,2-trifluoroethyl)piperidin-3-yl)benzoic acid and 4-((3R,4R)-4-((5-methoxy-7-methyl-1H-indol-4-yl)oxy)-1-(2,2,2-trifluoroethyl)piperidin-3-yl)benzoic acid

[0199] (±)-rel-(3S,4S)-5-methoxy-4-((3-(4-(methoxycarbonyl)phenyl)-1-(2,2,2- trifluoroethyl)piperidin-4-yl)oxy)-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester (5 g) was added to a reaction flask, methanol (120 mL), lithium hydroxide (6.25 g), water (100 mL) were added, nitrogen was bubbled through the solution for 10 minutes, the reaction solution was stirred at 70°C for 16 hours, the reaction solution was adjusted to pH = 6 with dilute hydrochloric acid (3M), diluted with water (100 mL) and extracted with ethyl acetate (3 x 500 mL), the organic phase was separated, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure to give a sand, which was purified by column chromatography (mobile phase: dichloromethane / methanol 5 / 1 (V / V)) to give the title compound enantiomer 1.7 g.

[0200] The (±)-rel-(3S,4S)-4-(4-((5-methoxy-7-methyl-1H-indol-4-yl)oxy)-1-(2,2,2- trifluoroethyl)piperidin-3-yl)benzoic acid was resolved into enantiomers 1a-1 (t r = 1.87 min) and 1a-2 (t r = 2.73 min) by chiral SFC, and the absolute configuration of 1a-2 was confirmed by X-ray single crystal diffraction experiment of experimental example 1, which was the absolute stereochemical configuration of 4-((3R,4R)-4-((5-methoxy-7-methyl-1H-indol-4-yl)oxy)-1-(2,2,2- trifluoroethyl)piperidin-3-yl)benzoic acid. (Resolution method: chromatographic column: 250*25 mm, 10 μm; mobile phase A: supercritical CO2; mobile phase B: methanol (+0.1% 7.0 mol / L ammonium methanol); A:B:75:25, flow rate: 100 mL / min; detection wavelength: 214 nm)

[0201] 1a-1,t r = 1.87 min

[0202] 1H NMR (400 MHz, DMSO-d6) δ 10.84 (s, 1H), 7.89 (d, J = 8.2 Hz, 2H), 7.55 (d, J = 8.2 Hz, 2H), 7.17 (t, J = 2.8 Hz, 1H), 6.63 (s, 1H), 6.21 - 6.16 (m, 1H), 4.47 (dd, J = 16.1, 7.7 Hz, 1H), 3.60 (s, 3H), 3.24 (d, J = 3.5 Hz, 2H), 3.16 - 3.08 (m, 1H), 2.94 (t, J = 12.7 Hz, 2H), 2.67 (t, J = 11.2 Hz, 1H), 2.47 - 2.41 (m, 1H), 2.34 (d, J = 11.4 Hz, 3H), 1.70 (d, J = 3.6 Hz, 2H).

[0203] LCMS m / z = 463.1 [M+H] + .

[0204] 1a-2, t r = 2.73 min

[0205] 1 H NMR (400 MHz, DMSO-d6) δ 10.81 (s, 1H), 7.86 (d, J = 8.2 Hz, 2H), 7.51 (d, J = 8.2 Hz, 2H), 7.14 (t, J = 2.8 Hz, 1H), 6.59 (s, 1H), 6.15 (dd, J = 3.0, 2.0 Hz, 1H), 4.44 (dd, J = 16.1, 7.8 Hz, 1H), 3.57 (s, 3H), 3.20 (d, J = 3.6 Hz, 2H), 3.12 - 3.05 (m, 1H), 2.89 (d, J = 13.0 Hz, 2H), 2.64 (t, J = 11.3 Hz, 1H), 2.42 (s, 1H), 2.32 (s, 3H), 1.67 (d, J = 3.5 Hz, 2H).

[0206] LCMS m / z = 463.1 [M+H] + .

[0207] Example 1b: (±)-rel-(3S,4R)-4-(4-((5-methoxy-7-methyl-1H-indol-4-yl)oxy)-1-(2,2,2- trifluoroethyl)piperidin-3-yl)benzoic acid

[0208] Prepared according to the procedure of Example 1a, substituting (±)-rel-(3S,4S)-4- hydroxy-3-(4-(methoxycarbonyl)phenyl)piperidine-1-carboxylic acid tert-butyl ester for (±)-rel-(3S,4R)-4-hydroxy-3-(4-(methoxycarbonyl)phenyl)piperidine-1-carboxylic acid tert-butyl ester in step a).

[0209] (±)-rel-(3S,4R)-4-(4-((5-methoxy-7-methyl-1H-indol-4-yl)oxy)-1-(2,2,2- trifluoroethyl)piperidin-3-yl)benzoic acid was resolved by chiral SFC to give 1b-1 (t r = 1.06 min) and 1b-2 (t r = 2.37 min). (Resolution method: Column: Chiralpak® IC (250*20 mm, 10 μm); mobile phase A: supercritical CO2; mobile phase B: methanol (+0.1% 7.0 mol / L ammonium methanolate); A:B: 75:25; flow rate: 100 mL / min; detection wavelength: 214 nm) 250*20 mm, 10 μm; mobile phase A: supercritical CO2; mobile phase B: methanol (+0.1% 7.0 mol / L ammonium methanolate); A:B: 75:25; flow rate: 100 mL / min; detection wavelength: 214 nm)

[0210] 1b-1, t r = 1.06 min

[0211] 1 HNMR (400 MHz, DMSO-d6) δ 10.83 (s, 1H), 7.89 (d, J = 8.3 Hz, 2H), 7.56 (d, J = 8.3 Hz, 2H), 7.09 (t, J = 2.8 Hz, 1H), 6.61 (s, 1H), 5.71 (dd, J = 3.0, 2.0 Hz, 1H), 4.65 (d, J = 2.5 Hz, 1H), 3.55 (s, 3H), 3.42 - 3.36 (m, 2H), 3.30 - 3.25 (m, 2H), 3.14 - 3.07 (m, 1H), 2.89 (d, J = 7.6 Hz, 1H), 2.68 (d, J = 10.9 Hz, 1H), 2.34 (s, 3H), 1.65 (s, 2H).

[0212] LCMS m / z = 463.1 [M+H] + .

[0213] 1b-2, t r = 2.37 min

[0214] 1HNMR (400 MHz, DMSO-d6) δ 10.84 (s, 1H), 7.90 (d, J = 8.3 Hz, 2H), 7.58 (d, J = 8.3 Hz, 2H), 7.09 (t, J = 2.7 Hz, 1H), 6.61 (s, 1H), 5.72 (dd, J = 2.9, 2.0 Hz, 1H), 4.66 (d, J = 2.4 Hz, 1H), 3.55 (s, 3H), 3.44 - 3.36 (m, 2H), 3.29 (d, J = 5.9 Hz, 2H), 3.12 (td, J = 10.6, 5.6 Hz, 1H), 2.89 (d, J = 7.8 Hz, 1H), 2.69 (d, J = 11.1 Hz, 1H), 2.34 (s, 3H), 1.66 (s, 2H).

[0215] LCMS m / z = 463.1 [M+H] + .

[0216] Example 2: Preparation of (2S,3S,4S,5R,6S)-3,4,5-trihydroxy-6-((4-((3R,4R)-4-((5-methoxy-7-methyl-1H-indol-4-yl)oxy)-1-(2,2,2-trifluoroethyl)piperidin-3-yl)benzoyl)oxy)tetrahydro-2H-pyran-2-carboxylic acid

[0217] a) Preparation of allyl (2S,3S,4S,5R)-3,4,5,6-tetrahydroxytetrahydro-2H-pyran-2-carboxylate

[0218] (2S,3S,4S,5R)-3,4,5,6-tetrahydroxytetrahydro-2H-pyran-2-carboxylic acid (4 g), N,N-dimethylformamide (40 mL) were added into a reaction flask, 1,8-diazobicyclo[5.4.0]undec-7-ene (3.92 g) was added at room temperature, stirred for 10 min in ice bath, 3-bromopropene (3.12 g) was added dropwise, protected by nitrogen replacement, stirred for 16 h at room temperature, the reaction solution was quenched with water, concentrated under reduced pressure to sand, purified by column chromatography (mobile phase: dichloromethane / methanol = 5 / 1 (V / V)) to give the title compound 5.4 g.

[0219] b) Preparation of allyl (2S,3S,4S,5R)-3,4,5-trihydroxy-6-((4-((3R,4R)-4-((5-methoxy-7-methyl-1H-indol-4-yl)oxy)-1-(2,2,2-trifluoroethyl)piperidin-3-yl)benzoyl)oxy

[0220] (2S,3S,4S,5R)-3,4,5-trihydroxy-6-((4-((3R,4R)-4-((5-methoxy-7-methyl-1H-indol-4- yl)oxy)-1-(2,2,2-trifluoroethyl)piperidin-3-yl)benzoyl)oxy)tetrahydro-2H-pyran-2-carboxylic acid (2.18 g) was added to acetonitrile (20 mL) and stirred for 10 minutes in an ice bath. Tetra(triphenylphosphine)palladium (742.4 mg) and tetrahydrofuran (274.1 mg) were added and the reaction was stirred for 3 hours at room temperature under nitrogen. Formic acid (0.3 mL) was added to quench the reaction and the reaction mixture was concentrated under reduced pressure. The residue was purified by column chromatography (mobile phase: dichloromethane / methanol = 8 / 1 (V / V)) to obtain the title compound 1.02 g.

[0221] c) Preparation of (2S,3S,4S,5R,6S)-3,4,5-trihydroxy-6-((4-((3R,4R)-4-((5-methoxy-7-methyl-1H- indol-4-yl)oxy)-1-(2,2,2-trifluoroethyl)piperidin-3-yl)benzyl)oxy)tetrahydro-2H-pyran-2- carboxylic acid

[0222] (2S,3S,4S,5R)-3,4,5-trihydroxy-6-((4-((3R,4R)-4-((5-methoxy-7-methyl-1H-indol-4- yl)oxy)-1-(2,2,2-trifluoroethyl)piperidin-3-yl)benzoyl)oxy)tetrahydro-2H-pyran-2-carboxylic acid (2.18 g) was added to acetonitrile (20 mL) and stirred for 10 minutes in an ice bath. Tetra(triphenylphosphine)palladium (742.4 mg) and tetrahydrofuran (274.1 mg) were added and the reaction was stirred for 3 hours at room temperature under nitrogen. Formic acid (0.3 mL) was added to quench the reaction and the reaction mixture was concentrated under reduced pressure. The residue was purified by column chromatography (mobile phase: dichloromethane / methanol = 8 / 1 (V / V)) to obtain the title compound 1.02 g.

[0223] Compound detection method: Column: packed with octadecylsilane-bonded silica gel (Inertsil ODS-3, 4.6 mm x 250 mm, 5 μm or a column of equivalent performance); mobile phase A: 0.1% phosphoric acid solution; mobile phase B: acetonitrile; column temperature: 40°C; flow rate: 1 mL / min; detection wavelength: 236 nm; injection volume: 10 μl; retention time: 28.7 min.

[0224] 1H NMR (400 MHz, DMSO-d6) δ 10.86 (s, 1H), 7.99 (d, J = 8.3 Hz, 2H), 7.64 (d, J = 8.3 Hz, 2H), 7.17 (t, J = 2.7 Hz, 1H), 6.62 (s, 1H), 6.19 - 6.14 (m, 1H), 5.53 (d, J = 7.8 Hz, 1H), 4.47 (dd, J = 16.1, 7.9 Hz, 1H), 3.60 (s, 3H), 3.37 (d, J = 9.8 Hz, 2H), 3.29 - 3.25 (m, 4H), 3.21 - 3.13 (m, 3H), 3.01 - 2.90 (m, 2H), 2.71 (t, J = 11.1 Hz, 1H), 2.48 - 2.41 (m, 1H), 2.35 (s, 3H), 1.90 (s, 1H), 1.72 (d, J = 3.0 Hz, 2H), 1.24 (s, 1H).

[0225] LCMS m / z = 639.1 [M+H] + .

[0226] Experimental Example 1: X-ray single crystal diffraction experiment

[0227] Preparation method: prepare a saturated solution of compound 1a-2 at high temperature (about 60°C) in a 3 mL glass bottle, the solvent is acetonitrile (1 mL), while hot, use a 2 mL syringe to suck the clear solution, filter with a hydrophilic PTFE needle filter (13 mm*0.45 μm), transfer the filtrate to another clean 3 mL glass bottle, then transfer it to room temperature and stand for one day to obtain transparent single crystals.

[0228] After integrating and reducing the diffraction data using the SAINT program, the data was empirically corrected for absorption using the SADABS program; the single crystal structure was solved by direct method using SHELXT2014, and the structure was refined by least squares method, the hydrogen atom refinement process was obtained by isotropic calculation, the hydrogen atom on C-H was obtained by calculation and hydrogenation, and was refined by riding model. The Flack constant is: 0.09(10), the chirality of C11 and C17 is R configuration. Figure 1 and Table 1 below are the single crystal results of compound 1a-2.

[0229] Structure description: single crystal X-ray diffraction and structure analysis show that the prepared single crystal is an acetonitrile solvate of 1a-2. The asymmetric unit of the crystal contains one molecule of 1a-2 and one molecule of acetonitrile, in which 1a-2 and acetonitrile form an acetonitrile solvate, and the structure is as follows:

[0230] Table 1. Single crystal diffraction data

[0231] Experimental Example 2: Human Complement Factor B TR-FRET Assay

[0232] Competitive binding assays were performed using Cy5-labeled small molecule inhibitors (+) or (-)-2-((1E,3E,5E)-5-(1-(6-((2-(3-(4-((R)-3-amino-3-phenylpropionyl)-1-(4-amino-6,7-dimethoxyquinazolin-2-yl)piperazin-2-yl)phenoxy)ethyl)amino)-6-oxohexyl)-3,3-dimethyl-5-sulfodihydroindole-2-yl)pent-1,3-dien-1-yl)-1-ethyl-3,3-dimethyl-5-sulfo-3H-indole-1-onium (prepared according to Example 2 of Biological Studies, CN201480050471.1) as probes to test the inhibitory activity of the compounds against complement factor B. Complement factor B (ComplementTech, A135) and EZ-Link TM Sulfo-NHS-LC-LC-Biotin (Thermo, 21338) was incubated on ice at a 1:20 ratio for 2 hours, followed by termination with 1M Tris (pH 7.5). Then, 2 mL of Zeba was added. TM Biotin-labeled complement factor B was obtained by purification twice using a desalt spin column (Thermo, 89890). In the experiment, biotin-labeled complement factor B at a final concentration of 25 nM was incubated with different concentrations of the compound in buffer (PBS containing 10 mM MgCl2 and 0.05% Chaps) at 4°C for 30 minutes. Cy5 fluorescently labeled probes and europium chelate-labeled streptavidin (PerkinElmer, AD0060) at final concentrations of 75 nM and 0.225 nM were added, and the reaction was carried out at 4°C for 2 hours. After the reaction, time-dependent fluorescence energy transfer (TR-FRET) data were read using a microplate reader (Tecan, SPARK; excitation light 337 nm, 615 nm, and 665 nm) to determine the IC50. 50 The test results are shown in Table 2 below.

[0233] Reference standard LNP023: synthesized according to Example 26 of CN201480050471.1, with the following structure:

[0234] Table 2. Inhibitory activity of compounds against complement factor B

[0235] Experimental Example 3: Serum Alternate Pathway Complement Deposition Experiment

[0236] use Complement System Bypass Pathway Kit ( Complement system Alternative pathway AP330 RUO) to detect the inhibitory activity of the compound on the complement alternative pathway in human serum. The human serum is diluted 18 times using the kit diluent Diluent, and the diluted serum is added to a 96-well plate at 130 μL / well. The compound titrator (Tecan, D300e) is used to add the corresponding concentration of the test compound. The test concentration of the test compound is 10 μM, which is diluted 3 times, 6 concentration points, single well detection, and all the drug addition holes are uniformly adjusted to 0.1% DMSO. The positive control hole adds 0.1% DMSO and 130 μL of diluted serum, and the negative control hole adds 0.1% DMSO and 130 μL of diluent Diluent. The pre-incubation is carried out at room temperature for 15 min; the mixture after incubation is transferred to a 96-well plate provided by the kit at 100 μL per well, and incubated at 37°C for 60 min. The liquid in the hole is discarded, 300 μL of washing solution in the kit is added to each hole, and washed 3 times. 100 μL of conjugate in the kit is added to each hole, and incubated at room temperature for 30 min. The liquid in the hole is removed, 300 μL of washing solution in the kit is added to each hole, and washed 3 times. 100 μL of substrate solution is added to each hole, and incubated at room temperature for 30 min. The enzyme-labeled instrument (Tecan, SPARK) is used for detection, and the absorbance value at 405 nm is read. The experimental data are shown in Table 3 below.

[0237] Table 3. Serum alternative pathway complement deposition results

[0238] Experimental Example 4: Mouse pharmacokinetic study test

[0239] Experimental purpose: To investigate the plasma pharmacokinetics of the compound of the application in male ICR (CD-1) mice after single intravenous injection and oral administration.

[0240] Experimental animals: male ICR (CD-1) mice, body weight 32-35 g; supplier: Vivotek Laboratory Animal Technology Co., Ltd.

[0241] Experimental process: injection administration (IV): oral administration (PO): the dose is 10 mg / kg (solvent: water (containing 0.5% methyl cellulose (w / v), 0.5% Tween 80 (v / v))).

[0242] Sample collection: 40 μL of whole blood sample was collected from the experimental animals at each set time point via the orbit, and the whole blood sample was placed in an anticoagulant tube containing EDTA-K2. The whole blood sample was centrifuged at 1500 g for 10 min to separate the plasma, and the upper plasma sample was collected into a sample tube for LC-MS / MS analysis.

[0243] Data analysis: WinNonlinTM Non-compartmental analysis of plasma concentration data was performed using WinNonlin® Version 6.3 (Pharsight, Mountain View, CA) pharmacokinetic software. Pharmacokinetic parameters Cl, T 1 / 2 , C max , AUC 0-24 were calculated using linear-log trapezoidal methods. Results are shown in the table below.

[0244] Table 4. Pharmacokinetic study results

[0245] Example 5: Efficacy study of the test substance in a CAIA mouse model

[0246] Objective: To evaluate the efficacy of the test drug on collagen antibody and lipopolysaccharide-induced arthritis (CAIA) in BALB / c mice.

[0247] Experimental animals: BALB / c mice, male, 6-8 weeks old, 18-20 grams; supplier: Shanghai Jihui Experimental Animal Breeding Co., Ltd.

[0248] Experimental procedure:

[0249] 1. Induction of the mouse CAIA model: On day 0, all mice were injected intravenously with 0.15 mL of 5 clone mixture type II collagen antibody (10 mg / mL, Chondrex); on day 3, the mice were injected intraperitoneally with 0.2 mL of LPS (E. coli 0111: B4 lipopolysaccharide, 0.5 mg / mL; Chondrex).

[0250] 2. Drug administration:

[0251] Table 5. Dosing groups and dosing regimen a: 0.5% methylcellulose (w / v), 0.5% Tween 80 (v / v) in water

[0252] Experimental data are expressed as mean ± S.E.M. Data were analyzed by One-way ANOVA / Dunnett's using Graphpad Prism and Repeat Measurement ANOVA / Bonferroni using SPSS. P<0.05 was considered to be significantly different.

[0253] Arthritis score: From the day of modeling, the incidence of arthritis of the limbs of animals in each group was observed three times a week until the end of the experiment. According to the different degrees (redness) of the lesions, the scores were scored according to the 0-4 standard. The scoring criteria are as follows: 0, no signs of redness or swelling; 1, redness or slight swelling of the midfoot (ankle); 2, redness and slight swelling from the ankle to the midfoot; 3, redness and moderate swelling from the ankle joint to the metatarsal joint; 4, redness and severe swelling of the toes or fingers to the ankle joint or wrist joint.

[0254] Score AUC: After the end of the experiment, the mean arthritis score of animals in each group was analyzed at each time point using GraphPad Prism 8.4.3 software. The Area under curve of XY analyses was selected to calculate the arthritis score AUC of each group of animals. The greater the AUC, the greater the severity of arthritis. The results of the AUC experiment are shown in Table 6.

[0255] Table 6. Arthritis score AUC

[0256] Experimental conclusion: According to the score results, compared with the model group, the compound of the application can significantly improve the degree of arthritis lesions in model animals, and the score AUC is significantly lower than that of LNP023.

[0257] Experimental Example 6: Study on the inhibition of red blood cell hemolysis of PNH patients

[0258] Experimental purpose: Through the detection of the percentage of CD59-negative red blood cells in PNH patients by flow cytometry, the inhibitory effect of compound 1a-2 and compound 2 on red blood cell hemolysis of PNH patients was evaluated.

[0259] Experimental method: PNH patient red blood cells were adjusted to 20% hematocrit with normal saline, and an appropriate amount of blood group matched healthy human serum was taken, 1M MgCl2 was added (final concentration 2.85mM), then an appropriate amount of 0.2M HCl was added for acidification, and the serum was adjusted to pH 6.4-6.6 to activate the complement pathway; 200μL / well of acidified serum was added to a 96-well deep well plate, 1μL of 220x final concentration of test compound (final concentration: 10, 3.33, 1.11, 0.74, 0.49, 0.37, 0.12, 0.04μM) was added, and at the same time, a negative control group (acidified serum without compound, 1μL DMSO was added, representing the maximum hemolysis group mediated by complement), an inactivated serum group (56°C heat treatment for 30min to inactivate complement, inactivated serum without compound, 1μL DMSO was added, representing the serum background control, the minimum hemolysis group) and an untreated group (without serum, 1μL DMSO was added, and the same volume of normal saline was added, which was used to calculate the hemolysis rate of PNH red blood cells) were set up, and the control group was set up with 2 duplicate wells. Incubate at 4°C for 10min, after incubation, add 20μL of 20% hematocrit PNH patient red blood cells (final hematocrit of red blood cells is about 2%) to each well, and incubate at 37°C for 24h; after incubation, each well is washed once with PBS, the cells are resuspended in PBS containing 3% BSA, and incubated at room temperature for 30min; after blocking, centrifuge, discard the supernatant, resuspend with pre-cooled PBS (without Ca 2+ 、Mg 2+ ), adjust the cell concentration to 1×10 6 cells / mL; the cell suspension was stained with PE (Phycoerythrin, phycoerythrin) conjugated CD59 monoclonal antibody (Abeam, ab36421) at a ratio of 100:1 (V / V), and incubated at room temperature for 40min in the dark; after incubation, centrifuge, discard the supernatant, and wash twice with pre-cooled PBS; resuspend the cells with 500μL PBS per tube, and use a flow cytometer (BECKMAN COULTER, DxFLEX) for flow cytometry analysis.

[0260] The flow cytometry histogram is obtained by analysis, and the left side of the flow cytometry histogram represents the CD59 negative cell group, i.e. the PNH red blood cell group, and the right side represents the CD59 positive cell group, i.e. the normal red blood cell group. The hemolysis rate was calculated by comparing the percentage of PNH red blood cells before and after drug addition (pre-culture: pre) and after culture (post) (based on the determination of residual normal red blood cells (N), the proportion of PNH red blood cells was normalized):

[0261] % hemolysis rate = 100-(% PNH post / % N post ) x (% N pre / % PNH pre ) x 100.

[0262] The hemolysis inhibition rate was calculated according to the following formula:

[0263] Hemolysis inhibition rate (%) = 100 - (Compound group hemolysis rate - Inactivated serum group hemolysis rate) / (Negative control group hemolysis rate - Inactivated serum group hemolysis rate) x 100.

[0264] After calculating the hemolysis inhibition rate of each group, the IC50value of the compound was obtained using the formula [Y = Bottom + (Top-Bottom) / (1 + 10^((LogIC 50 -X) * HillSlope))] by GraphPad Prism 5 software (X is the Log value of the compound concentration, Y is the hemolysis inhibition rate). 50

[0265] Experimental results: The experiment was independently performed four times using the erythrocytes of four PNH patients. The IC50values of the compound for inhibiting the hemolysis of the erythrocytes of the four PNH patients were summarized in Table 7 below. Figure 2 is the dose-response curve of the compound in the four experiments. 50

[0266] Table 7. Study on the effect of the compound on the hemolysis inhibition of the erythrocytes of PNH patients *: A and O represent the blood type of the patient

[0267] The above results show that the compound 1a-2 and the compound 2 can dose-dependently inhibit the hemolysis of the erythrocytes of PNH patients.

[0268] Example 7: A multicenter, randomized, open phase II clinical trial for evaluating the effectiveness and safety of the compound of formula I in treating patients with paroxysmal nocturnal hemoglobinuria

[0269] This study is a multicenter, randomized, open phase II clinical trial, which plans to include 24 patients with paroxysmal nocturnal hemoglobinuria, and is allocated to group A or group B in a ratio of 1:1, with about 12 patients in each group. The subjects in group A start to receive the compound of formula I treatment at a dose of 100 mg once a day from D1; the subjects in group B start to receive the compound of formula I treatment at a dose of 200 mg once a day from D1. The study includes an 8-week screening period, a 12-week treatment period, and an extended treatment period. After the end of the 12-week treatment, the subjects who benefit will enter the extended treatment period.

[0270] The subjects return to the hospital for visits at V3 (D1), V4 (D8), V5 (D15), V6 (D22), V7 (D29), V8 (D43), V9 (D57), V10 (D71), V11 (D85), complete the relevant examinations according to the visit week number, and collect the corresponding PK, PD blood samples to evaluate the safety and effectiveness. ​​

[0271] The study population was patients with paroxysmal nocturnal hemoglobinuria who had not received treatment with a complement inhibitor.

[0272] Some subjects have completed the 12 week (D85) visit. Hemoglobin (HB) and lactate dehydrogenase (LDH) are the pharmacodynamic markers for this study and are used to assess the efficacy of the compound of Formula I in treating PNH patients. High levels of LDH indicate that a subject can have hemolysis and low levels of HB indicate that a subject can have hemolytic anemia.

[0273] Subject 1 in the 100 mg dose group had a baseline HB of 79 g / L and a HB of 111 g / L at week 12, an increase of 32 g / L from baseline; and a baseline LDH of 1627 U / L, a LDH of 252 U / L at week 2, and a LDH of 345 U / L at week 12.

[0274] Subject 2 in the 100 mg dose group had a baseline HB of 67 g / L and a HB of 111 g / L at week 12, an increase of 44 g / L from baseline; and a baseline LDH of 858 U / L, a LDH of 179 U / L at week 2, and a LDH of 184 U / L at week 12.

[0275] Subject 3 in the 100 mg dose group had a baseline HB of 88 g / L and a HB of 128 g / L at week 12, an increase of 40 g / L from baseline; and a baseline LDH of 1188 U / L, a LDH of 223 U / L at week 2, and a LDH of 234 U / L at week 12.

[0276] All three subjects had an increase in HB of >20 g / L from baseline at week 12 and were close to normal levels. At week 2, the LDH was close to the normal range, hemolysis was controlled, and this was maintained through week 12.

Claims

1. Use of a compound having the structure of Formula A: ###00001### Formula A or a pharmaceutically acceptable salt thereof, or a hydrate thereof, in the manufacture of a medicament or pharmaceutical composition for the treatment and / or prevention of a disease or disorder associated with paroxysmal nocturnal hemoglobinuria. ​ wherein X is selected from H or glucuronyl; the pharmaceutical or pharmaceutical composition optionally further comprises one or more pharmaceutically acceptable carriers or other therapeutic agents Preferably, X is selected from H or D-glucopyranuronic acid.

2. Use of a compound having the structure of Formula A: ###0001### or a pharmaceutically acceptable salt thereof, or a hydrate thereof, in the manufacture of a medicament or pharmaceutical composition for reducing the incidence of paroxysmal nocturnal hemoglobinuria-associated hemolysis in a population of subjects. ###0002### Formula A ​ wherein X is selected from H or glucuronyl; the pharmaceutical or pharmaceutical composition optionally further comprises one or more pharmaceutically acceptable carriers or other therapeutic agents Preferably, X is selected from H or D-glucopyranuronic acid.

3. Use according to claim 1 or 2, characterized in that, X is selected from H or D-glucuronosyl; said compound is further illustrated by the following formula I: Alternatively, the compound is further represented by the following formula II-M: Alternatively, the compound is further represented by the following formula II:

4. Use according to claim 3, characterized in that, The compound is administered at a dose of 0.1-2000 mg per time; preferably 10-1000 mg per time; more preferably 50-700 mg per time; further preferably 75-600 mg per time; further preferably 100-600 mg per time; more further preferably 100 mg per time, 200 mg per time, 300 mg per time or 400 mg per time; The compound is administered at a frequency of once a day, twice a day, three times a day, once a week, three times a week, once in two weeks, once in three weeks or once in a month; preferably once a day, twice a day or three times a day; more preferably once a day. Preferably, the compound is administered at a dose of 200 mg per time, 300 mg per time or 400 mg per time, at a frequency of twice a day; preferably, the compound is administered at a dose of 100 mg per time, at a frequency of once a day; preferably, the compound is administered at a dose of 200 mg per time, at a frequency of once a day.

5. A method for preventing and / or treating a disease or disorder associated with paroxysmal nocturnal hemoglobinuria, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of Formula A as in claim 1, or a pharmaceutically acceptable salt thereof, or a hydrate thereof; preferably, the compound is further as shown in Formula I or Formula II-M or Formula II in claim 3.

6. A method for reducing the incidence of hemolysis associated with paroxysmal nocturnal hemoglobinuria in a population of subjects, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of Formula A as in claim 1, or a pharmaceutically acceptable salt thereof, or a hydrate thereof; preferably, the compound is further as shown in Formula I or Formula II-M or Formula II in claim 3.

7. The method of claim 5 or 6, wherein, The method comprises administering to a subject in need thereof 0.1-2000 mg of a compound of Formula A, or a pharmaceutically acceptable salt thereof, or a hydrate thereof; preferably, the method comprises administering to a subject in need thereof 10-1000 mg of a compound of Formula A, or a pharmaceutically acceptable salt thereof, or a hydrate thereof; more preferably, the method comprises administering to a subject in need thereof 50-700 mg of a compound of Formula A, or a pharmaceutically acceptable salt thereof, or a hydrate thereof; further preferably, the method comprises administering to a subject in need thereof 75-600 mg of a compound of Formula A, or a pharmaceutically acceptable salt thereof, or a hydrate thereof; more further preferably, the method comprises administering to a subject in need thereof 100 mg, 200 mg, 300 mg or 400 mg of a compound of Formula A, or a pharmaceutically acceptable salt thereof, or a hydrate thereof.

8. The method of any one of claims 5-7, wherein, The method is administered to a subject in need thereof a compound of Formula A or a pharmaceutically acceptable salt thereof or a hydrate thereof at a frequency of once a day, twice a day, three times a day, once a week, three times a week, once in two weeks, once in three weeks or once in a month; preferably once a day, twice a day or three times a day; more preferably once a day; and / or the compound of Formula A or a pharmaceutically acceptable salt thereof or a hydrate thereof is administered by oral, parenteral, rectal, pulmonary or topical administration.

9. A medicament or pharmaceutical composition for preventing and / or treating a disease or disorder associated with paroxysmal nocturnal hemoglobinuria, the medicament or pharmaceutical composition comprising a compound of Formula A as in claim 1 or a pharmaceutically acceptable salt thereof or a hydrate thereof; the medicament or pharmaceutical composition optionally further comprising one or more pharmaceutically acceptable carriers or other therapeutic agents.

10. A pharmaceutical composition for reducing the incidence of hemolysis associated with paroxysmal nocturnal hemoglobinuria in a population of subjects in need thereof, the medicament or pharmaceutical composition comprising a compound of Formula A as in claim 1 or a pharmaceutically acceptable salt thereof or a hydrate thereof; the medicament or pharmaceutical composition optionally further comprising one or more pharmaceutically acceptable carriers or other therapeutic agents.

11. Use of a compound or a pharmaceutically acceptable salt thereof or a hydrate thereof for preventing and / or treating a disease or condition mediated by complement factor B in a subject in need thereof; the compound having a structure of Formula A as in claim 1; preferably, the compound further having a structure of Formula I or Formula II-M or Formula II as in claim 3.

12. A compound of formula II-M: ###00013### II-M 13. A compound of formula II: ###0002### II

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