Use of heterocyclic compound in treatment of pulmonary disease

Abstract

The present application relates to use of a heterocyclic compound in the treatment of a pulmonary disease, and specifically to use of a heterocyclic compound in the treatment of chronic obstructive pulmonary disease (COPD).

Description

Use of heterocyclic compounds in the treatment of lung diseases

[0001] Cross-reference to Related Applications

[0002] This application claims priority to and the benefit of Chinese Patent Application No. 202411252733.4, filed September 6, 2024, and Chinese Patent Application No. 202511143366.9, filed August 15, 2025, in the China National Intellectual Property Office, the disclosures of which are incorporated herein in their entireties by reference. TECHNICAL FIELD

[0003] The present application belongs to the technical field of medicine, and relates to the use of heterocyclic compounds in the treatment of lung diseases, in particular to the use of the compounds of the present application in the treatment of chronic obstructive pulmonary disease (COPD). BACKGROUND

[0004] Chronic obstructive pulmonary disease (COPD) is a heterogeneous lung disease characterized by chronic respiratory symptoms (including dyspnea, cough, sputum production) due to abnormalities of the respiratory tract (bronchitis, bronchiolitis) and / or alveoli (emphysema) leading to persistent, repeatedly worsening airflow obstruction. The chronic airflow limitation of COPD is caused by both small airway disease and parenchymal destruction (emphysema). Inflammation is the core mechanism of COPD disease progression, and chronic inflammatory response leads to structural changes in the lung, small airway stenosis and lung parenchymal destruction (emphysema), and destroys normal repair and defense mechanisms (small airway fibrosis), reducing the elastic recoil capacity of the lung. These pathological changes lead to gas retention and progressive airflow limitation.

[0005] The number of COPD patients in China in 2015 was estimated to be 99.9 million, becoming the third largest epidemic after hypertension and diabetes. The pathogenesis of COPD is not yet fully understood, and it is generally believed that inflammation, oxidative stress, and imbalance between proteases and anti-proteases are important mechanisms of the pathogenesis of COPD. The purpose of COPD treatment is to relieve symptoms, improve activity tolerance, improve health status, prevent disease progression, prevent and treat acute exacerbation of COPD, and reduce disability.

[0006] Because current treatments for COPD cannot stop or reverse the inflammatory response and reduction in lung function, combined with the inability to adequately control the exacerbation of the disease, there is still a huge unmet need for COPD. The current strategy is to combine different types of drugs, or to develop new formulations and dosage forms for convenient administration, to improve patient compliance. Therefore, in the absence of a curative treatment, it is of great clinical significance to supplement new mechanism drugs. SUMMARY

[0007] The present application provides a method of treating or preventing COPD comprising administering to a subject a therapeutically effective amount of the compound of Formula I or a pharmaceutically acceptable salt thereof:

[0008] wherein,

[0009] R 6 is selected from hydrogen or hydroxyl;

[0010] T 1 is selected from CR 1 , T 2 , T 3 and T 4 are each independently selected from N, NH, N(C 1-3 alkyl), C=0, C(R 1 )2or O;

[0011] each R 1 is independently selected from hydrogen, amino, hydroxyl, cyano, halogen, C 1-3 alkyl, C 1-3 alkoxy or C 1 alkyl optionally substituted with halogen;

[0012] E m is selected from -(CH2) 2 - wherein m is 1, 2 or 3;

[0013] E 6 is selected from -0-, -NH-, -S- or a single bond.

[0014] In some embodiments, R 1 is selected from hydrogen, T 1 is selected from CR 2 , T 3 and T 4 are selected from N, T 1 is selected from NH or N(CH3), R 6 is selected from hydrogen, amino, hydroxyl, methyl or methoxy.

[0015] In some embodiments, R 1 is selected from hydrogen, E 2 is selected from a single bond, T 1 is selected from CR 1 , T 2 and T 3 are selected from N, T 4 is selected from NH or N(CH3), R 1 is selected from hydrogen, amino, hydroxyl, methyl or methoxy.

[0016] In some embodiments, R 6 is selected from hydrogen, E 1selected from -(CH2)2-, E 2 selected from a single bond, T 1 selected from CR 1 , T 2 and T 3 selected from N, T 4 selected from NH, R 1 selected from hydrogen, amino, methyl, or methoxy.

[0017] In some embodiments, the compound of Formula I, or a pharmaceutically acceptable salt thereof, is selected from Compound A, Compound B, Compound C, Compound D, Compound E, or a pharmaceutically acceptable salt thereof,

[0018] In some embodiments, the compound of Formula I, or a pharmaceutically acceptable salt thereof, is selected from Compound A, or a pharmaceutically acceptable salt thereof.

[0019] In some embodiments, the compound of Formula I, or a pharmaceutically acceptable salt thereof, is selected from Compound B, or a pharmaceutically acceptable salt thereof.

[0020] In some embodiments, the compound of Formula I, or a pharmaceutically acceptable salt thereof, is selected from Compound C, or a pharmaceutically acceptable salt thereof.

[0021] In some embodiments, the compound of Formula I, or a pharmaceutically acceptable salt thereof, is selected from Compound D, or a pharmaceutically acceptable salt thereof.

[0022] In some embodiments, the compound of Formula I, or a pharmaceutically acceptable salt thereof, is selected from Compound E, or a pharmaceutically acceptable salt thereof.

[0023] The present application provides a method of treating or preventing COPD, comprising administering to a subject a therapeutically effective amount of the compound of Formula I (e.g., Compound A-E) or a pharmaceutically acceptable salt thereof.

[0024] In another aspect, the present disclosure provides the compound of Formula I (e.g., Compound A-E) or a pharmaceutically acceptable salt thereof for use in treating or preventing COPD.

[0025] In another aspect, the present disclosure provides the use of the compound of Formula I (e.g., Compound A-E) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating or preventing COPD.

[0026] In another aspect, the present disclosure provides the use of the compound of Formula I (e.g., Compound A-E) or a pharmaceutically acceptable salt thereof in treating or preventing COPD.

[0027] In another aspect, the present disclosure provides a kit comprising the compound of Formula I (e.g., Compound A-E) or a pharmaceutically acceptable salt thereof, and instructions for using the compound of Formula I (e.g., Compound A-E) or a pharmaceutically acceptable salt thereof for treating or preventing COPD.

[0028] In another aspect, the present disclosure provides a use of the kit of the present disclosure in the manufacture of a medicament for treating or preventing COPD. The present disclosure provides a method for treating or preventing COPD, comprising administering to a subject in need thereof a therapeutically effective amount of the kit of the present disclosure. The present disclosure provides a use of the kit of the present disclosure in treating or preventing COPD. The present disclosure provides a kit of the present disclosure for use in treating or preventing COPD.

[0029] In another aspect, the present disclosure provides a pharmaceutical composition for treating or preventing COPD, comprising the compound of Formula I (e.g., Compound A-E) or a pharmaceutically acceptable salt thereof.

[0030] In another aspect, the present disclosure provides a method for treating or preventing COPD in a subject, comprising administering to the subject a pharmaceutical composition of the compound of Formula I (e.g., Compound A-E) or a pharmaceutically acceptable salt thereof.

[0031] In another aspect, the present disclosure provides a use of a pharmaceutical composition of the compound of Formula I (e.g., Compound A-E) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating or preventing COPD.

[0032] In another aspect, the present disclosure provides a use of a pharmaceutical composition of the compound of Formula I (e.g., Compound A-E) or a pharmaceutically acceptable salt thereof in treating or preventing COPD.

[0033] In some embodiments of the present disclosure, the pharmaceutical composition is packaged in a kit, which further comprises instructions for using the compound of Formula I (e.g., Compound A-E) or a pharmaceutically acceptable salt thereof for treating or preventing COPD.

[0034] In some embodiments of the present disclosure, the pharmaceutical composition further comprises a pharmaceutically acceptable excipient.

[0035] The present disclosure provides a method for improving or eliminating insomnia, lack of energy, breathlessness, wheezing, chest tightness, fatigue, limited activity, cough, or sputum symptoms in a COPD patient, comprising administering to the subject a therapeutically effective amount of the compound of Formula I (e.g., Compound A-E) or a pharmaceutically acceptable salt thereof.

[0036] In another aspect, the present disclosure provides the compound of Formula I (e.g., Compounds A-E) or a pharmaceutically acceptable salt thereof for use in improving or eliminating insomnia, lack of energy, breathlessness, wheezing, chest tightness, fatigue, limited activity, cough, or sputum symptoms in a COPD patient.

[0037] In another aspect, the present disclosure provides use of the compound of Formula I (e.g., Compounds A-E) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for improving or eliminating insomnia, lack of energy, breathlessness, wheezing, chest tightness, fatigue, limited activity, cough, or sputum symptoms in a COPD patient.

[0038] In another aspect, the present disclosure provides use of the compound of Formula I (e.g., Compounds A-E) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for improving or eliminating insomnia, lack of energy, breathlessness, wheezing, chest tightness, fatigue, limited activity, cough, or sputum symptoms in a COPD patient.

[0039] In another aspect, the present disclosure provides a kit comprising the compound of Formula I (e.g., Compounds A-E) or a pharmaceutically acceptable salt thereof, and instructions for use of the compound of Formula I (e.g., Compounds A-E) or a pharmaceutically acceptable salt thereof in improving or eliminating insomnia, lack of energy, breathlessness, wheezing, chest tightness, fatigue, limited activity, cough, or sputum symptoms in a COPD patient.

[0040] In another aspect, the present disclosure provides use of the kit of the present disclosure in the manufacture of a medicament for improving or eliminating insomnia, lack of energy, breathlessness, wheezing, chest tightness, fatigue, limited activity, cough, or sputum symptoms in a COPD patient.

[0041] The present disclosure provides a method for improving or eliminating insomnia, lack of energy, breathlessness, wheezing, chest tightness, fatigue, limited activity, cough, or sputum symptoms in a COPD patient, comprising administering to a subject in need thereof a therapeutically effective amount of the kit of the present disclosure.

[0042] The present disclosure provides use of the kit of the present disclosure in improving or eliminating insomnia, lack of energy, breathlessness, wheezing, chest tightness, fatigue, limited activity, cough, or sputum symptoms in a COPD patient.

[0043] The present disclosure provides the kit of the present disclosure for use in improving or eliminating insomnia, lack of energy, breathlessness, wheezing, chest tightness, fatigue, limited activity, cough, or sputum symptoms in a COPD patient.

[0044] In another aspect, the present disclosure provides a pharmaceutical composition for use in improving or eliminating insomnia, lack of energy, breathlessness, wheezing, chest tightness, fatigue, limited activity, cough, or sputum symptoms in a COPD patient, comprising the compound of Formula I (e.g., Compounds A-E) or a pharmaceutically acceptable salt thereof.

[0045] In another aspect, the present disclosure provides a method of improving or eliminating insomnia, lack of energy, breathlessness, wheezing, chest tightness, fatigue, activity limitation, cough, or sputum production in a COPD patient, comprising administering to the subject a pharmaceutical composition of the compound of Formula I (e.g., Compound A-E) or a pharmaceutically acceptable salt thereof.

[0046] In another aspect, the present disclosure provides the use of a pharmaceutical composition of the compound of Formula I (e.g., Compound A-E) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for improving or eliminating insomnia, lack of energy, breathlessness, wheezing, chest tightness, fatigue, activity limitation, cough, or sputum production in a COPD patient.

[0047] In another aspect, the present disclosure provides the use of a pharmaceutical composition of the compound of Formula I (e.g., Compound A-E) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for improving or eliminating insomnia, lack of energy, breathlessness, wheezing, chest tightness, fatigue, activity limitation, cough, or sputum production in a COPD patient.

[0048] In some embodiments of the present disclosure, the pharmaceutical composition is packaged in a kit, which further comprises instructions for using the compound of Formula I (e.g., Compound A-E) or a pharmaceutically acceptable salt thereof to improve or eliminate insomnia, lack of energy, breathlessness, wheezing, chest tightness, fatigue, activity limitation, cough, or sputum production in a COPD patient. In some embodiments of the present disclosure, the pharmaceutical composition further comprises a pharmaceutically acceptable excipient.

[0049] The present disclosure provides a method of improving reduced sleep quality in a COPD patient due to COPD, comprising administering to the subject a therapeutically effective amount of the compound of Formula I (e.g., Compound A-E) or a pharmaceutically acceptable salt thereof.

[0050] In another aspect, the present disclosure provides the compound of Formula I (e.g., Compound A-E) or a pharmaceutically acceptable salt thereof for use in improving reduced sleep quality in a COPD patient due to COPD.

[0051] In another aspect, the present disclosure provides the use of the compound of Formula I (e.g., Compound A-E) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for improving reduced sleep quality in a COPD patient due to COPD.

[0052] In another aspect, the present disclosure provides the use of the compound of Formula I (e.g., Compound A-E) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for improving reduced sleep quality in a COPD patient due to COPD.

[0053] In another aspect, the present disclosure provides a kit comprising the compound of Formula I (e.g., Compound A-E) or a pharmaceutically acceptable salt thereof, and instructions for using the compound of Formula I (e.g., Compound A-E) or a pharmaceutically acceptable salt thereof to improve a symptom of reduced sleep quality due to COPD in a patient with COPD.

[0054] In another aspect, the present disclosure provides a use of the kit of the present disclosure in the manufacture of a medicament for improving a symptom of reduced sleep quality due to COPD in a patient with COPD.

[0055] The present disclosure provides a method for improving a symptom of reduced sleep quality due to COPD in a patient with COPD, comprising administering to a subject in need thereof a therapeutically effective amount of the kit of the present disclosure.

[0056] The present disclosure provides a use of the kit of the present disclosure in improving reduced sleep quality due to COPD in a patient with COPD.

[0057] The present disclosure provides a kit of the present disclosure for use in improving reduced sleep quality due to COPD in a patient with COPD.

[0058] In another aspect, the present disclosure provides a pharmaceutical composition for use in improving a symptom of reduced sleep quality due to COPD in a patient with COPD, comprising the compound of Formula I (e.g., Compound A-E) or a pharmaceutically acceptable salt thereof.

[0059] In another aspect, the present disclosure provides a method for improving a symptom of reduced sleep quality due to COPD in a patient with COPD, comprising administering to a subject a pharmaceutical composition of the compound of Formula I (e.g., Compound A-E) or a pharmaceutically acceptable salt thereof.

[0060] In another aspect, the present disclosure provides a use of a pharmaceutical composition of the compound of Formula I (e.g., Compound A-E) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for improving a symptom of reduced sleep quality due to COPD in a patient with COPD.

[0061] In another aspect, the present disclosure provides a use of a pharmaceutical composition of the compound of Formula I (e.g., Compound A-E) or a pharmaceutically acceptable salt thereof in improving reduced sleep quality due to COPD in a patient with COPD.

[0062] In some embodiments of the present disclosure, the pharmaceutical composition is packaged in a kit, which further comprises instructions for using the compound of Formula I (e.g., Compound A-E) or a pharmaceutically acceptable salt thereof to improve a symptom of reduced sleep quality due to COPD in a patient with COPD. In some embodiments of the present disclosure, the pharmaceutical composition further comprises a pharmaceutically acceptable excipient.

[0063] In some embodiments, the methods, uses, compounds, compositions, kits, further comprise administering to the patient a therapeutically effective amount of one or more other drugs.

[0064] In some embodiments, the methods, uses, compounds, compositions, kits, further comprise administering to the patient a therapeutically effective amount of a monobracial or a bibracial expanding drug. In some embodiments, further comprising an anti-inflammatory drug. In some embodiments, further comprising an ICS. In some embodiments, the anti-inflammatory drug is selected from an ICS.

[0065] In some embodiments, the methods, uses, compounds, compositions, kits, further comprise administering to the patient a therapeutically effective amount of a LABA, a LAMA, and / or an ICS. In some embodiments, the methods, uses, compounds, compositions, kits, further comprise administering to the patient a therapeutically effective amount of one, two, or three of a LABA, a LAMA, or an ICS.

[0066] In some embodiments, the methods, uses, compounds, compositions, kits, further comprise administering to the patient a therapeutically effective amount of a LABA.

[0067] In some embodiments, the methods, uses, compounds, compositions, kits, further comprise administering to the patient a therapeutically effective amount of a LAMA.

[0068] In some embodiments, the methods, uses, compounds, compositions, kits, further comprise administering to the patient a therapeutically effective amount of a LABA and a LAMA.

[0069] In some embodiments, the methods, uses, compounds, compositions, kits, further comprise administering to the patient a therapeutically effective amount of a LABA, a LAMA, and an ICS.

[0070] In some embodiments, the methods, uses, compounds, compositions, kits, further comprise administering to the patient a therapeutically effective amount of a LABA and an ICS.

[0071] In some embodiments, the monobracial or bibracial expanding drug is used as a background therapy for COPD. In some embodiments, the monobracial or bibracial expanding drug is used as a background therapy for COPD, further comprising an ICS as a background therapy.

[0072] In some embodiments, the LABA, the LAMA, or the ICS is used as a background therapy for COPD.

[0073] In another aspect, the present disclosure provides a combination (or association) of a compound of Formula I (e.g., Compound A-E) or a pharmaceutically acceptable salt thereof and one or more other drugs.

[0074] In another aspect, the present disclosure provides the use of a compound of Formula I (e.g., Compound A-E), or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating or preventing COPD in combination with one or more other drugs.

[0075] In another aspect, the present disclosure provides the use of one or more other drugs in the manufacture of a medicament for treating or preventing COPD in combination with a compound of Formula I (e.g., Compound A-E), or a pharmaceutically acceptable salt thereof.

[0076] In another aspect, the present disclosure provides the use of a compound of Formula I (e.g., Compound A-E), or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating or preventing COPD, the treatment or prevention further comprising one or more other drugs.

[0077] In another aspect, the present disclosure provides the use of a compound of Formula I (e.g., Compound A-E), or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating or preventing COPD, the treatment or prevention further comprising one or more other drugs.

[0078] In another aspect, the present disclosure provides a kit comprising a compound of Formula I (e.g., Compound A-E), or a pharmaceutically acceptable salt thereof, and instructions for using a compound of Formula I (e.g., Compound A-E), or a pharmaceutically acceptable salt thereof, in combination with one or more other drugs for treating or preventing COPD.

[0079] In another aspect, the present disclosure provides a kit comprising a compound of Formula I (e.g., Compound A-E), or a pharmaceutically acceptable salt thereof, and instructions for using a compound of Formula I (e.g., Compound A-E), or a pharmaceutically acceptable salt thereof, in combination with one or more other drugs for treating or preventing COPD.

[0080] In another aspect, the present disclosure provides the use of a kit of the present disclosure in the manufacture of a medicament for treating or preventing COPD in combination with one or more other drugs.

[0081] In another aspect, the present disclosure provides the use of a kit of the present disclosure in the manufacture of a medicament for treating or preventing COPD, the treatment or prevention further comprising one or more other drugs.

[0082] In another aspect, the present disclosure provides the use of a kit of the present disclosure in the manufacture of a medicament for treating or preventing COPD in combination with one or more other drugs.

[0083] The present disclosure provides a method of treating or preventing COPD in which one or more other drugs are used as background therapy, comprising administering to an individual in need thereof a therapeutically effective amount of a kit of the present disclosure.

[0084] The present disclosure provides use of the kits of the present disclosure in the treatment or prevention of COPD as background therapy of one or more other drugs.

[0085] The present disclosure provides the kits of the present disclosure for use in the treatment or prevention of COPD as background therapy of one or more other drugs.

[0086] In some embodiments of the present disclosure, the pharmaceutical composition is packaged in a kit further comprising instructions for using the compound of Formula I (e.g., Compound A-E) or a pharmaceutically acceptable salt thereof for the treatment or prevention of COPD as background therapy of one or more other drugs.

[0087] The present disclosure provides a method of treating or preventing COPD, comprising administering to a subject a therapeutically effective amount of the compound of Formula I (e.g., Compound A-E) or a pharmaceutically acceptable salt thereof and one or more other drugs.

[0088] In another aspect, the present disclosure provides a combination of the compound of Formula I (e.g., Compound A-E) or a pharmaceutically acceptable salt thereof and one or more other drugs for use in the treatment or prevention of COPD.

[0089] In another aspect, the present disclosure provides use of a combination of the compound of Formula I (e.g., Compound A-E) or a pharmaceutically acceptable salt thereof and one or more other drugs in the manufacture of a medicament for the treatment or prevention of COPD.

[0090] In another aspect, the present disclosure provides use of a combination of the compound of Formula I (e.g., Compound A-E) or a pharmaceutically acceptable salt thereof and one or more other drugs in the treatment or prevention of COPD.

[0091] In another aspect, the present disclosure provides a kit comprising the compound of Formula I (e.g., Compound A-E) or a pharmaceutically acceptable salt thereof, and instructions for using the compound of Formula I (e.g., Compound A-E) or a pharmaceutically acceptable salt thereof and one or more other drugs in the treatment or prevention of COPD.

[0092] In some embodiments, the other drug is background therapy.

[0093] In some embodiments, the other drug is selected from a bronchodilator drug. In some embodiments, the other drug further comprises an anti-inflammatory drug.

[0094] In some embodiments, the other drug is selected from a monobronchodilator drug, a diabronchodilator drug, or an anti-inflammatory drug.

[0095] In some embodiments, the other drug is selected from a monobronchodilator drug, a diabronchodilator drug, or a triple drug comprising an anti-inflammatory component.

[0096] In some embodiments, the other drug is selected from one, two, or three of a LABA, a LAMA, or an ICS.

[0097] In some embodiments, the other drug is selected from a LABA and / or a LAMA.

[0098] In some embodiments, the other drug is a LABA.

[0099] In some embodiments, the other drug is a LAMA.

[0100] In some embodiments, the other drug is a LABA / LAMA.

[0101] In some embodiments, the other drug is a LABA / LAMA / ICS.

[0102] In some embodiments, the LAMA is selected from tiotropium, umeclidinium, aclidinium, glycopyrronium, rufinacain, darotropium, or glycopyrronium bromide; the LABA is selected from salmeterol, formoterol, arformoterol, indacaterol, vilanterol, olodaterol, abediterol, or carmoterol; and / or the ICS is selected from beclometasone, budesonide, fluticasone propionate, ciclesonide, mometasone, or fluticasone furoate.

[0103] In some embodiments, the LABA / LAMA is selected from umeclidinium / vilanterol, indacaterol / glycopyrronium, tiotropium / olodaterol, glycopyrronium / formoterol, budesonide / formoterol, aclidinium / formoterol, or salmeterol / fluticasone.

[0104] In some embodiments, the LABA / LAMA / ICS is selected from budesonide / formoterol / glycopyrronium, fluticasone / umeclidinium / vilanterol, or beclometasone / formoterol fumarate / glycopyrronium.

[0105] In another aspect, the present disclosure provides the use of a compound of Formula I (e.g., Compound A-E), or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating or preventing COPD in combination with a single- or dual- bronchodilator.

[0106] In another aspect, the present disclosure provides the use of a single- or dual- bronchodilator in the manufacture of a medicament for treating or preventing COPD in combination with a compound of Formula I (e.g., Compound A-E), or a pharmaceutically acceptable salt thereof.

[0107] In another aspect, the present disclosure provides the use of a compound of Formula I (e.g., Compound A-E), or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating or preventing COPD, the treatment or prevention further comprising a single- or dual- bronchodilator.

[0108] In another aspect, the present disclosure provides use of a compound of Formula I (e.g., Compound A-E) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating or preventing COPD in combination with a monobrush or a dibrush.

[0109] In another aspect, the present disclosure provides a kit comprising a compound of Formula I (e.g., Compound A-E) or a pharmaceutically acceptable salt thereof, and instructions for using a compound of Formula I (e.g., Compound A-E) or a pharmaceutically acceptable salt thereof in the treatment or prevention of COPD in combination with a monobrush or a dibrush.

[0110] In another aspect, the present disclosure provides a kit comprising a compound of Formula I (e.g., Compound A-E) or a pharmaceutically acceptable salt thereof, and instructions for using a compound of Formula I (e.g., Compound A-E) or a pharmaceutically acceptable salt thereof in the treatment or prevention of COPD in combination with a monobrush or a dibrush.

[0111] In another aspect, the present disclosure provides use of a kit of the present disclosure in the manufacture of a medicament for treating or preventing COPD in combination with a monobrush or a dibrush.

[0112] In another aspect, the present disclosure provides use of a kit of the present disclosure in the manufacture of a medicament for treating or preventing COPD in combination with a monobrush or a dibrush.

[0113] In another aspect, the present disclosure provides use of a kit of the present disclosure in the manufacture of a medicament for treating or preventing COPD in combination with a monobrush or a dibrush.

[0114] The present disclosure provides a method of treating or preventing COPD in combination with a monobrush or a dibrush as background therapy, comprising administering to an individual in need thereof a therapeutically effective amount of a kit of the present disclosure.

[0115] The present disclosure provides use of a kit of the present disclosure in the treatment or prevention of COPD in combination with a monobrush or a dibrush as background therapy.

[0116] The present disclosure provides a kit of the present disclosure for use in the treatment or prevention of COPD in combination with a monobrush or a dibrush as background therapy.

[0117] In some embodiments of the present disclosure, the pharmaceutical composition is packaged in a kit further comprising instructions for using a compound of Formula I (e.g., Compound A-E) or a pharmaceutically acceptable salt thereof in the treatment or prevention of COPD in combination with a monobrush or a dibrush as background therapy.

[0118] In some embodiments of the present disclosure, the pharmaceutical composition further comprises a pharmaceutically acceptable excipient.

[0119] In some embodiments, the treatment or prevention of COPD comprises improving lung function, or improving or eliminating one or more of insomnia, breathlessness, wheezing, chest tightness, fatigue, limited activity, cough, or sputum production in a COPD patient. In some embodiments, the treatment or prevention of COPD comprises improving or eliminating repeated acute exacerbations in a COPD patient. In some embodiments, the treatment or prevention of COPD comprises improving sleep quality in a COPD patient due to COPD. In some embodiments, the improvement or elimination of insomnia, lack of energy, breathlessness, wheezing, chest tightness, fatigue, limited activity, cough, or sputum production in a COPD patient can be one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, or 9) of insomnia, lack of energy, breathlessness, wheezing, chest tightness, fatigue, limited activity, cough, or sputum production in a COPD patient.

[0120] Chronic Obstructive Pulmonary Disease (COPD)

[0121] In some embodiments, the COPD is selected from moderate or severe COPD.

[0122] In some embodiments, the COPD is selected from moderate COPD.

[0123] In some embodiments, the COPD is selected from severe COPD.

[0124] In some embodiments, the COPD is selected from moderate to severe COPD.

[0125] In some embodiments, the COPD is not life-threatening COPD.

[0126] In some embodiments, the treatment or prevention of COPD is selected from maintenance therapy for COPD.

[0127] In some embodiments, the COPD is selected from COPD diagnosed according to the GOLD criteria.

[0128] In some embodiments, the COPD is selected from COPD diagnosed according to the 2023 or 2024 version of the GOLD criteria.

[0129] In some embodiments, the COPD is COPD diagnosed according to the 2023 or 2024 version of the GOLD criteria.

[0130] In some embodiments, the COPD patient has previously received (including is currently receiving) treatment with a single bronchodilator or a dual bronchodilator.

[0131] In some embodiments, the COPD patient is on maintenance therapy with a single-acting bronchodilator or a dual-acting bronchodilator.

[0132] In some embodiments, the COPD patient is concurrently receiving or not receiving background therapy. In some embodiments, the background therapy comprises a single-acting bronchodilator or a dual-acting bronchodilator. In some embodiments, the background therapy further comprises an anti-inflammatory drug. In some embodiments, the anti-inflammatory drug is selected from ICS. In some embodiments, the background therapy comprises one or more of a LAMA, a LABA, or an ICS. In some embodiments, the COPD patient has a prior history of (including is currently receiving) treatment with a LABA, a LAMA, and / or an ICS.

[0133] In some embodiments, the COPD patient is on maintenance therapy with a LABA, a LAMA, and / or an ICS.

[0134] In some embodiments, the COPD patient uses a LABA, a LAMA, and / or an ICS as background medication.

[0135] In some embodiments, the COPD patient is selected from COPD patients on background therapy during the washout period. In some embodiments, the COPD patient has not been previously diagnosed as a life- threatening COPD subject.

[0136] In some embodiments, the COPD patient is on background medication therapy prior to administration of the above-mentioned compound of Formula I (e.g., Compound A-E) or a pharmaceutically acceptable salt thereof. The background medication is selected from background inhaled medication. In some embodiments, the background medication therapy is stable for 4 weeks prior to screening.

[0137] In some embodiments, the COPD patient is administered the above-mentioned compound of Formula I (e.g., Compound A-E) or a pharmaceutically acceptable salt thereof prior to administration of the background medication therapy.

[0138] In some embodiments, the COPD patient is administered the above-mentioned compound of Formula I (e.g., Compound A-E) or a pharmaceutically acceptable salt thereof after administration of the background medication therapy.

[0139] In some embodiments, the COPD patient is administered the above-mentioned compound of Formula I (e.g., Compound A-E) or a pharmaceutically acceptable salt thereof concurrently with administration of the background medication therapy.

[0140] In some embodiments, the background medication comprises a single-branch expanding medication or a double-branch expanding medication. In some embodiments, the background medication is selected from a single-branch expanding medication or a double-branch expanding (further including or not including an inhaled corticosteroid (ICS) inhaled formulation) medication. In some embodiments, the background medication comprises or further comprises an anti-inflammatory medication. In some embodiments, the background medication further comprises an ICS medication. In some embodiments, the background medication is selected from one or more (in combination or in a combination formulation) of a long-acting muscarinic antagonist (LAMA), a long-acting beta-agonist (LABA), and an inhaled corticosteroid (ICS). In some embodiments, the background medication is a LAMA, a LABA, a LAMA / LABA, a LAMA / LABA / ICS, or a LABA / ICS (LAMA / LABA means a combination of the two or a combination formulation of the two, and similar expressions in the context mean similar meanings, for example, LAMA / LABA / ICS means a combination of LAMA, LABA, ICS or a combination formulation of the three).

[0141] In some embodiments, the single-branch expanding medication is selected from a LABA or a LAMA; in some embodiments, the single-branch expanding medication does not include a combined ICS. In some embodiments, an anti-inflammatory medication (e.g., an ICS) is further included on the basis of the single-branch expanding medication. In some embodiments, the double-branch expanding medication is selected from a LABA and / or a LAMA; in some embodiments, the double-branch expanding medication is a LABA / LAMA (LAMA / LABA combination formulation); in some embodiments, an anti-inflammatory medication (e.g., an ICS) is further included on the basis of the double-branch expanding medication. In some embodiments, the double-branch expanding medication does not include a further combined ICS. In some embodiments, an ICS medication is further included on the basis of the single-branch expanding medication or the double-branch expanding medication.

[0142] In some embodiments, the patient has not received a background medication treatment prior to administration of the above-mentioned compound of Formula I (e.g., Compound A-E) or a pharmaceutically acceptable salt thereof. For example, the patient can not have taken a background medication that is a long-acting muscarinic antagonist (LAMA), a long-acting beta-agonist (LABA), or an inhaled corticosteroid (ICS).

[0143] In some embodiments, the LAMA is selected from tiotropium, umeclidinium, aclidinium, glycopyrronium, rufinacain, darotropium, or glycopyrronium bromide.

[0144] In some embodiments, the LABA is selected from salmeterol, formoterol, arformoterol, indacaterol, vilanterol, olodaterol, abediterol, or carmoterol.

[0145] In some embodiments, the ICS is selected from beclometasone, budesonide, fluticasone propionate, ciclesonide, mometasone, or fluticasone furoate.

[0146] In some embodiments, the LABA / LAMA is selected from aclidinium / vilanterol, indacaterol / glycopyrronium bromide, tiotropium / olodaterol, glycopyrronium bromide / formoterol, budesonide / formoterol, aclidinium / formoterol, or salmeterol / ticlopidine.

[0147] In some embodiments, the LABA / LAMA / ICS is selected from budesonide / formoterol / glycopyrronium bromide, fluticasone / aclidinium / vilanterol, or beclometasone dipropionate / formoterol fumarate / glycopyrronium bromide.

[0148] In some embodiments, the LABA / LAMA is selected from aclidinium / vilanterol inhalation powder, indacaterol / glycopyrronium bromide inhalation powder, tiotropium / olodaterol inhalation spray, or glycopyrronium bromide / formoterol inhalation aerosol.

[0149] In some embodiments, the LABA / LAMA is administered 1-2 times per day, with each administration being in a dose of 2.5 μg - 110 μg.

[0150] In some embodiments, the LABA / LAMA is selected from aclidinium / vilanterol inhalation powder, and is administered 1 time per day, with each (e.g., each puff) being in a dose of 62.5 μg / 25 μg.

[0151] In some embodiments, the LABA / LAMA is selected from indacaterol / glycopyrronium bromide inhalation powder, and is administered 1 time per day, with each (e.g., each capsule) being in a dose of 110 μg / 50 μg.

[0152] In some embodiments, the LABA / LAMA is selected from tiotropium / olodaterol inhalation spray, and is administered 1 time per day, with each (e.g., each actuation) being in a dose of 2.5 μg / 2.5 μg.

[0153] In some embodiments, the LABA / LAMA is selected from glycopyrronium bromide / formoterol inhalation aerosol, and is administered 2 times per day, with each (e.g., each actuation) being in a dose of 7.2 μg / 5 μg.

[0154] In some embodiments, the COPD patient is selected from a subject capable of performing an acceptable and repeatable pulmonary function test.

[0155] In some embodiments, the patient has 30% predicted value < FEV1 < 70% predicted value, and FEV1 / FVC < 0.7 after inhalation of a bronchodilator (e.g., albuterol 4 puffs); in some embodiments, the subject has 30% predicted value < FEV1 < 80% predicted value, and FEV1 / FVC < 0.7 after inhalation of a bronchodilator (e.g., albuterol 4 puffs); or, 40% predicted value < FEV1 < 80% predicted value, and FEV1 / FVC < 0.7. There is some reversibility in the airways after inhalation of a bronchodilator (e.g., albuterol 4 puffs): FEV1 is improved by more than 100 mL in absolute value.

[0156] In some embodiments, the COPD is selected from 30% predicted value < FEV1 < 70% predicted value, and FEV1 / FVC ratio < 0.7 after application of a bronchodilator (e.g., albuterol 4 puffs).

[0157] In some embodiments, the COPD patient is selected from subjects who are clinically stable with COPD.

[0158] In some embodiments, the COPD patient is selected from subjects who have a modified British Medical Research Council (mMRC) Dyspnea Scale score of > 2.

[0159] Rescue medication of albuterol aerosol was provided during the study and used as needed for symptom exacerbation.

[0160] In some embodiments, the patient has 40% predicted value < FEV1.

[0161] In some embodiments, the patient has FEV1 < 80% predicted value.

[0162] In some embodiments, the patient has FEV1 / FVC < 0.7.

[0163] In some embodiments, the patient has 30% predicted value < FEV1 < 80% predicted value. In some embodiments, the patient has 30% predicted value < FEV1 < 80% predicted value, and FEV1 / FVC < 0.7. In some embodiments, the patient has 40% predicted value < FEV1 < 80% predicted value, and FEV1 / FVC < 0.7.

[0164] In some embodiments, the compound of Formula I (e.g., Compound A-E) or a pharmaceutically acceptable salt thereof is typically used as maintenance therapy.

[0165] In some embodiments, the compound of Formula I (e.g., Compound A-E) or a pharmaceutically acceptable salt thereof is typically used as maintenance therapy, which is particularly effective for increasing lung function in subjects with COPD. In particular, morning lung function in patients with COPD can be improved, which is particularly beneficial for patients with COPD who are susceptible to sleep disturbance (e.g., due to the presence of a comorbidity that affects sleep).

[0166] In some embodiments, the treatment or prevention of COPD comprises improving morning lung function in patients with COPD. In some embodiments, the treatment or prevention of COPD comprises increasing the trough value of lung function in patients with COPD.

[0167] In some embodiments, the use, method, kit, or compound of Formula I (e.g., Compound A-E) or a pharmaceutically acceptable salt thereof, further comprises the use or method of increasing the trough value of lung function in patients with COPD.

[0168] In some embodiments, the patient with COPD is a subject susceptible to sleep disturbance. The method can comprise increasing the morning trough value of lung function (i.e., the trough value of lung function after sleep). The morning lung function can be measured as part of maintenance therapy by determining the FEV1 of the patient shortly before administration of the compound of Formula I (e.g., Compound A-E) or a pharmaceutically acceptable salt thereof in the morning. For example, the FEV1 can be measured less than one hour before administration of the compound of Formula I (e.g., Compound A-E) or a pharmaceutically acceptable salt thereof in the morning. The morning FEV1 trough value can be the FEV1 measured between 11.5 and 12 hours after the previous night’s dose. The improvement in lung function can improve sleep in patients with COPD. This is particularly important for patients who are susceptible to sleep disturbance. Patients susceptible to sleep disturbance typically have a disease that directly affects the ability to sleep (e.g., insomnia or sleep apnoea) or a disease that indirectly causes difficulty sleeping (e.g., a skin disease such as psoriasis, eczema, or urticaria, which irritates the skin and causes sleep disturbance). The patient has more difficulty falling asleep or remaining asleep.

[0169] A “subject susceptible to sleep disturbance” is typically a subject having one or more diseases or conditions selected from obesity, insomnia, sleep apnoea, narcolepsy, restless leg syndrome, rapid eye movement sleep behaviour disorder, circadian rhythm sleep disorder, parasomnia, depression, anxiety, psoriasis, dermatitis, eczema, or urticaria. For example, the compound of Formula I (e.g., Compound A-E) or a pharmaceutically acceptable salt thereof can be used to treat COPD in a patient having COPD and sleep apnoea. The compound of Formula I (e.g., Compound A-E) or a pharmaceutically acceptable salt thereof can be used to treat COPD in a patient having COPD and a skin disease such as psoriasis, dermatitis, eczema, or urticaria.

[0170] In some embodiments, the patient can be using a beta receptor agonist (e.g., salbutamol) as a rescue (rescue) medication.

[0171] In some embodiments, the use, method, or compound of Formula I (e.g., Compound A-E) or pharmaceutically acceptable salt thereof, further comprises reducing the frequency and / or severity of acute exacerbations of COPD (AECOPD) in a patient with COPD.

[0172] Further comprising increasing the time to first acute exacerbation of COPD in a patient with COPD. Thus, the patient can not have experienced an acute exacerbation of COPD, and the compound of Formula I (e.g., Compound A-E) or pharmaceutically acceptable salt thereof can increase the time until the patient experiences a first acute exacerbation of COPD (i.e., the first acute exacerbation of COPD is delayed). Thus, the compound of Formula I (e.g., Compound A-E) or pharmaceutically acceptable salt thereof can reduce the risk of an acute exacerbation of COPD in a patient with COPD.

[0173] In some embodiments, the patient is susceptible to having an acute exacerbation of COPD.

[0174] In some embodiments, the patient is susceptible to having an acute exacerbation of COPD.

[0175] The subject can suffer from two or fewer (e.g., one or zero) acute exacerbations of COPD per year. The patient can experience one to three fewer acute exacerbations of COPD per year during treatment with the compound of Formula I (e.g., Compound A-E) or pharmaceutically acceptable salt thereof than the patient experienced per year prior to treatment with the compound.

[0176] An acute exacerbation of COPD typically includes one or more of dyspnea (shortness of breath), increased cough, increased sputum volume, purulent sputum, wheezing, sore throat, cold, and fever. Purulent sputum refers to the color of sputum coughed up spontaneously changing from colorless to greenish-yellow. The acute exacerbation of COPD can last for at least one day or at least two days.

[0177] An exacerbation of COPD (acute exacerbation) can include a worsening of two or more of the following major symptoms for at least two consecutive days: dyspnea, sputum volume, and purulent sputum, or any one major symptom in conjunction with a worsening of any one of the following minor symptoms for at least two consecutive days: sore throat, cold (runny nose and / or nasal congestion), fever without other cause (oral temperature > 37.5°C), and increased cough. For example, the acute exacerbation of COPD can include a worsening of two or more major symptoms (dyspnea, sputum volume, and purulent sputum) for at least two consecutive days.

[0178] The acute exacerbation of COPD can be a moderate acute exacerbation of COPD or a severe acute exacerbation of COPD.

[0179] Moderate exacerbations are defined as exacerbations of COPD symptoms (as described above) requiring at least three days of oral / systemic corticosteroids and / or antibiotic treatment. Severe exacerbations are defined as exacerbations of COPD (as described above) requiring hospitalisation. The compound of formula I (e.g. compounds A-E), or a pharmaceutically acceptable salt thereof, can reduce the severity of acute exacerbations of COPD in a patient, and thus the compound of formula I (e.g. compounds A-E), or a pharmaceutically acceptable salt thereof, can be used to prevent severe acute exacerbations of COPD in a patient. For example, a patient can not have a severe acute exacerbation of COPD within one year of first administration of the compound of formula I (e.g. compounds A-E), or a pharmaceutically acceptable salt thereof.

[0180] The compound of formula I (e.g. compounds A-E), or a pharmaceutically acceptable salt thereof, can prolong the time to acute exacerbation of COPD. For example, it can prolong the time to exacerbation by two months or more.

[0181] Patients are generally susceptible to acute exacerbations of COPD. Typically, a “patient susceptible to acute exacerbations of COPD” is a patient with one or more comorbidities (in addition to COPD). The patient typically has one or more diseases or conditions selected from: asthma, pulmonary hypertension, bronchiectasis, allergy, lung cancer, chest infection, cystic fibrosis, pulmonary fibrosis, pneumonia, hay fever, allergic rhinitis, bronchitis, emphysema, adult respiratory distress syndrome (ARDS), interstitial lung disease, or tuberculosis, optionally wherein asthma is allergic asthma, steroid resistant asthma, severe asthma, or childhood asthma. A patient susceptible to acute exacerbations of COPD can have a chronic bronchitis aetiology, can have impaired lung function (e.g. predicted FEV 1 of 30% to 70%), or can have COPD symptoms despite treatment with a long-acting muscarinic receptor antagonist (LAMA) or long-acting medication, beta-adrenergic receptor agonist (LABA).

[0182] Other risk factors for exacerbations of COPD include: high serum immunoglobulin (Ig), previous tuberculosis, severe airflow obstruction, chest infection, and one or more hospitalisations in the previous year for exacerbations of COPD.

[0183] In some cases, the patient has experienced one or more acute exacerbations of COPD within one year prior to the first administration of a compound of Formula I (e.g., Compounds A-E), or a pharmaceutically acceptable salt thereof. For example, the patient can have experienced two or more acute exacerbations of COPD within one year prior to the first administration of a compound of Formula I (e.g., Compounds A-E), or a pharmaceutically acceptable salt thereof. For example, the patient can have had at least one severe acute exacerbation of COPD (i.e., requiring hospitalization) in the previous year. The patient can have suffered one or more acute exacerbations of COPD within six months prior to the first administration of a compound of Formula I (e.g., Compounds A-E), or a pharmaceutically acceptable salt thereof, or one or more acute exacerbations of COPD within one month prior to the first administration of a compound of Formula I (e.g., Compounds A-E), or a pharmaceutically acceptable salt thereof.

[0184] In some embodiments, the methods, uses, kits, or compounds of Formula I (e.g., Compounds A-E), or a pharmaceutically acceptable salt thereof, wherein the FEVi is significantly increased. For example, the FEVi peak change from baseline (increase) is 100-350 mL; 100-300 mL; or 150-280 mL. For example, the FEVi mean change from baseline is 30-200 mL; or 59-150 mL.

[0185] Dosing regimen

[0186] In some embodiments, the daily dose of the compound of Formula I (e.g., Compound A-E), or a pharmaceutically acceptable salt thereof, is selected from the group consisting of 0.05-32 mg; or the daily dose is selected from the group consisting of 0.05-24 mg; or the daily dose is selected from the group consisting of 0.2-24 mg; or the daily dose is selected from the group consisting of 0.1-12 mg; or the daily dose is selected from the group consisting of 0.1 mg, 0.125 mg, 0.25 mg, 0.5 mg, 0.75 mg, 1 mg, 1.25 mg, 1.5 mg, 2 mg, 2.25 mg, 2.5 mg, 3 mg, 4 mg, 4.5 mg, 5 mg, 6 mg, 8 mg, 10 mg, 12 mg, 14 mg, 16 mg, 18 mg, 20 mg, 22 mg, 24 mg, 26 mg, 28 mg, 32 mg, or a range formed by any of the foregoing; or the daily dose is selected from the group consisting of 0.125 mg, 0.25 mg, 0.75 mg, 1.5 mg, 2.25 mg, 3 mg, 4.5 mg, 6 mg, or 12 mg; or the daily dose is selected from the group consisting of 1 mg, 1.5 mg, 2 mg, 3 mg, 6 mg, or 12 mg; or the daily dose is selected from the group consisting of 0.125 mg, 0.25 mg, 0.75 mg, 1.5 mg, 2.25 mg, 3 mg, or 4.5 mg; preferably, the daily dose is selected from the group consisting of 1 mg, 2 mg, 3 mg, 6 mg, or 12 mg, or a range formed by any of the foregoing; or the daily dose is selected from the group consisting of 6 mg or 12 mg; or, the daily dose is selected from the group consisting of 1 mg, 2 mg, or 3 mg.

[0187] In some embodiments, each dose of the compound of Formula I (e.g., Compound A-E), or a pharmaceutically acceptable salt thereof, is selected from the group consisting of 0.05-32 mg; or each dose is selected from the group consisting of 0.05-24 mg; or each dose is selected from the group consisting of 0.1-12 mg; or each dose is selected from the group consisting of 0.75-6 mg; or each dose is selected from the group consisting of 0.1 mg, 0.125 mg, 0.25 mg, 0.5 mg, 0.75 mg, 1 mg, 1.25 mg, 1.5 mg, 2 mg, 2.25 mg, 2.5 mg, 3 mg, 4 mg, 4.5 mg, 5 mg, 6 mg, 8 mg, 10 mg, 12 mg, 14 mg, 16 mg, 18 mg, 20 mg, 22 mg, 24 mg, 26 mg, 28 mg, 32 mg, or a range formed by any of the foregoing; or each dose is selected from the group consisting of 0.125 mg, 0.25 mg, 0.75 mg, 1.5 mg, 2.25 mg, 3 mg, 4.5 mg, 6 mg, or 12 mg; or each dose is selected from the group consisting of 0.5 mg, 0.75 mg, 1 mg, 1.5 mg, 3 mg, 6 mg, or a range formed by any of the foregoing; or each dose is selected from the group consisting of 0.125 mg, 0.25 mg, 0.75 mg, 1.5 mg, 2.25 mg, 3 mg, or 4.5 mg; preferably, each dose is selected from the group consisting of 0.5 mg, 1 mg, 1.5 mg, 3 mg, or 6 mg, or a range formed by any of the foregoing; or each dose is selected from the group consisting of 3 mg or 6 mg; or each dose is selected from the group consisting of 0.5 mg, 1 mg, or 1.5 mg.

[0188] In some embodiments, the compound of Formula I (e.g., Compound A-E), or a pharmaceutically acceptable salt thereof, is administered (or applied) in a single dose or multiple doses selected from the group consisting of 0.05-32 mg; or the single dose or multiple doses are selected from the group consisting of 0.05-24 mg; or the single dose or multiple doses are selected from the group consisting of 0.2-24 mg; or the single dose or multiple doses are selected from the group consisting of 0.1-12 mg; or the single dose or multiple doses are selected from the group consisting of 0.1 mg, 0.125 mg, 0.25 mg, 0.5 mg, 0.75 mg, 1 mg, 1.25 mg, 1.5 mg, 2 mg, 2.25 mg, 2.5 mg, 3 mg, 4 mg, 4.5 mg, 5 mg, 6 mg, 8 mg, 10 mg, 12 mg, 14 mg, 16 mg, 18 mg, 20 mg, 22 mg, 24 mg, 26 mg, 28 mg, 32 mg, or a range formed by any of the foregoing; or the single dose or multiple doses are selected from the group consisting of 0.125 mg, 0.25 mg, 0.75 mg, 1 mg, 1.5 mg, 2.25 mg, 3 mg, 4.5 mg, 6 mg, or 12 mg; or the single dose or multiple doses are selected from the group consisting of 0.125 mg, 0.25 mg, 0.75 mg, 1 mg, 1.5 mg, 2.25 mg, 3 mg, or 4.5 mg; or the single dose or multiple doses are selected from the group consisting of 3 mg, 6 mg, or 12 mg.

[0189] In some embodiments, the compound of Formula I (e.g., Compound A-E), or a pharmaceutically acceptable salt thereof, is administered to the subject one or more times (e.g., 2 times, 3 times, 4 times) per day.

[0190] In some embodiments, the compound of Formula I (e.g., Compound A-E), or a pharmaceutically acceptable salt thereof, is administered to the patient one or two times per day. In some embodiments, the compound of Formula I (e.g., Compound A-E), or a pharmaceutically acceptable salt thereof, is administered to the subject two times per day. In some embodiments, the compound of Formula I (e.g., Compound A-E), or a pharmaceutically acceptable salt thereof, is administered to the subject two times per day, each administration being 0.75 mg, 1 mg, or 1.5 mg; or each administration being 3 mg, 6 mg, or 12 mg. In some embodiments, the compound of Formula I (e.g., Compound A-E), or a pharmaceutically acceptable salt thereof, is administered to the patient one time in the morning and one time in the evening. The method can comprise administering a first dose of the compound of Formula I (e.g., Compound A-E), or a pharmaceutically acceptable salt thereof, in the morning (e.g., within 3 hours of waking) and a second dose of the compound of Formula I (e.g., Compound A-E), or a pharmaceutically acceptable salt thereof, in the evening (e.g., within 3 hours of bedtime). The morning and evening doses are administered 10 to 14 hours apart, e.g., about 12 hours apart.

[0191] The compound of Formula I (e.g., Compounds A-E) or a pharmaceutically acceptable salt thereof is typically used as maintenance therapy.

[0192] In some embodiments, the compound of Formula I (e.g., Compounds A-E) or a pharmaceutically acceptable salt thereof is administered to the subject daily for 1 week to 52 weeks or more; or for 4 weeks, 16 weeks, 24 weeks, 48 weeks, 52 weeks, or more, or any range formed by any of the above.

[0193] In some embodiments, the compound of Formula I (e.g., Compounds A-E) or a pharmaceutically acceptable salt thereof is administered daily for about 1 day to 7 days, about 1 week to 3 weeks, about 3 weeks to 6 weeks, about 6 weeks to 9 weeks, about 12 weeks. Or for about 12 weeks, about 12 weeks to 15 weeks, or about 15 weeks to 18 weeks, or about 15 weeks to 52 weeks, or more.

[0194] In some embodiments, the compound of Formula I (e.g., Compounds A-E) or a pharmaceutically acceptable salt thereof is administered by inhalation at the same time (± 1 hour) each day. In some embodiments, it is administered 2 times daily. In some embodiments, it is administered continuously for 12-52 weeks or more. In some embodiments, it is administered continuously for 12 weeks, 16 weeks, 24 weeks, 52 weeks, or more.

[0195] In some embodiments, the compound of Formula I (e.g., Compounds A-E) or a pharmaceutically acceptable salt thereof is administered to the subject by inhalation (e.g., by nebulization).

[0196] In some embodiments, the method comprises administering the compound of Formula I (e.g., Compounds A-E) or a pharmaceutically acceptable salt thereof to the subject by inhalation from a nebulizer. The nebulizer aerosolizes a liquid pharmaceutical composition into an aerosol that is inhaled into the respiratory tract of the subject. Examples of nebulizers include soft mist nebulizers, vibrating mesh nebulizers, jet nebulizers, and ultrasonic nebulizers. Suitable nebulizer devices include Philips l-neb TM (Philips), Philips SideStream (Philips), (Philips), Philips InnoSpire Go (Philips), Pari LC Sprint (Pari GmbH), AERx TM Pulmonary Delivery system (Aradigm Corp), PARI BOY Classic model (with PARI PARI PRO aerosol delivery system PARI LC Sprint jet nebulizer of a compressor. The compound can be inhaled through the nebulizer for 1 to 15 minutes.

[0197] In some embodiments, the compound of Formula I (e.g., Compound A-E) or a pharmaceutically acceptable salt thereof is administered by inhalation twice a day (once in the morning and once in the evening) at 0.75 to 6 mg (e.g., 3 mg or 6 mg) per administration.

[0198] In some embodiments, the compound of Formula I (e.g., Compound A-E) or a pharmaceutically acceptable salt thereof is administered by inhalation twice a day (once in the morning and once in the evening) at 0.75 to 6 mg (e.g., 3 mg or 6 mg) per administration, the COPD is selected from subjects with moderate to severe COPD.

[0199] In some embodiments, the pharmaceutical dosage form of the compound of Formula I (e.g., Compound A-E) or a pharmaceutically acceptable salt thereof is 6 mg / 2 mL.

[0200] In some specific embodiments, the method, use, compound, composition, kit, the compound E or a pharmaceutically acceptable salt thereof is selected from 1 mg, 1.5 mg, 3 mg or 6 mg per dose, administered twice a day.

[0201] In some specific embodiments, the compound E or a pharmaceutically acceptable salt thereof is administered as a suspension or as a solid formulation (e.g., dry powder formulation) at a dose selected from 1 mg, 1.5 mg, 3 mg or 6 mg per dose, administered twice a day. Optionally, by inhalation.

[0202] In some specific embodiments, the compound E or a pharmaceutically acceptable salt thereof is administered as a suspension at a dose selected from 3 mg or 6 mg per dose, administered twice a day. Optionally, by inhalation.

[0203] In some specific embodiments, the compound E or a pharmaceutically acceptable salt thereof is administered as a solid formulation (e.g., dry powder formulation) at a dose selected from 1 mg or 1.5 mg per dose, administered twice a day. Optionally, by inhalation.

[0204] In some embodiments, the compound or pharmaceutically acceptable salt thereof is Compound E or a pharmaceutically acceptable salt thereof, the compound or pharmaceutically acceptable salt thereof is administered in a suspension formulation, the COPD is selected from moderate or severe COPD, the treatment or prevention of COPD is selected from COPD maintenance therapy, and the daily dose of the compound or pharmaceutically acceptable salt thereof is selected from 6 mg or 12 mg. Optionally, the administration is twice daily. Optionally, the administration is by inhalation.

[0205] a compound of Formula I-1 or a pharmaceutically acceptable salt thereof

[0206] The compounds of the present disclosure (e.g., Compounds A-E) of Formula I can be administered in the form of their free bases, or in the form of a pharmaceutically acceptable salt, hydrate, and prodrug thereof, which can be converted to the free base form of the compounds of Formula I (e.g., Compounds A-E) in vivo.

[0207] The compounds of the present disclosure (e.g., Compounds A-E) of Formula I or a pharmaceutically acceptable salt thereof can also be administered in the form of a pharmaceutical composition. The pharmaceutical composition further comprises a pharmaceutically acceptable excipient. The compounds of the present disclosure (e.g., Compounds A-E) of Formula I or a pharmaceutically acceptable salt thereof are administered in a suspension formulation (i.e., a suspension) or a solid formulation (e.g., a dry powder formulation); optionally, the solid formulation is a dry powder formulation. Optionally, the compound or pharmaceutically acceptable salt thereof is administered by inhalation, optionally, the inhalation is by nebulization. The compounds of the present disclosure (e.g., Compounds A-E) of Formula I or a pharmaceutically acceptable salt thereof are administered in a suspension formulation or a solid formulation (e.g., a dry powder formulation), wherein the suspension comprises a particulate suspension of the compound in a diluent.

[0208] The pharmaceutical composition described above, comprising a compound of Formula I (e.g., Compounds A-E) or a pharmaceutically acceptable salt thereof, and a surfactant, a buffer, an osmotic pressure adjusting agent, a metal chelating agent, and a diluent.

[0209] In some embodiments, the pharmaceutical composition described above, wherein the concentration of the compound of Formula I (e.g., Compounds A-E) or a pharmaceutically acceptable salt thereof is about 0.001 to about 80 mg / mL, preferably 0.002 to 50 mg / mL, further preferably from 0.1 to 20 mg / mL; still further preferably 6 mg / 2 mL (i.e., 3 mg / mL) of the compound of Formula I (e.g., Compounds A-E).

[0210] The surfactant of the present application is a pharmaceutically acceptable surfactant, e.g., a wetting agent. The surfactant described above can be a non-ionic surfactant, an anionic surfactant, a cationic surfactant, or a zwitterionic surfactant. Preferably, the surfactant described above is a non-ionic surfactant.

[0211] In some embodiments, the above-mentioned surfactant is one or more selected from ethylene glycol polyoxyethylene, polypropylene glycol alkyl ether, alkyl polyglucoside, octylphenol polyoxyethylene, alkylphenol polyoxyethylene, glycerol alkyl ester, polyoxyethylene sorbitan fatty acid ester (polysorbate), sorbitan alkyl ester, sorbitan fatty acid ester, cocamide MEA, cocamide DEA, dodecyl dimethyl amine oxide, block copolymer of polyethylene glycol and polypropylene glycol (poloxamer), and polyethoxylated tallow amine (POEA).

[0212] Preferably, the above-mentioned surfactant is one or more selected from polyoxyethylene sorbitan fatty acid ester (e.g., Tween) and sorbitan fatty acid ester (e.g., Span).

[0213] In some embodiments, the above-mentioned polyoxyethylene sorbitan fatty acid ester is one or more selected from polysorbate 20 (polyoxyethylene sorbitan laurate; Tween 20), polysorbate 40 (polyoxyethylene sorbitan monopalmitate), polysorbate 60 (polyoxyethylene sorbitan monostearate), and polysorbate 80 (polyoxyethylene sorbitan monooleate; Tween 80).

[0214] In some embodiments, the above-mentioned sorbitan fatty acid ester is one or more selected from sorbitan monolaurate (Span 20), sorbitan monopalmitate, sorbitan monostearate, sorbitan tristearate, and sorbitan monooleate.

[0215] More preferably, the above-mentioned surfactant is one or more selected from Tween and Span.

[0216] In some specific embodiments, the above-mentioned surfactant is one or more selected from Tween 20, Tween 80, and Span 20.

[0217] In some embodiments, the concentration of the above-mentioned surfactant is about 0.01 to about 8 mg / mL. More typically, the concentration of the surfactant in the pharmaceutical composition is about 0.01 to 5 mg / mL, preferably about 0.02 to 3 mg / mL, further preferably about 0.05 to 2 mg / mL, and more further preferably about 0.1 to 1 mg / mL.

[0218] In some embodiments, in the above-mentioned pharmaceutical composition, the mass ratio between the compound of formula I (e.g., Compounds A-E) or a pharmaceutically acceptable salt thereof (based on the compound of formula I (e.g., Compounds A-E)) and the surfactant is about 1:200 to 100:1, preferably about 1:150 to 50:1, more preferably about 1:50 to 25:1, further more preferably about 1:1 to 15:1, for example, can be about 10:1.

[0219] In some embodiments, the above-mentioned buffering agent is a pharmaceutically acceptable buffering agent. The buffering agent can be any buffer suitable for use in a liquid pharmaceutical composition suitable for inhalation. The buffering agent is typically selected from one or more of sulfuric acid, hydrochloric acid, sodium hydroxide, citric acid, sodium citrate, lactic acid, sodium lactate, acetic acid, sodium acetate, trisodium phosphate, sodium dihydrogen phosphate, disodium hydrogen phosphate, potassium dihydrogen phosphate, tartaric acid, sodium tartrate, glycine, boric acid, and phthalic acid. Preferably, the buffering agent is selected from two or more of the group, and is more preferably selected from two or more of the group of citrate buffers or phosphate buffers, and even more preferably is selected from two or more of the group of sodium salts of citrate buffers or phosphate buffers. Citrate buffers include citric acid, sodium citrate, and mixtures thereof. Phosphate buffers include phosphoric acid, monosodium phosphate (i.e., sodium dihydrogen phosphate), disodium hydrogen phosphate, and mixtures thereof.

[0220] In some embodiments, the above-mentioned buffering agent is selected from citric acid, a citrate salt (e.g., sodium citrate), tartaric acid, a tartrate salt (e.g., sodium tartrate), phosphoric acid, or a phosphate salt (e.g., sodium dihydrogen phosphate and disodium hydrogen phosphate).

[0221] In some embodiments, the above-mentioned buffering agent is selected from a citrate salt (e.g., sodium citrate), a tartrate salt (e.g., sodium tartrate), or a phosphate salt (e.g., sodium dihydrogen phosphate and disodium hydrogen phosphate).

[0222] In some embodiments, the above-mentioned buffering agent is present in a concentration of about 0.01 to about 50 mg / mL, preferably about 0.05 to about 40 mg / mL, more preferably 0.1 to about 25 mg / mL; even more preferably 0.5 to about 6 mg / mL.

[0223] In some embodiments, the above-mentioned buffering agent is used to control the pH of the above-mentioned pharmaceutical composition to a pH of about 3.0 to about 8.5, preferably about 5 to about 7.

[0224] In some embodiments, the above-mentioned tonicity adjusting agent is typically selected from one or more of simple, non-toxic salts, such as sodium chloride, potassium chloride, and the like, or sugars, such as dextrose, mannitol, xylitol, and the like. In some embodiments, the above-mentioned tonicity adjusting agent is sodium chloride.

[0225] The concentration of the above-mentioned tonicity adjusting agent will depend on the amount needed to achieve isotonicity, e.g., isotonicity with blood plasma or lung fluid. The concentration of the tonicity adjusting agent is typically about 0.01 mg / mL to about 10 mg / mL, and more typically about 5 mg / mL to 9 mg / mL.

[0226] In some embodiments, the above-mentioned metal chelator is selected from one or more of the group of edetic acid, disodium edetate, calcium disodium edetate, and the like. Preferably, the metal chelator is an edetic acid salt (e.g., calcium salt, sodium salt), and even more preferably is disodium edetate (EDTA-2Na).

[0227] The concentration of the metal chelator depends on the amount of metal ion that can be introduced during the preparation of the pharmaceutical composition described above and is generally from about 0.01 to about 40 mg / mL, preferably from about 0.01 to about 20 mg / mL, more preferably from about 0.01 to about 5 mg / mL; and even more preferably from about 0.01 to about 2 mg / mL.

[0228] In some embodiments, the diluent in the pharmaceutical composition described above can be any pharmaceutically acceptable diluent. The diluent is suitable for inhalation administration. Typically, the diluent is selected from one or more of water, ethanol, and glycerol. The preferred diluent is water, and the more preferred diluent is sterile water.

[0229] In some embodiments, the diluent in the pharmaceutical composition described above can be used in an amount suitable to maintain the concentration of the compound of Formula I (e.g., Compounds A-E) or a pharmaceutically acceptable salt thereof or an excipient in the pharmaceutical composition described above within a certain range.

[0230] In some embodiments, the pharmaceutical composition described above comprises a compound of Formula I (e.g., Compounds A-E) and a Tween or a Span; and further the Tween or the Span is selected from one or more of Tween 20, Tween 80, and Span 20.

[0231] In some embodiments, the pharmaceutical composition described above further comprises a phosphate; and further the phosphate can be selected from sodium phosphate monobasic or monohydrate and sodium phosphate dibasic; and in some embodiments, the pharmaceutical composition described above further comprises sodium citrate or sodium tartrate.

[0232] In some embodiments, the pharmaceutical composition described above comprises a compound of Formula I (e.g., Compounds A-E), a Span mixed with a Tween (e.g., Tween 80, Tween 20, or Span 20), and water.

[0233] In some embodiments, the pharmaceutical composition described above comprises a compound of Formula I (e.g., Compounds A-E), a Span mixed with a Tween (e.g., Tween 80, Tween 20, or Span 20), sodium citrate or sodium tartrate, and water.

[0234] In some embodiments, the pharmaceutical composition described above comprises a compound of Formula I (e.g., Compounds A-E), a Tween (e.g., Tween 80 or Tween 20), sodium phosphate monobasic or monohydrate, sodium phosphate dibasic, disodium edetate, and water.

[0235] In some embodiments, the pharmaceutical composition described above comprises a compound of Formula I (e.g., Compounds A-E), a Tween (e.g., Tween 80 or Tween 20), sodium phosphate monobasic or monohydrate, sodium phosphate dibasic, sodium chloride, disodium edetate, and water.

[0236] In some embodiments, the pharmaceutical composition described above, which comprises a compound of Formula I (e.g., Compounds A-E), a Tween (e.g., Tween 80 or Tween 20), sodium citrate or sodium tartrate, sodium chloride, and water.

[0237] In some embodiments, the pharmaceutical composition described above, which comprises a compound of Formula I (e.g., Compounds A-E), a Tween (e.g., Tween 80 or Tween 20), sodium citrate or sodium tartrate, sodium chloride, and water.

[0238] In some embodiments, the pharmaceutical composition described above, which comprises a compound of Formula I (e.g., Compounds A-E), a surfactant, a buffering agent, an osmotic pressure adjusting agent, a metal chelating agent, and a diluent, wherein the concentration of the compound of Formula I (e.g., Compounds A-E) is 0.002 to 50 mg / mL, the concentration of the surfactant is 0.02 to 3 mg / mL, the concentration of the buffering agent is 0.1 to about 25 mg / mL, the concentration of the osmotic pressure adjusting agent is 5 mg / mL to 9 mg / mL, and the concentration of the metal chelating agent is 0.01 to about 5 mg / mL.

[0239] In some embodiments, the pharmaceutical composition described above, wherein the surfactant, the buffering agent, the osmotic pressure adjusting agent, the metal chelating agent, and the diluent are as defined above, respectively.

[0240] In some embodiments, the pharmaceutical composition described above, which comprises a compound of Formula I (e.g., Compounds A-E), a surfactant, a buffering agent, an osmotic pressure adjusting agent, a metal chelating agent, and a diluent, wherein the concentration of the compound of Formula I (e.g., Compounds A-E) is 0.002 to 50 mg / mL, the concentration of the surfactant is 0.02 to 3 mg / mL, the concentration of the buffering agent is 0.1 to about 25 mg / mL, the concentration of the osmotic pressure adjusting agent is 5 mg / mL to 9 mg / mL, and the concentration of the metal chelating agent is 0.01 to about 5 mg / mL; the surfactant is one or more of Tween 20, Tween 80, and Span 20, the buffering agent is one or more of sodium phosphate monobasic or monohydrate, sodium phosphate dibasic, tartaric acid, and citric acid, the osmotic pressure adjusting agent is sodium chloride, the metal chelating agent is one or more of disodium edetate and calcium disodium edetate, and the diluent is water.

[0241] In some embodiments, the pharmaceutical composition described above, comprising a compound of Formula I (e.g., Compounds A-E), Tween 80, sodium phosphate monobasic or monohydrate, sodium phosphate dibasic, sodium chloride, disodium edetate, and water; wherein the concentration of the compound of Formula I (e.g., Compounds A-E) is 0.002-50 mg / mL, the concentration of Tween 80 is 0.02 to 3 mg / mL, the concentration of sodium phosphate monobasic and sodium phosphate dibasic is 0.1 to 25 mg / mL, the concentration of sodium chloride is 5 mg / mL to 9 mg / mL, and the concentration of disodium edetate is 0.01 to about 5 mg / mL.

[0242] In some embodiments, the compound of Formula I (e.g., Compounds A-E) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof of the present disclosure is selected from 0.05-32 mg or 0.05-24 mg; or is selected from 0.1 mg, 0.125 mg, 0.25 mg, 0.5 mg, 0.75 mg, 1 mg, 1.25 mg, 1.5 mg, 2 mg, 2.25 mg, 2.5 mg, 3 mg, 4 mg, 4.5 mg, 5 mg, 6 mg, 8 mg, 10 mg, 12 mg, 14 mg, 16 mg, 18 mg, 20 mg, 22 mg, 24 mg, 26 mg, 28 mg, 32 mg, or a range formed by any of the above values. Or is selected from 0.125 mg, 0.25 mg, 0.75 mg, 1 mg, 1.5 mg, 2.25 mg, 3 mg, 4.5 mg, 6 mg, or 12 mg; or is selected from 0.125 mg, 0.25 mg, 0.75 mg, 1 mg, 1.5 mg, 2.25 mg, 3 mg, or 4.5 mg; or is selected from 6 mg or 12 mg.

[0243] In some embodiments, the pharmaceutical composition of the compound of Formula I (e.g., Compounds A-E) or a pharmaceutically acceptable salt thereof is selected from a solid or a liquid pharmaceutical composition.

[0244] In some embodiments, the pharmaceutical composition comprising a compound of Formula I (e.g., Compounds A-E) or a pharmaceutically acceptable salt thereof is a pharmaceutical composition having a single dose or multiple doses of 0.05-32 mg or 0.05-24 mg. In particular, the pharmaceutical composition has a single dose or multiple doses selected from any value in a range formed by 0.1 mg, 0.125 mg, 0.25 mg, 0.5 mg, 0.75 mg, 1 mg, 1.25 mg, 1.5 mg, 2 mg, 2.25 mg, 2.5 mg, 3 mg, 4 mg, 4.5 mg, 5 mg, 6 mg, 8 mg, 10 mg, 12 mg, 14 mg, 16 mg, 18 mg, 20 mg, 22 mg, 24 mg, 26 mg, 28 mg, 32 mg, or any value in a range formed by any of the foregoing; or the single dose or multiple doses are selected from 0.125 mg, 0.25 mg, 0.75 mg, 1 mg, 1.5 mg, 2.25 mg, 3 mg, 4.5 mg, 6 mg, or 12 mg; or the single dose or multiple doses are selected from 0.125 mg, 0.25 mg, 0.75 mg, 1 mg, 1.5 mg, 2.25 mg, 3 mg, or 4.5 mg; or the single dose or multiple doses are selected from 0.75 mg, 1 mg, or 1.5 mg; or the single dose or multiple doses are selected from 3 mg, 6 mg, or 12 mg; or the single dose or multiple doses are selected from 3 mg or 6 mg.

[0245] In some embodiments, the pharmaceutical composition comprising a compound of Formula I (e.g., Compounds A-E) or a pharmaceutically acceptable salt thereof is a single dose pharmaceutical composition. In some embodiments, the pharmaceutical composition comprising a compound of Formula I (e.g., Compounds A-E) or a pharmaceutically acceptable salt thereof is a multiple dose pharmaceutical composition, which can be comprised of multiple single dose pharmaceutical compositions comprising a compound of Formula I (e.g., Compounds A-E) or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition comprising a compound of Formula I (e.g., Compounds A-E) or a pharmaceutically acceptable salt thereof is a multiple dose pharmaceutical composition, which can be comprised of single dose pharmaceutical compositions comprising a compound of Formula I (e.g., Compounds A-E) or a pharmaceutically acceptable salt thereof having a single dose of 0.1 mg, 0.125 mg, 0.25 mg, 0.5 mg, 0.75 mg, 1 mg, 1.25 mg, 1.5 mg, 2 mg, 2.25 mg, 2.5 mg, 3 mg, 4 mg, 4.5 mg, 5 mg, or 6 mg.

[0246] In some embodiments, the compound of Formula I, or a pharmaceutically acceptable salt thereof, is selected from Compound A, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula I, or a pharmaceutically acceptable salt thereof, is selected from Compound B, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula I, or a pharmaceutically acceptable salt thereof, is selected from Compound C, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula I, or a pharmaceutically acceptable salt thereof, is selected from Compound D, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula I, or a pharmaceutically acceptable salt thereof, is selected from Compound E, or a pharmaceutically acceptable salt thereof.

[0247] In one embodiment, the pharmaceutical combination of the present disclosure can be formulated into a pharmaceutical composition suitable for single or multiple administration. In one embodiment, the pharmaceutical combination of the present disclosure can be a single dose or multiple doses of pharmaceutical composition.

[0248] Technical effects

[0249] The compounds of the present disclosure have good efficacy against COPD, better relieving the symptoms associated with COPD, including but not limited to the following: increased shortness of breath, accompanied by wheezing, chest tightness, increased cough, increased sputum, changes in sputum color and / or viscosity, and fever, etc. and other possible symptoms: tachycardia, general malaise, insomnia, drowsiness, fatigue, depression, and mental disorders, etc. The compounds of the present disclosure can improve the symptoms of COPD patients with reduced sleep quality due to COPD.

[0250] The treatment regimen of the compounds of the present disclosure can reduce the hydrolysis of intracellular secondary signaling molecules cAMP and cGMP by inhibiting PDE3 and PDE4 activity, increase cAMP levels, promote airway smooth muscle relaxation, and inhibit the inflammatory response of various inflammatory cells, thereby achieving the effect of relieving inflammation and airway resistance. It can be used for the treatment of obstructive lung diseases characterized by airway resistance caused by inflammation, and thus the compounds of the present disclosure can reduce the frequency and / or severity of acute exacerbations of COPD in subjects with COPD; delay the time of first moderate / severe COPD acute exacerbation.

[0251] The FEV1 peak after treatment for 0-12 hours, 2 weeks, 3 weeks, 4 weeks, 6 weeks, 12 weeks or more (e.g. 24 weeks, etc.) is improved significantly from baseline. Patients with moderate to severe COPD have an FEV1 of 40-80% of predicted value and an FEV1 / FVC <0.7 after inhalation of a bronchodilator. The bronchodilator effect reaches a peak FEV1 at about 2 hours. In terms of duration of effect, the 6 mg-Bid patients have a superior effect at 6 hours after dosing, with a bronchodilator effect of more than 100 mL remaining. In terms of symptom improvement, the change from baseline in CAT score is numerically improved in the 1.5 mg-QD, 3 mg-QD-BID, 3 mg-QD and 6 mg-QD groups. The compounds of the present application can improve sleep in patients with COPD, or increase the morning trough in lung function (i.e. the trough in lung function after sleep).

[0252] The mean Cmax and AUC(0-t) increase with dose, with the AUC(0-t) increasing proportionally close to the dose. Pulmonary deposition studies show that the product is mainly absorbed from the lungs into the systemic circulation. The compounds of the present disclosure are absorbed quickly, eliminated quickly, and do not accumulate significantly.

[0253] The compounds of the present disclosure are safe and well-tolerated, with a low incidence of adverse reactions, and no serious adverse events.

[0254] The compounds of the present disclosure are well-tolerated in treatment, have a quick onset of action, and a long duration of action (e.g. a rapid onset of action within 3 hours, and a duration of action of 12 hours).

[0255] The compounds of the present disclosure are observed to significantly increase FEV1 in patients with moderate and severe COPD, with particularly significant increases observed in the treatment of patients with moderate COPD.

[0256] The compounds of the present disclosure are effective in prolonging the time to first exacerbation (i.e. reducing the risk of exacerbation) and reducing the frequency of exacerbations in COPD.

[0257] Compared to Ensifentrine, a clinical-stage drug targeting the same target, the compounds of the present application have higher target binding capacity, stronger downstream airway dilation and anti-inflammatory effects, and better efficacy in animal disease models.

[0258] Definitions and Descriptions

[0259] The following terms are used in the present disclosure and have the following meanings, unless otherwise indicated. A particular term should not be construed as indefinite or unclear if not specifically defined, but should be understood according to the ordinary meaning in the art.

[0260] The word "comprise" or "comprising" and variations such as "comprises" or "comprising", and "including" and variations such as "includes" or "including", and "contain" and variations such as "contains" or "containing", and "hold" and variations such as "holds" or "holding", and the like, are to be construed in an open, non-exhaustive, and non-limiting sense as "including but not limited to".

[0261] The term "substituted" means that any one or more hydrogen atoms on the designated atom is replaced with a substituent, provided that the valence of the designated atom is not normally exceeded, and that the substituted compound is stable. When the substituent is oxo (i.e., =0), it is meant that two hydrogen atoms are replaced by the oxo group. Oxos are not present on aromatic groups.

[0262] The term "optionally" or "optional" means that the subsequently described event or circumstance can or can not occur, and this description includes instances where the event or circumstance occurs and instances where it does not. For example, an ethyl group "optionally" substituted with a halogen means that the ethyl group can be unsubstituted (-CH2CH3), mono-substituted (e.g., -CH2CH2F), poly-substituted (e.g., -CHFCH2F, -CH2CHF2, etc.), or fully substituted (-CF2CF3). It will be understood by those skilled in the art that, for any group containing one or more substituents, no substitution or substitution pattern is introduced that is not

[0263] C m-n herein means that the moiety has an integer number of carbon atoms in the given range. For example, "C 1-6 " means that the group can have 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, or 6 carbon atoms.

[0264] The term "halogen" means fluorine, chlorine, bromine, and iodine.

[0265] The term "alkyl" means a hydrocarbon group of formula C n H 2n+1 . The alkyl group can be straight or branched. For example, the term "C 1-6 alkyl" means an alkyl group containing 1 to 6 carbon atoms (e.g., methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, n-pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, neopentyl, hexyl, 2-methylpentyl, etc.). For example, the term "C 1-4 alkyl" means an alkyl group containing 1 to 4 carbon atoms (e.g., methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, etc.).

[0266] Unless otherwise indicated, the dosages provided herein for the compounds of Formula I, e.g., Compounds A-E, or pharmaceutically acceptable salts thereof, are based on the molecular weight of the free base of the compound of Formula I, e.g., Compounds A-E.

[0267] In the present disclosure, the phrase "the compound of Formula I, or a pharmaceutically acceptable salt thereof" is selected from the group consisting of "Compound A, Compound B, Compound C, Compound D, Compound E, or a pharmaceutically acceptable salt thereof" means that in the scheme, the compound of Formula I, or a pharmaceutically acceptable salt thereof, is replaced with Compound A, Compound B, Compound C, Compound D, Compound E, or a pharmaceutically acceptable salt thereof; preferably, Compound E, or a pharmaceutically acceptable salt thereof.

[0268] The terms "administer," "administering," "administration," or "give," or "giving," or "give," mean the physical introduction of a therapeutic agent or a composition comprising a therapeutic agent into a subject using any of a variety of methods and delivery systems known to those skilled in the art. The terms "administer," "administering," "administration," or "give," or "giving," or "give," are used interchangeably herein.

[0269] The term "treatment" generally refers to obtaining a desired pharmacologic and / or physiologic effect. The effect can be therapeutic in terms of partially or completely arresting or curing a disease and / or adverse effect attributed to the disease. As used herein, "treatment" covers any treatment of a patient, including: (a) inhibiting the disease state, i.e., arresting its development; or (b) relieving the disease state, i.e., causing regression of the disease or symptoms.

[0270] The term "treatment" means the administration of a compound or formulation described herein to improve or eliminate a disease or one or more symptoms associated with the disease, and includes:

[0271] (i) inhibiting the disease or condition, i.e., arresting its development;

[0272] (ii) relieving the disease or condition, i.e., causing regression of the disease or condition.

[0273] The term "prevent" means administering a compound or formulation described herein to prevent a disease or one or more symptoms associated with the disease, and includes: preventing the onset of a disease or disease state in a mammal, particularly when such mammal is predisposed to the disease state but has not yet been diagnosed as having it. The term "effective amount" or "therapeutically effective amount" means the amount of a compound of the disclosure that (i) treats or prevents the particular disease, condition, or disorder, (ii) attenuates, ameliorates, or eliminates one or more symptoms of the particular disease, condition, or disorder, or (iii) prevents or delays the onset of one or more symptoms of the particular disease, condition, or disorder described herein. The amount of a compound of the disclosure that will constitute a "therapeutically effective amount" will depend on the compound, the disease state and its severity, the manner of administration, and the age of the mammal to be treated, but can be determined routinely by the artisan without undue experimentation.

[0274] The terms "subject," "patient," or "host" are used interchangeably herein and refer to an animal, preferably a mammal, more preferably a primate, including humans and non-human primates (e.g., apes, monkeys, chimpanzees, and gorillas, such as cynomolgus monkeys, spider monkeys, and macaques, such as rhesus monkeys), and most preferably a human, who has been the object of treatment, observation or experiment. In some embodiments, the subject has experienced and / or exhibits at least one symptom of a disease or disorder to be treated and / or prevented.

[0275] As used in the present disclosure, the compound of Formula I (e.g., Compounds A-E) or a pharmaceutically acceptable salt thereof can be administered by any suitable route and method, for example, by inhalation.

[0276] The term "pharmaceutical composition" refers to a mixture of one or more compounds of the disclosure or a pharmaceutical combination thereof or a salt thereof with a pharmaceutically acceptable excipient. The objective of a pharmaceutical composition is to facilitate the administration of a compound of the disclosure or a pharmaceutical combination thereof to a subject.

[0277] The term "pharmaceutically acceptable excipient" refers to those excipients that are not biologically or otherwise undesirable, and that do not abrogate the biological activity and properties of the active compound. Suitable excipients are well known to those skilled in the art, e.g., carbohydrates, waxes, water soluble and / or swellable polymers, hydrophilic or hydrophobic materials, gelatin, oils, solvents, water, and the like.

[0278] The pharmaceutical compositions of the disclosure can be prepared by combining a compound of the disclosure with a suitable pharmaceutically acceptable excipient, e.g., can be formulated into solid or liquid preparations, such as tablets, pills, capsules, dry powder formulations, suspensions, and the like.

[0279] The pharmaceutical compositions of the present disclosure can be manufactured in a manner that is itself known, e.g., by means of conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, lyophilizing processes, and the like.

[0280] The term "pharmaceutically acceptable" pertains to those compounds, materials, compositions, and / or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio.

[0281] Solid pharmaceutical compositions or solid oral pharmaceutical compositions can be prepared by conventional mixing, compounding or tabletting processes. For example, the active compound can be mixed with a solid diluent and optionally ground, incorporating, if desired, other suitable accessory ingredients, and then processing the mixture into granules, which are subsequently compressed into tablets or filled into capsules or dragees. Suitable diluents include, but are not limited to, binders, diluents, disintegrants, lubricants, glidants, sweeteners, or flavoring agents.

[0282] The term "pharmaceutically acceptable salt" or "pharmaceutically acceptable salts" refers to those salts of the compounds of the present disclosure which are within the scope of the definition of "pharmaceutically acceptable."

[0283] The singular terms "a," "an," and "the" include plural referents unless context clearly indicates otherwise. The use of "or" means "and / or" unless context clearly indicates otherwise.

[0284] In this document, the terms "comprising," "including," and "containing" or any variation thereof, are intended to indicate that the products include the specified elements, but not excluding others. Thus, these terms specify the presence of the stated elements, but do not preclude the presence of additional elements.

[0285] The term "unit dose" refers to physically discrete unit of pharmaceutical agent appropriate for the patient to be treated. For example, a capsule can be a unit dose, or a bottle of a liquid medication can be a unit dose. The term "multiple unit dose" refers to a plurality of unit doses.

[0286] The terms "day," "daily," and the like, in connection with the dosage regimen, refer to the time of day of the calendar day that the administration begins and ends at midnight to midnight.

[0287] In this document, the singular terms "a," "an," and "the" include plural referents unless context clearly indicates otherwise. Similarly, the word "or" is intended to include "and" unless the context clearly indicates otherwise.

[0288] Unless otherwise indicated, herein, a parameter value representing the amount or a physico-chemical property of an ingredient or a reaction condition etc. should be understood as being modified in all instances by the term "about". When the term "about" is used in connection with a quantity, the term "about" means that the value exists within a range of values that are plus or minus 5%, e.g. plus or minus 1% or plus or minus 0.1% of a certain value.

[0289] For the purposes of description and disclosure, all patents, patent applications, and other publications referenced herein are expressly incorporated herein by reference. These publications are provided solely for their disclosure prior to the filing date of the present disclosure. All statements regarding the date(s) or contents of these publications are based on the information available to me and do not constitute any admission as to the correctness of the dates or contents of these publications. Further, nothing herein is to be construed as an admission that the publications cited herein are necessarily prior art in any country in which this application is filed.

[0290] Unless otherwise indicated, herein, a single bronchodilator drug refers to a medicament containing one bronchodilator drug ingredient, e.g. a LABA or a LAMA; a dual bronchodilator drug refers to a medicament containing two bronchodilator drug ingredients, e.g. can be a combination of a LABA and a LAMA or a combination formulation.

[0291] The Global Initiative for Chronic Obstructive Lung Disease (GOLD) classifies COPD into four different stages. These include mild COPD, moderate COPD, severe COPD or very severe COPD. The 2022 GOLD Report was published by the Global Initiative for Chronic Obstructive Lung Disease and the entire contents of this document are incorporated by reference.

[0292] The above stages of COPD can be classified as follows, where FEV1 is forced expiratory volume in 1 second and FVC is forced vital capacity.

[0293] • Mild COPD: FEV1 / FVC < 0.7 and FEV1 > 80% predicted;

[0294] • Moderate COPD: FEV1 / FVC < 0.7 and 50% predicted < FEV1 < 80% predicted;

[0295] • Severe COPD: FEV1 / FVC < 0.7 and 30% predicted < FEV1 < 50% predicted;

[0296] • Very severe COPD: FEV1 / FVC < 0.7 and FEV1 < 30% predicted.

[0297] In each case, the patient's actual FEV1 is compared to a predicted FEV1 value based on factors such as the patient's age and size.

[0298] FEV1 and FVC for determining COPD in a patient are measured by spirometry shortly after administration of a sufficient dose of at least one short-acting inhaled bronchodilator. Typically, the measurements of FEV1 and FVC for determining the severity of COPD are performed between 15 and 30 minutes after administration of salbutamol.

[0299] Typically, as used herein, FEV1 and FVC are determined as described in the article "Standardization of spirometry", Eur J 2005; 26; 319-338.

[0300] Thus, by measuring FEV1 / FVC < 0.7 and 50% predicted value < FEV1 < 80% predicted value, it can be determined that the patient has moderate COPD, wherein FEV1 is forced expiratory volume in one second and FVC is forced vital capacity measured between 15 and 30 minutes after taking a bronchodilator. Optionally, wherein the bronchodilator is salbutamol. The severity of COPD in the patient can be determined at least 1 day before the first administration of a compound of formula I (e.g. compounds A-E) or a pharmaceutically acceptable salt thereof.

[0301] Terminology

[0302] FEV1 / FVC ratio: ratio of forced expiratory volume in one second to forced vital capacity;

[0303] FEV1: forced expiratory volume in one second;

[0304] FEV1 predicted value: normal value of lung function calculated according to the formula of prediction from age, sex, height, weight of healthy subjects.

[0305] FVC: forced vital capacity;

[0306] GOLD: Global Initiative for Chronic Obstructive Lung Disease;

[0307] ICS: inhaled corticosteroid;

[0308] LABA: long-acting beta2-receptor agonist;

[0309] LAMA: long-acting anticholinergic;

[0310] SABA: short-acting beta2-receptor agonist;

[0311] SAMA: short-acting anticholinergic;

[0312] SD: standard deviation; SGRQ: St. George's Respiratory Questionnaire. DETAILED DESCRIPTION

[0313] For clarity, the present disclosure is further explained with examples, but the examples are not limiting the scope of the present disclosure. All reagents used in the present disclosure are commercially available and used without further purification.

[0314] The compound of formula I (e.g. compounds A-E) can be prepared according to the methods disclosed in WO2020011254.

[0315] Test Example 1

[0316] 1.1 Patient criteria:

[0317] Patient inclusion criteria

[0318] 1. Diagnosed as a patient with COPD according to the GOLD criteria (e.g. 2024 version).

[0319] 2. Not using or using COPD background inhaled therapy at least from the run-in period.

[0320] 3. Optionally, at screening visit (V1), a ratio of FEV1 / FVC < 0.7 after application of a bronchodilator (salbutamol 4 puffs), 30% predicted value ≤ FEV1 ≤ 70% predicted value or 40% predicted value ≤ FEV1 ≤ 80% predicted value or 30% predicted value ≤ FEV1 ≤ 80% predicted value.

[0321] 4. Optionally, a score of ≥ 2 on the modified British Medical Research Council (mMRC) scale of breathlessness at screening.

[0322] Patient exclusion criteria:

[0323] 1. History of life-threatening COPD, including hospitalization in an intensive care unit and / or need for intubation.

[0324] 2. Treatment with oral steroids or roflumilast for COPD within 3 months prior to screening visit (V1 visit) and treatment with oral theophylline and / or theophylline derivatives for COPD within 1 month prior to screening visit (V1 visit).

[0325] V1 screening visit (D21-D15), V2 run-in (D14-D2), V3 randomization (D1), V4 first dose (D1), V5-V8 treatment period visits (4-week treatment period with 1 visit per week, wherein V5 and V7 are telephone visits and V6 and V8 are on-site visits) and V9 telephone safety visit.

[0326] 1.2 Drug information:

[0327] Compound E suspension or capsule (dry powder formulation) with inhaler, bid or QD (0.1 mg to 12 mg each time, for example 3 mg / bid or 6 mg / bid, etc., Compound E suspension: 3 mg / bid or 6 mg / bid, etc., Compound E capsule (dry powder formulation) 1 mg / bid, or 1.5 mg / bid, etc., once in the morning and once in the evening), the administration time of the patient will be at approximately the same time (± 1 hour) every day, the administration time of the patient will be at approximately the same time (± 1 hour) every day.

[0328] Single or dual bronchodilator background inhaled medication will be administered at approximately the same time every day, once or twice daily as prescribed. According to the foregoing rules, the pulmonary function test needs to be stopped for 24-48 hours. Including but not limited to: single bronchodilator LAMA; single bronchodilator LABA; dual bronchodilator LABA / LAMA; triple drug LABA / LAMA / ICS. Specifically as described in the present disclosure. Background inhaled medication includes domestic or international guidelines recommended, including single or dual bronchodilator (or further containing ICS component), according to the usage specified in the guidelines, using DPI or MDI and other portable inhalation devices.

[0329] Albuterol aerosol

[0330] Ipratropium bromide aerosol

[0331] LABA / LAMA includes but is not limited to umclidinium / vilanterol, indacaterol / glycopyrronium bromide, tiotropium / olodaterol, glycopyrronium bromide / formoterol, budesonide / formoterol, aclidinium / formoterol, or salmeterol / ticarcillin.

[0332] LABA / LAMA / ICS includes but is not limited to budesonide / formoterol / glycopyrronium bromide, fluticasone / umclidinium / vilanterol, or beclometasone / formoterol fumarate / glycopyrronium bromide.

[0333] 1.3 Effectiveness analysis:

[0334] After treatment (for example 2 weeks-24 weeks or 2 weeks, 4 weeks, 6 weeks, 12 weeks, or 24 weeks, etc.):

[0335] The effectiveness of moderate to severe chronic obstructive pulmonary disease (COPD) patients includes but is not limited to the following indicators:

[0336] FEV1 peak, morning FEV1 trough, evening FEV1 trough, mean FEV1 AUC after administration 0-4h Change from baseline (determined 30 min ± 10 min before the first day of administration).

[0337] FEVi peak (change from baseline) within 4 hours post-dose.

[0338] Mean FEVi AUC 0-12h (change from baseline) post-dose.

[0339] Change in mean FEVi within 3h, within 12h post-morning dose; series of FEVi changes at each time point within 12h post-morning dose after 1 day of treatment (after first dose);

[0340] Change in FEVi peak, trough, mean FEVi AUC 0-4h within 4h post-dose, mean within 3h post-dose compared to baseline; FEVi peak (defined as the maximum value measured at 30min, 1h, 2h, 3h post-dose), mean FEVi within 3h, within 12h after 1 day of treatment (after first dose);

[0341] Change in series of FEVi changes at each time point within 12h post-morning dose after 1 day of treatment (after first dose); change in morning trough FEVi after treatment.

[0342] Change in FEVi peak, mean FEVi within 3h, within 12h after treatment compared to after 1 day of treatment (after first dose);

[0343] Mean FEVi AUC post-dose 6-12h (change from baseline)

[0344] Rescue medication during treatment compared to placebo.

[0345] Change in symptom scores (mMRC score, Chronic Obstructive Pulmonary Disease Assessment Test score (CAT) assessment, St George's Respiratory Questionnaire (SGRQ), Baseline Dyspnea Index (BDI) / Transition Dyspnea Index (TDI); total score of Evaluation of Respiratory Symptoms (E-RS) (change from mean baseline to mean weekly), total score of St George's Respiratory Questionnaire (SGRQ) (change from baseline), proportion of SGRQ responders (change from baseline), Transition Dyspnea Index (TDI) score (change from baseline) after treatment.

[0346] Patient quality of life.

[0347] Effect on inflammatory biomarkers.

[0348] IL-6, IL-8 and C-reactive protein.

[0349] Annualized rate of acute exacerbations of moderate / severe COPD.

[0350] Time to first acute exacerbation of moderate / severe COPD.

[0351] PD markers:

[0352] Change from baseline in FEVi peak (defined as the maximum value measured after dosing) on Day 1 (single dose baseline defined as the value measured within 1 h prior to D1 dosing).

[0353] Change from baseline in FEVi peak (defined as the maximum value measured after dosing) on Day 9 (multiple dose baseline defined as the value measured within 1 h prior to Day 3 dosing).

[0354] Change from baseline in morning trough FEVi (1 h prior to dosing) on Day 9.

[0355] Change from baseline in mean FEVi over 12 h after morning dosing on Day 1 and Day 9.

[0356] Change from baseline in mean FEVi over 3 h after morning dosing on Day 9.

[0357] Change from baseline in FEVi at each time point over 12 h after morning dosing on Day 1 and Day 9.

[0358] Change from baseline in symptom score (CAT assessment) on Day 9.

[0359] Assess change from Day 9 to D3 (first dose of multiple dosing) in FEVi peak (defined as the maximum value measured after dosing), mean FEVi over 3 h.

[0360] Change from baseline in trough FEVi prior to dosing on Day 6.

[0361] Number of salbutamol uses during multiple dosing compared to placebo.

[0362] Adverse events, serious adverse events, number of cases, number of episodes, incidence and severity of adverse events related to the investigational product (including the trial drug, the control drug), and abnormal laboratory test results.

[0363] 1.4 Trial Results

[0364] 1.41 The objective of a Phase Ila clinical trial was to assess the safety and efficacy of Compound E suspension in patients with COPD receiving stable washout period background therapy (i.e. patients were free of background therapy during the course of treatment).

[0365] This study was a randomized, double-blind, placebo-controlled, multiple dose escalation study. Subjects were patients with moderate to severe COPD, defined as FEV1 40-80% of predicted and FEV1 / FVC <0.7 following inhalation of a bronchodilator. Patients were randomized to receive single ascending doses of Compound E (twice daily: 0.75 mg, 1.5 mg, 3 mg; once daily: 1.5 mg, 3 mg, 6 mg) or placebo. The primary endpoint was the change from baseline in peak FEV1 (the maximum within 3 hours post-dose) at Week 4.

[0366] Study Results: A portion of the patients, for example, 75 patients, were randomized and treated. Peak FEV1 in subjects treated with the test drug (Compound E) for 4 weeks showed a significant and somewhat dose-dependent increase compared to baseline, ranging from 152.8 mL (0.75 mg BID, 95% CI: -2.94, 308.6 mL, P=0.543, n*=10) to 246.8 mL (6 mg QD, 95% CI: 91.1, 402.6 mL, P=0.0025, n=10). Mean FEV1 (0-12 h) at Week 4 was significantly increased: 6 mg QD dose (173.1 mL, 95% CI: 19.1, 327.2 mL, P=0.0284, n=10). At Week 4, clinically meaningful and numerical improvements in the COPD Assessment Test (CAT) were observed in the 3 mg QD (n=11) and 6 mg QD (n=10) dose groups. The frequency of adverse events was similar between the treatment and placebo groups.

[0367] The study found that Compound E was well tolerated, fast-acting, and long-lasting, specifically, rapid onset within 3 hours and lasting 12 hours.

[0368] The study found that a significant increase in FEV1 was observed for moderate and severe COPD. However, a particularly significant increase was observed in the treatment of moderate COPD patients. There was a statistically significant improvement in lung function for all COPD patient subgroups.

[0369] The study found that the morning FEV1 trough at Week 12 showed a statistically significant effect, confirming the twice-daily dosing interval. There was a statistically significant improvement in lung function for all COPD patient subgroups. It was particularly effective for improving lung function troughs, particularly by increasing the morning FEV1 trough.

[0370] *: n denotes the number of patients.

[0371] 1.42 A Phase II randomized, double-blind, placebo-controlled trial.

[0372] Patients with symptomatic chronic obstructive pulmonary disease (COPD) (on background therapy during the course of the study) with a FEV1 / FVC ratio < 0.7 after bronchodilator application and with a FEV1 of 30% to 70% predicted were randomized in a 1 : 1 : 1 ratio to receive 3 mg, 6 mg Compound E suspension or placebo nebulized twice daily for 4 weeks. Stratification by background therapy regimen was performed at randomization (ratio of single bronchodilator LAMA to dual bronchodilator LABA / LAMA as background therapy was approximately 3:7). The primary endpoint was the maximum FEV1 value over 4 weeks.

[0373] 240 patients were grouped as follows:

[0374] 81 patients: 3 mg BID Compound E suspension,

[0375] 79 patients: 6 mg BID Compound E suspension,

[0376] 80 patients: placebo.

[0377] Ipatropium bromide / Vilanterol inhalation powder once daily, 62.5 μg / 25 μg (per inhalation);

[0378] Indacaterol / glycopyrronium bromide inhalation powder once daily, 110 μg / 50 μg (per capsule);

[0379] Tiotropium / olodaterol inhalation spray once daily, 2.5 μg / 2.5 μg (per puff);

[0380] Glycopyrronium / formoterol inhalation aerosol twice daily, 7.2 μg / 5 μg (per puff).

[0381] Results for the 238 patients who completed the study were as follows:

[0382] At Week 4, the 3 mg BID Compound E suspension group improved by 194 mL (95% confidence interval 144-244 mL), the 6 mg BID Compound E suspension group improved by 241 mL (196-286 mL) and the placebo group improved by 86 mL (56-116 mL) from baseline in peak FEV1. The least squares mean change in peak FEV1 was superior for the 3 mg BID Compound E suspension group (100 [41-159] mL, P = 0.0011) and the 6 mg BID Compound E suspension group (147 [93-201] mL, P < 0.0001) compared to placebo.

[0383] In addition, the 6 mg BID Compound E suspension group was significantly superior to the placebo group in terms of mean area under the curve of FEV1 from 0 to 12 hours (87 [43, 131] mL, P < 0.0001) and symptom scores (St. George's Respiratory Questionnaire, -5.09 [-8.44, -1.74], P = 0.0031). The LAMA combination subgroup (239 [130, 348] mL, P < 0.0001) and the LABA / LAMA combination subgroup (also understood as LABA / LAMA as background therapy, 109 [47, 170] mL, P = 0.0006) were both superior to placebo in terms of peak FEV1 improvement at Week 4. The safety profile of Compound E suspension was similar to placebo. Neither dose of Compound E suspension triggered adverse events of special interest, such as weight loss or gastrointestinal disturbances. In COPD patients on concomitant long-acting bronchodilator therapy, either alone or in combination, Compound E suspension significantly improved lung function and symptoms compared to placebo and was well tolerated, supporting further development of Compound E suspension in COPD.

[0384] The study found that there can be a potential to reduce the frequency of COPD exacerbations to a greater extent than other therapies. There was a statistically significant improvement in lung function in all COPD patient subgroups. It was particularly effective in prolonging the time to first exacerbation (i.e., reducing the risk of exacerbation) and reducing the frequency of COPD exacerbations.

[0385] Safety, tolerability, and pharmacokinetics of Compound E inhalation suspension in healthy adult subjects

[0386] A randomized, double-blind, placebo-controlled Phase I study included 6 single ascending dose cohorts (SAD, 0.2 mg, 1 mg, 3 mg, 6 mg, 12 mg, 24 mg), 1 multiple dose cohort (12 mg once daily for 7 days), and 1 lung deposition cohort (2-period crossover design in the 3 mg cohort of the SAD study, with and without activated charcoal blocks). Safety, tolerability, and pharmacokinetic data were collected.

[0387] Sixty-four healthy subjects were enrolled (8 subjects per group received active drug, 2 subjects received placebo, except for the 0.2 mg dose group, which had 4 subjects receiving active drug). No dose-limiting toxicities, serious adverse events (SAEs), or grade 3 adverse events were observed. Only 1 subject experienced a grade 2 adverse event of anemia, and all other adverse events were grade 1. Nausea and vomiting were not observed in any of the dose groups. The incidence and severity of adverse events were not dose-related. No adverse events led to discontinuation of treatment. Following single-dose administration of Compound E suspension, median Cmaxoccurred at 0.25-0.5 hour, and t1 / 2was 32.9-49.4 hours. AUCo-twas approximately dose-proportional. Following 7 days of repeat dosing, AUCo-24hexposure and Cmaxexposure were 2.59-fold and 1.53-fold higher, respectively, than after single-dose administration. AUCo-tand Cmaxwere similar with / without activated charcoal, with ratios of 0.96 and 1.13, respectively.

[0388] Compound E suspension was safe and well tolerated. The plasma pharmacokinetic variables were well defined, and mass balance data indicated that about 4% of the total systemic exposure following inhalation of Compound E suspension was attributable to orally absorbed drug.

Claims

1. A method for treating or preventing COPD, comprising administering to a subject a therapeutically effective amount of compound E, compound D, compound C, compound B, compound A, or a pharmaceutically acceptable salt thereof:

2. A compound E, compound D, compound C, compound B, compound A, or a pharmaceutically acceptable salt thereof as claimed in claim 1 for use in the treatment or prevention of COPD.

3. Use of a compound E, compound D, compound C, compound B, compound A, or a pharmaceutically acceptable salt thereof as claimed in claim 1 in the manufacture of a medicament for the treatment or prevention of COPD.

4. A method of improving or eliminating insomnia, lack of energy, breathlessness, wheezing, chest tightness, fatigue, limited exercise capacity, cough, or sputum production in a COPD patient, comprising administering to the subject a therapeutically effective amount of a compound E, compound D, compound C, compound B, compound A, or a pharmaceutically acceptable salt thereof as claimed in claim 1.

5. A compound E, compound D, compound C, compound B, compound A, or a pharmaceutically acceptable salt thereof as claimed in claim 1 for use in improving or eliminating insomnia, lack of energy, breathlessness, wheezing, chest tightness, fatigue, limited exercise capacity, cough, or sputum production in a COPD patient.

6. Use of a compound E, compound D, compound C, compound B, compound A, or a pharmaceutically acceptable salt thereof as claimed in claim 1 in the manufacture of a medicament for improving or eliminating insomnia, lack of energy, breathlessness, wheezing, chest tightness, fatigue, limited exercise capacity, cough, or sputum production in a COPD patient.

7. The method, use, compound of any one of claims 1-6, wherein the COPD is selected from moderate or severe COPD; or, the treatment or prevention of COPD is selected from COPD maintenance therapy.

8. The method, use, compound of any one of claims 1-7, wherein the COPD patient has or has not been previously treated with a single or dual bronchodilator; the COPD patient has or has not been previously treated with a background medication; optionally, the background medication is selected from a LABA, a LAMA, and / or an ICS; optionally, the background medication is a LAMA, a LABA, a LAMA / LABA, a LAMA / LABA / ICS, or a LABA / ICS; optionally, the LAMA is selected from tiotropium, umeclidinium, aclidinium, glycopyrronium, rufinacudine, darotropium, or glycopyrronium; optionally, the LABA is selected from salmeterol, formoterol, arformoterol, indacaterol, vilanterol, olodaterol, abediterol, or carmoterol; optionally, the ICS is selected from beclometasone, budesonide, fluticasone propionate, ciclesonide, mometasone, or fluticasone furoate.

9. The method, use, compound of any one of claims 1-8, wherein the treatment or prevention further comprises administering to the subject a therapeutically effective amount of one or more additional medicaments selected from a bronchodilator; or, further comprising an anti-inflammatory medicament; or, the additional medicament is selected from one, two, or three of a LABA, a LAMA, or an ICS; or, the additional medicament is selected from a LABA, a LAMA, a LABA / LAMA, or a LABA / LAMA / ICS.

10. The method, use, compound, subject of any one of claims 1-9, wherein after administration of salbutamol 4 puffs, 40% predicted value < FEVi < 80% predicted value or 30% predicted value < FEVi < 70% predicted value, and FEVi / FVC < 0.

7.

11. The method, use, compound, of any one of claims 1-10, wherein the daily dose of Compound E, Compound D, Compound C, Compound B, Compound A, or a pharmaceutically acceptable salt thereof is selected from the group consisting of 0.05-32 mg; or the daily dose is selected from the group consisting of 0.05-24 mg; or the daily dose is selected from the group consisting of 0.2-24 mg; or the daily dose is selected from the group consisting of 0.1-12 mg; or the daily dose is selected from the group consisting of 1 mg, 1.5 mg, 2 mg, 3 mg, 6 mg, or 12 mg, or a range formed by any of the foregoing; or the daily dose is selected from the group consisting of 6 mg or 12 mg; or the daily dose is selected from the group consisting of 1 mg, 2 mg, or 3 mg.

12. The method, use, compound, of any one of claims 1-11, wherein the dose of Compound E, Compound D, Compound C, Compound B, Compound A, or a pharmaceutically acceptable salt thereof is selected from the group consisting of 0.05-32 mg; or the dose is selected from the group consisting of 0.05-24 mg; or the dose is selected from the group consisting of 0.1-12 mg; or the dose is selected from the group consisting of 0.75-6 mg; or the dose is selected from the group consisting of 0.5 mg, 0.75 mg, 1 mg, 1.5 mg, 3 mg, 6 mg, or a range formed by any of the foregoing; or the dose is selected from the group consisting of 3 mg or 6 mg; or the dose is selected from the group consisting of 0.5 mg, 1 mg, or 1.5 mg.

13. The method, use, compound, of any one of claims 1-12, wherein Compound E, Compound D, Compound C, Compound B, Compound A, or a pharmaceutically acceptable salt thereof is administered to the subject once or more times per day. optionally administered to the subject once or twice per day, optionally administered to the subject twice per day, once in the morning and once in the evening.

14. The method, use, compound, of any one of claims 1-13, wherein Compound E, Compound D, Compound C, Compound B, Compound A, or a pharmaceutically acceptable salt thereof is administered in a suspension formulation or a solid formulation, optionally wherein the solid formulation is a dry powder formulation; optionally wherein Compound E, Compound D, Compound C, Compound B, Compound A, or a pharmaceutically acceptable salt thereof is administered by inhalation, optionally wherein the inhalation is by nebulization.

15. The method, use, compound, of any one of claims 1-14, wherein the compound or a pharmaceutically acceptable salt thereof is Compound E or a pharmaceutically acceptable salt thereof, wherein the compound or a pharmaceutically acceptable salt thereof is administered in a suspension formulation, wherein the COPD is selected from the group consisting of moderate or severe COPD, wherein the treatment or prevention of COPD is selected from the group consisting of COPD maintenance therapy, wherein the daily dose of the compound or a pharmaceutically acceptable salt thereof is selected from the group consisting of 6 mg or 12 mg.

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