Use for preparing drug for treating non-obstructive hypertrophic cardiomyopathy

Abstract

Use for preparing a drug for treating non-obstructive hypertrophic cardiomyopathy. Specifically, use of a compound of formula I or a pharmaceutically acceptable salt thereof in the preparation of a drug for preventing and / or treating non-obstructive hypertrophic cardiomyopathy. Compared with Mavacamten and Aficamten, the compound of formula I or the pharmaceutically acceptable salt thereof has a shorter time to steady state, higher safety, and no complex drug combination limitation.

Description

Uses in the preparation of drugs for the treatment of non-obstructive hypertrophic cardiomyopathy

[0001] Cross-references

[0002] This application claims priority to Chinese application No. 202510066345.5 filed on January 16, 2025, Chinese application No. 202511501469.8 filed on October 21, 2025, and Chinese application No. 202511927509.5 filed on December 19, 2025, all of which are incorporated herein by reference in their entirety. Technical Field

[0003] This disclosure pertains to the pharmaceutical field and relates to the use of a preparation of a drug for treating non-obstructive hypertrophic cardiomyopathy. Background Technology

[0004] Hypertrophic cardiomyopathy (HCM) is a primary cardiomyopathy characterized by left ventricular hypertrophy. It is the most common hereditary heart disease and the leading cause of sudden cardiac death in adolescents and athletes. Based on hemodynamic characteristics, HCM is divided into obstructive HCM (oHCM) and non-obstructive HCM (nHCM), with non-obstructive HCM accounting for approximately one-third of all HCM cases. Treatment options for nHCM are limited, primarily involving lifestyle interventions and treatment of complications (such as heart failure and arrhythmias). Heart transplantation may be considered for end-stage patients. Current treatments are not disease-specific, leading to inadequate treatment or poor tolerability. Furthermore, compared to oHCM, nHCM patients lack indications for surgical treatment. Therefore, there is an urgent clinical need for drugs that target the pathological mechanisms of nHCM, have proven efficacy, and demonstrate good safety.

[0005] For the development of drugs targeting nHCM, mavacamten (MYK-461) and aficamten (CK-274) are the most advanced. In a phase II clinical trial, mavacamten demonstrated a significant reduction in NT-proBNP and cardiac troponin levels in nHCM patients, but no significant differences were observed in the exploratory endpoints (peak oxygen uptake [pVO2] and the NYHA composite endpoint). Aficamten also showed a significant reduction in Kansas City Cardiomyopathy Questionnaire-Clinical Summary Score (KCCQ-CSS), NT-proBNP, and cardiac troponin levels, and improved NYHA functional classification, in a phase II clinical trial. Currently, phase III studies of both mavacamten and aficamten are underway.

[0006] Incorporate by reference

[0007] All publications, patents and patent applications mentioned in this specification are incorporated herein by reference, as if each individual publication, patent or patent application were specifically and individually indicated to the extent of its incorporation by reference. Summary of the Invention

[0008] In a first aspect, this disclosure provides the use of a compound of formula I or a pharmaceutically acceptable salt thereof in the preparation of a medicament for the prevention and / or treatment of non-obstructive hypertrophic cardiomyopathy (nHCM).

[0009] In a second aspect, this disclosure provides a method for preventing and / or treating non-obstructive hypertrophic cardiomyopathy (nHCM), comprising administering to a patient a therapeutically effective amount of the compound of formula I above or a pharmaceutically acceptable salt thereof.

[0010] Thirdly, this disclosure provides a method for preventing and / or treating non-obstructive hypertrophic cardiomyopathy (nHCM) using a compound of formula I or a pharmaceutically acceptable salt thereof, the method comprising administering to a patient a therapeutically effective amount of the compound of formula I or a pharmaceutically acceptable salt thereof.

[0011] Fourthly, this disclosure provides a method for reducing cardiac troponin and / or NT-proBNP levels in patients with non-obstructive hypertrophic cardiomyopathy, comprising administering to the patient a therapeutically effective amount of the aforementioned compound of formula I or a pharmaceutically acceptable salt thereof.

[0012] Fifthly, this disclosure provides a method for reducing cardiac troponin and / or NT-proBNP levels using a compound of formula I or a pharmaceutically acceptable salt thereof, the method comprising administering a therapeutically effective amount of the compound of formula I or a pharmaceutically acceptable salt thereof to a patient suffering from non-obstructive hypertrophic cardiomyopathy.

[0013] In some implementations, such as the first, second, third, fourth, or fifth aspects, the patient with the non-obstructive hypertrophic cardiomyopathy has a left ventricular ejection fraction (LVEF) ≥50%.

[0014] In some implementations, such as the first, second, third, fourth, or fifth aspects, the LVEF of the patient with the non-obstructive hypertrophic cardiomyopathy is ≥55%.

[0015] In some implementations, such as the first, second, third, fourth, or fifth aspects, the LVEF of the patient with the non-obstructive hypertrophic cardiomyopathy is ≥60%.

[0016] In some implementations, such as the first, second, third, fourth, or fifth aspect, the resting left ventricular outflow tract pressure gradient (resting LVOT-G) of the patient with the non-obstructive hypertrophic cardiomyopathy is <30 mmHg.

[0017] In some implementations, such as the first, second, third, fourth, or fifth aspect, the left ventricular outflow tract pressure gradient (Valsalva LVOT-G) after Valsalva maneuver in the patient with the non-obstructive hypertrophic cardiomyopathy is <50 mmHg.

[0018] In some implementations, such as the first, second, third, fourth, or fifth aspect, the left ventricular outflow tract pressure gradient (Valsalva LVOT-G) after Valsalva maneuver in the patient with the non-obstructive hypertrophic cardiomyopathy is <40 mmHg.

[0019] In some implementations, such as the first, second, third, fourth, or fifth aspect, the left ventricular outflow tract pressure gradient (Valsalva LVOT-G) after Valsalva maneuver in the patient with the non-obstructive hypertrophic cardiomyopathy is <30 mmHg.

[0020] In some implementations, such as the first, second, third, fourth, or fifth aspects, the NT-proBNP of the patient with the non-obstructive hypertrophic cardiomyopathy is >300 pg / mL.

[0021] In some implementations, such as the first, second, third, fourth, or fifth aspects, the patients with the non-obstructive hypertrophic cardiomyopathy have a KCCQ-CSS score ≥25 and ≤90.

[0022] In some implementations, such as the first, second, third, fourth, or fifth aspects, the patients with the non-obstructive hypertrophic cardiomyopathy have a KCCQ-CSS score ≥30 and ≤85.

[0023] In some implementations, such as the first, second, third, fourth, or fifth aspects, the patients with the non-obstructive hypertrophic cardiomyopathy are classified as New York Heart Association (NYHA) Class II to III.

[0024] In some embodiments, for example, in the first, second, third, fourth, or fifth aspect, the unit dose or administered dose of the compound of formula I or a pharmaceutically acceptable salt thereof, calculated as the free base, is selected from 1-300 mg (e.g., 1 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 105 mg, 110 mg, 115 mg, 120 mg, 125 mg). 130mg, 135mg, 140mg, 145mg, 150mg, 155mg, 160mg, 165mg, 170mg, 175mg, 180mg, 185mg, 190mg, 195mg, 200mg, 205mg, 210mg, 215mg, 220mg, 225mg, 230mg, 235mg, 240mg, 245mg, 250mg, 255mg, 260mg, 265mg, 270mg, 275mg, 280mg, 285mg, 290mg, 295mg, 300mg, or any value between any two values). In some embodiments, for example, in the first, second, third, fourth, or fifth aspect, the unit dose or administered dose of the compound of formula I, or a pharmaceutically acceptable salt thereof, is selected from about 1 mg to about 300 mg (e.g., about 1 mg, about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, about 100 mg, about 105 mg, about 110 mg, about 115 mg, about 120 mg, about 125 mg, about 100 mg, about 105 mg, about 110 mg, about 115 mg, about 120 mg, about 125 mg, about 100 mg, about 105 mg, about 110 mg, about 115 mg, about 120 mg, about 125 mg, about 100 mg, about 125 mg, about 100 mg, about 125 mg, about 100 mg, about 125 mg, about 100 mg, about 125 mg, about 12 ...0 mg, about 125 mg, about 120 mg, about 120 mg, about The dosage is approximately 130 mg, 135 mg, 140 mg, 145 mg, 150 mg, 155 mg, 160 mg, 165 mg, 170 mg, 175 mg, 180 mg, 185 mg, 190 mg, 195 mg, 200 mg, 205 mg, 210 mg, 215 mg, 220 mg, 225 mg, 230 mg, 235 mg, 240 mg, 245 mg, 250 mg, 255 mg, 260 mg, 265 mg, 270 mg, 275 mg, 280 mg, 285 mg, 290 mg, 295 mg, 300 mg, or any value between any two of these values. In some embodiments, the unit dose or administered dose of the compound of Formula I or a pharmaceutically acceptable salt thereof is about 1 mg.In some embodiments, the unit dose or administered dose of the compound of formula I or a pharmaceutically acceptable salt thereof is about 5 mg. In some embodiments, the unit dose or administered dose of the compound of formula I or a pharmaceutically acceptable salt thereof is about 10 mg. In some embodiments, the unit dose or administered dose of the compound of formula I or a pharmaceutically acceptable salt thereof is about 15 mg. In some embodiments, the unit dose or administered dose of the compound of formula I or a pharmaceutically acceptable salt thereof is about 20 mg. In some embodiments, the unit dose or administered dose of the compound of formula I or a pharmaceutically acceptable salt thereof is about 25 mg. In some embodiments, the unit dose or administered dose of the compound of formula I or a pharmaceutically acceptable salt thereof is about 30 mg. In some embodiments, the unit dose or administered dose of the compound of formula I or a pharmaceutically acceptable salt thereof is about 35 mg. In some embodiments, the unit dose or administered dose of the compound of formula I or a pharmaceutically acceptable salt thereof is about 40 mg. In some embodiments, the unit dose or administered dose of the compound of formula I or a pharmaceutically acceptable salt thereof is about 45 mg. In some embodiments, the unit dose or administered dose of the compound of formula I or a pharmaceutically acceptable salt thereof is about 50 mg. In some embodiments, the unit dose or administered dose of the compound of formula I or a pharmaceutically acceptable salt thereof is about 55 mg. In some embodiments, the unit dose or administered dose of the compound of formula I or a pharmaceutically acceptable salt thereof is about 60 mg. In some embodiments, the unit dose or administered dose of the compound of formula I or a pharmaceutically acceptable salt thereof is about 65 mg. In some embodiments, the unit dose or administered dose of the compound of formula I or a pharmaceutically acceptable salt thereof is about 70 mg. In some embodiments, the unit dose or administered dose of the compound of formula I or a pharmaceutically acceptable salt thereof is about 75 mg. In some embodiments, the unit dose or administered dose of the compound of formula I or a pharmaceutically acceptable salt thereof is about 80 mg. In some embodiments, the unit dose or administered dose of the compound of formula I or a pharmaceutically acceptable salt thereof is about 85 mg. In some embodiments, the unit dose or administered dose of the compound of formula I or a pharmaceutically acceptable salt thereof is about 90 mg. In some embodiments, the unit dose or administered dose of the compound of formula I or a pharmaceutically acceptable salt thereof is about 95 mg. In some embodiments, the unit dose or administered dose of the compound of formula I or a pharmaceutically acceptable salt thereof is about 100 mg. In some embodiments, the unit dose or administered dose of the compound of formula I or a pharmaceutically acceptable salt thereof is about 105 mg. In some embodiments, the unit dose or administered dose of the compound of formula I or a pharmaceutically acceptable salt thereof is about 110 mg.In some embodiments, the unit dose or administered dose of the compound of formula I or a pharmaceutically acceptable salt thereof is about 115 mg. In some embodiments, the unit dose or administered dose of the compound of formula I or a pharmaceutically acceptable salt thereof is about 120 mg. In some embodiments, the unit dose or administered dose of the compound of formula I or a pharmaceutically acceptable salt thereof is about 125 mg. In some embodiments, the unit dose or administered dose of the compound of formula I or a pharmaceutically acceptable salt thereof is about 130 mg. In some embodiments, the unit dose or administered dose of the compound of formula I or a pharmaceutically acceptable salt thereof is about 135 mg. In some embodiments, the unit dose or administered dose of the compound of formula I or a pharmaceutically acceptable salt thereof is about 140 mg. In some embodiments, the unit dose or administered dose of the compound of formula I or a pharmaceutically acceptable salt thereof is about 145 mg. In some embodiments, the unit dose or administered dose of the compound of formula I or a pharmaceutically acceptable salt thereof is about 150 mg. In some embodiments, the unit dose or administered dose of the compound of formula I or a pharmaceutically acceptable salt thereof is about 155 mg. In some embodiments, the unit dose or administered dose of the compound of formula I or a pharmaceutically acceptable salt thereof is about 160 mg. In some embodiments, the unit dose or administered dose of the compound of formula I or a pharmaceutically acceptable salt thereof is about 165 mg. In some embodiments, the unit dose or administered dose of the compound of formula I or a pharmaceutically acceptable salt thereof is about 170 mg. In some embodiments, the unit dose or administered dose of the compound of formula I or a pharmaceutically acceptable salt thereof is about 175 mg. In some embodiments, the unit dose or administered dose of the compound of formula I or a pharmaceutically acceptable salt thereof is about 180 mg. In some embodiments, the unit dose or administered dose of the compound of formula I or a pharmaceutically acceptable salt thereof is about 185 mg. In some embodiments, the unit dose or administered dose of the compound of formula I or a pharmaceutically acceptable salt thereof is about 190 mg. In some embodiments, the unit dose or administered dose of the compound of formula I or a pharmaceutically acceptable salt thereof is about 195 mg. In some embodiments, the unit dose or administered dose of the compound of formula I or a pharmaceutically acceptable salt thereof is about 200 mg. In some embodiments, the unit dose or administered dose of the compound of formula I or a pharmaceutically acceptable salt thereof is about 205 mg. In some embodiments, the unit dose or administered dose of the compound of formula I or a pharmaceutically acceptable salt thereof is about 210 mg. In some embodiments, the unit dose or administered dose of the compound of formula I or a pharmaceutically acceptable salt thereof is about 215 mg. In some embodiments, the unit dose or administered dose of the compound of formula I or a pharmaceutically acceptable salt thereof is about 220 mg.In some embodiments, the unit dose or administered dose of the compound of formula I or a pharmaceutically acceptable salt thereof is about 225 mg. In some embodiments, the unit dose or administered dose of the compound of formula I or a pharmaceutically acceptable salt thereof is about 230 mg. In some embodiments, the unit dose or administered dose of the compound of formula I or a pharmaceutically acceptable salt thereof is about 235 mg. In some embodiments, the unit dose or administered dose of the compound of formula I or a pharmaceutically acceptable salt thereof is about 240 mg. In some embodiments, the unit dose or administered dose of the compound of formula I or a pharmaceutically acceptable salt thereof is about 245 mg. In some embodiments, the unit dose or administered dose of the compound of formula I or a pharmaceutically acceptable salt thereof is about 250 mg. In some embodiments, the unit dose or administered dose of the compound of formula I or a pharmaceutically acceptable salt thereof is about 255 mg. In some embodiments, the unit dose or administered dose of the compound of formula I or a pharmaceutically acceptable salt thereof is about 260 mg. In some embodiments, the unit dose or administered dose of the compound of formula I or a pharmaceutically acceptable salt thereof is about 265 mg. In some embodiments, the unit dose or administered dose of the compound of formula I or a pharmaceutically acceptable salt thereof is about 270 mg. In some embodiments, the unit dose or administered dose of the compound of formula I or a pharmaceutically acceptable salt thereof is about 275 mg. In some embodiments, the unit dose or administered dose of the compound of formula I or a pharmaceutically acceptable salt thereof is about 280 mg. In some embodiments, the unit dose or administered dose of the compound of formula I or a pharmaceutically acceptable salt thereof is about 285 mg. In some embodiments, the unit dose or administered dose of the compound of formula I or a pharmaceutically acceptable salt thereof is about 290 mg. In some embodiments, the unit dose or administered dose of the compound of formula I or a pharmaceutically acceptable salt thereof is about 295 mg. In some embodiments, the unit dose or administered dose of the compound of formula I or a pharmaceutically acceptable salt thereof is about 300 mg. In this disclosure, unless otherwise stated, the unit dose or administered dose of the compound of formula I or a pharmaceutically acceptable salt thereof is based on the free base of the compound of formula I.

[0025] In some embodiments, for example, in the first, second, third, fourth, or fifth aspect, the unit dose or administered dose of the compound of formula I or a pharmaceutically acceptable salt thereof is selected from 1-200 mg.

[0026] In some embodiments, for example, in the first, second, third, fourth, or fifth aspect, the unit dose or administered dose of the compound of formula I or a pharmaceutically acceptable salt thereof is selected from 5-100 mg.

[0027] In some embodiments, for example, in the first, second, third, fourth, or fifth aspect, the unit dose or administered dose of the compound of formula I or a pharmaceutically acceptable salt thereof is 10 mg, 20 mg, 30 mg, 40 mg, 50 mg, 60 mg, 70 mg, or 80 mg. In some embodiments, for example, in the first, second, third, fourth, or fifth aspect, the unit dose or administered dose of the compound of formula I or a pharmaceutically acceptable salt thereof is about 10 mg, about 20 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, or about 80 mg.

[0028] In some embodiments, such as the first, second, third, fourth, or fifth aspect, the unit dose or administered dose of the compound of formula I or a pharmaceutically acceptable salt thereof is 20 mg, 40 mg, or 60 mg.

[0029] In some embodiments, such as the first, second, third, fourth, or fifth aspect, the unit dose or administered dose of the compound of formula I or a pharmaceutically acceptable salt thereof is 20 mg or 40 mg.

[0030] In some embodiments, for example, in the first, second, third, fourth, or fifth aspect, the unit dose of the compound of formula I or a pharmaceutically acceptable salt thereof is 2.5 mg, 5 mg, 10 mg, 20 mg, or 40 mg. In some embodiments, for example, in the first, second, third, fourth, or fifth aspect, the unit dose of the compound of formula I or a pharmaceutically acceptable salt thereof is about 2.5 mg, about 5 mg, about 10 mg, about 20 mg, or about 40 mg.

[0031] In some implementations, such as the first, second, third, fourth, or fifth aspects, the compound of formula I or a pharmaceutically acceptable salt thereof is administered three times a day, twice a day, once a day, once every two days, once every three days, once every four days, once every five days, once every six days, or once a week.

[0032] In some implementations, such as the first, second, third, fourth, or fifth aspects, the compound of formula I or a pharmaceutically acceptable salt thereof is administered three times a day, twice a day, or once a day.

[0033] In some implementations, such as the first, second, third, fourth, or fifth aspects, the compound of formula I or a pharmaceutically acceptable salt thereof is administered twice or once a day.

[0034] In some implementations, such as the first, second, third, fourth, or fifth aspects, the compound of formula I or a pharmaceutically acceptable salt thereof is administered twice daily.

[0035] In some embodiments, for example, in the first, second, third, fourth, or fifth aspect, the unit dose or dosage of the compound of formula I or a pharmaceutically acceptable salt thereof is selected from 1-300 mg, and the dosage is administered three times a day, twice a day, once a day, once every two days, once every three days, once every four days, once every five days, once every six days, or once a week. In some embodiments, for example, in the first, second, third, fourth, or fifth aspect, the unit dose or dosage of the compound of formula I or a pharmaceutically acceptable salt thereof is selected from about 1 mg to about 300 mg, and the dosage is administered three times a day, twice a day, once a day, once every two days, once every three days, once every four days, once every five days, once every six days, or once a week.

[0036] In some embodiments, for example, in the first, second, third, fourth, or fifth aspect, the unit dose or dosage of the compound of formula I or a pharmaceutically acceptable salt thereof is selected from 1-200 mg, and the frequency of administration is three times a day, twice a day, or once a day. In some embodiments, for example, in the first, second, third, fourth, or fifth aspect, the unit dose or dosage of the compound of formula I or a pharmaceutically acceptable salt thereof is selected from about 1 mg to about 200 mg, and the frequency of administration is three times a day, twice a day, or once a day.

[0037] In some embodiments, for example, in the first, second, third, fourth, or fifth aspect, the unit dose or dosage of the compound of formula I or a pharmaceutically acceptable salt thereof is selected from 5-100 mg, and the frequency of administration is twice or once a day. In some embodiments, for example, in the first, second, third, fourth, or fifth aspect, the unit dose or dosage of the compound of formula I or a pharmaceutically acceptable salt thereof is selected from about 5 mg to about 100 mg, and the frequency of administration is twice or once a day.

[0038] In some embodiments, for example, in the first, second, third, fourth, or fifth aspect, the unit dose or administered dose of the compound of formula I or a pharmaceutically acceptable salt thereof is 10 mg, 20 mg, 30 mg, 40 mg, 50 mg, 60 mg, 70 mg, or 80 mg, and the frequency of administration is twice daily or once daily. In some embodiments, for example, in the first, second, third, fourth, or fifth aspect, the unit dose or administered dose of the compound of formula I or a pharmaceutically acceptable salt thereof is about 10 mg, about 20 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, or about 80 mg, and the frequency of administration is twice daily or once daily.

[0039] In some embodiments, for example, in the first, second, third, fourth, or fifth aspect, the unit dose or administered dose of the compound of formula I or a pharmaceutically acceptable salt thereof is 10 mg, 20 mg, 30 mg, 40 mg, 50 mg, 60 mg, 70 mg, or 80 mg, administered twice daily. In some embodiments, for example, in the first, second, third, fourth, or fifth aspect, the unit dose or administered dose of the compound of formula I or a pharmaceutically acceptable salt thereof is about 10 mg, about 20 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, or about 80 mg, administered twice daily.

[0040] In some embodiments, for example, in the first, second, third, fourth, or fifth aspect, the unit dose or administered dose of the compound of formula I or a pharmaceutically acceptable salt thereof is 20 mg, 40 mg, or 60 mg, administered twice daily. In some embodiments, for example, in the first, second, third, fourth, or fifth aspect, the unit dose or administered dose of the compound of formula I or a pharmaceutically acceptable salt thereof is about 20 mg, about 40 mg, or about 60 mg, administered twice daily.

[0041] In some embodiments, such as the first, second, third, fourth, or fifth aspect, the administration period of the compound of formula I or a pharmaceutically acceptable salt thereof is at least one week (e.g., 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, 16 weeks, 17 weeks, 18 weeks, 19 weeks, 20 weeks, 21 weeks, 22 weeks, 23 weeks, 24 weeks, 25 weeks, 26 weeks, 27 weeks, 28 weeks, 29 weeks, ...). The duration of administration may be 30 weeks, 31 weeks, 32 weeks, 33 weeks, 34 weeks, 35 weeks, 36 weeks, 37 weeks, 38 weeks, 39 weeks, 40 weeks, 41 weeks, 42 weeks, 43 weeks, 44 weeks, 45 weeks, 46 weeks, 47 weeks, 48 ​​weeks, 49 weeks, 50 weeks, 51 weeks, 52 weeks, 53 weeks, 54 weeks, 55 weeks, 56 weeks, 57 weeks, 58 weeks, 59 weeks, 60 weeks, 61 weeks, 62 weeks, 63 weeks, 64 weeks, 1.5 years, 2 years, 2.5 years, 3 years, 3.5 years, 4 years or longer, or even permanently. In some embodiments, for example, in the first, second, third, fourth or fifth aspect, the administration period of the compound of formula I or a pharmaceutically acceptable salt thereof is at least 4 weeks. In some embodiments, such as the first, second, third, fourth, or fifth aspect, the administration period of the compound of formula I or a pharmaceutically acceptable salt thereof is at least 12 weeks. In some embodiments, such as the first, second, third, fourth, or fifth aspect, the administration period of the compound of formula I or a pharmaceutically acceptable salt thereof is 12 weeks. In some embodiments, such as the first, second, third, fourth, or fifth aspect, the administration period of the compound of formula I or a pharmaceutically acceptable salt thereof is 24 weeks, 36 weeks, 48 ​​weeks, 60 weeks, 72 weeks, 84 weeks, 96 weeks, 108 weeks, 120 weeks, or longer. In some embodiments, such as the first, second, third, fourth, or fifth aspect, the administration period of the compound of formula I or a pharmaceutically acceptable salt thereof is permanent.

[0042] In some embodiments, such as the fourth or fifth aspect, the cardiac troponin is cardiac troponin I (cTnI) or cardiac troponin T (cTnT).

[0043] Sixthly, this disclosure provides a method for preventing and / or treating non-obstructive hypertrophic cardiomyopathy (nHCM), comprising the following steps:

[0044] (a) Administering an initial dose of the aforementioned Formula I compound or a pharmaceutically acceptable salt thereof to the patient.

[0045] (b) Assess the patient’s LVEF and then administer the original or adjusted dose of the Formula I compound or a pharmaceutically acceptable salt thereof to the patient, or discontinue the administration of the Formula I compound or a pharmaceutically acceptable salt thereof.

[0046] In a seventh aspect, this disclosure provides a method for preventing and / or treating non-obstructive hypertrophic cardiomyopathy (nHCM) using a compound of formula I or a pharmaceutically acceptable salt thereof, the method comprising the steps of:

[0047] (a) Administering an initial dose of the compound of formula I above or a pharmaceutically acceptable salt thereof to the patient.

[0048] (b) Assess the patient’s LVEF and then administer the original or adjusted dose of the Formula I compound or a pharmaceutically acceptable salt thereof to the patient, or discontinue the administration of the Formula I compound or a pharmaceutically acceptable salt thereof.

[0049] Eighthly, this disclosure provides a method for reducing cardiac troponin and / or NT-proBNP levels in patients with non-obstructive hypertrophic cardiomyopathy, comprising the following steps:

[0050] (a) Administering an initial dose of the aforementioned Formula I compound or a pharmaceutically acceptable salt thereof to the patient.

[0051] (b) Assess the patient’s LVEF and then administer the original or adjusted dose of the Formula I compound or a pharmaceutically acceptable salt thereof to the patient, or discontinue the administration of the Formula I compound or a pharmaceutically acceptable salt thereof.

[0052] Ninthly, this disclosure also provides a method for reducing cardiac troponin and / or NT-proBNP levels in patients with non-obstructive hypertrophic cardiomyopathy, comprising the aforementioned compound of formula I or a pharmaceutically acceptable salt thereof, the method comprising the steps of:

[0053] (a) Administering an initial dose of the compound of formula I above or a pharmaceutically acceptable salt thereof to the patient.

[0054] (b) Assess the patient’s LVEF and then administer the original or adjusted dose of the Formula I compound or a pharmaceutically acceptable salt thereof to the patient, or discontinue the administration of the Formula I compound or a pharmaceutically acceptable salt thereof.

[0055] In some implementations, such as the sixth, seventh, eighth, or ninth aspect, the patient with the non-obstructive hypertrophic cardiomyopathy has a left ventricular ejection fraction (LVEF) ≥50%.

[0056] In some implementations, such as the sixth, seventh, eighth, or ninth aspect, the LVEF of the patient with the non-obstructive hypertrophic cardiomyopathy is ≥55%.

[0057] In some implementations, such as the sixth, seventh, eighth, or ninth aspect, the LVEF of the patient with the non-obstructive hypertrophic cardiomyopathy is ≥60%.

[0058] In some implementations, such as the sixth, seventh, eighth, or ninth aspect, the resting left ventricular outflow tract pressure gradient (resting LVOT-G) of the patient with the non-obstructive hypertrophic cardiomyopathy is <30 mmHg.

[0059] In some implementations, such as the sixth, seventh, eighth, or ninth aspect, the left ventricular outflow tract pressure gradient (Valsalva LVOT-G) after Valsalva maneuver in the patient with the non-obstructive hypertrophic cardiomyopathy is <50 mmHg.

[0060] In some implementations, such as the sixth, seventh, eighth, or ninth aspect, the left ventricular outflow tract pressure gradient (Valsalva LVOT-G) after Valsalva maneuver in the patient with the non-obstructive hypertrophic cardiomyopathy is <40 mmHg.

[0061] In some implementations, such as the sixth, seventh, eighth, or ninth aspect, the left ventricular outflow tract pressure gradient (Valsalva LVOT-G) after Valsalva maneuver in the patient with the non-obstructive hypertrophic cardiomyopathy is <30 mmHg.

[0062] In some implementations, such as the sixth, seventh, eighth, or ninth aspect, the NT-proBNP of the patient with the non-obstructive hypertrophic cardiomyopathy is >300 pg / mL.

[0063] In some implementations, such as the sixth, seventh, eighth, or ninth aspect, the patients with the non-obstructive hypertrophic cardiomyopathy have a KCCQ-CSS score ≥25 and ≤90.

[0064] In some implementations, such as the sixth, seventh, eighth, or ninth aspect, the patients with the non-obstructive hypertrophic cardiomyopathy have a KCCQ-CSS score ≥30 and ≤85.

[0065] In some implementations, such as the sixth, seventh, eighth, or ninth aspects, the patients with the non-obstructive hypertrophic cardiomyopathy are classified as New York Heart Association (NYHA) Class II to III.

[0066] In some embodiments, such as the sixth, seventh, eighth or ninth aspects, in step (a), the initial dose, based on the free base of the compound of formula I, is selected from 5-80 mg (e.g. 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg or any value between any two values). In some embodiments, such as in aspects six, seven, eight, or nine, in step (a), the initial dose, based on the free base of the compound of formula I, is selected from about 5 mg to about 80 mg (e.g., about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, or any value between any two values). In some embodiments, the initial dose in step (a) is about 5 mg. In some embodiments, the initial dose in step (a) is about 10 mg. In some embodiments, the initial dose in step (a) is about 15 mg. In some embodiments, the initial dose in step (a) is about 20 mg. In some embodiments, the initial dose in step (a) is about 25 mg. In some embodiments, the initial dose in step (a) is about 30 mg. In some embodiments, the initial dose in step (a) is about 35 mg. In some embodiments, the initial dose in step (a) is about 40 mg. In some embodiments, the initial dose in step (a) is about 45 mg. In some embodiments, the initial dose in step (a) is about 50 mg. In some embodiments, the initial dose in step (a) is about 55 mg. In some embodiments, the initial dose in step (a) is about 60 mg. In some embodiments, the initial dose in step (a) is about 65 mg. In some embodiments, the initial dose in step (a) is about 70 mg. In some embodiments, the initial dose in step (a) is about 75 mg. In some embodiments, the initial dose in step (a) is about 80 mg.

[0067] In some embodiments, such as in the sixth, seventh, eighth, or ninth aspect, in step (a), the initial dose, calculated as a free base of the compound of formula I, is selected from 10-60 mg. In some embodiments, such as in the sixth, seventh, eighth, or ninth aspect, in step (a), the initial dose, calculated as a free base of the compound of formula I, is selected from about 10 mg to about 60 mg.

[0068] In some embodiments, such as in the sixth, seventh, eighth, or ninth aspect, in step (a), the initial dose, calculated as a free base of the compound of formula I, is selected from 10-40 mg. In some embodiments, such as in the sixth, seventh, eighth, or ninth aspect, in step (a), the initial dose, calculated as a free base of the compound of formula I, is selected from about 10 mg to about 40 mg.

[0069] In some embodiments, such as in the sixth, seventh, eighth, or ninth aspect, in step (a), the initial dose, calculated as the free base of the compound of formula I, is 20 mg or 40 mg. In some embodiments, such as in the sixth, seventh, eighth, or ninth aspect, in step (a), the initial dose, calculated as the free base of the compound of formula I, is about 20 mg or about 40 mg.

[0070] In some implementations, such as the sixth, seventh, eighth or ninth aspects, in step (a), the initial dose is 20 mg, calculated as the free base of the compound of formula I.

[0071] In some implementations, such as the sixth, seventh, eighth or ninth aspects, in step (a), the initial dose is administered three times a day, twice a day or once a day.

[0072] In some implementations, such as the sixth, seventh, eighth or ninth aspects, in step (a), the initial dose is administered twice a day or once a day.

[0073] In some implementations, such as the sixth, seventh, eighth or ninth aspects, in step (a), the initial dose is administered twice a day.

[0074] In some embodiments, such as in the sixth, seventh, eighth, or ninth aspect, in step (a), the initial dose is selected from 5-80 mg, and the dosing frequency is three times a day, twice a day, or once a day. In some embodiments, such as in the sixth, seventh, eighth, or ninth aspect, in step (a), the initial dose is selected from about 5 mg to about 80 mg, and the dosing frequency is three times a day, twice a day, or once a day.

[0075] In some embodiments, such as in the sixth, seventh, eighth, or ninth aspect, in step (a), the initial dose is selected from 10-60 mg, and the administration frequency is twice or once a day. In some embodiments, such as in the sixth, seventh, eighth, or ninth aspect, in step (a), the initial dose is selected from about 10 mg to about 60 mg, and the administration frequency is twice or once a day.

[0076] In some embodiments, such as in the sixth, seventh, eighth, or ninth aspect, in step (a), the initial dose is selected from 10-40 mg, and the administration frequency is twice a day.

[0077] In some embodiments, such as the sixth, seventh, eighth, or ninth aspect, in step (a), the initial dose is 20 mg, and the dosing frequency is twice a day. In some embodiments, such as the sixth, seventh, eighth, or ninth aspect, in step (a), the initial dose is approximately 20 mg, and the dosing frequency is twice a day.

[0078] In some implementations, such as the sixth, seventh, eighth, or ninth aspect, in step (a), the initial dose is administered for at least one week (e.g., 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, 16 weeks, 17 weeks, 18 weeks, 19 weeks, 20 weeks, 21 weeks, 22 weeks, 23 weeks, 24 weeks, 25 weeks, 26 weeks, 27 weeks, 28 weeks, 29 weeks, 30 weeks, 3...). The duration of administration can be 1 week, 32 weeks, 33 weeks, 34 weeks, 35 weeks, 36 weeks, 37 weeks, 38 weeks, 39 weeks, 40 weeks, 41 weeks, 42 weeks, 43 weeks, 44 weeks, 45 weeks, 46 weeks, 47 weeks, 48 ​​weeks, 49 weeks, 50 weeks, 51 weeks, 52 weeks, 53 weeks, 54 weeks, 55 weeks, 56 weeks, 57 weeks, 58 weeks, 59 weeks, 60 weeks, 61 weeks, 62 weeks, 63 weeks, 64 weeks, 1.5 years, 2 years, 2.5 years, 3 years, 3.5 years, 4 years or longer, or even permanently. In some embodiments, for example, in the sixth, seventh, eighth or ninth aspect, in step (a), the initial dose is administered for at least 4 weeks. In some embodiments, for example, in the sixth, seventh, eighth or ninth aspect, in step (a), the initial dose is administered for at least 12 weeks. In some embodiments, such as in the sixth, seventh, eighth, or ninth aspect, the initial dose is administered for 12 weeks in step (a). In some embodiments, such as in the sixth, seventh, eighth, or ninth aspect, the initial dose is administered for 24, 36, 48, 60, 72, 84, 96, 108, 120 weeks, or longer in step (a). In some embodiments, such as in the sixth, seventh, eighth, or ninth aspect, the initial dose is administered permanently in step (a).

[0079] In some implementations, such as the sixth, seventh, eighth, or ninth aspects, the adjustment in step (b) is an upward or downward adjustment.

[0080] In some embodiments, for example, in aspects six, seven, eight, or nine, in step (b), the adjustment (e.g., upward or downward) of the dosage is selected from 5-80 mg (e.g., 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, or any value between any two values). In some embodiments, for example, in aspects six, seven, eight, or nine, in step (b), the adjustment of the dosage is selected from 10-60 mg. In some embodiments, for example, in aspects six, seven, eight, or nine, in step (b), the adjustment of the dosage is selected from 20-40 mg. In some embodiments, for example, in aspects six, seven, eight, or nine, in step (b), the adjustment of the dosage is 20 mg. In some embodiments, for example, in the sixth, seventh, eighth, or ninth aspect, in step (b), the adjustment (e.g., upward or downward) of the dosage is selected from about 5 mg to about 80 mg (e.g., about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, or any value between any two values). In some embodiments, for example, in the sixth, seventh, eighth, or ninth aspect, in step (b), the adjustment of the dosage is selected from about 10 mg to about 60 mg. In some embodiments, for example, in the sixth, seventh, eighth, or ninth aspect, in step (b), the adjustment of the dosage is selected from about 20 mg to about 40 mg. In some implementations, such as the sixth, seventh, eighth or ninth aspects, in step (b), the dosage is adjusted by approximately 20 mg.

[0081] In some embodiments, such as in aspects six, seven, eight, or nine, in step (b), the dosage may be adjusted optionally during one or more weeks of week 1, week 2, week 3, and week 4 after initial administration. In some embodiments, such as in aspects six, seven, eight, or nine, in step (b), the dosage may be adjusted optionally during one or more weeks of week 2, week 3, and week 4 after initial administration. In some embodiments, such as in aspects six, seven, eight, or nine, in step (b), the dosage may be adjusted optionally during week 2 and / or week 3 after initial administration.

[0082] In some embodiments, such as the sixth, seventh, eighth, or ninth aspects, in step (b), the dosage can only be increased in the second and / or third week after the initial administration.

[0083] In some embodiments, the second week is day 8 after the initial administration. In some embodiments, the third week is day 15 after the initial administration. In some embodiments, the fourth week is day 22 after the initial administration.

[0084] In some implementations, such as the sixth, seventh, eighth, or ninth aspects, the adjustment magnitude in step (b) may be the same or different each time.

[0085] In some implementations, such as the sixth, seventh, eighth or ninth aspects, in step (b), the frequency of administration of the drug dose is the same as the frequency of administration of the original drug dose.

[0086] In some implementations, such as the sixth, seventh, eighth, or ninth aspects, in step (b), the original dosage or adjusted dosing time is at least one week (e.g., 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, 16 weeks, 17 weeks, 18 weeks, 19 weeks, 20 weeks, 21 weeks, 22 weeks, 23 weeks, 24 weeks, 25 weeks, 26 weeks, 27 weeks, 28 weeks, 29 weeks, 30 weeks). Weeks, 31 weeks, 32 weeks, 33 weeks, 34 weeks, 35 weeks, 36 weeks, 37 weeks, 38 weeks, 39 weeks, 40 weeks, 41 weeks, 42 weeks, 43 weeks, 44 weeks, 45 weeks, 46 weeks, 47 weeks, 48 ​​weeks, 49 weeks, 50 weeks, 51 weeks, 52 weeks, 53 weeks, 54 weeks, 55 weeks, 56 weeks, 57 weeks, 58 weeks, 59 weeks, 60 weeks, 61 weeks, 62 weeks, 63 weeks, 64 weeks, 1.5 years, 2 years, 2.5 years, 3 years, 3.5 years, 4 years or longer, or even permanently).

[0087] In some embodiments, such as in aspects six, seven, eight, or nine, step (b) may be repeated once or more, for example, two, three, or more times. In some embodiments, such as in aspects six, seven, eight, or nine, step (b) is repeated once. In some embodiments, such as in aspects six, seven, eight, or nine, step (b) is repeated twice. In some embodiments, such as in aspects six, seven, eight, or nine, step (b) is repeated three times.

[0088] In some implementations, such as the sixth, seventh, eighth, or ninth aspect, the method includes the following steps:

[0089] (a) Administering an initial dose of the compound of formula I above or a pharmaceutically acceptable salt thereof to the patient.

[0090] (b) Assess the patient’s LVEF and then administer the original or adjusted dose of the Formula I compound or a pharmaceutically acceptable salt thereof to the patient, or discontinue the administration of the Formula I compound or a pharmaceutically acceptable salt thereof.

[0091] (c) Assess the patient’s LVEF and then administer the original or adjusted dose of the Formula I compound or a pharmaceutically acceptable salt thereof to the patient, or discontinue the administration of the Formula I compound or a pharmaceutically acceptable salt thereof.

[0092] In some implementations, such as the sixth, seventh, eighth, or ninth aspect, the method includes the following steps:

[0093] (a) Administering an initial dose of the compound of formula I above or a pharmaceutically acceptable salt thereof to the patient.

[0094] (b) Assess the patient’s LVEF and then administer the original or adjusted dose of the Formula I compound or a pharmaceutically acceptable salt thereof to the patient, or discontinue the administration of the Formula I compound or a pharmaceutically acceptable salt thereof.

[0095] (c) Assess the patient’s LVEF and then administer the original or adjusted dose of the Formula I compound or a pharmaceutically acceptable salt thereof to the patient, or discontinue the administration of the Formula I compound or a pharmaceutically acceptable salt thereof.

[0096] (d) Assess the patient’s LVEF and then administer the original or adjusted dose of the Formula I compound or a pharmaceutically acceptable salt thereof to the patient, or discontinue the administration of the Formula I compound or a pharmaceutically acceptable salt thereof.

[0097] In some implementations, such as the sixth, seventh, eighth, or ninth aspects, after administering a Formula I compound or a pharmaceutically acceptable salt thereof to a patient for four weeks, a maintenance dose of the Formula I compound or a pharmaceutically acceptable salt thereof is subsequently administered to the patient, said maintenance dose being the same as the dose administered in the fourth week.

[0098] In some implementations, such as the sixth, seventh, eighth, or ninth aspect, the maintenance dose is administered for at least one week (e.g., 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, 16 weeks, 17 weeks, 18 weeks, 19 weeks, 20 weeks, 21 weeks, 22 weeks, 23 weeks, 24 weeks, 25 weeks, 26 weeks, 27 weeks, 28 weeks, 29 weeks, 30 weeks, 31 weeks, ...). 32 weeks, 33 weeks, 34 weeks, 35 weeks, 36 weeks, 37 weeks, 38 weeks, 39 weeks, 40 weeks, 41 weeks, 42 weeks, 43 weeks, 44 weeks, 45 weeks, 46 weeks, 47 weeks, 48 ​​weeks, 49 weeks, 50 weeks, 51 weeks, 52 weeks, 53 weeks, 54 weeks, 55 weeks, 56 weeks, 57 weeks, 58 weeks, 59 weeks, 60 weeks, 61 weeks, 62 weeks, 63 weeks, 64 weeks, 1.5 years, 2 years, 2.5 years, 3 years, 3.5 years, 4 years or longer, or even permanently).

[0099] In some embodiments, such as in aspects six, seven, eight, or nine, after administration of a maintenance dose of the Formula I compound or a pharmaceutically acceptable salt thereof to the patient, the dose is gradually reduced in increments of 5-80 mg for at least one week (e.g., one week) until the initial dose (e.g., 20 mg) is reached, followed by discontinuation. In some embodiments, the adjustment increment is selected from 10-60 mg. In some embodiments, the adjustment increment is selected from 20-40 mg. In some embodiments, the adjustment increment is 20 mg. In some embodiments, such as in aspects six, seven, eight, or nine, after administration of a maintenance dose of the Formula I compound or a pharmaceutically acceptable salt thereof to the patient, the dose is gradually reduced in increments of about 5 mg to about 80 mg for at least one week (e.g., one week) until the initial dose (e.g., about 20 mg) is reached, followed by discontinuation. In some embodiments, the adjustment increment is selected from about 10 mg to about 60 mg. In some embodiments, the adjustment increment is selected from about 20 mg to about 40 mg. In some implementations, the adjustment range is approximately 20 mg.

[0100] In some implementations, such as the sixth, seventh, eighth or ninth aspects, in step (b), when LVEF ≥ 55%, the dosage is increased based on the original dosage.

[0101] In some implementations, such as the sixth, seventh, eighth or ninth aspects, in step (b), when 50% ≤ LVEF < 55%, the original dosage is maintained.

[0102] In some implementations, such as the sixth, seventh, eighth or ninth aspects, in step (b), when 45% ≤ LVEF < 50%, the dosage is reduced from the original dosage.

[0103] In some embodiments, such as in aspects six, seven, eight, or nine, in step (b), when LVEF < 45% or a serious adverse reaction occurs, the administration of the Formula I compound or a pharmaceutically acceptable salt thereof is suspended. In some embodiments, the serious adverse reaction may be the appearance of symptoms of heart failure or a deterioration of clinical condition.

[0104] In some implementations, such as the sixth, seventh, eighth, or ninth aspects, in step (b), when LVEF < 45%, the administration of the Formula I compound or a pharmaceutically acceptable salt thereof is suspended.

[0105] In some implementations, such as the sixth, seventh, eighth, or ninth aspects, when the dose administered in step (b), (c), or (d) above is the same as the initial dose and 45% ≤ LVEF < 50%, the administration of the Formula I compound or its pharmaceutically acceptable salt may be suspended.

[0106] In some embodiments, such as in aspects six, seven, eight, or nine, administration of the Formula I compound or a pharmaceutically acceptable salt thereof may be suspended when the patient is given a dose of 20 mg and 45% ≤ LVEF < 50%.

[0107] In some implementations, such as the sixth, seventh, eighth, or ninth aspects, if a patient discontinues medication due to LVEF <45% and the dose administered before discontinuation is the same as the initial dose, then medication is not restarted.

[0108] In some embodiments, such as the sixth, seventh, eighth, or ninth aspect, when the patient discontinues administration because the dose is the same as the initial dose and 45% ≤ LVEF < 50%, the method further includes the step of restarting administration of the Formula I compound or a pharmaceutically acceptable salt thereof to the patient.

[0109] In some implementations, such as the sixth, seventh, eighth, or ninth aspect, when the patient discontinues administration due to LVEF <45% or a serious adverse reaction, the method further includes the step of restarting administration of the Formula I compound or a pharmaceutically acceptable salt thereof to the patient.

[0110] In some implementations, such as the sixth, seventh, eighth, or ninth aspect, when the patient suspends administration due to LVEF <45% or a serious adverse reaction, administration of the Formula I compound or a pharmaceutically acceptable salt thereof is restarted after the LVEF rises to LVEF ≥55% or the serious adverse reaction is resolved or stabilized.

[0111] In some implementations, such as the sixth, seventh, eighth, or ninth aspect, the dosage at which the drug is restarted is the same as or lower than the dosage before the drug was suspended.

[0112] In some implementations, such as the sixth, seventh, eighth, or ninth aspect, when the patient discontinues administration because the dosage is the same as the initial dosage and 45% ≤ LVEF < 50%, the restarted dosage is the same as the dosage before discontinuation.

[0113] In some implementations, such as the sixth, seventh, eighth, or ninth aspects, if the dose administered before the suspension is higher than the initial dose, the dose administered upon restarting is lower than the dose administered before the suspension.

[0114] In some implementations, such as the sixth, seventh, eighth, or ninth aspect, when a patient discontinues medication due to LVEF <45% and the pre-discontinuation dose was higher than the initial dose, the restarted dose is lower than the pre-discontinuation dose.

[0115] In some embodiments, for example, in aspects six, seven, eight, or nine, the reduction in dosage below the pre-pause level is selected from 5-80 mg (e.g., 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, or any value between any two values). In some embodiments, for example, in aspects six, seven, eight, or nine, the reduction in dosage below the pre-pause level is selected from 10-60 mg. In some embodiments, for example, in aspects six, seven, eight, or nine, the reduction in dosage below the pre-pause level is selected from 20-40 mg. In some embodiments, for example, in aspects six, seven, eight, or nine, the reduction in dosage below the pre-pause level is 20 mg. In some embodiments, for example, in aspects six, seven, eight, or nine, the reduction in dosage below the pre-pause level is selected from about 5 mg to about 80 mg (e.g., about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, or any value between any two values). In some embodiments, for example, in aspects six, seven, eight, or nine, the reduction in dosage below the pre-pause level is selected from about 10 mg to about 60 mg. In some embodiments, for example, in aspects six, seven, eight, or nine, the reduction in dosage below the pre-pause level is selected from about 20 mg to about 40 mg. In some embodiments, for example, in aspects six, seven, eight, or nine, the reduction in dosage below the pre-pause level is about 20 mg.

[0116] In some implementations, such as the sixth, seventh, eighth, or ninth aspect, the administration of the Formula I compound or a pharmaceutically acceptable salt thereof to the patient is restarted for at least one week (e.g., 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, 16 weeks, 17 weeks, 18 weeks, 19 weeks, 20 weeks, 21 weeks, 22 weeks, 23 weeks, 24 weeks, 25 weeks, 26 weeks, 27 weeks, 28 weeks, 29 weeks). 30 weeks, 31 weeks, 32 weeks, 33 weeks, 34 weeks, 35 weeks, 36 weeks, 37 weeks, 38 weeks, 39 weeks, 40 weeks, 41 weeks, 42 weeks, 43 weeks, 44 weeks, 45 weeks, 46 weeks, 47 weeks, 48 ​​weeks, 49 weeks, 50 weeks, 51 weeks, 52 weeks, 53 weeks, 54 weeks, 55 weeks, 56 weeks, 57 weeks, 58 weeks, 59 weeks, 60 weeks, 61 weeks, 62 weeks, 63 weeks, 64 weeks, 1.5 years, 2 years, 2.5 years, 3 years, 3.5 years, 4 years or longer, or even permanently).

[0117] In some implementations, such as the sixth, seventh, eighth, or ninth aspects, the pause and restart dosing process may be repeated multiple times (e.g., two, three, or more times).

[0118] In some embodiments, such as the eighth or ninth aspect, the cardiac troponin is cardiac troponin I (cTnI) or cardiac troponin T (cTnT).

[0119] Eleventhly, this disclosure also provides the use of the aforementioned Formula I compound or a pharmaceutically acceptable salt thereof in the preparation of a medicament for the prevention and / or treatment of non-obstructive hypertrophic cardiomyopathy, wherein the Formula I compound or a pharmaceutically acceptable salt thereof is used in combination with other therapeutic agents selected from at least one of β-blockers (e.g., bisoprolol, metoprolol, etc.), non-dihydropyridine calcium channel antagonists (e.g., verapamil, diltiazem, etc.), and disopyramide. In some embodiments, disopyramide and a β-blocker are used in combination.

[0120] In some embodiments, at least one of the following dosages, frequency of administration, and timing of administration for the patient with the non-obstructive hypertrophic cardiomyopathy, the compound of formula I, or a pharmaceutically acceptable salt thereof, is defined as in any of the uses described in the first aspect.

[0121] In a twelfth aspect, this disclosure also provides a method for preventing and / or treating non-obstructive hypertrophic cardiomyopathy, comprising administering to a patient a therapeutically effective amount of the aforementioned Formula I compound or a pharmaceutically acceptable salt thereof, wherein the Formula I compound or a pharmaceutically acceptable salt thereof is used in combination with other therapeutic agents selected from at least one of beta-blockers (e.g., bisoprolol, metoprolol, etc.), non-dihydropyridine calcium channel antagonists (e.g., verapamil, diltiazem, etc.), and disopyramide. In some embodiments, disopyramide is used in combination with a beta-blocker.

[0122] In some embodiments, at least one of the following dosages, frequency of administration, and timing of administration for the patient with the non-obstructive hypertrophic cardiomyopathy, the compound of formula I, or a pharmaceutically acceptable salt thereof, is defined as in any of the uses described in the first aspect.

[0123] In a thirteenth aspect, this disclosure also provides a compound of formula I or a pharmaceutically acceptable salt thereof for the prevention and / or treatment of non-obstructive hypertrophic cardiomyopathy, wherein the compound of formula I or a pharmaceutically acceptable salt thereof is used in combination with other therapeutic agents selected from at least one of beta-blockers (e.g., bisoprolol, metoprolol, etc.), non-dihydropyridine calcium channel antagonists (e.g., verapamil, diltiazem, etc.), and disopyramide. In some embodiments, disopyramide is used in combination with a beta-blocker.

[0124] In some embodiments, at least one of the following dosages, frequency of administration, and timing of administration for the patient with the non-obstructive hypertrophic cardiomyopathy, the compound of formula I, or a pharmaceutically acceptable salt thereof, is defined as in any of the uses described in the first aspect.

[0125] In a fourteenth aspect, this disclosure also provides the use of the aforementioned Formula I compound or a pharmaceutically acceptable salt thereof in the preparation of a medicament for the prevention and / or treatment of non-obstructive hypertrophic cardiomyopathy, wherein the Formula I compound or a pharmaceutically acceptable salt thereof is used in combination with other therapeutic agents selected from CYP enzyme inhibitors and CYP enzyme inducers.

[0126] In some embodiments, at least one of the following dosages, frequency of administration, and timing of administration for the patient with the non-obstructive hypertrophic cardiomyopathy, the compound of formula I, or a pharmaceutically acceptable salt thereof, is defined as in any of the uses described in the first aspect.

[0127] In a fifteenth aspect, this disclosure also provides a method for preventing and / or treating non-obstructive hypertrophic cardiomyopathy in patients in need, comprising administering to the patient a therapeutically effective amount of the aforementioned Formula I compound or a pharmaceutically acceptable salt thereof, wherein the Formula I compound or a pharmaceutically acceptable salt thereof is used in combination with other therapeutic agents selected from CYP enzyme inhibitors and CYP enzyme inducers.

[0128] In some embodiments, at least one of the following dosages, frequency of administration, and timing of administration for the patient with the non-obstructive hypertrophic cardiomyopathy, the compound of formula I, or a pharmaceutically acceptable salt thereof, is defined as in any of the uses described in the first aspect.

[0129] In a sixteenth aspect, this disclosure also provides a compound of formula I or a pharmaceutically acceptable salt thereof for the prevention and / or treatment of non-obstructive hypertrophic cardiomyopathy, wherein the compound of formula I or a pharmaceutically acceptable salt thereof is used in combination with other therapeutic agents selected from CYP enzyme inhibitors and CYP enzyme inducers.

[0130] In some embodiments, at least one of the following dosages, frequency of administration, and timing of administration for the patient with the non-obstructive hypertrophic cardiomyopathy, the compound of formula I, or a pharmaceutically acceptable salt thereof, is defined as in any of the uses described in the first aspect.

[0131] In a seventeenth aspect, this disclosure also provides a composition comprising a compound of formula I or a pharmaceutically acceptable salt thereof and other therapeutic agents selected from CYP enzyme inhibitors and CYP enzyme inducers.

[0132] In an eighteenth aspect, this disclosure also provides a method of administration of the aforementioned Formula I compound or a pharmaceutically acceptable salt thereof, wherein when used in combination with other therapeutic agents, it is not necessary to adjust the dosage of the Formula I compound or a pharmaceutically acceptable salt thereof, wherein the other therapeutic agents are selected from CYP enzyme inhibitors and CYP enzyme inducers.

[0133] In some embodiments, at least one of the dosage, frequency, and timing of administration of the compound of Formula I or a pharmaceutically acceptable salt thereof is defined as in any of the uses described in the first aspect.

[0134] In some embodiments, such as the fourteenth, fifteenth, sixteenth, seventeenth, or eighteenth aspects, the other therapeutic agents are selected from CYP2C19 inhibitors, CYP2C19 inducers, CYP3A4 inhibitors, and CYP3A4 inducers.

[0135] In some implementations, such as the fourteenth, fifteenth, sixteenth, seventeenth, or eighteenth aspects, the other therapeutic agents are selected from CYP3A4 inhibitors.

[0136] In some embodiments, the CYP2C19 inhibitor is selected from weak CYP2C19 inhibitors, intermediate-potency CYP2C19 inhibitors, and strong CYP2C19 inhibitors.

[0137] In some embodiments, the CYP2C19 inducer is selected from weak, medium and strong CYP2C19 inducers.

[0138] In some embodiments, the CYP3A4 inhibitor is selected from weak, intermediate, and strong CYP3A4 inhibitors. In some embodiments, the CYP3A4 inhibitor is selected from intermediate-potency CYP3A4 inhibitors (e.g., verapamil).

[0139] In some embodiments, the CYP3A4 inducer is selected from weak CYP3A4 inducers, medium-potency CYP3A4 inducers, and strong CYP3A4 inducers.

[0140] In some implementations of this disclosure, the patient meets at least one of the following criteria:

[0141] (1) Resting LVOT-G < 30 mmHg;

[0142] (2) Valsalva LVOT-G<50mmHg;

[0143] (3) LVEF ≥ 50%;

[0144] (4) Elevated cardiac troponin levels;

[0145] (5) Elevated NT-proBNP levels;

[0146] (6) KCCQ-CSS score ≥25 and ≤90;

[0147] (7) NYHA Classification II to III;

[0148] (8) Body mass index < 35 kg / m 2 .

[0149] In some implementations, the patient's LVEF is ≥55%. In some implementations, the patient's LVEF is ≥60%.

[0150] In some embodiments, the patient's Valsalva LVOT-G is <40 mmHg. In some embodiments, the patient's Valsalva LVOT-G is <30 mmHg.

[0151] In some implementations, the patient's NT-proBNP is >300 pg / mL.

[0152] In some implementations, the patient's KCCQ-CSS score is ≥30 and ≤85.

[0153] In some embodiments, the patients described in this disclosure have received treatment with at least one of a beta-blocker (e.g., bisoprolol, metoprolol, etc.), a non-dihydropyridine calcium channel antagonist (e.g., verapamil, diltiazem, etc.), and disopyramide prior to receiving treatment with a compound of formula I or a pharmaceutically acceptable salt thereof. In some embodiments, the duration of treatment with a beta-blocker (e.g., bisoprolol, metoprolol, etc.), a non-dihydropyridine calcium channel antagonist (e.g., verapamil, diltiazem, etc.), or disopyramide is 4 weeks or more. In some embodiments, disopyramide and a beta-blocker are used in combination.

[0154] In some embodiments, the compound of formula I described herein, or a pharmaceutically acceptable salt thereof, is used in combination with other therapeutic agents selected from at least one of beta-blockers (e.g., bisoprolol, metoprolol, etc.), non-dihydropyridine calcium channel antagonists (e.g., verapamil, diltiazem, etc.), and disoprolide. In some embodiments, disoprolide is used in combination with a beta-blocker (e.g., bisoprolol, metoprolol, etc.).

[0155] In some embodiments, the resting LVOT-G or Valsalva LVOT-G described in this disclosure is determined by transthoracic echocardiography (TTE).

[0156] In some embodiments, the LVEF described in this disclosure is determined by transthoracic echocardiography.

[0157] In some embodiments, the uses, methods, Formula I compounds, or pharmaceutically acceptable salts thereof described above in this disclosure can improve at least one of the following indicators in patients with said non-obstructive hypertrophic cardiomyopathy:

[0158] (1) LVEF, LVOT-VTI, LV-FS or LV-GLS;

[0159] (2) NYHA classification;

[0160] (3) NT-proBNP levels;

[0161] (4) Cardiac troponin levels;

[0162] (5) Kansas City Cardiomyopathy Questionnaire-Clinical Summary Scoring (KCCQ-CSS);

[0163] (6) Peak oxygen uptake (pVO2) or carbon dioxide ventilation equivalent (VE / VCO2);

[0164] (7) Seattle Angina Scale (SAQ-7).

[0165] In some implementations, the post-treatment LVOT-VTI decreases by 5%–95% compared to pre-treatment levels (e.g., 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or any value between any two of these values).

[0166] In some implementations, the LV-FS decreases by 5%-95% after treatment compared to before treatment (e.g., 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or any value between any two values).

[0167] In some implementations, the NYHA classification is improved by at least one level, for example, from NYHA Level III to Level II or from NYHA Level II to Level I.

[0168] In some implementations, NT-proBNP decreases by 10%-99% after treatment compared to pre-treatment levels (e.g., 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 99%, or any value between any two). In some implementations, NT-proBNP decreases by 30%-95% after treatment compared to pre-treatment levels. In some implementations, NT-proBNP decreases by 30%-90% after treatment compared to pre-treatment levels. In some implementations, NT-proBNP decreases by 40%-90% after treatment compared to pre-treatment levels. In some implementations, NT-proBNP decreases by 60%-90% after treatment compared to pre-treatment levels. In some implementations, NT-proBNP decreases by 30%-80% after treatment compared to pre-treatment levels. In some implementation schemes, NT-proBNP decreased by 40%-80% after treatment compared to before treatment.

[0169] In some implementations, the cardiac troponin level decreases by 10%–99% after treatment compared to before treatment (e.g., 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 99%, or any value between any two values).

[0170] In some implementations, the KCCQ-CSS score improves by at least 5 points after treatment compared to before treatment. In some implementations, the KCCQ-CSS score improves by 5 to 90 points after treatment compared to before treatment (e.g., 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, or any value between any two).

[0171] In some implementations, the peak oxygen uptake (pVO2) increases by 5%-95% after treatment compared to before treatment (e.g., 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or any value between any two values).

[0172] In some implementations, the post-treatment carbon dioxide ventilatory equivalent (VE / VCO2) is increased by 5%–95% compared to pre-treatment levels (e.g., 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or any value between any two values).

[0173] In some implementations, the score on any dimension of the SAQ-7 improves by at least 5 points after treatment compared to before treatment. In some implementations, the score on any dimension of the SAQ-7 improves by 5 to 90 points after treatment compared to before treatment (e.g., 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, or any value between any two values).

[0174] In some embodiments, the Formula I compound described in this disclosure, or a pharmaceutically acceptable salt thereof, is specifically a Formula I compound.

[0175] In some embodiments, the Formula I compound or a pharmaceutically acceptable salt thereof described herein may be present in any pharmaceutically acceptable formulation, such as tablets, capsules, pills, granules, solutions, suspensions, syrups, injections (including injection solutions, sterile powders for injection, and concentrated solutions for injection), suppositories, inhalers, or sprays. In some embodiments, the Formula I compound or a pharmaceutically acceptable salt thereof described herein is present in tablet form.

[0176] In some embodiments, the compound of formula I described herein or a pharmaceutically acceptable salt thereof is administered orally.

[0177] Compared to Mavacamten and Aficamten, the present disclosure offers the following advantages in treating non-obstructive hypertrophic cardiomyopathy using a compound of formula I or a pharmaceutically acceptable salt thereof:

[0178] (1) It has a shorter time to reach stability, can reach stability quickly, and shorten the dose adjustment cycle. The time to reach stability of Mavacamten is about 6 weeks, the time to reach stability of Aficamten is about 2 weeks, and the time to reach stability of Formula I compounds or their pharmaceutically acceptable salts is only about 1 week.

[0179] (2) It has higher security and has a smaller impact on the reduction of LVEF.

[0180] (3) There are no complex restrictions on drug combinations. The compound of Formula I is mainly excreted unchanged in the urine and does not have an inhibitory or inducing effect on CYP enzymes at clinically effective doses. The instructions for use of Mavacamten explicitly prohibit the combined use of moderate to strong CYP2C19 inhibitors or strong CYP3A4 inhibitors, and prohibit the combined use of moderate to strong CYP2C19 inducers or moderate to strong CYP3A4 inducers. In addition, when using Mavacamten, avoid using dipyridamole, ranolazine, verapamil and beta-blockers, or diltiazem and beta-blockers, as these drugs and combinations increase the risk of left ventricular systolic dysfunction and heart failure.

[0181] The results of Example 2 of this disclosure show that verapamil, when used in combination with the compound of Formula I, has no significant effect on the exposure level of the compound of Formula I, and can be used in combination. The compound of Formula I disclosed in this disclosure has significant advantages over Mavacamten in terms of drug combination therapy.

[0182] Terminology Definition

[0183] To facilitate understanding of this disclosure, certain technical and scientific terms are specifically defined below. Unless otherwise expressly defined herein, all other technical and scientific terms used herein have the meanings commonly understood by one of ordinary skill in the art to which this disclosure pertains.

[0184] Unless the context clearly requires otherwise, throughout the specification and claims, the words “comprising,” “having,” “including,” etc., should be understood as having an inclusive meaning, rather than an exclusive or exhaustive meaning; that is, the meaning of “including but not limited to.”

[0185] The term “and / or”, such as “X and / or Y”, should be understood to mean “X and Y” or “X or Y” and should be used to provide clear support for both meanings or either meaning.

[0186] "Optional" or "optionally" means that the event or circumstances described below may, but do not have to, occur, including the circumstances in which the event or circumstances may or may not occur.

[0187] The term "combination" as used in this disclosure refers to a route of administration in which at least one dose of a compound of formula I or a pharmaceutically acceptable salt thereof, and at least one dose of another therapeutic agent, are administered over a specified time period, wherein all administered drugs exhibit pharmacological effects. The time period may be within a dosing cycle, preferably within 4 weeks, 3 weeks, 2 weeks, 1 week, or within 24 hours, more preferably within 12 hours. The compound of formula I or a pharmaceutically acceptable salt thereof, and the other therapeutic agent may be administered simultaneously or sequentially. This period includes treatment in which the compound of formula I or a pharmaceutically acceptable salt thereof, and the other therapeutic agent, are administered via the same or different routes of administration. The routes of administration for the combination described in this disclosure are selected from simultaneous administration, independently formulated and co-administered administration, or independently formulated and sequentially administered administration.

[0188] The term "effective amount" or "therapeutic effective amount" as used in this disclosure includes an amount sufficient to improve or prevent symptoms or conditions of a medical condition. An effective amount also means an amount sufficient to allow or facilitate diagnosis. The effective amount for a particular patient or veterinary subject may vary depending on factors such as the condition to be treated, the patient's overall health, the route and dosage of administration, and the severity of side effects. An effective amount may be the maximum dose or administration regimen that avoids significant side effects or toxicity.

[0189] The “unit dose” or “dosage dose” mentioned in this disclosure refers to the amount calculated based on the free base of the compound of formula I.

[0190] The term "pharmaceutically acceptable salt" refers to both pharmaceutically acceptable acid addition salts and pharmaceutically acceptable base addition salts.

[0191] "Pharmaceutically acceptable acid addition salts" are salts formed with inorganic or organic acids that retain the bioavailability of the free base without other side effects. These salts can be prepared by methods known in the art.

[0192] "Pharmaceutically acceptable base addition salts" are salts formed with inorganic or organic bases that retain the bioavailability of the free acid without other side effects. These salts can be prepared by methods known in the art.

[0193] The numerical values ​​in this disclosure are subject to a certain degree of error, for example, as indicated by the term "about". Generally, ±10% is within the reasonable error range. Of course, the context in which the value is used must be considered, for example, the particle size of the active ingredient, where the value, representing a variation in error after measurement not exceeding ±10%, can be ±9%, ±8%, ±7%, ±6%, ±5%, ±4%, ±3%, ±2%, or ±1%, preferably ±5%.

[0194] As used publicly, the terms “subject,” “patient,” “subject,” or “individual” are used interchangeably to refer to mammals, especially primates, and particularly humans.

[0195] The term "elevated cardiac troponin level" refers to a concentration of cardiac troponin (cTn) complex protein in a blood sample that exceeds the concentration in a healthy reference population. The upper limit of normal (ULN) is typically determined most accurately by individual assays or detection methods. Cardiac troponin forms a trimeric complex (T:I:C) that binds to thin filaments. According to this disclosure, changes in the cardiac troponin complex or its protein components comprising said complex to be measured in a blood sample are preferably detected by detecting cardiac troponin I (cTnI) or cardiac troponin T (cTnT). In one embodiment, the blood sample is a plasma or serum sample. In one embodiment, elevated troponin levels are detected by an immunoassay.

[0196] The term "elevated NT-proBNP level" refers to an NT-proBNP concentration in a blood sample that is higher than normal. In some implementations, NT-proBNP >300 pg / mL is defined as the level in patients with non-obstructive hypertrophic cardiomyopathy.

[0197] The term “prevention” refers to any effect of inhibiting or delaying the onset of a disease (symptom) by administering a compound of Formula I or a pharmaceutically acceptable salt thereof.

[0198] The term "treatment" refers to any effect of improving or beneficially altering the symptoms of a suspected or ill individual by administering a compound of Formula I or a pharmaceutically acceptable salt thereof.

[0199] The term "improvement" refers to a beneficial change in the degree, severity, at least one indicator, frequency, and / or likelihood of a particular disease's symptoms or clinical signs. "Symptoms" refers to any subjective sign of a disease or individual condition.

[0200] BID: Twice a day.

[0201] MAD: Multiple dose escalation trials.

[0202] Wn refers to week n, for example, W2, W3, and W4 refer to week 2, week 3, and week 4 respectively. Attached Figure Description

[0203] The novel features of the invention are specifically set forth in the appended claims. The features and advantages of the invention will be better understood by referring to the following detailed description and accompanying drawings, which illustrate exemplary embodiments utilizing the principles of the invention, in which:

[0204] Figure 1 is a graph showing the percentage change in KCCQ-CSS from baseline over time. Detailed Implementation Plan

[0205] Example 1: Safety, tolerability, pharmacokinetics, and pharmacodynamics of oral administration of drug A to healthy subjects.

[0206] 1. Drug Information: Drug A, tablets, the active ingredient is a compound of formula I (prepared according to Example 16 in WO2022105852A1), manufactured by Shandong Shengdi Pharmaceutical Co., Ltd.

[0207] Specifications: 2.5mg / tablet, 10mg / tablet, 20mg / tablet

[0208] Usage and dosage:

[0209] Single dose, orally, once daily, 5, 15, 30, 50, or 75 mg.

[0210] Administer multiple times orally, twice daily, 10, 20, or 40 mg each time.

[0211] 2. Inclusion criteria

[0212] Healthy subjects:

[0213] (1) Age ≥ 18 years old and ≤ 55 years old, gender not limited;

[0214] (2) Body Mass Index (BMI) 19~28kg / m 2 (Including boundary values), male weight ≥ 50.0 kg and < 90.0 kg, female weight ≥ 45.0 kg and < 90.0 kg;

[0215] (3) No clinically significant abnormalities were found after a comprehensive physical examination and laboratory tests.

[0216] 3. Results

[0217] The distribution of adverse events in the drug A group and the placebo group of healthy subjects was relatively balanced, indicating good safety and tolerability.

[0218] In healthy subjects, single doses of drug A at doses of 5 mg, 15 mg, 30 mg, 50 mg, and 75 mg resulted in rapid absorption, reaching peak concentration approximately 1–2 hours after administration, with an average half-life of 56.4–92.0 hours. In healthy subjects, drug A was administered twice daily at doses of 10 mg, 20 mg, and 40 mg for 14 consecutive days. Steady-state concentrations were reached on day 8 after administration, and the pharmacokinetic (PK) characteristics at steady state were similar to those of the initial dose. max The accumulations were 1.5, 1.38, and 1.6, respectively; AUC tau The accumulations were 1.8, 2.05, and 2.63, respectively.

[0219] In healthy subjects, single doses of 15 mg, 30 mg, and 50 mg were administered. The results showed that the renal clearance rate of compound I within 0-120 h (168 h) was 28.0-43.1 mL / min, which was similar to the blood clearance rate during the corresponding time period, indicating that compound I was mainly excreted unchanged via the kidneys.

[0220] The LVEF value was slightly lower than the baseline, but the LVEF level of the subjects was greater than 50%.

[0221] Example 2: Study on the pharmacokinetic effects of verapamil tablets on drug A

[0222] 1. Study population: Healthy subjects aged 18–55 years (inclusive)

[0223] 2. Drug Information

[0224] Drug A, tablets, 20 mg / tablet, active ingredient is compound of formula I.

[0225] Verapamil, tablets, 40mg / tablet, manufactured by Tianjin Central Pharmaceutical Co., Ltd.

[0226] 3. Dosage regimen: On day 1, take 40 mg of drug A orally on an empty stomach once; from day 8 to day 18, take 80 mg of verapamil tablets orally three times a day; on day 12, take 40 mg of drug A on an empty stomach in the morning.

[0227] 4. Inclusion criteria

[0228] (1) Age 18-55 (inclusive), gender not limited;

[0229] (2) Body Mass Index (BMI) 19.0~28.0 kg / m 2 (Including boundary values), male weight ≥ 50.0 kg and < 90.0 kg, female weight ≥ 45.0 kg and < 90.0 kg;

[0230] (3) No clinically significant abnormalities were found in the comprehensive physical examination (vital signs, physical examination, etc.) and laboratory tests (complete blood count, blood biochemistry, routine urine, coagulation function), cardiac troponin, NT-proBNP, abdominal ultrasound and chest imaging examinations, or minor abnormalities (such as hemangioma, cyst, calcification, nodule, etc.) that the researchers judged would not affect the enrollment of the subjects.

[0231] (4) No clinically significant abnormalities were found in the 12-lead electrocardiogram;

[0232] (5) No clinically significant abnormalities on transthoracic echocardiography (LVEF must be ≥55%).

[0233] 5. Test Results

[0234] A total of 14 healthy subjects were enrolled. Both oral administration of 40 mg of drug A alone and in combination with verapamil showed good safety and tolerability.

[0235] In this study, during both the monotherapy and combination therapy periods with verapamil, the plasma AUC of drug A was measured after a single oral dose of 40 mg of drug A in the subjects. 0-t The geometric means were 7840 and 10200 h*ng / ml, respectively; AUC 0-inf The geometric means were 8870 and 11700 h*ng / ml, respectively; C max The geometric means were 1050 and 1120 ng / mL, respectively; the geometric means of CL / F were 75.2 and 56.8 mL / min, respectively; T max The median values ​​were 1.00 and 1.25h, respectively; t 1 / 2 The average values ​​were 79.2 and 80.3 h, respectively; V z The geometric mean of / F is 512 and 391L, respectively.

[0236] The results of the mixed-effects model analysis showed that the period of combined use of drug A and verapamil and the period of drug A monotherapy C max AUC 0-t AUC 0-inf The least squares geometric mean ratio (combination therapy / monotherapy phase) and its 90% confidence interval were 1.06 (0.89, 1.26), 1.30 (1.23, 1.39), and 1.32 (1.24, 1.41), respectively. These results indicate that the combination use of verapamil reduces the C of drug A. max Increase by 6%, AUC 0-t Increase by 30%, AUC 0-inf Increased by 32%, t 1 / 2 No significant changes.

[0237] In this study, during the monotherapy and combination therapy with verapamil phases of drug A, the cumulative urinary excretion after a single oral dose of 40 mg drug A was 17.9 mg and 24.0 mg, respectively. The renal clearance (CLr) was 40.7 and 41.2 mL / min, respectively, and the cumulative excretion fractions were 44.8% and 59.9%, respectively. The cumulative excretion of drug A during the combination therapy phase increased by 34% compared to the monotherapy phase, which paralleled the increase in plasma AUC. No significant change in CLr was observed.

[0238] The above results indicate that the combined use of verapamil did not significantly affect the exposure of drug A, suggesting that no dose adjustment is required when drug A is used in combination with verapamil, and supporting the combined use of verapamil and drug A.

[0239] Example 3: Efficacy and safety study of drug A in the treatment of non-obstructive hypertrophic cardiomyopathy

[0240] 1. Study population: Subjects with non-obstructive hypertrophic cardiomyopathy

[0241] 2. Drug Information: Drug A, tablets, active ingredient is compound of formula I, manufactured by Shandong Shengdi Pharmaceutical Co., Ltd.; specification: 20mg / tablet.

[0242] 3. Inclusion criteria

[0243] (1) Age 18-85 (inclusive), gender not limited;

[0244] (2) Body mass index < 35 kg / m 2 ;

[0245] (3) HCM is diagnosed according to the following criteria: (1) Any cardiac imaging examination, such as echocardiography, cardiac magnetic resonance imaging, or cardiac CT imaging, reveals a maximum end-diastolic ventricular wall thickness of ≥15 mm in one or more left ventricular segments. (2) For family members other than the proband in familial HCM, or individuals who test positive for gene testing (carrying HCM pathogenic gene variants), a maximum end-diastolic ventricular wall thickness of ≥13 mm can also be diagnosed as HCM;

[0246] (4) During screening, echocardiographic laboratory measurements showed LVEF ≥ 60%;

[0247] (5) Patients receiving beta-blockers, diltiazem, disopyramide, verapamil, or ranolazine should have been on a stable dose for at least 4 weeks prior to randomization and are expected to maintain the same treatment regimen throughout this trial. Patients taking disopyramide must also be taking a beta-blocker.

[0248] (6) At screening, both resting and Valsalva LVOT-G levels were <30 mmHg;

[0249] (7) NT-proBNP > 300 pg / mL during screening;

[0250] (8) The KCCQ-CSS score during screening must be ≥30 and ≤85;

[0251] (9) NYHA classification II to III during screening.

[0252] 4. Dosing regimen

[0253] 4.1 Treatment period

[0254] The starting dose is 20 mg twice daily (BID).

[0255] Low-dose titration group: Dose adjustments were made at W2 and W3 based on the LVEF results of TTE measurements performed on subjects at W2 and W3, with dose increases only permitted at W2. Each dose adjustment was in increments of 20 mg, with dose ranges of 20 mg BID and 40 mg BID. Treatment lasted for 12 weeks.

[0256] High-dose titration group: Dose adjustments were made at W2, W3, and W4 based on the LVEF results of TTE measurements performed on subjects at W2, W3, and W4, with dose increases only permitted at W2 and W3. Each dose adjustment increment was 20 mg, with dose ranges of 20 mg BID, 40 mg BID, and 60 mg BID. Treatment lasted for 12 weeks.

[0257] 4.2 Dosage tapering and discontinuation period

[0258] After completing the treatment period, subjects will enter a 0-2 week dose-stepping phase (depending on the dose at the end of the treatment period). Starting from the original treatment dose, subjects will gradually reduce the dose in increments of 20 mg BID, taking each reduced dose for one week before proceeding with the next dose reduction, until the dose is reduced to 20 mg BID. This is followed by another week of continued dose reduction, after which the medication will be completely discontinued. If the final maintenance dose for the treatment period is 20 mg BID, no dose-stepping phase is required.

[0259] 5. Dosage adjustment plan

[0260] 5.1 Dosage Adjustment

[0261] The specific rules are as follows:

[0262] 5.2 Discontinue medication:

[0263] If, when receiving a 20 mg BID dose, 45% ≤ LVEF < 50% in the subject, the investigator should assess the subject and consider discontinuing the medication.

[0264] If any of the following criteria are met during any random visit during the treatment period, administration of the investigational drug should be suspended upon receiving the results:

[0265] 1) During the study, LVEF was <45% twice on the same day;

[0266] 2) AEs that researchers determine require discontinuation of medication.

[0267] 5.3 Resuming dosing after a pause:

[0268] 6. Results

[0269] A total of 84 subjects were enrolled, with 28 in the low-dose group, 28 in the high-dose group, and 28 in the placebo group.

[0270] 6.1 Safety results: Drug A has good safety and tolerability.

[0271] 6.2 Validity Results:

[0272] KCCQ-CSS: As shown in Figure 1, after 12 weeks of treatment, drug A numerically improved KCCQ-CSS compared to the placebo group, and this improvement was maintained for 12 weeks.

[0273] NT-proBNP and cTnI: As shown in the table below, after 12 weeks of treatment, drug A significantly reduced NT-proBNP and cTnI levels compared to the placebo group. Furthermore, both the low-dose and high-dose groups of drug A were significantly better than the placebo group.

Claims

1. Use of a compound of formula I or a pharmaceutically acceptable salt thereof in the preparation of a medicament for the prevention and / or treatment of non-obstructive hypertrophic cardiomyopathy.

2. The use according to claim 1, wherein the patient with the non-obstructive hypertrophic cardiomyopathy meets at least one of the following criteria: (1) Resting LVOT-G < 30 mmHg; (2) Valsalva LVOT-G<50mmHg; (3) LVEF ≥ 50%; (4) NT-proBNP > 300 pg / mL; (5) KCCQ-CSS score ≥25 and ≤90; (6) NYHA classification II to III.

3. The use according to claim 2, wherein the patient's LVEF is ≥55%, preferably ≥60%; And / or, the patient's Valsalva LVOT-G < 40 mmHg, preferably Valsalva LVOT-G < 30 mmHg.

4. The use according to any one of claims 1-3, wherein the unit dose or administration dose of the compound of formula I or a pharmaceutically acceptable salt thereof, based on the free base of the compound, is selected from 1-300 mg, preferably from 1-200 mg, more preferably from 5-100 mg, further preferably 10 mg, 20 mg, 30 mg, 40 mg, 50 mg, 60 mg, 70 mg or 80 mg, and even more preferably 20 mg, 40 mg or 60 mg.

5. The use according to any one of claims 1-4, wherein the compound of formula I or a pharmaceutically acceptable salt thereof is administered three times a day, twice a day, once a day, once every two days, once every three days, once every four days, once every five days, once every six days, or once a week, preferably twice a day or once a day, more preferably twice a day.

6. The use according to any one of claims 1-5, wherein the dosage and frequency of administration of the compound of formula I or a pharmaceutically acceptable salt thereof are any of the following: (1) The unit dose or administration dose of the compound of Formula I or its pharmaceutically acceptable salt is selected from 1-200 mg, and the administration frequency is three times a day, twice a day or once a day. (2) The unit dose or administration dose of the compound of Formula I or its pharmaceutically acceptable salt is selected from 5-100 mg, and the administration frequency is twice a day or once a day. (3) The unit dose or administration dose of the compound of formula I or its pharmaceutically acceptable salt is 10 mg, 20 mg, 30 mg, 40 mg, 50 mg, 60 mg, 70 mg or 80 mg, and the administration frequency is twice a day or once a day; (4) The unit dose or administration dose of the compound of formula I or a pharmaceutically acceptable salt thereof is 10 mg, 20 mg, 30 mg, 40 mg, 50 mg, 60 mg, 70 mg or 80 mg, and the administration frequency is twice a day; (5) The unit dose or administration dose of the compound of formula I or a pharmaceutically acceptable salt thereof is 20 mg, 40 mg or 60 mg, and the administration frequency is twice a day.

7. The use according to any one of claims 1-6, wherein the administration period of the compound of formula I or a pharmaceutically acceptable salt thereof is at least 1 week, preferably at least 4 weeks, more preferably at least 12 weeks.

8. The use according to any one of claims 1-7, wherein the use improves at least one of the following indicators in patients with the non-obstructive hypertrophic cardiomyopathy: (1) LVEF, LVOT-VTI, LV-FS or LV-GLS; (2) NYHA classification; (3) NT-proBNP levels; (4) Cardiac troponin levels; (5) Kansas City Cardiomyopathy Questionnaire-Clinical Summary Scoring (KCCQ-CSS); (6) Peak oxygen uptake (pVO2) or carbon dioxide ventilation equivalent (VE / VCO2); (7) Seattle Angina Scale (SAQ-7).

9. Use of a compound of formula I or a pharmaceutically acceptable salt thereof in the preparation of a medicament for the prevention and / or treatment of non-obstructive hypertrophic cardiomyopathy, wherein the compound of formula I or a pharmaceutically acceptable salt thereof is used in combination with other therapeutic agents selected from at least one of β-blockers, non-dihydropyridine calcium channel antagonists, and disopyramide.

10. The use according to any one of claims 1-9, wherein the compound of formula I or a pharmaceutically acceptable salt thereof is a compound of formula I.

11. The use according to any one of claims 1-9, wherein the compound of formula I or a pharmaceutically acceptable salt thereof is present in tablet form; And / or, the compound of formula I or a pharmaceutically acceptable salt thereof is administered orally.

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