Use in preparation of drug for treating hypertrophic cardiomyopathy

Abstract

The present disclosure relates to a use in the preparation of a drug for treating hypertrophic cardiomyopathy. Specifically, the present disclosure relates to a use of a compound as represented by formula I, or a pharmaceutically acceptable salt thereof, in the preparation of a drug for preventing and / or treating hypertrophic cardiomyopathy. Compared with Mavacamten and Aficamten, the use of the present disclosure exhibits a shorter steady-state attainment time, a higher safety profile, and no complex restrictions on concomitant drug use.

Description

Uses in the preparation of drugs for treating hypertrophic cardiomyopathy

[0001] This application claims priority to application No. CN202411869183.0 filed on December 18, 2024 and application No. CN202511501373.1 filed on October 21, 2025, the disclosures of which are incorporated herein by reference in their entirety. Technical Field

[0002] This disclosure pertains to the pharmaceutical field and relates to the use of a preparation of a drug for treating hypertrophic cardiomyopathy. Background Technology

[0003] Hypertrophic cardiomyopathy (HCM) is a primary cardiomyopathy characterized by left ventricular hypertrophy. It is the most common inherited heart disease and the leading cause of sudden cardiac death in adolescents and athletes. Current treatment options for HCM are limited, primarily including lifestyle interventions, drug therapy, and ventricular septal reduction surgery (alcohol ventricular septal ablation and ventricular septal myocardectomy). Drug therapy includes beta-blockers (bisoprolol, metoprolol, etc.), non-dihydropyridine calcium channel blockers (verapamil, diltiazem), and disopyramide, but existing drugs are not disease-specific, leading to inadequate treatment or poor tolerability. Furthermore, surgical treatment carries risks such as arrhythmias and ventricular septal perforation, resulting in poor patient compliance. Therefore, there is an urgent clinical need for drugs that target the pathological mechanisms of HCM, have proven efficacy, and offer good safety profiles.

[0004] The most advanced myosin inhibitor currently under development is Mavacamten (MYK-461), the first small-molecule allosteric inhibitor targeting cardiac myosin, jointly developed by Myokardia / Bristol-Myers Squibb and LinkoBio. It is administered once daily and requires 6 weeks to reach stability. In April 2022, MYK-461 received FDA approval for the treatment of symptomatic oHCM in NYHA class II-III. In June 2023, MYK-461 received EMA approval for the treatment of symptomatic obstructive hypertrophic cardiomyopathy. However, Mavacamten, as a breakthrough therapy for hypertrophic cardiomyopathy, still has many limitations: (1) the response rate to reducing the left ventricular outflow tract pressure gradient needs to be improved; (2) the risk of heart failure: the safety window of Mavacamten is relatively narrow, which may increase the risk of heart failure caused by systolic dysfunction. Therefore, it is marketed with a "risk of heart failure" warning in Europe, the United States and China; (3) the dose can only be adjusted every 12 weeks, the dose adjustment cycle is as long as 9 months, and the dosing regimen is complicated; (4) there are many restrictions on drug interactions. Mavacamten is mainly metabolized by CYP2C19 and CYP3A4 enzymes. Thankfully, concomitant use of drugs that interact with these enzymes may lead to life-threatening drug interactions, such as heart failure or loss of efficacy. Its main metabolic pathways are CYP2C19 (74%), CYP3A4 (18%), and CYP2C9 (8%). After a single administration of 25 mg of radiolabeled MYK-461, the recovery rates in feces and urine were 7% (1% unchanged) and 85% (3% unchanged), respectively. The product information explicitly prohibits concomitant use with moderate to strong CYP2C19 inhibitors or strong CYP3A4 inhibitors, or moderate to strong CYP2C19 inducers or moderate to strong CYP3A4 inducers. These limitations significantly restrict its clinical use.

[0005] Aficamten (CK-274) is another small molecule inhibitor of cardiac myosin, jointly developed by Cytokinetics and Jixing Pharmaceutical. It is suitable for once-daily dosing and achieves stable results in two weeks. Summary of the Invention

[0006] 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 hypertrophic cardiomyopathy (HCM), wherein the patient with HCM has a left ventricular ejection fraction (LVEF) ≥50%.

[0007] Secondly, this disclosure provides a method for preventing and / or treating hypertrophic cardiomyopathy (HCM) in patients in need, comprising administering to the patient a therapeutically effective amount of the compound of formula I above or a pharmaceutically acceptable salt thereof, wherein, prior to administration of the compound of formula I above or a pharmaceutically acceptable salt thereof, the patient meets at least one of the following criteria:

[0008] (1) LVEF ≥ 50%;

[0009] (2) Elevated cardiac troponin levels;

[0010] (3) Elevated NT-proBNP.

[0011] Thirdly, this disclosure provides a method for preventing and / or treating hypertrophic cardiomyopathy (HCM) 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 who meets at least one of the following criteria:

[0012] (1) LVEF ≥ 50%;

[0013] (2) Elevated cardiac troponin levels;

[0014] (3) Elevated NT-proBNP.

[0015] Fourthly, this disclosure provides a method for reducing at least one of Valsalva LVOT-G, cardiac troponin, and NT-proBNP levels, comprising administering a therapeutically effective amount of the aforementioned compound of formula I or a pharmaceutically acceptable salt thereof to a patient suffering from hypertrophic cardiomyopathy.

[0016] Fifthly, this disclosure also provides a method for reducing at least one of Valsalva LVOT-G, cardiac troponin, and 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 hypertrophic cardiomyopathy.

[0017] In some implementation schemes, in the first, second, third, fourth, or fifth aspects, the hypertrophic cardiomyopathy is obstructive hypertrophic cardiomyopathy (oHCM).

[0018] In some implementation schemes, the hypertrophic cardiomyopathy is classified as New York Heart Association (NYHA) Class II to III in the first, second, third, fourth, or fifth aspects.

[0019] In some implementations, in the fourth or fifth aspect, the patient's LVEF is ≥50%.

[0020] In some implementations, in the first, second, third, fourth, or fifth aspect, the patient's LVEF is ≥55%.

[0021] In some implementations, in the first, second, third, fourth, or fifth aspect, the patient's LVEF is ≥60%.

[0022] In some implementations, in the first, second, third, fourth, or fifth aspect, the patient's resting left ventricular outflow tract pressure gradient (LVOT-G) is ≥50 mmHg.

[0023] In some implementations, in the first, second, third, fourth, or fifth aspect, the patient's resting LVOT-G is ≥30 mmHg and the left ventricular outflow tract pressure gradient (Valsalva LVOT-G) after Valsalva maneuver is ≥50 mmHg.

[0024] In some embodiments, 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).

[0025] In some embodiments, 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, 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 5-150 mg.

[0027] In some embodiments, 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 5 mg, 15 mg, 20 mg, 30 mg, 40 mg, 50 mg, 60 mg, 75 mg, 80 mg, 100 mg, or 120 mg.

[0028] In some embodiments, 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, 60 mg, 80 mg, or 120 mg.

[0029] In some embodiments, 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, 60 mg, or 80 mg.

[0030] In some embodiments, 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 40 mg, 80 mg, or 120 mg.

[0031] In some embodiments, 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, 10 mg, 20 mg, or 40 mg.

[0032] In some implementations, in the first, second, third, fourth, or fifth aspect, 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.

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

[0034] In some implementations, in the first, second, third, fourth, or fifth aspect, the compound of formula I or a pharmaceutically acceptable salt thereof is administered twice or once a day.

[0035] In some implementations, in the first, second, third, fourth, or fifth aspect, the compound of formula I or a pharmaceutically acceptable salt thereof is administered twice daily.

[0036] In some implementations, 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 frequency of administration is 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.

[0037] In some embodiments, 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.

[0038] In some embodiments, 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 5-150 mg, and the frequency of administration is twice or once a day.

[0039] In some embodiments, in the first, second, third, fourth or fifth aspect, the unit dose or administration dose of the compound of formula I or a pharmaceutically acceptable salt thereof is 5 mg, 15 mg, 20 mg, 30 mg, 40 mg, 50 mg, 60 mg, 75 mg, 80 mg, 100 mg or 120 mg, and the administration frequency is twice a day or once a day.

[0040] In some embodiments, in the first, second, third, fourth or fifth aspect, the unit dose or administration dose of the compound of formula I or a pharmaceutically acceptable salt thereof is 20 mg, 40 mg, 60 mg or 80 mg, and the administration frequency is twice a day.

[0041] In some embodiments, 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 40 mg, 80 mg or 120 mg, and the administration frequency is once a day.

[0042] In some embodiments, 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 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). The administration period may be 2 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, 2 years, 3 years, 4 years or longer, or even permanently. In some embodiments, 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, 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 12 weeks. In some embodiments, 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 12 to 16 weeks. In some embodiments, 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 12 weeks. In some embodiments, 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 24 to 36 weeks. In some embodiments, 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 permanent.

[0043] In some implementations, in the fourth or fifth aspect, the Valsalva LVOT-G is reduced to ≤50 mmHg (e.g., <50 mmHg).

[0044] In some implementations, in the fourth or fifth aspect, the Valsalva LVOT-G is reduced to ≤50 mmHg (e.g., <50 mmHg) and LVEF ≥50% (e.g., LVEF ≥55% or LVEF ≥60%).

[0045] In some implementations, in the fourth or fifth aspect, the Valsalva LVOT-G is reduced to ≤50 (e.g., <50 mmHg), and 50% ≤ LVEF ≤ 60%.

[0046] In some implementations, in the fourth or fifth aspect, the Valsalva LVOT-G is reduced to ≤50 mmHg (e.g., <50 mmHg), and 50% ≤ LVEF < 55%.

[0047] In some implementations, in the fourth or fifth aspect, the Valsalva LVOT-G is reduced to ≤30 mmHg (e.g., <30 mmHg).

[0048] In some implementations, in the fourth or fifth aspect, the Valsalva LVOT-G is reduced to ≤30 mmHg (e.g., <30 mmHg) and LVEF ≥50% (e.g., LVEF ≥55% or LVEF ≥60%).

[0049] In some implementations, in the fourth or fifth aspect, the Valsalva LVOT-G is reduced to ≤30 mmHg (e.g., <30 mmHg), and 50% ≤ LVEF ≤ 60%.

[0050] In some implementations, in the fourth or fifth aspect, the Valsalva LVOT-G is reduced to ≤30 mmHg (e.g., <30 mmHg) and 50% ≤ LVEF < 55%.

[0051] In some implementations, in the fourth or fifth aspect, the Valsalva LVOT-G is reduced to ≥30 mmHg and LVEF ≥50%.

[0052] In some implementations, in the fourth or fifth aspect, the Valsalva LVOT-G is reduced to 30 mmHg ≤ Valsalva LVOT-G ≤ 50 mmHg, and LVEF ≥ 50%.

[0053] In some implementations, in the fourth or fifth aspect, the Valsalva LVOT-G is reduced to ≥30 mmHg and 50% ≤ LVEF ≤ 60%.

[0054] In some implementations, in the fourth or fifth aspect, the Valsalva LVOT-G is reduced to 30 mmHg ≤ Valsalva LVOT-G ≤ 50 mmHg, and 50% ≤ LVEF ≤ 60%.

[0055] In some implementations, in the fourth or fifth aspect, the Valsalva LVOT-G is reduced to ≥30 mmHg and 50% ≤ LVEF < 55%.

[0056] In some implementations, in the fourth or fifth aspect, the Valsalva LVOT-G is reduced to 30 mmHg ≤ Valsalva LVOT-G ≤ 50 mmHg, and 50% ≤ LVEF < 55%.

[0057] In some implementations, in the fourth or fifth aspect, the patient's resting LVOT-G is reduced to ≤30 mmHg.

[0058] In some embodiments, in the fourth or fifth aspect, the cardiac troponin is cardiac troponin I (cTnI) or cardiac troponin T (cTnT).

[0059] In some implementations, in the first aspect, the use includes the following steps:

[0060] (a) After administration of the compound of Formula I or a pharmaceutically acceptable salt thereof at an initial dose for at least 1 week.

[0061] (b) Assess the patient’s Valsalva LVOT-G and / or LVEF, and then administer the Formula I compound or a pharmaceutically acceptable salt thereof at the original or adjusted dose for at least 1 week.

[0062] In some embodiments, in step (a), the initial dose is selected from 10-80 mg, based on the free base of the compound of formula I.

[0063] In some embodiments, in step (a), the initial dose is selected from 20-80 mg, based on the free base of the compound of formula I.

[0064] In some embodiments, in step (a), the initial dose is 20 mg, 40 mg, 60 mg or 80 mg, based on the free base of the compound of formula I.

[0065] In some embodiments, in step (a), the initial dose is selected from 20-60 mg, based on the free base of the compound of formula I.

[0066] In some embodiments, in step (a), the initial dose is 20 mg or 40 mg, calculated as the free base of the compound of formula I.

[0067] In some implementations, in step (a), the initial dose is administered three times a day, twice a day, or once a day.

[0068] In some implementations, in step (a), the initial dose is administered twice a day or once a day.

[0069] In some implementations, in step (a), the initial dose is administered twice a day.

[0070] In some implementations, in step (a), the initial dose is administered once a day.

[0071] In some implementations, in step (a), the initial dose is selected from 5-100 mg, and the dosing frequency is three times a day, twice a day, or once a day.

[0072] In some implementations, in step (a), the initial dose is selected from 10-80 mg, and the dosing frequency is three times a day, twice a day, or once a day.

[0073] In some implementations, in step (a), the initial dose is selected from 20-80 mg, and the dosing frequency is twice a day or once a day.

[0074] In some implementations, in step (a), the initial dose is selected from 20-60 mg, and the dosing frequency is twice a day or once a day.

[0075] In some implementations, in step (a), the initial dose is 20 mg or 40 mg, and the dosing frequency is twice a day.

[0076] In some implementations, in step (a), the initial dose is 40 mg, and the administration frequency is once a day.

[0077] In some embodiments, in step (b), the adjustment of the adjusted dosage (e.g., increasing or decreasing) 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, in step (b), the adjustment of the adjusted dosage is selected from 10-60 mg. In some embodiments, in step (b), the adjustment of the dosage is selected from 20-40 mg. In some embodiments, in step (b), the adjustment of the adjusted dosage is 20 mg or 40 mg. In some embodiments, in step (b), the adjustment of the adjusted dosage is 20 mg.

[0078] In some implementations, in step (b), the frequency of administration of the original dose or the adjusted dose is the same as the frequency of administration of the initial dose.

[0079] In some implementations, in step (b), when Valsalva LVOT-G ≥ 30 mmHg and LVEF ≥ 55%, the dosage is increased based on the original dosage.

[0080] In some implementations, in step (b), the original dosage is maintained when Valsalva LVOT-G < 30 mmHg and LVEF ≥ 55%, or Valsalva LVOT-G ≥ 30 mmHg and 50% ≤ LVEF < 55%.

[0081] In some implementations, in step (b), when Valsalva LVOT-G < 30 mmHg and 50% ≤ LVEF < 55%, the dosage is reduced from the original dosage.

[0082] In some implementations, in step (b), administration of the Formula I compound or its pharmaceutically acceptable salt is suspended when LVEF < 50% or a serious adverse reaction occurs.

[0083] In some implementations, in step (b), when LVEF < 50%, the administration of Formula I compound or its pharmaceutically acceptable salt is suspended.

[0084] In some implementations, 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, 31 weeks, 3...). 2 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, 2 years, 3 years, 4 years or longer, or even permanently).

[0085] In some implementations, step (b) may be repeated multiple times, such as two, three, or more times. In some implementations, step (b) is repeated twice. In some implementations, step (b) is repeated three times.

[0086] In some embodiments, the dosage may be adjusted optionally at week 2, week 3, or week 4 after initial administration. In some embodiments, week 2 is day 8 after initial administration. In some embodiments, week 3 is day 15 after initial administration. In some embodiments, week 4 is day 22 after initial administration.

[0087] In some implementations, in step (b), the administration period for the original or adjusted dosage 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, ...). (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, 2 years, 3 years, 4 years or longer, or even permanently). In some implementations, the adjustment magnitude in step (b) may be the same or different each time. In some implementations, the adjustment magnitude in step (b) may be the same each time.

[0088] In some implementations, in the first aspect, the use includes the following steps:

[0089] (a) After administration of the compound of Formula I or a pharmaceutically acceptable salt thereof at an initial dose for at least 1 week.

[0090] (b) Assess the patient’s Valsalva LVOT-G and / or LVEF, and then administer the Formula I compound or a pharmaceutically acceptable salt thereof at the original or adjusted dose for at least 1 week;

[0091] (c) Assess the patient’s Valsalva LVOT-G and / or LVEF, and then administer the Formula I compound or a pharmaceutically acceptable salt thereof at the original or adjusted dose for at least 1 week.

[0092] In some implementations, the use includes the following steps:

[0093] (a) After administration of the compound of Formula I or a pharmaceutically acceptable salt thereof at an initial dose for at least 1 week.

[0094] (b) Assess the patient’s Valsalva LVOT-G and / or LVEF, and then administer the Formula I compound or a pharmaceutically acceptable salt thereof at the original or adjusted dose for at least 1 week;

[0095] (c) Assess the patient’s Valsalva LVOT-G and / or LVEF, and then administer the Formula I compound or a pharmaceutically acceptable salt thereof at the original or adjusted dose for at least 1 week;

[0096] (d) Assess the patient’s Valsalva LVOT-G and / or LVEF, and then administer the Formula I compound or a pharmaceutically acceptable salt thereof at the original or adjusted dose for at least 1 week.

[0097] In some embodiments, after administration of the Formula I compound or a pharmaceutically acceptable salt thereof for 4 weeks, the Formula I compound or a pharmaceutically acceptable salt thereof is subsequently administered at a maintenance dose for at least 1 week, the maintenance dose being the same as the dose administered in the 4th week.

[0098] In some embodiments, 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, 3...). 3 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, 2 years, 3 years, 4 years or longer, or even permanently).

[0099] In some embodiments, 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 or 40 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 40 mg.

[0100] In some embodiments, when LVEF < 50% or a serious adverse reaction occurs, administration of Formula I compound or a pharmaceutically acceptable salt thereof is suspended, and the use further includes restarting administration of Formula I compound or a pharmaceutically acceptable salt thereof to the patient for at least 1 week. In some embodiments, administration of Formula I compound or a pharmaceutically acceptable salt thereof to the patient is restarted for at least 1 week after LVEF increases to LVEF ≥ 50% or the serious adverse reaction resolves or stabilizes.

[0101] In some implementations, the restarted dosing dose is the same as or lower than the dosing dose before the suspension.

[0102] In some implementations, administration of Formula I compound or its pharmaceutically acceptable salt to the patient is restarted for at least 1 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, 2 years, 3 years, 4 years or longer, or even permanently).

[0103] Sixthly, this disclosure provides a method for preventing and / or treating hypertrophic cardiomyopathy (HCM), comprising the following steps:

[0104] (a) After administering an initial dose of the aforementioned Formula I compound or a pharmaceutically acceptable salt thereof to the patient for at least one week.

[0105] (b) Assess the patient’s Valsalva LVOT-G and / or LVEF, and then administer the patient the original or adjusted dose of a Formula I compound or a pharmaceutically acceptable salt thereof for at least 1 week.

[0106] In a seventh aspect, this disclosure also provides a compound of formula I or a pharmaceutically acceptable salt thereof for a method of preventing and / or treating hypertrophic cardiomyopathy (HCM), the method comprising the steps of:

[0107] (a) After administering an initial dose of the compound of formula I above or a pharmaceutically acceptable salt thereof to the patient for at least one week.

[0108] (b) Assess the patient’s Valsalva LVOT-G and / or LVEF, and then administer the patient the original or adjusted dose of a Formula I compound or a pharmaceutically acceptable salt thereof for at least 1 week.

[0109] Eighthly, this disclosure provides a method for reducing at least one of Valsalva LVOT-G, cardiac troponin, and NT-proBNP levels, comprising the following steps:

[0110] (a) After administering an initial dose of the aforementioned Formula I compound or a pharmaceutically acceptable salt thereof to the patient for at least one week.

[0111] (b) Assess the patient’s Valsalva LVOT-G and / or LVEF, and then administer the patient the original or adjusted dose of a Formula I compound or a pharmaceutically acceptable salt thereof for at least 1 week.

[0112] Ninthly, this disclosure provides a method for reducing at least one of Valsalva LVOT-G, cardiac troponin, and NT-proBNP levels using a compound of formula I or a pharmaceutically acceptable salt thereof, the method comprising the steps of:

[0113] (a) After administering an initial dose of the compound of formula I above or a pharmaceutically acceptable salt thereof to the patient for at least one week.

[0114] (b) Assess the patient’s Valsalva LVOT-G and / or LVEF, and then administer the patient the original or adjusted dose of a Formula I compound or a pharmaceutically acceptable salt thereof for at least 1 week.

[0115] In some implementations, in the sixth, seventh, eighth, or ninth aspect, the hypertrophic cardiomyopathy is obstructive hypertrophic cardiomyopathy (oHCM).

[0116] In some implementations, in the sixth, seventh, eighth, or ninth aspect, the hypertrophic cardiomyopathy is classified as New York Heart Association (NYHA) Class II to III.

[0117] In some embodiments, in the sixth, seventh, eighth, or ninth aspect, the patient's LVEF is ≥50%. In some embodiments, in the sixth, seventh, eighth, or ninth aspect, the patient's LVEF is ≥55%. In some embodiments, in the sixth, seventh, eighth, or ninth aspect, the patient's LVEF is ≥60%.

[0118] In some embodiments, in the sixth, seventh, eighth, or ninth aspect, the patient's resting left ventricular outflow tract pressure gradient (LVOT-G) is ≥50 mmHg. In some embodiments, in the sixth, seventh, eighth, or ninth aspect, the patient's resting LVOT-G is ≥30 mmHg and the left ventricular outflow tract pressure gradient after Valsalva maneuver (Valsalva LVOT-G) is ≥50 mmHg.

[0119] In some embodiments, in the sixth, seventh, eighth or ninth aspect, in step (a), the initial dose is selected from 10-80 mg, based on the free base of the compound of formula I.

[0120] In some embodiments, in the sixth, seventh, eighth or ninth aspect, in step (a), the initial dose is selected from 20-80 mg, based on the free base of the compound of formula I.

[0121] In some embodiments, in the sixth, seventh, eighth or ninth aspect, in step (a), the initial dose is 20 mg, 40 mg, 60 mg or 80 mg, calculated as the free base of the compound of formula I.

[0122] In some embodiments, in the sixth, seventh, eighth or ninth aspect, in step (a), the initial dose is selected from 20-60 mg, based on the free base of the compound of formula I.

[0123] In some embodiments, in the sixth, seventh, eighth or ninth aspect, in step (a), the initial dose is 20 mg or 40 mg, calculated as the free base of the compound of formula I.

[0124] In some implementations, in the sixth, seventh, eighth or ninth aspect, in step (a), the initial dose is administered three times a day, twice a day or once a day.

[0125] In some implementations, in the sixth, seventh, eighth or ninth aspect, in step (a), the initial dose is administered twice a day or once a day.

[0126] In some implementations, in the sixth, seventh, eighth or ninth aspect, in step (a), the initial dose is administered twice a day.

[0127] In some implementations, in the sixth, seventh, eighth or ninth aspect, in step (a), the initial dose is administered once a day.

[0128] In some implementations, in the sixth, seventh, eighth or ninth aspect, in step (a), the initial dose is selected from 5-100 mg, and the dosing frequency is three times a day, twice a day or once a day.

[0129] In some implementations, in the sixth, seventh, eighth or ninth aspect, in step (a), the initial dose is selected from 10-80 mg, and the dosing frequency is three times a day, twice a day or once a day.

[0130] In some implementations, in the sixth, seventh, eighth or ninth aspect, in step (a), the initial dose is selected from 20-80 mg, and the dosing frequency is twice a day or once a day.

[0131] In some implementations, in the sixth, seventh, eighth or ninth aspect, in step (a), the initial dose is selected from 20-60 mg, and the dosing frequency is twice a day or once a day.

[0132] In some implementations, in the sixth, seventh, eighth or ninth aspect, in step (a), the initial dose is 20 mg or 40 mg, and the dosing frequency is twice a day.

[0133] In some implementations, in the sixth, seventh, eighth or ninth aspect, in step (a), the initial dose is 40 mg and the administration frequency is once a day.

[0134] In some embodiments, in the sixth, seventh, eighth, or ninth aspect, in step (a), the administration period of the initial dose 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, 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, 2 years, 3 years, 4 years or longer, or even permanently).

[0135] In some embodiments, in the sixth, seventh, eighth, or ninth aspect, in step (b), the adjustment range (e.g., upward or downward) of the adjusted 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, in the sixth, seventh, eighth, or ninth aspect, in step (b), the adjustment range of the adjusted dosage is selected from 10-60 mg. In some embodiments, in the sixth, seventh, eighth, or ninth aspect, in step (b), the adjustment range of the adjusted dosage is selected from 20-40 mg. In some embodiments, in the sixth, seventh, eighth, or ninth aspect, in step (b), the adjustment range of the adjusted dosage is 20 mg or 40 mg. In some implementations, in the sixth, seventh, eighth or ninth aspects, in step (b), the adjustment range of the adjusted dosage is 20 mg.

[0136] In some implementations, in the sixth, seventh, eighth or ninth aspect, in step (b), the frequency of administration of the original dose or the adjusted dose is the same as the frequency of administration of the initial dose.

[0137] In some implementations, in the sixth, seventh, eighth or ninth aspect, in step (b), when Valsalva LVOT-G ≥ 30 mmHg and LVEF ≥ 55%, the dosage is increased based on the original dosage.

[0138] In some implementations, in the sixth, seventh, eighth or ninth aspect, in step (b), when Valsalva LVOT-G < 30 mmHg and LVEF ≥ 55%, or Valsalva LVOT-G ≥ 30 mmHg and 50% ≤ LVEF < 55%, the original dosage is maintained.

[0139] In some implementations, in the sixth, seventh, eighth or ninth aspect, in step (b), when Valsalva LVOT-G < 30 mmHg and 50% ≤ LVEF < 55%, the dosage is reduced from the original dosage.

[0140] In some embodiments, in aspects six, seven, eight, or nine, in step (b), when LVEF < 50% or a serious adverse reaction occurs, 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.

[0141] In some implementations, in the sixth, seventh, eighth, or ninth aspect, in step (b), when LVEF < 50%, the administration of the Formula I compound or its pharmaceutically acceptable salt is suspended.

[0142] In some embodiments, step (b) may be repeated multiple times in aspects six, seven, eight, or nine, for example, two, three, or more times. In some embodiments, step (b) is repeated twice in aspects six, seven, eight, or nine. In some embodiments, step (b) is repeated three times.

[0143] In some embodiments, in the sixth, seventh, eighth, or ninth aspect, the dosage may be adjusted optionally at the second, third, or fourth week after initial administration. In some embodiments, the second week is the eighth day after initial administration. In some embodiments, the third week is the fifteenth day after initial administration. In some embodiments, the fourth week is the twenty-second day after initial administration.

[0144] In some implementations, in aspects six, seven, eight, or nine, in step (b), the original or adjusted dosage 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). 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, 2 years, 3 years, 4 years or longer, or even permanently). In some implementations, in the sixth, seventh, eighth or ninth aspect, in step (b), the adjustment range is the same or different each time. In some implementations, in the sixth, seventh, eighth or ninth aspect, in step (b), the adjustment range is the same each time.

[0145] In some implementations, specifically in the sixth, seventh, eighth, or ninth aspect, the method includes the following steps:

[0146] (a) After administering an initial dose of the compound of formula I above or a pharmaceutically acceptable salt thereof to the patient for at least one week.

[0147] (b) Assess the patient’s Valsalva LVOT-G and / or LVEF, and then administer the patient the original or adjusted dose of a Formula I compound or a pharmaceutically acceptable salt thereof for at least 1 week;

[0148] (c) Assess the patient’s Valsalva LVOT-G and / or LVEF, and then administer the patient the original or adjusted dose of a Formula I compound or a pharmaceutically acceptable salt thereof for at least 1 week.

[0149] In some implementations, specifically in the sixth, seventh, eighth, or ninth aspect, the method includes the following steps:

[0150] (a) After administering an initial dose of the compound of formula I above or a pharmaceutically acceptable salt thereof to the patient for at least one week.

[0151] (b) Assess the patient’s Valsalva LVOT-G and / or LVEF, and then administer the patient the original or adjusted dose of a Formula I compound or a pharmaceutically acceptable salt thereof for at least 1 week;

[0152] (c) Assess the patient’s Valsalva LVOT-G and / or LVEF, and then administer the patient the original or adjusted dose of a Formula I compound or a pharmaceutically acceptable salt thereof for at least 1 week;

[0153] (d) Assess the patient’s Valsalva LVOT-G and / or LVEF, and then administer the patient the original or adjusted dose of a Formula I compound or a pharmaceutically acceptable salt thereof for at least 1 week.

[0154] In some embodiments, in the sixth, seventh, eighth, or ninth aspect, after administering a Formula I compound or a pharmaceutically acceptable salt thereof to a patient for 4 weeks, the patient is subsequently administered a maintenance dose of the Formula I compound or a pharmaceutically acceptable salt thereof for at least 1 week, said maintenance dose being the same as the dose administered in the fourth week.

[0155] In some embodiments, in 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, or 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, 2 years, 3 years, 4 years or longer, or even permanently).

[0156] In some embodiments, specifically 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 or 40 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 40 mg.

[0157] In some implementations, in the sixth, seventh, eighth, or ninth aspect, when LVEF < 50% or a serious adverse reaction occurs, the administration of Formula I compound or a pharmaceutically acceptable salt thereof is suspended, and the method further includes the step of restarting the administration of Formula I compound or a pharmaceutically acceptable salt thereof to the patient for at least one week.

[0158] In some implementation schemes, in the sixth, seventh, eighth, or ninth aspect, once the LVEF increases to LVEF ≥ 50% or serious adverse reactions are resolved or stabilized, administration of the Formula I compound or its pharmaceutically acceptable salt to the patient is restarted for at least one week.

[0159] In some implementations, in 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.

[0160] In some implementations, in the sixth, seventh, eighth, or ninth aspect, when a patient discontinues medication due to LVEF < 50% and the pre-discontinuation dose was higher than the initial dose, the restarted dose is lower than the pre-discontinuation dose.

[0161] In some implementations, in the sixth, seventh, eighth, or ninth aspect, when the patient discontinues medication due to LVEF <50% and the dose administered before discontinuation is the same as the initial dose (e.g., 20 mg or 40 mg), the restarted dose is the same as the dose administered before discontinuation.

[0162] In some embodiments, 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, 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, the reduction in dosage below the pre-pause level is selected from 20-40 mg. In some embodiments, in aspects six, seven, eight, or nine, the reduction in dosage below the pre-pause level is 20 mg or 40 mg.

[0163] In some implementations, in the sixth, seventh, eighth, or ninth aspect, the administration of Formula I compound or its pharmaceutically acceptable salt 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, 2 years, 3 years, 4 years or longer, or even permanently).

[0164] In some implementations, in the eighth or ninth aspect, the Valsalva LVOT-G is reduced to ≤50 mmHg (e.g., <50 mmHg).

[0165] In some implementations, in the eighth or ninth aspect, the Valsalva LVOT-G is reduced to ≤50 mmHg (e.g., <50 mmHg) and LVEF ≥50% (e.g., LVEF ≥55% or LVEF ≥60%).

[0166] In some implementations, in the eighth or ninth aspect, the Valsalva LVOT-G is reduced to ≤50 (e.g., <50 mmHg), and 50% ≤ LVEF ≤ 60%.

[0167] In some implementations, in the eighth or ninth aspect, the Valsalva LVOT-G is reduced to ≤50 mmHg (e.g., <50 mmHg), and 50% ≤ LVEF < 55%.

[0168] In some implementations, in the eighth or ninth aspect, the Valsalva LVOT-G is reduced to ≤30 mmHg (e.g., <30 mmHg).

[0169] In some implementations, in the eighth or ninth aspect, the Valsalva LVOT-G is reduced to ≤30 mmHg (e.g., <30 mmHg) and LVEF ≥50% (e.g., LVEF ≥55% or LVEF ≥60%).

[0170] In some implementations, in the eighth or ninth aspect, the Valsalva LVOT-G is reduced to ≤30 mmHg (e.g., <30 mmHg), and 50% ≤ LVEF ≤ 60%.

[0171] In some embodiments, in the eighth or ninth aspect, the Valsalva LVOT-G is reduced to ≤30 mmHg (e.g., <30 mmHg) and 50% ≤ LVEF < 55%.

[0172] In some implementations, in the eighth or ninth aspect, the Valsalva LVOT-G is reduced to ≥30 mmHg and LVEF ≥50%.

[0173] In some implementations, in the eighth or ninth aspect, the Valsalva LVOT-G is reduced to 30 mmHg ≤ Valsalva LVOT-G ≤ 50 mmHg, and LVEF ≥ 50%.

[0174] In some implementations, in the eighth or ninth aspect, the Valsalva LVOT-G is reduced to ≥30 mmHg, and 50% ≤ LVEF ≤ 60%.

[0175] In some implementations, in the eighth or ninth aspect, the Valsalva LVOT-G is reduced to 30 mmHg ≤ Valsalva LVOT-G ≤ 50 mmHg, and 50% ≤ LVEF ≤ 60%.

[0176] In some implementations, in the eighth or ninth aspect, the Valsalva LVOT-G is reduced to ≥30 mmHg and 50% ≤ LVEF < 55%.

[0177] In some embodiments, in the eighth or ninth aspect, the Valsalva LVOT-G is reduced to 30 mmHg ≤ Valsalva LVOT-G ≤ 50 mmHg, and 50% ≤ LVEF < 55%.

[0178] In some implementations, in the eighth or ninth aspect, the patient's resting LVOT-G is reduced to ≤30 mmHg.

[0179] In some embodiments, in the eighth or ninth aspect, the cardiac troponin is cardiac troponin I (cTnI) or cardiac troponin T (cTnT).

[0180] In a tenth 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 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.

[0181] In some embodiments, at least one of the following dosages, frequency of administration, and time of administration of the hypertrophic cardiomyopathy, the compound of formula I, or a pharmaceutically acceptable salt thereof is as defined in any of the foregoing uses:

[0182] Eleventhly, this disclosure also provides a composition comprising the aforementioned compound of formula I or a pharmaceutically acceptable salt thereof, and 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 and a beta-blocker are used in combination.

[0183] In some embodiments, at least one of the following dosages, frequency of administration, and time of administration of the hypertrophic cardiomyopathy, the compound of formula I, or a pharmaceutically acceptable salt thereof is as defined in any of the foregoing uses:

[0184] In a twelfth aspect, this disclosure also provides a method for preventing and / or treating 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, said Formula I compound or a pharmaceutically acceptable salt thereof being 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.

[0185] In some embodiments, at least one of the following dosages, frequency of administration, and time of administration of the hypertrophic cardiomyopathy, the compound of formula I, or a pharmaceutically acceptable salt thereof is as defined in any of the foregoing uses:

[0186] 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 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.

[0187] In some embodiments, at least one of the following dosages, frequency of administration, and time of administration of the hypertrophic cardiomyopathy, the compound of formula I, or a pharmaceutically acceptable salt thereof is as defined in any of the foregoing uses:

[0188] 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 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.

[0189] In some embodiments, at least one of the following dosages, frequency of administration, and time of administration of the hypertrophic cardiomyopathy, the compound of formula I, or a pharmaceutically acceptable salt thereof is as defined in any of the foregoing uses:

[0190] In a fifteenth aspect, this disclosure also provides a method for preventing and / or treating 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.

[0191] In some embodiments, at least one of the following dosages, frequency of administration, and time of administration of the hypertrophic cardiomyopathy, the compound of formula I, or a pharmaceutically acceptable salt thereof is as defined in any of the foregoing uses:

[0192] 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 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.

[0193] In some embodiments, at least one of the following dosages, frequency of administration, and time of administration of the hypertrophic cardiomyopathy, the compound of formula I, or a pharmaceutically acceptable salt thereof is as defined in any of the foregoing uses:

[0194] 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.

[0195] 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.

[0196] 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 as defined in any of the foregoing uses.

[0197] In some embodiments, in aspects fourteen, fifteen, sixteen, seventeen, or eighteen, the other therapeutic agents are selected from CYP2C19 inhibitors, CYP2C19 inducers, CYP3A4 inhibitors, and CYP3A4 inducers.

[0198] In some embodiments, in aspects fourteen, fifteen, sixteen, seventeen, or eighteen, the other therapeutic agents are selected from CYP3A4 inhibitors.

[0199] In some embodiments, the CYP2C19 inhibitor is selected from weak CYP2C19 inhibitors, intermediate-potency CYP2C19 inhibitors, and strong CYP2C19 inhibitors.

[0200] In some embodiments, the CYP2C19 inducer is selected from weak, medium and strong CYP2C19 inducers.

[0201] 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).

[0202] In some embodiments, the CYP3A4 inducer is selected from weak CYP3A4 inducers, medium-potency CYP3A4 inducers, and strong CYP3A4 inducers.

[0203] In some implementations, the patients described in this disclosure meet at least one of the following criteria:

[0204] (1) Resting LVOT-G ≥ 50 mmHg, or resting LVOT-G ≥ 30 mmHg and Valsalva LVOT-G ≥ 50 mmHg;

[0205] (2) LVEF ≥ 50%;

[0206] (3) NYHA classification II to III;

[0207] (4) Body mass index < 35 kg / m 2 .

[0208] In some implementations, the patient's LVEF is ≥55%. In some implementations, the patient's LVEF is ≥60%.

[0209] 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.

[0210] In some embodiments, the compound of formula I described herein, or a pharmaceutically acceptable salt thereof, is used in combination with other therapeutic agents. In some embodiments, the other therapeutic agents are 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.).

[0211] In some embodiments, the resting LVOT-G or Valsalva LVOT-G described in this disclosure is determined by echocardiography.

[0212] In some embodiments, the LVEF described in this disclosure is determined by echocardiography.

[0213] In some embodiments, the uses, methods, Formula I compounds, or pharmaceutically acceptable salts thereof described above can improve at least one of the following indicators in patients:

[0214] (1) Valsalva LVOT-G, resting LVOT-G, LVEF, LVOT-VTI, LV-FS or LV-GLS;

[0215] (2) NYHA classification;

[0216] (3) NT-proBNP;

[0217] (4) Cardiac troponin;

[0218] (5) Kansas City Cardiomyopathy Questionnaire-Clinical Summary Scoring (KCCQ-CSS);

[0219] (6) Peak oxygen uptake (pVO2) or carbon dioxide ventilation equivalent (VE / VCO2).

[0220] In some implementations, the Valsalva LVOT-G is reduced to ≤50 mmHg (e.g., <50 mmHg).

[0221] In some implementations, the Valsalva LVOT-G is reduced to ≤50 mmHg (e.g., <50 mmHg) and LVEF ≥50% (e.g., LVEF ≥55% or LVEF ≥60%).

[0222] In some implementations, the Valsalva LVOT-G is reduced to ≤50 (e.g., <50 mmHg), and 50% ≤ LVEF ≤ 60%.

[0223] In some implementations, the Valsalva LVOT-G is reduced to ≤50 mmHg (e.g., <50 mmHg) and 50% ≤ LVEF < 55%.

[0224] In some implementations, the Valsalva LVOT-G is reduced to ≤30 mmHg (e.g., <30 mmHg).

[0225] In some implementations, the Valsalva LVOT-G is reduced to ≤30 mmHg (e.g., <30 mmHg) and LVEF ≥50% (e.g., LVEF ≥55% or LVEF ≥60%).

[0226] In some implementations, the Valsalva LVOT-G is reduced to ≤30 mmHg (e.g., <30 mmHg) and 50% ≤ LVEF ≤ 60%.

[0227] In some implementations, the Valsalva LVOT-G is reduced to ≤30 mmHg (e.g., <30 mmHg) and 50% ≤ LVEF < 55%.

[0228] In some implementations, the Valsalva LVOT-G is reduced to ≥30 mmHg and the LVEF is ≥50%.

[0229] In some implementations, the Valsalva LVOT-G is reduced to 30 mmHg ≤ Valsalva LVOT-G ≤ 50 mmHg, and LVEF ≥ 50%.

[0230] In some implementations, the Valsalva LVOT-G is reduced to ≥30 mmHg, and 50% ≤ LVEF ≤ 60%.

[0231] In some implementations, the Valsalva LVOT-G is reduced to 30 mmHg ≤ Valsalva LVOT-G ≤ 50 mmHg, and 50% ≤ LVEF ≤ 60%.

[0232] In some implementations, the Valsalva LVOT-G is reduced to ≥30 mmHg, and 50% ≤ LVEF < 55%.

[0233] In some implementations, the Valsalva LVOT-G is reduced to 30 mmHg ≤ Valsalva LVOT-G ≤ 50 mmHg, and 50% ≤ LVEF < 55%.

[0234] In some implementations, the resting LVOT-G is reduced to ≤30 mmHg.

[0235] 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).

[0236] 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).

[0237] 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.

[0238] 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 50%-95% after treatment compared to pre-treatment levels. In some implementations, NT-proBNP decreases by 60%-90% after treatment compared to pre-treatment levels.

[0239] 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).

[0240] 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).

[0241] 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).

[0242] 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).

[0243] In some embodiments, the Formula I compound described in this disclosure, or a pharmaceutically acceptable salt thereof, is specifically a Formula I compound.

[0244] 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.

[0245] In some embodiments, the compound of formula I described herein or a pharmaceutically acceptable salt thereof is administered orally.

[0246] Compared to Mavacamten and Aficamten, this disclosure offers the following advantages in treating hypertrophic cardiomyopathy using a compound of formula I or a pharmaceutically acceptable salt thereof:

[0247] (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.

[0248] (2) Shorter dose titration cycle (the compound of Formula I of this disclosure allows for dose adjustment every week, and the individualized optimal effective dose can be achieved by continuous administration for ≤4 weeks, while Mavacamten only allows dose adjustment every 12 weeks, with an adjustment cycle of up to 9 months) and clearer dose titration protocol.

[0249] (3) Compared with Mavacamten and Aficamten, the pressure difference in the left ventricular outflow tract decreased more significantly and the response rate was higher.

[0250] (4) It has higher safety, and while effectively reducing LVOT-G, it has less impact on the reduction of LVEF and the drug is washed away faster.

[0251] (5) There are no complex restrictions on drug combinations. This 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.

[0252] 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.

[0253] Terminology Definition

[0254] 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.

[0255] 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.”

[0256] 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.

[0257] "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.

[0258] 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.

[0259] 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.

[0260] 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.

[0261] The term "pharmaceutically acceptable salt" refers to both pharmaceutically acceptable acid addition salts and pharmaceutically acceptable base addition salts.

[0262] "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.

[0263] "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.

[0264] The numerical values ​​disclosed herein have a certain degree of error; generally, ±10% is within a reasonable error range. Of course, the context in which the value is used must be considered. For example, in the case of particle size of the active ingredient, where the error variation after measurement does not exceed ±10%, the value can be ±9%, ±8%, ±7%, ±6%, ±5%, ±4%, ±3%, ±2%, or ±1%, preferably ±5%.

[0265] As used publicly, the terms “subject,” “patient,” “subject,” or “individual” are used interchangeably to refer to mammals, especially primates, and particularly humans.

[0266] 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.

[0267] The term "elevated adjusted NT-proBNP level" refers to an NT-proBNP concentration in a blood sample that is above the normal range. In some embodiments, the upper limit of normal (ULN) for any specific measurement is provided in its product specifications. In some embodiments, such an ULN is 125 pg / ml. ULN can vary based on patient characteristics such as race, body mass index (BMI), age, and sex. For example, the ULN for African Americans may be below 125 pg / ml. Studies have indicated that there may be an inverse relationship between BMI and NT-proBNP levels. The ULN for NT-proBNP in older adults tends to increase with age. Other studies have indicated that healthy women under 80 years of age may have higher NT-proBNP levels than healthy men of the same age. In some studies, patients with atrial fibrillation have higher NT-proBNP levels (e.g., >750). In some embodiments, the elevated NT-proBNP level is an elevated adjusted NT-proBNP level.

[0268] 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.

[0269] 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.

[0270] 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.

[0271] QD: Once a day; BID: Twice a day

[0272] MAD: Multiple dose escalation trials

[0273] TRAE: an abbreviation for treatment-related adverse reactions, refers to adverse reactions or side effects that may occur when a patient receives a specific treatment or medication.

[0274] Wn refers to week n, for example, W2, W3, and W4 refer to week 2, week 3, and week 4 respectively. Attached Figure Description

[0275] Figure 1 shows the changes in LVOT-VTI in patients in drug group A and placebo group after drug administration.

[0276] Figure 2 shows the changes in LV-FS in patients in drug group A and placebo group after drug administration.

[0277] Figure 3 shows the changes in troponin levels in patients in drug group A and placebo group after drug administration.

[0278] Figure 4 shows the changes in NT-proBNP in patients in drug group A and placebo group after drug administration. Detailed Implementation Plan

[0279] Example 1: Safety, tolerability, pharmacokinetics, and pharmacodynamics of oral drug A in healthy subjects and subjects with obstructive hypertrophic cardiomyopathy.

[0280] 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.

[0281] Specifications: 2.5mg / tablet, 10mg / tablet, 20mg / tablet

[0282] Usage and dosage:

[0283] Single dose, orally, once daily, 5, 15, 30, 50, 75, or 100 mg;

[0284] Multiple doses, orally, twice daily. For healthy individuals, the doses are 10, 20, 40, or 60 mg each time; for oHCM patients, the doses are 40, 60, or 80 mg each time.

[0285] 2. Inclusion criteria

[0286] Healthy subjects:

[0287] (1) Age ≥ 18 years old and ≤ 55 years old, gender not limited;

[0288] (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;

[0289] (3) No clinically significant abnormalities were found after a comprehensive physical examination and laboratory tests.

[0290] Subjects with obstructive hypertrophic cardiomyopathy:

[0291] (1) Age 18-85 years, including both extreme values;

[0292] (2) 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;

[0293] (3) Echocardiographic laboratory measurements show resting LVOT-G ≥ 50 mmHg, or resting LVOT-G ≥ 30 mmHg and LVOT-G ≥ 50 mmHg after Valsalva maneuver;

[0294] (4) Echocardiographic laboratory measurements showed LVEF > 60%;

[0295] (5) No clinically significant abnormalities were found after a comprehensive physical examination, laboratory tests, abdominal ultrasound and chest X-ray, or minor abnormalities that the investigator determined would not affect the subject’s enrollment.

[0296] 3. Results

[0297] Safety: In healthy subjects and subjects with obstructive hypertrophic cardiomyopathy, the distribution of adverse events in the drug A group and the placebo group was relatively balanced, indicating good safety and tolerability.

[0298] Pharmacokinetics: T at first dose of 60 mg BID in oHCM subjects max The steady-state time was 3.06 hours. The drug reached steady state around the eighth day after administration. The steady-state T value was... max The duration of action was 3.99 hours; the C value after the first dose was [missing information]. max The concentration was 2470 ng / mL, and the C value after steady state was... max,ss The AUC for the first dose was 3210. tau The AUC at steady state is 10100 h*ng / mL. tau,ss The steady-state C is 20700 h*ng / mL. max With AUC tau The accumulation index was comparable to that of healthy subjects, at 1.30 and 2.04, respectively.

[0299] Urine data showed that the compound of formula I was primarily excreted unchanged via the kidneys. In oHCM subjects, the cumulative excretion over a steady-state dosing interval (0-12h) of 60 mg BID was 35.1 mg, with a cumulative excretion fraction of 58.0% and a renal clearance of 28.0 mL / min.

[0300] Pharmacodynamics: In healthy subjects, single doses of 5 mg, 15 mg, 30 mg, and 50 mg did not result in significant changes in LVEF; in healthy subjects, BIDs of 10 mg, 20 mg, and 40 mg and OHCM subjects, BIDs of 60 mg, were administered, and LVEF values ​​were ≥55% in all subjects during the administration period.

[0301] Drug A, administered at 60 mg twice daily, significantly reduced LVT-G levels in oHCM subjects. The baseline mean resting LVT-G was 71.2 mmHg. After 5 days of continuous administration, the mean resting LVT-G was 6.0 mmHg, representing a 91.0% reduction from baseline. This reduction persisted until the last dose (day 14), after which it gradually returned to baseline. Following Valsalva maneuver, the baseline mean LVT-G was 66.6 mmHg. After 5 days of continuous administration, the mean LVT-G following Valsalva maneuver was 8.0 mmHg, representing an 87.4% reduction from baseline. This reduction persisted until the last dose (day 14), after which it gradually returned to baseline. On day 14, the mean resting LVT-G was 8.2 mmHg, and the mean Valsalva LVT-G was 10.5 mmHg. Both resting LVOT-G and Valsalva LVOT-G returned to baseline levels two weeks after the last dose, with resting LVOT-G at 48.8 (32.5) mmHg and Valsalva LVOT-G at 60.3 (33.7) mmHg.

[0302] In patients receiving drug A, LVOT-VTI and LV-FS also showed a decreasing trend (Figures 1 and 2). At baseline, LVOT-VTI was 90.0 cm and LV-FS was 41%. After 5 consecutive days, LVOT-VTI decreased by 70.4% to 25.9 cm, and LV-FS decreased by 18.5% to 33.3%. Meanwhile, there were no significant changes in LVOT-VTI and LV-FS in the placebo group. For both drug A and placebo groups, LV-GLS did not change significantly from baseline to after administration.

[0303] Cardiac biomarkers showed a greater decrease in drug A compared to the placebo group (Figures 3 and 4). Cardiac troponin decreased slowly with continued treatment with drug A, reaching a 42.5% decrease from baseline by day 14, while troponin in the placebo group increased over time. NT-proBNP decreased significantly after administration. On day 2, NT-proBNP decreased by 60.1% from baseline and remained above 60% by day 14.

[0304] Example 2: Study on the pharmacokinetic effects of verapamil tablets on drug A

[0305] 1. Study population: Healthy subjects aged 18–55 years (inclusive)

[0306] 2. Drug Information

[0307] Drug A, tablets, 20 mg / tablet, active ingredient is compound of formula I.

[0308] Verapamil, tablets, 40mg / tablet, manufactured by Tianjin Central Pharmaceutical Co., Ltd.

[0309] 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; during this period, on the morning of day 12, take 40 mg of drug A on an empty stomach at the same time.

[0310] 4. Inclusion criteria

[0311] (1) Age 18-55 (inclusive), gender not limited;

[0312] (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;

[0313] (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.

[0314] (4) No clinically significant abnormalities were found in the 12-lead electrocardiogram;

[0315] (5) No clinically significant abnormalities on transthoracic echocardiography (LVEF must be ≥55%).

[0316] 5. Test Results

[0317] 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.

[0318] 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.

[0319] 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.

[0320] 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.

[0321] 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.

[0322] Example 3: Efficacy and safety study of drug A in the treatment of obstructive hypertrophic cardiomyopathy

[0323] 1. Study population: Subjects with obstructive hypertrophic cardiomyopathy

[0324] 2. Drug Information: Drug A, tablets, 20mg / tablet, active ingredient is compound of formula I, manufactured by Shandong Shengdi Pharmaceutical Co., Ltd.

[0325] Dosage and administration: Group 1 subjects received oral administration twice a day, 20 mg, 40 mg or 60 mg each time; Group 2 subjects received oral administration twice a day, 40 mg, 60 mg or 80 mg each time; Group 3 subjects received oral administration once a day in the morning, 40 mg, 80 mg or 120 mg each time.

[0326] Treatment duration: 12 weeks of continuous medication during the core treatment period and 52 weeks of continuous medication during the extended treatment period.

[0327] 3. Inclusion criteria

[0328] (1) Age 18-85 years old, gender not limited;

[0329] (2) Body mass index < 35 kg / m 2 ;

[0330] (3) Diagnosis of HCM based on the following criteria: (1) Echocardiography, cardiac magnetic resonance imaging, or cardiac CT scan.

[0331] (1) Any cardiac imaging examination, such as a heart examination, reveals that the maximum end-diastolic ventricular wall thickness of one or more left ventricular segments is ≥15 mm. (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.

[0332] (4) Echocardiographic laboratory measurements show resting LVOT-G ≥ 50 mmHg, or resting LVOT-G ≥ 30 mmHg and LVOT-G ≥ 50 mmHg after Valsalva maneuver;

[0333] (5) Echocardiographic laboratory measurements showed LVEF ≥ 60%;

[0334] (6) NYHA classification II to III;

[0335] (7) Patients receiving beta-blockers, diltiazem, disopyramide, or verapamil 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 the trial. Patients taking disopyramide must also be taking a beta-blocker.

[0336] 4. Dosing regimen

[0337] The plan was to enroll 42 participants, who were randomly divided into three groups: group 1, group 2, and group 3.

[0338] This study included a 4-week screening period, a 12-week core treatment period, a 0-3 week dose reduction and discontinuation period, a 4-12 week observation period after drug withdrawal, a 52-week extended treatment period, a 0-3 week dose reduction and discontinuation period, and a 4-week safety follow-up period.

[0339] (4.1) Core treatment period:

[0340] Group 1 started with a dose of 20 mg twice daily (BID). The dose could be adjusted on W2 (day 8 of administration), W3 (day 15 of administration), and W4 (day 22 of administration) based on the patient’s LVEF and Valsalva LVOT-G levels, with each adjustment increment being 20 mg. The dose range was 20 mg, 40 mg, and 60 mg.

[0341] Group 2 started with a dose of 40 mg twice daily (BID). The dose could be adjusted on W2 (day 8 of administration), W3 (day 15 of administration), and W4 (day 22 of administration) based on the patient’s LVEF and Valsalva LVOT-G levels. The dose adjustment range was 20 mg, 40 mg, 60 mg, and 80 mg.

[0342] The starting dose for group 3 is 40 mg once daily (QD). The dose can be adjusted on W2 (day 8 of administration), W3 (day 15 of administration), and W4 (day 22 of administration) according to the patient's LVEF and Valsalva LVOT-G levels. Each dose adjustment is 40 mg, and the dose range is 40 mg, 80 mg, and 120 mg.

[0343] (4.2) Gradual withdrawal period:

[0344] Based on the last dose, reduce the daily treatment dose by 40 mg for one week, reducing the dose once a week until it is reduced to 20 mg BID or 40 mg QD for one week, then completely discontinue the medication.

[0345] (4.3) Prolong the treatment period:

[0346] All subjects started with a dose of 40 mg twice daily (BID);

[0347] Dosage adjustments were made on day 8 after the first dose of extended treatment and on day 15 after the first dose of extended treatment, based on LVEF and Valsalva LVOT-G test results.

[0348] 5. Dosage adjustment plan

[0349] Dosage adjustment:

[0350] Based on the LVEF and Valsalva LVOT-G test results, the dosage adjustment rules for the investigational drug are as follows:

[0351] Discontinue medication:

[0352] 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:

[0353] 1) During the study, there were two instances where LVEF was <50% on the same day;

[0354] 2) AEs that researchers determine require discontinuation of medication.

[0355] Resumption of dosing after pause:

[0356] If dosing is interrupted due to LVEF < 50%, echocardiography (including LVEF, Valsalva LVOT-G, and Rest LVOT-G) should be performed at least once a week, and the investigational drug should be restarted according to the standards in the table below. (Note: If the minimum dose was not reached before the interruption, the dose should be reduced before restarting; if the minimum dose was reached before the interruption, the minimum dose should be restarted.)

[0357] If dosing is suspended due to adverse events (AEs) other than decreased LVEF, the investigator shall determine whether to restart the drug at the original dose or at a reduced dose after the AE is resolved / stabilized.

[0358] 5. Results

[0359] A total of 42 subjects were enrolled, with 14 subjects in each of the three groups.

[0360] In Group 1, the percentages of doses of 20mg, 40mg, and 60mg were 14.3% (2 / 14), 57.1% (8 / 14), and 28.6% (4 / 14), respectively; in Group 2, the percentages of doses of 20mg, 40mg, 60mg, and 80mg were 0% (0 / 14), 64.3% (9 / 14), 28.6% (4 / 14), and 7.1% (1 / 14), respectively; and in Group 3, the percentages of doses of 40mg, 80mg, and 120mg were 35.7% (5 / 14), 35.7% (5 / 14), and 28.6% (4 / 14), respectively.

[0361] (5.1) Safety results: Drug A was safe and well-tolerated; the left ventricular ejection fraction (LVEF) was slightly lower than baseline, but the LVEF level of the subjects was ≥55% (safe range: LVEF>50%).

[0362] (5.2) Validity results:

[0363] (5.2.1) Valsalva LVOT-G

[0364] The primary endpoint of this study was the change in left ventricular outflow tract pressure gradient (Valsalva LVOT-G) from baseline after 12 weeks of treatment with drug A. A significant decreasing trend in Valsalva LVOT-G was observed as early as day 5 of drug A administration; after dose adjustment (D22) and continued administration until week 12, the decrease in Valsalva LVOT-G was significant and maintained until the end of treatment.

[0365] In Group 1, the mean Valsalva LVOT-G value decreased from baseline 90.8 mmHg to 27.8 mmHg, representing a mean change of -63.0 mmHg from baseline and a mean percentage change of -65.6% from baseline.

[0366] In Group 2, the mean Valsalva LVOT-G value decreased from baseline 107.2 mmHg to 25.4 mmHg, representing a mean change of -81.8 mmHg from baseline and a mean percentage change of -77.1% from baseline.

[0367] In group 3, the mean Valsalva LVOT-G value decreased from baseline 103.1 mmHg to 29.1 mmHg, with a mean change from baseline of -74.0 mmHg and a mean percentage change from baseline of -69.1%.

[0368] Drug A has a dose adjustment cycle of 1 week, with a maximum of 3 weeks for individualized dose adjustment (D22). With continued administration until week 12, the decrease in Valsalva LVOT-G in subjects can be maintained until the end of administration. Compared to Mavacamten's approximately 40-day time to reach stable blood concentrations and the speed of dose adjustment every 12 weeks, Drug A has a shorter dose titration cycle (achieving the optimal individualized effective dose with ≤4 weeks of continuous administration) and a clearer dose titration protocol.

[0369] (5.2.2) LVOT-G response rate

[0370] In Group 1, the proportion of subjects with Rest LVOT-G < 30 mmHg was 85.7% (12 / 14); the proportion of subjects with Valsalva LVOT-G < 30 mmHg was 50.0% (7 / 14); and the proportion of subjects with Rest LVOT-G < 30 mmHg and Valsalva LVOT-G < 50 mmHg was 78.6% (11 / 14).

[0371] In Group 2, the proportion of subjects with Rest LVOT-G < 30 mmHg was 92.9% (13 / 14); the proportion of subjects with Valsalva LVOT-G < 30 mmHg was 85.7% (12 / 14); and the proportion of subjects with Rest LVOT-G < 30 mmHg and Valsalva LVOT-G < 50 mmHg was 92.9% (13 / 14).

[0372] In group 3, the proportion of subjects with Rest LVOT-G < 30 mmHg was 92.9% (13 / 14); the proportion of subjects with Valsalva LVOT-G < 30 mmHg was 71.4% (10 / 14); and the proportion of subjects with Rest LVOT-G < 30 mmHg and Valsalva LVOT-G < 50 mmHg was 78.6% (11 / 14).

[0373] After 12 weeks of treatment, the response rates for Rest LVOT-G < 30 mmHg and Valsalva LVOT-G < 50 mmHg were 78.6% (11 / 14), 92.9% (13 / 14), and 78.6% (11 / 14) in groups 1, 2, and 3, respectively. These rates were significantly higher than those of the Mavacamten Phase 3 study in China (EXPLORER-CN, 59.3%) and the Aficamten Phase 3 study in the international multicenter study (SEQUOIA-HCM, 68%).

[0374] (5.2.3) Other

[0375] All dose groups showed significant improvements in Rest LVOT-G, peak oxygen uptake (pVO2), NYHA classification, KCCQ-CSS score, and NT-proBNP level compared to baseline.

Claims

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 hypertrophic cardiomyopathy in patients with LVEF ≥ 50%. According to the use described in claim 1, the hypertrophic cardiomyopathy described therein is obstructive hypertrophic cardiomyopathy; And / or, the hypertrophic cardiomyopathy is classified as NYHA grade II to III. According to the use described in claim 1 or 2, wherein the patient's LVEF is ≥55%, preferably ≥60%. For the use according to any one of claims 1-3, wherein the patient’s resting left ventricular outflow tract pressure gradient (LVOT-G) is ≥50 mmHg, or the patient’s resting LVOT-G is ≥30 mmHg and the left ventricular outflow tract pressure gradient (Valsalva LVOT-G) after Valsalva maneuver is ≥50 mmHg. For use according to any one of claims 1-4, 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 5-150 mg, further preferably 5 mg, 15 mg, 20 mg, 30 mg, 40 mg, 50 mg, 60 mg, 75 mg, 80 mg, 100 mg or 120 mg, and even more preferably 20 mg, 40 mg, 60 mg, 80 mg or 120 mg. According to any one of claims 1-5, 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 three times a day, twice a day, or once a day, more preferably twice a day or once a day. According to the use described in claim 6, 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 5-150 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 5 mg, 15 mg, 20 mg, 30 mg, 40 mg, 50 mg, 60 mg, 75 mg, 80 mg, 100 mg or 120 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 20 mg, 40 mg, 60 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 40 mg, 80 mg or 120 mg, and the administration frequency is once a day. For the use according to any one of claims 1-7, 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, and more preferably at least 12 weeks. The use according to any one of claims 1-8, wherein the use improves at least one of the following indicators of the patient: (1) Valsalva LVOT-G, resting LVOT-G, LVEF, LVOT-VTI, LV-FS or LV-GLS; (2) NYHA classification; (3) NT-proBNP; (4) Cardiac troponin; (5) Kansas City Cardiomyopathy Questionnaire-Clinical Summary Scoring (KCCQ-CSS); (6) Peak oxygen uptake (pVO2) or carbon dioxide ventilation equivalent (VE / VCO2). 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 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. A composition comprising a compound of formula I or a pharmaceutically acceptable salt thereof and other therapeutic agents, said other therapeutic agents being selected from at least one of β-blockers, non-dihydropyridine calcium channel antagonists, and disopyramide. The use according to any one of claims 1-10 or the composition according to claim 11, 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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