Crystalline form of 7-azaspiro[4,5]decane-6,10-dione compound and its preparation method

Abstract

In the present invention, crystalline forms of 7-azaspiro[4,5]decane-6,10-dione compounds and methods for their preparation are disclosed. In particular, methods for the preparation of the compound of formula (I) and its crystalline forms, as well as uses of said compound and its crystalline forms are disclosed. TIFF2025504040000023.tif3356(I)

Description

[Technical Field]

[0001] This application is; CN202210103134.0 filed January 27, 2022; CN202211017556.2 filed on August 23, 2022 Claim priority of.

[0002] The present application discloses crystalline forms of 7-azaspiro[4,5]decane-6,10-dione compounds and methods for their preparation, and in particular, discloses methods for preparing and using the compound of formula (I) and its crystalline forms: [Background technology]

[0003] Hypertrophic cardiomyopathy (HCM) is a cardiac disease characterized by myocardial hypertrophy, often eroding the interventricular septum, narrowing the ventricular cavity, impeding blood filling of the left ventricle, and reducing its diastolic compliance. Hypertrophic cardiomyopathy is divided into obstructive and non-obstructive forms based on the presence or absence of left ventricular outflow tract obstruction, which may be related to genetic factors. HCM accounts for approximately 1 in 500 cases worldwide, and its clinical manifestations are diverse. It can be asymptomatic or can cause palpitations, exertional dyspnea, dull precordial pain, fatigue, syncope, and even sudden death. In the end-stage disease, symptoms of heart failure are observed on the left side of the heart.

[0004] Currently, there are limited drugs for the treatment of HCM. Treatment of HCM mainly involves improving symptoms through beta-blockers or calcium channel blockers, but these drugs cannot target the cause, slow the progression of myocardial hypertrophy, or improve prognosis. The therapeutic effect is limited.

[0005] Myosin and actin are the basis of myocardial contraction. Myosin crossbridges periodically bind and dissociate with actin, driving myofilament sliding and initiating myocardial contraction. Myosin has ATPase activity and provides the power for myocardial contraction through ATP hydrolysis. Myosin mutations result in prolonged myosin-actin binding, excessive contraction and impaired relaxation of the left ventricular myocardium, leading to left ventricular hypertrophy and fibrosis, resulting in HCM. MYK-461 is an allosteric modulator of cardiac myosin that slows the rate of phosphate hydrolysis, shortens the binding time of myosin and actin, exerts a negative inotropic effect, and alleviates pathological changes, such as myocardial hypertrophy caused by excessive left ventricular contraction. However, this drug is slowly eliminated from the body and remains in the body for too long, making it difficult to rapidly adjust the dose. Therefore, the development of myosin inhibitors with better activity and more ideal pharmacokinetic properties is of great clinical value and significance.

[0006] Furthermore, abnormalities in cardiac sarcomeres have been identified as a driving factor in various cardiac diseases and conditions, such as diastolic heart failure with preserved ejection fraction, ischemic heart disease, angina pectoris, and restrictive cardiomyopathy. Myosin ATPase inhibitors may also have potential therapeutic effects in alleviating the pathological processes of the above diseases by inhibiting myocardial contraction. Summary of the Invention

[0007] The present disclosure provides a compound of formula (I), characterized by an X-ray powder diffraction pattern (XRPD) having characteristic diffraction peaks at angles 2θ of 18.283±0.200°, 19.662±0.200°, and 22.420±0.200°; [ka] (I) The present invention provides crystalline form A of the compound of formula (I).

[0008] In some embodiments of the present disclosure, the crystalline form A has an X-ray powder diffraction pattern with characteristic diffraction peaks at angles 2θ of 11.143±0.200°, 18.283±0.200°, 19.662±0.200°, 22.420±0.200°, 26.259±0.200°, and 28.056±0.200°.

[0009] In some embodiments of the present disclosure, the crystalline form A has an X-ray powder diffraction pattern with characteristic diffraction peaks at angles 2θ of 11.143±0.200°, 18.283±0.200°, 19.662±0.200°, 22.420±0.200°, 26.259±0.200°, 27.261±0.200°, 28.056±0.200°, and 30.256±0.200°.

[0010] In some embodiments of the present disclosure, crystalline form A is disclosed, characterized by an X-ray powder diffraction pattern comprising at least 5, 6, 7, or 8 characteristic diffraction peaks at angles 2θ selected from the following angles: 11.143±0.200°, 18.283±0.200°, 19.662±0.200°, 22.420±0.200°, 26.259±0.200°, 27.261±0.200°, 28.056±0.200°, and 30.256±0.200°.

[0011] In some embodiments of the present disclosure, the crystalline form A has an X-ray powder diffraction pattern with characteristic diffraction peaks at angles 2θ of 11.143±0.200°, 16.522±0.200°, 17.053±0.200°, 18.283±0.200°, 19.662±0.200°, 22.420±0.200°, 23.909±0.200°, 26.259±0.200°, 27.261±0.200°, 28.056±0.200°, 30.256±0.200°, and 33.761±0.200°.

[0012] In some embodiments of the present disclosure, crystalline form A is disclosed, characterized by an X-ray powder diffraction pattern comprising at least 5, 6, 7, 8, 9, 10, 11, or 12 characteristic diffraction peaks at angles 2θ selected from the following angles: 11.143±0.200°, 16.522±0.200°, 17.053±0.200°, 18.283±0.200°, 19.662±0.200°, 22.420±0.200°, 23.909±0.200°, 26.259±0.200°, 27.261±0.200°, 28.056±0.200°, 30.256±0.200°, and 33.761±0.200°.

[0013] In some embodiments of the present disclosure, the crystalline form A has the following molecular weights: 11.143±0.200°, 13.260±0.200°, 16.522±0.200°, 17.053±0.200°, 18.283±0.200°, 19.662±0.200°, 22.420±0.200°, 23.568±0.200°, 23.909±0.200°, 24.020±0.200°, 25.020±0.200°, 26.020±0.200°, 27.020±0.200°, 28.020±0.200°, 29.020±0.200°, 30.020±0.200°, 31.020±0.200°, 32.020±0.200°, 33.020±0.200°, 34.020±0.200°, 35.020±0.200°, 36.020±0.200°, 37.020±0.200°, 38.020±0.200°, 39.020±0.200°, 40.020±0.200°, 41.020±0.200°, 42.020±0.200°, 43.020±0.200°, 44.020±0.200°, 45.020±0.200°, 46.020±0.200°, 47.020±0.2 It has a powder X-ray diffraction pattern with characteristic diffraction peaks at angles 2θ of 0.200°, 26.259±0.200°, 27.261±0.200°, 28.056±0.200°, 29.008±0.200°, 30.256±0.200°, 33.761±0.200°, and 35.404±0.200°.

[0014] In some embodiments of the present disclosure, the crystalline form A has the following molecular weights: 11.143±0.200°, 13.260±0.200°, 14.860±0.200°, 16.163±0.200°, 16.522±0.200°, 17.053±0.200°, 17.537±0.200°, 18.283±0.200°, 19.662±0.200°, 22.420±0.200°, 23.568±0.200°, 23.909±0.200°, 26.259±0.200°, 26.726±0.200°, 27.261±0.200°, It has a powder X-ray diffraction pattern with characteristic diffraction peaks at angles 2θ of 28.056±0.200°, 29.008±0.200°, 30.256±0.200°, 31.219±0.200°, 31.646±0.200°, 32.037±0.200°, 32.438±0.200°, 32.807±0.200°, 33.761±0.200°, 34.534±0.200°, 35.404±0.200°, 36.856±0.200°, 37.813±0.200°, and 39.456±0.200°.

[0015] In some embodiments of the present disclosure, the crystalline form A has the following molecular weights: 11.143±0.100°, 13.260±0.100°, 14.860±0.100°, 16.163±0.100°, 16.522±0.100°, 17.053±0.100°, 17.537±0.100°, 18.283±0.100°, 19.662±0.100°, 22.420±0.100°, 23.568±0.100°, 23.909±0.100°, 26.259±0.100°, 26.726±0.100°, 27.261±0.100°, It has a powder X-ray diffraction pattern with characteristic diffraction peaks at angles 2θ of 28.056±0.100°, 29.008±0.100°, 30.256±0.100°, 31.219±0.100°, 31.646±0.100°, 32.037±0.100°, 32.438±0.100°, 32.807±0.100°, 33.761±0.100°, 34.534±0.100°, 35.404±0.100°, 36.856±0.100°, 37.813±0.100°, and 39.456±0.100°.

[0016] In some embodiments of the present disclosure, the crystalline form A has the following molecular weights: 11.143°, 13.260°, 14.860°, 16.163°, 16.522°, 17.053°, 17.537°, 18.283°, 19.662°, 22.420°, 23.568°, 23.909°, 26.259°, 26.726°, 27.261°, 28. It has a powder X-ray diffraction pattern with characteristic diffraction peaks at angles 2θ of 056°, 29.008°, 30.256°, 31.219°, 31.646°, 32.037°, 32.438°, 32.807°, 33.761°, 34.534°, 35.404°, 36.856°, 37.813°, and 39.456°.

[0017] In some embodiments of the present disclosure, the crystalline form A has an angle of 18.283±0.200°, 19.662±0.200°, 22.420±0.200°, and / or 11.143±0.200°, and / or 13.260±0.200°, and / or 14.860±0.200°, and / or 16.163±0.200°, and / or 16.5 22±0.200°, and / or 17.053±0.200°, and / or 17.537±0.200°, and / or 23.568±0.200°, and / or 23.909±0.200°, and / or 26.259±0.200°, and / or 26.726±0.200°, and / or 27.261±0.200°, and / or is 28.056±0.200°, and / or 29.008±0.200°, and / or 30.256±0.200°, and / or 31.219±0.200°, and / or 31.646±0.200°, and / or 32.037±0.200°, and / or 32.438±0.200°, and / or 32.807±0.200°, and / or 33.761±0.200°, and / or 34.534±0.200°, and / or 35.404±0.200°, and / or 36.856±0.200°, and / or 37.813±0.200°, and / or 39.456±0.200°, and / or has a powder X-ray diffraction pattern with characteristic diffraction peaks at angles 2θ of 33.761±0.200°, and / or 34.534±0.200°, and / or 35.404±0.200°, and / or 36.856±0.200°, and / or 37.813±0.200°, and / or 39.456±0.200°.

[0018] In some embodiments of the present disclosure, the crystalline form A has an angle of 18.283±0.100°, 19.662±0.100°, 22.420±0.100°, and / or 11.143±0.100°, and / or 13.260±0.100°, and / or 14.860±0.100°, and / or 16.163±0.100°, and / or 16.5 22±0.100°, and / or 17.053±0.100°, and / or 17.537±0.100°, and / or 23.568±0.100°, and / or 23.909±0.100°, and / or 26.259±0.100°, and / or 26.726±0.100°, and / or 27.261±0.100°, and / or is 28.056±0.100°, and / or 29.008±0.100°, and / or 30.256±0.100°, and / or 31.219±0.100°, and / or 31.646±0.100°, and / or 32.037±0.100°, and / or 32.438±0.100°, and / or 32.807±0.100°, and / or 33.761±0.100°, and / or 34.534±0.100°, and / or 35.404±0.100°, and / or 36.856±0.100°, and / or 37.813±0.100°, and / or 39.456±0.100° 2θ angles.

[0019] In some embodiments of the present disclosure, the XRPD pattern of crystalline form A is substantially as shown in FIG.

[0020] In some embodiments of the present disclosure, the resolution data of the XRPD pattern for crystalline form A is shown in Table 1. Table 1. XRPD pattern resolution data for crystalline form A of compound of formula (I) [Table 1] [Table 2]

[0021] In some embodiments of the present disclosure, the crystalline form A is disclosed, which has a differential scanning calorimetry curve with endothermic peaks at 249.53±8°C and 306.12±8°C.

[0022] In some embodiments of the present disclosure, the crystalline form A is disclosed, which has a differential scanning calorimetry curve with endothermic peaks at 249.53±3°C and 306.12±3°C.

[0023] In some embodiments of the present disclosure, the crystalline form A is disclosed, having a DSC curve substantially as shown in FIG.

[0024] In some embodiments of the present disclosure, the crystalline form A is disclosed, having a thermogravimetric analysis curve with a maximum weight loss of 0.075% at 200±3°C and a maximum weight loss of 0.164% at 250±3°C.

[0025] In some embodiments of the present disclosure, the crystalline form A is disclosed, having a TGA curve substantially as shown in FIG. [ka] (I)

[0026] In some embodiments of the present disclosure, the crystalline form B has an X-ray powder diffraction pattern with characteristic diffraction peaks at angles 2θ of 12.861±0.200°, 14.135±0.200°, 17.788±0.200°, 18.099±0.200°, 21.659±0.200°, 21.912±0.200°, 22.410±0.200°, and 25.218±0.200°.

[0027] In some embodiments of the present disclosure, crystalline form B is disclosed, characterized by an X-ray powder diffraction pattern comprising at least 5, 6, 7, or 8 characteristic diffraction peaks at angles 2θ selected from the following angles: 12.861±0.200°, 14.135±0.200°, 17.788±0.200°, 18.099±0.200°, 21.659±0.200°, 21.912±0.200°, 22.410±0.200°, and 25.218±0.200°.

[0028] In some embodiments of the present disclosure, the crystalline form B has an X-ray powder diffraction pattern with characteristic diffraction peaks at angles 2θ of 8.262±0.200°, 12.861±0.200°, 14.135±0.200°, 16.303±0.200°, 17.788±0.200°, 18.099±0.200°, 19.053±0.200°, 21.659±0.200°, 21.912±0.200°, 22.410±0.200°, 25.218±0.200°, 27.230±0.200°, 27.526±0.200°, and 28.132±0.200°.

[0029] In some embodiments of the present disclosure, the following angles are used: 8.262±0.200°, 12.861±0.200°, 14.135±0.200°, 16.303±0.200°, 17.788±0.200°, 18.099±0.200°, 19.053±0.200°, 21.659±0.200°, 21.912±0.200°, 22.410±0.200°. The crystalline form B is disclosed as being characterized by a powder X-ray diffraction pattern comprising at least 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14 characteristic diffraction peaks at angles 2θ selected from 200°, 25.218±0.200°, 27.230±0.200°, 27.526±0.200°, and 28.132±0.200°.

[0030] In some embodiments of the present disclosure, the crystalline form B has the following molecular weights: 7.240±0.200°, 8.262±0.200°, 9.189±0.200°, 10.841±0.200°, 12.861±0.200°, 13.269±0.200°, 14.135±0.200°, 14.651±0.200°, 15.907±0.200°, 16.303±0.200°, 16.770±0.200°, 17.788±0.200°, 18.099±0.200°, 19.053±0.200°, 21.659±0.200°, 22.759±0.200°, 23.759±0.200°, 24.759±0.200°, 25.759±0.200°, 26.759±0.200°, 27.759±0.200°, 28.759±0.200°, 29.759±0.200°, 30.759±0.200°, 31.759±0.200°, 32.759±0.200°, 33.759±0.200°, 34.759±0.200°, 35.759±0.200°, 36.759±0.200°, 37.759±0.200°, 38.759±0.200°, 39.759±0.200° It has a powder X-ray diffraction pattern with characteristic diffraction peaks at angles 2θ of 0.200°, 21.912±0.200°, 22.410±0.200°, 22.829±0.200°, 24.408±0.200°, 25.218±0.200°, 26.009±0.200°, 27.230±0.200°, 27.526±0.200°, 28.132±0.200°, 29.630±0.200°, 32.150±0.200°, 32.961±0.200°, and 33.645±0.200°.

[0031] In some embodiments of the present disclosure, the crystalline form B has the following molecular weights: 7.240±0.100°, 8.262±0.100°, 9.189±0.100°, 10.841±0.100°, 12.861±0.100°, 13.269±0.100°, 14.135±0.100°, 14.651±0.100°, 15.907±0.100°, 16.303±0.100°, 16.770±0.100°, 17.788±0.100°, 18.099±0.100°, 19.053±0.100°, 21.659±0.100°, 22.759±0.100°, 23.759±0.100°, 24.759±0.100°, 25.759±0.100°, 26.759±0.100°, 27.759±0.100°, 28.759±0.100°, 29.759±0.100°, 30.759±0.100°, 31.759±0.100°, 32.759±0.100°, 33.759±0.100°, 34.759±0.100°, 35.759±0.100°, 36.759±0.100°, 37.759±0.100°, 38.759±0.100°, 39.759±0.100° It has a powder X-ray diffraction pattern with characteristic diffraction peaks at angles 2θ of 0.100°, 21.912±0.100°, 22.410±0.100°, 22.829±0.100°, 24.408±0.100°, 25.218±0.100°, 26.009±0.100°, 27.230±0.100°, 27.526±0.100°, 28.132±0.100°, 29.630±0.100°, 32.150±0.100°, 32.961±0.100°, and 33.645±0.100°.

[0032] In some embodiments of the present disclosure, the crystalline form B has the following molecular positions: 7.240°, 8.262°, 9.189°, 10.841°, 12.861°, 13.269°, 14.135°, 14.651°, 15.907°, 16.303°, 16.770°, 17.788°, 18.099°, 19.053°, 21.659°, It has a powder X-ray diffraction pattern with characteristic diffraction peaks at angles 2θ of 21.912°, 22.410°, 22.829°, 24.408°, 25.218°, 26.009°, 27.230°, 27.526°, 28.132°, 29.630°, 32.150°, 32.961°, and 33.645°.

[0033] In some embodiments of the present disclosure, the crystalline form B has an angle of 17.788°±0.200°, 18.099±0.200°, 21.659±0.200°, and / or 21.912±0.200°, and / or 7.240±0.200°, and / or 8.262±0.200°, and / or 9.189±0.200°, and / or 10.841±0.200°, and / or 12.861±0.200°, and / or 13.269±0.200°, and / or 14.135±0.200°, and / or 14.651±0.200°, and / or 15.907±0.200°, and / or 16.303±0.200°, and / or 16.770±0.2 and / or 27.230±0.200°, and / or 27.526±0.200°, and / or 28.132±0.200°, and / or 29.630±0.200°, and / or 32.150±0.200°, and / or 32.961±0.200°, and / or 33.645±0.200°.

[0034] In some embodiments of the present disclosure, the crystalline form B has an angle of 17.788°±0.100°, 18.099±0.100°, 21.659±0.100°, and / or 21.912±0.100°, and / or 7.240±0.100°, and / or 8.262±0.100°, and / or 9.189±0.100°, and / or 10.841±0.100°, and / or 12.861±0.100°, and / or 13.269±0.100°, and / or 14.135±0.100°, and / or 14.651±0.100°, and / or 15.907±0.100°, and / or 16.303±0.100°, and / or 16.770±0.1 and / or 27.230±0.100°, and / or 27.526±0.100°, and / or 28.132±0.100°, and / or 29.630±0.100°, and / or 32.150±0.100°, and / or 32.961±0.100°, and / or 33.645±0.100°.

[0035] In some embodiments of the present disclosure, the resolution data of the XRPD pattern of crystalline form B is shown in Table 2. Table 2. XRPD pattern resolution data for crystalline form B of compound of formula (I) [Table 3] [Table 4]

[0036] In some embodiments of the present disclosure, the crystalline form B is disclosed, which has a differential scanning calorimetry curve with an endothermic peak at 249.48±8°C.

[0037] In some embodiments of the present disclosure, the crystalline form B is disclosed, which has a differential scanning calorimetry curve with an endothermic peak at 249.48±3°C.

[0038] In some embodiments of the present disclosure, crystalline form B is disclosed, having a DSC curve substantially as shown in FIG.

[0039] This disclosure: 1) adding a compound of formula (I) to an alcohol solvent, such as ethyl acetate, tert-butyl methyl ether, tetrahydrofuran, or dichloromethane; 2) stirring at 15 to 100°C for 1 to 168 hours; 3) filtering, recovering a filter cake, and vacuum drying the filter cake at 30 to 45°C for 0.5 to 2 hours, or vacuum drying the filter cake at 35°C for 1 hour; A method for preparing crystalline form A of the compound of formula (I), wherein the compound of formula (I) has the formula (I): [ka] (I) Also provided is a method in which

[0040] In some embodiments of the present disclosure, the alcohol solvent is selected from methanol and ethanol.

[0041] The present disclosure also provides use of the compound of formula (I), crystalline form A of the compound of formula (I), crystalline form B of the compound of formula (I), or a method for preparing crystalline form A of the compound of formula (I), in the manufacture of a medicament for treating an LSD1-related disease.

[0042] The present disclosure also provides a use of the compound of formula (I), crystalline form A of the compound of formula (I), or a method for preparing crystalline form A of the compound of formula (I), in the manufacture of a medicament for treating an LSD1-related disease.

[0043] The present disclosure also provides a pharmaceutical composition comprising a therapeutically effective amount of the compound of formula (I), crystalline form A of the compound of formula (I), or crystalline form B of the compound of formula (I), and a pharmaceutically acceptable carrier.

[0044] The present disclosure also provides a pharmaceutical composition comprising a therapeutically effective amount of the compound of formula (I) above or crystalline form A of the compound of formula (I) above, and a pharmaceutically acceptable carrier.

[0045] The present disclosure also provides use of the compound of formula (I), crystalline form A of the compound of formula (I), crystalline form B of the compound of formula (I), or the pharmaceutical composition in the manufacture of a medicament as a cardiac myosin inhibitor.

[0046] The present disclosure also provides use of the compound of formula (I) above, use of crystalline form A of the compound of formula (I) above, or use of the pharmaceutical composition above in the manufacture of a medicament as a cardiac myosin inhibitor.

[0047] The present disclosure also provides use of the compound of formula (I), crystalline form A of the compound of formula (I), crystalline form B of the compound of formula (I), or the pharmaceutical composition in the manufacture of a medicament for treating heart failure and hypertrophic cardiomyopathy.

[0048] The present disclosure also provides the use of the compound of formula (I), the crystalline form A of the compound of formula (I), or the pharmaceutical composition in the manufacture of a medicament for treating heart failure and hypertrophic cardiomyopathy.

[0049] The present disclosure also provides a method for treating a cardiac myosin inhibitor-associated disease in a subject in need thereof, comprising providing to the subject an effective dose of the compound of formula (I), crystalline form A of the compound of formula (I), crystalline form B of the compound of formula (I), or a pharmaceutical composition defined in any of the above technical solutions.

[0050] The present disclosure also provides a method for treating a cardiac myosin inhibitor-associated disease in a subject in need thereof, comprising providing to the subject an effective dose of the compound of formula (I), crystalline form A of the compound of formula (I), or a pharmaceutical composition defined in any of the above technical solutions.

[0051] The present disclosure also provides a method for treating heart failure and hypertrophic cardiomyopathy in a subject in need thereof, comprising providing to the subject an effective dose of the compound of formula (I), crystalline form A of the compound of formula (I), crystalline form B of the compound of formula (I), or a pharmaceutical composition defined in any of the above technical solutions.

[0052] The present disclosure also provides a method for treating heart failure and hypertrophic cardiomyopathy in a subject in need thereof, comprising providing to the subject an effective dose of the compound of formula (I), crystalline form A of the compound of formula (I), or a pharmaceutical composition as defined in any of the above technical solutions.

[0053] (Technical Effects) The crystalline form A of the compound of formula (I) in the present disclosure is easy to obtain, has good physical and chemical stability, and has high industrial applicability and economic value. The compound of the present disclosure has good inhibitory effect on cardiac myosin ATPase and excellent pharmacokinetic properties.

[0054] (Definitions and Explanations) Unless otherwise specified, the following terms and phrases used herein shall have the following meanings. A particular phrase or term should not be deemed unclear or ambiguous due to the absence of a specific definition, but should be understood in its customary sense. When a trade name appears herein, it is intended to refer to the corresponding product or its active ingredient.

[0055] It should be noted that, unless the context requires otherwise or is clearly inconsistent with the present disclosure, as used herein and in the appended claims, the singular forms "a," "an," "the," and similar terms in the subject matter of this disclosure (and particularly in the subject matter of the appended claims) are to be construed as including both the singular and the plural, i.e., for example, reference to "the compound" includes a reference to one or more compounds, etc.

[0056] The terms "amorphous" or "amorphous form" mean that the substance, component, or product does not have a characteristic crystalline shape or structure, and is not substantially crystalline, for example, as determined by XRPD (X-ray powder diffraction), or that the substance, component, or product is not birefringent or cubic, for example, when viewed using a polarized light microscope, or does not have sharp peaks in an X-ray powder diffraction pattern. In certain embodiments, a sample comprising an amorphous form of a substance may be substantially free from other amorphous and / or crystalline forms.

[0057] Differential scanning calorimetry (DSC) of the crystalline forms of the present disclosure is subject to experimental error and is slightly affected by the dryness of the sample. The endothermic peak position and peak value may vary slightly from machine to machine and from sample to sample. The experimental error or value difference may be 10°C or less, or 9°C or less, or 8°C or less, or 7°C or less, or 6°C or less, or 5°C or less, or 4°C or less, or 3°C or less, or 2°C or less, or 1°C or less. Therefore, the DSC endothermic peak position or peak value cannot be considered absolute.

[0058] Intermediate compounds of the present disclosure can be prepared by a variety of synthetic methods known to those skilled in the art, including the specific embodiments described below, embodiments formed by combining the specific embodiments described below with other chemical synthetic methods, and other equivalent methods known to those skilled in the art. Alternative embodiments include, but are not limited to, the examples of the present disclosure.

[0059] Unless otherwise specified, a double bond structure, for example, a carbon-carbon double bond, a carbon-nitrogen double bond, and a nitrogen-nitrogen double bond, is present in a compound, and each atom on the double bond is bonded to two different substituents (in a double bond containing a nitrogen atom, the unshared electron pair of the nitrogen atom is considered to be a substituent bonded thereto), and in the compound, the atoms on the double bond and their substituents have the structure: [ka] When represented by the formula: it represents either the (Z)-isomer or the (E)-isomer of said compound, or a mixture of said two isomers.

[0060] The structure of the compounds disclosed herein can be determined by conventional methods known to those skilled in the art. Where the present disclosure relates to the absolute configuration of a compound, the absolute configuration can be determined by conventional techniques in the art, such as single crystal X-ray diffraction (SXRD). In single crystal X-ray diffraction (SXRD), the diffraction intensity data of a grown single crystal is collected using a Bruker D8 venture diffractometer (CuKα radiation, φ / ω scan mode), and after collecting the relevant data, the crystal structure is further analyzed by a direct method (ShelXs97) to determine its absolute configuration.

[0061] The chemical reactions in certain embodiments of the present disclosure are completed in suitable solvents, which must be appropriate for the chemical transformations of the present disclosure and the reagents and raw materials required. To obtain compounds of the present disclosure, one skilled in the art may need to modify or select synthetic steps or reaction schemes based on existing embodiments.

[0062] The present disclosure is described in detail below through examples, which should not be construed as limiting the present disclosure in any way.

[0063] All solvents used in this disclosure are commercially available and may be used without further purification.

[0064] The solvents used in this disclosure are commercially available.

[0065] In this disclosure, the following abbreviations are used: TEA represents triethylamine; DIEA represents N,N-diisopropylethylamine; PE represents petroleum ether; EtOAc represents ethyl acetate; EA represents ethyl acetate; THF represents tetrahydrofuran; MeOH represents methanol; MTBE represents methyl tert-butyl ether; DCM represents dichloromethane; EtOH represents ethanol; iPrOH represents isopropyl alcohol; BocO represents di-tert-butyl dicarbonate; L-selectride represents lithium trisec-butylborohydride; TCFH represents N,N,N',N'-tetramethylchloroformamidinium hexafluorophosphate; FA represents formic acid; TFA represents trifluoroacetic acid; AC N stands for acetonitrile; TLC stands for thin layer chromatography; HPLC stands for high performance liquid chromatography; LCMS stands for liquid chromatography-mass spectrometry; DMSO stands for dimethyl sulfoxide; DMF stands for N,N-dimethylformamide; LDA stands for lithium diisopropylamide; DMAC stands for N,N-dimethylacetamide; PEG-400 stands for polyethylene glycol 400; EGTA stands for ethylene glycol-bis(2-aminoethyl ether)-N,N,N',N'-tetraacetic acid; DMSO-d6 stands for deuterated dimethyl sulfoxide; CDCl3 stands for deuterated chloroform; BID stands for twice a day; QD stands for once a day; PO stands for oral administration; IV stands for intravenous administration.

[0066] Compounds are named manually or using ChemDraw® software, commercially available compounds are named by their supplier directory name.

[0067] (Devices and analytical methods in the present disclosure) X-ray powder diffraction (XRPD) method 1 in this disclosure: Test parameters for tested crystalline form A are shown in Table 3. Table 3 XRPD test parameters [Table 5]

[0068] X-ray powder diffraction (XRPD) method 2 in this disclosure: Data was obtained using a Bruker D2 Phaser instrument. Test parameters are listed in Table 4. Table 4 XRPD test parameters [Table 6]

[0069] Differential Scanning Calorimetry (DSC) Method 1: Test parameters for this disclosure are shown in Table 5. Table 5 DSC test parameters [Table 7]

[0070] Differential Scanning Calorimetry (DSC) Method 2: Test parameters for this disclosure are shown in Table 6. Table 6 DSC test parameters [Table 8]

[0071] Thermogravimetric analysis (TGA) Method 1: Test parameters for this disclosure are shown in Table 7. Table 7 TGA test parameters [Table 9] [Brief explanation of the drawings]

[0072] [Figure 1] Figure 1: XRPD pattern of crystalline form A of compound of formula (I) using Cu-Kα radiation. [Figure 2] FIG. 2 shows the DSC curve of crystalline form A of the compound of formula (I). [Figure 3] FIG. 3 shows the TGA curve of crystalline form A of the compound of formula (I). [Figure 4] FIG. 4 shows an ellipsoidal drawing of the three-dimensional structure of the compound of formula (I) in a single crystal X-ray diffraction (SC-XRD) analysis. [Figure 5] FIG. 5 shows the XRPD pattern of crystalline form B of compound of formula (I) using Cu-Kα radiation. [Figure 6] FIG. 6 shows the DSC curve of crystalline form B of the compound of formula (I).

[0073] (Detailed explanation) In order to better understand the contents of the present disclosure, the present disclosure will be further illustrated below in conjunction with specific examples, but the specific examples are not intended to limit the contents of the present disclosure. Example 1

[0074] Formula (I): [ka] (I) Synthetic Route: [ka]

[0075] Step A: 1-2 (4.66 g, 38.43 mmol, 1.2 equiv) and tetraethyl titanate (21.92 g, 96.07 mmol, 19.92 mL, 3 equiv) were added to a solution of 1-1 (5 g, 32.02 mmol, 4.07 mL, 1 equiv) in THF (50 mL) at 20° C. The reaction solution was stirred at 60° C. for 16 hours. Ethyl acetate (100 mL) was added to the reaction solution. The mixture was cooled to 0° C., and then water (20 mL) was slowly added. The mixture was stirred for 0.5 hours and filtered. The filtrate was washed with saturated brine (50 mL×3), dried over anhydrous sodium sulfate, filtered, and then concentrated to give compound 1-3.

[0076] Step B: L-selectride (1M, 41.65 mL, 1.2 equiv.) was slowly added dropwise to a solution of 1-3 (9 g, 34.71 mmol, 1 equiv.) in THF (100 mL) at −78° C. under nitrogen. The reaction solution was stirred at −78° C. for 2 hours and then slowly added to saturated aqueous ammonium chloride solution (100 mL). The mixture was extracted with EA (100 mL × 2). The combined organic layer was washed with saturated brine (100 mL × 3), dried over anhydrous sodium sulfate, filtered, and then concentrated. The residue was separated by column chromatography (PE: EtOAc = 5:1 to 3:1) to give compound 1-4.

[0077] Step C: HCl / MeOH (200 mmol, 50 mL, 7.92 equiv) was added to a solution of 1-4 (6.6 g) in MeOH (50 mL) at 20° C. The reaction solution was stirred for 16 h and then concentrated to give the hydrochloride salt of compound 1-5.

[0078] Step D: 1-6 (1.51 g, 7.74 mmol, 1.5 equiv, HCl) and DIEA (4.00 g, 30.96 mmol, 5.40 mL, 6 equiv) were added to a solution of the hydrochloride salt of 1-5 (1 g) in EtOH (10 mL) at 20° C. The reaction solution was stirred at 20° C. for 16 h and concentrated to give compound 1-7.

[0079] Step E: TEA (2.45 g, 24.24 mmol, 3.37 mL, 3 equiv) was added to a solution of 1-7 (1.54 g, 8.08 mmol, 1 equiv) in DCM (15 mL) at -20 °C under nitrogen. Then, a solution of 1-8 (1.39 g, 5.14 mmol, 6.37 e-1 equiv) in DCM (15 mL) was added. The reaction solution was stirred at 20 °C for 16 h and then concentrated. The residue was diluted with EA (30 mL), washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and then concentrated. The residue was separated by column chromatography (PE: EtOAc = 10:1 to 5:1) to give compound 1-9.

[0080] Step F: Sodium methoxide (1 M, 6.43 ml, 1 equiv.) was added to a solution of 1-9 (0.648 g, 1.53 mmol, 1 equiv.) in MeOH (7.6 mL) under nitrogen. The reaction solution was stirred at 20° C. for 16 hours. 1 M dilute hydrochloric acid was added to the reaction solution to adjust the pH to about 5, and then the mixture was extracted with EA (20 mL). The organic layer was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and then concentrated to give compound 1-10.

[0081] Step G: Hydrochloric acid (4 M, 4 mL, 17.40 equiv.) was added to a solution of 1-10 (348 mg, 919.74 μmol, 1 equiv.) in 1,4-dioxane (4 mL). The reaction solution was stirred at 50° C. for 16 hours. EA (30 mL) was added to the reaction solution, and then 1 M aqueous sodium hydroxide solution was added to adjust the pH to about 8. The layers were separated. The organic layer was then washed with saturated brine (50 mL×2), dried over anhydrous sodium sulfate, filtered, and then concentrated. MeOH (10 mL) was added to the residue, and the mixture was stirred for 20 minutes and filtered. The filter cake was dried under high vacuum to obtain the compound of formula (I). After XPRD testing, the obtained compound of formula (I) was identified as crystalline form A of compound of formula (I). 1 H NMR (DMSO-d6, 400 MHz): δ ppm 9.60 - 9.47 (m, 1H), 7.34 - 7.26 (m, 2H), 7.25 - 7.16 (m, 1H), 6.96 (br d, J = 6.0 Hz, 1H), 4.82 - 4.71 (m, 1H), 4.44 - 4.34 (m, 1H), 1.93 - 1.81 (m, 4H), 1.70 (br s, 4H), 1.48 (br d, J = 6.4 Hz, 3H); LCMS(ESI) m / z: 321.2(M+1). Example 2

[0082] (Preparation of Crystalline Form A of Compound of Formula (I)) The compound of formula (I) (80 mg, 249.74 μmol) was added to ethanol (3 mL), and the mixture was stirred at 80° C. for 16 hours. The mixture was cooled to room temperature and then filtered. The solid was dried under vacuum to obtain crystalline form A of the compound of formula (I). 1 H NMR (DMSO-d6, 400 MHz): δ ppm 9.60 - 9.47 (m, 1H), 7.34 - 7.26 (m, 2H), 7.25 - 7.16 (m, 1H), 6.96 (br d, J = 6.0 Hz, 1H), 4.82 - 4.71 (m, 1H), 4.44 - 4.34 (m, 1H), 1.93 - 1.81 (m, 4H), 1.70 (br s, 4H), 1.48 (br d, J = 6.4 Hz, 3H); LCMS(ESI) m / z: 321.2(M+1). XRPD, DSC and TGA of crystalline form A of compound of formula (I) were all tested using the corresponding method 1, and the test result patterns and curves are shown in Figures 1, 2 and 3, respectively.

[0083] When the solvent ethanol was replaced with methanol, dichloromethane, ethyl acetate, or tetrahydrofuran, crystalline form A of the compound of formula (I) was obtained at room temperature or heated in each case. The assay results are shown in Table 8. Table 8. Assay of crystalline forms obtained by stirring in different solvents [Table 10] Example 3

[0084] (Preparation of Crystalline Form B of Compound of Formula (I)) Approximately 60 mg of the crystalline form A was weighed and heated using a TGA from room temperature (20-25°C) to 250°C at a rate of 10°C / min, and then allowed to cool naturally to room temperature (the cooling rate was not controlled during the cooling process) to obtain crystalline form B of the compound of formula (I). 1H NMR (DMSO-d6, 400 MHz): δ ppm 9.57 (s, 1H), 7.32 - 7.27 (m, 2H), 7.22 - 7.15 (m, 1H), 6.96 (br d, J = 6.4 Hz, 1H), 4.78 - 4.72 (m, 1H), 4.38 (s, 1H), 1.86 - 1.82 (m, 4H), 1.70 - 1.67 (m, 4H), 1.47 (br d, J = 6.8 Hz, 3H). XRPD and DSC of crystalline form B of compound of formula (I) were both tested using the corresponding method 2, and the test pattern and curve are shown in Figures 5 and 6, respectively. Example 4

[0085] (Single crystal X-ray diffraction analysis of the compound of formula (I)) 1. Instrument Parameters and Data Acquisition Manufacturer:Bruker Corporation; Equipment model: Bruker D8 VENTURE; X-ray source: A high-intensity microfocus rotating anode light source was used; Cu rotating target: λ=1.54184Å; Power: 2.5kw; Tube voltage: 50 kV; Tube current: 50mA; Goniometer: 4-axis (Kappa, ω, 2θ, φ) goniometer; Detector: Large-area photon II detector, effective detector area 14cm x 10cm Distance from detector to sample: d = 45 mm.

[0086] 2.Crystal Growth A 14.3 mg sample was weighed and added to MeOH (2 mL). The sample was insoluble. DMSO (1 mL) was then added dropwise, and the mixture was stirred until completely dissolved. The dissolved sample was transferred to a 4 mL semi-sealed sample vial and slowly evaporated at room temperature. After 7 days, colorless block crystals were obtained and subjected to single crystal testing.

[0087] 3. Crystallographic Data Table Table 9. Single crystal structure data of compounds of formula (I) [Table 11]

[0088] 4. Conclusion The single crystal data indicated that the single crystal was the compound of formula (I). An ellipsoidal view of the three-dimensional structure of the compound of formula (I) from single crystal X-ray diffraction (SC-XRD) is shown in Figure 4. The single crystal structural data and parameters of the compound of formula (I) are shown in Table 9.

[0089] Biological Assay Data: Assay Example 1: Assay of inhibitory effect on cardiac myosin ATPase activity Assay Reagents: Cardiac tropomyosin / troponin complex (Cytoskeleton, Cat. #TT05) Cardiac myosin S1 (Cytoskeleton, Cat. #MYS03) Cardiac actin (Cytoskeleton, Cat. #AD99-A) ATPase assay biochem kit (Cytoskeleton, Cat. #BK051)

[0090] Assay steps: 1) Preparation of compounds a) The compounds were serially diluted in DMSO in Echo at 8 concentrations, each 4-fold, and 200 nL of each concentration of the compounds was transferred to a 96-well plate (Corning-3696). b) The plate was centrifuged at 1000 rpm for 15 seconds and sealed for later use. 2) Preparation of F-actin a) 5 mM Pipes-KOH buffer (pH 7.0), 500 μM ATP, and 500 μM dithiothreitol were prepared, and 2.5 mL of the buffer was added to dissolve 1 mg of F-actin, resulting in a protein concentration of 0.4 mg / mL. b) The mixture was allowed to stand at room temperature for 10 minutes to completely dissolve the protein. c) 2.0 mM MgCl2 and 2.0 mM EGTA were added, and the mixture was allowed to stand at room temperature for 20 minutes to form protein polymers. 3) Preparation of thin filaments a) 200 μL of ice water was added to dissolve 1 mg of cardiac tropomyosin / troponin complex, resulting in a protein concentration of 5 mg / mL. b) 1000 μL of F-actin prepared in step 1 was added and mixed well. c) The mixture was allowed to stand at room temperature for 20 minutes. d) The mixture was centrifuged at 87K×g at 4° C. for 1.5 hours. e) PM12 buffer (12 mM Pipes-KOH, pH 7.0, 2 mM MgCl2) was prepared and 1200 μL of the buffer was added to resuspend the protein. 4) Preparation of reaction solution and initiation of assay a) 250 μL of ice-cold PM12 buffer was added to 250 μg of S1 myosin to give a protein concentration of 1 mg / mL. b) The reagents were added sequentially in the following order and mixed to obtain a reaction mixture: 400 μL of PM12, 400 μL of 5× MSEG (from the biochem kit for the ATPase assay), 1200 μL actin / cardiac tropomyosin / troponin complex, 40 μL of myosin S1, 40 μL of 100× PNP (from the biochem kit for the ATPase assay), 10.4 μL of 100 mM ATP. c) 10 μL of 440 μM CaCl 2 solution was added to the 96-well plate, and the plate was transferred to a 37° C. incubator to preheat. d) 100 μL of the reaction mixture was added to the 96-well plate, and the plate was centrifuged at 1000 rpm for 10 seconds. e) The plate was read continuously for 10 minutes at 30 second intervals on a SpectraMax340PC at an instrument temperature of 37°C and a wavelength of 360 nm.

[0091] Data Analysis: Data was analyzed using Prism and the assay results are shown in Table 10. Table 10. Assay Results: IC of compounds of the present disclosure, which are inhibitory effects on cardiac myosin ATPase activity. 50 value [Table 12] Conclusion: The compounds of the present disclosure have good inhibitory activity against cardiac myosin ATPase.

[0092] Assay Example 2: Pharmacokinetic evaluation in rats Assay Objective: The pharmacokinetic parameters of compounds of the present disclosure were determined in rats. Assay scheme: 1) Assay Agent: A compound of the present disclosure; 2) Assay animals: Four male SD rats (7–9 weeks old) were randomly divided into two groups, each containing two rats; 3) Drug preparation: An appropriate amount of the drug was weighed and dissolved in a mixed solvent (DMAC:PEG-400:2-HP-β-CD (30%) = 5:25:70, adjusted to 0.2 mg / mL); Assay Procedure: Animals in Group 1 were administered the drug at a dose of 0.2 mg / kg via a single tail vein injection at a concentration of 0.2 mg / mL. Animals in Group 2 were administered the compound at a dose of 1 mg / kg via gavage at a concentration of 0.2 mg / mL. Plasma samples were collected from the animals at 0.0833 (tail vein injection group only), 0.25, 0.5, 1, 2, 4, 6, 8, and 24 hours after administration. Data Analysis: Drug concentrations in plasma samples were determined using an LC-MS / MS method. The pharmacokinetic assay results obtained for the assay drugs are shown in Table 11. Table 11. Pharmacokinetic assay results for compounds of the present disclosure [Table 13] -- indicates that no data is available. Conclusion: The compounds of the present disclosure have good pharmacokinetic properties in rats.

Claims

1. 2. A compound of formula (I), characterized by an X-ray powder diffraction pattern (XPRD) having characteristic diffraction peaks at angles 2θ of 18.283±0.200°, 19.662±0.200°, and 22.420±0.200°. 【Chemical 1】 (I) Crystal A of the compound of formula (I).

2. 2. The crystal of claim 1, characterized by an X-ray powder diffraction pattern (XPRD) having characteristic diffraction peaks at angles 2θ of 11.143±0.200°, 18.283±0.200°, 19.662±0.200°, 22.420±0.200°, 26.259±0.200°, and 28.056±0.200°.

3. The crystal described in claim 1, characterized by a powder X-ray diffraction pattern having characteristic diffraction peaks at angles 2θ of 11.143±0.200°, 18.283±0.200°, 19.662±0.200°, 22.420±0.200°, 26.259±0.200°, 27.261±0.200°, 28.056±0.200°, and 30.256±0.200°.

4. The crystal described in claim 1, characterized by an X-ray powder diffraction pattern having characteristic diffraction peaks at angles 2θ of 11.143±0.200°, 16.522±0.200°, 17.053±0.200°, 18.283±0.200°, 19.662±0.200°, 22.420±0.200°, 23.909±0.200°, 26.259±0.200°, 27.261±0.200°, 28.056±0.200°, 30.256±0.200°, and 33.761±0.200°.

5. The crystal described in claim 1, characterized by an X-ray powder diffraction pattern including at least 5, 6, 7, or 8 characteristic diffraction peaks represented by angles 2θ selected from the following angles: 11.143±0.200°, 18.283±0.200°, 19.662±0.200°, 22.420±0.200°, 26.259±0.200°, 27.261±0.200°, 28.056±0.200°, and 30.256±0.200°.

6. The compound is characterized by an X-ray powder diffraction pattern including at least 5, 6, 7, or 8 characteristic diffraction peaks represented by angles 2θ selected from the following angles: 11.143±0.200°, 18.283±0.200°, 19.662±0.200°, 22.420±0.200°, 26.259±0.200°, 27.261±0.200°, 28.056±0.200°, and 30.256±0.200°, and the characteristic diffraction peaks are represented by angles 2θ selected from the following angles: 11.143°, 13.260°, 14.860°, 16.163°, 16.522°, 17.053°, 2. The crystal of claim 1, characterized by an X-ray powder diffraction pattern having characteristic diffraction peaks at angles 2θ of 17.537°, 18.283°, 19.662°, 22.420°, 23.568°, 23.909°, 26.259°, 26.726°, 27.261°, 28.056°, 29.008°, 30.256°, 31.219°, 31.646°, 32.037°, 32.438°, 32.807°, 33.761°, 34.534°, 35.404°, 36.856°, 37.813°, and 39.456°.

7. The crystal described in claim 1, having a differential scanning calorimetry (DSC) curve with endothermic peak values ​​at 249.53±8°C and 306.12±8°C.

8. The crystal described in claim 1, having a differential scanning calorimetry (DSC) curve with endothermic peak values ​​at 249.53±3°C and 306.12±3°C.

9. The crystal described in claim 1, having a thermogravimetric analysis (TGA) curve with a maximum weight loss of 0.075% at 200±3°C and a maximum weight loss of 0.164% at 250±3°C.

10. The crystal described in claim 8, having a thermogravimetric analysis (TGA) curve with a maximum weight loss of 0.075% at 200±3°C and a maximum weight loss of 0.164% at 250±3°C. 11) adding a compound of formula (I) to an alcoholic solvent, ethyl acetate, tert-butyl methyl ether, tetrahydrofuran, or dichloromethane; wherein the alcoholic solvent is suitably selected from methanol and ethanol; 2) stirring at 15 to 100°C for 1 to 168 hours; 3) filtering, recovering the filter cake, and drying the filter cake under vacuum at 30-45°C for 0.5-2 hours; 2. A method for preparing a crystalline A of the compound of formula (I) according to claim 1, wherein the compound of formula (I) has the formula (I): 【Chemistry 2】 (I) That's the method.

12. The method of claim 11, wherein in step 3) the filter cake is vacuum dried at 35°C for 1 hour.

13. A pharmaceutical composition comprising a therapeutically effective amount of the compound of formula (I) or crystalline A of the compound of formula (I) described in any one of claims 1 to 10, and a pharmaceutically acceptable carrier.

14. A pharmaceutical composition for use as a cardiac myosin inhibitor, comprising the compound of formula (I) or crystalline A of the compound of formula (I) according to any one of claims 1 to 10.

15. A pharmaceutical composition for treating heart failure or hypertrophic cardiomyopathy, comprising the compound of formula (I) or crystalline A of the compound of formula (I) according to any one of claims 1 to 10.

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