Crystal form of nitrogen-containing heterocyclic ketone compound and preparation method thereof

Abstract

The invention relates to a crystal form of a nitrogen-containing heterocyclic ketone compound and a preparation method thereof. Specifically, the invention relates to a salt of a compound shown in a general formula (I), a crystal form, a preparation method, a pharmaceutical composition containing a therapeutically effective amount of the crystal form, and a pharmaceutical application of the crystal form in treatment of hypertrophic cardiomyopathy (HCM) and other forms of heart diseases or symptoms. # imgabs0 #

Description

A crystal form of nitrogen-containing heterocyclic ketone compound and preparation method thereof

[0001] The invention belongs to the field of drug synthesis, and specifically relates to a salt, a crystal form, a preparation method and an application of a nitrogen-containing heterocyclic ketone compound.

[0002] Hypertrophic cardiomyopathy (HCM) is a genetic disease that affects approximately 1 in 500 people in the general population. Patients with HCM are often diagnosed with left ventricular hypertrophy during clinical observation, which cannot be explained by other known causes. Other notable histopathological findings of HCM include enlarged cardiomyocytes, disorganization, and increased amounts of myocardial fibrosis. Heart function in patients with HCM is also disturbed by characteristic hyperdynamic contractions and impaired relaxation.

[0003] HCM patients with underlying familial or somatic mutations may experience symptoms including chest pain, shortness of breath, fatigue, palpitations and even sudden death. Despite its prevalence and severe symptoms, there are few targeted therapies available to improve HCM from the source and change the progression of the disease. Currently used drugs, such as beta-adrenergic receptor blockers or calcium channel blockers, can non-specifically reduce the contractility of the myocardium, thereby alleviating some symptoms, but these treatments cannot prevent the progression of the disease. Therefore, it is very important to develop drugs that can inhibit the progression of ventricular hypertrophy, cardiomyocyte disorders and myocardial fibrosis.

[0004] Selective inhibition of cardiac sarcomere hypercontractility is a promising targeted approach for HCM. New mechanisms of action may provide therapeutic advantages in alleviating symptoms, improving treatment access, and reducing patient mortality. Therefore, there is a need in the art for new selective cardiac sarcomere modulators.

[0005] PCT / CN2022 / 081361 discloses the structures of a series of polycyclic compounds containing nitrogen heterocycles. In subsequent research and development, in order to facilitate the handling, filtration and drying of the products, and to seek suitable crystals that are easy to store and have long-term stability, the present invention has conducted a comprehensive study on the crystal forms of the above-mentioned compounds.

[0006]

[0007] All contents involved in patent PCT / CN2022 / 081361 are added to the present invention by reference.

[0008] In one aspect, the present invention provides a crystalline form of a compound represented by general formula (I), and the structure of the compound is shown below:

[0009] in:

[0010] R1 is selected from C1-C3 alkyl, C1-C3 haloalkyl or C1-C3 alkoxy;

[0011] R2 and R3 together with their adjacent C atoms form a 5-6 membered heterocyclic group containing 1-2 atoms selected from N and O atoms;

[0012] R4 is independently selected from halogen, C1-C3 alkyl, C1-C3 alkoxy or C1-C3 haloalkyl.

[0013] In certain embodiments of the present invention, R1 is C1-C3 alkyl;

[0014] R4 and R5 together with their adjacent C atoms form and

[0015] R6 is independently selected from F, Cl and Br.

[0016] In certain embodiments of the present invention, the general formula (I) is selected from the following compounds:

[0017] In certain embodiments of the present invention, the crystalline form is a crystalline form of (S)-6-((1-(2,4-difluorophenyl)ethyl)amino)-3-(tetrahydro-2H-pyran-4-yl)-1,3,5-triazine-2,4(1H,3H)-dione, wherein the crystalline form is an anhydrous crystalline form.

[0018] In certain embodiments of the present invention, the crystalline form is a crystalline form of (S)-6-((1-(2,4-difluorophenyl)ethyl)amino)-3-(tetrahydro-2H-pyran-4-yl)-1,3,5-triazine-2,4(1H,3H)-dione, wherein the crystalline form is a hydrate containing 0.25 to 2 water, preferably 0.5 water, 1 water or 2 water.

[0019] In certain embodiments of the present invention, the water molecules of the hydrate are pipeline water or crystal water.

[0020] In certain embodiments of the present invention, the crystalline form is Form A of (S)-6-((1-(2,4-difluorophenyl)ethyl)amino)-3-(tetrahydro-2H-pyran-4-yl)-1,3,5-triazine-2,4(1H,3H)-dione, wherein:

[0021] The powder X-ray diffraction spectrum of Form A has a characteristic peak at 2θ of 8.0±0.2°, or at 2θ of 16.5±0.2°, or at 2θ of 18.3±0.2°, or at 2θ of 20.4±0.2°, or at 2θ of 14.9±0.2°, or at 2θ of 17.4±0.2°, or at 2θ of 17.7±0.2°, or at 2θ of 18.9±0.2°, or at 2θ of 10. The invention relates to a method for preparing an aqueous phase having a characteristic peak at 2θ of 14.7±0.2°, ...

[0022] In certain embodiments of the present invention, the powder X-ray diffraction pattern of Form A has one or more characteristic peaks at 8.0±0.2°, 16.5±0.2°, 18.3±0.2° or 20.4±0.2°; preferably 2-4 of them, more preferably 3-4, most preferably 4; optionally, further, it may also include one or more characteristic peaks at 2θ of 14.9±0.2°, 17.4±0.2°, 17.7±0.2°, 18.9±0.2°, 22.4±0.2° or 10.7±0.2°, preferably 2, 3, 4 or 6 of them. For example:

[0023] 8.0±0.2°, 16.5±0.2°, 18.3±0.2°;

[0024] 8.0±0.2°, 16.5±0.2°, 18.3±0.2°, 20.4±0.2°;

[0025] 8.0±0.2°, 16.5±0.2°, 18.3±0.2°, 20.4±0.2°, 14.9±0.2°, 17.4±0.2°;

[0026] 8.0±0.2°, 16.5±0.2°, 18.3±0.2°, 20.4±0.2°, 14.9±0.2°, 17.4±0.2°, 17.7±0.2°, 18.9±0.2°;

[0027] 8.0±0.2°, 16.5±0.2°, 18.3±0.2°, 20.4±0.2°, 17.7±0.2°, 18.9±0.2°, 22.4±0.2°, 10.7±0.2°.

[0028] In certain embodiments of the present invention, the powder X-ray diffraction pattern of Form A has characteristic peaks at 2θ of 8.0±0.2° and 16.5±0.2°; preferably, it also includes characteristic peaks at 2θ of 18.3±0.2° and 20.4±0.2°; more preferably, it also includes characteristic peaks at 2θ of 14.9±0.2°, 17.4±0.2°, 17.7±0.2° and 18.9±0.2°; further preferably, it also includes characteristic peaks at 2θ of 10.7±0.2° and 16.7±0.2°; further preferably, it also includes characteristic peaks at one or more of 21.3±0.2°, 22.4±0.2°, 24.9±0.2° and 27.6±0.2°.

[0029] In certain embodiments of the present invention, Cu-Kα radiation is used, and the characteristic peaks of X-rays expressed in terms of 2θ angles and interplanar spacing d values ​​are shown in Table 1.

[0030] Table 1

[0031] In certain embodiments of the present invention, the X-ray powder diffraction pattern of Form A is substantially as shown in FIG. 1 ; its DSC pattern is substantially as shown in FIG. 2 ; and its TGA pattern is substantially as shown in FIG. 3 .

[0032] In certain embodiments of the present invention, the crystalline form is (S)-6-((1-(2,4-difluorophenyl)ethyl)amino)-3-(tetrahydro-2H-pyran-4-yl)-1,3,5-triazine-2,4(1H,3H)-dione crystalline form B, and its powder X-ray diffraction spectrum has a characteristic peak at 2θ of 16.6±0.2°, or has a characteristic peak at 2θ of 18.3±0.2°, or has a characteristic peak at 2θ of 18.5±0.2°, or has a characteristic peak at 2θ of 10.7±0.2°, Or it has a characteristic peak at 2θ of 14.9±0.2°, or has a characteristic peak at 2θ of 20.4±0.2°, or has a characteristic peak at 2θ of 24.4±0.2°, or has a characteristic peak at 2θ of 24.9±0.2°, or has a characteristic peak at 2θ of 26.9±0.2°, or has a characteristic peak at 2θ of 20.7±0.2°, or has a characteristic peak at 2θ of 16.0±0.2°; preferably, it comprises 2, 4, 6, 8 or 10 of the characteristic peaks.

[0033] In certain embodiments of the present invention, the powder X-ray diffraction pattern of Form B has one or more characteristic peaks at 2θ of 16.6±0.2°, 18.3±0.2°, 18.5±0.2° or 10.7±0.2°; preferably 2-4 of them, more preferably 3-4 of them, and most preferably 4 of them; optionally, further, it may also include one or more characteristic peaks at 2θ of 14.9±0.2°, 20.4±0.2°, 24.4±0.2°, 24.9±0.2°, 26.9±0.2°, 20.7±0.2° or 16.0±0.2°, preferably 2, 3, 4 or 6 of them.

[0034] In certain embodiments of the present invention, the powder X-ray diffraction pattern of Form B has characteristic peaks at 2θ of 16.6±0.2° and 18.3±0.2°; preferably, it also includes characteristic peaks at 2θ of 10.7±0.2° and 18.5±0.2°; more preferably, it also includes characteristic peaks at 2θ of 14.9±0.2°, 16.0±0.2°, 20.4±0.2° and 20.7±0.2°; further preferably, it also includes characteristic peaks at one or more of 2θ of 24.4±0.2°, 24.9±0.2° and 26.9±0.2°.

[0035] In certain embodiments of the present invention, Cu-Kα radiation is used, and the X-ray characteristic peaks of Form B are represented by 2θ angles and interplanar spacing d values ​​as shown in Table 2.

[0036] Table 2

[0037] In certain embodiments of the present invention, the X-ray powder diffraction pattern of Form B is substantially as shown in FIG. 4 ; and the DSC pattern thereof is substantially as shown in FIG. 5 .

[0038] In certain embodiments of the present invention, the crystalline form is (S)-6-((1-(2,4-difluorophenyl)ethyl)amino)-3-(tetrahydro-2H-pyran-4-yl)-1,3,5-triazine-2,4(1H,3H)-dione crystalline form C, and its powder X-ray diffraction spectrum has a characteristic peak at 2θ of 17.4±0.2°, or a characteristic peak at 2θ of 18.3±0.2°, or a characteristic peak at 2θ of 19.6±0.2°, or a characteristic peak at 2θ of 5.5±0.2°, or a characteristic peak at 2θ of 9.4±0.2°, or The method comprises the following steps: the method comprises a characteristic peak at 2θ of 10.9±0.2°, 2θ of 16.5±0.2°, 2θ of 25.8±0.2°, 2θ of 27.5±0.2°, 2θ of 10.7±0.2°, 2θ of 18.8±0.2°, 2θ of 22.4±0.2°, 2θ of 26.8±0.2°; preferably, the method comprises characteristic peaks at any of 2, 4, 6, 8 or 10 locations.

[0039] In certain embodiments of the present invention, the powder X-ray diffraction pattern of Form C has one or more characteristic peaks at 2θ of 17.4±0.2°, 18.3±0.2°, 19.6±0.2° or 5.5±0.2°; preferably includes 2-4 of them, more preferably includes 3-4, and most preferably includes 4; optionally, further, it may also include one or more characteristic peaks at 2θ of 9.4±0.2°, 10.9±0.2°, 16.5±0.2°, 25.8±0.2°, 27.5±0.2° or 10.7±0.2°, preferably includes 2, 3, 4 or 6 of them.

[0040] In certain embodiments of the present invention, the powder X-ray diffraction pattern of Form C has characteristic peaks at 2θ of 5.5±0.2° and 19.6±0.2°; preferably, it also includes characteristic peaks at 2θ of 17.4±0.2° and 18.3±0.2°; more preferably, it also includes characteristic peaks at 2θ of 9.4±0.2°, 10.9±0.2°, 16.5±0.2° and 25.8±0.2°; further preferably, it also includes characteristic peaks at one or more of 2θ of 10.7±0.2°, 18.8±0.2°, 22.4±0.2°, 26.8±0.2° and 27.5±0.2°.

[0041] In certain embodiments of the present invention, the X-ray powder diffraction pattern of Form C has characteristic peaks at 2θ (±0.2°) of 17.4, 18.3 and 19.6; further includes characteristic peaks at 2θ (±0.2°) of 5.5, 9.4, 10.9, 16.5, 25.8 and 27.5; further includes characteristic peaks at 2θ (±0.2°) of 10.7, 18.8, 22.4 and 26.8.

[0042] In certain embodiments of the present invention, Cu-Kα radiation is used, and the X-ray characteristic peaks of Form C are expressed in terms of 2θ angles and interplanar spacing d values ​​as shown in Table 3.

[0043] Table 3

[0044] In certain embodiments of the present invention, Form C has an X-ray powder diffraction pattern substantially as shown in FIG. 6 ; and a DSC pattern substantially as shown in FIG. 7 .

[0045] In certain embodiments of the present invention, the crystalline form is (S)-6-((1-(2,4-difluorophenyl)ethyl)amino)-3-(tetrahydro-2H-pyran-4-yl)-1,3,5-triazine-2,4(1H,3H)-dione crystalline form D, wherein: the powder X-ray diffraction pattern of crystalline form D has a characteristic peak at 2θ of 17.2±0.2°, or has a characteristic peak at 2θ of 9.7±0.2°, or has a characteristic peak at 2θ of 13.8±0.2°, or has a characteristic peak at 2θ of 15.3±0.2°. The method comprises the following steps: wherein the peak is at 18.4±0.2°, 2θ is 21.6±0.2°, 2θ is 24.9±0.2°, 2θ is 14.9±0.2°, 2θ is 27.6±0.2°, 2θ is 30.1±0.2°, 2θ is 33.9±0.2°, or has a characteristic peak at 2θ of 33.9±0.2°; preferably, the method comprises 2, 4, 6, 8 or 10 characteristic peaks optionally selected therefrom.

[0046] In certain embodiments of the present invention, the powder X-ray diffraction pattern of Form D has one or more characteristic peaks at 2θ of 17.2±0.2°, 9.7±0.2°, 13.8±0.2° or 15.3±0.2°; preferably includes 2-4 of them, more preferably includes 3-4, and most preferably includes 4; optionally, further, it may also include one or more characteristic peaks at 2θ of 18.4±0.2°, 21.6±0.2°, 24.9±0.2°, 14.9±0.2°, 27.6±0.2° or 30.1±0.2°, preferably includes 2, 3, 4 or 6 of them.

[0047] In certain embodiments of the present invention, the powder X-ray diffraction pattern of Form D has characteristic peaks at 2θ of 9.7±0.2° and 17.2±0.2°; preferably, it also includes characteristic peaks at 2θ of 13.8±0.2° and 15.3±0.2°; more preferably, it also includes characteristic peaks at 2θ of 18.4±0.2°, 21.6±0.2°, 24.9±0.2° and 14.9±0.2°; further preferably, it also includes characteristic peaks at one or more of 2θ of 27.6±0.2°, 30.1±0.2° and 33.9±0.2°.

[0048] In certain embodiments of the present invention, Cu-Kα radiation is used, and the X-ray characteristic peaks of Form D are represented by 2θ angles and interplanar spacing d values ​​as shown in Table 4.

[0049] Table 4

[0050] In certain embodiments of the present invention, the X-ray powder diffraction pattern of Form D is substantially as shown in FIG8 ; and the DSC pattern thereof is substantially as shown in FIG9 .

[0051] In certain embodiments of the present invention, the crystalline form is (S)-6-((1-(2,4-difluorophenyl)ethyl)amino)-3-(tetrahydro-2H-pyran-4-yl)-1,3,5-triazine-2,4(1H,3H)-dione crystalline form E, wherein: the powder X-ray diffraction pattern of crystalline form E has a characteristic peak at 2θ of 8.0±0.2°, or has a characteristic peak at 2θ of 12.8±0.2°, or has a characteristic peak at 2θ of 18.0±0.2°, or has a characteristic peak at 2θ of 18.9±0.2°, or has a characteristic peak at 2θ of 19.8±0.2°, or has a characteristic peak at 2θ of 20.6±0.2°; preferably, it comprises characteristic peaks at any of 2, 4 or 6 positions.

[0052] In certain embodiments of the present invention, the powder X-ray diffraction spectrum of Form E has characteristic peaks at one or more of 2θ of 8.0±0.2°, 12.8±0.2°, 18.0±0.2° or 18.9±0.2°; preferably 2-4 of them, more preferably 3-4, most preferably 4; optionally, further, characteristic peaks may be included at 19.8±0.2° and 20.6±0.2°. For example:

[0053] 8.0±0.2°, 12.8±0.2°;

[0054] 8.0±0.2°, 12.8±0.2°, 18.0±0.2°;

[0055] 8.0±0.2°, 12.8±0.2°, 18.0±0.2°, 18.9±0.2°;

[0056] 8.0±0.2°, 12.8±0.2°, 18.0±0.2°, 18.9±0.2°, 9.8±0.2°, 20.6±0.2°.

[0057] In certain embodiments of the present invention, the powder X-ray diffraction pattern of Form E has characteristic peaks at 2θ of 8.0±0.2° and 12.8±0.2°; preferably, it also includes characteristic peaks at 2θ of 18.0±0.2° and 18.9±0.2°; more preferably, it also includes characteristic peaks at 2θ of 19.8±0.2° and 20.6±0.2°.

[0058] In certain embodiments of the present invention, Cu-Kα radiation is used, and the X-ray characteristic peaks of Form E are represented by 2θ angles and interplanar spacing d values ​​as shown in Table 5.

[0059] Table 5

[0060] In certain embodiments of the present invention, Form E has an X-ray powder diffraction pattern substantially as shown in FIG. 10 ; a DSC pattern substantially as shown in FIG. 11 ; and a TGA pattern substantially as shown in FIG. 12 .

[0061] In certain embodiments of the present invention, the crystalline form is (S)-6-((1-(2,4-difluorophenyl)ethyl)amino)-3-(tetrahydro-2H-pyran-4-yl)-1,3,5-triazine-2,4(1H,3H)-dione crystalline form F, wherein: the powder X-ray diffraction pattern of crystalline form F has a characteristic peak at 2θ of 7.3±0.2°, or has a characteristic peak at 2θ of 11.8±0.2°, or has a characteristic peak at 2θ of 14.5±0.2°, or has a characteristic peak at 2θ of 19.4±0.2°, or has a characteristic peak at 2θ of 21.7±0.2°. The invention relates to a method for preparing an aqueous phase-enhanced ...

[0062] In certain embodiments of the present invention, the powder X-ray diffraction pattern of Form F has one or more characteristic peaks at 2θ of 7.3±0.2°, 11.8±0.2°, 14.5±0.2° or 21.7±0.2°; preferably includes 2-4 of them, more preferably includes 3-4, and most preferably includes 4; optionally, further, it may also include one or more characteristic peaks at 2θ of 19.4±0.2°, 10.8±0.2°, 11.0±0.2°, 15.4±0.2°, 16.1±0.2° or 16.9±0.2°, preferably includes 2, 3, 4 or 6 of them.

[0063] In certain embodiments of the present invention, the powder X-ray diffraction pattern of Form F has characteristic peaks at 2θ of 7.3±0.2° and 11.8±0.2°; preferably, it also includes characteristic peaks at 2θ of 21.7±0.2° and 14.5±0.2°; more preferably, it also includes characteristic peaks at 2θ of 19.4±0.2°, 10.8±0.2°, 11.0±0.2° and 15.4±0.2°; further preferably, it also includes characteristic peaks at 2θ of 16.1±0.2° and 16.9±0.2°; further preferably, it also includes characteristic peaks at one or more of 17.7±0.2°, 18.0±0.2° and 20.4±0.2°.

[0064] In certain embodiments of the present invention, Cu-Kα radiation is used, and the X-ray characteristic peaks of Form F are represented by 2θ angles and interplanar spacing d values ​​as shown in Table 6.

[0065] Table 6

[0066] In certain embodiments of the present invention, Form F has an X-ray powder diffraction pattern substantially as shown in FIG. 13 .

[0067] In certain embodiments of the present invention, the crystalline form is (S)-6-((1-(2,4-difluorophenyl)ethyl)amino)-3-(tetrahydro-2H-pyran-4-yl)-1,3,5-triazine-2,4(1H,3H)-dione crystalline form G, wherein: the powder X-ray diffraction pattern of crystalline form G has a characteristic peak at 2θ of 7.7±0.2°, or has a characteristic peak at 2θ of 16.8±0.2°, or has a characteristic peak at 2θ of 17.0±0.2°, or has a characteristic peak at 2θ of 17.4±0.2°, or has a characteristic peak at 2θ of 17.7±0.2°, or has a characteristic peak at 2θ of 18.9±0.2°, or has a characteristic peak at 2θ of 19.3±0.2°. The invention relates to a method for preparing an aqueous phase-enhanced ...

[0068] In certain embodiments of the present invention, the powder X-ray diffraction pattern of Form G has one or more characteristic peaks at 2θ of 7.7±0.2°, 13.5±0.2°, 13.8±0.2° or 18.9±0.2°; preferably includes 2-4 of them, more preferably includes 3-4, and most preferably includes 4; optionally, further, it may also include one or more characteristic peaks at 2θ of 16.8±0.2°, 17.4±0.2°, 17.7±0.2°, 19.3±0.2°, 20.2±0.2° or 14.5±0.2°, preferably includes 2, 3, 4 or 6 of them.

[0069] In certain embodiments of the present invention, the powder X-ray diffraction pattern of Form G has characteristic peaks at 2θ of 7.7±0.2° and 16.8±0.2°; preferably, it also includes characteristic peaks at 2θ of 17.0±0.2° and 17.4±0.2°; more preferably, it also includes characteristic peaks at 2θ of 17.7±0.2°, 18.9±0.2°, 19.3±0.2° and 20.2±0.2°; further preferably, it also includes characteristic peaks at 2θ of 13.5±0.2° and 13.8±0.2°; further preferably, it also includes characteristic peaks at one or more of 14.5±0.2°, 15.4±0.2°, 19.8±0.2° and 21.7±0.2°.

[0070] In certain embodiments of the present invention, Cu-Kα radiation is used, and the X-ray characteristic peaks of Form G are represented by 2θ angles and interplanar spacing d values ​​as shown in Table 7.

[0071] Table 7

[0072] In certain embodiments of the present invention, Form G has an X-ray powder diffraction pattern substantially as shown in FIG. 14 .

[0073] In certain embodiments of the present invention, the crystalline form is (S)-6-((1-(2,4-difluorophenyl)ethyl)amino)-3-(tetrahydro-2H-pyran-4-yl)-1,3,5-triazine-2,4(1H,3H)-dione crystalline form H, wherein: the powder X-ray diffraction pattern of the crystalline form H has a diffraction peak at 2θ of 8.1±0.2°, or has a diffraction peak at 2θ of 10.5±0.2°. The invention also has a diffraction peak at 2θ of 13.0±0.2°, a diffraction peak at 2θ of 13.4±0.2°, a diffraction peak at 2θ of 14.1±0.2°, a diffraction peak at 2θ of 14.8±0.2°, a diffraction peak at 2θ of 15.3±0.2°, a diffraction peak at 2θ of 16.0±0.2°, or a diffraction peak at 2θ of 16. The diffraction peak is 16.9±0.2° at 2θ, 17.3±0.2° at 2θ, 17.6±0.2° at 2θ, 17.9±0.2° at 2θ, 19.1±0.2° at 2θ, or 20.4±0.2° at 2θ. The invention relates to a method for preparing a diffraction peak in an optical system comprising: providing a diffraction peak at 2θ of 20.6±0.2°, a diffraction peak at 2θ of 21.0±0.2°, a diffraction peak at 2θ of 21.4±0.2°, a diffraction peak at 2θ of 23.5±0.2°, or a diffraction peak at 2θ of 25.4±0.2°; preferably, the method comprises diffraction peaks at any of 2, 4, 6, 8 or 10 locations.

[0074] In certain embodiments of the present invention, the powder X-ray diffraction pattern of Form H has one or more diffraction peaks at 2θ of 8.1±0.2°, 10.5±0.2°, 17.6±0.2° or 19.1±0.2°; preferably 2-4 of them, more preferably 3-4, most preferably 4; optionally, further, it may also include one or more diffraction peaks at 2θ of 16.5±0.2°, 16.9±0.2°, 17.3±0.2°, 17.9±0.2°, 20.6±0.2° or 21.0±0.2°, preferably 2, 3, 4 or 6 of them, for example:

[0075] 8.1±0.2°, 10.5±0.2°, 17.6±0.2°, 19.1±0.2°;

[0076] 8.1±0.2°, 10.5±0.2°, 16.5±0.2°, 17.6±0.2°;

[0077] 8.1±0.2°、10.5±0.2°、16.9±0.2°、17.6±0.2°；

[0078] 8.1±0.2°、10.5±0.2°、17.3±0.2°、17.6±0.2°；

[0079] 8.1±0.2°、16.5±0.2°、17.6±0.2°、19.1±0.2°；

[0080] 8.1±0.2°、10.5±0.2°、17.6±0.2°、19.1±0.2°；

[0081] 10.5±0.2°、17.6±0.2°、17.3±0.2°、19.1±0.2°；

[0082] 17.3±0.2°、17.6±0.2°、19.1±0.2°、20.6±0.2°；

[0083] 8.1±0.2°、10.5±0.2°、17.6±0.2°、19.1±0.2°、20.6±0.2°；

[0084] 8.1±0.2°、10.5±0.2°、16.5±0.2°、17.6±0.2°、20.6±0.2°；

[0085] 8.1±0.2°、10.5±0.2°、16.9±0.2°、17.6±0.2°、19.1±0.2°；

[0086] 8.1±0.2°、10.5±0.2°、17.3±0.2°、17.6±0.2°、19.1±0.2°；

[0087] 8.1±0.2°、16.5±0.2°、17.6±0.2°、19.1±0.2°、20.6±0.2°；

[0088] 8.1±0.2°、10.5±0.2°、17.6±0.2°、19.1±0.2°、20.6±0.2°；

[0089] 10.5±0.2°、17.6±0.2°、17.3±0.2°、19.1±0.2°、20.6±0.2°；

[0090] 16.9±0.2°、17.3±0.2°、17.6±0.2°、19.1±0.2°、20.6±0.2°；

[0091] 8.1±0.2°, 10.5±0.2°, 17.3±0.2°, 17.6±0.2°, 19.1±0.2°, 20.6±0.2°;

[0092] 8.1±0.2°, 10.5±0.2°, 16.5±0.2°, 17.6±0.2°, 19.1±0.2°, 20.6±0.2°;

[0093] 8.1±0.2°, 10.5±0.2°, 16.9±0.2°, 17.6±0.2°, 19.1±0.2°, 20.6±0.2°;

[0094] 8.1±0.2°, 10.5±0.2°, 17.3±0.2°, 17.6±0.2°, 19.1±0.2°, 20.6±0.2°;

[0095] 8.1±0.2°, 16.5±0.2°, 16.9±0.2°, 17.3±0.2°, 17.6±0.2°, 19.1±0.2°;

[0096] 8.1±0.2°, 10.5±0.2°, 16.5±0.2°, 16.9±0.2°, 17.6±0.2°, 19.1±0.2°;

[0097] 10.5±0.2°, 16.9±0.2°, 17.6±0.2°, 17.3±0.2°, 19.1±0.2°, 20.6±0.2°;

[0098] 8.1±0.2°, 16.9±0.2°, 17.3±0.2°, 17.6±0.2°, 19.1±0.2°, 20.6±0.2°.

[0099] More preferably, the powder X-ray diffraction pattern optionally further comprises one or more diffraction peaks located at 2θ of 13.0±0.2°, 13.4±0.2°, 14.1±0.2°, 14.8±0.2°, 15.3±0.2° or 25.4±0.2°; preferably at least any 2-4, or 5-6 thereof, further preferably, any 4 or 6 thereof; for example:

[0100] 13.0±0.2°, 13.4±0.2°, 14.1±0.2°, 14.8±0.2°;

[0101] 13.0±0.2°, 13.4±0.2°, 14.1±0.2°, 15.3±0.2°;

[0102] 13.0±0.2°, 13.4±0.2°, 14.1±0.2°, 25.4±0.2°;

[0103] 13.0±0.2°, 13.4±0.2°, 15.3±0.2°, 25.4±0.2°;

[0104] 13.4±0.2°, 14.1±0.2°, 14.8±0.2°, 15.3±0.2°;

[0105] 13.0±0.2°, 13.4±0.2°, 14.1±0.2°, 14.8±0.2°, 15.3±0.2°;

[0106] 13.0±0.2°, 13.4±0.2°, 14.1±0.2°, 15.3±0.2°, 25.4±0.2°;

[0107] 13.0±0.2°, 13.4±0.2°, 14.1±0.2°, 14.8±0.2°, 15.3±0.2°, 25.4±0.2°.

[0108] In certain embodiments of the present invention, the powder X-ray diffraction pattern of Form H has characteristic peaks at 2θ of 17.6±0.2° and 19.1±0.2°; preferably, it also includes characteristic peaks at 2θ of 8.1±0.2°, 10.5±0.2°, 16.5±0.2° and 16.9±0.2°; more preferably, it also includes characteristic peaks at 2θ of 17.3±0.2° and 17.9±0.2°; further preferably, Preferably, it also includes characteristic peaks at 2θ of 20.6±0.2° and 25.4±0.2°, and more preferably, it also includes characteristic peaks at 13.0±0.2°, 13.4±0.2°, 14.1±0.2°, 14.8±0.2°, 15.3±0.2°, 16.0±0.2°, 20.4±0.2°, 21.0±0.2°, 21.4±0.2° and 23.5±0.2°.

[0109] In certain embodiments of the present invention, Cu-Kα radiation is used, and the X-ray characteristic peaks of Form H are represented by 2θ angles and interplanar spacing d values ​​as shown in Table 8.

[0110] Table 8

[0111] In certain embodiments of the present invention, Form H has an X-ray powder diffraction pattern substantially as shown in FIG. 15 .

[0112] In certain embodiments of the present invention, the crystalline form is (S)-6-((1-(2,4-difluorophenyl)ethyl)amino)-3-(tetrahydro-2H-pyran-4-yl)-1,3,5-triazine-2,4(1H,3H)-dione crystalline form I, wherein: the powder X-ray diffraction spectrum of crystalline form I has a diffraction peak at 2θ of 7.3±0.2°, or has a diffraction peak at 2θ of 9.8±0.2°. The invention also has a diffraction peak at 2θ of 10.7±0.2°, a diffraction peak at 2θ of 11.2±0.2°, a diffraction peak at 2θ of 11.8±0.2°, a diffraction peak at 2θ of 14.5±0.2°, a diffraction peak at 2θ of 15.3±0.2°, a diffraction peak at 2θ of 16.0±0.2°, or a diffraction peak at 2θ of 17. The diffraction peak is 2θ=3±0.2°, or 2θ=18.2±0.2°, or 2θ=18.9±0.2°, or 2θ=20.7±0.2°, or 2θ=21.6±0.2°, or 2θ=21.9±0.2°, or 2θ=22.4±0.2°. The invention relates to a method for preparing the present invention that has a diffraction peak at 2θ of 23.7±0.2°, a diffraction peak at 2θ of 23.7±0.2°, a diffraction peak at 2θ of 26.0±0.2°, a diffraction peak at 2θ of 26.2±0.2°, a diffraction peak at 2θ of 27.4±0.2°, or a diffraction peak at 2θ of 28.8±0.2°; preferably, the method comprises diffraction peaks at any of 2, 4, 6, 8 or 10 locations.

[0113] In certain embodiments of the present invention, the powder X-ray diffraction pattern comprises at least one or more diffraction peaks located at 2θ of 10.7±0.2°, 11.8±0.2°, 14.5±0.2° or 21.9±0.2°; preferably 2-4 of them, more preferably 3-4 of them, and most preferably 4 of them; optionally, further, it may also comprise one or more diffraction peaks at 2θ of 17.3±0.2°, 20.7±0.2°, 21.6±0.2°, 23.7±0.2° or 26.0±0.2°, preferably 2, 3, 4 or 5 of them; for example:

[0114] 10.7±0.2°, 11.8±0.2°, 14.5±0.2°, 21.9±0.2°;

[0115] 10.7±0.2°, 11.8±0.2°, 14.5±0.2°, 17.3±0.2°;

[0116] 10.7±0.2°、11.8±0.2°、14.5±0.2°、20.7±0.2°；

[0117] 10.7±0.2°、11.8±0.2°、14.5±0.2°、21.6±0.2°；

[0118] 10.7±0.2°、11.8±0.2°、14.5±0.2°、23.7±0.2°；

[0119] 10.7±0.2°、14.5±0.2°、17.3±0.2°、21.9±0.2°；

[0120] 10.7±0.2°、14.5±0.2°、20.7±0.2°、21.9±0.2°；

[0121] 11.8±0.2°、14.5±0.2°、17.3±0.2°、21.9±0.2°；

[0122] 10.7±0.2°、11.8±0.2°、14.5±0.2°、21.9±0.2°、23.7±0.2°；

[0123] 10.7±0.2°、11.8±0.2°、14.5±0.2°、17.3±0.2°、23.7±0.2°；

[0124] 10.7±0.2°、11.8±0.2°、14.5±0.2°、20.7±0.2°、23.7±0.2°；

[0125] 10.7±0.2°、11.8±0.2°、14.5±0.2°、21.6±0.2°、23.7±0.2°；

[0126] 10.7±0.2°、11.8±0.2°、14.5±0.2°、23.7±0.2°、26.0±0.2°；

[0127] 10.7±0.2°、14.5±0.2°、17.3±0.2°、21.9±0.2°、23.7±0.2°；

[0128] 10.7±0.2°、14.5±0.2°、20.7±0.2°、21.9±0.2°、23.7±0.2°；

[0129] 11.8±0.2°、14.5±0.2°、17.3±0.2°、21.9±0.2°、23.7±0.2°；

[0130] 10.7±0.2°, 11.8±0.2°, 14.5±0.2°, 21.9±0.2°, 23.7±0.2°, 26.0±0.2°;

[0131] 10.7±0.2°, 11.8±0.2°, 14.5±0.2°, 17.3±0.2°, 23.7±0.2°, 26.0±0.2°;

[0132] 10.7±0.2°, 11.8±0.2°, 14.5±0.2°, 20.7±0.2°, 23.7±0.2°, 26.0±0.2°;

[0133] 10.7±0.2°, 11.8±0.2°, 14.5±0.2°, 21.6±0.2°, 23.7±0.2°, 26.0±0.2°;

[0134] 10.7±0.2°, 11.8±0.2°, 14.5±0.2°, 17.3±0.2°, 20.7±0.2°, 26.0±0.2°;

[0135] 10.7±0.2°, 11.8±0.2°, 14.5±0.2°, 17.3±0.2°, 21.9±0.2°, 23.7±0.2°;

[0136] 10.7±0.2°, 14.5±0.2°, 20.7±0.2°, 21.9±0.2°, 23.7±0.2°, 26.0±0.2°;

[0137] 11.8±0.2°, 14.5±0.2°, 17.3±0.2°, 21.9±0.2°, 23.7±0.2°, 26.0±0.2°;

[0138] More preferably, the powder X-ray diffraction pattern optionally further comprises one or more diffraction peaks located at 2θ of 7.2±0.2°, 9.8±0.2°, 11.2±0.2°, 15.3±0.2°, 16.0±0.2° or 22.4±0.2°; preferably at least any 2-4, or 5-6 thereof, further preferably, any 4 or 6 thereof; for example:

[0139] 7.2±0.2°, 9.8±0.2°, 11.2±0.2°, 15.3±0.2°;

[0140] 7.2±0.2°, 9.8±0.2°, 11.2±0.2°, 16.0±0.2°;

[0141] 7.2±0.2°, 9.8±0.2°, 11.2±0.2°, 22.4±0.2°;

[0142] 7.2±0.2°, 11.2±0.2°, 15.3±0.2°, 16.0±0.2°;

[0143] 11.2±0.2°, 15.3±0.2°, 16.0±0.2°, 22.4±0.2°;

[0144] 7.2±0.2°, 9.8±0.2°, 11.2±0.2°, 15.3±0.2°, 16.0±0.2°;

[0145] 7.2±0.2°, 9.8±0.2°, 11.2±0.2°, 16.0±0.2°, 22.4±0.2°;

[0146] 7.2±0.2°, 9.8±0.2°, 11.2±0.2°, 15.3±0.2°, 16.0±0.2°, 22.4±0.2°.

[0147] In certain embodiments of the present invention, the powder X-ray diffraction pattern of Form I has characteristic peaks at 2θ of 11.8±0.2° and 21.9±0.2°; preferably, it also includes characteristic peaks at 2θ of 10.7±0.2°, 14.5±0.2°, 17.3±0.2° and 23.7±0.2°; more preferably, it also includes characteristic peaks at 2θ of 20.7±0.2° and 26.0±0.2°; further Preferably, the step further comprises characteristic peaks at 2θ of 21.6±0.2° and 22.4±0.2°, and further preferably, the step further comprises characteristic peaks at 7.2±0.2°, 9.8±0.2°, 11.2±0.2°, 15.3±0.2°, 16.0±0.2°, 18.2±0.2°, 18.9±0.2°, 26.2±0.2°, 27.4±0.2° and 28.8±0.2°.

[0148] In certain embodiments of the present invention, Cu-Kα radiation is used, and the X-ray characteristic peaks of Form I are represented by 2θ angles and interplanar spacing d values ​​as shown in Table 9.

[0149] Table 9

[0150] The X-ray powder diffraction spectrum of the crystalline form I of the compound represented by the general formula (I) of the present invention is basically shown in FIG16 ; and the DSC spectrum thereof is basically shown in FIG17 .

[0151] In certain embodiments of the present invention, the crystalline form is (S)-6-((1-(2,4-difluorophenyl)ethyl)amino)-3-(tetrahydro-2H-pyran-4-yl)-1,3,5-triazine-2,4(1H,3H)-dione crystalline form J, wherein: the powder X-ray diffraction pattern of crystalline form J has a diffraction peak at 2θ of 7.2±0.2°, or has a diffraction peak at 2θ of 10.8±0.2°. The invention also has a diffraction peak at 2θ of 11.0±0.2°, a diffraction peak at 2θ of 11.8±0.2°, a diffraction peak at 2θ of 14.4±0.2°, a diffraction peak at 2θ of 15.4±0.2°, a diffraction peak at 2θ of 16.1±0.2°, a diffraction peak at 2θ of 16.9±0.2°, or a diffraction peak at 2θ of 17. The diffraction peak is 2θ=7±0.2°, or 2θ=18.8±0.2°, or 2θ=19.4±0.2°, or 2θ=21.3±0.2°, or 2θ=21.7±0.2°, or 2θ=22.1±0.2°, or 2θ=23.3±0.2°. The invention relates to a method for preparing the present invention that has a diffraction peak at 2θ of 24.7±0.2°, a diffraction peak at 2θ of 25.2±0.2°, a diffraction peak at 2θ of 26.1±0.2°, a diffraction peak at 2θ of 27.8±0.2°, or a diffraction peak at 2θ of 29.7±0.2°; preferably, the method comprises diffraction peaks at any of 2, 4, 6, 8 or 10 locations.

[0152] In certain embodiments of the present invention, the powder X-ray diffraction pattern comprises at least one or more diffraction peaks located at 2θ of 10.8±0.2°, 11.0±0.2°, 11.8±0.2° or 16.1±0.2°; preferably 2-4 of them, more preferably 3-4 of them, and most preferably 4 of them; optionally, further, it may also comprise one or more diffraction peaks at 2θ of 7.2±0.2°, 14.4±0.2°, 15.4±0.2°, 19.4±0.2° or 21.7±0.2°, preferably 2, 3, 4 or 5 of them; for example:

[0153] 10.8±0.2°, 11.0±0.2°, 11.8±0.2°, 16.1±0.2°;

[0154] 10.8±0.2°、11.0±0.2°、11.8±0.2°、15.4±0.2°；

[0155] 10.8±0.2°、11.0±0.2°、11.8±0.2°、19.4±0.2°；

[0156] 10.8±0.2°、11.0±0.2°、14.4±0.2°、16.1±0.2°；

[0157] 7.2±0.2°、11.0±0.2°、11.8±0.2°、16.1±0.2°；

[0158] 7.2±0.2°、10.8±0.2°、11.0±0.2°、14.4±0.2°；

[0159] 7.2±0.2°、11.0±0.2°、14.4±0.2°、16.1±0.2°；

[0160] 10.8±0.2°、11.0±0.2°、19.4±0.2°、21.7±0.2°；

[0161] 10.8±0.2°、11.0±0.2°、11.8±0.2°、14.4±0.2°、16.1±0.2°；

[0162] 10.8±0.2°、11.0±0.2°、11.8±0.2°、14.4±0.2°、15.4±0.2°；

[0163] 10.8±0.2°、11.0±0.2°、11.8±0.2°、19.4±0.2°、21.7±0.2°；

[0164] 10.8±0.2°、11.0±0.2°、14.4±0.2°、16.1±0.2°、19.4±0.2°；

[0165] 7.2±0.2°、11.0±0.2°、11.8±0.2°、16.1±0.2°、19.4±0.2°；

[0166] 7.2±0.2°、10.8±0.2°、11.0±0.2°、14.4±0.2°、15.4±0.2°；

[0167] 7.2±0.2°、11.0±0.2°、14.4±0.2°、16.1±0.2°、19.4±0.2°、21.7±0.2°；

[0168] 10.8±0.2°, 11.0±0.2°, 11.8±0.2°, 16.1±0.2°, 19.4±0.2°, 21.7±0.2°;

[0169] 10.8±0.2°, 11.0±0.2°, 11.8±0.2°, 14.4±0.2°, 16.1±0.2°, 19.4±0.2°;

[0170] 10.8±0.2°, 11.0±0.2°, 11.8±0.2°, 14.4±0.2°, 15.4±0.2°, 19.4±0.2°;

[0171] 10.8±0.2°, 11.0±0.2°, 11.8±0.2°, 16.1±0.2°, 19.4±0.2°, 21.7±0.2°;

[0172] 10.8±0.2°, 11.0±0.2°, 14.4±0.2°, 16.1±0.2°, 19.4±0.2°, 21.7±0.2°;

[0173] 7.2±0.2°, 11.0±0.2°, 11.8±0.2°, 15.4±0.2°, 19.4±0.2°, 21.7±0.2°;

[0174] 7.2±0.2°, 10.8±0.2°, 11.0±0.2°, 14.4±0.2°, 15.4±0.2°, 19.4±0.2°;

[0175] 7.2±0.2°, 11.0±0.2°, 14.4±0.2°, 16.1±0.2°, 19.4±0.2°, 21.7±0.2°;

[0176] 10.8±0.2°, 11.0±0.2°, 11.8±0.2°, 15.4±0.2°, 19.4±0.2°, 21.7±0.2°.

[0177] More preferably, the powder X-ray diffraction pattern optionally further comprises one or more diffraction peaks located at 2θ of 16.9±0.2°, 17.7±0.2°, 18.8±0.2°, 21.3±0.2°, 22.1±0.2° or 23.3±0.2°; preferably at least any 2-4, or 5-6 thereof, further preferably, any 4 or 6 thereof; for example:

[0178] 16.9±0.2°, 17.7±0.2°, 18.8±0.2°, 21.3±0.2°;

[0179] 16.9±0.2°, 17.7±0.2°, 18.8±0.2°, 22.1±0.2°;

[0180] 16.9±0.2°, 17.7±0.2°, 18.8±0.2°, 23.3±0.2°;

[0181] 16.9±0.2°, 21.3±0.2°, 22.1±0.2°, 23.3±0.2°;

[0182] 16.9±0.2°, 18.8±0.2°, 21.3±0.2°, 22.1±0.2°;

[0183] 16.9±0.2°, 17.7±0.2°, 18.8±0.2°, 21.3±0.2°, 23.3±0.2°;

[0184] 16.9±0.2°, 17.7±0.2°, 18.8±0.2°, 22.1±0.2°, 23.3±0.2°;

[0185] 16.9±0.2°, 17.7±0.2°, 18.8±0.2°, 21.3±0.2°, 22.1±0.2°, 23.3±0.2°.

[0186] In certain embodiments of the present invention, Cu-Kα radiation is used, and the X-ray characteristic peaks of Form J are represented by 2θ angles and interplanar spacing d values ​​as shown in Table 10.

[0187] Table 10

[0188] In certain embodiments of the present invention, Form J has an X-ray powder diffraction pattern substantially as shown in FIG. 18 ; and a DSC pattern substantially as shown in FIG. 19 .

[0189] In certain embodiments of the present invention, the crystalline form is (S)-6-((1-(2,4-difluorophenyl)ethyl)amino)-3-(tetrahydro-2H-pyran-4-yl)-1,3,5-triazine-2,4(1H,3H)-dione crystalline form K, wherein: the powder X-ray diffraction pattern of crystalline form K has a diffraction peak at 2θ of 9.7±0.2°, or has a diffraction peak at 2θ of 12.8±0.2°. The invention also has a diffraction peak at 2θ of 13.7±0.2°, a diffraction peak at 2θ of 14.8±0.2°, a diffraction peak at 2θ of 15.2±0.2°, a diffraction peak at 2θ of 17.3±0.2°, a diffraction peak at 2θ of 18.3±0.2°, a diffraction peak at 2θ of 19.4±0.2°, or a diffraction peak at 2θ of 21. The diffraction peak is 25.5±0.2°, or 21.9±0.2°, or 22.8±0.2°, or 23.0±0.2°, or 24.9±0.2°, or 27.0±0.2°, or 27.6±0.2°. The invention relates to a method for preparing a diffraction peak in an optical system comprising: a diffraction peak at 2θ of 27.9±0.2°, a diffraction peak at 2θ of 29.0±0.2°, a diffraction peak at 2θ of 30.0±0.2°, a diffraction peak at 2θ of 30.6±0.2°, or a diffraction peak at 2θ of 33.8±0.2°; preferably, the method comprises diffraction peaks at any of 2, 4, 6, 8 or 10 locations.

[0190] In certain embodiments of the present invention, the powder X-ray diffraction pattern comprises at least one or more diffraction peaks located at 2θ of 9.7±0.2°, 13.7±0.2°, 15.2±0.2° or 17.3±0.2°; preferably 2-4 of them, more preferably 3-4 of them, and most preferably 4 of them; optionally, further, it may also comprise one or more diffraction peaks at 2θ of 18.3±0.2°, 21.5±0.2°, 21.9±0.2°, 24.9±0.2° or 33.8±0.2°, preferably 2, 3, 4 or 5 of them; for example:

[0191] 9.7±0.2°, 13.7±0.2°, 15.2±0.2°;

[0192] 9.7±0.2°, 13.7±0.2°, 15.2±0.2°, 17.3±0.2°;

[0193] 9.7±0.2°, 13.7±0.2°, 15.2±0.2°, 18.3±0.2°;

[0194] 9.7±0.2°、13.7±0.2°、15.2±0.2°、21.5±0.2°；

[0195] 9.7±0.2°、13.7±0.2°、15.2±0.2°、21.9±0.2°；

[0196] 9.7±0.2°、13.7±0.2°、15.2±0.2°、24.9±0.2°；

[0197] 9.7±0.2°、13.7±0.2°、17.3±0.2°、18.3±0.2°；

[0198] 9.7±0.2°、17.3±0.2°；18.3±0.2°、21.9±0.2°；

[0199] 13.7±0.2°、15.2±0.2°、17.3±0.2°、18.3±0.2°；

[0200] 9.7±0.2°、13.7±0.2°、15.2±0.2°、17.3±0.2°、18.3±0.2°；

[0201] 9.7±0.2°、13.7±0.2°、15.2±0.2°、18.3±0.2°、21.5±0.2°；

[0202] 9.7±0.2°、13.7±0.2°、15.2±0.2°、21.5±0.2°、21.9±0.2°；

[0203] 9.7±0.2°、13.7±0.2°、15.2±0.2°、21.9±0.2°、24.9±0.2°；

[0204] 9.7±0.2°、13.7±0.2°、15.2±0.2°、18.3±0.2°、24.9±0.2°；

[0205] 9.7±0.2°、13.7±0.2°、17.3±0.2°、18.3±0.2°、21.5±0.2°；

[0206] 9.7±0.2°、17.3±0.2°；18.3±0.2°、21.9±0.2°、24.9±0.2°；

[0207] 13.7±0.2°、15.2±0.2°、17.3±0.2°、18.3±0.2°、21.5±0.2°；

[0208] 9.7±0.2°, 13.7±0.2°, 15.2±0.2°, 17.3±0.2°, 18.3±0.2°, 21.5±0.2°;

[0209] 9.7±0.2°, 13.7±0.2°, 15.2±0.2°, 18.3±0.2°, 21.5±0.2°, 21.9±0.2°;

[0210] 9.7±0.2°, 13.7±0.2°, 15.2±0.2°, 17.3±0.2°, 18.3±0.2°, 21.5±0.2°, 21.9±0.2°, 33.8±0.2°;

[0211] 9.7±0.2°, 13.7±0.2°, 15.2±0.2°, 17.3±0.2°, 18.3±0.2°, 21.9±0.2°, 24.9±0.2°;

[0212] 9.7±0.2°, 13.7±0.2°, 15.2±0.2°, 17.3±0.2°, 18.3±0.2°, 21.9±0.2°, 24.9±0.2°, 33.8±0.2°;

[0213] 9.7±0.2°, 13.7±0.2°, 15.2±0.2°, 18.3±0.2°, 24.9±0.2°, 33.8±0.2°;

[0214] 9.7±0.2°, 13.7±0.2°, 17.3±0.2°, 18.3±0.2°, 21.5±0.2°, 21.9±0.2°;

[0215] 9.7±0.2°, 17.3±0.2°; 18.3±0.2°, 21.9±0.2°, 24.9±0.2°, 33.8±0.2°;

[0216] 13.7±0.2°, 15.2±0.2°, 17.3±0.2°, 18.3±0.2°, 21.5±0.2°, 21.9±0.2°.

[0217] More preferably, the powder X-ray diffraction pattern optionally further comprises one or more diffraction peaks located at 2θ of 12.8±0.2°, 14.8±0.2°, 19.4±0.2°, 22.8±0.2°, 23.0±0.2° or 29.0±0.2°; preferably at least any 2-4, or 5-6 thereof, further preferably, any 4 or 6 thereof; for example:

[0218] 12.8±0.2°, 14.8±0.2°, 19.4±0.2°, 22.8±0.2°;

[0219] 12.8±0.2°, 14.8±0.2°, 19.4±0.2°, 23.0±0.2°;

[0220] 12.8±0.2°, 14.8±0.2°, 19.4±0.2°, 29.0±0.2°;

[0221] 12.8±0.2°, 14.8±0.2°, 22.8±0.2°, 23.0±0.2°;

[0222] 14.8±0.2°, 19.4±0.2°, 22.8±0.2°, 23.0±0.2°;

[0223] 12.8±0.2°, 14.8±0.2°, 19.4±0.2°, 22.8±0.2°, 23.0±0.2°;

[0224] 12.8±0.2°, 14.8±0.2°, 19.4±0.2°, 22.8±0.2°, 29.0±0.2°;

[0225] 12.8±0.2°, 14.8±0.2°, 19.4±0.2°, 22.8±0.2°, 23.0±0.2°, 29.0±0.2°;

[0226] In certain embodiments of the present invention, the X-ray powder diffraction pattern of the crystalline form K has characteristic peaks at 2θ of 15.2±0.2° and 17.3±0.2°; preferably, it also includes characteristic peaks at 2θ of 9.7±0.2°, 13.7±0.2°, 18.3±0.2° and 24.9±0.2°; more preferably, it also includes characteristic peaks at 2θ of 21.9±0.2° and 33.8±0.2°; further Preferably, it also includes characteristic peaks at 2θ of 21.5±0.2° and 29.0±0.2°, and further preferably, it also includes characteristic peaks at 12.8±0.2°, 14.8±0.2°, 19.4±0.2°, 22.8±0.2°, 23.0±0.2°, 27.0±0.2°, 27.6±0.2°, 27.9±0.2°, 30.0±0.2° and 30.6±0.2°.

[0227] In certain embodiments of the present invention, Cu-Kα radiation is used, and the X-ray characteristic peaks of Form K are represented by 2θ angles and interplanar spacing d values ​​as shown in Table 11.

[0228] Table 11

[0229] In certain embodiments of the present invention, the X-ray powder diffraction pattern of Form K is substantially as shown in FIG. 20 ; and the DSC pattern thereof is substantially as shown in FIG. 21 .

[0230] In certain embodiments of the present invention, Form K is a hydrate.

[0231] In certain embodiments of the present invention, Form K is a hemihydrate.

[0232] In certain embodiments of the present invention, Form K is a monohydrate.

[0233] In certain embodiments of the present invention, Form K is a dihydrate.

[0234] In certain embodiments of the present invention, Form K contains 0.25 to 2 water.

[0235] In certain embodiments of the present invention, Form K contains 0.5 water.

[0236] In certain embodiments of the present invention, the water content of Form K measured by KF is 2.8% (API:water=1:0.5, molar ratio).

[0237] Form K has good reproducibility, high product purity, and controllable quality, and the obtained crystal morphology is blocky, which is more suitable for pharmaceutical use and industrial production.

[0238] In certain embodiments of the present invention, the crystalline form is (S)-6-((1-(2,4-difluorophenyl)ethyl)amino)-3-(tetrahydro-2H-pyran-4-yl)-1,3,5-triazine-2,4(1H,3H)-dione crystalline form L, wherein: the powder X-ray diffraction pattern of the crystalline form L has a diffraction peak at 2θ of 9.8±0.2°, or has a diffraction peak at 2θ of 12.8±0.2°. The invention also has a diffraction peak at 2θ of 13.9±0.2°, a diffraction peak at 2θ of 14.9±0.2°, a diffraction peak at 2θ of 15.3±0.2°, a diffraction peak at 2θ of 17.2±0.2°, a diffraction peak at 2θ of 18.5±0.2°, a diffraction peak at 2θ of 19.3±0.2°, or a diffraction peak at 2θ of 21. The diffraction peak is 26.6±0.2°, 2θ is 22.0±0.2°, 2θ is 23.4±0.2°, 2θ is 24.9±0.2°, 2θ is 27.0±0.2°, 2θ is 27.6±0.2°, 2θ is 28.1±0.2°, or 2θ is 28.1±0.2°. Peak, or has a diffraction peak at 2θ of 28.9±0.2°, or has a diffraction peak at 2θ of 29.3±0.2°; or has a diffraction peak at 2θ of 30.1±0.2°; or has a diffraction peak at 2θ of 31.1±0.2°; or has a diffraction peak at 2θ of 33.8±0.2°; preferably, comprises diffraction peaks at any of 2, 4, 6, 8 or 10 locations.

[0239] In certain embodiments of the present invention, the powder X-ray diffraction pattern of Form L has one or more diffraction peaks at 2θ of 9.8±0.2°, 13.9±0.2°, 17.2±0.2° or 18.5±0.2°; preferably 2-4 of them, more preferably 3-4, most preferably 4; optionally, further, it may also include one or more diffraction peaks at 2θ of 15.3±0.2°, 22.0±0.2°, 24.9±0.2°, 27.6±0.2° or 33.8±0.2°, preferably 2, 3, 4 or 5 of them, for example:

[0240] 10.7±0.2°, 11.8±0.2°, 14.5±0.2°, 21.9±0.2°;

[0241] 10.7±0.2°, 11.8±0.2°, 14.5±0.2°, 17.3±0.2°;

[0242] 10.7±0.2°, 11.8±0.2°, 14.5±0.2°, 20.7±0.2°;

[0243] 10.7±0.2°、11.8±0.2°、14.5±0.2°、21.6±0.2°；

[0244] 10.7±0.2°、11.8±0.2°、14.5±0.2°、23.7±0.2°；

[0245] 10.7±0.2°、14.5±0.2°、17.3±0.2°、21.9±0.2°；

[0246] 10.7±0.2°、14.5±0.2°、20.7±0.2°、21.9±0.2°；

[0247] 11.8±0.2°、14.5±0.2°、17.3±0.2°、21.9±0.2°；

[0248] 10.7±0.2°、11.8±0.2°、14.5±0.2°、21.9±0.2°、23.7±0.2°；

[0249] 10.7±0.2°、11.8±0.2°、14.5±0.2°、17.3±0.2°、23.7±0.2°；

[0250] 10.7±0.2°、11.8±0.2°、14.5±0.2°、20.7±0.2°、23.7±0.2°；

[0251] 10.7±0.2°、11.8±0.2°、14.5±0.2°、21.6±0.2°、23.7±0.2°；

[0252] 10.7±0.2°、11.8±0.2°、14.5±0.2°、23.7±0.2°、26.0±0.2°；

[0253] 10.7±0.2°、14.5±0.2°、17.3±0.2°、21.9±0.2°、23.7±0.2°；

[0254] 10.7±0.2°、14.5±0.2°、20.7±0.2°、21.9±0.2°、23.7±0.2°；

[0255] 11.8±0.2°、14.5±0.2°、17.3±0.2°、21.9±0.2°、23.7±0.2°；

[0256] 10.7±0.2°, 11.8±0.2°, 14.5±0.2°, 21.9±0.2°, 23.7±0.2°, 26.0±0.2°;

[0257] 10.7±0.2°, 11.8±0.2°, 14.5±0.2°, 17.3±0.2°, 23.7±0.2°, 26.0±0.2°;

[0258] 10.7±0.2°, 11.8±0.2°, 14.5±0.2°, 20.7±0.2°, 23.7±0.2°, 26.0±0.2°;

[0259] 10.7±0.2°, 11.8±0.2°, 14.5±0.2°, 21.6±0.2°, 23.7±0.2°, 26.0±0.2°;

[0260] 10.7±0.2°, 11.8±0.2°, 14.5±0.2°, 17.3±0.2°, 20.7±0.2°, 26.0±0.2°;

[0261] 10.7±0.2°, 11.8±0.2°, 14.5±0.2°, 17.3±0.2°, 21.9±0.2°, 23.7±0.2°;

[0262] 10.7±0.2°, 14.5±0.2°, 20.7±0.2°, 21.9±0.2°, 23.7±0.2°, 26.0±0.2°;

[0263] 11.8±0.2°, 14.5±0.2°, 17.3±0.2°, 21.9±0.2°, 23.7±0.2°, 26.0±0.2°.

[0264] More preferably, the powder X-ray diffraction pattern optionally further comprises one or more diffraction peaks located at 2θ of 7.2±0.2°, 9.8±0.2°, 11.2±0.2°, 15.3±0.2°, 16.0±0.2° or 22.4±0.2°; preferably at least any 2-4, or 5-6 thereof, further preferably, any 4 or 6 thereof; for example:

[0265] 7.2±0.2°, 9.8±0.2°, 11.2±0.2°, 15.3±0.2°;

[0266] 7.2±0.2°, 9.8±0.2°, 11.2±0.2°, 16.0±0.2°;

[0267] 7.2±0.2°, 9.8±0.2°, 11.2±0.2°, 22.4±0.2°;

[0268] 7.2±0.2°, 11.2±0.2°, 15.3±0.2°, 16.0±0.2°;

[0269] 11.2±0.2°, 15.3±0.2°, 16.0±0.2°, 22.4±0.2°;

[0270] 7.2±0.2°, 9.8±0.2°, 11.2±0.2°, 15.3±0.2°, 16.0±0.2°;

[0271] 7.2±0.2°, 9.8±0.2°, 11.2±0.2°, 16.0±0.2°, 22.4±0.2°;

[0272] 7.2±0.2°, 9.8±0.2°, 11.2±0.2°, 15.3±0.2°, 16.0±0.2°, 22.4±0.2°.

[0273] In certain embodiments of the present invention, the X-ray powder diffraction pattern of the crystalline form I has characteristic peaks at 2θ of 11.8±0.2° and 21.9±0.2°; preferably, it also includes characteristic peaks at 2θ of 10.7±0.2°, 14.5±0.2°, 17.3±0.2° and 23.7±0.2°; more preferably, it also includes characteristic peaks at 2θ of 20.7±0.2° and 26.0±0.2°; Preferably, the method further comprises characteristic peaks at 2θ of 21.6±0.2° and 22.4±0.2°, and further preferably, the method further comprises characteristic peaks at 7.2±0.2°, 9.8±0.2°, 11.2±0.2°, 15.3±0.2°, 16.0±0.2°, 18.2±0.2°, 18.9±0.2°, 26.2±0.2°, 27.4±0.2° and 28.8±0.2°.

[0274] In certain embodiments of the present invention, Cu-Kα radiation is used, and the X-ray characteristic peaks of Form L are represented by 2θ angles and interplanar spacing d values ​​as shown in Table 12.

[0275] Table 12

[0276] In certain embodiments of the present invention, Form L has an X-ray powder diffraction pattern substantially as shown in FIG. 22 .

[0277] Another object of the present invention is to provide a pharmaceutical composition comprising a therapeutically effective amount of the above-mentioned compound or its stereoisomers and salts, and one or more pharmaceutically acceptable carriers, diluents or excipients.

[0278] The present invention further relates to a method for treating hypertrophic cardiomyopathy (HCM) or a heart disease with pathophysiological characteristics of HCM in a subject in need thereof, comprising administering to the subject an effective amount of the above-mentioned compound or its stereoisomers and salts, or the above-mentioned pharmaceutical composition, wherein the HCM is obstructive or non-obstructive, or is caused by sarcomeric and / or non-sarcomeric mutations.

[0279] The present invention further relates to any compound or its stereoisomers and salts or the pharmaceutical composition of the present invention or the use of the pharmaceutical composition of the present invention for treating hypertrophic cardiomyopathy (HCM) and other forms of cardiac diseases or conditions; wherein the disease or condition is selected from heart failure with normal ejection fraction, ischemic heart disease, angina pectoris and restrictive cardiomyopathy.

[0280] FIG. 1 is an XRPD diagram of the free base Form A of Example 3.

[0281] FIG. 2 is a DSC diagram of the free base form A of Example 3.

[0282] FIG3 is a TGA diagram of the free base form A of Example 3.

[0283] FIG. 4 is an XRPD diagram of the free base Form B of Example 3.

[0284] FIG5 is a DSC diagram of the free base Form B of Example 3.

[0285] FIG. 6 is an XRPD diagram of the free base Form C of Example 3.

[0286] FIG. 7 is a DSC diagram of the free base Form C of Example 3.

[0287] FIG. 8 is an XRPD diagram of the free base Form D of Example 3.

[0288] FIG. 9 is a DSC diagram of the free base Form D of Example 3.

[0289] FIG. 10 is an XRPD diagram of the free base Form E of Example 3.

[0290] FIG. 11 is a DSC diagram of the free base Form E of Example 3.

[0291] FIG. 12 is a TGA diagram of the free base Form E of Example 3.

[0292] FIG. 13 is an XRPD diagram of the free base Form F of Example 3.

[0293] FIG. 14 is an XRPD diagram of the free base Form G of Example 3.

[0294] FIG. 15 is an XRPD diagram of the free base Form H of Example 3.

[0295] FIG. 16 is an XRPD diagram of the free base Form I of Example 3.

[0296] FIG. 17 is a DSC diagram of the free base Form I of Example 3.

[0297] FIG. 18 is an XRPD diagram of the free base Form J of Example 3.

[0298] FIG. 19 is a DSC diagram of the free base Form J of Example 3.

[0299] FIG. 20 is an XRPD diagram of the free base Form K of Example 3.

[0300] FIG. 21 is a DSC diagram of the free base Form K of Example 3.

[0301] FIG. 22 is an XRPD diagram of the free base Form L of Example 3.

[0302] FIG23 is a graph showing the effect of the compound of Example 3 on cardiac function measured at different doses in Spraw-Dawley rats.

[0303] Unless stated otherwise, the terms used in the specification and claims have the following meanings.

[0304] In the present invention, alkyl refers to a saturated aliphatic hydrocarbon group, which is a straight or branched chain group containing 1 to 20 carbon atoms, preferably an alkyl group containing 1 to 8 carbon atoms, more preferably an alkyl group containing 1 to 6 carbon atoms, and most preferably an alkyl group containing 1 to 3 carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, n-heptyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2, 3-Dimethylpentyl, 2,4-dimethylpentyl, 2,2-dimethylpentyl, 3,3-dimethylpentyl, 2-ethylpentyl, 3-ethylpentyl, n-octyl, 2,3-dimethylhexyl, 2,4-dimethylhexyl, 2,5-dimethylhexyl, 2,2-dimethylhexyl, 3,3-dimethylhexyl, 4,4-dimethylhexyl, 2-ethylhexyl, 3-ethylhexyl, 4-ethylhexyl, 2-methyl-2-ethylpentyl, 2-methyl-3-ethylpentyl, n-nonyl, 2-methyl-2-ethylhexyl, 2-methyl-3-ethylhexyl, 2,2-diethylpentyl, n-decyl, 3,3-diethylhexyl, 2,2-diethylhexyl, and various branched chain isomers thereof.

[0305] The alkyl group may be substituted or unsubstituted. When substituted, the substituent may be substituted at any available attachment point. The substituent is preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkyloxy, heterocycloalkyloxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxyl or carboxylate groups. Methyl, ethyl, isopropyl, tert-butyl, haloalkyl, deuterated alkyl, alkoxy-substituted alkyl and hydroxy-substituted alkyl are preferred in the present invention; the hydroxy-substituted alkyl may be 2-hydroxyisopropyl or 1-hydroxyethyl.

[0306] In the present invention, a heterocyclic group refers to a saturated or partially unsaturated monocyclic or polycyclic heterocyclic group containing 3 to 20 ring atoms, wherein one or more ring atoms are selected from nitrogen, oxygen or S(O) m(wherein m is an integer from 0 to 2) heteroatoms, but does not include -OO-, -OS- or -SS- ring parts, and the remaining ring atoms are carbon. Preferably, it contains 3 to 12 ring atoms, of which 1 to 4 are heteroatoms; more preferably, it contains 3 to 10 ring atoms; and further preferably, it contains 3 to 8 ring atoms. Non-limiting examples of monocyclic heterocyclic groups include pyrrolidinyl, pyrrolidonyl, piperidin-2-onyl, 3,4-dihydropyridine-2 (1H)-onyl, 4,5-dihydropyridazine-3 (2H)-onyl, azetidinyl, oxetanyl, oxanyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothienyl, dihydroimidazolyl, dihydrofuranyl, dihydropyrazolyl, dihydropyrrolyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, pyranyl, etc.; preferably pyrrolidyl, pyrrolidinone, piperidin-2-one, 3,4-dihydropyridine-2 (1H) -one, 4,5-dihydropyridazine-3 (2H) -one, azetidinyl, oxetanyl, dihydropyrrolyl, tetrahydrofuranyl, pyrazolidinyl, morpholinyl, more preferably, dihydropyrrolyl, pyrrolidyl, pyrrolidonyl, piperidin-2-onyl, 3,4-dihydropyridin-2(1H)-onyl, 4,5-dihydropyridazin-3(2H)-onyl, azetidinyl, oxetanyl, oxanyl, morpholinyl, piperidinyl, piperazinyl, Pyranyl. Polycyclic heterocyclic groups include spirocyclic, condensed and bridged heterocyclic groups; wherein the spirocyclic, condensed and bridged heterocyclic groups are optionally connected to other groups through single bonds, or further connected to other cycloalkyl, heterocyclic, aryl and heteroaryl groups through any two or more atoms on the ring.

[0307] The heterocyclyl group may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkyloxy, heterocycloalkyloxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxyl or carboxylate.

[0308] In the present invention, aryl refers to a 6-14-membered all-carbon monocyclic or fused polycyclic (i.e., a ring sharing adjacent carbon atom pairs) group having a conjugated π electron system, preferably 6-10 members, more preferably 6-8 members, such as phenyl and naphthyl, preferably phenyl. The aryl ring may be fused to a heteroaryl, heterocyclic or cycloalkyl ring, wherein the ring connected to the parent structure is an aryl ring, and non-limiting examples thereof include:

[0309] In the present invention, alkoxy refers to -O-(alkyl) and -O-(unsubstituted cycloalkyl), wherein the definition of alkyl is as described above, preferably an alkyl containing 1 to 8 carbon atoms, more preferably an alkyl containing 1 to 6 carbon atoms, and most preferably an alkyl containing 1 to 3 carbon atoms. Non-limiting examples of alkoxy include: methoxy, ethoxy, propoxy, butoxy, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy. Alkoxy may be optionally substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkyloxy, heterocycloalkyloxy, cycloalkylthio, heterocycloalkylthio, carboxyl or carboxylate;

[0310] Non-limiting examples of alkoxy also include propan-2-oxy and the like.

[0311] In the present invention, haloalkyl refers to an alkyl group substituted by one or more halogens, wherein alkyl is as defined above. Non-limiting examples of haloalkyl include: trifluoromethyl, trifluoroethyl;

[0312] Non-limiting examples of haloalkyl also include difluoromethyl, 1,1,2,2-tetrafluoroethyl, perfluoroethyl, and the like.

[0313] In the present invention, haloalkoxy refers to an alkoxy group substituted by one or more halogens, wherein alkoxy is as defined above;

[0314] The halogenated alkoxy group may be fully halogenated or partially halogenated, and the number of halogenations may be 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, etc.; the halogen is preferably F, Cl, Br, I; for example, it may be trifluoromethoxy, difluoromethoxy, 1,1,2,2-tetrafluoroethoxy, perfluoroethoxy, etc.

[0315] In the present invention, hydroxyalkyl refers to an alkyl group substituted by a hydroxy group, wherein the alkyl group is as defined above.

[0316] In the present invention, haloalkyl refers to an alkyl group substituted by one or more halogens, wherein alkyl is as defined above.

[0317] In the present invention, haloalkoxy refers to an alkoxy group substituted by one or more halogens, wherein the alkoxy group is as defined above.

[0318] "Hydroxy" refers to an -OH group.

[0319] "Halogen" refers to fluorine, chlorine, bromine or iodine.

[0320] "Amino" refers to -NH2.

[0321] "Cyano" refers to -CN.

[0322] "Nitro" refers to -NO2.

[0323] "THF" refers to tetrahydrofuran.

[0324] "EtOAc" means ethyl acetate.

[0325] "DMSO" refers to dimethyl sulfoxide.

[0326] "LDA" refers to lithium diisopropylamide.

[0327] "DMAP" refers to 4-dimethylaminopyridine.

[0328] "EtMgBr" refers to ethylmagnesium bromide.

[0329] "HOSu" refers to N-hydroxysuccinimide.

[0330] "EDCl" refers to 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride.

[0331] "IPA" refers to isopropyl alcohol.

[0332] "MeOH" refers to methanol.

[0333] "EtOH" refers to ethanol.

[0334] "DMF" refers to N,N-dimethylformamide.

[0335] "DIPEA" refers to N,N-diisopropylethylamine.

[0336] "HEPES" refers to 4-hydroxyethylpiperazineethanesulfonic acid.

[0337] Different expressions such as “X is selected from A, B, or C”, “X is selected from A, B and C”, “X is A, B or C”, “X is A, B and C” all express the same meaning, that is, X can be any one or more of A, B, C.

[0338] "Optional" or "optionally" means that the subsequently described event or circumstance may but need not occur, and that the description includes instances where the event or circumstance occurs and where it does not occur.

[0339] "Substituted" means that one or more hydrogen atoms, preferably up to 5, more preferably 1 to 3 hydrogen atoms in the group are replaced independently of each other by a corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, and the skilled person can determine (by experiment or theory) possible or impossible substitutions without undue effort. For example, amino or hydroxy groups with free hydrogen may be unstable when combined with carbon atoms with unsaturated (e.g. olefinic) bonds.

[0340] "Stereoisomerism" includes three types: geometric isomerism (cis-trans isomerism), optical isomerism, and conformational isomerism.

[0341] As used herein, the name of a compound is intended to encompass all possible isomeric forms, including stereoisomers (eg, enantiomers, diastereomers, racemates or racemic mixtures and any mixtures thereof) of the compound.

[0342] The hydrogen atoms described in the present invention can be replaced by their isotope deuterium, and any hydrogen atom in the example compounds of the present invention can also be replaced by a deuterium atom.

[0343] "Pharmaceutical composition" means a mixture containing one or more compounds described herein or their physiologically / pharmaceutically acceptable salts or prodrugs and other chemical components, as well as other components such as physiologically / pharmaceutically acceptable carriers and excipients. The purpose of a pharmaceutical composition is to facilitate administration to an organism, facilitate the absorption of the active ingredient, and thus exert biological activity.

[0344] X-ray powder diffraction pattern (XRPD) refers to the experimentally observed diffraction pattern or the parameters derived therefrom, and the X-ray powder diffraction pattern is characterized by the peak position (abscissa) and the peak intensity (ordinate). It will be understood by those skilled in the art that the experimental error depends on the conditions of the instrument, the preparation of the sample and the purity of the sample. In particular, it is well known to those skilled in the art that the X-ray diffraction pattern will usually change with the conditions of the instrument. It should be understood by those skilled in the art that the appropriate error tolerance of XRPD can be: 2θ±0.5°; 2θ±0.4°; 2θ±0.3°; 2θ±0.2°. It should be particularly noted that the relative intensity of the X-ray diffraction pattern may also change with changes in experimental conditions, so the order of peak intensity cannot be used as the only or decisive factor. In addition, due to the influence of experimental factors such as sample height, the overall deviation of the peak angle will be caused, and a certain deviation is usually allowed. Therefore, it will be understood by those skilled in the art that any crystal form having the same or similar characteristic peaks as the spectrum of the present invention belongs to the scope of the present invention.

[0345] "TGA" refers to a thermogravimetric analysis (TGA) experiment.

[0346] "DSC" refers to a differential scanning calorimetry (DSC) experiment.

[0347] "HPLC" refers to high performance liquid chromatography (HPLC) experiments.

[0348] "PK" refers to pharmacokinetic (PK) studies.

[0349] "KF" refers to the Karl Fischer titration (KF) experiment.

[0350] The present invention is further described below with reference to examples, but these examples are not intended to limit the scope of the present invention.

[0351] Preparation of compounds

[0352] The following examples are used to explain the present invention, but these examples should not be considered to limit the scope of the present invention. If the specific conditions of the experimental method are not specifically described in the examples of the present invention, the conventional conditions or recommended conditions of the raw materials and product manufacturers are generally followed. Reagents without specifying specific sources are commercially available conventional reagents.

[0353] The structure of each compound was identified by nuclear magnetic resonance (NMR) and / or mass spectrometry (MS). NMR chemical shifts (δ) were expressed in 10 -6 (ppm) are given. NMR was measured by Varian Mercury 300 MHz, Bruker Avance III 400 MHz machines. The solvents used were deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl3) and deuterated methanol (CD3OD).

[0354] Agilent 1200DAD high pressure liquid chromatograph (Sunfire C18 150×4.6 mm column) and Waters 2695-2996 high pressure liquid chromatograph (Gimini C18 150×4.6 mm column) were used for high performance liquid chromatography (HPLC). Agilent 1200 high pressure liquid chromatograph & mass spectrometer (Sunfire C18 4.6*50 mm 3.5 um column) and Agilent 19091S-433HP-5 high pressure liquid chromatograph & mass spectrometer (XBridge C18 4.6*50 mm 3.5 um column) were used for liquid chromatography mass spectrometry (LCMS).

[0355] SFC Thar 80&150&200 (waters) determination of chiral high performance liquid chromatography (HPLC).

[0356] The average ATPase inhibition rate and IC were determined by Victor Nivo multi-mode microplate reader (PerkinElmer, USA). 50 value.

[0357] The thin layer silica gel plate used in thin layer chromatography is Yantai Xinnuo silica gel plate. The size of the plate used in TLC is 0.15mm to 0.2mm, and the size of the plate used in thin layer chromatography for product purification is 0.4mm to 0.5mm.

[0358] Column chromatography generally uses Qingdao Haiyang 200 to 300 mesh silica gel as the carrier.

[0359] The known raw materials of the present invention can be prepared by conventional synthesis methods in the prior art, or can be purchased from ABCR GmbH & Co. KG, Acros Organics, Aldrich Chemical Company, Accela ChemBio Inc or Dari Chemical Company, etc.

[0360] MS is mass spectrometry, where (+) refers to the positive mode which usually gives M+1 (or M+H) absorption, where M = molecular weight.

[0361] General Procedure A

[0362] Benzyl bromide is condensed with thiourea to obtain a bromide salt, which is then condensed with carbonyl diimidazole to obtain carbonyl monoimidazole. It is then condensed with commercially available or custom amines to obtain ureas, which are then cyclized under the catalysis of carbonyl diimidazole to obtain a six-membered core structure. The six-membered core structure is then subjected to nucleophilic substitution with commercially available or custom primary amines under heating conditions to obtain triazinedione analogs.

[0363] Example 1

[0364] Step 1. Synthesis of intermediate 1-1

[0365] Thiourea (6.0 g, 78.9 mmol, 1.3 eq.) was added to a solution of (bromomethyl)benzene (10.0 g, 58.8 mmol) in CH3CN (100 mL). The resulting mixture was stirred at room temperature for 3 hours. The reaction solution was filtered, washed with CH3CN (50 mL), and the filter cake was dried under vacuum to obtain intermediate 1-1 (13.0 g, 90.2%) as a white solid.

[0366] 1 H NMR (400MHz, DMSO-d6) δ9.06 (s, 4H), 7.45–7.30 (m, 5H), 4.48 (s, 2H).

[0367] Step 2. Synthesis of intermediate 1-2

[0368] To a solution of intermediate 1-1 (10.0 g, 40.6 mmol) in THF (100 mL) was added CDI (8.8 g, 54.2 mmol, 1.3 eq.) and Et3N (5.4 g, 54.2 mmol, 1.3 eq.). The resulting mixture was stirred at room temperature under N2 protection for 2 hours until TLC showed that the reaction was complete. The reaction solution was filtered and the filtrate was concentrated in vacuo. The residue was purified by silica gel column (DCM: MeOH = 30: 1) to give a white solid intermediate 1-2 (7.0 g, 67.3%).

[0369] ESI-MS (EI + ,m / z):261.15.

[0370] 1 H NMR (400MHz, DMSO-d6) δ9.36(d,J=59.7Hz,2H),8.33–8.25(m,1H),7.61(t,J=1.3Hz,1H),7.44–7.24(m,5H),7.01–6.95(m,1H),4.43(s,2H).

[0371] Step 3. Synthesis of Intermediate 1-3

[0372] Tetrahydro-2H-pyran-4-amine (1.75 g, 17.3 mmol, 1.5 eq.) and Et3N (2.3 g, 23.0 mmol, 2.0 eq.) were added to a solution of intermediate 1-2 (3.0 g, 11.5 mmol) in DMF (10 mL). The resulting mixture was stirred at 80 ° C under N2 protection for 1 hour until TLC and LCMS showed that the reaction was complete. The reaction solution was diluted with water and extracted twice with EtOAc. The organic matter was washed with water and brine, dried over Na2SO4, filtered and concentrated in vacuo. The reaction mixture was purified by silica gel column (DCM: MeOH = 30: 1) to obtain yellow solid intermediate 1-3 (1.5 g, 44.6%).

[0373] ESI-MS (EI + ,m / z):294.20.

[0374] 1H NMR(400MHz, DMSO-d6)δ8.49(s,2H),7.41–7.34(m,2H),7.30(t,J= 7.4Hz,2H),7.23(dd,J=8.3,6.1Hz,1H),7.07(d,J=8.0Hz,1H),4.28(s,2H),3.87–3.76(m,2H),3.60(ddt,J=15. 0,7.7,4.4Hz,1H),3.35(d,J=1.7Hz,1H),3.29(d,J=1.8Hz,1H),1.73–1.62(m,2H),1.45(qd,J=12.1,4.4Hz,2H).

[0375] Step 4. Synthesis of Intermediate 1-4

[0376] To a solution of intermediate 1-3 (4.5 g, 15.3 mmol) in DMF (15 mL) was added CDI (4.8 g, 29.6 mmol, 2.0 eq.) and DIEA (3.9 g, 30.2 mmol, 2.0 eq.). The resulting mixture was stirred at 110° C. for 3 hours until TLC and LCMS showed that the reaction was complete. The reaction mixture was purified with a reverse phase column to give compound intermediate 1-4 (1.0 g, 21.2%) as a yellow liquid.

[0377] ESI-MS (EI + ,m / z):320.15.

[0378] 1 H NMR (400MHz, DMSO-d6) δ7.40–7.35(m,2H),7.30(t,J=7.4Hz,2H),7.23(dd,J=8.4,6.1Hz,1H),4.24(s,2H),3.89(d d,J=11.1,4.1Hz,2H),3.64–3.56(m,1H),3.30(t,J=11.2Hz,2H),2.59(qd,J=12.4,4.7Hz,2H),1.40–1.33(m,2H).

[0379] Step 5. Synthesis of Example 1

[0380] A solution of intermediate 1-4 (300 mg, 0.94 mmol) and (S)-1-cyclohexylethyl-1-amine (300 mg, 2.36 mmol) was placed in a sealed tube and stirred overnight at 90°C until LCMS showed that the reaction was complete. The reaction mixture was purified by preparative HPLC to obtain the title compound (45 mg, 14.9%) as a white compound.

[0381] ESI-MS (EI + ,m / z):323.23.

[0382] 1 H NMR (400MHz, DMSO-d6) δ10.32(s,1H),6.61(d,J=4.8Hz,1H),4.66(t,J=12.1Hz,1H),3.89(dd,J=11.2,4.2Hz,2H ),3.75(d,J=5.0Hz,1H),3.33(s,1H),3.28(s,1H),2.53(s,1H),2.45(dd,J=12.6,4.6Hz,1H),1.76–1.56(m,5H), 1.42(d,J=12.5Hz,3H),1.24–1.10(m,3H),1.05(d,J=6.7Hz,3H),0.99–0.86(m,2H).

[0383] Example 2

[0384] 6-(Benzylthio)-3-(tetrahydro-2H-pyran-4-yl)-1,3,5-triazine-2,4(1H,3H)-dione (200 mg, 0.063 mmol) and (S)-1-(m-tolyl)ethane-1-amine (127 mg, 0.094 mmol) were added to dioxane (5.0 mL) and placed in a 20.0 mL microwave tube and heated to 110°C. The resulting solution was concentrated to dryness under vacuum. The crude product was purified by preparative HPLC to give the title compound (101.4 mg, yield: 49.0%).

[0385] MS: m / z = 331.1 (M+1, ESI + ).

[0386] 1H NMR (400MHz, MeOD) δ7.15 (ddd, J=34.6, 21.0, 7.6Hz, 4H), 5.10 (q, J=6.8Hz, 1H), 4.80 (tt, J=12.2, 4.0Hz, 1H) ,3.99(dd,J=11.4,3.8Hz,2H),3.44(t,J=11.7Hz,2H),2.66(qd,J=12.4,4.8Hz,2H),1.51(t,J=11.8Hz,5H).

[0387] Example 3

[0388] Example 3 was prepared in the same manner as Example 2 from (S)-1-(2,4-difluorophenyl)ethyl-1-amine.

[0389] MS: m / z = 353.4 (M+1, ESI + ).

[0390] 1 HNMR(500MHz,MeOD)δ7.51–7.32(m,1H),6.95(ddt,J=13.8,8.4,2.6Hz,2H),5.33(q,J=7.0Hz,1H),4.79(tt,J=1 2.2,4.0Hz,1H),3.99(dd,J=11.6,3.8Hz,2H),3.44(t,J=12.0Hz,2H),2.74–2.57(m,2H),1.52(t,J=5.8Hz,5H).

[0391] Example 4

[0392] Example 4 was prepared in the same manner as General Procedure A and Example 2.

[0393] MS: m / z = 369.8 (M+1, ESI + ).

[0394] Example 5

[0395] Example 5 was prepared in the same manner as General Procedure A and Example 2.

[0396] MS: m / z = 345.2 (M+1, ESI + ).

[0397] Biological test evaluation

[0398] The present invention is further described and explained below in conjunction with test examples, but these embodiments are not intended to limit the scope of the present invention.

[0399] Experiment 1 Myosin inhibitory effect

[0400] For experimental background, the biochemical assay combines the ATPase activity of bovine cardiac myosin with an enzyme-coupled system consisting of pyruvate kinase and lactate dehydrogenase (PK / LDH), monitoring the absorbance of NADH (at 340 nm) over time to measure the inhibitory capacity of small molecule drugs. In this assay, PK converts ADP (adenosine diphosphate) to ATP (adenosine triphosphate) by converting PEP (phosphoenolpyruvate) to pyruvate. LDH then converts pyruvate to lactate by converting NADH (nicotinamide adenine dinucleotide) to NAD (oxidized nicotinamide adenine dinucleotide).

[0401] In our experiments, bovine skinned cardiac myofibrils were isolated from frozen bovine left ventricles as the source of myosin for ATPase assay. According to the literature (DOI:10.1074 / jbc.M117.776815), the myofibrils were selected to achieve a 50% (pCa 50 The calcium concentration activated by 12 mM PIPES (piperazine-N, N'-bis(2-ethanesulfonic acid) and 2 mM magnesium chloride (pH 6.8) was used as the final condition for evaluating activation activity. The myofibril ATPase activity was measured in a buffer solution containing 12 mM PIPES (piperazine-N, N'-bis(2-ethanesulfonic acid) and 2 mM magnesium chloride (pH 6.8). The final assay conditions were 1 mg / mL bovine cardiac myofibrils, 1:20 stock solution PK / LDH (Sigma-Aldrich, Cat. No. P0294-5X5ML), 50 uM ATP, 1 mM DTT (dithiothreitol), 0.75 mM NADH, 1.5 mM PEP, pCa 50(pCa = 6.25). The compounds were dissolved in DMSO (dimethyl sulfoxide). Serial dilutions of the compounds were performed to achieve the final desired compound concentration in a volume of 150 μL at a fixed DMSO concentration of 2% (v / v). 75 μL of a solution containing bovine myocardial fibrils, PK / LDH and calcium was added to a 96-well plate for a 7-point dose response experiment. In some cases, the ATPase assay was repeated for the compound of interest using a 10-point response method. The compound was added to the myofibril solution and incubated for 5 minutes. At the beginning of the enzymatic reaction, 75 μL of a solution containing ATP, PEP, NADH, compound and calcium was added. ATPase activity was determined by reading the absorbance at 340 nm in a PerkinElmer Victor Nivo plate reader in a kinetic mode at 25°C for 15 minutes using a transparent bottom plate. The slope of the absorbance change as a function of time in the first 10 minutes was normalized to the slope of the control well containing all reagents (including DMSO) but no compound. This normalized ratio was then plotted as a function of small molecule concentration in GraphPad Prism 9. The data were fitted to a four-parameter fit and the IC was calculated using Graphpad Prism 9. 50 Any agent that failed to achieve 50% inhibition at the highest concentration tested was reported as an IC greater than the highest concentration tested. 50 (i.e. IC 50 >200uM).

[0402] Table 1. Myosin inhibitory activity

[0403] Experiment 2. Comparison of myosin inhibition effects in cardiac and skeletal myofibrils

[0404] Bovine skinless cardiac myofibrils were isolated from frozen bovine left ventricles, and rabbit skinless skeletal myofibrils were isolated from frozen rabbit psoas major and psoas minor as the source of myosin in the ATPase assay. According to the literature (DOI: 10.1074 / jbc.M117.776815), the calcium concentration that achieved 50% activation of the myofibril system (pCa=6.25 for bovine cardiac myofibrils and pCa=6 for rabbit skeletal myofibrils) was selected as the final condition for evaluating the activation activity. The remaining ATPase assay conditions were the same as those described in Experiment 1.

[0405] Table 2. Comparison of myosin inhibitory activity in cardiac and skeletal myofibrils

[0406] The compounds of the present invention show great effects on cardiac myofibrils. In addition, Example 3 is much less effective in inhibiting skeletal myofibril activity. The data confirm that Example 3 has better cardiac-skeletal myosin selectivity, and therefore can bring stronger safety.

[0407] Experiment 3. Cardiomyocyte contractility measurement

[0408] The effects of compounds on sarcomere shortening in isolated rat ventricular myocytes were assessed using the IonOptix instrument.

[0409] Myocytes were placed in a chamber mounted on an inverted microscope stage and continuously perfused with oxygenated Tyrode's solution containing (in millimolar): 121 NaCl, 5 KCl, 2.8 NaCH3CO2, MgCl2.6H2O, glucose, NaHCO3, Na2HPO4.7H2O and 1.5 mM CaCl2. The solution was preheated at 36±1°C and electric field stimulation was performed at 1 Hz with 4 ms square wave bipolar pulses (10 V) through 2 platinum electrodes connected to a Myopacer field stimulator (IonOptix Corporation). The cells were illuminated by microscope light. Cell images were collected by a x40 UV fluorescent objective and transferred to the side port of the microscope, where the cell images were recorded by a charge coupled device (CCD) camera (MyoCam, IonOptix Corporation), converting optical brightness (pixels) into electrical signals (voltage). The MyoCam configuration is capable of collecting up to 240 images per second (240 Hz frame rate). The contractile properties of myocytes were analyzed in real time by a video detector and a personal computer-based data acquisition system (Ionwizard 6.0, IonOptix Corporation). Only myocytes with clear striations and a resting sarcomere length greater than or equal to 1.75 μm before pacing were used, as this is considered to represent the lower limit for healthy cells.

[0410] Monitor sarcomere shortening in the control solution (prodrug) until a stable record (baseline phase) is obtained. In order to determine the response to the compound, the myocytes were first perfused with Tyrode buffer for 60 seconds and then perfused with the compound for at least 5 minutes (or until a steady state is reached, up to 10 minutes). Each cell received 2 concentrations (5 and 15uM or 5 and 10uM) of the test compound. For some cells, a washout phase was entered after the last concentration. The duration of the washout phase is variable, resulting in variability in the washout data. In separate cells, a single concentration of isoproterenol (100nM) was applied. Data were recorded continuously using IonOptix software. Contractility data were analyzed using Ionwizard software (IonOptix). For each cell, 10-15 contractility transients after baseline and treatment were averaged and compared.

[0411] Table 3. Effects of compounds on fractional shortening of myocytes

[0412] * refers to %FS at 10uM, others refer to %FS at 15uM.

[0413] The fractional shortening ratio at 5uM, 10 or 15uM indicates the responsiveness of myocyte contractility to compound treatment. Lower ratios indicate that the compounds of the invention have a higher in vivo therapeutic window.

[0414] Experiment 4. Pharmacokinetic characteristics

[0415] IV (1mg / Kg) and PO (5mg / Kg) in male SD rats were used to determine the pharmacokinetic characteristics of the compound. The compound was used together with the free base and formulated in 5% DMAC+25% PEG-400+70% (30% 2-HP-β-CD aqueous solution). The compound was used intravenously at 1mg / kg and orally at 5mg / kg. For the IV group, blood samples were collected at 0, 0.083, 0.25, 0.5, 1, 2, 4, 8 and 24 hours after administration, and blood was collected continuously to obtain plasma. For the PO group, blood samples were collected at 0, 0.25, 0.5, 1, 2, 4, 6, 8 and 24 hours after administration, and blood was collected continuously. About 150 μL of whole blood / time point was collected in a K2EDTA tube through the jugular vein. The blood samples were placed on ice and centrifuged at 2000g for 5 minutes to obtain plasma samples within 15 minutes. PK parameters were estimated by non-compartmental model using WinNonlin 8.2.

[0416] Table 4. Pharmacokinetic parameters of the examples in male SD rats

[0417] The compounds of the present invention exhibit a shorter half-life. This is an advantage because a shorter half-life can reduce the time to reach steady-state equilibrium. It can also reduce or avoid clinical accumulation of drugs in the body and avoid the risks of accumulation.

[0418] Experiment 5. Echocardiographic Assessment of Acute Pharmacodynamic Effects on Myocardial Contractility in Rats

[0419] The effects of the compounds on cardiac function were determined by echocardiography in Spraw-Dawley rats. Rats were lightly anesthetized with 1-2% isoflurane. The compounds were administered as a single PO by oral gavage. Baseline cardiac function was measured 1 day before dosing. The effects of the compounds on cardiac function were measured 1, 3, 6 and 24 hours after dosing. Approximately 250 μL of whole blood was obtained through the tail vein immediately after the echocardiography procedure at approximately 1, 3, 6 and 24 hours after dosing. The blood was placed in a plasma separation tube containing K2EDTA and stored on wet ice until processing. The blood samples were centrifuged at 2,000g (4,400rpm, Eppendorf 5417R) for 10 minutes at 4°C. The plasma samples were then transferred to microtubes and stored at -80°C for subsequent LC / MS analysis. The data were plotted as reduction in short axis shortening vs plasma compound concentration. According to the literature (DOI: https: / / doi.org / 10.1021 / acs.jmedchem.1c01290), the therapeutic window was determined to be IC 50 / IC 10 .

[0420] Figure 23 shows that Example 3 is dose-dependent below 10 mpk and does not further inhibit cardiac contractility at 20 mpk. The results indicate that Example 3 has a stronger safety profile than the other tested compounds. The data plotted with plasma exposure (PK) vs. short axis shortening (OD, FS% to baseline) also confirm that Example 3 has a better therapeutic window with a smaller curve slope.

[0421] Crystal form research

[0422] 1.1 Experimental Instruments

[0423] 1.1.1 Some parameters of physical and chemical testing instruments

[0424] 1.2 Instruments and liquid phase analysis conditions

[0425] 1.2.1 Instruments and equipment

[0426] 1.2.2 Chromatographic conditions

[0427] Chromatographic column: XBridge (C18, 3.5μm, 4.6*150mm)

[0428] Flow rate: 1mL / min

[0429] Column temperature: 40°C

[0430] Detection wavelength: 230nm

[0431] Injection volume: 5.0 μL

[0432] Run time: 15 minutes

[0433] Diluent: ACN-water (v / v, 1:1)

[0434] Mobile phase: A: water (0.05% trifluoroacetic acid); B: acetonitrile (0.05% trifluoroacetic acid)

[0435] 1. Preparation of different crystal forms

[0436] 1.1 Preparation of free base form A

[0437] The crude product was purified by a rapid reverse column (MeCN / NH4HCO3 5%-30% 15min, 30%-35% 20min, 35%-95% 20min), and the sample solution was vacuum dried to obtain 30.8 g of the compound represented by the general formula (I) with a yield of 55.8%, as a white solid. After detection and analysis, it has the following XRPD diagram as shown in Figure 1, the DSC diagram as shown in Figure 2, and the TGA diagram as shown in Figure 3.

[0438] 1.2 Preparation of free base form B

[0439] Weigh 20 mg of free base crystal form A into a 2 ml glass bottle, add 200 μl of methanol, stir at 50° C. for 7 days, centrifuge to remove the supernatant, and dry the remaining solid in a 40° C. vacuum drying oven for 20 hours to obtain free base crystal form B. After detection and analysis, it has the following XRPD diagram as shown in FIG4 and the DSC diagram as shown in FIG5.

[0440] 1.3 Preparation of Free Base Form C

[0441] Weigh 20 mg of free base crystal form A into a 2 ml glass bottle, add 200 μl of ethanol, stir at 50° C. for 7 days, centrifuge to remove the supernatant, and dry the remaining solid in a 40° C. vacuum drying oven for 20 hours to obtain free base crystal form C. After detection and analysis, it has the following XRPD diagram as shown in FIG6 and the DSC diagram as shown in FIG7.

[0442] 1.4 Preparation of Free Base Form D

[0443] Weigh 20 mg of free base crystal form A into a 2 ml glass bottle, add 200 μl of water, stir at 50° C. for 7 days, centrifuge to remove the supernatant, and dry the remaining solid in a 40° C. vacuum drying oven for 20 hours to obtain free base crystal form D. After detection and analysis, it has the following XRPD diagram as shown in FIG8 and the DSC diagram as shown in FIG9.

[0444] 1.5 Preparation of Free Base Form E

[0445] Weigh 203.21 mg of free base crystal form F, add 4 mL of methanol, heat at 50°C, filter, add 2000 μL of water, continue stirring overnight after precipitation, and vacuum dry at 40°C to obtain crystal form E. Detection and analysis show the following XRPD graph as shown in Figure 10, the DSC graph as shown in Figure 11, and the TGA graph as shown in Figure 12.

[0446] 1.6 Preparation of Free Base Form F

[0447] 20g of 6-methylsulfanyl-3-tetrahydropyran-4-yl-1H-1,3,5-triazine-2,4-dione, 16.8g of (S)-1-(2,4-difluorophenyl)ethylamine and 60ml of NMP were added to a three-necked flask; nitrogen was replaced 3 times; the reaction was heated to 120°C and stirred for 16 hours; sampling was performed to control the reaction, and the reaction was completed; the reaction was cooled to 55°C and 40-60ml of water was slowly added dropwise to the reaction system (the system became turbid at this time); the reaction was stirred at 55°C for 1 hour (the solid content of the system increased significantly); 200ml of water was continued to be added dropwise; the reaction was stirred at 55°C for 3-4 hours (the solid content of the system continued to increase); the reaction was cooled to 0°C and stirred for 30 minutes; the solid was filtered and the wet cake was rinsed with water; the reaction was dried overnight at 50°C to obtain 24.8g of a light yellow solid (purity: 99.5%), and Form F was obtained. The detection analysis shows an XRPD pattern as shown in Figure 13.

[0448] 1.7 Preparation of Free Base Form G

[0449] Weigh 10 mg of Form F, add an appropriate amount of dichloromethane to dissolve, blow dry with nitrogen, add 100 μl of tert-butyl alcohol, stir at 50° C. for 7 days, centrifuge, and vacuum dry the solid at 40° C. to obtain Form G. After detection and analysis, it has the following XRPD pattern as shown in FIG14 .

[0450] 1.8 Preparation of Free Base Form H

[0451] Weigh 10 mg of Form F, add an appropriate amount of dichloromethane to dissolve, blow dry with nitrogen, add 100 μl of isopropanol, stir at 50° C. for 7 days, centrifuge, and vacuum dry the solid at 40° C. to obtain Form H. After detection and analysis, it has the following XRPD pattern as shown in FIG15 .

[0452] 1.9 Preparation of Free Base Form I

[0453] 10 mg of Form F was weighed, an appropriate amount of dichloromethane was added to dissolve, the mixture was dried with nitrogen, 100 μl of 1,4-dioxane was added, the mixture was stirred at room temperature for 7 days, centrifuged, and the solid was dried under vacuum at 40° C. to obtain Form I. The detection and analysis showed the following XRPD graph as shown in FIG16 and the DSC graph as shown in FIG17 .

[0454] 1.10 Preparation of Free Base Form J

[0455] 10 mg of Form F was weighed, an appropriate amount of dichloromethane was added to dissolve, the mixture was dried with nitrogen, 100 μl of ethyl acetate was added, the mixture was stirred at room temperature for 7 days, centrifuged, and the solid was vacuum dried at 40° C. to obtain Form J. The detection analysis showed the following XRPD diagram as shown in FIG18 and the DSC diagram as shown in FIG19 .

[0456] 1.11 Preparation of Free Base Form K

[0457] Take the compound, add an appropriate amount of dichloromethane to dissolve, filter, blow dry the filtrate with nitrogen, add 100 μl of methanol / water (v:v=1:1.2), stir at room temperature for 7 days, centrifuge, and dry the solid at 40°C in vacuum to obtain Form K. Detection and analysis show the XRPD diagram shown in Figure 20 and the DSC diagram shown in Figure 21.

[0458] 1.12 Preparation of Free Base Form L

[0459] Weigh 3 g of Form F, add 120 ml of methanol to dissolve at 40°C, filter, add 105 ml of water, stir at 40°C, add an appropriate amount of Form K as a seed, stir at room temperature overnight, filter, and air dry the solid at 60°C to obtain Form L. After detection and analysis, it has an XRPD pattern as shown in Figure 22.

[0460] 2. Solid stability test

[0461] 2.1 Experimental Purpose:

[0462] The chemical stability of the compound of Form A under high temperature, high humidity, high temperature and high humidity and light conditions was investigated to provide a basis for crystal screening and compound storage.

[0463] 2.2 Experimental plan:

[0464] About 2 mg of compound crystalline form A was taken and observed for 7 days and 14 days at 60°C, 95% RH, 50°C&75% RH and a light box (5000lx±500lx). It was detected by HPLC and the changes of related substances were calculated by the chromatographic peak area normalization method.

[0465] 2.3 Experimental results:

[0466] Chemical stability results of free base form A:

[0467] 2.4 Study on the stability of factors affecting crystal form K

[0468] The crystal form K was placed under light for 10 days (total illumination not less than 1.2×106 lux·hr), high temperature (60°C, 30 days), and high humidity (25°C RH90%, 30 days) and then sent for X-ray powder diffraction and compared with the 0-day data.

[0469] Research conclusion: After 10 days and 30 days of light exposure test (60°C, 25°C RH90%), the X-ray powder diffraction spectrum data of Form K was consistent with the initial data, and no crystal transformation occurred, indicating that Form K is stable.

[0470] In addition to crystal forms A and K, other crystal forms of the present invention also show good stability.

[0471] 3. Solubility experiments in different media

[0472] 3.1 Experimental Purpose

[0473] The solubility of free base crystal form A, crystal form E and crystal form K in different pH buffer solutions (pH1 is 0.1N HCl aqueous solution, pH2-pH8 is phosphate buffer solution containing 50mM phosphate ion concentration), water, artificial simulated gastric fluid (SGF), fasting artificial simulated intestinal fluid (FaSSIF) and non-fasting artificial simulated intestinal fluid (FeSSIF) was determined to provide a basis for the drugability evaluation.

[0474] 3.2 Experimental plan:

[0475] About 2 mg of free base crystal form A, crystal form E, and crystal form K were suspended in different media for 24 hours, and the thermodynamic solubility of the compound at 37° C. was determined by HPLC and external standard method.

[0476] 3.3 Experimental results: as shown in the following table

Claims

A crystalline form of a compound represented by general formula (I), the structure of the compound is shown below: in: R1 is selected from C1-C3 alkyl, C1-C3 haloalkyl or C1-C3 alkoxy; R2 and R3 together with their adjacent C atoms form a 5-6 membered heterocyclic group containing 1-2 atoms selected from N and O atoms; R4 is independently selected from halogen, C1-C3 alkyl, C1-C3 alkoxy or C1-C3 haloalkyl. The crystal form according to claim 1, characterized in that R1 is a C1-C3 alkyl group; R4 and R5 together with their adjacent C atoms form and R6 are independently selected from F, Cl and Br. The crystal form according to claim 1, characterized in that The general formula (I) is selected from the following compounds: The crystal form according to claim 1, characterized in that The crystal form is crystal form A to crystal form L of (S)-6-((1-(2,4-difluorophenyl)ethyl)amino)-3-(tetrahydro-2H-pyran-4-yl)-1,3,5-triazine-2,4(1H,3H)-dione, wherein: the powder X-ray diffraction spectrum of crystal form A has a characteristic peak at 2θ of 8.0±0.2°, or has a characteristic peak at 2θ of 16.5±0.2°, or has a characteristic peak at 2θ of 18.3±0.2°, or has a characteristic peak at 2θ of 20.4±0.2°, or has a characteristic peak at 2θ of 14.9±0.2°, or has a characteristic peak at 2θ of 17.4±0.2°, or has a characteristic peak at 2θ of 17.7±0.2° , or has a characteristic peak at 2θ of 18.9±0.2°, or has a characteristic peak at 2θ of 10.7±0.2°, or has a characteristic peak at 2θ of 16.7±0.2°, or has a characteristic peak at 2θ of 21.3±0.2°, or has a characteristic peak at 2θ of 22.4±0.2°, or has a characteristic peak at 2θ of 24.9±0.2°, or has a characteristic peak at 2θ of 27.6±0.2°; preferably, it comprises characteristic peaks at any of 2, 4, 6, 8, 10 or 12; the powder X-ray diffraction pattern of Form B has a characteristic peak at 2θ of 16.6±0.2°, or has a characteristic peak at 2θ of 18.3±0.2°, or The crystal form C has a characteristic peak at 2θ of 18.5±0.2°, or has a characteristic peak at 2θ of 10.7±0.2°, or has a characteristic peak at 2θ of 14.9±0.2°, or has a characteristic peak at 2θ of 20.4±0.2°, or has a characteristic peak at 2θ of 24.4±0.2°, or has a characteristic peak at 2θ of 24.9±0.2°, or has a characteristic peak at 2θ of 26.9±0.2°, or has a characteristic peak at 2θ of 20.7±0.2°, or has a characteristic peak at 2θ of 16.0±0.2°; preferably, it comprises characteristic peaks at any of 2, 4, 6, 8 or 10 positions; the powder X-ray diffraction pattern of the crystal form C has a characteristic peak at 2θ of 1 The characteristic peak is 7.4±0.2°, or 18.3±0.2°, or 19.6±0.2°, or 5.5±0.2°, or 9.4±0.2°, or 10.9±0.2°, or 16.5±0.2°, or 25.8±0.2°, or 27.5±0.2°, or 10.7±0.2°, or 18.8±0.2°, or 22.4±0.2θ has a characteristic peak at 17.2±0.2°, or has a characteristic peak at 2θ of 9.7±0.2°, or has a characteristic peak at 2θ of 13.8±0.2°, or has a characteristic peak at 2θ of 15.3±0.2°, or has a characteristic peak at 2θ of 18.4±0.2°, or has a characteristic peak at 2θ of 21.6±0.2°, or has a characteristic peak at 2θ of 24.9±0.2°, or has a characteristic peak at 2θ of 14.9±0.2°, Or it has a characteristic peak at 2θ of 27.6±0.2°, or it has a characteristic peak at 2θ of 30.1±0.2°, or it has a characteristic peak at 2θ of 33.9±0.2°; preferably, it contains characteristic peaks at any of 2, 4, 6, 8 or 10 positions; the powder X-ray diffraction pattern of Form E has a characteristic peak at 2θ of 8.0±0.2°, or it has a characteristic peak at 2θ of 12.8±0.2°, or it has a characteristic peak at 2θ of 18.0±0.2°, or it has a characteristic peak at 2θ of 18.9±0.2°, or it has a characteristic peak at 2θ of 19.8±0.2°, or it has a characteristic peak at 2θ of 20.6±0.2°; preferably, it contains any of The powder X-ray diffraction pattern of Form F has a characteristic peak at 2θ of 7.3±0.2°, or a characteristic peak at 2θ of 11.8±0.2°, or a characteristic peak at 2θ of 14.5±0.2°, or a characteristic peak at 2θ of 19.4±0.2°, or a characteristic peak at 2θ of 21.7±0.2°, or a characteristic peak at 2θ of 10.8±0.2°, or a characteristic peak at 2θ of 11.0±0.2°, or a characteristic peak at 2θ of 15.4±0.2°, or a characteristic peak at 2θ of 16.1±0.2°, or a characteristic peak at 2θ of 16.9±0.2°, or a characteristic peak at 2θ of 18. The crystal form G has a characteristic peak at 2θ of 17.7±0.2°, or at 2θ of 18.0±0.2°, or at 2θ of 20.4±0.2°; preferably, it contains characteristic peaks at any of 2, 4, 6, 8 or 10 positions; the powder X-ray diffraction pattern of the crystal form G has a characteristic peak at 2θ of 7.7±0.2°, or at 2θ of 16.8±0.2°, or at 2θ of 17.0±0.2°, or at 2θ of 17.4±0.2°, or at 2θ of 17.7±0.2°, or at 2θ of 18.9±0.2°, or at 2θ of 19.3±0.2θ has a characteristic peak at 20.2±0.2°, or has a characteristic peak at 2θ of 13.5±0.2°, or has a characteristic peak at 2θ of 13.8±0.2°, or has a characteristic peak at 2θ of 14.5±0.2°, or has a characteristic peak at 2θ of 15.4±0.2°, or has a characteristic peak at 2θ of 19.8±0.2°, or has a characteristic peak at 2θ of 21.7±0.2°, or has a characteristic peak at 2θ of 24.9±0.2°, or has a characteristic peak at 2θ of 25.4±0.2°, or has a characteristic peak at 2θ of 26.7±0.2°; preferably, it comprises 2 or 4 of the above optional , 6, 8 or 10; the powder X-ray diffraction spectrum of Form H has a diffraction peak at 2θ of 8.1±0.2°, or a diffraction peak at 2θ of 10.5±0.2°, or a diffraction peak at 2θ of 13.0±0.2°, or a diffraction peak at 2θ of 13.4±0.2°, or a diffraction peak at 2θ of 14.1±0.2°, or a diffraction peak at 2θ of 14.8±0.2°, or a diffraction peak at 2θ of 15.3±0.2°, or a diffraction peak at 2θ of 16.0±0.2°, or a diffraction peak at 2θ of 16.5±0.2°, or a diffraction peak at 2θ of 16.9±0.2°, or The invention relates to a diffraction peak at 2θ of 17.3±0.2°, or at 2θ of 17.6±0.2°, or at 2θ of 17.9±0.2°, or at 2θ of 19.1±0.2°, or at 2θ of 20.4±0.2°, or at 2θ of 20.6±0.2°, or at 2θ of 21.0±0.2°, or at 2θ of 21.4±0.2°, or at 2θ of 23.5±0.2°, or at 2θ of 25.4±0.2°; preferably, the invention comprises 2, 4, 6, 8 or 10 of which are optionally substituted. The powder X-ray diffraction pattern of Form I has a diffraction peak at 2θ of 7.3±0.2°, or at 2θ of 9.8±0.2°, or at 2θ of 10.7±0.2°, or at 2θ of 11.2±0.2°, or at 2θ of 11.8±0.2°, or at 2θ of 14.5±0.2°, or at 2θ of 15.3±0.2°, or at 2θ of 16.0±0.2°, or at 2θ of 17.3±0.2°, or at 2θ of 18.2±0.2°, or at 2θ of 18.9±0.2θ has a diffraction peak at 20.7±0.2°, or has a diffraction peak at 2θ of 21.6±0.2°, or has a diffraction peak at 2θ of 21.9±0.2°, or has a diffraction peak at 2θ of 22.4±0.2°, or has a diffraction peak at 2θ of 23.7±0.2°, or has a diffraction peak at 2θ of 26.0±0.2°, or has a diffraction peak at 2θ of 26.2±0.2°, or has a diffraction peak at 2θ of 27.4±0.2°, or has a diffraction peak at 2θ of 28. θ has a diffraction peak at 28.8±0.2°; preferably, it comprises diffraction peaks at any of 2, 4, 6, 8 or 10 positions; the powder X-ray diffraction pattern of Form J has a diffraction peak at 2θ of 7.2±0.2°, or at 2θ of 10.8±0.2°, or at 2θ of 11.0±0.2°, or at 2θ of 11.8±0.2°, or at 2θ of 14.4±0.2°, or at 2θ of 15.4±0.2°. The diffraction peak may be 16.1±0.2° at 2θ, 16.9±0.2° at 2θ, 17.7±0.2° at 2θ, 18.8±0.2° at 2θ, 19.4±0.2° at 2θ, 21.3±0.2° at 2θ, 21.7±0.2° at 2θ, 22.1±0.2° at 2θ, 23.3±0.2° at 2θ, or 24.7±0.2° at 2θ. The invention relates to a crystal form K having a diffraction peak at 2θ of 9.7±0.2°, a diffraction peak at 2θ of 24.7±0.2°, a diffraction peak at 2θ of 25.2±0.2°, a diffraction peak at 2θ of 26.1±0.2°, a diffraction peak at 2θ of 27.8±0.2°, or a diffraction peak at 2θ of 29.7±0.2°; preferably, the crystal form K has a diffraction peak at any of 2, 4, 6, 8 or 10 positions; the powder X-ray diffraction pattern of the crystal form K has a diffraction peak at 2θ of 9.7±0.2°, or a diffraction peak at 2θ of 29.7±0.2°. The diffraction peak is 12.8±0.2°, 13.7±0.2°, 14.8±0.2°, 15.2±0.2°, 17.3±0.2°, 18.3±0.2°, 19.4±0.2°, 21.5±0.2°, 21.9±0.2°, 22.8±0.2°, 23.0±0.2°, 24.4±0.2°, 25.8±0.2°, 26.9±0.2°, 27.1±0.2°, 28.8±0.2°, 29.9±0.2°, 30.9±0.2°, 31.7±0.2°, 32.9±0.2°, 33.9±0.2°, 34.7±0.2°, 35.9±0.2°, 36.9±0.2°, 37.9±0.2°, 38.9±0.2°, 39.8±0.2°, 40.9±0.2°, 41.7±0.2°, 42.9±0.2°, 43.7±0.2°, 44.7±0.2°, 45.9±0.2°, 47.9±0.2°, 48.9±0.2°, 49.9±0.2θ has a diffraction peak at 24.9±0.2°, or at 27.0±0.2°, or at 27.6±0.2°, or at 27.9±0.2°, or at 29.0±0.2°, or at 30.0±0.2°, or at 30.6±0.2°, or at 33.8±0.2°. The invention relates to a crystalline form L having a diffraction peak at 2θ of 9.8±0.2°; preferably, the crystalline form L comprises a diffraction peak at any of 2, 4, 6, 8 or 10 positions; the powder X-ray diffraction pattern of the crystalline form L has a diffraction peak at 2θ of 9.8±0.2°, or at 2θ of 12.8±0.2°, or at 2θ of 13.9±0.2°, or at 2θ of 14.9±0.2°, or at 2θ of 15.3±0.2°, or at 2θ of 17.2±0 .2°, or has a diffraction peak at 2θ of 18.5±0.2°, or has a diffraction peak at 2θ of 19.3±0.2°, or has a diffraction peak at 2θ of 21.6±0.2°, or has a diffraction peak at 2θ of 22.0±0.2°, or has a diffraction peak at 2θ of 23.4±0.2°, or has a diffraction peak at 2θ of 24.9±0.2°, or has a diffraction peak at 2θ of 27.0±0.2°, or has a diffraction peak at 2θ of 27.6 ±0.2°, or has a diffraction peak at 2θ of 28.1±0.2°, or has a diffraction peak at 2θ of 28.9±0.2°, or has a diffraction peak at 2θ of 29.3±0.2°; or has a diffraction peak at 2θ of 30.1±0.2°; or has a diffraction peak at 2θ of 31.1±0.2°; or has a diffraction peak at 2θ of 33.8±0.2°; preferably, it contains diffraction peaks at any of 2, 4, 6, 8 or 10 positions. . The crystal form according to claim 4, characterized in that The powder X-ray diffraction pattern of Form A has one or more characteristic peaks at 8.0±0.2°, 16.5±0.2°, 18.3±0.2° or 20.4±0.2°; preferably 2-4 of them, more preferably 3-4 of them, and most preferably 4 of them; optionally, further, it may also include one or more characteristic peaks at 2θ of 14.9±0.2°, 17.4±0.2°, 17.7±0.2°, 18.9±0.2°, 22.4±0.2° or 10.7±0.2°, preferably 2, 3, 4 or 6 of them; the powder X-ray diffraction pattern of Form B has one or more characteristic peaks at 2θ of 16.6±0.2°, 18.3±0.2°, 18.5±0.2° or 10 .7±0.2° one or more characteristic peaks; preferably 2-4 of them, more preferably 3-4 of them, most preferably 4 of them; optionally, further, it may also include 2θ of 14.9±0.2°, 20.4±0.2°, 24.4±0.2°, 24.9±0.2°, 20.7±0.2° or 16.0±0.2° one or more characteristic peaks, preferably 2, 3, 4 or 6 of them; the powder X-ray diffraction spectrum of Form C has one or more characteristic peaks in 2θ of 17.4±0.2°, 18.3±0.2°, 19.6±0.2° or 5.5±0.2°; preferably 2-4 of them, more preferably 3-4 of them, most preferably 4 of them ; Optionally, further, it may also include one or more characteristic peaks of 2θ of 9.4±0.2°, 10.9±0.2°, 16.5±0.2°, 25.8±0.2°, 27.5±0.2° or 10.7±0.2°, preferably including 2, 3, 4 or 6 thereof; the powder X-ray diffraction pattern of Form D has one or more characteristic peaks of 2θ of 17.2±0.2°, 9.7±0.2°, 13.8±0.2° or 15.3±0.2°; preferably including 2-4 thereof, more preferably including 3-4, most preferably including 4; Optionally, further, it may also include 2θ of 18.4±0.2°, 21.6±0.2°, 24.9±0.2°, The powder X-ray diffraction pattern of the crystalline form E has one or more characteristic peaks at 2θ of 8.0±0.2°, 12.8±0.2°, 18.0±0.2° or 18.9±0.2°, preferably 2-4 of them, more preferably 3-4, most preferably 4; optionally, further, it may also have characteristic peaks at 19.8±0.2° and 20.6±0.2°; the powder X-ray diffraction pattern of the crystalline form F has one or more characteristic peaks at 2θ of 7.3±0.2°, 11.8±0.2°, 14.5±0.2° or 21.7±0.2θ is 19.4±0.2°, 10.8±0.2°, 11.0±0.2°, 15.4±0.2°, 16.1±0.2° or 16.9±0.2°, preferably 2, 3, 4 or 6 thereof; the powder X-ray diffraction pattern of Form G is 7.7±0.2°, 13.5±0.2°, 13.8±0.2° or 18.9±0.2°, preferably 2-4 thereof, more preferably 3-4 thereof, most preferably 4 thereof; optionally, further, it may also include 2θ of 19.4±0.2°, 10.8±0.2°, 11.0±0.2°, 15.4±0.2°, 16.1±0.2° or 16.9±0.2°, preferably 2, 3, 4 or 6 thereof; the powder X-ray diffraction pattern of Form G is 7.7±0.2°, 13.5±0.2°, 13.8±0.2° or 18.9±0.2°, preferably 2-4 thereof, more preferably 3-4 thereof, most preferably 4 thereof; optionally , further, it may also include one or more characteristic peaks of 2θ of 16.8±0.2°, 17.4±0.2°, 17.7±0.2°, 19.3±0.2°, 20.2±0.2° or 14.5±0.2°, preferably including 2, 3, 4 or 6 thereof; the powder X-ray diffraction spectrum of Form H has one or more diffraction peaks of 2θ of 8.1±0.2°, 10.5±0.2°, 17.6±0.2° or 19.1±0.2°; preferably including 2-4 thereof, more preferably including 3-4, most preferably including 4; optionally, further, it may also include 2θ of 16.5±0.2°, 16.9±0.2°, 17.3±0.2°, 17 .9±0.2°, 20.6±0.2° or 21.0±0.2°, preferably including 2, 3, 4 or 6 of them; the powder X-ray diffraction spectrum of Form I has one or more diffraction peaks in 2θ of 10.7±0.2°, 11.8±0.2°, 14.5±0.2° or 21.9±0.2°; preferably including 2-4 of them, more preferably including 3-4, most preferably including 4; optionally, further, it can also include one or more diffraction peaks in 2θ of 17.3±0.2°, 20.7±0.2°, 21.6±0.2°, 23.7±0.2° or 26.0±0.2°, preferably including 2, 3, 4 or 5 of them The powder X-ray diffraction spectrum of Form J has one or more diffraction peaks at 2θ of 10.8±0.2°, 11.0±0.2°, 11.8±0.2° or 16.1±0.2°; preferably 2-4 of them, more preferably 3-4 of them, and most preferably 4 of them; optionally, further, it may also contain one or more diffraction peaks at 2θ of 7.2±0.2°, 14.4±0.2°, 15.4±0.2°, 19.4±0.2° or 21.7±0.2°, preferably 2, 3, 4 or 5 of them; the powder X-ray diffraction spectrum of Form K has one or more diffraction peaks at 2θ of 9.7±0.2°, 13.7±0.2°, 15.2±0.2° or 17.3±0.2θ is 9.8 ± 0.2°, 18.3 ± 0.2°, 21.5 ± 0.2°, 21.9 ± 0.2°, 24.9 ± 0.2° or 33.8 ± 0.2°, preferably 2, 3, 4 or 6 of them; the powder X-ray diffraction spectrum of the crystalline form L ... 0.2°, 13.9±0.2°, 17.2±0.2° or 18.5±0.2°; preferably 2-4 of them, more preferably 3-4, most preferably 4; optionally, further, it may also contain 2θ of 15.3±0.2°, 22.0±0.2°, 24.9±0.2°, 27.6±0.2° or 33.8±0.2°, preferably 2, 3, 4 or 5 of them. . The crystal form according to claim 4, characterized in that The powder X-ray diffraction pattern of Form A has characteristic peaks at 2θ of 8.0±0.2° and 16.5±0.2°; preferably, it also includes characteristic peaks at 2θ of 18.3±0.2° and 20.4±0.2°; more preferably, it also includes characteristic peaks at 2θ of 14.9±0.2°, 17.4±0.2°, 17.7±0.2° and 18.9±0.2°; further preferably, it also includes characteristic peaks at 2θ of 10.7±0.2° and 16.7±0.2°; further preferably, it also includes characteristic peaks at one or more of 21.3±0.2°, 22.4±0.2°, 24.9±0.2° and 27.6±0.2°; the powder of Form B has characteristic peaks at 2θ of 14.9±0.2°, 17.4±0.2°, 17.7±0.2° and 18.9±0.2°; further preferably, it also includes characteristic peaks at 2θ of 10.7±0.2° and 16.7±0.2°; further preferably, it also includes characteristic peaks at one or more of 21.3±0.2°, 22.4±0.2°, 24.9±0.2° and 27.6±0.2°; The X-ray diffraction spectrum has characteristic peaks at 2θ of 16.6±0.2° and 18.3±0.2°; preferably, it also includes characteristic peaks at 2θ of 10.7±0.2° and 18.5±0.2°; more preferably, it also includes characteristic peaks at 2θ of 14.9±0.2°, 16.0±0.2°, 20.4±0.2° and 20.7±0.2°; further preferably, it also includes characteristic peaks at one or more of 2θ of 24.4±0.2°, 24.9±0.2° and 26.9±0.2°; the powder X-ray diffraction spectrum of Form C has characteristic peaks at 2θ of 5.5±0.2° and 19.6±0.2°; preferably, it also includes characteristic peaks at 2θ of 17.4±0. The crystal form D has characteristic peaks at 2θ of 9.7±0.2° and 17.2±0.2°; preferably, it also has characteristic peaks at 2θ of 13.8±0.2° and 15.3±0.2°; more preferably, it also has characteristic peaks at 2θ of 18.4±0.2°, 10.9±0.2°, 16.5±0.2° and 25.8±0.2°; further preferably, it also has characteristic peaks at 2θ of 10.7±0.2°, 18.8±0.2°, 22.4±0.2°, 26.8±0.2° and 27.5±0.2°; the powder X-ray diffraction pattern of the crystal form D has characteristic peaks at 2θ of 9.7±0.2° and 17.2±0.2°; preferably, it also has characteristic peaks at 2θ of 13.8±0.2° and 15.3±0.2°; more preferably, it also has characteristic peaks at 2θ of 18.4 The crystal form E has characteristic peaks at 2θ of 8.0±0.2° and 12.8±0.2°; preferably, it also has characteristic peaks at 2θ of 18.0±0.2° and 18.9±0.2°; more preferably, it also has characteristic peaks at 2θ of 19.8±0.2° and 20.6±0.2°; the crystal form F has characteristic peaks at 2θ of 7.3±0.2° and 11.8±0.2°.2θ has characteristic peaks at 21.7±0.2° and 14.5±0.2°; more preferably, it also includes characteristic peaks at 19.4±0.2°, 10.8±0.2°, 11.0±0.2° and 15.4±0.2°; further preferably, it also includes characteristic peaks at 16.1±0.2° and 16.9±0.2°; further preferably, it also includes characteristic peaks at 17.7±0.2°, 18.0±0.2° and 20.4±0.2°; the powder X-ray diffraction spectrum of Form G has characteristic peaks at 7.7±0.2° and 16.8±0.2° at 2θ; preferably, it also includes characteristic peaks at 2θ. θ has characteristic peaks at 17.0±0.2° and 17.4±0.2°; more preferably, it also includes characteristic peaks at 2θ of 17.7±0.2°, 18.9±0.2°, 19.3±0.2° and 20.2±0.2°; further preferably, it also includes characteristic peaks at 2θ of 13.5±0.2° and 13.8±0.2°; further preferably, it also includes characteristic peaks at one or more of 14.5±0.2°, 15.4±0.2°, 19.8±0.2° and 21.7±0.2°; the powder X-ray diffraction pattern of Form H has characteristic peaks at 2θ of 17.6±0.2° and 19.1±0.2°; preferably, it also includes characteristic peaks at 2θ of 8.1±0.2°. More preferably, it also comprises characteristic peaks at 2θ of 17.3±0.2° and 17.9±0.2°; further preferably, it also comprises characteristic peaks at 2θ of 20.6±0.2° and 25.4±0.2°, and further preferably, it also comprises characteristic peaks at 13.0±0.2°, 13.4±0.2°, 14.1±0.2°, 14.8±0.2°, 15.3±0.2°, 16.0±0.2°, 20.4±0.2°, 21.0±0.2°, 21.4±0.2° and 23.5±0.2°; Powder X-ray diffraction pattern of Form I The spectrum has characteristic peaks at 2θ of 11.8±0.2° and 21.9±0.2°; preferably, it also includes characteristic peaks at 2θ of 10.7±0.2°, 14.5±0.2°, 17.3±0.2° and 23.7±0.2°; more preferably, it also includes characteristic peaks at 2θ of 20.7±0.2° and 26.0±0.2°; further preferably, it also includes characteristic peaks at 2θ of 21.6±0.2° and 22.4±0.2°, and further preferably, it also includes characteristic peaks at 7.2±0.2°, 9.8±0.2°, 11.2±0.2°, 15.3±0.2°, 16.0±0.2°, 18.2±0.2°, 18.9±0.2°, 26.The powder X-ray diffraction pattern of Form J has characteristic peaks at 2θ of 11.8±0.2° and 16.1±0.2°; preferably, it also includes characteristic peaks at 2θ of 10.8±0.2°, 11.0±0.2°, 14.4±0.2° and 15.4±0.2°; more preferably, it also includes characteristic peaks at 2θ of 19.4±0.2° and 21.7±0.2°; further preferably, it also includes characteristic peaks at 2θ of 7.2±0.2° and 16.9±0.2°, and further preferably, it also includes characteristic peaks at 17.7±0.2° and 21.7±0.2°. .2°, 18.8±0.2°, 21.3±0.2°, 22.1±0.2°, 23.3±0.2°, 24.7±0.2°, 25.2±0.2°, 26.1±0.2°, 27.8±0.2° and 29.7±0.2°; the powder X-ray diffraction pattern of Form K has characteristic peaks at 2θ of 15.2±0.2° and 17.3±0.2°; preferably, it also includes characteristic peaks at 2θ of 9.7±0.2°, 13.7±0.2°, 18.3±0.2° and 24.9±0.2°; more preferably, it also includes characteristic peaks at 2θ of 21.9±0.2° and 33.8±0.2°. ; further preferably, it also includes characteristic peaks at 2θ of 21.5±0.2° and 29.0±0.2°, and further preferably, it also includes characteristic peaks at 12.8±0.2°, 14.8±0.2°, 19.4±0.2°, 22.8±0.2°, 23.0±0.2°, 27.0±0.2°, 27.6±0.2°, 27.9±0.2°, 30.0±0.2° and 30.6±0.2°; the powder X-ray diffraction pattern of form L has characteristic peaks at 2θ of 17.2±0.2° and 18.5±0.2°; preferably, it also includes characteristic peaks at 2θ of 9.8±0.2°, 1 3.9±0.2°, 15.3±0.2° and 22.0±0.2°; more preferably, it also includes characteristic peaks at 2θ of 24.9±0.2° and 27.6±0.2°; further preferably, it also includes characteristic peaks at 2θ of 14.9±0.2° and 33.8±0.2°, and further preferably, it also includes characteristic peaks at 12.8±0.2°, 19.3±0.2°, 21.6±0.2°, 23.4±0.2°, 27.0±0.2°, 28.1±0.2°, 28.9±0.2°, 29.3±0.2°, 30.1±0.2° and 31.1±0.2°. . The crystal form according to claim 4, characterized in that The X-ray powder diffraction pattern of Form A is shown in Figure 1. Preferably, Form A has a DSC spectrum as shown in Figure 2, or has a TGA spectrum as shown in Figure 3; the powder X-ray diffraction pattern of Form B at 2θ is as shown in Figure 4, preferably, Form B has a DSC spectrum as shown in Figure 5; the powder X-ray diffraction pattern of Form C at 2θ is as shown in Figure 6, preferably, Form C has a DSC spectrum as shown in Figure 7; the powder X-ray diffraction pattern of Form D at 2θ is as shown in Figure 8, preferably, Form D has a DSC spectrum as shown in Figure 9; the powder X-ray diffraction pattern of Form E at 2θ is as shown in Figure 10, preferably, Form E has a DSC spectrum as shown in Figure 11, or has a DSC spectrum as shown in Figure 12. The TGA spectrum shown; the powder X-ray diffraction spectrum of Form F at 2θ is as shown in Figure 13; the powder X-ray diffraction spectrum of Form G at 2θ is as shown in Figure 14; the powder X-ray diffraction spectrum of Form H at 2θ is as shown in Figure 15; the powder X-ray diffraction spectrum of Form I at 2θ is as shown in Figure 16, preferably, Form I has a DSC spectrum as shown in Figure 17; the powder X-ray diffraction spectrum of Form J at 2θ is as shown in Figure 18, preferably, Form J has a DSC spectrum as shown in Figure 19; the powder X-ray diffraction spectrum of Form K at 2θ is as shown in Figure 20, preferably, Form K has a DSC spectrum as shown in Figure 21; the powder X-ray diffraction spectrum of Form L at 2θ is as shown in Figure 22. The crystal form according to claim 4, characterized in that The 2θ errors of the top ten diffraction peak positions with relative peak intensities in the X-ray powder diffraction patterns of Form A, Form B, Form C, Form D, Form E, Form F, Form G, Form H, Form I, Form J, Form K and Form L and the diffraction peaks at the corresponding positions in Figures 1, 4, 6, 8, 10, 13, 14, 15, 16, 18, 20 and 22 are ±0.2° to ±0.5°, preferably ±0.2° to ±0.3°, and more preferably ±0.2°. A method for preparing a crystalline form of the compound according to any one of claims 1 to 8, comprising the following steps: 1) weighing an appropriate amount of free base and suspending it with a poor solvent, wherein the suspension density is preferably 50 to 200 mg / mL; 2) shaking the above suspension, preferably at a temperature of 0 to 50° C., and preferably for 1 to 10 days; 3) rapidly centrifuging the above suspension, removing the supernatant, and drying the remaining solid to constant weight to obtain the target product; wherein: The poor solvent is selected from acetone, ethyl acetate, isopropyl acetate, acetonitrile, ethanol, tetrahydrofuran, 2-methyltetrahydrofuran, dichloromethane, 1,4-dioxane, benzene, toluene, methanol, ethanol, isopropanol, n-butanol, isobutanol, N,N-dimethylformamide, N,N-dimethylacetamide, n-propanol, tert-butanol, 2-butanone or 3-pentanone, methyl tert-butyl ether, water, heptane or n-pentane or a combination thereof; preferably isopropyl acetate, toluene, tert-butyl ether, water, heptane or n-pentane; or, 1) weigh an appropriate amount of free base and dissolve it with a good solvent; 2) add an anti-solvent to the above solution and stir until solid precipitates, the temperature is preferably 0-25°C; 3) the above suspension is quickly centrifuged, the supernatant is removed, and the remaining solid is dried to constant weight to obtain the target product; wherein: the good solvent is selected from methanol, acetone, ethyl acetate, acetonitrile, ethanol, tetrahydrofuran, dichloromethane, 1,4-dioxane, benzene, toluene, isopropanol, n-butanol, isobutanol, N,N-dimethylformamide, N,N-dimethylacetamide, n-propanol, tert-butanol, 2-butanone or 3-pentanone; preferably methanol, dichloromethane or ethyl acetate, the anti-solvent is selected from heptane, water, methyl tert-butyl ether, cyclohexane or isopropyl acetate; or, 1) weigh an appropriate amount of free base and dissolve it with a good solvent by heating; 2) the above solution is quickly placed at low temperature and stirred until solid precipitates, the temperature is Preferably -10 to 5°C; 3) rapidly centrifuging the above suspension, removing the supernatant, and drying the remaining solid to constant weight to obtain the target product; wherein: the good solvent is selected from methanol, acetone, ethyl acetate, acetonitrile, ethanol, tetrahydrofuran, dichloromethane, 1,4-dioxane, benzene, toluene, isopropanol, n-butanol, isobutanol, N,N-dimethylformamide, N,N-dimethylacetamide, n-propanol, tert-butanol or 2-butanone or tetrahydrofuran; preferably acetone. A pharmaceutical composition comprising a therapeutically effective amount of a crystalline form of the compound according to any one of claims 1 to 8, and one or more pharmaceutically acceptable carriers, diluents or excipients. Use of the crystalline form of the compound according to any one of claims 1 to 8, or the pharmaceutical composition according to claim 10, for preparing a drug for treating hypertrophic cardiomyopathy (HCM) or a heart disease with pathophysiological characteristics of HCM. The use according to claim 11, wherein the HCM is obstructive or non-obstructive, or is caused by sarcomeric and / or non-sarcomeric mutations. Use of a crystalline form of a compound according to any one of claims 1 to 8 or a pharmaceutical composition according to claim 10 for the preparation of a medicament for treating hypertrophic cardiomyopathy (HCM) and other forms of cardiac diseases or conditions, wherein the disease or condition is selected from heart failure with normal ejection fraction, ischemic heart disease, angina pectoris and restrictive cardiomyopathy.

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