TW202416997A - Crystal form of nitrogen-containing heterocyclic ketone compound and preparation method thereof - Google Patents

Abstract

The present invention relates to a crystalline form of a nitrogenous heterocyclone compound and a preparation method thereof. Specifically relates to a compound salt and crystal form indicated in general formula (I), a preparation method and a therapeutic effective amount of the crystal form pharmaceutical composition, and its drug use for the treatment of hypertrophic cardiomyopathy (HCM) and other forms of heart disease or conditions.

Description

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

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

Hypertrophic cardiomyopathy (HCM) is a hereditary disease that affects approximately 1 in 500 people in the general population. HCM patients 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, disorganized, and increased myocardial fibrosis of myocardial cells. Heart function in HCM patients is also disturbed by characteristic hyperdynamic contractions and impaired relaxation.

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 in the instructions, 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, myocardial cell disorder and myocardial fibrosis.

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, new selective cardiac sarcomere modulators are needed in this field.

PCT/CN2022/081361 discloses the structures of a series of nitrogen-containing heterocyclic polycyclic compounds. In subsequent research and development, in order to make the products easy to handle, filter and dry, 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 compounds.

All contents involved in patent PCT/CN2022/081361 are added to this invention by reference.

On the one hand, the present invention provides a crystalline form of a compound represented by general formula (I), and the structure of the compound is shown below:

in,

_R1 is selected from _C1 - _C3 alkyl, _C1 - _C3 halogenalkyl 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;

R ₄ is independently selected from halogen, C ₁ -C ₃ alkyl, C ₁ -C ₃ alkoxy or C ₁ -C ₃ halogenalkyl.

In certain embodiments of the present invention, R ₁ is C ₁ -C ₃ alkyl;

；和 _R4 and _R5 together with their adjacent C atoms form

;and

_R6 is independently selected from F, Cl and Br.

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

In certain embodiments of the present invention, the crystal form is a crystal 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 crystal form is an anhydrous crystal form.

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.

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

In certain embodiments of the present invention, the crystalline form is crystalline 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,

The powder X-ray diffraction spectrum of Form A has a characteristic peak at 8.0±0.2°, or at 16.5±0.2°, or at 18.3±0.2°, or at 20.4±0.2°, or at 14.9±0.2°, or at 17.4±0.2°, or at 17.7±0.2°, or at 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 includes 2, 4, 6, 8, 10 or 12 as needed.

In certain embodiments of the present invention, the powder X-ray diffraction spectrum 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, and most preferably 4; if necessary, 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:

8.0±0.2°, 16.5±0.2°, 18.3±0.2°;

8.0±0.2°, 16.5±0.2°, 18.3±0.2°, 20.4±0.2°;

8.0±0.2°, 16.5±0.2°, 18.3±0.2°, 20.4±0.2°, 14.9±0.2°, 17.4±0.2°;

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°;

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°.

In certain embodiments of the present invention, the powder X-ray diffraction spectrum 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°.

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

Table 1

In certain embodiments of the present invention, the X-ray powder diffraction spectrum of Form A is basically as shown in Figure 1; its DSC spectrum is basically as shown in Figure 2; and its TGA spectrum is basically as shown in Figure 3.

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

In certain embodiments of the present invention, the powder X-ray diffraction spectrum 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; if necessary, 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.

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

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 angle and interplanar spacing d value as shown in Table 2.

Table 2

In certain embodiments of the present invention, the X-ray powder diffraction spectrum of Form B is basically as shown in Figure 4; its DSC spectrum is basically as shown in Figure 5.

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 a characteristic peak at 2θ of 19.6±0.2°. There is a characteristic peak at 10.9±0.2°, or at 16.5±0.2°, or at 25.8±0.2°, or at 27.5±0.2°, or at 10.7±0.2°, or at 18.8±0.2°, or at 22.4±0.2°, or at 26.8±0.2°; preferably, there are characteristic peaks at 2, 4, 6, 8 or 10 as needed.

In certain embodiments of the present invention, the powder X-ray diffraction spectrum 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 2-4 of them, more preferably 3-4, and most preferably 4; if necessary, 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 2, 3, 4 or 6 of them.

In certain embodiments of the present invention, 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 has characteristic peaks at 2θ of 17.4±0.2° and 18.3±0.2°; more preferably, it also has characteristic peaks at 2θ of 9.4±0.2°, 10.9±0.2°, 16.5±0.2° and 25.8±0.2°; more 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°.

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

In certain embodiments of the present invention, Cu-Kα radiation is used, and the X-ray characteristic peaks of type C are represented by 2θ angle and crystal plane spacing d value as shown in Table 3.

table 3

In certain embodiments of the present invention, the X-ray powder diffraction spectrum of Form C is basically as shown in Figure 6; its DSC spectrum is basically as shown in Figure 7.

In certain embodiments of the present invention, the crystalline form is crystalline form D 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 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°, Or there is a characteristic peak at 2θ of 18.4±0.2°, or there is a characteristic peak at 2θ of 21.6±0.2°, or there is a characteristic peak at 2θ of 24.9±0.2°, or there is a characteristic peak at 2θ of 14.9±0.2°, or there is a characteristic peak at 2θ of 27.6±0.2°, or there is a characteristic peak at 2θ of 30.1±0.2°, or there is a characteristic peak at 2θ of 33.9±0.2°; preferably, there are characteristic peaks at 2, 4, 6, 8 or 10 as needed.

In certain embodiments of the present invention, the powder X-ray diffraction spectrum 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 2-4 of them, more preferably 3-4, and most preferably 4; if necessary, 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 2, 3, 4 or 6 of them.

In certain embodiments of the present invention, the powder X-ray diffraction spectrum of 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°, 21.6±0.2°, 24.9±0.2° and 14.9±0.2°; more preferably, it also has characteristic peaks at 2θ of 27.6±0.2°, 30.1±0.2° and 33.9±0.2°.

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 angle and interplanar spacing d value as shown in Table 4.

Table 4

In certain embodiments of the present invention, the X-ray powder diffraction spectrum of Form D is substantially as shown in FIG8 ; its DSC spectrum is substantially as shown in FIG9 .

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 spectrum of crystalline form E has a characteristic peak at 2θ of 8.0±0.2°, or at 2θ of 12.8±0.2°, or at 2θ of 18.0±0.2°, or at 2θ of 18.9±0.2°, or at 2θ of 19.8±0.2°, or at 2θ of 20.6±0.2°; preferably, it includes 2, 4 or 6 characteristic peaks as needed.

In certain embodiments of the present invention, the powder X-ray diffraction spectrum of 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, and most preferably 4; if necessary, further, it may also include characteristic peaks at 19.8±0.2° and 20.6±0.2°. For example:

8.0±0.2°, 12.8±0.2°;

8.0±0.2°, 12.8±0.2°, 18.0±0.2°;

8.0±0.2°, 12.8±0.2°, 18.0±0.2°, 18.9±0.2°;

8.0±0.2°, 12.8±0.2°, 18.0±0.2°, 18.9±0.2°, 9.8±0.2°, 20.6±0.2°.

In certain embodiments of the present invention, the powder X-ray diffraction spectrum of 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°.

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 angle and interplanar spacing d value as shown in Table 5.

table 5

In certain embodiments of the present invention, the X-ray powder diffraction spectrum of Form E is basically as shown in Figure 10; its DSC spectrum is basically as shown in Figure 11; and its TGA spectrum is basically as shown in Figure 12.

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 the 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°. , or having a characteristic peak at 2θ of 10.8±0.2°, or having a characteristic peak at 2θ of 11.0±0.2°, or having a characteristic peak at 2θ of 15.4±0.2°, or having a characteristic peak at 2θ of 16.1±0.2°, or having a characteristic peak at 2θ of 16.9±0.2°, or having a characteristic peak at 2θ of 17.7±0.2°, or having a characteristic peak at 2θ of 18.0±0.2°, or having a characteristic peak at 2θ of 20.4±0.2°; preferably, including 2, 4, 6, 8 or 10 as needed.

In certain embodiments of the present invention, the powder X-ray diffraction spectrum 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 2-4 of them, more preferably 3-4, and most preferably 4; if necessary, 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 2, 3, 4 or 6 of them.

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

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 angle and interplanar spacing d value as shown in Table 6.

Table 6

In certain embodiments of the present invention, the X-ray powder diffraction pattern of Form F is substantially as shown in Figure 13.

In certain embodiments of the present invention, the crystalline form is crystalline form G 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 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°, Or there is a characteristic peak at 20.2±0.2°, or there is a characteristic peak at 13.5±0.2°, or there is a characteristic peak at 13.8±0.2°, or there is a characteristic peak at 14.5±0.2°, or there is a characteristic peak at 15.4±0.2°, or there is a characteristic peak at 19.8±0.2°, or there is a characteristic peak at 21.7±0.2°, or there is a characteristic peak at 24.9±0.2°, or there is a characteristic peak at 25.4±0.2°, or there is a characteristic peak at 26.7±0.2°; preferably, there are characteristic peaks at 2, 4, 6, 8 or 10 as needed.

In certain embodiments of the present invention, the powder X-ray diffraction spectrum 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 2-4 of them, more preferably 3-4, and most preferably 4; if necessary, 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 2, 3, 4 or 6 of them.

In certain embodiments of the present invention, the powder X-ray diffraction spectrum 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°.

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 angle and interplanar spacing d value as shown in Table 7.

Table 7

In certain embodiments of the present invention, the X-ray powder diffraction pattern of Form G is substantially as shown in Figure 14.

In certain embodiments of the present invention, the crystalline form is crystalline form H 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 pattern of 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°. , or has a diffraction peak at 2θ of 13.0±0.2°, or has a diffraction peak at 2θ of 13.4±0.2°, or has a diffraction peak at 2θ of 14.1±0.2°, or has a diffraction peak at 2θ of 14.8±0.2°, or has a diffraction peak at 2θ of 15.3±0.2°, or has a diffraction peak at 2θ of 16.0±0.2°, or has a diffraction peak at 2θ of 16.5 The diffraction peak is 16.9±0.2°, 17.3±0.2°, 17.6±0.2°, 17.9±0.2°, 19.1±0.2°, 20.4±0.2°, or 20.4±0.2°. , or having a diffraction peak at 20.6±0.2°, or having a diffraction peak at 21.0±0.2°, or having a diffraction peak at 21.4±0.2°, or having a diffraction peak at 23.5±0.2°, or having a diffraction peak at 25.4±0.2°; preferably, including diffraction peaks at 2, 4, 6, 8 or 10 as needed.

In certain embodiments of the present invention, the powder X-ray diffraction spectrum 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, and most preferably 4; if necessary, 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:

8.1±0.2°, 10.5±0.2°, 17.6±0.2°, 19.1±0.2°;

8.1±0.2°, 10.5±0.2°, 16.5±0.2°, 17.6±0.2°;

8.1±0.2°, 10.5±0.2°, 16.9±0.2°, 17.6±0.2°;

8.1±0.2°, 10.5±0.2°, 17.3±0.2°, 17.6±0.2°;

8.1±0.2°, 16.5±0.2°, 17.6±0.2°, 19.1±0.2°;

8.1±0.2°, 10.5±0.2°, 17.6±0.2°, 19.1±0.2°;

10.5±0.2°, 17.6±0.2°, 17.3±0.2°, 19.1±0.2°;

17.3±0.2°, 17.6±0.2°, 19.1±0.2°, 20.6±0.2°;

8.1±0.2°, 10.5±0.2°, 17.6±0.2°, 19.1±0.2°, 20.6±0.2°;

8.1±0.2°, 10.5±0.2°, 16.5±0.2°, 17.6±0.2°, 20.6±0.2°;

8.1±0.2°, 10.5±0.2°, 16.9±0.2°, 17.6±0.2°, 19.1±0.2°;

8.1±0.2°, 10.5±0.2°, 17.3±0.2°, 17.6±0.2°, 19.1±0.2°;

8.1±0.2°, 16.5±0.2°, 17.6±0.2°, 19.1±0.2°, 20.6±0.2°;

8.1±0.2°, 10.5±0.2°, 17.6±0.2°, 19.1±0.2°, 20.6±0.2°;

10.5±0.2°, 17.6±0.2°, 17.3±0.2°, 19.1±0.2°, 20.6±0.2°;

16.9±0.2°, 17.3±0.2°, 17.6±0.2°, 19.1±0.2°, 20.6±0.2°;

8.1±0.2°, 10.5±0.2°, 17.3±0.2°, 17.6±0.2°, 19.1±0.2°, 20.6±0.2°;

8.1±0.2°, 10.5±0.2°, 16.5±0.2°, 17.6±0.2°, 19.1±0.2°, 20.6±0.2°;

8.1±0.2°, 10.5±0.2°, 16.9±0.2°, 17.6±0.2°, 19.1±0.2°, 20.6±0.2°;

8.1±0.2°, 10.5±0.2°, 17.3±0.2°, 17.6±0.2°, 19.1±0.2°, 20.6±0.2°;

8.1±0.2°, 16.5±0.2°, 16.9±0.2°, 17.3±0.2°, 17.6±0.2°, 19.1±0.2°;

8.1±0.2°, 10.5±0.2°, 16.5±0.2°, 16.9±0.2°, 17.6±0.2°, 19.1±0.2°;

10.5±0.2°, 16.9±0.2°, 17.6±0.2°, 17.3±0.2°, 19.1±0.2°, 20.6±0.2°;

8.1±0.2°, 16.9±0.2°, 17.3±0.2°, 17.6±0.2°, 19.1±0.2°, 20.6±0.2°.

More preferably, the powder X-ray diffraction pattern may also include one or more diffraction peaks 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° as needed; preferably at least any 2-4, or 5-6 of them, and more preferably any 4 or 6 of them; for example:

13.0±0.2°, 13.4±0.2°, 14.1±0.2°, 14.8±0.2°;

13.0±0.2°, 13.4±0.2°, 14.1±0.2°, 15.3±0.2°;

13.0±0.2°, 13.4±0.2°, 14.1±0.2°, 25.4±0.2°;

13.0±0.2°, 13.4±0.2°, 15.3±0.2°, 25.4±0.2°;

13.4±0.2°, 14.1±0.2°, 14.8±0.2°, 15.3±0.2°;

13.0±0.2°, 13.4±0.2°, 14.1±0.2°, 14.8±0.2°, 15.3±0.2°;

13.0±0.2°, 13.4±0.2°, 14.1±0.2°, 15.3±0.2°, 25.4±0.2°;

13.0±0.2°, 13.4±0.2°, 14.1±0.2°, 14.8±0.2°, 15.3±0.2°, 25.4±0.2°.

In certain embodiments of the present invention, the powder X-ray diffraction spectrum of Form H has characteristic peaks at 2θ of 17.6±0.2° and 19.1±0.2°; preferably, it also has 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 has characteristic peaks at 2θ of 17.3±0.2° and 17.9±0.2°; further 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°.

In certain embodiments of the present invention, Cu-Kα radiation is used, and the X-ray characteristic peaks of the crystal form H are represented by the 2θ angle and the interplanar spacing d value as shown in Table 8.

Table 8

In certain embodiments of the present invention, the X-ray powder diffraction pattern of Form H is substantially as shown in Figure 15.

In certain embodiments of the present invention, the crystalline form is crystalline form I 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 pattern of crystalline form I has a diffraction peak at 2θ of 7.3±0.2°, or a diffraction peak at 2θ of 9.8±0.2°. , or has a diffraction peak at 2θ of 10.7±0.2°, or has a diffraction peak at 2θ of 11.2±0.2°, or has a diffraction peak at 2θ of 11.8±0.2°, or has a diffraction peak at 2θ of 14.5±0.2°, or has a diffraction peak at 2θ of 15.3±0.2°, or has a diffraction peak at 2θ of 16.0±0.2°, or has a diffraction peak at 2θ of 17.3 The diffraction peak is 2θ=18.2±0.2°, 2θ=18.9±0.2°, 2θ=20.7±0.2°, 2θ=21.6±0.2°, 2θ=21.9±0.2°, 2θ=22.4±0.2°. , or having a diffraction peak at 2θ of 23.7±0.2°, or having a diffraction peak at 2θ of 26.0±0.2°, or having a diffraction peak at 2θ of 26.2±0.2°, or having a diffraction peak at 2θ of 27.4±0.2°, or having a diffraction peak at 2θ of 28.8±0.2°; preferably, including diffraction peaks at 2, 4, 6, 8 or 10 as needed.

In certain embodiments of the present invention, the powder X-ray diffraction spectrum contains 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; if necessary, further, it may also contain 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:

10.7±0.2°, 11.8±0.2°, 14.5±0.2°, 21.9±0.2°;

10.7±0.2°, 11.8±0.2°, 14.5±0.2°, 17.3±0.2°;

10.7±0.2°, 11.8±0.2°, 14.5±0.2°, 20.7±0.2°;

10.7±0.2°, 11.8±0.2°, 14.5±0.2°, 21.6±0.2°;

10.7±0.2°, 11.8±0.2°, 14.5±0.2°, 23.7±0.2°;

10.7±0.2°, 14.5±0.2°, 17.3±0.2°, 21.9±0.2°;

10.7±0.2°, 14.5±0.2°, 20.7±0.2°, 21.9±0.2°;

11.8±0.2°, 14.5±0.2°, 17.3±0.2°, 21.9±0.2°;

10.7±0.2°, 11.8±0.2°, 14.5±0.2°, 21.9±0.2°, 23.7±0.2°;

10.7±0.2°, 11.8±0.2°, 14.5±0.2°, 17.3±0.2°, 23.7±0.2°;

10.7±0.2°, 11.8±0.2°, 14.5±0.2°, 20.7±0.2°, 23.7±0.2°;

10.7±0.2°, 11.8±0.2°, 14.5±0.2°, 21.6±0.2°, 23.7±0.2°;

10.7±0.2°, 11.8±0.2°, 14.5±0.2°, 23.7±0.2°, 26.0±0.2°;

10.7±0.2°, 14.5±0.2°, 17.3±0.2°, 21.9±0.2°, 23.7±0.2°;

10.7±0.2°, 14.5±0.2°, 20.7±0.2°, 21.9±0.2°, 23.7±0.2°;

11.8±0.2°, 14.5±0.2°, 17.3±0.2°, 21.9±0.2°, 23.7±0.2°;

10.7±0.2°, 11.8±0.2°, 14.5±0.2°, 21.9±0.2°, 23.7±0.2°, 26.0±0.2°;

10.7±0.2°, 11.8±0.2°, 14.5±0.2°, 17.3±0.2°, 23.7±0.2°, 26.0±0.2°;

10.7±0.2°, 11.8±0.2°, 14.5±0.2°, 20.7±0.2°, 23.7±0.2°, 26.0±0.2°;

10.7±0.2°, 11.8±0.2°, 14.5±0.2°, 21.6±0.2°, 23.7±0.2°, 26.0±0.2°;

10.7±0.2°, 11.8±0.2°, 14.5±0.2°, 17.3±0.2°, 20.7±0.2°, 26.0±0.2°;

10.7±0.2°, 11.8±0.2°, 14.5±0.2°, 17.3±0.2°, 21.9±0.2°, 23.7±0.2°;

10.7±0.2°, 14.5±0.2°, 20.7±0.2°, 21.9±0.2°, 23.7±0.2°, 26.0±0.2°;

11.8±0.2°, 14.5±0.2°, 17.3±0.2°, 21.9±0.2°, 23.7±0.2°, 26.0±0.2°;

More preferably, the powder X-ray diffraction pattern may also include one or more diffraction peaks 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° as needed; preferably at least any 2-4, or 5-6 of them, and more preferably any 4 or 6 of them; for example:

7.2±0.2°, 9.8±0.2°, 11.2±0.2°, 15.3±0.2°;

7.2±0.2°, 9.8±0.2°, 11.2±0.2°, 16.0±0.2°;

7.2±0.2°, 9.8±0.2°, 11.2±0.2°, 22.4±0.2°;

7.2±0.2°, 11.2±0.2°, 15.3±0.2°, 16.0±0.2°;

11.2±0.2°, 15.3±0.2°, 16.0±0.2°, 22.4±0.2°;

7.2±0.2°, 9.8±0.2°, 11.2±0.2°, 15.3±0.2°, 16.0±0.2°;

7.2±0.2°, 9.8±0.2°, 11.2±0.2°, 16.0±0.2°, 22.4±0.2°;

7.2±0.2°, 9.8±0.2°, 11.2±0.2°, 15.3±0.2°, 16.0±0.2°, 22.4±0.2°.

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, it also includes characteristic peaks at 21.6±0.2° and 22.4±0.2°, and more 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°, 26.2±0.2°, 27.4±0.2° and 28.8±0.2°.

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 angle and interplanar spacing d value as shown in Table 9.

Table 9

The X-ray powder diffraction spectrum of the crystalline form I of the compound represented by the general formula (I) described in the present invention is basically as shown in Figure 16; its DSC spectrum is basically as shown in Figure 17.

In certain embodiments of the present invention, the crystalline form is crystalline form J 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 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°. , or has a diffraction peak at 2θ of 11.0±0.2°, or has a diffraction peak at 2θ of 11.8±0.2°, or has a diffraction peak at 2θ of 14.4±0.2°, or has a diffraction peak at 2θ of 15.4±0.2°, or has a diffraction peak at 2θ of 16.1±0.2°, or has a diffraction peak at 2θ of 16.9±0.2°, or has a diffraction peak at 2θ of 17.7 The diffraction peak is 2θ=18.8±0.2°, 2θ=19.4±0.2°, 2θ=21.3±0.2°, 2θ=21.7±0.2°, 2θ=22.1±0.2°, 2θ=23.3±0.2°. , or having a diffraction peak at 2θ of 24.7±0.2°, or having a diffraction peak at 2θ of 25.2±0.2°, or having a diffraction peak at 2θ of 26.1±0.2°, or having a diffraction peak at 2θ of 27.8±0.2°, or having a diffraction peak at 2θ of 29.7±0.2°; preferably, including diffraction peaks at 2, 4, 6, 8 or 10 as needed.

In certain embodiments of the present invention, the powder X-ray diffraction spectrum contains 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; if necessary, 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; for example:

10.8±0.2°, 11.0±0.2°, 11.8±0.2°, 16.1±0.2°;

10.8±0.2°, 11.0±0.2°, 11.8±0.2°, 15.4±0.2°;

10.8±0.2°, 11.0±0.2°, 11.8±0.2°, 19.4±0.2°;

10.8±0.2°, 11.0±0.2°, 14.4±0.2°, 16.1±0.2°;

7.2±0.2°, 11.0±0.2°, 11.8±0.2°, 16.1±0.2°;

7.2±0.2°, 10.8±0.2°, 11.0±0.2°, 14.4±0.2°;

7.2±0.2°, 11.0±0.2°, 14.4±0.2°, 16.1±0.2°;

10.8±0.2°, 11.0±0.2°, 19.4±0.2°, 21.7±0.2°;

10.8±0.2°, 11.0±0.2°, 11.8±0.2°, 14.4±0.2°, 16.1±0.2°;

10.8±0.2°, 11.0±0.2°, 11.8±0.2°, 14.4±0.2°, 15.4±0.2°;

10.8±0.2°, 11.0±0.2°, 11.8±0.2°, 19.4±0.2°, 21.7±0.2°;

10.8±0.2°, 11.0±0.2°, 14.4±0.2°, 16.1±0.2°, 19.4±0.2°;

7.2±0.2°, 11.0±0.2°, 11.8±0.2°, 16.1±0.2°, 19.4±0.2°;

7.2±0.2°, 10.8±0.2°, 11.0±0.2°, 14.4±0.2°, 15.4±0.2°;

7.2±0.2°, 11.0±0.2°, 14.4±0.2°, 16.1±0.2°, 19.4±0.2°, 21.7±0.2°;

10.8±0.2°, 11.0±0.2°, 11.8±0.2°, 16.1±0.2°, 19.4±0.2°, 21.7±0.2°;

10.8±0.2°, 11.0±0.2°, 11.8±0.2°, 14.4±0.2°, 16.1±0.2°, 19.4±0.2°;

10.8±0.2°, 11.0±0.2°, 11.8±0.2°, 14.4±0.2°, 15.4±0.2°, 19.4±0.2°;

10.8±0.2°, 11.0±0.2°, 11.8±0.2°, 16.1±0.2°, 19.4±0.2°, 21.7±0.2°;

10.8±0.2°, 11.0±0.2°, 14.4±0.2°, 16.1±0.2°, 19.4±0.2°, 21.7±0.2°;

7.2±0.2°, 11.0±0.2°, 11.8±0.2°, 15.4±0.2°, 19.4±0.2°, 21.7±0.2°;

7.2±0.2°, 10.8±0.2°, 11.0±0.2°, 14.4±0.2°, 15.4±0.2°, 19.4±0.2°;

7.2±0.2°, 11.0±0.2°, 14.4±0.2°, 16.1±0.2°, 19.4±0.2°, 21.7±0.2°;

10.8±0.2°, 11.0±0.2°, 11.8±0.2°, 15.4±0.2°, 19.4±0.2°, 21.7±0.2°.

More preferably, the powder X-ray diffraction pattern may also include one or more diffraction peaks 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° as needed; preferably at least any 2-4, or 5-6 of them, and more preferably any 4 or 6 of them; for example:

16.9±0.2°, 17.7±0.2°, 18.8±0.2°, 21.3±0.2°;

16.9±0.2°, 17.7±0.2°, 18.8±0.2°, 22.1±0.2°;

16.9±0.2°, 17.7±0.2°, 18.8±0.2°, 23.3±0.2°;

16.9±0.2°, 21.3±0.2°, 22.1±0.2°, 23.3±0.2°;

16.9±0.2°, 18.8±0.2°, 21.3±0.2°, 22.1±0.2°;

16.9±0.2°, 17.7±0.2°, 18.8±0.2°, 21.3±0.2°, 23.3±0.2°;

16.9±0.2°, 17.7±0.2°, 18.8±0.2°, 22.1±0.2°, 23.3±0.2°;

16.9±0.2°, 17.7±0.2°, 18.8±0.2°, 21.3±0.2°, 22.1±0.2°, 23.3±0.2°.

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 angle and interplanar spacing d value as shown in Table 10.

Table 10

In certain embodiments of the present invention, the X-ray powder diffraction spectrum of Form J is basically as shown in Figure 18; its DSC spectrum is basically as shown in Figure 19.

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°. , or has a diffraction peak at 2θ of 13.7±0.2°, or has a diffraction peak at 2θ of 14.8±0.2°, or has a diffraction peak at 2θ of 15.2±0.2°, or has a diffraction peak at 2θ of 17.3±0.2°, or has a diffraction peak at 2θ of 18.3±0.2°, or has a diffraction peak at 2θ of 19.4±0.2°, or has a diffraction peak at 2θ of 21.5± The invention has a diffraction peak at 2θ of 21.9±0.2°, or a diffraction peak at 2θ of 22.8±0.2°, or a diffraction peak at 2θ of 23.0±0.2°, or a diffraction peak at 2θ of 24.9±0.2°, or a diffraction peak at 2θ of 27.0±0.2°, or a diffraction peak at 2θ of 27.6±0.2°, Or it has a diffraction peak 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°; preferably, it includes diffraction peaks at 2, 4, 6, 8 or 10 as needed.

In certain embodiments of the present invention, the powder X-ray diffraction spectrum contains 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; if necessary, further, it may also contain 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:

9.7±0.2°, 13.7±0.2°, 15.2±0.2°;

9.7±0.2°, 13.7±0.2°, 15.2±0.2°, 17.3±0.2°;

9.7±0.2°, 13.7±0.2°, 15.2±0.2°, 18.3±0.2°;

9.7±0.2°, 13.7±0.2°, 15.2±0.2°, 21.5±0.2°;

9.7±0.2°, 13.7±0.2°, 15.2±0.2°, 21.9±0.2°;

9.7±0.2°, 13.7±0.2°, 15.2±0.2°, 24.9±0.2°;

9.7±0.2°, 13.7±0.2°, 17.3±0.2°, 18.3±0.2°;

9.7±0.2°, 17.3±0.2°; 18.3±0.2°, 21.9±0.2°;

13.7±0.2°, 15.2±0.2°, 17.3±0.2°, 18.3±0.2°;

9.7±0.2°, 13.7±0.2°, 15.2±0.2°, 17.3±0.2°, 18.3±0.2°;

9.7±0.2°, 13.7±0.2°, 15.2±0.2°, 18.3±0.2°, 21.5±0.2°;

9.7±0.2°, 13.7±0.2°, 15.2±0.2°, 21.5±0.2°, 21.9±0.2°;

9.7±0.2°, 13.7±0.2°, 15.2±0.2°, 21.9±0.2°, 24.9±0.2°;

9.7±0.2°, 13.7±0.2°, 15.2±0.2°, 18.3±0.2°, 24.9±0.2°;

9.7±0.2°, 13.7±0.2°, 17.3±0.2°, 18.3±0.2°, 21.5±0.2°;

9.7±0.2°, 17.3±0.2°; 18.3±0.2°, 21.9±0.2°, 24.9±0.2°;

13.7±0.2°, 15.2±0.2°, 17.3±0.2°, 18.3±0.2°, 21.5±0.2°;

9.7±0.2°, 13.7±0.2°, 15.2±0.2°, 17.3±0.2°, 18.3±0.2°, 21.5±0.2°;

9.7±0.2°, 13.7±0.2°, 15.2±0.2°, 18.3±0.2°, 21.5±0.2°, 21.9±0.2°;

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°;

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°;

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°;

9.7±0.2°, 13.7±0.2°, 15.2±0.2°, 18.3±0.2°, 24.9±0.2°, 33.8±0.2°;

9.7±0.2°, 13.7±0.2°, 17.3±0.2°, 18.3±0.2°, 21.5±0.2°, 21.9±0.2°;

9.7±0.2°, 17.3±0.2°; 18.3±0.2°, 21.9±0.2°, 24.9±0.2°, 33.8±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°.

More preferably, its powder X-ray diffraction spectrum may also include one or more diffraction peaks 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° as needed; preferably at least any 2-4, or 5-6 of them, and more preferably any 4 or 6 of them; for example:

12.8±0.2°, 14.8±0.2°, 19.4±0.2°, 22.8±0.2°;

12.8±0.2°, 14.8±0.2°, 19.4±0.2°, 23.0±0.2°;

12.8±0.2°, 14.8±0.2°, 19.4±0.2°, 29.0±0.2°;

12.8±0.2°, 14.8±0.2°, 22.8±0.2°, 23.0±0.2°;

14.8±0.2°, 19.4±0.2°, 22.8±0.2°, 23.0±0.2°;

12.8±0.2°, 14.8±0.2°, 19.4±0.2°, 22.8±0.2°, 23.0±0.2°;

12.8±0.2°, 14.8±0.2°, 19.4±0.2°, 22.8±0.2°, 29.0±0.2°;

12.8±0.2°, 14.8±0.2°, 19.4±0.2°, 22.8±0.2°, 23.0±0.2°, 29.0±0.2°;

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 21.5±0.2° and 29.0±0.2°, and more 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°.

In certain embodiments of the present invention, Cu-Kα radiation is used, and the X-ray characteristic peaks of the crystal form K are represented by the 2θ angle and the interplanar spacing d value as shown in Table 11.

Table 11

In certain embodiments of the present invention, the X-ray powder diffraction spectrum of Form K is basically as shown in Figure 20; its DSC spectrum is basically as shown in Figure 21.

In certain embodiments of the present invention, the crystal form K is a hydrate.

In certain embodiments of the present invention, the crystal form K is a hemihydrate.

In certain embodiments of the present invention, the crystal form K is a monohydrate.

In certain embodiments of the present invention, the crystal form K is a dihydrate.

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

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

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

Crystal form K has good reproducibility, high product purity, and controllable quality. The obtained crystal morphology is blocky, which is more suitable for pharmaceutical and industrial production.

In certain embodiments of the present invention, the crystalline form is crystalline 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 pattern of 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°. , or has a diffraction peak at 2θ of 13.9±0.2°, or has a diffraction peak at 2θ of 14.9±0.2°, or has a diffraction peak at 2θ of 15.3±0.2°, or has a diffraction peak 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 The diffraction peak 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°. , or having a diffraction peak at 2θ of 28.9±0.2°, or having a diffraction peak at 2θ of 29.3±0.2°; or having a diffraction peak at 2θ of 30.1±0.2°; or having a diffraction peak at 2θ of 31.1±0.2°; or having a diffraction peak at 2θ of 33.8±0.2°; preferably, including diffraction peaks at 2, 4, 6, 8 or 10 as needed.

In certain embodiments of the present invention, the powder X-ray diffraction spectrum of the crystalline 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 of them, and most preferably 4 of them; if necessary, further, it may also include 2θ of 15.3±0.2°, 22.0±0.2°, 24.9±0.2°, 27.6±0.2° or 33.8±0.2° One or more diffraction peaks, preferably 2, 3, 4 or 5 of them, for example:

10.7±0.2°, 11.8±0.2°, 14.5±0.2°, 21.9±0.2°;

10.7±0.2°, 11.8±0.2°, 14.5±0.2°, 17.3±0.2°;

10.7±0.2°, 11.8±0.2°, 14.5±0.2°, 20.7±0.2°;

10.7±0.2°, 11.8±0.2°, 14.5±0.2°, 21.6±0.2°;

10.7±0.2°, 11.8±0.2°, 14.5±0.2°, 23.7±0.2°;

10.7±0.2°, 14.5±0.2°, 17.3±0.2°, 21.9±0.2°;

10.7±0.2°, 14.5±0.2°, 20.7±0.2°, 21.9±0.2°;

11.8±0.2°, 14.5±0.2°, 17.3±0.2°, 21.9±0.2°;

10.7±0.2°, 11.8±0.2°, 14.5±0.2°, 21.9±0.2°, 23.7±0.2°;

10.7±0.2°, 11.8±0.2°, 14.5±0.2°, 17.3±0.2°, 23.7±0.2°;

10.7±0.2°, 11.8±0.2°, 14.5±0.2°, 20.7±0.2°, 23.7±0.2°;

10.7±0.2°, 11.8±0.2°, 14.5±0.2°, 21.6±0.2°, 23.7±0.2°;

10.7±0.2°, 11.8±0.2°, 14.5±0.2°, 23.7±0.2°, 26.0±0.2°;

10.7±0.2°, 14.5±0.2°, 17.3±0.2°, 21.9±0.2°, 23.7±0.2°;

10.7±0.2°, 14.5±0.2°, 20.7±0.2°, 21.9±0.2°, 23.7±0.2°;

11.8±0.2°, 14.5±0.2°, 17.3±0.2°, 21.9±0.2°, 23.7±0.2°;

10.7±0.2°, 11.8±0.2°, 14.5±0.2°, 21.9±0.2°, 23.7±0.2°, 26.0±0.2°;

10.7±0.2°, 11.8±0.2°, 14.5±0.2°, 17.3±0.2°, 23.7±0.2°, 26.0±0.2°;

10.7±0.2°, 11.8±0.2°, 14.5±0.2°, 20.7±0.2°, 23.7±0.2°, 26.0±0.2°;

10.7±0.2°, 11.8±0.2°, 14.5±0.2°, 21.6±0.2°, 23.7±0.2°, 26.0±0.2°;

10.7±0.2°, 11.8±0.2°, 14.5±0.2°, 17.3±0.2°, 20.7±0.2°, 26.0±0.2°;

10.7±0.2°, 11.8±0.2°, 14.5±0.2°, 17.3±0.2°, 21.9±0.2°, 23.7±0.2°;

10.7±0.2°, 14.5±0.2°, 20.7±0.2°, 21.9±0.2°, 23.7±0.2°, 26.0±0.2°;

11.8±0.2°, 14.5±0.2°, 17.3±0.2°, 21.9±0.2°, 23.7±0.2°, 26.0±0.2°.

More preferably, the powder X-ray diffraction pattern may also include one or more diffraction peaks 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° as needed; preferably at least any 2-4, or 5-6 of them, and more preferably any 4 or 6 of them; for example:

7.2±0.2°, 9.8±0.2°, 11.2±0.2°, 15.3±0.2°;

7.2±0.2°, 9.8±0.2°, 11.2±0.2°, 16.0±0.2°;

7.2±0.2°, 9.8±0.2°, 11.2±0.2°, 22.4±0.2°;

7.2±0.2°, 11.2±0.2°, 15.3±0.2°, 16.0±0.2°;

11.2±0.2°, 15.3±0.2°, 16.0±0.2°, 22.4±0.2°;

7.2±0.2°, 9.8±0.2°, 11.2±0.2°, 15.3±0.2°, 16.0±0.2°;

7.2±0.2°, 9.8±0.2°, 11.2±0.2°, 16.0±0.2°, 22.4±0.2°;

7.2±0.2°, 9.8±0.2°, 11.2±0.2°, 15.3±0.2°, 16.0±0.2°, 22.4±0.2°.

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°; further Preferably, it also includes characteristic peaks at 21.6±0.2° and 22.4±0.2°, and more 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°, 26.2±0.2°, 27.4±0.2° and 28.8±0.2°.

In certain embodiments of the present invention, Cu-Kα radiation is used, and the X-ray characteristic peaks of the crystal form L are represented by the 2θ angle and the interplanar spacing d value as shown in Table 12.

Table 12

In certain embodiments of the present invention, the X-ray powder diffraction pattern of Form L is substantially as shown in Figure 22.

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

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.

The present invention further relates to any of the compounds or their stereoisomers and salts or the pharmaceutical compositions of the present invention or the use of the pharmaceutical compositions of the present invention for the treatment of 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 and restrictive cardiomyopathy.

Figure 1 is the XRPD pattern of the free alkali crystal form A of Example 3.

Figure 2 is the DSC diagram of the free alkali crystal form A of Example 3.

Figure 3 is the TGA diagram of the free alkali crystal form A of Example 3.

Figure 4 is the XRPD pattern of the free alkali crystal form B of Example 3.

Figure 5 is the DSC diagram of the free alkali crystal form B of Example 3.

Figure 6 is the XRPD pattern of the free alkali crystal form C of Example 3.

Figure 7 is the DSC diagram of the free alkali crystal form C of Example 3.

Figure 8 is the XRPD pattern of the free alkali crystal form D of Example 3.

Figure 9 is the DSC diagram of the free alkali crystal form D of Example 3.

Figure 10 is the XRPD pattern of the free alkali crystal form E of Example 3.

Figure 11 is the DSC diagram of the free alkali crystal form E of Example 3.

Figure 12 is a TGA diagram of the free alkali crystal form E of Example 3.

Figure 13 is the XRPD pattern of the free alkali crystal form F of Example 3.

Figure 14 is the XRPD pattern of the free alkali crystal form G of Example 3.

Figure 15 is the XRPD pattern of the free alkali crystal form H of Example 3.

Figure 16 is the XRPD pattern of the free alkali crystal form I of Example 3.

Figure 17 is the DSC diagram of the free alkali crystal form I of Example 3.

Figure 18 is the XRPD pattern of the free alkali crystal form J of Example 3.

Figure 19 is the DSC pattern of the free alkali crystal form J of Example 3.

Figure 20 is the XRPD pattern of the free alkali crystal form K of Example 3.

Figure 21 is the DSC diagram of the free alkali crystal form K of Example 3.

Figure 22 is the XRPD pattern of the free alkali crystal form L of Example 3.

Figure 23 shows the effect of the compound of Example 3 on cardiac function measured at different doses in Spraw-Dawley rats.

Unless otherwise stated, the terms used in the specification and application have the following meanings.

In the present invention, an alkyl group refers to a saturated aliphatic hydrocarbyl group, which is a straight chain 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, t-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 isomers thereof.

The alkyl group may be substituted or unsubstituted. When substituted, the substituent may be substituted at any available connection point. The substituent is preferably one or more of the following groups, which are independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, alkyl, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, pendoxy, carboxyl or carboxylate. The preferred substituents of the present invention are methyl, ethyl, isopropyl, t-butyl, halogenated alkyl, deuterated alkyl, alkoxy-substituted alkyl and hydroxy-substituted alkyl; the hydroxy-substituted alkyl may be 2-hydroxyisopropyl or 1-hydroxyethyl.

、

等；較佳咯烷基、吡咯 烷酮基、哌啶-2-酮基、3,4-二氫吡啶-2(1H)-酮基、4,5-二氫噠嗪-3(2H)-酮基、氮雜環丁烷基、氧雜環丁烷基、二氫吡咯基、四氫呋喃基、吡唑烷基、嗎啉基、

、

、哌嗪基和吡喃基；更佳二氫吡咯基、咯烷基、吡咯烷酮基、哌啶-2-酮 基、3,4-二氫吡啶-2(1H)-酮基、4,5-二氫噠嗪-3(2H)-酮基、氮雜環丁烷基、 氧雜環丁烷基、氧雜環己烷基、嗎啉基、哌啶基、哌嗪基、

、

、吡喃基。 多環雜環基包括螺環、稠環和橋環的雜環基；其中涉及到的螺環、稠環和橋環的雜環基視需要與其他基團藉由單鍵相連接，或者藉由環上的任意兩個或者兩個以上的原子與其他環烷基、雜環基、芳基和雜芳基進一步并環連接。 In the present invention, a heterocyclic group refers to a saturated or partially unsaturated monocyclic or polycyclic heterocyclic group, which contains 3 to 20 ring atoms, wherein one or more ring atoms are heteroatoms selected from nitrogen, oxygen or S(O) _m (wherein m is an integer from 0 to 2), but does not include the ring part of -OO-, -OS- or -SS-, and the remaining ring atoms are carbon. Preferably, it contains 3 to 12 ring atoms, wherein 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-dihydropyridin-2(1H)-onyl, 4,5-dihydrooxazin-3(2H)-onyl, azocyclobutanyl, oxacyclobutanyl, oxacyclohexanyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothienyl, dihydroimidazolyl, dihydrofuranyl, dihydropyrazolyl, dihydropyrrolyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, pyranyl,

,

etc.; preferably pyrrolidinyl, pyrrolidinone, piperidin-2-one, 3,4-dihydropyridin-2(1H)-one, 4,5-dihydrooxazine-3(2H)-one, azetidine, oxadiazole, dihydropyrrolyl, tetrahydrofuranyl, pyrazolidinyl, oxolinyl,

,

, piperazinyl and pyranyl; more preferably dihydropyrrolyl, pyrrolidyl, pyrrolidonyl, piperidin-2-onyl, 3,4-dihydropyridin-2(1H)-onyl, 4,5-dihydrooxazine-3(2H)-onyl, azetidine cyclobutanyl, oxazolyl cyclobutanyl, oxazolyl cyclohexanyl, oxolinyl, piperidinyl, piperazinyl,

,

, pyranyl. Polycyclic heterocyclic groups include spirocyclic, fused-ring and bridged heterocyclic groups; the spirocyclic, fused-ring and bridged heterocyclic groups involved are connected to other groups through single bonds as needed, or are further connected to other cycloalkyl, heterocyclic, aryl and heteroaryl groups through any two or more atoms on the ring.

The heterocyclic group may be substituted or unsubstituted as required. When substituted, the substituent is preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, oxirane, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, pendoxy, carboxyl or carboxylate.

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

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, cyclopropoxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy. The alkoxy group may be substituted or unsubstituted as required. When substituted, the substituent is preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, alkyl, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxyl or carboxylate;

Non-limiting examples of alkoxy groups also include: propan-2-oxy, etc.

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

Non-limiting examples of halogen alkyl groups also include: difluoromethyl, 1,1,2,2-tetrafluoroethyl, perfluoroethyl, etc.

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

The halogenated alkoxy group may be fully halogenated or partially halogenated, and the number of halogens 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.

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

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

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

"Hydroxy" refers to the -OH group.

"Halogen" refers to fluorine, chlorine, bromine or iodine.

"Amine" refers to _-NH2 .

"Cyano" refers to -CN.

"Nitro" refers to _-NO2 .

"THF" refers to tetrahydrofuran.

"EtOAc" refers to ethyl acetate.

"DMSO" refers to dimethyl sulfoxide.

"LDA" refers to lithium diisopropylamide.

"DMAP" refers to 4-dimethylaminopyridine.

"EtMgBr" refers to ethylmagnesium bromide.

"HOSu" refers to N-hydroxysuccinimide.

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

"IPA" refers to isopropyl alcohol.

"MeOH" refers to methanol.

"EtOH" refers to ethanol.

"DMF" refers to N,N-dimethylformamide.

"DIPEA" refers to N,N-diisopropylethylamine.

"HEPES" refers to 4-hydroxyethylpiperazineethanesulfonic acid.

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, and C.

"As necessary" or "as necessary" means that the subsequently described event or circumstance may but need not occur, and the description includes instances where the event or circumstance occurs or does not occur.

"Substituted" means that one or more hydrogen atoms, preferably up to 5, more preferably 1 to 3 hydrogen atoms in the group are independently replaced by a corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, and a person with ordinary knowledge in the art can determine (by experiment or theory) possible or impossible substitutions without undue effort. For example, an amine or hydroxyl group with free hydrogen may be unstable when combined with a carbon atom with an unsaturated (such as olefinic) bond.

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

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

The hydrogen atoms described in the present invention can be replaced by their isotope deuterium, and any hydrogen atom in the embodiment compounds involved in the present invention can also be replaced by a deuterium atom.

"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 the pharmaceutical composition is to facilitate administration to an organism, facilitate the absorption of the active ingredient, and thus exert biological activity.

X-ray powder diffraction pattern (XRPD) refers to the experimentally observed diffraction pattern or parameters derived therefrom, and the X-ray powder diffraction pattern is characterized by the peak position (abscissa) and the peak intensity (ordinate). Those skilled in the art can understand that the experimental error depends on the conditions of the instrument, the preparation of the sample and the purity of the sample. In particular, those skilled in the art know that X-ray diffraction patterns usually change with the conditions of the instrument, and those skilled in the art should understand that the appropriate error tolerance of XRPD can be: 2θ±0.5°; 2θ±0.4°; 2θ±0.3°; 2θ±0.2°. It is particularly important to point out 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 shift of the peak angle will be caused, and a certain shift is usually allowed. Therefore, it can be understood by those with ordinary knowledge in the relevant technical field that any crystal form with the same or similar characteristic peaks as the spectrum of the present invention is within the scope of the present invention.

"TGA" refers to thermogravimetric analysis (TGA) experiment.

"DSC" refers to the Differential Scanning Calorimetry (DSC) experiment.

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

"PK" refers to drug metabolism kinetics (PK) experiment.

"KF" refers to the Karl Fischer water determination (KF) experiment.

The present invention is further described below in conjunction with embodiments, but these embodiments do not limit the scope of the present invention.

Preparation of compounds

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 material and product manufacturers are generally followed. Reagents without specifying the specific source are conventional reagents available on the market.

The structure of each compound was identified by nuclear magnetic resonance (NMR) and/or mass spectrometry (MS). NMR chemical shift (δ) was given in 10 ^-6 (ppm). NMR was measured by Varian Mercury 300 MHz, Bruker Avance III 400 MHz instruments. The solvents used were deuterated dimethyl sulfoxide (DMSO- d ₆ ), deuterated chloroform (CDCl ₃ ) and deuterated methanol (CD ₃ OD).

Agilent 1200DAD high pressure liquid chromatograph (Sunfire C18 150×4.6mm column) and Waters 2695-2996 high pressure liquid chromatograph (Gimini C18 150×4.6mm column) were used to measure high performance liquid chromatography (HPLC). Agilent 1200 high pressure liquid chromatograph & mass spectrometer (Sunfire C18 4.6*50mm 3.5um column) and Agilent 19091S-433 HP-5 high pressure liquid chromatograph & mass spectrometer (XBridge C184.6*50mm 3.5um column) were used to measure liquid chromatography mass spectrometry (LCMS).

SFC Thar 80 & 150 & 200 (waters) for chiral high performance liquid chromatography (HPLC).

The average ATPase inhibition rate and _IC50 value were determined by Victor Nivo multi-mode ELISA instrument (PerkinElmer, USA).

The thin layer silica plate used in thin layer chromatography is Yantai Xinnuo silica 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.

Column analysis generally uses Qingdao Haiyang 200 to 300 mesh silica gel as the carrier.

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.

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

General Procedure A

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

Implementation Example 1

Step 1. Synthesis of intermediate 1-1

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 CH ₃ CN (100 mL). The resulting mixture was stirred at room temperature for 3 hours. The reaction solution was filtered, washed with CH ₃ CN (50 mL), and the filter cake was dried under vacuum to obtain intermediate 1-1 (13.0 g, 90.2%) as a white solid.

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 9.06 (s, 4H), 7.45-7.30 (m, 5H), 4.48 (s, 2H).

Step 2. Synthesis of intermediate 1-2

To a solution of intermediate 1-1 (10.0 g, 40.6 mmol) in THF (100 mL) were added CDI (8.8 g, 54.2 mmol, 1.3 eq.) and Et ₃ N (5.4 g, 54.2 mmol, 1.3 eq.). The resulting mixture was stirred at room temperature under N ₂ 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 with a silica gel column (DCM: MeOH = 30: 1) to obtain a white solid intermediate 1-2 (7.0 g, 67.3%).

ESI-MS (EI ⁺ , m/z): 261.15.

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 9.36 (d, J =59.7 Hz, 2H), 8.33-8.25 (m, 1H), 7.61 (t, J =1.3 Hz, 1H), 7.44-7.24 (m, 5H), 7.01-6.95 (m, 1H), 4.43 (s, 2H).

Step 3. Synthesis of intermediates 1-3

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

ESI-MS (EI ⁺ , m/z): 294.20.

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.49 (s, 2H), 7.41-7.34 (m, 2H), 7.30 (t, J =7.4 Hz, 2H), 7.23 (dd, J =8.3, 6.1 Hz, 1H), 7.07 (d, J =8.0 Hz, 1H), 4.28 (s, 2H), 3.87-3.76 (m, 2H), 3.60 (ddt, J =15.0, 7.7, 4.4 Hz, 1H), 3.35 (d, J =1.7 Hz, 1H), 3.29 (d, J =1.8 Hz, 1H), 1.73-1.62 (m, 2H), 1.45 (qd, J =12.1, 4.4 Hz, 2H).

Step 4. Synthesis of intermediates 1-4

CDI (4.8 g, 29.6 mmol, 2.0 eq.) and DIEA (3.9 g, 30.2 mmol, 2.0 eq.) were added to a solution of intermediate 1-3 (4.5 g, 15.3 mmol) in DMF (15 mL). 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 obtain compound intermediate 1-4 (1.0 g, 21.2%) as a yellow liquid.

ESI-MS (EI ⁺ , m/z): 320.15.

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 7.40-7.35 (m, 2H), 7.30 (t, J =7.4 Hz, 2H), 7.23 (dd, J =8.4, 6.1 Hz, 1H), 4.24 (s, 2H), 3.89 (dd, J =11.1, 4.1 Hz, 2H), 3.64-3.56 (m, 1H), 3.30 (t, J =11.2 Hz, 2H), 2.59 (qd, J =12.4, 4.7 Hz, 2H), 1.40-1.33 (m, 2H).

Step 5. Synthesis of Example 1

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 the reaction was complete. The reaction mixture was purified by preparative HPLC to obtain the white title compound (45 mg, 14.9%).

ESI-MS (EI ⁺ , m/z): 323.23.

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 10.32 (s, 1H), 6.61 (d, J =4.8 Hz, 1H), 4.66 (t, J =12.1 Hz, 1H), 3.89 (dd, J =11.2, 4.2 Hz, 2H), 3.75 (d, J =5.0 Hz, 1H), 3.33 (s, 1H), 3.28 (s, 1H), 2.53 (s, 1H), 2.45 (dd, J =12.6, 4.6 Hz, 1H), 1.76-1.56 (m, 5H), 1.42 (d, J =12.5 Hz, 3H), 1.24-1.10 (m, 3H), 1.05 (d, J =6.7 Hz, 3H), 0.99-0.86 (m, 2H).

Example 2

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)ethan-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 obtain the title compound (101.4 mg, yield: 49.0%).

MS: m/z=331.1 (M+1, ESI ⁺ ).

¹ H NMR (400 MHz, MeOD) δ 7.15 (ddd, J = 34.6, 21.0, 7.6 Hz, 4H), 5.10 (q, J = 6.8 Hz, 1H), 4.80 (tt, J = 12.2, 4.0 Hz, 1H), 3.99 (dd, J = 11.4, 3.8 Hz, 2H), 3.44 (t, J = 11.7 Hz, 2H), 2.66 (qd, J = 12.4, 4.8 Hz, 2H), 1.51 (t, J = 11.8 Hz, 5H).

Example 3

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

MS: m/z=353.4 (M+1, ESI ⁺ ).

¹ H NMR (500 MHz, MeOD) δ 7.51-7.32 (m, 1H), 6.95 (ddt, J = 13.8, 8.4, 2.6 Hz, 2H), 5.33 (q, J = 7.0 Hz, 1H), 4.79 (tt, J = 12.2, 4.0 Hz, 1H), 3.99 (dd, J = 11.6, 3.8 Hz, 2H), 3.44 (t, J = 12.0 Hz, 2H), 2.74-2.57 (m, 2H), 1.52 (t, J = 5.8 Hz, 5H).

Example 4

4

4

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

MS: m/z=369.8 (M+1, ESI ⁺ ).

Example 5

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

MS: m/z=345.2 (M+1, ESI ⁺ ).

Biological test evaluation

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

Experiment 1 Myosin inhibition effect

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) to monitor 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).

In our experiments, bovine skinned cardiac myofibrils were isolated from frozen bovine left ventricles and used as the source of myosin for ATPase assays. Based on the literature (DOI: 10.1074/jbc.M117.776815), the calcium concentration that achieved 50% activation of the myofibril system (pCa ₅₀ or pCa = 6.25) was chosen as the final condition for evaluating activation activity. Myofibril ATPase activity was measured in a buffer solution containing 12 mM PIPES (piperazine-N,N'-bis(2-ethanesulfonic acid)) and 2 mM MgCl (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). Compounds were dissolved in DMSO (dimethyl sulfoxide). Serial dilutions of 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 myofibrils, PK/LDH and calcium was added to a 96-well plate for a 7-point dose response experiment. In some cases, ATPase assays were repeated for compounds of interest using a 10-point response method. Compounds were added to the myofibril solution and incubated for 5 minutes. At the start of the enzymatic reaction, 75 μL of a solution containing ATP, PEP, NADH, compound and calcium was added. ATPase activity was measured in a PerkinElmer Victor ELISA kit in kinetic mode at 25°C for 15 minutes using a transparent bottom plate. The absorbance at 340 nm was read in a Nivo plate reader. The slope of the absorbance change as a function of time over the first 10 minutes was normalized to the slope of a control well containing all reagents (including DMSO) but no compound. This normalized rate was then plotted as a function of small molecule concentration in GraphPad Prism 9. The data were fitted to a four-parameter fit and _IC50 was calculated using Graphpad Prism 9. Any agent that failed to achieve 50% inhibition at the highest tested concentration was reported as an _IC50 greater than the highest tested concentration (i.e., _IC50 >200uM).

Table 1. Myosin inhibitory activity

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

Bovine skinless cardiac myofibrils were isolated from frozen bovine left ventricle 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 activation activity. The rest of the ATPase assay conditions were the same as described in Experiment 1.

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

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

Experiment 3. Measurement of cardiac muscle contractile force

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

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 NaCH ₃ CO ₂ , MgCl ₂ .6H ₂ O, glucose, NaHCO ₃ , Na ₂ HPO ₄ .7H ₂ O, and 1.5 mM CaCl ₂ . The solution was pre-warmed at 36±1°C and electric field stimulation was performed at 1 Hz with 4 ms square wave bipolar pulses (10 V) via 2 platinum electrodes connected to a Myopacer field stimulator (IonOptix Corporation). Cells were illuminated by microscope light. Cell images were acquired by a x40 UV fluorescence objective and transferred to the side port of the microscope, where they were recorded by a charge-coupled device (CCD) camera (MyoCam, IonOptix Corporation) that converts optical brightness (pixels) into electrical signals (voltage). The MyoCam configuration is capable of acquiring up to 240 images per second (240 Hz frame rate). Contractile properties of myocytes were analyzed in real time by a video detector and a personal calculator-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.

Sarcomere shortening was monitored in a control solution (prodrug) until a stable recording was obtained (baseline period). To determine the response to compounds, myocytes were first perfused with Tyrode buffer for 60 seconds and then perfused with compounds for at least 5 minutes (or until a stable state was 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 period was entered after the last concentration. The duration of the washout period was variable, resulting in variability in the washout data. In individual cells, a single concentration of isoproterenol (100nM) was applied. Data were recorded continuously using IonOptix software. Contraction data were analyzed using Ionwizard software (IonOptix). For each cell, 10-15 contraction transients at baseline and after treatment were averaged and compared.

Table 3. Effects of compounds on fractional shortening of myocytes

The partial shortening ratio at 5uM, 10 or 15uM indicates the responsiveness of myocyte contractility to compound treatment. A lower ratio indicates that the compound of the present invention has a higher in vivo therapeutic window.

Experiment 4. Drug metabolic kinetic characteristics

IV (1 mg/Kg) and PO (5 mg/Kg) in male SD rats were used to determine the pharmacokinetic characteristics of the compound. The compound was used together with the free base, formulated in 5% DMAC + 25% PEG-400 + 70% (30% 2-HP-β-CD aqueous solution). The compound was used intravenously at 1 mg/kg and orally at 5 mg/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. Approximately 150 μL of whole blood/time point was collected in K2EDTA tubes via cervical venous infusion. Blood samples were placed on ice and centrifuged at 2000 g for 5 min, and plasma samples were obtained within 15 min. PK parameters were estimated by non-compartmental modeling using WinNonlin 8.2.

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

The compounds of the present invention show 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 the clinical accumulation of drugs in the body and avoid the risks brought about by accumulation.

Experiment 5. Echocardiographic evaluation of acute pharmacodynamic effects on myocardial contractility in rats

Effects of compounds on cardiac function were determined by echocardiography in Spraw-Dawley rats. Rats were lightly anesthetized with 1-2% isoflurane. Compounds were administered as a single PO dose by oral gavage. Baseline cardiac function was measured 1 day prior to dosing. Effects of compounds on cardiac function were measured 1, 3, 6, and 24 hours after dosing. Approximately 250 μL of whole blood was obtained by caudal vein immediately after the echocardiographic procedure at approximately 1, 3, 6, and 24 hours after dosing. Blood was placed in plasma separation tubes containing K2 EDTA and stored on wet ice until processing. Blood samples were centrifuged at 2,000 g (4,400 rpm, Eppendorf 5417R) for 10 minutes at 4°C. Plasma samples were then transferred to microtubes and stored at -80°C for later LC/MS analysis. Data were plotted as reduction in shorting vs plasma compound concentration. The therapeutic window was determined as IC ₅₀ /IC ₁₀ based on the literature (DOI: https://doi.org/10.1021/acs.jmedchem.1c01290).

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

Crystal form research

1.1 Experimental instruments

1.1.1 Some parameters of physical and chemical testing instruments

1.2 Instruments and liquid phase analysis conditions

1.2.1 Instruments and equipment

1.2.2 Chromatographic conditions

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

Flow rate: 1mL/min

Column temperature: 40℃

Detection wavelength: 230nm

Injection volume: 5.0μL

Running time: 15min

Diluent: ACN-water (v/v, 1:1)

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

1. Preparation of different crystal forms

1.1 Preparation of free alkali crystal form A

The crude product was purified by a rapid reverse column (MeCN/NH ₄ HCO ₃ 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.

1.2 Preparation of free alkali crystal form B

Weigh 20 mg of free alkali 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 alkali crystal form B. After detection and analysis, it has the XRPD diagram shown in Figure 4 and the DSC diagram shown in Figure 5.

1.3 Preparation of free alkali crystal form C

Weigh 20 mg of free alkali 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 alkali crystal form C. After detection and analysis, it has the following XRPD diagram as shown in Figure 6 and the DSC diagram as shown in Figure 7.

1.4 Preparation of free alkali crystal form D

Weigh 20 mg of free alkali 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 alkali crystal form D. After detection and analysis, it has the following XRPD diagram as shown in Figure 8 and the DSC diagram as shown in Figure 9.

1.5 Preparation of free alkali crystal form E

Weigh 203.21 mg of free alkali 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. The detection and analysis show the XRPD graph shown in Figure 10, the DSC graph shown in Figure 11, and the TGA graph shown in Figure 12.

1.6 Preparation of free alkali crystal form F

20 g of 6-methylsulfanyl-3-tetrahydropyran-4-yl-1H-1,3,5-triazine-2,4-dione, 16.8 g of (S)-1-(2,4-difluorophenyl)ethylamine and 60 ml NMP was 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 for control, and the reaction was completed; the reaction was cooled to 55°C, and 40-60 ml 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); 200 ml 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 washed with water; the reaction was dried overnight at 50°C by air blowing to obtain 24.8 g of a light yellow solid (purity: 99.5%), and Form F was obtained. The detection and analysis shows the XRPD pattern as shown in Figure 13.

1.7 Preparation of free alkali crystal form G

Weigh 10 mg of Form F, add 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 Figure 14.

1.8 Preparation of free alkali crystal form H

Weigh 10 mg of Form F, add 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 Figure 15.

1.9 Preparation of free alkali crystal form I

Weigh 10 mg of Form F, add appropriate amount of dichloromethane to dissolve, blow dry with nitrogen, add 100 μl 1.4-dioxane, stir at room temperature for 7 days, centrifuge, and vacuum dry the solid at 40°C to obtain Form I. Detection and analysis show the XRPD graph shown in Figure 16 and the DSC graph shown in Figure 17.

1.10 Preparation of free alkali crystal form J

Weigh 10 mg of Form F, add appropriate amount of dichloromethane to dissolve, blow dry with nitrogen, add 100 μl of ethyl acetate, stir at room temperature for 7 days, centrifuge, and vacuum dry the solid at 40°C to obtain Form J. The detection and analysis show the XRPD diagram shown in Figure 18 and the DSC diagram shown in Figure 19.

1.11 Preparation of free alkali crystal form K

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

1.12 Preparation of free alkali crystal form L

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

2. Solid stability experiment

2.1 Experimental purpose:

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

2.2 Experimental plan:

Take about 2 mg of compound crystalline form A and observe it for 7 days and 14 days at 60℃, 95%RH, 50℃ & 75%RH and light box (5000lx±500lx). Use HPLC to detect and calculate the changes of related substances by using the chromatographic peak area normalization method.

2.3 Experimental results:

Chemical stability results of free alkali crystal form A:

2.4 Study on the stability of factors affecting crystal form K

Crystal form K was placed in light for 10 days (total illumination not less than 1.2×106lux.hr), high temperature (60℃, 30 days), high humidity (25℃ RH90%, 30 days) and then sent for X-ray powder diffraction and compared with the 0-day data.

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

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

3. Solubility experiments in different media

3.1 Experimental Purpose

The solubility of free-base crystal form A, crystal form E, and crystal form K in different pH buffers (pH 1 is 0.1N HCl aqueous solution, pH 2-pH 8 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 evaluation of drugability.

3.2 Experimental plan:

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.

3.3 Experimental results: as shown in the following table

Claims (13)

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 halogenalkyl 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; R ₄ is independently selected from halogen, C ₁ -C ₃ alkyl, C ₁ -C ₃ alkoxy or C ₁ -C ₃ halogenalkyl. The crystal form as described in claim 1, wherein, _R1 is _C1 - _C3 alkyl; _R4 and _R5 together with their adjacent C atoms form

;and _R6 is independently selected from F, Cl and Br. The crystalline form as described in claim 1, wherein the general formula (I) is selected from the following compounds:

The crystal form as described in claim 1, wherein the crystal 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 crystal form A-crystal form L, wherein, The powder X-ray diffraction spectrum of Form A has a characteristic peak at 2θ of 8.0±0.2°, or a characteristic peak at 2θ of 16.5±0.2°, or a characteristic peak at 2θ of 18.3±0.2°, or a characteristic peak at 2θ of 20.4±0.2°, or a characteristic peak at 2θ of 14.9±0.2°, or a characteristic peak at 2θ of 17.4±0.2°, or a characteristic peak at 2θ of 17.7±0.2°, or a characteristic peak at 2θ of 18.9±0. 2θ has a characteristic peak at 10.7±0.2°, or at 16.7±0.2°, or at 21.3±0.2°, or at 22.4±0.2°, or at 24.9±0.2°, or at 27.6±0.2°; preferably, it includes characteristic peaks at 2, 4, 6, 8, 10 or 12 as needed; The powder X-ray diffraction pattern of Form B has a characteristic peak at 2θ of 16.6±0.2°, or a characteristic peak at 2θ of 18.3±0.2°, or a characteristic peak at 2θ of 18.5±0.2°, or a characteristic peak at 2θ of 10.7±0.2°, or a characteristic peak at 2θ of 14.9±0.2°, or a characteristic peak at 2θ of 20.4±0.2°, Or it has a characteristic peak at 2θ of 24.4±0.2°, or it has a characteristic peak at 2θ of 24.9±0.2°, or it has a characteristic peak at 2θ of 26.9±0.2°, or it has a characteristic peak at 2θ of 20.7±0.2°, or it has a characteristic peak at 2θ of 16.0±0.2°; preferably, it includes 2, 4, 6, 8 or 10 characteristic peaks as needed; The powder X-ray diffraction spectrum of Form C 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 a characteristic peak at 2θ of 10.9±0.2°, or a characteristic peak at 2θ of 16.5±0.2°, or or having a characteristic peak at 2θ of 25.8±0.2°, or having a characteristic peak at 2θ of 27.5±0.2°, or having a characteristic peak at 2θ of 10.7±0.2°, or having a characteristic peak at 2θ of 18.8±0.2°, or having a characteristic peak at 2θ of 22.4±0.2°, or having a characteristic peak at 2θ of 26.8±0.2°; preferably, including 2, 4, 6, 8 or 10 characteristic peaks as needed; The powder X-ray diffraction pattern of Form D has a characteristic peak at 2θ of 17.2±0.2°, or at 2θ of 9.7±0.2°, or at 2θ of 13.8±0.2°, or at 2θ of 15.3±0.2°, or at 2θ of 18.4±0.2°, or at 2θ of 21.6±0.2°, Or it has a characteristic peak at 2θ of 24.9±0.2°, or it 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 includes 2, 4, 6, 8 or 10 places as needed; The powder X-ray diffraction spectrum of Form E has a characteristic peak at 8.0±0.2°, or at 12.8±0.2°, or at 18.0±0.2°, or at 18.9±0.2°, or at 19.8±0.2°, or at 20.6±0.2°; preferably, it includes 2, 4 or 6 characteristic peaks as needed; The powder X-ray diffraction pattern of Form F has a characteristic peak at 7.3±0.2°, or at 11.8±0.2°, or at 14.5±0.2°, or at 19.4±0.2°, or at 21.7±0.2°, or at 10.8±0.2°, or at 11.0±0.2°, Or it has a characteristic peak at 2θ of 15.4±0.2°, or it has a characteristic peak at 2θ of 16.1±0.2°, or it has a characteristic peak at 2θ of 16.9±0.2°, or it has a characteristic peak at 2θ of 17.7±0.2°, or it has a characteristic peak at 2θ of 18.0±0.2°, or it has a characteristic peak at 2θ of 20.4±0.2°; preferably, it includes 2, 4, 6, 8 or 10 places as needed; The powder X-ray diffraction pattern of Form G has a characteristic peak at 7.7±0.2°, or at 16.8±0.2°, or at 17.0±0.2°, or at 17.4±0.2°, or at 17.7±0.2°, or at 18.9±0.2°, or at 19.3±0.2°, or at 20.2±0.2°, or at 13.5±0.2°, Or there is a characteristic peak at 2θ of 13.8±0.2°, or there is a characteristic peak at 2θ of 14.5±0.2°, or there is a characteristic peak at 2θ of 15.4±0.2°, or there is a characteristic peak at 2θ of 19.8±0.2°, or there is a characteristic peak at 2θ of 21.7±0.2°, or there is a characteristic peak at 2θ of 24.9±0.2°, or there is a characteristic peak at 2θ of 25.4±0.2°, or there is a characteristic peak at 2θ of 26.7±0.2°; preferably, there are characteristic peaks at 2, 4, 6, 8 or 10 as needed; The powder X-ray diffraction pattern of Form H has a diffraction peak at 8.1±0.2°, 2θ, or a diffraction peak at 10.5±0.2°, 2θ, or a diffraction peak at 13.0±0.2°, 2θ, or a diffraction peak at 13.4±0.2°, 2θ, or a diffraction peak at 14.1±0.2°, 2θ, or a diffraction peak at 14.8±0.2°, 2θ, or a diffraction peak at 15.3±0.2°, 2θ, or a diffraction peak at 16.0±0.2°, 2θ, or a diffraction peak at 16.5±0.2°, 2θ, or a diffraction peak at 16.9±0.2°, 2θ, or a diffraction peak at 17.3±0.2°. 0.2°, or 17.6±0.2°, or 17.9±0.2°, or 19.1±0.2°, or 20.4±0.2°, or 20.6±0.2°, or 21.0±0.2°, or 21.4±0.2°, or 23.5±0.2°, or 25.4±0.2°; preferably, including 2, 4, 6, 8 or 10 diffraction peaks as needed; The powder X-ray diffraction pattern of Form I has a diffraction peak at 7.3±0.2°, 2θ, or a diffraction peak at 9.8±0.2°, 2θ, or a diffraction peak at 10.7±0.2°, 2θ, or a diffraction peak at 11.2±0.2°, 2θ, or a diffraction peak at 11.8±0.2°, 2θ, or a diffraction peak at 14.5±0.2°, 2θ, or a diffraction peak at 15.3±0.2°, 2θ, or a diffraction peak at 16.0±0.2°, 2θ, or a diffraction peak at 17.3±0.2°, 2θ, or a diffraction peak at 18.2±0.2°, 2θ, or a diffraction peak at 18.9±0.2°. .2°, or 2θ has a diffraction peak at 20.7±0.2°, or 2θ has a diffraction peak at 21.6±0.2°, or 2θ has a diffraction peak at 21.9±0.2°, or 2θ has a diffraction peak at 22.4±0.2°, or 2θ has a diffraction peak at 23.7±0.2°, or 2θ has a diffraction peak at 26.0±0.2°, or 2θ has a diffraction peak at 26.2±0.2°, or 2θ has a diffraction peak at 27.4±0.2°, or 2θ has a diffraction peak at 28.8±0.2°; preferably, including diffraction peaks at 2, 4, 6, 8 or 10 as needed; The powder X-ray diffraction pattern of Form J has a diffraction peak at 7.2±0.2°, 2θ, or a diffraction peak at 10.8±0.2°, 2θ, or a diffraction peak at 11.0±0.2°, 2θ, or a diffraction peak at 11.8±0.2°, 2θ, or a diffraction peak at 14.4±0.2°, 2θ, or a diffraction peak at 15.4±0.2°, 2θ, or a diffraction peak at 16.1±0.2°, 2θ, or a diffraction peak at 16.9±0.2°, 2θ, or a diffraction peak at 17.7±0.2°, 2θ, or a diffraction peak at 18.8±0.2°, 2θ, or a diffraction peak at 19.4±0.2°. .2°, or 2θ has a diffraction peak at 21.3±0.2°, or 2θ has a diffraction peak at 21.7±0.2°, or 2θ has a diffraction peak at 22.1±0.2°, or 2θ has a diffraction peak at 23.3±0.2°, or 2θ has a diffraction peak at 24.7±0.2°, or 2θ has a diffraction peak at 25.2±0.2°, or 2θ has a diffraction peak at 26.1±0.2°, or 2θ has a diffraction peak at 27.8±0.2°, or 2θ has a diffraction peak at 29.7±0.2°; preferably, including diffraction peaks at 2, 4, 6, 8 or 10 as needed; The powder X-ray diffraction pattern of Form K has a diffraction peak at 9.7±0.2°, 2θ; or a diffraction peak at 12.8±0.2°, 2θ; or a diffraction peak at 13.7±0.2°, 2θ; or a diffraction peak at 14.8±0.2°, 2θ; or a diffraction peak at 15.2±0.2°, 2θ; or a diffraction peak at 17.3±0.2°, 2θ; or a diffraction peak at 18.3±0.2°, 2θ; or a diffraction peak at 19.4±0.2°, 2θ; or a diffraction peak at 21.5±0.2°, 2θ; or a diffraction peak at 21.9±0.2°, 2θ; or a diffraction peak at 22.8±0.2°, 2θ; or a diffraction peak at 23.9±0.2°, 2θ; or a diffraction peak at 24.8±0.2°, 2θ; or a diffraction peak at 25.8±0.2°, 2θ; or a diffraction peak at 26.8±0.2°, 2θ; or a diffraction peak at 27.9±0.2°, 2θ; or a diffraction peak at 28. 0.2°, or 2θ has a diffraction peak at 23.0±0.2°, or 2θ has a diffraction peak at 24.9±0.2°, or 2θ has a diffraction peak at 27.0±0.2°, or 2θ has a diffraction peak at 27.6±0.2°, or 2θ has a diffraction peak at 27.9±0.2°, or 2θ has a diffraction peak at 29.0±0.2°, or 2θ has a diffraction peak at 30.0±0.2°, or 2θ has a diffraction peak at 30.6±0.2°, or 2θ has a diffraction peak at 33.8±0.2°; preferably, including diffraction peaks at 2, 4, 6, 8 or 10 as needed; The powder X-ray diffraction pattern of Form L has a diffraction peak at 9.8±0.2°, 2θ, or a diffraction peak at 12.8±0.2°, 2θ, or a diffraction peak at 13.9±0.2°, 2θ, or a diffraction peak at 14.9±0.2°, 2θ, or a diffraction peak at 15.3±0.2°, 2θ, or a diffraction peak at 17.2±0.2°, 2θ, or a diffraction peak at 18.5±0.2°, 2θ, or a diffraction peak at 19.3±0.2°, 2θ, or a diffraction peak at 21.6±0.2°, 2θ, or a diffraction peak at 22.0±0.2°, 2θ, or a diffraction peak at 23.4±0.2°. .2°, or 2θ has a diffraction peak at 24.9±0.2°, or 2θ has a diffraction peak at 27.0±0.2°, or 2θ has a diffraction peak at 27.6±0.2°, or 2θ has a diffraction peak at 28.1±0.2°, or 2θ has a diffraction peak at 28.9±0.2°, or 2θ has a diffraction peak at 29.3±0.2°; or 2θ has a diffraction peak at 30.1±0.2°; or 2θ has a diffraction peak at 31.1±0.2°; or 2θ has a diffraction peak at 33.8±0.2°; preferably, including diffraction peaks at 2, 4, 6, 8 or 10 as needed. The crystal form as described in claim 4, wherein, The powder X-ray diffraction spectrum 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, and most preferably 4; if necessary, it may further 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 spectrum 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; if necessary, it may further 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°, 20.7±0.2° or 16.0±0.2°, preferably 2, 3, 4 or 6 of them; The powder X-ray diffraction spectrum 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 2-4 of them, more preferably 3-4, and most preferably 4; if necessary, it may further 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 2, 3, 4 or 6 of them; The powder X-ray diffraction spectrum 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 2-4 of them, more preferably 3-4 of them, and most preferably 4 of them; if necessary, it may further 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 2, 3, 4 or 6 of them; The powder X-ray diffraction spectrum of 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, and most preferably 4; if necessary, it may further include characteristic peaks at 19.8±0.2° and 20.6±0.2°; The powder X-ray diffraction spectrum 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 2-4 of them, more preferably 3-4, and most preferably 4; if necessary, it may further 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 2, 3, 4 or 6 of them; The powder X-ray diffraction spectrum 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 2-4 of them, more preferably 3-4, and most preferably 4; if necessary, it may further 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 2, 3, 4 or 6 of them; The powder X-ray diffraction spectrum of the crystalline 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, and most preferably 4; if necessary, it may further 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; The powder X-ray diffraction spectrum of Form I has one or more diffraction peaks 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, and most preferably 4; if necessary, it may further include 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; 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, and most preferably 4; if necessary, it may further include 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±0.2°; preferably 2-4 of them, more preferably 3-4, and most preferably 4; if necessary, it may further include one or more diffraction peaks at 2θ of 14.8+±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 crystal 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, and most preferably 4; if necessary, it may further 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. The crystal form as described in claim 4, wherein, The powder X-ray diffraction spectrum of Form A has characteristic peaks at 2θ of 8.0±0.2° and 16.5±0.2°; preferably, it also has characteristic peaks at 2θ of 18.3±0.2° and 20.4±0.2°; more preferably, it also 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 has characteristic peaks at 2θ of 10.7±0.2° and 16.7±0.2°; further preferably, it also has 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 X-ray diffraction spectrum of Form B has characteristic peaks at 2θ of 16.6±0.2° and 18.3±0.2°; preferably, it also has characteristic peaks at 2θ of 10.7±0.2° and 18.5±0.2°; more preferably, it also has characteristic peaks at 2θ of 14.9±0.2°, 16.0±0.2°, 20.4±0.2° and 20.7±0.2°; more preferably, it also has 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 has characteristic peaks at 2θ of 17.4±0.2° and 18.3±0.2°; more preferably, it also has 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 has 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°; The powder X-ray diffraction spectrum of 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°, 21.6±0.2°, 24.9±0.2° and 14.9±0.2°; more preferably, it also has characteristic peaks at one or more of 2θ of 27.6±0.2°, 30.1±0.2° and 33.9±0.2°; The powder X-ray diffraction spectrum of 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 powder X-ray diffraction spectrum of Form F has characteristic peaks at 2θ of 7.3±0.2° and 11.8±0.2°; preferably, it also has characteristic peaks at 2θ of 21.7±0.2° and 14.5±0.2°; more preferably, it also has 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 has characteristic peaks at 2θ of 16.1±0.2° and 16.9±0.2°; further preferably, it also has characteristic peaks at one or more of 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 2θ of 7.7±0.2° and 16.8±0.2°; preferably, it also has characteristic peaks at 2θ of 17.0±0.2° and 17.4±0.2°; more preferably, it also has 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 has characteristic peaks at 2θ of 13.5±0.2° and 13.8±0.2°; further preferably, it also has 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°, 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, it also includes characteristic peaks at 2θ of 17.3±0.2° and 17.9±0.2°. 2θ has characteristic peaks at 20.6±0.2° and 25.4±0.2°, and more preferably, also has 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°; 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, it also includes characteristic peaks at 2θ of 20.7±0.2° and 26.0±0.2°. Containing characteristic peaks at 2θ of 21.6±0.2° and 22.4±0.2°, and more preferably, also containing 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°; 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 19.4±0.2° and 21.7±0.2°. It has characteristic peaks at 2θ of 7.2±0.2° and 16.9±0.2°, and more preferably, it also has characteristic peaks at 17.7±0.2°, 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 21.9±0.2° and 33.8±0.2°. 2θ has characteristic peaks at 21.5±0.2° and 29.0±0.2°, and more preferably, also has 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°, 13.9±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 24.9±0.2° and 27.6±0.2°. 2θ has characteristic peaks at 14.9±0.2° and 33.8±0.2°, and more preferably, also has 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 as described in claim 4, wherein, The X-ray powder diffraction spectrum of Form A is shown in Figure 1. Preferably, Form A has a DSC spectrum as shown in Figure 2, or a TGA spectrum as shown in Figure 3; The powder X-ray diffraction spectrum of Form B at 2θ is shown in Figure 4. Preferably, Form B has a DSC spectrum as shown in Figure 5; The powder X-ray diffraction spectrum of Form C at 2θ is shown in Figure 6. Preferably, Form C has a DSC spectrum as shown in Figure 7; The powder X-ray diffraction spectrum of Form D at 2θ is as shown in FIG8 . Preferably, Form D has a DSC spectrum as shown in FIG9 . The powder X-ray diffraction spectrum of Form E at 2θ is as shown in Figure 10. Preferably, Form E has a DSC spectrum as shown in Figure 11, or a TGA spectrum as shown in Figure 12; The powder X-ray diffraction pattern of Form F at 2θ is shown in Figure 13; The powder X-ray diffraction pattern of Form G at 2θ is shown in Figure 14; The powder X-ray diffraction spectrum of Form H at 2θ is 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 FIG18 . Preferably, Form J has a DSC spectrum as shown in FIG19 . 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 pattern of Form L at 2θ is shown in Figure 22. The crystal form as described in claim 4, wherein the positions of the top ten diffraction peaks with the highest relative peak intensity in the X-ray powder diffraction patterns of crystal forms A, B, C, D, E, F, G, H, I, J, K and L are respectively the same as those of the corresponding positions of Figures 1, 4, 6, 8, 10, 13, 14, 15, 16, 18, 20 and 22, and the 2θ error of the diffraction peaks is ±0.2°~±0.5°, preferably ±0.2°~±0.3°, and more preferably ±0.2°. A method for preparing a crystalline form of a compound as described in any one of claims 1 to 8, specifically comprising the following steps: 1) Weigh an appropriate amount of free base and suspend it with a poor solvent. The optimal suspension density is 50~200mg/mL; 2) After shaking, the suspension obtained above should preferably be kept at a temperature of 0~50℃ for 1~10 days; 3) Rapidly centrifuge the above suspension, remove the supernatant, and dry the remaining solid to constant weight to obtain the target product; in, The poor solvent is selected from acetone, ethyl acetate, isopropyl acetate, acetonitrile, ethanol, tetrahydrofuran, 2-methyltetrahydrofuran, dichloromethane, 1,4-dioxane, benzene, toluene, methanol, ethanol, isopropyl alcohol, n-butanol, isobutyl alcohol, 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, methyl tert-butyl ether, water, heptane or n-pentane; or, 1) Weigh an appropriate amount of free alkali and dissolve it with a good solvent; 2) Add anti-solvent to the above solution and stir until solid precipitates. The temperature is preferably 0~25℃; 3) Rapidly centrifuge the above suspension, remove the supernatant, and dry the remaining solid to constant weight to obtain the target product; in, The good solvent is selected from methanol, acetone, ethyl acetate, acetonitrile, ethanol, tetrahydrofuran, dichloromethane, 1,4-dioxane, benzene, toluene, isopropyl alcohol, n-butyl alcohol, isobutyl alcohol, N,N-dimethylformamide, N,N-dimethylacetamide, n-propyl alcohol, tert-butyl alcohol, 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 alkali and dissolve it by heating with a good solvent; 2) Rapidly place the above solution at low temperature and stir until solid precipitates. The temperature is preferably -10~5℃; 3) Rapidly centrifuge the above suspension, remove the supernatant, and dry the remaining solid to constant weight to obtain the target product; in, 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; acetone is preferred. A pharmaceutical composition comprising a therapeutically effective amount of a crystalline form of a compound as described in any one of claims 1 to 8, and one or more pharmaceutically acceptable carriers, diluents or excipients. A crystalline form of a compound as described in any one of claims 1 to 8, or a pharmaceutical composition as described in claim 10, for use in preparing a drug for treating hypertrophic cardiomyopathy (HCM) or heart diseases with pathophysiological characteristics of HCM. The use as described in claim 11, wherein the HCM is obstructive or non-obstructive, or caused by sarcomeric and/or non-sarcomeric mutations. Use of a crystalline form of a compound as described in any one of claims 1 to 8 or a pharmaceutical composition as described in 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 and restrictive cardiomyopathy.