Pharmaceutically acceptable salts and polymorphs of substituted pyrazolo[1,5-a]pyrimidin-7-amine derivatives and uses thereof - Patent Application 20070122999

Abstract

The present application relates to pharmaceutically acceptable salts and polymorphs of substituted pyrazolo[1,5-a]pyrimidin-7-amine derivatives of formula (I), pharmaceutical compositions containing same, processes for their preparation, and the use of the pharmaceutically acceptable salts and polymorphs thereof in the treatment or prevention of diseases associated with or mediated by CDK9 activity.

Description

[Technical Field]

[0001] (CROSS-REFERENCE TO RELATED APPLICATIONS) This application claims priority to Chinese patent applications filed with the China Patent Office on July 22, 2022, bearing application number No. 202210866135.0 and entitled "Pharmaceutically acceptable salts and polymorphs of substituted pyrazolo[1,5-a]pyrimidin-7-amine derivatives, and uses thereof," and application number No. 202210870337.2 and entitled "Phosphate salts and polymorphs of CDK9 inhibitors, and uses thereof," and incorporates all of the disclosures therein by reference.

[0002] The present invention belongs to the pharmaceutical technical field, and specifically relates to pharmaceutically acceptable salts and polymorphs of substituted pyrazolo[1,5-a]pyrimidin-7-amine derivatives, pharmaceutical compositions containing the same, methods for preparing the same, and pharmaceutical uses thereof. [Background technology]

[0003] CDK9 is a member of the cell cycle-dependent kinase (CDK) protein family and plays an important role in regulating gene transcription. CDK9 regulates gene transcription elongation primarily by phosphorylating the carbon-terminal region of RNA-binding protein II. CDK9 is ubiquitously overexpressed in tumors and is also a key factor in tumor cell progression and maintenance. By inhibiting gene transcription elongation, CDK9 inhibitors reduce the expression of the related oncoprotein (MYC) and the apoptosis inhibitor protein Mcl-1, thereby promoting apoptosis in cancer cells. By regulating the epigenetic factor BRG1, CDK9 inhibitors reactivate silenced genes, including endogenous retroviruses (ERVs), in tumor cells, promote interferon expression, and make tumor cells more susceptible to immunotherapy.

[0004] Currently, many companies have developed CDK9 inhibitors, including the selective CDK9 inhibitor BAY1251152 developed by Bayer, the selective CDK9 inhibitor AZD4573 developed by AstraZeneca, the non-selective CDK9 inhibitor TP-1287 developed by Tolero, and the non-selective CDK9 inhibitor QHRD107 developed by Changzhou Qianhong Pharmaceutical Company.

[0005] The solubility and stability of active pharmaceutical ingredients have important influences on drug discovery research, and the solid form is advantageous for product quality control. Therefore, it is necessary to explore the solid form of the product. Summary of the Invention

[0006] Based on this, the object of the present invention is to provide pharmaceutically acceptable salts and polymorphs of substituted pyrazolo[1,5-a]pyrimidin-7-amine derivatives and uses thereof. Specifically, the pharmaceutically acceptable salts are L-tartrate and phosphate salts of the substituted pyrazolo[1,5-a]pyrimidin-7-amine derivatives. The substituted pyrazolo[1,5-a]pyrimidin-7-amine derivatives are CDK9 inhibitors, and have a molecular structure represented by formula (I): (1S,3S)-N1-(5-((S)-1-cyclobutylethyl)pyrazolo[1,5-a]pyrimidin-7-yl)cyclopentane-1,3-diamine.

[0007] A first aspect of the present invention is a pharmaceutically acceptable salt of a compound of formula (I): [ka] The pharmaceutically acceptable salts are selected from the group consisting of phosphate and L-tartrate salts of the compound of formula (I).

[0008] In some embodiments, the pharmaceutically acceptable salt of the compound of Formula (I) is in anhydrous, hydrated, or solvated form.

[0009] In some embodiments, the pharmaceutically acceptable salt of the compound represented by formula (I) is crystalline. In some embodiments, the pharmaceutically acceptable salt of the compound represented by formula (I) is amorphous.

[0010] In some embodiments, the pharmaceutically acceptable salt is a phosphate salt. In some embodiments, the phosphate salt is a first type phosphate salt of the compound represented by Formula (I), and the molar ratio of the phosphoric acid to the compound represented by Formula (I) (phosphoric acid:compound represented by Formula (I)) is (1.8-2.4):1. In some embodiments, the molar ratio of the phosphoric acid to the compound represented by Formula (I) (phosphoric acid:compound represented by Formula (I)) may be 1.8:1, 1.9:1, 2.0:1, 2.1:1, 2.2:1, 2.3:1, or 2.4:1. In some embodiments, the molar ratio of the phosphoric acid to the compound represented by Formula (I) (phosphoric acid:compound represented by Formula (I)) is (1.9-2.3):1. In one embodiment, the molar ratio of the phosphoric acid to the compound represented by Formula (I) (phosphoric acid:compound represented by Formula (I)) is 2:1.

[0011] In some embodiments, the phosphate salt is crystalline Form I of the phosphate salt of the compound represented by Formula (I), and an X-ray powder diffraction pattern has characteristic diffraction peaks at diffraction angles 2θ (°) of 18.234±0.2, 19.131±0.2, and 21.266±0.2. In some embodiments, the phosphate salt is crystalline Form I of the phosphate salt of the compound represented by Formula (I), and an X-ray powder diffraction pattern has characteristic diffraction peaks at diffraction angles 2θ (°) of 18.803±0.2, 18.234±0.2, 19.131±0.2, and 21.266±0.2.

[0012] In some embodiments, the X-ray powder diffraction pattern of crystalline Form I of the phosphate salt has characteristic diffraction peaks at diffraction angles 2θ (°) of 18.234±0.2, 19.131±0.2, and 21.266±0.2, as well as the following peaks: 2.121±0.2, 7.373±0.2, 9.556±0.2, 10.607±0.2, 11.105±0.2, 12.322±0.2, 12.917±0.2, 13.999±0.2, 14.902±0.2, 15.238±0.2, 18.8 The compound further has characteristic diffraction peaks at diffraction angle 2θ (°) values of two or more (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, etc.) selected from the group consisting of: 1.03±0.2, 19.881±0.2, 20.697±0.2, 22.01±0.2, 22.464±0.2, 23.247±0.2, 24.025±0.2, 26.367±0.2, 28.513±0.2, 30.297±0.2, 31.216±0.2, and 34.017±0.2.

[0013] In some embodiments, the X-ray powder diffraction pattern of crystalline Form I of the Phosphate Salt is 2.121±0.2, 7.373±0.2, 9.556±0.2, 10.607±0.2, 11.105±0.2, 12.322±0.2, 12.917±0.2, 13.999±0.2, 14.902±0.2, 15.238±0.2, 18.234±0.2, 18.803±0.2, 19.131±0.2, 19.881±0.2, 20.697±0.2. The crystal has characteristic diffraction peaks at three or more (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, etc.) or all diffraction angle 2θ (°) values selected from the group consisting of 2, 21.266±0.2, 22.01±0.2, 22.464±0.2, 23.247±0.2, 24.025±0.2, 26.367±0.2, 28.513±0.2, 30.297±0.2, 31.216±0.2, and 34.017±0.2.

[0014] In some embodiments, the X-ray powder diffraction pattern of crystalline Form I of the Phosphate Salt has characteristic diffraction peaks at diffraction angle 2θ (°) values of 13.999±0.2, 18.234±0.2, 18.803±0.2, 19.131±0.2, 21.266±0.2, 22.01±0.2 and 23.247±0.2.

[0015] In some embodiments, the X-ray powder diffraction pattern of crystalline Form I of the Phosphate Salt has characteristic diffraction peaks at diffraction angle 2θ (°) values of 7.373±0.2, 10.607±0.2, 11.105±0.2, 12.322±0.2, 12.917±0.2, 13.999±0.2, 14.902±0.2, 15.238±0.2, 18.234±0.2, 18.803±0.2, 19.131±0.2, 20.697±0.2, 21.266±0.2, 22.01±0.2, 22.464±0.2, 23.247±0.2, 24.025±0.2, 26.367±0.2, and 28.513±0.2.

[0016] In some embodiments, the X-ray powder diffraction pattern of crystalline Form I of the Phosphate Salt is 2.121±0.2, 7.373±0.2, 9.556±0.2, 10.607±0.2, 11.105±0.2, 12.322±0.2, 12.917±0.2, 13.999±0.2, 14.902±0.2, 15.238±0.2, 18.234±0.2, 18.803±0.2, 19.803±0.2, 20.803±0.2, 21.803±0.2, 22.803±0.2, 23.803±0.2, 24.803±0.2, 25.803±0.2, 26.803±0.2, 27.803±0.2, 28.803±0.2, 29.803±0.2, 30.803±0.2, 31.803±0.2, 32.803±0.2, 33.803±0.2, 34.803±0.2, 35.803±0.2, 36.803±0.2, 37.803±0.2, 38.803±0.2, 39.803±0.2, 40.803±0.2, 41.803±0.2, 42.803±0.2, 43.803±0.2, 44.803±0.2, 45.803±0.2, 46.803±0.2, 47.803±0 It has characteristic diffraction peaks at diffraction angle 2θ (°) values of 9.131±0.2, 19.881±0.2, 20.697±0.2, 21.266±0.2, 22.01±0.2, 22.464±0.2, 23.247±0.2, 24.025±0.2, 26.367±0.2, 28.513±0.2, 30.297±0.2, 31.216±0.2 and 34.017±0.2.

[0017] In some examples, the X-ray powder diffraction pattern of crystalline Form I of the phosphate salt of compound of Formula (I) has characteristic diffraction peaks represented by the 2θ (°) values and d values shown in Table 1, and the relative intensities of each peak are as shown in Table 1.

[0018] [Table 1]

[0019] In some embodiments, the molar ratio of phosphoric acid to the compound represented by Formula (I) (phosphoric acid:compound represented by Formula (I)) in Crystalline Form I of the phosphate salt of the compound represented by Formula (I) is 2:1.

[0020] In some embodiments, the X-ray powder diffraction pattern of crystalline Form I of the phosphate salt of compound of Formula (I) is essentially as shown in FIG.

[0021] In some embodiments, the differential scanning calorimetry curve for crystalline Form I of the phosphate salt of the compound of Formula (I) has an endothermic peak at 188.01°C ± 3°C, 188.01°C ± 2°C, 188.01°C ± 1°C, or 188.01°C ± 0.5°C. In some embodiments, the differential scanning calorimetry curve for crystalline Form I of the phosphate salt of the compound of Formula (I) has an onset temperature of 188.01°C ± 3°C, 188.01°C ± 2°C, 188.01°C ± 1°C, or 188.01°C ± 0.5°C, and a peak temperature of 193.69°C ± 3°C, 193.69°C ± 2°C, 193.69°C ± 1°C, or 193.69°C ± 0.5°C. In some embodiments, the differential scanning calorimetry pattern (DSC pattern) for crystalline Form I of the phosphate salt of the compound of Formula (I) is essentially as shown in Figure 2. In the example shown in Figure 2, the melting point of crystalline Form I of the phosphate salt of compound of formula (I) is about 188.01 ± 0.5°C.

[0022] In some examples, the thermogravimetric analysis pattern (TGA pattern) of crystalline Form I of the phosphate salt of the compound represented by Formula (I) is essentially as shown in Figure 2. In some examples, the TGA pattern of crystalline Form I of the phosphate salt of the compound represented by Formula (I) exhibits a weight loss of 1.139% at around 190°C.

[0023] In some examples, the dynamic sorption symmetry (DVS) pattern of crystalline Form I of the phosphate salt of compound of Formula (I) is essentially as shown in Figure 3. In some examples, the DVS pattern of crystalline Form I of the phosphate salt of compound of Formula (I) shows a 9% weight gain due to moisture absorption under 80% relative humidity (RH) conditions.

[0024] In some examples, a photomicrograph of crystalline Form I of the phosphate salt of compound of Formula (I) is essentially as shown in Figure 4. In some examples, a photomicrograph of crystalline Form I of the phosphate salt of compound of Formula (I) shows that crystalline Form I of the phosphate salt is rod-shaped and blocky.

[0025] In this first aspect, in some embodiments, the pharmaceutically acceptable salt is an L-tartrate salt. The molar ratio of L-tartaric acid to the compound represented by formula (I) in the L-tartrate salt (L-tartaric acid:compound represented by formula (I)) is (0.8-1.2):1. In some embodiments, the molar ratio of L-tartaric acid to the compound represented by formula (I) (L-tartaric acid:compound represented by formula (I)) may be 0.8:1, 0.9:1, 1.0:1, 1.1:1, or 1.2:1. In some embodiments, the molar ratio of L-tartaric acid to the compound represented by formula (I) (L-tartaric acid:compound represented by formula (I)) is (0.9-1.1):1. In one embodiment, the molar ratio of L-tartaric acid to the compound represented by formula (I) (L-tartaric acid:compound represented by formula (I)) is 1:1.

[0026] In some embodiments, the L-tartrate salt is crystalline Form I of the L-tartrate salt of the compound represented by Formula (I), and the crystalline Form I of the L-tartrate salt of the compound represented by Formula (I) has characteristic diffraction peaks at diffraction angle 2θ (°) values of 13.946±0.2, 16.881±0.2, 19.405±0.2, 21.505±0.2, and 24.262±0.2 in an X-ray powder diffraction pattern.

[0027] In some embodiments, the X-ray powder diffraction pattern of crystalline Form I of the L-tartrate salt has characteristic diffraction peaks at diffraction angles 2θ (°) of 13.946±0.2, 16.881±0.2, 19.405±0.2, 21.505±0.2, and 24.262±0.2, as well as the following peaks: 6.687±0.2, 7.436±0.2, 9.493±0.2, 10.615±0.2, 12.053±0.2, 12.776±0.2, 13.164±0.2, 14.875±0.2, 15.201±0.2, 16. The compound further has characteristic diffraction peaks at diffraction angle 2θ (°) values of two or more (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, etc.) selected from the group consisting of: 1.013±0.2, 18.175±0.2, 19.045±0.2, 20.659±0.2, 22.434±0.2, 23.04±0.2, 25.202±0.2, 26.452±0.2, 28.105±0.2, 29.692±0.2, 31.579±0.2, 34.139±0.2, and 34.543±0.2.

[0028] In some embodiments, the X-ray powder diffraction pattern of crystalline Form I of the L-tartrate salt is 6.687±0.2, 7.436±0.2, 9.493±0.2, 10.615±0.2, 12.053±0.2, 12.776±0.2, 13.164±0.2, 13.946±0.2, 14.875±0.2, 15.201±0.2, 16.013±0.2, 16.881±0.2, 18.175±0.2, 19.045±0.2, 19.405±0.2, 20.659±0.2 The compound has characteristic diffraction peaks at five or more (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, etc.) or all diffraction angle 2θ (°) values selected from the group consisting of 21.505±0.2, 22.434±0.2, 23.04±0.2, 24.262±0.2, 25.202±0.2, 26.452±0.2, 28.105±0.2, 29.692±0.2, 31.579±0.2, 34.139±0.2, and 34.543±0.2.

[0029] In some embodiments, the X-ray powder diffraction pattern of crystalline Form I of the L-tartrate salt has characteristic diffraction peaks at diffraction angle 2θ (°) values of 7.436±0.2, 13.946±0.2, 16.013±0.2, 16.881±0.2, 18.175±0.2, 19.045±0.2, 19.405±0.2, 21.505±0.2, 24.262±0.2, 25.202±0.2, 26.452±0.2, 28.105±0.2, and 31.579±0.2.

[0030] In some embodiments, the X-ray powder diffraction pattern of crystalline Form I of the L-tartrate salt is 6.687±0.2, 7.436±0.2, 10.615±0.2, 12.053±0.2, 13.164±0.2, 13.946±0.2, 14.875±0.2, 15.201±0.2, 16.013±0.2, 16.881±0.2, 18.175±0.2, 19.045±0.2 , and have characteristic diffraction peaks at diffraction angle 2θ (°) values of 19.405±0.2, 20.659±0.2, 21.505±0.2, 22.434±0.2, 23.04±0.2, 24.262±0.2, 25.202±0.2, 26.452±0.2, 28.105±0.2, 29.692±0.2, 31.579±0.2, 34.139±0.2 and 34.543±0.2.

[0031] In some embodiments, the X-ray powder diffraction pattern of crystalline Form I of the L-tartrate salt is 6.687±0.2, 7.436±0.2, 9.493±0.2, 10.615±0.2, 12.053±0.2, 12.776±0.2, 13.164±0.2, 13.946±0.2, 14.875±0.2, 15.201±0.2, 16.013±0.2, 16.881±0.2, 18.175±0.2, Characteristic diffraction peaks were observed at diffraction angle 2θ (°) values of 19.045±0.2, 19.405±0.2, 20.659±0.2, 21.505±0.2, 22.434±0.2, 23.04±0.2, 24.262±0.2, 25.202±0.2, 26.452±0.2, 28.105±0.2, 29.692±0.2, 31.579±0.2, 34.139±0.2 and 34.543±0.2.

[0032] In some examples, the X-ray powder diffraction pattern of crystalline Form I of the L-tartrate salt has characteristic diffraction peaks represented by the 2θ (°) values and d values shown in Table 2, and the relative intensities of each peak are as shown in Table 2.

[0033] [Table 2]

[0034] In some embodiments, the molar ratio of L-tartaric acid to the compound represented by Formula (I) (L-tartaric acid:compound represented by Formula (I)) in crystalline Form I of the L-tartrate salt is 1:1.

[0035] In some examples, the X-ray powder diffraction pattern of crystalline Form I of the L-tartrate salt of compound of Formula (I) is essentially as shown in FIG.

[0036] In some examples, the thermogravimetric analysis pattern of crystalline Form I of the L-tartrate salt of compound of Formula (I) is essentially as shown in Figure 6. In some examples, the TGA pattern of crystalline Form I of the L-tartrate salt of compound of Formula (I) shows a weight loss of 1.057% near 110°C and an additional weight loss of 3.482% near 178°C.

[0037] In some embodiments, the L-tartrate salt is crystalline Form II of the L-tartrate salt of the compound represented by Formula (I), and the crystalline Form II of the L-tartrate salt of the compound represented by Formula (I) has characteristic diffraction peaks at diffraction angle 2θ (°) values of 11.662±0.2 and 21.353±0.2 in an X-ray powder diffraction pattern.

[0038] In some embodiments, the X-ray powder diffraction pattern of the crystalline Form II of the L-tartrate salt has characteristic diffraction peaks at diffraction angles 2θ (°) of 11.662±0.2 and 21.353±0.2, as well as peaks at 6.985±0.2, 10.376±0.2, 10.884±0.2, 12.994±0.2, 14.244±0.2, 16.548±0.2, 17.481±0.2, 18.481±0.2, 19.481±0.2, 20.481±0.2, 21.481±0.2, 22.481±0.2, 23.481±0.2, 24.481±0.2, 25.481±0.2, 26.481±0.2, 27.481±0.2, 28.481±0.2, 29.481±0.2, 30.481±0.2, 31.481±0.2, 32.481±0.2, 33.481±0.2, 34.481±0.2, 35.481±0.2, 36.481±0.2, 37.481±0.2, 38.481±0.2, 39.481±0.2, 40.481±0.2, 41.481±0.2, 42.481±0.2, 43.481±0.2, 44.481±0.2, 45.481±0.2, 46.481±0.2, 47.481±0. and 31.784±0.2.

[0039] In some embodiments, the X-ray powder diffraction pattern of crystalline Form II of the L-tartrate salt is 6.985±0.2, 10.376±0.2, 10.884±0.2, 11.662±0.2, 12.994±0.2, 14.244±0.2, 16.548±0.2, 17.481±0.2, 18.349±0.2, 18.984±0.2, 2 It has characteristic diffraction peaks at three or more (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, etc.) or all diffraction angle 2θ (°) values selected from the group consisting of 1.026±0.2, 21.353±0.2, 26.925±0.2, 29.335±0.2, 30.896±0.2 and 31.784±0.2.

[0040] In some embodiments, the X-ray powder diffraction pattern of crystalline Form II of the L-tartrate salt has characteristic diffraction peaks at diffraction angle 2θ (°) values of 11.662±0.2, 14.244±0.2, 17.481±0.2, 18.349±0.2, 21.026±0.2, and 21.353±0.2.

[0041] In some embodiments, the X-ray powder diffraction pattern of crystalline Form II of the L-tartrate salt has characteristic diffraction peaks at diffraction angle 2θ (°) values of 10.376±0.2, 11.662±0.2, 14.244±0.2, 16.548±0.2, 17.481±0.2, 18.349±0.2, 18.984±0.2, 21.026±0.2, 21.353±0.2, 26.925±0.2, 29.335±0.2, and 31.784±0.2.

[0042] In some embodiments, the X-ray powder diffraction pattern of crystalline Form II of the L-tartrate salt has characteristic diffraction peaks at diffraction angle 2θ (°) values of 6.985±0.2, 10.376±0.2, 10.884±0.2, 11.662±0.2, 12.994±0.2, 14.244±0.2, 16.548±0.2, 17.481±0.2, 18.349±0.2, 18.984±0.2, 21.026±0.2, 21.353±0.2, 26.925±0.2, 29.335±0.2, 30.896±0.2, and 31.784±0.2.

[0043] In some embodiments, the X-ray powder diffraction pattern of the crystalline Form II of the L-tartrate salt has characteristic diffraction peaks represented by the 2θ (°) values and d values shown in Table 3, and the relative intensities of each peak are as shown in Table 3.

[0044] [Table 3]

[0045] In some embodiments, the molar ratio of L-tartaric acid to the compound represented by Formula (I) in crystalline Form II of the L-tartrate salt (L-tartaric acid:compound represented by Formula (I)) is 1:1.

[0046] In some embodiments, the X-ray powder diffraction pattern of crystalline Form II of the L-tartrate salt is essentially as shown in FIG.

[0047] In this first aspect, in some embodiments, the phosphate is a second type of phosphate of a compound represented by formula (I), and in the phosphate, the molar ratio of the compound represented by formula (I) to phosphoric acid (compound represented by formula (I) : phosphoric acid) is 1:(0.8 to 1.2). In some embodiments, the molar ratio of the compound represented by formula (I) to phosphoric acid (compound represented by formula (I) : phosphoric acid) is 1:(0.9 to 1.1). In some embodiments, the molar ratio of the compound represented by formula (I) to phosphoric acid (compound represented by formula (I) : phosphoric acid) may be 1:0.8, 1:0.9, 1:1, 1:1.1, or 1:1.2. In some embodiments, the molar ratio of the compound represented by formula (I) to phosphoric acid (compound represented by formula (I) : phosphoric acid) in the phosphate is 1:1.

[0048] In some embodiments, the phosphate salt of the compound of Formula (I) is in anhydrous, hydrated, or solvated form.

[0049] In some embodiments, the phosphate salt of the compound of Formula (I) is a crystalline powder that exists in crystalline form.

[0050] In some embodiments, the phosphate salt of the compound represented by formula (I) is crystalline form II of the phosphate salt, and the crystalline form II of the phosphate salt of the compound represented by formula (I) has characteristic diffraction peaks at diffraction angle 2θ (°) values of 18.230±0.2 and 21.144±0.2 in an X-ray powder diffraction pattern.

[0051] In some embodiments, in crystalline Form II of the phosphate salt, the molar ratio of the compound represented by Formula (I) to phosphoric acid (compound represented by Formula (I):phosphoric acid) is 1:1.

[0052] In some embodiments, the X-ray powder diffraction pattern of crystalline Form II of the phosphate salt has characteristic diffraction peaks at diffraction angles 2θ (°) of 18.230±0.2 and 21.144±0.2, as well as the following peaks: 10.584±0.2, 11.115±0.2, 11.813±0.2, 12.825±0.2, 13.969±0.2, 14.873±0.2, 15.313±0.2, 18.771±0.2, 19.85±0.2, 20.576±0.2, 22.01±0.2. The compound further has characteristic diffraction peaks at two or more (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, etc.) diffraction angle 2θ (°) values selected from the group consisting of 2, 22.492±0.2, 23.153±0.2, 23.96±0.2, 24.947±0.2, 26.273±0.2, 27.837±0.2, 28.432±0.2, 30.143±0.2, 31.072±0.2, 31.88±0.2, and 33.982±0.2.

[0053] In some embodiments, the X-ray powder diffraction pattern of crystalline Form II of the Phosphate Salt has characteristic diffraction peaks at two or more (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10) or all diffraction angle 2θ (°) values selected from the group consisting of 10.584±0.2, 13.969±0.2, 14.873±0.2, 18.230±0.2, 20.576±0.2, 21.144±0.2, 22.01±0.2, 22.492±0.2, 23.153±0.2, and 23.96±0.2.

[0054] In some embodiments, the X-ray powder diffraction pattern of crystalline Form II of the Phosphate Salt has characteristic diffraction peaks at diffraction angle 2θ (°) values of 10.584±0.2, 13.969±0.2, 14.873±0.2, 18.230±0.2, 20.576±0.2, 21.144±0.2, 22.01±0.2, 22.492±0.2, 23.153±0.2 and 23.96±0.2.

[0055] In some embodiments, the X-ray powder diffraction pattern of crystalline Form II of the Phosphate Salt is 10.584±0.2, 11.115±0.2, 11.813±0.2, 12.825±0.2, 13.969±0.2, 14.873±0.2, 15.313±0.2, 18.230±0.2, 18.771±0.2, 19.85±0.2, 20.576±0.2, 21.144±0.2, 22.01±0.2, 22.492±0.2, 23. The crystal has characteristic diffraction peaks at two or more (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, etc.) or all diffraction angle 2θ (°) values selected from the group consisting of 153±0.2, 23.96±0.2, 24.947±0.2, 26.273±0.2, 27.837±0.2, 28.432±0.2, 30.143±0.2, 31.072±0.2, 31.88±0.2, and 33.982±0.2.

[0056] In some embodiments, the X-ray powder diffraction pattern of crystalline Form II of the Phosphate Salt is 10.584±0.2, 11.115±0.2, 11.813±0.2, 12.825±0.2, 13.969±0.2, 14.873±0.2, 15.313±0.2, 18.230±0.2, 18.771±0.2, 19.85±0.2, 20.576±0.2, 21.1 Characteristic diffraction peaks are observed at diffraction angle 2θ (°) values of 44±0.2, 22.01±0.2, 22.492±0.2, 23.153±0.2, 23.96±0.2, 24.947±0.2, 26.273±0.2, 27.837±0.2, 28.432±0.2, 30.143±0.2, 31.072±0.2, 31.88±0.2 and 33.982±0.2.

[0057] In some embodiments, the X-ray powder diffraction pattern of crystalline Form II of the Phosphate Salt has characteristic diffraction peaks represented by the 2θ (°) values and d values shown in Table 4, and the relative intensities of each peak are as shown in Table 4.

[0058] [Table 4]

[0059] In some embodiments, the X-ray powder diffraction pattern (XRPD pattern) of crystalline Form II of the Phosphate Salt is essentially as shown in FIG.

[0060] In some embodiments, the differential scanning calorimetry curve for crystalline Form II of the phosphate salt has an endothermic peak at 207.48±3°C, ±2°C, ±1°C, or ±0.5°C. In some embodiments, the differential scanning calorimetry curve for crystalline Form II of the phosphate salt has an onset temperature of 207.48°C±3°C, 207.48°C±2°C, 207.48°C±1°C, or 207.48°C±0.5°C, and a peak temperature of 214.31°C±3°C, 214.31°C±2°C, 214.31°C±1°C, or 214.31°C±0.5°C. In some embodiments, the differential scanning calorimetry curve (DSC curve) for crystalline Form II of the phosphate salt is essentially as shown in Figure 11. In the example shown in Figure 11, the melting point of crystalline Form II of the phosphate salt of the compound represented by Formula (I) is 207.48±0.5°C.

[0061] In some examples, the thermogravimetric analysis curve (TGA curve) of crystalline Form II of the phosphate salt of compound represented by Formula (I) is essentially as shown in Figure 11. In some examples, the TGA curve of crystalline Form II of the phosphate salt of compound represented by Formula (I) shows little weight loss near 100°C and begins to melt when heated to near the melting point of 207.48°C. In some examples, the TGA curve of crystalline Form II of the phosphate salt of compound represented by Formula (I) shows that crystalline Form II of the phosphate salt is anhydrous.

[0062] In some examples, the dynamic sorption symmetry (DVS) pattern of crystalline Form II of the phosphate salt of compound of Formula (I) is essentially as shown in Figure 12. In some examples, the DVS pattern of crystalline Form II of the phosphate salt of compound of Formula (I) shows a moisture weight gain of 0.45% under 80% relative humidity (RH) conditions.

[0063] In some examples, a photomicrograph of crystalline Form II of the phosphate salt of compound of Formula (I) is essentially as shown in Figure 13. In some examples, the photomicrograph of crystalline Form II of the phosphate salt of compound of Formula (I) shows that crystalline Form II of the phosphate salt is rod-shaped.

[0064] A second aspect of the present invention provides a process for preparing the L-tartrate salt of the compound of formula (I). [ka]

[0065] In some embodiments, a method for preparing the L-tartrate salt of a compound of Formula (I) comprises reacting the compound of Formula (I) with L-tartaric acid to form the L-tartrate salt of the compound of Formula (I).

[0066] In some embodiments, in the method for preparing an L-tartrate salt, the molar ratio of L-tartaric acid to the compound represented by formula (I) (L-tartaric acid:compound represented by formula (I)) is (0.8-1.4):1. In some embodiments, the molar ratio of L-tartaric acid to the compound represented by formula (I) (L-tartaric acid:compound represented by formula (I)) is (0.9-1.2):1.

[0067] In some embodiments, in the method for preparing an L-tartrate salt of the compound represented by formula (I), the molar ratio of L-tartaric acid to the compound represented by formula (I) (L-tartaric acid:compound represented by formula (I)) in the formed L-tartrate salt of the compound represented by formula (I) is (0.8-1.2):1. In some embodiments, the molar ratio of L-tartaric acid to the compound represented by formula (I) (L-tartaric acid:compound represented by formula (I)) in the formed L-tartrate salt of the compound represented by formula (I) is (0.9-1.1):1. In one embodiment, the molar ratio of L-tartaric acid to the compound represented by formula (I) (L-tartaric acid:compound represented by formula (I)) in the formed L-tartrate salt of the compound represented by formula (I) is 1:1.

[0068] In some embodiments, there is provided a method for preparing a polymorph of the L-tartrate salt of the compound of Formula (I), wherein the polymorph is crystalline Form I of the L-tartrate salt, the method comprising: reacting the compound of formula (I) with L-tartaric acid in an organic solvent to form a salt; and gradually lowering the temperature of the reaction solution to obtain crystalline Form I of the L-tartrate salt.

[0069] In some embodiments, the organic solvent is one or more selected from the group consisting of ethanol, acetonitrile, ethyl acetate, acetone, and methanol.

[0070] In some embodiments, in the method for preparing crystalline Form I of the L-tartrate salt, the molar ratio of L-tartaric acid to the compound represented by formula (I) (L-tartaric acid:compound represented by formula (I)) is (0.8-1.4):1. In other embodiments, the molar ratio of L-tartaric acid to the compound represented by formula (I) (L-tartaric acid:compound represented by formula (I)) is (0.9-1.2):1.

[0071] In some embodiments, in the method for preparing crystalline Form I of the L-tartrate salt, the molar ratio of L-tartaric acid to the compound represented by formula (I) (L-tartaric acid:compound represented by formula (I)) in the obtained crystalline Form I of the L-tartrate salt is (0.8-1.2):1. In other embodiments, the molar ratio of L-tartaric acid to the compound represented by formula (I) (L-tartaric acid:compound represented by formula (I)) in the obtained crystalline Form I of the L-tartrate salt is (0.9-1.1):1. In one embodiment, the molar ratio of L-tartaric acid to the compound represented by formula (I) (L-tartaric acid:compound represented by formula (I)) in the obtained crystalline Form I of the L-tartrate salt is 1:1.

[0072] In some embodiments, there is provided a method for preparing crystalline Form II of the L-tartrate salt of compound of Formula (I), the method comprising: reacting the compound of formula (I) with L-tartaric acid in an organic solvent to form a salt; and gradually lowering the temperature of the reaction solution and adding an anti-solvent to obtain crystalline Form II of the L-tartrate salt of compound of formula (I).

[0073] In some embodiments, the organic solvent is one or more selected from the group consisting of ethanol, acetonitrile, ethyl acetate, acetone, and methanol.

[0074] In some embodiments, the anti-solvent is one or more selected from the group consisting of methyl tert-butyl ether, petroleum ether, n-heptane, n-hexane, cyclohexane, isopropanol, acetone, acetonitrile, and ethyl acetate, and the anti-solvent is different from the organic solvent. In other embodiments, the anti-solvent is one or more selected from the group consisting of methyl tert-butyl ether, n-heptane, isopropanol, and acetone.

[0075] In some embodiments, in the method for preparing crystalline Form II of the L-tartrate salt, the molar ratio of L-tartaric acid to the compound represented by formula (I) (L-tartaric acid:compound represented by formula (I)) is (0.8-1.4):1. In other embodiments, the molar ratio of L-tartaric acid to the compound represented by formula (I) (L-tartaric acid:compound represented by formula (I)) is (0.9-1.2):1.

[0076] In some embodiments, in the method for preparing crystalline Form II of the L-tartrate salt, the molar ratio of L-tartaric acid to the compound represented by Formula (I) (L-tartaric acid:compound represented by Formula (I)) in the obtained crystalline Form II of the L-tartrate salt is (0.8-1.2):1. In other embodiments, the molar ratio of L-tartaric acid to the compound represented by Formula (I) (L-tartaric acid:compound represented by Formula (I)) in the obtained crystalline Form II of the L-tartrate salt is (0.9-1.1):1. In one embodiment, the molar ratio of L-tartaric acid to the compound represented by Formula (I) (L-tartaric acid:compound represented by Formula (I)) in the obtained crystalline Form II of the L-tartrate salt is 1:1.

[0077] In some embodiments, the temperature of the salt-forming reaction is −10° C. to 90° C. For example, the temperature of the salt-forming reaction can be any range consisting of (and including) endpoints selected from the group consisting of −10° C., −5° C., 0° C., 5° C., 10° C., 15° C., 20° C., 25° C., 30° C., 35° C., 40° C., 45° C., 50° C., 55° C., 60° C., 65° C., 70° C., 75° C., 80° C., 85° C., and 90° C., and is not specifically limited.

[0078] In some embodiments, the reaction solution is slowly cooled to -10°C to 60°C. In some embodiments, the reaction solution is slowly cooled to 0°C to room temperature. In some embodiments, the reaction solution is slowly cooled to room temperature.

[0079] In some embodiments, the molar concentration of the L-tartaric acid is 0.1 to 5 mol / L. For example, the molar concentration of the L-tartaric acid may be 0.1 mol / L, 1 mol / L, 1.5 mol / L, 2 mol / L, 2.5 mol / L, 3 mol / L, 3.5 mol / L, 4 mol / L, 4.5 mol / L, or 5 mol / L. In some other embodiments, the molar concentration of the L-tartaric acid is 0.5 to 3 mol / L. In some other embodiments, the molar concentration of the L-tartaric acid is 1 to 2 mol / L.

[0080] In some embodiments, the method for preparing crystalline Form I of the L-tartrate salt of compound of Formula (I) comprises: Step (BI-a) of dissolving the compound represented by formula (I) in a solvent, adding an aqueous solution of L-tartaric acid, and stirring to react; and Step (BI-b) of cooling the reaction mixture obtained in Step (BI-a), precipitating a solid, separating the solid from the liquid, and collecting the solid to obtain Crystalline Form I of the L-tartrate salt of the compound of Formula (I).

[0081] In some embodiments, the temperature of the reaction in step (BI-a) is 10°C to 60°C.

[0082] In some examples, the molar ratio of the compound represented by formula (I) to the L-tartaric acid contained in the aqueous L-tartaric acid solution in step (BI-a) (compound represented by formula (I) : L-tartaric acid contained in the aqueous L-tartaric acid solution) is 1 : (0.8 to 1.4). In other examples, the molar ratio of the compound represented by formula (I) to the L-tartaric acid contained in the aqueous L-tartaric acid solution in step (BI-a) (compound represented by formula (I) : L-tartaric acid contained in the aqueous L-tartaric acid solution) is 1 : (0.9 to 1.2).

[0083] In some embodiments, the molar concentration of the L-tartaric acid aqueous solution in step (BI-a) is 0.1 to 5 mol / L. In some other embodiments, the molar concentration of the L-tartaric acid aqueous solution in step (BI-a) is 0.5 to 3 mol / L. In some other embodiments, the molar concentration of the L-tartaric acid aqueous solution in step (BI-a) is 1 to 2 mol / L.

[0084] In some embodiments, the solvent in step (BI-a) is ethanol.

[0085] In some embodiments, in step (BI-a), the mixture is stirred at 30-60° C., followed by stirring at room temperature. In some embodiments, in step (BI-a), the mixture is stirred at 30-60° C. for 2-5 hours, followed by stirring at room temperature. In some embodiments, in step (BI-a), the mixture is stirred at 30-60° C. for 2-5 hours, followed by stirring at room temperature for 7-16 hours.

[0086] In some embodiments, in step (BI-b), the reaction mixture is cooled to -10°C to 10°C. In some embodiments, the reaction mixture is cooled to -5°C to 5°C. In some embodiments, the reaction mixture is cooled to about 0°C.

[0087] In some embodiments, the reaction solution is cooled for 0.25 to 3 hours in step (BI-b). In some embodiments, the reaction solution is cooled for 0.5 to 2 hours. In some embodiments, the reaction solution is cooled for 0.5 to 1 hour.

[0088] In some embodiments, the separation method in step (BI-b) is selected from the group consisting of centrifugation and filtration separation.

[0089] In some embodiments, after the separation in step (BI-b), the method further comprises the step of evaporating or drying the solvent.

[0090] In some embodiments, the drying step after separation in step (BI-b) is carried out at 25 to 70°C.

[0091] In some embodiments, the method for preparing crystalline Form II of the L-tartrate salt of compound of Formula (I) comprises: (BII-a) a step of dissolving the compound represented by formula (I) in a solvent, adding an aqueous solution of L-tartaric acid, and stirring to react; and Step (BII-b) of cooling the reaction solution obtained in Step (BII-a), adding a poor solvent to cause crystallization, separating the solid phase, and collecting the solid phase to obtain Crystalline Form II of the L-tartrate salt of the compound represented by Formula (I).

[0092] In some embodiments, the temperature of the reaction in step (BII-a) is 10-60°C.

[0093] In some examples, the molar ratio of the compound represented by formula (I) to the L-tartaric acid contained in the aqueous L-tartaric acid solution in step (BII-a) (compound represented by formula (I) : L-tartaric acid contained in the aqueous L-tartaric acid solution) is 1 : (0.8 to 1.4). In other examples, the molar ratio of the compound represented by formula (I) to the L-tartaric acid contained in the aqueous L-tartaric acid solution in step (BII-a) (compound represented by formula (I) : L-tartaric acid contained in the aqueous L-tartaric acid solution) is 1 : (0.9 to 1.2).

[0094] In some embodiments, the molar concentration of the L-tartaric acid aqueous solution in step (BII-a) is 0.1 to 5 mol / L. In some embodiments, the molar concentration of the L-tartaric acid aqueous solution in step (BII-a) is 0.5 to 3 mol / L. In some other embodiments, the molar concentration of the L-tartaric acid aqueous solution in step (BII-a) is 1 to 2 mol / L.

[0095] In some embodiments, the solvent in step (BII-a) is methanol.

[0096] In some embodiments, in step (BII-a), the mixture is stirred at 30-60° C., followed by stirring at room temperature. In some embodiments, in step (BII-a), the mixture is stirred at 30-60° C. for 2-5 hours, followed by stirring at room temperature. In some embodiments, in step (BII-a), the mixture is stirred at 30-60° C. for 2-5 hours, followed by stirring at room temperature for 7-16 hours.

[0097] In some embodiments, in step (BII-b), the reaction mixture is cooled to -10°C to 10°C. In some embodiments, the reaction mixture is cooled to -5°C to 5°C. In some embodiments, the reaction mixture is cooled to about 0°C.

[0098] In some embodiments, the cooling time of the reaction solution in step (BII-b) is 0.25 to 3 hours. In some embodiments, the cooling time of the reaction solution is 0.5 to 2 hours. In some embodiments, the cooling time of the reaction solution is 0.5 to 1 hour.

[0099] In some embodiments, the anti-solvent in step (BII-b) is one or more selected from the group consisting of methyl tert-butyl ether, n-heptane, n-hexane, cyclohexane, acetone, acetonitrile, and ethyl acetate, and the solvent is different from the anti-solvent. In some embodiments, the anti-solvent is one or more selected from the group consisting of methyl tert-butyl ether, acetone, acetonitrile, and ethyl acetate. In some embodiments, the anti-solvent is methyl tert-butyl ether.

[0100] In some embodiments, the separation method in step (BII-b) is selected from the group consisting of centrifugation and filtration separation.

[0101] In some embodiments, after the separation in step (BII-b), the method further comprises the step of evaporating or drying the solvent.

[0102] In some embodiments, the drying step after separation in step (BII-b) is carried out at 25 to 70°C.

[0103] In some embodiments, a method for preparing an amorphous form of the L-tartrate salt of compound of Formula (I) comprises the steps of: Step (Ca) of dissolving the compound represented by formula (I) in a solvent, adding an aqueous solution of L-tartaric acid, and stirring to react; and step (Cb) of cooling the reaction solution obtained in step (Ca), precipitating a solid, separating the solid from the liquid, and collecting the solid phase to obtain an amorphous form of the L-tartrate salt.

[0104] In some embodiments, the temperature of the reaction in step (Ca) is 10-60°C.

[0105] In some examples, the molar ratio of the compound represented by formula (I) to the L-tartaric acid contained in the aqueous L-tartaric acid solution in step (Ca) (compound represented by formula (I):L-tartaric acid contained in the aqueous L-tartaric acid solution) is 1:(0.8-1.4). In some examples, the molar ratio of the compound represented by formula (I) to the L-tartaric acid contained in the aqueous L-tartaric acid solution in step (Ca) (compound represented by formula (I):L-tartaric acid contained in the aqueous L-tartaric acid solution) is 1:(0.9-1.2).

[0106] In some embodiments, the molar concentration of the L-tartaric acid aqueous solution in step (Ca) is 0.1 to 5 mol / L. In some embodiments, the molar concentration of the L-tartaric acid aqueous solution is 0.5 to 3 mol / L. In some embodiments, the molar concentration of the L-tartaric acid aqueous solution is 1 to 2 mol / L.

[0107] In certain embodiments, the solvent in step (Ca) is acetone.

[0108] In some embodiments, step (Ca) involves stirring at 30-60°C, followed by stirring at room temperature. In some embodiments, step (Ca) involves stirring at 30-60°C for 2-5 hours, followed by stirring at room temperature. In some embodiments, step (Ca) involves stirring at 30-60°C for 2-5 hours, followed by stirring at room temperature for 7-16 hours.

[0109] In some embodiments, in step (Cb), the reaction mixture is cooled to -10°C to 10°C. In some embodiments, the reaction mixture is cooled to -5°C to 5°C. In some embodiments, the reaction mixture is cooled to about 0°C.

[0110] In some embodiments, the reaction solution is cooled for 0.25 to 3 hours in step (Cb). In some embodiments, the reaction solution is cooled for 0.5 to 2 hours. In some embodiments, the reaction solution is cooled for 0.5 to 1 hour.

[0111] In some embodiments, the separation method in step (Cb) is selected from the group consisting of centrifugation and filtration separation.

[0112] In some embodiments, after the separation in step (Cb), the method further comprises the step of evaporating or drying the solvent.

[0113] In some embodiments, the drying step after separation in step (Cb) is carried out at 25 to 70°C.

[0114] A third aspect of the present invention provides a process for preparing the phosphate salt of the compound of formula (I). [ka]

[0115] The method for preparing the phosphate salt of the compound represented by formula (I) includes a step of reacting the compound represented by formula (I) with phosphoric acid in the presence of an organic solvent to form a salt of the compound represented by formula (I).

[0116] In some embodiments, the phosphate is a second type of phosphate of the compound represented by formula (I). In the step, the molar ratio of the compound represented by formula (I) to phosphoric acid (compound represented by formula (I):phosphoric acid) is 1:(0.8 to 1.2). For example, the molar ratio of the compound represented by formula (I) to phosphoric acid (compound represented by formula (I)):phosphoric acid) may be 1:0.8, 1:0.9, 1:1.0, 1:1.1, or 1:1.2.

[0117] In some examples, the molar ratio of the compound represented by formula (I) to phosphoric acid (compound represented by formula (I):phosphoric acid) is 1:(0.9 to 1.1). In some examples, the molar ratio of the compound represented by formula (I) to phosphoric acid (compound represented by formula (I)):phosphoric acid) is 1:1. In some examples, the molar ratio of the compound represented by formula (I) to phosphoric acid (compound represented by formula (I)):phosphoric acid) is 1:0.95.

[0118] In some embodiments, the molar ratio of the compound represented by Formula (I) to phosphoric acid in the phosphate salt (compound represented by Formula (I) : phosphoric acid) is 1: (0.8 to 1.2). In some embodiments, the molar ratio of the compound represented by Formula (I) to phosphoric acid in the phosphate salt (compound represented by Formula (I) : phosphoric acid) is 1: (0.9 to 1.1). In some embodiments, the molar ratio of the compound represented by Formula (I) to phosphoric acid in the phosphate salt (compound represented by Formula (I) : phosphoric acid) may be 1:0.8, 1:0.9, 1:1, 1:1.1, or 1:1.2. In some embodiments, the molar ratio of the compound represented by Formula (I) to phosphoric acid in the phosphate salt (compound represented by Formula (I) : phosphoric acid) is 1:1.

[0119] In some embodiments, the organic solvent is one or more selected from the group consisting of ethanol, ethyl acetate, acetonitrile, and acetone. In some embodiments, the organic solvent is ethanol, acetone, or a mixture thereof. In some embodiments, the organic solvent is ethanol.

[0120] In some embodiments, the organic solvent is one or more selected from the group consisting of methanol, ethyl acetate, and acetone. In some embodiments, the organic solvent is one or more selected from the group consisting of methanol and ethyl acetate. In some embodiments, the organic solvent is a mixture of methanol and ethyl acetate.

[0121] In some embodiments, the molar ratio of the compound represented by Formula (I) to phosphoric acid (compound represented by Formula (I):phosphoric acid) in the formed phosphate salt of the compound represented by Formula (I) is 1:1.

[0122] In some embodiments, there is provided a method for preparing crystalline Form II of the phosphate salt of compound of Formula (I), the method comprising: (i) reacting the compound represented by formula (I) with phosphoric acid in ethanol, methanol and / or acetone to form a salt, thereby precipitating a solid; (ii) collecting the solid to obtain crystalline Form II of the phosphate salt of compound represented by formula (I).

[0123] Here, the molar ratio of the compound represented by formula (I) to phosphoric acid (compound represented by formula (I) : phosphoric acid) is 1:(0.8 to 1.2), and may be, for example, 1:0.8, 1:0.9, 1:1.0, 1:1.1, or 1:1.2. In some embodiments, the molar ratio of the compound represented by formula (I) to phosphoric acid (compound represented by formula (I) : phosphoric acid) is 1:(0.9 to 1.1). In one embodiment, the molar ratio of the compound represented by formula (I) to phosphoric acid (compound represented by formula (I) : phosphoric acid) is 1:0.95. In another embodiment, the molar ratio of the compound represented by formula (I) to phosphoric acid (compound represented by formula (I) : phosphoric acid) is 1:1.

[0124] In some embodiments, the salt-forming reaction is carried out in one or both of ethanol and acetone.

[0125] In some embodiments, the salt-forming reaction is carried out in ethanol. In some embodiments, the salt-forming reaction is carried out in methanol.

[0126] In some embodiments, the method for preparing crystalline Form II of the phosphate salt of compound of Formula (I) comprises: a step (i-1) of reacting an ethanol solution of the compound represented by formula (I) with an ethanol solution of phosphoric acid to form a salt, thereby precipitating a solid; and (ii-1) collecting the solid to obtain crystalline Form II of the phosphate salt of compound of formula (I).

[0127] Here, the molar ratio of the compound represented by formula (I) to phosphoric acid (compound represented by formula (I) : phosphoric acid) is 1:(0.8-1.2), and may be, for example, 1:0.8, 1:0.9, 1:1.0, 1:1.1, or 1:1.2. In some embodiments, the molar ratio of the compound represented by formula (I) to phosphoric acid (compound represented by formula (I) : phosphoric acid) is 1:(0.9-1.1). In one embodiment, the molar ratio of the compound represented by formula (I) to phosphoric acid (compound represented by formula (I) : phosphoric acid) is 1:1.

[0128] In some embodiments, the method for preparing crystalline Form II of the phosphate salt of compound of Formula (I) comprises: a step (i-1) of reacting an ethanol solution of the compound represented by formula (I) with an ethanol solution of phosphoric acid at reflux temperature to form a salt, and then lowering the temperature to −10° C. to 60° C. to precipitate a solid; and (ii-1) collecting the solid to obtain crystalline Form II of the phosphate salt of compound of formula (I).

[0129] Here, the molar ratio of the compound represented by formula (I) to phosphoric acid (compound represented by formula (I) : phosphoric acid) is 1:(0.8-1.2), and may be, for example, 1:0.8, 1:0.9, 1:1.0, 1:1.1, or 1:1.2. In some embodiments, the molar ratio of the compound represented by formula (I) to phosphoric acid (compound represented by formula (I) : phosphoric acid) is 1:(0.9-1.1). In one embodiment, the molar ratio of the compound represented by formula (I) to phosphoric acid (compound represented by formula (I) : phosphoric acid) is 1:1.

[0130] In some embodiments, in crystalline Form II of the phosphate salt of the compound represented by Formula (I), the molar ratio of the compound represented by Formula (I) to phosphoric acid (compound represented by Formula (I):phosphoric acid) is 1:1.

[0131] In some embodiments, the temperature of the salt-forming reaction is -10°C to 90°C, and may be any range consisting of (and including) endpoints selected from the group consisting of -10°C, -5°C, 0°C, 5°C, 10°C, 15°C, 20°C, 25°C, 30°C, 35°C, 40°C, 45°C, 50°C, 55°C, 60°C, 65°C, 70°C, 75°C, 80°C, 85°C, and 90°C, and is not particularly limited.

[0132] In some embodiments, the collection of the solid in step (ii) or (ii-1) can be achieved by centrifugation and filtration.

[0133] In some embodiments, in step (ii) or (ii-1), after collecting the solid, the method further comprises evaporating the solvent to dryness or drying.

[0134] In some embodiments, the drying step is carried out at a temperature between 25°C and 70°C.

[0135] In some embodiments, the phosphate is a first type of phosphate of a compound represented by formula (I). In step (a), the molar ratio of the compound represented by formula (I) to phosphoric acid (compound represented by formula (I) : phosphoric acid) is 1:(1.8-2.6), and may be, for example, 1:1.8, 1:1.9, 1:2.0, 1:2.1, 1:2.2, 1:2.3, 1:2.4, 1:2.5, or 1:2.6. The molar ratio of the compound represented by formula (I) to phosphoric acid (compound represented by formula (I) : phosphoric acid) is preferably 1:(1.9-2.3), more preferably 1:(2.0-2.2).

[0136] In some embodiments, the molar ratio of phosphoric acid to the compound represented by formula (I) in the phosphate salt (phosphoric acid:compound represented by formula (I)) is (1.8-2.4):1. In some embodiments, the molar ratio of phosphoric acid to the compound represented by formula (I) (phosphoric acid:compound represented by formula (I)) may be 1.8:1, 1.9:1, 2.0:1, 2.1:1, 2.2:1, 2.3:1, or 2.4:1. In some embodiments, the molar ratio of phosphoric acid to the compound represented by formula (I) (phosphoric acid:compound represented by formula (I)) is (1.9-2.3):1. In one embodiment, the molar ratio of phosphoric acid to the compound represented by formula (I) (phosphoric acid:compound represented by formula (I)) is 2:1.

[0137] In some embodiments, the organic solvent is one or more selected from the group consisting of ethanol, ethyl acetate, acetone, and methanol.

[0138] In some embodiments, the molar ratio of phosphoric acid to the compound represented by Formula (I) (phosphoric acid:compound represented by Formula (I)) in the phosphate salt of the compound represented by Formula (I) formed is 2:1.

[0139] In one embodiment, the process for preparing crystalline Form I of the phosphate salt of compound of formula (I) comprises the steps of: a step (AI-a) of dissolving a compound represented by formula (I) in an organic solvent, adding an aqueous phosphoric acid solution, and stirring to cause a reaction; and Step (AI-b) of cooling the reaction solution obtained in Step (AI-a), adding a poor solvent to cause crystallization, performing solid-liquid separation, and collecting the solid phase to obtain Crystalline Form I of the phosphate salt of the compound represented by Formula (I).

[0140] In one embodiment, the reaction temperature in step (AI-a) is 10-60°C.

[0141] In one embodiment, the molar ratio of the compound represented by formula (I) to the phosphoric acid contained in the aqueous phosphoric acid solution (compound represented by formula (I) : phosphoric acid contained in the aqueous phosphoric acid solution) is 1:(1.8 to 2.6), and may be, for example, 1:1.8, 1:1.9, 1:2.0, 1:2.1, 1:2.2, 1:2.3, 1:2.4, 1:2.5, or 1:2.6. The molar ratio of the compound represented by formula (I) to the phosphoric acid contained in the aqueous phosphoric acid solution (compound represented by formula (I) : phosphoric acid contained in the aqueous phosphoric acid solution) is preferably 1:(1.9 to 2.3), and more preferably 1:(2.0 to 2.2).

[0142] In one embodiment, the molar concentration of the aqueous phosphoric acid solution is 0.1 to 5 mol / L, preferably 0.5 to 3 mol / L, and more preferably 1 to 2 mol / L.

[0143] In some embodiments, in step (AI-b), the reaction mixture is cooled to -10°C to 10°C, preferably -5°C to 5°C. In some of these embodiments, the reaction mixture is cooled to about 0°C.

[0144] In some embodiments, the reaction mixture is cooled for 0.5 to 2 hours in step (AI-b), and in some of these embodiments, the reaction mixture is cooled for 0.5 hours.

[0145] In one embodiment, the anti-solvent is one or more selected from the group consisting of methyl tert-butyl ether, petroleum ether, n-heptane, n-hexane, cyclohexane, isopropanol, acetone, acetonitrile, and ethyl acetate, and the anti-solvent is different from the solvent. Preferably, the anti-solvent is one or more selected from the group consisting of methyl tert-butyl ether, n-heptane, isopropanol, and acetone.

[0146] In one embodiment, the separation method in step (AI-b) is selected from the group consisting of centrifugation and filtration separation.

[0147] In one embodiment, after the separation in step (AI-b), the method further comprises a step of evaporating or drying the solvent.

[0148] In one embodiment, the drying step after the separation in step (AI-b) is carried out at 25 to 70°C, for example, 25°C, 30°C, 40°C, 50°C, 60°C, or 70°C, etc., but is not limited thereto.

[0149] In one embodiment, the reaction temperature in step (AI-a) is 10-60°C. The molar ratio of the compound represented by formula (I) to the phosphoric acid contained in the aqueous phosphoric acid solution (compound represented by formula (I) : phosphoric acid contained in the aqueous phosphoric acid solution) is 1:(1.8-2.4), preferably 1:(1.9-2.3), and more preferably 1:(2.0-2.2). The molar concentration of the aqueous phosphoric acid solution is 0.1-5 mol / L, preferably 0.5-3 mol / L, and more preferably 1-2 mol / L. In step (AI-b), the reaction solution is cooled to -10°C-10°C, preferably -5°C-5°C, and more preferably about 0°C. The cooling time for the reaction solution in step (AI-b) is 0.5-2 hours, and more preferably 0.5 hours. And / or, the anti-solvent is one or more selected from the group consisting of methyl tert-butyl ether, petroleum ether, n-heptane, n-hexane, cyclohexane, isopropanol, acetone, acetonitrile, and ethyl acetate, and the anti-solvent is different from the solvent. Preferably, the anti-solvent is one or more selected from the group consisting of methyl tert-butyl ether, n-heptane, isopropanol, and acetone. And / or, the separation method in step (AI-b) is selected from the group consisting of centrifugation and filtration separation. And / or, after the separation in step (AI-b), the method further comprises a step of evaporating the solvent to dryness or a drying step. And / or, the drying step after the separation in step (AI-b) is performed at 25 to 70°C.

[0150] A fourth aspect of the present invention provides a pharmaceutical composition comprising: (a) an L-tartrate or phosphate salt of a compound of formula (I) according to the first aspect of the present invention; and (b) a pharmaceutically acceptable carrier.

[0151] In some embodiments, the pharmaceutical composition comprises (a) an L-tartrate salt of a compound of Formula (I), a first type of phosphate salt of a compound of Formula (I), or a second type of phosphate salt of a compound of Formula (I) according to the first aspect of the present invention; and (b) a pharmaceutically acceptable carrier.

[0152] In some embodiments, the pharmaceutical composition comprises (a) crystalline Form I of the L-tartrate salt of compound of Formula (I), crystalline Form II of the L-tartrate salt of compound of Formula (I), amorphous L-tartrate salt of compound of Formula (I), crystalline Form I of the phosphate salt of compound of Formula (I), or crystalline Form II of the phosphate salt of compound of Formula (I) according to the first aspect of the present invention; and (b) a pharmaceutically acceptable carrier.

[0153] A fifth aspect of the present invention provides use of a pharmaceutically acceptable salt of a compound of Formula (I) according to the first aspect of the present invention or a pharmaceutical composition according to the fourth aspect of the present invention in the preparation of a kinase inhibitor. Specifically, the pharmaceutically acceptable salt of the compound of Formula (I) includes an L-tartrate salt of the compound of Formula (I), a first type of phosphate salt of the compound of Formula (I), and a second type of phosphate salt of the compound of Formula (I). In some embodiments, the pharmaceutically acceptable salt of the compound of Formula (I) includes crystalline Form I of the L-tartrate salt of the compound of Formula (I), crystalline Form II of the L-tartrate salt of the compound of Formula (I), an amorphous form of the L-tartrate salt of the compound of Formula (I), crystalline Form I of the phosphate salt of the compound of Formula (I), and crystalline Form II of the phosphate salt of the compound of Formula (I). In some embodiments, the kinase inhibitor is a CDK9 inhibitor.

[0154] A sixth aspect of the present invention provides use of a pharmaceutically acceptable salt of a compound represented by Formula (I) according to the first aspect of the present invention or a pharmaceutical composition according to the fourth aspect of the present invention in the preparation of a medicament for treating and / or preventing a disease associated with or mediated by CDK9 activity. Specifically, the pharmaceutically acceptable salt of the compound represented by Formula (I) includes an L-tartrate salt of the compound represented by Formula (I), a first type of phosphate salt of the compound represented by Formula (I), and a second type of phosphate salt of the compound represented by Formula (I). In some embodiments, the pharmaceutically acceptable salt of the compound represented by Formula (I) includes crystalline Form I of the L-tartrate salt of the compound represented by Formula (I), crystalline Form II of the L-tartrate salt of the compound represented by Formula (I), an amorphous form of the L-tartrate salt of the compound represented by Formula (I), crystalline Form I of the phosphate salt of the compound represented by Formula (I), and crystalline Form II of the phosphate salt of the compound represented by Formula (I).

[0155] The present invention further provides a pharmaceutically acceptable salt of a compound of formula (I) according to the first aspect of the invention, or a pharmaceutical composition according to the fourth aspect of the invention, for treating and / or preventing a disease associated with or mediated by CDK9 activity.

[0156] The present invention further provides a method of inhibiting CDK9 activity, comprising administering to a subject in need thereof a therapeutically effective amount of a pharmaceutically acceptable salt of a compound of formula (I) according to the first aspect of the invention, or a pharmaceutical composition according to the fourth aspect of the invention.

[0157] The present invention further provides a method for treating a disease associated with or mediated by CDK9 activity, comprising administering to a subject in need thereof an effective amount of a pharmaceutically acceptable salt of a compound of formula (I) according to the first aspect of the invention, or a pharmaceutical composition according to the fourth aspect of the invention.

[0158] In some embodiments, the disease comprises a hyperproliferative disease, a virally induced infectious disease, and a cardiovascular disease.

[0159] In some embodiments, the disease is a hyperproliferative disease. In some embodiments, the hyperproliferative disease includes angiogenic or vascular proliferative diseases, mesangial cell proliferative diseases, and solid tumors. The solid tumors include, for example, cancers of the breast, respiratory tract, brain, reproductive organs, gastrointestinal tract, urinary tract, eye, liver, skin, head and neck, thyroid, or parathyroid gland, and distant metastases thereof. In some embodiments, the disease is one or more selected from the group consisting of lymphoma, sarcoma, and leukemia. In some embodiments, the disease is cancer. The cancers include, for example, pancreatic cancer, breast cancer, ovarian cancer, cervical cancer, or leukemia. In some embodiments, the disease includes solid tumors and hematological tumors.

[0160] In the present invention, diseases associated with CDK9 activity or diseases mediated by CDK9 activity include diseases associated with CDK9 activity (e.g., CDK9 overactivity) or diseases involving CDK9 activity, and pathological conditions associated with these diseases. CDK9 overactivity refers to increased CDK9 enzyme activity compared to normal, non-diseased cells, or refers to CDK9 activity that leads to unwanted cell proliferation or reduced or insufficient programmed cell death (apoptosis), or refers to mutations that lead to constitutive activation of CDK9.

[0161] Hyperproliferative diseases include diseases involving undesired or uncontrolled proliferation of cells, and diseases involving a reduction or lack of programmed cell death (apoptosis). A pharmaceutically acceptable salt of a compound represented by formula (I) of the present invention, or a pharmaceutical composition containing a pharmaceutically acceptable salt of a compound represented by formula (I), can be used to prevent, inhibit, block, reduce, decrease, control, etc., cell growth and / or cell division, and / or to induce apoptosis. Treating and / or preventing diseases associated with or mediated by CDK9 activity comprises administering to a subject (including a mammal, e.g., a human) in need thereof an amount of a pharmaceutically acceptable salt of a compound represented by formula (I) of the present invention, or a pharmaceutical composition containing a pharmaceutically acceptable salt of a compound represented by formula (I), effective for treating or preventing the disease.

[0162] In the present invention, the phosphate and L-tartrate salts of the compound of formula (I) have higher solubility than the free base, and the crystalline form I of the L-tartrate salt of the compound of formula (I), the crystalline form II of the L-tartrate salt of the compound of formula (I), the amorphous form of the L-tartrate salt of the compound of formula (I), the crystalline form I of the phosphate salt of the compound of formula (I), and the crystalline form II of the phosphate salt of the compound of formula (I) all have good physical stability and are suitable for drug development.In particular, the crystalline form I of the phosphate salt of the compound of formula (I) can be converted into the more stable crystalline form II of the phosphate salt under appropriate conditions, such as in ethanol.Compared to the crystalline form I of the phosphate salt of the compound of formula (I), the crystalline form II of the phosphate salt of the compound of formula (I) has lower hygroscopicity and better crystallinity and stability. [Brief explanation of the drawings]

[0163] In order to more clearly explain the technical solutions in the embodiments of the present invention or the related art, the drawings necessary for describing the embodiments or the related art will be briefly described below. Obviously, the drawings in the following description are only embodiments of the present invention, and those skilled in the art can obtain other drawings based on the disclosed drawings without any creative efforts. [Figure 1] FIG. 1 is an X-ray powder diffraction (XRPD) pattern of crystalline Form I of the phosphate salt of the compound of formula (I). [Figure 2] FIG. 2 shows the differential scanning calorimetry (DSC) and thermogravimetric analysis (TGA) patterns of crystalline Form I of the phosphate salt of the compound of formula (I). [Figure 3] FIG. 3 is a dynamic moisture sorption curve (DVS) of crystalline form I of the phosphate salt of the compound of formula (I). [Figure 4] FIG. 4 is a photomicrograph of crystalline Form I of the phosphate salt of compound of formula (I). [Figure 5] FIG. 5 is an X-ray powder diffraction (XRPD) pattern of crystalline Form I of the L-tartrate salt of compound of formula (I). [Figure 6] FIG. 6 is a thermogravimetric analysis (TGA) pattern of crystalline Form I of the L-tartrate salt of compound of formula (I). [Figure 7] FIG. 7 is an X-ray powder diffraction (XRPD) pattern of crystalline Form II of the L-tartrate salt of compound of formula (I). [Figure 8] FIG. 8 is an X-ray powder diffraction (XRPD) pattern for the amorphous form of the L-tartrate salt of compound of formula (I). [Figure 9] FIG. 9 is an ellipsoidal diagram of the molecular conformation of a single crystal of the compound of formula (II). [Figure 10] FIG. 10 is an X-ray powder diffraction (XRPD) pattern of crystalline Form II of the phosphate salt of compound of formula (I). [Figure 11] FIG. 11 shows differential scanning calorimetry (DSC) and thermogravimetric analysis (TGA) patterns of crystalline Form II of the phosphate salt of the compound of formula (I). [Figure 12]FIG. 12 is a dynamic moisture sorption curve (DVS) of crystalline Form II of the phosphate salt of the compound of formula (I). [Figure 13] FIG. 13 is a photomicrograph of crystalline Form II of the phosphate salt of compound of formula (I). [Figure 14] FIG. 14 is a comparison of X-ray powder diffraction (XRPD) patterns obtained by converting crystalline Form I of the phosphate salt of compound of formula (I) to crystalline Form II of the phosphate salt of compound of formula (I) in ethanol. [Figure 15] FIG. 15 is an XRPD diagram of crystalline Form I of the L-tartrate salt of compound of formula (I) under high temperature (60° C.) and accelerated conditions (40° C. to 75% RH). [Figure 16] FIG. 16 is an XRPD change diagram of crystalline form I of the phosphate salt of the compound represented by formula (I) under high temperature conditions. [Figure 17] FIG. 17 is a graph showing changes in tumor volume after oral administration of compound D and the compound represented by formula (I) once a day. [Figure 18] FIG. 18 is a graph showing changes in body weight of mice after oral administration of compound D and the compound represented by formula (I) once a day. DETAILED DESCRIPTION OF THE INVENTION

[0164] In order to clarify and understand the above-mentioned objects, features, and advantages of the present invention, specific embodiments of the present invention will be described in detail below. In the following description, many specific details are set forth to fully understand the present invention. However, the present invention can be implemented in many other ways other than those described herein, and those skilled in the art can make similar modifications without departing from the spirit of the present invention, so the present invention is not limited to the specific examples invented below.

[0165] As used herein, the terms "crystal of the present invention," "crystalline form of the present invention," "polymorph of the present invention," etc. may be used interchangeably.

[0166] In the present invention, the compound represented by formula (I) is (1S,3S)-N1-(5-((S)-1-cyclobutylethyl)pyrazolo[1,5-a]pyrimidin-7-yl)cyclopentane-1,3-diamine, the structure of which is shown below. [ka]

[0167] The present invention also includes phosphate and L-tartrate salts of the compound of formula (I).

[0168] Polymorph: A solid exists in either an amorphous or crystalline form. In a crystalline form, molecules are located within three-dimensional lattice sites. When a compound is crystallized from a solution or slurry, it crystallizes in different spatial lattice arrangements (this property is called "polymorphism"), forming crystals with different crystalline forms called "polymorphs." Different polymorphs of a given substance may differ from each other in one or more physical properties (e.g., solubility and dissolution rate, true specific gravity, crystalline morphology, packing pattern, flowability, and / or solid-state stability).

[0169] Crystallization: Production-scale crystallization can be achieved by manipulating the solution to exceed the solubility limit of the compound of interest. This can be achieved by various methods, such as dissolving the compound at a relatively high temperature and then cooling the solution below the saturation limit. Alternatively, the volume of the liquid can be reduced by boiling, atmospheric evaporation, vacuum drying, or some other method. The solubility of the compound of interest can be reduced by adding an antisolvent, or a solvent in which the compound has low solubility, or a mixture of such solvents. Another alternative is to adjust the pH to reduce solubility. For a detailed description of crystallization, see Crystallization, Third Edition, J.W. Mullens, Butterworth-Heineman Ltd., 1993, ISBN 0750611294.

[0170] The "suspension shaking" described in the present invention refers to a method in which the compound represented by formula (I) and the corresponding acid or a solution of the corresponding acid are mixed in a suitable solvent to form a turbid liquid, and then the mixture is shaken to obtain crystals. The suitable solvent may be water or an organic solvent.

[0171] The "suspension centrifugation" described in the present invention refers to a method in which the compound represented by formula (I) and the corresponding acid or a solution of the corresponding acid are mixed in a suitable solvent to form a turbid liquid, and then centrifuged to obtain crystals. The suitable solvent may be water or an organic solvent.

[0172] The term "slow evaporation" used in the present invention refers to a method in which a solution containing the compound represented by formula (I) and the corresponding acid is placed at a specific temperature to slowly evaporate the solvent and obtain crystals.

[0173] The term "addition of an anti-solvent" or "adding an anti-solvent" used in the present invention refers to a method of adding another suitable solvent to a solution of the compound represented by formula (I) and then precipitating to obtain crystals.

[0174] If it is desired that the formation of a salt occur simultaneously with crystallization, the addition of an appropriate acid or base can result in the direct crystallization of the desired salt if the salt is less soluble in the reaction medium than the starting material. Similarly, completing a synthetic reaction in a medium in which the final desired form is less soluble than the reactants will result in the direct crystallization of the final product.

[0175] Crystal optimization can include seeding the crystals of the desired morphology in the crystallization medium. Furthermore, many crystallization methods use a combination of the above methods. One example involves dissolving the compound of interest in a solvent at high temperature, followed by adding an appropriate volume of anti-solvent in a controlled manner so that the system is just below the saturation level. At this point, seed crystals of the desired morphology can be added (while maintaining the integrity of the seed crystals), and the system can be cooled to complete the crystallization. As used herein, the term "about" means ±5 based on the given numerical value.

[0176] In this specification, when a unit is added only after the right endpoint of a data range, it indicates that the units of the left and right endpoints are the same. For example, in the case of 3 to 5 hours, both the left endpoint "3" and the right endpoint "5" are in hours.

[0177] It should be understood that the terms "preferable" and "better" used herein are merely used to describe embodiments or examples with better effects, and do not limit the scope of protection of the present invention. When multiple "preferable" terms appear in a technical solution, each "preferable" is independent of the other, unless otherwise specified and there is no contradiction or mutual restriction.

[0178] As used herein, the term "and / or," "or / and," and "and / or" includes any one item among two or more associated listed items, and also includes any and all combinations of the associated listed items, including any two associated listed items, any more associated listed items, or all combinations of the associated listed items. It should be understood that when at least two conjunctions selected from the group consisting of "and / or," "or / and," and "and / or" are used to connect at least three items, the technical solutions in this invention undoubtedly include technical solutions connected with "logical AND" and undoubtedly include technical solutions connected with "logical OR."

[0179] As used herein, unless otherwise specified, the terms "plurality," "multiple types," "multiple times," etc. mean that the number is two or more. For example, "multiple types" means two or more.

[0180] In this specification, technical features described in an open-ended manner include closed-ended technical solutions consisting of the recited features, and also include open-ended technical solutions including the recited features.

[0181] As used herein, the term "polymorphs of the present invention" includes, but is not limited to, crystalline Form I of the phosphate salt of the compound represented by Formula (I), crystalline Form II of the phosphate salt of the compound represented by Formula (I), crystalline Form I of the L-tartrate salt of the compound represented by Formula (I), and crystalline Form II of the L-tartrate salt of the compound represented by Formula (I).

[0182] The present invention also includes phosphate salts of the compound of formula (I), particularly the monophosphate salt, and crystalline Form II of the phosphate salt of the compound of formula (I).

[0183] "A compound of formula (I)," "a free base of a compound of formula (I)," and "free base" may be used interchangeably.

[0184] "Polymorphs of the compound of Formula (I)" and "polymorphs of the free base of the compound of Formula (I)" may be used interchangeably.

[0185] In the present invention, since some crystalline forms can be converted into each other, the present invention further provides a method for converting some crystalline forms into each other.

[0186] Pharmaceutical compositions and uses thereof In general, a pharmaceutically acceptable salt of the compound represented by formula (I) of the present invention can be administered as an active ingredient by formulating it into an appropriate dosage form together with one or more pharmaceutically acceptable carriers.

[0187] Specifically, the phosphate, L-tartrate, or polymorph thereof of the compound represented by formula (I) of the present invention can be formulated as an active ingredient together with one or more pharmaceutically acceptable carriers into an appropriate dosage form and administered.

[0188] A "pharmaceutically acceptable carrier" refers to a non-toxic, inert, solid, semi-solid or liquid filler, diluent, encapsulating material or auxiliary formulation or any type of auxiliary material that is compatible with the subject to which it is administered (in some embodiments, a mammal, in one embodiment, a human) and is suitable for delivering the active agent of the invention to its intended target without abolishing its activity.

[0189] The pharmaceutical compositions of the present invention are prepared, measured, and administered in a manner consistent with good medical practice. The "therapeutically effective amount" of the active ingredient administered will depend on factors such as the particular condition being treated, the individual being treated, the cause of the condition, the target of the drug, and the mode of administration.

[0190] The present invention provides that a pharmaceutically acceptable salt of the compound represented by formula (I) according to the first aspect of the present invention and a pharmaceutical composition according to the fourth aspect of the present invention can be used as a drug for treating and / or preventing a disease associated with CDK9 activity or a disease mediated by CDK9 activity.

[0191] The present invention provides a method for inhibiting CDK9 activity, comprising administering to a subject a therapeutically effective amount of a pharmaceutically acceptable salt of a compound of formula (I) according to the first aspect of the invention, or a pharmaceutical composition according to the fourth aspect of the invention.

[0192] As used herein, "therapeutically effective amount" refers to the amount of a pharmaceutically acceptable salt of a compound of formula (I) of the present invention that elicits a biological or medical response in a subject (e.g., reduction or inhibition of enzyme or protein activity, or amelioration of symptoms, alleviation of a condition, reduction or delay in progression of a disease, or prevention of a disease, etc.).

[0193] As used herein, "subject" refers to an animal, preferably a mammal, more preferably a human. The term "mammal" refers to warm-blooded vertebrates, including, for example, cats, dogs, rabbits, bears, foxes, wolves, monkeys, deer, mice, pigs, and humans.

[0194] "Treatment" means alleviating, slowing the progression of, attenuating, preventing, or maintaining an existing disease or condition (e.g., cancer). Treatment also includes curing, preventing the progression of, or alleviating to some extent, one or more symptoms of a disease or condition. Example

[0195] The present invention will be further described below with reference to specific examples. It should be understood that these examples are used to illustrate the present invention and do not limit the scope of the present invention. In the following examples, experimental methods for which specific conditions are not described generally follow conventional conditions or the conditions suggested by the manufacturer. Unless otherwise specified, "percentage" and "part" are based on weight. Unless otherwise specified, the terms used herein have the same meaning as those familiar to those skilled in the art. In addition, any methods and materials similar or equivalent to those described can be applied to the present invention.

[0196] Reagents and equipment In the present invention, the structure and purity of the compound can be determined by nuclear magnetic resonance ( 1 1 H NMR) and / or liquid chromatography mass spectrometry (LC-MS).

[0197] 1 1 H NMR: Bruker AVANCE-400 nuclear magnetic resonance spectrometer, internal standard is tetramethylsilane (TMS).

[0198] LC-MS: Agilent 1290 HPLC System / 6130 / 6150 MS liquid chromatography mass spectrometer (manufacturer: Agilent Technologies, Inc.), column: Waters BEH / CHS, 50 x 2.1 mm, 1.7 μm.

[0199] HPLC analysis was performed using an Agilent 1260 Infinity HPLC, OpenLAB CDS Chemstation workstation, an XBridge C18 4.6*250 mm chromatography column, an ID 5 μm column, and a DAD detector.

[0200] For elemental analysis, an inductively coupled plasma emission spectrometer was used, model number ICP 500, output power 1300W, and flow rate 1mL / min.

[0201] Known starting materials can be synthesized using or according to methods known in the art or can be purchased from companies such as ABCR GmbH & Co. KG, Acros Organics, Aldrich Chemical Company, Accela ChemBio Inc. and Darei Chemicals.

[0202] As used herein, room temperature in the following examples means about 20 to 30°C.

[0203] General Method X-ray powder diffraction (XRPD): In the present invention, the powder X-ray diffraction patterns of the above crystalline or amorphous forms are obtained using an ARL Equinox3000 X-ray powder diffraction analyzer according to methods known in the art, and the XRPD measurement parameters are shown in Table 5 below.

[0204] [Table 5]

[0205] In the powder X-ray diffraction pattern, the position of each peak is determined by 2θ (°) value. It is understood that different instruments and / or conditions may result in slight variations in the data generated, as well as variations in the position and relative intensity of each peak.

[0206] The intensity classification of peaks only reflects the approximate size of the peak at each position.In the present invention, for each crystalline form, the diffraction peak with the highest peak height is defined as the base peak, and its relative intensity is defined as 100%, and I0 (the peak with a 2θ(°) value of 18.803 for crystalline form I of the phosphate salt is the base peak, the peak with a 2θ(°) value of 20.27 for crystalline form I of the L-tartrate salt is the base peak, the peak with a 2θ(°) value of 21.353 for crystalline form II of the L-tartrate salt is the base peak, and the peak with a 2θ(°) value of 18.230 for crystalline form II of the phosphate salt is the base peak), and the ratio of the peak height of each other peak to the peak height of the base peak is defined as I / I0, and the definition of the relative intensity classification of each peak is as shown in Table 6 below.

[0207] [Table 6]

[0208] Single Crystal X-ray Diffraction (SXRD): In the present invention, the single crystal X-ray diffraction pattern of the compound represented by formula (II) was obtained using a D8 Venture diffractometer by methods known in the art, and the SXRD measurement parameters are shown in Table 7 below. After collecting the relevant data, the crystal structure can be further analyzed using a direct method (SHELXT2014) to confirm the absolute configuration.

[0209] [Table 7]

[0210] The acid-base molar ratio of the phosphate salt of the compound represented by formula (I) of the present invention and its crystalline form is determined by elemental analysis, and the L-tartrate salt of the compound represented by formula (I) and its crystalline form and amorphous form is determined by HPLC / IC or 1 Determine the acid-base molar ratio by 1 H NMR.

[0211] High Performance Liquid Chromatography: In the present invention, high performance liquid chromatography (HPLC) samples are collected on an Agilent 1260 HPLC.

[0212] Differential Scanning Calorimetry (DSC): In the present invention, the differential scanning calorimetry patterns of the above crystalline forms were obtained using a DSC25A differential scanning calorimeter by methods known in the art, and the DSC measurement parameters are shown in Table 8 below.

[0213] [Table 8]

[0214] Thermogravimetric analysis (TGA): In the present invention, the thermogravimetric analysis pattern of the above crystalline form was obtained using a TGA550 thermogravimetric analyzer by methods known in the art, and the TGA measurement parameters are shown in Table 9 below.

[0215] [Table 9]

[0216] Dynamic moisture sorption (DVS) curves were collected using a DVS Intrinsic from SMS (Surface Measurement Systems). The relative humidity at 25°C was corrected for the deliquescence points of LiCl, Mg(NO3)2, and KCl. The instrument measurement conditions are shown in Table 10 below.

[0217] [Table 10]

[0218] The Chinese Pharmacopoeia (2020) No. 9103 Guiding Principles for Drug Hygroscopicity Testing provides the following description of hygroscopic characteristics and the definition of hygroscopic weight gain: (1) Deliquescent: Absorbs a sufficient amount of water to form a liquid. (2) Extremely hygroscopic: The hygroscopic weight gain is 15% or more. (3) Hygroscopic: The hygroscopic weight gain is less than 15% but 2% or more. (4) Slightly hygroscopic: The hygroscopic weight gain is less than 2% but 0.2% or more. (5) No or little hygroscopicity: The hygroscopic weight gain is less than 0.2%.

[0219] It is understood that the quoted values should not be considered absolute, as other values may be obtained when using other types of equipment that function similarly to the above-described equipment, or when using measurement conditions that differ from those used in the present invention.

[0220] Those skilled in the art will understand that there may be slight differences in the above parameters for characterizing the physical properties of crystals due to variations in equipment and operators, and therefore the above parameters are merely supplementary for characterizing the polymorphs of the present invention and should not be considered as limiting the polymorphs of the present invention.

[0221] Unless otherwise specified, the terms "phosphoric acid solution" and "L-tartaric acid solution" used in the present invention refer to an aqueous solution of phosphoric acid and an aqueous solution of L-tartaric acid. The terms "phosphate" and "L-tartrate" used in the present invention refer to the phosphate salt of the compound represented by formula (I) and the L-tartrate salt of the compound represented by formula (I).

[0222] The solvents used in the present invention are analytically pure solvents, for example, ethanol is analytically pure ethanol (water content ≦0.3%).

[0223] Compound D in the present invention [ka] (CAS: 2416873-83-9) and Compound E [ka] (CAS:2416873-60-2) can be prepared with reference to prior published patent literature.

[0224] As used herein, MTBE refers to methyl tert-butyl ether, DMSO refers to dimethyl sulfoxide, THF refers to tetrahydrofuran, EA refers to ethyl acetate, PE refers to petroleum ether, DCM refers to dichloromethane, MeOH refers to methanol, CDI refers to N,N-carbonyldiimidazole, MOPS refers to 3-(N-morpholino)propanesulfonic acid, Tween-20 refers to Tween 20, DTT refers to dithiothreitol, EDTA refers to ethylenediaminetetraacetic acid, CDK1 refers to cell cycle-dependent kinase 1, CDK2 refers to cell cycle-dependent kinase 2, CDK9 refers to cell cycle-dependent kinase 9, K2EDTA refers to dipotassium ethylenediaminetetraacetate, IPA refers to isopropanol, and NH3 refers to ammonia.

[0225] Preparation Example 1. Preparation of Compound 6 [ka]

[0226] Step 1: Sodium hydride (18 g, 450.00 mmol, 60% purity) was dissolved in THF (300 mL) and cooled to 0°C. Triethyl 2-phosphonopropionate (100 g, 419.78 mmol) was slowly added dropwise. The reaction was stirred at 0-5°C for 1 hour, and then cyclobutanone (25 g, 356.69 mmol) dissolved in THF (50 mL) was slowly added dropwise. After the addition was complete, the reaction was allowed to proceed at 25°C for 15 hours. The reaction was quenched with saturated sodium chloride solution (600 mL) and then extracted with ethyl acetate (600 mL x 2). The combined organic phase was washed with saturated sodium chloride solution (500 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by CombiFlash (120 g x 2, 0-20% EA / PE) to give compound 2 (44 g, colorless oil). The yield was 80.00%.1 H NMR(400MHz,DMSO-d6)δ4.05(q,J=7.2Hz,2H),3.01-2.93(m,2H),2.78-2.71(m,2H),2.00-1.89(m,2H),1.61-1.58(m,3H),1.18(t,J=7.2Hz,3H).

[0227] Step 2: Compound 2 (44 g, 285.33 mmol) was dissolved in methanol (400 mL) and wet palladium on carbon (4.4 g, 10% purity) was added. A hydrogen balloon was added and the mixture was flushed with hydrogen gas three times. The mixture was stirred under a hydrogen atmosphere (15 psi) at 27 °C for 6–8 h. TLC confirmed the disappearance of the starting material spot. The Pd / C was filtered off, and the solvent was removed under reduced pressure to give crude compound 3 (44 g, colorless oil, boiling point approximately 182 °C). The yield was 98.71%. The product was used directly in the next step without further purification.

[0228] Step 3: Compound 3 (44 g, 281.65 mmol) was dissolved in methanol (400 mL), sodium hydroxide (45.06 g, 1.13 mol) and water (200 mL) were added, and the mixture was stirred at room temperature for 16 hours. LCMS confirmed the reaction was complete. After concentrating under reduced pressure to remove methanol, the mixture was extracted twice with dichloromethane. The aqueous phase was adjusted to pH 3 with dilute hydrochloric acid (6 M) and extracted with DCM (300 mL x 3). The combined organic phases were dried and rotary evaporated to give compound 4 (35 g, colorless oil, boiling point approximately 220 °C). The yield was 96.96%. The product was used directly in the next step without further purification. MS m / z (ESI): 127.1 [M−H] - . 1 H NMR(400MHz,DMSO-d6)δ11.91(s,1H),2.36-2.20(m,2H),1.99-1.90(m,2H),1.82-1.58(m,4H),0.93(d,J=6.8Hz,3H).

[0229] Step 4: In a reaction flask, compound 4 (36 g, 280.88 mmol) was dissolved in THF (300 mL), followed by the addition of CDI (68.32 g, 421.32 mmol). The mixture was allowed to react at room temperature for 16 hours (Solution A). In a separate reaction flask, monomethyl malonate potassium salt (143.42 g, 842.64 mmol) was added to anhydrous magnesium chloride (66.86 g, 702.20 mmol) and THF (900 mL). The mixture was allowed to react at 50 °C for 16 hours under argon gas protection (Solution B). Solution A was then added dropwise to Solution B at room temperature (approximately 10 minutes), and the mixture was stirred at 30 °C for 16 hours. LCMS confirmed the completion of the reaction, indicating the formation of the product. 800 mL of water was added to the reaction mixture, which was then extracted with ethyl acetate (800 mL x 3). The combined organic phases were washed with brine, dried over anhydrous sodium sulfate, and then rotary evaporated under reduced pressure. The residue was purified by CombiFlash (120 g x 2, 0-15% EA / PE) to obtain the product, Compound 5 (42 g, pale yellow oil, boiling point approximately 240 °C). The yield was 75.42%. MS m / z (ESI): 199.1 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ4.13-4.00(m,2H),3.55(d,J=0.8Hz,2H),2.63-2.54(m,1H),2.42-2.28(m,1H) ,1.97-1.85(m,2H),1.83-1.74(m,1H),1.73-1.61(m,3H),1.16(t,J=7.2Hz,3H),0.91(d,J=6.8Hz,3H).

[0230] Step 5: Compound 5 (42 g, 211.85 mmol) and 3-aminopyrazole (19.36 g, 233.03 mmol) were dissolved in glacial acetic acid (300 mL), heated to 120 °C, and reacted for 16 hours. LCMS confirmed the reaction was complete. The acetic acid was removed by concentration under reduced pressure, and the mixture was slurried with ethyl acetate (800 mL × 4). The solid precipitated, filtered, and dried to give compound 6 (41 g, pale yellow solid). The yield was 89.08%. The solid was used directly in the next step without further purification. MS m / z (ESI): 218.1 [M+H] + .

[0231] Preparation Example 2. Preparation of the compound represented by formula (I) [ka]

[0232] Step 1: Compound 6 (473.6 mg, 2.18 mmol) was dissolved in phosphorus oxychloride (6 mL), heated to 120 °C, and stirred for 3 h. The mixture was cooled to room temperature, poured into ice water (60 g), extracted with dichloromethane (80 mL), and the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was separated by silica gel column chromatography (20 g, 0%-40% EA / DCM) to give compound 7. MS m / z (ESI): 236.1 [M+H] + ; 1 H NMR(400MHz,DMSO-d6)δ8.25(d,J=2.4Hz,1H),7.35(s,1H),6.76(d,J=2.4Hz,1H),2.893-2 .84(m,1H),2.61-2.51(m,1H),2.12-2.01(m,1H),1.80-1.59(m,5H),1.14(d,J=6.8Hz,3H).

[0233] Step 2: Compound 7 (142.7 mg, 605.5 μmol) and tert-butyl ((1S,3S)-3-aminocyclopentyl)carbamate (121.27 mg, 605.52 μmol) were dissolved in acetonitrile (20 mL), followed by the addition of potassium carbonate (251.0 mg, 1.81 mmol). The reaction was stirred at 90° C. for 16 hours. After dilution with ethyl acetate (80 mL) and washing with saturated sodium chloride solution (80 mL×3), the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give compound 8. MS m / z (ESI): 400.3 [M+H] + ; 1H NMR(400MHz,DMSO-d6)δ8.00(d,J=2.0Hz,1H),7.58(d,J=7.6Hz,1H),6.97(d,J= 7.6Hz,1H),6.30(d,J=2.0Hz,1H),6.00(s,1H),4.19(q,J=7.2Hz,1H),4.02-3.9 3(m,1H),2.77-2.66(m,1H),2.61-2.53(m,1H),2.21-2.01(m,3H),1.97-1.88(m ,2H),1.80-1.63(m,6H),1.56-1.42(m,1H),1.40(s,9H),1.13(d,J=6.8Hz,3H).

[0234] Step 3: Compound 8 (174.7 mg, 437.38 μmol) was dissolved in 1,4-dioxane (3 mL) and hydrochloric acid solution (3.0 mL, 4 M) was added. The mixture was stirred at room temperature for 3 hours. The solvent was evaporated under reduced pressure, water (60 mL) was added, and the mixture was extracted with ethyl acetate (50 mL). The aqueous phase was adjusted to pH 9-10 with saturated sodium carbonate solution and extracted with ethyl acetate (60 mL x 2). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Compound 9 was obtained by preparative HPLC chromatography. MS m / z (ESI): 300.2 [M+H] + ; 1 H NMR(400MHz,DMSO-d6)δ7.97(s,1H),7.54(s,1H),6.28(s,1H),5.99(s,1H),4.13-4.22(m,1H),3.90-3.99(m,1H),2.75-2.6.3 (m,1H),2.51-2.57(m,1H),2.20-1.96(m,3H),1.85-1.94(m,2H),1.60-1.78(m,6H),1.40-1.49(m,1H),1.11(d,J=6.8Hz,3H).

[0235] Step 4: Compound 9 (94.46 mg, 315.48 μmol) was subjected to chiral separation (column type: IC-3 4.6*100 mm 3 μm; cosolvent: IPA [1% NH3 (7 M in MeOH)]; injection volume: 5.00 μL; wavelength: 220.0 nm; run time: 6.0 min; flow rate: 3.0 mL / min, force: 2000 psi; column temperature: 40 °C) to give compound of formula (I) (9.70 mg, retention time: 2.471 min). Yield: 9.89%, purity: 96.34%. MS m / z (ESI): 300.2 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ7.96(d,J=2.0Hz,1H),7.41(d,J=7.6Hz,1H),6.27(d ,J=2.0Hz,1H),5.96(s,1H),4.21(q,J=7.2Hz,1H),3.42(q,J=6.0Hz,1H),2. 65-2.74(m,1H),2.58-2.50(m,1H),2.16-2.24(m,1H),2.03-2.09(m,1H),1. 83-1.95(m,2H),1.80-1.61(m,7H),1.35-1.25(m,1H),1.11(d,J=6.8Hz,3H).

[0236] The compound of formula (II) was prepared from the compound of formula (I) so that the absolute configuration of the compound of formula (I) was determined by the absolute configuration of the compound of formula (II). [ka]

[0237] The compound of formula (I) (200 mg, 667.97 μmol) was dissolved in dichloromethane (10 mL), followed by the addition of 4-chlorobenzoyl chloride (175.4 mg, 1.00 mmol), followed by the addition of N,N-diisopropylethylamine (0.6 mL, 3.34 mmol). The reaction was stirred at room temperature for 2 hours, and LCMS confirmed the complete reaction of the starting material. Water (30 mL) was added, and the mixture was extracted with ethyl acetate (30 mL). The organic phase was washed with saturated sodium chloride solution (30 mL x 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the crude product. The crude product was purified by silica gel column chromatography to give the compound of formula (II) (160 mg, yield: 54.69%). LCMS (ESI) m / z: 438.2 [M+H] + .

[0238] Furthermore, single crystals of the compound represented by formula (II) were prepared. Figure 9 shows an ellipse diagram of the molecular conformation of the compound represented by formula (II). The Flack constant was 0.07(2), and C8, C10, and C19 were in the S configuration. That is, the absolute configurations of the three chiral centers of the compound represented by formula (II) were all S configurations, and the structure was as shown in the structure of the compound represented by formula (II). This confirmed that the absolute configurations of the three chiral centers of the compound represented by formula (I) were all S configurations, and the structure was as shown in the structure of the compound represented by formula (I).

[0239] Example 1. Preparation of Crystalline Form I of the Phosphate of Compound of Formula (I) A 20 mL sample bottle was charged with 500 mg of free base and 1 mL of methanol. After sonication, a 1 mol / L solution of phosphoric acid was added at a molar ratio of 2.5:1. The mixture was then stirred at 50 °C for 1 hour, then at 40 °C for 1 hour, and then at 30 °C for another hour. Finally, the mixture was heated and stirred overnight. After the reaction was complete, the temperature was slowly lowered to 0 °C, and acetone was added to precipitate the solid. The solid was collected by centrifugation, and the solvent was evaporated to dryness to obtain a solid. The resulting solid was Form I of the phosphate salt of the compound represented by formula (I). Elemental analysis of the resulting solid confirmed that the phosphorus content was 12.5%. This indicates that the molar ratio of the compound represented by formula (I) to phosphoric acid (compound represented by formula (I) / phosphoric acid) in the resulting solid was 1:2 (the theoretical phosphorus content was 12.5%). The XRPD pattern of the obtained solid was essentially as shown in FIG. 1, and the XRPD pattern of the obtained solid had peaks at the 2θ (°) values shown in Table 1, with the relative intensities of each peak being as shown in Table 1. The DSC and TGA patterns were as shown in FIG. 2, the DVS pattern thereof was as shown in FIG. 3, and the micrograph thereof was as shown in FIG. 4.

[0240] As can be seen from Figure 2, the DSC pattern showed a single melting absorption peak at 188.01°C, indicating good crystallinity. This indicates that the melting point of crystalline Form I of the phosphate salt of the compound represented by formula (I) was approximately 188.01°C. The TGA pattern showed that when the sample was heated to around 190°C, a weight loss of 1.139% occurred. This was due to the evaporation of the solvent.

[0241] As can be seen from Figure 3, the weight gain due to moisture absorption was 9% under 80% RH conditions in the DVS pattern, indicating that crystalline Form I of the phosphate salt of the compound represented by formula (I) is hygroscopic.

[0242] As can be seen from Figure 4, the polarized light micrograph shows that the crystalline form I of the phosphate salt of compound of formula (I) was rod-shaped and blocky.

[0243] Example 2. Preparation of crystalline form I of the L-tartrate salt of compound of formula (I) A 20 mL sample bottle was charged with 500 mg of free base and 1 mL of ethanol. The mixture was dissolved by ultrasonication, followed by the addition of a 1 mol / L L-tartaric acid solution at a molar ratio of 1.2:1. The mixture was then reacted at 50 °C for 1 hour, stirred at 40 °C for 1 hour, and then stirred at 30 °C for another hour. Finally, the mixture was heated and stirred at room temperature overnight. After the reaction was complete, the temperature was slowly lowered to 0 °C, and the solid was collected by centrifugation. The solvent was evaporated and dried to obtain a solid. The resulting solid was Form I of the L-tartrate salt of the compound represented by formula (I). The HPLC / IC analysis results indicated that the molar ratio of the compound represented by formula (I) to L-tartaric acid (compound represented by formula (I):L-tartaric acid) in the resulting solid was 1:1. The XRPD pattern was essentially as shown in FIG. 5, and the XRPD pattern of the obtained solid had peaks at the 2θ (°) values shown in Table 2, with the relative intensities of each peak being as shown in Table 2, and the TGA pattern was as shown in FIG.

[0244] As can be seen from Figure 6, the TGA pattern shows that when heated to around 110°C, a weight loss of 1.057% occurred. This is believed to be due to the evaporation of water. When heated to around 178°C, a weight loss of 3.482% continued to occur. This is believed to be due to the evaporation of the organic solvent. Continued heating resulted in melting and decomposition.

[0245] Example 3. Preparation of Crystalline Form II of the L-Tartrate Salt of Compound of Formula (I) A sample bottle was charged with approximately 100 mg of the free base and 0.2 mL to 0.3 mL of methanol. The mixture was then sonicated and dissolved. A 1 mol / L L-tartaric acid solution was then added, resulting in a 1.2:1 molar ratio of acid to base (acid:base). The reaction mixture was then allowed to react at 50°C for 1 hour, stirred at 40°C for 1 hour, and then stirred at 30°C for another 1 hour. The mixture was then cooled to room temperature, after which heating was stopped and the mixture was stirred overnight. After the reaction was complete, the mixture was slowly cooled to 0°C, and MTBE was added to cause crystallization. The solvent was evaporated and dried to obtain a solid. The resulting solid was subjected to HPLC / IC detection, confirming that the molar ratio of the compound represented by formula (I) to L-tartaric acid (the compound represented by formula (I):L-tartaric acid) was 1:1. The XRPD pattern of the resulting solid was as shown in FIG. 7. The XRPD pattern of the resulting solid had peaks at the 2θ (°) values shown in Table 3, with the relative intensities of each peak shown in Table 3. In the present invention, the crystalline form II of the L-tartrate salt of the compound represented by formula (I) is defined.

[0246] Example 4. Preparation of amorphous L-tartrate salt of compound of formula (I) The free base (approximately 100 mg) and acetone (0.2 mL to 0.3 mL) were added to a sample bottle and dissolved using ultrasound. A 1 mol / L L-tartaric acid solution was then added, with the molar ratio of the acid to the base (acid:base) being 1.2:1. The mixture was allowed to react at 50°C for 1 hour, stirred at 40°C for 1 hour, and then stirred at 30°C for another 1 hour. The mixture was then cooled to room temperature, after which heating was stopped and the mixture was stirred overnight. After the reaction was completed, the mixture was gradually cooled to 0°C to precipitate a solid. The solid was collected by centrifugation and the solvent was evaporated to dryness to obtain a solid. HPLC / IC analysis of the resulting solid confirmed that the molar ratio of the compound represented by formula (I) to L-tartaric acid (compound represented by formula (I):L-tartaric acid) was 1:1. The XRPD pattern of the resulting solid is shown in Figure 8, and in this invention, this solid was defined as an amorphous form of the L-tartrate salt.

[0247] Example 5. Preparation of Crystalline Form II of the Phosphate Salt of Compound of Formula (I) In a 50 mL sample bottle, 100 mg of the free base was dissolved in 15 mL of ethanol, and 5 mL of an ethanol solution of phosphoric acid was added dropwise at a molar ratio of 0.95:1 (acid:base). The mixture was stirred at room temperature for 4 hours, filtered, rinsed with ethanol, and rotary evaporated to obtain a white solid. Elemental analysis of the solid indicated a phosphorus content of 7.8%. The molar ratio of the compound represented by formula (I) to phosphoric acid (compound represented by formula (I):phosphoric acid) in the solid was 1:1 (theoretical phosphorus content was 7.79%). The XRPD pattern of the solid was as shown in Figure 10, and this solid was defined as Form II of the phosphate salt in the present invention.

[0248] The XRPD pattern of the obtained solid had peaks at the 2θ (°) values shown in Table 4, and the relative intensities of each peak were as shown in Table 4. The DSC and TGA curves were as shown in Figure 11, the DVS pattern was as shown in Figure 12, and the micrograph was as shown in Figure 13.

[0249] As can be seen from Figure 11, the DSC curve of the sample showed one melting absorption peak at 207.48°C, indicating good crystallinity. This indicates that the melting point of crystalline Form II of the phosphate salt of the compound represented by formula (I) was approximately 207.48°C. The TGA curve showed that the sample showed almost no weight loss when heated to around 100°C, but began to melt when heated to around 207°C, indicating that crystalline Form II of the phosphate salt of the compound represented by formula (I) was anhydrous.

[0250] As can be seen from Figure 12, the weight gain due to moisture absorption was 0.45% under 80% RH conditions in the DVS pattern, indicating that crystalline Form II of the phosphate salt of compound of formula (I) was slightly hygroscopic.

[0251] As can be seen from Figure 13, polarized light microscopy shows that crystalline Form II of the phosphate salt of compound of formula (I) was rod-shaped.

[0252] Example 6. Preparation of crystalline form II of the phosphate salt of compound of formula (I) The free base (100 mg) was dissolved in acetone (15 mL) in a 50 mL sample bottle, and then an ethanol solution of phosphoric acid (5 mL) was added dropwise at a molar ratio of 0.98:1 (acid:base). The mixture was stirred at room temperature for 4 hours, filtered, rinsed with ethanol, and rotary evaporated to obtain a white solid. Elemental analysis of the solid revealed a phosphorus content of 7.8%. This indicates that the molar ratio of the compound represented by formula (I) to phosphoric acid (compound represented by formula (I):phosphoric acid) in the solid was 1:1 (theoretical phosphorus content was 7.79%). The XRPD pattern of the solid was essentially as shown in Figure 10.

[0253] Example 7. Preparation of Crystalline Form II of the Phosphate Salt of Compound of Formula (I) In a 50 mL sample bottle, 100 mg of the free base was dissolved in 10 mL of ethanol, and then 10 mL of an ethanol solution of phosphoric acid was added dropwise at a molar ratio of 1.05:1 (acid:base). The mixture was stirred at room temperature for 4 hours, filtered, rinsed with ethanol, and rotary evaporated to obtain a white solid. Elemental analysis of the solid revealed a phosphorus content of 7.8%. This indicates that the molar ratio of the compound represented by formula (I) to phosphoric acid (compound represented by formula (I):phosphoric acid) in the solid was 1:1 (theoretical phosphorus content was 7.79%). The XRPD pattern of the solid was essentially as shown in Figure 10.

[0254] Example 8. Preparation of crystalline form II of the phosphate salt of compound of formula (I) 0.5 g of the free base was dissolved in methanol (15 ml), and phosphoric acid (commercially available) was added at a molar ratio of 1:1 (acid:base). After stirring for 2 hours, the mixture was rotary evaporated to remove the methanol, yielding a crude phosphate salt. The mixture was concentrated with ethanol (2.5 ml), further concentrated with ethanol (2.5 ml), and then further concentrated with ethanol (10 ml). The mixture was heated to 60°C and stirred for 3 hours, then cooled to room temperature and stirred overnight. The mixture was filtered, rinsed with ethanol, and rotary evaporated to obtain Form II of the phosphate salt of the compound represented by Formula (I). The yield was 75.8%. Elemental analysis of the resulting solid revealed a phosphorus content of 7.7%. This indicates that the molar ratio of the compound represented by Formula (I) to phosphoric acid (compound represented by Formula (I):phosphoric acid) in the resulting solid was 1:1 (theoretical phosphorus content was 7.79%). The resulting solid was analyzed by XRPD, and its XRPD pattern was essentially as shown in Figure 10.

[0255] Comparative Example 1. Salt formation reaction of the compound represented by formula (I) An appropriate amount of compound (100 mg) of formula (I) was weighed out using the weight loss method and placed in a transparent sample bottle. The appropriate solvent (0.2 mL to 0.3 mL) was added and dissolved using ultrasound. A 1 mol / L acid solution (aqueous solution) was then added at a molar ratio of 1.2:1 (acid:base). The mixture was then reacted at 50°C for 1 hour, stirred at 40°C for 1 hour, and then stirred at 30°C for another hour. The mixture was then cooled to room temperature, after which heating was stopped and the mixture was stirred overnight. After the reaction was complete, the temperature was slowly lowered until a solid precipitated. If the solution remained clear, crystallization was induced by adding an antisolvent. XRPD analysis of the reaction results showed that acids such as hydrochloric acid, sulfuric acid, and oxalic acid were unable to convert the compound of formula (I) into a salt after cooling and adding an antisolvent. The acid and solvent types were as shown in Table 11 below.

[0256] [Table 11]

[0257] Measurement example 1. Solubility measurement The solubilities of the phosphate and L-tartrate salts of the compound of formula (I) prepared in the above examples in water were measured at room temperature. The solubility of the phosphate salt was 26.6 mg / mL or less, the solubility of the L-tartrate salt was 17.3 mg / mL or less, and the free base was slightly soluble in water. The salts of the compound of formula (I) have significantly improved solubility in water, and in the salts formed, the phosphate salt has a higher solubility than the L-tartrate salt.

[0258] The crude solubilities (unit: mg / mL) of crystalline Form I of the phosphate salt and crystalline Form I of the L-tartrate salt of the compound represented by formula (I) in a pH 4.5 buffer solution (acetic acid-sodium acetate system) and a pH 6.8 buffer solution (sodium dihydrogen phosphate-sodium hydroxide system) were measured at room temperature. The results are shown in Table 12. As can be seen from the results in Table 12, crystalline Form I of the phosphate salt and crystalline Form I of the L-tartrate salt of the compound represented by formula (I) have high solubility in both pH 4.5 and pH 6.8 buffer solutions.

[0259] [Table 12]

[0260] An appropriate amount of crystalline Form I of the phosphate salt or crystalline Form II of the phosphate salt was weighed, and 0.1 mol / L hydrochloric acid solution (5 mL) and pH 6.8 phosphate buffer solution (5 mL) were added, respectively, and samples were taken after 24 hours (placed in an oven at 37°C) to measure the solubility. The results are shown in Table 13.

[0261] [Table 13]

[0262] Measurement example 2: Stability measurement (1) Samples (approximately 100 mg) of crystalline Form I of the phosphate salt of the compound represented by formula (I), crystalline Form II of the phosphate salt of the compound represented by formula (I), crystalline Form I of the L-tartrate salt of the compound represented by formula (I), and crystalline Form II of the L-tartrate salt of the compound represented by formula (I) were weighed and left at 60°C (high temperature) and at 40°C to 75% RH (accelerated). At the same time, another group of samples was stored sealed at 5°C as a control, and changes in the crystalline form were detected after 7 days, 20 days, 30 days, and 60 days.

[0263] As can be seen from the detection results, crystalline Form I of the L-tartrate salt of compound of formula (I), crystalline Form II of the L-tartrate salt of compound of formula (I), crystalline Form I of the phosphate salt of compound of formula (I), and crystalline Form II of the phosphate salt of compound of formula (I) all showed no significant changes under the above conditions, demonstrating high stability. When crystalline Form I of the L-tartrate salt of compound of formula (I) was stored under high-temperature conditions for 7 days and 2 months (60 days), the XRPD patterns of the crystalline forms showed no significant changes. When crystalline Form I of the L-tartrate salt of compound of formula (I) was stored under accelerated conditions for 7 days and 2 months (60 days), the XRPD pattern overlays of the crystalline forms showed no significant changes, as shown in Figure 15. This indicates that crystalline Form I of the L-tartrate salt of compound of formula (I) has high stability. Crystalline Form I of the phosphate salt of the compound represented by formula (I) was stored under high temperature conditions for 7 days and 30 days. The XRPD pattern overlays of the crystalline forms are shown in Figure 16, which show no obvious changes, indicating that Crystalline Form I of the phosphate salt of the compound represented by formula (I) has high stability.

[0264] (2) Approximately 40 mg of crystalline form I of the phosphate salt (prepared with reference to Example 1 of the present invention) was weighed into a glass vial, ethanol (1 mL) was added, the vial was sealed, and the mixture was shaken at 50°C and 150 r / min for 7 days. The solid was then collected by centrifugation, and the solvent was evaporated to dryness to obtain a solid. The obtained solid was subjected to XRPD detection, and its XRPD pattern was as shown in Figure 10. The obtained solid was crystalline form II of the phosphate salt. The measurement results in Figure 14 indicate that crystalline form I of the phosphate salt can be converted to crystalline form II of the phosphate salt, which is more thermodynamically stable.

[0265] (3) 25 mg of each of phosphate crystalline form I and phosphate crystalline form II was taken, and 5 mg of water was added to each. Then, the mixture was placed in an oven at 80°C for one week, and samples were taken to measure the related substances. The results are shown in Table 14. The results show that phosphate crystalline form I and phosphate crystalline form II have high chemical stability.

[0266] [Table 14]

[0267] Measurement example 3. Hygroscopicity measurement 3.1 Measurement of hygroscopicity of L-tartrate The hygroscopicity was measured according to the procedure of 9103 (Guideline for Hygroscopicity Test of Drugs) in the Chinese Pharmacopoeia (2020), which shows that the L-tartrate salt of compound of formula (I) is slightly hygroscopic.

[0268] 3.2 Determination of hygroscopicity of phosphate crystal forms DVS measurements were performed on crystalline Form I of the phosphate salt of the compound represented by formula (I) and crystalline Form II of the phosphate salt of the compound represented by formula (I). The DVS pattern of crystalline Form I of the phosphate salt is shown in Figure 3. In the DVS pattern of crystalline Form I of the phosphate salt, the weight gain due to moisture absorption was 9% under 80% RH conditions. This indicates that crystalline Form I of the phosphate salt of the compound represented by formula (I) is hygroscopic. In the DVS pattern of crystalline Form II of the phosphate salt, the weight gain due to moisture absorption was only 0.45% under 80% RH conditions. This indicates that crystalline Form II of the phosphate salt is slightly hygroscopic.

[0269] Measurement example 4. Measurement of activity inhibition against CDK family kinases In the following LANCE Ultra measurement method, the kinase reagent was purchased from Carna Bioscience, the reaction substrate and detection reagent were purchased from PerkinElmer, and the remaining reagents were purchased from Thermo scientific.

[0270] The inhibitory effects of the compounds on the kinase activities of CDK1 / CycB (Carna bioscience, #04-102), CDK2 / CycA (Carna bioscience, #04-103), and CDK9 / CycT (Carna bioscience, #04-110) were measured using the LANCE Ultra method.

[0271] Kinase activity measurements were performed using a 10 μL system containing a CDK kinase diluent, a substrate diluent prepared by mixing Ulight-Myelic basic protein (PerkinElmer, #TRF-0109, hereinafter referred to as U-MBP) and ATP (Thermo Scientific, #PV3227), and a compound represented by formula (I) of the present invention (i.e., the target substance). Each kinase in the measurement included three measurement groups: a background group (Blank), a non-inhibited group (PC), and a compound measurement group (Test). The components contained in each measurement group were as shown in Table 15 below.

[0272] [Table 15]

[0273] The working concentrations of each component in the Test group in different kinase reactions were as shown in Table 16.

[0274] Compounds: Dissolve the target compounds at 10 mM at room temperature and perform gradient dilutions with DMSO. Then, dilute the compounds to a 4x compound working solution with deionized water. The DMSO content was 2%. The highest compound concentrations used for CDK1 and CDK2 measurements were 10 μM, and for CDK9, 1 μM.

[0275] 1.33x Reaction Buffer: Constituents are 26.7 mM MOPS, 6.67 mM MgCl2, and 0.0133% Tween-20. After preparation, store in a refrigerator at 4°C protected from light. Before use, add freshly prepared DTT to a final concentration of 5.33 mM.

[0276] [Table 16]

[0277] The working concentration of DMSO in the reaction was 0.5%.

[0278] After mixing the above components, place on a shaker and incubate at room temperature in the dark for 1 hour. After that, 10 μL of detection solution was added to all measurement groups (including the Blank, PC, and Test groups).

[0279] The components contained in 10 μL of detection solution were 16 mM EDTA (Thermo scientific, #15575), 1 nM phosphorylated U-MBP protein antibody (PerkinElmer, #TRF-0201), and 1× detection buffer (PerkinElmer, #CR97-100).

[0280] After adding the detection solution, the plate was placed on a shaker and incubated for 1 hour at room temperature in the dark. After incubation, the signal was read using a PerkinElmer VictorX5 fluorescence microplate reader. The excitation wavelength was 320 nm, and the emission wavelengths were 615 nm and 665 nm. The inhibition rate was calculated as follows:

[0281] 1. The 665nm / 615nm values (hereinafter referred to as ratio values) were calculated for all groups, and the inhibition rate was calculated using the ratio values of each group. 2. Inhibition rate = (PC Ratio -Test Ratio ) / (PC Ratio -Blank Ratio) *100%. 3. Fitting was performed using XLFIT5.0 software (IDBS, UK). The logarithm of the compound concentration was plotted on the X-axis and the inhibition rate on the Y-axis, and the half inhibitory concentration (IC) of the compound was calculated using a four-parameter model. 50 The results are shown in Table 17.

[0282] [Table 17]

[0283] As can be seen from the results in Table 17, the compounds of the present invention represented by formula (I) have high inhibitory activity against CDK9 and high selectivity for CDK9 inhibition.

[0284] Measurement Example 5: Measurement of in vivo pharmacokinetics in mice Using LC / MS / MS, the plasma drug concentrations at different time points after intravenous and intragastric administration of Compound D, Compound E, and the compound represented by formula (I) to mice were measured to study the in vivo pharmacokinetic behavior of Compound D, Compound E, and the compound represented by formula (I) in mice and evaluate their pharmacokinetic characteristics.

[0285] Experimental proposal: Animals: Healthy adult male ICR mice (12 mice, weighing 30-40g) provided by Beijing Vital River Laboratory Animal Co., Ltd. The mice in the intravenous injection group were allowed to drink water and food ad libitum, while the mice in the intragastric administration group were fasted overnight and then allowed to drink water and food ad libitum 4 hours after administration.

[0286] Administration route and dose: ICR mice intravenously (2 mg / kg, 5% DMSO, pH 4.5 20% Captisol) and intragastrically (10 mg / kg, 5% DMSO, pH 4.5 20% Captisol).

[0287] Blood sample collection: Animals meeting the experimental requirements were selected, weighed, and marked before administration. Before blood samples were collected, mice were restrained. Approximately 100 μL of blood was collected from each administered mouse via the orbit at designated time points (intravenous administration: 0.083, 0.25, 0.5, 1, 2, 4, 6, 7.5, and 24 h post-administration, for a total of nine time points; intragastric administration: 0.083, 0.25, 0.5, 1, 2, 4, 6, 7.5, and 24 h post-administration, for a total of nine time points). The blood was transferred to a 1.5 mL tube containing pre-added K2EDTA and centrifuged (8000 rpm, 4°C) for 4 minutes to extract the plasma. The entire process was completed within 15 minutes of collection. All samples were stored in a -20°C freezer until analysis. Drug concentrations were measured using an LC / MS / MS method. Table 18 shows the in vivo pharmacokinetic profile parameters of Compound D, Compound E and the compound represented by formula (I) in mice at the same doses and administration methods.

[0288] [Table 18]

[0289] Measurement Example 6: In vivo drug efficacy experiment In vivo efficacy experiments were performed using BALB / c nude mice subcutaneously implanted with xenografts (CDX) based on the human tumor cell line derived from a patient with MV4-11 acute myeloid leukemia.

[0290] Experimental design: BALB / c nude mice, female, 6-10 weeks old, weighing approximately 20-23 g, were raised in a special pathogen-free environment and housed in individually ventilated cages (5 mice per cage, 10 mice in 2 cages per group). All cages, bedding, and water were sterilized before use. All animals were fed a standard certified commercial laboratory diet ad libitum. A total of 80 mice were used in the study. These mice were purchased from the Laboratory Animal Management Department of the Shanghai Institute of Family Planning Science (No. 3577 Jinke Road, Pudong, Shanghai). Tumor cells (1 × 10 7 The mice were subcutaneously implanted with 0.1 ml of PBS containing 0.1 ml of PBS containing 0.1 ml of Matrigel and allowed to grow tumors. When the average tumor volume reached approximately 165 cubic millimeters, they were randomly assigned to groups based on body weight and tumor volume, and treatment was initiated. Test compounds were administered orally by gavage daily. Antitumor efficacy was determined by dividing the average tumor volume of compound-treated animals by the average tumor volume of untreated animals.

[0291] Tumor volume was measured twice weekly using a two-dimensional caliper, and the volume was measured in cubic millimeters. The tumor volume TV was calculated as TV = 0.5a × b 2 where a is the longest diameter of the tumor and b is the shortest diameter of the tumor.

[0292] The relative tumor growth rate (T / C) (%) is the percentage of relative tumor volume (RTV) between the treatment group and the control group at a given time point. The formula is T / C% = T RTV / C RTV ×100%(T RTV is the mean RTV of the treatment group, and C RTV is the mean RTV of the solvent control group, and RTV = V t / V0, where V0 is the tumor volume of the animal at the time of grouping and Vt is the tumor volume of the animal after treatment). mpk refers to milligrams per kilogram of body weight.

[0293] The weight change (%) of tumor-bearing animals was calculated by (weight at time of measurement - weight at time of grouping) / weight at time of grouping x 100.

[0294] Figures showing the changes in tumor volume and body weight of mice after oral administration of compound D and the compound represented by formula (I) once daily are shown in Figure 17 and Figure 18, respectively, and the tumor inhibition results of the compounds in mice are shown in Table 19.

[0295] [Table 19]

[0296] All documents mentioned in this specification are incorporated herein by reference as if each were individually incorporated by reference. It should also be understood that, after reading the above teachings of the present invention, one skilled in the art may make various changes or modifications to the present invention, and that equivalents thereof are included within the scope defined by the claims appended hereto.

[0297] The technical features of the above embodiments can be combined in any way, and for the sake of brevity, not all possible combinations of the technical features in the above embodiments are described, but as long as there is no contradiction in the combination of these technical features, they should be considered within the scope described in this specification.

[0298] The above examples merely illustrate some embodiments of the present invention, and although the descriptions are specific and detailed, they should not be understood as limiting the patent scope of the present invention. It should be noted that a person skilled in the art can make some modifications and improvements without departing from the spirit of the present invention, and all of these fall within the scope of protection of the present disclosure. Therefore, the scope of protection of the present invention should be determined by the appended claims, and the specification and drawings can be used to interpret the content of the claims.

Claims

1. A pharmaceutically acceptable salt of a compound of formula (I): 【Chemistry 10】 The pharmaceutically acceptable salt of the compound of formula (I) is selected from the group consisting of phosphate and L-tartrate.

2. The pharmaceutically acceptable salt is the L-tartrate salt; The pharmaceutically acceptable salt of the compound of formula (I) according to claim 1, wherein in the L-tartrate salt, the molar ratio of L-tartaric acid to the compound of formula (I) (L-tartaric acid:compound of formula (I)) is (0.8-1.2):1, preferably (0.9-1.1):1, and more preferably 1:

1.

3. The pharmaceutically acceptable salt is a phosphate salt, The pharmaceutically acceptable salt of the compound of formula (I) according to claim 1, wherein in the phosphate salt, the molar ratio of phosphoric acid to the compound of formula (I) (phosphoric acid:compound of formula (I)) is (1.8-2.4):1, preferably (1.9-2.3):1, and more preferably 2:

1.

4. The pharmaceutically acceptable salt is a phosphate salt, The pharmaceutically acceptable salt of the compound of formula (I) according to claim 1, wherein in the phosphate salt, the molar ratio of phosphoric acid to the compound of formula (I) (phosphoric acid:compound of formula (I)) is (0.8-1.2):1, preferably 1:

1.

5. the L-tartrate salt is a polymorph; The polymorph is (1) Crystalline Form I of the L-tartrate salt, which has an X-ray powder diffraction pattern having characteristic diffraction peaks at diffraction angle 2θ (°) values of 13.946±0.2, 16.881±0.2, 19.405±0.2, 21.505±0.2, and 24.262±0.2; and (2) Crystalline Form II of the L-tartrate salt, which has an X-ray powder diffraction pattern with characteristic diffraction peaks at diffraction angles 2θ (°) of 11.662±0.2 and 21.353±0.

2.

3. The pharmaceutically acceptable salt of the compound of formula (I) according to claim 2, which is in a crystalline form selected from the group consisting of:

6. the L-tartrate salt is a polymorph; The polymorph is (1) Crystalline Form I of the L-tartrate salt, which has an X-ray powder diffraction pattern having characteristic diffraction peaks at diffraction angle 2θ (°) values of 7.436±0.2, 13.946±0.2, 16.013±0.2, 16.881±0.2, 18.175±0.2, 19.045±0.2, 19.405±0.2, 21.505±0.2, 24.262±0.2, 25.202±0.2, 26.452±0.2, 28.105±0.2, and 31.579±0.2; and (2) Crystalline Form II of the L-tartrate salt, which has an X-ray powder diffraction pattern having characteristic diffraction peaks at diffraction angles 2θ (°) of 11.662±0.2, 14.244±0.2, 17.481±0.2, 18.349±0.2, 21.026±0.2, and 21.353±0.

2.

3. The pharmaceutically acceptable salt of the compound of formula (I) according to claim 2, which is in a crystalline form selected from the group consisting of:

7. the L-tartrate salt is a polymorph; The polymorph is (1) X-ray powder diffraction patterns of 6.687±0.2, 7.436±0.2, 10.615±0.2, 12.053±0.2, 13.164±0.2, 13.946±0.2, 14.875±0.2, 15.201±0.2, 16.013±0.2, 16.881±0.2, 18.175±0.2, 19.045±0.2, 19.405±0.2, 2 Crystalline Form I of the L-tartrate salt having characteristic peaks at diffraction angle 2θ (°) values of 0.659±0.2, 21.505±0.2, 22.434±0.2, 23.04±0.2, 24.262±0.2, 25.202±0.2, 26.452±0.2, 28.105±0.2, 29.692±0.2, 34.139±0.2 and 34.543±0.2, and (2) Crystalline Form II of the L-tartrate salt, having an X-ray powder diffraction pattern with characteristic peaks at diffraction angle 2θ (°) values of 10.376±0.2, 11.662±0.2, 14.244±0.2, 16.548±0.2, 17.481±0.2, 18.349±0.2, 18.984±0.2, 21.026±0.2, 21.353±0.2, 26.925±0.2, 29.335±0.2, and 31.784±0.

2.

3. The pharmaceutically acceptable salt of the compound of formula (I) according to claim 2, which is in a crystalline form selected from the group consisting of:

8. the L-tartrate salt is a polymorph; The polymorph is (1) Crystalline Form I of the L-tartrate salt, having an X-ray powder diffraction (XRPD) pattern essentially as shown in FIG. 5; and (2) Crystalline Form II of the L-tartrate Salt, having an X-ray powder diffraction (XRPD) pattern essentially as shown in FIG.

7.

3. The pharmaceutically acceptable salt of the compound of formula (I) according to claim 2, which is in a crystalline form selected from the group consisting of:

9. 6. The pharmaceutically acceptable salt of the compound of formula (I) according to claim 5, wherein the crystalline form I of the L-tartrate salt has a thermogravimetric analysis (TGA) pattern essentially as shown in FIG.

10. 3. The pharmaceutically acceptable salt of the compound of formula (I) according to claim 2, wherein the L-tartrate salt is in an amorphous form.

11. 4. The pharmaceutically acceptable salt of the compound of formula (I) according to claim 3, wherein the phosphate is crystalline form I of the phosphate, whose X-ray powder diffraction pattern has characteristic diffraction peaks at diffraction angle 2θ (°) values of 18.234±0.2, 19.131±0.2, and 21.266±0.

2.

12. 4. The pharmaceutically acceptable salt of the compound of formula (I) according to claim 3, wherein the phosphate is crystalline form I of the phosphate, which has an X-ray powder diffraction pattern having characteristic diffraction peaks at diffraction angle 2θ (°) values of 13.999±0.2, 18.234±0.2, 18.803±0.2, 19.131±0.2, 21.266±0.2, 22.01±0.2 and 23.247±0.

2.

13. 4. The pharmaceutically acceptable salt of the compound of Formula (I) of claim 3, wherein the phosphate salt is crystalline Form I of the phosphate salt having an X-ray powder diffraction (XRPD) pattern essentially as shown in Figure 1.

14. The crystalline form I of the phosphate salt is having a differential scanning calorimetry (DSC) pattern essentially as shown in Figure 2; having a thermogravimetric analysis (TGA) pattern essentially as shown in FIG. 2; and Having a dynamic moisture sorption (DVS) pattern essentially as shown in FIG.

12. A pharmaceutically acceptable salt of a compound of formula (I) according to claim 11, having one or more characteristics selected from the group consisting of:

15. 5. The pharmaceutically acceptable salt of the compound of formula (I) according to claim 4, wherein the phosphate is crystalline form II of the phosphate, whose X-ray powder diffraction pattern has characteristic diffraction peaks at diffraction angle 2θ (°) values of 18.230±0.2 and 21.144±0.

2.

16. 5. The pharmaceutically acceptable salt of the compound of formula (I) according to claim 4, wherein the phosphate is crystalline form II of the phosphate, which has an X-ray powder diffraction pattern having characteristic diffraction peaks at diffraction angle 2θ (°) values of 10.584±0.2, 13.969±0.2, 14.873±0.2, 18.230±0.2, 20.576±0.2, 21.144±0.2, 22.01±0.2, 22.492±0.2, 23.153±0.2 and 23.96±0.

2.

17. 5. The pharmaceutically acceptable salt of the compound of Formula (I) of claim 4, wherein the phosphate salt is crystalline Form II of the phosphate salt having an X-ray powder diffraction (XRPD) pattern essentially as shown in Figure 10.

18. The crystalline form II of the phosphate salt is having a melting temperature of 207.48±0.5°C; having a differential scanning calorimetry (DSC) curve essentially as shown in Figure 11; having a thermogravimetric analysis (TGA) curve essentially as shown in FIG. 11; and Having a dynamic moisture sorption (DVS) pattern essentially as shown in FIG. A pharmaceutically acceptable salt of a compound of formula (I) according to any one of claims 15 to 17, having one or more characteristics selected from the group consisting of:

19. 18. The pharmaceutically acceptable salt of the compound of formula (I) according to any one of claims 15 to 17, wherein the crystalline form II of the phosphate salt is anhydrous.

20. 1. A process for preparing the L-tartrate salt of compound of formula (I), comprising the steps of: A method for preparing the L-tartrate salt of the compound represented by formula (I), comprising the step of reacting the compound represented by formula (I) with L-tartaric acid to form the L-tartrate salt of the compound represented by formula (I).

21. 1. A process for preparing crystalline Form I of the L-tartrate salt of compound of formula (I), comprising the steps of: a salt-forming reaction between the compound of formula (I) and L-tartaric acid in an organic solvent to form a reaction solution; and gradually lowering the temperature of the reaction solution to obtain crystalline Form I of the L-tartrate salt; The method for preparing crystalline Form I of the L-tartrate salt of the compound of formula (I), wherein the organic solvent is one or more selected from the group consisting of ethanol, acetonitrile, ethyl acetate, acetone, and methanol.

22. A process for preparing crystalline Form II of the L-tartrate salt of compound of formula (I), comprising the steps of: a salt-forming reaction between the compound of formula (I) and L-tartaric acid in an organic solvent to form a reaction solution; gradually lowering the temperature of the reaction solution and adding an anti-solvent to obtain crystalline Form II of the L-tartrate salt; the organic solvent is one or more selected from the group consisting of ethanol, acetonitrile, ethyl acetate, acetone, and methanol; The method for preparing crystalline Form II of the L-tartrate salt of compound of formula (I), wherein the anti-solvent is one or more selected from the group consisting of methyl tert-butyl ether, petroleum ether, n-heptane, n-hexane, cyclohexane, isopropanol, acetone, acetonitrile, and ethyl acetate, and the anti-solvent is different from the organic solvent.

23. 23. The method for preparing crystalline Form II of the L-tartrate salt of compound of formula (I) according to claim 22, wherein the anti-solvent is one or more selected from the group consisting of methyl tert-butyl ether, n-heptane, isopropanol, and acetone, and the anti-solvent is different from the organic solvent.

24. 5. A method for preparing the phosphate salt of the compound represented by formula (I) according to claim 3 or 4, comprising the step of reacting the compound represented by formula (I) with phosphoric acid in the presence of an organic solvent to form the phosphate salt of the compound represented by formula (I).

25. 25. The method for preparing the phosphate salt of the compound represented by formula (I) according to claim 24, wherein the molar ratio of the compound represented by formula (I) to phosphoric acid (compound represented by formula (I) : phosphoric acid) in the formed phosphate salt of the compound represented by formula (I) is 1:1 or 1:

2.

26. 25. The method for preparing the phosphate salt of the compound of formula (I) according to claim 24, wherein the organic solvent is one or more selected from the group consisting of ethanol, ethyl acetate, acetonitrile and acetone.

27. 25. The process for preparing the phosphate salt of compound of formula (I) according to claim 24, wherein the organic solvent is methanol.

28. 1. A process for preparing crystalline Form II of the phosphate salt of compound of formula (I), comprising the steps of: a step of reacting the compound represented by formula (I) with phosphoric acid in an organic solvent to form a salt, thereby precipitating a solid; collecting the solid to obtain crystalline Form II of the Phosphate Salt; The molar ratio of the compound represented by formula (I) to phosphoric acid (compound represented by formula (I):phosphoric acid) is 1:(0.8 to 1.2), The method for preparing crystalline Form II of the phosphate salt of the compound of formula (I), wherein the organic solvent is one or more selected from the group consisting of ethanol, methanol, and acetone, preferably the organic solvent is one or two selected from the group consisting of ethanol and acetone, preferably the organic solvent is methanol.

29. 29. The method for preparing crystalline Form II of the phosphate salt of compound of formula (I) according to claim 28, wherein the organic solvent is ethanol.

30. The method for preparing crystalline form II of the phosphate salt of the compound represented by formula (I) comprises the steps of: a step of reacting an ethanol solution of the compound represented by formula (I) with an ethanol solution of phosphoric acid to form a salt, thereby precipitating a solid; collecting the solid to obtain crystalline Form II of the Phosphate Salt; 30. The method for preparing crystalline form II of the phosphate salt of the compound of formula (I) according to claim 29, wherein the molar ratio of the compound of formula (I) to phosphoric acid (compound of formula (I):phosphoric acid) is 1:(0.8 to 1.2).

31. 1. A process for preparing crystalline Form I of the phosphate salt of compound of formula (I), comprising the steps of: a step (AI-a) of dissolving the compound represented by formula (I) in a solvent, adding an aqueous phosphoric acid solution, and stirring to cause a reaction; and step (AI-b) of cooling the reaction solution obtained in step (AI-a), adding a poor solvent to cause crystallization, performing solid-liquid separation, and collecting the solid phase to obtain crystalline form I of phosphate of the compound represented by formula (I).

32. A pharmaceutical composition comprising: (a) a pharmaceutically acceptable salt of a compound of formula (I) according to any one of claims 1 to 19; and (b) a pharmaceutically acceptable carrier.

33. Use of a pharmaceutically acceptable salt of a compound of formula (I) according to any one of claims 1 to 19, or a pharmaceutical composition according to claim 32, in the preparation of a medicament for the prevention or treatment of a disease associated with or mediated by CDK9 activity.

34. 34. The use according to claim 33, wherein the disease is one or more selected from the group consisting of hyperproliferative diseases, virally induced infectious diseases and cardiovascular diseases.

35. A method for treating a disease associated with CDK9 activity or a disease mediated by CDK9 activity, the method comprising administering to a subject an effective amount of a pharmaceutically acceptable salt of a compound represented by formula (I) according to any one of claims 1 to 19, or a pharmaceutical composition according to claim 32.

36. A pharmaceutically acceptable salt of the compound of formula (I) according to any one of claims 1 to 19, or the pharmaceutical composition according to claim 32, for preventing or treating a disease associated with or mediated by CDK9 activity.

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