Salts of 3,4-dihydroisoquinoline compounds and their applications

Abstract

The present invention provides a salt of the compound represented by formula (A), its solid form, crystalline form, pharmaceutical composition containing the same, and its use and preparation method. Compared with the compound of formula (A), the salt of the compound represented by formula (A) has higher solubility in water and biological solvent medium, is easily prepared and obtained in solid form, is easy to transfer and weigh, and has good application prospects. [Formula 1] TIFF2024546112000041.tif25170

Description

Technical Field

[0001] The present invention claims the priority of Chinese Patent Application No. 202111494667.8 with an application date of December 8, 2021. The present invention incorporates the entire text of the above Chinese patent application by reference.

[0002] The present invention belongs to the field of pharmaceutical technology, and relates to salts of 3,4-dihydroisoquinoline compounds, their crystal forms and specific crystal forms, pharmaceutical compositions containing the same, and their applications in the pharmaceutical field.

Background Art

[0003] Protein arginine methyltransferases (PRMTs) are S-adenosylmethionine (SAM or AdoMet)-dependent methyltransferases that can catalyze protein arginine methylation reactions. Specifically, they are responsible for transferring a methyl group derived from AdoMet to the guanidino nitrogen atom at the end of the arginine residue of histone or other proteins. PRMTs play an important role in protein methylation, for example, they are involved in alternative splicing, post-transcriptional regulation, RNA processing, cell proliferation, cell differentiation, apoptosis, and tumor formation. By various methods of catalyzing arginine methylation, members of the PRMT family can be classified into three types. PRMT1-4, PRMT6, and PRMT8 belong to type I and catalyze monomethylation and asymmetric dimethylation, while PRMT5 and PRMT9 belong to type II and catalyze symmetric dimethylation, and PRMT7 belongs to type III and catalyzes monomethylation.

[0004] Since PRMT5 was first isolated from a protein complex that binds to Jak2 (Janus tyrosine kinase 2) in a yeast two-hybrid study by Pollack et al., it is also called JBP1 (jak-binding protein 1). PRMT5 can not only regulate the processes of gene transcription and protein modification, but also play a role in regulating cell proliferation, differentiation, and apoptosis in the growth of tumor cells, and is an extremely potential target for tumor treatment. So far, all research and development of PRMT5 inhibitors are in the initial stage, and the most advanced one is GSK3326595 announced by GSK, which has entered phase I / II clinical trials. JNJ-64619178 first announced by Janssen, PF-06939999 announced by Pfizer, and PRT-543 announced by Prelude Therapeutics are all in the phase I clinical trial stage. Currently, the structural formulas of PF-06939999 and PRT-543 have not been made public yet. The structural formulas of GSK3326595 and JNJ-64619178 are as follows.

Chemical formula

[0005] Currently, since the sale of PRMT5 inhibitors has not been approved yet, the design and synthesis of new PRMT5 inhibitors that balance good therapeutic effects and good administrability have important clinical application values.

Summary of the Invention

[0006] According to a first aspect, the present invention provides a salt of a compound represented by formula (A) which is an inorganic acid addition salt or an organic acid addition salt.

Chemical formula

[0007] According to some embodiments of the present invention, the inorganic acid addition salt is a sulfate or a phosphate.

[0008] According to some embodiments of the present invention, the organic acid addition salt is selected from malate, oxalate, succinate, tartrate, adipate, citrate, gluconate, maleate, fumarate, lactate and gentisate, preferably malate, oxalate, succinate, L-tartrate, L-lactate, adipate, citrate or gluconate, preferably malate, oxalate, succinate, L-tartrate, adipate, citrate or gluconate, more preferably malate, oxalate, citrate or gluconate, even more preferably malate or oxalate, and even more preferably L-malate or oxalate.

[0009] According to some embodiments of the present invention, in the salt of the compound represented by the formula (A), the chemical compounding ratio of the compound represented by the formula (A) and the organic acid or inorganic acid molecule is 1:0.5 to 2, preferably 1:1 to 1.5, more preferably 1:1, 1:1.1, 1:1.2, 1:1.3, 1:1.4 or 1:1.5, more preferably 1:1, 1:1.3, 1:1.4 or 1:1.5, more preferably 1:1 or 1:1.5, and even more preferably 1:1.

[0010] According to some embodiments of the present invention, the salt of the compound represented by the formula (A) is a compound represented by the formula (A-1). [Chemical formula]

[0011] (Here, X is an inorganic acid or an organic acid, n is selected from 0.5 to 2, preferably 1 to 1.5, more preferably 1, 1.1, 1.2, 1.3, 1.4 or 1.5, more preferably 1, 1.3, 1.4 or 1.5, more preferably 1:1 or 1:1.5, and even more preferably 1.) According to some embodiments of the present invention, X is an inorganic acid and is selected from sulfuric acid and phosphoric acid.

[0012] According to some embodiments of the present invention, X is an organic acid selected from malic acid, oxalic acid, succinic acid, tartaric acid, adipic acid, citric acid, gluconic acid, maleic acid, fumaric acid, lactic acid, and gentisic acid, preferably malic acid, oxalic acid, succinic acid, L-tartaric acid, L-lactic acid, adipic acid, citric acid, or gluconic acid, more preferably malic acid, oxalic acid, succinic acid, L-tartaric acid, adipic acid, citric acid, or gluconic acid, still more preferably malic acid, oxalic acid, citric acid, or gluconic acid, even more preferably malic acid or oxalic acid, and even more preferably L-malic acid or oxalic acid.

[0013] According to some embodiments of the present invention, the salt of the compound represented by the formula (A) or the compound represented by the formula (A-1) is in a solid form.

[0014] According to some embodiments of the present invention, the salt of the compound represented by the formula (A) in the solid form or the compound represented by the formula (A-1) is in a crystalline form.

[0015] According to some embodiments of the present invention, the compound represented by the formula (A-1) is the compound represented by the formula (B).

Chemical formula

[0016] According to some embodiments of the present invention, the compound represented by the formula (B) is in a solid form.

[0017] According to some embodiments of the present invention, the infrared spectrum of the compound represented by the formula (B) in the solid form using the KBr tablet method has characteristic peaks at the following positions (±4 cm -1 ): 3301, 2940, 1611, 1528, 1456, 1368, 1045.

[0018] According to some embodiments of the present invention, the compound represented by the formula (B) in the solid form is in a crystalline form.

[0019] According to some embodiments of the present invention, the compound represented by the formula (B) is a compound represented by the formula (B-1).

Chemical formula

[0020] According to some embodiments of the present invention, the compound represented by the formula (B-1) is in a solid form.

[0021] According to some embodiments of the present invention, the compound represented by the formula (B-1) in the solid form is in a crystalline form.

[0022] According to some embodiments of the present invention, the compound represented by the formula (B) in the crystalline form is Crystal Form I, and has diffraction peaks characteristic of the following 2θ angles (±0.2°) in the X-ray powder diffraction pattern using Cu-Kα rays: 4.2, 6.5, 13.3, 19.1.

[0023] According to some embodiments of the present invention, the Crystal Form I has diffraction peaks characteristic of the following 2θ angles (±0.2°) in the X-ray powder diffraction pattern using Cu-Kα rays: 4.2, 6.5, 13.3, 19.1, 20.1, 22.0.

[0024] According to some embodiments of the present invention, the Crystal Form I has diffraction peaks characteristic of the following 2θ angles (±0.2°) in the X-ray powder diffraction pattern using Cu-Kα rays: 4.2, 6.5, 13.3, 18.3, 19.1, 20.1, 22.0.

[0025] According to some embodiments of the present invention, when using Cu-Kα rays, the Crystal Form I basically has the X-ray powder diffraction pattern shown in FIG. 1.

[0026] According to some embodiments of the present invention, the crystalline form I has an endothermic peak at 113 ± 5 °C in the differential scanning calorimetry curve.

[0027] According to some embodiments of the present invention, the crystalline form I has endothermic peaks at 102.15 ± 5 °C and 113 ± 5 °C in the differential scanning calorimetry curve.

[0028] According to some embodiments of the present invention, the crystalline form I has a weight loss of 8.6522% ± 0.2% between room temperature and 110 ± 5 °C in the thermogravimetric analysis curve.

[0029] According to some embodiments of the present invention, the compound represented by the formula (B) of the crystalline form is crystalline form II, and the X-ray powder diffraction pattern by Cu-Kα line has characteristic diffraction peaks at the following 2θ angles (±0.2°): 4.9, 6.6, 13.2, 18.7, 19.8.

[0030] According to some embodiments of the present invention, the crystalline form II has characteristic diffraction peaks at the following 2θ angles (±0.2°): 4.9, 6.6, 13.2, 18.7, 19.8, 22.1, 26.5 in the X-ray powder diffraction pattern by Cu-Kα line.

[0031] According to some embodiments of the present invention, the crystalline form II has characteristic diffraction peaks at the following 2θ angles (±0.2°): 4.9, 6.6, 13.2, 18.7, 19.8, 22.1, 23.3, 26.5 in the X-ray powder diffraction pattern by Cu-Kα line.

[0032] According to some embodiments of the present invention, the crystalline form II has characteristic diffraction peaks at the following 2θ angles (±0.2°): 4.9, 6.6, 13.2, 18.7, 19.8, 20.3, 22.1, 23.3, 26.5 in the X-ray powder diffraction pattern by Cu-Kα line.

[0033] According to some embodiments of the present invention, the crystalline form II has diffraction peaks characteristic of the following 2θ angles (±0.2°) in the X-ray powder diffraction pattern using Cu-Kα radiation: 4.9, 6.6, 12.3, 13.2, 18.7, 19.8, 20.3, 22.1, 23.3, 24.0, 26.5.

[0034] According to some embodiments of the present invention, the crystalline form II has diffraction peaks characteristic of the following 2θ angles (±0.2°) in the X-ray powder diffraction pattern using Cu-Kα radiation: 4.9, 6.6, 12.3, 13.2, 18.7, 19.8, 20.3, 22.1, 23.3, 24.0, 26.5, 28.8.

[0035] According to some embodiments of the present invention, when using Cu-Kα radiation, the crystalline form II basically has the X-ray powder diffraction pattern shown in Figure 2.

[0036] According to some embodiments of the present invention, the crystalline form II has an endothermic peak at 103.58 ± 5 °C in the differential scanning calorimetry curve.

[0037] According to some embodiments of the present invention, the crystalline form II has endothermic peaks at 89.8 ± 5 °C and 103.58 ± 5 °C in the differential scanning calorimetry curve.

[0038] According to some embodiments of the present invention, the crystalline form II has a weight loss of 2.6358% ± 0.2% between room temperature and 80 ± 5 °C in the thermogravimetric analysis curve.

[0039] According to some embodiments of the present invention, the compound represented by the formula (B) of the crystalline form is crystalline form III, and has diffraction peaks characteristic of the following 2θ angles (±0.2°) in the X-ray powder diffraction pattern using Cu-Kα radiation: 4.3, 6.9, 20.3.

[0040] According to some embodiments of the present invention, the crystalline form III has diffraction peaks characteristic of the following 2θ angles (±0.2°) in the X-ray powder diffraction pattern using Cu-Kα radiation: 4.3, 6.9, 8.8, 20.3, 21.2.

[0041] According to some embodiments of the present invention, the crystalline form III has diffraction peaks characteristic of the following 2θ angles (±0.2°) in the X-ray powder diffraction pattern by Cu-Kα rays: 4.3, 6.9, 8.8, 12.8, 13.3, 20.3, 21.2.

[0042] According to some embodiments of the present invention, the crystalline form III has diffraction peaks characteristic of the following 2θ angles (±0.2°) in the X-ray powder diffraction pattern by Cu-Kα rays: 4.3, 6.9, 8.8, 12.8, 13.3, 14.0, 15.9, 20.3, 21.2.

[0043] According to some embodiments of the present invention, when using Cu-Kα rays, the crystalline form III basically has the X-ray powder diffraction pattern shown in FIG. 3.

[0044] According to some embodiments of the present invention, the crystalline form III has an endothermic peak at 117.93 ± 5°C in the differential scanning calorimetry curve.

[0045] According to some embodiments of the present invention, the crystalline form III has endothermic peaks at 70.82 ± 5°C and 117.93 ± 5°C in the differential scanning calorimetry curve.

[0046] According to some embodiments of the present invention, the crystalline form III has a weight loss of 3.0001% ± 0.2% between room temperature and 75 ± 5°C in the thermogravimetric analysis curve.

[0047] According to some embodiments of the present invention, the compound represented by the formula (B) of the crystalline form is crystalline form IV and has diffraction peaks characteristic of the following 2θ angles (±0.2°) in the X-ray powder diffraction pattern by Cu-Kα rays: 4.4, 7.6, 8.9, 13.9, 20.6.

[0048] According to some embodiments of the present invention, the crystalline form IV has diffraction peaks characteristic of the following 2θ angles (±0.2°) in the X-ray powder diffraction pattern using Cu-Kα rays: 4.4, 7.6, 8.9, 12.1, 13.9, 15.2, 20.6.

[0049] According to some embodiments of the present invention, the crystalline form IV has diffraction peaks characteristic of the following 2θ angles (±0.2°) in the X-ray powder diffraction pattern using Cu-Kα rays: 4.4, 7.6, 8.9, 12.1, 13.9, 15.2, 17.8, 18.5, 20.6.

[0050] According to some embodiments of the present invention, the crystalline form IV has diffraction peaks characteristic of the following 2θ angles (±0.2°) in the X-ray powder diffraction pattern using Cu-Kα rays: 4.4, 7.6, 8.9, 12.1, 13.9, 15.2, 17.1, 17.8, 18.5, 20.6.

[0051] According to some embodiments of the present invention, when using Cu-Kα rays, the crystalline form IV basically has the X-ray powder diffraction pattern shown in FIG. 4.

[0052] According to some embodiments of the present invention, the crystalline form IV has an endothermic peak at 113.27 ± 5°C in the differential scanning calorimetry curve.

[0053] According to some embodiments of the present invention, the crystalline form IV has endothermic peaks at 77.91 ± 5°C and 113.27 ± 5°C in the differential scanning calorimetry curve.

[0054] According to some embodiments of the present invention, the crystalline form IV has a weight loss of 2.6271% ± 0.2% between room temperature and 60 ± 5°C in the thermogravimetric analysis curve.

[0055] According to some embodiments of the present invention, the compound represented by the formula (B) of the crystalline form is crystalline form V, and has diffraction peaks characteristic of the following 2θ angles (±0.2°) in the X-ray powder diffraction pattern using Cu-Kα rays: 5.0, 13.6, 18.6, 19.6, 20.2.

[0056] According to some embodiments of the present invention, the crystal form V has diffraction peaks characteristic of the following 2θ angles (±0.2°) in the X-ray powder diffraction pattern using Cu-Kα rays: 5.0, 6.8, 13.1, 13.6, 18.6, 19.6, 20.2.

[0057] According to some embodiments of the present invention, the crystal form V has diffraction peaks characteristic of the following 2θ angles (±0.2°) in the X-ray powder diffraction pattern using Cu-Kα rays: 5.0, 6.8, 13.1, 13.6, 16.7, 18.6, 19.6, 20.2, 24.3.

[0058] According to some embodiments of the present invention, the crystal form V has diffraction peaks characteristic of the following 2θ angles (±0.2°) in the X-ray powder diffraction pattern using Cu-Kα rays: 5.0, 6.8, 13.1, 13.6, 16.7, 18.6, 19.6, 20.2, 23.2, 24.3, 25.0.

[0059] According to some embodiments of the present invention, the crystal form V has diffraction peaks characteristic of the following 2θ angles (±0.2°) in the X-ray powder diffraction pattern using Cu-Kα rays: 5.0, 6.8, 13.1, 13.6, 16.7, 18.6, 19.6, 20.2, 23.2, 24.3, 25.0, 28.6.

[0060] According to some embodiments of the present invention, when using Cu-Kα rays, the crystal form V basically has the X-ray powder diffraction pattern shown in FIG. 5.

[0061] According to some embodiments of the present invention, the crystal form V has an endothermic peak at 104.69 ± 5°C in the differential scanning calorimetry curve.

[0062] According to some embodiments of the present invention, the crystal form V has endothermic peaks at 68.38 ± 5°C and 104.69 ± 5°C in the differential scanning calorimetry curve.

[0063] According to some embodiments of the present invention, the crystalline form V has a thermogravimetric analysis curve with a weight loss of 3.6041% ± 0.2% between room temperature and 75 ± 5°C.

[0064] According to some embodiments of the present invention, the compound represented by the formula (B) of the crystalline form is crystalline form VI, and the X-ray powder diffraction pattern by Cu-Kα line has diffraction peaks characteristic of the following 2θ angles (±0.2°): 4.5, 7.0, 9.0, 12.9, 20.2, 21.6.

[0065] According to some embodiments of the present invention, the crystalline form VI has diffraction peaks characteristic of the following 2θ angles (±0.2°) in the X-ray powder diffraction pattern by Cu-Kα line: 4.5, 7.0, 9.0, 12.9, 13.3, 15.8, 20.2, 21.6.

[0066] According to some embodiments of the present invention, the crystalline form VI has diffraction peaks characteristic of the following 2θ angles (±0.2°) in the X-ray powder diffraction pattern by Cu-Kα line: 4.5, 7.0, 9.0, 12.9, 13.3, 13.9, 15.8, 20.2, 21.6.

[0067] According to some embodiments of the present invention, the crystalline form VI has diffraction peaks characteristic of the following 2θ angles (±0.2°) in the X-ray powder diffraction pattern by Cu-Kα line: 4.5, 7.0, 9.0, 12.9, 13.3, 13.9, 15.8, 16.9, 20.2, 21.6, 25.4.

[0068] According to some embodiments of the present invention, when using Cu-Kα line, the crystalline form VI basically has the X-ray powder diffraction pattern shown in FIG. 6.

[0069] According to some embodiments of the present invention, the crystalline form VI has an endothermic peak at 113.29 ± 5°C in the differential scanning calorimetry curve.

[0070] According to some embodiments of the present invention, the crystal form VI has a weight loss of 0.34% ± 0.2% between room temperature and 120 ± 5 °C in the thermogravimetric analysis curve.

[0071] According to some embodiments of the present invention, the compound represented by the formula (B) of the crystal form is crystal form VII, and the X-ray powder diffraction pattern by Cu-Kα line has diffraction peaks characteristic of the following 2θ angles (±0.2°): 4.3, 6.9, 13.2, 19.1, 20.0.

[0072] According to some embodiments of the present invention, the crystal form VII has diffraction peaks characteristic of the following 2θ angles (±0.2°) in the X-ray powder diffraction pattern by Cu-Kα line: 4.3, 6.9, 8.9, 13.2, 19.1, 20.0, 21.7.

[0073] According to some embodiments of the present invention, the crystal form VII has diffraction peaks characteristic of the following 2θ angles (±0.2°) in the X-ray powder diffraction pattern by Cu-Kα line: 4.3, 6.9, 8.9, 13.2, 15.1, 19.1, 20.0, 21.1, 21.7.

[0074] According to some embodiments of the present invention, when using Cu-Kα line, the crystal form VII basically has the X-ray powder diffraction pattern shown in FIG. 7.

[0075] According to some embodiments of the present invention, the crystal form VII has an endothermic peak at 197.3 ± 5 °C in the differential scanning calorimetry curve.

[0076] According to some embodiments of the present invention, the crystal form VII has endothermic peaks at 92.4 ± 5 °C and 197.3 ± 5 °C in the differential scanning calorimetry curve.

[0077] According to some embodiments of the present invention, the crystal form VII has a weight loss of 7.88% ± 0.2% between room temperature and 110 ± 5 °C in the thermogravimetric analysis curve.

[0078] According to some embodiments of the present invention, the compound represented by the formula (A-1) is a compound represented by the formula (C). [Chemical formula] (Here, n is selected from 0.5 to 2, preferably 1 to 1.5, more preferably 1, 1.1, 1.2, 1.3, 1.4 or 1.5, and even more preferably 1 or 1.5.)

[0079] According to some embodiments of the present invention, the compound represented by the formula (C) is in a solid form.

[0080] According to some embodiments of the present invention, the infrared spectrum of the compound represented by the formula (C) in the solid form using the KBr tablet method is at the following positions (±4 cm -1 ): It includes characteristic peaks at 3320, 2937, 1615, 1526, 1456, 1368, 1047.

[0081] According to some embodiments of the present invention, the compound represented by the formula (C) in the solid form is in a crystalline form.

[0082] According to some embodiments of the present invention, the compound represented by the formula (C) is a compound represented by the formula (C-1) or the formula (C-2). [Chemical formula]

[0083] According to some embodiments of the present invention, the compound represented by the formula (C-1) or the compound represented by the formula (C-2) is in a solid form.

[0084] According to some embodiments of the present invention, the compound represented by the formula (C-1) and the compound represented by the formula (C-2) in the solid form are in a crystalline form.

[0085] According to some embodiments of the present invention, the compound represented by the formula (C) in the crystal form is crystal form I, and the X-ray powder diffraction pattern by Cu-Kα ray has diffraction peaks characteristic of the following 2θ angles (±0.2°): 4.7, 7.1, 10.7, 17.4, 21.2.

[0086] According to some embodiments of the present invention, the compound represented by the formula (C) in the crystal form is crystal form I, and the X-ray powder diffraction pattern by Cu-Kα ray has diffraction peaks characteristic of the following 2θ angles (±0.2°): 4.7, 7.1, 10.7, 16.1, 17.4, 20.1, 21.2.

[0087] According to some embodiments of the present invention, the compound represented by the formula (C) in the crystal form is crystal form I, and the X-ray powder diffraction pattern by Cu-Kα ray has diffraction peaks characteristic of the following 2θ angles (±0.2°): 4.7, 7.1, 10.7, 16.1, 17.4, 19.6, 20.1, 21.2, 23.2.

[0088] According to some embodiments of the present invention, the compound represented by the formula (C) in the crystal form is crystal form I, and when using Cu-Kα ray, it basically has the X-ray powder diffraction pattern shown in FIG. 8.

[0089] According to some embodiments of the present invention, the compound represented by the formula (C) in the crystal form is crystal form II, and the X-ray powder diffraction pattern by Cu-Kα ray has diffraction peaks characteristic of the following 2θ angles (±0.2°): 4.6, 13.0, 21.6.

[0090] According to some embodiments of the present invention, the compound represented by the formula (C) in the crystal form is crystal form II, and the X-ray powder diffraction pattern by Cu-Kα ray has diffraction peaks characteristic of the following 2θ angles (±0.2°): 4.6, 13.0, 21.6, 24.5, 25.0.

[0091] According to some embodiments of the present invention, the compound represented by the formula (C) in the crystal form is crystal form II, and the X-ray powder diffraction pattern by Cu-Kα line has diffraction peaks characteristic of the following 2θ angles (±0.2°): 4.6, 4.8, 13.0, 18.4, 19.4, 21.6, 24.5, 25.0.

[0092] According to some embodiments of the present invention, the compound represented by the formula (C) in the crystal form is crystal form II, and when using Cu-Kα line, it basically has the X-ray powder diffraction pattern shown in FIG. 9.

[0093] According to some embodiments of the present invention, the compound represented by the formula (C) in the crystal form is crystal form II, and its differential scanning calorimetry curve has an endothermic peak at 162.6 ± 5 °C.

[0094] According to some embodiments of the present invention, the compound represented by the formula (C) in the crystal form is crystal form II, and its thermogravimetric analysis curve has a weight loss of 3.2% ± 0.2% between room temperature and 160 ± 5 °C.

[0095] According to some embodiments of the present invention, the compound represented by the formula (C) in the crystal form is crystal form III, and the X-ray powder diffraction pattern by Cu-Kα line has diffraction peaks characteristic of the following 2θ angles (±0.2°): 4.6, 18.7, 19.4.

[0096] According to some embodiments of the present invention, the compound represented by the formula (C) in the crystal form is crystal form III, and the X-ray powder diffraction pattern by Cu-Kα line has diffraction peaks characteristic of the following 2θ angles (±0.2°): 4.6, 4.8, 14.0, 16.7, 18.7, 19.4, 23.3.

[0097] According to some embodiments of the present invention, the compound represented by the formula (C) in the crystal form is crystal form III, and when using Cu-Kα line, it basically has the X-ray powder diffraction pattern shown in FIG. 10.

[0098] According to some embodiments of the present invention, the compound represented by the formula (C) in the crystal form is crystal form III, and its differential scanning calorimetry curve has an endothermic peak at 204.9 ± 5 °C.

[0099] According to some embodiments of the present invention, the compound represented by the formula (C) in the crystal form is crystal form III, and its differential scanning calorimetry curve has endothermic peaks at 139.9 ± 5 °C and 204.9 ± 5 °C.

[0100] According to some embodiments of the present invention, the compound represented by the formula (C) in the crystal form is crystal form III, and its thermogravimetric analysis curve has a weight loss of 6.2% ± 0.2% between room temperature and 150 ± 5 °C.

[0101] According to some embodiments of the present invention, the compound represented by the formula (C) in the crystal form is crystal form IV, and its X-ray powder diffraction pattern using Cu-Kα radiation has characteristic diffraction peaks at the following 2θ angles (±0.2°): 4.6, 13.7, 19.5, 20.0, 22.9.

[0102] According to some embodiments of the present invention, the compound represented by the formula (C) in the crystal form is crystal form IV, and when using Cu-Kα radiation, it basically has the X-ray powder diffraction pattern shown in Figure 11.

[0103] According to some embodiments of the present invention, the compound represented by the formula (C) in the crystal form is crystal form IV, and its differential scanning calorimetry curve has an endothermic peak at 137.4 ± 5 °C.

[0104] According to some embodiments of the present invention, the compound represented by the formula (C) in the crystal form is crystal form IV, and its thermogravimetric analysis curve has a weight loss of 4.26 ± 0.2% between room temperature and 150 ± 5 °C.

[0105] According to some embodiments of the present invention, the compound represented by the formula (C) in the crystalline form is crystalline form V. The single crystal obtained using Cu-Kα rays is triclinic, space group P1, and its unit cell parameters are {a = 5.55690 (10) Å, b = 16.9102(2) Å, c = 18.9473 (2) Å, α = 99.1280(10)°, β = 90.1780(10)°, γ = 95.1340(10)°, V = 1750.57 (4) Å 3}.

[0106] According to a second aspect, the present invention provides a crystalline composition comprising one or more of crystalline form I, crystalline form II, crystalline form III, crystalline form IV, crystalline form V, crystalline form VI, and crystalline form VII of the compound represented by formula (B).

[0107] According to some embodiments of the present invention, in the crystalline composition, crystalline form I, crystalline form II, crystalline form III, crystalline form IV, crystalline form V, crystalline form VI, or crystalline form VII of the compound represented by formula (B) occupies 50% or more, 60% or more, 70% or more, 80% or more, 90% or more, or 95% or more of the weight of the crystalline composition.

[0108] According to a third aspect, the present invention provides a crystalline composition comprising one or more of crystalline form I, crystalline form II, crystalline form III, crystalline form IV, and crystalline form V of the compound represented by formula (C).

[0109] According to some embodiments of the present invention, in the crystalline composition, crystalline form I, crystalline form II, crystalline form III, crystalline form IV, or crystalline form V of the compound represented by formula (C) occupies 50% or more, 60% or more, 70% or more, 80% or more, 90% or more, or 95% or more of the weight of the crystalline composition.

[0110] According to a fourth aspect, the present invention provides a pharmaceutical composition comprising a salt of a compound represented by formula (A), a compound represented by formula (A-1), a solid form of the compound represented by formula (A-1), a crystalline form of the compound represented by formula (A-1), a compound represented by formula (B), a solid form of the compound represented by formula (B), a crystalline form of the compound represented by formula (B), a compound represented by formula (B-1), a solid form of the compound represented by formula (B-1), a crystalline form of the compound represented by formula (B-1), crystalline form I of the compound represented by formula (B), crystalline form II of the compound represented by formula (B), crystalline form III of the compound represented by formula (B), crystalline form IV of the compound represented by formula (B), crystalline form V of the compound represented by formula (B), crystalline form VI of the compound represented by formula (B), crystalline form VII of the compound represented by formula (B), a compound represented by formula (C), a solid form of the compound represented by formula (C), a crystalline form of the compound represented by formula (C), a compound represented by formula (C-1), a compound represented by formula (C-2), a solid form of the compound represented by formula (C-1) or formula (C-2), a crystalline form of the compound represented by formula (C-1) or formula (C-2), crystalline form I of the compound represented by formula (C), crystalline form II of the compound represented by formula (C), crystalline form III of the compound represented by formula (C), crystalline form IV of the compound represented by formula (C), crystalline form V of the compound represented by formula (C) or the crystalline composition according to the second or third aspect described above.

[0111] According to some embodiments of the present invention, the pharmaceutical composition further comprises a pharmaceutically acceptable carrier.

[0112] According to a fifth aspect, the present invention provides a salt of a compound represented by formula (A) as described in each of the above aspects, a compound represented by formula (A-1), a compound represented by formula (A-1) in solid form, a compound represented by formula (A-1) in crystalline form, a compound represented by formula (B), a compound represented by formula (B) in solid form, a compound represented by formula (B) in crystalline form, a compound represented by formula (B-1), a compound represented by formula (B-1) in solid form, a compound represented by formula (B-1) in crystalline form, crystalline form I of the compound represented by formula (B), crystalline form II of the compound represented by formula (B), crystalline form III of the compound represented by formula (B), crystalline form IV of the compound represented by formula (B), crystalline form V of the compound represented by formula (B), crystalline form VI of the compound represented by formula (B), crystalline form VII of the compound represented by formula (B), a compound represented by formula (C), a compound represented by formula (C) in solid form, a compound represented by formula (C) in crystalline form, a compound represented by formula (C-1), a compound represented by formula (C-2), a compound represented by formula (C-1) or a compound represented by formula (C-2) in solid form, a compound represented by formula (C-1) or a compound represented by formula (C-2) in crystalline form, crystalline form I of the compound represented by formula (C), crystalline form II of the compound represented by formula (C), crystalline form III of the compound represented by formula (C), crystalline form IV of the compound represented by formula (C), crystalline form V of the compound represented by formula (C), the crystalline composition according to the second or third aspect, or use as a drug or use in the manufacture of a drug of the pharmaceutical composition according to the fourth aspect.

[0113] According to some embodiments of the present invention, the drug is used for the prevention and / or treatment of cell proliferative diseases; preferably, the cell proliferative disease is a tumor or cancer; more preferably, the tumor or cancer is a hematological tumor or a solid tumor; even more preferably, it is a malignant hematological tumor or an advanced solid tumor; even more preferably, it is a relapsed / refractory hematological tumor or an advanced malignant solid tumor.

[0114] According to some embodiments of the present invention, the drug is used for the prevention and / or treatment of diseases mediated at least in part by PRMT5.

[0115] According to the sixth aspect, the present invention provides a salt of a compound represented by formula (A) as described in each of the above aspects, a compound represented by formula (A-1), a solid form of the compound represented by formula (A-1), a crystalline form of the compound represented by formula (A-1), a compound represented by formula (B), a solid form of the compound represented by formula (B), a crystalline form of the compound represented by formula (B), a compound represented by formula (B-1), a solid form of the compound represented by formula (B-1), a crystalline form of the compound represented by formula (B-1), crystalline form I of the compound represented by formula (B), crystalline form II of the compound represented by formula (B), crystalline form III of the compound represented by formula (B), crystalline form IV of the compound represented by formula (B), crystalline form V of the compound represented by formula (B), crystalline form VI of the compound represented by formula (B), crystalline form VII of the compound represented by formula (B), a compound represented by formula (C), a solid form of the compound represented by formula (C), a crystalline form of the compound represented by formula (C), a compound represented by formula (C-1), a compound represented by formula (C-2), a solid form of the compound represented by formula (C-1) or formula (C-2), a crystalline form of the compound represented by formula (C-1) or formula (C-2), crystalline form I of the compound represented by formula (C), crystalline form II of the compound represented by formula (C), crystalline form III of the compound represented by formula (C), crystalline form IV of the compound represented by formula (C), crystalline form V of the compound represented by formula (C), the crystal composition according to the second or third aspect, or the pharmaceutical composition according to the fourth aspect, which is a pharmaceutical composition for preventing and / or treating at least a partially PRMT5-mediated disease or a cell proliferative disease.

[0116] According to a seventh aspect, the present invention provides a method for preventing and / or treating a disease or a cell proliferative disease at least partially mediated by PRMT5, comprising administering to a subject in need thereof a therapeutically effective amount of a salt of a compound represented by formula (A) according to each of the above aspects, a compound represented by formula (A-1), a compound represented by formula (A-1) in solid form, a compound represented by formula (A-1) in crystalline form, a compound represented by formula (B), a compound represented by formula (B) in solid form, a compound represented by formula (B) in crystalline form, a compound represented by formula (B-1), a compound represented by formula (B-1) in solid form, a compound represented by formula (B-1) in crystalline form, crystalline form I of the compound represented by formula (B), crystalline form II of the compound represented by formula (B), crystalline form III of the compound represented by formula (B), crystalline form IV of the compound represented by formula (B), crystalline form V of the compound represented by formula (B), crystalline form VI of the compound represented by formula (B), crystalline form VII of the compound represented by formula (B), a compound represented by formula (C), a compound represented by formula (C) in solid form, a compound represented by formula (C) in crystalline form, a compound represented by formula (C-1), a compound represented by formula (C-2), a compound represented by formula (C-1) in solid form or a compound represented by formula (C-2), a compound represented by formula (C-1) in crystalline form or a compound represented by formula (C-2), crystalline form I of the compound represented by formula (C), crystalline form II of the compound represented by formula (C), crystalline form III of the compound represented by formula (C), crystalline form IV of the compound represented by formula (C), crystalline form V of the compound represented by formula (C), the crystalline composition according to the second or third aspect, or the pharmaceutical composition according to the fourth aspect.

[0117] According to some embodiments of the present invention, the disease at least partially mediated by PRMT5 according to the fifth, sixth or seventh aspect is a cell proliferative disease.

[0118] According to some embodiments of the present invention, the cell proliferative disease described in the above fifth, sixth or seventh aspect is a tumor or cancer, preferably, the tumor or cancer is a hematological tumor or a solid tumor, more preferably a malignant hematological tumor or an advanced solid tumor, and even more preferably a relapsed / refractory hematological tumor or an advanced malignant solid tumor.

[0119] According to some embodiments of the present invention, the tumor or cancer described in the above fifth, sixth or seventh aspect is lung cancer, bone cancer, gastric cancer, pancreatic cancer, adenoid cystic cancer, skin cancer, head and neck cancer, uterine cancer, ovarian cancer, testicular cancer, fallopian tube cancer, endometrial cancer, cervical cancer, vaginal cancer, brain cancer, Lower pituitary adenoma, melanoma, epidermal cancer squamous cell carcinoma, And selected from chronic and acute leukemia, preferably, the acute leukemia is acute myeloid leukemia (AML).

[0120] According to the eighth aspect, the present invention provides a method for producing a compound represented by formula (A-1), which comprises reacting a compound represented by formula (A) with an acid in a suitable solvent and separating to obtain the compound represented by formula (A-1).

[0121]

Chemical formula

[0122] According to some embodiments of the present invention, X is an inorganic acid and is selected from sulfuric acid and phosphoric acid.

[0123] According to some embodiments of the present invention, X is an organic acid selected from malic acid, oxalic acid, succinic acid, tartaric acid, adipic acid, citric acid, gluconic acid, maleic acid, fumaric acid, lactic acid, and gentisic acid, preferably malic acid, oxalic acid, succinic acid, L-tartaric acid, L-lactic acid, adipic acid, citric acid, or gluconic acid, preferably malic acid, oxalic acid, succinic acid, L-tartaric acid, adipic acid, citric acid, or gluconic acid, more preferably malic acid, oxalic acid, citric acid, or gluconic acid, even more preferably malic acid or oxalic acid, and even more preferably L-malic acid or oxalic acid.

[0124] According to the production method of the present invention, the molar ratio of the compound represented by the formula (A) to the acid is 1 to 2:0.5 to 2, preferably 1:1 to 2, and more preferably 1:1.1 to 2.

[0125] According to the production method of the present invention, the reaction temperature is 0 to 90 °C, preferably 5 to 80 °C, preferably 20 to 60 °C, and more preferably room temperature to 50 °C.

[0126] According to the production method of the present invention, the reaction solvent is one or a combination of two selected from alcohols, esters, nitriles, ketones, water, alkane solvents, ether solvents, or heterocycloalkane solvents, preferably one or a combination of two of ROH, RCOOR1, RCN, RCOR1, water, ROR1, RH, or heterocycloalkane solvents, where R and R1 are each independently selected from 1-6 linear or branched alkyl groups, preferably, R and R1 are each independently selected from 1-4 linear or branched alkyl groups, preferably, the reaction solvent is one or a combination of two selected from isopropanol, methanol, ethanol, ethyl acetate, acetone, butanone, acetonitrile, water, tetrahydrofuran, n-heptane, and 2-methyltetrahydrofuran. When it is a mixed solvent composed of two solvents, the volume ratio of the amounts used of both is 1 to 20:20 to 1, preferably 1 to 19:19 to 1, and preferably 1 to 10:10 to 1.

[0127] According to the production method of the present invention, after the reaction is completed, the temperature is selectively decreased to -15 to 15°C, and static crystallization is carried out for 0.5 h to 5 days, and then the solid is separated and dried to obtain the compound represented by formula (A-1). Preferably, the crystallization temperature is 5°C, and the crystallization time is 1 h to 3 days.

[0128] According to the production method of the present invention, the separation step includes separating the obtained compound represented by formula (A-1) from the crystallization solution by an appropriate method such as adsorption filtration, suction filtration, filtration, centrifugation, etc.

[0129] According to the production method of the present invention, any appropriate known method can be adopted for the drying method, and preferably, it is drying at room temperature, drying under vacuum at room temperature or drying under the condition of 50°C. Specific drying conditions are preferably, for example, the drying time is 1 h to 5 days, more preferably 3 h to 3 days, and still more preferably 3 h to 1 day. No matter which drying means is adopted, the solvent residue amount in the obtained product is preferably in conformity with the quality standard.

[0130] Definitions and Explanations Unless otherwise specified, the following terms and phrases used in this specification are intended to have the following meanings. A specific phrase or term should not be regarded as uncertain or unclear when it is not specifically defined, but should be understood according to its general meaning. When a trade name appears in this specification, it is intended to refer to the corresponding trade name or its active ingredient.

[0131] The compound represented by formula (A) referred to in the present invention may have a specific stereoisomeric form including cis and trans isomers, (R)- and (S)-enantiomers, and racemates thereof, etc., and the trans isomer is preferred.

[0132] As used in the present invention, the "salt of the compound represented by formula (A) in solid form or the compound represented by formula (A-1)", the "compound represented by formula (B) in solid form", or the "compound represented by formula (C) in solid form", etc. refer to the compound represented by formula (A-1) in solid form, the compound represented by formula (B) in solid form, the compound represented by formula (C) in solid form, etc., including the crystalline forms and amorphous forms of the compound represented by formula (A-1), the compound represented by formula (B), the compound represented by formula (C), or the compound represented by formula (C-2).

[0133] As used in the present invention, the "salt of the compound represented by formula (A) in crystalline form or the compound represented by formula (A-1)", the "compound represented by formula (B) in crystalline form", or the "compound represented by formula (C) in crystalline form", etc. refer to the compound represented by formula (A-1) in crystalline form, the compound represented by formula (B), the compound represented by formula (C), etc., including the anhydrous and solvent-free forms, hydrate forms, solvate forms, and eutectic forms of the compound represented by formula (A-1), the compound represented by formula (B), and the compound represented by formula (C).

[0134] The term "solvate" or "solvent adduct" refers to an aggregate formed by a stoichiometric or non-stoichiometric ratio of solvent molecules and a salt of the compound represented by formula (A) of the present invention, the compound represented by formula (A-1), the compound represented by formula (B), the compound represented by formula (C), etc., including aggregates containing water molecules and one or more other solvent molecules simultaneously, and aggregates containing only one or more other solvent molecules.

[0135] The term "hydrate" means an aggregate of water molecules in a stoichiometric or non-stoichiometric ratio and a salt of the compound represented by formula (A) of the present invention, the compound represented by formula (A-1), the compound represented by formula (B), the compound represented by formula (C), etc.

[0136] The term "anhydrous and solvent-free form" means that it does not contain water molecules or solvent molecules, or that water molecules or solvent molecules are bound in a manner other than intermolecular forces, such as by an adsorption method, and coexist with a salt of the compound represented by formula (A), the compound represented by formula (A-1), the compound represented by formula (B), the compound represented by formula (C), etc.

[0137] The term "crystalline composition" refers to a solid form containing one or more of the specific crystal forms of the compounds referred to in the present invention (such as a salt of the compound represented by formula (A), the compound represented by formula (A-1), the compound represented by formula (B), the compound represented by formula (C), etc.). For example, in one embodiment of the present invention, it contains one, two or more of crystal form I, crystal form II, crystal form III, crystal form IV, crystal form V, crystal form VI, and crystal form VII of the compound represented by formula (B) referred to in the present invention. And in addition to the crystal forms of the present invention, the crystalline composition can optionally contain other crystal forms, other crystal forms or other amorphous forms of compounds (such as the compound represented by formula (A-1), the compound represented by formula (B), the compound represented by formula (B-1), the compound represented by formula (C), the compound represented by formula (C-1), or the compound represented by formula (C-2)), or other impurities other than these. Those skilled in the art should understand that the total content of each component in the crystalline composition is 100%.

[0138] The term "room temperature" refers to the temperature of room temperature in the ordinary sense in the art, generally 10 to 30 °C, preferably 25 °C ± 5 °C.

[0139] In the context of the present invention, the 2θ values in the X-ray powder diffraction pattern are all in degrees (°) as the unit.

[0140] In an X-ray powder diffraction pattern, the terms "substantially" or "substantially as shown in the figure" mean that it is substantially a pure crystal form, and at least 50%, or at least 60%, or at least 70%, or at least 80%, or at least 90%, or at least 95%, or at least 96%, or at least 97%, or at least 98%, or at least 99% of the peaks appear in a predetermined pattern. Further, as the content of a certain crystal form in the product gradually decreases, depending on the detection sensitivity of the equipment, the diffraction peaks attributed to that crystal form in its X-ray powder diffraction pattern may decrease. Also, for any crystal form, there may be some error in the peak position, which is also known in the field of crystallography. For example, due to changes in temperature during sample analysis, movement of the sample, or calibration of the equipment, etc., the peak position can move, and the measurement error of the 2θ value is usually ±0.2°. Therefore, when determining each crystal structure, this error should be considered, and the terms "substantially" or "substantially as shown in the figure" are also intended to include such differences in the diffraction peak position.

[0141] In a DSC chart or TGA chart, the terms "substantially" or "substantially as shown in the figure" mean that for the same crystal form of the same kind of compound, in a continuous analysis, the error in the heat transfer start temperature, endothermic peak temperature, exothermic peak temperature, melting point, weight loss start temperature, or weight loss end point temperature, etc. is typically about 5°C and usually within about 3°C. When a certain compound has a certain predetermined heat transfer start temperature, endothermic peak temperature, exothermic peak temperature, melting point, weight loss start temperature, or weight loss end point temperature, etc., it means that it is within ±5°C of that temperature.

[0142] As used herein, the term "cell proliferative disorder" refers to a disease condition in which the growth rate of its cell population is lower or higher than the expected rate under a given physiological state and conditions.

[0143] The term "tumor" includes benign tumors, malignant tumors, and borderline malignant tumors, and malignant tumors are collectively referred to as cancers.

[0144] As used herein, the term "prevention" means that when administered in a disease or medical condition (e.g., cancer), the compound or medicament (e.g., the combination product according to the present application) can reduce the frequency of in vivo medical conditions of the subject or delay the onset thereof, as compared to a subject not administered with the compound or medicament.

[0145] As used herein, the term "treatment" refers to the alleviation or improvement of a disease or symptom, the improvement of symptoms due to potential metabolism, the suppression of a disease or symptom, e.g., the suppression of the progression of a disease or symptom, the reduction of a disease or symptom, the disappearance of a disease or symptom, the alleviation of symptoms due to a disease or medical condition, or the suppression of a disease or symptom.

[0146] The term "pharmaceutically acceptable carrier" or "pharmaceutically acceptable adjuvant" refers to those carriers that have no obvious stimulatory effect on the living body and do not impair the biological activity and performance of the active compound.

[0147] The compounds according to the present invention can be prepared by various synthetic methods well known to those skilled in the art, including the specific embodiments listed below, the embodiments formed by combining other chemical synthesis methods, and equivalent substitution methods known to those skilled in the art. Preferred embodiments include, but are not limited to, the examples according to the present invention.

[0148] The chemical reactions in the specific embodiments of the present invention are completed in a suitable solvent, and the solvent must be suitable for the chemical changes according to the present invention and the reagents or materials required therefor. Sometimes, it is necessary for those skilled in the art to modify or select the synthetic steps or reaction processes based on the existing embodiments to obtain the compounds according to the present invention.

[0149] Hereinafter, the present application will be specifically described by way of examples, but these examples do not limit the present application. All solvents used in the present application are commercially available and can be used without further purification.

[0150] The "chemical composition ratio" of the present invention means the molar ratio, that is, the molar ratio of the free-form compound to the acid.

[0151] The in vitro kinase activity inhibition test showed that the inhibition of the activity of the compound represented by formula (A) against PRMT5 and MV4-11 cells was better than that of the comparative compound.

[0152] The in vivo tumor suppression test results showed that the compound represented by formula (A) had significant tumor activity suppression compared to the comparative compound, that is, the inhibitory effect on tumor weight and tumor volume was significant.

[0153] The results of the in vivo pharmacokinetics test showed that the compound represented by formula (A) had better oral administration performance, a fast absorption rate, and good absorption.

[0154] In addition to any one or more of the effects of (1), (2), or (3) above, developing salts of the compound of formula (A) has a more valuable future for application.

[0155] The salt of the compound represented by formula (A) or the compound represented by formula (A-1) is obtained for the first time.

[0156] The salt of the compound represented by formula (A) in solid form or the compound represented by formula (A-1) and the salt of the compound represented by formula (A) in crystalline form or the compound represented by formula (A-1) are obtained for the first time, and they are easy to separate, transfer, and weigh.

[0157] The salt of the compound represented by formula (A) or the compound represented by formula (A-1) has a good dissolution effect.

[0158] The compound represented by formula (B), the compound represented by formula (B-1), the compound represented by formula (C), the compound represented by formula (C-1) or formula (C-2) in solid form are obtained, which have good properties and are easy to separate, transfer, and weigh.

[0159] The compounds represented by formula (B) in solid form, the compounds represented by formula (B-1), the compounds represented by formula (C), the compounds represented by formula (C-1) or formula (C-2) can be prepared and separated with high purity (over 95%) and / or yield (over 80%).

[0160] The compounds represented by formula (B) in crystalline form, the compounds represented by formula (B-1), the compounds represented by formula (C) in crystalline form, the compounds represented by formula (C-1) or the compounds represented by formula (C-2) have good crystals.

[0161] The compounds represented by formula (B) in crystalline form and their specific crystal forms, the compounds represented by formula (C) in crystalline form and their specific crystal forms are easy to purify and separate (e.g., by filtration), and the production is simple.

[0162] The crystal form preferably has good physical stability and chemical stability and has good medicinal future prospects.

Brief Description of Drawings

[0163]

Figure 1

Figure 2

Figure 3

Figure 4

Figure 5

Figure 6

Figure 7

Figure 8

Figure 9

Figure 10

Figure 11

Embodiments for Carrying out the Invention

[0164] 1. X-ray powder diffraction (X-ray powder diffractometer, XRPD)

Table 1

[0165] 2. Differential scanning calorimetry (Differential Scanning Calorimeter, DSC)

Table 2

[0166] 3. Thermogravimetric analysis (Thermal Gravimetric Analyzer, TGA)

Table 3

[0167] 4. Nuclear magnetic resonance pattern (NuclearmAgnetic Resonance Spectroscopy, NMR) Instrument model: Bruker 400M nuclear magnetic resonance apparatus (Bruker, GER) Content and test solvent: 1 For 1H-NMR, the test solvent is DMSO-d6.

[0168] 5. Infrared spectroscopy (Infrared Spectroscopy, IR) Detection instrument: Perkin Elmer Spectrum 100 FT-IR infrared spectroscopic analyzer Test method: Weigh 3 mg of the sample, dilute the tablet with KBr, and perform detection at room temperature. The specific parameters are as follows: detection range: 4000~400 cm -1 Wave number, resolution: 4 cm -1 That's it.

[0169] 6. Ion chromatography (IC)

Table 4

[0170] 7. High performance liquid chromatography (HPLC)

Table 5

[0171] 8. Single crystal diffraction

Table 6

[0172] 9. Solubility measurement FaSSIF: Simulates the intestinal fluid in the small intestine in a fasting state before a person eats; FeSSIF: Simulates the intestinal fluid in the small intestine in a full state after a person eats; SGF: Simulates the gastric juice on an empty stomach when a person is in a fasting state.

[0173] Test method: Add the sample to be measured to water or a biological solvent medium (4 mL), mix by rotation on a rotary shaker at 37 °C (~25 rpm), collect approximately 0.8 mL of the solution or suspension in a centrifuge tube at the sampling point (in the present invention, the sampling point is 24 hours), centrifuge, filter the supernatant through a filter membrane, and use the filtrate for solubility measurement.

[0174] To better understand the content of the present invention, further description will be given below with reference to specific examples. However, the specific embodiments do not limit the content of the present invention. Test methods for which specific conditions are not specified in the following production examples, examples, measurement examples or test examples are selected according to ordinary methods and conditions or according to the product handling instructions.

[0175] Production Example 1: Preparation of the compound of formula (A)

Chemical formula

[0176] Preparation of Intermediate T-0: 6-Chloro-pyrimidine-4-carbonyl chloride (0.63 g, 3.56 mmol) was dissolved in dichloromethane (10 mL) in a 100 mL reaction flask, and triethylamine (0.72 g, 7.12 mmol) was added under the condition of 0 °C. Then, (S)-1-Amino-3-(3,4-dihydroisoquinolin-2(1H)-yl)propan-2-ol (0.66 g, 3.20 mmol) was added. The reaction solution was stirred at 25 °C for 2 hours. The completion of the reaction was monitored by TLC, the reaction solution was diluted with water (5 mL), and extracted with dichloromethane (15 mL × 2). The combined organic layers were washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to remove the solvent, obtaining a residue. The residue was purified by column chromatography (dichloromethane / methanol = 10 / 1, v / v, the same hereinafter), and Intermediate Compound T-0 (yellow oil, 0.68 g, 61.28%) was obtained.

[0177] Preparation of Intermediate T1: (S)-6-Chloro-N-(3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)pyrimidine-4-formamide (T-0, 0.28 g, 0.81 mmol) was dissolved in isopropanol (20 mL), and triethylamine (0.25 g, 2.47 mmol) and tert-butyl 4-aminopiperidine-1-carboxylate (0.24 g, 1.2 mmol) were sequentially added. The reaction solution was heated to 85 °C and reacted for 8 hours. After indicating the completion of the reaction by TLC, the reaction solution was concentrated to dryness under reduced pressure and separated by column chromatography (dichloromethane / methanol = 30 / 1) to obtain intermediate compound T-1 (0.36 g, 87.32%).

[0178] Preparation of Intermediate T-2: tert-Butyl (S)-4-((6-((3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)carbamoyl)pyrimidin-4-yl)amino)piperidine-1-carboxylate (T-1, 0.36 g, 0.71 mmol) was dissolved in dichloromethane (20 mL), and trifluoroacetic acid (1 mL) was added, and the mixture was reacted at room temperature for 1 hour. It was concentrated to dryness under reduced pressure to obtain intermediate compound T-2 (0.25 g, 86.38%). LC-MS: m / z 411.54 [M+H] + 。

[0179] Preparation of Intermediate T-3: 2-Oxopropionic acid (0.69 g, 7.84 mmol, 1 eq) was dissolved in a mixed solvent of tetrahydrofuran (20 mL) and water (100 mL), KOH (0.48 g, 8.62 mmol, 1.1 eq) was added, and after stirring until clear, methoxyamine hydrochloride (1.31 g, 15.68 mmol, 2.0 eq) was added in one batch under ice bath conditions, and the mixture was reacted for 2 hours, followed by filtration to obtain intermediate compound T-3 (0.91 g, 77.78%). 1 H NMR (600 MHz, DMSO-d6): δ 1.920 (s, 3H), 3.953 (s, 3H), 12.985 (s, 1H).

[0180] Preparation of Compound A: Intermediate T-2 (0.25 g, 0.61 mmol) was dissolved in DMF (20 mL), and TEA (3 mL, pH > 10 is acceptable), Intermediate T-3 (0.085 g, 0.73 mmol), and HATU (0.30 g, 0.789 mmol) were added sequentially, followed by reacting at room temperature for 2 hours. After indicating the completion of the reaction by TLC, water and ethyl acetate were added and liquid separation was performed. The organic phase was washed once with water and saturated brine respectively, and then concentrated to dryness and separated by column chromatography (dichloromethane / methanol = 30 / 1) to obtain the target compound (0.22 g, 70.75%). LC-MS: m / z 510.34 [M+H] + 。 1 H NMR (600 MHz, CD3OD): δ 1.459 - 1.533 (m, 2H), 1.996 (s, 3H), 2.036 - 2.063 (m, 2H), 2.645 - 2.655 (m, 2H), 2.814 - 2.848 (m, 2H), 2.907 - 2.926 (m, 2H), 3.014 (m, 1H), 3.261 - 3.303 (m, 1H), 3.466 - 3.550 (m, 2H), 3.710 (s, 2H), 3.909 (s, 3H), 4.018 - 4.074 (m, 2H), 4.210 (s, 1H), 4.399 - 4.420 (d, 1H), 6.987 - 7.108 (m, 5H), 8.238 (s, 1H).

[0181] Example 1: Preparation of the Compound of Formula (B) A sample (0.5 g) of Production Example 1 was weighed, dissolved in isopropanol (5 mL), L-malic acid (2 eq) was added, and the mixture was stirred at room temperature for about 10 h, filtered, and dried at 50°C ± 5°C for 8 hours to obtain a solid with a yield of 92.5%. Detection was carried out, and it was confirmed that a salt had already been formed and the ratio of alkali / acid was 1:1. IR (KBr, cm -1 ): 3301.35, 2939.94, 1610.73, 1528.35, 1455.99, 1367.93, 1045.03.

[0182] When a sample was taken and X-ray powder diffraction was performed, it was shown to be a crystalline solid (crystal form I). The crystals were well formed, the pattern is shown in Figure 1, and the XRPD diffraction peak data are shown in Table 1. When a sample was taken and a DSC-TGA test was performed, there were endothermic peaks at 102.15 °C and 113 °C in the DSC chart, and the TGA chart showed that the sample had a weight loss of 8.6522% between room temperature and 110 °C.

Table 7

[0183] Example 2: Preparation of Crystal Form II of the Compound of Formula (B) The sample (30 mg) obtained in Example 1 was weighed, tetrahydrofuran (1.1 mL) was added to make a solution, n-heptane (0.4 mL) was added dropwise, stirred at room temperature for 7 days, filtered, and vacuum dried at 50 °C for 2 hours to obtain a solid. When a sample was taken and X-ray powder diffraction was performed, it was shown to be a crystalline solid (crystal form II). The crystals were well formed, the pattern is shown in Figure 2, and the XRPD diffraction peak data are shown in Table 2. When a sample was taken and a DSC-TGA test was performed, there was one endothermic peak at 89.8 °C and 103.58 °C respectively in the DSC chart, and the TGA chart showed that the sample had a weight loss of 2.6358% between room temperature and 80 °C.

Table 8

[0184] Example 3: Preparation of Crystal Form III of the Compound of Formula (B) A sample of Example 1 (about 50 mg) was weighed into a sample bottle, acetonitrile (1.5 mL) was added, stirred at room temperature for 7 days, and filtered to obtain a solid. When the sample was taken for X-ray powder diffraction, it was shown to be a crystalline solid (crystal form III). The crystals were well formed, the pattern is shown in Figure 3, and the XRPD diffraction peak data are shown in Table 3. When the sample was taken for DSC-TGA test, there were endothermic peaks at 70.82 °C and 117.93 °C in the DSC chart, and the TGA chart showed that the sample had a weight loss of 3.0001% between room temperature and 75 °C.

Table 9

[0185] Example 4: Preparation of Crystal Form IV of the Compound of Formula (B) A sample of Example 1 (about 50 mg) was weighed into a sample bottle, a mixed solution of methanol / methyl-t-butyl ether (1.5 mL, v / v = 1 / 3) was added, stirred at room temperature for 7 days, and filtered to obtain a solid. When the sample was taken for X-ray powder diffraction, it was shown to be a crystalline solid (crystal form IV). The crystals were well formed, the pattern is shown in Figure 4, and the XRPD diffraction peak data are shown in Table 4. When the sample was taken for DSC-TGA test, there were two endothermic peaks at 77.91 °C and 113.27 °C in the DSC chart, and the TGA chart showed that the sample had a weight loss of 2.6271% between room temperature and 60 °C.

Table 10

[0186] Example 5: Preparation of Crystal Form V of the Compound of Formula (B) A sample of Example 1 (about 50 mg) was weighed into a sample bottle, acetone (1.5 mL) was added, stirred at room temperature for 7 days, and filtered to obtain a solid. When the sample was taken for X-ray powder diffraction, it was shown to be a crystalline solid (Crystal Form V). The crystals were well formed, the pattern is shown in Figure 5, and the XRPD diffraction peak data are shown in Table 5. When the sample was taken for DSC-TGA test, the DSC chart had two endothermic peaks at 68.38 °C and 104.69 °C, and the TGA chart showed that the sample had a weight loss of 3.6041% between room temperature and 75 °C.

Table 11

[0187] Example 6: Preparation of Crystal Form VI of the Compound of Formula (B) An appropriate amount of the crystal form IV obtained in Example 4 was weighed and vacuum dried at 50 °C for 2 days to obtain a solid. When the sample was taken for X-ray powder diffraction, it was shown to be a crystalline solid (Crystal Form VI). The crystals were well formed, the pattern is shown in Figure 6, and the XRPD diffraction peak data are shown in Table 6. When the sample was taken for DSC-TGA test, the DSC chart had an endothermic peak at 113.29 °C, and the TGA chart showed that the sample had a weight loss of 0.34% between room temperature and 120 °C.

Table 12

[0188] Example 7: Preparation of Crystal Form VII of the Compound of Formula (B) A sample (501.3 mg) obtained in Production Example 1 was weighed into a 20 mL reaction flask, ethanol (12 mL) was added to prepare a solution, L-malic acid (131.6 mg) was added, magnetically stirred at room temperature for 8 days, the solid was centrifuged, and vacuum dried at room temperature for 1 day to obtain a purity of 98.22%. It was confirmed by nuclear magnetic detection that a salt had already been formed and the alkali / acid ratio was 1:1.5.

[0189] When a sample was taken and X-ray powder diffraction was performed, it was shown to be a crystalline solid (crystal form VII). The crystals were well formed, the pattern is shown in Figure 7, and the XRPD diffraction peak data are shown in Table 7. When a sample was taken and a DSC-TGA test was performed, there were endothermic peaks at 92.4 °C and 197.3 °C in the DSC chart, and the TGA chart showed that the sample had a weight loss of 7.88% between room temperature and 110 °C.

Table 13

[0190] Example 8: Preparation of Crystal Form I of the Compound of Formula (C) A sample (0.5 g) of Production Example 1 was weighed, dissolved in isopropanol (5 mL), oxalic acid (2 eq) was added, stirred at room temperature for about 10 h, filtered, and dried at 50 °C ± 5 °C for 6 h to obtain a solid with a yield of 90%. Detection was performed, and it was confirmed that a salt had already been formed. IR (KBr, cm -1 ): 3319.96, 2936.96, 1615.04, 1526.12, 1455.78, 1368.16, 1046.84.

[0191] When a sample was taken and X-ray powder diffraction was performed, it was shown to be a crystalline solid (crystal form I). The crystals were well formed, the pattern is shown in Figure 8, and the XRPD diffraction peak data are shown in Table 8.

Table 14

[0192] Example 9: Preparation of Crystal Form II of the Compound of Formula (C) Oxalic acid dihydrate (6.4 mg) was weighed and placed in a vial, and an ethanol solution (40 mg / mL, 0.5 mL) of the sample of Production Example 1 was added. It was magnetically stirred at room temperature for 3 days, the solid was centrifuged, and vacuum dried at room temperature for 1 day to obtain a purity of 98.56%. Detection was performed, and it was confirmed that a salt had already been formed and that the alkali / acid ratio was about 1:1.5.

[0193] Taking a sample and performing X-ray powder diffraction showed that it was a crystalline solid (crystal form II). The crystals were well formed, the pattern is shown in Figure 9, and the XRPD diffraction peak data are shown in Table 9. Taking a sample and performing a DSC-TGA test showed that there was an endothermic peak at 162.6 °C in the DSC chart, and the TGA chart showed that the sample had a 3.20% weight loss between room temperature and 160 °C.

Table 15

[0194] Example 10: Preparation of Crystal Form III of the Compound of Formula (C) Weighed oxalic acid dihydrate (6.3 mg) and placed it in a vial, added the 2-methyltetrahydrofuran solution (40 mg / mL, 0.5 mL) of the sample of Preparation Example 1, magnetically stirred at room temperature for 3 days, centrifuged the solid, and vacuum dried at room temperature for 1 day. It was detected that a salt had already been formed, and it was confirmed that the alkali / acid ratio was about 1:1.

[0195] Taking a sample and performing X-ray powder diffraction showed that it was a crystalline solid (crystal form III). The crystals were well formed, the pattern is shown in Figure 10, and the XRPD diffraction peak data are shown in Table 10. Taking a sample and performing a DSC-TGA test showed that there were endothermic peaks at 139.9 °C and 204.9 °C in the DSC chart, and the TGA chart showed that the sample had a 6.20% weight loss between room temperature and 150 °C.

Table 16

[0196] Example 11: Preparation of Crystal Form IV of the Compound of Formula (C) Oxalic acid dihydrate (123.9 mg) and the sample of Production Example 1 (503.0 mg) were weighed and placed in a reaction flask, ethanol (10 mL) was added, and the mixture was magnetically stirred at room temperature for 2 days. The solid was centrifuged and vacuum dried at room temperature for 3 days to obtain a purity of 98.96%. It was detected that a salt had already been formed, and it was confirmed that the alkali / acid ratio was approximately 1:1.

[0197] When the sample was taken and subjected to X-ray powder diffraction, it was shown to be a crystalline solid (crystal form IV). The crystals were well formed, and the pattern is shown in Figure 11, and the XRPD diffraction peak data are shown in Table 11. When the sample was taken and subjected to a DSC-TGA test, there was an endothermic peak at 137.4 °C in the DSC chart, and the TGA chart showed that the sample had a weight loss of 4.26% between room temperature and 150 °C.

Table 17

[0198] Example 12: Preparation of Crystal Form V of the Compound of Formula (C) The sample of Production Example 1 (41 mg) and oxalic acid dihydrate (12.9 mg) were weighed into a glass bottle, an acetone / water mixed solvent (0.5 mL, v / v = 1 / 1) was added, the temperature was raised to 80 °C and stirred for 12 hours, and then the temperature was gradually lowered to room temperature to obtain single crystals of the compound of formula (C) (acid-alkali ratio: 1:1). The single crystals obtained using Cu-Kα radiation were triclinic, space group P1, and the unit cell parameters were {a = 5.55690 (10) Å, b = 16.9102(2) Å, c = 18.9473 (2) Å, α = 99.1280(10)°, β = 90.1780(10)°, γ = 95.1340(10)°, V = 1750.57 (4) Å 3}.

[0199] Example 13: Preparation of Organic Acid Addition Salts of Other Compounds of Formula (A) The samples of Production Example 1 were each dissolved in the solvents shown in the following table to prepare solutions with a concentration of 40 mg / mL. Different acids were weighed and added to vials, and then the sample solution (0.5 mL) of Production Example 1 that had been prepared in advance was added. As shown in the following table for the specific test method, the solids were centrifuged and vacuum-dried at room temperature for 1 day.

[0200] When nuclear magnetic or HPLC content measurement was performed, the samples of Production Example 1 could form salts with any of the acids shown in the following table. The alkali / acid ratio was 1:1 in each case, and solids could be separated and obtained. Furthermore, when X-ray powder diffraction was performed on the samples, the specific results are shown in the following table.

Table 18

[0201] Example 14: Preparation of Inorganic Acid Addition Salts of the Compound of Formula (A) Prepared by the same method as in Example 13 to obtain the following salts. Specifically shown in the following table.

Table 19

[0202] Measurement Example 1: Solid Stability Experiment of Different Crystal Forms of the Compound of Formula (B) under Different Humidity Conditions Appropriate amounts of the samples of Example 2 (Crystal Form II of the compound of Formula (B)), Example 3 (Crystal Form III of the compound of Formula (B)), and Example 4 (Crystal Form IV of the compound of Formula (B)) were weighed and placed in vials, and left for 7 days under the conditions of 23 °C / 33% RH and 25 °C / 60% RH respectively. Samples were taken and X-ray powder diffraction was performed on each of them. The results of examining the stability of the samples under different conditions are shown in the following table.

Table 20

[0203] Measurement Example 2: Solid Stability Test of Different Crystal Forms of the Compound of Formula (B) Samples of Example 2 (Crystal Form II of the Compound of Formula (B)) and Example 5 (Crystal Form V of the Compound of Formula (B)) were weighed in appropriate amounts, placed in vials, left standing for 7 days under the conditions of high temperature (60 °C, sealed), samples were taken and X-ray powder diffraction was performed on each of them, and the results of examining the stability of the samples under different conditions are shown in the following table. [Table 21] Conclusion: Crystal Form II of Example 2 and Crystal Form V of Example 5 were left standing for 7 days under high temperature conditions, but the crystal forms remained stable.

[0204] Measurement Example 3: Long-Term (3-Month) Stability Test of Crystal Form I of the Compound of Formula (B) A sample of Example 1 (Crystal Form I of the Compound of Formula (B)) was weighed in an appropriate amount, placed in a vial, and the long-term stability was considered, and the results are shown in the following table. [Table 22] Conclusion: In the long-term experiment of 3 months, the purity of Crystal Form I of Example 1 hardly changed and the crystal form did not change.

[0205] Measurement Example 4: Solubility Measurement The salts of the compound of formula (A) obtained in the above examples have good solubility in water and biological solvent media, and representative examples are shown below.

[0206] At 37 °C, the 24-hour solubilities of Example 7 (the compound of formula (B), Crystal Form VII), Example 10 (the compound of formula (C), crystal form) and the free sample (Production Example 1) in water, SGF and FassIF were tested, and the results are shown in the following table.

[0207] [Table 23] The solubility of the crystalline form VII of the compound of formula (B) and the crystalline form IV of the compound of formula (C) in water and the FassIF medium was significantly higher than the solubility of the free base sample obtained in Production Example 1.

[0208] Test Example 1: In Vitro Efficacy Test 1. Enzymatic Experimental Method Using the radioisotope FlashPlate technique, the IC of the test substance was detected with PRMT5. 50 was detected.

[0209] Each test compound was dissolved in dimethyl sulfoxide, then added to an Echo384 well and diluted to the desired concentration. Using an Echo550 device, the test substance was transferred from the diluted Echo384 well to a 384-well reaction plate, and both the control well and the blank well were transferred to dimethyl sulfoxide. PRMT5 was added to a 1-fold reaction buffer (the 1-fold reaction buffer contains 10 mM Tris-HCl; pH 8.0; 0.01% Tween-20; 1 mM DTT) to form a 1.67-fold enzyme solution (enzyme concentration: 5 nM). The polypeptide substrate and [3H]-SAM were added to the 1-fold reaction buffer to form a 2.5-fold substrate solution (the final concentrations of the substrates were 100 nM and 250 nM, respectively). 15 μL / well of the 1.67-fold enzyme solution was added to the 384-well reaction plate. For the blank well, 15 μL of the 1-fold reaction buffer was used instead of the enzyme solution. Centrifuged at 1000 rpm for 1 min and incubated at room temperature for 15 min. 10 μL / well of the 2.5-fold substrate solution was added to the 384-well reaction plate. Centrifuged at 1000 rpm for 1 min. Reacted at 25 °C for 60 min. 5 μL / well of the reaction stop solution was added to the 384-well reaction plate to stop the reaction (reaction stop solution: 125 μM cold SAM solution). 25 μL / well was taken from the test well and transferred to the Flashplate and left at room temperature for 1 h. Next, the Flashplate was washed 3 times with a 0.1% Tween-20 solution. Counted with MicroBeta 2. The data was converted to inhibition rate data. Inhibition rate = (conversion rate コントロールウェル - conversion rate 化合物孔) / (conversion rate コントロールウェル -conversion rate ブランクウェル )×100%. Fitted with XLFit 5.4.0.8 to obtain IC 50 . Fitting formula: Y = Bottom + (Top - Bottom) / (1 + (IC 50 / X)^HillSlope

[0210] 2. Cell experiment method The complete medium required for culturing experimental human acute monocytic leukemia cells MV4-11 (Shanghai Cell Bank) is IMDM (Cat NO. 12440-053, gibco) supplemented with 10% fetal bovine serum FBS (Cat NO. SA311.02, cellmax). The cells were cultured at 37°C in a 5% CO2 incubator. Experimental reagents include dimethyl sulfoxide (Tianjin Kemiou Chemical Reagent Co., Ltd.) and MTT (THIAZOLYL BLUE TETRAZOLIUM BROMIDE, CAS. NO. 298-93-1, VWR). The test control GSK3326595 is either self-manufactured or purchased from commercial products. The test substance was sealed and stored at 4°C.

[0211] Using dimethyl sulfoxide as a solvent, the test substance was fully dissolved to a concentration of 5×10 -2A stock solution with a concentration of mol / L was prepared and stored at -20°C. Using the complete medium as the diluent, the test substance was serially diluted to different concentrations. 100 μL / well (2×103 cells / well) of a complete medium suspension of human acute monocytic leukemia cells MV4-11 was added to a 96-well culture plate, and then the corresponding test substances at different concentrations (100 μL / well) were added respectively. Each test substance had 8 concentration levels, and for each concentration, 3 duplicate well tests were set up. The cells were cultured in a 5% CO2 incubator at 37°C. On the 6th day, MTT (20 μL / well) was added, and the cells were cultured in a 5% CO2 incubator at 37°C for 4 h. The supernatant was discarded, dimethyl sulfoxide (150 μL / well) was added, and the mixture was shaken until homogeneous. The OD value was detected at a wavelength of 550 nm using a microplate reader. The well with only the cell suspension without the test substance was used as the control well, and the well with only the complete medium was used as the blank well. The cell growth inhibition rate was calculated using the following formula.

[0212] Inhibition rate = (OD value コントロールウェル - OD value 投与ウェル ) / (OD value コントロールウェル - OD value ブランクウェル ) × 100% From the inhibition rates at each concentration, the half-maximal inhibitory concentration IC 50 was calculated using SPSS software, and the results are shown in Table 18.

Table 24

Table 25

[0213] Test Example 2: In Vivo Efficacy Test SPF, 4 - 5 week - old female NOD - SCID mice for the experiment were purchased from Beijing Vital River Laboratory Animal Technology Co., Ltd. One day before cell inoculation, the mice were intraperitoneally administered cyclophosphamide at a dose of 100 mg / kg. Human acute monocytic leukemia cells MV4 - 11 (1×107 / 0.1 ml / mouse) were subcutaneously injected into the axilla of the forelimb of the mice to construct a subcutaneous transplanted tumor model. When the tumor volume reached approximately 110 mM3 (on the 10th day after inoculation), the mice were evenly divided into groups of 5 based on tumor volume, and were set as a solvent control group (2%DMSO + 98% (0.2 g / mL) hydroxypropyl - β - cyclodextrin) and a test drug administration group respectively. The administration dose of the test drug administration group was 100 mg / kg, the administration volume was 10 mL / kg, the administration frequency was BID. The tumor diameter was measured twice a week, and the data were recorded. After 11 consecutive days of administration, the experiment was terminated, and the tumors were excised and the tumor weights were measured.

[0214] The weight gain rate, tumor volume and tumor weight inhibition rate were calculated by formulas. Weight gain rate = X (Wi-W0) / X W0 ×100% In the formula, W i represents the body weight of the mice in each experimental group on the nth day, and W0 represents the body weight of the mice in each experimental group at the start of administration. Tumor volume (V)=1 / 2×a×b 2 In the formula, a and b represent the major axis and minor axis of the tumor respectively, d0 is before being divided into cages for administration, and d9 is the 9th day of administration. Relative tumor volume (RTV)=Tumor volume on d9 / Tumor volume on d0 Tumor weight inhibition rate=(Tumor weight 溶媒対照群 - Tumor weight 被験薬投与群 ) / Tumor weight 溶媒対照群 ×100%. The results are shown in Table 19.

Table 26

[0215] The in vivo efficacy test results of MV4-11 show that the compound of formula (A) of the present invention has significant antitumor activity, and the inhibitory effects on tumor volume and tumor weight are significantly superior to those of the control drug GSK3326595.

[0216] Test Example 3: Pharmacokinetic Study The test compound (solvent: 2% DMSO + 98% (0.2 g / mL) hydroxypropyl-β-cyclodextrin, dosing volume: 5 mL / kg) was administered intragastrically to SD rats (male, 180 - 200 g, Beijing Vital River Laboratory Animal Technology Co., Ltd.). Blood was collected from the orbital sinus of the rats at different time points (0.25, 0.5, 1, 2, 4, 8, 24 h) after administration. The collected whole blood was prevented from coagulating with sodium heparin and centrifuged at 3000 g to obtain plasma samples of the rats. Proteins were precipitated with methanol, and the drug concentration in the plasma of the rats after administration was measured by HPLC-MS / MS method. A drug-time curve was drawn, pharmacokinetic parameters were calculated, and the in vivo pharmacokinetic behavior of the compound in the rats after administration was represented by the parameters of the statistical moment of the non-compartmental model. The results are shown in Table 20.

Table 27

[0217] According to the pharmacokinetic study results, compared with the positive control drug GSK3326595, all the compounds of formula (A) of the present invention were well absorbed in the rats in vivo, with a short peak arrival time, a high peak concentration, and a significantly increased in vivo exposure.

[0218] For a more clear understanding, the present invention has been described in considerable detail through explanations and examples. However, according to the teachings of the present invention, it is obvious that those skilled in the art may make some changes and modifications without departing from the spirit or scope of the appended claims.

Claims

1. It is an inorganic acid addition salt or an organic acid addition salt of the compound represented by formula (A), wherein the inorganic acid addition salt is a sulfate or a phosphate, and the organic acid addition salt is a compound selected from the group consisting of malate, oxalate, succinate, tartrate, adipate, citrate, gluconate, maleate, fumarate, lactate, and gentisate. 【Chemical 1】

2. In the inorganic acid addition salt or organic acid addition salt of the compound represented by formula (A), the chemical compounding ratio of the compound represented by formula (A) to an organic acid or an inorganic acid molecule is 1:1 to 1.

5. The compound according to claim 1.

3. The organic acid addition salt is selected from L - malate and oxalate, and the chemical compounding ratio of the compound represented by formula (A) to an L - malic acid molecule or an oxalic acid molecule is 1:1 to 1.

5. The compound according to claim 1.

4. The organic acid addition salt is selected from L - malate and oxalate, and the chemical compounding ratio of the compound represented by formula (A) to an L - malic acid molecule or an oxalic acid molecule is 1:

1. The compound according to claim 3.

5. It is a crystal form of the compound represented by formula (B), 【Chemical 2】 where n is from 1 to 1.

5. The crystal form is Crystal form I having diffraction peaks characteristic of the following 2θ angles in the X - ray powder diffraction pattern by Cu - Kα ray: 4.2 ± 0.2°, 6.5 ± 0.2°, 13.3 ± 0.2°, and 19.1 ± 0.2°, Crystal form II having diffraction peaks characteristic of the following 2θ angles in the X - ray powder diffraction pattern by Cu - Kα ray: 4.9 ± 0.2°, 6.6 ± 0.2°, 13.2 ± 0.2°, 18.7 ± 0.2°, and 19.8 ± 0.2°, Crystal form III having diffraction peaks characteristic of the following 2θ angles in the X - ray powder diffraction pattern by Cu - Kα ray: 4.3 ± 0.2°, 6.9 ± 0.2°, and 20.3 ± 0.2°, Crystal form IV having diffraction peaks characteristic of the following 2θ angles in the X - ray powder diffraction pattern by Cu - Kα ray: 4.4 ± 0.2°, 7.6 ± 0.2°, 8.9 ± 0.2°, 13.9 ± 0.2°, and 20.6 ± 0.2°, Crystal form V having diffraction peaks characteristic of the following 2θ angles in the X - ray powder diffraction pattern by Cu - Kα ray: 5.0 ± 0.2°, 13.6 ± 0.2°, 18.6 ± 0.2°, 19.6 ± 0.2°, and 20.2 ± 0.2°. The crystalline form VI having diffraction peaks characteristic of the following 2θ angles in the X-ray powder diffraction pattern by Cu-Kα line: 4.5 ± 0.2°, 7.0 ± 0.2°, 9.0 ± 0.2°, 12.9 ± 0.2°, 20.2 ± 0.2°, and 21.6 ± 0.2°, and A crystalline form selected from the group consisting of crystalline form VII having diffraction peaks characteristic of the following 2θ angles in the X-ray powder diffraction pattern by Cu-Kα line: 4.3 ± 0.2°, 6.9 ± 0.2°, 13.2 ± 0.2°, 19.1 ± 0.2°, and 20.0 ± 0.2°.

6. A crystalline form of the compound represented by formula (C), [Chemical Formula 3] (where n is from 1 to 1.5). The crystalline form is Crystalline form I having diffraction peaks characteristic of the following 2θ angles in the X-ray powder diffraction pattern by Cu-Kα line: 4.7 ± 0.2°, 7.1 ± 0.2°, 10.7 ± 0.2°, 17.4 ± 0.2°, 21.2 ± 0.2°, Crystalline form II having diffraction peaks characteristic of the following 2θ angles in the X-ray powder diffraction pattern by Cu-Kα line: 4.6 ± 0.2°, 13.0 ± 0.2°, and 21.6 ± 0.2°, Crystalline form III having diffraction peaks characteristic of the following 2θ angles in the X-ray powder diffraction pattern by Cu-Kα line: 4.6 ± 0.2°, 18.7 ± 0.2°, and 19.4 ± 0.2°, and A crystalline form selected from the group consisting of crystalline form IV having diffraction peaks characteristic of the following 2θ angles in the X-ray powder diffraction pattern by Cu-Kα line: 4.6 ± 0.2°, 13.7 ± 0.2°, 19.5 ± 0.2°, 20.0 ± 0.2°, and 22.9 ± 0.2°.

7. A pharmaceutical composition comprising the compound according to any one of claims 1 to 4 and a pharmaceutically acceptable carrier.

8. Use of the compound according to any one of claims 1 to 4 in the manufacture of a drug, wherein the drug is for treating a tumor.

9. The use according to claim 8, wherein the tumor is a hematological tumor or a solid tumor.

10. The use according to claim 8, wherein the tumor is selected from lung cancer, bone cancer, gastric cancer, pancreatic cancer, adenoid cystic cancer, skin cancer, head and neck cancer, uterine cancer, ovarian cancer, testicular cancer, fallopian tube cancer, endometrial cancer, cervical cancer, vaginal cancer, brain cancer, pituitary adenoma, melanoma, epidermal cancer, and chronic and acute leukemia.

11. The use according to claim 10, wherein the acute leukemia is acute myeloid leukemia.

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