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 priority to Chinese patent application No. 202111494667.8, filed on December 8, 2021. The present invention incorporates the full 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 crystalline forms and specific crystalline forms, pharmaceutical compositions containing them, and applications of the same in the pharmaceutical field. [Background technology]

[0003] Protein arginine methyltransferases (PRMTs) are S-adenosylmethionine (SAM or AdoMet)-dependent methyltransferases that can catalyze protein arginine methylation reactions, specifically by transferring the methyl group derived from AdoMet to the terminal guanidino nitrogen atom of arginine residues in histones or other proteins. PRMTs play important roles in protein methylation, such as being involved in selective splicing, post-transcriptional regulation, RNA processing, cell proliferation, cell differentiation, apoptosis, and tumorigenesis. According to the different ways of catalyzing arginine methylation, the 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 catalyze monomethylation.

[0004] PRMT5 was first isolated from a protein complex that binds to Jak2 (Janus tyrosine kinase 2) in yeast two-hybrid studies by Pollack et al., and is therefore also called JBP1 (jak-binding protein 1). PRMT5 not only regulates the processes of gene transcription and protein modification, but also plays a role in regulating cell proliferation, differentiation, and apoptosis in tumor cell growth, making it a highly potential target for tumor therapy. So far, the research and development of PRMT5 inhibitors is all in the early stages, with the most advanced being GSK3326595, released by GSK, which has entered phase I / II clinical trials. JNJ-64619178, first released by Janssen, PF-06939999, released by Pfizer, and PRT-543, released by Prelude Therapeutics, are all in phase I clinical trials. At present, the structural formulas of PF-06939999 and PRT-543 have not yet been made public. The structural formulas of GSK3326595 and JNJ-64619178 are as follows: [ka]

[0005] Currently, no PRMT5 inhibitors have been approved for sale, so the design and synthesis of novel PRMT5 inhibitors that combine good therapeutic effect with good administrability has important clinical application value. Summary of the Invention

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

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

[0008] According to some embodiments of the 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, even more preferably L-malate or oxalate.

[0009] According to some embodiments of the present invention, in the salt of the compound represented by formula (A), the chemical ratio of the compound represented by formula (A) to 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 formula (A) is a compound represented by formula (A-1). [ka]

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

[0012] According to some embodiments of the invention, X is an organic acid and is 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, 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 formula (A) or the compound represented by formula (A-1) is in a solid form.

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

[0015] According to some embodiments of the present invention, the compound represented by formula (A-1) is a compound represented by formula (B). [ka] (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 preferably 1 or 1.5.)

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

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

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

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

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

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

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

[0023] According to some embodiments of the present invention, the crystalline form I has a powder X-ray diffraction pattern using Cu-Kα radiation, which has characteristic diffraction peaks at the following 2θ angles (±0.2°): 4.2, 6.5, 13.3, 19.1, 20.1, and 22.0.

[0024] According to some embodiments of the present invention, the crystalline form I has a powder X-ray diffraction pattern using Cu-Kα radiation having characteristic diffraction peaks at the following 2θ angles (±0.2°): 4.2, 6.5, 13.3, 18.3, 19.1, 20.1, and 22.0.

[0025] According to some embodiments of the present invention, the crystalline form I has an X-ray powder diffraction pattern essentially as shown in FIG. 1 using Cu-Kα radiation.

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

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

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

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

[0031] According to some embodiments of the present invention, the crystalline form II has a powder X-ray diffraction pattern using Cu-Kα radiation, which 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, and 26.5.

[0032] According to some embodiments of the present invention, the crystalline form II has a powder X-ray diffraction pattern using Cu-Kα radiation, which 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, and 26.5.

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

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

[0035] According to some embodiments of the present invention, the crystalline form II has an X-ray powder diffraction pattern using Cu-Kα radiation essentially as shown in FIG.

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

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

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

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

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

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

[0043] According to some embodiments of the present invention, the crystalline form III has an X-ray powder diffraction pattern using Cu-Kα radiation essentially as shown in FIG.

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

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

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

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

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

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

[0051] According to some embodiments of the present invention, the crystalline form IV has an X-ray powder diffraction pattern using Cu-Kα radiation essentially as shown in FIG.

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

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

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

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

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

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

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

[0060] According to some embodiments of the present invention, the crystalline form V has an X-ray powder diffraction pattern essentially as shown in FIG. 5 using Cu-Kα radiation.

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

[0062] According to some embodiments of the present invention, the crystalline form V has endothermic peaks at 68.38±5° C. and 104.69±5° C. in a 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 crystalline form of the compound of formula (B) is crystalline form VI, and has characteristic diffraction peaks at the following 2θ angles (±0.2°) using Cu-Kα radiation.

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

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

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

[0068] According to some embodiments of the present invention, the crystalline form VI has an X-ray powder diffraction pattern using Cu-Kα radiation essentially as shown in FIG.

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

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

[0071] According to some embodiments of the present invention, the crystalline form of the compound of formula (B) is crystalline form VII, and has characteristic diffraction peaks at the following 2θ angles (±0.2°) using Cu-Kα radiation.

[0072] According to some embodiments of the present invention, the crystalline form VII has a powder X-ray diffraction pattern using Cu-Kα radiation having characteristic diffraction peaks at the following 2θ angles (±0.2°): 4.3, 6.9, 8.9, 13.2, 19.1, 20.0, and 21.7.

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

[0074] According to some embodiments of the present invention, the crystalline form VII has an X-ray powder diffraction pattern essentially as shown in FIG. 7 using Cu-Kα radiation.

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

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

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

[0078] According to some embodiments of the present invention, the compound represented by formula (A-1) is a compound represented by formula (C). [ka] (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 of Formula (C) is in a solid form.

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

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

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

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

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

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

[0086] According to some embodiments of the present invention, the crystalline form of the compound of formula (C) is crystalline form I, and has characteristic diffraction peaks at the following 2θ angles (±0.2°) using Cu-Kα radiation: 4.7, 7.1, 10.7, 16.1, 17.4, 20.1, and 21.2.

[0087] According to some embodiments of the present invention, the crystalline form of the compound of Formula (C) is crystalline form I, and has characteristic diffraction peaks at the following 2θ angles (±0.2°) using Cu-Kα radiation: 4.7, 7.1, 10.7, 16.1, 17.4, 19.6, 20.1, 21.2, and 23.2.

[0088] According to some embodiments of the present invention, the crystalline form of the compound of Formula (C) is crystalline form I, and has an X-ray powder diffraction pattern using Cu-Kα radiation essentially as shown in FIG.

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

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

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

[0092] According to some embodiments of the present invention, the crystalline form of the compound of Formula (C) is crystalline form II, and has an X-ray powder diffraction pattern essentially as shown in FIG. 9 using Cu-Kα radiation.

[0093] According to some embodiments of the present invention, the crystalline form of the compound of Formula (C) is crystalline 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 crystalline form of the compound of Formula (C) is crystalline 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 crystalline form of the compound of formula (C) is crystalline form III, and has characteristic diffraction peaks at the following 2θ angles (±0.2°) in an X-ray powder diffraction pattern using Cu-Kα radiation: 4.6, 18.7, and 19.4.

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

[0097] According to some embodiments of the present invention, the crystalline form of the compound of Formula (C) is crystalline Form III and has an X-ray powder diffraction pattern essentially as shown in FIG. 10 using Cu-Kα radiation.

[0098] According to some embodiments of the present invention, the crystalline form of the compound of Formula (C) is crystalline Form III, the differential scanning calorimetry curve of which has an endothermic peak at 204.9±5° C.

[0099] According to some embodiments of the present invention, the crystalline form of the compound of Formula (C) is crystalline 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 crystalline form of the compound of Formula (C) is crystalline 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 crystalline form of the compound of formula (C) is crystalline form IV, and has characteristic diffraction peaks at the following 2θ angles (±0.2°) as measured by Cu-Kα radiation in an X-ray powder diffraction pattern: 4.6, 13.7, 19.5, 20.0, and 22.9.

[0102] According to some embodiments of the present invention, the crystalline form of the compound of Formula (C) is crystalline form IV, and has an X-ray powder diffraction pattern using Cu-Kα radiation essentially as shown in FIG.

[0103] According to some embodiments of the present invention, the crystalline form of the compound of Formula (C) is crystalline form IV, the differential scanning calorimetry curve of which has an endothermic peak at 137.4±5° C.

[0104] According to some embodiments of the present invention, the crystalline form of the compound of Formula (C) is crystalline 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 formula (C) in the crystalline form is crystalline form V, and the single crystal obtained using Cu-Kα radiation is in the triclinic system, P1 space group, 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 Form I, Form II, Form III, Form IV, Form V, Form VI, and Form VII of the compound of formula (B).

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

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

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

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

[0111] According to some embodiments of the invention, the pharmaceutical composition further comprises a pharma- ceutically acceptable carrier.

[0112] According to a fifth aspect, the present invention relates to a salt of the compound represented by formula (A), a compound represented by formula (A-1), a compound represented by formula (A-1) in a solid form, a compound represented by formula (A-1) in a crystalline form, a compound represented by formula (B), a compound represented by formula (B) in a solid form, a compound represented by formula (B) in a crystalline form, a compound represented by formula (B-1), a compound represented by formula (B-1) in a solid form, a compound represented by formula (B-1) in a crystalline form, a crystalline form of the compound represented by formula (B-1), ... the compound of formula (C), a solid form of the compound of formula (C), a crystalline form of the compound of formula (C), the compound of formula (C-1), the compound of formula (C-2), a solid form of the compound of formula (C-1) or the compound of formula (C-2), a crystalline form of the compound of formula (C-1) or the compound of formula (C-2), crystalline form I of the compound of formula (C), crystalline form II of the compound of formula (C), crystalline form III of the compound of formula (C), crystalline form IV of the compound of formula (C), crystalline form V of the compound of formula (C), the crystalline composition according to the second or third aspect above, or the pharmaceutical composition according to the fourth aspect above, are provided for use as a medicament or in the manufacture of a medicament.

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

[0114] According to some embodiments of the invention, the medicament is used for preventing and / or treating a disease mediated at least in part by PRMT5.

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

[0116] According to a seventh aspect, the present invention provides a method for preventing and / or treating a disease or a cell proliferative disorder mediated at least in part by PRMT5, comprising administering to an individual in need thereof a therapeutically effective amount of a salt of the compound of formula (A), a compound of formula (A-1), a compound of formula (A-1) in solid form, a compound of formula (A-1) in crystalline form, a compound of formula (B), a compound of formula (B) in solid form, a compound of formula (B) in crystalline form, a compound of formula (B-1), a compound of formula (B-1) in solid form, a compound of formula (B-1) in crystalline form, crystalline form I of the compound of formula (B), crystalline form II of the compound of formula (B), crystalline form III of the compound of formula (B), crystalline form IV ... The present invention provides a method for administering to a patient suffering from a vascular endothelial cell transplant, comprising administering to the patient a crystalline form V of the compound represented by formula (C), crystalline form VI of the compound represented by formula (B), crystalline form VII of the compound represented by formula (B), the 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 the compound represented by formula (C-2), a crystalline form of the compound represented by formula (C-1) or the 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 above, or the pharmaceutical composition according to the fourth aspect above.

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

[0118] According to some embodiments of the present invention, the cell proliferative disorder according to the 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 a terminal solid tumor, even more preferably a relapsed / refractory hematological tumor or a terminal malignant solid tumor.

[0119] According to some embodiments of the invention, the tumor or cancer according to the fifth, sixth or seventh aspect above is selected from lung cancer, bone cancer, gastric cancer, pancreatic cancer, adenoid cystic carcinoma, 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, epidermoid cancer, squamous cell carcinoma, and chronic and acute leukemia, preferably, said acute leukemia is acute myeloid leukemia (AML).

[0120] According to an eighth aspect, the present invention provides a process for preparing a compound of formula (A-1), comprising reacting a compound of formula (A) with an acid in a suitable solvent and isolating to obtain a compound of formula (A-1).

[0121] [ka] (wherein X is an acid, preferably an inorganic acid or an organic acid; and n is selected from 0.5 to 2.) According to some embodiments of the invention, n is selected from 1 to 1.5, preferably 1, 1.1, 1.2, 1.3, 1.4 or 1.5, more preferably 1, 1.3, 1.4 or 1.5, and even more preferably 1.

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

[0123] According to some embodiments of the invention, X is an organic acid and is 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, 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 1-2:0.5-2, preferably 1:1-2, and more preferably 1:1.1-2.

[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, 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, and heterocycloalkane solvents, and is preferably one or a combination of two selected from ROH, RCOOR1, RCN, RCOR1, water, ROR1, RH, and heterocycloalkane solvents, wherein R and R1 are each independently selected from C 1-6 Preferably, R and R are each independently selected from the group consisting of straight chain or branched chain alkyl groups, 1-4 The reaction solvent is selected from linear or branched alkyl groups, and 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. In the case of a mixed solvent consisting of two solvents, the volume ratio of the amounts of the two solvents used is 1-20:20-1, preferably 1-19:19-1, and preferably 1-10:10-1.

[0127] According to the production method of the present invention, when the reaction is completed, the temperature is optionally lowered to -15 to 15°C, and the mixture is left to stand for 0.5 h to 5 days for static crystallization, and 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 liquid by an appropriate method such as adsorptive filtration, suction filtration, filtration, or centrifugation.

[0129] According to the production method of the present invention, the drying method may be any suitable known method, and is preferably drying at room temperature, vacuum drying at room temperature, or drying at 50° C. Specific drying conditions, for example, are preferably a drying time of 1 hour to 5 days, more preferably 3 hours to 3 days, and even more preferably 3 hours to 1 day. Regardless of which drying method is used, it is preferable that the amount of residual solvent in the obtained product meets the quality standard.

[0130] Definitions and Explanations Unless otherwise specified, the following terms and phrases used herein are intended to have the following meanings. A particular phrase or term, unless specifically defined, should not be considered indefinite or unclear, 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 compounds of formula (A) according to the present invention may have certain stereoisomeric forms, including cis and trans isomers, (R)- and (S)-enantiomers, and racemates thereof, with trans isomers being preferred.

[0132] In the present invention, "a salt of a compound represented by formula (A) or a compound represented by formula (A-1) in a solid form," "a compound represented by formula (B) in a solid form," or "a compound represented by formula (C) in a solid form," etc., refers to a compound represented by formula (A-1) in a solid form, a compound represented by formula (B) in a solid form, a compound represented by formula (C) in a solid form, etc., and includes the crystalline form and amorphous form 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] In the present invention, "a salt of a compound represented by formula (A) in a crystalline form or a compound represented by formula (A-1)", "a compound represented by formula (B) in a crystalline form" or "a compound represented by formula (C) in a crystalline form" refers to a compound represented by formula (A-1), a compound represented by formula (B), a compound represented by formula (C), etc., which are in a crystalline form, and includes 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 "solvate" refers to an association 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., and includes an association containing water molecules and one or more types of other solvent molecules at the same time, and an association containing only one or more types of other solvent molecules.

[0135] The term "hydrate" refers to an association of water molecules in a stoichiometric or non-stoichiometric ratio 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., of the present invention.

[0136] The "anhydrous and solvent-free form" means that it does not contain water molecules or solvent molecules, or it coexists with the 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., so that the water molecules or the solvent molecules are bound by a force other than intermolecular forces, for example, by adsorption.

[0137] The term "crystalline composition" refers to a solid form containing one or more of the specific crystalline forms of the compound of 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), and the compound represented by formula (C)). For example, in one embodiment of the present invention, the crystalline composition contains one, two or more of the crystalline forms I, II, III, IV, V, VI, and VII of the compound represented by formula (B). In addition to the crystalline forms of the present invention, the crystalline composition may optionally contain other crystalline forms, other crystalline forms, or other amorphous forms of the compound (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. Those skilled in the art should understand that the total content of each component in the crystalline composition is 100%.

[0138] The "room temperature" mentioned above is the usual meaning of room temperature in the art, which is generally 10 to 30°C, and preferably 25°C±5°C.

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

[0140] In the context of X-ray powder diffraction patterns, the term "basic" or "essentially as shown in the figures" refers to a crystalline form that is essentially pure, and in which 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 given pattern in the powder X-ray diffraction pattern. Furthermore, as the content of a crystalline form in a product gradually decreases, the diffraction peaks attributable to that crystalline form in the X-ray powder diffraction pattern may be reduced due to the detection sensitivity of the instrument. In addition, for any crystalline form, there may be some errors in the positions of the peaks, which are also known in the field of crystallography. For example, the positions of the peaks may shift due to changes in temperature when analyzing the sample, movement of the sample, calibration of the instrument, etc., and the measurement error of the 2θ value is usually ±0.2°. Therefore, this error should be taken into account when determining the structure of each crystalline form, and the term "basic" or "essentially as shown in the figures" is also intended to include such differences in the positions of the diffraction peaks.

[0141] In a DSC chart or a TGA chart, the term "basically" or "basically as shown in the figure" means that for the same crystalline form of the same compound, in successive analyses, the error of the thermal transition onset temperature, endothermic peak temperature, exothermic peak temperature, melting point, weight loss onset temperature or weight loss end temperature, etc., is typically about 5° C., and usually within about 3° C. When a certain compound has a certain thermal transition onset temperature, endothermic peak temperature, exothermic peak temperature, melting point, weight loss onset temperature or weight loss end temperature, etc., it means that the error is within ±5° C. of that temperature.

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

[0143] The term "tumor" includes benign tumors, malignant tumors, and borderline malignant tumors, and malignant tumors are collectively called cancer.

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

[0145] As used herein, the term "treatment" refers to alleviating or ameliorating a disease or condition, ameliorating a symptom due to potential metabolism, inhibiting a disease or condition, for example inhibiting the progression of a disease or condition, alleviating a disease or condition, eliminating a disease or condition, alleviating symptoms due to a disease or illness, or inhibiting a disease or condition.

[0146] The terms "pharmacologically acceptable carrier" or "pharmacologically acceptable auxiliary" refer to those carriers that have no significant irritating 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 known to those skilled in the art, including the specific embodiments listed below, embodiments formed by combination of other chemical synthetic methods, as well as equivalent substitution methods known to those skilled in the art, and 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, which must be suitable for the chemical transformations of the present invention and the reagents or materials required therefor. In order to obtain the compounds of the present invention, it is sometimes necessary for those skilled in the art to modify or select synthetic steps or reaction processes based on existing embodiments.

[0149] The present application will be specifically described below with reference to examples, but these examples are not intended to limit the present application. All solvents used in this application are commercially available and can be used without further purification.

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

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

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

[0153] The in vivo pharmacokinetic study results showed that the compound represented by formula (A) had better oral administration performance, faster absorption rate and better absorption.

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

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

[0156] For the first time, a solid form of a salt of the compound of formula (A) or a compound of formula (A-1) and a crystalline form of a salt of the compound of formula (A) or a compound of formula (A-1) are obtained, which 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 dissolving effect.

[0158] A solid form of the compound of formula (B), the compound of formula (B-1), the compound of formula (C), the compound of formula (C-1) or the compound of formula (C-2) is obtained, which has good properties and is easy to separate, transfer and weigh.

[0159] Solid forms of the compound of formula (B), the compound of formula (B-1), the compound of formula (C), the compound of formula (C-1) or the compound of formula (C-2) can be prepared and isolated in high purity (greater than 95%) and / or yield (greater than 80%).

[0160] 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) in crystalline form have good crystallinity.

[0161] The compound of formula (B) in crystalline form and its specific crystalline form, and the compound of formula (C) in crystalline form and its specific crystalline form are easy to purify and separate (e.g., by filtration), and are convenient to prepare.

[0162] Preferably, the crystalline form has good physical and chemical stability and good pharmaceutical potential. [Brief description of the drawings]

[0163] [Figure 1] 1 is an X-ray powder diffraction pattern of crystalline form I of the compound of formula (B) of Example 1. [Diagram 2] 1 is an X-ray powder diffraction pattern of crystalline form II of the compound of formula (B) of Example 2. [Diagram 3] 1 is an X-ray powder diffraction pattern of crystalline form III of the compound of formula (B) of Example 3. [Figure 4] 1 is an X-ray powder diffraction pattern of crystalline form IV of the compound of formula (B) of Example 4. [Diagram 5] 1 is an X-ray powder diffraction pattern of crystalline form V of the compound of formula (B) of Example 5. [Figure 6] 1 is an X-ray powder diffraction pattern of crystalline form VI of the compound of formula (B) of Example 6. [Figure 7] 1 is an X-ray powder diffraction pattern of crystalline form VII of the compound of formula (B) of Example 7. [Figure 8] 1 is an X-ray powder diffraction pattern of crystalline form I of the compound of formula (C) of Example 8. [Figure 9] 1 is an X-ray powder diffraction pattern of crystalline form II of the compound of formula (C) of Example 9. [Figure 10] 1 is an X-ray powder diffraction pattern of crystalline form III of the compound of formula (C) of Example 10. [Figure 11] 1 is an X-ray powder diffraction pattern of crystalline form IV of the compound of formula (C) of Example 11. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

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

[0165] 2. Differential Scanning Calorimeter (DSC) [Table 2]

[0166] 3. Thermal Gravimetric Analyzer (TGA) [Table 3]

[0167] 4. Nuclear Magnetic Resonance Spectroscopy (NMR) Instrument type: Bruker 400M nuclear magnetic resonance spectrometer (Bruker, GER) Contents and test media: 1 H NMR, test solvent is DMSO-d6.

[0168] 5. Infrared Spectroscopy (IR) Detection equipment: Perkin Elmer Spectrum 100 FT-IR infrared spectrometer Test method: weigh 3 mg of sample, dilute the tablet with KBr, and perform detection at room temperature. Specific parameters are: detection range: 4000~400cm -1 Wavenumber, resolution: 4cm -1 It is.

[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 fluids in the small intestine when a human is in a starving state before eating; FeSSIF: Simulates the intestinal fluids in the small intestine when a human is in a fed state after eating; SGF: Simulates the gastric fluids in an empty stomach when a human is in a starving state.

[0173] Test method: The sample to be measured is added to water or a biological solvent medium (4 mL), and mixed by rotation (~25 rpm) on a rotary incubator at 37°C. At the sampling point (in this invention, the sampling point is 24 hours), approximately 0.8 mL of the solution or suspension is collected in a centrifuge tube and centrifuged, the supernatant is filtered through a filter membrane, and the filtrate is used for the solubility measurement.

[0174] In order to make the contents of the present invention more understandable, the following will be described in further detail with reference to specific examples, but the specific embodiments do not limit the contents of the present invention. In the following production examples, examples, measurement examples or test examples, the test methods not specified in terms of specific conditions are selected according to the usual methods and conditions or according to the product instructions.

[0175] Preparation Example 1: Preparation of Compound of Formula (A) [ka]

[0176] Preparation of intermediate T-0: In a 100 mL reaction flask, 6-chloro-pyrimidine-4-formyl chloride (0.63 g, 3.56 mmol) was dissolved in dichloromethane (10 mL) and triethylamine (0.72 g, 7.12 mmol) was added at 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, and the reaction solution was diluted with water (5 mL) and extracted with dichloromethane (15 mL x 2). The combined organic layer was washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to remove the solvent to obtain a residue. The residue was purified by column chromatography (dichloromethane / methanol=10 / 1, v / v, the same applies below) to obtain intermediate compound T-0 (yellow oil, 0.68 g, 61.28%).

[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), triethylamine (0.25 g, 2.47 mmol) and tert-butyl 4-aminopiperidine-1-carboxylate (0.24 g, 1.2 mmol) were added in sequence, and the reaction solution was heated to 85° C. and reacted for 8 hours. After TLC showed the completion of the reaction, 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: (S)-tert-butyl 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), trifluoroacetic acid (1 mL) was added, and the mixture was reacted at room temperature for 1 hour. Concentration to dryness under reduced pressure gave 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 the mixture was stirred until clear. Then, under ice bath conditions, methoxyamine hydrochloride (1.31 g, 15.68 mmol, 2.0 eq) was added in batches, reacted for 2 hours, and filtered 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 was sufficient), intermediate T-3 (0.085 g, 0.73 mmol) and HATU (0.30 g, 0.789 mmol) were added in sequence and reacted at room temperature for 2 hours. After the completion of the reaction was shown by TLC, water and ethyl acetate were added and the liquids were separated. The organic phase was washed once each with water and saturated saline, 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 Compounds of Formula (B) The sample (0.5 g) of Preparation Example 1 was weighed and dissolved in isopropanol (5 mL), L-malic acid (2 eq) was added, the mixture was stirred at room temperature for about 10 hours, filtered, and dried at 50°C ± 5°C for 8 hours to obtain a solid, with a yield of 92.5%. Detection confirmed that a salt had already been produced and that the alkali / acid ratio was 1:1. IR (KBr, cm -1 ):3301.35,2939.94,1610.73,1528.35,1455.99,1367.93,1045.03.

[0182] A sample was taken for X-ray powder diffraction, which showed that it was a crystalline solid (Form I). The crystals were well formed, the pattern is shown in Figure 1, and the XRPD diffraction peak data is shown in Table 1. A sample was taken for DSC-TGA test, the DSC chart showed endothermic peaks at 102.15℃ and 113℃, and the TGA chart showed that the sample had a weight loss of 8.6522% between room temperature and 110℃. [Table 7]

[0183] Example 2: Preparation of Crystalline Form II of 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, the solution was stirred at room temperature for 7 days, filtered, and vacuum dried at a temperature of 50°C for 2 hours to obtain a solid. The sample was taken and subjected to X-ray powder diffraction, which showed that it was a crystalline solid (crystal form II). The crystals were well formed, and the pattern is shown in Figure 2, and the data of the XRPD diffraction peaks are shown in Table 2. The sample was taken and subjected to DSC-TGA test, which showed that the DSC chart had one endothermic peak at 89.8°C and one at 103.58°C, 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 Crystalline Form III of Compound of Formula (B) A sample (about 50 mg) of Example 1 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. A sample was taken for X-ray powder diffraction, which showed that it was a crystalline solid (crystal form III). The crystals were well formed, the pattern is shown in Figure 3, and the XRPD diffraction peak data is shown in Table 3. A sample was taken for DSC-TGA test, and the DSC chart showed endothermic peaks at 70.82°C and 117.93°C, 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 Crystalline Form IV of Compound of Formula (B) A sample (about 50 mg) of Example 1 was weighed into a sample bottle, and 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. A sample was taken for X-ray powder diffraction, which showed that it was a crystalline solid (crystal form IV). The crystals were well formed, and the pattern is shown in Figure 4, and the XRPD diffraction peak data is shown in Table 4. A sample was taken for DSC-TGA test, and the DSC chart showed two endothermic peaks at 77.91 ° ​​C and 113.27 ° C, 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 crystalline form V of compound of formula (B) A sample (about 50 mg) of Example 1 was weighed into a sample bottle, acetone (1.5 mL) was added, and the mixture was stirred at room temperature for 7 days, and filtered to obtain a solid. A sample was taken for X-ray powder diffraction, which showed that it was a crystalline solid (crystal form V). The crystals were well formed, and the pattern is shown in FIG. 5, and the XRPD diffraction peak data is shown in Table 5. A sample was taken for DSC-TGA test, and the DSC chart showed 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 crystalline form VI of compound of formula (B) An appropriate amount of the crystalline form IV obtained in Example 4 was weighed and dried in vacuum at a temperature of 50°C for 2 days to obtain a solid. A sample was taken for X-ray powder diffraction, which showed that it was a crystalline solid (crystalline form VI). The crystals were well formed, and the pattern is shown in Figure 6, and the XRPD diffraction peak data is shown in Table 6. A sample was taken for DSC-TGA test, which showed that 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 Crystalline Form VII of Compound of Formula (B) The sample (501.3 mg) obtained in Preparation 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, magnetic stirring was performed 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 generated and that the alkali / acid ratio was 1:1.5.

[0189] A sample was taken for X-ray powder diffraction, which showed that it was a crystalline solid (Form VII). The crystals were well formed, and the pattern is shown in Figure 7, and the XRPD diffraction peak data is shown in Table 7. A sample was taken for DSC-TGA test, and the DSC chart showed endothermic peaks at 92.4℃ and 197.3℃, and the TGA chart showed that the sample had a weight loss of 7.88% between room temperature and 110℃. [Table 13]

[0190] Example 8: Preparation of crystalline form I of compound of formula (C) The sample (0.5 g) of Preparation Example 1 was weighed and dissolved in isopropanol (5 mL), and oxalic acid (2 eq) was added. The mixture was stirred at room temperature for about 10 hours, filtered, and dried at 50°C ± 5°C for 6 hours to obtain a solid. The yield was 90%. Detection confirmed that a salt had already been produced. IR (KBr, cm -1 ): 3319.96,2936.96,1615.04,1526.12,1455.78,1368.16,1046.84.

[0191] A sample was taken for X-ray powder diffraction which showed it to be a crystalline solid (Form I). The crystals were well formed and the pattern is shown in Figure 8 and the XRPD diffraction peak data is given in Table 8. [Table 14]

[0192] Example 9: Preparation of Crystalline Form II of 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 from Preparation Example 1 was added, and the mixture was stirred magnetically 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%. Upon detection, it was confirmed that a salt had already been produced and that the alkali / acid ratio was about 1:1.5.

[0193] A sample was taken for X-ray powder diffraction, which showed that it was a crystalline solid (Form II). The crystals were well formed, and the pattern is shown in Figure 9, and the XRPD diffraction peak data is shown in Table 9. A sample was taken for DSC-TGA test, and the DSC chart showed an endothermic peak at 162.6℃, and the TGA chart showed that the sample had a weight loss of 3.20% between room temperature and 160℃. [Table 15]

[0194] Example 10: Preparation of Crystalline Form III of Compound of Formula (C) Oxalic acid dihydrate (6.3 mg) was weighed and placed in a vial, and a 2-methyltetrahydrofuran solution (40 mg / mL, 0.5 mL) of the sample of Preparation Example 1 was added, followed by magnetic stirring at room temperature for 3 days, and the solid was centrifuged and vacuum dried at room temperature for 1 day. Upon detection, it was confirmed that a salt had already been produced and that the alkali / acid ratio was about 1:1.

[0195] A sample was taken for X-ray powder diffraction, which showed that it was a crystalline solid (Form III). The crystals were well formed, and the pattern is shown in Figure 10, and the XRPD diffraction peak data is shown in Table 10. A sample was taken for DSC-TGA test, and the DSC chart showed endothermic peaks at 139.9℃ and 204.9℃, and the TGA chart showed that the sample had a weight loss of 6.20% between room temperature and 150℃. [Table 16]

[0196] Example 11: Preparation of Crystalline Form IV of Compound of Formula (C) Oxalic acid dihydrate (123.9 mg) and the sample of Preparation 1 (503.0 mg) were weighed and placed in a reaction flask, ethanol (10 mL) was added, and the mixture was stirred magnetically 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%. Upon detection, it was confirmed that a salt had already been produced and that the alkali / acid ratio was about 1:1.

[0197] A sample was taken for X-ray powder diffraction, which showed that it was a crystalline solid (Form IV). The crystals were well formed, and the pattern is shown in Figure 11, and the XRPD diffraction peak data is shown in Table 11. A sample was taken for DSC-TGA test, and the DSC chart showed an endothermic peak at 137.4℃, and the TGA chart showed that the sample had a weight loss of 4.26% between room temperature and 150℃. [Table 17]

[0198] Example 12: Preparation of crystalline form V of compound of formula (C) The sample (41 mg) from Preparation Example 1 and oxalic acid dihydrate (12.9 mg) were weighed into a glass bottle, and acetone / water mixed solvent (0.5 mL, v / v=1 / 1) was added. The mixture was heated to 80°C and stirred for 12 hours, then cooled gradually to room temperature to obtain a single crystal of the compound of formula (C) (acid-alkali ratio: 1:1). The single crystal obtained using Cu-Kα radiation was a triclinic crystal with a P1 space group, and its 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} was.

[0199] Example 13: Preparation of other organic acid addition salts of compounds of formula (A) Each sample of Production Example 1 was dissolved in the solvent shown in the table below to prepare a solution with a concentration of 40 mg / mL. Each different acid was weighed and added to a vial, and the prepared sample solution of Production Example 1 (0.5 mL) was then added. The specific test method is shown in the table below. The solid was centrifuged and vacuum dried at room temperature for 1 day.

[0200] Nuclear magnetic or HPLC content measurements showed that the sample of Preparation Example 1 could form salts with any of the acids shown in the table below, with the alkali / acid ratios all being 1:1, and could be separated to obtain solids. Furthermore, samples were taken for X-ray powder diffraction, with the specific results shown in the table below. [Table 18]

[0201] Example 14: Preparation of inorganic acid addition salts of compounds of formula (A) The following salts were obtained by the same preparation method as in Example 13, specifically as shown in the table below. [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 samples of Example 2 (crystalline form II of the compound of formula (B)), Example 3 (crystalline form III of the compound of formula (B)) and Example 4 (crystalline form IV of the compound of formula (B)) were weighed and placed in vials, and left for 7 days under conditions of 23°C / 33% RH and 25°C / 60% RH, respectively. Samples were then taken and subjected to X-ray powder diffraction to investigate the stability of the samples under different conditions. The results are shown in the table below. [Table 20] Conclusion: Crystal Form II of Example 2, Crystal Form III of Example 3 and Crystal Form IV of Example 4 were left under different humidity conditions, but none of the crystal forms changed.

[0203] Measurement Example 2: Solid-state stability test of different crystal forms of the compound of formula (B) Appropriate amounts of 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 out and placed in vials and left at high temperature (60°C, sealed) for 7 days. Samples were then taken and subjected to X-ray powder diffraction to investigate the stability of the samples under different conditions. The results are shown in the table below. [Table 21] Conclusion: The crystal form II of Example 2 and the crystal form V of Example 5 were left under high temperature conditions for 7 days, but the crystal forms remained stable.

[0204] Measurement Example 3: Long-term (3-month) stability test of crystalline form I of compound of formula (B) An appropriate amount of the sample of Example 1 (crystalline form I of compound of formula (B)) was weighed and placed in a vial for the study of long-term stability, and the results are shown in the table below. [Table 22] Conclusion: The purity of the crystalline form I of Example 1 remained almost unchanged during the 3-month long-term experiment, and the crystalline 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] The solubility of Example 7 (compound of formula (B), crystalline form VII), Example 10 (compound of formula (C), crystalline form) and a free sample (Preparation Example 1) in water, SGF and FassIF at 37° C. for 24 hours was tested and the results are shown in the table below.

[0207] [Table 23] The solubilities of crystalline form VII of compound of formula (B) and crystalline form IV of compound of formula (C) in water and FassIF medium were obviously higher than those of the free base samples obtained in Preparation Example 1.

[0208] Test Example 1: In vitro efficacy test 1. Enzyme Experimental Method Using radioisotope FlashPlate technology, the IC 50 was detected.

[0209] Each test compound was dissolved in dimethyl sulfoxide, then added to Echo384 wells and diluted to the desired concentration. Using the Echo550 device, the test substance was transferred from the diluted Echo384 wells to a 384-well reaction plate, and both the control and blank wells were transferred to dimethyl sulfoxide. PRMT5 was added to 1x reaction buffer (1x reaction buffer contains 10mM Tris-HCl; pH8.0; 0.01% Tween-20; 1mM DTT) to form a 1.67x enzyme solution (enzyme concentration: 5nM). Polypeptide substrate and [3H]-SAM were added to 1x reaction buffer to form a 2.5x substrate solution (final substrate concentrations of 100nM and 250nM, respectively). 15μL / well of 1.67x enzyme solution was added to the 384-well reaction plate. 15μL of 1x reaction buffer was used instead of the enzyme solution for the blank wells. The plates were centrifuged at 1000rpm for 1min and incubated at room temperature for 15min. 10 μL of 2.5x substrate solution was added per well to a 384-well reaction plate. The plate was centrifuged at 1000 rpm for 1 min. The reaction was allowed to proceed at 25°C for 60 min. 5 μL of reaction stop solution was added per well to the 384-well reaction plate to stop the reaction (reaction stop solution: 125 μM cold SAM solution). 25 μL per well was taken from the test wells and transferred to a Flashplate and left at room temperature for 1 h. The Flashplate was then washed three times with 0.1% Tween-20 solution. The plate was counted using a MicroBeta 2. The data was converted to percent inhibition 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%. IC fitting with XLFit 5.4.0.8 50 obtained. 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) was IMDM (Cat No. 12440-053, Gibco) supplemented with 10% serum FBS (Cat No. SA311.02, Cellmax). The cells were cultured at 37°C in a 5% CO2 incubator. The experimental reagents included dimethyl sulfoxide (Tianjin Kemiou Chemical Reagent Co., Ltd.), MTT (THIAZOLYL BLUE TETRAZOLIUM BROMIDE, CAS. NO. 298-93-1, VWR). The test control GSK3326595 was either self-produced or purchased commercially. The test substances were sealed and stored at 4°C.

[0211] The test substance was dissolved sufficiently in dimethyl sulfoxide so that the concentration was 5×10 -2The stock solution was stored at -20°C, with 100μL / well (2×103 cells / well) of complete medium suspension of human acute monocytic leukemia cells MV4-11 added to a 96-well culture plate, and then the corresponding test substances (100μL / well) of different concentrations were added, and each test substance was prepared at 8 concentrations, with three double-well tests set up for each concentration, and cultured at 37°C in a 5% CO2 incubator. On the 6th day, MTT (20μL / well) was added, and the mixture was cultured at 37°C in a 5% CO2 incubator for 4h, the supernatant was discarded, dimethyl sulfoxide (150μL / well) was added, and the mixture was shaken until uniform, and the OD value was detected at a wavelength of 550nm using a microplate reader. Wells containing no test substance and containing only the cell suspension were used as control wells, and wells containing only the complete medium were used as blank wells. The cell growth inhibition rate was calculated according to 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 rate of each concentration, the half inhibitory concentration IC was calculated using SPSS software. 50 The results are shown in Table 18. [Table 24] [Table 25] As a result of enzymatic and cellular screening, the compound of formula (A) of the present invention showed superior inhibitory activity at both the enzyme and cellular levels compared to the positive control drug GSK3326595 (the 208th compound in WO2014100719).

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

[0214] The body weight increase rate, tumor volume and tumor weight inhibition rate were calculated by mathematical formulas. Weight gain rate = X (Wi-W0) / X W0 ×100% In the formula, W i represents the body weight of the mouse in each experimental group on day n, and W0 represents the body weight of the mouse 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 long and short diameters of the tumor, respectively, d0 is before administration into cages, and d9 is the 9th day after administration. Relative tumor volume (RTV) = d9 tumor volume / d0 tumor volume 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 MV4-11 in vivo efficacy test results show that the compound of formula (A) of the present invention has significant antitumor activity, and its inhibitory effect on tumor volume and tumor weight is significantly superior to that of the control drug GSK3326595.

[0216] Test Example 3: Pharmacokinetics test The test compound (solvent: 2% DMSO + 98% (0.2 g / mL) hydroxypropyl β-cyclodextrin, dosage: 5 mL / kg) was administered intragastrically to SD rats (male, 180-200 g, Beijing Vital River Laboratory Animal Technology Co., Ltd.), and blood was collected from the rat's orbit at different times after administration (0.25, 0.5, 1, 2, 4, 8, 24 h). The collected whole blood was treated with sodium heparin to prevent blood coagulation, and centrifuged at 3000 g to obtain rat plasma samples. Proteins were precipitated with methanol, and the drug concentration in rat plasma after administration was measured by HPLC-MS / MS method, drug-time curves were drawn, pharmacokinetic parameters were calculated, and the in vivo pharmacokinetic behavior of rats after compound administration was represented by parameters of statistical moments of the non-compartment model, and the results are shown in Table 20. [Table 27]

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

[0218] Although the invention has been described in considerable detail by way of illustration and example for purposes of clearer understanding, it will be apparent to those skilled in the art, in accordance with the teachings of the invention, that certain changes and modifications may be made thereto without departing from the spirit or scope of the appended claims.

Claims

1. A compound which is an inorganic acid addition salt or an organic acid addition salt of a compound represented by formula (A): 【Chemistry 1】

2. The compound according to claim 1 , wherein the inorganic acid addition salt is a sulfate or phosphate salt.

3. 2. The compound of claim 1, wherein the organic acid addition salt is selected from the group consisting of malate, oxalate, succinate, tartrate, adipate, citrate, gluconate, maleate, fumarate, lactate and gentisate.

4. The compound according to claim 1, wherein 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 the organic acid or inorganic acid molecule is 1:0.5-2, preferably 1:1-1.5, 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, and even more preferably 1:

1.

5. The compound according to claim 1 , wherein the compound is a compound represented by formula (B): 【Chemistry 2】 (wherein 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 preferably 1 or 1.5.)

6. 6. The compound according to claim 5, wherein the compound is a compound represented by formula (B) in the form of crystalline form I, and the X-ray powder diffraction pattern of the compound using Cu-Kα radiation has characteristic diffraction peaks at the following 2θ angles: 4.2±0.2°, 6.5±0.2°, 13.3±0.2°, and 19.1±0.2°.

7. 6. The compound according to claim 5, wherein the compound is a compound represented by formula (B) in the form of crystalline form II, and the X-ray powder diffraction pattern of the compound using Cu-Kα radiation has characteristic diffraction peaks at the following 2θ angles: 4.9±0.2°, 6.6±0.2°, 13.2±0.2°, 18.7±0.2°, and 19.8±0.2°.

8. 6. The compound according to claim 5, wherein the compound is a compound represented by formula (B) in the form of crystalline form III, and the X-ray powder diffraction pattern of the compound using Cu-Kα radiation has characteristic diffraction peaks at the following 2θ angles: 4.3±0.2°, 6.9±0.2°, and 20.3±0.2°.

9. 6. The compound according to claim 5, wherein the compound is a compound of formula (B) in the form of crystalline form IV, and the X-ray powder diffraction pattern of the compound using Cu-Kα radiation has characteristic diffraction peaks at the following 2θ angles: 4.4±0.2°, 7.6±0.2°, 8.9±0.2°, 13.9±0.2°, and 20.6±0.2°.

10. 6. The compound according to claim 5, wherein the compound is a compound of formula (B) in the form of crystalline form V, and the X-ray powder diffraction pattern of the compound using Cu-Kα radiation has characteristic diffraction peaks at the following 2θ angles: 5.0±0.2°, 13.6±0.2°, 18.6±0.2°, 19.6±0.2°, and 20.2±0.2°.

11. 6. The compound according to claim 5, wherein the compound is a compound of formula (B) in the form of crystalline form VI, and the X-ray powder diffraction pattern of the compound using Cu-Kα radiation has characteristic diffraction peaks at the following 2θ angles: 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°.

12. 6. The compound according to claim 5, wherein the compound is a compound of formula (B) in the form of crystalline form VII, and the X-ray powder diffraction pattern of the compound using Cu-Kα radiation has characteristic diffraction peaks at the following 2θ angles: 4.3±0.2°, 6.9±0.2°, 13.2±0.2°, 19.1±0.2°, and 20.0±0.2°.

13. The compound according to claim 1 , wherein the compound is a compound represented by formula (C): 【Chemistry 3】 (wherein 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.)

14. The compound according to claim 13, wherein the compound is a compound of formula (C) in the form of crystalline form I, and the X-ray powder diffraction pattern of the compound using Cu-Kα radiation has characteristic diffraction peaks at the following 2θ angles: 4.7±0.2°, 7.1±0.2°, 10.7±0.2°, 17.4±0.2°, and 21.2±0.2°.

15. The compound according to claim 13, wherein the compound is a compound represented by formula (C) in the form of crystalline form II, and the X-ray powder diffraction pattern of the compound using Cu-Kα radiation has characteristic diffraction peaks at the following 2θ angles: 4.6±0.2°, 13.0±0.2°, and 21.6±0.2°.

16. 14. The compound according to claim 13, wherein the compound is a compound represented by formula (C) in the form of crystalline form III, and the X-ray powder diffraction pattern of the compound using Cu-Kα radiation has characteristic diffraction peaks at the following 2θ angles: 4.6±0.2°, 18.7±0.2°, and 19.4±0.2°.

17. 14. The compound according to claim 13, wherein the compound is a compound of formula (C) in the form of crystalline form IV, and the X-ray powder diffraction pattern of the compound using Cu-Kα radiation has characteristic diffraction peaks at the following 2θ angles: 4.6±0.2°, 13.7±0.2°, 19.5±0.2°, 20.0±0.2°, and 22.9±0.2°.

18. 18. A pharmaceutical composition comprising a compound according to any one of claims 1 to 17, preferably further comprising a pharma- ceutically acceptable carrier.

19. 20. Use of a compound according to any one of claims 1 to 17 or a pharmaceutical composition according to claim 18 in the manufacture of a medicament.

20. The use according to claim 19, wherein the drug is used for preventing and / or treating a cell proliferative disorder, preferably wherein the cell proliferative disorder is a tumor or cancer, more preferably wherein the tumor or cancer is a hematological tumor or a solid tumor, even more preferably wherein the tumor or cancer is a malignant hematological tumor or a terminal solid tumor, even more preferably wherein the tumor or cancer is a relapsed / refractory hematological tumor or a terminal malignant solid tumor.

21. 20. The use according to claim 19, wherein the medicament is used for preventing and / or treating a disease mediated at least in part by PRMT5.

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