A salt of a heterocyclic antitumor compound and a crystal form thereof

Abstract

The present application provides a crystal form of a free base of compound I, a salt of compound I and a crystal form of the salt of compound I. Some crystal forms and salt types provided by the present application have excellent effects in physical stability, chemical stability, hygroscopicity and the like, have good clinical application value, and can be used as excellent alternative forms for subsequent drug development.

Description

[0001] Citation of relevant applications

[0002] This invention claims priority to Chinese patent application No. 202211410146.4, filed on November 11, 2022, entitled "A Salt of a Heterocyclic Antitumor Compound and its Crystal Form", the entire contents of which are incorporated herein by reference. Technical Field

[0003] This invention relates to the field of crystal drug technology, specifically to the crystal form, salt, and preparation method of compound I (or compound of formula I) methyl ketone (6-((1-benzoylpiperidin-4-yl)amino)-2-isopropoxypyrimidin-4-yl)((3R,4R)-4-(3,4-dihydroisoquinoline-2(1H)-yl)-3-hydroxypiperidin-1-yl) as a PRMT5 inhibitor. Furthermore, this invention also relates to the use of the crystal form and salt of compound I in the prevention and / or treatment of PRMT5-related diseases and / or conditions. Background Technology

[0004] PRMT5 is a protein arginine methyltransferase (PRMT), an abbreviation for Proteinarginine N-methyltransferase 5, and a novel anti-tumor target related to epigenetic modifications. It has several aliases, including Hsl7, Jbp1, Skb1, Capsuleen, and Dart5. PRMT5 is a major enzyme in arginine monomethylation and symmetrical dimethylation. Increasing literature demonstrates that protein arginine methyltransferases play crucial roles in various biological processes, such as cell growth and proliferation, apoptosis, and metastasis.

[0005] The function of protein arginine methyltransferases is to transfer a methyl group from S-adenosylmethionine (or AdoMet or SAM) to an arginine residue in histones or other proteins, forming methylarginine and S-adenosylhomocysteine ​​(or SAH). Currently, nine members of this family (PRMT1–9) have been identified. Based on their catalytic arginine methylation mechanisms, PRMTs can be divided into three types: Type I PRMTs, including PRMT1, PRMT2, PRMT3, PRMT4, PRMT6, and PRM8, catalyze monomethylarginine (MMA) and asymmetric dimethylarginine (aDMA); Type II PRMTs, including PRMT5 and PRMT9, catalyze MMA and symmetric dimethylarginine (sDMA); and Type III PRMT, PRMT7, catalyzes only MMA. PRMT5, an epigenetic enzyme, symmetrically methylates arginine residues of histone or non-histone substrates, affecting multiple target genes and signaling pathways. It plays a crucial role in protein methylation, participating in alternative splicing, post-transcriptional regulation, RNA processing, cell proliferation, cell differentiation, apoptosis, and tumorigenesis. Substances that selectively inhibit PRMT5 could serve as potential, potent new anticancer drugs. The development of new drugs targeting PRMT5 plays a significant role in addressing unmet clinical needs and filling gaps in research. Summary of the Invention

[0006] The technical problem solved by the invention

[0007] Chinese patent application 202210517649.5 and international patent application PCT / CN2022 / 092346 disclose compounds as PRMT5 inhibitors and their preparation methods, including compound I (structure shown below) and its preparation method.

[0008]

[0009] Compound I is an effective PRMT5 inhibitor. In vitro enzyme activity studies have shown that it has a strong inhibitory effect on PRMT5 enzyme. Furthermore, in subcutaneous xenografting of human B-cell non-Hodgkin lymphoma Z-138 cell line into NOD / SCID female mice, it has shown excellent tumor suppression effects. Therefore, compound I may be a promising compound for the prevention and / or treatment of PRMT5-mediated diseases.

[0010] Currently, there are no reports on the crystal forms of compound I and its salts. Comprehensive and systematic screening of polymorphs and salt forms is an essential part of this research. Therefore, it is necessary to further screen the crystal forms of compound I and its salts, and develop crystal or salt forms suitable for large-scale production, providing more and better options for subsequent drug development.

[0011] Technical solutions to the problem

[0012] One objective of this invention is to provide a crystal form A of compound I, wherein the crystal form A, when irradiated with Cu-Kα, exhibits characteristic peaks at 4.0±0.2°, 18.4±0.2°, 20.3±0.2°, and 21.8±0.2° in its X-ray powder diffraction (XRPD) pattern at 2θ angles.

[0013] Preferably, the crystal form A, using Cu-Kα radiation, has characteristic peaks in its XRPD spectrum expressed at 2θ angles at 4.0±0.2°, 14.7±0.2°, 15.8±0.2°, 18.4±0.2°, 20.3±0.2°, and 21.8±0.2°.

[0014] More preferably, the crystal form A, using Cu-Kα radiation, has characteristic peaks in its XRPD spectrum expressed at 2θ angles at 4.0±0.2°, 7.1±0.2°, 13.6±0.2°, 14.7±0.2°, 15.8±0.2°, 18.4±0.2°, 20.3±0.2°, 21.8±0.2°, and 27.7±0.2°.

[0015] More preferably, the crystal form A has substantially the following characteristics: Figure 1 The XRPD spectrum shown.

[0016] In some embodiments of the present invention, the differential scanning calorimetry (DSC) spectrum of crystal form A has an endothermic peak in the vicinity of 85.0°C to 150.0°C.

[0017] Preferably, the DSC spectrum of crystal form A has an endothermic peak at a temperature ranging from 85.0℃±5℃ to 150.0℃±5℃.

[0018] More preferably, the crystal form A has substantially the following characteristics: Figure 2 The DSC spectrum shown.

[0019] In some embodiments of the present invention, the thermogravimetric analysis (TGA) spectrum of crystal form A has a weight loss of about 2.0% near 100.0°C and a weight loss of about 3.5% near 150.0°C.

[0020] Preferably, the TGA spectrum of crystal form A has a weight loss of about 2.0% at 100.0℃±5℃ and a weight loss of about 3.5% at 150.0℃±5℃.

[0021] More preferably, the crystal form A has substantially the following characteristics: Figure 2 The TGA spectrum shown.

[0022] Another object of the present invention is to provide a salt of compound I, said salt being a hydrochloride, hydrobromide, phosphate, sulfate, methanesulfonate, p-toluenesulfonate, camphorsulfonate (e.g., L-camphorsulfonate), oxalate, maleate, tartrate (e.g., L-tartrate), fumarate, citrate, malate (e.g., L-malate), glycolate, or benzoate of compound I.

[0023] Another object of the present invention is to provide a hydrochloride salt of compound I (e.g., compound I-1), wherein the salting ratio (molar ratio) of compound I to hydrochloric acid is 1:2.

[0024]

[0025] Another object of the present invention is to provide a hydrochloride crystal form A of compound I, wherein the salt formation ratio (molar ratio) of compound I to hydrochloric acid in hydrochloride crystal form A is 1:2.

[0026] In some embodiments of the present invention, the hydrochloride crystal form A of compound I, when irradiated with Cu-Kα, exhibits characteristic peaks at 4.4±0.2°, 15.3±0.2°, 18.0±0.2°, 18.8±0.2°, and 19.3±0.2° in its XRPD spectrum at 2θ angles.

[0027] Preferably, the hydrochloride crystal form A of compound I, when irradiated with Cu-Kα, exhibits characteristic peaks at 4.4±0.2°, 11.5±0.2°, 12.7±0.2°, 15.3±0.2°, 18.0±0.2°, 18.8±0.2°, 19.3±0.2°, and 21.6±0.2° in its XRPD spectrum at 2θ angles.

[0028] More preferably, the hydrochloride crystal form A of compound I, when irradiated with Cu-Kα, exhibits characteristic peaks at 4.4±0.2°, 8.5±0.2°, 11.5±0.2°, 12.7±0.2°, 14.0±0.2°, 15.3±0.2°, 16.7±0.2°, 18.0±0.2°, 18.8±0.2°, 19.3±0.2°, 20.9±0.2°, 21.6±0.2°, and 23.3±0.2° in its XRPD spectrum expressed at 2θ angles.

[0029] More preferably, the hydrochloride crystal form A of compound I has substantially the following characteristics: Figure 3 The XRPD spectrum shown.

[0030] In some embodiments of the present invention, the DSC spectrum of the hydrochloride crystal form A of compound I has an endothermic peak near 149.4 °C.

[0031] Preferably, the DSC spectrum of the hydrochloride crystal form A of compound I has an endothermic peak at 149.4℃±5℃.

[0032] More preferably, the hydrochloride crystal form A of compound I has substantially the following characteristics: Figure 4 The DSC spectrum shown.

[0033] In some embodiments of the present invention, the TGA spectrum of the hydrochloride crystal form A of compound I has a weight loss of about 0.3% near 100.0°C and a weight loss of about 16.3% near 235.0°C.

[0034] Preferably, the TGA spectrum of the hydrochloride crystal form A of compound I has a weight loss of about 0.3% at 100.0℃±5℃ and a weight loss of about 16.3% at 235.0℃±5℃.

[0035] More preferably, the hydrochloride crystal form A of compound I has substantially the following characteristics: Figure 4 The TGA spectrum shown.

[0036] Another object of the present invention is to provide an oxalate crystal form A of compound I, which, when irradiated with Cu-Kα, has a characteristic peak at 4.5±0.2°, 8.4±0.2°, 18.8±0.2°, 20.1±0.2°, and 21.2±0.2° in an XRPD spectrum at a 2θ angle.

[0037] Preferably, the oxalate crystal form A of compound I, when irradiated with Cu-Kα, exhibits characteristic peaks at 4.5±0.2°, 6.1±0.2°, 8.4±0.2°, 10.4±0.2°, 16.8±0.2°, 18.8±0.2°, 20.1±0.2°, and 21.2±0.2° in its XRPD spectrum at 2θ angles.

[0038] More preferably, the oxalate crystal form A of compound I, when irradiated with Cu-Kα, exhibits characteristic peaks at 4.5±0.2°, 5.2±0.2°, 6.1±0.2°, 8.4±0.2°, 10.4±0.2°, 15.8±0.2°, 16.3±0.2°, 16.8±0.2°, 17.6±0.2°, 18.8±0.2°, 20.1±0.2°, 21.2±0.2°, 22.3±0.2°, and 23.0±0.2° in its XRPD spectrum expressed at 2θ angles.

[0039] More preferably, the oxalate crystal form A of compound I has substantially the following properties: Figure 5 The XRPD spectrum shown.

[0040] In some embodiments of the present invention, the DSC spectrum of the oxalate crystal form A of compound I has an endothermic peak near 157.2 °C.

[0041] Preferably, the DSC spectrum of the oxalate crystal form A of compound I has an endothermic peak at 157.2℃±5℃.

[0042] More preferably, the oxalate crystal form A of compound I has substantially the following properties: Figure 6 The DSC spectrum shown.

[0043] In some embodiments of the present invention, the TGA spectrum of the oxalate crystal form A of compound I has a weight loss of about 4.0% at around 150.0 °C.

[0044] Preferably, the TGA spectrum of the oxalate crystal form A of compound I has a weight loss of about 4.0% at 150.0℃±5℃.

[0045] More preferably, the oxalate crystal form A of compound I has substantially the following properties: Figure 6 The TGA spectrum shown.

[0046] Another object of the present invention is to provide a tartrate salt of compound I (e.g., L-tartrate, i.e., compound I-2), wherein the salting ratio (molar ratio) of compound I to tartaric acid is 1:1.5.

[0047]

[0048] Another object of the present invention is to provide a tartrate (e.g., L-tartrate) crystal form A of compound I, wherein the salting ratio (molar ratio) of compound I to tartaric acid in crystal form A is 1:1.5.

[0049] In some embodiments of the present invention, the tartrate crystal form A of compound I, when subjected to Cu-Kα radiation, exhibits characteristic peaks at 15.5±0.2°, 16.0±0.2°, 18.4±0.2°, and 20.5±0.2° in its XRPD spectrum expressed at 2θ angles.

[0050] Preferably, the tartrate crystal form A of compound I, when irradiated with Cu-Kα, exhibits characteristic peaks at 5.8±0.2°, 8.8±0.2°, 11.7±0.2°, 15.5±0.2°, 16.0±0.2°, 18.4±0.2°, and 20.5±0.2° in its XRPD spectrum at 2θ angles.

[0051] More preferably, the tartrate crystal form A of compound I, when irradiated with Cu-Kα, exhibits characteristic peaks at 3.0±0.2°, 5.8±0.2°, 8.8±0.2°, 11.7±0.2°, 15.5±0.2°, 16.0±0.2°, 16.7±0.2°, 18.4±0.2°, 20.5±0.2°, and 21.2±0.2° in its XRPD spectrum at 2θ angles.

[0052] More preferably, the tartrate crystal form A of compound I has substantially the following properties: Figure 7 The XRPD spectrum shown.

[0053] In some embodiments of the present invention, the DSC spectrum of tartrate crystal form A of compound I has an endothermic peak near 174.8 °C.

[0054] Preferably, the DSC spectrum of tartrate crystal form A of compound I has an endothermic peak at 174.8℃±5℃.

[0055] More preferably, the tartrate crystal form A of compound I has substantially the following properties: Figure 8 The DSC spectrum shown.

[0056] In some embodiments of the present invention, the TGA spectrum of tartrate crystal form A of compound I has a weight loss of about 5.8% at around 150.0°C.

[0057] Preferably, the TGA spectrum of tartrate crystal form A of compound I has a weight loss of about 5.8% at 150.0℃±5℃.

[0058] More preferably, the tartrate crystal form A of compound I has substantially the following properties: Figure 8 The TGA spectrum shown.

[0059] Another object of the present invention is to provide a p-toluenesulfonate of compound I (e.g., compound I-3), wherein the salting ratio (molar ratio) of compound I to p-toluenesulfonic acid is 1:2.

[0060]

[0061] Another object of the present invention is to provide a p-toluenesulfonate crystal form A of compound I, wherein the salting ratio (molar ratio) of compound I to p-toluenesulfonic acid in p-toluenesulfonate crystal form A is 1:2.

[0062] In some embodiments of the present invention, the p-toluenesulfonate crystal form A of compound I, when irradiated with Cu-Kα, exhibits characteristic peaks at 4.0±0.2°, 8.1±0.2°, 18.3±0.2°, and 20.0±0.2° in its XRPD spectrum at 2θ angles.

[0063] Preferably, the p-toluenesulfonate crystal form A of compound I, when irradiated with Cu-Kα, exhibits characteristic peaks at 4.0±0.2°, 8.1±0.2°, 11.7±0.2°, 12.7±0.2°, 14.6±0.2°, 18.3±0.2°, 20.0±0.2°, and 23.1±0.2° in its XRPD spectrum at 2θ angles.

[0064] More preferably, the p-toluenesulfonate crystal form A of compound I, when irradiated with Cu-Kα, exhibits characteristic peaks at 4.0±0.2°, 6.2±0.2°, 8.1±0.2°, 8.8±0.2°, 11.7±0.2°, 12.7±0.2°, 14.6±0.2°, 16.3±0.2°, 17.5±0.2°, 18.3±0.2°, 19.0±0.2°, 20.0±0.2°, and 23.1±0.2° in its XRPD spectrum at 2θ angles.

[0065] More preferably, the p-toluenesulfonate crystal form A of compound I has substantially the following properties: Figure 10 The XRPD spectrum shown.

[0066] In some embodiments of the present invention, the DSC spectrum of p-toluenesulfonate crystal form A of compound I has endothermic peaks near 88.5 °C and near 150.1 °C.

[0067] Preferably, the DSC spectrum of p-toluenesulfonate crystal form A of compound I has endothermic peaks at 88.5℃±5℃ and 150.1℃±5℃.

[0068] More preferably, the p-toluenesulfonate crystal form A of compound I has substantially the following properties: Figure 11 The DSC spectrum shown.

[0069] In some embodiments of the present invention, the TGA spectrum of p-toluenesulfonate crystal form A of compound I has a weight loss of about 5.7% at around 130.0°C and a weight loss of about 4.7% at around 220.0°C.

[0070] Preferably, the TGA spectrum of p-toluenesulfonate crystal form A of compound I has a weight loss of about 5.7% at 130.0℃±5℃ and a weight loss of about 4.7% at 220.0℃±5℃.

[0071] More preferably, the p-toluenesulfonate crystal form A of compound I has essentially the following properties: Figure 11 The TGA spectrum shown.

[0072] Another object of the present invention is to provide a p-toluenesulfonate crystal form B of compound I, wherein the salting ratio (molar ratio) of compound I to p-toluenesulfonic acid in p-toluenesulfonate crystal form B is 1:2.

[0073] In some embodiments of the present invention, the p-toluenesulfonate crystal form B of compound I, when irradiated with Cu-Kα, exhibits characteristic peaks at 4.3±0.2°, 19.1±0.2°, and 20.2±0.2° in its XRPD spectrum expressed at 2θ angles.

[0074] Preferably, the p-toluenesulfonate crystal form B of compound I, when irradiated with Cu-Kα, exhibits characteristic peaks at 4.3±0.2°, 9.8±0.2°, 11.5±0.2°, 19.1±0.2°, and 20.2±0.2° in its XRPD spectrum at 2θ angles.

[0075] More preferably, the p-toluenesulfonate crystal form B of compound I, when irradiated with Cu-Kα, exhibits characteristic peaks at 4.3±0.2°, 4.9±0.2°, 9.8±0.2°, 11.5±0.2°, 17.2±0.2°, 19.1±0.2°, 20.2±0.2°, and 21.5±0.2° in its XRPD spectrum expressed at 2θ angles.

[0076] More preferably, the p-toluenesulfonate crystal form B of compound I, when irradiated with Cu-Kα, exhibits characteristic peaks at 4.3±0.2°, 4.9±0.2°, 9.0±0.2°, 9.8±0.2°, 11.5±0.2°, 17.2±0.2°, 19.1±0.2°, 20.2±0.2°, 21.5±0.2°, and 25.7±0.2° in its XRPD spectrum expressed at 2θ angles.

[0077] More preferably, the p-toluenesulfonate crystal form B of compound I, when irradiated with Cu-Kα, exhibits characteristic peaks at 4.3±0.2°, 4.9±0.2°, 7.1±0.2°, 9.0±0.2°, 9.8±0.2°, 11.5±0.2°, 12.8±0.2°, 17.2±0.2°, 19.1±0.2°, 20.2±0.2°, 21.5±0.2°, and 25.7±0.2° in its XRPD spectrum at 2θ angles.

[0078] More preferably, the p-toluenesulfonate crystal form B of compound I has substantially the following properties: Figure 13 or Figure 15 The X-ray powder diffraction pattern shown is shown.

[0079] In some embodiments of the present invention, the DSC spectrum of p-toluenesulfonate crystal form B of compound I has an endothermic peak near 192.1 °C, and preferably also has an endothermic peak near 124.8 °C.

[0080] Preferably, the DSC spectrum of p-toluenesulfonate crystal form B of compound I has an endothermic peak at 192.1±5℃, and more preferably, it also has an endothermic peak at 124.8℃±5℃.

[0081] More preferably, the p-toluenesulfonate crystal form B of compound I has substantially the following properties: Figure 16 The DSC spectrum shown.

[0082] In some embodiments of the present invention, the TGA spectrum of p-toluenesulfonate crystal form B of compound I has a weight loss of about 2.0% at around 167.3°C and a weight loss of about 5.2% at around 233.7°C.

[0083] Preferably, the TGA spectrum of p-toluenesulfonate crystal form B of compound I has a weight loss of about 2.0% at 167.3℃±5℃ and a weight loss of about 5.2% at 233.7℃±5℃.

[0084] More preferably, the p-toluenesulfonate crystal form B of compound I has substantially the following properties: Figure 16 The TGA spectrum shown.

[0085] In some embodiments of the present invention, the p-toluenesulfonate of compound I having crystal form B (e.g., p-toluenesulfonate with a salting ratio of 1:2) is a hydrate, preferably a monohydrate.

[0086] Another object of the present invention is to provide a pharmaceutical composition comprising the hydrochloride, hydrobromide, phosphate, sulfate, methanesulfonate, p-toluenesulfonate, camphorsulfonate (e.g., L-camphorsulfonate), oxalate, maleate, tartrate (e.g., L-tartrate), fumarate, citrate, malate (e.g., L-malate), glycolate, or benzoate of the aforementioned compound I.

[0087] Another object of the present invention is to provide a pharmaceutical composition comprising crystal form A of the aforementioned compound I, crystal form A of the hydrochloride salt of compound I, crystal form A of the oxalate salt of compound I, crystal form A of the tartrate salt (e.g., L-tartrate) of compound I, crystal form A of the p-toluenesulfonate salt of compound I, or crystal form B of the p-toluenesulfonate salt of compound I.

[0088] Another object of the present invention is to provide the use of the hydrochloride, hydrobromide, phosphate, sulfate, methanesulfonate, p-toluenesulfonate, camphorsulfonate (e.g., L-camphorsulfonate), oxalate, maleate, tartrate (e.g., L-tartrate), fumarate, citrate, malate (e.g., L-malate), glycolate, or benzoate of the aforementioned compound I, or a pharmaceutical composition comprising a salt of the aforementioned compound I, in the preparation of a medicament for the prevention and / or treatment of PRMT5-mediated diseases and / or conditions.

[0089] Another object of the present invention is to provide the use of the hydrochloride, hydrobromide, phosphate, sulfate, methanesulfonate, p-toluenesulfonate, camphorsulfonate (e.g., L-camphorsulfonate), oxalate, maleate, tartrate (e.g., L-tartrate), fumarate, citrate, malate (e.g., L-malate), glycolate, or benzoate of the aforementioned compound I, or a pharmaceutical composition comprising a salt of the aforementioned compound I, in the preparation of a medicament for the prevention and / or treatment of tumor diseases.

[0090] Preferably, the tumor is a solid tumor or a hematologic tumor, and more preferably a malignant solid tumor or a hematologic tumor.

[0091] More preferably, the tumor disease is lymphoma.

[0092] Another object of the present invention is to provide the use of the crystal form A of the aforementioned compound I, the hydrochloride crystal form A of compound I, the oxalate crystal form A of compound I, the tartrate crystal form A of compound I, the p-toluenesulfonate crystal form A of compound I, or the p-toluenesulfonate crystal form B of compound I, or the aforementioned pharmaceutical compositions comprising the base crystal form of compound I, in the preparation of a medicament for the prevention and / or treatment of PRMT5-mediated diseases and / or conditions.

[0093] Another object of the present invention is to provide the use of the crystal form A of the aforementioned compound I, the hydrochloride crystal form A of compound I, the oxalate crystal form A of compound I, the tartrate crystal form A of compound I, the p-toluenesulfonate crystal form A of compound I, or the p-toluenesulfonate crystal form B of compound I, or the aforementioned pharmaceutical composition comprising the base crystal form of compound I, in the preparation of a medicament for the prevention and / or treatment of tumor diseases.

[0094] Preferably, the tumor is a solid tumor or a hematologic tumor, and more preferably a malignant solid tumor or a hematologic tumor.

[0095] More preferably, the tumor disease is lymphoma.

[0096] Another object of the present invention is to provide a pharmaceutical composition of the aforementioned compound I, including its hydrochloride, hydrobromide, phosphate, sulfate, methanesulfonate, p-toluenesulfonate, camphorsulfonate (e.g., L-camphorsulfonate), oxalate, maleate, tartrate (e.g., L-tartrate), fumarate, citrate, malate (e.g., L-malate), glycolate, or benzoate, or a salt thereof, for the prevention and / or treatment of PRMT5-mediated diseases and / or conditions.

[0097] Another object of the present invention is to provide a pharmaceutical composition of the aforementioned compound I, including its hydrochloride, hydrobromide, phosphate, sulfate, methanesulfonate, p-toluenesulfonate, camphorsulfonate (e.g., L-camphorsulfonate), oxalate, maleate, tartrate (e.g., L-tartrate), fumarate, citrate, malate (e.g., L-malate), glycolate, or benzoate, or a salt thereof, for the prevention and / or treatment of tumor diseases.

[0098] Preferably, the tumor is a solid tumor or a hematologic tumor, and more preferably a malignant solid tumor or a hematologic tumor.

[0099] More preferably, the tumor disease is lymphoma.

[0100] Another object of the present invention is to provide a crystal form A of the aforementioned compound I, a hydrochloride crystal form A of compound I, an oxalate crystal form A of compound I, a tartrate crystal form A of compound I, a p-toluenesulfonate crystal form A of compound I, or a p-toluenesulfonate crystal form B of compound I, or a pharmaceutical composition comprising a base crystal form of the aforementioned compound I, for the prevention and / or treatment of PRMT5-mediated diseases and / or conditions.

[0101] Another object of the present invention is to provide a crystal form A of the aforementioned compound I, a hydrochloride crystal form A of compound I, an oxalate crystal form A of compound I, a tartrate crystal form A of compound I, a p-toluenesulfonate crystal form A of compound I, or a p-toluenesulfonate crystal form B of compound I, or a pharmaceutical composition comprising a base crystal form of compound I, for the prevention and / or treatment of tumor diseases.

[0102] Preferably, the tumor is a solid tumor or a hematologic tumor, and more preferably a malignant solid tumor or a hematologic tumor.

[0103] More preferably, the tumor disease is lymphoma.

[0104] Another object of the present invention is to provide a method for preventing and / or treating PRMT5-mediated diseases and / or conditions, comprising the steps of: administering a preventive and / or therapeutically effective amount of the aforementioned compound I, in the form of a hydrochloride, hydrobromide, phosphate, sulfate, mesylate, p-toluenesulfonate, camphorsulfonate (e.g., L-camphorsulfonate), oxalate, maleate, tartrate (e.g., L-tartrate), fumarate, citrate, malate (e.g., L-malate), glycolate, or benzoate, or a pharmaceutical composition comprising a salt of the aforementioned compound I, to an individual in need.

[0105] Another object of the present invention is to provide a method for preventing and / or treating tumor diseases, comprising the steps of: administering a preventive and / or therapeutically effective amount of the aforementioned compound I, in the form of a hydrochloride, hydrobromide, phosphate, sulfate, methanesulfonate, p-toluenesulfonate, camphorsulfonate (e.g., L-camphorsulfonate), oxalate, maleate, tartrate (e.g., L-tartrate), fumarate, citrate, malate (e.g., L-malate), glycolate, or benzoate, or a pharmaceutical composition comprising a salt of the aforementioned compound I, to an individual in need.

[0106] Preferably, the tumor is a solid tumor or a hematologic tumor, and more preferably a malignant solid tumor or a hematologic tumor.

[0107] More preferably, the tumor disease is lymphoma.

[0108] Another object of the present invention is to provide a method for preventing and / or treating PRMT5-mediated diseases and / or conditions, comprising the steps of: administering a preventive and / or therapeutically effective amount of the aforementioned compound I crystal form A, compound I hydrochloride crystal form A, compound I oxalate crystal form A, compound I tartrate crystal form A, compound I p-toluenesulfonate crystal form A, or compound I p-toluenesulfonate crystal form B, or a pharmaceutical composition comprising a base crystal form of compound I, to an individual in need.

[0109] Another object of the present invention is to provide a method for preventing and / or treating tumor diseases, comprising the steps of: administering a preventive and / or therapeutically effective amount of the aforementioned compound I crystal form A, compound I hydrochloride crystal form A, compound I oxalate crystal form A, compound I tartrate crystal form A, compound I p-toluenesulfonate crystal form A, or compound I p-toluenesulfonate crystal form B, or the aforementioned pharmaceutical composition comprising a base crystal form of compound I to an individual in need.

[0110] Preferably, the tumor is a solid tumor or a hematologic tumor, and more preferably a malignant solid tumor or a hematologic tumor.

[0111] More preferably, the tumor disease is lymphoma.

[0112] For the treatment of tumor diseases, the hydrochloride, hydrobromide, phosphate, sulfate, methanesulfonate, p-toluenesulfonate, camphorsulfonate (e.g., L-camphorsulfonate), oxalate, maleate, tartrate (e.g., L-tartrate), fumarate, citrate, malate (e.g., L-malate), glycolate, or benzoate of the aforementioned compound I, or crystal form A of the aforementioned compound I, crystal form A of the hydrochloride of compound I, crystal form A of the oxalate of compound I, crystal form A of the tartrate of compound I, crystal form A of the p-toluenesulfonate of compound I, or crystal form B of the p-toluenesulfonate of compound I, may be co-administered with other therapeutic agents (e.g., chemotherapy drugs, biological therapeutic agents, etc.) or combined with other treatment methods, including but not limited to radiotherapy.

[0113] The effects of the invention

[0114] This invention provides for the first time multiple crystal forms and salt forms of compound I. Some of the crystal forms and salt forms provided by this invention exhibit excellent properties in at least one aspect, such as physical stability, chemical stability, and hygroscopicity, and have good clinical application value, serving as excellent alternatives for subsequent drug development. Attached Figure Description

[0115] Figure 1 This is the XRPD spectrum of compound I, crystal form A.

[0116] Figure 2 The images show the DSC and TGA spectra of crystal form A of compound I.

[0117] Figure 3 The image shows the XRPD spectrum of compound I hydrochloride crystal form A.

[0118] Figure 4 The images show the DSC and TGA spectra of crystal form A of compound I hydrochloride.

[0119] Figure 5The image shows the XRPD spectrum of oxalate form A of compound I.

[0120] Figure 6 The images show the DSC and TGA spectra of oxalate form A of compound I.

[0121] Figure 7 The image shows the XRPD spectrum of tartrate form A of compound I.

[0122] Figure 8 The images show the DSC and TGA spectra of tartrate form A of compound I.

[0123] Figure 9 For compound I tartrate crystal form A 1 H NMR spectrum.

[0124] Figure 10 The image shows the XRPD spectrum of compound I p-toluenesulfonate crystal form A.

[0125] Figure 11 The images show the DSC and TGA spectra of compound I, p-toluenesulfonate, crystal form A.

[0126] Figure 12 For compound I p-toluenesulfonate crystal form A 1 H NMR spectrum.

[0127] Figure 13 The image shows the XRPD spectrum of compound I, p-toluenesulfonate, crystal form B.

[0128] Figure 14 For compound I p-toluenesulfonate crystal form B 1 H NMR spectrum.

[0129] Figure 15 The image shows the XRPD spectrum of compound I, p-toluenesulfonate, crystal form B.

[0130] Figure 16 The images show the DSC and TGA spectra of compound I, p-toluenesulfonate, crystal form B.

[0131] Figure 17 This is the XRPD spectrum of compound I in its amorphous form. Detailed Implementation

[0132] The technical solution of the present invention will be further described in detail below with reference to specific embodiments. The following embodiments are merely illustrative and explanatory of the present invention and should not be construed as limiting the scope of protection of the present invention. All technologies implemented based on the above content of the present invention are covered within the scope of protection intended by the present invention.

[0133] Unless otherwise stated, the raw materials and reagents used in the following examples are commercially available products or can be prepared by known methods.

[0134] Test instruments used in the experiment

[0135] 1. Differential Scanning Calorimeter TA Discovery 2500 (TA, US): After weighing, the sample is placed in a perforated DSC Tzero sample pan and heated to the final temperature at a rate of 10℃ / min. The nitrogen purging rate in the furnace is 50mL / min.

[0136] 2. Thermogravimetric analyzer TA Discovery 55 (TA, US): The sample is placed in a pre-equilibrated open aluminum sample pan and automatically weighed in the TGA furnace. The sample is heated to the final temperature at a rate of 10℃ / min, with nitrogen purging at the sample at a rate of 60 mL / min and nitrogen purging at the balance at a rate of 40 mL / min.

[0137] 3. Synchronous thermal analyzer NETZSCH STA449F3 (NETZSCH, GER): The determination was carried out according to the thermal analysis method of General Chapter 0661 of Part IV of the 2015 edition of the Pharmacopoeia of the People's Republic of China. The range was 26℃-350℃ and the scanning speed was 20.0K / min.

[0138] 4. X-ray powder diffractometer Bruker D8 Advance (Bruker, GER): 2θ scanning angle from 3° to 45°, scanning step size of 0.02°, and exposure time of 0.12 seconds. The phototube voltage and current for the test sample were 40kV and 40mA, respectively, and the sample disk was a zero-background sample disk.

[0139] 5. Panalytical Empyrean X-ray powder diffractometer (Panalytical, NL): 2θ scanning angle from 3° to 45°, scanning step size of 0.013°, and exposure time of 20.4 seconds. The phototube voltage and current for the test sample were 45kV and 40mA, respectively, and the sample disk was a zero-background sample disk.

[0140] 6. Bruker D2 PHASER X-ray powder diffractometer: Cu target, tube voltage (30kV), tube current (10mA), 2θ scanning range 2-40°, scanning speed 0.10s, step size 0.020°.

[0141] 7. Nuclear magnetic resonance analysis (1H NMR): The solid sample was dissolved in deuterated dimethyl sulfoxide (DMSO-d6) solvent and subjected to nuclear magnetic resonance analysis on a Bruker AVANCE-III (Bruker, GER).

[0142] 8. Ion chromatography (IC) ICS 5000 (Thermo Fisher, US), instrument parameters are as follows:

[0143]

[0144] 9. Dynamic moisture adsorption-desorption analysis (DVS) was performed using DVS Intrinsic (SMS, UK): The test adopted a gradient mode with humidity changes ranging from 50% to 95% to 0% to 50%. Within the range of 0% to 90%, the humidity change for each gradient was 10%. The gradient endpoint was determined using the dm / dt method, with a dm / dt value less than 0.002% maintained for 10 minutes as the gradient endpoint. After the test, XRPD analysis was performed on the sample to confirm whether the solid form had changed.

[0145] 10. Nuclear Magnetic Resonance Imaging (NMR) 1 H NMR): Bruker AVANCE NEO 400MHz.

[0146] 11. Liquid chromatography-mass spectrometry (LC-MS): Waters ACQUITY UPLC H-Class PLUS or / and SQD2.

[0147] Example 1: Preparation of Compound I

[0148] Preparation of (6-((1-benzoylpiperidin-4-yl)amino)-2-isopropoxypyrimidin-4-yl)((3R,4R)-4-(3,4-dihydroisoquinoline-2(1H)-yl)-3-hydroxypiperidin-1-yl)methyl ketone (Compound I)

[0149] Step 1: Preparation of 6-((1-(tert-Butoxycarbonyl)piperidin-4-yl)amino)-2-chloropyrimidin-4-carboxylic acid

[0150]

[0151] Methyl 6-((1-(tert-Butoxycarbonyl)piperidin-4-yl)amino)-2-chloropyrimidin-4-carboxylate (500 mg, 1.347 mmol, 1.0 equiv.) was dissolved in acetonitrile (5 mL), and potassium trimethylsilanolate (0.1729 g, 1.347 mmol, 1.0 equiv.) was added. The mixture was stirred at 25 °C for 1 hour. After the reaction was completed by LC-MS, the solution was concentrated, dissolved in 10% dichloromethane-methanol solution, filtered, and the filtrate was concentrated to give the title compound (480 mg, yield: 99.8%).

[0152] LC-MS(ESI)[M+H] + =357.2.

[0153] Step 2: Preparation of 6-((1-(tert-butoxycarbonyl)piperidin-4-yl)amino)-2-isopropoxypyrimidine-4-carboxylic acid

[0154]

[0155] 6-((1-(tert-Butoxycarbonyl)piperidin-4-yl)amino)-2-chloropyrimidin-4-carboxylic acid (480 mg, 1.35 mmol, 1.0 equiv.) was dissolved in isopropanol (5 mL), and potassium tert-butoxide (628.8 mg, 5.4 mmol, 4.0 equiv.) was added. The mixture was stirred at 90 °C for 3 hours. The reaction was confirmed by LC-MS, concentrated, and purified by preparative TLC (MeOH:DCM = 10%, v / v) to give the title compound (529 mg, yield: 99.3%).

[0156] LC-MS(ESI)[M+H] + =381.3.

[0157] Step 3: Preparation of tert-butyl 4-((6-((3R,4R)-4-(3,4-dihydroisoquinoline-2(1H)-yl)-3-hydroxypiperidine-1-carbonyl)-2-isopropoxypyrimidine-4-yl)amino)piperidine-1-carboxylic acid

[0158]

[0159] 6-((1-(tert-Butoxycarbonyl)piperidin-4-yl)amino)-2-isopropoxypyrimidin-4-carboxylic acid (200 mg, 0.526 mmol, 1.0 equiv.) was dissolved in N,N-dimethylformamide (2 mL), followed by (3R,4R)-4-(3,4-dihydroisoquinoline-2(1H)-yl)piperidin-3-ol (146.6 mg, 0.631 mmol, 1.2 equiv.), HATU (299.8 mg, 0.789 mmol, 1.5 equiv.), and N,N-diisopropylethylamine (203.8 mg, 1.577 mmol, 3.0 equiv.). The mixture was stirred at room temperature for 2 hours. After the reaction was completed, the mixture was extracted and concentrated by LC-MS, and then separated by reversed-phase chromatography to give the compound (80 mg, yield: 25.6%).

[0160] LC-MS(ESI)[M+H] + =595.4.

[0161] Step 4: Preparation of ((3R,4R)-4-(3,4-dihydroisoquinoline-2(1H)-yl)-3-hydroxypiperidin-1-yl)(2-isopropoxy-6-(piperidin-4-ylamino)pyrimidin-4-yl)methyl ketone

[0162]

[0163] 4-((6-((3R,4R)-4-(3,4-dihydroisoquinoline-2(1H)-yl)-3-hydroxypiperidin-1-carbonyl)-2-isopropoxypyrimidin-4-yl)amino)piperidin-1-carboxylic acid tert-butyl ester (80 mg, 0.134 mmol, 1.0 equiv.) was dissolved in dichloromethane (2 mL), and trifluoroacetic acid (0.5 mL) was added. The mixture was stirred at 25 °C for 1 hour. After the reaction was completed as detected by LC-MS, the solution was concentrated to give the title compound (70 mg crude product).

[0164] LC-MS(ESI)[M+H] + =495.3.

[0165] Step 5: Preparation of (6-((1-benzoylpiperidin-4-yl)amino)-2-isopropoxypyrimidin-4-yl)((3R,4R)-4-(3,4-dihydroisoquinoline-2(1H)-yl)-3-hydroxypiperidin-1-yl)methyl ketone

[0166]

[0167] ((3R,4R)-4-(3,4-dihydroisoquinoline-2(1H)-yl)-3-hydroxypiperidin-1-yl)(2-isopropoxy-6-(piperidin-4-ylamino)pyrimidin-4-yl) methyl ketone (70 mg, 0.142 mmol, 1.0 equiv.) was dissolved in dichloromethane (1 mL), and N,N-diisopropylethylamine (54.77 mg, 0.425 mmol, 3.0 equiv.) was added. The mixture was stirred in an ice bath for 15 min, and then benzoyl chloride (21.96 mg, 0.156 mmol, 1.1 equiv.) was added. The mixture was gradually brought to room temperature and stirred for 2 h. After the reaction was completed as detected by LC-MS, the solution was concentrated to obtain the crude product, which was then separated by reversed-phase chromatography to obtain compound I (37 mg, yield: 43.7%).

[0168] Measurements were performed using instruments 10 and 11 mentioned above, and the LC-MS (ESI) [M+H] concentration was determined. + =599.3; 1H NMR (400MHz, CDCl3) δ7.49-7.36(m,5H),7.14(m,3H),7.07-6.95(m,1H),6.21(d,J=22.4Hz,1H),5.32-5.12(m,1H),5.09-4.55(m,3H),4. 29(m,1H),3.97(m,1H),3.85-3.59(m,3H),3.27-2.87(m,6H),2.85-2 .53(m,3H),2.07-2.01(m,3H),1.77-1.51(m,3H),1.41-1.28(m,6H).

[0169] The XRPD spectrum of compound I, as determined by instrument 4, is as follows: Figure 17 As shown.

[0170] Example 2: Preparation of salt of compound I

[0171] Using compound I prepared in Example 1 as a sample, 29.9 mg and 2 equivalents of 15 acidic compounds were weighed and added to a certain amount of selected solvent. The mixture was suspended at room temperature for 3 days. The suspension was then centrifuged, and the solid was dried under vacuum at room temperature. The obtained solid was subjected to XRPD testing using the aforementioned instrument 5. The results are shown in the table below.

[0172]

[0173] As can be seen from the table, the following crystal forms of salts were found after screening: hydrochloride crystal form A, p-toluenesulfonate crystal form A, p-toluenesulfonate crystal form B, tartrate crystal form A, and oxalate crystal form A.

[0174] Example 3: Preparation of crystal form A of compound I

[0175] Using compound I prepared in Example 1 as a sample, 19.8 mg was weighed and suspended in a mixed solvent of 0.2 mL ethyl acetate and 0.8 mL cyclohexane at room temperature for 7 days. The suspension was centrifuged and dried to obtain a solid, which was named crystal form A of compound I.

[0176] The XRPD spectrum of crystal form A of compound I, as detected by the aforementioned instrument 4, is as follows: Figure 1 As shown, the diffraction peak data are as follows; the DSC and TGA spectra detected by instruments 1 and 2 are as follows. Figure 2 As shown.

[0177] #peak 2θ angle (°) strength(%) #peak 2θ angle (°) strength(%) 1 4.01 98.5 6 16.22 64.9 2 7.10 50.5 7 18.37 80.0 3 13.63 58.5 8 20.28 100.0 4 14.68 64.6 9 21.83 80.9 5 15.79 66.2 10 27.68 32.1

[0178] Example 4: Crystal form A of the hydrochloride salt of compound I

[0179] Using compound I prepared in Example 1 as a sample, 28.5 mg (about 0.05 mmol) and 2 equivalents of hydrochloric acid (calculated as hydrogen chloride) were weighed and added to 1 mL of a mixed solvent of tetrahydrofuran / cyclohexane (v / v, 1:1). The mixture was stirred at room temperature for 2 days. The suspension was centrifuged and the solid was dried to obtain a new hydrochloride crystal form of compound I, which was named hydrochloride crystal form A of compound I.

[0180] The ion chromatography results obtained by the aforementioned instrument 8 showed that the chloride ion content was 10.2%, which is consistent with the theoretical content of 2 equivalent chloride ions (10.4%). Therefore, the salt formation ratio of compound I and hydrochloric acid (calculated as hydrogen chloride) is 1:2.

[0181] The XRPD spectrum of the hydrochloride crystal form A of compound I, as detected by the aforementioned instrument 5, is as follows: Figure 3 As shown, the diffraction peak data are as follows; the DSC and TGA spectra detected by instruments 1 and 2 are as follows. Figure 4 As shown.

[0182] #peak 2θ angle (°) strength(%) #peak 2θ angle (°) strength(%) 1 4.42 71.2 26 26.58 29.9 2 7.20 26.9 27 26.73 37.4 3 8.49 39.2 28 26.96 28.0 4 8.86 23.9 29 27.66 12.4 5 11.47 44.0 30 28.22 18.1 6 12.74 43.2 31 28.66 13.1 7 13.95 39.7 32 29.56 22.8 8 14.45 26.1 33 30.10 8.7 9 14.65 35.8 34 30.95 12.6 10 15.29 61.2 35 31.68 11.9 11 16.66 36.7 36 32.61 16.5 12 17.02 16.3 37 33.03 21.1 13 18.02 100.0 38 33.84 9.2 14 18.81 66.6 39 34.88 16.6 15 19.33 80.5 40 35.41 7.7 16 19.66 22.8 41 36.44 9.1 17 20.91 35.5 42 37.20 14.3 18 21.62 43.2 43 38.39 12.8 19 22.28 19.2 44 39.15 8.0 20 22.85 25.3 45 40.22 6.5 21 23.25 37.9 46 41.09 13.7 22 23.56 18.5 47 42.63 6.1 23 24.47 8.9 48 43.60 6.0 24 25.56 28.2 49 44.54 7.5 25 26.20 25.9

[0183] Example 5: Oxalate crystal form A of compound I

[0184] Using compound I prepared in Example 1 as a sample, 29.6 mg (about 0.05 mmol) and 2 equivalents of oxalic acid were weighed and added to 1 mL of a mixed solvent of ethanol / n-heptane (v / v, 3:7). The mixture was stirred at room temperature for 3 days. The suspension was centrifuged and the solid was dried to obtain a new oxalate crystal form of compound I, which was named oxalate crystal form A of compound I.

[0185] The XRPD spectrum of oxalate crystal form A of compound I, as detected by the aforementioned instrument 5, is as follows: Figure 5 As shown, the diffraction peak data are as follows; the DSC and TGA spectra detected by instruments 1 and 2 are as follows. Figure 6 As shown.

[0186] #peak 2θ angle (°) strength(%) #peak 2θ angle (°) strength(%) 1 4.51 92.4 15 20.14 95.4 2 5.15 59.9 16 21.20 91.6 3 6.07 55.4 17 22.29 61.7 4 8.37 100.0 18 23.01 60.8 5 10.39 59.6 19 24.31 44.2 6 12.22 49.8 20 25.70 44.2 7 12.73 44.4 21 27.33 29.2 8 14.87 40.9 22 28.80 26.7 9 15.74 54.6 23 29.90 24.1 10 16.27 59.9 24 31.86 20.3 11 16.75 75.9 25 34.20 19.8 12 17.02 69.0 26 35.80 16.4 13 17.61 65.8 27 38.20 16.1 14 18.77 93.9

[0187] Example 6: Tartrate crystal form A of compound I

[0188] Using compound I prepared in Example 1 as a sample, 29.9 mg (about 0.05 mmol) and 2 equivalents of tartaric acid were weighed and added to 1 mL of a mixed solvent of tetrahydrofuran / cyclohexane (v / v, 1:1). The mixture was suspended at room temperature for 3 days. The suspension was centrifuged and the solid was dried to obtain a new tartrate crystal form of compound I, which was named tartrate crystal form A of compound I.

[0189] The XRPD spectrum of tartrate crystal form A of compound I, as detected by the aforementioned instrument 5, is as follows: Figure 7 As shown, the diffraction peak data are as follows; the DSC and TGA spectra detected by instruments 1 and 2 are as follows. Figure 8 As shown; the NMR spectrum detected by the aforementioned instrument 7 is as follows. Figure 9 As shown, a tartaric acid signal peak is observed at 4.25 ppm. According to the integration results, the salt formation ratio of compound I to tartaric acid is 1:1.5.

[0190] #peak 2θ angle (°) strength(%) #peak 2θ angle (°) strength(%) 1 3.04 74.3 17 20.53 84.6 2 5.11 39.3 18 21.19 59.2 3 5.77 53.7 19 22.42 48.0 4 6.68 37.1 20 22.81 44.3 5 8.82 56.4 21 23.81 49.5 6 10.16 35.1 22 24.34 43.3 7 10.77 40.0 23 25.35 35.3 8 11.73 51.1 24 25.74 35.3 9 13.19 45.5 25 26.75 28.0 10 14.65 41.9 26 27.86 23.2 11 15.55 94.3 27 28.87 25.7 12 15.95 100.0 28 31.37 20.8 13 16.73 57.8 29 32.74 18.9 14 17.38 49.8 30 33.91 18.3 15 18.35 99.3 31 35.14 17.2 16 18.72 78.7 32 37.55 19.0

[0191] Example 7: Crystal form A of p-toluenesulfonate of compound I

[0192] Using compound I prepared in Example 1 as a sample, 29.8 mg (about 0.05 mmol) and 2 equivalents of p-toluenesulfonic acid were weighed and added to 1 mL of methyl tert-butyl ether. The mixture was stirred at room temperature for 3 days. The suspension was centrifuged and the solid was dried to obtain a new p-toluenesulfonate crystal form of compound I, which was named p-toluenesulfonate crystal form A of compound I.

[0193] The XRPD spectrum of p-toluenesulfonate crystal form A of compound I, as detected by the aforementioned instrument 5, is as follows: Figure 10 As shown, the diffraction peak data are as follows; the DSC and TGA spectra detected by instruments 1 and 2 are as follows. Figure 11 As shown; the NMR spectrum detected by the aforementioned instrument 7 is as follows. Figure 12 As shown, p-toluenesulfonic acid signal peaks are observed at 2.27 ppm, 7.10 ppm, and 7.45 ppm. According to the integration results, the salt formation ratio of compound I to p-toluenesulfonic acid is 1:2.

[0194] #peak 2θ angle (°) strength(%) #peak 2θ angle (°) strength(%) 1 3.97 100.0 11 18.34 52.3 2 6.19 24.5 12 19.01 49.0 3 8.07 43.5 13 20.03 65.0 4 8.83 36.0 14 20.44 51.4 5 11.65 24.4 15 23.10 29.9 6 12.72 27.6 16 24.44 22.3 7 14.55 27.2 17 25.90 19.6 8 15.30 23.8 18 27.33 14.7 9 16.34 26.6 19 29.16 15.1 10 17.51 34.3 20 30.85 12.1

[0195] Example 8: Crystal form B of p-toluenesulfonate of compound I

[0196] Using compound I prepared in Example 1 as a sample, 29.9 mg (about 0.05 mmol) and 2 equivalents of p-toluenesulfonic acid were weighed and added to 1 mL of a mixed solvent of tetrahydrofuran / cyclohexane (v / v, 1:1). The mixture was stirred at room temperature for 3 days. The suspension was centrifuged and the solid was dried to obtain a new p-toluenesulfonate crystal form of compound I, which was named p-toluenesulfonate crystal form B of compound I.

[0197] The XRPD spectrum of p-toluenesulfonate B of compound I, as detected by the aforementioned instrument 5, is as follows: Figure 13 As shown, the diffraction peak data are shown below; the NMR spectrum detected by the aforementioned instrument 7 is shown below. Figure 14As shown, p-toluenesulfonic acid signal peaks are observed at 2.27 ppm, 7.10 ppm, and 7.45 ppm. According to the integration results, the salt formation ratio of compound I to p-toluenesulfonic acid is 1:2.

[0198] #peak 2θ angle (°) strength(%) #peak 2θ angle (°) strength(%) 1 4.32 67.8 20 20.24 89.8 2 4.90 24.4 21 21.04 14.5 3 5.78 3.1 22 21.53 36.4 4 7.14 12.6 23 22.44 9.5 5 8.59 21.1 24 23.00 11.6 6 8.99 21.8 25 23.67 12.1 7 9.79 56.5 26 24.24 10.7 8 10.72 5.5 27 24.75 12.8 9 11.50 40.5 28 25.33 11.5 10 12.81 14.9 29 25.74 23.4 11 14.32 5.9 30 27.43 5.5 12 14.84 11.3 31 28.51 4.5 13 15.37 2.8 32 29.14 12.5 14 16.82 24.6 33 29.52 13.2 15 17.20 32.2 34 30.90 6.1 16 17.77 9.4 35 32.10 5.3 17 18.21 12.1 36 35.58 2.9 18 19.12 100.0 37 37.78 2.9 19 19.56 18.6 38 38.79 1.7

[0199] Example 9: Crystal form B of p-toluenesulfonate of compound I

[0200] Method 1:

[0201] Using compound I prepared in Example 1 as a sample, 2.9 g (approximately 5 mmol) and 2.5 equivalents of p-toluenesulfonic acid were weighed and added to 45 mL of acetone. The mixture was stirred at room temperature for 2 h. The suspension was centrifuged, and the solid was dried to obtain a p-toluenesulfonate crystal form of compound I. The XRPD spectrum detected by the aforementioned instrument 6 is shown below. Figure 15 As shown, it is displayed as p-toluenesulfonate crystal form B; the DSC and TGA spectra detected by the aforementioned instrument 3 are as follows. Figure 16 As shown, the TGA weight loss results indicate that crystal form B contains 1 molecule of bound water.

[0202] Method 2:

[0203] Using compound I prepared in Example 1 as a sample, 598.1 mg and 343.9 mg of p-toluenesulfonic acid were weighed and added to 20 mL of methyl tert-butyl ether / acetone mixed solvent (v / v, 1:1). The mixture was suspended at room temperature for 2 days. The suspension was then filtered and separated, and the solid was dried under vacuum at 40 °C to obtain the above-mentioned p-toluenesulfonate crystal form B.

[0204] The above results indicate that, for p-toluenesulfonate crystal form B, the solvent system used in the salt formation reaction can be further simplified from the MTBE / acetone binary solvent to the acetone single solvent.

[0205] Test Example 1: Evaluation of PRMT5 enzyme activity inhibition

[0206] 1. Test method:

[0207] Prepare a 1-fold enzyme reaction buffer (10 mM Tris 8.0 (Sigma, Cat. No. T2694-1L), 0.01% Tween-20 (Sigma, Cat. No. P2287-100ML), 1 mM DTT (Sigma, Cat. No. D0632-10G)). PRMT5 (ActiveMotif, Cat. No. 31921) and [3H]-SAM (PerkinElmer, Cat. No. NET155V001MC) were added to a 1-fold enzyme reaction buffer to prepare a 25 / 15-fold mixed solution (PRMT5 final concentration 5 nM, [3H]-SAM final concentration 0.3 μM). 15 μL of this solution was transferred to a 384-well microplate (Corning 384-well Polypropylene Storage Microplates, Cat. No. 3657) containing different concentrations of the compound (DMSO final concentration 1%) and incubated at room temperature for 60 minutes. The peptide substrate GL-27 (Ac-SGRGKGGKGLGKGGAKRHRKVGG-K) (Biotin) (GL Biochem, Cat. No. 342095) was added to a 1-fold enzyme reaction buffer to prepare a 25 / 10-fold substrate solution. Then, 10 μL of the peptide substrate solution (final peptide substrate concentration 100 nM) was added. After reacting at room temperature for 120 minutes, the reaction was terminated by adding 5 μL of 6-fold ice-cold SAM (Sigma, Cat. No. A7007-100MG) solution (final SAM concentration: 0.125 mM). Transfer 25 μL of the reaction mixture to a FlashPlate (StreptavidinFlashPlate HTS PLUS, High Capacity, 384-well, Perkin Elmer, Cat. No. SMP410A001PK), incubate at room temperature for 1 hour, wash the plate three times with distilled water containing 0.1% Tween-20, and then read the CPM data (Counts Per Minute) on a MicroBeta instrument. After obtaining the raw CPM data for different concentrations of the compound, the data was standardized according to the following formula: Inh% = (Max - Sample) / (Max - Min) * 100% to obtain the enzyme activity inhibition rate Inh% for each concentration point (where Max is the CPM value of the enzyme-positive well, Min is the CPM value of the enzyme-negative well, and Sample is the CPM value of the compound-treated sample well). Then, the inhibition rate Inh% (Y) corresponding to each concentration (X) was entered into EXCEL, and the XLfit plugin was used to fit the formula Y = Bottom + (Top - Bottom) / (1 + (IC)) using the built-in four-parameter fitting formula. 50The half-maximal inhibitory concentration (IC50) of each compound was calculated using the formula ( / X)*HillSlope). 50 value.

[0208] 2. Experimental Results:

[0209] The compound in Example 1 of this invention showed an IC50 assay for PRMT5 enzyme activity inhibition. 50 The IC50 value was 6.40 nM, demonstrating excellent biological activity. Compound 13, disclosed in WO2020182018A1, was used as a control compound (the structure and preparation method of the control compound can be found in Example 13 on pages 33-35 of WO2020182018A1), and its IC50 was determined using the same experimental method. 50 The value is 115.00 nM.

[0210]

[0211] Test Example 2: Evaluation of Growth Inhibitory Activity in Human B-cell Non-Hodgkin Lymphoma Z-138 Cells

[0212] 1. Experimental materials and instruments

[0213] 1) Cell lines and culture methods

[0214]

[0215] 2) Culture medium and reagents

[0216] Culture media and reagents Manufacturer Item number IMDM GIBCO 31980048 FBS Hyclone SH30084.03 penicillin streptomycin Thermo SV30010 DMSO SIGMA D2650 Promega CellTiter-Glo chemiluminescence assay kit for cell viability detection Promega Promega-G7573

[0217] 3) 384-hole plate

[0218] 384-well transparent flat-bottomed white polystyrene microplate (with cap, sterile), Corning, item number: 3765.

[0219] 4) Instruments

[0220] 2104 EnVision board reader, PerkinElmer;

[0221] Vi-Cell XR cell counter, beckmancoulter.

[0222] 2. Experimental methods and procedures

[0223] 1) Cell Culture

[0224] Resuscitate the cells and culture them in an incubator at 37°C and 5% CO2 according to the culture conditions shown in the table above. Passage the cells regularly, selecting healthy cell lines for plating after approximately two passages.

[0225] 2) Cell plating

[0226] 1. Remove cells from the incubator and transfer the cell suspension to a 50mL centrifuge tube. Centrifuge at 800-1000rpm for 3-5 minutes, then discard the supernatant. Add an appropriate volume of culture medium to the centrifuge tube and gently pipette to resuspend the cells evenly. Count the cells using a Vi-CellXR cell counter.

[0227] II. Adjust the cell suspension to an appropriate concentration based on the measured cell density.

[0228] III. Add the cell suspension to a 384-well plate, 40 μL / well, containing 700 cells / well, and add an equal volume of cell-free culture medium to the blank control wells.

[0229] 3) Compound preparation and dosing

[0230] I. The compound was dissolved in 100% DMSO to prepare a stock solution with a concentration of 10 mM.

[0231] II. Take a 10 mM stock solution, dilute it with DMSO to a 2 mM solution, and use this as the starting concentration to perform a 4× serial dilution at 9 points with DMSO.

[0232] III. Take 200 nL of each of the gradient concentration solutions of the above compounds and add them to each well. Add 200 nL of DMSO to the blank control well and the DMSO control well, with a final DMSO concentration of 0.5%.

[0233] IV. The cell plates were incubated in a carbon dioxide incubator for 5 days (120 hours).

[0234] 4) Reagent preparation and testing

[0235] The assay was performed according to the instructions for the Promega CellTiter-Glo chemiluminescence immunoassay kit (Promega-G7573):

[0236] I. Melt the CellTiter-Glo buffer and let it reach room temperature.

[0237] II. Allow the freeze-dried CellTiter-Glo substrate to reach room temperature.

[0238] III. Prepare CellTiter-Glo working solution by adding CellTiter-Glo buffer to a bottle of CellTiter-Glo substrate to dissolve the substrate.

[0239] IV. Slow vortexing ensures complete dissolution.

[0240] V. Remove the cell culture plate and allow it to equilibrate to room temperature.

[0241] VI. Add 25 μL of the mixed CellTiter Glo reagent to each well, shake in the dark for 10 minutes, and incubate for 10 minutes.

[0242] VII. Detect the light emission signal on the 2104EnVision reader.

[0243] 3. Data Analysis

[0244] The inhibition rate (IR) of the detected compound is calculated using the following formula:

[0245] IR(%) = (1 – (RLU) 化合物 –RLU 空白对照 ) / (RLU DMSO –RLU 空白对照 ))*100%;

[0246] XLFit was used to plot the drug efficacy inhibition rate curve and calculate the IC50. 50 The value is determined using the following 4-parameter model: [fit=(A+((BA) / (1+((C / x)^D))))].

[0247] 4. Experimental Results:

[0248] IC50 of the compound in Example 1 of this invention in the Z-138 cell growth inhibition assay 50 The IC50 value was 0.0466 μM, demonstrating excellent biological activity. Similarly, compound 13, disclosed in WO2020182018A1, was used as a control compound, and the IC50 of the control compound was determined using the same method. 50 The value is 2.7096 μM.

[0249] Test Example 3: Stability Test

[0250] The stability of p-toluenesulfonate crystal form B, tartrate crystal form A and hydrochloride crystal form A of the present invention was studied under high temperature (60°C), high humidity (25°C / 92.5%RH), light exposure (25°C / 4500Lux) and accelerated conditions (40°C / 75%RH). Samples were taken at 7 days and 15 days for testing, and the results are shown below.

[0251]

[0252] The results showed that p-toluenesulfonate crystal form B and tartrate crystal form A were stable under 15 days of high temperature, high humidity, light, and accelerated conditions, without any crystal transformation; hydrochloride crystal form A underwent crystal transformation after 7 and 15 days under high humidity conditions, but was stable under other conditions.

[0253] Test Example 4: Hygroscopicity Study

[0254] Dynamic water adsorption-desorption analysis was performed on the p-toluenesulfonate crystal form B, tartrate crystal form A, and hydrochloride crystal form A of the present invention using the aforementioned instrument 9 to study the hygroscopicity of each crystal form. The results are shown below.

[0255]

[0256] The results showed that, arranged in order of increasing hygroscopicity, p-toluenesulfonate crystal form B < hydrochloride crystal form A < tartrate crystal form A, and p-toluenesulfonate crystal form B had almost no hygroscopicity.

[0257] The embodiments of the present invention have been described above. However, the present invention is not limited to the above embodiments. Any modifications, equivalent substitutions, improvements, etc., made within the spirit and principles of the present invention should be included within the protection scope of the present invention.

Claims

1. A crystal form A of compound I, characterized in that, The structure of compound I is shown below. ， The crystal form A has an XRPD spectrum that is essentially as shown in Figure 1.

2. The crystal form A of compound I as described in claim 1, characterized in that, The crystal form A has a DSC spectrum that is essentially as shown in Figure 2.

3. The crystal form A of compound I as described in claim 1 or 2, characterized in that, The crystal form A has a TGA spectrum that is essentially as shown in Figure 2.

4. A salt of compound I, characterized in that, The structure of compound I is shown below. ， The salt is a hydrochloride, hydrobromide, phosphate, sulfate, methanesulfonate, p-toluenesulfonate, L-camphorsulfonate, oxalate, maleate, L-tartrate, fumarate, citrate, L-malate, glycolate, or benzoate of compound I.

5. A hydrochloride salt of compound I, characterized in that, The structure of compound I is shown below. ， In the hydrochloride salt, the salt formation ratio of compound I to hydrochloric acid is 1:

2.

6. A hydrochloride crystal form A of compound I, characterized in that, The structure of compound I is shown below. ， In the hydrochloride crystal form A, the salt formation ratio of compound I to hydrochloric acid is 1:

2.

7. The hydrochloride crystal form A of compound I as described in claim 6, characterized in that, The hydrochloride crystal form A of compound I, when irradiated with Cu-Kα, exhibits characteristic peaks at 4.4±0.2°, 15.3±0.2°, 18.0±0.2°, 18.8±0.2°, and 19.3±0.2° in its XRPD spectrum at 2θ angles.

8. The hydrochloride crystal form A of compound I as described in claim 6, characterized in that, The hydrochloride crystal form A of compound I, when irradiated with Cu-Kα, exhibits characteristic peaks at 4.4±0.2°, 11.5±0.2°, 12.7±0.2°, 15.3±0.2°, 18.0±0.2°, 18.8±0.2°, 19.3±0.2°, and 21.6±0.2° in its XRPD spectrum at 2θ angles.

9. The hydrochloride crystal form A of compound I as described in claim 6, characterized in that, The hydrochloride crystal form A of compound I, when irradiated with Cu-Kα, exhibits characteristic peaks at 4.4±0.2°, 8.5±0.2°, 11.5±0.2°, 12.7±0.2°, 14.0±0.2°, 15.3±0.2°, 16.7±0.2°, 18.0±0.2°, 18.8±0.2°, 19.3±0.2°, 20.9±0.2°, 21.6±0.2°, and 23.3±0.2° in its XRPD spectrum at 2θ angles.

10. The hydrochloride crystal form A of compound I as described in claim 6, characterized in that, The hydrochloride crystal form A of compound I has an XRPD spectrum that is essentially as shown in Figure 3.

11. The hydrochloride crystal form A of compound I according to any one of claims 6-10, characterized in that, The DSC spectrum of the hydrochloride crystal form A of compound I has an endothermic peak near 149.4 °C.

12. The hydrochloride crystal form A of compound I according to any one of claims 6-10, characterized in that, The DSC spectrum of the hydrochloride crystal form A of compound I has an endothermic peak at 149.4℃±5℃.

13. The hydrochloride crystal form A of compound I according to any one of claims 6-10, characterized in that, The hydrochloride crystal form A of compound I has a DSC spectrum that is essentially as shown in Figure 4.

14. The hydrochloride crystal form A of compound I according to any one of claims 6-10, characterized in that, The hydrochloride crystal form A of compound I has a TGA spectrum that is essentially as shown in Figure 4.

15. An oxalate crystal form A of compound I, characterized in that, The structure of compound I is shown below. ， The oxalate crystal form A of compound I, when irradiated with Cu-Kα, exhibits characteristic peaks at 4.5±0.2°, 8.4±0.2°, 18.8±0.2°, 20.1±0.2°, and 21.2±0.2° in its XRPD spectrum at 2θ angles.

16. The oxalate crystal form A of compound I as described in claim 15, characterized in that, The oxalate crystal form A of compound I, when irradiated with Cu-Kα, exhibits characteristic peaks at 4.5±0.2°, 6.1±0.2°, 8.4±0.2°, 10.4±0.2°, 16.8±0.2°, 18.8±0.2°, 20.1±0.2°, and 21.2±0.2° in its XRPD spectrum at 2θ angles.

17. The oxalate crystal form A of compound I as described in claim 15, characterized in that, The oxalate crystal form A of compound I has an XRPD spectrum that is essentially as shown in Figure 5.

18. The oxalate crystal form A of compound I according to any one of claims 15-17, characterized in that, The DSC spectrum of oxalate crystal form A of compound I has an endothermic peak near 157.2 °C.

19. The oxalate crystal form A of compound I according to any one of claims 15-17, characterized in that, The DSC spectrum of oxalate crystal form A of compound I has an endothermic peak at 157.2℃±5℃.

20. The oxalate crystal form A of compound I according to any one of claims 15-17, characterized in that, The oxalate crystal form A of compound I has a DSC spectrum that is essentially as shown in Figure 6.

21. The oxalate crystal form A of compound I according to any one of claims 15-17, characterized in that, The oxalate crystal form A of compound I has a TGA spectrum that is essentially as shown in Figure 6.

22. A tartrate salt of compound I, characterized in that, The structure of compound I is shown below. ， In the tartrate salt, the salt formation ratio of compound I to tartaric acid is 1:1.

5.

23. A tartrate crystal form A of compound I, characterized in that, The structure of compound I is shown below. ， In the tartrate crystal form A, the salt formation ratio of compound I to tartaric acid is 1:1.

5.

24. The tartrate crystal form A of compound I as described in claim 23, characterized in that, The tartrate crystal form A of compound I, when irradiated with Cu-Kα, exhibits characteristic peaks at 15.5±0.2°, 16.0±0.2°, 18.4±0.2°, and 20.5±0.2° in its XRPD spectrum at 2θ angles.

25. The tartrate crystal form A of compound I as described in claim 23, characterized in that, The tartrate crystal form A of compound I, when irradiated with Cu-Kα, exhibits characteristic peaks at 3.0±0.2°, 5.8±0.2°, 8.8±0.2°, 11.7±0.2°, 15.5±0.2°, 16.0±0.2°, 18.4±0.2°, and 20.5±0.2° in its XRPD spectrum at 2θ angles.

26. The tartrate crystal form A of compound I as described in claim 23, characterized in that, The tartrate crystal form A of compound I has an XRPD spectrum that is essentially as shown in Figure 7.

27. The tartrate crystal form A of compound I according to any one of claims 23-26, characterized in that, The DSC spectrum of tartrate crystal form A of compound I has an endothermic peak near 174.8 °C.

28. The tartrate crystal form A of compound I according to any one of claims 23-26, characterized in that, The DSC spectrum of tartrate crystal form A of compound I has an endothermic peak at 174.8℃±5℃.

29. The tartrate crystal form A of compound I according to any one of claims 23-26, characterized in that, The tartrate crystal form A of compound I has a DSC spectrum that is essentially as shown in Figure 8.

30. The tartrate crystal form A of compound I according to any one of claims 23-26, characterized in that, The tartrate crystal form A of compound I has a TGA spectrum that is essentially as shown in Figure 8.

31. A p-toluenesulfonate salt of compound I, characterized in that, The structure of compound I is shown below. ， In the p-toluenesulfonate, the salt formation ratio of compound I to p-toluenesulfonic acid is 1:

2.

32. A p-toluenesulfonate crystal form A of compound I, characterized in that, The structure of compound I is shown below. ， In the p-toluenesulfonate crystal form A, the salt formation ratio of compound I to p-toluenesulfonic acid is 1:

2.

33. The p-toluenesulfonate crystal form A of compound I as described in claim 32, characterized in that, The p-toluenesulfonate crystal form A of compound I, when irradiated with Cu-Kα, exhibits characteristic peaks at 4.0±0.2°, 8.1±0.2°, 18.3±0.2°, and 20.0±0.2° in its XRPD spectrum at 2θ angles.

34. The p-toluenesulfonate crystal form A of compound I as described in claim 32, characterized in that, The p-toluenesulfonate crystal form A of compound I, when irradiated with Cu-Kα, exhibits characteristic peaks at 4.0±0.2°, 8.1±0.2°, 11.7±0.2°, 12.7±0.2°, 14.6±0.2°, 18.3±0.2°, 20.0±0.2°, and 23.1±0.2° in its XRPD spectrum at 2θ angles.

35. The p-toluenesulfonate crystal form A of compound I as described in claim 32, characterized in that, The p-toluenesulfonate crystal form A of compound I has an XRPD spectrum that is essentially as shown in Figure 10.

36. The p-toluenesulfonate crystal form A of compound I according to any one of claims 32-35, characterized in that, The DSC spectrum of p-toluenesulfonate crystal form A of compound I has endothermic peaks near 88.5 °C and 150.1 °C.

37. The p-toluenesulfonate crystal form A of compound I according to any one of claims 32-35, characterized in that, The DSC spectrum of p-toluenesulfonate crystal form A of compound I showed endothermic peaks at 88.5℃±5℃ and 150.1℃±5℃.

38. The p-toluenesulfonate crystal form A of compound I according to any one of claims 32-35, characterized in that, The p-toluenesulfonate crystal form A of compound I has a DSC spectrum that is essentially as shown in Figure 11.

39. The p-toluenesulfonate crystal form A of compound I according to any one of claims 32-35, characterized in that, The p-toluenesulfonate crystal form A of compound I has a TGA spectrum that is essentially as shown in Figure 11.

40. A p-toluenesulfonate crystal form B of compound I, characterized in that, The structure of compound I is shown below. ， In the p-toluenesulfonate crystal form B, the salt formation ratio of compound I to p-toluenesulfonic acid is 1:

2.

41. The p-toluenesulfonate crystal form B of compound I as described in claim 40, characterized in that, The p-toluenesulfonate crystal form B of compound I, when irradiated with Cu-Kα, exhibits characteristic peaks at 4.3±0.2°, 19.1±0.2°, and 20.2±0.2° in its XRPD spectrum at 2θ angles.

42. The p-toluenesulfonate crystal form B of compound I as described in claim 40, characterized in that, The p-toluenesulfonate crystal form B of compound I, when irradiated with Cu-Kα, exhibits characteristic peaks at 4.3±0.2°, 9.8±0.2°, 11.5±0.2°, 19.1±0.2°, and 20.2±0.2° in its XRPD spectrum at 2θ angles.

43. The p-toluenesulfonate crystal form B of compound I as described in claim 40, characterized in that, The p-toluenesulfonate crystal form B of compound I, when irradiated with Cu-Kα, exhibits characteristic peaks at 4.3±0.2°, 4.9±0.2°, 9.8±0.2°, 11.5±0.2°, 17.2±0.2°, 19.1±0.2°, 20.2±0.2°, and 21.5±0.2° in its XRPD spectrum at 2θ angles.

44. The p-toluenesulfonate crystal form B of compound I as described in claim 40, characterized in that, The p-toluenesulfonate crystal form B of compound I, when irradiated with Cu-Kα, exhibits characteristic peaks at 4.3±0.2°, 4.9±0.2°, 9.0±0.2°, 9.8±0.2°, 11.5±0.2°, 17.2±0.2°, 19.1±0.2°, 20.2±0.2°, 21.5±0.2°, and 25.7±0.2° in its XRPD spectrum at 2θ angles.

45. The p-toluenesulfonate crystal form B of compound I as described in claim 40, characterized in that, The p-toluenesulfonate crystal form B of compound I, when irradiated with Cu-Kα, exhibits characteristic peaks at 4.3±0.2°, 4.9±0.2°, 7.1±0.2°, 9.0±0.2°, 9.8±0.2°, 11.5±0.2°, 12.8±0.2°, 17.2±0.2°, 19.1±0.2°, 20.2±0.2°, 21.5±0.2°, and 25.7±0.2° in its XRPD spectrum at 2θ angles.

46. ​​The p-toluenesulfonate crystal form B of compound I as described in claim 40, characterized in that, The p-toluenesulfonate crystal form B of compound I has an XRPD spectrum that is essentially as shown in Figure 13 or Figure 15.

47. The p-toluenesulfonate crystal form B of compound I according to any one of claims 40-46, characterized in that, The DSC spectrum of p-toluenesulfonate B of compound I showed an endothermic peak near 192.1 °C.

48. The p-toluenesulfonate crystal form B of compound I according to any one of claims 40-46, characterized in that, The DSC spectrum of p-toluenesulfonate crystal form B of compound I showed an endothermic peak at 192.1±5℃.

49. The p-toluenesulfonate crystal form B of compound I according to any one of claims 40-46, characterized in that, The p-toluenesulfonate crystal form B of compound I has a DSC spectrum that is essentially as shown in Figure 16.

50. The p-toluenesulfonate crystal form B of compound I according to any one of claims 40-46, characterized in that, The p-toluenesulfonate crystal form B of compound I has a TGA spectrum that is essentially as shown in Figure 16.

51. The p-toluenesulfonate crystal form B of compound I according to any one of claims 40-46, characterized in that, The p-toluenesulfonate crystal form B of compound I is a hydrate.

52. The p-toluenesulfonate crystal form B of compound I according to any one of claims 40-46, characterized in that, The p-toluenesulfonate crystal form B of compound I is a monohydrate.

53. A pharmaceutical composition, characterized in that, The pharmaceutical composition comprises a salt of compound I as described in any one of claims 4-52 or a crystal form thereof.

54. Use of a salt of compound I or its crystal form as described in any one of claims 4-52, or the pharmaceutical composition as described in claim 53, in the preparation of a medicament for treating PRMT5-mediated diseases.

55. Use of a salt of compound I as described in any one of claims 4-52 or its crystal form, or the pharmaceutical composition as described in claim 53, in the preparation of a medicament for treating tumor diseases.

56. The use as described in claim 55, characterized in that, The tumor disease is a solid tumor or a hematologic tumor.

57. The use as described in claim 55, characterized in that, The tumor is a malignant solid tumor.

58. The use as described in claim 55, characterized in that, The tumor disease is lymphoma.

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