Crystalline form of the compound

Abstract

The present application relates to a crystalline form of methanesulfonate, hydrochloride, and maleate of the compound of formula (I): The present application further relates to a method of treating EGFR exon 20 insertion mutant non-small cell lung cancer (NSCLC) using the crystalline forms: The present application further relates to a synthetic scheme for the compound of formula (I): TIFF2023531078000038.tif36153

Description

[Technical Field]

[0001] The present invention relates to a crystalline form of methanesulfonate, hydrochloride, and maleate of the compound of formula (I): The present application further relates to a method for treating EGFR exon 20 insertion mutant non-small cell lung cancer (NSCLC) using the crystalline forms, and a synthetic scheme for the compound of formula (I). [ka] [Background technology]

[0002] In the field of anticancer drugs, EGFR is known to be a member of the erbB receptor family of transmembrane protein tyrosine kinases. Homodimerization and / or heterodimerization of erbB receptors induces phosphorylation of several tyrosine residues in the intracellular domain and activates multiple intracellular signaling pathways involved in cell proliferation and survival. Dysregulation of erbB family signaling can cause cell proliferation, invasion, metastasis, and angiogenesis, and has been reported in cancers such as lung cancer, head and neck cancer, and breast cancer. Therefore, various drugs targeting EGFR as a target for anticancer drug development are currently being clinically applied.

[0003] Chinese Patent CN105461695B discloses a compound of formula (I) having multiple basic centers, whose inhibitory activity against EGFR activating mutations (e.g., exon 19 deletion activating mutation, L858R activating mutation, T790M resistance mutation, and exon 20 insertion mutation) is significantly higher than that against wild-type EGFR (WT EGFR), and thus has high selectivity, safety, and low toxicity and side effects.

[0004] Generally, salt formation studies are conducted on active organic basic compounds. However, those skilled in the art cannot predict which stable salts a specific organic basic compound can form with which acid, and cannot predict which of a specific organic basic compound and its acid addition salt is suitable for further drug development, and it goes without saying that they cannot predict which salt formed has better chemical stability, physical stability or solubility, and which salt has these better properties at the same time. In particular, if an organic basic compound has multiple basic centers, those skilled in the art cannot predict whether the salts formed by it with a specific acid at various equivalent ratios have the same or different properties, and it goes without saying that they cannot predict which equivalent ratio of an organic basic compound and an acid is suitable for further drug development.

[0005] After conducting salt formation studies on an active organic basic compound, it is common to further conduct crystallization studies on selected salts, because in addition to the properties due to salt formation, crystallization may provide the salt with additional properties, such as better stability, processability, and druggability, making it suitable for further drug development. However, while there is general guidance on crystallization in the prior art, those skilled in the art cannot easily determine based on such general guidance whether a specific salt formed between one specific organic basic compound and one specific acid will result in a specific crystallization. It goes without saying that it is not possible to reasonably determine whether a particular crystalline form can be formed, much less whether such a particular crystalline form has additional properties that make it suitable for further drug development. Summary of the Invention [Problem to be solved by the invention]

[0006] The present application aims to find a salt of the compound of formula (I) that is suitable for further drug development. Specifically, the present application aims to find a salt that has properties suitable for further drug development, such as a reasonable salt-forming equivalent ratio, better chemical stability, better physical stability, and / or better solubility. The present application aims to further find a crystalline salt form of the compound of formula (I) that is suitable for further drug development, based on the selected salt of the compound of formula (I). [Means for solving the problem]

[0007] According to one aspect of the present invention, the present application relates to a salt formed between a compound of formula (I) below and an acid. [ka] [The acid is selected from hydrochloric acid, methanesulfonic acid, benzenesulfonic acid, ethanesulfonic acid, maleic acid, hydrobromic acid, citric acid, L-tartaric acid, and p-toluenesulfonic acid.]

[0008] In another aspect, the present invention relates to a crystalline form of the methanesulfonate salt of the compound of formula (I), a crystalline form of the hydrochloride salt of the compound of formula (I), and a crystalline form of the maleate salt of the compound of formula (I).

[0009] Preferably, the crystalline form of the methanesulfonate salt of compound (I) is crystalline form II-A, which is characterized by having an X-ray powder diffraction pattern having characteristic peaks expressed in 2θ degrees at least at 15.12°±0.2°, 22.28°±0.2°, and 25.82°±0.2°.

[0010] Preferably, the crystalline form of the hydrochloride salt of compound of formula (I) is crystalline form III-A, which is characterized by comprising an X-ray powder diffraction pattern having characteristic peaks expressed in degrees 2θ at least at 24.85°±0.2°, 14.08°±0.2°, and 14.45°±0.2°.

[0011] Preferably, the crystalline form of the maleate salt of compound of formula (I) is crystalline form IV-C, which is characterized by comprising an X-ray powder diffraction pattern having characteristic peaks expressed in degrees 2θ at least at 20.71°±0.2°, 25.76°±0.2°, and 17.00°±0.2°.

[0012] In another aspect, the present invention relates to a pharmaceutical composition comprising a salt or crystalline form according to the present invention, the pharmaceutical composition comprising a salt or crystalline form according to the present invention and a pharmaceutically acceptable carrier.

[0013] According to another aspect of the present invention, the present application relates to a method for treating EGFR exon 20 insertion mutant non-small cell lung cancer (NSCLC), comprising administering to a patient a salt or crystalline form according to the present invention.

[0014] According to another aspect of the present invention, the present application relates to the use of a salt or crystalline form according to the present invention for the manufacture of a medicament for the treatment of EGFR exon 20 insertion mutant non-small cell lung cancer (NSCLC). [Brief explanation of the drawings]

[0015] The drawings are for a better understanding of the present application and are not intended to limit the present application. [Figure 1] FIG. 1 is the XRPD pattern of the amorphous free base (sample number: Y11526-45-RV-FWD1509-AF-SU12). [Figure 2] FIG. 2 is a DSC pattern of the amorphous free base (sample number: Y11526-45-RV-FWD1509-AF-SU12). [Figure 3] FIG. 3 is a TGA pattern of the amorphous free base (sample number: Y11526-45-RV-FWD1509-AF-SU12). [Figure 4] FIG. 4 is the 1H-NMR pattern of the amorphous free base (sample number: Y11526-45-RV-FWD1509-AF-SU12). [Figure 5]FIG. 5 is a PLM pattern of the amorphous free base (sample number: Y11526-45-RV-FWD1509-AF-SU12). [Figure 6] FIG. 6 is an XRPD pattern of one equivalent of the amorphous hydrochloride salt (sample number: Y11526-42-SU11-methanol-dichloromethane). [Figure 7] FIG. 7 is a DSC pattern of one equivalent of the amorphous hydrochloride salt (sample number: Y11526-42-SU11-methanol-dichloromethane). [Figure 8] FIG. 8 is a TGA pattern of one equivalent of the amorphous hydrochloride salt (sample number: Y11526-42-SU11-methanol-dichloromethane). [Figure 9] FIG. 9 is the 1H-NMR pattern of one equivalent of the amorphous hydrochloride salt (sample number: Y11526-42-SU11-methanol-dichloromethane). [Figure 10] FIG. 10 is a PLM photograph of one equivalent of amorphous hydrochloride salt (sample number: Y11526-42-SU11-methanol-dichloromethane). [Figure 11] FIG. 11 is an XRPD pattern of two equivalents of the amorphous hydrochloride salt (sample number: Y11526-28-SU5-methanol-dichloromethane). [Figure 12] FIG. 12 is a DSC pattern of two equivalents of the amorphous hydrochloride salt (sample number: Y11526-28-SU5-methanol-dichloromethane). [Figure 13] FIG. 13 is a TGA pattern of two equivalents of the amorphous hydrochloride salt (sample number: Y11526-28-SU5-methanol-dichloromethane). [Figure 14] FIG. 14 is the 1H-NMR pattern of two equivalents of the amorphous hydrochloride salt (sample number: Y11526-28-SU5-methanol-dichloromethane). [Figure 15] FIG. 15 is a PLM photograph of two equivalents of the amorphous hydrochloride salt (sample number: Y11526-28-SU5-methanol-dichloromethane). [Figure 16]FIG. 16 is an XRPD pattern of one equivalent of amorphous methanesulfonate salt (sample number: Y11526-42-SU10-methanol-dichloromethane). [Figure 17] FIG. 17 is a DSC pattern of one equivalent of amorphous methanesulfonate salt (sample number: Y11526-42-SU10-methanol-dichloromethane). [Figure 18] FIG. 18 is a TGA pattern of one equivalent of amorphous methanesulfonate salt (sample number: Y11526-42-SU10-methanol-dichloromethane). [Figure 19] FIG. 19 is the 1H-NMR pattern of one equivalent of amorphous methanesulfonate salt (sample number: Y11526-42-SU10-methanol-dichloromethane). [Figure 20] FIG. 20 is a PLM photograph of one equivalent of amorphous methanesulfonate salt (sample number: Y11526-42-SU10-methanol-dichloromethane). [Figure 21] FIG. 21 is an XRPD pattern of two equivalents of amorphous methanesulfonate salt (sample number: Y11526-28-SU4-methanol-dichloromethane). [Figure 22] FIG. 22 is a DSC pattern of two equivalents of amorphous methanesulfonate salt (sample number: Y11526-28-SU4-methanol-dichloromethane). [Figure 23] FIG. 23 is a TGA pattern of two equivalents of amorphous methanesulfonate salt (sample number: Y11526-28-SU4-methanol-dichloromethane). [Figure 24] FIG. 24 is the 1H-NMR pattern of two equivalents of the amorphous methanesulfonate salt (sample number: Y11526-28-SU4-methanol-dichloromethane). [Figure 25] FIG. 25 is a PLM photograph of two equivalents of amorphous methanesulfonate salt (sample number: Y11526-28-SU4-methanol-dichloromethane). [Figure 26]is the XRPD pattern of one equivalent of amorphous benzenesulfonate salt (sample number: Y11526-42-SU9-methanol-dichloromethane). [Figure 27] FIG. 27 is a DSC pattern of one equivalent of amorphous benzenesulfonate salt (sample number: Y11526-42-SU9-methanol-dichloromethane). [Figure 28] FIG. 28 is a TGA pattern of one equivalent of amorphous benzenesulfonate salt (sample number: Y11526-42-SU9-methanol-dichloromethane). [Figure 29] FIG. 29 is the 1H-NMR pattern of one equivalent of amorphous benzenesulfonate salt (sample number: Y11526-42-SU9-methanol-dichloromethane). [Figure 30] FIG. 30 is a PLM photograph of one equivalent of amorphous benzenesulfonate salt (sample number: Y11526-42-SU9-methanol-dichloromethane). [Figure 31] FIG. 31 is an XRPD pattern of two equivalents of amorphous benzenesulfonate salt (sample number: Y11526-30-SU1-water). [Figure 32] FIG. 32 is a DSC pattern of two equivalents of amorphous benzenesulfonate salt (sample number: Y11526-30-SU1-water). [Figure 33] FIG. 33 is a TGA pattern of two equivalents of amorphous benzenesulfonate salt (sample number: Y11526-30-SU1-water). [Figure 34] FIG. 34 is a 1H-NMR pattern of two equivalents of amorphous benzenesulfonate salt (sample number: Y11526-30-SU1-water). [Figure 35] FIG. 35 is a PLM photograph of two equivalents of amorphous benzenesulfonate salt (sample number: Y11526-30-SU1-water). [Figure 36] FIG. 36 is an XRPD pattern of one equivalent of amorphous ethanesulfonate salt (sample number: Y11526-28-SU7-methanol-dichloromethane). [Figure 37]FIG. 37 is a DSC pattern of one equivalent of amorphous ethanesulfonate salt (sample number: Y11526-28-SU7-methanol-dichloromethane). [Figure 38] FIG. 38 is a TGA pattern of one equivalent of amorphous ethanesulfonate salt (sample number: Y11526-28-SU7-methanol-dichloromethane). [Figure 39] FIG. 39 is the 1H-NMR pattern of one equivalent of amorphous ethanesulfonate salt (sample number: Y11526-28-SU7-methanol-dichloromethane). [Figure 40] FIG. 40 is a PLM photograph of one equivalent of amorphous ethanesulfonate salt (sample number: Y11526-28-SU7-methanol-dichloromethane). [Figure 41] FIG. 41 is an XRPD pattern of one equivalent of amorphous maleate salt (sample number: Y11526-30-SU2-water). [Figure 42] FIG. 42 is a DSC pattern of one equivalent of amorphous maleate salt (sample number: Y11526-30-SU2-water). [Figure 43] FIG. 43 is a TGA pattern of one equivalent of amorphous maleate salt (sample number: Y11526-30-SU2-water). [Figure 44] FIG. 44 is the 1H-NMR pattern of one equivalent of amorphous maleate salt (sample number: Y11526-30-SU2-water). [Figure 45] FIG. 45 is a PLM photograph of 1 equivalent of amorphous maleate salt (sample number: Y11526-30-SU2-water). [Figure 46] Figure 46 is the XRPD pattern of one equivalent of the crystalline hydrobromide salt (sample number: Y11526-33-SU8-methanol-dichloromethane). [Figure 47] Figure 47 is a DSC pattern of one equivalent of the crystalline hydrobromide salt (sample number: Y11526-33-SU8-methanol-dichloromethane). [Figure 48]Figure 48 is a TGA pattern of one equivalent of the crystalline hydrobromide salt (sample number: Y11526-33-SU8-methanol-dichloromethane). [Figure 49] FIG. 49 is the 1H-NMR pattern of one equivalent of the crystalline hydrobromide salt (sample number: Y11526-33-SU8-methanol-dichloromethane). [Figure 50] Figure 50 is a PLM photograph of 1 equivalent of crystalline hydrobromide salt (sample number: Y11526-33-SU8-methanol-dichloromethane). [Figure 51] Figure 51 is the XRPD pattern of the amorphous nitrate salt (sample number: Y11526-18-RV7-methanol-dichloromethane). [Figure 52] FIG. 52 is the 1H-NMR pattern of the amorphous nitrate salt (sample number: Y11526-18-RV7-methanol-dichloromethane). [Figure 53] Figure 53 is an XRPD pattern of the amorphous sulfate salt (sample number: Y11526-15-RV3-methanol-acetonitrile). [Figure 54] FIG. 54 is a DSC pattern of the amorphous sulfate salt (sample number: Y11526-15-RV3-methanol-acetonitrile). [Figure 55] Figure 55 is a TGA pattern of the amorphous sulfate salt (sample number: Y11526-15-RV3-methanol-acetonitrile). [Figure 56] FIG. 56 is the 1H-NMR pattern of the amorphous sulfate salt (sample number: Y11526-15-RV3-methanol-acetonitrile). [Figure 57] Figure 57 is a PLM photograph of the amorphous sulfate salt (sample number: Y11526-15-RV3-methanol-acetonitrile). [Figure 58] Figure 58 is an XRPD pattern of two equivalents of amorphous p-toluenesulfonate salt (sample number: Y11526-23-FD11-water). [Figure 59]FIG. 59 is a DSC pattern of two equivalents of amorphous p-toluenesulfonate salt (sample number: Y11526-23-FD11-water). [Figure 60] Figure 60 is a TGA pattern of two equivalents of amorphous p-toluenesulfonate salt (sample number: Y11526-23-FD11-water). [Figure 61] FIG. 61 is the 1H-NMR pattern of two equivalents of amorphous p-toluenesulfonate salt (sample number: Y11526-23-FD11-water). [Figure 62] FIG. 62 is a PLM photograph of two equivalents of amorphous p-toluenesulfonate salt (sample number: Y11526-23-FD11-water). [Figure 63] FIG. 63 is a photograph of two equivalents of amorphous p-toluenesulfonate salt (sample number: Y11526-23-FD11-water). [Figure 64] Figure 64 is an XRPD pattern of amorphous sulfosalicylate salt (sample number: Y11526-25-FD13-1,4-dioxane). [Figure 65] Figure 65 is a DSC pattern of amorphous sulfosalicylate (sample number: Y11526-25-FD13-1,4-dioxane). [Figure 66] Figure 66 is a TGA pattern of amorphous sulfosalicylate (sample number: Y11526-25-FD13-1,4-dioxane). [Figure 67] Figure 67 is the H-NMR pattern of amorphous sulfosalicylate (sample number: Y11526-25-FD13-1,4-dioxane). [Figure 68] Figure 68 is a PLM photograph of amorphous sulfosalicylate (sample number: Y11526-25-FD13-1,4-dioxane). [Figure 69] Figure 69 is an XRPD pattern of amorphous sulfosalicylate salt (sample number: Y11526-25-FD12-1,4-dioxane). [Figure 70] FIG. 70 is a DSC pattern of amorphous sulfosalicylate (sample number: Y11526-25-FD12-1,4-dioxane). [Figure 71] FIG. 71 is a TGA pattern of amorphous sulfosalicylate (sample number: Y11526-25-FD12-1,4-dioxane). [Figure 72] FIG. 72 is the 1H-NMR pattern of amorphous sulfosalicylate (sample number: Y11526-25-FD12-1,4-dioxane). [Figure 73] FIG. 73 is a PLM photograph of amorphous sulfosalicylate (sample number: Y11526-25-FD12-1,4-dioxane). [Figure 74] Figure 74 is an XRPD pattern of the amorphous L-malate salt (sample number: Y11526-17-RV6-methanol-dichloromethane). [Figure 75] Figure 75 is a DSC pattern of amorphous L-malate salt (sample number: Y11526-17-RV6-methanol-dichloromethane). [Figure 76] Figure 76 is a TGA pattern of amorphous L-malate salt (sample number: Y11526-17-RV6-methanol-dichloromethane). [Figure 77] Figure 77 is the 1H-NMR pattern of amorphous L-malate salt (sample number: Y11526-17-RV6-methanol-dichloromethane). [Figure 78] Figure 78 is a PLM photograph of amorphous L-malate salt (sample number: Y11526-17-RV6-methanol-dichloromethane). [Figure 79] Figure 79 is the XRPD pattern of 1 equivalent of amorphous citrate salt (sample number: Y11526-10-FD6-1,4-dioxane). [Figure 80] Figure 80 is a DSC pattern of one equivalent of amorphous citrate salt (sample number: Y11526-10-FD6-1,4-dioxane). [Figure 81] Figure 81 is a TGA pattern of one equivalent of amorphous citrate salt (sample number: Y11526-10-FD6-1,4-dioxane). [Figure 82]Figure 82 is the 1H-NMR pattern of one equivalent of amorphous citrate salt (sample number: Y11526-10-FD6-1,4-dioxane). [Figure 83] Figure 83 is a PLM photograph of 1 equivalent of amorphous citrate salt (sample number: Y11526-10-FD6-1,4-dioxane). [Figure 84] Figure 84 is the XRPD pattern of 1 equivalent of amorphous L-tartrate salt (sample number: Y11526-10-FD7-1,4-dioxane). [Figure 85] Figure 85 is a DSC pattern of one equivalent of amorphous L-tartrate salt (sample number: Y11526-10-FD7-1,4-dioxane). [Figure 86] Figure 86 is a TGA pattern of one equivalent of amorphous L-tartrate salt (sample number: Y11526-10-FD7-1,4-dioxane). [Figure 87] Figure 87 is the 1H-NMR pattern of one equivalent of amorphous L-tartrate salt (sample number: Y11526-10-FD7-1,4-dioxane). [Figure 88] Figure 88 is an overlay of the HPLC pattern of one equivalent of amorphous L-tartrate salt (sample number: Y11526-10-FD7-1,4-dioxane). [Figure 89] Figure 89 is an XRPD overlay of the amorphous free base from the solid storage safety study, in which, from top to bottom, the first trace is the XRPD of the control crystalline free base, the second trace is the XRPD of the solid obtained in study BS2, the third trace is the XRPD of the solid obtained in study BS1, and the fourth trace is the XRPD of the parent solid. [Figure 90] Figure 90 is an XRPD overlay of one equivalent of the amorphous hydrochloride salt from a solid storage safety study, in which the upper trace is the XRPD of the solid obtained in study BS2, the middle trace is the XRPD of the solid obtained in study BS1, and the lower trace is the XRPD of the original solid. [Figure 91]Figure 91 is an XRPD overlay of solid storage safety testing of two equivalents of the amorphous hydrochloride salt, in which the upper trace is the XRPD of the solid obtained in test BS2, the middle trace is the XRPD of the solid obtained in test BS1, and the lower trace is the XRPD of the original solid. [Figure 92] Figure 92 shows photographs of two equivalents of amorphous hydrochloride salt in a solid storage safety test, where the picture on the left is a photograph of the original solid and the picture on the right is a photograph of the solid obtained in test BS1. [Figure 93] Figure 93 is an XRPD overlay of one equivalent of the amorphous methanesulfonate salt from a solid storage safety study, in which the upper trace is the XRPD of the solid obtained in study BS2, the middle trace is the XRPD of the solid obtained in study BS1, and the lower trace is the XRPD of the original solid. [Figure 94] Figure 94 is an XRPD overlay of two equivalents of the amorphous methanesulfonate salt from a solid storage safety test, in which the upper trace is the XRPD of the solid obtained in test BS2, the middle trace is the XRPD of the solid obtained in test BS1, and the lower trace is the XRPD of the original solid. [Figure 95] Figure 95 shows photographs of two equivalents of amorphous methanesulfonate salt in a solid storage safety test, in which the left picture is a photograph of the original solid, the middle picture is a photograph of the solid obtained in test BS1, and the right picture is a photograph of the solid obtained in test BS2. [Figure 96] Figure 96 is an XRPD overlay of one equivalent of amorphous benzenesulfonate salt from a solid storage safety test, in which the upper trace is the XRPD of the solid obtained in test BS2, the middle trace is the XRPD of the solid obtained in test BS1, and the lower trace is the XRPD of the original solid. [Figure 97] Figure 97 shows photographs of two equivalents of amorphous benzenesulfonate salt in a solid storage safety test, where the picture on the left is a photograph of the original solid, and the picture on the right is a photograph of the solid obtained in test BS1. [Figure 98] Figure 98 is an XRPD overlay of two equivalents of amorphous benzenesulfonate salt from a solid storage safety test, in which the upper trace is the XRPD of the solid obtained in test BS2 and the lower trace is the XRPD of the original solid. [Figure 99] Figure 99 shows photographs of one equivalent of amorphous ethanesulfonate salt in a solid storage safety test, where the picture on the left is a photograph of the original solid, and the picture on the right is a photograph of the solid obtained in test BS1. [Figure 100] Figure 100 is an XRPD overlay of one equivalent of amorphous ethanesulfonate salt from a solid storage safety study, in which the upper trace is the XRPD of the solid obtained in study BS2 and the lower trace is the XRPD of the original solid. [Figure 101] Figure 101 is an XRPD overlay of solid storage safety testing of one equivalent of amorphous maleate salt, in which the upper trace is the XRPD of the solid obtained in test BS2, the middle trace is the XRPD of the solid obtained in test BS1, and the lower trace is the XRPD of the original solid. [Figure 102] Figure 102 shows photographs of one equivalent of amorphous maleate salt in a solid storage safety test, where the picture on the left is a photograph of the original solid, and the picture on the right is a photograph of the solid obtained in test BS1. [Figure 103] Figure 103 is an XRPD overlay of one equivalent of the crystalline hydrobromide salt from a solid storage safety study, in which the upper trace is the XRPD of the solid obtained in study BS2, the middle trace is the XRPD of the solid obtained in study BS1, and the lower trace is the XRPD of the original solid. [Figure 104] Figure 104 shows the XRPD pattern of the solid obtained in a 2-hour solid solubility test of one equivalent of the crystalline hydrobromide salt, where the upper trace is the XRPD of the solid obtained in the 2-hour solid solubility test and the lower trace is the XRPD of the original solid. [Figure 105]Figure 105 is a powder X-ray diffraction pattern for methanesulfonate salt crystalline form II-A. [Figure 106] Figure 106 is a thermogravimetric analysis diagram (TGA) / differential scanning calorimetry diagram (DSC) of methanesulfonate salt crystalline form II-A. [Figure 107] Figure 107 is the powder X-ray diffraction pattern of hydrochloride salt crystalline Form III-A. [Figure 108] Figure 108 is the thermogravimetric analysis diagram (TGA) / differential scanning calorimetry diagram (DSC) of the hydrochloride salt crystalline form III-A. [Figure 109] Figure 109 is the powder X-ray diffraction pattern of maleate salt crystalline form IV-C. [Figure 110] FIG. 110 is a thermogravimetric analysis diagram (TGA) / differential scanning calorimetry diagram (DSC) of maleate salt crystalline form IV-C. DETAILED DESCRIPTION OF THE INVENTION

[0016] In one embodiment, the present invention relates to a salt formed between a compound of formula (I) and an acid: [ka] [The acid is selected from hydrochloric acid, methanesulfonic acid, benzenesulfonic acid, ethanesulfonic acid, maleic acid, hydrobromic acid, citric acid, L-tartaric acid, and p-toluenesulfonic acid. Preferably, the acid is selected from hydrochloric acid, methanesulfonic acid, and maleic acid.] More preferably, the equivalent ratio of the compound of formula (I) to the acid is 1:1 or 1:2. Even more preferably, the acid is methanesulfonic acid. Even more preferably, the equivalent ratio of the compound of formula (I) to the acid is 1:1.

[0017] The inventors of the present application have unexpectedly found that when the compound of formula (I) is reacted with an organic or inorganic acid, the compound of formula (I) can form salts with some acids, but cannot form salts with other acids at all.

[0018] Even more surprisingly, when the compound of formula (I) is reacted with hydrochloric acid, methanesulfonic acid, benzenesulfonic acid, ethanesulfonic acid, maleic acid, hydrobromic acid, sulfosalicylic acid, L-malic acid, citric acid or L-tartaric acid at a molar ratio of the compound of formula (I):acid=1:1, some salts formed have a stoichiometric ratio of the compound of formula (I):acid=1:1, but the compound of formula (I) cannot form any salts with some acids at a stoichiometric ratio of the compound of formula (I):acid=1:1. Specifically, Hydrochloric acid, methanesulfonic acid, benzenesulfonic acid, ethanesulfonic acid, maleic acid, hydrobromic acid, citric acid and L-tartaric acid can give salts having a stoichiometric ratio of the compound of formula (I):acid=1:1 (the corresponding salts are hereinafter referred to as 1 equivalent of hydrochloride, 1 equivalent of methanesulfonate, 1 equivalent of benzenesulfonate, 1 equivalent of ethanesulfonate, 1 equivalent of maleate, 1 equivalent of hydrobromide, 1 equivalent of citrate and 1 equivalent of L-tartrate, respectively), while sulfosalicylic acid and L-malic acid cannot give salts having a stoichiometric ratio of the compound of formula (I):acid=1:1.

[0019] Furthermore, even more surprisingly, when the compound of formula (I) is reacted with hydrochloric acid, methanesulfonic acid, benzenesulfonic acid, nitric acid, sulfuric acid, p-toluenesulfonic acid or sulfosalicylic acid at a molar ratio of the compound of formula (I) to the acid of 1:2, some salts formed have a stoichiometric ratio of the compound of formula (I) to the acid of 1:2, but the compound of formula (I) cannot form salts with some acids in a stoichiometric ratio of the compound of formula (I) to the acid of 1:2. Specifically, Hydrochloric acid, methanesulfonic acid, benzenesulfonic acid and p-toluenesulfonic acid can give salts having a stoichiometric ratio of the compound of formula (I) to the acid of 1:2 (the corresponding salts are hereinafter referred to as 2 equivalents of hydrochloride, 2 equivalents of methanesulfonate, 2 equivalents of benzenesulfonate and 2 equivalents of p-toluenesulfonate, respectively), but nitric acid, sulfuric acid and sulfosalicylic acid cannot give salts having a stoichiometric ratio of the compound of formula (I) to the acid of 1:2.

[0020] More specifically, the salts obtained as described above include 1 equivalent of hydrochloride, 1 equivalent of methanesulfonate, 1 equivalent of benzenesulfonate, 1 equivalent of ethanesulfonate, 1 equivalent of maleate, 1 equivalent of hydrobromide, 1 equivalent of citrate, 1 equivalent of L-tartrate, 2 equivalents of hydrochloride, 2 equivalents of methanesulfonate, 2 equivalents of benzenesulfonate and 2 equivalents of p-toluenesulfonate, as well as sulfosalicylate, L-malate, nitrate and sulfate salts that do not have a reasonable salt-forming equivalent ratio. For example, salts obtained as described above include 1 equivalent of amorphous hydrochloride, 1 equivalent of amorphous methanesulfonate, 1 equivalent of amorphous benzenesulfonate, 1 equivalent of amorphous ethanesulfonate, 1 equivalent of amorphous maleate, 1 equivalent of crystalline hydrobromide, 1 equivalent of amorphous citrate, 1 equivalent of amorphous L-tartrate, 2 equivalents of amorphous hydrochloride, 2 equivalents of amorphous methanesulfonate, 2 equivalents of amorphous benzenesulfonate, and 2 equivalents of amorphous p-toluenesulfonate, as well as amorphous sulfosalicylate, amorphous L-malate, amorphous nitrate, and amorphous sulfate that do not have reasonable salt-forming equivalent ratios.

[0021] For the development of drugs, it is extremely important whether the salt obtained as described above has chemical and physical stability at the end of production. The chemical and physical stability of the salt at the end of production is as follows: the chemical stability of the salt at the end of its preparation, i.e., the purity of the salt obtained at the end of its preparation is not significantly reduced compared to the purity of the free base from which it is prepared; and the physical stability of the salt at the end of its production, i.e., the salt does not immediately undergo crystal form transformation, moisture absorption and / or discoloration at the end of its production; Includes.

[0022] Chemical and physical stability at the end of manufacturing revealed that different salts have different performances and it is unpredictable how a given salt will perform. 1 equivalent of citrate, 1 equivalent of L-tartrate, nitrate and L-malate are chemically unstable at the end of production. Two equivalents of p-toluenesulfonate and sulfate are physically unstable at the end of production, and 1 equivalent of hydrochloride, 2 equivalents of hydrochloride, 1 equivalent of methanesulfonate, 2 equivalents of methanesulfonate, 1 equivalent of benzenesulfonate, 2 equivalents of benzenesulfonate, 1 equivalent of ethanesulfonate, 1 equivalent of maleate, 1 equivalent of hydrobromide and sulfosalicylate must be chemically and physically stable at the end of production.

[0023] As described above, salts that have a reasonable salt-forming equivalent ratio and are chemically and physically stable at the end of production include 1 equivalent of hydrochloride, 2 equivalents of hydrochloride, 1 equivalent of methanesulfonate, 2 equivalents of methanesulfonate, 1 equivalent of benzenesulfonate, 2 equivalents of benzenesulfonate, 1 equivalent of ethanesulfonate, 1 equivalent of maleate, and 1 equivalent of hydrobromide. Whether these salts have chemical and physical stability even after storage is also extremely important for drug development. The chemical and physical stability of salts after storage is as follows: the chemical stability of the salt after storage, i.e., the purity of the salt after storage does not decrease significantly compared to the purity of the salt before storage; and The physical stability of the salt after storage, i.e., whether the salt undergoes crystal form transformation, moisture absorption, etc. before and after storage. and / or does not cause discoloration, etc. Includes.

[0024] Regarding chemical and physical stability after storage, different salts have different performances, and it has become clear that it is impossible to predict how a particular salt will perform. One equivalent of the hydrochloride, one equivalent of the benzenesulfonate, and one equivalent of the maleate are chemically unstable under the storage conditions of "solid / 25°C / 60%RH / open / 1 week" and / or "solid / 60°C / sealed container / 1 week." Two equivalents of the hydrochloride salt, two equivalents of the methanesulfonate salt, two equivalents of the benzenesulfonate salt, one equivalent of the ethanesulfonate salt, and one equivalent of the maleate salt are physically unstable under the storage conditions of "solid / 25°C / 60%RH / open / 1 week" and / or "solid / 60°C / sealed container / 1 week"; and One equivalent of the methanesulfonate salt and one equivalent of the hydrobromide salt are chemically and physically stable under the following storage conditions: solid / 25°C / 60%RH / open / 1 week and solid / 60°C / sealed container / 1 week.

[0025] As described above, salts that have a reasonable salt-forming equivalent ratio and are chemically and physically stable at the end of production include 1 equivalent of hydrochloride, 2 equivalents of hydrochloride, 1 equivalent of methanesulfonate, 2 equivalents of methanesulfonate, 1 equivalent of benzenesulfonate, 2 equivalents of benzenesulfonate, 1 equivalent of ethanesulfonate, 1 equivalent of maleate, and 1 equivalent of hydrobromide. Whether these salts have better solubility is also very important for drug development. The fact that different salts have different solubilities reveals that the solubility of a certain salt is unpredictable. Specifically, Two equivalents of the benzenesulfonate salt and one equivalent of the hydrobromide salt do not meet the solubility of 2 mg / mL in some solvents that simulate physiological conditions; and 1 equivalent of hydrochloride, 2 equivalents of hydrochloride, 1 equivalent of methanesulfonate, 2 equivalents of methanesulfonate, 1 equivalent of benzenesulfonate, 1 equivalent of ethanesulfonate, and 1 equivalent of maleate have solubilities of greater than 2 mg / mL in a variety of solvents simulating physiological conditions.

[0026] As can be seen from the above, surprisingly and unexpectedly, one equivalent of the methanesulfonate salt simultaneously has a reasonable salt-forming equivalent ratio, better chemical stability, better physical stability, and better solubility, making it a salt of the compound of formula (I) suitable for further drug development.

[0027] In another aspect, the present invention relates to a pharmaceutical composition comprising a salt according to the present invention, the pharmaceutical composition comprising a salt according to the present invention and a pharmaceutically acceptable carrier.

[0028] According to another aspect of the present invention, the present application relates to a method for treating EGFR exon 20 insertion mutant non-small cell lung cancer (NSCLC), comprising administering to a patient a salt according to the present invention.

[0029] According to another aspect of the present invention, the present application relates to the use of a salt according to the present invention for the manufacture of a medicament for treating EGFR exon 20 insertion mutant non-small cell lung cancer (NSCLC).

[0030] In addition to the properties of salt formation, crystallization can provide salts with additional properties such as better stability, processability, and druggability, making them suitable for further drug development. Therefore, after conducting the above salt formation study and screening for the compound of formula (I), a crystallization study is conducted for some of the prepared salts. After conducting the crystallization study for the prepared salts, the inventors of the present application have found that the methanesulfonate, hydrochloride, and maleate salts of the compound of formula (I) can form crystals, and that the salt crystal forms are It has been found that the methanesulfonate, hydrochloride and maleate salt crystalline forms of the compound of formula (I) have improved bioavailability and increased dynamic solubility.

[0031] Thus, the present invention provides the following technical solutions regarding crystalline morphology:

[0032] According to one aspect of the present invention, the present application relates to crystalline Form II-A of the methanesulfonate salt of compound of formula (I), wherein said crystalline Form II-A is characterized in that it comprises an X-ray powder diffraction pattern having characteristic peaks expressed in degrees 2θ at at least 15.12°±0.2°, 22.28°±0.2°, and 25.82°±0.2°. [ka]

[0033] The crystalline form II-A is further characterized in that it comprises a powder X-ray diffraction pattern having at least a characteristic peak expressed in 2θ degrees from one of 19.62°±0.2°, 26.24°±0.2° in total.

[0034] The crystalline form II-A is further characterized in that it comprises a powder X-ray diffraction pattern having at least a characteristic peak expressed in 2θ degrees from one of 10.36°±0.2°, 18.94°±0.2° in total.

[0035] The crystalline form II-A is further characterized in that it comprises an X-ray powder diffraction pattern having characteristic peaks expressed in degrees 2θ from at least one of: 7.22°±0.2°, 8.62°±0.2°, 9.48°±0.2°, 15.74°±0.2°, 16.46°±0.2°, 16.92°±0.2°, 17.70°±0.2°, 19.30°±0.2°, 20.36°±0.2°, 20.81°±0.2°, 24.06°±0.2°, 24.78°±0.2°, and 25.54°±0.2° in total.

[0036] Furthermore, its powder X-ray diffraction pattern is 7.22°±0.2°, 8.62°±0.2°, 9.48°±0.2°, 10.36°±0.2°, 15.12°±0.2°, 15.74°±0.2°, 16.46°±0.2°, 16.92°±0.2°, 17.70°±0.2°, 18.94°±0.2°, 19.30°±0.2°, 1 The above-mentioned crystalline form II-A, characterized by having characteristic peaks represented by diffraction angle 2θ values ​​at 9.62°±0.2°, 20.36°±0.2°, 20.81°±0.2°, 22.28°±0.2°, 24.06°±0.2°, 24.78°±0.2°, 25.54°±0.2°, 25.82°±0.2°, and 26.24°±0.2°.

[0037] The above-mentioned crystalline form II-A, characterized in that the powder X-ray diffraction pattern of said crystalline form II-A is substantially as shown in Figure 105.

[0038] Furthermore, the crystalline form II-A is characterized in that the weight loss at 200.0°C is 0.56%.

[0039] Furthermore, the crystalline form II-A exhibits an endothermic peak after heating to 255.9°C. The above-mentioned crystalline form II-A, characterized by:

[0040] The above-mentioned crystalline form II-A, further characterized by a thermogravimetric analysis diagram (TGA) / differential scanning calorimetry diagram (DSC) substantially as shown in Figure 106.

[0041] Further, the above crystalline form II-A is characterized in that the molar ratio of the compound of formula (I) to methanesulfonic acid is 1:1.

[0042] The present invention also provides a method for producing crystalline form II-A of the methanesulfonate salt of compound of formula (I), which comprises the following steps a) to c): a) Suspending the compound of formula (I) in a first solvent. b) The temperature is raised to 20 to 80°C, and a solution of methanesulfonic acid previously dissolved in the second solvent is added dropwise. c) Crystallization and filtration to obtain crystalline form II-A.

[0043] Furthermore, the first solvent is water, a ketone, a cyclic ether, or a nitrile solvent, or a mixed solvent thereof. The second solvent is water, a ketone, a cyclic ether, or a nitrile solvent, or a mixed solvent thereof. Furthermore, the first solvent is water, a ketone, a cyclic ether, or a nitrile solvent, or a mixed solvent thereof, and the second solvent is a ketone, a cyclic ether, or a nitrile solvent, or a mixed solvent of water and a ketone, a cyclic ether, or a nitrile solvent. Furthermore, the ketone solvent includes, but is not limited to, acetone, the cyclic ether solvent includes, but is not limited to, tetrahydrofuran or 1,4-dioxane, and the nitrile solvent includes, but is not limited to, acetonitrile.

[0044] Furthermore, in the mixed solvent of the ketone, cyclic ether or nitrile solvent and water, the volume ratio of the ketone, cyclic ether or nitrile solvent to water is 5:1 to 25:1, and even more preferably, the volume ratio of the ketone, cyclic ether or nitrile solvent to water is 9:1 to 15:1.

[0045] Furthermore, in step b), the temperature is raised to 20 to 50°C.

[0046] The present invention provides a method for preparing crystalline form II-A of the methanesulfonate salt of compound of formula (I), comprising the following steps a) to d): a) suspending a compound of formula (I) in a first solvent; b) The temperature is raised to 20 to 80°C, and a solution of methanesulfonic acid previously dissolved in the second solvent is added dropwise. c) Add the third solvent dropwise. d) Crystallization and filtration to obtain crystalline form II-A.

[0047] Further, the first solvent is water, a ketone, a cyclic ether, or a nitrile solvent, or a mixed solvent thereof. The second solvent is water, a ketone, a cyclic ether, or a nitrile solvent, or a mixed solvent thereof. Even more preferably, the first solvent is water, a ketone, a cyclic ether, or a nitrile solvent, or a mixed solvent thereof. The second solvent is a ketone, a cyclic ether, or a nitrile solvent, or a mixed solvent of water and a ketone, a cyclic ether, or a nitrile solvent. Even more preferably, the ketone solvent includes, but is not limited to, acetone, the cyclic ether solvent includes, but is not limited to, tetrahydrofuran or 1,4-dioxane, and the nitrile solvent includes, but is not limited to, acetonitrile.

[0048] Furthermore, among the mixed solvents of the ketone, cyclic ether or nitrile solvent and water, The volume ratio of the ketone, cyclic ether or nitrile solvent to water is 5:1 to 25:1, and more preferably, the volume ratio of the ketone, cyclic ether or nitrile solvent to water is 9:1 to 16:1.

[0049] Furthermore, in step b), the temperature is raised to 20 to 50°C.

[0050] Furthermore, the third solvent is C 6-7 The solvent is a paraffin, an ether, or an ester. 6-7 Paraffin solvents include, but are not limited to, n-heptane, ether solvents include, but are not limited to, tert-butyl methyl ether, and ester solvents include, but are not limited to, methyl formate, ethyl acetate, isopropyl acetate, propyl acetate, or butyl acetate.

[0051] According to one aspect of the present invention, the present application provides crystalline Form III-A of the hydrochloride salt of compound of formula (I), characterized in that said crystalline Form III-A has a powder X-ray diffraction pattern having characteristic peaks expressed in 2θ degrees at least at 24.85°±0.2°, 14.08°±0.2°, and 14.45°±0.2°. [ka]

[0052] The crystalline form III-A is further characterized in that it comprises a powder X-ray diffraction pattern having at least a characteristic peak expressed in 2θ degrees from one of 25.87°±0.2, 6.55°±0.2° in total.

[0053] The crystalline form III-A is further characterized in that it comprises a powder X-ray diffraction pattern having at least a characteristic peak expressed in 2θ degrees from one of 13.10°±0.2°, 19.07°±0.2° in total.

[0054] The crystalline form III-A is further characterized in that it comprises an X-ray powder diffraction pattern having characteristic peaks expressed in degrees 2θ from at least one of 10.36°±0.2°, 12.28°±0.2°, 15.98°±0.2°, 17.33°±0.2°, 19.57°±0.2°, 21.15°±0.2°, 21.72°±0.2°, 24.30°±0.2°, and 33.29°±0.2° in total.

[0055] The X-ray powder diffraction pattern of the crystalline form III-A is characterized by having characteristic peaks at diffraction angles 2θ values ​​of 6.55°±0.2°, 10.36°±0.2°, 12.28°±0.2°, 13.10°±0.2°, 14.08°±0.2°, 14.45°±0.2°, 15.98°±0.2°, 17.33°±0.2°, 19.07°±0.2°, 19.57°±0.2°, 21.15°±0.2°, 21.72°±0.2°, 24.30°±0.2°, 24.85°±0.2°, 25.87°±0.2°, and 33.29°±0.2°.

[0056] The above-mentioned crystalline form III-A, characterized in that the powder X-ray diffraction pattern of said crystalline form III-A is substantially as shown in Figure 107.

[0057] Furthermore, the crystalline form III-A exhibits a weight loss of 1.05% at 150.0°C. The above-mentioned crystalline form III-A, characterized in that

[0058] Furthermore, the crystalline form III-A is characterized in that an endothermic peak appears after heating to 193.3°C.

[0059] The above-mentioned crystalline form III-A, further characterized by a thermogravimetric analysis diagram (TGA) / differential scanning calorimetry diagram (DSC) substantially as shown in Figure 108.

[0060] Further, the above crystalline form III-A, characterized in that the molar ratio of the compound of formula (I) to hydrochloric acid is 1:1.

[0061] The present invention also provides a method for preparing crystalline form III-A of the hydrochloride salt of compound of formula (I), which comprises the following steps a) to c): a) suspending a compound of formula (I) in a first solvent; b) The temperature is raised to 20 to 80°C, and a solution of concentrated hydrochloric acid (approximately 37%) previously dissolved in the second solvent is added dropwise. c) Crystallization and filtration to obtain crystalline form III-A.

[0062] Further, the first solvent is water, a ketone, a cyclic ether or a nitrile solvent, or a mixed solvent thereof. The second solvent is water, a ketone, a cyclic ether or a nitrile solvent, or a mixed solvent thereof. Even more preferably, the first solvent is water, a ketone, a cyclic ether or a nitrile solvent, or a mixed solvent thereof. The second solvent is an alcohol or a nitrile solvent, or a mixed solvent of water and an alcohol or a nitrile solvent. Even more preferably, the ketone solvent includes, but is not limited to, acetone, the cyclic ether solvent includes, but is not limited to, tetrahydrofuran or 1,4-dioxane, the alcohol solvent includes, but is not limited to, ethanol, and the nitrile solvent includes, but is not limited to, acetonitrile.

[0063] Furthermore, in the mixed solvent of the alcohol or nitrile solvent and water, the volume ratio of the alcohol or nitrile solvent to water is 5:1 to 25:1, and more preferably, the volume ratio of the alcohol or nitrile solvent to water is 9:1 to 15:1.

[0064] Furthermore, in step b), the temperature is raised to 20 to 50°C. The present invention provides a method for preparing crystalline form III-A of the hydrochloride salt of compound of formula (I), comprising the following steps a) to d): a) suspending a compound of formula (I) in a first solvent; b) The temperature is raised to 20 to 80°C, and a solution of concentrated hydrochloric acid (approximately 37%) previously dissolved in the second solvent is added dropwise. c) Add the third solvent dropwise d) Crystallization and filtration to obtain crystalline form III-A.

[0065] Further, the first solvent is water, a ketone, a cyclic ether or a nitrile solvent, or a mixed solvent thereof. The second solvent is water, a ketone, a cyclic ether or a nitrile solvent, or a mixed solvent thereof. Even more preferably, the first solvent is water, a ketone, a cyclic ether or a nitrile solvent, or a mixed solvent thereof. The second solvent is an alcohol or a nitrile solvent, or a mixed solvent of water and an alcohol or a nitrile solvent. Even more preferably, the ketone solvent includes, but is not limited to, acetone, the cyclic ether solvent includes, but is not limited to, tetrahydrofuran or 1,4-dioxane, the alcohol solvent includes, but is not limited to, ethanol, and the nitrile solvent includes, but is not limited to, acetonitrile.

[0066] Furthermore, in the mixed solvent of the alcohol or nitrile solvent and water, the volume ratio of the alcohol or nitrile solvent to water is 5:1 to 25:1, and more preferably, the volume ratio of the alcohol or nitrile solvent to water is 9:1 to 15:1.

[0067] Furthermore, in step b), the temperature is raised to 20 to 50°C. Furthermore, the third solvent is C 6-7 The solvent is a paraffin, an ether, or an ester. 6-7 Paraffin solvents include, but are not limited to, n-heptane; ether solvents include, but are not limited to, tert-butyl methyl ether; and ester solvents include, but are not limited to, methyl formate, ethyl acetate, isopropyl acetate, propyl acetate, or butyl acetate.

[0068] According to one aspect of the present invention, the present application provides crystalline Form IV-C of maleate salt of compound of formula (I), characterized in that said crystalline Form IV-C has a powder X-ray diffraction pattern having characteristic peaks expressed in degrees 2θ at least at 20.71°±0.2°, 25.76°±0.2°, and 17.00°±0.2°. [ka]

[0069] The crystalline form IV-C is further characterized in that it comprises a powder X-ray diffraction pattern further having characteristic peaks expressed in 2θ degrees from at least one of 6.47°±0.2°, 10.63°±0.2° in total.

[0070] The crystalline form IV-C is further characterized in that it comprises a powder X-ray diffraction pattern having at least characteristic peaks expressed in 2θ degrees from one of 28.70°±0.2°, 16.42°±0.2° in total.

[0071] The crystalline form IV-C is further characterized in that it comprises an X-ray powder diffraction pattern having characteristic peaks expressed in degrees 2θ from at least one of 8.44°±0.2°, 9.15°±0.2°, 12.70°±0.2°, 15.48°±0.2°, 18.19°±0.2°, 22.43°±0.2°, and 31.39°±0.2° in total.

[0072] The powder X-ray diffraction pattern of the crystalline form IV-C is characterized by having characteristic peaks at diffraction angle 2θ values ​​of 6.47°±0.2°, 8.44°±0.2°, 9.15°±0.2°, 10.63°±0.2°, 12.70°±0.2°, 15.48°±0.2°, 16.42°±0.2°, 17.00°±0.2°, 18.19°±0.2°, 20.71°±0.2°, 22.43°±0.2°, 25.76°±0.2°, 28.70°±0.2°, and 31.39°±0.2°.

[0073] The above-mentioned crystalline form IV-C, further characterized in that the powder X-ray diffraction pattern of said crystalline form IV-C is substantially as shown in Figure 109.

[0074] Furthermore, the weight loss of the crystalline form IV-C at 220.0°C is 1.96%. The above-mentioned crystalline form IV-C, characterized in that

[0075] Furthermore, the above-mentioned crystalline form IV-C is characterized in that an endothermic peak appears after heating to 255.5°C.

[0076] The above-mentioned crystalline form IV-C further characterized by a thermogravimetric analysis diagram (TGA) / differential scanning calorimetry diagram (DSC) substantially as shown in Figure 110.

[0077] Further, the above-mentioned crystalline form IV-C, characterized in that the molar ratio of the compound of formula (I) to maleic acid is 1:1.

[0078] The present invention also provides a method for producing maleate crystalline form IV-C of compound of formula (I), which comprises the following steps a) to c): a) suspending a compound of formula (I) in a first solvent; b) The temperature is raised to 20 to 80°C, and a solution of maleic acid previously dissolved in the second solvent is added dropwise. c) Crystallization and filtration to obtain crystalline form IV-C.

[0079] Further, the first solvent is water, a ketone, a cyclic ether, or a nitrile solvent, or a mixed solvent thereof. The second solvent is water, a ketone, a cyclic ether, or a nitrile solvent, or a mixed solvent thereof. Even more preferably, the first solvent is water, a ketone, a cyclic ether, or a nitrile solvent, or a mixed solvent thereof. The second solvent is a ketone, a cyclic ether, or a nitrile solvent, or a mixed solvent of water and a ketone, a cyclic ether, or a nitrile solvent. Even more preferably, the ketone solvent includes, but is not limited to, acetone, the cyclic ether solvent includes, but is not limited to, tetrahydrofuran or 1,4-dioxane, and the nitrile solvent includes, but is not limited to, acetonitrile.

[0080] Furthermore, in the mixed solvent of the ketone, cyclic ether or nitrile solvent and water, the volume ratio of the ketone, cyclic ether or nitrile solvent to water is 5:1 to 25:1, and more preferably, the volume ratio of the ketone, cyclic ether or nitrile solvent to water is 9:1 to 15:1.

[0081] Furthermore, in step b), the temperature is raised to 20 to 50°C. The present invention provides a method for preparing crystalline Form IV-C of the maleate salt of compound of formula (I), comprising the following steps a) to d): a) suspending a compound of formula (I) in a first solvent; b) The temperature is raised to 20 to 80°C, and a solution of maleic acid previously dissolved in the second solvent is added dropwise. c) Add the third solvent dropwise d) Crystallization and filtration to obtain crystalline form IV-C.

[0082] Furthermore, the first solvent is water, a ketone, a cyclic ether, or a nitrile solvent, or a mixed solvent thereof. The second solvent is water, a ketone, a cyclic ether, or a nitrile solvent, or a mixed solvent thereof. Even more preferably, the first solvent is water, a ketone, a cyclic ether, or a nitrile solvent, or a mixed solvent thereof, and the second solvent is a ketone, a cyclic ether, or a nitrile solvent, or a mixed solvent of water and a ketone, a cyclic ether, or a nitrile solvent. Even more preferably, the ketone solvent includes, but is not limited to, acetone, the ether solvent includes, but is not limited to, tetrahydrofuran or 1,4-dioxane, and the nitrile solvent includes, but is not limited to, acetonitrile.

[0083] Furthermore, among the mixed solvents of the ketone, cyclic ether or nitrile solvent and water, The volume ratio of the ketone, cyclic ether or nitrile solvent to water is 5:1 to 25:1, and more preferably, the volume ratio of the ketone, cyclic ether or nitrile solvent to water is 9:1 to 16:1.

[0084] Furthermore, in step b), the temperature is raised to 20 to 50°C.

[0085] Furthermore, the third solvent is C 6-7 The solvent is a paraffin, an ether, or an ester. 6-7 Paraffin solvents include, but are not limited to, n-heptane; ether solvents include, but are not limited to, tert-butyl methyl ether; and ester solvents include, but are not limited to, methyl formate, ethyl acetate, isopropyl acetate, propyl acetate, or butyl acetate.

[0086] Because the formation of crystalline forms is fortuitous and unexpected, the obtaining of crystalline Form II-A of the methanesulfonate salt of Compound of Formula (I), crystalline Form III-A of the hydrochloride salt of Compound of Formula (I), and crystalline Form IV-C of the maleate salt of Compound of Formula (I) is itself surprising and unexpected. Furthermore, the present inventors have surprisingly and unexpectedly discovered that these crystalline forms have improved bioavailability and enhanced dynamic solubility.

[0087] According to one aspect of the present invention, the present application provides a method for preparing a compound of formula (I), comprising the steps of: [ka]

[0088] Furthermore, the method for preparing the compound of formula (I) is as follows. [ka]

[0089] Compound 1A is subjected to a substitution or coupling reaction with compound 1 to obtain compound 2, compound 2 is reacted with sodium methyl mercaptan to obtain compound 3, compound 3 is subjected to a substitution or coupling reaction with compound 3A to obtain compound 4, which is then subjected to a nucleophilic substitution reaction with compound 4A to obtain compound 5, the nitro group and methylthio group of compound 5 are reduced and removed, respectively, to obtain compound 6, and compound 6 is acylated with 3-chloropropionyl chloride 6A and removed under basic conditions to obtain compound (I). The nitro group can be reduced using conventional reducing agents well known in the art, including, but not limited to, iron powder, zinc powder, sodium sulfide, palladium / carbon (Pd / C) / hydrogen gas, Raney nickel (Raney-Ni) / hydrogen gas, platinum dioxide / hydrogen gas, etc.

[0090] According to one aspect of the present invention, the present application relates to a method for preparing the methanesulfonate salt of compound of formula (I), comprising the steps of: [ka]

[0091] Furthermore, the compound of formula (I) can be directly reacted with methanesulfonic acid in a solvent to form a salt, thereby obtaining the methanesulfonate salt of the compound of formula (I), and the solvent can include, but is not limited to, a mixture of acetone and water.

[0092] According to one aspect of the present invention, the present application relates to a process for preparing the hydrochloride salt of compound of formula (I), comprising the steps of: [ka]

[0093] Furthermore, the compound of formula (I) can be directly reacted with hydrochloric acid in a solvent to form a salt, thereby obtaining the hydrochloride salt of the compound of formula (I), and the solvent includes, but is not limited to, a mixture of ethanol and water.

[0094] According to one aspect of the present invention, the present application relates to a process for preparing the maleate salt of compound of formula (I), comprising the steps of: [ka]

[0095] Furthermore, the compound of formula (I) can be directly reacted with maleic acid in a solvent to form a salt, thereby obtaining the maleate salt of the compound of formula (I), and the solvent can include, but is not limited to, a mixture of ethanol and water.

[0096] The present invention provides a pharmaceutical composition comprising any one of the above salts or crystalline forms of the compound of formula (I) and a pharmaceutically acceptable carrier.

[0097] The present invention further provides any one of the above salts or crystalline forms of the compound of formula (I) for use as an antitumor agent.

[0098] The present invention further provides the use of any one of the above salts or crystalline forms of compound of formula (I) for the manufacture of a medicament for treating a disease, particularly cancer, mediated by an EGFR activating mutation, resistance mutation or exon 20 insertion mutation in a mammal, particularly a human.

[0099] The present invention further provides the use of any one of the above salts or crystalline forms of the compound of formula (I) in the manufacture of a medicament for treating cancer.

[0100] The present invention further provides the use of any one of the above salts or crystalline forms of compound of formula (I) for the treatment of a disease, particularly cancer, mediated by an EGFR activating mutation, resistance mutation or exon 20 insertion mutation in a mammal, particularly a human.

[0101] The present invention further provides a method for treating a disease, particularly cancer, mediated by an EGFR activating mutation, resistance mutation, or exon 20 insertion mutation in a mammal, particularly a human, said method comprising administering to a patient any one of the above salts or crystalline forms of the compound of formula (I) or a pharmaceutical composition comprising a therapeutically effective amount of any one of the above salts or crystalline forms of the compound of formula (I) and a pharmaceutically acceptable carrier, excipient, or diluent.

[0102] The present invention further provides a method of treating cancer, said method comprising administering to a patient any one of the above salts or crystalline forms of the compound of formula (I), or a pharmaceutical composition comprising a therapeutically effective amount of any one of the above salts or crystalline forms comprising the compound of formula (I), and a pharmaceutically acceptable carrier, excipient or diluent.

[0103] The cancers referred to in the present invention include, but are not limited to, ovarian cancer, non-small cell lung cancer, small cell lung cancer, cervical cancer, colorectal cancer, breast cancer, pancreatic cancer, glioma, glioblastoma, melanoma, prostate cancer, leukemia, lymphoma, non-Hodgkin's lymphoma, gastric cancer, lung cancer, hepatocellular carcinoma, gastrointestinal stromal tumor, thyroid cancer, bile duct cancer, endometrial cancer, kidney cancer, anaplastic large cell lymphoma, acute myeloid leukemia, multiple myeloma, and mesothelioma, and are particularly well suited to tumor classification of epidermal growth factor receptor exon 20 insertion mutations. Furthermore, the cancer is non-small cell lung cancer.

[0104] The epidermal growth factor receptor (EGFR) exon 20 insertion mutation referred to in the present invention includes, but is not limited to, a V774insHV insertion mutation, a D770insNPG insertion mutation, a N771insH insertion mutation, a V769insASV insertion mutation, a A763insFQEA insertion mutation, a D770insSVD insertion mutation, etc. For example, any one of the salts or crystalline forms of the compound of formula (I) of the present invention may be used as a drug for treating non-small cell lung cancer having an epidermal growth factor receptor exon 20 insertion mutation.

[0105] Any one of the above salts or crystalline forms of the compound of formula (I) of the present invention may be administered to mammals, including humans, orally, rectally, parenterally (intravenously, intramuscularly or subcutaneously), topically (as powders, ointments or drops) or intratumorally.

[0106] The dosage of any one of the salts or crystalline forms of the compound of formula (I) of the present invention is about 0.05 to 50 mg / kg body weight / day, for example, 0.1 to 45 mg / kg body weight / day, and further, for example, 0.5 to 35 mg / kg body weight / day, calculated as the free base.

[0107] Any one of the above salts or crystalline forms of the compound of formula (I) of the present invention can be prepared into solid formulations for oral administration, including, but not limited to, capsules, tablets, pills, powders, granules, etc. In these solid dosage forms, any one of the above salts or crystalline forms of the compound of formula (I) of the present invention is mixed as an active ingredient with at least one common inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or mixed with the following ingredients: (1) fillers or compatibilizers, such as starch, lactose, sucrose, glucose, mannitol, etc., (2) adhesives, such as hydroxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose, and gum arabic, etc., (3) humectants, such as glycerin, etc., (4) disintegrating agents, such as agar-agar, calcium carbonate, potato starch or tapioca starch, and alginic acid, etc., (5) solution retarders, such as paraffin, etc., (6) absorption accelerators, such as quaternary ammonium compounds, etc., (7) wetting agents, such as cetyl alcohol and glyceryl monostearate, etc., (8) adsorbents, such as kaolin, etc., and (9) lubricants, such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, etc., or mixtures thereof. Capsules, tablets, and pills may also contain buffering agents.

[0108] The solid dosage forms, such as tablets, sugar-coated tablets, capsules, pills and granules, can be coated or encapsulated with coating and shell materials, such as enteric coatings and other materials well known in the art.These may contain opacifying agents, and the release of the active ingredient in such compositions can be delayed in a certain part of the digestive tract.Examples of embedding compositions that can be used include polymeric substances and waxes.If necessary, the active ingredient can also be in the form of microcapsules with one or more of the above-mentioned excipients.

[0109] Any one of the salts or crystalline forms of the compound of formula (I) of the present invention can be prepared into liquid dosage forms for oral administration, including, but not limited to, pharmaceutically acceptable emulsions, solutions, suspensions, syrups, and elixirs. In addition to any one of the salts or crystalline forms of the compound of formula (I) as the active ingredient, the liquid dosage forms can contain inert diluents commonly used in the art, such as water and other solvents, solubilizers, and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (especially cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil, and sesame oil), or mixtures of these substances. In addition to these inert diluents, the liquid dosage forms of the present invention can also contain common auxiliary agents, such as wetting agents, emulsifiers, suspending agents, sweeteners, flavorings, and aromatics.

[0110] The suspending agents include, for example, ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide, agar, and the like, or mixtures of these substances.

[0111] Any one of the above salts or crystalline forms of the compound of formula (I) of the present invention can be prepared into dosage forms for parenteral injection, including, but not limited to, physiologically acceptable sterile aqueous or anhydrous solutions, dispersions, suspensions or emulsions, and sterile powders that can be reconstituted to give sterile injectable solutions or dispersions. Suitable carriers, diluents, solvents or excipients include water, ethanol, polyols, and suitable mixtures thereof.

[0112] Any one of the above salts or crystalline forms of the compound of formula (I) of the present invention can also be prepared into dosage forms for topical administration, including, but not limited to, ointments, powders, suppositories, drops, sprays, inhalants, etc. Any one of the above salts or crystalline forms of the compound of formula (I) of the present invention as an active ingredient can be mixed under sterile conditions and physiologically acceptable carriers, and any preservatives, buffers, or propellants as needed.

[0113] The present invention further provides a pharmaceutical composition comprising any one of the above salts or crystalline forms of the compound of formula (I) of the present invention and a pharmaceutically acceptable carrier, excipient or diluent. In preparing the pharmaceutical composition, typically, any one of the above salts or crystalline forms of the compound of formula (I) of the present invention is mixed with a pharmaceutically acceptable carrier, excipient or diluent.

[0114] According to common manufacturing methods, the composition of the present invention can be prepared into common pharmaceutical preparations, such as tablets, pills, capsules, powders, granules, emulsions, suspensions, dispersions, solutions, syrups, ointments, drops, suppositories, inhalants, sprays, etc.

[0115] Any one of the above salts or crystalline forms of the compound of formula (I) of the present invention may be administered alone or together with other pharmaceutically acceptable therapeutic agents, in particular in combination with other antitumor agents. The therapeutic agent may be, for example, an alkylating agent (e.g., cisplatin, oxaliplatin, carboplatin, cyclophosphamide, nitrochlormethine, melphalan, chlorambucil, busulfan, temozolomide, nitrosoureas), antimetabolites (e.g., gemcitabine and folate antagonists, e.g., fluoropyrimidines (e.g., 5-fluorouracil and tegafur), raltitrexed, methotrexate, cytarabine, hydroxyurea), antitumor antibiotics (e.g., anthracyclines such as adlibrastine, bleomycin, doxorubicin, daunorubicin, epirubicin, idarubicin, mitomycin C, actinomycin, and mithramycin), mitotic inhibitors (e.g., vinca alkaloids such as vincristine, vinblastine, vindesine, and vinorelbine, and taxanes such as paclitaxel and docetaxel), topoisomerase ... The combined components may be administered simultaneously or sequentially, and may be administered in the form of a single formulation or different formulations. The combination may include not only a combination of any one of the above-mentioned salts or crystalline forms of the compound of formula (I) of the present invention with other active substances, but also a combination of any one of the above-mentioned salts or crystalline forms of the compound of formula (I) of the present invention with two or more other active substances. [Example]

[0116] The present application is illustrated by the following examples.

[0117] Example The present invention will be further described below with reference to examples. However, the examples are intended to further explain and explain the present invention, and are not intended to limit the present invention.

[0118] Unless otherwise defined, relevant technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art. In testing or practical applications, the same or similar methods and materials as those described herein can be used, but the materials and methods are described below. In the event of any discrepancy, the definitions set forth herein will govern, and the materials, methods, and examples are for illustrative purposes only and not for limiting purposes. The present invention will be further described below with reference to specific examples, but not for limiting the scope of the present invention.

[0119] In the examples, the following test conditions are used: [Table 1] [Table 2] [Table 3] [Table 4] [Table 5] [Table 6] [Table 7]

[0120] The concentration of free base and the concentration of acid radical ions in the same sample are measured by IC, and then the stoichiometric ratio of base:acid in that sample is calculated as follows:

number

[0121] Example 1: Amorphous Free Base (Sample Number: Y11526-45-RV-FWD1509-AF-SU12) Approximately 300 mg of the compound of formula (I) (purity 99.9%) was weighed and placed in a 40 mL glass flask. 10 mL of methanol / acetonitrile (v:v=1:1) was added to obtain a clear solution. The solvent was removed from the clear solution by high-speed evaporation (i.e., rotary evaporation) to obtain approximately 290 mg of an off-white solid, with a yield of approximately 97%. HPLC showed the product to be 99.9% pure. The product showed an irregular sample (Figure 5). XRPD showed the product was amorphous (Figure 1). DSC showed the product had glass transition temperatures of 68.4°C and 104.7°C (Figure 2). TGA showed the product had a weight loss of about 5.1% at 150°C (Figure 3). The amorphous free base (sample number: Y11526-45-RV-FWD1509-AF-SU12) is chemically and physically stable at the end of manufacturing.

[0122] Example 2: 1 equivalent of amorphous hydrochloride salt (Sample number: Y11526-42-SU11-methanol-dichloromethane) Approximately 300 mg of the compound of formula (I) (purity 99.9%) was weighed and placed in a 40 mL glass flask. 20 mL of methanol / dichloromethane (v:v=1:1) and 1 equivalent of a diluted solution of hydrochloric acid (518 μL, 44 mg / mL, in methanol / dichloromethane (v:v=1:1)) were added and reacted at 50° C. for 2 hours to obtain a clear solution. The solvent was removed from the clear solution by high-speed evaporation to obtain approximately 306 mg of a pale yellow solid, with a yield of approximately 95%. HPLC showed that the product was 99.9% pure. PLM showed that the product was an irregular sample (Figure 10). XRPD showed that the product was amorphous (Figure 6). DSC showed that the product had a glass transition temperature of 128.5°C (Figure 7). TGA showed that the product had a weight loss of approximately 5.1% at 150°C (Figure 8). IC showed that the free base concentration of the product was 0.5 mg / mL and the chloride ion concentration was 33.7 mg / L, resulting in a base:acid stoichiometry of approximately 1:1 in the product. One equivalent of amorphous hydrochloride salt (sample number: Y11526-42-SU11-methanol-dichloromethane) is chemically and physically stable at the end of the preparation and is reasonable in terms of base:acid stoichiometry.

[0123] Example 3: 2 equivalents of amorphous hydrochloride salt (Sample number: Y11526-28-SU5-methanol-dichloromethane) Approximately 300 mg of the compound of formula (I) (purity 99.9%) was weighed and placed in a 40 mL glass flask. 5 mL of methanol / dichloromethane (v:v=1:1) and 2 equivalents of a diluted solution of hydrochloric acid (1010 μL, 44 mg / mL, in methanol / dichloromethane (v:v=1:1)) were added, and the mixture was reacted at 50°C for 2 hours. The temperature was lowered to 25°C and the mixture was reacted for another 2 hours to obtain a clear solution. The solvent was removed from the resulting clear solution by high-speed evaporation to obtain approximately 310 mg of a yellow solid, with a yield of approximately 90%. HPLC showed that the product was 99.9% pure. PLM showed that the product was an irregular sample (Figure 15). XRPD showed that the product was amorphous (Figure 11). DSC showed that the product had a glass transition temperature of 154.0°C (Figure 12). TGA showed that the product had a weight loss of approximately 4.3% at 110°C (Figure 13). IC showed that the concentration of the free base in the product was 0.5 mg / mL and the chloride ion concentration was 77.4 mg / L, resulting in a base:acid stoichiometry of approximately 1:2 in the product. Two equivalents of amorphous hydrochloride salt (sample number: Y11526-28-SU5-methanol-dichloromethane) are chemically and physically stable at the end of the preparation and are reasonable in terms of base:acid stoichiometry.

[0124] Example 4: 1 equivalent of amorphous methanesulfonate salt (sample number: Y11526-42-SU10-methanol-dichloromethane) With stirring, the weighed out compound of formula (I) was added to acetone (11.70 times the weighed out compound of formula (I) by weight), and the temperature was raised to 45-55°C. After dissolution, the reaction mixture was filtered while still hot, and the filtrate was heated to 45-55°C. Water (1 time the weighed out compound of formula (I) by weight) was added, and the mixture was stirred at 45-55°C for 30 minutes. A solution of 0.188 times the amount of the compound of formula (I) was added dropwise and stirred at 45-55°C for 60±10 minutes. The reaction mixture was cooled to 20-30°C within 1.0-2.0 hours, and crystallization was carried out at 10-30°C for 1.0-2.0 hours with stirring. The reaction mixture was filtered, and the filter cake was washed twice with acetone (2 times the amount of the compound of formula (I) weighed out). The filter cake was dried at 40±5°C and ≦-0.07 MPa until a constant weight was obtained, yielding a highly crystalline material. Approximately 300 mg of the resulting highly crystalline material was taken and approximately 50 mL of methanol / dichloromethane (v:v=1:1) was added to obtain a clear solution, which was then subjected to high-speed evaporation to remove the solvent, yielding approximately 268 mg of a pale yellow solid, with a yield of approximately 72%. HPLC showed the product to be 99.9% pure. PLM showed the product to be an irregular sample (Figure 20). XRPD showed the product to be amorphous (Figure 16). DSC showed the product had a glass transition temperature of 111.1°C (Figure 17). TGA showed the product had a weight loss of approximately 3.9% at 140°C (Figure 18). 1 H-NMR showed that the base:acid stoichiometry in the product was approximately 1:1 (Figure 19). One equivalent of amorphous methanesulfonate salt (sample number: Y11526-42-SU10-methanol-dichloromethane) is chemically and physically stable at the end of the preparation and is reasonable in terms of base:acid stoichiometry.

[0125] Example 5: 2 equivalents of amorphous methanesulfonate salt (Sample number: Y11526-28-SU4-methanol-dichloromethane) Approximately 300 mg of the compound of formula (I) (purity 99.9%) was weighed and placed in a 40 mL glass flask. 2 mL of methanol and 2 equivalents of a diluted solution of methanesulfonic acid (798 μL, 148 mg / mL in methanol) were added, causing the clear solution to turn yellow and opaque. 2 mL of dichloromethane was added, causing the solution to become clear. Subsequently, 1 mL of methanol / dichloromethane (v:v = 1:1) was added. The reaction was carried out at 50°C for 2 hours, then cooled to 25°C and continued for approximately 3 hours, yielding a clear solution. The solvent was removed from the resulting clear solution by high-speed evaporation, yielding approximately 380 mg of a yellow solid, with a yield of approximately 85%. HPLC showed the product to be 99.9% pure. PLM showed the product to be an irregular sample (Figure 25). XRPD showed the product to be amorphous (Figure 21). DSC showed the product had a glass transition temperature of 131.7°C (Figure 22). TGA showed the product had a weight loss of approximately 2.4% at 130°C (Figure 23). 1 H-NMR showed that the base:acid stoichiometry in the product was approximately 1:2 (Figure 24). Two equivalents of amorphous methanesulfonate salt (sample number: Y11526-28-SU4-methanol-dichloromethane) is chemically and physically stable at the end of the preparation and has a reasonable base:acid stoichiometry.

[0126] Example 6: 1 equivalent of amorphous benzenesulfonate salt (sample number: Y11526-42-SU9-methanol-dichloromethane) Approximately 300 mg of the compound of formula (I) (purity 99.9%) was weighed and placed in a 250 mL round-bottom flask with 1 equivalent of benzenesulfonic acid. 15 mL of water was added and the mixture was allowed to react at 50°C for 2 hours. A clear solution was obtained, followed by precipitation of a solid. The suspension was pre-frozen in a dry ice / ethanol mixture for 2 hours, and then the water was removed by freeze-drying to obtain a low-crystallinity sample. The freeze-dried sample was dissolved in 5 mL of methanol / dichloromethane (v:v = 1:1) to obtain a clear solution. The solvent from the clear solution was removed by high-speed evaporation to obtain approximately 320 mg of a pale yellow solid, with a yield of approximately 83%. HPLC showed that the product was 99.7% pure. PLM showed that the product was an irregular sample (Figure 30). XRPD showed that the product was amorphous (Figure 26). DSC showed that the product had a glass transition temperature of 100.7°C and The temperature was shown to be 114.7°C (Figure 27). TGA showed that the product had a weight loss of about 3.8% at 150°C (Figure 28). 1 H-NMR showed that the base:acid stoichiometry in the product was approximately 1:1 (Figure 29). One equivalent of amorphous benzenesulfonate (sample number: Y11526-42-SU9-methanol-dichloromethane) is chemically and physically stable at the end of the preparation and is reasonable in terms of base:acid stoichiometry.

[0127] Example 7: 2 equivalents of amorphous benzenesulfonate (sample number: Y11526-30-SU1-water) Approximately 300 mg of the compound of formula (I) (purity 99.9%) was weighed and placed in a 250 mL round-bottom flask together with 2 equivalents of benzenesulfonic acid, and 15 mL of water was added and reacted at 50°C for 2 hours to obtain a clear solution. The obtained clear solution was pre-frozen in a dry ice / ethanol mixture for 2 hours, and then the water was removed by freeze-drying to obtain approximately 380 mg of a yellow solid, with a yield of approximately 81%. HPLC showed the product to be 99.7% pure. PLM showed the product to be an irregular sample (Figure 35). XRPD showed the product to be amorphous (Figure 31). DSC showed the product had no glass transition temperature (Figure 32). TGA showed the product had a weight loss of approximately 1.9% at 100°C (Figure 33). 1 H-NMR showed that the base:acid stoichiometry in the product was approximately 1:2 (Figure 34). Two equivalents of amorphous benzenesulfonate (sample number: Y11526-30-SU1-water) is chemically and physically stable at the end of the preparation and is reasonable in terms of base:acid stoichiometry.

[0128] Example 8: 1 equivalent of amorphous ethanesulfonate salt (Sample No.: Y11526-28-SU7-methanol-dichloromethane) Approximately 300 mg of compound of formula (I) (purity 99.9%) was weighed and placed in a 40 mL glass flask. 5 mL of methanol / dichloromethane (v:v=1:1) and 1 equivalent of a diluted solution of ethanesulfonic acid (541 μL, 128 mg / mL, in methanol / dichloromethane (v:v=1:1)) were added, and the mixture was reacted at 50°C for 2 hours. The temperature was then lowered to 25°C and the mixture was reacted for another 2 hours to obtain a clear solution. The solvent was removed from the resulting clear solution by high-speed evaporation to obtain approximately 340 mg of a yellow solid, with a yield of approximately 90%. HPLC showed the product to be 99.9% pure. PLM showed the product to be an irregular sample (Figure 40). XRPD showed the product to be amorphous (Figure 36). DSC showed the product had a glass transition temperature of 102.4°C (Figure 37). TGA showed the product had a weight loss of approximately 1.6% at 101°C (Figure 38). 1 H-NMR showed that the base:acid stoichiometry in the product was approximately 1:1 (Figure 39). One equivalent of amorphous ethanesulfonate salt (sample number: Y11526-28-SU7-methanol-dichloromethane) is chemically and physically stable at the end of the preparation and is reasonable in terms of base:acid stoichiometry.

[0129] Example 9: 1 equivalent of amorphous maleate salt (sample number: Y11526-30-SU2-water) Approximately 300 mg of the compound of formula (I) (purity 99.9%) was weighed and placed in a 250 mL round-bottom flask together with 1 equivalent of maleic acid, and 20 mL of water was added and reacted at 50° C. for 2 hours to obtain a clear solution. The obtained clear solution was pre-frozen in a dry ice / ethanol mixture for 2 hours, and then the water was removed by freeze-drying to obtain approximately 330 mg of a pale yellow solid, with a yield of approximately 89%. HPLC showed the product to be 99.9% pure. The product showed an irregular sample (Figure 45). XRPD showed the product was amorphous (Figure 41). DSC showed the product had glass transition temperatures of 89.2°C and 125.2°C (Figure 42). TGA showed the product had a weight loss of about 0.9% at 100°C (Figure 43). 1 H-NMR showed that the base:acid stoichiometry in the product was approximately 1:1 (Figure 44). One equivalent of amorphous maleate salt (sample number: Y11526-30-SU2-water) is chemically and physically stable at the end of the preparation and is reasonable in terms of base:acid stoichiometry.

[0130] Example 10: 1 equivalent of crystalline hydrobromide salt (Sample number: Y11526-33-SU8-methanol-dichloromethane) Approximately 300 mg of compound of formula (I) (purity 99.9%) was weighed and placed in a 40 mL glass flask. 20 mL of methanol / dichloromethane (v:v=1:1) and 1 equivalent of a diluted solution of hydrobromic acid (728 μL, 70 mg / mL, in methanol / dichloromethane (v:v=1:1)) were added and the mixture was allowed to react at 50 °C for 2 hours to obtain a nearly clear solution (with traces of insoluble impurities). The impurities were filtered through a 0.45 μm filter membrane to obtain a clear solution. The solvent was removed from the resulting solution by rapid evaporation to obtain approximately 310 mg of a pale yellow solid, with a yield of approximately 90%. HPLC showed that the product was 99.9% pure. PLM showed that the product was a rod-like and blocky sample (Figure 50). XRPD showed that the product had high crystallinity (Figure 46). DSC showed that the product began to dehydrate at approximately 30°C (Figure 47). TGA showed that the product had a weight loss of approximately 1.8% at 110°C (Figure 48). KF showed that the product contained 1.9% water. IC showed that the free base concentration of the product was 0.5 mg / mL and the bromide ion concentration was 68.1 mg / L, indicating that the base:acid stoichiometry in the product was approximately 1:1. One equivalent of the crystalline hydrobromide salt (sample number: Y11526-33-SU8-methanol-dichloromethane) is chemically and physically stable at the end of the preparation and has a reasonable base:acid stoichiometry.

[0131] Example 11: Amorphous Nitrate (Sample Number: Y11526-18-RV7-Methanol-Dichloromethane) Approximately 100 mg of the compound of formula (I) (purity 99.9%) was weighed and placed in a 40 mL glass flask, and 10 mL of 1,4-dioxane was added. Two equivalents of a diluted solution of nitric acid (144 μL, 180 mg / mL, in 1,4-dioxane) were added and reacted for 2 hours at 50° C. The resulting clear solution was pre-frozen in a dry ice / ethanol mixture for 2 hours, and then the 1,4-dioxane was removed by freeze-drying to obtain a nearly amorphous substance. Approximately 80 mg of the resulting near-amorphous material was weighed out and placed in a 40 mL glass flask. Approximately 10 mL of methanol / dichloromethane (v:v=1:1) was added to obtain a clear solution. The solvent was removed from the clear solution by high-speed evaporation to obtain the amorphous nitrate salt. XRPD showed the product to be amorphous (Figure 51). 1 H-NMR showed the occurrence of decomposition of the product (Figure 52). The amorphous nitrate salt (sample number: Y11526-18-RV7-methanol-dichloromethane) is chemically unstable at least at the end of its manufacturing life.

[0132] Example 12: Amorphous Sulfate (Sample Number: Y11526-15-RV3-Methanol-Acetonitrile) Approximately 100 mg of the compound of formula (I) (purity 99.9%) was weighed and placed in a 40 mL glass flask. 10 mL of 1,4-dioxane was added, followed by the addition of 2 equivalents of a diluted sulfuric acid solution (228 μL, 180.3 mg / mL, in 1,4-dioxane), and the mixture was allowed to react at 50° C. for 2 hours. The resulting clear solution was pre-frozen in a dry ice / ethanol mixture for 2 hours, after which the 1,4-dioxane was removed by freeze-drying to yield a nearly amorphous material. Approximately 80 mg of the resulting near-amorphous material was placed in a 40 mL glass flask, and approximately 10 mL of methanol / acetonitrile (v:v=1:1) was added to obtain a clear solution. The solvent was removed from the clear solution by high-speed evaporation to obtain the amorphous sulfate salt. HPLC showed that the purity of the product was 99.7%. PLM showed that the product was an irregular sample (Figure 57). XRPD showed that the product was amorphous (Figure 53). DSC showed that the glass transition temperatures of the product were 103.3°C and 152.8°C (Figure 54). TGA showed that the weight loss of the product at 100°C was about 3.2% (Figure 55). IC showed that the concentration of the free base of the product was 0.5 mg / mL and the concentration of sulfate ion was 162.5 mg / L, which means that the stoichiometric ratio of base to acid in the product was about 1:1.7, which is unreasonable. The amorphous sulfate salt (sample number: Y11526-15-RV3-methanol-acetonitrile) is chemically stable at the end of production, but is physically unstable due to its hygroscopicity and the stoichiometric ratio of base to acid is unreasonable.

[0133] Example 13: 2 equivalents of amorphous p-toluenesulfonate salt (sample number: Y11526-23-FD11-water) Approximately 100 mg of compound of formula (I) (purity 99.9%) was weighed and placed in a 40 mL glass flask with 2 equivalents of p-toluenesulfonic acid. 10 mL of 1,4-dioxane was added and the mixture was allowed to react at 50°C for 2 hours. The resulting clear solution was pre-frozen in a dry ice / ethanol mixture for 2 hours, and then the 1,4-dioxane was removed by freeze-drying to obtain a nearly amorphous substance. The resulting nearly amorphous substance was thoroughly dissolved in 10 mL of water, and the resulting clear solution was pre-frozen in a dry ice / ethanol mixture for 2 hours, and then the water was removed by freeze-drying to obtain 2 equivalents of amorphous p-toluenesulfonic acid salt. HPLC showed the product to be 99.6% pure. PLM showed the product to be a bulky sample (Figure 62). XRPD showed the product to be amorphous (Figure 58). DSC showed the product had a glass transition temperature of 98.4°C (Figure 59). TGA showed the product had a weight loss of approximately 3.8% at 140°C (Figure 60). 1 H-NMR showed that the base:acid stoichiometry in the product was approximately 1:2 (Figure 61). Two equivalents of amorphous p-toluenesulfonate salt (sample number: Y11526-23-FD11-water) is chemically stable at the end of its preparation and has a reasonable base:acid stoichiometry, but is physically unstable as it quickly solidifies and fuses into a glassy state upon brief exposure to environmental conditions (Figure 63).

[0134] Example 14: Amorphous sulfosalicylate (sample number: Y11526-25-FD13-1,4-dioxane) Approximately 100 mg of the compound of formula (I) (purity 99.9%) was weighed and placed in a 40 mL glass flask together with 1 equivalent of sulfosalicylic acid. 10 mL of 1,4-dioxane was added and the mixture was allowed to react at 50°C for 2 hours. The resulting clear solution was pre-frozen in a dry ice / ethanol mixture for 2 hours, and then the 1,4-dioxane was removed by freeze-drying to obtain amorphous sulfosalicylic acid salt. HPLC showed the product to be 99.7% pure. PLM showed the product to be an irregular sample (Figure 68). XRPD showed the product to be amorphous (Figure 64). DSC showed the product had a glass transition temperature of 72.1°C (Figure 65). TGA showed the product had a weight loss of approximately 1.2% at 80°C (Figure 66). 1 H-NMR showed that the base:acid stoichiometry in the product was about 1:0.8 (Figure 67), which is unreasonable. Amorphous sulfosalicylate (sample number: Y11526-25-FD13-1,4-dioxide) Although the oxalanine is chemically and physically stable at the end of its production, it has an unreasonable base:acid stoichiometry.

[0135] Example 15: Amorphous sulfosalicylate (Sample No.: Y11526-25-FD12-1,4-dioxane) Approximately 100 mg of the compound of formula (I) (purity 99.9%) was weighed and placed in a 40 mL glass flask together with 2 equivalents of sulfosalicylic acid. 10 mL of 1,4-dioxane was added and the mixture was allowed to react at 50°C for 2 hours. The resulting clear solution was pre-frozen in a dry ice / ethanol mixture for 2 hours, and then the 1,4-dioxane was removed by freeze-drying to obtain amorphous sulfosalicylic acid salt. HPLC showed the product to be 99.8% pure. PLM showed the product to be an irregular sample (Figure 73). XRPD showed the product to be amorphous (Figure 69). DSC showed the product had a glass transition temperature of 86.3°C (Figure 70). TGA showed the product had a weight loss of approximately 2.7% at 110°C (Figure 71). 1 H-NMR showed that the base:acid stoichiometry in the product was about 1:1.5 (Figure 72), which is unreasonable. Amorphous sulfosalicylate (sample number: Y11526-25-FD12-1,4-dioxane) is chemically and physically stable at the end of its manufacturing process, but has an unreasonable base:acid stoichiometry.

[0136] Example 16: Amorphous L-Malate (Sample Number: Y11526-17-RV6-methanol-dichloromethane) Approximately 100 mg of the compound of formula (I) (purity 99.9%) was weighed and placed in a 40 mL glass flask together with 1 equivalent of L-malic acid, and 10 mL of 1,4-dioxane was added and reacted for 2 hours at 50° C. The resulting clear solution was pre-frozen in a dry ice / ethanol mixture for 2 hours, after which the 1,4-dioxane was removed by freeze-drying to obtain a highly crystalline material. Approximately 80 mg of the resulting highly crystalline material was placed in a 40 mL glass flask, and approximately 10 mL of methanol / dichloromethane (v:v=1:1) was added to obtain a clear solution, which was then subjected to high-speed evaporation to remove the solvent, yielding amorphous L-malate. HPLC showed that the purity of the product was 91.1%, i.e., the purity of the salt obtained at the end of the preparation was clearly reduced compared to the purity of the free base of the salt before preparation. PLM showed that the product was an irregular sample (Figure 78). XRPD showed that the product was amorphous (Figure 74). DSC showed that the glass transition temperature of the product was 80.8°C (Figure 75). TGA showed that the weight loss of the product at 120°C was approximately 3.3% (Figure 76). 1 H-NMR showed that the base:acid stoichiometry in the product was about 1:0.6 (Figure 77), which is unreasonable. The amorphous L-malate salt (sample number: Y11526-17-RV6-methanol-dichloromethane) is at least chemically unstable at the end of its manufacturing process and has an unreasonable base:acid stoichiometry.

[0137] Example 17: 1 equivalent of amorphous citrate salt (sample number: Y11526-10-FD6-1,4-dioxane) Approximately 100 mg of the compound of formula (I) (purity 99.9%) was weighed and placed in a 40 mL glass flask together with 1 equivalent of citric acid, and 10 mL of 1,4-dioxane was added and reacted for 2 hours at 50° C. The resulting clear solution was pre-frozen in a dry ice / ethanol mixture for 2 hours, after which the 1,4-dioxane was removed by freeze-drying to obtain 1 equivalent of amorphous citrate. HPLC showed that the purity of the product was 94.4%, i.e., the purity of the salt obtained at the end of the preparation was clearly reduced compared to the purity of the free base of the salt before preparation. PLM NMR analysis indicated that the product was an irregular sample (Figure 83). XRPD indicated that the product was amorphous (Figure 79). DSC indicated that the product had no glass transition temperature (Figure 80). TGA indicated that the product had a weight loss of approximately 9.6% at 120°C (Figure 81). 1 H-NMR showed that the base:acid stoichiometry in the product was approximately 1:1 (Figure 82). One equivalent of amorphous citrate (sample number: Y11526-10-FD6-1,4-dioxane) is at least chemically unstable, although the base:acid stoichiometry is reasonable at the end of the preparation.

[0138] Example 18: 1 equivalent of amorphous L-tartrate salt (sample number: Y11526-10-FD7-1,4-dioxane) Approximately 100 mg of the compound of formula (I) (purity 99.9%) was weighed and placed in a 40 mL glass flask together with 1 equivalent of L-tartaric acid, and 10 mL of 1,4-dioxane was added and reacted for 2 hours at 50° C. The resulting clear solution was pre-frozen in a dry ice / ethanol mixture for 2 hours, after which the 1,4-dioxane was removed by freeze-drying to obtain 1 equivalent of amorphous L-tartrate. HPLC showed that the product had decomposed (Figure 88). XRPD showed that the product was amorphous (Figure 84). DSC showed that the product had no glass transition temperature (Figure 85). TGA showed that the product had a weight loss of about 8.7% at 120°C (Figure 86). 1 H-NMR showed that the base:acid stoichiometry in the product was approximately 1:1 (Figure 87). One equivalent of amorphous L-tartrate salt (sample number: Y11526-10-FD7-1,4-dioxane) is at least chemically unstable, although the base:acid stoichiometry is reasonable at the end of the preparation.

[0139] As can be seen from Examples 1 to 18, When the molar ratio of base to acid is 1:1, sulfosalicylic acid and L-malic acid cannot provide a stoichiometric ratio of the compound of formula (I) to acid of 1:1 in the resulting salt. When the molar ratio of base to acid is 1:1, hydrochloric acid, methanesulfonic acid, benzenesulfonic acid, ethanesulfonic acid, maleic acid, hydrobromic acid, citric acid, and L-tartaric acid can provide a stoichiometric ratio of the compound of formula (I) to acid of 1:1 in the resulting salt; When the molar ratio of base to acid is 1:2, nitric acid, sulfuric acid, and sulfosalicylic acid cannot make the resulting salt have a stoichiometric ratio of the compound of formula (I) to acid=1:2; and When the molar ratio of base to acid is 1:2, hydrochloric acid, methanesulfonic acid, benzenesulfonic acid, and p-toluenesulfonic acid can give a salt having a stoichiometric ratio of the compound of formula (I):acid=1:2.

[0140] As can be seen from Examples 1 to 18, One equivalent of amorphous citrate, one equivalent of amorphous L-tartrate, amorphous nitrate, and amorphous L-malate are chemically unstable at the end of production. Two equivalents of amorphous p-toluenesulfonate and amorphous sulfate are physically unstable at the end of their preparation, and 1 equivalent of amorphous hydrochloride, 2 equivalents of amorphous hydrochloride, 1 equivalent of amorphous methanesulfonate, 2 equivalents of amorphous methanesulfonate, 1 equivalent of amorphous benzenesulfonate, 2 equivalents of amorphous benzenesulfonate, 1 equivalent of amorphous ethanesulfonate, 1 equivalent of amorphous maleate, 1 equivalent of crystalline hydrobromide, and amorphous sulfosalicylate are chemically and physically stable at the end of manufacture.

[0141] Example 19: Solid Storage Safety Test Various amorphous solid salts were weighed out (two 2 mg samples were weighed out) for use in solid storage safety studies. The amorphous solid salt was left in the open in a constant temperature and humidity box at 25°C / 60%RH, protected from light, for one week (i.e., "solid / 25°C / 60%RH / open / 1 week"). Also, in the solid storage safety test at 60°C, the amorphous solid salt was left in a sealed 60°C oven, protected from light, for one week (i.e., "solid / 60°C / sealed container / 1 week"). After that, the sample was removed and subjected to purity measurement, crystalline form detection, and appearance observation. The above-mentioned solid storage safety test was carried out on Examples 1 to 10, and the results are shown in Table 1.

[0142] [Table 8]

[0143] The amorphous free base exhibited good physical and chemical stability under the storage safety test conditions of "solid / 25°C / 60% RH / open / 1 week" and converted from amorphous to moderately crystalline under the storage safety test conditions of "solid / 60°C / sealed container / 1 week."

[0144] One equivalent of the amorphous hydrochloride salt exhibited good physical and chemical stability under the storage safety test conditions of "solid / 25°C / 60% RH / open / 1 week", but purity loss (approximately 2%) occurred under the storage safety test conditions of "solid / 60°C / sealed container / 1 week".

[0145] The 2-equivalent amorphous hydrochloride salt underwent a slight discoloration and showed some hygroscopicity (partial aggregation) under the storage safety test conditions of "solid / 25°C / 60% RH / open / 1 week," but showed good physical and chemical stability under the storage safety test conditions of "solid / 60°C / sealed container / 1 week."

[0146] One equivalent of the amorphous methanesulfonate salt showed good physical and chemical stability under two storage safety test conditions: solid / 25°C / 60% RH / open / 1 week and solid / 60°C / sealed container / 1 week.

[0147] Two equivalents of the amorphous methanesulfonate salt under the storage safety test conditions of "solid / 25°C / 60% RH / open / 1 week" changed from amorphous to low crystallinity and showed some hygroscopicity (aggregation), and also showed some hygroscopicity (partial aggregation) under the storage safety test conditions of "solid / 60°C / sealed container / 1 week".

[0148] One equivalent of amorphous benzenesulfonate salt underwent a purity loss (approximately 2%) under storage safety test conditions of "solid / 25°C / 60%RH / open / 1 week", but showed good physical and chemical stability under storage safety test conditions of "solid / 60°C / sealed container / 1 week".

[0149] Two equivalents of amorphous benzenesulfonate are stored in the following conditions: Solid / 25°C / 60% RH / Open / 1 week Under the storage safety test conditions of "solid / 60°C / sealed container / 1 week", the product showed slight discoloration and obvious hygroscopicity (solidified and fused to a glassy state), but showed good physical and chemical stability under the storage safety test conditions of "solid / 60°C / sealed container / 1 week".

[0150] One equivalent of the amorphous ethanesulfonate salt exhibited significant hygroscopicity (solidification and fusion to a glassy state) under the storage safety test conditions of "solid / 25°C / 60% RH / open / 1 week" but exhibited good physical and chemical stability under the storage safety test conditions of "solid / 60°C / sealed container / 1 week."

[0151] One equivalent of amorphous maleate under the storage safety test conditions of "solid / 25°C / 60%RH / open / 1 week" showed slight discoloration and a certain degree of hygroscopicity (aggregation), and under the storage safety test conditions of "solid / 60°C / sealed container / 1 week" a purity loss occurred (approximately 2%) and the amorphous form changed to a low crystallinity form.

[0152] One equivalent of the crystalline hydrobromide salt showed good physical and chemical stability under two storage safety test conditions: solid / 25°C / 60% RH / open / 1 week and solid / 60°C / sealed container / 1 week.

[0153] As can be seen from Example 19, One equivalent of amorphous benzenesulfonate, one equivalent of amorphous hydrochloride, and one equivalent of amorphous maleate are chemically unstable under the storage conditions of "solid / 25°C / 60%RH / open / 1 week" and / or "solid / 60°C / sealed container / 1 week." Two equivalents of the amorphous hydrochloride salt, two equivalents of the amorphous methanesulfonate salt, two equivalents of the amorphous benzenesulfonate salt, one equivalent of the amorphous ethanesulfonate salt, and one equivalent of the amorphous maleate salt are physically unstable under the storage conditions of "solid / 25°C / 60% RH / open / 1 week" and / or "solid / 60°C / sealed container / 1 week"; and One equivalent of the amorphous methanesulfonate salt and one equivalent of the crystalline hydrobromide salt are chemically and physically stable under the following storage conditions: solid / 25°C / 60% RH / open / 1 week and solid / 60°C / sealed container / 1 week.

[0154] Example 20: Solid solubility test Five portions of each amorphous solid salt (equivalent to 20 mg of free base) were weighed and added to 10 mL or less of each solvent (0.1 N HCl solution (pH 1.0), 50 mM phosphate buffer (pH 4.5), FeSSIF-V1 (pH 5.0), FaSSIF-V1 (pH 6.5), and SGF (pH 2.0)), followed by stirring at 37 °C for 2 hours. The suspensions were then centrifuged at 37 °C, and the solubility of the supernatants was measured by HPLC, and the XRPD of the solid fractions was measured. The target solubility was at least 2 mg (of free base) / mL.

[0155] The above-mentioned 2-hour solid solubility test was carried out for Examples 1 to 10, and the results are shown in Table 2. Similarly, the 24-hour solid solubility test was carried out for Examples 1 and 4, and the results are shown in Table 3.

[0156] [Table 9] [Table 10] [Table 11]

[0157] In a 2-hour solid-state solubility test, 2 equivalents of the amorphous benzenesulfonate salt did not meet a solubility of 2 mg / mL in 0.1 N HCl solution (pH 1.0), and 1 equivalent of the crystalline hydrobromide salt did not meet a solubility of 2 mg / mL in FaSSIF-V1 (pH 6.5). However, 1 equivalent of the amorphous hydrochloride salt, 2 equivalents of the amorphous hydrochloride salt, 1 equivalent of the amorphous methanesulfonate salt, 2 equivalents of the amorphous methanesulfonate salt, 1 equivalent of the amorphous benzenesulfonate salt, 1 equivalent of the amorphous ethanesulfonate salt, and 1 equivalent of the amorphous maleate salt all had solubilities greater than 2 mg / mL in all test solvents. In a 24-hour solid-state solubility test, the amorphous free base and 1 equivalent of the amorphous methanesulfonate salt had solubilities greater than 2 mg / mL in FeSSIF-V1 (pH 5.0) and FaSSIF-V1 (pH 6.5).

[0158] As can be seen from Examples 1 to 20, one equivalent of the amorphous methanesulfonate simultaneously has a reasonable salt-forming equivalent ratio, better chemical stability, better physical stability, and better solubility.

[0159] Example 21: Synthesis of N-(2-((2-(dimethylamino)ethyl(methyl)amino)-4-methoxy-5-((4-(1-methyl-1H-indol-3-yl)-1,3,5-triazin-2-yl)amino)phenyl)acrylamide [ka] A. Synthesis of Key Intermediate 6: [ka] Step 1: Toluene (6V) and o-xylene (6V) were added to a reaction flask, stirred, and heated to 60-70°C. Starting material 1 (1.0 eq) and compound 2 (1.2 eq) were added sequentially to the reaction flask. The temperature was raised to 110-120°C and the reaction was carried out with stirring for 16-19 hours. The temperature was lowered to 20-30°C and the crystallization was carried out with stirring for 3 hours. The mixture was filtered, and the filter cake was washed twice with acetonitrile (1V x 2). The filter cake was dried to a constant weight to obtain intermediate 3. The yield was 75% and the purity was 96%. 1 H NMR (CDCl3,400 MHz): δ 3.91(s,3 H),7.35 - 7.44(m,3 H),8.30(s,1 H),8.50 - 8.55(m,1 H) ppm. Step 2: Add intermediate 3 (1.0 eq) and tetrahydrofuran (20V) to a reaction flask and stir at 0-20°C. Slowly add 10% NaSCH3 (1.1 eq) to the reaction vessel and control the temperature at 0-20°C. Allow to react for 1-2 hours with stirring. Add water (40V) to the reaction solution and stir. Control the temperature at 0-20°C. Filter. Wash the filter cake twice with water (1V x 2). Dry the filter cake to a constant weight to obtain a crude product. The crude product and DMA (8V) were added sequentially to a reaction flask, and the temperature was raised to 70-80°C until the mixture was dissolved and transparent. Then, ACN (12V) was slowly added to the reaction vessel, the temperature was controlled at 70-80°C, and the mixture was stirred for 30 minutes. The mixture was then cooled to 20-30°C and stirred for 1-2 hours. The mixture was then filtered, and the filter cake was washed with acetonitrile (1V x 2). The filter cake was then dried to a constant weight to obtain intermediate 4 in a yield of 68% and a purity of 98%. 1 H NMR (DMSO-d6,400 MHz): δ 2.66(s,3 H),3.93(s,3 H),7.31-7.34(m,2 H),7.60 - 7.62(m,1 H),8.34 - 8.38(m,2 H),8.60(s,1 H) ppm. Step 3: ACN (15 V) and starting material 5 (1.1 eq) were added to a reaction flask. Furthermore, TsOH (0.2 eq) and intermediate 4 (1.0 eq) were added to the reaction flask. The mixture was heated to 70-80°C and stirred for 4-6 h. The mixture was filtered while still hot. The filter cake was added to ACN (5 V), heated to 60-70°C, stirred for 30 min, filtered while still hot, and washed twice with ACN (2 V × 2). The filter cake was dried to a constant weight to obtain intermediate 6 in 86% yield and 97% purity. 1 H NMR (DMSO-d6,400 MHz): δ 2.58(s,1 H),3.90(s,1 H),3.99(s,1 H),7.17(s,1 H),7.27(t,J=7.50 Hz,1 H),7.40(d,J=13.38 Hz,1 H),7.54(d,J=8.25 Hz,1 H),8.36(s,1 H),8.86(d,J=8.50 Hz,1 H),9.16(s,1 H) ppm. B. Synthesis of the target compound N-(2-((2-(dimethylamino)ethyl(methyl)amino)-4-methoxy-5-((4-(1-methyl-1H-indol-3-yl)-1,3,5-triazin-2-yl)amino)phenyl)acrylamide [ka] Step 4: DMA (4.68 g) was weighed and added to the reaction flask, and the mixture was stirred. The temperature was raised to 50-60°C. DIPEA (0.44 g) and starting material 7 (0.30 g) were weighed and added to the reaction mixture. The mixture was stirred at 50-60°C. Intermediate 6 (1 g) was weighed and added to the reaction mixture at 50-60°C. The mixture was heated to 75-85°C. The reaction mixture was stirred at 75-85°C for 4-5 hours, and samples were taken and analyzed by HPLC. The reaction was stopped when the intermediate 6 concentration reached 0.5% or less. (If the intermediate 6 concentration reached 0.5%, the reaction time was extended, and samples were taken every 1-2 hours. The reaction was stopped when the intermediate 6 concentration reached 0.5% or less.) The reaction mixture was chromatographed on a silica gel column to obtain intermediate 8, with a yield of 72% and a purity of 99%. 1 H NMR (DMSO-d6,400 MHz): δ 2.16(s,6 H),2.46 - 2.49(m,2 H),2.55(s,3 H),2.88(s,3 H),3.30(t,2 H),3.88(s,3 H),3.92(s,3 H),6.82(s,1 H),7.24(m,2 H),7.52(d,J=8.00 Hz,1 H),8.32- 8.40(m,3 H),8.90(s,1 H) ppm. Step 5: Raney-Ni (4.00 g) and water (4.50 g) were weighed and added to a high-pressure reactor. Intermediate 8 (1 g) was weighed and added to 2-MeTHF (12.90 g) and stirred. The mixture of intermediate 8 and 2-MeTHF was placed in a 10 L high-pressure reactor. The reaction system was purged with argon or nitrogen gas three times, then with hydrogen gas three times. The hydrogen gas pressure was controlled at 0.2-0.6 MPa and the mixture was stirred. The temperature was raised to 60-70°C, and the hydrogen gas pressure was maintained at 0.2-0.6 MPa for 10-12 hours with stirring. The reaction mixture was chromatographed on a silica gel column to obtain intermediate 9 in 63% yield and 98% purity. 1 H NMR (DMSO-d6,400 MHz): δ 2.18(s,6 H),2.38(t,J=6.57 Hz,2 H),2.65(s,3 H),2.91(t,J=6.38 Hz,2 H),3.35(s,3 H),3.88(s,3 H),4.67(br s,2 H),6.77(s,1 H),7.12(s,2 H),7.24(t,J=7.44 Hz,1 H),7.50(d,J=8.25 Hz,1 H),8.32(br s,2 H),8.53(s,1 H),8.67(s,1 H) ppm. Step 6: Tetrahydrofuran (8.90 g) was weighed and added to a glass reaction flask and stirred. Intermediate 9 (1 g) was weighed and added to the reaction flask and dissolved with stirring. The temperature was lowered to -30 to -20°C, and 3-chloropropionyl chloride (0.34 g) was weighed and slowly added dropwise to the reaction flask at -30 to -20°C. The mixture was then stirred at -30 to -10°C for 0.5 hours. The reaction took 0.5 to 1.0 hours. Step 7: Sodium hydroxide solution was added to the reaction flask (sodium hydroxide (0.45 g) was dissolved in water (2.00 g) and stirred until completely dissolved), and the temperature was raised to 45-55°C. The reaction mixture was stirred and reacted for 12-14 hours while maintaining the temperature. The reaction mixture was extracted and chromatographed on a silica gel column to obtain the target compound of formula (I), with a yield of 72% and a purity of 99%. 1 H NMR(CDCl3,400 MHz):δ 10.15(s,1H),9.92(s,1H),9.38(s,1H),8.74(s,1H),8.65(dd,J = 6.1,2.9 Hz,1H),7.80(s,1H),7.41(dd,J = 6.3,2.8 Hz,1H),7.37 - 7.22(m,2H),6.83(s,1H),6.57 - 6.46(m,1H),6.41(dd,J = 16.8,9.8 Hz,1H),5.77(dd,J = 9.8,1.9 Hz,1H),4.02(s,3H),3.93(s,3H),2.37(s,2H),2.36(d,J = 8.7 Hz,6H) ppm.

[0160] Example 22: Preparation of N-(2-((2-(dimethylamino)ethyl(methyl)amino)-4-methoxy-5-((4-(1-methyl-1H-indol-3-yl)-1,3,5-triazin-2-yl)amino)phenyl)acrylamido methanesulfonate crystalline form II-A [ka] 800 mg of N-(2-((2-(dimethylamino)ethyl(methyl)amino)-4-methoxy-5-((4-(1-methyl-1H-indol-3-yl)-1,3,5-triazin-2-yl)amino)phenyl)acrylamide was added to a round-bottom flask, 0.4 mL of water was added to the round-bottom flask, and 5 mL of acetone containing 152 mg of methanesulfonic acid was added to the round-bottom flask. The mixture was suspended at room temperature and stirred for approximately 3 days. The solid was then centrifuged and dried in vacuo at 50°C for 1 hour to obtain the target product. The yield was 85.0%. 1 H NMR(CDCl3,400 MHz):δ 10.15(s,1H),9.92(s,1H),9.38(s,1H),8.74(s,1H),8.65(dd,J = 6.1,2.9 Hz,1H),7.80(s,1H),7.41(dd,J = 6.3,2.8 Hz,1H),7.37 - 7.22(m,2H),6.83(s,1H),6.57 - 6.46(m,1H),6.41(dd,J = 16.8,9.8 Hz,1H),5.77(dd,J = 9.8,1.9 Hz,1H),4.02(s,3H),3.93(s,3H),2.30(s,3H),2.37(s,2H),2.36(d,J = 8.7 Hz,6H) ppm. The powder X-ray diffraction pattern of the crystalline form II-A obtained in this example was 7.22°±0.2°, 8.62°±0.2°, 9.48°±0.2°, 10.36°±0.2°, 15.12°±0.2°, 15.74°±0.2°, 16.46°±0.2°, 16.92°±0.2°, 17.70°±0.2°, 18.94°±0.2°. It has characteristic peaks represented by diffraction angle 2θ values ​​at 19.30°±0.2°, 19.62°±0.2°, 20.36°±0.2°, 20.81°±0.2°, 22.28°±0.2°, 24.06°±0.2°, 24.78°±0.2°, 25.54°±0.2°, 25.82°±0.2°, and 26.24°±0.2°. Its powder X-ray diffraction pattern (XRPD) is shown in Figure 105. That's right. It was found that the crystalline form II-A obtained in this example exhibited a weight loss of about 0.56% when heated to 200.0°C, and exhibited an endothermic peak when heated to 255.9°C. Its thermogravimetric analysis (TGA) / differential scanning calorimetry (DSC) diagram is shown in Figure 106.

[0161] Example 23: Preparation of N-(2-((2-(dimethylamino)ethyl(methyl)amino)-4-methoxy-5-((4-(1-methyl-1H-indol-3-yl)-1,3,5-triazin-2-yl)amino)phenyl)acrylamide hydrochloride crystalline form III-A [ka] 800 mg of N-(2-((2-(dimethylamino)ethyl(methyl)amino)-4-methoxy-5-((4-(1-methyl-1H-indol-3-yl)-1,3,5-triazin-2-yl)amino)phenyl)acrylamide was added to a round-bottom flask, and 5 mL of ethanol containing 132 μL of concentrated hydrochloric acid (approximately 37%) was added to the round-bottom flask. The mixture was suspended at room temperature and stirred for approximately 3 days. The solid was then centrifuged and vacuum dried at 50°C for 1 hour to obtain the target product. The yield was 79.4%. 1 H NMR(CDCl3,400 MHz):δ 10.15(s,1H),9.92(s,1H),9.38(s,1H),8.74(s,1H),8.65(dd,J = 6.1,2.9 Hz,1H),7.80(s,1H),7.41(dd,J = 6.3,2.8 Hz,1H),7.37 - 7.22(m,2H),6.83(s,1H),6.57 - 6.46(m,1H),6.41(dd,J = 16.8,9.8 Hz,1H),5.77(dd,J = 9.8,1.9 Hz,1H),4.02(s,3H),3.93(s,3H),2.37(s,2H),2.36(d,J = 8.7 Hz,6H) ppm. The powder X-ray diffraction pattern (XRPD) of the crystalline form III-A obtained in this example showed characteristic peaks at diffraction angles 2θ of 6.55°±0.2°, 10.36°±0.2°, 12.28°±0.2°, 13.10°±0.2°, 14.08°±0.2°, 14.45°±0.2°, 15.98°±0.2°, 17.33°±0.2°, 19.07°±0.2°, 19.57°±0.2°, 21.15°±0.2°, 21.72°±0.2°, 24.30°±0.2°, 24.85°±0.2°, 25.87°±0.2°, and 33.29°±0.2°. The powder X-ray diffraction pattern (XRPD) is shown in FIG. It was found that the crystalline form III-A obtained in this example lost about 1.05% weight when heated to 150.0°C, and showed an endothermic peak when heated to 193.3°C. Its thermogravimetric analysis (TGA) / differential scanning calorimetry (DSC) diagram is shown in Figure 108.

[0162] Example 24: Preparation of N-(2-((2-(dimethylamino)ethyl(methyl)amino)-4-methoxy-5-((4-(1-methyl-1H-indol-3-yl)-1,3,5-triazin-2-yl)amino)phenyl)acrylamide maleate crystalline form IV-C [ka] 800 mg of N-(2-((2-(dimethylamino)ethyl(methyl)amino)-4-methoxy-5-((4-(1-methyl-1H-indol-3-yl)-1,3,5-triazin-2-yl)amino)phenyl)acrylamide was added to a round-bottom flask, 0.4 mL of water was added to the round-bottom flask, and 5 mL of ethanol containing 184 mg of maleic acid was added to the round-bottom flask. The mixture was suspended at room temperature and stirred for approximately 3 days. The solid was then centrifuged and vacuum dried at 50°C for 1 hour to obtain the target product. The yield was 83.8%. 1 H NMR(CDCl3,400 MHz):δ 10.15(s,1H),9.92(s,1H),9.38(s,1H),8.74(s,1H),8.65(dd,J = 6.1,2.9 Hz,1H),7.80(s,1H),7.41(dd,J = 6.3,2.8 Hz,1H),7.37 - 7.22(m,2H),6.83(s,1H),6.57 - 6.46(m,1H),6.41(dd,J = 16.8,9.8 Hz,1H),6.02(s,2H),5.77(dd,J = 9.8,1.9 Hz,1H),4.02(s,3H),3.93(s,3H),2.37(s,2H),2.36(d,J = 8.7 Hz,6H) ppm. The powder X-ray diffraction pattern (XRPD) of crystalline form IV-C obtained in this example showed characteristic peaks at diffraction angles 2θ of 6.47°±0.2°, 8.44°±0.2°, 9.15°±0.2°, 10.63°±0.2°, 12.70°±0.2°, 15.48°±0.2°, 16.42°±0.2°, 17.00°±0.2°, 18.19°±0.2°, 20.71°±0.2°, 22.43°±0.2°, 25.76°±0.2°, 28.70°±0.2°, and 31.39°±0.2°. The powder X-ray diffraction pattern (XRPD) is shown in FIG. It was found that the crystalline form IV-C obtained in this example exhibited a weight loss of about 1.96% when heated to 220.0°C, and an endothermic peak appeared after heating to 255.5°C. Its thermogravimetric analysis (TGA) / differential scanning calorimetry (DSC) diagram is shown in Figure 110.

[0163] Measurement Example 1: Male Han-Wister rat drug absorption test Intravenous administration: A total of three healthy male Han-Wister rats weighing 250-350g were provided by Beijing Weitong Lihua Experimental Animal Technology Co., Ltd. The doses (calculated as free base) shown in Table 1 below were administered in the above examples. 21 The compound was administered intravenously, and 0.05 mL of blood was collected by jugular vein puncture before administration and 15 min, 0.5 h, 1.0 h, 2.0 h, 4.0 h, 8.0 h, 12 h, and 24 h after administration. The blood was separated to prepare plasma, and the drug concentration in the plasma was measured by liquid chromatography-mass spectrometry (LC-MS), and a drug concentration-time graph was obtained. The main pharmacokinetic parameters are shown in Table 1 below.

[0164] [Table 12]

[0165] Intragastric administration: A total of 12 healthy male Han-Wister rats weighing 250-350g were provided by Beijing Weitong Lihua Experimental Animal Technology Co., Ltd. and randomly divided into 4 groups. Each group received the same doses (calculated as free base) as shown in Table 2 below. 21 , Example 22 , Example 23 and Examples 24 The compound was administered intragastrically, and 0.05 mL of blood was collected by jugular vein puncture before administration and 15 min, 0.5 h, 1.0 h, 2.0 h, 4.0 h, 8.0 h, 12 h, and 24 h after administration. The blood was separated to prepare plasma, and the drug concentration in the plasma was measured by liquid chromatography-mass spectrometry (LC-MS), and a drug concentration-time graph was obtained. The main pharmacokinetic parameters are shown in Table 2 below.

[0166] [Table 13] Conclusion: The bioavailability of crystalline Form II-A of the methanesulfonate salt of Compound of Formula (I), crystalline Form III-A of the hydrochloride salt of Compound of Formula (I), and crystalline Form IV-C of the maleate salt of Compound of Formula (I) is shown in Examples. 21 The bioavailability of the compound of formula (I) is clearly superior to that of the compound of formula (I).

[0167] Measurement Example 2: Solubility Test Example 21 The kinetic solubilities of Compound of Formula (I), methanesulfonate salt crystalline Form II-A of Compound of Formula (I), hydrochloride salt crystalline Form III-A of Compound of Formula (I), and maleate salt crystalline Form IV-C of Compound of Formula (I) in water, SGF, FaSSIF, and FeSSIF were studied (time points taken at 0.5, 1, 2, 4, and 24 hours). Measurement method: According to the starting concentration of 10 mg / mL, weigh out about 50 mg of sample and add it to 5 mL of the corresponding medium, and dissolve the sample by rotation at -25 rpm under room temperature conditions. After rotating for 0.5, 1, 2, 4 and 24 hours, take 1 mL of sample and centrifuge at 12000 rpm for 2 minutes at room temperature, and use the supernatant liquid to detect the solubility. The solubility (mg / mL) results are shown in Table 3 below.

[0168] [Table 14] Conclusion: Crystalline Form II-A of the methanesulfonate salt of Compound (I), Crystalline Form III-A of the hydrochloride salt of Compound (I), and Crystalline Form IV-C of the maleate salt of Compound (I) all have high dynamic solubilities (>4.0 mg / mL) in water, SGF, FaSSIF, and FeSSIF, which are significantly superior to the dynamic solubilities of Compound (I) (free base) in the corresponding solvents.

[0169] The methanesulfonate salt of compound of formula (I) is suitable for further drug development since it has obtained surprising and unexpected technical effects in two aspects of salt formation and crystallization.

[0170] Although the above invention has been described in some detail by way of illustration and example for purposes of clarity of understanding, it will be understood that the scope of the present invention is not limited to these descriptions and examples.

Claims

1. A crystalline methanesulfonate salt of the compound of formula (I), the crystals are crystalline form II-A; The crystalline methanesulfonate salt of compound of formula (I) is characterized in that the crystalline form II-A exhibits a powder X-ray diffraction pattern having characteristic peaks at least at 2θ°: 15.12°±0.2°, 22.28°±0.2°, and 25.82°±0.2°. 【Chemical 1】

2. 2. The crystalline methanesulfonate salt of compound of formula (I) according to claim 1, wherein the crystalline form II-A comprises an X-ray powder diffraction pattern having characteristic peaks expressed in 2θ degrees at least at 19.62°±0.2° and 26.24°±0.2°.

3. 3. The crystalline methanesulfonate salt of compound of formula (I) according to claim 2, wherein the crystalline form II-A comprises an X-ray powder diffraction pattern having characteristic peaks expressed in 2θ degrees at least at 10.36°±0.2° and 18.94°±0.2°.

4. The crystalline form II-A has an X-ray powder diffraction pattern having characteristic peaks expressed in degrees 2θ at least at 7.22°±0.2°, 8.62°±0.2°, 9.48°±0.2°, 15.74°±0.2°, 16.46°±0.2°, 16.92°±0.2°, 17.70°±0.2°, 19.30°±0.2°, 20.36°±0.2°, 20.81°±0.2°, 24.06°±0.2°, 24.78°±0.2°, and 25.54°±0.2°.

4. The crystalline methanesulfonate salt of the compound of formula (I) according to claim 3, comprising:

5. 5. The methanesulfonate crystal of the compound of formula (I) according to any one of claims 1 to 4, wherein the molar ratio of the compound of formula (I) to methanesulfonic acid is 1:

1.

6. A pharmaceutical composition comprising the crystal according to any one of claims 1 to 5 and a pharmaceutically acceptable carrier.

7. Use of the crystal according to any one of claims 1 to 5 in the manufacture of a drug for treating EGFR exon 20 insertion mutant non-small cell lung cancer (NSCLC).

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