PHARMACEUTICAL SALTS AND CRYSTALLINE FORM OF QUINAZOLIN DERIVATIVES, AND METHODS OF THEIR PREPARATION

Abstract

The invention relates to a pharmaceutical salt and crystalline form of a quinazoline derivative, and a method for preparing them. Specifically, the invention proposes a pharmaceutical salt of, a crystalline form of, and a method for preparing 1-(endo-3-((4-((4-([1,2,4]triazolo[1,5-a]pyridine-7-yloxy)-2-fluoro-3-methylphenyl)amino)quinazolin-6-yl)oxy)-8-azabicyclo[3.2.1]oct-8-yl)prop-2-en-1-one; the corresponding salt is of good stability.

Description

A pharmaceutically acceptable salt of a quinazoline derivative, its crystalline form and use

[0001] The present invention claims the following priority:

[0002] Application number: CN202311255208.3, application date: September 27, 2023. Technical Field

[0003] The present disclosure belongs to the field of medical technology and relates to a pharmaceutically acceptable salt of a quinazoline derivative, a crystalline form thereof, and uses thereof. Background Art

[0004] Human epidermal growth factor receptor 2 (HER2; Neu, ERBB2) is a member of the type I receptor tyrosine kinase family, which also includes EGFR (ERBB1), HER3 (ERBB3), and HER4 (ERBB4). To date, no ligand has been found in the human body that can directly bind to HER2. HER2 must form homo- or heterodimers with other family members (such as HER3). Upon dimerization, HER2 undergoes conformational changes, activating intracellular tyrosine kinase activity and, subsequently, downstream pathways (MAPK signaling and PI3K / AKT signaling), thereby exerting its corresponding physiological effects.

[0005] According to statistics, approximately 2-4% of lung cancer patients carry activating mutations in HER2 exon 20. Currently approved ERBB-targeted tyrosine kinase inhibitors are rarely effective for these patients, primarily due to dose-limiting toxicities mediated by wild-type EGFR. Alectinib, ibrutinib, neratinib, poziotinib, and pyrotinib are known broad-spectrum ERBB inhibitors for HER2 exon 20 mutations. However, clinically, afatinib and other broad-spectrum ERBB inhibitors have shown only limited efficacy in NSCLC patients with HER2 exon 20 mutations due to limited effective doses.

[0006] PCT / CN2023 / 084265 provides a new inhibitor of HER2 exon 20 mutation that is selective for EGFR wild type. Its chemical name is 1-(endo-3-((4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-2-fluoro-3-methylphenyl)amino)quinazolin-6-yl)oxy)-8-azabicyclo[3.2.1]oct-8-yl)prop-2-en-1-one, and it has the structure shown in Formula 1.

[0007] Salt formation can improve certain undesirable physicochemical or biological properties of drugs. The development of salts with superior physicochemical or pharmaceutical properties compared to 1-(endo-3-((4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-2-fluoro-3-methylphenyl)amino)quinazolin-6-yl)oxy)-8-azabicyclo[3.2.1]oct-8-yl)prop-2-en-1-one is of great significance. Given the importance of solid drug crystal forms and their stability in clinical treatment, in-depth research on the polymorphic forms of pharmaceutically acceptable salts of the compound 1-(endo-3-((4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-2-fluoro-3-methylphenyl)amino)quinazolin-6-yl)oxy)-8-azabicyclo[3.2.1]oct-8-yl)prop-2-en-1-one is also of great significance for the development of drugs suitable for industrial production and with good biological activity.

[0008] Summary of the Invention

[0009] The present disclosure provides a pharmaceutically acceptable salt of a compound of formula 1, 1-(endo-3-((4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-2-fluoro-3-methylphenyl)amino)quinazolin-6-yl)oxy)-8-azabicyclo[3.2.1]oct-8-yl)prop-2-en-1-one, wherein the pharmaceutically acceptable salt is selected from hydrochloride, sulfate, phosphate, methanesulfonate, tartrate, p-toluenesulfonate, and fumarate.

[0010] In an optional embodiment, the chemical ratio of the compound of Formula 1, 1-(endo-3-((4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-2-fluoro-3-methylphenyl)amino)quinazolin-6-yl)oxy)-8-azabicyclo[3.2.1]oct-8-yl)prop-2-en-1-one and the acid is 3:1-1:3, including but not limited to 3:1, 2:1, 1:1, 1:2, and 1:3.

[0011] In another embodiment, the chemical ratio of the compound of Formula 1, 1-(endo-3-((4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-2-fluoro-3-methylphenyl)amino)quinazolin-6-yl)oxy)-8-azabicyclo[3.2.1]oct-8-yl)prop-2-en-1-one and the acid is 2:1-1:2.

[0012] In an optional embodiment, the chemical ratio of the compound of Formula 1, 1-(endo-3-((4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-2-fluoro-3-methylphenyl)amino)quinazolin-6-yl)oxy)-8-azabicyclo[3.2.1]oct-8-yl)prop-2-en-1-one and hydrochloric acid is 1:1.

[0013] In an optional embodiment, the chemical ratio of the compound of formula 1, 1-(endo-3-((4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-2-fluoro-3-methylphenyl)amino)quinazolin-6-yl)oxy)-8-azabicyclo[3.2.1]oct-8-yl)prop-2-en-1-one and sulfuric acid is 1:1 or 2:1.

[0014] In an optional embodiment, the chemical ratio of the compound of formula 1, 1-(endo-3-((4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-2-fluoro-3-methylphenyl)amino)quinazolin-6-yl)oxy)-8-azabicyclo[3.2.1]oct-8-yl)prop-2-en-1-one and phosphoric acid is 1:1 or 1:2.

[0015] In an optional embodiment, the chemical ratio of the compound of Formula 1, 1-(endo-3-((4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-2-fluoro-3-methylphenyl)amino)quinazolin-6-yl)oxy)-8-azabicyclo[3.2.1]oct-8-yl)prop-2-en-1-one and methanesulfonic acid is 1:1.

[0016] In an optional embodiment, the chemical ratio of the compound of formula 1, 1-(endo-3-((4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-2-fluoro-3-methylphenyl)amino)quinazolin-6-yl)oxy)-8-azabicyclo[3.2.1]oct-8-yl)prop-2-en-1-one and fumaric acid is 1:1 or 2:1.

[0017] In an optional embodiment, the chemical ratio of the compound of Formula 1, 1-(endo-3-((4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-2-fluoro-3-methylphenyl)amino)quinazolin-6-yl)oxy)-8-azabicyclo[3.2.1]oct-8-yl)prop-2-en-1-one and p-toluenesulfonic acid is 1:1.

[0018] In an optional embodiment, the chemical ratio of the compound of Formula 1, 1-(endo-3-((4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-2-fluoro-3-methylphenyl)amino)quinazolin-6-yl)oxy)-8-azabicyclo[3.2.1]oct-8-yl)prop-2-en-1-one and L-tartaric acid is 1:1.

[0019] The present disclosure also provides a method for preparing a pharmaceutically acceptable salt of a compound of Formula 1, comprising the step of reacting the compound of Formula 1, 1-(endo-3-((4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-2-fluoro-3-methylphenyl)amino)quinazolin-6-yl)oxy)-8-azabicyclo[3.2.1]oct-8-yl)prop-2-en-1-one with an acid selected from the group consisting of hydrochloric acid, sulfuric acid, phosphoric acid, methanesulfonic acid, tartaric acid, p-toluenesulfonic acid, and fumaric acid.

[0020] The solvent used for salt formation in the present invention is selected from but not limited to acetone, tetrahydrofuran, n-propanol, and propylene glycol methyl ether.

[0021] The hydrochloride salt form I of the compound of formula 1 provided in the present disclosure has an X-ray powder diffraction pattern expressed in terms of a diffraction angle 2θ, with characteristic peaks at 8.985, 13.114, 13.459, 17.385, 20.631 and 22.030.

[0022] In some embodiments, the hydrochloride form I of the compound of Formula 1 has an X-ray powder diffraction pattern expressed as a diffraction angle 2θ, with characteristic peaks at 8.985, 9.882, 12.201, 13.114, 13.459, 17.385, 19.936, 20.631 and 22.030.

[0023] In some embodiments, the hydrochloride salt form I of the compound of Formula 1 has an X-ray powder diffraction pattern expressed as a diffraction angle 2θ, with characteristic peaks at 8.985, 9.882, 12.201, 13.114, 13.459, 14.948, 15.316, 17.385, 19.936, 20.631, 22.030, 24.949, 25.476 and 28.632.

[0024] In some embodiments, the X-ray powder diffraction pattern of the hydrochloride form I of the compound of Formula 1 expressed in terms of a diffraction angle 2θ is shown in FIG1 .

[0025] The present disclosure also provides a method for preparing a crystalline form of hydrochloride of a compound of formula 1, comprising dissolving the compound of formula 1 in a solvent I, adding an aqueous hydrochloric acid solution, and stirring, wherein the solvent I is selected from acetone and tetrahydrofuran.

[0026] The hydrochloride II crystal form of the compound of Formula 1 provided in the present disclosure has an X-ray powder diffraction pattern represented by a diffraction angle 2θ, with characteristic peaks at 9.315, 12.380, 15.334, 20.554 and 25.413.

[0027] In some embodiments, the hydrochloride form II of the compound of Formula 1 has an X-ray powder diffraction pattern expressed in terms of a diffraction angle 2θ, with characteristic peaks at 9.315, 10.156, 12.380, 15.334, 20.554, 22.482, 25.413, and 31.048.

[0028] In some embodiments, the hydrochloride form II of the compound of Formula 1 has an X-ray powder diffraction pattern expressed as a diffraction angle 2θ, with characteristic peaks at 9.315, 10.156, 12.380, 15.334, 16.379, 17.371, 18.806, 20.554, 22.482, 25.413 and 31.048.

[0029] In some embodiments, the X-ray powder diffraction pattern of the hydrochloride salt form II of the compound of Formula 1 expressed in terms of a diffraction angle 2θ is shown in FIG2 .

[0030] The present disclosure also provides a method for preparing a hydrochloride II crystalline form of the compound of formula 1, the method comprising:

[0031] Method 1: Dissolve the compound of formula 1 in propylene glycol methyl ether, add aqueous hydrochloric acid solution and then add methyl tert-butyl ether, and stir;

[0032] Method 2: Heat the hydrochloride form I of the compound of formula 1 to 120°C.

[0033] The hydrochloride III crystal form of the compound of Formula 1 provided in the present disclosure has an X-ray powder diffraction pattern represented by a diffraction angle 2θ, with characteristic peaks at 8.244, 16.610, 20.856, 24.599 and 30.261.

[0034] In some embodiments, the hydrochloride form III of the compound of Formula 1 has an X-ray powder diffraction pattern expressed as a diffraction angle 2θ, with characteristic peaks at 8.244, 9.195, 12.834, 13.615, 16.610, 20.856, 24.599 and 30.261.

[0035] In some embodiments, the hydrochloride form III of the compound of Formula 1 has an X-ray powder diffraction pattern expressed as a diffraction angle 2θ, with characteristic peaks at 8.244, 9.195, 12.834, 13.615, 16.610, 17.173, 17.902, 19.230, 20.856, 24.599, 26.163, 26.471 and 30.261.

[0036] In some embodiments, the X-ray powder diffraction pattern of the hydrochloride form III of the compound of Formula 1 expressed in terms of a diffraction angle 2θ is shown in FIG3 .

[0037] The present disclosure also provides a method for preparing a hydrochloride III crystal form of the compound of formula 1, comprising adding the compound of formula 1 to a hydrochloric acid aqueous solution and stirring.

[0038] The sulfate salt crystalline form I of the compound of formula 1 provided in the present disclosure has an X-ray powder diffraction pattern represented by a diffraction angle 2θ, with characteristic peaks at 8.249, 8.600, 15.780, 21.562, 24.900 and 26.659.

[0039] In some embodiments, the sulfate salt of the compound of Formula 1, Form I, has an X-ray powder diffraction pattern expressed in terms of a diffraction angle 2θ, with characteristic peaks at 8.249, 8.600, 15.191, 15.780, 21.562, 22.265, 24.900, 25.444, and 26.659.

[0040] In some embodiments, the sulfate salt of the compound of Formula 1, Form I, has an X-ray powder diffraction pattern expressed in terms of a diffraction angle 2θ, with characteristic peaks at 8.249, 8.600, 15.191, 15.780, 16.723, 17.895, 18.628, 20.099, 21.562, 22.265, 24.900, 25.444, and 26.659.

[0041] In some embodiments, the X-ray powder diffraction pattern of the sulfate salt form I of the compound of Formula 1 expressed in terms of a diffraction angle 2θ is shown in FIG4 .

[0042] The present disclosure also provides a method for preparing a sulfate salt crystalline form I of the compound of formula 1, comprising dissolving the compound of formula 1 in a solvent II, adding a sulfuric acid aqueous solution, and stirring, wherein the solvent II is selected from acetone, tetrahydrofuran, and propylene glycol methyl ether.

[0043] The sulfate salt II crystal form of the compound of Formula 1 provided in the present disclosure has an X-ray powder diffraction pattern represented by a diffraction angle 2θ, with characteristic peaks at 8.462, 13.537, 18.209, 19.271, 22.193 and 24.694.

[0044] In some embodiments, the X-ray powder diffraction pattern of the crystalline form of the compound of Formula 1 expressed in terms of a diffraction angle 2θ is shown in FIG5 .

[0045] The present disclosure also provides a method for preparing a crystalline form of the compound of Formula 1, comprising heating the sulfate crystalline form I of the compound of Formula 1 to 120°C.

[0046] The phosphate form I of the compound of formula 1 provided in the present disclosure has an X-ray powder diffraction pattern represented by a diffraction angle 2θ, with characteristic peaks at 8.220, 15.308, 16.443, 18.865, 20.736 and 26.384.

[0047] In some embodiments, the phosphate form I of the compound of Formula 1 has an X-ray powder diffraction pattern expressed as a diffraction angle 2θ, with characteristic peaks at 7.595, 8.220, 15.308, 16.443, 18.536, 18.865, 20.736, 26.384 and 27.495.

[0048] In some embodiments, the phosphate form I of the compound of Formula 1 has an X-ray powder diffraction pattern expressed as a diffraction angle 2θ, with characteristic peaks at 7.595, 8.220, 13.847, 14.222, 15.308, 16.443, 18.536, 18.865, 20.736, 26.384 and 27.495.

[0049] In some embodiments, the X-ray powder diffraction pattern of the phosphate form I of the compound of Formula 1 expressed in terms of a diffraction angle 2θ is shown in FIG6 .

[0050] The present disclosure also provides a method for preparing a phosphate crystal form I of a compound of formula 1, comprising dissolving the compound of formula 1 in a solvent III, adding a phosphoric acid aqueous solution, and stirring, wherein the solvent III is selected from acetone and tetrahydrofuran.

[0051] The phosphate II crystal form of the compound of Formula 1 provided in the present disclosure has an X-ray powder diffraction pattern represented by a diffraction angle 2θ, with characteristic peaks at 7.659, 14.303, 15.921, 18.824, 20.380 and 26.730.

[0052] In some embodiments, the phosphate II crystalline form of the compound of Formula 1 has an X-ray powder diffraction pattern expressed as a diffraction angle 2θ, with characteristic peaks at 7.283, 7.659, 10.049, 14.303, 14.710, 15.921, 17.225, 18.373, 18.824, 19.642, 20.380, 26.357 and 26.730.

[0053] In some embodiments, the phosphate II crystalline form of the compound of Formula 1 has an X-ray powder diffraction pattern expressed as a diffraction angle 2θ, with characteristic peaks at 7.283, 7.659, 8.564, 10.049, 12.797, 13.465, 14.303, 14.710, 15.921, 17.225, 18.373, 18.824, 19.642, 20.380, 21.912, 23.628, 24.682, 26.357 and 26.730.

[0054] In some embodiments, the X-ray powder diffraction pattern of the phosphate II crystal form of the compound of Formula 1 expressed in terms of a diffraction angle 2θ is shown in FIG7 .

[0055] The present disclosure also provides a method for preparing a phosphate II crystal form of a compound of formula 1, comprising dissolving the compound of formula 1 in propylene glycol methyl ether, adding a phosphoric acid aqueous solution, and stirring.

[0056] The mesylate salt form I of the compound of Formula 1 provided in the present disclosure has an X-ray powder diffraction pattern represented by a diffraction angle 2θ, with characteristic peaks at 12.785, 14.363, 18.248, 19.608, 20.315 and 25.404.

[0057] In some embodiments, the mesylate salt form I of the compound of Formula 1 has an X-ray powder diffraction pattern expressed as a diffraction angle 2θ, with characteristic peaks at 8.311, 12.785, 14.363, 15.220, 17.817, 18.248, 19.318, 19.608, 20.315, 21.697, 22.256, 25.404 and 28.858.

[0058] In some embodiments, the mesylate salt Form I of the compound of Formula 1 has an X-ray powder diffraction pattern expressed as a diffraction angle 2θ, with characteristic peaks at 8.311, 9.846, 12.785, 14.363, 15.220, 16.576, 17.817, 18.248, 19.318, 19.608, 20.315, 21.697, 22.256, 24.601, 25.404, 27.594, 28.858, and 31.581.

[0059] In some embodiments, the X-ray powder diffraction pattern of the mesylate salt form I of the compound of Formula 1 expressed in terms of a diffraction angle 2θ is shown in FIG8 .

[0060] The present disclosure also provides a method for preparing a crystalline form I of a methanesulfonate salt of a compound of formula 1, comprising dissolving the compound of formula 1 in acetone, adding an aqueous solution of methanesulfonic acid, and stirring.

[0061] The mesylate salt II crystalline form of the compound of Formula 1 provided in the present disclosure has an X-ray powder diffraction pattern represented by a diffraction angle 2θ, with characteristic peaks at 8.305, 15.133, 20.915, 23.482 and 25.997.

[0062] In some embodiments, the mesylate salt form II of the compound of Formula 1 has an X-ray powder diffraction pattern expressed in terms of a diffraction angle 2θ, with characteristic peaks at 8.305, 13.430, 15.133, 16.680, 17.223, 20.915, 21.185, 23.482, 25.428, and 25.997.

[0063] In some embodiments, the mesylate salt form II of the compound of Formula 1 has an X-ray powder diffraction pattern expressed as a diffraction angle 2θ, with characteristic peaks at 8.305, 9.221, 13.430, 15.133, 16.680, 17.223, 17.943, 19.130, 19.536, 20.915, 21.185, 23.482, 25.428, 25.997, 26.714 and 28.195.

[0064] In some embodiments, the X-ray powder diffraction pattern of the mesylate salt form II of the compound of Formula 1 expressed in terms of a diffraction angle 2θ is shown in FIG9 .

[0065] The present disclosure also provides a method for preparing a crystal form II of a mesylate salt of a compound of Formula 1, comprising placing a crystal form I of a mesylate salt of a compound of Formula 1 under 92.5% RH for 8 days.

[0066] The tartrate salt form I of the compound of Formula 1 provided in the present disclosure has an X-ray powder diffraction pattern represented by a diffraction angle 2θ, with characteristic peaks at 8.150, 15.441, 16.466, 18.005 and 25.087.

[0067] In some embodiments, the tartrate salt form I of the compound of Formula 1 has an X-ray powder diffraction pattern expressed as a diffraction angle 2θ, with characteristic peaks at 8.150, 11.190, 12.659, 14.003, 15.441, 16.466, 18.005, 20.010, 20.454, 25.087 and 27.195.

[0068] In some embodiments, the X-ray powder diffraction pattern of the tartrate salt form I of the compound of Formula 1 expressed in terms of a diffraction angle 2θ is shown in FIG10 .

[0069] The present disclosure also provides a method for preparing a tartrate salt form I of a compound of formula 1, comprising dissolving the compound of formula 1 in a solvent IV, adding a tartaric acid aqueous solution, and stirring, wherein the solvent IV is selected from one or more of acetone, tetrahydrofuran, and propylene glycol methyl ether.

[0070] The p-toluenesulfonate salt form I of the compound of Formula 1 provided in the present disclosure has an X-ray powder diffraction pattern represented by a diffraction angle 2θ, with characteristic peaks at 6.708, 9.145, 15.275, 17.217, 20.971 and 22.499.

[0071] In some embodiments, the p-toluenesulfonate salt of the compound of Formula 1, Form I, has an X-ray powder diffraction pattern expressed as a diffraction angle 2θ, with characteristic peaks at 6.708, 8.935, 9.145, 13.450, 15.275, 16.934, 17.217, 18.123, 18.948, 20.971, 22.499 and 23.831.

[0072] In some embodiments, the p-toluenesulfonate salt of the compound of Formula 1, Form I, has an X-ray powder diffraction pattern expressed as a diffraction angle 2θ, with characteristic peaks at 6.579, 6.708, 8.935, 9.145, 12.699, 13.450, 15.275, 16.934, 17.217, 18.123, 18.948, 20.186, 20.971, 22.499, 23.831, 26.139 and 29.589.

[0073] In some embodiments, the p-toluenesulfonate salt of the compound of Formula 1, Form I, has an X-ray powder diffraction pattern represented by a diffraction angle of 2θ as shown in FIG11 .

[0074] The present disclosure also provides a method for preparing a crystalline form I of a p-toluenesulfonate salt of a compound of Formula 1, comprising dissolving the compound of Formula 1 in a solvent V, adding an aqueous p-toluenesulfonic acid solution, and stirring, wherein the solvent V is selected from one of acetone, acetone / n-propanol (v / v=7:3), tetrahydrofuran, and acetone / propylene glycol methyl ether (v / v=1:1 or 7:3).

[0075] The p-toluenesulfonate salt form II of the compound of Formula 1 provided in the present disclosure has an X-ray powder diffraction pattern represented by a diffraction angle 2θ, with characteristic peaks at 7.470, 13.033, 15.060, 18.754, 24.552 and 25.528.

[0076] In some embodiments, the p-toluenesulfonate salt form II of the compound of Formula 1 has an X-ray powder diffraction pattern expressed as a diffraction angle 2θ, with characteristic peaks at 7.470, 12.135, 13.033, 14.508, 15.060, 18.754, 24.552, 25.528, 26.561, 27.634 and 30.575.

[0077] In some embodiments, the p-toluenesulfonate salt form II of the compound of Formula 1 has an X-ray powder diffraction pattern expressed as a diffraction angle 2θ, with characteristic peaks at 7.470, 12.135, 13.033, 14.508, 15.060, 16.414, 17.415, 18.754, 19.902, 24.552, 25.528, 26.561, 27.634, 28.458, 29.227 and 30.575.

[0078] In some embodiments, the p-toluenesulfonate salt form II of the compound of Formula 1 has an X-ray powder diffraction pattern represented by a diffraction angle of 2θ as shown in FIG12 .

[0079] The present disclosure also provides a method for preparing a p-toluenesulfonate II crystalline form of the compound of Formula 1, comprising dissolving the compound of Formula 1 in propylene glycol methyl ether, adding an aqueous p-toluenesulfonic acid solution, and stirring.

[0080] The fumarate salt form I of the compound of Formula 1 provided in the present disclosure has an X-ray powder diffraction pattern represented by a diffraction angle 2θ, with characteristic peaks at 5.395, 11.651, 11.981, 16.295, 17.798, 19.316 and 22.420.

[0081] In some embodiments, the fumarate salt form I of the compound of Formula 1 has an X-ray powder diffraction pattern expressed as a diffraction angle 2θ, with characteristic peaks at 5.395, 11.651, 11.981, 13.483, 13.992, 14.973, 16.295, 16.893, 17.798, 19.316, 22.420, 26.663 and 27.471.

[0082] In some embodiments, the fumarate salt form I of the compound of Formula 1 has an X-ray powder diffraction pattern expressed as a diffraction angle 2θ, with characteristic peaks at 5.395, 11.651, 11.981, 13.483, 13.992, 14.973, 16.295, 16.893, 17.798, 19.316, 22.420, 23.600, 24.100, 25.194, 25.569, 26.663 and 27.471.

[0083] In some embodiments, the X-ray powder diffraction pattern of the fumarate salt form I of the compound of Formula 1 expressed in terms of a diffraction angle 2θ is shown in FIG13 .

[0084] The present disclosure also provides a method for preparing a crystalline form I of a fumarate salt of a compound of Formula 1, comprising dissolving the compound of Formula 1 in a solvent VI, adding solid fumaric acid, and stirring, wherein the solvent VI is selected from one or more of acetone, tetrahydrofuran, and propylene glycol methyl ether.

[0085] The present disclosure also provides a pharmaceutical composition containing a pharmaceutically acceptable salt of the aforementioned 1-(endo-3-((4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-2-fluoro-3-methylphenyl)amino)quinazolin-6-yl)oxy)-8-azabicyclo[3.2.1]oct-8-yl)prop-2-en-1-one, or the aforementioned 1-(endo-3-((4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-2-fluoro-3-methylphenyl)amino)quinazolin-6-yl)oxy)-8-azabicyclo[3.2.1]oct-8-yl)prop-2-en-1-one. methylphenyl)amino)quinazolin-6-yl)oxy)-8-azabicyclo[3.2.1]oct-8-yl)prop-2-en-1-one hydrochloride form I, hydrochloride form II, hydrochloride form III, sulfate form I, sulfate form II, phosphate form I, phosphate form II, methanesulfonate form I, methanesulfonate form II, tartaric acid form I, p-toluenesulfonate form I, p-toluenesulfonate form II or fumarate form I, and pharmaceutical excipients optionally selected from pharmaceutically acceptable excipients.

[0086] The present disclosure also provides a pharmaceutical composition, which is composed of a pharmaceutically acceptable salt of the aforementioned 1-(endo-3-((4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-2-fluoro-3-methylphenyl)amino)quinazolin-6-yl)oxy)-8-azabicyclo[3.2.1]oct-8-yl)prop-2-en-1-one, or the aforementioned 1-(endo-3-((4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-2-fluoro-3-methylphenyl)amino)quinazolin-6-yl)oxy)-8-azabicyclo[3.2.1]oct-8-yl)prop-2-en-1-one. -methylphenyl)amino)quinazolin-6-yl)oxy)-8-azabicyclo[3.2.1]oct-8-yl)prop-2-en-1-one hydrochloride form I, hydrochloride form II, hydrochloride form III, sulfate form I, sulfate form II, phosphate form I, phosphate form II, methanesulfonate form I, methanesulfonate form II, tartaric acid form I, p-toluenesulfonate form I, p-toluenesulfonate form II or fumarate form I, and optionally a pharmaceutically acceptable excipient.

[0087] The present disclosure also provides a method for preparing a pharmaceutical composition, comprising the steps of: reacting a pharmaceutically acceptable salt of the aforementioned 1-(endo-3-((4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-2-fluoro-3-methylphenyl)amino)quinazolin-6-yl)oxy)-8-azabicyclo[3.2.1]oct-8-yl)prop-2-en-1-one, or a pharmaceutically acceptable salt of the aforementioned 1-(endo-3-((4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-2-fluoro-3-methylphenyl)amino)quinazolin-6-yl)oxy)-8-azabicyclo[3.2.1]oct-8-yl)prop-2-en-1-one; a step of mixing the hydrochloride form I, hydrochloride form II, hydrochloride form III, sulfate form I, sulfate form II, phosphate form I, phosphate form II, methanesulfonate form I, methanesulfonate form II, tartaric acid form I, p-toluenesulfonate form I, p-toluenesulfonate form II or fumarate form I of 8-azabicyclo[3.2.1]oct-8-yl)prop-2-en-1-one with a pharmaceutically acceptable excipient.

[0088] The present disclosure also provides a pharmaceutically acceptable salt of the aforementioned 1-(endo-3-((4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-2-fluoro-3-methylphenyl)amino)quinazolin-6-yl)oxy)-8-azabicyclo[3.2.1]oct-8-yl)prop-2-en-1-one, or the aforementioned 1-(endo-3-((4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-2-fluoro-3-methylphenyl)amino)quinazolin-6-yl)oxy)-8-azabicyclo[3.2.1]oct-8-yl)prop-2-en-1-one. Use of hydrochloride form I, hydrochloride form II, hydrochloride form III, sulfate form I, sulfate form II, phosphate form I, phosphate form II, methanesulfonate form I, methanesulfonate form II, tartaric acid form I, p-toluenesulfonate form I, p-toluenesulfonate form II or fumarate form I of 8-azabicyclo[3.2.1]oct-8-yl)prop-2-en-1-one or the aforementioned composition as a HER2 inhibitor.

[0089] The present disclosure also provides a pharmaceutically acceptable salt of the aforementioned 1-(endo-3-((4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-2-fluoro-3-methylphenyl)amino)quinazolin-6-yl)oxy)-8-azabicyclo[3.2.1]oct-8-yl)prop-2-en-1-one, or the aforementioned 1-(endo-3-((4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-2-fluoro-3-methylphenyl)amino)quinazolin-6-yl)oxy)-8-azabicyclo[3.2.1]oct-8-yl)prop-2-en-1-one. Use of hydrochloride form I, hydrochloride form II, hydrochloride form III, sulfate form I, sulfate form II, phosphate form I, phosphate form II, methanesulfonate form I, methanesulfonate form II, tartaric acid form I, p-toluenesulfonate form I, p-toluenesulfonate form II or fumarate form I of 8-azabicyclo[3.2.1]oct-8-yl)-1-one or the aforementioned composition as a drug for preparing a HER2 inhibitor.

[0090] The present disclosure also provides a pharmaceutically acceptable salt of the aforementioned 1-(endo-3-((4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-2-fluoro-3-methylphenyl)amino)quinazolin-6-yl)oxy)-8-azabicyclo[3.2.1]oct-8-yl)prop-2-en-1-one, or the aforementioned 1-(endo-3-((4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-2-fluoro-3-methylphenyl)amino)quinazolin-6-yl)oxy)-8-azabicyclo[3.2.1]oct-8-yl)prop-2-en-1-one. Use of the hydrochloride form I, hydrochloride form II, hydrochloride form III, sulfate form I, sulfate form II, phosphate form I, phosphate form II, methanesulfonate form I, methanesulfonate form II, tartaric acid form I, p-toluenesulfonate form I, p-toluenesulfonate form II or fumarate form I of 8-azabicyclo[3.2.1]oct-8-yl)quinazolin-6-yl)oxy)-8-azabicyclo[3.2.1]oct-8-yl)prop-2-en-1-one or the aforementioned composition in the preparation of a composition for preventing and / or treating cancer.

[0091] The use disclosed herein, wherein the cancer is selected from breast cancer, ovarian cancer, gastric cancer, colorectal cancer, cervical cancer, endometrial cancer, bladder cancer, brain cancer, epithelial cancer, esophageal cancer, mesothelioma, nasopharyngeal cancer, oral cancer, thyroid cancer, skin cancer, squamous cell carcinoma, synovium, sweat gland cancer; preferably, the cancer is selected from breast cancer, ovarian cancer, cervical cancer, endometrial cancer, gastric cancer, colorectal cancer and lung cancer.

[0092] The "2θ or 2θ angle" mentioned in the present disclosure refers to the diffraction angle, θ is the Bragg angle, and the unit is ° or degree; the error range of each characteristic peak 2θ is ±0.20 (including the case where the number exceeding 1 decimal place is rounded off), specifically -0.20, -0.19, -0.18, -0.17, -0.16, -0.15, -0.14, -0.13, -0.12, -0.11, -0.10, -0.09, -0.08, -0.07, -0.06, -0.05, -0.04, -0.03, -0.02, -0.01, 0.00, 0.01, 0.02, 0.03, 0.04, 0.05, 0.06, 0.07, 0.08, 0.09, 0.10, 0.11, 0.12, 0.13, 0.14, 0.15, 0.16, 0.17, 0.18, 0.19, 0.20.

[0093] Numerical values ​​in this disclosure, such as those related to substance content, are derived from measurements and calculations, and therefore inevitably have a certain degree of error. Generally speaking, ±10% is considered within a reasonable error range. While there may be some degree of error depending on the context in which they are used, this error may not exceed ±10% and may include ±9%, ±8%, ±7%, ±6%, ±5%, ±4%, ±3%, ±2%, or ±1%, preferably ±5%.

[0094] The starting material used in the crystal form preparation method of the present invention can be a compound in any form, including but not limited to: amorphous, any crystal form, hydrate, solvate, etc.

[0095] The drying temperature in the present disclosure is generally 25°C-100°C, preferably 40°C-70°C, and can be dried under normal pressure or reduced pressure.

[0096] The crystallization methods described in the present disclosure include room temperature crystallization, cooling crystallization, volatile solvent crystallization, adding seed crystals to induce crystallization, etc. The cooling temperature is selected from below 65°C, preferably -10°C to 60°C, and stirring can also be performed during the crystallization process.

[0097] The "differential scanning calorimetry or DSC" described in this disclosure refers to measuring the temperature difference and heat flow difference between a sample and a reference object during the process of heating or maintaining the sample at a constant temperature to characterize all physical and chemical changes related to thermal effects and obtain phase change information of the sample.

[0098] According to the description of hygroscopic characteristics and the definition of hygroscopic weight gain in the "9103 Guiding Principles for Hygroscopicity of Drugs" in Part IV of the 2015 edition of the Chinese Pharmacopoeia,

[0099] Deliquescent: Absorbs sufficient water to form a liquid;

[0100] Highly hygroscopic: weight gain due to moisture absorption is not less than 15%;

[0101] Hygroscopic: weight gain due to moisture absorption is less than 15% but not less than 2%;

[0102] Slightly hygroscopic: weight gain due to moisture absorption is less than 2% but not less than 0.2%;

[0103] No or almost no hygroscopicity: weight gain due to moisture is less than 0.2%.

[0104] The "excipients" described in this disclosure include, but are not limited to, any adjuvant, carrier, glidant, sweetener, diluent, preservative, dye / colorant, flavoring agent, surfactant, wetting agent, dispersant, suspending agent, stabilizer, isotonic agent or emulsifier that has been approved by the U.S. Food and Drug Administration for use by humans or livestock animals. BRIEF DESCRIPTION OF THE DRAWINGS

[0105] Figure 1 is the XRPD spectrum of Compound 1 hydrochloride Form I.

[0106] Figure 2 is the XRPD spectrum of Compound 1 hydrochloride II crystal form.

[0107] Figure 3 is the XRPD spectrum of Compound 1 hydrochloride Form III.

[0108] Figure 4 is the XRPD spectrum of Compound 1 sulfate salt Form I.

[0109] Figure 5 is the XRPD spectrum of Compound 1 sulfate salt Form II.

[0110] Figure 6 is the XRPD spectrum of Compound 1 Phosphate Form I.

[0111] Figure 7 is the XRPD spectrum of Compound 1 phosphate II crystal form.

[0112] Figure 8 is an XRPD spectrum of Compound 1 mesylate salt Form I.

[0113] Figure 9 is an XRPD spectrum of Compound 1 mesylate salt Form II.

[0114] Figure 10 is the XRPD spectrum of Compound 1 tartrate salt Form I.

[0115] Figure 11 is the XRPD spectrum of Compound 1 p-toluenesulfonate salt Form I.

[0116] Figure 12 is the XRPD spectrum of Compound 1 p-toluenesulfonate salt Form II.

[0117] Figure 13 is the XRPD spectrum of Compound 1 fumarate salt Form I. DETAILED DESCRIPTION

[0118] The present disclosure will be explained in more detail below with reference to embodiments or experimental examples. The embodiments or experimental examples in the present disclosure are only used to illustrate the technical solutions in the present disclosure, and are not intended to limit the essence and scope of the present disclosure.

[0119] Test conditions of the instruments used in the experiment:

[0120] The structures of the compounds were confirmed by nuclear magnetic resonance (NMR) and / or mass spectrometry (MS). NMR shifts (δ) are given in units of 10⁻⁶ (ppm). NMR measurements were performed using a Bruker AVANCE-400 NMR spectrometer or a Bruker AVANCE NEO 500M NMR spectrometer. The solvents used were deuterated dimethyl sulfoxide (DMSO-d₆), deuterated chloroform (CDCl₃), or deuterated methanol (CD₃OD), with tetramethylsilane (TMS) as the internal standard.

[0121] MS was measured using an Agilent 1200 / 1290 DAD-6110 / 6120 Quadrupole MS liquid spectrometer-mass spectrometer (manufacturer: Agilent, MS model: 6110 / 6120 Quadrupole MS).

[0122] waters ACQuity UPLC-QD / SQD (Manufacturer: waters, MS model: waters ACQuity Qda Detec-tor / waters SQ Detector)

[0123] THERMO Ultimate 3000-Q Exactive (Manufacturer: THERMO, MS model: THERMO Q Exactive)

[0124] High performance liquid chromatography (HPLC) analysis was performed using Agilent HPLC 1200DAD, Agilent HPLC 1200VWD and Waters HPLC e2695-2489 high pressure liquid chromatographs.

[0125] Chiral HPLC analysis was performed using an Agilent 1260 DAD high performance liquid chromatograph.

[0126] High performance liquid chromatography (HPLC) was performed using Waters 2545-2767, Waters 2767-SQ Detecor2, Shimadzu LC-20AP, and Gilson GX-281 preparative chromatographs.

[0127] Chiral preparations were performed using a Shimadzu LC-20AP preparative chromatograph.

[0128] The CombiFlash rapid preparation instrument used was Combiflash Rf200 (TELEDYNE ISCO).

[0129] The thin layer chromatography silica gel plate uses Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plate. The specification of the silica gel plate used in thin layer chromatography (TLC) is 0.15mm~0.2mm, and the specification used for thin layer chromatography separation and purification products is 0.4mm~0.5mm.

[0130] Silica gel column chromatography generally uses Yantai Huanghai 200-300 mesh silica gel as the carrier.

[0131] The average kinase inhibition rate and IC50 value were determined using a NovoStar microplate reader (BMG, Germany).

[0132] The known starting materials disclosed herein can be synthesized by methods known in the art, or can be purchased from ABCR GmbH & Co. KG, Acros Organics, Aldrich Chemical Company, Accela ChemBio Inc, Darui Chemicals, and other companies.

[0133] Unless otherwise specified in the examples, all reactions can be carried out under an argon atmosphere or a nitrogen atmosphere.

[0134] Argon atmosphere or nitrogen atmosphere means that the reaction bottle is connected to an argon or nitrogen balloon with a capacity of about 1 L.

[0135] Hydrogen atmosphere means that the reaction bottle is connected to a hydrogen balloon with a capacity of about 1L.

[0136] The pressurized hydrogenation reaction uses a Parr 3916EKX hydrogenator and a Qinglan QL-500 hydrogen generator or an HC2-SS hydrogenator.

[0137] The hydrogenation reaction is usually carried out by evacuating the chamber and filling it with hydrogen, and the operation is repeated three times.

[0138] A CEM Discover-S 908860 microwave reactor was used for the microwave reaction.

[0139] Unless otherwise specified in the examples, the solution refers to an aqueous solution.

[0140] Unless otherwise specified in the examples, the reaction temperature is room temperature, 20°C to 30°C.

[0141] The reaction progress in the examples was monitored by thin layer chromatography (TLC). The developing solvent used in the reaction, the column chromatography eluent system used for purifying the compound, and the developing solvent system for thin layer chromatography included: A: dichloromethane / methanol system, B: n-hexane / ethyl acetate system, C: petroleum ether / ethyl acetate system, and D: ethyl acetate / methanol system. The volume ratio of the solvent was adjusted according to the polarity of the compound, and a small amount of alkaline or acidic reagents such as triethylamine and acetic acid could also be added for adjustment.

[0142] XRPD is X-ray powder diffraction detection: the measurement is carried out using a BRUKER D8 X-ray diffractometer, specific collection information: Cu anode (40kV, 40mA), radiation: monochromatic Cu-Ka radiation Scanning mode: θ / 2θ, scanning range: 3-48°.

[0143] DSC is differential scanning calorimetry: the measurement was performed using a METTLER TOLEDO DSC 3+ differential scanning calorimeter with a heating rate of 10°C / min. The specific temperature range was referred to the corresponding spectrum (mostly 25-300 or 25-350°C), and a nitrogen purge rate of 50 mL / min.

[0144] TGA is thermogravimetric analysis: the test was performed using a METTLER TOLEDO TGA 2 thermogravimetric analyzer with a heating rate of 10°C / min. The specific temperature range was referred to the corresponding spectrum (mostly 30-400°C), and a nitrogen purge rate of 50 mL / min.

[0145] DVS stands for dynamic moisture sorption: the test uses SMSDVS Advantage. At 25°C, the humidity changes from 50% to 95% to 0% to 95% to 50%, with a step of 10% (the last step is 5%) (the specific humidity range is based on the corresponding spectrum, and the method listed here is mostly used). The judgment standard is dm / dt no more than 0.002%.

[0146] Ion chromatography detection: instrument: American DIONEX AQUION ion chromatograph, detection mode: conductivity; separation column: Dionex IonPac AS27-4×250 mm, 4 μm; eluent: EGC 500KOH 35 mM; flow rate: 1.5 mL / min.

[0147] Example 1 Preparation of the compound of formula 1

[0148] 1-(endo-3-((4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-2-fluoro-3-methylphenyl)amino)quinazolin-6-yl)oxy)-8-azabicyclo[3.2.1]oct-8-yl)prop-2-en-1-one 1

[0149] first step

[0150] Endo-3-((4-chloroquinazolin-6-yl)oxy)-8-azabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester 1c

[0151] 4-Chloroquinazoline-6-ol 1b (20 mg, 110 μmol, prepared using the method disclosed in "European Journal of Medicinal Chemistry, 2018, vol. 147, pp. 130-149"), compound 1a (30 mg, 133 μmol), and triphenylphosphine (58 mg, 221 μmol) were dissolved in tetrahydrofuran (5 mL). Diisopropyl azodicarboxylate (34 mg, 166 μmol) was added dropwise under ice-cooling. The mixture was allowed to cool to room temperature and allowed to react for 16 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography using eluent C to afford the title compound 1c (40 mg, 92.6% yield). MS m / z (ESI): 390.2 [M+1].

[0152] Step 2

[0153] Tert-butyl endo-3-((4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-2-fluoro-3-methylphenyl)amino)quinazolin-6-yl)oxy)-8-azabicyclo[3.2.1]octane-8-carboxylate 1d

[0154] Compound 1c (1.2 g, 3 mmol) was dissolved in isopropanol (5 mL), and 4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-2-fluoro-3-methylaniline (845 mg, 3.27 mmol, prepared using the method disclosed in Example 95 on page 143 of patent application "WO2022003575A1") was added. The mixture was reacted at 80°C for 2 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent System A to obtain the title compound 1d (1.05 g, 55.7% yield). MS m / z (ESI): 612.2 [M+1].

[0155] Step 3

[0156] 6-((endo-8-azabicyclo[3.2.1]octan-3-yl)oxy)-N-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-2-fluoro-3-methylphenyl)quinazolin-4-amine hydrochloride 1e

[0157] Compound 1d (1.05 g, 1.7 mmol) was dissolved in methanol (10 mL). 0.1 mL of 4 M hydrogen chloride in dioxane was added and the mixture was stirred for 1 hour. The reaction solution was concentrated under reduced pressure to give the crude title compound 1e (940 mg). The crude product was used directly in the next step without purification. MS m / z (ESI): 512.2 [M+1].

[0158] Step 4

[0159] 1-(endo-3-((4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-2-fluoro-3-methylphenyl)amino)quinazolin-6-yl)oxy)-8-azabicyclo[3.2.1]oct-8-yl)prop-2-en-1-one 1

[0160] Crude compound 1e (250 mg, 488.7 μmol) was dissolved in 5 mL of dichloromethane, and N,N-diisopropylethylamine (126 mg, 974 μmol) was added. Acryloyl chloride (50 mg, 552.4 μmol) was then added under ice-cooling. The mixture was stirred for 1 hour, and the reaction solution was concentrated under reduced pressure. The residue was purified by preparative HPLC (Waters-2545, column: YMC Triart-Exrs C18, 30*150 mm, 5 μm; mobile phase: aqueous phase (10 mmol / L ammonium bicarbonate) and acetonitrile, gradient ratio: acetonitrile 30%-45%, flow rate: 30 mL / min) to obtain the title compound 1 (110 mg, yield: 39.7%). MS m / z (ESI): 566.2 [M+1]. 1 H NMR (500MHz, MeOD): δ8.80-8.78(d,1H),8.41(s,1H),8.33(s,1H),7.84-7. 82(m,1H),7.77(s,1H),7.60-7.56(m,2H),7.14-7.10(m,2H),7.02-7.01(m ,1H),6.79-6.74(m,1H),6.35(dd,1H),5.81(dd,1H),4.97-4.93(m,1H),4. 76-4.73(m,1H),4.61-4.59(m,1H),2.44-2.17(m,10H),2.06-2.02(m,1H).

[0161] Test Example 1 Ba / F3 cell proliferation experiment

[0162] Logarithmically growing EGFR wild-type Ba / F3 cells (Cobioer, Catalog No. CBP73110) were seeded into 96-well plates at a density of 2.5 × 10 cells / 100 μL of growth medium. Logarithmically growing HER2 wild-type Ba / F3 cells (Cobioer, Catalog No. CBP73110) or HER2 A775_G776insYVMA mutant Ba / F3 cells (Cobioer, Catalog No. CBP73184) were seeded into 96-well plates at a density of 5 × 10 cells / 100 μL of growth medium. The plates were incubated overnight at 37°C. The next day, 100 μL / well of compound, serially diluted threefold in culture medium, was added. All treatments were performed in triplicate. The plates were cultured at 37°C for 72 hours. Cell viability was then measured using the Celltiter-Glo Luminescent assay.

[0163] The cell proliferation rate for each well was calculated using the following formula: % Proliferation = (Average value of test compound wells G3 - G0) / (Average value of DMSO control wells G3 - Average value of G0) * 100. Prism GraphPad software was used to fit the cell proliferation gradient curve based on the proliferation rate and concentration of each gradient well, and the compound GI50 (GI50 is defined as the compound concentration that inhibits cell proliferation by 50%) was calculated.

[0164] The structure of the HER2 selective inhibitor tucatinib (synthesized according to Example 11 in patent WO2007059257A2) is as follows:

[0165] Table 1

[0166] Conclusion: The disclosed compounds have a potent inhibitory effect on the proliferation of Ba / F3 cells harboring HER2 exon 20YVMA insertion mutations and HER2 wild-type-dependent cells, and have strong selectivity relative to EGFR wild-type-dependent Ba / F3 cells; moreover, the disclosed compounds have significantly better inhibitory activity on the proliferation of Ba / F3 cells harboring HER2 exon 20YVMA insertion mutations than tucatinib.

[0167] Example 2 Preparation of Hydrochloride Form I

[0168] 8.5 mg of the compound of formula 1 was dissolved in 0.2 mL of acetone. 8.25 μL of 2M aqueous hydrochloric acid was added, stirred, and centrifuged. The solid was collected and vacuum dried to obtain the product. X-ray powder diffraction analysis identified the product as hydrochloride Form I. The XRPD spectrum is shown in Figure 1, and the positions of its characteristic peaks are shown in Table 2. Ion chromatography analysis revealed a chloride ion content of 5.58%. The DSC spectrum showed endothermic peaks at 60.82°C, 94.14°C, and 196.79°C. The TGA spectrum showed a weight loss of 3.50% between 30°C and 120°C, and a weight loss of 2.02% between 120°C and 220°C.

[0169] Table 2

[0170] Example 3: Preparation of Hydrochloride II Crystalline Form

[0171] 8.5 mg of the compound of formula 1 was dissolved in 0.2 mL of propylene glycol methyl ether. 8.25 μL of 2M aqueous hydrochloric acid was added, followed by 0.2 mL of methyl tert-butyl ether. The mixture was dissolved and crystallized, centrifuged, and the solid collected and dried under vacuum to obtain the product. X-ray powder diffraction analysis identified the product as Form II hydrochloride. The XRPD spectrum is shown in Figure 2, and the positions of its characteristic peaks are shown in Table 3. Ion chromatography analysis revealed a chloride ion content of 6.27%. The DSC spectrum showed endothermic peaks at 50.83°C and 213.48°C. The TGA spectrum showed a weight loss of 8.88% between 30°C and 240°C.

[0172] Table 3

[0173] Example 4: Preparation of Hydrochloride II Crystalline Form

[0174] The hydrochloride crystal form I of the compound of formula 1 is heated to 120° C. to obtain a product. X-ray powder diffraction analysis shows that the product is the hydrochloride crystal form II.

[0175] Example 5: Preparation of Hydrochloride III Crystalline Form

[0176] 20 mg of the compound of formula 1 was added to 2 mL of pH 1.0 hydrochloric acid aqueous solution, stirred, centrifuged, and the solid collected and dried under vacuum to obtain the product. X-ray powder diffraction analysis identified the product as hydrochloride Form III. The XRPD spectrum is shown in Figure 3, and the positions of its characteristic peaks are shown in Table 4. Ion chromatography analysis revealed a chloride ion content of 5.40%. The DSC spectrum showed endothermic peaks at 76.96°C, 94.62°C, and 196.79°C. The TGA spectrum showed a weight loss of 7.40% between 30°C and 120°C, and a weight loss of 2.20% between 120°C and 220°C.

[0177] Table 4

[0178] Example 6 Preparation of Sulfate Crystal Form I

[0179] 8.5 mg of the compound of Formula 1 was dissolved in 0.2 mL of acetone, and 8.25 μL of 2M aqueous sulfuric acid was added. The mixture was stirred and centrifuged. The solid was collected and dried under vacuum to obtain the product. X-ray powder diffraction analysis identified the product as sulfate salt Form I. The XRPD spectrum is shown in Figure 4, and the positions of its characteristic peaks are shown in Table 5. Ion chromatography analysis revealed a sulfate ion content of 15.74%. The DSC spectrum showed endothermic peaks at 110.48°C and 213.29°C. The TGA spectrum showed a weight loss of 2.40% between 30°C and 160°C.

[0180] Table 5

[0181] Example 7: Preparation of Sulfate Crystal Form I

[0182] 8.5 mg of the compound of formula 1 was dissolved in 0.2 mL of a solvent as shown in Table 6 below. 8.25 μL of a 2M aqueous sulfuric acid solution was added, stirred, centrifuged, and the solid collected and dried under vacuum to obtain the product. X-ray powder diffraction analysis showed that the product was sulfate salt Form I.

[0183] Table 6

[0184] Example 8: Preparation of Sulfate II Crystalline Form

[0185] The sulfate form I of the compound of formula 1 was heated to 120° C. to obtain a product. X-ray powder diffraction analysis identified the product as sulfate form II. The XRPD spectrum is shown in FIG5 , and the positions of its characteristic peaks are shown in Table 7.

[0186] Table 7

[0187] Example 9: Preparation of Phosphate I Crystalline Form

[0188] 8.5 mg of the compound of Formula 1 was dissolved in 0.2 mL of acetone. 8.25 μL of 2 M aqueous phosphoric acid was added, stirred, and centrifuged. The solid was collected and dried under vacuum to obtain the product. X-ray powder diffraction analysis identified the product as Form I phosphate. The XRPD spectrum is shown in Figure 6, and the positions of its characteristic peaks are shown in Table 8. Ion chromatography analysis revealed a phosphate ion content of 17.07%. The DSC spectrum showed endothermic peaks at 101.48°C, 127.48°C, 192.14°C, and 200.30°C. The TGA spectrum showed a weight loss of 1.69% between 30°C and 160°C.

[0189] Table 8

[0190] Example 10: Preparation of Phosphate I Crystalline Form

[0191] 8.5 mg of the compound of formula 1 was dissolved in 0.2 mL of tetrahydrofuran, and 8.25 μL of 2M phosphoric acid solution was added. The mixture was stirred and centrifuged. The solid was collected and dried under vacuum to obtain the product. X-ray powder diffraction analysis showed that the product was phosphate salt form I.

[0192] Example 11: Preparation of Phosphate II Crystalline Form

[0193] 8.5 mg of the compound of formula 1 was dissolved in 0.2 mL of propylene glycol methyl ether, and 8.25 μL of 2 M phosphoric acid aqueous solution was added. The mixture was stirred and centrifuged. The collected solid was vacuum dried to obtain the product. X-ray powder diffraction analysis identified the product as phosphate II crystal form. The XRPD spectrum is shown in Figure 7, and the positions of its characteristic peaks are shown in Table 9. Ion chromatography analysis revealed a phosphate ion content of 22.24%. The DSC spectrum showed an endothermic peak at 204.80°C. The TGA spectrum showed a weight loss of 0.32% from 30°C to 120°C.

[0194] Table 9

[0195] Example 12: Preparation of Methanesulfonate Crystal Form I

[0196] 100 mg of the compound of Formula 1 was dissolved in 1 mL of acetone, and 97.10 μL of a 2M methanesulfonic acid solution was added. The mixture was stirred and centrifuged. The collected solid was vacuum dried to obtain the product. X-ray powder diffraction analysis identified the product as mesylate salt Form I. The XRPD spectrum is shown in Figure 8, and the positions of its characteristic peaks are shown in Table 10. Ion chromatography analysis revealed a mesylate ion content of 14.76%. The DSC spectrum showed an endothermic peak at 261.30°C. The TGA spectrum showed no significant weight loss.

[0197] Table 10

[0198] Example 13: Preparation of Methanesulfonate Form II

[0199] The mesylate salt Form I of the compound of Formula 1 was placed under 92.5% RH for 8 days to obtain a product. X-ray powder diffraction analysis identified the product as mesylate salt Form II. The XRPD spectrum is shown in Figure 9, and the positions of its characteristic peaks are shown in Table 11. Ion chromatography analysis revealed a mesylate ion content of 14.60%. The DSC spectrum showed endothermic peaks at 57.99°C and 262.65°C. The TGA spectrum showed a weight loss of 1.75% from 30°C to 120°C.

[0200] Table 11

[0201] Example 14: Preparation of Tartrate Form I

[0202] 8.5 mg of the compound of formula 1 was dissolved in 0.2 mL of acetone, and 16.5 μL of a 2 M tartaric acid aqueous solution was added. The mixture was stirred and centrifuged. The collected solid was vacuum dried to obtain the product. X-ray powder diffraction analysis identified the product as tartrate salt Form I. The XRPD spectrum is shown in Figure 10, and the positions of its characteristic peaks are shown in Table 12. Ion chromatography analysis revealed a tartrate ion content of 23.90%. The DSC spectrum showed endothermic peaks at 80.16°C and 194.44°C. The TGA spectrum showed a weight loss of 0.73% between 30°C and 120°C.

[0203] Table 12

[0204] Example 15: Preparation of Tartrate Crystal Form I

[0205] 8.5 mg of the compound of Formula 1 was dissolved in 0.2 mL of a solvent as shown in Table 13 below. 16.5 μL of a 2M aqueous tartaric acid solution was added, stirred, centrifuged, and the solid collected and dried under vacuum to obtain the product. X-ray powder diffraction analysis showed that the product was tartrate salt Form I.

[0206] Table 13

[0207] Example 16: Preparation of p-toluenesulfonate Crystal Form I

[0208] 100 mg of the compound of Formula 1 was dissolved in 1 mL of acetone. 97.10 μL of a 2M aqueous solution of p-toluenesulfonic acid was added, stirred, centrifuged, and the solid collected and vacuum dried to obtain the product. X-ray powder diffraction analysis identified the product as p-toluenesulfonate Form I. The XRPD spectrum is shown in Figure 11, and the positions of its characteristic peaks are shown in Table 14. Ion chromatography analysis revealed a p-toluenesulfonate ion content of 22.63%. The DSC spectrum revealed an endothermic peak at 219.72°C. The TGA spectrum showed no significant weight loss. DVS analysis revealed that under normal storage conditions (i.e., 25°C, 60% RH), the sample experienced a moisture gain of approximately 1.18%; under accelerated storage conditions (i.e., 70% RH), the moisture gain was approximately 1.57%; and under extreme conditions (90% RH), the moisture gain was approximately 2.21%. Retesting the crystal form after DVS analysis revealed no change in form.

[0209] Table 14

[0210] Example 17: Preparation of p-toluenesulfonate Crystal Form I

[0211] 8.5 mg of the compound of formula 1 was dissolved in 0.2 mL of tetrahydrofuran, and 8.25 μL of 2M p-toluenesulfonic acid solution was added. The mixture was stirred and centrifuged. The solid was collected and dried under vacuum to obtain the product. X-ray powder diffraction analysis showed that the product was p-toluenesulfonate crystalline form I.

[0212] Example 18: Preparation of p-toluenesulfonate Crystal Form I

[0213] 30 mg of the compound of Formula 1 was dissolved in 0.6 mL of a solvent as shown in Table 15 below. 29.12 μL of a 2M aqueous p-toluenesulfonic acid solution was added, and crystallization was performed. The solution was centrifuged and the solid was collected and vacuum dried to obtain the product. X-ray powder diffraction analysis showed that the product was p-toluenesulfonate Form I.

[0214] Table 15

[0215] Example 19: Preparation of p-toluenesulfonate II Crystalline Form

[0216] 8.5 mg of the compound of formula 1 was dissolved in 0.2 mL of propylene glycol methyl ether, and 8.25 μL of a 2M aqueous p-toluenesulfonic acid solution was added. The mixture was eluted and crystallized, centrifuged, and the collected solid was vacuum dried to obtain the product. X-ray powder diffraction analysis identified the product as p-toluenesulfonate salt form II. The XRPD spectrum is shown in Figure 12, and the positions of its characteristic peaks are shown in Table 16. Ion chromatography analysis revealed a p-toluenesulfonate ion content of 21.59%. The DSC spectrum showed endothermic peaks at 168.81°C and 209.30°C. The TGA spectrum showed a weight loss of 10.98% from 30°C to 160°C.

[0217] Table 16

[0218] Example 20: Preparation of Fumarate Crystal Form I

[0219] 8.5 mg of the compound of Formula 1 was dissolved in 0.2 mL of acetone, followed by the addition of 1.91 mg of solid fumaric acid, stirred, centrifuged, and the collected solid was vacuum dried to obtain the product. X-ray powder diffraction analysis identified the product as fumarate salt Form I. The XRPD spectrum is shown in Figure 13, and the positions of its characteristic peaks are shown in Table 17. Ion chromatography analysis revealed a fumarate ion content of 20.57%. The DSC spectrum showed an endothermic peak at 190.54°C. The TGA spectrum showed no significant weight loss.

[0220] Table 17

[0221] Example 21: Preparation of Fumarate Crystal Form I

[0222] 8.5 mg of the compound of formula 1 was dissolved in 0.2 mL of a solvent as shown in Table 18 below. 1.91 mg of solid fumaric acid was then added, stirred, centrifuged, and the solid collected and dried under vacuum to obtain a product. X-ray powder diffraction analysis confirmed that the product was a fumarate salt in Form I.

[0223] Table 18

[0224] Example 22: Study on the stability of influencing factors

[0225] The p-toluenesulfonate salt form I was laid out openly, and the stability of the sample was investigated under light (4500 Lux), high temperature (40° C., 60° C.), and high humidity (RH 75%, RH 92.5%) conditions. The sampling period was 1 month.

[0226] Table 19 Factors affecting the stability of the p-toluenesulfonate I crystal form

[0227] Conclusion: The p-toluenesulfonate salt form I has good physical and chemical stability under high humidity and light conditions.

[0228] Experimental Example 23: Long-term / accelerated stability

[0229] The p-toluenesulfonate salt Form I was placed under 25°C / 60% RH and 40°C / 75% RH conditions to investigate its stability:

[0230] Table 20 Long-term / accelerated stability of p-toluenesulfonate Form I

[0231] Conclusion: The p-toluenesulfonate salt form I has good physical and chemical stability under long-term accelerated conditions.

Claims

1. A pharmaceutically acceptable salt of 1-(endo-3-((4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-2-fluoro-3-methylphenyl)amino)quinazolin-6-yl)oxy)-8-azabicyclo[3.2.1]oct-8-yl)prop-2-en-1-one as shown in formula 1, wherein the pharmaceutically acceptable salt is selected from the group consisting of hydrochloride, sulfate, phosphate, methanesulfonate, tartrate, p-toluenesulfonate, and fumarate.

2. The pharmaceutically acceptable salt according to claim 1, characterized in that The 1-(endo-3-((4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-2-fluoro-3-methylphenyl)amino)quinazolin-6-yl)oxy)-8-azabicyclo[ 3.2.1] The chemical ratio of oct-8-yl)prop-2-en-1-one to the acid is 3:1-1:3, preferably 2:1-1:2, more preferably 1:1 or 1:

2.

3. A 1-(endo-3-((4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-2-fluoro-3-methylphenyl)amino)quinazolin-6-yl)oxy)-8-azabicyclo[ 3.2.1]oct-8-yl)prop-2-en-1-one pharmaceutically acceptable salt, comprising 1-(endo-3-((4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-2-fluoro-3-methylphenyl)amino)quinazolin-6-yl)oxy)-8-azabicyclo[ 3.2.1] a step of reacting oct-8-yl)prop-2-en-1-one with an acid, wherein the acid is selected from hydrochloric acid, sulfuric acid, phosphoric acid, methanesulfonic acid, fumaric acid, p-toluenesulfonic acid and tartaric acid.

4. A 1-(endo-3-((4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-2-fluoro-3-methylphenyl)amino)quinazolin-6-yl)oxy)-8-azabicyclo[ 3.2.1] oct-8-yl) prop-2-en-1-one methanesulfonate, 1-(endo-3-((4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-2-fluoro-3-methylphenyl)amino)quinazolin-6-yl)oxy)-8-azabicyclo[ 3.2.1] The chemical ratio of oct-8-yl)prop-2-en-1-one and methanesulfonic acid is 1:

1.

5. A mesylate salt of a compound of formula 1 in form I, characterized in that: The X-ray powder diffraction pattern represented by the diffraction angle 2θ has characteristic peaks at 12.785, 14.363, 18.248, 19.608, 20.315 and 25.404, preferably at 8.311, 12.785, 14.363, 15.220, 17.817, 18.248, 19.318, 19.608, 20.315, 21.697, 22.256, 25 .404 and 28.858, more preferably 8.311, 9.846, 12.785, 14.363, 15.220, 16.576, 17.817, 18.248, 19.318, 19.608, 20.315, 21.697, 22.256, 24.601, 25.404, 27.594, 28.858, and 31.581, 6. The crystal form according to claim 5, characterized in that: The X-ray powder diffraction pattern expressed in terms of diffraction angle 2θ is shown in FIG8 .

7. A method for preparing the crystal form according to claim 5 or 6, comprising: dissolving the compound of formula 1 in acetone, adding an aqueous solution of methanesulfonic acid, and stirring.

8. A 1-(endo-3-((4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-2-fluoro-3-methylphenyl)amino)quinazolin-6-yl)oxy)-8-azabicyclo[ 3.2.1] oct-8-yl) prop-2-en-1-one p-toluenesulfonate, 1-(endo-3-((4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-2-fluoro-3-methylphenyl)amino)quinazolin-6-yl)oxy)-8-azabicyclo[ 3.2.1] The chemical ratio of oct-8-yl)prop-2-en-1-one and p-toluenesulfonic acid is 1:

1.

9. A p-toluenesulfonate salt of a compound of formula 1 in crystalline form I, characterized in that: The X-ray powder diffraction pattern represented by the diffraction angle 2θ has characteristic peaks at 6.708, 9.145, 15.275, 17.217, 20.971 and 22.499, preferably at 6.708, 8.935, 9.145, 13.450, 15.275, 16.934, 17.217, 18.123, 18.948, 20.971, 22. The invention discloses a novel nanostructured carbonyl carbonyl compound having characteristic peaks at 499, 23.831, and more preferably at 6.579, 6.708, 8.935, 9.145, 12.699, 13.450, 15.275, 16.934, 17.217, 18.123, 18.948, 20.186, 20.971, 22.499, 23.831, 26.139 and 29.

589.

10. The crystal form according to claim 9, characterized in that: The X-ray powder diffraction pattern expressed in terms of diffraction angle 2θ is shown in FIG11 .

11. A method for preparing the crystal form according to claim 9 or 10, the method comprising: dissolving the compound of formula 1 in a solvent V, adding an aqueous solution of p-toluenesulfonic acid, and stirring, wherein the solvent V is selected from one of acetone, tetrahydrofuran, acetone:propylene glycol methyl ether (v / v=1:1), acetone:propylene glycol methyl ether (v / v=7:3), and acetone:n-propanol (v / v=7:3).

12. According to the crystal form according to any one of claims 5-6, 9-10, the 2θ angle error range is ±0.

20.

13. A pharmaceutical composition comprising a pharmaceutically acceptable salt of 1-(endo-3-((4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-2-fluoro-3-methylphenyl)amino)quinazolin-6-yl)oxy)-8-azabicyclo[3.2.1]oct-8-yl)prop-2-en-1-one as described in any one of claims 1, 2, 4, and 8, or a crystalline form as described in any one of claims 5-6, 9-10, and optionally a pharmaceutically acceptable excipient.

14. A method for preparing a pharmaceutical composition, comprising the following steps: 1-(endo-3-((4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-2-fluoro-3-methylphenyl)amino)quinazolin-6-yl)oxy)-8-azabicyclo[ 3.2.1] a pharmaceutically acceptable salt of oct-8-yl) prop-2-en-1-one, or a crystalline form as described in any one of claims 5-6, 9-10 and a pharmaceutically acceptable excipient.

15. Use of a pharmaceutically acceptable salt of 1-(endo-3-((4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-2-fluoro-3-methylphenyl)amino)quinazolin-6-yl)oxy)-8-azabicyclo[3.2.1]oct-8-yl)prop-2-en-1-one according to any one of claims 1, 2, 4, and 8, or a crystalline form according to any one of claims 5-6, 9-10, or a pharmaceutical composition according to claim 13 in the preparation of a HER2 inhibitor.

16. 1-(endo-3-((4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-2-fluoro-3-methylphenyl)amino)quinazolin-6-yl)oxy)-8-azabicyclo[ 3.2.1] a pharmaceutically acceptable salt of oct-8-yl)prop-2-en-1-one, or a crystalline form according to any one of claims 5 to 6, 9 to 10, or a pharmaceutical composition according to claim 13 in the preparation of a medicament for treating and / or preventing cancer.