Medicinal salt of quinazoline derivative as well as crystal form and application of medicinal salt

Abstract

Relates to a pharmaceutically acceptable salt of a quinazoline derivative, and a crystal form and application thereof. Specifically, the invention provides a medicinal salt, a crystal form and a preparation method of 1-(inner-3-((4-((4-([1, 2, 4] triazolo [1, 5-a] pyridine-7-yloxy)-2-fluoro-3-methylphenyl) amino) quinazoline-6-yl) oxy)-8-azabicyclo [3.2. 1] oct-8-yl) prop-2-en-1-one, and the corresponding salt has good stability and can be better used for clinical treatment.

Description

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

[0001] This invention claims the following priority:

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

[0003] This disclosure belongs to the field of pharmaceutical technology and relates to a pharmaceutically acceptable salt of a quinazoline derivative, its crystalline form, and its uses.

[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 homodimers or heterodimers with other family members (such as HER3). After HER2 dimerization, its conformation changes, activating intracellular tyrosine kinase activity, which in turn activates downstream pathways (MAPK signaling pathway and PI3K / AKT signaling pathway), thereby exerting its corresponding physiological functions.

[0005] It is estimated that approximately 2-4% of lung cancer patients carry activating mutations in HER2 exon 20. Currently approved ERBB-targeting tyrosine kinase inhibitors are largely ineffective in these patients, primarily due to dose-limiting toxicity mediated by EGFR wild-type mutations. Afatinib, ibrutinib, neratinib, poziotinib, and pyrotinib are known broad-spectrum ERBB inhibitors targeting HER2 exon 20 mutations. However, clinically, due to effective dose limitations, afatinib and other broad-spectrum ERBB inhibitors have shown only limited efficacy in NSCLC patients with HER2 exon 20 mutations.

[0006] PCT / CN2023 / 084265 discloses a novel inhibitor selective for EGFR wild-type HER2 exon 20 mutations, chemically named 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, having the structure shown in Formula 1.

[0007] Salt formation can improve certain undesirable physicochemical or biological properties of drugs. Developing 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 polymorphs of pharmaceutically acceptable salts of 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 of great significance for developing drugs suitable for industrial production and with good biological activity.

[0008]

[0009] This disclosure provides a pharmaceutically acceptable salt of 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, wherein the pharmaceutically acceptable salt is selected from hydrochloride, sulfate, phosphate, methanesulfonate, tartrate, p-benzenesulfonate, fumarate,

[0010] In an optional embodiment, the chemical ratio of 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 to the acid is 3:1 to 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 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 to the acid is 2:1 to 1:2.

[0012] In an optional embodiment, the chemical ratio of 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 to hydrochloric acid is 1:1.

[0013] In an optional embodiment, the chemical ratio of 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 to sulfuric acid is 1:1 or 2:1.

[0014] In an optional embodiment, the chemical ratio of 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 to phosphoric acid is 1:1 or 1:2.

[0015] In an optional embodiment, the chemical ratio of 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 to methanesulfonic acid is 1:1.

[0016] In an optional embodiment, the chemical ratio of 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 to fumaric acid is 1:1 or 2:1.

[0017] In an optional embodiment, the chemical ratio of 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 to p-toluenesulfonic acid is 1:1.

[0018] In an optional embodiment, the chemical ratio of 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 to L-tartaric acid is 1:1.

[0019] This disclosure also provides a method for preparing a pharmaceutically acceptable salt of a compound of formula 1, comprising the step of reacting a compound of formula 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, wherein the acid is selected from hydrochloric acid, sulfuric acid, phosphoric acid, methanesulfonic acid, tartaric acid, p-benzenesulfonic acid, and fumaric acid.

[0020] The solvents used in the salt formation of this disclosure are selected from, but are not limited to, acetone, tetrahydrofuran, n-propanol, and propylene glycol methyl ether.

[0021] The hydrochloride I crystal form of the compound of Formula 1 provided in this disclosure has characteristic peaks at 8.985, 13.114, 13.459, 17.385, 20.631 and 22.030 in its X-ray powder diffraction pattern expressed as a diffraction angle 2θ.

[0022] In some embodiments, the X-ray powder diffraction pattern of the hydrochloride I crystal form of the compound of Formula 1, expressed as a diffraction angle 2θ, has 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 X-ray powder diffraction pattern of the hydrochloride I crystal form of the compound of Formula 1, expressed as a diffraction angle 2θ, has 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 I crystal form of the compound of Formula 1, expressed in terms of the diffraction angle 2θ, is shown in Figure 1.

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

[0026] The hydrochloride II crystal form of the compound of Formula 1 disclosed herein has characteristic peaks at 9.315, 12.380, 15.334, 20.554 and 25.413 in its X-ray powder diffraction pattern expressed as a diffraction angle 2θ.

[0027] In some embodiments, the X-ray powder diffraction pattern of the hydrochloride II crystal form of the compound of Formula 1, expressed as a diffraction angle 2θ, has 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 X-ray powder diffraction pattern of the hydrochloride II crystal form of the compound of Formula 1, expressed as a diffraction angle 2θ, has 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 II crystal form of the compound of Formula 1, expressed in terms of the diffraction angle 2θ, is shown in Figure 2.

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

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

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

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

[0034] In some embodiments, the X-ray powder diffraction pattern of the hydrochloride III crystal form of the compound of Formula 1, expressed as a diffraction angle 2θ, has 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 X-ray powder diffraction pattern of the hydrochloride III crystal form of the compound of Formula 1, expressed as a diffraction angle 2θ, has 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 III crystal form of the compound of formula 1, expressed in terms of the diffraction angle 2θ, is shown in Figure 3.

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

[0038] The sulfate I crystal form of the compound of Formula 1 provided in this disclosure has characteristic peaks at 8.249, 8.600, 15.780, 21.562, 24.900 and 26.659 in its X-ray powder diffraction pattern expressed as a diffraction angle 2θ.

[0039] In some embodiments, the sulfate I crystal form of the compound of Formula 1, as expressed in X-ray powder diffraction patterns at diffraction angles 2θ, has 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 X-ray powder diffraction pattern of the sulfate I crystal form of the compound of Formula 1, expressed as a diffraction angle 2θ, has 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 I crystal form of the compound of Formula 1, expressed in terms of the diffraction angle 2θ, is shown in Figure 4.

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

[0043] The sulfate II crystal form of the compound of Formula 1 disclosed herein, as expressed in X-ray powder diffraction patterns in terms of diffraction angle 2θ, has characteristic peaks at 8.462, 13.537, 18.209, 19.271, 22.193, and 24.694.

[0044] In some embodiments, the crystal form of the compound of Formula 1, expressed as an X-ray powder diffraction pattern in terms of the diffraction angle 2θ, is shown in Figure 5.

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

[0046] The phosphate I crystal form of the compound of Formula 1 provided in this disclosure has characteristic peaks at 8.220, 15.308, 16.443, 18.865, 20.736 and 26.384 in its X-ray powder diffraction pattern expressed as a diffraction angle 2θ.

[0047] In some embodiments, the phosphate I crystal form of the compound of formula 1, as expressed in X-ray powder diffraction patterns at diffraction angles 2θ, has 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 I crystal form of the compound of Formula 1, as expressed in X-ray powder diffraction patterns at diffraction angles of 2θ, has 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 I crystal form of the compound of Formula 1, expressed in terms of the diffraction angle 2θ, is shown in Figure 6.

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

[0051] The phosphate II crystal form of the compound of Formula 1 disclosed herein has characteristic peaks at 7.659, 14.303, 15.921, 18.824, 20.380 and 26.730 in its X-ray powder diffraction pattern expressed as a diffraction angle of 2θ.

[0052] In some embodiments, the phosphate II crystal form of the compound of formula 1, as expressed in X-ray powder diffraction patterns at diffraction angles of 2θ, has 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 crystal form of the compound of formula 1, as expressed in X-ray powder diffraction patterns at diffraction angles of 2θ, exhibits 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 the diffraction angle 2θ, is shown in Figure 7.

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

[0056] The methanesulfonate I crystal form of the compound of Formula 1 disclosed herein has characteristic peaks at 12.785, 14.363, 18.248, 19.608, 20.315 and 25.404 in its X-ray powder diffraction pattern expressed as a diffraction angle 2θ.

[0057] In some embodiments, the methanesulfonate I crystal form of the compound of formula 1, as expressed in X-ray powder diffraction patterns at diffraction angles of 2θ, has 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 methanesulfonate I crystal form of the compound of formula 1, as expressed in X-ray powder diffraction patterns at diffraction angles of 2θ, has 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 methanesulfonate I crystal form of the compound of Formula 1, expressed in terms of the diffraction angle 2θ, is shown in Figure 8.

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

[0061] The methanesulfonate II crystal form of the compound of Formula 1 disclosed herein has characteristic peaks at 8.305, 15.133, 20.915, 23.482 and 25.997 in its X-ray powder diffraction pattern expressed as a diffraction angle 2θ.

[0062] In some embodiments, the methanesulfonate II crystal form of the compound of formula 1, as expressed in X-ray powder diffraction patterns at diffraction angles of 2θ, has 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 methanesulfonate II crystal form of the compound of formula 1, as expressed in X-ray powder diffraction patterns at diffraction angles of 2θ, exhibits 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 methanesulfonate II crystal form of the compound of Formula 1, expressed in terms of the diffraction angle 2θ, is shown in Figure 9.

[0065] This disclosure also provides a method for preparing the crystal form of methanesulfonate II of compound 1, comprising placing the crystal form of methanesulfonate I of compound 1 under 92.5% RH conditions for 8 days.

[0066] The tartrate I crystal form of the compound of Formula 1 disclosed herein has characteristic peaks at 8.150, 15.441, 16.466, 18.005 and 25.087 in its X-ray powder diffraction pattern expressed as a diffraction angle 2θ.

[0067] In some embodiments, the X-ray powder diffraction pattern of the tartrate I crystal form of the compound of Formula 1, expressed as a diffraction angle 2θ, has 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 I crystal form of the compound of Formula 1, expressed in terms of the diffraction angle 2θ, is shown in Figure 10.

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

[0070] The p-toluenesulfonate I crystal form of the compound of Formula 1 disclosed herein has characteristic peaks at 6.708, 9.145, 15.275, 17.217, 20.971 and 22.499 in its X-ray powder diffraction pattern expressed as a diffraction angle 2θ.

[0071] In some embodiments, the X-ray powder diffraction pattern of the p-toluenesulfonate I crystal form of the compound of Formula 1, expressed as a diffraction angle 2θ, has 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 X-ray powder diffraction pattern of the p-toluenesulfonate I crystal form of the compound of Formula 1, expressed as a diffraction angle 2θ, has 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 X-ray powder diffraction pattern of the p-toluenesulfonate I crystal form of the compound of Formula 1, expressed in terms of the diffraction angle 2θ, is shown in Figure 11.

[0074] This disclosure also provides a method for preparing p-toluenesulfonate I crystal form of compound 1, comprising dissolving compound 1 in solvent V, adding an aqueous solution of p-toluenesulfonic acid, and stirring, wherein solvent V is selected from 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 II crystal form of the compound of Formula 1 disclosed herein has characteristic peaks at 7.470, 13.033, 15.060, 18.754, 24.552 and 25.528 in its X-ray powder diffraction pattern expressed as a diffraction angle 2θ.

[0076] In some embodiments, the p-toluenesulfonate II crystal form of the compound of Formula 1, as expressed in X-ray powder diffraction patterns at diffraction angles of 2θ, has 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 X-ray powder diffraction pattern of the p-toluenesulfonate II crystal form of the compound of Formula 1, expressed as a diffraction angle 2θ, has 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 X-ray powder diffraction pattern of the p-toluenesulfonate II crystal form of the compound of Formula 1, expressed in terms of the diffraction angle 2θ, is shown in Figure 12.

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

[0080] The fumarate I crystal form of the compound of Formula 1 provided in this disclosure has characteristic peaks at 5.395, 11.651, 11.981, 16.295, 17.798, 19.316 and 22.420 in its X-ray powder diffraction pattern expressed as a diffraction angle 2θ.

[0081] In some embodiments, the fumarate I crystal form of the compound of Formula 1, as expressed in X-ray powder diffraction patterns at diffraction angles of 2θ, has 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 I crystal form of the compound of Formula 1, as expressed in X-ray powder diffraction patterns at diffraction angles of 2θ, exhibits 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 I crystal form of the compound of Formula 1, expressed in terms of the diffraction angle 2θ, is shown in Figure 13.

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

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

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

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

[0088] This disclosure also provides pharmaceutically acceptable salts of the aforementioned 1-(lac-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-(lac-3-((4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-2-fluoro-3-methylphenyl) The use of the following crystal forms of oct-8-(3.2.1) oct-8-yl)prop-2-en-1-one hydrochloride I, hydrochloride II, hydrochloride III, sulfate I, sulfate II, phosphate I, phosphate II, methanesulfonate I, methanesulfonate II, tartaric acid I, p-toluenesulfonate I, p-toluenesulfonate II or fumarate I, or the aforementioned compositions, as HER2 inhibitors.

[0089] This disclosure also provides pharmaceutically acceptable salts of the aforementioned 1-(lac-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-(lac-3-((4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-2-fluoro-3-methylphenyl)amino) Use of quinazolin-6-yl)oxy)-8-azabicyclo[3.2.1]oct-8-yl)prop-2-en-1-one hydrochloride I, hydrochloride II, hydrochloride III, sulfate I, sulfate II, phosphate I, phosphate II, methanesulfonate I, methanesulfonate II, tartaric acid I, p-toluenesulfonate I, p-toluenesulfonate II or fumarate I, or the aforementioned compositions, in the preparation of a HER2 inhibitor.

[0090] This disclosure also provides pharmaceutically acceptable salts of the aforementioned 1-(lac-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-(lac-3-((4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-2-fluoro-3-methylphenyl)amino) The hydrochloride I, hydrochloride II, hydrochloride III, sulfate I, sulfate II, phosphate I, phosphate II, methanesulfonate I, methanesulfonate II, tartaric acid I, p-toluenesulfonate I, p-toluenesulfonate II or fumarate I forms of quinazolin-6-yl)oxy)-8-azabicyclo[3.2.1]oct-8-yl)prop-2-en-1-one, or the combination thereof, for use in the preparation of a solution for the prevention and / or treatment of cancer.

[0091] The uses described in this disclosure, 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 carcinoma, oral cancer, thyroid cancer, skin cancer, squamous cell carcinoma, synovoma, and 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 this disclosure refers to the diffraction angle, where θ is the Bragg angle, and the unit is ° or degree; the error range of 2θ for each characteristic peak is ±0.20 (including the case where the number has more than one decimal place after rounding), 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] The numerical values ​​in this disclosure, such as those relating to the content of certain substances, are calculated data and inevitably contain a certain degree of error. Generally, ±10% is within the reasonable error range. The error may vary to some extent depending on the context in which it is used, but this variation shall not exceed ±10%, and may be ±9%, ±8%, ±7%, ±6%, ±5%, ±4%, ±3%, ±2%, or ±1%, preferably ±5%.

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

[0095] The drying temperature described in this disclosure is generally 25℃-100℃, preferably 40℃-70℃, and can be dried under normal pressure or reduced pressure.

[0096] The crystallization methods described in this disclosure include room temperature crystallization, cooling crystallization, solvent evaporation crystallization, and seed crystallization induction. The cooling temperature is selected from below 65°C, preferably from -10°C to 60°C. 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 the sample and the reference material during the sample heating or isothermal process, in order to characterize all physical and chemical changes related to thermal effects and obtain phase transition information of the sample.

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

[0099] Deliquescence: Absorbs sufficient moisture to form a liquid;

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

[0101] It has hygroscopic properties: the weight gain due to hygroscopic absorption is less than 15% but not less than 2%;

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

[0103] It has little or no hygroscopicity: the weight gain due to moisture absorption is less than 0.2%.

[0104] The “excipients” described in this disclosure include, but are not limited to, any adjuvants, carriers, flow aids, sweeteners, diluents, preservatives, dyes / colorants, flavoring agents, surfactants, wetting agents, dispersants, suspending agents, stabilizers, isotonic agents, or emulsifiers that have been approved by the U.S. Food and Drug Administration for use in humans or livestock.

[0105] Figure 1 shows the XRPD spectrum of the crystal form of compound 1 hydrochloride I.

[0106] Figure 2 shows the XRPD spectrum of the crystal form of compound 1 hydrochloride II.

[0107] Figure 3 shows the XRPD spectrum of the crystal form of compound 1 hydrochloride III.

[0108] Figure 4 shows the XRPD spectrum of the sulfate I crystal form of compound 1.

[0109] Figure 5 shows the XRPD spectrum of the sulfate II crystal form of compound 1.

[0110] Figure 6 shows the XRPD spectrum of phosphate I crystal form of compound 1.

[0111] Figure 7 shows the XRPD spectrum of the phosphate II crystal form of compound 1.

[0112] Figure 8 shows the XRPD spectrum of the crystal form of compound 1 methanesulfonate I.

[0113] Figure 9 shows the XRPD spectrum of the crystal form of compound 1, methanesulfonate II.

[0114] Figure 10 shows the XRPD spectrum of tartrate I crystal form of compound 1.

[0115] Figure 11 shows the XRPD spectrum of compound 1 p-toluenesulfonate I crystal form.

[0116] Figure 12 shows the XRPD spectrum of the crystal form of compound 1, p-toluenesulfonate II.

[0117] Figure 13 shows the XRPD spectrum of the fumarate I crystal form of compound 1.

[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 substance and scope of the present disclosure.

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

[0120] The structure of the compounds was determined 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, with deuterated dimethyl sulfoxide (DMSO-d₆), deuterated chloroform (CDCl₃), or deuterated methanol (CD₃OD) as the solvents and tetramethylsilane (TMS) as the internal standard.

[0121] MS measurements were performed using an Agilent 1200 / 1290 DAD-6110 / 6120 Quadrupole MS liquid chromatography-mass spectrometry system (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 an Agilent HPLC 1200DAD, an Agilent HPLC 1200VWD, and a Waters HPLC e2695-2489 high-performance liquid chromatograph.

[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 preparation was performed using a Shimadzu LC-20AP preparative chromatograph.

[0128] The CombiFlash rapid preparation system uses a CombiFlash Rf200 (TELEDYNE ISCO).

[0129] Thin-layer chromatography silica gel plates are Yantai Huanghai HSGF254 or Qingdao GF254. The silica gel plates used in thin-layer chromatography (TLC) have a diameter of 0.15 mm to 0.2 mm, and the diameter of the silica gel plates used for thin-layer chromatography separation and purification products is 0.4 mm to 0.5 mm.

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

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

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

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

[0134] Argon or nitrogen atmosphere refers to a reaction flask connected to an argon or nitrogen gas balloon with a volume of approximately 1L.

[0135] A hydrogen atmosphere refers to a reaction flask connected to a hydrogen balloon with a volume of approximately 1L.

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

[0137] The hydrogenation reaction is usually carried out under vacuum, filled with hydrogen gas, and repeated 3 times.

[0138] The microwave reaction was performed using a CEM Discover-S 908860 microwave reactor.

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

[0140] Unless otherwise specified in the examples, the reaction temperature is room temperature, which is 20℃~30℃.

[0141] The reaction process in the examples was monitored using thin-layer chromatography (TLC). The developing solvent used in the reaction, the eluent system for column chromatography used to purify the compounds, and the developing solvent system for TLC 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 compounds, and small amounts of basic or acidic reagents such as triethylamine and acetic acid could also be added for adjustment.

[0142] XRPD (X-ray Powder Diffraction) was used for analysis. Measurements were performed using a BRUKER D8 X-ray diffractometer. Specific data acquisition information included: Cu anode (40 kV, 40 mA), and monochromatic Cu-Ka rays. Scanning mode: θ / 2θ, scanning range: 3-48°.

[0143] DSC stands for Differential Scanning Calorimetry: Measurements were performed using a METTLER TOLEDO DSC 3+ differential scanning calorimeter with a heating rate of 10℃ / min. The specific temperature range was referenced from the corresponding spectra (mostly 25-300 or 25-350℃). Nitrogen purging rate was 50mL / min.

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

[0145] DVS stands for Dynamic Moisture Adsorption: The detection method is SMSDVS Advantage. At 25℃, 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 subject to the corresponding spectrum. The methods listed here are the most commonly used methods.) The judgment standard is that dm / dt is not greater than 0.002%.

[0146] Ion chromatography detection: Instrument: Dionex Aquaion ion chromatograph (USA); Detection method: conductivity; Separation column: Dionex IonPac AS27-4×250mm, 4μm; Eluent: EGC 500KOH 35mM; Flow rate: 1.5mL / min.

[0147] Example 1: Preparation of Compound 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] 3-((4-chloroquinazoline-6-yl)oxy)-8-azabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester 1c

[0151] 4-Chloroquinazoline-6-phenol 1b (20 mg, 110 μmol, prepared according to the method disclosed in the 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 azodicarbonate (34 mg, 166 μmol) was added dropwise under ice bath conditions. After the mixture was allowed to return to room temperature, the reaction was carried out for 16 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography using elution system C to give the title compound 1c (40 mg, yield: 92.6%). MS m / z (ESI): 390.2 [M+1].

[0152] Step 2

[0153] 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-carboxylic acid tert-butyl ester 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 by 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 give title compound 1d (1.05 g, yield: 55.7%). MS m / z (ESI): 612.2 [M+1].

[0155] Step 3

[0156] 6-((endo-8-azabicyclo[3.2.1]oct-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), and 0.1 mL of 4 M dioxane hydrochloride solution was added. The mixture was stirred for 1 hour, and the reaction solution was concentrated under reduced pressure to obtain the crude title compound 1e (940 mg). The crude product was used directly in the next reaction 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] The 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 added under ice bath conditions. The mixture was stirred for 1 hour, and the reaction solution was concentrated under reduced pressure. The residue was purified by preparative high-performance liquid chromatography (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 give 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] Log-growing EGFR wild-type Ba / F3 cells (Cobioer, catalog number: CBP73110) were seeded into 96-well plates at 2.5 × 10³ cells / 100 μL of growth medium. Log-growing HER2 wild-type Ba / F3 cells (Cobioer, catalog number: CBP73110) or HER2 A775_G776insYVMA mutant Ba / F3 cells (Cobioer, catalog number: CBP73184) were seeded into 96-well plates at 5 × 10³ cells / 100 μL of growth medium. The plates were incubated overnight at 37°C. The next day, 100 μL / well of the compound, serially diluted three times with culture medium, was added. All treatments were performed in triplicate. Cells were then cultured at 37°C for another 72 hours. Celltiter-Glo Luminescent cell viability was then measured.

[0163] The cell proliferation rate for each well was calculated using the following formula: Proliferation % = (average value of G3-G0 in wells containing the test compound) / (average value of G3 in wells containing DMSO control - average value of G0 in wells) * 100. Based on the proliferation rate and concentration of each well with a gradient concentration, a gradient curve of cell proliferation was fitted using Prism Graphpad software, and the GI50 of the compound was calculated (GI50 is defined as the compound concentration corresponding to a cell proliferation inhibition rate of 50%).

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

[0165] Table 1

[0166] Conclusion: The compound disclosed herein exhibits potent inhibitory activity against HER2 exon 20YVMA insertion mutation and HER2 wild-type dependent Ba / F3 cells, and shows strong selectivity relative to EGFR wild-type dependent Ba / F3 cells; furthermore, the inhibitory activity of the compound disclosed herein against HER2 exon 20YVMA insertion mutation Ba / F3 cells is significantly superior to that of tucatinib.

[0167] Example 2: Preparation of Hydrochloride I Crystal Form

[0168] 8.5 mg of compound 1 was dissolved in 0.2 mL of acetone, followed by 8.25 μL of 2M hydrochloric acid aqueous solution. The mixture was stirred, centrifuged, and the solid was collected and dried under vacuum 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 characteristic peak positions are shown in Table 2. Ion chromatography showed a chloride ion content of 5.58%. DSC spectra showed endothermic peaks at 60.82℃, 94.14℃, and 196.79℃. TGA spectra showed a weight loss of 3.50% from 30℃ to 120℃ and 2.02% from 120℃ to 220℃.

[0169] Table 2

[0170] Example 3: Preparation of the II crystal form of hydrochloride

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

[0172] Table 3

[0173] Example 4: Preparation of the II crystal form of hydrochloride

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

[0175] Example 5: Preparation of the III crystal form of hydrochloride

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

[0177] Table 4

[0178] Example 6 Preparation of Sulfate I Crystal Form

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

[0180] Table 5

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

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

[0183] Table 6

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

[0185] The sulfate I crystal form of compound 1 was heated to 120℃ to obtain the product. X-ray powder diffraction analysis identified this product as sulfate II crystal form. The XRPD spectrum is shown in Figure 5, and the positions of its characteristic peaks are shown in Table 7.

[0186] Table 7

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

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

[0189] Table 8

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

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

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

[0193] 8.5 mg of compound 1 was dissolved in 0.2 mL of propylene glycol methyl ether, followed by 8.25 μL of 2M phosphoric acid aqueous solution. The mixture was stirred, centrifuged, and the solid was collected and dried under vacuum 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 characteristic peak positions are shown in Table 9. Ion chromatography showed 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 I Crystal Form

[0196] 100 mg of compound 1 was dissolved in 1 mL of acetone, followed by 97.10 μL of 2M methanesulfonic acid aqueous solution. The mixture was stirred, centrifuged, and the solid was collected and dried under vacuum to obtain the product. X-ray powder diffraction analysis identified the product as methanesulfonate I crystal form. The XRPD spectrum is shown in Figure 8, and the characteristic peak positions are shown in Table 10. Ion chromatography showed that the methanesulfonate ion content was 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 Ⅱ Crystal Form

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

[0200] Table 11

[0201] Example 14: Preparation of Tartrate I Crystal Form

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

[0203] Table 12

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

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

[0206] Table 13

[0207] Example 16: Preparation of p-Toluenesulfonate I crystal form

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

[0209] Table 14

[0210] Example 17: Preparation of p-Toluenesulfonate I crystal form

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

[0212] Example 18: Preparation of p-Toluenesulfonate I crystal form

[0213] 30 mg of compound 1 was dissolved in 0.6 mL of solvent (as shown in Table 15 below). Then, 29.12 μL of 2M p-toluenesulfonic acid aqueous solution was added, and crystals were precipitated. The crystals were collected by centrifugation and dried under vacuum to obtain the product. X-ray powder diffraction analysis confirmed that the product was p-toluenesulfonate I crystal form.

[0214] Table 15

[0215] Example 19: Preparation of p-Toluenesulfonate II crystal form

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

[0217] Table 16

[0218] Example 20: Preparation of fumarate I crystal form

[0219] 8.5 mg of compound 1 was dissolved in 0.2 mL of acetone, followed by the addition of 1.91 mg of solid fumaric acid. The mixture was stirred, centrifuged, and the solid was collected and dried under vacuum to obtain the product. X-ray powder diffraction analysis identified the product as fumarate I crystal form. The XRPD spectrum is shown in Figure 13, and the characteristic peak positions are shown in Table 17. Ion chromatography analysis showed that the fumarate ion content was 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 I crystal form

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

[0223] Table 18

[0224] Example 22: Stability Study of Influencing Factors

[0225] The p-toluenesulfonate I crystal form was laid flat in the open, and the stability of the sample was investigated under light (4500 Lux), high temperature (40℃, 60℃), and high humidity (RH 75%, RH 92.5%) conditions. The sampling period was 1 month.

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

[0227] Conclusion: p-Toluenesulfonate I crystal form exhibits good physical and chemical stability under high humidity and light conditions.

[0228] Experimental Example 23: Long-term / Accelerated Stability

[0229] The stability of p-toluenesulfonate I crystal form was investigated under conditions of 25℃ / 60%RH and 40℃ / 75%RH.

[0230] Table 20 Long-term / Accelerated Stability of p-Toluenesulfonate I Crystal Form

[0231] Conclusion: p-Toluenesulfonate I crystal form exhibits good physical and chemical stability under long-term accelerated conditions.

Claims

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] A pharmaceutically acceptable salt of oct-8-yl)prop-2-en-1-one, wherein the pharmaceutically acceptable salt is selected from hydrochloride, sulfate, phosphate, methanesulfonate, tartrate, p-benzenesulfonate, fumarate, The medicinal salt according to claim 1 is characterized in that, The 1-(intra-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 acid is 3:1-1:3, preferably 2:1-1:2, more preferably 1:1 or 1:

2. 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] A method for preparing pharmaceutically acceptable salts of oct-8-yl)prop-2-en-1-one, including 1-(lac-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 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. 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-(l-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 methanesulfonic acid is 1:

1. A methanesulfonate I crystal form of a compound of formula 1, characterized in that, The X-ray powder diffraction pattern, expressed as a diffraction angle 2θ, shows characteristic peaks at 12.785, 14.363, 18.248, 19.608, 20.315, and 25.404, with preferred peaks at 8.311, 12.785, 14.363, 15.220, 17.817, 18.248, 19.318, 19.608, 20.315, 21.697, 22.256, and 25. Characteristic peaks are present at 0.404 and 28.858, and more preferably 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. The crystal form according to claim 5 is characterized in that, The X-ray powder diffraction pattern expressed in terms of the diffraction angle 2θ is shown in Figure 8. A method for preparing the crystal form as described in claim 5 or 6, wherein the method comprises: dissolving the compound of formula 1 in acetone, adding an aqueous solution of methanesulfonic acid, and stirring. 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] p-Toluenesulfonate of oct-8-yl)prop-2-en-1-one, 1-(lac-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 p-toluenesulfonic acid is 1:

1. A p-toluenesulfonate I crystal form of a compound of formula 1, characterized in that, The X-ray powder diffraction pattern, expressed as a diffraction angle 2θ, has characteristic peaks at 6.708, 9.145, 15.275, 17.217, 20.971, and 22.499, with preferred peaks at 6.708, 8.935, 9.145, 13.450, 15.275, 16.934, 17.217, 18.123, 18.948, 20.971, and 22. Characteristic peaks are found at 499 and 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. The crystal form according to claim 9 is characterized in that, The X-ray powder diffraction pattern expressed in terms of the diffraction angle 2θ is shown in Figure 11. A method for preparing the crystal form as described in claim 9 or 10, wherein the method comprises: dissolving the compound of formula 1 in solvent V, adding an aqueous solution of p-toluenesulfonic acid, and stirring, wherein solvent V is selected from 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). According to any one of claims 5-6 and 9-10, the 2θ angle error range is ±0.

20. A pharmaceutical composition comprising, as described in any one of claims 1, 2, 4, and 8, 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 the crystal form as described in any one of claims 5-6, 9-10, and optionally a pharmaceutically acceptable excipient. A method for preparing a pharmaceutical composition, comprising the following steps: The 1-(intra-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 the step of mixing the crystal form and pharmaceutically acceptable excipient as described in any one of claims 5-6, 9-10. According to any one of claims 1, 2, 4, and 8, 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 pharmaceutically acceptable salt of oct-8-yl)prop-2-en-1-one, or the crystal form according to any one of claims 5-6, 9-10, or the use of the pharmaceutical composition according to claim 13 in the preparation of a HER2 inhibitor. According to any one of claims 1, 2, 4, and 8, 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 pharmaceutically acceptable salt of oct-8-yl)prop-2-en-1-one, or the crystal form according to any one of claims 5-6, 9-10, or the use of the pharmaceutical composition according to claim 13 in the preparation of a medicament for treating and / or preventing cancer.

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