Polymorphs of an EGFR inhibitor

Abstract

Provided are a compound of formula (A) N-(6-((5-bromo-2-((6-isopropyl-8-methoxy-3-methyl-3,4,5,6-tetrahydrobenzo[b]pyrazolo[4,3-d]azepin-9-yl)amino)-pyrimidin-4-yl)amino)-quinoxalin-5-yl)methanesulfonamide, a compound of formula (I), and polymorphs thereof, wherein the provided crystal forms have good chemical stability, physical stability, and low hygroscopicity, are less affected by heat, humidity, and light, and are convenient to store and formulate.

Description

[0001] This application claims priority to Chinese Patent Application No. 202111197313.7, No. 202111196875.X, and No. 202111197957.6, both filed on October 14, 2021, and the full text of the aforementioned Chinese patent applications is incorporated herein by reference. Technical Field

[0002] This invention discloses multiple crystal forms of an EGFR inhibitor, their preparation methods, and their applications in cancer treatment. Background Technology

[0003] EGFR, or epidermal growth factor receptor, is widely distributed on the surface of mammalian epithelial cells, fibroblasts, glial cells, and other cells. The EGFR signaling pathway plays a crucial role in physiological processes such as cell growth, proliferation, and differentiation. EGFR mutations are also one of the most common mutation types in NSCLC patients, especially in Asian populations, accounting for 40%–50%. Therefore, EGFR has always been one of the most popular targets in drug development.

[0004] Currently, marketed EGFR inhibitors are classified into first, second, and third generations. First-generation inhibitors are reversible targeted drugs, such as gefitinib, erlotinib, and icotinib. Second-generation inhibitors are irreversible targeted drugs, such as afatinib and dacomitinib. While first- and second-generation targeted drugs are highly effective, most patients develop resistance after 1-2 years of use. Among patients with EGFR inhibitor resistance, 50% of resistance is related to the T790M mutation. The third-generation EGFR targeted drug osimertinib can overcome tumor resistance caused by the T790M mutation, bringing better survival benefits to more lung cancer patients. However, third-generation targeted drugs inevitably develop resistance, primarily due to the C797S mutation. The C797S mutation manifests as a cysteine ​​residue mutation to a serine residue. This mutation disrupts the binding of the EGFR protein to third-generation targeted drugs, thus failing to prevent EGFR protein phosphorylation and activation of downstream signaling pathways. Currently, there are no mature treatment options for the two main cis-triple mutations that occur after osimertinib resistance: Del19 / T790M / C797S and L858R / T790M / C797S, and the clinical need is urgent.

[0005] The applicant disclosed a small-molecule EGFR inhibitor targeting the C797S mutation in patent PCT / CN2021 / 086941, the structure of which is shown in formula (A), and its chemical name is N-(6-((5-bromo-2-((6-isopropyl-8-methoxy-3-methyl-3,4,5,6-tetrahydrobenzo[b]pyrazolo[4,3-d]aza-9-yl)amino)-pyrimidin-4-yl)amino)-quinoxalin-5-yl)methanesulfonamide. This small-molecule inhibitor has good kinase inhibitory activity and anti-proliferative activity, and at the same time, it has shown good anti-tumor activity and tolerability in mouse models, and is expected to be developed into a clinical drug.

[0006] Summary of the Invention

[0007] This invention discloses a polymorph of an EGFR inhibitor, its preparation method, and its application in the treatment of cancer.

[0008] Specifically,

[0009] This invention provides crystal form I of compound (A) N-(6-((5-bromo-2-((6-isopropyl-8-methoxy-3-methyl-3,4,5,6-tetrahydrobenzo[b]pyrazolo[4,3-d]aza-9-yl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)methanesulfonamide, wherein the X-ray powder diffraction pattern of crystal form I has characteristic peaks at 2θ values ​​of 7.83, 13.85, 18.25, 20.22, and 24.37, with a 2θ error range of ±0.2°.

[0010] In some embodiments of the present invention, the X-ray powder diffraction pattern of the crystal form I has characteristic peaks at 2θ values ​​of 7.83, 9.86, 12.02, 12.42, 12.93, 13.20, 13.85, 15.68, 18.25, 20.22, 20.64, 21.82, 22.92, 24.37, and 26.48, with a 2θ error range of ±0.2°.

[0011] In some embodiments of the present invention, the X-ray powder diffraction pattern of the crystal form I described above has characteristic peaks at 2θ values ​​of 5.84, 7.03, 7.83, 9.86, 10.96, 12.02, 12.42, 12.93, 13.20, 13.85, 14.60, 14.94, 15.68, 16.15, 17.73, 18.25, 18.86, 19.44, 20.22, 20.64, 21.01, 21.21, 21.82, 22.36, 22.92, 24.37, 26.48, 27.67, and 28.73, with a 2θ error range of ±0.2°.

[0012] In some embodiments of the present invention, the X-ray powder diffraction pattern of the above-mentioned crystal form I is as follows: Figure 1 As shown.

[0013] In some embodiments of the present invention, the above-mentioned crystal form I has a characteristic peak in its DSC spectrum at around 212°C.

[0014] In some embodiments of the present invention, the above-mentioned crystal form I has a characteristic peak in its DSC spectrum at around 261°C.

[0015] In some embodiments of the present invention, the TGA-DSC spectrum of the above-mentioned crystal form I is basically as follows: Figure 18 As shown.

[0016] In some embodiments of the present invention, the XRPD diffraction peak analysis data of crystal form I of the above formula (A) are shown in Table 1.

[0017] Table 1 shows the XRPD diffraction peak analysis data for crystal form I of compound (A).

[0018]

[0019]

[0020] The present invention also provides crystal form II of compound (A) N-(6-((5-bromo-2-((6-isopropyl-8-methoxy-3-methyl-3,4,5,6-tetrahydrobenzo[b]pyrazolo[4,3-d]aza-9-yl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)methanesulfonamide, wherein the X-ray powder diffraction pattern of crystal form II has characteristic peaks at 2θ values ​​of 5.84, 9.92, 12.33, 15.90, 22.89, and 25.67, with a 2θ error range of ±0.2°.

[0021] In some embodiments of the present invention, the above-mentioned crystal form II has characteristic peaks in its X-ray powder diffraction pattern at 2θ values ​​of 5.84, 9.92, 10.40, 12.33, 13.81, 14.63, 15.90, 19.29, 20.28, 22.51, 22.89, 23.79, 24.23, 25.36, 25.67, and 26.09, with a 2θ error range of ±0.2°.

[0022] In some embodiments of the present invention, the X-ray powder diffraction pattern of the crystal form II described above has characteristic peaks at 2θ values ​​of 5.84, 9.92, 10.40, 11.16, 11.78, 12.33, 13.81, 14.63, 15.02, 15.90, 17.13, 17.60, 19.29, 20.28, 20.67, 21.34, 21.83, 22.16, 22.51, 22.89, 23.40, 23.79, 24.23, 25.36, 25.67, 26.09, 27.22, 29.90, and 30.67, with a 2θ error range of ±0.2°.

[0023] In some embodiments of the present invention, the X-ray powder diffraction pattern of the above-mentioned crystal form II is as follows: Figure 2 As shown.

[0024] In some embodiments of the present invention, the above-mentioned crystal form II has a characteristic peak in its DSC spectrum at around 262°C.

[0025] In some embodiments of the present invention, the above-mentioned crystal form II, the TGA-DSC spectrum of the crystal form is as follows Figure 19 As shown.

[0026] In some embodiments of the present invention, the XRPD diffraction peak analysis data of crystal form II of the above formula (A) are shown in Table 2.

[0027] Table 2 shows the XRPD diffraction peak analysis data for crystal form II of compound (A).

[0028]

[0029]

[0030] The present invention also provides a crystal form III of compound (A) N-(6-((5-bromo-2-((6-isopropyl-8-methoxy-3-methyl-3,4,5,6-tetrahydrobenzo[b]pyrazolo[4,3-d]aza-9-yl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)methanesulfonamide, wherein the X-ray powder diffraction pattern of the crystal form III has characteristic peaks at 2θ values ​​of 5.49, 11.05, 21.77, 22.30, and 24.36, with a 2θ error range of ±0.2°.

[0031] In some embodiments of the present invention, the above-mentioned crystal form III has characteristic peaks in its X-ray powder diffraction pattern at 2θ values ​​of 5.49, 9.10, 9.98, 11.05, 14.09, 15.47, 16.64, 19.34, 20.41, 21.36, 21.77, 22.30, 24.36, 26.68, and 26.96, with a 2θ error range of ±0.2°.

[0032] In some embodiments of the present invention, the above-mentioned crystal form III has characteristic peaks in its X-ray powder diffraction pattern at 2θ values ​​of 5.49, 9.10, 9.98, 10.30, 11.05, 12.11, 14.09, 15.47, 16.41, 16.64, 17.58, 18.37, 19.34, 20.41, 21.36, 21.77, 22.30, 24.36, 25.12, 25.65, 26.68, 26.96, 27.39, 28.18, and 31.91, with a 2θ error range of ±0.2°.

[0033] In some embodiments of the present invention, the X-ray powder diffraction pattern of the above-mentioned crystal form III is as follows: Figure 3 As shown.

[0034] In some embodiments of the present invention, the above-mentioned crystal form III has a characteristic peak in its DSC spectrum at around 253°C.

[0035] In some embodiments of the present invention, the above-mentioned crystal form III has a characteristic peak in its DSC spectrum at around 264°C.

[0036] In some embodiments of the present invention, the TGA-DSC spectrum of the above-mentioned crystal form III is essentially as follows: Figure 20 As shown.

[0037] In some embodiments of the present invention, the XRPD diffraction peak analysis data of crystal form III of the above formula (A) are shown in Table 3.

[0038] Table 3 shows the XRPD diffraction peak analysis data for crystal form III of compound (A).

[0039]

[0040]

[0041] This invention provides crystal form IV of compound (A) N-(6-((5-bromo-2-((6-isopropyl-8-methoxy-3-methyl-3,4,5,6-tetrahydrobenzo[b]pyrazolo[4,3-d]aza-9-yl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)methanesulfonamide, wherein the X-ray powder diffraction pattern of crystal form IV has characteristic peaks at 2θ values ​​of 5.68, 10.42, 21.64, 22.20, and 24.55, with a 2θ error range of ±0.2°.

[0042] In some embodiments of the present invention, the X-ray powder diffraction pattern of the above-mentioned crystal form IV has characteristic peaks at 2θ values ​​of 5.68, 8.33, 9.17, 10.42, 11.52, 12.23, 16.34, 16.79, 17.69, 17.95, 19.56, 20.16, 21.64, 22.20, 24.55, 26.85, and 27.14, with a 2θ error range of ±0.2°.

[0043] In some embodiments of the present invention, the X-ray powder diffraction pattern of the above-mentioned crystal form IV has characteristic peaks at 2θ values ​​of 5.68, 8.33, 9.17, 10.42, 10.72, 11.52, 12.23, 13.05, 13.84, 16.34, 16.79, 17.22, 17.69, 17.95, 18.92, 19.56, 20.16, 21.27, 21.64, 22.20, 23.00, 23.36, 23.80, 24.55, 25.55, 25.99, 26.85, 27.14, and 28.01, with a 2θ error range of ±0.2°.

[0044] In some embodiments of the present invention, the X-ray powder diffraction pattern of the above-mentioned crystal form IV is as follows: Figure 4 As shown.

[0045] In some embodiments of the present invention, the TGA-DSC spectrum of the above-mentioned crystal form IV is basically as follows: Figure 21 As shown.

[0046] In some embodiments of the present invention, the XRPD diffraction peak analysis data of crystal form IV of the above formula (A) compound are shown in Table 4.

[0047] Table 4 shows the XRPD diffraction peak analysis data for crystal form IV of compound (A).

[0048]

[0049]

[0050] The present invention also provides a crystal form V of compound (A) N-(6-((5-bromo-2-((6-isopropyl-8-methoxy-3-methyl-3,4,5,6-tetrahydrobenzo[b]pyrazolo[4,3-d]aza-9-yl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)methanesulfonamide, wherein the X-ray powder diffraction pattern of the crystal form V has characteristic peaks at 2θ values ​​of 5.57, 8.50, 10.03, 14.23, 20.00, and 22.60, with a 2θ error range of ±0.2°.

[0051] In some embodiments of the present invention, the above-mentioned crystal form V has characteristic peaks in its X-ray powder diffraction pattern at 2θ values ​​of 5.57, 8.50, 10.03, 14.23, 16.46, 18.72, 20.00, 21.38, 22.13, 22.60, 22.85, 23.95, 24.57, 26.17, 26.48, and 30.81, with a 2θ error range of ±0.2°.

[0052] In some embodiments of the present invention, the X-ray powder diffraction pattern of the crystal form V has characteristic peaks at 2θ values ​​of 4.21, 5.57, 8.50, 9.42, 10.03, 10.65, 11.86, 12.81, 13.43, 14.23, 15.83, 16.46, 17.32, 17.57, 18.34, 18.72, 19.12, 20.00, 20.66, 21.38, 22.13, 22.60, 22.85, 23.52, 23.95, 24.22, 24.57, 26.17, 26.48, 27.31, 27.93, 28.51, 30.13, and 30.81, with a 2θ error range of ±0.2°.

[0053] In some embodiments of the present invention, the X-ray powder diffraction pattern of the above-mentioned crystal form V is as follows: Figure 5 As shown.

[0054] In some embodiments of the present invention, the TGA-DSC spectrum of the above-mentioned crystal form V is basically as follows: Figure 22 As shown.

[0055] In some embodiments of the present invention, the XRPD diffraction peak analysis data of the crystal form V of the above formula (A) are shown in Table 5.

[0056] Table 5 shows the XRPD diffraction peak analysis data for crystal form V of compound (A).

[0057]

[0058]

[0059]

[0060] The present invention also provides a crystalline form VI of the compound of formula (A) N-(6-((5-bromo-2-((6-isopropyl-8-methoxy-3-methyl-3,4,5,6-tetrahydrobenzo[b]pyrazolo[4,3-d]aza-9-yl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)methanesulfonamide, wherein the X-ray powder diffraction pattern of the crystalline form VI has characteristic peaks at 2θ values ​​of 6.82, 9.61, 12.32, 13.75, 14.10, and 20.52, with a 2θ error range of ±0.2°.

[0061] In some embodiments of the present invention, the X-ray powder diffraction pattern of the crystal form VI has characteristic peaks at 2θ values ​​of 5.84, 6.82, 8.87, 9.61, 12.32, 12.48, 13.23, 13.75, 14.10, 15.24, 16.07, 18.43, 20.52, 21.05, 22.40, 22.89, 23.71, 24.47, and 25.28, with a 2θ error range of ±0.2°.

[0062] In some embodiments of the present invention, the X-ray powder diffraction pattern of the above-mentioned crystal form VI has characteristic peaks at 2θ values ​​of 5.84, 6.82, 8.87, 9.10, 9.61, 12.32, 12.48, 13.23, 13.75, 14.10, 15.24, 16.07, 17.84, 18.43, 19.70, 20.52, 21.05, 21.52, 22.40, 22.89, 23.71, 24.47, 24.87, 25.28, 26.76, 27.31, 27.87, and 30.50, with a 2θ error range of ±0.2°.

[0063] In some embodiments of the present invention, the X-ray powder diffraction pattern of the above-mentioned crystal form VI is as follows: Figure 6 As shown.

[0064] In some embodiments of the present invention, the TGA-DSC spectrum of the above-mentioned crystal form VI is basically as follows: Figure 23 As shown.

[0065] In some embodiments of the present invention, the XRPD diffraction peak analysis data of the crystal form VI of the above formula (A) are shown in Table 6.

[0066] Table 6 shows the XRPD diffraction peak analysis data for crystal form VI of compound (A).

[0067]

[0068]

[0069] The present invention also provides a crystalline form VII of the compound of formula (A) N-(6-((5-bromo-2-((6-isopropyl-8-methoxy-3-methyl-3,4,5,6-tetrahydrobenzo[b]pyrazolo[4,3-d]aza-9-yl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)methanesulfonamide, wherein the X-ray powder diffraction pattern of the crystalline form VII has characteristic peaks at 2θ values ​​of 14.54, 15.24, 17.48, 20.15, and 24.08, with a 2θ error range of ±0.2°.

[0070] In some embodiments of the present invention, the above-mentioned crystal form VII has characteristic peaks in its X-ray powder diffraction pattern at 2θ values ​​of 10.10, 10.30, 11.33, 12.20, 14.54, 15.24, 17.48, 17.66, 18.88, 20.15, 21.12, 22.99, 23.33, 23.78, 24.08, and 26.67, with a 2θ error range of ±0.2°.

[0071] In some embodiments of the present invention, the X-ray powder diffraction pattern of the crystal form VII described above has characteristic peaks at 2θ values ​​of 7.23, 8.80, 10.10, 10.30, 11.33, 12.20, 12.61, 13.23, 14.54, 15.24, 15.83, 16.87, 17.48, 17.66, 18.35, 18.88, 20.15, 21.12, 22.61, 22.99, 23.33, 23.78, 24.08, 24.61, 26.67, 27.87, 29.50, and 30.62, with a 2θ error range of ±0.2°.

[0072] In some embodiments of the present invention, the X-ray powder diffraction pattern of the above-mentioned crystal form VII is as follows: Figure 7 As shown.

[0073] In some embodiments of the present invention, the TGA-DSC spectrum of the above-mentioned crystal form VII is essentially as follows: Figure 24 As shown.

[0074] In some embodiments of the present invention, the XRPD diffraction peak analysis data of crystal form VII of the above formula (A) are shown in Table 7.

[0075] Table 7 shows the XRPD diffraction peak analysis data for crystal form VII of compound (A).

[0076]

[0077]

[0078] The present invention also provides a crystal form VIII of compound (A) N-(6-((5-bromo-2-((6-isopropyl-8-methoxy-3-methyl-3,4,5,6-tetrahydrobenzo[b]pyrazolo[4,3-d]aza-9-yl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)methanesulfonamide, wherein the X-ray powder diffraction pattern of the crystal form VIII has characteristic peaks at 2θ values ​​of 5.49, 13.58, 15.88, 21.11, and 22.48, with a 2θ error range of ±0.2°.

[0079] In some embodiments of the present invention, the above-mentioned crystal form VIII has characteristic peaks in its X-ray powder diffraction pattern at 2θ values ​​of 5.49, 10.08, 11.07, 11.74, 13.58, 13.77, 15.88, 16.99, 20.76, 21.11, 21.42, 22.48, 25.00, 25.63, 26.98, and 30.73, with a 2θ error range of ±0.2°.

[0080] In some embodiments of the present invention, the above-mentioned crystal form VIII has characteristic peaks in its X-ray powder diffraction pattern at 2θ values ​​of 4.47, 5.49, 9.00, 9.85, 10.08, 11.07, 11.74, 12.37, 13.03, 13.58, 13.77, 14.92, 15.88, 16.68, 16.99, 17.44, 18.59, 19.91, 20.76, 21.11, 21.42, 22.48, 23.57, 23.73, 25.00, 25.32, 25.63, 26.98, 27.79, 29.80, and 30.73, with a 2θ error range of ±0.2°.

[0081] In some embodiments of the present invention, the X-ray powder diffraction pattern of the above-mentioned crystal form VIII is as follows: Figure 8 As shown.

[0082] In some embodiments of the present invention, the TGA-DSC spectrum of the above-mentioned crystal form VIII is essentially as follows: Figure 25 As shown.

[0083] In some embodiments of the present invention, the XRPD diffraction peak analysis data of crystal form VIII of the above formula (A) are shown in Table 8.

[0084] Table 8 shows the XRPD diffraction peak analysis data for crystal form VIII of compound (A).

[0085]

[0086]

[0087] The present invention also provides a crystalline form IX of the compound of formula (A) N-(6-((5-bromo-2-((6-isopropyl-8-methoxy-3-methyl-3,4,5,6-tetrahydrobenzo[b]pyrazolo[4,3-d]aza-9-yl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)methanesulfonamide, wherein the X-ray powder diffraction pattern of the crystalline form IX has characteristic peaks at 2θ values ​​of 5.79, 8.84, 11.66, 21.96, and 24.74, with a 2θ error range of ±0.2°.

[0088] In some embodiments of the present invention, the above-mentioned crystal form IX has characteristic peaks in its X-ray powder diffraction pattern at 2θ values ​​of 5.79, 8.14, 8.84, 9.90, 11.66, 15.61, 17.12, 17.59, 19.93, 21.11, 21.74, 21.96, 23.48, 24.74, 25.13, 26.69, and 27.22, with a 2θ error range of ±0.2°.

[0089] In some embodiments of the present invention, the above-mentioned crystal form IX has characteristic peaks in its X-ray powder diffraction pattern at 2θ values ​​of 5.79, 8.14, 8.84, 9.04, 9.90, 11.66, 15.61, 17.12, 17.59, 17.90, 18.23, 18.61, 19.68, 19.93, 20.82, 21.11, 21.74, 21.96, 23.48, 24.39, 24.74, 25.13, 26.42, 26.69, 27.22, and 30.33, with a 2θ error range of ±0.2°.

[0090] In some embodiments of the present invention, the X-ray powder diffraction pattern of the above-mentioned crystal form IX is as follows: Figure 9 As shown.

[0091] In some embodiments of the present invention, the TGA-DSC spectrum of the above-mentioned crystal form IX is basically as follows: Figure 26 As shown.

[0092] In some embodiments of the present invention, the XRPD diffraction peak analysis data of the crystal form IX of the above formula (A) are shown in Table 9.

[0093] Table 9 shows the XRPD diffraction peak analysis data for crystal form IX of compound (A).

[0094]

[0095]

[0096] The present invention also provides a crystalline form XII of compound (A) N-(6-((5-bromo-2-((6-isopropyl-8-methoxy-3-methyl-3,4,5,6-tetrahydrobenzo[b]pyrazolo[4,3-d]aza-9-yl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)methanesulfonamide, wherein the X-ray powder diffraction pattern of crystalline form XII has characteristic peaks at 2θ values ​​of 5.83, 6.80, 20.48, 24.92, and 27.49, with a 2θ error range of ±0.2°.

[0097] In some embodiments of the present invention, the above-mentioned crystal form XII has characteristic peaks in its X-ray powder diffraction pattern at 2θ values ​​of 5.83, 6.80, 9.50, 11.84, 13.62, 14.23, 14.54, 16.72, 17.50, 18.42, 20.48, 20.85, 21.40, 23.35, 24.92, and 27.49, with a 2θ error range of ±0.2°.

[0098] In some embodiments of the present invention, the above-mentioned crystal form XII has characteristic peaks in its X-ray powder diffraction pattern at 2θ values ​​of 5.83, 6.80, 8.40, 9.50, 9.71, 10.82, 11.84, 12.90, 13.62, 14.23, 14.54, 16.72, 17.50, 18.42, 19.66, 20.48, 20.85, 21.40, 21.81, 23.35, 23.95, 24.92, 26.62, 27.49, 31.17, 32.45, and 33.62, with a 2θ error range of ±0.2°.

[0099] In some embodiments of the present invention, the X-ray powder diffraction pattern of the above-mentioned crystal form XII is as follows: Figure 10 As shown.

[0100] In some embodiments of the present invention, the TGA-DSC spectrum of the above-mentioned crystal form XII is basically as follows: Figure 27 As shown.

[0101] In some embodiments of the present invention, the XRPD diffraction peak analysis data of the crystal form XII of the above formula (A) are shown in Table 10.

[0102] Table 10 shows the XRPD diffraction peak analysis data for crystal form XII of compound (A).

[0103]

[0104]

[0105] The present invention also provides a crystalline form XIV of compound (A) N-(6-((5-bromo-2-((6-isopropyl-8-methoxy-3-methyl-3,4,5,6-tetrahydrobenzo[b]pyrazolo[4,3-d]aza-9-yl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)methanesulfonamide, wherein the X-ray powder diffraction pattern of crystalline form XIV has characteristic peaks at 2θ values ​​of 5.86, 11.73, 23.56, 29.55, and 35.65, with a 2θ error range of ±0.2°.

[0106] In some embodiments of the present invention, the above-mentioned crystal form XIV has characteristic peaks in its X-ray powder diffraction pattern at 2θ values ​​of 5.86, 11.73, 13.85, 20.91, 22.32, 23.56, 24.69, 25.30, 26.72, 29.55, 33.09, 35.65, and 38.91, with a 2θ error range of ±0.2°.

[0107] In some embodiments of the present invention, the X-ray powder diffraction pattern of the above-mentioned crystal form XIV is as follows: Figure 11 As shown.

[0108] In some embodiments of the present invention, the TGA-DSC spectrum of the above-mentioned crystal form XIV is basically as follows: Figure 28 As shown.

[0109] In some embodiments of the present invention, the XRPD diffraction peak analysis data of the crystal form XIV of the above formula (A) are shown in Table 11.

[0110] Table 11 shows the XRPD diffraction peak analysis data for crystal form XIV of compound (A).

[0111]

[0112]

[0113] This invention also provides compounds of formula (I),

[0114]

[0115] The present invention provides a crystal form A of the compound of formula (I), wherein the X-ray powder diffraction pattern of the crystal form A has characteristic peaks at 2θ values ​​of 7.38, 8.13, 12.62, 20.14, 21.41, and 23.72, and the 2θ error range is ±0.2°.

[0116] In some embodiments of the present invention, the above-mentioned crystal form A has characteristic peaks in its X-ray powder diffraction pattern at 2θ values ​​of 7.38, 7.69, 8.13, 12.62, 14.12, 14.95, 17.43, 18.79, 20.14, 20.32, 21.41, 23.72, 26.47, and 28.26, with a 2θ error range of ±0.2°.

[0117] In some embodiments of the present invention, the X-ray powder diffraction pattern of the aforementioned crystal form A has characteristic peaks at 2θ values ​​of 7.38, 7.69, 8.13, 9.31, 12.62, 14.12, 14.95, 15.96, 17.43, 18.44, 18.79, 19.09, 19.57, 19.93, 20.14, 20.32, 21.41, 22.66, 23.72, 25.08, 25.53, 26.47, 28.26, 30.02, and 31.91, with a 2θ error range of ±0.2°.

[0118] In some embodiments of the present invention, the X-ray powder diffraction pattern of the above-mentioned crystal form A is as follows: Figure 12 As shown.

[0119] In some embodiments of the present invention, the TGA-DSC spectrum of the above-mentioned crystal form A is basically as follows: Figure 29 As shown.

[0120] In some embodiments of the present invention, the XRPD diffraction peak analysis data of crystal form A of the above formula (I) are shown in Table 12.

[0121] Table 12 XRPD diffraction peak analysis data of crystal form A of compound (I)

[0122]

[0123]

[0124] The present invention also provides a crystal form B of the compound of formula (I), wherein the X-ray powder diffraction pattern of the crystal form B has characteristic peaks at 2θ values ​​of 5.89, 7.25, 9.37, 22.49, 25.45, and 27.05, and the 2θ error range is ±0.2°.

[0125] In some embodiments of the present invention, the above-mentioned crystal form B has characteristic peaks in its X-ray powder diffraction pattern at 2θ values ​​of 5.89, 6.43, 7.25, 9.37, 12.42, 12.95, 15.16, 17.37, 17.76, 18.64, 18.89, 21.14, 21.57, 21.99, 22.49, 25.45, and 27.05, with a 2θ error range of ±0.2°.

[0126] In some embodiments of the present invention, the X-ray powder diffraction pattern of the aforementioned crystal form B has characteristic peaks at 2θ values ​​of 5.89, 6.43, 7.25, 8.35, 9.37, 12.42, 12.95, 13.29, 14.04, 15.16, 15.84, 16.23, 16.83, 17.37, 17.76, 18.64, 18.89, 20.12, 21.14, 21.57, 21.99, 22.49, 22.84, 23.63, 24.58, 25.45, 27.05, and 30.01, with a 2θ error range of ±0.2°.

[0127] In some embodiments of the present invention, the X-ray powder diffraction pattern of the above-mentioned crystal form B is as follows: Figure 13 As shown.

[0128] In some embodiments of the present invention, the TGA-DSC spectrum of the above-mentioned crystal form B is basically as follows: Figure 30 As shown.

[0129] In some embodiments of the present invention, the XRPD diffraction peak analysis data of the crystal form B of the above formula (I) are shown in Table 13.

[0130] Table 13 XRPD diffraction peak analysis data for crystal form B of compound (I)

[0131]

[0132]

[0133] The present invention also provides a crystal form C of the compound of formula (I), wherein the X-ray powder diffraction pattern of the crystal form C has characteristic peaks at 2θ values ​​of 5.85, 12.41, 17.76, 22.48, and 27.03, and the 2θ error range is ±0.2°.

[0134] In some embodiments of the present invention, the X-ray powder diffraction pattern of the crystal form C has characteristic peaks at 2θ values ​​of 5.85, 9.35, 12.41, 15.82, 17.36, 17.76, 18.64, 18.88, 21.12, 21.57, 21.97, 22.48, 22.87, 23.73, 25.42, and 27.03, with a 2θ error range of ±0.2°.

[0135] In some embodiments of the present invention, the X-ray powder diffraction pattern of the above-mentioned crystal form C has characteristic peaks at 2θ values ​​of 5.85, 9.35, 11.75, 12.41, 13.18, 13.27, 14.04, 14.83, 15.07, 15.82, 16.22, 17.36, 17.76, 18.64, 18.88, 20.11, 21.12, 21.40, 21.57, 21.97, 22.48, 22.87, 23.73, 25.42, 27.03, 27.84, 28.32, and 29.96, with a 2θ error range of ±0.2°.

[0136] In some embodiments of the present invention, the X-ray powder diffraction pattern of the above-mentioned crystal form C is as follows: Figure 14 As shown.

[0137] In some embodiments of the present invention, the TGA-DSC spectrum of the above-mentioned crystal form C is basically as follows: Figure 31 As shown.

[0138] In some embodiments of the present invention, the XRPD diffraction peak analysis data of the crystal form C of the above formula (I) compound are shown in Table 14.

[0139] Table 14 XRPD diffraction peak analysis data for crystal form C of compound (I)

[0140]

[0141]

[0142] The present invention also provides a crystal form D of the compound of formula (I), wherein the X-ray powder diffraction pattern of the crystal form D has characteristic peaks at 2θ values ​​of 5.55, 13.03, 16.73, 22.48, and 24.17, and the 2θ error range is ±0.2°.

[0143] In some embodiments of the present invention, the crystal form D described above has characteristic peaks in its X-ray powder diffraction pattern at 2θ values ​​of 5.55, 11.16, 12.39, 12.70, 13.03, 13.42, 14.74, 16.73, 18.11, 20.96, 22.48, 23.33, 23.83, 24.17, 26.05, and 34.02, with a 2θ error range of ±0.2°.

[0144] In some embodiments of the present invention, the above-mentioned crystal form D has characteristic peaks in its X-ray powder diffraction pattern at 2θ values ​​of 5.55, 7.23, 8.70, 10.72, 11.16, 12.39, 12.70, 13.03, 13.42, 14.54, 14.74, 15.51, 16.32, 16.73, 18.11, 20.43, 20.96, 21.37, 22.48, 23.33, 23.83, 24.17, 25.62, 26.05, 26.42, 27.77, 27.93, 28.80, 32.72, 33.41, and 34.02, with a 2θ error range of ±0.2°.

[0145] In some embodiments of the present invention, the X-ray powder diffraction pattern of the above-mentioned crystal form D is as follows: Figure 15 As shown.

[0146] In some embodiments of the present invention, the crystal form D exhibits an endothermic peak at approximately 250°C and 256°C on its DSC spectrum. In some embodiments of the present invention, the crystal form D exhibits a 5.33% weight loss at approximately 220°C on its TGA spectrum.

[0147] In some embodiments of the present invention, the crystal form D described above exhibits a weight loss of 5.33% at approximately 150-225°C on its TGA spectrum.

[0148] In some embodiments of the present invention, the TGA-DSC spectrum of the above-mentioned crystal form D is basically as follows: Figure 32 As shown.

[0149] In some embodiments of the present invention, the XRPD diffraction peak analysis data of the crystal form D of the above formula (I) compound are shown in Table 15.

[0150] Table 15 XRPD diffraction peak analysis data for crystal form D of compound (I)

[0151]

[0152]

[0153] The present invention also provides a pharmaceutical composition comprising the above-described compound of formula (A) or formula (I) and a pharmaceutically acceptable carrier.

[0154] The present invention also provides a pharmaceutical composition comprising any one of the above-described crystal forms and a pharmaceutically acceptable carrier.

[0155] The present invention also provides the use of any of the above-described crystal forms or the above-described pharmaceutical compositions in the preparation of a medicament for treating EGFR mutation-mediated cancers.

[0156] The present invention also provides the use of any of the above-described crystal forms or the above-described pharmaceutical compositions in treating EGFR mutation-mediated cancers.

[0157] A drug for treating cancer, wherein the drug is any of the above-described crystal forms or a combination of the above-described drugs.

[0158] A drug for treating cancer EGFR mutation-mediated cancer, wherein the drug is any of the above-described crystal forms or a combination of the above-described drugs.

[0159] In some embodiments of the present invention, the aforementioned cancers include lymphoma, non-Hodgkin's lymphoma, ovarian cancer, cervical cancer, prostate cancer, colorectal cancer, breast cancer, pancreatic cancer, glioma, glioblastoma, melanoma, leukemia, gastric cancer, endometrial cancer, lung cancer, hepatocellular carcinoma, gastric cancer, gastrointestinal stromal tumor (GIST), acute myeloid leukemia (AML), cholangiocarcinoma, renal cancer, thyroid cancer, anaplastic large cell lymphoma, mesothelioma, multiple myeloma, and melanoma.

[0160] In some embodiments of the present invention, the aforementioned cancer is lung cancer. The present invention also provides the use of compounds of formula (A), formula (I), any of the aforementioned crystal forms, or the aforementioned pharmaceutical compositions in the preparation of EGFR inhibitors.

[0161] The present invention also provides a method for inhibiting EGFR mutations in patients in need, comprising administering to the patient a compound of formula (A), formula (I), any of the crystal forms described above, or the pharmaceutical composition described above.

[0162] The present invention also provides a method for inhibiting EGFR mutations in a biological sample, comprising administering to the patient a compound of formula (A), formula (I), any of the crystal forms described above, or the pharmaceutical composition described above.

[0163] In some embodiments of the present invention, the aforementioned EGFR mutations include L858R, T790M, C797S, and Del19 mutations.

[0164] In some embodiments of the present invention, the above-mentioned EGFR mutations include the L858R / T790M / C797S triple mutation and the Del19 / T790M / C797S triple mutation.

[0165] Technical effect

[0166] The crystal form in this application has good chemical stability, physical stability, and low hygroscopicity. It is less affected by heat, humidity, and light, making it easy to store and formulate.

[0167] Definitions and Explanations

[0168] Unless otherwise stated, the following terms and phrases used herein are intended to have the following meanings. A particular term or phrase should not be considered uncertain or unclear unless specifically defined, but should be understood in its ordinary sense.

[0169] The term "around" typically refers to a variation within a range of 0.01% to 5% above or below a specified value, such as a variation within the range of 0.01%, 0.02%, 0.05%, 0.1%, 0.2%, 0.5%, 1%, 1.5%, 2%, 2.5%, 3%, 3.5%, 4%, 4.5%, or 5% above or below a specified value. For example, "around 212°C" could include 212 ± 0.15°C, and "around 264°C" could include 264 ± 0.38°C.

[0170] The term "pharmaceutical-grade carrier" refers to a medium generally acceptable in the art for delivering a bioactive pharmaceutical agent to animals, particularly mammals. Depending on the route of administration and dosage form, this includes, for example, adjuvants, excipients, or excipients such as diluents, preservatives, fillers, flow modifiers, disintegrants, wetting agents, emulsifiers, suspending agents, sweeteners, flavoring agents, aromatizers, antibacterial agents, antifungal agents, lubricants, and dispersants. Pharmaceutically acceptable carriers are formulated based on a multitude of factors, within the scope of those skilled in the art. These include, but are not limited to, the type and nature of the active pharmaceutical agent being formulated, the recipient to whom the composition containing the pharmaceutical agent is to be administered, the intended route of administration of the composition, and the target therapeutic indication. Pharmaceutically acceptable carriers include both aqueous and non-aqueous media, as well as various solid and semi-solid dosage forms. In addition to the active pharmaceutical agent, such carriers include many different components and additives, and the inclusion of such additional components in the formulation for various reasons (e.g., stabilizing active pharmaceutical agents, binders, etc.) is well known to those skilled in the art.

[0171] As is known in the art, X-ray powder diffraction patterns have one or more measurement errors due to minute variations in measurement conditions. The structures of the crystals, crystalline forms, or crystal types disclosed or claimed in this invention may exhibit similar but not identical analytical characteristics within a reasonable error range, depending on experimental conditions, purity, equipment, and other constant variables known to those skilled in the art. For example, the diffraction angle (2θ) in powder X-ray powder diffraction typically produces an error within ±0.20°. Therefore, this invention includes not only crystals with perfectly uniform diffraction angles in powder X-ray powder diffraction, but also crystals with uniform diffraction angles within an error range of ±0.20°. The crystalline form of compound A of this invention is not limited to crystals having the same X-ray powder diffraction pattern as shown in the accompanying drawings; any crystal having a substantially identical X-ray powder diffraction pattern as shown in the accompanying drawings is within the scope of this invention.

[0172] The text refers to "X-ray powder diffraction patterns that are substantially the same as those shown in the accompanying figures." It should be understood that the term "substantially the same" used in this context also indicates that the 2θ angle values ​​of the X-ray powder diffraction patterns may vary slightly due to inherent experimental variations accompanying these measurements, and both are of the same crystalline form.

[0173] It should be understood that different types of equipment or different test conditions may yield slightly different DSC spectra and endothermic transition temperature readings. These values ​​will be affected by compound purity, sample weight, heating rate, particle size, and the calibration and maintenance of the testing equipment. The maximum endothermic transition temperature of the crystal form can be within ±5.0 °C of the specific values ​​disclosed above.

[0174] This disclosure also uses thermogravimetric analysis (TGA) to analyze the relationship between the degree of decomposition, sublimation, or evaporation of the crystal form (weight loss) and temperature. It should be understood that the values ​​obtained for the same crystal form may have some error due to factors such as sample purity, particle size, different types of equipment, and different testing methods. The temperature at which the crystal form decomposes, sublimates, or evaporates can be within ±3.0℃ of the specific values ​​disclosed above, for example, within ±2.0℃.

[0175] The "stability" of a crystal form includes "chemical stability" and / or "physical stability." "Chemical stability" refers to the degree to which the crystal form undergoes degradation reactions under certain temperature, humidity, and light conditions; it reflects the stability of the crystal form under storage conditions. "Physical stability" refers to the degree to which the crystal form undergoes a solid-state transformation under certain specific conditions, such as under conditions of high temperature, high humidity, grinding, tableting, solvent removal, or solvent adsorption, transforming into another crystal form. Therefore, "physical stability" can, to some extent, reflect the stability of the crystal form during its use in formulations and other processes.

[0176] The crystalline structure of the present invention can be prepared by various methods, including crystallization or recrystallization from a suitable solvent, sublimation, growth from a melt, solid-state transformation from another phase, crystallization from a supercritical fluid, and jet spraying. Techniques for crystallizing or recrystallizing the crystalline structure from a solvent mixture include solvent evaporation, lowering the temperature of the solvent mixture, crystallization of a supersaturated solvent mixture of the molecule and / or salt, lyophilizing the solvent mixture, and adding an antisolvent to the solvent mixture.

[0177] The intermediate compounds of the present invention can be prepared by various synthetic methods known to those skilled in the art, including the specific embodiments listed below, embodiments formed by combining them with other chemical synthetic methods, and equivalent substitutions known to those skilled in the art. Preferred embodiments include, but are not limited to, the embodiments of the present invention.

[0178] In this embodiment of the invention, the title compound was named using Chemdraw to convert the compound structure. If there is a discrepancy between the compound name and the compound structure, the name can be determined by combining relevant information and reaction routes; if it cannot be confirmed by other means, the given compound structure shall prevail.

[0179] The compounds of the present invention can be prepared by a variety of synthetic methods known to those skilled in the art, including the specific embodiments listed below, embodiments formed by combining them with other chemical synthetic methods, and equivalent substitutions known to those skilled in the art. Preferred embodiments include, but are not limited to, the embodiments of the present invention.

[0180] Instruments and analytical methods:

[0181] 1. X-ray powder diffraction (XRPD)

[0182] Solid samples were analyzed using an X-ray powder diffractometer (Bruker D8 advance). The sample was placed on a zero-background single-crystal silicon sample tray, and the solid surface was gently pressed with a spatula to flatten the sample. XRPD measurement parameters are shown in Table 16-1.

[0183] Table 16-1 XRPD Test Parameters

[0184]

[0185]

[0186] Alternatively, solid samples can be analyzed using an X-ray powder diffractometer (X'Pert PRO). Take an appropriate amount of the fine powder of the sample, place it in the groove of the sample holder, and press it into a flat and dense plane using a glass slide. XRPD measurement parameters are shown in Table 16-2.

[0187] Table 16-2 XRPD Test Parameters

[0188] light source Cu target Scanning angle 3-40°(2θ) Scan speed 8° / min Phototube voltage / current 40KV / 40mA Diverging slit 1 / 8°

[0189] 2. Thermogravimetric analysis (TGA)

[0190] Thermogravimetric analysis (TGA) of solids was performed using a TA Instrument thermogravimetric analyzer. Approximately 1-5 mg of sample was placed in a peeled aluminum sample pan, heated according to the parameters listed in Table 17, and the data were analyzed using TRIOS.

[0191] Table 17 TGA Analysis Method Parameters

[0192]

[0193] 3. Differential Scanning Calorimetry (DSC)

[0194] The solid was analyzed by differential scanning calorimetry (DSC) using a TA Instruments differential scanning calorimeter. Approximately 1-3 mg of sample was accurately weighed and placed in a perforated aluminum sample pan. The sample was heated according to the parameters listed in Table 18-1, and the data were analyzed using TRIOS.

[0195] Table 18-1 Parameters of DSC Analysis Method

[0196] Sample tray Perforated aluminum disc Temperature range 25-300℃ heating rate 10℃ / min purge gas Nitrogen Flow rate 50 mL / min

[0197] Alternatively, a Mettler Toledo simultaneous thermal analyzer can be used to perform thermogravimetric-differential scanning calorimetry (TGC) analysis on solids. Take an appropriate amount of the sample with a small spoon and place it in a crucible, spreading it evenly. Weigh the sample and heat it according to the parameters listed in Table 18-2. Analyze the data using STARE.

[0198] Table 18-2 Parameters of TGA-DSC Analysis Method

[0199]

[0200]

[0201] 4. Dynamic moisture adsorption-desorption analysis (DVS)

[0202] The hygroscopicity of the samples was determined using a DVS Intrinsic dynamic moisture adsorption analyzer. The samples were placed in a pre-peeled sample basket, and the instrument automatically weighed them. The samples were then analyzed according to the parameters in Table 19.

[0203] Table 19 DVS Analysis Method Parameters

[0204]

[0205] 5. Proton nuclear magnetic resonance spectrum (NMR) 1 H-NMR)

[0206] The NMR measurements were performed using a Bruker AVANCE III HD 400 or Bruker AVANCE III HD 300 NMR instrument, with deuterated dimethyl sulfoxide (DMSO-d6) as the solvent and tetramethylsilane (TMS) as the internal standard.

[0207] 6. High-performance liquid chromatography (HPLC)

[0208] The determination was performed using a SHIMADZU LCMS-2020 mass spectrometer (with electrospray ionization as the ion source).

[0209] HPLC determination was performed on the samples using SHIMADZU LC-20 AP XR and SPD-M20A high-performance liquid chromatography or Agilent HPLC 1260 series instruments.

[0210] 7. Ion chromatography (IC)

[0211] Thermo Fisher ICS-1100 ion chromatography system, Chameleon workstation, and AS-AP autosampler, serial number: 13070718.

[0212] Table 20 IC Analysis Method Parameters

[0213] detector Suppressed conductivity detector sampling frequency 5.0Hz Conductivity cell temperature 35.0℃ Suppressor External circulation mode Suppressor current 25mA Column temperature 30.0℃ Flow rate 1.0 mL / min runtime 10min Injection volume 10μL Attached Figure Description

[0214] Figure 1 The image shows the XRPD spectrum of crystal form I of compound (A).

[0215] Figure 2 The image shows the XRPD spectrum of crystal form II of compound (A).

[0216] Figure 3 The image shows the XRPD spectrum of crystal form III of compound (A).

[0217] Figure 4 The image shows the XRPD spectrum of crystal form IV of compound (A).

[0218] Figure 5 The image shows the XRPD spectrum of crystal form V of compound (A).

[0219] Figure 6 The image shows the XRPD spectrum of crystal form VI of compound (A).

[0220] Figure 7 The image shows the XRPD spectrum of crystal form VII of compound (A).

[0221] Figure 8 The image shows the XRPD spectrum of crystal form VIII of compound (A).

[0222] Figure 9 The image shows the XRPD spectrum of crystal form IX of compound (A).

[0223] Figure 10 The image shows the XRPD spectrum of the crystal form XII of compound (A).

[0224] Figure 11 The image shows the XRPD spectrum of the crystal form XIV of compound (A).

[0225] Figure 12 The image shows the XRPD spectrum of crystal form A of compound (I).

[0226] Figure 13 The image shows the XRPD spectrum of crystal form B of compound (I).

[0227] Figure 14 The image shows the XRPD spectrum of crystal form C of compound (I).

[0228] Figure 15 The image shows the XRPD spectrum of crystal form D of compound (I).

[0229] Figure 16 This is a growth curve of an animal tumor.

[0230] Figure 17 This is a graph showing the animal's body weight.

[0231] Figure 18 The TGA-DSC spectrum of crystal form I of compound (A) is shown.

[0232] Figure 19 The TGA-DSC spectrum of crystal form II of compound (A) is shown.

[0233] Figure 20 The TGA-DSC spectrum of crystal form III of compound (A) is shown.

[0234] Figure 21 The TGA-DSC spectrum of crystal form IV of compound (A) is shown.

[0235] Figure 22 The TGA-DSC spectrum of crystal form V of compound (A) is shown.

[0236] Figure 23 The TGA-DSC spectrum of crystal form VI of compound (A) is shown.

[0237] Figure 24 The TGA-DSC spectrum of crystal form VII of compound (A) is shown.

[0238] Figure 25 The TGA-DSC spectrum of crystal form VIII of compound (A) is shown.

[0239] Figure 26 The TGA-DSC spectrum of crystal form IX of compound (A) is shown.

[0240] Figure 27 The TGA-DSC spectrum of crystal form XII of compound (A) is shown.

[0241] Figure 28 The TGA-DSC spectrum of the crystal form XIV of compound (A) is shown.

[0242] Figure 29The TGA-DSC spectrum of crystal form A of compound (I) is shown.

[0243] Figure 30 The TGA-DSC spectrum of crystal form B of compound (I) is shown.

[0244] Figure 31 The TGA-DSC spectrum of crystal form C of compound (I) is shown.

[0245] Figure 32 The TGA-DSC spectrum of crystal form D of compound (I) is shown.

[0246] Figure 33 The image shows the DVS spectrum of crystal form I of compound (A).

[0247] Figure 34 The XRPD comparison spectra of compound I of formula (A) before and after the DVS experiment are shown.

[0248] Figure 35 The image shows the DVS spectrum of crystal form II of compound (A).

[0249] Figure 36 The XRPD comparison spectra of crystal form II of compound (A) before and after the DVS experiment are shown.

[0250] Figure 37 The image shows the DVS spectrum of crystal form III of compound (A).

[0251] Figure 38 The XRPD comparison spectra of compound (A) crystal form III before and after the DVS experiment are shown.

[0252] Figure 39 The image shows the DVS spectrum of crystal form D of compound (I).

[0253] Figure 40 The XRPD comparison spectra of crystal form D of compound (I) before and after the DVS experiment are shown.

[0254] Figure 41 The XRPD comparison spectra of compound (A) crystal form II before and after the compressive strength test are shown.

[0255] Figure 42 The XRPD comparison spectra before and after the stability experiment of crystal form D of compound (I) are shown. Detailed Implementation

[0256] The present invention will be described in detail below with reference to examples, but this does not imply any adverse limitation on the invention. The compounds of the present invention can be prepared by various synthetic methods well known to those skilled in the art, including the specific embodiments listed below, embodiments formed by combining them with other chemical synthetic methods, and equivalent substitutions well known to those skilled in the art. Preferred embodiments include, but are not limited to, the embodiments of the present invention. It will be apparent to those skilled in the art that various changes and modifications can be made to the specific embodiments of the present invention without departing from the spirit and scope of the invention.

[0257] Example 1: Preparation of compounds of formula (A) and formula (I):

[0258] 1.1 Preparation of intermediate 6A

[0259]

[0260] Compound 6A-1:

[0261] Compound 1C-4 (3.5 g, 15.5 mmol) was dissolved in acetonitrile (40 mL), and N-iodosuccinimide (4.9 g, 21.7 mmol) was added at 0 °C. The reaction was stirred at room temperature for 5 hours. After the starting material disappeared under LCMS monitoring, the mixture was concentrated under reduced pressure, and water (30 mL) was added. The mixture was extracted with dichloromethane (45 mL × 3 times). The organic phases were combined, washed with saturated brine (60 mL × 2 times), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: ethyl acetate / petroleum ether = 1 / 1) to give 3.57 g of compound 6A-1.

[0262] MS(ESI, m / z): 352.0 [M+H] + .

[0263] Compound 6A-2:

[0264] Compounds 6A-1 (3.4 g, 9.7 mmol) and 1A (3.7 g, 12.5 mmol) were dissolved in 1,4-dioxane (30 mL) and water (6 mL). Potassium carbonate (2.7 g, 19.4 mmol) and [1,1′-bis(diphenylphosphine)ferrocene]palladium dichloromethane dichloride complex (790 mg, 1.0 mmol) were added to the reaction mixture. Under nitrogen protection, the reaction mixture was heated to 80 °C and stirred for 2 hours. After the starting material disappeared as monitored by LCMS, the reaction mixture was cooled to room temperature, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: ethyl acetate / petroleum ether = 2 / 1) to give 2.8 g of compound 6A-2.

[0265] MS (ESI, m / z): 395.3 [M+H] + .

[0266] Compound 6A-3:

[0267] Compound 6A-2 (2.7 g, 6.8 mmol) was dissolved in N,N-dimethylformamide (28 mL). Potassium carbonate (1.9 g, 13.5 mmol) was then added to the reaction mixture. The reaction system was heated to 100 °C and stirred for 24 hours. After LCMS monitoring showed the disappearance of the starting material, the reaction mixture was cooled to room temperature and quenched with water (50 mL). The mixture was extracted with ethyl acetate (60 mL × 4 times), and the organic phases were combined. The organic phase was first washed with saturated brine (50 mL × 3 times), then dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: dichloromethane / ethyl acetate = 15 / 1) to give 1.2 g of compound 6A-3.

[0268] MS (ESI, m / z): 375.2 [M+H] + .

[0269] Compound 6A-4:

[0270] Compound 6A-3 (1.2 g, 3.3 mmol) was dissolved in a 1,4-dioxane solution of hydrogen chloride (4 M, 15 mL). The mixture was stirred at 30 °C for 6 hours. After the starting material disappeared under LC-MS monitoring, the reaction solution was concentrated, and water (40 mL) was added. The pH was adjusted to 9 with a saturated sodium bicarbonate solution. The mixture was extracted with chloroform / isopropanol = 3 / 1 (50 mL × 3 times). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol = 30 / 1) to give 842 mg of compound 6A-4.

[0271] MS(ESI, m / z): 275.0 [M+H] + .

[0272] Compound 6A-5:

[0273] Compound 6A-4 (300 mg, 1.1 mmol) and cesium carbonate (1.07 g, 3.3 mmol) were dissolved in N,N-dimethylformamide (6 mL). Iodopropane (1.86 g, 10.9 mmol) was then added to the reaction mixture. The reaction system was heated to 80 °C and stirred for 16 hours. After LCMS monitoring showed the disappearance of the starting material, the reaction mixture was cooled to room temperature and quenched with water (30 mL). The mixture was extracted with ethyl acetate (50 mL × 3 times), and the organic phases were combined. The organic phase was first washed with saturated brine (50 mL × 3 times), then dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol = 10 / 1) to give 75 mg of compound 6A-5.

[0274] MS (ESI, m / z): 317.2 [M+H] + .

[0275] Intermediate 6A:

[0276] Compound 6A-5 (75 mg, 0.2 mmol) was dissolved in ethanol (8 mL) and water (1.6 mL). Then, ammonium chloride (50.7 mg, 0.9 mmol) and reduced iron powder (132.4 mg, 2.4 mmol) were added to the reaction mixture. The reaction mixture was heated to 80 °C and stirred for 5 hours. After the starting material disappeared as monitored by LCMS, the reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol = 10 / 1) to give 48 mg of compound 6A.

[0277] MS (ESI, m / z): 287.2 [M+H] + .

[0278] 1.2 Preparation of intermediate 35A

[0279]

[0280] Compound 35A-1:

[0281] 6-Aminoquinoxaline (10 g, 68.89 mmol) was dissolved in concentrated sulfuric acid (20 mL). Potassium nitrate (9.054 g, 89.55 mmol) was added in portions to the reaction mixture at 0 °C, and stirring was continued for 30 minutes at this temperature. After the starting material disappeared as monitored by LCMS, the reaction mixture was poured into ice water (100 g). The pH was adjusted to 8 with 1 M sodium hydroxide aqueous solution. The mixture was extracted with ethyl acetate (200 mL × 2 times), and the organic phases were combined. The organic phase was first washed with saturated brine (100 mL × 3 times), then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol = 10 / 1) to give 2 g of compound 35A-1.

[0282] MS(ESI)M / Z: 191.2 [M+H] + .

[0283] Intermediate 35A:

[0284] Compound 35A-1 (2 g, 10.5 mmol) was dissolved in N,N-dimethylformamide (20 mL). The reaction mixture was cooled to 0 °C, and under nitrogen protection, sodium hydride (60 wt, 1.3 g, 31.5 mmol) was added in portions with stirring for 20 minutes. Subsequently, 2,4-dichloro-5-bromopyrimidine (4.8 g, 21.0 mmol) was added to the above reaction mixture, and the reaction was brought to room temperature and stirred for 1 hour. After LCMS monitoring showed the disappearance of the starting material, the reaction mixture was cooled to 0 °C and quenched with saturated ammonium chloride aqueous solution (80 mL). The mixture was extracted with ethyl acetate (100 mL × 3 times), and the organic phases were combined. The organic phase was first washed with saturated brine (80 mL × 3 times), then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: ethyl acetate / petroleum ether = 1 / 2) to give 2.7 g of compound 35A.

[0285] MS (ESI, m / z): 381.0, 383.0[M+H] + .

[0286] 1.3 Compound A

[0287]

[0288] 1.3.1 Compound 53A:

[0289] Compounds 6A (2.7 g, 9.43 mmol) and 35A (3.6 g, 9.43 mmol) were dissolved in N-methylpyrrolidone (30 mL). Then, methanesulfonic acid (2.72 g, 28.28 mmol) was added to the reaction mixture. The reaction system was heated to 95 °C and stirred for 3 hours. After the starting material disappeared as monitored by LCMS, the reaction mixture was cooled to room temperature and purified by reversed-phase C18 column. Purification conditions: 330 g C18 reversed-phase column; mobile phase: water (containing 0.1% formic acid) and acetonitrile; flow rate: 70 mL / min; gradient: acetonitrile from 10% to 50% over 20 minutes; detection wavelength: 254 nm. The product was collected and concentrated under reduced pressure to give 3.4 g of compound 53A.

[0290] MS (ESI, m / z): 631.2, 633.2[M+H] + .

[0291] 1.3.2 Compound 53B:

[0292] Compound 53A (3.4 g, 5.38 mmol) was dissolved in a mixed solvent of ethanol (40 mL) and water (8 mL). Then, iron powder (1.50 g, 26.92 mmol) and ammonium chloride (0.86 g, 16.15 mmol) were added to the reaction solution, and the reaction mixture was heated to 80 °C and stirred for 2 hours. After the starting material disappeared as monitored by LCMS, the reaction solution was cooled to room temperature and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol = 10 / 1) to give 2.8 g of compound 53B.

[0293] MS (ESI, m / z): 601.2, 603.2[M+H] + .

[0294] 1.3.3 Compound A:

[0295] Compound 53B (5 g, 8.31 mmol) was dissolved in pyridine (50 mL). Methylsulfonyl chloride (1.9 g, 16.62 mmol) was then added dropwise to the reaction mixture. The reaction mixture was heated to 50 °C and stirred for 2 hours. After the starting material disappeared as monitored by LCMS, the reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was dissolved in a mixture of methanol / tetrahydrofuran (1 / 1, 50 mL), and an aqueous solution of sodium hydroxide (2 M, 5 mL) was added to the reaction mixture at 0 °C. The reaction mixture was heated to room temperature and stirred for 1 hour, then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol = 10 / 1). The crude product was slurried in dichloromethane / methanol (20 / 1, 30 mL) and then lyophilized with acetonitrile / water (50 mL) to give 3 g of compound A.

[0296] MS (ESI, m / z): 679.0, 681.0[M+H] + .

[0297] 1 H NMR (400MHz, DMSO-d6) δ9.88 (br s, 1H), 8.94 (d, J = 2.0Hz, 1H), 8.85 (d, J = 2.0Hz, 1H), 8.76 (s, 1H), 8.67 (br s, 1H), 8.35 (s, 1H), 8.27 (s, 1H), 7.73 (s, 1H), 7.49 (s, 1H), 7.38 (s, 1H), 6.58 (s, 1H), 3.99-3.91 (m, 1H), 3 .76 (s, 3H), 3.71 (s, 3H), 3.21 (t, J=5.6Hz, 2H), 3.00 (s, 3H), 2.94 (t, J=5.6Hz, 2H), 1.29 (d, J=6.4Hz, 6H).

[0298] 1.4 Compound I:

[0299] Compound A (67 g, 98.59 mmol) was dissolved in a mixed solvent of dichloromethane (880 mL) and methanol (440 mL) and stirred at room temperature for 1 hour. Then, a methanol solution of hydrogen chloride (4 M, 24.65 mL, 98.59 mmol) was added dropwise to the reaction mixture at room temperature. The reaction mixture was stirred at room temperature for 4 hours, and then concentrated under reduced pressure to 70 mL. Methyl tert-butyl ether (880 mL) was added to the mixture, and stirring was continued at room temperature for 2 hours. The precipitated solid was filtered and lyophilized in acetonitrile / water (500 mL) to give 60.2 g of compound I.

[0300] MS(ESI)M / Z: 679.0, 681.0[M+H] + .

[0301] 1 H NMR (300MHz, DMSO-d6) δ9.97 (s, 1H), 9.30-9.16 (m, 2H), 8.99 (s, 1H), 8.91 (s, 1H), 8.43 (s, 2H), 7.75-7.30 (m, 3H), 6.57 (s, 1H), 3.95-3.86 (m, 1H), 3.79 (s, 3H), 3.69 (s, 3H), 3.28-3.14 (m, 2H), 3.03 (s, 3H), 2.98-2.88 (m, 2H), 1.27 (brs, 6H).

[0302] Example 2 Biological Test Evaluation:

[0303] (I) In vitro enzymatic experiments of EGFR WT and EGFR L858R / T790M / C797S

[0304] This experiment used fluorescence resonance energy transfer (TR-FRET) to test the inhibitory effect of the compound on the activity of EGFR WT (wild-type EGFR) and EGFRL858R / T790M / C797S kinases, and determined the half-maximal inhibitory concentration (IC50) of the compound on EGFR kinase activity. 50 .

[0305] 1. Experimental Materials

[0306] EGFR recombinase and EGFR L858R / T790M / C797S recombinase were purchased from Signalchem.

[0307] The HTRF KinEASE-TK kit was purchased from Cisbio.

[0308] DTT, MnCl2, and MgCl2 were purchased from Sigma.

[0309] ATP was purchased from Promega.

[0310] Brigatinib was purchased from Selleck.

[0311] 2. Experimental Methods

[0312] 1) Prepare 1X working solution: 5mM MgCl2; 1mM DTT; 1mM MnCl2 and 1× kinase buffer (included in the kit).

[0313] 2) Use an Echo 550 (Labcyte) to transfer 10 nL of serially diluted compound into a 384-well experimental plate.

[0314] 3) Add 5 μL of 2×EGFR WT or EGFR L858R / T790M / C797S recombinase solution to a 384-well experimental plate and incubate at room temperature for 10 minutes.

[0315] 4) Add 5 μL of 2×TK-substrate-biotin substrate solution (containing ATP) to a 384-well plate and incubate at room temperature for 40 minutes.

[0316] 5) Add 5 μL of Sa-XL 665 HTRF detection solution and 5 μL of LK-antibody-Cryptate, and incubate at room temperature for 1 hour.

[0317] 6) The Envision microplate reader (PerkinElmer) was used to detect the fluorescence signal values ​​at 615 nm and 665 nm in each well.

[0318] 7) Calculate the ratio of fluorescence signal at 665nm / 615nm for each well.

[0319] 8) Data analysis was performed using GraphPad Prism software to determine the IC50 of the compound. 50 .

[0320] The results of kinase activity inhibition of wild-type EGFR and L858R / T790M / C797S triple mutant EGFR are shown in Table 21.

[0321] As can be seen from Table 21, compound (A) has a good inhibitory effect on L858R / T790M / C797S triple mutant EGFR kinase.

[0322] Table 21 Results of enzyme inhibition

[0323] A 0.71 0.31

[0324] (II) Cell proliferation inhibition experiment

[0325] A431 cell proliferation inhibition experiment

[0326] This experiment used the CellTiter-Glo method to test the inhibitory effect of the compound on the proliferation of A431 cells and determined the IC50 concentration (IC50) of the compound that inhibits cell growth. 50 .

[0327] 1. Experimental Materials

[0328] A431 cells were purchased from ATCC.

[0329] DMEM medium, fetal bovine serum (FBS), and penicillin-streptomycin were purchased from GIBCO.

[0330] Brigatinib was purchased from Selleck.

[0331] CellTiter-Glo reagent, purchased from Promega.

[0332] 2. Experimental Methods

[0333] 1) Seed A431 cells at a density of 800 cells per well in a 384-well culture plate, 30 μl per well, and incubate in a cell culture incubator for 24 hours (37°C, 5% CO2).

[0334] 2) Day 0: Using Echo, add 30 nL of serially diluted test compound to the cells in the culture plate, with a final DMSO concentration of 0.1%. Incubate the culture plate in a cell culture incubator for 72 hours (37°C, 5% CO2). Add 30 nL of DMSO to each well for the blank control.

[0335] 3) Day 3: Add 30 μL of Cell Titer-Glo reagent to each well and incubate at room temperature in the dark for 30 minutes.

[0336] 4) Envision microplate reader (PerkinElmer) detects chemiluminescence signals.

[0337] 5) Data analysis was performed using GraphPad Prism software to determine the IC50 of the compound. 50 .

[0338] Ba / F3_L858R / T790M / C797S Cell Proliferation Inhibition Assay

[0339] This experiment used the CellTiter-Glo method to test the inhibitory effect of the compound on the proliferation of Ba / F3_L858R / T790M / C797S cells, and determined the half-maximal concentration (IC50) of the compound that inhibits cell growth. 50 .

[0340] 1. Experimental Materials

[0341] Ba / F3_L858R / T790M / C797S cells were constructed by Pharmaron (Beijing) New Drug Technology Co., Ltd.

[0342] 1640 medium, fetal bovine serum (FBS), penicillin-streptomycin, and GlutaMAX-ISupplement were purchased from GIBCO.

[0343] Brigatinib was purchased from Selleck.

[0344] CellTiter-Glo reagent, purchased from Promega.

[0345] 2. Experimental Methods

[0346] 1) Seed Ba / F3_L858R / T790M / C797S cells into 384-well culture plates at a density of 700 cells per well, 30 μL per well.

[0347] 2) Day 0: Using Echo, add 30 nL of serially diluted analyte to the cells in the culture plate, with a final DMSO concentration of 0.1%. Incubate the culture plate in a cell culture incubator for 72 hours (37°C, 5% CO2). For the blank control, add 30 nL of DMSO to each well.

[0348] 3) Day 3: Add 30 μL of Cell Titer-Glo reagent to each well and incubate at room temperature in the dark for 30 minutes.

[0349] 4) Envision microplate reader (PerkinElmer) detects chemiluminescence signals.

[0350] 5) Data analysis was performed using GraphPad Prism software to determine the IC50 of the compound. 50 .

[0351] Ba / F3_Del19 / T790M / C797S cell proliferation inhibition experiment

[0352] This experiment used the CellTiter-Glo method to test the inhibitory effect of the compound on the proliferation of Ba / F3_Del19 / T790M / C797S cells, and determined the half-maximal concentration (IC50) of the compound that inhibits cell growth. 50 .

[0353] 1. Experimental Materials

[0354] Ba / F3_Del19 / T790M / C797S was purchased from Kangyuan Bochuang Biotechnology (Beijing) Co., Ltd.

[0355] 1640 medium, fetal bovine serum (FBS), penicillin-streptomycin, and GlutaMAX-ISupplement were purchased from GIBCO.

[0356] Brigatinib was purchased from Selleck.

[0357] CellTiter-Glo reagent, purchased from Promega.

[0358] 2. Experimental Methods

[0359] 1) Seed Ba / F3_Del19 / T790M / C797S cells into 384-well culture plates at a density of 700 cells per well, 30 μL per well.

[0360] 2) Day 0: Using Echo, add 30 nL of serially diluted test compound to the cells in the culture plate, with a final DMSO concentration of 0.1%. Incubate the culture plate in a cell culture incubator for 72 hours (37°C, 5% CO2). Add 30 nL of DMSO to each well for the blank control.

[0361] 3) Day 3: Add 30 μL of Cell Titer-Glo reagent to each well and incubate at room temperature in the dark for 30 minutes.

[0362] 4) Envision microplate reader (PerkinElmer) detects chemiluminescence signals.

[0363] Data analysis was performed using GraphPad Prism 6 software to determine the IC50 of the compound. 50 .

[0364] The results of cell activity inhibition are shown in Table 22.

[0365] The experimental results in Table 22 show that compound A has a good inhibitory effect on the cell proliferation of Ba / F3 Del19 / T790M / C797S EGFR triple mutant cell lines and Ba / F3 L858R / T790M / C797S EGFR triple mutant cell lines; however, its inhibitory effect on the EGFR wild-type (EGFR WT) cell line A431 is weak. This indicates that compound A has good cell activity and selectivity.

[0366] Table 22 Results of Cell Proliferation Inhibition Assay

[0367]

[0368] (III) In vivo efficacy study experiments

[0369] 1. Experimental Objective

[0370] The antitumor activity and toxic side effects of compound A after 21 days of continuous oral administration were evaluated against PC9 (Del19 / T790M / C797S).

[0371] 2. Experimental Materials

[0372] BALB / c-nu mice, female, SPF grade, purchased from Beijing Vital River Laboratory Animal Technology Co., Ltd.

[0373] PC9 (Del19 / T790M / C797S) cells were constructed independently by Qilu Pharmaceutical Co., Ltd.

[0374] 3. Experimental Procedure

[0375] 3.1 Cell Culture

[0376] PC9 (Del19 / T790M / C797S) cells were cultured in RPMI 1640 medium containing 10% FBS at 37°C in a 5% CO2 incubator; cells in the exponential growth phase were collected and seeded.

[0377] 3.2 Cell Seeding

[0378] Under aseptic conditions, a suspension of in vitro cultured PC9 (Del19 / T790M / C797S) cells was taken, centrifuged, and the cell concentration was adjusted to 3 × 10⁻⁶ cells / mL. 7 0.1 mL / mouse was injected subcutaneously into the right axilla of mice, and the day of injection was designated as day 0.

[0379] 3.3 Tumor grouping, drug administration, and measurement

[0380] a. When the average tumor volume is approximately 150 mm 3 Thirty-five mice with moderate tumor volume were selected for the study and randomly divided into five groups according to tumor size: G1: solvent control group, G2: compound A (15 mg / kg), and G3: compound A (60 mg / kg), with seven mice per group.

[0381] b. After the animals were grouped, the administration was started. The administration volume was 10 mL / kg, orally (po); the animals were weighed and administered once a day for 21 consecutive days; the tumor diameter was measured twice a week.

[0382] c. Tumor volume (TV): Tumor volume was measured twice weekly to observe changes in tumor volume and growth rate. Tumor volume V = 1 / 2 × a × b 2 Where a and b represent the long and short diameters of the tumor, respectively. The growth-inhibiting effect of the compound on tumor tissue was evaluated using the tumor growth inhibition rate (TGI) (%). TGI (%) = [1 - (mean tumor volume of a treatment group - mean tumor volume of the treatment group on the day of grouping) / (mean tumor volume of the negative control group - mean tumor volume of the negative control group on the day of grouping)] × 100%. Data from the same day were used for both the treatment group and the negative control group.

[0383] d. Closely observe the mice's living conditions during the experiment, including physical signs, general behavior, mental state, feeding, respiratory status, fecal and urine characteristics, injection site and other toxic manifestations.

[0384] e. After the experiment reaches its endpoint, the mice are euthanized, and the animal carcasses are frozen in a freezer and transferred to a qualified medical waste disposal unit for disposal.

[0385] 4 Experimental Results

[0386] The experimental results are shown in Table 23 and Figure 16 and Figure 17 .

[0387] Table 23 Results of in vivo efficacy tests

[0388]

[0389] a, mean ± standard error;

[0390] b. Statistical analysis of tumor volume using P-values ​​showed that, compared with group G1, *P<0.05; **P<0.01.

[0391] 5. Experimental Conclusions

[0392] The results above show that compound A can significantly inhibit tumor growth. Figure 16 The study showed a clear dose-response relationship and was well tolerated by mice. Figure 17 ).

[0393] Example 3: Preparation of crystal form I:

[0394] Method 1:

[0395] Weigh approximately 20 mg of compound A into a 4 mL sample vial, add 1 mL of acetonitrile, stir for 3 days at room temperature, filter and collect the solid, and air dry at room temperature.

[0396] The obtained solid was characterized by XRPD and TGA-DSC tests, and the solid was identified as crystal form I.

[0397] XRPD spectrum as shown Figure 1 As shown.

[0398] TGA-DSC spectrum as shown Figure 18 As shown.

[0399] Method 2:

[0400] Weigh approximately 20 mg of compound A into a 4 mL sample vial, add 1 mL of water, stir at 50 °C for 1 day, filter and collect the solid, and air dry at room temperature. The XRPD spectrum of the obtained solid is basically as follows. Figure 1 As shown.

[0401] Example 4: Preparation of crystal form II:

[0402] Method 1:

[0403] At 50°C, 1.0 mL of tetrahydrofuran (THF) was added to 10 mg of compound A, stirred for 5 minutes, and then filtered to collect the filtrate. At room temperature, 4.0 mL of methyl tert-butyl ether was gradually added to the solution, stirred for 16 hours, filtered, and the solid was collected and air-dried at room temperature.

[0404] The obtained solid was characterized by XRPD and TGA-DSC tests, and the solid was found to be crystal form II.

[0405] XRPD spectrum as shown Figure 2 As shown.

[0406] TGA-DSC spectrum as shown Figure 19 As shown.

[0407] Method 2:

[0408] Approximately 10 mg of crystal form I was dissolved in 0.4 mL of dimethyl sulfoxide (DMSO) at 50 °C. Then, the solution was added dropwise to 1 mL of methyl tert-butyl ether at room temperature. After the solid precipitated, the suspension was stirred at room temperature for two hours, then filtered, the solid was collected, and dried at room temperature. The XRPD spectrum of the obtained solid is essentially as shown below. Figure 2 As shown.

[0409] Method 3:

[0410] Weigh 240 mg of compound A into a sample vial, add 3 mL of acetone, and stir overnight at 50 °C. Collect the solid by filtration and dry under vacuum at 50 °C. The XRPD spectrum of the obtained solid is basically as shown below. Figure 2 As shown.

[0411] Example 5: Preparation of crystal form III:

[0412] At 50°C, 20 mg of compound A was dissolved in 0.5 mL of dimethyl sulfoxide (DMSO). At room temperature, 2.0 mL of ethanol was gradually added to the solution and stirred for 16 hours. The mixture was then filtered, the solid was collected, and dried under vacuum at 50°C.

[0413] The obtained solid was characterized by XRPD and TGA-DSC tests, and the solid was found to be crystal form III.

[0414] XRPD spectrum as shown Figure 3 As shown.

[0415] TGA-DSC spectrum as shown Figure 20 As shown.

[0416] Example 6: Preparation of crystal form IV:

[0417] Weigh an appropriate amount of compound A into a sample vial and add toluene to prepare a suspension at a concentration of 20 mg / mL. These suspensions were then stirred at room temperature for 3 days. The solids were filtered and collected, and then air-dried at room temperature.

[0418] The obtained solid was characterized by XRPD and TGA-DSC tests, and the solid was found to be crystal form IV.

[0419] XRPD spectrum as shown Figure 4 As shown.

[0420] TGA-DSC spectrum as shown Figure 21 As shown.

[0421] Example 7: Preparation of crystal form V:

[0422] At 50°C, 20 mg of compound A was dissolved in 0.5 mL of dimethyl sulfoxide (DMSO). At room temperature, 1.0 mL of water was gradually added to the solution and stirred for 16 hours. The mixture was then filtered, the solid was collected, and dried under vacuum at 50°C.

[0423] The obtained solid was characterized by XRPD and TGA-DSC tests, and the solid was found to be crystal form V.

[0424] XRPD spectrum as shown Figure 5 As shown.

[0425] TGA-DSC spectrum as shown Figure 22 As shown.

[0426] Example 8: Preparation of crystal form VI:

[0427] Weigh 20 mg of compound A into a sample vial at 50 °C, then slowly add 1 mL of tetrahydrofuran at 50 °C to obtain a nearly clear solution. Filter and collect the filtrate. Cool the filtrate to room temperature with stirring and continue stirring for 16 hours until a solid precipitates. Filter and collect the solid, and air dry at room temperature.

[0428] The obtained solid was characterized by XRPD and TGA-DSC tests, and the solid was identified as crystal form VI.

[0429] XRPD spectrum as shown Figure 6 As shown.

[0430] TGA-DSC spectrum as shown Figure 23 As shown.

[0431] Example 9: Preparation of crystal form VII:

[0432] Weigh an appropriate amount of compound A into a sample vial and add dichloromethane to prepare a suspension at a concentration of 20 mg / mL. These suspensions were then stirred at room temperature for 3 days. The solids were filtered and collected, and then air-dried at room temperature for 1 hour.

[0433] The obtained solid was characterized by XRPD and TGA-DSC tests, and the solid was identified as crystal form VII.

[0434] XRPD spectrum as shown Figure 7 As shown.

[0435] TGA-DSC spectrum as shown Figure 24 As shown.

[0436] Example 10: Preparation of crystal form VIII:

[0437] Weigh an appropriate amount of compound A into a sample vial and add isopropanol to prepare a suspension at a concentration of 20 mg / mL. These suspensions were then stirred at room temperature for 3 days. The solids were filtered and collected, and then air-dried at room temperature.

[0438] The obtained solid was characterized by XRPD and TGA-DSC tests, and the solid was found to be crystal form VIII.

[0439] XRPD spectrum as shown Figure 8 As shown.

[0440] TGA-DSC spectrum as shown Figure 25 As shown.

[0441] Example 11 Preparation of crystal form IX:

[0442] Weigh an appropriate amount of compound A into a sample vial and add isobutanol to prepare a suspension at a concentration of 20 mg / mL. These suspensions were then stirred at room temperature for 3 days. The solids were filtered and collected, and then air-dried at room temperature.

[0443] The obtained solid was characterized by XRPD and TGA-DSC tests, and the solid was identified as crystal form IX.

[0444] XRPD spectrum as shown Figure 9 As shown.

[0445] TGA-DSC spectrum as shown Figure 26 As shown.

[0446] Example 12 Preparation of crystal form XII:

[0447] Weigh an appropriate amount of compound A into a sample vial and add methanol / water (1:1) to prepare a suspension of 10 mg / mL. These suspensions were then stirred at room temperature for 3 days. The solid was filtered and collected, and then air-dried at room temperature.

[0448] The obtained solid was characterized by XRPD and TGA-DSC tests, and the solid was found to be of crystal form XII.

[0449] XRPD spectrum as shown Figure 10 As shown.

[0450] TGA-DSC spectrum as shown Figure 27 As shown.

[0451] Example 13 Preparation of crystal form XIV:

[0452] Weigh 20 mg of sample into a sample vial at 50 °C, then slowly add 3.5 mL of methanol / 1,4-dioxane (volume ratio 2 / 1.5) at 50 °C to obtain an almost clear solution. Filter and collect the filtrate. Cool the filtrate to room temperature with stirring and continue stirring for 16–56 hours until a solid precipitates. Filter and collect the solid, and air dry at room temperature.

[0453] The obtained solid was characterized by XRPD and TGA-DSC tests, and the solid was found to be of crystal form XIV.

[0454] XRPD spectrum as shown Figure 11 As shown.

[0455] TGA-DSC spectrum as follows Figure 28 As shown.

[0456] Example 14 Preparation of crystal form A:

[0457] 25 mg of compound A was added to 2 ml of ethanol at room temperature, followed by the addition of 1 equivalent of 12 M hydrochloric acid and stirring for 1 day. The solid sample was collected by filtration and vacuum drying.

[0458] The obtained solid was characterized by XRPD and TGA-DSC tests, and the solid was identified as crystal form A.

[0459] XRPD spectrum as shown Figure 12 As shown.

[0460] TGA-DSC spectrum as follows Figure 29 As shown.

[0461] Example 15: Preparation of crystal form B:

[0462] 25 mg of compound A was added to 2 ml of acetone / water (100 / 1) at room temperature, followed by the addition of 1 equivalent of 12 M hydrochloric acid and stirring for 1 day. The solid sample was collected by filtration and vacuum dried.

[0463] The obtained solid was characterized by XRPD and TGA-DSC tests, and the solid was found to be crystal form B.

[0464] XRPD spectrum as shown Figure 13 As shown.

[0465] TGA-DSC spectrum as follows Figure 30 As shown.

[0466] Example 16 Preparation of crystal form C:

[0467] Weigh 19.67 mg of compound (I) into an 8 mL sample vial, add 1 mL of isopropanol, stir at 50 °C for 1 day and filter, and dry under vacuum at 50 °C.

[0468] The obtained solid was characterized by XRPD and TGA-DSC tests, and the solid was found to be crystalline form C.

[0469] XRPD spectrum as shown Figure 14 As shown.

[0470] TGA-DSC spectrum as follows Figure 31 As shown.

[0471] Example 17 Preparation of crystal form D:

[0472] Method 1:

[0473] Weigh 97.75 mg of compound (I) into a 20 mL sample vial, add 6 mL of acetone, stir overnight at 50 °C and filter, then vacuum dry at 50 °C for 4-5 hours.

[0474] 1 H NMR (400MHz, DMSO-d6) δ9.97 (s, 1H), 9.28-9.12 (m, 2H), 8.98 (s, 1H), 8.91 (s, 1H), 8.55-8.44 (m, 1H), 8.38 (s, 1H), 7.75-7.32 (m, 3H), 6.57(s, 1H), 4.11-3.96(m, 1H), 3.78(s, 3H), 3.69(s, 3H), 3.25-3.13(m, 2H), 3.03(s, 3H), 2.97-2.87(m, 2H), 1.28(brs, 6H)

[0475] Two approximately 25 mg samples of compound (I) crystal form D were accurately weighed into 25 mL volumetric flasks, dissolved and diluted with solvent, and the chloride ion content was detected by chloride ion chromatography. The results are shown in Table 24. Through formula conversion, it was found that the molar ratio of compound (I) crystal form D to hydrogen chloride is approximately 1:1.

[0476] Table 24 Chloride ion content test results

[0477]

[0478] The obtained solid was characterized by XRPD and TGA-DSC tests, and the solid was found to be crystal form D.

[0479] XRPD spectrum as shown Figure 15 As shown.

[0480] TGA-DSC spectrum as follows Figure 32 As shown.

[0481] Method 2:

[0482] 25 mg of compound (I) was added to 0.3 mL of dichloromethane / methanol (1 / 1, v / v) to prepare a saturated solution at room temperature. Then, 2.7 mL of acetone was gradually added to the solution until a solid precipitated. The suspension was stirred at room temperature for 4-5 hours. The solid was collected and dried under vacuum at 50 °C. The XRPD spectrum of the obtained solid is basically as shown in the figure. Figure 15 As shown.

[0483] Example 18 Hygroscopicity Test:

[0484] Referring to the "Guiding Principles for Hygroscopicity Testing of Drugs" in the Chinese Pharmacopoeia, the water adsorption / desorption data of crystal forms I, II, III, and D were tested.

[0485] Figure 33 The DVS curve for crystal form I is shown. Figure 34 The XRPD spectra before and after IDVS testing show the crystal form. The DVS results indicate that crystal form I has a moisture absorption weight gain of 0.59% at 80% RH and a moisture absorption weight gain of 0.77% at 90% RH, indicating that the crystal form is slightly hygroscopic. The XRPD of the remaining solid after the DVS experiment showed that the crystal form did not change.

[0486] Figure 35 The DVS curve is for crystal form II. Figure 36 The XRPD spectra of crystal form II before and after DVS testing are shown. The DVS results indicate that crystal form II is almost non-hygroscopic, with moisture absorption weight gains of 0.19% and 0.24% under 80% and 90% RH conditions, respectively. The XRPD of the remaining solid after the DVS experiment showed no change in crystal form.

[0487] Figure 37 The DVS curve for crystal form III is shown. Figure 38 The XRPD spectra of crystal form III before and after DVS testing are shown. The DVS results indicate that crystal form III is slightly hygroscopic, with hygroscopic weight gain of 0.8% and 1.0% under 80% and 90% RH conditions, respectively. The XRPD of the remaining solid after the DVS experiment showed no change in crystal form.

[0488] Figure 39 The DVS curve is for crystal form D. Figure 40 The XRPD spectra of crystal form D before and after DVS testing are shown. The DVS results indicate that crystal form D has slight hygroscopicity, with moisture absorption weight increases of 0.59% and 0.76% at 80% RH and 90% RH, respectively. After DVS testing, the crystal form of the remaining solid did not change.

[0489] Example 19: Thermal and moisture stability tests of crystal forms I-III:

[0490] Following the "Guidelines for Stability Testing of Drug Substances and Preparations" in the Chinese Pharmacopoeia, the stability of crystal forms I, II, and III under different temperatures and humidity conditions was investigated. Purity was determined by HPLC on days 0, 5, and 10, and crystal form was determined by XRPD.

[0491] The experimental results are shown in Table 25. Crystal forms I, II, and III degraded slightly under high temperature and high humidity conditions, but the overall purity did not change significantly, especially crystal form II, which remained basically stable under high temperature and high humidity conditions. The crystal forms of the three crystal forms did not change before and after the experiment.

[0492] Table 25 Thermal and hydrothermal stability of crystal forms I, II and III

[0493]

[0494]

[0495] Example 20: Stability test of crystal form D:

[0496] Following the guidelines for stability testing of active pharmaceutical ingredients and formulations in the Chinese Pharmacopoeia, the stability of crystal form D under high temperature, high humidity, and light conditions was investigated. Purity was determined by HPLC on days 0, 5, and 10, and crystal form was determined by XRPD.

[0497] The experimental results are shown in Table 26. Crystal form D remained basically stable under high temperature and high humidity conditions, but slightly degraded under light conditions. Furthermore, IC results showed that crystal form VIII of the hydrochloride did not dissociate under conditions of 60℃, 25℃ / 92.5%RH, and light exposure (Table 27), remaining a monohydrochloride salt. Crystal form D did not change before or after the experiment. Figure 42 ).

[0498] Table 26 Stability test results of crystal form D

[0499]

[0500] Table 27 Ion chromatography results after stability test of crystal form D

[0501]

[0502] Example 21: Pressure Experiment

[0503] Approximately 100 mg of crystal form II was placed in a single-punch tablet press, and the sample was manually compacted to form a 60 mm tablet without crumbling. The tablet was then gently crushed into powder. The XRPD pattern of the remaining solid remained unchanged. Figure 41 This indicates that crystal form II has good compressive strength.

Claims

1. The crystal form I of compound (A) N-(6-((5-bromo-2-((6-isopropyl-8-methoxy-3-methyl-3,4,5,6-tetrahydrobenzo[b]pyrazolo[4,3-d]aza-9-yl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)methanesulfonamide, Its features are, The X-ray powder diffraction pattern of crystal form I has characteristic peaks at 2θ values ​​of 7.83, 13.85, 18.25, 20.22, and 24.37, with a 2θ error range of ±0.2°.

2. The crystal form I as described in claim 1, characterized in that, The X-ray powder diffraction pattern of crystal form I has characteristic peaks at 2θ values ​​of 7.83, 9.86, 12.02, 12.42, 12.93, 13.20, 13.85, 15.68, 18.25, 20.22, 20.64, 21.82, 22.92, 24.37, and 26.48, with a 2θ error range of ±0.2°.

3. The crystal form I as described in claim 1, characterized in that, The X-ray powder diffraction pattern of crystal form I has characteristic peaks at 2θ values ​​of 5.84, 7.03, 7.83, 9.86, 10.96, 12.02, 12.42, 12.93, 13.20, 13.85, 14.60, 14.94, 15.68, 16.15, 17.73, 18.25, 18.86, 19.44, 20.22, 20.64, 21.01, 21.21, 21.82, 22.36, 22.92, 24.37, 26.48, 27.67, and 28.73, with a 2θ error range of ±0.2°.

4. The crystal form I as described in claim 1, characterized in that, The X-ray powder diffraction pattern of crystal form I is shown in Figure 1.

5. Crystal form II of N-(6-((5-bromo-2-((6-isopropyl-8-methoxy-3-methyl-3,4,5,6-tetrahydrobenzo[b]pyrazolo[4,3-d]aza-9-yl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)methanesulfonamide of formula (A), characterized in that, The X-ray powder diffraction pattern of crystal form II has characteristic peaks at 2θ values ​​of 5.84, 9.92, 12.33, 15.90, 22.89, and 25.67, with a 2θ error range of ±0.2°.

6. The crystal form II as described in claim 5, characterized in that, The X-ray powder diffraction pattern of crystal form II has characteristic peaks at 2θ values ​​of 5.84, 9.92, 10.40, 12.33, 13.81, 14.63, 15.90, 19.29, 20.28, 22.51, 22.89, 23.79, 24.23, 25.36, 25.67, and 26.09, with a 2θ error range of ±0.2°.

7. The crystal form II as described in claim 5, characterized in that, The X-ray powder diffraction pattern of crystal form II has characteristic peaks at 2θ values ​​of 5.84, 9.92, 10.40, 11.16, 11.78, 12.33, 13.81, 14.63, 15.02, 15.90, 17.13, 17.60, 19.29, 20.28, 20.67, 21.34, 21.83, 22.16, 22.51, 22.89, 23.40, 23.79, 24.23, 25.36, 25.67, 26.09, 27.22, 29.90, and 30.67, with a 2θ error range of ±0.2°.

8. The crystal form II as described in claim 5, characterized in that, The X-ray powder diffraction pattern of crystal form II is shown in Figure 2.

9. The crystal form III of N-(6-((5-bromo-2-((6-isopropyl-8-methoxy-3-methyl-3,4,5,6-tetrahydrobenzo[b]pyrazolo[4,3-d]aza-9-yl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)methanesulfonamide of formula (A), characterized in that, The X-ray powder diffraction pattern of crystal form III has characteristic peaks at 2θ values ​​of 5.49, 11.05, 21.77, 22.30, and 24.36, with a 2θ error range of ±0.2°.

10. Crystal form III as described in claim 9, characterized in that, The X-ray powder diffraction pattern of crystal form III has characteristic peaks at 2θ values ​​of 5.49, 9.10, 9.98, 11.05, 14.09, 15.47, 16.64, 19.34, 20.41, 21.36, 21.77, 22.30, 24.36, 26.68, and 26.96, with a 2θ error range of ±0.2°.

11. The crystal form III as described in claim 9, characterized in that, The X-ray powder diffraction pattern of crystal form III has characteristic peaks at 2θ values ​​of 5.49, 9.10, 9.98, 10.30, 11.05, 12.11, 14.09, 15.47, 16.41, 16.64, 17.58, 18.37, 19.34, 20.41, 21.36, 21.77, 22.30, 24.36, 25.12, 25.65, 26.68, 26.96, 27.39, 28.18, and 31.91, with a 2θ error range of ±0.2°.

12. The crystal form III as described in claim 9, characterized in that, The X-ray powder diffraction pattern of crystal form III is shown in Figure 3.

13. The crystal form IV of N-(6-((5-bromo-2-((6-isopropyl-8-methoxy-3-methyl-3,4,5,6-tetrahydrobenzo[b]pyrazolo[4,3-d]aza-9-yl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)methanesulfonamide of formula (A), characterized in that, The X-ray powder diffraction pattern of crystal form IV has characteristic peaks at 2θ values ​​of 5.68, 10.42, 21.64, 22.20, and 24.55, with a 2θ error range of ±0.2°.

14. Crystal form IV as described in claim 13, characterized in that, The X-ray powder diffraction pattern of crystal form IV has characteristic peaks at 2θ values ​​of 5.68, 8.33, 9.17, 10.42, 11.52, 12.23, 16.34, 16.79, 17.69, 17.95, 19.56, 20.16, 21.64, 22.20, 24.55, 26.85, and 27.14, with a 2θ error range of ±0.2°.

15. Crystal form IV as described in claim 13, characterized in that, The X-ray powder diffraction pattern of crystal form IV has characteristic peaks at 2θ values ​​of 5.68, 8.33, 9.17, 10.42, 10.72, 11.52, 12.23, 13.05, 13.84, 16.34, 16.79, 17.22, 17.69, 17.95, 18.92, 19.56, 20.16, 21.27, 21.64, 22.20, 23.00, 23.36, 23.80, 24.55, 25.55, 25.99, 26.85, 27.14, and 28.01, with a 2θ error range of ±0.2°.

16. Crystal form IV as described in claim 13, characterized in that, The X-ray powder diffraction pattern of crystal form IV is shown in Figure 4.

17. The crystal form V of N-(6-((5-bromo-2-((6-isopropyl-8-methoxy-3-methyl-3,4,5,6-tetrahydrobenzo[b]pyrazolo[4,3-d]aza-9-yl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)methanesulfonamide of formula (A), characterized in that, The X-ray powder diffraction pattern of the crystal form V has characteristic peaks at 2θ values ​​of 5.57, 8.50, 10.03, 14.23, 20.00, and 22.60, with a 2θ error range of ±0.2°.

18. The crystal form V as described in claim 17, characterized in that, The X-ray powder diffraction pattern of crystal form V has characteristic peaks at 2θ values ​​of 5.57, 8.50, 10.03, 14.23, 16.46, 18.72, 20.00, 21.38, 22.13, 22.60, 22.85, 23.95, 24.57, 26.17, 26.48, and 30.81, with a 2θ error range of ±0.2°.

19. The crystal form V as described in claim 17, characterized in that, The X-ray powder diffraction pattern of crystal form V has characteristic peaks at 2θ values ​​of 4.21, 5.57, 8.50, 9.42, 10.03, 10.65, 11.86, 12.81, 13.43, 14.23, 15.83, 16.46, 17.32, 17.57, 18.34, 18.72, 19.12, 20.00, 20.66, 21.38, 22.13, 22.60, 22.85, 23.52, 23.95, 24.22, 24.57, 26.17, 26.48, 27.31, 27.93, 28.51, 30.13, and 30.81, with a 2θ error range of ±0.2°.

20. The crystal form V as described in claim 17, characterized in that, The X-ray powder diffraction pattern of crystal form V is shown in Figure 5.

21. The crystal form VI of compound N-(6-((5-bromo-2-((6-isopropyl-8-methoxy-3-methyl-3,4,5,6-tetrahydrobenzo[b]pyrazolo[4,3-d]aza-9-yl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)methanesulfonamide of formula (A), characterized in that, The X-ray powder diffraction pattern of the crystal form VI has characteristic peaks at 2θ values ​​of 6.82, 9.61, 12.32, 13.75, 14.10, and 20.52, with a 2θ error range of ±0.2°.

22. The crystal form VI as described in claim 21, characterized in that, The X-ray powder diffraction pattern of crystal form VI has characteristic peaks at 2θ values ​​of 5.84, 6.82, 8.87, 9.61, 12.32, 12.48, 13.23, 13.75, 14.10, 15.24, 16.07, 18.43, 20.52, 21.05, 22.40, 22.89, 23.71, 24.47, and 25.28, with a 2θ error range of ±0.2°.

23. The crystal form VI as described in claim 21, characterized in that, The X-ray powder diffraction pattern of crystal form VI has characteristic peaks at 2θ values ​​of 5.84, 6.82, 8.87, 9.10, 9.61, 12.32, 12.48, 13.23, 13.75, 14.10, 15.24, 16.07, 17.84, 18.43, 19.70, 20.52, 21.05, 21.52, 22.40, 22.89, 23.71, 24.47, 24.87, 25.28, 26.76, 27.31, 27.87, and 30.50, with a 2θ error range of ±0.2°.

24. The crystal form VI as described in claim 21, characterized in that, The X-ray powder diffraction pattern of crystal form VI is shown in Figure 6.

25. The crystalline form VII of N-(6-((5-bromo-2-((6-isopropyl-8-methoxy-3-methyl-3,4,5,6-tetrahydrobenzo[b]pyrazolo[4,3-d]aza-9-yl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)methanesulfonamide of formula (A), characterized in that, The X-ray powder diffraction pattern of crystal form VII has characteristic peaks at 2θ values ​​of 14.54, 15.24, 17.48, 20.15, and 24.08, with a 2θ error range of ±0.2°.

26. The crystal form VII as described in claim 25, characterized in that, The X-ray powder diffraction pattern of crystal form VII has characteristic peaks at 2θ values ​​of 10.10, 10.30, 11.33, 12.20, 14.54, 15.24, 17.48, 17.66, 18.88, 20.15, 21.12, 22.99, 23.33, 23.78, 24.08, and 26.67, with a 2θ error range of ±0.2°.

27. The crystal form VII as described in claim 25, characterized in that, The X-ray powder diffraction pattern of crystal form VII has characteristic peaks at 2θ values ​​of 7.23, 8.80, 10.10, 10.30, 11.33, 12.20, 12.61, 13.23, 14.54, 15.24, 15.83, 16.87, 17.48, 17.66, 18.35, 18.88, 20.15, 21.12, 22.61, 22.99, 23.33, 23.78, 24.08, 24.61, 26.67, 27.87, 29.50, and 30.62, with a 2θ error range of ±0.2°.

28. The crystal form VII as described in claim 25, characterized in that, The X-ray powder diffraction pattern of crystal form VII is shown in Figure 7.

29. The crystalline form VIII of compound (A) N-(6-((5-bromo-2-((6-isopropyl-8-methoxy-3-methyl-3,4,5,6-tetrahydrobenzo[b]pyrazolo[4,3-d]aza-9-yl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)methanesulfonamide, characterized in that, The X-ray powder diffraction pattern of crystal form VIII has characteristic peaks at 2θ values ​​of 5.49, 13.58, 15.88, 21.11, and 22.48, with a 2θ error range of ±0.2°.

30. The crystal form VIII as described in claim 29, characterized in that, The X-ray powder diffraction pattern of crystal form VIII has characteristic peaks at 2θ values ​​of 5.49, 10.08, 11.07, 11.74, 13.58, 13.77, 15.88, 16.99, 20.76, 21.11, 21.42, 22.48, 25.00, 25.63, 26.98, and 30.73, with a 2θ error range of ±0.2°.

31. The crystal form VIII as described in claim 29, characterized in that, The X-ray powder diffraction pattern of crystal form VIII has characteristic peaks at 2θ values ​​of 4.47, 5.49, 9.00, 9.85, 10.08, 11.07, 11.74, 12.37, 13.03, 13.58, 13.77, 14.92, 15.88, 16.68, 16.99, 17.44, 18.59, 19.91, 20.76, 21.11, 21.42, 22.48, 23.57, 23.73, 25.00, 25.32, 25.63, 26.98, 27.79, 29.80, and 30.73, with a 2θ error range of ±0.2°.

32. The crystal form VIII as described in claim 29, characterized in that, The X-ray powder diffraction pattern of crystal form VIII is shown in Figure 8.

33. The crystal form IX of compound (A) N-(6-((5-bromo-2-((6-isopropyl-8-methoxy-3-methyl-3,4,5,6-tetrahydrobenzo[b]pyrazolo[4,3-d]aza-9-yl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)methanesulfonamide, characterized in that, The X-ray powder diffraction pattern of the crystal form IX has characteristic peaks at 2θ values ​​of 5.79, 8.84, 11.66, 21.96, and 24.74, with a 2θ error range of ±0.2°.

34. The crystal form IX as described in claim 33, characterized in that, The X-ray powder diffraction pattern of crystal form IX has characteristic peaks at 2θ values ​​of 5.79, 8.14, 8.84, 9.90, 11.66, 15.61, 17.12, 17.59, 19.93, 21.11, 21.74, 21.96, 23.48, 24.74, 25.13, 26.69, and 27.22, with a 2θ error range of ±0.2°.

35. The crystal form IX as described in claim 33, characterized in that, The X-ray powder diffraction pattern of crystal form IX has characteristic peaks at 2θ values ​​of 5.79, 8.14, 8.84, 9.04, 9.90, 11.66, 15.61, 17.12, 17.59, 17.90, 18.23, 18.61, 19.68, 19.93, 20.82, 21.11, 21.74, 21.96, 23.48, 24.39, 24.74, 25.13, 26.42, 26.69, 27.22, and 30.33, with a 2θ error range of ±0.2°.

36. The crystal form IX as described in claim 33, characterized in that, The X-ray powder diffraction pattern of crystal form IX is shown in Figure 9.

37. The crystalline form XII of compound (A) N-(6-((5-bromo-2-((6-isopropyl-8-methoxy-3-methyl-3,4,5,6-tetrahydrobenzo[b]pyrazolo[4,3-d]aza-9-yl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)methanesulfonamide, characterized in that, The X-ray powder diffraction pattern of the crystal form XII has characteristic peaks at 2θ values ​​of 5.83, 6.80, 20.48, 24.92, and 27.49, with a 2θ error range of ±0.2°.

38. The crystal form XII as described in claim 37, characterized in that, The X-ray powder diffraction pattern of the crystal form XII has characteristic peaks at 2θ values ​​of 5.83, 6.80, 9.50, 11.84, 13.62, 14.23, 14.54, 16.72, 17.50, 18.42, 20.48, 20.85, 21.40, 23.35, 24.92, and 27.49, with a 2θ error range of ±0.2°.

39. The crystal form XII as described in claim 37, characterized in that, The X-ray powder diffraction pattern of crystal form XII has characteristic peaks at 2θ values ​​of 5.83, 6.80, 8.40, 9.50, 9.71, 10.82, 11.84, 12.90, 13.62, 14.23, 14.54, 16.72, 17.50, 18.42, 19.66, 20.48, 20.85, 21.40, 21.81, 23.35, 23.95, 24.92, 26.62, 27.49, 31.17, 32.45, and 33.62, with a 2θ error range of ±0.2°.

40. The crystal form XII as described in claim 37, characterized in that, The X-ray powder diffraction pattern of the crystal form XII is shown in Figure 10.

41. The crystalline form XIV of compound (A) N-(6-((5-bromo-2-((6-isopropyl-8-methoxy-3-methyl-3,4,5,6-tetrahydrobenzo[b]pyrazolo[4,3-d]aza-9-yl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)methanesulfonamide, characterized in that, The X-ray powder diffraction pattern of the crystal form XIV has characteristic peaks at 2θ values ​​of 5.86, 11.73, 23.56, 29.55, and 35.65, with a 2θ error range of ±0.2°.

42. The crystal form XIV as described in claim 41, characterized in that, The X-ray powder diffraction pattern of the crystal form XIV has characteristic peaks at 2θ values ​​of 5.86, 11.73, 13.85, 20.91, 22.32, 23.56, 24.69, 25.30, 26.72, 29.55, 33.09, 35.65, and 38.91, with a 2θ error range of ±0.2°.

43. The crystal form XIV as described in claim 41, characterized in that, The X-ray powder diffraction pattern of the crystal form XIV is shown in Figure 11.

44. Compound of formula (I), 。 45. A crystal form A of the compound of formula (I) as described in claim 44, characterized in that, The X-ray powder diffraction pattern of crystal form A has characteristic peaks at 2θ values ​​of 7.38, 8.13, 12.62, 20.14, 21.41, and 23.72, with a 2θ error range of ±0.2°.

46. ​​Crystal form A as described in claim 45, characterized in that, The X-ray powder diffraction pattern of crystal form A has characteristic peaks at 2θ values ​​of 7.38, 7.69, 8.13, 12.62, 14.12, 14.95, 17.43, 18.79, 20.14, 20.32, 21.41, 23.72, 26.47, and 28.26, with a 2θ error range of ±0.2°.

47. Crystal form A as described in claim 45, characterized in that, The X-ray powder diffraction pattern of crystal form A has characteristic peaks at 2θ values ​​of 7.38, 7.69, 8.13, 9.31, 12.62, 14.12, 14.95, 15.96, 17.43, 18.44, 18.79, 19.09, 19.57, 19.93, 20.14, 20.32, 21.41, 22.66, 23.72, 25.08, 25.53, 26.47, 28.26, 30.02, and 31.91, with a 2θ error range of ±0.2°.

48. Crystal form A as described in claim 45, characterized in that, The X-ray powder diffraction pattern of crystal form A is shown in Figure 12.

49. A crystal form B of the compound of formula (I) as described in claim 44, characterized in that, The X-ray powder diffraction pattern of crystal form B has characteristic peaks at 2θ values ​​of 5.89, 7.25, 9.37, 22.49, 25.45, and 27.05, with a 2θ error range of ±0.2°.

50. Crystal form B as described in claim 49, characterized in that, The X-ray powder diffraction pattern of crystal form B has characteristic peaks at 2θ values ​​of 5.89, 6.43, 7.25, 9.37, 12.42, 12.95, 15.16, 17.37, 17.76, 18.64, 18.89, 21.14, 21.57, 21.99, 22.49, 25.45, and 27.05, with a 2θ error range of ±0.2°.

51. Crystal form B as described in claim 49, characterized in that, The X-ray powder diffraction pattern of crystal form B has characteristic peaks at 2θ values ​​of 5.89, 6.43, 7.25, 8.35, 9.37, 12.42, 12.95, 13.29, 14.04, 15.16, 15.84, 16.23, 16.83, 17.37, 17.76, 18.64, 18.89, 20.12, 21.14, 21.57, 21.99, 22.49, 22.84, 23.63, 24.58, 25.45, 27.05, and 30.01, with a 2θ error range of ±0.2°.

52. Crystal form B as described in claim 49, characterized in that, The X-ray powder diffraction pattern of crystal form B is shown in Figure 13.

53. A crystal form C of the compound of formula (I) as described in claim 44, characterized in that, The X-ray powder diffraction pattern of the crystal form C has characteristic peaks at 2θ values ​​of 5.85, 12.41, 17.76, 22.48, and 27.03, with a 2θ error range of ±0.2°.

54. The crystal form C as described in claim 53, characterized in that, The X-ray powder diffraction pattern of the crystal form C has characteristic peaks at 2θ values ​​of 5.85, 9.35, 12.41, 15.82, 17.36, 17.76, 18.64, 18.88, 21.12, 21.57, 21.97, 22.48, 22.87, 23.73, 25.42, and 27.03, with a 2θ error range of ±0.2°.

55. The crystal form C as described in claim 53, characterized in that, The X-ray powder diffraction pattern of crystal form C has characteristic peaks at 2θ values ​​of 5.85, 9.35, 11.75, 12.41, 13.18, 13.27, 14.04, 14.83, 15.07, 15.82, 16.22, 17.36, 17.76, 18.64, 18.88, 20.11, 21.12, 21.40, 21.57, 21.97, 22.48, 22.87, 23.73, 25.42, 27.03, 27.84, 28.32, and 29.96, with a 2θ error range of ±0.2°.

56. The crystal form C as described in claim 53, characterized in that, The X-ray powder diffraction pattern of crystal form C is shown in Figure 14.

57. A crystal form D of the compound of formula (I) as described in claim 44, characterized in that, The X-ray powder diffraction pattern of the crystal form D has characteristic peaks at 2θ values ​​of 5.55, 13.03, 16.73, 22.48, and 24.17, with a 2θ error range of ±0.2°.

58. The crystal form D as described in claim 57, characterized in that, The X-ray powder diffraction pattern of crystal form D has characteristic peaks at 2θ values ​​of 5.55, 11.16, 12.39, 12.70, 13.03, 13.42, 14.74, 16.73, 18.11, 20.96, 22.48, 23.33, 23.83, 24.17, 26.05, and 34.02, with a 2θ error range of ±0.2°.

59. The crystal form D as described in claim 57, characterized in that, The X-ray powder diffraction pattern of crystal form D has characteristic peaks at 2θ values ​​of 5.55, 7.23, 8.70, 10.72, 11.16, 12.39, 12.70, 13.03, 13.42, 14.54, 14.74, 15.51, 16.32, 16.73, 18.11, 20.43, 20.96, 21.37, 22.48, 23.33, 23.83, 24.17, 25.62, 26.05, 26.42, 27.77, 27.93, 28.80, 32.72, 33.41, and 34.02, with a 2θ error range of ±0.2°.

60. The crystal form D as described in claim 57, characterized in that, The X-ray powder diffraction pattern of crystal form D is shown in Figure 15.

61. A pharmaceutical composition comprising the crystal form of any one of claims 1-43, 45-60 or the compound of claim 44 and a pharmaceutically acceptable carrier.

62. Use of the crystal form of any one of claims 1-43, 45-60, the compound of claim 44, or the pharmaceutical composition of claim 61 in the preparation of a medicament for treating cancer, wherein the cancer is mediated by an EGFR mutation.

63. The use as described in claim 62, wherein the cancer is selected from lymphoma, ovarian cancer, cervical cancer, prostate cancer, colorectal cancer, breast cancer, pancreatic cancer, glioma, melanoma, leukemia, gastric cancer, endometrial cancer, lung cancer, hepatocellular carcinoma, gastrointestinal stromal tumor (GIST), cholangiocarcinoma, renal cancer, thyroid cancer, mesothelioma, and multiple myeloma.

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