TW202317098A - Polymorphs of egfr inhibitor - Google Patents
Polymorphs of egfr inhibitor Download PDFInfo
- Publication number
- TW202317098A TW202317098A TW111138877A TW111138877A TW202317098A TW 202317098 A TW202317098 A TW 202317098A TW 111138877 A TW111138877 A TW 111138877A TW 111138877 A TW111138877 A TW 111138877A TW 202317098 A TW202317098 A TW 202317098A
- Authority
- TW
- Taiwan
- Prior art keywords
- crystal form
- diffraction pattern
- ray powder
- powder diffraction
- error range
- Prior art date
Links
Images
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
Abstract
Description
本申請要求申請日為2021年10月14日的中國專利申請202111197313.7、申請日為2021年10月14日的中國專利申請202111196875.X的優先權，申請日為2021年10月14日的中國專利申請202111197957.6的優先權，本申請引用上述中國專利申請的全文。This application claims the priority of Chinese patent application 202111197313.7 with a filing date of October 14, 2021, Chinese patent application 202111196875.X with a filing date of October 14, 2021, and Chinese patent application with a filing date of October 14, 2021 The priority of application 202111197957.6, this application refers to the full text of the above-mentioned Chinese patent application.
本發明公開了一種EGFR抑制劑的多種晶型及其製備方法，以及它們在治療癌症中的應用。The invention discloses multiple crystal forms of an EGFR inhibitor, a preparation method thereof, and their application in treating cancer.
EGFR，即表皮生長因數受體（epidermal growth factor receptor），廣泛分佈於哺乳動物上皮細胞、成纖維細胞、膠質細胞等細胞表面。EGFR訊號通路對細胞的生長、增殖和分化等生理過程發揮著重要的作用。EGFR突變也是NSCLC患者中最常見的一種突變類型，尤其是在亞洲人群中可以占到40%~50%。因此EGFR一直是藥物研發領域的最熱門靶點之一。EGFR, the epidermal growth factor receptor (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 an important role in physiological processes such as cell growth, proliferation and differentiation. EGFR mutation is also the most common type of mutation in NSCLC patients, especially in Asian populations, accounting for 40% to 50%. Therefore, EGFR has always been one of the hottest targets in the field of drug development.
目前，上市的EGFR抑制劑分為第一、二、三代。第一代為可逆的靶向藥物，例如吉非替尼、厄洛替尼、埃克替尼。第二代為不可逆的靶向藥物，例如阿法替尼以及達克替尼。第一、二代靶向藥物雖然療效顯著，但多數患者都會在使用藥物1-2年後出現耐藥性。EGFR抑制劑耐藥的患者中，有50%的耐藥與T790M突變有關。第三代EGFR靶向藥物奧希替尼能克服由於T790M突變引起的腫瘤耐藥，給更多的肺癌患者帶來了更好的生存獲益。然而第三代靶向藥也不可避免的產生耐藥，其耐藥原因主要為C797S突變。C797S突變體現為半胱氨酸殘基突變成絲氨酸，這一突變破壞了EGFR蛋白與第三代靶向藥物結合，從而無法阻止EGFR蛋白的磷酸化以及下游訊號通路的活化。目前對於奧希替尼耐藥後主要出現的兩種順式三突變：Del19/T790M/C797S和L858R/T790M/C797S的應對尚無成熟的治療手段，臨床需求迫在眉睫。At present, the EGFR inhibitors on the market are divided into the first, second and third generations. The first generation is reversible targeted drugs, such as gefitinib, erlotinib, and icotinib. The second generation is irreversible targeted drugs, such as afatinib and dacomitinib. Although the first and second generation targeted drugs are effective, most patients will develop drug resistance after 1-2 years of drug use. Among patients with EGFR inhibitor resistance, 50% of drug resistance is related to T790M mutation. The third-generation EGFR-targeted drug osimertinib can overcome the tumor resistance caused by the T790M mutation, bringing better survival benefits to more lung cancer patients. However, the third-generation targeted drugs inevitably produce drug resistance, and the main cause of drug resistance is the C797S mutation. The C797S mutation is manifested by the mutation of the cysteine residue to serine, which destroys the binding of the EGFR protein to the third-generation targeted drugs, thus preventing the phosphorylation of the EGFR protein and the activation of downstream signaling pathways. At present, there are no mature treatment methods for the two main cis-type triple mutations after osimertinib resistance: Del19/T790M/C797S and L858R/T790M/C797S, and the clinical needs are imminent.
本申請人在專利PCT/CN2021/086941中公開了一種針對C797S突變的小分子EGFR抑制劑，其結構如式（A）所示，化學名稱為
N-(6-((5-溴-2-((6-異丙基-8-甲氧基-3-甲基-3,4,5,6-四氫苯並[b]吡唑並[4,3-d]氮雜-9-基)氨基)-嘧啶-4-基)氨基)-喹喔啉-5-基)甲磺醯胺。該小分子抑制劑具有良好的激酶抑制活性和細胞抗增殖活性，同時該分子在小鼠模型上體現了較好的抗腫瘤活性及耐受性，有望開發成臨床藥物。
本發明公開了一種EGFR抑制劑的多晶型、製備方法，以及它們在治療癌症疾病中的應用。The invention discloses a polymorphic form of an EGFR inhibitor, a preparation method and their application in treating cancer diseases.
具體的，本發明提供式（A）化合物 N-(6-((5-溴-2-((6-異丙基-8-甲氧基-3-甲基-3,4,5,6-四氫苯並[b]吡唑並[4,3-d]氮雜-9-基)氨基)-嘧啶-4-基)氨基)-喹喔啉-5-基)甲磺醯胺的晶型I，所述晶型I的X-射線粉末繞射圖譜在2θ值為7.83、13.85、18.25、20.22、24.37處有特徵峰，2θ誤差範圍為±0.2°。 Specifically, the present invention provides the compound 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 Crystal form I, the X-ray powder diffraction pattern of the crystal form I has characteristic peaks at 2θ values of 7.83, 13.85, 18.25, 20.22, and 24.37, and the 2θ error range is ±0.2°.
在本發明的一些方案中，上述晶型I，其X-射線粉末繞射圖譜在2θ值為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、26.48處有特徵峰，2θ誤差範圍為±0.2°。In some solutions of the present invention, the X-ray powder diffraction pattern of the above crystal form I has a 2θ value 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 have characteristic peaks, and the 2θ error range is ±0.2°.
在本發明的一些方案中，上述晶型I，其X-射線粉末繞射圖譜在2θ值為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、28.73處有特徵峰，2θ誤差範圍為±0.2°。In some solutions of the present invention, the X-ray powder diffraction pattern of the above crystal form I has a 2θ value 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, 28.73 have characteristic peaks, and the 2θ error range is ±0.2°.
在本發明的一些方案中，上述晶型I，其X-射線粉末繞射圖譜如圖1所示。In some solutions of the present invention, the X-ray powder diffraction pattern of the above-mentioned crystal form I is shown in FIG. 1 .
在本發明的一些方案中，上述晶型I，其DSC譜圖在212°C左右有特徵峰。In some solutions of the present invention, the DSC spectrum of the above crystal form I has a characteristic peak at around 212°C.
在本發明的一些方案中，上述晶型I，其DSC譜圖在261°C 左右有特徵峰。In some solutions of the present invention, the DSC spectrum of the above-mentioned crystal form I has a characteristic peak at around 261°C.
在本發明的一些方案中，上述晶型I，其TGA-DSC譜圖基本如圖18所示。In some solutions of the present invention, the TGA-DSC spectrum of the above crystal form I is basically as shown in FIG. 18 .
本發明的一些方案中，上述式（A）化合物晶型I的XRPD圖譜繞射峰解析資料如表1所示。In some solutions of the present invention, the XRPD spectrum diffraction peak analysis data of the crystal form I of the compound of the above formula (A) is shown in Table 1.
表
本發明還提供式（A）化合物 N-(6-((5-溴-2-((6-異丙基-8-甲氧基-3-甲基-3,4,5,6-四氫苯並[b]吡唑並[4,3-d]氮雜-9-基)氨基)-嘧啶-4-基)氨基)-喹喔啉-5-基)甲磺醯胺的晶型II，所述晶型II的X-射線粉末繞射圖譜在2θ值為5.84、9.92、12.33、15.90、22.89、25.67處有特徵峰，2θ誤差範圍為±0.2°。 The present invention also provides formula (A) compound N- (6-((5-bromo-2-((6-isopropyl-8-methoxy-3-methyl-3,4,5,6-tetra Crystalline form of hydrobenzo[b]pyrazolo[4,3-d]azepin-9-yl)amino)-pyrimidin-4-yl)amino)-quinoxalin-5-yl)methanesulfonamide II, the X-ray powder diffraction pattern of the crystal form II has characteristic peaks at 2θ values of 5.84, 9.92, 12.33, 15.90, 22.89, and 25.67, and the 2θ error range is ±0.2°.
在本發明的一些方案中，上述晶型II，其X-射線粉末繞射圖譜在2θ值為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、26.09處有特徵峰，2θ誤差範圍為±0.2°。In some solutions of the present invention, the X-ray powder diffraction pattern of the above crystal form II has a 2θ value 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 have characteristic peaks, and the 2θ error range is ±0.2°.
在本發明的一些方案中，上述晶型II，其X-射線粉末繞射圖譜在2θ值為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、30.67處有特徵峰，2θ誤差範圍為±0.2°。In some solutions of the present invention, the X-ray powder diffraction pattern of the above crystal form II has a 2θ value 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, 30.67 have characteristic peaks, and the 2θ error range is ±0.2°.
在本發明的一些方案中，上述晶型II，其X-射線粉末繞射圖譜如圖2所示。In some solutions of the present invention, the X-ray powder diffraction pattern of the above-mentioned crystal form II is shown in FIG. 2 .
在本發明的一些方案中，上述晶型II，所述晶型的DSC譜圖在262°C左右有特徵峰。In some solutions of the present invention, the above crystal form II, the DSC spectrum of the crystal form has a characteristic peak at around 262°C.
在本發明的一些方案中，上述晶型II，所述晶型的TGA-DSC譜圖如圖19所示。In some solutions of the present invention, the above crystal form II, the TGA-DSC spectrum of said crystal form is shown in FIG. 19 .
本發明的一些方案中，上述式（A）化合物晶型II的XRPD圖譜繞射峰解析資料如表2所示。In some schemes of the present invention, the XRPD spectrum diffraction peak analysis data of the crystal form II of the compound of formula (A) is shown in Table 2.
表
本發明還提供式（A）化合物N-(6-((5-溴-2-((6-異丙基-8-甲氧基-3-甲基-3,4,5,6-四氫苯並[b]吡唑並[4,3-d]氮雜-9-基)氨基)-嘧啶-4-基)氨基)-喹喔啉-5-基)甲磺醯胺的晶型III，所述晶型III的X-射線粉末繞射圖譜在2θ值為5.49、11.05、21.77、22.30、24.36處有特徵峰，2θ誤差範圍為±0.2°。The present invention also provides formula (A) compound N-(6-((5-bromo-2-((6-isopropyl-8-methoxy-3-methyl-3,4,5,6-tetra Crystalline form of hydrobenzo[b]pyrazolo[4,3-d]azepin-9-yl)amino)-pyrimidin-4-yl)amino)-quinoxalin-5-yl)methanesulfonamide III, 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, and the 2θ error range is ±0.2°.
在本發明的一些方案中，上述晶型III，其X-射線粉末繞射圖譜在2θ值為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、26.96處有特徵峰，2θ誤差範圍為±0.2°。In some solutions of the present invention, the X-ray powder diffraction pattern of the above crystal form III has a 2θ value 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 have characteristic peaks, and the 2θ error range is ±0.2°.
在本發明的一些方案中，上述晶型III，其X-射線粉末繞射圖譜在2θ值為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、31.91處有特徵峰，2θ誤差範圍為±0.2°。In some solutions of the present invention, the X-ray powder diffraction pattern of the above crystal form III has a 2θ value 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, 31.91 have characteristic peaks, and the 2θ error range is ±0.2°.
在本發明的一些方案中，上述晶型III，其X-射線粉末繞射圖譜如圖3所示。In some solutions of the present invention, the X-ray powder diffraction pattern of the above-mentioned crystal form III is shown in FIG. 3 .
在本發明的一些方案中，上述晶型III，其DSC譜圖在253°C左右有特徵峰。In some solutions of the present invention, the DSC spectrum of the above crystal form III has characteristic peaks at around 253°C.
在本發明的一些方案中，上述晶型III，其DSC譜圖在264°C左右有特徵峰。In some solutions of the present invention, the DSC spectrum of the above-mentioned crystal form III has characteristic peaks around 264°C.
在本發明的一些方案中，上述晶型III，其TGA-DSC譜圖基本如圖20所示。In some solutions of the present invention, the TGA-DSC spectrum of the above-mentioned crystal form III is basically as shown in FIG. 20 .
本發明的一些方案中，上述式（A）化合物晶型III的XRPD圖譜繞射峰解析資料如表3所示。In some solutions of the present invention, the XRPD spectrum diffraction peak analysis data of the above-mentioned compound of formula (A) crystal form III is shown in Table 3.
表
本發明提供式（A）化合物N-(6-((5-溴-2-((6-異丙基-8-甲氧基-3-甲基-3,4,5,6-四氫苯並[b]吡唑並[4,3-d]氮雜-9-基)氨基)-嘧啶-4-基)氨基)-喹喔啉-5-基)甲磺醯胺的晶型IV，所述晶型IV的射線粉末繞射圖譜在2θ值為5.68、10.42、21.64、22.20、24.55處有特徵峰，2θ誤差範圍為±0.2°。The present invention provides formula (A) compound N-(6-((5-bromo-2-((6-isopropyl-8-methoxy-3-methyl-3,4,5,6-tetrahydro Form IV of benzo[b]pyrazolo[4,3-d]azepin-9-yl)amino)-pyrimidin-4-yl)amino)-quinoxalin-5-yl)methanesulfonamide , the ray powder diffraction pattern of the crystal form IV has characteristic peaks at 2θ values of 5.68, 10.42, 21.64, 22.20, and 24.55, and the 2θ error range is ±0.2°.
在本發明的一些方案中，上述晶型IV其X-射線粉末繞射圖譜在2θ值為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、27.14處有特徵峰，2θ誤差範圍為±0.2°。In some solutions of the present invention, the X-ray powder diffraction pattern of the above crystal form IV has 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, There are characteristic peaks at 22.20, 24.55, 26.85, and 27.14, and the 2θ error range is ±0.2°.
在本發明的一些方案中，上述晶型IV其X-射線粉末繞射圖譜在2θ值為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、28.01處有特徵峰，2θ誤差範圍為±0.2°。In some solutions of the present invention, the X-ray powder diffraction pattern of the above-mentioned crystal form IV has a 2θ value 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, There are characteristic peaks at 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, and the 2θ error range is ±0.2°.
在本發明的一些方案中，上述晶型IV其X-射線粉末繞射圖譜如圖4所示。In some solutions of the present invention, the X-ray powder diffraction pattern of the above crystal form IV is shown in FIG. 4 .
在本發明的一些方案中，上述晶型IV，其TGA-DSC譜圖基本如圖21所示。In some solutions of the present invention, the TGA-DSC spectrum of the above crystal form IV is basically as shown in FIG. 21 .
本發明的一些方案中，上述式（A）化合物晶型IV的XRPD圖譜繞射峰解析資料如表4所示。In some schemes of the present invention, the XRPD spectrum diffraction peak analysis data of the crystal form IV of the compound of the above formula (A) is shown in Table 4.
表
本發明還提供式（A）化合物N-(6-((5-溴-2-((6-異丙基-8-甲氧基-3-甲基-3,4,5,6-四氫苯並[b]吡唑並[4,3-d]氮雜-9-基)氨基)-嘧啶-4-基)氨基)-喹喔啉-5-基)甲磺醯胺的晶型V，所述晶型V的X-射線粉末繞射圖譜在2θ值為5.57、8.50、10.03、14.23、20.00、22.60處有特徵峰，2θ誤差範圍為±0.2°。The present invention also provides formula (A) compound N-(6-((5-bromo-2-((6-isopropyl-8-methoxy-3-methyl-3,4,5,6-tetra Crystalline form of hydrobenzo[b]pyrazolo[4,3-d]azepin-9-yl)amino)-pyrimidin-4-yl)amino)-quinoxalin-5-yl)methanesulfonamide V, 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, and the 2θ error range is ±0.2°.
在本發明的一些方案中，上述晶型V，其X-射線粉末繞射圖譜在2θ值為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、30.81處有特徵峰，2θ誤差範圍為±0.2°。In some solutions of the present invention, the X-ray powder diffraction pattern of the above-mentioned crystal form V has a 2θ value 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 have characteristic peaks, and the 2θ error range is ±0.2°.
在本發明的一些方案中，上述晶型V，其X-射線粉末繞射圖譜在2θ值為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、30.81處有特徵峰，2θ誤差範圍為±0.2°。In some solutions of the present invention, the X-ray powder diffraction pattern of the above-mentioned crystal form V has a 2θ value 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, There is a characteristic peak at 30.81, 2θ error range is ±0.2°.
在本發明的一些方案中，上述晶型V，其X-射線粉末繞射圖譜如圖5所示。In some solutions of the present invention, the X-ray powder diffraction pattern of the above-mentioned crystal form V is shown in FIG. 5 .
在本發明的一些方案中，上述晶型V，其TGA-DSC譜圖基本如圖22所示。In some solutions of the present invention, the TGA-DSC spectrum of the above crystal form V is basically as shown in FIG. 22 .
本發明的一些方案中，上述式（A）化合物晶型V的XRPD圖譜繞射峰解析資料如表5所示。In some schemes of the present invention, the XRPD spectrum diffraction peak analysis data of the crystal form V of the compound of the above formula (A) is shown in Table 5.
表
本發明還提供式（A）化合物N-(6-((5-溴-2-((6-異丙基-8-甲氧基-3-甲基-3,4,5,6-四氫苯並[b]吡唑並[4,3-d]氮雜-9-基)氨基)-嘧啶-4-基)氨基)-喹喔啉-5-基)甲磺醯胺的晶型VI，所述晶型VI的X-射線粉末繞射圖譜在2θ值為6.82、9.61、12.32、13.75、14.10、20.52處有特徵峰，2θ誤差範圍為±0.2°。The present invention also provides formula (A) compound N-(6-((5-bromo-2-((6-isopropyl-8-methoxy-3-methyl-3,4,5,6-tetra Crystalline form of hydrobenzo[b]pyrazolo[4,3-d]azepin-9-yl)amino)-pyrimidin-4-yl)amino)-quinoxalin-5-yl)methanesulfonamide VI, 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, and the 2θ error range is ±0.2°.
在本發明的一些方案中，上述晶型VI，其X-射線粉末繞射圖譜在2θ值為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、25.28處有特徵峰，2θ誤差範圍為±0.2°。In some solutions of the present invention, the X-ray powder diffraction pattern of the above crystal form VI has a 2θ value 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 have characteristic peaks, and the 2θ error range is ±0.2°.
在本發明的一些方案中，上述晶型VI，其X-射線粉末繞射圖譜在2θ值為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、30.50處有特徵峰，2θ誤差範圍為±0.2°。In some solutions of the present invention, the X-ray powder diffraction pattern of the above crystal form VI has a 2θ value 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, 30.50 have characteristic peaks, and the 2θ error range is ±0.2°.
在本發明的一些方案中，上述晶型VI，其X-射線粉末繞射圖譜如圖6所示。In some solutions of the present invention, the X-ray powder diffraction pattern of the above-mentioned crystal form VI is shown in FIG. 6 .
在本發明的一些方案中，上述晶型VI，其TGA-DSC譜圖基本如圖23所示。In some solutions of the present invention, the TGA-DSC spectrum of the above crystal form VI is basically as shown in FIG. 23 .
本發明的一些方案中，上述式（A）化合物晶型VI的XRPD圖譜繞射峰解析資料如表6所示。In some schemes of the present invention, the XRPD spectrum diffraction peak analysis data of the crystal form VI of the compound of the above formula (A) is shown in Table 6.
表surface
66
式（Mode(
AA
）化合物晶型) compound crystal form
VIVI
的of
XRPDXRPD
繞射峰解析資料Diffraction peak analysis data
本發明還提供式（A）化合物N-(6-((5-溴-2-((6-異丙基-8-甲氧基-3-甲基-3,4,5,6-四氫苯並[b]吡唑並[4,3-d]氮雜-9-基)氨基)-嘧啶-4-基)氨基)-喹喔啉-5-基)甲磺醯胺的晶型VII，所述晶型VII的X-射線粉末繞射圖譜在2θ值為14.54、15.24、17.48、20.15、24.08處有特徵峰，2θ誤差範圍為±0.2°。The present invention also provides formula (A) compound N-(6-((5-bromo-2-((6-isopropyl-8-methoxy-3-methyl-3,4,5,6-tetra Crystalline form of hydrobenzo[b]pyrazolo[4,3-d]azepin-9-yl)amino)-pyrimidin-4-yl)amino)-quinoxalin-5-yl)methanesulfonamide VII, the X-ray powder diffraction pattern of the crystal form VII has characteristic peaks at 2θ values of 14.54, 15.24, 17.48, 20.15, and 24.08, and the 2θ error range is ±0.2°.
在本發明的一些方案中，上述晶型VII，其X-射線粉末繞射圖譜在2θ值為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、26.67處有特徵峰，2θ誤差範圍為±0.2°。In some solutions of the present invention, the X-ray powder diffraction pattern of the above crystal form VII has a 2θ value 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 have characteristic peaks, and the 2θ error range is ±0.2°.
在本發明的一些方案中，上述晶型VII，其X-射線粉末繞射圖譜在2θ值為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、30.62處有特徵峰，2θ誤差範圍為±0.2°。In some solutions of the present invention, the X-ray powder diffraction pattern of the above crystal form VII has a 2θ value 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, 30.62 have characteristic peaks, and the 2θ error range is ±0.2°.
在本發明的一些方案中，上述晶型VII，其X-射線粉末繞射圖譜如圖7所示。In some solutions of the present invention, the X-ray powder diffraction pattern of the above crystal form VII is shown in FIG. 7 .
在本發明的一些方案中，上述晶型VII，其TGA-DSC譜圖基本如圖24所示。In some solutions of the present invention, the TGA-DSC spectrum of the above crystal form VII is basically as shown in FIG. 24 .
本發明的一些方案中，上述式（A）化合物晶型VII的XRPD圖譜繞射峰解析資料如表7所示。In some schemes of the present invention, the XRPD spectrum diffraction peak analysis data of the compound of the above formula (A) crystal form VII is shown in Table 7.
表
本發明還提供式（A）化合物N-(6-((5-溴-2-((6-異丙基-8-甲氧基-3-甲基-3,4,5,6-四氫苯並[b]吡唑並[4,3-d]氮雜-9-基)氨基)-嘧啶-4-基)氨基)-喹喔啉-5-基)甲磺醯胺的晶型VIII，所述晶型VIII的X-射線粉末繞射圖譜在2θ值為5.49、13.58、15.88、21.11、22.48處有特徵峰，2θ誤差範圍為±0.2°。The present invention also provides formula (A) compound N-(6-((5-bromo-2-((6-isopropyl-8-methoxy-3-methyl-3,4,5,6-tetra Crystalline form of hydrobenzo[b]pyrazolo[4,3-d]azepin-9-yl)amino)-pyrimidin-4-yl)amino)-quinoxalin-5-yl)methanesulfonamide VIII, 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, and the 2θ error range is ±0.2°.
在本發明的一些方案中，上述晶型VIII，其X-射線粉末繞射圖譜在2θ值為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、30.73處有特徵峰，2θ誤差範圍為±0.2°。In some solutions of the present invention, the X-ray powder diffraction pattern of the above crystal form VIII has a 2θ value 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 have characteristic peaks, and the 2θ error range is ±0.2°.
在本發明的一些方案中，上述晶型VIII，其X-射線粉末繞射圖譜在2θ值為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、30.73處有特徵峰，2θ誤差範圍為±0.2°。In some solutions of the present invention, the X-ray powder diffraction pattern of the above crystal form VIII has a 2θ value 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, 30.73 have characteristic peaks, and the 2θ error range is ±0. 2°.
在本發明的一些方案中，上述晶型VIII，其X-射線粉末繞射圖譜如圖8所示。In some solutions of the present invention, the X-ray powder diffraction pattern of the above-mentioned crystal form VIII is shown in FIG. 8 .
在本發明的一些方案中，上述晶型VIII，其TGA-DSC譜圖基本如圖25所示。In some solutions of the present invention, the TGA-DSC spectrum of the above-mentioned crystal form VIII is basically as shown in FIG. 25 .
本發明的一些方案中，上述式（A）化合物晶型VIII的XRPD圖譜繞射峰解析資料如表8所示。In some schemes of the present invention, the XRPD spectrum diffraction peak analysis data of the compound of formula (A) crystal form VIII is shown in Table 8.
表
本發明還提供式（A）化合物N-(6-((5-溴-2-((6-異丙基-8-甲氧基-3-甲基-3,4,5,6-四氫苯並[b]吡唑並[4,3-d]氮雜-9-基)氨基)-嘧啶-4-基)氨基)-喹喔啉-5-基)甲磺醯胺的晶型IX，所述晶型IX的X-射線粉末繞射圖譜在2θ值為5.79、8.84、11.66、21.96、24.74處有特徵峰，2θ誤差範圍為±0.2°。The present invention also provides formula (A) compound N-(6-((5-bromo-2-((6-isopropyl-8-methoxy-3-methyl-3,4,5,6-tetra Crystalline form of hydrobenzo[b]pyrazolo[4,3-d]azepin-9-yl)amino)-pyrimidin-4-yl)amino)-quinoxalin-5-yl)methanesulfonamide IX, 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, and the 2θ error range is ±0.2°.
在本發明的一些方案中，上述晶型IX，其X-射線粉末繞射圖譜在2θ值為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、27.22處有特徵峰，2θ誤差範圍為±0.2°。In some solutions of the present invention, the X-ray powder diffraction pattern of the above crystal form IX has a 2θ value 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 have characteristic peaks, and the 2θ error range is ±0.2°.
在本發明的一些方案中，上述晶型IX，其X-射線粉末繞射圖譜在2θ值為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、30.33處有特徵峰，2θ誤差範圍為±0.2°。In some solutions of the present invention, the X-ray powder diffraction pattern of the above crystal form IX has a 2θ value 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, 30.33 have characteristic peaks, and the 2θ error range is ±0.2°.
在本發明的一些方案中，上述晶型IX，其X-射線粉末繞射圖譜如圖9所示。In some solutions of the present invention, the X-ray powder diffraction pattern of the above crystal form IX is shown in FIG. 9 .
在本發明的一些方案中，上述晶型IX，其TGA-DSC譜圖基本如圖26所示。In some solutions of the present invention, the TGA-DSC spectrum of the above crystal form IX is basically as shown in FIG. 26 .
本發明的一些方案中，上述式（A）化合物晶型IX的XRPD圖譜繞射峰解析資料如表9所示。In some schemes of the present invention, the XRPD spectrum diffraction peak analysis data of the compound of the above formula (A) crystal form IX is shown in Table 9.
表
本發明還提供式（A）化合物N-(6-((5-溴-2-((6-異丙基-8-甲氧基-3-甲基-3,4,5,6-四氫苯並[b]吡唑並[4,3-d]氮雜-9-基)氨基)-嘧啶-4-基)氨基)-喹喔啉-5-基)甲磺醯胺的晶型XII，所述晶型XII的X-射線粉末繞射圖譜在2θ值為5.83、6.80、20.48、24.92、27.49處有特徵峰，2θ誤差範圍為±0.2°。The present invention also provides formula (A) compound N-(6-((5-bromo-2-((6-isopropyl-8-methoxy-3-methyl-3,4,5,6-tetra Crystalline form of hydrobenzo[b]pyrazolo[4,3-d]azepin-9-yl)amino)-pyrimidin-4-yl)amino)-quinoxalin-5-yl)methanesulfonamide XII, 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, and the 2θ error range is ±0.2°.
在本發明的一些方案中，上述晶型XII，其X-射線粉末繞射圖譜在2θ值為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、27.49處有特徵峰，2θ誤差範圍為±0.2°。In some solutions of the present invention, the X-ray powder diffraction pattern of the above crystal form XII has a 2θ value 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 have characteristic peaks, and the 2θ error range is ±0.2°.
在本發明的一些方案中，上述晶型XII，其X-射線粉末繞射圖譜在2θ值為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、33.62處有特徵峰，2θ誤差範圍為±0.2°。In some solutions of the present invention, the X-ray powder diffraction pattern of the above crystal form XII has a 2θ value 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, 33.62 have characteristic peaks, and the 2θ error range is ±0.2°.
在本發明的一些方案中，上述晶型XII，其X-射線粉末繞射圖譜如圖10所示。In some solutions of the present invention, the X-ray powder diffraction pattern of the above crystal form XII is shown in FIG. 10 .
在本發明的一些方案中，上述晶型XII，其TGA-DSC譜圖基本如圖27所示。In some solutions of the present invention, the TGA-DSC spectrum of the above crystal form XII is basically as shown in FIG. 27 .
本發明的一些方案中，上述式（A）化合物晶型XII的XRPD圖譜繞射峰解析資料如表10所示。In some solutions of the present invention, the XRPD spectrum diffraction peak analysis data of the compound of the above formula (A) in crystal form XII is shown in Table 10.
表
本發明還提供式（A）化合物N-(6-((5-溴-2-((6-異丙基-8-甲氧基-3-甲基-3,4,5,6-四氫苯並[b]吡唑並[4,3-d]氮雜-9-基)氨基)-嘧啶-4-基)氨基)-喹喔啉-5-基)甲磺醯胺的晶型XIV，所述晶型XIV的X-射線粉末繞射圖譜在2θ值為5.86、11.73、23.56、29.55、35.65處有特徵峰，2θ誤差範圍為±0.2°。The present invention also provides formula (A) compound N-(6-((5-bromo-2-((6-isopropyl-8-methoxy-3-methyl-3,4,5,6-tetra Crystalline form of hydrobenzo[b]pyrazolo[4,3-d]azepin-9-yl)amino)-pyrimidin-4-yl)amino)-quinoxalin-5-yl)methanesulfonamide XIV, 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, and the 2θ error range is ±0.2°.
在本發明的一些方案中，上述晶型XIV，其X-射線粉末繞射圖譜在2θ值為5.86、11.73、13.85、20.91、22.32、23.56、24.69、25.30、26.72、29.55、33.09、35.65、38.91處有特徵峰，2θ誤差範圍為±0.2°。In some solutions of the present invention, the X-ray powder diffraction pattern of the above crystal form XIV has a 2θ value 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, 38.91 There are characteristic peaks at , and the 2θ error range is ±0.2°.
在本發明的一些方案中，上述晶型XIV，其X-射線粉末繞射圖譜如圖11所示。In some solutions of the present invention, the X-ray powder diffraction pattern of the above-mentioned crystal form XIV is shown in FIG. 11 .
在本發明的一些方案中，上述晶型XIV，其TGA-DSC譜圖基本如圖28所示。In some solutions of the present invention, the TGA-DSC spectrum of the above crystal form XIV is basically as shown in FIG. 28 .
本發明的一些方案中，上述式（A）化合物晶型XIV的XRPD圖譜繞射峰解析資料如表11所示。In some schemes of the present invention, the XRPD spectrum diffraction peak analysis data of the compound of formula (A) crystal form XIV is shown in Table 11.
表
本發明還提供式（I）化合物，
本發明提供式（I）化合物的晶型A，所述晶型A的X-射線粉末繞射圖譜在2θ值為7.38、8.13、12.62、20.14、21.41、23.72處有特徵峰，2θ誤差範圍為±0.2°。The present invention provides the crystal form A of the compound of formula (I). 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°.
在本發明的一些方案中，上述晶型A，其X-射線粉末繞射圖譜在2θ值為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、28.26處有特徵峰，2θ誤差範圍為±0.2°。In some solutions of the present invention, the X-ray powder diffraction pattern of the above crystal form A has a 2θ value 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 , There is a characteristic peak at 28.26, and the 2θ error range is ±0.2°.
在本發明的一些方案中，上述晶型A，其X-射線粉末繞射圖譜在2θ值為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、31.91處有特徵峰，2θ誤差範圍為±0.2°。In some solutions of the present invention, the X-ray powder diffraction pattern of the above crystal form A has a 2θ value 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, 31.91 have characteristic peaks, and the 2θ error range is ±0.2°.
在本發明的一些方案中，上述晶型A，其X-射線粉末繞射圖譜如圖12所示。In some solutions of the present invention, the X-ray powder diffraction pattern of the above crystal form A is shown in FIG. 12 .
在本發明的一些方案中，上述晶型A，其TGA-DSC譜圖基本如圖29所示。In some solutions of the present invention, the TGA-DSC spectrum of the above-mentioned crystal form A is basically as shown in FIG. 29 .
本發明的一些方案中，上述式（I）化合物晶型A的XRPD圖譜繞射峰解析資料如表12所示。In some schemes of the present invention, the XRPD spectrum diffraction peak analysis data of the crystal form A of the compound of formula (I) is shown in Table 12.
表
本發明還提供式（I）化合物的晶型B，所述晶型B的X-射線粉末繞射圖譜在2θ值為5.89、7.25、9.37、22.49、25.45、27.05處有特徵峰，2θ誤差範圍為±0.2°。The present invention also provides the crystal form B of the compound of formula (I), 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°.
在本發明的一些方案中，上述晶型B，其X-射線粉末繞射圖譜在2θ值為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、27.05處有特徵峰，2θ誤差範圍為±0.2°。In some solutions of the present invention, the X-ray powder diffraction pattern of the above crystal form B has a 2θ value 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 have characteristic peaks, and the 2θ error range is ±0.2°.
在本發明的一些方案中，上述晶型B，其X-射線粉末繞射圖譜在2θ值為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、30.01處有特徵峰，2θ誤差範圍為±0.2°。In some solutions of the present invention, the X-ray powder diffraction pattern of the above crystal form B has a 2θ value 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, 30.01 have characteristic peaks, and the 2θ error range is ±0.2°.
在本發明的一些方案中，上述晶型B，其X-射線粉末繞射圖譜如圖13所示。In some solutions of the present invention, the X-ray powder diffraction pattern of the above-mentioned crystal form B is shown in FIG. 13 .
在本發明的一些方案中，上述晶型B，其TGA-DSC譜圖基本如圖30所示。In some solutions of the present invention, the TGA-DSC spectrum of the above crystal form B is basically as shown in FIG. 30 .
本發明的一些方案中，上述式（I）化合物晶型B的XRPD圖譜繞射峰解析資料如表13所示。In some schemes of the present invention, the XRPD spectrum diffraction peak analysis data of the crystal form B of the compound of formula (I) is shown in Table 13.
表
本發明還提供式（I）化合物的晶型C，所述晶型C的X-射線粉末繞射圖譜在2θ值為5.85、12.41、17.76、22.48、27.03處有特徵峰，2θ誤差範圍為±0.2°。The present invention also provides the crystal form C of the compound of formula (I). 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°.
在本發明的一些方案中，上述晶型C，其X-射線粉末繞射圖譜在2θ值為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、27.03處有特徵峰，2θ誤差範圍為±0.2°。In some solutions of the present invention, the X-ray powder diffraction pattern of the above crystal form C has a 2θ value 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 have characteristic peaks, and the 2θ error range is ±0.2°.
在本發明的一些方案中，上述晶型C，其X-射線粉末繞射圖譜在2θ值為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、29.96處有特徵峰，2θ誤差範圍為±0.2°。In some solutions of the present invention, the X-ray powder diffraction pattern of the above crystal form C has a 2θ value 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, 29.96 have characteristic peaks, and the 2θ error range is ±0.2°.
在本發明的一些方案中，上述晶型C，其X-射線粉末繞射圖譜如圖14所示。In some solutions of the present invention, the X-ray powder diffraction pattern of the above crystal form C is shown in FIG. 14 .
在本發明的一些方案中，上述晶型C，其TGA-DSC譜圖基本如圖31所示。In some solutions of the present invention, the TGA-DSC spectrum of the above crystal form C is basically as shown in FIG. 31 .
本發明的一些方案中，上述式（I）化合物晶型C的XRPD圖譜繞射峰解析資料如表14所示。In some schemes of the present invention, the XRPD spectrum diffraction peak analysis data of the crystal form C of the compound of formula (I) above are shown in Table 14.
表surface
1414
式（Mode(
II
）化合物晶型) compound crystal form
CC
的of
XRPDXRPD
繞射峰解析資料Diffraction peak analysis data
本發明還提供式（I）化合物的晶型D，所述晶型D的X-射線粉末繞射圖譜在2θ值為5.55、13.03、16.73、22.48、24.17處有特徵峰，2θ誤差範圍為±0.2°。The present invention also provides the crystal form D of the compound of formula (I). 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°.
在本發明的一些方案中，上述晶型D，其X-射線粉末繞射圖譜在2θ值為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、34.02處有特徵峰，2θ誤差範圍為±0.2°。In some solutions of the present invention, the X-ray powder diffraction pattern of the above-mentioned crystal form D has a 2θ value 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 have characteristic peaks, and the 2θ error range is ±0.2°.
在本發明的一些方案中，上述晶型D，其X-射線粉末繞射圖譜在2θ值為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、34.02處有特徵峰，2θ誤差範圍為±0.2°。In some solutions of the present invention, the X-ray powder diffraction pattern of the above crystal form D has a 2θ value 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, 34.02 have characteristic peaks, and the 2θ error range is ±0. 2°.
在本發明的一些方案中，上述晶型D，其X-射線粉末繞射圖譜如圖15所示。In some solutions of the present invention, the X-ray powder diffraction pattern of the above-mentioned crystal form D is shown in FIG. 15 .
在本發明的一些方案中，上述晶型D，其DSC譜圖上在250°C以及256°C左右各有一個吸熱峰。In some solutions of the present invention, the above crystal form D has an endothermic peak at about 250°C and 256°C in its DSC spectrum.
在本發明的一些方案中，上述晶型D，其TGA譜圖上在220°C左右有一個5.33%的失重。In some solutions of the present invention, the above crystal form D has a weight loss of 5.33% at about 220°C on its TGA spectrum.
在本發明的一些方案中，上述晶型D，其TGA譜圖上在150-225°C左右有一個5.33%的失重。In some solutions of the present invention, the above crystal form D has a weight loss of 5.33% at about 150-225°C on its TGA spectrum.
在本發明的一些方案中，上述晶型D，其TGA-DSC譜圖基本如圖32所示。In some solutions of the present invention, the TGA-DSC spectrum of the above crystal form D is basically as shown in FIG. 32 .
本發明的一些方案中，上述式（I）化合物晶型D的XRPD圖譜繞射峰解析資料如表15所示。In some solutions of the present invention, the XRPD spectrum diffraction peak analysis data of the crystal form D of the compound of formula (I) above is shown in Table 15.
表surface
1515
式（Mode(
II
）化合物晶型) compound crystal form
DD.
的of
XRPDXRPD
繞射峰解析資料Diffraction peak analysis data
本發明還提供一種藥物組合物，其包含上述的式（A）或式（I）化合物及可藥用的載體。The present invention also provides a pharmaceutical composition, which comprises the above-mentioned compound of formula (A) or formula (I) and a pharmaceutically acceptable carrier.
本發明還提供一種藥物組合物，其包含上述任意一晶型及可藥用的載體。The present invention also provides a pharmaceutical composition, which comprises any one of the above crystal forms and a pharmaceutically acceptable carrier.
本發明還提供上述任意一晶型或上述藥物組合物在製備用於治療EGFR突變介導的癌症的藥物中的用途。The present invention also provides the use of any one of the above-mentioned crystal forms or the above-mentioned pharmaceutical composition in the preparation of a medicine for treating cancer mediated by EGFR mutation.
本發明還提供上述任意一晶型或上述藥物組合物治療EGFR突變介導癌症的用途。The present invention also provides the use of any one of the above-mentioned crystal forms or the above-mentioned pharmaceutical composition for treating cancer mediated by EGFR mutation.
用於治療癌症的藥物，所述藥物為上述任意一晶型或上述藥物組合物。A medicament for treating cancer, said medicament being any one of the above-mentioned crystal forms or the above-mentioned pharmaceutical composition.
用於治療癌症EGFR突變介導的藥物，所述藥物為上述任意一晶型或上述藥物組合物。A drug for treating cancer mediated by EGFR mutation, said drug being any one of the above-mentioned crystal forms or the above-mentioned pharmaceutical composition.
在本發明的一些方案中，上述癌症包括淋巴瘤、非霍奇金淋巴瘤、卵巢癌、宮頸癌、***癌、結腸直腸癌、乳腺癌、胰腺癌、膠質瘤、膠質母細胞瘤、黑色素瘤、白血病、胃癌、子宮內膜癌、肺癌、肝細胞癌、胃癌、胃腸道間質瘤(GIST)、急性髓細胞白血病(AML)、膽管癌、腎癌、甲狀腺癌、間變性大細胞淋巴瘤、間皮瘤、多發性骨髓瘤、黑色素瘤。In some aspects of the 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, kidney cancer, thyroid cancer, anaplastic large cell lymphoma , mesothelioma, multiple myeloma, melanoma.
在本發明的一些方案中，上述癌症為肺癌。本發明還提供式（A）、式（I）化合物、上述任意一晶型或上述藥物組合物在製備EGFR抑制劑中的用途。In some aspects of the present invention, the aforementioned cancer is lung cancer. The present invention also provides the use of the compound of formula (A), formula (I), any one of the above-mentioned crystal forms or the above-mentioned pharmaceutical composition in the preparation of EGFR inhibitors.
本發明還提供抑制有需要患者中EGFR突變的方法，其包括向所述患者施用上述式（A）、式（I）化合物、上述任意一晶型或上述藥物組合物。The present invention also provides a method for inhibiting EGFR mutation in a patient in need, which comprises administering the compound of formula (A), formula (I), any of the above crystal forms or the above pharmaceutical composition to the patient.
本發明還提供抑制生物樣品中的EGFR突變的方法，其包括向所述患者施用上述式（A）、式（I）化合物、上述任意一晶型或上述藥物組合物。The present invention also provides a method for inhibiting EGFR mutation in a biological sample, which comprises administering the compound of formula (A), formula (I), any of the above crystal forms or the above pharmaceutical composition to the patient.
在本發明的一些方案中，上述EGFR突變包括L858R、T790M、C797S、Del19突變。In some aspects of the present invention, the aforementioned EGFR mutations include L858R, T790M, C797S, and Del19 mutations.
在本發明的一些方案中，上述EGFR突變包括L858R/T790M/C797S三突變、Del19/T790M/C797S三突變。In some solutions of the present invention, the above-mentioned EGFR mutations include L858R/T790M/C797S triple mutation and Del19/T790M/C797S triple mutation.
技術效果technical effect
本申請中的晶型具有較好的化學穩定性、物理穩定性以及較低的吸濕性，受熱、濕度和光照影響較小，便於儲存及製劑。The crystal form in the present application has better chemical stability, physical stability and lower hygroscopicity, is less affected by heat, humidity and light, and is convenient for storage and preparation.
定義和說明Definition and Description
除非另有說明，本文所用的下列術語和短語旨在具有下列含義。一個特定的術語或短語在沒有特別定義的情況下不應該被認為是不確定的或不清楚的，而應該按照普通的含義去理解。Unless otherwise stated, the following terms and phrases used herein are intended to have the following meanings. A specific term or phrase should not be considered indeterminate or unclear if it is not specifically defined, but should be understood according to its ordinary meaning.
術語“左右”通常是指在指定數值以上或以下0.01％-5％的範圍內變動，例如在指定數值以上或以下0.01％、0.02％、0.05％、0.1％、0.2％、0.5％、1％、1.5％、2％、2.5％、3％、3.5％、4％、4.5％或5％的範圍內變動。例如，所述“212°C左右”可以包括212±0.15°C，所述“264°C左右”可以包括264±0.38°C。The term "around" usually refers to a range of 0.01%-5% above or below the specified value, such as 0.01%, 0.02%, 0.05%, 0.1%, 0.2%, 0.5%, 1% above or below the specified value , 1.5%, 2%, 2.5%, 3%, 3.5%, 4%, 4.5% or 5%. For example, the "about 212°C" may include 212±0.15°C, and the "about 264°C" may include 264±0.38°C.
術語“可藥用的載體”是指本領域通常可接受的用於將生物活性藥劑遞送給動物、特別是哺乳動物的介質，根據給藥方式和劑型的性質包括例如佐劑、賦形劑或賦形物，例如稀釋劑、防腐劑、填充劑、流動調節劑、崩解劑、潤濕劑、乳化劑、助懸劑、甜味劑、調味劑、芳香劑、抗菌劑、抗真菌劑、潤滑劑和分散劑。藥學上可接受的載體在本領域普通技術人員的眼界範圍內根據大量因素配製。其包括但不限於：配製的活性藥劑的類型和性質，要將含有該藥劑的組合物給藥的物件，組合物的預期給藥途徑，和目標治療適應症。藥學上可接受的載體包括含水介質和非水介質這兩者以及多種固體和半固體劑型。除了活性藥劑以外，這樣的載體包括許多不同的成分和添加劑，因多種原因(例如穩定活性藥劑、粘合劑等)在處方中包括的這樣的另外的成分對於本領域普通技術人員是眾所周知的。The term "pharmaceutically acceptable carrier" refers to a medium generally acceptable in the art for delivering biologically active agents to animals, especially mammals, including, for example, adjuvants, excipients or Excipients such as diluents, preservatives, fillers, flow regulators, disintegrants, wetting agents, emulsifiers, suspending agents, sweeteners, flavoring agents, fragrances, antibacterial agents, antifungal agents, Lubricants and dispersants. Pharmaceutically acceptable carriers are formulated according to a number of factors that are within the purview of those of ordinary skill in the art. These include, but are not limited to: the type and nature of the active agent being formulated, the article into which the composition containing the agent is to be administered, the intended route of administration of the composition, and the intended therapeutic indication. Pharmaceutically acceptable carriers include both aqueous and non-aqueous media and various solid and semisolid dosage forms. Such carriers include many different ingredients and additives in addition to the active agent, and such additional ingredients are well known to those of ordinary skill in the art to include in formulations for a variety of reasons (eg, to stabilize the active agent, binders, etc.).
本領域公知，X-射線粉末繞射圖譜根據測量條件的微小變化，而具有一種或多種測量誤差，本發明公開或要求保護的結晶、晶體或晶型的結構可能根據試驗條件、純度、設備和所屬技術領域中具有通常知識者已知的其它常幾變數在合理誤差範圍內表現出類似但不完全相同的分析特性。例如，粉末X-射線粉末繞射中的繞射角(2θ)通常產生±0.20°的範圍內的誤差，所以，本發明不僅包括粉末X-射線粉末繞射中的繞射角完全一致的結晶，更包括在±0.20°的誤差範圍內繞射角一致的結晶。本發明的化合物A的結晶形式並不僅限於具有與圖式中所示的X-射線粉末繞射圖譜相同的X 射線粉末繞射圖譜的晶體，具有基本上與圖式中所示相同的X-射線粉末繞射圖譜的任何晶體均屬於本發明範圍內。It is well known in the art that X-ray powder diffraction patterns have one or more measurement errors according to slight changes in measurement conditions, and the structure of the crystals, crystals or crystal forms disclosed or claimed in the present invention may vary depending on test conditions, purity, equipment and Other constant variables known to those of ordinary skill in the art exhibit similar, but not identical, analytical properties within reasonable error. For example, the diffraction angle (2θ) in powder X-ray powder diffraction usually produces an error in the range of ±0.20°, so the present invention not only includes crystals with completely consistent diffraction angles in powder X-ray powder diffraction , including crystals with consistent diffraction angles within the error range of ±0.20°. The crystalline form of Compound A of the present invention is not limited to crystals having the same X-ray powder diffraction pattern as shown in the drawings, having substantially the same X-ray powder diffraction patterns as shown in the drawings. Any crystal with an X-ray powder diffraction pattern is within the scope of the invention.
文中出現的“與圖式中所示X-射線粉末繞射圖譜基本上相同的X-射線粉末繞射圖譜。應瞭解，在該上下文中使用的術語“基本上相同”亦意指示X-射線粉末繞射圖譜的2θ角度值可因伴隨這些測量的固有實驗變化而具有輕微變化，兩者為同一晶體形式。Appears herein "X-ray powder diffraction pattern that is substantially the same as the X-ray powder diffraction pattern shown in the drawing. It should be understood that the term "substantially the same" as used in this context is also intended to indicate The 2Θ angle values of the powder diffraction patterns may vary slightly due to the inherent experimental variation accompanying these measurements, both for the same crystalline form.
應當理解用不同類型設備或用不同的測試條件可能給出稍微不同的DSC圖譜和吸熱轉變溫度讀數。該數值將受化合物純度、樣品重量、加熱速度、粒徑和測試設備的校驗和維修的影響。晶型的最大吸熱轉變溫度可以在上述公開的具體數值±5.0℃的範圍內。It should be understood that using different types of equipment or using different test conditions may give slightly different DSC patterns and endothermic transition temperature readings. This value will be affected by compound purity, sample weight, heating rate, particle size, and calibration and maintenance of testing equipment. The maximum endothermic transition temperature of the crystalline form may be within the range of ±5.0° C. from the specific value disclosed above.
本公開還採用熱失重分析(TGA)對晶型發生分解或昇華、蒸發的程度(失去重量)與溫度的關係進行了分析。應當理解同種晶型受樣品純度、粒徑、不同類型設備、不同的測試方法等的影響，所得到的數值存在一定誤差。晶型發生分解或昇華、蒸發時的溫度可以在上述公開的具體數值±3.0℃的範圍內，例如±2.0℃的範圍內。The present disclosure also uses thermogravimetric analysis (TGA) to analyze the relationship between the degree of decomposition, sublimation, and evaporation of the crystal form (weight loss) and temperature. It should be understood that the same crystal form is affected by sample purity, particle size, different types of equipment, different test methods, etc., and there are certain errors in the obtained values. The temperature at which the crystalline form decomposes, sublimes, and evaporates may be within the range of ±3.0°C, for example ±2.0°C, of the specific value disclosed above.
晶型的“穩定性”包括“化學穩定性”和/或“物理穩定性”。“化學穩定性”是指該晶型在一定溫度、濕度、光照條件下發生降解反應的程度，“化學穩定性”反應了該晶型在儲存條件下的穩定性。“物理穩定性”是指該晶型在某些特定條件下發生固態形式轉化的程度，例如在高溫、高濕、研磨、壓片、脫溶劑、吸附溶劑的條件下，轉化為另外一種晶型，因此“物理穩定性”可以在一定程度上反應晶型在製劑等使用過程中的穩定程度。The "stability" of a crystal form includes "chemical stability" and/or "physical stability". "Chemical stability" refers to the degree of degradation reaction of the crystal form under certain temperature, humidity and light conditions, and "chemical stability" reflects the stability of the crystal form under storage conditions. "Physical stability" refers to the degree to which the crystal form undergoes solid-state transformation under certain specific conditions, such as conversion to another crystal form under conditions of high temperature, high humidity, grinding, tableting, solvent removal, and solvent adsorption , so "physical stability" can to a certain extent reflect the stability of the crystal form during the use of preparations.
本發明的結晶結構可以透過各種方法製備，包括從合適的溶劑中結晶或重結晶、昇華、從熔融體中生長、從另一相固態轉化、從超臨界流體中結晶和射流噴霧等。結晶結構從溶劑混合物中結晶或重結晶的技術，包括溶劑蒸發、降低溶劑混合物的溫度、該分子和/或鹽的過飽和溶劑混合物的引晶、凍乾溶劑混合物、向溶劑混合物中加入反溶劑等。The crystalline structures of the present invention can be prepared by various methods including crystallization or recrystallization from suitable solvents, sublimation, growth from melts, solid state transformation from another phase, crystallization from supercritical fluids and jet spraying, etc. Techniques for crystallization or recrystallization of crystalline structures from solvent mixtures, including solvent evaporation, lowering the temperature of solvent mixtures, seeding of supersaturated solvent mixtures of the molecule and/or salt, lyophilization of solvent mixtures, addition of antisolvents to solvent mixtures, etc. .
本發明的中間體化合物可以透過所屬技術領域中具有通常知識者所熟知的多種合成方法來製備，包括下面列舉的具體實施方式、其與其他化學合成方法的結合所形成的實施方式以及本領域技術上人員所熟知的等同替換方式，優選的實施方式包括但不限於本發明的實施例。The intermediate compound of the present invention can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments listed below, the embodiments formed by its combination with other chemical synthesis methods, and the technical methods in the art Preferred implementations include, but are not limited to, the embodiments of the present invention.
在本發明實施例中，標題化合物的命名是借助Chemdraw透過化合物結構轉化過來的。若化合物名稱與化合物結構存在不一致的情況，可透過綜合相關資訊和反應路線輔助確定；無法透過其他來確認的，以給出的化合物結構式為准。In the examples of the present invention, the naming of the title compound was converted through the structure of the compound by means of Chemdraw. If there is any inconsistency between the name of the compound and the structure of the compound, it can be determined by comprehensively related information and reaction routes; if it cannot be confirmed by other means, the structural formula of the given compound shall prevail.
本發明的化合物可以透過所屬技術領域中具有通常知識者所熟知的多種合成方法來製備，包括下面列舉的具體實施方式、其與其他化學合成方法的結合所形成的實施方式以及本領域技術上人員所熟知的等同替換方式，優選的實施方式包括但不限於本發明的實施例。The compounds of the present invention can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments listed below, the embodiments formed by their combination with other chemical synthesis methods, and those skilled in the art Known equivalents, preferred embodiments include but are not limited to the examples of the present invention.
儀器及分析方法：Instruments and analysis methods:
1、X-射線粉末繞射（XRPD）1. X-ray powder diffraction (XRPD)
固體樣品用X-射線粉末繞射儀（Bruker D8 advance）進行分析。將樣品置於零背景單晶矽樣品盤上，用藥匙輕壓固體表面，使樣品平鋪。XRPD測量參數見表16-1。Solid samples were analyzed with an X-ray powder diffractometer (Bruker D8 advance). Place the sample on the zero-background monocrystalline silicon sample plate, and gently press the solid surface with a spatula to flatten the sample. The XRPD measurement parameters are shown in Table 16-1.
表surface
16-1 XRPD16-1XRPD
測試參數Test parameters
或者固體樣品用X-射線粉末繞射儀（X’Pert PRO）進行分析，取供試品細粉適量，置於樣品架凹槽中，用玻璃片壓製成平整緻密的平面，XRPD測量參數見表16-2。Or the solid sample is analyzed by X-ray powder diffractometer (X'Pert PRO). Take an appropriate amount of fine powder of the test sample, place it in the groove of the sample holder, and press it into a flat and dense plane with a glass sheet. For XRPD measurement parameters, see Table 16-2.
表surface
16-2 XRPD16-2XRPD
測試參數Test parameters
2、熱重分析（TGA）2. Thermogravimetric analysis (TGA)
使用TA Instrument的熱重分析儀對固體進行熱重分析。約1-5 mg樣品置於已去皮的鋁製樣品盤中，按照表17中所列參數對樣品進行加熱，使用TRIOS對資料進行分析。Solids were subjected to thermogravimetric analysis using a thermogravimetric analyzer from TA Instruments. About 1-5 mg samples were placed in peeled aluminum sample pans, the samples were heated according to the parameters listed in Table 17, and the data were analyzed using TRIOS.
表
3、差示掃描量熱分析（DSC）3. Differential scanning calorimetry (DSC)
使用TA Instrument的差示掃描量熱儀對固體進行DSC分析。約1-3 mg樣品經精確稱重後置於紮孔的鋁製樣品盤中，按照表18-1中所列參數對樣品進行加熱，使用TRIOS對資料進行分析。The solids were subjected to DSC analysis using a Differential Scanning Calorimeter from TA Instrument. About 1-3 mg of the 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 was analyzed using TRIOS.
表surface
18-1 DSC18-1DSC
分析方法參數Analytical method parameters
或者使用梅特勒托利多的同步熱分析儀對固體進行熱重-差示掃描量熱連用分析。用小勺取供試品適量置於坩堝中，使鋪布均勻，稱重其重量，按照表18-2中所列參數對樣品進行加熱，使用STARe對資料進行分析。Or use METTLER TOLEDO's Simultaneous Thermal Analyzer for combined TGA-DSC analysis of solids. Use a small spoon to take an appropriate amount of the test sample and place it in the crucible to spread it evenly, weigh its weight, heat the sample according to the parameters listed in Table 18-2, and use STARe to analyze the data.
表surface
18-2 TGA-DSC18-2 TGA-DSC
分析方法參數Analytical method parameters
4、動態水分吸脫附分析（DVS）4. Dynamic moisture adsorption and desorption analysis (DVS)
使用DVS Intrinsic動態水分吸附儀對樣品的吸濕性進行測定。將樣品置於已去皮的樣品籃中，儀器自動稱重，按照表19中的參數對樣品進行分析。The hygroscopicity of the samples was measured using a DVS Intrinsic dynamic moisture sorption instrument. Place the sample in the tared sample basket, weigh the instrument automatically, and analyze the sample according to the parameters in Table 19.
表
5、核磁共振氫譜（ 1H-NMR） 5. Proton nuclear magnetic resonance spectrum ( 1 H-NMR)
NMR的測定是用Bruker AVANCE III HD 400或者Bruker AVANCE III HD 300核磁儀器，測定溶劑為氘代二甲基亞碸（DMSO-d
6），內標為四甲基矽烷（TMS）。
The determination of NMR is carried out with Bruker AVANCE III
6、高效液相色譜（HPLC）6. High performance liquid chromatography (HPLC)
液質聯用色譜LC-MS的測定用SHIMADZU LCMS-2020質譜儀（離子源為電噴霧離子化）。The determination of liquid chromatography-mass chromatography LC-MS uses SHIMADZU LCMS-2020 mass spectrometer (the ion source is electrospray ionization).
HPLC的測定使用SHIMADZU LC-20 AP XR和SPD-M20A高壓液相色譜或Agilent HPLC 1260 series儀器對樣品進行高效液相色譜分析。Determination of HPLC Use SHIMADZU LC-20 AP XR and SPD-M20A high-pressure liquid chromatography or Agilent HPLC 1260 series instruments for high-performance liquid chromatography analysis of samples.
7、離子色譜（IC）7. Ion Chromatography (IC)
賽默飛 ICS-1100 離子色譜系統和變色龍工作站和 AS-AP 自動進樣器，序號：13070718。Thermo Scientific ICS-1100 Ion Chromatography System with Chameleon Workstation and AS-AP Autosampler, Serial No. 13070718.
表
下面透過實施例對本發明進行詳細描述，但並不意味著對本發明任何不利限制。本發明的化合物可以透過所屬技術領域中具有通常知識者所熟知的多種合成方法來製備，包括下面列舉的具體實施方式、其與其他化學合成方法的結合所形成的實施方式以及本領域技術上人員所熟知的等同替換方式，優選的實施方式包括但不限於本發明的實施例。對本領域的技術人員而言，在不脫離本發明精神和範圍的情況下針對本發明具體實施方式進行各種變化和改進將是顯而易見的。The present invention will be described in detail through examples below, but it does not imply any adverse limitation to the present invention. The compounds of the present invention can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments listed below, the embodiments formed by their combination with other chemical synthesis methods, and those skilled in the art Known equivalents, preferred embodiments include but are not limited to the examples of the present invention. Various changes and modifications to the specific embodiments of the invention will be apparent to those skilled in the art without departing from the spirit and scope of the invention.
實施例Example 11 式（Mode( AA ）和式（) and formula ( II ）化合物的製備：) compound preparation:
1.1 中間體 6A 的製備 
化合物compound 6A-1:6A-1:
將化合物 1C-4（3.5 g, 15.5 mmol）溶於乙腈（40 mL），在0°C條件下，加入N-碘代丁二醯亞胺（4.9 g, 21.7 mmol）。室溫反應攪拌5小時，LCMS監控顯示原料消失後，減壓濃縮，加入水（30 mL），用二氯甲烷（45 mL×3次）萃取，合併有機相，有機相先用飽和食鹽水（60 mL × 2次）洗滌，然後用無水硫酸鈉乾燥，過濾，減壓濃縮。所得殘餘物用矽膠柱層析純化（洗脫劑：乙酸乙酯/石油醚 = 1 / 1）得到3.57 g化合物 6A-1。 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 LCMS monitoring showed that the raw materials disappeared, it was concentrated under reduced pressure, water (30 mL) was added, extracted with dichloromethane (45 mL×3 times), and the organic phase was combined. The organic phase was first washed with saturated brine ( 60 mL × 2 times), then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: ethyl acetate/petroleum ether=1/1) to obtain 3.57 g of compound 6A-1 .
MS (ESI, m/z): 352.0 [M + H] +。 MS (ESI, m/z): 352.0 [M + H] + .
化合物compound 6A-2:6A-2:
將化合物6A-1（3.4 g, 9.7 mmol）和1A（3.7 g, 12.5 mmol）溶於1,4-二氧六環（30 mL）和水（6 mL）中，向上述反應液中加入碳酸鉀（2.7 g, 19.4 mmol）和[1,1'-雙(二苯基膦)二茂鐵]二氯化鈀二氯甲烷絡合物（790 mg, 1.0 mmol）。在氮氣保護下，將反應體系加熱至80 °C並繼續攪拌2小時。LCMS監控顯示原料消失後，將反應液冷卻至室溫，減壓濃縮，所得殘餘物用矽膠柱層析純化（洗脫劑：乙酸乙酯/石油醚 = 2 / 1）得到2.8 g化合物6A-2。Compound 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), and carbonic acid was added to the above reaction solution Potassium (2.7 g, 19.4 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (790 mg, 1.0 mmol). Under nitrogen protection, the reaction system was heated to 80 °C and continued to stir for 2 hours. After LCMS monitoring showed that the raw materials disappeared, the reaction solution was cooled to room temperature, concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate/petroleum ether = 2/1) to obtain 2.8 g of compound 6A- 2.
MS (ESI, m/z): 395.3 [M + H] +。 MS (ESI, m/z): 395.3 [M + H] + .
化合物compound 6A-3:6A-3:
將化合物6A-2（2.7 g, 6.8 mmol）溶於N,N-二甲基甲醯胺（28 mL）中。隨後，向上述反應液中加入碳酸鉀（1.9 g，13.5 mmol）。將反應體系加熱至100 °C並繼續攪拌24小時。LCMS監控顯示原料消失後，將反應液冷卻至室溫並加入水（50 mL）淬滅。混合液用乙酸乙酯（60 mL×4次）萃取，合併有機相，有機相先用飽和食鹽水（50 mL×3次）洗滌，然後用無水硫酸鈉乾燥，過濾，最後減壓濃縮。所得殘餘物用矽膠柱層析純化（洗脫劑：二氯甲烷/乙酸乙酯 = 15 / 1）得到1.2 g化合物6A-3。Compound 6A-2 (2.7 g, 6.8 mmol) was dissolved in N,N-dimethylformamide (28 mL). Subsequently, potassium carbonate (1.9 g, 13.5 mmol) was added to the above reaction solution. The reaction system was heated to 100 °C and stirring was continued for 24 hours. After LCMS monitoring showed that the starting material disappeared, the reaction solution was cooled to room temperature and quenched by adding water (50 mL). The mixture was extracted with ethyl acetate (60 mL×4 times), and the organic phases were combined. The organic phase was washed with saturated brine (50 mL×3 times), then dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: dichloromethane/ethyl acetate = 15/1) to obtain 1.2 g of compound 6A-3.
MS (ESI, m/z): 375.2 [M + H] +。 MS (ESI, m/z): 375.2 [M + H] + .
化合物compound 6A-4:6A-4:
將化合物6A-3（1.2 g, 3.3 mmol）溶於氯化氫的1,4-二氧六環溶液（4 M, 15 mL）中。在30 °C條件下攪拌6小時，LCMS監控顯示原料消失後，將反應液濃縮，加入水（40 mL），用飽和碳酸氫鈉水溶液調節其pH到9。混合液用氯仿/異丙醇= 3 / 1（50 mL×3次）萃取，合併有機相，然後用無水硫酸鈉乾燥，過濾，最後減壓濃縮。所得殘餘物用矽膠柱層析純化（洗脫劑：二氯甲烷/甲醇 = 30 / 1）得到842 mg化合物6A-4。Compound 6A-3 (1.2 g, 3.3 mmol) was dissolved in a solution of hydrogen chloride in 1,4-dioxane (4 M, 15 mL). After stirring at 30 °C for 6 hours, LCMS monitoring showed that the raw materials disappeared, the reaction solution was concentrated, water (40 mL) was added, and the pH was adjusted to 9 with saturated aqueous sodium bicarbonate solution. The mixture was extracted with chloroform/isopropanol = 3/1 (50 mL×3 times), and the organic phases were combined, then dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: dichloromethane/methanol = 30/1) to obtain 842 mg of Compound 6A-4.
MS (ESI, m/z): 275.0 [M + H] +。 MS (ESI, m/z): 275.0 [M + H] + .
化合物compound 6A-5:6A-5:
將化合物6A-4（300 mg，1.1 mmol）和碳酸銫（1.07 g，3.3 mmol）溶於N, N-二甲基甲醯胺（6 mL）中。隨後，向上述反應液中加入碘代異丙烷（1.86 g，10.9 mmol）。將反應體系加熱至80 °C並繼續攪拌16小時。LCMS監控顯示原料消失後，將反應液冷卻至室溫並加入水（30 mL）淬滅。混合液用乙酸乙酯（50 mL×3次）萃取，合併有機相，有機相先用飽和食鹽水（50 mL×3次）洗滌，然後用無水硫酸鈉乾燥，過濾，最後減壓濃縮。所得殘餘物用矽膠柱層析純化（洗脫劑：二氯甲烷/甲醇 = 10 / 1）得到75 mg化合物6A-5。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). Subsequently, iodoisopropane (1.86 g, 10.9 mmol) was added to the above reaction solution. The reaction system was heated to 80 °C and stirring was continued for 16 hours. After LCMS monitoring showed that the starting material disappeared, the reaction solution was cooled to room temperature and quenched by adding water (30 mL). The mixture was extracted with ethyl acetate (50 mL x 3 times), and the organic phases were combined. The organic phase was washed with saturated brine (50 mL x 3 times), then dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: dichloromethane/methanol = 10/1) to obtain 75 mg of compound 6A-5.
MS (ESI, m/z): 317.2 [M + H] +。 MS (ESI, m/z): 317.2 [M + H] + .
中間體intermediate 6A:6A:
將化合物6A-5（75 mg，0.2 mmol）溶於乙醇（8 mL）和水（1.6 mL）中。隨後，向上述反應液中加入氯化銨（50.7 mg，0.9 mmol）和還原鐵粉（132.4 mg，2.4 mmol）。將反應體系加熱至80 °C並繼續攪拌5小時。LCMS監控顯示原料消失後，將反應液冷卻至室溫並減壓濃縮。所得殘餘物用矽膠柱層析純化（洗脫劑：二氯甲烷/甲醇 = 10 / 1）得到48 mg化合物6A。Compound 6A-5 (75 mg, 0.2 mmol) was dissolved in ethanol (8 mL) and water (1.6 mL). Subsequently, ammonium chloride (50.7 mg, 0.9 mmol) and reduced iron powder (132.4 mg, 2.4 mmol) were added to the above reaction solution. The reaction system was heated to 80 °C and stirring was continued for 5 hours. After LCMS monitoring showed disappearance of starting material, the reaction solution was cooled to room temperature and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: dichloromethane/methanol = 10/1) to obtain 48 mg of Compound 6A.
MS (ESI, m/z): 287.2 [M + H] +。 MS (ESI, m/z): 287.2 [M + H] + .
1.2 中間體 35A 的製備 
化合物compound 35A-135A-1 ：:
將6-氨基喹喔啉（10 g, 68.89 mmol）溶於濃硫酸（20 mL）中。在0 °C條件下，向反應液中分批加入硝酸鉀（9.054 g, 89.55 mmol）並在該溫度下繼續攪拌30分鐘。LCMS監控顯示原料消失後，將反應液倒入冰水（100 g）中。用1 M氫氧化鈉水溶液調節其pH到8。混合液用乙酸乙酯（200 mL × 2次）萃取，合併有機相，有機相先用飽和食鹽水（100 mL × 3次）洗滌，然後用無水硫酸鈉乾燥，過濾，減壓濃縮。所得殘餘物用矽膠柱層析純化（洗脫劑：二氯甲烷/甲醇 = 10 / 1）得到2 g化合物35A-1。6-Aminoquinoxaline (10 g, 68.89 mmol) was dissolved in concentrated sulfuric acid (20 mL). At 0 °C, potassium nitrate (9.054 g, 89.55 mmol) was added in batches to the reaction solution and stirring was continued at this temperature for 30 minutes. After LCMS monitoring showed that the raw materials disappeared, the reaction solution was poured into ice water (100 g). Its pH was adjusted to 8 with 1 M aqueous sodium hydroxide solution. The mixture was extracted with ethyl acetate (200 mL × 2 times), and the organic phases were combined. The organic phase was washed with saturated brine (100 mL × 3 times), then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: dichloromethane/methanol = 10/1) to obtain 2 g of compound 35A-1.
MS (ESI) M/Z: 191.2 [M + H] +。 MS (ESI) M/Z: 191.2 [M + H] + .
中間體intermediate 35A35A ：:
將化合物35A-1（2 g, 10.5 mmol）溶於N, N-二甲基甲醯胺（20 mL）中。將反應液降至0 °C，氮氣保護下，分批加入氫化鈉（60wt, 1.3 g, 31.5 mmol）並繼續攪拌20分鐘。隨後，向上述反應液中加入2,4-二氯-5-溴嘧啶（4.8 g, 21.0 mmol），將反應升至室溫並繼續攪拌1小時。LCMS監控顯示原料消失後，將反應液降溫至0°C並加入飽和氯化銨水溶液（80 mL）淬滅。混合液用乙酸乙酯（100 mL × 3次）萃取，合併有機相，有機相先用飽和食鹽水（80 mL × 3次）洗滌，然後用無水硫酸鈉乾燥，過濾，減壓濃縮。所得殘餘物用矽膠柱層析純化（洗脫劑：乙酸乙酯/石油醚 = 1 / 2）得到2.7 g化合物35A。Compound 35A-1 (2 g, 10.5 mmol) was dissolved in N,N-dimethylformamide (20 mL). The reaction solution was lowered to 0 °C, under the protection of nitrogen, sodium hydride (60wt, 1.3 g, 31.5 mmol) was added in batches and stirring was continued for 20 minutes. Subsequently, 2,4-dichloro-5-bromopyrimidine (4.8 g, 21.0 mmol) was added to the above reaction solution, and the reaction was raised to room temperature and stirred for 1 hour. After LCMS monitoring showed that the raw materials disappeared, the reaction solution was cooled to 0 °C and quenched by adding saturated aqueous ammonium chloride solution (80 mL). The mixture was extracted with ethyl acetate (100 mL × 3 times), and the organic phases were combined. The organic phase was washed with saturated brine (80 mL × 3 times), then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate/petroleum ether = 1/2) to obtain 2.7 g of compound 35A.
MS (ESI, m/z): 381.0, 383.0 [M + H] +。 MS (ESI, m/z): 381.0, 383.0 [M + H] + .
1.3 化合物 A 
1.3.11.3.1 化合物compound 53A53A ：:
將化合物6A（2.7 g, 9.43 mmol）和35A（3.6 g, 9.43 mmol）溶於N-甲基吡咯烷酮（30 mL）中。隨後，向上述反應液中加入甲烷磺酸（2.72 g, 28.28 mmol）。將反應體系加熱至95 °C並繼續攪拌3小時。LCMS監控顯示原料消失後，將反應液冷卻至室溫並經反相C18柱純化。純化條件：色譜柱330 g C18反相柱；流動相水（含0.1%甲酸）和乙腈；流速70 mL/分鐘；梯度在20分鐘內，乙腈從10%升到50%；檢測波長254 nm。收集產品，減壓濃縮，得到3.4 g化合物53A。Compounds 6A (2.7 g, 9.43 mmol) and 35A (3.6 g, 9.43 mmol) were dissolved in N-methylpyrrolidone (30 mL). Subsequently, methanesulfonic acid (2.72 g, 28.28 mmol) was added to the above reaction solution. The reaction system was heated to 95 °C and stirring was continued for 3 hours. After LCMS monitoring showed that the starting material disappeared, the reaction solution was cooled to room temperature and purified by a reverse phase C18 column. Purification conditions: chromatographic column 330 g C18 reversed-phase column; mobile phase water (containing 0.1% formic acid) and acetonitrile; flow
MS (ESI, m/z): 631.2, 633.2 [M + H] +。 MS (ESI, m/z): 631.2, 633.2 [M + H] + .
1.3.21.3.2 化合物compound 53B53B ：:
將化合物53A（3.4 g, 5.38 mmol）溶於乙醇（40 mL）和水（8 mL）的混合溶劑中。隨後，向上述反應液中加入鐵粉（1.50 g, 26.92 mmol）和氯化銨（0.86 g, 16.15 mmol）並將反應體系加熱至80 °C並繼續攪拌2小時。LCMS監控顯示原料消失後，將反應液冷卻至室溫並減壓濃縮。所得殘餘物用矽膠柱層析純化（洗脫劑：二氯甲烷/甲醇 = 10 / 1），得到2.8 g化合物53B。Compound 53A (3.4 g, 5.38 mmol) was dissolved in a mixed solvent of ethanol (40 mL) and water (8 mL). Subsequently, iron powder (1.50 g, 26.92 mmol) and ammonium chloride (0.86 g, 16.15 mmol) were added to the above reaction solution, and the reaction system was heated to 80 °C and continued to stir for 2 hours. After LCMS monitoring showed disappearance of starting material, the reaction solution was cooled to room temperature and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: dichloromethane/methanol = 10/1) to obtain 2.8 g of compound 53B.
MS (ESI, m/z): 601.2, 603.2 [M + H] +。 MS (ESI, m/z): 601.2, 603.2 [M + H] + .
1.3.31.3.3 化合物compound AA ：:
將化合物53B（5g, 8.31 mmol）溶於吡啶（50 mL）中。隨後向反應液中滴加甲基磺醯氯（1.9 g, 16.62 mmol）。將反應體系升溫至50°C並繼續攪拌2小時。LCMS監控顯示原料消失後，將反應液冷卻至室溫並減壓濃縮。殘餘物溶於甲醇/四氫呋喃（1/1，50 mL）的混合溶劑中，在0°C條件下，向反應液中加入氫氧化鈉（2 M，5 mL）的水溶液。將反應體系升溫至室溫並繼續攪拌1小時後，減壓濃縮。所得殘餘物用矽膠柱層析純化（洗脫劑：二氯甲烷/甲醇 = 10/1），粗產品經過二氯甲烷/甲醇（20/1，30 mL）打漿後，用乙腈/水（50 mL）凍乾，得到3 g化合物A。Compound 53B (5 g, 8.31 mmol) was dissolved in pyridine (50 mL). Then methylsulfonyl chloride (1.9 g, 16.62 mmol) was added dropwise to the reaction solution. The reaction system was warmed to 50° C. and stirring was continued for 2 hours. After LCMS monitoring showed disappearance of starting material, the reaction solution was cooled to room temperature and concentrated under reduced pressure. The residue was dissolved in a mixed solvent of methanol/tetrahydrofuran (1/1, 50 mL), and an aqueous solution of sodium hydroxide (2 M, 5 mL) was added to the reaction solution at 0°C. The reaction system was warmed up 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). mL) was freeze-dried to obtain 3 g of compound A.
MS (ESI, m/z): 679.0, 681.0 [M + H] +。 MS (ESI, m/z): 679.0, 681.0 [M + H] + .
1H NMR (400 MHz, DMSO-d 6) δ 9.88 (br s, 1H), 8.94 (d, J = 2.0 Hz, 1H), 8.85 (d, J = 2.0 Hz, 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 = 5.6 Hz, 2H), 3.00 (s, 3H), 2.94 (t, J = 5.6 Hz, 2H), 1.29 (d, J = 6.4 Hz, 6H)。 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.88 (br s, 1H), 8.94 (d, J = 2.0 Hz, 1H), 8.85 (d, J = 2.0 Hz, 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 = 5.6 Hz, 2H), 3.00 (s, 3H), 2.94 (t, J = 5.6 Hz, 2H), 1.29 (d, J = 6.4 Hz, 6H).
1.41.4 化合物compound I:I:
將化合物A（67 g, 98.59 mmol）溶於二氯甲烷（880 mL）和甲醇（440 mL）的混合溶劑中並在室溫下繼續攪拌1小時。隨後在室溫條件下，向反應液中滴加氯化氫的甲醇溶液（4 M, 24.65 mL, 98.59 mmol）。該反應體系繼續在室溫攪拌4小時後，將反應液減壓濃縮至70 mL。向上述混合物中加入甲基叔丁基醚（880 mL）並繼續在室溫攪拌2小時。析出的固體經過過濾，乙腈/水（500 mL）凍乾，得到60.2 g化合物I。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, methanol solution of hydrogen chloride (4 M, 24.65 mL, 98.59 mmol) was added dropwise to the reaction solution at room temperature. After the reaction system continued to stir at room temperature for 4 hours, the reaction solution was concentrated to 70 mL under reduced pressure. Methyl tert-butyl ether (880 mL) was added to the above mixture and stirring was continued at room temperature for 2 hours. The precipitated solid was filtered and lyophilized with acetonitrile/water (500 mL) to obtain 60.2 g of compound I.
MS (ESI) M/Z: 679.0, 681.0 [M + H] +。 MS (ESI) M/Z: 679.0, 681.0 [M + H] + .
1H NMR (300 MHz, DMSO-d 6) δ 9.97 (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)。 1 H NMR (300 MHz, DMSO-d 6 ) δ 9.97 (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).
實施例Example 22 生物學測試評價：Biology Test Evaluation:
（一）(one) EGFR WTEGFR WT 和and EGFR L858R/T790M/C797SEGFR L858R/T790M/C797S 體外酶學實驗In vitro enzyme experiment
本實驗採用螢光共振能量轉移 (TR-FRET) 的方法測試化合物對 EGFR WT（野生型EGFR）和 EGFR L858R/T790M/C797S 激酶活性的抑制作用，並得出化合物對 EGFR 激酶活性的半數抑制濃度 IC 50。 In this experiment, the fluorescence resonance energy transfer (TR-FRET) method was used to test the inhibitory effect of the compound on the kinase activity of EGFR WT (wild-type EGFR) and EGFR L858R/T790M/C797S, and the half inhibitory concentration of the compound on the kinase activity of EGFR was obtained IC50 .
1.1. 實驗材料Experimental Materials
EGFR 重組酶和 EGFR L858R/T790M/C797S 重組酶，購自 Signalchem 公司。EGFR recombinase and EGFR L858R/T790M/C797S recombinase were purchased from Signalchem.
HTRF KinEASE-TK kit 試劑盒，購自 Cisbio 公司。HTRF KinEASE-TK kit was purchased from Cisbio.
DTT，MnCl 2，MgCl 2購自Sigma公司。 DTT, MnCl 2 , and MgCl 2 were purchased from Sigma.
ATP 購自 Promega 公司。ATP was purchased from Promega Corporation.
Brigatinib 購自 Selleck 公司。Brigatinib was purchased from Selleck Company.
2.2. 實驗方法experimental method
1）準備 1X 工作液： 5 mM MgCl 2；1 mM DTT；1 mM MnCl 2和 1×激酶緩衝液（試劑盒中）。 1) Prepare 1X working solution: 5 mM MgCl 2 ; 1 mM DTT; 1 mM MnCl 2 and 1X kinase buffer (in the kit).
2）使用 Echo 550 (Labcyte) 轉移 10nL梯度稀釋的化合物到 384 孔實驗板中。2) Use an Echo 550 (Labcyte) to transfer 10 nL of serially diluted compounds into a 384-well assay plate.
3）加入 5 μL 2× EGFR WT 或 EGFR L858R/T790M/C797S 重組酶溶液到 384 孔實驗板中，室溫孵育 10 分鐘。3) Add 5
4）加入 5 μL 2× TK-substrate-biotin 底物溶液（包含 ATP）到 384 孔實驗板中，室溫孵育 40 分鐘。4) Add 5
5）加入 5 μL含有Sa-XL 665 HTRF 檢測液，以及 5 μLTK-antibody-Cryptate，室溫孵育 1 小時。5) Add 5 μL detection solution containing Sa-XL 665 HTRF, and 5 μL TK-antibody-Cryptate, incubate at room temperature for 1 hour.
6）Envision 酶標儀（PerkinElmer）檢測各孔的 615 nm 和 665 nm 螢光訊號值。6) Envision microplate reader (PerkinElmer) detects the 615 nm and 665 nm fluorescence signal values of each well.
7）計算每孔螢光訊號 665 nm/615 nm 的比值。7) Calculate the ratio of the fluorescent signal 665 nm/615 nm in each well.
8）使用 GraphPad Prism 軟體進行資料分析，得出化合物的 IC 50。 8) Use GraphPad Prism software for data analysis to obtain the IC 50 of the compound.
野生型EGFR和L858R/T790M/C797S三突變型EGFR的激酶活性抑制結果見表21。The kinase activity inhibition results of wild-type EGFR and L858R/T790M/C797S triple mutant EGFR are shown in Table 21.
從表21中我們可以看出，式（A）化合物對L858R/T790M/C797S三突變型EGFR激酶有很好的抑制作用。From Table 21, we can see that the compound of formula (A) has a good inhibitory effect on L858R/T790M/C797S triple mutant EGFR kinase.
表surface
21twenty one
酶學抑制結果Enzyme Inhibition Results
（二）細胞增殖抑制實驗(2) Cell Proliferation Inhibition Experiment
A431A431 細胞增殖抑制實驗Cell Proliferation Inhibition Assay
本實驗採用 CellTiter-Glo 的方法測試化合物對 A431 細胞增殖的抑制作用，並得出化合物抑制細胞生長半數的濃度 IC 50。 In this experiment, the CellTiter-Glo method was used to test the inhibitory effect of the compound on the proliferation of A431 cells, and the concentration IC 50 of the compound inhibiting half of the cell growth was obtained.
1.1. 實驗材料Experimental Materials
A431 細胞購自 ATCC。A431 cells were purchased from ATCC.
DMEM 培養基，胎牛血清（FBS），Penicillin-Streptomycin購自GIBCO。DMEM medium, fetal bovine serum (FBS), and Penicillin-Streptomycin were purchased from GIBCO.
Brigatinib 購自 Selleck 公司。Brigatinib was purchased from Selleck Company.
CellTiter-Glo 試劑，購自 Promega 公司。CellTiter-Glo reagent was purchased from Promega.
2.2. 實驗方法experimental method
1）按照每孔 800 個細胞的密度將 A431 細胞接種於 384 孔培養板，每孔 30μl，置於細胞培養箱中培養 24 小時 (37 ℃，5％CO 2)。 1) A431 cells were seeded in a 384-well culture plate at a density of 800 cells per well, 30 μl per well, and cultured in a cell incubator for 24 hours (37°C, 5% CO 2 ).
2）Day 0：使用 Echo 向培養板細胞中加入 30 nL 梯度稀釋的待測化合物，DMSO終濃度為 0.1%，將培養板置於細胞培養箱中孵育 72 小時（37 ℃，5％CO 2）。空白對照加入每孔 30 nL的 DMSO。 2) Day 0: Use Echo to add 30 nL of the compound to be tested in serial dilutions to the culture plate cells, the final concentration of DMSO is 0.1%, and place the culture plate in a cell culture incubator for 72 hours (37 ℃, 5% CO 2 ) . For the blank control, 30 nL of DMSO was added to each well.
3）Day 3：每孔加入 30 μL Cell Titer-Glo 試劑，室溫避光 30 分鐘。3) Day 3: Add 30 μL of Cell Titer-Glo reagent to each well, and keep in the dark for 30 minutes at room temperature.
4）Envision 酶標儀（PerkinElmer）檢測化學發光訊號。4) Envision microplate reader (PerkinElmer) detects chemiluminescence signal.
5）使用 GraphPad Prism 軟體進行資料分析，得出化合物的 IC 50。 5) Use GraphPad Prism software for data analysis to obtain the IC 50 of the compound.
Ba/F3_L858R/T790M/C797SBa/F3_L858R/T790M/C797S 細胞增殖抑制實驗Cell Proliferation Inhibition Assay
本實驗採用 CellTiter-Glo 的方法測試化合物對 Ba/F3_L858R/T790M/C797S 細胞增殖的抑制作用，並得出化合物抑制細胞生長半數的濃度 IC 50。 In this experiment, the CellTiter-Glo method was used to test the inhibitory effect of the compound on the proliferation of Ba/F3_L858R/T790M/C797S cells, and the concentration IC 50 of the compound inhibiting half of the cell growth was obtained.
1.1. 實驗材料Experimental Materials
Ba/F3_L858R/T790M/C797S 細胞由康龍化成（北京）新藥技術股份有限公司構建。Ba/F3_L858R/T790M/C797S cells were constructed by Pharmaron Chemicals (Beijing) New Pharmaceutical Technology Co., Ltd.
1640 培養基，胎牛血清（FBS），Penicillin-Streptomycin，GlutaMAX-I Supplement購自 GIBCO。1640 medium, fetal bovine serum (FBS), Penicillin-Streptomycin, GlutaMAX-I Supplement were purchased from GIBCO.
Brigatinib 購自 Selleck 公司。Brigatinib was purchased from Selleck Company.
CellTiter-Glo 試劑，購自 Promega 公司。CellTiter-Glo reagent was purchased from Promega.
2.2. 實驗方法experimental method
1）按照每孔 700 個細胞的密度將 Ba/F3_L858R/T790M/C797S 細胞接種於 384 孔培養板，每孔 30 μL。1) Seed Ba/F3_L858R/T790M/C797S cells in a 384-well culture plate at a density of 700 cells per well, 30 μL per well.
2）Day 0：使用 Echo 向培養板細胞中加入 30 nL梯度稀釋的待測化物，DMSO終濃度為 0.1%，將培養板置於細胞培養箱中孵育 72 小時 (37 ℃，5％CO 2)。空白對照加入每孔 30 nL的 DMSO。 2) Day 0: Use Echo to add 30 nL of the compound to be tested in a gradient dilution to the culture plate cells, the final concentration of DMSO is 0.1%, and place the culture plate in a cell culture incubator for 72 hours (37 ℃, 5% CO 2 ) . For the blank control, 30 nL of DMSO was added to each well.
3）Day 3：每孔加入 30 μL Cell Titer-Glo 試劑，室溫避光 30 分鐘。3) Day 3: Add 30 μL of Cell Titer-Glo reagent to each well, and keep in the dark for 30 minutes at room temperature.
4）Envision 酶標儀（PerkinElmer）檢測化學發光訊號。4) Envision microplate reader (PerkinElmer) detects chemiluminescence signal.
5）使用 GraphPad Prism 軟體進行資料分析，得出化合物的 IC 50。 5) Use GraphPad Prism software for data analysis to obtain the IC 50 of the compound.
Ba/F3_Del19/T790M/C797SBa/F3_Del19/T790M/C797S 細胞增殖抑制實驗Cell Proliferation Inhibition Assay
本實驗採用CellTiter-Glo的方法測試化合物對Ba/F3_Del19/T790M/C797S 細胞增殖的抑制作用，並得出化合物抑制細胞生長半數的濃度 IC 50。 In this experiment, the CellTiter-Glo method was used to test the inhibitory effect of the compound on the proliferation of Ba/F3_Del19/T790M/C797S cells, and the concentration IC 50 of the compound inhibiting half of the cell growth was obtained.
1.1. 實驗材料Experimental Materials
Ba/F3_Del19/T790M/C797S 購自康源博創生物科技（北京）有限公司。Ba/F3_Del19/T790M/C797S was purchased from Kangyuan Bochuang Biotechnology (Beijing) Co., Ltd.
1640 培養基，胎牛血清（FBS），Penicillin-Streptomycin，GlutaMAX-I Supplement購自 GIBCO。1640 medium, fetal bovine serum (FBS), Penicillin-Streptomycin, GlutaMAX-I Supplement were purchased from GIBCO.
Brigatinib 購自 Selleck 公司。Brigatinib was purchased from Selleck Company.
CellTiter-Glo 試劑，購自 Promega 公司。CellTiter-Glo reagent was purchased from Promega.
2.2. 實驗方法experimental method
1）按照每孔 700 個細胞的密度將 Ba/F3_Del19/T790M/C797S 細胞接種於 384 孔培養板，每孔 30 μL。1) Seed Ba/F3_Del19/T790M/C797S cells in a 384-well culture plate at a density of 700 cells per well, 30 μL per well.
2）Day 0：使用 Echo 向培養板細胞中加入 30 nL梯度稀釋的待測化合物，DMSO終濃度為 0.1%，將培養板置於細胞培養箱中孵育72小時（37 ℃，5％CO 2）。空白對照加入每孔 30 nL的 DMSO。 2) Day 0: Use Echo to add 30 nL of the compound to be tested in serial dilutions to the culture plate cells, the final concentration of DMSO is 0.1%, and place the culture plate in a cell culture incubator for 72 hours (37 ℃, 5% CO 2 ) . For the blank control, 30 nL of DMSO was added to each well.
3）Day 3：每孔加入 30 μL Cell Titer-Glo 試劑，室溫避光 30 分鐘。3) Day 3: Add 30 μL of Cell Titer-Glo reagent to each well, and keep in the dark for 30 minutes at room temperature.
4）Envision 酶標儀（PerkinElmer）檢測化學發光訊號。4) Envision microplate reader (PerkinElmer) detects chemiluminescence signal.
使用GraphPad Prism 6 軟體進行資料分析，得出化合物的IC
50。
細胞活性抑制結果見表22。The cell activity inhibition results are shown in Table 22.
從表22中的實驗結果可以看出，化合物A對Ba/F3 Del19/T790M/C797S EGFR 三突變細胞系和 Ba/F3 L858R/T790M/C797S EGFR三突變細胞系的細胞增殖有較好的抑制作用；對 EGFR 野生型（EGFR WT）細胞系 A431的抑制作用較弱。這表明化合物A具有較好的細胞活性以及選擇性。From the experimental results in Table 22, it can be seen that compound A has a good inhibitory effect on the cell proliferation of the Ba/F3 Del19/T790M/C797S EGFR triple mutation cell line and the Ba/F3 L858R/T790M/C797S EGFR triple mutation cell line ; Weak inhibitory effect on EGFR wild-type (EGFR WT) cell line A431. This indicates that Compound A has better cell activity and selectivity.
表surface
22twenty two
細胞增殖抑制試驗資料結果Results of cell proliferation inhibition test data
（三）體內藥效研究實驗(3) In vivo drug efficacy research experiment
1.1. 實驗目的Purpose
評價化合物A連續21天口服給藥，對PC9（Del19/T790M/C797S）的抗腫瘤活性及毒副作用。To evaluate the antitumor activity and side effects of compound A on PC9 (Del19/T790M/C797S) after oral administration for 21 consecutive days.
2.2. 實驗材料Experimental Materials
BALB/c-nu小鼠，雌性，SPF級，購自北京維通利華實驗動物技術有限公司。BALB/c-nu mice, female, SPF grade, were purchased from Beijing Weitong Lihua Experimental Animal Technology Co., Ltd.
PC9（Del19/T790M/C797S）細胞，齊魯製藥有限公司自行構建。PC9 (Del19/T790M/C797S) cells were constructed by Qilu Pharmaceutical Co., Ltd.
3.3. 實驗步驟Experimental procedure
3.13.1 細胞培養cell culture
PC9（Del19/T790M/C797S）用含有10%FBS 的RPMI 1640 培養基，在37 ℃，5%二氧化碳培養箱中培養；收集指數生長期的細胞進行接種。PC9 (Del19/T790M/C797S) was cultured in RPMI 1640 medium containing 10% FBS at 37 °C in a 5% carbon dioxide incubator; cells in the exponential growth phase were collected for inoculation.
3.23.2 細胞接種cell seeding
在無菌條件下，取體外培養的PC9（Del19/T790M/C797S）細胞懸液，離心後調整細胞濃度至3×10
7個/mL，接種於小鼠右側腋窩皮下（0.1 mL/只），接種當天設為第0天。
Under sterile conditions, take the in vitro cultured PC9 (Del19/T790M/C797S) cell suspension, adjust the cell concentration to 3× 107 /mL after centrifugation, and inoculate it subcutaneously in the right armpit of mice (0.1 mL/mouse). The current day is set to
3.33.3 腫瘤分組、給藥及測量Tumor grouping, dosing and measurement
a.當平均腫瘤體積約150 mm 3時，挑選35只腫瘤體積適中小鼠入組，按照腫瘤體積大小隨機分為5組：G1：溶媒對照組、G2：化合物A（15 mg/kg）、G3：化合物A（60 mg/kg），7只/組。 a. When the average tumor volume was about 150 mm 3 , 35 mice with moderate tumor volume were selected and randomly divided into 5 groups according to the tumor volume: G1: vehicle control group, G2: compound A (15 mg/kg), G3: Compound A (60 mg/kg), 7 rats/group.
b.動物分組後開始給藥，給藥體積均為10 mL/kg，口服給藥（po）；每天稱重給藥1次，連續給藥21天；每週測量瘤徑2次。b. After the animals were divided into groups, the drug was started, and the volume of the drug was 10 mL/kg, and the drug was administered orally (po); the drug was weighed once a day, and the drug was administered continuously for 21 days; the tumor diameter was measured twice a week.
c.腫瘤體積（Tumor volume,TV）：每週測量2次腫瘤體積，以觀察瘤塊體積變化和生長速度。腫瘤體積V=1/2×a×b 2，其中a、b分別表示腫瘤長徑和短徑。化合物對腫瘤組織的生長抑制作用採用腫瘤生長抑制率TGI（%）評價。TGI（%）=[1-（某給藥組的平均腫瘤體積-該給藥組分組當天的平均腫瘤體積）/（陰性對照組的平均腫瘤體積-陰性對照組分組當天的平均腫瘤體積）]×100%。給藥組和陰性對照組取同一天數據。 c. Tumor volume (Tumor volume, TV): The tumor volume was measured twice a week to observe the volume change and growth rate of the tumor mass. Tumor volume V=1/2×a×b 2 , where a and b represent the long diameter and short diameter of the tumor, respectively. The growth inhibitory effect of compounds on tumor tissue was evaluated by tumor growth inhibition rate TGI (%). TGI (%)=[1-(Average tumor volume of a drug administration group-Average tumor volume of the administration group on the day of grouping)/(Average tumor volume of the negative control group-Average tumor volume of the day of grouping of the negative control group)] ×100%. The data of the administration group and the negative control group were collected on the same day.
d.在試驗過程中密切觀察小鼠生活狀態，包括外觀體征、一般行為活動、精神狀態、攝食情況、呼吸狀態、糞便和尿液性狀、注射局部及其它毒性表現。d. Closely observe the living conditions of the mice during the experiment, including appearance signs, general behavioral activities, mental state, food intake, respiratory state, feces and urine properties, injection site and other toxic manifestations.
e.試驗達到終點後，將小鼠實施安樂死，動物屍體凍存至冰櫃，移交至有資質的醫療廢棄物處理單位進行處置。e. After the end of the experiment, the mice were euthanized, and the animal corpses were stored in a freezer and handed over to a qualified medical waste disposal unit for disposal.
44 實驗結果Experimental results
實驗結果見表23以及圖16和圖17。The experimental results are shown in Table 23 and Figures 16 and 17.
表surface
23twenty three
體內藥效試驗結果In vivo efficacy test results
a，平均值±標準誤；a, mean ± standard error;
b，P值腫瘤體積進行統計分析，與G1組比較，*P﹤0.05；**P﹤0.01。b, P value for statistical analysis of tumor volume, compared with G1 group, *P﹤0.05; **P﹤0.01.
55 實驗結論Experimental results
從上數結果可以看出，化合物A能顯著抑制腫瘤生長（圖16），呈明顯的量效關係，且小鼠耐受性良好（圖17）。From the above results, it can be seen that compound A can significantly inhibit tumor growth (Figure 16), showing a clear dose-effect relationship, and the mice are well tolerated (Figure 17).
實施例Example 33 晶型crystal form II 的製備：Preparation of:
方法1：method 1:
稱取約20 mg化合物A於4 mL樣品瓶內，加入1 mL乙腈，室溫條件下攪拌3天，過濾並收集固體，在室溫條件下晾乾。Weigh about 20 mg of compound A into a 4 mL sample bottle, add 1 mL of acetonitrile, stir at room temperature for 3 days, filter and collect the solid, and dry at room temperature.
將所得固體，進行XRPD、TGA-DSC測試表徵，該固體為晶型I。The obtained solid was characterized by XRPD and TGA-DSC tests, and the solid was crystal form I.
XRPD譜圖如圖1所示。The XRPD spectrum is shown in FIG. 1 .
TGA-DSC譜圖如圖18所示。The TGA-DSC spectrum is shown in Figure 18.
方法2：Method 2:
稱取約20 mg化合物A於4 mL樣品瓶內，加入1 mL水，50 °C攪拌1天，過濾並收集固體，在室溫條件下晾乾。所得固體，其XRPD譜圖基本如圖1所示。Weigh about 20 mg of Compound A into a 4 mL sample bottle, add 1 mL of water, stir at 50 °C for 1 day, filter and collect the solid, and dry it at room temperature. The obtained solid has an XRPD spectrum basically as shown in FIG. 1 .
實施例Example 44 晶型crystal form IIII 的製備：Preparation of:
方法1：method 1:
在50 °C下，向10mg化合物A中加入1.0 mL四氫呋喃（THF），攪拌5分鐘後過濾收集濾液。室溫下，將4.0 mL甲基叔丁基醚逐漸加入藥液中，並攪拌16小時後過濾，收集固體並在室溫晾乾。At 50 °C, 1.0 mL of tetrahydrofuran (THF) was added to 10 mg of compound A, stirred for 5 min, and the filtrate was collected by filtration. At room temperature, 4.0 mL of methyl tert-butyl ether was gradually added to the drug solution, stirred for 16 hours, then filtered, and the solid was collected and dried at room temperature.
將所得固體，進行XRPD、TGA-DSC測試表徵，該固體為晶型II。The obtained solid was characterized by XRPD and TGA-DSC tests, and the solid was crystal form II.
XRPD譜圖如圖2所示。The XRPD spectrum is shown in FIG. 2 .
TGA-DSC譜圖如圖19所示。The TGA-DSC spectrum is shown in Figure 19.
方法2：Method 2:
將約10 mg晶型I在50 °C溶於0.4 mL二甲基亞碸（DMSO）中。然後，在室溫下將藥液滴加到1 mL甲基叔丁基醚中。析出固體後，混懸液在室溫條件下攪拌兩小時，然後過濾，收集固體，並在室溫晾乾。所得固體，其XRPD譜圖基本如圖2所示。About 10 mg of Form I was dissolved in 0.4 mL of dimethylsulfoxide (DMSO) at 50 °C. Then, the drug solution was added dropwise into 1 mL of methyl tert-butyl ether at room temperature. After precipitation of a solid, the suspension was stirred at room temperature for two hours, then filtered to collect the solid and allowed to dry at room temperature. The obtained solid has an XRPD spectrum basically as shown in FIG. 2 .
方法3：Method 3:
稱取240 mg化合物A至樣品瓶中，加入3 mL丙酮並在50°C攪拌過夜。過濾收集固體，於50°C真空乾燥。所得固體，其XRPD譜圖基本如圖2所示。Weigh 240 mg of Compound A into a sample bottle, add 3 mL of acetone and stir overnight at 50°C. The solid was collected by filtration and dried under vacuum at 50°C. The obtained solid has an XRPD spectrum basically as shown in FIG. 2 .
實施例Example 55 晶型crystal form IIIIII 的製備：Preparation of:
在50 °C下，將20mg化合物A溶於0.5 mL二甲基亞碸（DMSO），室溫下，將2.0 mL乙醇逐漸加入藥液中，並攪拌16小時後過濾，收集固體並在50 °C真空乾燥。Dissolve 20 mg of Compound A in 0.5 mL of dimethylsulfoxide (DMSO) at 50 °C, gradually add 2.0 mL of ethanol to the solution at room temperature, and stir for 16 hours before filtering, collecting the solids and drying at 50 °C. C vacuum dried.
將所得固體，進行XRPD、TGA-DSC測試表徵，該固體為晶型III。The obtained solid was characterized by XRPD and TGA-DSC tests, and the solid was crystal form III.
XRPD譜圖如圖3所示。The XRPD spectrum is shown in FIG. 3 .
TGA-DSC譜圖如圖20所示。The TGA-DSC spectrum is shown in Figure 20.
實施例Example 66 晶型crystal form IVIV 的製備：Preparation of:
稱取適量化合物A至樣品瓶中，加入甲苯配製成20 mg/mL的混懸液。這些混懸液隨後在室溫條件下攪拌3天。過濾並收集固體，在室溫條件下晾乾。Weigh an appropriate amount of Compound A into a sample bottle, and add toluene to prepare a 20 mg/mL suspension. These suspensions were then stirred at room temperature for 3 days. The solid was collected by filtration and allowed to dry at room temperature.
將所得固體，進行XRPD、TGA-DSC測試表徵，該固體為晶型IV。The obtained solid was characterized by XRPD and TGA-DSC tests, and the solid was crystal form IV.
XRPD譜圖如圖4所示。The XRPD spectrum is shown in FIG. 4 .
TGA-DSC譜圖如圖21所示。The TGA-DSC spectrum is shown in Figure 21.
實施例Example 77 晶型crystal form VV 的製備：Preparation of:
在50 °C下，將20mg化合物A溶於0.5 mL二甲基亞碸（DMSO），室溫下，將1.0 mL水逐漸加入藥液中，並攪拌16小時後過濾，收集固體並在50 °C真空乾燥。Dissolve 20 mg of Compound A in 0.5 mL of dimethylsulfoxide (DMSO) at 50 °C, gradually add 1.0 mL of water to the solution at room temperature, and stir for 16 hours before filtering, collecting the solid and drying at 50 °C C vacuum dried.
將所得固體，進行XRPD、TGA-DSC測試表徵，該固體為晶型V。The obtained solid was characterized by XRPD and TGA-DSC tests, and the solid was Form V.
XRPD譜圖如圖5所示。The XRPD spectrum is shown in FIG. 5 .
TGA-DSC譜圖如圖22所示。The TGA-DSC spectrum is shown in Figure 22.
實施例Example 88 晶型crystal form VIVI 的製備：Preparation of:
在50 °C下，稱取20 mg化合物A至樣品瓶中，然後在50 °C條件下緩慢加入1mL四氫呋喃，得到幾乎澄清的藥液，隨後過濾並收集濾液。將濾液在攪拌的條件下冷卻至室溫，並持續攪拌16小時，直到固體析出。過濾並收集固體，在室溫條件下晾乾。At 50 °C, 20 mg of compound A was weighed into a sample bottle, and then 1 mL of tetrahydrofuran was slowly added at 50 °C to obtain an almost clear drug solution, which was then filtered and the filtrate was collected. The filtrate was cooled to room temperature with stirring, and stirring was continued for 16 hours until a solid precipitated. The solid was collected by filtration and allowed to dry at room temperature.
將所得固體，進行XRPD、TGA-DSC測試表徵，該固體為晶型VI。The obtained solid was characterized by XRPD and TGA-DSC tests, and the solid was crystal form VI.
XRPD譜圖如圖6所示。The XRPD spectrum is shown in FIG. 6 .
TGA-DSC譜圖如圖23所示。The TGA-DSC spectrum is shown in Figure 23.
實施例Example 99 晶型crystal form VIIVII 的製備：Preparation of:
稱取適量化合物A至樣品瓶中，加入二氯甲烷配製成20 mg/mL的混懸液。這些混懸液隨後在室溫條件下攪拌3天。過濾並收集固體，在室溫條件下晾乾1小時。Weigh an appropriate amount of Compound A into a sample bottle, add dichloromethane to prepare a 20 mg/mL suspension. These suspensions were then stirred at room temperature for 3 days. The solid was collected by filtration and allowed to dry at room temperature for 1 hour.
將所得固體，進行XRPD、TGA-DSC測試表徵，該固體為晶型VII。The obtained solid was characterized by XRPD and TGA-DSC tests, and the solid was crystal form VII.
XRPD譜圖如圖7所示。The XRPD spectrum is shown in FIG. 7 .
TGA-DSC譜圖如圖24所示。The TGA-DSC spectrum is shown in Figure 24.
實施例Example 1010 晶型crystal form VIIIVIII 的製備：Preparation of:
稱取適量化合物A至樣品瓶中，加入異丙醇配製成20 mg/mL的混懸液。這些混懸液隨後在室溫條件下攪拌3天。過濾並收集固體，在室溫條件下晾乾。Weigh an appropriate amount of Compound A into a sample bottle, and add isopropanol to prepare a 20 mg/mL suspension. These suspensions were then stirred at room temperature for 3 days. The solid was collected by filtration and allowed to dry at room temperature.
將所得固體，進行XRPD、TGA-DSC測試表徵，該固體為晶型VIII。The obtained solid was characterized by XRPD and TGA-DSC tests, and the solid was crystal form VIII.
XRPD譜圖如圖8所示。The XRPD spectrum is shown in FIG. 8 .
TGA-DSC譜圖如圖25所示。The TGA-DSC spectrum is shown in Figure 25.
實施例Example 1111 晶型crystal form IXIX 的製備：Preparation of:
稱取適量化合物A至樣品瓶中，加入異丁醇配製成20 mg/mL的混懸液。這些混懸液隨後在室溫條件下攪拌3天。過濾並收集固體，在室溫條件下晾乾。Weigh an appropriate amount of compound A into a sample bottle, and add isobutanol to prepare a 20 mg/mL suspension. These suspensions were then stirred at room temperature for 3 days. The solid was collected by filtration and allowed to dry at room temperature.
將所得固體，進行XRPD、TGA-DSC測試表徵，該固體為晶型IX。The obtained solid was characterized by XRPD and TGA-DSC tests, and the solid was crystal form IX.
XRPD譜圖如圖9所示。The XRPD spectrum is shown in FIG. 9 .
TGA-DSC譜圖如圖26所示。The TGA-DSC spectrum is shown in Figure 26.
實施例Example 1212 晶型crystal form XIIXII 的製備：Preparation of:
稱取適量化合物A至樣品瓶中，加入甲醇/水（1:1）配製成10mg/mL的混懸液。這些混懸液隨後在室溫條件下攪拌3天。過濾並收集固體，在室溫條件下晾乾。Weigh an appropriate amount of Compound A into a sample bottle, add methanol/water (1:1) to prepare a 10 mg/mL suspension. These suspensions were then stirred at room temperature for 3 days. The solid was collected by filtration and allowed to dry at room temperature.
將所得固體，進行XRPD、TGA-DSC測試表徵，該固體為晶型XII。The obtained solid was characterized by XRPD and TGA-DSC tests, and the solid was crystal form XII.
XRPD譜圖如圖10所示。The XRPD spectrum is shown in FIG. 10 .
TGA-DSC譜圖如圖27所示。The TGA-DSC spectrum is shown in Figure 27.
實施例Example 1313 晶型crystal form XIVXIV 的製備：Preparation of:
在50 °C下，稱取20 mg樣品至樣品瓶中，然後在50 °C條件下緩慢加入甲醇/1,4-二氧六環（體積比2/1.5）3.5mL，得到幾乎澄清的藥液，隨後過濾並收集濾液。將濾液在攪拌的條件下冷卻至室溫，並持續攪拌16 – 56小時，直到固體析出。過濾並收集固體，在室溫條件下晾乾。At 50 °C, weigh 20 mg of the sample into a sample bottle, then slowly add 3.5 mL of methanol/1,4-dioxane (
將所得固體，進行XRPD、TGA-DSC測試表徵，該固體為晶型XIV。The obtained solid was characterized by XRPD and TGA-DSC tests, and the solid was crystal form XIV.
XRPD譜圖如圖11所示。The XRPD spectrum is shown in FIG. 11 .
TGA-DSC譜圖如圖28所示。The TGA-DSC spectrum is shown in Figure 28.
實施例Example 1414 晶型crystal form AA 的製備：Preparation of:
25 mg化合物A在室溫下加入到2ml乙醇中，然後加入1當量的12M鹽酸攪拌1天，固體樣品過濾收集，真空乾燥。25 mg of compound A was added to 2 ml of ethanol at room temperature, then 1 equivalent of 12M hydrochloric acid was added and stirred for 1 day, the solid sample was collected by filtration and dried in vacuo.
將所得固體，進行XRPD、TGA-DSC測試表徵，該固體為晶型A。The obtained solid was characterized by XRPD and TGA-DSC tests, and the solid was Form A.
XRPD譜圖如圖12所示。The XRPD spectrum is shown in FIG. 12 .
TGA-DSC譜圖如圖29所示。The TGA-DSC spectrum is shown in Figure 29.
實施例Example 1515 晶型crystal form BB 的製備：Preparation of:
25 mg的化合物A在室溫下加入到2ml丙酮/水（100/1）中，然後加入1當量的12M鹽酸攪拌1天，固體樣品過濾收集，真空乾燥。25 mg of compound A was added to 2 ml of acetone/water (100/1) at room temperature, then 1 equivalent of 12M hydrochloric acid was added and stirred for 1 day, the solid sample was collected by filtration and dried in vacuo.
將所得固體，進行XRPD、TGA-DSC測試表徵，該固體為晶型B。The obtained solid was characterized by XRPD and TGA-DSC tests, and the solid was crystal form B.
XRPD譜圖如圖13所示。The XRPD spectrum is shown in FIG. 13 .
TGA-DSC譜圖如圖30所示。The TGA-DSC spectrum is shown in Figure 30.
實施例Example 1616 晶型crystal form CC 的製備：Preparation of:
稱取19.67 mg式（I）化合物於8 mL樣品瓶中，加入1 mL異丙醇，置於50°C條件下攪拌1天並過濾，在50 °C下真空乾燥。Weighed 19.67 mg of the compound of formula (I) into an 8 mL sample bottle, added 1 mL of isopropanol, stirred at 50°C for 1 day, filtered, and dried under vacuum at 50°C.
將所得固體，進行XRPD、TGA-DSC測試表徵，該固體為晶型C。The obtained solid was characterized by XRPD and TGA-DSC tests, and the solid was Form C.
XRPD譜圖如圖14所示。The XRPD spectrum is shown in FIG. 14 .
TGA-DSC譜圖如圖31所示。The TGA-DSC spectrum is shown in Figure 31.
實施例Example 1717 晶型crystal form DD. 的製備：Preparation of:
方法1：method 1:
稱取97.75 mg式（I）化合物於20 mL樣品瓶中，加入6 mL丙酮，置於50 °C條件下攪拌過夜並過濾，在50 °C下真空乾燥4-5小時。Weigh 97.75 mg of the compound of formula (I) into a 20 mL sample bottle, add 6 mL of acetone, stir overnight at 50 °C, filter, and dry under vacuum at 50 °C for 4-5 hours.
1H NMR (400 MHz, DMSO-d 6) δ 9.97 (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) 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.97 (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)
精密稱取式（I）化合物晶型D兩份約25 mg樣品至25 mL 容量瓶中，加溶劑溶解稀釋定溶，透過氯離子色譜進行氯離子含量的檢測，結果如表24所示，透過公式換算，得知化合物（I）晶型D中，式A化合物與氯化氫的摩爾比約為1:1。Precisely weigh two samples of about 25 mg of compound crystal form D of formula (I) into a 25 mL volumetric flask, add a solvent to dissolve, dilute and fix the solution, and detect the chloride ion content through chloride ion chromatography. The results are shown in Table 24. Through According to the conversion of the formula, it is known that in the crystal form D of compound (I), the molar ratio of the compound of formula A to hydrogen chloride is about 1:1.
表surface
24twenty four
氯離子含量測試結果Chloride ion content test results
將所得固體，進行XRPD、TGA-DSC測試表徵，該固體為晶型D。The obtained solid was characterized by XRPD and TGA-DSC tests, and the solid was crystal form D.
XRPD譜圖如圖15所示。The XRPD spectrum is shown in FIG. 15 .
TGA-DSC譜圖如圖32所示。The TGA-DSC spectrum is shown in Figure 32.
方法2：Method 2:
將25 mg式（I）化合物加入到0.3 mL二氯甲烷/甲醇（1/1，v/v）中，在室溫條件下配製成飽和藥液，然後將2.7 mL丙酮逐漸加入到藥液中直至固體析出。混懸液在室溫條件下攪拌4-5小時。收集固體並在50 °C條件下真空乾燥，所得固體，其XRPD譜圖基本如圖15所示。Add 25 mg of the compound of formula (I) to 0.3 mL of dichloromethane/methanol (1/1, v/v) to prepare a saturated solution at room temperature, then gradually add 2.7 mL of acetone to the solution in until a solid precipitates out. The suspension was stirred at room temperature for 4-5 hours. The solid was collected and dried under vacuum at 50 °C, and the XRPD spectrum of the obtained solid was basically as shown in Figure 15.
實施例Example 1818 引濕性實驗：Moisture test:
參照中國藥典中的《藥物引濕性試驗指導原則》，測試晶型I、II、III、D的水分吸附/脫附數據。Refer to the "Guiding Principles of Drug Humidity Test" in the Chinese Pharmacopoeia to test the water adsorption/desorption data of crystal forms I, II, III, and D.
圖33為晶型I的DVS曲線，圖34為晶型I DVS測試前後的XRPD譜圖。DVS結果表明，晶型I在80%RH時吸濕增重0.59%，在90%RH時吸濕增重0.77%，說明該晶型略有引濕性，測試DVS實驗後剩餘固體的XRPD，晶型未發生改變。Figure 33 is the DVS curve of Form I, and Figure 34 is the XRPD spectrum of Form I before and after DVS testing. DVS results show that the 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 was tested. The crystal form did not change.
圖35為晶型II的DVS曲線，圖36為晶型II DVS測試前後的XRPD譜圖。DVS結果表明，DVS結果顯示，顯示晶型II幾乎不吸濕，在80%和90%RH條件下，其吸濕增重分別為0.19%和0.24%；測試DVS實驗後剩餘固體的XRPD，晶型未發生改變。Figure 35 is the DVS curve of Form II, and Figure 36 is the XRPD spectrum of Form II before and after DVS testing. The DVS results showed that the crystalline form II hardly absorbed moisture, and under the conditions of 80% and 90%RH, its moisture absorption weight gain was 0.19% and 0.24% respectively; after testing the XRPD of the remaining solid after the DVS experiment, the crystal type has not changed.
圖37為晶型III的DVS曲線，圖38為晶型III DVS測試前後的XRPD譜圖。DVS結果表明，晶型III具有輕微吸濕性，在80%和90%RH條件下，樣品的吸濕增重量分別為0.8%和1.0%；測試DVS實驗後剩餘固體的XRPD，晶型未發生改變。Figure 37 is the DVS curve of Form III, and Figure 38 is the XRPD spectrum of Form III before and after DVS testing. The DVS results show that the crystal form III is slightly hygroscopic. Under the conditions of 80% and 90% RH, the moisture absorption weight gain of the sample is 0.8% and 1.0% respectively; the XRPD of the remaining solid after the DVS experiment shows that the crystal form does not occur Change.
圖39為晶型D的DVS曲線，圖40為晶型D DVS測試前後的XRPD譜圖。DVS結果表明，晶型D具有輕微吸濕性，在80%RH和90%RH時吸濕增重量分別為0.59%和0.76%，DVS測試後，剩餘固體的晶型未發生改變。Figure 39 is the DVS curve of Form D, and Figure 40 is the XRPD spectrum of Form D before and after DVS testing. The DVS results showed that the crystalline form D was slightly hygroscopic, and the moisture absorption weight gain was 0.59% and 0.76% at 80%RH and 90%RH, respectively. After the DVS test, the crystalline form of the remaining solid did not change.
實施例Example 1919 晶型crystal form I-IIII-III 的熱、濕穩定性實驗：Heat and humidity stability test:
參照中國藥典中的《原料藥物與製劑穩定性試驗指導原則》，考察晶型I、II和III在不同溫度以及濕度下的穩定性。在第0、5天和10天使用HPLC測試純度，XRPD測試晶型。Referring to the "Guidelines for the Stability Test of Raw Materials and Preparations" in the Chinese Pharmacopoeia, the stability of crystal forms I, II and III at different temperatures and humidity was investigated. Purity was tested using HPLC and crystal form was tested by XRPD on
實驗結果如表25所示，晶型I、II和III在高溫、高濕條件下略有降解，但純度總體變化不大，尤其是晶型II，在高溫、高濕的環境下基本保持穩定。三種晶型在實驗前後，晶型均未發生轉變。The experimental results are shown in Table 25. The crystal forms I, II and III are slightly degraded under high temperature and high humidity conditions, but the overall purity does not change much, especially the crystal form II, which is 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.
表
實施例Example 2020 晶型crystal form DD. 的穩定性實驗：The stability experiment of:
參照中國藥典中的《原料藥物與製劑穩定性試驗指導原則》，考察晶型D在高溫、高濕、光照條件下的穩定性。在第0、5天 和10天使用HPLC測試純度，XRPD測試晶型。Referring to the "Guidelines for the Stability Test of Raw Materials and Preparations" in the Chinese Pharmacopoeia, the stability of the crystal form D under high temperature, high humidity, and light conditions was investigated. Purity was tested using HPLC and crystal form was tested by XRPD on
實驗結果如表26所示，晶型D在高溫、高濕條件基本保持穩定，光照條件下略有降解，且IC結果表明，在60°C、25°C/92.5%RH以及光照條件下鹽酸鹽晶型VIII沒有發生解離（表27），仍為單鹽酸鹽。在實驗前後，晶型D均未發生轉變（圖42）。The experimental results are shown in Table 26. Crystal form D is basically stable under high temperature and high humidity conditions, and slightly degraded under light conditions, and the IC results show that salt The hydrochloride form VIII did not dissociate (Table 27), and was still monohydrochloride. Form D was not transformed before and after the experiment (Fig. 42).
表
表
實施例Example 21twenty one 壓力實驗：Stress test:
取約100 mg晶型II放置於單衝壓片機中，手動壓實樣品成型、不鬆散，壓製成60 mm的藥片，然後輕輕碾碎成粉末狀，剩餘固體的XRPD圖譜未發生改變（圖41），說明晶型II具有良好的抗壓性。About 100 mg of Form II was placed in a single-punch tablet press, and the sample was manually compacted to form a shape without loosening. It was pressed into a 60 mm tablet, and then gently crushed into a powder. The XRPD pattern of the remaining solid did not change (Fig. 41), indicating that the crystal form II has good compression resistance.
無none
圖1為式（A）化合物晶型I的XRPD譜圖。 圖2為式（A）化合物晶型II的XRPD譜圖。 圖3為式（A）化合物晶型III的XRPD譜圖。 圖4為式（A）化合物晶型IV的XRPD譜圖。 圖5為式（A）化合物晶型V的XRPD譜圖。 圖6為式（A）化合物晶型VI的XRPD譜圖。 圖7為式（A）化合物晶型VII的XRPD譜圖。 圖8為式（A）化合物晶型VIII的XRPD譜圖。 圖9為式（A）化合物晶型IX的XRPD譜圖。 圖10為式（A）化合物晶型XII的XRPD譜圖。 圖11為式（A）化合物晶型XIV的XRPD譜圖。 圖12為式（I）化合物晶型A的XRPD譜圖。 圖13為式（I）化合物晶型B的XRPD譜圖。 圖14為式（I）化合物晶型C的XRPD譜圖。 圖15為式（I）化合物晶型D的XRPD譜圖。 圖16為動物腫瘤生長曲線圖。 圖17為動物體重曲線圖。 圖18為式（A）化合物晶型I的TGA-DSC譜圖。 圖19為式（A）化合物晶型II的TGA-DSC譜圖。 圖20為式（A）化合物晶型III的TGA-DSC譜圖。 圖21為式（A）化合物晶型IV的TGA-DSC譜圖。 圖22為式（A）化合物晶型V的TGA-DSC譜圖。 圖23為式（A）化合物晶型VI的TGA-DSC譜圖。 圖24為式（A）化合物晶型VII的TGA-DSC譜圖。 圖25為式（A）化合物晶型VIII的TGA-DSC譜圖。 圖26為式（A）化合物晶型IX的TGA-DSC譜圖。 圖27為式（A）化合物晶型XII的TGA-DSC譜圖。 圖28為式（A）化合物晶型XIV的TGA-DSC譜圖。 圖29為式（I）化合物晶型A的TGA-DSC譜圖。 圖30為式（I）化合物晶型B的TGA-DSC譜圖。 圖31為式（I）化合物晶型C的TGA-DSC譜圖。 圖32為式（I）化合物晶型D的TGA-DSC譜圖。 圖33為式（A）化合物晶型I的DVS譜圖。 圖34為式（A）化合物晶型I的DVS實驗前後XRPD對比譜圖。 圖35為式（A）化合物晶型II的DVS譜圖。 圖36為式（A）化合物晶型II的DVS實驗前後XRPD對比譜圖。 圖37為式（A）化合物晶型III的DVS譜圖。 圖38為式（A）化合物晶型III的DVS實驗前後XRPD對比譜圖。 圖39為式（I）化合物晶型D的DVS譜圖。 圖40為式（I）化合物晶型D的DVS實驗前後XRPD對比譜圖。 圖41為式（A）化合物晶型II抗壓性實驗前後XRPD對比譜圖。 圖42為式（I）化合物晶型D的穩定性實驗前後XRPD對比譜圖。 Figure 1 is the XRPD spectrum of the crystal form I of the compound of formula (A). Fig. 2 is the XRPD spectrum of the compound of formula (A) Form II. Fig. 3 is the XRPD spectrum of the compound of formula (A) crystal form III. Fig. 4 is the XRPD spectrum of the compound of formula (A) in form IV. Fig. 5 is the XRPD spectrum of the crystal form V of the compound of formula (A). Figure 6 is the XRPD spectrum of the compound of formula (A) in Form VI. Fig. 7 is the XRPD spectrum of the compound of formula (A) in the crystal form VII. Fig. 8 is the XRPD spectrum of the crystal form VIII of the compound of formula (A). Fig. 9 is an XRPD spectrum of the crystal form IX of the compound of formula (A). Fig. 10 is the XRPD spectrum of the compound of formula (A) in crystal form XII. Fig. 11 is the XRPD spectrum of the compound of formula (A) in crystal form XIV. Figure 12 is the XRPD spectrum of Form A of the compound of formula (I). Figure 13 is the XRPD spectrum of the crystal form B of the compound of formula (I). Figure 14 is the XRPD spectrum of Form C of the compound of formula (I). Fig. 15 is the XRPD spectrum of the crystal form D of the compound of formula (I). Fig. 16 is a graph showing tumor growth curves in animals. Figure 17 is a graph of animal body weight. Figure 18 is the TGA-DSC spectrum of the crystal form I of the compound of formula (A). Fig. 19 is a TGA-DSC spectrum of the compound of formula (A) Form II. Figure 20 is the TGA-DSC spectrum of the compound of formula (A) Form III. Fig. 21 is the TGA-DSC spectrum of the compound of formula (A) Form IV. Figure 22 is the TGA-DSC spectrum of Form V of the compound of formula (A). Fig. 23 is the TGA-DSC spectrum of the compound of formula (A) in the crystal form VI. Fig. 24 is the TGA-DSC spectrum of the compound of formula (A) in the crystal form VII. Fig. 25 is a TGA-DSC spectrum of the compound of formula (A) in the crystal form VIII. Fig. 26 is a TGA-DSC spectrum of the compound of formula (A) Form IX. Fig. 27 is a TGA-DSC spectrum of the compound of formula (A) in the crystal form XII. Fig. 28 is a TGA-DSC spectrum of the compound of formula (A) in the crystal form XIV. Fig. 29 is a TGA-DSC spectrum of the crystal form A of the compound of formula (I). Figure 30 is the TGA-DSC spectrum of the crystal form B of the compound of formula (I). Figure 31 is the TGA-DSC spectrum of the crystal form C of the compound of formula (I). Figure 32 is the TGA-DSC spectrum of the crystal form D of the compound of formula (I). Figure 33 is the DVS spectrum of the compound of formula (A) in Form I. Fig. 34 is a comparison of XRPD spectra before and after DVS experiment of compound crystal form I of formula (A). Figure 35 is the DVS spectrum of the compound of formula (A) in Form II. Figure 36 is a comparison of XRPD spectra before and after the DVS experiment of the compound of formula (A) Form II. Fig. 37 is the DVS spectrum of the compound of formula (A) Form III. Figure 38 is the comparison of XRPD spectra before and after the DVS experiment of the compound of formula (A) Form III. Fig. 39 is the DVS spectrum of the compound of formula (I) in the crystal form D. Fig. 40 is a comparison of XRPD spectra before and after DVS experiment of compound crystal form D of formula (I). Figure 41 is a comparison of XRPD spectra before and after the compression resistance test of the compound of formula (A) in Form II. Figure 42 is the comparison of XRPD spectra before and after the stability test of the compound crystal form D of formula (I).
Claims (29)
Applications Claiming Priority (6)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202111197957 | 2021-10-14 | ||
| CN202111197313 | 2021-10-14 | ||
| CN202111197313.7 | 2021-10-14 | ||
| CN202111196875 | 2021-10-14 | ||
| CN202111196875.X | 2021-10-14 | ||
| CN202111197957.6 | 2021-10-14 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| TW202317098A true TW202317098A (en) | 2023-05-01 |
Family
ID=85987315
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| TW111138877A TW202317098A (en) | 2021-10-14 | 2022-10-13 | Polymorphs of egfr inhibitor |
Country Status (2)
| Country | Link |
|---|---|
| TW (1) | TW202317098A (en) |
| WO (1) | WO2023061433A1 (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2024046405A1 (en) * | 2022-09-01 | 2024-03-07 | 齐鲁制药有限公司 | Use of egfr kinase inhibitor |
Family Cites Families (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107540661A (en) * | 2016-06-24 | 2018-01-05 | 正大天晴药业集团股份有限公司 | Crystallization as the Aniline pyrimidine compound of EGFR inhibitor |
| WO2020216371A1 (en) * | 2019-04-26 | 2020-10-29 | 江苏先声药业有限公司 | Egfr inhibitor and application thereof |
| US20220259235A1 (en) * | 2019-07-26 | 2022-08-18 | Betta Pharmaceuticals Co., Ltd | EGFR Inhibitor, Composition, and Preparation Method Therefor |
| EP4129996A4 (en) * | 2020-03-23 | 2023-07-12 | Qilu Pharmaceutical Co., Ltd. | Novel aminopyrimidine egfr inhibitor |
| EP4137484A4 (en) * | 2020-04-14 | 2023-12-20 | Qilu Pharmaceutical Co., Ltd. | Tricyclic compounds as egfr inhibitors |
| CN113717156B (en) * | 2020-05-25 | 2023-05-09 | 南京红云生物科技有限公司 | EGFR inhibitor, preparation method and application thereof |
-
2022
- 2022-10-13 WO PCT/CN2022/125056 patent/WO2023061433A1/en unknown
- 2022-10-13 TW TW111138877A patent/TW202317098A/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| WO2023061433A1 (en) | 2023-04-20 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| JP6986032B2 (en) | Crystals of pyrrolopyrimidine compounds as JAK inhibitors | |
| KR20060054300A (en) | Isethionate salt of a selective cdk4 inhibitor | |
| WO2014135028A1 (en) | Pyridopyrimidine or pyrimidopyrimidine compound, preparation method, pharmaceutical composition and use thereof | |
| TW201718583A (en) | New epidermal growth factor receptor inhibitor and application thereof | |
| TW202317098A (en) | Polymorphs of egfr inhibitor | |
| CN113248497B (en) | Fused ring derivatives useful as FGFR4 inhibitors | |
| TW202311259A (en) | Novel forms of compound ⅰ and use thereof | |
| WO2020221209A1 (en) | Cd73 inhibitor, preparation method therefor and application thereof | |
| WO2019228330A1 (en) | Substituted benzo[d]imidazole compound and pharmaceutical composition thereof | |
| WO2015014283A1 (en) | Protein tyrosine kinase inhibitor and application thereof | |
| WO2021249319A1 (en) | Tricyclic compound, pharmaceutical composition, and use thereof | |
| KR102270538B1 (en) | New polymorphic forms of icotinib phosphate and uses thereof | |
| CN110016026B (en) | Pyrimidopyridone compounds with antitumor activity, preparation method and application | |
| JP2022520083A (en) | Crystal form of JAK2 inhibitor | |
| CN112020357B (en) | Salt of indazolyl-containing tricyclic derivative and crystal form thereof | |
| WO2023041061A1 (en) | Fused bicyclic derivative, pharmaceutically acceptable salt, crystal form thereof and preparation method therefor | |
| WO2021073494A1 (en) | The salts of a compound and the crystalline forms thereof | |
| WO2024027825A1 (en) | Cdk inhibitor and polymorph of phosphate thereof | |
| WO2022083733A1 (en) | Bruton tyrosine kinase inhibitor compound in solid form and use thereof | |
| WO2021078141A1 (en) | Novel purine derivative, intermediate and application thereof in preparing anticancer medicine | |
| CN114867531B (en) | EGFR inhibitors | |
| TWI820414B (en) | Quinazoline compounds, preparation method and use thereof | |
| WO2022037704A1 (en) | Water-soluble anti-tumor prodrug, and pharmaceutical composition and use thereof | |
| TW202408510A (en) | Polymorphic forms of CDK inhibitors and phosphates thereof, preparation methods thereof, pharmaceutical compositions containing the same and uses thereof | |
| WO2020063636A1 (en) | Pyrazolopyrimidine compound and preparation method and use thereof in preparation of anti-cancer drug |