WO2023061433A1 - Polymorph of egfr inhibitor - Google Patents

Polymorph of egfr inhibitor Download PDF

Info

Publication number
WO2023061433A1
WO2023061433A1 PCT/CN2022/125056 CN2022125056W WO2023061433A1 WO 2023061433 A1 WO2023061433 A1 WO 2023061433A1 CN 2022125056 W CN2022125056 W CN 2022125056W WO 2023061433 A1 WO2023061433 A1 WO 2023061433A1
Authority
WO
WIPO (PCT)
Prior art keywords
crystal form
ray powder
powder diffraction
diffraction pattern
error range
Prior art date
Application number
PCT/CN2022/125056
Other languages
French (fr)
Chinese (zh)
Inventor
孙庄
李宇洁
姜辰
段洁
付强
信连鑫
郑善松
邓伟
李磊磊
Original Assignee
齐鲁制药有限公司
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by 齐鲁制药有限公司 filed Critical 齐鲁制药有限公司
Priority to CN202280067077.3A priority Critical patent/CN118076614A/en
Publication of WO2023061433A1 publication Critical patent/WO2023061433A1/en

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

Definitions

  • the invention discloses multiple crystal forms of an EGFR inhibitor, a preparation method thereof, and their application in treating cancer.
  • EGFR the epidermal growth factor receptor
  • 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.
  • 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.
  • the first and second generation targeted drugs are effective, most patients will develop drug resistance after 1-2 years of drug use.
  • 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 and bring better survival benefits to more lung cancer patients.
  • 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.
  • the applicant disclosed in the patent PCT/CN2021/086941 a small molecule EGFR inhibitor targeting the C797S mutation, its structure is shown in formula (A), and its chemical name is N-(6-((5-bromo-2 -((6-isopropyl-8-methoxy-3-methyl-3,4,5,6-tetrahydrobenzo[b]pyrazolo[4,3-d]azepine-9- (yl)amino)-pyrimidin-4-yl)amino)-quinoxalin-5-yl)methanesulfonamide.
  • the small molecule inhibitor has good kinase inhibitory activity and cell anti-proliferation activity, and at the same time, the molecule has shown good anti-tumor activity and tolerance in mouse models, and is expected to be developed into a clinical drug.
  • the invention discloses a polymorphic form of an EGFR inhibitor, a preparation method and their application in treating cancer diseases.
  • the present invention provides formula (A) compound N-(6-((5-bromo-2-((6-isopropyl-8-methoxy-3-methyl-3,4,5,6-tetrahydro Form I of benzo[b]pyrazolo[4,3-d]azepin-9-yl)amino)-pyrimidin-4-yl)amino)-quinoxalin-5-yl)methanesulfonamide,
  • the X-ray powder diffraction pattern of the crystal form I has characteristic peaks at 2 ⁇ values of 7.83, 13.85, 18.25, 20.22 and 24.37, and the 2 ⁇ error range is ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the above-mentioned crystal form I has a 2 ⁇ 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, There are characteristic peaks at 24.37 and 26.48, and the 2 ⁇ error range is ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the above-mentioned crystal form I has a 2 ⁇ 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, There are characteristic peaks at 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, and the 2 ⁇ error range is ⁇ 0.2°.
  • the above crystal form I has an X-ray powder diffraction pattern as shown in FIG. 1 .
  • the DSC spectrum of the above crystal form I has a characteristic peak at around 212°C.
  • the DSC spectrum of the above crystal form I has a characteristic peak at around 261°C.
  • the TGA-DSC spectrum of the above crystal form I is basically as shown in FIG. 18 .
  • 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 II of Hydrobenzo[b]pyrazolo[4,3-d]azepin-9-yl)amino)-pyrimidin-4-yl)amino)-quinoxalin-5-yl)methanesulfonamide , the X-ray powder diffraction pattern of the crystal form II has characteristic peaks at 2 ⁇ values of 5.84, 9.92, 12.33, 15.90, 22.89, and 25.67, and the 2 ⁇ error range is ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the above-mentioned crystal form II has a 2 ⁇ 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, There are characteristic peaks at 25.36, 25.67, and 26.09, and the 2 ⁇ error range is ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the above-mentioned crystal form II has a 2 ⁇ 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, There are characteristic peaks at 20.28, 20.67, 21.34, 21.83, 22.16, 22.51, 22.89, 23.40, 23.79, 24.23, 25.36, 25.67, 26.09, 27.22, 29.90, and 30.67.
  • the 2 ⁇ error range is ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the above-mentioned crystal form II is shown in FIG. 2 .
  • the DSC spectrum of the crystal form has a characteristic peak at around 262°C.
  • the above crystal form II, the TGA-DSC spectrum of said crystal form is shown in FIG. 19 .
  • the XRPD pattern diffraction peak analysis data of the above-mentioned compound of formula (A) crystalline form II is shown in Table 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 III of Hydrobenzo[b]pyrazolo[4,3-d]azepin-9-yl)amino)-pyrimidin-4-yl)amino)-quinoxalin-5-yl)methanesulfonamide , the X-ray powder diffraction pattern of the crystal form III has characteristic peaks at 2 ⁇ values of 5.49, 11.05, 21.77, 22.30, and 24.36, and the 2 ⁇ error range is ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the above-mentioned crystal form III has a 2 ⁇ 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, There are characteristic peaks at 26.68 and 26.96, and the 2 ⁇ error range is ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the above-mentioned crystal form III has a 2 ⁇ 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, There are characteristic peaks at 20.41, 21.36, 21.77, 22.30, 24.36, 25.12, 25.65, 26.68, 26.96, 27.39, 28.18, and 31.91, and the 2 ⁇ error range is ⁇ 0.2°.
  • the above crystal form III has an X-ray powder diffraction pattern as shown in FIG. 3 .
  • the DSC spectrum of the above crystal form III has a characteristic peak at around 253°C.
  • the DSC spectrum of the above crystal form III has a characteristic peak at around 264°C.
  • the TGA-DSC spectrum of the above-mentioned crystal form III is basically as shown in FIG. 20 .
  • 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 2 ⁇ values of 5.68, 10.42, 21.64, 22.20, and 24.55, and the 2 ⁇ error range is ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the above crystal form IV has a 2 ⁇ value of 5.68, 8.33, 9.17, 10.42, 11.52, 12.23, 16.34, 16.79, 17.69, 17.95, 19.56, 20.16, 21.64, 22.20 , 24.55, 26.85, and 27.14 have characteristic peaks, and the 2 ⁇ error range is ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the above crystal form IV has a 2 ⁇ 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, 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 have characteristic peaks, and the 2 ⁇ error range is ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the above crystal form IV is shown in FIG. 4 .
  • the TGA-DSC spectrum of the above crystal form IV is basically as shown in FIG. 21 .
  • 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 V of Hydrobenzo[b]pyrazolo[4,3-d]azepin-9-yl)amino)-pyrimidin-4-yl)amino)-quinoxalin-5-yl)methanesulfonamide , the X-ray powder diffraction pattern of the crystal form V has characteristic peaks at 2 ⁇ values of 5.57, 8.50, 10.03, 14.23, 20.00, and 22.60, and the 2 ⁇ error range is ⁇ 0.2°.
  • the above crystal form V has an X-ray powder diffraction pattern at 2 ⁇ values of 5.57, 8.50, 10.03, 14.23, 16.46, 18.72, 20.00, 21.38, 22.13, 22.60, 22.85, 23.95, 24.57, There are characteristic peaks at 26.17, 26.48, and 30.81, and the 2 ⁇ error range is ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the above-mentioned crystal form V has a 2 ⁇ 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, 30.81 have characteristic peaks in the error range ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the above-mentioned crystal form V is shown in FIG. 5 .
  • the TGA-DSC spectrum of the above crystal form V is basically as shown in FIG. 22 .
  • the XRPD pattern diffraction peak analysis data of the crystal form V of the compound of the above formula (A) is shown in Table 5.
  • 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 VI of Hydrobenzo[b]pyrazolo[4,3-d]azepin-9-yl)amino)-pyrimidin-4-yl)amino)-quinoxalin-5-yl)methanesulfonamide , the X-ray powder diffraction pattern of the crystal form VI has characteristic peaks at 2 ⁇ values of 6.82, 9.61, 12.32, 13.75, 14.10, and 20.52, and the 2 ⁇ error range is ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the above-mentioned crystal form VI has a 2 ⁇ 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, There are characteristic peaks at 21.05, 22.40, 22.89, 23.71, 24.47, and 25.28, and the 2 ⁇ error range is ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the above-mentioned crystal form VI has a 2 ⁇ 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, There are characteristic peaks at 18.43, 19.70, 20.52, 21.05, 21.52, 22.40, 22.89, 23.71, 24.47, 24.87, 25.28, 26.76, 27.31, 27.87, and 30.50, and the 2 ⁇ error range is ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the above-mentioned crystal form VI is shown in FIG. 6 .
  • the TGA-DSC spectrum of the above crystal form VI is basically as shown in FIG. 23 .
  • the present invention also provides formula (A) compound N-(6-((5-bromo-2-((6-isopropyl-8-methoxy-3-methyl-3,4,5,6-tetra Hydrobenzo[b]pyrazolo[4,3-d]azepin-9-yl)amino)-pyrimidin-4-yl)amino)-quinoxalin-5-yl)methanesulfonamide
  • Form VII the X-ray powder diffraction pattern of the crystal form VII has characteristic peaks at 2 ⁇ values of 14.54, 15.24, 17.48, 20.15, and 24.08, and the 2 ⁇ error range is ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the above crystal form VII has 2 ⁇ values of 10.10, 10.30, 11.33, 12.20, 14.54, 15.24, 17.48, 17.66, 18.88, 20.15, 21.12, 22.99, 23.33, There are characteristic peaks at 23.78, 24.08, and 26.67, and the 2 ⁇ error range is ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the above crystal form VII has a 2 ⁇ 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, There are characteristic peaks at 17.66, 18.35, 18.88, 20.15, 21.12, 22.61, 22.99, 23.33, 23.78, 24.08, 24.61, 26.67, 27.87, 29.50, and 30.62, and the 2 ⁇ error range is ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the above crystal form VII is shown in FIG. 7 .
  • the TGA-DSC spectrum of the above crystal form VII is basically as shown in FIG. 24 .
  • 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 VIII of Hydrobenzo[b]pyrazolo[4,3-d]azepin-9-yl)amino)-pyrimidin-4-yl)amino)-quinoxalin-5-yl)methanesulfonamide , the X-ray powder diffraction pattern of the crystal form VIII has characteristic peaks at 2 ⁇ values of 5.49, 13.58, 15.88, 21.11, and 22.48, and the 2 ⁇ error range is ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the above-mentioned crystal form VIII has a 2 ⁇ 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, There are characteristic peaks at 25.63, 26.98, and 30.73, and the 2 ⁇ error range is ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the above crystal form VIII has 2 ⁇ values of 4.47, 5.49, 9.00, 9.85, 10.08, 11.07, 11.74, 12.37, 13.03, 13.58, 13.77, 14.92, 15.88, There are characteristic peaks at 16.68, 16.99, 17.44, 18.59, 19.91, 20.76, 21.11, 21.42, 22.48, 23.57, 23.73, 25.00, 25.32, 25.63, 26.98, 27.79, 29.80, and 30.73.
  • the 2 ⁇ error range is ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the above crystal form VIII is shown in FIG. 8 .
  • the TGA-DSC spectrum of the above-mentioned crystal form VIII is basically as shown in FIG. 25 .
  • the present invention also provides formula (A) compound N-(6-((5-bromo-2-((6-isopropyl-8-methoxy-3-methyl-3,4,5,6-tetra Form IX of hydrobenzo[b]pyrazolo[4,3-d]azepin-9-yl)amino)-pyrimidin-4-yl)amino)-quinoxalin-5-yl)methanesulfonamide , the X-ray powder diffraction pattern of the crystal form IX has characteristic peaks at 2 ⁇ values of 5.79, 8.84, 11.66, 21.96, and 24.74, and the 2 ⁇ error range is ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the above crystal form IX has a 2 ⁇ 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, There are characteristic peaks at 24.74, 25.13, 26.69, and 27.22, and the 2 ⁇ error range is ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the above crystal form IX has a 2 ⁇ 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, There are characteristic peaks at 19.93, 20.82, 21.11, 21.74, 21.96, 23.48, 24.39, 24.74, 25.13, 26.42, 26.69, 27.22, and 30.33, and the 2 ⁇ error range is ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the above crystal form IX is shown in FIG. 9 .
  • the TGA-DSC spectrum of the above crystal form IX is basically as shown in FIG. 26 .
  • the present invention also provides formula (A) compound N-(6-((5-bromo-2-((6-isopropyl-8-methoxy-3-methyl-3,4,5,6-tetra Form XII of Hydrobenzo[b]pyrazolo[4,3-d]azepin-9-yl)amino)-pyrimidin-4-yl)amino)-quinoxalin-5-yl)methanesulfonamide , the X-ray powder diffraction pattern of the crystal form XII has characteristic peaks at 2 ⁇ values of 5.83, 6.80, 20.48, 24.92, and 27.49, and the 2 ⁇ error range is ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the above crystal form XII has a 2 ⁇ 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, There are characteristic peaks at 23.35, 24.92, and 27.49, and the 2 ⁇ error range is ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the above crystal form XII has a 2 ⁇ 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, There are characteristic peaks at 18.42, 19.66, 20.48, 20.85, 21.40, 21.81, 23.35, 23.95, 24.92, 26.62, 27.49, 31.17, 32.45, and 33.62, and the 2 ⁇ error range is ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the above crystal form XII is shown in FIG. 10 .
  • the TGA-DSC spectrum of the above crystal form XII is basically as shown in FIG. 27 .
  • 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 XIV of Hydrobenzo[b]pyrazolo[4,3-d]azepin-9-yl)amino)-pyrimidin-4-yl)amino)-quinoxalin-5-yl)methanesulfonamide , the X-ray powder diffraction pattern of the crystal form XIV has characteristic peaks at 2 ⁇ values of 5.86, 11.73, 23.56, 29.55, and 35.65, and the 2 ⁇ error range is ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the above crystal form XIV is at 2 ⁇ values of 5.86, 11.73, 13.85, 20.91, 22.32, 23.56, 24.69, 25.30, 26.72, 29.55, 33.09, 35.65, 38.91 There are characteristic peaks, and the 2 ⁇ error range is ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the above-mentioned crystal form XIV is shown in FIG. 11 .
  • the TGA-DSC spectrum of the above crystal form XIV is basically as shown in FIG. 28 .
  • the present invention also provides a compound of formula (I),
  • 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 2 ⁇ values of 7.38, 8.13, 12.62, 20.14, 21.41, and 23.72, and the 2 ⁇ error range is ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the above crystal form A has a 2 ⁇ 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 2 ⁇ error range is ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the above crystal form A has a 2 ⁇ 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, There are characteristic peaks at 19.93, 20.14, 20.32, 21.41, 22.66, 23.72, 25.08, 25.53, 26.47, 28.26, 30.02, and 31.91, and the 2 ⁇ error range is ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the above-mentioned crystal form A is shown in FIG. 12 .
  • the TGA-DSC spectrum of the above-mentioned crystal form A is basically as shown in FIG. 29 .
  • the XRPD pattern diffraction peak analysis data of the crystal form A of the compound of formula (I) is shown in Table 12.
  • 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 2 ⁇ values of 5.89, 7.25, 9.37, 22.49, 25.45, and 27.05, and the 2 ⁇ error range is ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the above crystal form B has 2 ⁇ values of 5.89, 6.43, 7.25, 9.37, 12.42, 12.95, 15.16, 17.37, 17.76, 18.64, 18.89, 21.14, 21.57, There are characteristic peaks at 21.99, 22.49, 25.45, and 27.05, and the 2 ⁇ error range is ⁇ 0.2°.
  • the above-mentioned crystal form B has an X-ray powder diffraction pattern whose 2 ⁇ value is 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, There are characteristic peaks at 17.37, 17.76, 18.64, 18.89, 20.12, 21.14, 21.57, 21.99, 22.49, 22.84, 23.63, 24.58, 25.45, 27.05, and 30.01, and the 2 ⁇ error range is ⁇ 0.2°.
  • the above crystal form B has an X-ray powder diffraction pattern as shown in FIG. 13 .
  • the TGA-DSC spectrum of the above crystal form B is basically as shown in FIG. 30 .
  • 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 2 ⁇ values of 5.85, 12.41, 17.76, 22.48, and 27.03, and the 2 ⁇ error range is ⁇ 0.2 °.
  • the X-ray powder diffraction pattern of the above-mentioned crystal form C has a 2 ⁇ 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, There are characteristic peaks at 23.73, 25.42, and 27.03, and the 2 ⁇ error range is ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the above-mentioned crystal form C has a 2 ⁇ 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, There are characteristic peaks at 18.64, 18.88, 20.11, 21.12, 21.40, 21.57, 21.97, 22.48, 22.87, 23.73, 25.42, 27.03, 27.84, 28.32, and 29.96, and the 2 ⁇ error range is ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the above crystal form C is shown in FIG. 14 .
  • the TGA-DSC spectrum of the above crystal form C is basically as shown in FIG. 31 .
  • the XRPD pattern diffraction peak analysis data of the crystal form C of the compound of formula (I) is shown in Table 14.
  • 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 2 ⁇ values of 5.55, 13.03, 16.73, 22.48, and 24.17, and the 2 ⁇ error range is ⁇ 0.2 °.
  • the X-ray powder diffraction pattern of the above-mentioned crystal form D has a 2 ⁇ 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, There are characteristic peaks at 24.17, 26.05, and 34.02, and the 2 ⁇ error range is ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the above crystal form D has a 2 ⁇ 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, There are characteristic peaks at 16.73, 18.11, 20.43, 20.96, 21.37, 22.48, 23.33, 23.83, 24.17, 25.62, 26.05, 26.42, 27.77, 27.93, 28.80, 32.72, 33.41, and 34.02.
  • the 2 ⁇ error range is ⁇ 0.2°.
  • the above crystal form D has an X-ray powder diffraction pattern as shown in FIG. 15 .
  • the above crystal form D has an endothermic peak at about 250°C and 256°C in the DSC spectrum.
  • the above crystal form D has a weight loss of 5.33% at about 220° C. in its TGA spectrum.
  • the above crystal form D has a weight loss of 5.33% at about 150-225° C. in its TGA spectrum.
  • the TGA-DSC spectrum of the above crystal form D is basically as shown in FIG. 32 .
  • 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.
  • the present invention also provides a pharmaceutical composition, which comprises any one of the above crystal forms and a pharmaceutically acceptable carrier.
  • 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.
  • 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.
  • a medicament for treating cancer is any of the above-mentioned crystal forms or the above-mentioned pharmaceutical composition.
  • 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.
  • the aforementioned cancers include lymphoma, non-Hodgkin's lymphoma, ovarian cancer, cervical cancer, prostate cancer, colorectal cancer, breast cancer, pancreatic cancer, glioma, glioblastoma, Melanoma, leukemia, gastric cancer, endometrial cancer, lung cancer, hepatocellular carcinoma, gastric cancer, gastrointestinal stromal tumor (GIST), acute myeloid leukemia (AML), cholangiocarcinoma, renal cancer, thyroid cancer, anaplastic Cellular lymphoma, mesothelioma, multiple myeloma, melanoma.
  • 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.
  • the present invention also provides a method for inhibiting EGFR mutation in a patient in need, comprising administering the compound of formula (A), formula (I), any of the above crystal forms or the above pharmaceutical composition to the patient.
  • 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.
  • the aforementioned EGFR mutations include L858R, T790M, C797S, and Del19 mutations.
  • the above-mentioned EGFR mutations include L858R/T790M/C797S triple mutation and Del19/T790M/C797S triple mutation.
  • 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.
  • 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%.
  • the "about 212°C” may include 212 ⁇ 0.15°C
  • the "about 264°C” may include 264 ⁇ 0.38°C.
  • 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.
  • compositions containing the agent include, but are not limited to: the type and nature of the active agent being formulated, the subject to whom 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, such additional ingredients being included in formulations for a variety of reasons (e.g., stabilizing the active agent, binders, etc.) are well known to those of ordinary skill in the art .
  • X-ray powder diffraction patterns have one or more measurement errors according to small 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, etc.
  • Other constant variables known to those skilled in the art exhibit similar, but not identical, analytical properties within reasonable error.
  • the diffraction angle (2 ⁇ ) 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, but also includes 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 accompanying drawings, having substantially the same X-ray powder diffraction patterns as shown in the accompanying drawings Any crystal with a diffraction pattern is within the scope of the invention.
  • the maximum endothermic transition temperature of the crystalline form may be within the range of ⁇ 5.0° C. from the specific value disclosed above.
  • 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.
  • TGA thermogravimetric analysis
  • 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.
  • 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 conditions, such as high temperature, high humidity, grinding, tableting, solvent removal, and solvent absorption. Therefore, “physical stability” can to a certain extent reflect the stability of the crystal form during the use of preparations.
  • the crystalline structures of the present invention can be prepared by various methods, including crystallization or recrystallization from a suitable solvent, sublimation, growth from a melt, solid state transformation from another phase, crystallization from a supercritical fluid, and jet spraying, 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 anti-solvent to solvent mixtures wait.
  • 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 methods described by those skilled in the art. Known equivalents, preferred embodiments include, but are not limited to, the examples of the present invention.
  • the name of the title compound was converted from the compound structure 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 methods, the structural formula of the given compound shall prevail.
  • 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 the methods well known to those skilled in the art Equivalent alternatives, preferred embodiments include but are not limited to the examples of the present invention.
  • the solid sample is analyzed by X-ray powder diffractometer (X'Pert PRO), and an appropriate amount of fine powder of the test sample is taken, placed in the groove of the sample holder, and pressed into a flat and compact plane with a glass sheet.
  • XRPD measurement parameters are shown in the table 16-2.
  • Thermogravimetric analysis of solids was performed using a TA Instrument thermogravimetric analyzer. Approximately 1-5 mg of the sample was placed in a peeled aluminum sample pan, the sample was heated according to the parameters listed in Table 17, and the data was analyzed using TRIOS.
  • the solids were subjected to DSC analysis using a Differential Scanning Calorimeter from TA Instruments. About 1-3mg of the sample is accurately weighed and placed in a perforated aluminum sample pan. The sample is heated according to the parameters listed in Table 18-1, and the data is analyzed using TRIOS.
  • Instrument information Discovery DSC 250 sample tray Perforated plate temperature range 25-300°C heating rate 1O°C/min purge gas Nitrogen flow rate 50mL/min
  • 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.
  • the determination of NMR is carried out with Bruker AVANCE III HD 400 or Bruker AVANCE III HD 300 nuclear magnetic instruments, the determination solvent is deuterated dimethyl sulfoxide (DMSO-d 6 ), and the internal standard is tetramethylsilane (TMS).
  • DMSO-d 6 deuterated dimethyl sulfoxide
  • TMS tetramethylsilane
  • liquid chromatography-mass chromatography LC-MS uses SHIMADZU LCMS-2020 mass spectrometer (the ion source is electrospray ionization).
  • Fig. 1 is the XRPD pattern 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) crystalline form IV.
  • Fig. 5 is the XRPD spectrum of the crystal form V of the compound of formula (A).
  • Fig. 6 is the XRPD spectrum of the compound of formula (A) in the crystal 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 compound of formula (A) in the crystal form VIII.
  • Fig. 9 is the 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) 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).
  • Fig. 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).
  • Figure 15 is the XRPD spectrum of 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.
  • Fig. 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 a TGA-DSC spectrum of the compound of formula (A) crystalline form IV.
  • Figure 22 is the TGA-DSC spectrum of Form V of the compound of formula (A).
  • Figure 23 is the TGA-DSC spectrum of the compound of formula (A) in Form VI.
  • Fig. 24 is a 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 the TGA-DSC spectrum of the crystal form A of the compound of formula (I).
  • Fig. 30 is the TGA-DSC spectrum of the crystal form B of the compound of formula (I).
  • Fig. 31 is a TGA-DSC spectrum of 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).
  • Fig. 33 is a DVS spectrum of Form I of the compound of formula (A).
  • Fig. 34 is a comparison of XRPD spectra before and after DVS experiment of compound crystal form I of formula (A).
  • Fig. 35 is the DVS spectrum of the compound of formula (A) Form II.
  • Fig. 36 is a comparison of XRPD spectra before and after DVS experiment of the compound of formula (A) crystalline form II.
  • Fig. 37 is a DVS spectrum of the compound of formula (A) Form III.
  • Fig. 38 is a comparison of XRPD spectra before and after DVS experiment of the compound of formula (A) Form III.
  • Fig. 39 is a DVS spectrum of Form D of the compound of formula (I).
  • Fig. 40 is a comparison of XRPD spectra before and after DVS experiment of compound D of formula (I).
  • Figure 41 is a comparison of XRPD spectra before and after the compression test of the compound of formula (A) in Form II.
  • Fig. 42 is a comparison of XRPD spectra before and after the stability test of the crystal form D of the compound of formula (I).
  • Embodiment 1 The preparation of formula (A) and formula (1) compound:
  • 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 portions to the reaction solution and stirring was continued at this temperature for 30 minutes. After LCMS monitoring showed that the starting material disappeared, the reaction solution was poured into ice water (100 g). Its pH was adjusted to 8 with 1M aqueous sodium hydroxide solution. The mixture was extracted with ethyl acetate (200 mL x 2 times), and the organic phases were combined.
  • Embodiment 2 Biological test evaluation:
  • TR-FRET fluorescence resonance energy transfer
  • EGFR recombinase and EGFR L858R/T790M/C797S recombinase were purchased from Signalchem.
  • HTRF KinEASE-TK kit was purchased from Cisbio.
  • ATP was purchased from Promega.
  • Envision microplate reader (PerkinElmer) detects the 615nm and 665nm fluorescence signal values of each well.
  • 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.
  • A431 cells were purchased from ATCC.
  • DMEM medium fetal bovine serum (FBS), and Penicillin-Streptomycin were purchased from GIBCO.
  • CellTiter-Glo reagent was purchased from Promega Company.
  • A431 cells were seeded in a 384-well culture plate at a density of 800 cells per well, 30 ⁇ l per well, and placed in a cell culture incubator for 24 hours (37° C., 5% CO 2 ).
  • Envision microplate reader detects chemiluminescent signal.
  • 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.
  • Ba/F3_L858R/T790M/C797S cells were constructed by Pharmaron Chemicals (Beijing) New Pharmaceutical Technology Co., Ltd.
  • FBS fetal bovine serum
  • Penicillin-Streptomycin Penicillin-Streptomycin
  • GlutaMAX-I Supplement purchased from GIBCO.
  • CellTiter-Glo reagent was purchased from Promega Company.
  • Envision microplate reader detects chemiluminescent signal.
  • 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.
  • Ba/F3_Del19/T790M/C797S was purchased from Kangyuan Bochuang Biotechnology (Beijing) Co., Ltd.
  • FBS fetal bovine serum
  • Penicillin-Streptomycin Penicillin-Streptomycin
  • GlutaMAX-I Supplement purchased from GIBCO.
  • CellTiter-Glo reagent was purchased from Promega Company.
  • Envision microplate reader detects chemiluminescent signal.
  • Compound A has a better inhibitory effect on the cell proliferation of the Ba/F3Del19/T790M/C797S EGFR triple mutant cell line and the Ba/F3 L858R/T790M/C797S EGFR triple mutant cell line;
  • the inhibitory effect on the EGFR wild-type (EGFR WT) cell line A431 is weak. This indicates that Compound A has better cell activity and selectivity.
  • mice Female, SPF grade, were purchased from Beijing Weitong Lihua Experimental Animal Technology Co., Ltd.
  • PC9 (Del19/T790M/C797S) cells were constructed by Qilu Pharmaceutical Co., Ltd.
  • 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.
  • 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.
  • the drug was administered, 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.
  • TGI tumor growth inhibition rate
  • mice 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.
  • mice were euthanized, and the animal corpses were stored in a freezer and handed over to a qualified medical waste disposal unit for disposal.
  • the obtained solid was characterized by XRPD and TGA-DSC tests, and the solid was crystal form I.
  • the XRPD spectrum is shown in FIG. 1 .
  • the TGA-DSC spectrum is shown in Figure 18.
  • the obtained solid was characterized by XRPD and TGA-DSC tests, and the solid was crystal form II.
  • the XRPD spectrum is shown in FIG. 2 .
  • the TGA-DSC spectrum is shown in Figure 19.
  • 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 .
  • DMSO dimethylsulfoxide
  • the obtained solid was characterized by XRPD and TGA-DSC tests, and the solid was crystal form III.
  • the XRPD spectrum is shown in FIG. 3 .
  • the TGA-DSC spectrum is shown in Figure 20.
  • the obtained solid was characterized by XRPD and TGA-DSC tests, and the solid was crystal form IV.
  • the XRPD spectrum is shown in FIG. 4 .
  • the TGA-DSC spectrum is shown in Figure 21.
  • the obtained solid was characterized by XRPD and TGA-DSC tests, and the solid was Form V.
  • the XRPD spectrum is shown in FIG. 5 .
  • the TGA-DSC spectrum is shown in Figure 22.
  • Embodiment 8 The preparation of crystal form VI:
  • the obtained solid was characterized by XRPD and TGA-DSC tests, and the solid was crystal form VI.
  • the XRPD spectrum is shown in FIG. 6 .
  • the TGA-DSC spectrum is shown in Figure 23.
  • the obtained solid was characterized by XRPD and TGA-DSC tests, and the solid was crystal form VII.
  • the XRPD spectrum is shown in FIG. 7 .
  • the TGA-DSC spectrum is shown in Figure 24.
  • the obtained solid was characterized by XRPD and TGA-DSC tests, and the solid was crystal form VIII.
  • the XRPD spectrum is shown in FIG. 8 .
  • the TGA-DSC spectrum is shown in Figure 25.
  • the obtained solid was characterized by XRPD and TGA-DSC tests, and the solid was crystal form IX.
  • the XRPD spectrum is shown in FIG. 9 .
  • the TGA-DSC spectrum is shown in Figure 26.
  • the obtained solid was characterized by XRPD and TGA-DSC tests, and the solid was crystal form XII.
  • the XRPD spectrum is shown in FIG. 10 .
  • the TGA-DSC spectrum is shown in Figure 27.
  • the obtained solid was characterized by XRPD and TGA-DSC tests, and the solid was crystal form XIV.
  • the XRPD spectrum is shown in FIG. 11 .
  • the TGA-DSC spectrum is shown in Figure 28.
  • the obtained solid was characterized by XRPD and TGA-DSC tests, and the solid was Form A.
  • the XRPD spectrum is shown in FIG. 12 .
  • the TGA-DSC spectrum is shown in Figure 29.
  • the obtained solid was characterized by XRPD and TGA-DSC tests, and the solid was crystal form B.
  • the XRPD spectrum is shown in FIG. 13 .
  • the TGA-DSC spectrum is shown in Figure 30.
  • the obtained solid was characterized by XRPD and TGA-DSC tests, and the solid was Form C.
  • the XRPD spectrum is shown in FIG. 14 .
  • the TGA-DSC spectrum is shown in Figure 31.
  • the obtained solid was characterized by XRPD and TGA-DSC tests, and the solid was crystal form D.
  • the XRPD spectrum is shown in FIG. 15 .
  • the TGA-DSC spectrum is shown in Figure 32.
  • Embodiment 18 Humidity test
  • Figure 33 is the DVS curve of Form I
  • Figure 34 is the XRPD spectrum of Form I before and after DVS testing.
  • the 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. After the XRPD test of the remaining solid after the DVS experiment, the crystal form did not changes happened.
  • Figure 35 is the DVS curve of Form II
  • 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 its moisture absorption weight gain was 0.19% and 0.24% under the conditions of 80% and 90% RH; changes happened.
  • Figure 37 is the DVS curve of Form III
  • Figure 38 is the XRPD spectrum before and after DVS testing of Form III.
  • the DVS results showed that the crystal form III was slightly hygroscopic. Under the conditions of 80% and 90% RH, the hygroscopic weight gain of the sample was 0.8% and 1.0%, respectively; the XRPD of the remaining solid after the DVS experiment showed that the crystal form did not change.
  • Figure 39 is the DVS curve of Form D
  • Figure 40 is the XRPD spectra of Form D before and after DVS testing.
  • the DVS results showed that the crystal form D was slightly hygroscopic, and the weight gain by moisture absorption was 0.59% and 0.76% at 80% RH and 90% RH, respectively. After the DVS test, the crystal form of the remaining solid did not change.
  • 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.
  • Embodiment 20 Stability experiment of crystal form D:
  • the experimental results are shown in Table 26.
  • the 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 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 ).
  • Embodiment 21 pressure test

Landscapes

  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Organic Chemistry (AREA)
  • Veterinary Medicine (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Public Health (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Epidemiology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
  • Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)

Abstract

Provided is a compound of formula (A), N-(6-((5-bromo-2-((6-isopropyl-8-methoxy-3-methyl-3,4,5,6-tetrahydrobenzo[b]pyrazolo[4,3-D]aza-9-yl)amino)-pyrimidin-4-yl)amino)-quinoxaline-5-yl)methanesulfonamide, and a compound of formula (I), and polymorphs thereof. The provided polymorphs have a good chemical stability, physical stability and low hygroscopicity, are less affected by heat, humidity and illumination, and are convenient to store and prepare.

Description

一种EGFR抑制剂的多晶型A polymorphic form of an EGFR inhibitor
本申请要求申请日为2021年10月14日的中国专利申请202111197313.7、申请日为2021年10月14日的中国专利申请202111196875.X的优先权，申请日为2021年10月14日的中国专利申请202111197957.6的优先权，本申请引用上述中国专利申请的全文。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.
技术领域technical field
本发明公开了一种EGFR抑制剂的多种晶型及其制备方法，以及它们在治疗癌症中的应用。The invention discloses multiple crystal forms of an EGFR inhibitor, a preparation method thereof, and their application in treating cancer.
背景技术Background technique
EGFR，即表皮生长因子受体(epidermal growth factor receptor)，广泛分布于哺乳动物上皮细胞、成纤维细胞、胶质细胞等细胞表面。EGFR信号通路对细胞的生长、增殖和分化等生理过程发挥着重要的作用。EGFR突变也是NSCLC患者中最常见的一种突变类型，尤其是在亚洲人群中可以占到40％～50％。因此EGFR一直是药物研发领域的最热门靶点之一。EGFR, the 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抑制剂分为第一、二、三代。第一代为可逆的靶向药物，例如吉非替尼、厄洛替尼、埃克替尼。第二代为不可逆的靶向药物，例如阿法替尼以及达克替尼。第一、二代靶向药物虽然疗效显著，但多数患者都会在使用药物1-2年后出现耐药性。EGFR抑制剂耐药的患者中，有50％的耐药与T790M突变有关。第三代EGFR靶向药物奥希替尼能克服由于T790M突变引起的肿瘤耐药，给更多的肺癌患者带来了更好的生存获益。然而第三代靶向药也不可避免的产生耐药，其耐药原因主要为C797S突变。C797S突变体现为半胱氨酸残基突变成丝氨酸，这一突变破坏了EGFR蛋白与第三代靶向药物结合，从而无法阻止EGFR蛋白的磷酸化以及下游信号通路的活化。目前对于奥希替尼耐药后主要出现的两种顺式三突变：Del19/T790M/C797S和L858R/T790M/C797S的应对尚无成熟的治疗手段，临床需求迫在眉睫。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 and bring 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.
本申请人在专利PCT/CN2021/086941中公开了一种针对C797S突变的小分子EGFR抑制剂，其结构如式(A)所示，化学名称为N-(6-((5-溴-2-((6-异丙基-8-甲氧基-3-甲基-3,4,5,6-四氢苯并[b]吡唑并[4,3-d]氮杂-9-基)氨基)-嘧啶-4-基)氨基)-喹喔啉-5-基)甲磺酰胺。该小分子抑制剂具有良好的激酶抑制活性和细胞抗增殖活性，同时该分子在小鼠模型上体现了较好的抗肿瘤活性及耐受性，有望开发成临床药物。The applicant disclosed in the patent PCT/CN2021/086941 a small molecule EGFR inhibitor targeting the C797S mutation, its structure is shown in formula (A), and its chemical name is N-(6-((5-bromo-2 -((6-isopropyl-8-methoxy-3-methyl-3,4,5,6-tetrahydrobenzo[b]pyrazolo[4,3-d]azepine-9- (yl)amino)-pyrimidin-4-yl)amino)-quinoxalin-5-yl)methanesulfonamide. The small molecule inhibitor has good kinase inhibitory activity and cell anti-proliferation activity, and at the same time, the molecule has shown good anti-tumor activity and tolerance in mouse models, and is expected to be developed into a clinical drug.
Figure PCTCN2022125056-appb-000001
Figure PCTCN2022125056-appb-000001
发明内容Contents of the invention
本发明公开了一种EGFR抑制剂的多晶型、制备方法，以及它们在治疗癌症疾病中的应用。The invention discloses a polymorphic form of an EGFR inhibitor, a preparation method and their application in treating cancer diseases.
具体的，specific,
本发明提供式(A)化合物N-(6-((5-溴-2-((6-异丙基-8-甲氧基-3-甲基-3,4,5,6-四氢苯并[b]吡唑并[4,3-d]氮杂-9-基)氨基)-嘧啶-4-基)氨基)-喹喔啉-5-基)甲磺酰胺的晶型I，所述晶型I的X-射线粉末衍射图谱在2θ值为7.83、13.85、18.25、20.22、24.37处有特征峰，2θ误差范围为±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 I of benzo[b]pyrazolo[4,3-d]azepin-9-yl)amino)-pyrimidin-4-yl)amino)-quinoxalin-5-yl)methanesulfonamide, 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°.
在本发明的一些方案中，上述晶型I，其X-射线粉末衍射图谱在2θ值为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处有特征峰，2θ误差范围为±0.2°。In some solutions of the present invention, the X-ray powder diffraction pattern of the above-mentioned 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, There are characteristic peaks at 24.37 and 26.48, and the 2θ error range is ±0.2°.
在本发明的一些方案中，上述晶型I，其X-射线粉末衍射图谱在2θ值为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处有特征峰，2θ误差范围为±0.2°。In some solutions of the present invention, the X-ray powder diffraction pattern of the above-mentioned 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, There are characteristic peaks at 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, and the 2θ error range is ±0.2°.
在本发明的一些方案中，上述晶型I，其X-射线粉末衍射图谱如图1所示。In some solutions of the present invention, the above crystal form I has an X-ray powder diffraction pattern as shown in FIG. 1 .
在本发明的一些方案中，上述晶型I，其DSC谱图在212℃左右有特征峰。In some solutions of the present invention, the DSC spectrum of the above crystal form I has a characteristic peak at around 212°C.
在本发明的一些方案中，上述晶型I，其DSC谱图在261℃左右有特征峰。In some solutions of the present invention, the DSC spectrum of the above crystal form I has a characteristic peak at around 261°C.
在本发明的一些方案中，上述晶型I，其TGA-DSC谱图基本如图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 .
本发明的一些方案中，上述式(A)化合物晶型I的XRPD图谱衍射峰解析数据如表1所示。In some schemes of the present invention, the XRPD pattern diffraction peak analysis data of the above formula (A) compound crystal form I are shown in Table 1.
表1 式(A)化合物晶型I的XRPD衍射峰解析数据Table 1 XRPD diffraction peak analysis data of formula (A) compound crystal form I
Figure PCTCN2022125056-appb-000002
Figure PCTCN2022125056-appb-000002
Figure PCTCN2022125056-appb-000003
Figure PCTCN2022125056-appb-000003
本发明还提供式(A)化合物N-(6-((5-溴-2-((6-异丙基-8-甲氧基-3-甲基-3,4,5,6-四氢苯并[b]吡唑并[4,3-d]氮杂-9-基)氨基)-嘧啶-4-基)氨基)-喹喔啉-5-基)甲磺酰胺的晶型II，所述晶型II的X-射线粉末衍射图谱在2θ值为5.84、9.92、12.33、15.90、22.89、25.67处有特征峰，2θ误差范围为±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 II of Hydrobenzo[b]pyrazolo[4,3-d]azepin-9-yl)amino)-pyrimidin-4-yl)amino)-quinoxalin-5-yl)methanesulfonamide , 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°.
在本发明的一些方案中，上述晶型II，其X-射线粉末衍射图谱在2θ值为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处有特征峰，2θ误差范围为±0.2°。In some solutions of the present invention, the X-ray powder diffraction pattern of the above-mentioned 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, There are characteristic peaks at 25.36, 25.67, and 26.09, and the 2θ error range is ±0.2°.
在本发明的一些方案中，上述晶型II，其X-射线粉末衍射图谱在2θ值为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处有特征峰，2θ误差范围为±0.2°。In some solutions of the present invention, the X-ray powder diffraction pattern of the above-mentioned 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, There are characteristic peaks at 20.28, 20.67, 21.34, 21.83, 22.16, 22.51, 22.89, 23.40, 23.79, 24.23, 25.36, 25.67, 26.09, 27.22, 29.90, and 30.67. The 2θ error range is ±0.2°.
在本发明的一些方案中，上述晶型II，其X-射线粉末衍射图谱如图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 .
在本发明的一些方案中，上述晶型II，所述晶型的DSC谱图在262℃左右有特征峰。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.
在本发明的一些方案中，上述晶型II，所述晶型的TGA-DSC谱图如图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 .
本发明的一些方案中，上述式(A)化合物晶型II的XRPD图谱衍射峰解析数据如表2所示。In some schemes of the present invention, the XRPD pattern diffraction peak analysis data of the above-mentioned compound of formula (A) crystalline form II is shown in Table 2.
表2 式(A)化合物晶型II的XRPD衍射峰解析数据Table 2 XRPD diffraction peak analysis data of formula (A) compound crystal form II
Figure PCTCN2022125056-appb-000004
Figure PCTCN2022125056-appb-000004
Figure PCTCN2022125056-appb-000005
Figure PCTCN2022125056-appb-000005
本发明还提供式(A)化合物N-(6-((5-溴-2-((6-异丙基-8-甲氧基-3-甲基-3,4,5,6-四氢苯并[b]吡唑并[4,3-d]氮杂-9- 基)氨基)-嘧啶-4-基)氨基)-喹喔啉-5-基)甲磺酰胺的晶型III，所述晶型III的X-射线粉末衍射图谱在2θ值为5.49、11.05、21.77、22.30、24.36处有特征峰，2θ误差范围为±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 III of Hydrobenzo[b]pyrazolo[4,3-d]azepin-9-yl)amino)-pyrimidin-4-yl)amino)-quinoxalin-5-yl)methanesulfonamide , 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°.
在本发明的一些方案中，上述晶型III，其X-射线粉末衍射图谱在2θ值为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处有特征峰，2θ误差范围为±0.2°。In some solutions of the present invention, the X-ray powder diffraction pattern of the above-mentioned 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, There are characteristic peaks at 26.68 and 26.96, and the 2θ error range is ±0.2°.
在本发明的一些方案中，上述晶型III，其X-射线粉末衍射图谱在2θ值为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处有特征峰，2θ误差范围为±0.2°。In some solutions of the present invention, the X-ray powder diffraction pattern of the above-mentioned 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, There are characteristic peaks at 20.41, 21.36, 21.77, 22.30, 24.36, 25.12, 25.65, 26.68, 26.96, 27.39, 28.18, and 31.91, and the 2θ error range is ±0.2°.
在本发明的一些方案中，上述晶型III，其X-射线粉末衍射图谱如图3所示。In some solutions of the present invention, the above crystal form III has an X-ray powder diffraction pattern as shown in FIG. 3 .
在本发明的一些方案中，上述晶型III，其DSC谱图在253℃左右有特征峰。In some solutions of the present invention, the DSC spectrum of the above crystal form III has a characteristic peak at around 253°C.
在本发明的一些方案中，上述晶型III，其DSC谱图在264℃左右有特征峰。In some solutions of the present invention, the DSC spectrum of the above crystal form III has a characteristic peak at around 264°C.
在本发明的一些方案中，上述晶型III，其TGA-DSC谱图基本如图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 .
本发明的一些方案中，上述式(A)化合物晶型III的XRPD图谱衍射峰解析数据如表3所示。In some schemes of the present invention, the XRPD pattern diffraction peak analysis data of the above formula (A) compound crystal form III is shown in Table 3.
表3 式(A)化合物晶型III的XRPD衍射峰解析数据Table 3 XRPD diffraction peak analysis data of formula (A) compound crystal form III
Figure PCTCN2022125056-appb-000006
Figure PCTCN2022125056-appb-000006
Figure PCTCN2022125056-appb-000007
Figure PCTCN2022125056-appb-000007
本发明提供式(A)化合物N-(6-((5-溴-2-((6-异丙基-8-甲氧基-3-甲基-3,4,5,6-四氢苯并[b]吡唑并[4,3-d]氮杂-9-基)氨基)-嘧啶-4-基)氨基)-喹喔啉-5-基)甲磺酰胺的晶型IV，所述晶型IV的射线粉末衍射图谱在2θ值为5.68、10.42、21.64、22.20、24.55处有特征峰，2θ误差范围为±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°.
在本发明的一些方案中，上述晶型IV其X-射线粉末衍射图谱在2θ值为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处有特征峰，2θ误差范围为±0.2°。In some solutions of the present invention, the X-ray powder diffraction pattern of the above crystal form IV has a 2θ value of 5.68, 8.33, 9.17, 10.42, 11.52, 12.23, 16.34, 16.79, 17.69, 17.95, 19.56, 20.16, 21.64, 22.20 , 24.55, 26.85, and 27.14 have characteristic peaks, and the 2θ error range is ±0.2°.
在本发明的一些方案中，上述晶型IV其X-射线粉末衍射图谱在2θ值为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处有特征峰，2θ误差范围为±0.2°。In some solutions of the present invention, the X-ray powder diffraction pattern of the above 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, 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 have characteristic peaks, and the 2θ error range is ±0.2°.
在本发明的一些方案中，上述晶型IV其X-射线粉末衍射图谱如图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 .
在本发明的一些方案中，上述晶型IV，其TGA-DSC谱图基本如图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 .
本发明的一些方案中，上述式(A)化合物晶型IV的XRPD图谱衍射峰解析数据如表4所示。In some schemes of the present invention, the XRPD pattern diffraction peak analysis data of the above formula (A) compound crystal form IV is shown in Table 4.
表4 式(A)化合物晶型IV的XRPD衍射峰解析数据Table 4 XRPD diffraction peak analysis data of formula (A) compound crystal form IV
Figure PCTCN2022125056-appb-000008
Figure PCTCN2022125056-appb-000008
Figure PCTCN2022125056-appb-000009
Figure PCTCN2022125056-appb-000009
本发明还提供式(A)化合物N-(6-((5-溴-2-((6-异丙基-8-甲氧基-3-甲基-3,4,5,6-四氢苯并[b]吡唑并[4,3-d]氮杂-9-基)氨基)-嘧啶-4-基)氨基)-喹喔啉-5-基)甲磺酰胺的晶型V，所述晶型V的X-射线粉末衍射图谱在2θ值为5.57、8.50、10.03、14.23、20.00、22.60处有特征峰，2θ误差范围为±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 V of Hydrobenzo[b]pyrazolo[4,3-d]azepin-9-yl)amino)-pyrimidin-4-yl)amino)-quinoxalin-5-yl)methanesulfonamide , 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°.
在本发明的一些方案中，上述晶型V，其X-射线粉末衍射图谱在2θ值为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处有特征峰，2θ误差范围为±0.2°。In some solutions of the present invention, the above crystal form V has an X-ray powder diffraction pattern at 2θ values of 5.57, 8.50, 10.03, 14.23, 16.46, 18.72, 20.00, 21.38, 22.13, 22.60, 22.85, 23.95, 24.57, There are characteristic peaks at 26.17, 26.48, and 30.81, and the 2θ error range is ±0.2°.
在本发明的一些方案中，上述晶型V，其X-射线粉末衍射图谱在2θ值为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处有特征峰，2θ误差范围为±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, 30.81 have characteristic peaks in the error range ±0.2°.
在本发明的一些方案中，上述晶型V，其X-射线粉末衍射图谱如图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 .
在本发明的一些方案中，上述晶型V，其TGA-DSC谱图基本如图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 .
本发明的一些方案中，上述式(A)化合物晶型V的XRPD图谱衍射峰解析数据如表5所示。In some schemes of the present invention, the XRPD pattern diffraction peak analysis data of the crystal form V of the compound of the above formula (A) is shown in Table 5.
表5 式(A)化合物晶型V的XRPD衍射峰解析数据Table 5 XRPD diffraction peak analysis data of formula (A) compound crystal form V
Figure PCTCN2022125056-appb-000010
Figure PCTCN2022125056-appb-000010
Figure PCTCN2022125056-appb-000011
Figure PCTCN2022125056-appb-000011
Figure PCTCN2022125056-appb-000012
Figure PCTCN2022125056-appb-000012
本发明还提供式(A)化合物N-(6-((5-溴-2-((6-异丙基-8-甲氧基-3-甲基-3,4,5,6-四氢苯并[b]吡唑并[4,3-d]氮杂-9-基)氨基)-嘧啶-4-基)氨基)-喹喔啉-5-基)甲磺酰胺的晶型VI，所述晶型VI的X-射线粉末衍射图谱在2θ值为6.82、9.61、12.32、13.75、14.10、20.52处有特征峰，2θ误差范围为±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 VI of Hydrobenzo[b]pyrazolo[4,3-d]azepin-9-yl)amino)-pyrimidin-4-yl)amino)-quinoxalin-5-yl)methanesulfonamide , 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°.
在本发明的一些方案中，上述晶型VI，其X-射线粉末衍射图谱在2θ值为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处有特征峰，2θ误差范围为±0.2°。In some solutions of the present invention, the X-ray powder diffraction pattern of the above-mentioned 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, There are characteristic peaks at 21.05, 22.40, 22.89, 23.71, 24.47, and 25.28, and the 2θ error range is ±0.2°.
在本发明的一些方案中，上述晶型VI，其X-射线粉末衍射图谱在2θ值为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处有特征峰，2θ误差范围为±0.2°。In some solutions of the present invention, the X-ray powder diffraction pattern of the above-mentioned 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, There are characteristic peaks at 18.43, 19.70, 20.52, 21.05, 21.52, 22.40, 22.89, 23.71, 24.47, 24.87, 25.28, 26.76, 27.31, 27.87, and 30.50, and the 2θ error range is ±0.2°.
在本发明的一些方案中，上述晶型VI，其X-射线粉末衍射图谱如图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 .
在本发明的一些方案中，上述晶型VI，其TGA-DSC谱图基本如图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 .
本发明的一些方案中，上述式(A)化合物晶型VI的XRPD图谱衍射峰解析数据如表6所示。In some schemes of the present invention, the XRPD pattern diffraction peak analysis data of the compound of the above formula (A) crystal form VI is shown in Table 6.
表6 式(A)化合物晶型VI的XRPD衍射峰解析数据Table 6 XRPD diffraction peak analysis data of formula (A) compound crystal form VI
Figure PCTCN2022125056-appb-000013
Figure PCTCN2022125056-appb-000013
Figure PCTCN2022125056-appb-000014
Figure PCTCN2022125056-appb-000014
本发明还提供式(A)化合物N-(6-((5-溴-2-((6-异丙基-8-甲氧基-3-甲基-3,4,5,6-四氢苯并[b]吡唑并[4,3-d]氮杂-9-基)氨基)-嘧啶-4-基)氨基)-喹喔啉-5-基)甲磺酰胺的晶型VII，所述晶型VII的X-射线粉末衍射图谱在2θ值为14.54、15.24、17.48、20.15、24.08处有特征峰，2θ误差范围为±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 Hydrobenzo[b]pyrazolo[4,3-d]azepin-9-yl)amino)-pyrimidin-4-yl)amino)-quinoxalin-5-yl)methanesulfonamide Form 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°.
在本发明的一些方案中，上述晶型VII，其X-射线粉末衍射图谱在2θ值为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处有特征峰，2θ误差范围为±0.2°。In some solutions of the present invention, the X-ray powder diffraction pattern of the above crystal form VII has 2θ values of 10.10, 10.30, 11.33, 12.20, 14.54, 15.24, 17.48, 17.66, 18.88, 20.15, 21.12, 22.99, 23.33, There are characteristic peaks at 23.78, 24.08, and 26.67, and the 2θ error range is ±0.2°.
在本发明的一些方案中，上述晶型VII，其X-射线粉末衍射图谱在2θ值为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处有特征峰，2θ误差范围为±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, There are characteristic peaks at 17.66, 18.35, 18.88, 20.15, 21.12, 22.61, 22.99, 23.33, 23.78, 24.08, 24.61, 26.67, 27.87, 29.50, and 30.62, and the 2θ error range is ±0.2°.
在本发明的一些方案中，上述晶型VII，其X-射线粉末衍射图谱如图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 .
在本发明的一些方案中，上述晶型VII，其TGA-DSC谱图基本如图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 .
本发明的一些方案中，上述式(A)化合物晶型VII的XRPD图谱衍射峰解析数据如表7所示。In some schemes of the present invention, the XRPD pattern diffraction peak analysis data of the above-mentioned compound of formula (A) crystal form VII is shown in Table 7.
表7 式(A)化合物晶型VII的XRPD衍射峰解析数据Table 7 XRPD diffraction peak analysis data of formula (A) compound crystal form VII
Figure PCTCN2022125056-appb-000015
Figure PCTCN2022125056-appb-000015
Figure PCTCN2022125056-appb-000016
Figure PCTCN2022125056-appb-000016
本发明还提供式(A)化合物N-(6-((5-溴-2-((6-异丙基-8-甲氧基-3-甲基-3,4,5,6-四氢苯并[b]吡唑并[4,3-d]氮杂-9-基)氨基)-嘧啶-4-基)氨基)-喹喔啉-5-基)甲磺酰胺的晶型VIII，所述晶型VIII的X-射线粉末衍射图谱在2θ值为5.49、13.58、15.88、21.11、22.48处有特征峰，2θ误差范围为±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 VIII of Hydrobenzo[b]pyrazolo[4,3-d]azepin-9-yl)amino)-pyrimidin-4-yl)amino)-quinoxalin-5-yl)methanesulfonamide , 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°.
在本发明的一些方案中，上述晶型VIII，其X-射线粉末衍射图谱在2θ值为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处有特征峰，2θ误差范围为±0.2°。In some solutions of the present invention, the X-ray powder diffraction pattern of the above-mentioned 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, There are characteristic peaks at 25.63, 26.98, and 30.73, and the 2θ error range is ±0.2°.
在本发明的一些方案中，上述晶型VIII，其X-射线粉末衍射图谱在2θ值为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处有特征峰，2θ误差范围为±0.2°。 在本发明的一些方案中，上述晶型VIII，其X-射线粉末衍射图谱如图8所示。In some solutions of the present invention, the X-ray powder diffraction pattern of the above crystal form VIII has 2θ values of 4.47, 5.49, 9.00, 9.85, 10.08, 11.07, 11.74, 12.37, 13.03, 13.58, 13.77, 14.92, 15.88, There are characteristic peaks at 16.68, 16.99, 17.44, 18.59, 19.91, 20.76, 21.11, 21.42, 22.48, 23.57, 23.73, 25.00, 25.32, 25.63, 26.98, 27.79, 29.80, and 30.73. The 2θ error range is ±0.2°. In some solutions of the present invention, the X-ray powder diffraction pattern of the above crystal form VIII is shown in FIG. 8 .
在本发明的一些方案中，上述晶型VIII，其TGA-DSC谱图基本如图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 .
本发明的一些方案中，上述式(A)化合物晶型VIII的XRPD图谱衍射峰解析数据如表8所示。In some schemes of the present invention, the XRPD pattern diffraction peak analysis data of the compound of the above formula (A) crystal form VIII is shown in Table 8.
表8 式(A)化合物晶型VIII的XRPD衍射峰解析数据Table 8 XRPD diffraction peak analysis data of formula (A) compound crystal form VIII
Figure PCTCN2022125056-appb-000017
Figure PCTCN2022125056-appb-000017
Figure PCTCN2022125056-appb-000018
Figure PCTCN2022125056-appb-000018
本发明还提供式(A)化合物N-(6-((5-溴-2-((6-异丙基-8-甲氧基-3-甲基-3,4,5,6-四氢苯并[b]吡唑并[4,3-d]氮杂-9-基)氨基)-嘧啶-4-基)氨基)-喹喔啉-5-基)甲磺酰胺的晶型IX，所述晶型IX的X-射线粉末衍射图谱在2θ值为5.79、8.84、11.66、21.96、24.74处有特征峰，2θ误差范围为±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 Form IX of hydrobenzo[b]pyrazolo[4,3-d]azepin-9-yl)amino)-pyrimidin-4-yl)amino)-quinoxalin-5-yl)methanesulfonamide , 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°.
在本发明的一些方案中，上述晶型IX，其X-射线粉末衍射图谱在2θ值为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处有特征峰，2θ误差范围为±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, There are characteristic peaks at 24.74, 25.13, 26.69, and 27.22, and the 2θ error range is ±0.2°.
在本发明的一些方案中，上述晶型IX，其X-射线粉末衍射图谱在2θ值为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处有特征峰，2θ误差范围为±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, There are characteristic peaks at 19.93, 20.82, 21.11, 21.74, 21.96, 23.48, 24.39, 24.74, 25.13, 26.42, 26.69, 27.22, and 30.33, and the 2θ error range is ±0.2°.
在本发明的一些方案中，上述晶型IX，其X-射线粉末衍射图谱如图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 .
在本发明的一些方案中，上述晶型IX，其TGA-DSC谱图基本如图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 .
本发明的一些方案中，上述式(A)化合物晶型IX的XRPD图谱衍射峰解析数据如表9所示。In some schemes of the present invention, the XRPD pattern diffraction peak analysis data of the above-mentioned compound of formula (A) crystal form IX is shown in Table 9.
表9 式(A)化合物晶型IX的XRPD衍射峰解析数据Table 9 XRPD diffraction peak analysis data of formula (A) compound crystal form IX
Figure PCTCN2022125056-appb-000019
Figure PCTCN2022125056-appb-000019
Figure PCTCN2022125056-appb-000020
Figure PCTCN2022125056-appb-000020
本发明还提供式(A)化合物N-(6-((5-溴-2-((6-异丙基-8-甲氧基-3-甲基-3,4,5,6-四氢苯并[b]吡唑并[4,3-d]氮杂-9-基)氨基)-嘧啶-4-基)氨基)-喹喔啉-5-基)甲磺酰胺的晶型XII，所述晶型XII的X-射线粉末衍射图谱在2θ值为5.83、6.80、20.48、24.92、27.49处有特征峰，2θ误差范围为±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 Form XII of Hydrobenzo[b]pyrazolo[4,3-d]azepin-9-yl)amino)-pyrimidin-4-yl)amino)-quinoxalin-5-yl)methanesulfonamide , 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°.
在本发明的一些方案中，上述晶型XII，其X-射线粉末衍射图谱在2θ值为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处有特征峰，2θ误差范围为±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, There are characteristic peaks at 23.35, 24.92, and 27.49, and the 2θ error range is ±0.2°.
在本发明的一些方案中，上述晶型XII，其X-射线粉末衍射图谱在2θ值为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处有特征峰，2θ误差范围为±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, There are characteristic peaks at 18.42, 19.66, 20.48, 20.85, 21.40, 21.81, 23.35, 23.95, 24.92, 26.62, 27.49, 31.17, 32.45, and 33.62, and the 2θ error range is ±0.2°.
在本发明的一些方案中，上述晶型XII，其X-射线粉末衍射图谱如图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 .
在本发明的一些方案中，上述晶型XII，其TGA-DSC谱图基本如图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 .
本发明的一些方案中，上述式(A)化合物晶型XII的XRPD图谱衍射峰解析数据如表10所示。In some schemes of the present invention, the XRPD pattern diffraction peak analysis data of the above-mentioned compound of formula (A) crystal form XII is shown in Table 10.
表10 式(A)化合物晶型XII的XRPD衍射峰解析数据Table 10 XRPD diffraction peak analysis data of formula (A) compound crystal form XII
Figure PCTCN2022125056-appb-000021
Figure PCTCN2022125056-appb-000021
Figure PCTCN2022125056-appb-000022
Figure PCTCN2022125056-appb-000022
本发明还提供式(A)化合物N-(6-((5-溴-2-((6-异丙基-8-甲氧基-3-甲基-3,4,5,6-四氢苯并[b]吡唑并[4,3-d]氮杂-9-基)氨基)-嘧啶-4-基)氨基)-喹喔啉-5-基)甲磺酰胺的晶型XIV，所述晶型XIV的X-射线粉末衍射图谱在2θ值为5.86、11.73、23.56、29.55、35.65处有特征峰，2θ误差范围为±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 XIV of Hydrobenzo[b]pyrazolo[4,3-d]azepin-9-yl)amino)-pyrimidin-4-yl)amino)-quinoxalin-5-yl)methanesulfonamide , 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°.
在本发明的一些方案中，上述晶型XIV，其X-射线粉末衍射图谱在2θ值为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处有特征峰，2θ误差范围为±0.2°。In some solutions of the present invention, the X-ray powder diffraction pattern of the above crystal form XIV is at 2θ values of 5.86, 11.73, 13.85, 20.91, 22.32, 23.56, 24.69, 25.30, 26.72, 29.55, 33.09, 35.65, 38.91 There are characteristic peaks, and the 2θ error range is ±0.2°.
在本发明的一些方案中，上述晶型XIV，其X-射线粉末衍射图谱如图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 .
在本发明的一些方案中，上述晶型XIV，其TGA-DSC谱图基本如图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 .
本发明的一些方案中，上述式(A)化合物晶型XIV的XRPD图谱衍射峰解析数据如表11所示。In some schemes of the present invention, the XRPD pattern diffraction peak analysis data of the compound of formula (A) crystal form XIV is shown in Table 11.
表11 式(A)化合物晶型XIV的XRPD衍射峰解析数据Table 11 XRPD diffraction peak analysis data of formula (A) compound crystal form XIV
Figure PCTCN2022125056-appb-000023
Figure PCTCN2022125056-appb-000023
Figure PCTCN2022125056-appb-000024
Figure PCTCN2022125056-appb-000024
本发明还提供式(I)化合物，The present invention also provides a compound of formula (I),
Figure PCTCN2022125056-appb-000025
Figure PCTCN2022125056-appb-000025
本发明提供式(I)化合物的晶型A，所述晶型A的X-射线粉末衍射图谱在2θ值为7.38、8.13、12.62、20.14、21.41、23.72处有特征峰，2θ误差范围为±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°.
在本发明的一些方案中，上述晶型A，其X-射线粉末衍射图谱在2θ值为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处有特征峰，2θ误差范围为±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°.
在本发明的一些方案中，上述晶型A，其X-射线粉末衍射图谱在2θ值为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处有特征峰，2θ误差范围为±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, There are characteristic peaks at 19.93, 20.14, 20.32, 21.41, 22.66, 23.72, 25.08, 25.53, 26.47, 28.26, 30.02, and 31.91, and the 2θ error range is ±0.2°.
在本发明的一些方案中，上述晶型A，其X-射线粉末衍射图谱如图12所示。In some solutions of the present invention, the X-ray powder diffraction pattern of the above-mentioned crystal form A is shown in FIG. 12 .
在本发明的一些方案中，上述晶型A，其TGA-DSC谱图基本如图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 .
本发明的一些方案中，上述式(I)化合物晶型A的XRPD图谱衍射峰解析数据如表12所示。In some schemes of the present invention, the XRPD pattern diffraction peak analysis data of the crystal form A of the compound of formula (I) is shown in Table 12.
表12 式(1)化合物晶型A的XRPD衍射峰解析数据Table 12 XRPD diffraction peak analysis data of compound crystal form A of formula (1)
Figure PCTCN2022125056-appb-000026
Figure PCTCN2022125056-appb-000026
Figure PCTCN2022125056-appb-000027
Figure PCTCN2022125056-appb-000027
本发明还提供式(I)化合物的晶型B，所述晶型B的X-射线粉末衍射图谱在2θ值为5.89、7.25、9.37、22.49、25.45、27.05处有特征峰，2θ误差范围为±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°.
在本发明的一些方案中，上述晶型B，其X-射线粉末衍射图谱在2θ值为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处有特征峰，2θ误差范围为±0.2°。In some solutions of the present invention, the X-ray powder diffraction pattern of the above crystal form B has 2θ values of 5.89, 6.43, 7.25, 9.37, 12.42, 12.95, 15.16, 17.37, 17.76, 18.64, 18.89, 21.14, 21.57, There are characteristic peaks at 21.99, 22.49, 25.45, and 27.05, and the 2θ error range is ±0.2°.
在本发明的一些方案中，上述晶型B，其X-射线粉末衍射图谱在2θ值为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处有特征峰，2θ误差范围为±0.2°。In some solutions of the present invention, the above-mentioned crystal form B has an X-ray powder diffraction pattern whose 2θ value is 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, There are characteristic peaks at 17.37, 17.76, 18.64, 18.89, 20.12, 21.14, 21.57, 21.99, 22.49, 22.84, 23.63, 24.58, 25.45, 27.05, and 30.01, and the 2θ error range is ±0.2°.
在本发明的一些方案中，上述晶型B，其X-射线粉末衍射图谱如图13所示。In some solutions of the present invention, the above crystal form B has an X-ray powder diffraction pattern as shown in FIG. 13 .
在本发明的一些方案中，上述晶型B，其TGA-DSC谱图基本如图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 .
本发明的一些方案中，上述式(I)化合物晶型B的XRPD图谱衍射峰解析数据如表13所示。In some schemes of the present invention, the XRPD pattern diffraction peak analysis data of the crystal form B of the compound of formula (I) above is shown in Table 13.
表13 式(1)化合物晶型B的XRPD衍射峰解析数据Table 13 XRPD diffraction peak analysis data of compound crystal form B of formula (1)
Figure PCTCN2022125056-appb-000028
Figure PCTCN2022125056-appb-000028
Figure PCTCN2022125056-appb-000029
Figure PCTCN2022125056-appb-000029
本发明还提供式(I)化合物的晶型C，所述晶型C的X-射线粉末衍射图谱在2θ值为5.85、12.41、17.76、22.48、27.03处有特征峰，2θ误差范围为±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 °.
在本发明的一些方案中，上述晶型C，其X-射线粉末衍射图谱在2θ值为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处有特征峰，2θ误差范围为±0.2°。In some solutions of the present invention, the X-ray powder diffraction pattern of the above-mentioned 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, There are characteristic peaks at 23.73, 25.42, and 27.03, and the 2θ error range is ±0.2°.
在本发明的一些方案中，上述晶型C，其X-射线粉末衍射图谱在2θ值为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处有特征峰，2θ误差范围为±0.2°。In some solutions of the present invention, the X-ray powder diffraction pattern of the above-mentioned 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, There are characteristic peaks at 18.64, 18.88, 20.11, 21.12, 21.40, 21.57, 21.97, 22.48, 22.87, 23.73, 25.42, 27.03, 27.84, 28.32, and 29.96, and the 2θ error range is ±0.2°.
在本发明的一些方案中，上述晶型C，其X-射线粉末衍射图谱如图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 .
在本发明的一些方案中，上述晶型C，其TGA-DSC谱图基本如图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 .
本发明的一些方案中，上述式(I)化合物晶型C的XRPD图谱衍射峰解析数据如表14所示。In some schemes of the present invention, the XRPD pattern diffraction peak analysis data of the crystal form C of the compound of formula (I) is shown in Table 14.
表14 式(1)化合物晶型C的XRPD衍射峰解析数据Table 14 XRPD diffraction peak analysis data of compound crystal form C of formula (1)
Figure PCTCN2022125056-appb-000030
Figure PCTCN2022125056-appb-000030
Figure PCTCN2022125056-appb-000031
Figure PCTCN2022125056-appb-000031
本发明还提供式(I)化合物的晶型D，所述晶型D的X-射线粉末衍射图谱在2θ值为5.55、13.03、16.73、22.48、24.17处有特征峰，2θ误差范围为±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 °.
在本发明的一些方案中，上述晶型D，其X-射线粉末衍射图谱在2θ值为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处有特征峰，2θ误差范围为±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, There are characteristic peaks at 24.17, 26.05, and 34.02, and the 2θ error range is ±0.2°.
在本发明的一些方案中，上述晶型D，其X-射线粉末衍射图谱在2θ值为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处有特征峰，2θ误差范围为±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, There are characteristic peaks at 16.73, 18.11, 20.43, 20.96, 21.37, 22.48, 23.33, 23.83, 24.17, 25.62, 26.05, 26.42, 27.77, 27.93, 28.80, 32.72, 33.41, and 34.02. The 2θ error range is ±0.2°.
在本发明的一些方案中，上述晶型D，其X-射线粉末衍射图谱如图15所示。In some solutions of the present invention, the above crystal form D has an X-ray powder diffraction pattern as shown in FIG. 15 .
在本发明的一些方案中，上述晶型D，其DSC谱图上在250℃以及256℃左右各有一个吸热峰。In some solutions of the present invention, the above crystal form D has an endothermic peak at about 250°C and 256°C in the DSC spectrum.
在本发明的一些方案中，上述晶型D，其TGA谱图上在220℃左右有一个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. in its TGA spectrum.
在本发明的一些方案中，上述晶型D，其TGA谱图上在150-225℃左右有一个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. in its TGA spectrum.
在本发明的一些方案中，上述晶型D，其TGA-DSC谱图基本如图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 .
本发明的一些方案中，上述式(I)化合物晶型D的XRPD图谱衍射峰解析数据如表15所示。In some schemes of the present invention, the XRPD pattern diffraction peak analysis data of the crystal form D of the compound of formula (I) above is shown in Table 15.
表15 式(1)化合物晶型D的XRPD衍射峰解析数据Table 15 XRPD diffraction peak analysis data of compound crystal form D of formula (1)
Figure PCTCN2022125056-appb-000032
Figure PCTCN2022125056-appb-000032
Figure PCTCN2022125056-appb-000033
Figure PCTCN2022125056-appb-000033
本发明还提供一种药物组合物，其包含上述的式(A)或式(I)化合物及可药用的载体。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.
本发明还提供一种药物组合物，其包含上述任意一晶型及可药用的载体。The present invention also provides a pharmaceutical composition, which comprises any one of the above crystal forms and a pharmaceutically acceptable carrier.
本发明还提供上述任意一晶型或上述药物组合物在制备用于治疗EGFR突变介导的癌症的药物中的用途。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.
本发明还提供上述任意一晶型或上述药物组合物治疗EGFR突变介导癌症的用途。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.
用于治疗癌症的药物，所述药物为上述任意一晶型或上述药物组合物。A medicament for treating cancer, the medicament is any of the above-mentioned crystal forms or the above-mentioned pharmaceutical composition.
用于治疗癌症EGFR突变介导的药物，所述药物为上述任意一晶型或上述药物组合物。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.
在本发明的一些方案中，上述癌症包括淋巴瘤、非霍奇金淋巴瘤、卵巢癌、宫颈癌、前列腺癌、结肠直肠癌、乳腺癌、胰腺癌、胶质瘤、胶质母细胞瘤，黑色素瘤、白血病、胃癌、子宫内膜癌、肺癌、肝细胞癌、胃癌、胃肠道间质瘤(GIST)、急性髓细胞白血病(AML)、胆管癌、肾癌、甲状腺癌、间变性大细胞淋巴瘤、间皮瘤、多发性骨髓瘤、黑色素瘤。In some aspects of the present invention, the aforementioned cancers include lymphoma, non-Hodgkin's lymphoma, ovarian cancer, cervical cancer, prostate cancer, colorectal cancer, breast cancer, pancreatic cancer, glioma, glioblastoma, Melanoma, leukemia, gastric cancer, endometrial cancer, lung cancer, hepatocellular carcinoma, gastric cancer, gastrointestinal stromal tumor (GIST), acute myeloid leukemia (AML), cholangiocarcinoma, renal cancer, thyroid cancer, anaplastic Cellular lymphoma, mesothelioma, multiple myeloma, melanoma.
在本发明的一些方案中，上述癌症为肺癌。本发明还提供式(A)、式(I)化合物、上述任意一晶型或上述药物组合物在制备EGFR抑制剂中的用途。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.
本发明还提供抑制有需要患者中EGFR突变的方法，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药物组合物。The present invention also provides a method for inhibiting EGFR mutation in a patient in need, comprising administering the compound of formula (A), formula (I), any of the above crystal forms or the above pharmaceutical composition to the patient.
本发明还提供抑制生物样品中的EGFR突变的方法，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药物组合物。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.
在本发明的一些方案中，上述EGFR突变包括L858R、T790M、C797S、Del19突变。In some aspects of the present invention, the aforementioned EGFR mutations include L858R, T790M, C797S, and Del19 mutations.
在本发明的一些方案中，上述EGFR突变包括L858R/T790M/C797S三突变、Del19/T790M/C797S三突变。In some aspects of the present invention, the above-mentioned EGFR mutations include L858R/T790M/C797S triple mutation and Del19/T790M/C797S triple mutation.
技术效果technical effect
本申请中的晶型具有较好的化学稳定性、物理稳定性以及较低的吸湿性，受热、湿度和光照影响较小，便于储存及制剂。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.
定义和说明Definition and Description
除非另有说明，本文所用的下列术语和短语旨在具有下列含义。一个特定的术语或短语在没有特别定义的情况下不应该被认为是不确定的或不清楚的，而应该按照普通的含义去理解。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.
术语“左右”通常是指在指定数值以上或以下0.01％-5％的范围内变动，例如在指定数值以上或以下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％的范围内变动。例如，所述“212℃左右”可以包括212±0.15℃，所述“264℃左右”可以包括264±0.38℃。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.
术语“可药用的载体”是指本领域通常可接受的用于将生物活性药剂递送给动物、特别是哺乳动物的介质，根据给药方式和剂型的性质包括例如佐剂、赋形剂或赋形物，例如稀释剂、防腐剂、填充剂、流动调节剂、崩解剂、润湿剂、乳化剂、助悬剂、甜味剂、调味剂、芳香剂、抗菌剂、抗真菌剂、润滑剂和分散剂。药学上可接受的载体在本领域普通技术人员的眼界范围内根据大量因素配制。其包括但不限于：配制的活性药剂的类型和性质，要将含有该药剂的组合物给药的对象，组合物的预期给药途径，和目标治疗适应症。药学上可接受的载体包括含水介质和非水介质这两者以及多种固体和半固体剂型。除了活性药剂以外，这样的载体包括许多不同的成分和添加剂，因多种原因(例如稳定活性药剂、粘合剂等)在处方中包括的这样的另外的成分对于本领域普通技术人员是众所周知的。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 subject to whom 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, such additional ingredients being included in formulations for a variety of reasons (e.g., stabilizing the active agent, binders, etc.) are well known to those of ordinary skill in the art .
本领域公知，X-射线粉末衍射图谱根据测量条件的微小变化，而具有一种或多种测量误差，本发明公开或要求保护的结晶、晶体或晶型的结构可能根据试验条件、纯度、设备和本领域技术人员已知的其它常几变量在合理误差范围内表现出类似但不完全相同的分析特性。例如，粉末X-射线粉末衍射中的衍射角(2θ)通常产生±0.20°的范围内的误差，所以，本发明不仅包括粉末X-射线粉末衍射中的衍射角完全一致的结晶，还包括在±0.20°的误差范围内衍射角一致的结晶。本发明的化合物A的结晶形式并不仅限于具有与附图中所示的X-射线粉末衍射图谱相同的X射线粉末衍射图谱的晶体，具有基本上与附图中所示相同的X-射线粉末衍射图谱的任何晶体均属于本发明范围内。It is well known in the art that X-ray powder diffraction patterns have one or more measurement errors according to small 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, etc. Other constant variables known to those skilled 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, but also includes 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 accompanying drawings, having substantially the same X-ray powder diffraction patterns as shown in the accompanying drawings Any crystal with a diffraction pattern is within the scope of the invention.
文中出现的“与附图中所示X-射线粉末衍射图谱基本上相同的X-射线粉末衍射图谱。应了解，在该上下文中使用的术语“基本上相同”亦意指示X-射线粉末衍射图谱的2θ角度值可因伴随这些测量的固有实验变化而具有轻微变化，两者为同一晶体形式。Appears herein "X-ray powder diffraction pattern that is substantially the same as the X-ray powder diffraction pattern shown in the accompanying drawings. It will be understood that the term "substantially the same" as used in this context is also meant to indicate that the X-ray powder diffraction pattern The 2Θ angle values of the spectra may vary slightly due to the inherent experimental variation accompanying these measurements, both for the same crystal form.
应当理解用不同类型设备或用不同的测试条件可能给出稍微不同的DSC图谱和吸热转变温度读数。该数值将受化合物纯度、样品重量、加热速度、粒径和测试设备的校验和维修的影响。晶型的最大吸热转变温度可以在上述公开的具体数值±5.0℃的范围内。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.
本公开还采用热失重分析(TGA)对晶型发生分解或升华、蒸发的程度(失去重量)与温度的关系进行了分析。应当理解同种晶型受样品纯度、粒径、不同类型设备、不同的测试方法等的影响，所得到的数值存在一定误差。晶型发生分解或升华、蒸发时的温度可以在上述公开的具体数值±3.0℃的范围内，例如±2.0℃的范围内。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“稳定性”包括“化学稳定性”和/或“物理稳定性”。“化学稳定性”是指该晶型在一定温度、湿度、光照条件下发生降解反应的程度，“化学稳定性”反映了该晶型在储存条件下的稳定性。“物理稳定性”是指该晶型在某些特定条件下发生固态形式转化的程度，例如在高温、高湿、研磨、压片、脱溶剂、吸附溶剂的条件下，转化为另外一种晶型，因此“物理稳定性”可以在一定程度上反应晶型在制剂等使用过程中的稳定程度。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 conditions, such as high temperature, high humidity, grinding, tableting, solvent removal, and solvent absorption. Therefore, "physical stability" can to a certain extent reflect the stability of the crystal form during the use of preparations.
本发明的结晶结构可以通过各种方法制备，包括从合适的溶剂中结晶或重结晶、升华、从熔融体中生长、从另一相固态转化、从超临界流体中结晶和射流喷雾等。结晶结构从溶剂混合物中结晶或重结晶的技术，包括溶剂蒸发、降低溶剂混合物的温度、该分子和/或盐的过饱和溶剂混合物的引晶、冻干溶剂混合物、向溶剂混合物中加入反溶剂等。The crystalline structures of the present invention can be prepared by various methods, including crystallization or recrystallization from a suitable solvent, sublimation, growth from a melt, solid state transformation from another phase, crystallization from a supercritical fluid, and jet spraying, 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 anti-solvent to solvent mixtures wait.
本发明的中间体化合物可以通过本领域技术人员所熟知的多种合成方法来制备，包括下面列举的具体实施方式、其与其他化学合成方法的结合所形成的实施方式以及本领域技术上人员所熟知的等同替换方式，优选的实施方式包括但不限于本发明的实施例。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 methods described by those skilled in the art. Known equivalents, preferred embodiments include, but are not limited to, the examples of the present invention.
在本发明实施例中，标题化合物的命名是借助Chemdraw通过化合物结构转化过来的。若化合物名称与化合物结构存在不一致的情况，可通过综合相关信息和反应路线辅助确定；无法通过其他来确认的，以给出的化合物结构式为准。In the examples of the present invention, the name of the title compound was converted from the compound structure 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 methods, the structural formula of the given compound shall prevail.
本发明的化合物可以通过本领域技术人员所熟知的多种合成方法来制备，包括下面列举的具体实施方式、其与其他化学合成方法的结合所形成的实施方式以及本领域技术上人员所熟知的等同替换方式，优选的实施方式包括但不限于本发明的实施例。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 the methods well known to those skilled in the art Equivalent alternatives, preferred embodiments include but are not limited to the examples of the present invention.
仪器及分析方法:Instrument and analysis method:
1、X-射线粉末衍射(XRPD)1. X-ray powder diffraction (XRPD)
固体样品用X-射线粉末衍射仪(Bruker D8 advance)进行分析。将样品置于零背景单晶硅样品盘上，用药匙轻压固体表面，使样品平铺。XRPD测量参数见表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16-1 XRPD测试参数Table 16-1 XRPD test parameters
Figure PCTCN2022125056-appb-000034
Figure PCTCN2022125056-appb-000034
Figure PCTCN2022125056-appb-000035
Figure PCTCN2022125056-appb-000035
或者固体样品用X-射线粉末衍射仪(X’Pert PRO)进行分析，取供试品细粉适量，置于样品架凹槽中，用玻璃片压制成平整致密的平面，XRPD测量参数见表16-2。Or the solid sample is analyzed by X-ray powder diffractometer (X'Pert PRO), and an appropriate amount of fine powder of the test sample is taken, placed in the groove of the sample holder, and pressed into a flat and compact plane with a glass sheet. The XRPD measurement parameters are shown in the table 16-2.
表16-2 XRPD测试参数Table 16-2 XRPD test parameters
仪器instrument pANalytical，X’Pert PRO型pANalytical, X’Pert PRO type
光源light source Cu靶Cu target
扫描角度scan angle 3-40°(20)3-40°(20)
扫描速度 scanning speed 8°/min8°/min
光管电压/电流Light tube voltage/current 40KV/40mA40KV/40mA
发散狭缝divergence slit 1/8°1/8°
2、热重分析(TGA)2. Thermogravimetric analysis (TGA)
使用TA Instrument的热重分析仪对固体进行热重分析。约1-5mg样品置于已去皮的铝制样品盘中，按照表17中所列参数对样品进行加热，使用TRIOS对数据进行分析。Thermogravimetric analysis of solids was performed using a TA Instrument thermogravimetric analyzer. Approximately 1-5 mg of the sample was placed in a peeled aluminum sample pan, the sample was heated according to the parameters listed in Table 17, and the data was analyzed using TRIOS.
表17 TGA分析方法参数Table 17 TGA analysis method parameters
Figure PCTCN2022125056-appb-000036
Figure PCTCN2022125056-appb-000036
3、差示扫描量热分析(DSC)3. Differential scanning calorimetry (DSC)
使用TA Instrument的差示扫描量热仪对固体进行DSC分析。约1-3mg样品经精确称重后置于扎孔的铝制样品盘中，按照表18-1中所列参数对样品进行加热，使用TRIOS对数据进行分析。The solids were subjected to DSC analysis using a Differential Scanning Calorimeter from TA Instruments. About 1-3mg of the sample is accurately weighed and placed in a perforated aluminum sample pan. The sample is heated according to the parameters listed in Table 18-1, and the data is analyzed using TRIOS.
表18-1 DSC分析方法参数Table 18-1 DSC analysis method parameters
仪器信息Instrument information Discovery DSC 250Discovery DSC 250
样品盘sample tray 带孔错盘Perforated plate
温度范围temperature range 25-300℃25-300℃
加热速率heating rate 1O℃/min1O℃/min
吹扫气体purge gas 氮气Nitrogen
流速flow rate 50mL/min50mL/min
或者使用梅特勒托利多的同步热分析仪对固体进行热重-差示扫描量热连用分析。用小勺取供试品适量置于坩埚中，使铺布均匀，称重其重量，按照表18-2中所列参数对样品进行加热，使用STARe对数据进行分析。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18-2 TCA-DSC分析方法参数Table 18-2 TCA-DSC analysis method parameters
仪器设备equipment 梅特勒托利多，TGA/DSC1Mettler Toledo, TGA/DSC1
样品盘sample tray 铝坩埚Aluminum crucible
温度范围temperature range 室温至300℃Room temperature to 300°C
加热速率heating rate 10℃/min10℃/min
吹扫气体purge gas 氮气Nitrogen
流速flow rate 平衡室:20mL/minBalance chamber: 20mL/min
 the 样品室：50mL/minSample chamber: 50mL/min
4、动态水分吸脱附分析(DVS)4. Dynamic moisture adsorption and desorption analysis (DVS)
使用DVS Intrinsic动态水分吸附仪对样品的吸湿性进行测定。将样品置于已去皮的样品篮中，仪器自动称重，按照表19中的参数对样品进行分析。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19 DVS分析方法参数Table 19 DVS analysis method parameters
Figure PCTCN2022125056-appb-000037
Figure PCTCN2022125056-appb-000037
5、核磁共振氢谱( 1H-NMR) 5. Proton nuclear magnetic resonance spectrum ( 1 H-NMR)
NMR的测定是用Bruker AVANCE III HD 400或者Bruker AVANCE III HD 300核磁仪器，测定溶剂为氘代二甲基亚砜(DMSO-d 6)，内标为四甲基硅烷(TMS)。 The determination of NMR is carried out with Bruker AVANCE III HD 400 or Bruker AVANCE III HD 300 nuclear magnetic instruments, the determination solvent is deuterated dimethyl sulfoxide (DMSO-d 6 ), and the internal standard is tetramethylsilane (TMS).
6、高效液相色谱(HPLC)6. High performance liquid chromatography (HPLC)
液质联用色谱LC-MS的测定用SHIMADZU LCMS-2020质谱仪(离子源为电喷雾离子化)。The determination of liquid chromatography-mass chromatography LC-MS uses SHIMADZU LCMS-2020 mass spectrometer (the ion source is electrospray ionization).
HPLC的测定使用SHIMADZU LC-20AP XR和SPD-M20A高压液相色谱或Agilent HPLC 1260series仪器对样品进行高效液相色谱分析。Determination of HPLC Use SHIMADZU LC-20AP XR and SPD-M20A high-pressure liquid chromatography or Agilent HPLC 1260series instruments for high-performance liquid chromatography analysis of samples.
7、离子色谱(IC)7. Ion Chromatography (IC)
赛默飞ICS-1100离子色谱系统和变色龙工作站和AS-AP自动进样器，序列号：13070718。Thermo Scientific ICS-1100 Ion Chromatography System with Chameleon Workstation and AS-AP Autosampler, serial number: 13070718.
表20 IC分析方法参数Table 20 IC analysis method parameters
流动相mobile phase 10mM氢氧化钠水溶液10mM sodium hydroxide aqueous solution
检测器Detector 抑制型电导检测器Suppressed conductivity detector
采集频率Acquisition frequency 5.0Hz5.0Hz
电导池温度Conductivity cell temperature 35.0℃35.0°C
抑制器suppressor 外循环模式Outer circulation mode
抑制器电流suppressor current 25mA25mA
柱温Column temperature 30.0℃30.0℃
流速flow rate 1.0mL/min1.0mL/min
运行时间operation hours 10min10min
进样体积Injection volume 10μL10μL
附图说明Description of drawings
图1为式(A)化合物晶型I的XRPD谱图。Fig. 1 is the XRPD pattern of the crystal form I of the compound of formula (A).
图2为式(A)化合物晶型II的XRPD谱图。Fig. 2 is the XRPD spectrum of the compound of formula (A) Form II.
图3为式(A)化合物晶型III的XRPD谱图。Fig. 3 is the XRPD spectrum of the compound of formula (A) crystal form III.
图4为式(A)化合物晶型IV的XRPD谱图。Fig. 4 is the XRPD spectrum of the compound of formula (A) crystalline form IV.
图5为式(A)化合物晶型V的XRPD谱图。Fig. 5 is the XRPD spectrum of the crystal form V of the compound of formula (A).
图6为式(A)化合物晶型VI的XRPD谱图。Fig. 6 is the XRPD spectrum of the compound of formula (A) in the crystal form VI.
图7为式(A)化合物晶型VII的XRPD谱图。Fig. 7 is the XRPD spectrum of the compound of formula (A) in the crystal form VII.
图8为式(A)化合物晶型VIII的XRPD谱图。Fig. 8 is the XRPD spectrum of the compound of formula (A) in the crystal form VIII.
图9为式(A)化合物晶型IX的XRPD谱图。Fig. 9 is the XRPD spectrum of the crystal form IX of the compound of formula (A).
图10为式(A)化合物晶型XII的XRPD谱图。Fig. 10 is the XRPD spectrum of the compound of formula (A) crystal form XII.
图11为式(A)化合物晶型XIV的XRPD谱图。Fig. 11 is the XRPD spectrum of the compound of formula (A) in crystal form XIV.
图12为式(I)化合物晶型A的XRPD谱图。Figure 12 is the XRPD spectrum of Form A of the compound of formula (I).
图13为式(I)化合物晶型B的XRPD谱图。Fig. 13 is the XRPD spectrum of the crystal form B of the compound of formula (I).
图14为式(I)化合物晶型C的XRPD谱图。Figure 14 is the XRPD spectrum of Form C of the compound of formula (I).
图15为式(I)化合物晶型D的XRPD谱图。Figure 15 is the XRPD spectrum of Form D of the compound of formula (I).
图16为动物肿瘤生长曲线图。Fig. 16 is a graph showing tumor growth curves in animals.
图17为动物体重曲线图。Figure 17 is a graph of animal body weight.
图18为式(A)化合物晶型I的TGA-DSC谱图。Fig. 18 is the TGA-DSC spectrum of the crystal form I of the compound of formula (A).
图19为式(A)化合物晶型II的TGA-DSC谱图。Fig. 19 is a TGA-DSC spectrum of the compound of formula (A) Form II.
图20为式(A)化合物晶型III的TGA-DSC谱图。Figure 20 is the TGA-DSC spectrum of the compound of formula (A) Form III.
图21为式(A)化合物晶型IV的TGA-DSC谱图。Fig. 21 is a TGA-DSC spectrum of the compound of formula (A) crystalline form IV.
图22为式(A)化合物晶型V的TGA-DSC谱图。Figure 22 is the TGA-DSC spectrum of Form V of the compound of formula (A).
图23为式(A)化合物晶型VI的TGA-DSC谱图。Figure 23 is the TGA-DSC spectrum of the compound of formula (A) in Form VI.
图24为式(A)化合物晶型VII的TGA-DSC谱图。Fig. 24 is a TGA-DSC spectrum of the compound of formula (A) in the crystal form VII.
图25为式(A)化合物晶型VIII的TGA-DSC谱图。Fig. 25 is a TGA-DSC spectrum of the compound of formula (A) in the crystal form VIII.
图26为式(A)化合物晶型IX的TGA-DSC谱图。Fig. 26 is a TGA-DSC spectrum of the compound of formula (A) Form IX.
图27为式(A)化合物晶型XII的TGA-DSC谱图。Fig. 27 is a TGA-DSC spectrum of the compound of formula (A) in the crystal form XII.
图28为式(A)化合物晶型XIV的TGA-DSC谱图。Fig. 28 is a TGA-DSC spectrum of the compound of formula (A) in the crystal form XIV.
图29为式(I)化合物晶型A的TGA-DSC谱图。Fig. 29 is the TGA-DSC spectrum of the crystal form A of the compound of formula (I).
图30为式(I)化合物晶型B的TGA-DSC谱图。Fig. 30 is the TGA-DSC spectrum of the crystal form B of the compound of formula (I).
图31为式(I)化合物晶型C的TGA-DSC谱图。Fig. 31 is a TGA-DSC spectrum of Form C of the compound of formula (I).
图32为式(I)化合物晶型D的TGA-DSC谱图。Figure 32 is the TGA-DSC spectrum of the crystal form D of the compound of formula (I).
图33为式(A)化合物晶型I的DVS谱图。Fig. 33 is a DVS spectrum of Form I of the compound of formula (A).
图34为式(A)化合物晶型I的DVS实验前后XRPD对比谱图。Fig. 34 is a comparison of XRPD spectra before and after DVS experiment of compound crystal form I of formula (A).
图35为式(A)化合物晶型II的DVS谱图。Fig. 35 is the DVS spectrum of the compound of formula (A) Form II.
图36为式(A)化合物晶型II的DVS实验前后XRPD对比谱图。Fig. 36 is a comparison of XRPD spectra before and after DVS experiment of the compound of formula (A) crystalline form II.
图37为式(A)化合物晶型III的DVS谱图。Fig. 37 is a DVS spectrum of the compound of formula (A) Form III.
图38为式(A)化合物晶型III的DVS实验前后XRPD对比谱图。Fig. 38 is a comparison of XRPD spectra before and after DVS experiment of the compound of formula (A) Form III.
图39为式(I)化合物晶型D的DVS谱图。Fig. 39 is a DVS spectrum of Form D of the compound of formula (I).
图40为式(I)化合物晶型D的DVS实验前后XRPD对比谱图。Fig. 40 is a comparison of XRPD spectra before and after DVS experiment of compound D of formula (I).
图41为式(A)化合物晶型II抗压性实验前后XRPD对比谱图。Figure 41 is a comparison of XRPD spectra before and after the compression test of the compound of formula (A) in Form II.
图42为式(I)化合物晶型D的稳定性实验前后XRPD对比谱图。Fig. 42 is a comparison of XRPD spectra before and after the stability test of the crystal form D of the compound of formula (I).
具体实施方式Detailed ways
下面通过实施例对本发明进行详细描述，但并不意味着对本发明任何不利限制。本发明的化合物可以通过本领域技术人员所熟知的多种合成方法来制备，包括下面列举的具体实施方式、其与其他化学合成方法的结合所形成的实施方式以及本领域技术上人员所熟知的等同替换方式，优选的实施方式包括但不限于本发明的实施例。对本领域的技术人员而言，在不脱离本发明精神和范围的情况下针对本发明具体实施方式进行各种变化和改进将是显而易见的。The present invention will be described in detail through examples below, but it does not imply any unfavorable 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 combining them with other chemical synthesis methods, and the methods well known to those skilled in the art Equivalent alternatives, 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.
实施例1 式(A)和式(1)化合物的制备: Embodiment 1 The preparation of formula (A) and formula (1) compound:
1.1中间体6A的制各1.1 Preparation of Intermediate 6A
Figure PCTCN2022125056-appb-000038
Figure PCTCN2022125056-appb-000038
化合物6A-1：Compound 6A-1:
将化合物1C-4(3.5g,15.5mmol)溶于乙腈(40mL)，在0℃条件下，加入N-碘代丁二酰亚胺(4.9g,21.7mmol)。室温反应搅拌5小时，LCMS监控显示原料消失后，减压浓缩，加入水(30mL)，用二氯甲烷(45mL×3次)萃取，合并有机相，有机相先用饱和食盐水(60mL×2次)洗涤，然后用无水硫酸钠干燥，过滤，减压浓缩。所得残余物用硅胶柱层析纯化(洗脱剂：乙酸乙酯/石油醚＝1/1)得到3.57g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, added water (30mL), extracted with dichloromethane (45mL×3 times), and combined the organic phases. The organic phases were first washed with saturated brine (60mL×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6A-2：Compound 6A-2:
将化合物6A-1(3.4g,9.7mmol)和1A(3.7g,12.5mmol)溶于1,4-二氧六环(30mL)和水(6mL)中，向上述反应液中加入碳酸钾(2.7g,19.4mmol)和[1,1'-双(二苯基膦)二茂铁]二氯化钯二氯甲烷络合物(790mg,1.0mmol)。在氮气保护下，将反应体系加热至80℃并继续搅拌2小时。LCMS监控显示原料消失后，将反应液冷却至室温，减压浓缩，所得残余物用硅胶柱层析纯化(洗脱剂：乙酸乙酯/石油醚＝2/1)得到2.8g化合物6A-2。Compound 6A-1 (3.4g, 9.7mmol) and 1A (3.7g, 12.5mmol) were dissolved in 1,4-dioxane (30mL) and water (6mL), and potassium carbonate ( 2.7 g, 19.4 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (790 mg, 1.0 mmol). Under the protection of nitrogen, the reaction system was heated to 80°C and stirring was continued 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 obtained 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6A-3：Compound 6A-3:
将化合物6A-2(2.7g,6.8mmol)溶于N,N-二甲基甲酰胺(28mL)中。随后，向上述反应液中加入碳酸钾(1.9g，13.5mmol)。将反应体系加热至100℃并继续搅拌24小时。LCMS监控显示原料消失后，将反应液冷却至室温并加入水(50mL)淬灭。混合液用乙酸乙酯(60mL×4次)萃取，合并有机相，有机相先用饱和食盐水(50mL×3次)洗涤，然后用无水硫酸钠干燥，过滤，最后减压浓缩。所得残余物用硅胶柱层析纯化(洗脱剂：二氯甲烷/乙酸乙酯＝15/1)得到1.2g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 liquid. The reaction system was heated to 100°C and stirring was continued for 24 hours. After LCMS monitoring showed disappearance of starting material, 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 obtained 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6A-4：Compound 6A-4:
将化合物6A-3(1.2g,3.3mmol)溶于氯化氢的1,4-二氧六环溶液(4M,15mL)中。在30℃条件下搅拌6小时，LCMS监控显示原料消失后，将反应液浓缩，加入水(40mL)，用饱和碳酸氢钠水溶液调节其pH到9。混合液用氯仿/异丙醇＝3/1(50mL×3次)萃取，合并有机相，然后用无水硫酸钠干燥，过滤，最后减压浓缩。所得残余物用硅胶柱层析纯化(洗脱剂：二氯甲烷/甲醇＝30/1)得到842mg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 (4M, 15 mL). Stirring at 30° C. for 6 hours, LCMS monitoring showed that the starting material 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 obtained 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6A-5：Compound 6A-5:
将化合物6A-4(300mg，1.1mmol)和碳酸铯(1.07g，3.3mmol)溶于N,N-二甲基甲酰胺(6mL)中。随后，向上述反应液中加入碘代异丙烷(1.86g，10.9mmol)。将反应体系加热至80℃并继续搅拌16小时。LCMS监控显示原料消失后，将反应液冷却至室温并加入水(30mL)淬灭。混合液用乙酸乙酯(50mL×3次)萃取，合并有机相，有机相先用饱和食盐水(50mL×3次)洗涤，然后用无水硫酸钠干燥，过滤，最后减压浓缩。所得残余物用硅胶柱层析纯化(洗脱剂：二氯甲烷/甲醇＝10/1)得到75mg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 liquid. The reaction system was heated to 80°C and stirring was continued for 16 hours. After LCMS monitoring showed disappearance of the starting material, the reaction 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 obtained 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] + .
中间体6A：Intermediate 6A:
将化合物6A-5(75mg，0.2mmol)溶于乙醇(8mL)和水(1.6mL)中。随后，向上述反应液中加入氯化铵(50.7mg，0.9mmol)和还原铁粉(132.4mg，2.4mmol)。将反应体系加热至80℃并继续搅拌5小时。LCMS监控显示原料消失后，将反应液冷却至室温并减压浓缩。所得残余物用硅胶柱层析纯化(洗脱剂：二氯甲烷/甲醇＝10/1)得到48mg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 liquid. 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 obtained 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中间体35A的制备1.2 Preparation of intermediate 35A
Figure PCTCN2022125056-appb-000039
Figure PCTCN2022125056-appb-000039
化合物35A-1：Compound 35A-1:
将6-氨基喹喔啉(10g,68.89mmol)溶于浓硫酸(20mL)中。在0℃条件下，向反应液中分批加入硝酸钾(9.054g,89.55mmol)并在该温度下继续搅拌30分钟。LCMS监控显示原料消失后，将反应液倒入冰水(100g)中。用1M氢氧化钠水溶液调节其pH到8。混合液用乙酸乙酯(200mL×2次)萃取，合并有机相，有机相先用饱和食盐水(100mL×3次)洗涤，然后用无水硫酸钠干燥，过滤，减压浓缩。所得残余物用硅胶柱层析纯化(洗脱剂：二氯甲烷/甲醇＝10/1)得到2g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 portions to the reaction solution and stirring was continued at this temperature for 30 minutes. After LCMS monitoring showed that the starting material disappeared, the reaction solution was poured into ice water (100 g). Its pH was adjusted to 8 with 1M aqueous sodium hydroxide solution. The mixture was extracted with ethyl acetate (200 mL x 2 times), and the organic phases were combined. The organic phase was washed with saturated brine (100 mL x 3 times), then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained 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] + .
中间体35A：Intermediate 35A:
将化合物35A-1(2g,10.5mmol)溶于N,N-二甲基甲酰胺(20mL)中。将反应液降至0℃，氮气保护下，分批加入氢化钠(60wt,1.3g,31.5mmol)并继续搅拌20分钟。随后，向上述反应液中加入2,4-二氯-5-溴嘧啶(4.8g,21.0mmol)，将反应升至室温并继续搅拌1小时。LCMS监控显示原料消失后，将反应液降温至0℃并加入饱和氯化铵水溶液(80mL)淬灭。混合液用乙酸乙酯(100mL×3次)萃取，合并有机相，有机相先用饱和食盐水(80mL×3次)洗涤，然后用无水硫酸钠干燥，过滤，减压浓缩。所得残余物用硅胶柱层析纯化(洗脱剂：乙酸乙酯/石油醚＝1/2)得到2.7g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 nitrogen protection, sodium hydride (60wt, 1.3g, 31.5mmol) 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 warmed 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 obtained 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A1.3 Compound A
Figure PCTCN2022125056-appb-000040
Figure PCTCN2022125056-appb-000040
1.3.1化合物53A：1.3.1 Compound 53A:
将化合物6A(2.7g,9.43mmol)和35A(3.6g,9.43mmol)溶于N-甲基吡咯烷酮(30mL)中。随后，向上述反应液中加入甲烷磺酸(2.72g,28.28mmol)。将反应体系加热至95℃并继续搅拌3小时。LCMS监控显示原料消失后，将反应液冷却至室温并经反相C18柱纯化。纯化条件：色谱柱330g C18反相柱；流动相水(含0.1％甲酸)和乙腈；流速70mL/分钟；梯度在20分钟内，乙腈从10％升到50％；检测波长254nm。收集产品，减压浓缩，得到3.4g化合物53A。Compound 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 liquid. 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 330g C18 reverse phase column; mobile phase water (containing 0.1% formic acid) and acetonitrile; flow rate 70mL/min; gradient within 20 minutes, acetonitrile rises from 10% to 50%; detection wavelength 254nm. The collected products were concentrated under reduced pressure to obtain 3.4 g of compound 53A.
MS(ESI,m/z):631.2,633.2[M+H] +。 MS (ESI, m/z): 631.2, 633.2 [M+H] + .
1.3.2化合物53B:1.3.2 Compound 53B:
将化合物53A(3.4g,5.38mmol)溶于乙醇(40mL)和水(8mL)的混合溶剂中。随后，向上述反应液中加入铁粉(1.50g,26.92mmol)和氯化铵(0.86g,16.15mmol)并将反应体系加热至80℃并继续搅拌2小时。LCMS监控显示原料消失后，将反应液冷却至室温并减压浓缩。所得残余物用硅胶柱层析纯化(洗脱剂：二氯甲烷/甲醇＝10 /1)，得到2.8g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] + .
1.3.3化合物A:1.3.3 Compound A:
将化合物53B(5g,8.31mmol)溶于吡啶(50mL)中。随后向反应液中滴加甲基磺酰氯(1.9g,16.62mmol)。将反应体系升温至50℃并继续搅拌2小时。LCMS监控显示原料消失后，将反应液冷却至室温并减压浓缩。残余物溶于甲醇/四氢呋喃(1/1，50mL)的混合溶剂中，在0℃条件下，向反应液中加入氢氧化钠(2M，5mL)的水溶液。将反应体系升温至室温并继续搅拌1小时后，减压浓缩。所得残余物用硅胶柱层析纯化(洗脱剂：二氯甲烷/甲醇＝10/1)，粗产品经过二氯甲烷/甲醇(20/1，30mL)打浆后，用乙腈/水(50mL)冻干，得到3g化合物A。Compound 53B (5 g, 8.31 mmol) was dissolved in pyridine (50 mL). Methanesulfonyl chloride (1.9 g, 16.62 mmol) was then 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 (2M, 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), the crude product was slurried with dichloromethane/methanol (20/1, 30mL), and washed with acetonitrile/water (50mL) After lyophilization, 3 g of compound A was obtained.
MS(ESI,m/z):679.0,681.0[M+H] +。 MS (ESI, m/z): 679.0, 681.0 [M+H] + .
1H NMR(400MHz,DMSO-d 6)δ9.88(br s,1H),8.94(d,J＝2.0Hz,1H),8.85(d,J＝2.0Hz,1H),8.76(s,1H),8.67(br s,1H),8.35(s,1H),8.27(s,1H),7.73(s,1H),7.49(s,1H),7.38(s,1H),6.58(s,1H),3.99-3.91(m,1H),3.76(s,3H),3.71(s,3H),3.21(t,J＝5.6Hz,2H),3.00(s,3H),2.94(t,J＝5.6Hz,2H),1.29(d,J＝6.4Hz,6H)。 1 H NMR (400MHz,DMSO-d 6 )δ9.88(br s,1H),8.94(d,J=2.0Hz,1H),8.85(d,J=2.0Hz,1H),8.76(s,1H ),8.67(br s,1H),8.35(s,1H),8.27(s,1H),7.73(s,1H),7.49(s,1H),7.38(s,1H),6.58(s,1H ),3.99-3.91(m,1H),3.76(s,3H),3.71(s,3H),3.21(t,J＝5.6Hz,2H),3.00(s,3H),2.94(t,J＝ 5.6Hz, 2H), 1.29 (d, J = 6.4Hz, 6H).
1.4化合物I：1.4 Compound I:
将化合物A(67g,98.59mmol)溶于二氯甲烷(880mL)和甲醇(440mL)的混合溶剂中并在室温下继续搅拌1小时。随后在室温条件下，向反应液中滴加氯化氢的甲醇溶液(4M,24.65mL,98.59mmol)。该反应体系继续在室温搅拌4小时后，将反应液减压浓缩至70mL。向上述混合物中加入甲基叔丁基醚(880mL)并继续在室温搅拌2小时。析出的固体经过过滤，乙腈/水(500mL)冻干，得到60.2g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 stirring was continued at room temperature for 1 hour. Then, methanol solution of hydrogen chloride (4M, 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(300MHz,DMSO-d 6)δ9.97(s,1H),9.30-9.16(m,2H),8.99(s,1H),8.91(s,1H),8.43(s,2H),7.75-7.30(m,3H),6.57(s,1H),3.95-3.86(m,1H),3.79(s,3H),3.69(s,3H),3.28-3.14(m,2H),3.03(s,3H),2.98-2.88(m,2H),1.27(brs,6H)。 1 H NMR (300MHz,DMSO-d 6 )δ9.97(s,1H),9.30-9.16(m,2H),8.99(s,1H),8.91(s,1H),8.43(s,2H), 7.75-7.30(m,3H),6.57(s,1H),3.95-3.86(m,1H),3.79(s,3H),3.69(s,3H),3.28-3.14(m,2H),3.03( s, 3H), 2.98-2.88 (m, 2H), 1.27 (brs, 6H).
实施例2 生物学测试评价: Embodiment 2 Biological test evaluation:
(一)EGFR WT和EGFR L858R/T790M/C797S体外酶学实验(1) EGFR WT and EGFR L858R/T790M/C797S in vitro enzyme experiments
本实验采用荧光共振能量转移(TR-FRET)的方法测试化合物对EGFR WT(野生型EGFR)和EGFR L858R/T790M/C797S激酶活性的抑制作用，并得出化合物对EGFR激酶活性的半数抑制浓度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 IC of the compound on the kinase activity of EGFR was obtained. 50 .
1.实验材料1. Experimental materials
EGFR重组酶和EGFR L858R/T790M/C797S重组酶，购自Signalchem公司。EGFR recombinase and EGFR L858R/T790M/C797S recombinase were purchased from Signalchem.
HTRF KinEASE-TK kit试剂盒，购自Cisbio公司。HTRF KinEASE-TK kit was purchased from Cisbio.
DTT，MnCl 2，MgCl 2购自Sigma公司。 DTT, MnCl 2 , and MgCl 2 were purchased from Sigma.
ATP购自Promega公司。ATP was purchased from Promega.
Brigatinib购自Selleck公司。Brigatinib was purchased from Selleck Company.
2.实验方法2. Experimental method
1)准备1X工作液：5mM MgCl 2；1mM DTT；1mM MnCl 2和1×激酶缓冲液(试剂盒中)。 1) Prepare 1X working solution: 5mM MgCl 2 ; 1mM DTT; 1mM MnCl 2 and 1X kinase buffer (in the kit).
2)使用Echo 550(Labcyte)转移10nL梯度稀释的化合物到384孔实验板中。2) Use Echo 550 (Labcyte) to transfer 10 nL of serially diluted compounds to a 384-well assay plate.
3)加入5μL 2×EGFR WT或EGFR L858R/T790M/C797S重组酶溶液到384孔实验板中，室温孵育10分钟。3) Add 5 μL of 2×EGFR WT or EGFR L858R/T790M/C797S recombinase solution to the 384-well plate and incubate at room temperature for 10 minutes.
4)加入5μL 2×TK-substrate-biotin底物溶液(包含ATP)到384孔实验板中，室温孵育40分钟。4) Add 5 μL of 2×TK-substrate-biotin substrate solution (including ATP) to the 384-well plate and incubate at room temperature for 40 minutes.
5)加入5μL含有Sa-XL 665HTRF检测液，以及5μLTK-antibody-Cryptate，室温孵育1小时。5) Add 5 μL detection solution containing Sa-XL 665HTRF, and 5 μL TK-antibody-Cryptate, and incubate at room temperature for 1 hour.
6)Envision酶标仪(PerkinElmer)检测各孔的615nm和665nm荧光信号值。6) Envision microplate reader (PerkinElmer) detects the 615nm and 665nm fluorescence signal values of each well.
7)计算每孔荧光信号665nm/615nm的比值。7) Calculate the ratio of the fluorescence signal 665nm/615nm of each well.
8)使用GraphPad Prism软件进行数据分析，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三突变型EGFR的激酶活性抑制结果见表21。The kinase activity inhibition results of wild-type EGFR and L858R/T790M/C797S triple mutant EGFR are shown in Table 21.
从表21中我们可以看出，式(A)化合物对L858R/T790M/C797S三突变型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21 酶学抑制结果Table 21 Enzyme inhibition results
化合物compound EGFR(WT)IC 50(nM) EGFR(WT) IC 50 (nM) EGFR(L858R/T790M/C797S)IC 50(nM) EGFR(L858R/T790M/C797S) IC 50 (nM)
AA 0.710.71 0.310.31
(二)细胞增殖抑制实验(2) Cell Proliferation Inhibition Experiment
A431细胞增殖抑制实验A431 cell proliferation inhibition experiment
本实验采用CellTiter-Glo的方法测试化合物对A431细胞增殖的抑制作用，并得出化合物抑制细胞生长半数的浓度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.实验材料1. Experimental materials
A431细胞购自ATCC。A431 cells were purchased from ATCC.
DMEM培养基，胎牛血清(FBS)，Penicillin-Streptomycin购自GIBCO。DMEM medium, fetal bovine serum (FBS), and Penicillin-Streptomycin were purchased from GIBCO.
Brigatinib购自Selleck公司。Brigatinib was purchased from Selleck Company.
CellTiter-Glo试剂，购自Promega公司。CellTiter-Glo reagent was purchased from Promega Company.
2.实验方法2. Experimental method
1)按照每孔800个细胞的密度将A431细胞接种于384孔培养板，每孔30μl，置于细胞培养箱中培养24小时(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 placed in a cell culture incubator for 24 hours (37° C., 5% CO 2 ).
2)Day 0：使用Echo向培养板细胞中加入30nL梯度稀释的待测化合物，DMSO终浓度为0.1％，将培养板置于细胞培养箱中孵育72小时(37℃，5％CO 2)。空白对照加入每孔30nL的DMSO。 2) Day 0: Add 30 nL of the compound to be tested in a gradient dilution to the culture plate cells using Echo, the final concentration of DMSO is 0.1%, and place the culture plate in a cell culture incubator for 72 hours (37° C., 5% CO 2 ). For the blank control, 30 nL of DMSO was added to each well.
3)Day 3：每孔加入30μL Cell Titer-Glo试剂，室温避光30分钟。3) Day 3: Add 30 μL Cell Titer-Glo reagent to each well, and keep it in the dark for 30 minutes at room temperature.
4)Envision酶标仪(PerkinElmer)检测化学发光信号。4) Envision microplate reader (PerkinElmer) detects chemiluminescent signal.
5)使用GraphPad Prism软件进行数据分析，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/C797S细胞增殖抑制实验Ba/F3_L858R/T790M/C797S cell proliferation inhibition experiment
本实验采用CellTiter-Glo的方法测试化合物对Ba/F3_L858R/T790M/C797S细胞增殖的抑制作用，并得出化合物抑制细胞生长半数的浓度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.实验材料1. Experimental materials
Ba/F3_L858R/T790M/C797S细胞由康龙化成(北京)新药技术股份有限公司构建。Ba/F3_L858R/T790M/C797S cells were constructed by Pharmaron Chemicals (Beijing) New Pharmaceutical Technology Co., Ltd.
1640培养基，胎牛血清(FBS)，Penicillin-Streptomycin，GlutaMAX-I Supplement购自GIBCO。1640 medium, fetal bovine serum (FBS), Penicillin-Streptomycin, GlutaMAX-I Supplement were purchased from GIBCO.
Brigatinib购自Selleck公司。Brigatinib was purchased from Selleck Company.
CellTiter-Glo试剂，购自Promega公司。CellTiter-Glo reagent was purchased from Promega Company.
2.实验方法2. Experimental method
1)按照每孔700个细胞的密度将Ba/F3_L858R/T790M/C797S细胞接种于384孔培养板，每孔30μL。1) Inoculate 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向培养板细胞中加入30nL梯度稀释的待测化物，DMSO终浓度为0.1％，将培养板置于细胞培养箱中孵育72小时(37℃，5％CO 2)。空白对照加入每孔30nL的DMSO。 2) Day 0: Add 30 nL of the compound to be tested in a gradient dilution to the culture plate cells using Echo, the final concentration of DMSO is 0.1%, and place the culture plate in a cell culture incubator for 72 hours (37° C., 5% CO 2 ). For the blank control, 30 nL of DMSO was added to each well.
3)Day 3：每孔加入30μL Cell Titer-Glo试剂，室温避光30分钟。3) Day 3: Add 30 μL Cell Titer-Glo reagent to each well, and keep it in the dark for 30 minutes at room temperature.
4)Envision酶标仪(PerkinElmer)检测化学发光信号。4) Envision microplate reader (PerkinElmer) detects chemiluminescent signal.
5)使用GraphPad Prism软件进行数据分析，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/C797S细胞增殖抑制实验Ba/F3_Del19/T790M/C797S cell proliferation inhibition experiment
本实验采用CellTiter-Glo的方法测试化合物对Ba/F3_Del19/T790M/C797S细胞增殖的抑制作用，并得出化合物抑制细胞生长半数的浓度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.实验材料1. Experimental materials
Ba/F3_Del19/T790M/C797S购自康源博创生物科技(北京)有限公司。Ba/F3_Del19/T790M/C797S was purchased from Kangyuan Bochuang Biotechnology (Beijing) Co., Ltd.
1640培养基，胎牛血清(FBS)，Penicillin-Streptomycin，GlutaMAX-I Supplement购自GIBCO。1640 medium, fetal bovine serum (FBS), Penicillin-Streptomycin, GlutaMAX-I Supplement were purchased from GIBCO.
Brigatinib购自Selleck公司。Brigatinib was purchased from Selleck Company.
CellTiter-Glo试剂，购自Promega公司。CellTiter-Glo reagent was purchased from Promega Company.
2.实验方法2. Experimental method
1)按照每孔700个细胞的密度将Ba/F3_Del19/T790M/C797S细胞接种于384孔培养板，每孔30μL。1) Inoculate 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向培养板细胞中加入30nL梯度稀释的待测化合物，DMSO终浓度为0.1％，将培养板置于细胞培养箱中孵育72小时(37℃，5％CO 2)。空白对照加入每孔30nL的DMSO。 2) Day 0: Add 30 nL of the compound to be tested in a gradient dilution to the culture plate cells using Echo, the final concentration of DMSO is 0.1%, and place the culture plate in a cell culture incubator for 72 hours (37° C., 5% CO 2 ). For the blank control, 30 nL of DMSO was added to each well.
3)Day 3：每孔加入30μL Cell Titer-Glo试剂，室温避光30分钟。3) Day 3: Add 30 μL Cell Titer-Glo reagent to each well, and keep it in the dark for 30 minutes at room temperature.
4)Envision酶标仪(PerkinElmer)检测化学发光信号。4) Envision microplate reader (PerkinElmer) detects chemiluminescent signal.
使用GraphPad Prism 6软件进行数据分析，得出化合物的IC 50。 Data analysis was performed using GraphPad Prism 6 software to obtain the IC 50 of the compound.
细胞活性抑制结果见表22。The cell activity inhibition results are shown in Table 22.
从表22中的实验结果可以看出，化合物A对Ba/F3Del19/T790M/C797S EGFR三突变细胞系和Ba/F3  L858R/T790M/C797S EGFR三突变细胞系的细胞增殖有较好的抑制作用；对EGFR野生型(EGFR WT)细胞系A431的抑制作用较弱。这表明化合物A具有较好的细胞活性以及选择性。As can be seen from the experimental results in Table 22, Compound A has a better inhibitory effect on the cell proliferation of the Ba/F3Del19/T790M/C797S EGFR triple mutant cell line and the Ba/F3 L858R/T790M/C797S EGFR triple mutant cell line; The inhibitory effect on the EGFR wild-type (EGFR WT) cell line A431 is weak. This indicates that Compound A has better cell activity and selectivity.
表22 细胞增殖抑制试验数据结果Table 22 Cell Proliferation Inhibition Test Data Results
Figure PCTCN2022125056-appb-000041
Figure PCTCN2022125056-appb-000041
(三)体内药效研究实验(3) In vivo drug efficacy research experiment
1.实验目的1. Purpose of the experiment
评价化合物A连续21天口服给药，对PC9(Del19/T790M/C797S)的抗肿瘤活性及毒副作用。The antitumor activity and toxic side effects of compound A on PC9 (Del19/T790M/C797S) were evaluated by oral administration for 21 consecutive days.
2.实验材料2. Experimental materials
BALB/c-nu小鼠，雌性，SPF级，购自北京维通利华实验动物技术有限公司。BALB/c-nu mice, female, SPF grade, were purchased from Beijing Weitong Lihua Experimental Animal Technology Co., Ltd.
PC9(Del19/T790M/C797S)细胞，齐鲁制药有限公司自行构建。PC9 (Del19/T790M/C797S) cells were constructed by Qilu Pharmaceutical Co., Ltd.
3.实验步骤3. Experimental steps
3.1细胞培养3.1 Cell culture
PC9(Del19/T790M/C797S)用含有10％FBS的RPMI 1640培养基，在37℃，5％二氧化碳培养箱中培养；收集指数生长期的细胞进行接种。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.
3.2细胞接种3.2 Cell inoculation
在无菌条件下，取体外培养的PC9(Del19/T790M/C797S)细胞悬液，离心后调整细胞浓度至3×10 7个/mL，接种于小鼠右侧腋窝皮下(0.1mL/只)，接种当天设为第0天。 Under sterile conditions, take the PC9 (Del19/T790M/C797S) cell suspension cultured in vitro, adjust the cell concentration to 3× 107 cells/mL after centrifugation, and inoculate it subcutaneously in the right armpit of mice (0.1 mL/mouse) , and the day of inoculation was set as day 0.
3.3肿瘤分组、给药及测量3.3 Tumor grouping, drug administration and measurement
a.当平均肿瘤体积约150mm 3时，挑选35只肿瘤体积适中小鼠入组，按照肿瘤体积大小随机分为5组：G1：溶媒对照组、G2：化合物A(15mg/kg)、G3：化合物A(60mg/kg)，7只/组。 a. When the average tumor volume is 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.动物分组后开始给药，给药体积均为10mL/kg，口服给药(po)；每天称重给药1次，连续给药21天；每周测量瘤径2次。b. After the animals were grouped, the drug was administered, 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.肿瘤体积(Tumor volume,TV)：每周测量2次肿瘤体积，以观察瘤块体积变化和生长速度。肿瘤体积V＝1/2×a×b 2，其中a、b分别表示肿瘤长径和短径。化合物对肿瘤组织的生长抑制作用采用肿瘤生长抑制率TGI(％)评价。TGI(％)＝[1-(某给药组的平均肿瘤体积-该给药组分组当天的平均肿瘤体积)/(阴性对照组的平均肿瘤体积-阴性对照组分组当天的平均肿瘤体积)]×100％。给药组和阴性对照组取同一天数据。 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-(the average tumor volume of a certain administration group-the average tumor volume of the administration group grouping day)/(the average tumor volume of the negative control group-the average tumor volume of the negative control group grouping day)] ×100%. The data of the administration group and the negative control group were collected on the same day.
d.在试验过程中密切观察小鼠生活状态，包括外观体征、一般行为活动、精神状态、摄食情况、呼吸状态、粪便和尿液性状、注射局部及其它毒性表现。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.试验达到终点后，将小鼠实施安乐死，动物尸体冻存至冰柜，移交至有资质的医疗废弃物处理单位进行处置。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.
4实验结果4 Experimental results
实验结果见表23以及图16和图17。The experimental results are shown in Table 23 and Figures 16 and 17.
表23 体内药效试验结果Table 23 In vivo efficacy test results
Figure PCTCN2022125056-appb-000042
Figure PCTCN2022125056-appb-000042
a，平均值±标准误；a, mean ± standard error;
b，P值肿瘤体积进行统计分析，与G1组比较，*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.
5实验结论5 Experimental conclusions
从上数结果可以看出，化合物A能显著抑制肿瘤生长(图16)，呈明显的量效关系，且小鼠耐受性良好(图17)。From the above results, it can be seen that Compound A can significantly inhibit tumor growth (Figure 16), showing an obvious dose-effect relationship, and the mice are well tolerated (Figure 17).
实施例3 晶型I的制备:The preparation of embodiment 3 crystal form I:
方法1：method 1:
称取约20mg化合物A于4mL样品瓶内，加入1mL乙腈，室温条件下搅拌3天，过滤并收集固体，在室温条件下晾干。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.
将所得固体，进行XRPD、TGA-DSC测试表征，该固体为晶型I。The obtained solid was characterized by XRPD and TGA-DSC tests, and the solid was crystal form I.
XRPD谱图如图1所示。The XRPD spectrum is shown in FIG. 1 .
TGA-DSC谱图如图18所示。The TGA-DSC spectrum is shown in Figure 18.
方法2：Method 2:
称取约20mg化合物A于4mL样品瓶内，加入1mL水，50℃搅拌1天，过滤并收集固体，在室温条件下晾干。所得固体，其XRPD谱图基本如图1所示。Weigh about 20mg of Compound A into a 4mL sample bottle, add 1mL 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 .
实施例4 晶型II的制备:The preparation of embodiment 4 crystal form II:
方法1：method 1:
在50℃下，向10mg化合物A中加入1.0mL四氢呋喃(THF)，搅拌5分钟后过滤收集滤液。室温下，将4.0mL甲基叔丁基醚逐渐加入药液中，并搅拌16小时后过滤，收集固体并在室温晾干。At 50°C, 1.0 mL of tetrahydrofuran (THF) was added to 10 mg of compound A, stirred for 5 minutes, 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, filtered, and the solid was collected and dried at room temperature.
将所得固体，进行XRPD、TGA-DSC测试表征，该固体为晶型II。The obtained solid was characterized by XRPD and TGA-DSC tests, and the solid was crystal form II.
XRPD谱图如图2所示。The XRPD spectrum is shown in FIG. 2 .
TGA-DSC谱图如图19所示。The TGA-DSC spectrum is shown in Figure 19.
方法2：Method 2:
将约10mg晶型I在50℃溶于0.4mL二甲基亚砜(DMSO)中。然后，在室温下将药液滴加到1mL甲基叔丁基醚中。析出固体后，混悬液在室温条件下搅拌两小时，然后过滤，收集固体，并在室温晾干。所得固体，其XRPD谱图基本如图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:
称取240mg化合物A至样品瓶中，加入3mL丙酮并在50℃搅拌过夜。过滤收集固体，于50℃真空干燥。所得固体，其XRPD谱图基本如图2所示。Weigh 240mg of Compound A into a sample bottle, add 3mL 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 .
实施例5 晶型III的制备：The preparation of embodiment 5 crystal form III:
在50℃下，将20mg化合物A溶于0.5mL二甲基亚砜(DMSO)，室温下，将2.0mL乙醇逐渐加入药液中，并搅拌16小时后过滤，收集固体并在50℃真空干燥。At 50°C, 20 mg of Compound A was dissolved in 0.5 mL of dimethyl sulfoxide (DMSO). At room temperature, 2.0 mL of ethanol was gradually added to the solution, stirred for 16 hours, filtered, and the solid was collected and dried in vacuo at 50°C. .
将所得固体，进行XRPD、TGA-DSC测试表征，该固体为晶型III。The obtained solid was characterized by XRPD and TGA-DSC tests, and the solid was crystal form III.
XRPD谱图如图3所示。The XRPD spectrum is shown in FIG. 3 .
TGA-DSC谱图如图20所示。The TGA-DSC spectrum is shown in Figure 20.
实施例6 晶型IV的制备:The preparation of embodiment 6 crystal form IV:
称取适量化合物A至样品瓶中，加入甲苯配制成20mg/mL的混悬液。这些混悬液随后在室温条件下搅拌3天。过滤并收集固体，在室温条件下晾干。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.
将所得固体，进行XRPD、TGA-DSC测试表征，该固体为晶型IV。The obtained solid was characterized by XRPD and TGA-DSC tests, and the solid was crystal form IV.
XRPD谱图如图4所示。The XRPD spectrum is shown in FIG. 4 .
TGA-DSC谱图如图21所示。The TGA-DSC spectrum is shown in Figure 21.
实施例7 晶型V的制备:The preparation of embodiment 7 crystal form V:
在50℃下，将20mg化合物A溶于0.5mL二甲基亚砜(DMSO)，室温下，将1.0mL水逐渐加入药液中，并搅拌16小时后过滤，收集固体并在50℃真空干燥。At 50°C, 20 mg of Compound A was dissolved in 0.5 mL of dimethyl sulfoxide (DMSO). At room temperature, 1.0 mL of water was gradually added to the drug solution, stirred for 16 hours, filtered, and the solid was collected and dried under vacuum at 50°C. .
将所得固体，进行XRPD、TGA-DSC测试表征，该固体为晶型V。The obtained solid was characterized by XRPD and TGA-DSC tests, and the solid was Form V.
XRPD谱图如图5所示。The XRPD spectrum is shown in FIG. 5 .
TGA-DSC谱图如图22所示。The TGA-DSC spectrum is shown in Figure 22.
实施例8 晶型VI的制备: Embodiment 8 The preparation of crystal form VI:
在50℃下，称取20mg化合物A至样品瓶中，然后在50℃条件下缓慢加入1mL四氢呋喃，得到几乎澄清的药液，随后过滤并收集滤液。将滤液在搅拌的条件下冷却至室温，并持续搅拌16小时，直到固体析出。过滤并收集固体，在室温条件下晾干。At 50°C, weigh 20 mg of compound A into a sample vial, then slowly add 1 mL of tetrahydrofuran at 50°C to obtain an almost clear drug solution, then filter and collect the filtrate. 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.
将所得固体，进行XRPD、TGA-DSC测试表征，该固体为晶型VI。The obtained solid was characterized by XRPD and TGA-DSC tests, and the solid was crystal form VI.
XRPD谱图如图6所示。The XRPD spectrum is shown in FIG. 6 .
TGA-DSC谱图如图23所示。The TGA-DSC spectrum is shown in Figure 23.
实施例9 晶型VII的制备:The preparation of embodiment 9 crystal form VII:
称取适量化合物A至样品瓶中，加入二氯甲烷配制成20mg/mL的混悬液。这些混悬液随后在室温条件下搅拌3天。过滤并收集固体，在室温条件下晾干1小时。Weigh an appropriate amount of Compound A into a sample vial, and 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.
将所得固体，进行XRPD、TGA-DSC测试表征，该固体为晶型VII。The obtained solid was characterized by XRPD and TGA-DSC tests, and the solid was crystal form VII.
XRPD谱图如图7所示。The XRPD spectrum is shown in FIG. 7 .
TGA-DSC谱图如图24所示。The TGA-DSC spectrum is shown in Figure 24.
实施例10 晶型VIII的制备：Example 10 Preparation of Form VIII:
称取适量化合物A至样品瓶中，加入异丙醇配制成20mg/mL的混悬液。这些混悬液随后在室温条件下搅拌3天。过滤并收集固体，在室温条件下晾干。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.
将所得固体，进行XRPD、TGA-DSC测试表征，该固体为晶型VIII。The obtained solid was characterized by XRPD and TGA-DSC tests, and the solid was crystal form VIII.
XRPD谱图如图8所示。The XRPD spectrum is shown in FIG. 8 .
TGA-DSC谱图如图25所示。The TGA-DSC spectrum is shown in Figure 25.
实施例11 晶型IX的制备：Example 11 Preparation of Form IX:
称取适量化合物A至样品瓶中，加入异丁醇配制成20mg/mL的混悬液。这些混悬液随后在室温条件下搅拌3天。过滤并收集固体，在室温条件下晾干。Weigh an appropriate amount of Compound A into a sample bottle, 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.
将所得固体，进行XRPD、TGA-DSC测试表征，该固体为晶型IX。The obtained solid was characterized by XRPD and TGA-DSC tests, and the solid was crystal form IX.
XRPD谱图如图9所示。The XRPD spectrum is shown in FIG. 9 .
TGA-DSC谱图如图26所示。The TGA-DSC spectrum is shown in Figure 26.
实施例12 晶型XII的制备:Example 12 Preparation of Form XII:
称取适量化合物A至样品瓶中，加入甲醇/水(1:1)配制成10mg/mL的混悬液。这些混悬液随后在室温条件下搅拌3天。过滤并收集固体，在室温条件下晾干。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.
将所得固体，进行XRPD、TGA-DSC测试表征，该固体为晶型XII。The obtained solid was characterized by XRPD and TGA-DSC tests, and the solid was crystal form XII.
XRPD谱图如图10所示。The XRPD spectrum is shown in FIG. 10 .
TGA-DSC谱图如图27所示。The TGA-DSC spectrum is shown in Figure 27.
实施例13 晶型XIV的制备:Example 13 Preparation of Form XIV:
在50℃下，称取20mg样品至样品瓶中，然后在50℃条件下缓慢加入甲醇/1,4-二氧六环(体积比2/1.5)3.5mL，得到几乎澄清的药液，随后过滤并收集滤液。将滤液在搅拌的条件下冷却至室温，并持续搅拌16–56小时，直到固体析出。过滤并收集固体，在室温条件下晾干。At 50°C, weigh 20mg of the sample into a sample bottle, then slowly add 3.5mL of methanol/1,4-dioxane (volume ratio 2/1.5) at 50°C to obtain an almost clear drug solution, and then Filter and collect the filtrate. The filtrate was cooled to room temperature with stirring, and stirring was continued for 16-56 hours until a solid precipitated. The solid was collected by filtration and allowed to dry at room temperature.
将所得固体，进行XRPD、TGA-DSC测试表征，该固体为晶型XIV。The obtained solid was characterized by XRPD and TGA-DSC tests, and the solid was crystal form XIV.
XRPD谱图如图11所示。The XRPD spectrum is shown in FIG. 11 .
TGA-DSC谱图如图28所示。The TGA-DSC spectrum is shown in Figure 28.
实施例14 晶型A的制备：Example 14 Preparation of Form A:
25mg化合物A在室温下加入到2ml乙醇中，然后加入1当量的12M盐酸搅拌1天，固体样品过滤收集，真空干燥。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.
将所得固体，进行XRPD、TGA-DSC测试表征，该固体为晶型A。The obtained solid was characterized by XRPD and TGA-DSC tests, and the solid was Form A.
XRPD谱图如图12所示。The XRPD spectrum is shown in FIG. 12 .
TGA-DSC谱图如图29所示。The TGA-DSC spectrum is shown in Figure 29.
实施例15 晶型B的制备:The preparation of embodiment 15 crystal form B:
25mg的化合物A在室温下加入到2ml丙酮/水(100/1)中，然后加入1当量的12M盐酸搅拌1天，固体样品过滤收集，真空干燥。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.
将所得固体，进行XRPD、TGA-DSC测试表征，该固体为晶型B。The obtained solid was characterized by XRPD and TGA-DSC tests, and the solid was crystal form B.
XRPD谱图如图13所示。The XRPD spectrum is shown in FIG. 13 .
TGA-DSC谱图如图30所示。The TGA-DSC spectrum is shown in Figure 30.
实施例16 晶型C的制备：Example 16 Preparation of Form C:
称取19.67mg式(I)化合物于8mL样品瓶中，加入1mL异丙醇，置于50℃条件下搅拌1天并过滤，在50℃下真空干燥。Weigh 19.67 mg of the compound of formula (I) into an 8 mL sample bottle, add 1 mL of isopropanol, stir at 50°C for 1 day, filter, and dry under vacuum at 50°C.
将所得固体，进行XRPD、TGA-DSC测试表征，该固体为晶型C。The obtained solid was characterized by XRPD and TGA-DSC tests, and the solid was Form C.
XRPD谱图如图14所示。The XRPD spectrum is shown in FIG. 14 .
TGA-DSC谱图如图31所示。The TGA-DSC spectrum is shown in Figure 31.
实施例17 晶型D的制备：Example 17 Preparation of Form D:
方法1：method 1:
称取97.75mg式(I)化合物于20mL样品瓶中，加入6mL丙酮，置于50℃条件下搅拌过夜并过滤，在50℃下真空干燥4-5小时。Weigh 97.75mg of the compound of formula (I) into a 20mL sample bottle, add 6mL of acetone, stir overnight at 50°C and filter, then vacuum dry at 50°C for 4-5 hours.
1H NMR(400MHz,DMSO-d 6)δ9.97(s,1H),9.28-9.12(m,2H),8.98(s,1H),8.91(s,1H),8.55-8.44(m,1H),8.38(s, 1H),7.75-7.32(m,3H),6.57(s,1H),4.11-3.96(m,1H),3.78(s,3H),3.69(s,3H),3.25-3.13(m,2H),3.03(s,3H),2.97-2.87(m,2H),1.28(brs,6H) 1 H NMR (400MHz,DMSO-d 6 )δ9.97(s,1H),9.28-9.12(m,2H),8.98(s,1H),8.91(s,1H),8.55-8.44(m,1H ),8.38(s, 1H),7.75-7.32(m,3H),6.57(s,1H),4.11-3.96(m,1H),3.78(s,3H),3.69(s,3H),3.25- 3.13(m,2H),3.03(s,3H),2.97-2.87(m,2H),1.28(brs,6H)
精密称取式(I)化合物晶型D两份约25mg样品至25mL容量瓶中，加溶剂溶解稀释定溶，通过氯离子色谱进行氯离子含量的检测，结果如表24所示，通过公式换算，得知化合物(I)晶型D中，式A化合物与氯化氢的摩尔比约为1:1。Precisely weigh two samples of about 25mg of the compound crystal form D of formula (I) into a 25mL volumetric flask, add a solvent to dissolve, dilute and fix the solution, and detect the chloride ion content by chloride ion chromatography. The results are shown in Table 24, and converted by 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24 氯离子含量测试结果Table 24 Chloride ion content test results
Figure PCTCN2022125056-appb-000043
Figure PCTCN2022125056-appb-000043
将所得固体，进行XRPD、TGA-DSC测试表征，该固体为晶型D。The obtained solid was characterized by XRPD and TGA-DSC tests, and the solid was crystal form D.
XRPD谱图如图15所示。The XRPD spectrum is shown in FIG. 15 .
TGA-DSC谱图如图32所示。The TGA-DSC spectrum is shown in Figure 32.
方法2：Method 2:
将25mg式(I)化合物加入到0.3mL二氯甲烷/甲醇(1/1，v/v)中，在室温条件下配制成饱和药液，然后将2.7mL丙酮逐渐加入到药液中直至固体析出。混悬液在室温条件下搅拌4-5小时。收集固体并在50℃条件下真空干燥，所得固体，其XRPD谱图基本如图15所示。Add 25mg of the compound of formula (I) into 0.3mL of dichloromethane/methanol (1/1, v/v), prepare a saturated solution at room temperature, then gradually add 2.7mL of acetone into the solution until solid Precipitate. 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 shown in FIG. 15 .
实施例18 引湿性实验: Embodiment 18 Humidity test:
参照中国药典中的《药物引湿性试验指导原则》，测试晶型I、II、III、D的水分吸附/脱附数据。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.
图33为晶型I的DVS曲线，图34为晶型I DVS测试前后的XRPD谱图。DVS结果表明，晶型I在80％RH时吸湿增重0.59％，在90％RH时吸湿增重0.77％，说明该晶型略有引湿性，测试DVS实验后剩余固体的XRPD，晶型未发生改变。Figure 33 is the DVS curve of Form I, and Figure 34 is the XRPD spectrum of Form I before and after DVS testing. The 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. After the XRPD test of the remaining solid after the DVS experiment, the crystal form did not changes happened.
图35为晶型II的DVS曲线，图36为晶型II DVS测试前后的XRPD谱图。DVS结果表明，DVS结果显示，显示晶型II几乎不吸湿，在80％和90％RH条件下，其吸湿增重分别为0.19％和0.24％；测试DVS实验后剩余固体的XRPD，晶型未发生改变。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 its moisture absorption weight gain was 0.19% and 0.24% under the conditions of 80% and 90% RH; changes happened.
图37为晶型III的DVS曲线，图38为晶型III DVS测试前后的XRPD谱图。DVS结果表明，晶型III具有轻微吸湿性，在80％和90％RH条件下，样品的吸湿增重量分别为0.8％和1.0％；测试DVS实验后剩余固体的XRPD，晶型未发生改变。Figure 37 is the DVS curve of Form III, and Figure 38 is the XRPD spectrum before and after DVS testing of Form III. The DVS results showed that the crystal form III was slightly hygroscopic. Under the conditions of 80% and 90% RH, the hygroscopic weight gain of the sample was 0.8% and 1.0%, respectively; the XRPD of the remaining solid after the DVS experiment showed that the crystal form did not change.
图39为晶型D的DVS曲线，图40为晶型D DVS测试前后的XRPD谱图。DVS结果表明，晶型D具有轻微吸湿性，在80％RH和90％RH时吸湿增重量分别为0.59％和0.76％，DVS测试后，剩余固体的晶型未发生改变。Figure 39 is the DVS curve of Form D, and Figure 40 is the XRPD spectra of Form D before and after DVS testing. The DVS results showed that the crystal form D was slightly hygroscopic, and the weight gain by moisture absorption was 0.59% and 0.76% at 80% RH and 90% RH, respectively. After the DVS test, the crystal form of the remaining solid did not change.
实施例19 晶型I-III的热、湿稳定性实验：Example 19 Heat and moisture stability experiments of crystal form I-III:
参照中国药典中的《原料药物与制剂稳定性试验指导原则》，考察晶型I、II和III在不同温度以及湿度下的稳定性。在第0、5天和10天使用HPLC测试纯度，XRPD测试晶型。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 days 0, 5 and 10.
实验结果如表25所示，晶型I、II和III在高温、高湿条件下略有降解，但纯度总体变化不大，尤其是晶型II，在高温、高湿的环境下基本保持稳定。三种晶型在实验前后，晶型均未发生转变。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25 晶型I、II和III的热、湿稳定性Table 25 Thermal and moisture stability of Form I, II and III
Figure PCTCN2022125056-appb-000044
Figure PCTCN2022125056-appb-000044
Figure PCTCN2022125056-appb-000045
Figure PCTCN2022125056-appb-000045
实施例20 晶型D的稳定性实验: Embodiment 20 Stability experiment of crystal form D:
参照中国药典中的《原料药物与制剂稳定性试验指导原则》，考察晶型D在高温、高湿、光照条件下的稳定性。在第0、5天和10天使用HPLC测试纯度，XRPD测试晶型。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 days 0, 5 and 10.
实验结果如表26所示，晶型D在高温、高湿条件基本保持稳定，光照条件下略有降解，且IC结果表明，在60℃、25℃/92.5％RH以及光照条件下盐酸盐晶型VIII没有发生解离(表27)，仍为单盐酸盐。在实验前后，晶型D均未发生转变(图42)。The experimental results are shown in Table 26. The 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 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26 晶型D的稳定性实验结果Table 26 Stability test results of Form D
Figure PCTCN2022125056-appb-000046
Figure PCTCN2022125056-appb-000046
表27 晶型D稳定性实验后离子色谱结果Table 27 Ion chromatogram results after the crystal form D stability test
Figure PCTCN2022125056-appb-000047
Figure PCTCN2022125056-appb-000047
实施例21 压力实验: Embodiment 21 pressure test:
取约100mg晶型II放置于单冲压片机中，手动压实样品成型、不松散，压制成60mm的药片，然后轻轻碾碎成粉末状，剩余固体的XRPD图谱未发生改变(图41)，说明晶型II具有良好的抗压性。Take about 100 mg of Form II and place it in a single-punch tablet press, manually compact the sample to form it without loosening, press it into a 60mm tablet, and then gently crush it into a powder, the XRPD pattern of the remaining solid remains unchanged (Figure 41) , indicating that Form II has good compression resistance.

Claims (29)

  1. 式(A)化合物N-(6-((5-溴-2-((6-异丙基-8-甲氧基-3-甲基-3,4,5,6-四氢苯并[b]吡唑并[4,3-d]氮杂-9-基)氨基)-嘧啶-4-基)氨基)-喹喔啉-5-基)甲磺酰胺的晶型I，Formula (A) compound N-(6-((5-bromo-2-((6-isopropyl-8-methoxy-3-methyl-3,4,5,6-tetrahydrobenzo[ b] crystal form I of pyrazolo[4,3-d]azepin-9-yl)amino)-pyrimidin-4-yl)amino)-quinoxalin-5-yl)methanesulfonamide,
    Figure PCTCN2022125056-appb-100001
    Figure PCTCN2022125056-appb-100001
    其特征在于，所述晶型I的X-射线粉末衍射图谱在2θ值为7.83、13.85、18.25、20.22、24.37处有特征峰，2θ误差范围为±0.2°。It is characterized in that 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°.
  2. 如权利要求1所述的晶型I，其特征在于，所述的晶型I的X-射线粉末衍射图谱在2θ值为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处有特征峰，2θ误差范围为±0.2°。The crystal form I according to claim 1, wherein the X-ray powder diffraction pattern of the 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, There are characteristic peaks at 20.22, 20.64, 21.82, 22.92, 24.37, and 26.48, and the 2θ error range is ±0.2°.
  3. 如权利要求1所述的晶型I，其特征在于，所述晶型I的X-射线粉末衍射图谱在2θ值为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处有特征峰，2θ误差范围为±0.2°；The crystal form I according to claim 1, wherein the X-ray powder diffraction pattern of the 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° ;
    优选地，所述晶型I的X-射线粉末衍射图谱如图1所示。Preferably, the X-ray powder diffraction pattern of the crystal form I is shown in FIG. 1 .
  4. 式(A)化合物N-(6-((5-溴-2-((6-异丙基-8-甲氧基-3-甲基-3,4,5,6-四氢苯并[b]吡唑并[4,3-d]氮杂-9-基)氨基)-嘧啶-4-基)氨基)-喹喔啉-5-基)甲磺酰胺的晶型II，其特征在于，所述晶型II的X-射线粉末衍射图谱在2θ值为5.84、9.92、12.33、15.90、22.89、25.67处有特征峰，2θ误差范围为±0.2°。Formula (A) compound N-(6-((5-bromo-2-((6-isopropyl-8-methoxy-3-methyl-3,4,5,6-tetrahydrobenzo[ b] crystal form II of pyrazolo[4,3-d]azepin-9-yl)amino)-pyrimidin-4-yl)amino)-quinoxalin-5-yl)methanesulfonamide, characterized in that , 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°.
  5. 如权利要求4所述的晶型II，其特征在于，所述晶型II的X-射线粉末衍射图谱在2θ值为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处有特征峰，2θ误差范围为±0.2°。The crystal form II according to claim 4, wherein the X-ray powder diffraction pattern of the 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°.
  6. 如权利要求4所述的晶型II，其特征在于，所述晶型II的X-射线粉末衍射图谱在2θ值为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处有特征峰，2θ误差范围为±0.2°；The crystal form II according to claim 4, wherein the X-ray powder diffraction pattern of the 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° ;
    优选地，所述晶型II的X-射线粉末衍射图谱如图2所示。Preferably, the X-ray powder diffraction pattern of the crystal form II is shown in FIG. 2 .
  7. 式(A)化合物N-(6-((5-溴-2-((6-异丙基-8-甲氧基-3-甲基-3,4,5,6-四氢苯并[b]吡唑并[4,3-d]氮杂-9-基)氨基)-嘧啶-4-基)氨基)-喹喔啉-5-基)甲磺酰胺的晶型III，其特征在于，所述晶型III的X-射线粉末衍射图谱在2θ值为5.49、11.05、21.77、22.30、24.36处有特征峰，2θ误差范围为±0.2°。Formula (A) compound N-(6-((5-bromo-2-((6-isopropyl-8-methoxy-3-methyl-3,4,5,6-tetrahydrobenzo[ b] crystal form III of pyrazolo[4,3-d]azepin-9-yl)amino)-pyrimidin-4-yl)amino)-quinoxalin-5-yl)methanesulfonamide, characterized in that , 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°.
  8. 如权利要求7所述的晶型III，其特征在于，所述晶型III的X-射线粉末衍射图谱在2θ值为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处有特征峰，2θ误差范围为±0.2°。The crystal form III according to claim 7, wherein the X-ray powder diffraction pattern of the 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°.
  9. 如权利要求7所述的晶型III，其特征在于，所述晶型III的X-射线粉末衍射图谱在2θ值为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处有特征峰，2θ误差范围为±0.2；The crystal form III according to claim 7, wherein the X-ray powder diffraction pattern of the 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;
    优选地，所述晶型III的X-射线粉末衍射图谱如图3所示。Preferably, the X-ray powder diffraction pattern of the crystal form III is shown in FIG. 3 .
  10. 式(A)化合物N-(6-((5-溴-2-((6-异丙基-8-甲氧基-3-甲基-3,4,5,6-四氢苯并[b]吡唑并[4,3-d]氮杂-9-基)氨基)-嘧啶-4-基)氨基)-喹喔啉-5-基)甲磺酰胺的晶型IV，其特征在于，所述晶型IV的X-射线粉末衍射图谱在2θ值为5.68、10.42、21.64、22.20、24.55处有特征峰，2θ误差范围为±0.2°；Formula (A) compound N-(6-((5-bromo-2-((6-isopropyl-8-methoxy-3-methyl-3,4,5,6-tetrahydrobenzo[ b] crystal form IV of pyrazolo[4,3-d]azepin-9-yl)amino)-pyrimidin-4-yl)amino)-quinoxalin-5-yl)methanesulfonamide, characterized in that , the X-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°;
    优选地，所述晶型IV的X-射线粉末衍射图谱在2θ值为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处有特征峰，2θ误差范围为±0.2°；Preferably, the X-ray powder diffraction pattern of the 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, 22.20, 24.55, 26.85 , There is a characteristic peak at 27.14, and the 2θ error range is ±0.2°;
    优选地，所述晶型IV的X-射线粉末衍射图谱在2θ值为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处有特征峰，2θ误差范围为±0.2°；Preferably, the X-ray powder diffraction pattern of the crystal form IV has 2θ values of 5.68, 8.33, 9.17, 10.42, 10.72, 11.52, 12.23, 13.05, 13.84, 16.34, 16.79, 17.22, 17.69, 17.95, 18.92, 19.56 , 20.16, 21.27, 21.64, 22.20, 23.00, 23.36, 23.80, 24.55, 25.55, 25.99, 26.85, 27.14, 28.01 have characteristic peaks, and the 2θ error range is ±0.2°;
    优选地，所述晶型IV的X-射线粉末衍射图谱如图4所示。Preferably, the X-ray powder diffraction pattern of the crystal form IV is shown in FIG. 4 .
  11. 式(A)化合物N-(6-((5-溴-2-((6-异丙基-8-甲氧基-3-甲基-3,4,5,6-四氢苯并[b]吡唑并[4,3-d]氮杂-9-基)氨基)-嘧啶-4-基)氨基)-喹喔啉-5-基)甲磺酰胺的晶型V，其特征在于，所述晶型V的X-射线粉末衍射图谱在2θ值为5.57、8.50、10.03、14.23、20.00、22.60处有特征峰，2θ误差范围为±0.2°；Formula (A) compound N-(6-((5-bromo-2-((6-isopropyl-8-methoxy-3-methyl-3,4,5,6-tetrahydrobenzo[ b] crystal form V of pyrazolo[4,3-d]azepin-9-yl)amino)-pyrimidin-4-yl)amino)-quinoxalin-5-yl)methanesulfonamide, characterized in that , the X-ray powder diffraction pattern of the crystal form V has characteristic peaks at 2θ values of 5.57, 8.50, 10.03, 14.23, 20.00, and 22.60, and the 2θ error range is ±0.2°;
    优选地，所述晶型V的X-射线粉末衍射图谱在2θ值为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处有特征峰，2θ误差范围为±0.2°；Preferably, the X-ray powder diffraction pattern of the crystal form V has 2θ values of 5.57, 8.50, 10.03, 14.23, 16.46, 18.72, 20.00, 21.38, 22.13, 22.60, 22.85, 23.95, 24.57, 26.17, 26.48, 30.81 There are characteristic peaks, and the 2θ error range is ±0.2°;
    优选地，所述晶型V的X-射线粉末衍射图谱在2θ值为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处有特征峰，2θ误差范围为±0.2°；Preferably, the X-ray powder diffraction pattern of the crystal form V has 2θ values of 4.21, 5.57, 8.50, 9.42, 10.03, 10.65, 11.86, 12.81, 13.43, 14.23, 15.83, 16.46, 17.32, 17.57, 18.34, 18.72 , 19.12, 20.00, 20.66, 21.38, 22.13, 22.60, 22.85, 23.52, 23.95, 24.22, 24.57, 26.17, 26.48, 27.31, 27.93, 28.51, 30.13, 30.81 have characteristic peaks, and the 2θ error range is ±0.2°;
    优选地，所述晶型V的X-射线粉末衍射图谱如图5所示。Preferably, the X-ray powder diffraction pattern of the crystal form V is shown in FIG. 5 .
  12. 式(A)化合物N-(6-((5-溴-2-((6-异丙基-8-甲氧基-3-甲基-3,4,5,6-四氢苯并[b]吡唑并[4,3-d]氮杂-9-基)氨基)-嘧啶-4-基)氨基)-喹喔啉-5-基)甲磺酰胺的晶型VI，其特征在于，所述晶型VI的X-射线粉末衍射图谱在2θ值为6.82、9.61、12.32、13.75、14.10、20.52处有特征峰，2θ误差范围为±0.2°；Formula (A) compound N-(6-((5-bromo-2-((6-isopropyl-8-methoxy-3-methyl-3,4,5,6-tetrahydrobenzo[ b] crystal form VI of pyrazolo[4,3-d]azepin-9-yl)amino)-pyrimidin-4-yl)amino)-quinoxalin-5-yl)methanesulfonamide, characterized in that , the X-ray powder diffraction pattern of the crystal form VI has characteristic peaks at 2θ values of 6.82, 9.61, 12.32, 13.75, 14.10, and 20.52, and the 2θ error range is ±0.2°;
    优选地，所述晶型VI的X-射线粉末衍射图谱在2θ值为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处有特征峰，2θ误差范围为±0.2°；Preferably, the X-ray powder diffraction pattern of the crystal form VI has 2θ values of 5.84, 6.82, 8.87, 9.61, 12.32, 12.48, 13.23, 13.75, 14.10, 15.24, 16.07, 18.43, 20.52, 21.05, 22.40, 22.89 , 23.71, 24.47, and 25.28 have characteristic peaks, and the 2θ error range is ±0.2°;
    优选地，所述晶型VI的X-射线粉末衍射图谱在2θ值为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处有特征峰，2θ误差范围为±0.2°；Preferably, the X-ray powder diffraction pattern of the crystal form VI has 2θ values of 5.84, 6.82, 8.87, 9.10, 9.61, 12.32, 12.48, 13.23, 13.75, 14.10, 15.24, 16.07, 17.84, 18.43, 19.70, 20.52 , 21.05, 21.52, 22.40, 22.89, 23.71, 24.47, 24.87, 25.28, 26.76, 27.31, 27.87, 30.50 have characteristic peaks, and the 2θ error range is ±0.2°;
    优选地，所述晶型VI的X-射线粉末衍射图谱如图6示。Preferably, the X-ray powder diffraction pattern of the crystal form VI is shown in FIG. 6 .
  13. 式(A)化合物N-(6-((5-溴-2-((6-异丙基-8-甲氧基-3-甲基-3,4,5,6-四氢苯并[b]吡唑并[4,3-d]氮杂-9-基)氨基)-嘧啶-4-基)氨基)-喹喔啉-5-基)甲磺酰胺的晶型VII，其特征在于，所述晶型VII的X-射线粉末衍射图谱在2θ值为14.54、15.24、17.48、20.15、24.08处有特征峰，2θ误差范围为±0.2°；Formula (A) compound N-(6-((5-bromo-2-((6-isopropyl-8-methoxy-3-methyl-3,4,5,6-tetrahydrobenzo[ b] crystal form VII of pyrazolo[4,3-d]azepin-9-yl)amino)-pyrimidin-4-yl)amino)-quinoxalin-5-yl)methanesulfonamide, characterized in that , 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°;
    优选地，所述晶型VII的X-射线粉末衍射图谱在2θ值为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处有特征峰，2θ误差范围为±0.2°；Preferably, the X-ray powder diffraction pattern of the crystal form VII has 2θ values of 10.10, 10.30, 11.33, 12.20, 14.54, 15.24, 17.48, 17.66, 18.88, 20.15, 21.12, 22.99, 23.33, 23.78, 24.08, 26.67 There are characteristic peaks, and the 2θ error range is ±0.2°;
    优选地，所述晶型VII的X-射线粉末衍射图谱在2θ值为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处有特征峰，2θ误差范围为±0.2°；Preferably, the X-ray powder diffraction pattern of the crystal form VII has 2θ values of 7.23, 8.80, 10.10, 10.30, 11.33, 12.20, 12.61, 13.23, 14.54, 15.24, 15.83, 16.87, 17.48, 17.66, 18.35, 18.88 , 20.15, 21.12, 22.61, 22.99, 23.33, 23.78, 24.08, 24.61, 26.67, 27.87, 29.50, 30.62 have characteristic peaks, and the 2θ error range is ±0.2°;
    优选地，所述晶型VII的X-射线粉末衍射图谱如图7所示。Preferably, the X-ray powder diffraction pattern of the crystal form VII is shown in FIG. 7 .
  14. 式(A)化合物N-(6-((5-溴-2-((6-异丙基-8-甲氧基-3-甲基-3,4,5,6-四氢苯并[b]吡唑并[4,3-d]氮杂-9-基)氨基)-嘧啶-4-基)氨基)-喹喔啉-5-基)甲磺酰胺的晶型VIII，其特征在于，所述晶型VIII的X-射线粉末衍射图谱在2θ值为5.49、13.58、15.88、21.11、22.48处有特征峰，2θ误差范围为±0.2°；Formula (A) compound N-(6-((5-bromo-2-((6-isopropyl-8-methoxy-3-methyl-3,4,5,6-tetrahydrobenzo[ b] crystal form VIII of pyrazolo[4,3-d]azepin-9-yl)amino)-pyrimidin-4-yl)amino)-quinoxalin-5-yl)methanesulfonamide, characterized in that , 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°;
    优选地，所述晶型VIII的X-射线粉末衍射图谱在2θ值为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处有特征峰，2θ误差范围为±0.2°；Preferably, the X-ray powder diffraction pattern of the crystal form VIII has 2θ values of 5.49, 10.08, 11.07, 11.74, 13.58, 13.77, 15.88, 16.99, 20.76, 21.11, 21.42, 22.48, 25.00, 25.63, 26.98, 30.73 There are characteristic peaks, and the 2θ error range is ±0.2°;
    优选地，所述晶型VIII的X-射线粉末衍射图谱在2θ值为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处有特征峰，2θ误差范围为±0.2°；Preferably, the X-ray powder diffraction pattern of the crystal form VIII has 2θ values of 4.47, 5.49, 9.00, 9.85, 10.08, 11.07, 11.74, 12.37, 13.03, 13.58, 13.77, 14.92, 15.88, 16.68, 16.99, 17.44 , 18.59, 19.91, 20.76, 21.11, 21.42, 22.48, 23.57, 23.73, 25.00, 25.32, 25.63, 26.98, 27.79, 29.80, 30.73 have characteristic peaks, and the 2θ error range is ±0.2°;
    优选地，所述晶型VIII的X-射线粉末衍射图谱如图8所示。Preferably, the X-ray powder diffraction pattern of the crystal form VIII is shown in FIG. 8 .
  15. 式(A)化合物N-(6-((5-溴-2-((6-异丙基-8-甲氧基-3-甲基-3,4,5,6-四氢苯并[b]吡唑并[4,3-d]氮杂-9-基)氨基)-嘧啶-4-基)氨基)-喹喔啉-5-基)甲磺酰胺的晶型IX，其特征在于，所述晶型IX的X-射线粉末衍射图谱在2θ值为5.79、8.84、11.66、21.96、24.74处有特征峰，2θ误差范围为±0.2°；Formula (A) compound N-(6-((5-bromo-2-((6-isopropyl-8-methoxy-3-methyl-3,4,5,6-tetrahydrobenzo[ b] crystal form IX of pyrazolo[4,3-d]azepin-9-yl)amino)-pyrimidin-4-yl)amino)-quinoxalin-5-yl)methanesulfonamide, characterized in that , the X-ray powder diffraction pattern of the crystal form IX has characteristic peaks at 2θ values of 5.79, 8.84, 11.66, 21.96, and 24.74, and the 2θ error range is ±0.2°;
    优选地，所述晶型IX的X-射线粉末衍射图谱在2θ值为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处有特征峰，2θ误差范围为±0.2°；Preferably, the X-ray powder diffraction pattern of the crystal form IX has 2θ values of 5.79, 8.14, 8.84, 9.90, 11.66, 15.61, 17.12, 17.59, 19.93, 21.11, 21.74, 21.96, 23.48, 24.74, 25.13, 26.69 , There is a characteristic peak at 27.22, and the 2θ error range is ±0.2°;
    优选地，所述晶型IX的X-射线粉末衍射图谱在2θ值为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处有特征峰，2θ误差范围为±0.2°；Preferably, the X-ray powder diffraction pattern of the crystal form IX has 2θ values of 5.79, 8.14, 8.84, 9.04, 9.90, 11.66, 15.61, 17.12, 17.59, 17.90, 18.23, 18.61, 19.68, 19.93, 20.82, 21.11 , 21.74, 21.96, 23.48, 24.39, 24.74, 25.13, 26.42, 26.69, 27.22, 30.33 have characteristic peaks, and the 2θ error range is ±0.2°;
    优选地，所述晶型IX的X-射线粉末衍射图谱如图9所示。Preferably, the X-ray powder diffraction pattern of the crystal form IX is shown in FIG. 9 .
  16. 式(A)化合物N-(6-((5-溴-2-((6-异丙基-8-甲氧基-3-甲基-3,4,5,6-四氢苯并[b]吡唑并[4,3-d]氮杂-9-基)氨基)-嘧啶-4-基)氨基)-喹喔啉-5-基)甲磺酰胺的晶型XII，其特征在于，所述晶型XII的X-射线粉末衍射图谱在2θ值为5.83、6.80、20.48、24.92、27.49处有特征峰，2θ误差范围为±0.2°；Formula (A) compound N-(6-((5-bromo-2-((6-isopropyl-8-methoxy-3-methyl-3,4,5,6-tetrahydrobenzo[ b] crystal form XII of pyrazolo[4,3-d]azepin-9-yl)amino)-pyrimidin-4-yl)amino)-quinoxalin-5-yl)methanesulfonamide, characterized in that , the X-ray powder diffraction pattern of the crystal form XII has characteristic peaks at 2θ values of 5.83, 6.80, 20.48, 24.92, and 27.49, and the 2θ error range is ±0.2°;
    优选地，所述晶型XII的X-射线粉末衍射图谱在2θ值为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处有特征峰，2θ误差范围为±0.2°；Preferably, the X-ray powder diffraction pattern of the crystal form XII has 2θ values of 5.83, 6.80, 9.50, 11.84, 13.62, 14.23, 14.54, 16.72, 17.50, 18.42, 20.48, 20.85, 21.40, 23.35, 24.92, 27.49 There are characteristic peaks, and the 2θ error range is ±0.2°;
    优选地，所述晶型XII的X-射线粉末衍射图谱在2θ值为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处有特征峰，2θ误差范围为±0.2°；Preferably, the X-ray powder diffraction pattern of the crystal form XII has 2θ values of 5.83, 6.80, 8.40, 9.50, 9.71, 10.82, 11.84, 12.90, 13.62, 14.23, 14.54, 16.72, 17.50, 18.42, 19.66, 20.48 , 20.85, 21.40, 21.81, 23.35, 23.95, 24.92, 26.62, 27.49, 31.17, 32.45, 33.62 have characteristic peaks, and the 2θ error range is ±0.2°;
    优选地，所述晶型XII的X-射线粉末衍射图谱如图10所示。Preferably, the X-ray powder diffraction pattern of the crystal form XII is shown in FIG. 10 .
  17. 式(A)化合物N-(6-((5-溴-2-((6-异丙基-8-甲氧基-3-甲基-3,4,5,6-四氢苯并[b]吡唑并[4,3-d]氮杂-9-基)氨基)-嘧啶-4-基)氨基)-喹喔啉-5-基)甲磺酰胺的晶型XIV，其特征在于，所述晶型XIV的X-射线粉末衍射图谱在2θ值为5.86、11.73、23.56、29.55、35.65处有特征峰，2θ误差范围为±0.2°；Formula (A) compound N-(6-((5-bromo-2-((6-isopropyl-8-methoxy-3-methyl-3,4,5,6-tetrahydrobenzo[ b] crystal form XIV of pyrazolo[4,3-d]azepin-9-yl)amino)-pyrimidin-4-yl)amino)-quinoxalin-5-yl)methanesulfonamide, characterized in that , the X-ray powder diffraction pattern of the crystal form XIV has characteristic peaks at 2θ values of 5.86, 11.73, 23.56, 29.55, and 35.65, and the 2θ error range is ±0.2°;
    优选地，所述晶型XIV的X-射线粉末衍射图谱在2θ值为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处有特征峰，2θ误差范围为±0.2°；Preferably, the X-ray powder diffraction pattern of the crystal form XIV has characteristic peaks at 2θ values of 5.86, 11.73, 13.85, 20.91, 22.32, 23.56, 24.69, 25.30, 26.72, 29.55, 33.09, 35.65, 38.91, 2θ The error range is ±0.2°;
    优选地，所述晶型XIV的X-射线粉末衍射图谱如图11所示。Preferably, the X-ray powder diffraction pattern of the crystal form XIV is shown in FIG. 11 .
  18. 式(I)化合物，A compound of formula (I),
    Figure PCTCN2022125056-appb-100002
    Figure PCTCN2022125056-appb-100002
  19. 式(I)化合物的晶型A，其特征在于，所述晶型A的X-射线粉末衍射图谱在2θ值为7.38、8.13、12.62、20.14、21.41、23.72处有特征峰，2θ误差范围为±0.2°；The crystal form A of the compound of formula (I), is characterized in that 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°;
    优选地，所述晶型A的X-射线粉末衍射图谱在2θ值为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处有特征峰，2θ误差范围为±0.2°；Preferably, the X-ray powder diffraction pattern of the crystal form A has characteristic peaks at 2θ values of 7.38, 7.69, 8.13, 12.62, 14.12, 14.95, 17.43, 18.79, 20.14, 20.32, 21.41, 23.72, 26.47, and 28.26 , the 2θ error range is ±0.2°;
    优选地，所述晶型A的X-射线粉末衍射图谱在2θ值为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处有特征峰，2θ误差范围为±0.2°；Preferably, the X-ray powder diffraction pattern of the crystal form A has 2θ values of 7.38, 7.69, 8.13, 9.31, 12.62, 14.12, 14.95, 15.96, 17.43, 18.44, 18.79, 19.09, 19.57, 19.93, 20.14, 20.32 , 21.41, 22.66, 23.72, 25.08, 25.53, 26.47, 28.26, 30.02, 31.91 have characteristic peaks, and the 2θ error range is ±0.2°;
    优选地，所述晶型A的X-射线粉末衍射图谱如图12所示。Preferably, the X-ray powder diffraction pattern of the crystal form A is shown in FIG. 12 .
  20. 式(I)化合物的晶型B，其特征在于，所述晶型B的X-射线粉末衍射图谱在2θ值为5.89、7.25、9.37、22.49、25.45、27.05处有特征峰，2θ误差范围为±0.2°；The crystal form B of the compound of formula (I) is characterized in that the X-ray powder diffraction spectrum 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°;
    优选地，所述晶型B的X-射线粉末衍射图谱在2θ值为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处有特征峰，2θ误差范围为±0.2°；Preferably, the X-ray powder diffraction pattern of the crystal form B has 2θ values of 5.89, 6.43, 7.25, 9.37, 12.42, 12.95, 15.16, 17.37, 17.76, 18.64, 18.89, 21.14, 21.57, 21.99, 22.49, 25.45 , There is a characteristic peak at 27.05, and the 2θ error range is ±0.2°;
    优选地，所述晶型B的X-射线粉末衍射图谱在2θ值为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处有特征峰，2θ误差范围为±0.2°；Preferably, the X-ray powder diffraction pattern of the crystal form B has 2θ values of 5.89, 6.43, 7.25, 8.35, 9.37, 12.42, 12.95, 13.29, 14.04, 15.16, 15.84, 16.23, 16.83, 17.37, 17.76, 18.64 , 18.89, 20.12, 21.14, 21.57, 21.99, 22.49, 22.84, 23.63, 24.58, 25.45, 27.05, 30.01 have characteristic peaks, and the 2θ error range is ±0.2°;
    优选地，所述晶型B的X-射线粉末衍射图谱如图13所示。Preferably, the X-ray powder diffraction pattern of the crystal form B is shown in FIG. 13 .
  21. 式(I)化合物的晶型C，其特征在于，所述晶型C的X-射线粉末衍射图谱在2θ值为5.85、12.41、17.76、22.48、27.03处有特征峰，2θ误差范围为±0.2°；The crystal form C of the compound of formula (I) is characterized in that the X-ray powder diffraction pattern of the crystal form C has characteristic peaks at 2θ values of 5.85, 12.41, 17.76, 22.48, and 27.03, and the 2θ error range is ±0.2 °;
    优选地，所述晶型C的X-射线粉末衍射图谱在2θ值为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处有特征峰，2θ误差范围为±0.2°；Preferably, the X-ray powder diffraction pattern of the crystal form C has 2θ values of 5.85, 9.35, 12.41, 15.82, 17.36, 17.76, 18.64, 18.88, 21.12, 21.57, 21.97, 22.48, 22.87, 23.73, 25.42, 27.03 There are characteristic peaks, and the 2θ error range is ±0.2°;
    优选地，所述晶型C的X-射线粉末衍射图谱在2θ值为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处有特征峰，2θ误差范围为±0.2°；Preferably, the X-ray powder diffraction pattern of the crystal form C has 2θ values of 5.85, 9.35, 11.75, 12.41, 13.18, 13.27, 14.04, 14.83, 15.07, 15.82, 16.22, 17.36, 17.76, 18.64, 18.88, 20.11 , 21.12, 21.40, 21.57, 21.97, 22.48, 22.87, 23.73, 25.42, 27.03, 27.84, 28.32, 29.96 have characteristic peaks, and the 2θ error range is ±0.2°;
    优选地，所述晶型C的X-射线粉末衍射图谱如图14所示。Preferably, the X-ray powder diffraction pattern of the crystal form C is shown in FIG. 14 .
  22. 式(I)化合物的晶型D，其特征在于，所述晶型D的X-射线粉末衍射图谱在2θ值为5.55、13.03、16.73、22.48、24.17处有特征峰，2θ误差范围为±0.2°。The crystal form D of the compound of formula (I), is characterized in that the X-ray powder diffraction pattern of the crystal form D has characteristic peaks at 2θ values of 5.55, 13.03, 16.73, 22.48, and 24.17, and the 2θ error range is ±0.2 °.
  23. 如权利要求22所述的晶型D，其特征在于，所述晶型D的X-射线粉末衍射图谱在2θ值为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处有特征峰， 2θ误差范围为±0.2°。The crystal form D according to claim 22, wherein the X-ray powder diffraction pattern of the 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°.
  24. 如权利要求22所述的晶型D，其特征在于，所述晶型D的X-射线粉末衍射图谱在2θ值为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处有特征峰，2θ误差范围为±0.2°；The crystal form D according to claim 22, wherein the X-ray powder diffraction pattern of the 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 . ±0.2°;
    优选地，所述晶型D的X-射线粉末衍射图谱如图15所示。Preferably, the X-ray powder diffraction pattern of the crystal form D is shown in FIG. 15 .
  25. 一种药物组合物，其包含权利要求1-17、19-24任意一项所述晶型或权利要求18所述化合物及可药用的载体。A pharmaceutical composition comprising the crystal form of any one of claims 1-17, 19-24 or the compound of claim 18 and a pharmaceutically acceptable carrier.
  26. 权利要求1-17、19-24任意一项所述晶型、权利要求18所述化合物或权利要求25所述的药物组合物在制备治疗癌症的药物中的用途，优选地，所述癌症由EGFR突变介导。Use of the crystal form described in any one of claims 1-17, 19-24, the compound described in claim 18, or the pharmaceutical composition described in claim 25 in the preparation of a drug for treating cancer, preferably, the cancer consists of EGFR mutation mediated.
  27. 权利要求1-17、19-24任意一项所述晶型、权利要求18所述化合物或权利要求25所述的药物组合物治疗癌症的用途，优选地，所述癌症由EGFR突变介导。Use of the crystal form of any one of claims 1-17, 19-24, the compound of claim 18 or the pharmaceutical composition of claim 25 for treating cancer, preferably, the cancer is mediated by EGFR mutation.
  28. 权利要求1-17、19-24任意一项所述晶型、权利要求18所述化合物或权利要求25所述的药物组合物用于制备EGFR抑制剂的用途。Use of the crystal form described in any one of claims 1-17, 19-24, the compound described in claim 18 or the pharmaceutical composition described in claim 25 for the preparation of an EGFR inhibitor.
  29. 如权利要求26-28任一项所述的用途，所述癌症包括淋巴瘤、非霍奇金淋巴瘤、卵巢癌、宫颈癌、前列腺癌、结肠直肠癌、乳腺癌、胰腺癌、胶质瘤、胶质母细胞瘤，黑色素瘤、白血病、胃癌、子宫内膜癌、肺癌、肝细胞癌、胃癌、胃肠道间质瘤(GIST)、急性髓细胞白血病(AML)、胆管癌、肾癌、甲状腺癌、间变性大细胞淋巴瘤、间皮瘤、多发性骨髓瘤、黑色素瘤；Use according to any one of claims 26-28, wherein said cancer comprises 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;
    优选地，所述癌症为肺癌。Preferably, the cancer is lung cancer.
PCT/CN2022/125056 2021-10-14 2022-10-13 Polymorph of egfr inhibitor WO2023061433A1 (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN202280067077.3A CN118076614A (en) 2021-10-14 2022-10-13 Polymorphic forms of EGFR inhibitors

Applications Claiming Priority (6)

Application Number Priority Date Filing Date Title
CN202111197313.7 2021-10-14
CN202111196875 2021-10-14
CN202111196875.X 2021-10-14
CN202111197957 2021-10-14
CN202111197957.6 2021-10-14
CN202111197313 2021-10-14

Publications (1)

Publication Number Publication Date
WO2023061433A1 true WO2023061433A1 (en) 2023-04-20

Family

ID=85987315

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2022/125056 WO2023061433A1 (en) 2021-10-14 2022-10-13 Polymorph of egfr inhibitor

Country Status (3)

Country Link
CN (1) CN118076614A (en)
TW (1) TW202317098A (en)
WO (1) WO2023061433A1 (en)

Cited By (1)

* Cited by examiner, † Cited by third party
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

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2017220007A1 (en) * 2016-06-24 2017-12-28 正大天晴药业集团股份有限公司 Crystals of aniline pyrimidine compound serving as 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
WO2021018009A1 (en) * 2019-07-26 2021-02-04 贝达药业股份有限公司 Egfr inhibitor, composition, and preparation method therefor
WO2021190417A1 (en) * 2020-03-23 2021-09-30 齐鲁制药有限公司 Novel aminopyrimidine egfr inhibitor
WO2021208918A1 (en) * 2020-04-14 2021-10-21 齐鲁制药有限公司 Tricyclic compounds as egfr inhibitors
WO2021238827A1 (en) * 2020-05-25 2021-12-02 南京红云生物科技有限公司 Egfr inhibitor and preparation method and use thereof

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2017220007A1 (en) * 2016-06-24 2017-12-28 正大天晴药业集团股份有限公司 Crystals of aniline pyrimidine compound serving as 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
WO2021018009A1 (en) * 2019-07-26 2021-02-04 贝达药业股份有限公司 Egfr inhibitor, composition, and preparation method therefor
WO2021190417A1 (en) * 2020-03-23 2021-09-30 齐鲁制药有限公司 Novel aminopyrimidine egfr inhibitor
WO2021208918A1 (en) * 2020-04-14 2021-10-21 齐鲁制药有限公司 Tricyclic compounds as egfr inhibitors
WO2021238827A1 (en) * 2020-05-25 2021-12-02 南京红云生物科技有限公司 Egfr inhibitor and preparation method and use thereof

Cited By (1)

* Cited by examiner, † Cited by third party
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

Also Published As

Publication number Publication date
CN118076614A (en) 2024-05-24
TW202317098A (en) 2023-05-01

Similar Documents

Publication Publication Date Title
RU2506264C2 (en) Pyrimidine-substituted purine compounds as kinase(s) inhibitors
TWI753918B (en) Crystallization of Pyrrolopyrimidine Compounds as JAK Inhibitors
KR20060054300A (en) Isethionate salt of a selective cdk4 inhibitor
KR20140145157A (en) Solid forms of an epidermal growth factor receptor kinase inhibitor
WO2020114388A1 (en) Substituted pyrazolo[1,5-a]pyridine compound, composition containing the same and use thereof
WO2020107987A1 (en) Erk inhibitor containing isoindoline, preparation method therefor and application thereof
WO2014135028A1 (en) Pyridopyrimidine or pyrimidopyrimidine compound, preparation method, pharmaceutical composition and use thereof
WO2022156059A1 (en) Cdk6/dyrk2 dual-target inhibitor, and preparation method therefor and use thereof
WO2017088746A1 (en) New epidermal growth factor receptor inhibitor and application thereof
WO2023061433A1 (en) Polymorph of egfr inhibitor
BR112021005750A2 (en) fgfr4 inhibitor and its use
WO2020034987A1 (en) Prodrug containing glucuronide derivative of jak inhibitor, preparation method therefor, and uses thereof
WO2021249319A1 (en) Tricyclic compound, pharmaceutical composition, and use thereof
CN111936470B (en) Amidopyrazoles useful as irreversible FGFR inhibitors
WO2020221209A1 (en) Cd73 inhibitor, preparation method therefor and application thereof
CN110016026B (en) Pyrimidopyridone compounds with antitumor activity, preparation method and application
KR102270538B1 (en) New polymorphic forms of icotinib phosphate and uses thereof
CN113072550B (en) High-selectivity fibroblast growth factor receptor inhibitor and application thereof
WO2020207419A1 (en) Piperazine amide derivative, preparation method therefor, and use thereof in medicine
JP2022520083A (en) Crystal form of JAK2 inhibitor
WO2021078141A1 (en) Novel purine derivative, intermediate and application thereof in preparing anticancer medicine
WO2017206904A1 (en) Pi3k inhibitor, and pharmaceutically acceptable salt, polycrystalline form, and application thereof
WO2021139794A1 (en) Crystal form of pyrrolidinyl urea derivative and application thereof
WO2024027825A1 (en) Cdk inhibitor and polymorph of phosphate thereof
WO2021073494A1 (en) The salts of a compound and the crystalline forms thereof

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 22880369

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE