WO2022223037A1 - Kras抑制剂的盐或多晶型物 - Google Patents

Kras抑制剂的盐或多晶型物 Download PDF

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WO2022223037A1
WO2022223037A1 PCT/CN2022/088577 CN2022088577W WO2022223037A1 WO 2022223037 A1 WO2022223037 A1 WO 2022223037A1 CN 2022088577 W CN2022088577 W CN 2022088577W WO 2022223037 A1 WO2022223037 A1 WO 2022223037A1
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crystal form
ray powder
powder diffraction
characteristic peaks
diffraction characteristic
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PCT/CN2022/088577
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English (en)
French (fr)
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赵金柱
周福生
刘祥超
曹煜东
兰炯
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劲方医药科技(上海)有限公司
浙江劲方药业有限公司
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Publication of WO2022223037A1 publication Critical patent/WO2022223037A1/zh

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    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/4985—Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems
    • 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
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/22—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains four or more hetero rings

Definitions

  • the invention belongs to the technical field of medicine, and in particular, relates to a salt or polymorph of a KRAS inhibitor, and a preparation method and use thereof.
  • Lung cancer is the cancer with the highest incidence in the world.
  • the incidence of lung cancer in China ranks first among all cancers, and it is also the cancer with the highest incidence and mortality in China.
  • NSCLC non-small cell lung cancer
  • about 32% of lung cancers have mutations in the RAS gene, and mutations in any of the three main subtypes of the RAS (HRAS, NRAS, or KRAS) gene can lead to human tumorigenesis. It has been reported that the KRAS gene has the highest mutation frequency in the RAS gene, and KRAS mutations are detected in 25-30% of tumors.
  • KRAS mutations are found at residues G12 and G13 in the P loop and at residue Q61.
  • the G12C mutation is a frequent mutation of the KRAS gene (glycine-12 mutation to cysteine). This mutation has been found in about 13% of cancers, about 43% of lung cancers, and almost 100% of MYH-associated polyposis (familial colon cancer syndrome). Therefore, it is a good direction to develop inhibitors that selectively inhibit KRAS mutations.
  • the purpose of the present invention is to provide a series of stable polymorphs of atropisomers of the compound represented by formula (I), and to provide their preparation methods and uses.
  • a first aspect of the present invention provides a polymorph of Compound Ia,
  • the polymorph is crystal form A, and the crystal form A has a characteristic peak of X-ray powder diffraction, and the characteristic peak of X-ray powder diffraction is at a 2 ⁇ value selected from the following group : 6.02 ⁇ 0.2°, 11.90 ⁇ 0.2°, 12.84 ⁇ 0.2°, 17.04 ⁇ 0.2°, 19.62 ⁇ 0.2°.
  • the crystal form A has X-ray powder diffraction characteristic peaks, and the X-ray powder diffraction characteristic peaks are at 2 ⁇ values selected from the following group: 6.02 ⁇ 0.2°, 11.90 ⁇ 0.2°, 12.84 ⁇ 0.2°, 17.04 ⁇ 0.2°, 17.34 ⁇ 0.2°, 19.62 ⁇ 0.2°, 21.04 ⁇ 0.2°, 24.10 ⁇ 0.2°, 26.00 ⁇ 0.2°.
  • the crystal form A has X-ray powder diffraction characteristic peaks, and the X-ray powder diffraction characteristic peaks are at 2 ⁇ values selected from the following group: 6.02 ⁇ 0.2°, 11.90 ⁇ 0.2°, 12.84 ⁇ 0.2°, 13.78 ⁇ 0.2°, 16.14 ⁇ 0.2°, 17.04 ⁇ 0.2°, 17.34 ⁇ 0.2°, 18.72 ⁇ 0.2°, 19.62 ⁇ 0.2°, 20.74 ⁇ 0.2°, 21.04 ⁇ 0.2°, 22.70 ⁇ 0.2°, 23.22 ⁇ 0.2°, 24.10 ⁇ 0.2°, 24.80 ⁇ 0.2°, 25.14 ⁇ 0.2°, 26.00 ⁇ 0.2°, 26.46 ⁇ 0.2°, 28.72 ⁇ 0.2°.
  • the crystal form A has X-ray powder diffraction characteristic peaks, and the X-ray powder diffraction characteristic peaks are in one or more selected from Table 1 (for example, 2, 3, 4 1, 5, 6, 7, 8, 9, more, or all) 2 ⁇ values.
  • the X-ray powder diffraction pattern of the crystal form A is substantially as shown in FIG. 1 .
  • the differential scanning calorimetry analysis spectrum of the crystal form A has characteristic peaks at 278.84 ⁇ 6°C and 292.69 ⁇ 6°C.
  • the differential scanning calorimetry analysis spectrum of the crystal form A has characteristic peaks at 278.84 ⁇ 3°C and 292.69 ⁇ 3°C.
  • the differential scanning calorimetry analysis spectrum of the crystal form A also has characteristic peaks at 96.96 ⁇ 6°C and 188.88 ⁇ 6°C.
  • the differential scanning calorimetry analysis spectrum of the crystal form A also has characteristic peaks at 96.96 ⁇ 3°C and 188.88 ⁇ 3°C.
  • the differential scanning calorimetry analysis spectrum of the crystal form A is substantially as shown in FIG. 2 .
  • thermogravimetric analysis spectrum of the crystal form A has a weight loss of 1.34% ⁇ 1% at 63.07 ⁇ 10°C.
  • thermogravimetric analysis spectrum of the crystal form A again loses weight by 5.93% ⁇ 1% at 288.52 ⁇ 10°C.
  • thermogravimetric analysis spectrum of the crystal form A is substantially as shown in FIG. 3 .
  • the polymorph is crystal form B, and the crystal form B has a characteristic peak of X-ray powder diffraction, and the characteristic peak of X-ray powder diffraction is at a 2 ⁇ value selected from the following group : 11.38 ⁇ 0.2°, 11.94 ⁇ 0.2°, 12.56 ⁇ 0.2°, 17.36 ⁇ 0.2°, 18.18 ⁇ 0.2°, 20.60 ⁇ 0.2°, 20.82 ⁇ 0.2°, 24.94 ⁇ 0.2°.
  • the crystal form B has X-ray powder diffraction characteristic peaks, and the X-ray powder diffraction characteristic peaks are at 2 ⁇ values selected from the following group: 10.02 ⁇ 0.2°, 11.38 ⁇ 0.2°, 11.94 ⁇ 0.2°, 12.18 ⁇ 0.2°, 12.56 ⁇ 0.2°, 13.32 ⁇ 0.2°, 13.66 ⁇ 0.2°, 17.36 ⁇ 0.2°, 18.18 ⁇ 0.2°, 18.96 ⁇ 0.2°, 20.20 ⁇ 0.2°, 20.60 ⁇ 0.2°, 20.82 ⁇ 0.2°, 24.94 ⁇ 0.2°, 26.24 ⁇ 0.2°, 29.92 ⁇ 0.2°, 30.60 ⁇ 0.2°.
  • the crystal form B has X-ray powder diffraction characteristic peaks, and the X-ray powder diffraction characteristic peaks are at 2 ⁇ values selected from the following group: 10.02 ⁇ 0.2°, 11.38 ⁇ 0.2°, 11.94 ⁇ 0.2°, 12.18 ⁇ 0.2°, 12.56 ⁇ 0.2°, 13.32 ⁇ 0.2°, 13.66 ⁇ 0.2°, 15.62 ⁇ 0.2°, 17.36 ⁇ 0.2°, 18.18 ⁇ 0.2°, 18.96 ⁇ 0.2°, 19.58 ⁇ 0.2°, 20.20 ⁇ 0.2°, 20.60 ⁇ 0.2°, 20.82 ⁇ 0.2°, 21.52 ⁇ 0.2°, 23.72 ⁇ 0.2°, 24.94 ⁇ 0.2°, 26.24 ⁇ 0.2°, 29.92 ⁇ 0.2°, 30.60 ⁇ 0.2°.
  • the crystal form B has X-ray powder diffraction characteristic peaks, and the X-ray powder diffraction characteristic peaks are in one or more selected from Table 2 (for example, 2, 3, 4 1, 5, 6, 7, 8, 9, more, or all) 2 ⁇ values.
  • the X-ray powder diffraction pattern of the crystal form B is substantially as shown in FIG. 4 .
  • the X-ray powder diffraction pattern of the crystal form B is substantially as shown in FIG. 13 .
  • the differential scanning calorimetry analysis spectrum of the crystal form B has a characteristic peak at 291.11 ⁇ 6°C.
  • the differential scanning calorimetry analysis spectrum of the crystal form B has a characteristic peak at 291.11 ⁇ 3°C.
  • the differential scanning calorimetry analysis spectrum of the crystal form B is substantially as shown in FIG. 5 .
  • thermogravimetric analysis spectrum of the crystal form B has a weight loss of 0.85% ⁇ 0.8% at 301.42 ⁇ 10°C.
  • thermogravimetric analysis spectrum of the crystal form B is basically as shown in FIG. 14 .
  • the polymorph is crystal form C, and the crystal form C has a characteristic peak of X-ray powder diffraction, and the characteristic peak of X-ray powder diffraction is at a 2 ⁇ value selected from the following group : 6.28 ⁇ 0.2°, 12.12 ⁇ 0.2°, 17.02 ⁇ 0.2°, 18.12 ⁇ 0.2°.
  • the crystal form C has X-ray powder diffraction characteristic peaks, and the X-ray powder diffraction characteristic peaks are at 2 ⁇ values selected from the following group: 6.28 ⁇ 0.2°, 12.12 ⁇ 0.2°, 12.46 ⁇ 0.2°, 14.98 ⁇ 0.2°, 17.02 ⁇ 0.2°, 18.12 ⁇ 0.2°, 19.40 ⁇ 0.2°, 20.22 ⁇ 0.2°, 23.66 ⁇ 0.2°.
  • the crystal form C has X-ray powder diffraction characteristic peaks, and the X-ray powder diffraction characteristic peaks are at 2 ⁇ values selected from the following group: 6.28 ⁇ 0.2°, 12.12 ⁇ 0.2°, 12.46 ⁇ 0.2°, 14.98 ⁇ 0.2°, 17.02 ⁇ 0.2°, 18.12 ⁇ 0.2°, 19.40 ⁇ 0.2°, 20.22 ⁇ 0.2°, 23.66 ⁇ 0.2°, 25.26 ⁇ 0.2°, 26.74 ⁇ 0.2°, 28.94 ⁇ 0.2°.
  • the crystal form C has X-ray powder diffraction characteristic peaks, and the X-ray powder diffraction characteristic peaks are in one or more selected from Table 3 (for example, 2, 3, 4 1, 5, 6, 7, 8, 9, more, or all) 2 ⁇ values.
  • the X-ray powder diffraction pattern of the crystal form C is substantially as shown in FIG. 6 .
  • the differential scanning calorimetry analysis spectrum of the crystal form C has a characteristic peak at 292.25 ⁇ 6°C.
  • the differential scanning calorimetry analysis spectrum of the crystal form C has a characteristic peak at 292.25 ⁇ 3°C.
  • the differential scanning calorimetry analysis spectrum of the crystal form C also has a characteristic peak at 122.79 ⁇ 6°C.
  • the differential scanning calorimetry analysis spectrum of the crystal form C also has characteristic peaks at 122.79 ⁇ 3°C.
  • the differential scanning calorimetry analysis spectrum of the crystal form C is substantially as shown in FIG. 7 .
  • thermogravimetric analysis spectrum of the crystal form C has a weight loss of 5.54% ⁇ 1% at 103.15 ⁇ 10°C.
  • thermogravimetric analysis spectrum of the crystal form C is basically as shown in FIG. 8 .
  • the polymorph is crystal form D, and the crystal form D has a characteristic peak of X-ray powder diffraction, and the characteristic peak of X-ray powder diffraction is at a 2 ⁇ value selected from the following group : 3.82 ⁇ 0.2°, 10.96 ⁇ 0.2°, 14.28 ⁇ 0.2°, 18.52 ⁇ 0.2°, 19.22 ⁇ 0.2°.
  • the crystal form D has X-ray powder diffraction characteristic peaks, and the X-ray powder diffraction characteristic peaks are at 2 ⁇ values selected from the group consisting of: 3.82 ⁇ 0.2°, 7.45 ⁇ 0.2°, 9.62 ⁇ 0.2°, 10.96 ⁇ 0.2°, 11.58 ⁇ 0.2°, 13.26 ⁇ 0.2°, 14.28 ⁇ 0.2°, 18.52 ⁇ 0.2°, 19.22 ⁇ 0.2°, 20.28 ⁇ 0.2°, 20.74 ⁇ 0.2°, 24.46 ⁇ 0.2°, 24.68 ⁇ 0.2°.
  • the crystal form D has X-ray powder diffraction characteristic peaks, and the X-ray powder diffraction characteristic peaks are at 2 ⁇ values selected from the group consisting of: 3.82 ⁇ 0.2°, 7.45 ⁇ 0.2°, 9.62 ⁇ 0.2°, 10.96 ⁇ 0.2°, 11.58 ⁇ 0.2°, 13.26 ⁇ 0.2°, 14.28 ⁇ 0.2°, 16.12 ⁇ 0.2°, 18.52 ⁇ 0.2°, 19.22 ⁇ 0.2°, 20.28 ⁇ 0.2°, 20.74 ⁇ 0.2°, 22.24 ⁇ 0.2°, 22.62 ⁇ 0.2°, 24.46 ⁇ 0.2°, 24.68 ⁇ 0.2°, 26.20 ⁇ 0.2°, 27.47 ⁇ 0.2°.
  • the crystal form D has X-ray powder diffraction characteristic peaks, and the X-ray powder diffraction characteristic peaks are in one or more selected from Table 5 (for example, 2, 3, 4 1, 5, 6, 7, 8, 9, more, or all) 2 ⁇ values.
  • the X-ray powder diffraction pattern of the crystal form D is substantially as shown in FIG. 10 .
  • the differential scanning calorimetry analysis spectrum of the crystal form D has a characteristic peak at 293.27 ⁇ 6°C.
  • the differential scanning calorimetry analysis spectrum of the crystal form D has a characteristic peak at 293.27 ⁇ 3°C.
  • the differential scanning calorimetry analysis spectrum of the crystal form D also has characteristic peaks at 91.23 ⁇ 6°C.
  • the differential scanning calorimetry analysis spectrum of the crystal form D also has a characteristic peak at 91.23 ⁇ 3°C.
  • the differential scanning calorimetry analysis spectrum of the crystal form D is substantially as shown in FIG. 11 .
  • thermogravimetric analysis spectrum of the crystal form D loses weight by 9.08 ⁇ 2% at 65.10 ⁇ 10°C.
  • thermogravimetric analysis spectrum of the crystal form D loses weight again by 13.72 ⁇ 2% at 219.18 ⁇ 10°C.
  • thermogravimetric analysis spectrum of the crystal form D is substantially as shown in FIG. 12 .
  • the polymorph is crystal form F, and the crystal form F has a characteristic peak of X-ray powder diffraction, and the characteristic peak of X-ray powder diffraction is at a 2 ⁇ value selected from the following group : 3.52 ⁇ 0.2°, 10.12 ⁇ 0.2°, 14.88 ⁇ 0.2°, 17.14 ⁇ 0.2°, 22.48 ⁇ 0.2°.
  • the crystal form F has X-ray powder diffraction characteristic peaks, and the X-ray powder diffraction characteristic peaks are at 2 ⁇ values selected from the following group: 3.52 ⁇ 0.2°, 10.12 ⁇ 0.2°, 14.88 ⁇ 0.2°, 15.70 ⁇ 0.2°, 17.14 ⁇ 0.2°, 22.48 ⁇ 0.2°, 26.52 ⁇ 0.2°, 27.56 ⁇ 0.2°.
  • the crystal form F has X-ray powder diffraction characteristic peaks, and the X-ray powder diffraction characteristic peaks are at 2 ⁇ values selected from the following group: 3.52 ⁇ 0.2°, 8.18 ⁇ 0.2°, 9.04 ⁇ 0.2°, 10.12 ⁇ 0.2°, 11.32 ⁇ 0.2°, 14.02 ⁇ 0.2°, 14.88 ⁇ 0.2°, 15.70 ⁇ 0.2°, 16.40 ⁇ 0.2°, 17.14 ⁇ 0.2°, 20.44 ⁇ 0.2°, 22.48 ⁇ 0.2°, 24.21 ⁇ 0.2°, 26.52 ⁇ 0.2°, 27.56 ⁇ 0.2°, 28.82 ⁇ 0.2°, 31.04 ⁇ 0.2°.
  • the crystal form F has X-ray powder diffraction characteristic peaks, and the X-ray powder diffraction characteristic peaks are in one or more selected from Table 6 (for example, 2, 3, 4 1, 5, 6, 7, 8, 9, more, or all) 2 ⁇ values.
  • the X-ray powder diffraction pattern of the crystal form F is substantially as shown in FIG. 15 .
  • the differential scanning calorimetry analysis spectrum of the crystal form F has a characteristic peak at 293.17 ⁇ 6°C.
  • the differential scanning calorimetry analysis spectrum of the crystal form F has a characteristic peak at 293.17 ⁇ 3°C.
  • the differential scanning calorimetry analysis spectrum of the crystal form F also has a characteristic peak at 93.69 ⁇ 6°C.
  • the differential scanning calorimetry analysis spectrum of the crystal form F also has a characteristic peak at 93.69 ⁇ 3°C.
  • the differential scanning calorimetry analysis spectrum of the crystal form F also has characteristic peaks at 128.9 ⁇ 6°C.
  • the differential scanning calorimetry analysis spectrum of the crystal form F also has a characteristic peak at 128.9 ⁇ 3°C.
  • the differential scanning calorimetry analysis spectrum of the crystal form F also has a characteristic peak at 188.58 ⁇ 6°C.
  • the differential scanning calorimetry analysis spectrum of the crystal form F also has a characteristic peak at 188.58 ⁇ 3°C.
  • the differential scanning calorimetry analysis spectrum of the crystal form F is substantially as shown in FIG. 16 .
  • thermogravimetric analysis spectrum of the crystal form F loses 8.20 ⁇ 2% in weight at 131.41 ⁇ 10°C.
  • thermogravimetric analysis spectrum of the crystal form F is basically as shown in FIG. 17 .
  • the polymorph is crystal form G, and the crystal form G has a characteristic peak of X-ray powder diffraction, and the characteristic peak of X-ray powder diffraction is at a 2 ⁇ value selected from the following group : 12.08 ⁇ 0.2°, 13.00 ⁇ 0.2°, 17.04 ⁇ 0.2°, 19.64 ⁇ 0.2°, 23.18 ⁇ 0.2°, 24.64 ⁇ 0.2°, 26.02 ⁇ 0.2°.
  • the crystal form G has X-ray powder diffraction characteristic peaks, and the X-ray powder diffraction characteristic peaks are at 2 ⁇ values selected from the following group: 12.08 ⁇ 0.2°, 13.00 ⁇ 0.2°, 17.04 ⁇ 0.2°, 19.64 ⁇ 0.2°, 21.62 ⁇ 0.2°, 22.61 ⁇ 0.2°, 23.18 ⁇ 0.2°, 24.64 ⁇ 0.2°, 25.52 ⁇ 0.2°, 26.02 ⁇ 0.2°, 26.90 ⁇ 0.2°, 31.32 ⁇ 0.2°.
  • the crystal form G has X-ray powder diffraction characteristic peaks, and the X-ray powder diffraction characteristic peaks are at 2 ⁇ values selected from the following group: 5.97 ⁇ 0.2°, 12.08 ⁇ 0.2°, 13.00 ⁇ 0.2°, 13.94 ⁇ 0.2°, 17.04 ⁇ 0.2°, 17.44 ⁇ 0.2°, 18.74 ⁇ 0.2°, 19.64 ⁇ 0.2°, 20.86 ⁇ 0.2°, 21.62 ⁇ 0.2°, 22.61 ⁇ 0.2°, 23.18 ⁇ 0.2°, 24.64 ⁇ 0.2°, 25.52 ⁇ 0.2°, 26.02 ⁇ 0.2°, 26.90 ⁇ 0.2°, 27.96 ⁇ 0.2°, 29.08 ⁇ 0.2°, 31.32 ⁇ 0.2°, 37.96 ⁇ 0.2°.
  • the crystal form G has X-ray powder diffraction characteristic peaks, and the X-ray powder diffraction characteristic peaks are one or more selected from Table 7 (for example, 2, 3, 4, 5, 6, 7, 8, 9, more, or all) 2 theta values.
  • the X-ray powder diffraction pattern of the crystal form G is substantially as shown in FIG. 18 .
  • the differential scanning calorimetry analysis spectrum of the crystal form G has a characteristic peak at 236.90 ⁇ 6°C.
  • the differential scanning calorimetry analysis spectrum of the crystal form G has a characteristic peak at 236.90 ⁇ 3°C.
  • the differential scanning calorimetry analysis spectrum of the crystal form G also has a characteristic peak at 115.47 ⁇ 6°C.
  • the differential scanning calorimetry analysis spectrum of the crystal form G also has a characteristic peak at 115.47 ⁇ 3°C.
  • the differential scanning calorimetry analysis spectrum of the crystal form G also has a characteristic peak at 188.86 ⁇ 6°C.
  • the differential scanning calorimetry analysis spectrum of the crystal form G also has a characteristic peak at 188.86 ⁇ 3°C.
  • the differential scanning calorimetry analysis spectrum of the crystal form G also has a characteristic peak at 212.67 ⁇ 6°C.
  • the differential scanning calorimetry analysis spectrum of the crystal form G also has a characteristic peak at 212.67 ⁇ 3°C.
  • the differential scanning calorimetry analysis spectrum of the crystal form G is substantially as shown in FIG. 19 .
  • thermogravimetric analysis spectrum of the crystal form G loses 36.72 ⁇ 5% in weight at 111.37 ⁇ 10°C.
  • thermogravimetric analysis spectrum of the crystal form G loses weight again by 7.11 ⁇ 2% at 198.38 ⁇ 10°C.
  • thermogravimetric analysis spectrum of the crystal form G loses weight again by 4.53 ⁇ 2% at 283.44 ⁇ 10°C.
  • thermogravimetric analysis spectrum of the crystal form G loses weight again by 1.60 ⁇ 1% at 328.53 ⁇ 10°C.
  • thermogravimetric analysis spectrum of the crystal form G is substantially as shown in FIG. 20 .
  • the polymorph is crystal form H, and the crystal form H has a characteristic peak of X-ray powder diffraction, and the characteristic peak of X-ray powder diffraction is at a 2 ⁇ value selected from the following group : 10.00 ⁇ 0.2°, 10.22 ⁇ 0.2°, 14.10 ⁇ 0.2°, 17.94 ⁇ 0.2°, 19.00 ⁇ 0.2°.
  • the crystal form H has X-ray powder diffraction characteristic peaks, and the X-ray powder diffraction characteristic peaks are at 2 ⁇ values selected from the following group: 10.00 ⁇ 0.2°, 10.22 ⁇ 0.2°, 11.74 ⁇ 0.2°, 12.12 ⁇ 0.2°, 14.10 ⁇ 0.2°, 14.38 ⁇ 0.2°, 14.82 ⁇ 0.2°, 15.94 ⁇ 0.2°, 17.94 ⁇ 0.2°, 19.00 ⁇ 0.2°, 19.22 ⁇ 0.2°, 20.22 ⁇ 0.2°, 22.26 ⁇ 0.2°, 25.10 ⁇ 0.2°, 26.84 ⁇ 0.2°.
  • the crystal form H has X-ray powder diffraction characteristic peaks, and the X-ray powder diffraction characteristic peaks are at 2 ⁇ values selected from the following group: 8.12 ⁇ 0.2°, 10.00 ⁇ 0.2°, 10.22 ⁇ 0.2°, 11.74 ⁇ 0.2°, 12.12 ⁇ 0.2°, 13.44 ⁇ 0.2°, 14.10 ⁇ 0.2°, 14.38 ⁇ 0.2°, 14.82 ⁇ 0.2°, 15.62 ⁇ 0.2°, 15.94 ⁇ 0.2°, 17.94 ⁇ 0.2°, 19.00 ⁇ 0.2°, 19.22 ⁇ 0.2°, 19.64 ⁇ 0.2°, 20.22 ⁇ 0.2°, 22.26 ⁇ 0.2°, 22.64 ⁇ 0.2°, 24.30 ⁇ 0.2°, 25.10 ⁇ 0.2°, 26.84 ⁇ 0.2°, 27.36 ⁇ 0.2°, 29.08 ⁇ 0.2°.
  • the crystal form H has X-ray powder diffraction characteristic peaks, and the X-ray powder diffraction characteristic peaks are in one or more selected from Table 8 (for example, 2, 3, 4 1, 5, 6, 7, 8, 9, more, or all) 2 ⁇ values.
  • the X-ray powder diffraction pattern of the crystal form H is substantially as shown in FIG. 21 .
  • the differential scanning calorimetry analysis spectrum of the crystal form H has a characteristic peak at 294.49 ⁇ 6°C.
  • the differential scanning calorimetry analysis spectrum of the crystal form H has a characteristic peak at 294.49 ⁇ 3°C.
  • the differential scanning calorimetry analysis spectrum of the crystal form H has a characteristic peak at 218.00 ⁇ 6°C.
  • the differential scanning calorimetry analysis spectrum of the crystal form H has a characteristic peak at 218.00 ⁇ 3°C.
  • the differential scanning calorimetry analysis spectrum of the crystal form H has a characteristic peak at 243.69 ⁇ 6°C.
  • the differential scanning calorimetry analysis spectrum of the crystal form H has a characteristic peak at 243.69 ⁇ 3°C.
  • the differential scanning calorimetry analysis spectrum of the crystal form H is substantially as shown in FIG. 22 .
  • thermogravimetric analysis spectrum of the crystal form H loses 8.73 ⁇ 2% in weight at 207.40 ⁇ 10°C.
  • thermogravimetric analysis spectrum of the crystal form H has a weight loss of 1.34 ⁇ 1% at 278.89 ⁇ 2°C.
  • thermogravimetric analysis spectrum of the crystal form H is substantially as shown in FIG. 23 .
  • the polymorph is crystal form I, and the crystal form I has a characteristic peak of X-ray powder diffraction, and the characteristic peak of X-ray powder diffraction is at a 2 ⁇ value selected from the following group : 6.92 ⁇ 0.2°, 8.54 ⁇ 0.2°, 10.70 ⁇ 0.2°, 17.28 ⁇ 0.2°.
  • the crystal form I has X-ray powder diffraction characteristic peaks, and the X-ray powder diffraction characteristic peaks are at 2 ⁇ values selected from the following group: 6.92 ⁇ 0.2°, 8.54 ⁇ 0.2°, 10.70 ⁇ 0.2°, 11.54 ⁇ 0.2°, 11.98 ⁇ 0.2°, 12.48 ⁇ 0.2°, 17.28 ⁇ 0.2°, 19.14 ⁇ 0.2°, 19.50 ⁇ 0.2°, 25.02 ⁇ 0.2°, 25.60 ⁇ 0.2°.
  • the crystal form I has X-ray powder diffraction characteristic peaks, and the X-ray powder diffraction characteristic peaks are at 2 ⁇ values selected from the following group: 6.92 ⁇ 0.2°, 8.54 ⁇ 0.2°, 10.70 ⁇ 0.2°, 11.26 ⁇ 0.2°, 11.54 ⁇ 0.2°, 11.98 ⁇ 0.2°, 12.48 ⁇ 0.2°, 13.14 ⁇ 0.2°, 15.12 ⁇ 0.2°, 15.94 ⁇ 0.2°, 17.28 ⁇ 0.2°, 19.14 ⁇ 0.2°, 19.50 ⁇ 0.2°, 25.02 ⁇ 0.2°, 25.60 ⁇ 0.2°, 26.52 ⁇ 0.2°, 30.62 ⁇ 0.2°.
  • the crystal form I has X-ray powder diffraction characteristic peaks, and the X-ray powder diffraction characteristic peaks are in one or more selected from Table 4 (for example, 2, 3, 4 1, 5, 6, 7, 8, 9, more, or all) 2 ⁇ values.
  • the X-ray powder diffraction pattern of the crystal form I is substantially as shown in FIG. 9 .
  • the second aspect of the present invention provides a pharmaceutically acceptable salt of Compound Ia, wherein the pharmaceutically acceptable salt is hydrochloride, phosphate, sulfate, formate or propionate.
  • Another aspect of the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising (a) the polymorph of the first aspect or the pharmaceutically acceptable salt of the second aspect; and (b) a pharmaceutically acceptable vector.
  • Another aspect of the present invention provides the use of the polymorphic form of the first aspect or the pharmaceutically acceptable salt of the second aspect for preparing a medicament for preventing or treating KRAS G12C mutation-related diseases.
  • the KRAS G12C mutation-related disease is cancer.
  • the cancer is a solid tumor.
  • one or more cancers selected from the group consisting of lung cancer (eg, non-small cell lung cancer), pancreatic cancer, colorectal cancer.
  • Another aspect of the present invention provides a method for preparing crystal form A, the method comprising the steps of:
  • the crystal form I was dissolved in acetone, then water was added to the solution, and the solution was filtered to obtain the crystal form A.
  • Another aspect of the present invention provides a method for preparing crystal form B, the method comprising the steps of:
  • the crystal form B is obtained by filtration; wherein the organic solvent is n-heptane or a mixture of dichloromethane and methyl tert-butyl ether ;or
  • the crystal form I is mixed with an organic solvent, stirred at 40-60° C., and then filtered to obtain the crystal form B; wherein the organic solvent is selected from the group consisting of toluene, chloroform, 1,2-dichloroethyl A mixture of alkane, chloroform and methyl tert-butyl ether, a mixture of acetonitrile and toluene; or
  • the crystal form I was mixed with acetonitrile, and then dichloromethane was added to dissolve it; then the acetonitrile and dichloromethane were removed to obtain the crystal form B.
  • Another aspect of the present invention provides a method for preparing crystal form C, the method comprising the steps of: stirring compound Ia in a mixture of ethyl acetate and n-heptane at 40-60° C., and filtering, thereby obtaining the Form C.
  • Another aspect of the present invention provides a method for preparing crystal form D, the method comprising the steps of: dissolving crystal form I in DMF at room temperature, and then adding water to the solution to obtain crystal form D.
  • Another aspect of the present invention provides a method for preparing crystal form F, the method comprising the steps of: stirring crystal form I in water at 40-60° C., and filtering to obtain the crystal form F.
  • Another aspect of the present invention provides a method for preparing crystal form G, the method comprising the steps of: mixing crystal form I with DMSO at room temperature, then adding water to the system, stirring and filtering to obtain the crystal form G.
  • Another aspect of the present invention provides a method for preparing crystal form H, the method comprising the steps of: dissolving crystal form B in a mixture of acetonitrile and toluene at room temperature, then adding toluene to the solution; °C, stirring, and filtering to obtain the crystal form H.
  • Another aspect of the present invention provides a method for preparing crystal form I, the method comprising the steps of:
  • step (b) at 55-65 ° C, the solid collected in step (a) is dissolved in methyl ethyl ketone, then methyl tert-butyl ether is added dropwise, and after the addition, seed crystals are added and stirred, and after the solid is precipitated The methyl tert-butyl ether was continued to be added dropwise with stirring, and then cooled to room temperature to obtain the crystal form I.
  • the seed crystal in step (b) is crystal form B.
  • the compound I and the compound Ia are the compound I and the compound Ia prepared in Preparation Example 1.
  • the main advantages of the present invention include: after intensive research, the inventors have obtained a series of polymorphs with good stability and low moisture absorption. These polymorphs have good physicochemical stability and can be further developed into medicines for the prevention and treatment of KRAS G12C mutation-related diseases.
  • FIG. 1 is the XRPD pattern of the crystal form A prepared in Example 1.
  • FIG. 1 is the XRPD pattern of the crystal form A prepared in Example 1.
  • FIG. 2 is the DSC chart of the crystal form A prepared in Example 1.
  • FIG. 3 is a TGA diagram of crystal form A prepared in Example 1.
  • FIG. 4 is the XRPD pattern of the crystal form B prepared in Examples 2-3, 9-12 and 15.
  • FIG. 4 is the XRPD pattern of the crystal form B prepared in Examples 2-3, 9-12 and 15.
  • FIG. 5 is the DSC chart of the crystal form B prepared in Example 2.
  • FIG. 6 is the XRPD pattern of the crystal form C prepared in Example 4.
  • FIG. 7 is the DSC chart of the crystal form C prepared in Example 4.
  • FIG. 8 is a TGA diagram of the crystal form C prepared in Example 4.
  • FIG. 8 is a TGA diagram of the crystal form C prepared in Example 4.
  • FIG. 9 is the XRPD pattern of the crystal form I prepared in Example 5.
  • FIG. 10 is the XRPD pattern of the crystal form D prepared in Example 7.
  • FIG. 10 is the XRPD pattern of the crystal form D prepared in Example 7.
  • FIG. 11 is the DSC chart of the crystal form D prepared in Example 7.
  • FIG. 12 is a TGA diagram of the crystal form D prepared in Example 7.
  • FIG. 12 is a TGA diagram of the crystal form D prepared in Example 7.
  • FIG. 13 is the XRPD pattern of the crystal form B prepared in Example 8.
  • FIG. 14 is a TGA diagram of Form B prepared in Example 8.
  • FIG. 14 is a TGA diagram of Form B prepared in Example 8.
  • FIG. 15 is the XRPD pattern of the crystal form F prepared in Example 13.
  • FIG. 15 is the XRPD pattern of the crystal form F prepared in Example 13.
  • FIG. 16 is the DSC chart of the crystal form F prepared in Example 13.
  • FIG. 17 is a TGA diagram of the crystal form F prepared in Example 13.
  • FIG. 17 is a TGA diagram of the crystal form F prepared in Example 13.
  • FIG. 18 is the XRPD pattern of the crystal form G prepared in Example 14.
  • FIG. 18 is the XRPD pattern of the crystal form G prepared in Example 14.
  • FIG. 19 is the DSC chart of the crystal form G prepared in Example 14.
  • FIG. 20 is a TGA diagram of the crystal form G prepared in Example 14.
  • FIG. 20 is a TGA diagram of the crystal form G prepared in Example 14.
  • FIG. 21 is the XRPD pattern of the crystal form H prepared in Example 16.
  • FIG. 22 is the DSC chart of the crystal form H prepared in Example 16.
  • FIG. 23 is a TGA diagram of the crystal form H prepared in Example 16.
  • FIG. 24 is an ellipsoid diagram of a molecular three-dimensional structure.
  • Figure 25-1 and Figure 25-2 show the fractional atomic coordinates and isotropic or equivalent isotropic displacement parameters of single crystal diffraction (fractional atomic coordinates and isotropic or equivalent isotropic displacement parameters). ).
  • Figure 26 is the single crystal diffraction atomic displacement parameters (Atomic displacement parameters) ).
  • Figure 27-1 and Figure 27-2 are the geometric parameters of single crystal diffraction (Geometric parameters) ).
  • the compounds of the present invention are in the form of compounds of formula (I) or atropisomers or mixtures thereof.
  • the structure of the compound of formula (I) is
  • the name is (4aR)-3-Acryloyl-11-chloro-10-(2-fluoro-6-hydroxyphenyl)-8-(2-isopropyl-4-methylpyridin-3-yl)-6 -(methyl- d3 )-2,3,4,4a,6,8-hexahydro-1H-pyrazino[1',2':4,5]pyrazino[2,3-c] [1,8]Naphthyridine-5,7-dione.
  • the compounds of formula (I) disclosed herein may exist in the form of isomers, which are conformational stereoisomers that occur when the rotation of a single bond in the molecule is prevented or greatly slowed down due to the generated by spatial interactions.
  • the compounds of formula (I) disclosed herein may be monomeric atropisomers or a mixture of all atropisomers, ie the compounds may exist either as individual atropisomers or as atropisomers body mixture. If the rotational barrier of the single bond is high enough and the interconversion between conformations is slow enough, separation of isomers can be allowed.
  • the compound of formula (I) has two atropisomer structures, namely compound Ia and compound Ib;
  • the two atropisomers obtained in the eleventh step of the preparation example 1 herein are compound Ia and compound Ib.
  • the compound of the present invention is preferably compound Ia.
  • Solids exist in either amorphous or crystalline form. In the case of crystalline forms, the molecules are localized within three-dimensional lattice sites. When a compound crystallizes out of a solution or slurry, it can crystallize in different spatial lattice arrangements (a property known as "polymorphism"), forming crystals with different crystalline forms that are referred to as "polymorphs”.
  • crystallization can be accomplished by various methods, specifically referring to the operation steps described in the examples of the present invention or referring to Crystallization, third edition, JW Mullens, Butterworth-Heineman Ltd., 1993, ISBN 0750611294. Seed crystals can be added to any crystallization mixture to promote crystallization.
  • Polymorphs of the present invention include polymorphs of Compound Ia or a polymorph of a pharmaceutically acceptable salt of Compound Ia.
  • crystal of the present invention crystalline form of the present invention
  • polymorph of the present invention and the like are used interchangeably.
  • the properties of the polymorphs of the present invention can be investigated by various means and instruments, eg, XRPD, DSC, TGA, and the like.
  • the polymorph of the present invention has a specific crystal form, and has a specific characteristic peak in the XRPD pattern.
  • the active ingredient of the present invention may be a pharmaceutically acceptable salt of a compound of the present invention or a polymorph of the present invention.
  • the active ingredient of the present invention can be used to inhibit the activity of KRAS G12C mutation. Therefore, the active ingredient of the present invention and the pharmaceutical composition comprising the active ingredient of the present invention can be used for the treatment or prevention of KRAS G12C mutation-related diseases, such as KRAS G12C mutation-related cancer.
  • the cancer can be a solid tumor.
  • the cancer includes, but is not limited to, one or more selected from the group consisting of lung cancer (eg, non-small cell lung cancer), pancreatic cancer, colorectal cancer, and the like.
  • the pharmaceutical composition of the present invention comprises the active ingredient of the present invention and a pharmaceutically acceptable carrier.
  • the pharmaceutical compositions of the present invention may also contain optional other therapeutic agents.
  • pharmaceutically acceptable carrier refers to a non-toxic, inert, solid, semi-solid substance or liquid filler, diluent, encapsulating material or adjuvant or any type of adjuvant, which is compatible with the patient, most Preferably a mammal, more preferably a human, is suitable for delivering an active agent to a target of interest without terminating the activity of the agent.
  • the medicament of the present invention may be used alone or in combination with one or more other therapeutic agents, depending on the situation.
  • the combined use may be the administration of one or more other therapeutic agents together with the use of the medicament of the present invention, or the administration of one or more other therapeutic agents prior to the use of the medicament of the present invention or the The drug is followed by one or more other therapeutic agents.
  • the active ingredients of the present invention may be administered in a suitable dosage form with one or more pharmaceutically acceptable carriers.
  • These dosage forms are suitable for oral, rectal, topical, intraoral, and other parenteral administration (eg, subcutaneous, intramuscular, intravenous, etc.).
  • dosage forms suitable for other parenteral administration include injections and the like.
  • the above-mentioned dosage forms can be prepared from the active ingredients of the present invention and one or more carriers or excipients through general pharmaceutical methods.
  • the aforementioned carriers need to be compatible with the active ingredients or other excipients of the present invention.
  • non-toxic carriers include, but are not limited to, mannitol, lactose, starch, magnesium stearate, glucose, sucrose, and the like.
  • Carriers for liquid preparations include water (preferably sterile water for injection) and the like.
  • the active ingredient of the present invention may be in solution or suspension with the above-mentioned carriers.
  • compositions of the present invention are formulated, dosed and administered in a manner consistent with standard medical practice.
  • a "therapeutically effective amount" of an active ingredient of the present invention to be administered is determined by factors such as the particular condition to be treated, the individual being treated, the cause of the condition, the target of the drug, and the mode of administration.
  • a “therapeutically effective amount” refers to an amount that produces function or activity in a patient (eg, a human and/or animal) and is acceptable to a human and/or animal.
  • the therapeutically effective amount of the active ingredient contained in the pharmaceutical composition of the present invention or the pharmaceutical composition is preferably 0.1 mg-5 g/kg (body weight).
  • the administered dose will generally be in the range of 0.02-5000 mg/day, eg, about 1-1500 mg/day.
  • the dose may be one dose, or concurrently administered doses, or divided doses at appropriate intervals, eg, two, three, four or more divided doses per day. It will be understood by those skilled in the art that although the above dosage range is given, the specific effective amount can be appropriately adjusted according to the patient's condition and in conjunction with the physician's diagnosis.
  • patient refers to an animal, preferably a mammal, more preferably a human.
  • mammal refers to warm-blooded vertebrate mammals including, for example, cats, dogs, rabbits, bears, foxes, wolves, monkeys, deer, mice, pigs and humans.
  • treating refers to alleviating, delaying the progression, attenuating, preventing or maintaining an existing disease or disorder (eg, cancer).
  • Treatment also includes curing, preventing the development or alleviating to some extent one or more symptoms of a disease or disorder.
  • a compound of formula (I) or a pharmaceutically acceptable salt thereof in the form of an atropisomer or mixture thereof or a pharmaceutically acceptable salt thereof as an active ingredient of the present invention A series of stable polymorphs can be prepared by a variety of synthetic methods well known to those skilled in the art, including the examples listed below, the embodiments formed by its combination with other chemical synthesis methods and the techniques in the art. Equivalent alternatives well known to the above persons, preferred embodiments include but are not limited to the embodiments of the present invention.
  • room temperature includes a temperature of 4-30°C, typically 15-30°C.
  • X-ray powder diffraction analysis adopts X'Pert3 X-ray powder diffraction analyzer, specific parameters: X-ray is Cu, k ⁇ ; K ⁇ 1 1.540598; K ⁇ 2 1.544426; intensity ratio K ⁇ 2/K ⁇ 1: 0.50; voltage is 45kV; current is 40mA; divergence slit: 1/8°; scanning mode: continuous; scanning range: 3° ⁇ 40°; scanning step: 0.0263°; each step Scanning time: 46.665s; Scanning time: 5min 03s.
  • X-ray powder diffraction analyzer specific parameters: X-ray: Cu, k ⁇ ; K ⁇ 1 1.540598; K ⁇ 2 1.544426; intensity ratio K ⁇ 2/K ⁇ 1: 0.50; voltage is 45kV; current is 40mA; divergence slit: automatic; scanning mode: continuous; scanning range: 3° ⁇ 40°; scanning step: 0.0167°; scanning time per step: 17.780s/33.020s; scan time: 5min 32s/10min 13s.
  • Thermogravimetric analysis was performed using a TA Q5000/Discovery 5500 thermogravimetric analyzer. Method: linear heating; sample pan: aluminum pan, open; temperature range: RT-350°C; heating rate: 10°C/min; protective gas: nitrogen.
  • DSC Differential Scanning Calorimetry
  • Single crystal test adopts D8Venture detection instrument, specific parameters: light source: Mo target; X-ray: Detector: CMOS area detector; Resolution: Current and voltage: 50kV, 1.4A; exposure time: 5s; distance from surface detector to sample: 40mm; test temperature: 170(2)K.
  • DCM dichloromethane
  • MTBE means methyl tert-butyl ether
  • MEK means methyl ethyl ketone
  • DMF means N,N-dimethylformamide.
  • Step 1 6,7-Dichloro-4-hydroxy-1-(2-isopropyl-4-methylpyridin-3-yl)-2-oxo-1,2-dihydro-1,8- Naphthyridine-3-carbonitrile (30.0 g, 77.319 mmol) was suspended in a mixed solution of 1,4-dioxane (120 mL) and water (120 mL), and concentrated sulfuric acid (120 mL) was slowly added. The reaction was stirred at 120°C for 36 hours.
  • Step 2 6,7-Dichloro-4-hydroxy-1-(2-isopropyl-4-methylpyridin-3-yl)-1,8-naphthyridin-2(1H)-one (3.16g , 8.705 mmol) was dissolved in acetic acid (15 mL), sodium nitrite (100 mg, 1.58 mmol) and concentrated nitric acid (5.0 mL, 74.52 mmol) were added successively, and the reaction was stirred at room temperature for 30 minutes.
  • Step 3 Add 6,7-dichloro-4-hydroxy-1-(2-isopropyl-4-methylpyridin-3-yl)-3-nitro-1,8 to a 100mL three-necked round bottom flask -Naphthyridin-2(1H)-one (3.5g, 8.570mmol), (2-fluoro-6-methoxyphenyl)boronic acid (5.8g, 34.10mmol), tetrakistriphenylphosphine palladium (1.15g, 0.9956 mmol), sodium carbonate (3.5 g, 33.02 mmol), 10 mL water and 40 mL dioxane. The system was replaced with nitrogen three times and then protected with a nitrogen balloon.
  • Step four 6-chloro-7-(2-fluoro-6-methoxyphenyl)-4-hydroxy-1-(2-isopropyl-4-methylpyridin-3-yl)-3-nitro Alkyl-1,8-naphthyridin-2(1H)-one (4.268 g, 8.57 mmol) was dissolved in acetonitrile (30 mL), followed by phosphorous oxychloride (7.5 g, 48.92 mmol) and N,N-diisopropyl Ethylamine (10.5 g, 81.24 mmol), the reaction was gradually warmed to 80 °C and stirred for 30 min.
  • reaction solution was concentrated, 30 mL of cold acetonitrile was added, added dropwise to 150 mL of saturated sodium bicarbonate solution under an ice-water bath, extracted with ethyl acetate (200 mL*2), the ethyl acetate phases were combined, and washed once with 200 mL of saturated brine.
  • Step 5 4,6-Dichloro-7-(2-fluoro-6-methoxyphenyl)-1-(2-isopropyl-4-methylpyridin-3-yl)-3-nitro -1,8-Naphthyridin-2(1H)-one (2.5 g, 4.843 mmol) was dissolved in N,N-dimethylacetamide (25 mL), followed by the addition of 1-(tert-butyl)3-methyl ( R)-piperazine-1,3-dicarboxylate (3.5 g, 14.34 mmol) and N,N-diisopropylethylamine (2.0 g, 15.47 mmol) and the reaction was stirred at 120°C for 2 hours.
  • Step Six 1-(tert-Butyl)3-methyl(3R)-4-(6-chloro-7-(2-fluoro-6-methoxyphenyl)-1-(2-isopropyl- 4-Methylpyridin-3-yl)-3-nitro-2-oxo-1,2-dihydro-1,8-naphthyridin-4-yl)piperazine-1,3-dicarboxylate (2.7 g, 3.728 mmol) was dissolved in acetic acid (30 mL), iron powder (835 mg, 14.91 mmol) was added, and the reaction was stirred at 80° C. for 30 minutes.
  • Step 7 Add tert-butyl(4aR)-11-chloro-10-(2-fluoro-6-methoxyphenyl)-8-(2-isopropyl-4-methyl) into the 150mL sealed tube in turn Pyridin-3-yl)-5,7-dioxo-1,2,4,4a,5,6,7,8-octahydro-3H-pyrazino[1',2':4,5]pyridine
  • Azino[2,3-c][1,8]naphthyridine-3-carboxylate 0.5 g, 0.7549 mmol
  • 10 mL of acetone anhydrous potassium carbonate (416 mg, 3.02 mmol), deuterated iodomethane (1.09 g, 7.549 mmol).
  • Step Eight tert-Butyl(4aR)-11-chloro-10-(2-fluoro-6-methoxyphenyl)-8-(2-isopropyl-4-methylpyridin-3-yl)- 6-(Methyl-d 3 )-5,7-dioxo-1,2,4,4a,5,6,7,8-octahydro-3H-pyrazino[1',2':4 ,5]pyrazino[2,3-c][1,8]naphthyridine-3-carboxylate (512.5 mg, 0.7549 mmol) was dissolved in dichloromethane (8 mL) and trifluoroacetic acid (2 mL) was added.
  • Step 9 (4aR)-11-chloro-10-(2-fluoro-6-methoxyphenyl)-8-(2-isopropyl-4-methylpyridin-3-yl)-6-( Methyl-d 3 )-2,3,4,4a,6,8-hexahydro-1H-pyrazino[1',2':4,5]pyrazino[2,3-c][1 ,8]Naphthyridine-5,7-dione (437.1 mg, 0.7549 mmol) was dissolved in dichloromethane (10 mL) and triethylamine (3.0 mL, 21.62 mmol) was added.
  • Step 10 Under ice-water bath conditions, (4aR)-3-acryloyl-11-chloro-10-(2-fluoro-6-methoxyphenyl)-8-(2-isopropyl-4-methyl) pyridin-3-yl)-6-(methyl- d3 )-2,3,4,4a,6,8-hexahydro-1H-pyrazino[1',2':4,5]pyridine
  • Azino[2,3-c][1,8]naphthyridine-5,7-dione (240 mg, 0.3791 mmol) was added to dry dichloromethane (6.0 mL) followed by boron tribromide (5.0 mL) , 5.0 mmol), warmed to room temperature and reacted overnight.
  • Structural analysis and refinement process After the diffraction data were integrated and reduced by the SAINT program, the data were subjected to empirical absorption correction by the SADABS program; the single crystal structure was analyzed by the direct method using SHELXT2014, and the structure was refined by the least squares method.
  • the atom refinement process is obtained by isotropic calculation, and the hydrogen atoms on C-H are obtained by computational hydrogenation, and the riding model is used for refinement.
  • the Flack constant is 0.02 (7), and the chiral center sees that C26 is R configuration.
  • the isomer 2 obtained in step eleven is compound Ia, and the structure is as follows:
  • Its XRPD data is shown in Table 8 and Figure 21. Its DSC data are shown in Figure 22. Its TGA data is shown in Figure 23.
  • NCI-H358 is a Kras G12C mutant human non-small cell lung cancer cell line, cultured in 10% FBS RPMI-1640 medium;
  • A549 is a Kras G12S mutant human lung adenocarcinoma cell line, cultured in 10% FBS F-12K base.
  • DMSO DMSO to prepare 1000X compound 3.16 times gradient concentration stock solution
  • use 2% FBS medium to dilute 100 times to 10X compound stock solution
  • the concentration is 1X and the DMSO content is 0.1%.
  • DMSO was used as experimental control (control)
  • 2% FBS medium was used as blank control (blank).
  • Proliferation inhibition rate IR(%) (RLU control-RLU compound)/(RLU control-RLU blank) ⁇ 100%, use Prism 6 four-parameter method to fit compound gradient dilution concentration and corresponding cell proliferation inhibition rate, and calculate IC 50 value.
  • Table 9 shows that compound I and its isomer 2 (retention time is 3.683 min, the same below) have higher inhibitory activity on Kras G12C mutant NCI-H358 cells, while the inhibitory activity on A549 cells is higher. Low, with obvious selective inhibitory activity.
  • MIA PaCa2 is a Kras G12C mutant human pancreatic cancer cell line, cultured in 10% FBS+2.5% Horse serum DMEM medium. Take the cells in the logarithmic growth phase, digest the cells with EDTA to collect and count and inoculate 2.5E4 cells in 96 wells in cell culture plates and cultured overnight. Use DMSO to prepare 1000X compound 3.16-fold gradient concentration stock solution, dilute 200-fold with medium to 5X compound stock solution, on the second day after cell inoculation, add 5X compound stock solution to each cell culture well, the final concentration is 1X, The DMSO content was 0.1%. DMSO was used as experimental control. After two hours of incubation with compound addition, residual medium was removed.
  • MIA PaCa-2 is a Kras G12C mutant human pancreatic cancer cell line, cultured in 10% FBS+2.5% Horse Serum DMEM medium; A549 is a Kras G12S mutant human lung adenocarcinoma cell line, cultured in 10% FBS F- 12K medium. The cells in the logarithmic growth phase were taken, digested with trypsin EDTA, collected and counted, and 200 MIAPaCa-2 or 400 A549 cells were respectively inoculated into 384-well spheroid plates and cultured overnight to establish a 3D cell model.
  • DMSO DMSO to prepare a 3.16-fold gradient concentration stock solution of 1000X compound, dilute 100-fold with medium to 10X compound stock solution, on the second day after cell seeding, add 10X compound stock solution to each cell culture well, the final concentration is 1X, The DMSO content was 0.1%. DMSO was used as the experimental control, and the medium was used as the blank control. After adding the compound and culturing the cells for 5 days, add 30 ⁇ L of CellTiter-Glo working solution to each well, mix and incubate for 30 minutes, and then transfer 40 ⁇ L of the mixture to a white bottom impermeable 384-well plate, read the luminescence chemiluminescence value, and count the cells.
  • Proliferation inhibition rate IR(%) (RLU control-RLU compound)/(RLU control-RLU blank) ⁇ 100%, using the XLFit four-parameter method to fit the compound gradient dilution concentration and the corresponding cell proliferation inhibition rate, and calculate the IC50 value. The results are shown in Table 11.
  • Test example 4 KRas G12C NEA-HTRF experiment
  • Compound 3.16-fold gradient stocks at 1000X were prepared in DMSO and diluted 250-fold to 4X compound stocks using reaction buffer (40 mM HEPES, 10 mM MgCl2 , 1 mM DTT, 0.002% Triton X-100).
  • KRas G12C-GDP/Tb working solution 40 nM KRas G12C-GDP, 1 ⁇ anti-his Tb
  • SOS1/GTP working solution 0.2 ⁇ M SOS1, 200 ⁇ M GTP
  • the T0 group was set to 10 ⁇ l reaction buffer + 10 ⁇ L KRas G12C-GDP/Tb working solution, and the fluorescence value was directly read.
  • RLU fluorescence signal ratio
  • IR(%) (RLU compound -RLU control )/(RLU T0 -RLU control ) ⁇ 100%, fit using four-parameter method
  • the compound serial dilution concentration and the corresponding inhibition rate were used to calculate the IC50 value. The results are shown in Table 12.
  • MIA PaCa-2 cells Female BALB/c nude mice, 6-8 weeks old, weighing 18-20 g. MIA PaCa-2 cells were cultured in DMEM medium supplemented with 10% FBS, 2.5% HS and 1% penicillin-streptomycin in an incubator at 37°C, 5% CO 2 , the cells were collected and seeded subcutaneously via the right back MIA PaCa- 2 cells (human pancreatic cancer cells) were inoculated with 2.0 x 106 cells per animal (0.1 mL per animal). When the tumor grows to 190-311 mm 3 , mice with appropriate tumor size are selected for administration into groups, and the dosage is shown in Table 13 below.
  • the animals were weighed with an electronic balance every day, and the tumor volume was investigated with a vernier caliper twice a week.
  • the tumor volume was used to calculate the tumor growth inhibition rate (TGI), and the TGI displayed as a percentage was used to indicate the antitumor activity of the drug.
  • TGI tumor growth inhibition rate
  • Tumor volume data are shown as mean ⁇ standard error (SEM).
  • SEM standard error

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Abstract

提供一种KRAS抑制剂的盐或多晶型物，具体地，提供式(Ia)所示化合物的药学上可接受的盐或该化合物的多晶型物，及其制备方法和在制备治疗或预防KRAS G12C突变相关疾病的药物中的应用。

Description

KRAS抑制剂的盐或多晶型物 技术领域
本发明属于医药技术领域，具体地，涉及一种KRAS抑制剂的盐或多晶型物，及其制法和用途。
背景技术
肺癌是全球发病率最高的癌症，在中国肺癌发病率位居所有癌症中第一位，也是中国发病率和死亡率最高的癌症，根据2016年美国癌症协会公布的数据，世界上一年中约180万人罹患肺癌，其中接近80％的肺癌为非小细胞肺癌(NSCLC)。在肺癌中，约32％的肺癌中确认有RAS基因的突变，RAS(HRAS、NRAS或KRAS)基因的三种主要亚型中的任意一个突变可导致人肿瘤的发生。有报道指出，在RAS基因中突变频率最高的为KRAS基因，在25-30％肿瘤中检测到KRAS突变。与之相比较，NRAS及HRAS家族成员中发生致癌性突变的比率低得多(分别为8％及3％)。最常见的KRAS突变发现于P环中的残基G12及G13上以及残基Q61上。G12C突变为KRAS基因的频繁突变(甘氨酸-12突变为半胱氨酸)。在约13％的癌症，约43％的肺癌及几乎100％的MYH相关息肉病(家族性结肠癌症候群)中已发现此突变。因此开发选择性抑制KRAS突变的抑制剂是一个较好的方向，为了提高对KRAS突变抑制活性的同时降低对野生型KRAS的抑制活性，开发活性更高、选择性更好、毒性更低的新型KRAS突变体选择性抑制剂具有重要的意义。
发明内容
本发明的目的在于提供式(I)所示化合物的阻转异构体的一系列稳定的多晶型物，并提供了它们的制备方法和用途。
本发明第一方面提供了一种化合物Ia的多晶型物，
Figure PCTCN2022088577-appb-000001
在另一优选例中，所述多晶型物为晶型A，所述晶型A具有X-射线粉末衍射特征峰，所述X-射线粉末衍射特征峰在选自下组的2θ值处：6.02±0.2°、11.90±0.2°、12.84±0.2°、17.04±0.2°、19.62±0.2°。
在另一优选例中，所述晶型A具有X-射线粉末衍射特征峰，所述X-射线粉末衍射特征峰在选自下组的2θ值处：6.02±0.2°、11.90±0.2°、12.84±0.2°、17.04±0.2°、17.34±0.2°、19.62±0.2°、21.04±0.2°、24.10±0.2°、26.00±0.2°。
在另一优选例中，所述晶型A具有X-射线粉末衍射特征峰，所述X-射线粉末衍射特征峰在选自下组的2θ值处：6.02±0.2°、11.90±0.2°、12.84±0.2°、13.78±0.2°、16.14±0.2°、17.04±0.2°、17.34±0.2°、18.72±0.2°、 19.62±0.2°、20.74±0.2°、21.04±0.2°、22.70±0.2°、23.22±0.2°、24.10±0.2°、24.80±0.2°、25.14±0.2°、26.00±0.2°、26.46±0.2°、28.72±0.2°。
在另一优选例中，所述晶型A具有X-射线粉末衍射特征峰，所述X-射线粉末衍射特征峰在选自表1中的一个或多个(例如2个、3个、4个、5个、6个、7个、8个、9个、更多或全部)2θ值处。
在另一优选例中，所述晶型A的X-射线粉末衍射图基本如图1所示。
在另一优选例中，所述晶型A的差示扫描量热法分析谱图在278.84±6℃和292.69±6℃处有特征峰。
在另一优选例中，所述晶型A的差示扫描量热法分析谱图在278.84±3℃和292.69±3℃处有特征峰。
在另一优选例中，所述晶型A的差示扫描量热法分析谱图还在96.96±6℃和188.88±6℃处有特征峰。
在另一优选例中，所述晶型A的差示扫描量热法分析谱图还在96.96±3℃和188.88±3℃处有特征峰。
在另一优选例中，所述晶型A的差示扫描量热法分析谱图基本如图2所示。
在另一优选例中，所述晶型A的热重分析谱图在63.07±10℃失重1.34％±1％。
在另一优选例中，所述晶型A的热重分析谱图在288.52±10℃再次失重5.93％±1％。
在另一优选例中，所述晶型A的热重分析谱图基本如图3所示。
在另一优选例中，所述多晶型物为晶型B，所述晶型B具有X-射线粉末衍射特征峰，所述X-射线粉末衍射特征峰在选自下组的2θ值处：11.38±0.2°、11.94±0.2°、12.56±0.2°、17.36±0.2°、18.18±0.2°、20.60±0.2°、20.82±0.2°、24.94±0.2°。
在另一优选例中，所述晶型B具有X-射线粉末衍射特征峰，所述X-射线粉末衍射特征峰在选自下组的2θ值处：10.02±0.2°、11.38±0.2°、11.94±0.2°、12.18±0.2°、12.56±0.2°、13.32±0.2°、13.66±0.2°、17.36±0.2°、18.18±0.2°、18.96±0.2°、20.20±0.2°、20.60±0.2°、20.82±0.2°、24.94±0.2°、26.24±0.2°、29.92±0.2°、30.60±0.2°。
在另一优选例中，所述晶型B具有X-射线粉末衍射特征峰，所述X-射线粉末衍射特征峰在选自下组的2θ值处：10.02±0.2°、11.38±0.2°、11.94±0.2°、12.18±0.2°、12.56±0.2°、13.32±0.2°、13.66±0.2°、15.62±0.2°、17.36±0.2°、18.18±0.2°、18.96±0.2°、19.58±0.2°、20.20±0.2°、20.60±0.2°、20.82±0.2°、21.52±0.2°、23.72±0.2°、24.94±0.2°、26.24±0.2°、29.92±0.2°、30.60±0.2°。
在另一优选例中，所述晶型B具有X-射线粉末衍射特征峰，所述X-射线粉末衍射特征峰在选自表2中的一个或多个(例如2个、3个、4个、5个、6个、7个、8个、9个、更多或全部)2θ值处。
在另一优选例中，所述晶型B的X-射线粉末衍射图基本如图4所示。
在另一优选例中，所述晶型B的X-射线粉末衍射图基本如图13所示。
在另一优选例中，所述晶型B的差示扫描量热法分析谱图在291.11±6℃处有特征峰。
在另一优选例中，所述晶型B的差示扫描量热法分析谱图在291.11±3℃处有特征峰。
在另一优选例中，所述晶型B的差示扫描量热法分析谱图基本如图5所示。
在另一优选例中，所述晶型B的热重分析谱图在301.42±10℃失重0.85％±0.8％。
在另一优选例中，所述晶型B的热重分析谱图基本如图14所示。
在另一优选例中，所述多晶型物为晶型C，所述晶型C具有X-射线粉末衍射特征峰，所述X-射线粉末衍射特征峰在选自下组的2θ值处：6.28±0.2°、12.12±0.2°、17.02±0.2°、18.12±0.2°。
在另一优选例中，所述晶型C具有X-射线粉末衍射特征峰，所述X-射线粉末衍射特征峰在选自下组的2θ值处：6.28±0.2°、12.12±0.2°、12.46±0.2°、14.98±0.2°、17.02±0.2°、18.12±0.2°、19.40±0.2°、20.22±0.2°、23.66±0.2°。
在另一优选例中，所述晶型C具有X-射线粉末衍射特征峰，所述X-射线粉末衍射特征峰在选自下组的 2θ值处：6.28±0.2°、12.12±0.2°、12.46±0.2°、14.98±0.2°、17.02±0.2°、18.12±0.2°、19.40±0.2°、20.22±0.2°、23.66±0.2°、25.26±0.2°、26.74±0.2°、28.94±0.2°。
在另一优选例中，所述晶型C具有X-射线粉末衍射特征峰，所述X-射线粉末衍射特征峰在选自表3中的一个或多个(例如2个、3个、4个、5个、6个、7个、8个、9个、更多或全部)2θ值处。
在另一优选例中，所述晶型C的X-射线粉末衍射图基本如图6所示。
在另一优选例中，所述晶型C的差示扫描量热法分析谱图在292.25±6℃处有特征峰。
在另一优选例中，所述晶型C的差示扫描量热法分析谱图在292.25±3℃处有特征峰。
在另一优选例中，所述晶型C的差示扫描量热法分析谱图还在122.79±6℃处有特征峰。
在另一优选例中，所述晶型C的差示扫描量热法分析谱图还在122.79±3℃处有特征峰。
在另一优选例中，所述晶型C的差示扫描量热法分析谱图基本如图7所示。
在另一优选例中，所述晶型C的热重分析谱图在103.15±10℃失重5.54％±1％。
在另一优选例中，所述晶型C的热重分析谱图基本如图8所示。
在另一优选例中，所述多晶型物为晶型D，所述晶型D具有X-射线粉末衍射特征峰，所述X-射线粉末衍射特征峰在选自下组的2θ值处：3.82±0.2°、10.96±0.2°、14.28±0.2°、18.52±0.2°、19.22±0.2°。
在另一优选例中，所述晶型D具有X-射线粉末衍射特征峰，所述X-射线粉末衍射特征峰在选自下组的2θ值处：3.82±0.2°、7.45±0.2°、9.62±0.2°、10.96±0.2°、11.58±0.2°、13.26±0.2°、14.28±0.2°、18.52±0.2°、19.22±0.2°、20.28±0.2°、20.74±0.2°、24.46±0.2°、24.68±0.2°。
在另一优选例中，所述晶型D具有X-射线粉末衍射特征峰，所述X-射线粉末衍射特征峰在选自下组的2θ值处：3.82±0.2°、7.45±0.2°、9.62±0.2°、10.96±0.2°、11.58±0.2°、13.26±0.2°、14.28±0.2°、16.12±0.2°、18.52±0.2°、19.22±0.2°、20.28±0.2°、20.74±0.2°、22.24±0.2°、22.62±0.2°、24.46±0.2°、24.68±0.2°、26.20±0.2°、27.47±0.2°。
在另一优选例中，所述晶型D具有X-射线粉末衍射特征峰，所述X-射线粉末衍射特征峰在选自表5中的一个或多个(例如2个、3个、4个、5个、6个、7个、8个、9个、更多或全部)2θ值处。
在另一优选例中，所述晶型D的X-射线粉末衍射图基本如图10所示。
在另一优选例中，所述晶型D的差示扫描量热法分析谱图在293.27±6℃处有特征峰。
在另一优选例中，所述晶型D的差示扫描量热法分析谱图在293.27±3℃处有特征峰。
在另一优选例中，所述晶型D的差示扫描量热法分析谱图还在91.23±6℃处有特征峰。
在另一优选例中，所述晶型D的差示扫描量热法分析谱图还在91.23±3℃处有特征峰。
在另一优选例中，所述晶型D的差示扫描量热法分析谱图基本如图11所示。
在另一优选例中，所述晶型D的热重分析谱图在65.10±10℃失重9.08±2％。
在另一优选例中，所述晶型D的热重分析谱图在219.18±10℃再次失重13.72±2％。
在另一优选例中，所述晶型D的热重分析谱图基本如图12所示。
在另一优选例中，所述多晶型物为晶型F，所述晶型F具有X-射线粉末衍射特征峰，所述X-射线粉末衍射特征峰在选自下组的2θ值处：3.52±0.2°、10.12±0.2°、14.88±0.2°、17.14±0.2°、22.48±0.2°。
在另一优选例中，所述晶型F具有X-射线粉末衍射特征峰，所述X-射线粉末衍射特征峰在选自下组的2θ值处：3.52±0.2°、10.12±0.2°、14.88±0.2°、15.70±0.2°、17.14±0.2°、22.48±0.2°、26.52±0.2°、27.56±0.2°。
在另一优选例中，所述晶型F具有X-射线粉末衍射特征峰，所述X-射线粉末衍射特征峰在选自下组的2θ值处：3.52±0.2°、8.18±0.2°、9.04±0.2°、10.12±0.2°、11.32±0.2°、14.02±0.2°、14.88±0.2°、15.70±0.2°、 16.40±0.2°、17.14±0.2°、20.44±0.2°、22.48±0.2°、24.21±0.2°、26.52±0.2°、27.56±0.2°、28.82±0.2°、31.04±0.2°。
在另一优选例中，所述晶型F具有X-射线粉末衍射特征峰，所述X-射线粉末衍射特征峰在选自表6中的一个或多个(例如2个、3个、4个、5个、6个、7个、8个、9个、更多或全部)2θ值处。
在另一优选例中，所述晶型F的X-射线粉末衍射图基本如图15所示。
在另一优选例中，所述晶型F的差示扫描量热法分析谱图在293.17±6℃处有特征峰。
在另一优选例中，所述晶型F的差示扫描量热法分析谱图在293.17±3℃处有特征峰。
在另一优选例中，所述晶型F的差示扫描量热法分析谱图还在93.69±6℃处有特征峰。
在另一优选例中，所述晶型F的差示扫描量热法分析谱图还在93.69±3℃处有特征峰。
在另一优选例中，所述晶型F的差示扫描量热法分析谱图还在128.9±6℃处有特征峰。
在另一优选例中，所述晶型F的差示扫描量热法分析谱图还在128.9±3℃处有特征峰。
在另一优选例中，所述晶型F的差示扫描量热法分析谱图还在188.58±6℃处有特征峰。
在另一优选例中，所述晶型F的差示扫描量热法分析谱图还在188.58±3℃处有特征峰。
在另一优选例中，所述晶型F的差示扫描量热法分析谱图基本如图16所示。
在另一优选例中，所述晶型F的热重分析谱图在131.41±10℃失重8.20±2％。
在另一优选例中，所述晶型F的热重分析谱图基本如图17所示。
在另一优选例中，所述多晶型物为晶型G，所述晶型G具有X-射线粉末衍射特征峰，所述X-射线粉末衍射特征峰在选自下组的2θ值处：12.08±0.2°、13.00±0.2°、17.04±0.2°、19.64±0.2°、23.18±0.2°、24.64±0.2°、26.02±0.2°。
在另一优选例中，所述晶型G具有X-射线粉末衍射特征峰，所述X-射线粉末衍射特征峰在选自下组的2θ值处：12.08±0.2°、13.00±0.2°、17.04±0.2°、19.64±0.2°、21.62±0.2°、22.61±0.2°、23.18±0.2°、24.64±0.2°、25.52±0.2°、26.02±0.2°、26.90±0.2°、31.32±0.2°。
在另一优选例中，所述晶型G具有X-射线粉末衍射特征峰，所述X-射线粉末衍射特征峰在选自下组的2θ值处：5.97±0.2°、12.08±0.2°、13.00±0.2°、13.94±0.2°、17.04±0.2°、17.44±0.2°、18.74±0.2°、19.64±0.2°、20.86±0.2°、21.62±0.2°、22.61±0.2°、23.18±0.2°、24.64±0.2°、25.52±0.2°、26.02±0.2°、26.90±0.2°、27.96±0.2°、29.08±0.2°、31.32±0.2°、37.96±0.2°。
在另一优选例中，所述晶型G具有X-射线粉末衍射特征峰，所述X-射线粉末衍射特征峰在选自表7中的-个或多个(例如2个、3个、4个、5个、6个、7个、8个、9个、更多或全部)2θ值处。
在另一优选例中，所述晶型G的X-射线粉末衍射图基本如图18所示。
在另一优选例中，所述晶型G的差示扫描量热法分析谱图在236.90±6℃处有特征峰。
在另一优选例中，所述晶型G的差示扫描量热法分析谱图在236.90±3℃处有特征峰。
在另一优选例中，所述晶型G的差示扫描量热法分析谱图还在115.47±6℃处有特征峰。
在另一优选例中，所述晶型G的差示扫描量热法分析谱图还在115.47±3℃处有特征峰。
在另一优选例中，所述晶型G的差示扫描量热法分析谱图还在188.86±6℃处有特征峰。
在另一优选例中，所述晶型G的差示扫描量热法分析谱图还在188.86±3℃处有特征峰。
在另一优选例中，所述晶型G的差示扫描量热法分析谱图还在212.67±6℃处有特征峰。
在另一优选例中，所述晶型G的差示扫描量热法分析谱图还在212.67±3℃处有特征峰。
在另一优选例中，所述晶型G的差示扫描量热法分析谱图基本如图19所示。
在另一优选例中，所述晶型G的热重分析谱图在111.37±10℃失重36.72±5％。
在另一优选例中，所述晶型G的热重分析谱图在198.38±10℃再次失重7.11±2％。
在另一优选例中，所述晶型G的热重分析谱图在283.44±10℃再次失重4.53±2％。
在另一优选例中，所述晶型G的热重分析谱图在328.53±10℃再次失重1.60±1％。
在另一优选例中，所述晶型G的热重分析谱图基本如图20所示。
在另一优选例中，所述多晶型物为晶型H，所述晶型H具有X-射线粉末衍射特征峰，所述X-射线粉末衍射特征峰在选自下组的2θ值处：10.00±0.2°、10.22±0.2°、14.10±0.2°、17.94±0.2°、19.00±0.2°。
在另一优选例中，所述晶型H具有X-射线粉末衍射特征峰，所述X-射线粉末衍射特征峰在选自下组的2θ值处：10.00±0.2°、10.22±0.2°、11.74±0.2°、12.12±0.2°、14.10±0.2°、14.38±0.2°、14.82±0.2°、15.94±0.2°、17.94±0.2°、19.00±0.2°、19.22±0.2°、20.22±0.2°、22.26±0.2°、25.10±0.2°、26.84±0.2°。
在另一优选例中，所述晶型H具有X-射线粉末衍射特征峰，所述X-射线粉末衍射特征峰在选自下组的2θ值处：8.12±0.2°、10.00±0.2°、10.22±0.2°、11.74±0.2°、12.12±0.2°、13.44±0.2°、14.10±0.2°、14.38±0.2°、14.82±0.2°、15.62±0.2°、15.94±0.2°、17.94±0.2°、19.00±0.2°、19.22±0.2°、19.64±0.2°、20.22±0.2°、22.26±0.2°、22.64±0.2°、24.30±0.2°、25.10±0.2°、26.84±0.2°、27.36±0.2°、29.08±0.2°。
在另一优选例中，所述晶型H具有X-射线粉末衍射特征峰，所述X-射线粉末衍射特征峰在选自表8中的一个或多个(例如2个、3个、4个、5个、6个、7个、8个、9个、更多或全部)2θ值处。
在另一优选例中，所述晶型H的X-射线粉末衍射图基本如图21所示。
在另一优选例中，所述晶型H的差示扫描量热法分析谱图在294.49±6℃处有特征峰。
在另一优选例中，所述晶型H的差示扫描量热法分析谱图在294.49±3℃处有特征峰。
在另一优选例中，所述晶型H的差示扫描量热法分析谱图在218.00±6℃处有特征峰。
在另一优选例中，所述晶型H的差示扫描量热法分析谱图在218.00±3℃处有特征峰。
在另一优选例中，所述晶型H的差示扫描量热法分析谱图在243.69±6℃处有特征峰。
在另一优选例中，所述晶型H的差示扫描量热法分析谱图在243.69±3℃处有特征峰。
在另一优选例中，所述晶型H的差示扫描量热法分析谱图基本如图22所示。
在另一优选例中，所述晶型H的热重分析谱图在207.40±10℃失重8.73±2％。
在另一优选例中，所述晶型H的热重分析谱图在278.89±2℃失重1.34±1％。
在另一优选例中，所述晶型H的热重分析谱图基本如图23所示。
在另一优选例中，所述多晶型物为晶型I，所述晶型I具有X-射线粉末衍射特征峰，所述X-射线粉末衍射特征峰在选自下组的2θ值处：6.92±0.2°、8.54±0.2°、10.70±0.2°、17.28±0.2°。
在另一优选例中，所述晶型I具有X-射线粉末衍射特征峰，所述X-射线粉末衍射特征峰在选自下组的2θ值处：6.92±0.2°、8.54±0.2°、10.70±0.2°、11.54±0.2°、11.98±0.2°、12.48±0.2°、17.28±0.2°、19.14±0.2°、19.50±0.2°、25.02±0.2°、25.60±0.2°。
在另一优选例中，所述晶型I具有X-射线粉末衍射特征峰，所述X-射线粉末衍射特征峰在选自下组的2θ值处：6.92±0.2°、8.54±0.2°、10.70±0.2°、11.26±0.2°、11.54±0.2°、11.98±0.2°、12.48±0.2°、13.14±0.2°、15.12±0.2°、15.94±0.2°、17.28±0.2°、19.14±0.2°、19.50±0.2°、25.02±0.2°、25.60±0.2°、26.52±0.2°、30.62±0.2°。
在另一优选例中，所述晶型I具有X-射线粉末衍射特征峰，所述X-射线粉末衍射特征峰在选自表4中的一个或多个(例如2个、3个、4个、5个、6个、7个、8个、9个、更多或全部)2θ值处。
在另一优选例中，所述晶型I的X-射线粉末衍射图基本如图9所示。
本发明第二方面提供了一种化合物Ia的药学上可接受的盐，所述药学上可接受的盐为盐酸盐、磷酸盐、 硫酸盐、甲酸盐或丙酸盐。
Figure PCTCN2022088577-appb-000002
本发明另一方面提供了一种药物组合物，包含(a)第一方面所述的多晶型物或第二方面所述的药学上可接受的盐；和(b)药学上可接受的载体。
本发明另一方面提供了第一方面所述的多晶型物或第二方面所述的药学上可接受的盐的用途，用于制备预防或治疗KRAS G12C突变相关疾病的药物。
在另一优选例中，所述KRAS G12C突变相关疾病为癌症。
在另一优选例中，所述癌症为实体瘤。例如选自下组的一种或多种癌症：肺癌(例如非小细胞肺癌)、胰腺癌、结肠直肠癌。
本发明另一方面提供了晶型A的制备方法，所述方法包括步骤：
在40-60℃下将化合物Ia在异丙醇中搅拌后，冷却至室温，过滤，从而得到所述的晶型A；或
在室温下，将晶型I溶于丙酮中，然后往溶液中添加水，过滤，从而得到所述的晶型A。
本发明另一方面提供了晶型B的制备方法，所述方法包括步骤：
在40-60℃下将化合物Ia在有机溶剂中搅拌后，过滤，从而得到所述的晶型B；其中所述有机溶剂为正庚烷或者为二氯甲烷和甲基叔丁基醚的混合物；或
将晶型I与有机溶剂混合后在40-60℃下搅拌，然后过滤，从而得到所述的晶型B；其中所述有机溶剂选自下组：甲苯、氯仿、1，2-二氯乙烷、氯仿和甲基叔丁基醚的混合物、乙腈和甲苯的混合物；或
在室温下，将晶型I与乙腈混合后加入二氯甲烷溶清；然后除去乙腈和二氯甲烷，从而得到所述的晶型B。
本发明另一方面提供了晶型C的制备方法，所述方法包括步骤：在40-60℃下，将化合物Ia在乙酸乙酯和正庚烷的混合物中搅拌后，过滤，从而得到所述的晶型C。
本发明另一方面提供了晶型D的制备方法，所述方法包括步骤：在室温下，将晶型I溶于DMF中，然后往溶液中添加水，从而得到所述的晶型D。
本发明另一方面提供了晶型F的制备方法，所述方法包括步骤：在40-60℃下，将晶型I在水中搅拌后，过滤，从而得到所述的晶型F。
本发明另一方面提供了晶型G的制备方法，所述方法包括步骤：在室温下，将晶型I与DMSO混合，然后往体系中添加水后搅拌并过滤，从而得到所述的晶型G。
本发明另一方面提供了晶型H的制备方法，所述方法包括步骤：在室温下，将晶型B溶于乙腈和甲苯的混合物中，然后往溶液中添加甲苯；然后升温至45-55℃并搅拌，过滤，从而得到所述的晶型H。
本发明另一方面提供了晶型I的制备方法，所述方法包括步骤：
(a)在40-30℃下，将化合物I溶于二氯甲烷中，然后滴加甲基叔丁基醚并搅拌，过滤收集析出的固体；和
(b)在55-65℃下，将步骤(a)收集到的固体溶于甲基乙基酮中，然后滴加甲基叔丁基醚，加完后加入晶种并搅拌，析出固体后继续滴加甲基叔丁基醚并搅拌，然后冷却至室温，从而得到所述的晶型I。
在一优选例中，步骤(b)所述晶种为晶型B。
在另一优选例中，所述化合物I、化合物Ia为制备例1制备的化合物I、化合物Ia。
本发明的主要优点包括：经过深入研究发明人获得了一系列稳定性好、不易吸湿的多晶型物。这些多晶型物具有良好的物理化学稳定性，可进一步开发成为药物，用于预防和治疗KRAS G12C突变相关的疾病。
应理解，在本发明范围内中，本发明的上述各技术特征和在下文(如实施例)中具体描述的各技术特征之间都可以互相组合，从而构成新的或优选的技术方案。限于篇幅，在此不再一一累述。
附图说明
图1为实施例1制备的晶型A的XRPD图。
图2为实施例1制备的晶型A的DSC图。
图3为实施例1制备的晶型A的TGA图。
图4为实施例2-3、9-12、15制备的晶型B的XRPD图。
图5为实施例2制备的晶型B的DSC图。
图6为实施例4制备的晶型C的XRPD图。
图7为实施例4制备的晶型C的DSC图。
图8为实施例4制备的晶型C的TGA图。
图9为实施例5制备的晶型I的XRPD图。
图10为实施例7制备的晶型D的XRPD图。
图11为实施例7制备的晶型D的DSC图。
图12为实施例7制备的晶型D的TGA图。
图13为实施例8制备的晶型B的XRPD图。
图14为实施例8制备的晶型B的TGA图。
图15为实施例13制备的晶型F的XRPD图。
图16为实施例13制备的晶型F的DSC图。
图17为实施例13制备的晶型F的TGA图。
图18为实施例14制备的晶型G的XRPD图。
图19为实施例14制备的晶型G的DSC图。
图20为实施例14制备的晶型G的TGA图。
图21为实施例16制备的晶型H的XRPD图。
图22为实施例16制备的晶型H的DSC图。
图23为实施例16制备的晶型H的TGA图。
图24为分子立体结构椭球图。
图25-1和图25-2为单晶衍射分数原子坐标和各向同性或等效各向同性位移参数(Fractional atomic coordinates and isotropic or equivalent isotropic displacement parameters
Figure PCTCN2022088577-appb-000003
)。
图26为单晶衍射原子位移参数(Atomic displacement parameters
Figure PCTCN2022088577-appb-000004
)。
图27-1和图27-2为单晶衍射几何参数(Geometric parameters
Figure PCTCN2022088577-appb-000005
)。
各图中“peak temperature”表示峰温度。
具体实施方式
本发明化合物为式(I)化合物或其阻转异构体或其混合物形式。式(I)化合物结构为
Figure PCTCN2022088577-appb-000006
名称为(4aR)-3-丙烯酰基-11-氯-10-(2-氟-6-羟基苯基)-8-(2-异丙基-4-甲基吡啶-3-基)-6-(甲基-d 3)-2，3，4，4a，6，8-六氢-1H-吡嗪并[1’，2’：4，5]吡嗪并[2，3-c][1，8]萘啶-5，7-二酮。本文中公开的式(I)化合物可能以异构体的形式存在，它们是当分子中单个键的旋转被阻止或大大减慢时发生的构象立体异构体，这是由于与分子其他部分的空间相互作用产生的。本文公开的式(I)化合物可以是单体阻转异构体(atropisomer)或所有阻转异构体的混合物，即该化合物既可以作为单个阻转异构体存在，也可以阻转异构体的混合物。如果单键的旋转位垒足够高，构象之间的相互转换足够慢，则可以允许同分异构体的分离。
本文中，式(I)化合物具有两个阻转异构体结构，分别是化合物Ia、化合物Ib；
Figure PCTCN2022088577-appb-000007
本文的制备例1的步骤十一拆分得到的两个阻转异构体为化合物Ia和化合物Ib。本发明化合物优选为化合物Ia。
本文中，“化合物I”、“式(I)化合物”、“式(I)化合物游离碱”、“游离态式(I)化合物”可互换使用。“化合物Ia”、“化合物Ia游离碱”、“游离态化合物Ia”可互换使用。“化合物Ib”、“化合物Ib游离碱”、“游离态化合物Ib”可互换使用。本发明的化合物的制备方法可以参考国际专利申请(PCT/CN2020/124226)中实施例26的步骤或如本文制备例步骤所述，均可以制备得到式(I)化合物及其两个阻转异构体化合物。
本发明的多晶型物
固体不是以无定形的形式就是以结晶的形式存在。在结晶形式的情况下，分子定位于三维晶格格位内。当化合物从溶液或浆液中结晶出来时，它可以不同的空间点阵排列结晶(这种性质被称作“多晶型现象”)，形成具有不同的结晶形式的晶体，这各种结晶形式被称作“多晶型物”。
所述的“结晶”可以通过多种方法来完成，具体可参见本发明实施例中所描述的操作步骤或参见Crystallization，第三版，J W Mullens，Butterworth-Heineman Ltd.，1993，ISBN 0750611294。可以将晶种添加到 任何结晶混合物中以促进结晶。
本发明的多晶型物包括化合物Ia的多晶型物或化合物Ia的药学上可接受的盐的多晶型物。本文中，术语“本发明的晶体”、“本发明的晶型”、“本发明的多晶型物”等可互换使用。
多晶型物的鉴定和性质
在制备本发明的多晶型物后，本发明可采用如下多种方式和仪器对其性质进行了研究，例如，XRPD、DSC、TGA等等。本发明的多晶型物具有特定的晶型形态，在XRPD图中具有特定的特征峰。
药物组合物及其应用
本发明的活性成分可以为本发明化合物的药学上可接受的盐或本发明的多晶型物。本发明的活性成分可以用于抑制KRAS G12C突变的活性。因此，本发明的活性成分和包含本发明活性成分的药物组合物可用于治疗或者预防KRAS G12C突变相关疾病，例如KRAS G12C突变相关的癌症。所述癌症可以为实体瘤。例如所述癌症包括(但不限于)选自下组的一种或多种：肺癌(例如非小细胞肺癌)、胰腺癌、结肠直肠癌等。
本发明的药物组合物包含本发明的活性成分和药学上可接受的载体。本发明的药物组合物还可以含有任选的其它治疗剂。如本文所用，“药学可接受的载体”是指无毒、惰性、固态、半固态的物质或液体灌装机、稀释剂、封装材料或辅助制剂或任何类型辅料，其与患者相兼容，最好为哺乳动物，更优选为人，其适合将活性试剂输送到目标靶点而不终止试剂的活性。
在治疗过程中，可以根据情况，单独使用本发明的药物或将本发明的药物与一种或多种其它治疗剂组合使用。所述组合使用可以是在使用本发明的药物的同时一起给予一种或多种其它治疗剂，也可以是在使用本发明的药物之前给予一种或多种其它治疗剂或在使用本发明的药物之后再给予一种或多种其它治疗剂。
通常，本发明的活性成分可以与一种或多种药用载体形成适合的剂型施用。这些剂型适用于口服、直肠给药、局部给药、口内给药以及其他非胃肠道施用(例如，皮下、肌肉、静脉等)。例如，适合其他非胃肠道给药的剂型包括注射剂等。上述剂型可由本发明的活性成分与一种或多种载体或辅料经由通用的药剂学方法制成。上述的载体需要与本发明的活性成分或其他辅料兼容。对于固体制剂，常用的无毒载体包括但不限于甘露醇、乳糖、淀粉、硬脂酸镁、葡萄糖、蔗糖等。用于液体制剂的载体包括水(优选注射用无菌水)等。本发明的活性成分可与上述载体形成溶液或是混悬液。
本发明的药物组合物以符合医学实践规范的方式配制、定量和给药。给予本发明的活性成分的“治疗有效量”由要治疗的具体病症、治疗的个体、病症的起因、药物的靶点以及给药方式等因素决定。如本文所用，“治疗有效量”是指可对患者(例如人和/或动物)产生功能或活性的且可被人和/或动物所接受的量。本发明的药物组合物或所述药用组合物中含有的活性成分的治疗有效量优选为0.1mg-5g/kg(体重)。通常，就成人治疗使用的剂量而言，施用剂量通常在0.02-5000mg/天，例如约1-1500mg/天的范围内。该剂量可以为一剂、或同时给药的剂量、或适当间隔的分剂量，例如每天二、三、四剂或更多分剂。本领域技术人员可以理解的是，尽管给出了上述剂量范围，但具体的有效量可根据患者的情况并结合医师诊断而适当调节。
如本文所用，“患者”是指一种动物，最好为哺乳动物，更好的为人。术语“哺乳动物”是指温血脊椎类哺乳动物，包括如猫、狗、兔、熊、狐狸、狼、猴子、鹿、鼠、猪和人类。
如本文所用，“治疗”是指减轻、延缓进展、衰减、预防或维持现有疾病或病症(例如癌症)。“治疗”还包括将疾病或病症的一个或多个症状治愈、预防其发展或减轻到某种程度。
作为本发明的活性成分的式(I)化合物或其阻转异构体或混合物形式的药学上可接受的盐或该化合物或其阻转异构体或混合物形式或其药学上可接受的盐的一系列稳定的多晶型物，可以通过本领域技术人员所 熟知的多种合成方法来制备，包括下面列举的实施例、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。
下面结合具体实施例，进一步阐述本发明。应理解，这些实施例仅用于说明本发明而不用于限制本发明的范围。下列实施例中未注明具体条件的实验方法，通常按照常规条件或按照制造厂商所建议的条件。
除非另外说明，否则百分比和份数按重量计算。除非另行定义，本文所用的术语与本领域熟练人员所熟悉的意义相同。除非另行定义，本文所用的任何试剂或仪器均市售可得。任何与所记载内容相似或同等的方法及材料皆可应用于本发明中。如本文所用，术语“室温”包括4-30℃的温度，一般是指15-30℃。
X-射线粉末衍射分析(XRPD)采用X’Pert3 X射线粉末衍射分析仪，具体参数：X射线为Cu，kα；Kα1
Figure PCTCN2022088577-appb-000008
1.540598；Kα2
Figure PCTCN2022088577-appb-000009
1.544426；强度比例Kα2/Kα1：0.50；电压为45kV；电流为40mA；发散狭缝：1/8°；扫描模式：连续；扫描范围：3°～40°；扫描步长：0.0263°；每步扫描时间：46.665s；扫描时间：5min 03s。或者采用PANalytical Empyrean X射线粉末衍射分析仪，具体参数：X射线：Cu，kα；Kα1
Figure PCTCN2022088577-appb-000010
1.540598；Kα2
Figure PCTCN2022088577-appb-000011
1.544426；强度比例Kα2/Kα1：0.50；电压为45kV；电流为40mA；发散狭缝：自动；扫描模式：连续；扫描范围：3°～40°；扫描步长：0.0167°；每步扫描时间：17.780s/33.020s；扫描时间：5min 32s/10min 13s。
热重分析(TGA)采用TA Q5000/Discovery 5500热重分析仪。方法：线性升温；样品盘：铝盘，敞开；温度范围：RT-350℃；加热速率：10℃/min；保护气体：氮气。
差示量热扫描分析(DSC)采用TA Discovery 2500差示扫描量热仪。方法：线性升温；样品盘：铝盘，压盖；温度范围：RT-目标温度；加热速率：10℃/min；保护气体：氮气。
单晶测试采用D8Venture检测仪器，具体参数：光源：Mo靶；X射线：
Figure PCTCN2022088577-appb-000012
探测器：CMOS面探测器；分辨率：
Figure PCTCN2022088577-appb-000013
电流电压：50kV，1.4A；曝光时间：5s；面探测器至样品距离：40mm；测试温度：170(2)K。
DCM表示二氯甲烷；MTBE表示甲基叔丁基醚；MEK表示甲基乙基酮；DMF表示N，N-二甲基甲酰胺。
可以理解的是，使用与上述仪器作用相同的其他类型的仪器或使用不同与本发明中使用的测试条件时，可能会得到另外的数值，因此，所引用的数值不应视为绝对的数值。由于仪器的误差或操作人员的区别，本领域技术人员能理解，以上用于表征晶体的物理性质的参数可能有微小的差别，所以上述的参数仅用于辅助表征本发明提供的多晶型物，而不能视为是对本发明的多晶型物的限制。
制备例1化合物I及其阻转异构体的制备
Figure PCTCN2022088577-appb-000014
步骤一：将6，7-二氯-4-羟基-1-(2-异丙基-4-甲基吡啶-3-基)-2-氧-1，2-二氢-1，8-萘啶-3-甲腈(30.0g，77.319mmol)悬浮于1，4-二氧六环(120mL)和水(120mL)的混合溶液，缓慢加入浓硫酸(120mL)。反应120℃下搅拌36小时。将冷却的反应液倒入200mL冰水中，用碳酸钠调pH2～3，用乙酸乙酯萃取(1000mL*2)，合并乙酸乙酯相，无水硫酸钠干燥，过滤，滤液减压浓缩后得到产物6，7-二氯-4-羟基-1-(2-异丙基-4-甲基吡啶-3-基)-1，8-萘啶-2(1H)-酮(24g，收率：85.5％)，淡棕色固体。ES-API：[M+H] +＝364.1。
步骤二：6，7-二氯-4-羟基-1-(2-异丙基-4-甲基吡啶-3-基)-1，8-萘啶-2(1H)-酮(3.16g，8.705mmol)溶于乙酸(15mL)，依次加入亚硝酸钠(100mg，1.58mmol)和浓硝酸(5.0mL，74.52mmol)，反应在室温下搅拌30分钟。将反应液缓慢倒入100mL冰水中，析出的固体过滤，滤饼用20ml冰水洗涤，在真空下干燥得到产物6，7-二氯-4-羟基-1-(2-异丙基-4-甲基吡啶-3-基)-3-硝基-1，8-萘啶-2(1H)-酮(3.5g，收率：98.5％)，黄色固体。ES-API：[M+H] +＝409.1
步骤三：向100mL三口圆底烧瓶中加入6，7-二氯-4-羟基-1-(2-异丙基-4-甲基吡啶-3-基)-3-硝基-1，8-萘啶-2(1H)-酮(3.5g，8.570mmol)、(2-氟-6-甲氧基苯基)硼酸(5.8g，34.10mmol)、四三苯基膦钯(1.15g，0.9956mmol)、碳酸钠(3.5g，33.02mmol)、10mL水和40mL二氧六环。体系用氮气置换三次，然后用氮气球保护。反应在100℃搅拌2～3小时。反应完毕，反应液冷却到室温，加入80mL水和100mL甲基叔丁基醚，萃取一次。水相用1M的盐酸溶液调pH 3～5，用乙酸乙酯萃取(200mL*2)，合并乙酸乙酯相，无水硫酸钠 干燥，过滤，滤液减压浓缩后得到产物6-氯-7-(2-氟-6-甲氧基苯基)-4-羟基-1-(2-异丙基-4-甲基吡啶-3-基)-3-硝基-1，8-萘啶-2(1H)-酮(4.5g，粗品)，淡黄色固体。ES-API：[M+H] +＝499.1
步骤四：6-氯-7-(2-氟-6-甲氧基苯基)-4-羟基-1-(2-异丙基-4-甲基吡啶-3-基)-3-硝基-1，8-萘啶-2(1H)-酮(4.268g，8.57mmol)溶于乙腈(30mL)，依次加入三氯氧磷(7.5g，48.92mmol)和N，N-二异丙基乙胺(10.5g，81.24mmol)，反应逐渐升至80℃并搅拌30分钟。将反应液浓缩，加入30mL冷的乙腈，冰水浴下滴加到150mL饱和碳酸氢钠溶液中，用乙酸乙酯萃取(200mL*2)，合并乙酸乙酯相，200mL饱和食盐水洗涤一次。无水硫酸钠干燥，过滤，有机相干燥浓缩后，粗品用快速硅胶柱(乙酸乙酯/石油醚：0-50％)纯化得4，6-二氯-7-(2-氟-6-甲氧基苯基)-1-(2-异丙基-4-甲基吡啶-3-基)-3-硝基-1，8-萘啶-2(1H)-酮(3.05g，收率：76％)，黄色固体。ES-API：[M+H] +＝517.2。
步骤五：4，6-二氯-7-(2-氟-6-甲氧基苯基)-1-(2-异丙基-4-甲基吡啶-3-基)-3-硝基-1，8-萘啶-2(1H)-酮(2.5g，4.843mmol)溶于N，N-二甲基乙酰胺(25mL)，依次加入1-(叔丁基)3-甲基(R)-哌嗪-1，3-二羧酸酯(3.5g，14.34mmol)和N，N-二异丙基乙胺(2.0g，15.47mmol)，反应在120℃搅拌2小时。反应液中加入80mL乙酸乙酯，用80mL饱和食盐水洗涤三次。乙酸乙酯相干燥浓缩，粗品用快速硅胶柱纯化(乙酸乙酯/石油醚：0-80％)得到目标产物1-(叔丁基)3-甲基(3R)-4-(6-氯-7-(2-氟-6-甲氧基苯基)-1-(2-异丙基-4-甲基吡啶-3-基)-3-硝基-2-氧代-1，2-二氢-1，8-萘啶-4-基)哌嗪-1，3-二羧酸酯(2.7g，收率：77％)，黄色固体。ES-API：[M+H] +＝725.2。
步骤六：1-(叔丁基)3-甲基(3R)-4-(6-氯-7-(2-氟-6-甲氧基苯基)-1-(2-异丙基-4-甲基吡啶-3-基)-3-硝基-2-氧代-1，2-二氢-1，8-萘啶-4-基)哌嗪-1，3-二羧酸酯(2.7g，3.728mmol)溶于乙酸(30mL)，加入铁粉(835mg，14.91mmol)，反应在80℃搅拌30分钟。反应液浓缩，依次加入200mL乙酸乙酯和100mL饱和碳酸氢钠，悬浮液用硅藻土过滤，滤饼用乙酸乙酯洗涤，有机相分离，依次用100mL饱和碳酸氢钠，150mL饱和食盐水洗涤，干燥浓缩得到目标产物叔丁基(4aR)-11-氯-10-(2-氟-6-甲氧基苯基)-8-(2-异丙基-4-甲基吡啶-3-基)-5，7-二氧-1，2，4，4a，5，6，7，8-八氢-3H-吡嗪并[1′，2′：4，5]吡嗪并[2，3-c][1，8]萘啶-3-羧酸酯(2.70g，粗品)，黄色固体。ES-API：[M+H]+＝663.2。
步骤七：向150mL封管中依次加入叔丁基(4aR)-11-氯-10-(2-氟-6-甲氧基苯基)-8-(2-异丙基-4-甲基吡啶-3-基)-5，7-二氧-1，2，4，4a，5，6，7，8-八氢-3H-吡嗪并[1′，2′：4，5]吡嗪并[2，3-c][1，8]萘啶-3-羧酸酯(0.5g，0.7549mmol)，10mL丙酮，无水碳酸钾(416mg，3.02mmol)，氘代碘甲烷(1.09g，7.549mmol)。密封封管，反应在55℃搅拌18小时。反应液加入150mL乙酸乙酯，用100mL饱和食盐水洗涤3次，干燥浓缩，粗品用快速硅胶柱纯化(乙酸乙酯/石油醚：0-80％)得到产物叔丁基(4aR)-11-氯-10-(2-氟-6-甲氧基苯基)-8-(2-异丙基-4-甲基吡啶-3-基)-6-(甲基-d 3)-5，7-二氧代-1，2，4，4a，5，6，7，8-八氢-3H-吡嗪并[1′，2′：4，5]吡嗪并[2，3-c][1，8]萘啶-3-羧酸酯(511mg，crude)，黄色固体。ES-API：[M+H] +＝680.2。本步骤的方法可参考如下文献的操作方法：Liu Yang；et al；Journal of Agricultural and Food Chemistry(2013)，61(12)，2970-2978。
步骤八：叔丁基(4aR)-11-氯-10-(2-氟-6-甲氧基苯基)-8-(2-异丙基-4-甲基吡啶-3-基)-6-(甲基-d 3)-5，7-二氧代-1，2，4，4a，5，6，7，8-八氢-3H-吡嗪并[1′，2′：4，5]吡嗪并[2，3-c][1，8]萘啶-3-羧酸酯(512.5mg，0.7549mmol)溶于二氯甲烷(8mL)，加入三氟乙酸(2mL)。室温搅拌2小时，反应液浓缩得产物(4aR)-11-氯-10-(2-氟-6-甲氧基苯基)-8-(2-异丙基-4-甲基吡啶-3-基)-6-(甲基-d 3)-2，3，4，4a，6，8-六氢-1H-吡嗪并[1′，2′：4，5]吡嗪并[2，3-c][1，8]萘啶-5，7-二酮(520mg，粗品)，直接用于下一步反应。ES-API：[M+H] +＝580.3。
步骤九：(4aR)-11-氯-10-(2-氟-6-甲氧基苯基)-8-(2-异丙基-4-甲基吡啶-3-基)-6-(甲基-d 3)-2，3，4，4a，6，8-六氢-1H-吡嗪并[1′，2′：4，5]吡嗪并[2，3-c][1，8]萘啶-5，7-二酮(437.1mg，0.7549mmol)溶于二氯甲烷(10mL)，加入三乙胺(3.0mL，21.62mmol)。将反应冷至0℃，向反应液中滴加丙烯酰氯(100mg，1.1048mmol)。反应在 0℃搅拌15分钟。向反应液中加入80mL二氯甲烷，用100mL饱和NaHCO 3水溶液，80mL饱和食盐水洗涤，有机相干燥后浓缩，粗品用快速硅胶柱纯化(乙酸乙酯/石油醚：0-60％)得到产物(4aR)-3-丙烯酰基-11-氯-10-(2-氟-6-甲氧基苯基)-8-(2-异丙基-4-甲基吡啶-3-基)-6-(甲基-d 3)-2，3，4，4a，6，8-六氢-1H-吡嗪并[1′，2′：4，5]吡嗪并[2，3-c][1，8]萘啶-5，7-二酮(232mg，收率：48％)，黄色固体。ES-API：[M+H] +＝634.2。
步骤十：冰水浴条件下，将(4aR)-3-丙烯酰基-11-氯-10-(2-氟-6-甲氧基苯基)-8-(2-异丙基-4-甲基吡啶-3-基)-6-(甲基-d 3)-2，3，4，4a，6，8-六氢-1H-吡嗪并[1′，2′：4，5]吡嗪并[2，3-c][1，8]萘啶-5，7-二酮(240mg，0.3791mmol)加入到干燥二氯甲烷中(6.0mL)，再加入三溴化硼(5.0mL，5.0mmol)，升至室温，反应过夜。冰水浴条件下，将上述反应液滴加入饱和碳酸氢钠饱和溶液中，二氯甲烷(80mL)萃取2次，干燥，浓缩，粗品用快速硅胶柱纯化(乙酸乙酯/石油醚：0-60％)得到产物(4aR)-3-丙烯酰基-11-氯-10-(2-氟-6-羟基苯基)-8-(2-异丙基-4-甲基吡啶-3-基)-6-(甲基-d 3)-2，3，4，4a，6，8-六氢-1H-吡嗪并[1′，2′：4，5]吡嗪并[2，3-c][1，8]萘啶-5，7-二酮(化合物I，187mg，收率：79％)。[M+H] +＝620.3。
步骤十一：将(4aR)-3-丙烯酰基-11-氯-10-(2-氟-6-羟基苯基)-8-(2-异丙基-4-甲基吡啶-3-基)-6-(甲基-d 3)-2，3，4，4a，6，8-六氢-1H-吡嗪并[1′，2′：4，5]吡嗪并[2，3-c][1，8]萘啶-5，7-二酮(187mg，0.302mmol)手性制备拆分(柱型：IA，10μm，30*250mm；流动相：己烷∶EtOH＝60∶40；流速：25mL/min；柱温：室温)得到两个阻转异构体：异构体1(isomer 1)；异构体2(isomer 2)。
异构体1(68.8mg，峰1，保留时间：2.525min，收率：36.7％)，淡黄色固体。核磁数据如下： 1H NMR(500MHz，DMSO-d 6)δ10.03(d，J＝18.0Hz，1H)，8.51(d，J＝7.5Hz，1H)，8.43(d，J＝5.0Hz，1H)，7.29-7.18(m，2H)，7.08(dd，J＝17.0，10.5Hz，1H)，6.74-6.61(m，2H)，6.15(d，J＝16.5Hz，1H)，5.75(d，J＝11.5Hz，1H)，4.73(d，J＝13.5Hz，1H)，4.46(d，J＝12.5Hz，1H)，4.00(s，1H)，3.61(d，J＝10.5Hz，1H)，3.50(s，1H)，3.22(s，1H)，2.65(d，J＝13.0Hz，1H)，1.98(d，J＝5.0Hz，3H)，1.25(d，J＝11.5Hz，1H)，1.02(d，J＝7.0Hz，3H)，0.86(t，J＝8.0Hz，3H)。ES-API：[M+H] +＝620.3。
异构体2(63.2mg，峰2，保留时间：3.683min，收率：33.79％)，淡黄色固体。核磁数据如下：仪器Bruker(布鲁克)AVANCE III 500MHz。 1H NMR(500MHz，CDCl 3)δ8.52(d，J＝5.0Hz，1H)，8.27(s，1H)，8.16(s，1H)，7.18-7.15(m，2H)，7.09-6.90(m，1H)，6.66-6.56(m，2H)，6.31(d，J＝17.0Hz，1H)，5.75(d，J＝10.5Hz，1H)，4.84(d，J＝13.0Hz，1H)，4.75(d，J＝13.0Hz，1H)，3.65-3.51(m，2H)，3.36(d，J＝12.0Hz，1H)，3.08(s，1H)，2.84(t，J＝12.0Hz，1H)，2.75-2.63(m，1H)，1.85(s，3H)，1.15(d，J＝6.5Hz，3H)，1.03(d，J＝6.5Hz，3H)。ES-API：[M+H] +＝620.3。
异构体化合物通过分析型手性HPLC方法(柱型：IA，5μm，4.6*150mm；流动相：己烷∶EtOH＝60∶40；流速：1mL/min；柱温＝30℃)进行检测。
单晶培养：向洁净试管中加入步骤十一拆分得到的异构体2(150mg，0.2419mmol，保留时间：3.683min)和2-丁酮(2.0mL)，超声使全部溶解；试管口密封；将密封好的试管45°斜放在试管架上，室温静置10天；10天后，在试管壁上小心取下单晶，其分子立体结构椭球图见图24。得到的单晶通过Bruker D8 Venture仪器进行X-射线单晶衍射测试。结果见下表A和图25-图27。
表A
Figure PCTCN2022088577-appb-000015
Figure PCTCN2022088577-appb-000016
结构解析与精修过程：采用SAINT程序对衍射数据进行积分还原后，采用SADABS程序对数据进行经验吸收校正；采用SHELXT2014通过直接法解析单晶结构，并采用最小二乘法对结构进行精修，氢原子精修过程采取各向同性计算处理获得，C-H上氢原子通过计算加氢获得，并采取骑式模型对其精修处理。Flack常数为0.02(7)，手性中心见C26为R构型。
即，步骤十一拆分得到的异构体2为化合物Ia，结构如下：
Figure PCTCN2022088577-appb-000017
实施例1制备晶型A
向10mL反应管中加入制备例1步骤十一制得的异构体2(保留时间为3.683min)(30mg)、异丙醇(1mL)，油浴升温至50℃，搅拌打浆4小时。自然冷却至室温，过滤，40℃旋蒸干燥，得到29mg白色固体，经检测为晶型A。其XRPD数据见表1和图1所示。其DSC数据如图2所示。其TGA数据如图3所示。
表1晶型A
# 2θ d(埃) 峰高 峰高％
1 6.02 14.6677 1901 100.0
2 7.01 12.6082 179 9.4
3 11.31 7.8206 66 3.5
4 11.90 7.4326 1187 62.5
5 12.84 6.8884 1164 61.2
6 13.78 6.4216 269 14.2
7 14.42 6.1355 62 3.3
8 15.36 5.7638 108 5.7
9 16.14 5.4867 328 17.2
10 17.04 5.1999 910 47.9
11 17.34 5.1094 556 29.3
12 17.58 5.0401 73 3.8
13 18.72 4.7360 279 14.7
14 19.22 4.6142 84 4.4
15 19.62 4.5205 657 34.5
16 20.48 4.3337 122 6.4
17 20.74 4.2786 215 11.3
18 21.04 4.2189 447 23.5
19 22.08 4.0233 53 2.8
20 22.70 3.9137 295 15.5
21 23.22 3.8276 278 14.6
22 23.86 3.7261 138 7.3
23 24.10 3.6896 389 20.5
24 24.80 3.5874 235 12.3
25 25.14 3.5394 152 8.0
26 25.78 3.4529 190 10.0
27 26.00 3.4243 588 30.9
28 26.46 3.3659 331 17.4
29 26.68 3.3385 119 6.3
30 27.54 3.2364 46 2.4
31 27.90 3.1954 76 4.0
32 28.10 3.1728 95 5.0
33 28.72 3.1056 173 9.1
34 29.10 3.0661 64 3.4
35 29.92 2.9840 119 6.3
36 31.00 2.8824 136 7.2
37 31.38 2.8484 131 6.9
38 31.82 2.8098 63 3.3
39 32.32 2.7677 69 3.6
40 32.60 2.7446 76 4.0
41 33.84 2.6471 64 3.4
42 34.54 2.5945 53 2.8
43 35.84 2.5037 66 3.5
44 36.12 2.4847 137 7.2
45 36.62 2.4522 53 2.8
46 37.10 2.4213 72 3.8
47 37.98 2.3670 47 2.5
实施例2制备晶型B
向10mL反应管中加入制备例1步骤十一制得的异构体2(保留时间为3.683min)(20mg)、正庚烷(2mL)，油浴升温至50℃，搅拌打浆4小时。自然冷却至室温，过滤，40℃旋蒸干燥，得到17mg白色固体，经检测为晶型B。其XRPD数据见表2和图4所示。其DSC数据如图5所示。
表2晶型B
# 2θ d(埃) 峰高 峰高％
1 10.02 8.8180 224 26.2
2 11.38 7.7696 285 33.4
3 11.94 7.4056 278 32.6
4 12.18 7.2602 238 27.9
5 12.56 7.0404 852 100.0
6 13.32 6.6422 194 22.8
7 13.66 6.4772 184 21.6
8 15.12 5.8535 62 7.3
9 15.62 5.6703 97 11.3
10 16.36 5.4130 40 4.7
11 17.36 5.1044 298 35.0
12 18.18 4.8753 278 32.6
13 18.52 4.7871 54 6.3
14 18.96 4.6764 173 20.3
15 19.58 4.5301 129 15.1
16 20.20 4.3929 163 19.1
17 20.60 4.3075 256 30.1
18 20.82 4.2624 323 37.8
19 21.52 4.1256 84 9.9
20 22.23 3.9952 46 5.4
21 22.61 3.9300 35 4.1
22 22.98 3.8676 51 5.9
23 23.72 3.7481 101 11.8
24 24.72 3.5986 158 18.5
25 24.94 3.5675 300 35.2
26 25.26 3.5225 87 10.2
27 25.94 3.4323 95 11.1
28 26.24 3.3932 164 19.2
29 26.46 3.3658 82 9.6
30 27.77 3.2095 61 7.1
31 28.23 3.1592 28 3.2
32 29.92 2.9841 111 13.1
33 30.60 2.9194 152 17.8
34 31.10 2.8737 55 6.5
35 31.40 2.8464 37 4.3
36 32.44 2.7574 69 8.1
37 32.99 2.7126 34 3.9
38 33.36 2.6838 29 3.4
39 35.21 2.5467 39 4.6
40 37.24 2.4123 34 4.0
实施例3制备晶型B
向10mL反应管中加入制备例1步骤十一制得的异构体2(保留时间为3.683min)(30mg)、二氯甲烷/ 甲基叔丁基醚(1V/4V，1mL)，油浴升温至50℃，搅拌打浆4小时。自然冷却至室温，过滤，40℃旋蒸干燥，得到26mg白色固体，经检测，其XRPD基本如图4所示，确定为晶型B。
实施例4制备晶型C
向10mL反应管中加入制备例1步骤十一制得的异构体2(保留时间为3.683min)(30mg)、乙酸乙酯/正庚烷(1V/4V，1mL)，油浴升温至50℃，搅拌打浆4小时。自然冷却至室温，过滤，40℃旋蒸干燥，得到27mg白色固体，经检测为晶型C。其XRPD数据见表3和图6所示。其DSC数据如图7所示。其TGA数据如图8所示。
表3晶型C
# 2θ d(埃) 峰高 峰高％
1 6.28 14.0706 1348 100.0
2 11.72 7.5434 71 5.3
3 12.12 7.2967 808 60.0
4 12.46 7.0971 184 13.7
5 12.84 6.8882 54 4.0
6 14.28 6.1966 43 3.2
7 14.98 5.9096 143 10.6
8 15.62 5.6678 72 5.4
9 17.02 5.2049 210 15.6
10 17.28 5.1279 114 8.5
11 18.12 4.8920 193 14.3
12 18.92 4.6864 44 3.3
13 19.40 4.5714 133 9.9
14 19.94 4.4492 45 3.3
15 20.22 4.3888 151 11.2
16 20.94 4.2393 52 3.8
17 22.04 4.0298 40 3.0
18 23.66 3.7568 166 12.3
19 24.32 3.6567 60 4.5
20 25.26 3.5227 104 7.7
21 26.74 3.3311 132 9.8
22 27.42 3.2503 30 2.3
23 27.91 3.1937 51 3.8
24 28.94 3.0831 85 6.3
25 29.26 3.0500 33 2.5
26 31.54 2.8346 57 4.2
实施例5制备晶型I
向250mL圆底烧瓶中加入制备例1步骤十制备的化合物I(15g)，DCM(45mL)，油浴升温至40℃，搅拌溶清。逐滴加入MTBE(45mL)，固体缓慢析出，加完后维持油浴40℃搅拌1小时。油浴冷却至30℃，搅拌16小时，过滤，滤饼干燥得到6.5g黄色固体。向100mL圆底烧瓶中加入上述固体(6.5g)，MEK(19.5mL)，油浴升温至60℃，搅拌溶清。逐滴加入MTBE(6.5mL)，加完后加入少量晶种(来自实施例2的晶种)，维持油浴60℃搅拌0.5小时，大量固体析出，逐滴加入MTBE(32.5mL)，加完后搅拌1小时，自然冷却至室温，过滤，滤饼干燥得到浅黄色固体(5.4g)，纯度100％，异构体0.12％，收率36％，经检测为晶型I。其XRPD数据见表4和图9所示。
表4晶型I
# 2θ d(埃) 背景 峰高 峰高％
1 6.92 12.7640 145 342 64.0
2 8.54 10.3481 126 534 100.0
3 10.70 8.2635 146 380 71.2
4 11.26 7.8492 119 121 22.7
5 11.54 7.6632 119 162 30.4
6 11.98 7.3811 145 139 26.1
7 12.48 7.0850 111 130 24.3
8 13.14 6.7329 125 99 18.6
9 15.12 5.8533 99 74 13.9
10 15.94 5.5550 107 74 13.8
11 17.28 5.1265 111 261 48.9
12 18.21 4.8676 119 57 10.6
13 19.14 4.6333 132 125 23.4
14 19.50 4.5487 125 112 21.0
15 20.73 4.2823 121 46 8.7
16 21.80 4.0738 102 48 9.0
17 22.82 3.8939 93 61 11.4
18 25.02 3.5562 113 160 30.0
19 25.60 3.4765 126 94 17.6
20 26.52 3.3581 115 59 11.1
21 27.70 3.2174 82 44 8.2
22 30.62 2.9173 84 79 14.8
实施例6制备晶型A
在室温下，将100mg实施例5制备的晶型I在2.5mL丙酮中溶清，缓慢加入5mL水，析出白色固体，搅拌0.5h后过滤，所得固体经检测，其XRPD基本如图1所示，确定为晶型A。
实施例7制备晶型D
在室温下，将100mg实施例5制备的晶型I在0.5mL DMF溶清，缓慢加入1mL水，析出白色固体，搅拌0.5h后过滤，所得固体经检测为晶型D。其XRPD数据见表5和图10所示。其DSC数据如图11所示。其TGA数据如图12所示。
表5晶型D
# 2θ d(埃) 峰高 峰高％
1 3.82 23.1254 403 96.6
2 7.45 11.8644 137 32.8
3 9.62 9.1854 135 32.4
4 10.96 8.0665 264 63.2
5 11.58 7.6353 143 34.3
6 13.26 6.6721 160 38.4
7 14.28 6.1982 417 100.0
8 15.62 5.6678 77 18.4
9 16.12 5.4943 107 25.7
10 16.37 5.4097 44 10.6
11 17.10 5.1802 59 14.1
12 18.12 4.8921 67 16.1
13 18.52 4.7868 237 56.9
14 19.22 4.6139 292 70.0
15 19.84 4.4714 81 19.5
16 20.28 4.3755 132 31.7
17 20.74 4.2794 163 39.1
18 22.24 3.9932 98 23.5
19 22.62 3.9278 73 17.5
20 23.16 3.8378 28 6.7
21 24.18 3.6773 74 17.8
22 24.46 3.6360 148 35.6
23 24.68 3.6044 155 37.2
24 26.20 3.3987 117 28.1
25 27.47 3.2438 56 13.4
实施例8制备晶型B
在室温下，100mg实施例5制备的晶型I加入2mL甲苯，不溶清，升温至50℃搅拌过夜，趁热过滤，所得固体经检测，其XRPD如图13所示，图13与图4基本相同，因此，确定所得固体为晶型B。其TGA如图14所示。
实施例9制备晶型B
在室温下，100mg实施例5制备的晶型I加入1mL氯仿和1mLMTBE，不溶清，50℃搅拌过夜，趁热过滤，所得固体经检测，其XRPD基本如图4所示，确定为晶型B。
实施例10制备晶型B
在室温下，100mg实施例5制备的晶型I加入1mL氯仿，不溶清，升温至50℃搅拌过夜，趁热过滤，所得固体经检测，其XRPD基本如图4所示，确定为晶型B。
实施例11制备晶型B
在室温下，100mg实施例5制备的晶型I加入0.5mL乙腈和5mL甲苯，不溶清，升温至50℃搅拌过夜，趁热过滤，所得固体经检测，其XRPD基本如图4所示，确定为晶型B。
实施例12制备晶型B
在室温下，100mg实施例5制备的晶型I加入2mL 1，2-二氯乙烷，不溶清，升温至50℃搅拌过夜，趁热过滤，所得固体经检测，其XRPD基本如图4所示，确定为晶型B。
实施例13制备晶型F
在室温下，100mg实施例5制备的晶型I加入2mL水，不溶清，升温至50℃搅拌过夜，趁热过滤，所得固体经检测为化合物晶型F。其XRPD数据见表6和图15所示。其DSC数据如图16所示。其TGA数据如图17所示。
表6晶型F
# 2θ d(埃) 峰高 峰高％
1 3.52 25.0822 668 90.7
2 8.18 10.7982 158 21.4
3 9.04 9.7740 81 11.0
4 10.12 8.7323 444 60.4
5 11.32 7.8076 82 11.1
6 12.64 6.9964 73 9.9
7 14.02 6.3111 116 15.8
8 14.88 5.9498 736 100.0
9 15.70 5.6401 278 37.8
10 16.40 5.4018 87 11.9
11 17.14 5.1689 500 67.9
12 18.30 4.8435 38 5.2
13 19.04 4.6570 75 10.3
14 20.44 4.3414 133 18.1
15 22.48 3.9516 426 57.8
16 24.21 3.6737 81 11.0
17 26.16 3.4035 104 14.1
18 26.52 3.3583 172 23.4
19 27.56 3.2340 297 40.3
20 28.82 3.0957 113 15.3
21 29.96 2.9798 69 9.3
22 31.04 2.8784 93 12.6
实施例14制备晶型G
在室温下，100mg实施例5制备的晶型I加入1mL DMSO中，然后缓慢滴加0.2mL水，析出固体，室温搅拌0.5小时，过滤，所得固体经检测为晶型G。其XRPD数据见表7和图18所示。其DSC数据如图19所示。其TGA数据如图20所示。
表7晶型G
# 2θ d(埃) 峰高 峰高％
1 5.97 14.8013 109 28.6
2 6.94 12.7309 73 19.3
3 12.08 7.3196 211 55.6
4 13.00 6.8033 294 77.5
5 13.94 6.3474 93 24.6
6 14.32 6.1785 33 8.6
7 14.67 6.0333 54 14.2
8 16.26 5.4470 69 18.2
9 17.04 5.1986 352 92.6
10 17.44 5.0815 150 39.4
11 17.91 4.9489 49 13.0
12 18.74 4.7301 133 35.0
13 19.64 4.5163 380 100.0
14 20.86 4.2552 103 27.2
15 21.62 4.1075 182 48.0
16 22.61 3.9287 142 37.4
17 23.18 3.8342 237 62.3
18 24.64 3.6106 224 59.0
19 25.52 3.4874 189 49.7
20 26.02 3.4217 222 58.3
21 26.90 3.3119 179 47.2
22 27.96 3.1887 99 26.1
23 29.08 3.0683 94 24.8
24 31.32 2.8538 138 36.3
25 31.79 2.8129 33 8.8
26 32.56 2.7476 61 16.0
27 33.56 2.6679 43 11.3
28 34.54 2.5947 30 8.0
29 35.19 2.5480 32 8.3
30 35.94 2.4966 53 13.8
31 36.72 2.4456 67 17.7
32 37.96 2.3684 77 20.2
实施例15制备晶型B
在室温下，1.0g实施例5制备的晶型I加入30mL乙腈，不溶清，继续加入2mL二氯甲烷溶清，溶液在约40℃下旋干，所得固体经检测，其XRPD基本如图4所示，确定为晶型B。
实施例16制备晶型H
在室温下，100mg实施例15制备的晶型B加入1mL乙腈和甲苯的混合溶液(乙腈∶甲苯＝1∶4)中，溶清，继续加入2mL甲苯，少量固体析出，升温至50℃，搅拌1小时，大量固体析出，过滤，所得固体经检测为晶型H。其XRPD数据见表8和图21所示。其DSC数据如图22所示。其TGA数据如图23所示。
表8晶型H
# 2θ d(埃) 峰高 峰高％
1 8.12 10.8778 104 8.0
2 10.00 8.8389 410 31.4
3 10.22 8.6489 721 55.2
4 11.74 7.5315 360 27.6
5 12.12 7.2976 312 23.9
6 12.56 7.0425 94 7.2
7 13.44 6.5826 205 15.7
8 14.10 6.2756 1306 100.0
9 14.38 6.1533 360 27.6
10 14.82 5.9732 372 28.5
11 15.62 5.6688 184 14.1
12 15.94 5.5556 294 22.5
13 16.27 5.4427 97 7.4
14 17.43 5.0832 107 8.2
15 17.94 4.9404 689 52.7
16 18.36 4.8280 119 9.1
17 19.00 4.6671 432 33.1
18 19.22 4.6137 355 27.2
19 19.64 4.5167 243 18.6
20 19.96 4.4453 171 13.1
21 20.22 4.3883 302 23.1
22 20.46 4.3371 126 9.6
23 21.12 4.2032 157 12.0
24 21.75 4.0827 73 5.6
25 22.26 3.9907 286 21.9
26 22.64 3.9246 189 14.5
27 23.02 3.8611 95 7.3
28 24.30 3.6600 174 13.4
29 25.10 3.5451 308 23.6
30 26.06 3.4167 107 8.2
31 26.60 3.3486 102 7.8
32 26.84 3.3195 241 18.4
33 27.36 3.2573 155 11.9
34 28.02 3.1820 113 8.7
35 29.08 3.0686 149 11.4
36 30.06 2.9705 86 6.6
测试例1细胞增殖抑制实验
NCI-H358为Kras G12C突变的人非小细胞肺癌细胞株，培养于10％FBS RPMI-1640培养基中；A549为Kras G12S突变的人肺腺癌细胞株，培养于10％FBS F-12K培养基中。取对数生长期的细胞，胰酶EDTA消化细胞收集计数并使用2％FBS RPMI-1640培养基将H358调整至1.8E4细胞/mL，用2％FBS F-12K培养基将A549调整至8.9E3细胞/mL；分别接种800个(45μL)H358或400个(45μL)A549细胞于384孔球体板中，培养过夜建立3D细胞模型。使用DMSO配制1000X的化合物3.16倍梯度浓度储液，使用2％FBS培养基稀释100倍至10X化合物储液，于细胞接种后的第二天，每个细胞培养孔加入5μL 10X化合物储液，终浓度为1X，DMSO含量为0.1％。使用DMSO作为实验对照(control)，2％FBS培养基作为空白对照(blank)。加入化合物细胞培养5天后，每孔加入25μl CellTiter-Glo工作液，400rpm混匀孵育30分钟，室温静止30分钟后转移40μL混液到白色底透384孔板中，读取luminescence化学发光值，计算细胞增殖抑制率IR(％)＝(RLU对照-RLU化合物)/(RLU对照-RLU空白)×100％，使用Prism 6四参数法拟合化合物梯度稀释浓度和对应的细胞增殖抑制率，计算出IC 50值。结果如表9所示，显示化合物I及其异构体2(保留时间为3.683min，下同)对Kras G12C突变的NCI-H358细胞具有较高的抑制活性，而对A549细胞的抑制活性较低，具有明显的选择抑制活性。
表9化合物对H358和A549细胞的抑制活性
  H358 IC 50(μM) A549 IC 50(μM)
化合物I 0.002 12.856
异构体2 0.003 ＞30
测试例2细胞p-ERK检测实验
MIA PaCa2为Kras G12C突变的人胰腺癌细胞株，培养于10％FBS+2.5％Horse serum DMEM培养基中.取对数生长期的细胞，酶EDTA消化细胞收集计数并接种2.5E4个细胞于96孔细胞培养板中，培养过夜。使用DMSO配制1000X的化合物3.16倍梯度浓度储液，使用培养基稀释200倍至5X化合物储液，于细胞接种后的第二天，每个细胞培养孔加入5X化合物储液，终浓度为1X，DMSO含量为0.1％。使用DMSO作为实验对照(control)。加入化合物培养两小时之后，去除残留的培养基。每孔加入50μL cell lysis buffer，混匀孵育30分钟后转移16μL混液至白色底不透的96孔板中，blank孔则加入16μL cell lysis buffer。转移完毕之后每个孔加入4μL p-ERK HTRF抗体混合液，孵育4小时后读取荧光值。计算化合物的抑制率IR(％)＝(RLU对照-RLU化合物)/(RLU对照-RLU空白)×100％，使用Prism 8四参数法拟合化合物梯度稀释浓度和对应的细胞增殖抑制率，计算出IC 50值。结果如表10所示。
表10化合物对p-ERK的抑制活性
  p-ERK IC 50(μM)
化合物I 0.039
异构体2 0.062
测试例3细胞增殖抑制实验
MIA PaCa-2为Kras G12C突变的人胰腺癌细胞株，培养于10％FBS+2.5％Horse Serum DMEM培养基中；A549为Kras G12S突变的人肺腺癌细胞株，培养于10％FBS F-12K培养基中。取对数生长期的细胞，胰酶EDTA消化细胞收集计数分别接种200个MIAPaCa-2或400个A549细胞于384孔球体板中，培养过夜建立3D细胞模型。使用DMSO配制1000X的化合物3.16倍梯度浓度储液，使用培养基稀释100倍至10X化合物储液，于细胞接种后的第二天，每个细胞培养孔加入10X化合物储液，终浓度为1X，DMSO含量为0.1％。使用DMSO作为实验对照(control)，培养基作为空白对照(blank)。加入化合物细胞培养5天后，每孔加入30μL CellTiter-Glo工作液，混匀孵育30分钟，室温静止30分钟后转移40μL混液到白色底不透384 孔板中，读取luminescence化学发光值，计算细胞增殖抑制率IR(％)＝(RLU对照-RLU化合物)/(RLU对照-RLU空白)×100％，使用XLFit四参数法拟合化合物梯度稀释浓度和对应的细胞增殖抑制率，计算出IC 50值。结果如表11所示。
表11化合物对MIA-PaCa2的抑制活性
  MIA-PaCa2 IC 50(μM)
化合物I 0.005
异构体2 0.005
测试例4 KRas G12C NEA-HTRF实验
使用均相时间分辨荧光(HTRF)方法检测化合物对SOS1催化KRas蛋白上GDP被GTP置换的影响。30μM 6×his标签的KRas G12C重组蛋白与80μM荧光染料DY647标记的GDP在标记缓冲液(1mM DTT，7.5mM EDTA，25mM Tris-HCl，45mM NaCl)中于20℃避光共孵育2小时，使用NAP-5柱子纯化后进行蛋白定量，确定KRas G12C-GDP的浓度。使用DMSO配制1000×的化合物3.16倍梯度浓度储液，使用反应缓冲液(40mM HEPES，10mM MgCl 2，1mM DTT，0.002％Triton X-100)稀释250倍至4×化合物储液。使用反应缓冲液配制KRas G12C-GDP/Tb工作液(40nM KRas G12C-GDP，1×anti-his Tb)和SOS1/GTP工作液(0.2μM SOS1，200μM GTP)。取白色底不透的96孔板，每孔加入5μL 4×化合物储液，10μl KRas G12C-GDP/Tb工作液，对照孔使用5μL反应缓冲液代替4×化合物储液，于20℃避光孵育15分钟后，加入5μL SOS1/GTP工作液，20℃避光孵育2小时后读取荧光值(激发波长：320nm，发射波长：615nm和665nm)。另设置T0组为10μl反应缓冲液+10μL KRas G12C-GDP/Tb工作液，直接读取荧光值。计算荧光信号比RLU＝(665nm信号/615nm信号)×10 4；化合物抑制率IR(％)＝(RLU 化合物-RLU 对照)/(RLU T0-RLU 对照)×100％，使用四参数法拟合化合物梯度稀释浓度和对应的抑制率，计算出IC 50值。结果见表12。
表12
  NEA IC 50(μM)
化合物I 0.034
异构体2 0.040
测试例5体内药效实验
雌性BALB/c裸小鼠，6-8周龄，体重18-20克。MIA PaCa-2细胞用DMEM培养基，添加10％FBS，2.5％HS和1％青霉素-链霉素，在37℃，5％CO 2的培养箱中培养，收集细胞，经右侧背部皮下接种MIA PaCa-2细胞(人源胰腺癌细胞)，每只动物接种2.0×10 6个细胞(每只接种0.1mL)。当肿瘤长到190-311mm 3时，挑选肿瘤大小合适的小鼠分组给药，给药剂量如下表13。每天用电子天平对动物进行称重，每周两次用游标卡尺调查肿瘤体积，肿瘤体积计算公式为：V＝0.5a×b 2，a和b分别表示肿瘤的长径和短径。肿瘤体积用于计算肿瘤生长抑制率(TGI)，百分数显示的TGI用于指示药物的抗肿瘤活性。TGI公式如下：TGI(％)＝[1-(avTi-0/avCi-0)]×100；其中avTi-0是给药组在特定天的平均肿瘤体积，减去该给药组在分组当天的平均肿瘤体积；其中avCi-0是溶媒对照组在特定天的平均肿瘤体积，减去溶媒对照组在分组当天的平均肿瘤体积。肿瘤体积数据用平均值±标准误(SEM)显示。实验结果见下表13。
表13
组别 给药后第14天肿瘤体积(mm 3) TGI(％)
溶剂对照组 670.99 --
AMG 510(1mg/kg，p.o.，QD) 314.28 82.8
AMG 510(3mg/kg，p.o.，QD) 205.35 109.1
AMG 510(10mg/kg，p.o.，QD) 81.72 138.9
异构体2(1mg/kg，p.o.，QD) 157.06 121.1
异构体2(3mg/kg，p.o.，QD) 67.66 143.8
异构体2(10mg/kg，p.o.，QD) 30.49 151.1
实验结论：异构体2在人胰腺癌MIA PaCa-2皮下异体移植肿瘤模型中展现出良好的体内药效。开始给药后14天，异构体2与参考化合物AMG 510相比，具有更显著的抑制肿瘤的作用。
测试例6稳定性测试
为了评估晶型B的稳定性，称取适量样品在60℃/75％RH条件下敞口放置一段时间后，测定样品的晶型变化、HPLC测试杂质来评估其稳定性。晶型B在稳定性测试前后的结果汇总于表14中。结果显示，晶型B在测试条件下HPLC杂质未见明显变化且晶型未发生改变。
表14稳定性评估结果
Figure PCTCN2022088577-appb-000018
测试例7溶解度测试
为了评估晶型B的溶解度性能，称取适量样品在不同介质中，放置在37℃水浴中震摇24h，测定样品的溶解度。结果汇总于表15中。
表15溶解度测试结果
Figure PCTCN2022088577-appb-000019
在本发明提及的所有文献都在本申请中引用作为参考，就如同每一篇文献被单独引用作为参考那样。此外应理解，在阅读了本发明的上述讲授内容之后，本领域技术人员可以对本发明作各种改动或修改，这些等价形式同样落于本申请所附权利要求书所限定的范围。

Claims (21)

  1. 一种化合物Ia的多晶型物，其特征在于，
    Figure PCTCN2022088577-appb-100001
  2. 如权利要求1所述的多晶型物，其特征在于，所述多晶型物为晶型A，所述晶型A具有X-射线粉末衍射特征峰，所述X-射线粉末衍射特征峰在选自下组的2θ值处：6.02±0.2°、11.90±0.2°、12.84±0.2°、17.04±0.2°、19.62±0.2°。
  3. 如权利要求1所述的多晶型物，其特征在于，所述多晶型物为晶型B，所述晶型B具有X-射线粉末衍射特征峰，所述X-射线粉末衍射特征峰在选自下组的2θ值处：11.38±0.2°、11.94±0.2°、12.56±0.2°、17.36±0.2°、18.18±0.2°、20.60±0.2°、20.82±0.2°、24.94±0.2°。
  4. 如权利要求1所述的多晶型物，其特征在于，所述多晶型物为晶型C，所述晶型C具有X-射线粉末衍射特征峰，所述X-射线粉末衍射特征峰在选自下组的2θ值处：6.28±0.2°、12.12±0.2°、17.02±0.2°、18.12±0.2°。
  5. 如权利要求1所述的多晶型物，其特征在于，所述多晶型物为晶型D，所述晶型D具有X-射线粉末衍射特征峰，所述X-射线粉末衍射特征峰在选自下组的2θ值处：3.82±0.2°、10.96±0.2°、14.28±0.2°、18.52±0.2°、19.22±0.2°。
  6. 如权利要求1所述的多晶型物，其特征在于，所述多晶型物为晶型F，所述晶型F具有X-射线粉末衍射特征峰，所述X-射线粉末衍射特征峰在选自下组的2θ值处：3.52±0.2°、10.12±0.2°、14.88±0.2°、17.14±0.2°、22.48±0.2°。
  7. 如权利要求1所述的多晶型物，其特征在于，所述多晶型物为晶型G，所述晶型G具有X-射线粉末衍射特征峰，所述X-射线粉末衍射特征峰在选自下组的2θ值处：12.08±0.2°、13.00±0.2°、17.04±0.2°、19.64±0.2°、23.18±0.2°、24.64±0.2°、26.02±0.2°。
  8. 如权利要求1所述的多晶型物，其特征在于，所述多晶型物为晶型H，所述晶型H具有X-射线粉末衍射特征峰，所述X-射线粉末衍射特征峰在选自下组的2θ值处：10.00±0.2°、10.22±0.2°、14.10±0.2°、17.94±0.2°、19.00±0.2°。
  9. 如权利要求1所述的多晶型物，其特征在于，所述多晶型物为晶型I，所述晶型I具有X-射线粉末衍射特征峰，所述X-射线粉末衍射特征峰在选自下组的2θ值处：6.92±0.2°、8.54±0.2°、10.70±0.2°、17.28±0.2°。
  10. 一种化合物Ia的药学上可接受的盐，其特征在于，所述药学上可接受的盐为盐酸盐、磷酸盐、硫酸盐、甲酸盐或丙酸盐：
    Figure PCTCN2022088577-appb-100002
  11. 一种药物组合物，其特征在于，包含(a)权利要求1-9任一项所述的多晶型物或权利要求10所述的药学上可接受的盐；和(b)药学上可接受的载体。
  12. 权利要求1-9任一项所述的多晶型物或权利要求10所述的药学上可接受的盐的用途，其特征在于，用于制备预防或治疗KRAS G12C突变相关疾病的药物。
  13. 如权利要求12所述的用途，其特征在于，所述KRAS G12C突变相关疾病为癌症。
  14. 如权利要求2所述的多晶型物的制备方法，其特征在于，所述方法包括步骤：
    在40-60℃下将化合物Ia在异丙醇中搅拌后，冷却至室温，过滤，从而得到所述的晶型A；或
    在室温下，将晶型I溶于丙酮中，然后往溶液中添加水，过滤，从而得到所述的晶型A。
  15. 如权利要求3所述的多晶型物的制备方法，其特征在于，所述方法包括步骤：
    在40-60℃下将化合物Ia在有机溶剂中搅拌后，过滤，从而得到所述的晶型B；其中所述有机溶剂为正庚烷或者为二氯甲烷和甲基叔丁基醚的混合物；或
    将晶型I与有机溶剂混合后在40-60℃下搅拌，然后过滤，从而得到所述的晶型B；其中所述有机溶剂选自下组：甲苯、氯仿、1，2-二氯乙烷、氯仿和甲基叔丁基醚的混合物、乙腈和甲苯的混合物；或
    在室温下，将晶型I与乙腈混合后加入二氯甲烷溶清；然后除去乙腈和二氯甲烷，从而得到所述的晶型B。
  16. 如权利要求4所述的多晶型物的制备方法，其特征在于，所述方法包括步骤：在40-60℃下，将化合物Ia在乙酸乙酯和正庚烷的混合物中搅拌后，过滤，从而得到所述的晶型C。
  17. 如权利要求5所述的多晶型物的制备方法，其特征在于，所述方法包括步骤：在室温下，将晶型I溶于DMF中，然后往溶液中添加水，从而得到所述的晶型D。
  18. 如权利要求6所述的多晶型物的制备方法，其特征在于，所述方法包括步骤：在40-60℃下，将晶型I在水中搅拌后，过滤，从而得到所述的晶型F。
  19. 如权利要求7所述的多晶型物的制备方法，其特征在于，所述方法包括步骤：在室温下，将晶型I与DMSO混合，然后往体系中添加水后搅拌并过滤，从而得到所述的晶型G。
  20. 如权利要求8所述的多晶型物的制备方法，其特征在于，所述方法包括步骤：在室温下，将晶型B溶于乙腈和甲苯的混合物中，然后往溶液中添加甲苯；然后升温至45-55℃并搅拌，过滤，从而得到所述的晶型H。
  21. 如权利要求9所述的多晶型物的制备方法，其特征在于，所述方法包括步骤：
    (a)在40-30℃下，将化合物I溶于二氯甲烷中，然后滴加甲基叔丁基醚并搅拌，过滤收集析出的固体；和
    (b)在55-65℃下，将步骤(a)收集到的固体溶于甲基乙基酮中，然后滴加甲基叔丁基醚，加完后加入晶种并搅拌，析出固体后继续滴加甲基叔丁基醚并搅拌，然后冷却至室温，从而得到所述的晶型I；其中，步骤(b)所述晶种为晶型B。
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