WO2023230968A1 - Shp2 inhibitor, and crystal form thereof, preparation method therefor, and use thereof - Google Patents

Shp2 inhibitor, and crystal form thereof, preparation method therefor, and use thereof Download PDF

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WO2023230968A1
WO2023230968A1 PCT/CN2022/096702 CN2022096702W WO2023230968A1 WO 2023230968 A1 WO2023230968 A1 WO 2023230968A1 CN 2022096702 W CN2022096702 W CN 2022096702W WO 2023230968 A1 WO2023230968 A1 WO 2023230968A1
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acid
formula
crystal form
compound
represented
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PCT/CN2022/096702
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Chinese (zh)
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查传涛
万惠新
马金贵
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上海凌达生物医药有限公司
上海凌济生物科技有限公司
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Priority to PCT/CN2022/096702 priority Critical patent/WO2023230968A1/en
Publication of WO2023230968A1 publication Critical patent/WO2023230968A1/en

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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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/438—The ring being spiro-condensed with carbocyclic or heterocyclic ring systems
    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/444—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
    • 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
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • 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
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • 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
    • C07D487/02—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 two hetero rings
    • C07D487/04—Ortho-condensed systems
    • 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 present invention relates to SHP2 inhibitors, their crystal forms and their preparation methods and uses, and belongs to the field of chemical drugs.
  • Protein tyrosine phosphatase plays an important role in the regulation of various cellular processes, such as cell growth, proliferation, cell differentiation, and oncogenic transformation.
  • the balance between dephosphorylation by protein tyrosine phosphatase (PTP) and phosphorylation by its counterpart tyrosine kinase is critical for normal physiological function. PTP is increasingly regarded as a valuable drug target.
  • SHP2 Src homology-2 domain-containing protein tyrosine phosphatase-2
  • PTPN11 tyrosine-protein phosphatase non-receptor type 11
  • SH2 Src Homology-2 domain-containing non-receptor protein tyrosine phosphatase
  • SHP2 The catalytic activity of SHP2 is required for full activation of the Ras-ERK1/2 cascade, which is mediated by SHP2-catalyzed dephosphorylation of substrates that are negatively regulated by tyrosine phosphorylation.
  • SHP2 was identified as a bona fide oncogene; gain-of-function SHP2 mutations result in increased phosphatase activity leading to Noonan syndrome, as well as various forms of leukemia (e.g., juvenile myelomonocytic leukemia, acute myelogenous leukemia, myelodysplastic syndrome, acute lymphoblastic leukemia) and various solid tumors (e.g., lung adenocarcinoma, colon cancer, neuroblastoma, glioblastoma, melanoma, hepatocellular carcinoma, and prostate cancer).
  • leukemia e.g., juvenile myelomonocytic leukemia, acute myelogenous leukemia
  • SHP2 represents a promising target in a variety of cancers (e.g., triple-negative and HER2+ breast cancer, cancers resulting from aberrant activation of receptor protein tyrosine kinases (PTK), some of which are less responsive to kinase inhibitor monotherapy). poor) and attracting increasing attention in the development of SHP2 inhibitors.
  • cancers e.g., triple-negative and HER2+ breast cancer, cancers resulting from aberrant activation of receptor protein tyrosine kinases (PTK), some of which are less responsive to kinase inhibitor monotherapy). poor
  • PTK receptor protein tyrosine kinases
  • the technical problem to be solved by the present invention is to improve (S)-1'-(8-(((2-amino-3-chloropyridyl-4-yl)thio)-7-methylimidazole in the prior art).
  • the physical and chemical properties of [1,2-c]pyrimidin-5-yl)-1,3-dihydrospiro[indene-2,4'-piperidine]-1-amine i.e., the compound represented by formula (I)
  • Chemical properties thus providing a (S)-1'-(8-(((2-amino-3-chloropyridyl-4-yl)thio)-7-methylimidazo[1,2 -Crystalline forms of -c]pyrimidin-5-yl)-1,3-dihydrospiro[indene-2,4'-piperidin]-1-amine, its salts and crystalline forms of salts and their preparation methods and applications.
  • the invention provides a compound represented by formula (II) or its crystal form:
  • M in formula (II) is citric acid, methanesulfonic acid, H 2 SO 4 , succinic acid, HCl, HNO 3 , HBr, HF, HI, phosphoric acid, 2,5-dihydroxybenzoic acid, 1 -Hydroxy-2-naphthoic acid, acetic acid, dichloroacetic acid, trichloroacetic acid, acetohydroxamic acid, adipic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, benzoic acid, 4-acetamidobenzoic acid, 4- Aminobenzoic acid, capric acid, caproic acid, caprylic acid, cinnamic acid, cyclohexane sulfamate, camphorsulfonic acid, aspartic acid, camphoric acid, gluconic acid, glucuronic acid, glutamic acid, erythorbic acid, lactic acid
  • x is 0, 0.5, 1, 1.5, 2, 2.5 or 3;
  • y 0, 1, 2 or 3;
  • x is 0.5.
  • x is 1.
  • y is 0.
  • the present invention provides crystal form A of the compound represented by formula (I).
  • the X-ray powder diffraction pattern of crystal form A of the compound represented by formula (I) is basically as shown in Figure 1.
  • the differential scanning calorimetry (DSC) curve of the crystal form of compound A represented by formula (I) has endothermic peaks at 188.96°C and 215.23°C.
  • the differential scanning calorimetry (DSC) pattern of the crystal form of compound A represented by formula (I) is shown in Figure 2.
  • thermogravimetric analysis (TGA) curve of the crystal form of compound A represented by formula (I) shows a weight loss of 0.21% from room temperature to 125°C.
  • thermogravimetric analysis (TGA) spectrum of the crystal form of compound A represented by formula (I) is shown in Figure 3.
  • the present invention provides the B crystal form of the compound represented by formula (I).
  • the X-ray powder diffraction pattern of the crystal form has characteristic diffraction peaks at the following 2 ⁇ angles: 14.2 ⁇ 0.2°, 12.53 ⁇ 0.2°, 17.44 ⁇ 0.2°, 17.76 ⁇ 0.2°, 19.88 ⁇ 0.2° and 22.54 ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the crystal form B of the compound represented by formula (I) has characteristic diffraction peaks at the following 2 ⁇ angles: 14.2 ⁇ 0.2°, 12.53 ⁇ 0.2°, 17.44 ⁇ 0.2°, 17.76 ⁇ 0.2°, 19.88 ⁇ 0.2°, 22.54 ⁇ 0.2°, 11.50 ⁇ 0.2°, 16.52 ⁇ 0.2°, 19.52 ⁇ 0.2°, 20.17 ⁇ 0.2°, 21.27 ⁇ 0.2°, 23.44 ⁇ 0.2°, 24.24 ⁇ 0.2° and 24.96 ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the crystal form B of the compound represented by formula (I) is substantially as shown in Figure 4.
  • the X-ray powder diffraction pattern analysis data of the compound B crystal form represented by the formula (I) is as shown in Table 1:
  • Table 1 X-ray powder diffraction pattern analysis data of compound B crystal form represented by formula (I)
  • the differential scanning calorimetry (DSC) curve of the crystal form B of the compound represented by formula (I) has an endothermic peak at 207.09°C.
  • the differential scanning calorimetry (DSC) pattern of the crystal form B of the compound represented by formula (I) is shown in Figure 5.
  • thermogravimetric analysis (TGA) curve of the crystal form B of the compound represented by formula (I) shows a weight loss of 0.41% from room temperature to 112.39°C, and a weight loss of 0.66% from room temperature to 224.70°C.
  • thermogravimetric analysis (TGA) spectrum of the crystal form B of the compound represented by formula (I) is shown in Figure 6.
  • the present invention provides the compound represented by formula (III) (i.e., the mesylate salt of the compound represented by formula (I)), its crystal form or hydrate;
  • the present invention provides the A crystal form of the compound represented by formula (III), wherein the X-ray powder diffraction pattern of the crystal form has characteristic diffraction peaks at the following 2 ⁇ angles: 10.2 ⁇ 0.2°, 12.2 ⁇ 0.2°, 15.9 ⁇ 0.2 °, 17.2 ⁇ 0.2°, 18.6 ⁇ 0.2° and 19.5 ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the A crystal form of the compound represented by formula (III) has characteristic diffraction peaks at the following 2 ⁇ angles: 10.2 ⁇ 0.2°, 11.0 ⁇ 0.2°, 12.2 ⁇ 0.2°, 13.4 ⁇ 0.2°, 13.9 ⁇ 0.2°, 14.4 ⁇ 0.2°, 15.9 ⁇ 0.2°, 16.9 ⁇ 0.2°, 17.2 ⁇ 0.2°, 18.6 ⁇ 0.2°, 19.5 ⁇ 0.2°, 20.2 ⁇ 0.2°, 20.7 ⁇ 0.2°, 21.5 ⁇ 0.2°, 22.5 ⁇ 0.2°, 22.9 ⁇ 0.2°, 24.5 ⁇ 0.2°, 25.0 ⁇ 0.2°, 25.5 ⁇ 0.2°, 27.2 ⁇ 0.2°, 28.6 ⁇ 0.2°, 28.7 ⁇ 0.2°, 29.6 ⁇ 0.2°, 30.1 ⁇ 0.2° and 30.5 ⁇ 0.2°.
  • the X-ray powder diffraction pattern of crystal form A of the compound represented by formula (III) is substantially as shown in Figure 7.
  • the X-ray powder diffraction pattern analysis data of the A crystal form of the compound represented by formula (III) is as shown in Table 2:
  • Table 2 X-ray powder diffraction pattern analysis data of crystal form A of the compound represented by formula (III)
  • the differential scanning calorimetry (DSC) curve of the A crystal form of the compound represented by formula (III) has endothermic peaks at 50.39°C and 204.24°C.
  • the differential scanning calorimetry (DSC) pattern of Form A of the compound represented by Formula (III) is shown in Figure 8.
  • thermogravimetric analysis (TGA) curve of Form A of the compound represented by formula (III) shows a weight loss of 3.5% from room temperature to 87°C.
  • thermogravimetric analysis (TGA) spectrum of Form A of the compound represented by Formula (III) is shown in Figure 9.
  • the present invention provides the compound represented by formula (IV) (i.e., the citrate salt of the compound represented by formula (I)), its crystal form or hydrate;
  • the present invention provides the A crystal form of the compound represented by formula (IV), wherein the X-ray powder diffraction pattern of the crystal form has characteristic diffraction peaks at the following 2 ⁇ angles: 9.5 ⁇ 0.2°, 11.5 ⁇ 0.2°, 11.8 ⁇ 0.2 °, 3.5 ⁇ 0.2°, 14.1 ⁇ 0.2°, 16.3 ⁇ 0.2°, 18.0 ⁇ 0.2°, 20.7 ⁇ 0.2° and 25.1 ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the A crystal form of the compound represented by formula (IV) has characteristic diffraction peaks at the following 2 ⁇ angles: 9.5 ⁇ 0.2°, 10.3 ⁇ 0.2°, 11.5 ⁇ 0.2°, 11.8 ⁇ 0.2°, 12.2 ⁇ 0.2°, 12.9 ⁇ 0.2°, 13.5 ⁇ 0.2°, 14.1 ⁇ 0.2°, 15.7 ⁇ 0.2°, 16.3 ⁇ 0.2°, 17.0 ⁇ 0.2°, 18.0 ⁇ 0.2°, 18.6 ⁇ 0.2°, 20.7 ⁇ 0.2°, 21.1 ⁇ 0.2°, 22.2 ⁇ 0.2°, 23.2 ⁇ 0.2°, 23.8 ⁇ 0.2°, 24.5 ⁇ 0.2°, 24.8 ⁇ 0.2°, 25.1 ⁇ 0.2°, 26.2 ⁇ 0.2°, 28.7 ⁇ 0.2°, 29.4 ⁇ 0.2°, 29.7 ⁇ 0.2°, 30.5 ⁇ 0.2°, 31.8 ⁇ 0.2°, 32.3 ⁇ 0.2°, 33.9 ⁇ 0.2°, 34.6 ⁇ 0.2°, 35.4 ⁇ 0.2°, 36.5 ⁇ 0.2° and 40.4 ⁇ 0.2°.
  • the X-ray powder diffraction pattern of crystal form A of the compound represented by formula (IV) is substantially as shown in Figure 10.
  • the X-ray powder diffraction pattern analysis data of the A crystal form of the compound represented by formula (IV) is as shown in Table 3:
  • Table 3 X-ray powder diffraction pattern analysis data of crystal form A of the compound represented by formula (IV)
  • the differential scanning calorimetry (DSC) curve of Form A of the compound represented by formula (IV) has endothermic peaks at 90.14°C, 162.81°C and 189.67°C.
  • the differential scanning calorimetry (DSC) pattern of Form A of the compound represented by formula (IV) is as shown in Figure 11.
  • thermogravimetric analysis (TGA) curve of Form A of the compound represented by Formula (IV) shows a weight loss of 3.64% from room temperature to 115°C.
  • thermogravimetric analysis (TGA) spectrum of Form A of the compound represented by Formula (IV) is shown in Figure 12.
  • the present invention provides the compound represented by formula (V) (i.e., the sulfate of the compound represented by formula (I)), its crystal form or hydrate;
  • the present invention provides the A crystal form of the compound represented by formula (V), wherein the X-ray powder diffraction pattern of the crystal form has characteristic diffraction peaks at the following 2 ⁇ angles: 10.02 ⁇ 0.2°, 16.06 ⁇ 0.2°, 16.58 ⁇ 0.2 °, 21.96 ⁇ 0.2°, 24.38 ⁇ 0.2° and 24.96 ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the A crystal form of the compound represented by formula (V) has characteristic diffraction peaks at the following 2 ⁇ angles: 9.70 ⁇ 0.2°, 10.02 ⁇ 0.2°, 10.80 ⁇ 0.2°, 11.84 ⁇ 0.2°, 13.38 ⁇ 0.2°, 14.14 ⁇ 0.2°, 15.18 ⁇ 0.2°, 14.1 ⁇ 0.2°, 16.06 ⁇ 0.2°, 16.58 ⁇ 0.2°, 17.16 ⁇ 0.2°, 18.36 ⁇ 0.2°, 19.54 ⁇ 0.2°, 21.96 ⁇ 0.2°, 22.40 ⁇ 0.2°, 23.80 ⁇ 0.2°, 24.38 ⁇ 0.2°, 24.96 ⁇ 0.2°, 27.02 ⁇ 0.2°, 27.63 ⁇ 0.2°, 28.74 ⁇ 0.2°, 30.30 ⁇ 0.2°, 32.08 ⁇ 0.2°, 33.67 ⁇ 0.2° and 34.47 ⁇ 0.2°.
  • the X-ray powder diffraction pattern of Form A of the compound represented by Formula (V) is substantially as shown in Figure 13.
  • the X-ray powder diffraction pattern analysis data of the A crystal form of the compound represented by formula (V) is as shown in Table 4:
  • Table 4 X-ray powder diffraction pattern analysis data of crystal form A of the compound represented by formula (V)
  • the differential scanning calorimetry (DSC) curve of the A crystal form of the compound represented by formula (V) has endothermic peaks at 51.72°C and 223°C.
  • the differential scanning calorimetry (DSC) pattern of Form A of the compound represented by Formula (V) is shown in Figure 14.
  • thermogravimetric analysis (TGA) curve of Form A of the compound represented by Formula (V) shows a weight loss of 3.37% from room temperature to 85°C.
  • thermogravimetric analysis (TGA) spectrum of Form A of the compound represented by formula (V) is shown in Figure 15.
  • the present invention provides the compound represented by formula (VI) (i.e., the succinate salt of the compound represented by formula (I)), its crystal form or hydrate;
  • the present invention provides the A crystal form of the compound represented by formula (VI), wherein the X-ray powder diffraction pattern of the crystal form has characteristic diffraction peaks at the following 2 ⁇ angles: 317.32 ⁇ 0.2°, 18.16 ⁇ 0.2°, 20.62 ⁇ 0.2 °, 20.86 ⁇ 0.2°, 22.46 ⁇ 0.2°, 24.00 ⁇ 0.2°, 24.34 ⁇ 0.2° and 25.02 ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the A crystal form of the compound represented by formula (VI) has characteristic diffraction peaks at the following 2 ⁇ angles: 9.10 ⁇ 0.2°, 11.06 ⁇ 0.2°, 11.46 ⁇ 0.2°, 13.46 ⁇ 0.2°, 14.34 ⁇ 0.2°, 15.50 ⁇ 0.2°, 16.63 ⁇ 0.2°, 16.96 ⁇ 0.2°, 17.32 ⁇ 0.2°, 18.16 ⁇ 0.2°, 19.08 ⁇ 0.2°, 20.62 ⁇ 0.2°, 20.86 ⁇ 0.2°, 22.46 ⁇ 0.2°, 23.36 ⁇ 0.2°, 24.00 ⁇ 0.2°, 24.34 ⁇ 0.2°, 25.02 ⁇ 0.2°, 25.92 ⁇ 0.2°, 26.28 ⁇ 0.2°, 27.84 ⁇ 0.2°, 28.10 ⁇ 0.2°, 28.88 ⁇ 0.2°, 30.45 ⁇ 0.2°.
  • the X-ray powder diffraction pattern of crystal form A of the compound represented by formula (VI) is substantially as shown in Figure 16.
  • the X-ray powder diffraction pattern analysis data of the A crystal form of the compound represented by formula (VI) is as shown in Table 5:
  • Table 5 X-ray powder diffraction pattern analysis data of crystal form A of the compound represented by formula (VI)
  • the differential scanning calorimetry (DSC) curve of crystal form A of the compound represented by formula (VI) has an endothermic peak at 164.53°C.
  • the differential scanning calorimetry (DSC) pattern of Form A of the compound represented by Formula (VI) is shown in Figure 17.
  • thermogravimetric analysis (TGA) curve of Form A of the compound represented by formula (VI) shows a weight loss of 1.42% from room temperature to 100°C.
  • thermogravimetric analysis (TGA) spectrum of Form A of the compound represented by Formula (VI) is shown in Figure 18.
  • the purity of the above-described crystalline forms is greater than 95%.
  • the invention provides a method for preparing a compound represented by formula (II), which includes the following steps: performing a salt-forming reaction on a compound represented by formula (I) and an acid in a solvent to obtain a compound represented by formula (II) .
  • M in formula (II) is citric acid, methanesulfonic acid, H 2 SO 4 , succinic acid, HCl, HNO 3 , HBr, HF, HI, phosphoric acid, 2,5-dihydroxybenzoic acid, 1 -Hydroxy-2-naphthoic acid, acetic acid, dichloroacetic acid, trichloroacetic acid, acetohydroxamic acid, adipic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, benzoic acid, 4-acetamidobenzoic acid, 4- Aminobenzoic acid, capric acid, caproic acid, caprylic acid, cinn
  • the solvent is one or more of halogenated hydrocarbons, dioxane, nitriles, alcohols and water.
  • it is one or more of DCM, acetonitrile, dioxane, water and ethanol.
  • the invention provides a method for preparing a compound represented by formula (III), which includes the following steps: performing a salt-forming reaction on a compound represented by formula (I) and an acid in a solvent to obtain a compound represented by formula (III) .
  • the acid is methanesulfonic acid.
  • the solvent is dioxane.
  • the invention provides a method for preparing a compound represented by formula (IV), which includes the following steps: performing a salt-forming reaction on a compound represented by formula (I) and an acid in a solvent to obtain a compound represented by formula (IV) .
  • the acid is citric acid.
  • the solvent is a mixture solution of acetonitrile and water.
  • the invention provides a method for preparing a compound represented by formula (V), which includes the following steps: performing a salt-forming reaction on a compound represented by formula (I) and an acid in a solvent to obtain a compound represented by formula (V) .
  • the acid is sulfuric acid.
  • the solvent is ethanol.
  • the invention provides a method for preparing a compound represented by formula (VI), which includes the following steps: performing a salt-forming reaction on a compound represented by formula (I) and an acid in a solvent to obtain a compound represented by formula (VI) .
  • the acid is succinic acid.
  • the solvent is dioxane.
  • the invention provides a method for preparing the crystal form of compound A represented by formula (I), which includes the following steps: reacting the compound represented by formula H in DCM and TFA as follows, and then extracting it with DCM, and drying the DCM phase to obtain the formula
  • the crystal form of compound A shown in (I) is sufficient.
  • the mass-to-volume ratio of the compound represented by formula H to DCM can be 15-45 mg/mL. Preferably it is 30 mg/mL.
  • the mass-to-volume ratio of the compound represented by formula H and TFA can be 100-200 mg/mL. Preferably it is 150 mg/mL.
  • the extraction operation is to add DCM and saturated Na 2 CO 3 aqueous solution to the reaction solution, and separate the DCM phase.
  • the drying condition is 30-40°C.
  • the reaction is performed at room temperature.
  • the specific operation of the method for preparing the crystal form of compound A represented by formula (I) is: dissolving the compound represented by formula H Add TFA to DCM at room temperature for reaction, concentrate the reaction solution, add DCM to dilute, add saturated Na 2 CO 3 aqueous solution, extract, take the DCM phase and spin it to dryness at 30-40°C.
  • the invention provides a method for preparing the crystal form of compound B represented by formula (I), which includes the following steps: mixing the crystal form of compound A represented by formula (I) with acetonitrile and then crystallizing to obtain formula (I) Compound B crystal form.
  • the mass volume ratio of the crystal form of compound A represented by formula (I) to acetonitrile can be 10-60 mg/mL. Preferably it is 30 mg/mL.
  • the mixing operation may be shaker shaking. It is preferred to shake on a shaker at 25°C. More preferably, it is shaken with a shaker at 25°C and 250 rpm. It is further preferred to shake with a shaker at 25°C and 250 rpm for 24 hours.
  • the crystallization operation may include the following steps: mixing the crystal form of compound A represented by formula (I) with acetonitrile in the system.
  • the solid is separated to obtain the crystal form B of the compound represented by formula (I).
  • the solids are further dried after being separated. More preferably, drying is performed at 50°C. It is further preferred to dry at 50° C. and a vacuum degree of -0.1 M. It is further preferred to dry for 6 hours at 50°C and vacuum degree -0.1M. It is further preferred to dry in a vacuum drying oven at 50°C and a vacuum degree of -0.1M for 6 hours.
  • the invention provides a method for preparing the crystal form of compound A represented by formula (III), which includes the following steps: after mixing the crystal form of compound A represented by formula (I) with dioxane, it is mixed with a methanol solution of methanesulfonic acid. The reaction crystallizes to obtain the crystal form A of the compound represented by formula (III).
  • the mixing operation may be stirring. It is preferred to stir magnetically while raising the temperature to 50°C.
  • the mass volume ratio of the crystal form of compound A represented by formula (I) to dioxane can be 20-90 mg/mL. Preferably 50 mg/mL.
  • the mass volume ratio of the crystal form of compound A represented by formula (I) and the methanol solution of methanesulfonic acid can be 200-900 mg/mL. . Preferably 500 mg/mL.
  • the concentration of the methanol solution of methanesulfonic acid can be 0.5-2 mol/L. Preferably it is 1 mol/L.
  • the reaction crystallization operation may include the following steps: mixing the crystal form of compound A represented by formula (I) and dioxane After reacting with the methanol solution of methanesulfonic acid, the temperature is lowered and the solid in the reaction mixture is separated.
  • the reaction in the method for preparing the crystal form of compound A represented by formula (III), can be carried out at a temperature of 50°C. Preferably, the reaction can be carried out at a temperature of 50°C for 3 hours.
  • the cooling operation may include cooling to room temperature at a cooling rate of 10°C/h, and then placing the compound in a refrigerator at 4°C for 24 hours.
  • the solid in the preparation method of the crystal form of compound A represented by formula (III), the solid can be further washed after being separated. Washing with dioxane solution is preferred. More preferably, it is washed with a 4°C dioxane solution. Further preferably, the mass-to-volume ratio of the crystal form of compound A represented by formula (I) to the dioxane solution is 150 mg/mL.
  • the solid in the preparation method of the crystal form of compound A represented by formula (III), can be further dried after being separated. Drying at 50°C is preferred. It is further preferred to dry at 50° C. and a vacuum degree of -0.1 M. It is further preferred to dry at 50°C and vacuum degree -0.1M for 24 hours. It is further preferred to dry in a vacuum drying oven at 50°C and a vacuum degree of -0.1M for 24 hours.
  • the invention provides a method for preparing the crystal form of compound A represented by formula (IV), which includes the following steps: after mixing the crystal form of compound A represented by formula (I) with acetonitrile and purified water, react with a citric acid methanol solution After crystallization, the crystal form A of the compound represented by formula (IV) is obtained.
  • the mixing operation may be stirring. It is preferred to stir while raising the temperature to 50°C. More preferably, stirring (200-300 rpm) is performed while raising the temperature to 50°C.
  • the mass-to-volume ratio of the crystal form of compound A represented by formula (I) to acetonitrile can be 5-25 mg/mL. Preferably 11.1 mg/mL.
  • the mass volume ratio of the crystal form of compound A represented by formula (I) and purified water can be 30-170 mg/mL. Preferably 100 mg/mL.
  • the mass volume ratio of the crystal form of compound A represented by formula (I) and the citric acid methanol solution may be 200-900 mg/mL. Preferably 500 mg/mL.
  • the concentration of the citric acid methanol solution may be 0.5-2 mol/L. Preferably it is 1 mol/L.
  • the reaction crystallization operation may include the following steps: mixing the crystal form of compound A represented by formula (I) with acetonitrile and purified water. After reacting with the methanol solution of citric acid, the temperature is lowered and the solid in the reaction mixture is separated.
  • the reaction in the method for preparing the crystal form of compound A represented by formula (IV), can be carried out at a temperature of 50°C.
  • the reaction can be carried out with stirring at a temperature of 50°C. More preferably, the reaction can be carried out with stirring at a temperature of 50°C (rotation speed 200-300 rpm) for 2 hours.
  • the temperature reduction operation may include cooling to 5°C at a temperature reduction rate of 15°C/h. It is preferred to cool down to 5°C at a cooling rate of 15°C/h, and then grow the crystal for 0.5h.
  • the solid in the preparation method of the crystal form of compound A represented by formula (IV), the solid can be further washed after being separated. Washing with acetonitrile solution is preferred. More preferably, it is washed with an acetonitrile solution at 4°C. Further preferably, the mass-to-volume ratio of the crystal form of compound A represented by formula (I) to the acetonitrile solution is 150 mg/mL.
  • the solid in the preparation method of the crystal form of compound A represented by formula (IV), can be further dried after being separated. Drying at 50°C is preferred. It is further preferred to dry at 50° C. and a vacuum degree of -0.1 M. It is further preferred to dry at 50°C and vacuum degree -0.1M for 24 hours. It is further preferred to dry in a vacuum drying oven at 50°C and a vacuum degree of -0.1M for 24 hours.
  • the invention provides a method for preparing the crystal form of compound A represented by formula (V), which includes the following steps: after mixing the crystal form of compound A represented by formula (I) with ethanol, it reacts with sulfuric acid methanol solution for crystallization to obtain Crystal form of compound A represented by formula (V).
  • the temperature is raised to 50°C after mixing.
  • the mass-to-volume ratio of the crystal form of compound A represented by formula (I) and ethanol may be 2-10 mg/mL. Preferably 5 mg/mL.
  • the mass volume ratio of the crystal form of compound A represented by formula (I) and the sulfuric acid methanol solution can be 200-900 mg/mL. Preferably 500 mg/mL.
  • the concentration of the sulfuric acid methanol solution may be 0.5-2 mol/L. Preferably it is 1 mol/L.
  • the reaction crystallization operation may include the following steps: mixing the crystal form of compound A represented by formula (I) with ethanol and then adding sulfuric acid After the reaction of the methanol solution, the temperature is lowered, concentrated, and the solid in the reaction mixture is separated.
  • the reaction in the method for preparing the crystal form of compound A represented by formula (V), can be carried out at a temperature of 50°C.
  • the reaction can be carried out with stirring at a temperature of 50°C. More preferably, the reaction can be carried out with stirring at a temperature of 50°C (rotation speed 200-300 rpm) for 3 hours.
  • the cooling operation may include cooling to 25°C at a cooling rate of 12.5°C/h, adding acetonitrile, and adding acetonitrile at a rate of 10°C/h.
  • the cooling speed is reduced to 5°C.
  • the mass-to-volume ratio of the crystal form of compound A represented by formula (I) to acetonitrile can be 10 mg/mL.
  • the concentration operation may include concentrating the cooled reaction solution at 60°C; preferably, placing it in a rotary evaporator. (60°C, 100rpm).
  • the solid separation operation may include placing the concentrated reaction liquid in an air environment to evaporate to dryness, and then evaporating the evaporated reaction solution to dryness.
  • the solid was further dried.
  • the drying is preferably performed at 50°C. It is further preferred to dry at 50° C. and a vacuum degree of -0.1 M. It is further preferred to dry at 50°C and vacuum degree -0.1M for 24 hours. It is further preferred to dry in a vacuum drying oven at 50°C and a vacuum degree of -0.1M for 24 hours.
  • the invention provides a method for preparing the crystal form of compound A represented by formula (VI), which includes the following steps: after mixing the crystal form of compound A represented by formula (I) with dioxane, it is mixed with succinic acid methanol solution The reaction crystallizes to obtain the crystal form A of the compound represented by formula (VI).
  • the mixing operation may be stirring. It is preferred to stir magnetically while raising the temperature to 50°C.
  • the mass volume ratio of the crystal form of compound A represented by formula (I) to dioxane can be 15-70 mg/mL. Preferably 37.5 mg/mL.
  • the mass-to-volume ratio of the crystal form of compound A represented by formula (I) and the succinic acid methanol solution can be 200-900 mg/mL. . Preferably 500 mg/mL.
  • the concentration of the methanol succinic acid solution may be 0.5-2 mol/L. Preferably it is 1 mol/L.
  • the reaction crystallization operation may include the following steps: mixing the crystal form of compound A represented by formula (I) with dioxane After reacting with the methanol solution of succinic acid, the temperature is lowered and the solid in the reaction mixture is separated.
  • the reaction in the method for preparing the crystal form of compound A represented by formula (VI), can be carried out at a temperature of 50°C. Preferably, the reaction can be carried out at a temperature of 50°C for 3 hours.
  • the cooling operation may include cooling to room temperature at a cooling rate of 10°C/h, and then placing the compound in a refrigerator at 4°C for 5 hours.
  • the solid in the preparation method of the crystal form of compound A represented by formula (VI), the solid can be further washed after being separated. Washing with dioxane solution is preferred. More preferably, it is washed with a 4°C dioxane solution. Further preferably, the mass-to-volume ratio of the crystal form of compound A represented by formula (I) to the dioxane solution is 150 mg/mL.
  • the solid in the preparation method of the crystal form of compound A represented by formula (VI), the solid can be further dried after being separated. Drying at 50°C is preferred. It is further preferred to dry at 50° C. and a vacuum degree of -0.1 M. It is further preferred to dry at 50°C and vacuum degree -0.1M for 24 hours. It is further preferred to dry in a vacuum drying oven at 50°C and a vacuum degree of -0.1M for 24 hours.
  • the present invention further provides a pharmaceutical composition, which contains a therapeutically effective amount of any compound or crystal form described in the present invention, and pharmaceutically acceptable excipients.
  • the pharmaceutical compositions are for oral administration.
  • the pharmaceutical compositions are used to formulate tablets or capsules.
  • the pharmaceutical composition contains 0.2-10% by weight of any of the crystalline forms of the compounds described herein.
  • the present invention further provides the use of any of the compounds, crystal forms or pharmaceutical compositions in the preparation of medicines.
  • the drug is a drug that treats, prevents, delays, or hinders the onset or progression of a disease associated with SHP2 protein activity or expression.
  • the drug is a drug that treats a disease associated with SHP2 protein activity or expression.
  • the disease is neoplasm.
  • the tumor is a tumor caused by an abnormality in the Ras-Raf-ERK or PD1/L1 signaling pathways.
  • the tumor is esophageal cancer, lung cancer, colorectal cancer, pancreatic cancer, leukemia, or gastric cancer.
  • the relative intensity of the peaks may fluctuate with experimental conditions and sample preparation such as the preferred orientation of the particles in the sample.
  • sample preparation such as the preferred orientation of the particles in the sample.
  • the use of automatic or fixed divergence slits also affects the calculation of relative intensity.
  • the intensities shown in the PXRD curves included here are exemplary only and should not be used as an absolute comparison.
  • thermogravimetric analysis (TGA) test starting temperature is not specified in the present invention, the starting temperature is room temperature, and room temperature is generally 20-35°C.
  • the term "therapeutically effective amount” means an amount of a compound that is sufficient to affect the treatment of a disease, or at least one clinical symptom of a disease or condition, when administered to a subject. quantity.
  • a “therapeutically effective amount” may vary with the compound, the disease, condition, and/or symptoms of the disease or condition, the severity of the disease, condition, and/or symptoms of the disease or condition, the age of the patient being treated, and/or the condition being treated. changes in the patient's weight.
  • a suitable amount in any particular case may be apparent to those skilled in the art or may be determined by routine experimentation.
  • a “therapeutically effective amount” refers to the total amount of the combination effective to treat the disease, disorder, or condition.
  • the salt form or crystal form of the present invention can be used in combination as an active component and mixed with a pharmaceutical carrier to form a pharmaceutical composition.
  • the pharmaceutical carrier can take a variety of forms, depending on the intended mode of administration, for example, oral or injection (including intravenous injection). Accordingly, the pharmaceutical compositions of the present invention may be in stand-alone forms suitable for oral administration. Such as capsules, cachets or tablets containing a predetermined dose of the active ingredient. Further, the pharmaceutical composition of the present invention can be in the form of powder, granule, solution, aqueous suspension, non-aqueous liquid, oil-in-water emulsion or water-in-oil emulsion.
  • the salt form or crystal form of the present invention can also be administered through a controlled release method and/or a delivery device.
  • the pharmaceutical composition of the present invention can be prepared by any pharmaceutical method. Generally, such methods include the step of bringing into association the active ingredient with the carrier which constitutes one or more essential ingredients.
  • the pharmaceutical compositions are prepared by uniformly intimate mixing of the active ingredient with a liquid carrier or a finely divided solid carrier or a mixture of both.
  • the product can be easily prepared to the desired appearance.
  • pharmaceutically acceptable carrier refers to conventional pharmaceutical carriers suitable for the desired pharmaceutical preparation, for example: diluents, excipients such as water, various organic solvents, etc.; such as starch, pregelatinized starch , sucrose, dextrin, mannitol, lactose, spray-dried lactose, microcrystalline cellulose, silicified microcrystalline cellulose, inorganic salts, etc.
  • fillers such as starch slurry, dextrin, sugar powder, syrup, glue, poly Binders such as ethylene glycol, cellulose derivatives, alginates, gelatin, hydroxypropylcellulose, copovidone and polyvinylpyrrolidone (PVP); humectants such as distilled water, ethanol and glycerol; such as dry starch , disintegrants such as low-substituted hydroxypropyl cellulose, hydroxypropyl starch, agar, calcium carbonate, sodium bicarbonate, crospovidone, croscarmellose sodium, sodium carboxymethyl starch, etc.; such as quaternary Absorption accelerators for ammonium compounds, amino acid ethylamine derivatives, acetoacetate esters, ⁇ -dicarboxylic acid esters, aromatic acidic compounds, aliphatic acidic compounds, etc.; such as sodium cetyl sulfate, sodium octadecyl sulfate,
  • excipients can be added to the pharmaceutical composition, such as antioxidants, colorants, preservatives, pH adjusters, hardeners, emulsifiers, propellants, dispersants, stabilizers, and thickeners. , complexing agents, buffers, penetration enhancers, polymers, aromatics, sweeteners and dyes. Preference is given to the use of excipients suitable for the desired dosage form and intended mode of administration.
  • the reagents and raw materials used in the present invention are all commercially available.
  • the positive progressive effect of the present invention lies in: the crystal forms A and B of the compound represented by formula (I), the crystal form of compound A represented by formula (III), the crystal form of compound A represented by formula (IV), the crystal form of compound represented by formula (IV) protected in this application
  • the crystal form of compound A shown in V) and the crystal form of compound A shown in formula (VI) have one or more of the following advantages: (1) stable properties; (2) good moisture absorption; (3) good bioavailability (4) It has good prospects as a patent medicine.
  • Figure 1 PXRD pattern - X-ray powder diffraction pattern of the crystal form of compound A represented by formula (I).
  • Figure 2 DSC spectrum of crystal form A of compound represented by formula (I) - differential scanning calorimetry spectrum.
  • FIG. 3 TGA spectrum of crystal form A of compound represented by formula (I) - thermogravimetric analysis spectrum.
  • FIG. 4 PXRD pattern of crystal form B of compound represented by formula (I).
  • FIG. 7 PXRD pattern of crystal form A of compound represented by formula (III).
  • FIG. 8 DSC spectrum of crystal form A of compound represented by formula (III).
  • FIG. 10 PXRD pattern of crystal form A of compound represented by formula (IV).
  • FIG. 11 DSC spectrum of crystal form A of compound represented by formula (IV).
  • FIG. 12 TGA spectrum of crystal form A of compound represented by formula (IV).
  • FIG. 13 PXRD pattern of crystal form A of compound represented by formula (V).
  • FIG. 14 DSC spectrum of crystal form A of compound represented by formula (V).
  • FIG. 15 TGA spectrum of crystal form A of compound represented by formula (V).
  • FIG. 16 PXRD pattern of crystal form A of compound represented by formula (VI).
  • FIG. 17 DSC spectrum of crystal form A of compound represented by formula (VI).
  • FIG. 18 TGA spectrum of crystal form A of compound represented by formula (VI).
  • Figure 24 Chart showing the effects of each test substance on tumor volume in human non-small cell lung cancer NCI-H358 nude mouse xenograft tumor model animals.
  • Figure 25 Chart showing the effects of each test substance on tumor weight in human non-small cell lung cancer NCI-H358 nude mouse xenograft tumor model animals.
  • Figure 26 Chart showing the effect of each test substance on tumor volume in human leukemia MV-4-11 mouse xenograft tumor model animals.
  • Figure 27 Chart showing the effect of each test substance on tumor weight in human leukemia MV-4-11 mouse xenograft tumor model animals.
  • Figure 28 Chart showing the effects of each test substance on tumor volume in human pancreatic cancer Mia PaCa-2 nude mouse xenograft tumor model animals.
  • Figure 29 Chart showing the effects of each test substance on tumor weight in human pancreatic cancer Mia PaCa-2 nude mouse xenograft tumor model animals.
  • the first step is the synthesis of compound B
  • a dynamic water adsorption instrument (DVS) was used to examine the adsorption and desorption experiments of the crystal forms of the above compounds at 25°C and a relative humidity range of 0 to 95% to determine the moisture-absorbing properties of various crystal forms.
  • the experimental results are shown in Table 6.
  • the weight gain of the crystal form B of the compound represented by formula (I) is less than 0.2% and has almost no hygroscopicity; the compound represented by formula (III), the compound represented by formula (VI) and the compound represented by formula (I)
  • the compound A shown has a moisture-absorbing weight gain of less than 2% but not less than 0.2%, and is slightly hygroscopic; the crystal form of compound A shown in formula (V) and the crystal form of compound A shown in formula (IV) have a moisture-absorbing weight gain of less than 15%. But not less than 2%, with hygroscopicity.
  • Phase A is 0.1% methanol aqueous solution
  • phase B is acetonitrile
  • A:B 10:90
  • solubility test results show that the solubility of the crystal form of the compound represented by formula (I) is obviously pH-dependent, and the solubility of the weakly basic drug increases as the pH value decreases.
  • the solubility of the crystal form of compound B shown in formula (I) in pH 2.0 buffer salt solution and pH 4.5 buffer salt solution is equivalent to the crystal form of compound A shown in formula (I), but in pH 6.8 buffer salt solution and deionized water
  • the solubility is much smaller than the crystal form of compound A shown in formula (I).
  • salt formation can significantly improve the solubility of the compound in pH 6.8 buffer salt solution and deionized water; compared with the compound A crystal form shown in formula (I), salt formation
  • the solubility in deionized water was also significantly improved.
  • the crystal form of compound A represented by formula (III) was the best, with an increase of 82 times.
  • the solubility in other pH buffer salt solutions was also equivalent.
  • High temperature test The powder is placed in a suitable sealed glass bottle and placed at 60°C for 10 days, and samples are taken on the 5th and 10th days to test solid PXRD.
  • High humidity test Place the powder opening in a constant temperature and humidity box at 25°C and 90% ⁇ 5% RH for 10 days, and take samples on the 5th and 10th days to test solid PXRD. Examine its hygroscopic and deliquescent properties.
  • Strong light irradiation test Place the powder opening in a stable light box equipped with a fluorescent lamp, place it for 10 days under the condition of illumination of 4500 ⁇ 500lx, and take samples on the 5th and 10th days to test solid PXRD.
  • Accelerated test (A): Place the powder opening in a constant temperature and humidity box at 40°C and 75% ⁇ 5% RH for 10 days, and take samples on the 5th and 10th days to test solid PXRD.
  • Example 10 Experiment on xenograft tumor model of compound A crystal form represented by formula (IV)
  • mice Balb/c nude mice, female, weighing 17-19g, provided by Zhejiang Weitong Lihua Experimental Animal Technology Co., Ltd.; raised at SPF level, temperature 20-26°C, humidity 40-70%, free access to food, city tap water Filter and autoclave before drinking. Mice were given adaptive feeding for at least 7 days before the experiment.
  • test substance RG001 i.e., the crystal form of compound A represented by formula (IV)
  • the test substance administration solution should be prepared freshly before use, and stored at 2-8°C, protected from light.
  • Human cancer cell lines Human non-small cell lung cancer cell NCI-H358 was provided by the Institute of Cell Biology, Chinese Academy of Sciences.
  • RPMI-1640 basic medium and fetal bovine serum (FBS) were purchased from GIBCO (Grand Island, NY, USA).
  • NCI-H358 cells were cultured in RPMI-1640 medium containing 10% FBS, and the cells were placed in a 5% CO 2 incubator at 37°C. Collect NCI-H358 cells in the logarithmic growth phase, count them and resuspend them in RPMI-1640 basic medium. Add Matrigel at a ratio of 1:1, adjust the cell suspension concentration to 1*10 8 mL, and inoculate 0.1 cells under sterile conditions. mL of cell suspension was subcutaneously placed on the right back of the mouse.
  • the compound A crystal form group represented by formula (IV) is orally administered once a day or once a week for three consecutive weeks, and the positive drug group is orally administered RMC4550 once a day for three consecutive weeks.
  • each administration group had significant tumor inhibition.
  • RG001 0.5mg/kg, 1mg/kg, 2mg/kg, 4mg/kg groups were administered orally every day for 21 consecutive days.
  • the relative tumor inhibition rates T/C of each group were 33.33% and 31.58 respectively. %, 12.4%, 10.06%; the 14mg/kg group of RG001 was administered once a week for three times in total, and the T/C on the 21st day was 23.39%.
  • the positive control RMC455015 mg/kg group was administered orally every day for 21 consecutive days, and the T/C was 20.70% on the 21st day.
  • the specific experimental results are shown in Figure 24.
  • mice SCID mice, female, weighing 15-18g, animals are from Beijing Vitong Lihua Experimental Animal Technology Co., Ltd.; raised at SPF level, temperature 20-26°C, humidity 40-70%, free access to food, city tap water is filtered Drink after autoclaving. Mice were given adaptive feeding for at least 7 days before the experiment.
  • test substance RG001 (crystalline form of compound A represented by formula (IV)) is 1% HPMC.
  • the test substance administration solution should be prepared freshly before use, and stored at 2-8°C, protected from light.
  • Human cancer cell line Human leukemia cell line MV-4-11 was provided by ATCC (American Type Culture Collection, USA).
  • IMDM basal medium IMDM basal medium and fetal bovine serum (FBS) were purchased from GIBCO (Grand Island, NY, USA).
  • FBS fetal bovine serum
  • MV-4-11 cells were cultured in IMDM medium containing 10% FBS, and the cells were placed in a 5% CO 2 incubator at 37°C. Collect MV-4-11 cells in the logarithmic growth phase, count them and resuspend them in IMDM basic medium. Add Matrigel at a ratio of 1:1, adjust the cell suspension concentration to 5*10 7 mL, and inoculate 0.1 cells under sterile conditions. mL of cell suspension was injected subcutaneously into the right back of the mouse, and the inoculation concentration was 5*10 6 /0.1mL/mouse.
  • the animals were divided into groups using random block method, with 8 mice in each group.
  • Day 0 was recorded on the day of grouping, and medication was started according to the average body weight. Animal body weight and tumor size were measured twice a week during the experiment.
  • the experimental group was orally administered once a day or once a week for three consecutive weeks, while the positive drug group was orally administered RMC4550 once a day for three consecutive weeks.
  • each administration group had significant tumor inhibition.
  • the 1 mg/kg, 2 mg/kg, and 4 mg/kg groups of RG001 were administered orally every day for 21 consecutive days.
  • the relative tumor proliferation rates T/C of the 1 mg/kg and 2 mg/kg dosage groups were 33.22% and 6.81% respectively.
  • the tumors in the 4 mg/kg group completely regressed; the 14 mg/kg group of RG001 was administered once a week for a total of three times, and the T/C on the 21st day was 12.95%.
  • the positive control RMC4550 15mg/kg group was administered orally every day for 21 consecutive days, and the T/C was 8.94% on the 21st day.
  • the specific results are shown in Figure 26.
  • mice Balb/c nude mice, female, weighing 17-19g, provided by Zhejiang Weitong Lihua Experimental Animal Technology Co., Ltd.; raised at SPF level, temperature 20-26°C, humidity 40-70%, free access to food, city tap water Filter and autoclave before drinking. Mice were given adaptive feeding for at least 7 days before the experiment.
  • test substance RG001 (crystalline form of compound A represented by formula (IV)) is 1% HPMC.
  • the test substance administration solution should be prepared freshly before use, and stored at 2-8°C, protected from light.
  • Human cancer cell line Human pancreatic cancer cell line Mia PaCa-2 was provided by ATCC (American Type Culture Collection, USA).
  • DMEM basic medium fetal bovine serum (FBS) were purchased from GIBCO (Grand Island, NY, USA).
  • Mia PaCa-2 cells were cultured in DMEM medium containing 10% FBS, and the cells were placed
  • the animals were divided into groups using random block method, with 8 mice in each group.
  • the group was divided into groups on Day 0, and medication was started according to the average body weight.
  • the experimental period was 28 days. Animal body weight and tumor size were measured twice a week during the experiment.
  • the compound A crystal form group represented by formula (IV) is orally administered once a day or once a week for four consecutive weeks, and the positive drug group is orally administered RMC4550 once a day for four consecutive weeks.
  • the experimental results showed that compared with the blank solvent control group, the tumor weight of each administration group was significantly reduced.
  • the 1 mg/kg, 2 mg/kg, and 4 mg/kg groups of RG001 were administered orally every day for 28 consecutive days.
  • the inhibition rates of tumor weight in each dose group were 76.36%, 79.08%, and 81.66% respectively; the 14 mg/kg group of RG001 kg group, administered once a week for four times in total, the tumor weight inhibition rate was 69.16%.
  • the positive control RMC4550 15mg/kg group was administered every day for 28 days, and the inhibition rate of tumor weight was 78.53%.
  • the specific results are shown in Figure 29.
  • * corresponds to P ⁇ 0.05
  • ** corresponds to P ⁇ 0.01
  • each administration group had significant tumor inhibition.
  • the 1 mg/kg, 2 mg/kg, and 4 mg/kg groups of RG001 were administered orally every day for 28 consecutive days.
  • the relative tumor proliferation rates T/C of each dose group were 27.61%, 20.55%, and 16.75% respectively;
  • the 14 mg/kg group was administered once a week for a total of four times, and the T/C on the 28th day was 30.77%.
  • the positive control RMC4550 15mg/kg group was administered orally every day for 28 consecutive days, and the T/C was 20.02% on the 28th day. The specific results are shown in Figure 28.
  • Example 11 Pharmacokinetic experiments on the crystal form of compound A represented by formula (I), the crystal form of compound A represented by formula (III) and the crystal form of compound A represented by formula (IV)
  • Test animals SPF grade SD rats were divided into the compound group represented by formula (I) and each salt form group of the compound represented by formula (I). Each group included 3 male rats.
  • Medication preparation Prepare on the day of administration.
  • the first step is to prepare the solvent preparation: measure the required amount of deionized water into a suitable container, weigh the required amount of HPMC, add it and mix until uniform to obtain a colorless and clear 1% HPMC solution.
  • Plasma samples were collected in EDTA-K pre-anticoagulated tubes. The plasma in the sample was separated by centrifugation at 4000 rpm for 10 min at 4°C. Plasma samples were collected and stored at -80°C until analysis. Samples were analyzed by TQ5500LC/MS combined with HPLC. Under liquid chromatography conditions, an ACQUITY UPLC HSS T3 1.8um (2.1*50mm) chromatographic column was used as the stationary phase, and 0.1% formic acid acetonitrile solution was used as the mobile phase. The specific experimental results are shown in Table 9:
  • the preparation process of the tablets is as follows:
  • the crystal form of the compound A represented by formula (IV) and an equal volume of colloidal silica are mixed and sieved at a rotation speed of 200rpm to 300rpm, passed through a 1.0mm round hole screen and passed through a crushing and granulating machine once, and then mixed with the remaining colloidal silica. Mix and sieve at 200rpm ⁇ 300rpm through a 1.0mm round hole screen and pass through the grinding and granulating machine once to be used as premix 2;
  • the tested mixing uniformity of the total mixed material is in the range of 95.0 to 105.0%, which meets the quality standards of the intermediate.
  • the theoretical tablet weight is the indicated tablet weight.
  • the ZP10A rotary tablet press is used for tableting, with a 5.5mm circular shallow concave punch.
  • the turntable speed is set to 15-25rpm
  • the feed speed is 10rpm-15rpm
  • the tablet weight difference is required to be ⁇ 7%
  • the tablet hardness is controlled to be 30-60N.
  • the ZP10A rotary tablet press is used for tableting, with 11mm circular shallow concave punching.
  • the turntable speed is set to 15-25rpm
  • the feed speed is 15rpm-20rpm
  • the tablet weight difference is required to be ⁇ 5%
  • the tablet hardness is controlled to be 70-100N.
  • the packaging materials are oral solid pharmaceutical high-density polyethylene bottles and oral solid pharmaceutical polypropylene-low-density polyethylene child-safe and moisture-proof combination bottle caps.

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Abstract

Provided are an SHP2 inhibitor, and a crystal form thereof, a preparation method therefor, and a use thereof. Provided are a crystal form B of a compound as shown in formula (I), a compound as shown in formula (II) and a crystal form A thereof, a compound as shown in formula (III) and a crystal form A thereof, a compound as shown in formula (IV) and a crystal form A thereof, a compound as shown in formula (V) and a crystal form A thereof, and a compound as shown in formula (VI) and a crystal form A thereof as well as a preparation method therefor and a use thereof. The compounds and the crystal forms thereof have one or more of the following advantages: being stable in property, good in hygroscopicity, and good in bioavailability, and having good drug development prospects.

Description

SHP2抑制剂、其晶型及其制备方法与用途SHP2 inhibitors, crystal forms thereof, preparation methods and uses thereof 技术领域Technical field
本发明涉及SHP2抑制剂、其晶型及其制备方法与用途，属于化学药物领域。The present invention relates to SHP2 inhibitors, their crystal forms and their preparation methods and uses, and belongs to the field of chemical drugs.
背景技术Background technique
蛋白酪氨酸磷酸酶(PTP)在多种细胞过程，如细胞生长、增殖、细胞分化和致癌性转化的调节中起重要作用。蛋白酪氨酸磷酸酶(PTP)导致的脱磷酸和其对应物酪氨酸激酶导致的磷酸化之间的平衡对于正常生理功能是关键的。PTP越来越被视为有价值的药物靶点。例如，通过酪氨酸-蛋白磷酸酶非受体类型11(PTPN11)编码的包含Src同源-2(SH2)结构域的蛋白酪氨酸磷酸酶-2(SHP2)，为包含两个串联Src同源-2(SH2)结构域的非受体蛋白酪氨酸磷酸酶(PTP)。SHP2在大多数组织广泛表达且在生长因子和细胞因子受体下游的多种信号转导途径中起积极作用，以调节多种细胞功能。SHP2的催化活性是完全活化Ras-ERK1/2级联所需的，该Ras-ERK1/2级联通过SHP2-催化的底物脱磷酸介导，该底物通过酪氨酸磷酸化负调节。SHP2被识别为一种真实的致癌基因；功能获得性SHP2突变导致了增加的磷酸酶活性导致的Noonan综合征，以及多种形式的白血病(例如，青少年髓单核细胞白血病、急性骨髓性白血病、骨髓增生异常综合征、急性淋巴白血病)和多种实体瘤(例如，肺腺癌、结肠癌、成神经细胞瘤、成胶质细胞瘤、黑素瘤、肝细胞癌和前列腺癌)。因此，SHP2代表了多种癌症的有希望的靶点(例如，三阴性和HER2+乳腺癌、受体蛋白酪氨酸激酶(PTK)异常活化导致的癌症，其中有些对激酶抑制剂单一治疗响应较差)，并在SHP2抑制剂的开发中吸引越来越多的关注。Protein tyrosine phosphatase (PTP) plays an important role in the regulation of various cellular processes, such as cell growth, proliferation, cell differentiation, and oncogenic transformation. The balance between dephosphorylation by protein tyrosine phosphatase (PTP) and phosphorylation by its counterpart tyrosine kinase is critical for normal physiological function. PTP is increasingly regarded as a valuable drug target. For example, the Src homology-2 (SH2) domain-containing protein tyrosine phosphatase-2 (SHP2) encoded by tyrosine-protein phosphatase non-receptor type 11 (PTPN11) contains two tandem Src Homology-2 (SH2) domain-containing non-receptor protein tyrosine phosphatase (PTP). SHP2 is widely expressed in most tissues and plays an active role in multiple signal transduction pathways downstream of growth factor and cytokine receptors to regulate a variety of cellular functions. The catalytic activity of SHP2 is required for full activation of the Ras-ERK1/2 cascade, which is mediated by SHP2-catalyzed dephosphorylation of substrates that are negatively regulated by tyrosine phosphorylation. SHP2 was identified as a bona fide oncogene; gain-of-function SHP2 mutations result in increased phosphatase activity leading to Noonan syndrome, as well as various forms of leukemia (e.g., juvenile myelomonocytic leukemia, acute myelogenous leukemia, myelodysplastic syndrome, acute lymphoblastic leukemia) and various solid tumors (e.g., lung adenocarcinoma, colon cancer, neuroblastoma, glioblastoma, melanoma, hepatocellular carcinoma, and prostate cancer). Therefore, SHP2 represents a promising target in a variety of cancers (e.g., triple-negative and HER2+ breast cancer, cancers resulting from aberrant activation of receptor protein tyrosine kinases (PTK), some of which are less responsive to kinase inhibitor monotherapy). poor) and attracting increasing attention in the development of SHP2 inhibitors.
因此，发现和寻找具有较好成药性的SHP2抑制剂逐渐成为工业界和学术界的一大热点研究领域。Therefore, discovering and searching for SHP2 inhibitors with good druggability has gradually become a hot research field in industry and academia.
式(I)所示化合物最早公开于PCT/CN2019/116386，该化合物对SHP2有很强的抑制作用，具有很高的选择性，是新一代SHP2抑制剂：The compound represented by formula (I) was first disclosed in PCT/CN2019/116386. This compound has a strong inhibitory effect on SHP2 and has high selectivity. It is a new generation of SHP2 inhibitor:
Figure PCTCN2022096702-appb-000001
Figure PCTCN2022096702-appb-000001
发明内容Contents of the invention
本发明所要解决的技术问题为改善现有技术中(S)-1'-(8-((((2-氨基-3-氯吡啶基-4-基)硫代)-7-甲基咪唑并[1,2-c]嘧啶-5-基)-1,3-二氢螺[茚-2,4'-哌啶]-1-胺(即式(I)所示化合物)的物理和化学性质，从而提供了一种(S)-1'-(8-((((2-氨基-3-氯吡啶基-4-基)硫代)-7-甲基咪唑并[1,2-c]嘧啶-5-基)-1,3-二氢螺[茚-2,4'-哌啶]-1-胺的晶型、其盐和盐的晶型及其制备方法和应用。本发明的(S)-1'-(8-((((2-氨基-3-氯吡啶基-4-基)硫代)-7-甲基咪唑并[1,2-c]嘧啶-5-基)-1,3-二氢螺[茚-2,4'-哌啶]-1-胺的晶型、其盐以及各晶型具有以下一个或多个优点：较好的溶解性、性质稳定、引湿性好、具有良好的成药前景。The technical problem to be solved by the present invention is to improve (S)-1'-(8-(((2-amino-3-chloropyridyl-4-yl)thio)-7-methylimidazole in the prior art). The physical and chemical properties of [1,2-c]pyrimidin-5-yl)-1,3-dihydrospiro[indene-2,4'-piperidine]-1-amine (i.e., the compound represented by formula (I)) Chemical properties, thus providing a (S)-1'-(8-(((2-amino-3-chloropyridyl-4-yl)thio)-7-methylimidazo[1,2 -Crystalline forms of -c]pyrimidin-5-yl)-1,3-dihydrospiro[indene-2,4'-piperidin]-1-amine, its salts and crystalline forms of salts and their preparation methods and applications. (S)-1'-(8-(((2-amino-3-chloropyridyl-4-yl)thio)-7-methylimidazo[1,2-c]pyrimidine- The crystalline forms of 5-yl)-1,3-dihydrospiro[indene-2,4'-piperidine]-1-amine, its salts and each crystalline form have one or more of the following advantages: better solubility , stable in nature, good in absorbing moisture, and has good prospects as a pharmaceutical.
本发明提供了一种式(II)所示化合物或其晶型：The invention provides a compound represented by formula (II) or its crystal form:
Figure PCTCN2022096702-appb-000002
Figure PCTCN2022096702-appb-000002
其中，式(II)中所述M为柠檬酸、甲磺酸、H 2SO 4、丁二酸、HCl、HNO 3、HBr、HF、HI、磷酸、2,5-二羟基苯甲酸、1-羟基-2-萘甲酸、醋酸、二氯醋酸、三氯醋酸、乙酰氧肟酸、己二酸、苯磺酸、4-氯苯磺酸、苯甲酸、4-乙酰氨基苯甲酸、4-氨基苯甲酸、癸酸、己酸、辛酸、肉桂酸、环己烷氨基磺酸、樟脑磺酸、天门冬氨酸、樟脑酸、葡萄糖酸、葡糖醛酸、谷氨酸、异抗坏血酸、乳酸、苹果酸、扁桃酸、焦谷氨酸、酒石酸、十二烷基硫酸、二苯甲酰酒石酸、乙烷-1,2-二磺酸、乙磺酸、蚁酸、富马酸、半乳糖酸、龙胆酸、戊二酸、2-酮戊二酸、乙醇酸、马尿酸、羟乙基磺酸、乳糖酸、抗坏血酸、天冬氨酸、月桂酸、樟脑酸、马来酸、丙二酸、1,5-萘二磺酸、萘-2-磺酸、烟酸、油酸、乳清酸、草酸、棕榈酸、双羟萘酸、丙酸、水杨酸、4-氨基水杨酸、癸二酸、硬脂酸、硫氰酸、十一碳烯酸、三氟乙酸、苯磺酸、对甲基苯磺酸和L-苹果酸；优选柠檬酸、甲磺酸、H 2SO 4、丁二酸、HCl、HNO 3、苯磺酸、马来酸、己二酸、对甲基苯磺酸、丙二酸和L-苹果酸、抗坏血酸、水杨酸、2-乙酸基苯甲酸、烟酸、异烟酸、胆酸、天冬氨酸或谷氨酸； Wherein, M in formula (II) is citric acid, methanesulfonic acid, H 2 SO 4 , succinic acid, HCl, HNO 3 , HBr, HF, HI, phosphoric acid, 2,5-dihydroxybenzoic acid, 1 -Hydroxy-2-naphthoic acid, acetic acid, dichloroacetic acid, trichloroacetic acid, acetohydroxamic acid, adipic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, benzoic acid, 4-acetamidobenzoic acid, 4- Aminobenzoic acid, capric acid, caproic acid, caprylic acid, cinnamic acid, cyclohexane sulfamate, camphorsulfonic acid, aspartic acid, camphoric acid, gluconic acid, glucuronic acid, glutamic acid, erythorbic acid, lactic acid , malic acid, mandelic acid, pyroglutamic acid, tartaric acid, dodecyl sulfate, dibenzoyltartaric acid, ethane-1,2-disulfonic acid, ethanesulfonic acid, formic acid, fumaric acid, galactose Acid, gentisic acid, glutaric acid, 2-oxoglutaric acid, glycolic acid, hippuric acid, isethionic acid, lactobionic acid, ascorbic acid, aspartic acid, lauric acid, camphoric acid, maleic acid, propionic acid Diacid, 1,5-naphthalenedisulfonic acid, naphthalene-2-sulfonic acid, nicotinic acid, oleic acid, orotic acid, oxalic acid, palmitic acid, pamoic acid, propionic acid, salicylic acid, 4-amino acid Cylic acid, sebacic acid, stearic acid, thiocyanic acid, undecenoic acid, trifluoroacetic acid, benzenesulfonic acid, p-toluenesulfonic acid and L-malic acid; preferably citric acid, methanesulfonic acid, H 2 SO 4 , succinic acid, HCl, HNO 3 , benzenesulfonic acid, maleic acid, adipic acid, p-toluenesulfonic acid, malonic acid and L-malic acid, ascorbic acid, salicylic acid, 2-acetic acid benzoic acid, nicotinic acid, isonicotinic acid, cholic acid, aspartic acid or glutamic acid;
x为0、0.5、1、1.5、2、2.5或3；x is 0, 0.5, 1, 1.5, 2, 2.5 or 3;
y为0、1、2或3；y is 0, 1, 2 or 3;
x和y不同时为0。x and y are not 0 at the same time.
在一些实施方案中，x为0.5。In some embodiments, x is 0.5.
在一些实施方案中，x为1。In some embodiments, x is 1.
在一些实施方案中，y为0。In some embodiments, y is 0.
本发明提供了式(I)所示化合物的A晶型，所述式(I)所示化合物A晶型的X射线粉末衍射图谱基本如图1所示。The present invention provides crystal form A of the compound represented by formula (I). The X-ray powder diffraction pattern of crystal form A of the compound represented by formula (I) is basically as shown in Figure 1.
Figure PCTCN2022096702-appb-000003
Figure PCTCN2022096702-appb-000003
在一些实施方案中，所述式(I)所示化合物A晶型的差示扫描量热(DSC)曲线在188.96℃和215.23℃处具有吸热峰。In some embodiments, the differential scanning calorimetry (DSC) curve of the crystal form of compound A represented by formula (I) has endothermic peaks at 188.96°C and 215.23°C.
在一些实施方案中，所述式(I)所示化合物A晶型的差示扫描量热(DSC)图谱如图2所示。In some embodiments, the differential scanning calorimetry (DSC) pattern of the crystal form of compound A represented by formula (I) is shown in Figure 2.
在一些实施方案中，所述式(I)所示化合物A晶型的热重分析(TGA)曲线显示在室温至125℃失重0.21％。In some embodiments, the thermogravimetric analysis (TGA) curve of the crystal form of compound A represented by formula (I) shows a weight loss of 0.21% from room temperature to 125°C.
在一些实施方案中，所述式(I)所示化合物A晶型的热重分析(TGA)图谱如图3所示。In some embodiments, the thermogravimetric analysis (TGA) spectrum of the crystal form of compound A represented by formula (I) is shown in Figure 3.
本发明提供了式(I)所示化合物的B晶型，所述晶型X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：14.2±0.2°、12.53±0.2°、17.44±0.2°、17.76±0.2°、19.88±0.2°和22.54±0.2°。The present invention provides the B crystal form of the compound represented by formula (I). The X-ray powder diffraction pattern of the crystal form has characteristic diffraction peaks at the following 2θ angles: 14.2±0.2°, 12.53±0.2°, 17.44±0.2°, 17.76±0.2°, 19.88±0.2° and 22.54±0.2°.
在一些实施方案中，所述式(I)所示化合物B晶型的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：14.2±0.2°、12.53±0.2°、17.44±0.2°、17.76±0.2°、19.88±0.2°、22.54±0.2°、11.50±0.2°、16.52±0.2°、19.52±0.2°、20.17±0.2°、21.27±0.2°、23.44±0.2°、24.24±0.2°和24.96±0.2°。In some embodiments, the X-ray powder diffraction pattern of the crystal form B of the compound represented by formula (I) has characteristic diffraction peaks at the following 2θ angles: 14.2±0.2°, 12.53±0.2°, 17.44±0.2°, 17.76 ±0.2°, 19.88±0.2°, 22.54±0.2°, 11.50±0.2°, 16.52±0.2°, 19.52±0.2°, 20.17±0.2°, 21.27±0.2°, 23.44±0.2°, 24.24±0.2° and 24.96 ±0.2°.
在一些实施方案中，所述式(I)所示化合物B晶型的X射线粉末衍射图谱基本如图4所示。In some embodiments, the X-ray powder diffraction pattern of the crystal form B of the compound represented by formula (I) is substantially as shown in Figure 4.
在一些实施方案中，所述式(I)所示化合物B晶型的X射线粉末衍射图谱解析数据如表1所示：In some embodiments, the X-ray powder diffraction pattern analysis data of the compound B crystal form represented by the formula (I) is as shown in Table 1:
表1：式(I)所示化合物B晶型的X射线粉末衍射图谱解析数据Table 1: X-ray powder diffraction pattern analysis data of compound B crystal form represented by formula (I)
Figure PCTCN2022096702-appb-000004
Figure PCTCN2022096702-appb-000004
Figure PCTCN2022096702-appb-000005
Figure PCTCN2022096702-appb-000005
Figure PCTCN2022096702-appb-000006
Figure PCTCN2022096702-appb-000006
在一些实施方案中，所述式(I)所示化合物B晶型的差示扫描量热(DSC)曲线在207.09℃处具有吸热峰。In some embodiments, the differential scanning calorimetry (DSC) curve of the crystal form B of the compound represented by formula (I) has an endothermic peak at 207.09°C.
在一些实施方案中，所述式(I)所示化合物B晶型的差示扫描量热(DSC)图谱如图5所示。In some embodiments, the differential scanning calorimetry (DSC) pattern of the crystal form B of the compound represented by formula (I) is shown in Figure 5.
在一些实施方案中，所述式(I)所示化合物B晶型的热重分析(TGA)曲线显示在室温至112.39℃失重0.41％，室温至224.70℃失重0.66％。In some embodiments, the thermogravimetric analysis (TGA) curve of the crystal form B of the compound represented by formula (I) shows a weight loss of 0.41% from room temperature to 112.39°C, and a weight loss of 0.66% from room temperature to 224.70°C.
在一些实施方案中，所述式(I)所示化合物B晶型的热重分析(TGA)图谱如图6所示。In some embodiments, the thermogravimetric analysis (TGA) spectrum of the crystal form B of the compound represented by formula (I) is shown in Figure 6.
本发明提供了式(III)所示化合物(即式(I)所示化合物的甲磺酸盐)、其晶型或水合物；The present invention provides the compound represented by formula (III) (i.e., the mesylate salt of the compound represented by formula (I)), its crystal form or hydrate;
Figure PCTCN2022096702-appb-000007
Figure PCTCN2022096702-appb-000007
本发明提供了式(III)所示化合物的A晶型，其中，所述晶型X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：10.2±0.2°、12.2±0.2°、15.9±0.2°、17.2±0.2°、18.6±0.2°和19.5±0.2°。The present invention provides the A crystal form of the compound represented by formula (III), wherein the X-ray powder diffraction pattern of the crystal form has characteristic diffraction peaks at the following 2θ angles: 10.2±0.2°, 12.2±0.2°, 15.9±0.2 °, 17.2±0.2°, 18.6±0.2° and 19.5±0.2°.
在一些实施方案中，所述式(III)所示化合物的A晶型的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：10.2±0.2°、11.0±0.2°、12.2±0.2°、13.4±0.2°、13.9±0.2°、14.4±0.2°、15.9±0.2°、16.9±0.2°、17.2±0.2°、18.6±0.2°、19.5±0.2°、20.2±0.2°、20.7±0.2°、21.5±0.2°、22.5±0.2°、22.9±0.2°、24.5±0.2°、25.0±0.2°、25.5±0.2°、27.2±0.2°、28.6±0.2°、28.7±0.2°、29.6±0.2°、30.1±0.2°和30.5±0.2°。In some embodiments, the X-ray powder diffraction pattern of the A crystal form of the compound represented by formula (III) has characteristic diffraction peaks at the following 2θ angles: 10.2±0.2°, 11.0±0.2°, 12.2±0.2°, 13.4±0.2°, 13.9±0.2°, 14.4±0.2°, 15.9±0.2°, 16.9±0.2°, 17.2±0.2°, 18.6±0.2°, 19.5±0.2°, 20.2±0.2°, 20.7±0.2°, 21.5±0.2°, 22.5±0.2°, 22.9±0.2°, 24.5±0.2°, 25.0±0.2°, 25.5±0.2°, 27.2±0.2°, 28.6±0.2°, 28.7±0.2°, 29.6±0.2°, 30.1±0.2° and 30.5±0.2°.
在一些实施方案中，所述式(III)所示化合物的A晶型的X射线粉末衍射图谱基本如图7所示。In some embodiments, the X-ray powder diffraction pattern of crystal form A of the compound represented by formula (III) is substantially as shown in Figure 7.
在一些实施方案中，所述式(III)所示化合物的A晶型的X射线粉末衍射图谱解析数据如表2所示：In some embodiments, the X-ray powder diffraction pattern analysis data of the A crystal form of the compound represented by formula (III) is as shown in Table 2:
表2：式(III)所示化合物的A晶型的X射线粉末衍射图谱解析数据Table 2: X-ray powder diffraction pattern analysis data of crystal form A of the compound represented by formula (III)
Figure PCTCN2022096702-appb-000008
Figure PCTCN2022096702-appb-000008
Figure PCTCN2022096702-appb-000009
Figure PCTCN2022096702-appb-000009
在一些实施方案中，所述式(III)所示化合物的A晶型的差示扫描量热(DSC)曲线在50.39℃和204.24℃处具有吸热峰。In some embodiments, the differential scanning calorimetry (DSC) curve of the A crystal form of the compound represented by formula (III) has endothermic peaks at 50.39°C and 204.24°C.
在一些实施方案中，所述式(III)所示化合物的A晶型的差示扫描量热(DSC)图谱如图8所示。In some embodiments, the differential scanning calorimetry (DSC) pattern of Form A of the compound represented by Formula (III) is shown in Figure 8.
在一些实施方案中，所述式(III)所示化合物的A晶型的热重分析(TGA)曲线显示在室温至87℃失重3.5％。In some embodiments, the thermogravimetric analysis (TGA) curve of Form A of the compound represented by formula (III) shows a weight loss of 3.5% from room temperature to 87°C.
在一些实施方案中，所述式(III)所示化合物的A晶型的热重分析(TGA)图谱如图9所示。In some embodiments, the thermogravimetric analysis (TGA) spectrum of Form A of the compound represented by Formula (III) is shown in Figure 9.
本发明提供了式(IV)所示化合物(即式(I)所示化合物的柠檬酸盐)、其晶型或水合物；The present invention provides the compound represented by formula (IV) (i.e., the citrate salt of the compound represented by formula (I)), its crystal form or hydrate;
Figure PCTCN2022096702-appb-000010
Figure PCTCN2022096702-appb-000010
本发明提供了式(IV)所示化合物的A晶型，其中，所述晶型X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：9.5±0.2°、11.5±0.2°、11.8±0.2°、3.5±0.2°、14.1±0.2°、16.3±0.2°、18.0±0.2°20.7±0.2°和25.1±0.2°。The present invention provides the A crystal form of the compound represented by formula (IV), wherein the X-ray powder diffraction pattern of the crystal form has characteristic diffraction peaks at the following 2θ angles: 9.5±0.2°, 11.5±0.2°, 11.8±0.2 °, 3.5±0.2°, 14.1±0.2°, 16.3±0.2°, 18.0±0.2°, 20.7±0.2° and 25.1±0.2°.
在一些实施方案中，所述式(IV)所示化合物的A晶型的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：9.5±0.2°、10.3±0.2°、11.5±0.2°、11.8±0.2°、12.2±0.2°、12.9±0.2°、13.5±0.2°、14.1±0.2°、15.7±0.2°、16.3±0.2°、17.0±0.2°、18.0±0.2°、18.6±0.2°、20.7±0.2°、21.1±0.2°、22.2±0.2°、23.2±0.2°、23.8±0.2°、24.5±0.2°、24.8±0.2°、25.1±0.2°、26.2±0.2°、28.7±0.2°、29.4±0.2°、29.7±0.2°、30.5±0.2°、31.8±0.2°、32.3±0.2°、33.9±0.2°、34.6±0.2°、35.4±0.2°、36.5±0.2°和40.4±0.2°。In some embodiments, the X-ray powder diffraction pattern of the A crystal form of the compound represented by formula (IV) has characteristic diffraction peaks at the following 2θ angles: 9.5±0.2°, 10.3±0.2°, 11.5±0.2°, 11.8±0.2°, 12.2±0.2°, 12.9±0.2°, 13.5±0.2°, 14.1±0.2°, 15.7±0.2°, 16.3±0.2°, 17.0±0.2°, 18.0±0.2°, 18.6±0.2°, 20.7±0.2°, 21.1±0.2°, 22.2±0.2°, 23.2±0.2°, 23.8±0.2°, 24.5±0.2°, 24.8±0.2°, 25.1±0.2°, 26.2±0.2°, 28.7±0.2°, 29.4±0.2°, 29.7±0.2°, 30.5±0.2°, 31.8±0.2°, 32.3±0.2°, 33.9±0.2°, 34.6±0.2°, 35.4±0.2°, 36.5±0.2° and 40.4±0.2°.
在一些实施方案中，所述式(IV)所示化合物的A晶型的X射线粉末衍射图谱基本如图10所示。In some embodiments, the X-ray powder diffraction pattern of crystal form A of the compound represented by formula (IV) is substantially as shown in Figure 10.
在一些实施方案中，所述式(IV)所示化合物的A晶型的X射线粉末衍射图谱解析数据如表3所示：In some embodiments, the X-ray powder diffraction pattern analysis data of the A crystal form of the compound represented by formula (IV) is as shown in Table 3:
表3：式(IV)所示化合物的A晶型的X射线粉末衍射图谱解析数据Table 3: X-ray powder diffraction pattern analysis data of crystal form A of the compound represented by formula (IV)
Figure PCTCN2022096702-appb-000011
Figure PCTCN2022096702-appb-000011
Figure PCTCN2022096702-appb-000012
Figure PCTCN2022096702-appb-000012
在一些实施方案中，所述式(IV)所示化合物的A晶型的差示扫描量热(DSC)曲线在90.14℃、162.81℃和189.67℃处具有吸热峰。In some embodiments, the differential scanning calorimetry (DSC) curve of Form A of the compound represented by formula (IV) has endothermic peaks at 90.14°C, 162.81°C and 189.67°C.
在一些实施方案中，所述式(IV)所示化合物的A晶型的差示扫描量热(DSC)图谱如图11所示。In some embodiments, the differential scanning calorimetry (DSC) pattern of Form A of the compound represented by formula (IV) is as shown in Figure 11.
在一些实施方案中，所述式(IV)所示化合物的A晶型的热重分析(TGA)曲线显示在室温至115℃失重3.64％。In some embodiments, the thermogravimetric analysis (TGA) curve of Form A of the compound represented by Formula (IV) shows a weight loss of 3.64% from room temperature to 115°C.
在一些实施方案中，所述式(IV)所示化合物的A晶型的热重分析(TGA)图谱如图12所示。In some embodiments, the thermogravimetric analysis (TGA) spectrum of Form A of the compound represented by Formula (IV) is shown in Figure 12.
本发明提供了式(V)所示化合物(即式(I)所示化合物的硫酸盐)、其晶型或水合物；The present invention provides the compound represented by formula (V) (i.e., the sulfate of the compound represented by formula (I)), its crystal form or hydrate;
Figure PCTCN2022096702-appb-000013
Figure PCTCN2022096702-appb-000013
本发明提供了式(V)所示化合物的A晶型，其中，所述晶型X射线粉末衍射图谱 在下列2θ角处具有特征衍射峰：10.02±0.2°、16.06±0.2°、16.58±0.2°、21.96±0.2°、24.38±0.2°和24.96±0.2°。The present invention provides the A crystal form of the compound represented by formula (V), wherein the X-ray powder diffraction pattern of the crystal form has characteristic diffraction peaks at the following 2θ angles: 10.02±0.2°, 16.06±0.2°, 16.58±0.2 °, 21.96±0.2°, 24.38±0.2° and 24.96±0.2°.
在一些实施方案中，所述式(V)所示化合物的A晶型的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：9.70±0.2°、10.02±0.2°、10.80±0.2°、11.84±0.2°、13.38±0.2°、14.14±0.2°、15.18±0.2°、14.1±0.2°、16.06±0.2°、16.58±0.2°、17.16±0.2°、18.36±0.2°、19.54±0.2°、21.96±0.2°、22.40±0.2°、23.80±0.2°、24.38±0.2°、24.96±0.2°、27.02±0.2°、27.63±0.2°、28.74±0.2°、30.30±0.2°、32.08±0.2°、33.67±0.2°和34.47±0.2°。In some embodiments, the X-ray powder diffraction pattern of the A crystal form of the compound represented by formula (V) has characteristic diffraction peaks at the following 2θ angles: 9.70±0.2°, 10.02±0.2°, 10.80±0.2°, 11.84±0.2°, 13.38±0.2°, 14.14±0.2°, 15.18±0.2°, 14.1±0.2°, 16.06±0.2°, 16.58±0.2°, 17.16±0.2°, 18.36±0.2°, 19.54±0.2°, 21.96±0.2°, 22.40±0.2°, 23.80±0.2°, 24.38±0.2°, 24.96±0.2°, 27.02±0.2°, 27.63±0.2°, 28.74±0.2°, 30.30±0.2°, 32.08±0.2°, 33.67±0.2° and 34.47±0.2°.
在一些实施方案中，所述式(V)所示化合物的A晶型的X射线粉末衍射图基本如图13所示。In some embodiments, the X-ray powder diffraction pattern of Form A of the compound represented by Formula (V) is substantially as shown in Figure 13.
在一些实施方案中，所述式(V)所示化合物的A晶型的X射线粉末衍射图谱解析数据如表4所示：In some embodiments, the X-ray powder diffraction pattern analysis data of the A crystal form of the compound represented by formula (V) is as shown in Table 4:
表4：式(V)所示化合物的A晶型的X射线粉末衍射图谱解析数据Table 4: X-ray powder diffraction pattern analysis data of crystal form A of the compound represented by formula (V)
Figure PCTCN2022096702-appb-000014
Figure PCTCN2022096702-appb-000014
Figure PCTCN2022096702-appb-000015
Figure PCTCN2022096702-appb-000015
在一些实施方案中，所述式(V)所示化合物的A晶型的差示扫描量热(DSC)曲线在51.72℃和223℃处具有吸热峰。In some embodiments, the differential scanning calorimetry (DSC) curve of the A crystal form of the compound represented by formula (V) has endothermic peaks at 51.72°C and 223°C.
在一些实施方案中，所述式(V)所示化合物的A晶型的差示扫描量热(DSC)图谱如图14所示。In some embodiments, the differential scanning calorimetry (DSC) pattern of Form A of the compound represented by Formula (V) is shown in Figure 14.
在一些实施方案中，所述式(V)所示化合物的A晶型的热重分析(TGA)曲线显示在室温至85℃失重3.37％。In some embodiments, the thermogravimetric analysis (TGA) curve of Form A of the compound represented by Formula (V) shows a weight loss of 3.37% from room temperature to 85°C.
在一些实施方案中，所述式(V)所示化合物的A晶型的热重分析(TGA)图谱如图15所示。In some embodiments, the thermogravimetric analysis (TGA) spectrum of Form A of the compound represented by formula (V) is shown in Figure 15.
本发明提供了式(VI)所示化合物(即式(I)所示化合物的丁二酸盐)、其晶型或水合物；The present invention provides the compound represented by formula (VI) (i.e., the succinate salt of the compound represented by formula (I)), its crystal form or hydrate;
Figure PCTCN2022096702-appb-000016
Figure PCTCN2022096702-appb-000016
本发明提供了式(VI)所示化合物的A晶型，其中，所述晶型X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：317.32±0.2°、18.16±0.2°、20.62±0.2°、20.86±0.2°、22.46±0.2°、24.00±0.2°、24.34±0.2°和25.02±0.2°。The present invention provides the A crystal form of the compound represented by formula (VI), wherein the X-ray powder diffraction pattern of the crystal form has characteristic diffraction peaks at the following 2θ angles: 317.32±0.2°, 18.16±0.2°, 20.62±0.2 °, 20.86±0.2°, 22.46±0.2°, 24.00±0.2°, 24.34±0.2° and 25.02±0.2°.
在一些实施方案中，所述式(VI)所示化合物的A晶型的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：9.10±0.2°、11.06±0.2°、11.46±0.2°、13.46±0.2°、14.34±0.2°、15.50±0.2°、16.63±0.2°、16.96±0.2°、17.32±0.2°、18.16±0.2°、19.08±0.2°、20.62±0.2°、20.86±0.2°、22.46±0.2°、23.36±0.2°、24.00±0.2°、24.34±0.2°、25.02±0.2°、25.92±0.2°、26.28±0.2°、27.84±0.2°、28.10±0.2°、28.88±0.2°、30.45±0.2°。In some embodiments, the X-ray powder diffraction pattern of the A crystal form of the compound represented by formula (VI) has characteristic diffraction peaks at the following 2θ angles: 9.10±0.2°, 11.06±0.2°, 11.46±0.2°, 13.46±0.2°, 14.34±0.2°, 15.50±0.2°, 16.63±0.2°, 16.96±0.2°, 17.32±0.2°, 18.16±0.2°, 19.08±0.2°, 20.62±0.2°, 20.86±0.2°, 22.46±0.2°, 23.36±0.2°, 24.00±0.2°, 24.34±0.2°, 25.02±0.2°, 25.92±0.2°, 26.28±0.2°, 27.84±0.2°, 28.10±0.2°, 28.88±0.2°, 30.45±0.2°.
在一些实施方案中，所述式(VI)所示化合物的A晶型的X射线粉末衍射图谱基本如图16所示。In some embodiments, the X-ray powder diffraction pattern of crystal form A of the compound represented by formula (VI) is substantially as shown in Figure 16.
在一些实施方案中，所述式(VI)所示化合物的A晶型的X射线粉末衍射图谱解析数据如表5所示：In some embodiments, the X-ray powder diffraction pattern analysis data of the A crystal form of the compound represented by formula (VI) is as shown in Table 5:
表5：式(VI)所示化合物的A晶型的X射线粉末衍射图谱解析数据Table 5: X-ray powder diffraction pattern analysis data of crystal form A of the compound represented by formula (VI)
Figure PCTCN2022096702-appb-000017
Figure PCTCN2022096702-appb-000017
Figure PCTCN2022096702-appb-000018
Figure PCTCN2022096702-appb-000018
在一些实施方案中，所述式(VI)所示化合物的A晶型的差示扫描量热(DSC)曲线在164.53℃处具有吸热峰。In some embodiments, the differential scanning calorimetry (DSC) curve of crystal form A of the compound represented by formula (VI) has an endothermic peak at 164.53°C.
在一些实施方案中，所述式(VI)所示化合物的A晶型的差示扫描量热(DSC)图谱如图17所示。In some embodiments, the differential scanning calorimetry (DSC) pattern of Form A of the compound represented by Formula (VI) is shown in Figure 17.
在一些实施方案中，所述式(VI)所示化合物的A晶型的热重分析(TGA)曲线显示在室温至100℃失重1.42％。In some embodiments, the thermogravimetric analysis (TGA) curve of Form A of the compound represented by formula (VI) shows a weight loss of 1.42% from room temperature to 100°C.
在一些实施方案中，所述式(VI)所示化合物的A晶型的热重分析(TGA)图谱如图18所示。In some embodiments, the thermogravimetric analysis (TGA) spectrum of Form A of the compound represented by Formula (VI) is shown in Figure 18.
在一些实施方案中，上述晶型的纯度为95％以上。In some embodiments, the purity of the above-described crystalline forms is greater than 95%.
本发明提供了一种式(II)所示化合物的制备方法，其包括如下步骤：将式(I)所示化合物和酸在溶剂中进行成盐反应，得到如式(II)所示的化合物。其中，式(II)中所述M为柠檬酸、甲磺酸、H 2SO 4、丁二酸、HCl、HNO 3、HBr、HF、HI、磷酸、2,5-二羟基苯甲酸、1-羟基-2-萘甲酸、醋酸、二氯醋酸、三氯醋酸、乙酰氧肟酸、己二酸、苯磺酸、4-氯苯磺酸、苯甲酸、4-乙酰氨基苯甲酸、4-氨基苯甲酸、癸酸、己酸、辛酸、肉桂酸、环己烷氨基磺酸、樟脑磺酸、天门冬氨酸、樟脑酸、葡萄糖酸、葡糖醛酸、谷氨酸、异抗坏血酸、乳酸、苹果酸、扁桃酸、焦谷氨酸、酒石酸、十二烷基硫酸、二苯甲酰酒石酸、乙烷-1,2-二磺酸、乙磺酸、蚁酸、富马酸、半乳糖酸、龙胆酸、戊二酸、2-酮戊二酸、乙 醇酸、马尿酸、羟乙基磺酸、乳糖酸、抗坏血酸、天冬氨酸、月桂酸、樟脑酸、马来酸、丙二酸、1,5-萘二磺酸、萘-2-磺酸、烟酸、油酸、乳清酸、草酸、棕榈酸、双羟萘酸、丙酸、水杨酸、4-氨基水杨酸、癸二酸、硬脂酸、硫氰酸、十一碳烯酸、三氟乙酸、苯磺酸、对甲基苯磺酸和L-苹果酸；优选柠檬酸、甲磺酸、H 2SO 4、丁二酸、HCl、HNO 3、苯磺酸、马来酸、己二酸、对甲基苯磺酸、丙二酸和L-苹果酸、抗坏血酸、水杨酸、2-乙酸基苯甲酸、烟酸、异烟酸、胆酸、天冬氨酸或谷氨酸。 The invention provides a method for preparing a compound represented by formula (II), which includes the following steps: performing a salt-forming reaction on a compound represented by formula (I) and an acid in a solvent to obtain a compound represented by formula (II) . Wherein, M in formula (II) is citric acid, methanesulfonic acid, H 2 SO 4 , succinic acid, HCl, HNO 3 , HBr, HF, HI, phosphoric acid, 2,5-dihydroxybenzoic acid, 1 -Hydroxy-2-naphthoic acid, acetic acid, dichloroacetic acid, trichloroacetic acid, acetohydroxamic acid, adipic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, benzoic acid, 4-acetamidobenzoic acid, 4- Aminobenzoic acid, capric acid, caproic acid, caprylic acid, cinnamic acid, cyclohexane sulfamate, camphorsulfonic acid, aspartic acid, camphoric acid, gluconic acid, glucuronic acid, glutamic acid, erythorbic acid, lactic acid , malic acid, mandelic acid, pyroglutamic acid, tartaric acid, dodecyl sulfate, dibenzoyltartaric acid, ethane-1,2-disulfonic acid, ethanesulfonic acid, formic acid, fumaric acid, galactose Acid, gentisic acid, glutaric acid, 2-oxoglutaric acid, glycolic acid, hippuric acid, isethionic acid, lactobionic acid, ascorbic acid, aspartic acid, lauric acid, camphoric acid, maleic acid, propionic acid Diacid, 1,5-naphthalenedisulfonic acid, naphthalene-2-sulfonic acid, nicotinic acid, oleic acid, orotic acid, oxalic acid, palmitic acid, pamoic acid, propionic acid, salicylic acid, 4-amino acid Cylic acid, sebacic acid, stearic acid, thiocyanic acid, undecenoic acid, trifluoroacetic acid, benzenesulfonic acid, p-toluenesulfonic acid and L-malic acid; preferably citric acid, methanesulfonic acid, H 2 SO 4 , succinic acid, HCl, HNO 3 , benzenesulfonic acid, maleic acid, adipic acid, p-toluenesulfonic acid, malonic acid and L-malic acid, ascorbic acid, salicylic acid, 2-acetic acid benzoic acid, niacin, isonicotinic acid, cholic acid, aspartic acid or glutamic acid.
在一些实施方案中，所述溶剂为卤代烃类、二氧六环、腈类、醇类和水中的一种或多种。优选为DCM、乙腈、二氧六环、水和乙醇中的一种或多种。In some embodiments, the solvent is one or more of halogenated hydrocarbons, dioxane, nitriles, alcohols and water. Preferably it is one or more of DCM, acetonitrile, dioxane, water and ethanol.
本发明提供了一种式(III)所示化合物的制备方法，其包括如下步骤：将式(I)所示化合物和酸在溶剂中进行成盐反应，得到如式(III)所示的化合物。其中，所述的酸为甲磺酸。所述溶剂为二氧六环。The invention provides a method for preparing a compound represented by formula (III), which includes the following steps: performing a salt-forming reaction on a compound represented by formula (I) and an acid in a solvent to obtain a compound represented by formula (III) . Wherein, the acid is methanesulfonic acid. The solvent is dioxane.
本发明提供了一种式(IV)所示化合物的制备方法，其包括如下步骤：将式(I)所示化合物和酸在溶剂中进行成盐反应，得到如式(IV)所示的化合物。其中，所述的酸为柠檬酸。所述溶剂为乙腈和水的混合物溶液。The invention provides a method for preparing a compound represented by formula (IV), which includes the following steps: performing a salt-forming reaction on a compound represented by formula (I) and an acid in a solvent to obtain a compound represented by formula (IV) . Wherein, the acid is citric acid. The solvent is a mixture solution of acetonitrile and water.
本发明提供了一种式(V)所示化合物的制备方法，其包括如下步骤：将式(I)所示化合物和酸在溶剂中进行成盐反应，得到如式(V)所示的化合物。其中，所述的酸为硫酸。所述溶剂为乙醇。The invention provides a method for preparing a compound represented by formula (V), which includes the following steps: performing a salt-forming reaction on a compound represented by formula (I) and an acid in a solvent to obtain a compound represented by formula (V) . Wherein, the acid is sulfuric acid. The solvent is ethanol.
本发明提供了一种式(VI)所示化合物的制备方法，其包括如下步骤：将式(I)所示化合物和酸在溶剂中进行成盐反应，得到如式(VI)所示的化合物。其中，所述的酸为丁二酸。所述溶剂为二氧六环。The invention provides a method for preparing a compound represented by formula (VI), which includes the following steps: performing a salt-forming reaction on a compound represented by formula (I) and an acid in a solvent to obtain a compound represented by formula (VI) . Wherein, the acid is succinic acid. The solvent is dioxane.
本发明提供了一种式(I)所示化合物A晶型的制备方法，其包括如下步骤：将式H所示化合物在DCM和TFA中进行如下反应，后用DCM萃取，干燥DCM相得到式(I)所示化合物A晶型即可。The invention provides a method for preparing the crystal form of compound A represented by formula (I), which includes the following steps: reacting the compound represented by formula H in DCM and TFA as follows, and then extracting it with DCM, and drying the DCM phase to obtain the formula The crystal form of compound A shown in (I) is sufficient.
Figure PCTCN2022096702-appb-000019
Figure PCTCN2022096702-appb-000019
在一些实施方案中，所述的式(I)所示化合物A晶型的制备方法中，式H所示化合物与DCM的质量体积比可以为15-45mg/mL。优选为30mg/mL。In some embodiments, in the method for preparing the crystal form of compound A represented by formula (I), the mass-to-volume ratio of the compound represented by formula H to DCM can be 15-45 mg/mL. Preferably it is 30 mg/mL.
在一些实施方案中，所述的式(I)所示化合物A晶型的制备方法中，式H所示化合物与TFA的质量体积比可以为100-200mg/mL。优选为150mg/mL。In some embodiments, in the method for preparing the crystal form of compound A represented by formula (I), the mass-to-volume ratio of the compound represented by formula H and TFA can be 100-200 mg/mL. Preferably it is 150 mg/mL.
在一些实施方案中，所述的式(I)所示化合物A晶型的制备方法中，所述萃取操作为向反应液中加入DCM和饱和Na 2CO 3水溶液，分离DCM相。 In some embodiments, in the method for preparing the crystal form of compound A represented by formula (I), the extraction operation is to add DCM and saturated Na 2 CO 3 aqueous solution to the reaction solution, and separate the DCM phase.
在一些实施方案中，所述的式(I)所示化合物A晶型的制备方法中，所述干燥条件为30-40℃。优选30-40℃旋干。In some embodiments, in the method for preparing the crystal form of compound A represented by formula (I), the drying condition is 30-40°C. Preferably spin dry at 30-40°C.
在一些实施方案中，所述的式(I)所示化合物A晶型的制备方法中，所述反应在室温下进行。In some embodiments, in the method for preparing the crystal form of compound A represented by formula (I), the reaction is performed at room temperature.
在一些实施方案中，所述的式(I)所示化合物A晶型的制备方法中，所述式(I)所示化合物A晶型制备方法的具体操作为：将式H所示化合物溶于DCM，室温下加入TFA进行反应，浓缩反应液，加入DCM稀释，加入饱和Na 2CO 3水溶液，萃取，取DCM相在30-40℃下旋干。 In some embodiments, in the method for preparing the crystal form of compound A represented by formula (I), the specific operation of the method for preparing the crystal form of compound A represented by formula (I) is: dissolving the compound represented by formula H Add TFA to DCM at room temperature for reaction, concentrate the reaction solution, add DCM to dilute, add saturated Na 2 CO 3 aqueous solution, extract, take the DCM phase and spin it to dryness at 30-40°C.
本发明提供了一种式(I)所示化合物B晶型的制备方法，其包括如下步骤：将式(I)所示化合物A晶型与乙腈混合后析晶，得到式(I)所示化合物B晶型。The invention provides a method for preparing the crystal form of compound B represented by formula (I), which includes the following steps: mixing the crystal form of compound A represented by formula (I) with acetonitrile and then crystallizing to obtain formula (I) Compound B crystal form.
在一些实施方案中，所述的式(I)所示化合物B晶型的制备方法中，式(I)所示化合物A晶型与乙腈的质量体积比可以为10-60mg/mL。优选为30mg/mL。In some embodiments, in the method for preparing the crystal form of compound B represented by formula (I), the mass volume ratio of the crystal form of compound A represented by formula (I) to acetonitrile can be 10-60 mg/mL. Preferably it is 30 mg/mL.
在一些实施方案中，所述的式(I)所示化合物B晶型的制备方法中，混合的操作可以为摇床震荡。优选在25℃的条件下摇床震荡。更优选在25℃，250rpm的条件下摇床震荡。进一步优选在25℃，250rpm的条件下摇床震荡24h。In some embodiments, in the method for preparing the crystal form B of the compound represented by formula (I), the mixing operation may be shaker shaking. It is preferred to shake on a shaker at 25°C. More preferably, it is shaken with a shaker at 25°C and 250 rpm. It is further preferred to shake with a shaker at 25°C and 250 rpm for 24 hours.
在一些实施方案中，所述的式(I)所示化合物B晶型的制备方法中，析晶的操作可以包括以下步骤：将式(I)所示化合物A晶型与乙腈混合后体系中的固体分离出来得到所述的式(I)所示化合物B晶型。优选地，固体分离出来后进一步进行干燥。更优选在50℃条件下干燥。进一步优选在50℃，真空度-0.1M的条件下干燥。进一步优选在50℃，真空度-0.1M的条件下干燥6h。进一步优选在50℃，真空度-0.1M的真空干燥箱中干燥6h。In some embodiments, in the method for preparing the crystal form of compound B represented by formula (I), the crystallization operation may include the following steps: mixing the crystal form of compound A represented by formula (I) with acetonitrile in the system. The solid is separated to obtain the crystal form B of the compound represented by formula (I). Preferably, the solids are further dried after being separated. More preferably, drying is performed at 50°C. It is further preferred to dry at 50° C. and a vacuum degree of -0.1 M. It is further preferred to dry for 6 hours at 50°C and vacuum degree -0.1M. It is further preferred to dry in a vacuum drying oven at 50°C and a vacuum degree of -0.1M for 6 hours.
本发明提供了一种式(III)所示化合物A晶型的制备方法，其包括如下步骤：将式(I)所示化合物A晶型与二氧六环混合后，与甲磺酸甲醇溶液反应析晶，得到式(III)所示化合物A晶型。The invention provides a method for preparing the crystal form of compound A represented by formula (III), which includes the following steps: after mixing the crystal form of compound A represented by formula (I) with dioxane, it is mixed with a methanol solution of methanesulfonic acid. The reaction crystallizes to obtain the crystal form A of the compound represented by formula (III).
在一些实施方案中，所述式(III)所示化合物A晶型的制备方法中，混合的操作可以为搅拌。优选磁力搅拌同时升温至50℃。In some embodiments, in the method for preparing the crystal form of compound A represented by formula (III), the mixing operation may be stirring. It is preferred to stir magnetically while raising the temperature to 50°C.
在一些实施方案中，所述式(III)所示化合物A晶型的制备方法中，式(I)所示化合物A晶型与二氧六环的质量体积比可以为20-90mg/mL。优选50mg/mL。In some embodiments, in the method for preparing the crystal form of compound A represented by formula (III), the mass volume ratio of the crystal form of compound A represented by formula (I) to dioxane can be 20-90 mg/mL. Preferably 50 mg/mL.
在一些实施方案中，所述式(III)所示化合物A晶型的制备方法中，式(I)所示化 合物A晶型与甲磺酸甲醇溶液的质量体积比可以为200-900mg/mL。优选500mg/mL。In some embodiments, in the method for preparing the crystal form of compound A represented by formula (III), the mass volume ratio of the crystal form of compound A represented by formula (I) and the methanol solution of methanesulfonic acid can be 200-900 mg/mL. . Preferably 500 mg/mL.
在一些实施方案中，所述式(III)所示化合物A晶型的制备方法中，甲磺酸甲醇溶液的浓度可以为0.5-2mol/L。优选为1mol/L。In some embodiments, in the method for preparing the crystal form of compound A represented by formula (III), the concentration of the methanol solution of methanesulfonic acid can be 0.5-2 mol/L. Preferably it is 1 mol/L.
在一些实施方案中，所述式(III)所示化合物A晶型的制备方法中，反应析晶的操作可以包括以下步骤：将式(I)所示化合物A晶型、二氧六环混合后和甲磺酸甲醇溶液反应后，降温，将反应后混合物中的固体分离出来。In some embodiments, in the method for preparing the crystal form of compound A represented by formula (III), the reaction crystallization operation may include the following steps: mixing the crystal form of compound A represented by formula (I) and dioxane After reacting with the methanol solution of methanesulfonic acid, the temperature is lowered and the solid in the reaction mixture is separated.
在一些实施方案中，所述式(III)所示化合物A晶型的制备方法中，所述反应可以在温度为50℃下进行。优选地，所述反应可以在温度为50℃下反应3h。In some embodiments, in the method for preparing the crystal form of compound A represented by formula (III), the reaction can be carried out at a temperature of 50°C. Preferably, the reaction can be carried out at a temperature of 50°C for 3 hours.
在一些实施方案中，所述式(III)所示化合物A晶型的制备方法中，所述降温操作可以包括以10℃/h的降温速度降温至室温，随后置于4℃冰箱中24h。In some embodiments, in the method for preparing the crystal form of compound A represented by formula (III), the cooling operation may include cooling to room temperature at a cooling rate of 10°C/h, and then placing the compound in a refrigerator at 4°C for 24 hours.
在一些实施方案中，所述式(III)所示化合物A晶型的制备方法中，固体分离出来后可以进一步进行洗涤。优选二氧六环溶液洗涤。更优选用4℃的二氧六环溶液洗涤。进一步优选，所述式(I)所示化合物A晶型与二氧六环溶液的质量体积比为150mg/mL。In some embodiments, in the preparation method of the crystal form of compound A represented by formula (III), the solid can be further washed after being separated. Washing with dioxane solution is preferred. More preferably, it is washed with a 4°C dioxane solution. Further preferably, the mass-to-volume ratio of the crystal form of compound A represented by formula (I) to the dioxane solution is 150 mg/mL.
在一些实施方案中，所述式(III)所示化合物A晶型的制备方法中，固体分离出来后可以进一步进行干燥。优选在50℃条件下干燥。进一步优选在50℃，真空度-0.1M的条件下干燥。进一步优选在50℃，真空度-0.1M的条件下干燥24h。进一步优选在50℃，真空度-0.1M的真空干燥箱中干燥24h。In some embodiments, in the preparation method of the crystal form of compound A represented by formula (III), the solid can be further dried after being separated. Drying at 50°C is preferred. It is further preferred to dry at 50° C. and a vacuum degree of -0.1 M. It is further preferred to dry at 50°C and vacuum degree -0.1M for 24 hours. It is further preferred to dry in a vacuum drying oven at 50°C and a vacuum degree of -0.1M for 24 hours.
本发明提供了一种式(IV)所示化合物A晶型的制备方法，其包括如下步骤：将式(I)所示化合物A晶型与乙腈、纯化水混合后，与柠檬酸甲醇溶液反应析晶，得到式(IV)所示化合物A晶型。The invention provides a method for preparing the crystal form of compound A represented by formula (IV), which includes the following steps: after mixing the crystal form of compound A represented by formula (I) with acetonitrile and purified water, react with a citric acid methanol solution After crystallization, the crystal form A of the compound represented by formula (IV) is obtained.
在一些实施方案中，所述式(IV)所示化合物A晶型的制备方法中，混合的操作可以为搅拌。优选搅拌同时升温至50℃。更优选搅拌(200-300rpm)同时升温至50℃。In some embodiments, in the method for preparing the crystal form of compound A represented by formula (IV), the mixing operation may be stirring. It is preferred to stir while raising the temperature to 50°C. More preferably, stirring (200-300 rpm) is performed while raising the temperature to 50°C.
在一些实施方案中，所述式(IV)所示化合物A晶型的制备方法中，式(I)所示化合物A晶型与乙腈的质量体积比可以为5-25mg/mL。优选11.1mg/mL。In some embodiments, in the method for preparing the crystal form of compound A represented by formula (IV), the mass-to-volume ratio of the crystal form of compound A represented by formula (I) to acetonitrile can be 5-25 mg/mL. Preferably 11.1 mg/mL.
在一些实施方案中，所述式(IV)所示化合物A晶型的制备方法中，式(I)所示化合物A晶型与纯化水的质量体积比可以为30-170mg/mL。优选100mg/mL。In some embodiments, in the method for preparing the crystal form of compound A represented by formula (IV), the mass volume ratio of the crystal form of compound A represented by formula (I) and purified water can be 30-170 mg/mL. Preferably 100 mg/mL.
在一些实施方案中，所述式(IV)所示化合物A晶型的制备方法中，式(I)所示化合物A晶型与柠檬酸甲醇溶液的质量体积比可以为200-900mg/mL。优选500mg/mL。In some embodiments, in the method for preparing the crystal form of compound A represented by formula (IV), the mass volume ratio of the crystal form of compound A represented by formula (I) and the citric acid methanol solution may be 200-900 mg/mL. Preferably 500 mg/mL.
在一些实施方案中，所述式(IV)所示化合物A晶型的制备方法中，柠檬酸甲醇溶液的浓度可以为0.5-2mol/L。优选为1mol/L。In some embodiments, in the method for preparing the crystal form of compound A represented by formula (IV), the concentration of the citric acid methanol solution may be 0.5-2 mol/L. Preferably it is 1 mol/L.
在一些实施方案中，所述式(IV)所示化合物A晶型的制备方法中，反应析晶的操 作可以包括以下步骤：将式(I)所示化合物A晶型与乙腈、纯化水混合后和柠檬酸甲醇溶液反应后，降温，将反应后混合物中的固体分离出来。In some embodiments, in the method for preparing the crystal form of compound A represented by formula (IV), the reaction crystallization operation may include the following steps: mixing the crystal form of compound A represented by formula (I) with acetonitrile and purified water. After reacting with the methanol solution of citric acid, the temperature is lowered and the solid in the reaction mixture is separated.
在一些实施方案中，所述式(IV)所示化合物A晶型的制备方法中，所述反应可以在温度为50℃下进行。优选地，所述反应可以在温度为50℃下搅拌进行。更优选地，所述反应可以在温度为50℃下搅拌(转速200-300rpm)反应2h。In some embodiments, in the method for preparing the crystal form of compound A represented by formula (IV), the reaction can be carried out at a temperature of 50°C. Preferably, the reaction can be carried out with stirring at a temperature of 50°C. More preferably, the reaction can be carried out with stirring at a temperature of 50°C (rotation speed 200-300 rpm) for 2 hours.
在一些实施方案中，所述式(IV)所示化合物A晶型的制备方法中，所述降温操作可以包括以15℃/h的降温速度降温至5℃。优选以15℃/h的降温速度降温至5℃，然后养晶0.5h。In some embodiments, in the method for preparing the crystal form of compound A represented by Formula (IV), the temperature reduction operation may include cooling to 5°C at a temperature reduction rate of 15°C/h. It is preferred to cool down to 5°C at a cooling rate of 15°C/h, and then grow the crystal for 0.5h.
在一些实施方案中，所述式(IV)所示化合物A晶型的制备方法中，固体分离出来后可以进一步进行洗涤。优选乙腈溶液洗涤。更优选用4℃的乙腈溶液洗涤。进一步优选地，所述式(I)所示化合物A晶型与乙腈溶液的质量体积比为150mg/mL。In some embodiments, in the preparation method of the crystal form of compound A represented by formula (IV), the solid can be further washed after being separated. Washing with acetonitrile solution is preferred. More preferably, it is washed with an acetonitrile solution at 4°C. Further preferably, the mass-to-volume ratio of the crystal form of compound A represented by formula (I) to the acetonitrile solution is 150 mg/mL.
在一些实施方案中，所述式(IV)所示化合物A晶型的制备方法中，固体分离出来后可以进一步进行干燥。优选在50℃条件下干燥。进一步优选在50℃，真空度-0.1M的条件下干燥。进一步优选在50℃，真空度-0.1M的条件下干燥24h。进一步优选在50℃，真空度-0.1M的真空干燥箱中干燥24h。In some embodiments, in the preparation method of the crystal form of compound A represented by formula (IV), the solid can be further dried after being separated. Drying at 50°C is preferred. It is further preferred to dry at 50° C. and a vacuum degree of -0.1 M. It is further preferred to dry at 50°C and vacuum degree -0.1M for 24 hours. It is further preferred to dry in a vacuum drying oven at 50°C and a vacuum degree of -0.1M for 24 hours.
本发明提供了一种式(V)所示化合物A晶型的制备方法，其包括如下步骤：将式(I)所示化合物A晶型与乙醇混合后，与硫酸甲醇溶液反应析晶，得到式(V)所示化合物A晶型。The invention provides a method for preparing the crystal form of compound A represented by formula (V), which includes the following steps: after mixing the crystal form of compound A represented by formula (I) with ethanol, it reacts with sulfuric acid methanol solution for crystallization to obtain Crystal form of compound A represented by formula (V).
在一些实施方案中，所述式(V)所示化合物A晶型的制备方法中，混合后升温至50℃。In some embodiments, in the preparation method of the crystal form of compound A represented by formula (V), the temperature is raised to 50°C after mixing.
在一些实施方案中，所述式(V)所示化合物A晶型的制备方法中，式(I)所示化合物A晶型与乙醇的质量体积比可以为2-10mg/mL。优选5mg/mL。In some embodiments, in the method for preparing the crystal form of compound A represented by formula (V), the mass-to-volume ratio of the crystal form of compound A represented by formula (I) and ethanol may be 2-10 mg/mL. Preferably 5 mg/mL.
在一些实施方案中，所述式(V)所示化合物A晶型的制备方法中，式(I)所示化合物A晶型与硫酸甲醇溶液的质量体积比可以为200-900mg/mL。优选500mg/mL。In some embodiments, in the method for preparing the crystal form of compound A represented by formula (V), the mass volume ratio of the crystal form of compound A represented by formula (I) and the sulfuric acid methanol solution can be 200-900 mg/mL. Preferably 500 mg/mL.
在一些实施方案中，所述式(V)所示化合物A晶型的制备方法中，硫酸甲醇溶液的浓度可以为0.5-2mol/L。优选为1mol/L。In some embodiments, in the method for preparing the crystal form of compound A represented by formula (V), the concentration of the sulfuric acid methanol solution may be 0.5-2 mol/L. Preferably it is 1 mol/L.
在一些实施方案中，所述式(V)所示化合物A晶型的制备方法中，反应析晶的操作可以包括以下步骤：将式(I)所示化合物A晶型与乙醇混合后和硫酸甲醇溶液反应后，降温，浓缩，将反应后混合物中的固体分离出来。In some embodiments, in the method for preparing the crystal form of compound A represented by formula (V), the reaction crystallization operation may include the following steps: mixing the crystal form of compound A represented by formula (I) with ethanol and then adding sulfuric acid After the reaction of the methanol solution, the temperature is lowered, concentrated, and the solid in the reaction mixture is separated.
在一些实施方案中，所述式(V)所示化合物A晶型的制备方法中，所述反应可以在温度为50℃下进行。优选地，所述反应可以在温度为50℃下搅拌进行。更优选地，所 述反应可以在温度为50℃下搅拌(转速200-300rpm)反应3h。In some embodiments, in the method for preparing the crystal form of compound A represented by formula (V), the reaction can be carried out at a temperature of 50°C. Preferably, the reaction can be carried out with stirring at a temperature of 50°C. More preferably, the reaction can be carried out with stirring at a temperature of 50°C (rotation speed 200-300 rpm) for 3 hours.
在一些实施方案中，所述式(V)所示化合物A晶型的制备方法中，所述降温操作可以包括以12.5℃/h的降温速度降温至25℃，加入乙腈，以10℃/h的降温速度降温至5℃。优选地，式(I)所示化合物A晶型与乙腈的质量体积比可以为10mg/mL。In some embodiments, in the method for preparing the crystal form of Compound A represented by Formula (V), the cooling operation may include cooling to 25°C at a cooling rate of 12.5°C/h, adding acetonitrile, and adding acetonitrile at a rate of 10°C/h. The cooling speed is reduced to 5℃. Preferably, the mass-to-volume ratio of the crystal form of compound A represented by formula (I) to acetonitrile can be 10 mg/mL.
在一些实施方案中，所述式(V)所示化合物A晶型的制备方法中，所述浓缩操作可以包括将降温后的反应液置于60℃的条件下浓缩；优选置于旋蒸瓶中(60℃，100rpm)浓缩。In some embodiments, in the method for preparing the crystal form of Compound A represented by Formula (V), the concentration operation may include concentrating the cooled reaction solution at 60°C; preferably, placing it in a rotary evaporator. (60°C, 100rpm).
在一些实施方案中，所述式(V)所示化合物A晶型的制备方法中，所述固体分离操作可以包括将浓缩后的反应液置于空气环境中挥干，然后将挥干后的固体进一步进行干燥。所述干燥优选在50℃条件下干燥。进一步优选在50℃，真空度-0.1M的条件下干燥。进一步优选在50℃，真空度-0.1M的条件下干燥24h。进一步优选在50℃，真空度-0.1M的真空干燥箱中干燥24h。In some embodiments, in the preparation method of the crystal form of compound A represented by formula (V), the solid separation operation may include placing the concentrated reaction liquid in an air environment to evaporate to dryness, and then evaporating the evaporated reaction solution to dryness. The solid was further dried. The drying is preferably performed at 50°C. It is further preferred to dry at 50° C. and a vacuum degree of -0.1 M. It is further preferred to dry at 50°C and vacuum degree -0.1M for 24 hours. It is further preferred to dry in a vacuum drying oven at 50°C and a vacuum degree of -0.1M for 24 hours.
本发明提供了一种式(VI)所示化合物A晶型的制备方法，其包括如下步骤：将式(I)所示化合物A晶型与二氧六环混合后，与丁二酸甲醇溶液反应析晶，得到式(VI)所示化合物A晶型。The invention provides a method for preparing the crystal form of compound A represented by formula (VI), which includes the following steps: after mixing the crystal form of compound A represented by formula (I) with dioxane, it is mixed with succinic acid methanol solution The reaction crystallizes to obtain the crystal form A of the compound represented by formula (VI).
在一些实施方案中，所述式(VI)所示化合物A晶型的制备方法中，混合的操作可以为搅拌。优选磁力搅拌同时升温至50℃。In some embodiments, in the method for preparing the crystal form of compound A represented by formula (VI), the mixing operation may be stirring. It is preferred to stir magnetically while raising the temperature to 50°C.
在一些实施方案中，所述式(VI)所示化合物A晶型的制备方法中，式(I)所示化合物A晶型与二氧六环的质量体积比可以为15-70mg/mL。优选37.5mg/mL。In some embodiments, in the method for preparing the crystal form of compound A represented by formula (VI), the mass volume ratio of the crystal form of compound A represented by formula (I) to dioxane can be 15-70 mg/mL. Preferably 37.5 mg/mL.
在一些实施方案中，所述式(VI)所示化合物A晶型的制备方法中，式(I)所示化合物A晶型与丁二酸甲醇溶液的质量体积比可以为200-900mg/mL。优选500mg/mL。In some embodiments, in the preparation method of the crystal form of compound A represented by formula (VI), the mass-to-volume ratio of the crystal form of compound A represented by formula (I) and the succinic acid methanol solution can be 200-900 mg/mL. . Preferably 500 mg/mL.
在一些实施方案中，所述式(VI)所示化合物A晶型的制备方法中，丁二酸甲醇溶液的浓度可以为0.5-2mol/L。优选为1mol/L。In some embodiments, in the method for preparing the crystal form of compound A represented by formula (VI), the concentration of the methanol succinic acid solution may be 0.5-2 mol/L. Preferably it is 1 mol/L.
在一些实施方案中，所述式(VI)所示化合物A晶型的制备方法中，反应析晶的操作可以包括以下步骤：将式(I)所示化合物A晶型与二氧六环混合后和丁二酸甲醇溶液反应后，降温，将反应后混合物中的固体分离出来。In some embodiments, in the method for preparing the crystal form of compound A represented by formula (VI), the reaction crystallization operation may include the following steps: mixing the crystal form of compound A represented by formula (I) with dioxane After reacting with the methanol solution of succinic acid, the temperature is lowered and the solid in the reaction mixture is separated.
在一些实施方案中，所述式(VI)所示化合物A晶型的制备方法中，所述反应可以在温度为50℃下进行。优选地，所述反应可以在温度为50℃下反应3h。In some embodiments, in the method for preparing the crystal form of compound A represented by formula (VI), the reaction can be carried out at a temperature of 50°C. Preferably, the reaction can be carried out at a temperature of 50°C for 3 hours.
在一些实施方案中，所述式(VI)所示化合物A晶型的制备方法中，所述降温操作可以包括以10℃/h的降温速度降温至室温，随后置于4℃冰箱中5h。In some embodiments, in the method for preparing the crystal form of Compound A represented by Formula (VI), the cooling operation may include cooling to room temperature at a cooling rate of 10°C/h, and then placing the compound in a refrigerator at 4°C for 5 hours.
在一些实施方案中，所述式(VI)所示化合物A晶型的制备方法中，固体分离出来 后可以进一步进行洗涤。优选二氧六环溶液洗涤。更优选用4℃的二氧六环溶液洗涤。进一步优选地，所述式(I)所示化合物A晶型与二氧六环溶液的质量体积比为150mg/mL。In some embodiments, in the preparation method of the crystal form of compound A represented by formula (VI), the solid can be further washed after being separated. Washing with dioxane solution is preferred. More preferably, it is washed with a 4°C dioxane solution. Further preferably, the mass-to-volume ratio of the crystal form of compound A represented by formula (I) to the dioxane solution is 150 mg/mL.
在一些实施方案中，所述式(VI)所示化合物A晶型的制备方法中，固体分离出来后可以进一步进行干燥。优选在50℃条件下干燥。进一步优选在50℃，真空度-0.1M的条件下干燥。进一步优选在50℃，真空度-0.1M的条件下干燥24h。进一步优选在50℃，真空度-0.1M的真空干燥箱中干燥24h。In some embodiments, in the preparation method of the crystal form of compound A represented by formula (VI), the solid can be further dried after being separated. Drying at 50°C is preferred. It is further preferred to dry at 50° C. and a vacuum degree of -0.1 M. It is further preferred to dry at 50°C and vacuum degree -0.1M for 24 hours. It is further preferred to dry in a vacuum drying oven at 50°C and a vacuum degree of -0.1M for 24 hours.
本发明进一步提供了一种药物组合物，其含有治疗有效量的本发明所述任一项化合物或晶型，和药学上可接受的辅料。The present invention further provides a pharmaceutical composition, which contains a therapeutically effective amount of any compound or crystal form described in the present invention, and pharmaceutically acceptable excipients.
在一些实施方案中，所述药物组合物用于口服给药。In some embodiments, the pharmaceutical compositions are for oral administration.
在一些实施方案中，所述药物组合物用于制作片剂或胶囊。In some embodiments, the pharmaceutical compositions are used to formulate tablets or capsules.
在一些实施方案中，所述药物组合物含有0.2-10重量％的本发明所述任一项化合物晶型。In some embodiments, the pharmaceutical composition contains 0.2-10% by weight of any of the crystalline forms of the compounds described herein.
本发明进一步提供了所述任一项化合物或晶型或药物组合物的在制备药物中的应用。The present invention further provides the use of any of the compounds, crystal forms or pharmaceutical compositions in the preparation of medicines.
在一些实施方案中，所述药物为治疗、预防、延迟或阻碍与SHP2蛋白活性或表达相关的疾病的发生或进展的药物。In some embodiments, the drug is a drug that treats, prevents, delays, or hinders the onset or progression of a disease associated with SHP2 protein activity or expression.
在一些实施方案中，所述药物为治疗与SHP2蛋白活性或表达相关的疾病的药物。In some embodiments, the drug is a drug that treats a disease associated with SHP2 protein activity or expression.
在一些实施方案中，所述疾病为肿瘤。In some embodiments, the disease is neoplasm.
在一些实施方案中，所述肿瘤为由Ras-Raf-ERK或PD1/L1信号通路异常导致的肿瘤。In some embodiments, the tumor is a tumor caused by an abnormality in the Ras-Raf-ERK or PD1/L1 signaling pathways.
在一些实施方案中，所述肿瘤为食管癌、肺癌、结直肠癌、胰腺癌、白血病或胃癌。In some embodiments, the tumor is esophageal cancer, lung cancer, colorectal cancer, pancreatic cancer, leukemia, or gastric cancer.
本发明中，“具有约如图所示的X射线粉末衍射图”或“其粉末衍射图基本上如图所示”中使用的“约”和“基本上”是表示附图中的峰的精确位置不应当被解释为绝对值。因为本领域技术人员可知，X射线粉末衍射图的2θ值可能会优于不同的测量条件(如所用的设备和仪器)和不同的样品而产生误差，X射线粉末衍射图的衍射角的测量误差为5％或更小，通常，给定的值±0.2°的差别被认为是恰当的。还应理解，峰值的相对强度可能随实验条件和样品制备诸如颗粒在样品中的优选的取向而波动。自动或固定的发散狭缝的使用也会影响相对强度的计算。在这里所包括的PXRD曲线所示强度只是示例性的，不能被用作绝对比较。In the present invention, "about" and "substantially" used in "having an X-ray powder diffraction pattern approximately as shown in the figure" or "having a powder diffraction pattern substantially as shown in the figure" refer to the peaks in the drawing. Precise positions should not be interpreted as absolute values. Because those skilled in the art know that the 2θ value of the X-ray powder diffraction pattern may be different due to different measurement conditions (such as the equipment and instruments used) and different samples, the measurement error of the diffraction angle of the X-ray powder diffraction pattern A difference of 5% or less, usually, a given value of ±0.2° is considered appropriate. It should also be understood that the relative intensity of the peaks may fluctuate with experimental conditions and sample preparation such as the preferred orientation of the particles in the sample. The use of automatic or fixed divergence slits also affects the calculation of relative intensity. The intensities shown in the PXRD curves included here are exemplary only and should not be used as an absolute comparison.
本领域的技术人员应当理解，优于样品纯度、样品制备以及测量条件(如加热速率)的变化，由DSC测量的数据可能会发生小的变化。通过其他种类仪器或使用不同于文中描述的条件，可能会给出可替换的熔点的读数。因此，本申请所使用的吸热图不能作为 绝对值，且当解释DSC数据时应考虑这样的测量误差。Those skilled in the art will appreciate that small changes in data measured by DSC may occur over changes in sample purity, sample preparation, and measurement conditions (such as heating rate). Alternative melting point readings may be given by other types of instruments or using conditions different from those described in the text. Therefore, the endotherms used in this application cannot be taken as absolute values, and such measurement errors should be taken into account when interpreting DSC data.
本发明中未指明热重分析(TGA)测试起始温度的，其起始温度为室温，室温一般为20-35℃。If the thermogravimetric analysis (TGA) test starting temperature is not specified in the present invention, the starting temperature is room temperature, and room temperature is generally 20-35°C.
本文所用术语“治疗有效量”是指一个化合物施用于治疗对象时对于治疗一种疾病、或一种疾病或病症的至少一种临床症状时，足以影响对疾病、病症或症状的这种治疗的量。“治疗有效量”可以随着化合物，疾病、病症和/或疾病或病症的症状，疾病、病症和/或疾病或病症的症状的严重程度，被治疗的患者的年龄，和/或被治疗的患者的体重等变化。在任意特定的情况下，一个合适的量对那些本领域的技术人员可以是显而易见的，也可以是用常规实验确定的。在联合治疗的情况下，“治疗有效量”是指有效治疗疾病、病症或病状的联用对象的总量。As used herein, the term "therapeutically effective amount" means an amount of a compound that is sufficient to affect the treatment of a disease, or at least one clinical symptom of a disease or condition, when administered to a subject. quantity. A "therapeutically effective amount" may vary with the compound, the disease, condition, and/or symptoms of the disease or condition, the severity of the disease, condition, and/or symptoms of the disease or condition, the age of the patient being treated, and/or the condition being treated. changes in the patient's weight. A suitable amount in any particular case may be apparent to those skilled in the art or may be determined by routine experimentation. In the context of a combination therapy, a "therapeutically effective amount" refers to the total amount of the combination effective to treat the disease, disorder, or condition.
本发明所述的盐型或晶型可以合并用药作为活性组分，与药物载体混合成药物组合物。所述药物载体可以采取各种各样的形式，取决于想采用的给药方式，例如，口服或注射(包括静脉注射)。因此，本发明的药物组合物可以采用适于口服给药的独立形式。如包含预先确定活性组分剂量的胶囊剂，扁囊剂或片剂。进一步地，本发明的药物组合物可采用粉末、颗粒、溶液、水性悬浮液、非水液体、水包油型乳液或油包水型乳液形式。另外，除上述提到的常见的剂型，本发明所述的盐型或晶型也可以通过控释的方式和/或输送装置给药。本发明的药物组合物可以采用任何制药学上的方法制备。一般情况下，这种方法包括使活性组分和构成一个或多个必要组分的载体缔合的步骤。一般情况下，所述药物组合物经由活性组分与液体载体或精细分割的固体载体或两者的混合物经过均匀的密切混合制得。另外，该产品可以方便地制备成所需要的外观。The salt form or crystal form of the present invention can be used in combination as an active component and mixed with a pharmaceutical carrier to form a pharmaceutical composition. The pharmaceutical carrier can take a variety of forms, depending on the intended mode of administration, for example, oral or injection (including intravenous injection). Accordingly, the pharmaceutical compositions of the present invention may be in stand-alone forms suitable for oral administration. Such as capsules, cachets or tablets containing a predetermined dose of the active ingredient. Further, the pharmaceutical composition of the present invention can be in the form of powder, granule, solution, aqueous suspension, non-aqueous liquid, oil-in-water emulsion or water-in-oil emulsion. In addition, in addition to the common dosage forms mentioned above, the salt form or crystal form of the present invention can also be administered through a controlled release method and/or a delivery device. The pharmaceutical composition of the present invention can be prepared by any pharmaceutical method. Generally, such methods include the step of bringing into association the active ingredient with the carrier which constitutes one or more essential ingredients. In general, the pharmaceutical compositions are prepared by uniformly intimate mixing of the active ingredient with a liquid carrier or a finely divided solid carrier or a mixture of both. In addition, the product can be easily prepared to the desired appearance.
本文所用术语“药学上可接受的载体”是指适合于期望药物制剂的常规的药用载体，例如：诸如水、各种有机溶剂等的稀释剂、赋形剂；诸如淀粉、预胶化淀粉、蔗糖、糊精、甘露醇、乳糖、喷雾干燥乳糖、微晶纤维素、硅化微晶纤维素、无机盐类等的填充剂；诸如淀粉浆、糊精、糖粉、糖浆、胶浆、聚乙二醇、纤维素衍生物、藻酸盐、明胶、羟丙纤维素、共聚维酮和聚乙烯吡咯烷酮(PVP)等的粘合剂；诸如蒸馏水、乙醇和甘油等的湿润剂；诸如干淀粉、低取代羟丙纤维素、羟丙基淀粉、琼脂、碳酸钙、碳酸氢钠、交联聚维酮、交联羧甲基纤维素钠、羧甲基淀粉钠等的崩解剂；诸如季铵化合物、氨基酸乙胺衍生物、乙酰醋酸酯类、β-二羧酸酯、芳香族酸性化合物、脂肪族酸性化合物等的吸收促进剂；诸如十六烷基硫酸钠、十八烷基硫酸钠、二辛基琥珀酸磺酸钠、十二烷基磺酸钠、苯扎溴铵、苯扎氯铵、杜灭芬、卵磷脂、十六烷醇、十二烷基硫酸钠、吐温和司盘等的表面活性剂；诸如聚乙二醇、卡波姆、纤维素衍生物、甘油明胶、聚乙烯醇、可可豆酯、合成或 全合成脂肪酸甘油酯、聚乙烯醇40硬脂酸酯、凡士林、固体石蜡、液体石蜡、二甲基硅油、羊毛脂、蜂蜡和豚酯等的载药基质；诸如高岭土和膨润土等的吸收载体；诸如滑石粉、微粉硅胶、二氧化硅、氢化植物油、十二烷基硫酸镁、十二烷基硫酸钠、硬脂酸、硬脂酸钙、硬脂酸镁、硬脂富马酸钠和聚乙二醇等的润滑剂。另外还可以在药物组合物中加入其它药学上可接受的辅料，如抗氧剂、着色剂、防腐剂、pH调节剂、硬化剂、乳化剂、抛射剂、分散剂、稳定剂、增稠剂、络合剂、缓冲剂、渗透促进剂、聚合物、芳香剂、甜味剂和染料。优选使用适合期望剂型和期望给药方式的辅料。The term "pharmaceutically acceptable carrier" used herein refers to conventional pharmaceutical carriers suitable for the desired pharmaceutical preparation, for example: diluents, excipients such as water, various organic solvents, etc.; such as starch, pregelatinized starch , sucrose, dextrin, mannitol, lactose, spray-dried lactose, microcrystalline cellulose, silicified microcrystalline cellulose, inorganic salts, etc. fillers; such as starch slurry, dextrin, sugar powder, syrup, glue, poly Binders such as ethylene glycol, cellulose derivatives, alginates, gelatin, hydroxypropylcellulose, copovidone and polyvinylpyrrolidone (PVP); humectants such as distilled water, ethanol and glycerol; such as dry starch , disintegrants such as low-substituted hydroxypropyl cellulose, hydroxypropyl starch, agar, calcium carbonate, sodium bicarbonate, crospovidone, croscarmellose sodium, sodium carboxymethyl starch, etc.; such as quaternary Absorption accelerators for ammonium compounds, amino acid ethylamine derivatives, acetoacetate esters, β-dicarboxylic acid esters, aromatic acidic compounds, aliphatic acidic compounds, etc.; such as sodium cetyl sulfate, sodium octadecyl sulfate , Sodium dioctyl succinate sulfonate, Sodium lauryl sulfonate, Benzalkonium bromide, Benzalkonium chloride, Difenfen, Lecithin, Cetyl alcohol, Sodium lauryl sulfate, Tween and Si Surfactants such as polyethylene glycol, carbomer, cellulose derivatives, glycerol gelatin, polyvinyl alcohol, cocoa bean esters, synthetic or fully synthetic fatty acid glycerides, polyvinyl alcohol 40 stearate, Drug-carrying matrices such as petroleum jelly, solid paraffin, liquid paraffin, dimethicone, lanolin, beeswax and porphyrin; absorption carriers such as kaolin and bentonite; such as talc, micronized silica gel, silicon dioxide, hydrogenated vegetable oil, ten Lubricants such as magnesium dialkyl sulfate, sodium lauryl sulfate, stearic acid, calcium stearate, magnesium stearate, sodium stearyl fumarate and polyethylene glycol. In addition, other pharmaceutically acceptable excipients can be added to the pharmaceutical composition, such as antioxidants, colorants, preservatives, pH adjusters, hardeners, emulsifiers, propellants, dispersants, stabilizers, and thickeners. , complexing agents, buffers, penetration enhancers, polymers, aromatics, sweeteners and dyes. Preference is given to the use of excipients suitable for the desired dosage form and intended mode of administration.
在符合本领域常识的基础上，上述各优选条件，可任意组合，即得本发明各较佳实例。On the basis of common sense in the field, the above preferred conditions can be combined arbitrarily to obtain preferred examples of the present invention.
本发明所用试剂和原料均市售可得。The reagents and raw materials used in the present invention are all commercially available.
本发明的积极进步效果在于：本申请中保护的式(I)所示化合物A、B晶型、式(III)所示化合物A晶型、式(IV)所示化合物A晶型、式(V)所示化合物A晶型和式(VI)所示化合物A晶型具有以下一个或多个优点：(1)性质稳定；(2)引湿性好；(3)生物利用度好(4)具有良好的成药前景。The positive progressive effect of the present invention lies in: the crystal forms A and B of the compound represented by formula (I), the crystal form of compound A represented by formula (III), the crystal form of compound A represented by formula (IV), the crystal form of compound represented by formula (IV) protected in this application The crystal form of compound A shown in V) and the crystal form of compound A shown in formula (VI) have one or more of the following advantages: (1) stable properties; (2) good moisture absorption; (3) good bioavailability (4) It has good prospects as a patent medicine.
附图说明Description of the drawings
图1：式(I)所示化合物A晶型的PXRD图谱--X射线粉末衍射图谱。Figure 1: PXRD pattern - X-ray powder diffraction pattern of the crystal form of compound A represented by formula (I).
图2：式(I)所示化合物A晶型DSC图谱--差式扫描量热图谱。Figure 2: DSC spectrum of crystal form A of compound represented by formula (I) - differential scanning calorimetry spectrum.
图3：式(I)所示化合物A晶型TGA图谱--热重分析图谱。Figure 3: TGA spectrum of crystal form A of compound represented by formula (I) - thermogravimetric analysis spectrum.
图4：式(I)所示化合物B晶型PXRD图谱。Figure 4: PXRD pattern of crystal form B of compound represented by formula (I).
图5：式(I)所示化合物B晶型DSC图谱。Figure 5: DSC spectrum of crystal form B of compound represented by formula (I).
图6：式(I)所示化合物B晶型TGA图谱。Figure 6: TGA spectrum of crystal form B of compound represented by formula (I).
图7：式(III)所示化合物A晶型PXRD图谱。Figure 7: PXRD pattern of crystal form A of compound represented by formula (III).
图8：式(III)所示化合物A晶型DSC图谱。Figure 8: DSC spectrum of crystal form A of compound represented by formula (III).
图9：式(III)所示化合物A晶型TGA图谱。Figure 9: TGA spectrum of crystal form A of compound represented by formula (III).
图10：式(IV)所示化合物A晶型PXRD图谱。Figure 10: PXRD pattern of crystal form A of compound represented by formula (IV).
图11：式(IV)所示化合物A晶型DSC图谱。Figure 11: DSC spectrum of crystal form A of compound represented by formula (IV).
图12：式(IV)所示化合物A晶型TGA图谱。Figure 12: TGA spectrum of crystal form A of compound represented by formula (IV).
图13：式(V)所示化合物A晶型PXRD图谱。Figure 13: PXRD pattern of crystal form A of compound represented by formula (V).
图14：式(V)所示化合物A晶型DSC图谱。Figure 14: DSC spectrum of crystal form A of compound represented by formula (V).
图15：式(V)所示化合物A晶型TGA图谱。Figure 15: TGA spectrum of crystal form A of compound represented by formula (V).
图16：式(VI)所示化合物A晶型PXRD图谱。Figure 16: PXRD pattern of crystal form A of compound represented by formula (VI).
图17：式(VI)所示化合物A晶型DSC图谱。Figure 17: DSC spectrum of crystal form A of compound represented by formula (VI).
图18：式(VI)所示化合物A晶型TGA图谱。Figure 18: TGA spectrum of crystal form A of compound represented by formula (VI).
图19：式(I)所示化合物B晶型的H 1NMR图谱。 Figure 19: H 1 NMR spectrum of compound B crystal form represented by formula (I).
图20：式(III)所示化合物A晶型的H 1NMR图谱。 Figure 20: H 1 NMR spectrum of the crystal form of compound A represented by formula (III).
图21：式(IV)所示化合物A晶型的H 1NMR图谱。 Figure 21: H 1 NMR spectrum of the crystal form of compound A represented by formula (IV).
图22：式(V)所示化合物A晶型的H 1NMR图谱。 Figure 22: H 1 NMR spectrum of the crystal form of compound A represented by formula (V).
图23：式(VI)所示化合物A晶型的H 1NMR图谱。 Figure 23: H 1 NMR spectrum of the crystal form of compound A represented by formula (VI).
图24：各受试物对人非小细胞肺癌NCI-H358裸鼠异种移植瘤模型动物肿瘤体积的影响图。Figure 24: Chart showing the effects of each test substance on tumor volume in human non-small cell lung cancer NCI-H358 nude mouse xenograft tumor model animals.
图25：各受试物对人非小细胞肺癌NCI-H358裸鼠异种移植瘤模型动物肿瘤重量的影响图。Figure 25: Chart showing the effects of each test substance on tumor weight in human non-small cell lung cancer NCI-H358 nude mouse xenograft tumor model animals.
图26：各受试物对人白血病MV-4-11小鼠异种移植瘤模型动物肿瘤体积的影响图。Figure 26: Chart showing the effect of each test substance on tumor volume in human leukemia MV-4-11 mouse xenograft tumor model animals.
图27：各受试物对人白血病MV-4-11小鼠异种移植瘤模型动物肿瘤重量的影响图。Figure 27: Chart showing the effect of each test substance on tumor weight in human leukemia MV-4-11 mouse xenograft tumor model animals.
图28：各受试物对人胰腺癌Mia PaCa-2裸鼠异种移植瘤模型动物肿瘤体积的影响图。Figure 28: Chart showing the effects of each test substance on tumor volume in human pancreatic cancer Mia PaCa-2 nude mouse xenograft tumor model animals.
图29：各受试物对人胰腺癌Mia PaCa-2裸鼠异种移植瘤模型动物肿瘤重量的影响图。Figure 29: Chart showing the effects of each test substance on tumor weight in human pancreatic cancer Mia PaCa-2 nude mouse xenograft tumor model animals.
具体实施方式Detailed ways
下面通过实施例的方式进一步说明本发明，但并不因此将本发明限制在所述的实施例范围之中。下列实施例中未注明具体条件的实验方法，按照常规方法和条件，或按照商品说明书选择。The present invention is further described below by means of examples, but the present invention is not limited to the scope of the described examples. Experimental methods that do not indicate specific conditions in the following examples should be selected according to conventional methods and conditions, or according to product specifications.
除非另有说明，本发明所用到的设备与检测方法如下：Unless otherwise stated, the equipment and detection methods used in the present invention are as follows:
Figure PCTCN2022096702-appb-000020
Figure PCTCN2022096702-appb-000020
Figure PCTCN2022096702-appb-000021
Figure PCTCN2022096702-appb-000021
实施例1：式(I)所示化合物的制备Example 1: Preparation of compounds represented by formula (I)
第一步，化合物B的合成The first step is the synthesis of compound B
Figure PCTCN2022096702-appb-000022
Figure PCTCN2022096702-appb-000022
反应釜R1中加入乙醇(5.33kg)，开启搅拌。加入A(1.35kg)。保温5～15℃下，滴加三乙胺(1.26kg)。保温5～15℃下，滴加A2(1.13kg)。滴完，保温5～15℃搅拌0.5h。体系升温到30～35℃搅拌反应，反应2～3h。HPLC检测，达到反应终点。R1浓缩去除乙醇。R1中加入水(5.40kg)，乙酸乙酯(4.86kg)，搅拌10分钟。静置分液，上层有机相暂存R1，下层水相转移入R2中。R2中加入乙酸乙酯(4.86kg)，搅拌10分钟。静置分液，上层有机相转入R1，下层水相暂存R2中。R2中加入乙酸乙酯(4.86kg)，搅拌10分钟。静置分液，上层有机相转入R1中合并，下层水相废弃。R1中加入水(5.40kg)，搅拌10分钟。静置分液，上层有机相收集，下层水相废弃。有机相浓缩干，得到黄色油状物1.89kg。Add ethanol (5.33kg) to reactor R1 and start stirring. Add A (1.35kg). While maintaining the temperature at 5 to 15°C, add triethylamine (1.26kg) dropwise. Keep the temperature at 5-15℃, add A2 (1.13kg) dropwise. After the dripping is completed, keep the mixture at 5-15℃ and stir for 0.5h. The system was heated to 30-35°C and stirred for 2-3 hours. HPLC detection showed that the reaction end point was reached. R1 is concentrated to remove ethanol. Add water (5.40kg) and ethyl acetate (4.86kg) to R1, and stir for 10 minutes. Let stand for liquid separation, the upper organic phase is temporarily stored in R1, and the lower aqueous phase is transferred to R2. Add ethyl acetate (4.86kg) to R2 and stir for 10 minutes. Let stand for liquid separation, transfer the upper organic phase to R1, and temporarily store the lower aqueous phase in R2. Add ethyl acetate (4.86kg) to R2 and stir for 10 minutes. Let stand for liquid separation, transfer the upper organic phase to R1 and combine, and discard the lower aqueous phase. Add water (5.40kg) to R1 and stir for 10 minutes. Let stand for liquid separation, collect the upper organic phase and discard the lower aqueous phase. The organic phase was concentrated to dryness to obtain 1.89kg of yellow oil.
1H NMR(400MHz,CDCl 3)δ6.15(s,1H),5.46(s,1H),4.49(t,J＝5.2Hz,1H),3.59–3.45(m,2H),3.42(s,6H),2.32(s,3H)。 1 H NMR (400MHz, CDCl 3 ) δ6.15 (s, 1H), 5.46 (s, 1H), 4.49 (t, J = 5.2Hz, 1H), 3.59–3.45 (m, 2H), 3.42 (s, 6H),2.32(s,3H).
第二步，化合物C的合成Second step, synthesis of compound C
Figure PCTCN2022096702-appb-000023
Figure PCTCN2022096702-appb-000023
反应釜R1中加入冰醋酸(6.51kg),开启搅拌。加入B(1.24kg)。加入NIS(1.33kg)。反应液升温到30～35℃下反应4～6h。HPLC检测，达到反应终点。体系降温到5～10℃，慢慢向体系中加入水(11.20kg)。滴完，保温5～15℃下搅拌16h。过滤，滤饼用水(2.50kg)淋洗。收集固体，50℃下真空干燥24h。得到固体粗品1.61kg，重量收率：130.1％。直接投入下一步反应。 1H NMR(400MHz,CDCl 3)δ5.87(s,1H),4.52(t,J＝5.2Hz,1H),3.67(t,J＝5.4Hz,2H),3.48(s,6H),2.59(s,3H)。 Add glacial acetic acid (6.51kg) to reactor R1 and start stirring. Add B (1.24kg). Add NIS (1.33kg). The reaction solution is heated to 30-35°C and reacted for 4-6 hours. HPLC detection showed that the reaction end point was reached. Cool the system to 5-10°C, and slowly add water (11.20kg) to the system. After the dripping is completed, keep the mixture at 5 to 15°C and stir for 16 hours. Filter, and rinse the filter cake with water (2.50kg). The solid was collected and dried under vacuum at 50°C for 24 h. 1.61kg of solid crude product was obtained, weight yield: 130.1%. Go directly to the next reaction. 1 H NMR (400MHz, CDCl 3 ) δ5.87 (s, 1H), 4.52 (t, J = 5.2Hz, 1H), 3.67 (t, J = 5.4Hz, 2H), 3.48 (s, 6H), 2.59 (s,3H).
第三步，化合物D的合成The third step, synthesis of compound D
Figure PCTCN2022096702-appb-000024
Figure PCTCN2022096702-appb-000024
反应釜R1中加入冰醋酸(6.72kg)，开启搅拌。加入C(0.80kg)。滴加浓盐酸(0.47kg)。滴完，升温至100～105℃反应1～2h。HPLC检测，达到反应终点。体系快速降温到10～20℃，过滤，滤饼用乙醇(0.63kg)淋洗。收集滤饼，转移入R1中。R1中加入水(5.60kg)，开启搅拌。碳酸氢钠(0.21kg)溶于水(2.40kg)中，配制成饱和溶液滴加到R1中。滴完，搅拌1h。过滤，滤饼用水(0.80kg)淋洗。收集固体，50℃下真空干燥12h，恒重得到0.34kg固体，重量收率：41.8％。 1H NMR(400MHz,DMSO)δ10.52(s,1H),6.85(s,1H),5.88(t,J＝5.9Hz,1H),3.83(dd,J＝15.4,7.2Hz,1H),3.42(dd,J＝15.5,1.8Hz,1H),2.21(s,3H)。 Add glacial acetic acid (6.72kg) to reactor R1 and start stirring. Add C (0.80kg). Add concentrated hydrochloric acid (0.47kg) dropwise. After the dripping is completed, the temperature is raised to 100~105°C for 1~2 hours. HPLC detection showed that the reaction end point was reached. The system was quickly cooled to 10-20°C, filtered, and the filter cake was rinsed with ethanol (0.63kg). Collect the filter cake and transfer it to R1. Add water (5.60kg) to R1 and start stirring. Dissolve sodium bicarbonate (0.21kg) in water (2.40kg), prepare a saturated solution and add it dropwise to R1. After dripping, stir for 1 hour. Filter, and rinse the filter cake with water (0.80kg). The solid was collected, dried under vacuum at 50°C for 12 hours, and 0.34 kg of solid was obtained at constant weight. Weight yield: 41.8%. 1 H NMR (400MHz, DMSO) δ10.52 (s, 1H), 6.85 (s, 1H), 5.88 (t, J = 5.9Hz, 1H), 3.83 (dd, J = 15.4, 7.2Hz, 1H), 3.42(dd,J＝15.5,1.8Hz,1H),2.21(s,3H).
第四步，化合物E的合成 Step 4, synthesis of compound E
Figure PCTCN2022096702-appb-000025
Figure PCTCN2022096702-appb-000025
反应釜R1中加入D(1.00kg)。加入三氯氧磷(8.38kg)，开启搅拌。升温到90～95℃下反应3～4h。保温90～95℃下，滴加DIPEA(2.65kg)。滴完，保温90～95℃下搅拌2h。HPLC检测，达到反应终点。反应液浓缩，尽可能的除掉三氯氧磷，得到黑色油状物。浓缩物中加入甲苯(5.00kg)，浓缩至基本无液滴。浓缩物中加入二氯甲烷(13.30kg)稀释。R2中加入水(20.00kg)，开启搅拌。将上面的二氯甲烷溶液缓慢倒入R2反应釜中进行淬灭，控制温度≤30℃。淬灭后，静置分层，分去下层。R2反应釜中加入二氯甲烷(13.30kg)，搅拌20分钟。静置分层，分去下层，水相暂存。合并二氯甲烷相，加入(5.00kg)2 N盐酸，搅拌20分钟。静置分层，所得水相与上面水相合并，二氯甲烷相暂存。向合并水相滴加30％氢氧化钠调节体系PH＝6，R2中加入乙酸乙酯(36.00kg)，搅拌30分钟。停止搅拌，过硅藻土过滤，分液，下层水相废弃，上层有机相暂存R2反应釜。R2反应釜中加入5％碳酸钠溶液(5.00kg)，搅拌10分钟。静置分液，下层水相废弃，上层有机相暂存R2反应釜。R2反应釜中加入5％碳酸钠溶液(5.00kg)，搅拌10分钟。静置分液，下层水相废弃，上层有机相暂存R2。R2中加入水(10.00kg，10.00X)，搅拌10分钟。静置分液，下层水洗废弃，上层有机相收集。有机相浓缩干，得到黄色固体。50℃下真空干燥24h，过筛。得到0.51kg产物，重量收率51.0％。Add D (1.00kg) to reaction kettle R1. Add phosphorus oxychloride (8.38kg) and start stirring. Raise the temperature to 90-95°C and react for 3-4 hours. Keep the temperature at 90~95℃, add DIPEA (2.65kg) dropwise. After the dripping is completed, keep the mixture at 90-95°C and stir for 2 hours. HPLC detection showed that the reaction end point was reached. The reaction solution was concentrated to remove as much phosphorus oxychloride as possible to obtain a black oily substance. Toluene (5.00kg) was added to the concentrate, and the mixture was concentrated until there were almost no droplets. Dichloromethane (13.30kg) was added to the concentrate to dilute. Add water (20.00kg) to R2 and start stirring. Slowly pour the above dichloromethane solution into the R2 reaction kettle for quenching, and control the temperature to ≤30°C. After quenching, let it stand for stratification and separate the lower layer. Add dichloromethane (13.30kg) to the R2 reaction kettle and stir for 20 minutes. Let stand and separate into layers, separate the lower layer, and store the water phase temporarily. Combine the dichloromethane phases, add (5.00kg) 2 N hydrochloric acid, and stir for 20 minutes. Let stand and separate into layers. The resulting water phase is combined with the water phase above, and the dichloromethane phase is temporarily stored. Add 30% sodium hydroxide dropwise to the combined aqueous phase to adjust the pH of the system to 6. Add ethyl acetate (36.00kg) to R2 and stir for 30 minutes. Stop stirring, filter through diatomaceous earth, and separate the liquids. The lower aqueous phase is discarded, and the upper organic phase is temporarily stored in the R2 reactor. Add 5% sodium carbonate solution (5.00kg) to the R2 reaction kettle and stir for 10 minutes. Let stand for liquid separation, discard the lower aqueous phase, and temporarily store the upper organic phase in the R2 reactor. Add 5% sodium carbonate solution (5.00kg) to the R2 reaction kettle and stir for 10 minutes. Let stand for liquid separation, discard the lower aqueous phase, and temporarily store R2 in the upper organic phase. Add water (10.00kg, 10.00X) to R2 and stir for 10 minutes. Let stand for liquid separation, wash the lower layer with water and discard it, and collect the upper organic phase. The organic phase was concentrated to dryness to obtain a yellow solid. Vacuum dry at 50°C for 24 hours and sieve. 0.51 kg of product was obtained, with a weight yield of 51.0%.
第五步，化合物F的合成 Step 5, synthesis of compound F
Figure PCTCN2022096702-appb-000026
Figure PCTCN2022096702-appb-000026
向反应瓶中加入E(10.00g，1.00eq)，E2(9.66g,1.03eq)，乙腈(150ml，15V)，室温条件下搅拌，加入DIPEA(22.02g，5.00eq)，升温至30℃，搅拌4h，取样送确认反应完毕。将体系在35℃条件下浓缩至体系2-3V，加入水(450ml，45V)搅拌过夜，抽滤，得到淡黄色固体，在49℃条件下烘干，得到产品(HPLC：97.4％，产率：99.8％)。 1H NMR(400MHz，DMSO)δ7.79(d，J＝1.3Hz，1H)，7.57(d，J＝1.3Hz，1H)，7.51(d，J＝6.9Hz，1H)，7.34–7.23(m，3H)，4.28(s，1H)，3.74(t，J＝13.5Hz，2H)，3.25–3.05(m，3H)，2.90(d，J＝16.0Hz，1H)，2.58(s，3H)，1.95(dd，J＝13.2，7.0Hz，2H)，1.57(s，2H)，MS:m/z＝460.2[M+1]。 Add E (10.00g, 1.00eq), E2 (9.66g, 1.03eq), acetonitrile (150ml, 15V) to the reaction flask, stir at room temperature, add DIPEA (22.02g, 5.00eq), and heat to 30°C. Stir for 4 hours and take a sample to confirm the reaction is complete. Concentrate the system to system 2-3V at 35°C, add water (450ml, 45V) and stir overnight, filter with suction to obtain a light yellow solid, dry it at 49°C to obtain the product (HPLC: 97.4%, yield :99.8%). 1 H NMR (400MHz, DMSO) δ7.79 (d, J=1.3Hz, 1H), 7.57 (d, J=1.3Hz, 1H), 7.51 (d, J=6.9Hz, 1H), 7.34–7.23 ( m, 3H), 4.28 (s, 1H), 3.74 (t, J = 13.5Hz, 2H), 3.25–3.05 (m, 3H), 2.90 (d, J = 16.0Hz, 1H), 2.58 (s, 3H ), 1.95 (dd, J=13.2, 7.0Hz, 2H), 1.57 (s, 2H), MS: m/z=460.2[M+1].
第六步，化合物G的合成 Step 6, synthesis of compound G
Figure PCTCN2022096702-appb-000027
Figure PCTCN2022096702-appb-000027
向反应瓶中加入F(5.0g，1.0eq)，MeOH(30ml，10V)，开启搅拌，使体系溶清，滴加DIPEA(2.21g，1.5eq)，降温至0-10℃，滴加BOC 2O(2.85g，1.2eq)的甲醇溶液(20ml)，滴加完毕后，保持0-10℃10min，然后升温至室温，体系旋干，加入水(50ml)，EA萃取(50ml*2)，水洗(50ml*2)，NaCl水溶液洗(50ml)，浓缩至干，得到4.88g产品。 1H NMR(400MHz,DMSO)δ7.81(d，J＝1.4Hz，1H)，7.54(d，J＝1.3Hz，1H)， 7.21(dd，J＝11.8，7.6Hz，5H)，4.85(d，J＝9.8Hz，1H)，3.62(dd,J＝25.8，13.3Hz，2H)，3.17(d，J＝5.2Hz，2H)，3.08(d，J＝15.8Hz，1H)，2.75(d，J＝15.8Hz，1H)，2.57(s，3H)，2.00–1.76(m，2H)，1.65(d，J＝13.7Hz，1H)，1.53–1.34(m，10H)，MS:m/z＝560.2[M+1]。 Add F (5.0g, 1.0eq) and MeOH (30ml, 10V) to the reaction flask, start stirring to dissolve the system, add DIPEA (2.21g, 1.5eq) dropwise, cool to 0-10°C, and add BOC dropwise 2 O (2.85g, 1.2eq) methanol solution (20ml), after the dropwise addition is completed, keep it at 0-10℃ for 10min, then heat it up to room temperature, spin the system to dryness, add water (50ml), and extract with EA (50ml*2) , washed with water (50ml*2), washed with NaCl aqueous solution (50ml), and concentrated to dryness to obtain 4.88g of product. 1 H NMR (400MHz, DMSO) δ7.81 (d, J=1.4Hz, 1H), 7.54 (d, J=1.3Hz, 1H), 7.21 (dd, J=11.8, 7.6Hz, 5H), 4.85 ( d, J=9.8Hz, 1H), 3.62 (dd, J=25.8, 13.3Hz, 2H), 3.17 (d, J=5.2Hz, 2H), 3.08 (d, J=15.8Hz, 1H), 2.75 ( d, J＝15.8Hz, 1H), 2.57 (s, 3H), 2.00–1.76 (m, 2H), 1.65 (d, J＝13.7Hz, 1H), 1.53–1.34 (m, 10H), MS:m /z=560.2[M+1].
第七步，化合物H的合成 Step 7, synthesis of compound H
Figure PCTCN2022096702-appb-000028
Figure PCTCN2022096702-appb-000028
向100ml三口瓶内，加入CuI(35mg，0.2eq)，TMEDA(63mg，0.6eq)，二氧六环(5ml，10V)，用氮气置换三次，室温条件下搅拌1h，加入G(500mg，1.0eq)，G2(239mg，1.5eq)，Cs 2CO 3(440mg，1.5eq)，再次用氮气置换三次，升温至101℃，搅拌24h，取样，确定反应情况，反应完毕后，加入10ml氨水，过滤(加硅藻土)，乙酸乙酯洗涤滤饼(5V)，震荡后，分液，乙酸乙酯萃取(50ml)，合并有机相，水洗，brine洗，无水硫酸钠干燥，抽滤，旋干，加入乙酸乙酯加热至全部溶解，滴加正庚烷(EA:正庚烷＝3:1)，缓慢降温至室温，搅拌16h后，过滤，将滤饼加入到100ml三口瓶内，加入10V丙酮，滴加2.5V水，室温搅拌4h后，过滤，送检测试纯度，将滤饼置于50℃条件下烘干得到淡黄色固体。 1H NMR(400MHz，DMSO)δ7.75(d，J＝1.2Hz，1H)，7.54(d，J＝5.4Hz，1H)，7.47(s，1H)，7.30–7.14(m，5H)，6.30(s，2H)，5.70(d，J＝5.4Hz，1H)，4.87(d，J＝9.8Hz，1H)，3.93–3.70(m，2H)，3.37(s，2H)，3.11(d，J＝15.8Hz，1H)，2.78(d，J＝15.7Hz，1H)，2.46(s，3H)，1.93–1.76(m，2H)，1.69(d，J＝13.4Hz，1H)，1.52(d，J＝13.6Hz，1H)，1.41(d，J＝11.7Hz，9H)，MS:m/z＝592.2[M+1]。 To a 100ml three-necked flask, add CuI (35mg, 0.2eq), TMEDA (63mg, 0.6eq), dioxane (5ml, 10V), replace with nitrogen three times, stir at room temperature for 1h, add G (500mg, 1.0 eq), G2 (239mg, 1.5eq), Cs 2 CO 3 (440mg, 1.5eq), replace it with nitrogen three times again, raise the temperature to 101°C, stir for 24h, take a sample to determine the reaction situation, after the reaction is completed, add 10ml ammonia water, Filter (add diatomaceous earth), wash the filter cake with ethyl acetate (5V), shake, separate the liquids, extract with ethyl acetate (50ml), combine the organic phases, wash with water, brine, dry with anhydrous sodium sulfate, and filter with suction. Spin dry, add ethyl acetate and heat until completely dissolved, add n-heptane (EA:n-heptane=3:1) dropwise, slowly cool to room temperature, stir for 16 hours, filter, and add the filter cake to a 100ml three-necked flask. Add 10V acetone, add 2.5V water dropwise, stir at room temperature for 4 hours, filter, and send to test for purity. The filter cake is dried at 50°C to obtain a light yellow solid. 1 H NMR (400MHz, DMSO) δ7.75 (d, J=1.2Hz, 1H), 7.54 (d, J=5.4Hz, 1H), 7.47 (s, 1H), 7.30–7.14 (m, 5H), 6.30 (s, 2H), 5.70 (d, J = 5.4Hz, 1H), 4.87 (d, J = 9.8Hz, 1H), 3.93–3.70 (m, 2H), 3.37 (s, 2H), 3.11 (d , J=15.8Hz, 1H), 2.78 (d, J=15.7Hz, 1H), 2.46 (s, 3H), 1.93–1.76 (m, 2H), 1.69 (d, J=13.4Hz, 1H), 1.52 (d, J=13.6Hz, 1H), 1.41 (d, J=11.7Hz, 9H), MS: m/z=592.2[M+1].
第八步，式(I)所示化合物的合成The eighth step, synthesis of compounds represented by formula (I)
Figure PCTCN2022096702-appb-000029
Figure PCTCN2022096702-appb-000029
将化合物H(0.3g，0.51mmol)，溶于DCM(10ml)，室温下滴加TFA(2mL)，室温下搅拌1小时。浓缩，用DCM稀释，倒入饱和Na 2CO 3水溶液，DCM萃取3次，30-40℃旋干得到白色固体(203mg)。 1H NMR(400MHz，DMSO)δ7.74(d，J＝1.1Hz，1H)，7.54(d，J＝5.4Hz，1H)，7.48(d，J＝1.2Hz，1H)，7.33(d，J＝6.3Hz，1H)，7.29–7.08 (m，4H)，6.31(s，2H)，5.71(d，J＝5.4Hz，1H)，3.31–3.20(m，2H)，3.08(d，J＝15.6Hz，1H)，2.66(d，J＝15.6Hz，1H)，2.47(s，3H)，2.06–1.88(m，3H)，1.79(s，2H)，1.63(d，J＝13.3Hz，1H)，1.25(d，J＝13.3Hz，1H)。MS:m/z＝492.2[M+1]。所得白色固体即为式(I)所示化合物，经PXRD图谱判断为晶态，其为本发明所称的式(I)所示化合物A晶型。PXRD图谱详见图1。 Compound H (0.3g, 0.51mmol) was dissolved in DCM (10ml), TFA (2mL) was added dropwise at room temperature, and stirred at room temperature for 1 hour. Concentrate, dilute with DCM, pour into saturated Na 2 CO 3 aqueous solution, extract with DCM three times, spin dry at 30-40°C to obtain a white solid (203 mg). 1 H NMR (400MHz, DMSO) δ7.74 (d, J=1.1Hz, 1H), 7.54 (d, J=5.4Hz, 1H), 7.48 (d, J=1.2Hz, 1H), 7.33 (d, J＝6.3Hz, 1H), 7.29–7.08 (m, 4H), 6.31 (s, 2H), 5.71 (d, J＝5.4Hz, 1H), 3.31–3.20 (m, 2H), 3.08 (d, J =15.6Hz, 1H), 2.66(d, J＝15.6Hz, 1H), 2.47(s, 3H), 2.06–1.88(m, 3H), 1.79(s, 2H), 1.63(d, J＝13.3Hz , 1H), 1.25 (d, J=13.3Hz, 1H). MS: m/z=492.2[M+1]. The obtained white solid is the compound represented by formula (I). It is judged to be in a crystalline state by the PXRD pattern, and it is the crystal form A of the compound represented by formula (I) called in the present invention. The details of the PXRD pattern are shown in Figure 1.
DSC图谱详见图2，结果显示式(I)所示化合物A晶型在30℃～300℃范围内呈现熔融吸热(Onset：180.54℃，Peak：188.96℃，H＝22.96J/g)转晶放热(Onset：190.55℃，Peak：191.68℃，H＝10.84J/g)熔融吸热(Onset：207.29℃，Peak：215.23℃，H＝73.75J/g)现象，提示该化合物在热力学上存在更稳定的晶型。TGA图谱详见图3，显示式(I)所示化合物A晶型在278±3℃左右开始分解，分解温度以前几乎无失重，表明该化合物为无水无溶剂晶型。The DSC spectrum is shown in Figure 2 for details. The results show that the crystal form of compound A shown in formula (I) exhibits melting endotherm (Onset: 180.54°C, Peak: 188.96°C, H=22.96J/g) in the range of 30°C to 300°C. Crystal exotherm (Onset: 190.55°C, Peak: 191.68°C, H=10.84J/g) and melting endotherm (Onset: 207.29°C, Peak: 215.23°C, H=73.75J/g) indicate that the compound is thermodynamically More stable crystalline forms exist. The TGA spectrum is detailed in Figure 3, which shows that the crystal form of compound A shown in formula (I) begins to decompose at about 278±3°C, and there is almost no weight loss before the decomposition temperature, indicating that the compound is an anhydrous and solvent-free crystal form.
实施例二：式(I)所示化合物B晶型的制备Example 2: Preparation of crystal form B of compound represented by formula (I)
称取式(I)所示化合物A晶型300.6mg于20mL样品瓶中，加入10ml乙腈中，置于摇床(25℃，250rpm)震荡24h。过滤，过滤所得固体置于50℃真空干燥箱(真空度-0.1MPa)干燥6h，得白色固体，收率64.45％。固体真空干燥后进行PXRD测定，图谱详见图4。DSC和TGA结果显示该化合物为无水无溶剂晶型，DSC图谱详见图5，TGA图谱详见图6，其H 1NMR图谱见图19。式(I)所示化合物B晶型为非溶剂化物，DSC结果显示其为热力学最稳定体系。 Weigh 300.6 mg of the crystal form A of the compound represented by formula (I) into a 20 mL sample bottle, add 10 ml of acetonitrile, and place it on a shaker (25°C, 250 rpm) to shake for 24 hours. Filter, and dry the solid obtained by filtration in a 50°C vacuum drying oven (vacuum degree -0.1MPa) for 6 hours to obtain a white solid with a yield of 64.45%. The solid was vacuum dried and then measured by PXRD. The details of the spectrum are shown in Figure 4. DSC and TGA results show that the compound is anhydrous and solvent-free crystal form. The DSC spectrum is shown in Figure 5, the TGA spectrum is shown in Figure 6, and its H 1 NMR spectrum is shown in Figure 19. The crystal form B of compound represented by formula (I) is an unsolvated product, and DSC results show that it is the most thermodynamically stable system.
实施例三：式(III)所示化合物A晶型的制备Example 3: Preparation of crystal form A of compound represented by formula (III)
Figure PCTCN2022096702-appb-000030
Figure PCTCN2022096702-appb-000030
称取式(I)所示化合物A晶型299.9mg于20mL样品瓶中，加入二氧六环6mL，升温至50℃同时磁力搅拌。待溶清后缓慢滴加600μL甲磺酸甲醇溶液(1mol/L)，反应温度为50℃，反应3h。随后以10℃/h的降温速度，降温至室温，随后置于4℃冰箱中24h。过滤，滤饼用4℃的二氧六环溶液2mL洗涤，过滤所得样品置于50℃真空干燥箱(真空度-0.1MPa)干燥24h，得白色固体，收率74.68％。产品进行PXRD测定，图 谱详见图7。DSC和TGA结果显示该化合物为无水无溶剂晶型，DSC图谱详见图8，TGA图谱详见图9，其H 1NMR图谱见图20。 Weigh 299.9 mg of the crystal form A of the compound represented by formula (I) into a 20 mL sample bottle, add 6 mL of dioxane, and raise the temperature to 50°C while stirring magnetically. After the solution is clear, 600 μL of methanol methanol solution (1 mol/L) was slowly added dropwise. The reaction temperature was 50°C and the reaction was carried out for 3 hours. Then, the temperature was cooled to room temperature at a cooling rate of 10°C/h, and then placed in a 4°C refrigerator for 24 hours. Filter, wash the filter cake with 2 mL of dioxane solution at 4°C, and dry the sample in a vacuum drying oven at 50°C (vacuum degree -0.1MPa) for 24 hours to obtain a white solid with a yield of 74.68%. The product was measured by PXRD, and the chart is shown in Figure 7. DSC and TGA results show that the compound is anhydrous and solvent-free crystal form. The DSC spectrum is shown in Figure 8, the TGA spectrum is shown in Figure 9, and its H 1 NMR spectrum is shown in Figure 20.
实施例四：式(IV)所示化合物A晶型的制备Example 4: Preparation of crystal form A of compound represented by formula (IV)
Figure PCTCN2022096702-appb-000031
Figure PCTCN2022096702-appb-000031
称取式(I)所示化合物A晶型300.6mg于50mL结晶器中，加入乙腈27mL与纯化水3mL，升温至50℃，搅拌均匀(200-300rpm)。缓慢滴加600μL柠檬酸甲醇溶液(1mol/L)，反应温度为50℃，转速200-300rpm，反应2h。以15℃/h的降温速度，降温至5℃，养晶0.5h。收料，滤饼用4℃的乙腈溶液2mL洗涤，过滤所得固体置于50℃真空干燥箱(真空度-0.1MPa)干燥24h，得白色固体，收率52.40％。产品进行PXRD测定，图谱详见图10。DSC和TGA结果显示该化合物为无水无溶剂晶型，DSC图谱详见图11，TGA图谱详见图12，其H 1NMR图谱见图21。 Weigh 300.6 mg of the crystal form A of the compound represented by formula (I) into a 50 mL crystallizer, add 27 mL of acetonitrile and 3 mL of purified water, raise the temperature to 50°C, and stir evenly (200-300 rpm). Slowly add 600 μL citric acid methanol solution (1 mol/L) dropwise, the reaction temperature is 50°C, the rotation speed is 200-300 rpm, and the reaction is carried out for 2 hours. At a cooling rate of 15°C/h, cool down to 5°C and grow the crystals for 0.5h. Collect the material, wash the filter cake with 2 mL of acetonitrile solution at 4°C, and dry the solid obtained by filtration in a vacuum drying oven at 50°C (vacuum degree -0.1MPa) for 24 hours to obtain a white solid with a yield of 52.40%. The product was measured by PXRD, and the details of the spectrum are shown in Figure 10. DSC and TGA results show that the compound is anhydrous and solvent-free crystal form. The DSC spectrum is shown in Figure 11, the TGA spectrum is shown in Figure 12, and its H 1 NMR spectrum is shown in Figure 21.
实施例五：式(V)所示化合物A晶型的制备Example 5: Preparation of crystal form A of compound represented by formula (V)
Figure PCTCN2022096702-appb-000032
Figure PCTCN2022096702-appb-000032
称取式(I)所示化合物A晶型300.0mg于100mL结晶器中，加乙醇60mL，升温至50℃溶清。缓慢滴加600μL硫酸甲醇溶液(1mol/L)，反应温度为50℃，转速200-300rpm，反应3h。随后以12.5℃/h的降温速度，降温至25℃，加入30mL乙腈(未见固体析出)。以10℃/h的降温速度，降温至5℃(仍未析出)，随后转移至250ml旋蒸瓶中(60℃，100rpm)浓缩至10mL左右(澄清)。将上述清液置于100mL烧杯中，敞口挥干，将挥干得到的固体置于50℃真空干燥箱(真空度-0.1MPa)干燥24h，得白色固体，收率91.16％。产品进行PXRD测定，图谱详见图13。DSC和TGA结果显示该化合物为无水无溶剂晶型，DSC图谱详见图14，TGA图谱详见图15，其H 1NMR图谱见图22。 Weigh 300.0 mg of the crystal form A of the compound represented by formula (I) into a 100 mL crystallizer, add 60 mL of ethanol, and heat to 50°C to dissolve. Slowly add 600 μL of sulfuric acid methanol solution (1 mol/L) dropwise, the reaction temperature is 50°C, the rotation speed is 200-300 rpm, and the reaction is carried out for 3 hours. Then, the temperature was lowered to 25°C at a cooling rate of 12.5°C/h, and 30 mL of acetonitrile was added (no solid precipitation was seen). Cool to 5°C at a cooling rate of 10°C/h (still not precipitated), then transfer to a 250ml rotary evaporator (60°C, 100rpm) and concentrate to about 10mL (clear). Place the above clear liquid in a 100 mL beaker, evaporate it to dryness with an open mouth, and place the solid obtained by evaporation in a 50°C vacuum drying oven (vacuum degree -0.1MPa) to dry for 24 hours to obtain a white solid with a yield of 91.16%. The product was measured by PXRD, and the details of the spectrum are shown in Figure 13. DSC and TGA results show that the compound is anhydrous and solvent-free crystal form. The DSC spectrum is shown in Figure 14, the TGA spectrum is shown in Figure 15, and its H 1 NMR spectrum is shown in Figure 22.
实施例六：式(VI)所示化合物A晶型的制备Example 6: Preparation of crystal form A of compound represented by formula (VI)
Figure PCTCN2022096702-appb-000033
Figure PCTCN2022096702-appb-000033
称取式(I)所示化合物A晶型300.3mg于20mL样品瓶中，加入二氧六环8mL，升温至50℃同时磁力搅拌。待溶清后缓慢滴加600μL丁二酸甲醇溶液(1mol/L)，反应温度为50℃，反应3h。随后以10℃/h的降温速度，降温至室温，随后置于4℃冰箱中5h。过滤，滤饼用4℃的二氧六环溶液2mL洗涤，过滤所得样品置于50℃真空干燥箱(真空度-0.1MPa)干燥24h，得白色固体，收率51.83％。产品进行PXRD测定，图谱详见图16。DSC和TGA结果显示该化合物为无水无溶剂晶型，DSC图谱详见图17，TGA图谱详见图18，其H 1NMR图谱见图23。 Weigh 300.3 mg of the crystal form A of the compound represented by formula (I) into a 20 mL sample bottle, add 8 mL of dioxane, and raise the temperature to 50°C while magnetically stirring. After the solution is clear, 600 μL of succinic acid methanol solution (1 mol/L) was slowly added dropwise. The reaction temperature was 50°C and the reaction was carried out for 3 hours. Then, the temperature was cooled to room temperature at a cooling rate of 10°C/h, and then placed in a 4°C refrigerator for 5 hours. Filter, wash the filter cake with 2 mL of dioxane solution at 4°C, and dry the sample in a vacuum drying oven at 50°C (vacuum degree -0.1MPa) for 24 hours to obtain a white solid with a yield of 51.83%. The product was measured by PXRD, and the details of the spectrum are shown in Figure 16. DSC and TGA results show that the compound is anhydrous and solvent-free crystal form. The DSC spectrum is shown in Figure 17, the TGA spectrum is shown in Figure 18, and its H 1 NMR spectrum is shown in Figure 23.
实施例七：化合物晶型水吸附与解吸附实验Example 7: Water adsorption and desorption experiments of compound crystal forms
采用动态水吸附仪(DVS)考察上述化合物晶型在25℃，0～95％相对湿度范围内的吸附与解吸实验，以确定各种不同晶型的引湿性能，实验结果见表6。A dynamic water adsorption instrument (DVS) was used to examine the adsorption and desorption experiments of the crystal forms of the above compounds at 25°C and a relative humidity range of 0 to 95% to determine the moisture-absorbing properties of various crystal forms. The experimental results are shown in Table 6.
表6：样品0～95％RH范围内重量变化Table 6: Weight change of sample in the range of 0~95%RH
晶型Crystal form 吸湿增重Hygroscopic weight gain
式(I)所示化合物A晶型Crystal form of compound A represented by formula (I) 0.26％0.26%
式(I)所示化合物B晶型Crystal form B of compound represented by formula (I) 0.13％0.13%
式(III)所示化合物A晶型Crystal form of compound A represented by formula (III) 1.37％1.37%
式(IV)所示化合物A晶型Crystal form of compound A represented by formula (IV) 3.25％3.25%
式(V)所示化合物A晶型Crystal form of compound A represented by formula (V) 5.38％5.38%
式(VI)所示化合物A晶型Crystal form of compound A represented by formula (VI) 1.28％1.28%
由所述检测结果可知，式(I)所示化合物B晶型引湿增重小于0.2％，几乎无引湿性；式(III)所示化合物、式(VI)所示化合物和式(I)所示化合物A引湿增重小于2％但不小于0.2％，略有引湿性；式(V)所示化合物A晶型、式(IV)所示化合物A晶型引湿增重小于15％但不小于2％，具有引湿性。It can be seen from the test results that the weight gain of the crystal form B of the compound represented by formula (I) is less than 0.2% and has almost no hygroscopicity; the compound represented by formula (III), the compound represented by formula (VI) and the compound represented by formula (I) The compound A shown has a moisture-absorbing weight gain of less than 2% but not less than 0.2%, and is slightly hygroscopic; the crystal form of compound A shown in formula (V) and the crystal form of compound A shown in formula (IV) have a moisture-absorbing weight gain of less than 15%. But not less than 2%, with hygroscopicity.
实施例八：化合物晶型溶解度测试Example 8: Solubility test of compound crystal form
称取10mg上述化合物晶型于10mL样品瓶中，分别加入水、pH 2.0、4.5、6.8缓冲液5mL，置25℃摇床震荡24h后过滤，滤液采用HPLC测定溶解度，以及pH值。Weigh 10 mg of the crystal form of the above compound into a 10 mL sample bottle, add 5 mL of water, pH 2.0, 4.5, and 6.8 buffer respectively, shake on a shaker at 25°C for 24 hours, and then filter. Use HPLC to measure the solubility and pH value of the filtrate.
色谱条件如下：The chromatographic conditions are as follows:
色谱柱：Unitary C18(5μm,100A,4.6×250mm)Column: Unitary C18 (5μm, 100A, 4.6×250mm)
流动相：A相为0.1％的甲醇水溶液，B相为乙腈，A:B＝10:90Mobile phase: Phase A is 0.1% methanol aqueous solution, phase B is acetonitrile, A:B=10:90
梯度表：Gradient table:
T(min)T(min) A(％)A(%) B(％)B(%)
00 9595 55
1010 55 9595
1313 9595 55
1515 9595 55
检测波长：254nmDetection wavelength: 254nm
柱温：40℃Column temperature: 40℃
进样量：20μLInjection volume: 20μL
溶解度测试结果如表7所示。The solubility test results are shown in Table 7.
表7：化合物晶型的溶解度(25℃,mg/mL)Table 7: Solubility of compound crystal form (25℃, mg/mL)
Figure PCTCN2022096702-appb-000034
Figure PCTCN2022096702-appb-000034
Figure PCTCN2022096702-appb-000035
Figure PCTCN2022096702-appb-000035
*盐的溶解度换算成游离碱的溶解度*Salt solubility converted to free base solubility
溶解度测试结果表明式(I)所示化合物晶型的溶解度呈明显的pH依赖性，该弱碱性药物溶解度随着pH值的降低而升高。式(I)所示化合物B晶型在pH 2.0缓冲盐溶液和pH 4.5缓冲盐溶液中的溶解度均与式(I)所示化合物A晶型相当，但在pH 6.8缓冲盐溶液和去离子水中的溶解度远小于式(I)所示化合物A晶型。与式(I)所示化合物稳定B晶型相比，成盐能显著提高化合物在pH 6.8缓冲盐溶液和去离子水中的溶解度；与式(I)所示化合物A晶型相比，成盐后在去离子水中的溶解度亦有显著提高，其中式(III)所示化合物A晶型最佳，提高了82倍，在其余pH缓冲盐溶液中的溶解度亦相当。The solubility test results show that the solubility of the crystal form of the compound represented by formula (I) is obviously pH-dependent, and the solubility of the weakly basic drug increases as the pH value decreases. The solubility of the crystal form of compound B shown in formula (I) in pH 2.0 buffer salt solution and pH 4.5 buffer salt solution is equivalent to the crystal form of compound A shown in formula (I), but in pH 6.8 buffer salt solution and deionized water The solubility is much smaller than the crystal form of compound A shown in formula (I). Compared with the stable B crystal form of the compound shown in formula (I), salt formation can significantly improve the solubility of the compound in pH 6.8 buffer salt solution and deionized water; compared with the compound A crystal form shown in formula (I), salt formation The solubility in deionized water was also significantly improved. Among them, the crystal form of compound A represented by formula (III) was the best, with an increase of 82 times. The solubility in other pH buffer salt solutions was also equivalent.
实施例九：化合物晶型稳定性的测定Example 9: Determination of the stability of the crystal form of the compound
高温试验(T)：粉末置于适宜的密封玻璃瓶中，60℃温度下放置10天，并于第5天和第10天取样，测试固体PXRD。High temperature test (T): The powder is placed in a suitable sealed glass bottle and placed at 60°C for 10 days, and samples are taken on the 5th and 10th days to test solid PXRD.
高湿试验(H)：将粉末开口置于恒温恒湿箱中，25℃、90％±5％RH条件下放置10天，并于第5天和第10天取样，测试固体PXRD。考察其吸湿潮解性能。High humidity test (H): Place the powder opening in a constant temperature and humidity box at 25°C and 90% ± 5% RH for 10 days, and take samples on the 5th and 10th days to test solid PXRD. Examine its hygroscopic and deliquescent properties.
强光照射试验(L)：将粉末开口放在装有日光灯的光照稳定箱内，于照度为4500±500lx的条件下放置10天，并于第5天和第10天取样，测试固体PXRD。Strong light irradiation test (L): Place the powder opening in a stable light box equipped with a fluorescent lamp, place it for 10 days under the condition of illumination of 4500±500lx, and take samples on the 5th and 10th days to test solid PXRD.
加速试验(A)：将粉末开口置于恒温恒湿箱中，40℃、75％±5％RH条件下放置10天，并于第5天和第10天取样，测试固体PXRD。Accelerated test (A): Place the powder opening in a constant temperature and humidity box at 40°C and 75% ± 5% RH for 10 days, and take samples on the 5th and 10th days to test solid PXRD.
稳定性试验结果如表8所示：The stability test results are shown in Table 8:
表8：各化合物晶型的稳定性Table 8: Stability of crystal forms of each compound
Figure PCTCN2022096702-appb-000036
Figure PCTCN2022096702-appb-000036
稳定性结果表明：式(I)所示化合物A、B、式(III)所示化合物A晶型、式(IV)所示化合物A晶型在各考察实验条件下均稳定，不会发生晶型转变；但式(V)所示化合物A晶型在加速条件下晶型部分发生转变，式(VI)所示化合物A晶型在高湿和加速条件下晶型发生转变。The stability results show that the crystal form of compounds A and B represented by formula (I), the crystal form of compound A represented by formula (III), and the crystal form of compound A represented by formula (IV) are stable under various experimental conditions, and no crystallization will occur. Form transformation; however, the crystal form of the compound A represented by the formula (V) partially transforms under accelerated conditions, and the crystal form of the compound A represented by the formula (VI) undergoes a crystal form transition under high humidity and accelerated conditions.
实施例十：式(IV)所示化合物A晶型的异种移植瘤模型实验Example 10: Experiment on xenograft tumor model of compound A crystal form represented by formula (IV)
实验一experiment one
动物：Balb/c裸小鼠，雌性，体重17-19g，由浙江维通利华实验动物技术有限公司提供；SPF级饲养，温度20-26℃，湿度40-70％，自由进食，城市自来水经过滤高压灭菌后饮用。实验前给予小鼠不低7天的适应性饲养.Animals: Balb/c nude mice, female, weighing 17-19g, provided by Zhejiang Weitong Lihua Experimental Animal Technology Co., Ltd.; raised at SPF level, temperature 20-26°C, humidity 40-70%, free access to food, city tap water Filter and autoclave before drinking. Mice were given adaptive feeding for at least 7 days before the experiment.
给药溶液配置：受试物RG001(即式(IV)所示化合物A晶型)溶媒为1％的HPMC。受试物给药溶液现用现配，2-8℃，避光保存。Preparation of dosing solution: The test substance RG001 (i.e., the crystal form of compound A represented by formula (IV)) has a solvent of 1% HPMC. The test substance administration solution should be prepared freshly before use, and stored at 2-8°C, protected from light.
人癌细胞株：人非小细胞肺癌细胞NCI-H358由中科院细胞生物研究所提供。Human cancer cell lines: Human non-small cell lung cancer cell NCI-H358 was provided by the Institute of Cell Biology, Chinese Academy of Sciences.
培养基：RPMI-1640基础培养基和胎牛血清(FBS)均购自于美国GIBCO公司(Grand Island,NY,USA)。Medium: RPMI-1640 basic medium and fetal bovine serum (FBS) were purchased from GIBCO (Grand Island, NY, USA).
肿瘤移植实验及检测：NCI-H358细胞培养于含10％FBS的RPMI-1640培养基中，细胞放置于5％CO 2培养箱中37℃培养。收集对数生长期的NCI-H358细胞，计数后重 悬于RPMI-1640基础培养基中，1：1加入Matrigel，调整细胞悬液浓度至1*10 8mL，在无菌条件下，接种0.1mL细胞悬液至小鼠右侧背部皮下。 Tumor transplantation experiment and detection: NCI-H358 cells were cultured in RPMI-1640 medium containing 10% FBS, and the cells were placed in a 5% CO 2 incubator at 37°C. Collect NCI-H358 cells in the logarithmic growth phase, count them and resuspend them in RPMI-1640 basic medium. Add Matrigel at a ratio of 1:1, adjust the cell suspension concentration to 1*10 8 mL, and inoculate 0.1 cells under sterile conditions. mL of cell suspension was subcutaneously placed on the right back of the mouse.
待肿瘤平均体积达120mm 3左右时，采用随机区组法将动物分组，每组8只小鼠。分组当日记Day0，并按照平均体重开始给药。实验期间每周测定两次动物体重和肿瘤大小。式(IV)所示化合物A晶型组口服给药，每天给药一次或每周给药一次，连续给药三周，阳性药组每日口服给药一次RMC4550，连续给药三周。 When the average tumor volume reached about 120 mm 3 , the animals were divided into groups using random block method, with 8 mice in each group. Day 0 was recorded on the day of grouping, and medication was started according to the average body weight. Animal body weight and tumor size were measured twice a week during the experiment. The compound A crystal form group represented by formula (IV) is orally administered once a day or once a week for three consecutive weeks, and the positive drug group is orally administered RMC4550 once a day for three consecutive weeks.
本研究中，实验数据均以MEAN±SEM表示。以时间点为X轴，肿瘤体积为Y轴绘制肿瘤生长曲线；以时间点为X轴，动物体重为Y轴绘制动物体重变化曲线。组间比较采用双尾t-检验，P<0.05为显著性差异，P<0.01为极显著差异。In this study, experimental data are expressed as MEAN ± SEM. Draw the tumor growth curve with the time point as the X-axis and the tumor volume as the Y-axis; draw the animal weight change curve with the time point as the X-axis and the animal weight as the Y-axis. Two-tailed t-test was used for comparison between groups, P<0.05 was considered a significant difference, and P<0.01 was considered a highly significant difference.
本次实验中，所有组动物状态良好，体重无明显改变，未出现动物死亡，给药周期中，动物对各受试物均能耐受。In this experiment, the animals in all groups were in good condition, with no significant change in body weight and no animal death. During the dosing cycle, the animals were able to tolerate each test substance.
实验结果显示，与空白溶剂对照组相比，各给药组的肿瘤重量显著降低。RG001 0.5mg/kg,1mg/kg,2mg/kg,4mg/kg组，每天口服给药，连续给药21天，第21天时，各组对瘤重的抑制率分别为66.75％，66.50％，88.67％，90.86％；RG001的14mg/kg组，每周给药一次，共给药三次，瘤重的抑制率80.88％。阳性对照RMC4550 15mg/kg组，对瘤重的抑制率79.42％。具体结果见图25。图25中*对应P<0.05，**对应P<0.01，**对应P<0.001。The experimental results showed that compared with the blank solvent control group, the tumor weight of each administration group was significantly reduced. RG001 0.5mg/kg, 1mg/kg, 2mg/kg, 4mg/kg groups were administered orally every day for 21 consecutive days. On the 21st day, the inhibition rates of tumor weight in each group were 66.75% and 66.50% respectively. 88.67%, 90.86%; the 14 mg/kg group of RG001 was administered once a week for three times in total, and the tumor weight inhibition rate was 80.88%. The positive control RMC4550 15mg/kg group had an inhibition rate of 79.42% on tumor weight. The specific results are shown in Figure 25. In Figure 25, * corresponds to P<0.05, ** corresponds to P<0.01, and ** corresponds to P<0.001.
与空白溶剂对照组相比，各给药组的对肿瘤均有显著抑制。Compared with the blank solvent control group, each administration group had significant tumor inhibition.
RG001 0.5mg/kg,1mg/kg,2mg/kg,4mg/kg组，每天口服给药，连续给药21天，第21天时，各组的相对肿瘤抑制率T/C分别为33.33％，31.58％，12.4％，10.06％；RG001的14mg/kg组，每周给药一次，共给药三次，第21天T/C为23.39％。阳性对照RMC455015mg/kg组，每天口服给药，连续给药21天，第21天时T/C为20.70％。具体实验结果见图24。RG001 0.5mg/kg, 1mg/kg, 2mg/kg, 4mg/kg groups were administered orally every day for 21 consecutive days. On the 21st day, the relative tumor inhibition rates T/C of each group were 33.33% and 31.58 respectively. %, 12.4%, 10.06%; the 14mg/kg group of RG001 was administered once a week for three times in total, and the T/C on the 21st day was 23.39%. The positive control RMC455015 mg/kg group was administered orally every day for 21 consecutive days, and the T/C was 20.70% on the 21st day. The specific experimental results are shown in Figure 24.
实验二 Experiment 2
动物：SCID小鼠，雌性，体重15-18g，动物来源于北京维通利华实验动物技术有限公司；SPF级饲养，温度20-26℃，湿度40-70％，自由进食，城市自来水经过滤高压灭菌后饮用。实验前给予小鼠不低7天的适应性饲养.Animals: SCID mice, female, weighing 15-18g, animals are from Beijing Vitong Lihua Experimental Animal Technology Co., Ltd.; raised at SPF level, temperature 20-26°C, humidity 40-70%, free access to food, city tap water is filtered Drink after autoclaving. Mice were given adaptive feeding for at least 7 days before the experiment.
给药溶液配置：受试物RG001(式(IV)所示化合物A晶型)溶媒为1％的HPMC。受试物给药溶液现用现配，2-8℃，避光保存。Preparation of dosing solution: The test substance RG001 (crystalline form of compound A represented by formula (IV)) is 1% HPMC. The test substance administration solution should be prepared freshly before use, and stored at 2-8°C, protected from light.
人癌细胞株：人白血病细胞株MV-4-11由ATCC(American Type Culture Collection,USA)提供。Human cancer cell line: Human leukemia cell line MV-4-11 was provided by ATCC (American Type Culture Collection, USA).
培养基：IMDM基础培养基和胎牛血清(FBS)均购自于美国GIBCO公司(Grand Island,NY,USA)。Medium: IMDM basal medium and fetal bovine serum (FBS) were purchased from GIBCO (Grand Island, NY, USA).
肿瘤移植实验及检测：MV-4-11细胞培养于含10％FBS的IMDM培养基中，细胞放置于5％CO 2培养箱中37℃培养。收集对数生长期的MV-4-11细胞，计数后重悬于IMDM基础培养基中，1：1加入Matrigel，调整细胞悬液浓度至5*10 7mL，在无菌条件下，接种0.1mL细胞悬液至小鼠右侧背部皮下，接种浓度为5*10 6/0.1mL/只。 Tumor transplantation experiment and detection: MV-4-11 cells were cultured in IMDM medium containing 10% FBS, and the cells were placed in a 5% CO 2 incubator at 37°C. Collect MV-4-11 cells in the logarithmic growth phase, count them and resuspend them in IMDM basic medium. Add Matrigel at a ratio of 1:1, adjust the cell suspension concentration to 5*10 7 mL, and inoculate 0.1 cells under sterile conditions. mL of cell suspension was injected subcutaneously into the right back of the mouse, and the inoculation concentration was 5*10 6 /0.1mL/mouse.
待肿瘤平均体积达120mm 3左右时，采用随机区组法将动物分组，每组8只小鼠。分组当日记Day0，并按照平均体重开始给药。实验期间每周测定两次动物体重和肿瘤大小。实验组口服给药，每天给药一次或每周给药一次，连续给药三周，阳性药组每日口服给药一次RMC4550，连续给药三周。 When the average tumor volume reached about 120 mm 3 , the animals were divided into groups using random block method, with 8 mice in each group. Day 0 was recorded on the day of grouping, and medication was started according to the average body weight. Animal body weight and tumor size were measured twice a week during the experiment. The experimental group was orally administered once a day or once a week for three consecutive weeks, while the positive drug group was orally administered RMC4550 once a day for three consecutive weeks.
本研究中，实验数据均以MEAN±SEM表示。以时间点为X轴，肿瘤体积为Y轴绘制肿瘤生长曲线；以时间点为X轴，动物体重为Y轴绘制动物体重变化曲线。组间比较采用双尾t-检验，P<0.05为显著性差异，P<0.01为极显著差异。In this study, experimental data are expressed as MEAN ± SEM. Draw the tumor growth curve with the time point as the X-axis and the tumor volume as the Y-axis; draw the animal weight change curve with the time point as the X-axis and the animal weight as the Y-axis. Two-tailed t-test was used for comparison between groups, P<0.05 was considered a significant difference, and P<0.01 was considered a highly significant difference.
本次实验中，所有组动物状态良好，体重无明显改变，未出现动物死亡，给药周期中，动物对各受试物均能耐受。In this experiment, the animals in all groups were in good condition, with no significant change in body weight and no animal death. During the dosing cycle, the animals were able to tolerate each test substance.
实验结果显示，与空白溶剂对照组相比，各给药组的肿瘤重量显著降低。RG001 1mg/kg,2mg/kg,4mg/kg组，每天口服给药，给药21天，1mg/kg,2mg/kg,对瘤重的抑制率分别为67.13％，93.72％；4mg/kg组肿瘤完全消退；RG001的14mg/kg组，每周给药一次，共给药三次，瘤重的抑制率88.46％。阳性对照RMC4550 15mg/kg组，每天给药，给药21天，对瘤重的抑制率88.37％。具体结果见图27。图27中*对应P<0.05，**对应P<0.01，**对应P<0.001。The experimental results showed that compared with the blank solvent control group, the tumor weight of each administration group was significantly reduced. RG001 1mg/kg, 2mg/kg, 4mg/kg group, oral administration every day for 21 days, 1mg/kg, 2mg/kg, the inhibition rate of tumor weight was 67.13%, 93.72% respectively; 4mg/kg group The tumor completely regressed; in the 14 mg/kg group of RG001, the tumor weight inhibition rate was 88.46% when administered once a week for three times in total. The positive control RMC4550 15mg/kg group was administered every day for 21 days, and the inhibition rate of tumor weight was 88.37%. The specific results are shown in Figure 27. In Figure 27, * corresponds to P<0.05, ** corresponds to P<0.01, and ** corresponds to P<0.001.
与空白溶剂对照组相比，各给药组的对肿瘤均有显著抑制。RG001的1mg/kg,2mg/kg,4mg/kg组，每天口服给药，连续给药21天，1mg/kg,2mg/kg剂量组的相对肿瘤增值率T/C分别为33.22％，6.81％；4mg/kg组肿瘤完全消退；RG001的14mg/kg组，每周给药一次，共给药三次，第21天的T/C为12.95％。阳性对照RMC4550 15mg/kg组，每天口服给药，连续给药21天，第21天时T/C为8.94％。具体结果见图26。Compared with the blank solvent control group, each administration group had significant tumor inhibition. The 1 mg/kg, 2 mg/kg, and 4 mg/kg groups of RG001 were administered orally every day for 21 consecutive days. The relative tumor proliferation rates T/C of the 1 mg/kg and 2 mg/kg dosage groups were 33.22% and 6.81% respectively. ; The tumors in the 4 mg/kg group completely regressed; the 14 mg/kg group of RG001 was administered once a week for a total of three times, and the T/C on the 21st day was 12.95%. The positive control RMC4550 15mg/kg group was administered orally every day for 21 consecutive days, and the T/C was 8.94% on the 21st day. The specific results are shown in Figure 26.
实验三 Experiment 3
动物：Balb/c裸小鼠，雌性，体重17-19g，由浙江维通利华实验动物技术有限公司提供；SPF级饲养，温度20-26℃，湿度40-70％，自由进食，城市自来水经过滤高压灭菌后饮用。实验前给予小鼠不低7天的适应性饲养.Animals: Balb/c nude mice, female, weighing 17-19g, provided by Zhejiang Weitong Lihua Experimental Animal Technology Co., Ltd.; raised at SPF level, temperature 20-26°C, humidity 40-70%, free access to food, city tap water Filter and autoclave before drinking. Mice were given adaptive feeding for at least 7 days before the experiment.
给药溶液配置：受试物RG001(式(IV)所示化合物A晶型)溶媒为1％的HPMC。 受试物给药溶液现用现配，2-8℃，避光保存。Preparation of dosing solution: The test substance RG001 (crystalline form of compound A represented by formula (IV)) is 1% HPMC. The test substance administration solution should be prepared freshly before use, and stored at 2-8°C, protected from light.
人癌细胞株：人胰腺癌细胞株Mia PaCa-2由ATCC(American Type Culture Collection,USA)提供。Human cancer cell line: Human pancreatic cancer cell line Mia PaCa-2 was provided by ATCC (American Type Culture Collection, USA).
培养基：DMEM基础培养基和胎牛血清(FBS)均购自于美国GIBCO公司(Grand Island,NY,USA)。Medium: DMEM basic medium and fetal bovine serum (FBS) were purchased from GIBCO (Grand Island, NY, USA).
肿瘤移植实验及检测：Mia PaCa-2细胞培养于含10％FBS的DMEM培养基中，细胞放置Tumor transplantation experiments and detection: Mia PaCa-2 cells were cultured in DMEM medium containing 10% FBS, and the cells were placed
于5％CO 2培养箱中37℃培养。收集对数生长期的NCI-H358细胞，计数后重悬于DMEM基础培养基中，1：1加入Matrigel，调整细胞悬液浓度，在无菌条件下，接种0.1mL细胞悬液至小鼠右侧背部皮下。 Culture at 37°C in a 5% CO2 incubator. Collect NCI-H358 cells in the logarithmic growth phase, count them and resuspend them in DMEM basic medium. Add Matrigel at a ratio of 1:1 to adjust the cell suspension concentration. Under sterile conditions, inoculate 0.1 mL of cell suspension into the right side of the mouse. Side and back subcutaneously.
待肿瘤平均体积达120mm 3左右时，采用随机区组法将动物分组，每组8只小鼠。分组当日记Day0，并按照平均体重开始给药，实验周期28天。实验期间每周测定两次动物体重和肿瘤大小。式(IV)所示化合物A晶型组口服给药，每天给药一次或每周给药一次，连续给药四周，阳性药组每日口服给药一次RMC4550，连续给药四周。 When the average tumor volume reached about 120 mm 3 , the animals were divided into groups using random block method, with 8 mice in each group. The group was divided into groups on Day 0, and medication was started according to the average body weight. The experimental period was 28 days. Animal body weight and tumor size were measured twice a week during the experiment. The compound A crystal form group represented by formula (IV) is orally administered once a day or once a week for four consecutive weeks, and the positive drug group is orally administered RMC4550 once a day for four consecutive weeks.
本研究中，实验数据均以MEAN±SEM表示。以时间点为X轴，肿瘤体积为Y轴绘制肿瘤生长曲线；以时间点为X轴，动物体重为Y轴绘制动物体重变化曲线。组间比较采用双尾t-检验，P<0.05为显著性差异，P<0.01为极显著差异。In this study, experimental data are expressed as MEAN ± SEM. Draw the tumor growth curve with the time point as the X-axis and the tumor volume as the Y-axis; draw the animal weight change curve with the time point as the X-axis and the animal weight as the Y-axis. Two-tailed t-test was used for comparison between groups, P<0.05 was considered a significant difference, and P<0.01 was considered a highly significant difference.
本次实验中，所有组动物状态良好，体重无明显改变，未出现动物死亡，给药周期中，动物对各受试物均能耐受。In this experiment, the animals in all groups were in good condition, with no significant change in body weight and no animal death. During the dosing cycle, the animals were able to tolerate each test substance.
实验结果显示，与空白溶剂对照组相比，各给药组的肿瘤重量显著降低。RG001的1mg/kg,2mg/kg,4mg/kg组，每天口服给药，连续给药28天，各剂量组对瘤重的抑制率分别为76.36％，79.08％，81.66％；RG001的14mg/kg组，每周给药一次，共给药四次，瘤重的抑制率69.16％。阳性对照RMC4550 15mg/kg组，每天给药，给药28天，对瘤重的抑制率78.53％。具体结果见图29。图29中*对应P<0.05，**对应P<0.01，**对应P<0.001。The experimental results showed that compared with the blank solvent control group, the tumor weight of each administration group was significantly reduced. The 1 mg/kg, 2 mg/kg, and 4 mg/kg groups of RG001 were administered orally every day for 28 consecutive days. The inhibition rates of tumor weight in each dose group were 76.36%, 79.08%, and 81.66% respectively; the 14 mg/kg group of RG001 kg group, administered once a week for four times in total, the tumor weight inhibition rate was 69.16%. The positive control RMC4550 15mg/kg group was administered every day for 28 days, and the inhibition rate of tumor weight was 78.53%. The specific results are shown in Figure 29. In Figure 29, * corresponds to P<0.05, ** corresponds to P<0.01, and ** corresponds to P<0.001.
与空白溶剂对照组相比，各给药组的对肿瘤均有显著抑制。RG001的1mg/kg,2mg/kg,4mg/kg组，每天口服给药，连续给药28天，各剂量组的相对肿瘤增值率T/C分别为27.61％，20.55％，16.75％；RG001的14mg/kg组，每周给药一次，共给药四次，第28天的T/C为30.77％。阳性对照RMC4550 15mg/kg组，每天口服给药，连续给药28天，第28天时T/C为20.02％。具体结果见图28。Compared with the blank solvent control group, each administration group had significant tumor inhibition. The 1 mg/kg, 2 mg/kg, and 4 mg/kg groups of RG001 were administered orally every day for 28 consecutive days. The relative tumor proliferation rates T/C of each dose group were 27.61%, 20.55%, and 16.75% respectively; The 14 mg/kg group was administered once a week for a total of four times, and the T/C on the 28th day was 30.77%. The positive control RMC4550 15mg/kg group was administered orally every day for 28 consecutive days, and the T/C was 20.02% on the 28th day. The specific results are shown in Figure 28.
实施例十一：式(I)所示化合物A晶型、式(III)所示化合物A晶型和式(IV)所示化合物A晶型的药代动力学实验Example 11: Pharmacokinetic experiments on the crystal form of compound A represented by formula (I), the crystal form of compound A represented by formula (III) and the crystal form of compound A represented by formula (IV)
药品和试剂：本研究所使用的(S)-1'-(8-((((2-氨基-3-氯吡啶基-4-基)硫代)-7-甲基咪唑并[1,2-c]嘧啶-5-基)-1,3-二氢螺[茚-2,4'-哌啶]-1-胺A晶型(即式(I)所示化合物A晶型)、式(III)所示化合物A晶型、式(IV)所示化合物A晶型被研磨成细颗粒。材料的含量(纯度)不低于95.0％。Drugs and reagents: (S)-1'-(8-((((2-amino-3-chloropyridyl-4-yl)thio)-7-methylimidazo[1, 2-c]pyrimidin-5-yl)-1,3-dihydrospiro[indene-2,4'-piperidine]-1-amine crystal form A (i.e., compound A crystal form represented by formula (I)), The crystal form of compound A represented by formula (III) and the crystal form of compound A represented by formula (IV) are ground into fine particles. The content (purity) of the material is not less than 95.0%.
试验动物：SPF级SD大鼠被分为式(I)所示化合物组和式(I)所示化合物的各个盐型组，每组包括3只雄鼠。Test animals: SPF grade SD rats were divided into the compound group represented by formula (I) and each salt form group of the compound represented by formula (I). Each group included 3 male rats.
药物配制：给药当天配制。Medication preparation: Prepare on the day of administration.
首先是溶媒制剂制备：量取需要量的去离子水到合适容器中，称取需要量HPMC加入并搅拌混合至均一，得无色澄清的1％HPMC溶液。The first step is to prepare the solvent preparation: measure the required amount of deionized water into a suitable container, weigh the required amount of HPMC, add it and mix until uniform to obtain a colorless and clear 1% HPMC solution.
称取所需量化合物至合适容器中，再加入适量1％HPMC溶液，搅拌至均一，再加入1％HPMC溶液至指定体积，搅拌均一，得类白色混悬液。最终各化合物浓度为0.5mg/mL。Weigh the required amount of compound into a suitable container, then add an appropriate amount of 1% HPMC solution, stir until uniform, then add 1% HPMC solution to the specified volume, stir uniformly, and obtain an off-white suspension. The final concentration of each compound was 0.5 mg/mL.
给药和样品收集：各悬浮液以10mL/kg的剂量体积，给药剂量5mg/kg口服给药于SD大鼠，口服给药组动物给药前禁食过夜(10-16小时)，给药4小时后给食。给药前(0h)和给药后0.25h，0.5h，1h，2h，4h，6h,8h，24h，经颈静脉采血，每个样品采集约0.20mL，K2EDTA抗凝，采集后放置冰上，并于1小时之内离心分离血浆(离心条件：6800g，6分钟，2-8℃)。血浆样本保存在-80℃条件下以备分析使用。Administration and sample collection: Each suspension was orally administered to SD rats with a dosage volume of 10 mL/kg and a dosage of 5 mg/kg. The animals in the oral administration group were fasted overnight (10-16 hours) before administration. Give food 4 hours after the medicine. Before administration (0h) and at 0.25h, 0.5h, 1h, 2h, 4h, 6h, 8h, 24h after administration, blood was collected through the jugular vein. Each sample was collected about 0.20mL. Anticoagulated with K2EDTA and placed on ice after collection. , and centrifuge to separate the plasma within 1 hour (centrifugation conditions: 6800g, 6 minutes, 2-8°C). Plasma samples were stored at -80°C until analysis.
将血液样品采集于EDTA-K的预抗凝管中。4℃下，经每分钟4000转的转速离心10min分离出样品中的血浆。收集血浆样品并保存在-80℃条件下以备分析使用。样品通过TQ5500LC/MS结合HPLC分析。液相色谱条件下利用ACQUITY UPLC HSS T3 1.8um(2.1*50mm)的色谱柱作为固定相，用0.1％的甲酸乙腈溶液作为流动相。具体实验结果如表9所示：Blood samples were collected in EDTA-K pre-anticoagulated tubes. The plasma in the sample was separated by centrifugation at 4000 rpm for 10 min at 4°C. Plasma samples were collected and stored at -80°C until analysis. Samples were analyzed by TQ5500LC/MS combined with HPLC. Under liquid chromatography conditions, an ACQUITY UPLC HSS T3 1.8um (2.1*50mm) chromatographic column was used as the stationary phase, and 0.1% formic acid acetonitrile solution was used as the mobile phase. The specific experimental results are shown in Table 9:
表9Table 9
Figure PCTCN2022096702-appb-000037
Figure PCTCN2022096702-appb-000037
Figure PCTCN2022096702-appb-000038
Figure PCTCN2022096702-appb-000038
实验结果可以看出：式(IV)所示化合物A晶型和式(III)所示化合物A晶型相对于式(I)所示化合物A晶型均表现出更优良的代谢性质，暴露量和最大血药浓度都有较大提高。It can be seen from the experimental results that the crystal form of compound A shown in formula (IV) and the crystal form of compound A shown in formula (III) both show better metabolic properties than the crystal form of compound A shown in formula (I), and the exposure amount and maximum plasma concentration were greatly improved.
实施例十二：片剂的制备方法Example 12: Preparation method of tablets
片剂的制备配方如表10所示：The preparation formula of tablets is shown in Table 10:
表10Table 10
Figure PCTCN2022096702-appb-000039
Figure PCTCN2022096702-appb-000039
1此处API特指式(IV)所示化合物A晶型。 1API here specifically refers to the crystal form A of the compound represented by formula (IV).
所述片剂的制备流程如下：The preparation process of the tablets is as follows:
1)原辅料预处理1) Pretreatment of raw materials and auxiliary materials
将API以及其余辅料过40目筛网，防止结块。Pass the API and other excipients through a 40-mesh screen to prevent clumping.
2)配料2) Ingredients
按批处方物料信息，称取原辅料备用。According to the batch prescription material information, weigh the raw and auxiliary materials for later use.
3)过筛、预混3) Sifting and premixing
0.25mg和2mg规格同时进行混合：0.25mg and 2mg specifications are mixed at the same time:
将大部分胶态二氧化硅(4/5)与部分微晶纤维素(3/5)以200rpm～300rpm转速混合过筛经1.0mm圆孔筛网过粉碎整粒机1次，作为混合物一；Mix most of the colloidal silica (4/5) and part of the microcrystalline cellulose (3/5) at a rotation speed of 200rpm to 300rpm, pass through a 1.0mm round hole screen into a grinding and granulating machine once, and use it as a mixture. ;
式(IV)所示化合物A晶型与等体积胶态二氧化硅以200rpm～300rpm转速混合过 筛经1.0mm圆孔筛网过粉碎整粒机1次，在与剩余胶态二氧化硅以200rpm～300rpm转速混合过筛经1.0mm圆孔筛网过粉碎整粒机1次，作为预混合物二；The crystal form of the compound A represented by formula (IV) and an equal volume of colloidal silica are mixed and sieved at a rotation speed of 200rpm to 300rpm, passed through a 1.0mm round hole screen and passed through a crushing and granulating machine once, and then mixed with the remaining colloidal silica. Mix and sieve at 200rpm~300rpm through a 1.0mm round hole screen and pass through the grinding and granulating machine once to be used as premix 2;
将混合物一、混合物二、交联聚维酮以及剩余微晶纤维素转移至料斗混合机中，设置转速15rpm，混合30min。 Transfer mixture 1, mixture 2, crospovidone and remaining microcrystalline cellulose to the hopper mixer, set the rotation speed to 15 rpm, and mix for 30 minutes.
4)总混4)Total mix
称取处方量硬脂酸镁加入预混物料中，设置转速15rpm，混合5min。总混结束后分别在混合机料斗内物料的上、中、下三层共取10个点测定混合均匀度，其中每层取样点数分别为5个、4个、1个。Weigh the prescribed amount of magnesium stearate and add it to the premixed materials, set the rotation speed to 15 rpm, and mix for 5 minutes. After the general mixing is completed, a total of 10 points are taken from the upper, middle and lower layers of the material in the mixer hopper to measure the mixing uniformity. The number of sampling points in each layer is 5, 4 and 1 respectively.
5)压片5) Tablet pressing
检测得到的总混合物料的混合均匀度在95.0～105.0％范围内，符合中间体质量标准，理论片重即为标示量片重。The tested mixing uniformity of the total mixed material is in the range of 95.0 to 105.0%, which meets the quality standards of the intermediate. The theoretical tablet weight is the indicated tablet weight.
0.25mg规格压片：0.25mg tablet size:
压片时采用ZP10A旋转压片机，5.5mm圆形浅凹冲，设置转台转速为15～25rpm，饲料速度为10rpm～15rpm，要求片重差异为±7％，控制片子硬度在30～60N。The ZP10A rotary tablet press is used for tableting, with a 5.5mm circular shallow concave punch. The turntable speed is set to 15-25rpm, the feed speed is 10rpm-15rpm, the tablet weight difference is required to be ±7%, and the tablet hardness is controlled to be 30-60N.
2mg规格压片：2mg tablet size:
压片时采用ZP10A旋转压片机，11mm圆形浅凹冲，设置转台转速为15～25rpm，饲料速度为15rpm～20rpm，要求片重差异为±5％，控制片子硬度在70～100N。The ZP10A rotary tablet press is used for tableting, with 11mm circular shallow concave punching. The turntable speed is set to 15-25rpm, the feed speed is 15rpm-20rpm, the tablet weight difference is required to be ±5%, and the tablet hardness is controlled to be 70-100N.
6)包装6)Packaging
包材为口服固体药用高密度聚乙烯瓶和口服固体药用聚丙烯-低密度聚乙烯儿童安全防潮组合瓶盖。The packaging materials are oral solid pharmaceutical high-density polyethylene bottles and oral solid pharmaceutical polypropylene-low-density polyethylene child-safe and moisture-proof combination bottle caps.
本领域的技术人员应当明了，尽管为了举例说明的目的，本文描述了本发明的具体实施方式，但可以对其进行各种修改而不偏离本发明的精神和范围。因此，本发明的具体实施方式和实施例不应当视为限制本发明的范围。本发明仅受所附权利要求的限制。本申请中引用的所有文献均完整地并入本文作为参考。It will be apparent to those skilled in the art that, although specific embodiments of the invention are described herein for purposes of illustration, various modifications may be made without departing from the spirit and scope of the invention. Therefore, the detailed description and examples of the present invention should not be considered as limiting the scope of the present invention. The invention is limited only by the appended claims. All documents cited in this application are incorporated by reference in their entirety.

Claims (9)

  1. 一种化合物或其晶型，所述化合物如式(II)所示；A compound or its crystal form, the compound is represented by formula (II);
    Figure PCTCN2022096702-appb-100001
    Figure PCTCN2022096702-appb-100001
    其中，式(II)中所述M为柠檬酸、甲磺酸、H 2SO 4、丁二酸、HCl、HNO 3、HBr、HF、HI、磷酸、2,5-二羟基苯甲酸、1-羟基-2-萘甲酸、醋酸、二氯醋酸、三氯醋酸、乙酰氧肟酸、己二酸、苯磺酸、4-氯苯磺酸、苯甲酸、4-乙酰氨基苯甲酸、4-氨基苯甲酸、癸酸、己酸、辛酸、肉桂酸、环己烷氨基磺酸、樟脑磺酸、天门冬氨酸、樟脑酸、葡萄糖酸、葡糖醛酸、谷氨酸、异抗坏血酸、乳酸、苹果酸、扁桃酸、焦谷氨酸、酒石酸、十二烷基硫酸、二苯甲酰酒石酸、乙烷-1,2-二磺酸、乙磺酸、蚁酸、富马酸、半乳糖酸、龙胆酸、戊二酸、2-酮戊二酸、乙醇酸、马尿酸、羟乙基磺酸、乳糖酸、抗坏血酸、天冬氨酸、月桂酸、樟脑酸、马来酸、丙二酸、1,5-萘二磺酸、萘-2-磺酸、烟酸、油酸、乳清酸、草酸、棕榈酸、双羟萘酸、丙酸、水杨酸、4-氨基水杨酸、癸二酸、硬脂酸、硫氰酸、十一碳烯酸、三氟乙酸、苯磺酸、对甲基苯磺酸和L-苹果酸；优选柠檬酸、甲磺酸、H 2SO 4、丁二酸、HCl、HNO 3、苯磺酸、马来酸、己二酸、对甲基苯磺酸、丙二酸和L-苹果酸、抗坏血酸、水杨酸、2-乙酸基苯甲酸、烟酸、异烟酸、胆酸、天冬氨酸或谷氨酸； Wherein, M in formula (II) is citric acid, methanesulfonic acid, H 2 SO 4 , succinic acid, HCl, HNO 3 , HBr, HF, HI, phosphoric acid, 2,5-dihydroxybenzoic acid, 1 -Hydroxy-2-naphthoic acid, acetic acid, dichloroacetic acid, trichloroacetic acid, acetohydroxamic acid, adipic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, benzoic acid, 4-acetamidobenzoic acid, 4- Aminobenzoic acid, capric acid, caproic acid, caprylic acid, cinnamic acid, cyclohexane sulfamate, camphorsulfonic acid, aspartic acid, camphoric acid, gluconic acid, glucuronic acid, glutamic acid, erythorbic acid, lactic acid , malic acid, mandelic acid, pyroglutamic acid, tartaric acid, dodecyl sulfate, dibenzoyltartaric acid, ethane-1,2-disulfonic acid, ethanesulfonic acid, formic acid, fumaric acid, galactose Acid, gentisic acid, glutaric acid, 2-oxoglutaric acid, glycolic acid, hippuric acid, isethionic acid, lactobionic acid, ascorbic acid, aspartic acid, lauric acid, camphoric acid, maleic acid, propionic acid Diacid, 1,5-naphthalenedisulfonic acid, naphthalene-2-sulfonic acid, nicotinic acid, oleic acid, orotic acid, oxalic acid, palmitic acid, pamoic acid, propionic acid, salicylic acid, 4-amino acid Cylic acid, sebacic acid, stearic acid, thiocyanic acid, undecenoic acid, trifluoroacetic acid, benzenesulfonic acid, p-toluenesulfonic acid and L-malic acid; preferably citric acid, methanesulfonic acid, H 2 SO 4 , succinic acid, HCl, HNO 3 , benzenesulfonic acid, maleic acid, adipic acid, p-toluenesulfonic acid, malonic acid and L-malic acid, ascorbic acid, salicylic acid, 2-acetic acid benzoic acid, nicotinic acid, isonicotinic acid, cholic acid, aspartic acid or glutamic acid;
    x为0、0.5、1、1.5、2、2.5或3；x is 0, 0.5, 1, 1.5, 2, 2.5 or 3;
    y为0、1、2或3；y is 0, 1, 2 or 3;
    x和y不同时为0。x and y are not 0 at the same time.
  2. 如权利要求1所述的化合物或其晶型，所述化合物如式(IV)、(III)、(V)或(VI)所示；The compound or its crystal form according to claim 1, said compound is represented by formula (IV), (III), (V) or (VI);
    Figure PCTCN2022096702-appb-100002
    Figure PCTCN2022096702-appb-100002
    Figure PCTCN2022096702-appb-100003
    Figure PCTCN2022096702-appb-100003
  3. 一种晶型，其为式(IV)所示化合物的A晶型、式(III)所示化合物的A晶型、式(V)所示化合物的A晶型、式(VI)所示化合物的A晶型或式(I)所示化合物的B晶型；A crystal form, which is crystal form A of the compound represented by formula (IV), crystal form A of the compound represented by formula (III), crystal form A of the compound represented by formula (V), or the compound represented by formula (VI) The A crystal form or the B crystal form of the compound represented by formula (I);
    Figure PCTCN2022096702-appb-100004
    Figure PCTCN2022096702-appb-100004
    Figure PCTCN2022096702-appb-100005
    Figure PCTCN2022096702-appb-100005
    其中，所述式(IV)所示化合物的A晶型的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：9.5±0.2°、11.5±0.2°、11.8±0.2°、3.5±0.2°、14.1±0.2°、16.3±0.2°、18.0±0.2°20.7±0.2°和25.1±0.2°；Among them, the X-ray powder diffraction pattern of the A crystal form of the compound represented by formula (IV) has characteristic diffraction peaks at the following 2θ angles: 9.5±0.2°, 11.5±0.2°, 11.8±0.2°, 3.5±0.2° , 14.1±0.2°, 16.3±0.2°, 18.0±0.2°, 20.7±0.2° and 25.1±0.2°;
    所述式(III)所示化合物的A晶型的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：10.2±0.2°、12.2±0.2°、15.9±0.2°、17.2±0.2°、18.6±0.2°和19.5±0.2°；The X-ray powder diffraction pattern of the A crystal form of the compound represented by formula (III) has characteristic diffraction peaks at the following 2θ angles: 10.2±0.2°, 12.2±0.2°, 15.9±0.2°, 17.2±0.2°, 18.6 ±0.2° and 19.5±0.2°;
    所述式(V)所示化合物的A晶型的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：10.02±0.2°、16.06±0.2°、16.58±0.2°、21.96±0.2°、24.38±0.2°和24.96±0.2°；The X-ray powder diffraction pattern of the A crystal form of the compound represented by formula (V) has characteristic diffraction peaks at the following 2θ angles: 10.02±0.2°, 16.06±0.2°, 16.58±0.2°, 21.96±0.2°, 24.38 ±0.2° and 24.96±0.2°;
    所述式(VI)所示化合物的A晶型的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：317.32±0.2°、18.16±0.2°、20.62±0.2°、20.86±0.2°、22.46±0.2°、24.00±0.2°、24.34±0.2°和25.02±0.2°；The X-ray powder diffraction pattern of the A crystal form of the compound represented by formula (VI) has characteristic diffraction peaks at the following 2θ angles: 317.32±0.2°, 18.16±0.2°, 20.62±0.2°, 20.86±0.2°, 22.46 ±0.2°, 24.00±0.2°, 24.34±0.2° and 25.02±0.2°;
    所述式(I)所示化合物的B晶型的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：14.2±0.2°、12.53±0.2°、17.44±0.2°、17.76±0.2°、19.88±0.2°和22.54±0.2°。The X-ray powder diffraction pattern of the B crystal form of the compound represented by the formula (I) has characteristic diffraction peaks at the following 2θ angles: 14.2±0.2°, 12.53±0.2°, 17.44±0.2°, 17.76±0.2°, 19.88 ±0.2° and 22.54±0.2°.
  4. 如权利要求3所述的晶型，其特征在于，所述式(I)所示化合物B晶型的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：14.2±0.2°、12.53±0.2°、17.44±0.2°、17.76±0.2°、19.88±0.2°、22.54±0.2°、11.50±0.2°、16.52±0.2°、19.52±0.2°、20.17±0.2°、21.27±0.2°、23.44±0.2°、24.24±0.2°、和24.96±0.2°；The crystal form according to claim 3, characterized in that the X-ray powder diffraction pattern of the compound B crystal form represented by the formula (I) has characteristic diffraction peaks at the following 2θ angles: 14.2±0.2°, 12.53±0.2 °, 17.44±0.2°, 17.76±0.2°, 19.88±0.2°, 22.54±0.2°, 11.50±0.2°, 16.52±0.2°, 19.52±0.2°, 20.17±0.2°, 21.27±0.2°, 23.44±0.2 °, 24.24±0.2°, and 24.96±0.2°;
    和/或，所述式(I)所示化合物B晶型的差示扫描量热(DSC)曲线在207.09℃处具有吸热峰；And/or, the differential scanning calorimetry (DSC) curve of the crystal form B of the compound represented by formula (I) has an endothermic peak at 207.09°C;
    和/或，所述式(I)所示化合物B晶型的热重分析(TGA)曲线显示在室温至112.39℃失重0.41％，室温至224.70℃失重0.66％；And/or, the thermogravimetric analysis (TGA) curve of the crystal form B of the compound represented by formula (I) shows a weight loss of 0.41% from room temperature to 112.39°C, and a weight loss of 0.66% from room temperature to 224.70°C;
    和/或，所述式(III)所示化合物的A晶型的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：10.2±0.2°、11.0±0.2°、12.2±0.2°、13.4±0.2°、13.9±0.2°、14.4±0.2°、15.9±0.2°、16.9±0.2°、17.2±0.2°、18.6±0.2°、19.5±0.2°、20.2±0.2°、20.7±0.2°、21.5±0.2°、22.5±0.2°、22.9±0.2°、24.5±0.2°、25.0±0.2°、25.5±0.2°、27.2±0.2°、28.6±0.2°、28.7±0.2°、29.6±0.2°、30.1±0.2°和30.5±0.2°；And/or, the X-ray powder diffraction pattern of the A crystal form of the compound represented by formula (III) has characteristic diffraction peaks at the following 2θ angles: 10.2±0.2°, 11.0±0.2°, 12.2±0.2°, 13.4± 0.2°, 13.9±0.2°, 14.4±0.2°, 15.9±0.2°, 16.9±0.2°, 17.2±0.2°, 18.6±0.2°, 19.5±0.2°, 20.2±0.2°, 20.7±0.2°, 21.5± 0.2°, 22.5±0.2°, 22.9±0.2°, 24.5±0.2°, 25.0±0.2°, 25.5±0.2°, 27.2±0.2°, 28.6±0.2°, 28.7±0.2°, 29.6±0.2°, 30.1± 0.2° and 30.5±0.2°;
    和/或，所述式(III)所示化合物的A晶型的差示扫描量热(DSC)曲线在50.39℃和204.24℃处具有吸热峰；And/or, the differential scanning calorimetry (DSC) curve of the A crystal form of the compound represented by formula (III) has endothermic peaks at 50.39°C and 204.24°C;
    和/或，所述式(III)所示化合物的A晶型的热重分析(TGA)曲线显示在室温至87℃失重3.5％；And/or, the thermogravimetric analysis (TGA) curve of the A crystal form of the compound represented by formula (III) shows a weight loss of 3.5% from room temperature to 87°C;
    和/或，所述式(IV)所示化合物的A晶型的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：9.5±0.2°、10.3±0.2°、11.5±0.2°、11.8±0.2°、12.2±0.2°、12.9±0.2°、13.5±0.2°、14.1±0.2°、15.7±0.2°、16.3±0.2°、17.0±0.2°、18.0±0.2°、18.6±0.2°、20.7±0.2°、21.1±0.2°、22.2±0.2°、23.2±0.2°、23.8±0.2°、24.5±0.2°、24.8±0.2°、25.1±0.2°、26.2±0.2°、28.7±0.2°、29.4±0.2°、29.7±0.2°、30.5±0.2°、31.8±0.2°、32.3±0.2°、33.9±0.2°、34.6±0.2°、35.4±0.2°、36.5±0.2°和40.4±0.2°；And/or, the X-ray powder diffraction pattern of the A crystal form of the compound represented by formula (IV) has characteristic diffraction peaks at the following 2θ angles: 9.5±0.2°, 10.3±0.2°, 11.5±0.2°, 11.8± 0.2°, 12.2±0.2°, 12.9±0.2°, 13.5±0.2°, 14.1±0.2°, 15.7±0.2°, 16.3±0.2°, 17.0±0.2°, 18.0±0.2°, 18.6±0.2°, 20.7± 0.2°, 21.1±0.2°, 22.2±0.2°, 23.2±0.2°, 23.8±0.2°, 24.5±0.2°, 24.8±0.2°, 25.1±0.2°, 26.2±0.2°, 28.7±0.2°, 29.4± 0.2°, 29.7±0.2°, 30.5±0.2°, 31.8±0.2°, 32.3±0.2°, 33.9±0.2°, 34.6±0.2°, 35.4±0.2°, 36.5±0.2° and 40.4±0.2°;
    和/或，所述式(IV)所示化合物的A晶型的差示扫描量热(DSC)曲线在90.14℃、162.81℃和189.67℃处具有吸热峰；And/or, the differential scanning calorimetry (DSC) curve of the A crystal form of the compound represented by formula (IV) has endothermic peaks at 90.14°C, 162.81°C and 189.67°C;
    和/或，所述式(IV)所示化合物的A晶型的热重分析(TGA)曲线显示在室温至115℃失重3.64％；And/or, the thermogravimetric analysis (TGA) curve of the A crystal form of the compound represented by formula (IV) shows a weight loss of 3.64% from room temperature to 115°C;
    和/或，所述式(V)所示化合物的A晶型的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：9.70±0.2°、10.02±0.2°、10.80±0.2°、11.84±0.2°、13.38±0.2°、14.14±0.2°、15.18±0.2°、14.1±0.2°、16.06±0.2°、16.58±0.2°、17.16±0.2°、18.36±0.2°、19.54±0.2°、21.96±0.2°、22.40±0.2°、23.80±0.2°、24.38±0.2°、24.96±0.2°、27.02±0.2°、27.63±0.2°、28.74±0.2°、30.30±0.2°、32.08±0.2°、33.67±0.2°和34.47±0.2°；And/or, the X-ray powder diffraction pattern of the A crystal form of the compound represented by formula (V) has characteristic diffraction peaks at the following 2θ angles: 9.70±0.2°, 10.02±0.2°, 10.80±0.2°, 11.84± 0.2°, 13.38±0.2°, 14.14±0.2°, 15.18±0.2°, 14.1±0.2°, 16.06±0.2°, 16.58±0.2°, 17.16±0.2°, 18.36±0.2°, 19.54±0.2°, 21.96± 0.2°, 22.40±0.2°, 23.80±0.2°, 24.38±0.2°, 24.96±0.2°, 27.02±0.2°, 27.63±0.2°, 28.74±0.2°, 30.30±0.2°, 32.08±0.2°, 33.67± 0.2° and 34.47±0.2°;
    和/或，所述式(V)所示化合物的A晶型的差示扫描量热(DSC)曲线在51.72℃和223℃处具有吸热峰；And/or, the differential scanning calorimetry (DSC) curve of the A crystal form of the compound represented by formula (V) has endothermic peaks at 51.72°C and 223°C;
    和/或，所述式(V)所示化合物的A晶型的热重分析(TGA)曲线显示在室温至85℃ 失重3.37％；And/or, the thermogravimetric analysis (TGA) curve of the A crystal form of the compound represented by formula (V) shows a weight loss of 3.37% from room temperature to 85°C;
    和/或，所述式(VI)所示化合物的A晶型的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：9.10±0.2°、11.06±0.2°、11.46±0.2°、13.46±0.2°、14.34±0.2°、15.50±0.2°、16.63±0.2°、16.96±0.2°、17.32±0.2°、18.16±0.2°、19.08±0.2°、20.62±0.2°、20.86±0.2°、22.46±0.2°、23.36±0.2°、24.00±0.2°、24.34±0.2°、25.02±0.2°、25.92±0.2°、26.28±0.2°、27.84±0.2°、28.10±0.2°、28.88±0.2°、30.45±0.2°；And/or, the X-ray powder diffraction pattern of the A crystal form of the compound represented by formula (VI) has characteristic diffraction peaks at the following 2θ angles: 9.10±0.2°, 11.06±0.2°, 11.46±0.2°, 13.46± 0.2°, 14.34±0.2°, 15.50±0.2°, 16.63±0.2°, 16.96±0.2°, 17.32±0.2°, 18.16±0.2°, 19.08±0.2°, 20.62±0.2°, 20.86±0.2°, 22.46± 0.2°, 23.36±0.2°, 24.00±0.2°, 24.34±0.2°, 25.02±0.2°, 25.92±0.2°, 26.28±0.2°, 27.84±0.2°, 28.10±0.2°, 28.88±0.2°, 30.45± 0.2°;
    和/或，所述式(VI)所示化合物的A晶型的差示扫描量热(DSC)曲线在164.53℃处具有吸热峰；And/or, the differential scanning calorimetry (DSC) curve of the A crystal form of the compound represented by formula (VI) has an endothermic peak at 164.53°C;
    和/或，所述式(VI)所示化合物的A晶型的热重分析(TGA)曲线显示在室温至100℃失重1.42％。And/or, the thermogravimetric analysis (TGA) curve of the A crystal form of the compound represented by formula (VI) shows a weight loss of 1.42% from room temperature to 100°C.
  5. 如权利要求4所述的晶型，其特征在于，所述式(I)所示化合物B晶型的X射线粉末衍射图谱解析数据如表1所示；优选地，所述式(I)所示化合物B晶型的X射线粉末衍射图谱基本如图4所示；The crystal form according to claim 4, characterized in that the X-ray powder diffraction pattern analysis data of the compound B crystal form represented by the formula (I) is as shown in Table 1; preferably, the formula (I) represented by The X-ray powder diffraction pattern showing the crystal form of compound B is basically as shown in Figure 4;
    表1Table 1
    Figure PCTCN2022096702-appb-100006
    Figure PCTCN2022096702-appb-100006
    Figure PCTCN2022096702-appb-100007
    Figure PCTCN2022096702-appb-100007
    和/或，所述式(I)所示化合物B晶型的差示扫描量热(DSC)图谱如图5所示；And/or, the differential scanning calorimetry (DSC) spectrum of the crystal form B of the compound represented by the formula (I) is shown in Figure 5;
    和/或，所述式(I)所示化合物B晶型的热重分析(TGA)图谱如图6所示；And/or, the thermogravimetric analysis (TGA) spectrum of the compound B crystal form represented by the formula (I) is as shown in Figure 6;
    和/或，所述式(III)所示化合物的A晶型的X射线粉末衍射图谱解析数据如表2所示；优选地，所述式(III)所示化合物的A晶型的X射线粉末衍射图谱基本如图7所示；And/or, the X-ray powder diffraction pattern analysis data of the A crystal form of the compound represented by the formula (III) is shown in Table 2; preferably, the X-ray powder diffraction pattern analysis data of the A crystal form of the compound represented by the formula (III) The powder diffraction pattern is basically as shown in Figure 7;
    表2Table 2
    Figure PCTCN2022096702-appb-100008
    Figure PCTCN2022096702-appb-100008
    Figure PCTCN2022096702-appb-100009
    Figure PCTCN2022096702-appb-100009
    Figure PCTCN2022096702-appb-100010
    Figure PCTCN2022096702-appb-100010
    和/或，所述式(III)所示化合物的A晶型的差示扫描量热(DSC)图谱如图8所示；And/or, the differential scanning calorimetry (DSC) spectrum of the A crystal form of the compound represented by formula (III) is shown in Figure 8;
    和/或，所述式(III)所示化合物的A晶型的热重分析(TGA)图谱如图9所示；And/or, the thermogravimetric analysis (TGA) spectrum of the A crystal form of the compound represented by formula (III) is shown in Figure 9;
    和/或，所述式(IV)所示化合物的A晶型的X射线粉末衍射图谱解析数据如表3所示；优选地，所述式(IV)所示化合物的A晶型的X射线粉末衍射图谱基本如图10所示；And/or, the X-ray powder diffraction pattern analysis data of the A crystal form of the compound represented by the formula (IV) is shown in Table 3; preferably, the X-ray powder diffraction pattern analysis data of the A crystal form of the compound represented by the formula (IV) The powder diffraction pattern is basically as shown in Figure 10;
    表3table 3
    Figure PCTCN2022096702-appb-100011
    Figure PCTCN2022096702-appb-100011
    Figure PCTCN2022096702-appb-100012
    Figure PCTCN2022096702-appb-100012
    和/或，所述式(IV)所示化合物的A晶型的差示扫描量热(DSC)图谱如图11所示；And/or, the differential scanning calorimetry (DSC) spectrum of the A crystal form of the compound represented by formula (IV) is as shown in Figure 11;
    和/或，所述式(IV)所示化合物的A晶型的热重分析(TGA)图谱如图12所示；And/or, the thermogravimetric analysis (TGA) spectrum of the A crystal form of the compound represented by the formula (IV) is as shown in Figure 12;
    和/或，所述式(V)所示化合物的A晶型的X射线粉末衍射图谱解析数据如表4所示；优选地，所述式(V)所示化合物的A晶型的X射线粉末衍射图基本如图13所示；And/or, the X-ray powder diffraction pattern analysis data of the A crystal form of the compound represented by the formula (V) is shown in Table 4; preferably, the X-ray powder diffraction pattern analysis data of the A crystal form of the compound represented by the formula (V) The powder diffraction pattern is basically as shown in Figure 13;
    表4Table 4
    Figure PCTCN2022096702-appb-100013
    Figure PCTCN2022096702-appb-100013
    Figure PCTCN2022096702-appb-100014
    Figure PCTCN2022096702-appb-100014
    和/或，所述式(V)所示化合物的A晶型的差示扫描量热(DSC)图谱如图14所示；And/or, the differential scanning calorimetry (DSC) spectrum of the A crystal form of the compound represented by formula (V) is as shown in Figure 14;
    和/或，所述式(V)所示化合物的A晶型的热重分析(TGA)图谱如图15所示；And/or, the thermogravimetric analysis (TGA) spectrum of the A crystal form of the compound represented by the formula (V) is as shown in Figure 15;
    和/或，所述式(VI)所示化合物的A晶型的X射线粉末衍射图谱解析数据如表5所示；优选地，所述式(VI)所示化合物的A晶型的X射线粉末衍射图谱基本如图16所示；And/or, the X-ray powder diffraction pattern analysis data of the A crystal form of the compound represented by the formula (VI) is shown in Table 5; preferably, the X-ray powder diffraction pattern analysis data of the A crystal form of the compound represented by the formula (VI) The powder diffraction pattern is basically as shown in Figure 16;
    表5table 5
    Figure PCTCN2022096702-appb-100015
    Figure PCTCN2022096702-appb-100015
    Figure PCTCN2022096702-appb-100016
    Figure PCTCN2022096702-appb-100016
    Figure PCTCN2022096702-appb-100017
    Figure PCTCN2022096702-appb-100017
    和/或，所述式(VI)所示化合物的A晶型的差示扫描量热(DSC)图谱如图17所示；And/or, the differential scanning calorimetry (DSC) spectrum of the A crystal form of the compound represented by formula (VI) is as shown in Figure 17;
    和/或，所述式(VI)所示化合物的A晶型的热重分析(TGA)图谱如图18所示。And/or, the thermogravimetric analysis (TGA) spectrum of crystal form A of the compound represented by formula (VI) is shown in Figure 18.
  6. 一种如权利要求1所述的化合物或如权利要求3所述的晶型的制备方法，其特征在于：A method for preparing the compound as claimed in claim 1 or the crystal form as claimed in claim 3, characterized in that:
    式(II)所示化合物的制备方法包括如下步骤：将式(I)所示化合物和酸在溶剂中进行成盐反应，得到如式(II)所示的化合物，其中，式(II)中所述M为柠檬酸、甲磺酸、H 2SO 4、丁二酸、HCl、HNO 3、HBr、HF、HI、磷酸、2,5-二羟基苯甲酸、1-羟基-2-萘甲酸、醋酸、二氯醋酸、三氯醋酸、乙酰氧肟酸、己二酸、苯磺酸、4-氯苯磺酸、苯甲酸、4-乙酰氨基苯甲酸、4-氨基苯甲酸、癸酸、己酸、辛酸、肉桂酸、环己烷氨基磺酸、樟脑磺酸、天门冬氨酸、樟脑酸、葡萄糖酸、葡糖醛酸、谷氨酸、异抗坏血酸、乳酸、苹果酸、扁桃酸、焦谷氨酸、酒石酸、十二烷基硫酸、二苯甲酰酒石酸、乙烷-1,2-二磺酸、乙磺酸、蚁酸、富马酸、半乳糖酸、龙胆酸、戊二酸、2-酮戊二酸、乙醇酸、马尿酸、羟乙基磺酸、乳糖酸、抗坏血酸、天冬氨酸、月桂酸、樟脑酸、马来酸、丙二酸、1,5-萘二磺酸、萘-2-磺酸、烟酸、油酸、乳清酸、草酸、棕榈酸、双羟萘酸、丙酸、水杨酸、4-氨基水杨酸、癸二酸、硬脂酸、硫氰酸、十一碳烯酸、三氟乙酸、苯磺酸、对甲基苯磺酸和L-苹果酸；优选柠檬酸、甲磺酸、H 2SO 4、丁二酸、HCl、HNO 3、苯磺酸、马来酸、己二酸、对甲基苯磺酸、丙二酸和L-苹果酸、抗坏血酸、水杨酸、2-乙酸基苯甲酸、烟酸、异烟酸、胆酸、天冬氨酸或谷氨酸； The preparation method of the compound represented by formula (II) includes the following steps: performing a salt-forming reaction on the compound represented by formula (I) and an acid in a solvent to obtain a compound represented by formula (II), wherein, in formula (II) The M is citric acid, methanesulfonic acid, H 2 SO 4 , succinic acid, HCl, HNO 3 , HBr, HF, HI, phosphoric acid, 2,5-dihydroxybenzoic acid, 1-hydroxy-2-naphthoic acid , acetic acid, dichloroacetic acid, trichloroacetic acid, acetohydroxamic acid, adipic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, benzoic acid, 4-acetamidobenzoic acid, 4-aminobenzoic acid, capric acid, Caproic acid, caprylic acid, cinnamic acid, cyclohexane sulfamic acid, camphorsulfonic acid, aspartic acid, camphoric acid, gluconic acid, glucuronic acid, glutamic acid, erythorbic acid, lactic acid, malic acid, mandelic acid, Pyroglutamic acid, tartaric acid, dodecyl sulfate, dibenzoyltartaric acid, ethane-1,2-disulfonic acid, ethanesulfonic acid, formic acid, fumaric acid, galactonic acid, gentisic acid, pentanoic acid Diacid, 2-oxoglutaric acid, glycolic acid, hippuric acid, isethionic acid, lactobionic acid, ascorbic acid, aspartic acid, lauric acid, camphoric acid, maleic acid, malonic acid, 1,5- Naphthalenedisulfonic acid, naphthalene-2-sulfonic acid, niacin, oleic acid, orotic acid, oxalic acid, palmitic acid, pamoic acid, propionic acid, salicylic acid, 4-aminosalicylic acid, sebacic acid, Stearic acid, thiocyanic acid, undecenoic acid, trifluoroacetic acid, benzenesulfonic acid, p-toluenesulfonic acid and L-malic acid; preferably citric acid, methanesulfonic acid, H 2 SO 4 , succinic acid , HCl, HNO 3 , benzenesulfonic acid, maleic acid, adipic acid, p-toluenesulfonic acid, malonic acid and L-malic acid, ascorbic acid, salicylic acid, 2-acetoxybenzoic acid, nicotinic acid, isonicotinic acid, cholic acid, aspartic acid, or glutamic acid;
    式(I)所示化合物的B晶型的制备方法包括如下步骤：将式(I)所示化合物A晶型与乙腈混合后析晶，得到式(I)所示化合物B晶型；The preparation method of crystal form B of the compound represented by formula (I) includes the following steps: mixing crystal form A of the compound represented by formula (I) and acetonitrile and then crystallizing to obtain crystal form B of the compound represented by formula (I);
    式(III)所示化合物的A晶型的制备方法包括如下步骤：将式(I)所示化合物A晶型与二氧六环混合后，与甲磺酸甲醇溶液反应析晶，得到式(III)所示化合物A晶型；The preparation method of crystal form A of the compound represented by formula (III) includes the following steps: after mixing crystal form A of the compound represented by formula (I) with dioxane, it is reacted and crystallized with a methanol solution of methanesulfonic acid to obtain formula ( III) Crystal form of compound A shown;
    式(IV)所示化合物的A晶型的制备方法包括如下步骤：将式(I)所示化合物A晶型与乙腈、纯化水混合后，与柠檬酸甲醇溶液反应析晶，得到式(IV)所示化合物A晶型；The preparation method of crystal form A of the compound represented by formula (IV) includes the following steps: mixing crystal form A of the compound represented by formula (I) with acetonitrile and purified water, and then reacting with citric acid methanol solution for crystallization to obtain formula (IV ) shows the crystal form of compound A;
    式(V)所示化合物的A晶型的制备方法包括如下步骤：将式(I)所示化合物A晶 型与乙醇混合后，与硫酸甲醇溶液反应析晶，得到式(V)所示化合物A晶型；The preparation method of crystal form A of the compound represented by formula (V) includes the following steps: after mixing crystal form A of the compound represented by formula (I) with ethanol, it is reacted with sulfuric acid methanol solution for crystallization to obtain the compound represented by formula (V) Crystal form A;
    式(VI)所示化合物的A晶型的制备方法包括如下步骤：将式(I)所示化合物A晶型与二氧六环混合后，与丁二酸甲醇溶液反应析晶，得到式(VI)所示化合物A晶型。The preparation method of crystal form A of the compound represented by formula (VI) includes the following steps: after mixing crystal form A of the compound represented by formula (I) with dioxane, it is reacted and crystallized with a methanol solution of succinic acid to obtain formula ( VI) Crystal form of compound A shown.
  7. 如权利要求6所述的制备方法，其特征在于，式(II)所示化合物的制备方法中，所述溶剂为卤代烃类、二氧六环、腈类、醇类和水中的一种或多种；优选为DCM、乙腈、二氧六环、水和乙醇中的一种或多种；The preparation method according to claim 6, characterized in that, in the preparation method of the compound represented by formula (II), the solvent is one of halogenated hydrocarbons, dioxane, nitriles, alcohols and water. or more; preferably one or more of DCM, acetonitrile, dioxane, water and ethanol;
    和/或，所述的式(I)所示化合物B晶型的制备方法中，式(I)所示化合物A晶型与乙腈的质量体积比可以为10-60mg/mL；优选为30mg/mL；And/or, in the preparation method of the crystal form of the compound B represented by the formula (I), the mass volume ratio of the crystal form of the compound A represented by the formula (I) and acetonitrile can be 10-60 mg/mL; preferably 30 mg/ mL;
    和/或，所述的式(I)所示化合物B晶型的制备方法中，混合的操作可以为摇床震荡；优选在25℃的条件下摇床震荡；更优选在25℃，250rpm的条件下摇床震荡；进一步优选在25℃，250rpm的条件下摇床震荡24h；And/or, in the preparation method of the crystal form B of the compound represented by formula (I), the mixing operation can be shaking with a shaker; preferably shaking with a shaker at 25°C; more preferably at 25°C, 250rpm. The shaking table is shaken under the conditions; further preferably, the shaking table is shaken under the conditions of 25°C and 250 rpm for 24 hours;
    和/或，所述的式(I)所示化合物B晶型的制备方法中，析晶的操作可以包括以下步骤：将式(I)所示化合物A晶型与乙腈混合后体系中的固体分离出来得到所述的式(I)所示化合物B晶型；优选地，固体分离出来后进一步进行干燥；更优选在50℃条件下干燥；进一步优选在50℃，真空度-0.1M的条件下干燥；进一步优选在50℃，真空度-0.1M的条件下干燥6h；进一步优选在50℃，真空度-0.1M的真空干燥箱中干燥6h；And/or, in the preparation method of the crystal form of the compound B represented by the formula (I), the crystallization operation may include the following steps: the solid in the system after mixing the crystal form of the compound A represented by the formula (I) and acetonitrile Separate to obtain the crystalline form B of the compound represented by formula (I); preferably, the solid is further dried after being separated; more preferably, it is dried under the condition of 50°C; further preferably, it is dried at 50°C and the vacuum degree is -0.1M. Drying at 50°C, vacuum degree -0.1M for 6 hours; further preferably, drying in a vacuum drying oven at 50°C, vacuum degree -0.1M for 6 hours;
    和/或，所述的式(III)所示化合物A晶型的制备方法中，混合的操作可以为搅拌；优选磁力搅拌同时升温至50℃；And/or, in the preparation method of the crystal form of compound A represented by formula (III), the mixing operation can be stirring; preferably magnetic stirring while raising the temperature to 50°C;
    和/或，所述的式(III)所示化合物A晶型的制备方法中，式(I)所示化合物A晶型与二氧六环的质量体积比可以为20-90mg/mL；优选50mg/mL；And/or, in the preparation method of the crystal form of compound A represented by formula (III), the mass volume ratio of the crystal form of compound A represented by formula (I) and dioxane can be 20-90 mg/mL; preferably 50mg/mL;
    和/或，所述的式(III)所示化合物A晶型的制备方法中，式(I)所示化合物A晶型与甲磺酸甲醇溶液的质量体积比可以为200-900mg/mL；优选500mg/mL；And/or, in the preparation method of the crystal form of compound A represented by formula (III), the mass volume ratio of the crystal form of compound A represented by formula (I) and the methanol solution of methanesulfonic acid can be 200-900 mg/mL; Preferably 500mg/mL;
    和/或，所述的式(III)所示化合物A晶型的制备方法中，甲磺酸甲醇溶液的浓度可以为0.5-2mol/L；优选为1mol/L；And/or, in the preparation method of the crystal form of compound A represented by formula (III), the concentration of the methanol solution of methanesulfonic acid can be 0.5-2mol/L; preferably 1mol/L;
    和/或，所述的式(III)所示化合物A晶型的制备方法中，反应析晶的操作可以包括以下步骤：将式(I)所示化合物A晶型、二氧六环混合后和甲磺酸甲醇溶液反应后，降温，将反应后混合物中的固体分离出来；And/or, in the preparation method of the crystal form of the compound A represented by the formula (III), the reaction crystallization operation may include the following steps: mixing the crystal form of the compound A represented by the formula (I) and dioxane. After reacting with the methanol solution of methanesulfonic acid, the temperature is lowered and the solid in the reaction mixture is separated;
    和/或，所述的式(III)所示化合物A晶型的制备方法中，所述反应可以在温度为50℃下进行；优选地，所述反应可以在温度为50℃下反应3h；And/or, in the preparation method of the crystal form of compound A represented by formula (III), the reaction can be carried out at a temperature of 50°C; preferably, the reaction can be carried out at a temperature of 50°C for 3 hours;
    和/或，所述的式(III)所示化合物A晶型的制备方法中，所述降温操作可以包括以10℃/h的降温速度降温至室温，随后置于4℃冰箱中24h；And/or, in the preparation method of the crystal form of compound A represented by formula (III), the cooling operation may include cooling to room temperature at a cooling rate of 10°C/h, and then placing it in a 4°C refrigerator for 24 hours;
    和/或，所述的式(III)所示化合物A晶型的制备方法中，固体分离出来后可以进一步进行洗涤；优选二氧六环溶液洗涤；更优选用4℃的二氧六环溶液洗涤；进一步优选，所述式(I)所示化合物A晶型与二氧六环溶液的质量体积比为150mg/mL；And/or, in the preparation method of the crystal form of compound A represented by formula (III), the solid can be further washed after being separated; preferably, it is washed with a dioxane solution; more preferably, it is washed with a dioxane solution at 4°C. Washing; further preferably, the mass volume ratio of the crystal form of compound A shown in the formula (I) and the dioxane solution is 150 mg/mL;
    和/或，所述的式(III)所示化合物A晶型的制备方法中，固体分离出来后可以进一步进行干燥；优选在50℃条件下干燥；进一步优选在50℃，真空度-0.1M的条件下干燥；进一步优选在50℃，真空度-0.1M的条件下干燥24h；进一步优选在50℃，真空度-0.1M的真空干燥箱中干燥24h；And/or, in the preparation method of the crystal form of compound A represented by formula (III), the solid can be further dried after being separated; preferably drying at 50°C; further preferably at 50°C, vacuum degree -0.1M Dry under conditions; further preferably, dry at 50°C, vacuum degree -0.1M for 24h; further preferably, dry in a vacuum drying oven at 50°C, vacuum degree -0.1M for 24h;
    和/或，所述的式(IV)所示化合物A晶型的制备方法中，混合的操作可以为搅拌；优选搅拌同时升温至50℃；更优选搅拌(200-300rpm)同时升温至50℃；And/or, in the preparation method of the crystal form of compound A represented by formula (IV), the mixing operation can be stirring; preferably stirring while raising the temperature to 50°C; more preferably stirring (200-300rpm) while raising the temperature to 50°C ;
    和/或，所述的式(IV)所示化合物A晶型的制备方法中，式(I)所示化合物A晶型与乙腈的质量体积比可以为5-25mg/mL；优选11.1mg/mL；And/or, in the preparation method of the crystal form of compound A represented by formula (IV), the mass volume ratio of the crystal form of compound A represented by formula (I) and acetonitrile can be 5-25 mg/mL; preferably 11.1 mg/ mL;
    和/或，所述的式(IV)所示化合物A晶型的制备方法中，式(I)所示化合物A晶型与纯化水的质量体积比可以为30-170mg/mL；优选100mg/mL；And/or, in the preparation method of the crystal form of compound A represented by formula (IV), the mass volume ratio of the crystal form of compound A represented by formula (I) and purified water can be 30-170 mg/mL; preferably 100 mg/ mL;
    和/或，所述的式(IV)所示化合物A晶型的制备方法中，式(I)所示化合物A晶型与柠檬酸甲醇溶液的质量体积比可以为200-900mg/mL；优选500mg/mL；And/or, in the preparation method of the crystal form of compound A represented by formula (IV), the mass volume ratio of the crystal form of compound A represented by formula (I) and the citric acid methanol solution can be 200-900 mg/mL; preferably 500mg/mL;
    和/或，所述的式(IV)所示化合物A晶型的制备方法中，柠檬酸甲醇溶液的浓度可以为0.5-2mol/L；优选为1mol/L；And/or, in the preparation method of the crystal form of compound A represented by formula (IV), the concentration of the citric acid methanol solution can be 0.5-2mol/L; preferably 1mol/L;
    和/或，所述的式(IV)所示化合物A晶型的制备方法中，反应析晶的操作可以包括以下步骤：将式(I)所示化合物A晶型与乙腈、纯化水混合后和柠檬酸甲醇溶液反应后，降温，将反应后混合物中的固体分离出来；And/or, in the preparation method of the crystal form of the compound A represented by the formula (IV), the reaction crystallization operation may include the following steps: mixing the crystal form of the compound A represented by the formula (I) with acetonitrile and purified water. After reacting with the methanol solution of citric acid, the temperature is lowered and the solid in the reaction mixture is separated;
    和/或，所述的式(IV)所示化合物A晶型的制备方法中，所述反应可以在温度为50℃下进行；优选地，所述反应可以在温度为50℃下搅拌进行；更优选地，所述反应可以在温度为50℃下搅拌(转速200-300rpm)反应2h；And/or, in the preparation method of the crystal form of compound A represented by formula (IV), the reaction can be carried out at a temperature of 50°C; preferably, the reaction can be carried out with stirring at a temperature of 50°C; More preferably, the reaction can be carried out with stirring at a temperature of 50°C (rotation speed 200-300 rpm) for 2 hours;
    和/或，所述的式(IV)所示化合物A晶型的制备方法中，所述降温操作可以包括以15℃/h的降温速度降温至5℃；优选以15℃/h的降温速度降温至5℃，然后养晶0.5h；And/or, in the preparation method of the crystal form of compound A represented by formula (IV), the cooling operation may include cooling to 5°C at a cooling rate of 15°C/h; preferably at a cooling rate of 15°C/h. Lower the temperature to 5℃, then grow the crystals for 0.5h;
    和/或，所述的式(IV)所示化合物A晶型的制备方法中，固体分离出来后可以进一步进行洗涤；优选乙腈溶液洗涤；更优选用4℃的乙腈溶液洗涤；进一步优选地，所述式(I)所示化合物A晶型与乙腈溶液的质量体积比为150mg/mL；And/or, in the preparation method of the crystal form of compound A represented by formula (IV), the solid can be further washed after being separated; preferably, it is washed with an acetonitrile solution; more preferably, it is washed with an acetonitrile solution at 4°C; further preferably, The mass volume ratio of the crystal form of compound A shown in the formula (I) to the acetonitrile solution is 150 mg/mL;
    和/或，所述的式(IV)所示化合物A晶型的制备方法中，固体分离出来后可以进一步进行干燥；优选在50℃条件下干燥；进一步优选在50℃，真空度-0.1M的条件下干燥；进一步优选在50℃，真空度-0.1M的条件下干燥24h；进一步优选在50℃，真空 度-0.1M的真空干燥箱中干燥24h；And/or, in the preparation method of the crystal form of compound A represented by formula (IV), the solid can be further dried after being separated; preferably drying at 50°C; further preferably at 50°C, vacuum degree -0.1M Dry under conditions; further preferably, dry at 50°C, vacuum degree -0.1M for 24h; further preferably, dry in a vacuum drying oven at 50°C, vacuum degree -0.1M for 24h;
    和/或，所述的式(V)所示化合物A晶型的制备方法中，混合后升温至50℃；And/or, in the preparation method of the crystal form of compound A represented by formula (V), after mixing, the temperature is raised to 50°C;
    和/或，所述的式(V)所示化合物A晶型的制备方法中，式(I)所示化合物A晶型与乙醇的质量体积比可以为2-10mg/mL；优选5mg/mL；And/or, in the preparation method of the crystal form of compound A represented by formula (V), the mass volume ratio of the crystal form of compound A represented by formula (I) and ethanol can be 2-10 mg/mL; preferably 5 mg/mL ;
    和/或，所述的式(V)所示化合物A晶型的制备方法中，式(I)所示化合物A晶型与硫酸甲醇溶液的质量体积比可以为200-900mg/mL；优选500mg/mL；And/or, in the preparation method of the crystal form of compound A represented by formula (V), the mass volume ratio of the crystal form of compound A represented by formula (I) and the sulfuric acid methanol solution can be 200-900 mg/mL; preferably 500 mg /mL;
    和/或，所述的式(V)所示化合物A晶型的制备方法中，硫酸甲醇溶液的浓度可以为0.5-2mol/L；优选为1mol/L；And/or, in the preparation method of the crystal form of compound A represented by formula (V), the concentration of the sulfuric acid methanol solution can be 0.5-2mol/L; preferably 1mol/L;
    和/或，所述的式(V)所示化合物A晶型的制备方法中，反应析晶的操作可以包括以下步骤：将式(I)所示化合物A晶型与乙醇混合后和硫酸甲醇溶液反应后，降温，浓缩，将反应后混合物中的固体分离出来；And/or, in the preparation method of the crystal form of the compound A represented by the formula (V), the reaction crystallization operation may include the following steps: mixing the crystal form of the compound A represented by the formula (I) with ethanol and then mixing it with methanol sulfate After the solution reacts, the temperature is lowered, concentrated, and the solid in the reaction mixture is separated;
    和/或，所述的式(V)所示化合物A晶型的制备方法中，所述反应可以在温度为50℃下进行；优选地，所述反应可以在温度为50℃下搅拌进行；更优选地，所述反应可以在温度为50℃下搅拌(转速200-300rpm)反应3h；And/or, in the preparation method of the crystal form of compound A represented by formula (V), the reaction can be carried out at a temperature of 50°C; preferably, the reaction can be carried out with stirring at a temperature of 50°C; More preferably, the reaction can be carried out with stirring at a temperature of 50°C (rotation speed 200-300 rpm) for 3 hours;
    和/或，所述的式(V)所示化合物A晶型的制备方法中，所述降温操作可以包括以12.5℃/h的降温速度降温至25℃，加入乙腈，以10℃/h的降温速度降温至5℃；优选地，式(I)所示化合物A晶型与乙腈的质量体积比可以为10mg/mL；And/or, in the preparation method of the crystal form of compound A represented by formula (V), the cooling operation may include cooling to 25°C at a cooling rate of 12.5°C/h, adding acetonitrile, and adding acetonitrile at a cooling rate of 10°C/h. The cooling rate is lowered to 5°C; preferably, the mass-to-volume ratio of the crystal form of compound A shown in formula (I) to acetonitrile can be 10 mg/mL;
    和/或，所述的式(V)所示化合物A晶型的制备方法中，所述浓缩操作可以包括将降温后的反应液置于60℃的条件下浓缩；优选置于旋蒸瓶中(60℃，100rpm)浓缩；And/or, in the preparation method of the crystal form of compound A represented by formula (V), the concentration operation may include concentrating the cooled reaction solution at 60°C; preferably, placing it in a rotary evaporation bottle (60°C, 100rpm) concentration;
    和/或，所述的式(V)所示化合物A晶型的制备方法中，所述固体分离操作可以包括将浓缩后的反应液置于空气环境中挥干，然后将挥干后的固体进一步进行干燥；所述干燥优选在50℃条件下干燥；进一步优选在50℃，真空度-0.1M的条件下干燥；进一步优选在50℃，真空度-0.1M的条件下干燥24h；进一步优选在50℃，真空度-0.1M的真空干燥箱中干燥24h；And/or, in the preparation method of the crystal form of compound A represented by formula (V), the solid separation operation may include placing the concentrated reaction liquid in an air environment to evaporate to dryness, and then evaporating the dried solid Further drying is performed; the drying is preferably performed at 50°C; further preferably at 50°C, with a vacuum of -0.1M; further preferably, at 50°C, with a vacuum of -0.1M for 24 hours; further preferably Dry in a vacuum drying oven at 50°C and vacuum degree -0.1M for 24 hours;
    和/或，所述的式(VI)所示化合物A晶型的制备方法中，混合的操作可以为搅拌；优选磁力搅拌同时升温至50℃；And/or, in the preparation method of the crystal form of compound A represented by formula (VI), the mixing operation may be stirring; preferably magnetic stirring while raising the temperature to 50°C;
    和/或，所述的式(VI)所示化合物A晶型的制备方法中，式(I)所示化合物A晶型与二氧六环的质量体积比可以为15-70mg/mL；优选37.5mg/mL；And/or, in the preparation method of the crystal form of compound A represented by formula (VI), the mass volume ratio of the crystal form of compound A represented by formula (I) and dioxane can be 15-70 mg/mL; preferably 37.5mg/mL;
    和/或，所述的式(VI)所示化合物A晶型的制备方法中，式(I)所示化合物A晶型与丁二酸甲醇溶液的质量体积比可以为200-900mg/mL；优选500mg/mL；And/or, in the preparation method of the crystal form of the compound A represented by the formula (VI), the mass volume ratio of the crystal form of the compound A represented by the formula (I) and the succinic acid methanol solution can be 200-900 mg/mL; Preferably 500mg/mL;
    和/或，所述的式(VI)所示化合物A晶型的制备方法中，丁二酸甲醇溶液的浓度可 以为0.5-2mol/L；优选为1mol/L；And/or, in the preparation method of the crystal form of compound A shown in the formula (VI), the concentration of the succinic acid methanol solution can be 0.5-2mol/L; preferably 1mol/L;
    和/或，所述的式(VI)所示化合物A晶型的制备方法中，反应析晶的操作可以包括以下步骤：将式(I)所示化合物A晶型与二氧六环混合后和丁二酸甲醇溶液反应后，降温，将反应后混合物中的固体分离出来；And/or, in the preparation method of the crystal form of the compound A represented by the formula (VI), the reaction crystallization operation may include the following steps: mixing the crystal form of the compound A represented by the formula (I) with dioxane. After reacting with the methanol solution of succinic acid, the temperature is lowered and the solid in the reaction mixture is separated;
    和/或，所述的式(VI)所示化合物A晶型的制备方法中，所述反应可以在温度为50℃下进行；优选地，所述反应可以在温度为50℃下反应3h；And/or, in the preparation method of the crystal form of compound A represented by formula (VI), the reaction can be carried out at a temperature of 50°C; preferably, the reaction can be carried out at a temperature of 50°C for 3 hours;
    和/或，所述的式(VI)所示化合物A晶型的制备方法中，所述降温操作可以包括以10℃/h的降温速度降温至室温，随后置于4℃冰箱中5h；And/or, in the preparation method of the crystal form of compound A represented by formula (VI), the cooling operation may include cooling to room temperature at a cooling rate of 10°C/h, and then placing it in a 4°C refrigerator for 5 hours;
    和/或，所述的式(VI)所示化合物A晶型的制备方法中，固体分离出来后可以进一步进行洗涤；优选二氧六环溶液洗涤；更优选用4℃的二氧六环溶液洗涤；进一步优选地，所述式(I)所示化合物A晶型与二氧六环溶液的质量体积比为150mg/mL；And/or, in the preparation method of the crystal form of compound A represented by formula (VI), the solid can be further washed after being separated; preferably, it is washed with a dioxane solution; more preferably, it is washed with a dioxane solution at 4°C. Washing; further preferably, the mass volume ratio of the crystal form of compound A shown in the formula (I) to the dioxane solution is 150 mg/mL;
    和/或，所述的式(VI)所示化合物A晶型的制备方法中，固体分离出来后可以进一步进行干燥；优选在50℃条件下干燥；进一步优选在50℃，真空度-0.1M的条件下干燥；进一步优选在50℃，真空度-0.1M的条件下干燥24h；进一步优选在50℃，真空度-0.1M的真空干燥箱中干燥24h。And/or, in the preparation method of the crystal form of compound A represented by formula (VI), the solid can be further dried after being separated; preferably drying at 50°C; further preferably at 50°C, vacuum degree -0.1M Dry under conditions; further preferably, dry at 50°C, vacuum degree -0.1M for 24h; further preferably, dry in a vacuum drying oven at 50°C, vacuum degree -0.1M for 24h.
  8. 一种药物组合物，其含有：A pharmaceutical composition containing:
    (1)治疗有效量的如权利要求1或2所述化合物或晶型、如权利要求3-5任一项所述的晶型，和(1) A therapeutically effective amount of the compound or crystal form of claim 1 or 2, the crystal form of any one of claims 3-5, and
    (2)药学上可接受的辅料；(2) Pharmaceutically acceptable excipients;
    优选地，所述药物组合物用于口服给药；更优选地，所述药物组合物用于制作片剂或胶囊；进一步优选地，所述药物组合物含有0.2重量％-10重量％的如权利要求1或2所述化合物或晶型、如权利要求3-5任一项所述的晶型。Preferably, the pharmaceutical composition is used for oral administration; more preferably, the pharmaceutical composition is used for making tablets or capsules; further preferably, the pharmaceutical composition contains 0.2% by weight to 10% by weight, such as The compound or crystal form described in claim 1 or 2, or the crystal form described in any one of claims 3-5.
  9. 如权利要求1或2所述化合物或晶型、如权利要求3-5任一项所述的晶型或如权利要求8所述的药物组合物在制备治疗、预防、延迟或阻碍与SHP2蛋白活性或表达相关的疾病的发生或进展的药物中的应用；优选地，所述药物为治疗与SHP2蛋白活性或表达相关的疾病的药物；更优选地，所述疾病为肿瘤；进一步优选地，所述肿瘤为由Ras-Raf-ERK或PD1/L1信号通路异常导致的肿瘤；进一步优选地，所述肿瘤为食管癌、肺癌、结直肠癌、胰腺癌、白血病或胃癌。The compound or crystal form according to claim 1 or 2, the crystal form according to any one of claims 3 to 5, or the pharmaceutical composition according to claim 8 can be used in the preparation of treating, preventing, delaying or hindering interactions with SHP2 protein. Application in drugs for the occurrence or progression of diseases related to activity or expression; Preferably, the drug is a drug for treating diseases related to SHP2 protein activity or expression; More preferably, the disease is a tumor; Further preferably, The tumor is a tumor caused by an abnormality of the Ras-Raf-ERK or PD1/L1 signaling pathway; further preferably, the tumor is esophageal cancer, lung cancer, colorectal cancer, pancreatic cancer, leukemia or gastric cancer.
PCT/CN2022/096702 2022-06-01 2022-06-01 Shp2 inhibitor, and crystal form thereof, preparation method therefor, and use thereof WO2023230968A1 (en)

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