WO2023230968A1 - Inhibiteur de shp2, forme cristalline de celui-ci, procédé de préparation correspondant et utilisation associée - Google Patents

Inhibiteur de shp2, forme cristalline de celui-ci, procédé de préparation correspondant et utilisation associée 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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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/fr
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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

L'invention concerne un inhibiteur de SHP2, une forme cristalline de celui-ci, un procédé de préparation correspondant et une utilisation associée. L'invention concerne une forme cristalline B d'un composé tel que représenté dans la formule (I), un composé tel que représenté dans la formule (II) et une forme cristalline A de celui-ci, un composé tel que représenté dans la formule (III) et une forme cristalline A de celui-ci, un composé tel que représenté dans la formule (IV) et une forme cristalline A de celui-ci, un composé tel que représenté dans la formule (V) et une forme cristalline A de celui-ci, et un composé tel que représenté dans la formule (VI) et une forme cristalline A de celui-ci ainsi qu'un procédé de préparation correspondant et une utilisation associée. Les composés et les formes cristallines de ceux-ci ont un ou plusieurs des avantages suivants : ils sont stables en termes de propriété, de bonne hygroscopicité et de bonne biodisponibilité, et ils ont de bonnes perspectives de développement de médicament.
PCT/CN2022/096702 2022-06-01 2022-06-01 Inhibiteur de shp2, forme cristalline de celui-ci, procédé de préparation correspondant et utilisation associée WO2023230968A1 (fr)

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CN111153901A (zh) * 2018-11-07 2020-05-15 如东凌达生物医药科技有限公司 一类含氮稠杂环类shp2抑制剂化合物、制备方法和用途
WO2020108590A1 (fr) * 2018-11-30 2020-06-04 上海拓界生物医药科技有限公司 Pyrimidine et dérivé hétérocycle pentagonal de nitrogène, leur procédé de préparation et applications médicales
CN111704611A (zh) * 2019-07-25 2020-09-25 上海凌达生物医药有限公司 一类芳基螺环类shp2抑制剂化合物、制备方法和用途
WO2020259679A1 (fr) * 2019-06-28 2020-12-30 上海拓界生物医药科技有限公司 Dérivé hétérocyclique azoté à cinq chaînons de pyrimidine, son procédé de préparation et son utilisation pharmaceutique
CN112839935A (zh) * 2018-09-26 2021-05-25 北京加科思新药研发有限公司 可用作shp2抑制剂的新型杂环衍生物

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN112839935A (zh) * 2018-09-26 2021-05-25 北京加科思新药研发有限公司 可用作shp2抑制剂的新型杂环衍生物
WO2020072656A1 (fr) * 2018-10-03 2020-04-09 Gilead Sciences, Inc. Dérivés d'imidozopyrimidine
CN111138412A (zh) * 2018-11-06 2020-05-12 上海奕拓医药科技有限责任公司 一种螺芳环化合物及其应用
CN111153901A (zh) * 2018-11-07 2020-05-15 如东凌达生物医药科技有限公司 一类含氮稠杂环类shp2抑制剂化合物、制备方法和用途
WO2020108590A1 (fr) * 2018-11-30 2020-06-04 上海拓界生物医药科技有限公司 Pyrimidine et dérivé hétérocycle pentagonal de nitrogène, leur procédé de préparation et applications médicales
WO2020259679A1 (fr) * 2019-06-28 2020-12-30 上海拓界生物医药科技有限公司 Dérivé hétérocyclique azoté à cinq chaînons de pyrimidine, son procédé de préparation et son utilisation pharmaceutique
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