WO2024061298A1 - Forme solide d'un dérivé de méthanone à substitution hétérocyclo et son utilisation - Google Patents

Forme solide d'un dérivé de méthanone à substitution hétérocyclo et son utilisation Download PDF

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WO2024061298A1
WO2024061298A1 PCT/CN2023/120247 CN2023120247W WO2024061298A1 WO 2024061298 A1 WO2024061298 A1 WO 2024061298A1 CN 2023120247 W CN2023120247 W CN 2023120247W WO 2024061298 A1 WO2024061298 A1 WO 2024061298A1
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compound
formula
solid form
present
solid
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PCT/CN2023/120247
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English (en)
Chinese (zh)
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陶涛
王吉标
薛原
彭春睿
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上海海雁医药科技有限公司
扬子江药业集团有限公司
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Publication of WO2024061298A1 publication Critical patent/WO2024061298A1/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
    • A61K31/495—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
    • A61K31/4965—Non-condensed pyrazines
    • A61K31/497—Non-condensed pyrazines containing further 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
    • C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
    • C07D513/04—Ortho-condensed systems

Definitions

  • the present invention relates to the field of medical technology. Specifically, the present invention relates to the solid form of a heterocyclic substituted ketone derivative and its application.
  • the derivative is (S)-(3-amino-5-(1-amino- 1,3-dihydrospiro[indene-2,4'-piperidin]-1'-yl)pyrazin-2-yl)(2-amino-7,7-difluoro-6,7-dihydrothiazole And [5,4-c]pyridin-5(4H)-yl)methanone.
  • Protein tyrosine phosphatase catalyzes the dephosphorylation of phosphotyrosine and is a key control element in mammalian signal transduction. Deviations in its biological functions can cause disorder of body regulation and lead to cancer, diabetes, and autoimmunity. diseases and many other diseases.
  • Src homology 2 domain-containing protein tyrosine phosphatase SHP2
  • Src homology-2 phosphatase SHP2 is a non-receptor protein tyrosine phosphatase encoded by the PTPN11 gene that contributes to multiple cellular functions including proliferation, differentiation, cell cycle maintenance and migration. SHP2 is implicated in signaling through Ras-mitogen-activated protein kinase (JAK-STAT or phosphoinositide 3-kinase-AKT pathway).
  • SHP2 is a highly attractive target for the development of new therapies for the treatment of various diseases.
  • the compounds of formula (I) of the present invention satisfy the need for small molecules that inhibit SHP2 activity.
  • the object of the present invention is to provide a new solid form and application of heterocyclic substituted ketone derivatives.
  • a first aspect of the invention provides solid forms of compounds of formula (I):
  • the solid forms described are polymorphs.
  • the polymorph is Form I, which has an X-ray powder diffraction (XRPD) pattern with characteristic diffraction angles at 2 ⁇ (°) values of 15.982 ⁇ 0.2, 20.367 ⁇ 0.2, and 21.114 ⁇ 0.2 peak.
  • XRPD X-ray powder diffraction
  • the XRPD pattern of Form I has a 2 ⁇ (°) diffraction angle at values of 15.982 ⁇ 0.2, 20.367 ⁇ 0.2, and 21.114 ⁇ 0.2, and selected from the group consisting of 8 ⁇ 0.2, 9.232 ⁇ 0.2, and 13.586 ⁇ 0.2 There is a characteristic diffraction peak at at least one value.
  • the XRPD pattern 2 ⁇ (°) diffraction angle of the crystalline Form I has characteristic diffraction peaks at values of 15.982 ⁇ 0.2, 20.367 ⁇ 0.2 and 21.114 ⁇ 0.2, and at least one value selected from 8 ⁇ 0.2, 9.232 ⁇ 0.2, 11.088 ⁇ 0.2, 12.438 ⁇ 0.2, 13.586 ⁇ 0.2, 17.181 ⁇ 0.2 and 19.523 ⁇ 0.2.
  • the XRPD pattern 2 ⁇ (°) diffraction angle of the crystalline Form I has characteristic diffraction peaks at values of 15.982 ⁇ 0.2, 20.367 ⁇ 0.2 and 21.114 ⁇ 0.2, and at least one value selected from 8 ⁇ 0.2, 9.232 ⁇ 0.2, 11.088 ⁇ 0.2, 12.438 ⁇ 0.2, 13.315 ⁇ 0.2, 13.586 ⁇ 0.2, 14.598 ⁇ 0.2, 15.025 ⁇ 0.2, 17.181 ⁇ 0.2, 19.523 ⁇ 0.2 and 19.943 ⁇ 0.2.
  • the XRPD pattern 2 ⁇ (°) diffraction angle of Form I is at 15.982 ⁇ 0.2, 20.367 ⁇ 0.2 and 21.114 ⁇ 0.2 values, and is selected from 8 ⁇ 0.2, 9.232 ⁇ 0.2, 11.088 ⁇ 0.2, 12.438 ⁇ 0.2, 13.315 ⁇ 0.2, 13.586 ⁇ 0.2, 14.598 ⁇ 0 .2, 15.025 ⁇ 0.2, 17.181 ⁇ 0.2, 19.523 ⁇ 0.2, 19.943 ⁇ 0.2, 22.19 ⁇ 0.2, 23.24 ⁇ 0.2, 24.776 ⁇ 0.2, 25.402 ⁇ 0.2, 26.064 ⁇ 0.2, 27.082 ⁇ 0.2 and 28.101 ⁇ 0.2 have a characteristic diffraction peak at at least one value.
  • the XRPD pattern of Form I has a 2 ⁇ (°) diffraction angle at values of 15.982 ⁇ 0.2, 20.367 ⁇ 0.2 and 21.114 ⁇ 0.2, and 1 or more (such as 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20 or 21) selected from 8 ⁇ 0.2, 9.232 ⁇ 0.2, 11.088 ⁇ 0.2, 12.438 ⁇ 0.2, 13.315 ⁇ 0.2, 13.586 ⁇ 0.2, 14.598 ⁇ 0.2, 15.025 ⁇ 0.2, 17.181 ⁇ 0.2, 18.168 ⁇ 0.2, 19.523 ⁇ 0.2, 19.943 ⁇ 0.2, 22.19 ⁇ 0.2, 23.24 ⁇ 0.2, 24.776 ⁇ 0.2, 25.402 ⁇ 0.2 , there are characteristic diffraction peaks at the values of 26.064 ⁇ 0.2, 27.082 ⁇ 0.2, 28.101 ⁇ 0.2, 29.505 ⁇ 0.2 and 34.098 ⁇ 0.2.
  • the XRPD pattern of Form I has characteristic diffraction peaks at 2 ⁇ (°) diffraction angles at at least three values selected from the following diffraction angles 2 ⁇ (°): 8 ⁇ 0.2, 9.232 ⁇ 0.2, 11.088 ⁇ 0.2,12.438 ⁇ 0.2,13.315 ⁇ 0.2,13.586 ⁇ 0.2,14.598 ⁇ 0.2,15.025 ⁇ 0.2,15.982 ⁇ 0.2,17.181 ⁇ 0.2,19.523 ⁇ 0.2,19.943 ⁇ 0.2,20.367 ⁇ 0.2,21 .114 ⁇ 0.2, 22.19 ⁇ 0.2, 23.24 ⁇ 0.2, 24.776 ⁇ 0.2, 25.402 ⁇ 0.2, 26.064 ⁇ 0.2, 27.082 ⁇ 0.2 and 28.101 ⁇ 0.2.
  • the XRPD pattern of Form I has a 2 ⁇ (°) diffraction angle at 3 or more (such as 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 , 15, 16, 17, 18, 19, 20, 21, 22, 23, 24) or all selected from the following diffraction angle 2 ⁇ (°) values with characteristic diffraction peaks: 8 ⁇ 0.2, 9.232 ⁇ 0.2, 11.088 ⁇ 0.2, 12.438 ⁇ 0.2, 13.315 ⁇ 0.2, 13.586 ⁇ 0.2, 14.598 ⁇ 0.2, 15.025 ⁇ 0.2, 15.982 ⁇ 0.2, 17.181 ⁇ 0.2, 18.168 ⁇ 0.2, 19.523 ⁇ 0.2, 19.943 ⁇ 0.2, 20.367 ⁇ 0. 2,21.114 ⁇ 0.2, 22.19 ⁇ 0.2, 23.24 ⁇ 0.2, 24.776 ⁇ 0.2, 25.402 ⁇ 0.2, 26.064 ⁇ 0.2, 27.082 ⁇ 0.2, 28.101 ⁇ 0.2, 29.505 ⁇ 0.2 and 34.098 ⁇ 0.2.
  • the XRPD pattern of Form I has characteristic diffraction peaks at 2 ⁇ (°) diffraction angles at values of 8 ⁇ 0.2, 9.232 ⁇ 0.2, 13.586 ⁇ 0.2, 15.982 ⁇ 0.2, 20.367 ⁇ 0.2, and 21.114 ⁇ 0.2 .
  • the XRPD pattern of Form I has a 2 ⁇ (°) diffraction angle at 8 ⁇ 0.2, 9.232 ⁇ 0.2, 11.088 ⁇ 0.2, 12.438 ⁇ 0.2, 13.586 ⁇ 0.2, 15.982 ⁇ 0.2, 17.181 ⁇ 0.2, 19.523 ⁇ 0.2, 20.367 ⁇ 0.2 and 21.114 ⁇ 0.2 There are characteristic diffraction peaks at the value.
  • the XRPD pattern of Form I has a 2 ⁇ (°) diffraction angle at 8 ⁇ 0.2, 9.232 ⁇ 0.2, 11.088 ⁇ 0.2, 12.438 ⁇ 0.2, 13.315 ⁇ 0.2, 13.586 ⁇ 0.2, 14.598 ⁇ 0.2, 15.025 There are characteristic diffraction peaks at values of ⁇ 0.2, 15.982 ⁇ 0.2, 17.181 ⁇ 0.2, 19.523 ⁇ 0.2, 19.943 ⁇ 0.2, 20.367 ⁇ 0.2 and 21.114 ⁇ 0.2.
  • the XRPD pattern of Form I has a 2 ⁇ (°) diffraction angle of 9.232 ⁇ 0.2, 12.438 ⁇ 0.2, 13.315 ⁇ 0.2, 13.586 ⁇ 0.2, 14.598 ⁇ 0.2, 15.025 ⁇ 0.2, 15.982 ⁇ 0.2, 17.181
  • the XRPD pattern of Form I has a 2 ⁇ (°) diffraction angle at 8 ⁇ 0.2, 9.232 ⁇ 0.2, 11.088 ⁇ 0.2, 12.438 ⁇ 0.2, 13.315 ⁇ 0.2, 13.586 ⁇ 0.2, 14.598 ⁇ 0.2, 15.025 ⁇ 0.2, 15.982 ⁇ 0.2, 17.181 ⁇ 0.2, 19.523 ⁇ 0.2, 19.943 ⁇ 0.2, 20.367 ⁇ 0.2, 21.114 ⁇ 0.2, 22.19 ⁇ 0.2, 23.24 ⁇ 0.2, 24.776 ⁇ 0.2, 25.402 ⁇ 0.2, 26.064 ⁇ 0.2, 27.082 ⁇ 0.2 There are characteristic diffraction peaks at 28.101 ⁇ 0.2.
  • the XRPD pattern of Form I has a 2 ⁇ (°) diffraction angle at 8 ⁇ 0.2, 9.232 ⁇ 0.2, 11.088 ⁇ 0.2, 12.438 ⁇ 0.2, 13.315 ⁇ 0.2, 13.586 ⁇ 0.2, 14.598 ⁇ 0.2, 15.025 ⁇ 0.2, 15.982 ⁇ 0.2, 17.181 ⁇ 0.2, 18.168 ⁇ 0.2, 19.523 ⁇ 0.2, 19.943 ⁇ 0.2, 20.367 ⁇ 0.2, 21.114 ⁇ 0.2, 22.19 ⁇ 0.2, 23.24 ⁇ 0.2, 24.776 ⁇ 0.2, 25.402 ⁇ 0.2, 26.064 ⁇ 0.2 , there are characteristic diffraction peaks at 27.082 ⁇ 0.2, 28.101 ⁇ 0.2, 29.505 ⁇ 0.2 and 34.098 ⁇ 0.2 values.
  • the X-ray powder diffraction pattern expressed in terms of 2 ⁇ (°) value and interplanar spacing (d) value of the crystalline form I has the characteristic diffraction peaks shown in Table 1, and the relative intensity of each peak is as shown in Table 1 As shown, among them, the diffraction peak with the highest peak height is used as the base peak, and its relative intensity is defined as 100%, as I 0 (the peak with a 2 ⁇ (°) value of 21.114 in Form I is the base peak), and the other peaks The ratio of its peak height to the base peak height is taken as its relative intensity I/I 0 :
  • the XRPD pattern of Form I is substantially as shown in Figure 2.
  • thermogravimetric analysis pattern (TGA pattern) of Form I is substantially as shown in Figure 3.
  • the TGA pattern of Form I shows a weight loss of no more than 0.6% between 0-120°C.
  • the TGA pattern of Form I shows a weight loss of 0.559% around 120°C.
  • the Form I is anhydrous.
  • the second aspect of the present invention provides a method for preparing a solid form of the compound of formula (I) according to the first aspect, comprising the following steps:
  • step (b) The liquid in step (a) is subjected to crystallization to obtain a solid form of the compound of formula (I).
  • the solid form of the compound of Formula (I) is Form I.
  • the free base of the compound of Formula (I) described in step (a) is in an amorphous form.
  • the mass volume ratio (w/v, in mg/mL) of the free base of the compound of formula (I) and the solvent in step (a) is 1:1-20:1; preferably 2:1 -18:1; more preferably 3:1-16:1.
  • the mass volume ratio (w/v, unit is mg/mL) of the free base of the compound of formula (I) and the solvent in step (a) is 3:1 or 15:1.
  • the solvent in step (a) is selected from the group consisting of methanol, ethanol, isopropyl alcohol, acetonitrile, ethyl acetate, dichloromethane, dichlorohexane, n-heptane, n-hexane, and methyl tert-butyl
  • ether isopropyl ether, acetone, 2-butanone, purified water, toluene, and tetrahydrofuran; preferably, selected from ethanol, ethyl acetate, dichlorohexane, n-heptane, methyl tert.
  • One or more butyl ethers are examples of butyl ethers.
  • the liquid of step (a) is a solution or suspension.
  • the crystallization treatment in step (b) is selected from suspension shaking, stirring, suspension centrifugation, slow volatilization, cooling crystallization, or/and adding an antisolvent. In some embodiments, the crystallization treatment in step (b) is stirring, and/or cooling and crystallization.
  • the temperature of the crystallization treatment in step (b) is 0-80°C, for example, it can be selected from 0°C, 5°C, 10°C, 15°C, 20°C, 25°C, 30°C , 35°C, 40°C, 45°C, 50°C, 55°C, 60°C, 65°C, 70°C, 75°C and 80°C.
  • the time of the crystallization treatment in step (b) is 0.25-10 days, for example, it can be selected from the group consisting of 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5 , 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5 and 10, any range consisting of end values, and there is no specific limit.
  • step (b) further includes separation, and/or drying steps.
  • the separation is filtration separation, centrifugation separation or a combination thereof.
  • the drying is vacuum drying or evaporation of the solvent.
  • the method for preparing Form I includes the following steps:
  • step (a) The liquid in step (a) is stirred at 10-35°C for 2-5 days, and the solid is collected to obtain a crystal of the compound of formula (I) Type I.
  • the solvent in step (a) is selected from one or more of methanol, ethanol, acetonitrile, acetone, 2-butanone, isopropyl ether, purified water, dichloromethane, methyl tert-butyl ether, toluene, n-heptane, ethyl acetate, tetrahydrofuran, and isopropanol.
  • the solvent in step (a) is selected from: one or more of methanol, acetonitrile, ethyl acetate, methylene chloride, n-heptane, ethanol, and methyl tert-butyl ether.
  • the solvent of step (a) is selected from: acetonitrile or ethanol.
  • the temperature in step (b) is 15-30°C, for example, it can be any range consisting of end values selected from 15°C, 16°C, 17°C, 18°C, 19°C, 20°C, 21°C, 22°C, 23°C, 24°C, 25°C, 26°C, 27°C, 28°C, 29°C and 30°C, without specific limitation.
  • the temperature in step (b) is 10-25°C, for example, it can be selected from 10°C, 11°C, 12°C, 13°C, 14°C, 15°C, 16°C, 17°C , 18°C, 19°C, 20°C, 21°C, 22°C, 23°C, 24°C and 25°C.
  • the time described in step (b) is 2.5-5 days, for example, it can be any end value selected from 2.5 days, 3 days, 3.5 days, 4 days, 4.5 days and 5 days.
  • the scope is not specifically limited.
  • step (b) collects the solid by solid-liquid separation.
  • the separation is filtration separation, centrifugation separation or a combination thereof.
  • step (b) further comprises a drying step after collecting the solid.
  • the drying is vacuum drying or evaporation of the solvent.
  • the method for preparing Form I includes the following steps:
  • step (a) The liquid in step (a) is stirred at the first temperature for a first period of time, lowered to the second temperature, and then stirred at the second temperature for a second period of time to obtain crystal form I of the compound of formula (I).
  • the solvent in step (a) is selected from one or more of ethanol, ethyl acetate, methylene chloride, n-heptane, and methyl tert-butyl ether.
  • the first temperature in step (b) is 45-70°C, for example, it can be selected from 45°C, 46°C, 47°C, 48°C, 49°C, 50°C, 51°C, 52°C, 53°C, 54°C, 55°C, 56°C, 57°C, 58°C, 59°C, 60°C, 61°C, 62°C, 63°C, 64°C, 65°C, 66°C, 67°C, 68°C Any range consisting of the end values of , 69°C and 70°C, with no specific limit.
  • the first period of time in step (b) is 2-6h, for example, it can be any range consisting of end values selected from 2h, 3h, 4h, 5h and 6h, and is not specifically limited.
  • the second temperature of step (b) is 10-40°C, for example, it can be any range consisting of end values selected from 10°C, 11°C, 12°C, 13°C, 14°C, 15°C, 16°C, 17°C, 18°C, 19°C, 20°C, 21°C, 22°C, 23°C, 24°C, 25°C, 26°C, 27°C, 28°C, 29°C, 30°C, 31°C, 32°C, 33°C, 34°C, 35°C, 36°C, 37°C, 38°C, 39°C and 40°C, without specific limitation.
  • the second period of time in step (b) is 0.25-3 days, for example, it can be selected from 0.25
  • the range may be any range consisting of the end values of days, 0.5 days, 1 day, 1.5 days, 2 days, 2.5 days and 3 days, without specific limitation.
  • a third aspect of the present invention provides a pharmaceutical composition, which pharmaceutical composition includes: a solid form of the compound of formula (I) described in the first aspect of the present invention, and a pharmaceutically acceptable carrier.
  • the pharmaceutical composition includes Form I of a compound of Formula (I), and a pharmaceutically acceptable carrier.
  • the fourth aspect of the present invention provides the use of a solid form of a compound of formula (I) as described in the first aspect of the present invention or a pharmaceutical composition as described in the third aspect of the present invention in the preparation of a medicament for treating and/or preventing diseases or conditions mediated by SHP2 or associated with abnormal SHP2 activity.
  • the fifth aspect of the present invention provides a method for treating diseases or conditions mediated by SHP2 or associated with abnormal SHP2 activity, the method comprising administering to a subject a therapeutically effective amount of a compound of formula (I) according to the first aspect of the present invention.
  • the solid form or the pharmaceutical composition according to the third aspect of the invention is provided.
  • Src homology-2 phosphatase is a protein tyrosine phosphatase encoded by the PTPN11 gene that contributes to multiple cellular functions including proliferation, differentiation, cell cycle maintenance, and migration. SHP2 is involved in signaling through Ras-mitogen-activated protein kinase, the JAK-STAT or phosphoinositide 3-kinase-AKT pathway.
  • SHP2 mediates extracellular regulated protein kinase (Erk)1 and Erk2 (Erkl/2) through receptor tyrosine kinases such as epidermal growth factor receptor (ErbB)1, ErbB2, and hepatocyte growth factor receptor (c-Met), Erk) activation of mitogen-activated protein kinase (MAP kinase).
  • Erk extracellular regulated protein kinase
  • Erkl/2 Erk2
  • receptor tyrosine kinases such as epidermal growth factor receptor (ErbB)1, ErbB2, and hepatocyte growth factor receptor (c-Met), Erk) activation of mitogen-activated protein kinase (MAP kinase).
  • SHP2 has two N-terminal Src homology 2 domains (N-SH2 and C-SH2), a protein tyrosine phosphatase (PTP) catalytic domain and a C-terminal tail.
  • the two SH2 domains control the subcellular localization and functional regulation of SHP2.
  • the compound molecule exists in an inactive conformation and inhibits its own activity through a binding network involving residues from both the N-SH2 and PTP domains.
  • SHP2 binds to specific tyrosine-phosphorylated sites on docking proteins such as cellular phosphorylated signal adapter molecules (Gab) 1 and Gab2 through its SH2 domain. This induces conformational changes that lead to SHP2 activation.
  • Gab cellular phosphorylated signal adapter molecules
  • diseases or conditions associated with aberrant SHP2 activity include solid tumors and hematologic tumors.
  • the SHP2-mediated disease or disorder is cancer, including, but not limited to, juvenile myelomonocytic leukemia (JMML), acute myeloid leukemia (AML), B-cell acute lymphoblastic leukemia (B -ALL), neuroblastoma, esophageal cancer, breast cancer, lung cancer, colon cancer, gastric cancer, head and neck cancer.
  • the crystal form I of the compound of formula (I) provided by the present invention has good stability at various temperatures (room temperature and high temperature) and in various solvents, which is more conducive to the development of preparations.
  • Figure 1 is a single crystal structure diagram of compound 5
  • Figure 2 is the XRPD pattern of crystal form I of the compound of formula (I);
  • FIG. 3 is the TGA spectrum of crystal form I of the compound of formula (I);
  • Figure 4 is the XRPD pattern of the compound of formula (I) obtained in Preparation Example 2.
  • the compound of formula (I) is (S)-(3-amino-5-(1-amino-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl) Pyrazin-2-yl)(2-amino-7,7-difluoro-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)methanone, which has the following structure :
  • the solid forms of the compounds of formula (I) of the present invention are polymorphs, including Form I of the compounds of formula (I).
  • Polymorphs Solids exist in either amorphous form or in crystalline form. In the case of crystalline form, the molecules are positioned in a three-dimensional lattice. When a compound crystallizes from a solution or slurry, it can crystallize in different spatial arrangements (a property known as "polymorphism"), forming crystals with different crystalline forms, which are known as "polymorphs". Different polymorphs of a given substance may differ from one another in one or more physical properties, such as solubility and dissolution rate, true specific gravity, crystal shape, packing pattern, flowability and/or solid state stability.
  • Production-scale crystallization can be accomplished by manipulating the solution so that the solubility limit of the compound of interest is exceeded. This can be accomplished by a variety of methods, such as dissolving the compound at a relatively high temperature and then cooling the solution below the saturation limit. Or reduce the liquid volume by boiling, normal pressure evaporation, vacuum drying or other methods.
  • the solubility of a compound of interest can be reduced by adding an antisolvent or a solvent or a mixture of such solvents in which the compound has low solubility. Another option is to adjust the pH to reduce solubility.
  • the "suspension centrifugation" mentioned in the present invention refers to a method in which the compound of formula (I) is mixed in a suitable solvent to form a turbid liquid and then centrifuged to obtain crystals.
  • suitable solvents can be water or organic solvents.
  • optimization of crystallization may include seeding the crystallization medium with crystals of the desired form. Additionally, many crystallization methods use a combination of the above strategies. One embodiment involves dissolving the compound of interest in a solvent at elevated temperatures and subsequently adding an appropriate volume of antisolvent in a controlled manner to bring the system just below saturation levels. At this point, the desired form of seed crystal can be added (and the integrity of the seed crystal maintained), and the system is cooled to complete crystallization. As used herein, the term "about” means ⁇ 5 based on a given numerical value.
  • solid form of the invention or “solid form of the compound of formula (I) of the invention” includes, but is not limited to, Form I of the compound of formula (I).
  • the solid form of the compound of formula (I) of the present invention as active ingredient can be administered in a suitable dosage form with one or more pharmaceutical carriers.
  • “Pharmaceutically acceptable carrier” refers to a non-toxic, inert, solid, semi-solid substance or liquid filler, diluent, encapsulating material or auxiliary formulation or any type of excipient, which is compatible with the subject to be administered (preferably a mammal, more preferably a human), and is suitable for delivering the active substance of the present invention to the target site without terminating its activity.
  • compositions of the present invention are formulated, dosed, and administered in a manner consistent with good medical practice.
  • the "therapeutically effective amount" of an active ingredient administered is determined by factors such as the specific condition to be treated, the individual being treated, the cause of the condition, the target of the drug, and the method of administration.
  • the present invention provides a solid form of the compound of formula (I) according to the first aspect of the present invention, and the pharmaceutical composition according to the third aspect of the present invention can be used to prepare the treatment and/or prevention of SHP2-mediated or related to abnormal SHP2 activity. medicine for a disease or condition.
  • the present invention provides a method for treating diseases or conditions mediated by SHP2 or related to abnormal SHP2 activity, comprising administering to a subject a therapeutically effective amount of a solid form of a compound of formula (I) described in the first aspect of the present invention, or the present invention.
  • the pharmaceutical composition according to the third aspect of the invention according to the third aspect of the invention.
  • a "therapeutically effective amount” refers to Formula (I of the present invention that will cause a biological or medical response in an individual, such as reducing or inhibiting enzymatic protein activity or improving symptoms, alleviating symptoms, alleviating or delaying disease progression, or preventing disease, etc. ) the amount of the solid form of the compound.
  • subject refers to an animal, preferably a mammal, and more preferably a human.
  • mammal refers to warm-blooded vertebrate mammals, including, for example, cats, dogs, rabbits, bears, foxes, wolves, monkeys, deer, rats, pigs, and humans.
  • Treatment means to alleviate, delay the progression, attenuate, prevent, or maintain an existing disease or condition (eg, cancer). Treatment also includes curing, preventing the progression of, or alleviating to some degree one or more symptoms of a disease or condition.
  • the structure and purity of the compound are determined by nuclear magnetic resonance ( 1 H-NMR) and/or liquid mass spectrometry (LC-MS).
  • LC-MS Agilent 1290 HPLC System/6130/6150 MS liquid mass spectrometer (manufacturer: Agilent), column Waters BEH/CHS, 50 ⁇ 2.1mm, 1.7 ⁇ m.
  • High-performance liquid chromatography (HPLC) analysis used Agilent 1260 Infinity HPLC, OpenLAB CDS Chemstation workstation, column XBridge C18 4.6*250mm, ID 5 ⁇ m column, and detector DAD.
  • Elemental analysis was performed using an inductively coupled plasma optical emission spectrometer, model icp 500; power 1300w; flow rate 1mL/min.
  • Known starting materials can be synthesized by methods known in the art, or can be purchased from ABCR GmbH&Co.KG, Acros Organics, Aldrich Chemical Company, Shaoyuan Chemical Technology (Accela ChemBio Inc) and Dari Chemicals, etc. company.
  • room temperature in the following examples refers to about 20-30°C, and overnight refers to about 10h to 16h.
  • X-ray powder diffraction In the present invention, the above-mentioned crystalline or amorphous powder X-ray diffraction pattern is obtained by known methods in the art, using the ARL Equinox3000 X-ray powder diffraction analyzer.
  • the XRPD test parameters are as follows in Table 2 Shown:
  • the position of each peak is determined by the 2 ⁇ (°) value. It is understood that different instruments and/or conditions may result in slightly different data, with variations in the position and relative intensity of each peak.
  • Single crystal X-ray diffraction (SXRD):
  • SXRD Single crystal X-ray diffraction
  • the single crystal X-ray diffraction pattern of compound 5 is obtained by known methods in the art, using a D8 Venture X diffractometer.
  • the SXRD test parameters are shown in Table 3 below.
  • the direct method SHELXT2014 is further used to analyze the crystal structure, and the absolute configuration can be confirmed.
  • High performance liquid chromatography In the present invention, high performance liquid chromatography (HPLC) was collected on Agilent1260 HPLC.
  • thermogravimetric analysis In the present invention, the thermogravimetric analysis spectrum of the above-mentioned crystal form is obtained by a known method in the art using a TGA550 thermogravimetric analyzer.
  • the TGA test parameters are shown in Table 4 below:
  • MTBE used in the present invention refers to methyl tert-butyl ether; P(tBu) 3 Pd G2: chloro[(tri-tert-butylphosphine)-2-(2-aminobiphenyl)]palladium(II); DMF: N,N-dimethylformamide; THF refers to tetrahydrofuran; LDA: lithium diisopropylamide; PE: petroleum ether; EA: ethyl acetate; Ti(OEt) 4 : tetrabutyl titanate; DIBAL-H: diisobutylaluminum hydride; DCM: dichloromethane; MeOH: methanol; HATU: 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate; TEA: triethylamine; DMSO: dimethyl sulfoxide; N-Boc-4-cyan
  • Step 1 Dissolve N-Boc-4-cyanopiperidine (648mg, 3.08mmol) in THF (10mL), and slowly add LDA (373.03mg, 3.48mmol, 1.74mL) under N 2 protection at -78°C. , stir the reaction for 45 minutes to obtain the reaction liquid.
  • the reaction mixture was purified by silica gel column chromatography (12g silica gel, 0-14% EA/100-86% PE) to obtain compound 2.
  • Step 2 Dissolve compound 2 (1.34mmol) in DMF (5mL) and water (500 ⁇ L), add P(tBu) 3 Pd G2 (138mg, 269.32 ⁇ mol) and triethylamine (326.48mg, 3.23mmol) under N 2 protection. , 450 ⁇ L), heated and stirred in an oil bath at 130°C for 12 hours. After the reaction was cooled to room temperature, 150 mL of water was added to quench the reaction, poured into a separatory funnel, and extracted with ethyl acetate (30 mL ⁇ 2). The organic phases were combined, washed with saturated brine (40 mL), and dried over anhydrous sodium sulfate. , filter, concentrate and spin to dryness. Purification by silica gel column (4g silica gel, 0-16% EA/100-84% PE) gave compound 3.
  • Step 1 Dissolve compound I-1 (2.35 g, 10 mmol), cyanamide (840 mg, 20 mmol), and sulfur powder (640 mg, 20 mmol) in pyridine (15 mL). The reaction was stirred at 130 ° C for 2 hours. After the reaction was completed, it was cooled to room temperature, 60 mL of ethyl acetate was added, and diatomaceous earth was filtered. The filter cake was washed with 50 mL of ethyl acetate for 3 times, and the organic phase was decompressed and dried to remove the solvent. Compound I-2 (3 g, 100% yield) was obtained. MS m/z (ESI): 292.1 [M+1] + .
  • Step 2 Dissolve compound I-2 (3g, 10.3mmol) in MeOH (40mL), and then add HCl in dioxane solution (4M (mol/L), 25mL). The reaction was stirred at 25°C for 2 hours. After the reaction is completed, the solvent is spin-dried under reduced pressure. Alkalized with DIPEA, and purified through column separation (20g silica gel, 1-12% MeOH/99-88% DCM), compound I-3 (2.5g, 100% yield) was obtained. MS m/z(ESI):192.0[M+1] + .
  • Step 3 Dissolve 3-amino-5-chloropyrazine-2-carboxylic acid (173mg, 1mmol) and compound I-3 (573mg, 3mmol) in ultra-dry DMF (10mL), add HATU (570mg, 1.5mmol) ), TEA (131 mg, 1.3 mmol), stir at room temperature for 1 hour. Add 50 mL of water, extract with ethyl acetate (30 mL , and after concentration under reduced pressure, compound I-4 (303 mg, 87.57% yield) was obtained. MS m/z(ESI):347.0[M+1] + .
  • Step 4 Dissolve compound I-4 (70 mg, 0.2 mmol) and compound 6 (73 mg, 0.24 mmol) in ultra-dry DMF (5 mL), add potassium carbonate (83 mg, 0.6 mmol), and stir at 70°C for 3 Hour. After concentration under reduced pressure, compound I-5 (59 mg, 47.9% yield) was purified through column separation (4g silica gel, 1-10% MeOH/99-90% DCM). MS m/z(ESI):617.2[M+1] + .
  • Step 5 Dissolve compound I-5 (59 mg, 0.096 mmol) in MeOH (3 mL), add dioxane hydrochloride solution (4 M (mol/L), 0.3 mL) to the reaction solution, keep at room temperature (24°C ) for 20 minutes. Preparative liquid phase separation and purification was performed to obtain the compound of formula (I) (21 mg, 42.85% yield). MS m/z(ESI):513.2[M+1] + .
  • the obtained solid was subjected to XRPD detection, and its XRPD pattern is shown in FIG2 , which is defined in the present application as the compound of formula (I)
  • the XRPD pattern of the obtained solid has peaks at the 2 ⁇ (°) values shown in the aforementioned Table 1, and the relative intensities of the peaks are shown in the aforementioned Table 1; its TGA pattern is shown in FIG3 , and in the TGA curve, the sample loses 0.559% of its weight when heated to about 120° C., so the crystal form I is an anhydrous substance.
  • Form I After being left open for 24 hours, the weight gain percentage of Form I was less than 2% but not less than 0.2%. According to the Chinese Pharmacopoeia's description of hygroscopic properties and the definition of hygroscopic weight gain, Crystal Form I was slightly hygroscopic.
  • Test example 1 Phosphatase activity detection
  • the IC 50 value was detected using the Homogeneous Full Length SHP-2 Assay Kit (BPS Bioscience #79330).
  • the kit uses 6,8-difluoro-4-methylumbelliferone phosphate (DiFMUP) as the reaction substrate. things.
  • SHP2 enzyme solution (diluted to 0.04ng/ ⁇ l with 1 ⁇ buffer) and 0.5 ⁇ M SHP-2 activating peptide (activating Peptide) in 1 ⁇ buffer solution containing 2.5mM dithiothreitol (DTT) Mix well to activate PTP, and at the same time add DMSO (0.1% (V/V)), compound free base of formula (I) or compound D1 (concentration: 0.5 nM-1 ⁇ M), mix well, and incubate for 1 hour. Add DiFMUP (50 ⁇ M, the total volume of the reaction solution is 20 ⁇ L) to start the reaction.
  • DMSO 0.1% (V/V)
  • compound free base of formula (I) or compound D1 Concentration: 0.5 nM-1 ⁇ M
  • MV-4-11 cells ATCC #CRL-9591, 20,000 cells/well
  • a culture medium of 80 ⁇ L/well containing 10% fetal bovine serum (FBS) (IMDM), Gibco #10099-141C).
  • FBS fetal bovine serum
  • IMDM fetal bovine serum
  • Table 10 IC 50 value of the compound of formula (I) on the inhibitory activity of MV-4-11 cell proliferation
  • the compound of formula (I) of the present invention has high inhibitory activity on the proliferation of MV-4-11 cells.
  • Test Example 3 Inhibitory effect on hERG potassium ion channel
  • the electrophysiological manual patch clamp method was used to test the effect of the free base of the compound of formula (I) on the hERG potassium channel (human Ether-a-go-go Related Gene potassium channel) current.
  • CHO cells stably expressing hERG are cultured in a cell culture dish with a diameter of 35 mm, placed in a 37°C, 5% CO2 incubator, and passaged every 48 hours at a ratio of 1:5.
  • the medium formula is: 90% F12 medium. (Invitrogen Company), 10% fetal calf serum (Gibco Company), 100 ⁇ g/mL G418 (Invitrogen Company) and 100 ⁇ g/mL Hygromycin B antibiotic (Invitrogen Company).
  • trypsin-EDTA Trypsin-EDTA
  • Invitrogen Company trypsin-EDTA
  • CHO (Chinese hamster ovary) cells stably expressing hERG potassium channels were used to record hERG potassium channel currents at room temperature using whole-cell patch clamp technology.
  • the glass microelectrode is drawn from a glass electrode blank (BF150-86-10, Sutter) by a drawing instrument. The tip resistance after infusion of the electrode liquid is about 2-5M ⁇ .
  • the glass microelectrode can be connected by inserting it into the amplifier probe. to the patch clamp amplifier. Clamping voltage and data recording were controlled and recorded via computer by pClamp 10 software, with a sampling frequency of 10kHz and a filtering frequency of 2kHz.
  • the cells were clamped at -80mV, and the step voltage of induced hERG potassium current (I hERG) was given a 2s depolarization voltage from -80mV to +20mV, and then repolarization to -50mV for 1s. then returns to -80mV.
  • This voltage stimulation was given every 10 s, and the administration process was started after confirming that the hERG potassium current was stable (1 minute).
  • Compounds were administered for at least 1 min at each concentration tested, and at least 2 cells were tested at each concentration (n ⁇ 2).
  • Inhibition% [1 – (I/Io)] ⁇ 100%. Among them, Inhibition% represents the compound’s inhibition of hERG potassium current. Fraction, I and Io represent the amplitude of the hERG potassium current after and before the addition of the drug, respectively.
  • Table 11 The results of the inhibition of hERG potassium channel current by the compound of formula (I) are shown in Table 11.
  • Table 11 IC 50 value of compound of formula (I) for inhibition of hERG potassium channel current
  • the culture conditions of human esophageal squamous cell carcinoma cell line KYSE-520 are RPMI 1640 medium containing 10% fetal calf serum, placed in a 37°C 5% CO 2 sterile incubator. Passage 2-3 times a week, digest with 0.25% trypsin-EDTA, terminate digestion with the above complete medium, centrifuge at 1000 rpm for 5 minutes, discard the supernatant, resuspend the cells at a ratio of 1:3-1:5 Proportional passage. Collect logarithmic growth phase cells, resuspend them in serum-free RPMI 1640 medium, count and adjust to appropriate density.
  • KYSE-520 cells (3 ⁇ 10 6 /mouse) were inoculated into the right ventral back of female Balb/C nude mice about 6-8 weeks old.
  • Administration was started on the day of grouping, once a day, and the day of grouping was defined as day 0.
  • Tumor diameter was measured twice a week with a vernier caliper.
  • the daily dosage and the obtained tumor reproliferation rate results are shown in Table 12.
  • Table 12 Tumor proliferation rate of compounds of formula (I) of the present invention
  • the culture conditions of the mouse colon cancer cell line MC38 were RPMI 1640 medium containing 10% fetal calf serum and placed in a 37°C 5% CO 2 sterile incubator. Passage 2-3 times a week, digest with 0.25% trypsin-EDTA, terminate digestion with the above complete medium, centrifuge at 1000 rpm for 5 minutes, discard the supernatant, resuspend the cells at a ratio of 1:4-1:8 Proportional passage. Collect logarithmic growth phase cells, resuspend them in serum-free RPMI 1640 medium, count and adjust to appropriate density.
  • Table 13 Tumor proliferation rate of compounds of formula (I) of the present invention

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Abstract

La présente invention concerne un dérivé de méthanone à substitution hétérocyclo et son utilisation. En particulier, la présente invention concerne une forme solide de (S)-(3-amino-5-(1-amino-1,3-dihydrospiro[indène-2,4'-pipéridin]-1'-yl)pyrazin-2-yl)(2-amino-7,7-difluoro-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)méthanone, et son utilisation. De plus, la présente invention concerne également une composition pharmaceutique contenant la forme solide et son utilisation.
PCT/CN2023/120247 2022-09-22 2023-09-21 Forme solide d'un dérivé de méthanone à substitution hétérocyclo et son utilisation WO2024061298A1 (fr)

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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2018172984A1 (fr) * 2017-03-23 2018-09-27 Jacobio Pharmaceuticals Co., Ltd. Nouveaux dérivés hétérocycliques utiles en tant qu'inhibiteurs de shp2
WO2020063760A1 (fr) * 2018-09-26 2020-04-02 Jacobio Pharmaceuticals Co., Ltd. Nouveaux dérivés hétérocycliques utiles en tant qu'inhibiteurs de shp2
CN112166110A (zh) * 2018-03-21 2021-01-01 传达治疗有限公司 Shp2磷酸酶抑制剂及其使用方法
WO2022199611A1 (fr) * 2021-03-23 2022-09-29 上海海雁医药科技有限公司 Dérivé de cétone substitué par un hétérocycle, et composition et son utilisation médicinale

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2018172984A1 (fr) * 2017-03-23 2018-09-27 Jacobio Pharmaceuticals Co., Ltd. Nouveaux dérivés hétérocycliques utiles en tant qu'inhibiteurs de shp2
CN112166110A (zh) * 2018-03-21 2021-01-01 传达治疗有限公司 Shp2磷酸酶抑制剂及其使用方法
WO2020063760A1 (fr) * 2018-09-26 2020-04-02 Jacobio Pharmaceuticals Co., Ltd. Nouveaux dérivés hétérocycliques utiles en tant qu'inhibiteurs de shp2
WO2022199611A1 (fr) * 2021-03-23 2022-09-29 上海海雁医药科技有限公司 Dérivé de cétone substitué par un hétérocycle, et composition et son utilisation médicinale

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