WO2025157261A1 - G12d抑制剂化合物晶型及其制备方法 - Google Patents

G12d抑制剂化合物晶型及其制备方法

Info

Publication number
WO2025157261A1
WO2025157261A1 PCT/CN2025/074649 CN2025074649W WO2025157261A1 WO 2025157261 A1 WO2025157261 A1 WO 2025157261A1 CN 2025074649 W CN2025074649 W CN 2025074649W WO 2025157261 A1 WO2025157261 A1 WO 2025157261A1
Authority
WO
WIPO (PCT)
Prior art keywords
cancer
methyl
compound
ray powder
powder diffraction
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
PCT/CN2025/074649
Other languages
English (en)
French (fr)
Inventor
吴琪
陆伟栋
杨俊然
邵启云
杜振兴
冯君
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Shanghai Hengrui Pharmaceutical Co Ltd
Jiangsu Hengrui Pharmaceutical Co Ltd
Original Assignee
Shanghai Hengrui Pharmaceutical Co Ltd
Jiangsu Hengrui Pharmaceutical Co Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Shanghai Hengrui Pharmaceutical Co Ltd, Jiangsu Hengrui Pharmaceutical Co Ltd filed Critical Shanghai Hengrui Pharmaceutical Co Ltd
Publication of WO2025157261A1 publication Critical patent/WO2025157261A1/zh
Anticipated expiration legal-status Critical
Pending legal-status Critical Current

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A61K31/553—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having at least one nitrogen and one oxygen as ring hetero atoms, e.g. loxapine, staurosporine
    • 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
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/22—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains four or more hetero rings

Definitions

  • the present disclosure belongs to the field of pharmaceuticals and relates to a G12D inhibitor compound crystal form and a preparation method thereof.
  • the KRAS protein lacks traditional small molecule binding sites on its surface and has an extremely high affinity for guanylate, making it extremely difficult to inhibit. Long considered an undruggable drug target, however, given the importance and prevalence of KRAS activation in cancer progression, KRAS has been and remains a highly sought-after target for drug development. As a mutant with widespread and overexpressed expression in various tumors, G12D, the development of inhibitors targeting it, holds significant clinical significance.
  • WO2024022444 discloses a novel G12D inhibitor compound, 2-amino-4-((5S,5aS,6S,9R)-12-((1-((4-(difluoromethylidene)piperidin-1-yl)methyl)cyclopropyl)methoxy)-1-fluoro-5-methyl-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methylnaphtho[1,8-ab]heptyl-2-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile (Compound A).
  • crystal structure of a pharmaceutically active ingredient often affects the chemical and physical stability of the drug. Differences in crystallization and storage conditions can lead to variations in the compound's crystal structure, sometimes resulting in the formation of alternative crystalline forms.
  • amorphous pharmaceutical products lack a regular crystal structure and often exhibit other drawbacks, such as poor product stability, difficulty in filtration, susceptibility to agglomeration, and poor flowability. Therefore, studying their crystal forms is crucial for developing drugs suitable for industrial production and possessing excellent biological activity.
  • the present disclosure provides a crystalline form A of the compound 2-amino-4-((5S,5aS,6S,9R)-12-((1-((4-(difluoromethylidene)piperidin-1-yl)methyl)cyclopropyl)methoxy)-1-fluoro-5-methyl-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methano[1,8-ab]heptan-2-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile, and an X-ray powder diffraction pattern expressed in terms of a diffraction angle 2 ⁇ , having characteristic peaks at 5.235, 6.954, 8.874, 14.709, and 21.043.
  • the A crystal form has an X-ray powder diffraction pattern represented by a diffraction angle of 2 ⁇ , with characteristic peaks at 5.235, 6.954, 8.874, 14.709, 16.053, 19.239, 19.776, and 21.043.
  • the X-ray powder diffraction pattern of the crystal form A expressed in terms of a diffraction angle 2 ⁇ is shown in FIG2 .
  • the present disclosure provides a crystalline form B of the compound 2-amino-4-((5S,5aS,6S,9R)-12-((1-((4-(difluoromethylidene)piperidin-1-yl)methyl)cyclopropyl)methoxy)-1-fluoro-5-methyl-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methano[1,8-ab]heptan-2-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile, and an X-ray powder diffraction pattern expressed in diffraction angle 2 ⁇ degrees, with characteristic peaks at 8.845, 12.746, 14.040, 14.480, 17.371, and 18.833.
  • the B crystalline form has an X-ray powder diffraction pattern represented by a diffraction angle of 2 ⁇ , with characteristic peaks at 8.845, 9.258, 12.746, 14.040, 14.480, 16.475, 17.371, and 18.833.
  • the B crystalline form has an X-ray powder diffraction pattern expressed as a diffraction angle 2 ⁇ , with characteristic peaks at 8.845, 9.258, 12.746, 14.040, 14.480, 15.800, 16.475, 17.371, 18.833, 20.883, and 28.999.
  • the X-ray powder diffraction pattern of the B crystal form expressed in terms of a diffraction angle 2 ⁇ is shown in FIG3 .
  • the present disclosure provides a crystalline form C of the compound 2-amino-4-((5S,5aS,6S,9R)-12-((1-((4-(difluoromethylidene)piperidin-1-yl)methyl)cyclopropyl)methoxy)-1-fluoro-5-methyl-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methanaptho[1,8-ab]heptylcyclo-2-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile, and an X-ray powder diffraction pattern expressed in terms of a diffraction angle 2 ⁇ , having characteristic peaks at 5.083, 10.326, 11.776, 13.543, and 15.564.
  • the C crystalline form has an X-ray powder diffraction pattern represented by a diffraction angle of 2 ⁇ , with characteristic peaks at 5.083, 10.326, 11.776, 13.543, 15.564, 16.060, and 17.675.
  • the C crystalline form has an X-ray powder diffraction pattern expressed as a diffraction angle 2 ⁇ , with characteristic peaks at 5.083, 10.326, 11.776, 13.543, 15.564, 16.060, 17.675, 18.451, 20.167, and 21.940.
  • the X-ray powder diffraction pattern of the C crystal form expressed in terms of a diffraction angle 2 ⁇ is shown in FIG4 .
  • the present disclosure provides a crystalline form D of the compound 2-amino-4-((5S,5aS,6S,9R)-12-((1-((4-(difluoromethylidene)piperidin-1-yl)methyl)cyclopropyl)methoxy)-1-fluoro-5-methyl-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methanaphtho[1,8-ab]heptylcyclo-2-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile, and an X-ray powder diffraction pattern expressed in terms of a diffraction angle 2 ⁇ , having characteristic peaks at 4.865, 8.452, 9.819, 12.795, 14.695, 16.052, and 19.632.
  • the D crystalline form has an X-ray powder diffraction pattern represented by a diffraction angle of 2 ⁇ , with characteristic peaks at 4.865, 8.452, 9.819, 10.763, 12.795, 14.695, 16.052, 17.818, and 19.632.
  • the D crystalline form has an X-ray powder diffraction pattern expressed as a diffraction angle 2 ⁇ , with characteristic peaks at 4.865, 8.452, 9.819, 10.763, 12.795, 14.695, 16.052, 16.954, 17.818, 19.632, and 21.197.
  • the X-ray powder diffraction pattern of the D crystal form expressed in terms of a diffraction angle of 2 ⁇ is shown in FIG5 .
  • the present disclosure provides a crystalline form E of the compound 2-amino-4-((5S,5aS,6S,9R)-12-((1-((4-(difluoromethylidene)piperidin-1-yl)methyl)cyclopropyl)methoxy)-1-fluoro-5-methyl-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methanaphtho[1,8-ab]heptylcyclo-2-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile, and an X-ray powder diffraction pattern expressed in terms of a diffraction angle 2 ⁇ , having characteristic peaks at 7.155, 9.117, 11.638, 16.461, 17.277, and 20.652.
  • the E crystalline form has an X-ray powder diffraction pattern represented by a diffraction angle of 2 ⁇ , with characteristic peaks at 7.155, 9.117, 11.638, 13.672, 15.285, 16.461, 17.277, and 20.652.
  • the E crystalline form has an X-ray powder diffraction pattern expressed as a diffraction angle 2 ⁇ , with characteristic peaks at 7.155, 9.117, 11.638, 13.672, 15.285, 16.461, 17.277, 20.652, 21.734, and 23.001.
  • the X-ray powder diffraction pattern of the E crystal form expressed in terms of a diffraction angle of 2 ⁇ is shown in FIG6 .
  • the present disclosure provides a crystalline form F of the compound 2-amino-4-((5S,5aS,6S,9R)-12-((1-((4-(difluoromethylidene)piperidin-1-yl)methyl)cyclopropyl)methoxy)-1-fluoro-5-methyl-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methanaptho[1,8-ab]heptyl-2-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile, and an X-ray powder diffraction pattern expressed in terms of a diffraction angle 2 ⁇ , having characteristic peaks at 4.684, 10.040, 13.134, 14.247, 17.432, and 20.421.
  • the F crystalline form has an X-ray powder diffraction pattern represented by a diffraction angle of 2 ⁇ , with characteristic peaks at 4.684, 10.040, 13.134, 14.247, 15.464, 17.432, 19.688, and 20.421.
  • the F crystalline form has an X-ray powder diffraction pattern expressed as a diffraction angle 2 ⁇ , with characteristic peaks at 4.684, 10.040, 13.134, 14.247, 15.464, 16.709, 17.432, 19.688, 20.421, and 22.909.
  • the X-ray powder diffraction pattern of the F crystal form expressed in terms of a diffraction angle of 2 ⁇ is shown in FIG7 .
  • the present disclosure provides a crystalline form G of the compound 2-amino-4-((5S,5aS,6S,9R)-12-((1-((4-(difluoromethylidene)piperidin-1-yl)methyl)cyclopropyl)methoxy)-1-fluoro-5-methyl-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methanaphtho[1,8-ab]heptylcyclo-2-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile, and an X-ray powder diffraction pattern expressed in terms of a diffraction angle 2 ⁇ , having characteristic peaks at 8.404, 11.861, 14.205, 15.114, 17.113, 19.116, and 21.354.
  • the G crystalline form has an X-ray powder diffraction pattern expressed as a diffraction angle 2 ⁇ , with characteristic peaks at 8.404, 10.099, 11.861, 14.205, 15.114, 15.570, 17.113, 19.116, 19.948, and 21.354.
  • the G crystalline form has an X-ray powder diffraction pattern expressed as a diffraction angle 2 ⁇ , with characteristic peaks at 8.404, 10.099, 11.861, 13.401, 14.205, 15.114, 15.570, 17.113, 19.116, 19.948, and 21.354.
  • the X-ray powder diffraction pattern of the G crystal form expressed in terms of a diffraction angle 2 ⁇ is shown in FIG8 .
  • the present disclosure provides a crystalline H form of the compound 2-amino-4-((5S,5aS,6S,9R)-12-((1-((4-(difluoromethylidene)piperidin-1-yl)methyl)cyclopropyl)methoxy)-1-fluoro-5-methyl-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methanaphtho[1,8-ab]heptylcyclo-2-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile, and an X-ray powder diffraction pattern expressed in terms of a diffraction angle 2 ⁇ , having characteristic peaks at 10.615, 12.690, 16.070, 17.610, 19.226, 21.218, and 24.456.
  • the H crystalline form has an X-ray powder diffraction pattern expressed as a diffraction angle 2 ⁇ , with characteristic peaks at 10.615, 12.690, 15.582, 16.070, 16.339, 17.610, 19.226, 21.218, and 24.456.
  • the H crystalline form has an X-ray powder diffraction pattern expressed as a diffraction angle 2 ⁇ , with characteristic peaks at 8.677, 10.615, 11.061, 12.690, 13.221, 15.582, 16.070, 16.339, 17.610, 19.226, 21.218, and 24.456.
  • the H crystal form has an X-ray powder diffraction pattern represented by a diffraction angle of 2 ⁇ as shown in FIG9 .
  • the present disclosure provides a crystalline form I of the compound 2-amino-4-((5S,5aS,6S,9R)-12-((1-((4-(difluoromethylidene)piperidin-1-yl)methyl)cyclopropyl)methoxy)-1-fluoro-5-methyl-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methanaphtho[1,8-ab]heptylcyclo-2-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile, and an X-ray powder diffraction pattern expressed in terms of a diffraction angle 2 ⁇ , having characteristic peaks at 5.063, 7.165, 9.911, 15.902, and 19.507.
  • the Form I has an X-ray powder diffraction pattern represented by a diffraction angle of 2 ⁇ , with characteristic peaks at 5.063, 7.165, 9.911, 15.902, 16.411, 17.311, and 19.507.
  • the Form I has an X-ray powder diffraction pattern expressed as a diffraction angle of 2 ⁇ , with characteristic peaks at 5.063, 7.165, 9.911, 13.484, 15.902, 16.411, 17.311, 17.762, and 19.507.
  • the X-ray powder diffraction pattern of the Form I expressed in terms of a diffraction angle of 2 ⁇ is shown in FIG10 .
  • the present disclosure provides a J crystalline form of the compound 2-amino-4-((5S,5aS,6S,9R)-12-((1-((4-(difluoromethylidene)piperidin-1-yl)methyl)cyclopropyl)methoxy)-1-fluoro-5-methyl-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methanaphtho[1,8-ab]heptylcyclo-2-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile, and an X-ray powder diffraction pattern expressed in terms of a diffraction angle 2 ⁇ , having characteristic peaks at 8.630, 10.574, 15.783, 17.686, 19.265, and 24.076.
  • the J crystalline form has an X-ray powder diffraction pattern expressed as a diffraction angle 2 ⁇ , with characteristic peaks at 8.630, 10.574, 15.783, 17.686, 19.265, 20.898, 24.076, and 25.093.
  • the J crystalline form has an X-ray powder diffraction pattern expressed as a diffraction angle 2 ⁇ , with characteristic peaks at 8.630, 10.574, 12.697, 15.783, 17.686, 19.265, 20.898, 21.274, 24.076, and 25.093.
  • the X-ray powder diffraction pattern of the J crystal form expressed in terms of a diffraction angle of 2 ⁇ is shown in FIG11 .
  • the present disclosure provides a K crystal form of the compound 2-amino-4-((5S,5aS,6S,9R)-12-((1-((4-(difluoromethylidene)piperidin-1-yl)methyl)cyclopropyl)methoxy)-1-fluoro-5-methyl-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methanaptho[1,8-ab]heptylcyclo-2-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile, and an X-ray powder diffraction pattern expressed in terms of a diffraction angle 2 ⁇ , having characteristic peaks at 8.434, 11.714, 13.979, 19.124, and 20.773.
  • the K crystal form has an X-ray powder diffraction pattern represented by a diffraction angle of 2 ⁇ , with characteristic peaks at 8.434, 9.603, 11.714, 13.979, 16.820, 19.124, and 20.773.
  • the K crystal form has an X-ray powder diffraction pattern represented by a diffraction angle of 2 ⁇ , with characteristic peaks at 8.434, 9.603, 10.524, 11.714, 13.407, 13.979, 16.820, 19.124, and 20.773.
  • the X-ray powder diffraction pattern of the K crystal form expressed in terms of a diffraction angle of 2 ⁇ is shown in FIG12 .
  • the present disclosure provides a crystalline form L of the compound 2-amino-4-((5S,5aS,6S,9R)-12-((1-((4-(difluoromethylidene)piperidin-1-yl)methyl)cyclopropyl)methoxy)-1-fluoro-5-methyl-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methanaphtho[1,8-ab]heptylcyclo-2-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile, and an X-ray powder diffraction pattern expressed in terms of a diffraction angle 2 ⁇ , having characteristic peaks at 4.959, 8.605, 10.908, 14.761, 16.656, and 19.649.
  • the L crystalline form has an X-ray powder diffraction pattern represented by a diffraction angle of 2 ⁇ , with characteristic peaks at 4.959, 8.605, 10.908, 12.928, 14.761, 16.167, 16.656, 18.089, 19.649, and 19.887.
  • the L crystalline form has an X-ray powder diffraction pattern expressed as a diffraction angle of 2 ⁇ , with characteristic peaks at 4.959, 8.605, 10.908, 12.928, 13.669, 14.761, 16.167, 16.656, 17.054, 18.089, 19.649, 21.286, 22.463, and 25.634.
  • the L crystal form has an X-ray powder diffraction pattern represented by a diffraction angle of 2 ⁇ as shown in FIG13 .
  • the present disclosure provides a crystalline form M of the compound 2-amino-4-((5S,5aS,6S,9R)-12-((1-((4-(difluoromethylidene)piperidin-1-yl)methyl)cyclopropyl)methoxy)-1-fluoro-5-methyl-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methanaptho[1,8-ab]heptylcyclo-2-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile, and an X-ray powder diffraction pattern expressed in terms of a diffraction angle 2 ⁇ , having characteristic peaks at 5.607, 7.457, 13.037, 13.940, 17.177, and 19.704.
  • the M crystalline form has an X-ray powder diffraction pattern expressed as a diffraction angle of 2 ⁇ , with characteristic peaks at 5.607, 7.457, 10.102, 11.312, 13.037, 13.940, 16.658, 17.177, 17.752, and 19.704.
  • the M crystalline form has an X-ray powder diffraction pattern expressed as a diffraction angle of 2 ⁇ , with characteristic peaks at 5.607, 7.457, 10.102, 11.312, 13.037, 13.940, 16.290, 16.658, 17.177, 17.752, 18.631, 19.704, and 22.663.
  • the X-ray powder diffraction pattern of the M crystal form expressed in terms of a diffraction angle of 2 ⁇ is shown in FIG14 .
  • the A, B, C, D, E, F, G, H, I, J, K, L or M crystal form of compound A described in the present disclosure has an X-ray powder diffraction pattern expressed in terms of a diffraction angle 2 ⁇ , wherein the error range of the 2 ⁇ angle is ⁇ 0.2.
  • the present disclosure also provides a method for preparing the aforementioned crystal form, which is selected from any of the following methods:
  • the method for preparing the aforementioned crystalline form of Compound A comprises (a) mixing the compound 2-amino-4-((5S,5aS,6S,9R)-12-((1-((4-(difluoromethylidene)piperidin-1-yl)methyl)cyclopropyl)methoxy)-1-fluoro-5-methyl-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methylnaphtho[1,8-ab]heptyl-2-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile with a solvent (1), wherein the solvent (1) is selected from n-heptane or water,
  • the method for preparing the aforementioned crystalline form of compound B comprises (a) mixing the compound 2-amino-4-((5S,5aS,6S,9R)-12-((1-((4-(difluoromethylidene)piperidin-1-yl)methyl)cyclopropyl)methoxy)-1-fluoro-5-methyl-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methylnaphtho[1,8-ab]heptyl-2-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile with a solvent (2), wherein the solvent (2) is selected from ethanol, isopropanol/ethanol (2:3, v/v), 10% water/methanol, 7% water/ethanol, ethyl acetate/ethanol (1:1, v/v) or tetrahydrofuran/ethanol (1
  • the method for preparing the aforementioned crystalline form of compound C comprises (a) mixing the compound 2-amino-4-((5S,5aS,6S,9R)-12-((1-((4-(difluoromethylidene)piperidin-1-yl)methyl)cyclopropyl)methoxy)-1-fluoro-5-methyl-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methylnaphtho[1,8-ab]heptyl-2-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile with a solvent (3), wherein the solvent (3) is selected from acetone,
  • the method for preparing the aforementioned crystalline form of compound D comprises (a) mixing the compound 2-amino-4-((5S,5aS,6S,9R)-12-((1-((4-(difluoromethylidene)piperidin-1-yl)methyl)cyclopropyl)methoxy)-1-fluoro-5-methyl-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methylnaphtho[1,8-ab]heptyl-2-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile with a solvent (4), wherein the solvent (4) is selected from acetonitrile,
  • the method for preparing the aforementioned crystalline form of Compound E comprises (a) mixing the compound 2-amino-4-((5S,5aS,6S,9R)-12-((1-((4-(difluoromethylidene)piperidin-1-yl)methyl)cyclopropyl)methoxy)-1-fluoro-5-methyl-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methylnaphtho[1,8-ab]heptyl-2-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile with a solvent (5), wherein the solvent (5) is selected from ethyl acetate, isopropyl acetate, methyl tert-butyl ether or ethyl acetate/n-heptane (1:1, v/v);
  • the method for preparing the aforementioned crystalline form of compound F comprises (a) mixing the compound 2-amino-4-((5S,5aS,6S,9R)-12-((1-((4-(difluoromethylidene)piperidin-1-yl)methyl)cyclopropyl)methoxy)-1-fluoro-5-methyl-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methylnaphtho[1,8-ab]heptyl-2-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile with a solvent (6), wherein the solvent (6) is selected from 10% water/acetone (v/v),
  • the method for preparing the aforementioned crystalline form of compound G comprises (a) mixing the compound 2-amino-4-((5S,5aS,6S,9R)-12-((1-((4-(difluoromethylidene)piperidin-1-yl)methyl)cyclopropyl)methoxy)-1-fluoro-5-methyl-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methylnaphtho[1,8-ab]heptyl-2-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile with a solvent (7), wherein the solvent (7) is selected from methanol/water (1:1, v/v);
  • the method for preparing the aforementioned crystalline form of Compound G comprises (a) mixing the compound 2-amino-4-((5S,5aS,6S,9R)-12-((1-((4-(difluoromethylidene)piperidin-1-yl)methyl)cyclopropyl)methoxy)-1-fluoro-5-methyl-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methylnaphtho[1,8-ab]heptylcyclo-2-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile with a solvent (8), stirring and dissolving the mixture or heating the mixture to dissolve the mixture, wherein the solvent (8) is selected from acetonitrile/methanol (1:1, v/v).
  • the method for preparing the aforementioned crystalline form of compound H comprises (a) mixing the compound 2-amino-4-((5S,5aS,6S,9R)-12-((1-((4-(difluoromethylidene)piperidin-1-yl)methyl)cyclopropyl)methoxy)-1-fluoro-5-methyl-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methylnaphtho[1,8-ab]heptylcyclo-2-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile with a solvent (9), wherein the solvent (9) is selected from isopropyl ether,
  • the method for preparing the aforementioned crystalline form of compound H comprises (a) mixing the compound 2-amino-4-((5S,5aS,6S,9R)-12-((1-((4-(difluoromethylidene)piperidin-1-yl)methyl)cyclopropyl)methoxy)-1-fluoro-5-methyl-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methylnaphtho[1,8-ab]heptylcyclo-2-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile with a solvent (10), stirring and dissolving the mixture or heating the mixture to dissolve the mixture, wherein the solvent (10) is selected from propylene glycol methyl ether or acetone,
  • the method for preparing the aforementioned crystalline form of Compound I comprises (a) mixing the compound 2-amino-4-((5S,5aS,6S,9R)-12-((1-((4-(difluoromethylidene)piperidin-1-yl)methyl)cyclopropyl)methoxy)-1-fluoro-5-methyl-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methylnaphtho[1,8-ab]heptyl-2-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile with a solvent (12), stirring and dissolving the mixture or heating the mixture to dissolve the mixture, wherein the solvent (12) is selected from dioxane,
  • the method for preparing the aforementioned crystalline form of Compound J comprises (a) mixing the compound 2-amino-4-((5S,5aS,6S,9R)-12-((1-((4-(difluoromethylidene)piperidin-1-yl)methyl)cyclopropyl)methoxy)-1-fluoro-5-methyl-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methylnaphtho[1,8-ab]heptylcyclo-2-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile with a solvent (14), stirring and dissolving the mixture or heating the mixture to dissolve the mixture, wherein the solvent (14) is selected from methanol,
  • the method for preparing the aforementioned compound K crystal form comprises (a) mixing the compound 2-amino-4-((5S,5aS,6S,9R)-12-((1-((4-(difluoromethylidene)piperidin-1-yl)methyl)cyclopropyl)methoxy)-1-fluoro-5-methyl-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methylnaphtho[1,8-ab]heptylcyclo-2-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile with a solvent (15), stirring and dissolving the mixture or heating the mixture to dissolve the mixture, wherein the solvent (15) is selected from water/methanol (1:9, v/v);
  • the method for preparing the aforementioned crystalline form of compound L comprises (a) mixing the compound 2-amino-4-((5S,5aS,6S,9R)-12-((1-((4-(difluoromethylidene)piperidin-1-yl)methyl)cyclopropyl)methoxy)-1-fluoro-5-methyl-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methylnaphtho[1,8-ab]heptyl-2-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile with a solvent (16), wherein the solvent (16) is selected from methyl acetate,
  • the method for preparing the aforementioned crystalline form of compound M comprises (a) mixing the compound 2-amino-4-((5S,5aS,6S,9R)-12-((1-((4-(difluoromethylidene)piperidin-1-yl)methyl)cyclopropyl)methoxy)-1-fluoro-5-methyl-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methylnaphtho[1,8-ab]heptyl-2-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile with a solvent (17), wherein the solvent (17) is selected from toluene,
  • the preparation method disclosed herein further comprises any one of the steps of crystallization, filtration, washing or drying.
  • the crystallization includes but is not limited to stirring crystallization (dissolution crystallization, slurry crystallization) and volatile crystallization.
  • the drying method includes but is not limited to forced air drying and vacuum drying.
  • the drying temperature is generally 25°C to 100°C, preferably 30°C to 70°C, such as 40°C, 50°C or 60°C.
  • the present disclosure also provides a pharmaceutical composition
  • a pharmaceutical composition comprising the aforementioned crystal form and a pharmaceutically acceptable excipient.
  • the present disclosure also provides a pharmaceutical composition prepared from the aforementioned crystal form and a pharmaceutically acceptable excipient.
  • the present disclosure also provides a method for preparing a pharmaceutical composition, comprising the step of mixing the aforementioned crystal form with a pharmaceutically acceptable excipient.
  • the present disclosure also provides the use of the aforementioned crystalline form or the aforementioned pharmaceutical composition in the preparation of a medicament for preventing and/or treating a disease or condition mediated by KRAS G12D.
  • the disease or condition mediated by KRAS G12D is selected from brain cancer, thyroid cancer, head and neck cancer, nasopharyngeal cancer, pharyngeal cancer, oral cancer, salivary gland cancer, esophageal cancer, gastric cancer, lung cancer, liver cancer, kidney cancer, pancreatic cancer, gallbladder cancer, bile duct cancer, colorectal cancer, small intestine cancer, gastrointestinal stromal tumor, urothelial cancer, urethral cancer, bladder cancer, breast cancer, vaginal cancer, ovarian cancer, endometrial cancer, cervical cancer, fallopian tube cancer, testicular cancer, prostate cancer, hemangioma, leukemia, lymphoma, myeloma, skin cancer, lipoma, bone cancer, soft
  • the present disclosure also provides the use of the aforementioned crystal form or the aforementioned pharmaceutical composition in the preparation of a drug for preventing and/or treating a tumor.
  • the tumor is selected from brain cancer, thyroid cancer, head and neck cancer, nasopharyngeal cancer, pharyngeal cancer, oral cancer, salivary gland cancer, esophageal cancer, gastric cancer, lung cancer, liver cancer, kidney cancer, pancreatic cancer, gallbladder cancer, bile duct cancer, colorectal cancer, small intestine cancer, gastrointestinal stromal tumor, urothelial cancer, urethral cancer, bladder cancer, breast cancer, vaginal cancer, ovarian cancer, endometrial cancer, cervical cancer, fallopian tube cancer, testicular cancer, prostate cancer, hemangioma, leukemia, lymphoma, myeloma, skin cancer, lipoma, bone cancer, soft tissue sarcoma, neurofibroma, glioma, neuroblastoma
  • the present disclosure also provides a method for preventing and/or treating a disease or condition mediated by KRAS G12D, which comprises administering the aforementioned crystalline form or the aforementioned pharmaceutical composition to a patient.
  • the present disclosure also provides a method for preventing and/or treating tumors, which includes administering the aforementioned crystal formation or the aforementioned pharmaceutical composition to a patient.
  • the tumor is selected from brain cancer, thyroid cancer, head and neck cancer, nasopharyngeal cancer, pharyngeal cancer, oral cancer, salivary gland cancer, esophageal cancer, gastric cancer, lung cancer, liver cancer, kidney cancer, pancreatic cancer, gallbladder cancer, bile duct cancer, colorectal cancer, small intestine cancer, gastrointestinal stromal tumors, urothelial cancer, urethral cancer, bladder cancer, breast cancer, vaginal cancer, ovarian cancer, endometrial cancer, cervical cancer, fallopian tube cancer, testicular cancer, prostate cancer, hemangioma, leukemia, lymphoma, myeloma, skin cancer, lipoma, bone cancer, soft tissue sarcoma, neurofibroma, glioma, neuroblasto
  • the present disclosure also provides the aforementioned crystal form or the aforementioned pharmaceutical composition for preventing and/or treating diseases or conditions mediated by KRAS G12D.
  • the present disclosure further provides the aforementioned crystal forms or the aforementioned pharmaceutical compositions for preventing and/or treating tumors.
  • the tumor is selected from brain cancer, thyroid cancer, head and neck cancer, nasopharyngeal cancer, pharyngeal cancer, oral cancer, salivary gland cancer, esophageal cancer, gastric cancer, lung cancer, liver cancer, kidney cancer, pancreatic cancer, gallbladder cancer, bile duct cancer, colorectal cancer, small intestine cancer, gastrointestinal stromal tumors, urothelial cancer, urethral cancer, bladder cancer, breast cancer, vaginal cancer, ovarian cancer, endometrial cancer, cervical cancer, fallopian tube cancer, testicular cancer, prostate cancer, hemangioma, leukemia, lymphoma, myeloma, skin cancer, lipoma, bone cancer, soft tissue sarcoma, neurofibroma, glioma, neuroblastoma and glioblastoma.
  • the "2 ⁇ or 2 ⁇ angle" mentioned in the present disclosure refers to the diffraction angle, ⁇ is the Bragg angle, and the unit is ° or degree; the error range of each characteristic peak 2 ⁇ is ⁇ 0.20 (including the case where the number exceeding 1 decimal place is rounded off), specifically -0.20, -0.19, -0.18, -0.17, -0.16, -0.15, -0.14, -0.13, -0.12, -0.11, -0.10, -0.09, -0.08, -0.07, -0.06, -0.05, -0.04, -0.03, -0.02, -0.01, 0.00, 0.01, 0.02, 0.03, 0.04, 0.05, 0.06, 0.07, 0.08, 0.09, 0.10, 0.11, 0.12, 0.13, 0.14, 0.15, 0.16, 0.17, 0.18, 0.19, 0.20.
  • the numerical values in this disclosure are instrumental measurements or calculated values after instrumental measurement, and are subject to a certain degree of error. Generally speaking, a value within a reasonable error range of plus or minus 10% is within the reasonable error range. Of course, the context in which the numerical value is used must be considered.
  • the total impurity content which is a value with an error variation of no more than plus or minus 10% after measurement, can be plus or minus 9%, plus or minus 8%, plus or minus 7%, plus or minus 6%, plus or minus 5%, plus or minus 4%, plus or minus 3%, plus or minus 2%, or plus or minus 1%, preferably plus or minus 5%.
  • the "differential scanning calorimetry or DSC” described in this disclosure refers to measuring the temperature difference and heat flow difference between a sample and a reference object during the process of heating or maintaining the sample at a constant temperature to characterize all physical and chemical changes related to thermal effects and obtain phase change information of the sample.
  • the drying temperature in the present disclosure is generally 25°C-100°C, preferably 30°C-70°C, and can be dried under normal pressure or reduced pressure.
  • the "pharmaceutically acceptable excipients” described in this disclosure include, but are not limited to, any adjuvant, carrier, glidant, sweetener, diluent, preservative, dye/colorant, flavoring agent, surfactant, wetting agent, dispersant, suspending agent, stabilizer, isotonic agent, or emulsifier approved by the U.S. Food and Drug Administration for use in humans or livestock.
  • “Pulping” as described in this disclosure refers to a purification method that utilizes the poor solubility of a substance in a solvent, but the good solubility of impurities in the solvent. Purification by pulping can remove color, change the crystal form, or remove a small amount of impurities.
  • the crystalline forms disclosed herein include but are not limited to solvates of Compound A, and the solvents include but are not limited to water.
  • Figure 1 is the XRPD spectrum of the amorphous form of compound A.
  • Figure 2 is the XRPD spectrum of Form A of Compound A.
  • Figure 3 is the XRPD spectrum of Form B of Compound A.
  • Figure 4 is the XRPD spectrum of Form C of Compound A.
  • Figure 5 is the XRPD spectrum of Form D of Compound A.
  • Figure 6 is the XRPD spectrum of Form E of Compound A.
  • FIG7 is an XRPD spectrum of Form F of Compound A.
  • FIG8 is an XRPD spectrum of Form G of Compound A.
  • Figure 9 is the XRPD spectrum of Form H of Compound A.
  • Figure 10 is the XRPD spectrum of Form I of Compound A.
  • Figure 11 is the XRPD spectrum of Form J of Compound A.
  • Figure 12 is the XRPD spectrum of Form K of Compound A.
  • FIG13 is an XRPD spectrum of Form L of Compound A.
  • FIG14 is an XRPD spectrum of Form M of Compound A.
  • NMR nuclear magnetic resonance
  • MS mass spectrometry
  • MS measurements were performed using an Agilent 1200/1290DAD-6110/6120 Quadrupole MS LC/MS instrument (Manufacturer: Agilent, MS model: 6110/6120 Quadrupole MS), a Waters ACQuity UPLC-QD/SQD (Manufacturer: Waters, MS model: Waters ACQuity Qda Detector/Waters SQ Detector), and a THERMO Ultimate 3000-Q Exactive (Manufacturer: THERMO, MS model: THERMO Q 15 Exactive).
  • HPLC determinations were performed using an Agilent 1260DAD high pressure liquid chromatograph (Sunfire C18 150 ⁇ 4.6 mm column) and a Thermo U3000 high pressure liquid chromatograph (Gimini C18 150 ⁇ 4.6 mm column).
  • XRPD is X-ray powder diffraction detection: the measurement is carried out using a BRUKER D8 X-ray diffractometer, specific collection information: Cu anode (40kV, 40mA), radiation: monochromatic Cu-Ka radiation Scanning mode: ⁇ /2 ⁇ , scanning range: 3-48 ° .
  • DSC stands for differential scanning calorimetry: the measurement was performed using a METTLER TOLEDO DSC 3+ differential scanning calorimeter with a heating rate of 10°C/min, 25-300°C or 25-350°C, and a nitrogen purge rate of 50 mL/min.
  • TGA thermogravimetric analysis: the test was performed using a METTLER TOLEDO TGA 2 thermogravimetric analyzer with a heating rate of 10°C/min. The specific temperature range was referred to the corresponding spectrum, and the nitrogen purge rate was 50 mL/min.
  • DVS dynamic moisture adsorption: using Surface Measurement Systems instrinsic, humidity starts from 50%, the humidity range is 0%-95%, the step is 10%, the judgment standard is each gradient mass change dM/dT ⁇ 0.002%, TMAX 360min, two cycles.
  • the known starting materials disclosed herein can be synthesized by methods known in the art, or can be purchased from ABCR GmbH & Co. KG, Acros Organics, Aldrich Chemical Company, Accela ChemBio Inc, Darui Chemicals, etc.
  • the reaction progress in the examples was monitored by thin layer chromatography (TLC).
  • TLC thin layer chromatography
  • the volume ratio of the solvent was adjusted according to the polarity of the compound, and a small amount of alkaline or acidic reagents such as triethylamine and acetic acid could also be added for adjustment.
  • the crude compound 1a (2 g, 8 mmol) was dissolved in phosphorus oxychloride (25 mL), and N,N-diisopropylethylamine (5.16 g, 40 mmol) was added. The mixture was stirred at 110°C for 14 hours. The reaction solution was cooled to room temperature and concentrated under reduced pressure. The residue was dissolved in 1,4-dioxane, and 20% potassium carbonate solution was added dropwise to adjust the pH to 2-3. The mixture was stirred for 2 hours and then filtered. The filter cake was washed with water and dried to obtain the crude title compound 1b (1.5 g). The product was used in the next step without purification.
  • the crude compound 1k (40 mg, 44.1 ⁇ mol) was dissolved in dichloromethane (0.5 mL), and trifluoroacetic acid (0.5 mL) was added. After stirring for 1 hour, the reaction was concentrated under reduced pressure. The residue was purified by high performance liquid chromatography (Waters-2545, column: YMC Triart-Exrs C18, 30*150 mm, 5 ⁇ m; mobile phase: aqueous phase (10 mmol/L ammonium bicarbonate) and acetonitrile, gradient ratio: acetonitrile 30%-45%, flow rate: 30 mL/min) to give the title compound A (2 mg, yield: 6.4%).
  • the inhibitory effect of the disclosed compounds on the KRAS target was evaluated by testing the 3D proliferation inhibitory effect of the disclosed compounds on GP2d and AGS cells.
  • GP2d cells were cultured in complete medium (DMEM/high glucose medium (Hyclone, SH30243.01) supplemented with 10% fetal bovine serum (Corning, 35-076-CV). On the first day of the experiment, GP2d cells were seeded at a density of 1000 cells/well in a 96-well low attachment plate (Corning, CLS7007-24EA) using complete medium. 90 ⁇ L of cell suspension was added to each well, centrifuged at 2000 rpm for 5 minutes at room temperature, and then incubated overnight at 37°C in a 5% CO2 incubator.
  • complete medium DMEM/high glucose medium (Hyclone, SH30243.01) supplemented with 10% fetal bovine serum (Corning, 35-076-CV).
  • GP2d cells were seeded at a density of 1000 cells/well in a 96-well low attachment plate (Corning, CLS7007-24EA) using complete medium. 90 ⁇ L of cell suspension
  • AGS cells were cultured in complete medium (RPMI1640 medium (Hyclone, SH30809.01) supplemented with 10% fetal bovine serum (Corning, 35-076-CV).
  • complete medium RPMI1640 medium (Hyclone, SH30809.01) supplemented with 10% fetal bovine serum (Corning, 35-076-CV).
  • AGS cells were seeded at a density of 1000 cells/well in a 96-well low attachment plate (Corning, CLS7007-24EA) using complete medium. 90 ⁇ L of cell suspension was added to each well, centrifuged at 2000 rpm for 5 minutes at room temperature, and then incubated overnight in a 37°C, 5% CO2 cell incubator.
  • 3D Cell Viability Assay reagent (Promega, G9682) was shaken at room temperature in the dark for 25 minutes, then pipetted to mix thoroughly and 100 ⁇ L was transferred from each well to a white opaque 96-well plate (PerkinElmer, 6005290). The luminescence signal was read using a multi-function microplate reader (PerkinElmer, EnVision2105).
  • a 20 mM DMSO-dissolved test compound was diluted with DMSO to a starting concentration of 2 mM. This was then serially diluted 5-fold to a total of nine concentration points, with DMSO as a control. The serially diluted compound was then further diluted 20-fold with culture medium. 10 ⁇ L of the test compound diluted with culture medium was added to each well of the plate for a final concentration of 10 ⁇ M starting at the 10 ⁇ M concentration and then serially diluted 5-fold to a total of nine concentration points. The wells containing 0.5% DMSO were set as vehicle control wells, and the wells containing only culture medium and 0.5% DMSO were set as blank control wells.
  • GraphPad Prism software was used to plot inhibition rate curves based on compound concentrations and calculate compound IC50 values.
  • Compound A had an IC50 of 3.7 nM.
  • the product was defined as Form A by X-ray powder diffraction analysis.
  • the XRPD spectrum is shown in FIG2 , and the positions of the characteristic peaks are shown in Table 1.
  • the DSC spectrum showed an endothermic peak at 142.68°C, and the TGA spectrum showed a weight loss of 3.17% from 31°C to 155°C.
  • X-ray powder diffraction analysis identified the product as Form C.
  • the XRPD spectrum is shown in Figure 4, and the positions of its characteristic peaks are shown in Table 4.
  • the DSC spectrum showed an endothermic peak at 170.02°C.
  • the TGA spectrum showed a weight loss of 0.53% from 31°C to 143°C.
  • X-ray powder diffraction analysis identified the product as Form D.
  • the XRPD spectrum is shown in Figure 5, and the positions of its characteristic peaks are shown in Table 5.
  • the DSC spectrum showed endothermic peaks at 68.66°C and 166.16°C.
  • the TGA spectrum showed a weight loss of 1.94% from 30°C to 145°C.
  • X-ray powder diffraction analysis identified the product as Form E.
  • the XRPD spectrum is shown in Figure 6, and the positions of its characteristic peaks are shown in Table 6.
  • the DSC spectrum showed an endothermic peak at 198.18°C.
  • the TGA spectrum showed a weight loss of 0.08% from 30°C to 197°C.
  • X-ray powder diffraction analysis identified the product as Form F.
  • the XRPD spectrum is shown in Figure 7, and the positions of its characteristic peaks are shown in Table 8.
  • the DSC spectrum showed an endothermic peak at 168.35°C.
  • the TGA spectrum showed a weight loss of 1.30% from 33°C to 117°C.
  • X-ray powder diffraction analysis identified the product as Form G.
  • the XRPD spectrum is shown in Figure 8, and the positions of its characteristic peaks are shown in Table 9.
  • the DSC spectrum showed endothermic peaks at 74.50°C and 151.50°C.
  • the TGA spectrum showed a weight loss of 2.28% from 32°C to 161°C.
  • X-ray powder diffraction analysis identified the product as Form H.
  • the XRPD spectrum is shown in Figure 9, and the positions of its characteristic peaks are shown in Table 10.
  • the DSC spectrum showed an endothermic peak at 219.42°C.
  • the TGA spectrum showed a weight loss of 0.46% from 30°C to 220°C.
  • X-ray powder diffraction analysis identified the product as Form I.
  • the XRPD spectrum is shown in Figure 10, and the positions of its characteristic peaks are shown in Table 11.
  • the DSC spectrum showed endothermic peaks at 154.00°C and 225.69°C.
  • the TGA spectrum showed a weight loss of 1.92% from 35°C to 163°C.
  • the product was defined as Form J by X-ray powder diffraction analysis.
  • the XRPD spectrum is shown in FIG11 , and the positions of the characteristic peaks are shown in Table 12 .
  • the product was defined as Form K by X-ray powder diffraction analysis.
  • the XRPD spectrum is shown in FIG12 , and the positions of the characteristic peaks are shown in Table 13 .
  • the product was defined as Form L by X-ray powder diffraction analysis.
  • the XRPD spectrum is shown in FIG13 , and the positions of the characteristic peaks are shown in Table 14 .
  • the product was defined as Form M by X-ray powder diffraction analysis.
  • the XRPD spectrum is shown in FIG14 , and the positions of the characteristic peaks are shown in Table 15 .
  • the above-mentioned crystal forms were exposed and spread out flat, and the stability of the samples was examined under light (4500 Lux), high temperature (40°C, 60°C), and high humidity (RH 75%, RH 92.5%) conditions.
  • the sampling period was 30 days.
  • Test Example 4 Long-term accelerated test

Landscapes

  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Organic Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Epidemiology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

本公开涉及G12D抑制剂化合物晶型及其制备方法。具体而言，本公开提供2-氨基-4-((5S,5aS,6S,9R)-12-((1-((4-(二氟甲亚基)哌啶-1-基)甲基)环丙基)甲氧基)-1-氟-5-甲基-5a,6,7,8,9,10-六氢-5H-4-氧杂-3,10a,11,13,14-五氮杂-6,9-甲桥萘并[1,8-ab]并庚环-2-基)-7-氟苯并[b]噻吩-3-甲腈的晶型及其制备方法。

Description

G12D抑制剂化合物晶型及其制备方法
本申请要求申请日为2024/1/26的中国专利申请2024101120466的优先权。本申请引用上述中国专利申请的全文。
技术领域
本公开属于制药领域，涉及G12D抑制剂化合物晶型及其制备方法。
背景技术
KRAS蛋白表面缺乏传统意义上的小分子结合位点，并与鸟苷酸有着超高亲和力而极难被抑制，长久以来被认为是不可成药的药物靶点。但基于KRAS异常激活在癌症进展中的重要性和普遍性，KRAS一直并仍然是药物开发非常关注的靶点。G12D，作为一个在多种肿瘤中广泛高表达的突变体，开发针对它的抑制剂有着重要的临床意义。
WO2024022444公开了一种新型G12D抑制剂化合物，2-氨基-4-((5S,5aS,6S,9R)-12-((1-((4-(二氟甲亚基)哌啶-1-基)甲基)环丙基)甲氧基)-1-氟-5-甲基-5a,6,7,8,9,10-六氢-5H-4-氧杂-3,10a,11,13,14-五氮杂-6,9-甲桥萘并[1,8-ab]并庚环-2-基)-7-氟苯并[b]噻吩-3-甲腈(化合物A)
作为药用活性成分的晶型结构往往影响到该药物的化学和物理稳定性，结晶条件及储存条件的不同有可能导致化合物的晶体结构的变化，有时还会伴随着产生其他形态的晶型。一般来说，无定形的药物产品没有规则的晶体结构，往往具有其它缺陷，比如产物稳定性较差，过滤较难，易结块，流动性差等。因此，研究其晶型对开发适合工业生产且生物活性良好的药物具有重要意义。
发明内容
本公开一方面提供化合物2-氨基-4-((5S,5aS,6S,9R)-12-((1-((4-(二氟甲亚基)哌啶-1-基)甲基)环丙基)甲氧基)-1-氟-5-甲基-5a,6,7,8,9,10-六氢-5H-4-氧杂-3,10a,11,13,14-五氮杂-6,9-甲桥萘并[1,8-ab]并庚环-2-基)-7-氟苯并[b]噻吩-3-甲腈的A晶型，以衍射角2θ角度表示的X-射线粉末衍射图谱，在5.235、6.954、8.874、14.709、21.043处有特征峰
在一些实施方案中，所述A晶型，以衍射角2θ角度表示的X-射线粉末衍射图谱，在5.235、6.954、8.874、14.709、16.053、19.239、19.776、21.043处有特征峰。
在另一些实施方案中，所述A晶型，以衍射角2θ角度表示的X-射线粉末衍射图谱如图2所示。
本公开一方面提供化合物2-氨基-4-((5S,5aS,6S,9R)-12-((1-((4-(二氟甲亚基)哌啶-1-基)甲基)环丙基)甲氧基)-1-氟-5-甲基-5a,6,7,8,9,10-六氢-5H-4-氧杂-3,10a,11,13,14-五氮杂-6,9-甲桥萘并[1,8-ab]并庚环-2-基)-7-氟苯并[b]噻吩-3-甲腈的B晶型，以衍射角2θ角度表示的X-射线粉末衍射图谱，在8.845、12.746、14.040、14.480、17.371、18.833处有特征峰
在一些实施方案中，所述B晶型，以衍射角2θ角度表示的X-射线粉末衍射图谱，在8.845、9.258、12.746、14.040、14.480、16.475、17.371、18.833处有特征峰。
在一些实施方案中，所述B晶型，以衍射角2θ角度表示的X-射线粉末衍射图谱，在8.845、9.258、12.746、14.040、14.480、15.800、16.475、17.371、18.833、20.883、28.999处有特征峰。
在另一些实施方案中，所述B晶型，以衍射角2θ角度表示的X-射线粉末衍射图谱如图3所示。
本公开一方面提供化合物2-氨基-4-((5S,5aS,6S,9R)-12-((1-((4-(二氟甲亚基)哌啶-1-基)甲基)环丙基)甲氧基)-1-氟-5-甲基-5a,6,7,8,9,10-六氢-5H-4-氧杂-3,10a,11,13,14-五氮杂-6,9-甲桥萘并[1,8-ab]并庚环-2-基)-7-氟苯并[b]噻吩-3-甲腈的C晶型，以衍射角2θ角度表示的X-射线粉末衍射图谱，在5.083、10.326、11.776、13.543、15.564处有特征峰。
在一些实施方案中，所述C晶型，以衍射角2θ角度表示的X-射线粉末衍射图谱，在5.083、10.326、11.776、13.543、15.564、16.060、17.675处有特征峰。
在一些实施方案中，所述C晶型，以衍射角2θ角度表示的X-射线粉末衍射图谱，在5.083、10.326、11.776、13.543、15.564、16.060、17.675、18.451、20.167、21.940处有特征峰。
在另一些实施方案中，所述C晶型，以衍射角2θ角度表示的X-射线粉末衍射图谱如图4所示。
本公开一方面提供化合物2-氨基-4-((5S,5aS,6S,9R)-12-((1-((4-(二氟甲亚基)哌啶-1-基)甲基)环丙基)甲氧基)-1-氟-5-甲基-5a,6,7,8,9,10-六氢-5H-4-氧杂-3,10a,11,13,14-五氮杂-6,9-甲桥萘并[1,8-ab]并庚环-2-基)-7-氟苯并[b]噻吩-3-甲腈的D晶型，以衍射角2θ角度表示的X-射线粉末衍射图谱，在4.865、8.452、9.819、12.795、14.695、16.052、19.632处有特征峰。
在一些实施方案中，所述D晶型，以衍射角2θ角度表示的X-射线粉末衍射图谱，在4.865、8.452、9.819、10.763、12.795、14.695、16.052、17.818、19.632处有特征峰。
在一些实施方案中，所述D晶型，以衍射角2θ角度表示的X-射线粉末衍射图谱，在4.865、8.452、9.819、10.763、12.795、14.695、16.052、16.954、17.818、19.632、21.197处有特征峰。
在另一些实施方案中，所述D晶型，以衍射角2θ角度表示的X-射线粉末衍射图谱如图5所示。
本公开一方面提供化合物2-氨基-4-((5S,5aS,6S,9R)-12-((1-((4-(二氟甲亚基)哌啶-1-基)甲基)环丙基)甲氧基)-1-氟-5-甲基-5a,6,7,8,9,10-六氢-5H-4-氧杂-3,10a,11,13,14-五氮杂-6,9-甲桥萘并[1,8-ab]并庚环-2-基)-7-氟苯并[b]噻吩-3-甲腈的E晶型，以衍射角2θ角度表示的X-射线粉末衍射图谱，在7.155、9.117、11.638、16.461、17.277、20.652处有特征峰。
在一些实施方案中，所述E晶型，以衍射角2θ角度表示的X-射线粉末衍射图谱，在7.155、9.117、11.638、13.672、15.285、16.461、17.277、20.652处有特征峰。
在一些实施方案中，所述E晶型，以衍射角2θ角度表示的X-射线粉末衍射图谱，在7.155、9.117、11.638、13.672、15.285、16.461、17.277、20.652、21.734、23.001处有特征峰。
在另一些实施方案中，所述E晶型，以衍射角2θ角度表示的X-射线粉末衍射图谱如图6所示。
本公开一方面提供化合物2-氨基-4-((5S,5aS,6S,9R)-12-((1-((4-(二氟甲亚基)哌啶-1-基)甲基)环丙基)甲氧基)-1-氟-5-甲基-5a,6,7,8,9,10-六氢-5H-4-氧杂-3,10a,11,13,14-五氮杂-6,9-甲桥萘并[1,8-ab]并庚环-2-基)-7-氟苯并[b]噻吩-3-甲腈的F晶型，以衍射角2θ角度表示的X-射线粉末衍射图谱，在4.684、10.040、13.134、14.247、17.432、20.421处有特征峰。
在一些实施方案中，所述F晶型，以衍射角2θ角度表示的X-射线粉末衍射图谱，在4.684、10.040、13.134、14.247、15.464、17.432、19.688、20.421处有特征峰。
在一些实施方案中，所述F晶型，以衍射角2θ角度表示的X-射线粉末衍射图谱，在4.684、10.040、13.134、14.247、15.464、16.709、17.432、19.688、20.421、22.909处有特征峰。
在另一些实施方案中，所述F晶型，以衍射角2θ角度表示的X-射线粉末衍射图谱如图7所示。
本公开一方面提供化合物2-氨基-4-((5S,5aS,6S,9R)-12-((1-((4-(二氟甲亚基)哌啶-1-基)甲基)环丙基)甲氧基)-1-氟-5-甲基-5a,6,7,8,9,10-六氢-5H-4-氧杂-3,10a,11,13,14-五氮杂-6,9-甲桥萘并[1,8-ab]并庚环-2-基)-7-氟苯并[b]噻吩-3-甲腈的G晶型，以衍射角2θ角度表示的X-射线粉末衍射图谱，在8.404、11.861、14.205、15.114、17.113、19.116、21.354处有特征峰。
在一些实施方案中，所述G晶型，以衍射角2θ角度表示的X-射线粉末衍射图谱，在8.404、10.099、11.861、14.205、15.114、15.570、17.113、19.116、19.948、21.354处有特征峰。
在一些实施方案中，所述G晶型，以衍射角2θ角度表示的X-射线粉末衍射图谱，在8.404、10.099、11.861、13.401、14.205、15.114、15.570、17.113、19.116、19.948、21.354处有特征峰。
在另一些实施方案中，所述G晶型，以衍射角2θ角度表示的X-射线粉末衍射图谱如图8所示。
本公开一方面提供化合物2-氨基-4-((5S,5aS,6S,9R)-12-((1-((4-(二氟甲亚基)哌啶-1-基)甲基)环丙基)甲氧基)-1-氟-5-甲基-5a,6,7,8,9,10-六氢-5H-4-氧杂-3,10a,11,13,14-五氮杂-6,9-甲桥萘并[1,8-ab]并庚环-2-基)-7-氟苯并[b]噻吩-3-甲腈的H晶型，以衍射角2θ角度表示的X-射线粉末衍射图谱，在10.615、12.690、16.070、17.610、19.226、21.218、24.456处有特征峰。
在一些实施方案中，所述H晶型，以衍射角2θ角度表示的X-射线粉末衍射图谱，在10.615、12.690、15.582、16.070、16.339、17.610、19.226、21.218、24.456处有特征峰。
在一些实施方案中，所述H晶型，以衍射角2θ角度表示的X-射线粉末衍射图谱，在8.677、10.615、11.061、12.690、13.221、15.582、16.070、16.339、17.610、19.226、21.218、24.456处有特征峰。
在另一些实施方案中，所述H晶型，以衍射角2θ角度表示的X-射线粉末衍射图谱如图9所示。
本公开一方面提供化合物2-氨基-4-((5S,5aS,6S,9R)-12-((1-((4-(二氟甲亚基)哌啶-1-基)甲基)环丙基)甲氧基)-1-氟-5-甲基-5a,6,7,8,9,10-六氢-5H-4-氧杂-3,10a,11,13,14-五氮杂-6,9-甲桥萘并[1,8-ab]并庚环-2-基)-7-氟苯并[b]噻吩-3-甲腈的I晶型，以衍射角2θ角度表示的X-射线粉末衍射图谱，在5.063、7.165、9.911、15.902、19.507处有特征峰。
在一些实施方案中，所述I晶型，以衍射角2θ角度表示的X-射线粉末衍射图谱，在5.063、7.165、9.911、15.902、16.411、17.311、19.507处有特征峰。
在一些实施方案中，所述I晶型，以衍射角2θ角度表示的X-射线粉末衍射图谱，在5.063、7.165、9.911、13.484、15.902、16.411、17.311、17.762、19.507处有特征峰。
在另一些实施方案中，所述I晶型，以衍射角2θ角度表示的X-射线粉末衍射图谱如图10所示。
本公开一方面提供化合物2-氨基-4-((5S,5aS,6S,9R)-12-((1-((4-(二氟甲亚基)哌啶-1-基)甲基)环丙基)甲氧基)-1-氟-5-甲基-5a,6,7,8,9,10-六氢-5H-4-氧杂-3,10a,11,13,14-五氮杂-6,9-甲桥萘并[1,8-ab]并庚环-2-基)-7-氟苯并[b]噻吩-3-甲腈的J晶型，以衍射角2θ角度表示的X-射线粉末衍射图谱，在8.630、10.574、15.783、17.686、19.265、24.076处有特征峰。
在一些实施方案中，所述J晶型，以衍射角2θ角度表示的X-射线粉末衍射图谱，在8.630、10.574、15.783、17.686、19.265、20.898、24.076、25.093处有特征峰。
在一些实施方案中，所述J晶型，以衍射角2θ角度表示的X-射线粉末衍射图谱，在8.630、10.574、12.697、15.783、17.686、19.265、20.898、21.274、24.076、25.093处有特征峰。
在另一些实施方案中，所述J晶型，以衍射角2θ角度表示的X-射线粉末衍射图谱如图11所示。
本公开一方面提供化合物2-氨基-4-((5S,5aS,6S,9R)-12-((1-((4-(二氟甲亚基)哌啶-1-基)甲基)环丙基)甲氧基)-1-氟-5-甲基-5a,6,7,8,9,10-六氢-5H-4-氧杂-3,10a,11,13,14-五氮杂-6,9-甲桥萘并[1,8-ab]并庚环-2-基)-7-氟苯并[b]噻吩-3-甲腈的K晶型，以衍射角2θ角度表示的X-射线粉末衍射图谱，在8.434、11.714、13.979、19.124、20.773处有特征峰。
在一些实施方案中，所述K晶型，以衍射角2θ角度表示的X-射线粉末衍射图谱，在8.434、9.603、11.714、13.979、16.820、19.124、20.773处有特征峰。
在一些实施方案中，所述K晶型，以衍射角2θ角度表示的X-射线粉末衍射图谱，在8.434、9.603、10.524、11.714、13.407、13.979、16.820、19.124、20.773处有特征峰。
在另一些实施方案中，所述K晶型，以衍射角2θ角度表示的X-射线粉末衍射图谱如图12所示。
本公开一方面提供化合物2-氨基-4-((5S,5aS,6S,9R)-12-((1-((4-(二氟甲亚基)哌啶-1-基)甲基)环丙基)甲氧基)-1-氟-5-甲基-5a,6,7,8,9,10-六氢-5H-4-氧杂-3,10a,11,13,14-五氮杂-6,9-甲桥萘并[1,8-ab]并庚环-2-基)-7-氟苯并[b]噻吩-3-甲腈的L晶型，以衍射角2θ角度表示的X-射线粉末衍射图谱，在4.959、8.605、10.908、14.761、16.656、19.649处有特征峰。
在一些实施方案中，所述L晶型，以衍射角2θ角度表示的X-射线粉末衍射图谱，在4.959、8.605、10.908、12.928、14.761、16.167、16.656、18.089、19.649、19.887处有特征峰。
在一些实施方案中，所述L晶型，以衍射角2θ角度表示的X-射线粉末衍射图谱，在4.959、8.605、10.908、12.928、13.669、14.761、16.167、16.656、17.054、18.089、19.649、21.286、22.463、25.634处有特征峰。
在另一些实施方案中，所述L晶型，以衍射角2θ角度表示的X-射线粉末衍射图谱如图13所示。
本公开一方面提供化合物2-氨基-4-((5S,5aS,6S,9R)-12-((1-((4-(二氟甲亚基)哌啶-1-基)甲基)环丙基)甲氧基)-1-氟-5-甲基-5a,6,7,8,9,10-六氢-5H-4-氧杂-3,10a,11,13,14-五氮杂-6,9-甲桥萘并[1,8-ab]并庚环-2-基)-7-氟苯并[b]噻吩-3-甲腈的M晶型，以衍射角2θ角度表示的X-射线粉末衍射图谱，在5.607、7.457、13.037、13.940、17.177、19.704处有特征峰。
在一些实施方案中，所述M晶型，以衍射角2θ角度表示的X-射线粉末衍射图谱，在5.607、7.457、10.102、11.312、13.037、13.940、16.658、17.177、17.752、19.704处有特征峰。
在一些实施方案中，所述M晶型，以衍射角2θ角度表示的X-射线粉末衍射图谱，在5.607、7.457、10.102、11.312、13.037、13.940、16.290、16.658、17.177、17.752、18.631、19.704、22.663处有特征峰。
在另一些实施方案中，所述M晶型，以衍射角2θ角度表示的X-射线粉末衍射图谱如图14所示。
进一步地，本公开所述化合物A的A、B、C、D、E、F、G、H、I、J、K、L或M晶型，以衍射角2θ角度表示的X-射线粉末衍射图，其中2θ角度的误差范围为±0.2。
另一方面，本公开还提供制备前述晶型的方法，选自如下任一方法，
方法一：
(a)将化合物2-氨基-4-((5S,5aS,6S,9R)-12-((1-((4-(二氟甲亚基)哌啶-1-基)甲基)环丙基)甲氧基)-1-氟-5-甲基-5a,6,7,8,9,10-六氢-5H-4-氧杂-3,10a,11,13,14-五氮杂-6,9-甲桥萘并[1,8-ab]并庚环-2-基)-7-氟苯并[b]噻吩-3-甲腈与溶剂混合，搅拌溶解或加热溶解，
(b)析晶；
或，方法二：
(a)将化合物2-氨基-4-((5S,5aS,6S,9R)-12-((1-((4-(二氟甲亚基)哌啶-1-基)甲基)环丙基)甲氧基)-1-氟-5-甲基-5a,6,7,8,9,10-六氢-5H-4-氧杂-3,10a,11,13,14-五氮杂-6,9-甲桥萘并[1,8-ab]并庚环-2-基)-7-氟苯并[b]噻吩-3-甲腈与溶剂混合，搅拌溶解或加热溶解，
(b)加入第二溶剂，搅拌；
或，方法三：
(a)将化合物2-氨基-4-((5S,5aS,6S,9R)-12-((1-((4-(二氟甲亚基)哌啶-1-基)甲基)环丙基)甲氧基)-1-氟-5-甲基-5a,6,7,8,9,10-六氢-5H-4-氧杂-3,10a,11,13,14-五氮杂-6,9-甲桥萘并[1,8-ab]并庚环-2-基)-7-氟苯并[b]噻吩-3-甲腈与溶剂混合，
(b)搅拌。
在一些实施方案中，制备前述化合物A晶型的方法，其包括(a)将化合物2-氨基-4-((5S,5aS,6S,9R)-12-((1-((4-(二氟甲亚基)哌啶-1-基)甲基)环丙基)甲氧基)-1-氟-5-甲基-5a,6,7,8,9,10-六氢-5H-4-氧杂-3,10a,11,13,14-五氮杂-6,9-甲桥萘并[1,8-ab]并庚环-2-基)-7-氟苯并[b]噻吩-3-甲腈与溶剂(1)混合，所述溶剂(1)选自正庚烷或水，
(b)搅拌。
在一些实施方案中，制备前述化合物B晶型的方法，其包括(a)将化合物2-氨基-4-((5S,5aS,6S,9R)-12-((1-((4-(二氟甲亚基)哌啶-1-基)甲基)环丙基)甲氧基)-1-氟-5-甲基-5a,6,7,8,9,10-六氢-5H-4-氧杂-3,10a,11,13,14-五氮杂-6,9-甲桥萘并[1,8-ab]并庚环-2-基)-7-氟苯并[b]噻吩-3-甲腈与溶剂(2)混合，所述溶剂(2)选自乙醇、异丙醇/乙醇(2:3,v/v)、10％水/甲醇、7％水/乙醇、乙酸乙酯/乙醇(1:1,v/v)或四氢呋喃/乙醇(1:1,v/v)，
(b)搅拌。
在一些实施方案中，制备前述化合物C晶型的方法，其包括(a)将化合物2-氨基-4-((5S,5aS,6S,9R)-12-((1-((4-(二氟甲亚基)哌啶-1-基)甲基)环丙基)甲氧基)-1-氟-5-甲基-5a,6,7,8,9,10-六氢-5H-4-氧杂-3,10a,11,13,14-五氮杂-6,9-甲桥萘并[1,8-ab]并庚环-2-基)-7-氟苯并[b]噻吩-3-甲腈与溶剂(3)混合，所述溶剂(3)选自丙酮，
(b)搅拌。
在一些实施方案中，制备前述化合物D晶型的方法，其包括(a)将化合物2-氨基-4-((5S,5aS,6S,9R)-12-((1-((4-(二氟甲亚基)哌啶-1-基)甲基)环丙基)甲氧基)-1-氟-5-甲基-5a,6,7,8,9,10-六氢-5H-4-氧杂-3,10a,11,13,14-五氮杂-6,9-甲桥萘并[1,8-ab]并庚环-2-基)-7-氟苯并[b]噻吩-3-甲腈与溶剂(4)混合，所述溶剂(4)选自乙腈，
(b)搅拌。
在一些实施方案中，制备前述化合物E晶型的方法，其包括(a)将化合物2-氨基-4-((5S,5aS,6S,9R)-12-((1-((4-(二氟甲亚基)哌啶-1-基)甲基)环丙基)甲氧基)-1-氟-5-甲基-5a,6,7,8,9,10-六氢-5H-4-氧杂-3,10a,11,13,14-五氮杂-6,9-甲桥萘并[1,8-ab]并庚环-2-基)-7-氟苯并[b]噻吩-3-甲腈与溶剂(5)混合，所述溶剂(5)选自乙酸乙酯、乙酸异丙酯、甲基叔丁基醚或乙酸乙酯/正庚烷(1:1,v/v)，
(b)搅拌。
在一些实施方案中，制备前述化合物F晶型的方法，其包括(a)将化合物2-氨基-4-((5S,5aS,6S,9R)-12-((1-((4-(二氟甲亚基)哌啶-1-基)甲基)环丙基)甲氧基)-1-氟-5-甲基-5a,6,7,8,9,10-六氢-5H-4-氧杂-3,10a,11,13,14-五氮杂-6,9-甲桥萘并[1,8-ab]并庚环-2-基)-7-氟苯并[b]噻吩-3-甲腈与溶剂(6)混合，所述溶剂(6)选自10％水/丙酮(v/v)，
(b)搅拌。
在一些实施方案中，制备前述化合物G晶型的方法，其包括(a)将化合物2-氨基-4-((5S,5aS,6S,9R)-12-((1-((4-(二氟甲亚基)哌啶-1-基)甲基)环丙基)甲氧基)-1-氟-5-甲基-5a,6,7,8,9,10-六氢-5H-4-氧杂-3,10a,11,13,14-五氮杂-6,9-甲桥萘并[1,8-ab]并庚环-2-基)-7-氟苯并[b]噻吩-3-甲腈与溶剂(7)混合，所述溶剂(7)选自甲醇/水(1:1,v/v)，
(b)搅拌。
在一些实施方案中，制备前述化合物G晶型的方法，其包括(a)将化合物2-氨基-4-((5S,5aS,6S,9R)-12-((1-((4-(二氟甲亚基)哌啶-1-基)甲基)环丙基)甲氧基)-1-氟-5-甲基-5a,6,7,8,9,10-六氢-5H-4-氧杂-3,10a,11,13,14-五氮杂-6,9-甲桥萘并[1,8-ab]并庚环-2-基)-7-氟苯并[b]噻吩-3-甲腈与溶剂(8)混合，搅拌溶解或加热溶解，所述溶剂(8)选自乙腈/甲醇(1:1,v/v)，
(b)析晶，如挥发析晶。
在一些实施方案中，制备前述化合物H晶型的方法，其包括(a)将化合物2-氨基-4-((5S,5aS,6S,9R)-12-((1-((4-(二氟甲亚基)哌啶-1-基)甲基)环丙基)甲氧基)-1-氟-5-甲基-5a,6,7,8,9,10-六氢-5H-4-氧杂-3,10a,11,13,14-五氮杂-6,9-甲桥萘并[1,8-ab]并庚环-2-基)-7-氟苯并[b]噻吩-3-甲腈与溶剂(9)混合，所述溶剂(9)选自异丙醚，
(b)搅拌。
在一些实施方案中，制备前述化合物H晶型的方法，其包括(a)将化合物2-氨基-4-((5S,5aS,6S,9R)-12-((1-((4-(二氟甲亚基)哌啶-1-基)甲基)环丙基)甲氧基)-1-氟-5-甲基-5a,6,7,8,9,10-六氢-5H-4-氧杂-3,10a,11,13,14-五氮杂-6,9-甲桥萘并[1,8-ab]并庚环-2-基)-7-氟苯并[b]噻吩-3-甲腈与溶剂(10)混合，搅拌溶解或加热溶解，所述溶剂(10)选自丙二醇甲醚或丙酮，
(b)加入溶剂(11)，搅拌，所述溶剂(11)选自正庚烷或异丙醚。
在一些实施方案中，制备前述化合物I晶型的方法，其包括(a)将化合物2-氨基-4-((5S,5aS,6S,9R)-12-((1-((4-(二氟甲亚基)哌啶-1-基)甲基)环丙基)甲氧基)-1-氟-5-甲基-5a,6,7,8,9,10-六氢-5H-4-氧杂-3,10a,11,13,14-五氮杂-6,9-甲桥萘并[1,8-ab]并庚环-2-基)-7-氟苯并[b]噻吩-3-甲腈与溶剂(12)混合，搅拌溶解或加热溶解，所述溶剂(12)选自二氧六环，
(b)加入溶剂(13)，搅拌，所述溶剂(13)选自异丙醚。
在一些实施方案中，制备前述化合物J晶型的方法，其包括(a)将化合物2-氨基-4-((5S,5aS,6S,9R)-12-((1-((4-(二氟甲亚基)哌啶-1-基)甲基)环丙基)甲氧基)-1-氟-5-甲基-5a,6,7,8,9,10-六氢-5H-4-氧杂-3,10a,11,13,14-五氮杂-6,9-甲桥萘并[1,8-ab]并庚环-2-基)-7-氟苯并[b]噻吩-3-甲腈与溶剂(14)混合，搅拌溶解或加热溶解，所述溶剂(14)选自甲醇，
(b)析晶，如挥发析晶。
在一些实施方案中，制备前述化合物K晶型的方法，其包括(a)将化合物2-氨基-4-((5S,5aS,6S,9R)-12-((1-((4-(二氟甲亚基)哌啶-1-基)甲基)环丙基)甲氧基)-1-氟-5-甲基-5a,6,7,8,9,10-六氢-5H-4-氧杂-3,10a,11,13,14-五氮杂-6,9-甲桥萘并[1,8-ab]并庚环-2-基)-7-氟苯并[b]噻吩-3-甲腈与溶剂(15)混合，搅拌溶解或加热溶解，所述溶剂(15)选自水/甲醇(1:9,v/v)，
(b)析晶，如挥发析晶。
在一些实施方案中，制备前述化合物L晶型的方法，其包括(a)将化合物2-氨基-4-((5S,5aS,6S,9R)-12-((1-((4-(二氟甲亚基)哌啶-1-基)甲基)环丙基)甲氧基)-1-氟-5-甲基-5a,6,7,8,9,10-六氢-5H-4-氧杂-3,10a,11,13,14-五氮杂-6,9-甲桥萘并[1,8-ab]并庚环-2-基)-7-氟苯并[b]噻吩-3-甲腈与溶剂(16)混合，所述溶剂(16)选自乙酸甲酯，
(b)搅拌。
在一些实施方案中，制备前述化合物M晶型的方法，其包括(a)将化合物2-氨基-4-((5S,5aS,6S,9R)-12-((1-((4-(二氟甲亚基)哌啶-1-基)甲基)环丙基)甲氧基)-1-氟-5-甲基-5a,6,7,8,9,10-六氢-5H-4-氧杂-3,10a,11,13,14-五氮杂-6,9-甲桥萘并[1,8-ab]并庚环-2-基)-7-氟苯并[b]噻吩-3-甲腈与溶剂(17)混合，所述溶剂(17)选自甲苯，
(b)搅拌。
在某些实施方案中，本公开所述制备方法还包析晶、过滤、洗涤或干燥中任一步骤。
在一些实施方案中，所述析晶包括但不限于搅拌析晶(溶析析晶、打浆析晶)和挥发析晶。
在一些实施方案中，所述干燥方式包括但不限于鼓风干燥、真空干燥。干燥温度一般为25℃～100℃，优选30℃～70℃，如40℃、50℃或60℃。
另一方面，本公开还提供一种药物组合物，其包括前述晶型和药学上可接受的赋形剂。
本公开还提供一种药物组合物，由前述晶型和药学上可接受的赋形剂制备得到。
本公开还提供了一种药物组合物的制备方法，包括前述晶型与药学上可接受的赋形剂混合的步骤。
本公开还提供了前述晶型或前述药物组合物在制备用于预防和/或治疗由KRAS G12D介导的疾病或病症的药物中的用途。在一些实施方案中，KRAS G12D介导的疾病或病症选自脑癌、甲状腺癌、头颈癌、鼻咽癌、咽喉癌、口腔癌、唾液腺癌、食道癌、胃癌、肺癌、肝癌、肾癌、胰腺癌、胆囊癌、胆管癌、结直肠癌、小肠癌、胃肠道间质瘤、尿路上皮癌、尿道癌、膀胱癌、乳腺癌、阴道癌、卵巢癌、子宫内膜癌、宫颈癌、输卵管癌、睾丸癌、前列腺癌、血管瘤、白血病、淋巴瘤、骨髓瘤、皮肤癌、脂肪瘤、骨癌、软组织肉瘤、神经纤维瘤、神经胶质瘤、成神经细胞瘤和胶质母细胞瘤。
本公开还提供了前述晶型或前述药物组合物在制备用于预防和/或治疗肿瘤的药物中的用途。在一些实施方案中，所述的肿瘤选自脑癌、甲状腺癌、头颈癌、鼻咽癌、咽喉癌、口腔癌、唾液腺癌、食道癌、胃癌、肺癌、肝癌、肾癌、胰腺癌、胆囊癌、胆管癌、结直肠癌、小肠癌、胃肠道间质瘤、尿路上皮癌、尿道癌、膀胱癌、乳腺癌、阴道癌、卵巢癌、子宫内膜癌、宫颈癌、输卵管癌、睾丸癌、前列腺癌、血管瘤、白血病、淋巴瘤、骨髓瘤、皮肤癌、脂肪瘤、骨癌、软组织肉瘤、神经纤维瘤、神经胶质瘤、成神经细胞瘤和胶质母细胞瘤。在另一些实施方案中，所述的肿瘤选自胰腺癌、结直肠癌和非小细胞肺癌。
本公开还提供一种预防和/或治疗由KRAS G12D介导的疾病或病症的方法，其包括向患者施用前述晶型或前述药物组合物。
本公开还提供一种预防和/或治疗肿瘤的方法，其包括向患者施用前述晶型或前述药物组合物。在一些实施方案中，所述的肿瘤选自脑癌、甲状腺癌、头颈癌、鼻咽癌、咽喉癌、口腔癌、唾液腺癌、食道癌、胃癌、肺癌、肝癌、肾癌、胰腺癌、胆囊癌、胆管癌、结直肠癌、小肠癌、胃肠道间质瘤、尿路上皮癌、尿道癌、膀胱癌、乳腺癌、阴道癌、卵巢癌、子宫内膜癌、宫颈癌、输卵管癌、睾丸癌、前列腺癌、血管瘤、白血病、淋巴瘤、骨髓瘤、皮肤癌、脂肪瘤、骨癌、软组织肉瘤、神经纤维瘤、神经胶质瘤、成神经细胞瘤和胶质母细胞瘤。在另一些实施方案中，所述的肿瘤选自胰腺癌、结直肠癌和非小细胞肺癌。
本公开另一方面还提供用于预防和/或治疗由KRAS G12D介导的疾病或病症的前述晶型或前述药物组合物。
本公开另一方面还提供用于预防和/或治疗肿瘤的前述晶型或前述药物组合物。在一些实施方案中，所述的肿瘤选自脑癌、甲状腺癌、头颈癌、鼻咽癌、咽喉癌、口腔癌、唾液腺癌、食道癌、胃癌、肺癌、肝癌、肾癌、胰腺癌、胆囊癌、胆管癌、结直肠癌、小肠癌、胃肠道间质瘤、尿路上皮癌、尿道癌、膀胱癌、乳腺癌、阴道癌、卵巢癌、子宫内膜癌、宫颈癌、输卵管癌、睾丸癌、前列腺癌、血管瘤、白血病、淋巴瘤、骨髓瘤、皮肤癌、脂肪瘤、骨癌、软组织肉瘤、神经纤维瘤、神经胶质瘤、成神经细胞瘤和胶质母细胞瘤。在另一些实施方案中，所述的肿瘤选自胰腺癌、结直肠癌和非小细胞肺癌。
本公开所述的“2θ或2θ角度”是指衍射角，θ为布拉格角，单位为°或度；每个特征峰2θ的误差范围为±0.20(包括超过1位小数的数字经过四舍五入后的情况)，具体为-0.20、-0.19、-0.18、-0.17、-0.16、-0.15、-0.14、-0.13、-0.12、-0.11、-0.10、-0.09、-0.08、-0.07、-0.06、-0.05、-0.04、-0.03、-0.02、-0.01、0.00、0.01、0.02、0.03、0.04、0.05、0.06、0.07、0.08、0.09、0.10、0.11、0.12、0.13、0.14、0.15、0.16、0.17、0.18、0.19、0.20。
本公开中数值为仪器测量值或仪器测量后计算值，存在一定程度的误差，一般而言，正负10％均属于合理误差范围内。当然需要考虑该数值所用之处的上下文，例如，总杂质的含量，该数值为测量后误差变化不超过正负10％，可以为正负9％、正负8％、正负7％、正负6％、正负5％、正负4％、正负3％、正负2％或正负1％，优选正负5％。
本公开中所述的“差示扫描量热分析或DSC”是指在样品升温或恒温过程中，测量样品与参考物之间的温度差、热流差，以表征所有与热效应有关的物理变化和化学变化，得到样品的相变信息。
本公开中所述干燥温度一般为25℃-100℃，优选30℃-70℃，可以常压干燥，也可以减压干燥。
本公开中所述的“药学上可接受的赋形剂”包括但不限于任何已经被美国食品和药物管理局批准对于人类或家畜动物使用可接受的任何助剂、载体、助流剂、甜味剂、稀释剂、防腐剂、染料/着色剂、增香剂、表面活性剂、润湿剂、分散剂、助悬剂、稳定剂、等渗剂或乳化剂。本公开所述的“打浆”是指利用物质在溶剂中溶解性差，但杂质在溶剂中溶解性好的特性进行纯化的方法，打浆提纯可以去色、改变晶型或去除少量杂质。
本公开所述的晶型包括但不限于化合物A的溶剂合物，所述的溶剂包括但不限于水。
附图说明
图1为化合物A的无定型XRPD谱图。
图2为化合物A的A晶型XRPD谱图。
图3为化合物A的B晶型XRPD谱图。
图4为化合物A的C晶型XRPD谱图。
图5为化合物A的D晶型XRPD谱图。
图6为化合物A的E晶型XRPD谱图。
图7为化合物A的F晶型XRPD谱图。
图8为化合物A的G晶型XRPD谱图。
图9为化合物A的H晶型XRPD谱图。
图10为化合物A的I晶型XRPD谱图。
图11为化合物A的J晶型XRPD谱图。
图12为化合物A的K晶型XRPD谱图。
图13为化合物A的L晶型XRPD谱图。
图14为化合物A的M晶型XRPD谱图。
具体实施方式
通过以下实施例和实验例进一步详细说明本公开。这些实施例和实验例仅用于说明性目的，并不用于限制本公开的范围。
实验所用仪器的测试条件：
化合物的结构是通过核磁共振(NMR)或/和质谱(MS)来确定的。NMR位移(δ)以10-6(ppm)的单位给出。NMR的测定是用Bruker AVANCE-400核磁仪，测定溶剂为氘代二甲基亚砜(DMSO-d6)、氘代氯仿(CDCl3)、氘代甲醇(CD3OD)，内标为四甲基硅烷(TMS)。
MS的测定用Agilent 1200/1290DAD-6110/6120Quadrupole MS液质联用仪(生产商：Agilent，MS型号：6110/6120Quadrupole MS)。waters ACQuity UPLC-QD/SQD(生产商：waters，MS型号：waters ACQuity Qda Detector/waters SQ Detector)THERMO Ultimate 3000-Q Exactive(生产商：THERMO，MS型号：THERMO Q 15Exactive)。
HPLC的测定使用安捷伦1260DAD高压液相色谱仪(Sunfire C18 150×4.6mm色谱柱)和Thermo U3000高压液相色谱仪(Gimini C18 150×4.6mm色谱柱)。
XRPD为X射线粉末衍射检测：测定使用BRUKER D8型X射线衍射仪进行，具体采集信息：Cu阳极(40kV，40mA)，射线：单色Cu-Ka射线扫描方式：θ/2θ，扫描范围：3-48o。
DSC为差示扫描量热：测定采用METTLER TOLEDO DSC 3+示差扫描量热仪，升温速率10℃/min，25-300℃或25-350℃，氮气吹扫速度50mL/min。
TGA为热重分析：检测采用METTLER TOLEDO TGA 2型热重分析仪，升温速率10℃/min，温度具体范围参照相应图谱，氮气吹扫速度50mL/min。
DVS为动态水分吸附：采用Surface Measurement Systems instrinsic，湿度从50％起，考察湿度范围为0％-95％，步进为10％，判断标准为每个梯度质量变化dM/dT≤0.002％，TMAX 360min，循环两圈。
本公开的已知的起始原料可以采用或按照本领域已知的方法来合成，或可购买自ABCR GmbH&Co.KG，Acros Organics，Aldrich Chemical Company，韶远化学30科技(Accela ChemBio Inc)、达瑞化学品等公司
实施例中的反应进程的监测采用薄层色谱法(TLC)，反应所使用的展开剂，纯化化合物采用的柱层析的洗脱剂的体系和薄层色谱法的展开剂体系包括：A：二氯甲烷/甲醇体系，B：正己烷/乙酸乙酯体系，溶剂的体积比根据化合物的极性不同而进行调节，也可以加入少量的三乙胺和醋酸等碱性或酸性试剂进行调节。
实施例1
第一步
2,5,7-三氯-8-氟吡啶并[4,3-d]嘧啶-4-酚1b
将粗品化合物1a(2g，8mmol)溶于三氯氧磷(25mL)，加入N,N-二异丙基乙胺(5.16g，40mmol)，110℃搅拌反应14小时，反应液冷却至室温后减压浓缩，残余物溶于1,4-二氧六环，滴加20％碳酸钾溶液调节pH至2-3，搅拌2小时后过滤，滤饼用水洗涤，干燥后即得粗品标题化合物1b(1.5g)，产物不经纯化直接用于下一步。
MS m/z(ESI):267.8[M+1]。
第二步
(1S,2S,5R)-2-((S)-1-((2,7-二氯-8-氟-4-羟基吡啶并[4,3-d]嘧啶-5-基)氧基)乙基)-3,8-二氮杂双环[3.2.1]辛烷-8-羧酸叔丁酯1d
将(1S,2S,5R)-2-((S)-1-羟乙基)-3,8-二氮杂双环[3.2.1]辛烷-8-羧酸叔丁酯1c(370mg，1.44mmol，采用专利申请“WO2022173678A1”中说明书第164页的Intermediate 29公开的方法制备而得))溶于四氢呋喃(10mL)，冰浴下加入氢化钠(201mg，5.2mmol，60％purity)，反应30分钟后加入化合物1b(353mg，1.31mmol)，搅拌反应2小时，反应液中加入水淬灭后减压浓缩，即得粗品标题化合物1d(600mg)，产物不经纯化，直接用于下一步。
MS m/z(ESI):488.2[M+1]。
第三步
(5S,5aS,6S,9R)-2,12-二氯-1-氟-5-甲基-5a,6,7,8,9,10-六氢-5H-4-氧杂-3,10a,11,13,14-五氮杂-6,9-甲桥萘并[1,8-ab]并庚环-14-羧酸叔丁酯1e
将化合物1d(78mg，159.7μmol)溶于二氯甲烷(2mL)，冰浴下加入N,N-二异丙基乙胺(61.9mg，478.9μmol)，三氯氧磷(122.4mg，798.2μmol)，搅拌反应2小时，反应液中加入饱和碳酸氢钠溶液淬灭，用二氯甲烷(10mL×2)，合并有机相，用无水硫酸钠干燥，过滤除去干燥剂后减压浓缩即得粗品标题化合物1e(75mg)，产物不经纯化直接用于下步反应。
MS m/z(ESI):470.2[M+1]。
第四步
(5S,5aS,6S,9R)-12-((1-(((叔丁基二甲基硅基)氧基)甲基)环丙基)甲氧基)-2-氯-1-氟-5-甲基-5a,6,7,8,9,10-六氢-5H-4-氧杂-3,10a,11,13,14-五氮杂-6,9-甲桥萘并[1,8-ab]并庚环-14-甲酸叔丁基酯1g
将(1-(((叔丁基二甲基硅基)氧基)甲基)环丙基)甲醇1f(1.4g，6.4mmol)溶于四氢呋喃(15mL)，冰浴下加入2M双(三甲基硅基)氨基钠的四氢呋喃溶液，保持温度搅拌30分钟后，冰浴下加入粗品化合物1e(2.3g，4.9mmol)的四氢呋喃溶液(20mL)，保持温度搅拌反应1小时，反应液中加入饱和氯化铵溶液淬灭，用乙酸乙酯(30mL×2)萃取，合并有机相，用无水硫酸钠干燥，过滤除去干燥剂后减压浓缩，残余物用硅胶柱色谱法以洗脱剂体系B纯化得到标题化合物1g(2g，产率：62.8％)。
MS m/z(ESI):650.2[M+1]。
第五步
(5S,5aS,6S,9R)-2-氯-1-氟-12-((1-(羟甲基)环丙基)甲氧基)-5-甲基-5a,6,7,8,9,10-六氢-5H-4-氧杂-3,10a,11,13,14-五氮杂-6,9-甲桥萘并[1,8-ab]并庚环-4-羧酸叔丁酯1h
将化合物1g(100mg，153.8μmol)溶于四氢呋喃(4mL)，加入1M四丁基氟化铵的四氢呋喃溶液(187μL)，搅拌反应2小时，反应液中加入饱和氯化铵水溶液淬灭，乙酸乙酯萃取(15mL×3)，合并有机相，依次用水，饱和氯化钠溶液洗涤，无水硫酸钠干燥，过滤除去干燥剂后滤液减压浓缩，即得到粗品标题化合物1h(82mg)，产品不经纯化直接用于下步反应。
MS m/z(ESI):536.2[M+1]。
第六步
(5S,5aS,6S,9R)-2-氯-1-氟-5-甲基-12-((1-((甲基磺酰基)氧基)甲基)环丙基)甲氧基)-5a,6,7,8,9,10-六氢-5H-4-氧杂-3,10a,11,13,14-五氮杂-6,9-甲桥萘并[1,8-ab]并庚环-14羧酸叔丁酯1i
将粗品化合物1h(83mg，154.9μmol)，N,N-二异丙基乙胺(60mg，464.2μmol)溶于二氯甲烷(3mL)中，冰浴下加入甲烷磺酰氯(25mg，218.2μmol)，自然恢复室温反应30分钟，反应液中加入饱和氯化铵水溶液淬灭，乙酸乙酯萃取(10mL×3)，有机相合并，依次用水，饱和氯化钠溶液洗涤，无水硫酸钠干燥，过滤除去干燥剂后滤液减压浓缩，即得到粗品标题化合物1i(95mg)，产品不经纯化直接用于下步反应。
MS m/z(ESI):614.2[M+1]。
第七步
(5S,5aS,6S,9R)-2-氯-12-((1-((4-(二氟甲亚基)哌啶-1-基)甲基)环丙基)甲氧基)-1-氟-5-甲基-5a,6,7,8,9,10-六氢-5H-4-氧杂-3,10a,11,13,14-五氮杂-6,9-甲桥萘并[1,8-ab]并庚环-14-甲酸叔丁酯1j
将粗品化合物1i(30mg，48.8μmol)、4-(二氟甲亚基)哌啶盐酸盐(12.4mg，73.2μmol)溶于乙腈(4mL)，加入无水碳酸钾(20.2mg，146.5μmol)和碘化钠(22mg，146.5μmol)，80℃搅拌反应1小时，反应液降至室温后过滤，滤液加水稀释，乙酸乙酯萃取(5mL×3)，有机相合并，依次用水、饱和氯化钠溶液洗涤，无水硫酸钠干燥，过滤除去干燥剂后滤液减压浓缩，即得到粗品标题化合物1j(31mg)，产品不经纯化直接用于下步反应。
MS m/z(ESI):651.2[M+1]。
第八步
(5S,5aS,6S,9R)-2-(2-((叔丁氧基羰基)氨基)-3-氰基-7-氟苯并[b]噻吩-4-基)-12-(1-((4-(二氟甲亚基)哌啶-1-基)甲基)环丙基)甲氧基)-1-氟-5-甲基-5a,6,7,8,9,10-六氢-5H-4-氧杂-3,10a,11,13,14-五氮杂-6,9-甲桥萘并[1,8-ab]并庚环-14-甲酸叔丁酯1k
将化合物1j(31mg，47.6μmol)、(3-氰基-4-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊-2-基)-7-氟苯并[b]噻吩-2-基)氨基甲酸叔丁酯(26.9mg，66.6μmol)、四(三苯基膦)钯(11mg，9.5μmol)、碳酸铯(46.5mg，142.8μmol)混于N,N-二甲基甲酰胺(1mL)，氮气氛下，100℃反应3小时，反应液降至室温后过滤，滤液减压浓缩即得粗品标题化合物1k(43mg)，产物不经纯化直接用于下步反应。
MS m/z(ESI)：907.2[M+1]。
第九步
2-氨基-4-((5S,5aS,6S,9R)-12-((1-((4-(二氟甲亚基)哌啶-1-基)甲基)环丙基)甲氧基)-1-氟-5-甲基-5a,6,7,8,9,10-六氢-5H-4-氧杂-3,10a,11,13,14-五氮杂-6,9-甲桥萘并[1,8-ab]并庚环-2-基)-7-氟苯并[b]噻吩-3-甲腈(化合物A)
将粗品化合物1k(40mg，44.1μmol)溶于二氯甲烷(0.5mL)，加入三氟醋酸(0.5mL)，搅拌反应1小时后，减压浓缩，残余物用高效液相制备色谱法纯化(Waters-2545，色谱柱：YMC Triart-Exrs C18,30*150mm,5μm；流动相：水相(10mmol/L碳酸氢铵)和乙腈，梯度配比：乙腈30％-45％，流速：30mL/min)得到标题化合物A(2mg，产率：6.4％)。
MS m/z(ESI):707.2[M+1]。
1H NMR(500MHz,CD3OD):δ7.39(dd,1H),7.04(t,1H),5.41(dd,1H),4.91(s,3H),4.54(d,1H),4.48(d,1H),4.39(d,1H),4.10(d,1H),3.71(d,1H),3.61(s,1H),3.19(d,1H),2.70–2.41(m,5H),2.22(s,3H),2.10(q,2H),2.01–1.83(m,2H),1.79(d,2H),1.61(d,3H),0.75(s,2H),0.52(s,2H)。
测试例1：GP2d、AGS细胞3D增殖抑制实验生物学评价
一、测试目的
通过测试本公开化合物对GP2d、AGS细胞的3D增殖抑制作用，评价本公开化合物对KRAS靶点的抑制作用。
二、实验方法
GP2d细胞用完全培养基即含有10％胎牛血清(Corning，35-076-CV)的DMEM/高糖培养基(Hyclone，SH30243.01)进行培养。实验第一天，使用完全培养基将GP2d细胞以1000个细胞/孔的密度种于96孔低吸附板(Corning，CLS7007-24EA)，每孔90μL细胞悬液，2000转室温离心5分钟后放置37℃，5％ CO2细胞培养箱培养过夜。
AGS细胞用完全培养基即含有10％胎牛血清(Corning，35-076-CV)的RPMI1640培养基(Hyclone，SH30809.01)进行培养。实验第一天，使用完全培养基将AGS细胞以1000个细胞/孔的密度种于96孔低吸附板(Corning，CLS7007-24EA)，每孔90μL细胞悬液，2000转室温离心5分钟后放置37℃，5％ CO2细胞培养箱培养过夜。
第二天，每孔加入10μL用完全培养基配制的梯度稀释的待测化合物，GP2d细胞的化合物终浓度是从1μM开始进行5倍梯度稀释的9个浓度点，AGS细胞的化合物终浓度是从10μM开始进行5倍梯度稀释的9个浓度点，都设置含有0.5％ DMSO的空白对照。孔板放置37℃，5％ CO2的细胞培养箱培养5天。第七天，取出96孔细胞培养板，每孔加入50μL3D Cell Viability Assay试剂(Promega，G9682)，室温避光震荡25分钟后，吹吸混匀并每孔取出100μL转移至白色不透底的96孔板(PerkinElmer，6005290)中，使用多功能微孔板酶标仪(PerkinElmer，EnVision2105)读取发光信号值。
三、数据分析
用Graphpad Prism软件计算化合物抑制活性的IC50值。化合物A GP2d细胞3D增殖抑制活性IC50＝0.4nM。
测试例2：AsPC-1细胞3D增殖抑制实验生物学评价
实验第一天，将生长良好、达70％-80％汇合度的AsPC-1细胞消化后，用含有10％ FBS的RPMI 1640(Hyclone，SH30809.01)培养基重悬，并调整细胞密度至所需。在U形低吸附96孔板中(Corning，CLS7007-24EA)每孔加入90μL细胞悬液，细胞密度为1500个/孔。将细胞板在2500转离心5分钟后，置于37℃，5％ CO2培养箱中培养过夜。第二天，将溶于DMSO的20mM受试化合物用DMSO稀释至首浓度2mM，然后再以5倍梯度稀释，共9个浓度点，对照孔为DMSO。然后用培养基将梯度稀释的化合物进一步稀释20倍。在细胞板每孔加入10μL培养基稀释后的受试化合物，化合物终浓度为首浓度10μM，5倍梯度稀释的9个浓度点。设置含有0.5％ DMSO的细胞孔为溶媒对照孔，仅有培养基和0.5％ DMSO的孔为空白对照孔。化合物各浓度和对照孔均设置复孔，每孔DMSO终浓度为0.5％。将细胞板在2500转离心3分钟后，置于37℃，5％ CO2培养箱中培养5天。第七天取出96孔细胞培养板，每孔加入50μL发光细胞活性检测试剂3D Cell Viability Assay(Promega，G9683)，于室温避光震荡25分钟，用移液器上下吹吸混匀后每孔转移100μL至白色不透底OptiPlateTM-96孔板(PerkinElmer，6005290)，使用多功能微孔板酶标仪(PerkinElmer，EnVision2105)读取发光信号值。
使用以下公式计算抑制率：抑制率＝(发光值溶媒对照孔-发光值受试化合物)/(发光值溶媒对照孔-发光值空白对照孔)×100％。用GraphPad Prism软件根据化合物各浓度与相应的抑制率绘出曲线，并计算化合物的IC50值。化合物A的IC50＝3.7nM。
实施例2：化合物A的无定型的制备
称取化合物A约6mg，溶于0.03mL 2-丁酮，室温挥发，得到固体。经X-射线粉末衍射检测，衍射角2θ角度表示的X-射线粉末衍射图没有明显特征峰，XRPD谱图如图1所示，该产物为无定型。
实施例3：化合物A的晶型A的制备
称取化合物A约6mg，加入0.4mL正庚烷，搅拌析晶，得到固体。
经X-射线粉末衍射检测，将该产物定义为晶型A，XRPD谱图如图2，其特征峰位置如表1所示。
DSC谱图显示，吸热峰峰值142.68℃。TGA谱图显示，31℃-155℃失重3.17％。
表1
实施例4：化合物A晶型B的制备
称取化合物A约6mg，加入0.5mL乙醇，室温搅拌析晶，离心后固体真空干燥，得到固体。经X-射线粉末衍射检测，将该产物定义为晶型B，XRPD谱图如图3，其特征峰位置如表2所示。DSC谱图显示，吸热峰峰值152.16℃。TGA谱图显示，32℃-130℃失重5.02％。
表2

实施例5：化合物A晶型B的制备
称取化合物A约6mg，加入0.5mL适当溶剂中(表3)，室温搅拌析晶，离心后固体真空干燥，得到固体。经X-射线粉末衍射检测为晶型B。
表3
实施例6：化合物A晶型C的制备
称取化合物A约6mg，加入0.03mL丙酮，搅拌析晶，得到固体。
经X-射线粉末衍射检测，将该产物定义为晶型C，XRPD谱图如图4，其特征峰位置如表4所示。DSC谱图显示，吸热峰峰值170.02℃。TGA谱图显示，31℃-143℃失重0.53％。
表4
实施例7：化合物A晶型D的制备
称取化合物A约6mg，加入0.4mL乙腈，搅拌析晶，离心后固体真空干燥，得到固体。
经X-射线粉末衍射检测，将该产物定义为晶型D，XRPD谱图如图5，其特征峰位置如表5所示。DSC谱图显示，吸热峰峰值68.66℃、166.16℃。TGA谱图显示，30℃-145℃失重1.94％。
表5
实施例8：化合物A晶型E的制备
称取化合物A约6mg，加入0.4mL乙酸异丙酯，搅拌析晶，得到固体。
经X-射线粉末衍射检测，将该产物定义为晶型E，XRPD谱图如图6，其特征峰位置如表6所示。DSC谱图显示，吸热峰峰值198.18℃。TGA谱图显示，30℃-197℃失重0.08％。
表6
实施例9：化合物A晶型E的制备
称取化合物A约6mg，加入0.5mL适当溶剂中(表7)，室温搅拌析晶，离心后固体真空干燥，得到固体。经X-射线粉末衍射检测为晶型E。
表7
实施例10：化合物A晶型F的制备
称取化合物A约6mg，加入0.03mL 10％水/丙酮(v/v)，搅拌析晶，得到固体。
经X-射线粉末衍射检测，将该产物定义为晶型F，XRPD谱图如图7，其特征峰位置如表8所示。DSC谱图显示，吸热峰峰值168.35℃。TGA谱图显示，33℃-117℃失重1.30％。
表8
实施例11：化合物A晶型G的制备
称取化合物A约6mg，加入0.5mL甲醇/水(1:1,v/v)，搅拌析晶，离心后固体真空干燥，得到固体。
经X-射线粉末衍射检测，将该产物定义为晶型G，XRPD谱图如图8，其特征峰位置如表9所示。DSC谱图显示，吸热峰峰值74.50℃、151.50℃。TGA谱图显示，32℃-161℃失重2.28％。
表9
实施例12：化合物A晶型G的制备
称取化合物A约6mg，加入0.5mL乙腈/甲醇(1:1,v/v)，挥发析晶，得到标题产物。
实施例13：化合物A晶型H的制备
称取化合物A约6mg，加入0.3mL异丙醚，搅拌析晶，得到固体。
经X-射线粉末衍射检测，将该产物定义为晶型H，XRPD谱图如图9，其特征峰位置如表10所示。DSC谱图显示，吸热峰峰值219.42℃。TGA谱图显示，30℃-220℃失重0.46％。
表10

实施例14：化合物A晶型H的制备
称取化合物A约6mg，溶于0.1mL丙酮中，加入1.0mL异丙醚，搅拌析晶，得到标题产物。
实施例15：化合物A晶型H的制备
称取化合物A约6mg，溶于0.1mL丙酮中，加入1.0mL正庚烷，搅拌析晶，得到标题产物。
实施例16：化合物A晶型H的制备
称取化合物A约6mg，溶于0.1mL丙二醇甲醚中，加入1.0mL正庚烷，搅拌析晶，得到标题产物。
实施例17：化合物A晶型I的制备
称取化合物A约6mg，溶于0.1mL二氧六环中，加入1.0mL异丙醚，搅拌析晶，得到固体。
经X-射线粉末衍射检测，将该产物定义为晶型I，XRPD谱图如图10，其特征峰位置如表11所示。DSC谱图显示，吸热峰峰值154.00℃、225.69℃。TGA谱图显示，35℃-163℃失重1.92％。
表11

实施例18：化合物A晶型J的制备
称取化合物A约6mg，溶于0.2mL甲醇中，挥发析晶，得到固体。
经X-射线粉末衍射检测，将该产物定义为晶型J，XRPD谱图如图11，其特征峰位置如表12所示。
表12
实施例19：化合物A晶型K的制备
称取化合物A约6mg，加入0.53mL水/甲醇(1:9,v/v)，挥发析晶，得到固体。
经X-射线粉末衍射检测，将该产物定义为晶型K，XRPD谱图如图12，其特征峰位置如表13所示。
表13

实施例20：化合物A晶型L的制备
称取化合物A约20mg，加入1mL乙酸甲酯，搅拌48h，得到固体产物。
经X-射线粉末衍射检测，将该产物定义为晶型L，XRPD谱图如图13，其特征峰位置如表14所示。
表14

实施例21：化合物A晶型M的制备
称取化合物A约50mg，加入0.5mL甲苯，搅拌48小时，得到固体产物。
经X-射线粉末衍射检测，将该产物定义为晶型M，XRPD谱图如图14，其特征峰位置如表15所示。
表15
实施例22：化合物A的晶型A的制备
称取化合物A约6mg，加入0.4mL水，搅拌析晶，得到目标产物。
测试例3：影响因素
将前述晶型敞口平摊放置，分别考察在光照(4500Lux)、高温(40℃、60℃)、高湿(RH 75％、RH 92.5％)条件下样品的稳定性，取样考察期为30天。
表16
表17
结论：影响因素实验表明：在光照、高温40℃和60℃、高湿75％和92.5％条件下30天，晶型D和晶型H晶型物理化学稳定性均良好。
测试例4：长期加速试验
将晶型D、晶型H分别放置25℃/60％RH和40℃/75％RH条件考察稳定性。
表18
表19
结论：长期加速实验表明：在25℃/60％RH和40℃/75％RH条件下9个月，晶型D和晶型H物理化学稳定性均良好。

Claims (19)

  1. 化合物2-氨基-4-((5S,5aS,6S,9R)-12-((1-((4-(二氟甲亚基)哌啶-1-基)甲基)环丙基)甲氧基)-1-氟-5-甲基-5a,6,7,8,9,10-六氢-5H-4-氧杂-3,10a,11,13,14-五氮杂-6,9-甲桥萘并[1,8-ab]并庚环-2-基)-7-氟苯并[b]噻吩-3-甲腈的A晶型，其特征在于，以衍射角2θ角度表示的X-射线粉末衍射图谱，在5.235、6.954、8.874、14.709、21.043处有特征峰，优选在5.235、6.954、8.874、14.709、16.053、19.239、19.776、21.043处有特征峰，更优选以衍射角2θ角度表示的X-射线粉末衍射图谱如图2所示。
  2. 化合物2-氨基-4-((5S,5aS,6S,9R)-12-((1-((4-(二氟甲亚基)哌啶-1-基)甲基)环丙基)甲氧基)-1-氟-5-甲基-5a,6,7,8,9,10-六氢-5H-4-氧杂-3,10a,11,13,14-五氮杂-6,9-甲桥萘并[1,8-ab]并庚环-2-基)-7-氟苯并[b]噻吩-3-甲腈的B晶型，其特征在于，以衍射角2θ角度表示的X-射线粉末衍射图谱，在8.845、12.746、14.040、14.480、17.371、18.833处有特征峰，优选在8.845、9.258、12.746、14.040、14.480、16.475、17.371、18.833处有特征峰，更优选在8.845、9.258、12.746、14.040、14.480、15.800、16.475、17.371、18.833、20.883、28.999处有特征峰，最优选以衍射角2θ角度表示的X-射线粉末衍射图谱如图3所示。
  3. 化合物2-氨基-4-((5S,5aS,6S,9R)-12-((1-((4-(二氟甲亚基)哌啶-1-基)甲基)环丙基)甲氧基)-1-氟-5-甲基-5a,6,7,8,9,10-六氢-5H-4-氧杂-3,10a,11,13,14-五氮杂-6,9-甲桥萘并[1,8-ab]并庚环-2-基)-7-氟苯并[b]噻吩-3-甲腈的C晶型，其特征在于，以衍射角2θ角度表示的X-射线粉末衍射图谱，在5.083、10.326、11.776、13.543、15.564处有特征峰，优选在5.083、10.326、11.776、13.543、15.564、16.060、17.675处有特征峰，更优选在5.083、10.326、11.776、13.543、15.564、16.060、17.675、18.451、20.167、21.940处有特征峰，最优选以衍射角2θ角度表示的X-射线粉末衍射图谱如图4所示。
  4. 化合物2-氨基-4-((5S,5aS,6S,9R)-12-((1-((4-(二氟甲亚基)哌啶-1-基)甲基)环丙基)甲氧基)-1-氟-5-甲基-5a,6,7,8,9,10-六氢-5H-4-氧杂-3,10a,11,13,14-五氮杂-6,9-甲桥萘并[1,8-ab]并庚环-2-基)-7-氟苯并[b]噻吩-3-甲腈的D晶型，其特征在于，以衍射角2θ角度表示的X-射线粉末衍射图谱，在4.865、8.452、9.819、12.795、14.695、16.052、19.632处有特征峰，优选在4.865、8.452、9.819、10.763、12.795、14.695、16.052、17.818、19.632处有特征峰，更优选在4.865、8.452、9.819、10.763、12.795、14.695、16.052、16.954、17.818、19.632、21.197处有特征峰，最优选以衍射角2θ角度表示的X-射线粉末衍射图谱如图5所示。
  5. 化合物2-氨基-4-((5S,5aS,6S,9R)-12-((1-((4-(二氟甲亚基)哌啶-1-基)甲基)环丙基)甲氧基)-1-氟-5-甲基-5a,6,7,8,9,10-六氢-5H-4-氧杂-3,10a,11,13,14-五氮杂-6,9-甲桥萘并[1,8-ab]并庚环-2-基)-7-氟苯并[b]噻吩-3-甲腈的E晶型，其特征在于，以衍射角2θ角度表示的X-射线粉末衍射图谱，在7.155、9.117、11.638、16.461、17.277、20.652处有特征峰，优选在7.155、9.117、11.638、13.672、15.285、16.461、17.277、20.652处有特征峰，更优选在7.155、9.117、11.638、13.672、15.285、16.461、17.277、20.652、21.734、23.001处有特征峰，最优选以衍射角2θ角度表示的X-射线粉末衍射图谱如图6所示。
  6. 化合物2-氨基-4-((5S,5aS,6S,9R)-12-((1-((4-(二氟甲亚基)哌啶-1-基)甲基)环丙基)甲氧基)-1-氟-5-甲基-5a,6,7,8,9,10-六氢-5H-4-氧杂-3,10a,11,13,14-五氮杂-6,9-甲桥萘并[1,8-ab]并庚环-2-基)-7-氟苯并[b]噻吩-3-甲腈的F晶型，其特征在于，以衍射角2θ角度表示的X-射线粉末衍射图谱，在4.684、10.040、13.134、14.247、17.432、20.421处有特征峰，优选在4.684、10.040、13.134、14.247、15.464、17.432、19.688、20.421处有特征峰，更优选在4.684、10.040、13.134、14.247、15.464、16.709、17.432、19.688、20.421、22.909处有特征峰，最优选以衍射角2θ角度表示的X-射线粉末衍射图谱如图7所示。
  7. 化合物2-氨基-4-((5S,5aS,6S,9R)-12-((1-((4-(二氟甲亚基)哌啶-1-基)甲基)环丙基)甲氧基)-1-氟-5-甲基-5a,6,7,8,9,10-六氢-5H-4-氧杂-3,10a,11,13,14-五氮杂-6,9-甲桥萘并[1,8-ab]并庚环-2-基)-7-氟苯并[b]噻吩-3-甲腈的G晶型，其特征在于，以衍射角2θ角度表示的X-射线粉末衍射图谱，在8.404、11.861、14.205、15.114、17.113、19.116、21.354处有特征峰，优选在8.404、10.099、11.861、14.205、15.114、15.570、17.113、19.116、19.948、21.354有特征峰，更优选在8.404、10.099、11.861、13.401、14.205、15.114、15.570、17.113、19.116、19.948、21.354处有特征峰，最优选以衍射角2θ角度表示的X-射线粉末衍射图谱如图8所示。
  8. 化合物2-氨基-4-((5S,5aS,6S,9R)-12-((1-((4-(二氟甲亚基)哌啶-1-基)甲基)环丙基)甲氧基)-1-氟-5-甲基-5a,6,7,8,9,10-六氢-5H-4-氧杂-3,10a,11,13,14-五氮杂-6,9-甲桥萘并[1,8-ab]并庚环-2-基)-7-氟苯并[b]噻吩-3-甲腈的H晶型，其特征在于，以衍射角2θ角度表示的X-射线粉末衍射图谱，在10.615、12.690、16.070、17.610、19.226、21.218、24.456处有特征峰，优选在10.615、12.690、15.582、16.070、16.339、17.610、19.226、21.218、24.456处有特征峰，更优选在8.677、10.615、11.061、12.690、13.221、15.582、16.070、16.339、17.610、19.226、21.218、24.456处有特征峰，最优选以衍射角2θ角度表示的X-射线粉末衍射图谱如图9所示。
  9. 化合物2-氨基-4-((5S,5aS,6S,9R)-12-((1-((4-(二氟甲亚基)哌啶-1-基)甲基)环丙基)甲氧基)-1-氟-5-甲基-5a,6,7,8,9,10-六氢-5H-4-氧杂-3,10a,11,13,14-五氮杂-6,9-甲桥萘并[1,8-ab]并庚环-2-基)-7-氟苯并[b]噻吩-3-甲腈的I晶型，其特征在于，以衍射角2θ角度表示的X-射线粉末衍射图谱，在5.063、7.165、9.911、15.902、19.507处有特征峰，优选在5.063、7.165、9.911、15.902、16.411、17.311、19.507处有特征峰，更优选在5.063、7.165、9.911、13.484、15.902、16.411、17.311、17.762、19.507处有特征峰，最优选以衍射角2θ角度表示的X-射线粉末衍射图谱如图10所示。
  10. 化合物2-氨基-4-((5S,5aS,6S,9R)-12-((1-((4-(二氟甲亚基)哌啶-1-基)甲基)环丙基)甲氧基)-1-氟-5-甲基-5a,6,7,8,9,10-六氢-5H-4-氧杂-3,10a,11,13,14-五氮杂-6,9-甲桥萘并[1,8-ab]并庚环-2-基)-7-氟苯并[b]噻吩-3-甲腈的J晶型，其特征在于，以衍射角2θ角度表示的X-射线粉末衍射图谱，在8.630、10.574、15.783、17.686、19.265、24.076处有特征峰，优选在8.630、10.574、15.783、17.686、19.265、20.898、24.076、25.093处有特征峰，更优选在8.630、10.574、12.697、15.783、17.686、19.265、20.898、21.274、24.076、25.093处有特征峰，最优选以衍射角2θ角度表示的X-射线粉末衍射图谱如图11所示。
  11. 化合物2-氨基-4-((5S,5aS,6S,9R)-12-((1-((4-(二氟甲亚基)哌啶-1-基)甲基)环丙基)甲氧基)-1-氟-5-甲基-5a,6,7,8,9,10-六氢-5H-4-氧杂-3,10a,11,13,14-五氮杂-6,9-甲桥萘并[1,8-ab]并庚环-2-基)-7-氟苯并[b]噻吩-3-甲腈的K晶型，其特征在于，以衍射角2θ角度表示的X-射线粉末衍射图谱，在8.434、11.714、13.979、19.124、20.773处有特征峰，优选在8.434、9.603、11.714、13.979、16.820、19.124、20.773处有特征峰，更优选在8.434、9.603、10.524、11.714、13.407、13.979、16.820、19.124、20.773处有特征峰，最优选以衍射角2θ角度表示的X-射线粉末衍射图谱如图12所示。
  12. 化合物2-氨基-4-((5S,5aS,6S,9R)-12-((1-((4-(二氟甲亚基)哌啶-1-基)甲基)环丙基)甲氧基)-1-氟-5-甲基-5a,6,7,8,9,10-六氢-5H-4-氧杂-3,10a,11,13,14-五氮杂-6,9-甲桥萘并[1,8-ab]并庚环-2-基)-7-氟苯并[b]噻吩-3-甲腈的L晶型，其特征在于，以衍射角2θ角度表示的X-射线粉末衍射图谱，在4.959、8.605、10.908、14.761、16.656、19.649处有特征峰，优选在4.959、8.605、10.908、12.928、14.761、16.167、16.656、18.089、19.649、19.887处有特征峰，更优选在4.959、8.605、10.908、12.928、13.669、14.761、16.167、16.656、17.054、18.089、19.649、21.286、22.463、25.634处有特征峰，最优选以衍射角2θ角度表示的X-射线粉末衍射图谱如图13所示。
  13. 化合物2-氨基-4-((5S,5aS,6S,9R)-12-((1-((4-(二氟甲亚基)哌啶-1-基)甲基)环丙基)甲氧基)-1-氟-5-甲基-5a,6,7,8,9,10-六氢-5H-4-氧杂-3,10a,11,13,14-五氮杂-6,9-甲桥萘并[1,8-ab]并庚环-2-基)-7-氟苯并[b]噻吩-3-甲腈的M晶型，其特征在于，以衍射角2θ角度表示的X-射线粉末衍射图谱，在5.607、7.457、13.037、13.940、17.177、19.704处有特征峰，优选在5.607、7.457、10.102、11.312、13.037、13.940、16.658、17.177、17.752、19.704处有特征峰，更优选在5.607、7.457、10.102、11.312、13.037、13.940、16.290、16.658、17.177、17.752、18.631、19.704、22.663处有特征峰，最优选以衍射角2θ角度表示的X-射线粉末衍射图谱如图14所示。
  14. 根据权利要求1-13任一项所述的晶型，其特征在于所述2θ值误差范围为±0.2。
  15. 制备权利要求1-14任一项所述的A、B、C、D、E、F、G、H、I、J、K、L或M晶型的制备方法，选自如下任一方法，
    方法一：
    (a)将化合物2-氨基-4-((5S,5aS,6S,9R)-12-((1-((4-(二氟甲亚基)哌啶-1-基)甲基)环丙基)甲氧基)-1-氟-5-甲基-5a,6,7,8,9,10-六氢-5H-4-氧杂-3,10a,11,13,14-五氮杂-6,9-甲桥萘并[1,8-ab]并庚环-2-基)-7-氟苯并[b]噻吩-3-甲腈与溶剂混合，搅拌溶解或加热溶解，
    (b)析晶；
    或，方法二：
    (a)将化合物2-氨基-4-((5S,5aS,6S,9R)-12-((1-((4-(二氟甲亚基)哌啶-1-基)甲基)环丙基)甲氧基)-1-氟-5-甲基-5a,6,7,8,9,10-六氢-5H-4-氧杂-3,10a,11,13,14-五氮杂-6,9-甲桥萘并[1,8-ab]并庚环-2-基)-7-氟苯并[b]噻吩-3-甲腈与溶剂混合，搅拌溶解或加热溶解，
    (b)加入第二溶剂，搅拌；
    或，方法三：
    (a)将化合物2-氨基-4-((5S,5aS,6S,9R)-12-((1-((4-(二氟甲亚基)哌啶-1-基)甲基)环丙基)甲氧基)-1-氟-5-甲基-5a,6,7,8,9,10-六氢-5H-4-氧杂-3,10a,11,13,14-五氮杂-6,9-甲桥萘并[1,8-ab]并庚环-2-基)-7-氟苯并[b]噻吩-3-甲腈与溶剂混合，
    (b)搅拌。
  16. 一种药物组合物，其包括如权利要求1-13任一项所述的晶型，和药学上可接受的赋形剂。
  17. 一种药物组合物，由如权利要求1-13任一项所述的晶型和药学上可接受的赋形剂制备得到。
  18. 权利要求1-13任一项所述的晶型，或权利要求14或15所述的药物组合物在制备用于预防和/或治疗由KRAS G12D介导的疾病或病症的药物中的用途。
  19. 权利要求1-13任一项所述的晶型，或权利要求14或15所述的药物组合物在制备用于预防和/或治疗肿瘤的药物中的用途，所述的肿瘤优选选自脑癌、甲状腺癌、头颈癌、鼻咽癌、咽喉癌、口腔癌、唾液腺癌、食道癌、胃癌、肺癌、肝癌、肾癌、胰腺癌、胆囊癌、胆管癌、结直肠癌、小肠癌、胃肠道间质瘤、尿路上皮癌、尿道癌、膀胱癌、乳腺癌、阴道癌、卵巢癌、子宫内膜癌、宫颈癌、输卵管癌、睾丸癌、前列腺癌、血管瘤、白血病、淋巴瘤、骨髓瘤、皮肤癌、脂肪瘤、骨癌、软组织肉瘤、神经纤维瘤、神经胶质瘤、成神经细胞瘤和胶质母细胞瘤；更优选选自胰腺癌、结直肠癌和非小细胞肺癌。
PCT/CN2025/074649 2024-01-26 2025-01-24 G12d抑制剂化合物晶型及其制备方法 Pending WO2025157261A1 (zh)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN202410112046.6 2024-01-26
CN202410112046 2024-01-26

Publications (1)

Publication Number Publication Date
WO2025157261A1 true WO2025157261A1 (zh) 2025-07-31

Family

ID=96544462

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2025/074649 Pending WO2025157261A1 (zh) 2024-01-26 2025-01-24 G12d抑制剂化合物晶型及其制备方法

Country Status (1)

Country Link
WO (1) WO2025157261A1 (zh)

Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2022194245A1 (zh) * 2021-03-17 2022-09-22 劲方医药科技(上海)有限公司 嘧啶并环类化合物及其制法和用途
WO2022268051A1 (zh) * 2021-06-21 2022-12-29 江苏恒瑞医药股份有限公司 稠合四环类化合物、其制备方法及其在医药上的应用
CN115557974A (zh) * 2021-07-02 2023-01-03 上海迪诺医药科技有限公司 Kras g12d抑制剂及其应用
WO2023001123A1 (zh) * 2021-07-19 2023-01-26 上海艾力斯医药科技股份有限公司 新型吡啶并嘧啶衍生物
WO2023103906A1 (zh) * 2021-12-07 2023-06-15 贝达药业股份有限公司 Kras g12d抑制剂及其在医药上的应用
CN116867792A (zh) * 2021-02-09 2023-10-10 基因泰克公司 四环氧氮杂䓬化合物及其用途
WO2024022444A1 (zh) * 2022-07-27 2024-02-01 江苏恒瑞医药股份有限公司 稠环类化合物、其制备方法及其在医药上的应用
WO2024125642A1 (zh) * 2022-12-15 2024-06-20 上海翰森生物医药科技有限公司 含嘧啶多元并环类衍生物抑制剂、其制备方法和应用

Patent Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN116867792A (zh) * 2021-02-09 2023-10-10 基因泰克公司 四环氧氮杂䓬化合物及其用途
WO2022194245A1 (zh) * 2021-03-17 2022-09-22 劲方医药科技(上海)有限公司 嘧啶并环类化合物及其制法和用途
WO2022268051A1 (zh) * 2021-06-21 2022-12-29 江苏恒瑞医药股份有限公司 稠合四环类化合物、其制备方法及其在医药上的应用
CN115557974A (zh) * 2021-07-02 2023-01-03 上海迪诺医药科技有限公司 Kras g12d抑制剂及其应用
WO2023001123A1 (zh) * 2021-07-19 2023-01-26 上海艾力斯医药科技股份有限公司 新型吡啶并嘧啶衍生物
WO2023103906A1 (zh) * 2021-12-07 2023-06-15 贝达药业股份有限公司 Kras g12d抑制剂及其在医药上的应用
WO2024022444A1 (zh) * 2022-07-27 2024-02-01 江苏恒瑞医药股份有限公司 稠环类化合物、其制备方法及其在医药上的应用
WO2024125642A1 (zh) * 2022-12-15 2024-06-20 上海翰森生物医药科技有限公司 含嘧啶多元并环类衍生物抑制剂、其制备方法和应用

Similar Documents

Publication Publication Date Title
JP6850922B2 (ja) Ｊａｋキナーゼ阻害剤としてのナフチリジン化合物
TW202430184A (zh) Kras g12d抑制劑的結晶形式及製備方法
CN119661555B (zh) 一种稠环类化合物的可药用盐、其结晶形式及用途
EA023350B1 (ru) Противомикробные соединения, способы их получения и применение
WO2025157260A1 (zh) G12d抑制剂化合物的可药用盐及其晶型
WO2011163430A9 (en) Polymorphs of osi-906
WO2024109871A1 (zh) 一种含氮杂环类化合物的可药用盐、晶型及制备方法
WO2022135610A1 (zh) 四并环化合物及其药物组合物和应用
JP7554007B2 (ja) Ｊａｋ阻害剤化合物及びその使用
WO2022127827A1 (zh) Kras g12c蛋白突变抑制剂、其制备方法、药物组合物及其应用
CN107793371B (zh) 一类溴结构域识别蛋白抑制剂及其制备方法和用途
US20200361913A1 (en) Salt form and crystal form serving as fgfr and vegfr inhibitor compounds, and preparation method therefor
CN111518045A (zh) 一种具有苯并七元环结构的化合物、其制备方法及用途
TWI820182B (zh) 四氫哌喃基胺基－吡咯并嘧啶酮化合物的固體形式
WO2025157261A1 (zh) G12d抑制剂化合物晶型及其制备方法
WO2024153219A1 (zh) 一种三氮唑类化合物的可药用盐、晶型及其制备方法
CN114478586B (zh) 一种含二并环类衍生物抑制剂盐或晶型及其制备方法和应用
AU2023256032A1 (en) Crystal of 7h-pyrrolo[2,3-d]pyrimidine-4-amine derivative
CN112500353A (zh) 一种左西孟旦的前药化合物、制备方法及其应用
TWI922947B (zh) 雜環化合物的晶型、其鹽、其鹽的晶型及應用
ES3058045T3 (en) Crystal form of pyrrolidinyl urea derivative and application thereof
CN102344443A (zh) 点击化学合成开环马来酰亚胺类化合物及其在治疗疾病中的应用
HK40120957A (zh) 新型四杂环化合物
WO2026061491A1 (zh) 一种苯并吲哚衍生物的晶型、盐型及其制备方法
WO2026002142A1 (zh) 一种蛋白酪氨酸激酶抑制剂的半琥珀酸盐晶型

Legal Events

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

Ref document number: 25744724

Country of ref document: EP

Kind code of ref document: A1