Crystal form of g12d inhibitor compound and preparation method

Abstract

The present invention relates to a crystal form of a G12D inhibitor compound and a preparation method. Specifically, the present invention provides a crystal form of 2-amino-4-((5S,5aS,6S,9R)-12-((1-((4-(difluoromethylidenyl)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-methanonaphtho[1,8-ab]heptalen-2-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile, and a preparation method.

Description

G12D inhibitor compound crystal form and preparation method thereof

[0001] This application claims the benefit of Chinese Patent Application No. 2024101120466, filed January 26, 2024. This application incorporates the entirety of the aforementioned Chinese Patent Application. Technical Field

[0002] The present disclosure belongs to the field of pharmaceuticals and relates to a G12D inhibitor compound crystal form and a preparation method thereof. Background Art

[0003] 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.

[0004] 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).

[0005] The 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. Generally speaking, 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. Summary of the Invention

[0006] 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 2θ, having characteristic peaks at 5.235, 6.954, 8.874, 14.709, and 21.043.

[0007] In some embodiments, the A crystal form has an X-ray powder diffraction pattern represented by a diffraction angle of 2θ, with characteristic peaks at 5.235, 6.954, 8.874, 14.709, 16.053, 19.239, 19.776, and 21.043.

[0008] In other embodiments, the X-ray powder diffraction pattern of the crystal form A expressed in terms of a diffraction angle 2θ is shown in FIG2 .

[0009] 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 2θ degrees, with characteristic peaks at 8.845, 12.746, 14.040, 14.480, 17.371, and 18.833.

[0010] In some embodiments, the B crystalline form has an X-ray powder diffraction pattern represented by a diffraction angle of 2θ, with characteristic peaks at 8.845, 9.258, 12.746, 14.040, 14.480, 16.475, 17.371, and 18.833.

[0011] In some embodiments, the B crystalline form has an X-ray powder diffraction pattern expressed as a diffraction angle 2θ, 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.

[0012] In other embodiments, the X-ray powder diffraction pattern of the Form B expressed in terms of a diffraction angle of 2θ is shown in FIG3 .

[0013] On the one hand, 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 2θ, having characteristic peaks at 5.083, 10.326, 11.776, 13.543, and 15.564.

[0014] In some embodiments, the C crystalline form has an X-ray powder diffraction pattern represented by a diffraction angle of 2θ, with characteristic peaks at 5.083, 10.326, 11.776, 13.543, 15.564, 16.060, and 17.675.

[0015] In some embodiments, the C crystalline form has an X-ray powder diffraction pattern expressed as a diffraction angle 2θ, 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.

[0016] In other embodiments, the X-ray powder diffraction pattern of the C crystal form expressed in terms of a diffraction angle 2θ is shown in FIG4 .

[0017] On the one hand, 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 2θ, having characteristic peaks at 4.865, 8.452, 9.819, 12.795, 14.695, 16.052, and 19.632.

[0018] In some embodiments, the D crystalline form has an X-ray powder diffraction pattern represented by a diffraction angle of 2θ, with characteristic peaks at 4.865, 8.452, 9.819, 10.763, 12.795, 14.695, 16.052, 17.818, and 19.632.

[0019] In some embodiments, the D crystalline form has an X-ray powder diffraction pattern expressed as a diffraction angle 2θ, 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.

[0020] In other embodiments, the X-ray powder diffraction pattern of the D crystal form expressed in terms of a diffraction angle of 2θ is shown in FIG5 .

[0021] On the one hand, 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 2θ, having characteristic peaks at 7.155, 9.117, 11.638, 16.461, 17.277, and 20.652.

[0022] In some embodiments, the E crystalline form has an X-ray powder diffraction pattern represented by a diffraction angle of 2θ, with characteristic peaks at 7.155, 9.117, 11.638, 13.672, 15.285, 16.461, 17.277, and 20.652.

[0023] In some embodiments, the E crystalline form has an X-ray powder diffraction pattern expressed as a diffraction angle 2θ, 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.

[0024] In other embodiments, the X-ray powder diffraction pattern of the E crystal form expressed in terms of a diffraction angle of 2θ is shown in FIG6 .

[0025] On the one hand, 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 2θ, having characteristic peaks at 4.684, 10.040, 13.134, 14.247, 17.432, and 20.421.

[0026] In some embodiments, the F crystalline form has an X-ray powder diffraction pattern represented by a diffraction angle of 2θ, with characteristic peaks at 4.684, 10.040, 13.134, 14.247, 15.464, 17.432, 19.688, and 20.421.

[0027] In some embodiments, the F crystalline form has an X-ray powder diffraction pattern expressed as a diffraction angle 2θ, 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.

[0028] In other embodiments, the X-ray powder diffraction pattern of the F crystal form expressed in terms of a diffraction angle of 2θ is shown in FIG7 .

[0029] On the one hand, 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 2θ, having characteristic peaks at 8.404, 11.861, 14.205, 15.114, 17.113, 19.116, and 21.354.

[0030] In some embodiments, the G crystalline form has an X-ray powder diffraction pattern expressed as a diffraction angle 2θ, 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.

[0031] In some embodiments, the G crystalline form has an X-ray powder diffraction pattern expressed as a diffraction angle 2θ, 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.

[0032] In other embodiments, the X-ray powder diffraction pattern of the G crystal form expressed in terms of a diffraction angle 2θ is shown in FIG8 .

[0033] On the one hand, 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 2θ, having characteristic peaks at 10.615, 12.690, 16.070, 17.610, 19.226, 21.218, and 24.456.

[0034] In some embodiments, the H crystalline form has an X-ray powder diffraction pattern expressed as a diffraction angle 2θ, with characteristic peaks at 10.615, 12.690, 15.582, 16.070, 16.339, 17.610, 19.226, 21.218, and 24.456.

[0035] In some embodiments, the H crystalline form has an X-ray powder diffraction pattern expressed as a diffraction angle 2θ, 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.

[0036] In other embodiments, the H crystal form has an X-ray powder diffraction pattern represented by a diffraction angle of 2θ as shown in FIG9 .

[0037] On the one hand, 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 2θ, having characteristic peaks at 5.063, 7.165, 9.911, 15.902, and 19.507.

[0038] In some embodiments, the Form I has an X-ray powder diffraction pattern represented by a diffraction angle of 2θ, with characteristic peaks at 5.063, 7.165, 9.911, 15.902, 16.411, 17.311, and 19.507.

[0039] In some embodiments, the Form I has an X-ray powder diffraction pattern expressed as a diffraction angle of 2θ, with characteristic peaks at 5.063, 7.165, 9.911, 13.484, 15.902, 16.411, 17.311, 17.762, and 19.507.

[0040] In other embodiments, the X-ray powder diffraction pattern of the Form I expressed in terms of a diffraction angle of 2θ is shown in FIG10 .

[0041] On the one hand, 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 2θ, having characteristic peaks at 8.630, 10.574, 15.783, 17.686, 19.265, and 24.076.

[0042] In some embodiments, the J crystalline form has an X-ray powder diffraction pattern expressed as a diffraction angle 2θ, with characteristic peaks at 8.630, 10.574, 15.783, 17.686, 19.265, 20.898, 24.076, and 25.093.

[0043] In some embodiments, the J crystalline form has an X-ray powder diffraction pattern expressed as a diffraction angle 2θ, 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.

[0044] In other embodiments, the X-ray powder diffraction pattern of the J crystal form expressed in terms of a diffraction angle of 2θ is shown in FIG11 .

[0045] On the one hand, 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 2θ, having characteristic peaks at 8.434, 11.714, 13.979, 19.124, and 20.773.

[0046] In some embodiments, the K crystal form has an X-ray powder diffraction pattern represented by a diffraction angle of 2θ, with characteristic peaks at 8.434, 9.603, 11.714, 13.979, 16.820, 19.124, and 20.773.

[0047] In some embodiments, the K crystal form has an X-ray powder diffraction pattern represented by a diffraction angle of 2θ, with characteristic peaks at 8.434, 9.603, 10.524, 11.714, 13.407, 13.979, 16.820, 19.124, and 20.773.

[0048] In other embodiments, the X-ray powder diffraction pattern of the K crystal form expressed in terms of a diffraction angle of 2θ is shown in FIG12 .

[0049] On the one hand, 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 2θ, having characteristic peaks at 4.959, 8.605, 10.908, 14.761, 16.656, and 19.649.

[0050] In some embodiments, the L crystalline form has an X-ray powder diffraction pattern represented by a diffraction angle of 2θ, 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.

[0051] In some embodiments, the L crystalline form has an X-ray powder diffraction pattern expressed as a diffraction angle of 2θ, 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.

[0052] In other embodiments, the L crystal form has an X-ray powder diffraction pattern represented by a diffraction angle of 2θ as shown in FIG13 .

[0053] On the one hand, 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 2θ, having characteristic peaks at 5.607, 7.457, 13.037, 13.940, 17.177, and 19.704.

[0054] In some embodiments, the M crystalline form has an X-ray powder diffraction pattern expressed as a diffraction angle of 2θ, 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.

[0055] In some embodiments, the M crystalline form has an X-ray powder diffraction pattern expressed as a diffraction angle of 2θ, 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.

[0056] In other embodiments, the X-ray powder diffraction pattern of the M crystal form expressed in terms of a diffraction angle of 2θ is shown in FIG14 .

[0057] Furthermore, 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 2θ, wherein the error range of the 2θ angle is ±0.2.

[0058] On the other hand, the present disclosure also provides a method for preparing the aforementioned crystal form, which is selected from any of the following methods:

[0059] Method 1:

[0060] (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, stirring and dissolving the mixture or heating the mixture to dissolve the mixture;

[0061] (b) crystallization;

[0062] Or, method 2:

[0063] (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, stirring and dissolving the mixture or heating the mixture to dissolve the mixture;

[0064] (b) adding a second solvent and stirring;

[0065] Or, method three:

[0066] (a) mixing a 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,

[0067] (b) stirring.

[0068] In some embodiments, 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,

[0069] (b) stirring.

[0070] In some embodiments, 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 (1:1, v / v),

[0071] (b) stirring.

[0072] In some embodiments, 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,

[0073] (b) stirring.

[0074] In some embodiments, 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,

[0075] (b) stirring.

[0076] In some embodiments, 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);

[0077] (b) stirring.

[0078] In some embodiments, 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),

[0079] (b) stirring.

[0080] In some embodiments, 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);

[0081] (b) stirring.

[0082] In some embodiments, 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).

[0083] (b) Crystallization, such as volatile crystallization.

[0084] In some embodiments, 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,

[0085] (b) stirring.

[0086] In some embodiments, 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,

[0087] (b) adding a solvent (11) and stirring, wherein the solvent (11) is selected from n-heptane or isopropyl ether.

[0088] In some embodiments, 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,

[0089] (b) adding a solvent (13) and stirring, wherein the solvent (13) is selected from isopropyl ether.

[0090] In some embodiments, 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,

[0091] (b) Crystallization, such as volatile crystallization.

[0092] In some embodiments, 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);

[0093] (b) Crystallization, such as volatile crystallization.

[0094] In some embodiments, 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,

[0095] (b) stirring.

[0096] In some embodiments, 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,

[0097] (b) stirring.

[0098] In certain embodiments, the preparation method disclosed herein further comprises any one of the steps of crystallization, filtration, washing or drying.

[0099] In some embodiments, the crystallization includes but is not limited to stirring crystallization (dissolution crystallization, slurry crystallization) and volatile crystallization.

[0100] In some embodiments, 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.

[0101] On the other hand, the present disclosure also provides a pharmaceutical composition comprising the aforementioned crystal form and a pharmaceutically acceptable excipient.

[0102] The present disclosure also provides a pharmaceutical composition prepared from the aforementioned crystal form and a pharmaceutically acceptable excipient.

[0103] 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.

[0104] 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. In some embodiments, 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 tissue sarcoma, neurofibroma, glioma, neuroblastoma and glioblastoma.

[0105] 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. In some embodiments, 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 and glioblastoma. In other embodiments, the tumor is selected from pancreatic cancer, colorectal cancer and non-small cell lung cancer.

[0106] The present disclosure also provides a method for preventing and / or treating a disease or condition mediated by KRAS G12D, comprising administering the aforementioned crystalline form or the aforementioned pharmaceutical composition to a patient.

[0107] 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. In some embodiments, 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. In other embodiments, the tumor is selected from pancreatic cancer, colorectal cancer and non-small cell lung cancer.

[0108] Another aspect of the present disclosure is to provide the aforementioned crystalline form or the aforementioned pharmaceutical composition for preventing and / or treating a disease or condition mediated by KRAS G12D.

[0109] The present disclosure further provides the aforementioned crystal forms or the aforementioned pharmaceutical compositions for preventing and / or treating tumors. In some embodiments, 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. In other embodiments, the tumor is selected from pancreatic cancer, colorectal cancer and non-small cell lung cancer.

[0110] The "2θ or 2θ angle" mentioned in the present disclosure refers to the diffraction angle, θ is the Bragg angle, and the unit is ° or degree; the error range of each characteristic peak 2θ 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.

[0111] 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. For example, 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%.

[0112] 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.

[0113] 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.

[0114] 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.

[0115] 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. BRIEF DESCRIPTION OF THE DRAWINGS

[0116] Figure 1 is the XRPD spectrum of the amorphous form of compound A.

[0117] Figure 2 is the XRPD spectrum of Form A of Compound A.

[0118] Figure 3 is the XRPD spectrum of Form B of Compound A.

[0119] Figure 4 is the XRPD spectrum of Form C of Compound A.

[0120] Figure 5 is the XRPD spectrum of Form D of Compound A.

[0121] Figure 6 is the XRPD spectrum of Form E of Compound A.

[0122] FIG7 is an XRPD spectrum of Form F of Compound A.

[0123] FIG8 is an XRPD spectrum of Form G of Compound A.

[0124] Figure 9 is the XRPD spectrum of Form H of Compound A.

[0125] Figure 10 is the XRPD spectrum of Form I of Compound A.

[0126] Figure 11 is the XRPD spectrum of Form J of Compound A.

[0127] Figure 12 is the XRPD spectrum of Form K of Compound A.

[0128] FIG13 is an XRPD spectrum of Form L of Compound A.

[0129] FIG14 is an XRPD spectrum of Form M of Compound A. DETAILED DESCRIPTION

[0130] The present disclosure is further described in detail by the following examples and experimental examples. These examples and experimental examples are for illustrative purposes only and are not intended to limit the scope of the present disclosure.

[0131] Test conditions of the instruments used in the experiment:

[0132] The structures of the compounds were determined by nuclear magnetic resonance (NMR) and / or mass spectrometry (MS). -6 The unit of ppm is given. NMR measurements were performed using a Bruker AVANCE-400 NMR spectrometer. The solvents used were deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl3), and deuterated methanol (CD3OD), and tetramethylsilane (TMS) was used as the internal standard.

[0133] MS measurements were performed using an Agilent 1200 / 1290 DAD-6110 / 6120 Quadrupole MS liquid chromatography-mass spectrometer (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).

[0134] HPLC analysis was 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).

[0135] 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: θ / 2θ, scanning range: 3-48 o .

[0136] DSC is differential scanning calorimetry: the measurement was performed using a METTLER TOLEDO DSC 3+ differential scanning calorimeter with a heating rate of 10°C / min, from 25 to 300°C or from 25 to 350°C, and a nitrogen purge rate of 50 mL / min.

[0137] TGA is 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.

[0138] DVS stands for dynamic moisture sorption: using the Surface Measurement Systems instrument, humidity starts at 50% and the humidity range is 0%-95% with a step of 10%. The judgment standard is that the mass change of each gradient dM / dT is ≤ 0.002%, TMAX is 360min, and there are two cycles.

[0139] 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.

[0140] The reaction progress in the examples was monitored by thin layer chromatography (TLC). The developing solvent used in the reaction, the eluent system for column chromatography used to purify the compound, and the developing solvent system for thin layer chromatography included: A: dichloromethane / methanol system, B: n-hexane / ethyl acetate system. 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.

[0141] Example 1

[0142] first step

[0143] 2,5,7-Trichloro-8-fluoropyrido[4,3-d]pyrimidin-4-ol 1b

[0144] 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.

[0145] MS m / z(ESI):267.8[M+1].

[0146] Step 2

[0147] tert-Butyl (1S,2S,5R)-2-((S)-1-((2,7-dichloro-8-fluoro-4-hydroxypyrido[4,3-d]pyrimidin-5-yl)oxy)ethyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate 1d

[0148] Tert-butyl (1S,2S,5R)-2-((S)-1-hydroxyethyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate 1c (370 mg, 1.44 mmol, prepared by the method disclosed in Intermediate 29 on page 164 of the specification of patent application "WO2022173678A1")) was dissolved in tetrahydrofuran (10 mL), and sodium hydride (201 mg, 5.2 mmol, 60% purity) was added under ice bath. After reacting for 30 minutes, compound 1b (353 mg, 1.31 mmol) was added and stirred for 2 hours. The reaction solution was quenched by adding water and concentrated under reduced pressure to obtain the crude title compound 1d (600 mg). The product was used directly in the next step without purification.

[0149] MS m / z(ESI):488.2[M+1].

[0150] Step 3

[0151] (5S,5aS,6S,9R)-2,12-Dichloro-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]heptyl-14-carboxylic acid tert-butyl ester 1e

[0152] Compound 1d (78 mg, 159.7 μmol) was dissolved in dichloromethane (2 mL). N,N-diisopropylethylamine (61.9 mg, 478.9 μmol) and phosphorus oxychloride (122.4 mg, 798.2 μmol) were added under ice-cooling and stirred for 2 hours. Saturated sodium bicarbonate solution was added to the reaction solution to quench the reaction. The organic phases were combined with dichloromethane (10 mL × 2), dried over anhydrous sodium sulfate, filtered to remove the desiccant, and concentrated under reduced pressure to obtain the crude title compound 1e (75 mg). The product was used directly in the next step without purification.

[0153] MS m / z(ESI):470.2[M+1].

[0154] Step 4

[0155] Tert-butyl (5S,5aS,6S,9R)-12-((1-((tert-butyldimethylsilyl)oxy)methyl)cyclopropyl)methoxy)-2-chloro-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]heptyl-14-carboxylate 1g

[0156] (1-(((tert-Butyldimethylsilyl)oxy)methyl)cyclopropyl)methanol 1f (1.4 g, 6.4 mmol) was dissolved in tetrahydrofuran (15 mL), and a 2M solution of sodium bis(trimethylsilyl)amide in tetrahydrofuran was added under ice-cooling. The mixture was stirred at the maintained temperature for 30 minutes. Then, a solution of crude compound 1e (2.3 g, 4.9 mmol) in tetrahydrofuran (20 mL) was added under ice-cooling. The mixture was stirred at the maintained temperature for 1 hour. Saturated ammonium chloride solution was added to the reaction solution to quench the reaction. The mixture was extracted with ethyl acetate (30 mL×2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered to remove the desiccant, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent System B to obtain the title compound 1g (2 g, yield: 62.8%).

[0157] MS m / z(ESI):650.2[M+1].

[0158] Step 5

[0159] tert-Butyl (5S,5aS,6S,9R)-2-chloro-1-fluoro-12-((1-(hydroxymethyl)cyclopropyl)methoxy)-5-methyl-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methano[1,8-ab]heptyl-4-carboxylate

[0160] Compound 1g (100 mg, 153.8 μmol) was dissolved in tetrahydrofuran (4 mL), and a 1 M tetrabutylammonium fluoride solution in tetrahydrofuran (187 μL) was added. The mixture was stirred for 2 hours. Saturated aqueous ammonium chloride was added to the reaction solution for quenching, and the mixture was extracted with ethyl acetate (15 mL × 3). The organic phases were combined, washed with water and saturated sodium chloride solution, dried over anhydrous sodium sulfate, and the desiccant was removed by filtration. The filtrate was concentrated under reduced pressure to obtain the crude title compound 1h (82 mg), which was used directly in the next step without purification.

[0161] MS m / z(ESI):536.2[M+1].

[0162] Step 6

[0163] tert-Butyl (5S,5aS,6S,9R)-2-chloro-1-fluoro-5-methyl-12-((1-((methylsulfonyl)oxy)methyl)cyclopropyl)methoxy)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methanaphtho[1,8-ab]heptyl-14-carboxylate 1i

[0164] The crude compound 1h (83 mg, 154.9 μmol) and N,N-diisopropylethylamine (60 mg, 464.2 μmol) were dissolved in dichloromethane (3 mL). Methanesulfonyl chloride (25 mg, 218.2 μmol) was added under ice bath and the reaction was allowed to return to room temperature for 30 minutes. Saturated aqueous ammonium chloride was added to the reaction solution for quenching. The mixture was extracted with ethyl acetate (10 mL × 3). The organic phases were combined, washed with water and saturated sodium chloride solution, dried over anhydrous sodium sulfate, and the desiccant was removed by filtration. The filtrate was concentrated under reduced pressure to obtain the crude title compound 1i (95 mg), which was used directly in the next step without purification.

[0165] MS m / z(ESI):614.2[M+1].

[0166] Step 7

[0167] tert-Butyl (5S,5aS,6S,9R)-2-chloro-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]heptyl-14-carboxylate 1j

[0168] The crude compound 1i (30 mg, 48.8 μmol) and 4-(difluoromethylidene)piperidine hydrochloride (12.4 mg, 73.2 μmol) were dissolved in acetonitrile (4 mL), and anhydrous potassium carbonate (20.2 mg, 146.5 μmol) and sodium iodide (22 mg, 146.5 μmol) were added. The mixture was stirred at 80°C for 1 hour. The reaction solution was cooled to room temperature and filtered. The filtrate was diluted with water and extracted with ethyl acetate (5 mL×3). The organic phases were combined, washed with water and saturated sodium chloride solution in sequence, and dried over anhydrous sodium sulfate. The desiccant was removed by filtration, and the filtrate was concentrated under reduced pressure to obtain the crude title compound 1j (31 mg). The product was used directly in the next step without purification.

[0169] MS m / z(ESI):651.2[M+1].

[0170] Step 8

[0171] tert-Butyl (5S,5aS,6S,9R)-2-(2-((tert-Butoxycarbonyl)amino)-3-cyano-7-fluorobenzo[b]thiophen-4-yl)-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]heptane-14-carboxylate 1k

[0172] Compound 1j (31 mg, 47.6 μmol), tert-butyl (3-cyano-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-7-fluorobenzo[b]thiophen-2-yl)carbamate (26.9 mg, 66.6 μmol), tetrakis(triphenylphosphine)palladium (11 mg, 9.5 μmol), and cesium carbonate (46.5 mg, 142.8 μmol) were mixed in N,N-dimethylformamide (1 mL) and reacted at 100°C under a nitrogen atmosphere for 3 hours. The reaction solution was cooled to room temperature and filtered, and the filtrate was concentrated under reduced pressure to obtain the crude title compound 1k (43 mg), which was used directly in the next step without purification.

[0173] MS m / z (ESI): 907.2 [M+1].

[0174] Step 9

[0175] 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]heptyl-2-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile (Compound A)

[0176] The crude compound 1k (40 mg, 44.1 μmol) 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 preparative high-performance liquid chromatography (Waters-2545, column: YMC Triart-Exrs C18, 30*150 mm, 5 μm; 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%).

[0177] MS m / z(ESI):707.2[M+1].

[0178] 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).

[0179] Test Example 1: Biological Evaluation of GP2d and AGS Cell 3D Proliferation Inhibition Experiment

[0180] 1. Test Purpose

[0181] 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.

[0182] 2. Experimental Methods

[0183] 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 μL 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.

[0184] AGS cells were cultured in complete medium (RPMI 1640 medium (Hyclone, SH30809.01) supplemented with 10% fetal bovine serum (Corning, 35-076-CV). On the first day of the experiment, 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 μL of cell suspension was added to each well. The cells were centrifuged at 2000 rpm for 5 minutes at room temperature and then incubated overnight at 37°C in a 5% CO2 incubator.

[0185] On the second day, 10 μL of a serial dilution of the test compound prepared in complete culture medium was added to each well. The final concentration of the compound for GP2d cells was 9 concentration points of a 5-fold serial dilution starting from 1 μM, and the final concentration of the compound for AGS cells was 9 concentration points of a 5-fold serial dilution starting from 10 μM. A blank control containing 0.5% DMSO was set up for both. The well plate was placed in a cell culture incubator at 37°C and 5% CO2 for 5 days. On the seventh day, the 96-well cell culture plate was removed and 50 μL of the test compound was added to each well. 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 μL 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).

[0186] 3. Data Analysis

[0187] The IC of the inhibitory activity of the compounds was calculated using Graphpad Prism software 50 Compound A GP2d cell 3D proliferation inhibitory activity IC 50 =0.4nM.

[0188] Test Example 2: Biological Evaluation of AsPC-1 Cell 3D Proliferation Inhibition Experiment

[0189] On the first day of the experiment, well-grown AsPC-1 cells reaching 70%-80% confluence were digested and resuspended in RPMI 1640 (Hyclone, SH30809.01) supplemented with 10% FBS. The cell density was adjusted to the desired level. 90 μL of the cell suspension was added to each well of a U-shaped low-adhesion 96-well plate (Corning, CLS7007-24EA) for a cell density of 1500 cells / well. The plate was centrifuged at 2500 rpm for 5 minutes and incubated overnight at 37°C in a 5% CO2 incubator. On the second day, 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 well. The serially diluted compound was then further diluted 20-fold with culture medium. 10 μL of the test compound diluted with culture medium was added to each well of the plate for a final concentration of 10 μM starting at the 10-fold concentration and then serially diluted to 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. Each concentration of compound and control wells were set up in duplicate, and the final DMSO concentration in each well was 0.5%. After centrifugation at 2500 rpm for 3 minutes, the cell plate was placed in a 37°C, 5% CO2 incubator for 5 days. On the seventh day, the 96-well cell culture plate was removed and 50 μL of luminescent cell viability detection reagent was added to each well. 3D Cell Viability Assay (Promega, G9683) was shaken in the dark at room temperature for 25 minutes. After mixing by pipetting up and down, 100 μL was transferred to each well of the white opaque OptiPlate. TM -96-well plate (PerkinElmer, 6005290), and the luminescence signal value was read using a multi-function microplate reader (PerkinElmer, EnVision2105).

[0190] The inhibition rate was calculated using the following formula: Inhibition rate = (luminescence value 溶媒对照孔 - Luminous value 受试化合物 ) / (luminous value 溶媒对照孔 - Luminous value 空白对照孔 ) × 100%. GraphPad Prism software was used to draw a curve based on the concentration of the compound and the corresponding inhibition rate, and the IC of the compound was calculated. 50 IC of compound A 50 =3.7nM.

[0191] Example 2: Preparation of amorphous form of compound A

[0192] Approximately 6 mg of Compound A was weighed and dissolved in 0.03 mL of 2-butanone. The mixture was evaporated at room temperature to obtain a solid. X-ray powder diffraction analysis revealed no distinct peaks in the X-ray powder diffraction pattern at a diffraction angle of 2θ. The XRPD spectrum is shown in Figure 1, indicating that the product is amorphous.

[0193] Example 3: Preparation of Form A of Compound A

[0194] About 6 mg of compound A was weighed, 0.4 mL of n-heptane was added, and the mixture was stirred for crystallization to obtain a solid.

[0195] 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.

[0196] 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.

[0197] Table 1

[0198] Example 4: Preparation of Compound A Crystal Form B

[0199] Approximately 6 mg of compound A was weighed and added to 0.5 mL of ethanol. The mixture was stirred at room temperature to crystallize. After centrifugation, the solid was vacuum dried to obtain a solid. X-ray powder diffraction analysis identified the product as Form B. The XRPD spectrum is shown in Figure 3, and the positions of its characteristic peaks are shown in Table 2. The DSC spectrum showed an endothermic peak at 152.16°C. The TGA spectrum showed a weight loss of 5.02% from 32°C to 130°C.

[0200] Table 2

[0201] Example 5: Preparation of Compound A Crystal Form B

[0202] About 6 mg of compound A was weighed and added to 0.5 mL of an appropriate solvent (Table 3). The mixture was stirred at room temperature to crystallize. After centrifugation, the solid was vacuum dried to obtain a solid. X-ray powder diffraction analysis confirmed the solid to be Form B.

[0203] Table 3

[0204] Example 6: Preparation of Compound A Crystalline Form C

[0205] About 6 mg of compound A was weighed, 0.03 mL of acetone was added, and the mixture was stirred for crystallization to obtain a solid.

[0206] 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.

[0207] Table 4

[0208] Example 7: Preparation of Compound A Crystalline Form D

[0209] About 6 mg of compound A was weighed, 0.4 mL of acetonitrile was added, and the mixture was stirred for crystallization. After centrifugation, the solid was vacuum dried to obtain a solid.

[0210] 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.

[0211] Table 5

[0212] Example 8: Preparation of Compound A Crystal Form E

[0213] About 6 mg of compound A was weighed, 0.4 mL of isopropyl acetate was added, and the mixture was stirred for crystallization to obtain a solid.

[0214] 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.

[0215] Table 6

[0216] Example 9: Preparation of Compound A Crystal Form E

[0217] About 6 mg of compound A was weighed and added to 0.5 mL of an appropriate solvent (Table 7). The mixture was stirred at room temperature to crystallize. After centrifugation, the solid was vacuum dried to obtain a solid. X-ray powder diffraction analysis confirmed the solid to be Form E.

[0218] Table 7

[0219] Example 10: Preparation of Compound A Crystal Form F

[0220] About 6 mg of compound A was weighed, 0.03 mL of 10% water / acetone (v / v) was added, and the mixture was stirred for crystallization to obtain a solid.

[0221] 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.

[0222] Table 8

[0223] Example 11: Preparation of Compound A Crystal Form G

[0224] About 6 mg of compound A was weighed, 0.5 mL of methanol / water (1:1, v / v) was added, and the mixture was stirred for crystallization. After centrifugation, the solid was vacuum dried to obtain a solid.

[0225] 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.

[0226] Table 9

[0227] Example 12: Preparation of Compound A Crystal Form G

[0228] About 6 mg of compound A was weighed, 0.5 mL of acetonitrile / methanol (1:1, v / v) was added, and the mixture was evaporated and crystallized to obtain the title product.

[0229] Example 13: Preparation of Compound A Crystalline Form H

[0230] About 6 mg of compound A was weighed, 0.3 mL of isopropyl ether was added, and the mixture was stirred for crystallization to obtain a solid.

[0231] 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.

[0232] Table 10

[0233] Example 14: Preparation of Compound A Crystalline Form H

[0234] About 6 mg of compound A was weighed and dissolved in 0.1 mL of acetone. 1.0 mL of isopropyl ether was added and stirred for crystallization to obtain the title product.

[0235] Example 15: Preparation of Compound A Crystalline Form H

[0236] About 6 mg of compound A was weighed and dissolved in 0.1 mL of acetone. 1.0 mL of n-heptane was added and stirred for crystallization to obtain the title product.

[0237] Example 16: Preparation of Compound A Crystalline Form H

[0238] About 6 mg of compound A was weighed and dissolved in 0.1 mL of propylene glycol methyl ether. 1.0 mL of n-heptane was added and stirred for crystallization to obtain the title product.

[0239] Example 17: Preparation of Compound A Crystalline Form I

[0240] About 6 mg of compound A was weighed and dissolved in 0.1 mL of dioxane. 1.0 mL of isopropyl ether was added and stirred for crystallization to obtain a solid.

[0241] 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.

[0242] Table 11

[0243] Example 18: Preparation of Compound A Crystal Form J

[0244] About 6 mg of compound A was weighed and dissolved in 0.2 mL of methanol. The solution was evaporated and crystallized to obtain a solid.

[0245] 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 .

[0246] Table 12

[0247] Example 19: Preparation of Compound A Crystalline Form K

[0248] About 6 mg of compound A was weighed, 0.53 mL of water / methanol (1:9, v / v) was added, and the solution was evaporated and crystallized to obtain a solid.

[0249] 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 .

[0250] Table 13

[0251] Example 20: Preparation of Compound A Crystal Form L

[0252] About 20 mg of compound A was weighed, 1 mL of methyl acetate was added, and the mixture was stirred for 48 h to obtain a solid product.

[0253] 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 .

[0254] Table 14

[0255] Example 21: Preparation of Compound A Crystalline Form M

[0256] About 50 mg of compound A was weighed, 0.5 mL of toluene was added, and the mixture was stirred for 48 hours to obtain a solid product.

[0257] 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 .

[0258] Table 15

[0259] Example 22: Preparation of Form A of Compound A

[0260] Weigh about 6 mg of compound A, add 0.4 mL of water, stir and crystallize to obtain the target product.

[0261] Test Case 3: Influencing Factors

[0262] The aforementioned crystal forms were laid out openly, and the stability of the samples was investigated under conditions of light (4500 Lux), high temperature (40° C., 60° C.), and high humidity (RH 75%, RH 92.5%) for 30 days.

[0263] Table 16

[0264] Table 17

[0265] Conclusion: The influencing factor experiment shows that under the conditions of light, high temperature of 40℃ and 60℃, high humidity of 75% and 92.5% for 30 days, both Form D and Form H have good physical and chemical stability.

[0266] Test Example 4: Long-term accelerated test

[0267] The stability of Form D and Form H was investigated under conditions of 25°C / 60% RH and 40°C / 75% RH, respectively.

[0268] Table 18

[0269] Table 19

[0270] Conclusion: Long-term accelerated experiments showed that both Form D and Form H had good physicochemical stability at 25°C / 60% RH and 40°C / 75% RH for 9 months.

Claims

1. The A 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-methano-naphtho[1,8-ab]azulene-2-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile, characterized in that, The X-ray powder diffraction pattern represented by the diffraction angle 2θ has characteristic peaks at 5.235, 6.954, 8.874, 14.709, 21.043, preferably at 5.235, 6.954, 8.874, 14.709, 16.053, 19.239, 19.776, 21.043, and more preferably the X-ray powder diffraction pattern represented by the diffraction angle 2θ is as shown in Figure 2.

2. B 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-methano-naphtho[1,8-ab]azulene-2-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile, characterized in that, The X-ray powder diffraction pattern represented by the diffraction angle 2θ has characteristic peaks at 8.845, 12.746, 14.040, 14.480, 17.371, 18.833, preferably at 8.845, 9.258, 12.746, 14.040, 14.480, 16.475, 17.371, 18.833, more preferably at 8.845, 9.258, 12.746, 14.040, 14.480, 15.800, 16.475, 17.371, 18.833, 20.883, 28.999, and most preferably the X-ray powder diffraction pattern represented by the diffraction angle 2θ is as shown in Figure 3.

3. The C 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-methano-naphtho[1,8-ab]azulen-2-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile, characterized in that, The X-ray powder diffraction pattern represented by the diffraction angle 2θ has characteristic peaks at 5.083, 10.326, 11.776, 13.543, 15.564, preferably at 5.083, 10.326, 11.776, 13.543, 15.564, 16.060, 17.675, more preferably at 5.083, 10.326, 11.776, 13.543, 15.564, 16.060, 17.675, 18.451, 20.167, 21.940, and most preferably the X-ray powder diffraction pattern represented by the diffraction angle 2θ is as shown in Figure 4.

4. D crystal form of the compound 2-amino-4-((5S,5aS,6S,9R)-12-((1-((4-(difluoromethylene)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-naphtho[1,8-ab]azulene-2-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile, which is characterized in that, The X-ray powder diffraction pattern represented by the diffraction angle 2θ has characteristic peaks at 4.865, 8.452, 9.819, 12.795, 14.695, 16.052, 19.632, preferably at 4.865, 8.452, 9.819, 10.763, 12.795, 14.695, 16.052, 17.818, 19.632, more preferably at 4.865, 8.452, 9.819, 10.763, 12.795, 14.695, 16.052, 16.954, 17.818, 19.632, 21.197, and most preferably the X-ray powder diffraction pattern represented by the diffraction angle 2θ is as shown in Figure 5. The E 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-methano-naphtho[1,8-ab]azulen-2-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile, which is characterized in that, The X-ray powder diffraction pattern expressed in terms of the diffraction angle 2θ has characteristic peaks at 7.155, 9.117, 11.638, 16.461, 17.277, 20.652, preferably at 7.155, 9.117, 11.638, 13.672, 15.285, 16.461, 17.277, 20.652, more preferably at 7.155, 9.117, 11.638, 13.672, 15.285, 16.461, 17.277, 20.652, 21.734, 23.001, and most preferably the X-ray powder diffraction pattern expressed in terms of the diffraction angle 2θ is as shown in Figure 6.

6. The F 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-methano-naphtho[1,8-ab]azulen-2-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile, which is characterized in that, The X-ray powder diffraction pattern expressed in terms of the diffraction angle 2θ has characteristic peaks at 4.684, 10.040, 13.134, 14.247, 17.432, 20.421, preferably at 4.684, 10.040, 13.134, 14.247, 15.464, 17.432, 19.688, 20.421, more preferably at 4.684, 10.040, 13.134, 14.247, 15.464, 16.709, 17.432, 19.688, 20.421, 22.909, and most preferably the X-ray powder diffraction pattern expressed in terms of the diffraction angle 2θ is as shown in Figure 7.

7. The G 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-methano-naphtho[1,8-ab]azulen-2-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile, which is characterized in that, The X-ray powder diffraction pattern expressed in terms of the diffraction angle 2θ has characteristic peaks at 8.404, 11.861, 14.205, 15.114, 17.113, 19.116, 21.354, preferably at 8.404, 10.099, 11.861, 14.205, 15.114, 15.570, 17.113, 19.116, 19.948, 21.354, more preferably at 8.404, 10.099, 11.861, 13.401, 14.205, 15.114, 15.570, 17.113, 19.116, 19.948, 21.354, and most preferably the X-ray powder diffraction pattern expressed in terms of the diffraction angle 2θ is as shown in Figure 8.

8. The H 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-methano-naphtho[1,8-ab]azulen-2-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile, which is characterized in that, The X-ray powder diffraction pattern expressed in terms of diffraction angle 2θ has characteristic peaks at 10.615, 12.690, 16.070, 17.610, 19.226, 21.218, 24.

456. Preferably, it has characteristic peaks at 10.615, 12.690, 15.582, 16.070, 16.339, 17.610, 19.226, 21.218, 24.

456. More preferably, it has 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, 24.

456. Most preferably, the X-ray powder diffraction pattern expressed in terms of diffraction angle 2θ is as shown in Figure 9.

9. The I crystal form of the compound 2-amino-4-((5S,5aS,6S,9R)-12-((1-((4-(difluoromethylene)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-naphtho[1,8-ab]azulen-2-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile, characterized in that, The X-ray powder diffraction pattern expressed in terms of diffraction angle 2θ has characteristic peaks at 5.063, 7.165, 9.911, 15.902, 19.

507. Preferably, it has characteristic peaks at 5.063, 7.165, 9.911, 15.902, 16.411, 17.311, 19.

507. More preferably, it has characteristic peaks at 5.063, 7.165, 9.911, 13.484, 15.902, 16.411, 17.311, 17.762, 19.

507. Most preferably, the X-ray powder diffraction pattern expressed in terms of diffraction angle 2θ is as shown in Figure 10.

10. The J crystal form of the compound 2-amino-4-((5S,5aS,6S,9R)-12-((1-((4-(difluoromethylene)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-naphtho[1,8-ab]azulen-2-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile, which is characterized in that, The X-ray powder diffraction pattern expressed in terms of diffraction angle 2θ has characteristic peaks at 8.630, 10.574, 15.783, 17.686, 19.265, 24.

076. Preferably, it has characteristic peaks at 8.630, 10.574, 15.783, 17.686, 19.265, 20.898, 24.076, 25.

093. More preferably, it has characteristic peaks at 8.630, 10.574, 12.697, 15.783, 17.686, 19.265, 20.898, 21.274, 24.076, 25.

093. Most preferably, the X-ray powder diffraction pattern expressed in terms of diffraction angle 2θ is as shown in Figure 11.

11. The 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-methano-naphtho[1,8-ab]azulene-2-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile, characterized in that, The X-ray powder diffraction pattern expressed in terms of diffraction angle 2θ has characteristic peaks at 8.434, 11.714, 13.979, 19.124, 20.

773. Preferably, it has characteristic peaks at 8.434, 9.603, 11.714, 13.979, 16.820, 19.124, 20.

773. More preferably, it has characteristic peaks at 8.434, 9.603, 10.524, 11.714, 13.407, 13.979, 16.820, 19.124, 20.

773. Most preferably, the X-ray powder diffraction pattern expressed in terms of diffraction angle 2θ is as shown in Figure 12.

12. The L 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-methano-naphtho[1,8-ab]azulene-2-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile, which is characterized in that, The X-ray powder diffraction pattern expressed in terms of the diffraction angle 2θ has characteristic peaks at 4.959, 8.605, 10.908, 14.761, 16.656, 19.649, preferably at 4.959, 8.605, 10.908, 12.928, 14.761, 16.167, 16.656, 18.089, 19.649, 19.887, more preferably 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, 25.634, and most preferably the X-ray powder diffraction pattern expressed in terms of the diffraction angle 2θ is as shown in Figure 13.

13. The M crystal form of the compound 2-amino-4-((5S,5aS,6S,9R)-12-((1-((4-(difluoromethylene)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-naphtho[1,8-ab]azulen-2-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile, characterized in that, The X-ray powder diffraction pattern expressed in terms of the diffraction angle 2θ has characteristic peaks at 5.607, 7.457, 13.037, 13.940, 17.177, 19.704, preferably at 5.607, 7.457, 10.102, 11.312, 13.037, 13.940, 16.658, 17.177, 17.752, 19.704, more preferably 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, 22.663, and most preferably the X-ray powder diffraction pattern expressed in terms of the diffraction angle 2θ is as shown in Figure 14.

14. The crystalline form according to any one of claims 1-13, characterized in that The error range of the 2θ value is ±0.

2.

15. The preparation method of crystal forms A, B, C, D, E, F, G, H, I, J, K, L or M described in any one of claims 1-14, selected from any one of the following methods, Method 1: (a) Mix the compound 2-amino-4-((5S,5aS,6S,9R)-12-((1-((4-(difluoromethylene)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]azulene-2-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile with a solvent, stir to dissolve or heat to dissolve, (b) Crystallize; Or, Method 2: (a) Mix the compound 2-amino-4-((5S,5aS,6S,9R)-12-((1-((4-(difluoromethylene)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]azulene-2-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile with a solvent, stir to dissolve or heat to dissolve, (b) Add a second solvent and stir; Or, Method 3: (a) Mix the compound 2-amino-4-((5S,5aS,6S,9R)-12-((1-((4-(difluoromethylene)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-naphtho[1,8-ab]azulene-2-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile with a solvent, (b) Stir.

16. A pharmaceutical composition, which comprises the crystalline form according to any one of claims 1-13 and a pharmaceutically acceptable excipient.

17. A pharmaceutical composition, which is prepared from the crystalline form according to any one of claims 1-13 and a pharmaceutically acceptable excipient.

18. Use of the crystalline form according to any one of claims 1-13, or the pharmaceutical composition according to claim 14 or 15, in the preparation of a medicament for preventing and / or treating a disease or disorder mediated by KRAS G12D.

19. Use of the crystalline form according to any one of claims 1-13, or the pharmaceutical composition according to claim 14 or 15, in the preparation of a medicament for preventing and / or treating a tumor, preferably selected from brain cancer, thyroid cancer, head and neck cancer, nasopharyngeal cancer, throat cancer, oral cancer, salivary gland cancer, esophageal cancer, gastric cancer, lung cancer, liver cancer, kidney cancer, pancreatic cancer, gallbladder cancer, cholangiocarcinoma, 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 and glioblastoma; more preferably selected from pancreatic cancer, colorectal cancer and non-small cell lung cancer.

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