Crystal form of pyridopyrazole compound and preparation method thereof

Abstract

Provided are crystal forms of compounds of formula (II) to (VIII) and compounds of formula (I) to (VIII-1) and methods for preparing the same, as well as uses of the crystal forms in preparing drugs for treating related diseases. #imgabs0#

Description

[0001] The present invention claims the following priority:

[0002] CN202011051252.9, application date September 29, 2020;

[0003] CN202011118921.X, application date October 19, 2020;

[0004] CN202110051653.2, application date January 13, 2021. Technical Field

[0005] The present invention relates to crystal forms of compounds of formula (II) to (VIII) and compounds of formula (I) to (VIII-1) and methods for preparing the same, and also includes use of the crystal forms in preparing drugs for treating related diseases. Background Art

[0006] RET protein is a receptor tyrosine kinase RTK and a transmembrane glycoprotein expressed by the proto-oncogene RET (REarranged during Transfection) located on chromosome 10. It plays an important role in the development of the kidney and enteric nervous system in the embryonic stage. It is also critical for the homeostasis of various tissues, such as neurons, neuroendocrine, hematopoietic tissues and male germ cells. Unlike other RTKs, RET does not directly bind to ligand molecules: such as artemin, glial cell-derived neurotrophic factor (GDNF), neurturin and persephin, which are all GNDF family ligands (GFLs). These ligand GFLs usually bind to GDNF family receptor α (GFRα), and the formed GFLs-GFRα complex mediates the self-dimerization of RET protein, causing trans-autophosphorylation of tyrosine on the intracellular domain, recruiting related adaptor proteins, and activating cascade reactions of signal transduction such as cell proliferation. The related signaling pathways include MAPK, PI3K, JAK-STAT, PKA, PKC, etc.

[0007] There are two main mechanisms of RET oncogenic activation: one is that chromosomal rearrangement produces a new fusion protein, usually a fusion of the RET kinase domain and a protein containing a self-dimerization domain; the other is that RET mutations directly or indirectly activate the kinase activity of RET. These changes at the somatic or germ cell level are involved in the pathogenesis of many cancers. 5%-10% of patients with papillary thyroid cancer have RET chromosomal rearrangements; 60% of medullary thyroid carcinomas have RET point mutations; 10-20% of all thyroid cancer patients have RET fusions, among which CCDC6 and NCOA4 are the most common fusions. Among all NSCLC patients, approximately 1-2% have RET fusion proteins, of which KIF5B-RET is the most common.

[0008] In summary, abnormal RET expression or activation has been found in a variety of tumors and gastrointestinal disorders such as irritable bowel syndrome. Therefore, RET inhibitors have potential clinical value in tumors or intestinal disorders. Summary of the invention

[0009] The present invention provides compounds represented by formula (II) to formula (VIII),

[0010]

[0011] Among them, n2, n3, n4, n5, n6, n7 and n8 are selected from 0.8 to 1.5.

[0012] In some embodiments of the present invention, the above n2, n3, n4, n5, n6, n7 and n8 are independently selected from 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4 and 1.5 respectively.

[0013] In some embodiments of the present invention, the above compound is selected from the group consisting of:

[0014]

[0015] The present invention provides a crystalline form A of a compound of formula (I), characterized in that its X-ray powder diffraction spectrum has characteristic diffraction peaks at the following 2θ angles: 16.30±0.20°, 21.69±0.20°, and 24.63±0.20°.

[0016]

[0017] In some embodiments of the present invention, the X-ray powder diffraction pattern of the above-mentioned crystal form A has characteristic diffraction peaks at the following 2θ angles: 14.88±0.20°, 15.51±0.20°, 16.30±0.20°, 18.49±0.20°, 19.16±0.20°, 19.70±0.20°, 21.69±0.20°, and 24.63±0.20°.

[0018] In some embodiments of the present invention, the X-ray powder diffraction pattern of the above-mentioned crystal form A has characteristic diffraction peaks at the following 2θ angles: 7.79±0.20°, 9.58±0.20°, 12.61±0.20°, 14.88±0.20°, 15.51±0.20°, 16.30±0.20°, 18.49±0.20°, 19.16±0.20°, 19.70±0.20°, 21.69±0.20°, and 24.63±0.20°.

[0019] In some embodiments of the present invention, the X-ray powder diffraction pattern of the above-mentioned crystal form A has characteristic diffraction peaks at the following 2θ angles: 6.19±0.20°, 7.79±0.20°, 9.58±0.20°, 12.61±0.20°, 14.88±0.20°, 15.51±0.20°, 16.30±0.20°, 17.65±0.20°, 18.49±0.20°, 19.16±0.20°, 19.70±0.20°, 20.45±0.20°, 21.69±0.20°, 23.38±0.20°, 24.63±0.20°, and 25.29±0.20°.

[0020] In some embodiments of the present invention, the X-ray powder diffraction pattern of the above-mentioned crystal form A has characteristic diffraction peaks at the following 2θ angles: 6.19°, 7.79°, 9.21°, 9.58°, 10.32°, 12.61°, 14.88°, 15.10°, 15.51°, 16.30°, 16.60°, 17.65°, 18.49°, 19.16°, 19.70°, 20.03°, 20.45°, 21.69°, 22.24°, 22.83°, 23.38°, 24.63°, 25.29°, 25.76°, 27.70°, 28.34°, and 29.06°.

[0021] In some embodiments of the present invention, the X-ray powder diffraction pattern of the above-mentioned crystalline form A has characteristic diffraction peaks at the following 2θ angles: 16.30±0.20°, 21.69±0.20°, and can also be at 24.63±0.20°, and / or 6.19±0.20°, and / or 7.79±0.20°, and / or 9.21±0.20°, and / or 9.58±0.20°, and / or 10.32±0.20°, and / or 12.61±0.20°, and / or 14.88±0.20°, and / or 15.1±0.20°, and / or 15.51±0.20°, and / or 16.6±0.20°. .20°, and / or 17.65±0.20°, and / or 18.49±0.20°, and / or 19.16±0.20°, and / or 19.7±0.20°, and / or 20.03±0.20°, and / or 20.45±0.20°, and / or 22.24±0.20°, and / or 22.83±0.20°, and / or 23.38±0.20°, and / or 25.29±0.20°, and / or 25.76±0.20°, and / or 27.7±0.20°, and / or 28.34±0.20°, and / or 29.06±0.20°, there are characteristic diffraction peaks.

[0022] In some embodiments of the present invention, the XRPD pattern of the above-mentioned Form A is as follows: Figure 1 shown.

[0023] In some embodiments of the present invention, the XRPD pattern of the above-mentioned Form A is as follows: Fig.39 shown.

[0024] In some embodiments of the present invention, the XRPD spectrum analysis data of the above-mentioned Form A is shown in Table 1-1:

[0025] Table 1-1. XRPD spectrum analysis data of the crystalline form A of the compound of formula (I)

[0026]

[0027]

[0028] In some embodiments of the present invention, the XRPD spectrum analysis data of the above-mentioned Form A is shown in Table 1-2:

[0029] Table 1-2. XRPD pattern analysis data of the crystalline form A of the compound of formula (I)

[0030]

[0031]

[0032] In some embodiments of the present invention, the differential scanning calorimetry curve of the above-mentioned Form A has a starting value of an endothermic peak at 188.7±2°C.

[0033] In some embodiments of the present invention, the DSC spectrum of the above-mentioned crystal form A is as follows Figure 2 shown.

[0034] In some embodiments of the present invention, the thermogravimetric analysis curve of the above-mentioned Form A shows a weight loss of 1.20% at 180.0±3°C.

[0035] In some embodiments of the present invention, the TGA spectrum of the above-mentioned crystal form A is as follows Figure 3 shown.

[0036] The present invention provides a crystalline form B of a compound of formula (I), characterized in that its X-ray powder diffraction spectrum has characteristic diffraction peaks at the following 2θ angles: 6.66±0.20°, 17.97±0.20°, and 22.63±0.20°.

[0037] In some embodiments of the present invention, the X-ray powder diffraction pattern of the above-mentioned form B has characteristic diffraction peaks at the following 2θ angles: 6.66±0.20°, 8.50±0.20°, 13.30±0.20°, 16.14±0.20°, 16.70±0.20°, 17.97±0.20°, 19.66±0.20°, and 22.63±0.20°.

[0038] In some embodiments of the present invention, the XRPD pattern of the above-mentioned Form B is as follows: Figure 4 shown.

[0039] In some embodiments of the present invention, the XRPD pattern analysis data of the above-mentioned Form B is shown in Table 2:

[0040] Table 2. XRPD pattern analysis data of the compound of formula (I) Form B

[0041]

[0042] The present invention provides a crystalline form C of a compound of formula (I), characterized in that its X-ray powder diffraction spectrum has characteristic diffraction peaks at the following 2θ angles: 16.66±0.20°, 19.22±0.20°, and 20.99±0.20°.

[0043] In some embodiments of the present invention, the X-ray powder diffraction pattern of the above-mentioned crystal form C has characteristic diffraction peaks at the following 2θ angles: 9.08±0.20°, 12.06±0.20°, 16.15±0.20°, 16.66±0.20°, 17.13±0.20°, 19.22±0.20°, 20.99±0.20°, and 24.52±0.20°.

[0044] In some embodiments of the present invention, the XRPD pattern of the above-mentioned Form C is as follows: Figure 5 shown.

[0045] In some embodiments of the present invention, the XRPD pattern analysis data of the above-mentioned Form C is shown in Table 3:

[0046] Table 3. XRPD pattern analysis data of the compound of formula (I) Form C

[0047]

[0048] In some embodiments of the present invention, the differential scanning calorimetry curve of the above-mentioned Form C has a starting value of an endothermic peak at 171.7±2°C.

[0049] In some embodiments of the present invention, the DSC spectrum of the above-mentioned crystal form C is as follows Figure 6 shown.

[0050] In some embodiments of the present invention, the thermogravimetric analysis curve of the above-mentioned Form C shows a weight loss of 10.08% at 140.0±3°C.

[0051] In some embodiments of the present invention, the TGA spectrum of the above-mentioned crystal form C is as follows Figure 7 shown.

[0052] The present invention provides a crystalline form D of a compound of formula (I), characterized in that its X-ray powder diffraction spectrum has characteristic diffraction peaks at the following 2θ angles: 4.79±0.20°, 14.89±0.20°, and 16.70±0.20°.

[0053] In some embodiments of the present invention, the X-ray powder diffraction pattern of the above-mentioned crystal form D has characteristic diffraction peaks at the following 2θ angles: 4.79±0.20°, 6.61±0.20°, 7.16±0.20°, 14.89±0.20°, 16.09±0.20°, 16.70±0.20°, 19.40±0.20°, and 20.73±0.20°.

[0054] In some embodiments of the present invention, the XRPD pattern of the above-mentioned crystal form D is as follows: Figure 8 shown.

[0055] In some embodiments of the present invention, the XRPD spectrum analysis data of the above-mentioned crystal form D is shown in Table 4:

[0056] Table 4. XRPD pattern analysis data of the compound of formula (I) Form D

[0057]

[0058]

[0059] The present invention provides a crystalline form E of a compound of formula (I), characterized in that its X-ray powder diffraction spectrum has characteristic diffraction peaks at the following 2θ angles: 8.01±0.20°, 17.80±0.20°, and 19.14±0.20°.

[0060] In some embodiments of the present invention, the X-ray powder diffraction pattern of the above-mentioned crystal form E has characteristic diffraction peaks at the following 2θ angles: 8.01±0.20°, 14.15±0.20°, 14.84±0.20°, 16.29±0.20°, 17.23±0.20°, 17.80±0.20°, 18.28±0.20°, and 19.14±0.20°.

[0061] In some embodiments of the present invention, the X-ray powder diffraction pattern of the above-mentioned crystal form E has characteristic diffraction peaks at the following 2θ angles: 5.98±0.20°, 8.01±0.20°, 9.21±0.20°, 12.9±0.20°, 14.15±0.20°, 14.84±0.20°, 16.29±0.20°, 17.23±0.20°, 17.8±0.20°, 18.28±0.20°, 19.14±0.20°, and 20.7±0.20°.

[0062] In some embodiments of the present invention, the XRPD pattern of the above-mentioned Form E is as follows Fig. 9 shown.

[0063] In some embodiments of the present invention, the XRPD pattern analysis data of the above-mentioned Form E is shown in Table 5:

[0064] Table 5. XRPD pattern analysis data of the compound of formula (I) Form E

[0065]

[0066] In some embodiments of the present invention, the differential scanning calorimetry curve of the above-mentioned Form E has a starting value of an endothermic peak at 170.6±2°C, and a starting value of another endothermic peak at 189.1±2°C.

[0067] In some embodiments of the present invention, the DSC spectrum of the above-mentioned crystal form E is as follows Fig.10 shown.

[0068] In some embodiments of the present invention, the thermogravimetric analysis curve of the above-mentioned Form E shows a weight loss of 5.59% at 150.0±3°C.

[0069] In some embodiments of the present invention, the TGA spectrum of the above-mentioned crystal form E is as follows Fig.11 shown.

[0070] The present invention provides a crystalline form F of a compound of formula (I), characterized in that its X-ray powder diffraction spectrum has characteristic diffraction peaks at the following 2θ angles: 4.95±0.20°, 7.13±0.20°, and 16.55±0.20°.

[0071] In some embodiments of the present invention, the X-ray powder diffraction pattern of the above-mentioned crystal form F has characteristic diffraction peaks at the following 2θ angles: 4.95±0.20°, 7.13±0.20°, 14.75±0.20°, 16.55±0.20°, 23.62±0.20°, and 24.96±0.20°.

[0072] In some embodiments of the present invention, the XRPD pattern of the above-mentioned Form F is as follows: Fig.12 shown.

[0073] In some embodiments of the present invention, the XRPD pattern analysis data of the above-mentioned Form F are shown in Table 6:

[0074] Table 6. XRPD pattern analysis data of the crystalline form F of the compound of formula (I)

[0075]

[0076] The present invention provides a crystalline form G of a compound of formula (II-1), characterized in that its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ angles: 11.98±0.20°, 17.90±0.20°, and 21.56±0.20°.

[0077]

[0078] In some embodiments of the present invention, the X-ray powder diffraction pattern of the above-mentioned crystal form G has characteristic diffraction peaks at the following 2θ angles: 11.98±0.20°, 12.39±0.20°, 16.53±0.20°, 17.90±0.20°, 21.56±0.20°, 23.36±0.20°, 24.05±0.20°, and 28.04±0.20°.

[0079] In some embodiments of the present invention, the X-ray powder diffraction pattern of the above-mentioned crystal form G has characteristic diffraction peaks at the following 2θ angles: 11.98±0.20°, 12.39±0.20°, 14.79±0.20°, 16.53±0.20°, 17.90±0.20°, 21.56±0.20°, 23.36±0.20°, 24.05±0.20°, 24.58±0.20°, 25.27±0.20°, 26.81±0.20°, and 28.04±0.20°.

[0080] In some embodiments of the present invention, the XRPD pattern of the above-mentioned crystal form G is as follows Fig.13 shown.

[0081] In some embodiments of the present invention, the XRPD pattern analysis data of the above-mentioned Form G is shown in Table 7:

[0082] Table 7. XRPD pattern analysis data of the compound of formula (II-1) Form G

[0083]

[0084]

[0085] In some embodiments of the present invention, the thermogravimetric analysis curve of the above-mentioned crystal form G shows a weight loss of 4.11% at 110.0±3°C.

[0086] In some embodiments of the present invention, the TGA spectrum of the above-mentioned crystal form G is as follows Fig.14 shown.

[0087] The present invention provides a crystalline form H of a compound of formula (II-1), characterized in that its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ angles: 4.90±0.20°, 12.05±0.20°, and 18.24±0.20°.

[0088] In some embodiments of the present invention, the X-ray powder diffraction pattern of the above-mentioned crystal form H has characteristic diffraction peaks at the following 2θ angles: 4.90±0.20°, 6.49±0.20°, 12.05±0.20°, 16.75±0.20°, 18.24±0.20°, 19.55±0.20°, 20.22±0.20°, and 22.06±0.20°.

[0089] In some embodiments of the present invention, the XRPD pattern of the above-mentioned crystal form H is as follows Fig.15 shown.

[0090] In some embodiments of the present invention, the XRPD pattern analysis data of the above-mentioned Form H is shown in Table 8:

[0091] Table 8. XRPD spectrum analysis data of the crystalline form H of the compound of formula (II-1)

[0092]

[0093]

[0094] In some embodiments of the present invention, the thermogravimetric analysis curve of the above-mentioned Form H shows a weight loss of 2.47% at 160.0±3°C.

[0095] In some embodiments of the present invention, the TGA spectrum of the above-mentioned crystal form H is as follows Fig.16 shown.

[0096] The present invention provides a crystalline form I of a compound of formula (III-1), characterized in that its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ angles: 4.84±0.20°, 19.22±0.20°, and 19.72±0.20°.

[0097]

[0098] In some embodiments of the present invention, the X-ray powder diffraction pattern of the above-mentioned form I has characteristic diffraction peaks at the following 2θ angles: 4.84±0.20°, 12.84±0.20°, 13.42±0.20°, 14.40±0.20°, 19.22±0.20°, 19.72±0.20°, 22.46±0.20°, and 30.87±0.20°.

[0099] In some embodiments of the present invention, the X-ray powder diffraction pattern of the above-mentioned form I has characteristic diffraction peaks at the following 2θ angles: 4.84±0.20°, 12.84±0.20°, 13.42±0.20°, 14.40±0.20°, 15.80±0.20°, 16.89±0.20°, 18.21±0.20°, 19.22±0.20°, 19.72±0.20°, 22.46±0.20°, 24.94±0.20°, and 30.87±0.20°.

[0100] In some embodiments of the present invention, the XRPD pattern of the above-mentioned Form I is as follows: Fig.17 shown.

[0101] In some embodiments of the present invention, the XRPD pattern analysis data of the above-mentioned Form I are shown in Table 9:

[0102] Table 9. XRPD pattern analysis data of the compound of formula (III-1) Form I

[0103]

[0104]

[0105] In some embodiments of the present invention, the differential scanning calorimetry curve of the above-mentioned Form I has a starting value of an endothermic peak at 203.6±2°C.

[0106] In some embodiments of the present invention, the DSC spectrum of the above-mentioned Form I is as follows: Fig.18 shown.

[0107] In some embodiments of the present invention, the thermogravimetric analysis curve of the above-mentioned Form I shows a weight loss of 2.04% at 180.0±3°C.

[0108] In some embodiments of the present invention, the TGA spectrum of the above-mentioned Form I is as follows Fig.19 shown.

[0109] The present invention provides a crystalline form J of a compound of formula (IV-1), characterized in that its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ angles: 8.62±0.20°, 11.12±0.20°, and 17.11±0.20°.

[0110]

[0111] In some embodiments of the present invention, the X-ray powder diffraction pattern of the above-mentioned crystal form J has characteristic diffraction peaks at the following 2θ angles: 6.53±0.20°, 8.62±0.20°, 11.12±0.20°, 12.26±0.20°, 17.11±0.20°, 19.71±0.20°, and 21.77±0.20°.

[0112] In some embodiments of the present invention, the XRPD pattern of the above-mentioned crystal form J is as follows Fig. 20 shown.

[0113] In some embodiments of the present invention, the XRPD pattern analysis data of the above-mentioned crystal form J is shown in Table 10:

[0114] Table 10. XRPD pattern analysis data of the crystal form J of the compound of formula (IV-1)

[0115]

[0116] In some embodiments of the present invention, the thermogravimetric analysis curve of the above-mentioned crystal form J shows a weight loss of 4.67% at 130.0±3°C.

[0117] In some embodiments of the present invention, the TGA spectrum of the above-mentioned crystal form J is as follows Fig.21 shown.

[0118] The present invention provides a crystalline form K of a compound of formula (V-1), characterized in that its X-ray powder diffraction spectrum has characteristic diffraction peaks at the following 2θ angles: 12.63±0.20°, 17.95±0.20°, and 21.66±0.20°.

[0119]

[0120] In some embodiments of the present invention, the X-ray powder diffraction pattern of the above-mentioned crystal form K has characteristic diffraction peaks at the following 2θ angles: 12.63±0.20°, 15.47±0.20°, 16.27±0.20°, 17.49±0.20°, 17.95±0.20°, 19.13±0.20°, 21.66±0.20°, and 24.99±0.20°.

[0121] In some embodiments of the present invention, the X-ray powder diffraction pattern of the above-mentioned crystal form K has characteristic diffraction peaks at the following 2θ angles: 10.21±0.20°, 12.63±0.20°, 15.47±0.20°, 16.27±0.20°, 17.95±0.20°, 19.13±0.20°, 20.00±0.20°, 21.66±0.20°, 22.51±0.20°, 23.97±0.20°, 24.99±0.20°, and 28.39±0.20°.

[0122] In some embodiments of the present invention, the XRPD pattern of the above-mentioned crystal form K is as follows Fig. 22 shown.

[0123] In some embodiments of the present invention, the XRPD pattern analysis data of the above-mentioned crystal form K is shown in Table 11:

[0124] Table 11. XRPD pattern analysis data of the compound of formula (V-1) Form K

[0125]

[0126] In some embodiments of the present invention, the thermogravimetric analysis curve of the above-mentioned crystal form K shows a weight loss of 5.03% at 140.0±3°C.

[0127] In some embodiments of the present invention, the TGA spectrum of the above-mentioned crystal form K is as follows Fig.23 shown.

[0128] The present invention provides a crystalline form L of a compound of formula (V-1), characterized in that its X-ray powder diffraction spectrum has characteristic diffraction peaks at the following 2θ angles: 5.93±0.20°, 13.45±0.20°, and 20.70±0.20°.

[0129] In some embodiments of the present invention, the X-ray powder diffraction pattern of the above-mentioned crystal form L has characteristic diffraction peaks at the following 2θ angles: 5.93±0.20°, 13.45±0.20°, 15.22±0.20°, 17.75±0.20°, 20.70±0.20°, 22.91±0.20°, 26.34±0.20°, and 27.80±0.20°.

[0130] In some embodiments of the present invention, the X-ray powder diffraction pattern of the above-mentioned crystal form L has characteristic diffraction peaks at the following 2θ angles: 5.93±0.20°, 10.37±0.20°, 13.45±0.20°, 15.22±0.20°, 16.70±0.20°, 17.75±0.20°, 18.56±0.20°, 20.70±0.20°, 22.91±0.20°, 25.35±0.20°, 26.34±0.20°, and 27.80±0.20°.

[0131] In some embodiments of the present invention, the XRPD pattern of the above-mentioned crystal form L is as follows Fig.24 shown.

[0132] In some embodiments of the present invention, the XRPD pattern analysis data of the above-mentioned crystal form L is shown in Table 12:

[0133] Table 12. XRPD pattern analysis data of the crystal form L of the compound of formula (V-1)

[0134]

[0135] In some embodiments of the present invention, the thermogravimetric analysis curve of the above-mentioned crystal form L shows a weight loss of 5.24% at 110.0±3°C.

[0136] In some embodiments of the present invention, the TGA spectrum of the above-mentioned crystal form L is as follows Fig.25 shown.

[0137] The present invention provides a crystalline form M of a compound of formula (VI-1), characterized in that its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ angles: 8.52±0.20°, 16.75±0.20°, 18.07±0.20°, and 21.72±0.20°.

[0138]

[0139] In some embodiments of the present invention, the XRPD pattern of the above-mentioned crystal form M is as follows Fig.26 shown.

[0140] In some embodiments of the present invention, the XRPD pattern analysis data of the above-mentioned crystal form M is shown in Table 13:

[0141] Table 13. XRPD pattern analysis data of the crystalline form M of the compound of formula (VI-1)

[0142]

[0143] In some embodiments of the present invention, the thermogravimetric analysis curve of the above-mentioned crystal form M shows a weight loss of 5.19% at 120.0±3°C.

[0144] In some embodiments of the present invention, the TGA spectrum of the above-mentioned crystal form M is as follows Fig. 27 shown.

[0145] The present invention provides a crystalline form N of a compound of formula (VII-1), characterized in that its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ angles: 18.53±0.20°, 19.05±0.20°, and 19.98±0.20°.

[0146]

[0147] In some embodiments of the present invention, the X-ray powder diffraction pattern of the above-mentioned crystal form N has characteristic diffraction peaks at the following 2θ angles: 9.98±0.20°, 11.71±0.20°, 12.25±0.20°, 13.24±0.20°, 16.19±0.20°, 18.53±0.20°, 19.05±0.20°, and 19.98±0.20°.

[0148] In some embodiments of the present invention, the X-ray powder diffraction pattern of the above-mentioned crystal form N has characteristic diffraction peaks at the following 2θ angles: 5.05±0.20°, 9.98±0.20°, 11.71±0.20°, 12.25±0.20°, 13.24±0.20°, 14.35±0.20°, 16.19±0.20°, 18.53±0.20°, 19.05±0.20°, 19.98±0.20°, 20.91±0.20°, and 24.56±0.20°.

[0149] In some embodiments of the present invention, the XRPD pattern of the above-mentioned crystal form N is as follows Fig.28 shown.

[0150] In some embodiments of the present invention, the XRPD pattern analysis data of the above-mentioned crystal form N is shown in Table 14:

[0151] Table 14. XRPD spectrum analysis data of the crystalline form N of the compound of formula (VII-1)

[0152]

[0153] In some embodiments of the present invention, the thermogravimetric analysis curve of the above-mentioned crystal form N shows a weight loss of 3.19% at 160.0±3°C.

[0154] In some embodiments of the present invention, the TGA spectrum of the above-mentioned crystal form N is as follows Fig.29 shown.

[0155] The present invention provides a crystalline form O of a compound of formula (VII-1), characterized in that its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ angles: 10.39±0.20°, 12.98±0.20°, and 18.17±0.20°.

[0156] In some embodiments of the present invention, the X-ray powder diffraction pattern of the above-mentioned crystal form O has characteristic diffraction peaks at the following 2θ angles: 10.39±0.20°, 11.33±0.20°, 12.98±0.20°, 15.62±0.20°, 18.17±0.20°, 19.96±0.20°, 21.54±0.20°, and 22.91±0.20°.

[0157] In some embodiments of the present invention, the X-ray powder diffraction pattern of the above-mentioned crystal form O has characteristic diffraction peaks at the following 2θ angles: 7.75±0.20°, 10.39±0.20°, 11.33±0.20°, 12.98±0.20°, 15.62±0.20°, 16.65±0.20°, 18.17±0.20°, 19.04±0.20°, 19.96±0.20°, 21.54±0.20°, 22.91±0.20°, and 24.05±0.20°.

[0158] In some embodiments of the present invention, the XRPD pattern of the above-mentioned crystal form O is as follows Fig.30 shown.

[0159] In some embodiments of the present invention, the XRPD pattern analysis data of the above-mentioned crystal form O is shown in Table 15:

[0160] Table 15. XRPD spectrum analysis data of the crystalline form O of the compound of formula (VII-1)

[0161]

[0162]

[0163] In some embodiments of the present invention, the thermogravimetric analysis curve of the above-mentioned crystal form O shows a weight loss of 9.32% at 140.0±3°C.

[0164] In some embodiments of the present invention, the TGA spectrum of the above-mentioned crystal form O is as follows Fig.31 shown.

[0165] The present invention provides a crystalline form P of a compound of formula (VII-1), characterized in that its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ angles: 6.49±0.20°, 11.83±0.20°, and 25.14±0.20°.

[0166] In some embodiments of the present invention, the X-ray powder diffraction pattern of the above-mentioned crystal form P has characteristic diffraction peaks at the following 2θ angles: 6.49±0.20°, 7.79±0.20°, 10.90±0.20°, 11.83±0.20°, 12.87±0.20°, 14.82±0.20°, 18.53±0.20°, and 25.14±0.20°.

[0167] In some embodiments of the present invention, the XRPD pattern of the above-mentioned crystal form P is as follows Fig.32 shown.

[0168] In some embodiments of the present invention, the XRPD pattern analysis data of the above-mentioned crystal form P is shown in Table 16:

[0169] Table 16. XRPD pattern analysis data of the crystalline form P of the compound of formula (VII-1)

[0170]

[0171] In some embodiments of the present invention, the thermogravimetric analysis curve of the above-mentioned crystal form P shows a weight loss of 4.58% at 90.0±3°C.

[0172] In some embodiments of the present invention, the TGA spectrum of the above-mentioned crystal form P is as follows Fig.33 shown.

[0173] The present invention provides a crystalline form Q of a compound of formula (VIII-1), characterized in that its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ angles: 3.39±0.20°, 6.75±0.20°, and 13.73±0.20°.

[0174]

[0175] In some embodiments of the present invention, the X-ray powder diffraction pattern of the above-mentioned crystal form Q has characteristic diffraction peaks at the following 2θ angles: 3.39±0.20°, 5.88±0.20°, 6.75±0.20°, 7.94±0.20°, 10.72±0.20°, 13.73±0.20°, 16.91±0.20°, and 19.15±0.20°.

[0176] In some embodiments of the present invention, the X-ray powder diffraction pattern of the above-mentioned crystal form Q has characteristic diffraction peaks at the following 2θ angles: 3.39±0.20°, 5.88±0.20°, 6.75±0.20°, 7.94±0.20°, 9.20±0.20°, 10.72±0.20°, 13.73±0.20°, 16.28±0.20°, 16.91±0.20°, 18.51±0.20°, 19.15±0.20°, and 21.66±0.20°.

[0177] The present invention provides a crystalline form Q of a compound of formula (VIII-1), characterized in that its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ angles: 6.75±0.20°, 10.72±0.20°, and 13.73±0.20°.

[0178]

[0179] In some embodiments of the present invention, the X-ray powder diffraction pattern of the above-mentioned crystal form Q has characteristic diffraction peaks at the following 2θ angles: 5.88±0.20°, 6.75±0.20°, 7.94±0.20°, 10.72±0.20°, 13.73±0.20°, 16.91±0.20°, 19.15±0.20°, and 24.60±0.20°.

[0180] In some embodiments of the present invention, the X-ray powder diffraction pattern of the above-mentioned crystal form Q has characteristic diffraction peaks at the following 2θ angles: 5.88±0.20°, 6.75±0.20°, 7.94±0.20°, 9.20±0.20°, 10.72±0.20°, 13.73±0.20°, 16.28±0.20°, 16.91±0.20°, 18.51±0.20°, 19.15±0.20°, 21.66±0.20°, and 24.60±0.20°.

[0181] In some embodiments of the present invention, the XRPD pattern of the above-mentioned crystal form Q is as follows Fig.34 shown.

[0182] In some embodiments of the present invention, the XRPD pattern analysis data of the above-mentioned crystal form Q is shown in Table 17:

[0183] Table 17. XRPD pattern analysis data of the compound of formula (VIII-1) crystal form Q

[0184]

[0185]

[0186] In some embodiments of the present invention, the thermogravimetric analysis curve of the above-mentioned crystal form Q shows a weight loss of 3.96% at 150.0±3°C.

[0187] In some embodiments of the present invention, the TGA spectrum of the above-mentioned crystal form Q is as follows Fig.35 shown.

[0188] The present invention provides a crystalline form R of a compound of formula (VIII-1), characterized in that its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ angles: 16.28±0.20°, 21.67±0.20°, and 24.59±0.20°.

[0189] In some embodiments of the present invention, the X-ray powder diffraction pattern of the above-mentioned crystal form R has characteristic diffraction peaks at the following 2θ angles: 14.85±0.20°, 15.49±0.20°, 16.28±0.20°, 18.48±0.20°, 19.13±0.20°, 19.68±0.20°, 21.67±0.20°, and 24.59±0.20°.

[0190] In some embodiments of the present invention, the X-ray powder diffraction pattern of the above-mentioned crystal form R has characteristic diffraction peaks at the following 2θ angles: 9.56±0.20°, 14.85±0.20°, 15.49±0.20°, 16.28±0.20°, 18.48±0.20°, 19.13±0.20°, 19.68±0.20°, 21.67±0.20°, 22.80±0.20°, 23.35±0.20°, 24.59±0.20°, and 25.27±0.20°.

[0191] In some embodiments of the present invention, the XRPD pattern of the above-mentioned crystal form R is as follows Fig.36 shown.

[0192] In some embodiments of the present invention, the XRPD pattern analysis data of the above-mentioned crystal form R is shown in Table 18:

[0193] Table 18. XRPD pattern analysis data of the crystalline form R of the compound of formula (VIII-1)

[0194]

[0195] In some embodiments of the present invention, the thermogravimetric analysis curve of the above-mentioned crystal form R shows a weight loss of 2.14% at 160.0±3°C.

[0196] In some embodiments of the present invention, the TGA spectrum of the above-mentioned crystal form R is as follows Fig.37 shown.

[0197] The present invention provides use of compounds of formula (II) to (VIII), crystal form A, crystal form B, crystal form C, crystal form D, crystal form E, crystal form F, crystal form G, crystal form H, crystal form I, crystal form J, crystal form K, crystal form L, crystal form M, crystal form N, crystal form O, crystal form P, crystal form Q and crystal form R in preparing drugs for treating solid tumors.

[0198] In some embodiments of the present invention, the solid tumor refers to a RET kinase-associated solid tumor.

[0199] Technical Effects

[0200] The compound of the present invention has RET kinase inhibitory effect, excellent PK properties and tumor growth inhibitory effect, the crystal form of the present invention has stable properties and good drug development prospects.

[0201] Definition and Description

[0202] Unless otherwise specified, the following terms and phrases used herein are intended to have the following meanings. A particular phrase or term should not be considered to be uncertain or unclear in the absence of a special definition, but should be understood according to its ordinary meaning. When a trade name appears in this article, it is intended to refer to its corresponding commercial product or its active ingredient.

[0203] The intermediate compounds of the present invention can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments listed below, embodiments formed by combining them with other chemical synthesis methods, and equivalent substitutions well known to those skilled in the art. Preferred embodiments include but are not limited to the embodiments of the present invention.

[0204] The chemical reactions of the specific embodiments of the present invention are carried out in a suitable solvent, which must be suitable for the chemical changes of the present invention and the reagents and materials required. In order to obtain the compounds of the present invention, it is sometimes necessary for those skilled in the art to modify or select the synthesis steps or reaction processes based on the existing embodiments.

[0205] The present invention will be described in detail below by way of examples, which are not intended to limit the present invention in any way. The present invention uses the following abbreviations, OTf represents trifluoromethanesulfonyl.

[0206] All solvents used in the present invention were commercially available and used without further purification.

[0207] The structure of the compound of the present invention can be confirmed by conventional methods known to those skilled in the art. If the present invention relates to the absolute configuration of the compound, the absolute configuration can be confirmed by conventional technical means in the art. For example, single crystal X-ray diffraction (SXRD) is used to collect diffraction intensity data of the cultured single crystal using a Bruker D8 venture diffractometer, the light source is CuKα radiation, and the scanning mode is: After scanning and collecting relevant data, the crystal structure is further analyzed using the direct method (Shelxs97) to confirm the absolute configuration.

[0208] Compounds are named according to the conventional nomenclature in the art or The software names were used, and commercially available compounds were named using the supplier's catalog names.

[0209] Powder X-ray diffractometer (XRPD) method of the present invention

[0210] The X-ray powder diffraction pattern of the present invention was collected on an X'Pert3 X-ray powder diffractometer of Panalytical. The method parameters of the X-ray powder diffraction of the present invention are as follows:

[0211] X-ray source: Cu, Kα

[0212] Kα1 1.54060; Kα2 1.54443

[0213] Kα2 / Kα1 intensity ratio: 0.50

[0214] Voltage: 45 kilovolts (kV)

[0215] Current: 40 milliamperes (mA)

[0216] Divergence slit: fixed 1 / 8 degree

[0217] Scan mode: Continuous

[0218] Scanning range: from 3.0 to 40.0 degrees (2θ angle)

[0219] Scan time per step: 46.665 seconds

[0220] Step size: 0.0263 degrees

[0221] The X-ray powder diffraction pattern of the present invention is also collected on a DX-2700BH X-ray powder diffractometer of Dandong Haoyuan Instrument Co., Ltd. The method parameters of the X-ray powder diffraction of the present invention are as follows:

[0222] X-ray: Cu, Kα

[0223] Light tube voltage: 40 kilovolts (kV)

[0224] Light tube current: 30 milliamperes (mA)

[0225] Divergence slit: 1mm

[0226] Primary scattering slit: 28mm

[0227] Secondary slit: 28mm

[0228] Detector slit: 0.3mm

[0229] Anti-scatter slit: 1mm

[0230] Scan axis: θs-θd

[0231] Step size: 0.02 degrees

[0232] Scan time: 0.5s

[0233] Scanning range: 3-40 degrees

[0234] Differential Scanning Calorimeter (DSC) method of the present invention

[0235] The differential scanning calorimetry (DSC) data described in the present invention are collected from a TA company Discovery DSC 2500 differential scanning calorimeter, the instrument control software is TRIOS, and the analysis software is Universal Analysis. Usually, 1 to 5 mg of sample is placed in a covered aluminum crucible, and the sample is heated from room temperature to a set temperature at a heating rate of 10°C / min under the protection of 50mL / min dry N2, and the TA software records the heat change of the sample during the heating process.

[0236] Thermogravimetric analysis (TGA) method of the present invention

[0237] Thermogravimetric analysis (TGA) data described in the present invention are collected from TA Instruments Q5000 and Discovery TGA 5500 thermogravimetric analyzers, the instrument control software is Q Series and TRIOS, and the analysis software is Universal Analysis. Usually, 1 to 5 mg of sample is placed in a platinum crucible, and the sample is heated from room temperature to 350°C at a heating rate of 10°C / min under the protection of 50mL / min dry N2.

[0238] Dynamic Vapor Sorption (DVS) method of the present invention

[0239] Instrument model: SMS DVS Intrinsic dynamic vapor adsorption instrument

[0240] Test conditions: Take a sample (10-15 mg) and place it in the DVS sample tray for testing.

[0241] The detailed DVS parameters are as follows:

[0242] Temperature: 25℃

[0243] Balance: dm / dt = 0.01% / min (minimum: 10min, maximum: 180min)

[0244] Drying: Drying at 0% RH for 120 minutes

[0245] RH(%) test level: 10%

[0246] RH(%) test step range: 0%-90%-0%

[0247] The moisture absorption evaluation is classified as follows:

[0248] Hygroscopicity classification ΔW% deliquescence Absorb enough water to form a liquid Highly hygroscopic ΔW%≥15% Hygroscopic 15%>ΔW%≥2% Slightly hygroscopic 2%>ΔW%≥0.2% No or almost no hygroscopicity ΔW%<0.2%

[0249] Note: ΔW% indicates the weight gain of the test sample at 25±1℃ and 80±2%RH. BRIEF DESCRIPTION OF THE DRAWINGS

[0250] Figure 1 . XRPD spectrum of Form A of the compound of formula (I) with Cu-Kα radiation.

[0251] Figure 2 .DSC spectrum of Form A of the compound of formula (I).

[0252] Figure 3 .TGA spectrum of Form A of the compound of formula (I).

[0253] Figure 4 . XRPD spectrum of the crystal form B of the compound of formula (I) with Cu-Kα radiation.

[0254] Figure 5 . XRPD spectrum of the crystal form C of the compound of formula (I) with Cu-Kα radiation.

[0255] Figure 6 .DSC spectrum of Form C of the compound of formula (I).

[0256] Figure 7 .TGA spectrum of Form C of the compound of formula (I).

[0257] Figure 8 . XRPD spectrum of the crystal form D of the compound of formula (I) with Cu-Kα radiation.

[0258] Fig. 9 . XRPD spectrum of the crystal form E of the compound of formula (I) with Cu-Kα radiation.

[0259] Fig.10 .DSC spectrum of Form E of the compound of formula (I).

[0260] Fig.11 .TGA spectrum of crystalline form E of the compound of formula (I).

[0261] Fig.12 . XRPD spectrum of the crystalline form F of the compound of formula (I) with Cu-Kα radiation.

[0262] Fig.13 . XRPD spectrum of the crystal form G of the compound of formula (II-1) with Cu-Kα radiation.

[0263] Fig.14 .TGA spectrum of Form G of the compound of formula (II-1).

[0264] Fig.15 . XRPD spectrum of the crystalline form H of the compound of formula (II-1) with Cu-Kα radiation.

[0265] Fig.16 .TGA spectrum of crystalline form H of the compound of formula (II-1).

[0266] Fig.17 . XRPD spectrum of the crystal form I of the compound of formula (III-1) with Cu-Kα radiation.

[0267] Fig.18 .DSC spectrum of Form I of the compound of formula (III-1).

[0268] Fig.19 .TGA spectrum of crystalline form I of the compound of formula (III-1).

[0269] Fig. 20 . XRPD spectrum of the crystal form J of the compound of formula (IV-1) with Cu-Kα radiation.

[0270] Fig.21 .TGA spectrum of crystal form J of compound of formula (IV-1).

[0271] Fig. 22 .XRPD spectrum of the crystal form K of the compound of formula (V-1) with Cu-Kα radiation.

[0272] Fig.23.TGA spectrum of crystal form K of the compound of formula (V-1).

[0273] Fig.24 .XRPD spectrum of the crystal form L of the compound of formula (V-1) with Cu-Kα radiation.

[0274] Fig.25 .TGA spectrum of crystalline form L of the compound of formula (V-1).

[0275] Fig.26 .XRPD spectrum of the crystal form M of the compound of formula (VI-1) with Cu-Kα radiation.

[0276] Fig. 27 .TGA spectrum of crystalline form M of the compound of formula (VI-1).

[0277] Fig.28 . XRPD spectrum of Cu-Kα radiation of crystalline form N of the compound of formula (VII-1).

[0278] Fig.29 .TGA spectrum of crystalline form N of the compound of formula (VII-1).

[0279] Fig.30 . XRPD spectrum of the crystal form O of the compound of formula (VII-1) with Cu-Kα radiation.

[0280] Fig.31 .TGA spectrum of crystal form O of the compound of formula (VII-1).

[0281] Fig.32 . XRPD spectrum of the crystal form P of the compound of formula (VII-1) with Cu-Kα radiation.

[0282] Fig.33 .TGA spectrum of crystalline form P of the compound of formula (VII-1).

[0283] Fig.34 . XRPD spectrum of the crystal form Q of the compound of formula (VIII-1) with Cu-Kα radiation.

[0284] Fig.35 .TGA spectrum of crystal form Q of the compound of formula (VIII-1).

[0285] Fig.36 .XRPD spectrum of the crystalline form R of the compound of formula (VIII-1) with Cu-Kα radiation.

[0286] Fig.37 .TGA spectrum of crystalline form R of the compound of formula (VIII-1).

[0287] Fig.38 .DVS diagram of Form A of the compound of formula (I).

[0288] Fig.39 . XRPD spectrum of Form A of the compound of formula (I) with Cu-Kα radiation. DETAILED DESCRIPTION

[0289] In order to better understand the content of the present invention, further description is given below in conjunction with specific embodiments, but the specific implementation methods are not intended to limit the content of the present invention.

[0290] Example 1: Preparation of the compound of formula (I) and its trifluoroacetate

[0291]

[0292]

[0293] Step 1

[0294] 2,5-Dibromopyrazine (4g, 16.82mmol), 6-tert-butyloxycarbonyl-3,6-diazabicyclo[3.1.1]-heptane (4.00g, 20.18mmol) were dissolved in N-methylpyrrolidone (50mL), diisopropylethylamine (6.52g, 50.45mmol, 8.79mL) was added, and stirred at 100°C for 16 hours. 60mL of water was added, and the mixture was extracted with ethyl acetate (100mL×3), the organic phases were combined, washed with water (150mL×5), washed with saturated sodium chloride solution (150mL×1), dried over anhydrous sodium sulfate, and finally the solvent was dried to obtain a crude product. The crude product was purified by an automatic column machine (petroleum ether: ethyl acetate = 4:1) to obtain compound 1.

[0295] LCMS (ESI) m / z: 354.9 [M+1] + , 356.9[M+3] + ;

[0296] 1 H NMR (400MHz, CDCl3) δ8.15 (d, J=1.2Hz, 1H), 7.77 (s, 1H), 4.28-4.31 (m, 2H), 3.90-4.12 (m, 2H), 3.42 (d, J=12.0Hz, 2H), 2.64-2.72 (m, 1H), 1.50 (d, J=12.4Hz, 1H), 1.38 (s, 9H).

[0297] Step 2

[0298] Compound 1 (3 g, 8.45 mmol) was dissolved in ethyl acetate (15 mL), and hydrogen chloride / ethyl acetate (4 M, 20 mL) was added, and stirred at 16° C. for 3 hours. The solvent was dried to obtain crude product 2, which was directly used in the next step without purification.

[0299] LCMS (ESI) m / z: 254.9 [M+1] + , 256.9[M+3] + .

[0300] Step 3

[0301] Compound 2 (2.45 g, 8.40 mmol) and 6-methoxy-3-pyridinecarboxaldehyde (2.30 g, 16.81 mmol) were added to DCM (50 mL), and sodium acetate borohydride (5.34 g, 25.21 mmol) was added, and stirred at 16 ° C for 1.5 hours. The reaction solution became clear, and 50 mL of water was added to the reaction solution, and extracted with dichloromethane (50 mL × 3), and the organic phases were combined, washed with saturated sodium chloride solution (100 mL × 1), dried over anhydrous sodium sulfate, and finally the solvent was dried to obtain a crude product. The crude product was purified by an automatic column machine (petroleum ether: ethyl acetate = 1: 3 to dichloromethane: methanol = 10: 1) to obtain compound 3.

[0302] LCMS (ESI) m / z: 376.0 [M+1] + , 378.0[M+3] + .

[0303] Step 4

[0304] Compound 3 (1.8 g, 4.78 mmol) and bis-xanaphthene alcohol borate (1.82 g, 7.18 mmol) were dissolved in 1,4-dioxane (15 mL), 1,1'-bis(diphenylphosphino)ferrocenepalladium dichloride (350.05 mg, 478.40 μmol) and potassium acetate (1.41 g, 14.35 mmol) were added, and stirred at 80°C for 16 hours under nitrogen protection. The reaction produced some dehalogenation byproducts, and the reaction solution was directly filtered, washed twice with ethyl acetate, and the filtrate was spin-dried to obtain crude product 4, which was directly used in the next step.

[0305] LCMS (ESI) m / z: 342.1 [M+1] + .

[0306] Step 5

[0307] 3,6-dihydro-2H-pyran-4-boronic acid pinacol ester (1.5g, 7.14mmol), compound 5 (1.80g, 7.14mmol), 1,1'-bis(diphenylphosphino)ferrocene palladium dichloride (261.23mg, 357.01μmol) and potassium phosphate (4.55g, 21.42mmol) were added to 1,4-dioxane (12mL) and water (6mL), and then heated to 100°C by a microwave synthesizer under nitrogen protection and stirred for 30 minutes. 20mL of water and 20mL of ethyl acetate were added to the reaction solution for extraction, separation, and the aqueous phase was extracted with 20mL of ethyl acetate, the organic phases were combined, dried over anhydrous sodium sulfate, and the solvent was removed by rotary evaporation to obtain a crude product. The crude product was purified by a rapid silica gel column (petroleum ether / ethyl acetate = 1 / 1) to obtain compound 6.

[0308] LCMS (ESI) m / z: 255.9 [M+1] + .

[0309] Step 6

[0310] Pyridine hydrochloride (4.53 g, 39.17 mmol) was added to compound 6 (1 g, 3.92 mmol), and then heated to 180°C by microwave under nitrogen protection and stirred for 20 minutes. Saturated sodium bicarbonate aqueous solution was added to the reaction solution until the pH value was 7. Then 50 mL of ethyl acetate was added for extraction, the liquids were separated, and the aqueous phase was extracted with 50 mL of ethyl acetate again. The organic phases were combined, dried over anhydrous sodium sulfate, and the solvent was removed by rotary evaporation to obtain crude product 7, which was directly used in the next step without further purification.

[0311] Step 7

[0312] Compound 7 (460 mg, 1.91 mmol), N-phenylbis(trifluoromethanesulfonyl)imide (1.02 g, 2.86 mmol) and diisopropylethylamine (739.31 mg, 5.72 mmol) were added to nitrogen, dimethylformamide (10 mL), and then stirred and reacted for 16 hours at 10-20° C. under nitrogen protection. The reaction solution was directly added to 50 mL of water, and then 20 mL of ethyl acetate was added for extraction, and the liquids were separated. The aqueous phase was extracted with 20 mL of ethyl acetate, and the organic phases were combined, dried over anhydrous sodium sulfate, and the solvent was removed by rotary evaporation to obtain a crude product 8.

[0313] Step 8

[0314] Compound 8 (560 mg, 1.50 mmol), compound 4 (511.79 mg, 1.50 mmol), 1,1'-bis(diphenylphosphino)ferrocenepalladium dichloride (54.88 mg, 75.01 μmol) and potassium phosphate (955.27 mg, 4.50 mmol) were added to 1,4-dioxane (12 mL) and water (6 mL), and then heated to 90° C. and stirred for 0.5 hours under nitrogen protection by microwave synthesizer. 20 mL of water and 20 mL of ethyl acetate were added to the reaction solution, and the liquid was separated. The aqueous phase was extracted with 20 mL of ethyl acetate, and the organic phases were combined, dried over anhydrous sodium sulfate, and rotary evaporated to obtain a crude product of formula (I). The crude product was separated by preparative chromatography (YMC-Triart Prep C18 150×40mm×7μm; mobile phase: [water (0.1% TFA)-ACN]; acetonitrile: 30%-40%, 10min) to obtain the trifluoroacetate salt of the compound of formula (I). The trifluoroacetate salt of the compound of formula (I) was added to a sodium bicarbonate solution, extracted with ethyl acetate, and the organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain the compound of formula (I).

[0315] LCMS (ESI) m / z: 521.1 [M+1] + ;

[0316] 1 H NMR (400MHz, CD3OD) δ8.81~8.80 (m, 1H), 8.71~8.65 (m, 1H), 8.48~8.45 (m, 1H), 8.40~ 8.30(m, 2H), 8.00~7.92(m, 1H), 7.90~7.92(m, 1H), 6.95~6.92(m, 2H), 6.53(s, 1H), 4. 74~4.71 (m, 2H), 4.63~4.61 (d, J=8Hz, 1H), 4.39~4.37 (m, 2H), 4.43~4.30 (m, 3H), 4.1 0~4.06 (m, 1H), 4.00~3.96 (m, 6H), 3.65~3.62 (m, 1H), 2.62 (s, 2H), 2.25~2.21 (m, 1H).

[0317] Example 2: Preparation of Form A of the Compound of Formula (I)

[0318] The crude product of formula (I) was mixed with silica gel and purified by an automatic column machine (dichloromethane: methanol = 20: 1) to obtain the compound of formula (I). 200 ml of methanol (40 times) was added to 5 g of the compound of formula (I) and the mixture was slurried for 16 hours overnight. Solids were precipitated and filtered to obtain the crystalline form A of the compound of formula (I). Its XRPD spectrum is shown as follows: Figure 1 As shown in the DSC spectrum Figure 2 As shown in the TGA spectrum Figure 3 shown.

[0319] About 400 g of the crude product of formula (I) was added to about 6 L of methanol, stirred at 20-30°C for 88-96 hours, the reaction solution was filtered, the filter cake was rinsed with methanol (0.5 L), and vacuum dried for 16-24 hours. 5.78 L of purified water was added to the obtained solid, the temperature was controlled at 90-100°C, stirred for 24-48 hours, cooled to 20-30°C, the reaction solution was filtered, and vacuum dried for 40-96 hours to obtain Form A. Its XRPD spectrum is shown as follows: Fig.39 shown.

[0320] Example 3: Preparation of Form B of the Compound of Formula (I)

[0321] The compound of formula (I) (20.9 mg) was added to 1.0 ml of 1,4-dioxane, stirred at room temperature to obtain a suspension, centrifuged, and dried to obtain a solid, which is the crystalline form B of the compound of formula (I). Its XRPD spectrum is shown in Figure 4 shown.

[0322] Example 4: Preparation of Form C of the Compound of Formula (I)

[0323] The crystal form B of the compound of formula (I) is left open at room temperature overnight, and the resulting solid is the crystal form C of the compound of formula (I). Its XRPD spectrum is as follows: Figure 5 As shown in the DSC spectrum Figure 6 As shown in the TGA spectrum Figure 7 shown.

[0324] Example 5: Preparation of Form D of the Compound of Formula (I)

[0325] The crystal form A (20.6 mg) of the compound of formula (I) was added to 0.5 ml of 1,4-dioxane / n-butanol (volume ratio 1:1), and stirred at room temperature for 5 days to obtain a suspension, which was centrifuged and dried to obtain the crystal form D of the compound of formula (I). Its XRPD spectrum is shown in Figure 8 shown.

[0326] Example 6: Preparation of Form E of the Compound of Formula (I)

[0327] The compound of formula (I) (20.6 mg) was added to 2.0 ml of acetone, stirred at 50°C for 1 hour to obtain a suspension, filtered to obtain a clear solution, cooled from 50°C to 5°C within 40 hours to precipitate a small amount of solid, transferred to -20°C and placed, and solid was obtained after 6 days, centrifuged and dried to obtain the crystalline form E of the compound of formula (I). Its XRPD spectrum is shown in Fig. 9 As shown in the DSC spectrum Fig.10 As shown in the TGA spectrum Fig.11 shown.

[0328] Example 7: Preparation of Form F of the Compound of Formula (I)

[0329] The compound of formula (I) (20.5 mg) was added to 2.0 ml of dimethyltetrahydrofuran, stirred at 50°C for 1 hour to obtain a suspension, filtered to obtain a clear solution, cooled from 50°C to 5°C within 40 hours to precipitate a small amount of solid, transferred to -20°C and placed, and solid was obtained after 6 days, centrifuged and dried to obtain the crystalline form F of the compound of formula (I). Its XRPD spectrum is shown in Fig.12 shown.

[0330] Example 8: Preparation of Form G of the Compound of Formula (II-1)

[0331]

[0332] The compound of formula (I) (19.9 mg) was added to 0.5 ml of ethanol / water (volume ratio 9:1) containing 4.8 mg of maleic acid, and stirred at room temperature for 2 days to obtain a suspension. After centrifugation, the solid was vacuumed at room temperature for 1 hour to obtain the solid, which was the crystalline form G of the compound of formula (II-1). Its XRPD spectrum is shown in FIG. Fig.13 As shown in the TGA spectrum Fig.14 shown.

[0333] Example 9: Preparation of Crystalline Form H of the Compound of Formula (II-1)

[0334] The compound of formula (I) (20.7 mg) was added to 0.5 ml of acetone containing 4.8 mg of maleic acid, and stirred at room temperature for 2 days to obtain a suspension. After centrifugation, the solid was vacuumed at room temperature for 1 hour to obtain a solid, which was the crystalline form H of the compound of formula (II-1). Its XRPD spectrum is shown in Fig.15 As shown in the TGA spectrum Fig.16 shown.

[0335] Example 10: Preparation of Form I of Compound of Formula (III-1)

[0336]

[0337] The compound of formula (I) (20.5 mg) was added to 0.5 ml of ethanol / water (volume ratio 9:1) containing 8.6 mg of mucic acid, and stirred at room temperature for 2 days to obtain a suspension. After centrifugation, the solid was vacuumed at room temperature for 1 hour to obtain a solid, which was the crystalline form I of the compound of formula (III-1). Its XRPD spectrum is shown in FIG. Fig.17 As shown in the DSC spectrum Fig.18 As shown in the TGA spectrum Fig.19 shown.

[0338] Example 11: Preparation of Crystalline Form J of the Compound of Formula (IV-1)

[0339]

[0340] The compound of formula (I) (19.1 mg) was added to 0.5 ml of ethanol / water (volume ratio 9:1) containing 5.8 mg of tartaric acid, and stirred at room temperature for 2 days to obtain a suspension. After centrifugation, the solid was vacuumed at room temperature for 1 hour to obtain a solid, which was the crystalline form J of the compound of formula (IV-1). Its XRPD spectrum is shown in Fig. 20 As shown in the TGA spectrum Fig.21 shown.

[0341] Example 12: Preparation of Crystalline Form K of the Compound of Formula (V-1)

[0342]

[0343] The compound of formula (I) (20.4 mg) was added to 0.5 ml of ethanol / water (volume ratio 9:1) containing 4.4 mg of fumaric acid, and stirred at room temperature for 2 days to obtain a suspension. After centrifugation, the solid was vacuumed at room temperature for 1 hour to obtain a solid, which was the crystalline form K of the compound of formula (V-1). Its XRPD spectrum is shown in FIG. Fig. 22 As shown in the TGA spectrum Fig.23 shown.

[0344] Example 13: Preparation of Crystalline Form L of the Compound of Formula (V-1)

[0345] The compound of formula (I) (20.7 mg) was added to 0.5 ml of acetone containing 4.6 mg of fumaric acid, and stirred at room temperature for 2 days to obtain a suspension. After centrifugation, the solid was vacuumed at room temperature for 1 hour to obtain a solid, which was the crystalline form L of the compound of formula (V-1). Its XRPD spectrum is shown in FIG. Fig.24 As shown in the TGA spectrum Fig.25 shown.

[0346] Example 14: Preparation of Crystalline Form M of the Compound of Formula (VI-1)

[0347]

[0348] The compound of formula (I) (19.4 mg) was added to 0.5 ml of acetone containing 7.4 mg of citric acid, and stirred at room temperature for 2 days to obtain a suspension. After centrifugation, the solid was vacuumed at room temperature for 1 hour to obtain a solid, which was the crystalline form M of the compound of formula (VI-1). Its XRPD spectrum is shown in FIG. Fig.26 As shown in the TGA spectrum Fig. 27 shown.

[0349] Example 15: Preparation of Form N of the Compound of Formula (VII-1)

[0350]

[0351] The compound of formula (I) (19.9 mg) was added to 0.5 ml of ethanol / water (volume ratio 9:1) containing 5.0 mg of oxalic acid, and stirred at room temperature for 2 days to obtain a suspension. After centrifugation, the solid was vacuumed at room temperature for 1 hour to obtain a solid, which was the crystalline form N of the compound of formula (VII-1). Its XRPD spectrum is shown in FIG. Fig.28 As shown in the TGA spectrum Fig.29 shown.

[0352] Example 16: Preparation of Crystalline Form O of the Compound of Formula (VII-1)

[0353] The compound of formula (I) (19.8 mg) was added to 0.5 ml of acetone containing 5.5 mg of oxalic acid, and stirred at room temperature for 2 days to obtain a suspension. After centrifugation, the solid was vacuumed at room temperature for 1 hour to obtain a solid, which was the crystalline form O of the compound of formula (VII-1). Its XRPD spectrum is shown in FIG. Fig.30 As shown in the TGA spectrum Fig.31 shown.

[0354] Example 17: Preparation of Crystalline Form P of the Compound of Formula (VII-1)

[0355] The compound of formula (I) (19.3 mg) was added to 0.5 ml of ethyl acetate containing 5.1 mg of oxalic acid, and stirred at room temperature for 2 days to obtain a suspension. After centrifugation, the solid was vacuumed at room temperature for 1 hour to obtain a solid, which was the crystalline form P of the compound of formula (VII-1). Its XRPD spectrum is shown in FIG. Fig.32 As shown in the TGA spectrum Fig.33 shown.

[0356] Example 18: Preparation of Crystalline Form Q of the Compound of Formula (VIII-1)

[0357]

[0358] The compound of formula (I) (19.3 mg) was added to 0.5 ml of ethanol / water (volume ratio 9:1) containing 3.9 mg of phosphoric acid, and stirred at room temperature for 2 days to obtain a suspension. After centrifugation, the solid was vacuumed at room temperature for 1 hour to obtain a solid, which was the crystalline form Q of the compound of formula (VIII-1). Its XRPD spectrum is shown in FIG. Fig.34 As shown in the TGA spectrum Fig.35 shown.

[0359] Example 19: Preparation of Crystalline Form R of the Compound of Formula (VIII-1)

[0360] The compound of formula (I) (19.7 mg) was added to 0.5 ml of acetone containing 4.4 mg of phosphoric acid, and stirred at room temperature for 2 days to obtain a suspension. After centrifugation, the solid was vacuumed at room temperature for 1 hour to obtain a solid, which was the crystalline form R of the compound of formula (VIII-1). Its XRPD spectrum is shown in FIG. Fig.36 As shown in the TGA spectrum Fig.37 shown.

[0361] Example 20: Hygroscopicity study of the crystalline form A of the compound of formula (I)

[0362] Experimental Materials:

[0363] SMS DVS Intrinsic Dynamic Vapor Sorption Instrument

[0364] Experimental methods:

[0365] 10-15 mg of the crystalline form A of the compound of formula (I) was placed in a DVS sample tray for testing.

[0366] Experimental results:

[0367] The DVS spectrum of the crystalline form A of the compound of formula (I) is as follows Fig.38 As shown, ΔW=0.8%.

[0368] Experimental conclusion:

[0369] The weight gain of the crystalline form A of the compound of formula (I) at 25° C. and 80% RH is 0.8%, which is slightly hygroscopic.

[0370] Example 21: Solid Stability Test of Form A of Compound of Formula (I)

[0371] According to the "Guidelines for Stability Testing of APIs and Preparations" (Chinese Pharmacopoeia 2015 Edition Part IV General Rules 9001), the stability of Form A of the compound of formula (I) under high temperature (60°C, open) and high humidity (room temperature / relative humidity 92.5%, open) conditions was investigated.

[0372] Weigh 15 mg of the crystalline form A of the compound of formula (I) and place it at the bottom of a glass sample bottle and spread it into a thin layer. The sample placed under high temperature and high humidity conditions is sealed with aluminum foil, and small holes are punched in the aluminum foil to ensure that the sample can fully contact with the ambient air. The samples placed under different conditions are sampled and tested (XRPD) on the 5th and 10th days, and the test results are compared with the initial test results on day 0. The test results are shown in Table 19 below:

[0373] Table 19 Solid stability test results of the crystalline form A of the compound of formula (I)

[0374]

[0375] Conclusion: Form A of the compound of formula (I) has good stability under high temperature and high humidity conditions.

[0376] Example 22: Solid Stability Study of Form A of Compound of Formula (I)

[0377] According to the "Guidelines for Stability Testing of APIs and Preparations" (Chinese Pharmacopoeia 2015 Edition Part IV General Rules 9001), the stability of Form A of the compound of formula (I) under long-term experimental conditions was investigated. About 10 mg of Form A of the compound of formula (I) was weighed and placed at the bottom of a glass sample bottle, spread into a thin layer, sealed with aluminum foil and pierced with small holes, and placed under (40°C / 75%RH) for 3 months and (25°C / 60%RH) for 3 months. The samples after placement were characterized by XRPD, and the test results were compared with the initial test results of day 0. The results are shown in Table 20. The crystal form of Form A of the compound of formula (I) did not change under all stability conditions.

[0378] The test results are shown in Table 20 below:

[0379] Table 20: Solid stability test results of the crystalline form A of the compound of formula (I)

[0380] Test conditions Conditions for taking points Crystal form Starting Form A / Crystalline Form A 40℃ / 75%RH March Crystalline Form A 25℃ / 60%RH March Crystalline Form A

[0381] Experimental conclusion: Form A of the compound of formula (I) has good stability.

[0382] Biological test data:

[0383] Experimental Example 1: In vitro enzyme activity test of the compounds of the present invention

[0384] Purpose

[0385] By Z′-LYTE TM Kinase assays are used to measure enzyme activity using the IC 50 The value was used as an indicator to evaluate the inhibitory effect of the compound on RET and RET(V804M) kinases.

[0386] Experimental methods

[0387] The compounds used in the assay for RET and RET(V804M) kinases were diluted 3-fold to 10 concentrations ranging from 3 μM to 0.152 nM;

[0388] The content of DMSO in the assay reaction was 1%.

[0389] Reagents:

[0390] Basic reaction buffer, 20 mM hydroxyethylpiperazine ethanesulfonic acid (Hepes) (pH 7.5) buffer, 10 mM MgCl2, 1 mM ethylene glycol bisaminoethyl ether tetraacetic acid (EGTA), 0.02% polyoxyethylene dodecyl ether (Brij35), 0.02 mg / mL bovine serum albumin, 0.1 mM Na3VO4, 2 mM dithiothreitol (DTT), 1% DMSO.

[0391] Compound:

[0392] The test compound was dissolved in 100% DMSO and diluted to 10 mM for use. The solution was diluted using Integra Viaflo Assist.

[0393] The reaction process of universal enzymes:

[0394] Test conditions: RET enzyme concentration was 3 μM, peptide substrate CHKtide concentration was 1000 μM, and ATP concentration was 20 μM; RET (V804M) enzyme concentration was 80 μM, substrate peptide concentration was 1000 μM, and ATP concentration was 30 μM.

[0395] Reaction process: Prepare kinase / peptide solution according to the test conditions. Add compound solution of different concentrations, incubate at room temperature for 20 minutes, add 33P-ATP of corresponding concentration, incubate at room temperature for 120 minutes. Detect radioactivity by filter-binding method.

[0396] Reaction detection:

[0397] The reaction was terminated by adding 0.5% phosphoric acid to the kinase reaction solution and the plate was read using the Envision instrument.

[0398] Data analysis

[0399] The data were converted into phosphorylation rate and inhibition rate, and the compound IC was obtained by parameter curve fitting (GraphPad Software). 50 data.

[0400] The experimental results are shown in Table 21:

[0401] Table 21 Kinase activity IC of the compounds of the present invention 50 Test Results

[0402]

[0403] Experimental conclusion: The compounds of the present invention have excellent inhibitory activity against RET and its mutation RET V804M, and will have excellent therapeutic effects in patients with RET abnormal tumors.

[0404] Experimental Example 2: Pharmacokinetic Evaluation of the Compounds of the Invention

[0405] Experimental procedure: A clear solution of the test compound at 0.1 mg / mL in the corresponding solvent (see Table 22) was injected into female Balb / c mice (overnight fasting, 7-9 weeks old) via the tail vein, and the dosage was 0.2 mg / kg. About 30 μL of blood was collected from the jugular vein or tail vein at 0.0833, 0.25, 0.5, 1.0, 2.0, 4.0, 8.0 and 24 hours after intravenous administration. The test compound suspended in the corresponding solvent (see Table 22) at 0.2 mg / mL was gavage-administered to female Balb / c mice (overnight fasting, 7-9 weeks old) at a dosage of 2 mg / kg. The experimental conditions are detailed in Table 22. About 30 μL of blood was collected from the jugular vein or tail vein of female Balb / c mice at 0.0833, 0.25, 0.5, 1.0, 2.0, 4.0, 6.0, 8.0 and 24 hours after oral administration. The samples were placed in an anticoagulant tube with EDTA-K2 added and centrifuged to separate plasma. The blood drug concentration was determined by LC-MS / MS using WinNonlin TM Version 6.3 (Pharsight, Mountain View, CA) pharmacokinetic software was used to calculate relevant pharmacokinetic parameters using the non-compartmental linear logarithmic trapezoidal method. The experimental results are shown in Table 23.

[0406] Table 22 Pharmacokinetic experimental conditions in mice

[0407]

[0408] Table 23 Mouse pharmacokinetic experimental results

[0409]

[0410] Note: Plasma clearance (Cl), steady-state apparent distribution volume (V dss ), elimination half-life (T 1 / 2 ), the area under the plasma concentration curve from point 0 to the last quantifiable time point (AUC 0-last ), bioavailability (F), peak concentration (C max ), peak time T max .

[0411] Conclusion: From the experimental results, the compounds of the present invention all showed low clearance, low distribution volume, long half-life and excellent drug exposure after intravenous administration. After oral administration, the compounds of the present invention all showed rapid peak, excellent oral absorption exposure, and overall excellent oral absorption bioavailability.

[0412] Experimental Example 3: Tumor Growth Inhibition (TGI) Analysis

[0413] Ba / F3-CCDC6-RET cell line was cultured in 1640 medium (Biological Industries) + 10% fetal bovine serum (BI) + 1% double antibody (Penicillin Streptomycin solution, Coring, USA), 37°C 5% CO2, and subcultured twice a week. When the cell saturation was 80% to 90%, the cells were collected, counted, and inoculated into the right axillary subcutaneous of BALB / cnude female mice (6-8 weeks). After the inoculation, the tumor growth status was observed daily, and the average tumor volume reached about 165.77mm 3 At 4 pm, the mice were randomly divided into groups according to tumor volume, with 6 mice in each group, and drug administration began.

[0414] The health status and mortality of the animals were monitored daily. Routine examinations included the growth of the tumor, activity, diet, body weight, eyes, hair and other abnormal behaviors of the animals. The tumor volume and body weight were measured twice a week (Tuesday and Friday).

[0415] The inhibitory effect of the compound on tumor growth is evaluated by the relationship between tumor volume and time. The tumor volume is measured by vernier calipers, and the formula is TV = 0.5a × b 2 , where a is the long diameter of the tumor and b is the short diameter of the tumor. TGI is calculated by the difference between the median tumor volume of mice in the solvent group and the median tumor volume of mice in the drug group, and is expressed as a percentage of the median tumor volume of the solvent control group.

[0416] Calculated using the following formula:

[0417] TGI(TGI(%)=[1-(T 23 -T0) / (V 23 -V0)]×100)

[0418] Unless otherwise specified, the data are expressed as mean ± standard error (Mean ± SE), and the tumor volume of the treatment group was compared with that of the control group using oneway ANOVA. P < 0.05 was considered significant. 5% DMSO + 10% polyethylene glycol-15 hydroxy stearate (Solutol) + 85% H2O was used as the negative control. The experimental results are shown in Table 24.

[0419] Table 24 Results of in vivo antitumor activity test in mice

[0420]

[0421] Note: BID: twice a day; QD: once a day; TGI%: tumor growth inhibition rate.

[0422] Conclusion: The compounds of the present invention showed excellent tumor growth inhibition effect in the tumor model Ba / F3-CCDC6-RET.

Claims

1. A compound represented by formula (II) to formula (VIII), in, n2, n3, n4, n5, n6, n7 and n8 are selected from 0.8 to 1.

5.

2. The compound according to claim 1, wherein n2, n3, n4, n5, n6, n7 and n8 are independently selected from 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4 and 1.5, respectively.

3. A compound according to claim 1 or 2, selected from:

4. Form A of the compound of formula (I), characterized in that Its X-ray powder diffraction spectrum has characteristic diffraction peaks at the following 2θ angles: 16.30±0.20°, 21.69±0.20°, 24.63±0.20° 5. The crystalline form A according to claim 4, whose X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ angles: 14.88±0.20°, 15.51±0.20°, 16.30±0.20°, 18.49±0.20°, 19.16±0.20°, 19.70±0.20°, 21.69±0.20°, and 24.63±0.20°.

6. The crystalline form A according to claim 5, whose X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ angles: 7.79±0.20°, 9.58±0.20°, 12.61±0.20°, 14.88±0.20°, 15.51±0.20°, 16.30±0.20°, 18.49±0.20°, 19.16±0.20°, 19.70±0.20°, 21.69±0.20°, and 24.63±0.20°.

7. The crystal form A according to any one of claims 4 to 6, whose XRPD pattern is shown in Figure 1.

8. The crystalline form A according to any one of claims 4 to 6, wherein the differential scanning calorimetry curve thereof has an onset value of an endothermic peak at 188.7±2°C.

9. The crystal form A according to claim 8, whose DSC spectrum is shown in Figure 2.

10. The crystal form A according to any one of claims 4 to 6, wherein the thermogravimetric analysis curve thereof shows a weight loss of 1.20% at 180.0±3°C.

11. The crystal form A according to claim 10, whose TGA spectrum is shown in Figure 3.

12. Use of the crystalline form A of the compound of formula (II) to (VIII) according to any one of claims 1 to 3 or the compound of formula (I) according to any one of claims 4 to 11 in the preparation of a drug for treating solid tumors, wherein the solid tumor refers to a RET kinase-related solid tumor.

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