Crystal form, salt form and application of heterocyclic antitumor compound

Abstract

The invention provides a crystal form of a free alkali of a compound I, a salt of the compound I and a crystal form of the salt of the compound I. In addition, the invention also relates to application of the crystal form and the salt form of the compound I in treating related diseases and symptoms such as tumors or cancers. Some salt forms, such as sulfate, phosphate, acetate, pamoate and the like, provided by the invention have better clinical application value, and can be used as an excellent alternative form for subsequent drug development.

Description

Technical Field

[0001] The present invention relates to the field of pharmaceutical chemistry technology, and in particular, to a crystalline form, a salt form, and a preparation method thereof of a compound (R)-1-(4-(4-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2-methyl-8,9-dihydroimidazole [1', 2': 1, 6] pyrido [2, 3-d] pyrimidin-6-yl)-3, 6-dihydropyridine-1 (2H)-yl)ethanone (hereinafter referred to as compound I or compound of formula I) as an SOS1 inhibitor. In addition, the present invention also relates to the use of the crystalline form and salt form of compound I in the treatment of SOS1-related diseases and disorders. Background Art

[0002] There are three known RAS family genes: KRAS (Kirsten rat sarcoma viral oncogene homolog), NRAS (neuroblastoma RAS viral oncogene homolog) and HRAS (Harvey rat sarcoma viral oncogene). RAS family proteins are a class of small molecule GTPases and are also the first oncogenes identified in human tumors. RAS family proteins have weak intrinsic GTPase activity and slow nucleotide exchange rate. The binding of GTPase activating proteins (GAPs) such as NF1 increases the GTPase activity of RAS family proteins.

[0003] Mutations in RAS enzymes are closely related to tumorigenesis, and the types of RAS mutations are different in different types of tumors. In human tumors, KRAS mutations (e.g., amino acids G12, G13, Q61, A146) are the most common, accounting for about 85%, while NRAS (e.g., amino acids G12, G13, Q61, A146) and HRAS (e.g., amino acids G12, G13, Q61) account for 12% and 3%, respectively. Changes in RAS family proteins (e.g., mutations, overexpression, gene amplification) have also been described as resistance mechanisms to cancer drugs such as the EGFR antibodies cetuximab and panitumumab and the EGFR tyrosine kinase inhibitor osimertinib. For oncogenic RAS mutants, GAP activity is weakened or greatly reduced, resulting in permanent activation, which is the basis of oncogenic RAS signaling. Direct inhibition of RAS has proven to be extremely challenging and elusive to drug due to the picomolar affinity of GTP for its binding site, the lack of other well-defined pockets, and the fact that RAS interacts with GEFs, GAPs, and effectors through extended and flat protein-protein interactions. Therefore, there may be new hope for inhibiting RAS activation by targeting the upstream guanine nucleotide exchange factor protein SOS.

[0004] There are two human isoforms of SOS, SOS1 and SOS2, but most studies have focused on SOS1. Human SOS1 consists of 1333 amino acids (15 kDa), which include an N-terminal histone-like domain, a Dbl homology (DH) domain, a pleckstrin homology (PH) domain, a helical linker (HL), a Ras exchanger motif (Rem) domain and a Cdc25 domain, as well as a C-terminal region. Among them, PH, Rem and Cdc25 are SOS cat Components of the core catalytic domain.

[0005] In the past few decades, RAS family protein-SOS1 protein interactions have gained increasing recognition. In addition, recently, studies have been conducted to combine rational design and screening platforms to screen and identify small molecule inhibitors of SOS1, that is, compounds that bind to SOS1 and inhibit protein-protein interactions with RAS family proteins. For example, WO2021105960A1 describes a variety of cyclic SOS1 inhibitors.

[0006] Although some small molecules of SOS1 inhibitors have been disclosed, no SOS1 inhibitors have been developed and marketed yet. Therefore, it is still urgently needed to develop new compounds with potential for marketing and better efficacy and pharmacokinetic results. Summary of the invention

[0007] Chinese patent application 202211629162.2 (filing date December 16, 2022) and international patent application PCT / CN2022 / 139447 (filing date December 16, 2022) describe compounds as SOS1 inhibitors and their preparation methods, including (R)-1-(4-(4-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2-methyl-8,9-dihydroimidazole [1', 2': 1, 6] pyrido [2, 3-d] pyrimidin-6-yl) -3, 6-dihydropyridine-1 (2H)-yl) ethanone (hereinafter referred to as compound I or compound of formula I, with the structure shown below) and its preparation method.

[0008]

[0009] Compound I is an effective SOS1 inhibitor. In vitro enzyme inhibition test studies have shown that compound I has a strong inhibitory effect on SOS1. Moreover, compound I also exhibits obvious inhibitory activity on NCI-H358 cell proliferation. Therefore, it can be used as a promising compound for preventing and / or treating diseases mediated by SOS1.

[0010] There is no report on the crystal form and salt form of Compound I. Comprehensive and systematic screening of polymorphs and salt forms is one of the indispensable and important research contents. Therefore, it is necessary to further screen the salt and crystal form of Compound I and develop a crystal form or salt form suitable for large-scale production to provide more and better options for the subsequent drug development.

[0011] One of the objects of the present invention is to provide a crystalline form I of compound I, characterized in that, using Cu-Kα radiation, X-ray powder diffraction expressed in 2θ angles has characteristic peaks at 5.4±0.2°, 8.0±0.2°, 16.1±0.2°, and 21.5±0.2°.

[0012] Preferably, the X-ray powder diffraction of the crystalline form I of the compound I expressed at 2θ angle also has one or more characteristic peaks at 8.9±0.2°, 11.4±0.2°, 16.6±0.2°, and 20.3±0.2°.

[0013] Further preferably, the X-ray powder diffraction of the crystalline form I of the compound I expressed at 2θ angle also has one or two characteristic peaks at 9.9±0.2° and 10.7±0.2°.

[0014] More preferably, the crystalline form I of compound I has substantially Figure 1 The X-ray powder diffraction spectrum is shown.

[0015] In some embodiments of the present invention, the differential scanning calorimetry curve of Form I of Compound I has an endothermic peak at 179°C±10°C.

[0016] Preferably, the differential scanning calorimetry curve of Form I of Compound I has an endothermic peak at 179°C±5°C.

[0017] Further preferably, the crystalline form I of the compound I has substantially Figure 2 DSC spectrum shown.

[0018] In some embodiments of the present invention, the crystalline form I of compound I has substantially Figure 3 TGA spectrum shown.

[0019] The present invention also aims to provide a salt of compound I, wherein the structure of compound I is as follows: The salt is benzenesulfonate, citrate, malate, phosphate, propionate, succinate, sulfate, tartrate, p-toluenesulfonate, pamoate, acetate, hydrochloride, lactobionate, and methanesulfonate of Compound I.

[0020] Another object of the present invention is to provide a benzenesulfonate crystalline form I of compound I, characterized in that, using Cu-Kα radiation, the X-ray powder diffraction expressed in 2θ angles has characteristic peaks at 10.5±0.2°, 11.5±0.2°, 19.5±0.2°, and 22.3±0.2°.

[0021] Preferably, the X-ray powder diffraction of the benzenesulfonate salt form I of the compound I expressed at 2θ angle also has one or more characteristic peaks at 13.1±0.2°, 14.5±0.2°, 17.7±0.2°, and 23.9±0.2°.

[0022] Further preferably, the X-ray powder diffraction of the benzenesulfonate salt form I of compound I expressed at 2θ angle also has one or more characteristic peaks at 8.3±0.2°, 16.1±0.2°, and 26.3±0.2°.

[0023] More preferably, the benzenesulfonate salt form I of compound I has substantially Figure 4 The X-ray powder diffraction spectrum is shown.

[0024] In some embodiments of the present invention, the benzenesulfonate salt form I of the compound I has an endothermic peak at 228°C±10°C in its differential scanning calorimetry curve.

[0025] Preferably, the benzenesulfonate salt form I of the compound I has an endothermic peak at 228°C±5°C in its differential scanning calorimetry curve.

[0026] Further preferably, the benzenesulfonate salt form I of compound I has substantially Figure 5 DSC spectrum shown.

[0027] In some embodiments of the present invention, the benzenesulfonate salt form I of compound I has substantially Figure 6 TGA spectrum shown.

[0028] Another object of the present invention is to provide a malate crystalline form I of compound I, characterized in that, using Cu-Kα radiation, the X-ray powder diffraction expressed in 2θ angles has characteristic peaks at 5.8±0.2°, 20.2±0.2°, 23.6±0.2°, and 24.5±0.2°.

[0029] Preferably, the X-ray powder diffraction of the malate salt form I of the compound I expressed at 2θ angle also has one or more characteristic peaks at 12.8±0.2°, 15.5±0.2°, and 19.1±0.2°.

[0030] Further preferably, the X-ray powder diffraction of the malate crystalline form I of the compound I expressed at 2θ angle also has one or more characteristic peaks at 14.4±0.2°, 15.0±0.2°, and 21.2±0.2°.

[0031] More preferably, the malate crystalline form I of Compound I has substantially Figure 7 The X-ray powder diffraction spectrum is shown.

[0032] In some embodiments of the present invention, the malate crystalline form I of the compound I has an endothermic peak at 177°C±10°C in its differential scanning calorimetry curve.

[0033] Preferably, the malate crystalline form I of the compound I has an endothermic peak in its differential scanning calorimetry curve at 177°C±5°C.

[0034] Further preferably, the malate crystalline form I of the compound I has substantially Figure 8 DSC spectrum shown.

[0035] In some embodiments of the present invention, the malate crystalline form I of Compound I has substantially Fig. 9 TGA spectrum shown.

[0036] Another object of the present invention is to provide a phosphate of compound I represented by formula (II), The salt formation ratio of compound I to phosphoric acid is 1:1.

[0037] Another object of the present invention is to provide a phosphate crystal form I of compound I, characterized in that, using Cu-Kα radiation, the X-ray powder diffraction expressed in 2θ angles has characteristic peaks at 4.8±0.2°, 11.6±0.2°, 16.3±0.2°, and 23.7±0.2°.

[0038] Preferably, the X-ray powder diffraction of the phosphate crystal form I of the compound I expressed at 2θ angle also has one or more characteristic peaks at 9.4±0.2°, 14.9±0.2°, and 17.3±0.2°.

[0039] More preferably, the phosphate crystalline form I of compound I has substantially Fig.10 The X-ray powder diffraction spectrum is shown.

[0040] In some embodiments of the present invention, the phosphate crystal form I of the compound I has an endothermic peak at 228°C±10°C in its differential scanning calorimetry curve.

[0041] Preferably, the phosphate crystal form I of the compound I has an endothermic peak at 228°C±5°C in its differential scanning calorimetry curve.

[0042] Further preferably, the phosphate crystal form I of the compound I has substantially Fig.11 DSC spectrum shown.

[0043] In some embodiments of the present invention, the phosphate crystalline form I of compound I has substantially Fig.12 TGA spectrum shown.

[0044] Another object of the present invention is to provide a phosphate crystal form II of compound I, characterized in that, using Cu-Kα radiation, the X-ray powder diffraction expressed in 2θ angles has characteristic peaks at 4.8±0.2°, 16.3±0.2°, 16.8±0.2°, and 22.3±0.2°.

[0045] Preferably, the X-ray powder diffraction of the phosphate crystal form II of the compound I expressed at 2θ angle also has one or more characteristic peaks at 19.6±0.2°, 21.0±0.2°, and 23.6±0.2°.

[0046] More preferably, the phosphate form II of compound I has substantially Fig.13 The X-ray powder diffraction spectrum is shown.

[0047] In some embodiments of the present invention, the phosphate crystal form II of the compound I has an endothermic peak at 221°C±10°C in its differential scanning calorimetry curve.

[0048] Preferably, the phosphate crystal form II of the compound I has an endothermic peak at 221±5° C. in its differential scanning calorimetry curve.

[0049] Further preferably, the phosphate crystal form II of the compound I has substantially Fig.14 DSC spectrum shown.

[0050] In some embodiments of the present invention, the phosphate crystal form II of compound I has substantially Fig.15 TGA spectrum shown.

[0051] In some embodiments of the present invention, the phosphate crystal form II of compound I, wherein the salt formation ratio of compound I to phosphoric acid is 1:1.

[0052] Another object of the present invention is to provide a propionate salt form I of compound I, characterized in that, using Cu-Kα radiation, X-ray powder diffraction expressed in 2θ angles has characteristic peaks at 7.4±0.2°, 10.3±0.2°, 17.0±0.2°, and 19.8±0.2°.

[0053] Preferably, the X-ray powder diffraction of the propionate salt form I of compound I expressed at 2θ angle also has one or more characteristic peaks at 8.9±0.2°, 21.3±0.2°, 23.8±0.2°, and 26.1±0.2°.

[0054] Further preferably, the X-ray powder diffraction of the propionate salt form I of compound I expressed at 2θ angle also has one or more characteristic peaks at 8.0±0.2°, 13.2±0.2°, and 14.5±0.2°.

[0055] More preferably, the propionate salt form I of compound I has substantially Fig.16 The X-ray powder diffraction spectrum is shown.

[0056] In some embodiments of the present invention, the propionate salt form I of compound I has an endothermic peak at 134°C±10°C in its differential scanning calorimetry curve.

[0057] Preferably, the propionate salt form I of compound I has an endothermic peak at 134°C±5°C in its differential scanning calorimetry curve.

[0058] Further preferably, the propionate salt form I of compound I has substantially Fig.17 DSC spectrum shown.

[0059] In some embodiments of the present invention, the propionate salt form I of compound I has substantially Fig.18 TGA spectrum shown.

[0060] Another object of the present invention is to provide a succinate salt form I of compound I, characterized in that, using Cu-Kα radiation, the X-ray powder diffraction expressed in 2θ angles has characteristic peaks at 5.8±0.2°, 6.6±0.2°, 15.0±0.2°, and 24.3±0.2°.

[0061] Preferably, the X-ray powder diffraction of the succinate salt form I of the compound I expressed at 2θ angle also has one or more characteristic peaks at 13.8±0.2°, 18.7±0.2°, 19.8±0.2°, and 25.0±0.2°.

[0062] Further preferably, the X-ray powder diffraction of the succinate salt form I of the compound I expressed at 2θ angle also has one or more characteristic peaks at 8.7±0.2°, 20.3±0.2°, 24.1±0.2°, and 26.2±0.2°.

[0063] More preferably, the succinate salt form I of compound I has substantially Fig.19 The X-ray powder diffraction spectrum is shown.

[0064] In some embodiments of the present invention, the succinate salt form I of the compound I has an endothermic peak at 168°C±10°C in its differential scanning calorimetry curve.

[0065] Preferably, the succinate salt form I of the compound I has an endothermic peak at 168°C±5°C in its differential scanning calorimetry curve.

[0066] Further preferably, the succinate salt form I of the compound I has substantially Fig. 20 DSC spectrum shown.

[0067] In some embodiments of the present invention, the succinate salt form I of compound I has substantially Fig.21 TGA spectrum shown.

[0068] Another object of the present invention is to provide a sulfate of compound I represented by formula (III), The salt formation ratio of compound I to sulfuric acid is 1:1.

[0069] Another object of the present invention is to provide a sulfate crystalline form I of compound I, characterized in that, using Cu-Kα radiation, the X-ray powder diffraction expressed in 2θ angles has characteristic peaks at 17.9±0.2°, 19.0±0.2°, 19.5±0.2°, and 27.2±0.2°.

[0070] Preferably, the X-ray powder diffraction of the sulfate crystalline form I of the compound I expressed at 2θ angle also has one or more characteristic peaks at 11.0±0.2°, 12.8±0.2°, 21.1±0.2°, and 26.1±0.2°.

[0071] Further preferably, the X-ray powder diffraction of the sulfate crystal form I of the compound I expressed at 2θ angle also has one or more characteristic peaks at 11.9±0.2°, 23.0±0.2°, and 24.0±0.2°.

[0072] More preferably, the sulfate salt crystalline form I of compound I has substantially Fig. 22 The X-ray powder diffraction spectrum is shown.

[0073] In some embodiments of the present invention, the sulfate crystal form I of the compound I has an endothermic peak near 259±10°C in its differential scanning calorimetry curve.

[0074] Preferably, the sulfate salt form I of the compound I has an endothermic peak at 259°C±5°C in its differential scanning calorimetry curve.

[0075] Further preferably, the sulfate crystalline form I of the compound I has substantially Fig.23 DSC spectrum shown.

[0076] In some embodiments of the present invention, the sulfate salt form I of compound I has substantially Fig.24 TGA spectrum shown.

[0077] In some embodiments of the present invention, the sulfate crystalline form I of compound I, wherein the salt formation ratio of compound I to sulfuric acid is 1:1.

[0078] Another object of the present invention is to provide a tartrate salt form I of compound I, characterized in that, using Cu-Kα radiation, the X-ray powder diffraction expressed in 2θ angles has characteristic peaks at 4.2±0.2°, 17.0±0.2°, 19.2±0.2°, and 20.1±0.2°.

[0079] Preferably, the X-ray powder diffraction of the tartrate salt form I of the compound I expressed at 2θ angle also has one or more characteristic peaks at 12.8±0.2°, 15.1±0.2°, and 22.1±0.2°.

[0080] Further preferably, the X-ray powder diffraction of the tartrate salt form I of compound I expressed at 2θ angle also has one or more characteristic peaks at 8.2±0.2°, 14.4±0.2°, 16.3±0.2°, 22.9±0.2°, and 25.1±0.2°.

[0081] More preferably, the tartrate salt form I of compound I has substantially Fig.25 The X-ray powder diffraction spectrum is shown.

[0082] In some embodiments of the present invention, the tartrate salt form I of the compound I has an endothermic peak at 132°C±10°C in its differential scanning calorimetry curve.

[0083] Preferably, the tartrate salt form I of the compound I has an endothermic peak in its differential scanning calorimetry curve at 132°C±5°C.

[0084] Further preferably, the tartrate salt form I of compound I has substantially Fig.26 DSC spectrum shown.

[0085] In some embodiments of the present invention, the tartrate salt form I of compound I has substantially Fig. 27 TGA spectrum shown.

[0086] Another object of the present invention is to provide a pamoate salt form I of compound I, characterized in that, using Cu-Kα radiation, the X-ray powder diffraction expressed in 2θ angles has characteristic peaks at 7.3±0.2°, 9.0±0.2°, 11.8±0.2°, and 24.1±0.2°.

[0087] Preferably, the X-ray powder diffraction of the pamoate salt form I of compound I expressed at 2θ angle also has one or more characteristic peaks at 13.2±0.2°, 19.2±0.2°, 21.0±0.2°, and 22.5±0.2°.

[0088] Further preferably, the X-ray powder diffraction of the pamoate salt form I of compound I expressed at 2θ angle also has one or more characteristic peaks at 9.6±0.2°, 14.5±0.2°, 16.3±0.2°, and 26.9±0.2°.

[0089] More preferably, the pamoate salt form I of compound I has substantially Fig.28 The X-ray powder diffraction spectrum is shown.

[0090] In some embodiments of the present invention, the pamoate salt form I of compound I has an endothermic peak at 249°C±10°C in its differential scanning calorimetry curve.

[0091] Preferably, the pamoate salt form I of compound I has an endothermic peak at 249°C±5°C in its differential scanning calorimetry curve.

[0092] Further preferably, the pamoate salt form I of compound I has substantially Fig.29 DSC spectrum shown.

[0093] In some embodiments of the present invention, the pamoate salt form I of compound I has substantially Fig.30 TGA spectrum shown.

[0094] Another object of the present invention is to provide a pamoate salt form II of compound I, characterized in that, using Cu-Kα radiation, the X-ray powder diffraction expressed in 2θ angles has characteristic peaks at 6.2±0.2°, 14.0±0.2°, 15.2±0.2°, and 16.1±0.2°.

[0095] Preferably, the X-ray powder diffraction of the pamoate salt form II of compound I expressed at 2θ angle also has one or more characteristic peaks at 7.6±0.2°, 9.0±0.2°, 12.1±0.2°, and 26.2±0.2°.

[0096] Further preferably, the X-ray powder diffraction of the pamoate salt form II of compound I expressed at 2θ angle also has one or more characteristic peaks at 16.7±0.2°, 18.7±0.2°, and 23.0±0.2°.

[0097] More preferably, the pamoate salt form II of compound I has substantially Fig.31 The X-ray powder diffraction spectrum is shown.

[0098] In some embodiments of the present invention, the pamoate salt form II of compound I has an endothermic peak at 173°C±10°C in its differential scanning calorimetry curve.

[0099] Preferably, the pamoate salt form II of compound I has an endothermic peak at 173°C±5°C in its differential scanning calorimetry curve.

[0100] Further preferably, the pamoate salt form II of compound I has substantially Fig.32 DSC spectrum shown.

[0101] In some embodiments of the present invention, the pamoate salt form II of compound I has substantially Fig.33 TGA spectrum shown.

[0102] Another object of the present invention is to provide a pamoate salt form III of compound I, characterized in that, using Cu-Kα radiation, the X-ray powder diffraction expressed in 2θ angles has characteristic peaks at 9.5±0.2°, 15.7±0.2°, 26.3±0.2°, and 29.9±0.2°.

[0103] Preferably, the X-ray powder diffraction of the pamoate salt form III of compound I expressed at 2θ angle also has one or more characteristic peaks at 11.1±0.2°, 19.4±0.2°, 23.2±0.2°, and 25.1±0.2°.

[0104] More preferably, the pamoate salt form III of compound I has substantially Fig.34 The X-ray powder diffraction spectrum is shown.

[0105] In some embodiments of the present invention, the pamoate salt form III of compound I has an endothermic peak at 249°C±10°C in its differential scanning calorimetry curve.

[0106] Preferably, the pamoate salt form III of compound I has an endothermic peak at 249°C±5°C in its differential scanning calorimetry curve.

[0107] Further preferably, the pamoate salt form III of compound I has substantially Fig.35 DSC spectrum shown.

[0108] In some embodiments of the present invention, the pamoate salt form III of compound I has substantially Fig.36 TGA spectrum shown.

[0109] Another object of the present invention is to provide an acetate crystalline form I of compound I, characterized in that, using Cu-Kα radiation, the X-ray powder diffraction expressed in 2θ angles has characteristic peaks at 7.4±0.2°, 8.0±0.2°, 11.3±0.2°, and 14.7±0.2°.

[0110] Preferably, the acetate crystalline form I of the compound I also has one or more characteristic peaks at 9.0±0.2°, 10.4±0.2°, and 13.3±0.2° in the X-ray powder diffraction represented by the 2θ angle.

[0111] More preferably, the acetate salt form I of compound I has substantially Fig.37 The X-ray powder diffraction spectrum is shown.

[0112] In some embodiments of the present invention, the acetate salt form I of the compound I has an endothermic peak at 180°C±10°C in its differential scanning calorimetry curve.

[0113] Preferably, the acetate salt form I of the compound I has an endothermic peak at 180°C±5°C in its differential scanning calorimetry curve.

[0114] Further preferably, the acetate crystalline form I of the compound I has substantially Fig.38 DSC spectrum shown.

[0115] In some embodiments of the present invention, the acetate salt form I of compound I has substantially Fig.39 TGA spectrum shown.

[0116] On the other hand, the present invention provides a pharmaceutical composition comprising the benzenesulfonate, citrate, malate, phosphate, propionate, succinate, sulfate, tartrate, p-toluenesulfonate, pamoate, acetate, hydrochloride, lactobionate, and methanesulfonate salts of Compound I.

[0117] The present invention also provides a pharmaceutical composition, which comprises the aforementioned compound I in crystalline form I, benzenesulfonate crystalline form I, malate crystalline form I, phosphate crystalline form I, phosphate crystalline form II, propionate crystalline form I, succinate crystalline form I, sulfate crystalline form I, tartrate crystalline form I, pamoate crystalline form I, pamoate crystalline form II, pamoate crystalline form III, and acetate crystalline form I.

[0118] In another aspect, the present invention provides the use of benzenesulfonate, citrate, malate, phosphate, propionate, succinate, sulfate, tartrate, p-toluenesulfonate, pamoate, acetate, hydrochloride, lactobionate, mesylate of Compound I or the pharmaceutical composition of the present invention in the preparation of a medicament for treating a disease mediated by SOS1. Preferably, the disease mediated by SOS1 is cancer or a tumor-related disease.

[0119] The present invention also provides the use of Form I, benzenesulfonate Form I, malate Form I, phosphate Form I, phosphate Form II, propionate Form I, succinate Form I, sulfate Form I, tartrate Form I, pamoate Form I, pamoate Form II, pamoate Form III, acetate Form I of Compound I or the pharmaceutical composition of the present invention in the preparation of a drug for treating a disease mediated by SOS1. Preferably, the disease mediated by SOS1 is cancer or a tumor-related disease.

[0120] Furthermore, the purpose of the present invention also includes providing the use of the benzenesulfonate, citrate, malate, phosphate, propionate, succinate, sulfate, tartrate, p-toluenesulfonate, pamoate, acetate, hydrochloride, lactobionate, methanesulfonate of compound I of the present invention or the pharmaceutical composition of the present invention in the preparation of a medicament for treating cancer or tumor-related diseases; preferably, the cancer or tumor-related disease is a solid tumor; more preferably, the cancer or tumor-related disease is lung cancer; more preferably, the cancer or tumor-related disease is non-small cell lung cancer.

[0121] Furthermore, the purpose of the present invention also includes providing the use of Form I, benzenesulfonate Form I, malate Form I, phosphate Form I, phosphate Form II, propionate Form I, succinate Form I, sulfate Form I, tartrate Form I, pamoate Form I, pamoate Form II, pamoate Form III, acetate Form I of Compound I of the present invention or the pharmaceutical composition of the present invention in the preparation of a medicament for treating cancer or tumor-related diseases; preferably, the cancer or tumor-related disease is a solid tumor; more preferably, the cancer or tumor-related disease is lung cancer; more preferably, the cancer or tumor-related disease is non-small cell lung cancer.

[0122] In order to treat cancer or tumor-related diseases, the benzenesulfonate, citrate, malate, phosphate, propionate, succinate, sulfate, tartrate, p-toluenesulfonate, pamoate, acetate, hydrochloride, lactobionate, methanesulfonate, crystalline form I of compound I, benzenesulfonate crystalline form I, malate crystalline form I, phosphate crystalline form I, phosphate crystalline form II, propionate crystalline form I, succinate crystalline form I, sulfate crystalline form I, tartrate crystalline form I, pamoate crystalline form I, pamoate crystalline form II, pamoate crystalline form III, and acetate crystalline form I of the compound I can be co-administered with other therapeutic agents (such as chemotherapeutic drugs, biotherapeutic drugs, etc.) or combined with other therapeutic means for treatment, and the other therapeutic means include but are not limited to radiotherapy.

[0123] In order to provide a more concise description, some quantitative data herein do not use the term "about". It should be understood that, regardless of whether the term "about" is used explicitly or not, each numerical value given here not only includes the actual value (given value), and it also means including the approximate value of this given value reasonably inferred based on a person of ordinary skill in the art, including the equivalent and approximate value of this given value produced due to experimental and / or measurement conditions. The approximate value is preferably ± 20%, ± 15%, ± 10%, ± 8%, ± 6%, ± 5%, ± 4%, ± 3%, 2%, ± 1% on the basis of the given value. In some embodiments, the given value is obtained by a person of ordinary skill in the art by a conventional method of taking approximate values ​​(e.g., rounding) based on experimental values ​​and / or measured values.

[0124] Beneficial Effects

[0125] The present invention provides for the first time a free base crystal form and a plurality of salt forms of compound I. Some salt forms provided by the present invention have good clinical application value and can be used as excellent alternative forms for subsequent drug development. BRIEF DESCRIPTION OF THE DRAWINGS

[0126] Figure 1 This is the XRPD spectrum of Compound 1 Form I.

[0127] Figure 2 This is the DSC spectrum of Compound I Form I.

[0128] Figure 3 This is the TGA spectrum of Compound I Form I.

[0129] Figure 4 This is the XRPD spectrum of Compound I benzenesulfonate Form I.

[0130] Figure 5 This is the DSC spectrum of Compound I benzenesulfonate Form I.

[0131] Figure 6 This is the TGA spectrum of Compound I benzenesulfonate Form I.

[0132] Figure 7 This is the XRPD spectrum of Compound 1 malate Form I.

[0133] Figure 8 This is the DSC spectrum of Compound I malate Form I.

[0134] Fig. 9 This is the TGA spectrum of Compound I malate form I.

[0135] Fig.10 This is the XRPD spectrum of Compound I phosphate form I.

[0136] Fig.11 This is the DSC spectrum of Compound I phosphate form I.

[0137] Fig.12 This is the TGA spectrum of Compound I phosphate form I.

[0138] Fig.13 This is the XRPD spectrum of Compound I phosphate form II.

[0139] Fig.14 This is the DSC spectrum of Compound I phosphate crystal form II.

[0140] Fig.15 This is the TGA spectrum of Compound I phosphate crystal form II.

[0141] Fig.16 This is the XRPD spectrum of Compound 1 propionate salt Form I.

[0142] Fig.17 This is the DSC spectrum of Compound I propionate salt Form I.

[0143] Fig.18 This is the TGA spectrum of Compound I propionate salt Form I.

[0144] Fig.19 This is the XRPD spectrum of Compound I succinate Form I.

[0145] Fig. 20 This is the DSC spectrum of Compound I succinate Form I.

[0146] Fig.21 This is the TGA spectrum of Compound I succinate Form I.

[0147] Fig. 22 This is the XRPD spectrum of Compound I sulfate Form I.

[0148] Fig.23This is the DSC spectrum of Compound I sulfate form I.

[0149] Fig.24 This is the TGA spectrum of Compound I sulfate form I.

[0150] Fig.25 This is the XRPD spectrum of Compound I tartrate salt Form I.

[0151] Fig.26 This is the DSC spectrum of Compound I tartrate salt Form I.

[0152] Fig. 27 This is the TGA spectrum of Compound I tartrate form I.

[0153] Fig.28 This is the XRPD spectrum of Compound I Pamoate Salt Form I.

[0154] Fig.29 This is the DSC spectrum of Compound I Pamoate Salt Form I.

[0155] Fig.30 This is the TGA spectrum of Compound I Pamoate Form I.

[0156] Fig.31 This is the XRPD spectrum of Compound I Pamoate Crystal Form II.

[0157] Fig.32 This is the DSC spectrum of Compound I Pamoate Crystal Form II.

[0158] Fig.33 This is the TGA spectrum of Compound I Pamoate Crystal Form II.

[0159] Fig.34 This is the XRPD spectrum of Compound I Pamoate Crystal Form III.

[0160] Fig.35 It is the DSC spectrum of compound I pamoate salt form III.

[0161] Fig.36 This is the TGA spectrum of Compound I Pamoate Crystal Form III.

[0162] Fig.37 This is the XRPD spectrum of Compound I acetate Form I.

[0163] Fig.38 This is the DSC spectrum of Compound I acetate form I.

[0164] Fig.39 This is the TGA spectrum of Compound I acetate form I. DETAILED DESCRIPTION

[0165] The technical scheme of the present invention will be further described in detail below in conjunction with specific embodiments. The following embodiments are only exemplary to illustrate and explain the present invention, and should not be construed as limiting the scope of protection of the present invention. All technologies implemented based on the above content of the present invention are included in the scope that the present invention is intended to protect.

[0166] Unless otherwise specified, the raw materials and reagents used in the following examples are commercially available or can be prepared by known methods.

[0167] Example 1 of the present invention is determined by nuclear magnetic resonance (NMR) or / and liquid chromatography-mass spectrometry (LC-MS) or / and liquid chromatography (HPLC). The instrument used for NMR determination is Bruker AVANCE III 600MHz, the instrument used for LC-MS is WATERS ACQUITY UPLC H-Class PLUS or / and SQD2; the instrument used for HPLC is WATERS e2695_2998 or / and Agilent 1100. The instruments and detection parameters used in the salt / salt type screening of Examples 2-16 are as follows:

[0168]

[0169]

[0170]

[0171]

[0172] Example 1: Synthesis of Compound I

[0173]

[0174] Synthesis of intermediate 5-1

[0175] 4,6-dichloro-2-methylpyrimidine-5-carboxaldehyde (2.00 g, 10.47 mmol) was dissolved in tetrahydrofuran (20 mL), followed by the addition of ethoxycarbonylmethylenetriphenylphosphine (5.47 g, 15.71 mmol) and triethylamine (2.12 g, 20.94 mmol). The system was reacted at 80 ° C for 6 h, and LC-MS monitored that there was no residual raw material. The reaction system was directly separated and purified by column chromatography (n-hexane: ethyl acetate = 20: 1-10: 1) to obtain 5-1 (1.71 g, 6.54 mmol, yield 63%). ESI-MS: m / z 260.85 [M+H] + .

[0176] Synthesis of intermediate 5-2

[0177] 5-1 (1.71 g, 6.54 mmol) was dissolved in N,N-dimethylformamide (20 mL), followed by the addition of tert-butyl (2-aminoethyl)carbamate (1.26 g, 7.85 mmol) and triethylamine (1.32 g, 13.08 mmol). The system was reacted at room temperature for 12 h. LC-MS monitoring showed that there was no residual raw material. Water (30 mL) was added to the reaction solution, and ethyl acetate was extracted (30 mL × 3). The organic phases were combined, washed with saturated sodium chloride (30 mL × 2), and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by thin layer chromatography (n-hexane: ethyl acetate = 10: 1-3: 1) to obtain 5-2 (2.30 g, 5.99 mmol, yield 92%). ESI-MS: m / z 385.15 [M+H] + .

[0178] Synthesis of intermediate 5-3

[0179] 5-2 (2.30 g, 5.99 mmol) was dissolved in methanol (30 mL), and then sodium methoxide (3.6 mL, 17.97 mmol, 30% w / w in methanol) was added. The system was reacted at room temperature for 12 h. Solids precipitated from the reaction solution. LC-MS monitoring showed that there was no residual raw material. Water (10 mL) was added to the reaction solution, and the solution was filtered to obtain a white solid 5-3 (1.60 g, 4.79 mmol, yield 80%), ESI-MS: m / z 335.07 [M+H] +.

[0180] Synthesis of intermediate 5-4

[0181] 5-3 (1.60 g, 4.79 mmol) was dissolved in dichloromethane (30 mL), and then bromine (1.15 g, 7.19 mmol) was added. The system was reacted at room temperature for 12 h. LC-MS monitored that there was no residual raw material. The reaction system was directly separated and purified by column chromatography (n-hexane: ethyl acetate = 5:1-3:1) to obtain 5-4 (1.80 g, 4.36 mmol, yield 91%). ESI-MS: m / z 412.98 / 415.00 [M+H] + .

[0182] Synthesis of intermediate 5-5

[0183] 5-4 (1.80 g, 4.36 mmol) was dissolved in dichloromethane (20 mL), and then 5 mL of trifluoroacetic acid was added. The system was reacted at room temperature for 4 h. LC-MS monitored that there was no residual raw material. The solvent was evaporated under reduced pressure, and 15 mL of water was added to the residue. The pH was adjusted to 8-9 with saturated sodium carbonate aqueous solution, and extracted with ethyl acetate (20 mL×3). The organic phases were combined, washed with saturated sodium chloride (20 mL×2), and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to obtain 5-5 (0.90 g, 2.88 mmol, yield 66%). ESI-MS: m / z 312.92 / 314.91 [M+H] + .

[0184] Synthesis of intermediate 5-6

[0185] 5-5 (0.90 g, 2.88 mmol) was dissolved in toluene (20 mL), and then trimethylaluminum (1.9 mL, 3.75 mmol, 2.0 M in toluene) was slowly added. The system was reacted at 120 ° C for 5 h. LC-MS monitored that there was no residual raw material. The reaction solution was quenched with saturated aqueous ammonium chloride solution, and toluene was evaporated under reduced pressure. 15 mL of water was added to the residue, and ethyl acetate was extracted (20 mL × 3). The organic phases were combined, washed with saturated sodium chloride (20 mL × 2), and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to obtain 5-6 (0.59 g, 2.01 mmol, yield 70%). ESI-MS: m / z 294.87 / 296.83 [M+H] + .

[0186] Synthesis of intermediate 5-7

[0187] 5-6 (0.59 g, 2.01 mmol) was dissolved in dichloromethane (10 mL), and boron tribromide (2.52 g, 10.05 mmol) was slowly added under ice bath. After the addition, the ice bath was removed. The system was reacted at room temperature for 72 h. LC-MS monitored that there was no residual raw material. Sodium carbonate solution was slowly added under ice bath to quench the reaction, and solid was precipitated. 5-7 (0.46 g, 1.64 mmol, yield 82%) was obtained by filtration. ESI-MS: m / z 280.82 / 282.84 [M+H]+.

[0188]

[0189] Synthesis of intermediate 7-1

[0190] 5-7 (100 mg, 0.36 mmol) was dissolved in N,N-dimethylformamide (15 mL), followed by the addition of (R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethylamine hydrochloride (121 mg, 0.54 mmol), benzotriazole-1-oxytris(dimethylamino)phosphine hexafluorophosphate (205 mg, 0.47 mmol), and 1,8-diazabicycloundec-7-ene (163 mg, 1.08 mmol). The system was reacted at room temperature for 8 h. LC-MS monitoring showed that there was no residual raw material. Water (30 mL) was added to the reaction solution, and ethyl acetate was extracted (30 mL×3). The organic phases were combined, washed with saturated sodium chloride (30 mL×2), and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by thin layer chromatography (dichloromethane: methanol = 20:1) to obtain 7-1 (110 mg, yield 68%). ESI-MS: m / z 451.93 / 453.93 [M+H] + .

[0191]

[0192] The intermediate 7-1 (99 mg, 0.22 mmol) was dissolved in dioxane (30 mL), followed by the addition of 1-acetyl-5,6-dihydro-2H-pyridine-4-boronic acid pinacol ester (68 mg, 0.27 mmol), tetrakis(triphenylphosphine)palladium (23 mg, 0.02 mmol), and cesium carbonate (143 mg, 0.44 mmol). The whole system was stirred at 100°C for 3 h. TLC monitoring showed that there was no residual raw material. 50 mL of water was added to the reaction solution, and ethyl acetate was extracted (30 mL×3). The organic phases were combined, washed with saturated sodium chloride (50 mL×2), dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The compound I (69 mg, 0.14 mmol, yield 64%) was obtained by column chromatography separation and purification (dichloromethane: methanol = 60:1-15:1). ESI-MS: m / z 497.24 [M+H] + . 1H NMR (600MHz, DMSO-d6): δ8.23(s,1H),8.00(s,1H),7.64(dd,J=7.2Hz,J=7.2Hz,1H) ,7.50(dd,J=7.2Hz,J=7.2Hz,1H),7.32-7.29(m,1H),7.23(t,J=54.0Hz,1H),6.82( d,J=87.6Hz,1H),5.75-5.70(m,1H),4.22-4.02(m,4H),3.95-3.92(m,2H),3.67-3. 62(m,2H),2.50(s,3H),2.26(s,3H),2.06(d,J=24.6Hz,2H),1.56(d,J=6.6Hz,3H).

[0193] Example 2 Preparation of Compound I Crystalline Form I

[0194] 50 mg of compound I was added to 10 ml of ethyl acetate, stirred at room temperature and allowed to stand overnight, the solution was filtered, and the solid was dried to obtain Form I of compound I. The XRPD test results of Form I are as follows: Figure 1 As shown, the DSC and TGA test results are as follows Figure 2 , 3 The XRPD diffraction peak data of this crystal form I are shown below.

[0195] 2θ angle (°) Peak height Relative strength (%) 5.403 241 38.7 8.031 623 100 8.923 167 26.8 9.860 123 19.7 10.734 93 14.9 11.367 173 27.8 16.090 339 54.4 16.605 138 22.2 20.338 186 29.9 21.484 581 93.3

[0196] Example 3 Preparation of Compound I Benzenesulfonate Form I

[0197] Take about 50 mg of compound I sample, dissolve it in 5.0 mL of ethyl acetate at 60°C to obtain solution 1; take about 19.5 mg of benzenesulfonic acid, dissolve it in 0.1 mL of ethyl acetate to obtain solution 2; at room temperature, add solution 2 dropwise to solution 1 to obtain solution 3; stir solution 3 at room temperature for 4 days to precipitate solid to obtain a suspension; centrifuge the suspension, and vacuum dry the obtained solid at 40°C overnight to obtain benzenesulfonate salt form I. The XRPD test results of this form I are as follows Figure 4 As shown, the DSC and TGA test results are as follows Figure 5 , 6 The XRPD diffraction peak data of this crystal form I are shown below.

[0198] 2θ angle (°) Peak height Relative strength (%) 8.282 260 35.7 10.524 589 80.8 11.462 729 100 13.118 471 64.6 14.472 422 57.9 16.071 343 47.1 17.693 410 56.2 19.522 672 92.2 22.342 516 70.8 23.925 403 55.3 26.346 344 47.2

[0199] Example 4 Preparation of Compound I Malate Form I

[0200] About 50 mg of compound I sample was taken and dissolved in 1.0 mL of tetrahydrofuran to obtain solution 1; about 14.9 mg of L-malic acid was taken and dissolved in 0.1 mL of tetrahydrofuran to obtain solution 2; solution 2 was added dropwise to solution 1 at room temperature to obtain solution 3; solution 3 was stirred at room temperature for 4 days, but no precipitation was observed. 4.0 mL of n-heptane was added to precipitate as oil, which was stirred at room temperature for 2 days, but no precipitation was observed. L-malate salt form I was obtained by evaporation at room temperature. The XRPD test results of this form I are as follows: Figure 7 As shown, the DSC and TGA test results are as follows Figure 8 , 9 The XRPD diffraction peak data of this crystal form I are shown below.

[0201] 2θ angle (°) Peak height Relative strength (%) 5.817 272 32.5 12.832 140 16.7 14.375 119 14.2 15.004 127 15.2 15.462 184 22 19.139 216 25.8 20.187 370 44.3 21.215 126 15.1 23.58 836 100 24.476 605 72.4

[0202] Example 5 Preparation of Compound I Phosphate Form I

[0203] Take about 50 mg of compound I sample, dissolve it in 1.0 mL of tetrahydrofuran, and obtain solution 1; take about 12.8 mg of phosphoric acid, add 0.1 mL of tetrahydrofuran to dilute, and obtain solution 2; at room temperature, add solution 2 dropwise to solution 1 to obtain a suspension; stir the suspension at room temperature for 4 days; centrifuge the suspension, and vacuum dry the obtained solid at 40°C overnight to obtain phosphate crystal form I. The XRPD test results of this crystal form I are as follows: Fig.10 As shown, the DSC and TGA test results are as follows Fig.11 , 12 The XRPD diffraction peak data of this crystal form I are shown below.

[0204] 2θ angle (°) Peak height Relative strength (%) 4.848 1468 100 9.422 158 10.8 11.613 279 19 14.947 150 10.2 16.320 511 34.8 17.271 141 9.6 23.749 162 11

[0205] Example 6 Preparation of Compound I Phosphate Crystalline Form II

[0206] Take about 300 mg of compound I sample, dissolve in 3.0 mL of tetrahydrofuran, dissolve at 50°C to obtain solution 1; take about 76.8 mg of phosphoric acid, add 0.1 mL of tetrahydrofuran to dilute, obtain solution 2; at room temperature, add solution 2 dropwise to solution 1 to obtain a suspension; add 2.0 mL of tetrahydrofuran and 4.0 mL of methyl tert-butyl ether to the suspension, stir at room temperature overnight; centrifuge the suspension, and vacuum dry the obtained solid at 40°C overnight to obtain phosphate crystal form II. The XRPD test results of this crystal form II are as follows: Fig.13 As shown, the DSC and TGA test results are as follows Fig.14 , 15 The salt ratio was determined to be 1:1 by IC method (ion chromatography). The XRPD diffraction peak data of this crystal form II are shown below.

[0207] 2θ angle (°) Peak height Relative strength (%) 4.847 427 100 16.357 264 61.8 16.818 339 79.4 19.595 88 20.6 21.045 115 26.9 22.284 160 37.5 23.579 144 33.7

[0208] Example 7 Preparation of Compound I Propionate Salt Form I

[0209] About 50 mg of compound I sample was dissolved in 3.0 mL of methanol to obtain solution 1; about 8.2 mg of propionic acid was dissolved in 0.1 mL of methanol to obtain solution 2; solution 2 was added dropwise to solution 1 at room temperature to obtain solution 3; solution 3 was stirred at 4°C for 5 days, but no precipitation was observed. 10.0 mL of methyl tert-butyl ether was added and stirred at room temperature for 2 days, but no precipitation was observed. The solution was then volatilized at room temperature to obtain propionate salt form I. The XRPD test results of this form I are as follows: Fig.16 As shown, the DSC and TGA test results are as follows Fig.17 , 18 The XRPD diffraction peak data of this crystal form I are shown below.

[0210] 2θ angle (°) Peak height Relative strength (%) 7.384 239 100 7.954 107 44.8 8.945 114 47.7 10.339 116 48.5 13.249 74 31 14.455 96 40.2 16.968 139 58.2 19.808 140 58.6 21.312 118 49.4 23.770 111 46.4 26.075 108 45.2

[0211] Example 8 Preparation of Compound I Succinate Form I

[0212] About 50 mg of compound I sample was dissolved in 1.0 mL of tetrahydrofuran to obtain solution 1; about 13.1 mg of succinic acid was dissolved in 0.1 mL of tetrahydrofuran to obtain solution 2; solution 2 was added dropwise to solution 1 at room temperature to obtain solution 3; solution 3 was stirred at room temperature for 4 days, but no precipitation occurred. 4.0 mL of n-heptane was added and stirred at room temperature for 2 days to precipitate oil, which was then volatilized at room temperature to obtain succinate salt form I. The XRPD test results of this form I are as follows: Fig.19 As shown, the DSC and TGA test results are as follows Fig. 20 , 21 The XRPD diffraction peak data of this crystal form I are shown below.

[0213] 2θ angle (°) Peak height Relative strength (%) 5.816 363 83.6 6.618 295 68 8.696 136 31.3 13.765 150 34.6 15.005 434 100 18.720 155 35.7 19.842 215 49.5 20.343 137 31.6 24.053 151 34.8 24.283 353 81.3 24.968 227 52.3 26.210 154 35.5

[0214] Example 9 Preparation of Compound I Sulfate Form I

[0215] Take about 300 mg of compound I sample, dissolve in 10.0 mL of isopropanol, dissolve at 60°C to obtain solution 1; take about 66.6 mg of sulfuric acid, add 0.1 mL of isopropanol to dilute, obtain solution 2; at room temperature, add solution 2 dropwise to solution 1, precipitate for about 1 hour, obtain a suspension; place the suspension at room temperature and stir overnight; centrifuge the suspension, and vacuum dry the obtained solid at 40°C overnight to obtain sulfate crystal form I. The XRPD test results of this crystal form I are as follows Fig. 22 As shown, the DSC and TGA test results are as follows Fig.23 , 24The salt ratio was determined to be 1:1 by IC method (ion chromatography). The XRPD diffraction peak data of this crystal form I are shown below.

[0216] 2θ angle (°) Peak height Relative strength (%) 11.020 371 42.2 11.917 242 27.5 12.778 362 41.1 17.864 880 100 18.969 582 66.1 19.503 456 51.8 21.081 262 29.8 22.972 242 27.5 23.962 212 24.1 26.115 272 30.9 27.222 446 50.7

[0217] Example 10 Preparation of Compound I Tartrate Form I

[0218] About 50 mg of compound I sample was dissolved in 1.0 mL of tetrahydrofuran to obtain solution 1; about 16.6 mg of L-tartaric acid was dissolved in 0.1 mL of tetrahydrofuran to obtain solution 2; solution 2 was added dropwise to solution 1 at room temperature to obtain a suspension; the suspension was stirred at room temperature for 4 days; the suspension was centrifuged, and the obtained solid was vacuum dried at 40° C. overnight to obtain L-tartrate salt form I. The XRPD test results of this form I are as follows: Fig.25 As shown, the DSC and TGA test results are as follows Fig.26 , 27 The XRPD diffraction peak data of this crystal form I are shown below.

[0219] 2θ angle (°) Peak height Relative strength (%) 4.178 1434 100 8.218 359 25 12.754 472 32.9 14.393 426 29.7 15.098 481 33.5 16.321 359 25 17.024 742 51.7 19.177 1341 93.5 20.131 546 38.1 22.056 461 32.1 22.879 411 28.7 25.067 333 23.2

[0220] Example 11 Preparation of Compound I Pamoate Salt Form I

[0221] About 50 mg of compound I sample was dissolved in 3.0 mL of methanol to obtain solution 1; about 43.9 mg of pamoic acid was dissolved in 0.1 mL of methanol, 0.2 mL of tetrahydrofuran and 0.6 mL of dimethyl sulfoxide to obtain solution 2; solution 2 was added dropwise to solution 1 at room temperature to obtain solution 3; solution 3 was stirred at 4°C for 5 days to precipitate a solid to obtain a suspension; the suspension was centrifuged, and the obtained solid was vacuum dried at 40°C overnight to obtain pamoic acid salt form I. The XRPD test results of this form I are as follows: Fig.28 As shown, the DSC and TGA test results are as follows Fig.29 , 30 The XRPD diffraction peak data of this crystal form I are shown below.

[0222] 2θ angle (°) Peak height Relative strength (%) 7.267 431 51.4 8.981 838 100 9.575 395 47.1 11.843 760 90.7 13.174 392 46.8 14.488 349 41.6 16.280 345 41.2 19.164 442 52.7 20.984 419 50 22.454 443 52.9 24.057 581 69.3 26.855 368 43.9

[0223] Example 12 Preparation of Compound I Pamoate Crystalline Form II

[0224] Take about 50 mg of compound I sample and dissolve it in 5.0 mL of isopropanol to obtain solution 1; take about 43.9 mg of pamoic acid and dissolve it in 0.6 mL of dimethyl sulfoxide to obtain solution 2; at room temperature, add solution 2 dropwise to solution 1 to obtain a suspension; stir the suspension at 4°C for 2 days; centrifuge the suspension, and vacuum dry the obtained solid at 40°C overnight to obtain pamoic acid salt form II. The XRPD test results of this form II are as follows: Fig.31 As shown, the DSC and TGA test results are as follows Fig.32 , 33 The XRPD diffraction peak data of this crystal form II are shown below.

[0225] 2θ angle (°) Peak height Relative strength (%) 6.222 334 97.9 7.648 205 60.1 9.024 206 60.4 12.051 201 58.9 13.957 340 99.7 15.179 341 100 16.149 225 66 16.700 163 47.8 18.700 169 49.6 22.986 166 48.7 26.209 217 63.6

[0226] Example 13 Preparation of Compound I Pamoate Crystalline Form III

[0227] Take about 50 mg of compound I sample and dissolve it in 1.0 mL of isopropanol to obtain solution 1; take about 21.9 mg of pamoic acid; add pamoic acid to solution 1 at room temperature to obtain a suspension; stir the suspension at room temperature for 2 days; centrifuge the suspension, and vacuum dry the obtained solid at 40°C overnight to obtain pamoic acid salt form III. The XRPD test results of this form III are as follows: Fig.34 As shown, the DSC and TGA test results are as follows Fig.35 , 36 The XRPD diffraction peak data of this crystal form III are shown below.

[0228] 2θ angle (°) Peak height Relative strength (%) 9.475 632 96.9 11.138 253 38.8 15.651 652 100 19.386 220 33.7 23.18 205 31.4 25.067 172 26.4 26.288 609 93.4 29.943 304 46.6

[0229] Example 14 Preparation of Acetate Form I of Compound I

[0230] About 50 mg of compound I sample was dissolved in 2.0 mL of acetonitrile to obtain solution 1; about 6.7 mg of acetic acid was dissolved in 0.1 mL of acetonitrile to obtain solution 2; solution 2 was added dropwise to solution 1 at room temperature to obtain solution 3; solution 3 was stirred at 4°C overnight to precipitate a solid to obtain a suspension; the suspension was centrifuged, and the obtained solid was vacuum dried at 40°C overnight to obtain acetate crystal form I. The XRPD test results of this crystal form I are as follows: Fig.37 As shown, the DSC and TGA test results are as follows Fig.38 , 39 The XRPD diffraction peak data of this crystal form I are shown below.

[0231] 2θ angle (°) Peak height Relative strength (%) 7.363 1073 100 7.994 817 76.1 9.002 149 13.9 10.393 146 13.6 11.347 218 20.3 13.250 145 13.5 14.698 224 20.9

[0232] Example 15 Preparation of p-toluenesulfonate of Compound I

[0233] Take about 50 mg of compound I sample, add it to 5.0 mL of ethyl acetate, dissolve it at 60°C to obtain solution 1; take about 19.1 mg of p-toluenesulfonic acid, add 0.1 mL of ethyl acetate to dissolve it, obtain solution 2; add solution 1 dropwise to the stirring solution 2, and immediately precipitate into an oily sticky wall, stir at room temperature for 4 days, precipitate solid, centrifuge, and vacuum dry the obtained solid at 40°C overnight to obtain p-toluenesulfonate. After determination, the XRPD of this p-toluenesulfonate has no diffraction peak, and is amorphous.

[0234] Example 16 Preparation of Compound I Lactobionate

[0235] About 50 mg of compound I sample was added to 1.0 mL of isopropanol and dissolved at 60°C to obtain solution 1; about 40.5 mg of lactobionic acid was added to the stirred solution 1, the suspension was centrifuged, and the obtained solid was vacuum dried at 40°C overnight to obtain lactobionic acid salt. The XRPD of this lactobionic acid salt was determined to have no diffraction peaks and was amorphous.

[0236] Example 17 Preparation of Compound I Citrate

[0237] Take about 50 mg of compound I sample, add 1.0 mL of isopropanol, dissolve at 60°C to obtain solution 1; take about 10.6 mg of citric acid, add 0.1 mL of isopropanol to dissolve, obtain solution 2; add solution 1 dropwise to stirring solution 2, stir at room temperature overnight, add 4.0 mL of methyl tert-butyl ether, precipitate, centrifuge, and vacuum dry the obtained solid at 40°C overnight to obtain citrate. After determination, the XRPD of this citrate has no diffraction peak and is amorphous.

[0238] Example 18 Preparation of Compound I Hydrochloride

[0239] About 50 mg of compound I sample was added to 1.0 mL of acetone and dissolved at 60°C to obtain solution 1; about 9.2 μL of hydrochloric acid was added dropwise to the stirring solution 1 and stirred at 4°C overnight. No precipitation was observed. 4.0 mL of methyl tert-butyl ether was added and stirred at room temperature for about 2 hours. Precipitation was observed and centrifuged. The obtained solid was vacuum dried at 40°C overnight to obtain hydrochloride. The XRPD of the hydrochloride was determined to have no diffraction peaks and was amorphous.

[0240] Example 19 Preparation of Compound I Methanesulfonate

[0241] Take about 50 mg of compound I sample, add it to 1.0 mL of acetone, dissolve it at 60°C to obtain solution 1; take about 10.6 mg of methanesulfonic acid, add 0.1 mL of acetone to dissolve it, obtain solution 2; add solution 1 dropwise to solution 2 under stirring, stir at 4°C overnight, no precipitation occurs, add 3.0 mL of n-heptane, precipitate occurs immediately, stir at room temperature for about 2 hours, centrifuge, and vacuum dry the obtained solid at 40°C overnight to obtain mesylate. After determination, the XRPD of this mesylate has no diffraction peak, and is amorphous.

[0242] Test Example 1:

[0243] Biological activity assay:

[0244] 1. K-Ras G12D Binding analysis with hSOS1

[0245] This assay can be used to examine the potency of compounds to inhibit the protein-protein interaction between SOS1 and KRAS G12D. GST-KRas bound by anti-GSK-Europium (FRET donor) was detected by homogeneous time-resolved fluorescence (HTRF). G12D The binding of compounds to K-Ras G12D Inhibitory effect on hSOS1.

[0246] 1.1 Reagents

[0247] Buffer (5 mM HEPES pH 7.4, 150 mM NaCl, 10 mM EDTA, 1 mM DTT, 0.05% BAS pH 7.0, 0.0025% Igepal and 100 mM KF);

[0248] GST-tagged hK-RasG12D (produced in-house);

[0249] His-tagged hSOS1 (produced in-house);

[0250] Preparation of Ras mixed solution

[0251] GST-hK-RasG12D 10 nM (final concentration) and anti-GSK-Europium 2 nM (final concentration) were mixed in the assay buffer and placed at room temperature until use.

[0252] Preparation of SOS mixed solution

[0253] His-tag hSOS1 20 nM (final concentration) and anti-6His-XL665 10 nM (final concentration) were mixed in the assay buffer and placed at room temperature until use.

[0254] Dissolve the compound to be tested in DMSO at a concentration of 100 times the experimental concentration. Use a Hummingbird liquid handler or Echo acoustic system to transfer 50 nL into a black microplate.

[0255] 1.2 Experimental procedures

[0256] All experimental steps were completed at 20°C. In the experiment, 2.5μL of Ras mixture was added to all wells of the detection plate through a multidrop dispenser. After 2 minutes of pre-incubation, 2.5μL of SOS mixture was added to all wells except the edge wells, and 2.5μL of compound control solution was added to the edge wells. After incubation for 60 minutes, the HTRF module of Pheraster (excitation light: 337nm, emission light 1: 620nm, emission light 2: 665nm) was used.

[0257] 1.3 Data Calculation

[0258] Calculate and analyze IC using a 4-parameter logic model 50 value.

[0259] 1.4 SOS1 inhibitory activity results

[0260] The representative compounds in the examples were tested according to the above method, and the SOS1 inhibitory activity data are shown in the table below.

[0261] Compound <![CDATA[Active IC 50 (nM)]]> I B

[0262] Where B represents 10nM≤IC 50 <50nM.

[0263] 2.3D cell proliferation inhibition assay

[0264] The cell proliferation inhibition assay was used to detect whether the compounds inhibited the proliferation and growth of SOS1-mediated tumor cell lines at the 3D cell level in vitro. 3D detection method.

[0265] 2.1 Reagents and Materials

[0266] NCI-H358: Non-small cell lung cancer (NSCLC) with KRAS G12C mutation;

[0267] CellTiter- 3D Cell Viability Assay, Promega, G9683;

[0268] RPMI 1640medium,Gibco,A10491-01;

[0269] FBS, Gibco, 10099141C;

[0270] 2.2 Test steps:

[0271] 2.2.1 Cell culture

[0272] Day 1, passage NCI-H358 into T75 cell culture flasks;

[0273] On Day 3, remove the culture medium, rinse once with DPBS, and use 2 mL of TrypLE TM The cells were digested with ExpressEnzyme until the cells fell off; 5 mL of fresh culture medium was added and centrifuged at 1000 rpm for 5 min; the supernatant was discarded, 5 mL of fresh culture medium was added to resuspend the cells, and after counting the cells, 40 μL / well was inoculated into a 3D cell plate (Echo Qualified 384-Well Polypropylene Microplate 2.0, Clear, Flat Bottom).

[0274] 2.2.2 3D cell proliferation inhibition

[0275] Day 1, dissolve the test compound in DMSO to prepare a 10mM stock solution; dilute 1000 times with DMSO solution, then perform 3-fold gradient dilution, 10 concentration gradients, and the starting concentration is 10μM; add 200nL of the compound to the culture plate;

[0276] Day 8: Add 40 μL / well 3D CTG reagent and use Envision to detect the signal value.

[0277] 2.3 Data Analysis

[0278] Fitting compound IC using Graphpad Prism 8 nonlinear regression equation 50 value;

[0279] Y=Bottom+(Top-Bottom) / (1+10^((LogIC50-X)*HillSlope));

[0280] X: Log of cpd concentration;

[0281] Y:Percent inhibition (%inh)

[0282] 2.4 NCI-H358 Cell Proliferation Inhibitory Activity Results

[0283] The compounds in the examples were tested according to the above method, and the NCI-H358 cell proliferation inhibitory activity data are shown in the table below.

[0284] Compound <![CDATA[Active IC 50 (nM)]]> I A

[0285] Among them, A represents IC 50 <50nM.

[0286] The above is an explanation of the embodiments of the present invention. However, the present invention is not limited to the above embodiments. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present invention shall be included in the protection scope of the present invention.

Claims

1. A crystalline form I of compound I of the following formula, characterized in that: Using Cu-Kα radiation, X-ray powder diffraction expressed in 2θ degrees had characteristic peaks at 5.4±0.2°, 8.0±0.2°, 16.1±0.2°, and 21.5±0.2°; Preferably, the X-ray powder diffraction of the crystalline form I of the compound I expressed at 2θ angle also has one or more characteristic peaks at 8.9±0.2°, 11.4±0.2°, 16.6±0.2°, and 20.3±0.2°; Further preferably, the X-ray powder diffraction of the crystalline form I of the compound I expressed at 2θ angle also has one or two characteristic peaks at 9.9±0.2° and 10.7±0.2°; More preferably, the crystalline form I of the compound I has an X-ray powder diffraction spectrum substantially as shown in FIG1 ; 2. The crystalline form I of compound I according to claim 1, characterized in that: Its differential scanning calorimetry curve has an endothermic peak at 179°C ± 10°C; Preferably, the crystalline form I of the compound I has an endothermic peak at 179°C±5°C in its differential scanning calorimetry curve; Further preferably, the crystalline form I of the compound I has a DSC spectrum substantially as shown in FIG2 .

3. The crystalline form I of compound I according to claim 1 or 2, characterized in that: It has a TGA spectrum substantially as shown in FIG3 .

4. A salt of compound I, characterized in that The structure of compound I is as follows: The salt is benzenesulfonate, citrate, malate, phosphate, propionate, succinate, sulfate, tartrate, p-toluenesulfonate, pamoate, acetate, hydrochloride, lactobionate, and methanesulfonate of Compound I.

5. A salt of compound I as claimed in claim 4, characterized in that The salt is benzenesulfonate crystalline form I, and using Cu-Kα radiation, X-ray powder diffraction expressed in 2θ angles has characteristic peaks at 10.5±0.2°, 11.5±0.2°, 19.5±0.2°, and 22.3±0.2°; Preferably, the benzenesulfonate salt form I of the compound I also has one or more characteristic peaks at 13.1±0.2°, 14.5±0.2°, 17.7±0.2°, and 23.9±0.2° in X-ray powder diffraction expressed at 2θ angles; Further preferably, the benzenesulfonate salt form I of the compound I also has one or more characteristic peaks at 8.3±0.2°, 16.1±0.2°, and 26.3±0.2° in X-ray powder diffraction expressed at 2θ angles; More preferably, the benzenesulfonate salt form I of Compound I has an X-ray powder diffraction spectrum substantially as shown in FIG. 4 .

6. The salt of Compound I according to claim 5, characterized in that The salt is benzenesulfonate crystal form I, and its differential scanning calorimetry curve has an endothermic peak at 228°C ± 10°C; Preferably, the benzenesulfonate salt form I of the compound I has an endothermic peak at 228°C±5°C in its differential scanning calorimetry curve; Further preferably, the benzenesulfonate salt form I of compound I has a DSC spectrum substantially as shown in FIG5 .

7. The salt of compound I according to claim 5 or 6, characterized in that It has a TGA spectrum substantially as shown in FIG6 .

8. A salt of compound I as claimed in claim 4, characterized in that The salt is a malate crystalline form I, characterized in that, using Cu-Kα radiation, X-ray powder diffraction expressed in 2θ angles has characteristic peaks at 5.8±0.2°, 20.2±0.2°, 23.6±0.2°, and 24.5±0.2°; Preferably, the X-ray powder diffraction of the malate crystalline form I of the compound I expressed at 2θ angle also has one or more characteristic peaks at 12.8±0.2°, 15.5±0.2°, and 19.1±0.2°; Further preferably, the X-ray powder diffraction of the malate crystalline form I of the compound I expressed at 2θ angle also has one or more characteristic peaks at 14.4±0.2°, 15.0±0.2°, and 21.2±0.2°; More preferably, the malate crystalline form I of Compound I has an X-ray powder diffraction spectrum substantially as shown in Figure 7.

9. The salt of Compound I according to claim 8, characterized in that The salt is malate crystal form I, and its differential scanning calorimetry curve has an endothermic peak at 177°C ± 10°C; Preferably, the malate crystalline form I of the compound I has an endothermic peak in its differential scanning calorimetry curve at 177°C±5°C; Further preferably, the malate crystalline form I of compound I has a DSC spectrum substantially as shown in FIG8 .

10. The salt of compound I according to claim 8 or 9, characterized in that It has a TGA spectrum substantially as shown in FIG9 .

11. A salt of compound I as claimed in claim 4, characterized in that The salt is a phosphate of compound I represented by formula (II), The salt formation ratio of compound I to phosphoric acid is 1:

1.

12. A salt of compound I as claimed in claim 4, characterized in that The salt is a phosphate crystal form I, and using Cu-Kα radiation, X-ray powder diffraction expressed in 2θ angles has characteristic peaks at 4.8±0.2°, 11.6±0.2°, 16.3±0.2°, and 23.7±0.2°; Preferably, the X-ray powder diffraction of the phosphate crystal form I of the compound I expressed at 2θ angle also has one or more characteristic peaks at 9.4±0.2°, 14.9±0.2°, and 17.3±0.2°; More preferably, the phosphate crystal form I of compound I has an X-ray powder diffraction spectrum substantially as shown in Figure 10.

13. The salt of Compound I according to claim 12, characterized in that The salt is a phosphate crystal form I, and its differential scanning calorimetry curve has an endothermic peak at 228°C ± 10°C; Preferably, the phosphate crystal form I of the compound I has an endothermic peak at 228°C±5°C in its differential scanning calorimetry curve; Further preferably, the phosphate crystal form I of the compound I has a DSC spectrum substantially as shown in Figure 11.

14. The salt of compound I according to claim 12 or 13, characterized in that It has a TGA spectrum substantially as shown in FIG12 .

15. A salt of compound I as claimed in claim 4, characterized in that The salt is a phosphate crystal form II, and using Cu-Kα radiation, X-ray powder diffraction expressed in 2θ angles has characteristic peaks at 4.8±0.2°, 16.3±0.2°, 16.8±0.2°, and 22.3±0.2°; Preferably, the X-ray powder diffraction of the phosphate crystal form II of the compound I expressed at 2θ angle also has one or more characteristic peaks at 19.6±0.2°, 21.0±0.2°, and 23.6±0.2°; More preferably, the phosphate crystal form II of compound I has an X-ray powder diffraction spectrum substantially as shown in Figure 13.

16. The salt of Compound I according to claim 15, characterized in that The salt is a phosphate crystal form II, and its differential scanning calorimetry curve has an endothermic peak at 221°C ± 10°C; Preferably, the phosphate crystal form II of the compound I has an endothermic peak at 221±5° C. in its differential scanning calorimetry curve; Further preferably, the phosphate crystal form II of the compound I has a DSC spectrum substantially as shown in Figure 14.

17. The salt of Compound I according to claim 15 or 16, characterized in that It has a TGA spectrum substantially as shown in FIG15 .

18. The salt of compound I according to any one of claims 15 to 17, characterized in that The salt is a phosphate crystal form II, wherein the salt formation ratio of compound I to phosphoric acid is 1:

1.

19. A salt of compound I as claimed in claim 4, characterized in that The salt is a propionate salt crystal form I, characterized in that, using Cu-Kα radiation, X-ray powder diffraction expressed in 2θ angles has characteristic peaks at 7.4±0.2°, 10.3±0.2°, 17.0±0.2°, and 19.8±0.2°; Preferably, the X-ray powder diffraction of the propionate salt form I of the compound I expressed at 2θ angle also has one or more characteristic peaks at 8.9±0.2°, 21.3±0.2°, 23.8±0.2°, and 26.1±0.2°; Further preferably, the X-ray powder diffraction of the propionate salt form I of the compound I expressed at 2θ angle also has one or more characteristic peaks at 8.0±0.2°, 13.2±0.2°, and 14.5±0.2°; More preferably, the propionate salt form I of compound I has an X-ray powder diffraction spectrum substantially as shown in Figure 16.

20. The salt of Compound I according to claim 19, characterized in that The salt is a propionate salt crystal form I, and its differential scanning calorimetry curve has an endothermic peak at 134°C ± 10°C; Preferably, the propionate salt form I of the compound I has an endothermic peak in its differential scanning calorimetry curve at 134°C±5°C; Further preferably, the propionate salt form I of compound I has a DSC spectrum substantially as shown in Figure 17.

21. The salt of Compound I according to claim 19 or 20, characterized in that It has a TGA spectrum substantially as shown in FIG18 .

22. The salt of compound I according to claim 4, characterized in that The salt is a succinate salt crystal form I, characterized in that, using Cu-Kα radiation, X-ray powder diffraction expressed in 2θ angles has characteristic peaks at 5.8±0.2°, 6.6±0.2°, 15.0±0.2°, and 24.3±0.2°; Preferably, the X-ray powder diffraction of the succinate salt form I of the compound I expressed at 2θ angle also has one or more characteristic peaks at 13.8±0.2°, 18.7±0.2°, 19.8±0.2°, and 25.0±0.2°; Further preferably, the X-ray powder diffraction of the succinate salt form I of the compound I expressed at 2θ angle also has one or more characteristic peaks at 8.7±0.2°, 20.3±0.2°, 24.1±0.2°, and 26.2±0.2°; More preferably, the succinate salt form I of compound I has an X-ray powder diffraction spectrum substantially as shown in Figure 19.

23. The salt of Compound 1 according to claim 22, characterized in that The salt is succinate crystal form I, and its differential scanning calorimetry curve has an endothermic peak at 168°C ± 10°C; Preferably, the succinate salt form I of the compound I has an endothermic peak in its differential scanning calorimetry curve at 168°C±5°C; Further preferably, the succinate salt form I of compound I has a DSC spectrum substantially as shown in Figure 20.

24. The salt of Compound I according to claim 22 or 23, characterized in that It has a TGA spectrum substantially as shown in FIG21 .

25. A salt of compound I as claimed in claim 4, characterized in that The salt is a sulfate of compound I of formula (III), The salt formation ratio of compound I to sulfuric acid is 1:

1.

26. The salt of compound I according to claim 4, characterized in that The salt is a sulfate crystal form I, characterized in that, using Cu-Kα radiation, X-ray powder diffraction expressed in 2θ angles has characteristic peaks at 17.9±0.2°, 19.0±0.2°, 19.5±0.2°, and 27.2±0.2°; Preferably, the X-ray powder diffraction of the sulfate crystalline form I of the compound I expressed at 2θ angle also has one or more characteristic peaks at 11.0±0.2°, 12.8±0.2°, 21.1±0.2°, and 26.1±0.2°; Further preferably, the X-ray powder diffraction of the sulfate crystalline form I of the compound I expressed at 2θ angle also has one or more characteristic peaks at 11.9±0.2°, 23.0±0.2°, and 24.0±0.2°; More preferably, the sulfate salt form I of compound I has an X-ray powder diffraction spectrum substantially as shown in Figure 22.

27. The salt of Compound I according to claim 26, characterized in that The salt is sulfate crystal form I, and its differential scanning calorimetry curve has an endothermic peak near 259±10°C; Preferably, the sulfate crystalline form I of the compound I has an endothermic peak at 259°C±5°C in its differential scanning calorimetry curve; Further preferably, the sulfate salt form I of compound I has a DSC spectrum substantially as shown in Figure 23.

28. The salt of compound I according to claim 26 or 27, characterized in that It has a TGA spectrum substantially as shown in FIG24 .

29. The salt of Compound I according to any one of claims 26 to 28, characterized in that The salt formation ratio of compound I and sulfuric acid is 1:

1.

30. The salt of compound I according to claim 4, characterized in that The salt is a tartrate salt form I, and using Cu-Kα radiation, X-ray powder diffraction expressed in 2θ angles has characteristic peaks at 4.2±0.2°, 17.0±0.2°, 19.2±0.2°, and 20.1±0.2°; Preferably, the X-ray powder diffraction of the tartrate salt form I of the compound I expressed at 2θ angle also has one or more characteristic peaks at 12.8±0.2°, 15.1±0.2°, and 22.1±0.2°; Further preferably, the X-ray powder diffraction of the tartrate salt form I of the compound I expressed at 2θ angle also has one or more characteristic peaks at 8.2±0.2°, 14.4±0.2°, 16.3±0.2°, 22.9±0.2°, and 25.1±0.2°; More preferably, the tartrate salt form I of compound I has an X-ray powder diffraction spectrum substantially as shown in Figure 25.

31. The salt of Compound I as claimed in claim 30, characterized in that The salt is a tartrate salt crystal form I, and its differential scanning calorimetry curve has an endothermic peak at 132°C ± 10°C; Preferably, the tartrate salt form I of the compound I has an endothermic peak in its differential scanning calorimetry curve at 132°C±5°C; Further preferably, the tartrate salt form I of compound I has a DSC spectrum substantially as shown in Figure 26.

32. The salt of compound I according to claim 30 or 31, characterized in that It has a TGA spectrum substantially as shown in FIG27 .

33. The salt of compound I according to claim 4, characterized in that The salt is a pamoate salt form I, and using Cu-Kα radiation, X-ray powder diffraction expressed in 2θ angles has characteristic peaks at 7.3±0.2°, 9.0±0.2°, 11.8±0.2°, and 24.1±0.2°; Preferably, the pamoate salt form I of the compound I also has one or more characteristic peaks at 13.2±0.2°, 19.2±0.2°, 21.0±0.2°, and 22.5±0.2° in X-ray powder diffraction expressed at 2θ angles; Further preferably, the X-ray powder diffraction of the pamoate salt form I of the compound I expressed at 2θ angle also has one or more characteristic peaks at 9.6±0.2°, 14.5±0.2°, 16.3±0.2°, and 26.9±0.2°; More preferably, the pamoate salt form I of compound I has an X-ray powder diffraction spectrum substantially as shown in Figure 28.

34. The salt of Compound I as claimed in claim 33, characterized in that The salt is a pamoate salt form I, and its differential scanning calorimetry curve has an endothermic peak at 249°C ± 10°C; Preferably, the pamoate salt form I of the compound I has an endothermic peak in its differential scanning calorimetry curve at 249°C±5°C; Further preferably, the pamoate salt form I of compound I has a DSC spectrum substantially as shown in Figure 29.

35. The salt of compound I according to claim 33 or 34, characterized in that It has a TGA spectrum substantially as shown in FIG30 .

36. The salt of Compound I according to claim 4, characterized in that The salt is a pamoate salt form II, and using Cu-Kα radiation, X-ray powder diffraction expressed in 2θ angles has characteristic peaks at 6.2±0.2°, 14.0±0.2°, 15.2±0.2°, and 16.1±0.2°; Preferably, the pamoate salt form II of the compound I also has one or more characteristic peaks at 7.6±0.2°, 9.0±0.2°, 12.1±0.2°, and 26.2±0.2° in X-ray powder diffraction expressed at 2θ angles; Further preferably, the pamoate salt form II of the compound I also has one or more characteristic peaks at 16.7±0.2°, 18.7±0.2°, and 23.0±0.2° in X-ray powder diffraction expressed at 2θ angles; More preferably, the pamoate salt form II of compound I has an X-ray powder diffraction spectrum substantially as shown in Figure 31.

37. The salt of Compound I according to claim 36, characterized in that The salt is a pamoate salt form II, and its differential scanning calorimetry curve has an endothermic peak at 173°C ± 10°C; Preferably, the pamoate salt form II of the compound I has an endothermic peak in its differential scanning calorimetry curve at 173°C±5°C; Further preferably, the pamoate salt form II of compound I has a DSC spectrum substantially as shown in Figure 32.

38. The salt of Compound I according to claim 36 or 37, characterized in that It has a TGA spectrum substantially as shown in FIG33 .

39. The salt of Compound I according to claim 4, characterized in that The salt is a pamoate salt form III, and using Cu-Kα radiation, X-ray powder diffraction expressed in 2θ angles has characteristic peaks at 9.5±0.2°, 15.7±0.2°, 26.3±0.2°, and 29.9±0.2°; Preferably, the pamoate salt form III of the compound I also has one or more characteristic peaks at 11.1±0.2°, 19.4±0.2°, 23.2±0.2°, and 25.1±0.2° in X-ray powder diffraction expressed at 2θ angles; More preferably, the pamoate salt form III of compound I has an X-ray powder diffraction spectrum substantially as shown in Figure 34.

40. The salt of Compound I as claimed in claim 39, characterized in that The salt is a pamoate salt form III, and its differential scanning calorimetry curve has an endothermic peak at 249°C ± 10°C; Preferably, the pamoate salt form III of the compound I has an endothermic peak at 249°C±5°C in its differential scanning calorimetry curve; Further preferably, the pamoate salt form III of compound I has a DSC spectrum substantially as shown in Figure 35.

41. The salt of Compound I according to claim 39 or 40, characterized in that It has a TGA spectrum substantially as shown in FIG36 .

42. The salt of Compound I according to claim 4, characterized in that The salt is acetate crystal form I, and using Cu-Kα radiation, X-ray powder diffraction expressed in 2θ angles has characteristic peaks at 7.4±0.2°, 8.0±0.2°, 11.3±0.2°, and 14.7±0.2°; Preferably, the acetate crystalline form I of the compound I also has one or more characteristic peaks at 9.0±0.2°, 10.4±0.2°, and 13.3±0.2° in X-ray powder diffraction expressed at 2θ angles; More preferably, the acetate salt form I of compound I has an X-ray powder diffraction spectrum substantially as shown in Figure 37.

43. The salt of Compound I as claimed in claim 42, characterized in that The salt is acetate crystal form I, and its differential scanning calorimetry curve has an endothermic peak at 180°C ± 10°C; Preferably, the acetate salt form I of the compound I has an endothermic peak in its differential scanning calorimetry curve at 180°C±5°C; Further preferably, the acetate salt form I of compound I has a DSC spectrum substantially as shown in Figure 38.

44. The salt of Compound I according to claim 42 or 43, characterized in that It has a TGA spectrum substantially as shown in Figure 39.

45. A pharmaceutical composition, characterized in that The composition comprises the crystalline form I of Compound I according to any one of claims 1 to 3 or the salt of Compound I according to any one of claims 4 to 44.

46. ​​Use of the crystalline form I of compound I according to any one of claims 1 to 3, the salt of compound I according to any one of claims 4 to 44, or the pharmaceutical composition according to claim 45 in the preparation of a medicament for treating a disease mediated by SOS1.

47. Use of the crystalline form I of compound I according to any one of claims 1 to 3, the salt of compound I according to any one of claims 4 to 44, or the pharmaceutical composition according to claim 45 in the preparation of a medicament for treating cancer or tumor-related diseases; preferably, the cancer or tumor-related disease is a solid tumor; more preferably, the cancer or tumor-related disease is lung cancer; more preferably, the cancer or tumor-related disease is non-small cell lung cancer.

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