A crystal form, salt form of a heterocyclic antitumor compound and use thereof

Abstract

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

Description

TECHNICAL FIELD

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

[0002] The three genes of the RAS family are currently known: 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 GTPases and the first oncogenes to be identified in human tumors. RAS family proteins have weak intrinsic GTPase activity and slow nucleotide exchange rates. 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%, 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 EGFR antibodies cetuximab and panitumumab, and EGFR tyrosine kinase inhibitor osimertinib. For oncogenic RAS mutants, GAP activity is impaired or greatly reduced, leading to permanent activation, which is the basis of oncogenic RAS signaling. Direct inhibition of RAS has proven to be extremely challenging and difficult to drug due to its picomolar affinity for its binding site, lack of other well-defined pockets, and RAS interaction with GEF, GAP, and effectors through extended and flat protein-protein interactions. Therefore, inhibition of RAS activation by targeting the upstream guanine nucleotide exchange factor protein SOS may have new hope.

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

[0005] In the past few decades, the RAS family protein-SOS1 protein interaction has gained more and more recognition. In addition, recently, studies have been carried out to combine rational design and screening platforms to screen and identify small molecule inhibitors of SOS1, i.e. compounds that bind to SOS1 and inhibit protein-protein interaction with RAS family proteins. As described in WO2021105960A1, various fused ring SOS1 inhibitors are described.

[0006] Although some SOS1 inhibitor small molecules have been disclosed, no SOS1 inhibitor has been developed on the market so far, and therefore it is still an urgent need to develop new compounds with market potential, which have better pharmacodynamics and pharmacokinetics. SUMMARY

[0007] Chinese Patent Application 202211629162.2 (filing date December 16, 2022) and International Patent Application PCT / CN2022 / 139447 (filing date December 16, 2022) disclose compounds as SOS1 inhibitors and methods for preparing the same, including (R)-1-(4-(4-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2-methyl-8,9-dihydroimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)-3,6-dihydropyridin-1(2H)-yl)ethanone (hereinafter referred to as Compound I or a compound of Formula I, the structure of which is shown below) and methods for preparing the same.

[0008]

[0009] Compound I is an effective SOS1 inhibitor. In vitro enzymatic inhibition studies show that Compound I has a strong inhibitory effect on SOS1, and Compound I also exhibits obvious inhibitory activity on NCI-H358 cell proliferation, and 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 polymorph and salt screening is one of the indispensable important research contents. Therefore, it is necessary to further screen the salt and crystal form of compound I, develop a crystal form or salt form suitable for large-scale production, and provide more and better choices for subsequent drug development.

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

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

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

[0014] Still further preferably, the crystal form I of compound I has an X-ray powder diffraction spectrum substantially as shown in Figure 1 .

[0015] In some schemes of the present application, the crystal form I of compound I has an endothermic peak at 179℃±10℃ in the differential scanning calorimetry curve.

[0016] Preferably, the crystal form I of compound I has an endothermic peak at 179℃±5℃ in the differential scanning calorimetry curve.

[0017] Further preferably, the crystal form I of compound I has a DSC spectrum substantially as shown in Figure 2 .

[0018] In some schemes of the present application, the crystal form I of compound I has a TGA spectrum substantially as shown in Figure 3 .

[0019] The present application also includes providing a salt of compound I, and the structure of compound I is as follows: The salt is a benzenesulfonate salt, a citrate salt, a malate salt, a phosphate salt, a propionate salt, a succinate salt, a sulfate salt, a tartrate salt, a p-toluenesulfonate salt, a pamoate salt, an acetate salt, a hydrochloride salt, a lactobionate salt, a methanesulfonate salt of compound I.

[0020] Another object of the present application also includes providing a benzenesulfonic acid salt Form I of Compound I, characterized by an X-ray powder diffraction pattern expressed in angles 2Θ using Cu-Kα radiation having characteristic peaks at 10.5±0.2°, 11.5±0.2°, 19.5±0.2°, 22.3±0.2°.

[0021] Preferably, the benzenesulfonic acid salt Form I of Compound I further has one or more characteristic peaks expressed in angles 2Θ of an X-ray powder diffraction pattern at 13.1±0.2°, 14.5±0.2°, 17.7±0.2°, 23.9±0.2°.

[0022] Further preferably, the benzenesulfonic acid salt Form I of Compound I further has one or more characteristic peaks expressed in angles 2Θ of an X-ray powder diffraction pattern at 8.3±0.2°, 16.1±0.2°, 26.3±0.2°.

[0023] Still further preferably, the benzenesulfonic acid salt Form I of Compound I has an X-ray powder diffraction pattern substantially as shown in FIG. 1. Figure 4

[0024] In some embodiments of the present application, the benzenesulfonic acid salt Form I of Compound I has a differential scanning calorimetry curve with an endothermic peak at 228°C±10°C.

[0025] Preferably, the benzenesulfonic acid salt Form I of Compound I has a differential scanning calorimetry curve with an endothermic peak at 228°C±5°C.

[0026] Further preferably, the benzenesulfonic acid salt Form I of Compound I has a DSC pattern substantially as shown in FIG. 2. Figure 5

[0027] In some embodiments of the present application, the benzenesulfonic acid salt Form I of Compound I has a TGA pattern substantially as shown in FIG. 3. Figure 6

[0028] Another object of the present application also includes providing a malate salt Form I of Compound I, characterized by an X-ray powder diffraction pattern expressed in angles 2Θ using Cu-Kα radiation having characteristic peaks at 5.8±0.2°, 20.2±0.2°, 23.6±0.2°, 24.5±0.2°.

[0029] Preferably, the malate salt Form I of Compound I further has one or more characteristic peaks expressed in angles 2Θ of an X-ray powder diffraction pattern at 12.8±0.2°, 15.5±0.2°, 19.1±0.2°.

[0030] ​​​Further preferably, the malate salt Form I of Compound I has an X-ray powder diffraction pattern substantially as shown in Figure 2.

[0031] More preferably, the malate salt Form I of Compound I has an X-ray powder diffraction pattern substantially as shown in Figure 2. Figure 7

[0032] In some embodiments of the present application, the malate salt Form I of Compound I has a differential scanning calorimetry curve with an endothermic peak at 177°C ± 10°C.

[0033] Preferably, the malate salt Form I of Compound I has a differential scanning calorimetry curve with an endothermic peak at 177°C ± 5°C.

[0034] Further preferably, the malate salt Form I of Compound I has a DSC pattern substantially as shown in Figure 3. Figure 8

[0035] In some embodiments of the present application, the malate salt Form I of Compound I has a TGA pattern substantially as shown in Figure 4. Figure 9

[0036] Another object of the present application also includes providing a phosphate salt of Compound I represented by Formula (II), wherein the salt formation ratio of Compound I to phosphoric acid is 1:1.

[0037] Another object of the present application also includes providing a phosphate salt Form I of Compound I, characterized in that the X-ray powder diffraction expressed in terms of 2θ angle has characteristic peaks at 4.8 ± 0.2°, 11.6 ± 0.2°, 16.3 ± 0.2°, 23.7 ± 0.2° using Cu-Kα radiation.

[0038] Preferably, the phosphate salt Form I of Compound I has an X-ray powder diffraction expressed in terms of 2θ angle further has one or more characteristic peaks at 9.4 ± 0.2°, 14.9 ± 0.2°, 17.3 ± 0.2°.

[0039] More preferably, the phosphate salt Form I of Compound I has an X-ray powder diffraction pattern substantially as shown in Figure 6. Figure 10

[0040] In some embodiments of the present application, the phosphate salt Form I of Compound I has a differential scanning calorimetry curve with an endothermic peak at 228°C ± 10°C.

[0041] Preferably, the phosphate salt Form I of Compound I has a differential scanning calorimetry curve with an endothermic peak at 228°C ± 5°C.​​​​

[0042] Further preferably, the phosphate salt crystalline Form I of Compound I has an X-ray powder diffraction pattern substantially as shown in Figure 11

[0043] In some embodiments of the present application, the phosphate salt crystalline Form I of Compound I has a differential scanning calorimetry curve having an endothermic peak at 221 °C ± 10 °C. Figure 12

[0044] Another object of the present application also includes providing a phosphate salt crystalline Form II of Compound I, characterized by an X-ray powder diffraction, expressed in terms of 2 theta angles, having characteristic peaks at 4.8 ± 0.2°, 16.3 ± 0.2°, 16.8 ± 0.2°, 22.3 ± 0.2°, using Cu-Ka radiation.

[0045] Preferably, the phosphate salt crystalline Form II of Compound I further has one or more characteristic peaks, expressed in terms of 2 theta angles, at 19.6 ± 0.2°, 21.0 ± 0.2°, 23.6 ± 0.2°, using Cu-Ka radiation.

[0046] More preferably, the phosphate salt crystalline Form II of Compound I has an X-ray powder diffraction pattern substantially as shown in Figure 13

[0047] In some embodiments of the present application, the phosphate salt crystalline Form II of Compound I has a differential scanning calorimetry curve having an endothermic peak at 221 °C ± 10 °C.

[0048] Preferably, the phosphate salt crystalline Form II of Compound I has a differential scanning calorimetry curve having an endothermic peak at 221 ± 5 °C.

[0049] Further preferably, the phosphate salt crystalline Form II of Compound I has a differential scanning calorimetry curve substantially as shown in Figure 14

[0050] In some embodiments of the present application, the phosphate salt crystalline Form II of Compound I has a differential scanning calorimetry curve substantially as shown in Figure 15

[0051] In some embodiments of the present application, the phosphate salt crystalline 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 application also includes providing a propionic acid salt crystalline Form I of Compound I, characterized by an X-ray powder diffraction, expressed in terms of 2 theta angles, having characteristic peaks at 7.4 ± 0.2°, 10.3 ± 0.2°, 17.0 ± 0.2°, 19.8 ± 0.2°, using Cu-Ka radiation.

[0053] ​​​​​Preferably, the propionate crystal form I of compound I 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° in X-ray powder diffraction at a 2θ angle.

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

[0055] More preferably, the propionate crystal form I of compound I has substantially the following characteristics: Figure 16 The X-ray powder diffraction pattern shown is shown.

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

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

[0058] More preferably, the propionate crystal form I of compound I has essentially the following properties: Figure 17 The DSC spectrum shown.

[0059] In some embodiments of the present invention, the propionate crystal form I of compound I has essentially the following characteristics: Figure 18 The TGA spectrum shown.

[0060] Another object of the present invention also includes providing a succinate crystal form I of compound I, characterized in that, using Cu-Kα radiation, X-ray powder diffraction 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 succinate crystal form I of compound I 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° in X-ray powder diffraction at a 2θ angle.

[0062] Further preferably, the succinate crystal form I of compound I 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° in X-ray powder diffraction at a 2θ angle.

[0063] More preferably, the succinate crystal form I of compound I has substantially the following properties: Figure 19 The X-ray powder diffraction pattern shown is shown.

[0064] In some embodiments of the present application, the succinate salt Form I of Compound I has a differential scanning calorimetry curve with an endothermic peak at 168°C ± 10°C.

[0065] Preferably, the succinate salt Form I of Compound I has a differential scanning calorimetry curve with an endothermic peak at 168°C ± 5°C.

[0066] Further preferably, the succinate salt Form I of Compound I has a DSC spectrum substantially as shown in Figure 20 Further preferably, the succinate salt Form I of Compound I has a DSC spectrum substantially as shown in

[0067] In some embodiments of the present application, the succinate salt Form I of Compound I has a TGA spectrum substantially as shown in Figure 21 Further preferably, the succinate salt Form I of Compound I has a TGA spectrum substantially as shown in

[0068] Another object of the present application also includes a sulfate salt of Compound I represented by the following formula (III), wherein the salt-forming ratio of Compound I to sulfuric acid is 1:1.

[0069] Another object of the present application also includes a sulfate salt Form I of Compound I, characterized in that it has characteristic peaks in X-ray powder diffraction expressed in terms of 2θ angle at 17.9 ± 0.2°, 19.0 ± 0.2°, 19.5 ± 0.2°, 27.2 ± 0.2° using Cu-Kα radiation.

[0070] Preferably, the sulfate salt Form I of Compound I has one or more characteristic peaks in X-ray powder diffraction expressed in terms of 2θ angle at 11.0 ± 0.2°, 12.8 ± 0.2°, 21.1 ± 0.2°, 26.1 ± 0.2°.

[0071] Further preferably, the sulfate salt Form I of Compound I has one or more characteristic peaks in X-ray powder diffraction expressed in terms of 2θ angle at 11.9 ± 0.2°, 23.0 ± 0.2°, 24.0 ± 0.2°.

[0072] Still further preferably, the sulfate salt Form I of Compound I has a X-ray powder diffraction spectrum substantially as shown in Figure 22 Still further preferably, the sulfate salt Form I of Compound I has a X-ray powder diffraction spectrum substantially as shown in

[0073] In some embodiments of the present application, the sulfate salt Form I of Compound I has a differential scanning calorimetry curve with an endothermic peak at about 259 ± 10°C.

[0074] Preferably, the sulfate salt Form I of Compound I has a differential scanning calorimetry curve with an endothermic peak at 259°C ± 5°C.

[0075] Further preferably, the sulfate salt crystalline Form I of Compound I has a DSC pattern substantially as shown in FIG. 4. Figure 23

[0076] In some embodiments of the present application, the sulfate salt crystalline Form I of Compound I has a TGA pattern substantially as shown in FIG. 5. Figure 24

[0077] In some embodiments of the present application, the sulfate salt 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 application also includes providing a tartrate salt crystalline Form I of Compound I, characterized in that it has X-ray powder diffraction peaks at 4.2±0.2°, 17.0±0.2°, 19.2±0.2°, 20.1±0.2°, using Cu-Ka radiation, expressed in terms of 2θ angles.

[0079] Preferably, the tartrate salt crystalline Form I of Compound I further has one or more X-ray powder diffraction peaks at 12.8±0.2°, 15.1±0.2°, 22.1±0.2°, expressed in terms of 2θ angles.

[0080] Further preferably, the tartrate salt crystalline Form I of Compound I further has one or more X-ray powder diffraction peaks at 8.2±0.2°, 14.4±0.2°, 16.3±0.2°, 22.9±0.2°, 25.1±0.2°, expressed in terms of 2θ angles.

[0081] Still further preferably, the tartrate salt crystalline Form I of Compound I has an X-ray powder diffraction pattern substantially as shown in FIG. 6. Figure 25

[0082] In some embodiments of the present application, the tartrate salt crystalline Form I of Compound I has a differential scanning calorimetry curve having an endothermic peak at 132℃±10℃.

[0083] Preferably, the tartrate salt crystalline Form I of Compound I has a differential scanning calorimetry curve having an endothermic peak at 132℃±5℃.

[0084] Further preferably, the tartrate salt crystalline Form I of Compound I has a DSC pattern substantially as shown in FIG. 7. Figure 26

[0085] In some embodiments of the present application, the tartrate salt crystalline Form I of Compound I has a TGA pattern substantially as shown in FIG. 8. Figure 27

[0086] ​​​​​Another object of the present application also includes providing a pamoate salt Form I of Compound I, characterized by an X-ray powder diffraction pattern, expressed in angles 2θ, using Cu-Kα radiation, having characteristic peaks at 7.3 ± 0.2°, 9.0 ± 0.2°, 11.8 ± 0.2°, 24.1 ± 0.2°.

[0087] Preferably, the pamoate salt Form I of Compound I further has one or more characteristic peaks in the X-ray powder diffraction pattern, expressed in angles 2θ, at 13.2 ± 0.2°, 19.2 ± 0.2°, 21.0 ± 0.2°, 22.5 ± 0.2°.

[0088] Further preferably, the pamoate salt Form I of Compound I further has one or more characteristic peaks in the X-ray powder diffraction pattern, expressed in angles 2θ, at 9.6 ± 0.2°, 14.5 ± 0.2°, 16.3 ± 0.2°, 26.9 ± 0.2°.

[0089] Still further preferably, the pamoate salt Form I of Compound I has an X-ray powder diffraction pattern substantially as shown in Figure 2. Figure 28

[0090] In some embodiments of the present application, the pamoate salt Form I of Compound I has a differential scanning calorimetry curve with an endothermic peak at 249 °C ± 10 °C.

[0091] Preferably, the pamoate salt Form I of Compound I has a differential scanning calorimetry curve with an endothermic peak at 249 °C ± 5 °C.

[0092] Further preferably, the pamoate salt Form I of Compound I has a DSC pattern substantially as shown in Figure 3. Figure 29

[0093] In some embodiments of the present application, the pamoate salt Form I of Compound I has a TGA pattern substantially as shown in Figure 4. Figure 30

[0094] Another object of the present application also includes providing a pamoate salt Form II of Compound I, characterized by an X-ray powder diffraction pattern, expressed in angles 2θ, using Cu-Kα radiation, having characteristic peaks at 6.2 ± 0.2°, 14.0 ± 0.2°, 15.2 ± 0.2°, 16.1 ± 0.2°.

[0095] Preferably, the pamoate salt Form II of Compound I further has one or more characteristic peaks in the X-ray powder diffraction pattern, expressed in angles 2θ, at 7.6 ± 0.2°, 9.0 ± 0.2°, 12.1 ± 0.2°, 26.2 ± 0.2°.

[0096] ​​​Further preferably, the pamoate salt Form II of Compound I has an X-ray powder diffraction pattern substantially as shown in

[0097] More preferably, the pamoate salt Form II of Compound I has an X-ray powder diffraction pattern substantially as shown in Figure 31

[0098] In some embodiments of the present application, the pamoate salt Form II of Compound I has a differential scanning calorimetry curve with an endothermic peak at 173°C ± 10°C.

[0099] Preferably, the pamoate salt Form II of Compound I has a differential scanning calorimetry curve with an endothermic peak at 173°C ± 5°C.

[0100] Further preferably, the pamoate salt Form II of Compound I has a DSC pattern substantially as shown in Figure 32

[0101] In some embodiments of the present application, the pamoate salt Form II of Compound I has a TGA pattern substantially as shown in Figure 33

[0102] Another object of the present application also includes providing a pamoate salt Form III of Compound I, which is characterized by having characteristic peaks in X-ray powder diffraction expressed in angles 2θ using Cu-Kα radiation at 9.5 ± 0.2°, 15.7 ± 0.2°, 26.3 ± 0.2°, 29.9 ± 0.2°.

[0103] Preferably, the pamoate salt Form III of Compound I has one or more characteristic peaks in X-ray powder diffraction expressed in angles 2θ at 11.1 ± 0.2°, 19.4 ± 0.2°, 23.2 ± 0.2°, 25.1 ± 0.2°.

[0104] More preferably, the pamoate salt Form III of Compound I has an X-ray powder diffraction pattern substantially as shown in Figure 34

[0105] In some embodiments of the present application, the pamoate salt Form III of Compound I has a differential scanning calorimetry curve with an endothermic peak at 249°C ± 10°C.

[0106] Preferably, the pamoate salt Form III of Compound I has a differential scanning calorimetry curve with an endothermic peak at 249°C ± 5°C.

[0107] Further preferably, the pamoate salt Form III of Compound I has a DSC pattern substantially as shown in​​​​Figure 35 the DSC pattern shown.

[0108] In some embodiments of the present application, the pamoate salt Form III of Compound I has a differential scanning calorimetry curve having an endothermic peak at 180 °C ± 10 °C. Figure 36 the TGA pattern shown.

[0109] In another aspect, the present application provides a pharmaceutical composition comprising the benzenesulfonate salt, citrate salt, malate salt, phosphate salt, propionate salt, succinate salt, sulfate salt, tartrate salt, p-toluenesulfonate salt, pamoate salt, acetate salt, hydrochloride salt, lactobionate salt, mesylate salt of Compound I.

[0110] Preferably, the acetate salt Form I of Compound I has one or more characteristic peaks at 9.0 ± 0.2°, 10.4 ± 0.2°, 13.3 ± 0.2° in X-ray powder diffraction expressed in terms of 2θ angle.

[0111] Further preferably, the acetate salt Form I of Compound I has a differential scanning calorimetry curve having an endothermic peak at 180 °C ± 10 °C. Figure 37 the X-ray powder diffraction pattern shown.

[0112] In some embodiments of the present application, the acetate salt Form I of Compound I has a differential scanning calorimetry curve having an endothermic peak at 180 °C ± 10 °C.

[0113] Preferably, the acetate salt Form I of Compound I has a differential scanning calorimetry curve having an endothermic peak at 180 °C ± 5 °C.

[0114] Further preferably, the acetate salt Form I of Compound I has a differential scanning calorimetry curve having an endothermic peak at 180 °C ± 10 °C. Figure 38 the DSC pattern shown.

[0115] In some embodiments of the present application, the acetate salt Form I of Compound I has a differential scanning calorimetry curve having an endothermic peak at 180 °C ± 10 °C. Figure 39 the TGA pattern shown.

[0116] In another aspect, the present application provides a pharmaceutical composition comprising the benzenesulfonate salt, citrate salt, malate salt, phosphate salt, propionate salt, succinate salt, sulfate salt, tartrate salt, p-toluenesulfonate salt, pamoate salt, acetate salt, hydrochloride salt, lactobionate salt, mesylate salt of Compound I.

[0117] In another aspect, the present application provides a pharmaceutical composition comprising the benzenesulfonate salt, citrate salt, malate salt, phosphate salt, propionate salt, succinate salt, sulfate salt, tartrate salt, p-toluenesulfonate salt, pamoate salt, acetate salt, hydrochloride salt, lactobionate salt, mesylate salt of Compound I.

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

[0119] The present application also provides the use of Form I of Compound I, Form I of a benzenesulfonate salt, Form I of a malate salt, Form I of a phosphate salt, Form II of a phosphate salt, Form I of a propionate salt, Form I of a succinate salt, Form I of a sulfate salt, Form I of a tartrate salt, Form I of a pamoate salt, Form I of a pamoate salt, Form II of a pamoate salt, Form III of a pamoate salt, Form I of an acetate salt, or a pharmaceutical composition as described herein in the manufacture of a medicament for treating a disease mediated by SOS1. Preferably, the disease mediated by SOS1 is a cancer or a tumor-related disease.

[0120] Further, the present application also provides the use of Form I of Compound I, Form I of a benzenesulfonate salt, Form I of a malate salt, Form I of a phosphate salt, Form II of a phosphate salt, Form I of a propionate salt, Form I of a succinate salt, Form I of a sulfate salt, Form I of a tartrate salt, Form I of a pamoate salt, Form I of a pamoate salt, Form II of a pamoate salt, Form III of a pamoate salt, Form I of an acetate salt, or a pharmaceutical composition as described herein in the manufacture of a medicament for treating a cancer or a tumor-related disease; preferably, the cancer or the tumor-related disease is a solid tumor; more preferably, the cancer or the tumor-related disease is lung cancer; more preferably, the cancer or the tumor-related disease is non-small cell lung cancer.

[0121] Further, the present application also provides the use of Form I of Compound I, Form I of a benzenesulfonate salt, Form I of a malate salt, Form I of a phosphate salt, Form II of a phosphate salt, Form I of a propionate salt, Form I of a succinate salt, Form I of a sulfate salt, Form I of a tartrate salt, Form I of a pamoate salt, Form I of a pamoate salt, Form II of a pamoate salt, Form III of a pamoate salt, Form I of an acetate salt, or a pharmaceutical composition as described herein in the manufacture of a medicament for treating a cancer or a tumor-related disease; preferably, the cancer or the tumor-related disease is a solid tumor; more preferably, the cancer or the tumor-related disease is lung cancer; more preferably, the cancer or the tumor-related disease is non-small cell lung cancer.

[0122] For treating cancer or tumor-related diseases, the benzenesulfonate salt, citrate salt, malate salt, phosphate salt, propionate salt, succinate salt, sulfate salt, tartrate salt, p-toluenesulfonate salt, pamoate salt, acetate salt, hydrochloride salt, lactobionate salt, methanesulfonate salt of Compound I, crystalline Form I of Compound I, benzenesulfonate salt Form I, malate salt Form I, phosphate salt Form I, phosphate salt Form II, propionate salt Form I, succinate salt Form I, sulfate salt Form I, tartrate salt Form I, pamoate salt Form I, pamoate salt Form II, pamoate salt Form III, acetate salt Form I can be co-administered with other therapeutic agents (e.g., chemotherapeutic drugs, biologic therapy drugs, etc.) or combined with other therapeutic means, including but not limited to radiotherapy.

[0123] For the sake of providing a more concise description, some quantitative data herein are not presented using the term "about". It should be understood that, whether the term "about" is expressly used or not, every numerical value given herein is only intended to include actual values given and it also means to include approximate values based on reasonable inferences of a person of ordinary skill in the art, including equivalents and approximations of such given values due to experimental and / or measurement conditions. The approximate values are preferably ±20%, ±15%, ±10%, ±8%, ±6%, ±5%, ±4%, ±3%, 2%, ±1% on the basis of the given values. In some embodiments, the given values are obtained by a person of ordinary skill in the art through conventional approximation methods (e.g., rounding method) on the basis of experimental and / or measured values.

[0124] Beneficial effects

[0125] The present application provides, for the first time, the free base crystalline form of Compound I and various salt forms. Some of the salt forms provided by the present application have good clinical application value and can be used as excellent candidates for subsequent drug development. BRIEF DESCRIPTION OF DRAWINGS

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

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

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

[0129] Figure 4 XRPD spectrum of Compound I benzenesulfonate salt Form I.

[0130] Figure 5 DSC spectrum of Compound I benzenesulfonate salt Form I.

[0131] Figure 6 TGA pattern for Compound I benzenesulfonate salt Form I.

[0132] Figure 7 XRPD pattern for Compound I malate salt Form I.

[0133] Figure 8 DSC pattern for Compound I malate salt Form I.

[0134] Figure 9 TGA pattern for Compound I malate salt Form I.

[0135] Figure 10 XRPD pattern for Compound I phosphate salt Form I.

[0136] Figure 11 DSC pattern for Compound I phosphate salt Form I.

[0137] Figure 12 TGA pattern for Compound I phosphate salt Form I.

[0138] Figure 13 XRPD pattern for Compound I phosphate salt Form II.

[0139] Figure 14 DSC pattern for Compound I phosphate salt Form II.

[0140] Figure 15 TGA pattern for Compound I phosphate salt Form II.

[0141] Figure 16 XRPD pattern for Compound I propionate salt Form I.

[0142] Figure 17 DSC pattern for Compound I propionate salt Form I.

[0143] Figure 18 TGA pattern for Compound I propionate salt Form I.

[0144] Figure 19 XRPD pattern for Compound I succinate salt Form I.

[0145] Figure 20 DSC pattern for Compound I succinate salt Form I.

[0146] Figure 21 TGA pattern for Compound I succinate salt Form I.

[0147] Figure 22 XRPD pattern for Compound I sulfate salt Form I.

[0148] Figure 23DSC pattern for Compound I sulfate salt Form I.

[0149] Figure 24 TGA pattern for Compound I sulfate salt Form I.

[0150] Figure 25 XRPD pattern for Compound I tartrate salt Form I.

[0151] Figure 26 DSC pattern for Compound I tartrate salt Form I.

[0152] Figure 27 TGA pattern for Compound I tartrate salt Form I.

[0153] Figure 28 XRPD pattern for Compound I pamoate salt Form I.

[0154] Figure 29 DSC pattern for Compound I pamoate salt Form I.

[0155] Figure 30 TGA pattern for Compound I pamoate salt Form I.

[0156] Figure 31 XRPD pattern for Compound I pamoate salt Form II.

[0157] Figure 32 DSC pattern for Compound I pamoate salt Form II.

[0158] Figure 33 TGA pattern for Compound I pamoate salt Form II.

[0159] Figure 34 XRPD pattern for Compound I pamoate salt Form III.

[0160] Figure 35 DSC pattern for Compound I pamoate salt Form III.

[0161] Figure 36 TGA pattern for Compound I pamoate salt Form III.

[0162] Figure 37 XRPD pattern for Compound I acetate salt Form I.

[0163] Figure 38 DSC pattern for Compound I acetate salt Form I.

[0164] Figure 39 TGA pattern for Compound I acetate salt Form I. DETAILED DESCRIPTION

[0165] The technical solutions of the present application will be further described in detail below in combination with specific embodiments. The following examples are only illustrative and explanatory of the present application, and should not be interpreted as limiting the scope of protection of the present application. Any technology realized based on the above description of the present application is covered within the scope of protection intended by the present application.

[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] The example 1 of the present application is determined by nuclear magnetic resonance (NMR) or / and liquid chromatography-mass spectrometry (LC-MS) or / and high performance 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 form 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] Dissolve 4,6-dichloro-2-methylpyrimidine-5-carboxaldehyde (2.00 g, 10.47 mmol) in tetrahydrofuran (20 mL), then add ethoxycarbonylmethylidene triphenylphosphonium (5.47 g, 15.71 mmol), triethylamine (2.12 g, 20.94 mmol), and the system is reacted at 80℃ for 6h, and LC-MS is used to monitor that there is no remaining raw material. The reaction system is directly column chromatography separation and purification (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] Dissolve 5-1 (1.71 g, 6.54 mmol) in N,N-dimethylformamide (20 mL), then add tert-butyl (2-aminoethyl)carbamate (1.26 g, 7.85 mmol), triethylamine (1.32 g, 13.08 mmol), the system is reacted at room temperature for 12 h, LC-MS monitoring until the raw material is not left, add water (30 mL) to the reaction solution, extract with ethyl acetate (30 mL x 3), combine the organic phase, wash with saturated sodium chloride (30 mL x 2), dry over anhydrous sodium sulfate. Remove the solvent under reduced pressure, purify the residue 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] Dissolve 5-2 (2.30 g, 5.99 mmol) in methanol (30 mL), then add sodium methoxide (3.6 mL, 17.97 mmol, 30% w / w in methanol), the system is reacted at room temperature for 12 h, the reaction solution precipitates solid, LC-MS monitoring until the raw material is not left, add water (10 mL) to the reaction solution, filter to obtain 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] Dissolve 5-3 (1.60 g, 4.79 mmol) in dichloromethane (30 mL), then add bromine (1.15 g, 7.19 mmol), the system is reacted at room temperature for 12 h, LC-MS monitoring until the raw material is not left. The reaction system is directly column chromatography separation and purification (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] Dissolve 5-4 (1.80 g, 4.36 mmol) in dichloromethane (20 mL), then add trifluoroacetic acid 5 mL, the system is reacted at room temperature for 4 h, LC-MS monitoring until the raw material is not left. The solvent is evaporated under reduced pressure, the residue is added to 15 mL of water, the pH is adjusted to 8-9 with saturated aqueous sodium carbonate solution, and extracted with ethyl acetate (20 mL x 3), the combined organic phase is washed with saturated sodium chloride (20 mL x 2), and dried over anhydrous sodium sulfate. The solvent is 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] Dissolve 5-5 (0.90 g, 2.88 mmol) in toluene (20 mL), then slowly add trimethylaluminum (1.9 mL, 3.75 mmol, 2.0 M in toluene), the system is reacted at 120°C for 5 h, LC-MS monitoring until the raw material is not left. The reaction solution is quenched with saturated aqueous ammonium chloride solution, the toluene is evaporated under reduced pressure, the residue is added to 15 mL of water, extracted with ethyl acetate (20 mL x 3), the combined organic phase is washed with saturated sodium chloride (20 mL x 2), and dried over anhydrous sodium sulfate. The solvent is 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] Dissolve 5-6 (0.59 g, 2.01 mmol) in dichloromethane (10 mL), slowly add boron tribromide (2.52 g, 10.05 mmol) under ice bath, remove the ice bath after addition, the system is reacted at room temperature for 72 h, LC-MS monitoring until the raw material is not left. Slowly add sodium carbonate solution under ice bath to quench the reaction, precipitate solid, filter to obtain 5-7 (0.46 g, 1.64 mmol, yield 82%). ESI-MS: m / z 280.82 / 282.84 [M+H]+.

[0188]

[0189] Synthesis of intermediate 7-1

[0190] Dissolve 5-7 (100 mg, 0.36 mmol) in N,N-dimethylformamide (15 mL), then add (R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethanamine hydrochloride (121 mg, 0.54 mmol), benzotriazol-1- oxytris(dimethylamino)phosphonium hexafluorophosphate (205 mg, 0.47 mmol), 1,8- diazabicycloundec-7-ene (163 mg, 1.08 mmol), and allow the system to react at room temperature for 8 h. Monitor the reaction by LC-MS until the starting material is consumed. Add water (30 mL) to the reaction mixture, extract with ethyl acetate (30 mL x 3), combine the organic phases, wash with saturated sodium chloride (30 mL x 2), and dry over anhydrous sodium sulfate. Remove the solvent under reduced pressure, and purify the residue 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] Dissolve intermediate 7-1 (99 mg, 0.22 mmol) in dioxane (30 mL), then add 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), and allow the entire system to stir and react at 100°C for 3 h. Monitor the reaction by TLC until the starting material is consumed. Add 50 mL of water to the reaction mixture, extract with ethyl acetate (30 mL x 3), combine the organic phases, wash with saturated sodium chloride (50 mL x 2), dry over anhydrous sodium sulfate, remove the solvent under reduced pressure, and purify the residue by column chromatography (dichloromethane:methanol = 60:1-15:1) to obtain compound I (69 mg, 0.14 mmol, yield 64%). ESI-MS: m / z 497.24 [M+H] + . 1H NMR (600 MHz, DMSO-d6): δ 8.23 (s, 1H), 8.00 (s, 1H), 7.64 (dd, J = 7.2 Hz, J = 7.2 Hz, 1H), 7.50 (dd, J = 7.2 Hz, J = 7.2 Hz, 1H), 7.32-7.29 (m, 1H), 7.23 (t, J = 54.0 Hz, 1H), 6.82 (d, J = 87.6 Hz, 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 = 24.6 Hz, 2H), 1.56 (d, J = 6.6 Hz, 3H).

[0193] Preparation of compound I crystalline form I of example 2

[0194] The compound I was added into 10 ml ethyl acetate, stirred at room temperature, and then left overnight. The solution was filtered, and the obtained solid was dried to obtain the compound I crystalline form I. The XRPD detection result of this crystalline form I is shown in Figure 1 , and the DSC, TGA detection results are shown in Figure 2 , 3 . The XRPD diffraction peak data of this crystalline form I are shown as follows.

[0195] 2 theta angle (°) peak height relative intensity (%) 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] Preparation of compound I benzenesulfonic acid salt crystalline form I of example 3

[0197] About 50 mg of compound I sample was dissolved in 5.0 mL of ethyl acetate at 60°C to obtain solution 1; about 19.5 mg of benzenesulfonic acid was dissolved in 0.1 mL of ethyl acetate to obtain solution 2; solution 2 was added dropwise into solution 1 at room temperature to obtain solution 3; solution 3 was stirred at room temperature for 4 days, and a solid was precipitated to obtain a suspension; the suspension was centrifuged, and the obtained solid was dried at 40°C under vacuum overnight to obtain the benzenesulfonic acid salt crystalline form I. The XRPD detection result of this crystalline form I is shown in Figure 4 , and the DSC, TGA detection results are shown in Figure 5 , 6 . The XRPD diffraction peak data of this crystalline form I are shown as follows.

[0198] 2 theta angle (°) peak height relative intensity (%) 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] Preparation of compound I malate salt crystalline form I of example 4

[0200] Take about 50 mg of Compound I sample, dissolved in 1.0 mL of tetrahydrofuran to obtain solution 1; take about 14.9 mg of L-malic acid, dissolved in 0.1 mL of tetrahydrofuran to obtain solution 2; drop solution 2 into solution 1 at room temperature to obtain solution 3; stir solution 3 at room temperature for 4 days, no precipitation, add 4.0 mL of n-heptane, precipitate as oil, stir at room temperature for 2 days, no precipitation, transfer to room temperature and open to volatilize to obtain L-malate salt crystal form I. The XRPD detection results of this crystal form I are shown in Figure 7 The detected DSC, TGA detection results are shown in Figure 8 , 9 The XRPD diffraction peak data of this crystal form I are shown as follows.

[0201] 2 theta angle (°) peak height relative intensity (%) 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] Preparation of Compound I phosphate salt crystal form I

[0203] Take about 50 mg of Compound I sample, dissolved in 1.0 mL of tetrahydrofuran to obtain solution 1; take about 12.8 mg of phosphoric acid, diluted with 0.1 mL of tetrahydrofuran to obtain solution 2; drop solution 2 into solution 1 at room temperature to obtain a suspension; stir the suspension at room temperature for 4 days; centrifuge the suspension, and the obtained solid is vacuum dried at 40°C overnight to obtain phosphate salt crystal form I. The XRPD detection results of this crystal form I are shown in Figure 10 The detected DSC, TGA detection results are shown in Figure 11 , 12 The XRPD diffraction peak data of this crystal form I are shown as follows.

[0204] 2 theta angle (°) peak height relative intensity (%) 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] Preparation of Compound I phosphate salt crystal form II

[0206] Take about 300 mg of Compound I sample, dissolved in 3.0 mL of tetrahydrofuran to obtain solution 1; take about 76.8 mg of phosphoric acid, diluted with 0.1 mL of tetrahydrofuran to obtain solution 2; drop solution 2 into solution 1 at room temperature to obtain a suspension; add 2.0 mL of tetrahydrofuran and 4.0 mL of methyl tert-butyl ether to the suspension, and stir at room temperature overnight; centrifuge the suspension, and the obtained solid is vacuum dried at 40°C overnight to obtain phosphate salt crystal form II. The XRPD detection results of this crystal form II are shown in Figure 13 The detected DSC, TGA detection results are shown in Figure 14 , 15 The salt formation ratio is 1:1 determined by IC method (ion chromatography). The XRPD diffraction peak data of this crystal form II are shown as follows.

[0207] 2 theta angle (°) peak height relative intensity (%) 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] Preparation of compound I propionate salt Form I

[0209] Take about 50 mg of compound I sample, dissolved in 3.0 mL of methanol to obtain solution 1; take about 8.2 mg of propionic acid, dissolved in 0.1 mL of methanol to obtain solution 2; drop solution 2 into solution 1 at room temperature to obtain solution 3; place solution 3 in 4 ℃ stirring for 5 days, no precipitation, add 10.0 mL of methyl tert-butyl ether, stir at room temperature for 2 days, no precipitation, transfer to room temperature open evaporation to obtain propionate salt Form I. The XRPD detection results of this Form I are shown in Figure 16 , the detected DSC, TGA detection results are shown in Figure 17 , 18 The XRPD diffraction peak data of this Form I are shown as follows.

[0210] 2 theta angle (°) peak height relative intensity (%) 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] Preparation of compound I succinate salt Form I

[0212] Take about 50 mg of compound I sample, dissolved in 1.0 mL of tetrahydrofuran to obtain solution 1; take about 13.1 mg of succinic acid, dissolved in 0.1 mL of tetrahydrofuran to obtain solution 2; drop solution 2 into solution 1 at room temperature to obtain solution 3; place solution 3 in room temperature stirring for 4 days, no precipitation, add 4.0 mL of n-heptane, stir at room temperature for 2 days, precipitate into oil, transfer to room temperature open evaporation to obtain succinate salt Form I. The XRPD detection results of this Form I are shown in Figure 19 , the detected DSC, TGA detection results are shown in Figure 20 , 21 The XRPD diffraction peak data of this Form I are shown as follows.

[0213] 2 theta angle (°) peak height relative intensity (%) 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] Preparation of compound I sulfate salt Form I

[0215] Take about 300 mg of compound I sample, dissolved in 10.0 mL of isopropyl alcohol to obtain solution 1; take about 66.6 mg of sulfuric acid, diluted with 0.1 mL of isopropyl alcohol to obtain solution 2; drop solution 2 into solution 1 at room temperature, precipitate in about 1 h to obtain a suspension; place the suspension in room temperature stirring overnight; centrifuge the suspension, the obtained solid is vacuum dried at 40 ℃ overnight to obtain sulfate salt Form I. The XRPD detection results of this Form I are shown in Figure 22 , the detected DSC, TGA detection results are shown in Figure 23 , 24The salt ratio was determined to be 1 : 1 by IC (ion chromatography). The XRPD diffraction peak data of this Form I are shown below.

[0216] 2 theta angle (°) peak height relative intensity (%) 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] Preparation of Compound I tartrate salt 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 dried at 40 °C under vacuum overnight to obtain L-tartrate salt Form I. The XRPD detection result of this Form I is shown below, and the detected DSC, TGA detection results are shown below. Figure 25 Figure 26 27 The XRPD diffraction peak data of this Form I are shown below.

[0219] 2 theta angle (°) peak height relative intensity (%) 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] 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 dried at 40 °C under vacuum overnight to obtain pamoate salt Form I. The XRPD detection result of this Form I is shown below, and the detected DSC, TGA detection results are shown below. Figure 28 Figure 29 30 The XRPD diffraction peak data of this Form I are shown below.

[0222] 2 theta angle (°) peak height relative intensity (%) 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] Preparation of Compound I pamoate salt Form II

[0224] ​​​​About 50 mg of Compound I sample was dissolved in 5.0 mL of isopropanol to obtain solution 1; about 43.9 mg of pamoic acid was dissolved in 0.6 mL of dimethylsulfoxide to obtain solution 2; solution 2 was added dropwise to solution 1 at room temperature to obtain a suspension; the suspension was stirred at 4 °C for 2 days; the suspension was centrifuged and the obtained solid was dried at 40 °C under vacuum overnight to obtain pamoate salt Form II. The XRPD detection results of this Form II are shown in Figure 31 The detected DSC, TGA detection results are shown in Figure 32 , 33 The XRPD diffraction peak data of this Form II are shown as follows.

[0225] 2 theta angle (°) peak height relative intensity (%) 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] Preparation of Compound I pamoate salt Form III

[0227] About 50 mg of Compound I sample was dissolved in 1.0 mL of isopropanol to obtain solution 1; about 21.9 mg of pamoic acid was added to solution 1 at room temperature to obtain a suspension; the suspension was stirred at room temperature for 2 days; the suspension was centrifuged and the obtained solid was dried at 40 °C under vacuum overnight to obtain pamoate salt Form III. The XRPD detection results of this Form III are shown in Figure 34 The detected DSC, TGA detection results are shown in Figure 35 , 36 The XRPD diffraction peak data of this Form III are shown as follows.

[0228] 2 theta angle (°) peak height relative intensity (%) 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] Preparation of Compound I acetate salt Form 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 dried at 40 °C under vacuum overnight to obtain acetate salt Form I. The XRPD detection results of this Form I are shown in Figure 37 The detected DSC, TGA detection results are shown in Figure 38 , 39 The XRPD diffraction peak data of this Form I are shown as follows.

[0231] 2 theta angle (°) peak height relative intensity (%) 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] Preparation of Compound I p-toluenesulfonate salt

[0233] About 50 mg of Compound I sample was taken and dissolved in 5.0 mL of ethyl acetate at 60 °C to get solution 1. About 19.1 mg of p-toluenesulfonic acid was taken and dissolved in 0.1 mL of ethyl acetate to get solution 2. Solution 1 was added dropwise to solution 2 under stirring. An oil was immediately precipitated and stuck to the wall. The mixture was stirred at room temperature for 4 days. A solid was precipitated and centrifuged. The solid was dried under vacuum at 40 °C overnight to get the p-toluenesulfonic acid salt. The XRPD of this p-toluenesulfonic acid salt was determined to have no diffraction peaks and was amorphous.

[0234] Example 16 Preparation of Compound I lactobionic acid salt

[0235] About 50 mg of Compound I sample was taken and dissolved in 1.0 mL of isopropyl alcohol at 60 °C to get solution 1. About 40.5 mg of lactobionic acid was taken and added to solution 1 under stirring. The mixture was centrifuged. The solid was dried under vacuum at 40 °C overnight to get the 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 citric acid salt

[0237] About 50 mg of Compound I sample was taken and dissolved in 1.0 mL of isopropyl alcohol at 60 °C to get solution 1. About 10.6 mg of citric acid was taken and dissolved in 0.1 mL of isopropyl alcohol to get solution 2. Solution 1 was added dropwise to solution 2 under stirring. The mixture was stirred at room temperature overnight. 4.0 mL of methyl tert-butyl ether was added and the mixture was centrifuged. The solid was dried under vacuum at 40 °C overnight to get the citric acid salt. The XRPD of this citric acid salt was determined to have no diffraction peaks and was amorphous.

[0238] Example 18 Preparation of Compound I hydrochloride salt

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

[0240] Example 19 Preparation of Compound I methanesulfonic acid salt

[0241] About 50 mg of Compound I sample was taken and dissolved in 1.0 mL of acetone at 60 °C to obtain solution 1; about 10.6 mg of methanesulfonic acid was taken and dissolved in 0.1 mL of acetone to obtain solution 2; solution 1 was added dropwise to solution 2 under stirring at 4 °C overnight, no precipitation occurred, 3.0 mL of n-heptane was added, precipitation occurred immediately, stirring at room temperature for about 2 h, centrifugation, the obtained solid was dried at 40 °C under vacuum overnight to obtain the methanesulfonate salt. It was determined that the XRPD of this methanesulfonate salt had no diffraction peaks, which was in amorphous form.

[0242] Test Example 1,

[0243] Bioactivity assay experiment:

[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. The binding of GST-KRas G12D His-tagged hSOS1 (FRET donor) bound to anti-6His-XL665 (FRET acceptor) measures the inhibition of K-Ras G12D with 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-Ras G12D (in-house production);

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

[0250] Ras mix preparation

[0251] GST-hK-Ras G12D 10 nM (final concentration) and anti-GSK-Europium 2 nM (final concentration) were mixed in assay buffer and left at room temperature until use.

[0252] SOS mix preparation

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

[0254] Dissolve the test compound in DMSO at 100 times the concentration of the experimental concentration. Take 50 nL into black microtiter plate by using Hummingbird liquid handler or Echo acoustic system.

[0255] 1.2 Experimental procedure

[0256] All experimental procedures were performed at 20 °C. In the experiment, 2.5 μL of Ras mix was added to all wells of the assay plate by Multidrop dispenser. After pre-incubation for 2 min, 2.5 μL of SOS mix was added to the test wells except the edge wells, and 2.5 μL of compound control solution was added to the edge wells. After incubation for 60 min, the HTRF module of Pheraster (excitation: 337 nm, emission 1: 620 nm, emission 2: 665 nm) was used.

[0257] 1.3 Data calculation

[0258] IC50values were calculated and analyzed using a 4-parameter logistic model. 50

[0259] 1.4 SOS1 inhibitory activity results

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

[0261] compound Active IC 50 (nM) I B

[0262] wherein B represents 10 nM < IC 50 < 50 nM.

[0263] 2.3 3D cell proliferation inhibition assay

[0264] The 3D cell proliferation inhibition assay was used to detect the inhibition of the proliferation and growth of SOS1 -mediated tumor cell lines at the 3D cell level in vitro by compounds. CellTiter-Glo® 3D Cell Viability Assay was used. 3D detection method.

[0265] 2.1 Reagents and materials

[0266] NCI-H358: KRAS G12C mutant non-small cell lung cancer (NSCLC);

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

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

[0269] FBS, Gibco, 10099141C;

[0270] 2.2 Test procedure:

[0271] 2.2.1 Cell culture

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

[0273] Day 3, remove medium, rinse once with DPBS, use 2 mL TrypLE Express at room temperature or 37°C to detach cells; TM Express Enzyme to detach cells; add 5 mL fresh medium, centrifuge at 1000 rpm for 5 min; discard supernatant, resuspend cells with 5 mL fresh medium, after cell counting, inoculate 40 μL / well into 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 test compound in DMSO, prepare 10 mM stock solution; after dilution with DMSO solution by 1000 times, carry out 3-fold gradient dilution in turn, 10 concentration gradients, initial concentration is 10 μM; add 200 nL compound into culture plate;

[0276] Day 8, add 40 μL / well 3D CTG reagent, use Envision to detect signal value.

[0277] 2.3 Data analysis

[0278] Use Graphpad Prism 8 nonlinear regression equation to fit compound IC 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 inhibition activity results

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

[0284] compound Active IC 50 (nM) I A

[0285] wherein A represents IC 50 < 50 nM.

[0286] The above describes the embodiments of the present application. However, the present application is not limited to the above-described embodiments. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present application should be included in the scope of protection of the present application.

Claims

1. A crystalline Form I of Compound I of the following formula: ###00001### Compound I Form I characterized by, X-ray powder diffraction, expressed in terms of 2θ angles, using Cu-Kα radiation, has characteristic peaks at 5.4 ± 0.2°, 8.0 ± 0.2°, 16.1 ± 0.2°, 21.5 ± 0.2°; the structure of said compound I is as follows:

2. The crystalline Form I of the compound I according to claim 1, characterized in that, The crystalline Form I of said compound I also has one or more characteristic peaks in X-ray powder diffraction, expressed in terms of 2θ angles, at 8.9 ± 0.2°, 11.4 ± 0.2°, 16.6 ± 0.2°, 20.3 ± 0.2°.

3. The crystalline Form I of the compound I according to claim 1 or 2, characterized in that, The crystalline Form I of said compound I also has one or two characteristic peaks in X-ray powder diffraction, expressed in terms of 2θ angles, at 9.9 ± 0.2°, 10.7 ± 0.2°.

4. The crystalline Form I of the compound I according to claim 1 or 2, characterized in that, The crystalline Form I of said compound I has an X-ray powder diffraction pattern substantially as shown in Figure 1.

5. The crystalline Form I of the compound I according to claim 1 or 2, characterized in that, The crystalline Form I of said compound I has a differential scanning calorimetry curve with an endothermic peak at 179 °C ± 10 °C.

6. The crystalline Form I of the compound I according to claim 5, characterized in that, The crystalline Form I of said compound I has a differential scanning calorimetry curve with an endothermic peak at 179 °C ± 5 °C.

7. The crystalline Form I of Compound I according to Claim 1 or 2, characterized in that, The crystalline Form I of said compound I has a DSC pattern substantially as shown in Figure 2.

8. The crystalline Form I of Compound I according to claim 1 or 2, characterized in that, The crystalline Form I of said compound I has a TGA pattern substantially as shown in Figure 3.

9. A salt of Compound I, characterized by, The structure of said compound I is as follows: The salt is a benzenesulfonate salt, a citrate salt, a malate salt, a phosphate salt, a propionate salt, a succinate salt, a sulfate salt, a tartrate salt, a p-toluenesulfonate salt, a pamoate salt, an acetate salt, a hydrochloride salt, a lactobionate salt, a mesylate salt of compound I.

10. A salt of compound I according to claim 9, characterized in that, The salt is a benzenesulfonate salt Form I, which has characteristic peaks in X-ray powder diffraction, expressed in terms of 2θ angles, using Cu-Kα radiation, at 10.5 ± 0.2°, 11.5 ± 0.2°, 19.5 ± 0.2°, 22.3 ± 0.2°.

11. The salt of compound I according to claim 10, wherein The benzenesulfonate salt Form I of said compound I also has one or more characteristic peaks in X-ray powder diffraction, expressed in terms of 2θ angles, at 13.1 ± 0.2°, 14.5 ± 0.2°, 17.7 ± 0.2°, 23.9 ± 0.2°.

12. The salt of compound I according to claim 10 or 11, characterized in that, The benzenesulfonate salt Form I of said compound I also has one or more characteristic peaks in X-ray powder diffraction, expressed in terms of 2θ angles, at 8.3 ± 0.2°, 16.1 ± 0.2°, 26.3 ± 0.2°.

13. The salt of compound I according to claim 10 or 11, characterized in that, The benzenesulfonate salt Form I of said compound I has an X-ray powder diffraction pattern substantially as shown in Figure 4.

14. The salt of compound I according to claim 10 or 11, characterized in that, The salt is a benzenesulfonate salt Form I, which has a differential scanning calorimetry curve with an endothermic peak at 228 °C ± 10 °C.

15. The salt of compound I according to claim 14, wherein, The benzenesulfonate salt Form I of said compound I has a differential scanning calorimetry curve with an endothermic peak at 228 °C ± 5 °C.

16. The salt of compound I according to claim 10 or 11, characterized in that, The benzenesulfonate salt Form I of said compound I has a DSC pattern substantially as shown in Figure 5.

17. The salt of compound I according to claim 10 or 11, wherein The benzenesulfonate salt Form I of said compound I has a TGA pattern substantially as shown in Figure 6.

18. A salt of Compound I according to claim 9, wherein, The salt is a malate salt Form I, which has characteristic peaks in X-ray powder diffraction, expressed in terms of 2θ angles, using Cu-Kα radiation, at 5.8 ± 0.2°, 20.2 ± 0.2°, 23.6 ± 0.2°, 24.5 ± 0.2°.

19. The salt of compound I according to claim 18, wherein, The malate salt Form I of the compound I has an X-ray powder diffraction pattern substantially as shown in Figure 7.

20. The salt of compound I according to claim 18 or 19, characterized in that, The malate salt Form I of the compound I has an X-ray powder diffraction pattern substantially as shown in Figure 7.

21. The salt of compound I according to claim 18 or 19, characterized in that, The malate salt Form I of the compound I has an X-ray powder diffraction pattern substantially as shown in Figure 7.

22. The salt of compound I according to claim 18 or 19, wherein The salt is malate salt Form I having a differential scanning calorimetry curve with an endothermic peak at 177°C ± 10°C.

23. The salt of compound I according to claim 22, wherein, The malate salt Form I of the compound I has a differential scanning calorimetry curve with an endothermic peak at 177°C ± 5°C.

24. The salt of compound I according to claim 18 or 19, wherein The malate salt Form I of the compound I has an X-ray powder diffraction pattern substantially as shown in Figure 7.

25. The salt of compound I according to claim 18 or 19, wherein The malate salt Form I of the compound I has an X-ray powder diffraction pattern substantially as shown in Figure 7.

26. A salt of Compound I according to claim 9, wherein, said salt is a phosphate salt of compound I according to formula (II), wherein the salt formation ratio of compound I to phosphoric acid is 1 :

1.

27. A salt of Compound I according to claim 9, wherein, The salt is phosphate salt Form I having an X-ray powder diffraction, expressed in terms of 2-theta angles, with characteristic peaks at 4.8 ± 0.2°, 11.6 ± 0.2°, 16.3 ± 0.2°, 23.7 ± 0.2° using Cu-Ka radiation.

28. The salt of compound I according to claim 27, wherein, The phosphate salt Form I of the compound I has an X-ray powder diffraction, expressed in terms of 2-theta angles, with one or more characteristic peaks at 9.4 ± 0.2°, 14.9 ± 0.2°, 17.3 ± 0.2°.

29. The salt of compound I according to claim 27 or 28, wherein The phosphate salt Form I of the compound I has an X-ray powder diffraction pattern substantially as shown in Figure 10.

30. The salt of compound I according to claim 27 or 28, wherein The phosphate salt Form I of the compound I has a differential scanning calorimetry curve with an endothermic peak at 228°C ± 10°C.

31. The salt of compound I according to claim 30, wherein The phosphate salt Form I of the compound I has a differential scanning calorimetry curve with an endothermic peak at 228°C ± 5°C.

32. The salt of compound I according to claim 27 or 28, wherein The phosphate salt Form I of the compound I has an X-ray powder diffraction pattern substantially as shown in Figure 11.

33. The salt of compound I according to claim 27 or 28, wherein The phosphate salt Form I of the compound I has an X-ray powder diffraction pattern substantially as shown in Figure 11.

34. A salt of Compound I according to claim 9, wherein, The salt is phosphate salt Form II having an X-ray powder diffraction, expressed in terms of 2-theta angles, with characteristic peaks at 4.8 ± 0.2°, 16.3 ± 0.2°, 16.8 ± 0.2°, 22.3 ± 0.2° using Cu-Ka radiation.

35. The salt of compound I according to claim 34, wherein, The phosphate salt Form II of the compound I has an X-ray powder diffraction, expressed in terms of 2-theta angles, with one or more characteristic peaks at 19.6 ± 0.2°, 21.0 ± 0.2°, 23.6 ± 0.2°.

36. The salt of compound I according to claim 34 or 35, wherein The phosphate salt Form II of the compound I has an X-ray powder diffraction pattern substantially as shown in Figure 13.

37. The salt of compound I according to claim 34 or 35, wherein The phosphate salt Form II of the compound I has a differential scanning calorimetry curve with an endothermic peak at 221°C ± 10°C.

38. The salt of compound I according to claim 37, wherein The phosphate salt Form II of the compound I has a differential scanning calorimetry curve with an endothermic peak at 221 ± 5°C.

39. The salt of compound I according to claim 34 or 35, wherein The phosphate salt Form II of the compound I has an X-ray powder diffraction pattern substantially as shown in Figure 14.

40. The salt of compound I according to claim 34 or 35, wherein The phosphate salt Form II of the compound I has an X-ray powder diffraction pattern substantially as shown in Figure 15.

41. The salt of compound I according to claim 34 or 35, wherein The salt is a phosphate salt Form II, wherein the salt formation ratio of Compound I to phosphoric acid is 1:

1.

42. A salt of Compound I according to claim 9, wherein, The salt is a propionate salt Form I, which has characteristic peaks in X-ray powder diffraction expressed in angles of 2-theta using Cu-Kalpha radiation at 7.4±0.2°, 10.3±0.2°, 17.0±0.2°, 19.8±0.2°.

43. The salt of compound I according to claim 42, wherein, The propionate salt Form I of the compound I further has one or more characteristic peaks in X-ray powder diffraction expressed in angles of 2-theta at 8.9±0.2°, 21.3±0.2°, 23.8±0.2°, 26.1±0.2°.

44. The salt of compound I according to claim 42 or 43, wherein The propionate salt Form I of the compound I further has one or more characteristic peaks in X-ray powder diffraction expressed in angles of 2-theta at 8.0±0.2°, 13.2±0.2°, 14.5±0.2°.

45. The salt of compound I according to claim 42 or 43, wherein The propionate salt Form I of the compound I has an X-ray powder diffraction pattern substantially as shown in Figure 16.

46. The salt of compound I according to claim 42 or 43, wherein The propionate salt Form I of the compound I has a differential scanning calorimetry curve with an endothermic peak at 134°C±10°C.

47. The salt of compound I according to claim 46, wherein, The propionate salt Form I of the compound I has a differential scanning calorimetry curve with an endothermic peak at 134°C±5°C.

48. The salt of compound I according to claim 42 or 43, wherein The propionate salt Form I of the compound I has a DSC pattern substantially as shown in Figure 17.

49. The salt of compound I as claimed in claims 42 or 43, wherein, The propionate salt Form I of the compound I has a TGA pattern substantially as shown in Figure 18.

50. The salt of compound I of claim 9, wherein, The salt is a succinate salt Form I, which has characteristic peaks in X-ray powder diffraction expressed in angles of 2-theta using Cu-Kalpha radiation at 5.8±0.2°, 6.6±0.2°, 15.0±0.2°, 24.3±0.2°.

51. The salt of compound I according to claim 50, wherein, The succinate salt Form I of the compound I further has one or more characteristic peaks in X-ray powder diffraction expressed in angles of 2-theta at 13.8±0.2°, 18.7±0.2°, 19.8±0.2°, 25.0±0.2°.

52. The salt of compound I according to claim 50 or 51, wherein The succinate salt Form I of the compound I further has one or more characteristic peaks in X-ray powder diffraction expressed in angles of 2-theta at 8.7±0.2°, 20.3±0.2°, 24.1±0.2°, 26.2±0.2°.

53. The salt of compound I according to claim 50 or 51, wherein The succinate salt Form I of the compound I has an X-ray powder diffraction pattern substantially as shown in Figure 19.

54. The salt of compound I as claimed in claims 50 or 51, wherein, The succinate salt Form I of the compound I has a differential scanning calorimetry curve with an endothermic peak at 168°C±10°C.

55. The salt of compound I according to claim 54, wherein, The succinate salt Form I of the compound I has a differential scanning calorimetry curve with an endothermic peak at 168°C±5°C.

56. The salt of compound I as claimed in claims 50 or 51, wherein, The succinate salt Form I of the compound I has a DSC pattern substantially as shown in Figure 20.

57. The salt of compound I as claimed in claims 50 or 51, wherein, The succinate salt Form I of the compound I has a TGA pattern substantially as shown in Figure 21.

58. A salt of Compound I according to claim 9, wherein, said salt is a sulfate salt of compound I according to formula (III), wherein the salt formation ratio of compound I to sulfuric acid is 1 :

1.

59. A salt of Compound I according to claim 9, wherein, The salt is a sulfate salt Form I, which has characteristic peaks in X-ray powder diffraction expressed in angles of 2-theta using Cu-Kalpha radiation at 17.9±0.2°, 19.0±0.2°, 19.5±0.2°, 27.2±0.2°.

60. The salt of compound I according to claim 59, wherein, The sulfate salt Form I of the compound I has an X-ray powder diffraction pattern substantially as shown in Figure 22.

61. The salt of compound I according to claim 59 or 60, wherein The sulfate salt Form I of the compound I has an X-ray powder diffraction pattern substantially as shown in Figure 22.

62. The salt of compound I according to claim 59 or 60, wherein The sulfate salt Form I of the compound I has an X-ray powder diffraction pattern substantially as shown in Figure 22.

63. The salt of compound I as claimed in claims 59 or 60, wherein, The sulfate salt Form I of the compound I has a differential scanning calorimetry curve with an endothermic peak at about 259 ± 10 °C.

64. The salt of compound I according to claim 63, wherein, The sulfate salt Form I of the compound I has a differential scanning calorimetry curve with an endothermic peak at 259 °C ± 5 °C.

65. The salt of compound I as claimed in claims 59 or 60, wherein, The sulfate salt Form I of the compound I has an X-ray powder diffraction pattern substantially as shown in Figure 22.

66. The salt of compound I as claimed in claims 59 or 60, wherein, The sulfate salt Form I of the compound I has an X-ray powder diffraction pattern substantially as shown in Figure 22.

67. The salt of compound I as claimed in claims 59 or 60, wherein, The salt is the sulfate salt Form I of the compound I, the salt-forming ratio of the compound I to sulfuric acid being 1 :

1.

68. A salt of Compound I as described in claim 9, wherein, The tartrate salt Form I has characteristic peaks in an X-ray powder diffraction pattern, expressed in angles of 2-theta, using Cu-Kalpha radiation at 4.2 ± 0.2°, 17.0 ± 0.2°, 19.2 ± 0.2°, 20.1 ± 0.2°.

69. The salt of compound I according to claim 68, wherein, The tartrate salt Form I of the compound I has one or more further characteristic peaks in an X-ray powder diffraction pattern, expressed in angles of 2-theta, at 12.8 ± 0.2°, 15.1 ± 0.2°, 22.1 ± 0.2°.

70. The salt of compound I according to claim 68 or 69, wherein The tartrate salt Form I of the compound I has one or more further characteristic peaks in an X-ray powder diffraction pattern, expressed in angles of 2-theta, at 8.2 ± 0.2°, 14.4 ± 0.2°, 16.3 ± 0.2°, 22.9 ± 0.2°, 25.1 ± 0.2°.

71. The salt of compound I according to claim 68 or 69, wherein The tartrate salt Form I of the compound I has an X-ray powder diffraction pattern substantially as shown in Figure 25.

72. The salt of compound I according to claim 68 or 69, wherein The tartrate salt Form I of the compound I has a differential scanning calorimetry curve with an endothermic peak at 132 °C ± 10 °C.

73. The salt of compound I of claim 72, wherein The tartrate salt Form I of the compound I has a differential scanning calorimetry curve with an endothermic peak at 132 °C ± 5 °C.

74. The salt of compound I according to claim 68 or 69, wherein The tartrate salt Form I of the compound I has an X-ray powder diffraction pattern substantially as shown in Figure 25.

75. The salt of compound I according to claim 68 or 69, wherein The tartrate salt Form I of the compound I has an X-ray powder diffraction pattern substantially as shown in Figure 25.

76. A salt of Compound I as described in claim 9, wherein, The salt is the pamoate salt Form I, which has characteristic peaks in an X-ray powder diffraction pattern, expressed in angles of 2-theta, using Cu-Kalpha radiation at 7.3 ± 0.2°, 9.0 ± 0.2°, 11.8 ± 0.2°, 24.1 ± 0.2°.

77. The salt of compound I according to claim 76, wherein The pamoate salt Form I of the compound I has one or more further characteristic peaks in an X-ray powder diffraction pattern, expressed in angles of 2-theta, at 13.2 ± 0.2°, 19.2 ± 0.2°, 21.0 ± 0.2°, 22.5 ± 0.2°.

78. The salt of compound I according to claim 76 or 77, wherein The pamoate salt Form I of Compound I has an X-ray powder diffraction pattern expressed in terms of 2 theta angles further having one or more characteristic peaks at 9.6 ± 0.2°, 14.5 ± 0.2°, 16.3 ± 0.2°, 26.9 ± 0.2°.

79. The salt of compound I according to claim 76 or 77, wherein The pamoate salt Form I of Compound I has an X-ray powder diffraction pattern substantially as shown in Figure 28.

80. The salt of compound I as claimed in claims 76 or 77, wherein, The pamoate salt Form I of Compound I has a differential scanning calorimetry curve having an endothermic peak at 249 °C ± 10 °C.

81. The salt of compound I according to claim 80, wherein The pamoate salt Form I of Compound I has a differential scanning calorimetry curve having an endothermic peak at 249 °C ± 5 °C.

82. The salt of compound I as claimed in claims 76 or 77, wherein, The pamoate salt Form I of Compound I has a DSC pattern substantially as shown in Figure 29.

83. The salt of compound I according to claim 76 or 77, wherein The pamoate salt Form I of Compound I has a TGA pattern substantially as shown in Figure 30.

84. A salt of Compound I as described in claim 9, wherein, The salt is pamoate salt Form II, which has characteristic peaks in an X-ray powder diffraction pattern expressed in terms of 2 theta angles at 6.2 ± 0.2°, 14.0 ± 0.2°, 15.2 ± 0.2°, 16.1 ± 0.2° using Cu-Ka radiation.

85. The salt of compound I according to claim 84, wherein, The pamoate salt Form II of Compound I has an X-ray powder diffraction pattern expressed in terms of 2 theta angles further having one or more characteristic peaks at 7.6 ± 0.2°, 9.0 ± 0.2°, 12.1 ± 0.2°, 26.2 ± 0.2°.

86. The salt of compound I according to claim 84 or 85, wherein The pamoate salt Form II of Compound I has an X-ray powder diffraction pattern expressed in terms of 2 theta angles further having one or more characteristic peaks at 16.7 ± 0.2°, 18.7 ± 0.2°, 23.0 ± 0.2°.

87. The salt of compound I according to claim 84 or 85, wherein The pamoate salt Form II of Compound I has an X-ray powder diffraction pattern substantially as shown in Figure 31.

88. The salt of compound I according to claim 84 or 85, wherein The pamoate salt Form II of Compound I has a differential scanning calorimetry curve having an endothermic peak at 173 °C ± 10 °C.

89. The salt of compound I according to claim 88, wherein The pamoate salt Form II of Compound I has a differential scanning calorimetry curve having an endothermic peak at 173 °C ± 5 °C.

90. The salt of compound I as claimed in claims 84 or 85, wherein, The pamoate salt Form II of Compound I has a DSC pattern substantially as shown in Figure 32.

91. The salt of compound I according to claim 84 or 85, wherein The pamoate salt Form II of Compound I has a TGA pattern substantially as shown in Figure 33.

92. A salt of Compound I as described in claim 9, wherein, The salt is pamoate salt Form III, which has characteristic peaks in an X-ray powder diffraction pattern expressed in terms of 2 theta angles at 9.5 ± 0.2°, 15.7 ± 0.2°, 26.3 ± 0.2°, 29.9 ± 0.2° using Cu-Ka radiation.

93. The salt of compound I according to claim 92, wherein, The pamoate salt Form III of Compound I has an X-ray powder diffraction pattern expressed in terms of 2 theta angles further having one or more characteristic peaks at 11.1 ± 0.2°, 19.4 ± 0.2°, 23.2 ± 0.2°, 25.1 ± 0.2°.

94. The salt of compound I according to claim 92 or 93, wherein The pamoate salt Form III of Compound I has an X-ray powder diffraction pattern substantially as shown in Figure 34.

95. The salt of compound I according to claim 92 or 93, wherein The pamoate salt Form III of Compound I has a differential scanning calorimetry curve having an endothermic peak at 249 °C ± 10 °C.

96. The salt of compound I according to claim 95, wherein, The pamoate salt Form III of Compound I has a differential scanning calorimetry curve having an endothermic peak at 249 °C ± 5 °C.

97. The salt of compound I according to claim 92 or 93, wherein The pamoate salt Form III of Compound I has a DSC pattern substantially as shown in FIG.

35.

98. The salt of compound I as claimed in claims 92 or 93, wherein, The pamoate salt Form III of Compound I has a TGA pattern substantially as shown in FIG.

36.

99. A salt of Compound I as described in claim 9, wherein, The salt is acetate salt Form I, which has characteristic peaks at 7.4±0.2°, 8.0±0.2°, 11.3±0.2°, 14.7±0.2° in X-ray powder diffraction using Cu-Ka radiation, expressed in terms of 2θ angles.

100. The salt of compound I according to claim 99, wherein, The acetate salt Form I of Compound I has one or more characteristic peaks at 9.0±0.2°, 10.4±0.2°, 13.3±0.2° in X-ray powder diffraction expressed in terms of 2θ angles.

101. The salt of compound I according to claim 99 or 100, wherein The acetate salt Form I of Compound I has an X-ray powder diffraction pattern substantially as shown in FIG.

37.

102. The salt of compound I according to claim 99 or 100, wherein The acetate salt Form I of Compound I has a differential scanning calorimetry curve with an endothermic peak at 180°C±10°C.

103. The salt of compound I according to claim 102, wherein The acetate salt Form I of Compound I has a differential scanning calorimetry curve with an endothermic peak at 180°C±5°C.

104. The salt of compound I as described in claims 99 or 100, wherein, The acetate salt Form I of Compound I has a DSC pattern substantially as shown in FIG.

38.

105. The salt of compound I as described in claims 99 or 100, wherein, The acetate salt Form I of Compound I has a TGA pattern substantially as shown in FIG.

39.

106. A pharmaceutical composition, characterized in that, The composition comprises the crystalline Form I of Compound I according to any one of claims 1-8 or a salt of Compound I according to any one of claims 9-105.

107. Use of the crystalline Form I of Compound I according to any one of claims 1-8 or a salt of Compound I according to any one of claims 9-105 or the pharmaceutical composition of claim 106 in the manufacture of a medicament for treating a disease mediated by SOS1.

108. Use of the crystalline Form I of Compound I according to any one of claims 1-8 or a salt of Compound I according to any one of claims 9-105 or the pharmaceutical composition of claim 106 in the manufacture of a medicament for treating a cancer or a tumor-related disease.

109. The use of claim 108, wherein the composition is administered to the subject in an amount sufficient to reduce the subject's risk of developing a disease or disorder associated with the genetic mutation. The cancer or tumor-related disease is a solid tumor.

110. The use of claim 109, wherein, The cancer or tumor-related disease is lung cancer.

111. The use of claim 110, wherein, The cancer or tumor-related disease is non-small cell lung cancer.

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