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

Abstract

A salt of a heterocyclic antitumor compound and a crystal form thereof. The present application provides a crystal form of a free base of compound I, a salt of compound I and a crystal form of the salt of compound I. Some crystal forms and salt types provided by the present application have excellent effects in physical stability, chemical stability, hygroscopicity 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 field of pharmaceutical chemistry, in particular, the present application relates to salts, crystalline forms of the compound (R)-4-ethynyl-1-(6-(3-methylmorpholinyl)-1-(1H-pyrazolyl-3-yl)-1H-pyrazolyl[3,4-b]pyridin-4-yl)cyclohexanol (hereinafter referred to as Compound I or compound of Formula I) as an ATR inhibitor, and processes for preparing the same. In addition, the present application also relates to the use of salts, crystalline forms of Compound I in the treatment of ATR-related diseases and disorders. BACKGROUND

[0002] ATR (Ataxia telangiectasia and Rad3-related protein) is a class of protein kinases involved in genomic stability and DNA damage repair, belonging to the PIKK family members. The activation of ATR can be activated by stalled replication forks or DNA single-strand damage (SSB). The activated ATR will recruit repair proteins or repair factors to repair the damaged site, delay the mitotic process (especially in the G2 / M phase of mitosis), both stabilize the replication fork and ensure the stability of the genome. After ATR is activated, it will activate three signal transduction pathways by regulating its downstream regulatory factors (mainly including Chk1, WRN and FANCI) to block cell cycle progression, promote DNA repair and stabilize replication forks. Because DNA repair in tumor cells may be defective due to the presence of various mutations, it shows greater dependence on undamaged DNA repair pathways. Therefore, it can kill specific tumor cells while preserving healthy cells by using the synthetic lethality theory. In current cancer treatment, both chemotherapy and ionizing radiation can induce DNA damage and replication fork stalling, thereby activating cell cycle checkpoints and causing cell cycle arrest. This response mechanism is an important mechanism to help cancer cells survive treatment. Broken double-stranded DNA or replication stress can quickly activate ATR, which in turn can initiate a series of downstream targets such as Chk1 (ATR substrate), p53, DNA topoisomerase 2 binding protein (TopBP1), etc. to cause DNA repair and cell cycle arrest. ATR gene is rarely mutated, so it is easily activated during cancer chemotherapy. Therefore, ATR inhibition can be used in combination with chemotherapy drugs to synergistically enhance the effect.

[0003] So far, there is still no ATR inhibitor on the market, so it is still necessary to find more effective and safe ATR inhibitors. SUMMARY

[0004] Chinese patent application 202211612192.2 (filing date December 15, 2022) and international patent application PCT / CN2022 / 139194 (filing date December 15, 2022) disclose compounds as ATR inhibitors and methods for their preparation, including (R)-4-ethynyl-1-(6-(3-methylmorpholinyl)-1-(1H-pyrazolyl-3-yl)-1H-pyrazolyl[3,4-b]pyridin-4-yl)cyclohexanol (hereinafter referred to as Compound I or a compound of Formula I, structure as shown below) and methods for their preparation.

[0005]

[0006] Compound I is an effective ATR inhibitor, in vitro enzyme activity inhibition studies show that Compound I has strong inhibitory effect on ATR enzyme, in vitro cell proliferation inhibition effect test studies show that Compound I has significant inhibitory effect on LoVo cell and SNU-601 cell proliferation, and therefore it can be used as a promising compound for treating ATR-mediated diseases.

[0007] There is no report on Compound I and its salts, crystal forms. Comprehensive and systematic polymorph, salt screening is one of the indispensable important research contents. Therefore, it is necessary to further screen Compound I and its salts, crystal forms, and develop crystal forms or salt forms suitable for large-scale production, so as to provide more and better choices for subsequent drug development.

[0008] One of the purposes of the present application is to provide a salt of Compound I, the structure of which is as follows,

[0009] The salt is a benzenesulfonate salt, a sulfate salt, a p-toluenesulfonate salt, a hydrochloride salt, a maleate salt, a hydrobromide salt, a methanesulfonate salt, a sodium salt, and a potassium salt of Compound I.

[0010] Another purpose of the present application also includes providing a benzenesulfonate salt crystal form I of Compound I, characterized in that the X-ray powder diffraction expressed in 2θ angle has characteristic peaks at 8.8±0.2°, 17.7±0.2°, 18.9±0.2°, 20.8±0.2° using Cu-Kα radiation.

[0011] Preferably, the benzenesulfonate salt crystal form I of Compound I has characteristic peaks at 8.8±0.2°, 9.4±0.2°, 13.7±0.2°, 16.3±0.2°, 17.7±0.2°, 18.9±0.2°, 20.8±0.2°, 23.2±0.2° using Cu-Kα radiation, expressed in 2θ angle.

[0012] More preferably, the benzenesulfonic acid salt Form I of Compound I has an X-ray powder diffraction pattern substantially as shown in Figure 1.

[0013] Further preferably, the benzenesulfonic acid salt Form I of Compound I has an X-ray powder diffraction pattern substantially as shown in Figure 1. Figure 1

[0014] 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 184.4°C ± 5°C.

[0015] Further preferably, the benzenesulfonic acid salt Form I of Compound I has a DSC pattern substantially as shown in Figure 2. Figure 2

[0016] In some embodiments of the present application, the benzenesulfonic acid salt Form I of Compound I has a TGA pattern substantially as shown in Figure 3. Figure 3

[0017] Another object of the present application also includes a benzenesulfonic acid salt Form II of Compound I, characterized by an X-ray powder diffraction pattern, expressed in angles 2-theta, using Cu-Kalpha radiation, with characteristic peaks at 7.1 ± 0.2°, 8.5 ± 0.2°, 14.9 ± 0.2°.

[0018] Preferably, the benzenesulfonic acid salt Form II of Compound I has an X-ray powder diffraction pattern, expressed in angles 2-theta, using Cu-Kalpha radiation, with characteristic peaks at 7.1 ± 0.2°, 8.5 ± 0.2°, 14.9 ± 0.2°, 20.1 ± 0.2°, 21.1 ± 0.2°, 25.3 ± 0.2°.

[0019] Further preferably, the benzenesulfonic acid salt Form II of Compound I has an X-ray powder diffraction pattern substantially as shown in Figure 4. Figure 4

[0020] In some embodiments of the present application, the benzenesulfonic acid salt Form II of Compound I has a differential scanning calorimetry curve with an endothermic peak at 190.6°C ± 5°C.

[0021] Further preferably, the benzenesulfonic acid salt Form II of Compound I has a DSC pattern substantially as shown in Figure 5. Figure 5

[0022] ​​​​​In some embodiments of the present application, the benzenesulfonic acid salt Form II of Compound I has an X-ray powder diffraction pattern substantially as shown in Figure 6

[0023] It is another object of the present application to provide a sulfate salt Form I of Compound I having an X-ray powder diffraction pattern, expressed in terms of 2 theta angles, using Cu-Ka radiation, with characteristic peaks at 5.8 ± 0.2°, 6.5 ± 0.2°, 8.5 ± 0.2°, 17.4 ± 0.2°, 18.5 ± 0.2°, 21.3 ± 0.2°, 22.3 ± 0.2°, 22.9 ± 0.2°.

[0024] Preferably, the sulfate salt Form I of Compound I has an X-ray powder diffraction pattern, expressed in terms of 2 theta angles, using Cu-Ka radiation, with characteristic peaks at 5.8 ± 0.2°, 6.5 ± 0.2°, 8.5 ± 0.2°, 15.4 ± 0.2°, 17.4 ± 0.2°, 18.5 ± 0.2°, 19.6 ± 0.2°, 21.3 ± 0.2°, 22.3 ± 0.2°, 22.9 ± 0.2°, 23.4 ± 0.2°, 27.0 ± 0.2°.

[0025] More preferably, the sulfate salt Form I of Compound I has an X-ray powder diffraction pattern, expressed in terms of 2 theta angles, using Cu-Ka radiation, with characteristic peaks at 5.8 ± 0.2°, 6.5 ± 0.2°, 8.5 ± 0.2°, 15.4 ± 0.2°, 17.4 ± 0.2°, 18.5 ± 0.2°, 19.6 ± 0.2°, 21.3 ± 0.2°, 22.3 ± 0.2°, 22.9 ± 0.2°, 23.4 ± 0.2°, 27.0 ± 0.2°.

[0026] Further preferably, the sulfate salt Form I of Compound I has an X-ray powder diffraction pattern substantially as shown in Figure 7

[0027] 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 120.7 °C ± 5 °C.

[0028] Further preferably, the sulfate salt Form I of Compound I has a differential scanning calorimetry curve substantially as shown in Figure 8

[0029] In some embodiments of the present application, the sulfate salt Form I of Compound I has an X-ray powder diffraction pattern substantially as shown in Figure 9

[0030] It is another object of the present application to provide a sulfate salt Form II of Compound I having an X-ray powder diffraction pattern, expressed in terms of 2 theta angles, using Cu-Ka radiation, with characteristic peaks at 9.1 ± 0.2°, 9.9 ± 0.2°, 21.2 ± 0.2°.

[0031] ​​​​Preferably, the sulfate salt crystalline Form II of Compound I has an X-ray powder diffraction pattern substantially as shown in Figure 1.

[0032] More preferably, the sulfate salt crystalline Form II of Compound I has an X-ray powder diffraction pattern substantially as shown in Figure 1.

[0033] Further preferably, the sulfate salt crystalline Form II of Compound I has an X-ray powder diffraction pattern substantially as shown in Figure 1. Figure 10

[0034] In some embodiments of the application, the sulfate salt crystalline Form II of Compound I has a differential scanning calorimetry curve with an endothermic peak at 151.4 °C ± 5 °C.

[0035] Further preferably, the sulfate salt crystalline Form II of Compound I has a DSC pattern substantially as shown in Figure 2. Figure 11

[0036] In some embodiments of the application, the sulfate salt crystalline Form II of Compound I has a TGA pattern substantially as shown in Figure 3. Figure 12

[0037] Another object of the present application also includes a sulfate salt crystalline Form III of Compound I having an X-ray powder diffraction pattern substantially as shown in Figure 4.

[0038] Preferably, the sulfate salt crystalline Form III of Compound I has an X-ray powder diffraction pattern substantially as shown in Figure 4.

[0039] ​​​More preferably, the sulfate salt Form III of Compound I has an X-ray powder diffraction pattern substantially as shown in Figure 1.

[0040] Further preferably, the sulfate salt Form III of Compound I has a DSC pattern substantially as shown in Figure 2. Figure 13

[0041] In some embodiments of the application, the sulfate salt Form III of Compound I has a differential scanning calorimetry curve with an endothermic peak at 143.2 °C ± 5 °C.

[0042] Further preferably, the sulfate salt Form III of Compound I has a DSC pattern substantially as shown in Figure 2. Figure 14

[0043] In some embodiments of the application, the sulfate salt Form III of Compound I has a TGA pattern substantially as shown in Figure 3. Figure 15

[0044] Another object of the present application also includes a sulfate salt Form IV of Compound I having an X-ray powder diffraction pattern expressed in terms of 2-theta angles with characteristic peaks at 9.2 ± 0.2°, 9.9 ± 0.2°, 21.0 ± 0.2°, 22.1 ± 0.2° using Cu-Ka radiation.

[0045] Preferably, the sulfate salt Form IV of Compound I has an X-ray powder diffraction pattern expressed in terms of 2-theta angles with characteristic peaks at 9.2 ± 0.2°, 9.9 ± 0.2°, 16.2 ± 0.2°, 17.3 ± 0.2°, 19.9 ± 0.2°, 21.0 ± 0.2°, 22.1 ± 0.2° using Cu-Ka radiation.

[0046] More preferably, the sulfate salt Form IV of Compound I has an X-ray powder diffraction pattern expressed in terms of 2-theta angles with characteristic peaks at 9.2 ± 0.2°, 9.9 ± 0.2°, 13.6 ± 0.2°, 15.4 ± 0.2°, 16.2 ± 0.2°, 17.3 ± 0.2°, 19.9 ± 0.2°, 21.0 ± 0.2°, 22.1 ± 0.2°, 24.4 ± 0.2° using Cu-Ka radiation.

[0047] Further preferably, the sulfate salt Form IV of Compound I has an X-ray powder diffraction pattern substantially as shown in Figure 4. Figure 16 Preferably, the sulfate salt Form IV of Compound I has an X-ray powder diffraction pattern expressed in terms of 2-theta angles with characteristic peaks at 9.2 ± 0.2°, 9.9 ± 0.2°, 16.2 ± 0.2°, 17.3 ± 0.2°, 19.9 ± 0.2°, 21.0 ± 0.2°, 22.1 ± 0.2° using Cu-Ka radiation.​​​

[0048] In some embodiments of the present application, the sulfate salt Form IV of Compound I has a differential scanning calorimetry curve with an endothermic peak at 153.3 °C ± 5 °C.

[0049] Further preferably, the sulfate salt Form IV of Compound I has a differential scanning calorimetry curve substantially as shown in Figure 17 Further preferably, the sulfate salt Form IV of Compound I has a differential scanning calorimetry curve substantially as shown in

[0050] In some embodiments of the present application, the sulfate salt Form IV of Compound I has a differential scanning calorimetry curve with an endothermic peak at 153.3 °C ± 5 °C. Figure 18

[0051] Another object of the present application also includes providing a p-toluenesulfonic acid salt Form I of Compound I, which has an X-ray powder diffraction pattern, expressed in angles 2θ, using Cu-Kα radiation, with characteristic peaks at 3.6 ± 0.2°, 4.5 ± 0.2°, 5.5 ± 0.2°.

[0052] Preferably, the p-toluenesulfonic acid salt Form I of Compound I has an X-ray powder diffraction pattern, expressed in angles 2θ, using Cu-Kα radiation, with characteristic peaks at 3.6 ± 0.2°, 4.5 ± 0.2°, 5.5 ± 0.2°, 7.1 ± 0.2°, 18.4 ± 0.2°, 19.6 ± 0.2°.

[0053] More preferably, the p-toluenesulfonic acid salt Form I of Compound I has an X-ray powder diffraction pattern, expressed in angles 2θ, using Cu-Kα radiation, with characteristic peaks at 3.6 ± 0.2°, 4.5 ± 0.2°, 5.5 ± 0.2°, 7.1 ± 0.2°, 8.6 ± 0.2°, 10.7 ± 0.2°, 18.4 ± 0.2°, 19.6 ± 0.2°.

[0054] Further preferably, the p-toluenesulfonic acid salt Form I of Compound I has an X-ray powder diffraction pattern substantially as shown in Figure 19 Further preferably, the p-toluenesulfonic acid salt Form I of Compound I has an X-ray powder diffraction pattern substantially as shown in

[0055] In some embodiments of the present application, the p-toluenesulfonic acid salt Form I of Compound I has a differential scanning calorimetry curve with an endothermic peak at 136.4 °C ± 5 °C.

[0056] Further preferably, the p-toluenesulfonic acid salt Form I of Compound I has a differential scanning calorimetry curve substantially as shown in Figure 20 Further preferably, the p-toluenesulfonic acid salt Form I of Compound I has a differential scanning calorimetry curve substantially as shown in

[0057] In some embodiments of the present application, the p-toluenesulfonic acid salt Form I of Compound I has a differential scanning calorimetry curve substantially as shown in Figure 21 In some embodiments of the present application, the p-toluenesulfonic acid salt Form I of Compound I has a differential scanning calorimetry curve substantially as shown in

[0058] Another object of the present application also includes providing a hydrochloride salt of Compound I, as shown in formula (II),​

[0059] wherein the salt formation ratio of Compound I to hydrochloric acid is 1:1.

[0060] It is another object of the present application to provide a hydrochloride salt Form I of Compound I, wherein the salt formation ratio of Compound I to hydrochloric acid is 1:1.

[0061] Preferably, the hydrochloride salt Form I of Compound I has X-ray powder diffraction peaks at 6.2±0.2°, 7.8±0.2°, 19.0±0.2°, 19.8±0.2°, using Cu-Ka radiation as expressed in terms of 2 theta angles.

[0062] More preferably, the hydrochloride salt Form I of Compound I has X-ray powder diffraction peaks at 6.2±0.2°, 7.3±0.2°, 7.8±0.2°, 12.1±0.2°, 18.1±0.2°, 19.0±0.2°, 19.8±0.2°, 25.9±0.2°, using Cu-Ka radiation as expressed in terms of 2 theta angles.

[0063] Still more preferably, the hydrochloride salt Form I of Compound I has X-ray powder diffraction peaks at 6.2±0.2°, 7.3±0.2°, 7.8±0.2°, 11.3±0.2°,

[0064] 12.1±0.2°, 14.8±0.2°, 18.1±0.2°, 19.0±0.2°, 19.8±0.2°, 23.9±0.2°,

[0065] 25.9±0.2°, 29.6±0.2°, using Cu-Ka radiation as expressed in terms of 2 theta angles.

[0066] Further preferably, the hydrochloride salt Form I of Compound I has an X-ray powder diffraction pattern substantially as shown in Figure 22 Further preferably, the hydrochloride salt Form I of Compound I has an X-ray powder diffraction pattern substantially as shown in

[0067] In some embodiments of the present application, the hydrochloride salt Form I of Compound I has a differential scanning calorimetry curve with an endothermic peak at 245.0°C±5°C.

[0068] Further preferably, the hydrochloride salt Form I of Compound I has a differential scanning calorimetry curve substantially as shown in Figure 23 Further preferably, the hydrochloride salt Form I of Compound I has a differential scanning calorimetry curve substantially as shown in

[0069] In some embodiments of the present application, the hydrochloride salt Form I of Compound I has a thermogravimetric analysis curve substantially as shown in Figure 24 In some embodiments of the present application, the hydrochloride salt Form I of Compound I has a thermogravimetric analysis curve substantially as shown in

[0070] It is another object of the present application to provide a maleate salt Form I of Compound I having an X-ray powder diffraction pattern, expressed in angles 2 theta, using Cu-Ka radiation, with characteristic peaks at 3.8 ± 0.2°, 4.9 ± 0.2°, 6.3 ± 0.2°, 17.7 ± 0.2°.

[0071] Preferably, the maleate salt Form I of Compound I has an X-ray powder diffraction pattern, expressed in angles 2 theta, using Cu-Ka radiation, with characteristic peaks at 3.8 ± 0.2°, 4.9 ± 0.2°, 6.3 ± 0.2°, 16.3 ± 0.2°, 17.7 ± 0.2°, 19.2 ± 0.2°, 20.6 ± 0.2°.

[0072] Further preferably, the maleate salt Form I of Compound I has an X-ray powder diffraction pattern substantially as shown in Figure 1. Figure 25

[0073] In some embodiments of the present application, the maleate salt Form I of Compound I has a differential scanning calorimetry curve with an endothermic peak at 96.9 °C ± 5 °C.

[0074] Further preferably, the maleate salt Form I of Compound I has a DSC pattern substantially as shown in Figure 2. Figure 26

[0075] In some embodiments of the present application, the maleate salt Form I of Compound I has a TGA pattern substantially as shown in Figure 3. Figure 27

[0076] It is another object of the present application to provide a hydrobromide salt Form I of Compound I having an X-ray powder diffraction pattern, expressed in angles 2 theta, using Cu-Ka radiation, with characteristic peaks at 6.3 ± 0.2°, 7.6 ± 0.2°, 18.7 ± 0.2°.

[0077] Preferably, the hydrobromide salt Form I of Compound I has an X-ray powder diffraction pattern, expressed in angles 2 theta, using Cu-Ka radiation, with characteristic peaks at 6.3 ± 0.2°, 7.6 ± 0.2°, 16.7 ± 0.2°, 18.7 ± 0.2°, 23.4 ± 0.2°, 25.9 ± 0.2°.

[0078] More preferably, the hydrobromide salt Form I of Compound I has an X-ray powder diffraction pattern, expressed in angles 2 theta, using Cu-Ka radiation, with characteristic peaks at 6.3 ± 0.2°, 7.6 ± 0.2°, 11.4 ± 0.2°, 16.7 ± 0.2°, 18.2 ± 0.2°, 18.7 ± 0.2°, 23.4 ± 0.2°, 25.0 ± 0.2°, 25.9 ± 0.2°, 28.6 ± 0.2°, 30.3 ± 0.2°. ​​​

[0079] Further preferably, the hydrobromide salt Form I of Compound I has an X-ray powder diffraction pattern substantially as shown in Figure 28 Further preferably, the hydrobromide salt Form I of Compound I has an X-ray powder diffraction pattern substantially as shown in

[0080] In some embodiments of the present application, the hydrobromide salt Form I of Compound I has a differential scanning calorimetry curve with an endothermic peak at 241.1 °C ± 5 °C.

[0081] Further preferably, the hydrobromide salt Form I of Compound I has an X-ray powder diffraction pattern substantially as shown in Figure 29 Further preferably, the hydrobromide salt Form I of Compound I has an X-ray powder diffraction pattern substantially as shown in

[0082] In some embodiments of the present application, the hydrobromide salt Form I of Compound I has a differential scanning calorimetry curve with an endothermic peak at 241.1 °C ± 5 °C. Figure 30 In some embodiments of the present application, the hydrobromide salt Form I of Compound I has a differential scanning calorimetry curve with an endothermic peak at 241.1 °C ± 5 °C.

[0083] Another object of the present application also includes providing a mesylate salt of Compound I shown in formula (III), wherein the salt formation ratio of Compound I to methanesulfonic acid is 1:1.

[0084] Another object of the present application also includes providing a mesylate salt Form I of Compound I, which has characteristic peaks at 5.1 ± 0.2°, 6.0 ± 0.2°, 20.4 ± 0.2° in X-ray powder diffraction expressed in terms of 2θ angle using Cu-Kα radiation.

[0085] Preferably, the mesylate salt Form I of Compound I has characteristic peaks at 5.1 ± 0.2°, 6.0 ± 0.2°, 10.4 ± 0.2°, 13.8 ± 0.2°, 17.6 ± 0.2°, 20.4 ± 0.2° in X-ray powder diffraction expressed in terms of 2θ angle using Cu-Kα radiation.

[0086] Further preferably, the mesylate salt Form I of Compound I has an X-ray powder diffraction pattern substantially as shown in Figure 31 Further preferably, the mesylate salt Form I of Compound I has an X-ray powder diffraction pattern substantially as shown in

[0087] In some embodiments of the present application, the mesylate salt Form I of Compound I has a differential scanning calorimetry curve with an endothermic peak at 117.9 °C ± 5 °C.

[0088] Further preferably, the mesylate salt Form I of Compound I has an X-ray powder diffraction pattern substantially as shown in Figure 32 Further preferably, the mesylate salt Form I of Compound I has an X-ray powder diffraction pattern substantially as shown in

[0089] In some embodiments of the present application, the mesylate salt Form I of Compound I has a differential scanning calorimetry curve with an endothermic peak at 117.9 °C ± 5 °C. Figure 33 In some embodiments of the present application, the mesylate salt Form I of Compound I has a differential scanning calorimetry curve with an endothermic peak at 117.9 °C ± 5 °C.

[0090] It is another object of the present application to provide a mesylate salt Form II of Compound I having characteristic peaks at 9.0±0.2°, 9.8±0.2°, 17.4±0.2°, 21.9±0.2° in X-ray powder diffraction expressed in terms of 2θ angles using Cu-Kα radiation.

[0091] Preferably, the mesylate salt Form II of Compound I has characteristic peaks at 9.0±0.2°, 9.8±0.2°, 16.8±0.2°, 17.4±0.2°, 19.5±0.2°, 21.3±0.2°, 21.9±0.2° in X-ray powder diffraction expressed in terms of 2θ angles using Cu-Kα radiation.

[0092] More preferably, the mesylate salt Form II of Compound I has characteristic peaks at 9.0±0.2°, 9.8±0.2°, 14.8±0.2°, 16.0±0.2°, 16.8±0.2°, 17.4±0.2°, 18.1±0.2°, 19.5±0.2°, 21.3±0.2°, 21.9±0.2° in X-ray powder diffraction expressed in terms of 2θ angles using Cu-Kα radiation.

[0093] Further preferably, the mesylate salt Form II of Compound I has an X-ray powder diffraction pattern substantially as shown in Figure 1. Figure 34 Further preferably, the mesylate salt Form II of Compound I has a DSC pattern substantially as shown in Figure 2.

[0094] In some embodiments of the present application, the mesylate salt Form II of Compound I has a differential scanning calorimetry curve having an endothermic peak at 170.3°C±5°C.

[0095] Further preferably, the mesylate salt Form II of Compound I has a DSC pattern substantially as shown in Figure 2. Figure 35 Further preferably, the mesylate salt Form II of Compound I has a DSC pattern substantially as shown in Figure 2.

[0096] In some embodiments of the present application, the mesylate salt Form II of Compound I has a TGA pattern substantially as shown in Figure 3. Figure 36 Further preferably, the mesylate salt Form II of Compound I has a DSC pattern substantially as shown in Figure 2.

[0097] It is another object of the present application to provide a mesylate salt Form III of Compound I, wherein the salt forming ratio of Compound I to methanesulfonic acid in the mesylate salt Form III is 1:1.

[0098] Preferably, the mesylate salt Form III of Compound I has characteristic peaks at 8.9±0.2°, 16.7±0.2°, 19.5±0.2°, 22.3±0.2° in X-ray powder diffraction expressed in terms of 2θ angles using Cu-Kα radiation.

[0099] More preferably, the mesylate salt Form III of Compound I has an X-ray powder diffraction pattern with characteristic peaks, expressed in angles 2Θ, using Cu-Kodiation, at 8.9±0.2°, 14.9±0.2°, 16.7±0.2°, 18.5±0.2°, 19.5±0.2°, 22.3±0.2°, 25.3±0.2°.

[0100] Still more preferably, the mesylate salt Form III of Compound I has an X-ray powder diffraction pattern with characteristic peaks, expressed in angles 2Θ, using Cu-Kodiation, at 6.2±0.2°, 8.9±0.2°, 12.0±0.2°, 13.5±0.2°, 14.9±0.2°, 16.7±0.2°, 18.5±0.2°, 19.5±0.2°, 21.5±0.2°, 22.3±0.2°, 25.3±0.2°

[0101] Still more preferably, the mesylate salt Form III of Compound I has an X-ray powder diffraction pattern with characteristic peaks, expressed in angles 2Θ, using Cu-Kodiation, at 6.2±0.2°, 8.9±0.2°, 12.0±0.2°, 13.5±0.2°, 14.9±0.2°, 16.7±0.2°, 18.5±0.2°, 19.5±0.2°, 21.5±0.2°, 22.3±0.2°, 25.3±0.2°

[0102] Further preferably, the mesylate salt Form III of Compound I has an X-ray powder diffraction pattern substantially as shown in Figure 1. Figure 37

[0103] In some embodiments of the present application, the mesylate salt Form III of Compound I has a differential scanning calorimetry curve with an endothermic peak at 174.0°C±5°C.

[0104] Further preferably, the mesylate salt Form III of Compound I has a DSC pattern substantially as shown in Figure 2. Figure 38

[0105] In some embodiments of the present application, the mesylate salt Form III of Compound I has a TGA pattern substantially as shown in Figure 3. Figure 39

[0106] Another object of the present application also includes providing a sodium salt of Compound I represented by Formula (IV),

[0107] wherein the salt-forming ratio of Compound I to sodium ion is 1:1.

[0108] In another aspect, the present application provides a pharmaceutical composition comprising a benzenesulfonic acid salt, a sulfate salt, a p-toluenesulfonic acid salt, a hydrochloride salt, a maleate salt, a hydrobromide salt, a mesylate salt, a sodium salt, a potassium salt of Compound I.

[0109] ​​​The present application also provides a pharmaceutical composition comprising the benzenesulfonate salt Form I, the benzenesulfonate salt Form II, the sulfate salt Form I, the sulfate salt Form II, the sulfate salt Form III, the sulfate salt Form IV, the p-toluenesulfonate salt Form I, the hydrochloride salt Form I, the maleate salt Form I, the hydrobromide salt Form I, the methanesulfonate salt Form I, the methanesulfonate salt Form II, the methanesulfonate salt Form III of Compound I as described above.

[0110] In another aspect, the present application provides the use of the benzenesulfonate salt, the sulfate salt, the p-toluenesulfonate salt, the hydrochloride salt, the maleate salt, the hydrobromide salt, the methanesulfonate salt, the sodium salt, the potassium salt of Compound I or the pharmaceutical composition of the present application in the manufacture of a medicament for treating a disease mediated by ATR. Preferably, the disease mediated by ATR is a cancer or a tumor-related disease.

[0111] The present application also provides the use of the benzenesulfonate salt Form I, the benzenesulfonate salt Form II, the sulfate salt Form I, the sulfate salt Form II, the sulfate salt Form III, the sulfate salt Form IV, the p-toluenesulfonate salt Form I, the hydrochloride salt Form I, the maleate salt Form I, the hydrobromide salt Form I, the methanesulfonate salt Form I, the methanesulfonate salt Form II, the methanesulfonate salt Form III of Compound I or the pharmaceutical composition of the present application in the manufacture of a medicament for treating a disease mediated by ATR. Preferably, the disease mediated by ATR is a cancer or a tumor-related disease.

[0112] Further, the present application also provides the use of the benzenesulfonate salt, the sulfate salt, the p-toluenesulfonate salt, the hydrochloride salt, the maleate salt, the hydrobromide salt, the methanesulfonate salt, the sodium salt, the potassium salt of Compound I or the pharmaceutical composition of the present application 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 a digestive tract tumor; more preferably, the cancer or the tumor-related disease is gastric cancer, colorectal cancer.

[0113] Further, the present application also provides the use of the benzenesulfonate salt Form I, the benzenesulfonate salt Form II, the sulfate salt Form I, the sulfate salt Form II, the sulfate salt Form III, the sulfate salt Form IV, the p-toluenesulfonate salt Form I, the hydrochloride salt Form I, the maleate salt Form I, the hydrobromide salt Form I, the methanesulfonate salt Form I, the methanesulfonate salt Form II, the methanesulfonate salt Form III of Compound I or the pharmaceutical composition of the present application 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 a digestive tract tumor; more preferably, the cancer or the tumor-related disease is gastric cancer, colorectal cancer.

[0114] For treating tumor diseases, the benzenesulfonate salt, the sulfate salt, the p-toluenesulfonate salt, the hydrochloride salt, the maleate salt, the hydrobromide salt, the methanesulfonate salt, the sodium salt, the potassium salt of Compound I, the benzenesulfonate salt Form I of Compound I, the benzenesulfonate salt Form II of Compound I, the sulfate salt Form I of Compound I, the sulfate salt Form II of Compound I, the sulfate salt Form III of Compound I, the sulfate salt Form IV of Compound I, the p-toluenesulfonate salt Form I of Compound I, the hydrochloride salt Form I of Compound I, the maleate salt Form I of Compound I, the hydrobromide salt Form I of Compound I, the methanesulfonate salt Form I of Compound I, the methanesulfonate salt Form II of Compound I, the methanesulfonate salt Form III of Compound I can be co-administered with other therapeutic agents (e.g. chemotherapeutic drugs, biotherapeutic drugs, etc.) or combined with other therapeutic means, including but not limited to radiotherapy.

[0115] Advantages

[0116] The present application provides, for the first time, a plurality of salt forms of Compound I. Some of the salt forms provided by the present application have excellent effects in physical stability, chemical stability, hygroscopicity, etc., have good clinical application value, and can be used as excellent alternative forms for subsequent drug development. BRIEF DESCRIPTION OF DRAWINGS

[0117] Figure 1 XRPD spectrum of the benzenesulfonate salt Form I of Compound I.

[0118] Figure 2 DSC spectrum of the benzenesulfonate salt Form I of Compound I.

[0119] Figure 3 TGA spectrum of the benzenesulfonate salt Form I of Compound I.

[0120] Figure 4 XRPD spectrum of the benzenesulfonate salt Form II of Compound I.

[0121] Figure 5 DSC spectrum of the benzenesulfonate salt Form II of Compound I.

[0122] Figure 6 TGA spectrum of the benzenesulfonate salt Form II of Compound I.

[0123] Figure 7 XRPD spectrum of the sulfate salt Form I of Compound I.

[0124] Figure 8 DSC spectrum of the sulfate salt Form I of Compound I.

[0125] Figure 9 TGA spectrum of the sulfate salt Form I of Compound I.

[0126] Figure 10 XRPD spectrum of the sulfate salt Form II of Compound I.

[0127] Figure 11 DSC pattern for Compound I sulfate salt Form II.

[0128] Figure 12 TGA pattern for Compound I sulfate salt Form II.

[0129] Figure 13 XRPD pattern for Compound I sulfate salt Form III.

[0130] Figure 14 DSC pattern for Compound I sulfate salt Form III.

[0131] Figure 15 TGA pattern for Compound I sulfate salt Form III.

[0132] Figure 16 XRPD pattern for Compound I sulfate salt Form IV.

[0133] Figure 17 DSC pattern for Compound I sulfate salt Form IV.

[0134] Figure 18 TGA pattern for Compound I sulfate salt Form IV.

[0135] Figure 19 XRPD pattern for Compound I p-toluenesulfonate salt Form I.

[0136] Figure 20 DSC pattern for Compound I p-toluenesulfonate salt Form I.

[0137] Figure 21 TGA pattern for Compound I p-toluenesulfonate salt Form I.

[0138] Figure 22 XRPD pattern for Compound I hydrochloride salt Form I.

[0139] Figure 23 DSC pattern for Compound I hydrochloride salt Form I.

[0140] Figure 24 TGA pattern for Compound I hydrochloride salt Form I.

[0141] Figure 25 XRPD pattern for Compound I maleate salt Form I.

[0142] Figure 26 DSC pattern for Compound I maleate salt Form I.

[0143] Figure 27 TGA pattern for Compound I maleate salt Form I.

[0144] Figure 28 XRPD pattern of Compound I hydrobromide Form I.

[0145] Figure 29 DSC pattern of Compound I hydrobromide Form I.

[0146] Figure 30 TGA pattern of Compound I hydrobromide Form I.

[0147] Figure 31 XRPD pattern of Compound I mesylate Form I.

[0148] Figure 32 DSC pattern of Compound I mesylate Form I.

[0149] Figure 33 TGA pattern of Compound I mesylate Form I.

[0150] Figure 34 XRPD pattern of Compound I mesylate Form II.

[0151] Figure 35 DSC pattern of Compound I mesylate Form II.

[0152] Figure 36 TGA pattern of Compound I mesylate Form II.

[0153] Figure 37 XRPD pattern of Compound I mesylate Form III.

[0154] Figure 38 DSC pattern of Compound I mesylate Form III.

[0155] Figure 39 TGA pattern of Compound I mesylate Form III.

[0156] Figure 40 H NMR pattern of Compound I mesylate Form III. 1 H NMR pattern of Compound I mesylate Form III. DETAILED DESCRIPTION

[0157] The technical solutions of the present application will be further described in detail below in combination with specific examples. 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.

[0158] Unless otherwise specified, the raw materials and reagents used in the following examples are commercially available or can be prepared by known methods.

[0159] The structure of the compound I of the embodiments 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 Agilent 400 / 54 Premium Shielded NMR Magnet System, the instrument used for LC-MS is Shimadzu LCMS2020; and the instrument used for HPLC is Agilent 1200. The instruments and detection parameters used in the salt / salt form screening of Examples 2-16 are as follows:

[0160]

[0161]

[0162]

[0163]

[0164] Example 1, Preparation of Compound I Preparation of (R)-4-ethynyl-1-(6-(3-methylmorpholinyl)-1-(1H-pyrazolyl-3-yl)-1H-pyrazolyl[3,4-b]pyridin-4-yl)cyclohexanol (Compound I):

[0165]

[0166] First step: Preparation of 4-((tert-butyldiphenylsilyl) methyl)cyclohexanone:

[0167]

[0168] 4-(hydroxymethyl)cyclohexanone (900.0 mg, 7.02 mmol, 1 equiv.) and imidazole (1.4 g, 21.07 mmol, 3 equiv.) were dissolved in dichloromethane (20 mL), tert-butyldiphenylsilyl chloride (2.9 g, 10.53 mmol, 1.5 equiv.) was added under ice bath, and stirred at room temperature for 2 hours. The reaction was complete by spot plate monitoring. The organic phase was combined, dried, filtered and concentrated, and the target compound (1.5 g, yield 58.2%) was obtained by column chromatography (petroleum ether: ethyl acetate = 50:1). 1H NMR (400 MHz, DMSO-d6) δ 7.65 (d, J = 3.6 Hz, 1H), 7.58 (d, J = 5.9 Hz, 4H), 7.41 (d, J = 6.7 Hz, 4H), 7.35 (s, 1H), 3.53 (d, J = 5.8 Hz, 2H), 2.40 - 2.31 (m, 2H), 2.15 (d, J = 14.0 Hz, 2H), 1.98 (s, 3H), 1.40 - 1.31 (m, 2H), 0.97 (s, 9H).

[0169] Second Step: Preparation of 4-((tert-butyldiphenylsilyl)oxy)methyl)cyclohex-1-en-1- yl trifluoromethanesulfonate:

[0170]

[0171] Dissolve 4-((tert-butyldiphenylsilyloxy)methyl)cyclohexanone (700.0 mg, 1.91 mmol, 1 equiv.) in tetrahydrofuran (5 mL), add lithium bis(trimethylsilyl)amide (2.4 mL, 14.65 mmol, 1.2 equiv.) at -78 °C, keep stirring at -78 °C for 45 min, add 1,1,1-trifluoro-N-phenyl-N-((trifluoromethyl)sulfonyl)methane sulfonamide (750.4 mg, 2.10 mmol, 1.1 equiv.) dissolved in tetrahydrofuran, stir at room temperature for 3 hours. Monitor by spotting on plate, the starting material is consumed completely. Partition with ethyl acetate and water, combine the organic phase, dry, filter and concentrate, get the target compound (560.0 mg, yield 58.8%) by column chromatography (petroleum ether: ethyl acetate = 100:1). 1 H NMR (400 MHz, DMSO-d6) δ 7.57 (d, J = 7.0 Hz, 4H), 7.41 (d, J = 7.1 Hz, 5H), 5.85 (s, 1H), 3.54 (d, J = 6.1 Hz, 2H), 2.24 (d, J = 18.9 Hz, 2H), 2.02 - 1.70 (m, 4H), 1.48 (s, 1H), 0.97 (s, 9H).

[0172] Third Step: Preparation of tert-butyldiphenyl((4-(4,4,5,5-tetramethyl-1,3,2-dioxobenzene-2- yl)cyclohex-3-en-1-yl)methoxy)silane:

[0173]

[0174] (560.0 mg, 1.12 mmol, 1 equiv.), pinacol diboronic acid (427.7 mg, 1.68 mmol, 1.5 equiv.), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (82.4 mg, 0.11 mmol, 0.1 equiv.) and potassium acetate (330.6 mg, 3.37 mmol, 3 equiv.) were dissolved in 1,4-dioxane (10 mL), replaced with nitrogen for three times, stirred at 90 °C for 16 hours, monitored by spotting on plate, the starting material was consumed completely. The reaction was filtered through celite, the filtrate was partitioned with ethyl acetate and water, the organic phase was combined, dried, filtered and concentrated, the target compound was obtained by column chromatography (petroleum ether: ethyl acetate = 100: 1) (340.0 mg, yield 63.2%). 1 H NMR (400 MHz, DMSO-d6) δ 7.57 (d, J = 6.5 Hz, 4H), 7.41 (d, J = 6.5 Hz, 6H), 5.29 (s, 1H), 3.50 (d, J = 5.9 Hz, 2H), 2.07 (d, J = 19.8 Hz, 1H), 1.99 - 1.92 (m, 4H), 1.70 (s, 4H), 1.42 (s, 1H), 1.15 (s, 12H), 0.96 (s, 9H).

[0175] Fourth step: Preparation of (3R)-4-(4-(tert-butyldiphenylsilyloxy)methyl)cyclohex-1-en-1-yl)-1-(1-(2-(trimethylsilyloxy)ethoxy)methyl)-1H-pyrazol-5-yl)-1H-pyrazol[3,4-b]pyridin-6-yl)-3-methylmorpholine:

[0176]

[0177] Tert-butyldiphenyl((4-(4,4,5,5-tetramethyl-1,3,2-dioxobenzene-2-yl)cyclohex-3- en-1-yl)methoxy)silane (340.0 mg, 0.36 mmol, 1 equiv.), (R)-4-(4-iodo-1-(1-((2- (trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5-yl)-1H-pyrazol[3,4-b]pyridin-6-yl)-3- methylmorpholine (385.6 mg, 0.36 mmol, 1 equiv.), sodium carbonate (75.6 mg, 0.71 mmol, 2 equiv.) and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (26.1 mg, 0.04 mmol, 0.1 equiv.) were dissolved in 1,4-dioxane (6 mL) and water (3 mL), stirred at 90 °C for 2 hours. LCMS monitoring, the reaction was complete. The reaction was filtered through celite, the filtrate was partitioned with ethyl acetate and water, the organic phase was combined, dried and filtered, concentrated to give the target compound (260.0 mg, yield 47.7%). 1 H NMR (400 MHz, CDC13) δ 8.04 (d, J = 5.1 Hz, 1H), 7.71 - 7.60 (m, 5H), 7.40 (t, J = 8.3 Hz, 6H), 6.59 (s, 2H), 6.42 (s, 1H), 6.36 (s, 1H), 5.71 (t, J = 12.6 Hz, 3H), 4.31 (d, J = 21.8 Hz, 1H), 3.97 (t, J = 14.3 Hz, 3H), 3.74 (dd, J = 29.1, 14.3 Hz, 3H), 3.63 (d, J = 5.8 Hz, 2H), 3.57 (s, 1H), 3.40 (d, J = 8.0 Hz, 3H), 3.25 (d, J = 12.9 Hz, 1H), 1.26 (dd, J = 11.4, 5.9 Hz, 9H), 1.06 (s, 9H), 0.78 - 0.70 (m, 3H), -0.17 (d, J = 4.4 Hz, 14H).

[0178] Fifth step: Preparation of (R)-4-((tert-butyldiphenylsilyl)oxy)methyl)-1-(6-(3- methylmorpholinyl)-1-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5-yl)-1H- pyrazolyl[3,4-b]pyridin-4-yl)cyclohexanol:

[0179]

[0180] (R)-4-(4-(tert-butyldiphenylsilyloxy)methyl)cyclohex-1-en-1-yl)-1-(1-(2- (trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5-yl)-1H-pyrazol[3,4-b]pyridin-6-yl)-3- methylmorpholine (260.0 mg, 0.34 mmol, 1 equiv.) was dissolved in isopropanol (3.5 mL) and dichloromethane (0.5 mL), and manganese tris(2,2,6,6-tetramethyl-3,5- heptanedionate) (41.4 mg, 0.07 mmol, 0.2 equiv.) and phenylsilane (73.7 mg, 0.68 mmol, 2 equiv.) were added under ice bath, and the oxygen was replaced for three times, and stirred at room temperature for 2 hours. LCMS monitoring, the raw material was completely reacted. The reaction liquid was separated with ethyl acetate and water, and the organic phase was combined, dried, filtered and concentrated. The target compound (200.0 mg, yield 75.1%) was obtained by purification through the large plate (petroleum ether: ethyl acetate = 2:1). LCMS (ESI) [M+H] + = 781.40.

[0181] Sixth step: Preparation of (R)-4-(hydroxymethyl)-1-(6-(3-methylmorpholinyl)-1-(1-((2- (trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5-yl)-1H-pyrazol[3,4-b]pyridin-4-yl)cyclohexanol:

[0182]

[0183] (R)-4-((tert-butyldiphenylsilyl)oxy)methyl)-1-(6-(3-methylmorpholinyl)-1-(1-((2- (trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5-yl)-1H-pyrazol[3,4-b]pyridin-4-yl)cyclohexanol (200.0 mg, 0.26 mmol, 1 equiv.) was dissolved in tetrahydrofuran (2 mL), and 1M tetrabutylammonium fluoride (2 mL) tetrahydrofuran solution was added, and stirred at room temperature overnight. LCMS monitoring, the reaction was complete. The reaction liquid was quenched with saturated aqueous ammonium chloride solution, extracted with ethyl acetate, and the organic phase was combined, dried, filtered and concentrated. The target compound (130.0 mg, yield 93.55%) was obtained by purification through the large plate (petroleum ether: ethyl acetate = 1:1). LCMS (ESI) [M+H] + = 543.55.

[0184] Seventh step: Preparation of (R)-4-hydroxy-4-(6-(3-methylmorpholinyl)-1-(1-((2- (trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5-yl)-1H-pyrazol[3,4-b]pyridin-4-yl)cyclohexanecarboxaldehyde:

[0185]

[0186] (R)-4-(hydroxymethyl)-l-(6-(3-methylmorpholinyl)-l-(l-((2- (trimethylsilyl)ethoxy)methyl)-lH-pyrazol-5-yl)-lH-pyrazol[3,4-b]pyridin-4- yl)cyclohexanol (130.0 mg, 0.24 mmol, 1 equiv.) was dissolved in dichloromethane (4 mL), Dess-Martin Oxidizing reagent (203.1 mg, 0.48 mmol, 2 equiv.) was added under ice-bath, stirred at room temperature for 2 hours. LCMS monitoring, the reaction was complete. The reaction was filtered through celite, the filtrate was quenched with saturated aqueous sodium thiosulfate solution, extracted with ethyl acetate, the organic phase was combined, dried, filtered and concentrated, the target compound (100.0 mg, yield 75.1%) was obtained by silica gel column (petroleum ether: ethyl acetate = 1:1). LCMS (ESI) [M+H] + = 541.30.

[0187] Eighth step: Preparation of ((R)-4-ethynyl-l-(6-(3-methylmorpholinyl)-l-(l-((2- (trimethylsilyl)ethoxy)methyl)-lH-pyrazol-5-yl)-lH-pyrazol[3,4-b]pyridin-4- yl)cyclohexanol:

[0188]

[0189] (R)-4-hydroxy-4-(6-(3-methylmorpholinyl)-l-(l-((2- (trimethylsilyl)ethoxy)methyl)-lH-pyrazol-5-yl)-lH-pyrazol[3,4-b]pyridin-4- yl)cyclohexanecarboxaldehyde (100.0 mg, 0.18 mmol, 1 equiv.), dimethyl (l-diazo-2- oxopropyl)phosphonate (42.6 mg, 0.22 mmol, 1.2 equiv.) and potassium carbonate (51.1 mg, 0.37 mmol, 2 equiv.) were dissolved in methanol (3 mL), stirred at room temperature overnight. LCMS monitoring, the reaction was complete. The reaction was partitioned with ethyl acetate and water, the organic phase was combined, dried, filtered and concentrated, the target compound (87.0 mg, yield 87.6%) was obtained by silica gel column (dichloromethane:methanol = 15:1). LCMS (ESI) [M+H] + = 537.35.

[0190] Ninth step: Preparation of (R)-4-ethynyl-l-(6-(3-methylmorpholinyl)-l-(lH- pyrazol-3-yl)-lH-pyrazol[3,4-b]pyridin-4-yl)cyclohexanol:

[0191]

[0192] (R)-4-ethynyl-1-(6-(3-methylmorpholinyl)-1-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H- pyrazol-5-yl)-1H-pyrazol[3,4-b]pyridin-4-yl)cyclohexanol (90.0 mg, 0.17 mmol, 1 equiv.) was dissolved in trifluoroacetic acid (2 mL) and dichloromethane (2 mL), triethylsilane (0.2 mL) was added, stirred at room temperature for 1 hour. LCMS monitoring, the reaction was complete. The reaction was adjusted to basic with saturated aqueous sodium bicarbonate solution, then extracted with ethyl acetate, the organic phase was combined, dried and filtered, concentrated, and the target compound was obtained by plate climbing (dichloromethane:methanol = 10:1) (46.2 mg, yield 67.7%). LCMS (ESI) [M+H] + = 407.20; 1 H NMR (400 MHz, DMSO-d6) δ 12.76 (s, 1H), 8.24 (s, 1H), 7.80 (s, 1H), 6.77 (d, J = 12.5 Hz, 2H), 5.23 (s, 1H), 4.40 (s, 1H), 4.03 - 3.90 (m, 2H), 3.73 (d, J = 10.9 Hz, 1H), 3.61 (d, J = 10.7 Hz, 1H), 3.46 (t, J = 11.3 Hz, 1H), 3.13 (t, J = 11.8 Hz, 1H), 2.86 (s, 1H), 2.54 (s, 1H), 1.96 (d, J = 12.5 Hz, 2H), 1.85 (dd, J = 24.4, 12.5 Hz, 2H), 1.76 (s, 2H), 1.67 (d, J = 12.1 Hz, 2H), 1.15 (d, J = 6.1 Hz, 3H).

[0193] Preparation of compound I benzenesulfonate salt crystal form I of example 2

[0194] About 50 mg of compound I sample was dissolved in 2.8 mL of acetone, and the solution was dissolved and cleared in a 60 °C water bath to obtain solution 1; about 24 mg of benzenesulfonic acid was dissolved in 0.1 mL of acetone to obtain solution 2; solution 2 was added dropwise to solution 1 under stirring at room temperature to obtain solution 3; solution 3 was immediately precipitated, and stirring was performed overnight to obtain a suspension; the suspension was centrifuged, and the solid was placed in a 40 °C vacuum drying oven overnight to obtain the benzenesulfonate salt crystal form I. The XRPD detection results of this crystal form I are shown in Figure 1 , the DSC and TGA detection results are shown in Figure 2 , 3 The XRPD diffraction peak data of this crystal form I are shown below.

[0195] 2 theta angle (°) peak height relative intensity (%) 8.808 4174 100.0 9.422 1076 25.8 11.459 563 13.5 13.710 936 22.4 14.175 467 11.2 15.293 432 10.3 16.340 974 23.3 17.719 2269 54.4 18.944 2518 60.3 20.843 2398 57.5 23.171 1311 31.4 24.732 451 10.8

[0196] Preparation of Compound I besylate Form II

[0197] About 50 mg of Compound I sample was dissolved in 3 mL of acetonitrile at 60 °C water bath to get solution 1; about 24 mg of besylate acid was dissolved in 0.1 mL of acetonitrile to get solution 2; solution 2 was added into solution 1 drop by drop under stirring at room temperature to get solution 3; a small amount of solid was precipitated from solution 3, which was transferred to stirring at 4 °C overnight to get a suspension; the suspension was centrifuged and the solid was dried at 40 °C under vacuum overnight to get the besylate Form II. The XRPD detection result of this Form II is shown in Figure 4 , the DSC and TGA detection results are shown in Figure 5 , 6 . The XRPD diffraction peak data of this Form II are shown as follows.

[0198] 2 theta angle (°) peak height relative intensity (%) 7.132 30341 100 8.490 2040 6.7 14.875 4918 16.2 20.051 714 2.4 21.078 921 3 25.326 721 2.4

[0199] Preparation of Compound I sulfate Form I

[0200] About 50 mg of Compound I sample was dissolved in 2.8 mL of acetone at 60 °C water bath to get solution 1; about 13 mg of sulfuric acid was dissolved in 0.1 mL of acetone to get solution 2; solution 2 was added into solution 1 drop by drop under stirring at room temperature to get solution 3; no solid was precipitated from solution 3, 8 mL of n-heptane was added to precipitate the solid, which was stirred and then dissolved, and then transferred to stirring at 4 °C overnight to get a suspension; the suspension was centrifuged and the solid was dried at 40 °C under vacuum overnight to get the sulfate Form I. The XRPD detection result of this Form I is shown in Figure 7 , the DSC and TGA detection results are shown in Figure 8 , 9 . The XRPD diffraction peak data of this Form I are shown as follows.

[0201] 2 theta angle (°) peak height relative intensity (%) 5.788 517 46.5 6.520 731 65.8 8.512 1111 100 15.392 421 37.9 17.426 948 85.3 18.533 738 66.4 19.616 430 38.7 21.316 433 39 22.345 767 69 22.874 457 41.1 23.446 424 38.2 27.044 390 35.1

[0202] Preparation of Compound I sulfate Form II

[0203] About 50 mg of Compound I sample was dissolved in 6 mL of ethyl acetate at 60 °C water bath to get solution 1; about 13 mg of sulfuric acid was dissolved in 0.1 mL of methanol to get solution 2; solution 2 was added into solution 1 drop by drop under stirring at room temperature to get solution 3; a suspension was immediately obtained from solution 3, which was stirred overnight to get a suspension; the suspension was centrifuged and the solid was dried at 40 °C under vacuum overnight to get the sulfate Form II. The XRPD detection result of this Form II is shown in Figure 10 , the DSC and TGA detection results are shown in Figure 11 , 12 . The XRPD diffraction peak data of this Form II are shown as follows.

[0204] 2 theta angle (°) peak height relative intensity (%) 9.144 1943 100 9.876 1834 94.4 15.208 821 42.3 16.296 1268 65.3 17.621 1227 63.1 19.832 607 31.2 21.236 1876 96.6 21.810 1331 68.5 24.438 600 30.9

[0205] Preparation of Compound I sulfate salt Form III

[0206] About 50 mg of Compound I sample was dissolved in 1 mL of tetrahydrofuran at 70 °C water bath, to get solution 1; about 13 mg of sulfuric acid was dissolved in 0.1 mL of tetrahydrofuran, to get solution 2; solution 2 was added to solution 1 drop by drop under stirring at room temperature, to get solution 3; solution 3 did not precipitate, and was stirred at 12 °C overnight without precipitation, 4 mL of n-heptane was added to precipitate to get a suspension; the suspension was centrifuged, and the solid was dried at 40 °C under vacuum overnight to get the sulfate salt Form III. The XRPD detection result of this Form III is shown in Figure 13 , the DSC and TGA detection results are shown in Figure 14 , 15 . The XRPD diffraction peak data of this Form III are shown as follows.

[0207] 2 theta angle (°) peak height relative intensity (%) 4.659 1363 57.8 5.882 1199 50.8 6.556 1732 73.4 8.550 2316 98.2 9.006 2359 100 13.254 1183 50.1 17.502 1351 57.3 18.866 2024 85.8 21.314 1572 66.6 22.441 1461 61.9

[0208] Preparation of Compound I sulfate salt Form IV

[0209] About 50 mg of Compound I sample was dissolved in 3 mL of acetonitrile at 60 °C water bath, to get solution 1; about 13 mg of sulfuric acid was dissolved in 0.1 mL of acetonitrile, to get solution 2; solution 2 was added to solution 1 drop by drop under stirring at room temperature, to get solution 3; solution 3 did not precipitate, and was stirred overnight, 10 mL of methyl tert-butyl ether was added to precipitate to get a suspension under stirring at 4 °C overnight; the suspension was centrifuged, and the solid was dried at 40 °C under vacuum overnight to get the sulfate salt Form IV. The XRPD detection result of this Form IV is shown in Figure 16 , the DSC and TGA detection results are shown in Figure 17 , 18 . The XRPD diffraction peak data of this Form IV are shown as follows.

[0210] 2 theta angle (°) peak height relative intensity (%) 9.181 1447 96.6 9.895 1498 100 13.590 414 27.6 15.366 417 27.8 16.178 582 38.9 17.324 539 36 19.893 589 39.3 20.996 698 46.6 22.145 605 40.4 24.358 347 23.2

[0211] Preparation of Compound I p-toluenesulfonate salt Form I

[0212] About 50 mg of Compound I sample was dissolved in 2.8 mL of acetone at 60 °C water bath, to get solution 1; about 26 mg of p-toluenesulfonic acid was dissolved in 0.1 mL of acetone, to get solution 2; solution 2 was added to solution 1 drop by drop under stirring at room temperature, to get solution 3; solution 3 did not precipitate, and was stirred overnight, 3 mL of n-heptane solution was added to precipitate to get a suspension; the suspension was centrifuged, and the solid was dried at 40 °C under vacuum overnight to get the p-toluenesulfonate salt Form I. The XRPD detection result of this Form I is shown in Figure 19The DSC, TGA results of the detection are shown as follows Figure 20 , 21 The XRPD diffraction peak data of this crystal form I are shown as follows.

[0213] 2 theta angle (°) peak height relative intensity (%) 3.591 3700 100 4.523 3090 83.5 5.529 3490 94.3 7.108 678 18.3 8.608 249 6.7 10.704 300 8.1 18.412 446 12.1 19.634 377 10.2

[0214] Preparation of compound I hydrochloride salt crystal form I in Example 9

[0215] About 300 mg of compound I sample was added to 16 mL of ethanol, and dissolved at 60°C to obtain solution 1; about 66 μL of hydrochloric acid was dissolved in 0.6 mL of ethanol to obtain solution 2; solution 2 was added dropwise to solution 1 under stirring at room temperature to obtain solution 3; solution 3 was stirred for 10 min and then precipitated, and a suspension was obtained after stirring for 3 days; the suspension was filtered under reduced pressure, and the solid was dried at 40°C under vacuum overnight to obtain the hydrochloride salt crystal form I (242 mg). The XRPD detection results of this crystal form I are shown as follows Figure 22 The DSC, TGA results of the detection are shown as follows Figure 23 , 24 The salt formation ratio was 1:1 as determined by IC method (ion chromatography). The XRPD diffraction peak data of this crystal form I are shown as follows.

[0216] 2 theta angle (°) peak height relative intensity (%) 6.236 6363 100 7.344 1906 30 7.797 3791 59.6 11.276 1883 29.6 12.148 2291 36 14.836 1544 24.3 18.115 2331 36.6 19.022 5074 79.7 19.752 3572 56.1 23.864 1340 21.1 25.881 2007 31.5 29.612 1276 20.1

[0217] Preparation of compound I maleate salt crystal form I in Example 10

[0218] About 50 mg of compound I sample was added to 1 mL of tetrahydrofuran, and dissolved at 70°C water bath to obtain solution 1; about 16 mg of maleic acid was dissolved in 0.1 mL of tetrahydrofuran to obtain solution 2; solution 2 was added dropwise to solution 1 under stirring at room temperature to obtain solution 3; solution 3 was not precipitated after being cooled at 12°C overnight, and 4 mL of n-heptane was added to precipitate the solid to obtain a suspension; the suspension was centrifuged, and the solid was dried at 40°C under vacuum overnight to obtain the maleate salt crystal form I. The XRPD detection results of this crystal form I are shown as follows Figure 25 The DSC, TGA results of the detection are shown as follows Figure 26 , 27 The XRPD diffraction peak data of this crystal form I are shown as follows.

[0219] 2 theta angle (°) peak height relative intensity (%) 3.849 4127 53 4.934 7790 100 6.300 2193 28.2 16.336 610 7.8 17.700 1506 19.3 19.160 483 6.2 20.604 568 7.3

[0220] Preparation of compound I hydrobromide salt crystal form I in Example 11

[0221] About 50 mg of Compound I sample was added to 4 mL of ethanol, dissolved at 60 °C water bath, to obtain solution 1; about 27 mg of hydrobromic acid was dissolved in 0.1 mL of ethanol to obtain solution 2; solution 2 was added dropwise to solution 1 under stirring at room temperature to obtain solution 3; solution 3 was immediately precipitated after stirring for 10 min, and was stirred overnight to obtain a suspension; the suspension was centrifuged, and the solid was dried at 40 °C under vacuum overnight to obtain the hydrobromide salt Form I. The XRPD detection result of this Form I is shown in Figure 28 , the detected DSC, TGA detection results are shown in Figure 29 , 30 .

[0222] The XRPD diffraction peak data of this Form I are shown as follows.

[0223] 2 theta angle (°) peak height relative intensity (%) 6.274 3000 68.8 7.579 4360 100 11.353 1127 25.8 16.671 1814 41.6 18.235 1671 38.3 18.704 3472 79.6 23.429 1951 44.7 24.990 1490 34.2 25.899 1821 41.8 28.568 1391 31.9 30.344 1172 26.9

[0224] Preparation of Compound I mesylate salt Form I

[0225] About 50 mg of Compound I sample was added to 2.8 mL of acetone, dissolved at 60 °C water bath, to obtain solution 1; about 13 mg of methanesulfonic acid was dissolved in 0.1 mL of acetone to obtain solution 2; solution 2 was added dropwise to solution 1 under stirring at room temperature to obtain solution 3; solution 3 was precipitated after stirring, and was stirred for 24 h to obtain a suspension; the suspension was centrifuged, and the solid was dried at 40 °C under vacuum overnight to obtain the mesylate salt Form I. The XRPD detection result of this Form I is shown in Figure 31 , the detected DSC, TGA detection results are shown in Figure 32 , 33 . The XRPD diffraction peak data of this Form I are shown as follows.

[0226] 2 theta angle (°) peak height relative intensity (%) 5.092 5504 100 5.963 1602 29.1 10.407 182 3.3 13.768 211 3.8 17.640 174 3.2 20.425 226 4.1

[0227] Preparation of Compound I mesylate salt Form II

[0228] About 50 mg of Compound I sample was added to 6 mL of ethyl acetate, dissolved at 60 °C water bath, to obtain solution 1; about 13 mg of methanesulfonic acid was dissolved in 0.1 mL of methanol to obtain solution 2; solution 2 was added dropwise to solution 1 under stirring at room temperature to obtain solution 3; a small amount of solid was precipitated from solution 3 after stirring at room temperature overnight, 6 mL of n-heptane was added, and the mixture was stirred at 4 °C overnight to obtain a suspension; the suspension was centrifuged, and the solid was dried at 40 °C under vacuum overnight to obtain the mesylate salt Form II. The XRPD detection result of this Form II is shown in Figure 34 , the detected DSC, TGA detection results are shown in Figure 35 , 36 . The XRPD diffraction peak data of this Form II are shown as follows.

[0229] 2 theta angle (°) peak height relative intensity (%) 8.969 2673 47.9 9.815 5577 100 14.814 1464 26.3 15.999 1318 23.6 16.770 1811 32.5 17.366 3362 60.3 18.132 963 17.3 19.498 1661 29.8 21.275 2296 41.2 21.907 4705 84.4

[0230] Example 14 Preparation of Compound I Methanesulfonate Crystal Form III

[0231] Approximately 300 mg of compound I sample was added to 36 mL of ethyl acetate and sonicated at 60 °C until it was mostly dissolved, yielding solution 1. Approximately 79 mg of methanesulfonic acid was dissolved in 0.6 mL of methanol, yielding solution 2. Under stirring at room temperature, solution 2 was added dropwise to solution 1 to obtain solution 3. Solution 3 was stirred for 0.5 h, and 36 mL of n-heptane was added, causing immediate precipitation. The mixture was stirred for 3 days to obtain a suspension. The suspension was filtered under reduced pressure, and the solid was vacuum dried overnight at 40 °C to obtain methanesulfonate crystal form III. The XRPD results for this crystal form III are as follows: Figure 37 As shown, the DSC and TGA test results are as follows: Figure 38 , 39 As shown. 1 H-NMR detection results are as follows Figure 40 As shown, based on the integration results, the salt formation ratio of the compound to methanesulfonic acid is 1:1. The XRPD diffraction peak data for this crystal form III are shown below.

[0232]

[0233]

[0234] Example 15 Preparation of sodium salt of compound I

[0235] Approximately 300 mg of free sample was added to 6 mL of tetrahydrofuran and dissolved at 60 °C to obtain solution 1. Approximately 33 mg of sodium hydroxide solid was added to solution 1 at room temperature and stirred for 1 h to dissolve, yielding solution 2. 12 mL of n-heptane was added dropwise to solution 2, and the solid immediately adhered to the bottle wall. The mixture was stirred at room temperature for 3 days, and the precipitated solid was oily. The solution was rapidly filtered under reduced pressure until the volume decreased to approximately 2 mL, and the solid precipitated. The crystallization was carried out for 0.5 h to obtain a suspension. The suspension was centrifuged, and the solid was vacuum-dried overnight at 40 °C to obtain sodium salt (275 mg). XRPD analysis showed that this sodium salt exhibited no diffraction peaks, indicating an amorphous state. The salt ratio was determined to be 1:1 by IC (ion chromatography).

[0236] Example 16 Preparation of potassium salt of compound I

[0237] Approximately 50 mg of compound I sample was added to 1 mL of tetrahydrofuran and dissolved in a water bath at 60 °C to obtain solution 1. Approximately 8 mg of potassium hydroxide was added directly to solution 1 and stirred at room temperature until dissolved to obtain solution 2. Solution 2 was stirred at 12 °C overnight without precipitation. After adding 4 mL of n-heptane and stirring, precipitation occurred, resulting in a suspension. The suspension was centrifuged, and the solid was vacuum dried overnight at 40 °C to obtain the potassium salt. XRPD analysis showed that this potassium salt exhibited no diffraction peaks, indicating it is an amorphous state.

[0238] Comparative Example 1: Compound RP103

[0239]

[0240] Reference compound RP103 was obtained by preparing according to the method of compound 103 in the specification of patent CN113454080A on page 119.

[0241] Reference Example 2: Compound RP3500

[0242]

[0243] Reference compound RP3500 was obtained by preparing according to the method of compound 121 in the specification of patent CN113454080A on page 122.

[0244] Test Example 1: Inhibitory effect of the compound of the present application on ATR enzyme

[0245] The following method was used to determine the inhibitory effect of the compound of the present application on ATR enzyme. The experimental method is briefly described as follows:

[0246] I. Experimental materials and instruments

[0247] 1. ATR enzyme (Eurofins Pharma Discovery Services, 14-953M)

[0248] 2. GST-tagged P53 protein (Eurofins Pharma Discovery Services, 14-952M)

[0249] 3. 384-well plate (Geriner bio-one, 784075)

[0250] 4. U-bottom 96-well plate (Geriner bio-one, 651201)

[0251] 5. Labeled europium cryptate compound anti-phosphorylated P53 protein antibody (cisbio, 61P08KAZ)

[0252] 6. Anti-GST antibody linked to d2 (cisbio, 61GSTDLB)

[0253] 7. ATP solution (Sigma, R0441)

[0254] 8. DTT (Sigma, D0632-259)

[0255] 9. HEPES (Sigma, 15630080)

[0256] 10. Enzyme reader (Envision 2104 Multilabel Reader).

[0257] II. Experimental procedure

[0258] ATR enzyme 15 nM, p53 protein 80 nM, 300 nM ATP (final concentration 40 nM and 150 nM, respectively), and different concentrations (ten points of final concentration (nM) 2985.0, 895.5, 298.5, 110.56, 33.17, 11.06, 4.09, 1.23, 0.41, 0.15, respectively. Final concentration of dimethyl sulfoxide is 0.498%) of small molecule compounds were mixed and incubated at room temperature for 90 minutes. 10 uL of 2x mixture buffer was added to the mixture of ATR, compounds and substrates in the analysis plate (detection buffer dilutes anti-phosphorylated p53-Eu and anti-GST-d2). Centrifugation at 1000 rpm for 30 seconds. Incubate overnight at 4°C in the dark (a total of 20 microliters in each well). Measure the FRET signal (end point) in the Envision instrument (calculate the HTRF 665 / 612 ratio according to the 665 nm emission and the 612 nm emission). Data is processed using GraphPad software.

[0259] III. Experimental results

[0260] The inhibitory activity of the compounds of the present application on ATR enzyme can be determined by the above experiment, and the IC50 values measured are shown in Table 1.

[0261] Table 1 IC50 values of the compounds of the present application on ATR enzyme inhibition

[0262] Compound IC50 / nM Compound 1 of the present invention 0.39 RP103 0.91 RP3500 1.6

[0263] Conclusion: The compounds of the present application have better inhibitory activity on ATR enzyme.

[0264] Test Example 2, cell proliferation experiment

[0265] The following method evaluates the inhibitory effect of the compounds of the present application on LoVo cell proliferation according to the IC50 size by detecting the ATP content in the cells. The experimental method is briefly described as follows:

[0266] I. Experimental materials and instruments

[0267] 1. LoVo, human colon cancer tumor cells (Nanjing Kebai, CBP60032)

[0268] 2. Fetal bovine serum (GIBCO, 10091-148)

[0269] 3. F-12K medium (ATCC, 30-2004)

[0270] 4. CellTite-Glo reagent (Promega, G7573)

[0271] 5. 96-well cell culture plate (corning, 3599)

[0272] 6. Trypsin (invitrogen, 25200-056)

[0273] 7. Microplate reader (Perkin Elmer).

[0274] II. Experimental procedure

[0275] LoVo cells were cultured in F-12K medium containing 10% FBS, and subcultured 2-3 times a week with a subculture ratio of 1:3 or 1:5. When subcultured, the cells were digested with trypsin and transferred to a centrifuge tube, centrifuged at 1000 rpm for 5 minutes, and the supernatant medium residue was discarded. The cells were resuspended by adding fresh medium. 100 μL of cell suspension was added to a 96-well cell culture plate at a density of 1.5 x 10 4 cells / mL, and 100 μL of complete medium was added only to the periphery of the 96-well plate. The culture plate was incubated in an incubator for 24 hours (37°C, 5% CO2).

[0276] The test sample was diluted to 1 mM with DMSO, and sequentially diluted 3 times to 8 concentrations. The 200X was prepared with cell culture medium, and blank and control wells were set. 5 μL of the test compound solution prepared in gradient concentrations was added to 95 μL of fresh medium. 100 μL (1X compound-containing medium) was further added to the culture plate. The culture plate was incubated in an incubator for 4 days (37°C, 5% CO2). In the 96-well cell culture plate, 50 μL of CellTiter-Glo reagent was added to each well, and it was placed at room temperature in the dark for 5-10 min. The chemiluminescence signal value was read in PHERAstar, and the data was processed using GraphPad software.

[0277] III. Experimental results

[0278] The inhibitory effect of the compound of the present application on LoVo cell proliferation can be determined by the above test, and the IC50 value measured is shown in Table 2

[0279] Table 2 IC50 value of the compound of the present application for LoVo cell proliferation

[0280] Compound IC50 / nM Compound 1 of the present invention 16.7 RP3500 80.6 RP103 86.1

[0281] Test Example 3, Cell proliferation test

[0282] The following method is used to evaluate the inhibitory effect of the compounds of the present application on the proliferation of SNU-601 cells by detecting the ATP content in the cells. The experimental method is briefly described as follows:

[0283] I. Experimental materials and instruments

[0284] 1. SNU-601, human gastric cancer tumor cells (Nanjing Kebai, CBP60507)

[0285] 2. Fetal bovine serum (GIBCO, 10099-141)

[0286] 3. RPMI 1640 medium (Gibco, A1049101)

[0287] 4. CellTite-Glo reagent (Promega, G7573)

[0288] 5. 96-well cell culture plate (corning, 3903)

[0289] 6. Trypsin (Gibco, 25200056)

[0290] 7. Enzyme marker (TECAN, INFINITE M Nano+).

[0291] II. Experimental steps

[0292] SNU-601 cells were cultured in RPMI 1640 medium containing 10% FBS, and subcultured 2-3 times a week with a subculture ratio of 1:5 or 1:10. When subcultured, the cells were trypsinized and transferred to a centrifuge tube, centrifuged at 1000 rpm for 5 minutes, the supernatant medium residue was discarded, and the cells were resuspended with fresh medium. Add 195 μL of cell suspension to a 96-well cell culture plate with a density of 5.128 x 10 3 Cells / mL, and only 200 μL of complete medium was added to the periphery of the 96-well plate. The culture plate was incubated in an incubator for 24 hours (37°C, 5% CO2).

[0293] The sample to be tested was diluted with DMSO to 2 mM, and diluted 3 times in turn to 10 concentrations, and blank and control wells were set. Take 10 μL of the prepared gradient concentration of the test compound solution and add to 50 μL of fresh medium. Add 5 μL of the above medium solution containing the drug to the culture plate. Incubate the culture plate in an incubator for 5 days (37°C, 5% CO2). In the 96-well cell culture plate, discard 100 μL per well, then add 50 μL of CellTiter-Glo reagent to each well, shake for 10 min at room temperature in the dark, and read the chemiluminescence signal value in PHERAstar. The data is processed using GraphPad software.

[0294] III. Experimental Results

[0295] The inhibitory effect of the compound of the present application on the proliferation of SNU-601 cells was measured by the above test, and the IC50 value thus measured is shown in Table 3

[0296] Table 3 IC50 value of the compound of the present application on the proliferation of SNU-601 cells

[0297] Compound IC50 / nM Compound 1 of the present invention 5.8 RP3500 15.8 RP103 23.0

[0298] Test Example 4: Stability Test

[0299] The solid state stability test was performed on the Compound I hydrochloride salt Form I obtained in Example 9, and the test conditions and results are as follows:

[0300]

[0301] Test Example 5: Hygroscopicity Study

[0302] The dynamic water sorption-desorption analysis was performed on the Compound I hydrochloride salt Form I (obtained in Example 9), mesylate salt Form III (obtained in Example 14), and sodium salt amorphous (obtained in Example 15) to study the hygroscopicity. The results are shown in the table below. According to the results, the hygroscopicity was: hydrochloride salt Form I < mesylate salt Form III < sodium salt amorphous.

[0303] Salt form Condition Test result hydrochloride salt Form I 50% RH - 90% RH about 0.1% (w / w) weight gain mesylate salt Form III 50% RH - 90% RH about 8.2% (w / w) weight gain sodium salt 50% RH - 90% RH about 25.0% (w / w) weight gain

[0304] 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 principles of the present application should be included in the scope of the present application.

Claims

1. A salt of Compound I, the structure of which is as follows, characterized in that the salt of Compound I is a besylate salt, a sulfate salt, a p-toluenesulfonate salt, a hydrochloride salt, a maleate salt, a hydrobromide salt, a methanesulfonate salt, a sodium salt, a potassium salt of Compound I.

2. A salt of compound I according to claim 1, characterized in that, which is a besylate salt Form I of Compound I, having characteristic peaks in the X-ray powder diffraction expressed in angles 2θ using Cu-Kα radiation at 8.8±0.2°, 17.7±0.2°, 18.9±0.2°, 20.8±0.2°.

3. The salt of compound I according to claim 2, wherein the besylate salt Form I of Compound I, having characteristic peaks in the X-ray powder diffraction expressed in angles 2θ using Cu-Kα radiation at 8.8±0.2°, 9.4±0.2°, 13.7±0.2°, 16.3±0.2°, 17.7±0.2°, 18.9±0.2°, 20.8±0.2°, 23.2±0.2°.

4. The salt of compound I according to claim 3, wherein the besylate salt Form I of Compound I, having characteristic peaks in the X-ray powder diffraction expressed in angles 2θ using Cu-Kα radiation at 8.8±0.2°, 9.4±0.2°, 11.5±0.2°, 13.7±0.2°, 14.2±0.2°, 15.3±0.2°, 16.3±0.2°, 17.7±0.2°, 18.9±0.2°, 20.8±0.2°, 23.2±0.2°, 24.7±0.2°.

5. A salt of Compound I according to claim 2 or 3 or 4, wherein the besylate salt Form I of Compound I has an X-ray powder diffraction pattern substantially as shown in Figure 1.

6. A salt of Compound I according to claim 2 or 3 or 4, wherein the besylate salt Form I of Compound I has a differential scanning calorimetry curve with an endothermic peak at 184.4°C ± 5°C.

7. The salt of compound I according to claim 6, wherein the besylate salt Form I of Compound I has a DSC pattern substantially as shown in Figure 2.

8. A salt of Compound I according to claim 2 or 3 or 4, wherein the besylate salt Form I of Compound I has a TGA pattern substantially as shown in Figure 3.

9. A salt of Compound I according to claim 1, wherein, which is a besylate salt Form II of Compound I, having characteristic peaks in the X-ray powder diffraction expressed in angles 2θ using Cu-Kα radiation at 7.1±0.2°, 8.5±0.2°, 14.9±0.2°.

10. The salt of compound I according to claim 9, wherein the besylate salt Form II of Compound I, having characteristic peaks in the X-ray powder diffraction expressed in angles 2θ using Cu-Kα radiation at 7.1±0.2°, 8.5±0.2°, 14.9±0.2°, 20.1±0.2°, 21.1±0.2°, 25.3±0.2°.

11. A salt of Compound I according to claim 9 or 10, wherein the besylate salt Form II of Compound I has an X-ray powder diffraction pattern substantially as shown in Figure 4.

12. The salt of compound I according to claim 9 or 10, characterized in that, the besylate salt Form II of Compound I has a differential scanning calorimetry curve with an endothermic peak at 190.6°C ± 5°C.

13. The salt of compound I according to claim 12, wherein the besylate salt Form II of Compound I has a DSC pattern substantially as shown in Figure 5.

14. The salt of compound I according to claim 9 or 10, characterized in that, the besylate salt Form II of Compound I has a TGA pattern substantially as shown in Figure 6.

15. A salt of Compound I according to claim 1, wherein, which is a sulfate salt Form I of Compound I, having an X-ray powder diffraction pattern, expressed in angles 2Θ, using Cu-Kα radiation, with characteristic peaks at 6.5 ± 0.2°, 8.5 ± 0.2°, 17.4 ± 0.2°, 18.5 ± 0.2°, 22.3 ± 0.2°.

16. The salt of compound I according to claim 15, wherein, which is a sulfate salt Form I of Compound I, having an X-ray powder diffraction pattern, expressed in angles 2Θ, using Cu-Kα radiation, with characteristic peaks at 5.8 ± 0.2°, 6.5 ± 0.2°, 8.5 ± 0.2°, 17.4 ± 0.2°, 18.5 ± 0.2°, 21.3 ± 0.2°, 22.3 ± 0.2°, 22.9 ± 0.2°.

17. The salt of compound I according to claim 16, wherein which is a sulfate salt Form I of Compound I, having an X-ray powder diffraction pattern, expressed in angles 2Θ, using Cu-Kα radiation, with characteristic peaks at 5.8 ± 0.2°, 6.5 ± 0.2°, 8.5 ± 0.2°, 15.4 ± 0.2°, 17.4 ± 0.2°, 18.5 ± 0.2°, 19.6 ± 0.2°, 21.3 ± 0.2°, 22.3 ± 0.2°, 22.9 ± 0.2°, 23.4 ± 0.2°, 27.0 ± 0.2°.

18. A salt of Compound I as claimed in claim 15 or 16 or 17, wherein which is a sulfate salt Form I of Compound I, having an X-ray powder diffraction pattern substantially as set out in Figure 7.

19. The salt of compound I according to claim 15 or 16 or 17, characterized in that, which is a sulfate salt Form I of Compound I, having a differential scanning calorimetry curve with an endothermic peak at 120.7 °C ± 5 °C.

20. The salt of compound I according to claim 19, wherein, which is a sulfate salt Form I of Compound I, having a differential scanning calorimetry curve substantially as set out in Figure 8.

21. The salt of compound I according to claim 15 or 16 or 17, characterized in that, which is a sulfate salt Form I of Compound I, having a TGA curve substantially as set out in Figure 9.

22. A salt of Compound I according to claim 1, wherein, which is a sulfate salt Form II of Compound I, having an X-ray powder diffraction pattern, expressed in angles 2Θ, using Cu-Kα radiation, with characteristic peaks at 9.1 ± 0.2°, 9.9 ± 0.2°, 21.2 ± 0.2°.

23. The salt of compound I according to claim 22, wherein, which is a sulfate salt Form II of Compound I, having an X-ray powder diffraction pattern, expressed in angles 2Θ, using Cu-Kα radiation, with characteristic peaks at 9.1 ± 0.2°, 9.9 ± 0.2°, 16.3 ± 0.2°, 17.6 ± 0.2°, 21.2 ± 0.2°, 21.8 ± 0.2°.

24. The salt of compound I according to claim 23, wherein, which is a sulfate salt Form II of Compound I, having an X-ray powder diffraction pattern, expressed in angles 2Θ, using Cu-Kα radiation, with characteristic peaks at 9.1 ± 0.2°, 9.9 ± 0.2°, 15.2 ± 0.2°, 16.3 ± 0.2°, 17.6 ± 0.2°, 19.8 ± 0.2°, 21.2 ± 0.2°, 21.8 ± 0.2°, 24.4 ± 0.2°.

25. The salt of compound I according to claim 22 or 23 or 24, wherein which is a sulfate salt Form II of Compound I, having an X-ray powder diffraction pattern substantially as set out in Figure 10.

26. The salt of compound I according to claim 22 or 23 or 24, wherein which is a sulfate salt Form II of Compound I, having a differential scanning calorimetry curve with an endothermic peak at 151.4 °C ± 5 °C.

27. The salt of compound I according to claim 26, wherein which is a sulfate salt Form II of Compound I, having a differential scanning calorimetry curve substantially as set out in Figure 11.

28. The salt of compound I according to claim 22 or 23 or 24, wherein which is a sulfate salt Form II of Compound I, having a TGA curve substantially as set out in Figure 12.

29. A salt of Compound I according to claim 1, wherein, which is a sulfate salt Form III of Compound I, having an X-ray powder diffraction pattern, expressed in angles 2 theta, using Cu-K alpha radiation, with characteristic peaks at 6.6 ± 0.2°, 8.6 ± 0.2°, 9.0 ± 0.2°, 18.9 ± 0.2°.

30. The salt of compound I according to claim 29, wherein, which is a sulfate salt Form III of Compound I, having an X-ray powder diffraction pattern, expressed in angles 2 theta, using Cu-K alpha radiation, with characteristic peaks at 6.6 ± 0.2°, 8.6 ± 0.2°, 9.0 ± 0.2°, 18.9 ± 0.2°, 21.3 ± 0.2°, 22.4 ± 0.2°.

31. The salt of compound I according to claim 30, wherein which is a sulfate salt Form III of Compound I, having an X-ray powder diffraction pattern, expressed in angles 2 theta, using Cu-K alpha radiation, with characteristic peaks at 4.7 ± 0.2°, 5.9 ± 0.2°, 6.6 ± 0.2°, 8.6 ± 0.2°, 9.0 ± 0.2°, 13.3 ± 0.2°, 17.5 ± 0.2°, 18.9 ± 0.2°, 21.3 ± 0.2°, 22.4 ± 0.2°.

32. The salt of compound I according to claim 29 or 30 or 31, wherein which is a sulfate salt Form III of Compound I, having an X-ray powder diffraction pattern substantially as set out in Figure 13.

33. The salt of compound I according to claim 29 or 30 or 31, wherein which is a sulfate salt Form III of Compound I, having a differential scanning calorimetry curve with an endothermic peak at 143.2 °C ± 5 °C.

34. The salt of compound I according to claim 33, wherein which is a sulfate salt Form III of Compound I, having a DSC pattern substantially as set out in Figure 14.

35. The salt of compound I as claimed in claims 29 or 30 or 31, wherein, which is a sulfate salt Form III of Compound I, having a TGA pattern substantially as set out in Figure 15.

36. A salt of Compound I according to claim 1, wherein, which is a sulfate salt Form IV of Compound I, having an X-ray powder diffraction pattern, expressed in angles 2 theta, using Cu-K alpha radiation, with characteristic peaks at 9.2 ± 0.2°, 9.9 ± 0.2°, 21.0 ± 0.2°, 22.1 ± 0.2°.

37. The salt of compound I according to claim 36, wherein which is a sulfate salt Form IV of Compound I, having an X-ray powder diffraction pattern, expressed in angles 2 theta, using Cu-K alpha radiation, with characteristic peaks at 9.2 ± 0.2°, 9.9 ± 0.2°, 16.2 ± 0.2°, 17.3 ± 0.2°, 19.9 ± 0.2°, 21.0 ± 0.2°, 22.1 ± 0.2°.

38. The salt of compound I according to claim 37, wherein which is a sulfate salt Form IV of Compound I, having an X-ray powder diffraction pattern, expressed in angles 2 theta, using Cu-K alpha radiation, with characteristic peaks at 9.2 ± 0.2°, 9.9 ± 0.2°, 13.6 ± 0.2°, 15.4 ± 0.2°, 16.2 ± 0.2°, 17.3 ± 0.2°, 19.9 ± 0.2°, 21.0 ± 0.2°, 22.1 ± 0.2°, 24.4 ± 0.2°.

39. The salt of compound I according to claim 36 or 37 or 38, wherein which is a sulfate salt Form IV of Compound I, having an X-ray powder diffraction pattern substantially as set out in Figure 16.

40. The salt of compound I as claimed in claims 36 or 37 or 38, wherein, which is a sulfate salt Form IV of Compound I, having a differential scanning calorimetry curve with an endothermic peak at 153.3 °C ± 5 °C.

41. The salt of compound I according to claim 40, wherein, which is a sulfate salt Form IV of Compound I, having a DSC pattern substantially as set out in Figure 17.

42. The salt of compound I as claimed in claims 36 or 37 or 38, wherein, which is a sulfate salt Form IV of Compound I, having a TGA pattern substantially as set out in Figure 18.

43. A salt of Compound I according to claim 1, wherein, It is a p-toluenesulfonic acid salt of compound I, Form I, which has an X-ray powder diffraction pattern with characteristic peaks expressed in angles of 2θ, using Cu-Kα radiation, at 3.6±0.2°, 4.5±0.2°, 5.5±0.2°.

44. The salt of compound I according to claim 43, wherein, It is a p-toluenesulfonic acid salt of compound I, Form I, which has an X-ray powder diffraction pattern with characteristic peaks expressed in angles of 2θ, using Cu-Kα radiation, at 3.6±0.2°, 4.5±0.2°, 5.5±0.2°, 7.1±0.2°, 18.4±0.2°, 19.6±0.2°.

45. The salt of compound I according to claim 44, wherein, It is a p-toluenesulfonic acid salt of compound I, Form I, which has an X-ray powder diffraction pattern with characteristic peaks expressed in angles of 2θ, using Cu-Kα radiation, at 3.6±0.2°, 4.5±0.2°, 5.5±0.2°, 7.1±0.2°, 8.6±0.2°, 10.7±0.2°, 18.4±0.2°, 19.6±0.2°.

46. The salt of compound I according to claim 43 or 44 or 45, wherein The p-toluenesulfonic acid salt of compound I, Form I, has an X-ray powder diffraction pattern substantially as shown in Figure 19.

47. The salt of compound I as claimed in claims 43 or 44 or 45, wherein, The p-toluenesulfonic acid salt of compound I, Form I, has a differential scanning calorimetry curve with an endothermic peak at 136.4°C ± 5°C.

48. The salt of compound I according to claim 47, wherein, The p-toluenesulfonic acid salt of compound I, Form I, has a DSC pattern substantially as shown in Figure 20.

49. The salt of compound I as claimed in claims 43 or 44 or 45, wherein, The p-toluenesulfonic acid salt of compound I, Form I, has a TGA pattern substantially as shown in Figure 21.

50. A salt of Compound I as described in claim 1, wherein, It is a hydrochloride salt of compound I, Form I, of formula (II) wherein the salt formation ratio of compound I to hydrochloric acid is 1:

1.

51. A salt of Compound I according to claim 1, wherein, It is a hydrochloride salt of compound I, Form I, wherein the salt formation ratio of compound I to hydrochloric acid is 1:1; The hydrochloride salt of compound I, Form I, has an X-ray powder diffraction pattern with characteristic peaks expressed in angles of 2θ, using Cu-Kα radiation, at 6.2±0.2°, 7.8±0.2°, 19.0±0.2°, 19.8±0.2°.

52. The salt of compound I according to claim 51, wherein, The hydrochloride salt of compound I, Form I, has an X-ray powder diffraction pattern with characteristic peaks expressed in angles of 2θ, using Cu-Kα radiation, at 6.2±0.2°, 7.3±0.2°, 7.8±0.2°, 12.1±0.2°, 18.1±0.2°, 19.0±0.2°, 19.8±0.2°, 25.9±0.2°.

53. The salt of compound I according to claim 52, wherein, The hydrochloride salt of compound I, Form I, has an X-ray powder diffraction pattern with characteristic peaks expressed in angles of 2θ, using Cu-Kα radiation, at 6.2±0.2°, 7.3±0.2°, 7.8±0.2°, 11.3±0.2°, 12.1±0.2°, 14.8±0.2°, 18.1±0.2°, 19.0±0.2°, 19.8±0.2°, 23.9±0.2°, 25.9±0.2°, 29.6±0.2°.

54. The salt of compound I according to claim 51 or 52 or 53, wherein The hydrochloride salt of compound I, Form I, has an X-ray powder diffraction pattern substantially as shown in Figure 22.

55. The salt of compound I as claimed in claims 51 or 52 or 53, wherein, The hydrochloride salt of compound I, Form I, has a differential scanning calorimetry curve with an endothermic peak at 245.0°C ± 5°C.

56. The salt of compound I according to claim 55, wherein, The hydrochloride salt of compound I, Form I, has a DSC pattern substantially as shown in Figure 23.

57. The salt of compound I as claimed in claims 51 or 52 or 53, wherein, The hydrochloride salt Form I of the compound I has a TGA pattern substantially as shown in Figure 24.

58. A salt of Compound I as described in claim 1, wherein, It is a maleate salt Form I of the compound I, which has characteristic peaks in X-ray powder diffraction expressed in angles of 2-theta using Cu-Kalpha radiation at 3.8±0.2°, 4.9±0.2°, 6.3±0.2°, 17.7±0.2°.

59. The salt of compound I according to claim 58, wherein, The maleate salt Form I of the compound I, which has characteristic peaks in X-ray powder diffraction expressed in angles of 2-theta using Cu-Kalpha radiation at 3.8±0.2°, 4.9±0.2°, 6.3±0.2°, 16.3±0.2°, 17.7±0.2°, 19.2±0.2°, 20.6±0.2°.

60. The salt of compound I according to claim 58 or 59, wherein The maleate salt Form I of the compound I has an X-ray powder diffraction pattern substantially as shown in Figure 25.

61. The salt of compound I according to claim 58 or 59, wherein The maleate salt Form I of the compound I has a differential scanning calorimetry curve with an endothermic peak at 96.9°C±5°C.

62. The salt of compound I according to claim 61, wherein, The maleate salt Form I of the compound I has a DSC pattern substantially as shown in Figure 26.

63. The salt of compound I according to claim 58 or 59, wherein The maleate salt Form I of the compound I has a TGA pattern substantially as shown in Figure 27.

64. A salt of Compound I as described in claim 1, wherein, It is a hydrobromide salt Form I of the compound I, which has characteristic peaks in X-ray powder diffraction expressed in angles of 2-theta using Cu-Kalpha radiation at 6.3±0.2°, 7.6±0.2°, 18.7±0.2°.

65. The salt of compound I according to claim 64, wherein, The hydrobromide salt Form I of the compound I, which has characteristic peaks in X-ray powder diffraction expressed in angles of 2-theta using Cu-Kalpha radiation at 6.3±0.2°, 7.6±0.2°, 16.7±0.2°, 18.7±0.2°, 23.4±0.2°, 25.9±0.2°.

66. The salt of compound I according to claim 65, wherein, The hydrobromide salt Form I of the compound I, which has characteristic peaks in X-ray powder diffraction expressed in angles of 2-theta using Cu-Kalpha radiation at 6.3±0.2°, 7.6±0.2°, 11.4±0.2°, 16.7±0.2°, 18.2±0.2°, 18.7±0.2°, 23.4±0.2°, 25.0±0.2°, 25.9±0.2°, 28.6±0.2°, 30.3±0.2°.

67. The salt of compound I as claimed in claims 64 or 65 or 66, wherein, The hydrobromide salt Form I of the compound I has an X-ray powder diffraction pattern substantially as shown in Figure 28.

68. The salt of compound I as claimed in claims 64 or 65 or 66, wherein, The hydrobromide salt Form I of the compound I has a differential scanning calorimetry curve with an endothermic peak at 241.1°C±5°C.

69. The salt of compound I according to claim 68, wherein, The hydrobromide salt Form I of the compound I has a DSC pattern substantially as shown in Figure 29.

70. The salt of compound I as claimed in claims 64 or 65 or 66, wherein, The hydrobromide salt Form I of the compound I has a TGA pattern substantially as shown in Figure 30.

71. A salt as described in claim 1, characterized in that, which is a mesylate salt of compound I of formula (III), wherein the salt formation ratio of compound I to methanesulfonic acid is 1 :

1.

72. A salt of Compound I as described in claim 1, wherein, It is a methanesulfonate salt Form I of the compound I, which has characteristic peaks in X-ray powder diffraction expressed in angles of 2-theta using Cu-Kalpha radiation at 5.1±0.2°, 6.0±0.2°, 20.4±0.2°.

73. The salt of compound I of claim 72, wherein The mesylate salt crystalline Form I of the compound I has an X-ray powder diffraction pattern with characteristic peaks, expressed in angles 2 theta, using Cu-Kalpha radiation, at 5.1 ± 0.2°, 6.0 ± 0.2°, 10.4 ± 0.2°, 13.8 ± 0.2°, 17.6 ± 0.2°, 20.4 ± 0.2°.

74. The salt of compound I according to claim 72 or 73, wherein The mesylate salt crystalline Form I of the compound I has an X-ray powder diffraction pattern substantially as set out in Figure 31.

75. The salt of compound I according to claim 72 or 73, wherein The mesylate salt crystalline Form I of the compound I has a differential scanning calorimetry curve with an endothermic peak at 117.9 °C ± 5 °C.

76. The salt of compound I according to claim 75, wherein, The mesylate salt crystalline Form I of the compound I has a DSC pattern substantially as set out in Figure 32.

77. The salt of compound I according to claim 72 or 73, wherein The mesylate salt crystalline Form I of the compound I has a TGA pattern substantially as set out in Figure 33.

78. A salt of Compound I as described in claim 1, wherein, The mesylate salt crystalline Form II of the compound I has an X-ray powder diffraction pattern with characteristic peaks, expressed in angles 2 theta, using Cu-Kalpha radiation, at 9.0 ± 0.2°, 9.8 ± 0.2°, 17.4 ± 0.2°, 21.9 ± 0.2°.

79. The salt of compound I according to claim 78, wherein The mesylate salt crystalline Form II of the compound I has an X-ray powder diffraction pattern with characteristic peaks, expressed in angles 2 theta, using Cu-Kalpha radiation, at 9.0 ± 0.2°, 9.8 ± 0.2°, 16.8 ± 0.2°, 17.4 ± 0.2°, 19.5 ± 0.2°, 21.3 ± 0.2°, 21.9 ± 0.2°.

80. The salt of compound I according to claim 79, wherein The mesylate salt crystalline Form II of the compound I has an X-ray powder diffraction pattern with characteristic peaks, expressed in angles 2 theta, using Cu-Kalpha radiation, at 9.0 ± 0.2°, 9.8 ± 0.2°, 14.8 ± 0.2°, 16.0 ± 0.2°, 16.8 ± 0.2°, 17.4 ± 0.2°, 18.1 ± 0.2°, 19.5 ± 0.2°, 21.3 ± 0.2°, 21.9 ± 0.2°.

81. The salt of compound I according to claim 78 or 79 or 80, wherein The mesylate salt crystalline Form II of the compound I has an X-ray powder diffraction pattern substantially as set out in Figure 34.

82. The salt of compound I as claimed in claims 78 or 79 or 80, wherein, The mesylate salt crystalline Form II of the compound I has a differential scanning calorimetry curve with an endothermic peak at 170.3 °C ± 5 °C.

83. The salt of compound I according to claim 82, wherein The mesylate salt crystalline Form II of the compound I has a DSC pattern substantially as set out in Figure 35.

84. The salt of compound I as claimed in claims 78 or 79 or 80, wherein, The mesylate salt crystalline Form II of the compound I has a TGA pattern substantially as set out in Figure 36.

85. A salt of Compound I as described in claim 1, wherein, The mesylate salt crystalline Form III of the compound I, wherein the salt forming ratio of compound I to methanesulfonic acid is 1 : 1; The mesylate salt crystalline Form III of the compound I has an X-ray powder diffraction pattern with characteristic peaks, expressed in angles 2 theta, using Cu-Kalpha radiation, at 8.9 ± 0.2°, 16.7 ± 0.2°, 19.5 ± 0.2°, 22.3 ± 0.2°.

86. The salt of compound I according to claim 85, wherein, The mesylate salt crystalline Form III of the compound I has an X-ray powder diffraction pattern with characteristic peaks, expressed in angles 2 theta, using Cu-Kalpha radiation, at 8.9 ± 0.2°, 14.9 ± 0.2°, 16.7 ± 0.2°, 18.5 ± 0.2°, 19.5 ± 0.2°, 22.3 ± 0.2°, 25.3 ± 0.2°.

87. The salt of compound I according to claim 86, wherein The mesylate salt Form III of Compound I has an X-ray powder diffraction pattern with characteristic peaks, expressed in angles of 2-theta, using Cu-Kalpha radiation at 6.2±0.2°, 8.9±0.2°, 12.0±0.2°, 13.5±0.2°, 14.9±0.2°, 16.7±0.2°, 18.5±0.2°, 19.5±0.2°, 21.5±0.2°, 22.3±0.2°, 25.3±0.2°.

88. The salt of compound I as claimed in claims 85 or 86 or 87, wherein, The mesylate salt Form III of Compound I has an X-ray powder diffraction pattern substantially as set out in Figure 37.

89. The salt of compound I as claimed in claims 85 or 86 or 87, wherein, The mesylate salt Form III of Compound I has a differential scanning calorimetry curve with an endothermic peak at 174.0°C±5°C.

90. The salt of compound I according to claim 89, wherein The mesylate salt Form III of Compound I has a DSC pattern substantially as set out in Figure 38.

91. The salt of compound I as claimed in claims 85 or 86 or 87, wherein, The mesylate salt Form III of Compound I has a TGA pattern substantially as set out in Figure 39.

92. A salt of Compound I as described in claim 1, wherein, which is a sodium salt of Compound I represented by Formula (IV), wherein the salt formation ratio of compound I to sodium ions is 1 :

1.

93. A pharmaceutical composition, characterized in that, The composition comprises a salt of Compound I as defined in any of the preceding claims 1-92.

94. Use of a salt of Compound I as defined in any of the preceding claims 1-92 or a pharmaceutical composition of claim 93 for the manufacture of a medicament for the treatment of a disease mediated by ATR.

95. Use of a salt of Compound I as defined in any of the preceding claims 1-92 or a pharmaceutical composition of claim 93 for the manufacture of a medicament for the treatment of a cancer or a tumor-related disease.

96. The use of claim 95, wherein, The cancer or tumor-related disease is a solid tumor.

97. The use of claim 96, wherein, The cancer or tumor-related disease is a gastrointestinal tumor.

98. The use of claim 97, wherein, The cancer or tumor-related disease is gastric cancer, colorectal cancer.

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