Salt of heterocyclic antitumor compound and crystal form thereof

Abstract

The invention relates to a salt of a heterocyclic antitumor compound and a crystal form thereof. The present invention provides crystalline forms of compound I free base, salts of compound I, and crystalline forms of compound I salts. Some crystal forms and salt forms provided by the invention have excellent effects in the aspects of physical stability, chemical stability, hygroscopicity and the like, have better clinical application value, and can be used as excellent alternative forms for subsequent drug development.

Description

Technical Field

[0001] The present invention relates to the field of pharmaceutical chemistry technology, and specifically, to a salt, a crystal form, and a preparation method thereof of a compound (R)-4-ethynyl-1-(6-(3-methylmorpholinyl)-1-(1H-pyrazol-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. In addition, the present invention also relates to the use of a salt and a crystal form of Compound I in treating ATR-related diseases and disorders. Background Art

[0002] ATR (Ataxia telangiectasia and Rad3-related protein) is a class of protein kinases involved in genome stability and DNA damage repair, and is a member of the PIKK family. ATR activation can be activated by stalled replication forks or DNA single-strand damage (SSB). Activated ATR will recruit repair proteins or repair factors to repair damaged sites, delay the mitotic process (especially in the G2 / M phase of mitosis), 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 the cell cycle process, promote DNA repair, and stabilize replication forks. Since DNA repair in tumor cells may be defective due to the presence of multiple mutations, it shows greater dependence on undamaged DNA repair pathways. Therefore, the synthetic lethality theory can be used to kill specific tumor cells while retaining healthy cells. In current cancer treatments, 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, and the corresponding ATR can initiate a series of downstream targets such as Chk1 (ATR substrate), p53, DNA topoisomerase 2 binding protein (TopBP1), leading to DNA repair and cell cycle arrest. Since the ATR gene rarely mutates, 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 discover more effective and safe ATR inhibitors. Summary of the invention

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

[0005]

[0006] Compound I is an effective ATR inhibitor. In vitro enzyme inhibition activity studies have shown that compound I has a strong inhibitory effect on the ATR enzyme. In vitro cell proliferation inhibition test studies have shown that compound I has a significant inhibitory effect on the proliferation of LoVo cells and SNU-601 cells. Therefore, it can be used as a promising compound for the treatment of ATR-mediated diseases.

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

[0008] One of the purposes of the present invention is to provide a salt of compound I, wherein the structure of compound I is as follows:

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

[0010] Another object of the present invention is to provide a benzenesulfonate crystalline form I of compound I, characterized in that, using Cu-Kα radiation, the X-ray powder diffraction expressed in 2θ angles has characteristic peaks at 8.8±0.2°, 17.7±0.2°, 18.9±0.2°, and 20.8±0.2°.

[0011] Preferably, the benzenesulfonate salt form I of the compound I uses Cu-Kα radiation, and the X-ray powder diffraction expressed in 2θ angles 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°, and 23.2±0.2°.

[0012] More preferably, the benzenesulfonate salt form I of the compound I uses Cu-Kα radiation, and the X-ray powder diffraction expressed in 2θ angles has characteristic peaks 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°, and 24.7±0.2°.

[0013] Further preferably, the benzenesulfonate salt form I of compound I has substantially Figure 1 The X-ray powder diffraction spectrum is shown.

[0014] In some embodiments of the present invention, the benzenesulfonate salt form I of the compound I has an endothermic peak at 184.4°C±5°C in its differential scanning calorimetry curve.

[0015] Further preferably, the benzenesulfonate salt form I of compound I has substantially Figure 2 DSC spectrum shown.

[0016] In some embodiments of the present invention, the benzenesulfonate salt form I of compound I has substantially Figure 3 TGA spectrum shown.

[0017] Another object of the present invention is to provide a benzenesulfonate crystalline form II of compound I, characterized in that, using Cu-Kα radiation, X-ray powder diffraction expressed in 2θ angles has characteristic peaks at 7.1±0.2°, 8.5±0.2°, and 14.9±0.2°.

[0018] Preferably, the benzenesulfonate salt form II of the compound I uses Cu-Kα radiation, and the X-ray powder diffraction expressed in 2θ angles has characteristic peaks at 7.1±0.2°, 8.5±0.2°, 14.9±0.2°, 20.1±0.2°, 21.1±0.2°, and 25.3±0.2°.

[0019] Further preferably, the benzenesulfonate salt form II of compound I has substantially Figure 4 The X-ray powder diffraction spectrum is shown.

[0020] In some embodiments of the present invention, the benzenesulfonate salt form II of the compound I has an endothermic peak at 190.6°C±5°C in its differential scanning calorimetry curve.

[0021] Further preferably, the benzenesulfonate salt form II of compound I has substantially Figure 5 DSC spectrum shown.

[0022] In some embodiments of the present invention, the benzenesulfonate salt form II of compound I has substantially Figure 6 TGA spectrum shown.

[0023] Another object of the present invention is to provide a sulfate crystalline form I of compound I, which uses Cu-Kα radiation and has characteristic peaks in X-ray powder diffraction expressed in 2θ angles at 6.5±0.2°, 8.5±0.2°, 17.4±0.2°, 18.5±0.2°, and 22.3±0.2°.

[0024] Preferably, the sulfate crystalline form I of the compound I uses Cu-Kα radiation, and the X-ray powder diffraction expressed in 2θ angles has 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°, and 22.9±0.2°.

[0025] More preferably, the sulfate form I of the compound I uses Cu-Kα radiation, and the X-ray powder diffraction expressed in 2θ angles has 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°, and 27.0±0.2°.

[0026] Further preferably, the sulfate crystalline form I of compound I has substantially Figure 7 The X-ray powder diffraction spectrum is shown.

[0027] In some embodiments of the present invention, the sulfate salt form I of the compound I has an endothermic peak at 120.7°C±5°C in its differential scanning calorimetry curve.

[0028] Further preferably, the sulfate crystalline form I of the compound I has substantially Figure 8 DSC spectrum shown.

[0029] In some embodiments of the present invention, the sulfate salt form I of compound I has substantially Fig. 9 TGA spectrum shown.

[0030] Another object of the present invention is to provide a sulfate crystalline form II of compound I, which uses Cu-Kα radiation and has characteristic peaks in X-ray powder diffraction expressed in 2θ angles at 9.1±0.2°, 9.9±0.2°, and 21.2±0.2°.

[0031] Preferably, the sulfate crystalline form II of the compound I uses Cu-Kα radiation, and the X-ray powder diffraction expressed in 2θ angles has characteristic peaks at 9.1±0.2°, 9.9±0.2°, 16.3±0.2°, 17.6±0.2°, 21.2±0.2°, and 21.8±0.2°.

[0032] More preferably, the sulfate form II of the compound I uses Cu-Kα radiation, and the X-ray powder diffraction expressed in 2θ angles has 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°, and 24.4±0.2°.

[0033] Further preferably, the sulfate crystalline form II of compound I has substantially Fig.10 The X-ray powder diffraction spectrum is shown.

[0034] In some embodiments of the present invention, the sulfate crystal form II of the compound I has an endothermic peak at 151.4°C±5°C in its differential scanning calorimetry curve.

[0035] Further preferably, the sulfate salt form II of compound I has substantially Fig.11 DSC spectrum shown.

[0036] In some embodiments of the present invention, the sulfate salt form II of compound I has substantially Fig.12 TGA spectrum shown.

[0037] Another object of the present invention is to provide a sulfate crystalline form III of compound I, which uses Cu-Kα radiation and has characteristic peaks in X-ray powder diffraction expressed in 2θ angles at 6.6±0.2°, 8.6±0.2°, 9.0±0.2°, and 18.9±0.2°.

[0038] Preferably, the sulfate crystalline form III of the compound I uses Cu-Kα radiation, and the X-ray powder diffraction expressed in 2θ angles has characteristic peaks at 6.6±0.2°, 8.6±0.2°, 9.0±0.2°, 18.9±0.2°, 21.3±0.2°, and 22.4±0.2°.

[0039] More preferably, the sulfate form III of the compound I uses Cu-Kα radiation, and the X-ray powder diffraction expressed in 2θ angles has 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°, and 22.4±0.2°.

[0040] Further preferably, the sulfate crystalline form III of compound I has substantially Fig.13 The X-ray powder diffraction spectrum is shown.

[0041] In some embodiments of the present invention, the sulfate crystal form III of the compound I has an endothermic peak at 143.2°C±5°C in its differential scanning calorimetry curve.

[0042] Further preferably, the sulfate salt form III of compound I has substantially Fig.14 DSC spectrum shown.

[0043] In some embodiments of the present invention, the sulfate salt form III of compound I has substantially Fig.15 TGA spectrum shown.

[0044] Another object of the present invention is to provide a sulfate crystalline form IV of compound I, which uses Cu-Kα radiation and has characteristic peaks in X-ray powder diffraction expressed in 2θ angles at 9.2±0.2°, 9.9±0.2°, 21.0±0.2°, and 22.1±0.2°.

[0045] Preferably, the sulfate form IV of the compound I uses Cu-Kα radiation, and the X-ray powder diffraction expressed in 2θ angles has 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°, and 22.1±0.2°.

[0046] More preferably, the sulfate form IV of the compound I uses Cu-Kα radiation, and the X-ray powder diffraction expressed in 2θ angles has 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°, and 24.4±0.2°.

[0047] Further preferably, the sulfate crystalline form IV of compound I has substantially Fig.16 The X-ray powder diffraction spectrum is shown.

[0048] In some embodiments of the present invention, the sulfate crystal form IV of the compound I has an endothermic peak at 153.3°C±5°C in its differential scanning calorimetry curve.

[0049] Further preferably, the sulfate crystalline form IV of the compound I has substantially Fig.17 DSC spectrum shown.

[0050] In some embodiments of the present invention, the sulfate salt form IV of compound I has substantially Fig.18 TGA spectrum shown.

[0051] Another object of the present invention is to provide a p-toluenesulfonate crystalline form I of compound I, which uses Cu-Kα radiation and has characteristic peaks in X-ray powder diffraction expressed in 2θ angles at 3.6±0.2°, 4.5±0.2°, and 5.5±0.2°.

[0052] Preferably, the p-toluenesulfonate crystalline form I of the compound I uses Cu-Kα radiation, and the X-ray powder diffraction expressed in 2θ angles has characteristic peaks at 3.6±0.2°, 4.5±0.2°, 5.5±0.2°, 7.1±0.2°, 18.4±0.2°, and 19.6±0.2°.

[0053] More preferably, the p-toluenesulfonate salt form I of the compound I uses Cu-Kα radiation, and the X-ray powder diffraction expressed in 2θ angles has 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°, and 19.6±0.2°.

[0054] Further preferably, the p-toluenesulfonate crystalline form I of compound I has substantially Fig.19 The X-ray powder diffraction spectrum is shown.

[0055] In some embodiments of the present invention, the p-toluenesulfonate crystalline form I of the compound I has an endothermic peak at 136.4°C±5°C in its differential scanning calorimetry curve.

[0056] Further preferably, the p-toluenesulfonate crystalline form I of the compound I has substantially Fig. 20 DSC spectrum shown.

[0057] In some embodiments of the present invention, the p-toluenesulfonate crystalline form I of compound I has substantially Fig.21 TGA spectrum shown.

[0058] Another object of the present invention is to provide a hydrochloride salt of compound I as shown in formula (II),

[0059] The salt formation ratio of compound I to hydrochloric acid is 1:1.

[0060] Another object of the present invention is to provide a hydrochloride crystal form I of compound I, wherein the salt-forming ratio of compound I to hydrochloric acid is 1:1.

[0061] Preferably, the hydrochloride form I of the compound I has characteristic peaks at 6.2±0.2°, 7.8±0.2°, 19.0±0.2°, and 19.8±0.2° in X-ray powder diffraction expressed in 2θ angles using Cu-Kα radiation.

[0062] More preferably, the hydrochloride form I of the compound I has characteristic 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°, and 25.9±0.2° in X-ray powder diffraction expressed in 2θ angles using Cu-Kα radiation.

[0063] More preferably, the hydrochloride form I of the compound I uses Cu-Kα radiation, and the X-ray powder diffraction expressed in 2θ angles is 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] There are characteristic peaks at 25.9±0.2° and 29.6±0.2°.

[0066] Further preferably, the hydrochloride salt form I of compound I has substantially Fig. 22 The X-ray powder diffraction spectrum is shown.

[0067] In some embodiments of the present invention, the hydrochloride form I of the compound I has an endothermic peak at 245.0°C±5°C in its differential scanning calorimetry curve.

[0068] Further preferably, the hydrochloride salt form I of the compound I has substantially Fig.23 DSC spectrum shown.

[0069] In some embodiments of the present invention, the hydrochloride salt form I of compound I has substantially Fig.24 TGA spectrum shown.

[0070] Another object of the present invention is to provide a maleate crystalline form I of compound I, which uses Cu-Kα radiation and has characteristic peaks in X-ray powder diffraction expressed in 2θ angles at 3.8±0.2°, 4.9±0.2°, 6.3±0.2°, and 17.7±0.2°.

[0071] Preferably, the maleate salt form I of the compound I uses Cu-Kα radiation, and the X-ray powder diffraction expressed in 2θ angles has 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°, and 20.6±0.2°.

[0072] Further preferably, the maleate salt form I of compound I has substantially Fig.25 The X-ray powder diffraction spectrum is shown.

[0073] In some embodiments of the present invention, the maleate salt form I of the compound I has an endothermic peak at 96.9°C±5°C in its differential scanning calorimetry curve.

[0074] Further preferably, the maleate salt form I of compound I has substantially Fig.26 DSC spectrum shown.

[0075] In some embodiments of the present invention, the maleate salt form I of compound I has substantially Fig. 27 TGA spectrum shown.

[0076] Another object of the present invention is to provide a hydrobromide salt form I of compound I, which uses Cu-Kα radiation and has characteristic peaks in X-ray powder diffraction expressed in 2θ angles at 6.3±0.2°, 7.6±0.2°, and 18.7±0.2°.

[0077] Preferably, the hydrobromide salt form I of the compound I uses Cu-Kα radiation, and the X-ray powder diffraction expressed in 2θ angles has characteristic peaks at 6.3±0.2°, 7.6±0.2°, 16.7±0.2°, 18.7±0.2°, 23.4±0.2°, and 25.9±0.2°.

[0078] More preferably, the hydrobromide salt form I of the compound I uses Cu-Kα radiation, and the X-ray powder diffraction expressed in 2θ angles has 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°, and 30.3±0.2°.

[0079] Further preferably, the hydrobromide salt form I of compound I has substantially Fig.28 The X-ray powder diffraction spectrum is shown.

[0080] In some embodiments of the present invention, the hydrobromide salt form I of the compound I has an endothermic peak at 241.1°C±5°C in its differential scanning calorimetry curve.

[0081] Further preferably, the hydrobromide salt form I of the compound I has substantially Fig.29 DSC spectrum shown.

[0082] In some embodiments of the present invention, the hydrobromide salt form I of compound I has substantially Fig.30 TGA spectrum shown.

[0083] Another object of the present invention is to provide a mesylate salt of compound I represented by formula (III), The salt formation ratio of compound I to methanesulfonic acid is 1:1.

[0084] Another object of the present invention is to provide a mesylate crystalline form I of compound I, which uses Cu-Kα radiation and has characteristic peaks in X-ray powder diffraction expressed in 2θ angles at 5.1±0.2°, 6.0±0.2°, and 20.4±0.2°.

[0085] Preferably, the mesylate salt form I of the compound I uses Cu-Kα radiation, and the X-ray powder diffraction expressed in 2θ angles has characteristic peaks at 5.1±0.2°, 6.0±0.2°, 10.4±0.2°, 13.8±0.2°, 17.6±0.2°, and 20.4±0.2°.

[0086] Further preferably, the mesylate salt form I of compound I has substantially Fig.31 The X-ray powder diffraction spectrum is shown.

[0087] In some embodiments of the present invention, the mesylate salt form I of the compound I has an endothermic peak at 117.9°C±5°C in its differential scanning calorimetry curve.

[0088] Further preferably, the mesylate salt form I of compound I has substantially Fig.32 DSC spectrum shown.

[0089] In some embodiments of the present invention, the mesylate salt form I of compound I has substantially Fig.33 TGA spectrum shown.

[0090] Another object of the present invention is to provide a mesylate crystalline form II of compound I, which uses Cu-Kα radiation and has characteristic peaks in X-ray powder diffraction expressed in 2θ angles at 9.0±0.2°, 9.8±0.2°, 17.4±0.2°, and 21.9±0.2°.

[0091] Preferably, the mesylate salt form II of the compound I uses Cu-Kα radiation, and the X-ray powder diffraction expressed in 2θ angles 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°, and 21.9±0.2°.

[0092] More preferably, the mesylate form II of the compound I uses Cu-Kα radiation, and the X-ray powder diffraction expressed in 2θ angles 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°, and 21.9±0.2°.

[0093] Further preferably, the mesylate salt form II of compound I has substantially Fig.34 The X-ray powder diffraction spectrum is shown.

[0094] In some embodiments of the present invention, the mesylate crystal form II of the compound I has an endothermic peak at 170.3°C±5°C in its differential scanning calorimetry curve.

[0095] Further preferably, the mesylate salt form II of compound I has substantially Fig.35 DSC spectrum shown.

[0096] In some embodiments of the present invention, the mesylate salt form II of compound I has substantially Fig.36 TGA spectrum shown.

[0097] Another object of the present invention is to provide a mesylate crystalline form III of compound I, wherein the salt ratio of compound I to methanesulfonic acid in the mesylate crystalline form III is 1:1.

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

[0099] More preferably, the mesylate salt form III of the compound I uses Cu-Kα radiation, and the X-ray powder diffraction expressed in 2θ angles has characteristic peaks 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°, and 25.3±0.2°.

[0100] More preferably, the mesylate salt form III of the compound I uses Cu-Kα radiation, and the X-ray powder diffraction expressed in 2θ angles is 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] There are characteristic peaks.

[0102] Further preferably, the mesylate salt form III of compound I has substantially Fig.37 The X-ray powder diffraction spectrum is shown.

[0103] In some embodiments of the present invention, the mesylate crystal form III of the compound I has an endothermic peak at 174.0°C±5°C in its differential scanning calorimetry curve.

[0104] Further preferably, the mesylate salt form III of compound I has substantially Fig.38 DSC spectrum shown.

[0105] In some embodiments of the present invention, the mesylate salt form III of compound I has substantially Fig.39 TGA spectrum shown.

[0106] Another object of the present invention is to provide a sodium salt of compound I represented by formula (IV),

[0107] The salt formation ratio of compound I to sodium ion is 1:1.

[0108] In yet another aspect, the present invention provides a pharmaceutical composition comprising the benzenesulfonate, sulfate, p-toluenesulfonate, hydrochloride, maleate, hydrobromide, methanesulfonate, sodium salt, and potassium salt of Compound I.

[0109] The present invention also provides a pharmaceutical composition, which comprises the benzenesulfonate crystalline form I, benzenesulfonate crystalline form II, sulfate crystalline form I, sulfate crystalline form II, sulfate crystalline form III, sulfate crystalline form IV, p-toluenesulfonate crystalline form I, hydrochloride crystalline form I, maleate crystalline form I, hydrobromide crystalline form I, methanesulfonate crystalline form I, methanesulfonate crystalline form II, and methanesulfonate crystalline form III of the aforementioned compound I.

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

[0111] The present invention also provides the use of benzenesulfonate crystalline form I, benzenesulfonate crystalline form II, sulfate crystalline form I, sulfate crystalline form II, sulfate crystalline form III, sulfate crystalline form IV, p-toluenesulfonate crystalline form I, hydrochloride crystalline form I, maleate crystalline form I, hydrobromide crystalline form I, methanesulfonate crystalline form I, methanesulfonate crystalline form II, methanesulfonate crystalline form III or the pharmaceutical composition of the present invention in the preparation of a drug for treating a disease mediated by ATR. Preferably, the disease mediated by ATR is cancer or a tumor-related disease.

[0112] Furthermore, the purpose of the present invention also includes providing the use of the benzenesulfonate, sulfate, p-toluenesulfonate, hydrochloride, maleate, hydrobromide, methanesulfonate, sodium salt, potassium salt of the compound I of the present invention or the pharmaceutical composition of the present invention in the preparation of a medicament for treating cancer or tumor-related diseases; preferably, the cancer or tumor-related disease is a solid tumor; more preferably, the cancer or tumor-related disease is a digestive tract tumor; more preferably, the cancer or tumor-related disease is gastric cancer or colorectal cancer.

[0113] Furthermore, the purpose of the present invention also includes providing the use of benzenesulfonate salt form I, benzenesulfonate salt form II, sulfate salt form I, sulfate salt form II, sulfate salt form III, sulfate salt form IV, p-toluenesulfonate salt form I, hydrochloride salt form I, maleate salt form I, hydrobromide salt form I, methanesulfonate salt form I, methanesulfonate salt form II, methanesulfonate salt form III or the pharmaceutical composition of the present invention in the preparation of a medicament for treating cancer or tumor-related diseases; preferably, the cancer or tumor-related disease is a solid tumor; more preferably, the cancer or tumor-related disease is a digestive tract tumor; more preferably, the cancer or tumor-related disease is gastric cancer or colorectal cancer.

[0114] In order to treat tumor diseases, the benzenesulfonate, sulfate, p-toluenesulfonate, hydrochloride, maleate, hydrobromide, methanesulfonate, sodium salt, potassium salt, benzenesulfonate crystal form I, benzenesulfonate crystal form II, sulfate crystal form I, sulfate crystal form II, sulfate crystal form III, sulfate crystal form IV, p-toluenesulfonate crystal form I, hydrochloride crystal form I, maleate crystal form I, hydrobromide crystal form I, methanesulfonate crystal form I, methanesulfonate crystal form II, and methanesulfonate crystal form III of the compound I can be co-administered with other therapeutic agents (such as chemotherapeutic drugs, biotherapeutic drugs, etc.) or combined with other therapeutic means for treatment, and the other therapeutic means include but are not limited to radiotherapy.

[0115] Beneficial Effects

[0116] The present invention provides for the first time a variety of salt forms of compound I. Some salt forms provided by the present invention have excellent effects in terms of 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 THE DRAWINGS

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

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

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

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

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

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

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

[0124] Figure 8 This is the DSC spectrum of Compound I sulfate form I.

[0125] Fig. 9 This is the TGA spectrum of Compound I sulfate form I.

[0126] Fig.10 This is the XRPD spectrum of Compound I sulfate form II.

[0127] Fig.11 This is the DSC spectrum of Compound I sulfate crystal form II.

[0128] Fig.12 This is the TGA spectrum of Compound I sulfate crystal form II.

[0129] Fig.13 This is the XRPD spectrum of Compound I sulfate form III.

[0130] Fig.14 This is the DSC spectrum of Compound I sulfate form III.

[0131] Fig.15 This is the TGA spectrum of Compound I sulfate form III.

[0132] Fig.16 This is the XRPD spectrum of Compound I sulfate form IV.

[0133] Fig.17 This is the DSC spectrum of Compound I sulfate crystal form IV.

[0134] Fig.18 This is the TGA spectrum of Compound I sulfate crystal form IV.

[0135] Fig.19 This is the XRPD spectrum of Compound 1 p-toluenesulfonate Form I.

[0136] Fig. 20 This is the DSC spectrum of Compound I p-toluenesulfonate Form I.

[0137] Fig.21 This is the TGA spectrum of Compound I p-toluenesulfonate Form I.

[0138] Fig. 22 This is the XRPD spectrum of Compound 1 hydrochloride Form I.

[0139] Fig.23 This is the DSC spectrum of Compound I hydrochloride Form I.

[0140] Fig.24 This is the TGA spectrum of Compound I hydrochloride Form I.

[0141] Fig.25 This is the XRPD spectrum of Compound I maleate salt Form I.

[0142] Fig.26 This is the DSC spectrum of Compound I maleate salt Form I.

[0143] Fig. 27 This is the TGA spectrum of Compound I maleate salt Form I.

[0144] Fig.28 This is the XRPD spectrum of Compound 1 hydrobromide salt Form I.

[0145] Fig.29 This is the DSC spectrum of Compound I hydrobromide salt Form I.

[0146] Fig.30 This is the TGA spectrum of Compound I hydrobromide salt Form I.

[0147] Fig.31 This is the XRPD spectrum of Compound 1 mesylate Form I.

[0148] Fig.32 This is the DSC spectrum of Compound I mesylate Form I.

[0149] Fig.33 This is the TGA spectrum of Compound I mesylate Form I.

[0150] Fig.34 This is the XRPD spectrum of Compound I mesylate Form II.

[0151] Fig.35 This is the DSC spectrum of Compound I mesylate Form II.

[0152] Fig.36 This is the TGA spectrum of Compound I mesylate Form II.

[0153] Fig.37 This is the XRPD spectrum of Compound I mesylate Form III.

[0154] Fig.38 This is the DSC spectrum of Compound I mesylate Form III.

[0155] Fig.39 This is the TGA spectrum of Compound I mesylate Form III.

[0156] Fig.40 Compound I mesylate salt form III 1 H NMR spectrum. DETAILED DESCRIPTION

[0157] The technical scheme of the present invention will be further described in detail below in conjunction with specific embodiments. The following embodiments are only exemplary to illustrate and explain the present invention, and should not be construed as limiting the scope of protection of the present invention. All technologies implemented based on the above content of the present invention are included in the scope that the present invention is intended to protect.

[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 Compound I in the present invention is determined by nuclear magnetic resonance (NMR) or / and liquid chromatography-mass spectrometry (LC-MS) or / and liquid chromatography (HPLC). The instrument used for NMR determination is Agilent 400 / 54 PremiumShielded NMR Magnet System, the instrument used for LC-MS is Shimadzu LCMS2020; the instrument used for HPLC is Agilent 1200. The instruments and detection parameters used for the salt / salt type 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-pyrazol-3-yl)-1H-pyrazolyl[3,4-b]pyridin-4-yl)cyclohexanol (Compound I):

[0165]

[0166] Step 1: Preparation of 4-((tert-butyldiphenylsilyloxy)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 the mixture was heated to room temperature and stirred for 2 hours. The reaction was complete by spot plate monitoring. The organic phases were separated by water and dichloromethane, and the organic phases were combined, dried, filtered, and concentrated. The target compound (1.5 g, yield 58.2%) was obtained by column chromatography (petroleum ether: ethyl acetate = 50:1). 1H NMR (400MHz, DMSO-d6) δ7.65(d,J=3.6Hz,1H),7.58(d,J=5.9Hz,4H),7.41(d,J=6.7Hz,4H),7.35(s,1H),3. 53(d,J=5.8Hz,2H),2.40–2.31(m,2H),2.15(d,J=14.0Hz,2H),1.98(s,3H),1.40–1.31(m,2H),0.97(s,9H).

[0169] Step 2: Preparation of 4-((tert-butyldiphenylsilyl)oxy)methyl)cyclohex-1-ene-1-yl trifluoromethylsulfonate:

[0170]

[0171] 4-((tert-butyldiphenylsilyloxy)methyl)cyclohexanone (700.0 mg, 1.91 mmol, 1 equiv.) was dissolved in tetrahydrofuran (5 mL), and lithium bistrimethylsilylamide (2.4 mL, 14.65 mmol, 1.2 equiv.) was added at -78°C, and stirred at -78°C for 45 minutes. 1,1,1-trifluoro-N-phenyl-N-((trifluoromethyl)sulfonyl)methanesulfonamide (750.4 mg, 2.10 mmol, 1.1 equiv.) dissolved in tetrahydrofuran was added, and stirred at room temperature for 3 hours. The reaction of the raw material was completed by spot plate monitoring. The organic phases were separated by ethyl acetate and water, and the organic phases were combined, dried, filtered, and concentrated. The target compound (560.0 mg, yield 58.8%) was obtained by column chromatography (petroleum ether: ethyl acetate = 100:1). 1 H NMR(400MHz,DMSO-d6)δ7.57(d,J=7.0Hz,4H),7.41(d,J=7.1Hz,5H),5.85(s,1H),3.54 (d,J=6.1Hz,2H),2.24(d,J=18.9Hz,2H),2.02–1.70(m,4H),1.48(s,1H),0.97(s,9H).

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

[0173]

[0174] 4-((tert-butyldiphenylsilyl)oxy)methyl)cyclohex-1-en-1-yl trifluoromethanesulfonate (560.0 mg, 1.12 mmol, 1 equiv.), biboric acid pinacol ester (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 three times, stirred at 90°C for 16 hours, and the reaction was completed with a plate spot monitor. The reaction solution was filtered through diatomaceous earth, the filtrate was separated with ethyl acetate and water, the organic phases were combined, dried, filtered and concentrated, and purified by column chromatography (petroleum ether: ethyl acetate = 100: 1) to obtain the target compound (340.0 mg, yield 63.2%). 1 H NMR (400MHz, DMSO-d6) δ7.57(d,J=6.5Hz,4H),7.41(d,J=6.5Hz,6H),5.29(s,1H),3.50(d,J=5.9Hz, 2H), 2.07(d,J=19.8Hz,1H),1.99–1.92(m,4H),1.70(s,4H),1.42(s,1H),1.15(s,12H),0.96(s,9H).

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

[0176]

[0177] Tert-butyldiphenyl((4-(4,4,5,5-tetramethyl-1,3,2-dioxybenzaldehyde-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-pyrazolo[3,4-b]pyridine-6-yl)- 1,4-dioxane (6 mL) and water (3 mL) were stirred at 90°C for 2 hours. The reaction was complete as monitored by LCMS. The reaction solution was filtered through celite, and the filtrate was separated by ethyl acetate and water. The organic phases were combined, dried, filtered, and concentrated. The target compound (260.0 mg, yield 47.7%) was obtained by HPLC (petroleum ether: ethyl acetate = 3:1). 1 H NMR(400MHz, CDCl3)δ8.04(d,J=5.1Hz,1H),7.71–7.60(m,5H),7.40(t,J=8.3Hz,6H),6.59(s,2H), 6.42(s,1H),6.36(s,1H),5.71(t,J=12.6Hz,3H),4.31(d,J=21.8Hz,1H),3.97(t,J=14.3Hz,3H),3 .74(dd,J=29.1,14.3Hz,3H),3.63(d,J=5.8Hz,2H),3.57(s,1H),3.40(d,J=8.0Hz,3H),3.25(d,J= 12.9Hz, 1H), 1.26 (dd, J = 11.4, 5.9Hz, 9H), 1.06 (s, 9H), 0.78–0.70 (m, 3H), -0.17 (d, J = 4.4Hz, 14H).

[0178] Step 5: 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] (3R)-4-(4-(tert-Butyldiphenylsilyloxy)methyl)cyclohex-1-en-1-yl)-1-(1-(2-(trimethylsilyloxy)ethoxy)methyl)-1H-pyrazol-5-yl)-1H-pyrazolyl[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). Tris(2,2,6,6-tetramethyl-3,5-heptanedione)manganese (41.4 mg, 0.07 mmol, 0.2 equiv.) and phenylsilane (73.7 mg, 0.68 mmol, 2 equiv.) were added under ice bath. Oxygen was replaced three times and the mixture was stirred at room temperature for 2 hours. LCMS monitoring showed that the reaction of the raw material was complete. The reaction solution was separated by ethyl acetate and water, the organic phases were combined, dried, filtered and concentrated, and purified by HPLC (petroleum ether: ethyl acetate = 2:1) to obtain the target compound (200.0 mg, yield 75.1%). LCMS (ESI) [M+H] + =781.40.

[0181] Step 6: Preparation of (R)-4-(hydroxymethyl)-1-(6-(3-methylmorpholinyl)-1-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5-yl)-1H-pyrazolo[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-pyrazolyl[3,4-b]pyridin-4-yl)cyclohexanol (200.0 mg, 0.26 mmol, 1 equiv.) was dissolved in tetrahydrofuran (2 mL), and a 1 M tetrabutylammonium fluoride (2 mL) tetrahydrofuran solution was added, and the mixture was stirred at room temperature overnight. The reaction was complete as monitored by LCMS. The reaction solution was quenched with saturated aqueous ammonium chloride solution, extracted with ethyl acetate, and the organic phases were combined, dried, filtered, and concentrated. The target compound (130.0 mg, yield 93.55%) was obtained by HPLC (petroleum ether:ethyl acetate = 1:1). LCMS (ESI) [M+H] + =543.55.

[0184] Step 7: Preparation of (R)-4-hydroxy-4-(6-(3-methylmorpholinyl)-1-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5-yl)-1H-pyrazolo[3,4-b]pyridin-4-yl)cyclohexanecarbaldehyde:

[0185]

[0186] (R)-4-(Hydroxymethyl)-1-(6-(3-methylmorpholinyl)-1-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5-yl)-1H-pyrazolo[3,4-b]pyridin-4-yl)cyclohexanol (130.0 mg, 0.24 mmol, 1 equiv.) was dissolved in dichloromethane (4 mL), and Dess-Martin periodinane (203.1 mg, 0.48 mmol, 2 equiv.) was added under ice bath, and the mixture was heated to room temperature and stirred for 2 hours. LCMS monitoring showed that the reaction was complete. The reaction solution was filtered through celite, and the filtrate was quenched with saturated aqueous sodium thiosulfate solution, extracted with ethyl acetate, and the organic phases were combined, dried, filtered, and concentrated. The target compound (100.0 mg, yield 75.1%) was obtained by climbing a large plate (petroleum ether: ethyl acetate = 1:1). LCMS (ESI) [M+H] + =541.30.

[0187] Step 8: Preparation of ((R)-4-ethynyl-1-(6-(3-methylmorpholinyl)-1-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolyl-5-yl)-1H-pyrazolyl[3,4-b]pyridin-4-yl)cyclohexanol:

[0188]

[0189] (R)-4-hydroxy-4-(6-(3-methylmorpholinyl)-1-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5-yl)-1H-pyrazolo[3,4-b]pyridin-4-yl)cyclohexanecarbaldehyde (100.0 mg, 0.18 mmol, 1 equiv.), dimethyl (1-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) and stirred at room temperature overnight. The reaction was complete as monitored by LCMS. The reaction solution was partitioned between ethyl acetate and water, the organic phases were combined, dried, filtered and concentrated, and purified by agar plate (dichloromethane: methanol = 15: 1) to give the target compound (87.0 mg, yield 87.6%). LCMS (ESI) [M+H] + =537.35.

[0190] Step 9: Preparation of (R)-4-ethynyl-1-(6-(3-methylmorpholinyl)-1-(1H-pyrazolyl-3-yl)-1H-pyrazolyl[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-pyrazolyl[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), and triethylsilane (0.2 mL) was added and stirred at room temperature for 1 hour. LCMS monitoring showed that the reaction was complete. The reaction solution was adjusted to alkalinity with saturated sodium bicarbonate aqueous solution and extracted with ethyl acetate. The organic phases were combined, dried, filtered, and concentrated. The target compound (46.2 mg, yield 67.7%) was obtained by HPLC (dichloromethane: methanol = 10:1). LCMS (ESI) [M+H] + =407.20; 1 H NMR (400MHz, DMSO-d6) δ12.76(s,1H),8.24(s,1H),7.80(s,1H),6.77(d,J=12.5Hz,2H),5.2 3(s,1H),4.40(s,1H),4.03–3.90(m,2H),3.73(d,J=10.9Hz,1H),3.61(d,J=10.7Hz,1H),3.4 6(t,J=11.3Hz,1H),3.13(t,J=11.8Hz,1H),2.86(s,1H),2.54(s,1H),1.96(d,J=12.5Hz,2H ), 1.85 (dd, J = 24.4, 12.5Hz, 2H), 1.76 (s, 2H), 1.67 (d, J = 12.1Hz, 2H), 1.15 (d, J = 6.1Hz, 3H).

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

[0194] About 50 mg of compound I sample was added to 2.8 mL of acetone and dissolved 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 stirred overnight to obtain a suspension; the suspension was centrifuged and the solid was placed at 40°C and vacuum dried overnight to obtain benzenesulfonate salt form I. The XRPD test results of this form I are as follows Figure 1 As shown, the DSC and TGA test results are as follows Figure 2 , 3 The XRPD diffraction peak data of this crystal form I are shown below.

[0195] 2θ angle (°) Peak height Relative strength (%) 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] Example 3 Preparation of Compound I Benzenesulfonate Crystalline Form II

[0197] About 50 mg of compound I sample was added to 3 mL of acetonitrile and dissolved in a water bath at 60°C to obtain solution 1; about 24 mg of benzenesulfonic acid was dissolved in 0.1 mL of acetonitrile 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 precipitated from solution 3, and the solution was stirred at 4°C overnight to precipitate a large amount of solid to obtain a suspension; the suspension was centrifuged, and the solid was placed at 40°C and vacuum dried overnight to obtain benzenesulfonate salt form II. The XRPD test results of this form II are as follows Figure 4 As shown, the DSC and TGA test results are as follows Figure 5 , 6 The XRPD diffraction peak data of this crystal form II are shown below.

[0198] 2θ angle (°) Peak height Relative strength (%) 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] Example 4 Preparation of Compound I Sulfate Form I

[0200] About 50 mg of compound I sample was added to 2.8 mL of acetone and dissolved in a water bath at 60°C to obtain solution 1; about 13 mg of sulfuric 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; if solution 3 did not precipitate, 8 mL of n-heptane was added to precipitate and stirred to dissolve, and the mixture was stirred at 4°C overnight to precipitate solids to obtain a suspension; the suspension was centrifuged, and the solids were placed at 40°C and dried in vacuum overnight to obtain sulfate crystal form I. The XRPD test results of this crystal form I are as follows: Figure 7 As shown, the DSC and TGA test results are as follows Figure 8 , 9 The XRPD diffraction peak data of this crystal form I are shown below.

[0201] 2θ angle (°) Peak height Relative strength (%) 5.788 517 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] Example 5 Preparation of Compound I Sulfate Crystalline Form II

[0203] About 50 mg of compound I sample was added to 6 mL of ethyl acetate and dissolved in a water bath at 60°C to obtain solution 1; about 13 mg of sulfuric 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; solution 3 was immediately precipitated to obtain a suspension, which was continued to be stirred overnight to obtain a suspension; the suspension was centrifuged, and the solid was placed at 40°C and vacuum dried overnight to obtain sulfate crystal form II. The XRPD test results of this crystal form II are as follows Fig.10 As shown, the DSC and TGA test results are as follows Fig.11 , 12 The XRPD diffraction peak data of this crystal form II are shown below.

[0204] 2θ angle (°) Peak height Relative strength (%) 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] Example 6 Preparation of Compound I Sulfate Form III

[0206] About 50 mg of compound I sample was added to 1 mL of tetrahydrofuran, dissolved in a water bath at 70°C to obtain solution 1; about 13 mg of sulfuric 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 did not precipitate, and was stirred at 12°C overnight without precipitation, and 4 mL of n-heptane was added to precipitate to obtain a suspension; the suspension was centrifuged, and the solid was placed at 40°C and vacuum dried overnight to obtain sulfate crystal form III. The XRPD test results of this crystal form III are as follows Fig.13 As shown, the DSC and TGA test results are as follows Fig.14 , 15 The XRPD diffraction peak data of this crystal form III are shown below.

[0207] 2θ angle (°) Peak height Relative strength (%) 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] Example 7 Preparation of Compound I Sulfate Form IV

[0209] About 50 mg of compound I sample was added to 3 mL of acetonitrile and dissolved in a water bath at 60°C to obtain solution 1; about 13 mg of sulfuric acid was dissolved in 0.1 mL of acetonitrile 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 overnight without precipitation, 10 mL of methyl tert-butyl ether was added and stirred at 4°C overnight to precipitate to obtain a suspension; the suspension was centrifuged, and the solid was placed at 40°C and vacuum dried overnight to obtain sulfate crystal form IV. The XRPD test results of this crystal form IV are as follows Fig.16 As shown, the DSC and TGA test results are as follows Fig.17 , 18 The XRPD diffraction peak data of this crystal form IV are shown below.

[0210] 2θ angle (°) Peak height Relative strength (%) 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] Example 8 Preparation of Compound I p-Toluenesulfonate Crystal Form I

[0212] About 50 mg of compound I sample was added to 2.8 mL of acetone and dissolved in a water bath at 60°C to obtain solution 1; about 26 mg of p-toluenesulfonic 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 did not precipitate, and 3 mL of n-heptane solution was added to turn blue, and the solution was stirred overnight to precipitate solids to obtain a suspension; the suspension was centrifuged, and the solid was placed at 40°C and vacuum dried overnight to obtain p-toluenesulfonate salt form I. The XRPD test results of this form I are as follows: Fig.19As shown, the DSC and TGA test results are as follows Fig. 20 , 21 The XRPD diffraction peak data of this crystal form I are shown below.

[0213] 2θ angle (°) Peak height Relative strength (%) 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] Example 9 Preparation of Compound I Hydrochloride Form I

[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 minutes to precipitate, and stirred for 3 days to obtain a suspension; the suspension was filtered under reduced pressure, and the solid was placed at 40°C and vacuum dried overnight to obtain hydrochloride crystal form I (242 mg). The XRPD test results of this crystal form I are as follows Fig. 22 As shown, the DSC and TGA test results are as follows Fig.23 , 24 The salt ratio was determined to be 1:1 by IC method (ion chromatography). The XRPD diffraction peak data of this crystal form I are shown below.

[0216] 2θ angle (°) Peak height Relative strength (%) 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] Example 10 Preparation of Compound I Maleate Salt Form I

[0218] About 50 mg of compound I sample was added to 1 mL of tetrahydrofuran, dissolved in a 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 transferred to 12°C overnight without precipitation, and 4 mL of n-heptane was added to precipitate solid to obtain a suspension; the suspension was centrifuged, and the solid was placed at 40°C and vacuum dried overnight to obtain maleate salt form I. The XRPD test results of this form I are as follows: Fig.25 As shown, the DSC and TGA test results are as follows Fig.26 , 27 The XRPD diffraction peak data of this crystal form I are shown below.

[0219] 2θ angle (°) Peak height Relative strength (%) 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] Example 11 Preparation of Compound I Hydrobromide Form I

[0221] About 50 mg of compound I sample was added to 4 mL of ethanol and dissolved in a water bath at 60°C 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 stirred for 10 minutes and immediately precipitated, and stirred overnight to obtain a suspension; the suspension was centrifuged, and the solid was placed at 40°C and vacuum dried overnight to obtain hydrobromide salt form I. The XRPD test results of this form I are as follows: Fig.28 As shown, the DSC and TGA test results are as follows Fig.29 , 30 shown.

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

[0223] 2θ angle (°) Peak height Relative strength (%) 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] Example 12 Preparation of Compound I Methanesulfonate Form I

[0225] About 50 mg of compound I sample was added to 2.8 mL of acetone and dissolved in a 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 stirred to precipitate and stirred for 24 hours to a suspension; the suspension was centrifuged and the solid was placed at 40°C and vacuum dried overnight to obtain mesylate salt form I. The XRPD test results of this form I are as follows Fig.31 As shown, the DSC and TGA test results are as follows Fig.32 , 33 The XRPD diffraction peak data of this crystal form I are shown below.

[0226] 2θ angle (°) Peak height Relative strength (%) 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] Example 13 Preparation of Compound I Methanesulfonate Form II

[0228] About 50 mg of compound I sample was added to 6 mL of ethyl acetate and dissolved in a water bath at 60°C 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; solution 3 was stirred at room temperature overnight to precipitate a small amount of solid, 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 placed at 40°C and vacuum dried overnight to obtain mesylate salt form II. The XRPD test results of this form II are as follows: Fig.34 As shown, the DSC and TGA test results are as follows Fig.35 , 36 The XRPD diffraction peak data of this crystal form II are shown below.

[0229] 2θ angle (°) Peak height Relative strength (%) 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 Form III

[0231] About 300 mg of compound I sample was added to 36 mL of ethyl acetate and dissolved by ultrasound at 60°C to obtain solution 1; about 79 mg of methanesulfonic acid was dissolved in 0.6 mL of methanol 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 0.5 h, 36 mL of n-heptane was added to precipitate immediately, and stirred for 3 days to obtain a suspension; the suspension was filtered under reduced pressure, and the solid was placed at 40°C and vacuum dried overnight to obtain mesylate salt form III. The XRPD test results of this form III are as follows Fig.37 As shown, the DSC and TGA test results are as follows Fig.38 , 39 shown. 1 The results of H-NMR test are as follows Fig.40 As shown, according to the integration results, the salt formation ratio of the compound and methanesulfonic acid is 1: 1. The XRPD diffraction peak data of this crystal form III are shown below.

[0232]

[0233]

[0234] Example 15 Preparation of Compound I Sodium Salt

[0235] About 300 mg of free state sample was added to 6 mL of tetrahydrofuran, dissolved at 60 ° C to obtain solution 1; about 33 mg of sodium hydroxide solid was added to solution 1 at room temperature and stirred for 1 h to dissolve to obtain solution 2; 12 mL of n-heptane was added to solution 2 and solid immediately attached to the bottle wall, stirred at room temperature for 3 days, and the precipitated solid was oily; the solution was quickly decompressed and filtered until it was reduced to about 2 mL, and solid was precipitated, and the crystal slurry was stirred for 0.5 h to obtain a suspension; the suspension was centrifuged, and the solid was placed at 40 ° C and vacuum dried overnight to obtain sodium salt (275 mg). It was determined that the XRPD of this sodium salt had no diffraction peaks and was amorphous. The salt ratio was determined to be 1:1 by IC method (ion chromatography).

[0236] Example 16 Preparation of Compound I Potassium Salt

[0237] About 50 mg of compound I sample was added with 1 mL of tetrahydrofuran, dissolved in a water bath at 60°C to obtain solution 1; about 8 mg of potassium hydroxide was directly added to solution 1, stirred at room temperature until dissolved to obtain solution 2; solution 2 was stirred at 12°C overnight without precipitation, and 4 mL of n-heptane was added and stirred to obtain a suspension; the suspension was centrifuged, and the solid was placed at 40°C and dried in vacuum overnight to obtain a potassium salt. After determination, the XRPD of this potassium salt had no diffraction peaks and was amorphous.

[0238] Comparative Example 1: Compound RP103

[0239]

[0240] The reference compound RP103 was prepared by referring to the method for compound 103 on page 119 of the specification of patent CN113454080A.

[0241] Comparative Example 2: Compound RP3500

[0242]

[0243] The reference compound RP3500 was prepared by referring to the method of compound 121 on page 122 of the specification of patent CN113454080A.

[0244] Test Example 1: Inhibitory effect of the compounds of the present invention on ATR enzyme

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

[0246] 1. 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-shaped bottom 96-well plate (Geriner bio-one, 651201)

[0251] 5. Labeling of 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. Microplate reader (Envision 2104 Multilabel Reader).

[0257] 2. Experimental steps

[0258] ATR enzyme 15nM, P53 protein 80nM, 300nM ATP (final concentrations were 40nM and 150nM, respectively), and small molecule compounds of different concentrations (the final concentrations (nM) of the ten points were 2985.0, 895.5, 298.5, 110.56, 33.17, 11.06, 4.09, 1.23, 0.41, 0.15, respectively. The final dimethyl sulfoxide concentration was 0.498%) were mixed and incubated at room temperature for 90 minutes. 10uL of 2× mixture buffer was added to the mixture of ATR, compound and substrate in the analysis plate (anti-phosphorylated p53-Eu and anti-GST-d2 were diluted in detection buffer). Centrifuge at 1000rpm for 30 seconds. Incubate overnight at 4°C in the dark (a total of 20 microliters in each well). The FRET signal (endpoint) was measured in an Envision instrument (HTRF665 / 612 ratio was calculated based on the 665 nm emission and the 612 nm emission). The data were processed using GraphPad software.

[0259] 3. Experimental Results

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

[0261] Table 1 IC50 values ​​of the compounds of the present invention for 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 invention have better inhibitory activity on ATR enzyme.

[0264] Test Example 2: Cell Proliferation Experiment

[0265] The following method evaluates the inhibitory effect of the compound of the present invention on LoVo cell proliferation by detecting the intracellular ATP content according to the IC50 value. The experimental method is briefly described as follows:

[0266] 1. 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. Pancreatin (Invitrogen, 25200-056)

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

[0274] 2. Experimental steps

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

[0276] The sample to be tested was diluted to 1mM with DMSO, and then diluted to 8 concentrations in 3 times, and prepared to 200X with cell culture medium, and blank and control wells were set. Take 5μL of the compound solution prepared in gradient concentrations and add it to 95μL of fresh culture medium. Then add 100μL (1X culture medium containing compound) to the culture plate. Incubate the culture plate in an incubator for 4 days (37°C, 5% CO2). In a 96-well cell culture plate, add 50μL CellTiter-Glo reagent to each well, place it at room temperature away from light for 5-10 minutes, read the chemiluminescent signal value in PHERAstar, and process the data using GraphPad software.

[0277] 3. Experimental Results

[0278] The inhibitory effect of the compounds of the present invention on LoVo cell proliferation can be determined by the above test, and the measured IC50 values ​​are shown in Table 2

[0279] Table 2 IC50 values ​​of the compounds of the present invention for inhibition of 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 Experiment

[0282] The following method evaluates the inhibitory effect of the compound of the present invention on the proliferation of SNU-601 cells by detecting the intracellular ATP content according to the IC50 value. The experimental method is briefly described as follows:

[0283] 1. Experimental Materials and Instruments

[0284] 1.SNU-601, human gastric cancer cell line (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. Pancreatin (Gibco, 25200056)

[0290] 7. Microplate reader (TECAN, INFINITE M Nano+).

[0291] 2. Experimental steps

[0292] SNU-601 cells were cultured in RPMI 1640 medium containing 10% FBS and passaged 2-3 times a week at a passage ratio of 1:5 or 1:10. During passage, the cells were digested with trypsin and transferred to a centrifuge tube. Centrifuged at 1000 rpm for 5 minutes, the supernatant medium was discarded, and fresh medium was added to resuspend the cells. 195 μL of cell suspension was added to a 96-well cell culture plate at a density of 5.128×10 3 cells / mL, only 200 μL of complete medium was added to the periphery of the 96-well plate. The culture plate was cultured in an incubator for 24 hours (37°C, 5% CO2).

[0293] Dilute the sample to be tested with DMSO to 2mM, and dilute it 3 times in sequence to 10 concentrations, and set up blank and control wells. Take 10μL of the solution of the compound to be tested prepared in gradient concentrations and add it to 50μL of fresh culture medium. Then add 5μL of the above-mentioned drug-containing culture medium solution to the culture plate. Incubate the culture plate in an incubator for 5 days (37°C, 5% CO2). In a 96-well cell culture plate, discard 100μL / well, then add 50μL of CellTiter-Glo reagent to each well, shake at room temperature in the dark for 10 minutes, read the chemiluminescent signal value in PHERAstar, and process the data using GraphPad software.

[0294] 3. Experimental Results

[0295] The inhibitory effect of the compounds of the present invention on the proliferation of SNU-601 cells can be determined by the above test, and the measured IC50 values ​​are shown in Table 3

[0296] Table 3 IC50 values ​​of the compounds of the present invention for inhibition of SNU-601 cell proliferation

[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 Form I obtained in Example 9. The test conditions and test results are as follows:

[0300]

[0301] Test Example 5: Hygroscopicity Study

[0302] Dynamic water adsorption and desorption analysis was performed on the hydrochloride crystal form I (obtained in Example 9), the methanesulfonate crystal form III (obtained in Example 14), and the sodium salt amorphous form (obtained in Example 15) of Compound I to study the hygroscopicity. The results are shown in the following table. According to the research results, the hygroscopicity: hydrochloride crystal form I < methanesulfonate crystal form III < sodium salt amorphous form.

[0303] Salt type condition Test Results Hydrochloride Form I 50%RH-90%RH Weight gain: about 0.1% (w / w) Methanesulfonate Form III 50%RH-90%RH Weight gain: about 8.2% (w / w) Sodium salt 50%RH-90%RH Weight gain: about 25.0% (w / w)

[0304] The above is an explanation of the embodiments of the present invention. However, the present invention is not limited to the above embodiments. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present invention shall be included in the protection scope of the present invention.

Claims

1. A salt of compound I, wherein the compound I has the following structure: It is characterized in that The salt of compound I is benzenesulfonate, sulfate, p-toluenesulfonate, hydrochloride, maleate, hydrobromide, methanesulfonate, sodium salt, potassium salt of compound I.

2. A salt of compound I according to claim 1, characterized in that It is a benzenesulfonate salt form I of compound I, and using Cu-Kα radiation, X-ray powder diffraction expressed in 2θ angles has characteristic peaks at 8.8±0.2°, 17.7±0.2°, 18.9±0.2°, and 20.8±0.2°; Preferably, the benzenesulfonate salt form I of the 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°, and 23.2±0.2° in X-ray powder diffraction expressed in 2θ angles using Cu-Kα radiation; More preferably, the benzenesulfonate salt form I of the compound I has characteristic peaks 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°, and 24.7±0.2° in X-ray powder diffraction expressed in 2θ angles using Cu-Kα radiation; Further preferably, the benzenesulfonate salt form I of compound I has an X-ray powder diffraction spectrum substantially as shown in Figure 1.

3. The salt of Compound I according to claim 2, wherein the benzenesulfonate crystalline form I of Compound I has an endothermic peak at 184.4°C±5°C in its differential scanning calorimetry curve; Preferably, the benzenesulfonate salt form I of the compound I has a DSC spectrum substantially as shown in FIG2 ; Alternatively, the benzenesulfonate salt form I of the compound I has a TGA spectrum substantially as shown in FIG3 .

4. A salt of compound I according to claim 1, characterized in that It is a benzenesulfonate salt form II of compound I, and using Cu-Kα radiation, X-ray powder diffraction expressed in 2θ angles has characteristic peaks at 7.1±0.2°, 8.5±0.2°, and 14.9±0.2°; Preferably, the benzenesulfonate salt form II of the compound I has characteristic peaks at 7.1±0.2°, 8.5±0.2°, 14.9±0.2°, 20.1±0.2°, 21.1±0.2°, and 25.3±0.2° in X-ray powder diffraction expressed in 2θ angles using Cu-Kα radiation; Further preferably, the benzenesulfonate salt form II of compound I has an X-ray powder diffraction spectrum substantially as shown in FIG. 4 .

5. The salt of Compound I according to claim 4, wherein the benzenesulfonate crystalline form II of Compound I has an endothermic peak at 190.6°C±5°C in its differential scanning calorimetry curve; Preferably, the benzenesulfonate salt form II of the compound I has a DSC spectrum substantially as shown in FIG5 ; Alternatively, the benzenesulfonate salt form II of the compound I has a TGA spectrum substantially as shown in FIG6 .

6. A salt of compound I according to claim 1, characterized in that It is the sulfate crystalline form I of compound I, and using Cu-Kα radiation, X-ray powder diffraction expressed in 2θ angles has characteristic peaks at 6.5±0.2°, 8.5±0.2°, 17.4±0.2°, 18.5±0.2°, and 22.3±0.2°; Preferably, the sulfate crystalline form I of the compound I has 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°, and 22.9±0.2° in X-ray powder diffraction expressed in 2θ angle using Cu-Kα radiation; More preferably, the sulfate crystalline form I of the compound I has 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°, and 27.0±0.2° in X-ray powder diffraction expressed in 2θ angle using Cu-Kα radiation; Further preferably, the sulfate salt crystalline form I of compound I has an X-ray powder diffraction spectrum substantially as shown in FIG. 7 .

7. The salt of Compound I according to claim 6, wherein the sulfate crystalline form I of Compound I has an endothermic peak at 120.7°C±5°C in its differential scanning calorimetry curve; Preferably, the sulfate salt form I of the compound I has a DSC spectrum substantially as shown in FIG8 ; Alternatively, the sulfate salt form I of the compound I has a TGA spectrum substantially as shown in FIG9 .

8. A salt of compound I according to claim 1, characterized in that It is the sulfate crystal form II of compound I, and using Cu-Kα radiation, X-ray powder diffraction expressed in 2θ angles has characteristic peaks at 9.1±0.2°, 9.9±0.2°, and 21.2±0.2°; Preferably, the sulfate crystalline form II of the compound I has characteristic peaks at 9.1±0.2°, 9.9±0.2°, 16.3±0.2°, 17.6±0.2°, 21.2±0.2°, and 21.8±0.2° in X-ray powder diffraction expressed in 2θ angle using Cu-Kα radiation; More preferably, the sulfate crystalline form II of the compound I has 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°, and 24.4±0.2° in X-ray powder diffraction expressed in 2θ angle using Cu-Kα radiation; Further preferably, the sulfate salt form II of compound I has an X-ray powder diffraction spectrum substantially as shown in FIG. 10 .

9. The salt of Compound I according to claim 8, wherein the sulfate crystal form II of Compound I has an endothermic peak at 151.4°C±5°C in its differential scanning calorimetry curve; Preferably, the sulfate salt form II of the compound I has a DSC spectrum substantially as shown in FIG11 ; Alternatively, the sulfate salt form II of compound I has a TGA spectrum substantially as shown in FIG12 .

10. A salt of compound I according to claim 1, characterized in that It is the sulfate crystal form III of compound I, and using Cu-Kα radiation, X-ray powder diffraction expressed in 2θ angles has characteristic peaks at 6.6±0.2°, 8.6±0.2°, 9.0±0.2°, and 18.9±0.2°; Preferably, the sulfate crystalline form III of the compound I has characteristic peaks at 6.6±0.2°, 8.6±0.2°, 9.0±0.2°, 18.9±0.2°, 21.3±0.2°, and 22.4±0.2° in X-ray powder diffraction expressed in 2θ angle using Cu-Kα radiation; More preferably, the sulfate crystalline form III of the compound I has 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°, and 22.4±0.2° in X-ray powder diffraction expressed in 2θ angle using Cu-Kα radiation; Further preferably, the sulfate salt form III of compound I has an X-ray powder diffraction spectrum substantially as shown in Figure 13.

11. The salt of Compound I according to claim 10, wherein the sulfate salt crystalline form III of Compound I has an endothermic peak at 143.2°C±5°C in its differential scanning calorimetry curve; Preferably, the sulfate salt form III of compound I has a DSC spectrum substantially as shown in FIG14 ; Alternatively, the sulfate salt form III of compound I has a TGA spectrum substantially as shown in FIG15 .

12. A salt of compound I according to claim 1, characterized in that It is the sulfate crystal form IV of compound I, and using Cu-Kα radiation, X-ray powder diffraction expressed in 2θ angles has characteristic peaks at 9.2±0.2°, 9.9±0.2°, 21.0±0.2°, and 22.1±0.2°; Preferably, the sulfate crystalline form IV of the compound I has 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°, and 22.1±0.2° in X-ray powder diffraction expressed in 2θ angle using Cu-Kα radiation; More preferably, the sulfate crystalline form IV of the compound I has 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°, and 24.4±0.2° in X-ray powder diffraction expressed in 2θ angles using Cu-Kα radiation; Further preferably, the sulfate crystalline form IV of Compound I has an X-ray powder diffraction spectrum substantially as shown in Figure 16.

13. The salt of Compound I according to claim 12, wherein the sulfate crystal form IV of Compound I has an endothermic peak at 153.3°C±5°C in its differential scanning calorimetry curve; Preferably, the sulfate salt form IV of the compound I has a DSC spectrum substantially as shown in FIG17 ; Alternatively, the sulfate salt form IV of the compound I has a TGA spectrum substantially as shown in Figure 18.

14. A salt of compound I according to claim 1, characterized in that It is a p-toluenesulfonate salt form I of compound I, and using Cu-Kα radiation, X-ray powder diffraction expressed in 2θ angles has characteristic peaks at 3.6±0.2°, 4.5±0.2°, and 5.5±0.2°; Preferably, the p-toluenesulfonate crystalline form I of the compound I has characteristic peaks at 3.6±0.2°, 4.5±0.2°, 5.5±0.2°, 7.1±0.2°, 18.4±0.2°, and 19.6±0.2° in X-ray powder diffraction expressed in 2θ angles using Cu-Kα radiation; More preferably, the p-toluenesulfonate salt form I of the compound I has 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°, and 19.6±0.2° in X-ray powder diffraction expressed in 2θ angles using Cu-Kα radiation; Further preferably, the p-toluenesulfonate salt form I of compound I has an X-ray powder diffraction spectrum substantially as shown in Figure 19.

15. The salt of Compound I according to claim 14, wherein the p-toluenesulfonate crystalline form I of Compound I has an endothermic peak at 136.4°C±5°C in its differential scanning calorimetry curve; Preferably, the p-toluenesulfonate salt form I of the compound I has a DSC spectrum substantially as shown in FIG20 ; Alternatively, the p-toluenesulfonate salt form I of the compound I has a TGA spectrum substantially as shown in Figure 21.

16. A salt according to claim 1, characterized in that It is the hydrochloride salt of compound I represented by formula (II), Wherein, the salt formation ratio of compound I and hydrochloric acid is 1:

1.

17. A salt of compound I according to claim 1, characterized in that It is the hydrochloride crystal form I of compound I, wherein the salt formation ratio of compound I to hydrochloric acid is 1:

1.

18. A salt of compound I according to claim 1, characterized in that It is the hydrochloride crystal form I of compound I, and using Cu-Kα radiation, X-ray powder diffraction expressed in 2θ angles has characteristic peaks at 6.2±0.2°, 7.8±0.2°, 19.0±0.2°, and 19.8±0.2°; Preferably, the hydrochloride form I of the compound I has characteristic 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°, and 25.9±0.2° in X-ray powder diffraction expressed in 2θ angles using Cu-Kα radiation; More preferably, the hydrochloride form I of the compound I, using Cu-Kα radiation, has characteristic peaks in X-ray powder diffraction expressed in 2θ angles 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°, and 29.6±0.2°; Further preferably, the hydrochloride salt form I of compound I has an X-ray powder diffraction spectrum substantially as shown in Figure 22.

19. The salt of Compound I according to claim 18, wherein the hydrochloride crystalline form I of Compound I has an endothermic peak at 245.0°C±5°C in its differential scanning calorimetry curve; Preferably, the hydrochloride salt form I of the compound I has a DSC spectrum substantially as shown in FIG23; Alternatively, the hydrochloride salt form I of the compound I has a TGA spectrum substantially as shown in Figure 24.

20. A salt of compound I according to claim 1, characterized in that It is the maleate crystalline form I of compound I, and using Cu-Kα radiation, X-ray powder diffraction expressed in 2θ angles has characteristic peaks at 3.8±0.2°, 4.9±0.2°, 6.3±0.2°, and 17.7±0.2°; Preferably, the maleate salt form I of the compound I has 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°, and 20.6±0.2° in X-ray powder diffraction expressed in 2θ angle using Cu-Kα radiation; Further preferably, the maleate salt form I of compound I has an X-ray powder diffraction spectrum substantially as shown in Figure 25.

21. The salt of Compound I according to claim 20, wherein the maleate salt crystalline form I of Compound I has an endothermic peak at 96.9°C±5°C in its differential scanning calorimetry curve; Preferably, the maleate salt form I of the compound I has a DSC spectrum substantially as shown in FIG26 ; Alternatively, the maleate salt form I of compound I has a TGA spectrum substantially as shown in Figure 27.

22. A salt of compound I according to claim 1, characterized in that It is a hydrobromide salt form I of compound I, and using Cu-Kα radiation, X-ray powder diffraction expressed in 2θ angles has characteristic peaks at 6.3±0.2°, 7.6±0.2°, and 18.7±0.2°; Preferably, the hydrobromide salt form I of the compound I has characteristic peaks at 6.3±0.2°, 7.6±0.2°, 16.7±0.2°, 18.7±0.2°, 23.4±0.2°, and 25.9±0.2° in X-ray powder diffraction expressed in 2θ angles using Cu-Kα radiation; More preferably, the hydrobromide salt form I of the compound I has 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°, and 30.3±0.2° in X-ray powder diffraction expressed in 2θ angle using Cu-Kα radiation; Further preferably, the hydrobromide salt form I of compound I has an X-ray powder diffraction spectrum substantially as shown in Figure 28.

23. The salt of Compound I according to claim 22, wherein the hydrobromide salt crystalline form I of Compound I has an endothermic peak at 241.1°C±5°C in its differential scanning calorimetry curve; Preferably, the hydrobromide salt form I of the compound I has a DSC spectrum substantially as shown in FIG29 ; Alternatively, the hydrobromide salt form I of the compound I has a TGA spectrum substantially as shown in Figure 30.

24. A salt according to claim 1, characterized in that It is a mesylate salt of compound I represented by formula (III), The salt formation ratio of compound I to methanesulfonic acid is 1:

1.

25. A salt of Compound I according to claim 1, characterized in that It is a mesylate salt form I of compound I, and using Cu-Kα radiation, X-ray powder diffraction expressed in 2θ angles has characteristic peaks at 5.1±0.2°, 6.0±0.2°, and 20.4±0.2°; Preferably, the mesylate salt form I of the 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°, and 20.4±0.2° in X-ray powder diffraction expressed in 2θ angle using Cu-Kα radiation; Further preferably, the mesylate salt form I of Compound I has an X-ray powder diffraction spectrum substantially as shown in Figure 31.

26. The salt of Compound I according to claim 25, wherein the mesylate crystalline form I of Compound I has an endothermic peak in its differential scanning calorimetry curve at 117.9°C±5°C; Preferably, the mesylate salt form I of the compound I has a DSC spectrum substantially as shown in FIG32 ; Alternatively, the mesylate salt form I of compound I has a TGA spectrum substantially as shown in Figure 33.

27. A salt of Compound I according to claim 1, characterized in that It is a mesylate salt form II of compound I, and using Cu-Kα radiation, X-ray powder diffraction expressed in 2θ angles has characteristic peaks at 9.0±0.2°, 9.8±0.2°, 17.4±0.2°, and 21.9±0.2°; Preferably, the mesylate salt form II of the 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°, and 21.9±0.2° in X-ray powder diffraction expressed in 2θ angles using Cu-Kα radiation; More preferably, the mesylate salt form II of the 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°, and 21.9±0.2° in X-ray powder diffraction expressed in 2θ angles using Cu-Kα radiation; Further preferably, the mesylate salt form II of compound I has an X-ray powder diffraction spectrum substantially as shown in Figure 34.

28. The salt of Compound I according to claim 27, wherein the mesylate crystalline form II of Compound I has an endothermic peak at 170.3°C±5°C in its differential scanning calorimetry curve; Preferably, the mesylate salt form II of the compound I has a DSC spectrum substantially as shown in FIG35 ; Alternatively, the mesylate salt form II of compound I has a TGA spectrum substantially as shown in Figure 36.

29. A salt of Compound I according to claim 1, characterized in that It is the mesylate crystal form III of compound I, wherein the salt formation ratio of compound I to methanesulfonic acid is 1:

1.

30. The salt of Compound 1 according to claim 1, characterized in that It is the mesylate salt form III of compound I, and using Cu-Kα radiation, X-ray powder diffraction expressed in 2θ angles has characteristic peaks at 8.9±0.2°, 16.7±0.2°, 19.5±0.2°, and 22.3±0.2°; Preferably, the mesylate salt form III of the compound I has characteristic peaks 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°, and 25.3±0.2° in X-ray powder diffraction expressed in 2θ angles using Cu-Kα radiation; More preferably, the mesylate salt form III of the compound I has characteristic peaks 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°, and 25.3±0.2° in X-ray powder diffraction expressed in 2θ angles using Cu-Kα radiation; Further preferably, the mesylate salt form III of compound I has an X-ray powder diffraction spectrum substantially as shown in Figure 37.

31. The salt of Compound I according to claim 30, wherein the mesylate crystalline form III of Compound I has an endothermic peak at 174.0°C±5°C in its differential scanning calorimetry curve; Preferably, the mesylate salt form III of compound I has a DSC spectrum substantially as shown in FIG38 ; Alternatively, the mesylate salt form III of compound I has a TGA spectrum substantially as shown in Figure 39.

32. A salt of Compound I according to claim 1, characterized in that It is the sodium salt of compound I represented by formula (IV), The salt formation ratio of compound I to sodium ion is 1:

1.

33. A pharmaceutical composition, characterized in that The composition comprises a salt of Compound 1 as described in any one of claims 1 to 32.

34. Use of a salt of Compound I according to any one of claims 1 to 32 or a pharmaceutical composition according to claim 33 in the preparation of a medicament for treating a disease mediated by ATR.

35. Use of a salt of Compound I as described in any one of the preceding claims 1-32 or a pharmaceutical composition as described in claim 33 in the preparation of a medicament for treating cancer or tumor-related diseases; preferably, the cancer or tumor-related disease is a solid tumor; more preferably, the cancer or tumor-related disease is a digestive tract tumor; more preferably, the cancer or tumor-related disease is gastric cancer or colorectal cancer.

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