TW202340184A

TW202340184A - Polymorphic form of cyclin-dependent kinase 9 (CDK9) inhibitor and preparation method and use thereof which is a more stable and more suitable for preparing a CDK9 inhibitor

Info

Publication number: TW202340184A
Application number: TW112122913A
Authority: TW
Inventors: 周福生; 趙金柱; 炯蘭
Original assignee: 大陸商勁方醫藥科技(上海)有限公司; 大陸商浙江勁方藥業有限公司
Priority date: 2020-11-20
Filing date: 2020-11-20
Publication date: 2023-10-16

Abstract

The present invention provides a polymorphic form of a cyclin-dependent kinase 9 (CDK9) inhibitor and a preparation method and uses thereof. Specifically, the present invention discloses 4-(((4-(5-chloro-2-(((1R,4r)-4-((R)-1-methoxypropyl-2-yl)amino) cyclohexyl)amino)pyridin-4-yl)thiazol-2-yl)amino)methyl)tetrahydro-2H-pyran-4-formonitrile maleate or fumarate or their polymorphic forms and uses thereof. In addition, the present invention further discloses pharmaceutical compositions containing the above substances and uses thereof.

Description

CDK9抑制劑的多晶型物及其製法和用途Polymorphs of CDK9 inhibitors and preparation methods and uses thereof

本發明屬於醫藥技術領域，具體地，涉及一種CDK9抑制劑的多晶型物及其製法和用途。The present invention belongs to the field of medical technology, and specifically relates to a polymorphic form of a CDK9 inhibitor and its preparation method and use.

真核細胞的增殖***是一個精確而複雜的調控過程。增殖過程是通過細胞週期來完成的，細胞週期的有序進行是通過其嚴格的分子調控機制。目前已發現主要有三大類分子參與細胞週期調控：細胞週期蛋白依賴性激酶(cyclin-dependent kinases，CDK)、細胞週期蛋白(cyclins)、細胞週期蛋白依賴性激酶抑制劑(cyclin-dependent kinase inhibitors，CKI)，其中CDK處於中心地位。CDK家族已發現13個成員(CDK1-CDK13)，按其胞內功能不同分為兩類：控制細胞週期的CDK和控制細胞轉錄的CDK。CDK9屬於絲氨酸類激酶，它與對應細胞週期蛋白(cyclin)結合形成的複合物稱為正性轉錄延長因數b(P-TEFb)，該複合物能夠磷酸化RNA聚合酶Ⅱ(RNApolymerase Ⅱ)和一些負性轉錄延長因數(NELF和N-TEF)從而使轉錄從起始部位得以延伸，是轉錄得以延長的核心分子(Sims RJ 3rd等 Genes Dev, 2004, 18：2437-68；Yamaguchi Y等 Mol Cell Biol, 2002, 22：2918-27)。研究發現CDK9的表達水準或/和激酶活性的異常會引起細胞內多種蛋白表達或/和其mRNA水準異常。已經證實與腫瘤密切相關的就有抗凋亡蛋白(如Bcl-2)、細胞週期相關調節蛋白(如cyclin D1)、p53途徑相關蛋白、NF-κB途徑的某些蛋白和以及與腫瘤微環境有關的蛋白(如VEGF)等。可見CDK9是腫瘤發生發展過程中最關鍵分子之一。The proliferation and division of eukaryotic cells is a precise and complex regulatory process. The proliferation process is completed through the cell cycle, and the orderly progression of the cell cycle is through its strict molecular regulatory mechanism. Currently, three major categories of molecules have been found to be involved in cell cycle regulation: cyclin-dependent kinases (CDKs), cyclins, and cyclin-dependent kinase inhibitors (CKIs). ), in which CDK plays a central role. The CDK family has discovered 13 members (CDK1-CDK13), which are divided into two categories according to their different intracellular functions: CDKs that control the cell cycle and CDKs that control cell transcription. CDK9 is a serine kinase that combines with the corresponding cyclin to form a complex called positive transcription elongation factor b (P-TEFb). This complex can phosphorylate RNA polymerase II (RNApolymerase II) and some Negative transcription elongation factors (NELF and N-TEF) allow transcription to extend from the start site and are the core molecules for elongation of transcription (Sims RJ 3rd et al. Genes Dev, 2004, 18: 2437-68; Yamaguchi Y et al. Mol Cell Biol, 2002, 22: 2918-27). Studies have found that abnormalities in the expression level or/and kinase activity of CDK9 can cause abnormalities in the expression of multiple proteins or/and their mRNA levels in cells. It has been confirmed that anti-apoptotic proteins (such as Bcl-2), cell cycle-related regulatory proteins (such as cyclin D1), p53 pathway-related proteins, certain proteins of the NF-κB pathway, and the tumor microenvironment are closely related to tumors. Related proteins (such as VEGF), etc. It can be seen that CDK9 is one of the most critical molecules in the occurrence and development of tumors.

因此，開發用於調節CDK9的藥物對於預防和治療與CDK9相關的疾病至關重要。Therefore, the development of drugs to modulate CDK9 is critical for the prevention and treatment of CDK9-related diseases.

本發明的目的在於提供一類更穩定、更適合成藥的CDK9抑制劑。具體地，本發明的目的是提供化合物4-(((4-(5-氯-2-(((1R,4r)-4-(((R)-1-甲氧基丙基-2-基)氨基)環己基)氨基)吡啶-4-基)噻唑-2-基)氨基)甲基)四氫-2H-吡喃-4-甲腈的鹽及其一系列穩定的多晶型物，並提供上述多晶型物的製備方法和用途。The purpose of the present invention is to provide a class of CDK9 inhibitors that are more stable and more suitable for pharmaceutical preparation. Specifically, the object of the present invention is to provide compound 4-(((4-(5-chloro-2-(((1R,4r)-4-((R)-1-methoxypropyl-2- base)amino)cyclohexyl)amino)pyridin-4-yl)thiazol-2-yl)amino)methyl)tetrahydro-2H-pyran-4-carbonitrile salt and a series of stable polymorphs thereof , and provide preparation methods and uses of the above polymorphs.

第一方面中，本發明提供式(I)化合物的藥學上可接受鹽或其多晶型物； (I) 所述藥學上可接受鹽為馬來酸鹽或富馬酸鹽。 In a first aspect, the present invention provides a pharmaceutically acceptable salt of a compound of formula (I) or a polymorph thereof; (I) The pharmaceutically acceptable salt is maleate or fumarate.

在另一優選例中，所述式(I)化合物的藥學上可接受鹽為式(I)化合物馬來酸鹽。In another preferred embodiment, the pharmaceutically acceptable salt of the compound of formula (I) is the maleate salt of the compound of formula (I).

在另一優選例中，所述式(I)化合物的藥學上可接受鹽為式(I)化合物富馬酸鹽。In another preferred embodiment, the pharmaceutically acceptable salt of the compound of formula (I) is the fumarate salt of the compound of formula (I).

在另一優選例中，式(I)化合物馬來酸鹽中，式(I)化合物和馬來酸的莫耳比為1：2。In another preferred embodiment, in the maleate salt of the compound of formula (I), the molar ratio of the compound of formula (I) and maleic acid is 1:2.

在另一優選例中，式(I)化合物富馬酸鹽中，式(I)化合物和富馬酸的莫耳比為2：1。In another preferred example, in the fumarate salt of the compound of formula (I), the molar ratio of the compound of formula (I) and fumaric acid is 2:1.

在另一優選例中，所述多晶型物為式(I)化合物馬來酸鹽的晶型1，所述晶型1的X射線粉末衍射圖包含選自下組的衍射角2θ(°)值：5.48±0.2°、14.26±0.2°、19.68±0.2°、22.44±0.2°。In another preferred embodiment, the polymorph is crystal form 1 of the maleate salt of the compound of formula (I), and the X-ray powder diffraction pattern of the crystal form 1 includes a diffraction angle 2θ (° ) values: 5.48±0.2°, 14.26±0.2°, 19.68±0.2°, 22.44±0.2°.

在另一優選例中，所述晶型1的X射線粉末衍射圖還包含選自下組一個或多個(例如2個、3個、4個、5個、6個、7個、8個、9個、10個、11個、12個、13個、14個或全部)的衍射角2θ(°)值：5.02±0.2°、9.86±0.2°、10.88±0.2°、11.22±0.2°、15.06±0.2°、16.82±0.2°、17.48±0.2°、18.18±0.2°、20.50±0.2°、23.24±0.2°、24.90±0.2°、26.76±0.2°、27.16±0.2°、28.48±0.2°、30.86±0.2°。In another preferred embodiment, the X-ray powder diffraction pattern of the crystal form 1 also includes one or more selected from the following group (for example, 2, 3, 4, 5, 6, 7, 8 , 9, 10, 11, 12, 13, 14 or all) diffraction angle 2θ (°) value: 5.02±0.2°, 9.86±0.2°, 10.88±0.2°, 11.22±0.2°, 15.06±0.2°, 16.82±0.2°, 17.48±0.2°, 18.18±0.2°, 20.50±0.2°, 23.24±0.2°, 24.90±0.2°, 26.76±0.2°, 27.16±0.2°, 28.48±0.2°, 30.86±0.2°.

在另一優選例中，所述晶型1的X射線粉末衍射圖還包含選自下組的衍射角2θ(°)值：9.86±0.2°、11.22±0.2°、15.06±0.2°、23.24±0.2°、24.90±0.2°。In another preferred example, the X-ray powder diffraction pattern of the crystal form 1 also includes a diffraction angle 2θ (°) value selected from the following group: 9.86±0.2°, 11.22±0.2°, 15.06±0.2°, 23.24± 0.2°, 24.90±0.2°.

在另一優選例中，所述晶型1的X射線粉末衍射圖還包含選自下組的衍射角2θ(°)值：5.02±0.2°、16.82±0.2°、26.76±0.2°、27.16±0.2°。In another preferred example, the X-ray powder diffraction pattern of the crystal form 1 also includes a diffraction angle 2θ (°) value selected from the following group: 5.02±0.2°, 16.82±0.2°, 26.76±0.2°, 27.16± 0.2°.

在另一優選例中，所述晶型1的X射線粉末衍射圖還包含選自下組的衍射角2θ(°)值：18.18±0.2°、20.50±0.2°。In another preferred example, the X-ray powder diffraction pattern of the crystal form 1 also includes a diffraction angle 2θ (°) value selected from the following group: 18.18±0.2°, 20.50±0.2°.

在另一優選例中，所述晶型1的X射線粉末衍射圖還包含選自表2中的一個或多個(例如2個、3個、4個、5個、6個、7個、8個、9個、更多個或全部)的衍射角2θ(°)值。In another preferred example, the X-ray powder diffraction pattern of the crystalline form 1 also includes one or more selected from Table 2 (for example, 2, 3, 4, 5, 6, 7, 8, 9, more or all) diffraction angle 2θ (°) values.

在另一優選例中，所述晶型1的X射線粉末衍射圖基本如圖1所示。In another preferred example, the X-ray powder diffraction pattern of the crystal form 1 is basically as shown in Figure 1.

在另一優選例中，所述晶型1的差示掃描量熱法分析譜圖在162.45±5℃處有特徵峰。In another preferred example, the differential scanning calorimetry analysis spectrum of the crystal form 1 has a characteristic peak at 162.45±5°C.

在另一優選例中，所述晶型1的差示掃描量熱法分析譜圖在162.45±2℃(或162.45±1℃)處有特徵峰。In another preferred example, the differential scanning calorimetry analysis spectrum of the crystal form 1 has a characteristic peak at 162.45±2°C (or 162.45±1°C).

在另一優選例中，所述晶型1的差示掃描量熱法分析譜圖基本如圖2所示。In another preferred example, the differential scanning calorimetry analysis spectrum of the crystal form 1 is basically as shown in Figure 2.

在另一優選例中，所述晶型1的熱重分析譜圖在179.19±5℃和366.44±5℃處有特徵峰。In another preferred example, the thermogravimetric analysis spectrum of the crystal form 1 has characteristic peaks at 179.19±5°C and 366.44±5°C.

在另一優選例中，所述晶型1的熱重分析譜圖在179.19±2℃和366.44±2℃處有特徵峰。In another preferred example, the thermogravimetric analysis spectrum of the crystal form 1 has characteristic peaks at 179.19±2°C and 366.44±2°C.

在另一優選例中，所述晶型1的熱重分析譜圖基本如圖3所示。In another preferred example, the thermogravimetric analysis spectrum of the crystal form 1 is basically as shown in Figure 3.

在另一優選例中，所述晶型1的紅外譜圖在以下位置具有特徵峰：3423.90±5 cm ^-1、2956.16±5 cm ^-1、2854.93±5 cm ^-1、1647.45±5 cm ^-1、1565.70±5 cm ^-1、1491.36±5 cm ^-1、1384.83±5 cm ^-1、1365.96±5 cm ^-1、1179.36±5 cm ^-1、1105.37±5 cm ^-1、1013.09±5 cm ^-1、875.53±5 cm ^-1、865.08±5 cm ^-1、177.45±5 cm ^-1、568.10±5 cm ^-1。 In another preferred example, the infrared spectrum of the crystal form 1 has characteristic peaks at the following positions: 3423.90±5 cm ^-1 , 2956.16±5 cm ^-1 , 2854.93±5 cm ^-1 , 1647.45±5 cm ^-1 , 1565.70±5 cm ^-1 , 1491.36±5 cm ^-1 , 1384.83±5 cm ^-1 , 1365.96±5 cm ^-1 , 1179.36±5 cm ^-1 , 1105.37±5 cm ^-1 , 1013.09±5 cm ^-1 , 875.53±5 cm ^-1 , 865.08±5 cm ^-1 , 177.45±5 cm ^-1 , 568.10±5 cm ^-1 .

在另一優選例中，所述晶型1的紅外譜圖基本如圖4所示。In another preferred example, the infrared spectrum of the crystal form 1 is basically as shown in Figure 4.

在另一優選例中，所述多晶型物為式(I)化合物馬來酸鹽的晶型2，所述晶型2的X射線粉末衍射圖包含選自下組的衍射角2θ(°)值：5.02±0.2°、5.36±0.2°、14.04±0.2°、20.96±0.2°、21.42±0.2°、23.00±0.2°。In another preferred embodiment, the polymorph is crystal form 2 of the maleate salt of the compound of formula (I), and the X-ray powder diffraction pattern of the crystal form 2 includes a diffraction angle 2θ (° ) values: 5.02±0.2°, 5.36±0.2°, 14.04±0.2°, 20.96±0.2°, 21.42±0.2°, 23.00±0.2°.

在另一優選例中，所述晶型2的X射線粉末衍射圖還包含選自下組一個或多個(例如2個、3個、4個、5個、6個、7個、8個、9個、10個、11個、12個或全部)的衍射角2θ(°)值：8.56±0.2°、9.00±0.2°、15.16±0.2°、17.40±0.2°、18.10±0.2°、19.22±0.2°、21.96±0.2°、24.46±0.2°、26.90±0.2°、27.34±0.2°、28.02±0.2°、31.40±0.2°、32.08±0.2°。In another preferred example, the X-ray powder diffraction pattern of the crystalline form 2 also includes one or more selected from the following group (for example, 2, 3, 4, 5, 6, 7, 8 , 9, 10, 11, 12 or all) diffraction angle 2θ (°) value: 8.56±0.2°, 9.00±0.2°, 15.16±0.2°, 17.40±0.2°, 18.10±0.2°, 19.22 ±0.2°, 21.96±0.2°, 24.46±0.2°, 26.90±0.2°, 27.34±0.2°, 28.02±0.2°, 31.40±0.2°, 32.08±0.2°.

在另一優選例中，所述晶型2的X射線粉末衍射圖還包含選自下組的衍射角2θ(°)值：8.56±0.2°、9.00±0.2°、17.40±0.2°、19.22±0.2°、24.46±0.2°、27.34±0.2°、28.02±0.2°、32.08±0.2°。In another preferred example, the X-ray powder diffraction pattern of the crystal form 2 also includes a diffraction angle 2θ (°) value selected from the following group: 8.56±0.2°, 9.00±0.2°, 17.40±0.2°, 19.22± 0.2°, 24.46±0.2°, 27.34±0.2°, 28.02±0.2°, 32.08±0.2°.

在另一優選例中，所述晶型2的X射線粉末衍射圖還包含選自下組的衍射角2θ(°)值：15.16±0.2°、18.10±0.2°。In another preferred example, the X-ray powder diffraction pattern of the crystal form 2 also includes a diffraction angle 2θ (°) value selected from the following group: 15.16±0.2°, 18.10±0.2°.

在另一優選例中，所述晶型2的X射線粉末衍射圖還包含選自表3中的一個或多個(例如2個、3個、4個、5個、6個、7個、8個、9個、更多個或全部)的衍射角2θ(°)值。In another preferred example, the X-ray powder diffraction pattern of the crystal form 2 also includes one or more selected from Table 3 (for example, 2, 3, 4, 5, 6, 7, 8, 9, more or all) diffraction angle 2θ (°) values.

在另一優選例中，所述晶型2的X射線粉末衍射圖基本如圖5所示。In another preferred example, the X-ray powder diffraction pattern of the crystal form 2 is basically as shown in Figure 5.

在另一優選例中，所述晶型2的差示掃描量熱法分析譜圖在159.25±5℃處有特徵峰。In another preferred example, the differential scanning calorimetry analysis spectrum of the crystal form 2 has a characteristic peak at 159.25±5°C.

在另一優選例中，所述晶型2的差示掃描量熱法分析譜圖在159.25±2℃(或159.25±1℃)處有特徵峰。In another preferred example, the differential scanning calorimetry analysis spectrum of the crystal form 2 has a characteristic peak at 159.25±2°C (or 159.25±1°C).

在另一優選例中，所述晶型2的差示掃描量熱法分析譜圖基本如圖6所示。In another preferred example, the differential scanning calorimetry analysis spectrum of the crystal form 2 is basically as shown in Figure 6.

在另一優選例中，所述晶型2的熱重分析譜圖在174.38±5℃和366.44±5℃處有特徵峰。In another preferred example, the thermogravimetric analysis spectrum of the crystal form 2 has characteristic peaks at 174.38±5°C and 366.44±5°C.

在另一優選例中，所述晶型2的熱重分析譜圖在174.38±2℃和366.44±2℃處有特徵峰。In another preferred example, the thermogravimetric analysis spectrum of the crystal form 2 has characteristic peaks at 174.38±2°C and 366.44±2°C.

在另一優選例中，所述晶型2的紅外譜圖在以下位置具有特徵峰：3382.52±5 cm ^-1、2960.69±5 cm ^-1、2850.44±5 cm ^-1、1647.70±5 cm ^-1、1560.25±5 cm ^-1、1474.41±5 cm ^-1、1354.95±5 cm ^-1、1202.41±5 cm ^-1、1178.29±5 cm ^-1、1106.85±5 cm ^-1、1012.71±5 cm ^-1、867.82±5 cm ^-1、712.49±5 cm ^-1、663.08±5 cm ^-1、570.85±5 cm ^-1。 In another preferred example, the infrared spectrum of the crystal form 2 has characteristic peaks at the following positions: 3382.52±5 cm ^-1 , 2960.69±5 cm ^-1 , 2850.44±5 cm ^-1 , 1647.70±5 cm ^-1 , 1560.25±5 cm ^-1 , 1474.41±5 cm ^-1 , 1354.95±5 cm ^-1 , 1202.41±5 cm ^-1 , 1178.29±5 cm ^-1 , 1106.85±5 cm ^-1 , 1012.71±5 cm ^-1 , 867.82±5 cm ^-1 , 712.49±5 cm ^-1 , 663.08±5 cm ^-1 , 570.85±5 cm ^-1 .

在另一優選例中，所述晶型2的熱重分析譜圖基本如圖7所示。In another preferred example, the thermogravimetric analysis spectrum of the crystal form 2 is basically as shown in Figure 7.

在另一優選例中，所述晶型2的紅外譜圖基本如圖8所示。In another preferred example, the infrared spectrum of the crystal form 2 is basically as shown in Figure 8.

在另一優選例中，所述多晶型物為式(I)化合物馬來酸鹽的晶型3，所述晶型3的X射線粉末衍射圖包含選自下組的衍射角2θ(°)值：5.64±0.2°、11.28±0.2°、16.96±0.2°、24.92±0.2°。In another preferred embodiment, the polymorph is crystalline form 3 of the maleate salt of the compound of formula (I), and the X-ray powder diffraction pattern of the crystalline form 3 includes a diffraction angle 2θ(° selected from the following group ) values: 5.64±0.2°, 11.28±0.2°, 16.96±0.2°, 24.92±0.2°.

在另一優選例中，所述晶型3的X射線粉末衍射圖還包含選自下組一個或多個(例如2個、3個、4個、5個、6個、7個、8個、9個、10個、11個、12個或全部)的衍射角2θ(°)值：8.26±0.2°、12.21±0.2°、16.22±0.2°、18.52±0.2°、19.18±0.2°、21.28±0.2°、22.40±0.2°、22.98±0.2°、23.54±0.2°、24.50±0.2°、26.62±0.2°、29.42±0.2°、37.48±0.2°。In another preferred example, the X-ray powder diffraction pattern of the crystalline form 3 also includes one or more selected from the following group (for example, 2, 3, 4, 5, 6, 7, 8 , 9, 10, 11, 12 or all) diffraction angle 2θ (°) value: 8.26±0.2°, 12.21±0.2°, 16.22±0.2°, 18.52±0.2°, 19.18±0.2°, 21.28 ±0.2°, 22.40±0.2°, 22.98±0.2°, 23.54±0.2°, 24.50±0.2°, 26.62±0.2°, 29.42±0.2°, 37.48±0.2°.

在另一優選例中，所述晶型3的X射線粉末衍射圖還包含選自下組的衍射角2θ(°)值：19.18±0.2°、26.62±0.2°、29.42±0.2°。In another preferred example, the X-ray powder diffraction pattern of the crystal form 3 also includes a diffraction angle 2θ (°) value selected from the following group: 19.18±0.2°, 26.62±0.2°, 29.42±0.2°.

在另一優選例中，所述晶型3的X射線粉末衍射圖還包含選自下組的衍射角2θ(°)值：8.26±0.2°、16.22±0.2°、18.52±0.2°、23.54±0.2°、24.50±0.2°。In another preferred example, the X-ray powder diffraction pattern of the crystal form 3 also includes a diffraction angle 2θ (°) value selected from the following group: 8.26±0.2°, 16.22±0.2°, 18.52±0.2°, 23.54± 0.2°, 24.50±0.2°.

在另一優選例中，所述晶型3的X射線粉末衍射圖包含選自表4的一個或多個(例如2個、3個、4個、5個、6個、7個、8個、9個、更多個或全部)的衍射角2θ(°)值。In another preferred example, the X-ray powder diffraction pattern of the crystalline form 3 contains one or more (for example, 2, 3, 4, 5, 6, 7, 8) selected from Table 4. , 9, more or all) diffraction angle 2θ (°) values.

在另一優選例中，所述晶型3的X射線粉末衍射圖基本如圖9所示。In another preferred example, the X-ray powder diffraction pattern of the crystal form 3 is basically as shown in Figure 9.

在另一優選例中，所述晶型3的差示掃描量熱法分析譜圖在114.72±5℃處有特徵峰。In another preferred example, the differential scanning calorimetry analysis spectrum of the crystal form 3 has a characteristic peak at 114.72±5°C.

在另一優選例中，所述晶型3的差示掃描量熱法分析譜圖在114.72±2℃(或114.72±1℃)處有特徵峰。In another preferred example, the differential scanning calorimetry analysis spectrum of the crystal form 3 has a characteristic peak at 114.72±2°C (or 114.72±1°C).

在另一優選例中，所述晶型3的差示掃描量熱法分析譜圖基本如圖10所示。In another preferred example, the differential scanning calorimetry analysis spectrum of the crystal form 3 is basically as shown in Figure 10.

在另一優選例中，所述多晶型物為式(I)化合物馬來酸鹽的晶型4，所述晶型4的X射線粉末衍射圖包含選自下組的衍射角2θ(°)值：5.08±0.2°、5.62±0.2°、13.98±0.2°、22.72±0.2°。In another preferred embodiment, the polymorph is crystalline form 4 of the maleate salt of the compound of formula (I), and the X-ray powder diffraction pattern of the crystalline form 4 includes a diffraction angle 2θ(° selected from the following group ) values: 5.08±0.2°, 5.62±0.2°, 13.98±0.2°, 22.72±0.2°.

在另一優選例中，所述晶型4的X射線粉末衍射圖還包含選自下組一個或多個(例如2個、3個、4個、5個、6個、7個、8個、9個、10個、11個、12個、13個、14個或全部)的衍射角2θ(°)值：8.54±0.2°、11.32±0.2°、15.78±0.2°、17.08±0.2°、18.10±0.2°、20.66±0.2°、21.56±0.2°、23.50±0.2°、25.76±0.2°、27.08±0.2°、28.02±0.2°、28.45±0.2°、28.55±0.2°、32.16±0.2°、34.48±0.2°。In another preferred embodiment, the X-ray powder diffraction pattern of the crystal form 4 also includes one or more selected from the following group (for example, 2, 3, 4, 5, 6, 7, 8 , 9, 10, 11, 12, 13, 14 or all) diffraction angle 2θ (°) value: 8.54±0.2°, 11.32±0.2°, 15.78±0.2°, 17.08±0.2°, 18.10±0.2°, 20.66±0.2°, 21.56±0.2°, 23.50±0.2°, 25.76±0.2°, 27.08±0.2°, 28.02±0.2°, 28.45±0.2°, 28.55±0.2°, 32.16±0.2°, 34.48±0.2°.

在另一優選例中，所述晶型4的X射線粉末衍射圖還包含選自下組的衍射角2θ(°)值：8.54±0.2°、11.32±0.2°、17.08±0.2°、18.10±0.2°、20.66±0.2°、25.76±0.2°。In another preferred example, the X-ray powder diffraction pattern of the crystalline form 4 also includes a diffraction angle 2θ (°) value selected from the following group: 8.54±0.2°, 11.32±0.2°, 17.08±0.2°, 18.10± 0.2°, 20.66±0.2°, 25.76±0.2°.

在另一優選例中，所述晶型4的X射線粉末衍射圖包含選自表5的一個或多個(例如2個、3個、4個、5個、6個、7個、8個、9個、更多個或全部)的衍射角2θ(°)值。In another preferred example, the X-ray powder diffraction pattern of the crystalline form 4 contains one or more (for example, 2, 3, 4, 5, 6, 7, 8) selected from Table 5. , 9, more or all) diffraction angle 2θ (°) values.

在另一優選例中，所述晶型4的X射線粉末衍射圖基本如圖11所示。In another preferred example, the X-ray powder diffraction pattern of the crystal form 4 is basically as shown in Figure 11.

在另一優選例中，所述晶型4的差示掃描量熱法分析譜圖在175.74±5℃處有特徵峰。In another preferred example, the differential scanning calorimetry analysis spectrum of the crystal form 4 has a characteristic peak at 175.74±5°C.

在另一優選例中，所述晶型4的差示掃描量熱法分析譜圖在175.74±2℃(或175.74±1℃)處有特徵峰。In another preferred example, the differential scanning calorimetry analysis spectrum of the crystal form 4 has a characteristic peak at 175.74±2°C (or 175.74±1°C).

在另一優選例中，所述晶型4的差示掃描量熱法分析譜圖基本如圖12所示。In another preferred example, the differential scanning calorimetry analysis spectrum of the crystal form 4 is basically as shown in Figure 12.

在另一優選例中，所述多晶型物為式(I)化合物馬來酸鹽的晶型I，所述晶型I的X射線粉末衍射圖包含選自下組的衍射角2θ(°)值：5.00±0.2°、5.40±0.2°、14.23±0.2°、22.40±0.2°、23.28±0.2°。In another preferred embodiment, the polymorph is Form I of the maleate salt of the compound of formula (I), and the X-ray powder diffraction pattern of the Form I includes a diffraction angle 2θ(° ) values: 5.00±0.2°, 5.40±0.2°, 14.23±0.2°, 22.40±0.2°, 23.28±0.2°.

在另一優選例中，所述晶型I的X射線粉末衍射圖還包含選自下組的衍射角2θ(°)值：8.64±0.2°、9.80±0.2°、15.04±0.2°、16.60±0.2°、17.40±0.2°、18.13±0.2°、19.64±0.2°、20.41±0.2°、24.72±0.2°、27.09±0.2°、28.40±0.2°。In another preferred example, the X-ray powder diffraction pattern of the crystalline form I also includes a diffraction angle 2θ (°) value selected from the following group: 8.64±0.2°, 9.80±0.2°, 15.04±0.2°, 16.60± 0.2°, 17.40±0.2°, 18.13±0.2°, 19.64±0.2°, 20.41±0.2°, 24.72±0.2°, 27.09±0.2°, 28.40±0.2°.

在另一優選例中，所述晶型I的X射線粉末衍射圖還包含選自下組的衍射角2θ(°)值：11.16±0.2°、31.00±0.2°。In another preferred example, the X-ray powder diffraction pattern of the crystal form I also includes a diffraction angle 2θ (°) value selected from the following group: 11.16±0.2°, 31.00±0.2°.

在另一優選例中，所述晶型I的X射線粉末衍射圖包含選自表1的一個或多個(例如2個、3個、4個、5個、6個、7個、8個、9個、更多個或全部)的衍射角2θ(°)值。In another preferred embodiment, the X-ray powder diffraction pattern of the crystalline form I contains one or more (for example, 2, 3, 4, 5, 6, 7, 8) selected from Table 1. , 9, more or all) diffraction angle 2θ (°) values.

在另一優選例中，所述晶型I的X射線粉末衍射圖基本如圖17所示。In another preferred example, the X-ray powder diffraction pattern of the crystal form I is basically as shown in Figure 17.

在另一優選例中，所述晶型I的差示掃描量熱法分析譜圖在159.91±5℃處有特徵峰。In another preferred example, the differential scanning calorimetry analysis spectrum of the crystal form I has a characteristic peak at 159.91±5°C.

在另一優選例中，所述晶型I的差示掃描量熱法分析譜圖在159.91±2℃(或159.91±1℃)處有特徵峰。In another preferred example, the differential scanning calorimetry analysis spectrum of the crystal form I has a characteristic peak at 159.91±2°C (or 159.91±1°C).

在另一優選例中，所述晶型I的差示掃描量熱法分析譜圖基本如圖18所示。In another preferred example, the differential scanning calorimetry analysis spectrum of the crystal form I is basically as shown in Figure 18.

在另一優選例中，所述多晶型物為式(I)化合物富馬酸鹽的晶型A，所述晶型A的X射線粉末衍射圖包含選自下組的衍射角2θ(°)值：14.24±0.2°、19.44±0.2°、21.24±0.2°、23.77±0.2°、24.57±0.2°。In another preferred embodiment, the polymorph is crystalline form A of the fumarate salt of the compound of formula (I), and the X-ray powder diffraction pattern of the crystalline form A includes a diffraction angle 2θ(° selected from the following group ) values: 14.24±0.2°, 19.44±0.2°, 21.24±0.2°, 23.77±0.2°, 24.57±0.2°.

在另一優選例中，所述晶型A的X射線粉末衍射圖還包含選自下組一個或多個(例如2個、3個、4個、5個、6個、7個、8個、9個、10個、11個、12個、13個、14個、15個、16個、17個、18個、19個、20個、21個、22個、23個、24個、25個、26個或全部)的衍射角2θ(°)值：10.60±0.2°、12.95±0.2°、14.72±0.2°、15.88±0.2°、16.79±0.2°、17.93±0.2°、18.41±0.2°、18.93±0.2°、20.67±0.2°、22.16±0.2°、22.80±0.2°、24.88±0.2°、25.32±0.2°、26.13±0.2°、27.24±0.2°、27.64±0.2°、28.15±0.2°、28.64±0.2°、29.33±0.2°、29.64±0.2°、32.08±0.2°、32.73±0.2°、33.36±0.2°、35.36±0.2°、35.96±0.2°、38.28±0.2°、38.64±0.2°。In another preferred embodiment, the X-ray powder diffraction pattern of the crystalline form A also includes one or more selected from the following group (for example, 2, 3, 4, 5, 6, 7, 8 , 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25 Diffraction angle 2θ (°) value of 1, 26 or all): 10.60±0.2°, 12.95±0.2°, 14.72±0.2°, 15.88±0.2°, 16.79±0.2°, 17.93±0.2°, 18.41±0.2° , 18.93±0.2°, 20.67±0.2°, 22.16±0.2°, 22.80±0.2°, 24.88±0.2°, 25.32±0.2°, 26.13±0.2°, 27.24±0.2°, 27.64±0.2°, 28.15±0.2° , 28.64±0.2°, 29.33±0.2°, 29.64±0.2°, 32.08±0.2°, 32.73±0.2°, 33.36±0.2°, 35.36±0.2°, 35.96±0.2°, 38.28±0.2°, 38.64±0.2° .

在另一優選例中，所述晶型A的X射線粉末衍射圖還包含選自下組的衍射角2θ(°)值：10.60±0.2°、12.95±0.2°、15.88±0.2°、16.79±0.2°、17.93±0.2°、18.41±0.2°、20.67±0.2°、22.80±0.2°、29.64±0.2°、33.36±0.2°。In another preferred example, the X-ray powder diffraction pattern of the crystal form A also includes a diffraction angle 2θ (°) value selected from the following group: 10.60±0.2°, 12.95±0.2°, 15.88±0.2°, 16.79± 0.2°, 17.93±0.2°, 18.41±0.2°, 20.67±0.2°, 22.80±0.2°, 29.64±0.2°, 33.36±0.2°.

在另一優選例中，所述晶型A的X射線粉末衍射圖還包含選自下組的衍射角2θ(°)值：14.72±0.2°、22.16±0.2°、24.88±0.2°、28.15±0.2°、28.64±0.2°、29.33±0.2°、32.08±0.2°、35.36±0.2°。In another preferred example, the X-ray powder diffraction pattern of the crystal form A also includes a diffraction angle 2θ (°) value selected from the following group: 14.72±0.2°, 22.16±0.2°, 24.88±0.2°, 28.15± 0.2°, 28.64±0.2°, 29.33±0.2°, 32.08±0.2°, 35.36±0.2°.

在另一優選例中，所述晶型A的X射線粉末衍射圖包含選自表6的一個或多個(例如2個、3個、4個、5個、6個、7個、8個、9個、更多個或全部)的衍射角2θ(°)值。In another preferred example, the X-ray powder diffraction pattern of the crystal form A contains one or more (for example, 2, 3, 4, 5, 6, 7, 8) selected from Table 6. , 9, more or all) diffraction angle 2θ (°) values.

在另一優選例中，所述晶型A的X射線粉末衍射圖基本如圖13所示。In another preferred example, the X-ray powder diffraction pattern of the crystal form A is basically as shown in Figure 13.

在另一優選例中，所述晶型A的差示掃描量熱法分析譜圖在218.67±5℃有特徵峰。In another preferred example, the differential scanning calorimetry analysis spectrum of the crystal form A has a characteristic peak at 218.67±5°C.

在另一優選例中，所述晶型A的差示掃描量熱法分析譜圖在218.67±2℃(或218.67±1℃)有特徵峰。In another preferred example, the differential scanning calorimetry analysis spectrum of the crystal form A has a characteristic peak at 218.67±2°C (or 218.67±1°C).

在另一優選例中，所述晶型A的差示掃描量熱法分析譜圖基本如圖14所示。In another preferred example, the differential scanning calorimetry analysis spectrum of the crystal form A is basically as shown in Figure 14.

第二方面中，本發明提供一種藥物組合物，包含本發明第一方面所述的式(I)化合物的藥學上可接受鹽或其多晶型物和藥學上可接受的載體。In a second aspect, the present invention provides a pharmaceutical composition comprising a pharmaceutically acceptable salt or polymorph thereof of the compound of formula (I) described in the first aspect of the present invention and a pharmaceutically acceptable carrier.

協力廠商面中，本發明提供第一方面所述的式(I)化合物的藥學上可接受鹽或其多晶型物或第二方面所述的藥物組合物的用途，用於製備預防或治療CDK9相關疾病的藥物。In terms of collaboration, the present invention provides the use of pharmaceutically acceptable salts of the compound of formula (I) described in the first aspect or polymorphs thereof or the pharmaceutical compositions described in the second aspect for the preparation of prevention or treatment. Drugs for CDK9-related diseases.

在另一優選例中，所述CDK9相關疾病為癌症。In another preferred embodiment, the CDK9-related disease is cancer.

在另一優選例中，所述癌症選自下組的一種或多種：非小細胞肺癌、小細胞肺癌、肺腺癌、肺鱗癌、胰腺癌、***癌、膀胱癌、肝癌、皮膚癌、神經膠質瘤、乳腺癌、黑色素瘤、惡性膠質瘤、橫紋肌肉瘤、卵巢癌、星形細胞瘤、尤因氏肉瘤、成視網膜細胞瘤、上皮細胞癌、結腸癌、腎癌、胃腸間質瘤、白血病、組織細胞性淋巴癌和鼻咽癌。In another preferred embodiment, the cancer is selected from one or more of the following group: non-small cell lung cancer, small cell lung cancer, lung adenocarcinoma, lung squamous cell carcinoma, pancreatic cancer, prostate cancer, bladder cancer, liver cancer, skin cancer, Glioma, breast cancer, melanoma, malignant glioma, rhabdomyosarcoma, ovarian cancer, astrocytoma, Ewing's sarcoma, retinoblastoma, epithelial cell carcinoma, colon cancer, renal cancer, gastrointestinal stromal tumor, Leukemia, histiocytic lymphoma and nasopharyngeal carcinoma.

第四方面中，本發明提供第一方面所述的式(I)化合物的藥學上可接受鹽或其多晶型物的製備方法，所述多晶型物為式(I)化合物馬來酸鹽的晶型I，所述方法包括步驟： (1) 將式(I)化合物與馬來酸在有機溶劑中攪拌，從而形成式(I)化合物馬來酸鹽的晶型I；其中，式(I)化合物和馬來酸的莫耳比為1：2。 In the fourth aspect, the present invention provides a method for preparing a pharmaceutically acceptable salt of the compound of formula (I) or a polymorph thereof according to the first aspect, and the polymorph is maleic acid, the compound of formula (I) Crystalline Form I of the salt, the method comprising the steps: (1) Stir the compound of formula (I) and maleic acid in an organic solvent to form Form I of the maleate salt of the compound of formula (I); wherein, the molar ratio of the compound of formula (I) and maleic acid is is 1:2.

在另一優選例中，步驟(1)中，所述攪拌為：先在50至85℃(優選70至85℃或75至80℃)下攪拌(例如1至4小時或1至2小時)；然後將混合體系降溫到0至35℃(優選10至25℃)並繼續攪拌(例如1至4小時或2至3小時)。In another preferred example, in step (1), the stirring is: first stirring at 50 to 85°C (preferably 70 to 85°C or 75 to 80°C) (for example, 1 to 4 hours or 1 to 2 hours) ; Then cool the mixed system to 0 to 35°C (preferably 10 to 25°C) and continue stirring (for example, 1 to 4 hours or 2 to 3 hours).

在另一優選例中，步驟(1)中，所述有機溶劑為乙腈、乙醇、或它們的組合。In another preferred example, in step (1), the organic solvent is acetonitrile, ethanol, or a combination thereof.

在另一優選例中，步驟(1)包括步驟： (1-1) 將式(I)化合物溶解在有機溶劑中，得到式(I)化合物的溶液1； (1-2) 將馬來酸溶解在有機溶劑中，得到馬來酸的溶液2； (1-3) 在50至85℃(優選70至85℃或75至80℃)下，將式(I)化合物的溶液1滴加入馬來酸的溶液2中並攪拌(例如1至4小時或1至2小時)；然後將混合體系降溫到0至35℃(優選10至25℃)並繼續攪拌(例如1至4小時或2至3小時)；過濾，收集固體，從而得到所述式(I)化合物馬來酸鹽的晶型I。 In another preferred example, step (1) includes the steps: (1-1) Dissolve the compound of formula (I) in an organic solvent to obtain solution 1 of the compound of formula (I); (1-2) Dissolve maleic acid in an organic solvent to obtain maleic acid solution 2; (1-3) Add solution 1 dropwise of the compound of formula (I) to solution 2 of maleic acid at 50 to 85°C (preferably 70 to 85°C or 75 to 80°C) and stir (for example, 1 to 4 hours or 1 to 2 hours); then cool the mixed system to 0 to 35°C (preferably 10 to 25°C) and continue stirring (for example, 1 to 4 hours or 2 to 3 hours); filter and collect the solids to obtain the formula (I) Crystalline Form I of compound maleate salt.

在另一優選例中，步驟(1)中，式(I)化合物和馬來酸的莫耳比為1：(1.5至3)。In another preferred embodiment, in step (1), the molar ratio of the compound of formula (I) and maleic acid is 1: (1.5 to 3).

在另一優選例中，步驟(1)中，式(I)化合物和馬來酸的莫耳比為1：(2至3)，優選1：(2.1至2.2)。In another preferred example, in step (1), the molar ratio of the compound of formula (I) and maleic acid is 1: (2 to 3), preferably 1: (2.1 to 2.2).

在另一優選例中，步驟(1-3)中，過濾後收集的固體用乙腈淋洗並乾燥，從而得到所述式(I)化合物馬來酸鹽的晶型I。In another preferred embodiment, in step (1-3), the solid collected after filtration is rinsed with acetonitrile and dried, thereby obtaining crystal form I of the maleate salt of the compound of formula (I).

第五方面中，本發明提供了第一方面所述的式(I)化合物的藥學上可接受鹽或其多晶型物的製備方法，所述多晶型物為式(I)化合物馬來酸鹽的晶型1，所述方法包括步驟： (1) 將式(I)化合物與馬來酸在有機溶劑中攪拌，從而形成式(I)化合物馬來酸鹽；其中，式(I)化合物和馬來酸的莫耳比為1：2； (2a) 將步驟(1)得到的式(I)化合物馬來酸鹽溶解在第一結晶溶劑中，從而得到含有式(I)化合物馬來酸鹽的溶液； (3a) 將步驟(2a)得到的溶液析晶；析晶後過濾，收集固體，從而得到式(I)化合物馬來酸鹽的晶型1。 In the fifth aspect, the present invention provides a method for preparing pharmaceutically acceptable salts of the compound of formula (I) or polymorphs thereof according to the first aspect, and the polymorphs are the compounds of formula (I) male. Crystalline Form 1 of the acid salt, the method includes the steps: (1) Stir the compound of formula (I) and maleic acid in an organic solvent to form the maleate salt of the compound of formula (I); wherein the molar ratio of the compound of formula (I) and maleic acid is 1:2 ; (2a) Dissolve the maleate salt of the compound of formula (I) obtained in step (1) in the first crystallization solvent, thereby obtaining a solution containing the maleate salt of the compound of formula (I); (3a) Crystallize the solution obtained in step (2a); filter after crystallization and collect the solid, thereby obtaining crystal form 1 of the maleate salt of the compound of formula (I).

在另一優選例中，步驟(3a)為：將步驟(2a)得到的溶液在0至25℃析晶；析晶後過濾，收集固體，從而得到式(I)化合物馬來酸鹽的晶型1。In another preferred embodiment, step (3a) is: crystallize the solution obtained in step (2a) at 0 to 25°C; filter after crystallization and collect the solid, thereby obtaining crystals of the maleate salt of the compound of formula (I). Type 1.

在另一優選例中，步驟(3a)為：將步驟(2a)得到的溶液在70至80℃(優選75℃)析晶；析晶後，將混合物降溫並過濾，收集固體，從而得到式(I)化合物馬來酸鹽的晶型1。In another preferred example, step (3a) is: crystallizing the solution obtained in step (2a) at 70 to 80°C (preferably 75°C); after crystallization, the mixture is cooled and filtered, and the solids are collected to obtain the formula (I) Crystalline form 1 of compound maleate salt.

在另一優選例中，步驟(3a)為：將步驟(2a)得到的溶液在70至80℃(優選75℃)析晶；析晶後，將混合物降溫到0至30℃ (優選0至15℃或2至10℃)並過濾，收集固體，從而得到式(I)化合物馬來酸鹽的晶型1。In another preferred example, step (3a) is: crystallize the solution obtained in step (2a) at 70 to 80°C (preferably 75°C); after crystallization, the mixture is cooled to 0 to 30°C (preferably 0 to 75°C). 15°C or 2 to 10°C) and filtered to collect the solid, thereby obtaining crystal form 1 of the maleate salt of the compound of formula (I).

在另一優選例中，步驟(3a)中，過濾後收集的固體在55至65℃(優選60℃)下乾燥，從而得到式(I)化合物馬來酸鹽的晶型1。In another preferred embodiment, in step (3a), the solid collected after filtration is dried at 55 to 65°C (preferably 60°C), thereby obtaining crystal form 1 of the maleate salt of the compound of formula (I).

在另一優選例中，步驟(3a)中，過濾後收集的固體還可以通過一次或兩次重結晶，從而得到所述的晶型1。所述重結晶過程中可以任選地添加晶型1的晶種。In another preferred embodiment, in step (3a), the solid collected after filtration can be recrystallized once or twice to obtain the crystal form 1. Seed crystals of Form 1 may optionally be added during the recrystallization process.

在另一優選例中，步驟(1)得到的式(I)化合物馬來酸鹽為步驟(1)得到的式(I)化合物馬來酸鹽的晶型I。In another preferred example, the maleate salt of the compound of formula (I) obtained in step (1) is the crystal form I of the maleate salt of the compound of formula (I) obtained in step (1).

在另一優選例中，所述第一結晶溶劑為乙腈或乙腈和水的混合溶劑。In another preferred example, the first crystallization solvent is acetonitrile or a mixed solvent of acetonitrile and water.

在另一優選例中，所述第一結晶溶劑為乙腈和水的混合溶劑。In another preferred embodiment, the first crystallization solvent is a mixed solvent of acetonitrile and water.

在另一優選例中，所述第一結晶溶劑為乙腈和水的混合溶劑；其中，乙腈和水的體積比為50：1~1：1(較佳地為50：1~10：1)；較佳地，40：1~1：1(較佳地為40：1~10：1)；更佳地，30：1~1：1(較佳地為30：1~10：1)或25：1~1：1(較佳地為25：1~4：1或25：1~15：1)。In another preferred example, the first crystallization solvent is a mixed solvent of acetonitrile and water; wherein the volume ratio of acetonitrile and water is 50:1~1:1 (preferably 50:1~10:1) ; Preferably, 40:1~1:1 (preferably 40:1~10:1); More preferably, 30:1~1:1 (preferably 30:1~10:1) Or 25:1~1:1 (preferably 25:1~4:1 or 25:1~15:1).

在另一優選例中，步驟(2a)包括步驟：在氮氣保護下，將式(I)化合物馬來酸鹽與第一結晶溶劑混合後在回流溫度下溶清，從而得到含有式(I)化合物馬來酸鹽的溶液。In another preferred embodiment, step (2a) includes the step of: under nitrogen protection, mixing the maleate salt of the compound of formula (I) with the first crystallization solvent and then dissolving at reflux temperature to obtain a compound containing formula (I). Solution of compound maleate salt.

在另一優選例中，步驟(3a)在氮氣保護下進行。In another preferred embodiment, step (3a) is performed under nitrogen protection.

在另一優選例中，步驟(1)包括步驟： (1-1) 將式(I)化合物溶解在有機溶劑中，得到式(I)化合物的溶液1； (1-2) 將馬來酸溶解在有機溶劑中，得到馬來酸的溶液2； (1-3) 先在50至85℃(優選70至85℃或75至80℃)下，將式(I)化合物的溶液1滴加入馬來酸的溶液2中並攪拌(例如1至4小時或1至2小時)；然後將混合體系降溫到0至35℃(優選10至25℃)並繼續攪拌(例如1至4小時或2至3小時)；過濾，收集固體，從而得到所述式(I)化合物馬來酸鹽的晶型I。 In another preferred example, step (1) includes the steps: (1-1) Dissolve the compound of formula (I) in an organic solvent to obtain solution 1 of the compound of formula (I); (1-2) Dissolve maleic acid in an organic solvent to obtain maleic acid solution 2; (1-3) First, add the solution of the compound of formula (I) dropwise to the maleic acid solution 2 at 50 to 85°C (preferably 70 to 85°C or 75 to 80°C) and stir (for example, 1 to 4 hour or 1 to 2 hours); then cool the mixed system to 0 to 35°C (preferably 10 to 25°C) and continue stirring (for example, 1 to 4 hours or 2 to 3 hours); filter and collect the solid to obtain the Crystalline Form I of the maleate salt of the compound of formula (I).

在另一優選例中，步驟(1)中，式(I)化合物和馬來酸的莫耳比為1： (1.5至3)。In another preferred example, in step (1), the molar ratio of the compound of formula (I) and maleic acid is 1: (1.5 to 3).

在另一優選例中，步驟(1)中，式(I)化合物和馬來酸的莫耳比為1： (2至3)，優選1：(2.1至2.2)。In another preferred example, in step (1), the molar ratio of the compound of formula (I) and maleic acid is 1: (2 to 3), preferably 1: (2.1 to 2.2).

第六方面中，本發明提供了第一方面所述的式(I)化合物的藥學上可接受鹽或其多晶型物的製備方法，所述多晶型物為式(I)化合物馬來酸鹽的晶型2；所述方法包括步驟： (1) 將式(I)化合物與馬來酸在有機溶劑中攪拌，從而形成式(I)化合物馬來酸鹽；其中，式(I)化合物和馬來酸的莫耳比為1：2； (2b) 在0至50℃(優選10至30或20至25℃)下，將步驟(1)得到的式(I)化合物馬來酸鹽在第二結晶溶劑中攪拌(例如6至36小時或8至24小時)；然後過濾，收集固體，從而得到含有式(I)化合物馬來酸鹽的晶型2。 In the sixth aspect, the present invention provides a method for preparing pharmaceutically acceptable salts of the compound of formula (I) or polymorphs thereof according to the first aspect, and the polymorphs are the compounds of formula (I) male. Crystalline Form 2 of the acid salt; the method includes the steps: (1) Stir the compound of formula (I) and maleic acid in an organic solvent to form the maleate salt of the compound of formula (I); wherein the molar ratio of the compound of formula (I) and maleic acid is 1:2 ; (2b) Stir the maleate salt of the compound of formula (I) obtained in step (1) in the second crystallization solvent at 0 to 50°C (preferably 10 to 30 or 20 to 25°C) (for example, 6 to 36 hours or 8 to 24 hours); then filter and collect the solid, thereby obtaining crystal form 2 containing the maleate salt of the compound of formula (I).

在另一優選例中，步驟(2b)中，過濾後收集的固體在35至55℃(優選40至50℃)下乾燥，從而得到含有式(I)化合物馬來酸鹽的晶型2。In another preferred embodiment, in step (2b), the solid collected after filtration is dried at 35 to 55°C (preferably 40 to 50°C), thereby obtaining crystal form 2 containing the maleate salt of the compound of formula (I).

在另一優選例中，步驟(1)中，所述攪拌為：先在50至85℃(優選70至85℃或75至80℃)下攪拌(例如1至4小時或1至2小時)；然後將混合體系降溫到0至35℃(優選10-25℃)並繼續攪拌(例如1至4小時或2至3小時)。In another preferred example, in step (1), the stirring is: first stirring at 50 to 85°C (preferably 70 to 85°C or 75 to 80°C) (for example, 1 to 4 hours or 1 to 2 hours) ; Then cool the mixed system to 0 to 35°C (preferably 10-25°C) and continue stirring (for example, 1 to 4 hours or 2 to 3 hours).

在另一優選例中，所述第二結晶溶劑為甲基第三丁基醚、乙酸乙酯或其組合。In another preferred embodiment, the second crystallization solvent is methyl tert-butyl ether, ethyl acetate or a combination thereof.

第七方面中，本發明提供了第一方面所述的式(I)化合物的藥學上可接受鹽或其多晶型物的製備方法，所述多晶型物為式(I)化合物馬來酸鹽的晶型3，所述方法包括步驟： (1) 將式(I)化合物與馬來酸在有機溶劑中攪拌，從而形成式(I)化合物馬來酸鹽；其中，式(I)化合物和馬來酸的莫耳比為1：2； (2c) 在45至55℃(優選50℃)下，將步驟(1)得到的式(I)化合物馬來酸鹽在第三結晶溶劑中攪拌(例如6至48小時或12至36小時)；然後過濾，收集固體，從而得到含有式(I)化合物馬來酸鹽的晶型3。 In the seventh aspect, the present invention provides a method for preparing pharmaceutically acceptable salts of the compound of formula (I) or polymorphs thereof according to the first aspect, and the polymorphs are the compounds of formula (I) male. Crystalline form 3 of the acid salt, the method includes the steps: (1) Stir the compound of formula (I) and maleic acid in an organic solvent to form the maleate salt of the compound of formula (I); wherein the molar ratio of the compound of formula (I) and maleic acid is 1:2 ; (2c) Stir the maleate salt of the compound of formula (I) obtained in step (1) in the third crystallization solvent at 45 to 55°C (preferably 50°C) (for example, 6 to 48 hours or 12 to 36 hours) ; Then filter and collect the solid, thereby obtaining crystal form 3 containing the maleate salt of the compound of formula (I).

在另一優選例中，步驟(2c)中，過濾後收集的固體經乾燥，從而得到含有式(I)化合物馬來酸鹽的晶型3。In another preferred embodiment, in step (2c), the solid collected after filtration is dried to obtain crystal form 3 containing the maleate salt of the compound of formula (I).

在另一優選例中，所述第三結晶溶劑為丙酮和水的混合溶劑。In another preferred embodiment, the third crystallization solvent is a mixed solvent of acetone and water.

在另一優選例中，所述第三結晶溶劑為丙酮和水的混合溶劑；其中，丙酮和水的體積比為20：1~5：1；較佳地，15：1~10：1。In another preferred example, the third crystallization solvent is a mixed solvent of acetone and water; wherein the volume ratio of acetone and water is 20:1~5:1; preferably, 15:1~10:1.

第八方面中，本發明提供了第一方面所述的式(I)化合物的藥學上可接受鹽或其多晶型物的製備方法，所述多晶型物為式(I)化合物馬來酸鹽的晶型4，所述方法包括步驟： (1) 將式(I)化合物與馬來酸在有機溶劑中攪拌，從而形成式(I)化合物馬來酸鹽；其中，式(I)化合物和馬來酸的莫耳比為1：2； (2d) 在20至60℃(優選25至50℃)下，將步驟(1)得到的式(I)化合物馬來酸鹽在第四結晶溶劑中攪拌(例如6至48小時或12至36小時)；然後過濾，收集固體，從而得到含有式(I)化合物馬來酸鹽的晶型4。 In the eighth aspect, the present invention provides a method for preparing a pharmaceutically acceptable salt of the compound of formula (I) or a polymorph thereof according to the first aspect, and the polymorph is the compound of formula (I) male. Crystalline form 4 of the acid salt, the method includes the steps: (1) Stir the compound of formula (I) and maleic acid in an organic solvent to form the maleate salt of the compound of formula (I); wherein the molar ratio of the compound of formula (I) and maleic acid is 1:2 ; (2d) Stir the maleate salt of the compound of formula (I) obtained in step (1) in the fourth crystallization solvent at 20 to 60°C (preferably 25 to 50°C) (for example, 6 to 48 hours or 12 to 36 hours); then filter and collect the solid, thereby obtaining crystal form 4 containing the maleate salt of the compound of formula (I).

在另一優選例中，步驟(2d)中，過濾後收集的固體經乾燥，從而得到含有式(I)化合物馬來酸鹽的晶型4。In another preferred embodiment, in step (2d), the solid collected after filtration is dried, thereby obtaining crystal form 4 containing the maleate salt of the compound of formula (I).

在另一優選例中，所述第四結晶溶劑為乙醇、異丙醇、乙醇和水的混合溶劑、或異丙醇和水的混合溶劑。In another preferred embodiment, the fourth crystallization solvent is ethanol, isopropyl alcohol, a mixed solvent of ethanol and water, or a mixed solvent of isopropyl alcohol and water.

在另一優選例中，所述第四結晶溶劑為乙醇和水的混合溶劑；其中，乙醇和水的體積比為20：1~5：1；較佳地，15：1~10：1。In another preferred embodiment, the fourth crystallization solvent is a mixed solvent of ethanol and water; wherein the volume ratio of ethanol and water is 20:1~5:1; preferably, 15:1~10:1.

在另一優選例中，所述第四結晶溶劑為異丙醇和水的混合溶劑；其中，異丙醇和水的體積比為20：1~5：1；較佳地，15：1~10：1。In another preferred example, the fourth crystallization solvent is a mixed solvent of isopropyl alcohol and water; wherein the volume ratio of isopropyl alcohol and water is 20:1~5:1; preferably, 15:1~10: 1.

第九方面中，本發明提供了第一方面所述的式(I)化合物的藥學上可接受鹽或其多晶型物的製備方法，所述多晶型物為式(I)化合物富馬酸鹽的晶型A，所述方法包括步驟： (a) 在40至60℃(優選45至55℃)下，將式(I)化合物與富馬酸在有機溶劑中攪拌(例如0.1至2小時或0.5至1小時)； (b) 然後將混合體系降溫到10至30℃(優選20至25℃)並攪拌(例如0.5至3小時或1至2小時)；然後過濾，收集固體，從而得到式(I)化合物富馬酸鹽的晶型A。 In the ninth aspect, the present invention provides a method for preparing a pharmaceutically acceptable salt of the compound of formula (I) or a polymorph thereof according to the first aspect, and the polymorph is the compound of formula (I) fuma. Crystalline Form A of the acid salt, the method includes the steps: (a) stirring the compound of formula (I) and fumaric acid in an organic solvent at 40 to 60°C (preferably 45 to 55°C) (for example, 0.1 to 2 hours or 0.5 to 1 hour); (b) Then the mixed system is cooled to 10 to 30°C (preferably 20 to 25°C) and stirred (for example, 0.5 to 3 hours or 1 to 2 hours); then filtered to collect the solid, thereby obtaining compound fumar of formula (I) Form A of the acid salt.

在另一優選例中，所述方法包括步驟： (i) 將式(I)化合物溶解在有機溶劑(例如乙腈)中，得到式(I)化合物的溶液1’； (ii) 將富馬酸溶解在有機溶劑(例如乙醇)中，得到富馬酸的溶液2’； (iii) 在40至60℃(優選45至55℃)下，將式(I)化合物的溶液1’滴加入富馬酸的溶液2’中並攪拌(例如1至4小時或1至2小時)；然後將混合體系降溫到10至30℃(優選20至25℃)並繼續攪拌(例如1至4小時或2至3小時)；過濾，收集固體，從而得到所述式(I)化合物富馬酸鹽的晶型A。 In another preferred embodiment, the method includes the steps: (i) Dissolve the compound of formula (I) in an organic solvent (such as acetonitrile) to obtain a solution 1' of the compound of formula (I); (ii) Dissolve fumaric acid in an organic solvent (such as ethanol) to obtain a solution 2' of fumaric acid; (iii) Add the solution 1' of the compound of formula (I) dropwise to the solution 2' of fumaric acid at 40 to 60°C (preferably 45 to 55°C) and stir (for example, 1 to 4 hours or 1 to 2 hours ); then cool the mixed system to 10 to 30°C (preferably 20 to 25°C) and continue stirring (for example, 1 to 4 hours or 2 to 3 hours); filter and collect the solids, thereby obtaining the compound of formula (I) rich in Form A of the maleate salt.

在另一優選例中，各個步驟中，所述有機溶劑各自獨立地為乙腈、乙醇、或它們的組合。In another preferred embodiment, in each step, the organic solvent is independently acetonitrile, ethanol, or a combination thereof.

在另一優選例中，式(I)化合物和富馬酸的用量莫耳比為1：(0.5至0.7)，優選1：(0.5至0.6)。In another preferred example, the molar ratio of the compound of formula (I) and fumaric acid is 1: (0.5 to 0.7), preferably 1: (0.5 to 0.6).

在另一優選例中，過濾後收集的固體用乙腈淋洗並乾燥(例如在45至55℃或50℃下)，得到所述式(I)化合物富馬酸鹽的晶型A。In another preferred embodiment, the solid collected after filtration is rinsed with acetonitrile and dried (for example, at 45 to 55°C or 50°C) to obtain crystal form A of the fumarate salt of the compound of formula (I).

本發明的主要優點包括：發明人經過長期且深入地研究，意外地從眾多種鹽中發現了式(I)化合物的馬來酸鹽或富馬酸鹽具有良好的物化性能。據此，本發明提供式(I)化合物的馬來酸鹽或富馬酸鹽的多種多晶型物，分別是式(I)化合物馬來酸鹽的晶型I、晶型1、晶型2、晶型3和晶型4以及式(I)化合物馬酸鹽的晶型A。本發明的多晶型物穩定性好、溶解性好且不易吸濕，解決游離鹼化合物溶解性差、吸濕性強、穩定性差的缺陷，同時本發明的多晶型物保持對CDK9良好的抑制活性，可進一步開發成為藥物，用於預防和治療CDK9相關的疾病。The main advantages of the present invention include: after long-term and in-depth research, the inventor unexpectedly discovered that the maleate or fumarate of the compound of formula (I) has good physical and chemical properties from many kinds of salts. Accordingly, the present invention provides multiple polymorphs of the maleate or fumarate salt of the compound of formula (I), which are respectively crystal form I, crystal form 1, and crystal form of the maleate salt of the compound of formula (I). 2. Crystal Forms 3 and 4 and Form A of the maleate salt of the compound of formula (I). The polymorph of the present invention has good stability, good solubility and is not easy to absorb moisture, which solves the defects of poor solubility, strong hygroscopicity and poor stability of free base compounds. At the same time, the polymorph of the present invention maintains good inhibition of CDK9 activity and can be further developed into drugs for the prevention and treatment of CDK9-related diseases.

應理解，在本發明範圍內中，本發明的上述各技術特徵和在下文(如實施例)中具體描述的各技術特徵之間都可以互相組合，從而構成新的或優選的技術方案。限於篇幅，在此不再一一累述。It should be understood that within the scope of the present invention, the above-mentioned technical features of the present invention and the technical features specifically described below (such as embodiments) can be combined with each other to form new or preferred technical solutions. Due to space limitations, they will not be described one by one here.

本發明的式Formula of the present invention (I)(I) 化合物compound

本發明所述的式(I)化合物如下式所示， (I) The compound of formula (I) according to the present invention is represented by the following formula: (I)

該化合物名稱為4-(((4-(5-氯-2-(((1R,4r)-4-(((R)-1-甲氧基丙基-2-基)氨基)環己基)氨基)吡啶-4-基)噻唑-2-基)氨基)甲基)四氫-2H-吡喃-4-甲腈，其名稱也可以為4-[[[4-[5-氯-2-[[反式-4-[[(1R)- 2-甲氧基-1-甲基乙基]氨基]環己基]氨基]-4-吡啶基]-2-噻唑基]氨基]甲基]-四氫-2H-吡喃-4-氰基。該化合物的具體製備方法可參照CN108727363A中實施例1的製備方法，其可以用於抑制細胞週期蛋白依賴性激酶(cyclin-dependentkinases，CDK)、細胞週期蛋白(cyclins)的活性，尤其是CDK9的活性。The name of the compound is 4-(((4-(5-chloro-2-(((1R,4r))-4-(((R)-1-methoxypropyl-2-yl)amino)cyclohexyl) )amino)pyridin-4-yl)thiazol-2-yl)amino)methyl)tetrahydro-2H-pyran-4-carbonitrile, its name can also be 4-[[[4-[5-chloro- 2-[[trans-4-[[(1R)- 2-methoxy-1-methylethyl]amino]cyclohexyl]amino]-4-pyridyl]-2-thiazolyl]amino]methyl [base]-tetrahydro-2H-pyran-4-cyano. The specific preparation method of this compound can refer to the preparation method of Example 1 in CN108727363A, which can be used to inhibit the activity of cyclin-dependent kinases (cyclin-dependentkinases, CDK) and cyclins, especially the activity of CDK9 .

本發明中，「式(I)化合物」與「式(I)化合物游離鹼」可互換使用。In the present invention, "compound of formula (I)" and "compound of formula (I) free base" can be used interchangeably.

本發明的多晶型物Polymorphs of the invention

固體不是以無定形的形式就是以結晶的形式存在。在結晶形式的情況下，分子定位於三維晶格格位內。當化合物從溶液或漿液中結晶出來時，它可以不同的空間點陣排列結晶(這種性質被稱作「多晶型現象」)，形成具有不同的結晶形式的晶體，這各種結晶形式被稱作“多晶型物”。給定物質的不同多晶型物可在一個或多個物理屬性方面(如溶解度和溶解速率、真比重、晶形、堆積方式、流動性和/或固態穩定性)彼此不同。Solids exist in either amorphous or crystalline form. In the case of the crystalline form, the molecules are positioned within a three-dimensional lattice site. When a compound crystallizes out of a solution or slurry, it can crystallize in different spatial lattice arrangements (a property known as "polymorphism"), forming crystals with different crystal forms, called As "polymorph". Different polymorphs of a given substance may differ from one another in one or more physical properties, such as solubility and dissolution rate, true specific gravity, crystalline form, packing pattern, flowability, and/or solid state stability.

所述的「結晶」可以通過操作溶液，使得感興趣化合物的溶解度極限被超過，從而完成生產規模的結晶。這可以通過多種方法來完成，例如，在相對高的溫度下溶解化合物，然後通過冷卻溶液至飽和極限以下，或者通過沸騰、常壓蒸發、真空乾燥或其它的一些方法來減小液體體積，或者通過加入抗溶劑或化合物在其中具有低的溶解度的溶劑或這樣的溶劑的混合物來降低感興趣化合物的溶解度。另一種可選方法是調節pH值以降低溶解度。有關結晶方面的詳細描述請參見「Crystallization, 第三版, J W Mullens, Butterworth-Heineman Ltd.，1993, ISBN 0750611294」。The "crystallization" described can be accomplished by operating the solution so that the solubility limit of the compound of interest is exceeded, thereby completing production-scale crystallization. This can be accomplished by a variety of methods, for example, by dissolving the compound at a relatively high temperature and then reducing the liquid volume by cooling the solution below the saturation limit, or by reducing the volume of the liquid by boiling, atmospheric evaporation, vacuum drying, or some other method, or The solubility of a compound of interest is reduced by adding an antisolvent or a solvent or a mixture of such solvents in which the compound has low solubility. Another option is to adjust the pH to reduce solubility. For a detailed description of crystallization, see "Crystallization, 3rd Edition, J W Mullens, Butterworth-Heineman Ltd., 1993, ISBN 0750611294".

所述的「結晶」可通過將式(I)化合物和相應的酸或相應酸的溶液在合適的溶劑中混合形成渾濁液，或者將式(I)化合物與合適的溶劑混合形成渾濁液後攪拌得到晶體的一種方法。合適的溶劑可以為水或有機溶劑。The "crystallization" can be achieved by mixing the compound of formula (I) with the corresponding acid or a solution of the corresponding acid in a suitable solvent to form a turbid liquid, or by mixing the compound of formula (I) with a suitable solvent to form a turbid liquid and then stirring. A way to get crystals. Suitable solvents can be water or organic solvents.

所述的「結晶」可通過將式(I)化合物的溶液或含式(I)化合物和相應酸的溶液置於一定溫度下緩慢揮發掉溶劑來得到晶體。The "crystallization" can obtain crystals by placing a solution of a compound of formula (I) or a solution containing a compound of formula (I) and a corresponding acid at a certain temperature to slowly evaporate the solvent.

本發明所述的「加入抗溶劑」或「加入反溶劑」是指向式(I)化合物的一種溶液中加入另一種合適溶劑後析出得到晶體的一種方法。The "adding antisolvent" or "adding antisolvent" described in the present invention refers to a method of adding another suitable solvent to a solution of the compound of formula (I) and then precipitating to obtain crystals.

假如期望鹽的形成與結晶同時發生，如果鹽在反應介質中比原料溶解度小，那麼加入適當的酸或鹼可導致所需鹽的直接結晶。同樣，在最終想要的形式比反應物溶解度小的介質中，合成反應的完成可使最終產物直接結晶。If it is desired that salt formation occurs simultaneously with crystallization, then the addition of an appropriate acid or base can lead to direct crystallization of the desired salt if the salt is less soluble in the reaction medium than the starting material. Likewise, completion of the synthesis reaction allows direct crystallization of the final product in a medium in which the final desired form is less soluble than the reactants.

結晶的優化可包括用所需形式的晶體作為晶種接種於結晶介質中。另外，許多結晶方法使用上述策略的組合。一個實施例是在高溫下將感興趣的化合物溶解在溶劑中，隨後通過受控方式加入適當體積的抗溶劑，以使體系正好在飽和水準之下。此時，可加入所需形式的晶種(並保持晶種的完整性)，將體系冷卻以完成結晶。Optimization of crystallization may include seeding the crystallization medium with crystals of the desired form. Additionally, many crystallization methods use a combination of the above strategies. One example is to dissolve the compound of interest in a solvent at elevated temperatures and then add an appropriate volume of antisolvent in a controlled manner to bring the system just below saturation levels. At this point, the desired form of seed crystal can be added (and the integrity of the seed crystal maintained), and the system is cooled to complete crystallization.

如本文所用，「本發明的晶體」、「本發明的晶型」、「本發明的多晶型物」等可互換使用。As used herein, "crystals of the present invention," "crystalline forms of the present invention," "polymorphs of the present invention" and the like are used interchangeably.

如本文所用，術語「本發明的多晶型物」包括式(I)化合物或其藥學上可接受鹽(如馬來酸鹽、富馬酸鹽)的多晶型物，還包括相同鹽的不同多晶型物。As used herein, the term "polymorph of the invention" includes polymorphs of a compound of formula (I) or a pharmaceutically acceptable salt thereof (eg, maleate, fumarate), and also includes salts of the same. Different polymorphs.

優選地，本發明的多晶型物包括(但並不限於)：式(I)化合物馬來酸鹽的晶型I、晶型1、晶型2、晶型3或晶型4；式(I)化合物富馬酸鹽的晶型A。Preferably, the polymorphs of the present invention include (but are not limited to): crystal form I, crystal form 1, crystal form 2, crystal form 3 or crystal form 4 of the maleate salt of the compound of formula (I); formula ( I) Form A of compound fumarate.

在本發明中，某些晶型可以相互轉化，因此本發明還提供了部分晶型相互轉化的方法。In the present invention, certain crystal forms can be converted into each other, so the present invention also provides a method for interconverting some crystal forms.

多晶型物的鑒定和性質Identification and characterization of polymorphs

本發明在製備式(I)化合物的多晶型物後，採用如下多種方式和儀器對其性質進行了研究，例如，X射線粉末衍射(XRD)、差示量熱掃描分析(DSC)、TGA、IR等等。After preparing the polymorphic form of the compound of formula (I), the present invention uses the following various methods and instruments to study its properties, for example, X-ray powder diffraction (XRD), differential scanning calorimetry (DSC), TGA , IR, etc.

X射線粉末衍射：測定晶型的X射線粉末衍射的方法在本領域中是已知的。例如使X射線粉末衍射儀，以2°每分鐘的掃描速度，採用銅輻射靶獲取圖譜。X-ray powder diffraction: Methods for determining X-ray powder diffraction of crystalline forms are known in the art. For example, use an X-ray powder diffractometer to obtain a pattern using a copper radiation target at a scanning speed of 2° per minute.

本發明的式(I)化合物的鹽的多晶型物，具有特定的晶型形態，在X-射線粉末衍射(XRPD)圖中具有特定的特徵峰。The polymorphic form of the salt of the compound of formula (I) of the present invention has a specific crystal form and has specific characteristic peaks in an X-ray powder diffraction (XRPD) pattern.

示差掃描量熱分析：又稱「差示量熱掃描分析 (DSC) 」，是在加熱過程中，測量被測物質與參比物之間的能量差與溫度之間關係的一種技術。DSC圖譜上的峰位置、形狀和峰數目與物質的性質有關，故可以定性地用來鑒定物質。本領域常用該方法來檢測物質的相變溫度、玻璃化轉變溫度、反應熱等多種參數。Differential Scanning Calorimetry: Also known as "Differential Scanning Calorimetry (DSC)", it is a technology that measures the relationship between the energy difference and temperature between the substance being measured and the reference substance during the heating process. The peak position, shape and number of peaks on the DSC spectrum are related to the properties of the substance, so they can be used to identify the substance qualitatively. This method is commonly used in this field to detect various parameters such as phase transition temperature, glass transition temperature, heat of reaction, etc. of substances.

藥物組合物及其應用Pharmaceutical compositions and their applications

本發明的活性成分為本發明的多晶型物，例如式(I)化合物馬來酸鹽或其多晶型物或式(I)化合物富馬酸鹽或其多晶型物。The active ingredient of the present invention is a polymorphic form of the present invention, such as the maleate salt of the compound of formula (I) or its polymorphic form or the fumarate salt of the compound of formula (I) or its polymorphic form.

本發明的活性成分可以用於抑制細胞週期蛋白依賴性激酶(cyclin-dependentkinases，CDK)、細胞週期蛋白(cyclins)的活性，尤其是CDK9的活性。因此，本發明的活性成分和包含本發明活性成分的藥物組合物可用於治療或者預防CDK9相關疾病，例如癌症，包括(但不限於)選自下組的一種或多種疾病：非小細胞肺癌、小細胞肺癌、肺腺癌、肺鱗癌、胰腺癌、***癌、膀胱癌、肝癌、皮膚癌、神經膠質瘤、乳腺癌、黑色素瘤、惡性膠質瘤、橫紋肌肉瘤、卵巢癌、星形細胞瘤、尤因氏肉瘤、成視網膜細胞瘤、上皮細胞癌、結腸癌、腎癌、胃腸間質瘤、白血病、組織細胞性淋巴癌和鼻咽癌。The active ingredient of the present invention can be used to inhibit the activity of cyclin-dependent kinases (CDK) and cyclins, especially the activity of CDK9. Therefore, the active ingredients of the present invention and pharmaceutical compositions containing the active ingredients of the present invention can be used to treat or prevent CDK9-related diseases, such as cancer, including (but not limited to) one or more diseases selected from the following group: non-small cell lung cancer, Small cell lung cancer, lung adenocarcinoma, lung squamous cell carcinoma, pancreatic cancer, prostate cancer, bladder cancer, liver cancer, skin cancer, glioma, breast cancer, melanoma, malignant glioma, rhabdomyosarcoma, ovarian cancer, astrocytoma , Ewing's sarcoma, retinoblastoma, epithelial cell carcinoma, colon cancer, renal cancer, gastrointestinal stromal tumor, leukemia, histiocytic lymphoma and nasopharyngeal carcinoma.

本發明的藥物組合物包含本發明的活性成分和藥學上可接受的載體。本發明的藥物組合物還可以含有任選的其它治療劑。The pharmaceutical composition of the present invention contains the active ingredient of the present invention and a pharmaceutically acceptable carrier. The pharmaceutical compositions of the present invention may also contain optional other therapeutic agents.

如本文所用，「藥學可接受的載體」是指無毒、惰性、固態、半固態的物質或液體灌裝機、稀釋劑、封裝材料或輔助製劑或任何類型輔料，其與患者相相容，最好為哺乳動物，更優選為人，其適合將活性試劑輸送到目標靶點而不終止試劑的活性。As used herein, "pharmaceutically acceptable carrier" means a nontoxic, inert, solid, semi-solid substance or liquid filling machine, diluent, encapsulating material or auxiliary preparation or excipient of any type that is compatible with the patient and preferably is a mammal, more preferably a human, which is suitable for delivering the active agent to the target site of interest without terminating the activity of the agent.

在治療過程中，可以根據情況，單獨使用本發明的藥物或將本發明的藥物與一種或多種其它治療劑組合使用。所述組合使用可以是在使用本發明的藥物的同時一起給予一種或多種其它治療劑，也可以是在使用本發明的藥物之前給予一種或多種其它治療劑或在使用本發明的藥物之後再給予一種或多種其它治療劑。During the treatment, the medicine of the present invention can be used alone or in combination with one or more other therapeutic agents according to the situation. The combined use may be to administer one or more other therapeutic agents together with the medicine of the present invention, or to administer one or more other therapeutic agents before using the medicine of the present invention or after using the medicine of the present invention. One or more other therapeutic agents.

通常，本發明的活性成分可以與一種或多種藥用載體形成適合的劑型施用。這些劑型適用於口服、直腸給藥、局部給藥、口內給藥以及其他非胃腸道施用(例如，皮下、肌肉、靜脈等)。上述劑型可由本發明的活性成分與一種或多種載體或輔料經由通用的藥劑學方法製成。上述的載體需要與本發明的活性成分或其他輔料相容。對於固體製劑，常用的無毒載體包括但不限於甘露醇、乳糖、澱粉、硬脂酸鎂、纖維素、葡萄糖、蔗糖等。用於液體製劑的載體包括水(優選注射用無菌水)、生理鹽水、葡萄糖水溶液、乙二醇和聚乙二醇等。本發明的活性成分可與上述載體形成溶液或是混懸液。Generally, the active ingredients of the present invention can be administered in a suitable dosage form with one or more pharmaceutical carriers. These dosage forms are suitable for oral, rectal, topical, intraoral, and other parenteral administration (e.g., subcutaneous, intramuscular, intravenous, etc.). The above dosage form can be prepared from the active ingredient of the present invention and one or more carriers or excipients through general pharmaceutical methods. The above-mentioned carrier needs to be compatible with the active ingredients or other excipients of the present invention. For solid preparations, commonly used non-toxic carriers include but are not limited to mannitol, lactose, starch, magnesium stearate, cellulose, glucose, sucrose, etc. Carriers for liquid preparations include water (preferably sterile water for injection), physiological saline, aqueous glucose solution, ethylene glycol, polyethylene glycol, and the like. The active ingredient of the present invention can form a solution or suspension with the above-mentioned carrier.

本發明的藥物組合物以符合醫學實踐規範的方式配製，定量和給藥。給予本發明的活性成分的「治療有效量」由要治療的具體病症、治療的個體、病症的起因、藥物的靶點以及給藥方式等因素決定。The pharmaceutical compositions of the invention are formulated, dosed and administered in a manner consistent with good medical practice. The "therapeutically effective amount" of an active ingredient administered in the present invention is determined by factors such as the specific condition to be treated, the individual being treated, the cause of the condition, the target of the drug, and the mode of administration.

如本文所用，「治療有效量」是指可對患者(例如人和/或動物)產生功能或活性的且可被人和/或動物所接受的量。As used herein, a "therapeutically effective amount" refers to an amount that produces a function or activity in a patient (eg, human and/or animal) and is acceptable to the human and/or animal.

本發明的藥物組合物或所述藥用組合物中含有的活性成分的治療有效量優選為0.1mg/kg(體重)至 5 g/kg(體重)。通常，就成人治療使用的劑量而言，施用劑量通常在0.02至5000 mg/天，例如約1至1500 mg/天的範圍內。該劑量可以為一劑、或同時給藥的劑量、或適當間隔的分劑量，例如每天二、三、四劑或更多分劑。本領域技術人員可以理解的是，儘管給出了上述劑量範圍，但具體的有效量可根據患者的情況並結合醫師診斷而適當調節。The therapeutically effective amount of the pharmaceutical composition of the present invention or the active ingredient contained in the pharmaceutical composition is preferably 0.1 mg/kg (body weight) to 5 g/kg (body weight). Typically, with respect to dosages for therapeutic use in adults, the dosage administered will generally be in the range of 0.02 to 5000 mg/day, such as about 1 to 1500 mg/day. The dose may be in the form of one dose, or doses administered simultaneously, or suitably spaced divided doses, for example two, three, four or more divided doses per day. Those skilled in the art can understand that although the above dosage range is given, the specific effective amount can be appropriately adjusted according to the patient's condition and in conjunction with the physician's diagnosis.

如本文所用，「患者」是指一種動物，最好為哺乳動物，更好的為人。術語「哺乳動物」是指溫血脊椎類哺乳動物，包括如貓、狗、兔、熊、狐狸、狼、猴子、鹿、鼠、豬和人類。As used herein, "patient" refers to an animal, preferably a mammal, and more preferably a human. The term "mammal" refers to warm-blooded vertebrate mammals, including, for example, cats, dogs, rabbits, bears, foxes, wolves, monkeys, deer, rats, pigs and humans.

如本文所用，「治療」是指減輕、延緩進展、衰減、預防或維持現有疾病或病症(例如癌症)。「治療」還包括將疾病或病症的一個或多個症狀治癒、預防其發展或減輕到某種程度。As used herein, "treatment" means alleviating, delaying progression, attenuating, preventing or maintaining an existing disease or condition (eg, cancer). "Treatment" also includes curing, preventing the progression of, or alleviating to some extent one or more symptoms of a disease or condition.

本發明的活性成分可以通過本領域技術人員所熟知的多種合成方法來製備，包括下面列舉的具體實施方式、其與其他化學合成方法的結合所形成的實施方式以及本領域技術上人員所熟知的等同替換方式，優選的實施方式包括但不限於本發明的實施例。The active ingredients of the present invention can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments listed below, embodiments formed by their combination with other chemical synthesis methods, and methods well known to those skilled in the art. Equivalent alternatives and preferred embodiments include, but are not limited to, embodiments of the present invention.

下面結合具體實施例，進一步闡述本發明。應理解，這些實施例僅用於說明本發明而不用於限制本發明的範圍。下列實施例中未注明具體條件的實驗方法，通常按照常規條件或按照製造廠商所建議的條件。除非另外說明，否則百分比和份數按重量計算。The present invention will be further described below in conjunction with specific embodiments. It should be understood that these examples are only used to illustrate the invention and are not intended to limit the scope of the invention. Experimental methods without specifying specific conditions in the following examples usually follow conventional conditions or conditions recommended by the manufacturer. Unless otherwise stated, percentages and parts are by weight.

除非另行定義，本文所用的術語與本領域熟練人員所熟悉的意義相同。Unless otherwise defined, terms used herein have the same meaning as is familiar to those skilled in the art.

除非另行定義，本文所用的任何試劑或儀器均市售可得。Unless otherwise defined, any reagents or instruments used herein are commercially available.

任何與所記載內容相似或同等的方法及材料皆可應用于本發明中。Any methods and materials similar or equivalent to those described can be used in the present invention.

如本文所用，術語「室溫」一般指4至30℃，較佳地指25±5℃。As used herein, the term "room temperature" generally refers to 4 to 30°C, preferably 25±5°C.

縮寫說明：ACN表示乙腈。Abbreviation explanation: ACN stands for acetonitrile.

參照CN108727363A中實施例1的製備方法製備式(I)化合物游離鹼，獲得純度99.99%的式(I)化合物游離鹼。送檢XRPD，結果發現式(I)化合物游離鹼為無定形物。XRPD如圖19所示。The free base of the compound of formula (I) was prepared with reference to the preparation method of Example 1 in CN108727363A, and the free base of the compound of formula (I) with a purity of 99.99% was obtained. XRPD was sent for inspection, and it was found that the free base of the compound of formula (I) was amorphous. The XRPD is shown in Figure 19.

實施例Example 11 製備式preparation formula (I)(I) 化合物馬來酸鹽compound maleate

將34.4g式(I)化合物游離鹼用150mL乙腈溶清，作為游離鹼溶液，備用。向反應瓶中加入乙腈300mL，反應瓶中加入馬來酸16.9g(2.2eq)，升溫至75~80℃溶清後，逐滴加入上述游離鹼溶液，加完後攪拌1~2h，冷卻至室溫，繼續攪拌2h，抽濾，濾餅用300mL乙腈淋洗，乾燥得到44g 式(I)化合物馬來酸鹽的晶型I，其中，式(I)化合物和馬來酸的莫耳比為1：2。送檢XRPD、DSC。晶型I的XRPD如圖17和表1所示。晶型I的DSC如圖18所示。Dissolve 34.4g of the free base of the compound of formula (I) in 150 mL of acetonitrile to prepare a free base solution for later use. Add 300 mL of acetonitrile to the reaction flask, add 16.9g (2.2eq) of maleic acid to the reaction flask, heat it to 75~80°C and dissolve it, add the above free base solution dropwise, stir for 1~2h after the addition, and cool to Room temperature, continue stirring for 2 hours, suction filtration, rinse the filter cake with 300 mL acetonitrile, and dry to obtain 44 g of crystal form I of the maleate salt of the compound of formula (I), in which the molar ratio of the compound of formula (I) and maleic acid is is 1:2. Submit XRPD and DSC for inspection. The XRPD of Form I is shown in Figure 17 and Table 1. The DSC of Form I is shown in Figure 18.

表1 峰號 2θ[°] d[埃] 相對強度% 1 5.00 17.6641 70.4 2 5.40 16.3505 100.0 3 6.72 13.1432 11.5 4 8.64 10.2211 24.5 5 9.80 9.0189 21.6 6 10.73 8.2394 12.6 7 11.16 7.9191 16.8 8 13.61 6.5019 9.6 9 14.23 6.2192 39.1 10 15.04 5.8860 26.0 11 16.60 5.3358 19.6 12 17.40 5.0919 25.7 13 18.13 4.8898 17.0 14 18.72 4.7372 9.1 15 19.64 4.5170 32.5 16 20.41 4.3486 34.9 17 22.40 3.9658 89.7 18 23.28 3.8186 65.2 19 24.72 3.5983 14.0 20 27.09 3.2892 30.9 21 28.40 3.1398 13.1 22 31.00 2.8826 12.9 Table 1 Peak number 2θ[°] d[angstrom] Relative strength % 1 5.00 17.6641 70.4 2 5.40 16.3505 100.0 3 6.72 13.1432 11.5 4 8.64 10.2211 24.5 5 9.80 9.0189 21.6 6 10.73 8.2394 12.6 7 11.16 7.9191 16.8 8 13.61 6.5019 9.6 9 14.23 6.2192 39.1 10 15.04 5.8860 26.0 11 16.60 5.3358 19.6 12 17.40 5.0919 25.7 13 18.13 4.8898 17.0 14 18.72 4.7372 9.1 15 19.64 4.5170 32.5 16 20.41 4.3486 34.9 17 22.40 3.9658 89.7 18 23.28 3.8186 65.2 19 24.72 3.5983 14.0 20 27.09 3.2892 30.9 twenty one 28.40 3.1398 13.1 twenty two 31.00 2.8826 12.9

實施例Example 1.11.1 製備式preparation formula (I)(I) 化合物馬來酸鹽compound maleate

稱取200mg 式(I)化合物游離鹼於反應瓶中，加入10mL乙腈溶清。然後加熱至50℃，邊攪拌邊滴加0.33M馬來酸(2.1eq)的乙腈溶液，攪拌1小時後，自然冷卻至室溫，繼續攪拌1小時，過濾，濾餅用少量乙腈沖洗，乾燥後得到255mg類白色固體，產率88.2%。產品送檢XRPD和DSC。確定為式(I)化合物馬來酸鹽晶型I；其中，式(I)化合物和馬來酸的莫耳比為1：2。其XRPD基本如圖17和表1所示。DSC基本如圖18所示。 ¹H NMR (400 MHz, DMSO- d6) δ 8.35 (s, 1H), 8.22 (s, 1H), 8.12 (t, J = 6.3 Hz, 1H), 7.99 (s, 1H), 7.36 (s, 1H), 7.05 (s, 1H), 6.77 (d, J = 7.4 Hz, 1H), 6.15 (s, 4H), 3.92 (m, 2H), 3.67 (d, J = 6.3 Hz, 2H), 3.60 (s, 1H), 3.57 ~3.41 (m, 5H), 3.35 (s, 3H), 3.13 (s, 1H), 2.05 (d, J = 10.9 Hz, 4H), 1.87 (d, J = 13.5 Hz, 2H), 1.73 ~ 1.66 (m, 2H), 1.50~1.37 (m, 2H), 1.28 (m, 2H), 1.21(d, J = 6.4 Hz , 3H). Weigh 200 mg of the free base of the compound of formula (I) into the reaction bottle, and add 10 mL of acetonitrile to dissolve the solution. Then heat to 50°C, add 0.33M maleic acid (2.1eq) acetonitrile solution dropwise while stirring, stir for 1 hour, then naturally cool to room temperature, continue stirring for 1 hour, filter, rinse the filter cake with a small amount of acetonitrile, and dry. Finally, 255 mg of off-white solid was obtained, with a yield of 88.2%. Products are sent for XRPD and DSC inspection. It was determined to be the maleate crystal form I of the compound of formula (I); wherein, the molar ratio of the compound of formula (I) and maleic acid was 1:2. Its XRPD is basically as shown in Figure 17 and Table 1. The DSC is basically shown in Figure 18. ¹ H NMR (400 MHz, DMSO- d6 ) δ 8.35 (s, 1H), 8.22 (s, 1H), 8.12 (t, J = 6.3 Hz, 1H), 7.99 (s, 1H), 7.36 (s, 1H ), 7.05 (s, 1H), 6.77 (d, J = 7.4 Hz, 1H), 6.15 (s, 4H), 3.92 (m, 2H), 3.67 (d, J = 6.3 Hz, 2H), 3.60 (s , 1H), 3.57 ~3.41 (m, 5H), 3.35 (s, 3H), 3.13 (s, 1H), 2.05 (d, J = 10.9 Hz, 4H), 1.87 (d, J = 13.5 Hz, 2H) , 1.73 ~ 1.66 (m, 2H), 1.50 ~ 1.37 (m, 2H), 1.28 (m, 2H), 1.21 (d, J = 6.4 Hz, 3H).

實施例Example 22 製備式preparation formula (I)(I) 化合物馬來酸鹽晶型Compound maleate crystal form 11

將34g 實施例1製備的式(I)化合物馬來酸鹽加入反應瓶中，向反應瓶中加入乙腈和水(體積比為20：1)的混合溶劑340ml，反應體系在氮氣保護下，升溫至回流溶清(80至85℃)；將反應體系降溫至75℃並養晶1至2h；然後，將體系自然降溫到2至10℃，抽濾，固體在60℃下真空乾燥，得到產品式(I)化合物馬來酸鹽晶型1，產率80%。熔點在156至160℃。純度99.91%。送檢XRPD、DSC、TGA和IR。晶型1的XRPD如圖1和表2所示。晶型1的DSC如圖2所示。晶型1的TGA如圖3所示。晶型1的IR如圖4所示。 ¹H NMR (600 MHz, DMSO- d6) δ 8.38 (s, 1H), 8.25 (s, 1H), 8.12 (t, J = 6.3 Hz, 1H), 8.00 (s, 1H), f7.37 (s, 1H), 7.06 (s, 1H), 6.78 (s, 1H), 6.16 (s, 4H), 3.92 (m, 2H), 3.67 (d, J = 6.1 Hz, 2H), 3.62 (s, 1H), 3.56 ~ 3.42 (m, 5H), 3.35 (s, 3H), 3.14 (s, 1H), 2.05 (m, 4H), 1.87 (d, J = 13.8 Hz, 2H), 1.73~1.68 (m, 2H), 1.53~1.39 (m, 2H), 1.28 (m, 2H), 1.22 (d, J = 6.5 Hz , 3H). Add 34g of the maleate salt of the compound of formula (I) prepared in Example 1 into the reaction bottle, add 340 ml of a mixed solvent of acetonitrile and water (volume ratio is 20:1) to the reaction bottle, and heat the reaction system under nitrogen protection. to reflux and dissolve (80 to 85°C); cool the reaction system to 75°C and grow the crystals for 1 to 2 hours; then, naturally cool the system to 2 to 10°C, filter with suction, and vacuum dry the solid at 60°C to obtain the product The compound of formula (I) maleate crystal form 1, the yield is 80%. The melting point is 156 to 160°C. Purity 99.91%. Submit XRPD, DSC, TGA and IR for inspection. The XRPD of Form 1 is shown in Figure 1 and Table 2. The DSC of Form 1 is shown in Figure 2. The TGA of Form 1 is shown in Figure 3. The IR of Form 1 is shown in Figure 4. ¹ H NMR (600 MHz, DMSO- d6 ) δ 8.38 (s, 1H), 8.25 (s, 1H), 8.12 (t, J = 6.3 Hz, 1H), 8.00 (s, 1H), f7.37 (s , 1H), 7.06 (s, 1H), 6.78 (s, 1H), 6.16 (s, 4H), 3.92 (m, 2H), 3.67 (d, J = 6.1 Hz, 2H), 3.62 (s, 1H) , 3.56 ~ 3.42 (m, 5H), 3.35 (s, 3H), 3.14 (s, 1H), 2.05 (m, 4H), 1.87 (d, J = 13.8 Hz, 2H), 1.73~1.68 (m, 2H ), 1.53~1.39 (m, 2H), 1.28 (m, 2H), 1.22 (d, J = 6.5 Hz, 3H).

表2 峰號 2θ[°] d[埃] 相對強度% 1 5.02 17.5866 13.1 2 5.48 16.1183 48.9 3 8.78 10.0656 4.6 4 9.12 9.6905 1.6 5 9.86 8.9624 16.9 6 10.88 8.1283 5.6 7 11.22 7.8797 13.7 8 13.66 6.4772 2.5 9 14.26 6.2063 28.1 10 15.06 5.8778 19.4 11 16.28 5.4411 3.4 12 16.82 5.2672 10.8 13 17.48 5.0701 5.5 14 18.18 4.8759 9.0 15 18.72 4.7362 1.1 16 19.68 4.5073 27.9 17 20.10 4.4141 3.7 18 20.50 4.3289 7.9 19 21.40 4.1487 1.4 20 22.44 3.9590 100.0 21 22.82 3.8941 7.4 22 23.24 3.8244 18.2 23 24.90 3.5733 20.0 24 26.07 3.4159 4.0 25 26.76 3.3287 11.5 26 27.16 3.2805 10.9 27 28.10 3.1727 1.5 28 28.48 3.1315 5.1 29 29.84 2.9915 2.7 30 30.30 2.9475 3.4 31 30.86 2.8950 5.9 32 31.42 2.8447 4.6 33 31.72 2.8186 2.7 34 32.66 2.7396 1.0 35 34.94 2.5657 2.3 36 35.24 2.5447 2.0 37 35.92 2.4980 2.0 38 36.44 2.4636 2.8 Table 2 Peak number 2θ[°] d[angstrom] Relative strength % 1 5.02 17.5866 13.1 2 5.48 16.1183 48.9 3 8.78 10.0656 4.6 4 9.12 9.6905 1.6 5 9.86 8.9624 16.9 6 10.88 8.1283 5.6 7 11.22 7.8797 13.7 8 13.66 6.4772 2.5 9 14.26 6.2063 28.1 10 15.06 5.8778 19.4 11 16.28 5.4411 3.4 12 16.82 5.2672 10.8 13 17.48 5.0701 5.5 14 18.18 4.8759 9.0 15 18.72 4.7362 1.1 16 19.68 4.5073 27.9 17 20.10 4.4141 3.7 18 20.50 4.3289 7.9 19 21.40 4.1487 1.4 20 22.44 3.9590 100.0 twenty one 22.82 3.8941 7.4 twenty two 23.24 3.8244 18.2 twenty three 24.90 3.5733 20.0 twenty four 26.07 3.4159 4.0 25 26.76 3.3287 11.5 26 27.16 3.2805 10.9 27 28.10 3.1727 1.5 28 28.48 3.1315 5.1 29 29.84 2.9915 2.7 30 30.30 2.9475 3.4 31 30.86 2.8950 5.9 32 31.42 2.8447 4.6 33 31.72 2.8186 2.7 34 32.66 2.7396 1.0 35 34.94 2.5657 2.3 36 35.24 2.5447 2.0 37 35.92 2.4980 2.0 38 36.44 2.4636 2.8

實施例Example 2.12.1 製備式preparation formula (I)(I) 化合物馬來酸鹽晶型Compound maleate crystal form 11

將200 mg 實施例1製備的式(I)化合物馬來酸鹽加入反應瓶中，向反應瓶中加入乙腈和水(體積比為4：1)的混合溶劑10ml，反應體系在氮氣保護下，升溫至回流溶清(80至85℃)；將反應體系降溫至75℃並養晶1至2h；然後，將體系自然降溫至室溫，抽濾，異丙醇淋洗濾餅。濾餅在45℃下真空乾燥，得到產品，產率81%。產品送檢XRPD和DSC。確定為式(I)化合物馬來酸鹽晶型1。其XRPD基本如圖1和表2所示。DSC基本如圖2所示。200 mg of the maleate salt of the compound of formula (I) prepared in Example 1 was added to the reaction bottle, and 10 ml of a mixed solvent of acetonitrile and water (volume ratio of 4:1) was added to the reaction bottle. The reaction system was protected by nitrogen. Raise the temperature to reflux and dissolve (80 to 85°C); cool the reaction system to 75°C and grow the crystals for 1 to 2 hours; then, naturally cool the system to room temperature, filter with suction, and rinse the filter cake with isopropyl alcohol. The filter cake was vacuum dried at 45°C to obtain the product with a yield of 81%. Products are sent for XRPD and DSC inspection. It was determined to be the maleate crystal form 1 of the compound of formula (I). Its XRPD is basically as shown in Figure 1 and Table 2. DSC is basically shown in Figure 2.

實施例Example 2.22.2 製備式preparation formula (I)(I) 化合物馬來酸鹽晶型Compound maleate crystal form 11

將100mg 實施例1.1製備的式(I)化合物馬來酸鹽加入到1至2ml乙腈中，溫度控制在0℃攪拌24小時後，過濾反應液，收集固體，乾燥得到產品。純度99.99%。產品送檢XRPD和DSC。確定為式(I)化合物馬來酸鹽晶型1。其XRPD基本如圖1和表2所示。DSC基本如圖2所示。Add 100 mg of the maleate salt of the compound of formula (I) prepared in Example 1.1 to 1 to 2 ml of acetonitrile, control the temperature at 0°C and stir for 24 hours. The reaction solution is filtered, the solid is collected, and dried to obtain the product. Purity 99.99%. Products are sent for XRPD and DSC inspection. It was determined to be the maleate crystal form 1 of the compound of formula (I). Its XRPD is basically as shown in Figure 1 and Table 2. DSC is basically shown in Figure 2.

實施例Example 2.32.3 製備式preparation formula (I)(I) 化合物馬來酸鹽晶型Compound maleate crystal form 11

將100mg 實施例1.1製備的式(I)化合物馬來酸鹽加入到1至2ml乙腈中，溫度控制在25℃攪拌24小時後，過濾反應液，收集固體，乾燥得到產品。純度99.99%。產品送檢XRPD和DSC。確定為式(I)化合物馬來酸鹽晶型1。其XRPD基本如圖1和表2所示。DSC基本如圖2所示。Add 100 mg of the maleate salt of the compound of formula (I) prepared in Example 1.1 to 1 to 2 ml of acetonitrile, control the temperature at 25°C and stir for 24 hours. The reaction solution is filtered, the solid is collected, and dried to obtain the product. Purity 99.99%. Products are sent for XRPD and DSC inspection. It was determined to be the maleate crystal form 1 of the compound of formula (I). Its XRPD is basically as shown in Figure 1 and Table 2. DSC is basically shown in Figure 2.

實施例Example 2.42.4 製備式preparation formula (I)(I) 化合物馬來酸鹽晶型Compound maleate crystal form 11

將100mg 實施例1.1製備的式(I)化合物馬來酸鹽加入到1至2ml乙腈和水(體積比為10：1)的混合溶劑中，溫度控制在0℃攪拌24小時後，過濾反應液，收集固體，乾燥得到產品。純度99.91%。產品送檢XRPD和DSC。確定為式(I)化合物馬來酸鹽晶型1。其XRPD基本如圖1和表2所示。DSC基本如圖2所示。Add 100 mg of the maleate salt of the compound of formula (I) prepared in Example 1.1 to a mixed solvent of 1 to 2 ml of acetonitrile and water (volume ratio is 10:1), control the temperature at 0°C and stir for 24 hours, then filter the reaction solution , collect the solid, and dry to obtain the product. Purity 99.91%. Products are sent for XRPD and DSC inspection. It was determined to be the maleate crystal form 1 of the compound of formula (I). Its XRPD is basically as shown in Figure 1 and Table 2. DSC is basically shown in Figure 2.

實施例Example 33 製備式preparation formula (I)(I) 化合物馬來酸鹽晶型Compound maleate crystal form 22

將10g 實施例1製備的式(I)化合物馬來酸鹽加入到100ml甲基第三丁基醚中，在氮氣保護下，溫度控制在25℃，反應過夜後，過濾反應液，收集固體40至50℃旋幹，得到產品式(I)化合物馬來酸鹽晶型2，產率70%。熔點在152至156℃。純度99.13%。送檢XRPD、DSC、TGA和IR。晶型2的XRPD如圖5和表3所示。晶型2的DSC如圖6所示。晶型2的TGA如圖7所示。晶型2的IR如圖8所示。Add 10 g of the maleate salt of the compound of formula (I) prepared in Example 1 to 100 ml of methyl tert-butyl ether. Under nitrogen protection, the temperature is controlled at 25°C. After the reaction overnight, the reaction liquid is filtered and the solid 40 is collected. Spin to dryness at 50°C to obtain the maleate salt form 2 of the product formula (I) with a yield of 70%. The melting point is 152 to 156°C. Purity 99.13%. Submit XRPD, DSC, TGA and IR for inspection. The XRPD of Form 2 is shown in Figure 5 and Table 3. The DSC of Form 2 is shown in Figure 6. The TGA of Form 2 is shown in Figure 7. The IR of Form 2 is shown in Figure 8.

表3 峰號 2θ[°] d[埃] 相對強度% 1 5.02 17.5879 100.0 2 5.36 16.4713 54.5 3 8.56 10.3219 15.7 4 9.00 9.8162 15.7 5 14.04 6.3028 53.6 6 15.16 5.8396 8.5 7 16.36 5.4132 5.3 8 17.40 5.0929 11.8 9 18.10 4.8974 6.9 10 19.22 4.6141 11.8 11 20.96 4.2348 53.4 12 21.42 4.1451 67.1 13 21.96 4.0436 5.3 14 23.00 3.8637 49.1 15 24.46 3.6364 19.9 16 25.68 3.4662 3.8 17 26.05 3.4184 3.7 18 26.90 3.3118 10.7 19 27.34 3.2594 15.5 20 28.02 3.1818 18.7 21 31.40 2.8465 7.3 22 32.08 2.7879 15.6 23 35.24 2.5449 3.3 24 38.95 2.3107 3.0 table 3 Peak number 2θ[°] d[angstrom] Relative strength % 1 5.02 17.5879 100.0 2 5.36 16.4713 54.5 3 8.56 10.3219 15.7 4 9.00 9.8162 15.7 5 14.04 6.3028 53.6 6 15.16 5.8396 8.5 7 16.36 5.4132 5.3 8 17.40 5.0929 11.8 9 18.10 4.8974 6.9 10 19.22 4.6141 11.8 11 20.96 4.2348 53.4 12 21.42 4.1451 67.1 13 21.96 4.0436 5.3 14 23.00 3.8637 49.1 15 24.46 3.6364 19.9 16 25.68 3.4662 3.8 17 26.05 3.4184 3.7 18 26.90 3.3118 10.7 19 27.34 3.2594 15.5 20 28.02 3.1818 18.7 twenty one 31.40 2.8465 7.3 twenty two 32.08 2.7879 15.6 twenty three 35.24 2.5449 3.3 twenty four 38.95 2.3107 3.0

實施例Example 3.13.1 製備式preparation formula (I)(I) 化合物馬來酸鹽晶型Compound maleate crystal form 22

將100 mg 實施例1.1製備的式(I)化合物馬來酸鹽加入到1至2 ml甲基第三丁基醚中，溫度控制在0 ℃攪拌24小時後，過濾反應液，收集固體，乾燥得到產品。純度99.99%。產品送檢XRPD和DSC。確定為式(I)化合物馬來酸鹽晶型2。其XRPD基本如圖5和表3所示。DSC基本如圖6所示。Add 100 mg of the maleate salt of the compound of formula (I) prepared in Example 1.1 to 1 to 2 ml of methyl tert-butyl ether, control the temperature at 0°C and stir for 24 hours, filter the reaction solution, collect the solid, and dry Get the product. Purity 99.99%. Products are sent for XRPD and DSC inspection. It was determined to be the maleate crystal form 2 of the compound of formula (I). Its XRPD is basically shown in Figure 5 and Table 3. DSC is basically shown in Figure 6.

實施例Example 3.23.2 製備式preparation formula (I)(I) 化合物馬來酸鹽晶型Compound maleate crystal form 22

將100 mg 實施例1.1製備的式(I)化合物馬來酸鹽加入到1至2 ml甲基第三丁基醚中，溫度控制在50 ℃攪拌24小時後，過濾反應液，收集固體，乾燥得到產品。純度99.88%。產品送檢XRPD和DSC。確定為式(I)化合物馬來酸鹽晶型2。其XRPD基本如圖5和表3所示。DSC基本如圖6所示。Add 100 mg of the maleate salt of the compound of formula (I) prepared in Example 1.1 to 1 to 2 ml of methyl tert-butyl ether, control the temperature at 50°C and stir for 24 hours, filter the reaction solution, collect the solid, and dry Get the product. Purity 99.88%. Products are sent for XRPD and DSC inspection. It was determined to be the maleate crystal form 2 of the compound of formula (I). Its XRPD is basically shown in Figure 5 and Table 3. DSC is basically shown in Figure 6.

實施例Example 3.33.3 製備式preparation formula (I)(I) 化合物馬來酸鹽晶型Compound maleate crystal form 22

將100 mg 實施例1.1製備的式(I)化合物馬來酸鹽加入到1至2 ml乙酸乙酯中，溫度控制在50 ℃攪拌24小時後，過濾反應液，收集固體，乾燥得到產品。純度99.81%。產品送檢XRPD和DSC。確定為式(I)化合物馬來酸鹽晶型2。其XRPD基本如圖5和表3所示。DSC基本如圖6所示。Add 100 mg of the maleate salt of the compound of formula (I) prepared in Example 1.1 to 1 to 2 ml of ethyl acetate, control the temperature at 50°C and stir for 24 hours, then filter the reaction solution, collect the solid, and dry to obtain the product. Purity 99.81%. Products are sent for XRPD and DSC inspection. It was determined to be the maleate crystal form 2 of the compound of formula (I). Its XRPD is basically shown in Figure 5 and Table 3. DSC is basically shown in Figure 6.

實施例Example 44 製備式preparation formula (I)(I) 化合物馬來酸鹽晶型Compound maleate crystal form 33

將100mg 實施例1.1製備的式(I)化合物馬來酸鹽置於1至2ml丙酮和水的混合溶劑(丙酮和水的體積比為10： 1)中，在50℃下攪拌24小時，然後過濾，收集固體並乾燥，得到產品式(I)化合物馬來酸鹽晶型3，產率50%，純度99.99%。送檢XRPD和DSC。晶型3的XRPD如圖9和表4所示。晶型3的DSC如圖10所示。Place 100 mg of the maleate salt of the compound of formula (I) prepared in Example 1.1 into a mixed solvent of 1 to 2 ml of acetone and water (the volume ratio of acetone and water is 10: 1), stir at 50°C for 24 hours, and then Filter, collect the solid and dry it to obtain the maleate salt form 3 of product formula (I), with a yield of 50% and a purity of 99.99%. Submit XRPD and DSC for inspection. The XRPD of Form 3 is shown in Figure 9 and Table 4. The DSC of Form 3 is shown in Figure 10.

表4 峰號 2θ[°] d[埃] 相對強度% 1 5.64 15.6566 100.0 2 8.26 10.6970 9.6 3 11.28 7.8370 35.4 4 12.21 7.2452 5.8 5 12.50 7.0732 4.4 6 14.56 6.0785 4.6 7 16.22 5.4603 12.1 8 16.96 5.2234 35.5 9 18.52 4.7869 10.1 10 19.18 4.6234 22.5 11 21.28 4.1720 5.7 12 22.40 3.9662 5.5 13 22.98 3.8676 8.8 14 23.54 3.7763 10.5 15 24.50 3.6306 9.9 16 24.92 3.5704 38.4 17 25.93 3.4327 3.4 18 26.62 3.3459 28.9 19 28.79 3.0981 3.6 20 29.42 3.0336 14.0 21 30.02 2.9743 3.2 22 31.56 2.8325 2.4 23 32.38 2.7629 3.1 24 33.32 2.6867 3.9 25 34.96 2.5645 2.3 26 35.58 2.5214 3.4 27 35.88 2.5010 2.3 28 37.48 2.3976 5.0 Table 4 Peak number 2θ[°] d[angstrom] Relative strength % 1 5.64 15.6566 100.0 2 8.26 10.6970 9.6 3 11.28 7.8370 35.4 4 12.21 7.2452 5.8 5 12.50 7.0732 4.4 6 14.56 6.0785 4.6 7 16.22 5.4603 12.1 8 16.96 5.2234 35.5 9 18.52 4.7869 10.1 10 19.18 4.6234 22.5 11 21.28 4.1720 5.7 12 22.40 3.9662 5.5 13 22.98 3.8676 8.8 14 23.54 3.7763 10.5 15 24.50 3.6306 9.9 16 24.92 3.5704 38.4 17 25.93 3.4327 3.4 18 26.62 3.3459 28.9 19 28.79 3.0981 3.6 20 29.42 3.0336 14.0 twenty one 30.02 2.9743 3.2 twenty two 31.56 2.8325 2.4 twenty three 32.38 2.7629 3.1 twenty four 33.32 2.6867 3.9 25 34.96 2.5645 2.3 26 35.58 2.5214 3.4 27 35.88 2.5010 2.3 28 37.48 2.3976 5.0

實施例Example 55 製備式preparation formula (I)(I) 化合物馬來酸鹽晶型Compound maleate crystal form 44

將100mg 實施例1製備的式(I)化合物馬來酸鹽置於1至2ml乙醇和水的混合溶劑(乙醇和水的體積比為10：：1)中，在25℃下攪拌24小時，然後過濾，收集固體並乾燥，得到產品式(I)化合物馬來酸鹽晶型4，產率45%，純度99.99%。熔點在171-176℃。送檢XRPD和DSC。晶型4的XRPD如圖11和表5所示。晶型4的DSC如圖12所示。100 mg of the maleate salt of the compound of formula (I) prepared in Example 1 was placed in a mixed solvent of 1 to 2 ml of ethanol and water (the volume ratio of ethanol and water is 10::1), and stirred at 25°C for 24 hours. Then filter, collect the solid and dry to obtain product formula (I) compound maleate salt crystal form 4, with a yield of 45% and a purity of 99.99%. The melting point is 171-176℃. Submit XRPD and DSC for inspection. The XRPD of Form 4 is shown in Figure 11 and Table 5. The DSC of Form 4 is shown in Figure 12.

表5 峰號 2θ[°] d[埃] 相對強度% 1 5.08 17.3812 95.4 2 5.62 15.7139 100.0 3 8.54 10.3433 18.8 4 11.32 7.8119 17.2 5 13.98 6.3303 39.4 6 15.78 5.6122 6.5 7 17.08 5.1874 29.7 8 18.10 4.8967 19.8 9 19.01 4.6635 7.2 10 20.66 4.2963 18.6 11 21.56 4.1193 6.5 12 22.72 3.9108 87.3 13 23.50 3.7827 12.0 14 25.76 3.4560 14.7 15 27.08 3.2898 9.0 16 28.02 3.1822 9.2 17 28.45 3.1352 7.5 18 28.55 3.1237 9.9 19 32.16 2.7810 7.9 20 34.48 2.5988 7.0 21 34.76 2.5791 4.9 22 38.14 2.3574 4.4 table 5 Peak number 2θ[°] d[angstrom] Relative strength % 1 5.08 17.3812 95.4 2 5.62 15.7139 100.0 3 8.54 10.3433 18.8 4 11.32 7.8119 17.2 5 13.98 6.3303 39.4 6 15.78 5.6122 6.5 7 17.08 5.1874 29.7 8 18.10 4.8967 19.8 9 19.01 4.6635 7.2 10 20.66 4.2963 18.6 11 21.56 4.1193 6.5 12 22.72 3.9108 87.3 13 23.50 3.7827 12.0 14 25.76 3.4560 14.7 15 27.08 3.2898 9.0 16 28.02 3.1822 9.2 17 28.45 3.1352 7.5 18 28.55 3.1237 9.9 19 32.16 2.7810 7.9 20 34.48 2.5988 7.0 twenty one 34.76 2.5791 4.9 twenty two 38.14 2.3574 4.4

實施例Example 66 製備式preparation formula (I)(I) 化合物馬來酸鹽晶型Compound maleate crystal form 44

將100mg 實施例1製備的式(I)化合物馬來酸鹽置於1至2ml異丙醇和水的混合溶劑(異丙醇和水的體積比為10：：1)中，在25℃下攪拌24小時，然後過濾，收集固體並乾燥，得到產品式(I)化合物馬來酸鹽晶型4，產率38%，純度99.92%。送檢XRPD和DSC。結果XRPD基本如圖11所示，DSC基本如圖12所示。100 mg of the maleate salt of the compound of formula (I) prepared in Example 1 was placed in a mixed solvent of 1 to 2 ml of isopropanol and water (the volume ratio of isopropanol and water is 10::1), and stirred at 25°C for 24 hours, and then filtered, collected the solid and dried to obtain the product formula (I) compound maleate crystal form 4, with a yield of 38% and a purity of 99.92%. Submit XRPD and DSC for inspection. The XRPD results are basically as shown in Figure 11, and the DSC results are basically as shown in Figure 12.

實施例Example 77 製備式preparation formula (I)(I) 化合物馬來酸鹽晶型Compound maleate crystal form 44

將100mg 實施例1製備的式(I)化合物馬來酸鹽置於1至2ml乙醇中，在50℃下攪拌24小時，然後過濾，收集固體並乾燥，得到產品式(I)化合物馬來酸鹽晶型4，產率42%，純度99.97%。送檢XRPD和DSC。結果XRPD基本如圖11所示，DSC基本如圖12所示。100 mg of the maleate salt of the compound of formula (I) prepared in Example 1 was placed in 1 to 2 ml of ethanol, stirred at 50° C. for 24 hours, and then filtered, and the solids were collected and dried to obtain the product of the compound of formula (I) maleic acid. Salt crystal form 4, yield 42%, purity 99.97%. Submit XRPD and DSC for inspection. The XRPD results are basically as shown in Figure 11, and the DSC results are basically as shown in Figure 12.

實施例Example 88 製備式preparation formula (I)(I) 化合物馬來酸鹽晶型Compound maleate crystal form 44

將100mg 實施例1製備的式(I)化合物馬來酸鹽置於1至2ml異丙醇中，在50℃下攪拌24小時，然後過濾，收集固體並乾燥，得到產品式(I)化合物馬來酸鹽晶型4，產率35%，純度99.99%。送檢XRPD和DSC。結果XRPD基本如圖11所示，DSC基本如圖12所示。100 mg of the maleate salt of the compound of formula (I) prepared in Example 1 was placed in 1 to 2 ml of isopropyl alcohol, stirred at 50° C. for 24 hours, and then filtered, and the solids were collected and dried to obtain the compound of the formula (I) maleate. Leate salt crystal form 4, yield 35%, purity 99.99%. Submit XRPD and DSC for inspection. The XRPD results are basically as shown in Figure 11, and the DSC results are basically as shown in Figure 12.

實施例Example 99 製備式preparation formula (I)(I) 化合物富馬酸鹽晶型Compound fumarate crystal form AA

將2g 式(I)化合物游離鹼溶於30mL乙腈中，得游離鹼的乙腈澄清溶液；置於50℃水浴中，攪拌下逐滴加入9.236mL 0.25M富馬酸(268mg，0.6eq)的乙醇溶液；逐漸有固體析出；50℃下保溫攪拌0.5小時，停止加熱，自然冷卻至室溫並攪拌1小時；過濾，用40mL乙腈沖洗濾餅；50℃真空乾燥，得產品式(I)化合物富馬酸鹽晶型A，其中，式(I)化合物和富馬酸的莫耳比為1：0.5，產率94.0%。熔點為217至218℃。純度99.38%。送檢XRPD和DSC。晶型A的XRPD如圖13和表6所示。晶型A的DSC如圖14所示。 ¹H NMR (400 MHz, DMSO- d6) δ 8.10 (t, J = 6.4 Hz 1H), 7.95 (s, 1H), 7.31 (s, 1H), 6.99 (s, 1H), 6.65 (d, J = 7.6 Hz, 1H), 6.39 (s, 1H), 3.90 (m, 2H), 3.62(d, J = 6.1 Hz, 2H) ,3.55 (s, 1H), 3.47~3.39(m, 2H), 3.31~3.25 (m, 2H), 3.23 (s, 3H), 3.13 (m, 1H), 2.70 (s, 1H), 1.95~1.82 (m, 6H), 1.66~1.62 (m, 2H), 1.26~1.17 (m, 4H), 1.00 (d, J = 6.4 Hz , 3H). Dissolve 2g of the free base of the compound of formula (I) in 30 mL of acetonitrile to obtain a clear acetonitrile solution of the free base; place it in a 50°C water bath, and add 9.236 mL of 0.25 M fumaric acid (268 mg, 0.6 eq) in ethanol dropwise while stirring. Solution; solids gradually precipitate; keep stirring at 50°C for 0.5 hours, stop heating, naturally cool to room temperature and stir for 1 hour; filter, rinse the filter cake with 40 mL acetonitrile; dry under vacuum at 50°C to obtain product formula (I) compound rich Maleate crystal form A, wherein the molar ratio of the compound of formula (I) and fumaric acid is 1:0.5, and the yield is 94.0%. The melting point is 217 to 218°C. Purity 99.38%. Submit XRPD and DSC for inspection. The XRPD of Form A is shown in Figure 13 and Table 6. The DSC of Form A is shown in Figure 14. ¹ H NMR (400 MHz, DMSO- d6 ) δ 8.10 (t, J = 6.4 Hz 1H), 7.95 (s, 1H), 7.31 (s, 1H), 6.99 (s, 1H), 6.65 (d, J = 7.6 Hz, 1H), 6.39 (s, 1H), 3.90 (m, 2H), 3.62(d, J = 6.1 Hz, 2H), 3.55 (s, 1H), 3.47~3.39(m, 2H), 3.31~ 3.25 (m, 2H), 3.23 (s, 3H), 3.13 (m, 1H), 2.70 (s, 1H), 1.95~1.82 (m, 6H), 1.66~1.62 (m, 2H), 1.26~1.17 ( m, 4H), 1.00 (d, J = 6.4 Hz, 3H).

表6 峰號 2θ[°] d[埃] 相對強度% 1 10.60 8.3414 34.7 2 12.95 6.8297 20.4 3 14.24 6.2160 100.0 4 14.72 6.0142 14.5 5 15.88 5.5764 19.4 6 16.79 5.2766 41.4 7 17.54 5.0536 6.1 8 17.93 4.9444 30.5 9 18.41 4.8157 19.5 10 18.93 4.6831 7.9 11 19.44 4.5633 78.7 12 20.67 4.2927 6.5 13 21.24 4.1800 57.0 14 22.16 4.0091 13.3 15 22.80 3.8970 44.7 16 23.77 3.7400 46.9 17 24.57 3.6208 45.6 18 24.88 3.5754 12.9 19 25.32 3.5150 5.3 20 26.13 3.4081 7.7 21 27.24 3.2714 8.6 22 27.64 3.2246 5.5 23 28.15 3.1673 11.7 24 28.64 3.1138 11.6 25 29.33 3.0428 11.9 26 29.64 3.0116 27.1 27 30.16 2.9608 2.8 28 30.52 2.9265 3.0 29 31.48 2.8397 3.6 30 32.08 2.7879 9.5 31 32.73 2.7341 5.4 32 33.36 2.6837 29.7 33 34.36 2.6076 3.4 34 35.36 2.5366 12.6 35 35.96 2.4953 7.3 36 36.24 2.4767 3.9 37 37.28 2.4097 3.9 38 38.28 2.3496 7.1 39 38.64 2.3283 6.4 Table 6 Peak number 2θ[°] d[angstrom] Relative strength % 1 10.60 8.3414 34.7 2 12.95 6.8297 20.4 3 14.24 6.2160 100.0 4 14.72 6.0142 14.5 5 15.88 5.5764 19.4 6 16.79 5.2766 41.4 7 17.54 5.0536 6.1 8 17.93 4.9444 30.5 9 18.41 4.8157 19.5 10 18.93 4.6831 7.9 11 19.44 4.5633 78.7 12 20.67 4.2927 6.5 13 21.24 4.1800 57.0 14 22.16 4.0091 13.3 15 22.80 3.8970 44.7 16 23.77 3.7400 46.9 17 24.57 3.6208 45.6 18 24.88 3.5754 12.9 19 25.32 3.5150 5.3 20 26.13 3.4081 7.7 twenty one 27.24 3.2714 8.6 twenty two 27.64 3.2246 5.5 twenty three 28.15 3.1673 11.7 twenty four 28.64 3.1138 11.6 25 29.33 3.0428 11.9 26 29.64 3.0116 27.1 27 30.16 2.9608 2.8 28 30.52 2.9265 3.0 29 31.48 2.8397 3.6 30 32.08 2.7879 9.5 31 32.73 2.7341 5.4 32 33.36 2.6837 29.7 33 34.36 2.6076 3.4 34 35.36 2.5366 12.6 35 35.96 2.4953 7.3 36 36.24 2.4767 3.9 37 37.28 2.4097 3.9 38 38.28 2.3496 7.1 39 38.64 2.3283 6.4

實施例Example 1010 穩定性試驗Stability test

將實施例9製備的式(I)化合物富馬酸鹽晶型A和實施例2製備的式(I)化合物馬來酸鹽的晶型1置於60℃乾燥箱中，不同天數(0天、7天、21天)取樣、檢測，以考察晶型的穩定性。結果如下表7所示。The fumarate crystal form A of the compound of formula (I) prepared in Example 9 and the crystal form 1 of the maleate salt of the compound of formula (I) prepared in Example 2 were placed in a drying oven at 60° C. for different days (0 days , 7 days, 21 days) sampling and testing to examine the stability of the crystal form. The results are shown in Table 7 below.

表7 樣品實驗條件總雜% 含量% 實施例9製備的式(I)化合物富馬酸鹽晶型A 0天 0.62 99.38 7天 0.69 99.31 21天 0.78 99.22 實施例2製備的式(I)化合物馬來酸鹽的晶型1 0天 0.09 99.91 7天 0.12 99.88 21天 0.14 99.86 式(I)化合物游離鹼 0天 0.50 99.50 7天 1.58 98.42 14天 2.56 97.44 Table 7 sample Experimental conditions Total impurities% content% Form A of the fumarate salt of the compound of formula (I) prepared in Example 9 0 days 0.62 99.38 7 days 0.69 99.31 21 days 0.78 99.22 Crystal Form 1 of the maleate salt of the compound of formula (I) prepared in Example 2 0 days 0.09 99.91 7 days 0.12 99.88 21 days 0.14 99.86 Free base of compound of formula (I) 0 days 0.50 99.50 7 days 1.58 98.42 14 days 2.56 97.44

結果顯示：式(I)化合物富馬酸鹽晶型A和式(I)化合物馬來酸鹽晶型1在高溫下經過21天，含量基本無變化，XRPD圖譜特徵峰基本無變化，晶型十分穩定。The results show that after 21 days at high temperature, the contents of the fumarate crystal form A of the compound of formula (I) and the maleate crystal form 1 of the compound of formula (I) have basically remained unchanged, and the characteristic peaks of the XRPD spectrum have basically remained unchanged. Very stable.

而將式(I)化合物游離鹼無定形物同樣地進行上述穩定性的研究。結果發現：式(I)化合物游離鹼無定型物穩定性差，在第7天和第14天時，無定型物性狀發生明顯變化，由黃色固體變成類似硬膠狀物，雜質種類增多，雜質含量增大。The stability of the free base amorphous form of the compound of formula (I) was similarly studied as described above. The results showed that the free base amorphous form of the compound of formula (I) has poor stability. On the 7th and 14th day, the properties of the amorphous form changed significantly, from a yellow solid to a hard gel-like substance. The types of impurities increased, and the impurity content increased. increase.

實施例Example 1111 溶解性試驗Solubility test

每個瓶中稱量約50 mg實施例2製備的式(I)化合物馬來酸鹽的晶型1；配製不同pH值PBS緩衝液；室溫下，向不同瓶中加入不同溶劑，少量多次，直到剛好溶解，記錄溶劑用量，計算溶解度。結果如下表8所示。Weigh about 50 mg of the maleate crystal form 1 of the compound of formula (I) prepared in Example 2 into each bottle; prepare PBS buffer solutions with different pH values; add different solvents to different bottles at room temperature, a small amount may be more times until it is just dissolved, record the amount of solvent used, and calculate the solubility. The results are shown in Table 8 below.

表8 樣品實驗條件溶解度 (S, mg/mL) 式(I)化合物馬來酸鹽的晶型1 PBS 6.0 41 PBS 6.5 45 PBS 7.0 57 PBS7.5 62 水 31 生理鹽水 50 Table 8 sample Experimental conditions Solubility (S, mg/mL) Crystal form 1 of the maleate salt of the compound of formula (I) PBS 6.0 41 PBS 6.5 45 PBS 7.0 57 PBS7.5 62 water 31 saline 50

將式(I)化合物游離鹼無定形物同樣地進行上述溶解性的研究。結果發現：式(I)化合物游離鹼在相同試驗條件下，其溶解度明顯低很多；尤其是在水中的溶解度非常低。如表9所示。The above-mentioned solubility study was conducted similarly for the free base amorphous product of the compound of formula (I). The results show that the solubility of the free base of the compound of formula (I) is significantly lower under the same test conditions; especially the solubility in water is very low. As shown in Table 9.

表9 樣品實驗條件溶解度 (S，mg/ml) 式(I)化合物游離鹼 PBS pH=6.5 約15.10 PBS pH=7.0 約12.5 PBS pH=7.2 約10.10 PBS pH=7.5 約0.44 水約0.1 Table 9 sample Experimental conditions Solubility (S, mg/ml) Free base of compound of formula (I) PBS pH=6.5 About 15.10 PBS pH=7.0 About 12.5 PBS pH=7.2 About 10.10 PBS pH=7.5 About 0.44 water About 0.1

結果顯示：式(I)化合物的馬來酸鹽晶型1，在上述溶劑中的溶解度明顯提高，溶解度可達30至60 mg/mL，大大地改善式(I)化合物的溶解度。The results show that the solubility of the maleate crystal form 1 of the compound of formula (I) in the above solvent is significantly improved, and the solubility can reach 30 to 60 mg/mL, which greatly improves the solubility of the compound of formula (I).

實施例Example 1212 吸濕性試驗Hygroscopicity test

實驗方法：通過動態水分吸附儀來檢測，稱取10mg固體樣品放置到天平上，程式控制樣品室內濕度，在同一溫度不同濕度的條件下放置7天，測定受試樣品隨相對濕度的品質變化。檢測程式：濕度變化依序為0%-95%-0%；測試溫度25℃。Experimental method: Detect by dynamic moisture adsorption instrument, weigh 10mg solid sample and place it on the balance. The program controls the indoor humidity of the sample. Place it under the same temperature and different humidity conditions for 7 days, and measure the quality change of the tested sample with relative humidity. Detection program: Humidity changes in sequence from 0% to 95% to 0%; test temperature is 25°C.

實驗結果如圖15(實施例2製備的式(I)化合物馬來酸鹽的晶型1)和圖16(實施例9製備的式(I)化合物富馬酸鹽晶型A)所示。結果顯示：兩種鹽型吸濕性相當，在環境濕度RH=60%下，吸濕增重約1%，吸濕性弱，明顯優於游離態。The experimental results are shown in Figure 15 (crystal form 1 of the maleate salt of the compound of formula (I) prepared in Example 2) and Figure 16 (crystal form A of the fumarate salt of the compound of formula (I) prepared in Example 9). The results show that the hygroscopicity of the two salt types is equivalent. Under the ambient humidity RH=60%, the weight gain is about 1% due to hygroscopicity. The hygroscopicity is weak and obviously better than the free state.

而將式(I)化合物游離鹼無定形物同樣地進行上述吸濕性的研究。結果發現：式(I)化合物游離鹼無定型物穩定性差，在環境濕度RH高於60%，表現出較強的吸濕性，且吸濕後的樣品性狀明顯改變(有團聚現象)。送DVS檢測，其結果如圖20所示。可見，式(I)化合物游離鹼無定形物具有較強的吸濕性，會隨著環境濕度的增大，持續吸濕。在相對濕度95%時，吸濕增重可達9.5%，且吸濕後的樣品不易脫附。The hygroscopicity of the free base amorphous product of the compound of formula (I) was similarly studied as described above. The results showed that the free base amorphous form of the compound of formula (I) has poor stability. When the ambient humidity RH is higher than 60%, it shows strong hygroscopicity, and the sample properties after moisture absorption change significantly (there is agglomeration phenomenon). Send it to DVS for testing, and the results are shown in Figure 20. It can be seen that the amorphous free base of the compound of formula (I) has strong hygroscopicity and will continue to absorb moisture as the environmental humidity increases. When the relative humidity is 95%, the moisture absorption weight gain can reach 9.5%, and the sample after moisture absorption is not easy to desorb.

實施例Example 1313 穩定性研究Stability studies

將實施例3製備的式(I)化合物馬來酸鹽的晶型2置於60℃乾燥箱中，不同天數(0天、7天、14天和30天)取樣、檢測，以考察晶型的穩定性。如表10所示。The crystal form 2 of the maleate salt of the compound of formula (I) prepared in Example 3 was placed in a drying oven at 60°C, and samples were taken and detected on different days (0 days, 7 days, 14 days and 30 days) to examine the crystal form. stability. As shown in Table 10.

表10 樣品實驗條件總雜% 含量% 晶型2 0天 0.87 99.13 7天 1.44 98.56 14天 2.27 97.73 Table 10 sample Experimental conditions Total impurities% content% Crystal form 2 0 days 0.87 99.13 7 days 1.44 98.56 14 days 2.27 97.73

結果顯示：晶型2在高溫下經過14天，XRPD圖譜特徵峰基本無變化，晶型十分穩定，為原先晶型。The results show that after 14 days at high temperature, the characteristic peaks of the XRPD spectrum of crystal form 2 have basically remained unchanged, and the crystal form is very stable and is the original crystal form.

實施例Example 1414 生物實驗Biological experiments

稱取5.61 mg實施例2製備的式(I)化合物馬來酸鹽晶型1，將其溶於74.7μL的DMSO中，配製濃度為100 mM，在-20℃冰箱中保存。Weigh 5.61 mg of the maleate crystal form 1 of the compound of formula (I) prepared in Example 2, dissolve it in 74.7 μL of DMSO, prepare a concentration of 100 mM, and store it in a -20°C refrigerator.

配置1000×化合物儲存板(或稱為1000×儲存藥板)，將100mM的化合物儲存液用DMSO進行稀釋，起始濃度10 mM，9個濃度梯度(儲液濃度分別為10 mM、3 mM、1 mM、0.3 mM、0.1 mM、0.03 mM、0.01 mM、0.001 mM和0.0001 mM)。化合物儲存板用封板膠帶密封，放入-20℃冰箱保存備用。Configure a 1000× compound storage plate (or 1000× storage plate), dilute the 100mM compound storage solution with DMSO, with a starting concentration of 10 mM, and 9 concentration gradients (the storage concentration is 10 mM, 3 mM, 1mM, 0.3mM, 0.1mM, 0.03mM, 0.01mM, 0.001mM and 0.0001mM). The compound storage plate was sealed with sealing tape and stored in a -20°C refrigerator for later use.

選擇急性髓系白血病細胞MV-4-11(購自ATCC)，按照5000/孔的密度接種到96孔板中(每孔體積為140 μL)，放入37℃，5% CO ₂培養箱中培養過夜。 Select acute myeloid leukemia cells MV-4-11 (purchased from ATCC), inoculate them into a 96-well plate at a density of 5000/well (the volume of each well is 140 μL), and place it in a 37°C, 5% CO ₂ incubator Incubate overnight.

取出1000×儲存藥板，室溫避光融化，然後配製15×中間藥板(78.8 μL培養基加1.2 μL 含藥DMSO儲存液)，充分混勻。轉移10 μL 含藥培養基(15×)到96孔細胞板中(終濃度為10 μM、3 μM、1 μM、0.3 μM、0.1 μM、0.03 μM、0.01 μM、0.001 μM和0.0001 μM，DMSO終濃度為0.01%)，輕拍混勻，然後放入37℃，5% CO ₂培養箱中，繼續培養24小時。 Take out the 1000× storage drug plate, thaw it at room temperature away from light, then prepare a 15× intermediate drug plate (78.8 μL culture medium plus 1.2 μL drug-containing DMSO storage solution), and mix thoroughly. Transfer 10 μL of drug-containing medium (15×) to a 96-well cell plate (final concentrations are 10 μM, 3 μM, 1 μM, 0.3 μM, 0.1 μM, 0.03 μM, 0.01 μM, 0.001 μM, and 0.0001 μM, DMSO final concentration (0.01%), tap gently to mix, then place in a 37°C, 5% CO ₂ incubator and continue culturing for 24 hours.

然後用CellTiter-Glo方法檢測各個藥物濃度條件下的細胞活力，並計算相應條件下的細胞增殖抑制率。Then the CellTiter-Glo method was used to detect cell viability under various drug concentration conditions, and the cell proliferation inhibition rate under corresponding conditions was calculated.

在MV-4-11細胞上，式(I)化合物馬來酸鹽晶型1在0.0001 μM到0.01 μM濃度範圍內，細胞生長無明顯變化，在0.03μM到10 μM濃度範圍內，對細胞生長有顯著的抑制作用；式(I)化合物馬來酸鹽晶型1對MV-4-11細胞的絕對半數抑制濃度(ABsIC50)為0.032 μM。On MV-4-11 cells, the maleate crystal form 1 of the compound of formula (I) has no obvious change in cell growth in the concentration range of 0.0001 μM to 0.01 μM, and has no significant effect on cell growth in the concentration range of 0.03 μM to 10 μM. It has a significant inhibitory effect; the absolute half inhibitory concentration (ABsIC50) of compound maleate crystal form 1 of formula (I) on MV-4-11 cells is 0.032 μM.

對比例Comparative ratio 11

同樣採用實施例1或實施例9描述的方法，用檸檬酸、L-酒石酸、硫酸或磷酸替換馬來酸或富馬酸，來與式(I)化合物成鹽。結果發現，用檸檬酸、酒石酸、硫酸或磷酸與式(I)化合物成鹽後根本無法獲得晶體形態的固體。The method described in Example 1 or Example 9 is also used to replace maleic acid or fumaric acid with citric acid, L-tartaric acid, sulfuric acid or phosphoric acid to form a salt with the compound of formula (I). It was found that it was impossible to obtain a crystalline solid after using citric acid, tartaric acid, sulfuric acid or phosphoric acid to form a salt with the compound of formula (I).

對比例Comparative ratio 22

同樣採用實施例1或實施例9描述的方法，用鹽酸替換馬來酸或富馬酸，來與式(I)化合物成鹽。結果發現，雖然鹽酸與式(I)化合物成鹽後可以獲得晶體形態的固體，但是，式(I)化合物鹽酸鹽的吸濕性非常強，無法進行後續應用。The method described in Example 1 or Example 9 is also used, and hydrochloric acid is used to replace maleic acid or fumaric acid to form a salt with the compound of formula (I). It was found that although a crystalline solid can be obtained by forming a salt between hydrochloric acid and the compound of formula (I), the hydrochloride of the compound of formula (I) is very hygroscopic and cannot be used for subsequent applications.

對比例Comparative ratio 33

經過揮發、冷卻、溶析等方法對式(I)化合物游離鹼無定形物進行結晶，結果都無法得到良好的晶體形態。The free base amorphous substance of the compound of formula (I) is crystallized through methods such as volatilization, cooling, and elution, but the result is that no good crystal form can be obtained.

揮發：將利用表11所示溶劑完全溶解式(I)化合物游離鹼後的溶液置於25℃真空烘箱中在真空(0.1MPa)揮發7天。結果發現所得物質均為油膠狀物。再往這些油膠狀物中加入相應等量的同種溶劑重新溶解，放置室溫(T=20±2℃)下自然揮發。結果發現均未得到良好的固態樣品。Volatilization: The solution after completely dissolving the free base of the compound of formula (I) using the solvent shown in Table 11 is placed in a 25°C vacuum oven and volatilized under vacuum (0.1MPa) for 7 days. It was found that the obtained substances were all oily colloids. Then add corresponding equal amounts of the same solvent to these oil colloids to re-dissolve them, and leave them to naturally evaporate at room temperature (T=20±2℃). It was found that no good solid samples were obtained.

表11 溶劑首次揮幹後實驗操作實驗現象(23天) 甲醇呈油膠狀物重新溶解，室溫自然揮發油膠狀乙醇呈油膠狀物重新溶解，室溫自然揮發油膠狀異丙醇呈油膠狀物重新溶解，室溫自然揮發油膠狀丙酮呈油膠狀物重新溶解，室溫自然揮發油膠狀 2-丁酮呈油膠狀物重新溶解，室溫自然揮發油膠狀四氫呋喃呈油膠狀物重新溶解，室溫自然揮發油膠狀乙酸乙酯呈油膠狀物重新溶解，室溫自然揮發油膠狀乙酸異丙酯呈油膠狀物重新溶解，室溫自然揮發油膠狀二氯甲烷呈油膠狀物重新溶解，室溫自然揮發油膠狀二甲亞碸呈油膠狀物重新溶解，室溫自然揮發液體狀 N,N-二甲基甲醯胺呈油膠狀物重新溶解，室溫自然揮發液體狀 N-甲基吡咯烷酮呈油膠狀物重新溶解，室溫自然揮發液體狀乙腈呈油膠狀物重新溶解，室溫自然揮發油膠狀 Table 11 Solvent After drying for the first time Experimental operation Experimental phenomena (23 days) Methanol Oily jelly-like substance Re-dissolve and evaporate naturally at room temperature Oil gelatinous ethanol Oily jelly-like substance Re-dissolve and evaporate naturally at room temperature Oil gelatinous Isopropyl alcohol Oily jelly-like substance Re-dissolve and evaporate naturally at room temperature Oil gelatinous acetone Oily jelly-like substance Re-dissolve and evaporate naturally at room temperature Oil gelatinous 2-Butanone Oily jelly-like substance Re-dissolve and evaporate naturally at room temperature Oil gelatinous Tetrahydrofuran Oily jelly-like substance Re-dissolve and evaporate naturally at room temperature Oil gelatinous Ethyl acetate Oily jelly-like substance Re-dissolve and evaporate naturally at room temperature Oil gelatinous Isopropyl acetate Oily jelly-like substance Re-dissolve and evaporate naturally at room temperature Oil gelatinous Dichloromethane Oily jelly-like substance Re-dissolve and evaporate naturally at room temperature Oil gelatinous dimethyl sulfate Oily jelly-like substance Re-dissolve and evaporate naturally at room temperature liquid N,N-dimethylformamide Oily jelly-like substance Re-dissolve and evaporate naturally at room temperature liquid N-methylpyrrolidone Oily jelly-like substance Re-dissolve and evaporate naturally at room temperature liquid Acetonitrile Oily jelly-like substance Re-dissolve and evaporate naturally at room temperature Oil gelatinous

冷卻：每個瓶中稱量約50mg式(I)化合物游離鹼，分別添加表12的不同溶劑1mL，室溫(T=20℃)溶解，置於0℃2h，記錄是否析出，繼續降溫到-20℃過夜，記錄是否析出。結果如表12所示。結果發現冷卻後無法獲得良好的固態樣品。Cooling: Weigh about 50 mg of the free base of the compound of formula (I) in each bottle, add 1 mL of different solvents in Table 12, dissolve at room temperature (T=20°C), place at 0°C for 2 hours, record whether it precipitates, and continue to cool to -20°C overnight, record whether precipitation occurs. The results are shown in Table 12. It was found that good solid samples could not be obtained after cooling.

表12 溶劑 0℃是否析出 -20℃是否析出甲醇否否乙醇否否異丙醇否否丙酮否否 2-丁酮否否四氫呋喃否否乙酸乙酯否析出極少量乙酸異丙酯否否二氯甲烷否否二甲亞碸否否 N,N-二甲基甲醯胺否否 N-甲基吡咯烷酮否否乙腈否析出極少量 Table 12 Solvent Whether it precipitates at 0℃ Whether it precipitates at -20℃ Methanol no no ethanol no no Isopropyl alcohol no no acetone no no 2-Butanone no no Tetrahydrofuran no no Ethyl acetate no A very small amount of precipitation Isopropyl acetate no no Dichloromethane no no dimethyl sulfate no no N,N-dimethylformamide no no N-methylpyrrolidone no no Acetonitrile no A very small amount of precipitation

溶析：每個瓶中稱量約50mg式(I)化合物游離鹼，分別添加表12的不同溶劑1mL，室溫(T=20℃)溶解，向其中加一定量的反溶劑(緩慢滴加)，觀察是否有固體析出。結果如表13所示。結果發現添加反溶劑後無法獲得良好的固態樣品。Dissolution: Weigh about 50 mg of the free base of the compound of formula (I) in each bottle, add 1 mL of different solvents in Table 12, dissolve at room temperature (T=20°C), and add a certain amount of anti-solvent (slowly dropwise) ), observe whether there is solid precipitation. The results are shown in Table 13. It was found that good solid samples could not be obtained after adding antisolvent.

表13 溶劑反溶劑種類溶劑量(ml) 是否析出甲醇 MTBE(與環己烷不互溶) 3 否乙醇環己烷 3 否異丙醇環己烷 3 否丙酮水 2 油析 2-丁酮水(與環己烷不互溶) 3 否四氫呋喃環己烷 3 否乙酸乙酯環己烷 3 否乙酸異丙酯環己烷 3 否二氯甲烷環己烷 2 油析二甲亞碸水 2 油析 N,N-二甲基甲醯胺水 2.7 油析 N-甲基吡咯烷酮水 3 油析乙腈水 2.5 油析 Table 13 Solvent Antisolvent type Solvent volume (ml) Whether to precipitate Methanol MTBE (immiscible with cyclohexane) 3 no ethanol cyclohexane 3 no Isopropyl alcohol cyclohexane 3 no acetone water 2 oil separation 2-Butanone Water (immiscible with cyclohexane) 3 no Tetrahydrofuran cyclohexane 3 no Ethyl acetate cyclohexane 3 no Isopropyl acetate cyclohexane 3 no Dichloromethane cyclohexane 2 oil separation dimethyl sulfate water 2 oil separation N,N-dimethylformamide water 2.7 oil separation N-methylpyrrolidone water 3 oil separation Acetonitrile water 2.5 oil separation

可見發明人通過大量實驗研究後發現了式(I)化合物相關的幾種各項性能均非常穩定和良好的晶型，分別是其馬來酸鹽的晶型I、晶型1、晶型2、晶型3、晶型4以及其富馬酸鹽的晶型A。It can be seen that the inventor has discovered through extensive experimental research several crystal forms related to the compound of formula (I) that are very stable and good in various properties, namely crystal form I, crystal form 1, and crystal form 2 of its maleate salt. , crystalline form 3, crystalline form 4 and crystalline form A of its fumarate salt.

實施例Example 1515 藥物組合物pharmaceutical composition

由以下組分製備晶型1的片劑：實施例2製備的式(I)化合物馬來酸鹽晶型1 20g 澱粉 20g 乳糖 20g PVPP 3g PVP 3g 滑石粉 1.6 g 十二烷基硫酸鈉 5g Tablets of Form 1 are prepared from the following ingredients: Crystalline form 1 of the maleate salt of the compound of formula (I) prepared in Example 2 20g starch 20g lactose 20g PVPP 3g PVP 3g talcum powder 1.6g sodium lauryl sulfate 5g

按照常規方法，將式(I)化合物馬來酸鹽晶型1與澱粉混合過篩後再與其他組分混合均勻，直接壓片。According to a conventional method, the maleate crystal form 1 of the compound of formula (I) is mixed with starch and sieved, then mixed evenly with other components, and directly compressed into tablets.

實施例Example 1616 藥物組合物pharmaceutical composition

由以下組分製備晶型A的片劑：實施例9製備的式(I)化合物富馬酸鹽晶型A 20g 澱粉 20g 乳糖 20g PVPP 3g PVP 3g 滑石粉 1.6 g 十二烷基硫酸鈉 5g Tablets of Form A are prepared from the following components: Form A of the fumarate salt of the compound of formula (I) prepared in Example 9 20g starch 20g lactose 20g PVPP 3g PVP 3g talcum powder 1.6 g sodium lauryl sulfate 5g

按照常規方法，將式(I)化合物富馬酸鹽晶型A與澱粉混合過篩後再與其他組分混合均勻，直接壓片。According to a conventional method, the fumarate crystal form A of the compound of formula (I) is mixed with starch and sieved, then mixed evenly with other components, and directly compressed into tablets.

本發明的其他的特徵及功效，將於參照圖式的實施方式中清楚地呈現，其中：圖1為實施例2製備的式(I)化合物馬來酸鹽晶型1的XRPD圖；圖2為實施例2製備的式(I)化合物馬來酸鹽晶型1的DSC圖；圖3為實施例2製備的式(I)化合物馬來酸鹽晶型1的TGA圖；圖4為實施例2製備的式(I)化合物馬來酸鹽晶型1的IR圖；圖5為實施例3製備的式(I)化合物馬來酸鹽晶型2的XRPD圖；圖6為實施例3製備的式(I)化合物馬來酸鹽晶型2的DSC圖；圖7為實施例3製備的式(I)化合物馬來酸鹽晶型2的TGA圖；圖8為實施例3製備的式(I)化合物馬來酸鹽晶型2的IR圖；圖9為實施例4製備的式(I)化合物馬來酸鹽晶型3的XRPD圖；圖10為實施例4製備的式(I)化合物馬來酸鹽晶型3的DSC圖；圖11為實施例5製備的式(I)化合物馬來酸鹽晶型4的XRPD圖；圖12為實施例5製備的式(I)化合物馬來酸鹽晶型4的DSC圖；圖13為實施例9製備的式(I)化合物富馬酸鹽晶型A的XRPD圖；圖14為實施例9製備的式(I)化合物富馬酸鹽晶型A的DSC圖；圖15為實施例2製備的式(I)化合物馬來酸鹽晶型1的DVS圖；圖16為實施例9製備的式(I)化合物富馬酸鹽晶型A的DVS圖；圖17為實施例1製備的式(I)化合物馬來酸鹽晶型I的XRPD圖；圖18為實施例1製備的式(I)化合物馬來酸鹽晶型I的DSC圖；圖19為式(I)化合物游離鹼的XRPD圖；及圖20為式(I)化合物游離鹼的DVS圖。 Other features and effects of the present invention will be clearly presented in the embodiments with reference to the drawings, in which: Figure 1 is an XRPD pattern of the maleate salt form 1 of the compound of formula (I) prepared in Example 2; Figure 2 is a DSC chart of the maleate salt form 1 of the compound of formula (I) prepared in Example 2; Figure 3 is a TGA diagram of the maleate salt form 1 of the compound of formula (I) prepared in Example 2; Figure 4 is an IR pattern of the maleate salt form 1 of the compound of formula (I) prepared in Example 2; Figure 5 is an XRPD pattern of the maleate salt form 2 of the compound of formula (I) prepared in Example 3; Figure 6 is a DSC chart of the maleate salt form 2 of the compound of formula (I) prepared in Example 3; Figure 7 is a TGA diagram of the maleate salt form 2 of the compound of formula (I) prepared in Example 3; Figure 8 is an IR pattern of the maleate salt form 2 of the compound of formula (I) prepared in Example 3; Figure 9 is an XRPD pattern of the maleate salt form 3 of the compound of formula (I) prepared in Example 4; Figure 10 is a DSC chart of the maleate salt form 3 of the compound of formula (I) prepared in Example 4; Figure 11 is an XRPD pattern of the maleate salt form 4 of the compound of formula (I) prepared in Example 5; Figure 12 is a DSC chart of the maleate salt form 4 of the compound of formula (I) prepared in Example 5; Figure 13 is an XRPD pattern of the fumarate crystal form A of the compound of formula (I) prepared in Example 9; Figure 14 is a DSC chart of the fumarate salt form A of the compound of formula (I) prepared in Example 9; Figure 15 is a DVS diagram of the maleate salt form 1 of the compound of formula (I) prepared in Example 2; Figure 16 is a DVS diagram of the fumarate salt form A of the compound of formula (I) prepared in Example 9; Figure 17 is an XRPD pattern of the maleate salt form I of the compound of formula (I) prepared in Example 1; Figure 18 is a DSC chart of the maleate salt form I of the compound of formula (I) prepared in Example 1; Figure 19 is the XRPD pattern of the free base of the compound of formula (I); and Figure 20 is a DVS diagram of the free base of the compound of formula (I).

Claims

一種式(I)化合物的藥學上可接受鹽或其多晶型物； (I) 其中，所述藥學上可接受鹽為馬來酸鹽或富馬酸鹽。 A pharmaceutically acceptable salt of a compound of formula (I) or a polymorph thereof; (I) wherein the pharmaceutically acceptable salt is maleate or fumarate.

如請求項1所述的式(I)化合物的藥學上可接受鹽或其多晶型物，其中，式(I)化合物馬來酸鹽中，式(I)化合物和馬來酸的莫耳比為1：2。The pharmaceutically acceptable salt or polymorph of the compound of formula (I) as described in claim 1, wherein in the maleate salt of the compound of formula (I), the mole of the compound of formula (I) and maleic acid is The ratio is 1:2.

如請求項2所述的式(I)化合物的藥學上可接受鹽或其多晶型物，其中，所述多晶型物為式(I)化合物馬來酸鹽的晶型1，所述晶型1的X射線粉末衍射圖包含選自下組的衍射角2θ(°)值：5.48±0.2°、14.26±0.2°、19.68±0.2°、22.44±0.2°。The pharmaceutically acceptable salt of the compound of formula (I) or its polymorph as described in claim 2, wherein the polymorph is crystal form 1 of the maleate salt of the compound of formula (I), and the The X-ray powder diffraction pattern of Form 1 includes diffraction angle 2θ (°) values selected from the group consisting of: 5.48±0.2°, 14.26±0.2°, 19.68±0.2°, 22.44±0.2°.

如請求項3所述的式(I)化合物的藥學上可接受鹽或其多晶型物，其中，所述晶型1的差示掃描量熱法分析譜圖在162.45±5℃處有特徵峰。The pharmaceutically acceptable salt of the compound of formula (I) or its polymorph as described in claim 3, wherein the differential scanning calorimetry analysis spectrum of the crystalline form 1 is characterized at 162.45±5°C peak.

如請求項2所述的式(I)化合物的藥學上可接受鹽或其多晶型物，其中，所述多晶型物為式(I)化合物馬來酸鹽的晶型2，所述晶型2的X射線粉末衍射圖包含選自下組的衍射角2θ(°)值：5.02±0.2°、5.36±0.2°、14.04±0.2°、20.96±0.2°、21.42±0.2°、23.00±0.2°。The pharmaceutically acceptable salt of the compound of formula (I) or the polymorph thereof as described in claim 2, wherein the polymorph is the crystal form 2 of the maleate salt of the compound of formula (I), and the The X-ray powder diffraction pattern of Form 2 contains diffraction angle 2θ (°) values selected from the following group: 5.02±0.2°, 5.36±0.2°, 14.04±0.2°, 20.96±0.2°, 21.42±0.2°, 23.00± 0.2°.

如請求項5所述的式(I)化合物的藥學上可接受鹽或其多晶型物，其中，所述晶型2的差示掃描量熱法分析譜圖在159.25±5℃處有特徵峰。The pharmaceutically acceptable salt of the compound of formula (I) or its polymorph as described in claim 5, wherein the differential scanning calorimetry analysis spectrum of the crystalline form 2 is characterized at 159.25±5°C peak.

如請求項2所述的式(I)化合物的藥學上可接受鹽或其多晶型物，其中，所述多晶型物為式(I)化合物馬來酸鹽的晶型3，所述晶型3的X射線粉末衍射圖包含選自下組的衍射角2θ(°)值：5.64±0.2°、11.28±0.2°、16.96±0.2°、24.92±0.2°。The pharmaceutically acceptable salt of the compound of formula (I) or its polymorph as described in claim 2, wherein the polymorph is crystal form 3 of the maleate salt of the compound of formula (I), The X-ray powder diffraction pattern of Form 3 includes diffraction angle 2θ (°) values selected from the group consisting of: 5.64±0.2°, 11.28±0.2°, 16.96±0.2°, 24.92±0.2°.

如請求項7所述的式(I)化合物的藥學上可接受鹽或其多晶型物，其中，所述晶型3的差示掃描量熱法分析譜圖在114.72±5℃處有特徵峰。The pharmaceutically acceptable salt of the compound of formula (I) or the polymorph thereof as described in claim 7, wherein the differential scanning calorimetry analysis spectrum of the crystalline form 3 is characterized at 114.72±5°C peak.

如請求項2所述的式(I)化合物的藥學上可接受鹽或其多晶型物，其中，所述多晶型物為式(I)化合物馬來酸鹽的晶型4，所述晶型4的X射線粉末衍射圖包含選自下組的衍射角2θ(°)值：5.08±0.2°、5.62±0.2°、13.98±0.2°、22.72±0.2°。The pharmaceutically acceptable salt of the compound of formula (I) or its polymorph as described in claim 2, wherein the polymorph is crystal form 4 of the maleate salt of the compound of formula (I), and the The X-ray powder diffraction pattern of Form 4 includes diffraction angle 2θ (°) values selected from the group consisting of: 5.08±0.2°, 5.62±0.2°, 13.98±0.2°, 22.72±0.2°.

如請求項9所述的式(I)化合物的藥學上可接受鹽或其多晶型物，其中，所述晶型4的差示掃描量熱法分析譜圖在175.74±5℃處有特徵峰。The pharmaceutically acceptable salt of the compound of formula (I) or its polymorph as described in claim 9, wherein the differential scanning calorimetry analysis spectrum of the crystalline form 4 is characterized at 175.74±5°C peak.

如請求項2所述的式(I)化合物的藥學上可接受鹽或其多晶型物，其中，所述多晶型物為式(I)化合物馬來酸鹽的晶型I，所述晶型I的X射線粉末衍射圖包含選自下組的衍射角2θ(°)值：5.00±0.2°、5.40±0.2°、14.23±0.2°、22.40±0.2°、23.28±0.2°。The pharmaceutically acceptable salt of the compound of formula (I) or its polymorph as described in claim 2, wherein the polymorph is the crystal form I of the maleate salt of the compound of formula (I), and the The X-ray powder diffraction pattern of Form I includes diffraction angle 2θ (°) values selected from the group consisting of: 5.00±0.2°, 5.40±0.2°, 14.23±0.2°, 22.40±0.2°, 23.28±0.2°.

如請求項11所述的式(I)化合物的藥學上可接受鹽或其多晶型物，其中，所述晶型I的差示掃描量熱法分析譜圖在159.91±5℃處有特徵峰。The pharmaceutically acceptable salt of the compound of formula (I) or its polymorph as described in claim 11, wherein the differential scanning calorimetry analysis spectrum of the crystalline form I is characterized at 159.91±5°C peak.

如請求項1所述的式(I)化合物的藥學上可接受鹽或其多晶型物，其中，式(I)化合物富馬酸鹽中，式(I)化合物和富馬酸的莫耳比為2：1。The pharmaceutically acceptable salt or polymorph of the compound of formula (I) as described in claim 1, wherein in the fumarate salt of the compound of formula (I), the mole of the compound of formula (I) and fumaric acid is The ratio is 2:1.

如請求項13所述的式(I)化合物的藥學上可接受鹽或其多晶型物，其中，所述多晶型物為式(I)化合物富馬酸鹽的晶型A，所述晶型A的X射線粉末衍射圖包含選自下組的衍射角2θ(°)值：14.24±0.2°、19.44±0.2°、21.24±0.2°、23.77±0.2°、24.57±0.2°。The pharmaceutically acceptable salt of the compound of formula (I) or its polymorph as described in claim 13, wherein the polymorph is the crystal form A of the fumarate salt of the compound of formula (I), and the The X-ray powder diffraction pattern of Form A includes diffraction angle 2θ (°) values selected from the following group: 14.24±0.2°, 19.44±0.2°, 21.24±0.2°, 23.77±0.2°, 24.57±0.2°.

如請求項14所述的式(I)化合物的藥學上可接受鹽或其多晶型物，其中，所述晶型A的差示掃描量熱法分析譜圖在218.67±5℃有特徵峰。The pharmaceutically acceptable salt of the compound of formula (I) or its polymorph as described in claim 14, wherein the differential scanning calorimetry analysis spectrum of the crystalline form A has a characteristic peak at 218.67±5°C .

一種藥物組合物，包含請求項1至15中任一項所述的式(I)化合物的藥學上可接受鹽或其多晶型物，和藥學上可接受的載體。A pharmaceutical composition comprising a pharmaceutically acceptable salt or a polymorph thereof of the compound of formula (I) described in any one of claims 1 to 15, and a pharmaceutically acceptable carrier.

一種如請求項1至15中任一項所述的式(I)化合物的藥學上可接受鹽或其多晶型物或請求項16所述的藥物組合物的用途，用於製備預防或治療CDK9相關疾病的藥物。Use of a pharmaceutically acceptable salt of the compound of formula (I) as described in any one of claims 1 to 15 or a polymorph thereof or a pharmaceutical composition as described in claim 16 for the preparation of prevention or treatment Drugs for CDK9-related diseases.

如請求項17所述的用途，其中，所述CDK9相關疾病為癌症。The use as described in claim 17, wherein the CDK9-related disease is cancer.

一種如請求項11所述的式(I)化合物的藥學上可接受鹽或其多晶型物的製備方法，其中，所述多晶型物為式(I)化合物馬來酸鹽的晶型I，所述方法包括步驟： (1) 將式(I)化合物與馬來酸在有機溶劑中攪拌，從而形成式(I)化合物馬來酸鹽的晶型I，其中，式(I)化合物和馬來酸的莫耳比為1：2。 A method for preparing a pharmaceutically acceptable salt of a compound of formula (I) or a polymorph thereof as described in claim 11, wherein the polymorph is the crystal form of the maleate salt of the compound of formula (I) I. The method includes the steps: (1) The compound of formula (I) and maleic acid are stirred in an organic solvent to form Form I of the maleate salt of the compound of formula (I), where the molar ratio of the compound of formula (I) and maleic acid is is 1:2.

一種如請求項3所述的式(I)化合物的藥學上可接受鹽或其多晶型物的製備方法，其中，所述多晶型物為式(I)化合物馬來酸鹽的晶型1，所述方法包括步驟： (1) 將式(I)化合物與馬來酸在有機溶劑中攪拌，從而形成式(I)化合物馬來酸鹽，其中，式(I)化合物和馬來酸的莫耳比為1：2； (2a) 將步驟(1)得到的式(I)化合物馬來酸鹽溶解在第一結晶溶劑中，從而得到含有式(I)化合物馬來酸鹽的溶液； (3a) 將步驟(2a)得到的溶液析晶，析晶後過濾，收集固體，從而得到式(I)化合物馬來酸鹽的晶型1。 A method for preparing a pharmaceutically acceptable salt of a compound of formula (I) or a polymorph thereof as described in claim 3, wherein the polymorph is the crystal form of the maleate salt of the compound of formula (I) 1. The method includes the steps: (1) Stir the compound of formula (I) and maleic acid in an organic solvent to form the maleate salt of the compound of formula (I), wherein the molar ratio of the compound of formula (I) and maleic acid is 1:2 ; (2a) Dissolve the maleate salt of the compound of formula (I) obtained in step (1) in the first crystallization solvent, thereby obtaining a solution containing the maleate salt of the compound of formula (I); (3a) Crystallize the solution obtained in step (2a), filter after crystallization, and collect the solid to obtain crystal form 1 of the maleate salt of the compound of formula (I).

一種如請求項5所述的式(I)化合物的藥學上可接受鹽或其多晶型物的製備方法，其中，所述多晶型物為式(I)化合物馬來酸鹽的晶型2，所述方法包括步驟： (1) 將式(I)化合物與馬來酸在有機溶劑中攪拌，從而形成式(I)化合物馬來酸鹽，其中，式(I)化合物和馬來酸的莫耳比為1：2； (2b) 在0至50℃下，將步驟(1)得到的式(I)化合物馬來酸鹽在第二結晶溶劑中攪拌，然後過濾，收集固體，從而得到含有式(I)化合物馬來酸鹽的晶型2。 A method for preparing a pharmaceutically acceptable salt of the compound of formula (I) or a polymorph thereof as described in claim 5, wherein the polymorph is the crystal form of the maleate salt of the compound of formula (I) 2. The method includes the steps: (1) Stir the compound of formula (I) and maleic acid in an organic solvent to form the maleate salt of the compound of formula (I), wherein the molar ratio of the compound of formula (I) and maleic acid is 1:2 ; (2b) Stir the maleate salt of the compound of formula (I) obtained in step (1) in the second crystallization solvent at 0 to 50°C, and then filter it to collect the solid, thereby obtaining the maleate of the compound of formula (I). Crystalline form 2 of the acid salt.

一種如請求項7所述的式(I)化合物的藥學上可接受鹽或其多晶型物的製備方法，其中，所述多晶型物為式(I)化合物馬來酸鹽的晶型3，所述方法包括步驟： (1) 將式(I)化合物與馬來酸在有機溶劑中攪拌，從而形成式(I)化合物馬來酸鹽，其中，式(I)化合物和馬來酸的莫耳比為1：2； (2c) 在45至55℃下，將步驟(1)得到的式(I)化合物馬來酸鹽在第三結晶溶劑中攪拌，然後過濾，收集固體，從而得到含有式(I)化合物馬來酸鹽的晶型3。 A method for preparing a pharmaceutically acceptable salt of a compound of formula (I) or a polymorph thereof as described in claim 7, wherein the polymorph is the crystal form of the maleate salt of the compound of formula (I) 3. The method includes the steps: (1) Stir the compound of formula (I) and maleic acid in an organic solvent to form the maleate salt of the compound of formula (I), wherein the molar ratio of the compound of formula (I) and maleic acid is 1:2 ; (2c) Stir the maleate salt of the compound of formula (I) obtained in step (1) in the third crystallization solvent at 45 to 55°C, and then filter it to collect the solid, thereby obtaining the maleate of the compound of formula (I). Crystalline form 3 of the acid salt.

一種如請求項9所述的式(I)化合物的藥學上可接受鹽或其多晶型物的製備方法，其中，所述多晶型物為式(I)化合物馬來酸鹽的晶型4，所述方法包括步驟： (1) 將式(I)化合物與馬來酸在有機溶劑中攪拌，從而形成式(I)化合物馬來酸鹽，其中，式(I)化合物和馬來酸的莫耳比為1：2； (2d) 在20至60℃下，將步驟(1)得到的式(I)化合物馬來酸鹽在第四結晶溶劑中攪拌，然後過濾，收集固體，從而得到含有式(I)化合物馬來酸鹽的晶型4。 A method for preparing a pharmaceutically acceptable salt of the compound of formula (I) or a polymorph thereof as described in claim 9, wherein the polymorph is the crystal form of the maleate salt of the compound of formula (I) 4. The method includes the steps: (1) Stir the compound of formula (I) and maleic acid in an organic solvent to form the maleate salt of the compound of formula (I), wherein the molar ratio of the compound of formula (I) and maleic acid is 1:2 ; (2d) Stir the maleate salt of the compound of formula (I) obtained in step (1) in the fourth crystallization solvent at 20 to 60°C, and then filter it to collect the solid, thereby obtaining the maleate of the compound of formula (I). Form 4 of the acid salt.

一種如請求項14所述的式(I)化合物的藥學上可接受鹽或其多晶型物的製備方法，其中，所述多晶型物為式(I)化合物富馬酸鹽的晶型A，所述方法包括步驟： (a) 在40至60℃下，將式(I)化合物與富馬酸在有機溶劑中攪拌； (b) 然後將混合體系降溫至10至30℃並攪拌，然後過濾，收集固體，從而得到式(I)化合物富馬酸鹽的晶型A。 A method for preparing a pharmaceutically acceptable salt of the compound of formula (I) or a polymorph thereof as described in claim 14, wherein the polymorph is the crystal form of the fumarate salt of the compound of formula (I) A. The method includes the steps: (a) Stir the compound of formula (I) and fumaric acid in an organic solvent at 40 to 60°C; (b) The mixed system is then cooled to 10 to 30°C and stirred, and then filtered to collect the solid, thereby obtaining crystal form A of the fumarate salt of the compound of formula (I).