TW202231634A - Salt, solvate, polymorph, preparation method and use of benzazepine derivative - Google Patents

Salt, solvate, polymorph, preparation method and use of benzazepine derivative Download PDF

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TW202231634A
TW202231634A TW111104049A TW111104049A TW202231634A TW 202231634 A TW202231634 A TW 202231634A TW 111104049 A TW111104049 A TW 111104049A TW 111104049 A TW111104049 A TW 111104049A TW 202231634 A TW202231634 A TW 202231634A
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付敏
劉曉斌
趙坤
蔡麗朋
古亮
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大陸商上海迪諾醫藥科技有限公司
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Abstract

A salt, a solvate, a polymorph, a preparation method and the use of a benzazepine derivative. Specifically disclosed is a compound as shown in formula (I). The crystal form of the compound as shown in formula (I) has better solubility and stability, is more suitable for the preparation of a pharmaceutical dosage form, and the drug prepared from the compound as shown in formula (I) has better absorption and metabolic effects in the body.

Description

苯并氮雜卓衍生物的鹽、溶劑合物、多晶型物、製備方法及應用Salts, solvates, polymorphs, preparation methods and applications of benzazepine derivatives

本申請要求申請日為2021年2月5日的中國專利申請2021101636940和申請日為2022年1月24日的中國專利申請2022100800656的優先權。本申請引用上述中國專利申請的全文。This application claims the priority of Chinese patent application 2021101636940 with a filing date of February 5, 2021 and Chinese patent application 2022100800656 with a filing date of January 24, 2022. This application cites the full text of the above Chinese patent application.

本發明涉及苯并氮雜卓衍生物的鹽、溶劑合物、多晶型物、製備方法及應用。The present invention relates to salts, solvates, polymorphs, preparation methods and applications of benzazepine derivatives.

Toll樣受體家族（TLRs）是識別病原相關分子模式重要蛋白家族，可以感應並啟動固有免疫反應並促進適應性免疫反應的發展。TLR8在不同亞型的免疫細胞中均有表現。調節性T細胞（Treg）具有強有力的免疫反應抑制能力，是有效的癌症免疫治療的主要障礙。TLR8訊息途徑被證明是逆轉Treg細胞抑制功能導致強烈腫瘤抑制所必要且充分的條件。TLR8選擇性激動劑有效的激活多種免疫細胞，包括mDCs及單核細胞（Gorden, et al, 2005），可促進針對癌症細胞的適應性免疫反應的產生（Krug, et al, 2003; Schnurr, et al, 2005）。激活的mDCs吞噬凋亡及死亡的腫瘤細胞，接著，與pDCs相比，更有效的向CD8 +CTLs交叉呈遞腫瘤相關抗原（Berard, et al, 2000; Dalgaard, et al, 2005）。此外，mDCs激活，導致TNFα及白介素12（IL-12）的釋放可刺激T細胞及NK細胞的活化。NK細胞的激活是抗體介導的細胞毒性（ADCC）的主要機制。因而，通過ADCC加強對腫瘤細胞的殺傷可能為TLR8選擇性抑制劑呈現出重要的治療機遇（Lu, et al, 2011）。一些單株抗體療法被廣泛用於癌症患者的治療，如利妥昔單抗及曲妥單抗，它們可通過ADCC起到治療作用（Ferris, et al, 2010）。事實上，在mAb治療方法中加入TLR8激動劑可增強ADCC從而增加mAb治療的療效（Ferris, et al, 2015）。此外，最近的研究還表明TLR8激動劑可直接起到抗腫瘤的作用，而不依賴於它的免疫調節功能（Ignatz-Hoover, et al, 2015）。因此，TLR8激動劑不僅可作為單藥治療而起作用，還可通過增強宿主免疫反應提高多種化療及標靶抗癌藥物的療效。 Toll-like receptors (TLRs) are a family of proteins important for recognizing pathogen-associated molecular patterns, which can sense and initiate innate immune responses and promote the development of adaptive immune responses. TLR8 is expressed in different subtypes of immune cells. Regulatory T cells (Treg) have potent immune response suppressive capacity and are a major obstacle to effective cancer immunotherapy. The TLR8 signaling pathway was shown to be a necessary and sufficient condition for reversing the suppressive function of Treg cells leading to strong tumor suppression. TLR8 selective agonists potently activate a variety of immune cells, including mDCs and monocytes (Gorden, et al, 2005), and promote the generation of adaptive immune responses against cancer cells (Krug, et al, 2003; Schnurr, et al. al, 2005). Activated mDCs phagocytose apoptotic and dying tumor cells and then, more efficiently than pDCs, cross-present tumor-associated antigens to CD8 + CTLs (Berard, et al, 2000; Dalgaard, et al, 2005). In addition, activation of mDCs, resulting in the release of TNFα and interleukin 12 (IL-12), can stimulate the activation of T cells and NK cells. Activation of NK cells is the primary mechanism of antibody-mediated cytotoxicity (ADCC). Thus, enhanced killing of tumor cells by ADCC may present an important therapeutic opportunity for TLR8-selective inhibitors (Lu, et al, 2011). Several monoclonal antibody therapies, such as rituximab and trastuzumab, are widely used in the treatment of cancer patients, which can be used to treat cancer through ADCC (Ferris, et al, 2010). In fact, adding a TLR8 agonist to a mAb therapy approach enhances ADCC and thus increases the efficacy of mAb therapy (Ferris, et al, 2015). In addition, recent studies have also shown that TLR8 agonists can directly exert anti-tumor effects independent of its immunomodulatory function (Ignatz-Hoover, et al, 2015). Therefore, TLR8 agonists can not only act as monotherapy, but also improve the efficacy of various chemotherapy and targeted anticancer drugs by enhancing the host immune response.

在識別病原微生物核酸的TLRs家族成員中，TLR7和TLR8具有很高同源性，可以識別一些人工合成的具有抗病毒作用的小分子，例如Imidazoquinolines咪唑喹啉類小分子化合物（TLR7和TLR8的配體）。在由HSV感染的天竺鼠生殖器皰疹模型中對Imidazoquinolines進行研究，發現該化合物對體外病毒複製效果較小，但在體內有較強的效果，表明該類化合物促進免疫細胞生成前發炎性細胞激素及調節細胞激素，導致抗病毒反應（Int Immunopharmacol 2002; 2: 443-451）。更重要的是TLR7和TLR8可以識別病毒ssRNA。研究證明，ssRNA病毒是TLR7和TLR8的天然配體，例如I型人類免疫缺陷病毒（HIV）、流感病毒、仙台病毒、登革熱病毒、新城疫病毒（NDV）、水泡性口炎病毒（VSV）、B型肝炎病毒（HBV）及C型肝炎病毒（HCV）等。TLR8能識別抗病毒化合物、ssRNA病毒、人工合成的寡核苷酸等，通過MyD88依賴訊息途徑誘導Th1、抑制Th2細胞激素分泌和Tregs增殖，介導抗病毒免疫，發揮抗感染、抗過敏效應。Among the TLRs family members that recognize nucleic acid of pathogenic microorganisms, TLR7 and TLR8 have high homology and can recognize some artificially synthesized small molecules with antiviral effects, such as Imidazoquinolines imidazoquinoline small molecule compounds (ligands of TLR7 and TLR8) . Imidazoquinolines were studied in a guinea pig genital herpes model infected with HSV, and it was found that the compound had little effect on virus replication in vitro, but had a strong effect in vivo, indicating that these compounds promote immune cells to generate pro-inflammatory cytokines and Regulates cytokines, leading to antiviral responses (Int Immunopharmacol 2002; 2: 443-451). More importantly, TLR7 and TLR8 can recognize viral ssRNA. Studies have shown that ssRNA viruses are natural ligands for TLR7 and TLR8, such as human immunodeficiency virus type I (HIV), influenza virus, Sendai virus, dengue virus, Newcastle disease virus (NDV), vesicular stomatitis virus (VSV), Hepatitis B virus (HBV) and hepatitis C virus (HCV). TLR8 can recognize antiviral compounds, ssRNA viruses, synthetic oligonucleotides, etc., induce Th1 through MyD88-dependent signaling pathway, inhibit Th2 cytokine secretion and Tregs proliferation, mediate antiviral immunity, and exert anti-infection and anti-allergic effects.

中國專利申請CN107344931A中披露了一系列作為TLR8激動劑的苯并氮雜卓類化合物，特別是披露了以下化合物（CN107344931A中公開的化合物1-8-5）：

Figure 02_image003
Chinese patent application CN107344931A discloses a series of benzazepines as TLR8 agonists, especially the following compounds (compounds 1-8-5 disclosed in CN107344931A):
Figure 02_image003

根據CN107344931A化合物1-8-5的製備方法得到的是非晶形化合物，穩定性較差，不適合工業化生產及保存。According to the preparation method of CN107344931A compound 1-8-5, it is an amorphous compound, which has poor stability and is not suitable for industrial production and storage.

本發明所要解決的技術問題是現有技術中作為TLR8激動劑的苯并氮雜卓類化合物是非晶形化合物，溶解度和穩定性較差，為此，本發明提供了一種苯并氮雜卓衍生物：2-胺基-8-(2-(2-(甲磺醯基)乙基)-1-氧代-1,2-二氫酞嗪-6-基)-N,N-二異丙基-3H-苯并氮雜卓-4-甲醯胺的鹽、溶劑合物、多晶型物、製備方法及應用。本發明得到的晶型具有較佳的溶解度和穩定性，更適用於藥物製劑的製備及存儲。The technical problem to be solved by the present invention is that the benzoazepine compounds used as TLR8 agonists in the prior art are amorphous compounds with poor solubility and stability. Therefore, the present invention provides a benzoazepine derivative: 2 -Amino-8-(2-(2-(methylsulfonyl)ethyl)-1-oxo-1,2-dihydrophthalazin-6-yl)-N,N-diisopropyl- Salt, solvate, polymorph, preparation method and application of 3H-benzazepine-4-carboxamide. The crystal form obtained by the present invention has better solubility and stability, and is more suitable for the preparation and storage of pharmaceutical preparations.

本發明提供了如式（I）所示化合物：

Figure 02_image001
其中，X為H 2O、CH 3CH 2OH、CH 3C(O)OH、CH 3C(O)OCH 2CH 3、CH 3C(O)CH 3或(CH 3) 2CHOH； n為0-1的任意數值；m為0-3的任意數值；且m和n不同時為0。 The present invention provides compounds represented by formula (I):
Figure 02_image001
Wherein, X is H 2 O, CH 3 CH 2 OH, CH 3 C(O)OH, CH 3 C(O)OCH 2 CH 3 , CH 3 C(O)CH 3 or (CH 3 ) 2 CHOH; n is any value from 0 to 1; m is any value from 0 to 3; and m and n are not 0 at the same time.

本發明中，所述X優選為H 2O、CH 3CH 2OH或CH 3C(O)OH，更優選為H 2O。 In the present invention, the X is preferably H 2 O, CH 3 CH 2 OH or CH 3 C(O)OH, more preferably H 2 O.

本發明中，所述n可為0或1，優選為1。In the present invention, the n can be 0 or 1, preferably 1.

本發明中，所述m可為0、1、1.5、2、2.5或3，優選為0、1、1.5或2，更優選為1、1.5或2。In the present invention, the m may be 0, 1, 1.5, 2, 2.5 or 3, preferably 0, 1, 1.5 or 2, more preferably 1, 1.5 or 2.

在某一實施方案中，n為1，m為1.5或2；或者，n為0，m為1或2。In a certain embodiment, n is 1 and m is 1.5 or 2; alternatively, n is 0 and m is 1 or 2.

在某一實施方案中，n為1，m為0。In one embodiment, n is 1 and m is 0.

本發明中，所述如式（I）所示化合物選自如下任一化合物：

Figure 02_image005
、
Figure 02_image007
、
Figure 02_image009
Figure 02_image011
、
Figure 02_image013
、
Figure 02_image015
。 In the present invention, the compound represented by formula (I) is selected from any of the following compounds:
Figure 02_image005
,
Figure 02_image007
,
Figure 02_image009
Figure 02_image011
,
Figure 02_image013
,
Figure 02_image015
.

在某一實施方案中，當n為1，m為2，X為H 2O時，所述如式（I）所示化合物的結晶形式為鹽酸鹽水合物晶型I；使用Cu-Kα輻射，其以2θ角表示的X-射線粉末衍射圖，在9.8±0.2°、10.5±0.2°、17.4±0.2°、19.7±0.2°和22.7±0.2°處具有衍射峰。 In a certain embodiment, when n is 1, m is 2, and X is H 2 O, the crystalline form of the compound represented by formula (I) is hydrochloride hydrate crystal form I; using Cu-Kα radiation , which has an X-ray powder diffraction pattern expressed in 2θ angles with diffraction peaks at 9.8±0.2°, 10.5±0.2°, 17.4±0.2°, 19.7±0.2° and 22.7±0.2°.

在某一實施方案中，使用Cu-Kα輻射，所述鹽酸鹽水合物晶型I以2θ角表示的X-射線粉末衍射圖，還可在如下一個或多個2θ角處有衍射峰：7.1±0.2°、12.5±0.2°、14.0±0.2°、15.7±0.2°、18.0±0.2°和20.3±0.2°。In a certain embodiment, using Cu-Kα radiation, the X-ray powder diffraction pattern of the hydrochloride hydrate Form I, expressed at 2 theta angles, may also have diffraction peaks at one or more of the following 2 theta angles: 7.1 ±0.2°, 12.5±0.2°, 14.0±0.2°, 15.7±0.2°, 18.0±0.2° and 20.3±0.2°.

在某一實施方案中，使用Cu-Kα輻射，所述鹽酸鹽水合物晶型I以2θ角表示的X-射線粉末衍射圖，還可在如下一個或多個2θ角處有衍射峰：12.9±0.2°、21.5±0.2°、22.0±0.2°、25.2±0.2°、26.0±0.2°、26.8±0.2°和29.3±0.2°。In one embodiment, using Cu-Kα radiation, the X-ray powder diffraction pattern of the hydrochloride hydrate Form I, expressed at 2 theta angles, also has diffraction peaks at one or more of the following 2 theta angles: 12.9 ±0.2°, 21.5±0.2°, 22.0±0.2°, 25.2±0.2°, 26.0±0.2°, 26.8±0.2° and 29.3±0.2°.

在某一實施方案中，使用Cu-Kα輻射，所述鹽酸鹽水合物晶型I以2θ角表示的X-射線粉末衍射圖，還可在如下一個或多個2θ角處有衍射峰：18.7±0.2°、19.0±0.2°、24.8±0.2°、29.9±0.2°和34.1±0.2°。In a certain embodiment, using Cu-Kα radiation, the X-ray powder diffraction pattern of the hydrochloride hydrate Form I, expressed at 2 theta angles, also has diffraction peaks at one or more of the following 2 theta angles: 18.7 ±0.2°, 19.0±0.2°, 24.8±0.2°, 29.9±0.2° and 34.1±0.2°.

在某一實施方案中，使用Cu-Kα輻射，所述鹽酸鹽水合物晶型I以2θ角表示的X-射線粉末衍射圖，其衍射峰和相對強度還可如下表所示。 角度2θ/° 相對強度% 角度2θ/° 相對強度% 角度2θ/° 相對強度% 7.082 9.7 9.793 100.0 10.477 54.9 12.470 20.7 12.834 6.9 13.987 15.5 15.635 23.8 17.404 33.69 17.937 14.8 18.686 6.8 19.027 16.6 19.674 48.6 20.294 15.8 21.534 9.8 22.000 11.0 22.669 70.2 23.613 6.5 24.438 10.6 24.803 15.1 25.191 22.0 26.005 9.6 26.815 26.3 29.283 11.3 29.937 6.0 32.029 5.2 34.121 9.1     In a certain embodiment, using Cu-Kα radiation, the X-ray powder diffraction pattern of the hydrochloride hydrate crystal form I expressed at 2θ angle, the diffraction peaks and relative intensities thereof can also be shown in the following table. Angle 2θ/° Relative Strength% Angle 2θ/° Relative Strength% Angle 2θ/° Relative Strength% 7.082 9.7 9.793 100.0 10.477 54.9 12.470 20.7 12.834 6.9 13.987 15.5 15.635 23.8 17.404 33.69 17.937 14.8 18.686 6.8 19.027 16.6 19.674 48.6 20.294 15.8 21.534 9.8 22.000 11.0 22.669 70.2 23.613 6.5 24.438 10.6 24.803 15.1 25.191 22.0 26.005 9.6 26.815 26.3 29.283 11.3 29.937 6.0 32.029 5.2 34.121 9.1

在某一實施方案中，使用Cu-Kα輻射，所述鹽酸鹽水合物晶型I以2θ角表示的X-射線粉末衍射圖還可基本上如圖18所示。In a certain embodiment, the X-ray powder diffraction pattern at 2 theta angles of the hydrochloride hydrate Form I can also be substantially as shown in FIG. 18 using Cu-Kα radiation.

在某一實施方案中，所述鹽酸鹽水合物晶型I的差示掃描量熱圖（DSC）中在136.3±5℃（例如136.3±3℃）處有吸收峰。In a certain embodiment, the differential scanning calorimetry (DSC) of the hydrochloride hydrate crystalline form I has an absorption peak at 136.3±5°C (eg, 136.3±3°C).

在某一實施方案中，所述鹽酸鹽水合物晶型I的差示掃描量熱圖還可基本上如圖19所示。In a certain embodiment, the differential scanning calorimetry of the hydrochloride hydrate Form I can also be substantially as shown in FIG. 19 .

在某一實施方案中，所述鹽酸鹽水合物晶型I的熱重分析圖在70℃至100℃有重量損失，所述重量損失可為6±0.5%（例如6±0.2%）。In a certain embodiment, the thermogravimetric analysis profile of the hydrochloride hydrate Form I has a weight loss between 70°C and 100°C, and the weight loss may be 6±0.5% (eg, 6±0.2%).

在某一實施方案中，所述鹽酸鹽水合物晶型I的熱重分析圖（TGA）還可基本上如圖20所示。In a certain embodiment, the thermogravimetric analysis (TGA) of the hydrochloride hydrate Form I can also be substantially as shown in FIG. 20 .

在某一實施方案中，當n為1，m為2，X為CH 3C(O)OH時，所述如式（I）所示化合物的結晶形式為鹽酸鹽醋酸溶劑合物晶型I；使用Cu-Kα輻射，其以2θ角表示的X-射線粉末衍射圖的衍射峰和相對強度如下表所示。 角度2θ/° 相對強度% 角度2θ/° 相對強度% 角度2θ/° 相對強度% 6.539 100.0 7.019 2.8 7.534 4.6 15.942 1.6 18.416 1.9 18.763 3.8 19.441 2.9 19.739 4.4 20.700 3.4 20.898 6.3 21.741 2.0 22.720 2.0 24.505 2.7 24.878 3.3 26.421 4.2 In a certain embodiment, when n is 1, m is 2, and X is CH 3 C(O)OH, the crystalline form of the compound represented by formula (I) is hydrochloride acetic acid solvate crystalline form I; Using Cu-Kα radiation, the diffraction peaks and relative intensities of the X-ray powder diffraction pattern expressed in 2θ angles are shown in the table below. Angle 2θ/° Relative Strength% Angle 2θ/° Relative Strength% Angle 2θ/° Relative Strength% 6.539 100.0 7.019 2.8 7.534 4.6 15.942 1.6 18.416 1.9 18.763 3.8 19.441 2.9 19.739 4.4 20.700 3.4 20.898 6.3 21.741 2.0 22.720 2.0 24.505 2.7 24.878 3.3 26.421 4.2

在某一實施方案中，使用Cu-Kα輻射，所述鹽酸鹽醋酸溶劑合物晶型I以2θ角表示的X-射線粉末衍射圖還可基本上如圖16所示。In a certain embodiment, the X-ray powder diffraction pattern of the hydrochloride acetic acid solvate Form I in 2 theta angles is also substantially as shown in FIG. 16 using Cu-Kα radiation.

在某一實施方案中，當n為1，m為1.5，X為CH 3CH 2OH時，所述如式（I）所示化合物的結晶形式為鹽酸鹽乙醇溶劑合物晶型I；使用Cu-Kα輻射，其以2θ角表示的X-射線粉末衍射圖譜的衍射峰和相對強度如下表所示。 角度2θ/° 相對強度% 角度2θ/° 相對強度% 角度2θ/° 相對強度% 6.454 100.0 7.239 27.0 9.157 11.9 11.702 12.5 12.966 7.2 13.417 4.9 16.183 4.5 19.496 7.5 20.229 10.5 20.679 7.3 21.964 12.8 22.397 6.7 23.545 8.8 25.181 9.0 26.068 9.5 In a certain embodiment, when n is 1, m is 1.5, and X is CH 3 CH 2 OH, the crystalline form of the compound represented by formula (I) is hydrochloride ethanol solvate crystal form I; Using Cu-Kα radiation, the diffraction peaks and relative intensities of the X-ray powder diffraction pattern expressed in 2θ angles are shown in the table below. Angle 2θ/° Relative Strength% Angle 2θ/° Relative Strength% Angle 2θ/° Relative Strength% 6.454 100.0 7.239 27.0 9.157 11.9 11.702 12.5 12.966 7.2 13.417 4.9 16.183 4.5 19.496 7.5 20.229 10.5 20.679 7.3 21.964 12.8 22.397 6.7 23.545 8.8 25.181 9.0 26.068 9.5

在某一實施方案中，使用Cu-Kα輻射，所述鹽酸鹽乙醇溶劑合物晶型I以2θ角表示的X-射線粉末衍射圖還可基本上如圖14所示。In a certain embodiment, the X-ray powder diffraction pattern of the hydrochloride ethanol solvate Form I in 2 theta angles is also substantially as shown in FIG. 14 using Cu-Kα radiation.

在某一實施方案中，所述鹽酸鹽乙醇溶劑合物晶型I的熱重分析圖在50℃至125℃有重量損失，所述重量損失可為12.7±0.5%（例如12.7±0.2%）。In a certain embodiment, the thermogravimetric analysis profile of the hydrochloride ethanol solvate Form I has a weight loss between 50°C and 125°C, and the weight loss may be 12.7±0.5% (eg, 12.7±0.2%). ).

在某一實施方案中，所述鹽酸鹽乙醇溶劑合物晶型I的熱重分析圖（TGA）還可基本上如圖15所示。In a certain embodiment, the thermogravimetric analysis plot (TGA) of the hydrochloride ethanol solvate Form I can also be substantially as shown in FIG. 15 .

在某一實施方案中，當n為0，m為1，X為CH 3C(O)OH時，所述如式（I）所示化合物的結晶形式為醋酸溶劑合物晶型I；使用Cu-Kα輻射，其以2θ角表示的X-射線粉末衍射圖，在5.3±0.2°、8.5±0.2°、10.8±0.2°、18.7±0.2°和20.4±0.2°處具有衍射峰。 In a certain embodiment, when n is 0, m is 1, and X is CH 3 C(O)OH, the crystal form of the compound represented by formula (I) is acetic acid solvate crystal form I; using Cu-Kα radiation, which has an X-ray powder diffraction pattern expressed in 2Θ angles, has diffraction peaks at 5.3 ± 0.2°, 8.5 ± 0.2°, 10.8 ± 0.2°, 18.7 ± 0.2° and 20.4 ± 0.2°.

在某一實施方案中，使用Cu-Kα輻射，所述醋酸溶劑合物晶型I以2θ角表示的X-射線粉末衍射圖，還可在如下一個或多個2θ角處有衍射峰：4.9±0.2°、10.1±0.2°、11.8±0.2°、12.8±0.2°、14.0±0.2°、15.2±0.2°、15.8±0.2°、17.1±0.2°、17.6±0.2°、21.7±0.2°、23.7±0.2°和25.9±0.2°。In a certain embodiment, using Cu-Kα radiation, the X-ray powder diffraction pattern of the acetic acid solvate Form I at 2 theta angles further has diffraction peaks at one or more of the following 2 theta angles: 4.9 ±0.2°, 10.1±0.2°, 11.8±0.2°, 12.8±0.2°, 14.0±0.2°, 15.2±0.2°, 15.8±0.2°, 17.1±0.2°, 17.6±0.2°, 21.7±0.2°, 23.7 ±0.2° and 25.9±0.2°.

在某一實施方案中，使用Cu-Kα輻射，所述醋酸溶劑合物晶型I以2θ角表示的X-射線粉末衍射圖，其衍射峰和相對強度還可如下表所示。 角度2θ/° 相對強度% 角度2θ/° 相對強度% 角度2θ/° 相對強度% 4.911 26.0 5.337 38.6 5.849 6.8 8.467 55.7 10.129 50.2 10.761 100.0 11.803 49.8 12.851 9.6 13.953 21.5 15.184 20.9 15.766 30.2 17.074 19.9 17.605 10.5 18.738 41.4 20.442 30.7 21.671 24.5 23.670 10.3 23.940 9.1 25.875 12.6         In a certain embodiment, using Cu-Kα radiation, the X-ray powder diffraction pattern of the acetic acid solvate Form I expressed at 2θ angle, the diffraction peaks and relative intensities thereof can also be shown in the table below. Angle 2θ/° Relative Strength% Angle 2θ/° Relative Strength% Angle 2θ/° Relative Strength% 4.911 26.0 5.337 38.6 5.849 6.8 8.467 55.7 10.129 50.2 10.761 100.0 11.803 49.8 12.851 9.6 13.953 21.5 15.184 20.9 15.766 30.2 17.074 19.9 17.605 10.5 18.738 41.4 20.442 30.7 21.671 24.5 23.670 10.3 23.940 9.1 25.875 12.6

在某一實施方案中，使用Cu-Kα輻射，所述醋酸溶劑合物晶型I以2θ角表示的X-射線粉末衍射圖還可基本上如圖6所示。In a certain embodiment, the X-ray powder diffraction pattern of the acetic acid solvate Form I in 2 theta angles can also be substantially as shown in FIG. 6 using Cu-Kα radiation.

在某一實施方案中，所述醋酸溶劑合物晶型I的差示掃描量熱圖（DSC）中分別在167.2±5℃（例如167.2±3℃）和238.5±5℃（例如238.5±3℃）處有吸收峰。In a certain embodiment, the differential scanning calorimetry (DSC) of the acetic acid solvate Form I is at 167.2±5°C (eg 167.2±3°C) and 238.5±5°C (eg 238.5±3°C), respectively ℃) has an absorption peak.

在某一實施方案中，所述醋酸溶劑合物晶型I的差示掃描量熱圖還可基本上如圖7所示。In a certain embodiment, the differential scanning calorimetry of the acetic acid solvate Form I can also be substantially as shown in FIG. 7 .

在某一實施方案中，所述醋酸溶劑合物晶型I的熱重分析圖在100℃至160℃有重量損失，所述重量損失可為10±0.5%（例如10±0.2%）。In a certain embodiment, the thermogravimetric analysis profile of the acetic acid solvate Form I has a weight loss between 100°C and 160°C, and the weight loss may be 10±0.5% (eg, 10±0.2%).

在某一實施方案中，所述醋酸溶劑合物晶型I的熱重分析圖（TGA）還可基本上如圖8所示。In a certain embodiment, the thermogravimetric analysis plot (TGA) of the acetic acid solvate Form I can also be substantially as shown in FIG. 8 .

在某一實施方案中，當n為0，m為2，X為CH 3C(O)OH時，所述如式（I）所示化合物的結晶形式為醋酸溶劑合物晶型II；使用Cu-Kα輻射，其以2θ角表示的X-射線粉末衍射圖，在6.5±0.2°、7.1±0.2°、7.5±0.2°、13.7±0.2°和24.5±0.2°處具有衍射峰。 In a certain embodiment, when n is 0, m is 2, and X is CH 3 C(O)OH, the crystal form of the compound represented by formula (I) is acetic acid solvate crystal form II; using Cu-Kα radiation, which has an X-ray powder diffraction pattern expressed in 2Θ angles, has diffraction peaks at 6.5±0.2°, 7.1±0.2°, 7.5±0.2°, 13.7±0.2° and 24.5±0.2°.

在某一實施方案中，使用Cu-Kα輻射，所述醋酸溶劑合物晶型II以2θ角表示的X-射線粉末衍射圖，還可在如下一個或多個2θ角處有衍射峰：19.4±0.2°、20.8±0.2°、23.1±0.2°和24.8±0.2°。In a certain embodiment, using Cu-Kα radiation, the X-ray powder diffraction pattern of the acetic acid solvate Form II, expressed at 2 theta angles, also has diffraction peaks at one or more of the following 2 theta angles: 19.4 ±0.2°, 20.8±0.2°, 23.1±0.2° and 24.8±0.2°.

在某一實施方案中，使用Cu-Kα輻射，所述醋酸溶劑合物晶型II以2θ角表示的X-射線粉末衍射圖，其衍射峰和相對強度還可如下表所示。 角度2θ/° 相對強度% 角度2θ/° 相對強度% 角度2θ/° 相對強度% 6.518 100.0 7.081 62.3 7.491 6.1 13.700 9.1 14.739 3.9 15.059 3.8 18.501 3.9 18.759 3.8 19.404 5.7 20.099 18.2 20.799 4.5 21.838 3.6 23.081 4.0 24.543 6.8 24.835 5.2 In a certain embodiment, using Cu-Kα radiation, the X-ray powder diffraction pattern of the acetic acid solvate crystal form II expressed at 2 theta angle, the diffraction peaks and relative intensities thereof can also be shown in the table below. Angle 2θ/° Relative Strength% Angle 2θ/° Relative Strength% Angle 2θ/° Relative Strength% 6.518 100.0 7.081 62.3 7.491 6.1 13.700 9.1 14.739 3.9 15.059 3.8 18.501 3.9 18.759 3.8 19.404 5.7 20.099 18.2 20.799 4.5 21.838 3.6 23.081 4.0 24.543 6.8 24.835 5.2

在某一實施方案中，使用Cu-Kα輻射，所述醋酸溶劑合物晶型II以2θ角表示的X-射線粉末衍射圖還可基本上如圖10所示。In a certain embodiment, the X-ray powder diffraction pattern of the acetic acid solvate Form II in 2 theta angles can also be substantially as shown in FIG. 10 using Cu-Kα radiation.

在某一實施方案中，所述醋酸溶劑合物晶型II的差示掃描量熱圖（DSC）中在115.8±5℃（例如115.8±3℃）處有吸收峰。In a certain embodiment, the differential scanning calorimetry (DSC) of the acetic acid solvate crystalline form II has an absorption peak at 115.8±5°C (eg, 115.8±3°C).

在某一實施方案中，所述醋酸溶劑合物晶型II的差示掃描量熱圖還可基本上如圖11所示。In a certain embodiment, the differential scanning calorimetry of the acetic acid solvate Form II can also be substantially as shown in FIG. 11 .

在某一實施方案中，所述醋酸溶劑合物晶型II的熱重分析圖可在100℃至160℃有重量損失；所述重量損失可為11.6±0.5%（例如11.6±0.2%）。In a certain embodiment, the thermogravimetric analysis profile of the acetic acid solvate crystal form II may have a weight loss at 100°C to 160°C; the weight loss may be 11.6±0.5% (eg, 11.6±0.2%).

在某一實施方案中，所述醋酸溶劑合物晶型II的熱重分析圖（TGA）還可基本上如圖12所示。In a certain embodiment, the thermogravimetric analysis plot (TGA) of the acetic acid solvate Form II can also be substantially as shown in FIG. 12 .

本發明還提供了化合物A的結晶形式：

Figure 02_image017
。 The present invention also provides a crystalline form of Compound A:
Figure 02_image017
.

所述化合物A的結晶形式為化合物A的晶型I；使用Cu-Kα輻射，其以2θ角表示的X-射線粉末衍射圖，在6.3±0.2°、7.4±0.2°、8.7±0.2°、15.3±0.2°和17.5±0.2°處具有衍射峰。The crystalline form of the compound A is the crystalline form I of the compound A; using Cu-Kα radiation, its X-ray powder diffraction pattern expressed at 2θ angle, at 6.3±0.2°, 7.4±0.2°, 8.7±0.2°, There are diffraction peaks at 15.3±0.2° and 17.5±0.2°.

在某一實施方案中，使用Cu-Kα輻射，所述化合物A的晶型I以2θ角表示的X-射線粉末衍射圖，還可在如下一個或多個2θ角處有衍射峰：12.4±0.2°、14.9±0.2°、15.7±0.2°、17.3±0.2°、18.9±0.2°、20.5±0.2°、21.6±0.2°、22.3±0.2°、22.9±0.2°、23.1±0.2°、24.0±0.2°和26.0±0.2°。In a certain embodiment, using Cu-Kα radiation, the X-ray powder diffraction pattern of the Form I of Compound A at 2 theta angles may also have diffraction peaks at one or more of the following 2 theta angles: 12.4±12.4± 0.2°, 14.9±0.2°, 15.7±0.2°, 17.3±0.2°, 18.9±0.2°, 20.5±0.2°, 21.6±0.2°, 22.3±0.2°, 22.9±0.2°, 23.1±0.2°, 24.0± 0.2° and 26.0±0.2°.

在某一實施方案中，使用Cu-Kα輻射，所述化合物A的晶型I以2θ角表示的X-射線粉末衍射圖，還可在如下一個或多個2θ角處有衍射峰：20.7±0.2°、21.9±0.2°、23.7±0.2°、24.3±0.2°和25.4±0.2°。In a certain embodiment, using Cu-Kα radiation, the X-ray powder diffractogram of Form I of Compound A at 2 theta angles may also have diffraction peaks at one or more of the following 2 theta angles: 20.7± 0.2°, 21.9±0.2°, 23.7±0.2°, 24.3±0.2° and 25.4±0.2°.

在某一實施方案中，使用Cu-Kα輻射，所述化合物A的晶型I以2θ角表示的X-射線粉末衍射圖還可基本上如圖2所示。In a certain embodiment, the X-ray powder diffraction pattern of Form I of Compound A in 2 theta angles can also be substantially as shown in FIG. 2 using Cu-Kα radiation.

在某一實施方案中，所述化合物A的晶型I的差示掃描量熱圖（DSC）中在235.1±5℃（例如235.1±3℃）處有吸收峰。In a certain embodiment, the Differential Scanning Calorimetry (DSC) of Form I of Compound A has an absorption peak at 235.1±5°C (eg, 235.1±3°C).

在某一實施方案中，所述化合物A的晶型I的差示掃描量熱圖還可基本上如圖3所示。In a certain embodiment, the differential scanning calorimetry map of Form I of Compound A can also be substantially as shown in FIG. 3 .

在某一實施方案中，所述化合物A的晶型I的熱重分析圖（TGA）還可基本上如圖4所示。In a certain embodiment, the thermogravimetric analysis plot (TGA) of Form I of Compound A can also be substantially as shown in FIG. 4 .

本發明提供了如式（I）所示化合物的製備方法，其包括以下方法一、方法二或方法三： 方法一： 將化合物A溶於X中，析晶，得到如式（I）所示化合物，

Figure 02_image019
方法一中，n為0，m和X的定義如前所述； 方法二： 將化合物A置於X中和HCl反應，析晶，得到如式（I）所示化合物，
Figure 02_image021
方法二中，n為1，m為0-3的任意數值；X的定義如前所述； 方法三： 將如式（II）所示化合物溶於有機溶劑-水的混合溶液中，析晶，得到如式（I）所示化合物，
Figure 02_image023
方法三中，n為0-1的任意數值，m和m’獨立地為0-3的任意數值，且n和m均不為0；X為H 2O；Y為CH 3CH 2OH、CH 3C(O)OH、CH 3C(O)OCH 2CH 3、CH 3C(O)CH 3或(CH 3) 2CHOH。 The present invention provides a method for preparing a compound represented by formula (I), which includes the following method 1, method 2 or method 3: Method 1: Compound A is dissolved in X, and crystallized to obtain the compound represented by formula (I) compound,
Figure 02_image019
In Method 1, n is 0, and the definitions of m and X are as described above; Method 2: Compound A is placed in X, reacted with HCl, and crystallized to obtain a compound represented by formula (I),
Figure 02_image021
In the second method, n is 1, and m is any value from 0 to 3; the definition of X is as described above; Method 3: Dissolve the compound represented by formula (II) in a mixed solution of organic solvent and water, and crystallize , to obtain a compound of formula (I),
Figure 02_image023
In the third method, n is any value from 0 to 1, m and m' are any value from 0 to 3 independently, and both n and m are not 0; X is H 2 O; Y is CH 3 CH 2 OH, CH3C (O)OH, CH3C (O) OCH2CH3 , CH3C (O) CH3 or ( CH3 ) 2CHOH .

所述方法一中，所述化合物A溶於X的過程可通過如下方法實現：將化合物A溶解在有機溶劑中形成混合物，再將所述混合物溶解於X中；或者，將化合物A置於X中加熱，使其溶清即可。In the first method, the process of dissolving the compound A in X can be achieved by the following methods: dissolving the compound A in an organic solvent to form a mixture, and then dissolving the mixture in X; or, placing the compound A in X Heat in medium until it dissolves.

所述方法一中，當化合物A溶解在有機溶劑中形成混合物時，所述有機溶劑的種類可為本領域常規，以能溶解化合物A並能和X混溶即可，例如，當X為醋酸時，所述有機溶劑可為二氯甲烷和/或甲醇。In the first method, when compound A is dissolved in an organic solvent to form a mixture, the type of the organic solvent can be conventional in the art, as long as it can dissolve compound A and be miscible with X, for example, when X is acetic acid , the organic solvent may be dichloromethane and/or methanol.

所述方法一中，當化合物A溶解在有機溶劑中形成混合物時，所述有機溶劑的量可不做限定，以使化合物A溶解即可。In the first method, when compound A is dissolved in an organic solvent to form a mixture, the amount of the organic solvent is not limited, so long as compound A is dissolved.

所述方法一中，當將化合物A置於X中並加熱時，較佳地，將其加熱至本領域常規的溫度，例如60℃~120℃，又例如60℃~85℃，再例如79.5℃或80℃。In the first method, when compound A is placed in X and heated, preferably, it is heated to a temperature conventional in the art, such as 60°C to 120°C, another example is 60°C to 85°C, and another example is 79.5°C. ℃ or 80℃.

所述方法一中，當將化合物A置於X中加熱使其溶清時，所述X的量可不做限定，以使化合物A溶清即可。所述方法二中，當X為H 2O時，所述反應還進一步包含醇類和/或酮類溶劑；所述醇類溶劑的種類可為本領域常規，例如：異丙醇和/或乙醇，優選為異丙醇；所述酮類溶劑的種類可為本領域常規，例如丙酮。所述方法二中，所述化合物A置於X中的溫度可為本領域常規，例如10℃~85℃，又例如10℃~30℃或60℃。 In the first method, when compound A is heated in X to dissolve it, the amount of X may not be limited, so long as compound A is dissolved. In the second method, when X is H 2 O, the reaction further includes alcohols and/or ketone solvents; the types of the alcohols can be conventional in the field, for example: isopropanol and/or ethanol , preferably isopropanol; the type of the ketone solvent can be conventional in the field, such as acetone. In the second method, the temperature at which the compound A is placed in X may be conventional in the art, for example, 10°C to 85°C, and for example, 10°C to 30°C or 60°C.

所述方法二中，所述HCl可為氯化氫氣體、鹽酸（例如：濃鹽酸）、鹽酸醇溶液（例如：鹽酸乙醇溶液、鹽酸甲醇溶液、鹽酸異丙醇溶液）、鹽酸酮溶液（例如：鹽酸丙酮溶液）、氯化氫醇溶液（例如：氯化氫乙醇溶液、氯化氫甲醇溶液、氯化氫異丙醇溶液）、氯化氫酮溶液（氯化氫丙酮溶液）等，較佳地為鹽酸的乙醇溶液、濃鹽酸、氯化氫乙醇溶液（例如2M的氯化氫乙醇溶液）或鹽酸異丙醇溶液。所述化合物A和HCl的莫耳比可為本領域常規，例如1：（1~15），又例如1:1、1:1.2、1:1.5、1:2、1:3或1:10。所述方法三中，所述有機溶劑的種類可為本領域常規，以使能溶解如式（II）所示化合物以及能與水混溶即可，優選為二氯甲烷和甲醇、異丙醇和丙酮的一種或多種。In the second method, the HCl can be hydrogen chloride gas, hydrochloric acid (for example: concentrated hydrochloric acid), hydrochloric acid alcohol solution (for example: hydrochloric acid ethanol solution, hydrochloric acid methanol solution, hydrochloric acid isopropanol solution), hydrochloric acid ketone solution (for example: hydrochloric acid solution) acetone solution), hydrogen chloride alcohol solution (for example: hydrogen chloride ethanol solution, hydrogen chloride methanol solution, hydrogen chloride isopropanol solution), hydrogen chloride ketone solution (hydrogen chloride acetone solution), etc., preferably hydrochloric acid ethanol solution, concentrated hydrochloric acid, hydrogen chloride ethanol solution (eg 2M hydrogen chloride in ethanol) or hydrochloric acid in isopropanol. The molar ratio of the compound A and HCl can be conventional in the art, such as 1:(1~15), and another example is 1:1, 1:1.2, 1:1.5, 1:2, 1:3 or 1:10 . In the third method, the type of the organic solvent can be conventional in the field, so as to be able to dissolve the compound shown in formula (II) and to be miscible with water, preferably dichloromethane and methanol, isopropanol and One or more of acetone.

所述方法三中，所述有機溶劑-水的混合溶液的量可不做限定，以使如式（II）所示化合物溶清即可。In the third method, the amount of the organic solvent-water mixed solution may not be limited, as long as the compound represented by formula (II) is completely dissolved.

所述方法三中，所述有機溶劑-水的混合溶液中，所述有機溶劑的體積百分數可為本領域常規，優選為50%~98%，例如50%、75%、85%或95%。In the third method, in the organic solvent-water mixed solution, the volume percentage of the organic solvent can be conventional in the field, preferably 50% to 98%, such as 50%, 75%, 85% or 95%. .

所述方法三中，所述如式（II）所示化合物還可經加熱溶解於有機溶劑-水的混合溶液中；較佳地，將其加熱至本領域常規的溫度（例如：10℃~80℃），優選30℃~80℃，例如50℃。In the third method, the compound represented by formula (II) can also be dissolved in a mixed solution of organic solvent-water by heating; 80°C), preferably 30°C to 80°C, such as 50°C.

所述方法三中，Y優選為CH 3CH 2OH、CH 3C(O)OH或(CH 3) 2CHOH。 In the third method, Y is preferably CH 3 CH 2 OH, CH 3 C(O)OH or (CH 3 ) 2 CHOH.

所述方法三中，所述如式（II）所示化合物可由所述方法二製備得到。In the third method, the compound represented by the formula (II) can be prepared by the second method.

本發明還提供了一種藥物組合物，其包括治療有效量的活性組分以及藥學上可接受的輔料；所述活性組分包括如式（I）所示化合物。The present invention also provides a pharmaceutical composition, which includes a therapeutically effective amount of an active component and a pharmaceutically acceptable adjuvant; the active component includes a compound represented by formula (I).

所述藥物組合物中，所述活性組分還可包括癌症、病毒感染或自身免疫疾病的其它治療劑。In the pharmaceutical composition, the active ingredient may also include other therapeutic agents for cancer, viral infections or autoimmune diseases.

所述藥物組合物中，所述藥學上可接受的輔料可包括藥學上可接受的載體、稀釋劑和/或賦形劑。In the pharmaceutical composition, the pharmaceutically acceptable adjuvants may include pharmaceutically acceptable carriers, diluents and/or excipients.

根據治療目的，可將藥物組合物製成各種類型的給藥單位劑型，如片劑、丸劑、粉劑、液體、懸浮液、乳液、顆粒劑、膠囊、栓劑和注射劑（包括注射液、注射用無菌粉末（粉針）與注射用濃溶液）等，優選液體、懸浮液、乳液、栓劑和針劑（溶液及懸浮液）等。According to the purpose of treatment, the pharmaceutical composition can be made into various types of administration unit dosage forms, such as tablets, pills, powders, liquids, suspensions, emulsions, granules, capsules, suppositories and injections (including injections, sterile injections Powder (powder injection) and concentrated solution for injection), etc., preferably liquid, suspension, emulsion, suppository, injection (solution and suspension), etc.

為了使片劑形式的藥物組合物成形，可使用本領域任何已知並廣泛使用的賦形劑。例如，載體，如乳糖、白糖、氯化鈉、葡萄糖、尿素、澱粉、碳酸鈣、高嶺土、結晶纖維素和矽酸等；粘合劑，如水、乙醇、丙醇、普通糖漿、葡萄糖溶液、澱粉溶液、明膠溶液，羧甲基纖維素、紫膠、甲基纖維素和磷酸鉀、聚乙烯吡咯烷酮等；崩解劑，如乾澱粉、藻酸鈉、瓊脂粉和海帶粉，碳酸氫鈉、碳酸鈣、聚乙烯脫水山梨醇的脂肪酸酯、十二烷基硫酸鈉、硬脂酸單甘酯、澱粉和乳糖等；崩解抑制劑，如白糖、甘油三硬脂酸酯、椰子油和氫化油；吸附促進劑，如季胺鹼和十二烷基硫酸鈉等；潤濕劑，如甘油、澱粉等；吸附劑，如澱粉、乳糖、高嶺土、膨潤土和膠體矽酸等；以及潤滑劑，如純淨的滑石，硬脂酸鹽、硼酸粉和聚乙二醇等。還可以根據需要選用通常的塗漬材料製成糖衣片劑、塗明膠膜片劑、腸衣片劑、塗膜片劑、雙層膜片劑及多層片劑。In order to shape the pharmaceutical composition in tablet form, any of the excipients known and widely used in the art can be used. For example, carriers such as lactose, white sugar, sodium chloride, glucose, urea, starch, calcium carbonate, kaolin, crystalline cellulose and silicic acid, etc.; binders such as water, ethanol, propanol, common syrup, glucose solution, starch Solution, gelatin solution, carboxymethyl cellulose, shellac, methyl cellulose and potassium phosphate, polyvinylpyrrolidone, etc.; disintegrating agents, such as dry starch, sodium alginate, agar powder and kelp powder, sodium bicarbonate, carbonic acid Calcium, fatty acid esters of polyethylene sorbitan, sodium lauryl sulfate, monoglyceryl stearate, starch and lactose, etc.; disintegration inhibitors, such as white sugar, glyceryl tristearate, coconut oil, and hydrogenated Oils; adsorption promoters, such as quaternary amine bases and sodium lauryl sulfate, etc.; wetting agents, such as glycerol, starch, etc.; adsorbents, such as starch, lactose, kaolin, bentonite and colloidal silicic acid, etc.; and lubricants, Such as pure talc, stearate, boric acid powder and polyethylene glycol. The usual coating materials can also be used to make sugar-coated tablets, gelatin-coated tablets, enteric-coated tablets, film-coated tablets, double-layered film tablets and multi-layered tablets as required.

為了使丸劑形式的藥物組合物成形，可使用本領域任何已知的並廣泛使用的賦形劑，例如，載體，如乳糖，澱粉，椰子油，硬化植物油，高嶺土和滑石粉等；粘合劑，如***樹膠粉，黃蓍膠粉，明膠和乙醇等；崩解劑，如瓊脂和海帶粉等。In order to shape the pharmaceutical composition in pill form, any excipient known and widely used in the art can be used, for example, carriers such as lactose, starch, coconut oil, hardened vegetable oils, kaolin and talc, etc.; binders , such as gum arabic powder, tragacanth powder, gelatin and ethanol, etc.; disintegrating agents, such as agar and kelp powder.

為了使栓劑形式的藥物組合物成形，可使用本領域任何已知並廣泛使用的賦性劑，例如，聚乙二醇，椰子油，高級醇，高級醇的酯，明膠和半合成的甘油酯等。To shape the pharmaceutical composition in the form of a suppository, any excipient known and widely used in the art may be used, for example, polyethylene glycols, coconut oil, higher alcohols, esters of higher alcohols, gelatin and semi-synthetic glycerides Wait.

為了製備注射劑形式的藥物組合物，可使用本領域任何已知並廣泛使用的載體或賦性劑，所用載體或賦形劑包含注射用水、林格氏液和等滲氯化鈉溶液，也可根據藥物的性質加入適宜的附加劑例如抗氧化劑、增溶劑、PH調節劑和抑菌劑。For the preparation of pharmaceutical compositions in the form of injections, any known and widely used carriers or excipients in the art can be used. The carriers or excipients used include water for injection, Ringer's solution and isotonic sodium chloride solution. Appropriate additives such as antioxidants, solubilizers, pH regulators and bacteriostatic agents are added according to the properties of the drug.

本發明中，所述藥物組合物中的所述活性組分的含量無特殊限制，可在很寬的範圍內進行選擇，通常可為質量百分比的5~95%，較佳的為質量百分比30~80%。In the present invention, the content of the active component in the pharmaceutical composition is not particularly limited, and can be selected within a wide range, usually 5-95% by mass, preferably 30% by mass ~80%.

本發明中，所述藥物組合物的給藥方法沒有特殊限制。可根據病人年齡、性別和其它條件及症狀，選擇各種劑型的製劑給藥。例如，片劑、丸劑、溶液、懸浮液、乳液、顆粒劑或膠囊口服給藥；注射劑可以單獨給藥，或者和注射用輸送液（如葡萄糖溶液及胺基酸溶液）混合進行靜脈注射、肌肉注射或病灶局部注射；栓劑為給藥到直腸。In the present invention, the administration method of the pharmaceutical composition is not particularly limited. Various dosage forms can be selected for administration according to the patient's age, sex and other conditions and symptoms. For example, tablets, pills, solutions, suspensions, emulsions, granules, or capsules are administered orally; injections can be administered alone or in admixture with injectable delivery fluids (such as glucose solutions and amino acid solutions) for intravenous, intramuscular administration Injection or topical injection; suppository for administration to the rectum.

本發明還提供了如式（I）所示化合物、或所述藥物組合物在製備TLRs調節劑中的應用。The present invention also provides the use of the compound represented by formula (I) or the pharmaceutical composition in the preparation of a TLRs modulator.

所述在製備TLRs調節劑中的應用中，所述TLRs調節劑包括TLRs完全激動劑或者TLRs部分激動劑。所述TLRs優選TLR7、TLR8和TLR9中的一種或者多種，更優選為TLR8。In the application in the preparation of TLRs modulators, the TLRs modulators include TLRs full agonists or TLRs partial agonists. The TLRs are preferably one or more of TLR7, TLR8 and TLR9, more preferably TLR8.

本發明還提供了如式（I）所示化合物、或所述藥物組合物在製備調節T細胞藥物中的應用。The present invention also provides the use of the compound represented by formula (I) or the pharmaceutical composition in the preparation of a T cell regulating drug.

本發明還提供了如式（I）所示化合物、或所述藥物組合物在製備治療、緩解和/或預防由TLRs介導的相關疾病的藥物中的應用。The present invention also provides the use of the compound represented by formula (I) or the pharmaceutical composition in the preparation of a medicament for treating, relieving and/or preventing related diseases mediated by TLRs.

本發明中，所述如式（I）所示化合物、或所述藥物組合物在製備治療和/或緩解由TLRs介導的相關疾病的藥物中的應用中，較佳地，所述由TLRs介導的相關疾病的藥物為由TLR8介導的相關疾病的藥物；所述疾病包括腫瘤和非腫瘤性疾病。所述疾病包括但不限於：癌症、病毒感染，以及自身免疫性疾病等；所述癌症優選免疫製劑相關的癌症，所述免疫抑制是指腫瘤特異性地免疫抑制。In the present invention, in the application of the compound represented by formula (I) or the pharmaceutical composition in the preparation of a medicine for treating and/or alleviating related diseases mediated by TLRs, preferably, the TLRs Drugs for related diseases mediated by TLR8 are drugs for related diseases mediated by TLR8; the diseases include tumors and non-tumor diseases. The diseases include, but are not limited to, cancer, viral infection, and autoimmune diseases, etc. The cancer is preferably an immunologic agent-related cancer, and the immunosuppression refers to tumor-specific immunosuppression.

本發明中，所述如式（I）所示化合物、或所述藥物組合物在製備治療和/或緩解癌症、病毒感染以及自身免疫性疾病的藥物中的應用。In the present invention, the compound represented by formula (I) or the pharmaceutical composition is used in the preparation of medicines for treating and/or alleviating cancer, viral infections and autoimmune diseases.

本發明還進一步提供了用所述如式（I）所示化合物，或所述藥物組合物治療、緩解和/或預防癌症、病毒感染或自身免疫性疾病的方法，包括：給予哺乳動物治療所需劑量的如式（I）所述化合物，或藥物組合物。The present invention further provides a method for treating, alleviating and/or preventing cancer, viral infection or autoimmune disease with the compound represented by formula (I), or the pharmaceutical composition, comprising: administering to a mammal for the treatment of A desired dose of the compound of formula (I), or the pharmaceutical composition.

所述哺乳動物，優選人。Said mammal, preferably human.

本發明還進一步提供了所述如式（I）所示化合物、或所述藥物組合物和一種或多種其它種類的治療劑和/或治療方法聯合用於治療、緩解和/或預防由TLRs介導的相關疾病，尤其指由TLR8介導的相關疾病。所述的TLR8介導的相關疾病是指由TLR8介導的免疫抑制而引起的疾病，所述的疾病可包括：癌症、病毒感染或自身免疫性疾病等。The present invention further provides the compound represented by formula (I), or the pharmaceutical composition and one or more other kinds of therapeutic agents and/or therapeutic methods in combination for the treatment, remission and/or prevention of TLRs-mediated related diseases, especially related diseases mediated by TLR8. The TLR8-mediated related diseases refer to diseases caused by TLR8-mediated immunosuppression, and the diseases may include cancer, viral infection or autoimmune diseases.

本發明優選用所述如式（I）所示化合物，或所述藥物組合物和一種或多種其它種類的治療劑聯合用於治療和/或緩解由TLR8介導的疾病，所述疾病優選為癌症。The present invention preferably uses the compound represented by formula (I), or the pharmaceutical composition in combination with one or more other types of therapeutic agents for the treatment and/or alleviation of diseases mediated by TLR8, and the diseases are preferably cancer.

本發明還進一步提供了所述如式（I）所示化合物、或所述藥物組合物和一種或多種其它種類的治療劑聯合用於治療和/或緩解癌症、病毒感染以及自身免疫性疾病。The present invention further provides that the compound represented by formula (I), or the pharmaceutical composition and one or more other kinds of therapeutic agents are used in combination for the treatment and/or alleviation of cancer, viral infection and autoimmune diseases.

本發明還進一步提供了所述如式（I）所示化合物、或所述藥物組合物和一種或多種其它種類的治療劑聯合用於治療和/或緩解癌症。The present invention further provides that the compound represented by formula (I), or the pharmaceutical composition and one or more other kinds of therapeutic agents are used in combination for treating and/or alleviating cancer.

所述其它種類的治療劑（例如：用於治療癌症的其它種類的治療劑）可以和所述的如式（I）所示化合物做成單一給藥的治療劑型，或者分別先後給藥的治療劑型。The other kinds of therapeutic agents (for example: other kinds of therapeutic agents for the treatment of cancer) can be combined with the compound represented by formula (I) to form a single-administered therapeutic dosage form, or a treatment that is administered separately and sequentially dosage form.

所述病毒感染可包括：由流感病毒、仙台病毒、柯薩奇病毒、登革熱病毒、新城疫病毒（NDV）、水泡性口炎病毒（VSV）吧、B型肝炎病毒（HBV）、C型肝炎病毒（HCV）、人類乳頭狀瘤病毒（HPV）、巨細胞病毒（CMV）、愛潑斯坦-巴爾病毒（EBV）、脊髓灰質炎病毒、皰疹病毒（HSV）（例如：水痘帶狀皰疹病毒、單純皰疹病毒及其他人類皰疹病毒）或I型人類免疫缺陷病毒（HIV）等病毒引起的感染。The viral infection may include: Influenza virus, Sendai virus, Coxsackie virus, Dengue virus, Newcastle disease virus (NDV), Vesicular stomatitis virus (VSV), Hepatitis B virus (HBV), Hepatitis C Viruses (HCV), Human Papilloma Virus (HPV), Cytomegalovirus (CMV), Epstein-Barr Virus (EBV), Poliovirus, Herpes Virus (HSV) (eg: Varicella zoster) Viruses, herpes simplex virus and other human herpes viruses) or human immunodeficiency virus type I (HIV) and other viruses.

所述的癌症包括轉移性的和非轉移性的癌症，也包括家族遺傳性的和偶發性的癌症，還可包括固體腫瘤和非固體腫瘤。Said cancer includes metastatic and non-metastatic cancer, also includes familial hereditary and sporadic cancer, and also includes solid tumor and non-solid tumor.

所述固體腫瘤的具體例子可包括但不限於：眼癌、骨癌、肺癌、胃癌、胰腺癌、乳腺癌、***癌、腦癌（包括惡性膠質瘤、成神經管細胞瘤）、卵巢癌、膀胱癌、子宮頸癌、睾丸癌、腎癌（包括腺癌和腎母細胞癌）、口腔癌（包括鱗狀細胞癌）、舌癌、喉癌、鼻咽癌、頭頸癌、結腸癌、小腸癌、直腸癌、甲狀旁腺癌、甲狀腺癌、食管癌、膽囊癌、膽管癌、肝癌、肺癌、肉瘤、和皮膚癌中的一種或多種。Specific examples of such solid tumors may include, but are not limited to, eye cancer, bone cancer, lung cancer, stomach cancer, pancreatic cancer, breast cancer, prostate cancer, brain cancer (including glioblastoma, medulloblastoma), ovarian cancer, Bladder, cervix, testicular, kidney (including adenocarcinoma and Wilms), oral cavity (including squamous cell carcinoma), tongue, larynx, nasopharyngeal, head and neck, colon, small intestine One or more of cancer, rectal cancer, parathyroid cancer, thyroid cancer, esophageal cancer, gallbladder cancer, bile duct cancer, liver cancer, lung cancer, sarcoma, and skin cancer.

所述非固體腫瘤（包括血液學腫瘤）的具體例子可包括但不限於：淋巴性白血病（包括急性淋巴細胞白血病、淋巴瘤、骨髓瘤、慢性淋巴細胞白血病、霍奇金淋巴瘤、非霍奇金淋巴瘤、T細胞慢性淋巴性白血病、B細胞慢性淋巴性白血病）、髓性相關的白血病（包括急性骨髓性白血病、慢性骨髓性白血病）和AIDs相關的白血病中的一種或多種。Specific examples of such non-solid tumors (including hematological tumors) may include, but are not limited to: lymphocytic leukemia (including acute lymphocytic leukemia, lymphoma, myeloma, chronic lymphocytic leukemia, Hodgkin lymphoma, non-Hodgkin's One or more of gold lymphoma, T-cell chronic lymphocytic leukemia, B-cell chronic lymphocytic leukemia), myeloid-related leukemia (including acute myeloid leukemia, chronic myeloid leukemia), and AIDs-related leukemia.

所述的自身免疫性疾病可包括但不限於：類風濕性關節炎、全身性紅斑狼瘡、混合性結締組織病（MCTD）、全身性硬化症（包括：CREST症候群）、皮肌炎、結節性脈管炎、腎病（包括：肺出血腎炎症候群、急性腎小球腎炎、原發性膜增殖性腎小球腎炎等）、內分泌相關疾病（包括：I型糖尿病、性腺機能不全、惡性貧血、甲狀腺機能亢進等）、肝病（包括：原發性膽汁性肝硬化、自身免疫性膽管炎、自身免疫性肝炎、原發性硬化性膽管炎等）和由於感染引起的自身免疫反應（例如：愛滋病、瘧疾等）中的一種或多種。The autoimmune diseases may include, but are not limited to: rheumatoid arthritis, systemic lupus erythematosus, mixed connective tissue disease (MCTD), systemic sclerosis (including: CREST syndrome), dermatomyositis, nodular Vasculitis, nephropathy (including: pulmonary hemorrhagic nephritis syndrome, acute glomerulonephritis, primary membranous proliferative glomerulonephritis, etc.), endocrine-related diseases (including: type I diabetes, hypogonadism, pernicious anemia, thyroid hyperactivity, etc.), liver diseases (including: primary biliary cirrhosis, autoimmune cholangitis, autoimmune hepatitis, primary sclerosing cholangitis, etc.) and autoimmune reactions due to infections (eg: AIDS, one or more of malaria, etc.).

在不違背本領域常識的基礎上，上述各優選條件，可任意組合，即得本發明各較佳實例。On the basis of not violating common knowledge in the art, the above preferred conditions can be combined arbitrarily to obtain preferred examples of the present invention.

本發明所用試劑和原料均市售可得。The reagents and raw materials used in the present invention are all commercially available.

本發明的積極進步效果在於：本發明如式（I）所示化合物的晶型具有較佳的溶解度和穩定性，更適用於藥物劑型的製備，且由如式（I）所示化合物製備得到的藥物在體內具有較佳地吸收和代謝效果。The positive improvement effect of the present invention is that: the crystal form of the compound represented by formula (I) of the present invention has better solubility and stability, is more suitable for the preparation of pharmaceutical dosage forms, and is prepared from the compound represented by formula (I) The drug has better absorption and metabolism in the body.

下面通過實施例的方式進一步說明本發明，但並不因此將本發明限制在所述的實施例範圍之中。下列實施例中未註明具體條件的實驗方法，按照常規方法和條件，或按照商品說明書選擇。The present invention is further described below by way of examples, but the present invention is not limited to the scope of the described examples. The experimental methods that do not specify specific conditions in the following examples are selected according to conventional methods and conditions, or according to the product description.

1H NMR化學位移（δ）以PPM記錄（10 -6）。NMR通過Bruker Avance III HD 400光譜儀進行。合適的溶劑是氘代氯仿（CDCl 3），氘代甲醇（CD 3OD），氘代二甲亞碸（DMSO-d6），四甲基矽烷作為內標（TMS）。 1 H NMR chemical shifts (δ) are reported in PPM ( 10-6 ). NMR was performed on a Bruker Avance III HD 400 spectrometer. Suitable solvents are deuterated chloroform (CDCl 3 ), deuterated methanol (CD 3 OD), deuterated dimethylsulfite (DMSO-d6), tetramethylsilane as internal standard (TMS).

固體樣品用粉末X射線衍射分析儀(Bruker D8 advance)進行分析。該儀器配備了SSD160探測器，樣品的2θ掃描角度範圍為3°到40°，掃描步長為0.02°。測定樣品時的光管電壓和光管電流分別為40KV和40mA。Solid samples were analyzed with a powder X-ray diffraction analyzer (Bruker D8 advance). The instrument is equipped with an SSD160 detector, and the 2θ scan angle of the sample ranges from 3° to 40° with a scan step size of 0.02°. The light tube voltage and light tube current when measuring the sample were 40KV and 40mA, respectively.

示差掃描量熱分析(DSC)的儀器型號為TA Discovery DSC 250。樣品經精確稱重後置於加蓋Tzero樣品盤中，並記錄下樣品的準確質量。樣品以10℃/min的升溫速率加熱至最終溫度。The instrument model for differential scanning calorimetry (DSC) was TA Discovery DSC 250. The sample is accurately weighed and placed in a capped Tzero sample pan, and the exact mass of the sample is recorded. The sample was heated to the final temperature at a ramp rate of 10°C/min.

熱重分析(TGA)的儀器型號為Discovery TGA 550。將樣品置於已平衡的樣品盤中，樣品量在TGA加熱爐內自動稱量。樣品以10℃/min的速率加熱至最終溫度。The instrument model for thermogravimetric analysis (TGA) was Discovery TGA 550. The sample is placed in an equilibrated sample pan and the sample amount is automatically weighed in a TGA oven. The sample was heated to the final temperature at a rate of 10°C/min.

氣相分析色譜（GC）的儀器型號為安捷倫7890B氣相色譜儀。The instrument model of gas analytical chromatography (GC) is Agilent 7890B gas chromatograph.

K-F水分檢測使用870 KF Titrino plus 水分滴定儀。The K-F moisture test uses the 870 KF Titrino plus moisture titrator.

離子色譜使用Thermo Fisher ICS-1100離子色譜儀，色譜柱：AS11-HC 4*250mm，沖提液25mmol的氫氧化鉀水溶液，流速：1mL/分鐘。Ion chromatography uses Thermo Fisher ICS-1100 ion chromatograph, chromatographic column: AS11-HC 4*250mm, 25 mmol potassium hydroxide aqueous solution of eluent, flow rate: 1 mL/min.

以下實施例中，化合物1-8-5指參照專利CN107344931A實施例52的方法制得的化合物1-8-5，用粉末X射線衍射分析儀(Bruker D8 advance)對其產物進行分析，其XRPD圖譜如圖1所示，結果顯示，該方法製得的化合物為非晶形（無定形）化合物。In the following examples, compound 1-8-5 refers to compound 1-8-5 obtained by referring to the method in Example 52 of Patent CN107344931A. The product was analyzed by powder X-ray diffraction analyzer (Bruker D8 advance), and its XRPD The spectrum is shown in Figure 1, and the results show that the compound prepared by this method is an amorphous (amorphous) compound.

實施例 12-胺基-8-(2-(2-(甲磺醯基)乙基)-1-氧代-1,2-二氫酞嗪-6-基)-N,N-二異丙基-3H-苯并氮雜卓-4-甲醯胺（化合物A）的合成 Example 1 2-amino-8-(2-(2-(methylsulfonyl)ethyl)-1-oxo-1,2-dihydrophthalazin-6-yl)-N,N-di Synthesis of isopropyl-3H-benzazepine-4-carboxamide (compound A)

方法1：

Figure 02_image025
Figure 02_image027
method 1:
Figure 02_image025
Figure 02_image027

步驟1：氮氣保護下，向化合物1.10（2.1g，1eq）的四氫呋喃（90mL）溶液中依次加入化合物22.7（2.7g，1.5eq）、碳酸鈉水溶液（29.2mL，2.0M）和Pd(dppf) 2Cl 2（369mg，0.1當量），加畢，反應體系用氮氣置換三次，反應體系在70℃下攪拌直到TLC檢測反應完成（約1.5小時）。向反應體系中加入水（50mL）淬滅反應，混合物用乙酸乙酯（150mL×3）萃取，合併有機相，有機相用飽和食鹽水洗滌，分離有機相，用無水硫酸鈉乾燥，過濾、濃縮，得到的殘留物用矽膠柱層析（石油醚/乙酸乙酯=4/1~1/1）純化得到中間體1（3.16g）為淺黃色泡沫狀固體。 Step 1: Under nitrogen protection, to a solution of compound 1.10 (2.1 g, 1 eq) in tetrahydrofuran (90 mL) was added compound 22.7 (2.7 g, 1.5 eq), aqueous sodium carbonate (29.2 mL, 2.0 M) and Pd(dppf) in sequence 2 Cl 2 (369 mg, 0.1 equiv) was added, the reaction was flushed with nitrogen three times, and the reaction was stirred at 70°C until complete by TLC (about 1.5 hours). Water (50 mL) was added to the reaction system to quench the reaction, the mixture was extracted with ethyl acetate (150 mL×3), the organic phases were combined, the organic phases were washed with saturated brine, the organic phase was separated, dried over anhydrous sodium sulfate, filtered and concentrated , the obtained residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate=4/1~1/1) to obtain Intermediate 1 (3.16g) as a pale yellow foamy solid.

步驟2：冰浴條件下，向中間體1（2.16g）的二氯甲烷（22mL）溶液中加入三氟乙酸（3.24 mL），加畢，反應體系在室溫下攪拌4小時。減壓除去溶劑，得到的殘留物重新加入到二氯甲烷（50mL）中，溶清後加入活性炭（2g）攪拌10分鐘，過濾，濾液減壓濃縮，得到的固體重新溶解在二氯甲烷（50mL）和甲醇（5mL）中，加入飽和的碳酸氫鈉水溶液（20mL），攪拌10分鐘，靜置分層。分離有機相，水相用二氯甲烷萃取（20mL×2），合併有機相並用無水硫酸鈉乾燥，過濾，濾液減壓濃縮得到化合物A（1.01g）為類白色固體。Step 2: Trifluoroacetic acid (3.24 mL) was added to a solution of intermediate 1 (2.16 g) in dichloromethane (22 mL) under ice bath condition, and the reaction system was stirred at room temperature for 4 hours. The solvent was removed under reduced pressure, and the obtained residue was re-added to dichloromethane (50 mL). After dissolving, activated carbon (2 g) was added to stir for 10 minutes, filtered, and the filtrate was concentrated under reduced pressure. The obtained solid was redissolved in dichloromethane (50 mL). ) and methanol (5 mL), added saturated aqueous sodium bicarbonate solution (20 mL), stirred for 10 minutes, and allowed to stand to separate the layers. The organic phase was separated, the aqueous phase was extracted with dichloromethane (20 mL×2), the organic phases were combined and dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain compound A (1.01 g) as an off-white solid.

方法2：向化合物A的鹽酸鹽醋酸溶劑合物（15g）中分別加入二氯甲烷（210mL）和無水乙醇（105mL），室溫攪拌溶清；加入飽和碳酸氫鈉水溶液約（113mL）調pH至8左右，分液；有機層用飽和氯化鈉溶液（200mL）洗滌1次，分離有機層並用無水硫酸鈉乾燥，過濾，濾液在40℃下減壓濃縮至乾，得到化合物A（12.5g）為淺黃色固體。Method 2: Add dichloromethane (210 mL) and absolute ethanol (105 mL) to the hydrochloride acetic acid solvate (15 g) of compound A, respectively, and stir to dissolve at room temperature; add saturated aqueous sodium bicarbonate solution (113 mL) to adjust The pH was about 8, and the layers were separated; the organic layer was washed once with saturated sodium chloride solution (200 mL), the organic layer was separated and dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure at 40 °C to obtain compound A (12.5 g) is a pale yellow solid.

實施例 2化合物A的晶型I Example 2 Crystal Form I of Compound A

將化合物A（1g）加入無水乙醇（40mL），溶清後超音波5-10分鐘，析出固體後繼續攪拌1小時，過濾，濾餅室溫下真空乾燥過夜得到化合物A，其為類白色固體，為化合物A的晶型I。並分別進行了XRPD、DSC、TGA和 1H NMR表徵，其結果分別如圖2、圖3、圖4和圖5所示。 Compound A (1 g) was added to absolute ethanol (40 mL), and after dissolving, ultrasonicated for 5-10 minutes. After the solid was precipitated, the mixture was stirred for 1 hour, filtered, and the filter cake was vacuum-dried at room temperature overnight to obtain compound A, which was an off-white solid. , which is the crystal form I of compound A. The XRPD, DSC, TGA and 1 H NMR characterizations were carried out respectively, and the results are shown in Figure 2, Figure 3, Figure 4 and Figure 5, respectively.

實施例 3化合物A的醋酸溶劑合物晶型I Example 3 The acetic acid solvate crystal form I of compound A

將化合物A（1g，1eq）溶解在二氯甲烷（8mL）和甲醇（4mL）的混合溶劑中，加入醋酸（224mg，2eq），得到的溶液室溫攪拌0.5小時後加入乙酸乙酯（20mL）繼續攪拌1h析晶，過濾，得到的固體50℃真空乾燥4小時得到相應的化合物A的醋酸溶劑合物晶型I。樣品為類白色粉末，並分別進行了XRPD、DSC、TGA和 1H NMR表徵。 Compound A (1 g, 1 eq) was dissolved in a mixed solvent of dichloromethane (8 mL) and methanol (4 mL), acetic acid (224 mg, 2 eq) was added, the resulting solution was stirred at room temperature for 0.5 hours, and then ethyl acetate (20 mL) was added. Continue stirring for 1 hour for crystallization, filter, and vacuum dry the obtained solid at 50° C. for 4 hours to obtain the corresponding acetic acid solvate crystal form I of compound A. The samples were off-white powders, and were characterized by XRPD, DSC, TGA and 1 H NMR, respectively.

如圖9所示， 1H NMR結果顯示樣品無溶劑殘留，且游離鹼和醋酸的比例約為1:1。如圖8所示，TGA在175℃之前有10.16%的失重。如圖7所示，DSC圖譜顯示其吸熱峰的溫度約在167.21℃和238.50℃。如圖6所示XRPD檢測證明為化合物A的醋酸溶劑合物晶型I。化合物A的醋酸溶劑合物晶型I的XRPD衍射峰如表1所示。 As shown in Figure 9, the 1 H NMR results showed that the sample had no solvent residue and that the ratio of free base to acetic acid was approximately 1:1. As shown in Figure 8, TGA has a weight loss of 10.16% before 175 °C. As shown in Fig. 7, the DSC spectrum shows that the temperature of its endothermic peak is about 167.21°C and 238.50°C. As shown in Figure 6, XRPD detection proved to be the acetic acid solvate crystal form I of compound A. The XRPD diffraction peaks of the acetic acid solvate crystal form I of Compound A are shown in Table 1.

表1. 化合物A的醋酸溶劑合物晶型I的XRPD衍射峰列表 角度2θ/° 相對強度% 角度2θ/° 相對強度% 角度2θ/° 相對強度% 4.911 26.0 5.337 38.6 5.849 6.8 8.467 55.7 10.129 50.2 10.761 100.0 11.803 49.8 12.851 9.6 13.953 21.5 15.184 20.9 15.766 30.2 17.074 19.9 17.605 10.5 18.738 41.4 20.442 30.7 21.671 24.5 23.670 10.3 23.940 9.1 25.875 12.6         Table 1. XRPD Diffraction Peak List of Compound A's Acetic Acid Solvate Form I Angle 2θ/° Relative Strength% Angle 2θ/° Relative Strength% Angle 2θ/° Relative Strength% 4.911 26.0 5.337 38.6 5.849 6.8 8.467 55.7 10.129 50.2 10.761 100.0 11.803 49.8 12.851 9.6 13.953 21.5 15.184 20.9 15.766 30.2 17.074 19.9 17.605 10.5 18.738 41.4 20.442 30.7 21.671 24.5 23.670 10.3 23.940 9.1 25.875 12.6

實施例 4化合物A的醋酸溶劑合物晶型II Example 4 The acetic acid solvate crystal form II of compound A

方法1：取化合物A（506mg），加入醋酸（1.25mL），升溫至79.5℃溶清，立刻滴加乙酸乙酯（10mL），約30秒加完，加的過程即有白色固體析出，立刻置於室溫下攪拌析晶2.5小時，過濾，濾餅用乙酸乙酯（1mL）淋洗。得到的固體40℃真空乾燥4小時得到相應的化合物A的醋酸溶劑合物晶型II。樣品為類白色粉末。Method 1: Take compound A (506 mg), add acetic acid (1.25 mL), warm up to 79.5 ℃ to dissolve the clear liquid, immediately add ethyl acetate (10 mL) dropwise, and finish the addition in about 30 seconds. The mixture was stirred and crystallized at room temperature for 2.5 hours, filtered, and the filter cake was rinsed with ethyl acetate (1 mL). The obtained solid was dried under vacuum at 40° C. for 4 hours to obtain the corresponding acetic acid solvate crystal form II of Compound A. The sample is an off-white powder.

方法2：取化合物A（7.26g），加入醋酸（18mL），升溫至80℃溶清，保溫80℃滴加乙酸乙酯（180mL），約30秒加完，加的過程即有白色固體析出，立刻置於室溫下攪拌析晶0.5小時，冰水浴0.5小時，過濾，濾餅用乙酸乙酯（20mL）淋洗。得到的固體45℃真空乾燥1.5小時得到相應的化合物A的醋酸溶劑合物晶型II。樣品為類白色粉末。Method 2: Take compound A (7.26g), add acetic acid (18mL), heat up to 80°C to dissolve the liquid, keep at 80°C and add dropwise ethyl acetate (180mL), the addition is completed in about 30 seconds, and a white solid is precipitated during the addition process , immediately placed at room temperature and stirred for crystallization for 0.5 hours, ice-water bath for 0.5 hours, filtered, and the filter cake was rinsed with ethyl acetate (20 mL). The obtained solid was dried under vacuum at 45°C for 1.5 hours to obtain the corresponding acetic acid solvate crystal form II of compound A. The sample is an off-white powder.

化合物A的醋酸溶劑合物晶型II的檢測結果如下：如圖13所示， 1H NMR結果顯示樣品無溶劑殘留，且游離鹼和醋酸的比例約為1:2。如圖12所示，TGA在175℃之前有11.58%的失重。如圖11所示，DSC圖譜顯示其吸熱峰的溫度約在115.79℃。如圖10所示XRPD檢測證明為化合物A的醋酸溶劑合物晶型II。化合物A的醋酸溶劑合物晶型II的XRPD衍射峰如表2所示。如圖23所示，光照4500lux和40℃-92.5%RH帶包裝條件下放置31天，晶型均不變。 The detection results of the acetic acid solvate crystal form II of Compound A are as follows: As shown in Figure 13, 1 H NMR results show that the sample has no solvent residue, and the ratio of free base to acetic acid is about 1:2. As shown in Fig. 12, TGA has a weight loss of 11.58% before 175 °C. As shown in Figure 11, the DSC spectrum shows that the temperature of its endothermic peak is about 115.79°C. As shown in Figure 10, XRPD detection proved to be the acetic acid solvate crystal form II of Compound A. The XRPD diffraction peaks of the acetic acid solvate crystal form II of Compound A are shown in Table 2. As shown in Figure 23, the crystal form remained unchanged after being placed under the conditions of 4500 lux and 40 ℃-92.5% RH with packaging for 31 days.

表2. 化合物A的醋酸溶劑合物晶型II的XRPD衍射峰列表 角度2θ/° 相對強度% 角度2θ/° 相對強度% 角度2θ/° 相對強度% 6.518 100.0 7.081 62.3 7.491 6.1 13.700 9.1 14.739 3.9 15.059 3.8 18.501 3.9 18.759 3.8 19.404 5.7 20.099 18.2 20.799 4.5 21.838 3.6 23.081 4.0 24.543 6.8 24.835 5.2 Table 2. XRPD Diffraction Peak List of Compound A's Acetic Acid Solvate Form II Angle 2θ/° Relative Strength% Angle 2θ/° Relative Strength% Angle 2θ/° Relative Strength% 6.518 100.0 7.081 62.3 7.491 6.1 13.700 9.1 14.739 3.9 15.059 3.8 18.501 3.9 18.759 3.8 19.404 5.7 20.099 18.2 20.799 4.5 21.838 3.6 23.081 4.0 24.543 6.8 24.835 5.2

實施例 5化合物A的鹽酸鹽乙醇溶劑合物晶型I Example 5 The hydrochloride ethanol solvate crystal form I of compound A

取實施例1製備的化合物A（100mg），加入乙醇（4mL），得到的渾濁液在室溫攪拌下加入濃鹽酸（21mg）的乙醇溶液，析出固體，室溫下攪拌3天，過濾，濾餅45℃鼓風乾燥2小時得到化合物A的鹽酸鹽乙醇溶劑合物晶型I。樣品為白色粉末。並分別進行了XRPD和TGA表徵。Take Compound A (100 mg) prepared in Example 1, add ethanol (4 mL), and add an ethanol solution of concentrated hydrochloric acid (21 mg) to the resulting turbid solution at room temperature with stirring to precipitate a solid, stir at room temperature for 3 days, filter, filter The cake was air-dried at 45°C for 2 hours to obtain the crystalline form I of the hydrochloride ethanol solvate of Compound A. The sample is a white powder. And XRPD and TGA characterizations were carried out, respectively.

如圖15所示，TGA在125℃之前有12.74%的失重，GC色譜檢測乙醇含量約為10.5%，游離鹼和乙醇的比例約為1:1.5，如圖14所示XRPD檢測證明為化合物A的鹽酸鹽乙醇溶劑合物晶型，化合物A的鹽酸鹽乙醇溶劑合物晶型I的XRPD衍射峰如表3所示。As shown in Figure 15, TGA has a weight loss of 12.74% before 125 °C, the ethanol content detected by GC chromatography is about 10.5%, and the ratio of free base to ethanol is about 1:1.5. As shown in Figure 14, XRPD detection proved to be Compound A Table 3 shows the XRPD diffraction peaks of the hydrochloride ethanol solvate crystal form of Compound A, and the hydrochloride ethanol solvate crystal form I of Compound A.

表3. 化合物A的鹽酸鹽乙醇溶劑合物晶型I的XRPD衍射峰列表 角度2θ/° 相對強度% 角度2θ/° 相對強度% 角度2θ/° 相對強度% 6.454 100.0 7.239 27.0 9.157 11.9 11.702 12.5 12.966 7.2 13.417 4.9 16.183 4.5 19.496 7.5 20.229 10.5 20.679 7.3 21.964 12.8 22.397 6.7 23.545 8.8 25.181 9.0 26.068 9.5 Table 3. XRPD Diffraction Peak List of Compound A Hydrochloride Ethanol Solvate Form I Angle 2θ/° Relative Strength% Angle 2θ/° Relative Strength% Angle 2θ/° Relative Strength% 6.454 100.0 7.239 27.0 9.157 11.9 11.702 12.5 12.966 7.2 13.417 4.9 16.183 4.5 19.496 7.5 20.229 10.5 20.679 7.3 21.964 12.8 22.397 6.7 23.545 8.8 25.181 9.0 26.068 9.5

實施例 6化合物A的鹽酸鹽醋酸溶劑合物晶型I Example 6 The hydrochloride acetic acid solvate crystal form I of compound A

方法1：取化合物A（300mg，1eq），加入醋酸（6mL），加熱至60℃，攪拌十分鐘後加入濃鹽酸（60mg，1.05eq），降至室溫析出固體，然後在室溫下攪拌1天，過濾，濾餅45℃鼓風乾燥4小時得到化合物A的鹽酸鹽醋酸溶劑合物晶型I。樣品為白色粉末。Method 1: Take compound A (300mg, 1eq), add acetic acid (6mL), heat to 60°C, stir for ten minutes, add concentrated hydrochloric acid (60mg, 1.05eq), cool to room temperature to precipitate solids, then stir at room temperature 1 day, filtered, and the filter cake was dried at 45° C. for 4 hours to obtain the crystalline form I of the hydrochloride acetic acid solvate of Compound A. The sample is a white powder.

方法2：取化合物1-8-5（100g，1eq），加入醋酸（750mL），加熱至60℃。加入活性炭（10g）攪拌10分鐘，過濾（重複兩次），攪拌下40℃條件下加入氯化氫乙醇溶液（10%，112g，2eq），加入醋酸（100mL）後降溫析出固體，過濾，濾餅加入到預熱的醋酸（500mL）中，加畢，向體系中繼續加入醋酸（500mL），90℃下攪拌1小時，冷卻至室溫析晶體。過濾，濾餅45℃鼓風乾燥6小時得到化合物A的鹽酸鹽醋酸溶劑合物晶型I。樣品為類白色粉末。Method 2: Take compound 1-8-5 (100 g, 1 eq), add acetic acid (750 mL), and heat to 60°C. Add activated carbon (10g), stir for 10 minutes, filter (repeated twice), add hydrogen chloride ethanol solution (10%, 112g, 2eq) under stirring at 40°C, add acetic acid (100mL), cool down and precipitate solids, filter, add to filter cake Add to preheated acetic acid (500 mL), add acetic acid (500 mL) to the system, stir at 90°C for 1 hour, cool to room temperature for crystallization. After filtration, the filter cake was dried by air at 45°C for 6 hours to obtain the crystalline form I of the hydrochloride acetic acid solvate of Compound A. The sample is an off-white powder.

化合物A的鹽酸鹽醋酸溶劑合物晶型I的檢測結果如下：如圖17所示， 1H NMR顯示化合物A和醋酸比例為1:2。如圖16所示XRPD檢測證明為化合物A的鹽酸鹽醋酸溶劑合物晶型I，化合物A的鹽酸鹽醋酸溶劑合物晶型I的XRPD衍射峰如表4所示。 The detection results of the hydrochloride acetic acid solvate crystal form I of Compound A are as follows: As shown in Figure 17, 1 H NMR shows that the ratio of Compound A and acetic acid is 1:2. As shown in Figure 16, XRPD detection proved to be the hydrochloride acetic acid solvate crystal form I of Compound A, and the XRPD diffraction peaks of the hydrochloride acetic acid solvate crystal form I of Compound A are shown in Table 4.

表4. 化合物A的鹽酸鹽醋酸溶劑合物晶型I的XRPD衍射峰列表 角度2θ/° 相對強度% 角度2θ/° 相對強度% 角度2θ/° 相對強度% 6.539 100.0 7.019 2.8 7.534 4.6 15.942 1.6 18.416 1.9 18.763 3.8 19.441 2.9 19.739 4.4 20.700 3.4 20.898 6.3 21.741 2.0 22.720 2.0 24.505 2.7 24.878 3.3 26.421 4.2 Table 4. XRPD Diffraction Peak List of Compound A's Hydrochloride Acetic Acid Solvate Form I Angle 2θ/° Relative Strength% Angle 2θ/° Relative Strength% Angle 2θ/° Relative Strength% 6.539 100.0 7.019 2.8 7.534 4.6 15.942 1.6 18.416 1.9 18.763 3.8 19.441 2.9 19.739 4.4 20.700 3.4 20.898 6.3 21.741 2.0 22.720 2.0 24.505 2.7 24.878 3.3 26.421 4.2

實施例 7化合物A的鹽酸鹽的製備 Example 7 Preparation of the hydrochloride of compound A

向化合物A（200mg，1eq）中加入乙醇（4mL），向得到的渾濁液中加入氯化氫乙醇溶液（2M，0.6mL，3.2eq），繼續攪拌1小時，加入水（20mL）後直接冷凍乾燥得到化合物A的鹽酸鹽，為類白色粉末。如圖25所示， 1H NMR結果顯示樣品無乙醇溶劑殘留。 Ethanol (4 mL) was added to compound A (200 mg, 1 eq), and ethanolic hydrogen chloride solution (2M, 0.6 mL, 3.2 eq) was added to the resulting turbid solution, and the stirring was continued for 1 hour. After adding water (20 mL), it was directly lyophilized to obtain The hydrochloride salt of compound A is an off-white powder. As shown in Figure 25, the 1 H NMR results showed that the sample had no residual ethanol solvent.

m/z: [M+H] +535.8; 1H NMR (400 MHz, DMSO-d 6): δ 12.39 (s, 1H), 9.93 (s, 1H), 9.10 (s, 1H), 8.57 (s, 1H), 8.40 (d, J=8.4 Hz, 1H), 8.35 (d, J=1.2 Hz, 1H), 8.22 (dd, J=8.4 Hz, J=1.6 Hz, 1H), 7.88-7.74 (m, 3H), 7.07 (s, 1H), 4.60 (d, J=6.8 Hz, 2H), 3.66 (d, J=6.8 Hz, 2H), 3.36 (6H,被溶劑峰覆蓋), 3.10 (s, 3H), 1.59 (d, J=7.2 Hz, 4H), 0.91-0.82 (m, 6H)。 m/z: [M+H] + 535.8; 1 H NMR (400 MHz, DMSO-d 6 ): δ 12.39 (s, 1H), 9.93 (s, 1H), 9.10 (s, 1H), 8.57 (s , 1H), 8.40 (d, J=8.4 Hz, 1H), 8.35 (d, J=1.2 Hz, 1H), 8.22 (dd, J=8.4 Hz, J=1.6 Hz, 1H), 7.88-7.74 (m , 3H), 7.07 (s, 1H), 4.60 (d, J=6.8 Hz, 2H), 3.66 (d, J=6.8 Hz, 2H), 3.36 (6H, covered by solvent peak), 3.10 (s, 3H ), 1.59 (d, J=7.2 Hz, 4H), 0.91-0.82 (m, 6H).

實施例 8化合物A的鹽酸鹽水合物晶型I Example 8 Hydrochloride Hydrate Hydrate Form I of Compound A

方法1：向化合物A的鹽酸鹽乙醇溶劑合物（1g）中加入水（3mL），加熱至65℃，溶清，向體系中加入異丙醇（3mL），體系降至室溫攪拌1小時後冰浴冷卻下析晶，過濾，得到的固體45℃鼓風乾燥2小時得到相應的化合物A的鹽酸鹽水合物晶型I。樣品為類白色粉末。Method 1: Add water (3 mL) to the hydrochloride ethanol solvate of Compound A (1 g), heat to 65 °C, dissolve it, add isopropanol (3 mL) to the system, and the system is cooled to room temperature and stirred for 1 After 1 hour, it was crystallized under ice-cooling, filtered, and the obtained solid was dried at 45° C. for 2 hours to obtain the corresponding crystalline form I of the hydrochloride salt of Compound A. The sample is an off-white powder.

方法2：向化合物A的鹽酸鹽醋酸溶劑合物（100mg）中加入75%異丙醇-水混合溶液（0.8mL），先溶清後繼續攪拌約0.5小時析出固體，過濾，得到的固體45℃鼓風乾燥2小時得到相應的化合物A的鹽酸鹽水合物晶型I。樣品為白色粉末。Method 2: Add 75% isopropanol-water mixed solution (0.8 mL) to the hydrochloride acetic acid solvate of Compound A (100 mg), dissolve it first, then continue to stir for about 0.5 hours to precipitate a solid, filter to obtain a solid Blow drying at 45°C for 2 hours to obtain the corresponding crystalline form I of the hydrochloride salt of Compound A. The sample is a white powder.

方法3：向化合物A的鹽酸鹽醋酸溶劑合物（100mg）中加入85%異丙醇-水混合溶液（0.9mL），加熱至50℃溶清，立即取出置於室溫下晶漿，約10分鐘後析出固體，過濾，得到的固體45℃鼓風乾燥2小時得到相應的化合物A的鹽酸鹽水合物晶型I。樣品為白色粉末。Method 3: Add 85% isopropanol-water mixed solution (0.9 mL) to the hydrochloride acetic acid solvate of compound A (100 mg), heat to 50 °C to dissolve, immediately take out the crystal slurry and place it at room temperature, After about 10 minutes, a solid was precipitated, which was filtered, and the obtained solid was air-dried at 45° C. for 2 hours to obtain the corresponding crystalline form I of the hydrochloride salt of Compound A. The sample is a white powder.

方法4：向化合物A的鹽酸鹽（100mg）中加入75%異丙醇-水混合溶液（0.8mL），先溶清後繼續攪拌約1小時析出固體，過濾，得到的固體45℃鼓風乾燥2小時得到相應的化合物A的鹽酸鹽水合物晶型I。樣品為類白色粉末。Method 4: Add 75% isopropanol-water mixed solution (0.8 mL) to the hydrochloride of compound A (100 mg), dissolve it first, then continue to stir for about 1 hour to precipitate a solid, filter, and the obtained solid is blown at 45°C Drying for 2 hours gave the corresponding Compound A hydrochloride hydrate Form I. The sample is an off-white powder.

方法5：將化合物A（1g，1eq）溶解在二氯甲烷（8mL）和甲醇（4mL）的混合溶劑中，加入氯化氫乙醇溶液（30%，0.45g，2eq），溶清後加入乙酸乙酯（20mL），析出固體，減壓濃縮除去溶劑後加入二氯甲烷和甲醇混合溶液（5mL，2/1），再加入水（20mL）和丙酮（20mL），過濾，得到的固體50℃真空乾燥4小時得到相應的化合物A的鹽酸鹽水合物晶型I。樣品為類白色固體。Method 5: Dissolve compound A (1g, 1eq) in a mixed solvent of dichloromethane (8mL) and methanol (4mL), add ethanolic hydrogen chloride solution (30%, 0.45g, 2eq), add ethyl acetate after dissolving (20 mL), a solid was precipitated, concentrated under reduced pressure to remove the solvent, and then a mixed solution of dichloromethane and methanol (5 mL, 2/1) was added, and then water (20 mL) and acetone (20 mL) were added, filtered, and the obtained solid was vacuum-dried at 50 °C The corresponding Compound A hydrochloride hydrate Form I was obtained in 4 hours. The sample was an off-white solid.

方法6：向化合物A（12.47g，1eq）中加入異丙醇（36mL），得到的渾濁液用冰水浴保溫，攪拌下加入濃鹽酸（2.46g，1.05eq）和水（5mL）的混合液，加完後再加入水（31mL），除去冰水浴，室溫攪拌，溶清，室溫攪拌10分鐘後加入約5mg左右的晶種（晶種是根據上述方法1~5任一方案製備得到的化合物A的鹽酸水合物晶型I），慢慢大量固體析出，1小時後補加50%異丙醇-水混合溶液（10mL），繼續攪拌約45分鐘，過濾，濾餅用少量50%異丙醇-水混合液淋洗，得到的固體35℃鼓風乾燥5小時得到相應的化合物A的鹽酸鹽水合物晶型I。樣品為類白色粉末。Method 6: To compound A (12.47g, 1eq) was added isopropanol (36mL), the resulting turbid solution was kept in an ice-water bath, and a mixture of concentrated hydrochloric acid (2.46g, 1.05eq) and water (5mL) was added under stirring , add water (31 mL) after adding, remove the ice-water bath, stir at room temperature, dissolve clear, stir at room temperature for 10 minutes, and then add about 5 mg of seed crystals (the seed crystals are prepared according to any of the above methods 1 to 5) The hydrochloric acid hydrate crystal form I of compound A) slowly precipitated out a large amount of solid, add 50% isopropanol-water mixed solution (10 mL) after 1 hour, continue to stir for about 45 minutes, filter, filter cake with a small amount of 50% The isopropanol-water mixture was rinsed, and the obtained solid was dried at 35° C. for 5 hours by blowing to obtain the corresponding crystalline form I of the hydrochloride salt of Compound A. The sample is an off-white powder.

化合物A的鹽酸鹽水合物晶型I的檢測結果如下：如圖21所示， 1H NMR結果顯示樣品無溶劑殘留。如圖20所示，TGA在125℃之前有6.052%的失重（與結構中含2分子結晶水的理論值（5.93%）基本相符）。K-F水分檢測，含水量約為6.2%，游離鹼和水的比例約為1:2。如圖19所示，DSC圖譜顯示其吸熱峰的溫度約在136.25℃。離子色譜分析檢測氯離子含量測定平均值%為5.81（理論值為5.83%），說明游離鹼和鹽酸的比例為1:1。如圖18所示，XRPD檢測證明為鹽酸鹽水合物晶型。如圖22所示，樣品分別在高溫60℃、光照4500lux、高濕92.5%RH、40℃-92.5%RH裸放和40℃-92.5%RH帶包裝條件下放置31天，晶型均無明顯變化。如圖24所示，樣品在溫度25℃±2℃，相對濕度為60%±5%條件下放置12個月晶型無明顯變化。化合物A的鹽酸鹽水合物晶型I的XRPD衍射峰列表如表5所示。 The detection results of the hydrochloride hydrate crystal form I of Compound A are as follows: As shown in Figure 21, 1 H NMR results show that the sample has no solvent residue. As shown in Figure 20, TGA has a weight loss of 6.052% before 125 °C (which is basically consistent with the theoretical value (5.93%) containing 2 molecules of crystal water in the structure). KF moisture test, the moisture content is about 6.2%, and the ratio of free alkali and water is about 1:2. As shown in Figure 19, the DSC spectrum shows that the temperature of its endothermic peak is about 136.25°C. The average % of chloride ion content determined by ion chromatography was 5.81 (theoretical value was 5.83%), indicating that the ratio of free base and hydrochloric acid was 1:1. As shown in Figure 18, XRPD detection proved to be the hydrochloride hydrate crystalline form. As shown in Figure 22, the samples were placed under the conditions of high temperature 60℃, light 4500lux, high humidity 92.5%RH, 40℃-92.5%RH bare and 40℃-92.5%RH with packaging for 31 days, and there was no obvious crystal form. Variety. As shown in Figure 24, the crystal form of the sample has no obvious change after being placed for 12 months at a temperature of 25 °C ± 2 °C and a relative humidity of 60% ± 5%. The XRPD diffraction peak list of the hydrochloride hydrate crystal form I of Compound A is shown in Table 5.

表5. 化合物A的鹽酸鹽水合物晶型I的XRPD衍射峰列表 角度2θ/° 相對強度% 角度2θ/° 相對強度% 角度2θ/° 相對強度% 7.082 9.7 9.793 100.0 10.477 54.9 12.470 20.7 12.834 6.9 13.987 15.5 15.635 23.8 17.404 33.69 17.937 14.8 18.686 6.8 19.027 16.6 19.674 48.6 20.294 15.8 21.534 9.8 22.000 11.0 22.669 70.2 23.613 6.5 24.438 10.6 24.803 15.1 25.191 22.0 26.005 9.6 26.815 26.3 29.283 11.3 29.937 6.0 32.029 5.2 34.121 9.1     Table 5. XRPD Diffraction Peak List of Compound A's Hydrochloride Hydrate Crystalline Form I Angle 2θ/° Relative Strength% Angle 2θ/° Relative Strength% Angle 2θ/° Relative Strength% 7.082 9.7 9.793 100.0 10.477 54.9 12.470 20.7 12.834 6.9 13.987 15.5 15.635 23.8 17.404 33.69 17.937 14.8 18.686 6.8 19.027 16.6 19.674 48.6 20.294 15.8 21.534 9.8 22.000 11.0 22.669 70.2 23.613 6.5 24.438 10.6 24.803 15.1 25.191 22.0 26.005 9.6 26.815 26.3 29.283 11.3 29.937 6.0 32.029 5.2 34.121 9.1

實施例 9穩定性試驗 Example 9 Stability Test

為考察化合物A的溶劑合物的晶型以及化合物A的鹽酸鹽溶劑合物的晶型的穩定性，分別測試，In order to investigate the stability of the crystalline form of the solvate of Compound A and the crystalline form of the hydrochloride solvate of Compound A, test, respectively,

1）高溫60℃、光照4500lux和高濕92.5%RH條件下對樣品穩定性的影響，影響因素測試條件如下： 高溫60℃：取樣品適量，平鋪於培養皿中，厚度不超過3mm，敞口置於60℃高溫箱內。 高濕92.5%RH：取樣品適量，平鋪於培養皿中，厚度不超過3mm，敞口置於硝酸鉀飽和溶液飽和的乾燥器內。 光照4500lux：取樣品適量，平鋪於培養皿中，厚度不超過3mm，敞口置於4500lux強度的光照箱內。 分別在第0天、5天、10天和30天通過HPLC測試樣品純度。 1) The influence of high temperature 60°C, light 4500lux and high humidity 92.5%RH on the stability of the sample, the influencing factors test conditions are as follows: High temperature 60°C: Take an appropriate amount of sample, spread it in a petri dish with a thickness of no more than 3mm, and place it in a 60°C high temperature box. High humidity 92.5% RH: Take an appropriate amount of sample, spread it in a petri dish with a thickness of no more than 3 mm, and place the open mouth in a desiccator saturated with potassium nitrate saturated solution. Illumination 4500 lux: Take an appropriate amount of the sample, spread it in a petri dish with a thickness of no more than 3 mm, and place the open opening in a light box with an intensity of 4500 lux. Sample purity was tested by HPLC on days 0, 5, 10 and 30, respectively.

色譜分析方法示例如下： 色譜柱：waters Xselect CSH TMC18，4.6mm*250mm，5μm。 移動相A：10mM磷酸二氫鉀（用磷酸調pH值至值2.5）；移動相B：乙腈；流速：1.0毫升/分鐘；柱溫：35℃；波長：262nm；進樣量：10μL；如表6所示為沖提梯度。 Examples of chromatographic analysis methods are as follows: Chromatographic column: waters Xselect CSH ™ C18, 4.6mm*250mm, 5μm. Mobile phase A: 10 mM potassium dihydrogen phosphate (adjust pH to 2.5 with phosphoric acid); mobile phase B: acetonitrile; flow rate: 1.0 ml/min; column temperature: 35 °C; wavelength: 262 nm; injection volume: 10 μL; Table 6 shows the elution gradients.

表6 時間（min） A（%） B（%） 0 85 15 15 65 35 25 50 50 30 30 70 30.1 85 15 45 85 15 Table 6 time (min) A (%) B (%) 0 85 15 15 65 35 25 50 50 30 30 70 30.1 85 15 45 85 15

如表7所示為CN107344931A公開的化合物1-8-5、化合物A的溶劑合物的晶型以及化合物A的鹽酸鹽溶劑合物的晶型的影響因素檢測結果。Table 7 shows the detection results of influencing factors of compound 1-8-5, the crystal form of compound A solvate and the crystal form of compound A hydrochloride solvate disclosed in CN107344931A.

表7 樣品名稱   0天 高溫60℃ 高濕92.5%RH 光照4500lux 5天 10天 30天 5天 10天 30天 5天 10天 30天 化合物1-8-5 雜質個數 7 9 11 11 9 10 10 未放置 未放置 未放置 HPLC純度(%) 95.53 95.04 92.26 91.65 95.25 92.48 91.76 / / / 性狀 類白色粉末 淺黃色粉末 黃色粉末 黃色粉末 與0天一致 與0天一致 淺黃色粉末 / / / 醋酸溶劑合物晶型II 雜質個數 15 25 25 30 21 21 23 21 20 27 HPLC純度(%) 98.51 97.54 97.23 94.26 98.33 98.31 98.27 98.32 98.32 98.10 性狀 類白色粉末 與0天一致 淺黃色粉末 淺黃色粉末 與0天一致 與0天一致 與0天一致 與0天一致 與0天一致 淺黃色粉末 鹽酸鹽醋酸溶劑合物晶型I 雜質個數 21 27 26 32 29 24 27 32 35 56 HPLC純度(%) 97.18 96.94 96.84 95.95 97.07 97.18 97.05 96.77 96.77 93.12 性狀 類白色粉末 與0天一致 淺黃色粉末 淺黃色粉末 與0天一致 與0天一致 與0天一致 與0天一致 黃色粉末 黃色粉末 鹽酸鹽水合物晶型I 雜質個數 26 26 23 23 26 23 24 24 21 23 HPLC純度(%) 97.48 97.42 97.55 97.46 97.48 97.58 97.50 97.52 97.63 97.52 性狀 類白色粉末 與0天一致 與0天一致 與0天一致 與0天一致 與0天一致 與0天一致 與0天一致 與0天一致 與0天一致 Table 7 sample name 0 days High temperature 60℃ High humidity 92.5%RH Lighting 4500lux 5 days 10 days 30 days 5 days 10 days 30 days 5 days 10 days 30 days Compound 1-8-5 Number of impurities 7 9 11 11 9 10 10 not placed not placed not placed HPLC purity (%) 95.53 95.04 92.26 91.65 95.25 92.48 91.76 / / / traits off-white powder light yellow powder yellow powder yellow powder Same as 0 days Same as 0 days light yellow powder / / / Acetic acid solvate crystal form II Number of impurities 15 25 25 30 twenty one twenty one twenty three twenty one 20 27 HPLC purity (%) 98.51 97.54 97.23 94.26 98.33 98.31 98.27 98.32 98.32 98.10 traits off-white powder Same as 0 days light yellow powder light yellow powder Same as 0 days Same as 0 days Same as 0 days Same as 0 days Same as 0 days light yellow powder Hydrochloride Acetic Acid Solvate Form I Number of impurities twenty one 27 26 32 29 twenty four 27 32 35 56 HPLC purity (%) 97.18 96.94 96.84 95.95 97.07 97.18 97.05 96.77 96.77 93.12 traits off-white powder Same as 0 days light yellow powder light yellow powder Same as 0 days Same as 0 days Same as 0 days Same as 0 days yellow powder yellow powder Hydrochloride Hydrate Form I Number of impurities 26 26 twenty three twenty three 26 twenty three twenty four twenty four twenty one twenty three HPLC purity (%) 97.48 97.42 97.55 97.46 97.48 97.58 97.50 97.52 97.63 97.52 traits off-white powder Same as 0 days Same as 0 days Same as 0 days Same as 0 days Same as 0 days Same as 0 days Same as 0 days Same as 0 days Same as 0 days

2）25℃±2℃；60%RH±5%RH條件下模擬市售包裝的長期穩定性測試（12個月），測試項包括性狀、水分、有關物質、含量、微生物限度及細菌內毒素。2) Long-term stability test (12 months) under the condition of 25℃±2℃; 60%RH±5%RH simulating commercial packaging, the test items include character, moisture, related substances, content, microbial limit and bacterial endotoxin .

結果顯示：鹽酸鹽水合物晶型I長期試驗條件下放置12個月，已知雜質、單雜和總雜無明顯變化，其餘檢測指標（性狀、水分、含量）與0天相比，無明顯變化；微生物限度及細菌內毒素檢測符合規定限度（需氧菌總數不得過10 3cfu/g、黴菌和酵母菌總數不得過10 2cfu/g、大腸桿菌：不得檢出/g、細菌內毒素：＜10EU/mg）。 The results showed that the hydrochloride hydrate crystal form I was placed under the long-term test conditions for 12 months, and the known impurities, single impurities and total impurities did not change significantly. Changes; microbial limit and bacterial endotoxin detection meet the specified limits (the total number of aerobic bacteria should not exceed 10 3 cfu/g, the total number of mold and yeast should not exceed 10 2 cfu/g, Escherichia coli: no detectable/g, bacterial endotoxin : <10EU/mg).

實施例 10溶解度測試 Example 10 Solubility Test

測試目的：考察化合物A的溶劑合物的晶型以及化合物A的鹽酸鹽溶劑合物的晶型在水中溶解度。Test purpose: To investigate the solubility of the crystalline form of compound A solvate and the crystalline form of compound A hydrochloride solvate in water.

測試方法：取化合物A的晶型I、CN107344931A公開的化合物1-8-5和化合物A的溶劑合物的晶型以及化合物A的鹽酸鹽溶劑合物的晶型樣品約10mg，置20mL具有塞子的西林瓶中，在各西林瓶中分別加入水、5%乙醇水溶液約5mL，使其成為過飽和溶液，於25℃水浴震盪器中振搖或2-8℃磁力攪拌，分別於2小時、24小時取過飽和溶液（每個時間點對應配製一份溶液），3000 rpm/min離心15min。取上清液作為供試品溶液。另取化合物A的晶型I、CN107344931A公開的化合物1-8-5和化合物A的溶劑合物的晶型以及化合物A的鹽酸鹽溶劑合物的晶型樣品約10mg，精密稱定於20mL容量瓶中，用30%乙腈水溶液溶解並稀釋至刻度線，作為對照溶液。分別精密量取空白溶液（30%乙腈水溶液）、對照溶液、供試品溶液各10μl注入液相色譜儀，記錄色譜圖。Test method: Take about 10 mg of the crystal form of Compound A, Compound 1-8-5 disclosed in CN107344931A, the crystal form of the solvate of Compound A, and the crystal form of the hydrochloride solvate of Compound A. In the vial with stopper, add about 5 mL of water and 5% ethanol aqueous solution to each vial to make it a supersaturated solution, shake in a water bath shaker at 25°C or magnetically stir at 2-8°C, respectively, for 2 hours, Take the supersaturated solution after 24 hours (one solution is prepared for each time point) and centrifuge at 3000 rpm/min for 15 min. Take the supernatant as the test solution. In addition, about 10 mg of the crystal form I of Compound A, the crystal form of Compound 1-8-5 disclosed in CN107344931A and the solvate of Compound A, and the crystal form of the hydrochloride solvate of Compound A were taken and accurately weighed in 20 mL. In a volumetric flask, dissolve and dilute to the mark with 30% acetonitrile aqueous solution as a control solution. Precisely measure each 10 μl of blank solution (30% acetonitrile aqueous solution), control solution and test solution and inject them into the liquid chromatograph, and record the chromatogram.

色譜分析方法如下： 色譜柱：waters Xselect CSH TMC18，4.6mm*150mm，3.5μm。 移動相A：10mM磷酸二氫鉀（用磷酸調pH值至值2.5）；移動相B：乙腈；流速：1.0毫升/分鐘；柱溫：35℃；波長：262nm；進樣量：10μL；如表8所示為沖提梯度。 The chromatographic analysis method is as follows: Chromatographic column: waters Xselect CSH ™ C18, 4.6mm*150mm, 3.5μm. Mobile phase A: 10 mM potassium dihydrogen phosphate (adjust pH to 2.5 with phosphoric acid); mobile phase B: acetonitrile; flow rate: 1.0 ml/min; column temperature: 35 °C; wavelength: 262 nm; injection volume: 10 μL; Table 8 shows the elution gradients.

表8 時間（min） A（%） B（%） 0 85 15 15 65 35 25 50 50 30 30 70 30.1 85 15 35 85 15 Table 8 time (min) A (%) B (%) 0 85 15 15 65 35 25 50 50 30 30 70 30.1 85 15 35 85 15

如表9所示為化合物A的晶型I、CN107344931A公開的化合物1-8-5、化合物A的溶劑合物的晶型以及化合物A的鹽酸鹽溶劑合物的晶型在水中溶解度的結果。As shown in Table 9, the results of the solubility in water of the crystal form I of compound A, the compound 1-8-5 disclosed in CN107344931A, the crystal form of the solvate of compound A and the crystal form of the hydrochloride solvate of compound A .

表9 樣品名稱 25℃溶解度(mg/mL) 2℃溶解度(mg/mL) 純水 5%乙醇-水 純水 5%乙醇-水 2小時 24小時 2小時 24小時 2小時 24小時 2小時 24小時 化合物A的晶型I 0.01 0.01 0.01 0.01 0.00 0.01 0.00 0.01 CN107344931A公開的化合物1-8-5 1.14 1.09 1.12 1.14 1.10 1.13 1.12 1.13 醋酸溶劑合物晶型II 17.32 17.76 16.54 17.09 18.72 17.95 18.59 16.80 鹽酸鹽水合物晶型I 1.48 1.46 1.44 1.58 1.40 1.38 1.57 1.55 Table 9 sample name Solubility at 25℃(mg/mL) Solubility at 2℃(mg/mL) pure water 5% ethanol-water pure water 5% ethanol-water 2 hours 24 hours 2 hours 24 hours 2 hours 24 hours 2 hours 24 hours Form I of Compound A 0.01 0.01 0.01 0.01 0.00 0.01 0.00 0.01 Compound 1-8-5 disclosed by CN107344931A 1.14 1.09 1.12 1.14 1.10 1.13 1.12 1.13 Acetic acid solvate crystal form II 17.32 17.76 16.54 17.09 18.72 17.95 18.59 16.80 Hydrochloride Hydrate Form I 1.48 1.46 1.44 1.58 1.40 1.38 1.57 1.55

實施例 11藥代動力學測試 Example 11 Pharmacokinetic testing

如表10所示為藥物及試劑：待測化合物分別用以下溶媒配成溶液，其它試劑均為分析純。Drugs and reagents are shown in Table 10: the compounds to be tested were prepared into solutions with the following solvents, and other reagents were of analytical grade.

表10 化合物A 40%PEG400+60%葡萄糖（5%），配製為2mg/mL的溶液 CN107344931A公開的化合物1-8-5 葡萄糖（5%）溶液，配製為2mg/mL的溶液 化合物A的鹽酸鹽 葡萄糖（5%）溶液，配製為2mg/mL的溶液 備註：表10中“40%PEG400+60%葡萄糖（5%）”中的百分數均為體積百分數。 Table 10 Compound A 40% PEG400 + 60% glucose (5%), formulated as a 2 mg/mL solution Compound 1-8-5 disclosed by CN107344931A Glucose (5%) solution, prepared as a 2 mg/mL solution Compound A hydrochloride Glucose (5%) solution, prepared as a 2 mg/mL solution Note: The percentages in "40% PEG400+60% glucose (5%)" in Table 10 are volume percentages.

測試用動物：雄性SPF級別SD大鼠（每組3只），購於上海西普爾-必凱實驗動物有限公司，給藥前動物體重範圍為：206.9~222.6 g。Test animals: male SPF SD rats (3 rats in each group), purchased from Shanghai Sipple-Bikai Laboratory Animal Co., Ltd., and the animal weight range before administration was 206.9-222.6 g.

給藥劑量：皮下注射（SC）10 mg/Kg，給藥濃度：2 mg/Kg，給藥體積：5 mL/kg。Dosage: subcutaneous injection (SC) 10 mg/Kg, administration concentration: 2 mg/Kg, administration volume: 5 mL/kg.

藥代動力學測試：將待測化合物通過皮下注射給藥方式給予SD雄性大鼠，血樣經頸靜脈穿刺採血，每個樣品採集約0.25 mL，肝素鈉抗凝，採血時間點如下：給藥前，給藥後0.083 h，0.25 h，0.5 h，1 h，2 h，4 h，6 h，8 h，12h，24 h。血液樣本採集後置於冰上，離心分離血漿（離心條件：8000轉/分鐘，6分鐘，2-8℃）。收集的血漿分析前存放於-80℃。血漿樣品採用LC-MS/MS（API5500）進行分析，根據藥物的血藥濃度資料，使用藥代動力學計算軟體WinNonlin5.2非房室模型分別計算供試品的藥時曲線下面積（AUC）、半衰期（t 1/2）、達峰時間（T max）、峰濃度（C max）、平均滯留時間（MRT）。結果見表11。 Pharmacokinetic test: The compound to be tested was administered to SD male rats by subcutaneous injection, and blood samples were collected by jugular vein puncture. About 0.25 mL of each sample was collected, and heparin sodium was used for anticoagulation. The blood collection time points were as follows: Before administration , 0.083 h, 0.25 h, 0.5 h, 1 h, 2 h, 4 h, 6 h, 8 h, 12 h, 24 h after administration. The blood samples were placed on ice after collection and centrifuged to separate the plasma (centrifugation conditions: 8000 rpm, 6 minutes, 2-8°C). The collected plasma was stored at -80°C until analysis. Plasma samples were analyzed by LC-MS/MS (API5500), and the area under the drug-time curve (AUC) of the test product was calculated using the pharmacokinetic calculation software WinNonlin5.2 non-compartmental model according to the blood concentration data of the drug. , half-life (t 1/2 ), time to peak (T max ), peak concentration (C max ), mean residence time (MRT). The results are shown in Table 11.

表11 化合物名稱 t 1/2 T max C max AUC (0- ∞ ) MRT (0- ∞ ) h h ng/mL ng/mL*h h 化合物A 4.26 1.00 415.63 1494.61 4.15 CN107344931A公開的化合物1-8-5 5.93 0.83 1586.76 5365.33 3.83 化合物A的鹽酸鹽 7.08 0.33 2026.03 5828.55 4.10 Table 11 Compound name t 1/2 Tmax Cmax AUC (0- ∞ ) MRT (0- ∞ ) h h ng/mL ng/mL*h h Compound A 4.26 1.00 415.63 1494.61 4.15 Compound 1-8-5 disclosed by CN107344931A 5.93 0.83 1586.76 5365.33 3.83 Compound A hydrochloride 7.08 0.33 2026.03 5828.55 4.10

雖然以上描述了本發明的具體實施方式，但是本領域的技術人員應當理解，這些僅是舉例說明，在不背離本發明的原理和實質的前提下，可以對這些實施方式做出多種變更或修改。因此，本發明的保護範圍由所附申請專利範圍限定。Although the specific embodiments of the present invention are described above, those skilled in the art should understand that these are only examples, and various changes or modifications can be made to these embodiments without departing from the principle and essence of the present invention . Therefore, the protection scope of the present invention is defined by the appended claims.

圖1為CN107344931A公開的化合物1-8-5的XRPD圖譜。 圖2為實施例2中化合物A的晶型I的XRPD圖譜。 圖3為實施例2中化合物A的晶型I的DSC圖譜。 圖4為實施例2中化合物A的晶型I的TGA圖譜。 圖5為實施例2中化合物A的晶型I的 1H NMR圖譜。 圖6為實施例3中化合物A的醋酸溶劑合物晶型I的XRPD圖譜。 圖7為實施例3中化合物A的醋酸溶劑合物晶型I的DSC圖譜。 圖8為實施例3中化合物A的醋酸溶劑合物晶型I的TGA圖譜。 圖9為實施例3中化合物A的醋酸溶劑合物晶型I的 1H NMR圖譜。 圖10為實施例4中化合物A的醋酸溶劑合物晶型II的XRPD圖譜。 圖11為實施例4中化合物A的醋酸溶劑合物晶型II的DSC圖譜。 圖12為實施例4中化合物A的醋酸溶劑合物晶型II的TGA圖譜。 圖13為實施例4中化合物A的醋酸溶劑合物晶型II的 1H NMR圖譜。 圖14為實施例5中化合物A的鹽酸鹽乙醇溶劑合物晶型I的XRPD圖譜。 圖15為實施例5中化合物A的鹽酸鹽乙醇溶劑合物晶型I的TGA圖譜。 圖16為實施例6中化合物A的鹽酸鹽醋酸溶劑合物晶型I的XRPD圖譜。 圖17為實施例6中化合物A的鹽酸鹽醋酸溶劑合物晶型I的 1H NMR圖譜。 圖18為實施例8中化合物A的鹽酸鹽水合物晶型I的XRPD圖譜。 圖19為實施例8中化合物A的鹽酸鹽水合物晶型I的DSC圖譜。 圖20為實施例8中化合物A的鹽酸鹽水合物晶型I的TGA圖譜。 圖21為實施例8中化合物A的鹽酸鹽水合物晶型I的 1H NMR圖譜。 圖22為實施例8中化合物A的鹽酸鹽水合物晶型I晶型穩定性測試前後的XRPD疊加圖。 圖23為實施例4中化合物A的醋酸溶劑合物晶型II晶型穩定性測試前後的XRPD疊加圖。 圖24為實施例8中化合物A的鹽酸鹽水合物晶型I長期穩定性測試前後的XRPD疊加圖。 圖25為實施例7中化合物A的鹽酸鹽的 1H NMR圖譜。 Fig. 1 is the XRPD pattern of compound 1-8-5 disclosed in CN107344931A. FIG. 2 is the XRPD pattern of the crystal form I of Compound A in Example 2. FIG. FIG. 3 is the DSC chart of the crystal form I of Compound A in Example 2. FIG. FIG. 4 is the TGA spectrum of the crystal form I of Compound A in Example 2. FIG. FIG. 5 is the 1 H NMR spectrum of the crystal form I of compound A in Example 2. FIG. FIG. 6 is the XRPD pattern of the acetic acid solvate crystal form I of Compound A in Example 3. FIG. 7 is the DSC spectrum of the acetic acid solvate crystal form I of Compound A in Example 3. FIG. FIG. 8 is the TGA spectrum of the acetic acid solvate crystal form I of Compound A in Example 3. FIG. 9 is the 1 H NMR spectrum of the acetic acid solvate crystal form I of Compound A in Example 3. FIG. FIG. 10 is the XRPD pattern of the acetic acid solvate crystal form II of Compound A in Example 4. FIG. 11 is the DSC chart of the acetic acid solvate crystal form II of Compound A in Example 4. FIG. 12 is the TGA spectrum of the acetic acid solvate crystal form II of Compound A in Example 4. FIG. 13 is the 1 H NMR spectrum of the acetic acid solvate crystal form II of Compound A in Example 4. FIG. 14 is the XRPD pattern of the hydrochloride ethanol solvate crystal form I of Compound A in Example 5. FIG. 15 is the TGA spectrum of the hydrochloride ethanol solvate crystal form I of Compound A in Example 5. FIG. 16 is the XRPD pattern of the hydrochloride acetic acid solvate crystal form I of Compound A in Example 6. FIG. 17 is the 1 H NMR spectrum of the hydrochloride acetic acid solvate crystal form I of Compound A in Example 6. FIG. 18 is the XRPD pattern of the hydrochloride hydrate crystal form I of Compound A in Example 8. FIG. 19 is the DSC chart of the hydrochloride hydrate crystal form I of Compound A in Example 8. FIG. 20 is the TGA spectrum of the hydrochloride hydrate crystal form I of Compound A in Example 8. FIG. 21 is the 1 H NMR spectrum of the hydrochloride hydrate crystal form I of Compound A in Example 8. FIG. FIG. 22 is the XRPD overlay diagram before and after the stability test of the hydrochloride hydrate crystal form I of Compound A in Example 8. FIG. FIG. 23 is the XRPD overlay diagram before and after the stability test of the acetic acid solvate crystal form II of Compound A in Example 4. FIG. FIG. 24 is the XRPD overlay diagram before and after the long-term stability test of the hydrochloride hydrate crystal form I of Compound A in Example 8. FIG. 25 is the 1 H NMR spectrum of the hydrochloride salt of Compound A in Example 7. FIG.

Figure 111104049-A0101-11-0001-2
Figure 111104049-A0101-11-0001-2

無。none.

Claims (26)

一種如式（I）所示化合物，
Figure 03_image001
其中，X為H 2O、CH 3CH 2OH、CH 3C(O)OH、CH 3C(O)OCH 2CH 3、CH 3C(O)CH 3或(CH 3) 2CHOH； n為0-1的任意數值；m為0-3的任意數值；且m和n不同時為0。 A compound represented by formula (I),
Figure 03_image001
Wherein, X is H 2 O, CH 3 CH 2 OH, CH 3 C(O)OH, CH 3 C(O)OCH 2 CH 3 , CH 3 C(O)CH 3 or (CH 3 ) 2 CHOH; n is any value from 0 to 1; m is any value from 0 to 3; and m and n are not 0 at the same time. 如請求項1所述的如式（I）所示化合物，其中，X為H 2O、CH 3CH 2OH或CH 3C(O)OH，優選為H 2O； 和/或，n為0或1，優選為1； 和/或，m為0、1、1.5、2、2.5或3，優選為0、1、1.5或2。 The compound represented by formula (I) according to claim 1, wherein X is H 2 O, CH 3 CH 2 OH or CH 3 C(O)OH, preferably H 2 O; and/or, n is 0 or 1, preferably 1; and/or, m is 0, 1, 1.5, 2, 2.5 or 3, preferably 0, 1, 1.5 or 2. 如請求項1所述的如式（I）所示化合物，其中，n為1，m為1.5或2；或者，n為0，m為1或2；或者，n為1，m為0。The compound represented by formula (I) according to claim 1, wherein n is 1, and m is 1.5 or 2; or, n is 0, and m is 1 or 2; or, n is 1, and m is 0. 如請求項1所述的如式（I）所示化合物，其中，所述如式（I）所示化合物選自如下任一化合物：
Figure 03_image005
、
Figure 03_image007
、
Figure 03_image009
、
Figure 03_image011
、
Figure 03_image013
、
Figure 03_image015
。 The compound represented by formula (I) according to claim 1, wherein the compound represented by formula (I) is selected from any of the following compounds:
Figure 03_image005
,
Figure 03_image007
,
Figure 03_image009
,
Figure 03_image011
,
Figure 03_image013
,
Figure 03_image015
. 如請求項1-4任一項所述的如式（I）所示化合物，其中，當n為1，m為2，X為H 2O時，所述如式（I）所示化合物的結晶形式為鹽酸鹽水合物晶型I，使用Cu-Kα輻射，其以2θ角表示的X-射線粉末衍射圖，在9.8±0.2°、10.5±0.2°、17.4±0.2°、19.7±0.2°和22.7±0.2°處具有衍射峰。 The compound represented by formula (I) according to any one of claims 1-4, wherein, when n is 1, m is 2, and X is H 2 O, the compound represented by formula (I) has The crystalline form is hydrochloride hydrate, Form I, using Cu-Kα radiation, its X-ray powder diffraction pattern expressed at 2θ angles at 9.8±0.2°, 10.5±0.2°, 17.4±0.2°, 19.7±0.2° and diffraction peaks at 22.7±0.2°. 如請求項5所述的如式（I）所示化合物，其中，使用Cu-Kα輻射，所述鹽酸鹽水合物晶型I以2θ角表示的X-射線粉末衍射圖，還在如下一個或多個2θ角處有衍射峰： 7.1±0.2°、12.5±0.2°、14.0±0.2°、15.7±0.2°、18.0±0.2°和20.3±0.2°。The compound of formula (I) according to claim 5, wherein, using Cu-Kα radiation, the X-ray powder diffraction pattern of the hydrochloride hydrate crystal form I at 2θ angle is further one of the following or There are diffraction peaks at multiple 2Θ angles: 7.1±0.2°, 12.5±0.2°, 14.0±0.2°, 15.7±0.2°, 18.0±0.2° and 20.3±0.2°. 如請求項6所述的如式（I）所示化合物，其中，使用Cu-Kα輻射，所述鹽酸鹽水合物晶型I以2θ角表示的X-射線粉末衍射圖，還在如下一個或多個2θ角處有衍射峰： 12.9±0.2°、21.5±0.2°、22.0±0.2°、25.2±0.2°、26.0±0.2°、26.8±0.2°和29.3±0.2°。The compound of formula (I) according to claim 6, wherein, using Cu-Kα radiation, the X-ray powder diffraction pattern of the hydrochloride hydrate crystal form I at 2θ angle is further one of the following or There are diffraction peaks at multiple 2θ angles: 12.9±0.2°, 21.5±0.2°, 22.0±0.2°, 25.2±0.2°, 26.0±0.2°, 26.8±0.2° and 29.3±0.2°. 如請求項7所述的如式（I）所示化合物，其中，使用Cu-Kα輻射，所述鹽酸鹽水合物晶型I以2θ角表示的X-射線粉末衍射圖，還在如下一個或多個2θ角處有衍射峰：18.7±0.2°、19.0±0.2°、24.8±0.2°、29.9±0.2°和34.1±0.2°。The compound represented by formula (I) according to claim 7, wherein, using Cu-Kα radiation, the X-ray powder diffraction pattern of the hydrochloride hydrate crystal form I at 2θ angle is further one of the following or There are diffraction peaks at multiple 2θ angles: 18.7±0.2°, 19.0±0.2°, 24.8±0.2°, 29.9±0.2° and 34.1±0.2°. 如請求項8所述的如式（I）所示化合物，其中，使用Cu-Kα輻射，所述鹽酸鹽水合物晶型I以2θ角表示的X-射線粉末衍射圖，其衍射峰和相對強度如下表所示： 角度2θ/° 相對強度% 角度2θ/° 相對強度% 角度2θ/° 相對強度% 7.082 9.7 9.793 100.0 10.477 54.9 12.470 20.7 12.834 6.9 13.987 15.5 15.635 23.8 17.404 33.69 17.937 14.8 18.686 6.8 19.027 16.6 19.674 48.6 20.294 15.8 21.534 9.8 22.000 11.0 22.669 70.2 23.613 6.5 24.438 10.6 24.803 15.1 25.191 22.0 26.005 9.6 26.815 26.3 29.283 11.3 29.937 6.0 32.029 5.2 34.121 9.1    
；進一步地，所述鹽酸鹽水合物晶型I以2θ角表示的X-射線粉末衍射圖基本上如圖18所示； 和/或，所述鹽酸鹽水合物晶型I的差示掃描量熱圖中在136.3±5℃（例如136.3±3℃）處有吸收峰；較佳地，所述鹽酸鹽水合物晶型I的差示掃描量熱圖基本上如圖19所示； 和/或，所述鹽酸鹽水合物晶型I的熱重分析圖在70℃至100℃有重量損失，所述重量損失為6±0.5%（例如6±0.2%）；較佳地，所述鹽酸鹽水合物晶型I的熱重分析圖基本上如圖20所示。 The compound represented by formula (I) according to claim 8, wherein, using Cu-Kα radiation, the X-ray powder diffraction pattern of the hydrochloride hydrate crystal form I at 2θ angle, the diffraction peaks and the relative The strengths are shown in the table below: Angle 2θ/° Relative Strength% Angle 2θ/° Relative Strength% Angle 2θ/° Relative Strength% 7.082 9.7 9.793 100.0 10.477 54.9 12.470 20.7 12.834 6.9 13.987 15.5 15.635 23.8 17.404 33.69 17.937 14.8 18.686 6.8 19.027 16.6 19.674 48.6 20.294 15.8 21.534 9.8 22.000 11.0 22.669 70.2 23.613 6.5 24.438 10.6 24.803 15.1 25.191 22.0 26.005 9.6 26.815 26.3 29.283 11.3 29.937 6.0 32.029 5.2 34.121 9.1
; Further, the X-ray powder diffraction pattern of the hydrochloride hydrate crystal form I represented by a 2θ angle is substantially as shown in FIG. 18 ; and/or, the differential scanning amount of the hydrochloride hydrate crystal form I The heat map has an absorption peak at 136.3±5°C (eg, 136.3±3°C); preferably, the differential scanning calorimetry of the hydrochloride hydrate crystal form I is substantially as shown in FIG. 19 ; and/ Or, the thermogravimetric analysis chart of the hydrochloride hydrate crystal form I has a weight loss at 70°C to 100°C, and the weight loss is 6±0.5% (for example, 6±0.2%); preferably, the hydrochloric acid The thermogravimetric analysis profile of salt hydrate Form I is substantially as shown in FIG. 20 . 如請求項1-4任一項所述的如式（I）所示化合物，其中，當n為1，m為2，X為CH 3C(O)OH時，所述如式（I）所示化合物的結晶形式為鹽酸鹽醋酸溶劑合物晶型I， 使用Cu-Kα輻射，其以2θ角表示的X-射線粉末衍射圖的衍射峰和相對強度如下表所示： 角度2θ/° 相對強度% 角度2θ/° 相對強度% 角度2θ/° 相對強度% 6.539 100.0 7.019 2.8 7.534 4.6 15.942 1.6 18.416 1.9 18.763 3.8 19.441 2.9 19.739 4.4 20.700 3.4 20.898 6.3 21.741 2.0 22.720 2.0 24.505 2.7 24.878 3.3 26.421 4.2
；較佳地，所述鹽酸鹽醋酸溶劑合物晶型I以2θ角表示的X-射線粉末衍射圖基本上如圖16所示。 The compound represented by formula (I) according to any one of claims 1-4, wherein, when n is 1, m is 2, and X is CH 3 C(O)OH, the compound represented by formula (I) The crystalline form of the compound shown is the hydrochloride acetic acid solvate crystal form I, using Cu-Kα radiation, the diffraction peaks and relative intensities of the X-ray powder diffraction pattern expressed at 2θ angles are shown in the following table: Angle 2θ/° Relative Strength% Angle 2θ/° Relative Strength% Angle 2θ/° Relative Strength% 6.539 100.0 7.019 2.8 7.534 4.6 15.942 1.6 18.416 1.9 18.763 3.8 19.441 2.9 19.739 4.4 20.700 3.4 20.898 6.3 21.741 2.0 22.720 2.0 24.505 2.7 24.878 3.3 26.421 4.2
; Preferably, the X-ray powder diffraction pattern of the hydrochloride acetic acid solvate crystal form I represented by 2θ angle is substantially as shown in FIG. 16 . 如請求項1-4任一項所述的如式（I）所示化合物，其中，當n為1，m為1.5，X為CH 3CH 2OH時，所述如式（I）所示化合物的結晶形式為鹽酸鹽乙醇溶劑合物晶型I，使用Cu-Kα輻射，其以2θ角表示的X-射線粉末衍射圖譜的衍射峰和相對強度如下表所示： 角度2θ/° 相對強度% 角度2θ/° 相對強度% 角度2θ/° 相對強度% 6.454 100.0 7.239 27.0 9.157 11.9 11.702 12.5 12.966 7.2 13.417 4.9 16.183 4.5 19.496 7.5 20.229 10.5 20.679 7.3 21.964 12.8 22.397 6.7 23.545 8.8 25.181 9.0 26.068 9.5
；較佳地，所述鹽酸鹽乙醇溶劑合物晶型I以2θ角表示的X-射線粉末衍射圖基本上如圖14所示； 和/或，所述鹽酸鹽乙醇溶劑合物晶型I的熱重分析圖基本上如圖15所示。 The compound represented by the formula (I) according to any one of claims 1 to 4, wherein, when n is 1, m is 1.5, and X is CH 3 CH 2 OH, the compound represented by the formula (I) The crystalline form of the compound is hydrochloride ethanol solvate crystal form I, using Cu-Kα radiation, the diffraction peaks and relative intensities of the X-ray powder diffraction pattern represented by the 2θ angle are shown in the following table: Angle 2θ/° Relative Strength% Angle 2θ/° Relative Strength% Angle 2θ/° Relative Strength% 6.454 100.0 7.239 27.0 9.157 11.9 11.702 12.5 12.966 7.2 13.417 4.9 16.183 4.5 19.496 7.5 20.229 10.5 20.679 7.3 21.964 12.8 22.397 6.7 23.545 8.8 25.181 9.0 26.068 9.5
Preferably, the X-ray powder diffraction pattern of the hydrochloride ethanol solvate crystal form I represented by 2θ angle is substantially as shown in Figure 14; and/or, the hydrochloride ethanol solvate crystal form The thermogravimetric analysis profile of Form I is substantially as shown in FIG. 15 . 如請求項1-4任一項所述的如式（I）所示化合物，其中，當n為0，m為1，X為CH 3C(O)OH時，所述如式（I）所示化合物的結晶形式為醋酸溶劑合物晶型I，使用Cu-Kα輻射，其以2θ角表示的X-射線粉末衍射圖，在5.3±0.2°、8.5±0.2°、10.8±0.2°、18.7±0.2°和20.4±0.2°處具有衍射峰。 The compound represented by formula (I) according to any one of claims 1-4, wherein, when n is 0, m is 1, and X is CH 3 C(O)OH, the compound represented by formula (I) The crystalline form of the compound shown is acetic acid solvate crystal form I, using Cu-Kα radiation, its X-ray powder diffraction pattern expressed at 2Θ angles at 5.3 ± 0.2°, 8.5 ± 0.2°, 10.8 ± 0.2°, There are diffraction peaks at 18.7±0.2° and 20.4±0.2°. 如請求項12所述的如式（I）所示化合物，其中，使用Cu-Kα輻射，所述醋酸溶劑合物晶型I以2θ角表示的X-射線粉末衍射圖，還在如下一個或多個2θ角處有衍射峰：4.9±0.2°、10.1±0.2°、11.8±0.2°、12.8±0.2°、14.0±0.2°、15.2±0.2°、15.8±0.2°、17.1±0.2°、17.6±0.2°、21.7±0.2°、23.7±0.2°和25.9±0.2°。The compound represented by formula (I) according to claim 12, wherein, using Cu-Kα radiation, the X-ray powder diffraction pattern of the acetic acid solvate crystal form I at 2θ angle is further one of the following or Diffraction peaks at multiple 2θ angles: 4.9±0.2°, 10.1±0.2°, 11.8±0.2°, 12.8±0.2°, 14.0±0.2°, 15.2±0.2°, 15.8±0.2°, 17.1±0.2°, 17.6 ±0.2°, 21.7±0.2°, 23.7±0.2° and 25.9±0.2°. 如請求項13所述的如式（I）所示化合物，其中，使用Cu-Kα輻射，所述醋酸溶劑合物晶型I以2θ角表示的X-射線粉末衍射圖，其衍射峰和相對強度如下表所示： 角度2θ/° 相對強度% 角度2θ/° 相對強度% 角度2θ/° 相對強度% 4.911 26.0 5.337 38.6 5.849 6.8 8.467 55.7 10.129 50.2 10.761 100.0 11.803 49.8 12.851 9.6 13.953 21.5 15.184 20.9 15.766 30.2 17.074 19.9 17.605 10.5 18.738 41.4 20.442 30.7 21.671 24.5 23.670 10.3 23.940 9.1 25.875 12.6        
；進一步地，所述醋酸溶劑合物晶型I以2θ角表示的X-射線粉末衍射圖基本上如圖6所示； 和/或，所述醋酸溶劑合物晶型I的差示掃描量熱圖中分別在167.2±5℃（例如167.2±3℃）和238.5±5℃（例如238.5±3℃）處有吸收峰；較佳地，所述醋酸溶劑合物晶型I的差示掃描量熱圖基本上如圖7所示； 和/或，所述醋酸溶劑合物晶型I的熱重分析圖在100℃至160℃有重量損失，所述重量損失為10±0.5%（例如10±0.2%）；較佳地，所述醋酸溶劑合物晶型I的熱重分析圖基本上如圖8所示。 The compound represented by formula (I) according to claim 13, wherein, using Cu-Kα radiation, the X-ray powder diffraction pattern of the acetic acid solvate crystal form I at 2θ angle, the diffraction peaks and the relative The strengths are shown in the table below: Angle 2θ/° Relative Strength% Angle 2θ/° Relative Strength% Angle 2θ/° Relative Strength% 4.911 26.0 5.337 38.6 5.849 6.8 8.467 55.7 10.129 50.2 10.761 100.0 11.803 49.8 12.851 9.6 13.953 21.5 15.184 20.9 15.766 30.2 17.074 19.9 17.605 10.5 18.738 41.4 20.442 30.7 21.671 24.5 23.670 10.3 23.940 9.1 25.875 12.6
; Further, the X-ray powder diffraction pattern of the acetic acid solvate crystal form I represented by a 2θ angle is substantially as shown in Figure 6; and/or, the differential scanning amount of the acetic acid solvate crystal form I There are absorption peaks at 167.2±5°C (eg 167.2±3°C) and 238.5±5°C (eg 238.5±3°C) in the heat map; preferably, the differential scan of the acetic acid solvate crystal form I The calorimetry diagram is substantially as shown in FIG. 7; and/or, the thermogravimetric analysis diagram of the acetic acid solvate crystal form I has a weight loss at 100°C to 160°C, the weight loss being 10±0.5% (e.g. 10±0.2%); preferably, the thermogravimetric analysis diagram of the acetic acid solvate crystal form I is substantially as shown in FIG. 8 . 如請求項1-4任一項所述的如式（I）所示化合物，其中，當n為0，m為2，X為CH 3C(O)OH時，所述如式（I）所示化合物的結晶形式為醋酸溶劑合物晶型II，使用Cu-Kα輻射，其以2θ角表示的X-射線粉末衍射圖，在6.5±0.2°、7.1±0.2°、7.5±0.2°、13.7±0.2°和24.5±0.2°處具有衍射峰。 The compound represented by formula (I) according to any one of claims 1-4, wherein, when n is 0, m is 2, and X is CH 3 C(O)OH, the compound represented by formula (I) The crystalline form of the compound shown is acetic acid solvate crystal form II, using Cu-Kα radiation, its X-ray powder diffraction pattern expressed at 2Θ angles at 6.5 ± 0.2°, 7.1 ± 0.2°, 7.5 ± 0.2°, There are diffraction peaks at 13.7±0.2° and 24.5±0.2°. 如請求項15所述的如式（I）所示化合物，其中，使用Cu-Kα輻射，所述醋酸溶劑合物晶型II以2θ角表示的X-射線粉末衍射圖，還在如下一個或多個2θ角處有衍射峰：19.4±0.2°、20.8±0.2°、23.1±0.2°和24.8±0.2°。The compound represented by formula (I) according to claim 15, wherein, using Cu-Kα radiation, the X-ray powder diffraction pattern of the acetic acid solvate crystal form II at 2θ angle is further one of the following or There are diffraction peaks at multiple 2θ angles: 19.4±0.2°, 20.8±0.2°, 23.1±0.2° and 24.8±0.2°. 如請求項16所述的如式（I）所示化合物，其中，使用Cu-Kα輻射，所述醋酸溶劑合物晶型II以2θ角表示的X-射線粉末衍射圖，其衍射峰和相對強度如下表所示： 角度2θ/° 相對強度% 角度2θ/° 相對強度% 角度2θ/° 相對強度% 6.518 100.0 7.081 62.3 7.491 6.1 13.700 9.1 14.739 3.9 15.059 3.8 18.501 3.9 18.759 3.8 19.404 5.7 20.099 18.2 20.799 4.5 21.838 3.6 23.081 4.0 24.543 6.8 24.835 5.2
；進一步地，所述醋酸溶劑合物晶型II以2θ角表示的X-射線粉末衍射圖基本上如圖10所示； 和/或，所述醋酸溶劑合物晶型II的差示掃描量熱圖中在115.8±5℃（例如115.8±3℃）處有吸收峰；較佳地，所述醋酸溶劑合物晶型II的差示掃描量熱圖基本上如圖11所示； 和/或，所述醋酸溶劑合物晶型II的熱重分析圖在100℃至160℃有重量損失；所述重量損失可為11.6±0.5%（例如11.6±0.2%）；較佳地，所述醋酸溶劑合物晶型II的熱重分析圖基本上如圖12所示。 The compound represented by formula (I) according to claim 16, wherein, using Cu-Kα radiation, the X-ray powder diffraction pattern of the acetic acid solvate crystal form II at 2θ angle, the diffraction peaks and the relative The strengths are shown in the table below: Angle 2θ/° Relative Strength% Angle 2θ/° Relative Strength% Angle 2θ/° Relative Strength% 6.518 100.0 7.081 62.3 7.491 6.1 13.700 9.1 14.739 3.9 15.059 3.8 18.501 3.9 18.759 3.8 19.404 5.7 20.099 18.2 20.799 4.5 21.838 3.6 23.081 4.0 24.543 6.8 24.835 5.2
; Further, the X-ray powder diffraction pattern of the acetic acid solvate crystal form II at a 2θ angle is substantially as shown in FIG. 10 ; and/or, the differential scanning amount of the acetic acid solvate crystal form II The heat map has an absorption peak at 115.8±5°C (eg, 115.8±3°C); preferably, the differential scanning calorimetry of the acetic acid solvate crystal form II is substantially as shown in FIG. 11 ; and/ Or, the thermogravimetric analysis diagram of the acetic acid solvate crystal form II has a weight loss at 100°C to 160°C; the weight loss may be 11.6±0.5% (for example, 11.6±0.2%); preferably, the The thermogravimetric analysis diagram of the acetic acid solvate crystal form II is substantially as shown in FIG. 12 . 一種化合物A的結晶形式，其中，所述化合物A的結晶形式為化合物A的晶型I；使用Cu-Kα輻射，其以2θ角表示的X-射線粉末衍射圖，在6.3±0.2°、7.4±0.2°、8.7±0.2°、15.3±0.2°和17.5±0.2°處具有衍射峰，
Figure 03_image017
。 A crystalline form of compound A, wherein the crystalline form of compound A is the crystalline form I of compound A; using Cu-Kα radiation, its X-ray powder diffraction pattern represented by 2θ angle is at 6.3±0.2°, 7.4 There are diffraction peaks at ±0.2°, 8.7±0.2°, 15.3±0.2° and 17.5±0.2°,
Figure 03_image017
. 如請求項18所述的化合物A的結晶形式，其中，使用Cu-Kα輻射，所述化合物A的晶型I以2θ角表示的X-射線粉末衍射圖，還在如下一個或多個2θ角處有衍射峰：12.4±0.2°、14.9±0.2°、15.7±0.2°、17.3±0.2°、18.9±0.2°、20.5±0.2°、21.6±0.2°、22.3±0.2°、22.9±0.2°、23.1±0.2°、24.0±0.2°和26.0±0.2°；較佳地，所述化合物A的晶型I以2θ角表示的X-射線粉末衍射圖，還在如下一個或多個2θ角處有衍射峰：20.7±0.2°、21.9±0.2°、23.7±0.2°、24.3±0.2°和25.4±0.2°；更佳地，所述化合物A的晶型I以2θ角表示的X-射線粉末衍射圖基本上如圖2所示； 和/或，所述化合物A的晶型I的差示掃描量熱圖中在235.1±5℃（例如235.1±3℃）處有吸收峰；較佳地，所述化合物A的晶型I的差示掃描量熱圖基本上如圖3所示； 和/或，所述化合物A的晶型I的熱重分析圖基本上如圖4所示。 The crystalline form of Compound A as claimed in claim 18, wherein, using Cu-Kα radiation, the X-ray powder diffraction pattern of the crystalline form I of Compound A at 2θ angles, and further one or more of the following 2θ angles There are diffraction peaks at: 12.4±0.2°, 14.9±0.2°, 15.7±0.2°, 17.3±0.2°, 18.9±0.2°, 20.5±0.2°, 21.6±0.2°, 22.3±0.2°, 22.9±0.2°, 23.1±0.2°, 24.0±0.2° and 26.0±0.2°; preferably, the X-ray powder diffraction pattern of the crystal form I of the compound A expressed at 2θ angle, also has the following one or more 2θ angles. Diffraction peaks: 20.7±0.2°, 21.9±0.2°, 23.7±0.2°, 24.3±0.2° and 25.4±0.2°; more preferably, the X-ray powder diffraction of the crystal form I of the compound A at 2θ angle The diagram is basically as shown in Figure 2; And/or, there is an absorption peak at 235.1±5°C (eg 235.1±3°C) in the differential scanning calorimetry of the crystal form I of the compound A; preferably, the crystal form I of the compound A has an absorption peak. The differential scanning calorimetry map is basically as shown in Figure 3; And/or, the thermogravimetric analysis diagram of the crystal form I of compound A is substantially as shown in FIG. 4 . 如請求項1~17任一項所述的如式（I）所示化合物的製備方法，其中，其包括以下方法一、方法二或方法三： 方法一： 將化合物A溶於X中，析晶，得到如式（I）所示化合物，
Figure 03_image019
方法一中，n為0，m和X的定義如請求項1~3任一項所述； 方法二： 將化合物A置於X中和HCl反應，析晶，得到如式（I）所示化合物，
Figure 03_image036
方法二中，n為1，m為0-3的任意數值；X的定義如請求項1~3任一項所述； 方法三： 將如式（II）所示化合物溶於有機溶劑-水的混合溶液中，析晶，得到如式（I）所示化合物，
Figure 03_image023
方法三中，n為0-1的任意數值，m和m’獨立地為0-3的任意數值，且n和m均不為0；X為H 2O；Y為CH 3CH 2OH、CH 3C(O)OH、CH 3C(O)OCH 2CH 3、CH 3C(O)CH 3或(CH 3) 2CHOH。 The method for preparing a compound represented by formula (I) according to any one of claims 1 to 17, wherein it includes the following method 1, method 2 or method 3: Method 1: Dissolve compound A in X, analyze crystal to obtain a compound represented by formula (I),
Figure 03_image019
In method 1, n is 0, and the definitions of m and X are as described in any of claim 1 to 3; compound,
Figure 03_image036
In the second method, n is 1, and m is any value from 0 to 3; the definition of X is as described in any one of claims 1 to 3; Method three: Dissolve the compound represented by formula (II) in an organic solvent-water In the mixed solution of , crystallize to obtain the compound represented by formula (I),
Figure 03_image023
In the third method, n is any value from 0 to 1, m and m' are any value from 0 to 3 independently, and both n and m are not 0; X is H 2 O; Y is CH 3 CH 2 OH, CH3C (O)OH, CH3C (O) OCH2CH3 , CH3C (O) CH3 or ( CH3 ) 2CHOH . 如請求項20所述的如式（I）所示化合物的製備方法，其中，所述方法一中，所述化合物A溶於X的過程通過如下方法實現：將化合物A溶解在有機溶劑中形成混合物，再將所述混合物溶解於X中；或者，將化合物A置於X中加熱，使其溶清即可；較佳地，所述方法一中，當化合物A溶解在有機溶劑中形成混合物時，所述有機溶劑以能溶解化合物A並能和X混溶即可；例如當X為醋酸時，所述有機溶劑為二氯甲烷和/或甲醇；當將化合物A置於X中並加熱時，將其加熱至60℃~120℃，例如60℃~85℃，又例如79.5℃或80℃； 和/或，所述方法二中，當X為H 2O時，所述反應還進一步包含醇類和/或酮類溶劑；所述醇類溶劑可為異丙醇和/或乙醇，優選為異丙醇；所述酮類溶劑可為丙酮； 和/或，所述方法二中，所述化合物A置於X中的溫度為10℃~85℃，例如10℃~30℃或60℃； 和/或，所述方法二中，所述化合物A和HCl的莫耳比為1：（1~15），又例如1:1、1:1.2、1:1.5、1:2、1:3或1:10； 和/或，所述方法三中，所述有機溶劑以使能溶解如式（II）所示化合物以及能與水混溶即可，優選為異丙醇和/或丙酮； 和/或，所述方法三中，所述有機溶劑-水的混合溶液中，所述有機溶劑的體積百分數可為50%~98%，例如50%、75%、85%或95%； 和/或，所述方法三中，所述如式（II）所示化合物經加熱溶解於有機溶劑-水的混合溶液中；較佳地，將其加熱至30℃~80℃，例如50℃； 和/或，所述方法三中，Y為CH 3CH 2OH、CH 3C(O)OH或(CH 3) 2CHOH； 和/或，所述方法三中，所述如式（II）所示化合物由所述方法二製備得到。 The method for preparing a compound represented by formula (I) according to claim 20, wherein, in the first method, the process of dissolving the compound A in X is achieved by the following method: dissolving the compound A in an organic solvent to form mixture, and then dissolving the mixture in X; or, heating compound A in X to make it dissolve; preferably, in the first method, when compound A is dissolved in an organic solvent to form a mixture When X is acetic acid, the organic solvent is dichloromethane and/or methanol; when compound A is placed in X and heated and/or, in the second method, when X is H 2 O, the reaction is further Including alcohol and/or ketone solvent; the alcohol solvent may be isopropanol and/or ethanol, preferably isopropanol; the ketone solvent may be acetone; and/or, in the second method, the The temperature at which the compound A is placed in X is 10°C to 85°C, for example, 10°C to 30°C or 60°C; and/or, in the second method, the molar ratio of the compound A and HCl is 1:( 1~15), another example is 1:1, 1:1.2, 1:1.5, 1:2, 1:3 or 1:10; and/or, in the third method, the organic solvent can dissolve such as The compound shown in formula (II) can be miscible with water, preferably isopropanol and/or acetone; and/or, in the third method, in the organic solvent-water mixed solution, the organic solvent The volume percentage can be 50%~98%, such as 50%, 75%, 85% or 95%; and/or, in the method three, the compound shown in the formula (II) is dissolved in an organic solvent by heating -in a mixed solution of water; preferably, it is heated to 30°C to 80°C, such as 50°C; and/or, in the third method, Y is CH 3 CH 2 OH, CH 3 C(O)OH or (CH 3 ) 2 CHOH; and/or, in the third method, the compound represented by the formula (II) is prepared by the second method. 一種藥物組合物，其中，其包括治療有效量的活性組分以及藥學上可接受的輔料；所述活性組分包括如請求項1~17任一項所述的如式（I）所示化合物。A pharmaceutical composition, wherein, it comprises a therapeutically effective amount of an active component and a pharmaceutically acceptable adjuvant; the active component comprises a compound shown in formula (I) as described in any one of claims 1 to 17 . 如式（I）所示化合物或藥物組合物在製備治療、緩解和/或預防由TLRs介導的相關疾病的藥物中的應用，其中，所述如式（I）所示化合物如請求項1~17任一項所述；所述藥物組合物如請求項22所述。Use of a compound or pharmaceutical composition of formula (I) in the preparation of a medicine for treating, relieving and/or preventing related diseases mediated by TLRs, wherein the compound of formula (I) is as claimed in item 1 According to any one of ~17; the pharmaceutical composition is as described in claim 22. 如請求項23所述的如式（I）所示化合物或藥物組合物在製備治療和/或緩解由TLRs介導的相關疾病的藥物中的應用，其中，所述由TLRs介導的相關疾病的藥物為由TLR8介導的相關疾病的藥物； 和/或，所述由TLRs介導的相關疾病包括癌症、病毒感染以及自身免疫性疾病。 The use of the compound represented by formula (I) or the pharmaceutical composition according to claim 23 in the preparation of a medicine for treating and/or alleviating a related disease mediated by TLRs, wherein the related disease mediated by TLRs The drugs are drugs for related diseases mediated by TLR8; And/or, the related diseases mediated by TLRs include cancer, viral infections and autoimmune diseases. 如式（I）所示化合物或藥物組合物在製備治療和/或緩解癌症、病毒感染以及自身免疫性疾病的藥物中的應用，其中，所述如式（I）所示化合物如請求項1~17任一項所述；所述藥物組合物如請求項22所述。Application of the compound or pharmaceutical composition represented by formula (I) in the preparation of medicines for treating and/or relieving cancer, viral infection and autoimmune diseases, wherein the compound represented by formula (I) is as claimed in item 1 According to any one of ~17; the pharmaceutical composition is as described in claim 22. 如請求項25所述的如式（I）所示化合物或藥物組合物在製備治療和/或緩解癌症、病毒感染以及自身免疫性疾病的藥物中的應用，其中，所述如式（I）所示化合物、或所述藥物組合物和一種或多種其它種類的治療劑聯合用於治療和/或緩解癌症、病毒感染以及自身免疫性疾病。The use of the compound or pharmaceutical composition of formula (I) according to claim 25 in the preparation of a medicine for treating and/or alleviating cancer, viral infection and autoimmune diseases, wherein the formula (I) The compounds shown, or the pharmaceutical compositions described, in combination with one or more other classes of therapeutic agents are used in the treatment and/or amelioration of cancer, viral infections, and autoimmune diseases.
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