TW201805289A - Salts as HCV inhibitors - Google Patents

Salts as HCV inhibitors Download PDF

Info

Publication number
TW201805289A
TW201805289A TW106126760A TW106126760A TW201805289A TW 201805289 A TW201805289 A TW 201805289A TW 106126760 A TW106126760 A TW 106126760A TW 106126760 A TW106126760 A TW 106126760A TW 201805289 A TW201805289 A TW 201805289A
Authority
TW
Taiwan
Prior art keywords
salt
compound
amorphous
hcv
acid
Prior art date
Application number
TW106126760A
Other languages
Chinese (zh)
Inventor
任青雲
陳亮
單岳峰
羅慧超
梁金勝
黃建洲
熊金峰
張道俊
張英俊
健存 張
Original Assignee
廣東東陽光藥業有限公司
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by 廣東東陽光藥業有限公司 filed Critical 廣東東陽光藥業有限公司
Publication of TW201805289A publication Critical patent/TW201805289A/en

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/08—Tripeptides
    • C07K5/0802—Tripeptides with the first amino acid being neutral
    • C07K5/0804—Tripeptides with the first amino acid being neutral and aliphatic
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/56—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms
    • C07D233/58—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/02—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms containing only hydrogen and carbon atoms in addition to the ring hetero elements

Abstract

Salts of compound (I) and pharmaceutically compositions thereof, specially a base addition salt, an acid addition salt of compound (I) and a pharmaceutically composition thereof, future the use of the compound and the pharmaceutical composition in the manufacture of a medicament for preventing, managing, treating or lessening hepatitis C virus (HCV) infection.

Description

作為丙型肝炎病毒抑制劑的鹽 Salts as inhibitors of hepatitis C virus

本發明屬於藥物領域，涉及式(I)所示化合物的鹼加成鹽、酸加成鹽及其藥物組合物，進一步涉及所述化合物和所述藥物組合物在製備藥物中的用途，尤其是在製備用於預防、處理、治療或減輕丙型肝炎病毒(HCV)感染的藥物中的用途。 The invention belongs to the field of medicine, and relates to a base addition salt, an acid addition salt of a compound represented by the formula (I) and a pharmaceutical composition thereof, and further relates to the use of the compound and the pharmaceutical composition in the preparation of a medicament, especially Use in the manufacture of a medicament for the prevention, treatment, treatment or alleviation of a hepatitis C virus (HCV) infection.

HCV是主要的人類病原體，估計全球感染約1.7億人，為人免疫缺陷病毒1型感染人數的5倍。而大部分HCV感染個體會發展成嚴重的進行性肝病，包括肝硬化和肝細胞癌。因此，慢性HCV感染將是全球患者因肝病而過早死亡的主要原因。 HCV is the major human pathogen, and it is estimated to infect approximately 170 million people worldwide, five times the number of human immunodeficiency virus type 1 infections. Most individuals with HCV infection develop severe progressive liver disease, including cirrhosis and hepatocellular carcinoma. As a result, chronic HCV infection will be the leading cause of premature deaths in patients worldwide due to liver disease.

HCV是正鏈RNA病毒。根據對推導出的氨基酸序列和5’非翻譯區廣泛相似性的比較，HCV被歸類到黃病毒科(Flaviviridae family)單獨的一個屬內。黃病毒科的所有成員都是含正鏈RNA基因組的有包膜病毒粒子，該基因組通過單個不間斷開放閱讀框(ORF)的翻譯，編碼所有已知的病毒特異性蛋白。 HCV is a positive-strand RNA virus. Based on a comparison of the deduced amino acid sequence and the broad similarity of the 5 'untranslated region, HCV was classified into a separate genus of the Flaviviridae family. All members of the Flaviviridae family are enveloped virions containing a positive-stranded RNA genome that encodes all known virus-specific proteins through translation of a single uninterrupted open reading frame (ORF).

在整個HCV基因組的核苷酸和所編碼的氨基酸序列記憶體在相當多的異質性。已經鑑定出至少7個主要的基因型，並且披露了50多個亞型。在受HCV感染的細胞中，病毒RNA被翻譯為多聚蛋白，並***為10種個體蛋白。在氨基末端為結構蛋白，E1和E2緊隨其後。另外，還有6種非結構蛋白，即NS2、NS3、NS4A、NS4B、NS5A和NS5B，其在HCV生命週期中扮演著非常重要的角色(參見，例如，Lindenbach,B.D.和C.M.Rice,Nature.436,933-938,2005)。 There is considerable heterogeneity in nucleotides and encoded amino acid sequence memories throughout the HCV genome. At least 7 major genotypes have been identified, and more than 50 subtypes have been disclosed. In HCV-infected cells, viral RNA is translated into polyproteins and splits into 10 individual proteins. There are structural proteins at the amino terminus, followed by E1 and E2. In addition, there are six non-structural proteins, namely NS2, NS3, NS4A, NS4B, NS5A and NS5B, which play a very important role in the HCV life cycle (see, for example, Lindenbach, BD and CMRice, Nature.436,933 -938, 2005).

HCV的主要基因型在全球的分佈不同，雖然進行了大量基因型對發病機制和治療作用的研究，但仍不清楚HCV遺傳異質性的臨床重要性。 The global distribution of major HCV genotypes is different. Although a large number of studies have been performed on the pathogenesis and therapeutic effects of HCV, the clinical significance of HCV genetic heterogeneity is still unclear.

由於單鏈HCV RNA基因組長度約為9500個核苷酸，具有單個開放閱讀框，編碼單個約3000個氨基酸的大型多聚蛋白。在感染細胞中，該多聚蛋白在多個位點上被細胞蛋白酶和病毒蛋白酶切割，產生結構和非結構(NS)蛋白。就HCV而言，成熟非結構蛋白(NS2、NS3、NS4A、NS4B、NS5A和NS5B)的形成是通過兩種病毒蛋白酶實現的。一般認為第一種是金屬蛋白酶，在NS2-NS3接點進行切割；第二種是包含在NS3(本文中亦稱為NS3蛋白酶)N端區域的絲氨酸蛋白酶，它介導NS3下游所有的後續切割，在NS3-NS4A切割位點為順式，在其餘NS4A-NS4B、NS4B-NS5A、NS5A-NA5B位點則為反式。NS4A蛋白似乎有多種功能，起NS3蛋白酶輔因數的作用，並可能協助NS3和其他病毒複製酶組分進行膜定位。NS3蛋白與NS4A複合物的形成似乎是加工事件，在所有位點上提高蛋白水解效率所必需的。NS3蛋白還顯示出核苷三磷酸酶和RNA解旋酶活性。NS5B(本文中亦稱HCV聚合酶)是參與HCV複製的依賴RNA的RNA聚合酶。 Because the single-stranded HCV RNA genome is approximately 9,500 nucleotides in length, it has a single open reading frame and encodes a single large polyprotein of approximately 3000 amino acids. In infected cells, the multiprotein is cleaved by cellular and viral proteases at multiple sites, producing structural and non-structural (NS) proteins. In the case of HCV, the formation of mature non-structural proteins (NS2, NS3, NS4A, NS4B, NS5A, and NS5B) is achieved by two viral proteases. The first is generally considered to be a metalloproteinase, which cuts at the NS2-NS3 junction; the second is a serine protease contained in the N-terminal region of NS3 (also referred to herein as the NS3 protease), which mediates all subsequent cleavage downstream of NS3 In the NS3-NS4A cleavage site is cis, while in the remaining NS4A-NS4B, NS4B-NS5A, NS5A-NA5B sites are trans. The NS4A protein appears to have multiple functions, acting as a cofactor for the NS3 protease, and may assist in membrane localization of NS3 and other viral replicase components. The formation of NS3 protein and NS4A complexes appears to be a processing event, necessary to improve proteolytic efficiency at all sites. NS3 protein also shows nucleoside triphosphatase and RNA helicase activity. NS5B (also referred to herein as HCV polymerase) is an RNA-dependent RNA polymerase involved in HCV replication.

目前，最有效的HCV療法是採用α-干擾素和利巴韋林的聯合用藥，在40%患者中產生持續功效。最新臨床結果表明，作為單一療法時，聚乙二醇化α-干擾素優於未修飾的α-干擾素。然而，即使是使用包括聚乙二醇化α-干擾素和利巴韋林組合的實驗性治療方案，大部分患者也無法持續降低病毒負荷，且很多患者往往會伴隨一些副反應，而不能長久治療。因此，目前迫切需要新的有效治療HCV感染的方法。 Currently, the most effective HCV therapy is a combination of alpha-interferon and ribavirin that produces sustained efficacy in 40% of patients. Recent clinical results indicate that pegylated α-interferon is superior to unmodified α-interferon as a monotherapy. However, even with experimental treatment regimens that include a combination of pegylated α-interferon and ribavirin, most patients are unable to continuously reduce the viral load, and many patients are often accompanied by some side effects and cannot be treated for a long time. . Therefore, there is an urgent need for new and effective methods for treating HCV infection.

申請號為CN 2016100772777.8的專利記載了很多HCV抑制劑化合物，其中式(I)所示化合物是對HCV NS3/4A蛋白有較好的抑制活性，但其暴露量並不理想。 The patent with the application number of CN 2016100772777.8 describes many HCV inhibitor compounds. Among them, the compound represented by formula (I) has good inhibitory activity on HCV NS3 / 4A protein, but its exposure is not ideal.

Figure TW201805289AD00001
Figure TW201805289AD00001

藥物活性成分的不同鹽和固體形式可能具有不同的性質。不同鹽和固體形式在性質方面的改變可以提供改良配方。因此，為了尋找具有更好成藥性的固體形式，發明人通過大量的實驗研究，意外地得到如式(I)所示化合物的藥學上可接受的鹼加成鹽、酸加成鹽及其藥物組合物，其具有較好的生物活性，並且明顯改善了式(I)所示化合物的藥代動力學性質，具有更優良的成藥性。 Different salt and solid forms of pharmaceutically active ingredients may have different properties. Changes in properties of different salt and solid forms can provide improved formulations. Therefore, in order to find a solid form with better drugability, the inventors unexpectedly obtained a pharmaceutically acceptable base addition salt, acid addition salt of a compound represented by the formula (I) and a drug thereof through a large number of experimental studies. The composition has better biological activity, and obviously improves the pharmacokinetic properties of the compound represented by formula (I), and has better drug-forming properties.

本發明的目的是提供一類HCV病毒蛋白，如具有NS3蛋白酶抑制活性的鹽，並且其可用於製備治療或緩解HCV感染及其相關疾病的藥物。 The object of the present invention is to provide a class of HCV viral proteins, such as salts having NS3 protease inhibitory activity, and which can be used to prepare medicines for treating or alleviating HCV infection and related diseases.

本發明涉及式(I)所示化合物的鹼加成鹽、酸加成鹽及其藥物組合物，進一步涉及所述化合物或所述藥物組合物在製備藥物中的用途，尤其是在製備用於預防、處理、治療或減輕丙型肝炎病毒(HCV)感染的藥物中的用途。本發明的式(I)所示化合物的鹼加成鹽或酸加成鹽包含水合物或溶劑化物形式。 The present invention relates to a base addition salt, an acid addition salt of a compound represented by the formula (I), and a pharmaceutical composition thereof, and further relates to the use of the compound or the pharmaceutical composition in the preparation of a medicament, especially in the preparation for Use in a medicament for the prevention, treatment, treatment or alleviation of a hepatitis C virus (HCV) infection. The base addition salt or acid addition salt of the compound represented by the formula (I) of the present invention includes a hydrate or solvate form.

一方面，本發明涉及式(I)所示化合物的藥學上可接受的鹼加成鹽：

Figure TW201805289AD00002
In one aspect, the invention relates to a pharmaceutically acceptable base addition salt of a compound of formula (I):
Figure TW201805289AD00002

一些實施例中，本發明所述的鹼加成鹽為選自鋰鹽、鈉鹽、鉀鹽、鈣鹽、鎂鹽、鋁鹽、鐵鹽、鋅鹽、銨鹽的至少一種；或所述的鹽為選自式(I)所示化合物與甲胺、二甲胺、三甲胺、乙胺、二乙胺、三乙胺、氨基丁三醇、二乙氨基乙醇、異丙胺、2-乙氨基乙醇、吡啶、甲基吡啶、乙醇胺、二乙醇胺、銨、二甲基乙醇胺、四甲基銨、四乙基銨、三乙醇胺、呱啶、呱嗪、嗎啉、咪唑、賴氨酸、精氨酸、L-精氨酸、組氨酸、N-甲基葡糖胺、二甲基葡糖胺、乙基葡糖胺、二環己基胺、1,6-己二胺、乙二胺、葡糖胺、肌氨酸、絲氨醇、氨基丙二醇、1-氨基-2,3,4-丁三醇、L-賴氨酸、鳥氨酸形成的鹽的至少一種。 In some embodiments, the base addition salt according to the present invention is at least one selected from the group consisting of lithium, sodium, potassium, calcium, magnesium, aluminum, iron, zinc, and ammonium salts; or Is a salt selected from the compound of formula (I) and methylamine, dimethylamine, trimethylamine, ethylamine, diethylamine, triethylamine, tromethamine, diethylaminoethanol, isopropylamine, 2-ethyl Aminoethanol, pyridine, methylpyridine, ethanolamine, diethanolamine, ammonium, dimethylethanolamine, tetramethylammonium, tetraethylammonium, triethanolamine, pyridine, verazine, morpholine, imidazole, lysine, refined L -Arginine, L -Arginine, Histidine, N -methylglucosamine, dimethylglucosamine, ethylglucosamine, dicyclohexylamine, 1,6-hexanediamine, ethylenediamine At least one of glucosamine, sarcosine, serine, aminopropanediol, 1-amino-2,3,4-butanetriol, L -lysine, and ornithine.

一些實施例中，本發明所述的鹼加成鹽為N-甲基葡糖胺鹽無定形，其中，N-甲基葡糖胺鹽無定形具有基本上如圖1所示的X射線粉末衍射圖。 In some embodiments, the base addition salt of the present invention is an N -methylglucamine salt amorphous, wherein the N -methylglucamine salt amorphous has an X-ray powder substantially as shown in FIG. 1 Diffraction pattern.

一些實施例中，本發明所述的鹼加成鹽為L-精氨酸鹽無定形，其中，L-精氨酸鹽無定形具有基本上如圖2所示的X射線粉末衍射圖。 In some embodiments, the alkali addition salt of the present invention is L -arginine salt amorphous, wherein the L -arginine salt amorphous has an X-ray powder diffraction pattern substantially as shown in FIG. 2.

一些實施例中，本發明所述的鹼加成鹽為L-賴氨酸鹽無定形，其中，L-賴氨酸鹽無定形具有基本上如圖3所示的X射線粉末衍射圖。 In some embodiments, the alkali addition salt according to the present invention is L -lysine salt amorphous, wherein the L -lysine salt amorphous has an X-ray powder diffraction pattern substantially as shown in FIG. 3.

一些實施例中，本發明所述的鹼加成鹽為鈉鹽無定形，其中，鈉鹽無定形具有基本上如圖4所示的X射線粉末衍射圖。 In some embodiments, the alkali addition salt according to the present invention is a sodium salt amorphous, wherein the sodium salt amorphous has an X-ray powder diffraction pattern substantially as shown in FIG. 4.

一些實施例中，本發明所述的鹼加成鹽為鈣鹽無定形，其中，鈣鹽無定形具有基本上如圖5所示的X射線粉末衍射圖。 In some embodiments, the alkali addition salt according to the present invention is a calcium salt amorphous, wherein the calcium salt amorphous has an X-ray powder diffraction pattern substantially as shown in FIG. 5.

一些實施例中，本發明所述的鹼加成鹽為鉀鹽無定形，其中，鉀鹽無定形具有基本上如圖6所示的X射線粉末衍射圖。 In some embodiments, the alkali addition salt according to the present invention is a potassium salt amorphous, wherein the potassium salt amorphous has an X-ray powder diffraction pattern substantially as shown in FIG. 6.

一些實施例中，本發明所述的鹼加成鹽為鋰鹽無定形，其中，鋰鹽無定形具有基本上如圖7所示的X射線粉末衍射圖。 In some embodiments, the alkali addition salt according to the present invention is a lithium salt amorphous, wherein the lithium salt amorphous has an X-ray powder diffraction pattern substantially as shown in FIG. 7.

一些實施例中，本發明所述的鹼加成鹽為二乙胺鹽無定形，其中，二乙胺鹽無定形具有基本上如圖8所示的X射線粉末衍射圖。 In some embodiments, the base addition salt according to the present invention is a diethylamine salt amorphous, wherein the diethylamine salt amorphous has an X-ray powder diffraction pattern substantially as shown in FIG. 8.

一些實施例中，本發明所述的鹼加成鹽為氨基丁三醇鹽無定形，其中，氨基丁三醇鹽無定形具有基本上如圖9所示的X射線粉末衍射圖。 In some embodiments, the base addition salt according to the present invention is a tromethamine amorphous, wherein the tromethamine amorphous has an X-ray powder diffraction pattern substantially as shown in FIG. 9.

一些實施例中，本發明所述的鹼加成鹽為二乙氨基乙醇鹽無定形，其中，二乙胺基乙醇鹽無定形具有基本上如圖10所示的X射線粉末衍射圖。 In some embodiments, the base addition salt according to the present invention is a diethylaminoethanol salt amorphous, wherein the diethylaminoethanol salt amorphous has an X-ray powder diffraction pattern substantially as shown in FIG. 10.

一些實施例中，本發明所述的鹼加成鹽為呱嗪鹽無定形，其中，呱嗪鹽無定形具有基本上如圖11所示的X射線粉末衍射圖。 In some embodiments, the alkali addition salt according to the present invention is a oxazine salt amorphous, wherein the oxazine salt amorphous has an X-ray powder diffraction pattern substantially as shown in FIG. 11.

一些實施例中，本發明所述的鹼加成鹽為鎂鹽無定形，其中，鎂鹽無定形具有基本上如圖12所示的X射線粉末衍射圖。 In some embodiments, the alkali addition salt according to the present invention is a magnesium salt amorphous, wherein the magnesium salt amorphous has an X-ray powder diffraction pattern substantially as shown in FIG. 12.

一些實施例中，本發明所述的鹼加成鹽為二甲基乙醇胺鹽無定形，其中，二甲基乙醇胺鹽無定形具有基本上如圖13所示的X射線粉末衍射圖。 In some embodiments, the base addition salt according to the present invention is a dimethylethanolamine salt amorphous, wherein the dimethylethanolamine salt amorphous has an X-ray powder diffraction pattern substantially as shown in FIG. 13.

一些實施例中，本發明所述的鹼加成鹽為乙二胺鹽無定形，其中，乙二胺鹽無定形具有基本上如圖14所示的X射線粉末衍射圖。 In some embodiments, the alkali addition salt according to the present invention is an ethylenediamine salt amorphous, wherein the ethylenediamine salt amorphous has an X-ray powder diffraction pattern substantially as shown in FIG. 14.

一些實施例中，本發明所述的鹼加成鹽為三乙醇胺鹽無定形，其中，三乙醇胺鹽無定形具有基本上如圖15所示的X射線粉末衍射圖。 In some embodiments, the base addition salt according to the present invention is a triethanolamine salt amorphous, wherein the triethanolamine salt amorphous has an X-ray powder diffraction pattern substantially as shown in FIG. 15.

一些實施例中，本發明所述的鹼加成鹽為乙醇胺鹽無定形，其中，乙醇胺鹽無定形具有基本上如圖16所示的X射線粉末衍射圖。 In some embodiments, the alkali addition salt according to the present invention is an ethanolamine salt amorphous, wherein the ethanolamine salt amorphous has an X-ray powder diffraction pattern substantially as shown in FIG. 16.

一些實施例中，本發明所述的鹼加成鹽為咪唑鹽無定形，其中，咪唑鹽無定形具有基本上如圖17所示的X射線粉末衍射圖。 In some embodiments, the base addition salt according to the present invention is an imidazole salt amorphous, wherein the imidazole salt amorphous has an X-ray powder diffraction pattern substantially as shown in FIG. 17.

另一方面，本發明涉及式(I)所示化合物的藥學上可接受的酸加成鹽：

Figure TW201805289AD00003
In another aspect, the invention relates to a pharmaceutically acceptable acid addition salt of a compound of formula (I):
Figure TW201805289AD00003

一些實施例中，本發明所述的酸加成鹽為無機酸鹽或有機酸鹽，其中，所述無機酸鹽選自鹽酸鹽、硫酸鹽、硫酸氫鹽、硝酸鹽、氫溴酸鹽、氫碘酸鹽、碳酸鹽、碳酸氫鹽、亞硫酸鹽、亞硫酸氫鹽、焦硫酸鹽、磷酸一氫鹽、磷酸二氫鹽、高氯酸鹽、過硫酸鹽、半硫酸鹽、重硫酸鹽、硫氰酸鹽、磷酸鹽、焦磷酸鹽和偏磷酸鹽中的至少一種；所述有機酸鹽選自甲酸鹽、乙酸鹽、丙酸鹽、丁酸鹽、苯甲酸鹽、丙二酸鹽、丁二酸鹽、丙酮酸鹽、甲磺酸鹽、乙磺酸鹽、丙磺酸鹽、檸檬酸鹽、4-硝基苯甲酸鹽、苯磺酸鹽、對甲苯磺酸鹽、1,2-乙二磺酸鹽、β-萘磺酸鹽、蘋果酸鹽、丙炔酸鹽、2-丁炔酸鹽、2-羥基-乙烷磺酸鹽、乙烯基乙酸鹽、酒石酸鹽、L-酒石酸鹽、富馬酸鹽、羥乙基磺酸鹽、馬來酸鹽、乳酸鹽、乳糖酸鹽、雙羥萘酸鹽、水楊酸鹽、半乳糖二酸鹽、葡庚糖酸鹽、扁桃酸鹽、1,2-乙烷基二磺酸鹽、2-萘磺酸鹽、草酸鹽、三氟乙酸鹽、三氟甲磺酸鹽、己二酸鹽、辛二酸鹽、癸二酸鹽、丁炔-1,4-二酸鹽、己炔-1,6-二酸鹽、羥基乙酸鹽、藻酸鹽、抗壞血酸鹽、異抗壞血酸鹽、天冬氨酸鹽、L-天冬氨酸鹽、谷氨酸鹽、L-谷氨酸鹽、2-苯氧基苯甲酸鹽、2-(4-羥基苯甲醯基)苯甲酸鹽、乙醯乙酸鹽、2-羥基乙磺酸鹽、硼酸鹽、氯代苯甲酸鹽、樟腦酸鹽、衣康酸鹽、樟腦磺酸鹽、左旋樟腦磺酸鹽、甲基苯甲酸鹽、二硝基苯甲酸鹽、氨基磺酸鹽、乳糖醛酸鹽、半乳糖醛酸鹽、環戊基丙酸鹽、十二烷基硫酸鹽、丙烯酸鹽、環戊烷丙酸鹽、甘油磷酸鹽、甲氧基苯甲酸鹽、二葡萄糖酸鹽、葡萄糖酸鹽、庚酸鹽、己酸鹽、三甲基乙酸鹽、葡糖醛酸鹽、月桂酸鹽、鄰苯二甲酸鹽、苯乙酸鹽、月桂基硫酸鹽、2-乙醯氧基苯甲酸鹽、煙酸鹽、肉桂酸鹽、油酸鹽、棕櫚酸 鹽、果膠酸鹽、苯二甲酸鹽、戊二酸鹽、羥基馬來酸鹽、羥基苯甲酸鹽、苯乙酸鹽、3-羥基-2-萘甲酸鹽、3-苯基丙酸鹽、異丁酸鹽、新戊酸鹽、苦味酸鹽、硬脂酸鹽、2,2-二氯乙酸鹽、醯化氨基酸鹽、海藻酸鹽、4-乙醯氨基苯磺酸鹽、癸酸鹽、膽酸鹽、辛酸鹽、壬酸鹽、環拉酸鹽、酞酸鹽、鹽酸半胱氨酸鹽、山梨酸鹽、鹽酸甘氨酸鹽、1,5-萘二磺酸鹽、二甲苯磺酸鹽、二鹽酸胱氨酸鹽、十一酸鹽、聚乙烯磺酸鹽、磺基水楊酸鹽、苯基丁酸鹽、4-羥基丁酸鹽、聚乙烯硫酸鹽、萘-1-磺酸鹽、萘-2-磺酸鹽和戊酸鹽中的至少一種。 In some embodiments, the acid addition salt according to the present invention is an inorganic acid salt or an organic acid salt, wherein the inorganic acid salt is selected from the group consisting of hydrochloride, sulfate, hydrogen sulfate, nitrate, and hydrobromide. , Hydroiodate, carbonate, bicarbonate, sulfite, bisulfite, pyrosulfate, monohydrogen phosphate, dihydrogen phosphate, perchlorate, persulfate, hemisulfate, heavy At least one of sulfate, thiocyanate, phosphate, pyrophosphate, and metaphosphate; the organic acid salt is selected from the group consisting of formate, acetate, propionate, butyrate, benzoate, Malonate, succinate, pyruvate, mesylate, ethanesulfonate, propanesulfonate, citrate, 4-nitrobenzoate, benzenesulfonate, p-toluenesulfonate Acid salt, 1,2-ethanedisulfonate, β-naphthalenesulfonate, malate, propionate, 2-butynate, 2-hydroxy-ethanesulfonate, vinyl acetate , Tartrate, L -tartrate, fumarate, isethionate, maleate, lactate, lactate, paraben, salicylate, galactate, Portuguese Sugar salt, mandelate, 1,2-ethanedisulfonate, 2-naphthalenesulfonate, oxalate, trifluoroacetate, triflate, adipate, suberate Acid salt, sebacate salt, butyne-1,4-diacrate, hexyne-1,6-diactoate, glycolate, alginate, ascorbate, erythorbic acid, aspartate , L -aspartate, glutamate, L -glutamate, 2-phenoxybenzoate, 2- (4-hydroxybenzyl) benzoate, acetoacetic acid Salt, 2-hydroxyethanesulfonate, borate, chlorobenzoate, camphor, itaconic acid, camphor sulfonate, l-camphorsulfonate, methylbenzoate, dinitro Benzoate, sulfamate, lactobionate, galacturonate, cyclopentylpropionate, dodecyl sulfate, acrylate, cyclopentane propionate, glyceryl phosphate, formazan Oxybenzoate, digluconate, gluconate, heptanoate, hexanoate, trimethylacetate, glucuronate, laurate, phthalate, phenylacetate , Lauryl sulfate, 2-ethoxybenzoate, Salt, cinnamate, oleate, palmitate, pectate, phthalate, glutarate, hydroxymaleate, hydroxybenzoate, phenylacetate, 3-hydroxy -2-naphthoate, 3-phenylpropionate, isobutyrate, pivalate, picrate, stearate, 2,2-dichloroacetate, tritiated amino acid salt, seaweed Acid salt, 4-acetamidine benzenesulfonic acid salt, capric acid salt, cholic acid salt, caprylic acid salt, nonanoic acid salt, citric acid salt, phthalic acid salt, cysteine hydrochloride, sorbate, glycine hydrochloride Salt, 1,5-naphthalene disulfonate, xylene sulfonate, cystine dihydrochloride, undecanoate, polyethylene sulfonate, sulfosalicylate, phenylbutyrate, 4 -At least one of hydroxybutyrate, polyethylene sulfate, naphthalene-1-sulfonate, naphthalene-2-sulfonate, and valerate.

一些實施例中，本發明所述的酸加成鹽為檸檬酸鹽無定形，其中，檸檬酸鹽無定形具有基本上如圖18所示的X射線粉末衍射圖。 In some embodiments, the acid addition salt according to the present invention is a citrate amorphous, wherein the citrate amorphous has an X-ray powder diffraction pattern substantially as shown in FIG. 18.

一些實施例中，本發明所述的酸加成鹽為對甲苯磺酸鹽無定形，其中，對甲苯磺酸鹽無定形具有基本上如圖19所示的X射線粉末衍射圖。 In some embodiments, the acid addition salt according to the present invention is a p-toluenesulfonate amorphous form, wherein the p-toluenesulfonate amorphous form has an X-ray powder diffraction pattern substantially as shown in FIG. 19.

一些實施例中，本發明所述的酸加成鹽為苯磺酸鹽無定形，其中，苯磺酸鹽無定形具有基本上如圖20所示的X射線粉末衍射圖。 In some embodiments, the acid addition salt according to the present invention is a benzenesulfonate amorphous, wherein the benzenesulfonate amorphous has an X-ray powder diffraction pattern substantially as shown in FIG. 20.

一些實施例中，本發明所述的酸加成鹽為甲磺酸鹽無定形，其中，甲磺酸鹽無定形具有基本上如圖21所示的X射線粉末衍射圖。 In some embodiments, the acid addition salt according to the present invention is a mesylate amorphous, wherein the mesylate amorphous has an X-ray powder diffraction pattern substantially as shown in FIG. 21.

一些實施例中，本發明所述的酸加成鹽為硫酸鹽無定形，其中，硫酸鹽無定形具有基本上如圖22所示的X射線粉末衍射圖。 In some embodiments, the acid addition salt according to the present invention is a sulfate amorphous, wherein the sulfate amorphous has an X-ray powder diffraction pattern substantially as shown in FIG. 22.

一些實施例中，本發明所述的酸加成鹽為磷酸鹽無定形，其中，磷酸鹽無定形具有基本上如圖23所示的X射線粉末衍射圖。 In some embodiments, the acid addition salt according to the present invention is a phosphate amorphous, wherein the phosphate amorphous has an X-ray powder diffraction pattern substantially as shown in FIG. 23.

一些實施例中，本發明所述的酸加成鹽為硝酸鹽無定形，其中，硝酸鹽無定形具有基本上如圖24所示的X射線粉末衍射圖。 In some embodiments, the acid addition salt according to the present invention is a nitrate amorphous, wherein the nitrate amorphous has an X-ray powder diffraction pattern substantially as shown in FIG. 24.

一些實施例中，本發明所述的酸加成鹽為1,5-萘二磺酸鹽無定形，其中，1,5-萘二磺酸鹽無定形具有基本上如圖25所示的X射線粉末衍射圖。 In some embodiments, the acid addition salt according to the present invention is 1,5-naphthalene disulfonate amorphous, wherein the 1,5-naphthalene disulfonate amorphous has X substantially as shown in FIG. 25. Ray powder diffraction pattern.

一些實施例中，本發明所述的酸加成鹽為1,2-乙二磺酸鹽無定形，其中，1,2-乙二磺酸鹽無定形具有基本上如圖26所示的X射線粉末衍射圖。 In some embodiments, the acid addition salt according to the present invention is 1,2-ethanedisulfonate amorphous, wherein the 1,2-ethanedisulfonate amorphous has X substantially as shown in FIG. 26. Ray powder diffraction pattern.

一些實施例中，本發明所述的酸加成鹽為β-萘磺酸鹽無定形，其中，β-萘磺酸鹽無定形具有基本上如圖27所示的X射線粉末衍射圖。 In some embodiments, the acid addition salt according to the present invention is β-naphthalenesulfonate amorphous, wherein the β-naphthalenesulfonate amorphous has an X-ray powder diffraction pattern substantially as shown in FIG. 27.

一些實施例中，本發明所述的酸加成鹽為環拉酸鹽無定形，其中，環拉酸鹽無定形具有基本上如圖28所示的X射線粉末衍射圖。 In some embodiments, the acid addition salt according to the present invention is a cyclamate amorphous, wherein the cyclamate amorphous has an X-ray powder diffraction pattern substantially as shown in FIG. 28.

一些實施例中，本發明所述的酸加成鹽為羥乙基磺酸鹽無定形，其中，羥乙基磺酸鹽無定形具有基本上如圖29所示的X射線粉末衍射圖。 In some embodiments, the acid addition salt according to the present invention is isethionate amorphous, wherein the isethionate amorphous has an X-ray powder diffraction pattern substantially as shown in FIG. 29.

一些實施例中，本發明所述的酸加成鹽為馬來酸鹽無定形，其中，馬來酸鹽無定形具有基本上如圖30所示的X射線粉末衍射圖。 In some embodiments, the acid addition salt according to the present invention is a maleate amorphous form, wherein the maleate amorphous form has an X-ray powder diffraction pattern substantially as shown in FIG. 30.

一些實施例中，本發明所述的酸加成鹽為氫溴酸鹽無定形，其中，氫溴酸鹽無定形具有基本上如圖31所示的X射線粉末衍射圖。 In some embodiments, the acid addition salt according to the present invention is a hydrobromide amorphous, wherein the hydrobromide amorphous has an X-ray powder diffraction pattern substantially as shown in FIG. 31.

一些實施例中，本發明所述的酸加成鹽為鹽酸鹽無定形，其中，鹽酸鹽無定形具有基本上如圖32所示的X射線粉末衍射圖。 In some embodiments, the acid addition salt according to the present invention is a hydrochloride amorphous, wherein the hydrochloride amorphous has an X-ray powder diffraction pattern substantially as shown in FIG. 32.

另一方面，本發明涉及一種藥物組合物，該藥物組合物含有本發明所述的式(I)所示化合物的酸加成鹽或式(I)所示化合物的鹼加成鹽。任選地，所述藥物組合物進一步包括藥學上可接受的輔料。 In another aspect, the present invention relates to a pharmaceutical composition containing an acid addition salt of a compound represented by formula (I) or a base addition salt of a compound represented by formula (I) according to the present invention. Optionally, the pharmaceutical composition further comprises a pharmaceutically acceptable excipient.

一些實施例中，本發明所述的藥物組合物，其進一步地包含其他的抗HCV的藥物；其中所述其他的抗HCV的藥物為干擾素、利巴韋林、白介素2、白介素6、白介素12、促進產生1型輔助性T細胞應答的化合物、干擾RNA、反義RNA、咪喹莫德、肌苷5’-單磷酸脫氫酶抑制劑、金剛烷胺、金剛乙胺、利托那韋、巴維昔單抗(Bavituximab)、CivacirTM、波普瑞韋(boceprevir)、替拉瑞韋(telaprevir)、索非布韋(sofosbuvir)、雷迪帕韋(ledipasvir)、達卡他韋(daclatasvir)、丹諾普韋(danoprevir)、西魯瑞韋(ciluprevir)、那拉匹韋(narlaprevir)、deleobuvir(BI-207127)、dasabuvir(ABT-333)、beclabuvir(BMS-791325)、elbasvir(MK-8742)、ombitasvir(ABT-267)、neceprevir(ACH-2684)、tegobuvir(GS-9190)、grazoprevir(MK-5172)、sovaprevir(ACH-1625)、samatasvir(IDX-719)、veruprevir(ABT-450)、埃羅替尼(erlotinib)、simeprevir(TMC-435)、asunaprevir(BMS-650032)、vaniprevir(MK-7009)、faldaprevir(BI-2013335)、VX-135、CIGB-230、furaprevir(TG-2349)、pibrentasvir(ABT-530)、glecaprevir(ABT-493)、uprifosbuvir(IDX-21437)、radalbuvir(GS-9669)、JHJ-56914845、vedroprevir(GS-9451)、BZF-961、GS-9256、ANA975、EDP239、ravidasvir hydrochloride(PPI-668)、velpatasvir(GS-5816)、MK-8325、GSK-2336805、PPI-461、ACH-1095、VX-985、IDX-375、VX-500、VX-813、PHX-1766、PHX-2054、IDX-136、IDX-316、modithromycin(EP-013420)、VBY-376、TMC-649128、mericitabine(R-7128)、INX-189、IDX-184、IDX102、R1479、UNX-08189、PSI-6130、PSI-938、PSI-879、 HCV-796、nesbuvir(HCV-371)、VCH-916、lomibuvir(VCH-222)、setrobuvir(ANA-598)、MK-3281、ABT-072、filibuvir(PF-00868554)、A-837093、JKT-109、Gl-59728、GL-60667、AZD-2795、TMC-647055或其組合；其中所述干擾素為干擾素α-2b、聚乙二醇化的干擾素α、干擾素α-2a、聚乙二醇化的干擾素α-2a、複合α-干擾素、干擾素γ中的一種或其組合。 In some embodiments, the pharmaceutical composition of the present invention further comprises other anti-HCV drugs; wherein the other anti-HCV drugs are interferon, ribavirin, interleukin 2, interleukin 6, interleukin 12.Compounds that promote the production of type 1 helper T cell responses, interfering RNA, antisense RNA, imiquimod, inosine 5'-monophosphate dehydrogenase inhibitors, amantadine, amantadine, ritona Wei, Bavituximab, Civacir TM , boceprevir, telaprevir, sofosbuvir, ledipasvir, daclatasvir (daclatasvir), danoprevir, ciluprevir, narlaprevir, deleobuvir (BI-207127), dasabuvir (ABT-333), beclabuvir (BMS-791325), elbasvir (MK-8742), ombitasvir (ABT-267), neceprevir (ACH-2684), tegobuvir (GS-9190), grazoprevir (MK-5172), sovaprevir (ACH-1625), samatasvir (IDX-719), veruprevir ( ABT-450), erlotinib, simeprevir (TMC-435), asunaprevir (BMS-650032), vaniprevir (MK-7009), faldapre vir (BI-2013335), VX-135, CIGB-230, furaprevir (TG-2349), pibrentasvir (ABT-530), glecaprevir (ABT-493), uprifosbuvir (IDX-21437), radarbubu (GS-9669), JHJ-56914845, vedroprevir (GS-9451), BZF-961, GS-9256, ANA975, EDP239, ravidasvir hydrochloride (PPI-668), velpatasvir (GS-5816), MK-8325, GSK-2336805, PPI-461, ACH-1095, VX-985, IDX-375, VX-500, VX-813, PHX-1766, PHX-2054, IDX-136, IDX-316, modithromycin (EP-013420), VBY-376, TMC-649128 Mericitabine (R-7128), INX-189, IDX-184, IDX102, R1479, UNX-08189, PSI-6130, PSI-938, PSI-879, HCV-796, nesbuvir (HCV-371), VCH-916 , Lomibuvir (VCH-222), setrobuvir (ANA-598), MK-3281, ABT-072, filibuvir (PF-00868554), A-837093, JKT-109, Gl-59728, GL-60667, AZD-2795, TMC-647055 or a combination thereof; wherein the interferon is interferon alpha-2b, pegylated interferon alpha, interferon alpha-2a, pegylated interferon alpha-2a, complex alpha-interferon One or a combination of interferon gamma.

一些實施例中，本發明所述的藥物組合物，其進一步地包含至少一種HCV抑制劑，其中所述HCV抑制劑用於抑制HCV複製過程和/或抑制HCV病毒蛋白功能；其中所述HCV複製過程選自HCV進入、脫殼、翻譯、複製、組裝和釋放的過程的至少之一；所述的HCV病毒蛋白選自金屬蛋白酶、NS2、NS3、NS4A、NS4B、NS5A、NS5B、以及HCV病毒複製所需要的內部核糖體進入點(IRES)和肌苷單磷酸脫氫酶(IMPDH)。 In some embodiments, the pharmaceutical composition of the present invention further comprises at least one HCV inhibitor, wherein the HCV inhibitor is used to inhibit the HCV replication process and / or inhibit the HCV viral protein function; wherein the HCV replication The process is selected from at least one of the processes of HCV entry, unshelling, translation, replication, assembly and release; the HCV viral protein is selected from metalloproteinases, NS2, NS3, NS4A, NS4B, NS5A, NS5B, and HCV virus replication Required internal ribosome entry point (IRES) and inosine monophosphate dehydrogenase (IMPDH).

另一方面，本發明涉及式(I)所示化合物的酸加成鹽或鹼加成鹽或其藥物組合物在製備藥物中的用途，所述藥物用於抑制HCV複製和/或抑制HCV病毒蛋白功能，其中所述HCV複製過程選自HCV進入、脫殼、翻譯、複製、組裝和釋放的過程的至少之一；所述的HCV病毒蛋白選自金屬蛋白酶、NS2、NS3、NS4A、NS4B、NS5A、NS5B、以及HCV病毒複製所需要的內部核糖體進入點(IRES)和肌苷單磷酸脫氫酶(IMPDH)。 In another aspect, the present invention relates to the use of an acid addition salt or a base addition salt of a compound represented by formula (I) or a pharmaceutical composition thereof in the manufacture of a medicament for inhibiting HCV replication and / or HCV virus Protein function, wherein the HCV replication process is selected from at least one of the processes of HCV entry, unshelling, translation, replication, assembly and release; the HCV viral protein is selected from metalloproteinases, NS2, NS3, NS4A, NS4B, NS5A, NS5B, and internal ribosome entry points (IRES) and inosine monophosphate dehydrogenase (IMPDH) required for HCV virus replication.

另一方面，本發明涉及式(I)所示化合物的酸加成鹽或鹼加成鹽或其藥物組合物在製備藥物中的用途，所述藥物用於預防、處理、治療或減輕患者的HCV感染或丙型肝炎疾病。 In another aspect, the present invention relates to the use of an acid addition salt or a base addition salt of a compound represented by formula (I) or a pharmaceutical composition thereof in the manufacture of a medicament for the prevention, treatment, treatment or alleviation of a patient's HCV infection or hepatitis C disease.

圖1為式(I)所示化合物N-甲基葡糖胺鹽無定形的X射線粉末衍射(XRPD)圖；圖2為式(I)所示化合物L-精氨酸鹽無定形的X射線粉末衍射(XRPD)圖；圖3為式(I)所示化合物L-賴氨酸鹽無定形的X射線粉末衍射(XRPD)圖；圖4為式(I)所示化合物鈉鹽無定形的X射線粉末衍射(XRPD)圖；圖5為式(I)所示化合物鈣鹽無定形的X射線粉末衍射(XRPD)圖；圖6為式(I)所示化合物鉀鹽無定形的X射線粉末衍射(XRPD)圖； 圖7為式(I)所示化合物鋰鹽無定形的X射線粉末衍射(XRPD)圖；圖8為式(I)所示化合物二乙胺鹽無定形的X射線粉末衍射(XRPD)圖；圖9為式(I)所示化合物氨基丁三醇鹽無定形的X射線粉末衍射(XRPD)圖；圖10為式(I)所示化合物二乙氨基乙醇鹽無定形的X射線粉末衍射(XRPD)圖；圖11為式(I)所示化合物呱嗪鹽無定形的X射線粉末衍射(XRPD)圖；圖12為式(I)所示化合物鎂鹽無定形的X射線粉末衍射(XRPD)圖；圖13為式(I)所示化合物二甲基乙醇胺無定形的X射線粉末衍射(XRPD)圖；圖14為式(I)所示化合物乙二胺鹽無定形的X射線粉末衍射(XRPD)圖；圖15為式(I)所示化合物三乙醇胺鹽無定形的X射線粉末衍射(XRPD)圖；圖16為式(I)所示化合物乙醇胺鹽無定形的X射線粉末衍射(XRPD)圖；圖17為式(I)所示化合物咪唑鹽無定形的X射線粉末衍射(XRPD)圖；圖18為式(I)所示化合物檸檬酸鹽無定形的X射線粉末衍射(XRPD)圖；圖19為式(I)所示化合物對甲苯磺酸鹽無定形的X射線粉末衍射(XRPD)圖；圖20為式(I)所示化合物苯磺酸鹽無定形的X射線粉末衍射(XRPD)圖；圖21為式(I)所示化合物甲磺酸鹽無定形的X射線粉末衍射(XRPD)圖；圖22為式(I)所示化合物硫酸鹽無定形的X射線粉末衍射(XRPD)圖；圖23為式(I)所示化合物磷酸鹽無定形的X射線粉末衍射(XRPD)圖；圖24為式(I)所示化合物硝酸鹽無定形的X射線粉末衍射(XRPD)圖；圖25為式(I)所示化合物1,5-萘二磺酸鹽無定形的X射線粉末衍射(XRPD)圖；圖26為式(I)所示化合物1,2-乙二磺酸鹽無定形的X射線粉末衍射(XRPD)圖；圖27為式(I)所示化合物β-萘磺酸鹽無定形的X射線粉末衍射(XRPD)圖；圖28為式(I)所示化合物環拉酸鹽無定形的X射線粉末衍射(XRPD)圖；圖29為式(I)所示化合物羥乙基磺酸鹽無定形的X射線粉末衍射(XRPD)圖；圖30為式(I)所示化合物馬來酸鹽無定形的X射線粉末衍射(XRPD)圖； 圖31為式(I)所示化合物氫溴酸鹽無定形的X射線粉末衍射(XRPD)圖；圖32為式(I)所示化合物鹽酸鹽無定形的X射線粉末衍射(XRPD)圖；以及圖33為式(I)所示化合物無定形的X射線粉末衍射(XRPD)圖。 FIG. 1 is an X-ray powder diffraction (XRPD) pattern of an amorphous form of a compound of formula (I) N -methylglucamine salt; FIG. 2 is an amorphous X of an L -arginine salt of a compound of formula (I) X-ray powder diffraction (XRPD) pattern; FIG. 3 is an X-ray powder diffraction (XRPD) pattern of the compound L -lysine salt amorphous of the formula (I); FIG. 4 is a sodium salt amorphous form of the compound of the formula (I) X-ray powder diffraction (XRPD) pattern; Figure 5 is an X-ray powder diffraction (XRPD) pattern of the calcium salt of the compound of formula (I); Figure 6 is an X-ray powder amorphous X of the compound of the formula (I) X-ray powder diffraction (XRPD) diagram; FIG. 7 is an X-ray powder diffraction (XRPD) diagram of an amorphous lithium salt of a compound represented by formula (I); FIG. 8 is an X-ray powder amorphous X-ray diffraction of a compound of formula (I) X-ray powder diffraction (XRPD) diagram; FIG. 9 is an amorphous X-ray powder diffraction (XRPD) diagram of the aminobutanetriol salt of the compound represented by formula (I); FIG. 10 is a diethylaminoethanol salt of the compound represented by formula (I) Amorphous X-ray powder diffraction (XRPD) pattern; FIG. 11 is an amorphous X-ray powder diffraction (XRPD) pattern of the compound oxazine salt of the formula (I); FIG. 12 is a magnesium salt of the compound of the formula (I) without Shaped X-ray powder diffraction (XRPD) pattern; 13 is an amorphous X-ray powder diffraction (XRPD) pattern of the compound dimethylethanolamine shown by formula (I); FIG. 14 is an amorphous X-ray powder diffraction (XRPD) pattern of the compound of formula (I) ethylenediamine salt FIG. 15 is an X-ray powder diffraction (XRPD) pattern of the amorphous triethanolamine salt of the compound of formula (I); FIG. 16 is an X-ray powder diffraction (XRPD) pattern of the amorphous ethanolamine salt of the compound of the formula (I); FIG. 17 is an X-ray powder diffraction (XRPD) pattern of the compound of formula (I) imidazole salt amorphous; FIG. 18 is an X-ray powder diffraction (XRPD) pattern of the compound of formula (I) citrate amorphous; 19 is an X-ray powder diffraction (XRPD) pattern of the p-toluenesulfonate amorphous compound of the formula (I); FIG. 20 is an X-ray powder diffraction (XRPD) of the benzenesulfonate amorphous compound of the formula (I) FIG. 21 is an X-ray powder diffraction (XRPD) pattern of the mesylate salt of the compound of the formula (I); FIG. 22 is an X-ray powder diffraction (XRPD) pattern of the sulfate of the compound of the formula (I). FIG. 23 is an X-ray powder diffraction (XRPD) pattern of a compound of the formula (I) phosphate amorphous; FIG. 24 is an X-ray powder diffraction (XRP) of an amorphous form of a compound of the formula (I) D) Figure; Figure 25 is an amorphous X-ray powder diffraction (XRPD) pattern of the compound 1,5-naphthalene disulfonate represented by formula (I); Figure 26 is a compound 1,2-ethyl represented by formula (I) Amorphous X-ray powder diffraction (XRPD) pattern of disulfonate; FIG. 27 is an X-ray powder diffraction (XRPD) pattern of β-naphthalenesulfonate amorphous of compound represented by formula (I); FIG. 28 is formula (I Amorphous X-ray powder diffraction (XRPD) pattern of the compound shown by); Figure 29 is an X-ray powder diffraction (XRPD) pattern of the isethionate amorphous compound of formula (I); Figure 30 Is an X-ray powder diffraction (XRPD) pattern of the maleate salt of the compound of formula (I); FIG. 31 is an X-ray powder diffraction (XRPD) pattern of the hydrobromide salt of the compound of the formula (I); FIG. 32 is an X-ray powder diffraction (XRPD) pattern of the compound hydrochloride salt of formula (I); and FIG. 33 is an X-ray powder diffraction (XRPD) pattern of the compound of formula (I) amorphous.

術語定義Definition of Terms

除非另有說明，本發明使用的所有技術和科學術語與本發明所屬領域的普通技術人員所通常理解的具有相同含義。本發明涉及的所有專利和公開出版物通過引用方式整體併入本發明。儘管在本發明的實踐或者測試中可以使用與本發明所述相似或者相同的任何方法和物質，但是本發明中所描述的是較佳的方法、設備和物質。 Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. All patents and publications related to the present invention are incorporated herein by reference in their entirety. Although any methods and materials similar or identical to those described herein can be used in the practice or testing of the present invention, the preferred methods, devices and materials are described in the present invention.

本發明中“室溫”指的是溫度由大約10℃到大約40℃。在一些實施例中，”室溫”指的是溫度由大約20℃到大約30℃；在另一些實施例中，“室溫”指的是溫度由大約25℃到大約30℃；在又一些實施例中，“室溫”指的是10℃、15℃、20℃、25℃、30℃、35℃、40℃等等。 In the present invention, "room temperature" means a temperature from about 10 ° C to about 40 ° C. In some embodiments, "room temperature" refers to a temperature from about 20 ° C to about 30 ° C; in other embodiments, "room temperature" refers to a temperature from about 25 ° C to about 30 ° C; in still other In the examples, "room temperature" means 10 ° C, 15 ° C, 20 ° C, 25 ° C, 30 ° C, 35 ° C, 40 ° C, and the like.

本發明使用的術語“藥學上可接受”是指從毒理學觀點來看可接受用於製藥應用且不會不利地與活性成分相互作用的物質。 The term "pharmaceutically acceptable" as used herein refers to a substance that is acceptable from a toxicological point of view for pharmaceutical applications and does not adversely interact with the active ingredients.

“藥學上可接受的鹽”表示處於健全醫學判斷的範圍內、適用於與人類和低等動物組織接觸而無過度毒性、刺激性、變應性反應等且具有相當合理的益處/風險比的鹽，是本領域所熟知的，如文獻：Berge et al.,describe pharmaceutically acceptable salts in detail in J.Pharmacol Sci,1997,66：1-19詳細描述了藥學上可接受的鹽，其通過引用併入本文。 "Pharmaceutically acceptable salt" means within the scope of sound medical judgment, suitable for contact with humans and lower animal tissues without excessive toxicity, irritation, allergic reactions, etc., and has a reasonable benefit / risk ratio Salts are well known in the art, such as the literature: Berge et al., Describe pharmaceutically acceptable salts in detail in J. Pharmacol Sci, 1997, 66: 1-19, which are described in detail by reference and Into this article.

本文所用術語“約”具有常規含義。在一些實施方案中，當與數值相關時，可理解為數值±10%、或±5%、或±2%、或±1%、或±0.5%、或±0.1%。在其他實施方案中，省略詞語“約”以表明精確值。 The term "about" as used herein has its conventional meaning. In some embodiments, when related to a numerical value, it can be understood as a numerical value of ± 10%, or ± 5%, or ± 2%, or ± 1%, or ± 0.5%, or ± 0.1%. In other embodiments, the word "about" is omitted to indicate an exact value.

本發明“藥學上可接受的酸加成鹽”是指式(I)所示化合物同無機酸或有機酸形成的加成鹽。適宜的無機酸鹽包括，但不限於：鹽酸鹽、硫酸鹽、硫酸氫鹽、硝酸鹽、氫溴酸鹽、氫碘酸鹽、碳酸鹽、碳酸氫鹽、亞硫酸鹽、亞硫酸氫鹽、焦硫酸鹽、磷酸一氫鹽、磷酸二氫鹽、高氯酸鹽、過硫酸鹽、半硫酸鹽、重硫酸鹽、硫氰酸鹽、磷酸鹽、焦磷酸鹽、偏磷酸鹽；適宜的有機酸鹽 包括，但不限於：甲酸鹽、乙酸鹽、丙酸鹽、丁酸鹽、苯甲酸鹽、丙二酸鹽、丁二酸鹽、丙酮酸鹽、甲磺酸鹽、乙磺酸鹽、丙磺酸鹽、檸檬酸鹽、4-硝基苯甲酸鹽、苯磺酸鹽、對甲苯磺酸鹽、蘋果酸鹽、丙炔酸鹽、2-丁炔酸鹽、2-羥基-乙烷磺酸鹽、乙烯基乙酸鹽、酒石酸鹽、L-酒石酸鹽、富馬酸鹽、羥乙基磺酸鹽、馬來酸鹽、乳酸鹽、乳糖酸鹽、雙羥萘酸鹽、水楊酸鹽、半乳糖二酸鹽、葡庚糖酸鹽、扁桃酸鹽、1,2-乙烷基二磺酸鹽、2-萘磺酸鹽、草酸鹽、三氟乙酸鹽、三氟甲磺酸鹽、己二酸鹽、辛二酸鹽、癸二酸鹽、丁炔-1,4-二酸鹽、己炔-1,6-二酸鹽、羥基乙酸鹽、藻酸鹽、抗壞血酸鹽、異抗壞血酸鹽、天冬氨酸鹽、L-天冬氨酸鹽、谷氨酸鹽、L-谷氨酸鹽、2-苯氧基苯甲酸鹽、2-(4-羥基苯甲醯基)苯甲酸鹽、乙醯乙酸鹽、2-羥基乙磺酸鹽、硼酸鹽、氯代苯甲酸鹽、樟腦酸鹽、衣康酸鹽、樟腦磺酸鹽、左旋樟腦磺酸鹽、甲基苯甲酸鹽、二硝基苯甲酸鹽、氨基磺酸鹽、半乳糖醛酸鹽、環戊基丙酸鹽、十二烷基硫酸鹽、丙烯酸鹽、環戊烷丙酸鹽、甘油磷酸鹽、甲氧基苯甲酸鹽、二葡萄糖酸鹽、葡萄糖酸鹽、庚酸鹽、己酸鹽、三甲基乙酸鹽、葡糖醛酸鹽、月桂酸鹽、鄰苯二甲酸鹽、苯乙酸鹽、月桂基硫酸鹽、2-乙醯氧基苯甲酸鹽、煙酸鹽、肉桂酸鹽、油酸鹽、棕櫚酸鹽、果膠酸鹽、苯二甲酸鹽、戊二酸鹽、羥基馬來酸鹽、羥基苯甲酸鹽、苯乙酸鹽、3-羥基-2-萘甲酸鹽、3-苯基丙酸鹽、異丁酸鹽、新戊酸鹽、苦味酸鹽、硬脂酸鹽、2,2-二氯乙酸鹽、醯化氨基酸鹽、海藻酸鹽、4-乙醯氨基苯磺酸鹽、葵酸鹽、膽酸鹽、辛酸鹽、壬酸鹽、環拉酸鹽、酞酸鹽、鹽酸半胱氨酸鹽、山梨酸鹽、鹽酸甘氨酸鹽、萘二磺酸鹽、二甲苯磺酸鹽、二鹽酸胱氨酸鹽、十一酸鹽、聚乙烯磺酸鹽、磺基水楊酸鹽、苯基丁酸鹽、4-羥基丁酸鹽、聚乙烯硫酸鹽、萘-1-磺酸鹽、萘-2-磺酸鹽和戊酸鹽。 The "pharmaceutically acceptable acid addition salt" in the present invention refers to an addition salt of a compound represented by the formula (I) with an inorganic acid or an organic acid. Suitable inorganic acid salts include, but are not limited to, hydrochloride, sulfate, bisulfate, nitrate, hydrobromide, hydroiodate, carbonate, bicarbonate, sulfite, bisulfite , Pyrosulfate, monohydrogen phosphate, dihydrogen phosphate, perchlorate, persulfate, hemisulfate, double sulfate, thiocyanate, phosphate, pyrophosphate, metaphosphate; suitable Organic acid salts include, but are not limited to, formate, acetate, propionate, butyrate, benzoate, malonate, succinate, pyruvate, mesylate, and ethylsulfonate Acid salt, propionate, citrate, 4-nitrobenzoate, benzenesulfonate, p-toluenesulfonate, malate, propionate, 2-butynate, 2- Hydroxy-ethane sulfonate, vinyl acetate, tartrate, L -tartrate, fumarate, isethionate, maleate, lactate, lactate, paraben , Salicylate, galactate, glucoheptanoate, mandelate, 1,2-ethanedisulfonate, 2-naphthalenesulfonate, oxalate, trifluoroacetate, three Mesylate, adipate, suberate, sebacate, butyne-1,4-diacid, hexyne-1,6-diacid, glycolate, alginate, Ascorbate, erythorbic acid, aspartate, L -aspartate, glutamate, L -glutamate, 2-phenoxybenzoate, 2- (4-hydroxybenzene (Formamyl) benzoate, acetoacetate, 2-hydroxyethanesulfonate, borate, chlorobenzoate, camphor salt, itaconic acid salt, camphor sulfonate, l-camphorsulfonic acid Salt, methylbenzoate, dinitrobenzoate, sulfamate, galacturonate, cyclopentylpropionate, dodecyl sulfate, acrylate, cyclopentanepropionic acid Salt, glyceryl phosphate, methoxybenzoate, digluconate, gluconate, heptanoate, hexanoate, trimethylacetate, glucuronate, laurate, phthalate Formate, phenylacetate, lauryl sulfate, 2-acetoxybenzoate, nicotinate, cinnamate, oleate, palmitate, pectate, phthalate , Glutarate, hydroxymaleate, hydroxy Benzoate, phenylacetate, 3-hydroxy-2-naphthoate, 3-phenylpropionate, isobutyrate, pivalate, picrate, stearate, 2,2 -Dichloroacetate, tritiated amino acid salt, alginate, 4-acetamidobenzenebenzenesulfonate, citrate, cholate, caprylate, nonanoate, citric acid, phthalate, hydrochloric acid Cysteine, sorbate, glycine hydrochloride, naphthalene disulfonate, xylene sulfonate, cystine dihydrochloride, undecanoate, polyethylene sulfonate, sulfosalicylate , Phenylbutyrate, 4-hydroxybutyrate, polyethylene sulfate, naphthalene-1-sulfonate, naphthalene-2-sulfonate, and valerate.

本發明“藥學上可接受的鹼加成鹽”是指式(I)所示化合物與鹼形成的加成鹽。適宜的鹼加成鹽包括，但不限於：鋰鹽、鈉鹽、鉀鹽、鈣鹽、鎂鹽、鋁鹽、鐵鹽、亞鐵鹽、錳鹽、亞錳鹽、銅鹽、鋅鹽和銨鹽；或式(I)所示化合物與甲胺、二甲胺、三甲胺、乙胺、二乙胺、三乙胺、氨基丁三醇、二乙氨基乙醇、異丙胺、2-乙氨基乙醇、吡啶、甲基吡啶、乙醇胺、二乙醇胺、銨、二甲基乙醇胺、四甲基銨、四乙基銨、三乙醇胺、呱啶、呱嗪、嗎啉、咪唑、賴氨酸、精氨酸、L-精氨酸、組氨酸、N-甲基葡糖胺、二甲基葡糖胺、乙基葡糖胺、 二環己基胺、1,6-己二胺、乙二胺、葡糖胺、肌氨酸、絲氨醇、氨基丙二醇、1-氨基-2,3,4-丁三醇、L-賴氨酸和鳥氨酸形成的鹽。 The "pharmaceutically acceptable base addition salt" in the present invention means an addition salt formed by a compound represented by formula (I) and a base. Suitable base addition salts include, but are not limited to: lithium, sodium, potassium, calcium, magnesium, aluminum, iron, ferrous, manganese, manganese, copper, zinc, and Ammonium salt; or a compound of formula (I) with methylamine, dimethylamine, trimethylamine, ethylamine, diethylamine, triethylamine, tromethamine, diethylaminoethanol, isopropylamine, 2-ethylamino Ethanol, pyridine, methylpyridine, ethanolamine, diethanolamine, ammonium, dimethylethanolamine, tetramethylammonium, tetraethylammonium, triethanolamine, pyridine, verazine, morpholine, imidazole, lysine, arginine Acid, L -arginine, histidine, N -methylglucosamine, dimethylglucosamine, ethylglucosamine, dicyclohexylamine, 1,6-hexanediamine, ethylenediamine, Glucosamine, sarcosine, serine, aminopropanediol, 1-amino-2,3,4-butanetriol, L -lysine and ornithine.

“無定形”或“無定形形式”是指物質的質點(分子、原子、離子)在三維空間排列無週期性時形成的物質，其特徵是具有漫射之不具尖峰的X射線粉末衍射圖。無定形是固體物質的一種特殊的物理形式，其局部有序的結構特徵，提示其與晶型物質有著千絲萬縷的聯繫。物質的無定形形式可通過本領域已知的許多方法得到。這種方法包括，但不限於，驟冷法、反溶劑絮凝法、球磨法、噴霧乾燥法、冷凍乾燥法、濕法製粒法和固體分散體技術等等。 "Amorphous" or "amorphous form" refers to a substance formed when the particle points (molecules, atoms, ions) of a substance are arranged in a three-dimensional space without periodicity, and is characterized by a diffuse X-ray powder diffraction pattern without sharp peaks. Amorphous is a special physical form of solid matter, and its locally ordered structural features suggest that it has inextricable links with crystalline matter. Amorphous forms of matter can be obtained by many methods known in the art. Such methods include, but are not limited to, quenching, antisolvent flocculation, ball milling, spray drying, freeze drying, wet granulation, solid dispersion technology, and the like.

“溶劑”是指一種物質(典型地是一種液體)，該物質能夠完全地或部分地溶解另一種物質(典型地是一種固體)。用於本發明實施的溶劑包括但並不限於：水、乙酸、***、異丙醚、石油醚、乙酸異丙酯、乙酸正丙酯、甲基叔丁基醚、正庚烷、體積比為10：90~90：10的乙醇和水的混合溶劑、體積比為2：1~1：2的甲醇和二氯甲烷的混合物溶劑、丙酮、乙腈、苯、氯仿、四氯化碳、二氯甲烷、二甲基亞碸、1,4-二氧六環、乙醇、乙酸乙酯、正丁醇、叔丁醇、N,N-二甲基乙醯胺、N,N-二甲基甲醯胺、甲醯胺、蟻酸、己烷、異丙醇、甲醇、甲基乙基酮、1-甲基-2-吡咯烷酮、均三甲苯、硝基甲烷、聚乙二醇、正丙醇、2-丙酮、吡啶、四氫呋喃、甲乙酮、甲苯、二甲苯、它們的混合物等等。 "Solvent" refers to a substance (typically a liquid) that is capable of completely or partially dissolving another substance (typically a solid). The solvents used in the practice of the present invention include, but are not limited to, water, acetic acid, diethyl ether, isopropyl ether, petroleum ether, isopropyl acetate, n-propyl acetate, methyl tert-butyl ether, n-heptane, and the volume ratio is 10: 90 ~ 90: 10 mixed solvent of ethanol and water, mixed solvent of methanol and dichloromethane in a volume ratio of 2: 1 ~ 1: 2, acetone, acetonitrile, benzene, chloroform, carbon tetrachloride, dichloride Methane, dimethyl sulfene, 1,4-dioxane, ethanol, ethyl acetate, n-butanol, t-butanol, N, N -dimethylacetamide, N, N -dimethylformamide Hydrazine, formamidine, formic acid, hexane, isopropanol, methanol, methyl ethyl ketone, 1-methyl-2-pyrrolidone, mesitylene, nitromethane, polyethylene glycol, n-propanol, 2-acetone, pyridine, tetrahydrofuran, methyl ethyl ketone, toluene, xylene, mixtures thereof, and the like.

本發明的“溶劑化物”是指一個或多個溶劑分子與本發明化合物的鹽所形成的締合物，或溶劑分子吸附在本發明化合物的鹽無定形表面。形成溶劑化物的溶劑包括，但並不限於，水，異丙醇，乙醇，甲醇，二甲亞碸，二氯甲烷、乙酸乙酯，乙酸，氨基乙醇、體積比為2：1~1：2的甲醇和二氯甲烷的混合物溶劑。術語“水合物”是指溶劑分子是水所形成的締合物或水分子吸附在本發明的化合物的鹽無定形表面。 The "solvate" of the present invention means an association formed by one or more solvent molecules and a salt of a compound of the present invention, or a solvent molecule adsorbed on an amorphous surface of a salt of a compound of the present invention. Solvents that form solvates include, but are not limited to, water, isopropanol, ethanol, methanol, dimethyl sulfoxide, dichloromethane, ethyl acetate, acetic acid, aminoethanol, and a volume ratio of 2: 1 to 1: 2 A solvent mixture of methanol and dichloromethane. The term "hydrate" refers to an association of a solvent molecule formed by water or a salt amorphous surface of a compound of the present invention adsorbed on a water molecule.

無定形可以通過多種技術手段進行鑑別，例如X射線粉末衍射(XRPD)、紅外吸收光譜法(IR)、熔點法、差示掃描量熱法(DSC)、熱重分析法(TGA)、核磁共振法、拉曼光譜、X射線單晶衍射、溶解量熱法、掃描電子顯微鏡(SEM)、定量分析、溶解度和溶解速度等等。 Amorphous can be identified by a variety of techniques, such as X-ray powder diffraction (XRPD), infrared absorption spectroscopy (IR), melting point method, differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), nuclear magnetic resonance Method, Raman spectroscopy, X-ray single crystal diffraction, dissolution calorimetry, scanning electron microscope (SEM), quantitative analysis, solubility and dissolution rate, etc.

在本發明中，所述的鹼加成鹽或酸加成鹽中可以含有溶劑，常見的溶劑包括水、乙醇、甲醇、異丙醇、乙酸正丙酯、四氫呋喃、丙酮、異丙醚、***、乙酸異丙酯、正庚烷、乙酸乙酯、體積比為2：1~1：2的甲醇和二氯甲烷的 混合物溶劑等。含有一定量水或其他溶劑的鹼加成鹽或酸加成鹽只要具有本發明所述的鹼加成鹽或酸加成鹽的任一特徵，均應認為包含在本發明的範圍內。 In the present invention, the base addition salt or acid addition salt may contain a solvent. Common solvents include water, ethanol, methanol, isopropanol, n-propyl acetate, tetrahydrofuran, acetone, isopropyl ether, and ether. , Isopropyl acetate, n-heptane, ethyl acetate, methanol and dichloromethane in a volume ratio of 2: 1 to 1: 2 Mixture solvent and so on. Alkali addition salts or acid addition salts containing a certain amount of water or other solvents should be considered to be included in the scope of the present invention as long as they have any of the characteristics of the base addition salts or acid addition salts described in the present invention.

在本發明的上下文中，X-射線粉末衍射圖中的2θ值均以度(°)為單位。 In the context of the present invention, all 2θ values in the X-ray powder diffraction pattern are in degrees (°).

術語“基本上如圖所示”是指X-射線粉末衍射圖至少50%，或至少60%，或至少70%，或至少80%，或至少90%，或至少95%，或至少99%的峰顯示在其圖中。 The term "substantially as shown" means that the X-ray powder diffraction pattern is at least 50%, or at least 60%, or at least 70%, or at least 80%, or at least 90%, or at least 95%, or at least 99% The peaks are shown in its graph.

當提及譜圖或/和出現在圖中的資料時，“峰”指本領域技術人員能夠識別的不會歸屬於背景雜音的一個特徵。 When referring to a spectrum or / and the material appearing in the figure, "peak" refers to a feature that can be recognized by those skilled in the art and does not belong to background noise.

“相對強度”是指X-射線粉末衍射圖(XRPD)的所有衍射峰中第一強峰的強度為100%時，其它峰的強度與第一強峰的強度的比值。 "Relative intensity" refers to the ratio of the intensity of the other strong peak to the intensity of the first strong peak when the intensity of the first strong peak among all the diffraction peaks of the X-ray powder diffraction pattern (XRPD) is 100%.

在本發明的上下文中，當使用或者無論是否使用“大約”或”約”等字眼時，表示在給定的值或範圍的10%以內，適當地在5%以內，特別是在1%以內。或者，對於本領域普通技術人員而言，術語”大約”或”約”表示在平均值的可接受的標準誤差範圍內。每當公開一個具有N值的數字時，任何具有N+/-1%，N+/-2%，N+/-3%，N+/-5%，N+/-7%，N+/-8%或N+/-10%值以內的數字會被明確地公開，其中”+/-”是指加或減。 In the context of the present invention, when the words "about" or "about" are used or not, it means within 10% of a given value or range, suitably within 5%, and especially within 1% . Alternatively, for those of ordinary skill in the art, the term "about" or "about" means within an acceptable standard error of the mean. Whenever a number with a value of N is disclosed, any with a number of N +/- 1%, N +/- 2%, N +/- 3%, N +/- 5%, N +/- 7%, N +/- 8% or N + Numbers within the / -10% value will be explicitly disclosed, where "+/-" means plus or minus.

除非其他方面表明，本發明所描述的結構式包括所有的同分異構形式(如對映異構，非對映異構，和幾何異構(或構象異構))：例如含有不對稱中心的R、S構型，雙鍵的(Z)、(E)異構體，和(Z)、(E)的構象異構體。因此，本發明的化合物的單個立體化學異構體或其對映異構體，非對映異構體，或幾何異構體(或構象異構體)的混合物都屬於本發明的範圍。 Unless otherwise indicated, the structural formulae described herein include all isomeric forms (such as enantiomers, diastereomers, and geometric isomers (or conformers)): for example, containing asymmetric centers R, S configuration, (Z), (E) isomers of double bonds, and (Z), (E) isomers. Therefore, the single stereochemical isomers of the compounds of the invention or their enantiomers, diastereomers, or mixtures of geometric isomers (or conformers) are within the scope of the invention.

除非其他方面表明，本發明的化合物的所有互變異構形式都包含在本發明的範圍之內。另外，除非其他方面表明，本發明所描述的化合物的結構式包括一個或多個不同的原子的富集同位素。同位素富集的化合物具有本發明給出的結構，除了一個或多個原子被具有所選擇原子量或質量數的原子替換。可引入本發明化合物中的示例性同位素包括氫、碳、氮、氧、磷、硫、氟和氯的同位素，如2H、3H、11C、13C、14C、15N、17O、18O、18F、31P、32P、35S、36Cl和125I。 Unless otherwise indicated, all tautomeric forms of the compounds of the invention are included within the scope of the invention. In addition, unless otherwise indicated, the structural formula of the compounds described herein includes enriched isotopes of one or more different atoms. Isotopically enriched compounds have the structure given in the present invention, except that one or more atoms are replaced by an atom having a selected atomic mass or mass number. Exemplary isotopes that can be incorporated into compounds of the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine, such as 2 H, 3 H, 11 C, 13 C, 14 C, 15 N, 17 O , 18 O, 18 F, 31 P, 32 P, 35 S, 36 Cl, and 125 I.

另一方面，本發明所述化合物包括同位素富集的本發明所定義的化合物，例如，其中存在放射性同位素，如3H、14C和18F的化合物，或者其中存在非放射性同位素，如2H和13C的化合物。該類同位素富集的化合物可用於代謝研究(使用14C)、反應動力學研究(使用例如2H或3H)、檢測或成像技術，如正電子發射斷層掃描術(PET)或包括藥物或底物組織分佈測定的單光子發射電腦斷層成像術(SPECT)，或可用於患者的放療中。18F富集的化合物對PET或SPECT研究而言是特別理想的。同位素富集的式(I)所示化合物可以通過本領域技術人員熟悉的常規技術或本發明中的實施例和製備過程所描述使用合適的同位素標記試劑替代原來使用過的未標記試劑來製備。 In another aspect, the compounds described herein include isotopically enriched compounds as defined by the invention, for example, compounds in which radioisotopes are present, such as 3 H, 14 C, and 18 F, or in which non-radioactive isotopes are present, such as 2 H And 13 C compounds. This class of isotopically enriched compounds can be used in metabolic studies (using 14 C), reaction kinetic studies (using, for example, 2 H or 3 H), detection or imaging techniques such as positron emission tomography (PET) or including drugs or Single tissue photon emission computed tomography (SPECT) for the determination of substrate tissue distribution may be used in patients with radiotherapy. 18 F-enriched compounds are particularly desirable for PET or SPECT studies. Isotopically enriched compounds of formula (I) can be prepared by conventional techniques familiar to those skilled in the art or as described in the examples and preparation procedures of the present invention, using suitable isotopically labeled reagents instead of unlabeled reagents that were previously used.

此外，較重同位素特別是氘(即，2H或D)的取代可提供某些治療優點，這些優點是由代謝穩定性更高帶來的。例如，體內半衰期增加或劑量需求降低或治療指數得到改善帶來的。應當理解，本發明中的氘被看作式(I)所示化合物的取代基。可以用同位素富集因數來定義該類較重同位素特別是氘的濃度。本發明所使用的術語”同位素富集因數”是指所指定同位素的同位素豐度和天然豐度之間的比例。如果本發明化合物的取代基被指定為氘，該化合物對各指定的氘原子而言具有至少3500(各指定氘原子處52.5%的氘摻入)、至少4000(60%的氘摻入)、至少4500(67.5%的氘摻入)，至少5000(75%的氘摻入)，至少5500(82.5%的氘摻入)、至少6000(90%的氘摻入)、至少6333.3(95%的氘摻入)、至少6466.7(97%的氘摻入)、至少6600(99%的氘摻入)或至少6633.3(99.5%的氘摻入)的同位素富集因數。本發明可藥用的溶劑化物包括其中結晶溶劑可以是同位素取代的例如D2O、丙酮-d 6、DMSO-d 6的那些溶劑化物。 In addition, the substitution of heavier isotopes, especially deuterium (ie, 2 H or D), can provide certain therapeutic advantages that result from higher metabolic stability. For example, increased half-life in the body or reduced dose requirements or improved therapeutic index. It should be understood that deuterium in the present invention is regarded as a substituent of the compound represented by formula (I). The concentration of such heavier isotopes, especially deuterium, can be defined by the isotopic enrichment factor. The term "isotopic enrichment factor" used in the present invention refers to the ratio between the isotopic abundance and the natural abundance of a specified isotope. If the substituent of a compound of the present invention is designated as deuterium, the compound has at least 3500 (52.5% deuterium incorporation at each specified deuterium atom), at least 4000 (60% deuterium incorporation) for each specified deuterium atom, At least 4500 (67.5% deuterium incorporation), at least 5000 (75% deuterium incorporation), at least 5500 (82.5% deuterium incorporation), at least 6000 (90% deuterium incorporation), at least 6333.3 (95% Deuterium incorporation), at least 6466.7 (97% deuterium incorporation), at least 6600 (99% deuterium incorporation), or at least 6633.3 (99.5% deuterium incorporation) isotope enrichment factors. The pharmaceutically acceptable solvates of the present invention include those in which the crystalline solvent may be isotopically substituted, such as D 2 O, acetone- d 6 , DMSO- d 6 .

本發明中立體化學的定義和慣例的使用通常參考以下文獻：S.P.Parker,Ed.,McGraw-Hill Dictionary of Chemical Terms(1984)McGraw-Hill Book Company,New York；and Eliel,E.and Wilen,S.,“Stereochemistry of Organic Compounds”,John Wiley&Sons,Inc.,New York,1994．本發明的化合物可以包含不對稱中心或手性中心，因此存在不同的立體異構體。本發明的化合物所有的立體異構形式，包括但絕不限於，非對映異構體，對映異構體，阻轉異構體，和它們的混合物，如外消旋混合物，組成了本發明的一部分。很多有機化合物都以光學活性形式存在，即它們有能力旋轉平面偏振光的平面。在描述光學活性化合物時，首碼D、L或R、S用來表示分子手性中心的絕對構型。首碼d、l或 (+)、(-)用來命名化合物平面偏振光旋轉的符號，(-)或l是指化合物是左旋的，首碼(+)或d是指化合物是右旋的。這些立體異構體的化學結構是相同的，但是它們的立體結構不一樣。特定的立體異構體可以是對映體，異構體的混合物通常稱為對映異構體混合物。50：50的對映體混合物被稱為外消旋混合物或外消旋體，這可能導致化學反應過程中沒有立體選擇性或立體定向性。術語”外消旋混合物”和”外消旋體”是指等摩爾的兩個對映異構體的混合物，缺乏光學活性。 The definitions and conventions of stereochemistry in the present invention are generally referred to the following documents: SPParker, Ed., McGraw-Hill Dictionary of Chemical Terms (1984) McGraw-Hill Book Company, New York; and Eliel, E. and Wilen, S. "Stereochemistry of Organic Compounds", John Wiley & Sons, Inc., New York, 1994. The compounds of the present invention may contain asymmetric centers or chiral centers and therefore exist in different stereoisomers. All stereoisomeric forms of the compounds of the present invention, including but by no means limited to, diastereomers, enantiomers, atropisomers, and mixtures thereof, such as racemic mixtures, constitute the present invention. Part of the invention. Many organic compounds exist in optically active forms, that is, they have the ability to rotate the plane of plane-polarized light. When describing optically active compounds, the first code D, L or R , S is used to indicate the absolute configuration of the chiral center of the molecule. The first code d, l or (+), (-) is a symbol used to name the compound ’s plane polarized light rotation. (-) Or l means that the compound is left-handed, and the first code (+) or d means that the compound is right-handed . The chemical structures of these stereoisomers are the same, but their stereostructures are different. Specific stereoisomers can be enantiomers, and mixtures of isomers are often referred to as enantiomeric mixtures. A 50:50 mixture of enantiomers is called a racemic mixture or a racemate, which may result in no stereoselectivity or stereospecificity during the chemical reaction. The terms "racemic mixture" and "racemate" refer to an equimolar mixture of two enantiomers, lacking optical activity.

本發明化合物的鹼加成鹽或酸加成鹽或所述的藥物組合物適用於治療患有HCV感染或患有HCV感染相關病症的哺乳動物(尤其是人)的方法，所述方法包括給予需要治療的哺乳動物式(I)所示化合物的無定形鹽。 The base addition salt or acid addition salt of the compound of the present invention or the pharmaceutical composition is suitable for a method for treating a mammal (especially a human) suffering from HCV infection or a condition related to HCV infection, said method comprising An amorphous salt of a compound of formula (I) in a mammal in need of treatment.

本發明化合物鹽的藥物組合物，製劑和給藥Pharmaceutical composition, preparation and administration of a compound salt of the present invention

像本發明所描述的，本發明藥物組合物包含任何一種本發明的式(I)所示化合物的鹼加成鹽或酸加成鹽，進一步包含藥學上可接受的輔料，比如載體、稀釋劑、填充劑、黏合劑、矯味劑或賦形劑，這些像本發明所應用的，包括任何溶劑、稀釋劑或其他液體賦形劑、分散劑或懸浮劑、表面活性劑、等滲劑、增稠劑、乳化劑、防腐劑、固體黏合劑或潤滑劑等，適合於特定的目標劑型。如以下文獻所描述的：In Remington：The Science and Practice of Pharmacy,21st edition,2005,ed.D.B.Troy,Lippincott Williams& Wilkins,Philadelphia,and Encyclopedia of Pharmaceutical Technology,eds.J.Swarbrick and J.C.Boylan,1988-1999,Marcel Dekker,New York，綜合此處文獻的內容，表明不同的輔料可應用於藥學上可接受的藥物組合物的製劑和它們公知的製備方法。除了任何常規的輔料與本發明的化合物不相容的範圍，例如所產生的任何不良的生物效應或與藥學上可接受的藥物組合物的任何其他組分以有害的方式產生的相互作用，它們的用途也是本發明所考慮的範圍。 As described in the present invention, the pharmaceutical composition of the present invention comprises any one of a base addition salt or an acid addition salt of the compound represented by formula (I) of the present invention, and further comprises a pharmaceutically acceptable excipient such as a carrier, a diluent , Fillers, binders, flavoring agents or excipients, as used in the present invention, include any solvents, diluents or other liquid excipients, dispersants or suspending agents, surfactants, isotonicity agents, extenders Thickeners, emulsifiers, preservatives, solid binders or lubricants, etc. are suitable for specific target dosage forms. As described in: In Remington: The Science and Practice of Pharmacy, 21st edition, 2005, ed. DBTroy, Lippincott Williams & Wilkins, Philadelphia, and Encyclopedia of Pharmaceutical Technology, eds. J. Swarbrick and JC Boylan, 1988- 1999, Marcel Dekker, New York, synthesizing the content of the literature herein, shows that different excipients can be applied to the formulation of pharmaceutically acceptable pharmaceutical compositions and their well-known preparation methods. Except to the extent that any conventional excipients are incompatible with the compounds of the invention, such as any adverse biological effects produced or interactions with any other component of the pharmaceutically acceptable pharmaceutical composition in a harmful manner, they The use is also within the scope of the present invention.

可作為藥學上可接受輔料的物質包括，但並不限於，離子交換劑；鋁；硬脂酸鋁；卵磷脂；血清蛋白，如人血清蛋白；緩衝物質如磷酸鹽；甘氨酸；山梨酸；山梨酸鉀；飽和植物脂肪酸的部分甘油酯混合物；水；鹽或電解質，如硫酸魚精蛋白，磷酸氫二鈉，磷酸氫鉀，氯化鈉，鋅鹽；膠體矽；三矽酸鎂；聚乙烯吡咯烷酮；聚丙烯酸脂；蠟；聚乙烯-聚氧丙烯-阻斷聚合體；羊毛脂；糖，如乳糖，葡萄糖和蔗糖；澱粉如玉米澱粉和土豆澱粉；纖維素和 它的衍生物如羧甲基纖維素鈉，乙基纖維素和乙酸纖維素；樹膠粉；麥芽；明膠；滑石粉；輔料如可哥豆脂和栓劑蠟狀物；油如花生油，棉子油，紅花油，麻油，橄欖油，玉米油和豆油；二醇類化合物，如丙二醇和聚乙二醇；酯類如乙基油酸酯和乙基月桂酸酯；瓊脂；緩衝劑如氫氧化鎂和氫氧化鋁；海藻酸；無熱原的水；等滲鹽；林格(氏)溶液；乙醇；磷酸緩衝溶液；和其他無毒的合適的潤滑劑如月桂硫酸鈉和硬脂酸鎂；著色劑；釋放劑；包衣衣料；甜味劑；調味劑；香料；防腐劑和抗氧化劑。 Substances that can be used as pharmaceutically acceptable excipients include, but are not limited to, ion exchangers; aluminum; aluminum stearate; lecithin; serum proteins such as human serum proteins; buffer substances such as phosphate; glycine; sorbic acid; sorbic acid Potassium acid; partial glyceride mixture of saturated vegetable fatty acids; water; salts or electrolytes such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts; colloidal silicon; magnesium trisilicate; polyethylene Pyrrolidone; polyacrylates; waxes; polyethylene-polyoxypropylene-blocking polymers; lanolin; sugars such as lactose, glucose and sucrose; starches such as corn starch and potato starch; cellulose and Its derivatives such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; gum powder; malt; gelatin; talcum powder; excipients such as cocoa butter and suppository waxes; oils such as peanut oil, cottonseed Oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; glycol compounds such as propylene glycol and polyethylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffers such as hydroxide Magnesium and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic salts; Ringer's solution; ethanol; phosphate buffer solution; and other non-toxic suitable lubricants such as sodium lauryl sulfate and magnesium stearate; Coloring agents; release agents; coatings; sweeteners; flavoring agents; flavors; preservatives and antioxidants.

所述藥物組合物進一步包含抗HCV的藥物。所述抗HCV的藥物可以為任何已知的不同於本發明化合物的其他用於抗HCV的藥物。例如，可以為干擾素、利巴韋林、白介素2、白介素6、白介素12、促進產生1型輔助性T細胞應答的化合物、干擾RNA、反義RNA、咪喹莫德、肌苷5’-單磷酸脫氫酶抑制劑、金剛烷胺、金剛乙胺、利托那韋、巴維昔單抗(Bavituximab)、CivacirTM、波普瑞韋(boceprevir)、替拉瑞韋(telaprevir)、索非布韋(sofosbuvir)、雷迪帕韋(ledipasvir)、達卡他韋(daclatasvir)、丹諾普韋(danoprevir)、西魯瑞韋(ciluprevir)、那拉匹韋(narlaprevir)、deleobuvir(BI-207127)、dasabuvir(ABT-333)、beclabuvir(BMS-791325)、elbasvir(MK-8742)、ombitasvir(ABT-267)、neceprevir(ACH-2684)、tegobuvir(GS-9190)、grazoprevir(MK-5172)、sovaprevir(ACH-1625)、samatasvir(IDX-719)、veruprevir(ABT-450)、埃羅替尼(erlotinib)、simeprevir(TMC-435)、asunaprevir(BMS-650032)、vaniprevir(MK-7009)、faldaprevir(BI-2013335)、VX-135、CIGB-230、furaprevir(TG-2349)、pibrentasvir(ABT-530)、glecaprevir(ABT-493)、uprifosbuvir(IDX-21437)、radalbuvir(GS-9669)、JHJ-56914845、vedroprevir(GS-9451)、BZF-961、GS-9256、ANA975、EDP239、ravidasvir hydrochloride(PPI-668)、velpatasvir(GS-5816)、MK-8325、GSK-2336805、PPI-461、ACH-1095、VX-985、IDX-375、VX-500、VX-813、PHX-1766、PHX-2054、IDX-136、IDX-316、modithromycin(EP-013420)、VBY-376、TMC-649128、mericitabine(R-7128)、INX-189、IDX-184、IDX102、R1479、UNX-08189、PSI-6130、PSI-938、PSI-879、HCV-796、nesbuvir(HCV-371)、VCH-916、lomibuvir(VCH-222)、setrobuvir(ANA-598)、MK-3281、ABT-072、filibuvir(PF-00868554)、deleobuvir(BI-207127)、A-837093、JKT-109、Gl-59728、GL-60667、AZD-2795、TMC-647055或其組合；其中所述干擾素為干擾素α-2b、 聚乙二醇化的干擾素α、干擾素α-2a、聚乙二醇化的干擾素α-2a、複合α-干擾素、干擾素γ或其組合。所述藥物組合物，進一步包含至少一種HCV抑制劑，所述HCV抑制劑用於抑制HCV複製過程和/或抑制HCV病毒蛋白的功能；所述HCV複製過程包括HCV進入、HCV脫殼、HCV翻譯、HCV複製、HCV組裝和HCV釋放；所述的HCV病毒蛋白選自金屬蛋白酶、NS2、NS3、NS4A、NS4B、NS5A或NS5B，以及HCV病毒複製所需要的內部核糖體進入點(IRES)和肌苷單磷酸脫氫酶(IMPDH)。 The pharmaceutical composition further comprises an anti-HCV drug. The anti-HCV drug may be any other anti-HCV drug known to be different from the compound of the present invention. For example, it can be interferon, ribavirin, interleukin 2, interleukin 6, interleukin 12, compounds that promote the production of type 1 helper T cell responses, interfering RNA, antisense RNA, imiquimod, inosine 5'- Monophosphate dehydrogenase inhibitors, amantadine, rimantadine, ritonavir, bavituximab, Civacir TM , boceprevir, telaprevir, solanum Sofosbuvir, ledipasvir, daclatasvir, danoprevir, ciluprevir, narlaprevir, deleobuvir (BI -207127), dasabuvir (ABT-333), beclabuvir (BMS-791325), elbasvir (MK-8742), ombitasvir (ABT-267), neceprevir (ACH-2684), tegobuvir (GS-9190), grazoprevir (MK- 5172), sovaprevir (ACH-1625), samatasvir (IDX-719), veruprevir (ABT-450), erlotinib, simeprevir (TMC-435), asunaprevir (BMS-650032), vaniprevir (MK- 7009), faldaprevir (BI-2013335), VX-135, CIGB-230, furaprevir (TG-2349), pibrentasvir (ABT-530), glecaprevir (ABT-493), uprifosbuvir (IDX-21 437), radarbuvir (GS-9669), JHJ-56914845, vedroprevir (GS-9451), BZF-961, GS-9256, ANA975, EDP239, ravidasvir hydrochloride (PPI-668), velpatasvir (GS-5816), MK- 8325, GSK-2336805, PPI-461, ACH-1095, VX-985, IDX-375, VX-500, VX-813, PHX-1766, PHX-2054, IDX-136, IDX-316, modithromycin (EP- 013420), VBY-376, TMC-649128, mericitabine (R-7128), INX-189, IDX-184, IDX102, R1479, UNX-08189, PSI-6130, PSI-938, PSI-879, HCV-796, nesbuvir (HCV-371), VCH-916, lomibuvir (VCH-222), setrobuvir (ANA-598), MK-3281, ABT-072, filibuvir (PF-00868554), deleobuvir (BI-207127), A-837093 , JKT-109, Gl-59728, GL-60667, AZD-2795, TMC-647055, or a combination thereof; wherein the interferon is interferon alpha-2b, pegylated interferon alpha, interferon alpha-2a , Pegylated interferon alpha-2a, complex alpha-interferon, interferon gamma, or a combination thereof. The pharmaceutical composition further comprises at least one HCV inhibitor, the HCV inhibitor is used to inhibit the HCV replication process and / or inhibit the function of the HCV viral protein; the HCV replication process includes HCV entry, HCV husking, and HCV translation , HCV replication, HCV assembly, and HCV release; the HCV viral protein is selected from metalloproteinases, NS2, NS3, NS4A, NS4B, NS5A, or NS5B, and the internal ribosome entry point (IRES) and muscle required for HCV virus replication Glycoside monophosphate dehydrogenase (IMPDH).

當可用於治療時，治療有效量的本發明化合物的鹽，尤其是式(I)所示化合物的鹼加成鹽或酸加成鹽可作為未加工的化學藥品給予，還可作為藥物組合物的活性成分提供。因此，本發明內容還提供藥物組合物，該藥物組合物包括治療有效量的本發明化合物的鹽，尤其是式(I)所示化合物的鹼加成鹽或酸加成鹽和一種或多種藥學上可接受的載體、稀釋劑或賦形劑。本文所使用的術語”治療有效量”是指足以顯示出有意義的患者益處(例如病毒負荷減少)的各活性組分的總量。當使用單獨的活性成分單獨給藥時，該術語僅指該成分。當組合應用時，該術語則是指不論組合，依次或同時給藥時，都引起治療效果的活性成分的組合量。本發明化合物的鹽，尤其是式(I)所示化合物的鹼加成鹽或酸加成鹽如上所述。從與製劑其他成分相容以及對其接受者無害的意義上來講，載體、稀釋劑或賦形劑必須是可接受的。根據本發明內容的另一方面，還提供用於製備藥物製劑的方法，該方法包括將本發明化合物的鹽，尤其是式(I)所示化合物的鹼加成鹽或酸加成鹽與一種或多種藥學上可接受的載體、稀釋劑或賦形劑混勻。本發明所使用的術語”藥學上可接受的”是指這樣的化合物、原料、組合物和/或劑型，它們在合理醫學判斷的範圍內，適用於與患者組織接觸而無過度毒性、刺激性、變態反應或與合理的利益/風險比相對稱的其他問題和併發症，並有效用於既定用途。 When available for treatment, a therapeutically effective amount of a salt of a compound of the present invention, especially a base addition salt or an acid addition salt of a compound represented by formula (I), can be administered as a raw chemical or as a pharmaceutical composition. The active ingredients are provided. Therefore, the present invention also provides a pharmaceutical composition comprising a therapeutically effective amount of a salt of a compound of the present invention, particularly a base addition salt or acid addition salt of a compound represented by formula (I) and one or more pharmaceuticals Acceptable carrier, diluent or excipient. The term "therapeutically effective amount" as used herein refers to the total amount of each active ingredient sufficient to show a meaningful patient benefit, such as a reduction in viral load. When administered separately using a separate active ingredient, the term refers only to that ingredient. When used in combination, the term refers to the combined amount of active ingredients that, whether administered in combination, sequentially or simultaneously, causes a therapeutic effect. The salt of the compound of the present invention, especially the base addition salt or acid addition salt of the compound represented by the formula (I) is as described above. The carrier, diluent or excipient must be acceptable in the sense of being compatible with the other ingredients of the formulation and not harmful to its recipient. According to another aspect of the content of the present invention, there is also provided a method for preparing a pharmaceutical preparation, which method comprises combining a salt of a compound of the present invention, particularly a base addition salt or acid addition salt of a compound of formula (I) with a Or more pharmaceutically acceptable carriers, diluents or excipients. The term "pharmaceutically acceptable" as used in the present invention refers to such compounds, raw materials, compositions and / or dosage forms which, within the scope of sound medical judgment, are suitable for contact with patient tissues without excessive toxicity or irritation , Allergies, or other problems and complications commensurate with a reasonable benefit / risk ratio, and effectively used for the intended purpose.

藥物製劑可呈單位劑型，每個單位劑量含有預定量的活性成分。本發明內容的化合物的劑量水準介於約0.01毫克/千克(mg/kg)體重/天和約250毫克/千克體重/天之間，較佳介於約0.05mg/kg體重/天與約100mg/kg體重/天之間，常常以單一療法用於預防或治療HCV介導的疾病。通常可按每天約1至約5次或者作為連續輸注給予本發明內容的藥物組合物。這類給藥法可用作長期或短期療法。與載體材料混合以製備單一劑型的活性成分的量將根據待治療的疾病、 疾病的嚴重程度、給藥時間、給藥途徑、所用化合物的***速率、治療時間和患者年齡、性別、體重和情況而改變。較佳的單位劑型是含有本文上述活性成分的日劑量或分劑量或其適宜分數的單位劑型。可用顯然低於化合物最佳劑量的小劑量開始治療。此後，以較小的增量來加大劑量直到在這種情況下達到最佳效果。一般而言，最理想地給予化合物的濃度水準是通常可在抗病毒方面提供有效結果而又不至於引起任何有害或有毒的副作用。 Pharmaceutical preparations may be in unit dosage form, each unit dose containing a predetermined amount of the active ingredient. The dosage levels of the compounds of the present invention are between about 0.01 mg / kg (mg / kg) body weight / day and about 250 mg / kg body weight / day, preferably between about 0.05 mg / kg body weight / day and about 100 mg / day. Between kg body weight / day, monotherapy is often used to prevent or treat HCV-mediated diseases. The pharmaceutical composition of the present invention may generally be administered at about 1 to about 5 times per day or as a continuous infusion. This type of administration can be used as a long-term or short-term therapy. The amount of active ingredient that is mixed with the carrier material to produce a single dosage form will depend on the disease to be treated, The severity of the disease, the time of administration, the route of administration, the excretion rate of the compound used, the duration of treatment and the age, sex, weight and condition of the patient will vary. A preferred unit dosage form is a unit dosage form containing a daily or divided dose of the above-mentioned active ingredients or a suitable fraction thereof. Treatment can be initiated with small doses that are clearly below the optimal dose of the compound. Thereafter, the dose is increased in smaller increments until the best effect is achieved in this case. In general, the level of concentration optimally administered to a compound is such that it generally provides effective results in antivirals without causing any harmful or toxic side effects.

當本發明內容的藥物組合物包含本發明內容的化合物和一種或多種其他治療藥物或預防藥物的組合時，化合物和另外的藥物的劑量水準通常在單一療法方案中，占正常給藥劑量的約10-150%，更佳占正常給藥劑量的約10-80%。藥物製劑適於通過任何合適的途徑給藥，例如通過口服(包括口腔或舌下)、直腸、鼻、局部(包括口腔、舌下或經皮)、***或胃腸外(包括皮下、皮內、肌內、關節內、滑膜內、胸骨內、鞘內、病灶內、靜脈內或者真皮下注射或輸注)途徑。可按藥劑學領域的任何已知方法製備這類製劑，例如通過將活性成分與載體或賦形劑混合。較佳口服給藥或注射給藥。 When the pharmaceutical composition of the present invention comprises a combination of the compound of the present invention and one or more other therapeutic or prophylactic drugs, the dosage level of the compound and the additional drug is usually in a monotherapy regimen, which accounts for about 10-150%, more preferably about 10-80% of the normal administered dose. Pharmaceutical formulations are suitable for administration by any suitable route, such as by oral (including oral or sublingual), rectal, nasal, topical (including oral, sublingual, or transdermal), vaginal or parenteral (including subcutaneous, intradermal, Intramuscular, intraarticular, intrasynovial, intrasternal, intrathecal, intralesional, intravenous or subdermal injection or infusion) route. Such formulations may be prepared by any method known in the pharmaceutical arts, for example by mixing the active ingredient with a carrier or excipient. It is preferably administered orally or by injection.

適於口服給藥的藥物製劑按獨立的單位提供，例如膠囊劑或片劑；散劑或顆粒劑；水性或非水性液體中的溶液劑或混懸劑；可食用泡沫製劑或起泡製劑(whip)；或水包油乳液劑或油包水乳液劑。 Pharmaceutical preparations suitable for oral administration are provided in separate units such as capsules or tablets; powders or granules; solutions or suspensions in aqueous or non-aqueous liquids; edible foam or foaming preparations (whip ); Or an oil-in-water emulsion or a water-in-oil emulsion.

舉例來說，對於以片劑或膠囊劑形式的口服給藥，活性藥物組分可與藥學上可接受的口服無毒惰性載體(例如乙醇、甘油、水等)相混合。通過將化合物粉碎成合適的微細尺寸，並與被同樣粉碎的藥用載體(例如澱粉或甘露醇等可食用的糖類)混勻來製備散劑。還可存在矯味劑、防腐劑、分散劑和著色劑。 For example, for oral administration in the form of a tablet or capsule, the active pharmaceutical ingredient may be mixed with a pharmaceutically acceptable oral non-toxic inert carrier such as ethanol, glycerol, water, and the like. The powder is prepared by pulverizing the compound to a suitable fine size and mixing it with a similarly pulverized pharmaceutical carrier (such as starch or edible sugars such as mannitol). Flavoring agents, preservatives, dispersants and colorants may also be present.

通過製備如上所述的粉狀混合物，並裝填到成形的明膠殼內，來製備膠囊劑。在裝填操作之前，可將助流劑和潤滑劑(例如膠態二氧化矽、滑石粉、硬脂酸鎂、硬脂酸鈣或固態聚乙二醇)加到粉狀混合物中。還可加入當服下膠囊劑時將改進藥物可利用性的崩解劑或增溶劑(例如瓊脂、碳酸鈣或碳酸鈉)。 Capsules are prepared by preparing a powdery mixture as described above and filling it into a shaped gelatin shell. Prior to the filling operation, glidants and lubricants (such as colloidal silica, talc, magnesium stearate, calcium stearate, or solid polyethylene glycol) can be added to the powder mixture. Disintegrating or solubilizing agents (such as agar, calcium carbonate, or sodium carbonate) that will improve the availability of the drug when the capsule is taken may also be added.

此外需要或必需時，也可將合適的黏合劑、潤滑劑、崩解劑和著色劑摻到混合物中。合適的黏合劑包括澱粉、明膠、天然糖(例如葡萄糖或β-乳糖)、玉米甜味劑、天然和合成樹膠(例如***樹膠、西黃蓍膠或藻酸鈉)、羧甲基纖維素、聚乙二醇等。用於這些劑型的潤滑劑包括油酸鈉、氯化鈉等。崩解劑包括但並不限於澱粉、甲基纖維素、瓊脂、皂土、黃原膠等。例如，通過 製成粉狀混合物，製粒或預壓片，加入潤滑劑和崩解劑，壓製成片，從而製成片劑。將適當粉碎的化合物與如上述所述的稀釋劑或基料、任選與黏合劑(例如羧甲基纖維素、藻酸鹽、明膠或聚乙烯吡咯烷酮)、溶解阻止劑(例如石蠟)、吸收加速劑(如季鹽)和/或吸收劑(例如皂土、高嶺土或磷酸二鈣)混合，來製備粉狀混合物。可用黏合劑(例如糖漿、澱粉漿、***膠漿(acadiamucilage)或纖維素材料或聚合材料溶液)潤濕後加壓過篩，將粉狀混合物製粒。製粒的一個替代方法是，可將粉狀混合物通過壓片機，結果是將形成不佳的團塊再擊碎製成顆粒。可通過加入硬脂酸、硬脂酸鹽，滑石粉或礦物油使顆粒潤滑以防止黏到壓片機的沖模上。然後將經潤滑的混合物壓製成片。本發明內容的化合物還可與自由流動的惰性載體混合，無需通過製粒或預壓片步驟便可壓製成片。可提供透明或不透明的由蟲膠密封衣、糖衣或聚合材料衣和蠟質拋光衣(polish coating of wax)組成的保護性包衣材料。可將染料加到這些包衣材料中以區分不同的單位劑量。 In addition, when desired or necessary, suitable binders, lubricants, disintegrating agents, and coloring agents can also be incorporated into the mixture. Suitable binders include starch, gelatin, natural sugars (e.g. glucose or β-lactose), corn sweeteners, natural and synthetic gums (e.g. gum arabic, tragacanth or sodium alginate), carboxymethyl cellulose, Polyethylene glycol, etc. Lubricants used in these dosage forms include sodium oleate, sodium chloride, and the like. Disintegrating agents include, but are not limited to, starch, methyl cellulose, agar, bentonite, xanthan gum, and the like. For example, It is made into a powdery mixture, granulated or pre-compressed, added with a lubricant and a disintegrant, and compressed into tablets to form tablets. Appropriately pulverized compound with a diluent or base as described above, optionally with a binder (e.g., carboxymethyl cellulose, alginate, gelatin or polyvinylpyrrolidone), a dissolution inhibitor (e.g., paraffin), absorption An accelerator (such as a quaternary salt) and / or an absorbent (such as bentonite, kaolin, or dicalcium phosphate) are mixed to prepare a powdery mixture. The powdery mixture can be granulated with a binder (for example, syrup, starch syrup, acadiamucilage, or a solution of a cellulose material or a polymeric material) and then sieved under pressure. An alternative method of granulation is to pass the powdery mixture through a tablet press, with the result that the poorly formed agglomerates are crushed and granulated. The granules can be lubricated by adding stearic acid, stearates, talc or mineral oil to prevent sticking to the die of the tablet press. The lubricated mixture is then compressed into tablets. The compounds of the present invention can also be mixed with a free-flowing inert carrier and compressed into tablets without the need for granulation or pre-pressing steps. Transparent or opaque protective coating materials consisting of a shellac sealer, a sugar coat or a polymeric coat and a wax coating of wax can be provided. Dyes can be added to these coating materials to distinguish different unit doses.

口服液體製劑例如溶液劑、糖漿劑和酏劑可以劑量單位形式製備。糖漿劑可通過將化合物溶於適當調味的水溶液中來製備，而酏劑可通過使用無毒溶媒來製備。還可加入增溶劑和乳化劑(例如乙氧基化異硬脂醇和聚氧乙烯山梨醇醚)、防腐劑、矯味添加劑(例如薄荷油或天然甜味劑或糖精或其他人造甜味劑)等。 Oral liquid preparations such as solutions, syrups and elixirs can be prepared in the form of dosage units. Syrups can be prepared by dissolving the compound in a suitably flavored aqueous solution, and elixirs can be prepared by using a non-toxic vehicle. Solubilizers and emulsifiers (such as ethoxylated isostearyl alcohol and polyoxyethylene sorbitol ether), preservatives, flavoring additives (such as peppermint oil or natural sweeteners or saccharin or other artificial sweeteners), etc. .

如果適當的話，可將用於口服給藥的劑量單位製劑微膠囊化。也可將製劑製成延時或持續釋放，例如通過包衣或包埋在聚合物、蠟等微粒材料中。 If appropriate, dosage unit formulations for oral administration may be microencapsulated. The formulations can also be formulated for delayed or sustained release, for example by coating or embedding in particulate materials such as polymers, waxes and the like.

本發明式(I)所示化合物的鹼加成鹽或酸加成鹽或其藥物組合物還可以脂質體遞藥系統給予，例如小單層脂質體、大單層脂質體和多層脂質體。脂質體可由多種磷脂(例如膽固醇、十八烷基胺或磷脂醯膽鹼)構成。 The base addition salt or acid addition salt of the compound represented by formula (I) of the present invention or a pharmaceutical composition thereof can also be administered in a liposome delivery system, such as a small monolayer liposome, a large monolayer liposome, and a multilayer liposome. Liposomes can be composed of a variety of phospholipids, such as cholesterol, stearylamine, or phospholipids choline.

本發明式(I)所示化合物的鹼加成鹽或酸加成鹽或其藥物組合物也可通過使用單克隆抗體作為單獨的載體(化合物分子與之偶聯)遞藥。化合物也可與作為靶向藥物載體的可溶性聚合物偶聯。這類聚合物可包括聚乙烯吡咯烷酮、吡喃共聚物、聚羥丙基甲基丙烯醯胺苯酚、聚羥乙基天冬醯胺苯酚或被棕櫚醯殘基取代的聚氧化乙烯聚賴氨酸。此外，化合物可與一類生物可降解的聚合物偶聯，用於達到藥物的控釋，這類聚合物例如聚乳酸、聚ε-己內酯、聚羥基 丁酸、聚原酸酯、聚縮醛、聚二氫吡喃、聚氰基丙烯酸酯和水凝膠的交聯共聚物或兩親性嵌段共聚物。 The base addition salt or acid addition salt of the compound represented by the formula (I) of the present invention or a pharmaceutical composition thereof can also be delivered by using a monoclonal antibody as a separate carrier to which a compound molecule is coupled. The compounds can also be coupled with soluble polymers as targeted drug carriers. Such polymers may include polyvinylpyrrolidone, pyran copolymer, polyhydroxypropylmethacrylamide phenol, polyhydroxyethylaspartamine phenol, or polyoxyethylene polylysine substituted with palmitoyl residues . In addition, compounds can be coupled with a class of biodegradable polymers, such as polylactic acid, polyε-caprolactone, polyhydroxy Cross-linked or amphiphilic block copolymers of butyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates, and hydrogels.

適於經皮給藥的藥物製劑可作為離散的貼劑(discrete patch)以在長時間內保持與接受者表皮密切接觸。例如，活性成分可由通過離子導入貼劑遞藥，通常可參見Pharmaceutical Research 1986,3(6),318。 Pharmaceutical formulations suitable for transdermal administration can be used as discrete patches to maintain close contact with the epidermis of the recipient for a long time. For example, the active ingredient can be delivered by an iontophoretic patch, generally see Pharmaceutical Research 1986, 3 (6), 318.

適於局部給藥的藥物製劑可製成軟膏劑、乳膏劑、混懸劑、洗劑、散劑、溶液劑、糊劑、凝膠劑、噴霧劑、氣霧劑、油製劑或透皮貼劑。 Pharmaceutical preparations suitable for topical administration can be prepared as ointments, creams, suspensions, lotions, powders, solutions, pastes, gels, sprays, aerosols, oil preparations or transdermal patches .

適於直腸給藥的藥物製劑可作為栓劑或作為灌腸劑提供。 Pharmaceutical formulations suitable for rectal administration can be provided as suppositories or as enemas.

適於經鼻給藥的藥物製劑(其中載體為固體)包括粒徑為例如20-500微米範圍的粗粉劑，通過以鼻吸方式給藥，即通過鼻通道從接近鼻子的粗粉劑容器中快速吸入。其中載體為液體、適於作為鼻腔噴霧劑或滴鼻劑給藥的合適製劑包括活性成分的水性溶液劑或油性溶液劑。 Pharmaceutical formulations suitable for nasal administration (where the carrier is a solid) include coarse powders with a particle size in the range of, for example, 20-500 microns, which are administered by nasal suction, that is, quickly from a coarse powder container near the nose through the nasal passage Inhale. Suitable formulations in which the carrier is a liquid and suitable for administration as a nasal spray or nasal drop include aqueous solutions or oily solutions of the active ingredient.

適於通過吸入給藥的藥物製劑包括微細粒子粉劑(dust)或細霧劑(mist)，可用不同類型計量的劑量壓縮氣溶膠、霧化吸入器、吹入器或其他適宜遞送氣溶膠噴霧劑的裝置中製備。 Pharmaceutical formulations suitable for administration by inhalation include fine particle dust or mist, compressed aerosols, nebulizers, insufflators, or other aerosol sprays suitable for different types of metered doses In the device.

適於***給藥的藥物製劑可以***栓、***塞、乳膏劑、霜劑、凝膠劑、糊劑、泡沫劑或噴霧劑提供。 Pharmaceutical preparations suitable for vaginal administration can be provided as pessaries, vaginal plugs, creams, creams, gels, pastes, foams or sprays.

適於胃腸外給藥的藥物製劑包括水性和非水性無菌注射溶液劑及水性和非水性無菌混懸劑，水性和非水性無菌注射溶液劑可含有抗氧化劑、緩衝劑、抑菌劑和使所述製劑與待接受者血液等滲的溶質，水性和非水性無菌混懸劑可包括懸浮劑和增稠劑。製劑可以單位劑量或多劑量容器提供，例如密封的小瓶，並可保存在冷凍乾燥(凍乾)條件下，只需在臨用前加入無菌液體載體，例如注射用水。臨用時配置的注射溶液劑和混懸劑可由無菌粉針劑、顆粒劑和片劑製備。 Pharmaceutical formulations suitable for parenteral administration include aqueous and non-aqueous sterile injectable solutions and aqueous and non-aqueous sterile suspensions. Aqueous and non-aqueous sterile injectable solutions may contain antioxidants, buffers, bacteriostatic agents and agents. The formulations are sootonic with the blood of the recipient, the aqueous and non-aqueous sterile suspensions may include suspending agents and thickening agents. The formulations can be provided in unit-dose or multi-dose containers, such as sealed vials, and can be stored under freeze-dried (lyophilized) conditions by adding a sterile liquid carrier, such as water for injection, just before use. The ready-to-use injection solutions and suspensions can be prepared from sterile powder injections, granules and tablets.

應當瞭解的是，除了以上特別提到的成分以外，製劑還包括與所述製劑類型有關之本領域常用的其它成分，例如適於口服給藥的這類製劑可包括矯味劑。 It should be understood that, in addition to the ingredients specifically mentioned above, the formulation also includes other ingredients commonly used in the art in relation to the type of formulation, for example, such formulations suitable for oral administration may include flavoring agents.

本發明鹽和藥物組合物的用途Uses of the salts and pharmaceutical compositions of the invention

本發明提供了本發明式(I)所示化合物的鹼加成鹽或酸加成鹽或其藥物組合物在製備藥物中的用途，所述藥物可以用於抑制HCV複製過程和/或抑制HCV病毒蛋白的功能；所述HCV複製過程包括HCV進入、HCV脫殼、HCV翻譯、HCV複製、HCV組裝和HCV釋放；所述的HCV病毒蛋白選自金屬蛋白酶、NS2、NS3、NS4A、NS4B、NS5A或NS5B，以及HCV病毒複製所需要的內部核糖體進入點(IRES)和肌苷單磷酸脫氫酶(IMPDH)。本發明所述任一化合物或藥物組合物可以用於治療丙型肝炎病毒(HCV)感染或丙型肝炎疾病，特別地，其對HCV NS3/4A蛋白有很好的抑制作用。 The present invention provides the use of a base addition salt or acid addition salt of a compound represented by formula (I) of the present invention or a pharmaceutical composition thereof in the preparation of a medicament, which can be used to inhibit the HCV replication process and / or inhibit HCV The function of the viral protein; the HCV replication process includes HCV entry, HCV unshelling, HCV translation, HCV replication, HCV assembly, and HCV release; the HCV viral protein is selected from metalloproteinases, NS2, NS3, NS4A, NS4B, NS5A Or NS5B, and the internal ribosome entry point (IRES) and inosine monophosphate dehydrogenase (IMPDH) required for HCV virus replication. Any one of the compounds or pharmaceutical compositions of the present invention can be used to treat hepatitis C virus (HCV) infection or hepatitis C disease. In particular, it has a good inhibitory effect on HCV NS3 / 4A protein.

包含本發明式(I)所示化合物的鹼加成鹽或酸加成鹽或藥物組合物給藥的治療方法，進一步包括對患者給予其他抗HCV藥物，由此，可以將本發明的式(I)所示化合物的鹼加成鹽或酸加成鹽或藥物組合物與其他抗HCV藥物進行聯合治療，其中所述的其他抗HCV的藥物為干擾素、利巴韋林、白介素2、白介素6、白介素12、促進產生1型輔助性T細胞應答的化合物、干擾RNA、反義RNA、咪喹莫德、肌苷5’-單磷酸脫氫酶抑制劑、金剛烷胺、金剛乙胺、利托那韋、巴維昔單抗(Bavituximab)、CivacirTM、波普瑞韋(boceprevir)、替拉瑞韋(telaprevir)、索非布韋(sofosbuvir)、雷迪帕韋(ledipasvir)、達卡他韋(daclatasvir)、丹諾普韋(danoprevir)、西魯瑞韋(ciluprevir)、那拉匹韋(narlaprevir)、deleobuvir(BI-207127)、dasabuvir(ABT-333)、beclabuvir(BMS-791325)、elbasvir(MK-8742)、ombitasvir(ABT-267)、neceprevir(ACH-2684)、tegobuvir(GS-9190)、grazoprevir(MK-5172)、sovaprevir(ACH-1625)、samatasvir(IDX-719)、setrobuvir、veruprevir(ABT-450)、埃羅替尼(erlotinib)、simeprevir(TMC-435)、asunaprevir(BMS-650032)、vaniprevir(MK-7009)、faldaprevir(BI-2013335)、VX-135、CIGB-230、furaprevir(TG-2349)、pibrentasvir(ABT-530)、glecaprevir(ABT-493)、uprifosbuvir(IDX-21437)、radalbuvir(GS-9669)、JHJ-56914845、vedroprevir(GS-9451)、BZF-961、GS-9256、ANA975、EDP239、ravidasvir hydrochloride(PPI-668)、velpatasvir(GS-5816)、MK-8325、GSK-2336805、PPI-461、ACH-1095、VX-985、IDX-375、VX-500、VX-813、PHX-1766、PHX-2054、IDX-136、IDX-316、modithromycin(EP-013420)、VBY-376、TMC-649128、mericitabine(R-7128)、sofosbuvir(PSI-7977)、INX-189、IDX-184、IDX102、R1479、UNX-08189、PSI-6130、PSI-938、PSI-879、HCV-796、nesbuvir(HCV-371)、VCH-916、lomibuvir (VCH-222)、setrobuvir(ANA-598)、MK-3281、ABT-072、filibuvir(PF-00868554)、deleobuvir(BI-207127)、A-837093、JKT-109、Gl-59728、GL-60667、AZD-2795、TMC-647055或其組合；其中所述干擾素為干擾素α-2b、聚乙二醇化的干擾素α、干擾素α-2a、聚乙二醇化的干擾素α-2a、複合α-干擾素、干擾素γ或其組合。 The method of treating a base or an acid addition salt or a pharmaceutical composition comprising a compound represented by the formula (I) of the present invention further comprises administering another anti-HCV drug to the patient, whereby the formula ( I) Combined treatment of the base addition salt or acid addition salt of the compound shown with other anti-HCV drugs, wherein the other anti-HCV drugs are interferon, ribavirin, interleukin 2, interleukin 6, interleukin 12, compounds that promote the production of type 1 helper T cell responses, interference RNA, antisense RNA, imiquimod, inosine 5'-monophosphate dehydrogenase inhibitors, amantadine, amantadine, Ritonavir, Bavituximab, Civacir TM , boceprevir, telaprevir, sofosbuvir, ledipasvir, davidasvir Daclatasvir, danoprevir, ciluprevir, narlaprevir, deleobuvir (BI-207127), dasabuvir (ABT-333), beclabuvir (BMS-791325) ), Elbasvir (MK-8742), ombitasvir (ABT-267), neceprevir (ACH-2684), tegobuvir (GS-9190) grazoprevir (MK-5172), sovaprevir (ACH-1625), samatasvir (IDX-719), setrobuvir, veruprevir (ABT-450), erlotinib, simeprevir (TMC-435), asunaprevir (BMS-650032) ), Vaniprevir (MK-7009), faldaprevir (BI-2013335), VX-135, CIGB-230, furaprevir (TG-2349), pirentasvir (ABT-530), glecaprevir (ABT-493), uprifosbuvir (IDX-21437 ), Radarbuvir (GS-9669), JHJ-56914845, vedroprevir (GS-9451), BZF-961, GS-9256, ANA975, EDP239, ravidasvir hydrochloride (PPI-668), velpatasvir (GS-5816), MK-8325 , GSK-2336805, PPI-461, ACH-1095, VX-985, IDX-375, VX-500, VX-813, PHX-1766, PHX-2054, IDX-136, IDX-316, modithromycin (EP-013420 ), VBY-376, TMC-649128, mericitabine (R-7128), sofosbuvir (PSI-7977), INX-189, IDX-184, IDX102, R1479, UNX-08189, PSI-6130, PSI-938, PSI- 879, HCV-796, nesbuvir (HCV-371), VCH-916, lomibuvir (VCH-222), setrobuvir (ANA-598), MK-3281, ABT-072, filibuvir (PF-00868554), deleobuvir (BI- 207127), A-837093, JKT-109, Gl-59728, GL-60667, AZD-27 95. TMC-647055 or a combination thereof; wherein the interferon is interferon alpha-2b, pegylated interferon alpha, interferon alpha-2a, pegylated interferon alpha-2a, complex alpha- Interferon, interferon gamma, or a combination thereof.

並且包含本發明式(I)所示化合物的鹼加成鹽、酸加成鹽或藥物組合物給藥的治療方法，進一步包含其他抗HCV藥物的給藥，其中，其他抗HCV藥物可以和本發明式(I)所示化合物的鹼加成鹽、酸加成鹽或其藥物組合物聯合給藥，本發明式(I)所示化合物的鹼加成鹽、酸加成鹽或藥物組合物作為單個劑型，或分開作為多劑型的一部分。其他抗HCV藥物可以與本發明式(I)所示化合物的的鹼加成鹽或酸加成鹽同時給藥或不同時給藥。後者的情況，給藥可以錯開進行如6小時、12小時、1天、2天、3天、1周、2周、3周、1個月或2個月進行。 The method for the administration of a base addition salt, an acid addition salt or a pharmaceutical composition comprising a compound represented by the formula (I) of the present invention further comprises administration of other anti-HCV drugs, wherein other anti-HCV drugs may be combined with the present The base addition salt, the acid addition salt of the compound represented by the formula (I) or a pharmaceutical composition thereof is administered in combination. The base addition salt, the acid addition salt, or the pharmaceutical composition of the compound represented by the formula (I) of the present invention As a single dosage form or separately as part of multiple dosage forms. Other anti-HCV drugs may be administered simultaneously or simultaneously with the base addition salt or acid addition salt of the compound represented by formula (I) of the present invention. In the latter case, administration can be staggered, such as 6 hours, 12 hours, 1 day, 2 days, 3 days, 1 week, 2 weeks, 3 weeks, 1 month, or 2 months.

本發明的化合物或藥學上可接受的組合物的”有效量”或”有效劑量”是指處理或減輕一個或多個本發明所提到病症的嚴重度的有效量。根據本發明的方法，式(I)所示化合物的的鹼加成鹽或酸加成鹽和組合物可以是任何給藥量和任何給藥途徑來有效地用於處理或減輕疾病的嚴重程度。必需的準確的量將根據患者的情況而改變，這取決於種族，年齡，患者的一般條件，感染的嚴重程度、特殊的因素、給藥方式，等等。化合物或組合物可以和一個或多個其他治療劑聯合給藥，如本發明所討論的。 An "effective amount" or "effective dose" of a compound or pharmaceutically acceptable composition of the present invention refers to an effective amount that treats or reduces the severity of one or more of the conditions mentioned in the present invention. According to the method of the present invention, the base addition salt or acid addition salt and the composition of the compound represented by the formula (I) can be used in any amount and any route to effectively treat or reduce the severity of the disease . The exact amount necessary will vary depending on the patient, depending on race, age, general condition of the patient, severity of infection, special factors, mode of administration, and so on. The compound or composition can be administered in combination with one or more other therapeutic agents, as discussed herein.

一般合成方法General Synthesis Method

下面所描述的實施例，除非其他方面表明，所有的溫度定為攝氏度(℃)。除非其他方面表明，試劑購買於商品供應商如Aldrich Chemical Company,Arco Chemical Company and Alfa Chemical Company，使用時都沒有經過進一步純化。一般的試劑從汕頭西隴化工廠，廣東光華化學試劑廠，廣州化學試劑廠，天津好寓宇化學品有限公司，青島騰龍化學試劑有限公司和青島海洋化工廠購買得到。 In the examples described below, all temperatures are given in degrees Celsius (° C) unless otherwise indicated. Unless otherwise indicated, reagents were purchased from commercial suppliers such as Aldrich Chemical Company, Arco Chemical Company, and Alfa Chemical Company and were used without further purification. General reagents were purchased from Shantou Xilong Chemical Factory, Guangdong Guanghua Chemical Reagent Factory, Guangzhou Chemical Reagent Factory, Tianjin Haoyuyu Chemical Co., Ltd., Qingdao Tenglong Chemical Reagent Co., Ltd. and Qingdao Ocean Chemical Plant.

核磁共振光譜資料通過Bruker Avance 400核磁共振譜儀或Bruker Avance III HD 600核磁共振譜儀來測定，以CDCl3,DMSO-d6,CD3OD或d6-丙酮為溶劑(報導以ppm為單位)，用TMS(0ppm)或氯仿(7.25ppm)作為參照標準。當出現多重峰的時候，將使用下面的縮寫：s(singlet，單峰),d(doublet，雙 峰),t(triplet，三重峰),m(multiplet，多重峰),br(broadened，寬峰),dd(doublet of doublets，雙二重峰),ddd(doublet of doublet of doublets，雙雙二重峰),dt(doublet of triplets，雙三重峰),ddt(doublet of doublet of triplets，雙雙三重峰),td(triplet of doublets，三雙重峰)，br.s(broadened singlet，寬單峰)。偶合常數J，單位用赫茲(Hz)表示。 Nuclear magnetic resonance spectrum data were measured by Bruker Avance 400 nuclear magnetic resonance spectrometer or Bruker Avance III HD 600 nuclear magnetic resonance spectrometer, using CDCl3, DMSO-d6, CD3OD or d6-acetone as the solvent (reported in ppm), using TMS ( 0ppm) or chloroform (7.25ppm) as the reference standard. When multiple peaks appear, the following abbreviations will be used: s (singlet, singlet), d (doublet, double Peak), t (triplet, triplet), m (multiplet, multiple peaks), br (broadened, broad peaks), dd (doublet of doublets, double doublet), ddd (doublet of doublet of doublets, double doublet Peak), dt (doublet of triplets), ddt (doublet of doublet of triplets), td (triplet of doublets), br.s (broadened singlet). Coupling constant J, expressed in Hertz (Hz).

本發明所用X射線粉末衍射分析方法為：Empyrean衍射儀，使用Cu-Kα輻射(45KV,40mA)獲得X射線粉末衍射圖。在單晶矽樣品架上將粉末狀樣品製備成薄層，放在旋轉樣品臺上，在3°-40°的範圍內以0.0168°步長進行分析。使用Data Collector軟體收集資料，HighScore Plus軟體處理資料，Data Viewer軟體讀取資料。 The X-ray powder diffraction analysis method used in the present invention is: an Empyrean diffractometer, using Cu-Kα radiation (45KV, 40mA) to obtain an X-ray powder diffraction pattern. The powder sample was prepared into a thin layer on a single crystal silicon sample holder, and the sample was placed on a rotating sample stage, and the analysis was performed in steps of 0.0168 ° in a range of 3 ° -40 °. Data is collected using Data Collector software, HighScore Plus software processes the data, and Data Viewer software reads the data.

本發明元素含量檢測資料通過配備G31XXB真空系統的Agilent 7700X系列的ICP-MS來測定的，HMI高基體系統進樣器和新型雙模式檢測器應用於分析，電感耦合等離子體(ICP)源應用於ICP-MS質譜儀。 The element content detection data of the present invention is measured by an ICP-MS of an Agilent 7700X series equipped with a G31XXB vacuum system. An HMI high matrix system sampler and a new dual-mode detector are used for analysis, and an inductively coupled plasma (ICP) source is used ICP-MS mass spectrometer.

本發明的溶解度採用Aglient 1200高效液相色譜儀VWD檢測器測定，色譜柱型號為Waters Xbridge-C18(4.6×150mm，5μm)。檢測波長為250nm，流速為1.0mL/min，柱溫為35℃，流動相為乙腈-水(v/v=40/60)。 The solubility of the present invention is measured by an Aglient 1200 high performance liquid chromatograph VWD detector, and the chromatographic column model is Waters Xbridge-C18 (4.6 × 150 mm, 5 μm). The detection wavelength was 250 nm, the flow rate was 1.0 mL / min, the column temperature was 35 ° C, and the mobile phase was acetonitrile-water (v / v = 40/60).

低解析度質譜(MS)資料通過配備G1312A二元泵和a G1316A TCC(柱溫保持在30℃)的Agilent 6320系列LC-MS的光譜儀來測定的，G1329A自動採樣器和G1315B DAD檢測器應用於分析，ESI源應用於LC-MS光譜儀。 Low-resolution mass spectrometry (MS) data was measured by an Agilent 6320 series LC-MS spectrometer equipped with a G1312A binary pump and a G1316A TCC (column temperature maintained at 30 ° C). The G1329A autosampler and G1315B DAD detector were used. For analysis, the ESI source was applied to an LC-MS spectrometer.

低解析度質譜(MS)資料通過配備G1311A四元泵和G1316A TCC(柱溫保持在30℃)的Agilent 6120系列LC-MS的光譜儀來測定的，G1329A自動採樣器和G1315D DAD檢測器應用於分析，ESI源應用於LC-MS光譜儀。 Low-resolution mass spectrometry (MS) data was measured by an Agilent 6120 series LC-MS spectrometer equipped with a G1311A quaternary pump and G1316A TCC (column temperature maintained at 30 ° C). The G1329A autosampler and G1315D DAD detector were used for analysis. , ESI source is applied to LC-MS spectrometer.

以上兩種光譜儀都配備了Agilent Zorbax SB-C18柱，規格為2.1×30mm，5μm。注射體積是通過樣品濃度來確定；流速為0.6mL/min；HPLC的峰值是通過在210nm和254nm處的UV-Vis波長來記錄讀取的。流動相為0.1%的甲酸乙腈溶液(相A)和0.1%的甲酸超純水溶液(相B)。梯度洗脫條件如表1所示。 Both spectrometers are equipped with an Agilent Zorbax SB-C18 column, with specifications of 2.1 × 30mm and 5μm. The injection volume was determined by the sample concentration; the flow rate was 0.6 mL / min; and the peak value of HPLC was recorded by UV-Vis wavelengths at 210 nm and 254 nm. The mobile phase was a 0.1% formic acid acetonitrile solution (phase A) and a 0.1% formic acid ultrapure aqueous solution (phase B). The gradient elution conditions are shown in Table 1.

Figure TW201805289AD00004
Figure TW201805289AD00004

化合物純度是通過Agilent 1100系列高效液相色譜(HPLC)來評價的，其中UV檢測在210nm和254nm處，Zorbax SB-C18柱，規格為2.1×30mm，4μm，10分鐘，流速為0.6mL/min，5-95%的(0.1%甲酸乙腈溶液)的(0.1%甲酸水溶液)，柱溫保持在40℃。 The purity of the compounds was evaluated by Agilent 1100 series high performance liquid chromatography (HPLC), where UV detection was at 210nm and 254nm, Zorbax SB-C18 column, specifications 2.1 × 30mm, 4μm, 10 minutes, flow rate 0.6mL / min , 5-95% (0.1% formic acid acetonitrile solution) (0.1% formic acid aqueous solution), the column temperature was maintained at 40 ° C.

化合物色譜製備分離是通過Agilent 1260系列高效液相色譜(HPLC)來實現的，其中UV檢測在278nm處，Calesil ODS-120(4.6×250mm,120A,10u)柱，流速為1.0mL/min，流動相為(10mM ZnSO4+20mM L-纈氨酸緩衝液)：甲醇(v：v)=50：50，柱溫保持在30℃。 Compound chromatographic preparation and separation were achieved by Agilent 1260 series high performance liquid chromatography (HPLC), where UV detection was at 278nm, Calesil ODS-120 (4.6 × 250mm, 120A, 10u) column, flow rate was 1.0mL / min, flow The phases were (10 mM ZnSO 4 +20 mM L -valine buffer): methanol (v: v) = 50:50, and the column temperature was maintained at 30 ° C.

下面簡寫詞的使用貫穿本發明： The following abbreviations are used throughout the invention:

Ac 乙醯基 Ac

Ac2O 乙酸酐 Ac 2 O acetic anhydride

BOC，Boc 叔丁氧基羰基 BOC, Boc tert-butoxycarbonyl

(Boc)2O 二碳酸二叔丁酯 (Boc) 2 O Di-tert-butyl dicarbonate

CHCl3 氯仿 CHCl 3 chloroform

CDCl3 氘代氯仿 CDCl 3 deuterated chloroform

CH2Cl2,DCM 二氯甲烷 CH 2 Cl 2 , DCM dichloromethane

CDI N,N'-羰基二咪唑 CDI N, N '-carbonyldiimidazole

DBU 1,8-二氮雜雙環[5.4.0]-十一碳-7-烯 DBU 1,8-diazabicyclo [5.4.0] -undec-7-ene

DMF N,N-二甲基甲醯胺 DMF N, N -dimethylformamide

DMAP 4-二甲氨基吡啶 DMAP 4-dimethylaminopyridine

DMSO 二甲基亞碸 DMSO dimethyl sulfene

DIPEA 二異丙基乙基胺 DIPEA diisopropylethylamine

DIAD 偶氮二甲酸二異丙酯 DIAD Diisopropyl azodicarboxylate

DME 乙二醇二甲醚 DME ethylene glycol dimethyl ether

EDC，EDCI 1-(3-二甲氨基丙基)-3-乙基碳二亞胺鹽酸鹽 EDC, EDCI 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride

EtOAc 乙酸乙酯 EtOAc ethyl acetate

EA 乙酸乙酯 EA ethyl acetate

Et3N，TEA 三乙胺 Et 3 N, TEA triethylamine

EtOH 乙醇 EtOH ethanol

MeCN，CH3CN 乙腈 MeCN, CH 3 CN acetonitrile

THF 四氫呋喃 THF tetrahydrofuran

HCl．EA，HCl/EA 氯化氫的乙酸乙酯溶液 HCl. EA, HCl / EA hydrogen chloride in ethyl acetate

HOAt，HOAT 1-羥基-7-氮雜苯並*** HOAt, HOAT 1-hydroxy-7-azabenzotriazole

HOAc 乙酸 HOAc acetic acid

g 克 g grams

mg 毫克 mg

ml，mL 毫升 ml

IPA 異丙醇 IPA isopropanol

Pd(PPh3)4 四三苯基磷鈀 Pd (PPh 3 ) 4 Tetratriphenylphosphonium palladium

RT，rt 室溫 RT, rt room temperature

rf 回流 rf reflux

Rt 保留時間 Rt retention time

具體實施方式detailed description

下面的實施例可以對本發明做進一步的描述，然而，這些實施例不應作為對本發明範圍的限制。 The following examples can further describe the present invention, however, these examples should not be used to limit the scope of the present invention.

化合物(I)無定形的合成方法Amorphous synthesis method of compound (I)

Figure TW201805289AD00005
Figure TW201805289AD00005

Figure TW201805289AD00006
Figure TW201805289AD00006

步驟1：化合物1-2的合成Step 1: Synthesis of compound 1-2

將化合物1-1(50g,216mmol)、三苯基膦(68g，259mmol)和二氯甲烷(375mL)加入反應瓶中，氮氣保護下，降溫至-10℃，緩慢滴加DIAD(52.5g，260mmol)，滴完後繼續在-10℃下攪拌3小時，待反應完全後，加入甲磺酸(62.5g，650mmol)升溫至40℃攪拌2小時。反應完全後，冷卻至室溫，過濾，濾餅用 少量二氯甲烷洗滌一次，所得固體於40℃下真空乾燥4小時，得到白色固體化合物1-2(40g，產率88.4%)。 Compound 1-1 (50 g, 216 mmol), triphenylphosphine (68 g, 259 mmol) and dichloromethane (375 mL) were added to the reaction flask. Under nitrogen protection, the temperature was lowered to -10 ° C, and DIAD (52.5 g, 260 mmol). After the dropwise addition, stirring was continued at -10 ° C for 3 hours. After the reaction was completed, methanesulfonic acid (62.5 g, 650 mmol) was added and the temperature was raised to 40 ° C and stirred for 2 hours. After the reaction was completed, it was cooled to room temperature, filtered, and the filter cake was washed once with a small amount of dichloromethane. The obtained solid was dried under vacuum at 40 ° C for 4 hours to obtain a white solid compound 1-2 (40 g, yield 88.4%).

步驟2：化合物1-3的合成Step 2: Synthesis of compounds 1-3

將化合物1-2(10g,47.8mmol)、化合物7(10g，36.8mmol)、2-肟氰乙酸乙酯(1.3g,9.1mmol)、DIPEA(9.0mL,54mmol)以及二氯甲烷(250mL)加入到圓底燒瓶中，氮氣保護加入EDCI(0.85g,4.4mmol)，反應混合物在室溫下反應3小時。待反應完全後，向反應液中加入250mL水分液，有機相依次用10%檸檬酸水溶液(250mL)、飽和碳酸氫鈉(250mL)和飽和氯化鈉溶液(250mL)洗滌一次，再用無水硫酸鈉乾燥，最後減壓濃縮，得到棕紅色油狀液體化合物1-3(12.7g，產率94.1%)。 Compound 1-2 (10 g, 47.8 mmol), compound 7 (10 g, 36.8 mmol), ethyl 2-oxime cyanoacetate (1.3 g, 9.1 mmol), DIPEA (9.0 mL, 54 mmol), and dichloromethane (250 mL) Add to a round bottom flask, add EDCI (0.85 g, 4.4 mmol) under nitrogen protection, and react the reaction mixture at room temperature for 3 hours. After the reaction was completed, 250 mL of water was added to the reaction solution, and the organic phase was washed once with 10% aqueous citric acid solution (250 mL), saturated sodium bicarbonate (250 mL), and saturated sodium chloride solution (250 mL), and then with anhydrous sulfuric acid. Sodium was dried and finally concentrated under reduced pressure to obtain brown-red oily liquid compound 1-3 (12.7 g, yield 94.1%).

步驟3：化合物1-5的合成Step 3: Synthesis of compound 1-5

將化合物1-3(13.37g,36.49mmol)加入到250mL單口瓶中，再加入甲苯(13mL)和水(130mL)，最後加入化合物1-4(11.66g,37.20mmol)以及異辛酸鈉(10.00g,54.85mmol)，所得混合物於室溫下反應過夜。反應完全後，加入乙酸乙酯(150mL×2)萃取，合併的有機相依次用飽和碳酸氫鈉溶液(150mL)、鹽酸(1mol/L,150mL)和飽和氯化鈉洗滌，無水硫酸鈉乾燥，減壓旋乾有機溶劑，得到棕紅色油狀液體化合物1-5(18.52g，收率：100%)。 Add compound 1-3 (13.37g, 36.49mmol) to a 250mL single-necked flask, add toluene (13mL) and water (130mL), and finally add compound 1-4 (11.66g, 37.20mmol) and sodium isooctanoate (10.00 g, 54.85 mmol), and the resulting mixture was reacted at room temperature overnight. After the reaction was completed, ethyl acetate (150 mL × 2) was added for extraction, and the combined organic phases were sequentially washed with a saturated sodium bicarbonate solution (150 mL), hydrochloric acid (1 mol / L, 150 mL) and saturated sodium chloride, and dried over anhydrous sodium sulfate. The organic solvent was spin-dried under reduced pressure to obtain a brown-red oily liquid compound 1-5 (18.52 g, yield: 100%).

步驟4：化合物1-7的合成Step 4: Synthesis of compounds 1-7

將化合物取1-5(18.5g,36.4mmol)、化合物1-6(10.48g，47.3mmol)以及甲苯(100mL)加入到250mL單口瓶中，反應混合物降溫至-10℃，再將叔丁醇鉀(6.12g，54.6mmol)的無水四氫呋喃(20mL)溶液緩慢滴加到上述反應混合物中，控制反應溫度不高於-5℃，滴完後，反應混合物在-5℃繼續攪拌3小時。待反應完全後，加入1鹽酸溶液(100mL,1mol/L)，反應混合物升溫至室溫攪拌30分鐘，然後分液，水相用甲苯(100mL)萃取，合併有機相。合併的有機相分別用飽和碳酸氫鈉溶液(100mL)和鹽酸(150mL，1mol/L)洗滌一次，最後再用飽和氯化鈉洗滌，無水硫酸鈉乾燥，減壓旋乾有機溶劑，得到棕紅色油狀液體化合物1-7(24.0g，收率97.6%)。 Compounds 1-5 (18.5g, 36.4mmol), compounds 1-6 (10.48g, 47.3mmol) and toluene (100mL) were added to a 250mL single-necked flask, the reaction mixture was cooled to -10 ° C, and tert-butanol An anhydrous tetrahydrofuran (20 mL) solution of potassium (6.12 g, 54.6 mmol) was slowly added dropwise to the above reaction mixture to control the reaction temperature not higher than -5 ° C. After the dropping was completed, the reaction mixture was further stirred at -5 ° C for 3 hours. After the reaction was completed, 1 hydrochloric acid solution (100 mL, 1 mol / L) was added, the reaction mixture was warmed to room temperature and stirred for 30 minutes, and then the layers were separated. The aqueous phase was extracted with toluene (100 mL), and the organic phases were combined. The combined organic phases were washed once with a saturated sodium bicarbonate solution (100 mL) and hydrochloric acid (150 mL, 1 mol / L), and finally with saturated sodium chloride, dried over anhydrous sodium sulfate, and dried under reduced pressure to obtain a brown-red color. Oily liquid compound 1-7 (24.0 g, yield 97.6%).

步驟5：化合物1-9的合成Step 5: Synthesis of compounds 1-9

將化合物1-7(24g,35.4mmol)、化合物1-8(10g，31.8mmol)、碳酸銫(15g，46mmol)以及N-甲基吡咯烷酮(70mL)加入到250毫升單口瓶中，升溫至50℃攪拌過夜。待反應完全後，加入水(100mL)以及甲基叔丁基醚(70mL)，分液，水相用甲基叔丁基醚(70mL)萃取，合併的有機相依次用飽和碳酸氫鈉水溶液(70mL)和飽和氯化鈉水溶液洗滌，無水硫酸鈉乾燥，減壓旋乾有機溶劑，得到棕紅色油狀液體，然後用異丙醇(210mL)升溫溶解棕紅色油狀液體，再冷卻至室溫，析出白色固體化合物1-9(20.0g，收率80%)。 Add compounds 1-7 (24g, 35.4mmol), compounds 1-8 (10g, 31.8mmol), cesium carbonate (15g, 46mmol), and N -methylpyrrolidone (70mL) to a 250ml single-necked flask and warm to 50 Stir overnight at ° C. After the reaction was completed, water (100 mL) and methyl tert-butyl ether (70 mL) were added, and the layers were separated. The aqueous phase was extracted with methyl tert-butyl ether (70 mL), and the combined organic phases were sequentially with a saturated aqueous sodium hydrogen carbonate solution ( 70mL) and saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, spin-drying the organic solvent under reduced pressure to obtain a brown-red oily liquid, and then warming with isopropanol (210mL) to dissolve the brown-red oily liquid, and then cooled to room temperature As a white solid compound 1-9 (20.0 g, yield 80%).

步驟6：化合物1-10的合成Step 6: Synthesis of compound 1-10

將化合物取1-9(20g,24.8mmol)和甲苯(1400mL)加入到反應瓶中，升溫至110℃回流並攪拌一小時。將詹氏催化劑(0.08g，0.1mmol)溶解在甲苯(200mL)中，氮氣保護下緩慢滴加到反應液中，滴加時間為3小時，滴完後，反應液繼續回流攪拌2小時。反應完全後，減壓旋乾溶劑，得到棕灰色油狀液體，加入甲基叔丁基醚(80mL)，並升溫至回流溶解該棕灰色油狀液體，反應完後，然後冷卻至室溫，析出白色固體化合物1-10(15.0g，收率：80%)。 1-9 (20 g, 24.8 mmol) of the compound and toluene (1400 mL) were added to the reaction flask, and the mixture was heated to 110 ° C. with refluxing and stirred for one hour. Zhan's catalyst (0.08 g, 0.1 mmol) was dissolved in toluene (200 mL), and the reaction solution was slowly added dropwise under the protection of nitrogen for 3 hours. After the dropwise addition, the reaction solution was stirred under reflux for 2 hours. After the reaction was completed, the solvent was spin-dried under reduced pressure to obtain a brown-grey oily liquid. Methyl tert-butyl ether (80 mL) was added, and the temperature was raised to reflux to dissolve the brown-grey oily liquid. After the reaction was completed, the mixture was cooled to room temperature. Compound 1-10 (15.0 g, yield: 80%) was precipitated as a white solid.

步驟7：化合物1-11的合成Step 7: Synthesis of compound 1-11

將化合物1-10(10g,12.89mmol)、一水合氫氧化鋰(1.1g，26mmol)、甲醇(40mL)、四氫呋喃(40mL)以及水(20mL)加入到250mL單口瓶中，室溫攪拌過夜。反應完全後，減壓旋乾有機溶劑，加入鹽酸(50mL,1mol/L)和乙酸乙酯(50mL)，分液，水相用乙酸乙酯(50mL)萃取，合併的有機相用飽和氯化鈉(50mL)洗滌，無水硫酸鈉乾燥，過濾，減壓旋乾有機溶劑，得到白色固體1-11(9.15g，收率：93.2%)。 Compound 1-10 (10 g, 12.89 mmol), lithium hydroxide monohydrate (1.1 g, 26 mmol), methanol (40 mL), tetrahydrofuran (40 mL), and water (20 mL) were added to a 250 mL single-necked flask and stirred at room temperature overnight. After the reaction was completed, the organic solvent was spin-dried under reduced pressure, hydrochloric acid (50 mL, 1 mol / L) and ethyl acetate (50 mL) were added, and the layers were separated. The aqueous phase was extracted with ethyl acetate (50 mL). The combined organic phases were saturated with chlorinated Wash with sodium (50 mL), dry over anhydrous sodium sulfate, filter, and spin dry the organic solvent under reduced pressure to obtain 1-11 (9.15 g, yield: 93.2%) as a white solid.

步驟8：化合物1-13的合成Step 8: Synthesis of compound 1-13

將化合物取1-11(2g,2.625mmol)、CDI(0.87g，5.3mmol)和二氯甲烷(20mL)加入到圓底燒瓶中，室溫攪拌3小時，然後再加入DBU(0.82g，5.3mmol)以及化合物1-12(0.72g，5.3mmol)，反應混合物室溫下攪拌過夜。待反應完全後，加入鹽酸(40mL，1mol/L)，分液，水相用二氯甲烷(10mL)萃取，合併的有機相用50毫升飽和氯化鈉洗滌，無水硫酸鈉乾燥，過濾，減壓旋乾有機溶劑，得到淡黃色固體化合物1-13(2.2g，收率：94.42%)。 Add the compound 1-11 (2g, 2.625mmol), CDI (0.87g, 5.3mmol) and dichloromethane (20mL) to a round bottom flask, stir at room temperature for 3 hours, and then add DBU (0.82g, 5.3 mmol) and compound 1-12 (0.72 g, 5.3 mmol), and the reaction mixture was stirred at room temperature overnight. After the reaction was completed, hydrochloric acid (40 mL, 1 mol / L) was added, and the layers were separated. The aqueous phase was extracted with dichloromethane (10 mL). The combined organic phases were washed with 50 mL of saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, and reduced. The organic solvent was spin-dried to obtain compound 1-13 (2.2 g, yield: 94.42%) as a pale yellow solid.

MS(ESI,pos.ion)m/z：880.8[M+1]+； 1H NMR(600MHz,CDCl3)：δ 10.31(s,1H),8.03(d,J=7.5Hz,1H),7.93(s,1H),7.84-7.79(m,2H),7.54(s,1H),7.06-7.01(m,2H),5.70(dd,J=17.9,8.7Hz,1H),5.52(s,1H),5.03-4.98(m,1H),4.76-4.69(m,2H),4.65-4.60(m,1H),4.13-4.09(m,1H),3.89(s,3H),3.73(s,3H),3.26-3.19(m,2H),2.75(dd,J=13.8,7.4Hz,1H),2.65(s,3H),2.31(d,J=8.6Hz,1H),2.07-2.04(m,1H),1.85(dd,J=15.5,9.2Hz,2H),1.78(dd,J=10.5,5.1Hz,1H),1.66-1.62(m,1H),1.50(d,J=7.3Hz,4H),1.40(d,J=6.9Hz,7H),1.26(d,J=4.2Hz,3H),1.20(s,3H),0.86-0.77(m,3H)ppm。 MS (ESI, pos.ion) m / z: 880.8 [M + 1] + ; 1 H NMR (600MHz, CDCl 3 ): δ 10.31 (s, 1H), 8.03 (d, J = 7.5Hz, 1H), 7.93 (s, 1H), 7.84-7.79 (m, 2H), 7.54 (s, 1H), 7.06-7.01 (m, 2H), 5.70 (dd, J = 17.9, 8.7Hz, 1H), 5.52 (s, 1H), 5.03-4.98 (m, 1H), 4.76-4.69 (m, 2H), 4.65-4.60 (m, 1H), 4.13-4.09 (m, 1H), 3.89 (s, 3H), 3.73 (s, 3H), 3.26-3.19 (m, 2H), 2.75 (dd, J = 13.8, 7.4Hz, 1H), 2.65 (s, 3H), 2.31 (d, J = 8.6Hz, 1H), 2.07-2.04 (m , 1H), 1.85 (dd, J = 15.5,9.2Hz, 2H), 1.78 (dd, J = 10.5,5.1Hz, 1H), 1.66-1.62 (m, 1H), 1.50 (d, J = 7.3Hz, 4H), 1.40 (d, J = 6.9Hz, 7H), 1.26 (d, J = 4.2Hz, 3H), 1.20 (s, 3H), 0.86-0.77 (m, 3H) ppm.

步驟9：化合物(I)的合成Step 9: Synthesis of compound (I)

將化合物1-13(0.2g,0.2mmol)溶解在異丙醇(2mL)中，冷卻至0℃，然後加入的氯化氫的異丙醇溶液(品質分數40%，5mL)，直至沒有氣體放出時反應結束。過濾，所得白色固體用乙酸乙酯(5mL)沖洗。將所得白色固體、化合物1-14(0.1g,0.7mmol)、EDCI(0.2g,1.5mmol)以及HOAT(0.15g,1.1mmol)加入到圓底燒瓶中，氮氣保護下，加入二氯甲烷(10mL)，然後冷卻至0℃，加入DIPEA(0.5mL,3mmol)，反應混合物升溫至30℃，並攪拌6小時。反應完後，用水(10mL)淬滅反應，所得混合物用二氯甲烷(10mL×2)萃取，合併的有機相用飽和食鹽水(10mL)洗滌，無水硫酸鈉乾燥，過濾，減壓下除去有機溶劑，所得殘留物用矽膠柱層析純化，洗脫劑為石油醚/乙酸乙酯(V/V)=2/1，得到白色固體化合物(I)(0.150g，產率70%)。 Compound 1-13 (0.2g, 0.2mmol) was dissolved in isopropanol (2mL), cooled to 0 ° C, and then a solution of hydrogen chloride in isopropanol (mass fraction 40%, 5mL) was added until no gas was evolved. The reaction is over. Filtered and the resulting white solid was rinsed with ethyl acetate (5 mL). The obtained white solid, compound 1-14 (0.1 g, 0.7 mmol), EDCI (0.2 g, 1.5 mmol), and HOAT (0.15 g, 1.1 mmol) were added to a round-bottomed flask. Under the protection of nitrogen, dichloromethane ( 10 mL), then cooled to 0 ° C, DIPEA (0.5 mL, 3 mmol) was added, and the reaction mixture was warmed to 30 ° C and stirred for 6 hours. After the reaction was completed, the reaction was quenched with water (10 mL). The resulting mixture was extracted with dichloromethane (10 mL x 2). The combined organic phases were washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and the organics were removed under reduced pressure. The solvent, and the obtained residue was purified by silica gel column chromatography. The eluent was petroleum ether / ethyl acetate (V / V) = 2/1 to obtain a white solid compound (I) (0.150 g, yield 70%).

MS(ESI,pos.ion)m/z：874.3[M+1]+；1H NMR(600MHz,CDCl3)：δ 10.30(s,1H),8.40(s,1H),7.95(d,J=7.4Hz,1H),7.87(d,J=9.1Hz,1H),7.81(s,1H),7.55(s,1H),7.04(d,J=9.2Hz,2H),6.57(s,1H),5.63(dd,J=17.8,8.6Hz,1H),5.51(d,J=27.3Hz,1H),4.92(t,J=9.4Hz,1H),4.76(t,J=7.3Hz,1H),4.70(t,J=7.8Hz,1H),4.58(d,J=11.4Hz,1H),4.16-4.10(m,1H),3.88(s,3H),3.26-3.20(m,2H),2.75(dd,J=13.6,7.7Hz,1H),2.65(d,J=18.3Hz,4H),2.54-2.48(m,1H),2.38(s,1H),2.26(dd,J=17.2,8.5Hz,1H),2.05(dd,J=21.8,10.4Hz,1H),1.89-1.83(m,1H),1.79-1.69(m,2H),1.43(d,J=5.5Hz,2H),1.39(d,J=6.9Hz,7H),1.28-1.23(m,3H),1.19(s,3H),0.96-0.66(m,3H)ppm。 MS (ESI, pos.ion) m / z: 874.3 [M + 1] + ; 1 H NMR (600 MHz, CDCl 3 ): δ 10.30 (s, 1H), 8.40 (s, 1H), 7.95 (d, J = 7.4Hz, 1H), 7.87 (d, J = 9.1Hz, 1H), 7.81 (s, 1H), 7.55 (s, 1H), 7.04 (d, J = 9.2Hz, 2H), 6.57 (s, 1H ), 5.63 (dd, J = 17.8, 8.6 Hz, 1H), 5.51 (d, J = 27.3 Hz, 1H), 4.92 (t, J = 9.4 Hz, 1H), 4.76 (t, J = 7.3 Hz, 1H ), 4.70 (t, J = 7.8Hz, 1H), 4.58 (d, J = 11.4Hz, 1H), 4.16-4.10 (m, 1H), 3.88 (s, 3H), 3.26-3.20 (m, 2H) , 2.75 (dd, J = 13.6, 7.7Hz, 1H), 2.65 (d, J = 18.3Hz, 4H), 2.54-2.48 (m, 1H), 2.38 (s, 1H), 2.26 (dd, J = 17.2 , 8.5Hz, 1H), 2.05 (dd, J = 21.8, 10.4Hz, 1H), 1.89-1.83 (m, 1H), 1.79-1.69 (m, 2H), 1.43 (d, J = 5.5Hz, 2H) , 1.39 (d, J = 6.9 Hz, 7H), 1.28-1.23 (m, 3H), 1.19 (s, 3H), 0.96-0.66 (m, 3H) ppm.

通過Empyrean X射線粉末衍射(XRPD)分析鑑定：使用Cu-K α輻射，實驗結果如圖33所示。 Empyrean X-ray powder diffraction (XRPD) analysis identified that Cu-K α radiation was used. The experimental results are shown in FIG. 33.

實施例1化合物(I)N-甲基葡糖胺鹽無定形的製備和鑑定Example 1 Preparation and Identification of Compound (I) Amorphous N -methylglucamine Salt 1.化合物(I)N-甲基葡糖胺鹽無定形的製備 1. Amorphous preparation of compound (I) N -methylglucamine salt

將化合物(I)(0.437g,0.491mmol)和N-甲基葡糖胺(0.106g,0.543mmol)加入到甲醇(20.0mL)中，固體緩慢溶解，反應混合物在室溫下反應7小時，反應完後，減壓除去溶劑，固體經室溫真空乾燥，得到化合物(I)N-甲基葡糖胺鹽無定形為白色固體粉末(0.523g,0.489mmol,99.61%)。 Compound (I) (0.437 g, 0.491 mmol) and N -methylglucamine (0.106 g, 0.543 mmol) were added to methanol (20.0 mL), and the solid was slowly dissolved. The reaction mixture was reacted at room temperature for 7 hours. After the reaction, the solvent was removed under reduced pressure, and the solid was dried under vacuum at room temperature to obtain the compound (I) N -methylglucamine salt as an amorphous white solid powder (0.523 g, 0.489 mmol, 99.61%).

2.化合物(I)N-甲基葡糖胺鹽無定形的鑑定 2. Amorphous identification of compound (I) N -methylglucamine salt

1)1H NMR(600MHz,DMSO-d 6)δ 9.07(s,1H),8.45(d,J=5.6Hz,1H),8.01(d,J=9.1Hz,2H),7.50(d,J=31.5Hz,2H),7.35(d,J=9.3Hz,1H),6.82(s,1H),5.62(s,1H),5.51(t,J=9.7Hz,1H),5.34(d,J=6.8Hz,1H),4.77(s,1H),4.57-4.37(m,3H),4.21(d,J=9.7Hz,1H),3.93(s,3H),3.81(d,J=4.1Hz,1H),3.66(d,J=4.3Hz,1H),3.60(dd,J=10.7,3.2Hz,2H),3.52-3.47(m,2H),3.45-3.41(m,4H),3.21-3.12(m,2H),2.88(dt,J=11.9,8.7Hz,3H),2.58(s,3H),2.53(d,J=9.4Hz,2H),2.27-1.87(m,5H),1.74(s,1H),1.51-1.10(m,20H),0.48(s,2H)ppm。 1) 1 H NMR (600MHz, DMSO- d 6 ) δ 9.07 (s, 1H), 8.45 (d, J = 5.6Hz, 1H), 8.01 (d, J = 9.1Hz, 2H), 7.50 (d, J = 31.5Hz, 2H), 7.35 (d, J = 9.3Hz, 1H), 6.82 (s, 1H), 5.62 (s, 1H), 5.51 (t, J = 9.7Hz, 1H), 5.34 (d, J = 6.8Hz, 1H), 4.77 (s, 1H), 4.57-4.37 (m, 3H), 4.21 (d, J = 9.7Hz, 1H), 3.93 (s, 3H), 3.81 (d, J = 4.1Hz , 1H), 3.66 (d, J = 4.3Hz, 1H), 3.60 (dd, J = 10.7, 3.2Hz, 2H), 3.52-3.47 (m, 2H), 3.45-3.41 (m, 4H), 3.21- 3.12 (m, 2H), 2.88 (dt, J = 11.9, 8.7Hz, 3H), 2.58 (s, 3H), 2.53 (d, J = 9.4Hz, 2H), 2.27-1.87 (m, 5H), 1.74 (s, 1H), 1.51-1.10 (m, 20H), 0.48 (s, 2H) ppm.

2)通過Empyrean X射線粉末衍射(XRPD)分析鑑定：使用Cu-K α輻射，實驗結果如圖1所示。 2) Identification by Empyrean X-ray powder diffraction (XRPD) analysis: Cu-K α radiation was used, and the experimental results are shown in FIG. 1.

實施例2 化合物(I)L-精氨酸鹽無定形的製備和鑑定Example 2 Preparation and Identification of Compound (I) L -Arginine Amorphous 1.化合物(I)L-精氨酸鹽無定形的製備 1. Preparation of Compound (I) L -Arginine Amorphous

將化合物(I)(0.437g,0.50mmol)和L-精氨酸(0.092g,0.531mmol)加入到甲醇(20.0mL)中，固體緩慢溶解，反應混合物在室溫下反應過夜，反應完後，減壓除去溶劑，殘留物經室溫真空乾燥，得到化合物(I)L-精氨酸鹽無定形為白色固體粉末(0.52g,0.497mmol,99.31%)。 Compound (I) (0.437 g, 0.50 mmol) and L -arginine (0.092 g, 0.531 mmol) were added to methanol (20.0 mL), and the solid was slowly dissolved. The reaction mixture was reacted at room temperature overnight. After the reaction was completed The solvent was removed under reduced pressure, and the residue was dried under vacuum at room temperature to obtain compound (I) L -arginine salt as an amorphous white solid powder (0.52 g, 0.497 mmol, 99.31%).

2.化合物(I)L-精氨酸鹽無定形的鑑定 2. Amorphous identification of compound (I) L -arginine

1)1H NMR(600MHz,DMSO-d 6)δ 9.07(d,J=1.2Hz,1H),8.43(s,1H),8.16-7.95(m,2H),7.49(d,J=30.5Hz,5H),7.35(d,J=9.3Hz,1H),6.82(d,J=1.2Hz,1H),5.56(dd,J=24.0,13.9Hz,2H),5.33(dd,J=16.5,9.5Hz,1H),4.78(s, 1H),4.53(t,J=7.8Hz,1H),4.42(d,J=11.6Hz,1H),4.20(d,J=8.2Hz,1H),3.92(s,3H),3.30(d,J=6.0Hz,3H),3.21-3.02(m,4H),2.57(s,5H),2.22-1.84(m,4H),1.79-1.06(m,24H),0.46(s,2H)ppm。 1) 1 H NMR (600MHz, DMSO- d 6 ) δ 9.07 (d, J = 1.2Hz, 1H), 8.43 (s, 1H), 8.16-7.95 (m, 2H), 7.49 (d, J = 30.5Hz , 5H), 7.35 (d, J = 9.3Hz, 1H), 6.82 (d, J = 1.2Hz, 1H), 5.56 (dd, J = 24.0, 13.9Hz, 2H), 5.33 (dd, J = 16.5, 9.5Hz, 1H), 4.78 (s, 1H), 4.53 (t, J = 7.8Hz, 1H), 4.42 (d, J = 11.6Hz, 1H), 4.20 (d, J = 8.2Hz, 1H), 3.92 (s, 3H), 3.30 (d, J = 6.0 Hz, 3H), 3.21-3.02 (m, 4H), 2.57 (s, 5H), 2.22-1.84 (m, 4H), 1.79-1.06 (m, 24H ), 0.46 (s, 2H) ppm.

2)通過Empyrean X射線粉末衍射(XRPD)分析鑑定：使用Cu-K α輻射，實驗結果如圖2所示。 2) Identification by Empyrean X-ray powder diffraction (XRPD) analysis: Cu-K α radiation was used, and the experimental results are shown in FIG. 2.

實施例3 化合物(I)L-賴氨酸鹽無定形的製備和鑑定Example 3 Preparation and identification of compound (I) L -lysine salt amorphous 1.化合物(I)L-賴氨酸鹽無定形的製備 1. Preparation of Compound (I) L -lysine Amorphous

將化合物(I)(0.449g,0.514mmol)和L-賴氨酸(0.083g,0.568mmol)加入到甲醇(20.0mL)中，固體緩慢溶解，反應混合物在室溫下反應4.5小時，反應完後，減壓除去溶劑，殘留物經室溫真空乾燥，得到化合物(I)L-賴氨酸鹽無定形為白色固體粉末(0.524g,0.514mmol,99.98%)。 Compound (I) (0.449 g, 0.514 mmol) and L -lysine (0.083 g, 0.568 mmol) were added to methanol (20.0 mL), and the solid was slowly dissolved. The reaction mixture was reacted at room temperature for 4.5 hours. Then, the solvent was removed under reduced pressure, and the residue was vacuum-dried at room temperature to obtain compound (I) L -lysine salt as an amorphous white solid powder (0.524 g, 0.514 mmol, 99.98%).

2.化合物(I)L-賴氨酸鹽無定形的鑑定 2. Amorphous identification of compound (I) L -lysine salt

1)1H NMR(600MHz,DMSO-d 6)δ 9.08(s,1H),8.41(s,1H),8.10-7.88(m,2H),7.50(d,J=29.0Hz,2H),7.36(d,J=9.3Hz,1H),6.83(s,1H),5.56(dd,J=24.7,14.4Hz,2H),5.31(dd,J=16.9,9.3Hz,1H),4.79(s,1H),4.52(t,J=7.8Hz,1H),4.42(d,J=11.5Hz,1H),4.22(d,J=9.6Hz,1H),3.93(s,3H),3.16(dd,J=14.4,7.2Hz,3H),2.73(t,J=7.1Hz,2H),2.56(d,J=16.2Hz,5H),2.17-1.84(m,5H),1.81-1.54(m,4H),1.53-1.03(m,24H),0.45(s,2H)ppm。 1) 1 H NMR (600MHz, DMSO- d 6 ) δ 9.08 (s, 1H), 8.41 (s, 1H), 8.10-7.88 (m, 2H), 7.50 (d, J = 29.0Hz, 2H), 7.36 (d, J = 9.3Hz, 1H), 6.83 (s, 1H), 5.56 (dd, J = 24.7, 14.4Hz, 2H), 5.31 (dd, J = 16.9, 9.3Hz, 1H), 4.79 (s, 1H), 4.52 (t, J = 7.8Hz, 1H), 4.42 (d, J = 11.5Hz, 1H), 4.22 (d, J = 9.6Hz, 1H), 3.93 (s, 3H), 3.16 (dd, J = 14.4, 7.2Hz, 3H), 2.73 (t, J = 7.1Hz, 2H), 2.56 (d, J = 16.2Hz, 5H), 2.17-1.84 (m, 5H), 1.81-1.54 (m, 4H ), 1.53-1.03 (m, 24H), 0.45 (s, 2H) ppm.

2)通過Empyrean X射線粉末衍射(XRPD)分析鑑定：使用Cu-K α輻射，實驗結果如圖3所示。 2) Identification by Empyrean X-ray powder diffraction (XRPD) analysis: Cu-K α radiation was used, and the experimental results are shown in FIG. 3.

實施例4 化合物(I)鈉鹽無定形的製備和鑑定Example 4 Preparation and Identification of Amorphous Sodium Salt of Compound (I) 1.化合物(I)鈉鹽無定形的製備 1. Amorphous preparation of compound (I) sodium salt

將化合物(I)(501mg,0.573mmol)分散於甲醇(15mL)中，並向其中加入氫氧化鈉(23mg,0.564mmol)的水(1.4mL)溶液，反應混合物在室溫下反應5.5小時，反應完後，減壓蒸除溶劑，殘留物經60℃真空乾燥過夜，得到化合物(I)鈉鹽無定形為微黃色固體(0.502g,0.56mmol,97.7%)。 Compound (I) (501 mg, 0.573 mmol) was dispersed in methanol (15 mL), and a solution of sodium hydroxide (23 mg, 0.564 mmol) in water (1.4 mL) was added thereto, and the reaction mixture was reacted at room temperature for 5.5 hours. After completion of the reaction, the solvent was distilled off under reduced pressure, and the residue was dried under vacuum at 60 ° C. overnight to obtain Compound (I) sodium salt as an amorphous yellowish solid (0.502 g, 0.56 mmol, 97.7%).

2.化合物(I)鈉鹽無定形的鑑定 2. Amorphous identification of compound (I) sodium salt

1)1H NMR(600MHz,DMSO-d 6)δ 9.08(s,1H),8.41(d,J=6.5Hz,1H),8.05-7.91(m,2H),7.53(s,1H),7.46(s,1H),7.35(d,J=9.3Hz,1H),6.84(d,J=1.3Hz,1H),5.66-5.54(m,2H),5.32(dd,J=16.7,9.5Hz,1H),4.80(s,1H),4.53(t,J=7.8Hz,1H),4.41(d,J=11.6Hz,1H),4.21(d,J=8.4Hz,1H),3.93(s,3H),3.16(dt,J=13.7,6.8Hz,1H),2.56(d,J=13.8Hz,4H),2.12(s,2H),1.93(dt,J=17.9,7.9Hz,2H),1.75(t,J=12.2Hz,1H),1.51-1.10(m,20H),0.47(s,2H)ppm。 1) 1 H NMR (600MHz, DMSO- d 6 ) δ 9.08 (s, 1H), 8.41 (d, J = 6.5Hz, 1H), 8.05-7.91 (m, 2H), 7.53 (s, 1H), 7.46 (s, 1H), 7.35 (d, J = 9.3Hz, 1H), 6.84 (d, J = 1.3Hz, 1H), 5.66-5.54 (m, 2H), 5.32 (dd, J = 16.7,9.5Hz, 1H), 4.80 (s, 1H), 4.53 (t, J = 7.8Hz, 1H), 4.41 (d, J = 11.6Hz, 1H), 4.21 (d, J = 8.4Hz, 1H), 3.93 (s, 3H), 3.16 (dt, J = 13.7, 6.8Hz, 1H), 2.56 (d, J = 13.8Hz, 4H), 2.12 (s, 2H), 1.93 (dt, J = 17.9, 7.9Hz, 2H), 1.75 (t, J = 12.2Hz, 1H), 1.51-1.10 (m, 20H), 0.47 (s, 2H) ppm.

2)通過Empyrean X射線粉末衍射(XRPD)分析鑑定：使用Cu-K α輻射，實驗結果如圖4所示。 2) Identification by Empyrean X-ray powder diffraction (XRPD) analysis: Cu-K α radiation was used, and the experimental results are shown in FIG. 4.

3)通過金屬元素含量的檢測分析：化合物(I)與鈉離子的摩爾比為1：1。 3) Analysis by detecting the content of metal elements: The molar ratio of compound (I) to sodium ion is 1: 1.

實施例5化合物(I)鈣鹽無定形的製備和鑑定Example 5 Preparation and Identification of Compound (I) Amorphous Calcium Salt 1.化合物(I)鈣鹽無定形的製備 1. Preparation of Compound (I) Calcium Salt Amorphous

將化合物(I)的鈉鹽(2000mg,2.232mmol)加入到甲醇(40mL)中，混合物加熱回流，固體溶解，再向其中滴加氯化鈣(123.9mg,1.116mmol)的水溶液(60mL)，1小時內滴完，所得混合物保溫攪拌3小時，停止加熱，將反應自然冷卻降至室溫，攪拌過夜，然後向其中滴加水(60mL)，析出固體，混合物在室溫下繼續攪拌2小時，抽濾，濾餅用甲醇和水的混合溶劑(甲醇/水(V/V)=1/1)洗滌，再經70℃真空乾燥過夜，得到化合物(I)鈣鹽無定形為淡黃色粉末(1.10g,0.62mmol,55%)。 The sodium salt of compound (I) (2000 mg, 2.232 mmol) was added to methanol (40 mL), the mixture was heated under reflux, the solid was dissolved, and an aqueous solution (60 mL) of calcium chloride (123.9 mg, 1.116 mmol) was added dropwise thereto, After dripping within 1 hour, the resulting mixture was kept under stirring for 3 hours, heating was stopped, the reaction was naturally cooled to room temperature, stirred overnight, and then water (60 mL) was added dropwise to precipitate a solid. The mixture was stirred at room temperature for 2 hours. Suction filtration, the filter cake was washed with a mixed solvent of methanol and water (methanol / water (V / V) = 1/1), and then dried under vacuum at 70 ° C overnight to obtain the compound (I) calcium salt as an amorphous light yellow powder ( 1.10 g, 0.62 mmol, 55%).

2.化合物(I)鈣鹽無定形的鑑定 2. Amorphous identification of compound (I) calcium salt

1)1H NMR(600MHz,DMSO-d 6)δ 9.08(s,1H),8.42(d,J=6.1Hz,1H),8.08(s,1H),8.02(d,J=9.2Hz,1H),7.53(s,1H),7.46(s,1H),7.36(d,J=9.3Hz,1H),6.83(s,1H),5.67-5.50(m,2H),5.35(d,J=7.3Hz,1H),4.77(s,1H),4.53(t,J=7.8Hz,1H),4.42(d,J=11.3Hz,1H),4.19(d,J=8.0Hz,1H),3.93(s,3H),3.16(dt,J=13.6,6.7Hz,1H),2.64-2.52(m,5H),2.24-1.66(m,5H),1.53-1.07(m,19H),0.51(s,2H)。 1) 1 H NMR (600MHz, DMSO- d 6 ) δ 9.08 (s, 1H), 8.42 (d, J = 6.1Hz, 1H), 8.08 (s, 1H), 8.02 (d, J = 9.2Hz, 1H ), 7.53 (s, 1H), 7.46 (s, 1H), 7.36 (d, J = 9.3Hz, 1H), 6.83 (s, 1H), 5.67-5.50 (m, 2H), 5.35 (d, J = 7.3Hz, 1H), 4.77 (s, 1H), 4.53 (t, J = 7.8Hz, 1H), 4.42 (d, J = 11.3Hz, 1H), 4.19 (d, J = 8.0Hz, 1H), 3.93 (s, 3H), 3.16 (dt, J = 13.6,6.7Hz, 1H), 2.64-2.52 (m, 5H), 2.24-1.66 (m, 5H), 1.53-1.07 (m, 19H), 0.51 (s , 2H).

2)通過Empyrean X射線粉末衍射(XRPD)分析鑑定：使用Cu-K α輻射，實驗結果如圖5所示。 2) Identification by Empyrean X-ray powder diffraction (XRPD) analysis: Cu-K α radiation was used, and the experimental results are shown in FIG. 5.

實施例6化合物(I)鉀鹽無定形的製備和鑑定Example 6 Preparation and Identification of Amorphous Potassium Salt of Compound (I) 1.化合物(I)鉀鹽無定形的製備 1. Amorphous preparation of potassium salt of compound (I)

方法一：將化合物(I)(498mg,0.557mmol)溶於甲醇和二氯甲烷的混合溶劑(15mL，甲醇/二氯甲烷(V/V)=1/1)中，室溫攪拌下，再向其中緩慢滴加異辛酸鉀(102mg,0.557mmol)的甲醇和二氯甲烷(5mL，甲醇/二氯甲烷(V/V)=1/1)溶液，所得混合物在室溫下攪拌過夜，反應完後，減壓蒸除溶劑，殘留物經室溫真空乾燥4小時，得到化合物(I)鉀鹽無定形為淺黃色固體(0.506g,0.555mmol,99.6%)。 Method 1: Dissolve Compound (I) (498mg, 0.557mmol) in a mixed solvent of methanol and dichloromethane (15mL, methanol / dichloromethane (V / V) = 1/1), stir at room temperature, and then A solution of potassium isooctanoate (102 mg, 0.557 mmol) in methanol and dichloromethane (5 mL, methanol / dichloromethane (V / V) = 1/1) was slowly added dropwise thereto, and the resulting mixture was stirred at room temperature overnight to react After completion, the solvent was distilled off under reduced pressure, and the residue was dried under vacuum at room temperature for 4 hours to obtain Compound (I) potassium salt as an amorphous light yellow solid (0.506 g, 0.555 mmol, 99.6%).

方法二：將化合物(I)(502mg,0.574mmol)分散於甲醇中(15mL)，然後向其中緩慢滴加氫氧化鉀(32mg,0.570mmol)的水(0.58mL)溶液，體系慢慢變澄清，所得混合物在室溫下攪拌過夜，反應完後，減壓蒸除溶劑，殘留物經60℃真空乾燥過夜，得到化合物(I)鉀鹽無定形為微黃色固體(0.50g,0.55mmol,95.0%)。 Method 2: Disperse Compound (I) (502mg, 0.574mmol) in methanol (15mL), and slowly add a solution of potassium hydroxide (32mg, 0.570mmol) in water (0.58mL) slowly. The system gradually becomes clear. The resulting mixture was stirred at room temperature overnight. After the reaction was completed, the solvent was distilled off under reduced pressure. The residue was dried under vacuum at 60 ° C overnight to obtain the potassium salt of compound (I) as an amorphous yellowish solid (0.50 g, 0.55 mmol, 95.0). %).

2.化合物(I)鉀鹽無定形的鑑定 2. Amorphous identification of compound (I) potassium salt

1)1H NMR(600MHz,DMSO-d 6)δ 9.07(s,1H),8.47(s,1H),8.01(d,J=9.1Hz,2H),7.53(s,1H),7.45(s,1H),7.34(d,J=9.2Hz,1H),6.83(s,1H),5.78-5.24(m,3H),4.76(s,1H),4.64-4.33(m,2H),4.16(dd,J=24.8,7.1Hz,1H),3.92(s,3H),3.23-3.10(m,1H),2.57(s,4H),2.19(s,1H),1.97(s,3H),1.72(s,1H),1.55-1.00(m,20H),0.51(s,2H)ppm。 1) 1 H NMR (600MHz, DMSO- d 6 ) δ 9.07 (s, 1H), 8.47 (s, 1H), 8.01 (d, J = 9.1Hz, 2H), 7.53 (s, 1H), 7.45 (s , 1H), 7.34 (d, J = 9.2Hz, 1H), 6.83 (s, 1H), 5.78-5.24 (m, 3H), 4.76 (s, 1H), 4.64-4.33 (m, 2H), 4.16 ( dd, J = 24.8, 7.1 Hz, 1H), 3.92 (s, 3H), 3.23-3.10 (m, 1H), 2.57 (s, 4H), 2.19 (s, 1H), 1.97 (s, 3H), 1.72 (s, 1H), 1.55-1.00 (m, 20H), 0.51 (s, 2H) ppm.

2)通過Empyrean X射線粉末衍射(XRPD)分析鑑定：使用Cu-K α輻射，實驗結果如圖6所示。 2) Identification by Empyrean X-ray powder diffraction (XRPD) analysis: Cu-K α radiation was used, and the experimental results are shown in FIG. 6.

實施例7 化合物(I)鋰鹽無定形的製備和鑑定Example 7 Preparation and Identification of Amorphous Lithium Salt of Compound (I) 1.化合物(I)鋰鹽無定形的製備 1. Amorphous preparation of compound (I) lithium salt

將化合物(I)(500mg,0.572mmol)分散於甲醇(10mL)中，室溫攪拌下，再向其中緩慢滴加自製氫氧化鋰(24mg,0.572mmol)的水(1mL)溶液，滴完後，所得混合物在室溫攪拌過夜，反應完後，減壓蒸除溶劑，殘留物經60°℃真空乾燥4小時，得到化合物(I)鋰鹽無定形為微黃色固體(0.49g,0.557mmol,97.3%)。 Compound (I) (500 mg, 0.572 mmol) was dispersed in methanol (10 mL), and a solution of homemade lithium hydroxide (24 mg, 0.572 mmol) in water (1 mL) was slowly added dropwise thereto under stirring at room temperature. The resulting mixture was stirred at room temperature overnight. After the reaction was completed, the solvent was distilled off under reduced pressure. The residue was dried under vacuum at 60 ° C for 4 hours to obtain the lithium salt of compound (I) as an amorphous yellowish solid (0.49 g, 0.557 mmol, 97.3%).

2.化合物(I)鋰鹽無定形的鑑定 2. Amorphous identification of compound (I) lithium salt

1)1H NMR(600MHz,DMSO-d 6)δ 9.07(s,1H),8.43(s,1H),8.05(s,1H),8.02(d,J=9.2Hz,1H),7.54(s,1H),7.46(s,1H),7.36(d,J=9.3Hz,1H),6.83(s,1H),5.58(d,J=29.7Hz,2H),5.36(s,1H),4.77(s,1H),4.53(t,J=7.8Hz,1H),4.42(d,J=10.3Hz,1H),4.19(d,J=9.0Hz,1H),3.93(s,3H),3.24-3.11(m,1H),2.58(s,5H),2.18(s,1H),2.07(s,1H),1.96(s,2H),1.73(s,1H),1.52-1.32(m,16H),1.24-1.08(m,3H),0.50(s,2H)ppm。 1) 1 H NMR (600MHz, DMSO- d 6 ) δ 9.07 (s, 1H), 8.43 (s, 1H), 8.05 (s, 1H), 8.02 (d, J = 9.2Hz, 1H), 7.54 (s , 1H), 7.46 (s, 1H), 7.36 (d, J = 9.3Hz, 1H), 6.83 (s, 1H), 5.58 (d, J = 29.7Hz, 2H), 5.36 (s, 1H), 4.77 (s, 1H), 4.53 (t, J = 7.8Hz, 1H), 4.42 (d, J = 0.33Hz, 1H), 4.19 (d, J = 9.0Hz, 1H), 3.93 (s, 3H), 3.24 -3.11 (m, 1H), 2.58 (s, 5H), 2.18 (s, 1H), 2.07 (s, 1H), 1.96 (s, 2H), 1.73 (s, 1H), 1.52-1.32 (m, 16H ), 1.24-1.08 (m, 3H), 0.50 (s, 2H) ppm.

2)通過Empyrean X射線粉末衍射(XRPD)分析鑑定：使用Cu-K α輻射，實驗結果如圖7所示。 2) Identification by Empyrean X-ray powder diffraction (XRPD) analysis: Cu-K α radiation was used, and the experimental results are shown in FIG. 7.

實施例8化合物(I)二乙胺鹽無定形的製備和鑑定Example 8 Preparation and Identification of Compound (I) Diethylamine Salt Amorphous 1.化合物(I)二乙胺鹽無定形的製備 1. Amorphous preparation of compound (I) diethylamine salt

向50mL單口瓶中加入化合物(I)(499mg,0.561mmol)，再加入甲醇(10mL)，室溫攪拌，然後向其中緩慢滴加二乙胺(41.8mg,0.561mmol)的甲醇(1mL)溶液，滴完後，所得混合物在室溫下攪拌過夜，反應完後，減壓蒸除溶劑，殘留物經室溫真空乾燥，得到化合物(I)二乙胺鹽無定形為微黃色固體粉末(0.522g,0.551mmol,98.3%)。 Add a compound (I) (499mg, 0.561mmol) to a 50mL single-necked flask, then add methanol (10mL), stir at room temperature, and slowly add a solution of diethylamine (41.8mg, 0.561mmol) in methanol (1mL) dropwise. After the dropping, the resulting mixture was stirred at room temperature overnight. After the reaction was completed, the solvent was distilled off under reduced pressure, and the residue was dried under vacuum at room temperature to obtain the compound (I) diethylamine salt as an amorphous yellowish powder (0.522). g, 0.551 mmol, 98.3%).

2.化合物(I)二乙胺鹽無定形的鑑定 2. Amorphous identification of compound (I) diethylamine salt

1)1H NMR(600MHz,DMSO-d 6)δ 9.07(d,J=1.2Hz,1H),8.56(s,1H),8.27(s,1H),8.03(d,J=9.2Hz,1H),7.54(s,1H),7.46(s,1H),7.35(d,J=9.3Hz,1H),6.82(d,J=1.2Hz,1H),5.64(s,1H),5.41(s,2H),4.72(s,1H),4.50(dd,J=14.8,7.1Hz,2H),4.17(d,J=8.4Hz,1H),3.93(s,3H),3.17(dt,J=13.6,6.8Hz,2H),2.90(q,J=7.2Hz,4H),2.58(s,5H),2.29(s,1H),1.99(d,J=11.0Hz,3H),1.69(s,1H),1.53-1.09(m,25H),0.57(s,2H)ppm。 1) 1 H NMR (600MHz, DMSO- d 6 ) δ 9.07 (d, J = 1.2Hz, 1H), 8.56 (s, 1H), 8.27 (s, 1H), 8.03 (d, J = 9.2Hz, 1H ), 7.54 (s, 1H), 7.46 (s, 1H), 7.35 (d, J = 9.3Hz, 1H), 6.82 (d, J = 1.2Hz, 1H), 5.64 (s, 1H), 5.41 (s , 2H), 4.72 (s, 1H), 4.50 (dd, J = 14.8, 7.1Hz, 2H), 4.17 (d, J = 8.4Hz, 1H), 3.93 (s, 3H), 3.17 (dt, J = 13.6, 6.8Hz, 2H), 2.90 (q, J = 7.2Hz, 4H), 2.58 (s, 5H), 2.29 (s, 1H), 1.99 (d, J = 11.0Hz, 3H), 1.69 (s, 1H), 1.53-1.09 (m, 25H), 0.57 (s, 2H) ppm.

2)通過Empyrean X射線粉末衍射(XRPD)分析鑑定：使用Cu-K α輻射，實驗結果如圖8所示。 2) Identification by Empyrean X-ray powder diffraction (XRPD) analysis: Cu-K α radiation was used, and the experimental results are shown in FIG. 8.

實施例9 化合物(I)氨基丁三醇鹽無定形的製備和鑑定Example 9 Preparation and identification of the compound (I) tromethamine amorphous 1.化合物(I)氨基丁三醇鹽無定形的製備 1. Amorphous preparation of compound (I) tromethamine

向50mL單口瓶中加入化合物(I)(500mg,0.562mmol)，再加入甲醇和二氯甲烷的混合溶劑(15mL，甲醇/二氯甲烷(V/V)=1/1)，室溫攪拌溶解，然後緩慢滴加氨基丁三醇(69.5mg,0.562mmol)的甲醇(2mL)溶液，滴完後，所得混合物在室溫下攪拌60分鐘，反應完後，減壓蒸除溶劑，殘留物經室溫真空乾燥，得到化合物(I)氨基丁三醇鹽無定形為淺黃色固體(0.551g,0.554mmol,99.3%)。 Add compound (I) (500mg, 0.562mmol) to a 50mL single-necked flask, and then add a mixed solvent of methanol and dichloromethane (15mL, methanol / dichloromethane (V / V) = 1/1), and stir to dissolve at room temperature. Then, a solution of tromethamine (69.5mg, 0.562mmol) in methanol (2mL) was slowly added dropwise. After the dropwise addition, the resulting mixture was stirred at room temperature for 60 minutes. After the reaction was completed, the solvent was distilled off under reduced pressure. Drying under vacuum at room temperature gave compound (I) tromethamine as an amorphous light yellow solid (0.551 g, 0.554 mmol, 99.3%).

2.化合物(I)氨基丁三醇鹽無定形的鑑定 2. Amorphous identification of compound (I) tromethamine

1)1H NMR(600MHz,DMSO-d 6)δ 9.07(d,J=0.8Hz,1H),8.48(d,J=6.2Hz,1H),8.24-7.95(m,2H),7.54(s,1H),7.46(s,1H),7.35(d,J=9.3Hz,1H),6.82(d,J=1.1Hz,1H),5.62(s,1H),5.48(t,J=9.9Hz,1H),5.35(dd,J=16.7,9.4Hz,1H),5.02(s,3H),4.76(s,1H),4.59-4.39(m,2H),4.21(d,J=8.2Hz,1H),3.92(s,3H),3.45(s,6H),3.17(dt,J=16.1,6.9Hz,2H),2.57(s,5H),2.19(s,1H),1.99(dt,J=17.6,8.4Hz,3H),1.73(s,1H),1.57-1.08(m,20H),0.50(s,2H)ppm。 1) 1 H NMR (600MHz, DMSO- d 6 ) δ 9.07 (d, J = 0.8Hz, 1H), 8.48 (d, J = 6.2Hz, 1H), 8.24-7.95 (m, 2H), 7.54 (s , 1H), 7.46 (s, 1H), 7.35 (d, J = 9.3Hz, 1H), 6.82 (d, J = 1.1Hz, 1H), 5.62 (s, 1H), 5.48 (t, J = 9.9Hz , 1H), 5.35 (dd, J = 16.7, 9.4Hz, 1H), 5.02 (s, 3H), 4.76 (s, 1H), 4.59-4.39 (m, 2H), 4.21 (d, J = 8.2Hz, 1H), 3.92 (s, 3H), 3.45 (s, 6H), 3.17 (dt, J = 16.1, 6.9Hz, 2H), 2.57 (s, 5H), 2.19 (s, 1H), 1.99 (dt, J = 17.6, 8.4Hz, 3H), 1.73 (s, 1H), 1.57-1.08 (m, 20H), 0.50 (s, 2H) ppm.

2)通過Empyrean X射線粉末衍射(XRPD)分析鑑定：使用Cu-K α輻射，實驗結果如圖9所示。 2) Identification by Empyrean X-ray powder diffraction (XRPD) analysis: Cu-K α radiation was used, and the experimental results are shown in FIG. 9.

實施例10 化合物(I)二乙氨基乙醇鹽無定形的製備和鑑定Example 10 Preparation and Identification of Compound (I) Diethylaminoethanol Salt Amorphous 1.化合物(I)二乙氨基乙醇鹽無定形的製備 1. Preparation of Compound (I) Diethylaminoethanol Salt Amorphous

向25mL單口瓶中加入化合物(I)(501mg,0.563mmol)，再加入甲醇和二氯甲烷的混合溶劑(15mL，甲醇/二氯甲烷(V/V)=1/1)，室溫攪拌溶解，再向其中緩慢滴加N,N-二甲基乙醇胺(67.2mg,0.563mmol)的乙醇(0.95mL)溶液，滴完後，所得混合物在室溫下攪拌2.5小時，反應完後，減壓蒸除溶劑，殘留物經室溫真空乾燥，得到化合物(I)二乙氨基乙醇鹽無定形為淺黃色固體(0.552g,0.557mmol,98.9%)。 Add compound (I) (501mg, 0.563mmol) to a 25mL single-necked flask, and then add a mixed solvent of methanol and dichloromethane (15mL, methanol / dichloromethane (V / V) = 1/1), and stir to dissolve at room temperature. Then, a solution of N, N -dimethylethanolamine (67.2mg, 0.563mmol) in ethanol (0.95mL) was slowly added dropwise thereto . After the dropping was completed, the resulting mixture was stirred at room temperature for 2.5 hours. After the reaction was completed, the pressure was reduced. The solvent was distilled off, and the residue was dried under vacuum at room temperature to obtain compound (I) diethylaminoethanol salt as an amorphous light yellow solid (0.552 g, 0.557 mmol, 98.9%).

2.化合物(I)二乙氨基乙醇鹽無定形的鑑定 2. Amorphous identification of compound (I) diethylaminoethanol salt

1)1H NMR(600MHz,DMSO-d 6)δ 9.07(s,1H),8.65(s,1H),8.44(s,1H),8.04(d,J=9.1Hz,1H),7.55(s,1H),7.46(s,1H),7.34(d,J=9.3Hz,1H),6.80(s,1H),5.65(s,1H),5.38(d,J=53.9Hz,2H),4.67(s,1H),4.58-4.44(m,2H),4.14(d,J=9.1Hz,1H),3.93(s,3H),3.58(t,J=5.7Hz,2H),3.17(dt,J=13.6,6.8Hz,2H), 2.83(s,6H),2.69-2.55(m,4H),2.38(s,1H),2.13(s,1H),2.04-1.85(m,2H),1.65(s,1H),1.55-1.18(m,20H),1.08(t,J=7.1Hz,6H),0.66(s,2H)ppm。 1) 1 H NMR (600MHz, DMSO- d 6 ) δ 9.07 (s, 1H), 8.65 (s, 1H), 8.44 (s, 1H), 8.04 (d, J = 9.1Hz, 1H), 7.55 (s , 1H), 7.46 (s, 1H), 7.34 (d, J = 9.3Hz, 1H), 6.80 (s, 1H), 5.65 (s, 1H), 5.38 (d, J = 53.9Hz, 2H), 4.67 (s, 1H), 4.58-4.44 (m, 2H), 4.14 (d, J = 9.1Hz, 1H), 3.93 (s, 3H), 3.58 (t, J = 5.7Hz, 2H), 3.17 (dt, J = 13.6, 6.8Hz, 2H), 2.83 (s, 6H), 2.69-2.55 (m, 4H), 2.38 (s, 1H), 2.13 (s, 1H), 2.04-1.85 (m, 2H), 1.65 (s, 1H), 1.55-1.18 (m, 20H), 1.08 (t, J = 7.1 Hz, 6H), 0.66 (s, 2H) ppm.

2)通過Empyrean X射線粉末衍射(XRPD)分析鑑定：使用Cu-K α輻射，實驗結果如圖10所示。 2) Identification by Empyrean X-ray powder diffraction (XRPD) analysis: Cu-K α radiation was used, and the experimental results are shown in FIG. 10.

實施例11化合物(I)呱嗪鹽無定形的製備和鑑定Example 11 Preparation and Identification of Compound (I) Pyrazine Salt Amorphous 1.化合物(I)呱嗪鹽無定形的製備 1. Amorphous preparation of compound (I) oxazine salt

將化合物(I)(0.212g,0.243mmol)和呱嗪(0.029g,0.337mmol)加入到甲醇(10.0mL)中，固體緩慢溶解，反應混合物在室溫下反應過夜，反應完後，減壓除去溶劑，殘留物經室溫真空乾燥，得到化合物(I)呱嗪鹽無定形為白色固體粉末(0.23g,0.24mmol,98.75%)。 Compound (I) (0.212 g, 0.243 mmol) and verazine (0.029 g, 0.337 mmol) were added to methanol (10.0 mL), and the solid was slowly dissolved. The reaction mixture was reacted at room temperature overnight. After the reaction was completed, the pressure was reduced. The solvent was removed, and the residue was dried under vacuum at room temperature to obtain the compound (I) oxazine salt as an amorphous white solid powder (0.23 g, 0.24 mmol, 98.75%).

2.化合物(I)呱嗪鹽無定形的鑑定 2. Amorphous identification of compound (I)

1)1H NMR(600MHz,DMSO-d 6)δ 9.08(s,1H),8.43(d,J=5.7Hz,1H),8.13-7.97(m,2H),7.53(s,1H),7.46(s,1H),7.36(d,J=9.3Hz,1H),6.83(s,1H),5.58(dd,J=21.4,11.3Hz,2H),5.34(dd,J=16.5,9.7Hz,1H),4.78(s,1H),4.53(t,J=7.8Hz,1H),4.42(d,J=11.6Hz,1H),4.19(d,J=8.1Hz,1H),3.93(s,3H),3.16(dt,J=13.7,6.9Hz,1H),2.80(s,8H),2.61-2.52(m,5H),2.01(ddd,J=30.3,27.2,21.7Hz,4H),1.72(d,J=12.0Hz,1H),1.51-1.05(m,21H),0.47(s,2H)ppm。 1) 1 H NMR (600MHz, DMSO- d 6 ) δ 9.08 (s, 1H), 8.43 (d, J = 5.7Hz, 1H), 8.13-7.97 (m, 2H), 7.53 (s, 1H), 7.46 (s, 1H), 7.36 (d, J = 9.3Hz, 1H), 6.83 (s, 1H), 5.58 (dd, J = 21.4, 11.3Hz, 2H), 5.34 (dd, J = 16.5, 9.7Hz, 1H), 4.78 (s, 1H), 4.53 (t, J = 7.8Hz, 1H), 4.42 (d, J = 11.6Hz, 1H), 4.19 (d, J = 8.1Hz, 1H), 3.93 (s, 3H), 3.16 (dt, J = 13.7, 6.9Hz, 1H), 2.80 (s, 8H), 2.61-2.52 (m, 5H), 2.01 (ddd, J = 30.3, 27.2, 21.7Hz, 4H), 1.72 (d, J = 12.0Hz, 1H), 1.51-1.05 (m, 21H), 0.47 (s, 2H) ppm.

2)通過Empyrean X射線粉末衍射(XRPD)分析鑑定：使用Cu-K α輻射，實驗結果如圖11所示。 2) Identification by Empyrean X-ray powder diffraction (XRPD) analysis: Cu-K α radiation was used, and the experimental results are shown in FIG. 11.

實施例12 化合物(I)鎂鹽無定形的製備和鑑定Example 12 Amorphous Preparation and Identification of Compound (I) Magnesium Salt 1.化合物(I)鎂鹽無定形的製備 1. Amorphous preparation of compound (I) magnesium salt

將化合物(I)(500mg,0.562mmol)分散於甲醇(15mL)中，並向其中滴加氫氧化鎂(16.4mg,0.281mmol)的水(1mL)溶液，所得混合物在室溫下攪拌過夜，反應完後，減壓蒸除溶劑，殘留物經60℃真空乾燥過夜，得到化合物(I)鎂鹽無定形為微黃色固體粉末(0.497g,0.279mmol,99.1%)。 Compound (I) (500 mg, 0.562 mmol) was dispersed in methanol (15 mL), and a solution of magnesium hydroxide (16.4 mg, 0.281 mmol) in water (1 mL) was added dropwise thereto, and the resulting mixture was stirred at room temperature overnight, After the reaction was completed, the solvent was distilled off under reduced pressure, and the residue was dried under vacuum at 60 ° C. overnight to obtain the magnesium salt of compound (I) as an amorphous yellowish solid powder (0.497 g, 0.279 mmol, 99.1%).

2.化合物(I)鎂鹽無定形的鑑定 2. Amorphous identification of compound (I) magnesium salt

1)1H NMR(600MHz,DMSO-d 6)δ 9.07(s,1H),8.44(s,1H),8.02(d,J=8.8Hz,1H),7.54(s,1H),7.46(s,1H),7.36(d,J=9.2Hz,1H),6.82(s,1H),5.63 (s,2H),5.39(s,1H),4.74(s,1H),4.59-4.35(m,2H),4.30-4.02(m,1H),3.93(s,3H),3.25-3.08(m,1H),2.58(s,5H),1.97(t,J=101.9Hz,5H),1.61-0.81(m,20H),0.57(s,2H)ppm。 1) 1 H NMR (600MHz, DMSO- d 6 ) δ 9.07 (s, 1H), 8.44 (s, 1H), 8.02 (d, J = 8.8Hz, 1H), 7.54 (s, 1H), 7.46 (s , 1H), 7.36 (d, J = 9.2Hz, 1H), 6.82 (s, 1H), 5.63 (s, 2H), 5.39 (s, 1H), 4.74 (s, 1H), 4.59-4.35 (m, 2H), 4.30-4.02 (m, 1H), 3.93 (s, 3H), 3.25-3.08 (m, 1H), 2.58 (s, 5H), 1.97 (t, J = 101.9Hz, 5H), 1.61-0.81 (m, 20H), 0.57 (s, 2H) ppm.

2)通過Empyrean X射線粉末衍射(XRPD)分析鑑定：使用Cu-K α輻射，實驗結果如圖12所示。 2) Identification by Empyrean X-ray powder diffraction (XRPD) analysis: Cu-K α radiation was used, and the experimental results are shown in FIG. 12.

實施例13 化合物(I)二甲基乙醇胺鹽無定形的製備和鑑定Example 13 Amorphous preparation and identification of compound (I) dimethylethanolamine salt 1.化合物(I)二甲基乙醇胺鹽無定形的製備 1. Amorphous preparation of compound (I) dimethylethanolamine salt

將化合物(I)(500mg,0.562mmol)加入到甲醇和二氯甲烷的混合溶劑(15mL，甲醇/二氯甲烷(V/V)=1/1)中，室溫攪拌溶解，然後再向其中加入二甲基乙醇胺(51.1mg,0.562mmol)的甲醇(1mL)溶液，所得混合物在室溫下攪拌3小時，反應完後，減壓除去溶劑，所得殘留物經室溫真空乾燥，得到化合物(I)二甲基乙醇胺鹽無定形為微黃色固體粉末(0.526g,0.546mmol,97.2%)。 Compound (I) (500 mg, 0.562 mmol) was added to a mixed solvent of methanol and dichloromethane (15 mL, methanol / dichloromethane (V / V) = 1/1), and dissolved by stirring at room temperature, and then into it A solution of dimethylethanolamine (51.1 mg, 0.562 mmol) in methanol (1 mL) was added, and the resulting mixture was stirred at room temperature for 3 hours. After the reaction was completed, the solvent was removed under reduced pressure, and the obtained residue was dried under vacuum at room temperature to obtain the compound ( I) The dimethylethanolamine salt is amorphous as a slightly yellow solid powder (0.526 g, 0.546 mmol, 97.2%).

2.化合物(I)二甲基乙醇胺鹽無定形的鑑定 2. Amorphous identification of compound (I) dimethylethanolamine salt

1)1H NMR(600MHz,DMSO-d 6)δ 9.07(s,1H),8.68(d,J=5.4Hz,1H),8.49(s,1H),8.04(d,J=9.2Hz,1H),7.56(s,1H),7.47(s,1H),7.34(d,J=9.3Hz,1H),6.80(s,1H),5.66(s,1H),5.48(dd,J=17.5,8.5Hz,1H),5.30(t,J=9.3Hz,1H),4.79(s,1H),4.66(s,1H),4.55(d,J=11.5Hz,1H),4.49(t,J=8.1Hz,1H),4.13(d,J=8.2Hz,1H),3.93(s,3H),3.57(t,J=5.8Hz,2H),3.17(dt,J=14.3,6.9Hz,2H),2.69(t,J=5.8Hz,2H),2.63(dd,J=13.7,7.5Hz,1H),2.58(s,3H),2.44(s,6H),2.15(d,J=8.2Hz,1H),1.97(dd,J=24.2,13.6Hz,2H),1.69-1.18(m,21H),0.68(s,2H)ppm。 1) 1 H NMR (600MHz, DMSO- d 6 ) δ 9.07 (s, 1H), 8.68 (d, J = 5.4Hz, 1H), 8.49 (s, 1H), 8.04 (d, J = 9.2Hz, 1H ), 7.56 (s, 1H), 7.47 (s, 1H), 7.34 (d, J = 9.3Hz, 1H), 6.80 (s, 1H), 5.66 (s, 1H), 5.48 (dd, J = 17.5, 8.5Hz, 1H), 5.30 (t, J = 9.3Hz, 1H), 4.79 (s, 1H), 4.66 (s, 1H), 4.55 (d, J = 11.5Hz, 1H), 4.49 (t, J = 8.1Hz, 1H), 4.13 (d, J = 8.2Hz, 1H), 3.93 (s, 3H), 3.57 (t, J = 5.8Hz, 2H), 3.17 (dt, J = 14.3, 6.9Hz, 2H) , 2.69 (t, J = 5.8Hz, 2H), 2.63 (dd, J = 13.7, 7.5Hz, 1H), 2.58 (s, 3H), 2.44 (s, 6H), 2.15 (d, J = 8.2Hz, 1H), 1.97 (dd, J = 24.2, 13.6 Hz, 2H), 1.69-1.18 (m, 21H), 0.68 (s, 2H) ppm.

2)通過Empyrean X射線粉末衍射(XRPD)分析鑑定：使用Cu-K α輻射，實驗結果如圖13所示。 2) Identification by Empyrean X-ray powder diffraction (XRPD) analysis: Cu-K α radiation was used, and the experimental results are shown in FIG. 13.

實施例14 化合物(I)乙二胺鹽無定形的製備和鑑定Example 14 Amorphous Preparation and Identification of Compound (I) Ethylenediamine Salt 1.化合物(I)乙二胺鹽無定形的製備 1. Amorphous preparation of compound (I) ethylenediamine salt

將化合物(I)(503mg,0.565mmol)溶於甲醇和二氯甲烷的混合溶劑(15mL，甲醇/二氯甲烷(V/V)=1/1)中，室溫攪拌下，再向所得溶液中加入乙二胺(34.7mg,0.565mmol)的甲醇(1mL)溶液，所得混合物在室溫下攪拌3小 時，反應完後，減壓除去溶劑，殘留物經室溫真空乾燥，得到化合物(I)乙二胺鹽無定形為微黃色固體粉末(0.523g,0.560mmol,99.1%)。 Compound (I) (503 mg, 0.565 mmol) was dissolved in a mixed solvent of methanol and dichloromethane (15 mL, methanol / dichloromethane (V / V) = 1/1), and the obtained solution was stirred at room temperature. A solution of ethylenediamine (34.7mg, 0.565mmol) in methanol (1mL) was added, and the resulting mixture was stirred at room temperature for 3 hours. At this time, after the reaction was completed, the solvent was removed under reduced pressure, and the residue was dried under vacuum at room temperature to obtain Compound (I) ethylenediamine salt as an amorphous yellowish solid powder (0.523 g, 0.560 mmol, 99.1%).

2.化合物(I)乙二胺鹽無定形的鑑定 2. Amorphous identification of compound (I) ethylenediamine salt

1)1H NMR(600MHz,DMSO-d 6)δ 9.08(s,1H),8.43(s,1H),8.01(d,J=9.2Hz,2H),7.54(s,1H),7.46(s,1H),7.36(d,J=9.3Hz,1H),6.83(s,1H),5.62(s,1H),5.55(t,J=10.0Hz,1H),5.33(dd,J=16.5,9.6Hz,1H),4.78(d,J=6.0Hz,1H),4.52(t,J=7.8Hz,1H),4.43(d,J=11.6Hz,1H),4.20(d,J=7.8Hz,1H),3.93(s,3H),3.74(s,4H),3.17(dq,J=13.7,6.9Hz,2H),2.74(s,4H),2.58(s,3H),2.23-2.01(m,2H),2.02-1.86(m,2H),1.74(s,1H),1.51-1.05(m,20H),0.47(s,2H)ppm。 1) 1 H NMR (600MHz, DMSO- d 6 ) δ 9.08 (s, 1H), 8.43 (s, 1H), 8.01 (d, J = 9.2Hz, 2H), 7.54 (s, 1H), 7.46 (s , 1H), 7.36 (d, J = 9.3Hz, 1H), 6.83 (s, 1H), 5.62 (s, 1H), 5.55 (t, J = 10.0Hz, 1H), 5.33 (dd, J = 16.5, 9.6Hz, 1H), 4.78 (d, J = 6.0Hz, 1H), 4.52 (t, J = 7.8Hz, 1H), 4.43 (d, J = 11.6Hz, 1H), 4.20 (d, J = 7.8Hz , 1H), 3.93 (s, 3H), 3.74 (s, 4H), 3.17 (dq, J = 13.7, 6.9Hz, 2H), 2.74 (s, 4H), 2.58 (s, 3H), 2.23-2.01 ( m, 2H), 2.02-1.86 (m, 2H), 1.74 (s, 1H), 1.51-1.05 (m, 20H), 0.47 (s, 2H) ppm.

2)通過Empyrean X射線粉末衍射(XRPD)分析鑑定：使用Cu-K α輻射，實驗結果如圖14所示。 2) Identification by Empyrean X-ray powder diffraction (XRPD) analysis: Cu-K α radiation was used, and the experimental results are shown in FIG. 14.

實施例15 化合物(I)三乙醇胺鹽無定形的製備和鑑定Example 15 Amorphous preparation and identification of compound (I) triethanolamine salt 1.化合物(I)三乙醇胺鹽無定形的製備 1. Amorphous preparation of compound (I) triethanolamine salt

將化合物(I)(505mg,0.565mmol)溶於甲醇和二氯甲烷的混合溶劑(15mL，甲醇/二氯甲烷(V/V)=1/2)中，室溫攪拌下，再向所得溶液中加入三乙醇胺(85.9mg,0.565mmol)的甲醇(1.5mL)溶液，所得混合物在室溫下攪拌3.5小時，反應完後，減壓蒸除溶劑，殘留物經室溫真空乾燥，得到化合物(I)三乙醇胺鹽無定形為微黃色固體粉末(0.565g,0.552mmol,97.8%)。 Compound (I) (505 mg, 0.565 mmol) was dissolved in a mixed solvent of methanol and dichloromethane (15 mL, methanol / dichloromethane (V / V) = 1/2), and the obtained solution was stirred at room temperature. A solution of triethanolamine (85.9 mg, 0.565 mmol) in methanol (1.5 mL) was added to the obtained mixture, and the resulting mixture was stirred at room temperature for 3.5 hours. After the reaction was completed, the solvent was distilled off under reduced pressure, and the residue was dried under vacuum at room temperature to obtain the compound ( I) Triethanolamine salt is amorphous as a slightly yellow solid powder (0.565 g, 0.552 mmol, 97.8%).

2.化合物(I)三乙醇胺鹽無定形的鑑定 2. Amorphous identification of compound (I) triethanolamine salt

1)1H NMR(600MHz,DMSO-d 6)δ 9.07(d,J=1.4Hz,1H),8.83(s,2H),8.32-8.29(m,1H),8.05(d,J=9.2Hz,1H),7.57(s,1H),7.47(s,1H),7.34(d,J=9.3Hz,1H),6.79(d,J=1.2Hz,1H),5.62(d,J=48.4Hz,2H),5.16(s,1H),5.16(s,2H),4.50(dd,J=35.3,27.2Hz,6H),4.10(s,1H),3.94(s,3H),3.48(s,6H),3.17(dt,J=13.6,6.8Hz,2H),2.63(d,J=36.4Hz,10H),2.33(s,1H),2.14-1.72(m,2H),1.65-1.14(m,21H),0.80(s,2H)ppm。 1) 1 H NMR (600MHz, DMSO- d 6 ) δ 9.07 (d, J = 1.4Hz, 1H), 8.83 (s, 2H), 8.32-8.29 (m, 1H), 8.05 (d, J = 9.2Hz , 1H), 7.57 (s, 1H), 7.47 (s, 1H), 7.34 (d, J = 9.3Hz, 1H), 6.79 (d, J = 1.2Hz, 1H), 5.62 (d, J = 48.4Hz , 2H), 5.16 (s, 1H), 5.16 (s, 2H), 4.50 (dd, J = 35.3, 27.2Hz, 6H), 4.10 (s, 1H), 3.94 (s, 3H), 3.48 (s, 6H), 3.17 (dt, J = 13.6, 6.8Hz, 2H), 2.63 (d, J = 36.4Hz, 10H), 2.33 (s, 1H), 2.14-1.72 (m, 2H), 1.65-1.14 (m 21H), 0.80 (s, 2H) ppm.

2)通過Empyrean X射線粉末衍射(XRPD)分析鑑定：使用Cu-K α輻射，實驗結果如圖15所示。 2) Identification by Empyrean X-ray powder diffraction (XRPD) analysis: Cu-K α radiation was used, and the experimental results are shown in FIG. 15.

實施例16 化合物(I)乙醇胺鹽無定形的製備和鑑定Example 16 Amorphous Preparation and Identification of Compound (I) Ethanolamine Salt 1.化合物(I)乙醇胺鹽無定形的製備 1. Amorphous preparation of compound (I) ethanolamine salt

將化合物(I)(503mg,0.565mmol)溶於甲醇和二氯甲烷的混合溶劑(15mL，甲醇/二氯甲烷(V/V)=1/2)中，室溫攪拌下，再向所得溶液中加入乙醇胺(35.2mg,0.565mmol)的甲醇(1mL)溶液，所得混合物在室溫下攪拌3.5小時，反應完後，減壓蒸除溶劑，殘留物經室溫真空乾燥，得到化合物(I)乙醇胺鹽無定形為微黃色固體粉末(0.52g,0.560mmol,98.0%)。 Compound (I) (503 mg, 0.565 mmol) was dissolved in a mixed solvent of methanol and dichloromethane (15 mL, methanol / dichloromethane (V / V) = 1/2), and the obtained solution was stirred at room temperature. A solution of ethanolamine (35.2 mg, 0.565 mmol) in methanol (1 mL) was added, and the resulting mixture was stirred at room temperature for 3.5 hours. After the reaction was completed, the solvent was distilled off under reduced pressure, and the residue was dried under vacuum at room temperature to obtain compound (I). The ethanolamine salt was amorphous as a slightly yellow solid powder (0.52 g, 0.560 mmol, 98.0%).

2.化合物(I)乙醇胺鹽無定形的鑑定 2. Amorphous identification of compound (I) ethanolamine salt

1)1H NMR(600MHz,DMSO-d 6)δ 9.08(d,J=0.9Hz,1H),8.43(d,J=5.3Hz,1H),8.01(d,J=8.9Hz,2H),7.53(s,1H),7.46(s,1H),7.35(d,J=9.3Hz,1H),6.83(d,J=1.0Hz,1H),5.56(dd,J=24.7,14.5Hz,2H),5.33(dd,J=16.6,9.8Hz,1H),4.78(s,1H),4.60-4.36(m,2H),4.21(d,J=8.1Hz,1H),3.93(s,3H),3.56-3.53(m,2H),3.17(dq,J=13.8,6.9Hz,2H),2.82(t,J=5.4Hz,2H),2.56(d,J=13.0Hz,5H),2.22-1.86(m,4H),1.74(t,J=12.1Hz,1H),1.55-1.04(m,20H),0.47(s,2H)ppm。 1) 1 H NMR (600MHz, DMSO- d 6 ) δ 9.08 (d, J = 0.9Hz, 1H), 8.43 (d, J = 5.3Hz, 1H), 8.01 (d, J = 8.9Hz, 2H), 7.53 (s, 1H), 7.46 (s, 1H), 7.35 (d, J = 9.3Hz, 1H), 6.83 (d, J = 1.0Hz, 1H), 5.56 (dd, J = 24.7, 14.5Hz, 2H ), 5.33 (dd, J = 16.6, 9.8Hz, 1H), 4.78 (s, 1H), 4.60-4.36 (m, 2H), 4.21 (d, J = 8.1Hz, 1H), 3.93 (s, 3H) , 3.56-3.53 (m, 2H), 3.17 (dq, J = 13.8, 6.9Hz, 2H), 2.82 (t, J = 5.4Hz, 2H), 2.56 (d, J = 13.0Hz, 5H), 2.22- 1.86 (m, 4H), 1.74 (t, J = 12.1Hz, 1H), 1.55-1.04 (m, 20H), 0.47 (s, 2H) ppm.

2)通過Empyrean X射線粉末衍射(XRPD)分析鑑定：使用Cu-K α輻射，實驗結果如圖16所示。 2) Identification by Empyrean X-ray powder diffraction (XRPD) analysis: Cu-K α radiation was used, and the experimental results are shown in FIG. 16.

實施例17 化合物(I)咪唑鹽無定形的製備和鑑定Example 17 Amorphous preparation and identification of compound (I) imidazole salt 1.化合物(I)咪唑鹽無定形的製備 1. Amorphous preparation of compound (I) imidazole salt

將化合物(I)(0.38g,0.435mmol)和咪唑(0.03g,0.441mmol)加入到丙酮(10mL)中，固體溶解，混合物在室溫下反應7.5小時，反應完後，減壓除去溶劑，殘留物經室溫真空乾燥，得到化合物(I)咪唑鹽無定形為白色固體粉末(0.39g,0.414mmol,95.21%)。 Compound (I) (0.38 g, 0.435 mmol) and imidazole (0.03 g, 0.441 mmol) were added to acetone (10 mL), and the solid was dissolved. The mixture was reacted at room temperature for 7.5 hours. After the reaction was completed, the solvent was removed under reduced pressure. The residue was dried under vacuum at room temperature to obtain compound (I) imidazole salt as an amorphous white solid powder (0.39 g, 0.414 mmol, 95.21%).

2.化合物(I)咪唑鹽無定形的鑑定 2. Amorphous identification of compound (I) imidazole salt

1)1H NMR(600MHz,DMSO-d 6)δ 9.07(s,1H),8.98-8.73(m,2H),8.06(d,J=9.2Hz,1H),7.71(s,1H),7.57(s,1H),7.47(s,1H),7.34(d,J=9.3Hz,1H),7.05(s,2H),6.78(d,J=1.3Hz,1H),5.76-5.50(m,2H),5.12(t,J=9.5Hz,1H),4.65(d,J=11.5Hz,1H),4.55(s,1H),4.49-4.43(m,1H),4.06(d,J=8.8Hz,1H),3.94(s,3H),3.17(dt,J=13.6,6.8Hz,1H),2.75-2.54(m,5H),2.49-2.30(m,2H), 2.00(d,J=10.9Hz,1H),1.77(d,J=5.1Hz,1H),1.64-1.13(m,20H),0.91-0.75(m,2H)ppm。 1) 1 H NMR (600MHz, DMSO- d 6 ) δ 9.07 (s, 1H), 8.98-8.73 (m, 2H), 8.06 (d, J = 9.2Hz, 1H), 7.71 (s, 1H), 7.57 (s, 1H), 7.47 (s, 1H), 7.34 (d, J = 9.3Hz, 1H), 7.05 (s, 2H), 6.78 (d, J = 1.3Hz, 1H), 5.76-5.50 (m, 2H), 5.12 (t, J = 9.5Hz, 1H), 4.65 (d, J = 11.5Hz, 1H), 4.55 (s, 1H), 4.49-4.43 (m, 1H), 4.06 (d, J = 8.8 Hz, 1H), 3.94 (s, 3H), 3.17 (dt, J = 13.6, 6.8Hz, 1H), 2.75-2.54 (m, 5H), 2.49-2.30 (m, 2H), 2.00 (d, J = 10.9Hz, 1H), 1.77 (d, J = 5.1Hz, 1H), 1.64-1.13 (m, 20H), 0.91-0.75 (m, 2H) ppm.

2)通過Empyrean X射線粉末衍射(XRPD)分析鑑定：使用Cu-K α輻射，實驗結果如圖17所示。 2) Identification by Empyrean X-ray powder diffraction (XRPD) analysis: Cu-K α radiation was used, and the experimental results are shown in FIG. 17.

實施例18 化合物(I)檸檬酸鹽無定形的製備和鑑定Example 18 Preparation and Identification of Compound (I) Citrate Amorphous 1.化合物(I)檸檬酸鹽無定形的製備 1. Preparation of Compound (I) Citrate Amorphous

將化合物(I)(204mg,0.228mmol)分散於甲醇(4.0mL)中，然後加入檸檬酸(46.1mg,0.239mmol)的甲醇(1.0mL)溶液，再加入二氯甲烷(4.0mL)，室溫攪拌4小時，減壓蒸除溶劑，殘留物60℃真空乾燥過夜，得到化合物(I)檸檬酸鹽無定形為淺黃色固體(206mg,0.201mmol,88.2%)。 Compound (I) (204 mg, 0.228 mmol) was dispersed in methanol (4.0 mL), and then a solution of citric acid (46.1 mg, 0.239 mmol) in methanol (1.0 mL) was added, and then dichloromethane (4.0 mL) was added. Stir at temperature for 4 hours, evaporate the solvent under reduced pressure, and dry the residue under vacuum at 60 ° C. overnight to obtain compound (I) citrate as an amorphous light yellow solid (206 mg, 0.201 mmol, 88.2%).

2.化合物(I)檸檬酸鹽無定形的鑑定 2. Amorphous identification of compound (I) citrate

1)1H NMR(400MHz,CDCl3)δ 10.16(s,1H),8.44(d,J=1.5Hz,1H),8.03(d,J=7.1Hz,1H),7.91(d,J=9.1Hz,1H),7.64(d,J=7.6Hz,1H),7.57(s,1H),7.27(s,1H),7.11(d,J=9.2Hz,1H),7.06(s,1H),6.62(d,J=1.5Hz,1H),5.73(dd,J=18.1,8.6Hz,1H),5.09-4.93(m,1H),4.80(t,J=7.2Hz,1H),4.70(t,J=7.9Hz,1H),4.58(d,J=11.5Hz,1H),4.16(dd,J=11.4,3.6Hz,1H),3.93(s,3H),3.24(dt,J=13.8,6.9Hz,1H),2.97(s,2H),2.89(s,2H),2.79-2.73(m,2H),2.70(s,3H),2.58(s,1H),2.31(dd,J=17.4,8.8Hz,1H),2.06(dd,J=23.1,11.4Hz,1H),1.83(ddd,J=27.3,19.0,9.2Hz,8H),1.53-1.48(m,6H),1.41(d,J=6.9Hz,6H),1.30(d,J=14.1Hz,2H),0.87-0.79(m,2H)ppm。 1) 1 H NMR (400MHz, CDCl 3 ) δ 10.16 (s, 1H), 8.44 (d, J = 1.5Hz, 1H), 8.03 (d, J = 7.1Hz, 1H), 7.91 (d, J = 9.1 Hz, 1H), 7.64 (d, J = 7.6 Hz, 1H), 7.57 (s, 1H), 7.27 (s, 1H), 7.11 (d, J = 9.2Hz, 1H), 7.06 (s, 1H), 6.62 (d, J = 1.5Hz, 1H), 5.73 (dd, J = 18.1, 8.6Hz, 1H), 5.09-4.93 (m, 1H), 4.80 (t, J = 7.2Hz, 1H), 4.70 (t , J = 7.9Hz, 1H), 4.58 (d, J = 11.5Hz, 1H), 4.16 (dd, J = 11.4, 3.6Hz, 1H), 3.93 (s, 3H), 3.24 (dt, J = 13.8, 6.9Hz, 1H), 2.97 (s, 2H), 2.89 (s, 2H), 2.79-2.73 (m, 2H), 2.70 (s, 3H), 2.58 (s, 1H), 2.31 (dd, J = 17.4 , 8.8Hz, 1H), 2.06 (dd, J = 23.1, 11.4Hz, 1H), 1.83 (ddd, J = 27.3, 19.0, 9.2Hz, 8H), 1.53-1.48 (m, 6H), 1.41 (d, J = 6.9Hz, 6H), 1.30 (d, J = 14.1Hz, 2H), 0.87-0.79 (m, 2H) ppm.

2)通過Empyrean X射線粉末衍射(XRPD)分析鑑定：使用Cu-K α輻射，實驗結果如圖18所示。 2) Identification by Empyrean X-ray powder diffraction (XRPD) analysis: Cu-K α radiation was used, and the experimental results are shown in FIG. 18.

實施例19 化合物(I)對甲苯磺酸鹽無定形的製備和鑑定Example 19 Preparation and identification of compound (I) p-toluenesulfonate amorphous 1.化合物(I)對甲苯磺酸鹽無定形的製備 1. Amorphous preparation of compound (I) p-toluenesulfonate

將化合物(I)(623mg,0.705mmol)分散於甲醇(12.0mL)和二氯甲烷(7.0mL)的混合溶劑中，然後緩慢加入對甲苯磺酸(137mg,0.706mmol)的甲醇(4.5mL)溶液，室溫攪拌4小時，減壓蒸除溶劑，殘留物經60℃真空乾燥過夜，得到化合物(I)對甲苯磺酸鹽無定形為黃色固體(720mg,0.69mmol,97.9%)。 Compound (I) (623 mg, 0.705 mmol) was dispersed in a mixed solvent of methanol (12.0 mL) and dichloromethane (7.0 mL), and then p-toluenesulfonic acid (137 mg, 0.706 mmol) in methanol (4.5 mL) was slowly added. The solution was stirred at room temperature for 4 hours, and the solvent was evaporated under reduced pressure. The residue was dried under vacuum at 60 ° C. overnight to obtain compound (I) p-toluenesulfonate as an amorphous yellow solid (720 mg, 0.69 mmol, 97.9%).

2.化合物(I)對甲苯磺酸鹽無定形的鑑定 2. Amorphous identification of compound (I) p-toluenesulfonate

1)1H NMR(400MHz,CDCl3)δ 10.37(s,1H),8.38(s,1H),8.20(s,1H),8.07(d,J=9.1Hz,1H),7.95(s,1H),7.78(d,J=7.7Hz,2H),7.48(d,J=7.1Hz,1H),7.36(s,1H),7.18(dd,J=19.0,8.5Hz,3H),6.48(s,1H),5.80(s,1H),5.65(dd,J=18.1,8.5Hz,1H),5.05(t,J=9.5Hz,1H),4.87(t,J=7.8Hz,1H),4.65(s,1H),4.37(d,J=11.7Hz,1H),4.12(d,J=8.9Hz,1H),3.93(s,5H),3.40(dd,J=13.5,6.7Hz,1H),2.82-2.61(m,2H),2.56(s,3H),2.41(s,1H),2.39-2.20(m,4H),2.01(dd,J=23.5,11.7Hz,2H),1.80-1.64(m,3H),1.56(dd,J=9.0,5.7Hz,1H),1.41(dd,J=21.4,15.2Hz,12H),1.27(s,2H),0.80(d,J=12.1Hz,2H)ppm。 1) 1 H NMR (400MHz, CDCl 3 ) δ 10.37 (s, 1H), 8.38 (s, 1H), 8.20 (s, 1H), 8.07 (d, J = 9.1Hz, 1H), 7.95 (s, 1H ), 7.78 (d, J = 7.7Hz, 2H), 7.48 (d, J = 7.1Hz, 1H), 7.36 (s, 1H), 7.18 (dd, J = 19.0, 8.5Hz, 3H), 6.48 (s , 1H), 5.80 (s, 1H), 5.65 (dd, J = 18.1, 8.5Hz, 1H), 5.05 (t, J = 9.5Hz, 1H), 4.87 (t, J = 7.8Hz, 1H), 4.65 (s, 1H), 4.37 (d, J = 11.7Hz, 1H), 4.12 (d, J = 8.9Hz, 1H), 3.93 (s, 5H), 3.40 (dd, J = 13.5, 6.7Hz, 1H) , 2.82-2.61 (m, 2H), 2.56 (s, 3H), 2.41 (s, 1H), 2.39-2.20 (m, 4H), 2.01 (dd, J = 23.5, 11.7Hz, 2H), 1.80-1.64 (m, 3H), 1.56 (dd, J = 9.0, 5.7 Hz, 1H), 1.41 (dd, J = 21.4, 15.2 Hz, 12H), 1.27 (s, 2H), 0.80 (d, J = 12.1 Hz, 2H) ppm.

2)通過Empyrean X射線粉末衍射(XRPD)分析鑑定：使用Cu-K α輻射，實驗結果如圖19所示。 2) Identification by Empyrean X-ray powder diffraction (XRPD) analysis: Cu-K α radiation was used, and the experimental results are shown in FIG. 19.

實施例20 化合物(I)苯磺酸鹽無定形的製備和鑑定Example 20 Amorphous preparation and identification of compound (I) besylate 1.化合物(I)苯磺酸鹽無定形的製備 1. Amorphous preparation of compound (I) besylate

將化合物(I)(633mg,0.716mmol)分散於甲醇(12.0mL)和二氯甲烷(1.0mL)的混合溶劑中，然後緩慢加入苯磺酸(118mg,0.709mmol)的甲醇(4.5mL)溶液，室溫攪拌4小時，減壓蒸除溶劑，殘留物經60℃真空乾燥過夜，得到化合物(I)苯磺酸鹽無定形為黃色固體(710mg,0.69mmol,96.4%)。 Compound (I) (633 mg, 0.716 mmol) was dispersed in a mixed solvent of methanol (12.0 mL) and dichloromethane (1.0 mL), and then a solution of benzenesulfonic acid (118 mg, 0.709 mmol) in methanol (4.5 mL) was slowly added. The mixture was stirred at room temperature for 4 hours, and the solvent was evaporated under reduced pressure. The residue was dried under vacuum at 60 ° C. overnight to obtain compound (I) benzenesulfonate as an amorphous yellow solid (710 mg, 0.69 mmol, 96.4%).

2.化合物(I)苯磺酸鹽無定形的鑑定 2. Amorphous identification of compound (I) besylate

1)1H NMR(400MHz,CDCl3)δ 10.38(s,1H),8.38(s,1H),8.27(s,1H),8.11(d,J=9.0Hz,1H),7.98(s,1H),7.89(s,2H),7.47(d,J=7.0Hz,1H),7.37(d,J=13.1Hz,3H),7.23(d,J=9.1Hz,1H),6.47(s,1H),5.85(s,1H),5.64(dd,J=17.9,8.2Hz,1H),5.04(t,J=9.5Hz,1H),4.89(d,J=7.0Hz,1H),4.64(s,1H),4.39(d,J=11.6Hz,1H),4.17(d,J=10.3Hz,2H),3.94(s,4H),3.52-3.32(m,2H),2.71(d,J=29.9Hz,2H),2.56(s,3H),2.47-2.25(m,2H),1.97(s,2H),1.83-1.62(m,3H),1.56(s,1H),1.47-1.36(m,11H),1.27(d,J=6.9Hz,2H),0.78(s,2H)ppm。 1) 1 H NMR (400MHz, CDCl 3 ) δ 10.38 (s, 1H), 8.38 (s, 1H), 8.27 (s, 1H), 8.11 (d, J = 9.0Hz, 1H), 7.98 (s, 1H ), 7.89 (s, 2H), 7.47 (d, J = 7.0Hz, 1H), 7.37 (d, J = 13.1Hz, 3H), 7.23 (d, J = 9.1Hz, 1H), 6.47 (s, 1H ), 5.85 (s, 1H), 5.64 (dd, J = 17.9, 8.2Hz, 1H), 5.04 (t, J = 9.5Hz, 1H), 4.89 (d, J = 7.0Hz, 1H), 4.64 (s , 1H), 4.39 (d, J = 11.6Hz, 1H), 4.17 (d, J = 10.3Hz, 2H), 3.94 (s, 4H), 3.52-3.32 (m, 2H), 2.71 (d, J = 29.9Hz, 2H), 2.56 (s, 3H), 2.47-2.25 (m, 2H), 1.97 (s, 2H), 1.83-1.62 (m, 3H), 1.56 (s, 1H), 1.47-1.36 (m , 11H), 1.27 (d, J = 6.9Hz, 2H), 0.78 (s, 2H) ppm.

2)通過Empyrean X射線粉末衍射(XRPD)分析鑑定：使用Cu-K α輻射，實驗結果如圖20所示。 2) Identification by Empyrean X-ray powder diffraction (XRPD) analysis: Cu-K α radiation was used, and the experimental results are shown in FIG. 20.

實施例21 化合物(I)甲磺酸鹽無定形的製備和鑑定Example 21 Preparation and Identification of Compound (I) Methanesulfonate Amorphous 1.化合物(I)甲磺酸鹽無定形的製備 1. Amorphous preparation of compound (I) mesylate

將化合物(I)(644mg,0.729mmol)溶於四氫呋喃(13.0mL)，然後緩慢滴加入甲磺酸(74.3mg,0.765mmol)的四氫呋喃(2.0mL)溶液，室溫攪拌過夜，減壓蒸除溶劑，加入甲醇(19.0mL)，室溫攪拌溶解，再次減壓蒸除溶劑，殘留物經60℃真空乾燥過夜，得到化合物(I)甲磺酸鹽無定形為黃色固體(680mg,0.70mmol,96.0%)。 Compound (I) (644 mg, 0.729 mmol) was dissolved in tetrahydrofuran (13.0 mL), and then a solution of methanesulfonic acid (74.3 mg, 0.765 mmol) in tetrahydrofuran (2.0 mL) was slowly added dropwise, stirred at room temperature overnight, and evaporated under reduced pressure. The solvent was added with methanol (19.0 mL), stirred and dissolved at room temperature, and the solvent was distilled off under reduced pressure again. The residue was dried under vacuum at 60 ° C. overnight to obtain compound (I) methanesulfonate as an amorphous yellow solid (680 mg, 0.70 mmol, 96.0%).

2.化合物(I)甲磺酸鹽無定形的鑑定 2. Amorphous identification of compound (I) mesylate

1)1H NMR(400MHz,CDCl3)δ 10.34(s,1H),8.42(d,J=1.6Hz,1H),8.07(d,J=9.2Hz,1H),7.99(s,1H),7.89(s,1H),7.54(d,J=7.5Hz,1H),7.33(s,1H),7.26(s,1H),6.57(d,J=1.5Hz,1H),5.86(s,1H),5.68(dd,J=18.3,8.5Hz,1H),5.10(t,J=9.6Hz,1H),4.85-4.59(m,2H),4.46-4.31(m,2H),3.96(s,3H),3.71(s,3H),3.47(dt,J=13.6,6.8Hz,2H),2.87-2.76(m,5H),2.64-2.55(m,3H),2.50-2.38(m,1H),2.30(d,J=8.8Hz,1H),2.09-1.95(m,2H),1.89-1.69(m,3H),1.64-1.51(m,5H),1.47(d,J=6.9Hz,6H),1.27(s,2H),0.82(t,J=5.8Hz,2H)ppm。 1) 1 H NMR (400MHz, CDCl 3 ) δ 10.34 (s, 1H), 8.42 (d, J = 1.6Hz, 1H), 8.07 (d, J = 9.2Hz, 1H), 7.99 (s, 1H), 7.89 (s, 1H), 7.54 (d, J = 7.5Hz, 1H), 7.33 (s, 1H), 7.26 (s, 1H), 6.57 (d, J = 1.5Hz, 1H), 5.86 (s, 1H ), 5.68 (dd, J = 18.3, 8.5Hz, 1H), 5.10 (t, J = 9.6Hz, 1H), 4.85-4.59 (m, 2H), 4.46-4.31 (m, 2H), 3.96 (s, 3H), 3.71 (s, 3H), 3.47 (dt, J = 13.6, 6.8Hz, 2H), 2.87-2.76 (m, 5H), 2.64-2.55 (m, 3H), 2.50-2.38 (m, 1H) , 2.30 (d, J = 8.8Hz, 1H), 2.09-1.95 (m, 2H), 1.89-1.69 (m, 3H), 1.64-1.51 (m, 5H), 1.47 (d, J = 6.9Hz, 6H ), 1.27 (s, 2H), 0.82 (t, J = 5.8Hz, 2H) ppm.

2)通過Empyrean X射線粉末衍射(XRPD)分析鑑定：使用Cu-K α輻射，實驗結果如圖21所示。 2) Identification by Empyrean X-ray powder diffraction (XRPD) analysis: Cu-K α radiation was used, and the experimental results are shown in FIG. 21.

實施例22 化合物(I)硫酸鹽無定形的製備和鑑定Example 22 Preparation and Identification of Compound (I) Sulfate Amorphous 1.化合物(I)硫酸鹽無定形的製備 1. Preparation of Compound (I) Sulfate Amorphous

將化合物(I)(718mg,0.803mmol)溶於四氫呋喃(14.0mL)，並緩慢加入將硫酸(80.1mg,0.803mmol)的四氫呋喃(1.0mL)溶液，室溫攪拌過夜，減壓蒸除溶劑，殘留物60℃真空乾燥過夜，得到化合物(I)硫酸鹽無定形為黃色固體(730mg,0.75mmol,93.4%)。 Compound (I) (718 mg, 0.803 mmol) was dissolved in tetrahydrofuran (14.0 mL), and a solution of sulfuric acid (80.1 mg, 0.803 mmol) in tetrahydrofuran (1.0 mL) was slowly added, stirred at room temperature overnight, and the solvent was evaporated under reduced pressure. The residue was dried under vacuum at 60 ° C. overnight to give Compound (I) sulfate as an amorphous yellow solid (730 mg, 0.75 mmol, 93.4%).

2.化合物(I)硫酸鹽無定形的鑑定 2. Identification of Compound (I) Sulfate Amorphous

1)1H NMR(400MHz,CDCl3)δ 10.55(s,1H),8.41(d,J=1.5Hz,1H),8.15(d,J=9.3Hz,1H),7.92(d,J=10.7Hz,2H),7.57(d,J=7.6Hz,1H),7.45(s,1H),7.35(d,J=9.4Hz,1H),6.58(s,1H),5.88(s,1H),5.66(dd,J=18.5,8.6Hz,1H),5.11(t,J=9.6Hz,1H),4.88(t,J=8.0Hz,1H),4.79(t,J=7.1Hz,1H),4.52(d, J=9.7Hz,1H),4.36(d,J=11.4Hz,1H),3.99(s,3H),3.47(dd,J=13.8,6.9Hz,1H),2.86(dd,J=17.2,8.7Hz,2H),2.57(s,3H),2.44-2.18(m,2H),2.15-1.96(m,2H),1.91-1.78(m,2H),1.73-1.60(m,2H),1.46(dd,J=7.8,4.5Hz,12H),1.38-1.26(m,3H),0.89(d,J=7.0Hz,1H),0.78(s,2H)ppm。 1) 1 H NMR (400MHz, CDCl 3 ) δ 10.55 (s, 1H), 8.41 (d, J = 1.5Hz, 1H), 8.15 (d, J = 9.3Hz, 1H), 7.92 (d, J = 10.7 Hz, 2H), 7.57 (d, J = 7.6 Hz, 1H), 7.45 (s, 1H), 7.35 (d, J = 9.4 Hz, 1H), 6.58 (s, 1H), 5.88 (s, 1H), 5.66 (dd, J = 18.5, 8.6 Hz, 1H), 5.11 (t, J = 9.6 Hz, 1H), 4.88 (t, J = 8.0 Hz, 1H), 4.79 (t, J = 7.1 Hz, 1H), 4.52 (d, J = 9.7Hz, 1H), 4.36 (d, J = 11.4Hz, 1H), 3.99 (s, 3H), 3.47 (dd, J = 13.8, 6.9Hz, 1H), 2.86 (dd, J = 17.2, 8.7Hz, 2H), 2.57 (s, 3H), 2.44-2.18 (m, 2H), 2.15-1.96 (m, 2H), 1.91-1.78 (m, 2H), 1.73-1.60 (m, 2H ), 1.46 (dd, J = 7.8, 4.5 Hz, 12H), 1.38-1.26 (m, 3H), 0.89 (d, J = 7.0 Hz, 1H), 0.78 (s, 2H) ppm.

2)通過Empyrean X射線粉末衍射(XRPD)分析鑑定：使用Cu-K α輻射，實驗結果如圖22所示。 2) Identification by Empyrean X-ray powder diffraction (XRPD) analysis: Cu-K α radiation was used, and the experimental results are shown in FIG. 22.

實施例23 化合物(I)磷酸鹽無定形的製備和鑑定Example 23 Preparation and Identification of Compound (I) Phosphate Amorphous 1.化合物(I)磷酸鹽無定形的製備 1. Preparation of Compound (I) Phosphate Amorphous

將化合物(I)(967mg,1.095mmol)溶於四氫呋喃(20.0mL)，然後緩慢加入磷酸(126mg,1.093mmol)的四氫呋喃(2.0mL)溶液，室溫攪拌4小時，減壓蒸除溶劑，殘留物經60℃真空乾燥過夜，得到化合物(I)磷酸鹽無定形為黃色固體(980mg,1.0mmol,91.3%)。 Compound (I) (967 mg, 1.095 mmol) was dissolved in tetrahydrofuran (20.0 mL), and then a solution of phosphoric acid (126 mg, 1.093 mmol) in tetrahydrofuran (2.0 mL) was slowly added, and the mixture was stirred at room temperature for 4 hours. The solvent was evaporated under reduced pressure, and the residue The material was dried under vacuum at 60 ° C overnight to obtain compound (I) phosphate as an amorphous yellow solid (980 mg, 1.0 mmol, 91.3%).

2.化合物(I)磷酸鹽無定形的鑑定 2. Identification of Compound (I) Phosphate Amorphous

1)1H NMR(400MHz,CDCl3)δ 10.18(s,1H),8.43(d,J=1.5Hz,1H),7.90(d,J=9.1Hz,1H),7.70(d,J=7.6Hz,1H),7.57(s,1H),7.32(s,1H),7.10(d,J=9.2Hz,1H),7.05(s,1H),6.61(d,J=1.4Hz,1H),5.80-5.65(m,1H),5.58(s,1H),5.05-4.96(m,1H),4.80(t,J=7.4Hz,1H),4.69(t,J=7.9Hz,1H),4.58(d,J=11.4Hz,1H),4.16(dd,J=11.2,3.5Hz,1H),4.02-3.82(m,4H),3.78-3.63(m,1H),3.23(dt,J=13.6,6.8Hz,1H),2.83-2.64(m,5H),2.52(dd,J=17.0,8.5Hz,1H),2.39-2.21(m,1H),2.12-1.99(m,2H),1.91-1.85(m,3H),1.82-1.65(m,3H),1.51(s,4H),1.41(d,J=6.9Hz,6H),1.29(dd,J=19.5,7.4Hz,2H),0.91-0.77(m,2H)ppm。 1) 1 H NMR (400MHz, CDCl 3 ) δ 10.18 (s, 1H), 8.43 (d, J = 1.5Hz, 1H), 7.90 (d, J = 9.1Hz, 1H), 7.70 (d, J = 7.6 Hz, 1H), 7.57 (s, 1H), 7.32 (s, 1H), 7.10 (d, J = 9.2Hz, 1H), 7.05 (s, 1H), 6.61 (d, J = 1.4Hz, 1H), 5.80-5.65 (m, 1H), 5.58 (s, 1H), 5.05-4.96 (m, 1H), 4.80 (t, J = 7.4Hz, 1H), 4.69 (t, J = 7.9Hz, 1H), 4.58 (d, J = 11.4Hz, 1H), 4.16 (dd, J = 11.2, 3.5Hz, 1H), 4.02-3.82 (m, 4H), 3.78-3.63 (m, 1H), 3.23 (dt, J = 13.6 , 6.8Hz, 1H), 2.83-2.64 (m, 5H), 2.52 (dd, J = 17.0, 8.5Hz, 1H), 2.39-2.21 (m, 1H), 2.12-1.99 (m, 2H), 1.91- 1.85 (m, 3H), 1.82-1.65 (m, 3H), 1.51 (s, 4H), 1.41 (d, J = 6.9Hz, 6H), 1.29 (dd, J = 19.5, 7.4Hz, 2H), 0.91 -0.77 (m, 2H) ppm.

2)通過Empyrean X射線粉末衍射(XRPD)分析鑑定：使用Cu-K α輻射，實驗結果如圖23所示。 2) Identification by Empyrean X-ray powder diffraction (XRPD) analysis: Cu-K α radiation was used, and the experimental results are shown in FIG. 23.

實施例24 化合物(I)硝酸鹽無定形的製備和鑑定Example 24 Preparation and Identification of Compound (I) Nitrate Amorphous 1.化合物(I)硝酸鹽無定形的製備 1. Preparation of Compound (I) Nitrate Amorphous

將化合物(I)(672mg,0.755mmol)溶於四氫呋喃(14.0mL)，然後緩慢加入硝酸(73.5mg,0.758mmol)的四氫呋喃(2.0mL)溶液，室溫攪拌過夜， 減壓蒸除溶劑，殘留物經60℃真空乾燥過夜，得到化合物(I)硝酸鹽無定形為黃色固體(650mg,0.69mmol,91.4%)。 Compound (I) (672 mg, 0.755 mmol) was dissolved in tetrahydrofuran (14.0 mL), and then a solution of nitric acid (73.5 mg, 0.758 mmol) in tetrahydrofuran (2.0 mL) was slowly added and stirred at room temperature overnight. The solvent was distilled off under reduced pressure, and the residue was dried under vacuum at 60 ° C. overnight to obtain Compound (I) nitrate as an amorphous yellow solid (650 mg, 0.69 mmol, 91.4%).

2.化合物(I)硝酸鹽無定形的鑑定 2. Amorphous identification of compound (I) nitrate

1)1H NMR(400MHz,CDCl3)δ 10.32(s,1H),8.42(d,J=1.5Hz,1H),8.09(d,J=9.2Hz,1H),7.97(s,1H),7.77(s,1H),7.50(d,J=7.3Hz,1H),7.36(s,1H),7.29(d,J=4.9Hz,1H),6.53(d,J=1.5Hz,1H),5.80-5.61(m,2H),5.13-5.02(m,1H),4.83(t,J=7.9Hz,1H),4.73(t,J=6.9Hz,1H),4.53(d,J=11.8Hz,1H),4.25(dd,J=11.7,3.6Hz,1H),3.97(s,3H),3.38(dd,J=13.7,6.9Hz,1H),2.77(d,J=7.6Hz,2H),2.60(s,3H),2.46(d,J=9.1Hz,1H),2.32(dd,J=17.5,8.8Hz,1H),2.00(dd,J=15.9,6.9Hz,2H),1.79(ddd,J=32.8,14.6,8.8Hz,3H),1.59(dd,J=8.8,5.2Hz,1H),1.54-1.39(m,13H),1.28(dd,J=20.6,10.6Hz,3H),0.90-0.76(m,2H)ppm。 1) 1 H NMR (400MHz, CDCl 3 ) δ 10.32 (s, 1H), 8.42 (d, J = 1.5Hz, 1H), 8.09 (d, J = 9.2Hz, 1H), 7.97 (s, 1H), 7.77 (s, 1H), 7.50 (d, J = 7.3Hz, 1H), 7.36 (s, 1H), 7.29 (d, J = 4.9Hz, 1H), 6.53 (d, J = 1.5Hz, 1H), 5.80-5.61 (m, 2H), 5.13-5.02 (m, 1H), 4.83 (t, J = 7.9Hz, 1H), 4.73 (t, J = 6.9Hz, 1H), 4.53 (d, J = 11.8Hz , 1H), 4.25 (dd, J = 11.7, 3.6Hz, 1H), 3.97 (s, 3H), 3.38 (dd, J = 13.7, 6.9Hz, 1H), 2.77 (d, J = 7.6Hz, 2H) , 2.60 (s, 3H), 2.46 (d, J = 9.1Hz, 1H), 2.32 (dd, J = 17.5, 8.8Hz, 1H), 2.00 (dd, J = 15.9, 6.9Hz, 2H), 1.79 ( ddd, J = 32.8, 14.6, 8.8 Hz, 3H), 1.59 (dd, J = 8.8, 5.2 Hz, 1H), 1.54-1.39 (m, 13H), 1.28 (dd, J = 20.6, 10.6 Hz, 3H) , 0.90-0.76 (m, 2H) ppm.

2)通過Empyrean X射線粉末衍射(XRPD)分析鑑定：使用Cu-K α輻射，實驗結果如圖24所示。 2) Identification by Empyrean X-ray powder diffraction (XRPD) analysis: Cu-K α radiation was used, and the experimental results are shown in FIG. 24.

實施例25 化合物(I)1,5-萘二磺酸鹽無定形的製備和鑑定Example 25 Preparation and identification of compound (I) 1,5-naphthalene disulfonate amorphous 1.化合物(I)1,5-萘二磺酸鹽無定形的製備 1. Amorphous preparation of compound (I) 1,5-naphthalene disulfonate

將化合物(I)(665mg,0.747mmol)分散於甲醇(14.0mL)中，然後緩慢滴入1,5-萘二磺酸(216.8mg,0.745mmol)的甲醇(2.0mL)溶液，室溫攪拌過夜，減壓蒸除溶劑，殘留物經60℃真空乾燥過夜，得到化合物(I)1,5-萘二磺酸鹽無定形為黃色固體(780mg,0.67mmol,89.7%)。 Compound (I) (665 mg, 0.747 mmol) was dispersed in methanol (14.0 mL), and then a solution of 1,5-naphthalenedisulfonic acid (216.8 mg, 0.745 mmol) in methanol (2.0 mL) was slowly added dropwise, and stirred at room temperature Overnight, the solvent was distilled off under reduced pressure, and the residue was dried under vacuum at 60 ° C. overnight to obtain compound (I) 1,5-naphthalenedisulfonate as an amorphous yellow solid (780 mg, 0.67 mmol, 89.7%).

2.化合物(I)1,5-萘二磺酸鹽無定形的鑑定 2. Amorphous identification of compound (I) 1,5-naphthalene disulfonate

1)1H NMR(400MHz,CDCl3)δ 10.59(s,1H),8.54(s,1H),8.47(s,1H),8.39(d,J=8.0Hz,1H),7.88(d,J=9.3Hz,1H),7.70(d,J=6.9Hz,1H),7.48(d,J=7.8Hz,1H),7.34(s,1H),7.17(s,1H),7.10(d,J=9.5Hz,1H),6.70(d,J=7.1Hz,1H),6.55(s,1H),5.76-5.61(m,1H),5.47(s,1H),5.17-5.03(m,1H),4.90(d,J=7.7Hz,1H),4.70(s,1H),4.44(d,J=11.6Hz,1H),4.12-3.93(m,3H),3.74(dd,J=14.0,6.9Hz,1H),3.26(dd,J=13.5,6.8Hz,1H),2.57(s,3H),2.44(d,J=8.7Hz,2H),2.15(s,7H),1.85-1.60(m,4H),1.59-1.23(m,16H),0.84(d,J=5.9Hz,2H)ppm。 1) 1 H NMR (400MHz, CDCl 3 ) δ 10.59 (s, 1H), 8.54 (s, 1H), 8.47 (s, 1H), 8.39 (d, J = 8.0Hz, 1H), 7.88 (d, J = 9.3Hz, 1H), 7.70 (d, J = 6.9Hz, 1H), 7.48 (d, J = 7.8Hz, 1H), 7.34 (s, 1H), 7.17 (s, 1H), 7.10 (d, J = 9.5Hz, 1H), 6.70 (d, J = 7.1Hz, 1H), 6.55 (s, 1H), 5.76-5.61 (m, 1H), 5.47 (s, 1H), 5.17-5.03 (m, 1H) , 4.90 (d, J = 7.7Hz, 1H), 4.70 (s, 1H), 4.44 (d, J = 11.6Hz, 1H), 4.12-3.93 (m, 3H), 3.74 (dd, J = 14.0,6.9 Hz, 1H), 3.26 (dd, J = 13.5, 6.8Hz, 1H), 2.57 (s, 3H), 2.44 (d, J = 8.7Hz, 2H), 2.15 (s, 7H), 1.85-1.60 (m , 4H), 1.59-1.23 (m, 16H), 0.84 (d, J = 5.9Hz, 2H) ppm.

2)通過Empyrean X射線粉末衍射(XRPD)分析鑑定：使用Cu-K α輻射，實驗結果如圖25所示。 2) Identification by Empyrean X-ray powder diffraction (XRPD) analysis: Cu-K α radiation was used, and the experimental results are shown in FIG. 25.

實施例26 化合物(I)1,2-乙二磺酸鹽無定形的製備和鑑定Example 26 Preparation and Identification of Compound (I) 1,2-ethanedisulfonate Amorphous 1.化合物(I)1,2-乙二磺酸鹽無定形的製備 1. Preparation of Compound (I) 1,2-ethanedisulfonate Amorphous

將化合物(I)(695mg,0.781mmol)分散於甲醇(14.0mL)中，然後緩慢加入1,2-乙二磺酸(153.1mg,0.781mmol)的甲醇(2.0mL)溶液，室溫攪拌過夜，減壓蒸除溶劑，殘留物經60℃真空乾燥過夜，得到化合物(I)1,2-乙二磺酸鹽無定形為黃色固體(810mg,0.76mmol,97.3%)。 Compound (I) (695 mg, 0.781 mmol) was dispersed in methanol (14.0 mL), and then a solution of 1,2-ethanedisulfonic acid (153.1 mg, 0.781 mmol) in methanol (2.0 mL) was slowly added and stirred at room temperature overnight The solvent was evaporated under reduced pressure, and the residue was dried under vacuum at 60 ° C. overnight to obtain Compound (I) 1,2-ethanedisulfonate as an amorphous yellow solid (810 mg, 0.76 mmol, 97.3%).

2.化合物(I)1,2-乙二磺酸鹽無定形的鑑定 2. Amorphous identification of compound (I) 1,2-ethanedisulfonate

1)1H NMR(400MHz,CDCl3)δ 10.33(s,1H),8.43(t,J=7.3Hz,1H),8.12-7.98(m,1H),7.69(d,J=7.4Hz,1H),7.60(d,J=7.3Hz,1H),7.25(s,1H),7.22(d,J=4.4Hz,1H),6.69(s,1H),6.61(s,1H),5.69(dd,J=18.6,7.8Hz,2H),5.33(dd,J=48.2,38.5Hz,1H),5.10-4.96(m,1H),4.84(ddd,J=25.3,15.9,7.1Hz,2H),4.55(d,J=11.4Hz,1H),4.25(t,J=19.1Hz,1H),3.98(d,J=10.2Hz,3H),3.49(s,1H),3.30(d,J=6.8Hz,3H),2.79(dd,J=27.7,8.3Hz,2H),2.63(d,J=5.7Hz,4H),2.37-2.17(m,2H),2.16-1.85(m,3H),1.85-1.64(m,3H),1.61-1.55(m,2H),1.50(s,3H),1.43(t,J=6.6Hz,8H),1.28(s,2H),0.83(dd,J=8.0,6.6Hz,2H)ppm。 1) 1 H NMR (400MHz, CDCl 3 ) δ 10.33 (s, 1H), 8.43 (t, J = 7.3Hz, 1H), 8.12-7.98 (m, 1H), 7.69 (d, J = 7.4Hz, 1H ), 7.60 (d, J = 7.3Hz, 1H), 7.25 (s, 1H), 7.22 (d, J = 4.4Hz, 1H), 6.69 (s, 1H), 6.61 (s, 1H), 5.69 (dd , J = 18.6, 7.8Hz, 2H), 5.33 (dd, J = 48.2, 38.5Hz, 1H), 5.10-4.96 (m, 1H), 4.84 (ddd, J = 25.3, 15.9, 7.1Hz, 2H), 4.55 (d, J = 11.4Hz, 1H), 4.25 (t, J = 19.1Hz, 1H), 3.98 (d, J = 10.2Hz, 3H), 3.49 (s, 1H), 3.30 (d, J = 6.8 Hz, 3H), 2.79 (dd, J = 27.7, 8.3 Hz, 2H), 2.63 (d, J = 5.7 Hz, 4H), 2.37-2.17 (m, 2H), 2.16-1.85 (m, 3H), 1.85 -1.64 (m, 3H), 1.61-1.55 (m, 2H), 1.50 (s, 3H), 1.43 (t, J = 6.6Hz, 8H), 1.28 (s, 2H), 0.83 (dd, J = 8.0 , 6.6Hz, 2H) ppm.

2)通過Empyrean X射線粉末衍射(XRPD)分析鑑定：使用Cu-K α輻射，實驗結果如圖26所示。 2) Identification by Empyrean X-ray powder diffraction (XRPD) analysis: Cu-K α radiation was used, and the experimental results are shown in FIG. 26.

實施例27 化合物(I)β-萘磺酸鹽無定形的製備和鑑定Example 27 Preparation and Identification of Compound (I) β-Naphthalene Sulfonate Amorphous 1.化合物(I)β-萘磺酸鹽無定形的製備 1. Preparation of Compound (I) β-naphthalenesulfonate amorphous

將化合物(I)(693mg,0.775mmol)懸浮於甲醇(14.0mL)中，然後緩慢滴加β-萘磺酸(179.6mg,0.78mmol)的甲醇(2.0mL)溶液，再加入二氯甲烷(6.0mL)，室溫攪拌過夜，減壓蒸除溶劑，殘留物經60℃真空乾燥過夜，得到化合物(I)β-萘磺酸鹽為黃色固體(790mg,0.73mmol,94.2%)。 Compound (I) (693 mg, 0.775 mmol) was suspended in methanol (14.0 mL), and then a solution of β -naphthalenesulfonic acid (179.6 mg, 0.78 mmol) in methanol (2.0 mL) was slowly added dropwise, and dichloromethane ( 6.0 mL), stirred overnight at room temperature, evaporated off the solvent under reduced pressure, and dried the residue under vacuum at 60 ° C. overnight to obtain compound (I) β-naphthalenesulfonate as a yellow solid (790 mg, 0.73 mmol, 94.2%).

2.化合物(I)β-萘磺酸鹽無定形的鑑定 2. Amorphous identification of compound (I) β-naphthalenesulfonate

1)1H NMR(400MHz,CDCl3)δ 10.43(s,1H),8.37(d,J=10.5Hz,2H),8.27(s,1H),8.09(d,J=9.2Hz,1H),7.92(d,J=8.4Hz,2H),7.82(d,J=7.8Hz,1H),7.76(t,J=7.0Hz,2H),7.47(dd,J=18.4,7.1Hz,3H),7.33(s,1H),7.11(d,J=9.4Hz,1H),6.46(s,1H),5.90(s,1H),5.63(dd,J=18.1,8.3Hz,1H),5.06(t,J=9.6Hz,1H),4.95(t,J=7.9Hz,1H),4.64(s,1H),4.39(d,J=11.7Hz,1H),4.18(d,J=9.1Hz,1H),3.86(s,3H),3.42-3.23(m,5H),2.90-2.61(m,2H),2.52(s,3H),2.45-2.22(m,2H),1.96(s,2H),1.79-1.64(m,3H),1.58(dd,J=9.2,5.7Hz,1H),1.48(s,3H),1.38-1.33(m,7H),1.28(s,2H),0.84-0.72(m,2H)ppm。 1) 1 H NMR (400MHz, CDCl 3 ) δ 10.43 (s, 1H), 8.37 (d, J = 10.5Hz, 2H), 8.27 (s, 1H), 8.09 (d, J = 9.2Hz, 1H), 7.92 (d, J = 8.4Hz, 2H), 7.82 (d, J = 7.8Hz, 1H), 7.76 (t, J = 7.0Hz, 2H), 7.47 (dd, J = 18.4, 7.1Hz, 3H), 7.33 (s, 1H), 7.11 (d, J = 9.4Hz, 1H), 6.46 (s, 1H), 5.90 (s, 1H), 5.63 (dd, J = 18.1,8.3Hz, 1H), 5.06 (t , J = 9.6Hz, 1H), 4.95 (t, J = 7.9Hz, 1H), 4.64 (s, 1H), 4.39 (d, J = 11.7Hz, 1H), 4.18 (d, J = 9.1Hz, 1H ), 3.86 (s, 3H), 3.42-3.23 (m, 5H), 2.90-2.61 (m, 2H), 2.52 (s, 3H), 2.45-2.22 (m, 2H), 1.96 (s, 2H), 1.79-1.64 (m, 3H), 1.58 (dd, J = 9.2, 5.7Hz, 1H), 1.48 (s, 3H), 1.38-1.33 (m, 7H), 1.28 (s, 2H), 0.84-0.72 ( m, 2H) ppm.

2)通過Empyrean X射線粉末衍射(XRPD)分析鑑定：使用Cu-K α輻射，實驗結果如圖27所示。 2) Identification by Empyrean X-ray powder diffraction (XRPD) analysis: Cu-K α radiation was used, and the experimental results are shown in FIG. 27.

實施例28 化合物(I)環拉酸鹽無定形的製備和鑑定Example 28 Preparation and identification of compound (I) 1.化合物(I)環拉酸鹽無定形的製備 1. Amorphous preparation of compound (I)

將化合物(I)(730mg,0.816mmol)分散於甲醇(22.0mL)中，然後緩慢加入環拉酸(149.3mg,0.816mmol)的甲醇(2.0mL)溶液，室溫攪拌過夜，減壓蒸除溶劑，殘留物經60℃真空乾燥過夜，得到化合物(I)環拉酸鹽無定形為黃色固體(820mg,0.78mmol,95.6%)。 Compound (I) (730 mg, 0.816 mmol) was dispersed in methanol (22.0 mL), and then a solution of cyclolatamic acid (149.3 mg, 0.816 mmol) in methanol (2.0 mL) was slowly added, stirred overnight at room temperature, and evaporated under reduced pressure. The solvent and the residue were dried under vacuum at 60 ° C. overnight to obtain compound (I) cyclamate as an amorphous yellow solid (820 mg, 0.78 mmol, 95.6%).

2.化合物(I)環拉酸鹽無定形的鑑定 2. Amorphous identification of compound (I)

1)1H NMR(400MHz,CDCl3)δ 10.22(s,1H),8.44(d,J=1.6Hz,1H),7.97(d,J=9.1Hz,1H),7.63(d,J=7.5Hz,1H),7.58(s,1H),7.51(s,1H),7.16(s,2H),6.62(d,J=1.6Hz,1H),5.72(dd,J=18.3,8.5Hz,1H),5.62(s,1H),5.06(t,J=9.5Hz,1H),4.91-4.65(m,2H),4.54(d,J=11.6Hz,1H),4.21(dd,J=11.3,3.3Hz,1H),3.93(s,3H),3.44(d,J=11.0Hz,1H),3.25(dt,J=20.7,6.9Hz,2H),2.78(p,J=14.2Hz,3H),2.65(s,3H),2.52(d,J=9.2Hz,1H),2.37-2.16(m,3H),1.94(ddd,J=26.6,14.0,9.0Hz,4H),1.76(t,J=11.6Hz,4H),1.65-1.54(m,3H),1.52(s,4H),1.48(d,J=6.5Hz,3H),1.42(d,J=6.9Hz,6H),1.30(d,J=16.3Hz,4H),1.23-1.13(m,1H),0.86-0.76(m,2H)ppm。 1) 1 H NMR (400MHz, CDCl 3 ) δ 10.22 (s, 1H), 8.44 (d, J = 1.6Hz, 1H), 7.97 (d, J = 9.1Hz, 1H), 7.63 (d, J = 7.5 Hz, 1H), 7.58 (s, 1H), 7.51 (s, 1H), 7.16 (s, 2H), 6.62 (d, J = 1.6Hz, 1H), 5.72 (dd, J = 18.3, 8.5Hz, 1H ), 5.62 (s, 1H), 5.06 (t, J = 9.5Hz, 1H), 4.91-4.65 (m, 2H), 4.54 (d, J = 11.6Hz, 1H), 4.21 (dd, J = 11.3, 3.3Hz, 1H), 3.93 (s, 3H), 3.44 (d, J = 11.0Hz, 1H), 3.25 (dt, J = 20.7, 6.9Hz, 2H), 2.78 (p, J = 14.2Hz, 3H) , 2.65 (s, 3H), 2.52 (d, J = 9.2Hz, 1H), 2.37-2.16 (m, 3H), 1.94 (ddd, J = 26.6, 14.0, 9.0Hz, 4H), 1.76 (t, J = 11.6Hz, 4H), 1.65-1.54 (m, 3H), 1.52 (s, 4H), 1.48 (d, J = 6.5Hz, 3H), 1.42 (d, J = 6.9Hz, 6H), 1.30 (d , J = 16.3Hz, 4H), 1.23-1.13 (m, 1H), 0.86-0.76 (m, 2H) ppm.

2)通過Empyrean X射線粉末衍射(XRPD)分析鑑定：使用Cu-K α輻射，實驗結果如圖28所示。 2) Identification by Empyrean X-ray powder diffraction (XRPD) analysis: Cu-K α radiation was used, and the experimental results are shown in FIG. 28.

實施例29 化合物(I)羥乙基磺酸鹽無定形的製備和鑑定Example 29 Preparation and Identification of Compound (I) Isethionate Amorphous 1.化合物(I)羥乙基磺酸鹽無定形的製備 1. Amorphous preparation of isethionate of compound (I)

將化合物(I)(651mg,0.732mmol)分散於甲醇(14.0mL)中，然後緩慢加入羥乙基磺酸(115.9mg,0.735mmol)的甲醇(2.0mL)溶液，再加入二氯甲烷(2.0mL)，室溫攪拌過夜，減壓蒸除溶劑，殘留物經60℃真空乾燥過夜，得到化合物(I)羥乙基磺酸鹽無定形為黃色固體(710mg,0.71mmol,97.0%)。 Compound (I) (651 mg, 0.732 mmol) was dispersed in methanol (14.0 mL), and then a solution of isethionate (115.9 mg, 0.735 mmol) in methanol (2.0 mL) was slowly added, followed by dichloromethane (2.0 mL), stirred at room temperature overnight, and evaporated off the solvent under reduced pressure. The residue was dried under vacuum at 60 ° C. overnight to obtain compound (I) isethionate as an amorphous yellow solid (710 mg, 0.71 mmol, 97.0%).

2.化合物(I)羥乙基磺酸鹽無定形的鑑定 2. Amorphous identification of compound (I) isethionate

1)1H NMR(400MHz,CDCl3)δ 10.37(s,1H),8.43(d,J=1.2Hz,1H),8.24-8.04(m,2H),7.82(s,1H),7.49(d,J=7.3Hz,1H),7.39(s,1H),7.31(d,J=9.5Hz,1H),6.54(d,J=1.2Hz,1H),5.90(s,1H),5.67(dd,J=17.9,8.4Hz,1H),5.06(t,J=9.6Hz,1H),4.87(t,J=8.0Hz,1H),4.71(t,J=6.9Hz,1H),4.49(d,J=11.6Hz,1H),4.30(d,J=8.5Hz,1H),3.99(d,J=10.1Hz,5H),3.43(dt,J=13.5,6.7Hz,1H),3.16-3.04(m,2H),2.82(dd,J=19.8,11.8Hz,2H),2.59(s,3H),2.45(s,1H),2.32(dd,J=17.4,8.7Hz,1H),2.00(dd,J=23.7,10.9Hz,2H),1.85-1.67(m,3H),1.61(dd,J=9.4,5.8Hz,1H),1.55-1.39(m,13H),1.29(d,J=15.1Hz,3H),0.81(s,2H)ppm。 1) 1 H NMR (400MHz, CDCl 3 ) δ 10.37 (s, 1H), 8.43 (d, J = 1.2Hz, 1H), 8.24-8.04 (m, 2H), 7.82 (s, 1H), 7.49 (d , J = 7.3Hz, 1H), 7.39 (s, 1H), 7.31 (d, J = 9.5Hz, 1H), 6.54 (d, J = 1.2Hz, 1H), 5.90 (s, 1H), 5.67 (dd , J = 17.9, 8.4 Hz, 1H), 5.06 (t, J = 9.6 Hz, 1H), 4.87 (t, J = 8.0 Hz, 1H), 4.71 (t, J = 6.9 Hz, 1H), 4.49 (d , J = 11.6Hz, 1H), 4.30 (d, J = 8.5Hz, 1H), 3.99 (d, J = 10.1Hz, 5H), 3.43 (dt, J = 13.5, 6.7Hz, 1H), 3.16-3.04 (m, 2H), 2.82 (dd, J = 19.8, 11.8Hz, 2H), 2.59 (s, 3H), 2.45 (s, 1H), 2.32 (dd, J = 17.4, 8.7Hz, 1H), 2.00 ( dd, J = 23.7, 10.9 Hz, 2H), 1.85-1.67 (m, 3H), 1.61 (dd, J = 9.4, 5.8 Hz, 1H), 1.55-1.39 (m, 13H), 1.29 (d, J = 15.1Hz, 3H), 0.81 (s, 2H) ppm.

2)通過Empyrean X射線粉末衍射(XRPD)分析鑑定：使用Cu-K α輻射，實驗結果如圖29所示。 2) Identification by Empyrean X-ray powder diffraction (XRPD) analysis: Cu-K α radiation was used, and the experimental results are shown in FIG. 29.

實施例30 化合物(I)馬來酸鹽無定形的製備和鑑定Example 30 Preparation and Identification of Compound (I) Maleate Amorphous 1.化合物(I)馬來酸鹽無定形的製備 1. Preparation of Compound (I) Maleate Amorphous

將化合物(I)(622mg,0.699mmol)溶於丙酮(12.0mL)，然後緩慢加入馬來酸(81.5mg,0.699mmol)的丙酮(3.0mL)溶液，室溫攪拌過夜，減壓蒸除溶劑，殘留物經60℃真空乾燥過夜，得到化合物(I)馬來酸鹽無定形為黃色固體(650mg,0.66mmol,94.4%)。 Compound (I) (622 mg, 0.699 mmol) was dissolved in acetone (12.0 mL), and then a solution of maleic acid (81.5 mg, 0.699 mmol) in acetone (3.0 mL) was slowly added, and the mixture was stirred overnight at room temperature, and the solvent was evaporated under reduced pressure. The residue was dried under vacuum at 60 ° C. overnight to give compound (I) maleate as an amorphous yellow solid (650 mg, 0.66 mmol, 94.4%).

2.化合物(I)馬來酸鹽無定形的鑑定 2. Amorphous identification of compound (I) maleate

1)1H NMR(400MHz,CDCl3)δ 10.23(s,1H),8.45(d,J=1.3Hz,1H),8.01(d,J=9.2Hz,1H),7.68-7.49(m,3H),7.19(t,J=4.6Hz,2H),6.61(d,J=1.3Hz,1H),6.33(s,2H),5.78-5.57(m,2H),5.11-4.95(m,1H),4.76(t,J=7.5Hz,2H),4.61(d,J=11.7Hz,1H),4.16(s,1H),3.96(s,3H),3.27(dt,J=13.7,6.9Hz, 1H),2.84-2.69(m,2H),2.65(s,3H),2.53(s,1H),2.32(dd,J=17.3,8.6Hz,1H),2.14-1.83(m,3H),1.82-1.68(m,2H),1.62-1.22(m,18H),0.92-0.77(m,2H)。 1) 1 H NMR (400MHz, CDCl 3 ) δ 10.23 (s, 1H), 8.45 (d, J = 1.3Hz, 1H), 8.01 (d, J = 9.2Hz, 1H), 7.68-7.49 (m, 3H ), 7.19 (t, J = 4.6 Hz, 2H), 6.61 (d, J = 1.3 Hz, 1H), 6.33 (s, 2H), 5.78-5.57 (m, 2H), 5.11-4.95 (m, 1H) , 4.76 (t, J = 7.5Hz, 2H), 4.61 (d, J = 11.7Hz, 1H), 4.16 (s, 1H), 3.96 (s, 3H), 3.27 (dt, J = 13.7, 6.9Hz, 1H), 2.84-2.69 (m, 2H), 2.65 (s, 3H), 2.53 (s, 1H), 2.32 (dd, J = 17.3, 8.6Hz, 1H), 2.14-1.83 (m, 3H), 1.82 -1.68 (m, 2H), 1.62-1.22 (m, 18H), 0.92-0.77 (m, 2H).

2)通過Empyrean X射線粉末衍射(XRPD)分析鑑定：使用Cu-K α輻射，實驗結果如圖30所示。 2) Identification by Empyrean X-ray powder diffraction (XRPD) analysis: Cu-K α radiation was used, and the experimental results are shown in FIG. 30.

實施例31 化合物(I)氫溴酸鹽無定形的製備和鑑定Example 31 Preparation and Identification of Compound (I) Hydrobromide Amorphous 1.化合物(I)氫溴酸鹽無定形的製備 1. Amorphous preparation of compound (I) hydrobromide

將化合物(I)(697mg,0.789mmol)溶於四氫呋喃(14.0mL)，然後緩慢滴入氫溴酸(146.3mg,0.868mmol)，室溫攪拌過夜，抽濾，濾餅用四氫呋喃(0.5mL×2)洗滌，抽至近乾，再經60℃真空乾燥過夜，得到化合物(I)氫溴酸鹽無定形為黃色固體(520mg,0.54mmol,68.4%)。 Compound (I) (697 mg, 0.789 mmol) was dissolved in tetrahydrofuran (14.0 mL), and then hydrobromic acid (146.3 mg, 0.868 mmol) was slowly added dropwise. The mixture was stirred overnight at room temperature, and filtered with suction. 2) Wash, pump to near dryness, and dry under vacuum at 60 ° C. overnight to obtain compound (I) hydrobromide as an amorphous yellow solid (520 mg, 0.54 mmol, 68.4%).

2.化合物(I)氫溴酸鹽無定形的鑑定 2. Amorphous identification of compound (I) hydrobromide

1)1H NMR(400MHz,CDCl3)δ 10.20(s,1H),8.42(d,J=1.4Hz,2H),8.04(d,J=8.9Hz,1H),7.54(s,1H),7.43(d,J=7.1Hz,1H),7.36(s,1H),7.28-7.22(m,1H),6.54(s,1H),5.93(s,1H),5.73(dd,J=18.5,9.0Hz,1H),5.18-4.94(m,1H),4.78(s,1H),4.44(s,1H),3.99(s,3H),3.62(s,1H),2.88(s,1H),2.79(d,J=6.8Hz,1H),2.65(s,3H),2.49(s,1H),2.30(dd,J=16.7,7.9Hz,1H),2.02-1.75(m,10H),1.60-1.47(m,10H),1.29(d,J=11.2Hz,4H),0.85(d,J=10.9Hz,2H)ppm。 1) 1 H NMR (400MHz, CDCl 3 ) δ 10.20 (s, 1H), 8.42 (d, J = 1.4Hz, 2H), 8.04 (d, J = 8.9Hz, 1H), 7.54 (s, 1H), 7.43 (d, J = 7.1Hz, 1H), 7.36 (s, 1H), 7.28-7.22 (m, 1H), 6.54 (s, 1H), 5.93 (s, 1H), 5.73 (dd, J = 18.5, 9.0Hz, 1H), 5.18-4.94 (m, 1H), 4.78 (s, 1H), 4.44 (s, 1H), 3.99 (s, 3H), 3.62 (s, 1H), 2.88 (s, 1H), 2.79 (d, J = 6.8Hz, 1H), 2.65 (s, 3H), 2.49 (s, 1H), 2.30 (dd, J = 16.7, 7.9Hz, 1H), 2.02-1.75 (m, 10H), 1.60 -1.47 (m, 10H), 1.29 (d, J = 11.2Hz, 4H), 0.85 (d, J = 10.9Hz, 2H) ppm.

2)通過Empyrean X射線粉末衍射(XRPD)分析鑑定：使用Cu-K α輻射，實驗結果如圖31所示。 2) Identification by Empyrean X-ray powder diffraction (XRPD) analysis: Cu-K α radiation was used, and the experimental results are shown in FIG. 31.

實施例32 化合物(I)鹽酸鹽無定形的製備和鑑定Example 32 Preparation and Identification of Amorphous Hydrochloride of Compound (I) 1.化合物(I)鹽酸鹽無定形的製備 1. Preparation of Compound (I) Hydrochloride Amorphous

將化合物(I)(685mg,0.766mmol)分散於甲醇(14.0mL)中，然後緩慢加入氯化氫的乙酸乙酯(1.91mmol,0.1mL)溶液，室溫攪拌4小時，再加入二氯甲烷(1.0mL)，減壓蒸除溶劑，殘留物經室溫真空乾燥過夜，得到化合物(I)鹽酸鹽無定形為黃色固體(655mg,0.719mmol,93.9%)。 Compound (I) (685 mg, 0.766 mmol) was dispersed in methanol (14.0 mL), and then a solution of hydrogen chloride in ethyl acetate (1.91 mmol, 0.1 mL) was slowly added, stirred at room temperature for 4 hours, and then dichloromethane (1.0 mL), the solvent was distilled off under reduced pressure, and the residue was dried under vacuum at room temperature overnight to obtain Compound (I) hydrochloride as an amorphous yellow solid (655 mg, 0.719 mmol, 93.9%).

2.化合物(I)鹽酸鹽無定形的鑑定 2. Amorphous identification of compound (I) hydrochloride

1)1H NMR(400MHz,CDCl3)δ 10.17(s,1H),8.44(s,1H),7.93(d,J=9.2Hz,1H),7.71(s,1H),7.55(d,J=7.0Hz,1H),7.18-7.06(m,3H),6.63(s,1H), 5.74(dd,J=18.0,8.5Hz,1H),5.62(s,1H),5.04(t,J=9.4Hz,1H),4.80(t,J=7.4Hz,1H),4.69(t,J=7.8Hz,1H),4.54(d,J=11.5Hz,1H),4.23(s,1H),3.95(s,3H),3.28(s,1H),2.77(d,J=5.2Hz,2H),2.69(s,3H),2.54(s,1H),2.47(dd,J=14.7,7.3Hz,1H),2.31(dd,J=17.5,8.7Hz,1H),2.16(s,1H),2.05(dd,J=23.1,12.2Hz,1H),1.99-1.88(m,2H),1.79(d,J=10.8Hz,2H),1.53(d,J=7.9Hz,6H),1.43(d,J=6.8Hz,6H),1.35-1.26(m,2H),1.08(t,J=7.3Hz,1H),0.88-0.79(m,2H)ppm。 1) 1 H NMR (400MHz, CDCl 3 ) δ 10.17 (s, 1H), 8.44 (s, 1H), 7.93 (d, J = 9.2Hz, 1H), 7.71 (s, 1H), 7.55 (d, J = 7.0Hz, 1H), 7.18-7.06 (m, 3H), 6.63 (s, 1H), 5.74 (dd, J = 18.0, 8.5Hz, 1H), 5.62 (s, 1H), 5.04 (t, J = 9.4Hz, 1H), 4.80 (t, J = 7.4Hz, 1H), 4.69 (t, J = 7.8Hz, 1H), 4.54 (d, J = 11.5Hz, 1H), 4.23 (s, 1H), 3.95 (s, 3H), 3.28 (s, 1H), 2.77 (d, J = 5.2Hz, 2H), 2.69 (s, 3H), 2.54 (s, 1H), 2.47 (dd, J = 14.7,7.3Hz, 1H), 2.31 (dd, J = 17.5, 8.7Hz, 1H), 2.16 (s, 1H), 2.05 (dd, J = 23.1, 12.2Hz, 1H), 1.99-1.88 (m, 2H), 1.79 (d , J = 10.8Hz, 2H), 1.53 (d, J = 7.9Hz, 6H), 1.43 (d, J = 6.8Hz, 6H), 1.35-1.26 (m, 2H), 1.08 (t, J = 7.3Hz , 1H), 0.88-0.79 (m, 2H) ppm.

2)通過Empyrean X射線粉末衍射(XRPD)分析鑑定：使用Cu-K α輻射，實驗結果如圖32所示。 2) Identification by Empyrean X-ray powder diffraction (XRPD) analysis: Cu-K α radiation was used, and the experimental results are shown in FIG. 32.

實施例33：本發明化合物(I)的鹽在雄性SD大鼠體內的PK測定實驗Example 33: PK determination experiment of a salt of the compound (I) of the present invention in male SD rats 1、實驗方法： 1. Experimental method:

取190-250g雄性SD大鼠，按照每個鹽型3隻動物分組，分別口服給予100mg/kg測試化合物，給藥後按時間點0.25、0.5、1、2、5、7和24h採血。根據樣品濃度建立合適範圍的標準曲線，使用AB SCIEX API4000型LC-MS/MS，在MRM模式下測定血漿樣品中測試化合物的濃度。根據藥物濃度-時間曲線，採用WinNonLin 6.3軟體非房室模型法計算藥動學參數。 190-250 g of male SD rats were divided into three animals of each salt type, and 100 mg / kg of the test compound was orally administered. Blood was collected at time points of 0.25, 0.5, 1, 2, 5, 7, and 24 hours after administration. Establish a standard curve of appropriate range according to the sample concentration, and use the AB SCIEX API4000 LC-MS / MS to determine the concentration of the test compound in the plasma sample in the MRM mode. According to the drug concentration-time curve, WinNonLin 6.3 software was used to calculate the pharmacokinetic parameters.

2、實驗結果：見表2 2. Experimental results: see Table 2

Figure TW201805289AD00007
Figure TW201805289AD00007

表2結果顯示：SD大鼠口服給藥後，本發明化合物(I)的鹽的暴露量較高，特別是化合物(I)鈉鹽無定形、化合物(I)L-精氨酸鹽無定形和化合物(I)硝酸鹽無定形，它們的暴露量分別為14110h*ng/ml、15000h*ng/ml和16100h*ng/ml，說明本發明化合物(I)的鹽在體內的吸收良好。 The results in Table 2 show that after oral administration in SD rats, the salt exposure of the compound (I) of the present invention is relatively high, especially that the compound (I) sodium salt is amorphous and the compound (I) L -arginine salt is amorphous And compound (I) nitrate are amorphous, and their exposures are 14110 h * ng / ml, 15000 h * ng / ml, and 16100 h * ng / ml, indicating that the salt of compound (I) of the present invention is well absorbed in the body.

雖然，上文中已經用一般性說明、具體實施方式及試驗，對本發明作了詳盡的描述，但在本發明基礎上，可以對之作一些修改或改進，這對本領域技術人員而言是顯而易見的。因此，在不偏離本發明精神的基礎上所做的這些修改或改進，均屬於本發明要求保護的範圍。 Although the present invention has been described in detail with the general description, specific embodiments, and tests, it is obvious to those skilled in the art that some modifications or improvements can be made based on the present invention. . Therefore, these modifications or improvements made without departing from the spirit of the present invention belong to the scope of protection of the present invention.

Claims (9)

一種式(I)所示化合物的藥學上可接受的鹼加成鹽：
Figure TW201805289AC00001
 A pharmaceutically acceptable base addition salt of a compound of formula (I):
Figure TW201805289AC00001
 如申請專利範圍第1項所述的鹼加成鹽，其中所述的鹽為選自鋰鹽、鈉鹽、鉀鹽、鈣鹽、鎂鹽、鋁鹽、鐵鹽、鋅鹽、銨鹽的至少一種；或所述的鹽為選自式(I)所示化合物與甲胺、二甲胺、三甲胺、乙胺、二乙胺、三乙胺、氨基丁三醇、二乙氨基乙醇、異丙胺、2-乙氨基乙醇、吡啶、甲基吡啶、乙醇胺、二乙醇胺、銨、二甲基乙醇胺、四甲基銨、四乙基銨、三乙醇胺、呱啶、呱嗪、嗎啉、咪唑、L-精氨酸、組氨酸、N-甲基葡糖胺、二甲基葡糖胺、乙基葡糖胺、二環己基胺、1,6-己二胺、乙二胺、葡糖胺、肌氨酸、絲氨醇、氨基丙二醇、1-氨基-2,3,4-丁三醇、L-賴氨酸、鳥氨酸形成的鹽的至少一種。 The alkali addition salt according to item 1 of the scope of patent application, wherein the salt is selected from the group consisting of lithium salt, sodium salt, potassium salt, calcium salt, magnesium salt, aluminum salt, iron salt, zinc salt, and ammonium salt. At least one; or the salt is selected from the group consisting of a compound represented by formula (I) and methylamine, dimethylamine, trimethylamine, ethylamine, diethylamine, triethylamine, tromethamine, diethylaminoethanol, Isopropylamine, 2-ethylaminoethanol, pyridine, methylpyridine, ethanolamine, diethanolamine, ammonium, dimethylethanolamine, tetramethylammonium, tetraethylammonium, triethanolamine, pyridine, verazine, morpholine, imidazole , L -arginine, histidine, N -methylglucosamine, dimethylglucosamine, ethylglucosamine, dicyclohexylamine, 1,6-hexanediamine, ethylenediamine, glucose At least one of glycosamine, sarcosine, serine, aminopropanediol, 1-amino-2,3,4-butanetriol, L -lysine, and ornithine. 一種式(I)所示化合物的藥學上可接受的酸加成鹽：
Figure TW201805289AC00002
 A pharmaceutically acceptable acid addition salt of a compound of formula (I):
Figure TW201805289AC00002
 如申請專利範圍第3項所述的酸加成鹽，其中，所述的鹽為無機酸鹽或有機酸鹽，其中，所述的無機酸鹽選自鹽酸鹽、硫酸鹽、硫酸氫鹽、硝酸鹽、氫溴酸鹽、氫碘酸鹽、碳酸鹽、碳酸氫鹽、亞硫酸鹽、亞硫酸氫鹽、焦硫酸鹽、磷酸一氫鹽、磷酸二氫鹽、高氯酸鹽、過硫酸鹽、半硫酸鹽、重硫酸鹽、硫氰酸鹽、磷酸鹽、焦磷酸鹽和偏磷酸鹽中的至少一種；所述的有機酸鹽選自甲酸鹽、乙酸鹽、丙酸鹽、丁酸鹽、苯甲酸鹽、丙二酸鹽、丁二酸鹽、丙酮酸鹽、甲磺酸鹽、乙磺酸鹽、丙磺酸鹽、檸檬酸鹽、4-硝基苯甲酸鹽、苯磺酸鹽、 對甲苯磺酸鹽、1,2-乙二磺酸鹽、β-萘磺酸鹽、蘋果酸鹽、丙炔酸鹽、2-丁炔酸鹽、2-羥基-乙烷磺酸鹽、乙烯基乙酸鹽、酒石酸鹽、富馬酸鹽、羥乙基磺酸鹽、馬來酸鹽、乳酸鹽、乳糖酸鹽、雙羥萘酸鹽、水楊酸鹽、半乳糖二酸鹽、葡庚糖酸鹽、扁桃酸鹽、1,2-乙烷基二磺酸鹽、2-萘磺酸鹽、草酸鹽、三氟乙酸鹽、三氟甲磺酸鹽、己二酸鹽、辛二酸鹽、癸二酸鹽、丁炔-1,4-二酸鹽、己炔-1,6-二酸鹽、羥基乙酸鹽、藻酸鹽、抗壞血酸鹽、天冬氨酸鹽、谷氨酸鹽、2-苯氧基苯甲酸鹽、2-(4-羥基苯甲醯基)苯甲酸鹽、乙醯乙酸鹽、2-羥基乙磺酸鹽、硼酸鹽、氯代苯甲酸鹽、樟腦酸鹽、衣康酸鹽、樟腦磺酸鹽、甲基苯甲酸鹽、二硝基苯甲酸鹽、氨基磺酸鹽、半乳糖醛酸鹽、環戊基丙酸鹽、十二烷基硫酸鹽、丙烯酸鹽、環戊烷丙酸鹽、甘油磷酸鹽、甲氧基苯甲酸鹽、二葡萄糖酸鹽、葡萄糖酸鹽、庚酸鹽、己酸鹽、三甲基乙酸鹽、葡糖醛酸鹽、月桂酸鹽、鄰苯二甲酸鹽、苯乙酸鹽、月桂基硫酸鹽、2-乙醯氧基苯甲酸鹽、煙酸鹽、肉桂酸鹽、油酸鹽、棕櫚酸鹽、果膠酸鹽、苯二甲酸鹽、戊二酸鹽、羥基馬來酸鹽、羥基苯甲酸鹽、苯乙酸鹽、3-羥基-2-萘甲酸鹽、3-苯基丙酸鹽、異丁酸鹽、新戊酸鹽、苦味酸鹽、硬脂酸鹽、2,2-二氯乙酸鹽、醯化氨基酸鹽、海藻酸鹽、4-乙醯氨基苯磺酸鹽、癸酸鹽、膽酸鹽、辛酸鹽、壬酸鹽、環拉酸鹽、酞酸鹽、鹽酸半胱氨酸鹽、山梨酸鹽、鹽酸甘氨酸鹽、1,5-萘二磺酸鹽、二甲苯磺酸鹽、二鹽酸胱氨酸鹽、十一酸鹽、聚乙烯磺酸鹽、磺基水楊酸鹽、苯基丁酸鹽、4-羥基丁酸鹽、聚乙烯硫酸鹽、萘-1-磺酸鹽、萘-2-磺酸鹽和戊酸鹽中的至少一種。 The acid addition salt according to item 3 of the scope of patent application, wherein the salt is an inorganic acid salt or an organic acid salt, wherein the inorganic acid salt is selected from the group consisting of hydrochloride, sulfate, and hydrogen sulfate , Nitrate, hydrobromide, hydroiodate, carbonate, bicarbonate, sulfite, bisulfite, pyrosulfate, monohydrogen phosphate, dihydrogen phosphate, perchlorate, perchlorate At least one of sulfate, hemisulfate, bisulfate, thiocyanate, phosphate, pyrophosphate and metaphosphate; the organic acid salt is selected from formate, acetate, propionate, Butyrate, benzoate, malonate, succinate, pyruvate, mesylate, ethanesulfonate, propionate, citrate, 4-nitrobenzoate , Besylate, P-Toluenesulfonate, 1,2-ethanedisulfonate, β-naphthalenesulfonate, malate, propionate, 2-butynate, 2-hydroxy-ethanesulfonate, ethylene Glycolate, tartrate, fumarate, isethionate, maleate, lactate, lactate, paraben, salicylate, galactate, glucoheptanate Sugar salt, mandelate, 1,2-ethanedisulfonate, 2-naphthalenesulfonate, oxalate, trifluoroacetate, triflate, adipate, suberate Acid salt, sebacate salt, butyne-1,4-dianate salt, hexyne-1,6-dianate salt, glycolate, alginate, ascorbate, aspartate, glutamic acid Salt, 2-phenoxybenzoate, 2- (4-hydroxybenzyl) benzoate, acetoacetate, 2-hydroxyethanesulfonate, borate, chlorobenzoate , Camphor salt, itaconic acid salt, camphor sulfonate, methylbenzoate, dinitrobenzoate, sulfamate, galacturonate, cyclopentylpropionate, twelve Alkyl sulfate, acrylate, cyclopentane propionate, glycerol phosphate, methoxybenzoate, Gluconate, gluconate, heptanoate, hexanoate, trimethylacetate, glucuronate, laurate, phthalate, phenylacetate, lauryl sulfate, 2- Acetyloxybenzoate, nicotinate, cinnamate, oleate, palmitate, pectate, phthalate, glutarate, hydroxymaleate, hydroxybenzoate Acid salt, phenylacetate, 3-hydroxy-2-naphthoate, 3-phenylpropionate, isobutyrate, pivalate, picrate, stearate, 2,2-bis Chloroacetate, tritiated amino acid salt, alginate, 4-acetamidoaminobenzene sulfonate, caprate, cholate, caprylate, nonanoate, citric acid, phthalate, cyste hydrochloride Glutamate, sorbate, glycine hydrochloride, 1,5-naphthalene disulfonate, xylene sulfonate, cystine dihydrochloride, undecanoate, polyethylene sulfonate, sulfosalicylate Acid salt, phenylbutyrate, 4-hydroxybutyrate, polyethylene sulfate, naphthalene-1-sulfonate, naphthalene-2-sulfonate, and valerate. 一種藥物組合物，其包含如申請專利範圍第1項或第2項所述的鹼加成鹽或如申請專利範圍第3項或第4項所述的酸加成鹽，任選地，所述藥物組合物進一步包括藥學上可接受的輔料。 A pharmaceutical composition comprising a base addition salt as described in claim 1 or 2, or an acid addition salt as described in claim 3 or 4, optionally, The pharmaceutical composition further includes a pharmaceutically acceptable excipient. 如申請專利範圍第5項所述的藥物組合物，其進一步包含其他的抗HCV的藥物；其中所述抗HCV的藥物為干擾素、利巴韋林、白介素2、白介素6、白介素12、促進產生1型輔助性T細胞應答的化合物、干擾RNA、反義RNA、咪喹莫德、肌苷5’-單磷酸脫氫酶抑制劑、金剛烷胺、金剛乙胺、利托那韋、巴維昔單抗、CivacirTM、波普瑞韋、替拉瑞韋、索非布韋、雷迪帕韋、達卡他韋、丹諾普韋、西魯瑞韋、那拉匹韋、deleobuvir、dasabuvir、beclabuvir、elbasvir、ombitasvir、neceprevir、tegobuvir、grazoprevir、sovaprevir、samatasvir、veruprevir、 埃羅替尼、simeprevir、asunaprevir、vaniprevir、faldaprevir、VX-135、CIGB-230、furaprevir、pibrentasvir、glecaprevir、uprifosbuvir、radalbuvir、JHJ-56914845、vedroprevir、BZF-961、GS-9256、ANA975、EDP239、ravidasvir hydrochloride、velpatasvir、MK-8325、GSK-2336805、PPI-461、ACH-1095、VX-985、IDX-375、VX-500、VX-813、PHX-1766、PHX-2054、IDX-136、IDX-316、modithromycin、VBY-376、TMC-649128、mericitabine、INX-189、IDX-184、IDX102、R1479、UNX-08189、PSI-6130、PSI-938、PSI-879、HCV-796、nesbuvir、VCH-916、lomibuvir、setrobuvir、MK-3281、ABT-072、filibuvir、A-837093、JKT-109、Gl-59728、GL-60667、AZD-2795、TMC-647055或其組合；其中所述干擾素為干擾素α-2b、聚乙二醇化的干擾素α、干擾素α-2a、聚乙二醇化的干擾素α-2a、複合α-干擾素、干擾素γ或其組合。 The pharmaceutical composition according to item 5 of the scope of patent application, further comprising other anti-HCV drugs; wherein the anti-HCV drugs are interferon, ribavirin, interleukin 2, interleukin 6, interleukin 12, promotion Compounds that produce type 1 helper T cell response, interfering RNA, antisense RNA, imiquimod, inosine 5'-monophosphate dehydrogenase inhibitor, amantadine, rimantadine, ritonavir, barbados Vexiximab, Civacir TM , Popprevir, Tilariver, Sofosbuvir, Redipavir, Dacatavir, Danoprevir, Cyrusvir, Nalapivir, deleobuvir, dasabuvir, beclabuvir, elbasvir, ombitasvir, neceprevir, tegobuvir, grazoprevir, sovaprevir, samatasvir, veruprevir, erlotinib, simeprevir, asunaprevir, vaniprevir, faldaprevir, VB-135, CIGB-230, furapreviros, pibrentvirup, vibrreviras , JHJ-56914845, vedroprevir, BZF-961, GS-9256, ANA975, EDP239, ravidasvir hydrochloride, velpatasvir, MK-8325, GSK-2336805, PPI-461, ACH-1095, VX-985, IDX-375, VX- 500, VX-813, PHX-1766, PHX-2054, IDX-136, IDX-316, modithromycin, VBY-376, TMC-649128, mericitabine, INX-189, IDX-184, IDX102, R1479, UNX-08189, PSI-6130, PSI-938, PSI-879, HCV-796, nesbuvir, VCH-916, lomibuvir, setrobuvir, MK-3281, ABT-072, filibuvir, A-837093, JKT-109, Gl-59728, GL- 60667, AZD-2795, TMC-647055, or a combination thereof; wherein the interferon is interferon alpha-2b, pegylated interferon alpha, interferon alpha-2a, pegylated interferon alpha-2a , Complex alpha-interferon, interferon gamma, or a combination thereof. 如申請專利範圍5項所述的藥物組合物，其更進一步包含至少一種HCV抑制劑，其中所述其他的HCV抑制劑用於抑制HCV複製過程和/或抑制HCV病毒蛋白功能；其中所述HCV複製過程選自HCV進入、脫殼、翻譯、複製、組裝和釋放的過程的至少之一；所述的HCV病毒蛋白選自金屬蛋白酶、NS2、NS3、NS4A、NS4B、NS5A、NS5B、以及HCV病毒複製所需要的內部核糖體進入點和肌苷單磷酸脫氫酶的至少之一。 The pharmaceutical composition according to claim 5 of the application, further comprising at least one HCV inhibitor, wherein the other HCV inhibitor is used to inhibit HCV replication process and / or inhibit HCV viral protein function; wherein the HCV The replication process is selected from at least one of the processes of HCV entry, unshelling, translation, replication, assembly and release; the HCV viral protein is selected from metalloproteinases, NS2, NS3, NS4A, NS4B, NS5A, NS5B, and HCV virus At least one of the internal ribosome entry point and inosine monophosphate dehydrogenase required for replication. 一種如申請專利範圍第1項或第2項所述鹼加成鹽或如申請專利範圍第3項或第4項所述的酸加成鹽或如申請專利範圍第5項至第7項中任一項所述的藥物組合物在製備藥物中的用途，所述藥物用於抑制HCV複製和/或抑制HCV病毒蛋白功能，其中所述HCV複製過程選自HCV進入、脫殼、翻譯、複製、組裝和釋放的過程的至少之一；所述的HCV病毒蛋白選自金屬蛋白酶、NS2、NS3、NS4A、NS4B、NS5A、NS5B、以及HCV病毒複製所需要的內部核糖體進入點和肌苷單磷酸脫氫酶。 An alkali addition salt as described in item 1 or 2 of the scope of patent application or an acid addition salt as described in item 3 or 4 of the scope of patent application or as in items 5 to 7 of the scope of patent application Use of the pharmaceutical composition of any one in the preparation of a medicament for inhibiting HCV replication and / or inhibiting HCV viral protein function, wherein the HCV replication process is selected from the group consisting of HCV entry, unshelling, translation, and replication At least one of the processes of assembly, assembly and release; the HCV viral protein is selected from the group consisting of metalloproteinases, NS2, NS3, NS4A, NS4B, NS5A, NS5B, and internal ribosome entry points and inosine mononucleotides required for HCV virus replication Phosphate dehydrogenase. 一種如申請專利範圍第1項或第2項所述的鹼加成鹽或如申請專利範圍第3項或第4項所述的酸加成鹽或如申請專利範圍第5項至第7項中任一項所述的藥物組合物在製備藥物中的用途，所述藥物用於預防、處理、治療或減輕患者的HCV感染或丙型肝炎疾病。 An alkali addition salt as described in item 1 or 2 of the scope of patent application or an acid addition salt as described in item 3 or 4 of the scope of patent application or as items 5 to 7 of the scope of patent application Use of the pharmaceutical composition according to any one of the claims for preparing a medicament for preventing, treating, treating or reducing HCV infection or hepatitis C disease in a patient.
TW106126760A 2016-08-11 2017-08-08 Salts as HCV inhibitors TW201805289A (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN201610655907 2016-08-11
??201610655907.0 2016-08-11

Publications (1)

Publication Number Publication Date
TW201805289A true TW201805289A (en) 2018-02-16

Family

ID=61162862

Family Applications (1)

Application Number Title Priority Date Filing Date
TW106126760A TW201805289A (en) 2016-08-11 2017-08-08 Salts as HCV inhibitors

Country Status (4)

Country Link
CN (1) CN107722014B (en)
HK (1) HK1245775A1 (en)
TW (1) TW201805289A (en)
WO (1) WO2018028634A1 (en)

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN110117287B (en) * 2018-02-07 2020-09-11 广东东阳光药业有限公司 Salts as hepatitis c virus inhibitors

Family Cites Families (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101580535B (en) * 2008-05-16 2012-10-03 太景生物科技股份有限公司 Hcv protease inhibitors
EP2393493A4 (en) * 2009-01-30 2013-07-17 Glaxosmithkline Llc Compounds
US20120095211A1 (en) * 2010-09-22 2012-04-19 Intermune, Inc. Substituted proline inhibitors of hepatitis c virus replication
WO2016127859A1 (en) * 2015-02-13 2016-08-18 Sunshine Lake Pharma Co., Ltd. Compounds as hepatitis c inhibitors and uses thereof in medicine

Also Published As

Publication number Publication date
HK1245775A1 (en) 2018-08-31
CN107722014B (en) 2020-07-07
CN107722014A (en) 2018-02-23
WO2018028634A1 (en) 2018-02-15

Similar Documents

Publication Publication Date Title
EP3492464B1 (en) Intermediates for preparing inhibitors of hepatitis c virus
CN108299532B (en) Antiviral nucleoside analogue prodrug and composition and application thereof
EP2861604B1 (en) Macrocyclic inhibitors of flaviviridae viruses
CN106432254B (en) The antiviral compound inhibitor of HCV NS5A
TWI610916B (en) Bridged ring compounds as hepatitis c virus (hcv) inhibitors and pharmaceuticals applications thereof
CN106065009A (en) As the compound of hepatitis c inhibitor and the application in medicine thereof
WO2010118009A1 (en) Hcv inhibitor and therapeutic agent combinations
CN107011350A (en) Antiviral compound
TWI585082B (en) Spiro ring compound as hepatitis c virus (hcv) inhibitor and uses thereof
CN103880823B (en) Application as the spiro-compound of hepatitis c inhibitor and its in medicine
TWI675029B (en) Bridged ring compounds as hepatitis c virus inhibitors and preparation thereof
TWI703141B (en) Compounds as hepatitis c virus inhibitors and pharmaceutical uses thereof
CN104744444A (en) 9, 9, 10, 10-tetrafluoro-9, 10-dihydrophenanthrene hepatitis c virus inhibitor and application thereof
CN103848819A (en) Spiro compound serving as hepatitis C inhibitor, drug composition and applications of spiro compound and drug composition in drugs
CN103848820A (en) Spiro compound serving as hepatitis C inhibitor and applications thereof in drugs
TWI600653B (en) Fused ring compounds as hepatitis c virus inhibitors and uses thereof
CN104003980A (en) Bridged-ring compound used as hepatitis C inhibitor, pharmaceutical composition of bridged-ring compound and purposes of bridged-ring compound and pharmaceutical composition
CN107722014B (en) Salts as hepatitis c virus inhibitors
CN107722109B (en) Crystalline forms as hepatitis c virus inhibitors
CN110117287B (en) Salts as hepatitis c virus inhibitors