TW201910330A - Sulfonamide derivatives, preparation method thereof and use thereof in medicine - Google Patents

Sulfonamide derivatives, preparation method thereof and use thereof in medicine Download PDF

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TW201910330A
TW201910330A TW107127540A TW107127540A TW201910330A TW 201910330 A TW201910330 A TW 201910330A TW 107127540 A TW107127540 A TW 107127540A TW 107127540 A TW107127540 A TW 107127540A TW 201910330 A TW201910330 A TW 201910330A
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aryl
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cancer
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呂賀軍
趙雯雯
王成喜
陳磊
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大陸商浙江海正藥業股份有限公司
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Abstract

The present invention relates to a sulfonamide derivative, a process for its preparation and a pharmaceutical use. In particular, the present invention relates to sulfonamide derivatives of the formula (I), processes for their preparation and pharmaceutically acceptable salts thereof, and their use as therapeutic agents, in particular as bromodomain protein inhibitors, wherein the definition of each substituent in the formula (I) is the same as defined in the specification.

Description

磺醯胺類衍生物、其製備方法及其在醫藥上的用途Sulfonamide derivatives, preparation method and application thereof in medicine

本發明屬於醫藥領域，具體涉及一種新的磺醯胺類衍生物、其製備方法及含有該衍生物的藥物組合物，以及它們作為治療劑、特別是作為溴結構域蛋白抑制劑的用途。The invention belongs to the field of medicine, and particularly relates to a novel sulfonamide derivative, a preparation method thereof and a pharmaceutical composition containing the derivative, and uses thereof as a therapeutic agent, particularly as a bromodomain protein inhibitor.

近年來，腫瘤成為全球範圍內導致人類死亡的主要原因之一。腫瘤普遍具有總體治癒率低且復發率高等特點，因此預防、治療以及抑制腫瘤復發具有重要的科研價值，實現腫瘤的預防和治癒具有相當的緊迫性和挑戰性。表觀遺傳調控的異常是導致腫瘤發生的重要因素之一。In recent years, tumors have become one of the leading causes of human death worldwide. Tumors generally have the characteristics of low overall cure rate and high recurrence rate. Therefore, prevention, treatment, and suppression of tumor recurrence have important scientific research value. The prevention and cure of tumors is quite urgent and challenging. Abnormal epigenetic regulation is one of the important factors leading to tumorigenesis.

溴結構域(bromodomain)是一種能識別N-乙醯化賴胺酸殘基的蛋白結構域。含溴結構域的蛋白質的BET家族包括四個成員(BRD2、BRD3、BRD4 和BRDt)。BET家族的每個成員都使用兩個溴結構域來識別，主要(但並非排外地)在組蛋白蛋白質的胺基末端尾巴(amino-terminal tail)發現N-乙醯化的賴胺酸殘基。藉由將轉錄因子募集至染色質內的具體基因組位置來調節基因表達。例如，組蛋白連接的BRD4將轉錄因子P-TEFb募集至啟動子，導致表達涉及細胞週期進程的基因子集(Yang et al., Mol. Cell. Biol. 28: 967-976 (2008))。BRD2和BRD3還起生長促進基因的轉錄調節劑的作用。近來的研究已經證實以BET溴結構域為靶點來治療多種癌症((Zuber et al., Nature 478: 524-528(2011)；Mertz et al.,Proc. Natl. Acad. Sci. 108: 16669-16674 (2011)；Delmore et al., Cell 146: 1-14, (2011)；Dawson et al., Nature 478: 529-533 (2011))、動脈粥樣硬化、炎症(Huang et al., Mol. Cell.Biol. 29: 1375-1387 (2009))和HIV感染。The bromodomain is a protein domain that recognizes N-acetylated lysine residues. The BET family of bromodomain-containing proteins includes four members (BRD2, BRD3, BRD4, and BRDt). Each member of the BET family uses two bromodomains for identification, and mainly (but not exclusively) N-acetylated lysine residues are found at the amino-terminal tail of histone proteins . Gene expression is regulated by recruiting transcription factors to specific genomic locations within the chromatin. For example, histone-linked BRD4 recruits the transcription factor P-TEFb to a promoter, resulting in expression of a subset of genes involved in cell cycle progression (Yang et al., Mol. Cell. Biol. 28: 967-976 (2008)). BRD2 and BRD3 also function as transcriptional regulators of growth-promoting genes. Recent studies have confirmed the use of the BET bromodomain as a target to treat a variety of cancers ((Zuber et al., Nature 478: 524-528 (2011); Mertz et al., Proc. Natl. Acad. Sci. 108: 16669 -16674 (2011); Delmore et al., Cell 146: 1-14, (2011); Dawson et al., Nature 478: 529-533 (2011)), atherosclerosis, inflammation (Huang et al., Mol. Cell. Biol. 29: 1375-1387 (2009)) and HIV infection.

最新研究發現，BRD4蛋白介導的表觀遺傳異常與癌基因的過表達密切相關，並與癌細胞的生長增殖關係密切。BRD4是含溴結構域和額外終端域家族蛋白(Bromo and extra C-terminal domain, BET)蛋白家族的一員，由於在抗腫瘤方面的潛在價值，引起了各大製藥公司和科研機構的極大關注。近期還發現BRD4在病毒基因的轉錄調控中也扮演了重要角色，並且與病毒瘤的發病機制存在一定聯繫。這些研究結果說明BRD4與多種腫瘤存在密切聯繫，尤其在一些至今難以治癒或者尚無有效治療手段的腫瘤中具有重要作用，其與腫瘤關係的研究為腫瘤治療提供了新的策略。藉由作用於BRD4蛋白溴結構域的小分子化合物，干擾溴結構域與乙醯化賴胺酸的特異性結合，影響腫瘤細胞內的轉錄調節和其它細胞過程，可以實現對腫瘤的靶向治療。因此，BRD4蛋白是一個非常有前景的表觀遺傳新靶點，而作用於BRD4蛋白溴結構域的小分子抑制劑在腫瘤研究中也有著廣闊的應用前景，而且有可能從中開發出新型抗腫瘤藥物。Recent studies have found that epigenetic abnormalities mediated by BRD4 protein are closely related to overexpression of oncogenes and are closely related to the growth and proliferation of cancer cells. BRD4 is a member of the Bromo and extra C-terminal domain (BET) protein family. Due to its potential value in antitumor, it has attracted great attention from major pharmaceutical companies and research institutions. Recently, it has been found that BRD4 also plays an important role in the transcriptional regulation of viral genes, and it is related to the pathogenesis of viral tumors. These research results indicate that BRD4 is closely related to many tumors, especially in some tumors that have been difficult to cure or have no effective treatment methods. The study of their relationship with tumors provides new strategies for tumor treatment. Small molecules acting on the bromine domain of the BRD4 protein interfere with the specific binding of the bromine domain to acetylated lysine, affect the transcriptional regulation and other cellular processes in tumor cells, and can achieve targeted treatment of tumors . Therefore, BRD4 protein is a promising new epigenetic target, and small molecule inhibitors acting on the bromine domain of BRD4 protein also have broad application prospects in tumor research, and it is possible to develop new anti-tumor from them. drug.

目前已經公開了一系列的溴結構域蛋白抑制劑專利，其中包括WO2011054846、WO2008092231、WO2012075383和WO2016139292等，其中WO2016139292公開了實施例1化合物。目前處於臨床III期的藥物為Apabetalone，處於臨床II期的藥物包括GSK-525762A、INCB-54329和BMS-986158等，處於臨床I期的藥物包括mivebresib等。但這些對於抗腫瘤的研究是遠遠不夠的，先前技術中公開的化合物以及試驗藥物在有效性、安全性或適用性等方面仍不能令人滿意，仍有必要研究和開發新的溴結構域蛋白抑制劑，以滿足人們日益增長的醫療和健康需要。A series of patents for bromodomain protein inhibitors have been published, including WO2011054846, WO2008092231, WO2012075383, and WO2016139292, among which WO2016139292 discloses the compound of Example 1. Apabetalone is currently in Phase III, and GSK-525762A, INCB-54329, and BMS-986158 are included in Phase II. Mivebresib is included in Phase I. However, these studies on antitumor are far from enough. The compounds disclosed in the prior art and the test drugs are still not satisfactory in terms of effectiveness, safety or applicability. It is still necessary to research and develop new bromine domains. Protein inhibitors to meet people's growing medical and health needs.

本發明人藉由大量實驗研究意外地發現，下式(I)的化合物可以有效用作溴結構域蛋白抑制劑，用於治療或預防與溴結構域蛋白相關的疾病。The inventors have unexpectedly discovered through a large number of experimental studies that the compound of the following formula (I) can be effectively used as a bromodomain protein inhibitor for treating or preventing a disease related to the bromodomain protein.

因此，在第一個方面，本發明提供一種式(I)所示的磺醯胺類化合物：， 包括其立體異構體、互變異構體或其可藥用的鹽， 其中： R1 選自芳基或雜芳基，優選為苯基，其中所述的芳基或雜芳基任選進一步被一個或多個選自羥基、鹵素、硝基、氰基、烷基、環烷基、雜環基、芳基、雜芳基、-NR6 R7 、-C(O)NR6 R7 、-OR8 、-C(O)R8 、-C(O)OR8 或-NR6 C(O)R7 的取代基所取代； R2 和R3 各自獨立地選自氫原子、烷基、氰基、鹵素、環烷基、雜環基、芳基、雜芳基、-NR6 R7 、-C(O)NR6 R7 、-OR8 、-C(O)R8 、-C(O)OR8 或-NR6 C(O)R7 ，其中所述的烷基、環烷基、雜環基、芳基或雜芳基任選進一步被一個或多個選自羥基、鹵素、硝基、氰基、烷基、環烷基、雜環基、芳基、雜芳基、-NR6 R7 、-C(O)NR6 R7 、-OR8 、-C(O)R8 、-C(O)OR8 或-NR6 C(O)R7 的取代基所取代；條件是R2 和R3 至少一個選自-OR8 ； R4 選自氫原子或烷基；優選為甲基或乙基； R5 選自氫原子、烷氧基或鹵素；優選為氫原子； R6 、R7 和R8 各自獨立地選自氫原子、烷基、環烷基、雜環基、芳基或雜芳基，其中所述的烷基、環烷基、雜環基、芳基或雜芳基任選進一步被一個或多個選自羥基、鹵素、硝基、氰基、烷基、烷氧基、環烷基、雜環基、芳基、雜芳基、-NR9 R10 、-C(O)NR9 R10 、-C(O)R11 、-C(O)OR11 或-NR9 C(O)R10 的取代基所取代； 或者，R6 和R7 與相連接的N原子一起形成一個4～8元雜環基，其中4～8元雜環內含有一個或多個N、O、S(O)m 原子，並且4～8元雜環上任選進一步被一個或多個選自羥基、鹵素、硝基、氰基、烷基、烷氧基、環烷基、雜環基、芳基、雜芳基、=O、-NR9 R10 、-C(O)NR9 R10 、-C(O)R11 、-C(O)OR11 或-NR9 C(O)R10 的取代基所取代； R9 、R10 和R11 各自獨立地選自氫原子、烷基、環烷基、雜環基、芳基或雜芳基，其中所述的烷基、環烷基、雜環基、芳基或雜芳基任選進一步被一個或多個選自羥基、鹵素、硝基、氰基、烷基、烷氧基、環烷基、雜環基、芳基、雜芳基、羧基或羧酸酯基的取代基所取代；且 m為0、1或2。Therefore, in a first aspect, the present invention provides a sulfonamide compound represented by formula (I): , Including its stereoisomers, tautomers or pharmaceutically acceptable salts thereof, wherein: R 1 is selected from aryl or heteroaryl, preferably phenyl, wherein said aryl or heteroaryl is optionally Is further selected from one or more of hydroxy, halogen, nitro, cyano, alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -NR 6 R 7 , -C (O) NR 6 R 7 , -OR 8 , -C (O) R 8 , -C (O) OR 8 or -NR 6 C (O) R 7 are substituted by a substituent; R 2 and R 3 are each independently selected from a hydrogen atom, Alkyl, cyano, halogen, cycloalkyl, heterocyclyl, aryl, heteroaryl, -NR 6 R 7 , -C (O) NR 6 R 7 , -OR 8 , -C (O) R 8 , -C (O) OR 8 or -NR 6 C (O) R 7 , wherein said alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally further selected from one or more Hydroxyl, halogen, nitro, cyano, alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -NR 6 R 7 , -C (O) NR 6 R 7 , -OR 8 , -C (O) R 8 , -C (O) OR 8 or -NR 6 C (O) R 7 is substituted by a substituent; provided that at least one of R 2 and R 3 is selected from -OR 8 ; R 4 is selected from a hydrogen atom Or alkyl; preferably methyl or ethyl; R 5 is selected from hydrogen R 6 , R 7 and R 8 are each independently selected from a hydrogen atom, an alkyl group, a cycloalkyl group, a heterocyclic group, an aryl group or a heteroaryl group, wherein Alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally further selected from one or more of hydroxy, halogen, nitro, cyano, alkyl, alkoxy, cycloalkyl, hetero Cyclic, aryl, heteroaryl, -NR 9 R 10 , -C (O) NR 9 R 10 , -C (O) R 11 , -C (O) OR 11 or -NR 9 C (O) R Substituted by a substituent of 10 ; or, R 6 and R 7 together with the connected N atom form a 4- to 8-membered heterocyclic group, wherein the 4- to 8-membered heterocyclic ring contains one or more N, O, S ( O) m atom, and optionally a 4- to 8-membered heterocyclic ring further selected from one or more selected from the group consisting of hydroxyl, halogen, nitro, cyano, alkyl, alkoxy, cycloalkyl, heterocyclic, and aryl , Heteroaryl, = O, -NR 9 R 10 , -C (O) NR 9 R 10 , -C (O) R 11 , -C (O) OR 11 or -NR 9 C (O) R 10 substituents; R 9, R 10 and R 11 are each independently selected from hydrogen atom, alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein the alkyl, cycloalkyl, Group, heterocyclyl, aryl or heteroaryl is optionally further selected from one or more of hydroxy, halogen, nitro, cyano, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, Substituted with a heteroaryl, carboxyl, or carboxylate substituent; and m is 0, 1, or 2.

在本發明的一些優選方案中，提供了一種式(I)所述的化合物，其中R1 為苯基，所述的苯基可以進一步被一個或多個鹵素所取代，其中所述的鹵素優選為氟。In some preferred embodiments of the present invention, a compound of formula (I) is provided, wherein R 1 is a phenyl group, and the phenyl group may be further substituted with one or more halogens, wherein the halogens are preferably For fluorine.

在本發明的一些優選方案中，提供了一種式(I)所述的化合物， 其中： R2 選自-OR8 ，R3 為氫原子； 或者，R2 為氫原子，R3 選自-OR8 ；且 R8 選自烷基，更優選為甲基。In some preferred embodiments of the present invention, a compound according to formula (I) is provided, wherein: R 2 is selected from -OR 8 , R 3 is a hydrogen atom; or, R 2 is a hydrogen atom, and R 3 is selected from- OR 8 ; and R 8 is selected from alkyl, more preferably methyl.

本發明的典型化合物包括但不限於 ，包括其立體異構體、互變異構體或其可藥用的鹽。Typical compounds of the invention include, but are not limited to Including stereoisomers, tautomers, or pharmaceutically acceptable salts thereof.

進一步，本發明提供了一種式(I)化合物的製備方法，該方法包括：使式(Id)化合物與R4 取代的磺醯鹵（優選為R4 取代的磺醯氯）反應，得到式(Ie)化合物；然後使式(Ie)化合物在鹼性條件下水解，脫去保護基，得到式(I)化合物； 其中： PG為N的保護基，優選為取代的苯磺醯基，更優選為對甲苯磺醯基； R4 選自烷基；且 R1 ～R3 和R5 的定義如式(I)中所述。Further, the present invention provides a method for preparing a compound of formula (I), which method comprises: The compound of formula (Id) is reacted with R 4 substituted sulfonium halide (preferably R 4 substituted sulfonium chloride) to obtain a compound of formula (Ie); then the compound of formula (Ie) is hydrolyzed under alkaline conditions and removed. protecting group of formula (I) compound; wherein: PG is an N protecting group, preferably a substituted phenyl sulfonic acyl, more preferably p-toluenesulfonic acyl; R 4 is selected from alkyl; and R 1 ~ R 3 And R 5 are as defined in formula (I).

本發明還提供了一種式(Id)所示的化合物，包括其立體異構體、互變異構體或其可藥用的鹽，其中： PG為N的保護基，優選為取代的苯磺醯基，更優選為對甲苯磺醯基；且 R1 ～R5 的定義如式(I)中所述。The present invention also provides a compound represented by formula (Id), including a stereoisomer, a tautomer or a pharmaceutically acceptable salt thereof, Wherein: PG is a protecting group of N, preferably substituted benzenesulfenylfluorenyl, more preferably p-toluenesulfonyl; and R 1 to R 5 are as defined in formula (I).

式(Id)的典型化合物包括但不限於 ，包括其立體異構體、互變異構體或其可藥用的鹽。Typical compounds of formula (Id) include, but are not limited to Including stereoisomers, tautomers, or pharmaceutically acceptable salts thereof.

進一步，本發明提供了一種式(Id)化合物的製備方法，該方法包括：藉由還原式(Ia)化合物的硝基得到式(Ib)化合物；使式(Ib)化合物與式(Ic)化合物在鈀催化劑存在下反應，得到式(Id)化合物； 其中： Ra 選自硼酸基或硼酸酯基；所述的硼酸酯基優選為：； PG為N的保護基，優選為取代的苯磺醯基，更優選為對甲苯磺醯基； X選自鹵素，優選為氯或溴；且 R1 ～R5 的定義如式(I)中所述； 在上述製備方法中，鹼性條件由有機鹼或無機鹼提供，所述有機鹼優選自二異丙基乙胺、二異丙胺、吡啶、三乙胺、呱啶、N-甲基呱口井、4-二甲胺吡啶，更優選為二異丙胺和三乙胺；所述無機鹼優選自碳酸鈉、碳酸鉀、碳酸銫、氫氧化鈉、氫氧化鉀，更優選為氫氧化鈉；所述鈀催化劑為1,1’-雙(二-叔丁基膦基)二茂鐵二氯化鈀。Further, the present invention provides a method for preparing a compound of formula (Id), which method includes: A compound of formula (Ib) is obtained by reducing a nitro group of a compound of formula (Ia); a compound of formula (Ib) and a compound of formula (Ic) are reacted in the presence of a palladium catalyst to obtain a compound of formula (Id); wherein: R a is selected from Borate group or borate group; the borate group is preferably: ; PG is a protecting group of N, preferably substituted benzenesulfonyl, more preferably p-toluenesulfonyl; X is selected from halogen, preferably chlorine or bromine; and R 1 to R 5 are defined as formula (I) In the above preparation method, the basic condition is provided by an organic base or an inorganic base, and the organic base is preferably selected from diisopropylethylamine, diisopropylamine, pyridine, triethylamine, pyridine, N-formyl Base, 4-dimethylamine pyridine, more preferably diisopropylamine and triethylamine; the inorganic base is preferably from sodium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide, potassium hydroxide, and more preferably hydrogen Sodium oxide; the palladium catalyst is 1,1'-bis (di-tert-butylphosphino) ferrocene palladium dichloride.

更進一步，本發明提供一種藥物組合物，所述的藥物組合物含有有效劑量的式(I)化合物（包括其立體異構體、互變異構體或其可藥用的鹽），以及可藥用的載體、賦形劑或它們的組合。Still further, the present invention provides a pharmaceutical composition containing an effective dose of a compound of formula (I) (including stereoisomers, tautomers or pharmaceutically acceptable salts thereof), and a pharmaceutically acceptable Used carriers, excipients or combinations thereof.

本發明還提供了一種抑制溴結構域蛋白的方法，包括將所述的蛋白與式(I)所述的化合物（包括其立體異構體、互變異構體或其可藥用的鹽）或其藥物組合物相接觸，其中所述的溴結構域蛋白優選為BRD2、BRD3和BRD4，更優選為BRD4。The present invention also provides a method for inhibiting a bromodomain protein, comprising combining the protein with a compound of formula (I) (including a stereoisomer, tautomer or a pharmaceutically acceptable salt thereof) or The pharmaceutical composition is contacted, wherein the bromodomain protein is preferably BRD2, BRD3 and BRD4, and more preferably BRD4.

本發明進一步提供了一種式(I)所述的化合物（包括其立體異構體、互變異構體或其可藥用的鹽）或其藥物組合物在製備用作溴結構域蛋白抑制劑的藥物中的用途，其中所述的溴結構域蛋白優選為BRD2、BRD3和BRD4，更優選為BRD4。The present invention further provides a compound (including stereoisomers, tautomers or pharmaceutically acceptable salts thereof) of the formula (I) or a pharmaceutical composition thereof for preparing a bromodomain protein inhibitor. Use in medicine, wherein the bromodomain protein is preferably BRD2, BRD3, and BRD4, and more preferably BRD4.

本發明進一步提供了一種式(I)所述的化合物（包括其立體異構體、互變異構體或其可藥用的鹽）或其藥物組合物在製備用於治療或預防與溴結構域蛋白相關的疾病的藥物中的用途，其中所述的疾病優選為癌症或炎症；其中所述的炎症優選為類風濕性關節炎、克隆恩病、濕疹、巨細胞性動脈炎、肝炎、炎性腸病、骨關節炎、胰腺炎、肺炎、銀屑病、銀屑病性關節炎、系統性紅斑狼瘡、腎小球性腎炎、狼瘡性腎炎、膜性腎小球腎炎或心肌炎；所述的炎症更優選為類風濕性關節炎；其中所述的癌症優選為小細胞肺癌、非小細胞肺癌、乳腺癌、結直腸癌、***癌、黑色素瘤、胰腺癌、神經膠質瘤、腦瘤、宮頸癌、卵巢癌、胰腺癌、***癌、腎細胞癌、胃癌、膀胱癌、肝癌、睾丸核蛋白中線癌、多發性骨髓瘤、急性髓性白血病、急性淋巴細胞性白血病、慢性淋巴細胞性白血病、慢性髓細胞性白血病或慢性骨髓性白血病。The present invention further provides a compound (including stereoisomers, tautomers or pharmaceutically acceptable salts thereof) of formula (I) or a pharmaceutical composition thereof for the preparation or treatment of bromide domains. Use of a protein-related disease, wherein the disease is preferably cancer or inflammation; wherein the inflammation is preferably rheumatoid arthritis, Crohn's disease, eczema, giant cell arteritis, hepatitis, inflammation Bowel disease, osteoarthritis, pancreatitis, pneumonia, psoriasis, psoriatic arthritis, systemic lupus erythematosus, glomerulonephritis, lupus nephritis, membranous glomerulonephritis or myocarditis; said The inflammation is more preferably rheumatoid arthritis; wherein the cancer is preferably small cell lung cancer, non-small cell lung cancer, breast cancer, colorectal cancer, prostate cancer, melanoma, pancreatic cancer, glioma, brain tumor, Cervical cancer, ovarian cancer, pancreatic cancer, prostate cancer, renal cell carcinoma, gastric cancer, bladder cancer, liver cancer, testicular nucleoprotein midline cancer, multiple myeloma, acute myeloid leukemia, acute lymphocytic leukemia, Lymphocytic leukemia, chronic myelogenous leukemia, or chronic myelogenous leukemia.

本發明還提供了一種式(I)所述的化合物（包括其立體異構體、互變異構體或其可藥用的鹽）或其藥物組合物在製備用於治療或預防糖尿病性腎病、高血壓性腎病、HIV-相關的腎病、多囊性腎病、肥胖、血脂異常、高膽固醇血症、阿爾茨海默病、代謝綜合症、脂肪肝、II型糖尿病、胰島素抵抗、糖尿病性視網膜病或糖尿病性神經病的藥物中的用途。The present invention also provides a compound (including stereoisomers, tautomers or pharmaceutically acceptable salts thereof) or a pharmaceutical composition thereof for use in the treatment or prevention of diabetic nephropathy, Hypertensive nephropathy, HIV-related nephropathy, polycystic kidney disease, obesity, dyslipidemia, hypercholesterolemia, Alzheimer's disease, metabolic syndrome, fatty liver, type II diabetes, insulin resistance, diabetic retinopathy Or use in medicine for diabetic neuropathy.

除非有相反陳述，否則本發明在說明書和申請專利範圍中所使用的部分術語定義如下：Unless stated to the contrary, some terms used in the specification and patent application scope of the present invention are defined as follows:

“烷基”當作一基團或一基團的一部分時是指包括直鏈或者帶有支鏈的C1 -C20 脂肪烴基團。優選為C1 -C10 烷基，更優選為C1 -C6 烷基，特別優選為C1 -C4 烷基。烷基基團的實施例包括但不限於甲基、乙基、正丙基、異丙基、正丁基、異丁基、叔丁基、仲丁基、正戊基、1,1-二甲基丙基、1,2-二甲基丙基、2,2-二甲基丙基、1-乙基丙基、2-甲基丁基、3-甲基丁基、正己基、1-乙基-2-甲基丙基、1,1,2-三甲基丙基、1,1-二甲基丁基、1,2-二甲基丁基、2,2-二甲基丁基、1,3-二甲基丁基、2-乙基丁基、2-甲基戊基、3-甲基戊基、4-甲基戊基、2,3-二甲基丁基等。烷基可以是取代或未取代的。When "alkyl" as a group or part of a group is meant to include a straight-chain or branched with C 1 -C 20 aliphatic hydrocarbon group. C 1 -C 10 alkyl is preferred, C 1 -C 6 alkyl is more preferred, and C 1 -C 4 alkyl is particularly preferred. Examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-di Methylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1 -Ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethyl Butyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl Wait. The alkyl group may be substituted or unsubstituted.

“烯基”指由至少兩個碳原子和至少一個碳-碳雙鍵組成的如上定義的烷基，代表性實例包括但不限於乙烯基、1-丙烯基、2-丙烯基、1-，2-或3-丁烯基等。烯基可以是任選取代的或未取代的。"Alkenyl" refers to an alkyl group, as defined above, consisting of at least two carbon atoms and at least one carbon-carbon double bond. Representative examples include, but are not limited to, vinyl, 1-propenyl, 2-propenyl, 1-, 2- or 3-butenyl and the like. Alkenyl can be optionally substituted or unsubstituted.

“炔基”作為一基團或一基團的一部分時是指含有一個碳碳三鍵的脂肪烴基團，可為直鏈也可以帶有支鏈。優先選擇的是C2 -C10 的炔基，更優選C2 -C6 炔基，最優選C2 -C4 炔基。炔基基團的實施例包括，但不限於乙炔基、1-丙炔基、2-丙炔基、1-、2-或3-丁炔基等。炔基可以是取代或未取代的。"Alkynyl" as a group or part of a group refers to an aliphatic hydrocarbon group containing a carbon-carbon triple bond, which may be straight or branched. C 2 -C 10 alkynyl is preferred, C 2 -C 6 alkynyl is more preferred, and C 2 -C 4 alkynyl is most preferred. Examples of alkynyl groups include, but are not limited to, ethynyl, 1-propynyl, 2-propynyl, 1-, 2-, or 3-butynyl, and the like. An alkynyl can be substituted or unsubstituted.

“環烷基”是指飽和或部分飽和的單環、稠環、橋環或螺環的碳環。優選為C3 -C12 環烷基，更優選為C3 -C8 環烷基，最優選為C3 -C6 環烷基。單環環烷基的實施例包括但不限於環丙基、環丁基、環戊基、環戊烯基、環己基、環己烯基、環己二烯基、環庚基、環庚三烯基、環辛基等，優選環丙基、環己烯基。"Cycloalkyl" refers to a saturated or partially saturated monocyclic, fused, bridged or spiro carbocyclic ring. It is preferably a C 3 -C 12 cycloalkyl group, more preferably a C 3 -C 8 cycloalkyl group, and most preferably a C 3 -C 6 cycloalkyl group. Examples of monocyclic cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptyl Alkenyl, cyclooctyl and the like are preferably cyclopropyl or cyclohexenyl.

“螺環烷基”指5至18元的、含有兩個或兩個以上環狀結構的且單環之間彼此共用一個碳原子(稱螺原子)的多環基團，環內可含有1個或多個雙鍵，但沒有一個環具有完全共軛的π電子的芳香系統。優選為6至14元，更優選為7至10元。根據環與環之間共用螺原子的數目將螺環烷基分為單螺、雙螺或多螺環烷基，優選為單螺和雙螺環烷基，優選為4元/5元、4元/6元、5元/5元或5元/6元。“螺環烷基”的非限制性實施例包括但不限於：螺[4.5] 癸基、螺[4.4] 壬基、螺[3.5]壬基、螺[2.4]庚基。"Spirocycloalkyl" refers to a 5- to 18-membered polycyclic group containing two or more cyclic structures and a single ring sharing a carbon atom (called a spiro atom) with each other. The ring may contain 1 Aromatic systems with one or more double bonds, but none of which has a fully conjugated π electron. It is preferably 6 to 14 yuan, and more preferably 7 to 10 yuan. Spirocycloalkyl is divided into monospiro, bisspiro, or polyspirocycloalkyl according to the number of common spiro atoms between the rings, preferably monospiro and bisspirocycloalkyl, and is preferably 4-membered / 5-membered, 4 RMB / 6 yuan, 5 yuan / 5 yuan, or 5 yuan / 6 yuan. Non-limiting examples of "spirocycloalkyl" include, but are not limited to: spiro [4.5] decyl, spiro [4.4] nonyl, spiro [3.5] nonyl, spiro [2.4] heptyl.

“稠環烷基”指5至18元的、含有兩個或兩個以上環狀結構的彼此公用一對碳原子的全碳多環基團，其中一個或多個環可以含有一個或多個雙鍵，但沒有一個環具有完全共軛的π電子的芳香系統，優選為6至12元，更優選為7至10元。根據組成環的數目可以分為雙環、三環、吡啶酮或多環稠環烷基，優選為雙環或三環，更優選為5元/5元或5元/6元雙環烷基。“稠環烷基”的非限制性實施例包括但不限於：二環[3.1.0]己基、二環[3.2.0]庚-1-烯基、二環[3.2.0]庚基、十氫化萘基或十四氫菲基。"Fused cycloalkyl" refers to a 5- to 18-membered, all-carbon polycyclic group containing two or more cyclic structures that share a pair of carbon atoms with each other, where one or more rings may contain one or more A double bond, but without an aromatic system in which a ring has a completely conjugated π electron, is preferably 6 to 12 members, and more preferably 7 to 10 members. It can be divided into bicyclic, tricyclic, pyridone or polycyclic fused cycloalkyl according to the number of constituent rings, preferably bicyclic or tricyclic, more preferably 5-membered / 5-membered or 5-membered / 6-membered bicyclic alkyl. Non-limiting examples of "fused cycloalkyl" include, but are not limited to: bicyclo [3.1.0] hexyl, bicyclo [3.2.0] hept-1-enyl, bicyclo [3.2.0] heptyl, Decahydronaphthyl or tetradecyl phenanthryl.

“橋環烷基”指 5至18元的、含有兩個或兩個以上環狀結構的彼此共用兩個不直接相連接碳原子的全碳多環基團，其中一個或多個環可以含有一個或多個雙鍵，但沒有一個環具有完全共軛的π電子的芳香系統。優選為6至14元，更優選為7至10元。根據組成環的數目可以分為雙環、三環、吡啶酮或多環橋環烷基，優選為雙環、三環或吡啶酮，更有選為雙環或三環。“橋環烷基”的非限制性實施例包括但不限於：(1s,4s)-二環[2.2.1] 庚基、二環[3.2.1]辛基、(1s,5s)-二環[3.3.1]壬基、二環[2.2.2]辛基、(1r,5r)-二環[3.3.2]癸基。"Bridged cycloalkyl" refers to a 5- to 18-membered, all-carbon polycyclic group containing two or more cyclic structures that share two carbon atoms that are not directly connected to each other. One or more of the rings may contain An aromatic system with one or more double bonds, but none of which has a fully conjugated π electron. It is preferably 6 to 14 yuan, and more preferably 7 to 10 yuan. It can be divided into bicyclic, tricyclic, pyridone or polycyclic bridged cycloalkyl according to the number of constituent rings, preferably bicyclic, tricyclic or pyridone, and more preferably bicyclic or tricyclic. Non-limiting examples of "bridged cycloalkyl" include, but are not limited to: (1s, 4s) -bicyclo [2.2.1] heptyl, bicyclo [3.2.1] octyl, (1s, 5s) -di Ring [3.3.1] nonyl, bicyclic [2.2.2] octyl, (1r, 5r) -bicyclic [3.3.2] decyl.

所述環烷基環可以稠合於芳基、雜芳基或雜環基環上，其中與母體結構連接在一起的環為環烷基，非限制性實施例包括茚滿基、四氫萘基、苯并環庚烷基等。環烷基可以是任選取代的或未取代的。The cycloalkyl ring may be fused to an aryl, heteroaryl or heterocyclic ring, wherein the ring connected to the parent structure is a cycloalkyl group, and non-limiting examples include indanyl, tetrahydronaphthalene Radical, benzocycloheptyl and the like. A cycloalkyl group can be optionally substituted or unsubstituted.

“雜環基”、“雜環”或“雜環的”在本申請中可交換使用，都是指非芳香性雜環基，其中一個或多個成環的原子是雜原子，如氧、氮、硫原子等，包括單環、稠環、橋環和螺環。優選具有5至7元單環或7至10元雙-或三環，其可以包含1，2或3個選自氮、氧和/或硫中的原子。“雜環基”的實例包括但不限於嗎啉基，氧雜環丁烷基，硫代嗎啉基，四氫吡喃基，1，1-二氧代-硫代嗎啉基，呱啶基，2-氧代-呱啶基，吡咯烷基，2-氧代-吡咯烷基，呱口井-2-酮，8-氧雜-3-氮雜-雙環[3.2.1]辛基和呱口井基。雜環基可以是取代或未取代的。"Heterocyclyl", "heterocyclic" or "heterocyclic" are used interchangeably in this application and refer to non-aromatic heterocyclic groups in which one or more ring-forming atoms are heteroatoms, such as oxygen, Nitrogen, sulfur, etc., including monocyclic, fused, bridged and spiro rings. It preferably has a 5- to 7-membered monocyclic or 7 to 10-membered bi- or tricyclic ring, which may contain 1, 2 or 3 atoms selected from nitrogen, oxygen and / or sulfur. Examples of "heterocyclyl" include, but are not limited to, morpholinyl, oxetanyl, thiomorpholinyl, tetrahydropyranyl, 1,1-dioxo-thiomorpholinyl, pyridine , 2-oxo-pyridinyl, pyrrolidinyl, 2-oxo-pyrrolidinyl, Horiguchi-2-one, 8-oxa-3-aza-bicyclo [3.2.1] octyl And Yankou Jingji. Heterocyclyl can be substituted or unsubstituted.

“螺雜環基”指5至18元的、含有兩個或兩個以上環狀結構的且單環之間彼此共用一個原子的多環基團，其環內含有1個或多個雙鍵，但沒有一個環具有完全共軛的π電子的芳香系統，其中一個或多個環原子選自氮、氧或S(O)m (其中m選自0、1或2)的雜原子，其餘環原子為碳。優選為6至14元，更優選為7至10元。根據環與環之間共用螺原子的數目將螺環烷基分為單螺雜環基、雙螺雜環基或多螺雜環基，優選為單螺雜環基和雙螺雜環基。更優選為4元/4元、4元/5元、4元/6元、5元/5元或5元/6元單螺雜環基。“螺雜環基”的非限制性實施例包括但不限於：1,7-二氧雜螺[4.5] 癸基、2-氧雜-7-氮雜螺[4.4]壬基、7-氧雜螺[3.5] 壬基和5-氧雜螺[2.4]庚基。"Spiroheterocyclyl" means a 5- to 18-membered polycyclic group containing two or more cyclic structures and sharing a single atom between each other in a single ring, the ring containing one or more double bonds , But there is no aromatic system in which the ring has a completely conjugated π electron, in which one or more ring atoms are selected from heteroatoms of nitrogen, oxygen, or S (O) m (where m is selected from 0, 1 or 2), and the rest Ring atoms are carbon. It is preferably 6 to 14 yuan, and more preferably 7 to 10 yuan. Spirocycloalkyl is divided into monospiroheterocyclyl, bispiroheterocyclyl, or polyspiroheterocyclyl according to the number of common spiro atoms between the rings, preferably monospiroheterocyclyl and bispiroheterocyclyl. More preferred are 4-membered / 4-membered, 4-membered-5-membered, 4-membered-6-membered, 5-membered / 5-membered, or 5-membered / 6-membered monospiroheterocyclyl. Non-limiting examples of "spiroheterocyclyl" include, but are not limited to: 1,7-dioxaspiro [4.5] decyl, 2-oxa-7-azaspiro [4.4] nonyl, 7-oxo Heterospiro [3.5] nonyl and 5-oxaspiro [2.4] heptyl.

“稠雜環基”指含有兩個或兩個以上環狀結構彼此共用一對原子的全碳多環基團，其中一個或多個環可以含有一個或多個雙鍵，但沒有一個環具有完全共軛的π電子的芳香系統，其中一個或多個環原子為選自氮、氧或S(O)m (其中m選自0、1或2)的雜原子，其餘環原子為碳。優選為6至14元，更優選為7至10元。根據組成環的數目可以分為雙環、三環、吡啶酮或多環稠雜環基，優選為雙環或三環，更優選為5元/5元或5元/6元雙環稠雜環基。“稠雜環基”的非限制性實施例包括但不限於：八氫吡咯并[3,4-c]吡咯基、八氫-1H-異吲哚基，3-氮雜二環[3.1.0]己基，八氫苯并[b][1,4] 二㗁英(dioxine)。"Fused heterocyclyl" refers to a full-carbon polycyclic group containing two or more cyclic structures that share a pair of atoms with each other. One or more rings may contain one or more double bonds, but no ring has A completely conjugated pi-electron aromatic system in which one or more ring atoms are heteroatoms selected from nitrogen, oxygen, or S (O) m (where m is selected from 0, 1 or 2) and the remaining ring atoms are carbon. It is preferably 6 to 14 yuan, and more preferably 7 to 10 yuan. It can be divided into bicyclic, tricyclic, pyridone or polycyclic fused heterocyclic group according to the number of constituent rings, preferably bicyclic or tricyclic, more preferably 5-membered / 5-membered or 5-membered / 6-membered bicyclic fused heterocyclic group. Non-limiting examples of "fused heterocyclyl" include, but are not limited to: octahydropyrrolo [3,4-c] pyrrolyl, octahydro-1H-isoindolyl, 3-azabicyclo [3.1. 0] hexyl, octahydrobenzo [b] [1,4] dioxine.

“橋雜環基”指5至18元、優選5至14元，含有兩個或兩個以上環狀結構且彼此共用兩個不直接相連接的原子的多環基團，其中一個或多個環可以含有一個或多個雙鍵，但沒有一個環具有完全共軛的π電子的芳香系統，其中一個或多個環原子選自氮、氧或S(O)m (其中m選自0、1或2)的雜原子，其餘環原子為碳。優選為6至14元，更優選為7至10元。根據組成環的數目可以分為雙環、三環、吡啶酮或多環橋雜環基，優選為雙環、三環或吡啶酮，更有選為雙環或三環。“稠雜環基”的非限制性實施例包括但不限於：2-氮雜二環[2.2.1]庚基，2-氮雜二環[2.2.2]辛基和2-氮雜二環[3.3.2]癸基。所述雜環基環可以稠合於芳基、雜芳基或環烷基環上，其中與母體結構連接在一起的環為雜環基。雜環基可以是任選取代的或未取代的。A "bridged heterocyclyl" refers to a polycyclic group of 5 to 18 members, preferably 5 to 14 members, containing two or more cyclic structures and sharing two atoms that are not directly connected to each other, one or more of which A ring may contain one or more double bonds, but none of the rings has a completely conjugated π-electron aromatic system in which one or more ring atoms are selected from nitrogen, oxygen, or S (O) m (where m is selected from 0, 1 or 2), and the remaining ring atoms are carbon. It is preferably 6 to 14 yuan, and more preferably 7 to 10 yuan. It can be divided into bicyclic, tricyclic, pyridone or polycyclic bridged heterocyclic groups according to the number of constituent rings, preferably bicyclic, tricyclic or pyridone, and more preferably bicyclic or tricyclic. Non-limiting examples of "fused heterocyclyl" include, but are not limited to: 2-azabicyclo [2.2.1] heptyl, 2-azabicyclo [2.2.2] octyl, and 2-azabi Ring [3.3.2] decyl. The heterocyclic ring may be fused to an aryl, heteroaryl or cycloalkyl ring, wherein the ring connected to the parent structure is a heterocyclic group. Heterocyclyl can be optionally substituted or unsubstituted.

“芳基”是指含有一個或者兩個環的碳環芳香系統，其中所述環可以以稠合的方式連接在一起。術語“芳基”包括比如苯基、萘基、四氫萘基的芳香基團。優選芳基為C6 -C10 芳基，更優選芳基為苯基和萘基，最優選為苯基。芳基可以是取代或未取代的。所述“芳基”可與雜芳基、雜環基或環烷基稠合，其中與母體結構連接在一起的為芳基環，非限制性實施例包括但不限於： 和。"Aryl" refers to a carbocyclic aromatic system containing one or two rings, where the rings can be linked together in a fused manner. The term "aryl" includes aromatic groups such as phenyl, naphthyl, tetrahydronaphthyl. Preferred aryl groups are C 6 -C 10 aryl groups, more preferred aryl groups are phenyl and naphthyl, and most preferred is phenyl. Aryl may be substituted or unsubstituted. The "aryl group" may be fused with a heteroaryl group, a heterocyclic group, or a cycloalkyl group, wherein an aryl ring is connected to the parent structure. Non-limiting examples include, but are not limited to: with .

“雜芳基”是指芳香族5至6元單環或9至10元雙環，其可以包含1至4個選自氮、氧和/或硫中的原子。“雜芳基”的實施例包括但不限於呋喃基，吡啶基，2-氧代-1，2-二氫吡啶基，嗒口井基，嘧啶基，吡口井基，噻吩基，異㗁唑基，㗁唑基，㗁二唑基，咪唑基，吡咯基，吡唑基，***基，四氮唑基，噻唑基，異噻唑基，1，2，3-噻二唑基，苯并間二氧雜環戊烯基，苯并咪唑基，吲哚基，異吲哚基，1，3-二氧代-異吲哚基，喹啉基，吲唑基，苯并異噻唑基，苯并㗁唑基和苯并異㗁唑基。雜芳基可以是取代或未取代的。所述雜芳基環可以稠合於芳基、雜環基或環烷基環上，其中與母體結構連接在一起的環為雜芳基環，非限制性實施例包括但不限於： 和。"Heteroaryl" refers to an aromatic 5- to 6-membered monocyclic or 9 to 10-membered bicyclic ring, which may contain 1 to 4 atoms selected from nitrogen, oxygen, and / or sulfur. Examples of "heteroaryl" include, but are not limited to, furyl, pyridyl, 2-oxo-1,2-dihydropyridyl, daguyl, pyrimidinyl, pyridyl, thienyl, isofluorene Oxazolyl, oxazolyl, oxadiazolyl, imidazolyl, pyrrolyl, pyrazolyl, triazolyl, tetrazolyl, thiazolyl, isothiazolyl, 1,2,3-thiadiazolyl, benzene Acene dioxopentyl, benzimidazolyl, indolyl, isoindolyl, 1,3-dioxo-isoindolyl, quinolinyl, indazolyl, benzoisothiazolyl , Benzoxazolyl and benzoisoxazolyl. Heteroaryl may be substituted or unsubstituted. The heteroaryl ring may be fused to an aryl, heterocyclic or cycloalkyl ring, wherein the ring connected to the parent structure is a heteroaryl ring. Non-limiting examples include, but are not limited to: with .

“烷氧基”是指（烷基-O-）的基團。其中，烷基見本文有關定義。C1 -C6 的烷氧基為優先選擇，尤其優選C1 -C4 烷氧基。其實例包括，但不限於：甲氧基、乙氧基、正丙氧基、異丙氧基、正丁氧基、異丁氧基、叔丁氧基等。"Alkoxy" refers to a (alkyl-O-) group. Among them, alkyl is defined herein. C 1 -C 6 alkoxy is preferred, and C 1 -C 4 alkoxy is particularly preferred. Examples thereof include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, and the like.

“羥基”指-OH基團。"Hydroxy" refers to the -OH group.

“鹵素”是指氟、氯、溴和碘。"Halogen" means fluorine, chlorine, bromine and iodine.

“胺基”指-NH2 。"Amino" means -NH 2.

“氰基”指-CN。"Cyano" refers to -CN.

“硝基”指-NO2 。"Nitro" refers to -NO 2.

“苄基”指-CH2 -苯基。"Benzyl" refers to -CH 2 - phenyl.

“羧基”指-C(O)OH。"Carboxy" refers to -C (O) OH.

“羧酸酯基”指-C(O)O(烷基)或-C(O)O (環烷基)，其中烷基、環烷基的定義如上所述。"Carboxylate" means -C (O) O (alkyl) or -C (O) O (cycloalkyl), wherein alkyl and cycloalkyl are as defined above.

“Ts”指對甲苯磺醯基。"Ts" refers to p-toluenesulfonyl.

“DMSO”指二甲基亞碸。"DMSO" refers to dimethylsulfinium.

“取代的”指基團中的一個或多個氫原子，優選為最多5個，更優選為1～3個氫原子彼此獨立地被相應數目的取代基替換。不言而喻，取代基僅處在它們的可能的化學位置，本領域技術人員能夠在不付出過多努力的情況下確定(藉由實驗或理論)可能或不可能的取代。例如，具有游離氫的胺基或羥基與具有不飽和鍵(如烯鍵)的碳原子結合時可能是不穩定的。"Substituted" refers to one or more hydrogen atoms in a group, preferably up to 5 and more preferably 1 to 3 hydrogen atoms are replaced independently of one another by a corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, and those skilled in the art can determine (by experiment or theory) possible or impossible substitutions without undue effort. For example, an amine or hydroxyl group having free hydrogen may be unstable when combined with a carbon atom having an unsaturated bond, such as an ethylenic bond.

本說明書所述的“取代”或“取代的”，如無特別指出，均是指基團可被一個或多個選自以下的基團取代：烷基、烯基、炔基、烷氧基、烷硫基、烷基胺基、鹵素、巰基、羥基、硝基、氰基、環烷基、雜環基、芳基、雜芳基、環烷氧基、雜環烷氧基、環烷硫基、雜環烷硫基、胺基、鹵代烷基、羥烷基、羧基、羧酸酯基、=O、-NR6 R7 、-C(O)NR6 R7 、-OR8 、-C(O)R8 、-C(O)OR8 或-NR6 C(O)R7 。"Substituted" or "substituted" in this specification, unless otherwise specified, means that the group may be substituted by one or more groups selected from the group consisting of: alkyl, alkenyl, alkynyl, and alkoxy , Alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkane Thio, heterocycloalkylthio, amine, haloalkyl, hydroxyalkyl, carboxyl, carboxylate, = O, -NR 6 R 7 , -C (O) NR 6 R 7 , -OR 8 ,- C (O) R 8 , -C (O) OR 8 or -NR 6 C (O) R 7 .

“可藥用的鹽”是指上述化合物能保持原有生物活性並且適合於醫藥用途的某些鹽類。式(I)化合物的可藥用的鹽可以為金屬鹽、與合適的酸形成的胺鹽。金屬鹽優選鹼金屬、鹼土金屬鹽，合適的酸包括無機酸和有機酸。"Pharmaceutically acceptable salt" refers to certain salts of the aforementioned compounds that retain their original biological activity and are suitable for medical use. A pharmaceutically acceptable salt of a compound of formula (I) may be a metal salt, an amine salt with a suitable acid. The metal salt is preferably an alkali metal or alkaline earth metal salt, and suitable acids include inorganic and organic acids.

“藥物組合物”表示含有一種或多種本文所述化合物（包括其生理學上可藥用的鹽或前體藥物等形式）與任選的其他藥物活性成分的混合物，其可以包含其他任選組分例如可藥用的載體和/或賦形劑。藥物組合物的目的是促進對生物體的給藥，利於活性成分的吸收進而發揮生物活性。 本發明化合物的合成方法"Pharmaceutical composition" means a mixture containing one or more of the compounds described herein, including physiologically pharmaceutically acceptable salts or prodrugs thereof, and optionally other pharmaceutically active ingredients, which may contain other optional groups For example, pharmaceutically acceptable carriers and / or excipients. The purpose of the pharmaceutical composition is to promote the administration to the organism, which is beneficial to the absorption of the active ingredient and then exerts the biological activity. Method for synthesizing compounds of the present invention

為了完成本發明的目的，本發明採用如下技術方案： 本發明式(I)化合物的製備方法，包括以下步驟：使式(Ia)化合物的硝基還原得到式(Ib)化合物；使式(Ib)化合物與式(Ic)化合物在鈀催化劑條件下反應，得到式(Id)化合物；使式(Id)化合物與R4 取代的磺醯鹵（優選為R4 取代的磺醯氯）反應，得到通式(Ie)化合物；使式(Ie)化合物在鹼性條件下水解，脫去保護基，得到式(I)化合物； 其中： Ra 選自硼酸基或硼酸酯基；所述的硼酸酯基優選為：； PG為N的保護基，優選為取代的苯磺醯基，更優選為對甲苯磺醯基； X選自鹵素，優選為氯或溴； 所述鈀催化劑優選為1,1’-雙(二-叔丁基膦基)二茂鐵二氯化鈀；且 R4 選自烷基；且 R1 ～R3 和R5 的定義如式(I)中所述。In order to achieve the purpose of the present invention, the present invention adopts the following technical scheme: The method for preparing the compound of formula (I) of the present invention includes the following steps: Reducing the nitro group of the compound of formula (Ia) to obtain a compound of formula (Ib); reacting the compound of formula (Ib) with a compound of formula (Ic) under the conditions of a palladium catalyst to obtain a compound of formula (Id); The R 4 substituted sulfonium halide (preferably R 4 substituted sulfonium chloride) is reacted to obtain a compound of general formula (Ie); the compound of formula (Ie) is hydrolyzed under basic conditions, and the protecting group is removed to obtain formula (I ) A compound; wherein: R a is selected from a boronic acid group or a boronic acid ester group; the boronic acid ester group is preferably: ; PG is a protecting group of N, preferably substituted benzenesulfonyl, more preferably p-toluenesulfonyl; X is selected from halogen, preferably chlorine or bromine; the palladium catalyst is preferably 1,1'-bis ( Di-t-butylphosphino) ferrocene palladium dichloride; and R 4 is selected from alkyl; and R 1 to R 3 and R 5 are as defined in formula (I).

在上述製備方法中，鹼性條件由有機鹼或無機鹼提供，有機鹼優選自二異丙基乙胺、二異丙胺、吡啶、三乙胺、呱啶、N-甲基呱口井、4-二甲胺吡啶，更優選為二異丙胺和三乙胺；無機鹼優選自碳酸鈉、碳酸鉀、碳酸銫、氫氧化鈉、氫氧化鉀，更優選為氫氧化鈉。In the above preparation method, the basic condition is provided by an organic base or an inorganic base, and the organic base is preferably selected from diisopropylethylamine, diisopropylamine, pyridine, triethylamine, pyridine, N-methyl hydrazone, 4 -Dimethylamine pyridine, more preferably diisopropylamine and triethylamine; the inorganic base is preferably from sodium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide, potassium hydroxide, and more preferably sodium hydroxide.

以下結合實施例用於進一步描述本發明，但這些實施例並非限制著本發明的範圍。 實施例 The following examples are used to further describe the present invention, but these examples do not limit the scope of the present invention. Examples

實施例給出了式(I )所表示的代表性化合物的製備及相關結構鑒定資料。必須說明，下述實施例是用於說明本發明而不是對本發明的限制。1 H NMR圖譜是用Bruker儀器(400MHz)測定而得，化學位移用ppm表示。使用四甲基矽烷內標準(0.00ppm)。1 H NMR的表示方法：s=單峰，d=雙重峰，t=三重峰，m=多重峰，br=變寬的，dd=雙重峰的雙重峰，dt=三重峰的雙重峰。若提供偶合常數時，其單位為Hz。The examples show the preparation of the representative compounds represented by formula ( I ) and related structural identification data. It must be noted that the following examples are intended to illustrate the present invention and not to limit the present invention. The 1 H NMR spectrum was measured with a Bruker instrument (400 MHz), and the chemical shift was expressed in ppm. Tetramethylsilane internal standard (0.00ppm) was used. 1 H NMR: s = single peak, d = doublet, t = triplet, m = multiple peak, br = broadened, dd = double peak of double peak, dt = double peak of triplet. If a coupling constant is provided, the unit is Hz.

質譜是用LC/MS儀測定得到，離子化方式可為ESI或APCI。The mass spectrum is determined by LC / MS instrument, and the ionization method can be ESI or APCI.

薄層層析矽膠板使用煙臺黃海HSGF254或青島GF254矽膠板，薄層色譜法(TLC)。Thin-layer chromatography silica gel plate used Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plate, thin-layer chromatography (TLC).

使用的矽膠板採用的規格是0.15 mm～0.2 mm，薄層層析分離純化產品採用的規格是0.4 mm～0.5 mm。The size of the silica gel plate used is 0.15 mm to 0.2 mm, and the size of the thin layer chromatography purification product is 0.4 mm to 0.5 mm.

柱層析一般使用煙臺黃海矽膠200~300目矽膠為載體。Column chromatography generally uses Yantai Yellow Sea Silicone 200-300 mesh silica gel as the carrier.

在下列實施例中，除非另有指明，所有溫度為攝氏溫度，除非另有指明，各種起始原料和試劑來自市售或者是根據已知的方法合成，市售原料和試劑均不經進一步純化直接使用，除非另有指明，市售廠家包括但不限於Aldrich Chemical Company，ABCR GmbH & Co.KG，Acros Organics，廣贊化工科技有限公司和景顏化工科技有限公司等處購買。In the following examples, unless otherwise specified, all temperatures are in degrees Celsius, and unless otherwise specified, various starting materials and reagents are commercially available or synthesized according to known methods, and the commercially available materials and reagents are used without further purification. For direct use, unless otherwise specified, commercially available manufacturers include, but are not limited to, Aldrich Chemical Company, ABCR GmbH & Co. KG, Acros Organics, Guangzan Chemical Technology Co., Ltd. and Jingyan Chemical Technology Co., Ltd.

CD3 OD：氘代甲醇。CD 3 OD: deuterated methanol.

CDCl3 ：氘代氯仿。CDCl 3 : deuterated chloroform.

DMSO-d6 ：氘代二甲基亞碸。DMSO-d 6 : deuterated dimethylsulfinium.

氬氣氛是指反應瓶連接一個約1L容積的氬氣氣球。The argon atmosphere refers to the connection of an argon balloon with a volume of about 1 L to the reaction flask.

實施例中若無特殊說明，反應中的溶液是指水溶液。Unless otherwise specified in the examples, the solution in the reaction refers to an aqueous solution.

對化合物進行純化，採用矽膠柱層析和薄層色譜法，其中洗脫劑體系選自：A：石油醚和乙酸乙酯體系；B：二氯甲烷和甲醇體系；C：二氯甲烷：乙酸乙酯；其中溶劑的體積比根據化合物的極性不同而不同，也可以加入少量的酸性或鹼性試劑進行調節，如醋酸或三乙胺等。 實施例1 N-(4-(2,4-二氟苯氧基)-2-甲氧基-5-(6-甲基-7-氧代-6,7-二氫-1H-吡咯并[2,3-c]吡啶-4-基)苯基)乙磺醯胺 第一步 4-(2,4-二氟苯氧基)-2-甲氧基-1-硝基苯The compounds were purified by silica gel column chromatography and thin layer chromatography, where the eluent system was selected from: A: petroleum ether and ethyl acetate system; B: dichloromethane and methanol system; C: dichloromethane: acetic acid Ethyl ester; the volume ratio of the solvent varies according to the polarity of the compound, and it can also be adjusted by adding a small amount of acidic or basic reagents, such as acetic acid or triethylamine. Example 1 N- (4- (2,4-difluorophenoxy) -2-methoxy-5- (6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo [2,3-c] pyridin-4-yl) phenyl) ethanesulfonamide First step 4- (2,4-difluorophenoxy) -2-methoxy-1-nitrobenzene

將4-氟-2-甲氧基-1-硝基苯1a (1 g, 5.85 mmol)、2,4-二氟苯酚1b (760 mg, 5.85 mmol)和碳酸銫(1.9 g, 5.85 mmol)溶於50 mL二甲亞碸中，110℃反應2小時。將反應液冷卻至室溫，加入100 mL水和50 mL乙酸乙酯，分層，收集有機相，水相以乙酸乙酯(30 mL×3)萃取，合併有機相，以飽和氯化鈉水溶液(50 mL×1)洗滌，以無水硫酸鈉乾燥，減壓濃縮，得到4-(2,4-二氟苯氧基)-2-甲氧基-1-硝基苯1c (1.4 g，白色固體)，產率：85.4%。 MS m/z(ESI)：281.9[M+1] 第二步 1-溴-2-(2,4-二氟苯氧基)-4-甲氧基-5-硝基苯Add 4-fluoro-2-methoxy-1-nitrobenzene 1a (1 g, 5.85 mmol), 2,4-difluorophenol 1b (760 mg, 5.85 mmol), and cesium carbonate (1.9 g, 5.85 mmol) It was dissolved in 50 mL of dimethylarsine and reacted at 110 ° C for 2 hours. The reaction solution was cooled to room temperature, 100 mL of water and 50 mL of ethyl acetate were added, the layers were separated, and the organic phase was collected. The aqueous phase was extracted with ethyl acetate (30 mL × 3), and the organic phases were combined with a saturated sodium chloride aqueous solution. (50 mL × 1), washed with anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 4- (2,4-difluorophenoxy) -2-methoxy-1-nitrobenzene 1c (1.4 g, white (Solid), yield: 85.4%. MS m / z (ESI): 281.9 [M + 1] Second step 1-bromo-2- (2,4-difluorophenoxy) -4-methoxy-5-nitrobenzene

將4-(2,4-二氟苯氧基)-2-甲氧基-1-硝基苯1c (1.4 g, 5 mmol)溶於20 mL醋酸中，降溫至0℃。將液溴(1.58 g, 10 mmol)溶於5 mL醋酸中，0℃下滴加到上述溶液中，室溫下反應2小時。將反應液減壓濃縮，將得到的殘留物溶於50 mL乙酸乙酯中，依次以飽和硫代硫酸鈉水溶液(30 mL×3)、水(50 mL×1)和飽和氯化鈉水溶液(50 mL×1)洗滌，分去水層，有機相以無水硫酸鈉乾燥，減壓濃縮，得到1-溴-2-(2,4-二氟苯氧基)-4-甲氧基-5-硝基苯1d (1.58 g，淡黃色固體)，產率：88%。1 H NMR (400 MHz, CDCl3 ): δ 8.27 (s, 1H), 7.19-7.17 (m, 1H), 7.04-7.01 (m, 1H), 6.98-6.97 (m, 1H), 6.32 (s, 1H), 3.77 (s, 3H). 第三步 5-溴-4-(2,4-二氟苯氧基)-2-甲氧基苯胺4- (2,4-difluorophenoxy) -2-methoxy-1-nitrobenzene 1c (1.4 g, 5 mmol) was dissolved in 20 mL of acetic acid, and the temperature was lowered to 0 ° C. Liquid bromine (1.58 g, 10 mmol) was dissolved in 5 mL of acetic acid, and the solution was added dropwise to the above solution at 0 ° C., and reacted at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure, and the obtained residue was dissolved in 50 mL of ethyl acetate, followed by saturated aqueous sodium thiosulfate solution (30 mL × 3), water (50 mL × 1), and saturated sodium chloride solution ( 50 mL × 1) was washed, and the aqueous layer was separated. The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give 1-bromo-2- (2,4-difluorophenoxy) -4-methoxy-5. -Nitrobenzene 1d (1.58 g, pale yellow solid), yield: 88%. 1 H NMR (400 MHz, CDCl 3 ): δ 8.27 (s, 1H), 7.19-7.17 (m, 1H), 7.04-7.01 (m, 1H), 6.98-6.97 (m, 1H), 6.32 (s, 1H), 3.77 (s, 3H). The third step is 5-bromo-4- (2,4-difluorophenoxy) -2-methoxyaniline

將1-溴-2-(2,4-二氟苯氧基)-4-甲氧基-5-硝基苯1d (1.58 g, 4.38 mmol)、鐵屑(1.23 mg, 21.89 mmol)和氯化銨(1.17 mg, 21.89 mmol)溶於35 mL乙醇/水(V:V = 6:1)中，回流反應2小時。待反應液降至室溫，過濾，以乙酸乙酯(20 mL)淋洗濾餅，收集濾液，減壓濃縮，得到的殘留物用矽膠柱層析法(洗脫劑：A體系)純化，得到5-溴-4-(2,4-二氟苯氧基)-2-甲氧基苯胺1e (1.35 g，棕色固體)，產率：93%。1 H NMR (400 MHz, DMSO-d6 ): δ 7.42-7.38 (m, 1H), 6.99-6.95 (m, 1H), 6.91 (s, 1H), 6.75 (s, 1H), 6.74-6.69 (m, 1H), 4.99 (s, 2H), 3.73 (s, 3H). 第四步 4-(5-胺基-2-(2,4-二氟苯氧基)-4-甲氧基苯基)-6-甲基-1-對甲苯磺醯基-1H-吡咯并[2,3-c]吡啶-7(6H)-酮Add 1-bromo-2- (2,4-difluorophenoxy) -4-methoxy-5-nitrobenzene 1d (1.58 g, 4.38 mmol), iron filings (1.23 mg, 21.89 mmol) and chlorine Ammonium chloride (1.17 mg, 21.89 mmol) was dissolved in 35 mL of ethanol / water (V: V = 6: 1) and reacted at reflux for 2 hours. After the reaction solution was cooled to room temperature, filtered, the filter cake was rinsed with ethyl acetate (20 mL), and the filtrate was collected and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: A system). 5-Bromo-4- (2,4-difluorophenoxy) -2-methoxyaniline 1e (1.35 g, brown solid) was obtained in a yield of 93%. 1 H NMR (400 MHz, DMSO-d 6 ): δ 7.42-7.38 (m, 1H), 6.99-6.95 (m, 1H), 6.91 (s, 1H), 6.75 (s, 1H), 6.74-6.69 ( m, 1H), 4.99 (s, 2H), 3.73 (s, 3H). Fourth step 4- (5-amino-2- (2,4-difluorophenoxy) -4-methoxybenzene ) -6-methyl-1-p-toluenesulfonyl-1H-pyrrolo [2,3-c] pyridin-7 (6H) -one

氬氣保護下，將5-溴-4-(2,4-二氟苯氧基)-2-甲氧基苯胺1e (165 mg, 0.5 mmol)、6-甲基-4-(4,4,5,5-四甲基-1,3,2-二氧硼雜環戊烷-2-基)-1-對甲苯磺醯基-1H-吡咯并[2,3-c]吡啶-7(6H)-酮1f (214 mg, 0.5 mmol, 根據專利WO2013097601製得)、1,1’-雙(二-叔丁基膦基)二茂鐵二氯化鈀 (32.6 mg, 0.03 mmol)和碳酸銫(325.8 mg, 1.0 mmol)溶於10 mL四氫呋喃/水(V:V = 1:1)中，室溫下反應2小時。將反應液過濾，濾餅以乙酸乙酯(10 mL×2)淋洗，濾液依次以水(50 mL×1)和飽和氯化鈉水溶液(30 mL×12)洗滌，分去水層，有機相以無水硫酸鈉乾燥，減壓濃縮，得到的殘留物用薄層色譜法(展開劑：A體系)純化，得到4-(5-胺基-2-(2,4-二氟苯氧基)-4-甲氧基苯基)-6-甲基-1-對甲苯磺醯基-1H-吡咯并[2,3-c]吡啶-7(6H)-酮1g (100 mg，棕色固體)，產率：36.93%。 MS m/z(ESI)：551.8[M+1] 第五步 N-(4-(2,4-二氟苯氧基)-2-甲氧基-5-(6-甲基-7-氧代-1-對甲苯磺醯基-6,7-二氫-1H-吡咯并[2,3-c]吡啶-4-基)苯基)-N-(乙基磺醯基)乙磺醯胺Under the protection of argon, 5-bromo-4- (2,4-difluorophenoxy) -2-methoxyaniline 1e (165 mg, 0.5 mmol), 6-methyl-4- (4,4 , 5,5-tetramethyl-1,3,2-dioxorane-2-yl) -1-p-toluenesulfonyl-1H-pyrrolo [2,3-c] pyridine-7 (6H) -one 1f (214 mg, 0.5 mmol, prepared according to patent WO2013097601), 1,1'-bis (di-tert-butylphosphino) ferrocene palladium dichloride (32.6 mg, 0.03 mmol) and Cesium carbonate (325.8 mg, 1.0 mmol) was dissolved in 10 mL of tetrahydrofuran / water (V: V = 1: 1) and reacted at room temperature for 2 hours. The reaction solution was filtered, the filter cake was rinsed with ethyl acetate (10 mL × 2), and the filtrate was washed with water (50 mL × 1) and a saturated aqueous sodium chloride solution (30 mL × 12) in this order. The aqueous layer was separated and the organic layer was separated. The phases were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained residue was purified by thin layer chromatography (developing solvent: system A) to obtain 4- (5-amino-2- (2,4-difluorophenoxy) ) -4-methoxyphenyl) -6-methyl-1-p-toluenesulfonyl-1H-pyrrolo [2,3-c] pyridin-7 (6H) -one 1g (100 mg, brown solid ), Yield: 36.93%. MS m / z (ESI): 551.8 [M + 1] Step 5 N- (4- (2,4-difluorophenoxy) -2-methoxy-5- (6-methyl-7- Oxo-1-p-toluenesulfonyl-6,7-dihydro-1H-pyrrolo [2,3-c] pyridin-4-yl) phenyl) -N- (ethylsulfonyl) ethanesulfonate Amidine

將4-(5-胺基-2-(2,4-二氟苯氧基)-4-甲氧基苯基)-6-甲基-1-對甲苯磺醯基-1H-吡咯并[2,3-c]吡啶-7(6H)-酮1g (100 mg, 0.18 mmol)溶於10 mL二氯甲烷中，0℃依次滴加三乙胺(72.8 mg, 0.72 mmol)、乙磺醯氯1h (46.6 mg, 0.36 mmol)，滴加完畢，升至室溫後繼續反應1小時。加入30 mL二氯甲烷和30 mL水，攪拌分層，收集有機相，水相以二氯甲烷(30 mL×2)萃取，合併有機相，以飽和氯化鈉水溶液(30 mL×1)洗滌，以無水硫酸鈉乾燥，減壓濃縮，得到粗品N-(4-(2,4-二氟苯氧基)-2-甲氧基-5-(6-甲基-7-氧代-1-對甲苯磺醯基-6,7-二氫-1H-吡咯并[2,3-c]吡啶-4-基)苯基)-N-(乙基磺醯基)乙磺醯胺1i (100 mg，棕色固體)直接用於下一步，產率：93%。 MS m/z(ESI)：735.7[M+1] 第六步 N-(4-(2,4-二氟苯氧基)-2-甲氧基-5-(6-甲基-7-氧代-6,7-二氫-1H-吡咯并[2,3-c]吡啶-4-基)苯基)乙磺醯胺4- (5-Amino-2- (2,4-difluorophenoxy) -4-methoxyphenyl) -6-methyl-1-p-toluenesulfonyl-1H-pyrrolo [ 1 g (100 mg, 0.18 mmol) of 2,3-c] pyridine-7 (6H) -one was dissolved in 10 mL of dichloromethane, and triethylamine (72.8 mg, 0.72 mmol) and ethylsulfonium were added dropwise in order at 0 ° C. Chlorine 1h (46.6 mg, 0.36 mmol) was added dropwise, and the reaction was continued for 1 hour after the temperature was raised to room temperature. 30 mL of dichloromethane and 30 mL of water were added, the layers were stirred and the organic phase was collected. The aqueous phase was extracted with dichloromethane (30 mL × 2). The organic phases were combined and washed with a saturated sodium chloride aqueous solution (30 mL × 1). , Dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain crude N- (4- (2,4-difluorophenoxy) -2-methoxy-5- (6-methyl-7-oxo-1 -P-toluenesulfonyl-6,7-dihydro-1H-pyrrolo [2,3-c] pyridin-4-yl) phenyl) -N- (ethylsulfonyl) ethanesulfonamide 1i ( 100 mg, brown solid) was used directly in the next step, yield: 93%. MS m / z (ESI): 735.7 [M + 1] Step 6 N- (4- (2,4-difluorophenoxy) -2-methoxy-5- (6-methyl-7- Oxo-6,7-dihydro-1H-pyrrolo [2,3-c] pyridin-4-yl) phenyl) ethanesulfonamide

將N-(4-(2,4-二氟苯氧基)-2-甲氧基-5-(6-甲基-7-氧代-1-對甲苯磺醯基-6,7-二氫-1H-吡咯并[2,3-c]吡啶-4-基)苯基)-N-(乙基磺醯基)乙磺醯胺1i (100 mg, 0.135 mmol)溶於5 mL四氫呋喃中；將氫氧化鈉(37.4 mg, 0.936 mmol)溶於1 mL水中，滴加至上述溶液中，90℃下反應3小時。將反應液減壓濃縮，在殘留物中加入30 mL乙酸乙酯和30 mL水，攪拌，以1N的鹽酸水溶液調節pH≈7，分層，收集有機相，水相以乙酸乙酯(20 mL×2)萃取，合併有機相，以無水硫酸鈉乾燥，減壓濃縮，得到的殘留物用矽膠柱層析法(洗脫劑：A體系)純化，得到N-(4-(2,4-二氟苯氧基)-2-甲氧基-5-(6-甲基-7-氧代-6,7-二氫-1H-吡咯并[2,3-c]吡啶-4-基)苯基)乙磺醯胺1 (70 mg，棕紅色固體)，產率：92%。 MS m/z(ESI)：490.0[M+1]1 H NMR (400 MHz, CDCl3 ): δ 10.47 (s, 1H), 7.69 (s, 1H), 7.39 - 7.19 (m, 1H), 7.11 (s, 1H), 6.94 - 6.76 (m, 2H), 6.71 (d,J = 12.3 Hz, 2H), 6.51 (s, 1H), 6.43 (t,J = 2.5 Hz, 1H), 3.82 (s, 3H), 3.66 (s, 3H), 3.11 (q,J = 7.4 Hz, 2H), 1.47 -1.32 (m, 3H). 實施例2 N-(4-(2,4-二氟苯氧基)-3-甲氧基-5-(6-甲基-7-氧代-6,7-二氫-1H-吡咯并[2,3-c]吡啶-4-基)苯基)乙磺醯胺 第一步 2-溴-6-甲氧基-4-硝基苯胺N- (4- (2,4-difluorophenoxy) -2-methoxy-5- (6-methyl-7-oxo-1-p-toluenesulfonyl-6,7-di Hydrogen-1H-pyrrolo [2,3-c] pyridin-4-yl) phenyl) -N- (ethylsulfonyl) ethanesulfonamide 1i (100 mg, 0.135 mmol) was dissolved in 5 mL of tetrahydrofuran ; Sodium hydroxide (37.4 mg, 0.936 mmol) was dissolved in 1 mL of water, added dropwise to the above solution, and reacted at 90 ° C for 3 hours. The reaction solution was concentrated under reduced pressure, 30 mL of ethyl acetate and 30 mL of water were added to the residue, and the mixture was stirred. The pH was adjusted to 7 with a 1N aqueous hydrochloric acid solution. The layers were separated and the organic phase was collected. × 2) extraction, the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: A system) to obtain N- (4- (2,4- Difluorophenoxy) -2-methoxy-5- (6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo [2,3-c] pyridin-4-yl) Phenyl) ethanesulfonamide 1 (70 mg, brown-red solid), yield: 92%. MS m / z (ESI): 490.0 [M + 1] 1 H NMR (400 MHz, CDCl 3 ): δ 10.47 (s, 1H), 7.69 (s, 1H), 7.39-7.19 (m, 1H), 7.11 (s, 1H), 6.94-6.76 (m, 2H), 6.71 (d, J = 12.3 Hz, 2H), 6.51 (s, 1H), 6.43 (t, J = 2.5 Hz, 1H), 3.82 (s, 3H), 3.66 (s, 3H), 3.11 (q, J = 7.4 Hz, 2H), 1.47 -1.32 (m, 3H). Example 2 N- (4- (2,4-difluorophenoxy) -3-methoxy-5- (6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo [2,3-c] pyridin-4-yl) phenyl) ethanesulfonium amine Step 1 2-bromo-6-methoxy-4-nitroaniline

將2-甲氧基-4-硝基苯胺2a (5.0 g, 29.7 mmol)溶於10 mL四氫呋喃中，降溫至-78℃，分批加入N-溴代丁二醯亞胺(5.29 g, 29.7 mmol)，-78℃下攪拌0.5小時，然後室溫反應2小時。減壓濃縮，除去溶劑，加入100 mL乙酸乙酯和100 mL水，分液，分去水層，有機相以飽和氯化鈉水溶液(20 mL×1)洗滌，無水硫酸鈉乾燥，減壓濃縮，得到2-溴-6-甲氧基-4-硝基苯胺2b (7.3 g，棕色固體)，產率：100%。 MS m/z(ESI)：246.8[M+1] 第二步 1-溴-2-氯-3-甲氧基-5-硝基苯Dissolve 2-methoxy-4-nitroaniline 2a (5.0 g, 29.7 mmol) in 10 mL of tetrahydrofuran, lower the temperature to -78 ° C, and add N-bromosuccinimide (5.29 g, 29.7) in portions. mmol), stirred at -78 ° C for 0.5 hours, and then reacted at room temperature for 2 hours. It was concentrated under reduced pressure, the solvent was removed, 100 mL of ethyl acetate and 100 mL of water were added, and the layers were separated. The aqueous layer was separated. The organic phase was washed with a saturated sodium chloride aqueous solution (20 mL × 1), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. To give 2-bromo-6-methoxy-4-nitroaniline 2b (7.3 g, brown solid), yield: 100%. MS m / z (ESI): 246.8 [M + 1] Second step 1-bromo-2-chloro-3-methoxy-5-nitrobenzene

將2-溴-6-甲氧基-4-硝基苯胺2b (2.48 g, 10 mmol)溶於15 mL濃鹽酸中，0℃下攪拌0.5小時。將硝酸鈉(1.38 g, 20 mmol)溶於10 mL水中，0℃下滴加到上述濃鹽酸溶液中，滴加完畢後室溫下攪拌1小時，製得A溶液。將氯化亞銅溶於15 mL濃鹽酸中，升溫至60℃，加入溶液A(0.5小時內加完)。將反應液升溫至80℃，繼續反應0.5小時。將反應液升至室溫，加入30 mL鹽水，以乙酸乙酯(30 mL×3)萃取，合併有機相，以飽和氯化鈉水溶液(20 mL×1)洗滌，無水硫酸鈉乾燥，減壓濃縮，得到的殘留物用矽膠柱層析法(洗脫劑：A體系)純化，得到1-溴-2-氯-3-甲氧基-5-硝基苯2c (2.5 g，白色固體)，產率：94%。1 H NMR (400 MHz, DMSO-d6 ): δ 8.18 (s, 1H), 7.91 (s, 1H), 4.03 (s, 3H). 第三步 1-溴-2-(2,4-二氟苯氧基)-3-甲氧基-5-硝基苯Dissolve 2-bromo-6-methoxy-4-nitroaniline 2b (2.48 g, 10 mmol) in 15 mL of concentrated hydrochloric acid and stir at 0 ° C for 0.5 hour. Sodium nitrate (1.38 g, 20 mmol) was dissolved in 10 mL of water, and the solution was added dropwise to the above concentrated hydrochloric acid solution at 0 ° C. After the dropwise addition was completed, the solution was stirred at room temperature for 1 hour to obtain solution A. Dissolve cuprous chloride in 15 mL of concentrated hydrochloric acid, warm to 60 ° C, and add solution A (addition in 0.5 hours). The reaction solution was warmed to 80 ° C and the reaction was continued for 0.5 hours. The reaction solution was warmed to room temperature, 30 mL of brine was added, and the mixture was extracted with ethyl acetate (30 mL × 3). The organic phases were combined, washed with a saturated sodium chloride aqueous solution (20 mL × 1), dried over anhydrous sodium sulfate, and decompressed. After concentration, the obtained residue was purified by silica gel column chromatography (eluent: system A) to obtain 1-bromo-2-chloro-3-methoxy-5-nitrobenzene 2c (2.5 g, white solid). Yield: 94%. 1 H NMR (400 MHz, DMSO-d 6 ): δ 8.18 (s, 1H), 7.91 (s, 1H), 4.03 (s, 3H). The third step is 1-bromo-2- (2,4-di (Fluorophenoxy) -3-methoxy-5-nitrobenzene

將1-溴-2-氯-3-甲氧基-5-硝基苯2c (1.0 g, 3.75 mmol)、2,4-二氟苯酚1b (585 mg, 4.5 mmol)、碘化亞銅(20 mg, 0.075 mmol)和碳酸鉀(1.03 g, 7.5 mmol)溶於10 mL N,N-二甲基甲醯胺中，130℃下反應3小時。將反應液冷卻至室溫，加入50 mL冰水，以乙酸乙酯(30 mL×3)萃取，合併有機相，以飽和氯化鈉水溶液(30 mL×1)洗滌，無水硫酸鈉乾燥，減壓濃縮，得到的殘留物用矽膠柱層析法(洗脫劑：A體系)純化，得到1-溴-2-(2,4-二氟苯氧基)-3-甲氧基-5-硝基苯2d (1g，白色固體)，產率：74%。1 H NMR (400 MHz, DMSO-d6 ): δ 8.22 (d,J = 4.0 Hz, 1H), 8.0 (d,J = 4.0 Hz, 1H), 7.50-7.44 (m, 1H), 6.96-6.94 (m, 1H), 6.80-6.75 (m, 1H), 3.87 (s, 3H). 第四步 3-溴-4-(2,4-二氟苯氧基)-5-甲氧基苯胺1-bromo-2-chloro-3-methoxy-5-nitrobenzene 2c (1.0 g, 3.75 mmol), 2,4-difluorophenol 1b (585 mg, 4.5 mmol), cuprous iodide ( 20 mg, 0.075 mmol) and potassium carbonate (1.03 g, 7.5 mmol) were dissolved in 10 mL of N, N-dimethylformamide and reacted at 130 ° C for 3 hours. The reaction solution was cooled to room temperature, 50 mL of ice water was added, and the mixture was extracted with ethyl acetate (30 mL × 3). The organic phases were combined, washed with a saturated sodium chloride aqueous solution (30 mL × 1), and dried over anhydrous sodium sulfate. The solution was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: system A) to obtain 1-bromo-2- (2,4-difluorophenoxy) -3-methoxy-5-. Nitrobenzene 2d (1 g, white solid), yield: 74%. 1 H NMR (400 MHz, DMSO-d 6 ): δ 8.22 (d, J = 4.0 Hz, 1H), 8.0 (d, J = 4.0 Hz, 1H), 7.50-7.44 (m, 1H), 6.96-6.94 (m, 1H), 6.80-6.75 (m, 1H), 3.87 (s, 3H). Fourth step 3-bromo-4- (2,4-difluorophenoxy) -5-methoxyaniline

將1-溴-2-(2,4-二氟苯氧基)-3-甲氧基-5-硝基苯2d (720 mg, 2 mmol)、鐵屑(560 mg, 10 mmol)和氯化銨(162 mg, 3 mmol)溶於12 mL四氫呋喃/乙醇/水(V:V:V = 5:5:2)中，95℃下反應2小時。待反應液降至室溫，過濾，以乙醇(20 mL)淋洗濾餅，收集濾液，減壓濃縮，將殘留物溶於20 mL乙酸乙酯中，依次以飽和碳酸氫鈉水溶液(20 mL×1)和飽和鹽水(20 mL×1)洗滌，有機相以無水硫酸鈉乾燥，減壓濃縮，得到的殘留物用矽膠柱層析法(洗脫劑：A體系)純化，得到3-溴-4-(2,4-二氟苯氧基)-5-甲氧基苯胺2e (500 mg，黃色固體)，產率：75.8%。 MS m/z(ESI)：329.8[M+1]1 H NMR (400 MHz, DMSO-d6 ): δ 7.38-7.32 (m, 1H), 6.90 (t,J = 8.0 Hz, 1H), 6.50-6.49 (m, 1H), 6.44 (s, 1H), 6.36 (s, 1H), 5.43 (s, 2H), 5.65 (s, 3H). 第五步 4-(5-胺基-2-(2,4-二氟苯氧基)-3-甲氧基苯基)-6-甲基-1-對甲苯磺醯基-1H-吡咯并[2,3-c]吡啶-7(6H)-酮Add 1-bromo-2- (2,4-difluorophenoxy) -3-methoxy-5-nitrobenzene 2d (720 mg, 2 mmol), iron filings (560 mg, 10 mmol) and chlorine Ammonium chloride (162 mg, 3 mmol) was dissolved in 12 mL of tetrahydrofuran / ethanol / water (V: V: V = 5: 5: 2) and reacted at 95 ° C for 2 hours. After the reaction solution was cooled to room temperature, filtered, the filter cake was rinsed with ethanol (20 mL), and the filtrate was collected, concentrated under reduced pressure, and the residue was dissolved in 20 mL of ethyl acetate, followed by saturated sodium bicarbonate aqueous solution (20 mL). × 1) and saturated brine (20 mL × 1), the organic phase was dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: A system) to obtain 3-bromo -4- (2,4-difluorophenoxy) -5-methoxyaniline 2e (500 mg, yellow solid), yield: 75.8%. MS m / z (ESI): 329.8 [M + 1] 1 H NMR (400 MHz, DMSO-d 6 ): δ 7.38-7.32 (m, 1H), 6.90 (t, J = 8.0 Hz, 1H), 6.50 -6.49 (m, 1H), 6.44 (s, 1H), 6.36 (s, 1H), 5.43 (s, 2H), 5.65 (s, 3H). The fifth step 4- (5-amino-2- ( 2,4-difluorophenoxy) -3-methoxyphenyl) -6-methyl-1-p-toluenesulfonyl-1H-pyrrolo [2,3-c] pyridine-7 (6H) -ketone

氬氣保護下，將3-溴-4-(2,4-二氟苯氧基)-5-甲氧基苯胺2e (115 mg, 0.35 mmol)、6-甲基-4-(4,4,5,5-四甲基-1,3,2-二氧硼雜環戊烷-2-基)-1-對甲苯磺醯基-1H-吡咯并[2,3-c]吡啶-7(6H)-酮1f (150 mg, 0.35 mmol, 根據專利WO2013097601製得)、1,1’-雙(二-叔丁基膦基)二茂鐵二氯化鈀 (23 mg, 0.035 mmol)和碳酸銫(230 mg, 0.7 mmol)溶於4 mL四氫呋喃/水(V:V = 1:1)中，室溫下反應3小時。加入100 mL乙酸乙酯稀釋反應液，以鹽水(100 mL×1)洗滌，分去水層，有機相以無水硫酸鈉乾燥，減壓濃縮，得到的殘留物用薄層色譜法(展開劑：A體系)純化，得到4-(5-胺基-2-(2,4-二氟苯氧基)-3-甲氧基苯基)-6-甲基-1-對甲苯磺醯基-1H-吡咯并[2,3-c]吡啶-7(6H)-酮2f (75 mg，黃色固體)，產率：38.9%。 MS m/z(ESI)：551.8[M+1] 第六步 N-(4-(2,4-二氟苯氧基)-3-甲氧基-5-(6-甲基-7-氧代-1-對甲苯磺醯基-6,7-二氫-1H-吡咯并[2,3-c]吡啶-4-基)苯基)-N-(乙基磺醯基)乙磺醯胺Under the protection of argon, 3-bromo-4- (2,4-difluorophenoxy) -5-methoxyaniline 2e (115 mg, 0.35 mmol), 6-methyl-4- (4,4 , 5,5-tetramethyl-1,3,2-dioxorane-2-yl) -1-p-toluenesulfonyl-1H-pyrrolo [2,3-c] pyridine-7 (6H) -one 1f (150 mg, 0.35 mmol, prepared according to patent WO2013097601), 1,1'-bis (di-tert-butylphosphino) ferrocene palladium dichloride (23 mg, 0.035 mmol), and Cesium carbonate (230 mg, 0.7 mmol) was dissolved in 4 mL of tetrahydrofuran / water (V: V = 1: 1) and reacted at room temperature for 3 hours. 100 mL of ethyl acetate was added to dilute the reaction solution, and the reaction solution was washed with brine (100 mL × 1), and the aqueous layer was separated. The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained residue was subjected to thin layer chromatography (developing solvent: System A) was purified to give 4- (5-amino-2- (2,4-difluorophenoxy) -3-methoxyphenyl) -6-methyl-1-p-toluenesulfonyl- 1H-pyrrolo [2,3-c] pyridine-7 (6H) -one 2f (75 mg, yellow solid), yield: 38.9%. MS m / z (ESI): 551.8 [M + 1] Step 6 N- (4- (2,4-difluorophenoxy) -3-methoxy-5- (6-methyl-7- Oxo-1-p-toluenesulfonyl-6,7-dihydro-1H-pyrrolo [2,3-c] pyridin-4-yl) phenyl) -N- (ethylsulfonyl) ethanesulfonate Amidine

將4-(5-胺基-2-(2,4-二氟苯氧基)-3-甲氧基苯基)-6-甲基-1-對甲苯磺醯基-1H-吡咯并[2,3-c]吡啶-7(6H)-酮2f (75 mg, 0.136 mmol)溶於3 mL二氯甲烷中，0℃依次滴加三乙胺(55 mg, 0.544 mmol)、乙磺醯氯1h (52.5 mg, 0.408 mmol)，升至室溫反應1小時。加入10 mL二氯甲烷稀釋反應液，以飽和氯化鈉水溶液(10 mL×1)洗滌，分去水層，有機相以無水硫酸鈉乾燥，減壓濃縮，得到N-(4-(2,4-二氟苯氧基)-3-甲氧基-5-(6-甲基-7-氧代-1-對甲苯磺醯基-6,7-二氫-1H-吡咯并[2,3-c]吡啶-4-基)苯基)-N-(乙基磺醯基)乙磺醯胺2g (100 mg，棕色油狀)，產率：100%。 MS m/z(ESI)：735.8[M+1] 第七步 N-(4-(2,4-二氟苯氧基)-3-甲氧基-5-(6-甲基-7-氧代-6,7-二氫-1H-吡咯并[2,3-c]吡啶-4-基)苯基)乙磺醯胺4- (5-Amino-2- (2,4-difluorophenoxy) -3-methoxyphenyl) -6-methyl-1-p-toluenesulfonyl-1H-pyrrolo [ 2,3-c] pyridine-7 (6H) -one 2f (75 mg, 0.136 mmol) was dissolved in 3 mL of dichloromethane, and triethylamine (55 mg, 0.544 mmol) and ethylsulfonium were added dropwise in order at 0 ° C. Chlorine for 1 h (52.5 mg, 0.408 mmol), warm to room temperature and react for 1 hour. 10 mL of dichloromethane was added to dilute the reaction solution, and the mixture was washed with a saturated sodium chloride aqueous solution (10 mL × 1), and the aqueous layer was separated. The organic phase was dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain N- (4- (2, 4-difluorophenoxy) -3-methoxy-5- (6-methyl-7-oxo-1-p-toluenesulfonyl-6,7-dihydro-1H-pyrrolo [2, 3-c] pyridin-4-yl) phenyl) -N- (ethylsulfonyl) ethanesulfonamide 2 g (100 mg, brown oil), yield: 100%. MS m / z (ESI): 735.8 [M + 1] Step 7 N- (4- (2,4-difluorophenoxy) -3-methoxy-5- (6-methyl-7- Oxo-6,7-dihydro-1H-pyrrolo [2,3-c] pyridin-4-yl) phenyl) ethanesulfonamide

將N-(4-(2,4-二氟苯氧基)-3-甲氧基-5-(6-甲基-7-氧代-1-對甲苯磺醯基-6,7-二氫-1H-吡咯并[2,3-c]吡啶-4-基)苯基)-N-(乙基磺醯基)乙磺醯胺2g (100 mg, 0.136 mmol)、十六烷基三甲基溴化銨(2.5 mg, 0.0068 mmol)和氫氧化鉀(152 mg, 2.72 mmol)溶於7 mL四氫呋喃/水(V:V = 5:2)中，90℃下反應16小時。在反應液中滴加1N鹽酸水溶液，調節pH至7左右，以乙酸乙酯(10 mL×2)萃取，合併有機相，以無水硫酸鈉乾燥，減壓濃縮，得到的殘留物用矽膠柱層析法(洗脫劑：B體系)純化，得到N-(4-(2,4-二氟苯氧基)-3-甲氧基-5-(6-甲基-7-氧代-6,7-二氫-1H-吡咯并[2,3-c]吡啶-4-基)苯基)乙磺醯胺2 (10 mg，黃色固體)，產率：15%。 MS m/z(ESI)：489.8[M+1]1 H NMR(400 MHz, DMSO-d6): 12.06 (s, 1H), 9.93 (s, 1H), 7.28-7.18 (m, 3H), 7.14-7.13 (m, 2H), 6.78-6.74 (m, 1H), 6.53-6.48 (m, 1H), 6.19 (s, 1H), 3.75 (s, 3H), 3.46 (s, 3H), 3.23-3.17 (m, 2H), 1.27-1.23(m, 3H).生物學評價 測試例 1 、本發明化合物對 BRD4 蛋白活性測定 N- (4- (2,4-difluorophenoxy) -3-methoxy-5- (6-methyl-7-oxo-1-p-toluenesulfonyl-6,7-di Hydrogen-1H-pyrrolo [2,3-c] pyridin-4-yl) phenyl) -N- (ethylsulfonyl) ethanesulfonamide 2g (100 mg, 0.136 mmol), cetyltri Methyl ammonium bromide (2.5 mg, 0.0068 mmol) and potassium hydroxide (152 mg, 2.72 mmol) were dissolved in 7 mL of tetrahydrofuran / water (V: V = 5: 2) and reacted at 90 ° C for 16 hours. A 1N aqueous hydrochloric acid solution was added dropwise to the reaction solution, the pH was adjusted to about 7, and the mixture was extracted with ethyl acetate (10 mL × 2). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Purification (eluent: system B) to obtain N- (4- (2,4-difluorophenoxy) -3-methoxy-5- (6-methyl-7-oxo-6 , 7-dihydro-1H-pyrrolo [2,3-c] pyridin-4-yl) phenyl) ethanesulfonamide 2 (10 mg, yellow solid), yield: 15%. MS m / z (ESI): 489.8 [M + 1] 1 H NMR (400 MHz, DMSO-d6): 12.06 (s, 1H), 9.93 (s, 1H), 7.28-7.18 (m, 3H), 7.14 -7.13 (m, 2H), 6.78-6.74 (m, 1H), 6.53-6.48 (m, 1H), 6.19 (s, 1H), 3.75 (s, 3H), 3.46 (s, 3H), 3.23-3.17 (m, 2H), 1.27-1.23 (m, 3H). Biological evaluation test example 1 , determination of BRD4 protein activity of the compound of the present invention

本發明的示例化合物藉由以下方法測試其針對BRD4蛋白的生物活性。Exemplary compounds of the invention were tested for their biological activity against the BRD4 protein by the following method.

本測試方法採用Cisbio Assays公司的EPIGENEOUS™ BROMODOMAIN ASSAY在體外條件下，測試化合物對重組人源BRD4蛋白與乙醯化組蛋白多肽底物之間基於FRET(螢光能量共振轉移)的相互作用的影響來表述化合物針對BRD4的生物活性。其中GST標記的重組人源BRD4(1/2)蛋白來源於BPS Bioscience，乙醯化組蛋白多肽底物[Lys(5,8,12,16)Ac] H4(1-21)-biotin peptide購於AnaSpec。This test method uses Cisbio Assays' EPIGENEOUS ™ BROMODOMAIN ASSAY to test the effect of compounds on the interaction between recombinant human BRD4 protein and acetylated histone peptide substrates based on FRET (fluorescent energy resonance transfer) under in vitro conditions. To express the biological activity of the compound against BRD4. The GST-labeled recombinant human BRD4 (1/2) protein was derived from BPS Bioscience, and the acetylated histone peptide substrate [Lys (5,8,12,16) Ac] H4 (1-21) -biotin peptide was purchased At AnaSpec.

具體實驗方法和流程可參考EPIGENEOUS™ BROMODOMAIN ASSAY試劑盒說明書，實驗流程簡述如下： 本發明中的化合物先溶解於DMSO中，隨後以試劑盒中提供的緩衝液將其稀釋至測試所需濃度(終濃度範圍10 μM-0.1 nM)。將2 μL化合物加入到384孔微孔板中，隨後分別加入4 uL以緩衝液稀釋的GST標記的重組人源BRD4(1/2)蛋白和4 μL乙醯化組蛋白多肽底物，最後向孔中加入偶聯有銪系元素化合物的抗GST抗體和偶聯有鏈酶親和素的FRET受體d2各5 uL，振盪混勻後以封板膜密封，並在室溫下振盪孵育3～5小時。化合物每個濃度設複孔對照，對照孔和空白孔中加入2 μL DMSO。隨後在相容TF-FRET模式的酶標儀上測定讀取各孔在對應銪系元素激發波長下，發射波長為620 nM和665 nM下的螢光強度。藉由與對照組的螢光強度數值進行比較計算化合物在各濃度點下的抑制率，進而藉由GraphPad Prism 5軟體中以化合物濃度對數-抑制率進行非線性回歸分析並得到化合物抑制BRD4蛋白與乙醯化組蛋白多肽底物相互作用的IC50 值。 表1 本發明示例化合物對BRD4蛋白活性抑制的IC50 資料 結論：本發明的優選化合物對於BRD4蛋白具有較好的抑制作用。 備註：mivebresib的結構式如下式所示，其製備方法參見WO2013097601。 測試例 2 本發明化合物對***癌細胞 (LNCaP) 增殖抑制測定 For specific experimental methods and procedures, refer to the EPIGENEOUS ™ BROMODOMAIN ASSAY kit instruction manual. The experimental procedure is briefly described as follows: The compounds in the present invention are first dissolved in DMSO, and then diluted with the buffer solution provided in the kit to the concentration required for the test ( (Final concentration range 10 μM-0.1 nM). Add 2 μL of the compound to a 384-well microplate, then add 4 uL of GST-labeled recombinant human BRD4 (1/2) protein diluted in buffer and 4 μL of acetylated histone peptide substrate, and finally add Add 5 uL each of anti-GST antibody conjugated to actinide compound and FRET receptor d2 conjugated to streptavidin. After shaking and mixing, seal with sealing membrane and incubate at room temperature for 3 ～ 5 hours. Compounds were set in duplicate wells at each concentration, and 2 μL DMSO was added to the control wells and blank wells. Subsequently, the fluorescence intensity of each well at the emission wavelengths of 620 nM and 665 nM at the excitation wavelength of the actinide element was measured and read on a microplate reader compatible with TF-FRET mode. The inhibition rate of the compound at each concentration point was calculated by comparing the fluorescence intensity values with the control group, and then the non-linear regression analysis of the compound concentration log-inhibition rate in GraphPad Prism 5 software was performed to obtain the compound inhibiting BRD4 protein and acetylated histone peptide substrate interaction IC 50 values. Table 1 IC 50 data for the inhibition of BRD4 protein activity by exemplary compounds of the present invention Conclusion: The preferred compounds of the present invention have good inhibitory effect on BRD4 protein. Note: The structural formula of mivebresib is shown in the following formula, and its preparation method is described in WO2013097601. Test Example 2 Inhibition of Proliferation of Prostate Cancer Cells (LNCaP) by Compounds of the Invention

本發明示例化合物的細胞水準活性藉由CCK-8 (Dojindo，東仁化學科技)以吸光度方法來檢測化合物對細胞增殖的抑制作用。將處於對數生長期的***癌細胞LNCaP (購於中國科學院上海生命科學研究院細胞資源中心)以4000個每孔的密度接種至96孔培養板中，培養過夜後，加入不同濃度的測試化合物(終濃度濃度範圍30 μM～0.1 nM)。在37℃，5％ CO2 條件下培養細胞72小時。培養結束後，向每孔加入適宜體積的CCK-8試劑 (購於東仁化學科技(上海)有限公司，貨號CK04)並在37℃下繼續培養1～5小時，隨後在酶標儀上讀取各孔的在450 nM下的吸光度數值。藉由與對照組的吸光度數值進行比較計算化合物在各濃度點下的抑制率，進而藉由GraphPad Prism 5軟體中以化合物濃度對數-抑制率進行非線性回歸分析並得到化合物抑制細胞增殖的IC50 值。 表2 本發明示例化合物對LNCaP增殖抑制的IC50 資料 The cell-level activity of the exemplified compounds of the present invention was examined by CCK-8 (Dojindo, Dongren Chemical Technology) using an absorbance method to detect the inhibitory effect of the compounds on cell proliferation. Prostate cancer cells LNCaP (purchased from the Cell Resource Center of Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences) were inoculated into 96-well culture plates at a density of 4000 per well, and cultured overnight, then added test compounds of different concentrations ( The final concentration ranges from 30 μM to 0.1 nM). Cells were cultured at 37 ° C, 5% CO 2 for 72 hours. After the incubation, add an appropriate volume of CCK-8 reagent (purchased from Dongren Chemical Technology (Shanghai) Co., Ltd., CK04) to each well and continue incubation at 37 ° C for 1 to 5 hours. Then read on a microplate reader. Take the absorbance of each well at 450 nM. The inhibition rate of the compound at each concentration point was calculated by comparing the absorbance values with the control group, and then the non-linear regression analysis of the compound concentration log-inhibition rate in GraphPad Prism 5 software was performed to obtain the IC 50 of the compound to inhibit cell proliferation. value. Table IC exemplary inventive compound inhibited proliferation of LNCaP 2 50 Data

結論：本發明的示例化合物對於***癌細胞LNCaP增殖具有較好的抑制作用，顯著優於mivebresib。測試例 3 、本發明優選化合物的藥代動力學測試 Conclusion: The exemplary compounds of the present invention have a better inhibitory effect on the proliferation of prostate cancer cells LNCaP, and are significantly better than mivebresib. Test Example 3 , Pharmacokinetic Test of Preferred Compounds of the Invention

1、實驗目的 以SD大鼠為受試動物，採用LC/MS/MS法測定大鼠灌胃給予mivebresib和實施例2化合物後，測定其不同時刻血漿中的藥物濃度，研究本發明化合物在大鼠體內的藥代動力學特徵。 2、實驗方案 2.1實驗藥品與動物 Mivebresib和實施例2化合物； 健康成年SD雄性大鼠6隻，購自維通利華實驗動物技術有限公司，生產許可證號：11400700109943。 2.2藥物配置與給藥 稱取適量的mivebresib和實施例2化合物，加入DMA (二甲基乙醯胺)，超聲至溶液後，加入Solutol HS 15 (30%, w/v, 聚乙二醇-15 羥基硬脂酸酯)和生理鹽水，其中DMA： Solutol HS 15：生理鹽水 = 5:10:85, (v/v/v)，同時渦旋混合，配置成0.6 mg/mL； 健康成年SD雄性大鼠6隻，禁食過夜後分別灌胃給藥，給藥體積5 mL/kg，給藥劑量為3 mg/kg。 2.3操作 於給藥前和給藥後15分鐘、30 分鐘、1小時、2小時、4小時、8小時、12小時和24小時喉部靜脈採血0.15 mL，置於肝素化試管中，5500轉/分鐘，離心10分鐘，於-20℃保存，給藥4小時後進食。用LC-MS/MS法測定不同的化合物灌胃給藥後SD雄性大鼠血漿中的待測化合物的含量。 3、藥代動力學參數結果 本發明的優選化合物的藥代動力學參數如表3所示。 表3 實施例2化合物的藥代動力學資料表 結論：本發明實施例2化合物與mivebresib相比，血藥濃度和曲線下面積較高，半衰期長，滯留時間短，具有明顯的藥代動力學優勢。1. Experimental purpose SD rats were used as test animals. LC / MS / MS method was used to determine the concentration of drug in plasma at different times after intragastric administration of mivebresib and the compound of Example 2 to rats. Pharmacokinetic Characteristics in Rats. 2. Experimental protocol 2.1 Experimental drugs and animals Mivebresib and the compound of Example 2; 6 healthy adult SD male rats, purchased from Weitong Lihua Experimental Animal Technology Co., Ltd., production license number: 11400700109943. 2.2 Drug configuration and administration Weigh appropriate amounts of mivebresib and the compound of Example 2, add DMA (dimethylacetamide), and sonicate to the solution, then add Solutol HS 15 (30%, w / v, polyethylene glycol- 15 hydroxystearate) and physiological saline, where DMA: Solutol HS 15: physiological saline = 5:10:85, (v / v / v), while vortexing, configured to 0.6 mg / mL; healthy adult SD Six male rats were administered intragastrically after fasting overnight, with a dose of 5 mL / kg and a dose of 3 mg / kg. 2.3 Operate 0.15 mL of laryngeal vein blood before and 15 minutes, 30 minutes, 1 hour, 2 hours, 4 hours, 8 hours, 12 hours, and 24 hours after administration, and place it in a heparinized test tube at 5500 rpm / Centrifuge for 10 minutes, store at -20 ° C, and eat 4 hours after administration. LC-MS / MS was used to determine the content of test compounds in SD male rats' plasma after oral administration of different compounds. 3. Results of pharmacokinetic parameters The pharmacokinetic parameters of the preferred compounds of the present invention are shown in Table 3. Table 3 Pharmacokinetic data of the compound of Example 2 Conclusion: Compared with mivebresib, the compound of Example 2 of the present invention has higher plasma concentration and area under the curve, longer half-life, shorter residence time, and has obvious pharmacokinetic advantages.

在本發明提及的所有文獻都在本申請中引用作為參考，就如同每一篇文獻被單獨引用作為參考那樣。此外應理解，在閱讀了本發明的上述公開內容之後，本領域技術人員可以對本發明作各種改動或修改，這些等價形式同樣落於本申請所附申請專利範圍所限定的範圍。All documents mentioned in the present invention are incorporated by reference in this application, as if each document was individually incorporated by reference. In addition, it should be understood that after reading the above disclosure of the present invention, those skilled in the art can make various changes or modifications to the present invention, and these equivalent forms also fall within the scope defined by the scope of the patents attached to this application.

Claims (14)

一種式(I)所示的化合物：包括其立體異構體、互變異構體或其可藥用的鹽， 其中： R1 選自芳基或雜芳基，優選為苯基，其中所述的芳基或雜芳基任選進一步被一個或多個選自羥基、鹵素、硝基、氰基、烷基、環烷基、雜環基、芳基、雜芳基、-NR6 R7 、-C(O)NR6 R7 、-OR8 、-C(O)R8 、-C(O)OR8 或-NR6 C(O)R7 的取代基所取代； R2 和R3 各自獨立地選自氫原子、烷基、氰基、鹵素、環烷基、雜環基、芳基、雜芳基、-NR6 R7 、-C(O)NR6 R7 、-OR8 、-C(O)R8 、-C(O)OR8 或-NR6 C(O)R7 ，其中所述的烷基、環烷基、雜環基、芳基或雜芳基任選進一步被一個或多個選自羥基、鹵素、硝基、氰基、烷基、環烷基、雜環基、芳基、雜芳基、-NR6 R7 、-C(O)NR6 R7 、-OR8 、-C(O)R8 、-C(O)OR8 或-NR6 C(O)R7 的取代基所取代；條件是R2 和R3 至少一個選自-OR8 ； R4 選自氫原子或烷基；優選為甲基或乙基； R5 選自氫原子、烷氧基或鹵素；優選為氫原子； R6 、R7 和R8 各自獨立地選自氫原子、烷基、環烷基、雜環基、芳基或雜芳基，其中所述的烷基、環烷基、雜環基、芳基或雜芳基任選進一步被一個或多個選自羥基、鹵素、硝基、氰基、烷基、烷氧基、環烷基、雜環基、芳基、雜芳基、-NR9 R10 、-C(O)NR9 R10 、-C(O)R11 、-C(O)OR11 或-NR9 C(O)R10 的取代基所取代； 或者，R6 和R7 與相連接的N原子一起形成一個4～8元雜環基，其中4～8元雜環內含有一個或多個N、O、S(O)m 原子，並且4～8元雜環上任選進一步被一個或多個選自羥基、鹵素、硝基、氰基、烷基、烷氧基、環烷基、雜環基、芳基、雜芳基、=O、-NR9 R10 、-C(O)NR9 R10 、-C(O)R11 、-C(O)OR11 或-NR9 C(O)R10 的取代基所取代； R9 、R10 和R11 各自獨立地選自氫原子、烷基、環烷基、雜環基、芳基或雜芳基，其中所述的烷基、環烷基、雜環基、芳基或雜芳基任選進一步被一個或多個選自羥基、鹵素、硝基、氰基、烷基、烷氧基、環烷基、雜環基、芳基、雜芳基、羧基或羧酸酯基的取代基所取代；且 m為0、1或2。A compound represented by formula (I): Including its stereoisomers, tautomers or pharmaceutically acceptable salts thereof, wherein: R 1 is selected from aryl or heteroaryl, preferably phenyl, wherein said aryl or heteroaryl is optionally further Is selected from one or more of hydroxy, halogen, nitro, cyano, alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -NR 6 R 7 , -C (O) NR 6 R 7 , -OR 8 , -C (O) R 8 , -C (O) OR 8 or -NR 6 C (O) R 7 are substituted by a substituent; R 2 and R 3 are each independently selected from a hydrogen atom, an alkane Group, cyano, halogen, cycloalkyl, heterocyclyl, aryl, heteroaryl, -NR 6 R 7 , -C (O) NR 6 R 7 , -OR 8 , -C (O) R 8 , -C (O) OR 8 or -NR 6 C (O) R 7 , wherein said alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally further selected from one or more hydroxyl groups , Halogen, nitro, cyano, alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -NR 6 R 7 , -C (O) NR 6 R 7 , -OR 8 , -C ( O) R 8 , -C (O) OR 8 or -NR 6 C (O) R 7 is substituted by a substituent; provided that at least one of R 2 and R 3 is selected from -OR 8 ; R 4 is selected from a hydrogen atom or alkyl; preferably methyl or ethyl; R 5 is selected from a hydrogen atom Alkoxy or halogen; preferably a hydrogen atom; R 6, R 7 and R 8 are each independently selected from hydrogen atom, alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein the alkoxy Group, cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally further selected from one or more of hydroxy, halogen, nitro, cyano, alkyl, alkoxy, cycloalkyl, heterocyclyl , Aryl, heteroaryl, -NR 9 R 10 , -C (O) NR 9 R 10 , -C (O) R 11 , -C (O) OR 11 or -NR 9 C (O) R 10 Substituted by a substituent; or, R 6 and R 7 together with the connected N atom form a 4- to 8-membered heterocyclic group, wherein the 4- to 8-membered heterocyclic ring contains one or more N, O, S (O) m atom, and optionally a 4- to 8-membered heterocyclic ring further selected from one or more selected from hydroxyl, halogen, nitro, cyano, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, hetero Aryl, = O, -NR 9 R 10 , -C (O) NR 9 R 10 , -C (O) R 11 , -C (O) OR 11 or -NR 9 C (O) R 10 substituted; R 9, R 10 and R 11 are each independently selected from hydrogen atom, alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein said alkyl, cycloalkyl , Heterocyclyl, aryl, or heteroaryl is optionally further selected from one or more of hydroxy, halogen, nitro, cyano, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, hetero Aryl, carboxyl or carboxylate is substituted by a substituent; and m is 0, 1 or 2. 如請求項1所述的化合物，其中R1 為苯基，所述的苯基進一步被一個或多個鹵素所取代，其中所述的鹵素優選為氟。The compound according to claim 1, wherein R 1 is phenyl, said phenyl is further substituted with one or more halogens, wherein said halogens are preferably fluorine. 如請求項1所述的化合物，其中： R2 選自-OR8 ；R3 為氫原子； 或者，R2 為氫原子；R3 選自-OR8 ；且 R8 選自烷基，優選為甲基。The compound according to claim 1, wherein: R 2 is selected from -OR 8 ; R 3 is a hydrogen atom; or, R 2 is a hydrogen atom; R 3 is selected from -OR 8 ; and R 8 is selected from an alkyl group, preferably Is methyl. 如請求項1所述的化合物，其選自：或。The compound of claim 1, which is selected from: or . 一種製備如請求項1所述的式(I)化合物的方法，所述方法包括：使式(Id)化合物與R4 取代的磺醯鹵、優選R4 取代的磺醯氯反應，得到式(Ie)化合物；使式(Ie)化合物在鹼性條件下水解，脫去保護基，得到式(I)化合物； 其中： PG為N的保護基，優選為取代的苯磺醯基，更優選為對甲苯磺醯基； R4 選自烷基；且 R1 ～R3 和R5 的定義如請求項1中所述。A method for preparing a compound of formula (I) according to claim 1, the method comprising: Reacting a compound of formula (Id) with an R 4 substituted sulfonium halide, preferably R 4 substituted sulfonium chloride, to obtain a compound of formula (Ie); subjecting a compound of formula (Ie) to hydrolysis under basic conditions to remove the protecting group, A compound of formula (I) is obtained; wherein: PG is a protecting group of N, preferably substituted benzenesulfonyl, and more preferably p-toluenesulfonyl; R 4 is selected from alkyl; and R 1 to R 3 and R 5 The definition is as described in claim 1. 一種式(Id)所示的化合物：包括其立體異構體、互變異構體或其可藥用的鹽， 其中： PG為N的保護基，優選為取代的苯磺醯基，更優選為對甲苯磺醯基；且 R1 ～R5 的定義如請求項1中所述。A compound represented by formula (Id): Including its stereoisomers, tautomers or pharmaceutically acceptable salts thereof, wherein: PG is a protecting group of N, preferably a substituted benzenesulfonylsulfonyl group, more preferably a p-toluenesulfonylsulfonyl group; and R 1 to R 5 is defined as described in claim 1. 如請求項6所述的化合物，其選自：或。The compound of claim 6, which is selected from: or . 一種製備如請求項6所述的式(Id)化合物的方法，所述方法包括：藉由使式(Ia)化合物的硝基還原得到式(Ib)化合物；使式(Ib)化合物與式(Ic)化合物在鈀催化劑條件下反應，得到式(Id)化合物； 其中： Ra 選自硼酸基或硼酸酯基；所述的硼酸酯基優選為：； PG為N的保護基，優選為取代的苯磺醯基，更優選為對甲苯磺醯基； X選自鹵素，優選為氯或溴；且 R1 ～R5 的定義如請求項1中所述。A method for preparing a compound of formula (Id) according to claim 6, the method comprising: By the formula (Ia) reduction of nitro compounds to give a compound of formula (Ib); formula (Ib) with a compound of formula (Ic) under reaction conditions of a palladium catalyst, to give a compound of formula (Id); wherein: R a is selected from From boric acid group or borate group; the borate group is preferably: PG is a protecting group of N, preferably substituted benzenesulfonyl, more preferably p-toluenesulfonyl; X is selected from halogen, preferably chlorine or bromine; and R 1 to R 5 are defined as in claim 1 As described. 一種藥物組合物，所述的藥物組合物含有有效劑量的如請求項1~4中任一項所述的化合物，及可藥用的載體、賦形劑或它們的組合。A pharmaceutical composition comprising an effective dose of the compound according to any one of claims 1 to 4, and a pharmaceutically acceptable carrier, excipient, or a combination thereof. 一種如請求項1~4中任一項所述的化合物或如請求項9所述的藥物組合物在製備用作溴結構域蛋白抑制劑的藥物中的用途，其中所述的溴結構域蛋白優選為BRD2、BRD3和BRD4，更優選為BRD4。A compound according to any one of claims 1 to 4 or a pharmaceutical composition according to claim 9 for use in preparing a medicament for use as a bromodomain protein inhibitor, wherein the bromodomain protein BRD2, BRD3 and BRD4 are preferred, and BRD4 is more preferred. 一種如請求項1~4中任一項所述的化合物或如請求項9所述的藥物組合物在製備用於治療或預防與溴結構域蛋白相關的疾病的藥物中的用途，其中所述的疾病優選為癌症或炎症；其中所述的炎症優選為類風濕性關節炎、克隆恩病、濕疹、巨細胞性動脈炎、肝炎、炎性腸病、骨關節炎、胰腺炎、肺炎、銀屑病、銀屑病性關節炎、系統性紅斑狼瘡、腎小球性腎炎、狼瘡性腎炎、膜性腎小球腎炎或心肌炎；所述的炎症更優選為類風濕性關節炎。Use of a compound according to any one of claims 1 to 4 or a pharmaceutical composition according to claim 9 in the manufacture of a medicament for treating or preventing a disease associated with a bromodomain protein, wherein The disease is preferably cancer or inflammation; wherein the inflammation is preferably rheumatoid arthritis, Crohn's disease, eczema, giant cell arteritis, hepatitis, inflammatory bowel disease, osteoarthritis, pancreatitis, pneumonia, Psoriasis, psoriatic arthritis, systemic lupus erythematosus, glomerulonephritis, lupus nephritis, membranous glomerulonephritis or myocarditis; the inflammation is more preferably rheumatoid arthritis. 如請求項11所述的用途，其中所述的癌症為小細胞肺癌、非小細胞肺癌、乳腺癌、結直腸癌、***癌、黑色素瘤、胰腺癌、神經膠質瘤、腦瘤、宮頸癌、卵巢癌、胰腺癌、***癌、腎細胞癌、胃癌、膀胱癌、肝癌、睾丸核蛋白中線癌、多發性骨髓瘤、急性髓性白血病、急性淋巴細胞性白血病、慢性淋巴細胞性白血病、慢性髓細胞性白血病或慢性骨髓性白血病。The use according to claim 11, wherein the cancer is small cell lung cancer, non-small cell lung cancer, breast cancer, colorectal cancer, prostate cancer, melanoma, pancreatic cancer, glioma, brain tumor, cervical cancer, Ovarian cancer, pancreatic cancer, prostate cancer, renal cell cancer, gastric cancer, bladder cancer, liver cancer, testicular nucleoprotein midline cancer, multiple myeloma, acute myeloid leukemia, acute lymphocytic leukemia, chronic lymphocytic leukemia, chronic Myeloid leukemia or chronic myelogenous leukemia. 一種如請求項1~4中任一項所述的化合物或如請求項9所述的藥物組合物在製備用於治療或預防糖尿病性腎病、高血壓性腎病、HIV-相關的腎病、多囊性腎病、肥胖、血脂異常、高膽固醇血症、阿爾茨海默病、代謝綜合症、脂肪肝、II型糖尿病、胰島素抵抗、糖尿病性視網膜病或糖尿病性神經病的藥物中的用途。A compound according to any one of claims 1 to 4 or a pharmaceutical composition according to claim 9, which is prepared for treating or preventing diabetic nephropathy, hypertensive nephropathy, HIV-related nephropathy, polycystic Use of medulla nephropathy, obesity, dyslipidemia, hypercholesterolemia, Alzheimer's disease, metabolic syndrome, fatty liver, type II diabetes, insulin resistance, diabetic retinopathy or diabetic neuropathy. 一種治療或預防與溴結構域蛋白相關的疾病的方法，包括向有此需要的物件施用如請求項1至4中任一項所述的化合物或如請求項9所述的藥物組合物。A method for treating or preventing a disease associated with a bromodomain protein, comprising administering a compound according to any one of claims 1 to 4 or a pharmaceutical composition according to claim 9 to an object in need thereof.
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