TWI642667B

TWI642667B - Pyridino pyrimidine derivatives, preparation method and medical use thereof

Info

Publication number: TWI642667B
Application number: TW103115479A
Authority: TW
Inventors: 李心; 孫飄揚; 蘭炯; 彭建彪; 陳陽; 王斌; 董慶
Original assignee: 上海恆瑞醫藥有限公司; 江蘇恆瑞醫藥股份有限公司
Priority date: 2013-05-17
Filing date: 2014-04-30
Publication date: 2018-12-01
Also published as: HK1206025A1; CN104470921A; WO2014183520A1; TW201444838A; CN104470921B

Abstract

本發明涉及吡啶並嘧啶類衍生物、其製備方法及其在醫藥上的應用。具體而言，本發明涉及一種通式(I)所示吡啶並嘧啶類衍生物及其可藥用鹽，其製備方法以及它們作為癌症治療劑特別是作為CDK4和/或CDK6抑制劑的用途，其中通式(I)中的各取代基的定義與說明書中的定義相同。 The invention relates to a pyridopyrimidine derivative, a preparation method thereof and application in medicine. Specifically, the present invention relates to a pyridopyrimidine derivative represented by the general formula (I) and a pharmaceutically acceptable salt thereof, a preparation method thereof, and use thereof as a cancer treatment agent, particularly as a CDK4 and / or CDK6 inhibitor, The definition of each substituent in the general formula (I) is the same as that in the specification.

Description

吡啶並嘧啶類衍生物、其製備方法及其在醫藥上的應用 Pyridopyrimidine derivatives, preparation method and application thereof in medicine

本發明涉及一種新型吡啶並嘧啶類衍生物、其製備方法及含有該衍生物的醫藥組成物，以及其作為癌症治療劑特別是作為CDK4和/或CDK6抑制劑的用途。 The invention relates to a novel pyridopyrimidine derivative, a preparation method thereof, and a pharmaceutical composition containing the derivative, and use thereof as a cancer treatment agent, particularly as a CDK4 and / or CDK6 inhibitor.

大量研究發現腫瘤與細胞週期反常相關，大部分腫瘤都存在有絲***信號蛋白的大量突變/抗有絲***信號蛋白缺陷，基因組不穩定性(GIN)和染色體組不穩定性(CIN)，這三種基本的細胞週期缺陷都直接或間接由細胞週期蛋白依賴性激酶(CDKs)的失控引起。CDK藉由與其調節性亞單元cyclins(細胞週期蛋白)結合發揮作用，而4大類cyclins(A-,B-,D-,E-型cyclins)在整個細胞週期的不同階段發揮其不同的作用，至少有16種哺乳動物細胞週期蛋白已被鑒別。細胞週期蛋白Cyclin B/CDK1、Cyclin A/CDK2、Cyclin E/CDK2、Cyclin D/CDK4、Cyclin D/CDK6和其他雜二聚物(包括CDK3和CDK7)是細胞週期進展的重要調節劑。Cyclin/CDK雜二聚物的另外功能包括對轉錄、DNA修復、分化和細胞程式性死亡的調節。 A large number of studies have found that tumors are abnormally related to the cell cycle. Most tumors have a large number of mutations in mitotic signal proteins / deficient mitotic signal protein defects, genomic instability (GIN) and genomic instability (CIN). These three basic cells Cycle defects are caused directly or indirectly by the loss of cyclin-dependent kinases (CDKs). CDK works by binding to its regulatory subunit cyclins (cyclin), and the four major types of cyclins (A-, B-, D-, E-type cyclins) play different roles at different stages of the entire cell cycle. At least 16 mammalian cyclins have been identified. Cyclin B / CDK1, Cyclin A / CDK2, Cyclin E / CDK2, Cyclin D / CDK4, Cyclin D / CDK6 and other heterodimers (including CDK3 and CDK7) are important regulators of cell cycle progression. Additional functions of Cyclin / CDK heterodimers include regulation of transcription, DNA repair, differentiation, and programmed cell death.

研究顯示細胞週期蛋白依賴性激酶的活性增加或者活化異常會導致人類腫瘤的形成。事實上，人類腫瘤的形成普遍與CDK蛋白本身或其調節劑的改變有關。體外實驗發現天然存在的CDK的蛋白質抑制劑例如p16和p27能夠抑制肺癌細胞系的生長。 Studies show increased cyclin-dependent kinase activity or Abnormal activation can lead to the formation of human tumors. In fact, the formation of human tumors is generally related to changes in the CDK protein itself or its regulators. In vitro experiments have found that protein inhibitors of naturally occurring CDKs such as p16 and p27 can inhibit the growth of lung cancer cell lines.

研究發現，CDK4和CDK6高度同源，CDK4單基因剔除老鼠存在糖尿病徴和細胞缺陷，CDK6單基因敲除老鼠因造血細胞增值缺陷導致輕微的貧血症狀，而CDK4和CDK6(CDK4/6)雙基因敲除則會使造血前體細胞增殖能力受損，導致雙敲除老鼠胚胎晚期的死亡。在腫瘤細胞中，普遍發現CDK4/6-cyclin D/Rb信號通路的超活化。在胞內外各種有絲***信號刺激下，cyclin D高表達，調節CDK4/6蛋白與cyclin D的相互作用，促進CDK4/6的定位和激酶活性。啟動的CDK4/6藉由磷酸化抑制Rb腫瘤抑制蛋白的活性，使Rb-E2F複合物解離，釋放游離的E2F入核，調節蛋白轉錄，啟動細胞週期的進行。在上皮細胞惡性腫瘤中常發現CDK4的超活化，而間質細胞腫瘤如肉瘤和血液性癌症中常發現CDK6的超活化。構建乳腺癌荷瘤鼠模型發現，野生型裸鼠全部成瘤，而CDK4剔除裸鼠完全無法成瘤；而用anti-CDK4 siRNA干擾CDK4的表達，則發現裸鼠的腫瘤生長顯著受抑制。 The study found that CDK4 and CDK6 are highly homologous. CDK4 single-gene knockout mice have diabetic crests and cell defects. CDK6 single-gene knockout mice have mild anemia symptoms due to defects in hematopoietic cell proliferation. Knockout will impair the proliferation ability of hematopoietic precursor cells, leading to late death of double-knockout embryos. In tumor cells, the CDK4 / 6-cyclin D / Rb signaling pathway is commonly found to be over-activated. Under the stimulation of various mitotic signals inside and outside the cell, cyclin D is highly expressed, which regulates the interaction between CDK4 / 6 protein and cyclin D, and promotes the localization of CDK4 / 6 and kinase activity. The activated CDK4 / 6 inhibits the activity of Rb tumor suppressor protein by phosphorylation, dissociates the Rb-E2F complex, releases free E2F into the nucleus, regulates protein transcription, and initiates the cell cycle. CDK4 hyperactivation is often found in epithelial malignant tumors, while CDK6 hyperactivation is often found in mesenchymal tumors such as sarcomas and hematological cancers. Constructing a breast cancer tumor-bearing mouse model found that all wild-type nude mice formed tumors, but CDK4 eliminated nude mice could not form tumors at all; and anti-CDK4 siRNA interfered with CDK4 expression, and found that tumor growth of nude mice was significantly inhibited.

除了抑制腫瘤的生長，小分子CDK抑制劑也可以用於治療心血管障礙，例如再狹窄和動脈粥樣硬化和其他由異常細胞增殖引起的血管障礙；用於治療由多種感染劑導致的疾病，包括真菌、原生動物寄生蟲(例如惡性瘧原蟲)和DNA與RNA病毒；還可用於改善各種自身免疫障礙，研究發現，在關節炎的大鼠模型中，關節腫脹基本上被p16表達性腺病毒處理所抑制，CDK抑制劑可以有效對抗其他細胞增殖障礙，包括牛皮癖(以角質形成細胞過度增殖為特徵)、腎小球性腎炎和狼瘡。 In addition to inhibiting tumor growth, small molecule CDK inhibitors can also be used to treat cardiovascular disorders such as restenosis and atherosclerosis and other vascular disorders caused by abnormal cell proliferation; for the treatment of diseases caused by various infectious agents, Including fungi, protozoan parasites (such as Plasmodium falciparum), and DNA and RNA viruses; it can also be used to improve various autoimmune disorders. Studies have found that in rat models of arthritis, joint swelling is largely p16-expressing adenovirus CDK inhibition The formulation is effective against other cell proliferation disorders, including psoriasis (characterized by excessive proliferation of keratinocytes), glomerulonephritis and lupus.

研究發現，在細胞週期中，G1/S轉換期和G2/M期細胞對DNA損傷劑如電離輻射(IR)極為敏感，而細胞從G1期向S期轉換的過程至少需要藉由3種細胞週期蛋白依賴性激酶(CDK2、CDK4和CDK6)及其調節性亞單元cyclins共同磷酸化Rb家族蛋白進行調節。選擇性CDK4/6抑制劑可以誘導細胞G1期阻滯，進而提高造血乾/祖細胞對DNA損傷劑如IR的耐受性，有效減少由輻射引起的各種造血毒性，包括骨髓抑制、嗜中性白血球減少症、白細胞減少症、貧血等。 Studies have found that during the cell cycle, G1 / S transition and G2 / M cells are extremely sensitive to DNA damaging agents such as ionizing radiation (IR), and the process of cell transition from G1 to S phase requires at least three types of cells Cyclin-dependent kinases (CDK2, CDK4, and CDK6) and their regulatory subunit cyclins co-phosphorylate Rb family proteins for regulation. Selective CDK4 / 6 inhibitors can induce G1 phase arrest of cells, thereby increasing the tolerance of hematopoietic stem / progenitor cells to DNA-damaging agents such as IR, and effectively reducing various hematopoietic toxicity caused by radiation, including bone marrow suppression, neutrophil Leukopenia, leukopenia, anemia, etc.

目前，小分子CDK抑制劑很難鑒別只特異性抑制CDK蛋白而不抑制其他酶的化合物。因而，儘管具有治療多種疾病的潛力，CDK抑制劑目前尚未獲得批准用於商業目的。 At present, small molecule CDK inhibitors are difficult to identify compounds that specifically inhibit only the CDK protein and not other enzymes. Thus, despite its potential to treat multiple diseases, CDK inhibitors are currently not approved for commercial purposes.

近幾年各大公司分別鑒定發現了一系列選擇性抑制CDK4和CDK6的抑制劑，用於治療癌症，心血管障礙及炎症等疾病。目前有3個特異性抑制CDK4和CDK6的小分子化合物進入臨床，分別是Pfizer和Onyx製藥公司的PD-0332991(臨床三期)、Eli Lilly的LY-2835219(臨床二期)和Novartis的LEE-011(臨床一期)。PD-0332991藉由抑制CDK4和CDK6的活性，抑制Rb的磷酸化，使E2F-Rb複合物留滯在胞漿中，阻斷細胞週期的啟動。臨床試驗結果顯示，來曲唑單藥治療的患者的無進展存活期(Progression-free survival,PFS)為7.5月，而來曲唑和PD-0332991藥物聯用治療的患者其無進展存活期則延長至26.1月。 In recent years, major companies have identified a series of inhibitors that selectively inhibit CDK4 and CDK6, and are used to treat cancer, cardiovascular disorders and inflammation. There are currently three small molecule compounds that specifically inhibit CDK4 and CDK6 entering the clinic, namely PD-0332991 (Phase III) from Pfizer and Onyx Pharmaceuticals, LY-2835219 (Phase II) from Eli Lilly, and LEE- 011 (Clinical Phase I). PD-0332991 inhibits the activity of CDK4 and CDK6, inhibits the phosphorylation of Rb, makes the E2F-Rb complex stay in the cytoplasm, and blocks the start of the cell cycle. The results of clinical trials show that Letrozole monotherapy patients have Progression-free survival (PFS) of 7.5 months, while patients treated with Letrozole and PD-0332991 drugs have no progression survival Extend to 26.1 months.

公開的選擇性抑制CDK4和CDK6的抑制劑專利申請包括WO2003062236、WO2006008874、WO2009126584、WO2010075074、WO2011101409、和WO2012129344等。 Published patent application for inhibitors that selectively inhibit CDK4 and CDK6 Please include WO2003062236, WO2006008874, WO2009126584, WO2010075074, WO2011101409, and WO2012129344.

為了達到更好的腫瘤治療效果的目的，更好的滿足市場需求，我們希望能開發出新一代的高效低毒的選擇性CDK4和CDK6抑制劑。本發明將提供一種新型結構的選擇性CDK4和CDK6抑制劑，並發現具有此類結構的化合物表現出優異的效果和作用，特別是優異的藥物代謝吸收活性。 In order to achieve better tumor treatment effect and better meet market demand, we hope to develop a new generation of high-efficiency and low-toxicity selective CDK4 and CDK6 inhibitors. The present invention will provide a novel structure of selective CDK4 and CDK6 inhibitors, and it is found that compounds having such structures exhibit excellent effects and effects, especially excellent drug metabolism absorption activity.

本發明的目的在於提供一種通式(I)所示的化合物或其互變異構體、內消旋體、外消旋體、對映異構體、非對映異構體或其混合物形式，或其可藥用鹽：其中：為單鍵或雙鍵；A¹或A²各自獨立地選自-CR’或N；R’選自氫原子、鹵素、氰基、硝基、烷基、鹵烷基、羥烷基或烷氧基；Y選自S或O；R¹選自氫原子、鹵素、烷基、鹵烷基、羥烷基或環烷基； R²選自氫原子、鹵素、氰基、硝基、烷基、烯基、炔基、環烷基、雜環烷基、芳基、雜芳基、-OR⁷、-C(O)R⁷、-C(O)OR⁷、或-OC(O)R⁷，其中該烷基、烯基、炔基、環烷基、雜環烷基、芳基或雜芳基各自獨立地視需要進一步被一個或多個選自鹵素、氰基、硝基、胺基、羥基、側氧基、烷基、鹵烷基、羥烷基、烷氧基、環烷基、雜環烷基、芳基、雜芳基、羧基或羧酸酯基的取代基所取代；R³選自氫原子、烷基、環烷基、雜環烷基、芳基或雜芳基，其中該烷基、環烷基、雜環烷基、芳基或雜芳基各自獨立地視需要進一步被一個或多個選自鹵素、氰基、硝基、胺基、羥基、側氧基、烷基、鹵烷基、羥烷基、烷氧基、環烷基、雜環烷基、芳基、雜芳基、羧基或羧酸酯基的取代基所取代；R⁴選自氫原子、烷基、烯基、炔基、環烷基、雜環烷基、芳基、雜芳基、-OR⁷、-C(O)R⁷或-C(O)OR⁷，其中該烷基、烯基、炔基、環烷基、雜環烷基、芳基或雜芳基各自獨立地視需要進一步被一個或多個選自鹵素、氰基、硝基、胺基、羥基、側氧基、烷基、鹵烷基、羥烷基、烷氧基、環烷基、雜環烷基、芳基、雜芳基、羧基或羧酸酯基的取代基所取代；R⁵或R⁶各自獨立地選自氫原子、鹵素、氰基、硝基、側氧基、烷基、烯基、炔基、環烷基、雜環烷基、芳基、雜芳基、-OR⁷、-C(O)R⁷、-C(O)OR⁷或-OC(O)R⁷，其中該烷基、烯基、炔基、環烷基、雜環烷基、芳基或雜芳基各自獨立地視需要進一步被一個或多個選自鹵素、氰基、硝基、胺基、羥基、側氧基、烷基、鹵烷基、羥烷基、烷氧基、環烷基、雜環烷基、芳基、雜芳基、羧基或羧酸酯基的取代基所取代；R⁷選自氫原子、烷基、羥基、鹵素、烷氧基、環烷基、雜環烷基、芳基或雜芳基，其中該烷基、烷氧基、環烷基、雜環烷基、芳基或雜芳基各自獨立地視需要進一步被一個或多個選自鹵素、氰基、硝基、胺基、羥基、側氧基、烷基、鹵烷基、羥烷基、烷氧基、環烷基、雜環烷基、芳基、雜芳基、羧基或羧酸酯基的取代基所取代。 The object of the present invention is to provide a compound represented by the general formula (I) or a tautomer, a racemate, a racemate, an enantiomer, a diastereomer or a mixture thereof, Or a pharmaceutically acceptable salt thereof: among them: Is a single or double bond; A ¹ or A ² are each independently selected from -CR 'or N; R' is selected from a hydrogen atom, halogen, cyano, nitro, alkyl, haloalkyl, hydroxyalkyl, or alkane Oxygen; Y is selected from S or O; R ^{1 is} selected from hydrogen atom, halogen, alkyl, haloalkyl, hydroxyalkyl or cycloalkyl; R ^{2 is} selected from hydrogen atom, halogen, cyano, nitro, alkane Group, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, -OR ⁷ , -C (O) R ⁷ , -C (O) OR ⁷ , or -OC (O) R ⁷ , wherein the alkyl group, alkenyl group, alkynyl group, cycloalkyl group, heterocycloalkyl group, aryl group or heteroaryl group are each independently further selected from one or more selected from halogen, cyano, nitro, Substituents for amino, hydroxy, pendant, alkyl, haloalkyl, hydroxyalkyl, alkoxy, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, carboxyl or carboxylate substituents Substitution; R ^{3 is} selected from a hydrogen atom, an alkyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, or a heteroaryl group, wherein the alkyl group, the cycloalkyl group, the heterocycloalkyl group, the aryl group, or the heteroaryl group are each independently If necessary, it is further selected from one or more of halogen, cyano, nitro, amine, hydroxyl, and pendant oxygen. Substituted with alkyl, alkyl, haloalkyl, hydroxyalkyl, alkoxy, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, carboxy, or carboxylate substituents; R ^{4 is} selected from hydrogen Atom, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, -OR ⁷ , -C (O) R ⁷ or -C (O) OR ⁷ , wherein the alkane Group, alkenyl group, alkynyl group, cycloalkyl group, heterocycloalkyl group, aryl group or heteroaryl group are each independently further optionally selected from one or more of halogen, cyano, nitro, amine, hydroxyl, pendant Substituted with an oxy, alkyl, haloalkyl, hydroxyalkyl, alkoxy, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, carboxyl, or carboxylate substituent; R ⁵ or R ⁶ are each independently selected from a hydrogen atom, halogen, cyano, nitro, pendant oxy, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, -OR ⁷ , -C (O) R ⁷ , -C (O) OR ⁷ or -OC (O) R ⁷ , wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl group Each independently is further optionally selected from one or more of halogen, cyano, nitro, amine, hydroxyl, pendant , Alkyl, haloalkyl, hydroxyalkyl, alkoxy, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, carboxy, or carboxylate substituents; R ^{7 is} selected from a hydrogen atom , Alkyl, hydroxy, halogen, alkoxy, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein the alkyl, alkoxy, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl The aryl groups are each independently further optionally selected from one or more of halogen, cyano, nitro, amine, hydroxyl, pendant oxygen, alkyl, haloalkyl, hydroxyalkyl, alkoxy, cycloalkyl , Heterocycloalkyl, aryl, heteroaryl, carboxyl or carboxylate.

在本發明一個較佳的實施方案中，一種通式(I)所示的化合物或其互變異構體、內消旋體、外消旋體、對映異構體、非對映異構體或其混合物形式，或其可藥用鹽，其中A¹或A²各自獨立地為-CH。 In a preferred embodiment of the present invention, a compound represented by the general formula (I) or a tautomer, a racemate, a racemate, an enantiomer, a diastereomer Or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein A ¹ or A ² are each independently -CH.

在本發明一個較佳的實施方案中，一種通式(I)所示的化合物或其互變異構體、內消旋體、外消旋體、對映異構體、非對映異構體或其混合物形式，或其可藥用鹽，其中Y為O。 In a preferred embodiment of the present invention, a compound represented by the general formula (I) or a tautomer, a racemate, a racemate, an enantiomer, a diastereomer Or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein Y is O.

在本發明一個較佳的實施方案中，一種通式(I)所示的化合物或其互變異構體、內消旋體、外消旋體、對映異構體、非對映異構體或其混合物形式，或其可藥用鹽，其中R¹為烷基。 In a preferred embodiment of the present invention, a compound represented by the general formula (I) or a tautomer, a racemate, a racemate, an enantiomer, a diastereomer Or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R ¹ is an alkyl group.

在本發明一個較佳的實施方案中，一種通式(I)所示的化合物或其互變異構體、內消旋體、外消旋體、對映異構體、非對映異構體或其混合物形式，或其可藥用鹽，其中R¹為甲基。 In a preferred embodiment of the present invention, a compound represented by the general formula (I) or a tautomer, a racemate, a racemate, an enantiomer, a diastereomer Or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R ¹ is methyl.

在本發明一個較佳的實施方案中，一種通式(I)所示的化合物或其互變異構體、內消旋體、外消旋體、對映異構體、非對映異構體或其混合物形式，或其可藥用鹽，其中R²為-C(O)R⁷；且R⁷為烷基。 In a preferred embodiment of the present invention, a compound represented by the general formula (I) or a tautomer, a racemate, a racemate, an enantiomer, a diastereomer Or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R ² is -C (O) R ⁷ ; and R ⁷ is an alkyl group.

在本發明一個較佳的實施方案中，一種通式(I)所示的化合物或其互變異構體、內消旋體、外消旋體、對映異構體、非對映異構體或其混合物形式，或其可藥用鹽，其中R²為-C(O)R⁷；且R⁷為甲基。 In a preferred embodiment of the present invention, a compound represented by the general formula (I) or a tautomer, a racemate, a racemate, an enantiomer, a diastereomer Or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R ² is -C (O) R ⁷ ; and R ⁷ is methyl.

在本發明一個較佳的實施方案中，一種通式(I)所示的化合物或其互變異構體、內消旋體、外消旋體、對映異構體、非對映異構體或其混合物形式，或其可藥用鹽，其中R³為環烷基。 In a preferred embodiment of the present invention, a compound represented by the general formula (I) or a tautomer, a racemate, a racemate, an enantiomer, a diastereomer Or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R ³ is a cycloalkyl group.

在本發明一個較佳的實施方案中，一種通式(I)所示的化合物或其互變異構體、內消旋體、外消旋體、對映異構體、非對映異構體或其混合物形式，或其可藥用鹽，其中R³為環戊基。 In a preferred embodiment of the present invention, a compound represented by the general formula (I) or a tautomer, a racemate, a racemate, an enantiomer, a diastereomer Or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R ³ is cyclopentyl.

在本發明一個較佳的實施方案中，一種通式(I)所示的化合物或其互變異構體、內消旋體、外消旋體、對映異構體、非對映異構體或其混合物形式，或其可藥用鹽，其中R⁵或R⁶各自獨立地選自氫原子、鹵素、烷基或羥基。 In a preferred embodiment of the present invention, a compound represented by the general formula (I) or a tautomer, a racemate, a racemate, an enantiomer, a diastereomer Or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R ⁵ or R ⁶ are each independently selected from a hydrogen atom, a halogen, an alkyl group, or a hydroxyl group.

在本發明一個較佳的實施方案中，一種通式(I)所示的化合物或其互變異構體、內消旋體、外消旋體、對映異構體、非對映異構體或其混合物形式，或其可藥用鹽，其中R⁴選自氫原子或烷基，其中該烷基視需要進一步被一個或多個選自鹵素、羥基或環烷基的取代基所取代。 In a preferred embodiment of the present invention, a compound represented by the general formula (I) or a tautomer, a racemate, a racemate, an enantiomer, a diastereomer Or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R ^{4 is} selected from a hydrogen atom or an alkyl group, wherein the alkyl group is further optionally substituted with one or more substituents selected from a halogen group, a hydroxyl group, or a cycloalkyl group.

在本發明一個較佳的實施方案中，一種通式(I)所示的化合物或其互變異構體、內消旋體、外消旋體、對映異構體、非對映異構體或其混合物形式，或其可藥用鹽，其為通式(II)所示的化合物或其互變異構體、內消旋體、外消旋體、對映異構體、非對映異構體或其混合物形式，或其可藥用鹽：其中：，R¹至R⁶的定義如通式(I)中所定義。 In a preferred embodiment of the present invention, a compound represented by the general formula (I) or a tautomer, a racemate, a racemate, an enantiomer, a diastereomer Or a mixture thereof, or a pharmaceutically acceptable salt thereof, which is a compound represented by the general formula (II) or a tautomer, meso, racemate, enantiomer, diastereomer The structure or a mixture thereof, or a pharmaceutically acceptable salt thereof: wherein: R ¹ to R ⁶ are as defined in the general formula (I).

在本發明一個較佳的實施方案中，一種通式(I)所示的化合物或其互變異構體、內消旋體、外消旋體、對映異構體、非對映異構體或其混合物形式，或其可藥用鹽，其為通式(III)所示的化合物或其互變異構體、內消旋體、外消旋體、對映異構體、非對映異構體或其混合物形式，或其可藥用鹽：其中，R¹至R⁶的定義如通式(I)中所定義。 In a preferred embodiment of the present invention, a compound represented by the general formula (I) or a tautomer, a racemate, a racemate, an enantiomer, a diastereomer Or a mixture thereof, or a pharmaceutically acceptable salt thereof, which is a compound represented by the general formula (III) or a tautomer, meso, racemate, enantiomer, diastereomer Structure or mixture thereof, or a pharmaceutically acceptable salt thereof: Here, the definitions of R ¹ to R ⁶ are as defined in the general formula (I).

本發明典型的化合物包括，但不限於：或其互變異構體、內消旋體、外消旋體、對映異構體、非對映異構體或其混合物形式，或其可藥用鹽。 Typical compounds of the invention include, but are not limited to: Or a tautomer, a racemate, a racemate, an enantiomer, a diastereomer or a mixture thereof, or a pharmaceutically acceptable salt thereof.

本發明還提供一種通式(I-C)所示的化合物或其互變異構體、內消旋體、外消旋體、對映異構體、非對映異構體或其混合物形式，可用作合成或進一步合成通式(I)所示的化合物或其互變異構體、內消旋體、外消旋體、對映異構體、非對映異構體的中間體：其中：為單鍵或雙鍵；Boc為第三丁氧羰基；R為烷基；A¹或A²各自獨立地選自-CR’或N；R’選自氫原子、鹵素、氰基、硝基、烷基、鹵烷基、羥烷基或烷氧基；Y選自S或O； R¹選自氫原子、鹵素、烷基、鹵代烷基、羥烷基或環烷基；R³選自氫原子、烷基、環烷基、雜環烷基、芳基或雜芳基，其中該烷基、環烷基、雜環烷基、芳基或雜芳基各自獨立地視需要進一步被一個或多個選自鹵素、氰基、硝基、胺基、羥基、側氧基、烷基、鹵烷基、羥烷基、烷氧基、環烷基、雜環烷基、芳基、雜芳基、羧基或羧酸酯基的取代基所取代；R⁵或R⁶各自獨立地選自氫原子、鹵素、氰基、硝基、側氧基、烷基、烯基、炔基、環烷基、雜環烷基、芳基、雜芳基、-OR⁷、-C(O)R⁷、-C(O)OR⁷或-OC(O)R⁷，其中該烷基、烯基、炔基、環烷基、雜環烷基、芳基或雜芳基各自獨立地視需要進一步被一個或多個選自鹵素、氰基、硝基、胺基、羥基、側氧基、烷基、鹵烷基、羥烷基、烷氧基、環烷基、雜環烷基、芳基、雜芳基、羧基或羧酸酯基的取代基所取代；R⁷選自氫原子、烷基、羥基、鹵素、烷氧基、環烷基、雜環烷基、芳基或雜芳基，其中該烷基、烷氧基、環烷基、雜環烷基、芳基或雜芳基各自獨立地視需要進一步被一個或多個選自鹵素、氰基、硝基、胺基、羥基、側氧基、烷基、鹵烷基、羥烷基、烷氧基、環烷基、雜環烷基、芳基、雜芳基、羧基或羧酸酯基的取代基所取代。 The present invention also provides a compound represented by the general formula (IC) or a tautomer, a racemate, a racemate, an enantiomer, a diastereomer or a mixture thereof. To synthesize or further synthesize the compound represented by general formula (I) or its tautomer, meso, racemate, enantiomer, diastereomer intermediate: among them: Is a single or double bond; Boc is a third butoxycarbonyl group; R is an alkyl group; A ¹ or A ^{2 is} each independently selected from -CR 'or N; R' is selected from a hydrogen atom, a halogen, a cyano group, and a nitro group , Alkyl, haloalkyl, hydroxyalkyl or alkoxy; Y is selected from S or O; R ^{1 is} selected from hydrogen atom, halogen, alkyl, haloalkyl, hydroxyalkyl or cycloalkyl; R ^{3 is} selected from A hydrogen atom, an alkyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, or a heteroaryl group, wherein the alkyl group, the cycloalkyl group, the heterocycloalkyl group, the aryl group, or the heteroaryl group are each further independently Or more selected from halogen, cyano, nitro, amine, hydroxyl, pendant oxy, alkyl, haloalkyl, hydroxyalkyl, alkoxy, cycloalkyl, heterocycloalkyl, aryl, hetero Substituted by aryl, carboxyl or carboxylate substituents; R ⁵ or R ⁶ are each independently selected from hydrogen atom, halogen, cyano, nitro, pendant oxygen, alkyl, alkenyl, alkynyl, ring Alkyl, heterocycloalkyl, aryl, heteroaryl, -OR ⁷ , -C (O) R ⁷ , -C (O) OR ⁷ or -OC (O) R ⁷ , wherein the alkyl, alkenyl , Alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl are each independently further One or more selected from halogen, cyano, nitro, amine, hydroxyl, pendant oxy, alkyl, haloalkyl, hydroxyalkyl, alkoxy, cycloalkyl, heterocycloalkyl, aryl, Substituted by a substituent of a heteroaryl, carboxyl or carboxylate group; R ^{7 is} selected from a hydrogen atom, an alkyl group, a hydroxyl group, a halogen, an alkoxy group, a cycloalkyl group, a heterocycloalkyl group, an aryl group or a heteroaryl group, Wherein the alkyl, alkoxy, cycloalkyl, heterocycloalkyl, aryl or heteroaryl are each independently further optionally selected from one or more of halogen, cyano, nitro, amine, hydroxyl, Substituted by a substituent of a pendant oxygen, alkyl, haloalkyl, hydroxyalkyl, alkoxy, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, carboxyl or carboxylate group.

在本發明一個較佳的實施方案中，一種通式(I-C)所示的化合物或其互變異構體、內消旋體、外消旋體、對映異構體、非對映異構體或其混合物形式，或其可藥用鹽，其中R為丁基。 In a preferred embodiment of the present invention, a compound represented by the general formula (IC) or a tautomer, meso, racemate, enantiomer, diastereomer Or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R is butyl.

本發明還提供一種製備通式(I)所示的化合物或其互變異構體、內消旋體、外消旋體、對映異構體、非對映異構體或其混合物形式，或其可藥用鹽的方法，該方法包括： The present invention also provides a compound represented by the general formula (I) or a tautomer, a racemate, a racemate, an enantiomer, a diastereomer or a mixture thereof, or A method for pharmaceutically acceptable salts thereof, the method comprising:

通式(I-A)化合物與通式(I-B)化合物在鹼性條件下，視需要在催化劑作用下進行取代反應得到通式(I-C)化合物；通式(I-C)化合物在溶劑中，酸性條件下，進行脫保護反應，視需要進一步進行取代反應，得到通式(I)化合物；其中：X為鹵素；Boc為第三丁氧羰基；R如通式(I-C)中所定義；，A¹，A²，Y，R¹至R⁶的定義如通式(I)中所定義；R⁴較佳為氫原子或烷基，其中該烷基視需要進一步被一個或多個選自鹵素、羥基或環烷基的取代基所取代。 The compound of the general formula (IA) and the compound of the general formula (IB) are subjected to a substitution reaction under the action of a catalyst under basic conditions to obtain a compound of the general formula (IC); the compound of the general formula (IC) is in a solvent under acidic conditions. A deprotection reaction is performed, and a substitution reaction is further performed as necessary to obtain a compound of the general formula (I); wherein: X is a halogen; Boc is a third butoxycarbonyl group; R is as defined in the general formula (IC); , A ¹ , A ² , Y, R ¹ to R ⁶ are as defined in the general formula (I); R ^{4 is} preferably a hydrogen atom or an alkyl group, wherein the alkyl group is further selected by one or more as necessary. Substituted by a substituent from halogen, hydroxy or cycloalkyl.

本發明進一步涉及一種醫藥組成物，該醫藥組成物含有治療有效量的通式(I)所示的化合物或其互變異構體、內消旋體、外消旋體、對映異構體、非對映異構體或其混合物形式，或其可藥用鹽，以及一種或多種藥學上可接受的載體、稀釋劑或賦形劑。 The invention further relates to a pharmaceutical composition containing a therapeutically effective amount of a compound represented by the general formula (I) or a tautomer, a racemate, a racemate, an enantiomer, Diastereomers or mixtures thereof, or pharmaceutically acceptable salts thereof, and one or more pharmaceutically acceptable carriers, diluents or excipients.

本發明進一步涉及通式(I)所示的化合物或其互變異構體、內消旋體、外消旋體、對映異構體、非對映異構體或其混合物形式，或其可藥用鹽，或包含其的醫藥組成物在製備抑制 CDK4和/或CDK6的藥物中的用途。 The present invention further relates to a compound represented by the general formula (I) or a tautomer, a racemate, a racemate, an enantiomer, a diastereomer or a mixture thereof, or a compound thereof Pharmaceutical salts, or pharmaceutical compositions containing the same Use of CDK4 and / or CDK6 in medicine.

本發明進一步涉及通式(I)所示的化合物或其互變異構體、內消旋體、外消旋體、對映異構體、非對映異構體或其混合物形式，或其可藥用鹽，或包含其的醫藥組成物在製備治療異常細胞增殖性疾病、感染(例如病毒感染，如皰疹、HIV，真菌感染等)、炎性病症(例如類風濕性關節炎、骨關節炎等)、自身免疫性疾病(例如牛皮癬、狼瘡、I型糖尿病、糖尿病性腎病、多發性硬化、腎小球性腎炎等)、心血管疾病(例如心肌梗塞、中風、動脈粥樣硬化、手術後血管狹窄、再狹窄等)或神經變性疾病(例如阿爾茨海默氏病、帕金森病等)的藥物中的用途，其中該異常細胞增殖性疾病可以為癌症(如下所定義)。 The present invention further relates to a compound represented by the general formula (I) or a tautomer, a racemate, a racemate, an enantiomer, a diastereomer or a mixture thereof, or a compound thereof Pharmaceutical salts, or pharmaceutical compositions containing them, are being prepared to treat abnormal cell proliferative diseases, infections (such as viral infections such as herpes, HIV, fungal infections, etc.), inflammatory conditions (such as rheumatoid arthritis, bone and joints) Inflammation), autoimmune diseases (such as psoriasis, lupus, type I diabetes, diabetic nephropathy, multiple sclerosis, glomerulonephritis, etc.), cardiovascular diseases (such as myocardial infarction, stroke, atherosclerosis, surgery Post-vascular stenosis, restenosis, etc.) or neurodegenerative diseases (such as Alzheimer's disease, Parkinson's disease, etc.), wherein the abnormal cell proliferative disease can be cancer (as defined below).

本發明進一步涉及通式(I)所示的化合物或其互變異構體、內消旋體、外消旋體、對映異構體、非對映異構體或其混合物形式，或其可藥用鹽，或包含其的醫藥組成物在製備治療癌症的藥物中的用途，其中該癌症選自乳腺癌、卵巢癌、***癌、黑色素瘤、腦瘤(例如具有惡性的星形神經膠質和少突神經膠質細胞瘤成分的神經膠質瘤等)、食管癌、胃癌、肝癌、胰腺癌、結腸直腸癌(例如結腸癌、直腸癌等)、肺癌(例如非小細胞肺癌、小細胞肺癌、原發或轉移性鱗狀癌等)、腎癌、皮膚癌、成膠質細胞瘤、神經母細胞瘤、肉瘤、脂肪肉瘤、骨軟骨瘤、骨瘤、骨肉瘤、精原細胞瘤、睾丸腫瘤、子宮癌(例如子宮頸癌、子宮內膜癌等)、頭頸腫瘤(例如上頜骨癌、喉癌、咽癌、舌癌、口內癌等)、多發性骨髓瘤、惡性淋巴瘤(例如網狀細胞肉瘤、淋巴肉瘤、霍奇金淋巴瘤、套細胞淋巴瘤等)、真性紅細胞增多症、白血病(例如急性粒細胞白血病、慢性粒細胞白血病、急性淋巴細胞白血病、慢性淋巴細胞白血病等)、甲狀腺腫瘤、輸尿管腫瘤、膀胱腫瘤、膽囊癌、膽管癌、絨毛膜上皮癌或兒科腫瘤(例如尤因家族性肉瘤、維爾姆斯肉瘤、橫紋肌肉瘤、血管肉瘤、胚胎睾丸癌、成神經細胞瘤、視網膜母細胞瘤、肝胚細胞瘤、腎母細胞瘤等)等；其中該藥物可以進一步與另外一種或多種抗癌劑聯合應用，該抗癌劑選自烷化劑(例如環磷醯胺、異環磷醯胺、美法侖、白消安、尼莫司丁、雷莫司汀、達卡巴嗪、替莫唑胺、鹽酸氮芥、二溴甘露醇等)、鉑絡合劑(例如順鉑、卡鉑、奧沙利鉑等)、代謝拮抗劑(例如甲氨蝶呤、5-氟尿嘧啶、替加氟、吉西他濱、卡培他濱、氟維司群、培美曲塞等)、植物生物鹼(例如長春新鹼、長春鹼、長春地辛、依託泊苷、多西他賽、紫杉醇、伊立替康、長春瑞濱、米托蒽醌、長春氟寧、拓撲替康等)、抗體藥物(例如曲妥單抗、帕妥珠單抗、利妥昔單抗、西妥昔單抗、帕尼單抗、貝伐單抗等)、激素抗癌劑(例如亮丙瑞林、戈舍瑞林、度他雄胺、***、他莫昔芬等)、蛋白酶體抑制劑(例如硼替佐米、來那度胺等)、芳香化酶抑制劑(例如依西美坦、來曲唑、阿那曲唑等)、VEGFR或EGFR抑制劑(例如舒尼替尼、索拉非尼、伊馬替尼、吉非替尼、埃羅替尼、凡德他尼、帕唑帕尼、拉帕替尼等)、mTOR抑制劑(例如依維莫司、西羅莫司、佐他莫司等)、PI3K激酶抑制劑(例如BKM-120、XL-147、BEZ-235等)、B-Raf抑制劑(例如威羅菲尼、GSK-2118436等)或AKT抑制劑(例如哌立福新、MK-2206等)等；較佳為芳香化酶抑制劑，更佳為來曲唑或阿那曲唑。 The present invention further relates to a compound represented by the general formula (I) or a tautomer, a racemate, a racemate, an enantiomer, a diastereomer or a mixture thereof, or a compound thereof Use of a pharmaceutically acceptable salt, or a pharmaceutical composition comprising the same, in the manufacture of a medicament for the treatment of cancer, wherein the cancer is selected from breast cancer, ovarian cancer, prostate cancer, melanoma, brain tumor (for example, malignant astroglial and Oligodendroglioma component of glioma, etc.), esophageal cancer, gastric cancer, liver cancer, pancreatic cancer, colorectal cancer (e.g., colon cancer, rectal cancer, etc.), lung cancer (e.g., non-small cell lung cancer, small cell lung cancer, protozoa (Metastatic or metastatic squamous cell carcinoma, etc.), kidney cancer, skin cancer, glioblastoma, neuroblastoma, sarcoma, liposarcoma, osteochondroma, osteoma, osteosarcoma, seminoma, testicular tumor, uterus Cancer (e.g. cervical cancer, endometrial cancer, etc.), head and neck tumors (e.g., maxillary cancer, laryngeal cancer, pharyngeal cancer, tongue cancer, intraoral cancer, etc.), multiple myeloma, malignant lymphoma (e.g., reticulocytes) Sarcoma, lymphosarcoma, Hodgkin's lymphoma Carcinoma, mantle cell lymphoma, etc.), polycythemia vera, leukemia (e.g., acute Myeloid leukemia, chronic myelogenous leukemia, acute lymphocytic leukemia, chronic lymphocytic leukemia, etc.), thyroid tumors, ureteral tumors, bladder tumors, gallbladder cancer, cholangiocarcinoma, chorionic epithelial cancer, or pediatric tumors (e.g. Ewing's family sarcoma) , Wilms sarcoma, rhabdomyosarcoma, hemangiosarcoma, embryonic testicular cancer, neuroblastoma, retinoblastoma, hepatoblastoma, nephroblastoma, etc.), etc .; where the drug can be further resistant to one or more other A combination of cancer agents, the anticancer agent is selected from alkylating agents (such as cyclophosphamide, ifosfamide, melphalan, busulfan, nimustine, ramustine, dacarbazine, temozolomide , Nitrogen mustard hydrochloride, dibromomannitol, etc.), platinum complexing agents (e.g. cisplatin, carboplatin, oxaliplatin, etc.), metabolic antagonists (e.g. methotrexate, 5-fluorouracil, tegafur, gemcitabine, Capecitabine, fulvestrant, pemetrexed, etc.), plant alkaloids (e.g., vincristine, vincristine, vincristine, etoposide, docetaxel, paclitaxel, irinotecan, vinorelide coast, Toxantrone, Vincristine, Topotecan, etc.), antibody drugs (e.g. trastuzumab, pertuzumab, rituximab, cetuximab, panitumumab, bevacizumab Etc.), hormonal anticancer agents (e.g. leuprolide, goserelin, dutasteride, dexamethasone, tamoxifen, etc.), proteasome inhibitors (e.g. bortezomib, lenalidomide, etc.) ), Aromatase inhibitors (e.g. exemestane, letrozole, anastrozole, etc.), VEGFR or EGFR inhibitors (e.g. sunitinib, sorafenib, imatinib, gefitinib, Erlotinib, Vandetanib, Pazopanib, Lapatinib, etc.), mTOR inhibitors (e.g. everolimus, sirolimus, zotamolimus, etc.), PI3K kinase inhibitors (e.g. BKM-120, XL-147, BEZ-235, etc.), B-Raf inhibitors (e.g. Verofinib, GSK-2118436, etc.) or AKT inhibitors (e.g. perifasine, MK-2206, etc.), etc .; Preferably it is an aromatase inhibitor, and more preferably letrozole or anastrozole.

本發明涉及通式(I)所示的化合物或其互變異構體、內消旋體、外消旋體、對映異構體、非對映異構體或其混合物形式，或其可藥用鹽，或包含其的醫藥組成物在製備預防或治療由輻射引起的造血毒性疾病的藥物中的用途，其中該輻射引起的造血毒性疾病包括但不限於骨髓抑制、嗜中性白血球減少症、白細胞減少症、貧血。 The present invention relates to a compound represented by the general formula (I) or a tautomer thereof, Mesomers, racemates, enantiomers, diastereomers or mixtures thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing the same in the preparation or prevention of radiation-induced Use in a medicine for a hematopoietic toxic disease, wherein the radiation-induced hematopoietic toxic disease includes, but is not limited to, bone marrow suppression, neutropenia, leukopenia, and anemia.

本發明還涉及一種抑制CDK4和/或CDK6活性的方法，其包括給予所需患者治療有效量的通式(I)所示的化合物或其互變異構體、內消旋體、外消旋體、對映異構體、非對映異構體或其混合物形式，或其可藥用鹽，或包含其的醫藥組成物。 The present invention also relates to a method for inhibiting the activity of CDK4 and / or CDK6, which comprises administering to a patient in need thereof a therapeutically effective amount of a compound represented by general formula (I) or a tautomer, meso, racemate , Enantiomers, diastereomers, or a mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same.

換言之，本發明涉及一種治療異常細胞增殖性疾病、感染(例如病毒感染，如皰疹、HIV，真菌感染等)、炎性病症(例如類風濕性關節炎、骨關節炎等)、自身免疫性疾病(例如牛皮癬、狼瘡、I型糖尿病、糖尿病性腎病、多發性硬化、腎小球性腎炎等)、心血管疾病(例如心肌梗塞、中風、動脈粥樣硬化、手術後血管狹窄、再狹窄等)或神經變性疾病(例如阿爾茨海默氏病、帕金森病等)的方法，其包括給予所需患者治療有效量的通式(I)所示的化合物或其互變異構體、內消旋體、外消旋體、對映異構體、非對映異構體或其混合物形式，或其可藥用鹽，或包含其的醫藥組成物，其中該異常細胞增殖性疾病可以是癌症(如下所定義)。 In other words, the present invention relates to the treatment of abnormal cell proliferative diseases, infections (such as viral infections such as herpes, HIV, fungal infections, etc.), inflammatory disorders (such as rheumatoid arthritis, osteoarthritis, etc.), autoimmunity Diseases (e.g. psoriasis, lupus, type I diabetes, diabetic nephropathy, multiple sclerosis, glomerulonephritis, etc.), cardiovascular diseases (e.g. myocardial infarction, stroke, atherosclerosis, postoperative vascular stenosis, restenosis, etc. ) Or a method of neurodegenerative disease (such as Alzheimer's disease, Parkinson's disease, etc.), which comprises administering to a desired patient a therapeutically effective amount of a compound represented by the general formula (I) or a tautomer, The form of a racem, a racemate, an enantiomer, a diastereomer or a mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, wherein the abnormal cell proliferative disease may be cancer (As defined below).

本發明進一步涉及一種治療癌症的方法，其包括給予所需患者治療有效量的通式(I)所示的化合物或其互變異構體、內消旋體、外消旋體、對映異構體、非對映異構體或其混合物形式，或其可藥用鹽，或包含其的醫藥組成物，其中該癌症選自乳腺癌、卵巢癌、***癌、黑色素瘤、腦瘤(例如具有惡性的星形神經膠質和少突神經膠質細胞瘤成分的神經膠質瘤等)、食管癌、胃癌、肝癌、胰腺癌、結腸直腸癌(例如結腸癌、直腸癌等)、肺癌(例如非小細胞肺癌、小細胞肺癌、原發或轉移性鱗狀癌等)、腎癌、皮膚癌、成膠質細胞瘤、神經母細胞瘤、肉瘤、脂肪肉瘤、骨軟骨瘤、骨瘤、骨肉瘤、精原細胞瘤、睾丸腫瘤、子宮癌(例如子宮頸癌、子宮內膜癌等)、頭頸腫瘤(例如上頜骨癌、喉癌、咽癌、舌癌、口內癌等)、多發性骨髓瘤、惡性淋巴瘤(例如網狀細胞肉瘤、淋巴肉瘤、霍奇金淋巴瘤、套細胞淋巴瘤等)、真性紅細胞增多症、白血病(例如急性粒細胞白血病、慢性粒細胞白血病、急性淋巴細胞白血病、慢性淋巴細胞白血病等)、甲狀腺腫瘤、輸尿管腫瘤、膀胱腫瘤、膽囊癌、膽管癌、絨毛膜上皮癌或兒科腫瘤(例如尤因家族性肉瘤、維爾姆斯肉瘤、橫紋肌肉瘤、血管肉瘤、胚胎睾丸癌、成神經細胞瘤、視網膜母細胞瘤、肝胚細胞瘤、腎母細胞瘤等)等。 The present invention further relates to a method for treating cancer, which comprises administering to a desired patient a therapeutically effective amount of a compound represented by the general formula (I) or a tautomer, meso, racemate, enantiomer thereof Or a diastereomer or a mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, wherein the cancer is selected from milk Adenocarcinoma, ovarian cancer, prostate cancer, melanoma, brain tumors (such as gliomas with malignant astroglial and oligodendroglioma components, etc.), esophageal cancer, gastric cancer, liver cancer, pancreatic cancer, colorectal Cancer (such as colon cancer, rectal cancer, etc.), lung cancer (such as non-small cell lung cancer, small cell lung cancer, primary or metastatic squamous cell carcinoma, etc.), kidney cancer, skin cancer, glioblastoma, neuroblastoma, Sarcoma, liposarcoma, osteochondroma, osteoma, osteosarcoma, seminoma, testicular tumor, uterine cancer (such as cervical cancer, endometrial cancer, etc.), head and neck tumor (such as maxillary cancer, laryngeal cancer, pharynx Cancer, tongue cancer, intraoral cancer, etc.), multiple myeloma, malignant lymphoma (e.g., reticulosarcoma, lymphosarcoma, Hodgkin's lymphoma, mantle cell lymphoma, etc.), polycythemia vera, leukemia (e.g. Acute myeloid leukemia, chronic myeloid leukemia, acute lymphocytic leukemia, chronic lymphocytic leukemia, etc.), thyroid tumor, ureter tumor, bladder tumor, gallbladder cancer, bile duct cancer, chorionic epithelium Or pediatric tumor (e.g. sarcoma Ewing's family, Wilms' sarcoma, rhabdomyosarcoma, vascular sarcoma, embryonal testicle cancer, neuroblastoma, retinoblastoma, hepatoblastoma, nephroblastoma etc.) and the like.

本發明還涉及一種治療癌症的方法，其包括給予所需患者治療有效量的通式(I)所示的化合物或其互變異構體、內消旋體、外消旋體、對映異構體、非對映異構體或其混合物形式，或其可藥用鹽，或包含其的醫藥組成物，與另外一種或多種抗癌劑聯合應用，該抗癌劑選自烷化劑(例如環磷醯胺、異環磷醯胺、美法侖、白消安、尼莫司丁、雷莫司汀、達卡巴嗪、替莫唑胺、鹽酸氮芥、二溴甘露醇等)、鉑絡合劑(例如順鉑、卡鉑、奧沙利鉑等)、代謝拮抗劑(例如甲氨蝶呤、5-氟尿嘧啶、替加氟、吉西他濱、卡培他濱、氟維司群、培美曲塞等)、植物生物鹼(例如長春新鹼、長春鹼、長春地辛、依託泊苷、多西他賽、紫杉醇、伊立替康、長春瑞濱、米托蒽醌、長春氟寧、拓撲替康等)、抗體藥物(例如曲妥單抗、帕妥珠單抗、利妥昔單抗、西妥昔單抗、帕尼單抗、貝伐單抗等)、激素抗癌劑(例如亮丙瑞林、戈舍瑞林、度他雄胺、***、他莫昔芬等)、蛋白酶體抑制劑(例如硼替佐米、來那度胺等)、芳香化酶抑制劑(例如依西美坦、來曲唑、阿那曲唑等)、VEGFR或EGFR抑制劑(例如舒尼替尼、索拉非尼、伊馬替尼、吉非替尼、埃羅替尼、凡德他尼、帕唑帕尼、拉帕替尼等)、mTOR抑制劑(例如依維莫司、西羅莫司、佐他莫司等)、PI3K激酶抑制劑(例如BKM-120、XL-147、BEZ-235等)、B-Raf抑制劑(例如威羅菲尼、GSK-2118436等)或AKT抑制劑(例如哌立福新、MK-2206等)等；較佳為芳香化酶抑制劑，更佳為來曲唑或阿那曲唑。 The invention also relates to a method for treating cancer, which comprises administering to a patient in need thereof a therapeutically effective amount of a compound represented by the general formula (I) or a tautomer, meso, racemate, enantiomer Isomers, diastereomers or mixtures thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, in combination with one or more anticancer agents selected from alkylating agents (e.g., Cyclophosphamide, ifosfamide, melphalan, busulfan, nimustine, ramustine, dacarbazine, temozolomide, nitrogen mustard hydrochloride, dibromomannitol, etc.), platinum complexing agents ( (E.g. cisplatin, carboplatin, oxaliplatin, etc.), metabolic antagonists (e.g. methotrexate, 5-fluorouracil, tegafur, gemcitabine, capecitabine, fulvestrant, pemetrexed, etc.) Plant alkaloids (e.g. Changchun Nephrine, vinblastine, vinblastine, etoposide, docetaxel, paclitaxel, irinotecan, vinorelbine, mitoxantrone, vinblastine, topotecan, etc.), antibody drugs (such as trastutine Monoclonal antibodies, Pertuzumab, Rituximab, Cetuximab, Panitumumab, Bevacizumab, etc.), Hormone anticancer agents (e.g. Leuprolide, Goserelin, Degrees Tasteride, dexamethasone, tamoxifen, etc.), proteasome inhibitors (such as bortezomib, lenalidomide, etc.), aromatase inhibitors (such as exemestane, letrozole, anastrol Azole, etc.), VEGFR or EGFR inhibitors (e.g. sunitinib, sorafenib, imatinib, gefitinib, erlotinib, vandetanib, pazopanib, lapatinib, etc. ), MTOR inhibitors (e.g. everolimus, sirolimus, zotamolimus, etc.), PI3K kinase inhibitors (e.g. BKM-120, XL-147, BEZ-235, etc.), B-Raf inhibitors ( For example, willofinib, GSK-2118436, etc.) or AKT inhibitors (for example, perifoxine, MK-2206, etc.); etc .; aromatase inhibitors are preferred, and letrozole or anastrozole is more preferred.

本發明還涉及作為抑制CDK4和/或CDK6活性的藥物的通式(I)所示的化合物或其互變異構體、內消旋體、外消旋體、對映異構體、非對映異構體或其混合物形式，或其可藥用鹽，或包含其的醫藥組成物。 The present invention also relates to a compound represented by the general formula (I) or a tautomer, a racemate, a racemate, an enantiomer, a diastereomer as a drug that inhibits the activity of CDK4 and / or CDK6. An isomer or a mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing the same.

本發明還涉及作為治療異常細胞增殖性疾病、感染(例如病毒感染，如皰疹、HIV，真菌感染等)、炎性病症(例如類風濕性關節炎、骨關節炎等)、自身免疫性疾病(例如牛皮癬、狼瘡、I型糖尿病、糖尿病性腎病、多發性硬化、腎小球性腎炎等)、心血管疾病(例如心肌梗塞、中風、動脈粥樣硬化、手術後血管狹窄、再狹窄等)或神經變性疾病(例如阿爾茨海默氏病、帕金森病等)的藥物的通式(I)所示的化合物或其互變異構體、內消旋體、外消旋體、對映異構體、非對映異構體或其混合物形式，或其可藥用鹽，或包含其的醫藥組成物，其中該異常細胞增殖性疾病可以是癌症(如下所定義)。 The invention also relates to the treatment of abnormal cell proliferative diseases, infections (such as viral infections such as herpes, HIV, fungal infections, etc.), inflammatory disorders (such as rheumatoid arthritis, osteoarthritis, etc.), autoimmune diseases (E.g. psoriasis, lupus, type 1 diabetes, diabetic nephropathy, multiple sclerosis, glomerulonephritis, etc.), cardiovascular diseases (e.g. myocardial infarction, stroke, atherosclerosis, postoperative vascular stenosis, restenosis, etc.) Or a neurodegenerative disease (e.g. Alzheimer's disease, Parkinson's disease, etc.) A compound represented by the general formula (I) or a tautomer, meso, Racemate, enantiomer, diastereomer or mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, wherein the abnormal cell proliferative disease may be cancer (as defined below ).

本發明進一步涉及作為治療癌症的藥物的通式(I)所示的化合物或其互變異構體、內消旋體、外消旋體、對映異構體、非對映異構體或其混合物形式，或其可藥用鹽，或包含其的醫藥組成物，其中該癌症選自乳腺癌、卵巢癌、***癌、黑色素瘤、腦瘤(例如具有惡性的星形神經膠質和少突神經膠質細胞瘤成分的神經膠質瘤等)、食管癌、胃癌、肝癌、胰腺癌、結腸直腸癌(例如結腸癌、直腸癌等)、肺癌(例如非小細胞肺癌、小細胞肺癌、原發或轉移性鱗狀癌等)、腎癌、皮膚癌、成膠質細胞瘤、神經母細胞瘤、肉瘤、脂肪肉瘤、骨軟骨瘤、骨瘤、骨肉瘤、精原細胞瘤、睾丸腫瘤、子宮癌(例如子宮頸癌、子宮內膜癌等)、頭頸腫瘤(例如上頜骨癌、喉癌、咽癌、舌癌、口內癌等)、多發性骨髓瘤、惡性淋巴瘤(例如網狀細胞肉瘤、淋巴肉瘤、霍奇金淋巴瘤、套細胞淋巴瘤等)、真性紅細胞增多症、白血病(例如急性粒細胞白血病、慢性粒細胞白血病、急性淋巴細胞白血病、慢性淋巴細胞白血病等)、甲狀腺腫瘤、輸尿管腫瘤、膀胱腫瘤、膽囊癌、膽管癌、絨毛膜上皮癌或兒科腫瘤(例如尤因家族性肉瘤、維爾姆斯肉瘤、橫紋肌肉瘤、血管肉瘤、胚胎睾丸癌、成神經細胞瘤、視網膜母細胞瘤、肝胚細胞瘤、腎母細胞瘤等)等。 The present invention further relates to a compound represented by the general formula (I) or a tautomer, a racemate, a racemate, an enantiomer, a diastereomer, or a compound thereof represented as a drug for treating cancer. In the form of a mixture, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, wherein the cancer is selected from breast cancer, ovarian cancer, prostate cancer, melanoma, brain tumor (e.g., malignant astroglial and oligodendrocytes) Glioblastoma component of glioma, etc.), esophageal cancer, gastric cancer, liver cancer, pancreatic cancer, colorectal cancer (e.g., colon cancer, rectal cancer, etc.), lung cancer (e.g., non-small cell lung cancer, small cell lung cancer, primary or metastatic Squamous cell carcinoma, etc.), kidney cancer, skin cancer, glioblastoma, neuroblastoma, sarcoma, liposarcoma, osteochondroma, osteoma, osteosarcoma, seminoma, testicular tumor, uterine cancer (e.g. Cervical cancer, endometrial cancer, etc.), head and neck tumors (e.g. maxillary cancer, laryngeal cancer, pharyngeal cancer, tongue cancer, intraoral cancer, etc.), multiple myeloma, malignant lymphoma (e.g. reticulosarcoma, lymph Sarcoma, Hodgkin's lymphoma, sleeve Cell lymphoma, etc.), polycythemia vera, leukemia (e.g., acute myelogenous leukemia, chronic myelogenous leukemia, acute lymphocytic leukemia, chronic lymphocytic leukemia, etc.), thyroid tumor, ureter tumor, bladder tumor, gallbladder cancer, bile duct cancer Chorionic epithelial cancer or pediatric tumors (e.g. Ewing's familial sarcoma, Wilms sarcoma, rhabdomyosarcoma, hemangiosarcoma, embryonic testicular cancer, neuroblastoma, retinoblastoma, hepatoblastoma, nephroblastoma and many more.

本發明還涉及作為治療癌症的藥物的通式(I)所示的化合物或其互變異構體、內消旋體、外消旋體、對映異構體、非對映異構體或其混合物形式，或其可藥用鹽，或包含其的醫藥組成物，以及另外一種或多種抗癌劑，該抗癌劑選自烷化劑(例如環磷醯胺、異環磷醯胺、美法侖、白消安、尼莫司丁、雷莫司汀、達卡巴嗪、替莫唑胺、鹽酸氮芥、二溴甘露醇等)、鉑絡合劑(例如順鉑、卡鉑、奧沙利鉑等)、代謝拮抗劑(例如甲氨蝶呤、5-氟尿嘧啶、替加氟、吉西他濱、卡培他濱、氟維司群、培美曲塞等)、植物生物鹼(例如長春新鹼、長春鹼、長春地辛、依託泊苷、多西他賽、紫杉醇、伊立替康、長春瑞濱、米托蒽醌、長春氟寧、拓撲替康等)、抗體藥物(例如曲妥單抗、帕妥珠單抗、利妥昔單抗、西妥昔單抗、帕尼單抗、貝伐單抗等)、激素抗癌劑(例如亮丙瑞林、戈舍瑞林、度他雄胺、***、他莫昔芬等)、蛋白酶體抑制劑(例如硼替佐米、來那度胺等)、芳香化酶抑制劑(例如依西美坦、來曲唑、阿那曲唑等)、VEGFR或EGFR抑制劑(例如舒尼替尼、索拉非尼、伊馬替尼、吉非替尼、埃羅替尼、凡德他尼、帕唑帕尼、拉帕替尼等)、mTOR抑制劑(例如依維莫司、西羅莫司、佐他莫司等)、PI3K激酶抑制劑(例如BKM-120、XL-147、BEZ-235等)、B-Raf抑制劑(例如威羅菲尼、GSK-2118436等)或AKT抑制劑(例如哌立福新、MK-2206等)等；較佳為芳香化酶抑制劑，更佳為來曲唑或阿那曲唑。 The present invention also relates to a compound represented by the general formula (I) or a tautomer, a racemate, a racemate, an enantiomer, a diastereomer, or a compound thereof as a medicine for treating cancer. In the form of a mixture, or a pharmaceutically acceptable salt thereof, or a pharmaceutical group comprising the same Products, and one or more anticancer agents selected from alkylating agents (e.g., cyclophosphamide, ifosfamide, melphalan, busulfan, nimustine, ramos) Ting, dacarbazine, temozolomide, nitrogen mustard hydrochloride, dibromomannitol, etc.), platinum complexing agents (e.g. cisplatin, carboplatin, oxaliplatin, etc.), metabolic antagonists (e.g. methotrexate, 5-fluorouracil) , Tegafur, gemcitabine, capecitabine, fulvestrant, pemetrexed, etc.), plant alkaloids (such as vincristine, vincristine, vinblastine, etoposide, docetaxel, paclitaxel , Irinotecan, vinorelbine, mitoxantrone, vinblastine, totopecan, etc.), antibody drugs (e.g. trastuzumab, pertuzumab, rituximab, cetuximab , Panitumumab, bevacizumab, etc.), hormonal anticancer agents (e.g. leuprorelin, goserelin, dutasteride, dexamethasone, tamoxifen, etc.), proteasome inhibitors ( (E.g. bortezomib, lenalidomide, etc.), aromatase inhibitors (e.g. exemestane, letrozole, anastrozole, etc.), VEGFR or EGFR inhibitors (e.g. sunil Tenib, Sorafenib, Imatinib, Gefitinib, Erlotinib, Vandetanib, Pazopanib, Lapatinib, etc.), mTOR inhibitors (e.g. everolimus, western Romox, Zotamox, etc.), PI3K kinase inhibitors (e.g. BKM-120, XL-147, BEZ-235, etc.), B-Raf inhibitors (e.g. Verofinib, GSK-2118436, etc.) or AKT Inhibitors (such as perifaxin, MK-2206, etc.); aromatase inhibitors are preferred, and letrozole or anastrozole are more preferred.

含活性成分的醫藥組成物可以是適用於口服的形式，例如片劑、糖錠劑、錠劑、水或油混懸液、可分散粉末或顆粒、乳液、硬或軟膠囊，或糖漿劑或酏劑。可按照本領域任何已知製備藥用組合物的方法製備口服組合物，此類組合物可含有一種或多種選自以下的成分：甜味劑、矯味劑、著色劑和防腐劑，以提供悅目和可口的藥用製劑。片劑含有活性成分和用於混合的適宜製備片劑的無毒的可藥用的賦形劑。這些賦形劑可以是惰性賦形劑，如碳酸鈣、碳酸鈉、乳糖、磷酸鈣或磷酸鈉；造粒劑和崩解劑，例如微晶纖維素、交聯羧甲基纖維素鈉、玉米澱粉或藻酸；粘合劑，例如澱粉、明膠、聚乙烯吡咯烷酮或***膠；和潤滑劑，例如硬脂酸鎂、硬脂酸或滑石粉。這些片劑可以不包衣或可藉由掩蓋藥物的味道或在胃腸道中延遲崩解和吸收，因而在較長時間內提供緩釋作用的已知技術將其包衣。例如，可使用水溶性味道掩蔽物質，例如羥丙基甲基纖維素或羥丙基纖維素，或延長時間物質例如乙基纖維素、醋酸丁酸纖維素。 The active ingredient-containing pharmaceutical composition may be in a form suitable for oral administration, such as tablets, dragees, lozenges, water or oil suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or Tincture. Oral compositions may be prepared according to any method known in the art for preparing pharmaceutical compositions, and such compositions may contain one or more ingredients selected from the group consisting of sweeteners, flavoring agents, colorants, and preservatives to provide pleasing looks And delicious medicinal preparations. Tablets contain active ingredients and Non-toxic pharmaceutically acceptable excipients suitable for the preparation of tablets. These excipients can be inert excipients such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating agents and disintegrating agents such as microcrystalline cellulose, croscarmellose sodium, corn Starch or alginic acid; binders such as starch, gelatin, polyvinylpyrrolidone or gum arabic; and lubricants such as magnesium stearate, stearic acid or talc. These tablets can be uncoated or they can be coated by known techniques that mask the taste of the drug or delay disintegration and absorption in the gastrointestinal tract, thereby providing a sustained release over a longer period. For example, water-soluble taste-masking substances, such as hydroxypropyl methyl cellulose or hydroxypropyl cellulose, or prolonged substances, such as ethyl cellulose, cellulose acetate butyrate, can be used.

也可用其中活性成分與惰性固體稀釋劑例如碳酸鈣、磷酸鈣或高嶺土混合的硬明膠膠囊，或其中活性成分與水溶性載體例如聚乙二醇或油溶媒例如花生油、液體石蠟或橄欖油混合的軟明膠膠囊提供口服製劑。 Hard gelatin capsules in which the active ingredient is mixed with an inert solid diluent such as calcium carbonate, calcium phosphate or kaolin, or in which the active ingredient is mixed with a water-soluble carrier such as polyethylene glycol or an oil vehicle such as peanut oil, liquid paraffin, or olive oil Soft gelatin capsules are provided as an oral preparation.

水懸浮液含有活性物質和用於混合的適宜製備水懸浮液的賦形劑。此類賦形劑是懸浮劑，例如羧基甲基纖維素鈉、甲基纖維素、羥丙基甲基纖維素、藻酸鈉、聚乙烯吡咯烷酮和***膠；分散劑或濕潤劑可以是天然產生的磷脂例如卵磷脂，或烯化氧與脂肪酸的縮合產物例如聚氧乙烯硬脂酸酯，或環氧乙烷與長鏈脂肪醇的縮合產物，例如十七碳亞乙基氧基鯨蠟醇(heptadecaethyleneoxy cetanol)，或環氧乙烷與由脂肪酸和己糖醇衍生的部分酯的縮合產物，例如聚環氧乙烷山梨醇單油酸酯，或環氧乙烷與由脂肪酸和己糖醇酐衍生的偏酯的縮合產物，例如聚環氧乙烷脫水山梨醇單油酸酯。水混懸液也可以含有一種或多種防腐劑例如尼泊金乙酯或尼泊金正丙酯、一種或多種著色劑、一種或多種矯味劑和一種或多種甜味劑，例如蔗糖、糖精或阿司帕坦。 Aqueous suspensions contain the active substance and excipients suitable for the preparation of the aqueous suspension for mixing. Such excipients are suspending agents such as sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, and gum arabic; dispersants or wetting agents may be naturally occurring Phospholipids such as lecithin, or condensation products of alkylene oxides with fatty acids such as polyoxyethylene stearate, or condensation products of ethylene oxide with long-chain fatty alcohols, such as heptadecyloxycetyl alcohol (heptadecaethyleneoxy cetanol), or a condensation product of ethylene oxide with a partial ester derived from a fatty acid and hexitol, such as polyethylene oxide sorbitol monooleate, or ethylene oxide with a derivative of fatty acid and hexitol anhydride Condensation products of partial esters, such as polyethylene oxide sorbitan monooleate. The aqueous suspension may also contain one or more preservatives such as ethyl paraben or n-propyl paraben, one or more coloring agents, one One or more flavoring agents and one or more sweetening agents, such as sucrose, saccharin or aspartame.

油混懸液可藉由使活性成分懸浮於植物油如花生油、橄欖油、芝麻油或椰子油，或礦物油例如液體石蠟中配製而成。油懸浮液可含有增稠劑，例如蜂蠟、硬石蠟或鯨蠟醇。可加入上述的甜味劑和矯味劑，以提供可口的製劑。可藉由加入抗氧化劑例如丁羥茴醚或α-生育酚保存這些組合物。 Oily suspensions can be formulated by suspending the active ingredient in a vegetable oil such as peanut oil, olive oil, sesame oil or coconut oil, or a mineral oil such as liquid paraffin. The oil suspension may contain a thickening agent, such as beeswax, hard paraffin or cetyl alcohol. The sweeteners and flavoring agents described above can be added to provide a palatable formulation. These compositions can be preserved by the addition of an antioxidant such as fenoxyfen or alpha-tocopherol.

藉由加入水可使適用於製備水混懸液的可分散粉末和顆粒提供活性成分和用於混合的分散劑或濕潤劑、懸浮劑或一種或多種防腐劑。適宜的分散劑或濕潤劑和懸浮劑可說明上述的例子。也可加入其他賦形劑例如甜味劑、矯味劑和著色劑。藉由加入抗氧化劑例如抗壞血酸保存這些組合物。 Dispersible powders and granules suitable for use in the preparation of aqueous suspensions can be provided with active ingredients and dispersing or wetting agents, suspending agents or one or more preservatives for mixing by adding water. Suitable dispersing or wetting agents and suspending agents can illustrate the above examples. Other excipients such as sweeteners, flavors and colorants can also be added. These compositions are preserved by the addition of an antioxidant such as ascorbic acid.

本發明的醫藥組成物也可以是水包油乳劑的形式。油相可以是植物油例如橄欖油或花生油，或礦物油例如液體石蠟或其混合物。適宜的乳化劑可以是天然產生的磷脂，例如大豆卵磷脂和由脂肪酸和己糖醇酐衍生的酯或偏酯例如山梨坦單油酸酯，和該偏酯和環氧乙烷的縮合產物，例如聚環氧乙烷山梨醇單油酸酯。乳劑也可以含有甜味劑、矯味劑、防腐劑和抗氧劑。可用甜味劑例如甘油、丙二醇、山梨醇或蔗糖配製糖漿和酏劑。此類製劑也可含有緩和劑、防腐劑、著色劑和抗氧劑。 The pharmaceutical composition of the present invention may also be in the form of an oil-in-water emulsion. The oily phase may be a vegetable oil such as olive oil or peanut oil, or a mineral oil such as liquid paraffin or a mixture thereof. Suitable emulsifiers may be naturally occurring phospholipids, such as soybean lecithin and esters or partial esters derived from fatty acids and hexitol anhydrides, such as sorbitan monooleate, and the condensation products of the partial esters and ethylene oxide, such as Polyethylene oxide sorbitol monooleate. Emulsions may also contain sweeteners, flavoring agents, preservatives and antioxidants. Syrups and elixirs can be formulated with sweetening agents such as glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also contain a demulcent, a preservative, a colorant, and an antioxidant.

醫藥組成物可以是無菌注射水溶液形式。可在使用的可接受的溶媒和溶劑中有水、林格氏液和等滲氯化鈉溶液。無菌注射製劑可以是其中活性成分溶於油相的無菌注射水包油微乳。例如將活性成分溶於大豆油和卵磷脂的混合物中。然後將油溶液加入水和甘油的混合物中處理形成微乳。可藉由局部大量注射，將注射液或微乳注入患者的血流中。或者，最好按可保持本發明化合物恒定迴圈濃度的方式給予溶液和微乳。為保持這種恒定濃度，可使用連續靜脈內遞藥裝置。這種裝置的實例是Deltec CADD-PLUS.TM.5400型靜脈注射泵。 The pharmaceutical composition may be in the form of a sterile injectable aqueous solution. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution. The sterile injectable preparation may be a sterile injectable oil-in-water microemulsion in which the active ingredient is dissolved in the oil phase. For example, the active ingredient is dissolved in a mixture of soybean oil and lecithin. The oil solution is then added to a mixture of water and glycerol to form a microemulsion. Local bets Inject the injection or microemulsion into the bloodstream of the patient. Alternatively, the solution and microemulsion are preferably administered in a manner that maintains a constant loop concentration of the compound of the invention. To maintain this constant concentration, continuous intravenous drug delivery devices can be used. An example of such a device is the Deltec CADD-PLUS.TM. 5400 intravenous pump.

醫藥組成物可以是用於肌內和皮下給藥的無菌注射水或油混懸液的形式。可按已知技術，用上述那些適宜的分散劑或濕潤劑和懸浮劑配製該混懸液。無菌注射製劑也可以是在無毒腸胃外可接受的稀釋劑或溶劑中製備的無菌注射溶液或混懸液，例如1,3-丁二醇中製備的溶液。此外，可方便地用無菌固定油作為溶劑或懸浮介質。為此目的，可使用包括合成甘油單或二酯在內的任何調和固定油。此外，脂肪酸例如油酸也可以製備注射劑。 The pharmaceutical composition may be in the form of a sterile injectable water or oily suspension for intramuscular and subcutaneous administration. This suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents which have been mentioned above. The sterile injectable preparation may also be a sterile injectable solution or suspension prepared in a non-toxic parenterally acceptable diluent or solvent, for example, a solution prepared in 1,3-butanediol. In addition, a sterile fixed oil can be conveniently used as a solvent or suspension medium. For this purpose, any blended fixing oil including synthetic mono- or diesters can be used. In addition, fatty acids such as oleic acid can also be prepared for injection.

可按用於直腸給藥的栓劑形式給予本發明化合物。可藉由將藥物與在普通溫度下為固體但在直腸中為液體，因而在直腸中會溶化而釋放藥物的適宜的無刺激性賦形劑混合來製備這些醫藥組成物。此類物質包括可哥脂、甘油明膠、氫化植物油、各種分子量的聚乙二醇和聚乙二醇的脂肪酸酯的混合物。 The compounds of the invention may be administered in the form of suppositories for rectal administration. These pharmaceutical compositions can be prepared by mixing the drug with a suitable non-irritating excipient that is solid at ordinary temperatures but liquid in the rectum and therefore will dissolve in the rectum to release the drug. Such materials include cocoa butter, glycerin gelatin, hydrogenated vegetable oils, polyethylene glycols of various molecular weights and mixtures of fatty acid esters of polyethylene glycols.

本領域技術人員所熟知的，藥物的給藥劑量依賴於多種因素，包括但並非限定以下因素：所用特定化合物的活性、病人的年齡、病人的體重、病人的健康狀況、病人的表現、病人的飲食、給藥時間、給藥方式、***的速率、藥物的組合等；另外，最佳的治療方式如治療的模式、通式化合物(I)的日用量或可藥用的鹽的種類可以根據傳統的治療方案來驗證。 As known to those skilled in the art, the dosage of a drug depends on many factors, including but not limited to the following factors: the activity of the specific compound used, the age of the patient, the weight of the patient, the patient's health, the patient's performance, the patient's Diet, time of administration, mode of administration, rate of excretion, combination of drugs, etc. In addition, the optimal treatment such as the mode of treatment, the daily dosage of the general compound (I), or the type of pharmaceutically acceptable salt can be based on Traditional treatment options to verify.

(發明詳述) (Detailed invention)

除非有相反陳述，否則下列用在說明書和權利要求書中的術語具有下述含義。 Unless stated to the contrary, the following is used in the description and claims The terms in the book have the following meanings.

術語“烷基”指飽和的脂肪族烴基團，包括1至20個碳原子的直鏈和支鏈基團。較佳含有1至10個碳原子的烷基，更佳含有1至6個碳原子的烷基，最佳含有1至4個碳原子的烷基，最佳為甲基。非限制性實施例包括甲基、乙基、正丙基、異丙基、正丁基、異丁基、第三丁基、第二丁基、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、正庚基、2-甲基己基、3-甲基己基、4-甲基己基、5-甲基己基、2,3-二甲基戊基、2,4-二甲基戊基、2,2-二甲基戊基、3,3-二甲基戊基、2-乙基戊基、3-乙基戊基、正辛基、2,3-二甲基己基、2,4-二甲基己基、2,5-二甲基己基、2,2-二甲基己基、3,3-二甲基己基、4,4-二甲基己基、2-乙基己基、3-乙基己基、4-乙基己基、2-甲基-2-乙基戊基、2-甲基-3-乙基戊基、正壬基、2-甲基-2-乙基己基、2-甲基-3-乙基己基、2,2-二乙基戊基、正癸基、3,3-二乙基己基、2,2-二乙基己基，及其各種支鏈異構體等。更佳的是含有1至6個碳原子的低級烷基，非限制性實例包括甲基、乙基、正丙基、異丙基、正丁基、異丁基、第三丁基、第二丁基、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。烷基可以是取代的或未取代的，當被取代時，取代基可以在任何可使用的連接點上被取代，該取代基較佳為一個或多個以下基團，獨立地選自烷基、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、雜環烷基、芳基、雜芳基、環烷氧基、雜環烷氧基、環烷硫基、雜環烷硫基、側氧基、胺基、鹵烷基、羥烷基、羧基或羧酸酯基。 The term "alkyl" refers to saturated aliphatic hydrocarbon groups, including straight and branched chain groups of 1 to 20 carbon atoms. An alkyl group containing 1 to 10 carbon atoms is preferred, an alkyl group containing 1 to 6 carbon atoms is more preferred, an alkyl group containing 1 to 4 carbon atoms is most preferred, and a methyl group is most preferred. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, third butyl, second butyl, n-pentyl, 1,1-dimethylpropyl Methyl, 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-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, n-heptyl Methyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2,3-dimethylpentyl, 2,4-dimethylpentyl, 2,2- Dimethylpentyl, 3,3-dimethylpentyl, 2-ethylpentyl, 3-ethylpentyl, n-octyl, 2,3-dimethylhexyl, 2,4-dimethyl Hexyl, 2,5-dimethylhexyl, 2,2-dimethylhexyl, 3,3-dimethylhexyl, 4,4-dimethylhexyl, 2-ethylhexyl, 3-ethylhexyl, 4-ethylhexyl, 2-methyl-2-ethylpentyl, 2-methyl-3-ethylpentyl, n-nonyl, 2-methyl-2-ethylhexyl, 2-methyl- 3-ethylhexyl , 2,2-diethyl-pentyl, n-decyl, 3,3-diethylhexyl, 2,2-diethylhexyl group, and various branched chain isomers thereof. More preferred are lower alkyl groups containing 1 to 6 carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, third butyl, second Butyl, n-pentyl, 1,1-dimethylpropyl, 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-di Methylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methyl Amyl, 2,3-dimethylbutyl and the like. The alkyl group may be substituted or unsubstituted. When substituted, the substituent may be substituted at any available point of attachment. The substituent is preferably one or more of the following groups, independently selected from the alkyl group. , Alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkane Oxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, pendant oxygen, amine, haloalkyl, hydroxyalkyl, carboxyl, or carboxylate.

術語“環烷基”指飽和或部分不飽和單環或多環環狀烴取代基，其包括3至20個碳原子，較佳包括3至12個碳原子，更佳環烷基環包含3至10個碳原子，最佳環烷基環包含3至6個碳原子，最佳為環丙基或環戊基。單環環烷基的非限制性實例包含環丙基、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，較佳為環丙基、環戊基。多環環烷基包括螺環、稠環和橋環的環烷基。環烷基可以是視需要取代的或未取代的，當被取代時，取代基較佳為一個或多個以下基團，獨立地選自烷基、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、雜環烷基、芳基、雜芳基、環烷氧基、雜環烷氧基、環烷硫基、雜環烷硫基、側氧基、胺基、鹵烷基、羥烷基、羧基或羧酸酯基。 The term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent that includes 3 to 20 carbon atoms, preferably 3 to 12 carbon atoms, and more preferably a cycloalkyl ring containing 3 To 10 carbon atoms, the most preferred cycloalkyl ring contains 3 to 6 carbon atoms, most preferably cyclopropyl or cyclopentyl. Non-limiting examples of monocyclic cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatriene And cyclooctyl are preferably cyclopropyl or cyclopentyl. Polycyclic cycloalkyl includes spiro, fused and bridged cycloalkyl. Cycloalkyl can be optionally substituted or unsubstituted. When substituted, the substituent is preferably one or more of the following groups, independently selected from alkyl, alkenyl, alkynyl, alkoxy, and alkane Thio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkanethio Group, heterocycloalkylthio group, pendant oxygen group, amino group, haloalkyl group, hydroxyalkyl group, carboxyl group or carboxylate group.

術語“烯基”指由至少由兩個碳原子和至少一個碳-碳雙鍵組成的如上定義的烷基，例如乙烯基、1-丙烯基、2-丙烯基、1-、2-或3-丁烯基等。較佳為C_2-10烯基，更佳為C_2-6烯基，最佳為C_2-4烯基，最佳為乙烯基。烯基可以是取代的或非取代的，當被取代時，取代基較佳為一個或多個以下基團，其獨立地選自烷基、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、雜環烷基、芳基、雜芳基、環烷氧基、雜環烷氧基、環烷硫基、雜環烷硫基、側氧基、胺基、鹵烷基、羥烷基、羧基或羧酸酯基。 The term "alkenyl" refers to an alkyl group, as defined above, consisting of at least two carbon atoms and at least one carbon-carbon double bond, such as vinyl, 1-propenyl, 2-propenyl, 1-, 2-, or 3 -Butenyl and the like. C _2-10 alkenyl is preferred, C _2-6 alkenyl is more preferred, C _2-4 alkenyl is most preferred, and vinyl is most preferred. Alkenyl may be substituted or unsubstituted. When substituted, the substituent is preferably one or more of the following groups, which are independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, and alkylthio , Alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, Heterocycloalkylthio, pendant oxygen, amine, haloalkyl, hydroxyalkyl, carboxy, or carboxylate.

術語“炔基”指至少由兩個碳原子和至少一個碳-碳三鍵組成的如上所定義的烷基，例如乙炔基、1-丙炔基、2-丙炔基、1-、2-或3-丁炔基等。較佳為C_2-10炔基，更佳為C_2-6炔基，最佳為C_2-4炔基。炔基可以是取代的或非取代的，當被取代時，取代基較佳為一個或多個以下基團，其獨立地選自烷基、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、雜環烷基、芳基、雜芳基、環烷氧基、雜環烷氧基、環烷硫基、雜環烷硫基、側氧基、胺基、鹵烷基、羥烷基、羧基或羧酸酯基。 The term "alkynyl" refers to an alkyl group, as defined above, consisting of at least two carbon atoms and at least one carbon-carbon triple bond, such as ethynyl, 1-propynyl, 2-propynyl, 1-, 2- Or 3-butynyl and the like. C _2-10 alkynyl is preferred, C _2-6 alkynyl is more preferred, and C _2-4 alkynyl is most preferred. The alkynyl group may be substituted or unsubstituted. When substituted, the substituent is preferably one or more of the following groups, which are independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, and alkylthio , Alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, Heterocycloalkylthio, pendant oxygen, amine, haloalkyl, hydroxyalkyl, carboxy, or carboxylate.

術語“雜環烷基”指飽和或部分不飽和單環或多環環狀烴取代基，其包括3至20個環原子，其中一個或多個環原子選自氮、氧或S(O)_m(其中m是0至2的整數)的雜原子，但不包括-O-O-、-O-S-或-S-S-的環部分，其餘環原子為碳。較佳包括3至12個環原子，其中1至4個是雜原子，更佳雜環烷基環包含3至10個環原子，更佳雜環烷基環包含5至6個環原子。單環雜環烷基的非限制性實例包含吡咯烷基、哌啶基、哌嗪基、嗎啉基、硫嗎啉基、高哌嗪基、吡喃基、四氫呋喃基等。多環雜環烷基包括螺環、稠環和橋環的雜環烷基。雜環烷基可以是視需要取代的或未取代的，當被取代時，取代基較佳為一個或多個以下基團，獨立地選自烷基、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、雜環烷基、芳基、雜芳基、環烷氧基、雜環烷氧基、環烷硫基、雜環烷硫基、側氧基、胺基、鹵烷基、羥烷基、羧基或羧酸酯基。 The term "heterocycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent that includes 3 to 20 ring atoms, wherein one or more ring atoms are selected from nitrogen, oxygen, or S (O) A heteroatom of _m (where m is an integer from 0 to 2), excluding the ring portion of -OO-, -OS-, or -SS-, and the remaining ring atoms are carbon. It preferably includes 3 to 12 ring atoms, of which 1 to 4 are heteroatoms, more preferably a heterocycloalkyl ring contains 3 to 10 ring atoms, and more preferably a heterocycloalkyl ring contains 5 to 6 ring atoms. Non-limiting examples of monocyclic heterocycloalkyl include pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, pyranyl, tetrahydrofuranyl, and the like. Polycyclic heterocycloalkyl includes spiro, fused and bridged heterocycloalkyl. Heterocycloalkyl may be optionally substituted or unsubstituted. When substituted, the substituent is preferably one or more of the following groups, independently selected from alkyl, alkenyl, alkynyl, alkoxy, Alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkane Thio, heterocycloalkylthio, pendant oxygen, amine, haloalkyl, hydroxyalkyl, carboxyl, or carboxylate.

術語“芳基”指具有共軛的π電子體系的6至14員全碳單環或稠合多環(也就是共用毗鄰碳原子對的環)基團，較佳為6至10員，更佳苯基和萘基，最佳苯基。所述芳基環可以稠合於雜芳基、雜環烷基或環烷基環上，其中與母體結構連接在一起的環為芳基環，非限制性實例包含：芳基可以是取代的或未取代的，當被取代時，取代基較佳為一個或多個以下基團，獨立地選自烷基、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、雜環烷基、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、鹵烷基、羥烷基、羧基或羧酸酯基。 The term "aryl" refers to a 6 to 14 membered all-carbon monocyclic or fused polycyclic (ie, rings sharing adjacent pairs of carbon atoms) group having a conjugated pi-electron system, preferably 6 to 10 members, more Best phenyl and naphthyl, best phenyl. The aryl ring may be fused to a heteroaryl, heterocycloalkyl or cycloalkyl ring, wherein the ring connected to the parent structure is an aryl ring, and non-limiting examples include: Aryl may be substituted or unsubstituted. When substituted, the substituent is preferably one or more of the following groups, independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, Alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, hetero A cycloalkylthio, amine, haloalkyl, hydroxyalkyl, carboxyl, or carboxylate group.

術語“雜芳基”指包含1至4個雜原子、5至14個環原子的雜芳族體系，其中雜原子選自氧、硫和氮。雜芳基較佳為5至10員，更佳為5員或6員，例如噻二唑基、吡唑基、噁唑基、噁二唑基、咪唑基、***基、噻唑基、呋喃基、噻吩基、吡啶基、吡咯基、N-烷基吡咯基、嘧啶基、吡嗪基、咪唑基、四唑基等。該雜芳基環可以稠合於芳基、雜環烷基或環烷基環上，其中與母體結構連接在一起的環為雜芳基環，其非限制性實例包括：雜芳基可以是視需要取代的或未取代的，當被取代時，取代基較佳為一個或多個以下基團，獨立地選自烷基、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、雜環烷基、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、鹵烷基、羥烷基、羧基或羧酸酯基。 The term "heteroaryl" refers to a heteroaromatic system containing 1 to 4 heteroatoms, 5 to 14 ring atoms, wherein the heteroatoms are selected from oxygen, sulfur, and nitrogen. Heteroaryl is preferably 5 to 10 members, more preferably 5 or 6 members, such as thiadiazolyl, pyrazolyl, oxazolyl, oxadiazolyl, imidazolyl, triazolyl, thiazolyl, furan Group, thienyl, pyridyl, pyrrolyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, imidazolyl, tetrazolyl, and the like. The heteroaryl ring may be fused to an aryl, heterocycloalkyl or cycloalkyl ring, wherein the ring connected to the parent structure is a heteroaryl ring. Non-limiting examples include: Heteroaryl may be optionally substituted or unsubstituted. When substituted, the substituent is preferably one or more of the following groups, independently selected from alkyl, alkenyl, alkynyl, alkoxy, and alkane Thio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkanethio Radical, heterocycloalkylthio, amine, haloalkyl, hydroxyalkyl, carboxyl or carboxylate.

術語“烷氧基”指-O-(烷基)和-O-(未取代的環烷基)，其中烷基、環烷基的定義如上所述。非限制性實例包含甲氧基、乙氧基、丙氧基、丁氧基、環丙氧基、環丁氧基、環戊氧基、環己氧基等。烷氧基可以是視需要取代的或未取代的，當被取代時，取代基較佳為一個或多個以下基團，獨立地選自為烷基、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、雜環烷基、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、鹵烷基、羥烷基、羧基或羧酸酯基。 The term "alkoxy" refers to -O- (alkyl) and -O- (unsubstituted cycloalkyl), wherein alkyl and cycloalkyl are as defined above. Non-limiting examples include methoxy, ethoxy, propoxy, butoxy, cyclopropoxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy and the like. The alkoxy group may be optionally substituted or unsubstituted. When substituted, the substituent is preferably one or more of the following groups, independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, Alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkane Thio, heterocycloalkylthio, amine, haloalkyl, hydroxyalkyl, carboxyl or carboxylate.

“鹵烷基”指烷基被一個或多個鹵素取代，其中烷基的定義如上所述。 "Haloalkyl" refers to an alkyl group substituted with one or more halogens, where alkyl is as defined above.

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

“羥烷基”指被羥基取代的烷基，其中烷基的定義如上所述。 "Hydroxyalkyl" refers to an alkyl group substituted with a hydroxy group, wherein the alkyl group is as defined above.

“鹵素”指氟、氯、溴或碘，較佳氟或碘。 "Halogen" means fluorine, chlorine, bromine or iodine, preferably fluorine or 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.

“側氧基”指=O。 "Side oxygen" means = O.

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

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

“視需要”或“視需要地”意味著隨後所描述地事件或環境可以但不必發生，該說明包括該事件或環境發生或不發生的場合。例如，“視需要被烷基取代的雜環烷基團”意味著烷基可以但不必須存在，該說明包括雜環烷基團被烷基取代的情形和雜環烷基團不被烷基取代的情形。 "As needed" or "as needed" means that the event or environment described later can, but does not have to occur, and the description includes situations where the event or environment occurs or does not occur. For example, "heterocycloalkyl group substituted with an alkyl group as necessary" means that the alkyl group may but need not exist, and this description includes the case where the heterocycloalkyl group is substituted with an alkyl group and the heterocycloalkyl group is not substituted with an alkyl group Replacement situation.

“取代的”指基團中的一個或多個氫原子，較佳為最多5個，更佳為1至3個氫原子彼此獨立地被相應數目的取代基取代。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(如烯屬)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 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 (eg, olefinic) bond.

“醫藥組成物”表示含有一種或多種本文所述化合物或其生理學上/可藥用的鹽或前體藥物與其他化學組分的混合物，以及其他組分例如生理學/可藥用的載體和賦形劑。醫藥組成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。 "Pharmaceutical composition" means a mixture containing one or more of the compounds described herein, or a physiological / pharmaceutically acceptable salt or prodrug thereof, with other chemical components, and other components such as physiological / pharmaceutically acceptable carriers And excipients. The purpose of the pharmaceutical composition is to promote the administration to the living body, which is beneficial to the absorption of the active ingredient and then exerts the biological activity.

本發明的合成方法 Synthesis method of the present invention

為了完成本發明的合成目的，本發明採用如下的合成技術方案：一種製備通式(I)所示的化合物或其互變異構體、內消旋體、外消旋體、對映異構體、非對映異構體或其混合物形式，或其可藥用鹽的方法，該方法包括： In order to accomplish the synthetic purpose of the present invention, the present invention adopts the following synthetic technical scheme: a method for preparing a compound represented by the general formula (I) or a tautomer, a racemate, a racemate, an enantiomer thereof , A method of diastereomers or mixtures thereof, or a pharmaceutically acceptable salt thereof, the method comprising:

通式(I-A)化合物與通式(I-B)化合物在鹼性條件下，視需要在催化劑作用下進行取代反應得到通式(I-C)化合物；通式(I-C)化合物在溶劑中，酸性條件下，進行脫保護反應，視需要進一步進行取代反應得到通式(I)化合物；其中：X為鹵素；Boc為第三丁氧羰基；R為烷基，較佳為丁基；，A¹，A²，Y，R¹至R⁶的定義如通式(I)中所定義；R⁴較佳為氫原子或烷基，其中該烷基視需要進一步被一個或多個選自鹵素、羥基或環烷基的取代基所取代；R²較佳為-C(O)R⁷；且R⁷為烷基。 The compound of the general formula (IA) and the compound of the general formula (IB) are subjected to a substitution reaction under the action of a catalyst under basic conditions to obtain a compound of the general formula (IC); the compound of the general formula (IC) is in a solvent under acidic conditions. A deprotection reaction is performed, and a substitution reaction is further performed as necessary to obtain a compound of the general formula (I); wherein: X is a halogen; Boc is a third butoxycarbonyl group; R is an alkyl group, preferably butyl; , A ¹ , A ² , Y, R ¹ to R ⁶ are as defined in the general formula (I); R ^{4 is} preferably a hydrogen atom or an alkyl group, wherein the alkyl group is further selected by one or more as necessary. Substituted with a substituent from halogen, hydroxy or cycloalkyl; R ^{2 is} preferably -C (O) R ⁷ ; and R ⁷ is alkyl.

一種製備通式(II)所示的化合物或其互變異構體、內消旋體、外消旋體、對映異構體、非對映異構體或其混合物形式，或其可藥用鹽的方法，該方法包括： A method for preparing a compound represented by general formula (II) or a tautomer, a racemate, a racemate, an enantiomer, a diastereomer or a mixture thereof, or a pharmaceutically acceptable form thereof Salt method, the method includes:

通式(II-A)化合物與通式(I-B)化合物在鹼性條件下，視需要在催化劑作用下進行取代反應得到通式(II-C)化合物；通式(II-C)化合物在溶劑中，酸性條件下，進行脫保護反應，視需要進一步進行取代反應得到通式(II)化合物；其中：X為鹵素；Boc為第三丁氧羰基；R為烷基，較佳為丁基；，A¹，A²，Y，R¹至R⁶的定義如通式(I)中所定義；R⁴較佳為氫原子或烷基，其中該烷基視需要進一步被一個或多個選自鹵素、羥基或環烷基的取代基所取代；R²較佳為-C(O)R⁷；且R⁷為烷基。 The compound of the general formula (II-A) and the compound of the general formula (IB) are subjected to a substitution reaction under a basic condition under the action of a catalyst to obtain a compound of the general formula (II-C); the compound of the general formula (II-C) is in a solvent Under acidic conditions, a deprotection reaction is performed, and a substitution reaction is further performed as necessary to obtain a compound of general formula (II); wherein: X is a halogen; Boc is a third butoxycarbonyl group; R is an alkyl group, preferably butyl; , A ¹ , A ² , Y, R ¹ to R ⁶ are as defined in the general formula (I); R ^{4 is} preferably a hydrogen atom or an alkyl group, wherein the alkyl group is further selected by one or more as necessary. Substituted with a substituent from halogen, hydroxy or cycloalkyl; R ^{2 is} preferably -C (O) R ⁷ ; and R ⁷ is alkyl.

一種製備通式(III)所示的化合物或其互變異構體、內消旋體、外消旋體、對映異構體、非對映異構體或其混合物形式，或其可藥用鹽的方法，該方法包括： A method for preparing a compound represented by general formula (III) or a tautomer, a racemate, a racemate, an enantiomer, a diastereomer or a mixture thereof, or a pharmaceutically acceptable form thereof Salt method, the method includes:

通式(III-A)化合物與通式(I-B)化合物在鹼性條件下，視需要在催化劑作用下進行取代反應得到通式(III-C)化合物；通式(III-C)化合物在溶劑中，酸性條件下，進行脫保護反應，視需要進一步進行取代反應得到通式(III)化合物；其中：X為鹵素；Boc為第三丁氧羰基；R為烷基，較佳為丁基；，A¹，A²，Y，R¹至R⁶的定義如通式(I)中所定義；R⁴較佳為氫原子或烷基，其中該烷基視需要進一步被一個或多個選自鹵素、羥基或環烷基的取代基所取代；R²較佳為-C(O)R⁷；且R⁷為烷基。 The compound of the general formula (III-A) and the compound of the general formula (IB) are subjected to a substitution reaction under a basic condition under the action of a catalyst to obtain a compound of the general formula (III-C); the compound of the general formula (III-C) is in a solvent Under acidic conditions, a deprotection reaction is performed, and a substitution reaction is further performed as necessary to obtain a compound of the general formula (III); wherein: X is a halogen; Boc is a third butoxycarbonyl group; R is an alkyl group, preferably butyl; , A ¹ , A ² , Y, R ¹ to R ⁶ are as defined in the general formula (I); R ^{4 is} preferably a hydrogen atom or an alkyl group, wherein the alkyl group is further selected by one or more as necessary. Substituted with a substituent from halogen, hydroxy or cycloalkyl; R ^{2 is} preferably -C (O) R ⁷ ; and R ⁷ is alkyl.

提供鹼性條件的試劑包括有機鹼和無機鹼類，該有機鹼類包括但不限於六甲基二矽基胺基鋰、六甲基二矽基胺基鈉、二異丙基胺基鋰、三乙胺、吡啶、2,6-二甲基吡啶、N,N-二異丙基乙基胺、正丁基鋰、第三丁醇鉀或四丁基溴化銨，該無機鹼類包括但不限於碳酸銫、碳酸鈉、碳酸氫鈉、碳酸鉀、碳酸氫鉀、氫氧化鋰、氫氧化鈉、氫氧化鉀或氫化鈉。 Reagents that provide basic conditions include organic bases and inorganic bases. The organic bases include, but are not limited to, lithium hexamethyldisilazide, sodium hexamethyldisilazide, lithium diisopropylamide, Triethylamine, pyridine, 2,6-dimethylpyridine, N , N -diisopropylethylamine, n-butyllithium, potassium tert-butoxide or tetrabutylammonium bromide, the inorganic bases include It is not limited to cesium carbonate, sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, lithium hydroxide, sodium hydroxide, potassium hydroxide, or sodium hydride.

提供酸性的條件包括但不限於甲酸、乙酸、鹽酸、硫酸、甲磺酸、三氟乙酸和羥基乙磺酸，較佳三氟乙酸或羥基乙磺酸。 Conditions for providing acidity include, but are not limited to, formic acid, acetic acid, hydrochloric acid, sulfuric acid, methanesulfonic acid, trifluoroacetic acid, and isethionate, preferably trifluoroacetic acid or isethionate.

催化劑包括但不限於4,5-雙二苯基膦-9,9-二甲基氧雜蒽、三(二亞苄基丙酮)二鈀、1,1'-聯萘-2,2'-二苯膦、[1,1'-雙(二苯基磷)二茂鐵]二氯化鈀、二(三苯基膦)二氯化鈀、三苯基膦、二氯化鈀、醋酸鈀、碘化亞銅、鈀/碳或蘭尼鎳。 Catalysts include, but are not limited to, 4,5-bisdiphenylphosphine-9,9-dimethylxanthene, tris (dibenzylideneacetone) dipalladium, 1,1'-binaphalene-2,2'- Diphenylphosphine, [1,1'-bis (diphenylphosphonium) ferrocene] palladium dichloride, bis (triphenylphosphine) palladium dichloride, triphenylphosphine, palladium dichloride, palladium acetate , Cuprous iodide, palladium / carbon, or Raney nickel.

所用溶劑包括但不限於：1,4-二噁烷、甲苯、水、乙腈、四氫呋喃、二氯甲烷、1,2-二氯乙烷、甲醇、乙醇、正丁醇、二甲基亞碸或N,N-二甲基甲醯胺。 Solvents used include, but are not limited to: 1,4-dioxane, toluene, water, acetonitrile, tetrahydrofuran, dichloromethane, 1,2-dichloroethane, methanol, ethanol, n-butanol, dimethylsulfinium or N, N -dimethylformamide.

以下結合實施例進一步描述本發明，但這些實施例並非限制本發明的範圍。 The present invention is further described with reference to the following examples, but these examples do not limit the scope of the present invention.

本發明實施例中未注明具體條件的實驗方法，通常按照常規條件，或按照原料或商品製造廠商所建議的條件。未注明具體來源的試劑，為市場購買的常規試劑。 The experimental methods without specific conditions in the examples of the present invention generally follow conventional conditions or conditions recommended by raw material or commodity manufacturers. The reagents without specific sources are conventional reagents purchased on the market.

(實施例) (Example)

化合物的結構是藉由核磁共振(NMR)或/和質譜(MS)來確定的。NMR位移(δ)以10^-6(ppm)的單位給出。NMR的測定是用Bruker AVANCE-400核磁儀，測定溶劑為氘代二甲基亞碸(DMSO-d ₆)，氘代氯仿(CDCl₃)，內標為四甲基矽烷(TMS)。 The structure of the compound is determined by nuclear magnetic resonance (NMR) or / and mass spectrometry (MS). The NMR shift ( δ ) is given in units of 10 ^-6 (ppm). The NMR measurement was performed using a Bruker AVANCE-400 nuclear magnetic analyzer. The measurement solvents were deuterated dimethylsulfinium (DMSO- d ₆ ), deuterated chloroform (CDCl ₃ ), and the internal standard was tetramethylsilane (TMS).

MS的測定用FINNIGAN LCQAd(ESI)質譜儀(生產商：Thermo，型號：Finnigan LCQ advantage MAX)。 MS was measured using a FINNIGAN LCQAd (ESI) mass spectrometer (manufacturer: Thermo, model: Finnigan LCQ advantage MAX).

HPLC的測定使用安捷倫1200DAD高壓液相色譜儀(Sunfire C18 150×4.6mm色譜管柱)和Waters 2695-2996高壓液相色譜儀(Gimini C18 150×4.6mm色譜管柱)。 The HPLC was measured using an Agilent 1200 DAD high-pressure liquid chromatography (Sunfire C18 150 × 4.6 mm column) and a Waters 2695-2996 high-pressure liquid chromatography (Gimini C18 150 × 4.6 mm column).

薄層色譜矽膠板使用煙臺黃海HSGF254或青島GF254矽膠板，薄層色譜法(TLC)使用的矽膠板採用的規格是0.15mm至0.2mm，薄層色譜分離純化產品採用的規格是0.4mm至0.5mm。 The thin-layer chromatography silica gel plate uses Yantai Huanghai HSGF254 or Qingdao GF254 silicone plate. The thin-layer chromatography (TLC) silicon plate uses a size of 0.15mm to 0.2mm. The thin-layer chromatography separation and purification product uses a size of 0.4mm to 0.5. mm.

管柱色譜一般使用煙臺黃海矽膠200~300目矽膠為載體。 Column chromatography generally uses Yantai Huanghai Silicone 200 ~ 300 mesh silica gel as the carrier.

本發明的已知的起始原料可以採用或按照本領域已知的方法來合成，或可購買自ABCR GmbH & Co.KG、Acros Organics、Aldrich Chemical Company、韶遠化學科技(Accela ChemBio Inc)、達瑞化學品等公司。 The known starting materials of the present invention can be synthesized by or in accordance with methods known in the art, or can be purchased from ABCR GmbH & Co. KG, Acros Organics, Aldrich Chemical Company, Accela ChemBio Inc, Dari Chemicals and other companies.

實施例中無特殊說明，反應能夠均在氬氣氛或氮氣氛下進行。 There is no special description in the examples, and the reaction can be performed under an argon atmosphere or a nitrogen atmosphere.

氬氣氛或氮氣氛是指反應瓶連接一個約1L容積的氬氣或氮氣氣球。 An argon or nitrogen atmosphere means that the reaction flask is connected to an argon or nitrogen balloon with a volume of about 1 L.

氫氣氛是指反應瓶連接一個約1L容積的氫氣氣球。 The hydrogen atmosphere means that a reaction balloon is connected to a hydrogen gas balloon with a volume of about 1 L.

加壓氫化反應使用Parr 3916EKX型氫化儀和清藍QL-500型氫氣發生器或HC2-SS型氫化儀。 Pressurized hydrogenation reaction uses Parr 3916EKX type hydrogenation instrument and clear blue QL-500 type hydrogen generator or HC2-SS type hydrogenation instrument.

氫化反應通常抽真空，充入氫氣，重複操作3次。 The hydrogenation reaction is usually evacuated and filled with hydrogen, and the operation is repeated 3 times.

實施例中無特殊說明，溶液是指水溶液。 There is no special description in the examples, and the solution means an aqueous solution.

實施例中無特殊說明，反應的溫度為室溫，為20℃至30℃。 There is no special description in the examples, and the reaction temperature is room temperature, which is 20 ° C to 30 ° C.

實施例中的反應進程的監測採用薄層色譜法(TLC)，反應所使用的展開劑的體系有：A：二氯甲烷和甲醇體系，B：正己烷和乙酸乙酯體系，C：石油醚和乙酸乙酯體系，溶劑的體積比根據化合物的極性不同而進行調節。 The monitoring of the reaction progress in the examples uses thin layer chromatography (TLC). The developing systems used in the reaction are: A: dichloromethane and methanol system, B: n-hexane and ethyl acetate system, C: petroleum ether With ethyl acetate, the volume ratio of the solvent is adjusted according to the polarity of the compound.

純化化合物採用的管柱色譜的洗脫劑的體系和薄層色譜法的展開劑體系包括：A：二氯甲烷和甲醇體系，B：正己烷和乙酸乙酯體系，C：二氯甲烷、甲醇和乙酸乙酯體系，溶劑的體積比根據化合物的極性不同而進行調節，也可以加入少量的三乙胺和醋酸等鹼性或酸性試劑進行調節。 The eluent system for column chromatography and the eluent system for thin-layer chromatography for purification of compounds include: A: dichloromethane and methanol system, B: n-hexane and ethyl acetate system, C: dichloromethane and methanol And ethyl acetate system, the volume ratio of the solvent is adjusted according to the polarity of the compound, and a small amount of three Adjust with alkaline or acidic reagents such as ethylamine and acetic acid.

實施例1 Example 1

6-乙醯基-8-環戊基-5-甲基-2-((1',2',3',6'-四氫-[3,4'-聯吡啶]-6-基)胺基)吡啶並[2,3-d]嘧啶-7(8H)-酮 6-Ethyl-8-cyclopentyl-5-methyl-2-((1 ', 2', 3 ', 6'-tetrahydro- [3,4'-bipyridine] -6-yl) Amine) pyrido [2,3- d ] pyrimidin-7 ( 8H ) -one

第一步 first step 2-胺基-6-溴-8-環戊基-5-甲基吡啶並[2,3-d]嘧啶-7(8H)-酮 2-amino-6-bromo-8-cyclopentyl-5-methylpyrido [2,3- d ] pyrimidin-7 ( 8H ) -one

依次將6-溴-2-氯-8-環戊基-5-甲基吡啶並[2,3-d]嘧啶-7(8H)-酮1a(5g，14.59mmol，採用“專利申請WO2008032157” 公開的方法製備而得)、2mL氨水和20mL N,N-二甲基甲醯胺加入50mL茄形瓶中，70℃下攪拌反應1小時。冷卻至室溫，白色晶體析出，加入50mL正己烷，攪拌5分鐘，抽濾，濾餅用乙酸乙酯和正己烷(V/V=1：10)的混合溶液洗滌，固體直接乾燥，得到粗品標題產物2-胺基-6-溴-8-環戊基-5-甲基吡啶並[2,3-d]嘧啶-7(8H)-酮1b(5.0g，淺黃色固體)。 Sequentially bromo-2-chloro-8-cyclopentyl-5-methyl-pyrido [2,3- d] pyrimidin -7 (8 H) - one 1a (5g, 14.59mmol, a "patent application WO2008032157 It was prepared by the disclosed method), 2 mL of ammonia water and 20 mL of N, N -dimethylformamide were added to a 50 mL eggplant-shaped bottle, and the reaction was stirred at 70 ° C. for 1 hour. Cooled to room temperature, white crystals precipitated, added 50 mL of n-hexane, stirred for 5 minutes, filtered with suction, washed the filter cake with a mixed solution of ethyl acetate and n-hexane (V / V = 1: 10), and dried the solid directly to obtain a crude product. The title product 2-amino-6-bromo-8-cyclopentyl-5-methylpyrido [2,3- d ] pyrimidin-7 ( 8H ) -one 1b (5.0 g, light yellow solid).

MS m/z(ESI)：324.9[M+1] MS m / z (ESI): 324.9 [M + 1]

第二步 Second step 2-胺基-6-(1-丁氧基乙烯基)-8-環戊基-5-甲基吡啶並[2,3-d]嘧啶-7(8H)-酮 2-amino-6- (1-butoxyvinyl) -8-cyclopentyl-5-methylpyrido [2,3- d ] pyrimidin-7 ( 8H ) -one

氬氣氛下，依次將粗品2-胺基-6-溴-8-環戊基-5-甲基吡啶並[2,3-d]嘧啶-7(8H)-酮1b(4.7g，14.54mmol)、乙烯基丁醚(3.76mL，29.20mmol)、[1,1'-雙(二苯基磷)二茂鐵]二氯化鈀(1.10g，1.50mmool、N,N-二異丙基乙基胺(5mL，29.2mmol)和30mL正丁醇加入100mL茄形瓶中，95℃下攪拌反應12小時。冷卻至室溫，減壓濃縮，用矽膠管柱色譜法以洗脫劑體系B純化所得殘餘物，得到標題產物2-胺基-6-(1-丁氧基乙烯基)-8-環戊基-5-甲基吡啶並[2,3-d]嘧啶-7(8H)-酮1c(3.0g，淺黃色固體)，產率60.0%。 Under an argon atmosphere, followed by the crude 2-amino-6-bromo-8-cyclopentyl-5-methyl-pyrido [2,3- d] pyrimidin -7 (8 H) - one 1b (4.7g, 14.54 mmol), vinyl butyl ether (3.76mL, 29.20mmol), [1,1'-bis (diphenylphosphine) ferrocene] palladium dichloride (1.10g, 1.50mmool, N , N -diisopropyl Ethylethylamine (5mL, 29.2mmol) and 30mL n-butanol were added to a 100mL eggplant-shaped flask, and the reaction was stirred at 95 ° C for 12 hours. Cool to room temperature, concentrate under reduced pressure, and use silica gel column chromatography to elute the system B The resulting residue was purified to give the title product 2-amino-6- (1-butoxyvinyl) -8-cyclopentyl-5-methylpyrido [2,3- d ] pyrimidine-7 (8 H ) -one 1c (3.0 g, pale yellow solid), yield 60.0%.

MS m/z(ESI)：343.2[M+1] MS m / z (ESI): 343.2 [M + 1]

第三步 third step 6-氯-5',6'-二氫-[3,4'-聯吡啶]-1'(2'H)-羧酸第三丁酯 6-chloro-5 ', 6'-dihydro- [3,4'-bipyridine] -1' (2 ' H ) -carboxylic acid tert-butyl ester

依次將5-溴-2-氯吡啶1d(6.20g，0.032mol)、4-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)-5,6-二氫吡啶-1(2H)-羧酸第三丁酯1e(10g，0.032mol)、碳酸鈉(6.86g，0.068mol)和102.3mL 二噁烷和水(V/V=10：1)的混合溶劑加入250mL反應瓶中，氬氣氛下，加入[1,1'-雙(二苯基膦)二茂鐵]二氯化鈀二氯甲烷絡合物(1.89g，0.027mol)，108℃反應7小時。冷卻至室溫，過濾，濾餅用二氯甲烷(30mL×3)洗滌，濾液減壓濃縮，用矽膠管柱色譜法以洗脫劑體系B純化所得殘餘物，得到標題產物6-氯-5',6'-二氫-[3,4'-聯吡啶]-1'(2'H)-羧酸第三丁酯1f(8.11g，黃色液體)，產率86.2%。 5-bromo-2-chloropyridine 1d (6.20 g, 0.032 mol), 4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2 -Yl) -5,6-dihydropyridine-1 ( 2H ) -carboxylic acid third butyl ester 1e (10 g, 0.032 mol), sodium carbonate (6.86 g, 0.068 mol), and 102.3 mL of dioxane and water ( V / V = 10: 1) mixed solvent was added to a 250 mL reaction flask. Under an argon atmosphere, [1,1'-bis (diphenylphosphine) ferrocene] palladium dichloromethane complex ( 1.89 g, 0.027 mol), and reacted at 108 ° C for 7 hours. Cool to room temperature, filter, wash the filter cake with dichloromethane (30 mL x 3), concentrate the filtrate under reduced pressure, and purify the resulting residue with silica gel column chromatography using eluent system B to give the title product 6-chloro-5 ', 6'-dihydro - [3,4'-bipyridine] -1' (2 'H) - carboxylic acid tert-butyl ester 1f (8.11g, yellow liquid), a yield of 86.2%.

MS m/z(ESI)：295.3[M+1] MS m / z (ESI): 295.3 [M + 1]

第四步 the fourth step 6-((6-(1-丁氧基乙烯基)-8-環戊基-5-甲基-7-側氧基-7,8-二氫吡啶並[2,3-d]嘧啶-2-基)胺基)-5',6'-二氫-[3,4'-聯吡啶]-1'(2'H)-羧酸第三丁酯 6-((6- (1-butoxyvinyl) -8-cyclopentyl-5-methyl-7- pendantoxy-7,8-dihydropyrido [2,3- d ] pyrimidine- 2- yl) amino) -5 ', 6'-dihydro - [3,4'-bipyridine] -1' (2 'H) - carboxylic acid tert-butyl ester

依次將6-氯-5',6'-二氫-[3,4'-聯吡啶]-1'(2'H)-羧酸第三丁酯1f(500mg，1.70mmol)、2-胺基-6-(1-丁氧基乙烯基)-8-環戊基-5-甲基吡啶並[2,3-d]嘧啶-7(8H)-酮1c(586mg，1.70mmol)、碳酸銫(1.10g，3.40mmol)和4,5-雙二苯基膦-9,9-二甲基氧雜蒽(156mg，0.27mmol)加入裝有15mL二噁烷的反應瓶中。氬氣氛下，加入三(二亞苄基丙酮)二鈀(125mg，0.14mmol)，104℃反應15小時。停止反應，冷卻至室溫，過濾，濾餅用二氯甲烷洗滌(15mL×3)，濾液減壓濃縮，用薄層色譜法以展開劑體系C純化所得殘餘物，得到粗品標題產物6-((6-(1-丁氧基乙烯基)-8-環戊基-5-甲基-7-側氧基-7,8-二氫吡啶並[2,3-d]嘧啶-2-基)胺基)-5',6'-二氫-[3,4'-聯吡啶]-1'(2'H)-羧酸第三丁酯1g(1.12g，黃色固體)。 Sequentially chloro-5 ', 6'-dihydro - [3,4'-bipyridine] -1' (2 'H) - carboxylic acid tert-butyl ester 1f (500mg, 1.70mmol), 2- amine -6- (1-butoxy-vinyl) -8-cyclopentyl-5-methyl-pyrido [2,3- d] pyrimidin -7 (8 H) - -one 1c (586mg, 1.70mmol), Cesium carbonate (1.10 g, 3.40 mmol) and 4,5-bisdiphenylphosphine-9,9-dimethylxanthene (156 mg, 0.27 mmol) were added to a reaction flask containing 15 mL of dioxane. Under an argon atmosphere, tris (dibenzylideneacetone) dipalladium (125 mg, 0.14 mmol) was added, and the mixture was reacted at 104 ° C for 15 hours. The reaction was stopped, cooled to room temperature, filtered, the filter cake was washed with dichloromethane (15 mL × 3), the filtrate was concentrated under reduced pressure, and the resulting residue was purified by thin layer chromatography with developing system C to give the crude title product 6- ( (6- (1-butoxyvinyl) -8-cyclopentyl-5-methyl-7- pendantoxy-7,8-dihydropyrido [2,3- d ] pyrimidin-2-yl ) amino) -5 ', 6'-dihydro - [3,4'-bipyridine] -1' (2 'H) - carboxylic acid tert-butyl ester 1g (1.12g, yellow solid).

MS m/z(ESI)：601.2[M+1] MS m / z (ESI): 601.2 [M + 1]

第五步 the fifth step 6-乙醯基-8-環戊基-5-甲基-2-((1',2',3',6'-四氫-[3,4'-聯吡啶]-6-基)胺基)吡啶並[2,3-d]嘧啶-7(8H)-酮 6-Ethyl-8-cyclopentyl-5-methyl-2-((1 ', 2', 3 ', 6'-tetrahydro- [3,4'-bipyridine] -6-yl) Amine) pyrido [2,3- d ] pyrimidin-7 ( 8H ) -one

將粗品6-((6-(1-丁氧基乙烯基)-8-環戊基-5-甲基-7-側氧基-7,8-二氫吡啶並[2,3-d]嘧啶-2-基)胺基)-5',6'-二氫-[3,4'-聯吡啶]-1'(2'H)-羧酸第三丁酯1g(750mg，1.25mmol)溶於6mL二氯甲烷中，加入2mL三氟乙酸，室溫反應1.5小時。減壓濃縮除去溶劑，加入10mL二氯甲烷和2mL甲醇，滴加氨水調節pH為8。減壓濃縮除去溶劑，加入二氯甲烷和甲醇(V/V=10：1)的混合溶劑(10mL×1)洗滌，過濾，濾液減壓濃縮，得到粗品標題產物6-乙醯基-8-環戊基-5-甲基-2-((1',2',3',6'-四氫-[3,4'-聯吡啶]-6-基)胺基)吡啶並[2,3-d]嘧啶-7(8H)-酮1(750mg，黃色固體)。取150mg標題產物，用薄層色譜法以展開劑體系A純化，得到70mg產物。 The crude 6-((6- (1-butoxyvinyl) -8-cyclopentyl-5-methyl-7- pendantoxy-7,8-dihydropyrido [2,3- d ] pyrimidin-2-yl) amino) -5 ', 6'-dihydro - [3,4'-bipyridine] -1' (2 'H) - carboxylic acid tert-butyl ester 1g (750mg, 1.25mmol) Dissolve in 6 mL of dichloromethane, add 2 mL of trifluoroacetic acid, and react at room temperature for 1.5 hours. The solvent was removed by concentration under reduced pressure, 10 mL of dichloromethane and 2 mL of methanol were added, and aqueous ammonia was added dropwise to adjust the pH to 8. The solvent was removed by concentration under reduced pressure, and a mixed solvent (10 mL × 1) of dichloromethane and methanol (V / V = 10: 1) was added for washing, filtration, and the filtrate was concentrated under reduced pressure to give the crude title product 6-ethylamyl-8- Cyclopentyl-5-methyl-2-((1 ', 2', 3 ', 6'-tetrahydro- [3,4'-bipyridine] -6-yl) amino) pyrido [2, 3- d ] Pyrimidine-7 ( 8H ) -one 1 (750 mg, yellow solid). 150 mg of the title product was taken and purified by developing solvent system A using thin layer chromatography to obtain 70 mg of product.

MS m/z(ESI)：445.3[M+1] MS m / z (ESI): 445.3 [M + 1]

¹H NMR(400MHz,DMSO-d ₆)δ 10.38(s,1H),9.01(s,1H),8.40(s,1H),8.05(d,1H),7.87(d,1H),6.27(s,1H),5.88-5.85(m,1H),2.94-2.91(m,2H),2.40(s,3H),2.36(s,1H),2.32(s,3H),2.27-2.24(m,3H),1.94-1.90(m,2H),1.82-1.79(m,2H),1.62-1.60(m,2H),1.25-1.22(m,3H) ¹ H NMR (400MHz, DMSO- d ₆ ) δ 10.38 (s, 1H), 9.01 (s, 1H), 8.40 (s, 1H), 8.05 (d, 1H), 7.87 (d, 1H), 6.27 (s , 1H), 5.88-5.85 (m, 1H), 2.94-2.91 (m, 2H), 2.40 (s, 3H), 2.36 (s, 1H), 2.32 (s, 3H), 2.27-2.24 (m, 3H ), 1.94-1.90 (m, 2H), 1.82-1.79 (m, 2H), 1.62-1.60 (m, 2H), 1.25-1.22 (m, 3H)

實施例2 Example 2

6-乙醯基-8-環戊基-5-甲基-2-((1'-甲基-1',2',3',6'-四氫-[3,4'-聯吡啶]-6-基)胺基)吡啶並[2,3-d]嘧啶-7(8H)-酮 6-Ethyl-8-cyclopentyl-5-methyl-2-((1'-methyl-1 ', 2', 3 ', 6'-tetrahydro- [3,4'-bipyridine ] -6-yl) amino) pyrido [2,3- d ] pyrimidin-7 ( 8H ) -one

依次將6-乙醯基-8-環戊基-5-甲基-2-((1',2',3',6'-四氫-[3,4'-聯吡啶]-6-基)胺基)吡啶並[2,3-d]嘧啶-7(8H)-酮1(100mg，0.22mmol)、37%甲醛水溶液(120mg，1.48mmol)和10mL 1,2-二氯乙烷加入到反應瓶中，加入醋酸硼氫化鈉(95mg，1.48mmol)。室溫反應15小時，停止反應，加入4mL甲醇，滴加氨水調節pH至8~9，減壓蒸餾濃縮，得到標題產物6-乙醯基-8-環戊基-5-甲基-2-((1'-甲基-1',2',3',6'-四氫-[3,4'-聯吡啶]-6-基)胺基)吡啶並[2,3-d]嘧啶-7(8H)-酮2(35mg，黃色固體)，產率：34.7%。 6-Ethyl-8-cyclopentyl-5-methyl-2-((1 ', 2', 3 ', 6'-tetrahydro- [3,4'-bipyridine] -6- yl) amino) pyrido [2,3- d] pyrimidin -7 (8 H) - one 1 (100mg, 0.22mmol), 37 % aqueous formaldehyde (120mg, 1.48mmol) and 10mL 1,2- dichloroethane The alkane was added to the reaction flask, and sodium acetate borohydride (95 mg, 1.48 mmol) was added. The reaction was allowed to take place at room temperature for 15 hours. The reaction was stopped, 4 mL of methanol was added, and the pH was adjusted to 8-9 by dropwise addition of ammonia water. The residue was concentrated under reduced pressure to obtain the title product 6-ethylamyl-8-cyclopentyl-5-methyl-2- ((1'-methyl-1 ', 2', 3 ', 6'-tetrahydro- [3,4'-bipyridine] -6-yl) amino) pyrido [2,3- d ] pyrimidine -7 ( 8H ) -one 2 (35 mg, yellow solid), yield: 34.7%.

MS m/z(ESI)：459.3[M+1] MS m / z (ESI): 459.3 [M + 1]

¹H NMR(400MHz,DMSO-d ₆)δ 10.49(s,1H),9.02(s,1H),8.48(s,1H),8.12(d,1H),7.96(d,1H),6.27(s,1H),5.88-5.85(m,1H),3.73(s,2H),2.77(s,4H),2.33(s,3H),2.26(s,3H),2.27-2.24(m,2H),1.97-1.95(m,2H),1.84-1.81(m,2H),1.64-1.61(m,2H),1.25-1.22(m,3H) ¹ H NMR (400MHz, DMSO- d ₆ ) δ 10.49 (s, 1H), 9.02 (s, 1H), 8.48 (s, 1H), 8.12 (d, 1H), 7.96 (d, 1H), 6.27 (s , 1H), 5.88-5.85 (m, 1H), 3.73 (s, 2H), 2.77 (s, 4H), 2.33 (s, 3H), 2.26 (s, 3H), 2.27-2.24 (m, 2H), 1.97-1.95 (m, 2H), 1.84-1.81 (m, 2H), 1.64-1.61 (m, 2H), 1.25-1.22 (m, 3H)

實施例3 Example 3

6-乙醯基-8-環戊基-2-((5-(4-羥基哌啶-4-基)吡啶-2-基)胺基)-5-甲基吡啶並[2,3-d]嘧啶-7(8H)-酮 6-Ethyl-8-cyclopentyl-2-(((5- (4-hydroxypiperidin-4-yl) pyridin-2-yl) amino) -5-methylpyrido [2,3- d ) pyrimidine-7 ( 8H ) -one

第一步 first step 4-(6-氯吡啶-3-基)-4-羥基哌啶-1-羧酸第三丁酯 4- (6-chloropyridin-3-yl) -4-hydroxypiperidine-1-carboxylic acid tert-butyl ester

在氬氣保護下，將5-溴-2-氯吡啶1d(500mg，2.60mmol)和20mL四氫呋喃加入100mL茄形瓶中，乾冰-丙酮浴冷卻至-70℃，往反應液中加入1.6M的正丁基鋰(1.8mL，2.86mmol)，並在此溫度下攪拌30分鐘，然後往反應物中加入預製的4-羰基哌啶-1-羧酸第三丁酯(570mg，2.86mmol)的四氫呋喃溶液，然後在乾冰-丙酮浴保護下反應1小時。加入20mL飽和氯化銨溶液淬滅反應，用乙酸乙酯萃取(50mL×3)，合併有機相，無水硫酸鈉乾燥，過濾，濾液減壓濃縮，用薄層色譜法以展開劑體系A純化所得殘餘物，得到標題產物4-(6-氯吡啶-3-基)-4-羥基哌啶-1-羧酸第三丁酯3a(80mg，黃色固體)，產率：10%。 Under the protection of argon gas, 5-bromo-2-chloropyridine 1d (500mg, 2.60mmol) and 20mL tetrahydrofuran were added to a 100mL eggplant-shaped flask, and the dry ice-acetone bath was cooled to -70 ° C, and 1.6M of the reaction solution was added to the reaction solution. N-butyllithium (1.8 mL, 2.86 mmol), and stirred at this temperature for 30 minutes, and then added the preformed 4-carbonyl piperidine-1-carboxylic acid third butyl ester (570 mg, 2.86 mmol) to Tetrahydrofuran solution, then reacted for 1 hour under the protection of a dry ice-acetone bath. 20 mL of saturated ammonium chloride solution was added to quench the reaction, and the mixture was extracted with ethyl acetate (50 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue gave the title product 4- (6-chloropyridin-3-yl) -4-hydroxypiperidine-1-carboxylic acid tert-butyl Ester 3a (80 mg, yellow solid), yield: 10%.

MS m/z(ESI)：313.1[M+1] MS m / z (ESI): 313.1 [M + 1]

第二步 Second step 4-(6-((6-(1-丁氧基乙烯基)-8-環戊基-5-甲基-7-側氧基-7,8-二氫吡啶並[2,3-d]嘧啶-2-基)胺基)吡啶-3-基)-4-羥基哌啶-1-羧酸第三丁酯 4- (6-((6- (1-butoxyvinyl) -8-cyclopentyl-5-methyl-7- pendantoxy-7,8-dihydropyrido [2,3- d ] Pyrimidin-2-yl) amino) pyridin-3-yl) -4-hydroxypiperidine-1-carboxylic acid tert-butyl ester

依次將4-(6-氯吡啶-3-基)-4-羥基哌啶-1-羧酸第三丁酯3a(80mg，0.26mmol)、2-胺基-6-(1-丁氧基乙烯基)-8-環戊基-5-甲基吡啶並[2,3-d]嘧啶-7(8H)-酮1c(80mg，0.26mmol)、三(二亞苄基丙酮)二鈀(24mg，0.026mmol)、1,1'-聯萘-2,2'-二苯膦(32mg，0.052mmol)和碳酸銫(170mg，0.52mmol)分別加入50mL的茄形瓶中，然後加入20mL的二噁烷，氬氣氛下，在90℃條件下攪拌反應16小時，將反應液減壓蒸餾，用薄層色譜法以展開劑體系A純化所得殘餘物，得到標題產物4-(6-((6-(1-丁氧基乙烯基)-8-環戊基-5-甲基-7-側氧基-7,8-二氫吡啶並[2,3-d]嘧啶-2-基)胺基)吡啶-3-基)-4-羥基哌啶-1-羧酸第三丁酯3b(60mg，黃色固體)，產率37.3%。 4- (6-chloropyridin-3-yl) -4-hydroxypiperidine-1-carboxylic acid third butyl ester 3a (80 mg, 0.26 mmol), 2-amino-6- (1-butoxy vinyl) -8-cyclopentyl-5-methyl-pyrido [2,3- d] pyrimidin -7 (8 H) - -one 1c (80mg, 0.26mmol), tris (dibenzylideneacetone) dipalladium (24mg, 0.026mmol), 1,1'-binapthyl-2,2'-diphenylphosphine (32mg, 0.052mmol) and cesium carbonate (170mg, 0.52mmol) were added to a 50mL eggplant-shaped bottle, and then 20mL The reaction was stirred at 90 ° C for 16 hours under an argon atmosphere under dioxane, and the reaction solution was distilled under reduced pressure. The obtained residue was purified by thin-layer chromatography with developing system A to obtain the title product 4- (6- ( (6- (1-butoxyvinyl) -8-cyclopentyl-5-methyl-7- pendantoxy-7,8-dihydropyrido [2,3- d ] pyrimidin-2-yl ) Amino) pyridin-3-yl) -4-hydroxypiperidine-1-carboxylic acid third butyl ester 3b (60 mg, yellow solid), yield 37.3%.

MS m/z(ESI)：619.2[M+1] MS m / z (ESI): 619.2 [M + 1]

第三步 third step 6-乙醯基-8-環戊基-2-((5-(4-羥基哌啶-4-基)吡啶-2-基)胺基)-5-甲基吡啶並[2,3-d]嘧啶-7(8H)-酮 6-Ethyl-8-cyclopentyl-2-(((5- (4-hydroxypiperidin-4-yl) pyridin-2-yl) amino) -5-methylpyrido [2,3- d ) pyrimidine-7 ( 8H ) -one

將4-(6-((6-(1-丁氧基乙烯基)-8-環戊基-5-甲基-7-側氧基-7,8-二氫吡啶並[2,3-d]嘧啶-2-基)胺基)吡啶-3-基)-4-羥基哌啶-1-羧酸第三丁酯3b(60mg，0.097mmol)和羥基乙磺酸(50mg，0.387mmol)加入25mL茄形瓶中，然後加入2mL 30%的甲醇水溶液，攪拌均勻，在60℃條件下反應1小時，然後往反應液中加入 10mL的飽和碳酸氫鈉水溶液，用乙酸乙酯萃取(15mL×3)，合併有機相，無水硫酸鈉乾燥，過濾，濾液減壓濃縮，用薄層色譜法以展開劑體系A純化所得殘餘物，得到標題產物6-乙醯基-8-環戊基-2-((5-(4-羥基哌啶-4-基)吡啶-2-基)胺基)-5-甲基吡啶並[2,3-d]嘧啶-7(8H)-酮3(30mg，淺黃色固體)，產率66.8%。 4- (6-((6- (1-butoxyvinyl) -8-cyclopentyl-5-methyl-7- pendantoxy-7,8-dihydropyrido [2,3- d ) Pyrimidin-2-yl) amino) pyridin-3-yl) -4-hydroxypiperidine-1-carboxylic acid third butyl ester 3b (60 mg, 0.097 mmol) and isethionate (50 mg, 0.387 mmol) Add to a 25mL eggplant-shaped bottle, then add 2mL of a 30% methanol aqueous solution, stir well, and react at 60 ° C for 1 hour. Then add 10mL of a saturated sodium bicarbonate aqueous solution to the reaction solution, and extract with ethyl acetate (15mL × 3) The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, and the resulting residue was purified by thin layer chromatography using developing system A to obtain the title product 6-ethylamyl-8-cyclopentyl-2 -((5- (4-hydroxypiperidin-4-yl) pyridin-2-yl) amino) -5-methylpyrido [2,3- d ] pyrimidin-7 ( 8H ) -one 3 ( 30 mg, pale yellow solid), yield 66.8%.

MS m/z(ESI)：463.1[M+1] MS m / z (ESI): 463.1 [M + 1]

¹H NMR(400MHz,DMSO-d ₆)δ 10.38(s,1H),8.97(s,1H),8.42(s,1H),8.06(d,1H),7.87(d,1H),5.83-5.82(m,1H),5.60-5.58(m,1H),2.82(s,3H),2.54-2.52(m,1H),2.42(s,3H),2.35-2.32(m,2H),2.28-2.26(m,2H),2.20-2.17(m,1H),1.92-1.90(m,5H),1.80-1.77(m,2H),1.60-1.58(m,2H),1.25-1.23(m,2H) ¹ H NMR (400MHz, DMSO- d ₆ ) δ 10.38 (s, 1H), 8.97 (s, 1H), 8.42 (s, 1H), 8.06 (d, 1H), 7.87 (d, 1H), 5.83-5.82 (m, 1H), 5.60-5.58 (m, 1H), 2.82 (s, 3H), 2.54-2.52 (m, 1H), 2.42 (s, 3H), 2.35-2.32 (m, 2H), 2.28-2.26 (m, 2H), 2.20-2.17 (m, 1H), 1.92-1.90 (m, 5H), 1.80-1.77 (m, 2H), 1.60-1.58 (m, 2H), 1.25-1.23 (m, 2H)

實施例4 Example 4

6-乙醯基-8-環戊基-2-((5-(4-羥基-1-甲基哌啶-4-基)吡啶-2-基)胺基)-5-甲基吡啶並[2,3-d]嘧啶-7(8H)-酮 6-Ethyl-8-cyclopentyl-2-(((5- (4-hydroxy-1-methylpiperidin-4-yl) pyridin-2-yl) amino) -5-methylpyrido [2,3- d ] pyrimidin-7 (8 H ) -one

將6-乙醯基-8-環戊基-2-((5-(4-羥基哌啶-4-基)吡啶-2-基)胺基)-5-甲基吡啶並[2,3-d]嘧啶-7(8H)-酮3(20mg，0.043mmol)、36%甲醛水溶液(6.5mg，0.065mmol)和10mL二氯甲烷加入到25mL的茄形瓶中，在室溫條件下攪拌2小時後，加入醋酸硼氫化鈉(27mg，0.129mmol)，並在室溫條件下繼續攪拌16小時，停止反應，加入1mL氨水，減壓濃縮蒸乾，用薄層色譜法以展開劑體系A純化所得殘餘物，得到標題產物6-乙醯基-8-環戊基-2-((5-(4-羥基-1-甲基哌啶-4-基)吡啶-2-基)胺基)-5-甲基吡啶並[2,3-d]嘧啶-7(8H)-酮4(10mg，黃色固體)，產率：50.0%。 6-Ethyl-8-cyclopentyl-2-(((5- (4-hydroxypiperidin-4-yl) pyridin-2-yl) amino) -5-methylpyrido [2,3 -d ] Pyrimidine-7 (8 H ) -one 3 (20 mg, 0.043 mmol), 36% aqueous formaldehyde solution (6.5 mg, 0.065 mmol) and 10 mL of dichloromethane were added to a 25 mL eggplant-shaped bottle at room temperature After stirring for 2 hours, sodium acetate borohydride (27 mg, 0.129 mmol) was added, and stirring was continued at room temperature for 16 hours to stop the reaction. 1 mL of ammonia water was added, and concentrated to dryness under reduced pressure. Thin layer chromatography was used to develop the solvent system. A The obtained residue was purified to give the title product 6-ethylamyl-8-cyclopentyl-2-((5- (4-hydroxy-1-methylpiperidin-4-yl) pyridin-2-yl) amine Yl) -5-methylpyrido [2,3- d ] pyrimidin-7 ( 8H ) -one 4 (10 mg, yellow solid), yield: 50.0%.

MS m/z(ESI)：477.3[M+1] MS m / z (ESI): 477.3 [M + 1]

¹H NMR(400MHz,DMSO-d ₆)δ 10.42(s,1H),9.02(s,1H),8.46(s,1H),8.09(d,1H),7.90(d,1H),5.88-5.86(m,1H),5.69-5.64(m,1H),2.80(s,3H),2.55-2.53(m,1H),2.44(s,3H),2.38-2.36(m,2H),2.33(s,3H),2.27-2.25(m,2H),2.19-2.17(m,1H),1.91-1.88(m,4H),1.82-1.79(m,2H),1.61-1.59(m,2H),1.26-1.24(m,2H) ¹ H NMR (400MHz, DMSO- d ₆ ) δ 10.42 (s, 1H), 9.02 (s, 1H), 8.46 (s, 1H), 8.09 (d, 1H), 7.90 (d, 1H), 5.88-5.86 (m, 1H), 5.69-5.64 (m, 1H), 2.80 (s, 3H), 2.55-2.53 (m, 1H), 2.44 (s, 3H), 2.38-2.36 (m, 2H), 2.33 (s , 3H), 2.27-2.25 (m, 2H), 2.19-2.17 (m, 1H), 1.91-1.88 (m, 4H), 1.82-1.79 (m, 2H), 1.61-1.59 (m, 2H), 1.26 -1.24 (m, 2H)

實施例5 Example 5

6-乙醯基-8-環戊基-2-((5-(4-氟-1-甲基哌啶-4-基)吡啶-2-基)胺基)-5-甲基吡啶並[2,3-d]嘧啶-7(8H)-酮 6-Ethyl-8-cyclopentyl-2-(((5- (4-fluoro-1-methylpiperidin-4-yl) pyridin-2-yl) amino) -5-methylpyrido [2,3- d ] pyrimidin-7 (8 H ) -one

將6-乙醯基-8-環戊基-2-((5-(4-羥基-1-甲基哌啶-4-基)吡啶-2-基)胺基)-5-甲基吡啶並[2,3-d]嘧啶-7(8H)-酮4(10mg，0.021mmol)溶於5mL的二氯甲烷中，然後在乾冰-丙酮浴冷卻下，加入二甲胺基三氟化硫(2滴)，攪拌30分鐘後TLC監測反應的進行，大部分原料未反應，補加2滴二甲胺基三氟化硫，攪拌1小時後，終止反應。加入15mL水淬滅反應，攪拌10分鐘後，分液分離出有機相，減壓濃縮蒸乾，用薄層色譜法以展開劑體系A純化所得殘餘物，得到標題產物6-乙醯基-8-環戊基-2-((5-(4-氟-1-甲基哌啶-4-基)吡啶-2-基)胺基)-5-甲基吡啶並[2,3-d]嘧啶-7(8H)-酮5(6mg，黃色固體)，產率60%。 6-Ethyl-8-cyclopentyl-2-(((5- (4-hydroxy-1-methylpiperidin-4-yl) pyridin-2-yl) amino) -5-methylpyridine [2,3- d ] pyrimidin-7 (8 H ) -one 4 (10 mg, 0.021 mmol) was dissolved in 5 mL of dichloromethane, and then in a dry ice-acetone bath, dimethylamino trifluoride was added Sulfur (2 drops). After stirring for 30 minutes, the progress of the reaction was monitored by TLC. Most of the raw materials were not reacted. Two drops of dimethylamino sulfur trifluoride were added. After stirring for 1 hour, the reaction was terminated. 15 mL of water was added to quench the reaction, and after stirring for 10 minutes, the organic phase was separated and separated. The organic layer was concentrated under reduced pressure and evaporated to dryness. The resulting residue was purified by thin layer chromatography using developing system A to give the title product 6-ethylamyl-8 -Cyclopentyl-2-((5- (4-fluoro-1-methylpiperidin-4-yl) pyridin-2-yl) amino) -5-methylpyrido [2,3- d ] Pyrimidine-7 ( 8H ) -one 5 (6 mg, yellow solid), yield 60%.

MS m/z(ESI)：479.3[M+1] MS m / z (ESI): 479.3 [M + 1]

¹H NMR(400MHz,DMSO-d ₆)δ 10.28(s,1H),9.02(s,1H),8.42(s,1H),8.12(d,1H),7.69-7.66(m,3H),5.87-5.84(m,1H),2.42(s,3H),2.32(s,1H),2.24-2.21(m,3H),1.99-1.96(m,4H),1.96-1.93(m,3H),1.92-1.89(m,3H),1.78(s,3H),1.60(s,3H) ¹ H NMR (400MHz, DMSO- d ₆ ) δ 10.28 (s, 1H), 9.02 (s, 1H), 8.42 (s, 1H), 8.12 (d, 1H), 7.69-7.66 (m, 3H), 5.87 -5.84 (m, 1H), 2.42 (s, 3H), 2.32 (s, 1H), 2.24-2.21 (m, 3H), 1.99-1.96 (m, 4H), 1.96-1.93 (m, 3H), 1.92 -1.89 (m, 3H), 1.78 (s, 3H), 1.60 (s, 3H)

實施例6 Example 6

6-乙醯基-8-環戊基-5-甲基-2-((5-(哌啶-4-基)吡啶-2-基)胺基)吡啶並[2,3-d]嘧啶-7(8H)-酮 6-Ethyl-8-cyclopentyl-5-methyl-2-((5- (piperidin-4-yl) pyridin-2-yl) amino) pyrido [2,3- d ] pyrimidine -7 (8 H ) -one

第一步 first step 6-硝基-5',6'-二氫-[3,4'-聯吡啶]-1'(2'H)-羧酸第三丁酯 6-nitro-5 ', 6'-dihydro - [3,4'-bipyridine] -1' (2 'H) - carboxylic acid tert-butyl ester

依次將5-溴-2-硝基吡啶6a(720mg，3.56mmol)、4-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)-5,6-二氫吡啶-1(2H)-羧酸第三丁酯1e(1g，3.24mmol)、碳酸銫(2.12g，6.50mmol)和17mL二噁烷和水(V/V=16：1)的混合溶劑加入封管中，氬氣氛下，加入[1,1'-雙(二苯基膦)二茂鐵]二氯化鈀二氯甲烷絡合物(230mg，0.32mmol)，85℃反應12小時。冷卻至室溫，減壓濃縮，用矽膠管柱色譜法以洗脫劑體系B純化所得殘餘物，得到標題產物6-硝基-5',6'-二氫-[3,4'-聯吡啶]-1'(2'H)-羧酸第三丁酯6b(677mg，淡黃色固體)，產率67.7%。 5-Bromo-2-nitropyridine 6a (720 mg, 3.56 mmol), 4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2 -Yl) -5,6-dihydropyridine-1 (2 H ) -carboxylic acid third butyl ester 1e (1 g, 3.24 mmol), cesium carbonate (2.12 g, 6.50 mmol) and 17 mL of dioxane and water (V / V = 16: 1) mixed solvent was added to the sealed tube, and [1,1'-bis (diphenylphosphine) ferrocene] palladium dichloromethane complex (230 mg, 0.32 mmol), and reacted at 85 ° C for 12 hours. It was cooled to room temperature, concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography using eluent system B to obtain the title product 6-nitro-5 ', 6'-dihydro- [3,4'-linked pyridinyl] -1 '(2' H) - carboxylic acid tert-butyl ester 6b (677mg, as a pale yellow solid), yield 67.7%.

MS m/z(ESI)：306.2[M+1] MS m / z (ESI): 306.2 [M + 1]

第二步 Second step 4-(6-胺基吡啶-3-基)哌啶-1-羧酸第三丁酯 Tert-butyl 4- (6-aminopyridin-3-yl) piperidine-1-carboxylic acid

將6-硝基-5',6'-二氫-[3,4'-聯吡啶]-1'(2'H)-羧酸第三丁酯6b(650mg，2.13mmol)溶於45mL甲醇中，加入10%鈀碳(250mg，cat)，氫氣置換三次，3個大氣壓下室溫反應12小時。停止反應，少量矽藻土過濾，濾餅用二氯甲烷和甲醇(V/V=10：1)的混合溶劑洗滌(20mL×1)，收集濾液，減壓濃縮，得到粗品標題產物4-(6-胺基吡啶-3-基)哌啶-1-羧酸第三丁酯6c(595mg，透明稠狀物)，直接用於下一步。 The 6-nitro-5 ', 6'-dihydro - [3,4'-bipyridine] -1' (2 'H) - carboxylic acid tert-butyl ester 6b (650mg, 2.13mmol) was dissolved in 45mL methanol Then, 10% palladium on carbon (250 mg, cat) was added, and hydrogen was substituted three times, and the reaction was performed at room temperature under 3 atmospheres for 12 hours. The reaction was stopped, and a small amount of celite was filtered. The filter cake was washed with a mixed solvent of dichloromethane and methanol (V / V = 10: 1) (20 mL × 1). The filtrate was collected and concentrated under reduced pressure to give the crude title product 4- ( 6-aminopyridin-3-yl) piperidine-1-carboxylic acid tert-butyl ester 6c (595 mg, transparent thick substance) was used directly in the next step.

MS m/z(ESI)：278.3[M+1] MS m / z (ESI): 278.3 [M + 1]

第三步 third step 4-(6-((6-溴-8-環戊基-5-甲基-7-側氧基-7,8-二氫吡啶並[2,3-d]嘧啶-2-基)胺基)吡啶-3-基)哌啶-1-羧酸第三丁酯 4- (6-((6-bromo-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido [2,3- d ] pyrimidin-2-yl) amine Propyl) pyridin-3-yl) piperidine-1-carboxylic acid tert-butyl ester

將粗品4-(6-胺基吡啶-3-基)哌啶-1-羧酸第三丁酯6c(480mg，1.73mmol)溶於8mL甲苯中，加熱溶解後，加入六甲基二矽基胺基鋰(1.7mL，1.73mmol)，室溫反應20分鐘，加入溶於3mL甲苯的6-溴-2-氯-8-環戊基-5-甲基吡啶並[2,3-d]嘧啶-7(8H)-酮1a(540mg，1.57mmol)，室溫反應1.5小時。加入20mL飽和氯化銨溶液淬滅反應，用乙酸乙酯萃取(20mL×3)，用飽和氯化鈉溶液洗滌(30mL×2)，無水硫酸鈉乾燥，過濾，濾液減壓濃縮，用薄層色譜法以展開劑體系A純化所得殘餘物，得到標題產物4-(6-((6-溴-8-環戊基-5-甲基-7-側氧基-7,8-二氫吡啶並[2,3-d]嘧啶-2-基)胺基)吡啶-3-基)哌啶-1-羧酸第三丁酯6d(110mg，淡黃色固體)，產率：12.1%。 The crude 4- (6-aminopyridin-3-yl) piperidine-1-carboxylic acid third butyl ester 6c (480 mg, 1.73 mmol) was dissolved in 8 mL of toluene. After heating and dissolving, hexamethyldisilazyl was added. Lithium amino (1.7 mL, 1.73 mmol), react at room temperature for 20 minutes, and add 6-bromo-2-chloro-8-cyclopentyl-5-methylpyrido [2,3- d ] dissolved in 3 mL of toluene pyrimidin -7 (8 H) - one 1a (540mg, 1.57mmol), at room temperature 1.5 hours. 20 mL of saturated ammonium chloride solution was added to quench the reaction, extracted with ethyl acetate (20 mL × 3), washed with saturated sodium chloride solution (30 mL × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, using a thin layer The resulting residue was purified by chromatography using developing system A to give the title product 4- (6-((6-bromo-8-cyclopentyl-5-methyl-7-sideoxy-7,8-dihydropyridine) [2,3- d ] Pyrimidin-2-yl) amino) pyridin-3-yl) piperidine-1-carboxylic acid third butyl ester 6d (110 mg, pale yellow solid), Yield: 12.1%.

MS m/z(ESI)：583.3[M+1] MS m / z (ESI): 583.3 [M + 1]

第四步 the fourth step 4-(6-((6-(1-丁氧基乙烯基)-8-環戊基-5-甲基-7-側氧基-7,8-二氫吡啶[2,3-d]嘧啶-2-基)胺基)吡啶-3-基)哌啶-1-羧酸第三丁酯 4- (6-((6- (1-butoxyvinyl) -8-cyclopentyl-5-methyl-7- pendantoxy-7,8-dihydropyridine [2,3- d ] Pyrimidin-2-yl) amino) pyridin-3-yl) piperidine-1-carboxylic acid tert-butyl ester

依次將4-(6-((6-溴-8-環戊基-5-甲基-7-側氧基-7,8-二氫吡啶並[2,3-d]嘧啶-2-基)胺基)吡啶-3-基)哌啶-1-羧酸第三丁酯6d(100mg，0.17mmol)、[1,1'-雙(二苯基磷)二茂鐵]二氯化鈀(10mg，0.015mmol)、N,N-二異丙基乙基胺(105mg，0.73mmol)和4mL正丁醇加入反應瓶中，氬氣氛下，加入乙烯基丁醚(160mg，1.36mmol)，加熱至95℃，反應12小時。冷卻至室溫，減壓濃縮，得到粗品標題產物4-(6-((6-(1-丁氧基乙烯基)-8-環戊基-5-甲基-7-側氧基-7,8-二氫吡啶[2,3-d]嘧啶-2-基)胺基)吡啶-3-基)哌啶-1-羧酸第三丁酯6e(152mg，褐色稠狀物，粗產率>100%)，直接用於下一步。 4- (6-((6-Bromo-8-cyclopentyl-5-methyl-7- pendantoxy-7,8-dihydropyrido [2,3- d ] pyrimidin-2-yl ) Amino) pyridin-3-yl) piperidine-1-carboxylic acid third butyl ester 6d (100mg, 0.17mmol), [1,1'-bis (diphenylphosphonium) ferrocene] palladium dichloride (10 mg, 0.015 mmol), N , N -diisopropylethylamine (105 mg, 0.73 mmol) and 4 mL of n-butanol were added to the reaction flask. Under argon atmosphere, vinyl butyl ether (160 mg, 1.36 mmol) was added. It was heated to 95 ° C and reacted for 12 hours. Cool to room temperature and concentrate under reduced pressure to give the crude title product 4- (6-((6- (1-butoxyvinyl) -8-cyclopentyl-5-methyl-7- pendantoxy-7 , 8-dihydropyridine [2,3- d ] pyrimidin-2-yl) amino) pyridin-3-yl) piperidine-1-carboxylic acid tert-butyl ester 6e (152 mg, brown thick substance, crude product Rate> 100%), used directly in the next step.

MS m/z(ESI)：603.2[M+1] MS m / z (ESI): 603.2 [M + 1]

第五步 the fifth step 6-乙醯基-8-環戊基-5-甲基-2-((5-(哌啶-4-基)吡啶-2-基)胺基)吡啶並[2,3-d]嘧啶-7(8H)-酮 6-Ethyl-8-cyclopentyl-5-methyl-2-((5- (piperidin-4-yl) pyridin-2-yl) amino) pyrido [2,3- d ] pyrimidine -7 (8 H ) -one

將粗品4-(6-((6-(1-丁氧基乙烯基)-8-環戊基-5-甲基-7-側氧基-7,8-二氫吡啶[2,3-d]嘧啶-2-基)胺基)吡啶-3-基)哌啶-1-羧酸第三丁酯6e(25mg，0.041mmol)溶於2mL甲醇和水(V/V=40：1)的混合溶劑中，加入羥基乙磺酸(20mg，0.16mmol)，加熱至60℃，反應1小時。依次加入15mL二氯甲烷、2mL甲醇和2滴水，攪拌均勻，加入碳酸鈉固體(150mg)，攪拌20分鐘，過濾，濾液減壓濃縮，用薄層色譜法以展開劑體系A純化所得殘餘物，得到標題產物6-乙醯基-8-環戊基-5-甲基-2-((5-(哌啶-4-基)吡啶-2-基)胺基)吡啶並[2,3-d]嘧啶-7(8H)-酮6(8mg，土黃色固體)，產率：50.0%。 The crude 4- (6-((6- (1-butoxyvinyl) -8-cyclopentyl-5-methyl-7- pendantoxy-7,8-dihydropyridine [2,3- d ) Pyrimidin-2-yl) amino) pyridin-3-yl) piperidine-1-carboxylic acid third butyl ester 6e (25mg, 0.041mmol) dissolved in 2mL methanol and water (V / V = 40: 1) To the mixed solvent was added isethionate (20 mg, 0.16 mmol), and the mixture was heated to 60 ° C and reacted for 1 hour. 15 mL of dichloromethane, 2 mL of methanol, and 2 drops of water were added in order, and stirred well. Sodium carbonate solid (150 mg) was added, stirred for 20 minutes, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by thin layer chromatography with developing system A, The title product 6-ethenyl-8-cyclopentyl-5-methyl-2-((5- (piperidin-4-yl) pyridin-2-yl) amino) pyrido [2,3- d ] Pyrimidine-7 ( 8H ) -one 6 (8 mg, khaki solid), yield: 50.0%.

MS m/z(ESI)：447.3[M+1] MS m / z (ESI): 447.3 [M + 1]

¹H NMR(400MHz,DMSO-d ₆)δ 10.38(s,1H),8.99(s,1H),8.24(s,1H),8.02(d,1H),7.69(d,1H),5.87-5.83(m,1H),2.97-2.94(m,2H),2.94-2.91(m,1H),2.42(s,3H),2.32(s,3H),2.27-2.24(m,4H),1.93-1.88(m,4H),1.81-1.77(m,4H),1.58(s,2H),1.25(s,1H) ¹ H NMR (400MHz, DMSO- d ₆ ) δ 10.38 (s, 1H), 8.99 (s, 1H), 8.24 (s, 1H), 8.02 (d, 1H), 7.69 (d, 1H), 5.87-5.83 (m, 1H), 2.97-2.94 (m, 2H), 2.94-2.91 (m, 1H), 2.42 (s, 3H), 2.32 (s, 3H), 2.27-2.24 (m, 4H), 1.93-1.88 (m, 4H), 1.81-1.77 (m, 4H), 1.58 (s, 2H), 1.25 (s, 1H)

實施例7 Example 7

6-乙醯基-8-環戊基-5-甲基-2-((5-(1-甲基哌啶-4-基)吡啶-2-基)胺基)吡啶並[2,3-d]嘧啶-7(8H)-酮 6-acetamyl-8-cyclopentyl-5-methyl-2-((5- (1-methylpiperidin-4-yl) pyridin-2-yl) amino) pyrido [2,3 -d ] pyrimidine-7 (8 H ) -one

將6-乙醯基-8-環戊基-5-甲基-2-((5-(哌啶-4-基)吡啶-2-基)胺基)吡啶並[2,3-d]嘧啶-7(8H)-酮6(25mg，0.056mmol)和37%甲醛溶液(6.8mg，0.084mmol)溶於4mL 1,2-二氯乙烷中，反應10 分鐘，加入醋酸硼氫化鈉(35mg，0.17mmol)，室溫反應12小時。停止反應，加入2mL甲醇，攪拌10分鐘，減壓濃縮，用薄層色譜法以展開劑體系A純化所得殘餘物，得到標題產物6-乙醯基-8-環戊基-5-甲基-2-((5-(1-甲基哌啶-4-基)吡啶-2-基)胺基)吡啶並[2,3-d]嘧啶-7(8H)-酮7(20mg，淡黃色固體)，產率：77.8%。 6-Ethyl-8-cyclopentyl-5-methyl-2-((5- (piperidin-4-yl) pyridin-2-yl) amino) pyrido [2,3- d ] Pyrimidine-7 (8 H ) -one 6 (25 mg, 0.056 mmol) and 37% formaldehyde solution (6.8 mg, 0.084 mmol) were dissolved in 4 mL of 1,2-dichloroethane, reacted for 10 minutes, and sodium acetate borohydride was added (35 mg, 0.17 mmol) and reacted at room temperature for 12 hours. The reaction was stopped, 2 mL of methanol was added, the mixture was stirred for 10 minutes, and concentrated under reduced pressure. The obtained residue was purified by thin layer chromatography using developing system A to obtain the title product 6-ethylfluorenyl-8-cyclopentyl-5-methyl- 2 - ((5- (1-methyl-piperidin-4-yl) pyridin-2-yl) amino) pyrido [2,3- d] pyrimidin -7 (8 H) - one 7 (20mg, light Yellow solid), yield: 77.8%.

MS m/z(ESI)：461.3[M+1] MS m / z (ESI): 461.3 [M + 1]

¹H NMR(400MHz,DMSO-d ₆)δ 10.34(s,1H),9.00(s,1H),8.26(s,1H),8.03(d,1H),7.72(d,1H),5.87-5.83(m,1H),2.96(s,2H),2.70(s,3H),2.42(s,3H),2.32(s,3H),2.26(s,2H),1.99(s,4H),1.90(s,2H),1.78(s,2H),1.59(s,2H),1.25(s,3H) ¹ H NMR (400MHz, DMSO- d ₆ ) δ 10.34 (s, 1H), 9.00 (s, 1H), 8.26 (s, 1H), 8.03 (d, 1H), 7.72 (d, 1H), 5.87-5.83 (m, 1H), 2.96 (s, 2H), 2.70 (s, 3H), 2.42 (s, 3H), 2.32 (s, 3H), 2.26 (s, 2H), 1.99 (s, 4H), 1.90 ( s, 2H), 1.78 (s, 2H), 1.59 (s, 2H), 1.25 (s, 3H)

實施例8 Example 8

6-乙醯基-8-環戊基-2-((5-(1-乙基哌啶-4-基)吡啶-2-基)胺基)-5-甲基吡啶並[2,3-d]嘧啶-7(8H)-酮 6-Ethyl-8-cyclopentyl-2-(((5- (1-ethylpiperidin-4-yl) pyridin-2-yl) amino) -5-methylpyrido [2,3 -d ] pyrimidine-7 (8 H ) -one

依次將6-乙醯基-8-環戊基-5-甲基-2-((5-(哌啶-4-基) 吡啶-2-基)胺基)吡啶並[2,3-d]嘧啶-7(8H)-酮6(20mg，0.047mmol)、乙醛(20mg，0.45mmol)、4mL 1,2-二氯乙烷和醋酸硼氫化鈉(25mg，0.11mmol)加入反應瓶中，室溫反應12小時。停止反應，加入3mL甲醇，攪拌5分鐘，減壓濃縮，用薄層色譜法以展開劑體系A純化所得殘餘物，得到標題產物6-乙醯基-8-環戊基-2-((5-(1-乙基哌啶-4-基)吡啶-2-基)胺基)-5-甲基吡啶並[2,3-d]嘧啶-7(8H)-酮8(10mg，黃色固體)，產率：45.4%。 6-Ethyl-8-cyclopentyl-5-methyl-2-((5- (piperidin-4-yl) pyridin-2-yl) amino) pyrido [2,3- d ] Pyrimidine-7 (8 H ) -one 6 (20 mg, 0.047 mmol), acetaldehyde (20 mg, 0.45 mmol), 4 mL of 1,2-dichloroethane and sodium borohydride acetate (25 mg, 0.11 mmol) were added to the reaction flask The reaction was conducted at room temperature for 12 hours. The reaction was stopped, 3 mL of methanol was added, the mixture was stirred for 5 minutes, and concentrated under reduced pressure. The obtained residue was purified by thin layer chromatography using developing system A to obtain the title product 6-ethylamyl-8-cyclopentyl-2-((5 -(1-ethylpiperidin-4-yl) pyridin-2-yl) amino) -5-methylpyrido [2,3- d ] pyrimidin-7 ( 8H ) -one 8 (10 mg, yellow (Solid), yield: 45.4%.

MS m/z(ESI)：475.2[M+1] MS m / z (ESI): 475.2 [M + 1]

¹H NMR(400MHz,DMSO-d ₆)δ 10.32(s,1H),9.00(s,1H),8.24(s,1H),8.01(d,1H),7.71(d,1H),5.87-5.83(m,1H),2.85(s,3H),2.75(s,1H),2.69-2.65(m,4H),2.42(s,3H),2.31(s,3H),2.25(s,2H),1.94-1.90(m,4H),1.78(s,3H),1.58(s,4H),1.45(s,1H) ¹ H NMR (400MHz, DMSO- d ₆ ) δ 10.32 (s, 1H), 9.00 (s, 1H), 8.24 (s, 1H), 8.01 (d, 1H), 7.71 (d, 1H), 5.87-5.83 (m, 1H), 2.85 (s, 3H), 2.75 (s, 1H), 2.69-2.65 (m, 4H), 2.42 (s, 3H), 2.31 (s, 3H), 2.25 (s, 2H), 1.94-1.90 (m, 4H), 1.78 (s, 3H), 1.58 (s, 4H), 1.45 (s, 1H)

實施例9 Example 9

6-乙醯基-8-環戊基-2-((5-(1-(2-羥乙基)哌啶-4-基)吡啶-2-基)胺基)-5-甲基吡啶並[2,3-d]嘧啶-7(8H)-酮 6-Ethyl-8-cyclopentyl-2-((5- (1- (2-hydroxyethyl) piperidin-4-yl) pyridin-2-yl) amino) -5-methylpyridine Benzo [2,3- d ] pyrimidin-7 ( 8H ) -one

將6-乙醯基-8-環戊基-5-甲基-2-((5-(哌啶-4-基)吡啶-2-基)胺基)吡啶並[2,3-d]嘧啶-7(8H)-酮6(15mg，0.033mmol)溶於2.5mL N,N-二甲基甲醯胺中，加入2-溴乙醇(10mg，0.080mmol)和碳酸鉀(12.5mg，0.091mmol)，室溫反應12小時，TLC檢測反應，原料沒有反應完，補加1滴2-溴乙醇，加熱至70℃，反應2.5小時，TLC檢測反應，原料沒有反應完，加熱至90℃，補加碳酸鉀15mg，反應3小時，停止反應。冷卻至室溫，過濾，濾液減壓濃縮，用薄層色譜法以展開劑體系A純化所得殘餘物，得到標題產物6-乙醯基-8-環戊基-2-((5-(1-(2-羥乙基)哌啶-4-基)吡啶-2-基)胺基)-5-甲基吡啶並[2,3-d]嘧啶-7(8H)-酮9(10mg，淡黃色固體)，產率：62.5%。 6-Ethyl-8-cyclopentyl-5-methyl-2-((5- (piperidin-4-yl) pyridin-2-yl) amino) pyrido [2,3- d ] Pyrimidine-7 (8 H ) -one 6 (15 mg, 0.033 mmol) was dissolved in 2.5 mL of N, N -dimethylformamide, and 2-bromoethanol (10 mg, 0.080 mmol) and potassium carbonate (12.5 mg, 0.091mmol), react at room temperature for 12 hours, TLC detects the reaction, the raw materials are not reacted, add a drop of 2-bromoethanol, and heat to 70 ° C, react for 2.5 hours, TLC detects the reaction, the raw materials are not reacted, heat to 90 ° C Add 15 mg of potassium carbonate, and react for 3 hours to stop the reaction. It was cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by thin layer chromatography using developing system A to obtain the title product 6-ethylamyl-8-cyclopentyl-2-((5- (1 -(2-hydroxyethyl) piperidin-4-yl) pyridin-2-yl) amino) -5-methylpyrido [2,3- d ] pyrimidin-7 ( 8H ) -one 9 (10mg , Light yellow solid), yield: 62.5%.

MS m/z(ESI)：491.3[M+1] MS m / z (ESI): 491.3 [M + 1]

¹H NMR(400MHz,DMSO-d ₆)δ 10.34(s,1H),8.99(s,1H),8.23(s,1H),7.98(d,1H),7.72(d,1H),7.68(s,1H),5.87-5.83(m,1H),2.98(d,2H),2.42(s,3H),2.32(s,3H),2.27-2.22(m,2H),2.02-1.98(m,3H),1.98-1.95(m,3H),1.90(s,2H),1.74-1.70(m,4H),1.69-1.63(m,3H),1.45(s,2H) ¹ H NMR (400MHz, DMSO- d ₆ ) δ 10.34 (s, 1H), 8.99 (s, 1H), 8.23 (s, 1H), 7.98 (d, 1H), 7.72 (d, 1H), 7.68 (s , 1H), 5.87-5.83 (m, 1H), 2.98 (d, 2H), 2.42 (s, 3H), 2.32 (s, 3H), 2.27-2.22 (m, 2H), 2.02-1.98 (m, 3H ), 1.98-1.95 (m, 3H), 1.90 (s, 2H), 1.74-1.70 (m, 4H), 1.69-1.63 (m, 3H), 1.45 (s, 2H)

實施例10 Example 10

6-乙醯基-8-環戊基-2-((5-(1-(環丙基甲基)哌啶-4-基)吡啶-2-基)胺基)-5-甲基吡啶並[2,3-d]嘧啶-7(8H)-酮 6-Ethyl-8-cyclopentyl-2-((5- (1- (cyclopropylmethyl) piperidin-4-yl) pyridin-2-yl) amino) -5-methylpyridine Benzo [2,3- d ] pyrimidin-7 ( 8H ) -one

依次將6-乙醯基-8-環戊基-5-甲基-2-((5-(哌啶-4-基)吡啶-2-基)胺基)吡啶並[2,3-d]嘧啶-7(8H)-酮6(15mg，0.033mmol)、環丙基溴甲烷(8.37mg，0.062mmol)、碳酸鉀(20.7mg，0.15mmol)和3mL乙腈加入反應瓶中，加熱至80℃，反應2小時，停止反應。冷卻至室溫，過濾，濾液減壓濃縮，用薄層色譜法以展開劑體系A純化所得殘餘物，得到標題產物6-乙醯基-8-環戊基-2-((5-(1-(環丙基甲基)哌啶-4-基)吡啶-2-基)胺基)-5-甲基吡啶並[2,3-d]嘧啶-7(8H)-酮10(6mg，黃色固體)，產率：40.0%。 6-Acetyl-8-cyclopentyl-5-methyl-2-((5- (piperidin-4-yl) pyridin-2-yl) amino) pyrido [2,3- d ] Pyrimidine-7 (8 H ) -one 6 (15 mg, 0.033 mmol), cyclopropyl bromide (8.37 mg, 0.062 mmol), potassium carbonate (20.7 mg, 0.15 mmol) and 3 mL of acetonitrile were added to the reaction flask and heated to 80 The reaction was stopped at 2 ° C for 2 hours. It was cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by thin layer chromatography using developing system A to obtain the title product 6-ethylamyl-8-cyclopentyl-2-((5- (1 -(Cyclopropylmethyl) piperidin-4-yl) pyridin-2-yl) amino) -5-methylpyrido [2,3- d ] pyrimidin-7 ( 8H ) -one 10 (6mg , Yellow solid), yield: 40.0%.

MS m/z(ESI)：501.2[M+1] MS m / z (ESI): 501.2 [M + 1]

¹H NMR(400MHz,DMSO-d ₆)δ 10.28(s,1H),8.99(s,1H),8.24(s,1H),7.97(d,1H),7.74(d,1H),5.87-5.83(m,1H),3.22-3.18(m,3H),2.42(s,3H),2.36(s,2H),2.31(s,3H),2.27-2.22(m,5H),2.01-1.97 (m,1H),1.90(s,3H),1.79(s,6H),1.59(s,3H),1.45(s,1H) ¹ H NMR (400MHz, DMSO- d ₆ ) δ 10.28 (s, 1H), 8.99 (s, 1H), 8.24 (s, 1H), 7.97 (d, 1H), 7.74 (d, 1H), 5.87-5.83 (m, 1H), 3.22-3.18 (m, 3H), 2.42 (s, 3H), 2.36 (s, 2H), 2.31 (s, 3H), 2.27-2.22 (m, 5H), 2.01-1.97 (m , 1H), 1.90 (s, 3H), 1.79 (s, 6H), 1.59 (s, 3H), 1.45 (s, 1H)

實施例11 Example 11

6-乙醯基-8-環戊基-2-((5-(1-(2,2-二氟乙基)哌啶-4-基)吡啶-2-基)胺基)-5-甲基吡啶[2,3-d]嘧啶-7(8H)-酮 6-Ethyl-8-cyclopentyl-2-((5- (1- (2,2-difluoroethyl) piperidin-4-yl) pyridin-2-yl) amino) -5- Methylpyridine [2,3- d ] pyrimidin-7 ( 8H ) -one

將6-乙醯基-8-環戊基-5-甲基-2-((5-(哌啶-4-基)吡啶-2-基)胺基)吡啶並[2,3-d]嘧啶-7(8H)-酮6(15mg，0.033mmol)溶於4mL乙腈中，加入1-溴-2,2-二氟乙烷(24.36mg，0.168mmol)和碳酸鉀(30mg，0.22mmol)加熱至80℃，反應6小時，停止反應。冷卻至室溫，過濾，濾餅用二氯甲烷洗滌(3mL×2)，濾液減壓濃縮，用薄層色譜法以展開劑體系A純化所得殘餘物，得到標題產物6-乙醯基-8-環戊基-2-((5-(1-(2,2-二氟乙基)哌啶-4-基)吡啶-2-基)胺基)-5-甲基吡啶[2,3-d]嘧啶-7(8H)-酮11(6mg，淡黃色固體)，產率：35.7%。 6-Ethyl-8-cyclopentyl-5-methyl-2-((5- (piperidin-4-yl) pyridin-2-yl) amino) pyrido [2,3- d ] Pyrimidine-7 (8 H ) -one 6 (15 mg, 0.033 mmol) was dissolved in 4 mL of acetonitrile, and 1-bromo-2,2-difluoroethane (24.36 mg, 0.168 mmol) and potassium carbonate (30 mg, 0.22 mmol) were added. ) Heat to 80 ° C and react for 6 hours to stop the reaction. Cool to room temperature, filter, wash the filter cake with dichloromethane (3 mL x 2), concentrate the filtrate under reduced pressure, and purify the resulting residue by thin layer chromatography with developer system A to give the title product 6-acetamyl-8 -Cyclopentyl-2-((5- (1- (2,2-difluoroethyl) piperidin-4-yl) pyridin-2-yl) amino) -5-methylpyridine [2,3 -d ] pyrimidine-7 ( 8H ) -one 11 (6 mg, pale yellow solid), yield: 35.7%.

MS m/z(ESI)：511.2[M+1] MS m / z (ESI): 511.2 [M + 1]

¹H NMR(400MHz,DMSO-d ₆)δ 10.28(s,1H),8.99(s,1H),8.24(s,1H),7.99(d,1H),7.74(d,1H),5.87-5.83(m,1H),3.28(m,2H),2.77-2.73(m,2H),2.42(s,3H),2.30-2.24(m,3H),2.01-1.97(m,4H),1.90(s,2H),1.75-1.71(m,4H),1.61-1.58(m,3H),1.50-1.45(m,3H) ¹ H NMR (400MHz, DMSO- d ₆ ) δ 10.28 (s, 1H), 8.99 (s, 1H), 8.24 (s, 1H), 7.99 (d, 1H), 7.74 (d, 1H), 5.87-5.83 (m, 1H), 3.28 (m, 2H), 2.77-2.73 (m, 2H), 2.42 (s, 3H), 2.30-2.24 (m, 3H), 2.01-1.97 (m, 4H), 1.90 (s , 2H), 1.75-1.71 (m, 4H), 1.61-1.58 (m, 3H), 1.50-1.45 (m, 3H)

測試例： Test example:

生物學評價 Biological evaluation

測試例1、本發明化合物對CDK激酶活性的測定 Test Example 1. Determination of CDK kinase activity of the compound of the present invention

體外CDK(CDK4、CDK6、CDK1、CDK2、CDK9)激酶活性藉由以下的方法進行測試。 CDK (CDK4, CDK6, CDK1, CDK2, CDK9) kinase activity in vitro was tested by the following method.

本實驗使用的CDK激酶：CDK4/人細胞週期蛋白D1(Invitrogen，貨號PV4400)或CDK4/CycD3(Carna biosciences，貨號04-105)；CDK6/人細胞週期蛋白D1(Invitrogen，貨號PV4401)或CDK6/CycD3(Carna biosciences，貨號04-107)；CDK1/人細胞週期蛋白B(Invitrogen，貨號PV3292)；CDK2/人細胞週期蛋白A(Invitrogen，貨號PV3267)或CDK2/CycA2(Carna biosciences，貨號04-103)；CDK9/人細胞週期蛋白T1(Invitrogen，貨號PR7541B)或CDK9/CycT1(Carna biosciences，貨號04-110)。 CDK kinases used in this experiment: CDK4 / human cyclin D1 (Invitrogen, catalog number PV4400) or CDK4 / CycD3 (Carna biosciences, catalog number 04-105); CDK6 / human cyclin D1 (Invitrogen, catalog number PV4401) or CDK6 / CycD3 (Carna biosciences, article number 04-107); CDK1 / human cyclin B (Invitrogen, article number PV3292); CDK2 / human cyclin A (Invitrogen, article number PV3267) or CDK2 / CycA2 (Carna biosciences, article number 04-103) ); CDK9 / human cyclin T1 (Invitrogen, Cat. No. PR7541B) or CDK9 / CycT1 (Carna biosciences, Cat. No. 04-110).

使用試劑盒：Z'-LYTE^TM Kinase Assay Kit-Ser/Thr 12 Peptide(Invitrogen，貨號PV3673)。 Kit used: Z'-LYTE ^™ Kinase Assay Kit-Ser / Thr 12 Peptide (Invitrogen, Cat. No. PV3673).

以下所述的體外激酶實驗可測定受試化合物對CDK(CDK4、CDK6、CDK1、CDK2、CDK9)激酶的抑制活性。配製1×緩衝液A(Invitrogen，貨號PV3189)；將測試化合物溶解於二甲亞碸中，並根據試驗需要稀釋至各濃度梯度，加入1×緩衝液A配製成4%二甲亞碸溶液；用1×緩衝液A稀釋ATP得到400μM ATP溶液；將適量試劑盒中的Z'-LYTE^TM Ser/Thr12多肽基質(Invitrogen，貨號PV3674)，CDK激酶與1×緩衝液A混合；適量試劑盒中的Z'-LYTE^TM Ser/Thr 12磷酸化多肽基質(Invitrogen，貨號PV3675)和1×緩衝液A配成磷酸化多肽混合液待用；在反應孔中加上2.5μL配置好的測試化合物溶液，2.5μL 400μM ATP溶液和5μL酶和基質混合液；對照孔1中加上5μL酶和基質混合液，2.5μL 4%二甲亞碸溶液和2.5μ L1×緩衝液A；對照孔2中加上5μL酶和基質混合液，2.5μL 4%二甲亞碸溶液和2.5μL 400μM ATP溶液；對照孔3中加上5μL磷酸化多肽混合液，2.5μL 4%二甲亞碸溶液和2.5μL 1×緩衝液A。25℃孵育24小時(CDK4、CDK6、CDK9)或25℃孵育1小時(CDK1、CDK2)後，在反應孔中加入5μL試劑A(Invitrogen，貨號PV3295)和緩衝液B(Invitrogen，貨號P3127)的混合液(試劑A：緩衝液B=1：4095)，25℃孵育60分鐘後，使用NovoStar酶標儀讀螢光(激發波長：400nm，發射波長：445nm和520nm)。 In vitro kinase experiments described below can determine the inhibitory activity of test compounds on CDK (CDK4, CDK6, CDK1, CDK2, CDK9) kinase. Prepare 1 × buffer solution A (Invitrogen, article number PV3189); dissolve the test compound in dimethylformamide, and dilute to each concentration gradient according to the test requirements, add 1 × buffer solution A to prepare a 4% dimethylformamide solution ; Dilute ATP with 1 × Buffer A to obtain 400 μM ATP solution. Mix the Z'-LYTE ^TM Ser / Thr12 peptide matrix (Invitrogen, Cat. No. PV3674), CDK kinase and 1 × Buffer A in the appropriate kit; Z'-LYTE ^TM Ser / Thr 12 phosphorylated peptide matrix (Invitrogen, Cat. No. PV3675) and 1 × buffer A were mixed into a phosphorylated peptide mixture for use; 2.5 μL of the configured test compound was added to the reaction well. Solution, 2.5 μL of 400 μM ATP solution and 5 μL of enzyme and matrix mixed solution; 5 μL of enzyme and matrix mixed solution, 2.5 μL of 4% dimethylarsine solution and 2.5 μL of 1 × buffer solution A; in control well 2 Add 5 μL of enzyme and matrix mixture, 2.5 μL of 4% dimethylarsine solution and 2.5 μL of 400 μM ATP solution; add 5 μL of phosphorylated peptide mixture, 2.5 μL of 4% dimethylarsine solution and 2.5 μL to control well 3. 1 × Buffer A. After incubation at 25 ° C for 24 hours (CDK4, CDK6, CDK9) or incubation at 25 ° C for 1 hour (CDK1, CDK2), add 5 μL of reagent A (Invitrogen, catalog number PV3295) and buffer B (Invitrogen, catalog number P3127) to the reaction wells. The mixed solution (Reagent A: Buffer B = 1: 4095) was incubated at 25 ° C for 60 minutes, and the fluorescence was read using an NovoStar microplate reader (excitation wavelength: 400 nm, emission wavelength: 445 nm and 520 nm).

本發明化合物的CDK(CDK4、CDK6、CDK1、CDK2、CDK9)激酶生化抑制活性藉由以上的試驗進行測定，測得的IC₅₀值見表1(CDK4、CDK6)，表2(CDK1、CDK2、CDK9)。 CDK (CDK4, CDK6, CDK1, CDK2, CDK9) kinase biochemical inhibitory activity of the compounds of the present invention was determined by the above test. The measured IC ₅₀ values are shown in Table 1 (CDK4, CDK6) and Table 2 (CDK1, CDK2, CDK9).

結論：本發明化合物對CDK激酶(CDK4、CDK6)活性具有明顯的抑制作用，相比對CDK激酶(CDK1、CDK2、CDK9)活性的抑制作用，本發明化合物對CDK激酶(CDK4、CDK6)的抑制具有選擇性。 Conclusion: The compounds of the present invention have significant inhibitory effects on the activity of CDK kinases (CDK4, CDK6). Compared with the inhibitory effects of CDK kinases (CDK1, CDK2, CDK9), the compounds of the present invention inhibit the CDK kinases (CDK4, CDK6) Be selective.

測試例2、本發明化合物對人結腸癌細胞株Colo205的增殖抑制測定 Test Example 2. Determination of the compound of the present invention on the proliferation inhibition of human colon cancer cell line Colo205

下面的體外試驗是用來測定本發明化合物對人結腸癌細胞株 Colo205的增殖抑制活性。 The following in vitro test is used to determine the compounds of the invention against human colon cancer cell lines Colo205 proliferation inhibitory activity.

以下所述的體外細胞試驗可測定受試化合物對人結腸癌細胞株的增殖抑制活性，其活性可用IC₅₀值來表示。此類試驗的一般方案如下：首先將Colo205細胞(中科院細胞庫，貨號TCHu102)以適宜細胞濃度500個細胞/孔接種在384孔培養板上，然後將細胞在二氧化碳恒溫箱內37℃進行培養，生長至過夜，更換培養基為加有一系列濃度遞度(1000nM、250nM、62.5nM、15.62nM、3.91nM、0.98nM、0.24nM、0.06nM、0.02nM)受試化合物溶液的培養基，將培養板重新放回培養箱，連續培養72個小時。72小時後，可用CCK8(Cell Counting Kit-8，貨號：CK04，購於同仁化學)方法進行測試化合物對於抑制細胞增殖活性。IC₅₀值可藉由一系列不同濃度下，受試化合物對於細胞的抑制數值進行計算。 The following in vitro test of the test compound can be determined on human colon cancer cell line proliferation inhibitory activity, which activity can be expressed by IC ₅₀ values. The general protocol for such experiments is as follows: First, Colo205 cells (Cell Bank of the Chinese Academy of Sciences, Cat. No. TCHu102) are seeded at a suitable cell concentration of 500 cells / well on a 384-well culture plate, and then the cells are cultured in a carbon dioxide incubator at 37 ° C. Grow to overnight, replace the culture medium with a series of concentration gradients (1000nM, 250nM, 62.5nM, 15.62nM, 3.91nM, 0.98nM, 0.24nM, 0.06nM, 0.02nM) of the test compound solution, and re-culture the plate Return to the incubator and incubate for 72 hours. After 72 hours, CCK8 (Cell Counting Kit-8, article number: CK04, purchased from Tongren Chemical) method can be used to test the compound for inhibiting cell proliferation activity. IC ₅₀ values can be by a series of different concentrations of the test compound was calculated values for inhibition of cell.

本發明化合物活性本發明化合物生物活性由上述分析所得，計算所得的IC₅₀值如下表3： Activity of the compound of the present invention The biological activity of the compound of the present invention is obtained from the above analysis, and the calculated IC ₅₀ value is shown in Table 3 below:

結論：本發明較佳化合物均對Colo205細胞具有明顯的增殖抑制活性。 Conclusion: The preferred compounds of the present invention all have significant proliferation inhibitory activity on Colo205 cells.

測試例3、本發明化合物對人乳腺癌細胞株MCF-7的增殖抑制測定 Test Example 3. Increase of the compound of the present invention on human breast cancer cell line MCF-7 Colony inhibition assay

下面的體外試驗是用來測定本發明化合物對人乳腺癌細胞株MCF-7的增殖抑制活性。 The following in vitro test is used to determine the inhibitory activity of the compound of the present invention on the human breast cancer cell line MCF-7.

以下所述的體外細胞試驗可測定受試化合物對人乳腺癌細胞株的增殖抑制活性，其活性可用IC₅₀值來表示。此類試驗的一般方案如下：首先將MCF-7細胞(購於Institute of biochemistry and cell biology)以適宜細胞濃度4000個細胞/mL介質接種在96孔培養板上，然後將細胞在二氧化碳恒溫箱內37℃進行培養，生長至過夜，更換培養基為加有一系列濃度遞度(10000nM、1000nM、100nM、10nM、1nM、0.1nM)受試化合物溶液的培養基，將培養板重新放回培養箱，連續培養72個小時。72小時後，可用CCK8(Cell Counting Kit-8，貨號：CK04，購於同仁化學)方法進行測試化合物對於抑制細胞增殖活性。IC₅₀值可藉由一系列不同濃度下，受試化合物對於細胞的抑制數值進行計算。 Below can be determined in vitro cell assay test compound on the proliferation of human breast cancer cell line inhibitory activity, which activity can be expressed by IC ₅₀ values. The general protocol for such experiments is as follows: First, MCF-7 cells (purchased from the Institute of biochemistry and cell biology) are seeded on a 96-well culture plate at a suitable cell concentration of 4000 cells / mL medium, and then the cells are placed in a carbon dioxide incubator. Incubate at 37 ° C and grow to overnight. Change the medium to a medium with a series of concentration gradients (10000nM, 1000nM, 100nM, 10nM, 1nM, 0.1nM) of the test compound solution. Return the culture plate to the incubator for continuous culture. 72 hours. After 72 hours, CCK8 (Cell Counting Kit-8, article number: CK04, purchased from Tongren Chemical) method can be used to test the compound for inhibiting cell proliferation activity. IC ₅₀ values can be by a series of different concentrations of the test compound was calculated values for inhibition of cell.

本發明化合物生物活性由上述分析所得，計算所得的IC₅₀值如下表4： The biological activity of the compound of the present invention is obtained from the above analysis, and the calculated IC ₅₀ value is shown in Table 4 below:

結論：本發明較佳化合物均對MCF-7細胞具有明顯的增殖抑制活性。 Conclusion: The preferred compounds of the present invention all have obvious proliferation inhibitory activity on MCF-7 cells.

藥物代謝動力學評價 Pharmacokinetic evaluation

測試例4、本發明實施例6和實施例7化合物的藥物代謝動力學測試 Test example 4, pharmacokinetic test of compounds of Example 6 and Example 7 of the present invention

1、摘要 1.Abstract

以SD大鼠為受試動物，應用LC/MS/MS法測定了大鼠灌胃給予實施例7化合物後不同時刻血漿中的藥物濃度。研究本發明的化合物在大鼠體內的藥物代謝動力學行為，評價其藥動學特徵。 SD rats were used as test animals. LC / MS / MS method was used to determine the drug concentration in plasma of rats at different times after intragastric administration of the compound of Example 7. The pharmacokinetic behavior of the compound of the present invention in rats was studied, and its pharmacokinetic characteristics were evaluated.

2、試驗方案 2. Test plan

2.1試驗藥品：PD-0332991，實施例6和實施例7化合物。 2.1 Test drug: PD-0332991, the compound of Example 6 and Example 7. 2.2試驗動物 2.2 Test animals

健康成年SD大鼠12隻，雌雄各半，購自上海西普爾-必凱實驗動物有限公司，動物生產許可證號：SCXK(滬)2008-0016。 Twelve healthy adult SD rats, half male and half female, purchased from Shanghai Xippel-Bikai Experimental Animal Co., Ltd., animal production license number: SCXK (Shanghai) 2008-0016.

2.3藥物配製 2.3 Drug Formulation

稱取適量樣品，加入0.5% CMC-Na至終體積，超音波製成0.5mg/mL混懸液。 Weigh an appropriate amount of sample, add 0.5% CMC-Na to the final volume, and make a 0.5 mg / mL suspension by ultrasonic.

2.4給藥 2.4 Administration

SD大鼠12隻，分成3組，每組4隻，雌雄各半，禁食一夜後分別灌胃給藥，劑量為5.0mg/kg，給藥體積10ml/kg。 Twelve SD rats were divided into three groups, four in each group, half male and half female. After fasting overnight, they were administered by gavage at a dose of 5.0 mg / kg and a dose volume of 10 ml / kg.

3、操作 3.Operation

於給藥前及給藥後0.5、1、2、4、6、8、11、24小時採血，置於肝素化抗凝試管中，3500rpm離心10分鐘，分離血漿，於-20℃保存。給藥後2小時進食。 Blood was collected before administration and 0.5, 1, 2, 4, 6, 8, 11, 24 hours after administration, placed in a heparinized anticoagulation test tube, centrifuged at 3500 rpm for 10 minutes, and the plasma was separated and stored at -20 ° C. Eat 2 hours after dosing.

用LC/MS/MS法測定灌胃給藥後大鼠血漿中的待測化合物含量。分析方法的線性範圍為1.00-500ng/mL，定量下限為1.00ng/mL；血漿樣品經沉澱蛋白預處理後進行分析。 LC / MS / MS method was used to determine the content of test compounds in rat plasma after intragastric administration. The linear range of the analytical method was 1.00-500ng / mL, and the lower limit of quantification was 1.00ng / mL. The plasma samples were analyzed after pretreatment with the precipitated protein.

4、藥物代謝動力學參數結果 4. Results of pharmacokinetic parameters

本發明化合物的藥物代謝動力學參數如下： The pharmacokinetic parameters of the compounds of the invention are as follows:

結論：本發明較佳化合物的給藥劑量為5mg/kg時，與PD-0332991比較，大鼠藥物代謝吸收良好，半衰期長，具有明顯的口服吸收效果。 CONCLUSION: Compared with PD-0332991, when the dosage of the preferred compound of the present invention is 5 mg / kg, the rats have good drug metabolism and absorption, long half-life, and obvious oral absorption effect.

測試例5、本發明實施例6和7化合物的犬藥物代謝動 Test Example 5, Canine Drug Metabolism of Compounds of Examples 6 and 7 of the Invention

力學測試 Mechanical test

1、摘要 1.Abstract

以Beagle犬為受試動物，應用LC/MS/MS法測定了犬灌胃給予PD-0332991，實施例6和7化合物後不同時刻血漿中的藥物濃度。研究本發明的化合物在大鼠體內的藥物代謝動力學行為，評價其藥動學特徵。 Using Beagle dogs as test animals, the plasma concentrations of PD-0332991, the compounds of Examples 6 and 7 at different time points after intragastric administration of PD-0332991 to dogs were measured by LC / MS / MS. The pharmacokinetic behavior of the compound of the present invention in rats was studied, and its pharmacokinetic characteristics were evaluated.

2、試驗方案 2. Test plan

健康成年Beagle犬20隻，雌雄各半，購自蘇州西山中科實驗動物有限公司。 Twenty healthy adult Beagle dogs, male and female, purchased from Suzhou Xishan Zhongke Experimental Animal Co., Ltd.

2.3藥物配製 2.3 Drug Formulation

稱取適量樣品，加入二甲基乙醯胺和丙二醇使溶解，後加入生理鹽水至終體積，製成1.0mg/mL溶液。 Weigh an appropriate amount of sample, add dimethylacetamide and propylene glycol to dissolve it, and then add physiological saline to the final volume to make a 1.0 mg / mL solution.

稱取適量樣品，加入0.5%吐溫80，檸檬酸和0.5% CMC-Na至終體積，製成1.0mg/mL溶液。 Weigh an appropriate amount of sample, add 0.5% Tween 80, citric acid, and 0.5% CMC-Na to the final volume to make a 1.0 mg / mL solution.

2.4給藥 2.4 Administration

Beagle犬20隻，雌雄各半，平均分成5組，每組4隻；禁食一夜後分別靜脈注射及灌胃給藥，靜脈注射給藥劑量為2.0mg/kg，灌胃給藥劑量為5.0mg/kg。靜脈注射給藥體積為2.0mL/kg，灌胃給藥體積為5.0mL/kg。 Twenty Beagle dogs, male and female, divided equally into 5 groups, 4 in each group; after fasting overnight, they were given intravenously and intragastrically, the intravenous dose was 2.0mg / kg, and the intragastric dose was 5.0 mg / kg. The intravenous administration volume was 2.0 mL / kg, and the intragastric administration volume was 5.0 mL / kg.

3、操作 3.Operation

靜脈注射給藥組於給藥前及給藥後5分鐘，0.25,0.5,1.0,2.0,4.0,8.0,12.0,24.0小時由前肢靜脈採血1.0mL，置於肝素化試管中，3500rpm離心10分鐘分離血漿，於-20℃保存。灌胃給藥組於給藥前及給藥後0.5,1.0,2.0,4.0,6.0,8.0,12.0,24.0小時采血，處理方法同靜脈注射給藥組。給藥後3小時進食。 In the intravenous injection group, 1.0 mL of blood was collected from the forelimb vein before and 5 minutes after the administration, 0.25, 0.5, 1.0, 2.0, 4.0, 8.0, 12.0, 24.0 hours, placed in a heparinized test tube, and centrifuged at 3500 rpm for 10 minutes The plasma was separated and stored at -20 ° C. The intragastric administration group took blood before, and 0.5, 1.0, 2.0, 4.0, 6.0, 8.0, 12.0, 24.0 hours after administration. The treatment method was the same as that of the intravenous administration group. Eat 3 hours after dosing.

用LC/MS/MS法測定靜脈注射及灌胃給藥後大鼠血漿中的待測化合物含量。 LC / MS / MS method was used to determine the content of test compounds in rat plasma after intravenous injection and intragastric administration.

4、藥物代謝動力學參數結果 4. Results of pharmacokinetic parameters

結論：本發明化合物的藥物代謝吸收良好，生物利用度高，具有明顯的口服吸收效果。 Conclusion: The compound of the present invention has good drug metabolism and absorption, high bioavailability, and obvious oral absorption effect.

反應性代謝物篩查 Reactive metabolite screening

測試例6：本發明實施例6化合物與PD-0332991對比生成反應性代謝物的能力的測試 Test Example 6: Test of the ability of the compound of Example 6 of the present invention to produce a reactive metabolite in comparison with PD-0332991

1、摘要 1.Abstract

以人和大鼠肝微粒體，利用谷胱甘肽(GSH)捕獲反應性代謝物，利用LC-MS/MS系統，採用前體離子掃描篩選各類型的GSH加合物。研究實施例6化合物與PD-0332991生成反應性代謝物的能力。 Human and rat liver microsomes were used to capture reactive metabolites using glutathione (GSH), and LC-MS / MS systems were used to screen for various types of GSH adducts using precursor ion scanning. The ability of the compound of Example 6 to produce reactive metabolites with PD-0332991 was investigated.

2、試驗方案 2. Test plan

2.1試驗藥品：PD-0332991，實施例6化合物。 2.1 Test drug: PD-0332991, compound of Example 6. 2.2試驗試劑 2.2 Test reagents

男性受試者肝微粒體，蛋白濃度20mg/mL，購於美國BD Gentest^TM；雄性大鼠肝微粒體，蛋白濃度20mg/mL，購於美國BD Gentest^TM；β-NADPH，化學純度93-100%，購於美國Sigma公司。 L-還原型谷胱甘肽，純度>98%，購於美國Sigma公司。 Male subject liver microsomes, protein concentration 20mg / mL, purchased from BD Gentest ^TM in the United States; male rat liver microsomes, protein concentration 20mg / mL, purchased from US BD Gentest ^TM ; β-NADPH, chemical purity 93-100 %, Purchased from American Sigma Company. L-reduced glutathione, purity> 98%, purchased from American Sigma Company.

2.3藥物配製 2.3 Drug Formulation

稱取適量樣品，採用DMSO溶解至終體積，超音波製成50mM儲備液，採用100mM磷酸緩衝液(PBS，pH7.4)稀釋上述儲備液至100μM。 Weigh an appropriate amount of sample, dissolve it in DMSO to the final volume, make a 50 mM stock solution by ultrasound, and dilute the above stock solution to 100 μM with 100 mM phosphate buffer (PBS, pH 7.4).

2.4體外孵化體系 2.4 In vitro hatching system

孵化體系總體積為100μL，介質為100mM磷酸緩衝液(PBS，pH7.4)。於1mL 96孔板中，加入人或大鼠肝微粒體溶液(PBS配製)，待測化合物，和GSH溶液，使其終濃度為10μM的待測化合物，5mM GSH溶液和1.0mg/mL肝微粒體蛋白，採用熱混儀於37℃進行孵育。孵育3分鐘後，加入NADPH啟始反應，NADPH終濃度為2mM。反應60分鐘後加入200μL冰冷乙腈終止反應，3200rpm離心10分鐘，去上清液進行LC-MS/MS分析。 The total volume of the incubation system was 100 μL, and the medium was 100 mM phosphate buffered saline (PBS, pH 7.4). In a 1 mL 96-well plate, add human or rat liver microsomal solution (prepared by PBS), test compound, and GSH solution to a final concentration of 10 μM test compound, 5 mM GSH solution, and 1.0 mg / mL liver particles The body protein was incubated at 37 ° C using a thermal mixer. After 3 minutes of incubation, NADPH was added to start the reaction, and the final NADPH concentration was 2 mM. After reacting for 60 minutes, 200 μL of ice-cold acetonitrile was added to stop the reaction. The mixture was centrifuged at 3200 rpm for 10 minutes, and the supernatant was removed for LC-MS / MS analysis.

3、操作 3.Operation

利用Qtrap API4000 LC-MS/MS系統，採用前體離子掃描檢測可能的GSH加合物，以待測化合物生成的總GSH加合物色譜峰面積與氯氮平生成的總GSH加合物色譜峰面積比值(Ratio)評價化合物生成反應性代謝物的能力。 Using the Qtrap API4000 LC-MS / MS system to detect possible GSH adducts using precursor ion scanning, the total GSH adduct chromatographic peak area generated by the test compound and the total GSH adduct chromatographic peak generated by clozapine The area ratio (Ratio) evaluates a compound's ability to produce reactive metabolites.

4、實驗結果 4. Experimental results

本發明例6在人和大鼠肝微粒體孵化系統均未見明顯的GSH加合物產生，具有低的生成反應性代謝物的能力。 In Example 6 of the present invention, no obvious GSH adduct was generated in the human and rat liver microsomal incubation systems, and it had a low ability to generate reactive metabolites.

PD-0332991在人肝微粒體Ratio為0.76，具有中強程度生成反應性代謝物的能力。 PD-0332991 has a ratio of 0.76 in human liver microsomes, and has the ability to produce reactive metabolites at a moderately strong level.

結論：本發明例6化合物在人和大鼠肝微粒體具有低的生成反應性代謝物的能力，PD-0332991在人肝微粒體具有中強程度的生成反應性代謝物的能力。 Conclusion: The compound of Example 6 of the present invention has low production in human and rat liver microsomes The ability of reactive metabolites, PD-0332991 has the ability to generate reactive metabolites in human liver microsomes to a moderate degree.

Claims

一種通式(II)所示的化合物或其互變異構體、內消旋體、外消旋體、對映異構體、非對映異構體或其混合物形式或其可藥用鹽，

其中，

為單鍵或雙鍵；R¹選自氫原子或C1-6烷基；R²選自氫原子、C1-6烷基、或-C(O)R⁷；R³選自氫原子、C1-6烷基、C3-6環烷基；R⁴選自氫原子或C1-6烷基，其中該C1-6烷基視需要進一步被一個或多個選自鹵素、羥基、C1-6鹵烷基、C1-6烷氧基、或C3-6環烷基的取代基所取代；R⁵或R⁶各自獨立地選自氫原子；R⁷選自氫原子或C1-6烷基。A compound represented by the general formula (II) or a tautomer, a racemate, a racemate, an enantiomer, a diastereomer or a mixture thereof or a pharmaceutically acceptable salt thereof,

among them,

Is a single or double bond; R ^{1 is} selected from a hydrogen atom or C1-6 alkyl; R ^{2 is} selected from a hydrogen atom, C1-6 alkyl, or -C (O) R ⁷ ; R ^{3 is} selected from a hydrogen atom, C1 -6 alkyl, C3-6 cycloalkyl; R ^{4 is} selected from a hydrogen atom or a C1-6 alkyl, wherein the C1-6 alkyl is further optionally selected from one or more of halogen, hydroxyl, and C1-6 halogen alkyl, C1-6 alkoxy, or C3-6 cycloalkyl substituents; R ⁵ or R ⁶ are each independently selected from a hydrogen atom; R ⁷ is selected from a hydrogen atom or a C1-6 alkyl group.

如申請專利範圍第1項所述的通式(II)所示的化合物或其互變異構體、內消旋體、外消旋體、對映異構體、非對映異構體或其混合物形式或其可藥用鹽，其中R¹為C1-6烷基。The compound represented by the general formula (II) or its tautomer, meso, racemate, enantiomer, diastereomer or its In the form of a mixture or a pharmaceutically acceptable salt thereof, wherein R ¹ is C1-6 alkyl.

如申請專利範圍第1項所述的通式(II)所示的化合物或其互變異構體、內消旋體、外消旋體、對映異構體、非對映異構體或其混合物形式或其可藥用鹽，其中R²為-C(O)R⁷；且R⁷為C1-6烷基。The compound represented by the general formula (II) or its tautomer, meso, racemate, enantiomer, diastereomer or its A mixture or a pharmaceutically acceptable salt thereof, wherein R ² is -C (O) R ⁷ ; and R ⁷ is C1-6 alkyl.

如申請專利範圍第1項所述的通式(II)所示的化合物或其互變異構體、內消旋體、外消旋體、對映異構體、非對映異構體或其混合物形式或其可藥用鹽，其中R³為C3-6環烷基。The compound represented by the general formula (II) or its tautomer, meso, racemate, enantiomer, diastereomer or its In the form of a mixture or a pharmaceutically acceptable salt thereof, wherein R ³ is C3-6 cycloalkyl.

如申請專利範圍第1項所述的通式(II)所示的化合物或其互變異構體、內消旋體、外消旋體、對映異構體、非對映異構體或其混合物形式或其可藥用鹽，其中R⁴選自氫原子或C1-6烷基，其中該C1-6烷基視需要進一步被一個或多個選自鹵素、羥基或C3-6環烷基的取代基所取代。The compound represented by the general formula (II) or its tautomer, meso, racemate, enantiomer, diastereomer or its In the form of a mixture or a pharmaceutically acceptable salt thereof, wherein R ^{4 is} selected from a hydrogen atom or a C 1-6 alkyl group, wherein the C 1-6 alkyl group is further optionally selected from one or more halogen, hydroxy or C 3-6 cycloalkyl groups Is substituted with.

如申請專利範圍第1項所述的通式(II)所示的化合物或其互變異構體、內消旋體、外消旋體、對映異構體、非對映異構體或其混合物形式或其可藥用鹽，其為通式(III)所示的化合物或其互變異構體、內消旋體、外消旋體、對映異構體、非對映異構體或其混合物形式，或其可藥用鹽，

其中，R¹至R⁶的定義如申請專利範圍第1項中所定義。The compound represented by the general formula (II) or its tautomer, meso, racemate, enantiomer, diastereomer or its A mixture or a pharmaceutically acceptable salt thereof, which is a compound represented by the general formula (III) or a tautomer, meso, racemate, enantiomer, diastereomer, or In the form of a mixture, or a pharmaceutically acceptable salt thereof,

Among them, the definition of R ¹ to R ^{6 is} the same as that defined in item 1 of the scope of patent application.

如申請專利範圍第1項所述的通式(II)所示的化合物或其互變異構體、內消旋體、外消旋體、對映異構體、非對映異構體或其混合物形式或其可藥用鹽，其中該化合物選自：

The compound represented by the general formula (II) or its tautomer, meso, racemate, enantiomer, diastereomer or its A mixture or a pharmaceutically acceptable salt thereof, wherein the compound is selected from:

一種通式(II-C)所示的化合物或其互變異構體、內消旋體、外消旋體、對映異構體、非對映異構體或其混合物形式或其可藥用鹽，

其中，

為單鍵或雙鍵；Boc為第三丁氧羰基；R為C1-6烷基；Y選自O；R¹選自氫原子或C1-6烷基；R³選自氫原子、C1-6烷基或C3-6環烷基；R⁵或R⁶各自獨立地選自氫原子。A compound represented by the general formula (II-C) or a tautomer, a racemate, a racemate, an enantiomer, a diastereomer or a mixture thereof or a pharmaceutically acceptable compound thereof salt,

among them,

Is a single or double bond; Boc third butoxycarbonyl group; R is C1-6 alkyl; the Y is selected from O; R ¹ is selected from a hydrogen atom or a C1-6 alkyl group; R ³ is selected from a hydrogen atom, C1- 6 alkyl or C3-6 cycloalkyl; R ⁵ or R ⁶ are each independently selected from a hydrogen atom.

一種製備如申請專利範圍第1項所述的通式(II)所示的化合物或其互變異構體、內消旋體、外消旋體、對映異構體、非對映異構體或其混合物形式或其可藥用鹽的方法，該方法包括：

通式(II-A)化合物與通式(I-B)化合物在鹼性條件下，視需要在催化劑作用下進行取代反應得到通式(II-C)化合物；通式(II-C)化合物在溶劑中，酸性條件下，進行脫保護反應，視需要進一步進行取代反應，得到通式(II)化合物；其中，Y為O；X為鹵素；Boc為第三丁氧羰基；R為C1-6烷基；R²為-C(O)R⁷；

、R¹、R³至R⁷的定義如申請專利範圍第1項中所述。A method for preparing a compound represented by the general formula (II) or the tautomer, meso, racemate, enantiomer, diastereomer as described in item 1 of the scope of patent application Or a method of a mixture thereof or a pharmaceutically acceptable salt thereof, the method comprising:

The compound of the general formula (II-A) and the compound of the general formula (IB) are subjected to a substitution reaction under a basic condition under the action of a catalyst to obtain a compound of the general formula (II-C); the compound of the general formula (II-C) is in a solvent Under acidic conditions, a deprotection reaction is performed, and a substitution reaction is further performed as necessary to obtain a compound of general formula (II); wherein Y is O; X is halogen; Boc is a third butoxycarbonyl group; R is a C1-6 alkane R ² is -C (O) R ⁷ ;

, R ¹ , R ³ to R ⁷ are defined as described in item 1 of the scope of patent application.

如申請專利範圍第9項所述的方法，其中R⁴為氫原子或C1-6烷基，其中該烷基視需要進一步被一個或多個選自鹵素、羥基或C3-6環烷基的取代基所取代。The method according to item 9 of the scope of patent application, wherein R ⁴ is a hydrogen atom or a C1-6 alkyl group, wherein the alkyl group is further optionally selected from one or more halogen, hydroxy, or C3-6 cycloalkyl groups Substituted by a substituent.

一種醫藥組成物，該醫藥組成物含有治療有效量的如申請專利範圍第1至7項中任意一項所述的化合物或其互變異構體、內消旋體、外消旋體、對映異構體、非對映異構體或其混合物形式或其可藥用鹽，以及一種或多種藥學上可接受的載體、稀釋劑或賦形劑。A medicinal composition containing a therapeutically effective amount of a compound as described in any one of claims 1 to 7 or a tautomer, meso, racemate, enantiomer thereof Isomers, diastereomers or mixtures thereof or pharmaceutically acceptable salts thereof, and one or more pharmaceutically acceptable carriers, diluents or excipients.

一種如申請專利範圍第1至7項中任意一項所述的化合物或其互變異構體、內消旋體、外消旋體、對映異構體、非對映異構體或其混合物形式或其可藥用鹽的用途，其係用在製備抑制CDK4和/或CDK6的藥物。A compound or a tautomer, meso, racemate, enantiomer, diastereomer or a mixture thereof according to any one of claims 1 to 7 of the scope of patent application Use of a form or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for inhibiting CDK4 and / or CDK6.

一種如申請專利範圍第11項所述的醫藥組成物的用途，其係用在製備抑制CDK4和/或CDK6的藥物。A use of the pharmaceutical composition according to item 11 of the scope of patent application, which is used for preparing a medicine for inhibiting CDK4 and / or CDK6.

一種如申請專利範圍第1至7項中任意一項所述的化合物或其互變異構體、內消旋體、外消旋體、對映異構體、非對映異構體或其混合物形式或其可藥用鹽的用途，其係用在製備治療異常細胞增殖性疾病、感染、炎性病症、自身免疫性疾病、心血管疾病或神經變性疾病的藥物。A compound or a tautomer, meso, racemate, enantiomer, diastereomer or a mixture thereof according to any one of claims 1 to 7 of the scope of patent application A form or a pharmaceutically acceptable salt thereof, which is used for preparing a medicament for treating abnormal cell proliferative diseases, infections, inflammatory disorders, autoimmune diseases, cardiovascular diseases or neurodegenerative diseases.

一種如申請專利範圍第11項所述的醫藥組成物的用途，其係用在製備治療異常細胞增殖性疾病、感染、炎性病症、自身免疫性疾病、心血管疾病或神經變性疾病的藥物。The use of the medicinal composition according to item 11 of the scope of patent application is used for preparing medicines for treating abnormal cell proliferative diseases, infections, inflammatory diseases, autoimmune diseases, cardiovascular diseases or neurodegenerative diseases.

一種如申請專利範圍第1至7項中任意一項所述的化合物或其互變異構體、內消旋體、外消旋體、對映異構體、非對映異構體或其混合物形式或其可藥用鹽的用途，其係用在製備治療癌症的藥物，其中該癌症選自乳腺癌、卵巢癌、***癌、黑色素瘤、腦瘤、食管癌、胃癌、肝癌、胰腺癌、結腸直腸癌、肺癌、腎癌、皮膚癌、成膠質細胞瘤、神經母細胞瘤、肉瘤、脂肪肉瘤、骨軟骨瘤、骨瘤、骨肉瘤、精原細胞瘤、睾丸腫瘤、子宮癌、頭頸腫瘤、多發性骨髓瘤、惡性淋巴瘤、真性紅細胞增多症、白血病、甲狀腺腫瘤、輸尿管腫瘤、膀胱腫瘤、膽囊癌、膽管癌、絨毛膜上皮癌或兒科腫瘤。A compound or a tautomer, meso, racemate, enantiomer, diastereomer or a mixture thereof according to any one of claims 1 to 7 of the scope of patent application Form or a pharmaceutically acceptable salt thereof, which is used for preparing a medicine for treating cancer, wherein the cancer is selected from breast cancer, ovarian cancer, prostate cancer, melanoma, brain tumor, esophageal cancer, gastric cancer, liver cancer, pancreatic cancer, Colorectal cancer, lung cancer, kidney cancer, skin cancer, glioblastoma, neuroblastoma, sarcoma, liposarcoma, osteochondroma, osteoma, osteosarcoma, seminoma, testicular tumor, uterine cancer, head and neck tumor , Multiple myeloma, malignant lymphoma, polycythemia vera, leukemia, thyroid tumor, ureteral tumor, bladder tumor, gallbladder cancer, bile duct cancer, chorionic epithelial cancer or pediatric tumor.

一種如申請專利範圍第11項所述的醫藥組成物的用途，其係用在製備治療癌症的藥物，其中該癌症選自乳腺癌、卵巢癌、***癌、黑色素瘤、腦瘤、食管癌、胃癌、肝癌、胰腺癌、結腸直腸癌、肺癌、腎癌、皮膚癌、成膠質細胞瘤、神經母細胞瘤、肉瘤、脂肪肉瘤、骨軟骨瘤、骨瘤、骨肉瘤、精原細胞瘤、睾丸腫瘤、子宮癌、頭頸腫瘤、多發性骨髓瘤、惡性淋巴瘤、真性紅細胞增多症、白血病、甲狀腺腫瘤、輸尿管腫瘤、膀胱腫瘤、膽囊癌、膽管癌、絨毛膜上皮癌或兒科腫瘤。The use of the medicinal composition according to item 11 of the scope of patent application, which is used for preparing medicine for treating cancer, wherein the cancer is selected from breast cancer, ovarian cancer, prostate cancer, melanoma, brain tumor, esophageal cancer, Gastric cancer, liver cancer, pancreatic cancer, colorectal cancer, lung cancer, kidney cancer, skin cancer, glioblastoma, neuroblastoma, sarcoma, liposarcoma, osteochondroma, osteoma, osteosarcoma, seminoma, testis Tumor, uterine cancer, head and neck tumor, multiple myeloma, malignant lymphoma, polycythemia vera, leukemia, thyroid tumor, ureteral tumor, bladder tumor, gallbladder cancer, bile duct cancer, chorionic epithelial cancer or pediatric tumor.

如申請專利範圍第16或17項所述的用途，其中該藥物進一步與另外一種或多種抗癌劑聯合應用。The use as described in claim 16 or 17, wherein the drug is further used in combination with another anticancer agent.

一種如申請專利範圍第1至7項中任意一項所述的化合物或其互變異構體、內消旋體、外消旋體、對映異構體、非對映異構體或其混合物形式或其可藥用鹽的用途，其係用在製備治療由輻射引起的造血毒性疾病的藥物，其中該輻射引起的造血毒性疾病包括骨髓抑制、嗜中性白血球減少症、白細胞減少症、貧血。A compound or a tautomer, meso, racemate, enantiomer, diastereomer or a mixture thereof according to any one of claims 1 to 7 of the scope of patent application Form or a pharmaceutically acceptable salt thereof for use in the manufacture of a medicament for the treatment of hematopoietic diseases caused by radiation, wherein the radiation-induced hematopoietic diseases include bone marrow suppression, neutropenia, leukopenia, anemia .

一種如申請專利範圍第11項所述的醫藥組成物的用途，其係用在製備治療由輻射引起的造血毒性疾病的藥物，其中該輻射引起的造血毒性疾病包括骨髓抑制、嗜中性白血球減少症、白細胞減少症、貧血。The use of the medicinal composition according to item 11 of the scope of patent application, which is used for preparing medicine for treating hematopoietic toxic diseases caused by radiation, wherein the hematopoietic toxic diseases caused by radiation include bone marrow suppression, neutrophil reduction Disease, leukopenia, anemia.

如申請專利範圍第16或17項的用途，其中該腦瘤包括具有惡性的星形神經膠質和少突神經膠質細胞瘤成分的神經膠質瘤。For example, the use of item 16 or 17 of the patent application scope, wherein the brain tumor includes a glioma with malignant astroglial and oligodendroglioma components.

如申請專利範圍第18項所述的用途，其中該抗癌劑選自烷化劑、鉑絡合劑、代謝拮抗劑、植物生物鹼、抗體藥物、激素抗癌劑、蛋白酶體抑制劑、芳香化酶抑制劑、VEGFR或EGFR抑制劑、mTOR抑制劑、PI3K激酶抑制劑、B-Raf抑制劑或AKT抑制劑。The use according to item 18 of the scope of the patent application, wherein the anticancer agent is selected from the group consisting of alkylating agents, platinum complexing agents, metabolic antagonists, plant alkaloids, antibody drugs, hormone anticancer agents, proteasome inhibitors, aromatization Enzyme inhibitor, VEGFR or EGFR inhibitor, mTOR inhibitor, PI3K kinase inhibitor, B-Raf inhibitor or AKT inhibitor.

如申請專利範圍第22項所述的用途，其中該代謝拮抗劑包括甲氨蝶呤、5-氟尿嘧啶、替加氟、吉西他濱、卡培他濱、氟維司群和培美曲塞。Use according to item 22 of the scope of patent application, wherein the metabolic antagonist includes methotrexate, 5-fluorouracil, tegafur, gemcitabine, capecitabine, fulvestrant, and pemetrexed.

如申請專利範圍第18項所述的用途，其中該抗癌劑為芳香化酶抑制劑。The use as described in item 18 of the scope of patent application, wherein the anticancer agent is an aromatase inhibitor.

如申請專利範圍第18項所述的用途，其中該抗癌劑為來曲唑或阿那曲唑。Use according to item 18 of the scope of patent application, wherein the anticancer agent is letrozole or anastrozole.