TW201444838A

TW201444838A - Pyridino pyrimidine derivatives, preparation method and medical use thereof

Info

Publication number: TW201444838A
Application number: TW103115479A
Authority: TW
Inventors: Xin Li; piao-yang Sun; Jiong Lan; jian-biao Peng; Yang Chen; Bin Wang; Qing Dong
Original assignee: Shanghai Hengrui Pharm Co Ltd; Jiangsu Hengrui Medicine Co
Priority date: 2013-05-17
Filing date: 2014-04-30
Publication date: 2014-12-01
Also published as: CN104470921B; CN104470921A; TWI642667B; HK1206025A1; WO2014183520A1

Abstract

The present invention relates to pyridino pyrimidine derivatives, preparation method and medical use thereof. Specifically, the present invention relates to pyridino pyrimidine derivatives of general formula (I), pharmaceutically acceptable salts thereof, and the preparation methods thereof, as well as their use as a cancer therapeutic agent, especially their use as a CDK4 and/or CDK6 inhibitor, wherein each substitute of general formula (I) is defined as 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 methods thereof and their application 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 present invention relates to a novel pyridopyrimidine derivative, a process for the preparation thereof, and a pharmaceutical composition containing the same, and its use as a cancer therapeutic 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 associated with the cell cycle. Most tumors have large numbers of mitotic signaling proteins/anti-mitotic signaling protein defects, genomic instability (GIN) and genomic instability (CIN), the three basic cells. Cyclic defects are caused directly or indirectly by the loss of control of cyclin-dependent kinases (CDKs). CDK functions by binding to its regulatory subunit cyclins (cyclins), while the four major classes of cyclins (A-, B-, D-, E-type cyclins) play different roles in different stages of the 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 the Cyclin/CDK heterodimer 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 have shown increased activity of cyclin-dependent kinases or Abnormal activation leads to the formation of human tumors. In fact, the formation of human tumors is generally associated with changes in the CDK protein itself or its modulators. In vitro experiments have found that protein inhibitors of naturally occurring CDK, such as p16 and p27, are capable of inhibiting 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 knockout mice have diabetes spasms and cell defects, and CDK6 single knockout mice have mild anemia symptoms due to defects in hematopoietic cell proliferation, while CDK4 and CDK6 (CDK4/6) double genes Knockout can impair the proliferative capacity of hematopoietic precursor cells, leading to double knockout of mouse embryonic death. Superactivation of the CDK4/6-cyclin D/Rb signaling pathway is commonly found in tumor cells. Under the stimulation of various mitotic signals inside and outside the cell, cyclin D is highly expressed, regulates the interaction between CDK4/6 protein and cyclin D, and promotes the localization and kinase activity of CDK4/6. 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 cell cycle progression. Superactivation of CDK4 is often found in epithelial malignancies, whereas superactivation of CDK6 is often found in stromal cell tumors such as sarcomas and hematological cancers. Construction of a breast cancer-bearing mouse model revealed that wild-type nude mice all formed tumors, while CDK4 knocked out nude mice completely unable to form tumors; while using anti-CDK4 siRNA to interfere with CDK4 expression, it was found that tumor growth in 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 a variety of infectious agents, Including fungi, protozoan parasites (such as Plasmodium falciparum) and DNA and RNA viruses; can also be used to improve a variety of autoimmune disorders, studies have found that in the rat model of arthritis, joint swelling is basically p16-expressing adenovirus Treatment inhibition, CDK suppression The formulation is effective against other cell proliferation disorders, including psoriasis (characterized by hyperproliferation 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。 The study found that in the cell cycle, G1/S transition phase and G2/M phase cells are extremely sensitive to DNA damaging agents such as ionizing radiation (IR), and the process of cell transition from G1 phase to S phase requires at least three 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 arrest in cells, thereby increasing the tolerance of hematopoietic stem/progenitor cells to DNA damaging agents such as IR, and effectively reducing various hematopoietic toxicities caused by radiation, including myelosuppression and neutrophils. 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 CDK protein but not other enzymes. Thus, despite the potential to treat a variety of diseases, CDK inhibitors have not yet been 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 for the treatment of cancer, cardiovascular disorders and inflammation. There are currently three small molecule compounds that specifically inhibit CDK4 and CDK6, which are PDKizer and Onyx Pharmaceuticals' PD-0332991 (Clinical Phase III), Eli Lilly's LY-2835219 (Clinical Phase II) and Novartis' LEE- 011 (clinical phase I). PD-0332991 inhibits the phosphorylation of Rb by inhibiting the activity of CDK4 and CDK6, leaving the E2F-Rb complex in the cytosol, blocking the initiation of the cell cycle. Clinical trials showed that progression-free survival (PFS) was 7.5 months in patients treated with letrozole monotherapy, whereas progression-free survival was observed in patients treated with letrozole and PD-0332991. Extended 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 selective inhibition of inhibitors of CDK4 and CDK6 Please include WO2003062236, WO2006008874, WO2009126584, WO2010075074, WO2011101409, and WO2012129344, and the like.

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 effects and better meet market demand, we hope to develop a new generation of highly efficient and low toxicity selective CDK4 and CDK6 inhibitors. The present invention provides a novel structure of selective CDK4 and CDK6 inhibitors, and has found that compounds having such structures exhibit excellent effects and effects, particularly excellent drug metabolism-absorbing activities.

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 of the formula (I) or a tautomer, a mesophil, a racemate, an enantiomer, a diastereomer or a mixture thereof, Or a pharmaceutically acceptable salt thereof: among them: Is a single bond or a double bond; A ¹ or A ² are each independently selected from -CR' or N; R' is selected from a hydrogen atom, a halogen, a cyano group, a nitro group, an alkyl group, a haloalkyl group, a hydroxyalkyl group or an alkane O is selected from S or O; R ^{1 is} selected from a hydrogen atom, a halogen, an alkyl group, a haloalkyl group, a hydroxyalkyl group or a cycloalkyl group; and R ^{2 is} selected from a hydrogen atom, a halogen, a cyano group, a nitro group, and an alkyl group. Base, 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 is each independently further optionally one or more selected from the group consisting of halogen, cyano, nitro, Substituents for amine, hydroxy, pendant oxy, alkyl, haloalkyl, hydroxyalkyl, alkoxy, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, carboxy or carboxylate groups Substituted; 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 Further need to be further selected by one or more selected from the group consisting of halogen, cyano, nitro, amine, hydroxyl, and side oxygen Substituted by a substituent of a group, an alkyl group, a haloalkyl group, a hydroxyalkyl group, an alkoxy group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, a heteroaryl group, a carboxyl group or a carboxylate group; 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 The base, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl are each independently further optionally one or more selected from the group consisting of halogen, cyano, nitro, amine, hydroxy, side, as desired Substituted by a substituent of an oxy, alkyl, haloalkyl, hydroxyalkyl, alkoxy, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, carboxy or carboxylate group; R ⁵ or R ⁶ are each independently selected from the group consisting of a hydrogen atom, a halogen, a cyano group, a nitro group, a pendant oxy group, an alkyl group, an alkenyl group, an alkynyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, a heteroaryl group, -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 of them is further independently selected from one or more selected from the group consisting of halogen, cyano, nitro, amine, hydroxyl, and pendant oxy groups, as needed. Substituted with a substituent of an alkyl group, a haloalkyl group, a hydroxyalkyl group, an alkoxy group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, a heteroaryl group, a carboxyl group or a carboxylate group; 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 hetero The aryl groups are each independently further optionally selected from one or more selected from the group consisting of halogen, cyano, nitro, amine, hydroxy, pendant oxy, alkyl, haloalkyl, hydroxyalkyl, alkoxy, cycloalkyl Substituted by a heterocycloalkyl, aryl, heteroaryl, carboxy or carboxylate 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A¹或A²各自獨立地為-CH。 In a preferred embodiment of the invention, a compound of the formula (I) or a tautomer, a mesogen, a racemate, an enantiomer or a diastereomer thereof Or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein each of A ¹ or A ^{2 is} 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 invention, a compound of the formula (I) or a tautomer, a mesogen, a racemate, an enantiomer or a diastereomer thereof 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 invention, a compound of the formula (I) or a tautomer, a mesogen, a racemate, an enantiomer or a diastereomer thereof 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 invention, a compound of the formula (I) or a tautomer, a mesogen, a racemate, an enantiomer or a diastereomer thereof 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 invention, a compound of the formula (I) or a tautomer, a mesogen, a racemate, an enantiomer or a diastereomer thereof Or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R ² is -C(O)R ⁷ ; and R ⁷ is alkyl.

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 invention, a compound of the formula (I) or a tautomer, a mesogen, a racemate, an enantiomer or a diastereomer thereof 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 invention, a compound of the formula (I) or a tautomer, a mesogen, a racemate, an enantiomer or a diastereomer thereof Or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R ³ is cycloalkyl.

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 invention, a compound of the formula (I) or a tautomer, a mesogen, a racemate, an enantiomer or a diastereomer thereof 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 invention, a compound of the formula (I) or a tautomer, a mesogen, a racemate, an enantiomer or a diastereomer thereof 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 invention, a compound of the formula (I) or a tautomer, a mesogen, a racemate, an enantiomer or a diastereomer thereof 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 substituted with one or more substituents selected from a halogen, a hydroxyl group or a cycloalkyl group as needed.

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 invention, a compound of the formula (I) or a tautomer, a mesogen, a racemate, an enantiomer or a diastereomer thereof Or a mixture thereof, or a pharmaceutically acceptable salt thereof, which is a compound of the formula (II) or a tautomer, a mesogen, a racemate, an enantiomer, a diastereomer a form or a mixture thereof, or a pharmaceutically acceptable salt thereof: wherein: R ¹ to R ⁶ are as defined in the 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 invention, a compound of the formula (I) or a tautomer, a mesogen, a racemate, an enantiomer or a diastereomer thereof Or a mixture thereof, or a pharmaceutically acceptable salt thereof, which is a compound of the formula (III) or a tautomer, a mesogen, a racemate, an enantiomer, a diastereomer a conformation or a mixture thereof, or a pharmaceutically acceptable salt thereof: Wherein R ¹ to R ⁶ are as defined in the 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 meso form, 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 of the formula (IC) or a tautomer, a mesophil, a racemate, an enantiomer, a diastereomer or a mixture thereof, which is usable For the synthesis or further synthesis of a compound of the formula (I) or an intermediate thereof, a tautomer, a mesomer, a racemate, an enantiomer or a diastereomer: among them: Is a single bond or a double bond; Boc is a third butoxycarbonyl group; R is an alkyl group; A ¹ or A ² are each independently selected from -CR' or N; R' is selected from a hydrogen atom, a halogen, a cyano group, a nitro group. , an alkyl group, a haloalkyl group, a hydroxyalkyl group or an alkoxy group; Y is selected from S or O; R ^{1 is} selected from a hydrogen atom, a halogen, an alkyl group, a halogenated alkyl group, a hydroxyalkyl group or a cycloalkyl group; and 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, cycloalkyl group, heterocycloalkyl group, aryl group or heteroaryl group are each independently further optionally one by one Or a plurality selected from the group consisting of halogen, cyano, nitro, amine, hydroxy, pendant oxy, alkyl, haloalkyl, hydroxyalkyl, alkoxy, cycloalkyl, heterocycloalkyl, aryl, hetero Substituted with a substituent of an aryl group, a carboxyl group or a carboxylate group; R ⁵ or R ⁶ are each independently selected from the group consisting of a hydrogen atom, a halogen, a cyano group, a nitro group, a pendant oxy group, an alkyl group, an alkenyl group, an alkynyl group, and a ring. An alkyl group, a heterocycloalkyl group, an aryl group, a heteroaryl group, -OR ⁷ , -C(O)R ⁷ , -C(O)OR ⁷ or -OC(O)R ⁷ , wherein the alkyl group, the alkenyl group , alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl are each independently further optionally One or more selected from the group consisting of halogen, cyano, nitro, amine, hydroxy, pendant oxy, alkyl, haloalkyl, hydroxyalkyl, alkoxy, cycloalkyl, heterocycloalkyl, aryl, Substituted by a substituent of a heteroaryl group, a carboxyl group or a 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 one or more selected from the group consisting of halogen, cyano, nitro, amine, hydroxy, Substituents of pendant oxy, alkyl, haloalkyl, hydroxyalkyl, alkoxy, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, carboxy or carboxylate groups are substituted.

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 invention, a compound of the formula (IC) or a tautomer, a mesogen, a racemate, an enantiomer or a diastereomer thereof 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 of the formula (I) or a tautomer, a mesomer, a racemate, an enantiomer, a diastereomer or a mixture thereof, or A method of 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 formula (IA) and the compound of the formula (IB) are subjected to a substitution reaction under a basic condition, if necessary, under the action of a catalyst to obtain a compound of the formula (IC); the compound of the formula (IC) is in a solvent, under acidic conditions, The deprotection reaction is carried out, and a further substitution reaction is carried out as needed to obtain a compound of the formula (I): wherein: X is a halogen; Boc is a third butoxycarbonyl group; and R is as defined in the formula (IC); , A ¹ , A ² , Y, R ¹ to R ⁶ are as defined in the formula (I); R ^{4 is} preferably a hydrogen atom or an alkyl group, wherein the alkyl group is further selected by one or more Substituted by a substituent of a halogen, a hydroxyl group or a cycloalkyl group.

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 comprising a therapeutically effective amount of a compound of the formula (I) or a tautomer, a mesomer, a racemate, an enantiomer thereof, A diastereomer or a mixture thereof, or a pharmaceutically acceptable salt 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 invention further relates to a compound of the formula (I) or a tautomer, a mesophil, a racemate, an enantiomer, a diastereomer or a mixture thereof, or Medicinal salt, or pharmaceutical composition comprising the same, inhibits preparation Use in drugs for CDK4 and/or CDK6.

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 invention further relates to a compound of the formula (I) or a tautomer, a mesophil, a racemate, an enantiomer, a diastereomer or a mixture thereof, or A pharmaceutically acceptable salt, or a pharmaceutical composition comprising the same, for the treatment of abnormal cell proliferative diseases, infections (eg, viral infections such as herpes, HIV, fungal infections, etc.), inflammatory conditions (eg, rheumatoid arthritis, bone and joint) Inflammation, etc., autoimmune diseases (such as psoriasis, lupus, type I diabetes, diabetic nephropathy, multiple sclerosis, glomerulonephritis, etc.), cardiovascular diseases (such as myocardial infarction, stroke, atherosclerosis, surgery) Use in a medicament for a posterior vessel stenosis, restenosis, or the like, or a neurodegenerative disease (such as Alzheimer's disease, Parkinson's disease, etc.), wherein the abnormal cell proliferative disorder may 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 invention further relates to a compound of the formula (I) or a tautomer, a mesophil, a racemate, an enantiomer, a diastereomer or a mixture thereof, or Use of a pharmaceutically acceptable salt, or a pharmaceutical composition comprising the same, for the preparation of a medicament for treating cancer, wherein the cancer is selected from the group consisting of breast cancer, ovarian cancer, prostate cancer, melanoma, brain tumor (eg, malignant astrocyte and Glioma of oligodendroglioma, etc.), esophageal cancer, gastric cancer, liver cancer, pancreatic cancer, colorectal cancer (eg colon cancer, rectal cancer, etc.), lung cancer (eg non-small cell lung cancer, small cell lung cancer, original Hair or metastatic squamous cell carcinoma, etc., kidney cancer, skin cancer, glioblastoma, neuroblastoma, sarcoma, liposarcoma, osteochondroma, osteoma, osteosarcoma, seminoma, testicular tumor, uterus Cancer (eg cervical cancer, endometrial cancer, etc.), head and neck cancer (eg maxillary cancer, laryngeal cancer, pharyngeal cancer, tongue cancer, intraoral cancer, etc.), multiple myeloma, malignant lymphoma (eg reticulocytes) Sarcoma, lymphosarcoma, Hodgkin Carcinoma, mantle cell lymphoma, etc.), polycythemia vera, leukemia (e.g., acute Granulocyte leukemia, chronic myeloid leukemia, acute lymphocytic leukemia, chronic lymphocytic leukemia, etc.), thyroid tumor, ureteral tumor, bladder tumor, gallbladder cancer, cholangiocarcinoma, chorionic epithelial cancer or pediatric tumor (eg Ewing familial sarcoma) , Wilms sarcoma, rhabdomyosarcoma, angiosarcoma, embryonic testicular cancer, neuroblastoma, retinoblastoma, hepatic blastoma, nephroblastoma, etc.; etc.; wherein the drug can be further resistant to one or more other In combination with a cancer agent, the anticancer agent is selected from an alkylating agent (eg, cyclophosphamide, ifosfamide, melphalan, busulfan, nimodin, ramustine, dacarbazine, temozolomide) , nitrogen mustard, dibromomannitol, etc.), platinum complexing agents (eg cisplatin, carboplatin, oxaliplatin, etc.), metabolic antagonists (eg methotrexate, 5-fluorouracil, tegafur, gemcitabine, Capecitabine, fulvestrant, pemetrexed, etc.), plant alkaloids (eg, vincristine, vinblastine, vindesine, etoposide, docetaxel, paclitaxel, irinotecan, vinorelbine coast,蒽醌, vinflunine, topotecan, etc.), antibody drugs (eg trastuzumab, pertuzumab, rituximab, cetuximab, panitumumab, bevacizumab Etc., hormone anticancer agents (such as leuprolide, goserelin, dutasteride, dexamethasone, tamoxifen, etc.), proteasome inhibitors (such as bortezomib, lenalidomide, etc.) ), aromatase inhibitors (eg, exemestane, letrozole, anastrozole, etc.), VEGFR or EGFR inhibitors (eg, sunitinib, sorafenib, imatinib, gefitinib, Erlotinib, vandetanib, pazopanib, lapatinib, etc.), mTOR inhibitors (eg, everolimus, sirolimus, zotarolimus, etc.), PI3K kinase inhibitors (eg BKM-120, XL-147, BEZ-235, etc.), B-Raf inhibitors (such as vemurafenib, GSK-2118436, etc.) or AKT inhibitors (such as piperfine, MK-2206, etc.); Preferably, it is an aromatase inhibitor, 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 formula (I) or a tautomer thereof, a meso form, a racemate, an enantiomer, a diastereomer or a mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, in the preparation of a prophylactic or therapeutic radiation-induced Use in a medicament for hematopoietic diseases, wherein the radiation-induced hematopoietic diseases include, but are not limited to, myelosuppression, neutropenia, leukopenia, 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 invention also relates to a method of inhibiting the activity of CDK4 and/or CDK6 comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula (I) or a tautomer, mesogen, racemate thereof. , enantiomers, diastereomers or mixtures 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 (eg, viral infections such as herpes, HIV, fungal infections, etc.), inflammatory conditions (eg, rheumatoid arthritis, osteoarthritis, etc.), autoimmune Diseases (eg psoriasis, lupus, type I diabetes, diabetic nephropathy, multiple sclerosis, glomerulonephritis, etc.), cardiovascular disease (eg myocardial infarction, stroke, atherosclerosis, postoperative vascular stenosis, restenosis, etc.) Or a method of a neurodegenerative disease (eg, Alzheimer's disease, Parkinson's disease, etc.) comprising administering to a subject in need thereof a therapeutically effective amount of a compound of the formula (I) or a tautomer thereof, internal elimination a rot, 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 disorder 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 invention further relates to a method of treating cancer comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula (I) or a tautomer, mesogen, racemate, enantiomer thereof , 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 the group consisting of milk Adenocarcinoma, ovarian cancer, prostate cancer, melanoma, brain tumor (such as glioma with malignant astrogliosis and oligodendroglioma), esophageal cancer, gastric cancer, liver cancer, pancreatic cancer, colorectal Cancer (eg colon cancer, rectal cancer, etc.), lung cancer (eg 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 (eg cervical cancer, endometrial cancer, etc.), head and neck cancer (eg maxillary cancer, laryngeal cancer, pharynx) Cancer, tongue cancer, intraoral cancer, etc.), multiple myeloma, malignant lymphoma (eg reticulum sarcoma, lymphosarcoma, Hodgkin's lymphoma, mantle cell lymphoma, etc.), polycythemia vera, leukemia (eg Acute myeloid leukemia, chronic myeloid leukemia, acute lymphocytic leukemia, chronic lymphocytic leukemia, etc.), thyroid tumor, ureteral tumor, bladder tumor, gallbladder cancer, cholangiocarcinoma, 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 of treating cancer comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula (I) or a tautomer, mesogen, racemate, enantiomer thereof a form, a diastereomer or a mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, in combination with another anti-cancer agent selected from the group consisting of an alkylating agent (for example Cyclophosphamide, ifosfamide, melphalan, busulfan, nimodin, ramustine, dacarbazine, temozolomide, nitrogen mustard, dibromomannitol, etc., platinum complexing agent ( For example, cisplatin, carboplatin, oxaliplatin, etc.), metabolic antagonists (such as methotrexate, 5-fluorouracil, tegafur, gemcitabine, capecitabine, fulvestrant, pemetrexed, etc.) Plant alkaloids (eg Changchun Neobase, vinblastine, vindesine, etoposide, docetaxel, paclitaxel, irinotecan, vinorelbine, mitoxantrone, vinflunine, topotecan, etc.), antibody drugs (eg, orbital) Monoclonal antibody, pertuzumab, rituximab, cetuximab, panitumumab, bevacizumab, etc.), hormone anticancer agents (eg leuprolide, goserelin, degree Otaidine, dexamethasone, tamoxifen, etc.), proteasome inhibitors (such as bortezomib, lenalidomide, etc.), aromatase inhibitors (such as exemestane, letrozole, anazepine) Oxazole, etc., VEGFR or EGFR inhibitors (eg, sunitinib, sorafenib, imatinib, gefitinib, erlotinib, vandetanib, pazopanib, lapatinib, etc. ), mTOR inhibitors (eg, everolimus, sirolimus, zotarolimus, etc.), PI3K kinase inhibitors (eg, BKM-120, XL-147, BEZ-235, etc.), B-Raf inhibitors ( For example, vemurafenib, GSK-2118436, etc.) or AKT inhibitors (such as piperfine, MK-2206, etc.), etc.; preferably an aromatase inhibitor, more preferably letrozole or anastrozole.

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 of the formula (I) or a tautomer, a mesogen, a racemate, an enantiomer, a diastereomer thereof, which is a drug which inhibits the activity of CDK4 and/or CDK6. An isomer or a mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising 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 (eg viral infections such as herpes, HIV, fungal infections, etc.), inflammatory conditions (eg rheumatoid arthritis, osteoarthritis, etc.), autoimmune diseases (eg psoriasis, lupus, type I diabetes, diabetic nephropathy, multiple sclerosis, glomerulonephritis, etc.), cardiovascular disease (eg myocardial infarction, stroke, atherosclerosis, postoperative vascular stenosis, restenosis, etc.) Or a compound represented by the formula (I) or a tautomer, a mesogen, or a drug of a drug for a neurodegenerative disease (for example, Alzheimer's disease, Parkinson's disease, etc.) 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 disorder 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 formula (I) or a tautomer, a mesophil, a racemate, an enantiomer, a diastereomer thereof or the like as a medicament for treating cancer a mixture, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, wherein the cancer is selected from the group consisting of breast cancer, ovarian cancer, prostate cancer, melanoma, brain tumor (eg, malignant astrocytes and oligodendrocytes) Glioma, glioma, etc.), esophageal cancer, gastric cancer, liver cancer, pancreatic cancer, colorectal cancer (eg colon cancer, rectal cancer, etc.), lung cancer (eg 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 (eg Cervical cancer, endometrial cancer, etc.), head and neck cancer (such as maxillary cancer, laryngeal cancer, pharyngeal cancer, tongue cancer, intraoral cancer, etc.), multiple myeloma, malignant lymphoma (such as reticulum sarcoma, lymph Sarcoma, Hodgkin's lymphoma, set Lymphocytoma, etc., polycythemia vera, leukemia (eg acute myeloid leukemia, chronic myeloid leukemia, acute lymphocytic leukemia, chronic lymphocytic leukemia, etc.), thyroid neoplasms, ureteral tumors, bladder tumors, gallbladder cancer, cholangiocarcinoma , chorionic epithelial cancer or pediatric tumor (eg Ewing familial sarcoma, Wilms' sarcoma, rhabdomyosarcoma, angiosarcoma, embryonic testicular cancer, neuroblastoma, retinoblastoma, hepatic blastoma, 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 formula (I) or a tautomer, a mesophil, a racemate, an enantiomer, a diastereomer thereof or the like as a medicament for treating cancer a mixture form, or a pharmaceutically acceptable salt thereof, or a pharmaceutical group comprising the same a compound, and one or more additional anticancer agents selected from the group consisting of alkylating agents (eg, cyclophosphamide, ifosfamide, melphalan, busulfan, nimestin, remus) Tetamine, dacarbazine, temozolomide, nitrogen mustard, dibromomannitol, etc.), platinum complexing agents (eg cisplatin, carboplatin, oxaliplatin, etc.), metabolic antagonists (eg methotrexate, 5-fluorouracil) , tegafur, gemcitabine, capecitabine, fulvestrant, pemetrexed, etc.), plant alkaloids (eg vincristine, vinblastine, vindesine, etoposide, docetaxel, paclitaxel) , irinotecan, vinorelbine, mitoxantrone, vinorelbine, topotecan, etc.), antibody drugs (eg trastuzumab, pertuzumab, rituximab, cetuximab , panitumumab, bevacizumab, etc.), hormone anticancer agents (such as leuprolide, goserelin, dutasteride, dexamethasone, tamoxifen, etc.), proteasome inhibitors ( For example, bortezomib, lenalidomide, etc.), aromatase inhibitors (such as exemestane, letrozole, anastrozole, etc.), VEGFR or EGFR inhibitors (such as Shuni) Tini, sorafenib, imatinib, gefitinib, erlotinib, vandetanib, pazopanib, lapatinib, etc.), mTOR inhibitors (eg everolimus, west Rohmose, zotarolimus, etc.), PI3K kinase inhibitors (eg BKM-120, XL-147, BEZ-235, etc.), B-Raf inhibitors (eg, velocino, GSK-2118436, etc.) or AKT An inhibitor (e.g., perifosine, MK-2206, etc.) or the like; preferably an aromatase inhibitor, more preferably letrozole or anastrozole.

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 pharmaceutical composition containing the active ingredient may be in a form suitable for oral administration, such as tablets, troches, lozenges, water or oil suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or Tincture. Oral compositions can be prepared according to any method known in the art for preparing pharmaceutical compositions, such compositions may contain one or more ingredients selected from the group consisting of sweeteners, flavoring, coloring, and preservatives to provide a pleasing And delicious pharmaceutical preparations. Tablets contain active ingredients and are used for mixing Non-toxic pharmaceutically acceptable excipients suitable for the preparation of tablets. These excipients may 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; a binder such as starch, gelatin, polyvinylpyrrolidone or gum arabic; and a lubricant such as magnesium stearate, stearic acid or talc. These tablets may be uncoated or may be coated by a known technique which provides a sustained release effect over a longer period of time by masking the taste of the drug or delaying disintegration and absorption in the gastrointestinal tract. For example, water-soluble taste masking materials such as hydroxypropylmethylcellulose or hydroxypropylcellulose, or extended-time materials such as ethylcellulose, cellulose acetate butyrate may 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。 It is also possible to use 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 provide oral preparations.

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。 The aqueous suspension contains 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 acacia; dispersing or wetting agents may be naturally occurring a phospholipid such as lecithin, or a condensation product of an alkylene oxide with a fatty acid such as polyoxyethylene stearate, or a condensation product of ethylene oxide with a long chain fatty alcohol, such as heptadecylethyleneoxy cetyl alcohol (heptadecaethyleneoxy cetanol), or a condensation product of ethylene oxide with a partial ester derived from a fatty acid and a hexitol, such as polyethylene oxide sorbitol monooleate, or ethylene oxide with derivatives derived from fatty acids and hexitols A condensation product of a partial ester such as polyethylene oxide sorbitan monooleate. The aqueous suspensions may also contain one or more preservatives such as ethylparaben or n-propylparaben, one or more coloring agents, one Or a plurality of flavoring agents and one or more sweeteners 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。 The oil suspension 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 oily suspensions may contain a thickening agent, such as beeswax, hard paraffin or cetyl alcohol. The above sweeteners and flavoring agents may be added to provide a palatable preparation. These compositions can be preserved by the addition of an anti-oxidant such as butylated hydroxyanisole 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 employed in the preparation of aqueous dispersions in the form of active ingredients and dispersions or wetting agents, suspending agents or one or more preservatives. Suitable dispersing or wetting agents and suspending agents can be used to illustrate the above examples. Other excipients such as sweetening, flavoring, and coloring agents may also be added. These compositions are preserved by the addition of an anti-oxidant 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 oil 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 soy lecithin and esters or partial esters derived from fatty acids and hexitol anhydrides such as sorbitan monooleate, and condensation products of the partial esters and ethylene oxide, for example Polyethylene oxide sorbitol monooleate. The emulsions may also contain sweeteners, flavoring agents, preservatives, and antioxidants. Syrups and elixirs may 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 can 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 oily 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 glycerin to form a microemulsion. By a large number of local injections Shoot, inject the injection or microemulsion into the patient's bloodstream. 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, a continuous intravenous delivery device 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 can be in the form of a sterile injectable aqueous or oily suspension for intramuscular and subcutaneous administration. The suspension may be formulated according to known techniques using those suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution or suspension, such as a solution prepared in 1,3-butanediol, in a non-toxic parenterally acceptable diluent or solvent. In addition, sterile fixed oils may conveniently be employed as a solvent or suspension medium. For this purpose, any blended fixed oil including synthetic mono- or diglycerides can be used. In addition, fatty acids such as oleic acid can also be prepared as an 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 a suppository for rectal administration. These pharmaceutical compositions can be prepared by mixing the drug with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid in the rectum and thus dissolves in the rectum to release the drug. Such materials include mixtures of cocoa butter, glycerin gelatin, hydrogenated vegetable oils, polyethylene glycols of various molecular weights, and fatty acid esters of polyethylene glycol.

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 is well known to those skilled in the art, the dosage of the drug depends on a variety of factors including, but not limited to, the activity of the particular compound employed, the age of the patient, the weight of the patient, the health of the patient, the performance of the patient, the patient's Diet, time of administration, mode of administration, rate of excretion, combination of drugs, etc.; alternatively, the preferred mode of treatment, such as the mode of treatment, the daily amount of the compound of formula (I) or the type of pharmaceutically acceptable salt, may be Traditional treatment options to verify.

(發明詳述) (details of the 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 are used in the specification 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 a saturated aliphatic hydrocarbon group, including straight chain and branched chain groups of 1 to 20 carbon atoms. An alkyl group having 1 to 10 carbon atoms is preferred, an alkyl group having 1 to 6 carbon atoms is preferred, and an alkyl group having 1 to 4 carbon atoms is preferred, most preferably a methyl group. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, t-butyl, n-pentyl, 1,1-dimethylpropane 1,1,2-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-glycol Base, 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-decyl, 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 having 1 to 6 carbon atoms, non-limiting examples including methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-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 Methyl butyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methyl Butyl, 2,3-dimethylbutyl and the like. The alkyl group may be substituted or unsubstituted, and when substituted, the substituent may be substituted at any available point of attachment, preferably one or more of the following groups, independently selected from an alkyl group. , alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, fluorenyl, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, naphthenic Oxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, pendant oxy, amine, haloalkyl, hydroxyalkyl, carboxy 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 comprising from 3 to 20 carbon atoms, preferably from 3 to 12 carbon atoms, more preferably a cycloalkyl ring comprising 3 Up to 10 carbon atoms, the most preferred cycloalkyl ring contains 3 to 6 carbon atoms, most preferably a cyclopropyl or cyclopentyl group. Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatriene The group, the cyclooctyl group and the like are preferably a cyclopropyl group or a cyclopentyl group. Polycyclic cycloalkyl groups include spiro, fused, and bridged cycloalkyl groups. The cycloalkyl group may be optionally substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkane. Thio group, alkylamino group, halogen, fluorenyl group, hydroxy group, nitro group, cyano group, cycloalkyl group, heterocycloalkyl group, aryl group, heteroaryl group, cycloalkoxy group, heterocycloalkoxy group, cycloalkyl sulfide A heterocyclic alkylthio group, a pendant oxy group, an amine group, a haloalkyl group, a hydroxyalkyl group, a carboxyl group or a 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 ethenyl, 1-propenyl, 2-propenyl, 1-, 2- or -butenyl and the like. Preferred is a C _2-10 alkenyl group, more preferably a C _2-6 alkenyl group, most preferably a C _2-4 alkenyl group, most preferably a vinyl group. The alkenyl group may be substituted or unsubstituted, and 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, fluorenyl, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, Heterocycloalkylthio, pendant oxy, 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. It is preferably C _2-10 alkynyl groups, more preferably C _2-6 alkynyl group, most preferably C _2-4 alkynyl groups. The alkynyl group may be substituted or unsubstituted, and 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, fluorenyl, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, Heterocycloalkylthio, pendant oxy, 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 comprising from 3 to 20 ring atoms wherein one or more ring atoms are selected from nitrogen, oxygen or S(O) The hetero atom of _m (where m is an integer from 0 to 2), but excluding the ring moiety of -OO-, -OS- or -SS-, the remaining ring atoms are carbon. It preferably comprises from 3 to 12 ring atoms, wherein from 1 to 4 are heteroatoms, more preferably the heterocycloalkyl ring contains from 3 to 10 ring atoms, and more preferably the heterocycloalkyl ring contains from 5 to 6 ring atoms. Non-limiting examples of monocyclic heterocycloalkyl groups include pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, pyranyl, tetrahydrofuranyl and the like. Polycyclic heterocycloalkyl groups include spiro, fused, and bridged heterocycloalkyl groups. The heterocycloalkyl group may be optionally substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, Alkylthio, alkylamino, halogen, decyl, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, naphthenic Thio, heterocycloalkylthio, pendant oxy, amine, haloalkyl, hydroxyalkyl, carboxy 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 ring (i.e., a ring that shares a pair of adjacent carbon atoms) having a conjugated π-electron system, preferably 6 to 10 members, more preferably Good phenyl and naphthyl, the best phenyl. The aryl ring may be fused to a heteroaryl, heterocycloalkyl or cycloalkyl ring wherein the ring to which the parent structure is attached is an aryl ring, non-limiting examples comprising: The aryl group may be substituted or unsubstituted, and 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, fluorenyl, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, hetero A cycloalkylthio group, an amine group, a haloalkyl group, a hydroxyalkyl group, a carboxyl group or a 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 from 1 to 4 heteroatoms, from 5 to 14 ring atoms, wherein the heteroatoms are selected from the group consisting of oxygen, sulfur and nitrogen. The heteroaryl group is preferably from 5 to 10 members, more preferably 5 members or 6 members, such as thiadiazolyl, pyrazolyl, oxazolyl, oxadiazolyl, imidazolyl, triazolyl, thiazolyl, furan A group, a thienyl group, a pyridyl group, a pyrrolyl group, an N-alkylpyrrolyl group, a pyrimidinyl group, a pyrazinyl group, an imidazolyl group, a tetrazolyl group, and the like. The heteroaryl ring may be fused to an aryl, heterocycloalkyl or cycloalkyl ring, wherein the ring to which the parent structure is attached is a heteroaryl ring, non-limiting examples of which include: The heteroaryl group may be optionally substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups, independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkane. Thio group, alkylamino group, halogen, fluorenyl group, hydroxy group, nitro group, cyano group, cycloalkyl group, heterocycloalkyl group, aryl group, heteroaryl group, cycloalkoxy group, heterocycloalkoxy group, cycloalkyl sulfide A heterocycloalkylthio group, an amine group, a haloalkyl group, a hydroxyalkyl group, a carboxyl group or a carboxylate group.

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, 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, and when substituted, the substituent is preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, Alkylthio, alkylamino, halogen, decyl, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkane A thio group, a heterocycloalkylthio group, an amine group, a haloalkyl group, a hydroxyalkyl group, a carboxyl group or a carboxylate group.

“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" means that the alkyl group is substituted by one or more halogens, wherein alkyl is as defined above.

“羥基”指-OH基團。 "Hydroxy" refers to an -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" means an alkyl group substituted by 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 fluoro, chloro, bromo or iodo, preferably fluoro or iodo.

“胺基”指-NH₂。 "Amino" means -NH _2.

“氰基”指-CN。 "Cyano" means -CN.

“硝基”指-NO₂。 "Nitro" means -NO ₂ .

“側氧基”指=O。 "Sideoxy" means =0.

“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。 "Carboxylic acid ester group" means -C(O)O(alkyl) or (cycloalkyl) wherein alkyl, 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 subsequently described event or environment may, but need not, occur, including where the event or environment occurs or does not occur. For example, "heterocycloalkyl group optionally substituted by an alkyl group" means that an alkyl group may be, but is not necessarily, present, and the 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. The situation of substitution.

“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 the group, preferably up to 5, more preferably 1 to 3 hydrogen atoms, independently of each other, substituted 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 will be able to determine (by experiment or theory) substitutions that may or may not be possible without undue effort. For example, an amine group or a hydroxyl group having a free hydrogen may be unstable when combined with a carbon atom having an unsaturated (e.g., 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 comprising one or more of the compounds described herein, or a physiologically/pharmaceutically acceptable salt or prodrug thereof, and other chemical components, as well as other components such as physiological/pharmaceutically acceptable carriers. And excipients. The purpose of the pharmaceutical composition is to promote the administration of the organism, and to facilitate the absorption of the active ingredient to exert biological activity.

本發明的合成方法 Synthetic 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 purposes of the present invention, the present invention employs the following synthetic scheme: a compound of the formula (I) or a tautomer, a mesogen, a racemate, an enantiomer thereof. Or a mixture 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 formula (IA) and the compound of the formula (IB) are subjected to a substitution reaction under a basic condition, if necessary, under the action of a catalyst to obtain a compound of the formula (IC); the compound of the formula (IC) is in a solvent, under acidic conditions, The deprotection reaction is carried out, and a further substitution reaction is carried out as needed to obtain a compound of the formula (I): wherein: X is a halogen; Boc is a third butoxycarbonyl group; and R is an alkyl group, preferably a butyl group; ^{^{, A 1, A 2, Y}} , R ¹ to R ⁶ defined in the general formula (I) as defined; R ⁴ is preferably a hydrogen atom or an alkyl group, wherein the alkyl optionally further substituted with one or more selected from Substituted by a substituent of a halogen, a hydroxyl group or a cycloalkyl group; R ^{2 is} preferably -C(O)R ⁷ ; and R ⁷ is an alkyl group.

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 preparation of a compound of the formula (II) or a tautomer, a mesophil, a racemate, an enantiomer, a diastereomer or a mixture thereof, or a pharmaceutically acceptable form thereof a method of salt, the method comprising:

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 formula (II-A) and the compound of the formula (IB) are subjected to a substitution reaction under a basic condition, if necessary, under the action of a catalyst to obtain a compound of the formula (II-C); a compound of the formula (II-C) in a solvent In the acidic conditions, the deprotection reaction is carried out, and further, if necessary, a substitution reaction is carried out to obtain a compound of the formula (II); wherein: X is a halogen; Boc is a third butoxycarbonyl group; and R is an alkyl group, preferably a butyl group; , A ¹ , A ² , Y, R ¹ to R ⁶ are as defined in the formula (I); R ^{4 is} preferably a hydrogen atom or an alkyl group, wherein the alkyl group is further selected by one or more from halogen, hydroxy or cycloalkyl substituents; R ² is preferably -C (O) R ^7; and R ⁷ is an alkyl group.

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 compound of the formula (III) or a tautomer, a mesophil, a racemate, an enantiomer, a diastereomer or a mixture thereof, or a pharmaceutically acceptable form thereof a method of salt, the method comprising:

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 formula (III-A) and the compound of the formula (IB) are subjected to a substitution reaction under a basic condition, if necessary, under the action of a catalyst to obtain a compound of the formula (III-C); the compound of the formula (III-C) is in a solvent. In the acidic conditions, the deprotection reaction is carried out, and further, if necessary, a substitution reaction is carried out to obtain a compound of the formula (III); wherein: X is a halogen; Boc is a third butoxycarbonyl group; and R is an alkyl group, preferably a butyl group; , A ¹ , A ² , Y, R ¹ to R ⁶ are as defined in the formula (I); R ^{4 is} preferably a hydrogen atom or an alkyl group, wherein the alkyl group is further selected by one or more Substituted by a substituent of a halogen, a hydroxyl group or a cycloalkyl group; R ^{2 is} preferably -C(O)R ⁷ ; and R ⁷ is an alkyl group.

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。 The reagents providing basic conditions include organic bases and inorganic bases including, but not limited to, lithium hexamethyldidecylamine, sodium hexamethyldiscylamino, lithium diisopropylamide, Triethylamine, pyridine, 2,6-lutidine, N , N -diisopropylethylamine, n-butyllithium, potassium t-butoxide or tetrabutylammonium bromide, the inorganic bases including However, it is not limited to barium carbonate, sodium carbonate, sodium hydrogencarbonate, potassium carbonate, potassium hydrogencarbonate, 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 which provide acidity include, but are not limited to, formic acid, acetic acid, hydrochloric acid, sulfuric acid, methanesulfonic acid, trifluoroacetic acid, and hydroxyethanesulfonic acid, preferably trifluoroacetic acid or hydroxyethanesulfonic acid.

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-bisdiphenylphosphino-9,9-dimethyloxaxime, tris(dibenzylideneacetone)dipalladium, 1,1'-binaphthyl-2,2'- Diphenylphosphine, [1,1'-bis(diphenylphosphino)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, dimethyl hydrazine 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 invention is further described in the following examples, which are not intended to limit the scope of the 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 in the examples of the present invention which do not specify the specific conditions are usually in accordance with conventional conditions or according to the conditions recommended by the raw material or the manufacturer of the commodity. Reagents without specific source are routine reagents purchased from 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 was measured by a Bruker AVANCE-400 nuclear magnetic apparatus, and the solvent was deuterated dimethyl hydrazine (DMSO- d ₆ ), deuterated chloroform (CDCl ₃ ), and the internal standard was tetramethyl decane (TMS).

MS的測定用FINNIGAN LCQAd(ESI)質譜儀(生產商：Thermo，型號：Finnigan LCQ advantage MAX)。 The measurement of the MS was carried out 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 chromatograph (Sunfire C18 150 x 4.6 mm chromatography column) and a Waters 2695-2996 high pressure liquid chromatograph (Gimini C18 150 x 4.6 mm chromatography 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。 Thin layer chromatography gelatinized sheets use Yantai Yellow Sea HSGF254 or Qingdao GF254 tannin sheets. The specifications of thin layer chromatography (TLC) used for thin layer chromatography are 0.15mm to 0.2mm. The specifications for thin layer chromatography separation and purification are 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。 Tube column chromatography generally uses Yantai Huanghai Tanji 200~300 mesh tannin as 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 may be synthesized by or according to methods known in the art, or may be purchased from ABCR GmbH & Co. KG, Acros Organics, Aldrich Chemical Company, Accela ChemBio Inc, Companies such as Dare Chemicals.

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。 Unless otherwise specified in the examples, the reactions can all be carried out 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 atmosphere or a nitrogen atmosphere means that the reaction flask is connected to an argon or nitrogen balloon having 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 the reaction flask is connected to a hydrogen balloon of about 1 L volume.

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。 The pressurized hydrogenation reaction was carried out using a Parr Model 3916EKX hydrogenation apparatus and a clear blue QL-500 type hydrogen generator or a HC2-SS type hydrogenation apparatus.

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, charged 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。 Unless otherwise stated in the examples, 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 particular description in the examples, and the reaction temperature is room temperature and 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 progress of the reaction in the examples was monitored by thin layer chromatography (TLC). The system used for the reaction was: A: dichloromethane and methanol system, B: n-hexane and ethyl acetate system, C: petroleum ether With the ethyl acetate system, the volume ratio of the solvent is adjusted depending on 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 system of the eluent for column chromatography and the developer system for thin layer chromatography using the purified compound include: A: dichloromethane and methanol system, B: n-hexane and ethyl acetate system, C: dichloromethane, methanol And the ethyl acetate system, the volume ratio of the solvent is adjusted according to the polarity of the compound, and a small amount of three may be added. Alkaline or acidic reagents such as ethylamine and acetic acid are adjusted.

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'-bipyridyl]-6-yl) Amino)pyrido[2,3- d ]pyrimidin-7(8 H )-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(8 H )-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 "disclosed a process for preparing derived), 2 mL of aqueous ammonia and 20mL N, N - dimethylformamide was added 50mL eggplant-shaped flask, and stirred at 70 deg.] C for 1 hour. After cooling to room temperature, white crystals were precipitated, 50 mL of n-hexane was added, stirred for 5 minutes, suction filtered, and the filter cake was washed with a mixed solution of ethyl acetate and n-hexane (V/V = 1:10), and the solid was directly dried 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, pale 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 Ment), vinyl butyl ether (3.76 mL, 29.20 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (1.10 g, 1.50 mmool, N , N -diisopropyl Base ethylamine (5 mL, 29.2 mmol) and 30 mL of n-butanol were added to a 100 mL eggplant-shaped flask, and the reaction was stirred at 95 ° C for 12 hours, cooled to room temperature, concentrated under reduced pressure, and chromatographic column chromatography to eluent system The obtained residue was purified to give the title product 2-amino-6-(1-butoxyvinyl)-8-cyclopentyl-5-methylpyrido[2,3- d ]pyrimidine-7 (8) H )-ketone 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'-bipyridyl]-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 tert-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, and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride dichloromethane complex was added under an argon atmosphere ( 1.89 g, 0.027 mol), reacted at 108 ° C for 7 hours. After cooling to room temperature, filtration, the cake was washed with dichloromethane (30 mL × 3), and the filtrate was concentrated under reduced pressure, and the residue obtained was purified by eluent column chromatography with 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-yloxy-7,8-dihydropyrido[2,3- d ]pyrimidine- 2-yl)amino)-5',6'-dihydro-[3,4'-bipyridyl]-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)。 6-chloro turn-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-bisdiphenylphosphino-9,9-dimethyloxaxan (156 mg, 0.27 mmol) were added to a reaction flask containing 15 mL of dioxane. Tris(dibenzylideneacetone)dipalladium (125 mg, 0.14 mmol) was added under an argon atmosphere, and the mixture was reacted at 104 ° C for 15 hours. The reaction was quenched, cooled to room temperature, filtered, and then filtered, mjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj (6-(1-Butoxyvinyl)-8-cyclopentyl-5-methyl-7-yloxy-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'-bipyridyl]-6-yl) Amino)pyrido[2,3- d ]pyrimidin-7(8 H )-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-yloxy-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) Dissolved in 6 mL of dichloromethane, added with 2 mL of trifluoroacetic acid, and reacted at room temperature for 1.5 hours. The solvent was concentrated under reduced pressure, and 10 mL of dichloromethane and 2 mL of methanol were added, and aqueous ammonia was added dropwise to adjust to pH 8. The solvent was concentrated under reduced pressure. EtOAc was evaporated. Cyclopentyl-5-methyl-2-((1',2',3',6'-tetrahydro-[3,4'-bipyridyl]-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 EtOAc (EtOAc) eluting

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(8 H )-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 borohydride (95 mg, 1.48 mmol) was added. After reacting at room temperature for 15 hours, the reaction was stopped, 4 mL of methanol was added, and aqueous ammonia was added dropwise to adjust the pH to 8-9, and concentrated under reduced pressure to give the title product 6-ethyl-n-yl-8-cyclopentyl-5-methyl-2- ((1'-Methyl-1',2',3',6'-tetrahydro-[3,4'-bipyridyl]-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 (400 MHz, 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. , 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(8 H )-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%。 5-Bromo-2-chloropyridine 1d (500 mg, 2.60 mmol) and 20 mL of tetrahydrofuran were added to a 100 mL eggplant-shaped flask under argon atmosphere, cooled to -70 ° C in a dry ice-acetone bath, and 1.6 M was added to the reaction solution. n-Butyllithium (1.8 mL, 2.86 mmol), and stirred at this temperature for 30 minutes, then the pre-formed 3-butyl piperazine-1-carboxylic acid tert-butyl ester (570 mg, 2.86 mmol) was added to the reaction. The tetrahydrofuran solution was then reacted for 1 hour under the protection of a dry ice-acetone bath. The reaction was quenched by the addition of 20 mL of EtOAc EtOAc (EtOAc) The residue obtained the title product 4-(6-chloropyridin-3-yl)-4-hydroxypiperidine-1-carboxylic acid tertidine 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-yloxy-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%。 3-(6-chloropyridin-3-yl)-4-hydroxypiperidine-1-carboxylic acid tert-butyl ester 3a (80 mg, 0.26 mmol), 2-amino-6-(1-butoxy group) 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'-binaphthyl-2,2'-diphenylphosphine (32mg, 0.052mmol) and cesium carbonate (170mg, 0.52mmol) were added to a 50mL eggplant bottle, then added to 20mL The dioxane was stirred under an argon atmosphere at 90 ° C for 16 hours, and the reaction liquid was evaporated under reduced pressure, and the obtained residue was purified by silica gel chromatography to afford the title product 4-(6-( (6-(1-Butoxyvinyl)-8-cyclopentyl-5-methyl-7-yloxy-7,8-dihydropyrido[2,3- d ]pyrimidin-2-yl Amino)pyridin-3-yl)-4-hydroxypiperidine-1-carboxylic acid tert-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(8 H )-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-yloxy-7,8-dihydropyrido[2,3- d ]pyrimidin-2-yl)amino)pyridin-3-yl)-4-hydroxypiperidine-1-carboxylic acid tert-butyl ester 3b (60 mg, 0.097 mmol) and hydroxyethanesulfonic acid (50 mg, 0.387 mmol) Adding to a 25 mL eggplant-shaped bottle, then adding 2 mL of a 30% aqueous methanol solution, stirring uniformly, and reacting at 60 ° C for 1 hour, then adding 10 mL of a saturated aqueous solution of sodium hydrogencarbonate to the reaction mixture, and extracting with ethyl acetate (15 mL × 3), the organic phase was combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated to dryness. -((5-(4-hydroxypiperidin-4-yl)pyridin-2-yl)amino)-5-methylpyrido[2,3- d ]pyrimidin-7(8 H )-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-methylpyridine [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 flask at room temperature After stirring for 2 hours, sodium borohydride (27 mg, 0.129 mmol) was added, and stirring was continued at room temperature for 16 hours, the reaction was stopped, 1 mL of aqueous ammonia was added, and concentrated under reduced pressure and evaporated to dryness. The resulting residue was purified to give the title product 6-ethyl-n-yl-8-cyclopentyl-2-((5-(4-hydroxy-1-methylpiperidin-4-yl)pyridin-2-yl)amine 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 (400 MHz, 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-methylpyridine [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 and [d 2,3-] (8 H) pyrimidin-7 - one 4 (10mg, 0.021mmol) was dissolved in 5mL of dichloromethane, and then in a dry ice - acetone bath cooling, was added dimethylamino trifluoride Sulfur (2 drops), after stirring for 30 minutes, the reaction was monitored by TLC. Most of the starting materials were unreacted, and 2 drops of dimethylaminosulfur trifluoride were added. After stirring for 1 hour, the reaction was terminated. After the reaction was quenched by the addition of 15 mL of water, and the mixture was stirred for 10 min, the organic phase was separated, evaporated, evaporated, evaporated, evaporated. -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 (400 MHz, 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 )-ketone

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'-bipyridyl]-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( 2H )-carboxylic acid tert-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) The mixed solvent was added to the sealing tube, and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride dichloromethane complex (230 mg, was added under an argon atmosphere). 0.32 mmol), reacted at 85 ° C for 12 hours. After cooling to room temperature and concentration under reduced pressure, the obtained residue was purified eluting with EtOAc EtOAc EtOAc EtOAc 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 4-(6-Aminopyridin-3-yl)piperidine-1-carboxylic acid tert-butyl ester

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 Into, 10% palladium on carbon (250 mg, cat) was added, and the hydrogen was replaced three times, and the reaction was carried out at room temperature for 3 hours at 3 atm. The reaction was stopped, a small amount of celite was filtered, and the filter cake was washed with a mixed solvent of dichloromethane and methanol (V/V = 10:1) (20 mL × 1). 6-Aminopyridin-3-yl)piperidine-1-carboxylic acid tert-butyl ester 6c (595 mg, transparent viscous) 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 Tert-butyl pyridin-3-yl)piperidine-1-carboxylic acid

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 tert-butyl ester 6c (480 mg, 1.73 mmol) was dissolved in 8 mL of toluene and dissolved by heating. Amino lithium (1.7 mL, 1.73 mmol), reacted at room temperature for 20 minutes, and added 6-bromo-2-chloro-8-cyclopentyl-5-methylpyridine [2,3- d ] dissolved in 3 mL of toluene. pyrimidin -7 (8 H) - one 1a (540mg, 1.57mmol), at room temperature 1.5 hours. The reaction was quenched by the addition of EtOAc (EtOAc) (EtOAc (EtOAc) Chromatography Purification of the obtained residue in EtOAc EtOAc (EtOAc) And [2,3- d ]pyrimidin-2-yl)amino)pyridin-3-yl)piperidine-1-carboxylic acid tert-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-yloxy-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-yloxy-7,8-dihydropyrido[2,3- d ]pyrimidin-2-yl) Amino)pyridin-3-yl)piperidine-1-carboxylic acid tert-butyl ester 6d (100 mg, 0.17 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (10 mg, 0.015 mmol), N , N -diisopropylethylamine (105 mg, 0.73 mmol) and 4 mL of n-butanol were placed in a reaction flask, and vinyl butyl ether (160 mg, 1.36 mmol) was added under an argon atmosphere. Heat to 95 ° C and react for 12 hours. Cooling to room temperature and concentrating under reduced pressure afforded the crude title product 4-(6-((6-(1-butoxyvinyl)-8-cyclopentyl-5-methyl-7- </RTI> ,8-Dihydropyridine [2,3- d ]pyrimidin-2-yl)amino)pyridin-3-yl)piperidine-1-carboxylic acid tert-butyl ester 6e (152 mg, brown thick, crude 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 )-ketone

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-yloxy-7,8-dihydropyridine [2,3- d ]pyrimidin-2-yl)amino)pyridin-3-yl)piperidine-1-carboxylic acid tert-butyl ester 6e (25 mg, 0.041 mmol) dissolved in 2 mL of methanol and water (V/V = 40:1) To the mixed solvent, hydroxyethanesulfonic acid (20 mg, 0.16 mmol) was added, and the mixture was heated to 60 ° C for 1 hour. 15 mL of dichloromethane, 2 mL of methanol and 2 drops of water were added in this order, and the mixture was stirred uniformly. Sodium carbonate solid (150 mg) was added, stirred for 20 minutes, filtered, and the filtrate was concentrated under reduced pressure. The title product 6-Ethyl-8-cyclopentyl-5-methyl-2-((5-(piperidin-4-yl)pyridin-2-yl)amino)pyridinyl[2,3- d ] Pyrimidine-7(8 H )-one 6 (8 mg, EtOAc), 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-Ethyl-8-cyclopentyl-5-methyl-2-((5-(1-methylpiperidin-4-yl)pyridin-2-yl)amino)pyridin[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 ] pyrimidin -7 (8 H) - one 6 (25mg, 0.056mmol) and 37% formaldehyde solution (6.8mg, 0.084mmol) was dissolved in 4mL 1,2- dichloroethane, for 10 minutes, sodium acetate is added boron hydride (35 mg, 0.17 mmol), reacted at room temperature for 12 hours. The reaction was quenched, 2 mL of methanol was added, and the mixture was stirred for 10 min. 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)pyridin[2,3- d] ] pyrimidin -7 (8 H) - one 6 (20mg, 0.047mmol), acetaldehyde (20mg, 0.45mmol), 4mL 1,2- dichloroethane, acetic acid and sodium borohydride (25mg, 0.11mmol) added to the reaction flask The reaction was carried out at room temperature for 12 hours. The reaction was quenched, 3 mL of methanol was added, and the mixture was stirred for 5 min. -(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 And [2,3- d ]pyrimidin-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(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 ] pyrimidin -7 (8 H) - one 6 (15mg, 0.033mmol) was dissolved in 2.5mL N, N - dimethylformamide was added 2-bromoethanol (10mg, 0.080mmol) and potassium carbonate (12.5mg, 0.091mmol), reacted at room temperature for 12 hours, detected by TLC, the starting material was not reacted, added 1 drop of 2-bromoethanol, heated to 70 ° C, reacted for 2.5 hours, detected by TLC, the raw materials were not reacted, heated to 90 ° C Further, 15 mg of potassium carbonate was added, and the reaction was stopped for 3 hours. The mixture was cooled to room temperature, filtered, and the filtrate was evaporated, evaporated, evaporated,jjjjjjjjjjjjjjjjjjjjj -(2-hydroxyethyl)piperidin-4-yl)pyridin-2-yl)amino)-5-methylpyrido[2,3- d ]pyrimidin-7( 8H )-one 9 (10 mg , pale 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 And [2,3- d ]pyrimidin-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(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-Ethyl-8-cyclopentyl-5-methyl-2-((5-(piperidin-4-yl)pyridin-2-yl)amino)pyridin[2,3- d] ] pyrimidin -7 (8 H) - one 6 (15mg, 0.033mmol), cyclopropyl bromide (8.37mg, 0.062mmol), potassium carbonate (20.7mg, 0.15mmol), and 3mL of acetonitrile was added a reaction flask and heated to 80 At ° C, the reaction was stopped for 2 hours. The mixture was cooled to room temperature, filtered, and the filtrate was evaporated, evaporated, evaporated,jjjjjjjjjjjjjjjjjjjjj -(cyclopropylmethyl)piperidin-4-yl)pyridin-2-yl)amino)-5-methylpyrido[2,3- d ]pyrimidin-7(8 H )-one 10 (6 mg , 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(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(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 ] pyrimidin -7 (8 H) - one 6 (15mg, 0.033mmol) was dissolved in 4mL of acetonitrile, 1-bromo-2,2-difluoroethane (24.36mg, 0.168mmol) and potassium carbonate (30mg, 0.22mmol The mixture was heated to 80 ° C and reacted for 6 hours to stop the reaction. The mixture was cooled to room temperature, filtered, and the filtered cake was washed with dichloromethane (3mL×2), and the filtrate was concentrated under reduced pressure. -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 case:

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 by 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。 In vitro CDK (CDK4, CDK6, CDK1, CDK2, CDK9) kinase activity 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 kinase used in this experiment: CDK4/human cyclin D1 (Invitrogen, Cat. No. PV4400) or CDK4/CycD3 (Carna biosciences, Cat. No. 04-105); CDK6/human cyclin D1 (Invitrogen, Cat. No. PV4401) or CDK6/ CycD3 (Carna biosciences, Cat. No. 04-107); CDK1/Human cyclin B (Invitrogen, Cat. No. PV3292); CDK2/Human cyclin A (Invitrogen, Cat. No. PV3267) or CDK2/CycA2 (Carna biosciences, Cat. No. 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)。 Using the ^{kit: Z'-LYTE TM Kinase Assay Kit} -Ser / Thr 12 Peptide (Invitrogen, Product Number 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)。 The in vitro kinase assay described below can determine the inhibitory activity of a test compound against CDK (CDK4, CDK6, CDK1, CDK2, CDK9) kinase. Prepare 1×buffer A (Invitrogen, Cat. No. PV3189); dissolve the test compound in dimethyl sulfoxide and dilute to each concentration gradient according to the test. Add 1×buffer A to prepare 4% dimethyl sulfoxide solution. ; 400μM ATP resulting solution was diluted with 1 × buffer solution a of ATP; the Z'-LYTE ^TM Ser amount kit / Thr12 polypeptide substrate (Invitrogen, Product Number PV3674), CDK kinase buffer solution a was mixed with 1 ×; amount kit the Z'-LYTE ^TM Ser / Thr 12 phosphorylation of the substrate polypeptide (Invitrogen, Product Number PV3675) and 1 × buffer a formulated mixture stand phosphorylated polypeptide; with 2.5μL reaction wells arranged in a good test compound Solution, 2.5 μL 400 μM ATP solution and 5 μL enzyme and matrix mixture; control well 1 plus 5 μL enzyme and matrix mixture, 2.5 μL 4% dimethyl sulfoxide solution and 2.5 μL 1× buffer A; control well 2 Add 5 μL of enzyme and matrix mixture, 2.5 μL of 4% dimethyl sulfoxide solution and 2.5 μL of 400 μM ATP solution; add 5 μL of phosphorylated peptide mixture to control well 3, 2.5 μL of 4% dimethyl sulfoxide solution and 2.5 μL 1 x 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, Cat. No. PV3295) and Buffer B (Invitrogen, Cat. No. P3127) to the well. The mixed solution (Reagent A: Buffer B = 1:4095) was incubated at 25 ° C for 60 minutes, and fluorescence was read using a NovoStar plate 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)。 The CDK (CDK4, CDK6, CDK1, CDK2, CDK9) kinase biochemical inhibitory activity of the compounds of the present invention was determined by the above test, and the measured IC ₅₀ values are shown in Table 1 (CDK4, CDK6), 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 a significant inhibitory effect on the activity of CDK kinase (CDK4, CDK6), and the inhibition of CDK kinase (CDK4, CDK6) by the compounds of the present invention compared to the inhibition of the activity of CDK kinase (CDK1, CDK2, CDK9). 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: Inhibition of proliferation of human colon cancer cell line Colo205 by the compound of the present invention

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 assay is used to determine the compounds of the invention against human colon cancer cell lines Proliferation inhibitory activity of Colo205.

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 in vitro cell assay described below can determine the proliferation inhibitory activity of a test compound against a human colon cancer cell line, and its activity can be expressed by an IC ₅₀ value. The general protocol for such an experiment is as follows: First, Colo205 cells (Chinese Academy of Sciences cell bank, article number TCHu102) were seeded on a 384-well culture plate at a suitable cell concentration of 500 cells/well, and then the cells were cultured in a carbon dioxide incubator at 37 °C. After growing overnight, the medium was changed to a medium containing a concentration of a concentration (1000 nM, 250 nM, 62.5 nM, 15.62 nM, 3.91 nM, 0.98 nM, 0.24 nM, 0.06 nM, 0.02 nM) of the test compound solution, and the culture plate was re-introduced. Return to the incubator and continue to culture for 72 hours. After 72 hours, the test compound was assayed for inhibition of cell proliferation activity using CCK8 (Cell Counting Kit-8, Cat. No.: CK04, purchased from Tongren Chemical). The IC ₅₀ value can be calculated from the inhibition values of the test compound for the cells by a series of different concentrations.

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 Compounds of the Invention The biological activity of the compounds of the present invention was obtained from the above analysis, and the calculated IC ₅₀ values are 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 against 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, the increase of the compound of the present invention on human breast cancer cell line MCF-7 Colonization 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 assay was used to determine the proliferation inhibitory activity of the compounds of the invention against 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。 The in vitro cell assay described below can determine the proliferation inhibitory activity of a test compound on a human breast cancer cell line, and its activity can be expressed by an IC ₅₀ value. The general protocol for such an experiment is as follows: First, MCF-7 cells (purchased in Institute of biochemistry and cell biology) are seeded on a 96-well culture plate at a suitable cell concentration of 4000 cells/mL, and then the cells are placed in a carbon dioxide incubator. The medium was cultured at 37 ° C, and grown to overnight. The medium was changed to a medium containing a concentration of the test compound solution (10000 nM, 1000 nM, 100 nM, 10 nM, 1 nM, 0.1 nM), and the plate was returned to the incubator for continuous culture. 72 hours. After 72 hours, the test compound was assayed for inhibition of cell proliferation activity using CCK8 (Cell Counting Kit-8, Cat. No.: CK04, purchased from Tongren Chemical). The IC ₅₀ value can be calculated from the inhibition values of the test compound for the cells by a series of different concentrations.

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 compounds of the present invention was obtained from the above analysis, and the calculated IC ₅₀ values are 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 significant proliferation inhibitory activity against 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 Testing of Compounds of Inventive Example 6 and Example 7

1、摘要 1. Summary

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, and the concentration of the drug in plasma at different times after administration of the compound of Example 7 by intragastric administration was determined by LC/MS/MS method. The pharmacokinetic behavior of the compounds of the invention in rats was investigated and their pharmacokinetic characteristics were evaluated.

2、試驗方案 2, the 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, Example 6 and Example 7 compounds. 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, male and female, purchased from Shanghai Xipuer-Beikai Experimental Animal Co., Ltd., animal production license number: SCXK (Shanghai) 2008-0016.

2.3藥物配製 2.3 drug preparation

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。 An appropriate amount of the sample was weighed, 0.5% CMC-Na was added to a final volume, and a 0.5 mg/mL suspension was prepared by ultrasonication.

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 3 groups, 4 rats in each group, half male and half female. After fasting overnight, they were intragastrically administered at a dose of 5.0 mg/kg and a dose 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, and 24 hours after administration, placed in a heparinized anticoagulation tube, centrifuged at 3500 rpm for 10 minutes, and plasma was separated and stored at -20 °C. Eat 2 hours after administration.

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。 The content of the test compound in the plasma of rats after intragastric administration was determined by LC/MS/MS. The analytical method has a linear range of 1.00-500 ng/mL and a lower limit of quantification of 1.00 ng/mL; the plasma sample is analyzed by pre-precipitation of the precipitated protein.

4、藥物代謝動力學參數結果 4, pharmacokinetic parameters results

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: When the preferred compound of the present invention is administered at a dose of 5 mg/kg, compared with PD-0332991, the drug has good metabolic absorption and long half-life, and has 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. Summary

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。 The Beagle dog was used as the test animal, and the drug concentration in plasma was determined by LC/MS/MS method in dogs after administration of PD-0332991 and the compounds of Examples 6 and 7 at different times. The pharmacokinetic behavior of the compounds of the invention in rats was investigated and their pharmacokinetic characteristics were evaluated.

2、試驗方案 2, the 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, half male and half female, were purchased from Suzhou Xishan Zhongke Experimental Animal Co., Ltd.

2.3藥物配製 2.3 drug preparation

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。 An appropriate amount of the sample was weighed, dissolved by adding dimethylacetamide and propylene glycol, and then physiological saline was added to a final volume to prepare 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。 An appropriate amount of the sample was weighed, and 0.5% Tween 80, citric acid and 0.5% CMC-Na were added to a final volume to prepare 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。 There were 20 Beagle dogs, half male and half female, divided into 5 groups, 4 in each group. After fasting overnight, they were given intravenously and intragastrically. The intravenous dose was 2.0 mg/kg, and the intragastric dose was 5.0. Mg/kg. The volume of intravenous administration was 2.0 mL/kg, and the volume of intragastric administration 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。 The intravenous administration group received 1.0 mL of blood from the forelimb vein before and 5 minutes after administration, 0.25, 0.5, 1.0, 2.0, 4.0, 8.0, 12.0, 24.0 hours, placed in heparinized tubes, centrifuged at 3500 rpm for 10 minutes. Plasma was separated and stored at -20 °C. The rats in the gavage administration group were subjected to blood collection before administration and 0.5, 1.0, 2.0, 4.0, 6.0, 8.0, 12.0, 24.0 hours after administration, and the treatment method was the same as that of the intravenous administration group. Eat 3 hours after administration.

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。 The content of the test compound in the plasma of rats after intravenous injection and intragastric administration was determined by LC/MS/MS.

4、藥物代謝動力學參數結果 4, pharmacokinetic parameters results

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 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. Summary

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 various types of GSH adducts were screened by precursor ion scanning using an LC-MS/MS system. The ability of the compound of Example 6 to generate a reactive metabolite with PD-0332991 was investigated.

2、試驗方案 2, the test plan

2.1試驗藥品：PD-0332991，實施例6化合物。 2.1 Test drug: PD-0332991, the 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 subjects liver microsomes, protein concentration 20mg/mL, purchased from BD Gentest ^TM in the United States; male rat liver microsomes, protein concentration 20mg / mL, purchased in the United States BD Gentest ^TM ; β-NADPH, chemical purity 93-100 %, purchased from Sigma, USA. L-reduced glutathione, purity >98%, was purchased from Sigma, USA.

2.3藥物配製 2.3 drug preparation

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。 An appropriate amount of the sample was weighed, dissolved in DMSO to a final volume, and made into a 50 mM stock solution by ultrasonication, and the above stock solution was diluted to 100 μM with 100 mM phosphate buffer (PBS, pH 7.4).

2.4體外孵化體系 2.4 in vitro incubation 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 hatching system volume was 100 μL and the medium was 100 mM phosphate buffer (PBS, pH 7.4). In a 1 mL 96-well plate, human or rat liver microsome solution (formulated in PBS), test compound, and GSH solution were added to give a final concentration of 10 μM of the test compound, 5 mM GSH solution, and 1.0 mg/mL liver microparticles. Body protein was incubated at 37 ° C using a hot mix. After 3 minutes of incubation, NADPH was added to initiate the reaction with a final NADPH concentration of 2 mM. After 60 minutes of reaction, the reaction was terminated by adding 200 μL of ice-cold acetonitrile, 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。 The Qtrap API4000 LC-MS/MS system was used to detect possible GSH adducts by precursor ion scanning, and the total GSH adduct peak area generated by the test compound and the total GSH adduct peak formed by clozapine were used. The area ratio (Ratio) evaluates the ability of a compound to generate a reactive metabolite.

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。 Inventive Example 6 showed no significant GSH adduct production in both human and rat liver microsome incubation systems, and 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 capacity of 0.76 in human liver microsomes, and has the ability to generate reactive metabolites in a moderately strong manner.

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 a moderately strong ability to produce reactive metabolites in human liver microsomes.

Claims

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、鹵代烷基、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，其中所述的烷基、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。 a compound of the formula (I) or a tautomer, a mesophil, a racemate, an enantiomer, a diastereomer or a mixture thereof, or a pharmaceutically acceptable salt thereof : among them: Is a single bond or a double bond; A ¹ or A ² are each independently selected from -CR' or N; R' is selected from a hydrogen atom, a halogen, a cyano group, a nitro group, an alkyl group, a haloalkyl group, a hydroxyalkyl group or an alkane Alkyl; Y is selected from S or O; R ^{1 is} selected from a hydrogen atom, a halogen, an alkyl group, a halogenated alkyl group, a hydroxyalkyl group or a cycloalkyl group; and R ^{2 is} selected from a hydrogen atom, a halogen, a cyano group, a nitro group, an alkyl 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, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl group is each independently further optionally one or more selected from the group consisting of halogen, cyano, nitro, amine Substituted by a substituent of a hydroxy group, a hydroxyl group, an alkyl group, a haloalkyl group, a hydroxyalkyl group, an alkoxy group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, a heteroaryl group, a carboxyl group or a carboxylate group 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 Further selected from one or more selected from the group consisting of halogen, cyano, nitro, amine, hydroxy, side, as needed Substituted by a substituent of an oxy group, an alkyl group, a haloalkyl group, a hydroxyalkyl group, an alkoxy group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, a heteroaryl group, a carboxyl group or a carboxylate group; R ^{4 is} selected from a hydrogen atom, an alkyl group, an alkenyl group, an alkynyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, a heteroaryl group, -OR ⁷ , -C(O)R ⁷ or -C(O)OR ⁷ , wherein The alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl groups are each independently further optionally one or more selected from the group consisting of halogen, cyano, nitro, amine, hydroxy, Substituted by a substituent of a pendant oxy, alkyl, haloalkyl, hydroxyalkyl, alkoxy, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, carboxy or carboxylate group; R ⁵ or R ^{6 is} each independently selected from the group consisting of a hydrogen atom, a halogen, a cyano group, a nitro group, a pendant oxy group, an alkyl group, an alkenyl group, an alkynyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, a heteroaryl group, and -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 Each of the groups is further independently selected from one or more selected from the group consisting of halogen, cyano, nitro, amine, hydroxyl, and side oxygen, as needed. Substituted by a substituent of a group, an alkyl group, a haloalkyl group, a hydroxyalkyl group, an alkoxy group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, a heteroaryl group, a carboxyl group or a carboxylate group; R ^{7 is} selected from hydrogen Atom, alkyl, hydroxy, halogen, alkoxy, cycloalkyl, heterocycloalkyl, aryl or heteroaryl, wherein said alkyl, alkoxy, cycloalkyl, heterocycloalkyl, aryl The base or heteroaryl group is each independently further optionally one or more selected from the group consisting of halogen, cyano, nitro, amine, hydroxy, pendant oxy, alkyl, haloalkyl, hydroxyalkyl, alkoxy, Substituents of cycloalkyl, heterocycloalkyl, aryl, heteroaryl, carboxy or carboxylate groups are substituted.

如申請專利範圍第1項所述的通式(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，其中A¹或A²各自獨立地為-CH。 a compound represented by the formula (I) or a tautomer, a mesophil, a racemate, an enantiomer, a diastereomer thereof or the In the form of a mixture, or a pharmaceutically acceptable salt thereof, wherein A ¹ or A ² are each independently -CH.

如申請專利範圍第1至2項中任意一項所述的通式(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，其中Y為O。 The compound of the formula (I) or a tautomer, a mesogen, a racemate, an enantiomer or a non-pair thereof, as described in any one of claims 1 to 2; Or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein Y is O.

如申請專利範圍第1至3項中任意一項所述的通式(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，其中R¹為烷基。 A compound represented by the formula (I) or a tautomer, a mesogen, a racemate, an enantiomer or a non-pair thereof, as described in any one of claims 1 to 3. or a mixture of enantiomeric isomers thereof, or a pharmaceutically acceptable salt thereof, wherein R ¹ is an alkyl group.

如申請專利範圍第1至4項中任意一項所述的通式(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，其中R²為-C(O)R⁷；且R⁷為烷基。 A compound of the formula (I) or a tautomer, a mesogen, a racemate, an enantiomer or a non-pair thereof, as described in any one of claims 1 to 4 Or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R ² is -C(O)R ⁷ ; and R ⁷ is alkyl.

如申請專利範圍第1至5項中任意一項所述的通式(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，其中R³為環烷基。 A compound represented by the formula (I) or a tautomer, a mesogen, a racemate, an enantiomer or a non-pair thereof, as described in any one of claims 1 to 5 Or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R ³ is cycloalkyl.

如申請專利範圍第1至6項中任意一項所述的通式(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，其中R⁵或R⁶各自獨立地選自氫原子、鹵素、烷基或羥基。 A compound of the formula (I) or a tautomer, a mesogen, a racemate, an enantiomer or a non-pair thereof, as described in any one of claims 1 to 6 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.

如申請專利範圍第1至7項中任意一項所述的通式(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，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。 A compound represented by the formula (I) or a tautomer, a mesogen, a racemate, an enantiomer or a non-pair thereof according to any one of claims 1 to 7. 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 by one or more selected from halogen, hydroxy or cycloalkyl. Substituted by the base.

如申請專利範圍第1項所述的通式(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，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的定義如申請專利範圍第1項中所定義。 a compound represented by the formula (I) or a tautomer, a mesophil, a racemate, an enantiomer, a diastereomer thereof or the a mixture, or a pharmaceutically acceptable salt thereof, which is a compound of the formula (II) or a tautomer, a mesogen, a racemate, an enantiomer or a diastereomer thereof Or a mixture thereof, or a pharmaceutically acceptable salt thereof: among them: The definition of R ¹ to R ^{6 is} as defined in the first item of the patent application.

如申請專利範圍第1項所述的通式(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，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。 a compound represented by the formula (I) or a tautomer, a mesophil, a racemate, an enantiomer, a diastereomer thereof or the a mixture, or a pharmaceutically acceptable salt thereof, which is a compound of the formula (III) or a tautomer, a mesogen, a racemate, an enantiomer or a diastereomer thereof Or a mixture thereof, or a pharmaceutically acceptable salt thereof: Wherein: R ⁶ R ¹ to define the scope of the patent as defined in paragraph 1.

如申請專利範圍第1至10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，其中該化合物選自： A compound according to any one of claims 1 to 10, or a tautomer, a mesophil, a racemate, an enantiomer, a diastereomer or a mixture thereof Or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of:

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：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、鹵代烷基、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。 a compound of the formula (IC) or a tautomer, a mesophil, a racemate, an enantiomer, a diastereomer or a mixture thereof, or a pharmaceutically acceptable salt thereof : among them: Is a single bond or a double bond; Boc is a third butoxycarbonyl group; R is an alkyl group; A ¹ or A ² are each independently selected from -CR' or N; R' is selected from a hydrogen atom, a halogen, a cyano group, a nitro group. Or an alkyl group, a haloalkyl group, a hydroxyalkyl group or an alkoxy group; Y is selected from S or O; R ^{1 is} selected from a hydrogen atom, a halogen, an alkyl group, a halogenated alkyl group, a hydroxyalkyl group or a cycloalkyl group; and R ^{3 is} selected from the group consisting of a hydrogen atom, an alkyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group or a heteroaryl group, wherein the alkyl group, cycloalkyl group, heterocycloalkyl group, aryl group or heteroaryl group are each independently further optionally one by one Or a plurality selected from the group consisting of halogen, cyano, nitro, amine, hydroxy, pendant oxy, alkyl, haloalkyl, hydroxyalkyl, alkoxy, cycloalkyl, heterocycloalkyl, aryl, hetero Substituted with a substituent of an aryl group, a carboxyl group or a carboxylate group; R ⁵ or R ⁶ are each independently selected from the group consisting of a hydrogen atom, a halogen, a cyano group, a nitro group, a pendant oxy group, an alkyl group, an alkenyl group, an alkynyl group, and a 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 optionally And one or more selected from the group consisting of halogen, cyano, nitro, amine, hydroxy, pendant oxy, alkyl, haloalkyl, hydroxyalkyl, alkoxy, cycloalkyl, heterocycloalkyl, aryl, Substituted by a substituent of a heteroaryl group, a carboxyl group or a 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 one or more selected from the group consisting of halogen, cyano, nitro, amine, hydroxy, Substituents of pendant oxy, alkyl, haloalkyl, hydroxyalkyl, alkoxy, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, carboxy or carboxylate groups are substituted.

一種製備申請專利範圍第1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，或其可藥用鹽的方法，該方法包括：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；，A¹，A²，Y，R¹至R⁶的定義如申請專利範圍第1項中所述。 A compound according to the first aspect of the invention, or a tautomer, a mesophil, a racemate, an enantiomer, a diastereomer or a mixture thereof, or a pharmaceutically acceptable drug thereof Using a salt method, the method includes: The compound of the formula (IA) and the compound of the formula (IB) are subjected to a substitution reaction under a basic condition, if necessary, under the action of a catalyst to obtain a compound of the formula (IC); the compound of the formula (IC) is in a solvent, under acidic conditions, The deprotection reaction is carried out, and further, if necessary, a substitution reaction is carried out to obtain a compound of the formula (I): wherein: X is a halogen; Boc is a third butoxycarbonyl group; and R is an alkyl group; , A ¹ , A ² , Y, and R ¹ to R ⁶ are as defined in the first item of the patent application.

如申請專利範圍第13項所述的方法，其中R⁴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 method of claim 13, wherein R ⁴ is a hydrogen atom or an alkyl group, wherein the alkyl group is further substituted with one or more substituents selected from a halogen, a hydroxyl group or a cycloalkyl group as needed.

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12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 pharmaceutical composition comprising a therapeutically effective amount of a compound according to any one of claims 1 to 12, or a tautomer, a mesogen, a racemate, an enantiomer thereof. Isomers, diastereomers or mixtures thereof, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, diluents or excipients.

一種申請專利範圍第1至12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，其係用醫藥組成物在製備抑制CDK4和/或CDK6的藥物。 A compound according to any one of claims 1 to 12, or a tautomer, a mesophil, a racemate, an enantiomer, a diastereomer or a mixture thereof Or a pharmaceutically acceptable salt thereof for use in the manufacture of a medicament for inhibiting CDK4 and/or CDK6.

一種申請專利範圍第15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。 Use of a pharmaceutical composition according to item 15 of the patent application for the preparation of a medicament for inhibiting CDK4 and/or CDK6.

一種如申請專利範圍第1至12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 according to any one of claims 1 to 12, or a tautomer, a mesophil, a racemate, an enantiomer, a diastereomer or a mixture thereof A form, or use thereof, of a pharmaceutically acceptable salt thereof, for use in the manufacture of a medicament for the treatment of aberrant cell proliferative diseases, infections, inflammatory conditions, autoimmune diseases, cardiovascular diseases or neurodegenerative diseases.

一種申請專利範圍第15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。 Use of a pharmaceutical composition according to claim 15 for the preparation of a medicament for the treatment of abnormal cell proliferative diseases, infections, inflammatory conditions, autoimmune diseases, cardiovascular diseases or neurodegenerative diseases.

一種申請專利範圍第1至12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 according to any one of claims 1 to 12, or a tautomer, a mesogen, a racemate, an enantiomer or a diastereomer thereof. Or a mixture thereof, or a pharmaceutically acceptable salt thereof, for use in the preparation of a medicament for treating cancer, wherein the cancer is selected from the group consisting of 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 cancer, multiple myeloma, malignant lymphoma, polycythemia vera, leukemia, thyroid tumor, ureteral tumor, bladder tumor, gallbladder cancer, cholangiocarcinoma, chorionic epithelial cancer or pediatric tumor.

一種申請專利範圍第15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 pharmaceutical composition according to claim 15 for the preparation of a medicament for treating cancer, wherein the cancer is selected from the group consisting of 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 cancer, multiple myeloma, malignant lymphoma, polycythemia vera, leukemia, thyroid tumor, ureteral tumor, bladder tumor, gallbladder cancer, cholangiocarcinoma, chorionic epithelial cancer or pediatric tumor.

如申請專利範圍第20或21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 of claim 20 or 21, wherein the medicament is further used in combination with another one or more anticancer agents.

如申請專利範圍第22項所述的用途，其中該抗癌劑為芳香化酶抑制劑。 The use of claim 22, wherein the anticancer agent is an aromatase inhibitor.

如申請專利範圍第23項所述的用途，其中該抗癌劑為來曲唑或阿那曲唑。 The use of claim 23, wherein the anticancer agent is letrozole or anastrozole.

一種申請專利範圍第1至12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，其係用在製備預防或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。 A compound according to any one of claims 1 to 12, or a tautomer, a mesogen, a racemate, an enantiomer or a diastereomer thereof. Or a mixture thereof, or a pharmaceutically acceptable salt thereof, for use in the preparation of a medicament for preventing or treating a hematopoietic toxic disease caused by radiation, wherein the radiation-induced hematopoietic toxic diseases include, but are not limited to, myelosuppression, hooliganism Leukopenia, leukopenia, anemia.

一種申請專利範圍第15項所述的醫藥組成物的用途，其係用在備預防或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 use of the pharmaceutical composition according to claim 15 for use in the preparation of a medicament for preventing or treating a hematopoietic toxic disease caused by radiation, wherein the radiation-induced hematopoietic toxic diseases include, but are not limited to, myelosuppression and hobby Neutrophilic leukopenia, leukopenia, anemia.

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申請專利範圍第1至12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，或包含其的醫藥組成物。 A method of inhibiting the activity of CDK4 and/or CDK6, which comprises administering a therapeutically effective amount of a compound according to any one of claims 1 to 12, or a tautomer, a mesogen thereof, or a a racemate, an enantiomer, a diastereomer or a mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same.

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申請專利範圍第1至12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，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。 A treatment for abnormal cell proliferative diseases, infections (eg, viral infections such as herpes, HIV, fungal infections, etc.), inflammatory conditions (eg, rheumatoid arthritis, osteoarthritis, etc.), autoimmune diseases (eg, psoriasis, Lupus, type I diabetes, diabetic nephropathy, multiple sclerosis, glomerulonephritis, etc., cardiovascular disease (eg myocardial infarction, stroke, atherosclerosis, postoperative vascular stenosis, restenosis, etc.) or neurodegenerative diseases (A method of, for example, Alzheimer's disease, Parkinson's disease, etc.), which comprises administering to a patient in need thereof a therapeutically effective amount of a compound according to any one of claims 1 to 12, or a tautomer thereof, a meso form, 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 disorder may It is cancer.

一種治療癌症的方法，其包括給予所需患者治療有效量的申請專利範圍第1至12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，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。 A method of treating cancer, comprising administering a therapeutically effective amount of a compound of any one of claims 1 to 12, or a tautomer, a mesogen, a racemate, a pair thereof, in a therapeutically effective amount. a pharmaceutically acceptable salt, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, wherein the cancer is selected from the group consisting of breast cancer, ovarian cancer, prostate cancer, melanoma, brain tumor (eg, glioblastoma with malignant astroglia and oligodendroglioma, etc.), esophageal cancer, gastric cancer, liver cancer, pancreatic cancer, colorectal cancer (eg colon cancer, rectal cancer, etc.), lung cancer (eg 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 cancer (such as maxillary cancer, laryngeal cancer, pharyngeal cancer, tongue cancer, intraoral cancer, etc.), multiple bone marrow Tumor, malignant lymphoma (eg net Cell sarcoma, lymphosarcoma, Hodgkin's lymphoma, mantle cell lymphoma, etc.), polycythemia vera, leukemia (eg acute myeloid leukemia, chronic myeloid leukemia, acute lymphocytic leukemia, chronic lymphocytic leukemia, etc.), thyroid Tumor, ureteral tumor, bladder tumor, gallbladder cancer, cholangiocarcinoma, chorionic epithelial cancer or pediatric tumor (eg Ewing familial sarcoma, Wilms' sarcoma, rhabdomyosarcoma, angiosarcoma, embryonic testicular cancer, neuroblastoma, retina Blastoma, hepatic blastoma, nephroblastoma, etc.).

一種治療癌症的方法，其包括給予所需患者治療有效量的申請專利範圍第1至12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，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。 A method of treating cancer, comprising administering a therapeutically effective amount of a compound of any one of claims 1 to 12, or a tautomer, a mesogen, a racemate, a pair thereof, in a therapeutically effective amount. , a diastereomer or a mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, and another Combination of one or more anticancer agents selected from alkylating agents (eg, cyclophosphamide, ifosfamide, melphalan, busulfan, nimestin, ramustine, da Carbazine, temozolomide, nitrogen mustard, dibromomannitol, etc.), platinum complexing agents (eg cisplatin, carboplatin, oxaliplatin, etc.), metabolic antagonists (eg methotrexate, 5-fluorouracil, tega Fluorine, gemcitabine, capecitabine, fulvestrant, pemetrexed, etc.), plant alkaloids (eg vincristine, vinblastine, vindesine, etoposide, docetaxel, paclitaxel, irinotene) Kang, vinorelbine, mitoxantrone, vinorelbine, topotecan, etc.), antibody drugs (eg trastuzumab, pertuzumab, rituximab, cetuximab, Pani Monoclonal antibody, bevacizumab, etc.), hormone anticancer agents (eg, leuprolide, goserelin, dutasteride, dexamethasone, tamoxifen, etc.), proteasome inhibitors (eg, bortezole) Rice, lenalidomide, etc.), aromatase inhibitors (eg, exemestane, letrozole, anastrozole, etc.), VEGFR or EGFR inhibitors (eg, sunitinib, sol Rafinib, imatinib, gefitinib, erlotinib, vandetanib, pazopanib, lapatinib, etc.), mTOR inhibitors (eg everolimus, sirolimus, Zotarolimus, etc.), PI3K kinase inhibitors (eg BKM-120, XL-147, BEZ-235, etc.), B-Raf inhibitors (eg, vemurafenib, GSK-2118436, etc.) or AKT inhibitors (eg Piperfine, MK-2206, etc.).

如申請專利範圍第30項所述的方法，其中該抗癌劑為芳香化酶抑制劑。 The method of claim 30, wherein the anticancer agent is an aromatase inhibitor.

如申請專利範圍第31項所述的方法，其中該抗癌劑為來曲唑或阿那曲唑。 The method of claim 31, wherein the anticancer agent is letrozole or anastrozole.