TW200804352A

TW200804352A - Novel cysteine protease inhibitors

Info

Publication number: TW200804352A
Application number: TW095132088A
Authority: TW
Inventors: Martin Maria Jesus Chaparro; Lopez Jose-Miguel Coteron; Velando Esther Pilar Fernandez; Roman Jose Maria Fiandor; Martin Maria Marco
Original assignee: Glaxo Group Ltd
Priority date: 2005-09-02
Filing date: 2006-08-31
Publication date: 2008-01-16
Also published as: PE20070332A1; WO2007025776A3; WO2007025774A3; TW200804351A; PE20070612A1; WO2007025774A2; AR057110A1; WO2007025776A2; AR055624A1; WO2007025775A2

Abstract

Substituted heteroaryl nitrile derivatives of formula I, processes for their preparation, pharmaceutical compositions comprising such compounds and use of the compounds as cysteine protease inhibitors are provided.

Description

200804352 九、發明說明：【發明所屬之技術領域】本發明係關於某些經取代的雜芳基腈衍生物，其係蛋白酶抑制劑。更確定地說，該化合物是半胱胺酸蛋白酶之抑制劑。具體地說，該化合物抑制木瓜蛋白酶總科之半胱胺酸蛋白酶，更確定的是彼等鐮形木瓜蛋白酶(falcipain) 科，其係在癔疾寄生蟲之惡性瘧原蟲中發現的半胱胺酸蛋白酶，以及組織蛋白酶科例如組織蛋白酶K、L、S及B中的半胱胺酸蛋白酶。【先前技術】瘧疾是開發中國家的其中一種主要疾病問題。在人類中最毒造成瘧疾的寄生蟲是惡性瘧原蟲，其係每年數億瘧疾病例的原因，且咸信每年造成超過一百萬人死亡，Berman, J· G·，et al·，（2001) Am. Trop· Med· Hyg. 64, 1-11。在瘧疾治療中遭遇的一個問題是寄生蟲對現有藥劑累積抵抗性。因此需要發展新穎的抗瘧疾藥劑。鑑定具有抗瘧疾活性的潛在新穎藥劑之一個方法是研究在惡性瘧原蟲寄生蟲中發現的生物標的，轉而調查其中可以鑑定特定標的之生物通道。在惡性癔原蟲中，血色素是輸送至酸性食物液泡，其在此經分解。其顯示多種酶，包括食物液泡半胱胺酸、天冬胺酸、及金屬蛋白酶，及細胞溶質胺基肽酶，促進血色素水解，Francis S.E. et al.，（1997) Annu. Rev. Microbiol. 51, 97-123; Rosenthal P.J. Protease inhibitors. In: Rosenthal P.J·，ed. Antimalarial Chemotherapy: 5 200804352200804352 IX. INSTRUCTIONS OF THE INVENTION: TECHNICAL FIELD OF THE INVENTION The present invention relates to certain substituted heteroaryl nitrile derivatives, which are protease inhibitors. More specifically, the compound is an inhibitor of cysteine protease. Specifically, the compound inhibits the cysteine protease of the papain superfamily, more specifically the falcipain family, which is a cyste found in the dysentery parasite Plasmodium falciparum Amino acid proteases, as well as cysteine proteases in the cathepsin family such as cathepsins K, L, S and B. [Prior Art] Malaria is one of the major disease problems in developing countries. The most toxic parasitic malaria in humans is Plasmodium falciparum, which is the cause of hundreds of millions of malaria cases each year, and has caused more than one million deaths each year, Berman, J. G., et al. 2001) Am. Trop· Med· Hyg. 64, 1-11. One problem encountered in malaria treatment is that the parasite is cumulatively resistant to existing agents. Therefore, it is necessary to develop novel anti-malarial agents. One method for identifying potential novel agents with anti-malarial activity is to study the biological targets found in Plasmodium falciparum parasites and to investigate biological pathways in which specific targets can be identified. In M. falciparum, hemoglobin is delivered to acidic food vacuoles where it is broken down. It exhibits a variety of enzymes, including food vacuolar cysteine, aspartic acid, and metalloproteinases, and cytosolic aminopeptidase, which promotes hemoglobin hydrolysis, Francis SE et al., (1997) Annu. Rev. Microbiol. , 97-123; Rosenthal PJ Protease inhibitors. In: Rosenthal PJ·, ed. Antimalarial Chemotherapy: 5 200804352

Mechanisms of Action，Resistance，and New Directions in Drug Discovery, Totowa，N.J·: Humana Press，（2001) 325-345。瘧原蟲的血色素酶因此是可能的醫療標的。數年前的半胱胺酸蛋白酶抑制劑顯示阻止經由紅血球寄生蟲的血色素分解，造成特徵性的形態失常其中食物液泡充滿未分解的血色素並阻止寄生蟲發育，Rosenthal P. J.， et aL? (1998) J. Clin. Invest. 82, 1560-6; Gamboa de Dominguez N.D. and Rosenthal P.J.? (1996) Blood 87, 4448-54。鑑定與血色素分解相關的酶之努力，導致鑑定“鐮形木瓜蛋白酶”是營養體食物液泡半胱胺酸蛋白酶， Rosenthal P.J. and Nelson R.G., (1992) Mol Biochem Parasitol 51，143-52; Salas F· et al·，（1995) Infect. Immun. 63 2120-5。最近發現“鐮形木瓜蛋白酶”實際上包含三種相關的木瓜蛋白酶科半胱胺酸蛋白酶其共有多個不尋常的特徵，稱為鐮形木瓜蛋白酶_1、鐮形木瓜蛋白酶-2及鐮形木瓜蛋白酶-3，Rosenthal，P. J·，et al·，（2002) Curr· Pharm· Des· 8, 1659-1672。鐮形木瓜蛋白酶_2是惡性瘧原蟲營養體的主要半胱胺酸蛋白酶，ShenaiB.R, etal.，（2000) J Biol Chem 275, 29000-10。重要的是，抑制鐮形木瓜蛋白酶_2之半胱胺酸蛋白酶抑制劑一致地阻止血色素水解及寄生蟲發育。這些數據建議鐮形木瓜蛋白酶_2是關鍵的標的酶，但是似乎其他兩種鐮形木瓜蛋白酶也是合適之標的，且在許多情形中，其可經由活性對抗鐮形木瓜蛋白酶-2之相同化合物抑制。相同於鐮形木瓜蛋白酶_2，鐮形木瓜蛋白酶-3在溫 6 200804352 和還原條件下容易水解天然血色素，此類似於在生理系統中的發現，Shenai B.R. et al·，（2000) J Biol Chem 275， 29000-10; Sijwali P.S· et al·，（2001) Biochem· J· 360, 481-9; Shenai B.R. and Rosenthal P.J., (2002) Mol. Biochem. Parasitol· 122, 99-104。鐮形木瓜蛋白酶-2及鐮形木瓜蛋白酶-3有類似的結構但是鐮形木瓜蛋白酶-1是一個更遠的親屬；咸信此酶在紅血球被惡性瘧原蟲裂殖體的侵入扮演關鍵的角色，但是其不是紅血球階段的正常發育所必需， Sijwali P.S. et al.? Proceedings of the National Academy of Sciences of the United States of America 101，8721-8726。鐮形木瓜蛋白酶-1是否也參與血色素處理仍未知。就在最近，發現第四種木瓜蛋白酶科半胱胺酸蛋白酶，現稱為鐮形木瓜蛋白酶-2’。鐮形木瓜蛋白酶_2，之序列幾乎相同於鐮形木瓜蛋白酶-2，只有3個胺基酸不同，其都不是位在活性位置。鐮形木瓜蛋白酶_2，之結構未知，但是可能非常類似於鐮形木瓜蛋白酶-2。鐮形木瓜蛋白酶_2,之生物角色也預期非常類似於鐮形木瓜蛋白酶_2，雖然可能不是相同。在任何事件中，半胱胺酸蛋白酶抑制作用，特別是鐮形木瓜蛋白酶-2之抑制作用，阻止寄生蟲發育。鐮形木瓜蛋白酶 -2及相關癌原蟲的半胱胺酸蛋白酶據此是抗瘧疾化學療法之邏輯標的，且因此有需求是這些標的之抑制劑的化合物。間曰遽原蟲是第二種最重要的人類瘧疾寄生蟲，次於惡性癌原蟲。雖然毒害低於惡性瘧原蟲，間日瘧原蟲是最廣泛分布的人類瘧疾寄生蟲，且其造成嚴重的死亡（Mendis， 7 200804352Mechanisms of Action, Resistance, and New Directions in Drug Discovery, Totowa, N.J.: Humana Press, (2001) 325-345. The hemochromatase of Plasmodium is therefore a possible medical target. Cysteine protease inhibitors several years ago showed resistance to hemoglobin breakdown via erythrocyte parasites, causing characteristic morphological disorders in which food vacuoles are filled with undecomposed hemoglobin and prevent parasite development, Rosenthal PJ, et aL? (1998) J. Clin. Invest. 82, 1560-6; Gamboa de Dominguez ND and Rosenthal PJ? (1996) Blood 87, 4448-54. Efforts to identify enzymes associated with hemochromatosis led to the identification of "scorpion papain" as a vegetative food vacuolar cysteine protease, Rosenthal PJ and Nelson RG, (1992) Mol Biochem Parasitol 51, 143-52; Salas F· Et al., (1995) Infect. Immun. 63 2120-5. It has recently been discovered that "scorpion papaya protease" actually contains three related papainase cysteines proteases which share a number of unusual features called scorpion papain_1, scorpion papain-2 and scorpion papaya. Protease-3, Rosenthal, P. J., et al., (2002) Curr. Pharm· Des. 8, 1659-1672. Scorpion papain-2 is the major cysteinyl protease of Plasmodium falciparum trophozoites, Shenai B. R, et al., (2000) J Biol Chem 275, 29000-10. Importantly, inhibition of the caspase-2 cysteinyl protease inhibitor consistently prevented hemoglobin hydrolysis and parasite development. These data suggest that scorpion papain-2 is a key target enzyme, but it appears that the other two scorpion papain are also suitable targets, and in many cases, they can inhibit the same compound against scorpion papain-2 via activity. . Similar to the scorpion papain-2, the scorpion papain-3 readily hydrolyzes natural hemoglobin at a temperature of 6200804352 and under reducing conditions, similar to the discovery in physiological systems, Shenai BR et al., (2000) J Biol Chem 275, 29000-10; Sijwali PS· et al., (2001) Biochem J. 360, 481-9; Shenai BR and Rosenthal PJ, (2002) Mol. Biochem. Parasitol 122, 99-104. The papain-2 and the papain-3 have a similar structure, but the papain-1 is a farther relative; it is believed that this enzyme plays a key role in the invasion of erythrocytes by Plasmodium falciparum schizonts. Role, but it is not required for normal development of the red blood cell stage, Sijwali PS et al.? Proceedings of the National Academy of Sciences of the United States of America 101, 8721-8726. It is still unknown whether 镰-shaped papain-1 is also involved in hemoglobin treatment. Just recently, a fourth papain cysteine protease, now known as the scorpion papain-2', was discovered. The sequence of the papain-2 is almost the same as that of the papain-2, and only three amino acids are different, and they are not in the active position. The structure of the papain-2 is unknown, but may be very similar to the papain-2. The biological role of the scorpion papain-2 is also expected to be very similar to the scorpion papain-2, although it may not be the same. In any event, cysteine protease inhibition, particularly the inhibition of scorpion papain-2, prevents parasite development. The papain-2 of the scorpion papain-2 and related cancer protozoa are thus the logical targets for antimalarial chemotherapy, and therefore there is a need for compounds which are inhibitors of these targets. Protozoa is the second most important human malaria parasite, second to malignant cancer. Although the toxicity is lower than Plasmodium falciparum, Plasmodium vivax is the most widely distributed human malaria parasite, and it causes severe death (Mendis, 7 200804352)

Sina5 B J.9 Marchesini, P. and Carter, R. (2001) uThe neglected burden of Plasmodium vivax malaria^ Am. J. Trop. Med· Hyg. 64, 97-106)。這兩種寄生蟲與超過90%的人類瘧疾相關，每年造成數百萬人死亡。但是，間日瘧原蟲之理解研究因為技術短缺而被限制。值得注意的是，不同於惡性瘧原蟲之情形，間日瘧原蟲之例行性試管内培養液沒有供應，且動物模式限制在靈長目動物。就在最近(Na，B.K.，Sina5 B J.9 Marchesini, P. and Carter, R. (2001) uThe neglected burden of Plasmodium vivax malaria^ Am. J. Trop. Med· Hyg. 64, 97-106). These two parasites are associated with more than 90% of human malaria, causing millions of deaths each year. However, the understanding of Plasmodium vivax has been limited due to technical shortages. It is worth noting that, unlike the case of Plasmodium falciparum, routine in vitro cultures of Plasmodium vivax are not supplied and animal models are restricted to primates. Just recently (Na, B.K.,

Shenai，Β· R·，Sijwali，P.S·，Choe，Y·，Pandey，K.C” Singh， A·，Craik，C.S·，Rosenthal，P.J· (2004) identification and biochemical characterization of vivapains, cysteine proteases of the malaria parasite Plasmodium vivax. Biochem. J. 378, 529-538)，從間日瘧原蟲的兩種半胱胺酸蛋白酶基因 (vivapain-2及vivapain-3)經鏗定並無性繁殖且異種表達的基因產物經生物化學地鏗定。發現這些半胱胺酸蛋白酶是鐮形木瓜蛋白酶-2及鐮形木瓜蛋白酶_3的視同種，但是在逢原蟲蛋白酶的生物化學性質之關鍵差異證明在評估抗瘧疾蛋白酶抑制劑時需注意各酶之抑制作用。組織蛋白酶是屬於酶科，其是半胱胺酸蛋白酶的木瓜蛋白酶總科之—部份。部份組織蛋白酶，㈣組織蛋白酶 κ、B、示在文獻中。組織蛋白酶〖聚肽及編碼此聚肽之cDNA經揭示在美國專利5,5〇ι，969號。組織蛋白酶K在文獻中也曾不同地稱為組織蛋白酶〇或組織蛋白酶 02。組織蛋白酶K之名稱被視為最合適且⑽本文。組織蛋白酶K經表達、純化、及鑑定，Bqss㈣，M.j.,etai.，（而） 8 200804352 J. Biol· Chem· 271，12517-12524; Drake，F.H·，et al·，（1996) J· Biol· Chem· 271，12511-12516; Bromme，D·，et al·，（1996) J· Biol· Chem· 271，2126_2132 〇組織蛋白酶在包括人類之動物中，作用在蛋白質分解的正常生理過程，例如在連接組織的分解。但是，這些酶的量在體内增加可產生病理情形而導致疾病。據此，組織蛋白酶在多種疾病狀態中涉及作為病因劑，包括但不限於卡氏肺囊蟲、克氏錐蟲、布氏錐蟲及短膜蟲感染，以及在裂體吸蟲病、瘧疾、癌症例如胰臟癌（見joycej.A.etal·，Shenai,Β·R·,Sijwali,PS·,Choe,Y·,Pandey,KC” Singh, A·,Craik,CS·,Rosenthal,PJ· (2004) identification and biochemical characterization of vivapains, cysteine proteases of the malaria Parasite Plasmodium vivax. Biochem. J. 378, 529-538), two cysteinyl protease genes (vivapain-2 and vivapain-3) from Plasmodium vivax have been sexually propagated and heterologously expressed The gene products were biochemically determined. These cysteine proteases were found to be isoforms of scorpion papain-2 and scorpion papain _3, but the key differences in the biochemical properties of protozoal proteases were demonstrated in the evaluation of resistance. In the case of malaria protease inhibitors, attention should be paid to the inhibition of various enzymes. Cathepsin belongs to the family of enzymes, which is part of the papain of the cysteine protease. Part of cathepsin, (4) cathepsin κ, B, shows In the literature, cathepsin, a polypeptide, and a cDNA encoding the polypeptide are disclosed in U.S. Patent No. 5,5, ι, 969. Cathepsin K has also been referred to as a group in the literature. Protease 组织 or cathepsin 02. The name of cathepsin K is considered to be the most suitable and (10). Cathepsin K is expressed, purified, and identified, Bqss (4), Mj, etai., (and) 8 200804352 J. Biol·Chem· 271,12517-12524; Drake, FH·, et al., (1996) J. Biol Chem 271, 12511-12516; Bromme, D., et al., (1996) J. Biol Chem 271, 2126_2132 〇Cathepsin acts on normal physiological processes of protein breakdown in animals including humans, such as in the breakdown of connective tissues. However, the increase in the amount of these enzymes in the body can cause pathological conditions leading to disease. Involved as a causative agent in a variety of disease states, including but not limited to Pneumocystis carinii, Trypanosoma cruzi, Trypanosoma brucei and Clostridium infection, and in schistosomiasis, malaria, cancer such as pancreatic cancer (see joycej.A.etal·,

Cancer Cell (2004) 5，443-453 及 Gocheva V·，Genes & Development (2006) 20, 543-556)、腫瘤侵入及腫瘤轉移、異染性腦白質病、肌肉營養失調症、肌萎縮症、發炎、類風濕性關節炎、骨關節炎、骨質疏鬆症、冠狀動脈疾病、動脈粥樣硬化症、自發免疫疾病、呼吸道疾病例如阻塞性肺病（COPD)、免疫仲介的疾病（例如移植排斥）、及其他相關的疾病，見：1994年3月3日出版的internati〇nal Publication Number WO 94/04172 及其中提到的文獻；也見：European Patent Application EP 0 603 873 A1 及其中提到的文獻。從Ρ· gingivallis的兩種細菌半胱胺酸蛋白酶，稱為gingipains，涉及齒齦炎之發病機理，P〇tempa，j.，以al (1994) Perspectives in Drug Discovery and Design 2， 445-458 。組織蛋白酶K在過度骨或軟骨流失的疾病中咸信扮、、寅病因的角色。骨是由蛋白質基體組成其中摻混羥基罐灰石' 9 200804352 的纺錘或板形結晶。第z型膠原代表含約9〇%蛋白質基體的骨之主要結構蛋白質。其餘的10%基體是由多種非膠原性蛋白負組成，包括骨|弓素(〇ste〇calcin)、蛋白聚糖、骨普丁（osteopontin)、骨尼丁（OS|；eonectin)、血栓普丁 (thrombospondin)、纖維連結蛋白及骨涎蛋白 (sialoprotein)。在整個壽命中，骨胳在分離的疫源點中進行改組。這些疫源點或改組單元，進行包括骨質再吸收期及隨後骨質替代期之循環。骨質再吸收是藉由蝕骨細胞進行，其係造血系的多核細胞。在數種疾病狀態中，例如骨質疏鬆症及Paget氏症，骨質再吸收及形成之間的正常平衡被破壞，且在再吸收與形成之各循環中骨質有淨損失。最後，此導致骨質脆弱且可能造成在很小的創傷增加骨折的風險。數個出版的研究證明半胱胺酸蛋白酶之抑制劑可以有效地抑制蝕骨細胞仲介的骨質再吸收，據此指出半胱胺酸蛋白酶在骨質再吸收中的必要角色。例如，Delaisse，et al·，（1980) Biochem. J·， 192,365建議半胱胺酸蛋白酶之抑制劑（例如亮肽素、 Z-Phe-Ala-CHN2)預防骨質再吸收，而絲胺酸蛋白酶抑制劑無效。Delaisse，et al·，（1984) Biochem. Biophys. Res· Commun· 125, 441揭示E-64 (L-反-環氧琥珀基-亮胺醯胺基 -(4-胍基）丁烷）及亮肽素在大鼠活體内也可以有效地預防骨質再吸收。Lerner，et al·，（1992) J. Bone Min. Res· 7, 433 200804352 揭示西達丁（cystatin), —種内生性半胱胺酸蛋白酶抑制劑，在小鼠顱蓋中抑制PTH刺激的骨質再吸收。其他研究報導半胱胺酸蛋白酶活性之抑制作用與骨質再吸收之間的相關性。Tezuka，et al·，（1994) J· Biol. Chen· 269, 1106; Inaoka，et al·，（1995) Biochem· Biophys. Res· Commun·，206, 89 及 Shi， et al·，（1995) FEBS Lett· 357, 129揭示在正常條件下，組織蛋白酶K是大量表達在蝕骨細胞且可能是存在這些細胞中的主要半胱胺酸蛋白酶。組織蛋白酶Κ在蝕骨細胞中的大量選擇性表達，強烈建議此酶是骨質再吸收所必需。據此，組織蛋白酶κ之抑制作用可以提供過度骨質流失的疾病之有效治療，包括但不限於骨質疏鬆症、齒齦疾病例如齒齦炎及牙週病、Paget 氏症、惡性高金妈症、及代謝性骨質疾病。（組織蛋白酶K 的量也經證明在骨關節滑膜的破軟骨細胞中增加。組織蛋白酶K也表達在從骨關節炎病人取出的滑膜巨細胞(Dodds, et al·，（1999) Arthritis & Rheumatism，42，1588,及 Hou，et al·， (2002)，American Journal of Pathology 159, 2167)。在骨關節炎以及類風濕性關節炎樣本中觀察組織蛋白酶K染色（h〇u et al”（2002), American Journal of Pathology 159, 2167)。組Cancer Cell (2004) 5, 443-453 and Gocheva V., Genes & Development (2006) 20, 543-556), tumor invasion and metastasis, metachromatic leukoencephalopathy, muscular dystrophy, muscular dystrophy , inflammation, rheumatoid arthritis, osteoarthritis, osteoporosis, coronary artery disease, atherosclerosis, spontaneous immune disease, respiratory diseases such as obstructive pulmonary disease (COPD), immune-mediated diseases (eg transplant rejection) And other related diseases, see: internati〇nal Publication Number WO 94/04172 published on March 3, 1994 and the documents mentioned therein; see also: European Patent Application EP 0 603 873 A1 and the documents mentioned therein . Two bacterial cysteine proteases from Ρ·gingivallis, called gingipains, are involved in the pathogenesis of gingivitis, P〇tempa, j., al al (1994) Perspectives in Drug Discovery and Design 2, 445-458. The role of cathepsin K in the disease of excessive bone or cartilage loss. Bone is a spindle or plate-shaped crystal composed of a protein matrix in which a hydroxy tank limestone ' 9 200804352 is blended. The z-type collagen represents the major structural protein of bone containing about 9% protein matrix. The remaining 10% of the matrix is composed of a variety of non-collagen protein negatives, including |ste〇calcin, proteoglycan, osteopontin, bone nitin (OS|; eonectin), thrombosis Thrombospondin, fibronectin and sialoprotein. Throughout life, bones are shuffled in separate foci. These foci or reorganization units perform cycles including bone resorption and subsequent bone replacement. Bone resorption is performed by osteoclasts, which are multinucleated cells of the hematopoietic lineage. In several disease states, such as osteoporosis and Paget's disease, the normal balance between bone resorption and formation is disrupted, and there is a net loss of bone in each cycle of resorption and formation. Finally, this leads to fragility of the bone and may result in increased risk of fractures at very small wounds. Several published studies have demonstrated that inhibitors of cysteine proteases are effective in inhibiting bone resorption by osteoclasts, and therefore indicate the essential role of cysteine proteases in bone resorption. For example, Delaisse, et al., (1980) Biochem. J., 192, 365 suggests that inhibitors of cysteine proteases (eg, leupeptin, Z-Phe-Ala-CHN2) prevent bone resorption, while serine proteases The inhibitor is ineffective. Delaisse, et al., (1984) Biochem. Biophys. Res· Commun. 125, 441 discloses E-64 (L-trans-epoxy succinyl-leucine amide-(4-mercapto)butane) and Leupeptin is also effective in preventing bone resorption in rats. Lerner, et al., (1992) J. Bone Min. Res· 7, 433 200804352 Reveals that cistatin, an endogenous cysteine protease inhibitor, inhibits PTH stimulation in the mouse calvaria Resorption of bone. Other studies have reported a correlation between inhibition of cysteine protease activity and bone resorption. Tezuka, et al., (1994) J. Biol. Chen· 269, 1106; Inaoka, et al., (1995) Biochem·Biophys. Res· Commun·, 206, 89 and Shi, et al., (1995) FEBS Lett. 357, 129 reveals that under normal conditions, cathepsin K is a major cysteine protease that is abundantly expressed in osteoblasts and may be present in these cells. A large number of selective expression of cathepsin in osteoblasts is strongly recommended for bone resorption. Accordingly, inhibition of cathepsin κ can provide an effective treatment for diseases with excessive bone loss, including but not limited to osteoporosis, gingival diseases such as gingivitis and periodontal disease, Paget's disease, malignant hypergold, and metabolism. Sexual bone disease. (The amount of cathepsin K has also been shown to increase in the chondrocytes of the synovial membrane of the joint. Cathepsin K is also expressed in synovial giant cells taken from patients with osteoarthritis (Dodds, et al., (1999) Arthritis & Rheumatism, 42, 1588, and Hou, et al., (2002), American Journal of Pathology 159, 2167). Observation of cathepsin K staining in osteoarthritis and rheumatoid arthritis samples (h〇u et al (2002), American Journal of Pathology 159, 2167). Group

織蛋白酶κ之表達也經定域在軟骨組織且在軟骨中的pH 下降與傷害的嚴重性相關（Konttinen，et al.，（2〇〇q Arthritis & Rheumatism，46, 953)。此觀察，結合組織蛋白酶K是酸性溶酶體的蛋白酶之事實，強烈建議組織蛋白酶 200804352 κ在軟骨翻轉以及骨質再吸收中的生理角色。這些研究者也證實組織蛋白酶Κ可以分解聚集蛋白聚糖及第π型膠原，軟骨基質之兩種主要蛋白質成份。據此，組織蛋白酶 κ之抑制作用也可以用於治療過度軟骨或基質分解的疾病，包括但不限於骨關節炎及類風濕性關節炎。組織蛋白酶κ經證明不正常或過度表達在多種腫瘤及***癌 (Littlewood_Evans，et al·，（1997)，Cancer Res·，57，5386 及 Brubaker，et al·，（2003)，J· Bone Miner，Res·，18, 222)。而且，在***癌的骨轉移中偵測到骨質再吸收標記的量增加，建議組織蛋白酶K抑制劑可以用於預防腫瘤轉移到骨 (Ishikawa，et al·, (2001)，Mol. Carcinog·，32, 84 及 Brubaker， et al·，（2003)，J. Bone Miner· Res·，18, 222)。轉移性增殖細胞也通常表達高量的其他蛋白水解酶例如組織蛋白酶B、S 及L其分解周圍的基質。據此，組織蛋白酶K之抑制作用也可以用於治療某些腫瘤及增殖性疾病。組織蛋白酶L涉及數種疾病，包括骨質疏鬆症、骨關印k、類風濕性關郎炎、淋巴增生症、癌症例如騰臟癌、轉移、動脈粥樣硬化症（Lecaille，et al.，（2002) Chem. Rev. 102, 4459 及 Liu，et al·，（2004)，Arterioscler Throm Vase Biol. 24，1359)。缺乏組織蛋白酶l的小鼠也證實在卵巢切除術後增加骨質疏鬆症的抵抗性，建議其在骨質疏鬆症中的價值（Potts，et al·，（2004) Int· J· Exp· Path· 85, 85)。組織蛋白酶 L是内皮祖細胞誘發的金管增生所需⑴rbid，et ah，（2〇〇5) Nat· Med· 11，206)。類似地，藉由特定核酶標的組織蛋白 12 200804352 酶L在類風濕性關節炎中降低組織蛋白酶l蛋白質合成及軟骨破壞(Schedel，et al·，（2004) Gene Ther· 11，1040)，建議其在類風濕性關節炎中的有用角色。組織蛋白酶S涉及數種疾病，包括免疫及自發免疫障礙、類風濕性關節炎、發炎、發炎性腸疾、肌肉感覺墜積、動脈粥樣硬化症、淋巴增生症、癌症例如腺臟癌、轉移 (Lecaille，et al·，（2002) Chem· Rev· 102, 4459 及 Liu，et al·， (2004)，Arterioscler Throm Vase Biol· 24, 1359)。咸信組織蛋白酶S涉及不變的鏈分解及抗原呈現且組織蛋白酶S裸小鼠經證實減少膠原誘發的關節炎(Nakagawa，et al.，（1999) Immunity，10, 207)，建議其在類風濕性關節炎中的有用角色。組織蛋白酶B涉及免疫及自發免疫障礙、類風濕性關節炎、發炎、發炎性腸疾、肌肉感覺墜積、骨關節炎、淋巴增生症、癌症例如胰臟癌、轉移（Lecaille，（2002)Chem. Rev. 102, 4459 及 Lang，et al·，（2000)，J· Rheumatol. 27， 1970)。組織蛋白酶B涉及不變的鏈之發展（Zhang，et al.， (2000) Immunology，100，13)，建議其在例如上述之免疫障礙中的角色。組織蛋白酶B是在軟骨中最大量表達半胱胺酸蛋白酶者之一，組織蛋白酶B之抑制劑經證實可抑制軟骨分解。組織蛋白酶B經由解離軟骨基質的兩種成份之聚集蛋白聚糖與膠原，可以導致基質分解(Mort et al·，（1998)， Biochem· J·，335, 491)。此外，組織蛋白酶B經由解離在滑膜液中豐富的潤滑性蛋白質之潤滑素（lubricin)，可以導致 13 200804352 骨關節炎之機械負荷成份。經由組織蛋白酶B解離潤滑素，經證實增加滑膜液與完整關節的摩擦係數(Elsaid，KA, et al·，（2005)，Transactions of the Orthopedic Research Society， 51th Annual Meeting，Abstract 924)。這些數據建議組織蛋白酶B抑制劑在骨關節炎中的價值。鑑於多種生理回應及病情是由組織蛋白酶K、L、S及 B仲介，需求這些組織蛋白酶之抑制劑其可以用於治療多種病情。 W0 2005/085210 A1揭示作為組織蛋白酶K之抑制劑之某些稠合的二環嘧啶化合物，用於治療骨疾例如骨質疏鬆症等。WO 2005/103012 A1揭示作為組織蛋白酶K之抑制劑之某些肼-雜環腈化合物，用於治療骨疾例如骨質疏鬆症等。【發明内容】發明概述本發明係關於新穎的雜芳基腈衍生物及其作為蛋白酶抑制劑之用途，更確定地說，是半胱胺酸蛋白酶之抑制劑，再更具體地說，是木瓜蛋白酶總科之半胱胺酸蛋白酶的抑制劑。在本發明的一個方面中，該半胱胺酸蛋白酶是彼等鐮形木瓜蛋白酶科，例如鐮形木瓜蛋白酶-2及鐮形木瓜蛋白酶-3，其係適應在瘧疾的半胱胺酸蛋白酶之實例。在本电明的另一個方面中，該半胱胺酸蛋白酶是彼專組織蛋白酶科例如組織蛋白酶K、L、§及8，其為適應在例如特徵疋月貝過度流失的病情例如骨質疏鬆症及骨轉移，及其他 14 200804352 骨與關節疾病例如骨關節炎的半胱胺酸蛋白酶。本發明包括下面代表的化合物，含此化合物之較成物及該化合物作為蛋白酶抑制劑之用途。面/、汲發明之詳細說明本發明提供至少一種選自式丨化合物之化學實體：Expression of chymotrypsin κ is also localized in cartilage tissue and the pH drop in cartilage is associated with the severity of the injury (Konttinen, et al., (2〇〇q Arthritis & Rheumatism, 46, 953). This observation, The fact that cathepsin K is an acidic lysosomal protease strongly suggests the physiological role of cathepsin 200804352 κ in cartilage turnover and bone resorption. These investigators also confirmed that cathepsin can decompose aggrecan and type π Collagen, the two major protein components of the cartilage matrix. According to this, the inhibition of cathepsin κ can also be used to treat diseases of excessive cartilage or matrix decomposition, including but not limited to osteoarthritis and rheumatoid arthritis. Abnormal or overexpressed in a variety of tumors and prostate cancers (Littlewood_Evans, et al., (1997), Cancer Res., 57, 5386 and Brubaker, et al., (2003), J. Bone Miner, Res, 18, 222). Moreover, an increase in the amount of bone resorption markers detected in bone metastases of prostate cancer suggests that cathepsin K inhibitors can be used. Prevention of tumor metastasis to bone (Ishikawa, et al., (2001), Mol. Carcinog, 32, 84 and Brubaker, et al., (2003), J. Bone Miner. Res., 18, 222). Metastatic Proliferating cells also typically express high amounts of other proteolytic enzymes such as cathepsins B, S and L which decompose the surrounding matrix. Accordingly, the inhibition of cathepsin K can also be used to treat certain tumors and proliferative diseases. L involves several diseases, including osteoporosis, bone seal k, rheumatoid sclerotherapy, lymphoproliferative, cancer such as smear cancer, metastasis, atherosclerosis (Lecaille, et al., (2002) Chem. Rev. 102, 4459 and Liu, et al., (2004), Arterioscler Throm Vase Biol. 24, 1359). Mice lacking cathepsin-1 also demonstrated increased resistance to osteoporosis after ovariectomy, It is recommended for its value in osteoporosis (Potts, et al., (2004) Int J. Exp. Path 85, 85). Cathepsin L is required for endothelial progenitor-induced gold tube hyperplasia (1) rbid, et ah, (2〇〇5) Nat· Med· 11,206). Similarly, tissue protein 12 200804352 by specific ribozymes reduces tissue proteinase 1 protein synthesis and cartilage destruction in rheumatoid arthritis (Schedel, et al., (2004) Gene Ther· 11, 1040), suggesting Its useful role in rheumatoid arthritis. Cathepsin S is involved in several diseases including immune and spontaneous immune disorders, rheumatoid arthritis, inflammation, inflammatory bowel disease, muscle sensation, atherosclerosis, lymphoproliferative, cancer such as squamous cell carcinoma, metastasis (Lecaille, et al., (2002) Chem. Rev. 102, 4459 and Liu, et al., (2004), Arterioscler Throm Vase Biol. 24, 1359). Salined cathepsin S involves constant chain decomposition and antigen presentation and cathepsin S nude mice have been shown to reduce collagen-induced arthritis (Nakagawa, et al., (1999) Immunity, 10, 207), suggesting that they are in class A useful role in rheumatoid arthritis. Cathepsin B is involved in immune and spontaneous immune disorders, rheumatoid arthritis, inflammation, inflammatory bowel disease, muscle dysfunction, osteoarthritis, lymphoproliferative, cancer such as pancreatic cancer, metastasis (Lecaille, (2002) Chem Rev. 102, 4459 and Lang, et al., (2000), J. Rheumatol. 27, 1970). Cathepsin B is involved in the development of a constant chain (Zhang, et al., (2000) Immunology, 100, 13), suggesting its role in, for example, the aforementioned immune disorders. Cathepsin B is one of the largest expressions of cysteine protease in cartilage, and inhibitors of cathepsin B have been shown to inhibit soft bone breakdown. Cathepsin B can cause matrix breakdown by dissociating aggrecan and collagen, two components of the cartilage matrix (Mort et al., (1998), Biochem J., 335, 491). In addition, cathepsin B can cause mechanical load components of osteoarthritis in 200804352 by dissociating lubricin, which is a rich lubricity protein in synovial fluid. Dissociation of lubricin via cathepsin B has been shown to increase the coefficient of friction of synovial fluid with intact joints (Elsaid, KA, et al., (2005), Transactions of the Orthopedic Research Society, 51th Annual Meeting, Abstract 924). These data suggest the value of tissue kinase B inhibitors in osteoarthritis. In view of the fact that various physiological responses and conditions are mediated by cathepsins K, L, S and B, these inhibitors of cathepsins are required for the treatment of various conditions. WO 2005/085210 A1 discloses certain fused bicyclic pyrimidine compounds as inhibitors of cathepsin K for the treatment of bone diseases such as osteoporosis and the like. WO 2005/103012 A1 discloses certain guanidine-heterocyclic nitrile compounds as inhibitors of cathepsin K for the treatment of bone diseases such as osteoporosis and the like. SUMMARY OF THE INVENTION The present invention relates to novel heteroaryl nitrile derivatives and their use as protease inhibitors, more specifically, inhibitors of cysteine proteases, and more particularly papaya Inhibitor of the cysteine protease of the superfamily of the protease. In one aspect of the invention, the cysteine proteases are in the form of their scorpion papain, such as the scorpion papain-2 and the scorpion papain-3, which are adapted to the cysteine protease of malaria. Example. In another aspect of the present invention, the cysteine protease is a histochemical protease family such as cathepsins K, L, § and 8, which is adapted to, for example, a condition characterized by excessive loss of ecchymus such as osteoporosis. And bone metastases, and other 14 200804352 bone and joint diseases such as osteoarthritis cysteine protease. The present invention includes the compounds represented below, the analogs containing the compounds and the use of the compounds as protease inhibitors. DETAILED DESCRIPTION OF THE INVENTION The present invention provides at least one chemical entity selected from the group consisting of:

其中： R4代表鹵素； R2代表苯基伸院基_Χ、_σ比咬基_苯基心伸燒基基夂.3伸炫基其+苯基是視 ^ cf3的基取代；或、自函素或 ii) -Y-CV3 伸烷基_x 或-Y-Cw 伸烷基·x_Rj; 含有一個含有一至四個選自N、0及8的雜原早的 -J貝、銥之芳族基，該環視需要稠合至苯環；、、、 RJ代表z、-cN4伸烷基^或/⑴从； X及z獨立地代表： i)含有一個氮原子之單環4_員飽和烴基； 1】）含有一個氮原子之單環5_員飽 …)含有-或兩個氮原子及视需要 15 200804352 飽和、部份飽和或芳族烴基；其中X及Z是獨立地視需要經a)—個選自下列的基：Cw 烷基、Cw烷基OH、CK4烷基OCw烷基OH、OH、-Cw 烷基 CXCOCw 烷基、-CCCOOCw 烷基、NReRf、-Cm 烷基 NReRf、-NC(0)C〗_3 烷基、-NCCCOOCw 烷基及-C(0)NReRf 及b)視需要是C!_4烧基的額外基取代； REA R獨立地代表氫或Cy烧基或C〗-4稀基；及其藥學上可接受的衍生物。關於式I化合物及其藥學上可接受的衍生物：在本發明的一個具體實施例中，R4代表氯、溴或碘。在另一個具體實施例中，R4代表氯或溴。在又另一個具體實施例中，R4 代表溴。關於式I化合物及其藥學上可接受的衍生物：在本發明Wherein: R4 represents a halogen; R2 represents a phenyl group; Χ, _σ is more than a bite group _ phenyl heart stretching base 夂. 3 炫基 base + phenyl is a base substitution of cf3; or, an element Or ii) -Y-CV3 alkylene group _x or -Y-Cw alkylene group x_Rj; containing an aromatic group containing one to four heterologous atoms selected from N, 0 and 8 , the ring needs to be fused to the benzene ring;,, RJ represents z, -cN4 alkyl or ^ (1) from; X and z independently represent: i) a monocyclic 4_membered saturated hydrocarbon group containing a nitrogen atom; 1]) a single ring containing a nitrogen atom is filled with - or two nitrogen atoms and, if necessary, 15 200804352 saturated, partially saturated or aromatic hydrocarbon groups; wherein X and Z are independently dependent on a) a group selected from the group consisting of Cw alkyl, Cw alkyl OH, CK4 alkyl OCw alkyl OH, OH, -Cw alkyl CXCOCw alkyl, -CCCOOCw alkyl, NReRf, -Cm alkyl NReRf, -NC (0)C〗 _3 alkyl, -NCCCOOCw alkyl and -C(0)NReRf and b) additional base substitutions of C!_4 alkyl as desired; REA R independently represents hydrogen or Cy alkyl or C- 4 dilute base; and pharmaceutically acceptable derivatives thereof. With respect to compounds of formula I and pharmaceutically acceptable derivatives thereof: In a particular embodiment of the invention, R4 represents chlorine, bromine or iodine. In another specific embodiment, R4 represents chlorine or bromine. In yet another embodiment, R4 represents bromine. With regard to compounds of formula I and pharmaceutically acceptable derivatives thereof: in the present invention

基-X-R，其中苯基是視需要經一個選自南素或CF3的基取代。在又另—個具體實施例中，r2代表_口㈣基.苯基々3 伸烧基-X，其中苯基是視需要經—個選自4素或❿的基取代。在又另-個具體實施例中，r2代表_苯基々3伸烧基 -X，其中本基是視需要經一個選自鹵素或CF3的基取代。 16 200804352 在一個具體實施例中，其中在R2之苯基是視需要經取代，該視需要選用的取代基是氟。在另一個具體實施例中，在 R2之苯基是未經取代。在一個具體實施例中，直接鍵結至在R2的苯基之基（不包括視需要選用的取代基）是彼此對位定向。在另一個具體實施例中，直接鍵結至在R2的苯基之基（不包括視需要選用的取代基）是彼此間位定向。在一個具體實施例中，其中R2含有一個吡啶基，直接鍵結至吡啶基之基（不包括視需要選用的取代基）是彼此對位定向。在一個具體實施例中，其中R2含有一個吡啶基，直接鍵結至吡啶基之基（不包括視需要選用的取代基）是彼此間位定向。在一個具體實施例中，R2代表-Y-Cy伸烷基-X或 -Y-Cy伸烷基-X-Rj。在另一個具體實施例中，R2代表 K 伸燒基-X。在另一個具體實施例中，R2代表-Y-Ci _3 伸烷基-X-R*1。在一個具體實施例中，在R2中的伸烷基是亞曱基。關於式I化合物及其藥學上可接受的衍生物：在本發明之一個具體實施例中，Y代表吱喃、σ塞吩、異4嗤或苯並咬喃。關於式I化合物及其藥學上可接受的衍生物：在本發明之一個具體實施例中，R·1代表Ζ。在一個具體實施例中，The base -X-R wherein the phenyl group is optionally substituted with a group selected from the group consisting of a nitrite or a CF3. In yet another embodiment, r2 represents _ ((tetra)yl.phenylindole-3-exoalkyl-X, wherein phenyl is optionally substituted with a group selected from 4 or fluorene. In yet another embodiment, r2 represents _phenylindole-3-exoalkyl-X, wherein the group is optionally substituted with a group selected from halogen or CF3. 16 200804352 In a particular embodiment, wherein the phenyl group at R2 is optionally substituted, the optional substituent selected is fluorine. In another embodiment, the phenyl group at R2 is unsubstituted. In a particular embodiment, the groups directly bonded to the phenyl group at R2 (excluding the substituents optionally selected) are oriented in alignment with each other. In another embodiment, the direct bonding to the phenyl group at R2 (excluding optional substituents as desired) is oriented in orientation with each other. In a particular embodiment, wherein R2 contains a pyridyl group, the group directly bonded to the pyridyl group (excluding optionally selected substituents) is oriented in alignment with each other. In a particular embodiment, wherein R2 contains a pyridyl group, the group directly bonded to the pyridyl group (excluding the substituents optionally selected) is oriented to each other. In a particular embodiment, R2 represents -Y-Cyalkyl-X or -Y-Cyalkyl-X-Rj. In another embodiment, R2 represents K-alkyl-X. In another specific embodiment, R2 represents -Y-Ci_3 alkylene-X-R*1. In a particular embodiment, the alkylene group in R2 is an anthracenylene group. With respect to the compound of formula I and its pharmaceutically acceptable derivatives: In one embodiment of the invention, Y represents oxime, σ-sept, iso-indole or benzoin. With respect to the compound of formula I and its pharmaceutically acceptable derivatives: In a particular embodiment of the invention, R·1 represents hydrazine. In a specific embodiment,

Rj代表-Cw伸烷基-Ζ。在另一個方面，Rj代表-C(0)Z。關於式I化合物及其藥學上可接受的衍生物··在本發明之一個具體實施例中，X及Z獨立地代表含有一個氮原子之視需要經取代的單環4-員飽和烴基。在另一個具體實施 17 200804352 例中，x及z獨立地代表含有一個氮原子之視需要經取代的單環5-員飽和或部份飽和烴基。在另一個具體實施例中， X及Z獨立地代表含有一或兩個氮原子及視需要一個氧原子之視需要經取代的單環6-員飽和、部份飽和或芳族烴基。關於式I化合物及其藥學上可接受的衍生物··在本發明之一個具體實施例中，X代表六氫吡啶、六氫吡畊或嗎福啡，其各視需要經取代。在另一個具體實施例中，X代表六氫吡啶或六氫吡畊，其各視需要經取代。在另一個具體實施例中，X代表六氫批σ定其視需要經取代。在一個具體實施例中，X代表吡咯啶或吡咯咁，其各視需要經取代。在另一個具體實施例中，X代表吡咯啶其視需要經取代。在一個具體實施例中，X是未經取代。關於式I化合物及其藥學上可接受的衍生物：在本發明之一個具體實施例中，ζ代表六氫吡啶、六氫吡畊或嗎福咁，其各視需要經取代。在另一個具體實施例中，ζ代表六氫吡啶或六氫吡畊，其各視需要經取代。在另一個具體實施例中，Ζ代表六氫吡畊其視需要經取代。在一個具體實施例中，X代表吡咯啶其視需要經取代。在一個具體實施例中，Ζ是未經取代。關於式I化合物及其藥學上可接受的衍生物：在本發明之一個具體實施例中，X是視需要經a) —個選自下列的基：（^4烷基、C〗_4烷基OH、-Cw烷基OCw烷基OH、 OH、-Ci.4 烷基 CCCOCw 烷基、-CCCOOCw 烷基、nrerf、 -Cw 烷基 NReRf、-NCCCOCh 烷基、-NQOPCw 烷基及 200804352 -C(0)NReRf及b)視需要是Cw烷基的額外基取代。在另一個具體實施例中，X是視需要經a)—個選自下列的基：Cw 烧基、C!_4 烧基 OH、-Ci_4 烧基〇C〗.4 烧基 OH、OH、-C1-4 烷基 CCCOCw 烷基、-CXCOOCw 烷基、NRERF、-NCCCOCw 烷基、-NCCC^OCu烷基及-C(0)NRERF及b)視需要是Cw 烷基的額外基取代。在另一個具體實施例中，Ci_4烷基取代基是選自甲基及丙基。在又另一個具體實施例中，Cm 烷基取代基是甲基。在又另一個具體實施例中，X是經兩個甲基取代。在一個具體實施例中，z是視需要經cN4烷基取代。在另一個具體實施例中，Z是視需要經曱基取代。關於式I化合物及其藥學上可接受的衍生物··在本發明之一個具體實施例中，#及RF代表Cm烷基。在另一個具體實施例中，RE及RF代表甲基、乙基或丙基。在又另一個具體實施例中，#及以代表甲基。在本發明之一個具體實施例中，R及R代表c i 烯基。在另一個具體實施例中，re及rf代表丙烯基。在式I或任何其次式中，任何一次在其上面出現的任何官能基或取代基，其思義或任何其他官能基或取代基的意義在每次出現是彼此獨立，除非另外說明。當然本發明包括根據上述本發明不同方面的基團之全部組合。在本發明替代的具體實施例中，提供至少一種選自式 IA化合物之化學實體： 19 200804352Rj represents -Cw alkyl-hydrazine. In another aspect, Rj represents -C(0)Z. With respect to the compound of formula I and its pharmaceutically acceptable derivatives, in one embodiment of the invention, X and Z independently represent an optionally substituted monocyclic 4-membered saturated hydrocarbon group containing a nitrogen atom. In another embodiment 17 200804352, x and z independently represent a optionally substituted monocyclic 5-membered saturated or partially saturated hydrocarbon group containing a nitrogen atom. In another embodiment, X and Z independently represent a monocyclic 6-membered saturated, partially saturated or aromatic hydrocarbon group optionally substituted with one or two nitrogen atoms and optionally an oxygen atom. With respect to compounds of formula I and pharmaceutically acceptable derivatives thereof, in one embodiment of the invention, X represents hexahydropyridine, hexahydropyridin or morphine, each of which is optionally substituted. In another specific embodiment, X represents hexahydropyridine or hexahydropyridinium, each of which is optionally substituted. In another specific embodiment, X represents a six-hydrogen batch which is optionally substituted. In a particular embodiment, X represents pyrrolidine or pyrrolidine, each of which is optionally substituted. In another specific embodiment, X represents pyrrolidine and is optionally substituted. In a particular embodiment, X is unsubstituted. With respect to the compound of formula I and its pharmaceutically acceptable derivatives: In one embodiment of the invention, hydrazine represents hexahydropyridine, hexahydropyridinium or hydrazone, each of which is optionally substituted. In another embodiment, hydrazine represents hexahydropyridine or hexahydropyridinium, each of which is optionally substituted. In another specific embodiment, hydrazine represents hexahydropyrrole which is optionally substituted. In a particular embodiment, X represents pyrrolidine and is optionally substituted. In a specific embodiment, hydrazine is unsubstituted. With respect to compounds of formula I and pharmaceutically acceptable derivatives thereof: In a particular embodiment of the invention, X is optionally a) a group selected from the group consisting of: (^4 alkyl, C _4 alkyl) OH, -Cw alkyl OCw alkyl OH, OH, -Ci.4 alkyl CCCOCw alkyl, -CCCOOCw alkyl, nrerf, -Cw alkyl NReRf, -NCCCOCh alkyl, -NQOPCw alkyl and 200804352 -C ( 0) NReRf and b) are additional base substitutions of the Cw alkyl group as needed. In another embodiment, X is optionally subjected to a) a group selected from the group consisting of Cw alkyl, C!_4 alkyl OH, -Ci_4 alkyl hydrazine C. 4 alkyl OH, OH, - C1-4 Alkyl CCCOCw alkyl, -CXCOOCw alkyl, NRERF, -NCCCOCw alkyl, -NCCC^OCualkyl, and -C(0)NRERF and b) are optionally substituted with a Cw alkyl group as desired. In another specific embodiment, the Ci-4 alkyl substituent is selected from the group consisting of methyl and propyl. In yet another embodiment, the Cm alkyl substituent is methyl. In yet another embodiment, X is substituted with two methyl groups. In a particular embodiment, z is optionally substituted with a cN4 alkyl group. In another embodiment, Z is optionally substituted with a thiol group. With respect to the compound of formula I and its pharmaceutically acceptable derivatives, in one embodiment of the invention, # and RF represent a Cm alkyl group. In another specific embodiment, RE and RF represent methyl, ethyl or propyl. In yet another embodiment, # and to represent a methyl group. In a particular embodiment of the invention, R and R represent c i alkenyl. In another embodiment, re and rf represent a propylene group. In Formula I or any of the following formulas, the meaning of any functional group or substituent present thereon, any of its meaning or any other functional group or substituent, is independent of each other in each occurrence unless otherwise stated. Of course, the invention includes all combinations of groups according to various aspects of the invention described above. In an alternative embodiment of the invention, at least one chemical entity selected from the group consisting of compounds of formula IA is provided: 19 200804352

其中： R1代表Cw烷基、-Cw伸烷基NRERF、-Cw伸烧基 NRgC(0)0Ci_6 烷基、-C"伸烷基 NRGCXCOCk 烷基或-Cw 伸烷基-環烷基； R3代表氫、烷基、烷氧基、或-C(0)0烷基； R4代表氫、鹵素、烷氧基、芳基、-NHCu伸烷基- 芳基、-no2、cf3 或 ocf3 ; 先決條件是R3及R4不同時是氫，且當R3是Cl 3烷基則R4 不是氫；且 a) A代表C(O)且 i)R2代表R2a4 R2b，其中 R代表_NRH-芳基、-NRH_雜芳基、_nrh_芳基一 R2b代表-Cm伸烷基R'芳基、聯芳基、·芳基_ ^芳基、-雜芳基-芳基、-芳基-雜環基、_芳基〜垸基··雜％基、_芳基_0_C13伸垸基-雜環基芳基义_3伸院基·㈣基、·芳基·雜芳基伸燒基 20 200804352 -雜環基、-雜芳基-芳基-c^伸烷基-雜環基、芳氧基、雜方基、壞烧基、-環烧基-芳基、環烧氧基、雜環基、-NRH-芳基·雜環基、_NRh-環烷基、 •N(Rb)C〗-6伸烷基Rc、-NH-NiCw烷基)-雜芳基、 -0Ci_6伸貌基RD、-〇Ci_6稀基、-芳基-Ci-3伸烧基 -雜環基-R1、-芳基-Cw伸烷基-雜芳基-RK、Cl_3 伸烧基(NH2)-芳基、或-芳基-Cu伸烧基_ΝΗ_(^3 伸烷基-OH ; 且 R5代表氫、C〗-6烷基、Ci_6烯基、-C(0)R2a、-Cw 伸烷基-雜環基、-Cw伸烷基NRGCCCO-Cw烷基、伸烷基NRGqCOOCK烷基、-Cw伸烷基 NRERF、N-酞醯亞胺基-Cw伸烷基-或{(0)(：“ 烧基，或 ii)R2及R5與分別和其連接的碳及氮一起形成選自下面的基Wherein: R1 represents Cw alkyl, -Cw alkylene NRERF, -Cw alkyl NRgC(0)0Ci_6 alkyl, -C"alkyl NRGCXCOCk alkyl or -Cw alkyl-cycloalkyl; R3 represents Hydrogen, alkyl, alkoxy, or -C(0)0 alkyl; R4 represents hydrogen, halogen, alkoxy, aryl, -NHCualkyl-aryl, -no2, cf3 or ocf3; R3 and R4 are not hydrogen at the same time, and R4 is not hydrogen when R3 is Cl3 alkyl; and a) A represents C(O) and i) R2 represents R2a4 R2b, wherein R represents _NRH-aryl, -NRH _heteroaryl, _nrh_aryl-R2b represents -Cm alkyl R' aryl, biaryl, aryl-aryl, -heteroaryl-aryl, -aryl-heterocyclyl, _aryl~ fluorenyl·.heteroyl group, _aryl group_0_C13 hydrazinyl-heterocyclylaryl meaning _3 stretching group (4) group, aryl group, heteroaryl stretching group 20 200804352 - heterocyclic ring , -heteroaryl-aryl-c^alkyl-heterocyclyl, aryloxy, heteroaryl, decyl, -cycloalkyl-aryl, cycloalkoxy, heterocyclic, NRH-aryl·heterocyclyl, _NRh-cycloalkyl, •N(Rb)C -6alkylene Rc, —NH—NiCw alkyl)-heteroaryl, —0Ci_6 extensibility RD, —〇 Ci_6 dilute base, -fang基-Ci-3alkylene-heterocyclyl-R1,-aryl-Cwalkyl-heteroaryl-RK, Cl_3 extended alkyl (NH2)-aryl, or -aryl-Cu extended alkyl _ΝΗ_(^3 alkyl-OH; and R5 represents hydrogen, C -6 alkyl, Ci_6 alkenyl, -C(0)R2a, -Cw alkyl-heterocyclyl, -Cw alkyl NRGCCCO -Cw alkyl, alkylene NRGqCOOCK alkyl, -Cw alkylene NRERF, N-indenyl-Cw alkyl- or {(0) (: "alkyl, or ii" R2 and R5 Together with the carbon and nitrogen to which they are attached, a base selected from the group below

0 或代表-S〇2_且 R2代表Cw烷基、芳基、C〗-6芳烷基或-Cw伸烷基雜環基； 21 200804352 且 R5代表氫、Cw烷基、c!_6烯基、-Ci_8伸烷基-雜環基、-Cw伸烧基NR^CXC^-Ck烧基、-Cu伸烧基 NRGcCCOOCk 烷基、_CK8 伸烷基 NRERF、N-酞醯亞胺基-Cw伸烷基-或/(0)0^6烷基； RA、RC&RD獨立地代表氫、鹵素、_NRERF、氰基、CC13、 <(0)(^_6烷基、Cm烷基、環烷基、雜環基、芳基、聯芳基、-方基-雜芳基、-芳基_〇1_3伸烧基"雜環基、-芳基-〇-Ci_；3 伸烷基-雜環基、-Cw烯基芳基、雜芳基、Cw芳烷基、 -NHC^COCk 烷基、-NHQCOOCu 烷基、-NHCXCOCk 芳烷基或-NHC^COOCu芳烷基； RB代表氫或CN8烷基； #及1^獨立地代表氫或Cy烷基；或Re代表環烷基且rf 代表氫；或#及Rf與一連接的氮原子一起形成或6_員雜環； ' RG代表氫或CN3烷基； RH代表氫、CN6烷基、-Cl_6伸烷基NReRf、-Ck6伸烷基 NjHC(〇)Cl-4 烷基、或Ά·6 伸烷基 NHCCCOOCm 烷基； R代表芳基、雜芳基、雜環基、-Ci 3伸烷基（芳基h、《η 伸烷基-雜芳基、-C1_3芳烷基、-C1_3伸烷基_0(0)_雜環基、 -(^cccocV3伸烷基-芳基、或_〇-c(〇)c】·3伸烷基_芳基； RK代表一或兩個芳基取代基；及其鹽類或溶劑化物。在本發明另一個替代的具體實施例中，提供至少一種 22 200804352 選自式IB化合物之化學實體：0 or represents -S〇2_ and R2 represents Cw alkyl, aryl, C -6 aralkyl or -Cw alkylcyclohetero; 21 200804352 and R 5 represents hydrogen, Cw alkyl, c!_6 olefin , -Ci_8 alkylene-heterocyclyl, -Cw alkyl NR^CXC^-Ck alkyl, -Cu extended alkyl NRGcCCOOCk alkyl, _CK8 alkylene NRERF, N-nonyleneimine-Cw Alkyl- or /(0)0^6 alkyl; RA, RC&RD independently represents hydrogen, halogen, _NRERF, cyano, CC13, <(0)(^_6 alkyl, Cm alkyl, ring Alkyl, heterocyclic, aryl, biaryl, -aryl-heteroaryl, -aryl_〇1_3 alkyl) "heterocyclyl,-aryl-hydrazine-Ci_;3 alkylene- Heterocyclyl, -Cw alkenylaryl, heteroaryl, Cw aralkyl, -NHC^COCk alkyl, -NHQCOOCu alkyl, -NHCXCOCk aralkyl or -NHC^COOCu aralkyl; RB stands for hydrogen or CN8 alkyl; # and 1^ independently represent hydrogen or Cy alkyl; or Re represents a cycloalkyl group and rf represents hydrogen; or # and Rf are formed together with a linked nitrogen atom or a 6-membered heterocyclic ring; 'RG represents Hydrogen or CN3 alkyl; RH represents hydrogen, CN6 alkyl, -Cl_6 alkylene NReRf, -Ck6 alkylene NjHC(〇)Cl-4 alkyl, or Ά6 alkylene NHCCC OOCm alkyl; R represents aryl, heteroaryl, heterocyclic, -Ci 3 alkyl (aryl h, "n-alkyl-heteroaryl, -C1_3 aralkyl, -C1_3 alkyl" 0(0)_heterocyclyl, -(^cccocV3alkyl-aryl, or _〇-c(〇)c]3alkylalkyl-aryl; RK represents one or two aryl substituents; And a salt or solvate thereof. In another alternative embodiment of the invention, at least one chemical entity selected from the group consisting of the compound of formula IB is provided:

r2/A\N/N、 R5R2/A\N/N, R5

IB 其中： R1代表Cw烷基、-Cw伸烷基NRERF、-Cw伸烷基 NRGqcOOCw 烷基、_(^_8 伸烧基 NRGcCCOCw 烷基或-Cw 伸烷基-環烷基； R3代表氫、CN3烷基、烷氧基、或_c(〇)〇烷基； R4代表氫、鹵素、烷氧基、-CeC-芳基、-NHCu伸烷基· 芳基、-N02、CF3 或〇cf3; 先決條件是R3及R4不同時是氩，且當R3是C13烷基則R4 不是氫； a) A代表c(〇)且 1)以2代表1^或&'其中 R，表”芳基、视\雜芳基、_nrH_芳基雜芳基或 -雜芳基-芳基；且 H表伸烧基rA、芳基、聯芳基、·芳基-雜芳基、，传基、"芳基·雜環基、芳基-C1·3伸烧基-雜環基、^ 才方土-方基伸烷基-雜環基、芳基_〇_Ci_3伸烷基_雜環 23 200804352 基、芳基-Cw伸烷基-雜芳基、-芳基-雜芳基伸烷基_ 雜％基、-雜方基-方基-Ci_3伸烧基-雜環基、芳氧基雜芳基、環炫基、-環烧基-芳基、環烧氧基、雜環基、_nrH_* 基-雜環基、-NRh-環烧基、_N(Rb)CN6伸烧基rC、_nh_n(Cu 烷基)-雜芳基、-ocw伸烷基rd、-0Cl_6烯基、-芳基_〇13 伸烷基-雜環基-R*1、-芳基-Cw伸烷基-雜芳基_rk、Cl_3伸烷基(NH2)-芳基、或-芳基-C!·3伸烷基_NH-CK3伸烷基_〇H，· R5代表氫、Cu烧基、C!_6烯基、-C(0)R2a、-Cu伸烧基_ 雜環基、-C^伸烷基NF^CXCO-Cw烷基、-Cl_8伸烷基 NRGQCOOCw烷基、-Cw伸烷基nrerf、n-敗醯亞胺基-Cl_ 伸烷基-或-CXCOCk烷基；或 ii)R2及R5與分別和其連接的碳及氮一起形成選自下面的基IB wherein: R1 represents Cw alkyl, -Cw alkylene NRERF, -Cw alkylene NRGqcOOCw alkyl, _(^_8 extended alkyl NRGcCCOCw alkyl or -Cw alkyl-cycloalkyl; R3 represents hydrogen, CN3 alkyl, alkoxy, or _c(〇) fluorenyl; R4 represents hydrogen, halogen, alkoxy, -CeC-aryl, -NHCualkylalkyl, aryl, -N02, CF3 or 〇cf3 Prerequisite is that R3 and R4 are not argon at the same time, and R4 is not hydrogen when R3 is C13 alkyl; a) A represents c(〇) and 1) represents 2^ or & 'where R, Table' Or a heteroaryl group, or a heteroaryl-aryl group; , "aryl-heterocyclyl, aryl-C1·3-alkylene-heterocyclyl, ^ squary-tertiary alkyl-heterocyclyl, aryl_〇_Ci_3 alkylene-heterocycle 23 200804352 aryl, aryl-Cw alkyl-heteroaryl, -aryl-heteroarylalkylene, heteroaryl, heteroaryl-aryl-Ci_3 alkylene-heterocyclic, aryloxy Heteroaryl, cyclohexyl, -cycloalkyl-aryl, cycloalkyloxy, heterocyclyl, _nrH_*yl-heterocyclyl, -NRh-cycloalkyl, _N(Rb)CN6 extendable rC, _nh_n(Cu alkyl)-heteroaryl, -ocwalkylene rd, -0Cl_6 alkenyl, -aryl_〇13 alkylene-heterocyclyl-R*1,-aryl-Cw alkylene- Heteroaryl_rk, Cl_3 alkyl (NH2)-aryl, or -aryl-C!·3 alkylene_NH-CK3 alkylene_〇H, · R5 represents hydrogen, Cu alkyl, C !_6 alkenyl, -C(0)R2a, -Cu stretching group _ heterocyclic group, -C^alkyl group NF^CXCO-Cw alkyl group, -Cl_8 alkylene group NRGQCOOCw alkyl group, -Cw alkylene group Nrerf, n-inarene-amino-Cl_alkylene- or -CXCOCk alkyl; or ii) R2 and R5 together with the carbon and nitrogen respectively attached thereto form a group selected from the group consisting of

或 b) A代表-S02-且 R2代表CN6烷基、芳基、Cw芳烷基或-Cw伸烷基雜環基；且 R5代表氫、Cw烷基、Cu烯基、-Cw伸烷基-雜環基、-CM 伸烷基NRGqOK^烷基、-Cw伸烷基NRGC(0)0CV6烷 24 200804352 基、-Ci-8伸烧基NRERF、N-醜·亞胺基-C1-8伸烧基-或 -CXCOCk 烷基； RA、1^及^°獨立地代表氫、鹵素、-NRERF、氰基、CC13、 -C(0)Ci_6：J：完基、Cu烧基、環烧基、雜環基、芳基、聯芳基、-芳基-雜芳基、-芳基_C!_3伸烷基-雜環基、_芳基-〇-Ci_3 伸烧基-雜環基、-Cu烯基芳基、雜芳基、Ck芳烧基、 -NHCWCw 烷基、-NHCWOCw 烧基、-NHC^OX^ 芳烧基或-NHC^COOCk芳烷基； rb代表氫或CN8烷基；Or b) A represents -S02- and R2 represents a CN6 alkyl group, an aryl group, a Cw aralkyl group or a -Cw alkylene heterocyclic group; and R5 represents hydrogen, Cw alkyl group, Cu alkenyl group, -Cw alkylene group -heterocyclic group, -CM alkyl group NRGqOK^alkyl group, -Cw alkylene group NRGC(0)0CV6 alkane 24 200804352 base, -Ci-8 extendable group NRERF, N-ugly-imino group-C1-8 Stretching base- or -CXCOCk alkyl; RA, 1^ and ^° independently represent hydrogen, halogen, -NRERF, cyano, CC13, -C(0)Ci_6: J: complete, Cu alkyl, ring burn Base, heterocyclic group, aryl group, biaryl group, -aryl-heteroaryl group, -aryl group -C!_3 alkylene group-heterocyclic group, aryl group-〇-Ci_3 alkylene group-heterocyclic group , -Cu alkenyl aryl, heteroaryl, Ck arylalkyl, -NHCWCw alkyl, -NHCWOCw alkyl, -NHC^OX^ aryl or -NHC^COOCk aralkyl; rb represents hydrogen or CN8 alkane base;

Re及R/獨立地代表氫或Ci_3烧基；或re代表環烧基且rF 代表氫，·或Re及Rf與一連接的氮原子一起形成5_或6_員雜壞， RG代表氫或Cy烷基； RH代表氫、Cw烷基、-c^伸烷基NRERF、-CK6伸燒基 NHC(〇)ci-4烧基、或-Ck伸烧基NHCXOpCu烧基； RJ代表芳基、雜芳基、雜環基、_Cl-3伸烷基（芳基h、_c" 伸烷基-雜芳基、-C!_3芳烷基、_cK3伸烷基_c(〇)_雜環基 -〇c(o)Cl_3伸烷基·芳基、_c(0)_0_Ci 3伸烷基_芳基或= 伸烧基-雜環基； 4 RK代表一或兩個芳基取代基；及其鹽類或溶劑化物。關於式IA、式IB化合物及其鹽類或溶劑化物：在本發明之一個具體實施例中，Ri代表烷基或_Cw伸烷基_ 環烷基。在另一個具體實施例中，Ri代表異丁基(2_甲^丙 25 200804352 基）。在，一個具體實施例中，Rl代表-亞甲基_環戊基或_ 亞甲基環己基。在另一個具體實施例中，Rl代表-亞 _ 環戊基。 & 關於式ΙΑ、式IB化合物及其鹽類或溶劑化物：在本發明之一個具體實施例中，R3代表氫、烷基或_c(〇)〇烷基；在另一個具體實施例中，R3代表氫。Re and R/ independently represent hydrogen or Ci_3 alkyl; or re represents a cycloalkyl group and rF represents hydrogen, or Re and Rf together with a linked nitrogen atom form a 5- or 6-membered impurity, RG represents hydrogen or Cyalkyl; RH represents hydrogen, Cw alkyl, -c^alkylene NRERF, -CK6 extended alkyl NHC (〇) ci-4 alkyl, or -Ck extended alkyl NHCXOpCu alkyl; RJ stands for aryl, Heteroaryl, heterocyclic, _Cl-3 alkyl (aryl h, _c" alkyl-heteroaryl, -C!_3 aralkyl, _cK3 alkylene_c(〇)_heterocyclyl -〇c(o)Cl_3alkyl-aryl, _c(0)_0_Ci 3 alkyl-aryl or =alkylene-heterocyclyl; 4 RK represents one or two aryl substituents; Salts or Solvates. Regarding the compounds of Formula IA, Formula IB, and salts or solvates thereof: In one embodiment of the invention, Ri represents an alkyl group or a _Cw alkyl group - a cycloalkyl group. In the examples, Ri represents isobutyl (2-methylpropanoid 25 200804352). In one embodiment, R1 represents -methylene-cyclopentyl or _methylenecyclohexyl. In another specific In the examples, R1 represents -sub-cyclopentyl. & And their salts or solvates thereof: In the present invention a particular embodiment, R3 represents hydrogen, alkyl or _c (square) square alkyl; In another particular embodiment, R3 represents hydrogen.

關於式IA、式IB化合物及其鹽類或溶劑化物：在本發明之一個具體實施例中，R4代表鹵素。 XWith respect to the compounds of formula IA, formula IB and salts or solvates thereof: In a particular embodiment of the invention, R4 represents halogen. X

關於式IA、式IB化合物及其鹽類或溶劑化物：在本發明之一個具體實施例中，A代表C(O)且R2代表R2a或R2b 其:R2a代表_nrh_芳基；且代表_c"伸烧基rA、芳基、，芳基、·芳基-雜芳基、_雜芳基_芳基、_芳基_雜環基、_、芳基伸烷基_雜環基、-芳基_〇_c㈠伸烷基_雜環基、芳基-Cw伸烷基-雜芳基、雜芳基、-環烷基_芳基、_nrB^m 伸烷基R 伸烷基rd、_芳基3伸烷基_雜環基_rJ 基伸烷基_雜芳基_R' 伸烷基(NH2)_芳基；且、 R代表氫、Cw烷基、cN6烯基、或_Ci 8伸烷基nrerf。關於式ΙΑ、式IB化合物及其鹽類或溶劑化物：在本發明之一個具體實施例中，A代表c(〇)且以及R5與分別和其連接的碳及氮原子形成下面的基 ΓΛ 芳基，Νγ^ν 26 200804352 關於式IA、式m化合物明之一個具體實施例中，A代李幾頰或洛劑化物：在本發芳烧基或-Ck伸烧基雜環基·且$2、’尺代表务基、Ck CK6烯基。 R代表氫、cK6烷基或關於式IA、式IB化合物及其骑；：明之一個具體實施例中，ra |類或〉谷劑化物··在本發基、-芳基_Cw伸烷基-雜環基、、-芳及RD獨立地代表氫、芳或-NHCCCOOCw烷基。方基_0_C1-3伸烷基_雜環基、關於式IA、式明之-個具體實施例中，#、二錢溶劑化物：在本發關於式ΙΑ、式IB化合物及| 土明之-個具體實施射，溶劑化物··在本發基；或RE及RF與和其連接的氮原子— 丁起幵》成5-或6-貝雜關於式IA、4 IB化合物及其鹽類或溶劑化物：在本發明之-個具體實施例中，…代表氫、h縣或々6钱基 NRERF。在式IA或IB或任何其次式中，任何一次在其上面出現的任何官能基或取代基，其意義或任何其他官能基或取代基的意義在每次出現是彼此獨立，除非另外說明。當然本發明包括根據上述本發明不同方面的基團之全部組合。名詞及定義在本文中使用時，名凋烧基”作為基或基的一部份時， 27 200804352 係指含有所指數量的碳原子之直鏈或支鏈燒基。此基之實，包括f基二乙基、正丙基、異丙基、正丁基、異丁基、弟丁基、第三丁基、正戊基、異戍基、新戍基或己基、 3,3_二f基丁基等。士在本文中使用時，名詞“伸烷基，，作為基或基的一部份拉盆係礼3有所扣數1的碳原子之直鏈或支鏈飽和烴基連此基之實例包括亞甲基、伸乙基等。在一個具體實施例中，伸烷基是亞甲基。、私=本文中使用時，4詞“烯基，，作為基或基的一部份時，古、曰3有一或多個碳-碳雙鍵並含有所指數量的碳原子之鏈基。此基之實例包括乙烯基、丙烯基、丁埽土、戊稀基或己晞基等。 f本文甲使用時，4詞“烧氧基，，作為基或基的一部份氣美、丙-2-氧基、T氧基、丁-2-乳基或甲基‘2_氧基、戊氧基、己氧基等。基經本文定義本文定義之炫基，該燒 =文中使用時，名詞“芳基，，作為基或基的一部份二或三個共輛或铜合的環其中至少一個環具’ /、ιι9π甩子系統之視需要經取代的烴貫例包括視需要經取代之苯基、萘基或四氣萃i等=之個具體實施例中，絲絲苯基。在另—㈣體實施^中―， 28 200804352 芳基代表萘基。在一個具體實施例中，芳基基團是未經取代。在另一個具體實施例中，芳基基團是經單取代、二取代或三取代。在又另一個具體實施例中，芳基基團是經單取代或二取代。視需要選用的芳基取代基包括Cp4烷基、 Cu烷氧基、鹵素、硝基、三鹵甲基、三鹵曱氧基、-c(o)ch3、 -Ν((^3烷基)2及-SOrCw烷基。在本文中使用時，名詞“芳氧基”作為基或基的一部份時，係指-0-芳基其中芳基是根據本文之定義。在本文中使用時，名詞“聯芳基”作為基或基的一部份時，係指芳基其直接經第二個芳基取代，其中芳基是根據本文之定義。在本文中使用時，名詞“雜芳基”作為基或基的一部份時，係指含有一至四個選自Ν、Ο及S的雜原子之視需要經取代的芳族基，該芳族基含有一、二或三個5-或6-員共輛或稠合的環，其中至少一個環具有共軛的π-電子系統。單環雜芳基（單環）之實例包括視需要經取代之噻嗯基、呋喃基、吱咱基、吡嘻基、三峻基、四ϋ坐基、咪嗤基、畤嗤基、ϋ塞嗤基、畤二嗤基、異嗔嗤基、異呤嗤基、嗔二唾基、吡喃基、吡唑基、嘧咬基、嗒畊基、吡畊基、吡啶基、三畊基、四畊基等。稠合的芳族環之實例包括喳咁基、異喳啉基、喳唾啉基、喳崎啉基、喋σ定基、唓咁基、酞畊基、萘啶基、吲哚基、異吲哚基、氮雜吲哚基、吲哚畊基、吲 σ坐基、嘌呤基、吡洛並吡咬基、吱喃並吡σ定基、苯並呋喃基、異苯並吱喃基、苯並ϋ塞嗯基、苯並哺σ圭基、苯並4 σ坐 29 200804352 基、苯並異崎唑基、苯並噻唑基、苯並異噻唑基、笨並哼二唑基、苯並噻二唑基、二苯並呋喃基、四氫喳唯基、四氫異喳咁基、苯並[1，3]-二氧戊環等。在一個具體實施例中，雜芳基基團是吡啶基、嘧啶基、噚唑基、苯並呋喃基、二’ 苯並呋喃基、苯並噻唑基、吲哚基或吲唑基。在另一個具體貫施例中，雜芳基基團是。比σ定基、嘴U定基、異σ号ϋ坐基、苯並吱鳴基、二苯並呋喃基、苯並噻唑基、吲哚基或吲唑基。在又另一個具體實施例中，視需要經取代的雜芳基基團是苯並呋喃基、吡啶基、二苯並呋喃基、咪唑基及異噚唾基。在一個具體實施例中，雜芳基基團是未經取代。在另一個具體實施例中，雜芳基基團是經單取代、二取代或三取代。在又另一個具體實施例中，雜芳基基團是經單取代或二取代。視需要選用的雜芳基取代基包括Cl_4烷基、 c 1 -4烧氧基及1¾素。在本文中使用時，名詞“環烷基，，作為基或基的一部份係指含有3至7個碳原子之飽和環狀煙基。此基之實例包括視需要經取代之環丙基、環丁基、環戊基、環己基或環庚基。在本文中使用時，名詞“環烷氧基，，作為基或基的一部份時，係指-0-環烷基，其中該環烷基是根據本文之定義。在本文中使用時，名詞“雜環基，，或“雜環，，作為基或基的一部份時，係指i)含有一至四個選自Ν、Ο及S的雜原子之視需要經取代的單環3-至7-員飽和或部份飽和的烴基以及ii)多環基例如二環及三環基，其係含有一至四個選自N、 30 200804352 0及S的雜原子之視需要經取代的3-至7-員飽和或部份飽和的烴基之稠合的環。單環基之實例包括吡咯啶基、吖丁 α定基、味嗤σ定基、氧咪嗤咬基、咐吐σ定基、噚17坐咬基、六氳外b定基、六氫咐σ井基、嗎福4基、硫嗎福ϋ林基、嗔嗤咬基、海因基、戊内醯胺基、環氧乙烧基、啐σ旦基（oxetanyl)、二氧戊環基、二啐烧基、啐嗔烧基(oxathiolany 1)、哼噻基 (oxathianyl)、二噻烷基、二氫呋喃基、四氫呋喃基、二氫口比喃基、四氫17比喃基、四氫吼咬基、四氫σ密咬基、四氫口塞吩基、四氫硫吡喃基、二氮雜輩基、氮雜箪基等。二環基之實例包括吲哚基、異吲哚基、苯並呋喃基、奎寧環基、 2,3,4,5-四氫-1Η·3-苯並口丫庚因基、四氫異^1奎嚇基、六氫口比咯並[l，2-a]吡畊-2(1Η)-基等。在一個具體實施例中，雜環基是視需要經取代的5-或6-員單環基、或9-員二環基。在另一個具體實施例中，雜環基是視需要經取代的5-或6-員單環基。在又另一個具體實施例中，雜環基基團是視需要 :至取代的咐嘻咬基、味嗤咬基、六氫吼咬基、六氫吼11井基或嗎福啉基。在又另一個具體實施例中，雜環基基團是視需要經取代的六氫吡畊基。在又另一個具體實施例中，雜環基基團是未經取代。在又另一個具體實施例中，雜環基基團是經單取代、二取代或三取代或四取代。在又另一個具體實施例中，雜環基基團是經單取代。視需要選用的雜環基取代基包括烷基、-CXCOCw烷基、-0(0)0(^4烷基、-NqCOCw 烷基、-NCCCOOCw 烷基、-C(0)NR8Ci_4 烷基、-Cw伸烷基OH、-Cu伸烷基0(0)0(^3烷基、-Cw 31 200804352 伸烷基_〇·。〗·3伸烷基〇H、-CM伸烷基-NH-Cu伸烷基〇H、 -C!·6伸烷基NRERF、氰基、羥基、-NRerf、螺乙縮醛、及酮基。在本文中使用時，名詞“鹵素，，或“鹵基，，係指氟（氟基）、氣（氣基）、漠（漠基）或破(硬基)原子。在一個具體實施例中鹵素取代基是氟或氯原子. ’ 在本文中使用時，關於包含在用藥至病人的醫藥調製物中使用的成份（活性成份例如活性成份、其鹽類或賦幵^With respect to formula IA, a compound of formula IB, and salts or solvates thereof: In a particular embodiment of the invention, A represents C(O) and R2 represents R2a or R2b: R2a represents _nrh_aryl; and represents _ c"Extended base rA, aryl, aryl, aryl-heteroaryl, _heteroaryl-aryl, _aryl-heterocyclyl, _, arylalkylene-heterocyclyl, - Aryl-〇_c(1)alkylene-heterocyclyl, aryl-Cwalkyl-heteroaryl, heteroaryl, cycloalkyl-aryl, _nrB^m alkylene R alkyl rd, _ aryl 3 alkylene _ heterocyclyl _rJ alkylalkyl _ heteroaryl _R 'alkyl (NH2) aryl; and, R represents hydrogen, Cw alkyl, cN6 alkenyl, or _Ci 8 stretch alkyl nrerf. With respect to the formula, the compound of the formula IB and the salts or solvates thereof: In a specific embodiment of the invention, A represents c(〇) and R5 and the carbon and nitrogen atoms respectively bonded thereto form the following group Base, Νγ^ν 26 200804352 In a specific embodiment of the formula IA, the compound of the formula m, the A-generation Li or chewable compound: in the present aromatic aryl group or -Ck-extended heterocyclic group and $2 'The ruler stands for the base, Ck CK6 alkenyl. R represents hydrogen, cK6 alkyl or a compound of formula IA, formula IB and its riding;: In a specific embodiment of the invention, ra | class or > phenate compound in the present hair base, - aryl - Cw alkyl - Heterocyclyl, -aryl and RD independently represent hydrogen, aryl or -NHCCCOOCw alkyl.方基_0_C1-3alkylene-heterocyclyl, for the formula IA, the formula - in a specific embodiment, #, 二钱solvate: in the present invention, the formula IB, the compound of formula IB and | Specific implementation of the solvate, in the present hair base; or RE and RF and the nitrogen atom to which it is attached - butyl oxime into a 5- or 6-shell hybrid with respect to the compound of formula IA, 4 IB and its salts or solvents Compound: In a specific embodiment of the invention, ... represents hydrogen, h county or 々6 money based NRERF. In formula IA or IB or any of the following formulas, the meaning of any functional group or substituent present thereon, any meaning or any other functional group or substituent, is independent of each other in each occurrence unless otherwise stated. Of course, the invention includes all combinations of groups according to various aspects of the invention described above. Nouns and definitions, as used herein, when a radical is used as part of a radical or radical, 27 200804352 is a straight or branched chain radical containing the indicated number of carbon atoms. F-diethyl, n-propyl, isopropyl, n-butyl, isobutyl, butyl, tert-butyl, n-pentyl, isodecyl, neodecyl or hexyl, 3,3_2 F-butyl and the like. When used herein, the term "alkyl", as a part of a radical or a group of a linear or branched saturated hydrocarbon group with a number of 1 carbon atoms Examples of such a group include a methylene group, an ethyl group, and the like. In a particular embodiment, the alkylene group is a methylene group. , private = when used herein, the 4 word "alkenyl," as a part of a group or a group, the ancient, 曰3 has one or more carbon-carbon double bonds and contains the chain of the indicated number of carbon atoms. Examples of the base include vinyl, propenyl, buckwheat, pentyl or hexyl, etc. f When used herein, the word "alkoxy", as a part of a base or a group of gas, C, -2-oxy, T-oxy, but-2-yry or methyl '2-oxy, pentyloxy, hexyloxy and the like. A radix as defined herein, as defined herein, is used in the context of the term "aryl, as part of a base or a group of two or three common or copper rings, at least one of which" /, The specific examples of the hydrocarbons to be substituted by the ιι 9π甩 subsystem include a phenyl group, a naphthyl group or a tetragas extract which is optionally substituted, etc., in the specific embodiment, the filament phenyl group is implemented in another (four) body ^中-, 28 200804352 Aryl represents a naphthyl group. In one particular embodiment, the aryl group is unsubstituted. In another embodiment, the aryl group is mono-, di- or tri-substituted. In yet another embodiment, the aryl group is mono- or di-substituted. The optional aryl substituents include Cp4 alkyl, Cu alkoxy, halogen, nitro, trihalomethyl, tri Halomethoxy, -c(o)ch3, -Ν((3 alkyl)2 and -SOrCw alkyl. As used herein, the term "aryloxy" as a part of a radical or radical, Means -O-aryl wherein aryl is as defined herein. As used herein, the term "biaryl" is used as a part of a radical or radical. Wherein, it refers to an aryl group which is directly substituted by a second aryl group, wherein the aryl group is as defined herein. When used herein, the term "heteroaryl" as a part of a group or group means One to four optionally substituted aromatic groups selected from the group consisting of ruthenium, osmium and S, the aromatic group containing one, two or three 5- or 6-membered or fused rings, at least One ring has a conjugated π-electron system. Examples of monocyclic heteroaryl (monocyclic) include optionally substituted thiol, furyl, fluorenyl, pyridyl, trisyl, and tetradecyl. , mercapto, fluorenyl, hydrazino, hydrazinyl, isodecyl, isodecyl, hydrazinyl, pyranyl, pyrazolyl, pyrimidine, argon , pyridinyl, pyridyl, tri-cultivating, tetra-cultivating, etc. Examples of fused aromatic rings include fluorenyl, isoindolyl, hydrazinoyl, indolinyl, 喋σ, 唓Sulfhydryl, hydrazine, naphthyridinyl, fluorenyl, isodecyl, azaindole, hydrazine, 吲σ, fluorenyl, pyridinopyridyl, 吱pyrr Sytidine Benzofuranyl, isobenzopyranyl, benzopyrene, benzoxanthyl, benzo-4-sine 29 200804352, benzoisoxazolyl, benzothiazolyl, benziso Thiazolyl, benzodiazolyl, benzothiadiazolyl, dibenzofuranyl, tetrahydroindenyl, tetrahydroisodecyl, benzo[1,3]-dioxolane, and the like. In a particular embodiment, the heteroaryl group is pyridinyl, pyrimidinyl, oxazolyl, benzofuranyl, bis-benzofuranyl, benzothiazolyl, indolyl or carbazolyl. In a specific embodiment, the heteroaryl group is a sigma group, a snail group, a sigma group, a benzofluorenyl group, a dibenzofuranyl group, a benzothiazolyl group, a fluorenyl group or Carbazolyl. In yet another embodiment, optionally substituted heteroaryl groups are benzofuranyl, pyridyl, dibenzofuranyl, imidazolyl and isoindolyl. In a particular embodiment, the heteroaryl group is unsubstituted. In another specific embodiment, the heteroaryl group is monosubstituted, disubstituted or trisubstituted. In yet another embodiment, the heteroaryl group is monosubstituted or disubstituted. Heteroaryl substituents optionally selected include Cl 4 alkyl, c 1 -4 alkoxy and 13⁄4. As used herein, the term "cycloalkyl, as a part of a group or a group, refers to a saturated cyclic group of cigarettes containing from 3 to 7 carbon atoms. Examples of such groups include optionally substituted cyclopropyl groups. , cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl. As used herein, the term "cycloalkoxy", when used as a part of a group or a group, refers to a -0-cycloalkyl group, wherein The cycloalkyl group is as defined herein. As used herein, the term "heterocyclyl," or "heterocycle, as a moiety of a radical or radical, refers to i) as needed, containing one to four heteroatoms selected from the group consisting of ruthenium, osmium, and S. Substituted monocyclic 3- to 7-membered saturated or partially saturated hydrocarbyl group and ii) polycyclic group such as bicyclic and tricyclic radicals containing from one to four heteroatoms selected from N, 30 200804352 0 and S A fused ring of a substituted 3- to 7-membered saturated or partially saturated hydrocarbon group is required. Examples of the monocyclic group include pyrrolidinyl, agmatine α-based, miso sigma, oxymymidine, oxime sigma, 噚17 sitting base, hexamethylene b-based, hexahydro 咐 σ well base,吗福四基, thiophene oxalinyl, acenaphthyl, hydanyl, valerodecyl, epoxidized oxime, oxetanyl, dioxolane, diterpenoid Base, oxathiolany 1, oxathianyl, dithiaalkyl, dihydrofuranyl, tetrahydrofuranyl, dihydroperylpyranyl, tetrahydroindolyl, tetrahydroindenyl , tetrahydro σ-density base, tetrahydro-n-thiophene group, tetrahydrothiopyranyl group, diaza-based group, azaindole group and the like. Examples of the bicyclic group include an anthracenyl group, an isodecyl group, a benzofuranyl group, a quinuclidinyl group, a 2,3,4,5-tetrahydro-1 Η·3-benzoxazepine group, a tetrahydro group. Isoquinone, hexahydroport, and [l,2-a]pyrazine-2(1Η)-yl and the like. In a particular embodiment, the heterocyclic group is a 5- or 6-membered monocyclic group or a 9-membered bicyclic group which is optionally substituted. In another specific embodiment, the heterocyclic group is a 5- or 6-membered monocyclic group which is optionally substituted. In yet another embodiment, the heterocyclyl group is optionally: to a substituted tick base, a miso bite, a hexahydrocarbazide, a hexahydroindole 11 or a morpholinyl group. In yet another embodiment, the heterocyclyl group is an optionally substituted hexahydropyrrole. In yet another embodiment, the heterocyclyl group is unsubstituted. In yet another embodiment, the heterocyclyl group is monosubstituted, disubstituted or trisubstituted or tetrasubstituted. In yet another specific embodiment, the heterocyclyl group is monosubstituted. Optionally selected heterocyclyl substituents include alkyl, -CXCOCw alkyl, -0(0)0(^4 alkyl, -NqCOCw alkyl, -NCCCOOCw alkyl, -C(0)NR8Ci_4 alkyl, - Cw alkyl OH, -Cu alkylalkyl 0 (0) 0 (^3 alkyl, -Cw 31 200804352 alkyl _ 〇 · · · 3 alkyl hydrazine H, -CM alkyl alkyl - NH- Cu alkyl hydrazine H, -C!·6 alkylene NRERF, cyano, hydroxy, -NRerf, snail acetal, and keto. As used herein, the term "halogen," or "halo, By fluorine (fluoro), gas (gas based), desert (molyd) or broken (hard) atoms. In one particular embodiment the halogen substituent is a fluorine or chlorine atom. 'When used herein, Ingredients for use in a pharmaceutical preparation for administration to a patient (active ingredients such as active ingredients, salts thereof or fumes)

所使用的名詞“藥學上可接受的，，，係指該成份在與存在^ J 醫藥調製物中的其他成份可以相容且不會傷害其受治療方面是可以接受。 σ 在本文中使用時，名詞“Ν_酞醯亞胺基，，係指一個經由原子鍵結的敵酿亞胺基。 & 在本文中使用時，名詞“蛋白酶，，是催化在醯胺鍵藉由親核性取代作用分解肽的醯胺鍵，最後導致水解的酶。蛋白酶包括·半胱胺酸蛋白酶、絲胺酸蛋白酶、天冬胺酸蛋白酶及金屬蛋白酶。蛋白酶“抑制劑，，比作用物更強烈地鍵結至酶且通#酶經由親核物催化地攻擊後不會分解。其因此旁兄爭性地防止蛋白酶被辨識及水解天然的作用物且因而為抑制劑。在本發明之一個方面，提供至少一種選自下面的化風實體：予 N’-(5-溴-2-氰基-4-嘧啶基)_4_[(4_甲基六氫吡畊基）甲基]-N’-(2-曱基丙基）苯曱醯肼； 32 200804352 N’- (5->臭-2_氣基_4-^密σ定基)-N’- (2-曱基丙基)-4-[(4 -丙基-1- 六氫吡畊基）曱基]苯曱醯胼； N’-(5-溴-2-氰基-4-嘧啶基)-N’-(2-曱基丙基)-3-[(4-丙基-1-六氫吡畊基）曱基]苯曱醯胼； Ν’- (5 -氣-2 -乱基- 4-17密17定基)-N’- (2_曱基丙基)-4-[(4 -丙基-1 _ 六氫吡畊基）曱基]苯曱醯胼； N’-(5-氣-2-氰基-4-嘧啶基)-N’-(2-甲基丙基)-3-[(4-丙基-1-六氫吡畊基）甲基]苯曱醯胼； N’- (5->臭-2 -氣基-4-口密σ定基)-4-氣-N’-(2·甲基丙基)-3_[(4 -丙基-1-六氫吡畊基）甲基]苯甲醯胼； N’-(5-氯-2-氰基-4-嘧啶基)-4·氟-N’-(2-甲基丙基)-3-[(4-丙基-1-六氫吡畊基）甲基]苯曱醯胼； 4-(1，4’-聯六氫吡啶-1’-基曱基）以’-(5-氯-2-氰基-4-嘧啶基)-N’-(2-甲基丙基）苯曱醯胼； N’- (5->臭-2 -鼠基-4_^σ定基）-N’-(2 -曱基丙基）-4-(1-六鼠ϋ比咬丄甲基）苯甲醯胼； Ν’-(5-溴-2-氰基-4-嘧啶基)-Ν’-(2-曱基丙基）-4-(1-吡咯啶基曱基）苯曱醯肼； N’-(5-氯-2-氰基-4-嘧啶基)-4-[(2,6-二曱基-1-六氫吡啶基）曱基]-N’-(2-曱基丙基）苯曱醯胼； 1 -[(4-{[2-(5-氯-2-氰基-4-嘧啶基)-2-(2-曱基丙基)月井基]羰基} 苯基）曱基>4-六氫吡啶羧酸乙酯； N-{(3R)-l-[(4-{[2-(5-氣-2-氰基-4-嘧啶基)-2-(2-曱基丙基）耕基]獄基}苯基）曱基]-3 -ϋ比17各σ定基}乙驢胺， 33 200804352 {1-[(4-{[2-(5-氯_2_氰基-4-嘧啶基)-2-(2-甲基丙基)胼基]幾基}苯基）甲基]-3-批咯咬基}胺基甲酸1，1_二甲基乙醋； N’-(5-氣-2-氰基-4-嘧啶基)-4-[(4-{2-[(2-羥基乙基）氧基]乙基}小六氫吡畊基）甲基]-N，-(2_甲基丙基）苯甲醯肼； N’-(5_氣_2_氰基I嘧啶基)·ν’_(2_甲基丙基)4_(丨_六氫吡咬基甲基）苯甲醯胼； Ν’-(5-氣-2-氰基冰嘧啶基)冬{[(2R)-2-(羥基甲基)小吼口各 σ疋基]甲基卜Ν’_(2·甲基丙基）苯甲醯胼； Ν’-(5-氣-2-氰基-4-嘧啶基)-Ν，-(2-甲基丙基)-4-(1-吡咯啶基曱基）苯甲醯胼； N’-(5-氣：氰基-4-嘧啶基)-4_(2,5-二氫-1H-吡咯小基甲基)-N’-(2-甲基丙基）苯甲酿胼； ^-(5-氣-2-氰基-4_嘧啶基)_4-[(2,5-二曱基_2,5-二氫_11^-吡略-1-基）曱基]甲基丙基）苯甲醯肼； {1-[(4」[2-(5-氯基_4_嘧啶基)_2_(2_曱基丙基)胼基]羰基}苯基）甲基]-4-六氫吡啶基}胺基曱酸ι，ι_二甲基乙酯； N’-(5-氣士氰基-4-嘧啶基)-4-({4-[3-(二甲胺基）丙基]小六氫吼畊基}甲基)_N，-(2-甲基丙基）苯甲醯胼； N’_(5-氣-2-氰基冰嘧啶基>Ν，_(2_曱基丙基)_4_({4_[3-(‘嗎福咐基）丙基]_1_六氫吡畊基}曱基）苯曱醯胼三氟乙酸鹽； Ν、(54_2-氰基-4-嘧啶基)_4_({4_[3-(二乙胺基）丙基]小六氫吼喷基}甲基)_Ν，-(2-曱基丙基）苯甲醯胼； Ν’-(5·氣1氰基-4-嘧啶基）_4-({4-[3-(二丙胺基）丙基]小六氫吼喷基}曱基)-]^(2_曱基丙基）苯曱醯胼； 34 200804352 N、(5-氣_2_氰基_4_嘧啶基)_4-({4_[3仁冬丙婦_卜基胺基）丙基>1-六氫吡畊基}甲基)_N，-(2_f基丙基）苯甲醯肼； N -(5-氣-2-氰基-4-嘧啶基)_4_({4_[(1_甲基-4_六氫吡啶基）曱基]-1-六氫吡畊基}甲基甲基丙基）苯曱醯肼； N -(5-氣_2_氰基-4-嘧啶基)_4-{[4_(卜曱基_4_六氫吡啶基)-1-六氫吡畊基]曱基卜N，_(2_甲基丙基）苯甲醯胼； {l-[(M[2-(5-氣_2_氰基_4_嘧啶基)_2_(2_甲基丙基)胼基]羰基}苯基）甲基>3-六氫吡啶基}乙酸乙酯； N’-(5-氣-2-氰基-4-嘧啶基)-4-({4-[2-(二乙胺基）乙基]-1-六氫吡畊基}甲基)_N’-(2-曱基丙基）苯曱醯胼； N’-(5-氣-2-氰基-4-嘧啶基)-4-({4-[2-(二-2-丙婦小基胺基）乙基>1-六氫吡呻基}曱基)-N，-(2-曱基丙基）苯曱醯肼； 1^’_(5-氣_2-氰基-4-嘧啶基)-4-({4-[2-(二丙胺基）乙基]小六氫ϋ比畊基}甲基)-N’-〇曱基丙基）苯曱醯肼； N’-(5-氣-2-氰基-4-嘧啶基)-3-[(2,6-二曱基小六氫吡啶基） f基]-N’-(2-曱基丙基）苯甲醯胼； 3-(1，4’-聯六氫吡啶_1’_基甲基>，_(5_氣_2-氰基-4_嘧啶基)-N’-(2-曱基丙基）苯曱酸胼； N’-(5-氣-2-氰基-4-嘧啶基)-N，-(2-曱基丙基)-3-(1-六氫吡啶基曱基）笨曱醯肼； N’-(5U-氰基-4-嘧啶基)-3-({4-[3-(二丙胺基）丙基]-1-六氫17比σ井基}曱基)-N’-(2 -曱基丙基）苯曱酿耕； N’-(5-氣-2-氰基-4-嘧啶基）-3-({4-[3-(二乙胺基）丙基]-1-六氫吡畊基}曱基)-N，-(2-曱基丙基）苯曱醯肼； 35 200804352 N’-(5-氣-2-氰基-4-嘧啶基)-4-[(4-羥基-丨_六氫吡啶基）曱基]-Ν’-(2-曱基丙基）苯曱醯胼； Ν’-(5-氣-2-氰基-4-嘧啶基)-4-{[4-(2_羥基乙基六氫吡啶基]曱基卜Ν’-(2-曱基丙基）苯曱醯胼； Ν’-(5胃氯-2-氰基-4-嘧啶基)-4-{[4-(2-羥基乙基）六氫吡畊基]曱基卜Ν’-(2-曱基丙基）苯甲醯胼； Ν’-(5-氯-2-氰基-4-嘧啶基)-4-{[4-(羥基曱基)_丨_六氫吡啶基] 曱基}-Ν’-(2-曱基丙基）苯曱醯胼； ^[(^{[2-(5-氣-2-氰基-4-嘧啶基)-2-(2-曱基丙基）醯胼基]羰基}苯基）曱基]-N，N-二甲基脯胺醯胺； 4-(N吖丁啶基甲基)-N’-(5-溴-2-氰基-4-嘧啶基)-N，-(2-甲基丙基）苯曱醯胼； N’-(H2_氰基+嘧啶基)_N，_(2_甲基丙基)_ 口比咯啶基羰基)-1-吡咯啶基]甲基}苯曱醯胼； ΝΌϋ氰基·4_嘧啶基)-N’_(2-曱基丙基)-4-{[4-(4-嗎福 ϋ林基）-1-吡咯啶基]甲基}苯曱醯胼； N’-(5-氯-2-氰基-4-嘧啶基)-N’-(2-曱基丙基)-4-({4-[2-(1-六氫吼啶基）乙基]-1-六氫吡畊基}甲基）苯曱醯胼； N’-(5-氯-2-氰基-4-嘧啶基)-4-({4-[(1-曱基-3-六氫吡啶基）甲基>1-六氫吡畊基}曱基)-N，-(2-曱基丙基）苯曱醯胼； N’-(5-氣-2-氰基-4-嘧啶基)_N’-(2-曱基丙基)-4-({4-[3-(1-六氫吡啶基）丙基]-1-六氫吡畊基}曱基）苯曱醯胼；氣-2-氰基-4-嘧啶基)-4-{[4-(二乙胺基）-1-六氫吡啶基] 曱基}-N’-(2-曱基丙基）苯曱酸胼； 36 200804352 N’-(5-氣-2-氰基-4_嘧啶基)-4-{[4-(4-曱基小六氫吡畊基)-1 - /、鼠吼ϋ疋基]甲基} -Ν’ -(2-甲基丙基）苯甲酿月井； Ν’-(5-氣-2-氰基-4-嘧啶基)-Ν，-(2-甲基丙基)-4-{[4-(4-吡啶基)-1-六氫吡畊基]曱基}苯曱醯胼；叩_(5_氣冬氰基_4_嘧啶基)_N，_(2_甲基丙基）_4_({4_[2_(卜吡咯啶基）乙基]-1_六氫吡畊基}曱基）苯甲醯胼； N’-(5-氣-2-氰基_4·,咬基)-4-({4-[2-(二甲胺基）乙基]小六氫吡畊基}甲基）-N’-(2-甲基丙基）苯甲醯胼； ’-(5-氣-2_氰基-4-嘧咬基)-：^’_(2-曱基丙基)-3-(1』比咯啶基曱基）苯甲醯肼； N’-(5-氣-2-氰基-4-嘧啶基)-N’-(2-曱基丙基)-3-{[4-(4-嗎福咁基:)-1-六氫吡啶基]甲基}苯甲醯肼； Ν’-(5-氣-2-氰基_4_嘧啶基)_3-{[4-(2-羥基乙基）小六氫吡畊基]曱基卜Ν’-(2_甲基丙基）苯曱醯胼； Ν’-(5-氣-2-氰基-4-嘧啶基)冬{[4-(羥基曱基)小六氫吼畊基] 曱基卜Ν’-(2-曱基丙基）苯甲醯肼； Ν’-(5-氣-2-氰基-4-嘧啶基)-Ν’-(2-曱基丙基)-3-({4-[3-(1_六氫吼咬基）丙基]-1 -六氫u比ϋ井基}曱基）苯曱醯胼； Ν’-(5-氣-2-氰基-4-嘧啶基)-3-{[4-(4·曱基-1-六氫吡畊基六氫吡啶基]曱基}-Ν，-(2-甲基丙基）苯曱醯胼； Ν’-(5-氣-2-氰基-4-嘧啶基)-3-{[4-(二乙胺基)-1-六氫吡啶基] 曱基卜N’-(2-曱基丙基）苯曱醯胼； N’-(5-氯-2-氰基-4-嘧啶基)-3-({4-[2-(二乙胺基）乙基]小六氫吡畊基}曱基)-N，-(2-曱基丙基）苯曱醯胼； 37 200804352 N’-(5-氣-2-氣基-4_ 口密咬基)-3-{[4-(l-曱基-4-六鼠口比咬基六氫吡畊基]甲基}-N’-(2-曱基丙基）苯曱醯胼； N’-(5-氣-2-氰基-4-嘧啶基)-N’-(2-甲基丙基)-3-({4-[3-(4-嗎福ϋ林基）丙基]-1 -六氫1:7比σ井基}曱基）苯甲酿耕； Ν’-(5-氣-2 -氣基-4-。密咬基)-Ν’-(2-甲基丙基)-3-({4-[2_( 1 -吼咯啶基）乙基]-1-六氫吡畊基}曱基）苯甲醯肼； N’-(5-氣-2-氰基-4-嘧啶基)·3-({4-[(1-曱基-4-六氫吡啶基）甲基]-1-六氫吡畊基}曱基)-Ν，-(2-曱基丙基）苯曱醯胼； Ν’-(5-氣-2-氰基-4-嘧啶基)-Ν’-(2-甲基丙基)-3-({4-[2-(1-六氫吡啶基）乙基]-1-六氫吡畊基}曱基）苯曱醯肼； Ν’-(5-氣_2_氰基-4-嘧啶基)-4-氟-Ν，-(2-曱基丙基)_3-{[4-(4-嗎福咁基）-1-六氫吡啶基]曱基}苯曱醯肼； N’*"(5-氣-2-氰基-4-嘧啶基>4-氟-3-{[4-(羥基曱基)小六氫吼啶基]甲基卜N’-O曱基丙基）苯曱醯肼； 3_(1，4、聯六氫吡啶_1，-基曱基)屮，_(5_氯_2-氰基_4-嘧啶基M-氟-N，-(2-甲基丙基）苯曱醯胼； N’-(5-氣-2-氰基-4-嘧啶基）-4-氟-3-[(4-曱基-1-六氳吡畊基）甲基]-N’-(2-曱基丙基）苯曱醯肼； N、(5-溴-2-氰基-4-嘧啶基）-4-{[4-(4-曱基-1-六氫吡畊基VI-六氫吡啶基]甲基卜N，-(2_甲基丙基）苯曱醯胼； N -(5-溴-2-氰基-4-嘧啶基)_5_[(4-甲基-1-六氫吡畊基）曱土] N (2_曱基丙基）_3_異口号唾卡巴肼（carb〇hydrazide); N’#-漠_2_氰基_4_嘧啶基)_H(4_甲基六氫吡畊基）曱基>Ν’-(2-曱基丙基)_丨-苯並呋喃_2_卡巴胼； 38 200804352 N’-(5-溴-2-氰基-4-嘧啶基)_5_[(4_甲基六氳吡畊基）甲基]-N’-(2-甲基丙基>2-呋喃卡巴胼‘甲基苯磺酸鹽； N’-(5-溴-2-氰基-4-嘧啶基)-6_{3-[(4_甲基六氬吡畊基）曱基]苯基}-N’-(2-甲基丙基>3 —吡ϋ定卡巴肼； Ν’-(5-溴-2-氰基-4-嘧啶基>6_{4-[(4_甲基六氫吡畊基）甲基]苯基卜N’_(2-曱基内基)·3』比啶卡巴肼； Ν’·(5-溴-2-氰基-4-喷啶基>5_{4_[(4_甲基六氫吡畊基）甲基]苯基}-Ν’_(2-甲基丙基)_3』比咬卡巴胼； Ν’-(5-溴-2-氰基-4-嘧啶基)_5_{3-[(4-甲基-1-六氫吡畊基）曱基]苯基}-Ν’_(2-曱基丙基)_3-σ比咬卡巴胼； Ν’-(5-漠-2-氰基_4_嘧啶基)_5-[(4-曱基小六氫吡畊基）甲基]_Ν’-(2-曱基丙基)-1-苯並吱喃_2_卡巴胼； N’-(5-溴-2-氰基-4-嘧咬基)-5-[(4-甲基-1-六氳吡畊基）甲基]-N’-(2-曱基丙基)-2-嗔吩卡巴胼；及其藥學上可接受的衍生物。在本文使用時，名詞“藥學上可接受的衍生物，，係指式I、 IA或IB化合物之任何藥學上可接受的鹽、溶劑化物或前藥例如酯或胺基曱酸鹽，其用藥至受治療者後，可以提供 (直接或間接）式I、IA或IB化合物，或其活性代謝物或殘留物。此衍生物是從事此藝者不需要實驗即可了解。然而，可以參考 Burger’s Medicinal Chemistry and Drug Discovery， 5th Edition，Vol 1: Principles and Practice,之說明，其併於本文供參考以延伸此衍生物之說明。在本發明的一個方面中，藥學上可接受的衍生物是鹽、溶劑化物、酯及胺基甲酸鹽 39 200804352 類。在本發明的另一個方面中，藥學上可接受的衍生物是鹽、溶劑化物及酯類。在又另一個方面中，藥學上可接受的衍生物是鹽及溶劑化物類。本發明化合物可以在自由態形式及/或作為藥學上可接受的鹽用藥。實際上，在本發明之一些具體實施例中，根據式I、IA或IB化合物之藥學上可接受的鹽可能優於各自由態鹼或自由態酸，因為這些鹽類之安定性或溶解度大於分子因而促進調製成給藥的形式。據此，本發明還關於根據式I、IA或IB化合物之藥學上可接受的鹽。在本文使用時，名詞“藥學上可接受的鹽”係指保留各化合物之所要的生物活性並顯現最小的不欲毒性效應之鹽類。對於合適鹽類之回顧，見Berge et al，J. Pharm. Sci·， 1977, 66, 1_19。名詞“藥學上可接受的鹽”包括藥學上可接受的酸加成鹽及藥學上可接受的驗加成鹽。這些藥學上可接受的鹽在化合物的最後分離及純化中可以當場製備，或者是使純化後的化合物在其自由態酸或自由態鹼的形式另外分別與合適的鹼或酸反應。該鹽可從溶液沈澱並經由過濾、收集或藉由將溶劑蒸發而回收。藥學上可接受的酸加成鹽可以經由式I、IA或IB化合物與合適的無機或有機酸(例如氫溴酸、氫氯酸、硫酸、胺基磺酸、硝酸、磷酸、琥珀酸、馬來酸、羥基馬來酸、丙烯酸、曱酸、醋酸、羥基醋酸、苯基醋酸、丁酸、異丁酸、丙酸、富馬酸、擰檬酸、酒石酸、乳酸、扁桃酸、苯曱酸、鄰-乙醯氧基本曱酸、氯苯甲酸、甲基苯曱酸、二硝基苯曱 40 200804352 酸、羥基苯曱酸、曱氧基苯甲酸、水揚酸、谷胺酸、硬脂酸、抗壞血酸、棕櫚酸、油酸、丙酮酸、巴莫酸、丙二酸、月桂酸、戊二酸、天冬胺酸、對-曱苯磺酸、苯磺酸、曱磺酸、乙磺酸、2-羥基乙磺酸、萘磺酸(例如2-萘磺酸）、對-胺基苯磺酸(也就是磺胺酸）、己酸、庚酸或酞酸），視需要在合適的溶劑例如有機溶劑中反應而製備，得到的鹽通常藉由例如結晶及過濾而分離。式（I)化合物之藥學上可接受的酸加成鹽可包括或例如是溴酸鹽、鹽酸鹽、碘酸鹽、硫酸鹽、硫酸氫鹽、硝酸鹽、磷酸鹽、磷酸氫鹽、琥珀酸鹽、馬來酸鹽、蘋果酸鹽、甲酸鹽、醋酸鹽、三氟醋酸鹽、糖酸鹽、丙酸鹽、富馬酸鹽、檸檬酸鹽、酒石酸鹽、乳酸鹽、苯曱酸鹽、水揚酸鹽、谷胺酸鹽、天冬胺酸鹽、對-曱苯磺酸鹽、苯磺酸鹽、曱磺酸鹽、乙磺酸鹽、萘磺酸鹽（例如2-萘石黃酸鹽）、曱石黃酸、乙石黃酸、對-曱苯續酸、羥乙石黃酸鹽或己酸鹽。在一個具體實施例中，提供本發明化合物之三氟醋酸鹽。在另一個具體實施例中，提供本發明化合物之鹽酸鹽。藥學上可接受的鹼加成鹽可以經由式I、IA或IB化合物與合適的無機或有機鹼(例如氨、三乙胺、乙醇胺、三乙醇胺、膽鹼、精胺酸、賴胺酸或組織胺酸），視需要在合適的溶劑例如有機溶劑中反應而製備，得到的鹼加成鹽通常藉由例如結晶及過濾而分離。藥學上可接受的鹼鹽包括銨鹽及與有機鹼之鹽類，包括一級、二級及三級胺之鹽類，包括脂族胺、芳族胺、脂族二胺及羥基烷基胺，例如曱胺、 41 200804352 乙胺、異丙胺、二乙胺、乙二胺、乙醇胺、三曱胺、二環己胺、二乙醇胺、環己胺及N-曱基-D-葡糖胺。其他合適的藥學上可接受的驗鹽包括藥學上可接受的金屬鹽，例如藥學上可接受的驗金屬或驗土金屬鹽例如納、鉀、裡、妈、鎂、鋁及鋅之氫氧化物、碳酸鹽及碳酸氳鹽；特別是存在於式I、IA或IB化合物中的一或多個羧酸基團之藥學上可接受的金屬鹽。其他非藥學上可接受的鹽，例如草酸鹽，可以用於例如分離本發明之化合物。本發明在其範圍内包括全部可能的化學計量及非化學計量形式之式I、IA或IB化合物的鹽類。在本文中使用時，名詞“本發明化合物”係指根據式I、 IA或IB化合物及其藥學上可接受的衍生物。名詞“一種本發明化合物”係指根據上述定義之任何其中一種本發明化合物。在本文中使用時，名詞“至少一種化學實體”係指選自式 I、IA或IB化合物及其藥學上可接受的衍生物所組成的化合物群組中的至少一種化學物質。本發明化合物可以存在為固體或液體，兩者都包括在本發明内。在固體狀態中，本發明化合物可以存在為無定形物質或結晶形式或其混合物。當然可以形成本發明化合物之溶劑化物其中溶劑分子是在結晶過中摻混至晶格内。溶劑化物可涉及非水性溶劑例如乙醇、異丙醇、DMSO、醋酸、乙醇胺及醋酸乙酯，或其可以涉及水作為溶劑而摻 42 200804352 混至晶格内。其中水是溶劑並摻混至晶格内的溶劑化物通常稱為水合物。本發明包括全部這些溶劑化物。還可了解本發明化合物之全部結晶形式、多晶形、幾何異購物、立體異購物（包括對掌異構物及非對掌異構物）及互受異構物或其混合物，都包括在本發明之範圍内。根據本發明之另一個方面，提供選自式〗、IA或IB化合物及其藥學上可接受的衍生物之至少一種化學實體供在人類或獸醫醫療中使用。 ' 本發明化合物是半胱胺酸蛋白酶抑制劑，例如木瓜蛋白酶總科之半胱胺酸蛋白酶之抑制劑，例如鐮形木瓜蛋白酶科，包括鐮形木瓜蛋白酶-2或鐮形木瓜蛋白酶-3。本發明化合物也是木瓜蛋白酶總科例如組織蛋白酶科例如組織蛋白酶=、L、S及B中的半胱胺酸蛋白酶之抑制劑。月化合物可以用於治療其中涉及半胱胺酸蛋白酶包括最毒造顏疾的寄生蟲惡性瘧原蟲及間日癔以及'疼彳氏肺展蟲、克氏錐蟲、布氏錐蟲及短膜蟲感染，炉入:骑例如裂體吸蟲病、瘧疾、癌症例如胰臟癌、腫瘤 ..r 瘤轉移、異染性腦白質病、肌肉營養失調症、肌中f性阻塞性肺病（C0PD)、動脈粥樣硬化症；且尤复級織蛋白酶K涉及的病情，包括過度骨質或軟骨 /；，L /、他骨與關節的疾病例如骨質疏鬆症、骨質轉移、 uuka%包括齒齦炎及牙週病）、關節炎（包括骨關節炎及類風濕性關能火、所即火）、PaSet氏症、惡性高鈣血症及代謝性骨、；、；此外，轉移性增殖細胞也通常表達高量的蛋白水 43 200804352 解周圍的基質，且某些腫瘤及轉移性血管生成可這些病物有效地治療。據此，本發明也關於治療在本發明之一個方面，提供選自及其藥學上可接受的衍生物之至少一種化學實^匕1 總科例如鐮米L 別是抑制木瓜蛋白酶鐮化木瓜蛋白酶科中的半耽胺形木瓜蛋白酶-2或鐮形木瓜蛋白酶·3,例如癌疾，。匕括鐮在本發明之另一個方面，提供選自式I工藥學上可接受的衍生物之至少-種化學實體用; 制半胱胺酸蛋白酶仲介的病情，特別是抑制木瓜史白酶總科例如組織蛋白酶科例木The term "pharmaceutically acceptable" as used herein means that the ingredient is compatible with the other ingredients present in the pharmaceutical composition and does not impair its treatment. σ When used herein The term "Ν_酞醯imino" refers to an entrained imine group bonded via an atom. & As used herein, the term "protease," is an enzyme that catalyzes the breakdown of a peptide by a nucleophilic substitution of a guanamine bond, which ultimately leads to hydrolysis. Proteases include cysteine protease, silkamine Acid proteases, aspartic proteases and metalloproteinases. Protease "inhibitors, which bind more strongly to the enzyme than the substrate and do not decompose after being catalyzed by the nucleophile. It therefore contends to prevent proteases from being recognized and hydrolyzed by natural agents and thus as inhibitors. In one aspect of the invention, there is provided at least one chemical entity selected from the group consisting of: N'-(5-bromo-2-cyano-4-pyrimidinyl)_4_[(4-methylhexahydropyridinyl) Methyl]-N'-(2-mercaptopropyl)phenylhydrazine; 32 200804352 N'- (5->Smell-2_gas base_4-^密σ定基)-N'- (2 -mercaptopropyl)-4-[(4-propyl-1-hexahydropyrryl)indenyl]phenylhydrazine; N'-(5-bromo-2-cyano-4-pyrimidinyl) -N'-(2-mercaptopropyl)-3-[(4-propyl-1-hexahydropyrryl)indenyl]phenylhydrazine; Ν'- (5-gas-2 - chaotic - 4-17密17定基)-N'-(2_mercaptopropyl)-4-[(4-propyl-1_hexahydropyrryl)indenyl]phenylhydrazine; N'-( 5-Gas-2-cyano-4-pyrimidinyl)-N'-(2-methylpropyl)-3-[(4-propyl-1-hexahydropyrryl)methyl]phenylhydrazine '; N'- (5-> odor-2 - gas-based 4-mouth dense sigma)-4-gas-N'-(2.methylpropyl)-3_[(4-propyl-1 -hexahydropyrrole)methyl]benzamide; N'-(5-chloro-2-cyano-4-pyrimidinyl)-4.fluoro-N'-(2-methylpropyl)- 3-[(4-propyl-1-hexahydropyrryl)methyl]phenylhydrazine; 4-(1,4'-bihexahydropyridine-1'-ylindenyl) as '-(5) -chloro-2-cyano 4-pyrimidinyl)-N'-(2-methylpropyl)phenylhydrazine; N'-(5->Smell-2-murine-4_^σ定基)-N'-(2 - Mercaptopropyl)-4-(1-hexamethylpyrrolidyl) methyl benzoquinone; Ν'-(5-bromo-2-cyano-4-pyrimidinyl)-Ν'-(2- Mercaptopropyl)-4-(1-pyrrolidinyl)phenylhydrazine; N'-(5-chloro-2-cyano-4-pyrimidinyl)-4-[(2,6-di Mercapto-1-hexahydropyridyl) fluorenyl]-N'-(2-mercaptopropyl)phenylhydrazine; 1 -[(4-{[2-(5-chloro-2-cyano)- 4-pyrimidinyl)-2-(2-mercaptopropyl) sulphate]carbonyl]phenyl)indolyl>4-hexahydropyridinecarboxylate; N-{(3R)-l-[( 4-{[2-(5-Gas-2-cyano-4-pyrimidinyl)-2-(2-mercaptopropyl) cultivating base] Prison base} Phenyl) fluorenyl]-3 - ϋ ratio 17 σ定基}Acetamine, 33 200804352 {1-[(4-{[2-(5-Chloro-2-cyano-4-pyrimidinyl)-2-(2-methylpropyl)indolyl) N-(5-Gas-2-cyano-4-pyrimidinyl)-4-, phenyl)methyl]-3-batchyl}amino carboxylic acid 1,1-dimethylacetate [(4-{2-[(2-hydroxyethyl)oxy]ethyl} hexahydropyranyl)methyl]-N,-(2-methylpropyl)benzhydrazide; N' -(5_gas_2_cyano-pyrimidinyl)·ν'_(2_methyl Base) 4_(丨_hexahydropyridylmethyl)benzimid; Ν'-(5-Gas-2-cyano pralinyl) winter {[(2R)-2-(hydroxymethyl) small疋各 ] ]] methyl Ν Ν '_ (2 · methyl propyl) benzamidine; Ν '- (5-Gas-2-cyano-4-pyrimidinyl) -methylpropyl)-4-(1-pyrrolidinyl)benzamide; N'-(5-gas: cyano-4-pyrimidinyl)-4_(2,5-dihydro-1H -pyrrolidylmethyl)-N'-(2-methylpropyl)benzazole; ^-(5-Gas-2-cyano-4-pyrimidinyl)_4-[(2,5-di Mercapto-2,5-dihydro-11(2-pyridin-1-yl)indolyl]methylpropyl)benzamide; {1-[(4"[2-(5-chloro)_4 _Pyrimidinyl)_2_(2-mercaptopropyl)indolyl]carbonyl}phenyl)methyl]-4-hexahydropyridinyl}aminoguanidine ι,ι_dimethylethyl ester; N'-( 5-gas cyano-4-pyrimidinyl)-4-({4-[3-(dimethylamino)propyl] hexahydrohydroquinone] methyl)_N,-(2-methylpropyl Benzoquinone; N'_(5-Gas-2-cyano pralinyl)>Ν,_(2_mercaptopropyl)_4_({4_[3-(')) ]_1_hexahydropyridinyl}mercapto)phenylhydrazine trifluoroacetate; hydrazine, (54_2-cyano-4-pyrimidinyl)_4_({4_[3-(diethylamino) Propyl] small hexahydroindole} methyl) Ν, -(2-mercaptopropyl) benzamidine; Ν'-(5·gas 1 cyano-4-pyrimidinyl)_4-({4 -[3-(dipropylamino)propyl] hexahydroindolein} fluorenyl)-]^(2_mercaptopropyl)phenylhydrazine; 34 200804352 N, (5-gas_2_cyanide Base_4_pyrimidinyl)_4-({4_[3仁冬丙妇_基基基基)propyl>1-hexahydropyrryl}methyl)_N,-(2_f-propyl)benzamide N-(5-Gas-2-cyano-4-pyrimidinyl)_4_({4_[(1_methyl-4_hexahydropyridyl)indolyl]-1-hexahydropyrrole} Methylmethylpropyl)phenylhydrazine; N-(5-gas_2-cyano-4-pyrimidinyl)_4-{[4_(didecyl-4_hexahydropyridyl)-1-hexahydropyridyl Plough base] 曱基卜 N, _(2_methylpropyl) benzamidine; {l-[(M[2-(5-gas_2_cyano_4_pyrimidinyl))_2_(2_ Methylpropyl)indenyl]carbonyl}phenyl)methyl>3-hexahydropyridinyl}ethyl acetate; N'-(5-Gas-2-cyano-4-pyrimidinyl)-4-( {4-[2-(Diethylamino)ethyl]-1-hexahydropyranyl}methyl)_N'-(2-mercaptopropyl)phenylhydrazine; N'-(5-gas -2-cyano-4-pyrimidinyl-4-({4-[2-(di-2-propanyl)amino}>1-hexahydropyridinyl}indenyl)-N -(2-mercaptopropyl)phenylhydrazine; 1^'_(5-gas_2-cyano-4-pyrimidinyl)-4-({4-[2-(dipropylamino)ethyl) Small hexahydroindole cultivating base}methyl)-N'-mercaptopropyl)phenylhydrazine; N'-(5-Gas-2-cyano-4-pyrimidinyl)-3-[( 2,6-dimercaptosuccinylpyridinyl)f-yl]-N'-(2-mercaptopropyl)benzhydrazide; 3-(1,4'-biphenylpyridin-1'-yl Methyl>, _(5_gas_2-cyano-4_pyrimidinyl)-N'-(2-mercaptopropyl)benzoate; N'-(5-gas-2-cyano 4-pyrimidinyl)-N,-(2-mercaptopropyl)-3-(1-hexahydropyridinyl) alum; N'-(5U-cyano-4-pyrimidinyl) -3-({4-[3-(dipropylamino)propyl]-1-hexahydro 17-rhesteryl} fluorenyl)-N'-(2-mercaptopropyl)phenylhydrazine; '-(5-Gas-2-cyano-4-pyrimidinyl)-3-({4-[3-(diethylamino)propyl]-1-hexahydropyranyl}indenyl)-N ,-(2-mercaptopropyl)phenylhydrazine; 35 200804352 N'-(5-Gas-2-cyano-4-pyrimidinyl)-4-[(4-hydroxy-indole_hexahydropyridyl) ) fluorenyl]-Ν'-(2-mercaptopropyl)phenylhydrazine; Ν'-(5-Gas-2-cyano-4-pyrimidinyl)-4-{[4-(2-hydroxyl) Ethyl hexahydropyridinyl] hydrazinium -'-(2 -mercaptopropyl)phenylhydrazine; Ν'-(5 gastric chloro-2-cyano-4-pyrimidinyl)-4-{[4-(2-hydroxyethyl)hexahydropyranyl]曱Ν'-(2-mercaptopropyl)benzimid; Ν'-(5-chloro-2-cyano-4-pyrimidinyl)-4-{[4-(hydroxyindenyl)-丨_ hexahydropyridyl] fluorenyl}- Ν '-(2-mercaptopropyl) phenylhydrazine; ^[(^{[2-(5-Gas-2-cyano-4-pyrimidinyl)- 2-(2-mercaptopropyl)indenyl]carbonyl}phenyl)indenyl]-N,N-dimethylindodecylamine; 4-(N-azetidinylmethyl)-N'-(5 -Bromo-2-cyano-4-pyrimidinyl)-N,-(2-methylpropyl)phenylhydrazine; N'-(H2-cyano+pyrimidinyl)_N,_(2-methyl Propyl)-r-pyridylcarbonyl)-1-pyrrolidinyl]methyl}phenylhydrazine; cyanocyano-4-pyrimidinyl)-N'-(2-mercaptopropyl)-4- {[4-(4-Isofolin)-1-pyrrolidinyl]methyl}phenylhydrazine; N'-(5-chloro-2-cyano-4-pyrimidinyl)-N'- (2-mercaptopropyl)-4-({4-[2-(1-hexahydroacridinyl)ethyl]-1-hexahydropyranyl}methyl)phenylhydrazine; N'- (5-chloro-2-cyano-4-pyrimidinyl)-4-({4-[(1-indolyl-3-hexahydropyridinyl)methyl> 1-hexahydropyranyl} fluorenyl )-N,-(2-mercaptopropyl) Benzoquinone; N'-(5-Gas-2-cyano-4-pyrimidinyl)_N'-(2-mercaptopropyl)-4-({4-[3-(1-hexahydropyridine) Propyl]-1-hexahydropyranyl}indenyl)phenylhydrazine; gas-2-cyano-4-pyrimidinyl)-4-{[4-(diethylamino)-1- Hexahydropyridyl] fluorenyl}-N'-(2-mercaptopropyl) benzoate; 36 200804352 N'-(5-Gas-2-cyano-4-pyrimidinyl)-4-{[ 4-(4-indolyl hexahydropyridinyl)-1 - /, murmuryl]methyl} -Ν' -(2-methylpropyl)benzoquinone; Ν'-( 5-oxo-2-cyano-4-pyrimidinyl)-indole,-(2-methylpropyl)-4-{[4-(4-pyridyl)-1-hexahydropyrryl] fluorenyl Phenylhydrazine; 叩_(5_gastocyanato_4_pyrimidinyl)_N,_(2_methylpropyl)_4_({4_[2_(byrrolidinyl)ethyl]-1_ Hexahydropyranyl}indenyl)benzidine; N'-(5-gas-2-cyano-4, dimethyl)-4-({4-[2-(dimethylamino)) ]]Small hexahydropyranyl}methyl)-N'-(2-methylpropyl)benzamide; '-(5-Gas-2-cyano-4-pyrimidinyl)-:^ '_(2-Mercaptopropyl)-3-(1'pyrrolidyl)-benzamide; N'-(5-Gas-2-cyano-4-pyrimidinyl)-N'- (2-mercaptopropyl)-3-{[4-(4-? :)-1-hexahydropyridyl]methyl}benzamide; Ν'-(5-Gas-2-cyano-4-pyrimidinyl)_3-{[4-(2-hydroxyethyl) small Hexahydropyrryl] 曱 Ν Ν '-(2_methylpropyl)phenylhydrazine; Ν'-(5-Gas-2-cyano-4-pyrimidinyl) Winter {[4-(hydroxyl曱-)(5-mercapto-4-pyrimidinyl)-Ν' -(2-mercaptopropyl)-3-({4-[3-(1_hexahydroindolyl)propyl]-1 -hexahydrou-pyrene) Ν'-(5-Gas-2-cyano-4-pyrimidinyl)-3-{[4-(4.mercapto-1-hexahydropyrrole hexahydropyridyl)indolyl}-oxime,- (2-methylpropyl)phenylhydrazine; Ν'-(5-Gas-2-cyano-4-pyrimidinyl)-3-{[4-(diethylamino)-1-hexahydropyridine N-(2-chloro-2-cyano-4-pyrimidinyl)-3-({4-[2-( Diethylamino)ethyl]sodium hexahydropyranyl}indenyl)-N,-(2-mercaptopropyl)phenylhydrazine; 37 200804352 N'-(5-Gas-2-Gasyl- 4_ 口密基基)-3-{[4-(l-曱基-4-六鼠口比咬基六氢丙耕基]methyl}-N'-(2-mercaptopropyl)phenylhydrazine '; N'-(5-gas-2-cyanide 4-pyrimidinyl)-N'-(2-methylpropyl)-3-({4-[3-(4-?-fulinyl)propyl]-1-hexahydro 1:7 ratio σ Well base} 曱 base) Benzene brewing; Ν '- (5-gas-2 - gas base -4-.密Ν)-Ν'-(2-methylpropyl)-3-({4-[2_(1-indolyl)ethyl]-1-hexahydropyranyl}indenyl)benzamide N'-(5-Gas-2-cyano-4-pyrimidinyl)-3-({4-[(1-indolyl-4-hexahydropyridyl)methyl]-1-hexahydro) Pyridinyl}fluorenyl)-hydrazine, -(2-mercaptopropyl)phenylhydrazine; Ν'-(5-Gas-2-cyano-4-pyrimidinyl)-Ν'-(2-A Propyl)-3-({4-[2-(1-hexahydropyridinyl)ethyl]-1-hexahydropyrrole}indenyl)phenylhydrazine; Ν'-(5-gas_ 2-(cyano-4-pyrimidinyl)-4-fluoro-indole,-(2-mercaptopropyl)_3-{[4-(4-isfoyl)-1-hexahydropyridinyl]fluorenyl Phenylhydrazine; N'*"(5-gas-2-cyano-4-pyrimidinyl)4-fluoro-3-{[4-(hydroxyindenyl) hexahydroacridinyl]A Benzene N'-O-mercaptopropyl) phenylhydrazine; 3_(1,4, hexahydropyridin-1,-ylhydrazino) hydrazine, _(5-chloro-2-cyano-4-pyrimidine) M-fluoro-N,-(2-methylpropyl)phenylhydrazine; N'-(5-Gas-2-cyano-4-pyrimidinyl)-4-fluoro-3-[(4- Methyl]-N'-(2-mercaptopropyl)phenylhydrazine; N,(5-bromo-2-cyano-4-pyrimidinyl)-4 -{[4-(4-mercapto-1-hexahydropyridinyl VI-hexahydropyridyl) Nb-(2-methylpropyl)phenylhydrazine; N-(5-bromo-2-cyano-4-pyrimidinyl)-5-[(4-methyl-1-hexahydropyrrole Bauxite] N (2_mercaptopropyl)_3_iso-salt carb〇hydrazide; N'#-漠_2_cyano_4_pyrimidinyl)_H(4-methylhexahydro) Pyridinyl) mercapto group >Ν'-(2-mercaptopropyl)_丨-benzofuran_2_carbazide; 38 200804352 N'-(5-bromo-2-cyano-4-pyrimidinyl) )_5_[(4_methylhexafluoropyridyl)methyl]-N'-(2-methylpropyl>2-furancarbazide' methylbenzenesulfonate; N'-(5-bromo) -2-cyano-4-pyrimidinyl-6-{3-[(4-methylhexafluoropyranyl)indolyl]phenyl}-N'-(2-methylpropyl>3-pyridyl ϋ定卡巴肼; Ν '-(5-Bromo-2-cyano-4-pyrimidinyl)>6_{4-[(4-methylhexahydropyrrolidinyl)methyl]phenyl bene N'_( 2-indolyl)·3′′ pyridine carbazone; Ν'·(5-bromo-2-cyano-4-indanyl)>5_{4_[(4-methylhexahydropyrryl) Methyl]phenyl}-Ν'_(2-methylpropyl)_3" is a bit of kappa; Ν'-(5-bromo-2-cyano-4-pyrimidinyl)_5_{3-[(4 -methyl-1-hexahydropyrrole) fluorenyl]phenyl}-Ν'_(2-mercaptopropyl)_3-σ ratio bite kaba 胼; Ν -(5-Irid-2-cyano-4-pyrimidinyl)_5-[(4-indolyl hexahydropyranyl)methyl]_Ν'-(2-mercaptopropyl)-1-benzo吱 _2_2_carbazide; N'-(5-bromo-2-cyano-4-pyrimidinyl)-5-[(4-methyl-1-hexafluoropyridyl)methyl]-N '-(2-Mercaptopropyl)-2-nonphene carbazone; and pharmaceutically acceptable derivatives thereof. As used herein, the term "pharmaceutically acceptable derivative," refers to any pharmaceutically acceptable salt, solvate or prodrug of a compound of Formula I, IA or IB, such as an ester or an amine decanoate, for administration thereof. Upon treatment with a subject, a compound of formula I, IA or IB, or an active metabolite or residue thereof, may be provided (directly or indirectly). This derivative is known to those skilled in the art without prior experimentation. However, reference is made to Burger's. Medicinal Chemistry and Drug Discovery, 5th Edition, Vol 1: Principles and Practice, the disclosure of which is hereby incorporated by reference in its entirety in its entirety in its entirety in its entirety in the the the the the the , solvates, esters and urethanes 39 200804352. In another aspect of the invention, the pharmaceutically acceptable derivatives are salts, solvates and esters. In yet another aspect, the pharmaceutically acceptable Accepted derivatives are salts and solvates. The compounds of the invention may be administered in free form and/or as a pharmaceutically acceptable salt. In fact, some of the present invention In the embodiments, the pharmaceutically acceptable salts of the compounds according to formula I, IA or IB may be preferred over the respective base or free acids, since these salts have greater stability or solubility than the molecules and thus facilitate modulation into administration. The invention accordingly also relates to a pharmaceutically acceptable salt of a compound according to formula I, IA or IB. As used herein, the term "pharmaceutically acceptable salt" means retaining the desired biological activity of each compound and Salts exhibiting minimal toxic effects. For a review of suitable salts, see Berge et al, J. Pharm. Sci., 1977, 66, 1-19. The term "pharmaceutically acceptable salts" includes pharmaceutically acceptable Acid addition salts and pharmaceutically acceptable addition salts. These pharmaceutically acceptable salts can be prepared in situ during the final isolation and purification of the compound, or in the free state or free state of the purified compound. The form of the base is additionally separately reacted with a suitable base or acid. The salt can be precipitated from the solution and recovered by filtration, collection or by evaporation of the solvent. The pharmaceutically acceptable acid addition salt can be passed through I, IA or IB compound with a suitable inorganic or organic acid (eg hydrobromic acid, hydrochloric acid, sulfuric acid, aminosulfonic acid, nitric acid, phosphoric acid, succinic acid, maleic acid, hydroxymaleic acid, acrylic acid, citric acid) , acetic acid, hydroxyacetic acid, phenylacetic acid, butyric acid, isobutyric acid, propionic acid, fumaric acid, citric acid, tartaric acid, lactic acid, mandelic acid, benzoic acid, o-ethoxylated phthalic acid, chlorobenzene Formic acid, methyl benzoic acid, dinitrophenyl hydrazine 40 200804352 acid, hydroxybenzoic acid, decyloxybenzoic acid, salicylic acid, glutamic acid, stearic acid, ascorbic acid, palmitic acid, oleic acid, pyruvic acid , bamoic acid, malonic acid, lauric acid, glutaric acid, aspartic acid, p-toluenesulfonic acid, benzenesulfonic acid, sulfonic acid, ethanesulfonic acid, 2-hydroxyethanesulfonic acid, naphthalenesulfonic acid (for example, 2-naphthalenesulfonic acid), p-aminobenzenesulfonic acid (also known as sulfamic acid), hexanoic acid, heptanoic acid or decanoic acid, if necessary, reacted in a suitable solvent such as an organic solvent to obtain a salt. It is usually separated by, for example, crystallization and filtration. The pharmaceutically acceptable acid addition salts of the compounds of formula (I) may include or be, for example, bromates, hydrochlorides, iodates, sulfates, hydrogen sulfates, nitrates, phosphates, hydrogen phosphates, amber Acid salt, maleate, malate, formate, acetate, trifluoroacetate, sugar, propionate, fumarate, citrate, tartrate, lactate, benzoic acid Salt, salicylate, glutamate, aspartate, p-toluenesulfonate, besylate, sulfonate, ethanesulfonate, naphthalenesulfonate (eg 2-naphthalene) Rhammamate), fluorite, acenaphine, p-nonylbenzene acid, hydroxyethyl citrate or hexanoate. In a specific embodiment, a trifluoroacetate salt of a compound of the invention is provided. In another embodiment, a hydrochloride salt of a compound of the invention is provided. A pharmaceutically acceptable base addition salt can be via a compound of formula I, IA or IB with a suitable inorganic or organic base (for example ammonia, triethylamine, ethanolamine, triethanolamine, choline, arginine, lysine or tissue) The amine acid) is prepared by reacting in a suitable solvent such as an organic solvent, and the obtained base addition salt is usually isolated by, for example, crystallization and filtration. The pharmaceutically acceptable base salts include ammonium salts and salts with organic bases, including salts of primary, secondary and tertiary amines, including aliphatic amines, aromatic amines, aliphatic diamines and hydroxyalkylamines, For example, decylamine, 41 200804352 ethylamine, isopropylamine, diethylamine, ethylenediamine, ethanolamine, tridecylamine, dicyclohexylamine, diethanolamine, cyclohexylamine, and N-mercapto-D-glucosamine. Other suitable pharmaceutically acceptable salts include pharmaceutically acceptable metal salts such as pharmaceutically acceptable metal or soil metal salts such as sodium, potassium, lanthanum, magnesium, aluminum and zinc hydroxides. a carbonate and cesium carbonate salt; in particular a pharmaceutically acceptable metal salt of one or more carboxylic acid groups present in the compound of formula I, IA or IB. Other non-pharmaceutically acceptable salts, such as oxalates, can be used, for example, to isolate the compounds of the present invention. The invention includes within its scope salts of all possible stoichiometric and non-stoichiometric forms of the compounds of formula I, IA or IB. As used herein, the term "compound of the invention" refers to a compound according to formula I, IA or IB, and pharmaceutically acceptable derivatives thereof. The term "a compound of the invention" means any one of the compounds of the invention according to the above definition. As used herein, the term "at least one chemical entity" refers to at least one chemical selected from the group consisting of compounds of Formula I, IA or IB and pharmaceutically acceptable derivatives thereof. The compounds of the invention may be present as a solid or a liquid, both of which are included in the present invention. In the solid state, the compound of the present invention may be present as an amorphous substance or a crystalline form or a mixture thereof. It is of course possible to form solvates of the compounds of the invention in which the solvent molecules are incorporated into the crystal lattice during crystallization. The solvate may be in a non-aqueous solvent such as ethanol, isopropanol, DMSO, acetic acid, ethanolamine, and ethyl acetate, or it may involve water as a solvent and blended into the crystal lattice. Solvates in which water is a solvent and incorporated into the crystal lattice are commonly referred to as hydrates. The invention includes all such solvates. It is also understood that all crystalline forms, polymorphs, geometric shopping, stereoscopic shopping (including palmar isomers and non-palphasomers) and inter-isomers or mixtures thereof are included in the present invention. Within the scope of the invention. According to another aspect of the invention, at least one chemical entity selected from the group consisting of a compound of formula, IA or IB and a pharmaceutically acceptable derivative thereof is provided for use in human or veterinary medicine. The compound of the present invention is a cysteine protease inhibitor such as an inhibitor of a cysteine protease of the papain superfamily, such as the scorpion papaya proteinase family, including scorpion papain-2 or scorpion papain-3. The compounds of the present invention are also inhibitors of the cysteine proteases in the papain superfamily such as the cathepsin family such as cathepsins =, L, S and B. The monthly compound can be used to treat parasites of Plasmodium falciparum and S. cerevisiae, which are involved in the most toxic inflammatory diseases, as well as 'L. sinensis, Trypanosoma cruzi, Trypanosoma brucei and short Membrane infection, ingestion: riding such as schistosomiasis, malaria, cancer such as pancreatic cancer, tumor.. tumor metastasis, metachromatic leukoencephalopathy, muscular dystrophy, intramuscular f-obstructive pulmonary disease ( C0PD), atherosclerosis; and especially the condition of complex proteinase K, including excessive bone or cartilage/;, L /, his bone and joint diseases such as osteoporosis, bone metastasis, uuka% including gingivitis And periodontal disease), arthritis (including osteoarthritis and rheumatoid arthritis, fire), PaSet's disease, malignant hypercalcemia and metabolic bone,;,; A high amount of protein water 43 200804352 is usually expressed to resolve the surrounding matrix, and certain tumors and metastatic angiogenesis can be effectively treated by these diseases. Accordingly, the present invention also relates to the treatment of at least one chemical moiety selected from the group consisting of pharmaceutically acceptable derivatives thereof, such as glutinous rice L, which inhibits papain degraded papain. A half-melamine-like papain-2 or a scorpion papain-3, such as a cancerous disease. In another aspect of the invention, there is provided at least one chemical entity selected from the group consisting of a pharmaceutically acceptable derivative of formula I; a condition for the production of a cysteine protease, in particular a total inhibition of papain For example, the cathepsin family

及Β中的半胱胺酸蛋白酶，i)在一個且體 L、S =2;，如特徵是過度骨質流失的病情例如骨質:ί π)在^貝/私，及其他骨與關節的疾病例如骨關節炎，戍 :)在另-個具體實施例中，組織蛋白酶L或S，例:騰臟在本發明之另一個方面，提供選物及其藥學切接受的衍生物之至少二化ΐ 包括嫌形木瓜一或嫌形=: 在本發明之另一個方面，提供選自式I、1八或扭化合 44 200804352 物及其藥學上可接受的衍生物之藥劑供治療藉由抑制半胱胺酸蛋白，匕孥實體，製造特別是抑制木瓜蛋白酶總科例如情之用途，白酶K、L、S及B中的半胱胺酸蛋=白t例如組織蛋例如骨質疏鬆症及骨質轉移，質流失的病情 S，例如胰臟癌。 1 ，組織蛋白酶L·或在本發明之另一個方面，提供罹蛋白酶仲介的病情之人類或動物二/卩制半胱胺酸抑制木瓜蛋白酶總科例如鐮形木。特= 蛋白酶，包括鐮形木瓜蛋白酶_2或鐮形太胱月女酸如癔疾，該方法包括用藥有效量的選'1^白酶_3,例物及其藥學上可接受的衍生物之至少= 卜種化學實體的醫藥組成物予上了接㈣衍生物之至在本發明之另-財面，提供罹患藉由蛋白酶仲介的病情之人類或動物患者之治療方& ，制木瓜蛋白酶總科例如組織蛋白酶科例如組織蛋白酶疋 :、L :及B中的半脱胺酸蛋白酶，〇在—個具體實施例組織蛋白酶K，例如特徵是過度骨質流失的病情例如二貝疏鬆症及骨質轉移’及其他骨與關節的疾病例如骨關即炎，或u)在另-個具體實施例中，組織蛋白酶例如胰臟癌，該方法包括用藥有效量的選自式j ia 45 200804352 化合物及其藥學上可接受的衍生物之至少一種化學實體或含有選自式I、IA或IB化合物及其藥學上可接受的衍生物之至少一種化學實體的醫藥組成物。本發明化合物是半胱胺酸蛋白酶抑制劑且可以用於治療藉由抑制半胱胺酸蛋白酶仲介的病情，特別是抑制木瓜蛋白酶總科例如鐮形木瓜蛋白酶科中的半胱胺酸蛋白酶，包括錄形木瓜蛋白酶-2或錄形木瓜蛋白酶-3，例如癔疾之治療，或彼等組織蛋白酶科例如組織蛋白酶K、L、S及B， i)在一個具體實施例中，組織蛋白酶K，例如特徵是過度骨質流失的病情例如骨質疏鬆症及骨質轉移，及其他骨與關節的疾病例如骨關節炎，或ii)在另一個具體實施例中，組織蛋白酶L或S，例如胰臟癌。據此，本發明還關於含有選自式I、IA或IB化合物及其藥學上可接受的衍生物之至少一種化學實體的醫藥組成物。在本文中使用時，“過度骨質流失”是一種疾病狀態，其中骨質再吸收與形成之間的正常平衡被破壞，且骨質在各循環中有淨流失。過度骨質流失特徵之疾病包括但不限於骨質疏鬆症及齒齦疾病，過度軟骨或基質分解包括骨關節炎及類風濕性關節炎。本發明之治療方法包括將安全且有效量的選自式I、IA 或IB化合物及其藥學上可接受的衍生物之至少一種化學實體，或含有選自式I、IA或IB化合物及其藥學上可接受的衍生物之至少一種化學實體的醫藥組成物用藥至對其有需要的患者。 46 200804352 沾乂本文中使用時，“治療”包括：⑴改善或預防被治療的病t月或被治療的病情之一或多種生物現象，⑺干預⑷導致或與被治療的病情有關的生物級聯中的一或多點或(b) :广棒f的病^之—或多種生物現象，或（3)減輕與被治療的嘀，，月目曰關的一或多個症狀或效應。從事此藝者將了解“預 ^綠不f —個二絕對名詞。在藥學中，“預防，，係指預防性用藥樂別以貫質上消除病情或其生物現象的可能性或嚴重又，或延遲發生此病情或其生物現象。 r 2本文中使用時，“安全且有效的量’，係指在醫學評量的 “低可==觸引發正面改善被治療的情形但旦=了以防止嚴重副作用（在合理的效益/風險比例）的用筚、二-、疋於化合物之效力、效應及半衰期）；選擇的二療:r，重病情如之殿與麻由、體#貝、重夏及身體情形；被治療的患者 ::[史；治療的期間；同時醫療之本質；所要的醫療效應專因素而改變’但是從事此藝者可以例行地決定，文中使用時’“患者”係指人類或其他動物。身性用rr匕合物可以經由合適的用藥途徑用藥，包括全道用==部用藥。全身性用藥包括口服用藥、不經腸用荦伟扑=1 樂、直腸用藥及經由吸入用藥。不經腸道由:=2^不是食入、經皮或經由吸入，且通常經射或雇輸。不經腸道用華#拓注射或灌卜m 内、肌肉内及皮下 4輸及入係指用藥至患者的肺不論是經由嘴或經 47 200804352 藥局部用藥包括—内、眼本發明化合物可以一次用藥或根據給藥攝生法其中多個，量是在給定的時間内在不同的時間間隔下用藥^例二，背J畺可以母天用藥一、一、二或四次。劑量可以用藥直到 $成所要的醫療效應或不明確地保持所要的醫療效應。本發明化合物之合適的給藥攝生法決定於該化合物之藥物動力學性質，例如吸收、分布及半衰期，期可經由從事此蓺者決定。此外，本發明化合物之合適的給藥攝生法，包二 =藥，攝生法之期間，決定於被治療的病情、被治療的病 =之嚴重性、被治療的患者之年齡及健康狀況、被治療的 :者=醫療歷史、同時醫療的本質、所要的醫療效應等因 r =些都是在從事此藝者之知識及專業範圍内。從事此可了解合適的給藥攝生法可能需要根據個別患者對、七条攝生法的回應而調整或個別患者隨著時間需要改變。典型的每日劑量可根據選擇的特定用二：用藥之典型的每日劑量範圍是從_至約25;克/ 么斤，在一個具體實施例中，從約〇.1至約14毫克/公斤。 ^腸道用藥之典型的每日劑量範圍是從約0厕至約10 =/公斤’在一個具體實施例中，從約請至約6毫克/ 可；料療劑使用。 , 個方面獒供含有式I、ΙΑ或IB化合物或二=上可接受的衍生物以及其他醫療劑之組合。當式！、或1B化合物或其藥學上可接受的衍生物是與第二種醫 48 200804352 療劑結合使用，活性對抗相同的疾病狀態時，各化合物之劑量可以異於當該化合物是單獨使用時之劑量。從事此藝者可以很容易了解合適的劑量。當然本發明化合物用於治療所需的量將隨著被治療的病情及患者之年齡及病情而改變，且最後將由參與的醫生或獸醫決定。本發明化合物可以單獨或結合一或多種其他活性劑使用，例如半胱胺酸及絲胺酸蛋白酶之其他抑制劑、抗瘧疾藥劑或治療過度骨質流失的藥劑。此其他活性藥劑包括骨質再吸收或其他骨疾病之抑制劑，例如雙磷酸鹽類（也就是阿蘭多鹽（allendronate)、瑞司多鹽（risedronate)、伊地多鹽（etidronate)及伊巴多鹽 (ibandronate))、荷爾蒙替代醫療、抗***、降鈣素及同化劑例如骨質形態生成蛋白質、伊普隆(iproflavone)及 PTH。或者是，此其他活性劑包括抗瘧疾劑例如葉酸鹽（例如氯奎、美奎(mefloquine)、伯氨奎、乙氨嘧啶、奎寧苦艾素、哈咯芬(halofantrine)、脫氧土黴素、阿莫奎、阿脫奎 (atovaquine)、達芬奎（tafenoquine))及抗葉酸鹽（例如氨苯石風、氯脈、周效磺胺、乙氨嘧啶、氯環寧⑽丨⑽⑽叩仙他）、玉衣丁（cycloguanil))或求又囷劑例如阿口各徽素（aZithr〇mycin)、脫氧土彳放素、西普洛黴素（Cipr〇£|〇xacin)及氣林可黴素。在另一個替代中，此其他活性劑包括抗癌劑。上述組合可以方便地在醫藥調製物之形式存在供使用，且因此含有上述定義的組合與藥學上可接受的載劑或賦形劑之醫藥調製物構成本發明之另一個方面。此組合之 49 200804352 個別成份可以經由方便的途徑在分開或結合的醫藥調製物中依序或同時用藥。當依序用藥時，可以先用藥本發明化合物或第二種醫療劑。當同時用藥時，該組合可以在相同或不同醫藥組成物中用藥。當結合在相同的調製物時，兩種化合物必須是安定且彼此及與調製物之其他成份相容。當分開調製時，其可以在任何方便的調製物中提供，此方便的方法為此化合物在此項技藝中已知。組成物本發明化合物在用藥至患者前，通常但非必要調製成醫藥組成物。在一個方面，本發明是關於含有本發明化合物之醫藥組成物。在另一個方面，本發明是關於含有本發明化合物及要學上可接受的載劑及/或賦形劑之醫藥組成物。該載劑及/或賦形劑在與調製物其他成份之相容性及不會傷害受治療者之項目必須是“可接受’’。本發明之醫藥組成物可以製備及包裝成大體積形式，其中安全且有效量的本發明化合物可以取出且隨後提供給病患例如以粉劑或漿劑。或者是，本發明之醫藥組成物可以製備及包裝成單元給藥形式，其中各物理上分開的單元含有安全且有效量的本發明化合物。當製備成單元給藥形式時，本發明之醫藥組成物通常含有從約0.5毫克至約1750 毫克，例如從約5毫克至約1000毫克用於口服給藥形式及從約0.05毫克至約700毫克例如從約0.5毫克至約500毫克用於不經腸道給藥形式。 50 200804352 s 組成物通常含有—種本發明化合物。作疋，卜ir二施例中，本發明之醫藥組成物含有一種醫藥組成物可以視需要二=:。此外，本發明之 .^ 受3有一或多種其他藥學活性化八醫藥組成物含有，藥學上可接中’本發明之藥使用本文中使用％’名同“樂學上可接受的’’係指合適供醫常是二受^ 式。例如^开Λ Λ 合適用藥至患者之給藥形膠嚢劑拿片市二彼等調適供⑴口服用藥例如片劑、溶液、懸浮液、皮貼劑；⑷直腸用鐘⑴ ^，（3)經皮用藥例如經液;及⑹局部噴劑、泡沫劑及膠體。、…先以、浴液、糊劑、藥形定於選擇的特定給用於組成物之特定功能:、例如了形::以選擇而受的卿劑，因為其能夠促進：擇一些樂學上可接以選擇一些荜風上可垃、$產一致性的給藥形式。可 — 可接文的職形劑，因為其能夠促進生產 51 200804352 安定的給藥形式。可以選擇一此因為其能進本發明化合物;===形劑， :-個器官或身體的-邹份攜帶或輪送至體的一部份。可以選擇—些藥風方個益官或身其能夠強化病患的順從性': 接㈣賦形劑，因為合適的藥學上可接受的賦形劑包括下類賦、分解劑、潤滑劑、助分散劑、粒化劑、 = 劑、溶劑、輔助溶劑、懸浮劑乳化, 、化 ^ ^ 4、孔化别、甜化劑、調味劑遮味切、h劑、抗結塊劑、保濕劑、螯合劑、塑化劑、雜度增加劑、抗氧化劑、防腐劑、#定劑、表面活性劑及緩衝劑。從事此藝者將了解—些藥學上可接受的賦形劑可作為一個以上的功能且作為替代功能，決定於多少的賦形劑存在於調製物中及何種其他成份存在於調製物中。從事此蟄者具有知識及技能可以選擇適當量合適的藥學上可接受的賦形劑用於本發明。此外，從事此藝者有許多來源其說明藥學上可接受的賦形劑且可以用於選擇合適的藥學上可接受的賦形劑。實例包括Remington’s Pharmaceutical Sciences (Mack Publishing Company), The Handbook of Pharmaceutical Additives (Gower Publishing Limited)及 The Handbook of Pharmaceutical Excipients (the American Pharmaceutical Association and theAnd cysteine proteases in sputum, i) in a body L, S = 2; such as a condition characterized by excessive bone loss such as bone mass: ί π) in the shell / private, and other bone and joint diseases For example, osteoarthritis, 戍:) In another specific embodiment, cathepsin L or S, for example: in another aspect of the invention, provides at least two alternatives to the selection and pharmaceutically acceptable derivatives thereof包括 Included in the form of papaya or suspicion =: In another aspect of the invention, an agent selected from the group consisting of Formula I, VIII or Twisted 44 200804352 and a pharmaceutically acceptable derivative thereof is provided for treatment by inhibiting half The use of cystine protein, anthraquinone, and in particular for the inhibition of papain, for example, cysteine in white enzymes K, L, S and B = white t such as tissue eggs such as osteoporosis and bone Metastasis, a disease that is lost, such as pancreatic cancer. 1. Cathepsin L· or In another aspect of the present invention, a human or animal di- succinylcysteine which provides a chymotrypsin-mediated condition inhibits papain superfamily such as scorpion. Special = protease, including scorpion papain-2 or scorpion serotonin, such as dysentery, the method comprises administering an effective amount of '1^白酶_3, an example thereof and a pharmaceutically acceptable derivative thereof At least = the pharmaceutical composition of the chemical entity is attached to the (four) derivative to the other side of the present invention, providing a treatment for a human or animal patient suffering from a condition of a protease intermediary, papaya Protease superfamilies such as the cathepsin family, for example, cathepsin 疋:, a semi-deaminase protease in L: and B, in a specific example of cathepsin K, for example, a condition characterized by excessive bone loss such as bacon and Bone metastases and other bone and joint diseases such as bone inflammation, or u. In another specific embodiment, a cathepsin such as pancreatic cancer, the method comprising administering an effective amount of a compound selected from the group consisting of formula j ia 45 200804352 And at least one chemical entity of a pharmaceutically acceptable derivative thereof or a pharmaceutical composition comprising at least one chemical entity selected from the group consisting of a compound of Formula I, IA or IB and a pharmaceutically acceptable derivative thereof. The compound of the present invention is a cysteine protease inhibitor and can be used for treating a condition by inhibiting cysteine protease mediated, in particular, inhibiting a cysteine protease in a papain superfamily such as a scorpion papain family, including Recording papain-2 or phage protease-3, such as the treatment of dysentery, or their cathepsin families such as cathepsins K, L, S and B, i) In a particular embodiment, cathepsin K, For example, conditions characterized by excessive bone loss such as osteoporosis and bone metastases, and other bone and joint diseases such as osteoarthritis, or ii) in another specific embodiment, cathepsin L or S, such as pancreatic cancer. Accordingly, the present invention is also directed to a pharmaceutical composition comprising at least one chemical entity selected from the group consisting of a compound of Formula I, IA or IB and a pharmaceutically acceptable derivative thereof. As used herein, "excessive bone loss" is a disease state in which the normal balance between bone resorption and formation is disrupted and bone mass is lost in each cycle. Diseases characterized by excessive bone loss include, but are not limited to, osteoporosis and gum disease, and excessive cartilage or matrix breakdown including osteoarthritis and rheumatoid arthritis. The method of treatment of the present invention comprises a safe and effective amount of at least one chemical entity selected from the group consisting of a compound of Formula I, IA or IB and a pharmaceutically acceptable derivative thereof, or a compound selected from Formula I, IA or IB and a pharmaceutical thereof. A pharmaceutical composition of at least one chemical entity of an acceptable derivative is administered to a patient in need thereof. 46 200804352 As used herein, "treatment" includes: (1) improving or preventing one or more biological phenomena of a disease being treated or a condition being treated, (7) intervention (4) a biological grade that is caused by or associated with the condition being treated. One or more points in the association or (b): a disease of a wide rod f - or a variety of biological phenomena, or (3) alleviating one or more symptoms or effects of the eyelid being treated. Those who are engaged in this art will understand that “pre-green” is not a double noun. In pharmacy, “prevention,” refers to the possibility of preventive use of drugs to eliminate the disease or its biological phenomena. Or delay the occurrence of this condition or its biological phenomenon. r 2 When used in this article, “safe and effective amount” refers to the situation in which the medical evaluation “low can = positively improve the treated condition but to prevent serious side effects (at reasonable benefit/risk) The ratio of the use of bismuth, di-, 疋 to the efficacy, effect and half-life of the compound); the choice of two treatments: r, serious illness such as the temple and hemp, body #贝, heavy summer and physical conditions; treated patients: : [History; the period of treatment; at the same time the nature of medical care; the desired medical effects are changed by special factors', but those who engage in this art can routinely decide that 'patients' refers to humans or other animals when used herein. The body rr complex can be administered via a suitable route of administration, including whole-course == partial use. Systemic medications include oral administration, parenteral use, sputum, sputum, rectal medication, and inhalation. Parenteral By: =2^ Not ingested, percutaneous or via inhalation, and usually delivered or hired. Intestinal use of Huatuo injection or infusion of m, intramuscular and subcutaneous 4 infusion and into the patient's lungs whether through the mouth or through the 47 200804352 topical drug includes - internal, eye compounds of the invention can be One dose or one dose according to the method of administration, the dose is administered at different time intervals in a given time, and the second dose can be administered one, one, two or four times a day. The dose can be administered until the desired medical effect is achieved or the desired medical effect is not clearly maintained. A suitable method of administration of a compound of the invention depends on the pharmacokinetic properties of the compound, such as absorption, distribution, and half-life, as determined by the person skilled in the art. In addition, a suitable method of administration of the compound of the present invention, including a drug, a period of the birth method, is determined by the condition being treated, the severity of the disease being treated, the age and health of the patient being treated, and Therapeutic: the medical history, the nature of the medical treatment, the desired medical effects, etc. are all within the knowledge and professional scope of the artist. In doing so, it can be understood that a suitable dosing regimen may need to be adjusted according to the individual patient's response to seven regimens or individual patients may change over time. Typical daily dosages may vary depending on the particular application selected: the typical daily dosage range for administration is from _ to about 25; gram per gram, in one embodiment from about 〇1 to about 14 mg/ kg. The typical daily dosage range for enteral administration ranges from about 0 toilets to about 10 =/kg' in one particular embodiment, from about to about 6 mg/can; the therapeutic agent is used. In one aspect, a combination comprising a compound of formula I, hydrazine or IB or a derivative of arsenic and other medical agents. When! Or a compound of 1B or a pharmaceutically acceptable derivative thereof, in combination with a second therapeutic agent, 200804352, wherein the activity is against the same disease state, the dose of each compound may be different from the dose when the compound is used alone . It is easy to understand the appropriate dosage for this artist. Of course, the amount of the compound of the invention required for treatment will vary with the condition being treated and the age and condition of the patient, and will ultimately be determined by the participating physician or veterinarian. The compounds of the invention may be used alone or in combination with one or more other active agents, such as other inhibitors of cysteine and serine proteases, anti-malarial agents or agents for the treatment of excessive bone loss. Such other active agents include inhibitors of bone resorption or other bone diseases, such as bisphosphonates (ie, allendronate, risedronate, etidronate, and Ibado). Ibandronate, hormone replacement therapy, antiestrogens, calcitonin and assimilating agents such as bone morphogenetic proteins, iproflavone and PTH. Alternatively, the other active agents include anti-malarial agents such as folate (eg, chloroquine, mefloquine, primaquine, acetaminophen, quinine avidin, halofantrine, deoxynivalus) , Amoquine, atovaquine, tafenoquine, and antifolates (eg, amphetamine, chloride, sulfonamide, acetaminophen, chlorcycline (10) 丨 (10) (10) 叩Xiantan), guanidine (cycloguanil) or 囷囷例如例如例如 a a a a a a a a a a a a a a a a a a a a a a a a a a a a a a a a a a a a a a a a a a a a a a a a a a Cocomycin. In another alternative, the other active agent includes an anticancer agent. The above combinations may conveniently be presented in the form of a pharmaceutical preparation, and thus a pharmaceutical composition comprising a combination as defined above and a pharmaceutically acceptable carrier or excipient constitutes another aspect of the invention. 49 200804352 Individual components can be administered sequentially or simultaneously in separate or combined pharmaceutical preparations via a convenient route. When administered sequentially, the compound of the invention or the second therapeutic agent can be administered first. When administered simultaneously, the combination can be administered in the same or different pharmaceutical compositions. When combined in the same preparation, the two compounds must be stable and compatible with each other and with the other components of the preparation. When separately modulated, it can be provided in any convenient formulation, and this convenient method is known in the art for this compound. Composition The compound of the present invention is usually, but not necessarily, formulated into a pharmaceutical composition prior to administration to a patient. In one aspect, the invention is directed to a pharmaceutical composition comprising a compound of the invention. In another aspect, the invention is directed to a pharmaceutical composition comprising a compound of the invention and a carrier and/or excipient that is to be scientifically acceptable. The carrier and/or excipient must be "acceptable" in compatibility with the other ingredients of the preparation and does not harm the subject. The pharmaceutical compositions of the present invention can be prepared and packaged in bulk form. Wherein a safe and effective amount of a compound of the invention may be removed and subsequently provided to a patient, for example, as a powder or slurry. Alternatively, the pharmaceutical compositions of the invention may be prepared and packaged in unit dosage form, wherein each physically separate The unit contains a safe and effective amount of a compound of the invention. When prepared in a unit dosage form, the pharmaceutical compositions of the invention typically contain from about 0.5 mg to about 1750 mg, for example from about 5 mg to about 1000 mg, for oral administration. The pharmaceutical form is from about 0.05 mg to about 700 mg, for example from about 0.5 mg to about 500 mg, for parenteral administration. 50 200804352 s The composition usually contains a compound of the invention. In one embodiment, the pharmaceutical composition of the present invention contains a pharmaceutical composition which can be optionally used as needed. In addition, the present invention is one of three or more other pharmaceutically active medicinal herbs. Composition contains, can be accessed in a pharmaceutically 'agent used according to the present invention used herein,%' with the name "pharmaceutically music school '' means suitable for receiving two doctors often ^ formula. For example, Λ Λ Λ 合适合适合适至至至患者患者患者患者患者患者患者患者患者患者患者患者患者患者患者患者患者患者患者患者患者患者患者患者患者患者调调调调调调调调调调调调调调调调调调调调调调调调调Transdermal administration such as menstrual fluid; and (6) topical sprays, foaming agents and colloids. First, the bath, the paste, the form of the drug are selected for the specific function of the composition: for example, the shape: the choice of the agent, because it can promote: choose some music It can be selected to select some forms of administration that are hurricane-free and consistent. Yes – an acceptable form of agent because it promotes the production of a stable form of administration. One may choose one because it can enter the compound of the present invention; ===former, :- an organ or body-Zou share carries or transfers to a part of the body. You can choose to have some medicinal remedies or to be able to strengthen the patient's compliance': (4) Excipients, as suitable pharmaceutically acceptable excipients include the following types of decomposers, decomposers, lubricants, Co-dispersant, granulating agent, agent, solvent, auxiliary solvent, emulsification of suspending agent, chemical compound, phlegm, sweetener, flavoring agent, taste mask, h agent, anti-caking agent, moisturizer , chelating agents, plasticizers, increase agents, antioxidants, preservatives, #定剂, surfactants and buffers. Those skilled in the art will appreciate that some pharmaceutically acceptable excipients may function as one or more functions and as an alternative function, depending on how much excipient is present in the preparation and what other ingredients are present in the preparation. Those skilled in the art will have the knowledge and skill to select the appropriate amount of suitable pharmaceutically acceptable excipient for use in the present invention. In addition, there are many sources of pharmaceutically acceptable excipients that can be used to select suitable pharmaceutically acceptable excipients. Examples include Remington's Pharmaceutical Sciences (Mack Publishing Company), The Handbook of Pharmaceutical Additives (Gower Publishing Limited) and The Handbook of Pharmaceutical Excipients (the American Pharmaceutical Association and the

Pgarmaceutical Press) 〇本發明之醫藥組成物是使用從事此藝者已知的技術及方法製備。經常用於此項技藝之部份方法是揭示在 52 200804352Pgarmaceutical Press) The pharmaceutical compositions of the present invention are prepared using techniques and methods known to those skilled in the art. Part of the method often used in this technique is revealed at 52 200804352

Remington’s Pharmaceutical Sciences (Mack Publishing Company) 〇在一個方面，本發明是關於固體或液體口服給藥形式例如液體、片劑、錠劑或膠囊劑，含有安全且有效量的本發明化合物及載劑。該載劑可以是稀釋劑或填充劑之形式。合適的稀釋劑及填充劑通常包括乳糖、蔗糖、葡萄糖、甘露醇、山梨糖醇、澱粉(例如玉米澱粉、馬鈴薯澱粉、及預明膠化的殿粉）、纖維素及其衍生物（例如微晶纖維素）、硫酸鈣及二元磷酸鈣。液體給藥形式通常是由化合物或鹽在液體載劑例如乙醇、撖欖油、甘油、葡萄糖（漿劍）或水(例如添加調味劑、懸浮劑或染劑）之懸浮液或溶液組成。當組成物是在片劑或錠劑之形式時，可以使用例行性用於製備固體调製物之任何藥學載劑。此載劑之實例包括硬脂酸鎂、白土、滑石、明膠、***膠、硬脂酸、殿粉、乳糖及蔗糖。當組成物是在膠囊劑之形式時，合適是任何例行的封膠物，例如使用上述載劑或半固體例如已酸之單二甘油酯、 GelucireTM&Labrasol™、或硬膠殼例如明膠。當組成物是在軟殼膠囊例如明膠之形式時，可以考慮例行性用於製備为散液或懸浮液的任何醫藥載劑，例如水膠或油，且可以摻混在軟膠殼内。口服固體給藥形式還可以含有黏著劑形式之赋形劑。合適的黏著劑包括殿粉（例如玉米澱粉、馬鈴薯澱粉、及預明膠化的澱粉）、明膠、***膠、藻酸鈉、藻酸、西黃蓍膠、瓜耳膠、吡咯烷酮、纖維素及其衍生物（例如微晶纖維 53 200804352 素）。口服固體給藥形式還可以含有分解劑形式之賦形劑。合適的分解劑包括交叉吼咯烧酮（crospovidone)、澱粉經基乙酸鈉、交叉卡美17各(croscarmelose)、藻酸及叛曱基纖維素鈉。口服固體給藥形式還可以含有潤滑劑形式之賦形劑。合適的潤滑劑包括硬脂酸、硬脂酸鎂、硬脂酸鈣及滑石。本發明還提供製備醫藥組成物之方法，該方法包括將至少一種式I、IA或IB化合物或其藥學上可接受的衍生物與藥學上可接受的載劑及/或賦形劑混合。口服用藥之製劑可以適當地調製而得到控制性/延長性釋放活性化合物。全部出版物，包括但不限於本說明書中提到的專利及專利申請案，是併於本文供參考，如同各獨立的出版物是特定且個別地指出而併於本文供參考以充分說明。縮寫在描述本發明時，根據元素週期表辨認化學元素。其中使用的縮寫及符號是根據從事化學技藝者慣用的縮寫及符號。文中使用下列縮寫： ACN 乙腈 AcOEt 醋酸乙酯 AFC 7_酸胺基·4-二亂曱基香立素 AMC 7-醯胺基-4-甲基香豆素 CDC13 氘化氯仿 CHAPS 3-[(3-氯醯胺基丙基）二曱胺基]-1-丙磺酸鹽 CYS 半胱胺酸 54 200804352Remington's Pharmaceutical Sciences (Mack Publishing Company) In one aspect, the invention relates to a solid or liquid oral administration form such as a liquid, tablet, lozenge or capsule containing a safe and effective amount of a compound of the invention and a carrier. The carrier can be in the form of a diluent or a filler. Suitable diluents and fillers generally include lactose, sucrose, glucose, mannitol, sorbitol, starch (eg, corn starch, potato starch, and pregelatinized powder), cellulose and its derivatives (eg, microcrystalline Cellulose), calcium sulfate and dibasic calcium phosphate. The liquid administration form usually consists of a suspension or solution of the compound or salt in a liquid carrier such as ethanol, eucalyptus oil, glycerin, glucose (sword) or water (e.g., a flavoring, suspending or dyeing agent). When the composition is in the form of a tablet or lozenge, any of the pharmaceutical carriers conventionally used in the preparation of solid preparations may be employed. Examples of such carriers include magnesium stearate, terra alba, talc, gelatin, acacia, stearic acid, phylum powder, lactose and sucrose. When the composition is in the form of a capsule, it is suitably any conventional sealant, for example, a carrier or a semisolid such as an acid mono-diglyceride, GelucireTM & LabrasolTM, or a hard shell such as gelatin. When the composition is in the form of a soft shell capsule such as gelatin, any pharmaceutical carrier such as a water gel or oil which is conventionally used for the preparation of a dispersion or suspension may be considered and may be incorporated in the soft shell. Oral solid administration forms may also contain excipients in the form of an adhesive. Suitable adhesives include temple powder (such as corn starch, potato starch, and pregelatinized starch), gelatin, gum arabic, sodium alginate, alginic acid, tragacanth, guar gum, pyrrolidone, cellulose and Derivatives (eg microcrystalline fiber 53 200804352). Oral solid administration forms may also contain excipients in the form of a decomposing agent. Suitable decomposing agents include crospovidone, starch via sodium acetate, croscarmelose, alginic acid and sodium cytosolic cellulose. Oral solid administration forms may also contain excipients in the form of a lubricant. Suitable lubricants include stearic acid, magnesium stearate, calcium stearate and talc. The invention further provides a process for the preparation of a pharmaceutical composition comprising admixing at least one compound of formula I, IA or IB, or a pharmaceutically acceptable derivative thereof, with a pharmaceutically acceptable carrier and/or excipient. Formulations for oral administration can be suitably formulated to give controlled/prolonged release of the active compound. All of the publications, including but not limited to, the patents and patent applications mentioned in the specification, are hereby incorporated by reference in their entirety in their entirety in the extent of the disclosure of the disclosure. Abbreviations In describing the present invention, chemical elements are identified based on the periodic table of elements. The abbreviations and symbols used therein are based on abbreviations and symbols that are commonly used by chemists. The following abbreviations are used herein: ACN Acetonitrile AcOEt Ethyl Acetate AFC 7_Acetylamine·4-Di-Chloryl-Based AMC 7-Amidino-4-methylcoumarin CDC13 Deuterated Chloroform CHAPS 3- [( 3-Chloroaminopropyl propyl) bis-amino]-1-propane sulfonate CYS cysteine 54 200804352

DABCO DCM DIPEA DMAP DMSO-d6 DMSO DTT E64 EDCI EDTA ES+MS ES-MS EtOH h H-D-VLR- AFC Hex HOBt HPLC i_PrOH kg KQKLR- AMC MeOH 1，4-二氮雜二環[2.2.2]辛烷二氯曱烷二異丙胺 4-二甲胺基吡啶氘化二曱亞砜二曱亞颯二硫蘇糖醇反-¾乳號拍酿基-L-白胺驢基（4-脈基）丁烧 N·(3-二曱胺基丙基)-N’ -乙基碳化二亞胺 (乙二氮基）四醋酸陽極電子霧化光譜法陰極電子霧化光譜法乙醇小時 HD -顯胺酿基-白胺酿基-精胺酿基-7 -酿胺基 -4-二氣甲基香丑素己烷 1 -經基苯並三嗤高壓液相層析法異丙醇公斤 N -乙醯基-賴胺醯基-谷醯胺基-賴胺醯基-白胺醯基-精胺醯基-7-醯胺基-4-甲基香豆素曱醇 55 200804352 MES 2 - (N-嗎福ϋ林基）乙石黃酸 MgS04 硫酸鎮 min 分鐘 mg 毫克 NaHC03 硫酸氫鈉 Na2S04 硫酸鈉 nM 毫微莫耳濃度 NMR 核磁共振光譜法 Pt02 氧化鉑 TEA 三乙胺 TFA 三氟醋酸 THF 四氫呋喃 Z-LR-AMC 苄氧羰基-白胺醯基-精胺醯基-7-醯胺基-4-曱基香丑素化合物製備用於合成式ΙΑ化合物之通則方法揭示在反應圖示1-15 並於實例中說明。從事此藝者將容易理解式ΙΒ化合物及式 I化合物可以根據相同或類似於下面式ΙΑ說明的方法合 200804352 一在整份說明書中，通式是由羅馬數字认、n、m、IV 等命名。式ΙΑ化合物之子集是定義為Ia、此、比⑴、此⑴)、 Ib(iii)、Ib(iv)、Ic、lc(i)&ld。式la之半卡巴肼，其係式IA化合物其中R3及R4是根據上述用於式I之定義，r1是Ci 8烷基/Ci 8伸烷基烷基)2、-CN8伸烷基nrGc^COOCk烷基或-C"伸烷基 NI^CCCOCk 烷基，A 是 C(O)，R5 是氫、Cl6烷基、Ci6 烯基、-Cu伸烧基Ν((^·3烧基Ku伸烧基NRGc^C^OCk 烧基或-C〗·8伸烷基NRGqCOCi-6烷基，且R2是-NRh-芳基-雜環基、-NRH-環烧基、-爾^“伸烧基Rc、烷基)-雜芳基、-NRH-芳基、-NRH-雜芳基、_NRH-芳基-雜芳基或-NRH-雜芳基-芳基；其中rh是根據上述用於式IA之定義，可以根據圖示1從式II之對應的肼化合物製備，其中R3及R4是根據上述用於式I之定義，R1是Cl_8烷基、 -C^伸烷基Ν(<^3烷基)2、-Cu伸烷基NRGqcOOCw烷基或-Cw伸烷基NRGqCOCk烷基，且R5是氳、Cy烷基、 Cw烯基、-Cw伸烷基Ν((^-3烷基)2、-C^伸烷基 NRGcXCOOCk烷基或-Cw伸烷基NRGQCOCw烷基。此轉化可以根據一或多種不同的方法進行，方法A或方法b。方法A ··式Ila化合物，其為式II化合物，其中R5是氫，與1當量的異氰酸酯R2xNCO，其中R2xN是根據上述在式la中用於R2之定義，在合適的鹼例如三乙胺存在下，在合適的溶劑例如DCM中反應，得到式la化合物其中r5 是氫且RH是氫。 57 200804352 方法B :將一級胺R10_NH2或二級胺R10-NH-Rh，其中 RH是根據上述用於式la之定義，且R10是芳基、雜芳基务基-雜务基、雜芳基-芳基、芳基-雜環基、n(cm燒基)_ 雜芳基、環烷基或-Ck伸烷基RC，其中Rc是氫、（^3院基芳基或鹵素，溶解在合適的溶劑例如無水THF並冷卻至合適的溫度例如-10°C至1(TC，然後與三光氣反應，並將所^ 的混合物在合適的鹼例如碳酸铯或三乙胺存在下添加至式 II化合物。此混合物可以在合適的溫度攪拌合適長的時間使完成反應，例如在室溫精6小時，得到式la化合物其中 R、R1G及RH是根據上述用於式ja之定義。DABCO DCM DIPEA DMAP DMSO-d6 DMSO DTT E64 EDCI EDTA ES+MS ES-MS EtOH h HD-VLR- AFC Hex HOBt HPLC i_PrOH kg KQKLR- AMC MeOH 1,4-diazabicyclo[2.2.2]octane Dichlorodecane diisopropylamine 4-dimethylaminopyridine pyridinium disulfoxide diterpenoid dithiothreitol anti-3⁄4 milk number brewing base-L-leucine fluorenyl (4-velocyl) N-(3-diaminopropyl)-N'-ethylcarbodiimide (ethylenediazide) tetraacetic acid anodic electron atomization spectroscopy cathode electron atomization spectroscopy ethanol hour HD-experiment Stuffed base - leucine brewing base - spermine brewing base-7 - stearylamino-4-dimethyl methyl ugly hexane 1 - benzotriazole high pressure liquid chromatography isopropanol kg N - Ethyl-lysyl-lysine-glutamyl-lysyl-alkamine-spermine-indenyl-7-nonylamino-4-methylcoumarin sterol 55 200804352 MES 2 - ( N-Fofu sulphate) sulphate MgS04 sulphuric acid town min min mg mg NaHC03 sodium hydrogen sulphate Na2S04 sodium sulphate nM nanomolar concentration NMR nuclear magnetic resonance spectroscopy Pt02 platinum oxide TEA triethylamine TFA trifluoroacetic acid THF tetrahydrofuran Z-LR-AMC benzyloxycarbonyl- Acyl amine - spermine acyl-7-acyl-amino-4-yl Yue Su Hong ugly for preparing a compound of General synthesis of compounds of formula ΙΑ disclosed and described in the reaction illustrated in Example 1-15. Those skilled in the art will readily appreciate that the hydrazine compound and the compound of formula I may be according to the same or similar method as described in the following formula: 200804352. In the entire specification, the formula is identified by Roman numerals, n, m, IV, etc. . A subset of the hydrazine compounds are defined as Ia, this, ratio (1), this (1)), Ib (iii), Ib (iv), Ic, lc(i) & ld. A compound of formula la IA wherein R3 and R4 are as defined above for formula I, r1 is Ci 8 alkyl/Ci 8 alkylene alkyl) 2, -CN8 alkylene nrGc^ COOCk alkyl or -C"alkylene NI^CCCOCk alkyl, A is C(O), R5 is hydrogen, Cl6 alkyl, Ci6 alkenyl, -Cu extended alkyl ((^·3) Ku extension Alkyl NRGc^C^OCk alkyl or -C〗 8-alkylalkyl NRGqCOCi-6 alkyl, and R2 is -NRh-aryl-heterocyclyl, -NRH-cycloalkyl, - er ^" a base Rc, alkyl)-heteroaryl, -NRH-aryl, -NRH-heteroaryl, _NRH-aryl-heteroaryl or -NRH-heteroaryl-aryl; wherein rh is used according to the above The definition of formula IA can be prepared according to the corresponding oxime compound of formula II according to the scheme of Figure 1, wherein R3 and R4 are according to the above definition for formula I, R1 is Cl_8 alkyl, -C^alkyl hydrazine (< ^3 alkyl) 2, -Cu alkylene NRGqcOOCw alkyl or -Cw alkylene NRGqCOCk alkyl, and R5 is anthracene, Cy alkyl, Cw alkenyl, -Cw alkyl hydrazine ((^-3 alkane) 2, -C^alkylalkyl NRGcXCOOCk alkyl or -Cw alkylene NRGQCOCw alkyl. This conversion can be carried out according to one or more different methods, Method A or Method b. A compound of the formula Ila, which is a compound of the formula II, wherein R5 is hydrogen, and 1 equivalent of isocyanate R2xNCO, wherein R2xN is according to the above definition for R2 in formula la, in the presence of a suitable base such as triethylamine Reacts in a suitable solvent such as DCM to give the compound of formula la wherein r5 is hydrogen and RH is hydrogen. 57 200804352 Method B: a primary amine R10_NH2 or a secondary amine R10-NH-Rh, wherein RH is according to the above formula Definition of la, and R10 is aryl, heteroaryl-hetero, heteroaryl-aryl, aryl-heterocyclyl, n(cm alkyl)_heteroaryl, cycloalkyl or Ck alkyl RC, wherein Rc is hydrogen, (^3 aryl or halogen, dissolved in a suitable solvent such as anhydrous THF and cooled to a suitable temperature, for example -10 ° C to 1 (TC, then reacted with triphosgene And adding the mixture to a compound of formula II in the presence of a suitable base such as cesium carbonate or triethylamine. The mixture can be stirred at a suitable temperature for a suitable period of time to complete the reaction, for example, 6 hours at room temperature. The compound of formula la is obtained wherein R, R1G and RH are as defined above for the formula ja.

II la 圖示1 ★,式la化合物其中Ri、R3及R4是根據上述用於式以之定義，R2是芳基、Cy伸烷基R' n(rh)芳基，；[^是（^6 伸烷基NRERF且Re&Rf都是氫，R5是氫或伸烷基-雜環基，可以從其他式la化合物製備，其中Ri、r3及R4是根據^上述用於式la之定義，R2*n(rh)芳基，rH是c]_6伸烷基 NHC(0)〇Cl_4烧基’ R5是氫，或式Ia化合物之胺基^酸鹽衍生物其中112是Cm伸烷基(NH2)_芳基，根據圖示2在: 適的酸例如三氟醋酸或對.甲苯磺酸存在下，經由去除保^ 58 200804352 而製備亙其胺基曱酸鹽II la Figure 1 ★, a compound of the formula la wherein Ri, R3 and R4 are defined according to the above formula, R2 is an aryl group, a Cyalkyl group R'n(rh)aryl group; [^ is (^ 6 alkyl NRERF and Re & Rf are hydrogen, R5 is hydrogen or alkyl-heterocyclic group, can be prepared from other compounds of formula la, wherein Ri, r3 and R4 are based on the above definition of formula la, R2*n(rh)aryl, rH is c]_6alkylene NHC(0)〇Cl_4 alkyl"R5 is hydrogen, or an amine acid salt derivative of the compound of formula Ia wherein 112 is Cm alkylene ( NH2)-aryl, according to Figure 2: in the presence of a suitable acid such as trifluoroacetic acid or p-toluenesulfonic acid, by removing the ^ 58 2008 2008 352

R' R laR' R la

CN 〇 R la 式lb之醯基肼化合物，其係式〗八化合物其中Ri、R3 及R4是根據上述用於式la之定義（例如R1代表Gy烷基例如異丁基，R3代表氳且R4代表鹵素），A是C(O)，R5是氫、 Cu烷基、-Cw伸烷基-雜環基、—Cw伸烷基N(CM烷基)2、 -Cu 伸烷基 NRGc^COOCk 烷基、-Cu 伸烷基 nrGc^COCk 烷基(例如R5是氫）；且R2是芳基、雜芳基、環烷基、雜環基、-芳基-雜環基、聯芳基、芳基-雜芳基、-雜芳基-芳基 -芳基-c〗-3伸烷基-雜環基、-雜芳基-芳基_Ci_3伸烷基_雜環基、-芳基-Cm伸烷基-雜環基_芳基-〇-Ci_3伸烷基_雜環基或Cw伸烷基R\其中Ra是氫、c] 3烷基、鹵素、/ · Ν((^_3烧基)2、芳基、聯芳基、環烷基、-芳基伸垸基· 雜環基或-芳基-0-C〗-3伸烷基-雜環基(例如R2是_苯基_c 伸烧基-X、，啶基-苯基-Cw伸烷基-X或_苯基_Ci 3伸垸1 -X-Rj，其中苯基是視需要經一個選自鹵素或CF3的基取代）；可以根據圖示3從式Π對應的肼化合物製備，其中 59 200804352 R1、R3及R4是根據上述用於式la之定義（例如R1代表C〗-8 烷基例如異丁基，R3代表氫且R4代表鹵素），且R5是氫、 Cu烷基、-Cw伸烷基-雜環基、-Cw伸烷基NCCw烷基)2、 -C〗_8伸烷基NRGc^COOCk烷基或-Cw伸烷基NRGqCOCw 烷基(例如R5是氳）。式II化合物是與醯基氯R2COHal，其中R2是根據上述用於式lb之定義，且Hal是C1或Br，在合適的溶劑例如吡啶中反應而得到式lb化合物。CN 〇R la lb 醯醯醯肼肼 , 八八八其中其中其中其中其中其中其中其中八八八八八八八八八八八八八八八八八八八八八八八八八八八八八八八八八八八Representative halogen), A is C(O), R5 is hydrogen, Cu alkyl, -Cw alkyl-heterocyclyl, -Cw alkyl N (CM alkyl) 2, -Cu alkyl NRGc^COOCk An alkyl group, -Cu alkylene group nrGc^COCk alkyl group (for example, R5 is hydrogen); and R2 is an aryl group, a heteroaryl group, a cycloalkyl group, a heterocyclic group, an -aryl-heterocyclic group, a biaryl group, Aryl-heteroaryl, -heteroaryl-aryl-aryl-c--3alkyl-heterocyclyl,-heteroaryl-aryl-Ci_3alkylene-heterocyclyl,-aryl -Cmalkyl-heterocyclyl-aryl-fluorene-Ci_3alkylene-heterocyclyl or Cwalkylene R\ wherein Ra is hydrogen, c] 3 alkyl, halogen, / · Ν ((^_3) An alkyl group, an aryl group, a biaryl group, a cycloalkyl group, an arylalkyl group, a heterocyclic group or an -aryl-0-C--3 alkylene group-heterocyclic group (for example, R2 is a phenyl group). — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — Base substitution); can be based on the map 3 is prepared from a hydrazine compound corresponding to the formula ,, wherein 59 200804352 R1, R3 and R4 are according to the above definition for the formula la (for example, R1 represents C-8-8 alkyl such as isobutyl, R3 represents hydrogen and R4 represents halogen) And R5 is hydrogen, Cu alkyl, -Cw alkyl-heterocyclyl, -Cw alkylene NCCw alkyl) 2, -C _8 alkylene NRGc^COOCk alkyl or -Cw alkylene NRGqCOCw Alkyl (eg, R5 is hydrazine). The compound of formula II is a compound of formula lb which is reacted with mercapto chloride R2COHal wherein R2 is as defined above for formula lb and Hal is C1 or Br in a suitable solvent such as pyridine.

圖示3 式Ibi之醯基胼化合物，其係式Ib (且因此是式IA)化合物其中R、R3及R4是根據上述用於式IA之定義（例如代表C!_8烷基例如異丁基，R3代表氬且R4代表鹵素）， A是C(O)，R5是氫、C〗-6烷基、_CV8伸烷基Nd;烷基)2、 -C“8 伸烧基 Νί^(0)〇(^_6 烷基、-Cu 伸烷基 nrGcccoCk 烷基(例如R5是氫）；且R2是-芳基_Ci 3伸烷基_雜環基、_ 芳基-Cw伸烷基-雜環基-R】、-雜芳基_芳基-Ci 3伸烷基_雜環基(例如R2是-苯基-Cw伸烷基〇(、_吡啶基-苯基_Ci 3伸烷基-X或-苯基-Cy伸烷基-X-RJ，其中苯基是視需要經一個選自鹵素或CF3的基取代）；可以根據圖示4從式χιι對應的醯基胼化合物製備，其中r1、R3&R4是根據上述用 60 200804352 於式ΙΑ之定義（例如R1代表Cl·8烷基例如異丁美氫且R4代表函素R5气氫、Cl_8烧基、_Ci8伸烷基)2、-Cm伸烷基NR C(〇)〇Cl_6烷基或_Ci8 NRGC(0)Ci_6烷基(例如R5是氫）；且Rx是-芳基伸烷基或-雜芳基-芳基i基Cl_3伸烷基，經由：匕：合物，該化合物是雜環基或雜環基·RJ，例如化疋義，在鹼例如無機驗例如碳酸鉀，《有機Figure 3 is a fluorenyl compound of formula Ibi, which is a compound of formula Ib (and thus formula IA) wherein R, R3 and R4 are as defined above for use in formula IA (e.g., representing C!-8 alkyl such as isobutyl , R3 represents argon and R4 represents halogen), A is C(O), R5 is hydrogen, C -6 alkyl, _CV8 alkyl Nd; alkyl) 2, -C "8 extended alkyl Ν ί ^ (0 〇(^_6 alkyl, -Cu alkylene nrGcccoCk alkyl (for example, R5 is hydrogen); and R2 is -aryl-Ci3alkylene-heterocyclyl, _aryl-Cwalkyl-hetero Cyclo-R], -heteroaryl-aryl-Ci 3 alkylene-heterocyclyl (for example, R2 is -phenyl-Cw alkyl hydrazine (, pyridine group - phenyl-Ci 3 alkyl) -X or -Phenyl-Cyalkyl-X-RJ, wherein the phenyl group is optionally substituted with a group selected from halogen or CF3; it can be prepared from the fluorenyl hydrazine compound corresponding to the formula χιι according to Figure 4, Wherein r1, R3&R4 are as defined above for 60 200804352 (for example, R1 represents a Cl.8 alkyl group such as isobutyrene and R4 represents a functional element R5 gas hydrogen, Cl_8 alkyl, _Ci8 alkyl) 2 , -Cm alkyl NR C (〇) 〇Cl_6 alkyl or _Ci8 NRGC (0) Ci_6 alkyl (for example, R5 is hydrogen); and Rx is -fang Alkylalkyl or -heteroaryl-aryl iylCl_3 alkylene, via: hydrazine, which is a heterocyclic or heterocyclic group, RJ, such as hydrazine, in a base such as inorganic, for example, carbonic acid Potassium, "Organic

mPEA存在下，錢需要在视物存在下，例如加入HIn the presence of mPEA, money needs to be in the presence of an object, such as adding H

圖示4 式XII化合物可以使用類似於圖示3說明之方法製備，經由式II化合物與RxCHal反應，其中Rx是-芳基鹵基伸烷基或-雜芳基-芳基鹵基Cw伸烷基，且Hal是ci或Br，在鹼例如無機鹼例如碳酸鉀，或有機鹼例如胺例如DIpEA 存在下進行。式IA化合物可以根據圖示5從式III化合物製備，其中R、R、R、R及R是根據上述用於式IA之定義，經由氰基化、經由使用多種條件替代式ΙΠ化合物之氯取代基，例如用鉀或鈉氰化物在合適的鹼例如DABCO存在下 61 200804352 在合適的溶劑例如DMSO中進行。Scheme 4 Compounds of formula XII can be prepared using procedures analogous to those illustrated in Scheme 3, by reacting a compound of formula II with RxCHal, wherein Rx is an -arylhaloalkylene or-heteroaryl-arylhalo Cw alkylene group. And Hal is ci or Br, which is carried out in the presence of a base such as an inorganic base such as potassium carbonate or an organic base such as an amine such as DIpEA. Compounds of formula IA can be prepared from compounds of formula III according to Scheme 5, wherein R, R, R, R and R are substituted according to the above definitions for formula IA, via cyanation, via the use of various conditions in place of the hydrazine compound. The base is, for example, carried out with potassium or sodium cyanide in the presence of a suitable base such as DABCO 61 200804352 in a suitable solvent such as DMSO.

圖示5 式Ic之烷氧羰基胼化合物，其係式IA化合物其中R1、 R3及R4是根據上述用於式IA之定義，A是C(O)，且R5 疋鼠、Ci_6烧基、Ci_6稀基、-Ci_8伸烧基N(C】_3烧基)2、-Cu 伸烷基NRGqCOOCk烷基或伸烷基NRGc^COCk烷基且R2是OR11其中R11是Cw烯基或-Cw伸烷基RD，其中 RD是氫、烷基、芳基、雜芳基、雜環基、環烷基、雜環基、CC13、氰基、-NHC^COCw 烷基、-NHCXCOOCk 烷基或-CCC^Cw烷基，可以根據圖示6從式II對應的肼化合物製備，其中R5是氫、Ci_8烷基、Ci_6烯基、-Cw伸烷基 Nd;烷基)2、-Cw伸烷基NRGcCCOOCk烷基或-Cw伸烷基NRGC(0)C〗·6烷基且R1、R3及R4是根據上述用於式IA 之定義。式II化合物與甲醯氯RnOCOCl，其中R11是根據上述用於式Ic之定義，在合適的溶劑例如DCM中，在合適的鹼例如二異丙基乙基胺與DMAP之混合物存在下反應，得到式Ic化合物。甲醯氣Rn〇c〇Cl是有商業化供應或得自對應商業化供應的醇Rn〇H，其中R11是根據上述用於式Ic之定義，與三光氣在合適的溶劑例如THF中反應， 62 200804352 其可以與式Π化合物在合適的鹼的溶劑例如吼。定中直接反應，得，^乙胺存在下載合適丁，式Ic化合物。Figure 5 is an alkoxycarbonyl oxime compound of the formula Ic, wherein R1, R3 and R4 are as defined above for the formula IA, A is C(O), and R5 squirrel, Ci_6 alkyl, Ci_6 Dilute, -Ci_8 extended alkyl N(C)_3 alkyl) 2, -Cu alkyl NRGqCOOCk alkyl or alkyl NRGc^COCk alkyl and R2 is OR11 wherein R11 is Cw alkenyl or -Cw alkylene a group RD wherein RD is hydrogen, alkyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, heterocyclyl, CC13, cyano, -NHC^COCw alkyl, -NHCXCOOCk alkyl or -CCC^ Cw alkyl, which can be prepared from the indole compound corresponding to formula II according to Scheme 6, wherein R5 is hydrogen, Ci-8 alkyl, Ci-6 alkenyl, -Cw alkylene Nd; alkyl)2, -Cw alkyl NRGcCCOOCk The base or -Cw alkylene NRGC(0)C.6 alkyl and R1, R3 and R4 are as defined above for Formula IA. a compound of the formula II and a formazan chloride RnOCOCl, wherein R11 is reacted in the presence of a suitable base such as a mixture of diisopropylethylamine and DMAP in a suitable solvent such as DCM according to the above definition for the formula Ic. a compound of formula Ic. N-helium Rn〇c〇Cl is commercially available or available from a corresponding commercial supply of alcohol Rn〇H, wherein R11 is reacted with triphosgene in a suitable solvent such as THF according to the above definition for formula Ic, 62 200804352 It can be combined with a hydrazine compound in a suitable base solvent such as hydrazine. Direct reaction in the middle of the reaction, the presence of ethylamine can be downloaded as a suitable compound of formula Ic.

式Ila化合物，其為式Π化合物其中r5是氫，可以根據圖示7從式IV化合物製備，其中Rl、尺3及尺4是根據』述用於式II之定義（例如Ri代表Ci8燒基例如異丁基r: 代表氫_i_R4代表鹵素），在合適的_如三氟醋酸存在下經由去除保護。A compound of the formula Ila, which is a hydrazine compound of the formula wherein r5 is hydrogen, can be prepared from a compound of the formula IV according to the scheme of Figure 7, wherein R1, 3 and 4 are used according to the definition of formula II (for example, Ri represents a Ci8 alkyl group). For example, isobutyl r: represents hydrogen _i_R4 represents halogen) and is protected by removal in the presence of a suitable _ such as trifluoroacetic acid.

/,το ο/,το ο

Μ :除去 a 酸 CNΜ : except for a acid CN

CN 圖示7 式IV化合物可以根據圖示8從式v化合物製備，其中 R1、R3及R4是根據上述用於式Η之定義（例如Ri代表Cu 烷基例如異丁基，例如環烷基甲基，R3代表氫且R4代表鹵素），經由氰基化、經由使用多種條件替代式V化合物之氣取代基，例如用鉀或鈉氰化物在合適的驗例如DABCO存 63 200804352 在下在合適的溶劑例如DMS0中進行。CN Illustrative compounds of formula IV can be prepared from compounds of formula v according to Scheme 8, wherein R1, R3 and R4 are as defined above for the formula (eg, Ri represents a Cu alkyl group such as an isobutyl group, such as a cycloalkyl group) a group, R3 represents hydrogen and R4 represents a halogen, via a cyanation, via a gas substitution of a compound of formula V using a plurality of conditions, for example with potassium or sodium cyanide in a suitable assay such as DABCO storage 63 200804352 under suitable solvent For example, it is done in DMS0.

To .〇To .〇

CNCN

IV 圖示8 式V化合物可以根據圖示9從式VI化合物製備，其中 R1是根據上述用於式V之定義（例如R1代表Cw烷基例如異丁基，例如環烷基甲基），經由式VI化合物與式VII化合物反應，其中R3及R4是根據上述用於式V之定義（例如 R3代表氫且R4代表鹵素）(商業化從FLUKA或SIGMA供應），在合適的溶劑例如EtOH中，例如根據Bagley J. R. et al·，（1989) J. Med. Chem. 32, 663-671 提供的文獻方法在室溫進行3-4天。IV. Scheme 8 Compounds of formula V can be prepared from compounds of formula VI according to Scheme 9, wherein R1 is via the above definition for formula V (eg, R1 represents a Cw alkyl group such as an isobutyl group, such as a cycloalkylmethyl group), via A compound of formula VI is reacted with a compound of formula VII, wherein R3 and R4 are as defined above for use in formula V (eg, R3 represents hydrogen and R4 represents halogen) (commercially supplied from FLUKA or SIGMA), in a suitable solvent such as EtOH, For example, the literature method provided by Bagley JR et al., (1989) J. Med. Chem. 32, 663-671 is carried out at room temperature for 3-4 days.

ο /.Toο /.To

cl 圖示9 式VI化合物可以根據圖示10從式VIII化合物經由與酸I之還原性胺化反應而製備，其中R13是比R1之鏈長少 64 200804352 一個碳，其中R1是Cw烷基、-Cw伸烷基NRERF、-cK8 伸烷基NRGc^COOCw烧基、-Cw伸烧基NRGQCOCw烷基或-C〗—8伸烷基-環烷基(例如R1代表Cl_8烷基，例如異丁基）。式VIII化合物胼基曱酸第三丁酯是可得自商業化供應 (ALDRICH) 〇式VIII化合物與式IX的醛之還原性胺化是在合適的還原劑例如氫氣及合適的觸媒例如鉑或鈀或氧化舶存在下，在合適的溶劑例如i—PrOH、EtOH或其混合物中進行，例如根據 Hilpert，H. (2001) Tetrahedron，57， 7675-7683 或 Dyker，Η· et al，（2001) J. Org· Chem· 66， 3760-3766提供的文獻方法。Cl Figure 9 A compound of formula VI can be prepared from a compound of formula VIII via a reductive amination reaction with acid I according to Figure 10, wherein R13 is less than the chain length of R1. 64 200804352 One carbon, wherein R1 is Cw alkyl, -Cw alkylene NRERF, -cK8 alkylene NRGc^COOCw alkyl, -Cw extended alkyl NRGQCOCw alkyl or -C-8-8 alkyl-cycloalkyl (for example R1 represents Cl_8 alkyl, such as isobutyl base). The compound of formula VIII, tert-butyl decyl decanoate, is a commercially available (ALDRICH) quinone VIII compound and the reductive amination of an aldehyde of formula IX is in a suitable reducing agent such as hydrogen and a suitable catalyst such as platinum. Or in the presence of palladium or oxidizer, in a suitable solvent such as i-PrOH, EtOH or mixtures thereof, for example according to Hilpert, H. (2001) Tetrahedron, 57, 7675-7683 or Dyker, Η· et al, (2001) The literature method provided by J. Org Chem. 66, 3760-3766.

圖示10 式IX的酸是可得自商業化供應，例如異丁醛，或其可以根據圖示11製備，丨)從式X之對應的商業化供應之二甲基或二乙基乙縮醛化合物其中是根據上述用於式以之定義，經由使用合適的酸例如氫氯酸之酸水解，或ii)經由式XI之商業化供應的醇化合物之氧化，其中Ri3是根據上述用於式IX之定義，根據Swern氧化或Dess-Martin氧化之標準方法。 65 200804352 C1.2alkyl一Ο ^-R13 C^alkyl—Ο 酸水解The acid of formula IX is available from a commercial supply, such as isobutyraldehyde, or it can be prepared according to Figure 11, 丨) from the corresponding commercial supply of dimethyl or diethyl condensate of formula X An aldehyde compound which is oxidized according to the above formula for the hydrolysis of an acid by a suitable acid such as hydrochloric acid, or ii) an alcohol compound supplied via commercialization of the formula XI, wherein Ri3 is used according to the above formula The definition of IX is based on standard methods of Swern oxidation or Dess-Martin oxidation. 65 200804352 C1.2alkyl 一Ο ^-R13 C^alkyl—Ο Acid hydrolysis

XX

R 圖不11 式Ib(iii)化合物，其係式IA化合物其中R2、R3、R4及 R5是根據上述用於式ΙΑ之定義，R1是Cw伸烷基NH2且 A是C(0)，可以根據圖示12從式lb化合物製備，其中R2、 R3、R4及R5是根據上述用於式Ib(iii)之定義，且R1是-Cw 伸烷基Ν(3(0)0(^_6烧基，經由在合適的酸例如三氟醋酸存在下，在合適的溶劑例如二氯甲烧中，或氫溴酸在合適的溶劑例如醋酸中的去除保護反應R Figure 11 is a compound of the formula Ib(iii), which is a compound of the formula IA wherein R2, R3, R4 and R5 are as defined above for the formula ,, R1 is Cw alkylene NH2 and A is C(0), Prepared from the compound of formula lb according to Scheme 12, wherein R2, R3, R4 and R5 are as defined above for the formula Ib(iii), and R1 is -Cw alkyl hydrazine (3(0)0 (^_6 burnt) Removal of the protective reaction via a suitable solvent such as trifluoroacetic acid in a suitable solvent such as dichloromethane, or hydrobromic acid in a suitable solvent such as acetic acid.

RR

〇 Cw伸烷基νη2 Ib(iii) lb 圖示12 式Ib(iv)化合物，其係式ΙΑ化合物其中R2、R3、R4及 R5是根據上述用於式Ib(iii)之定義，R1是-Cw伸烷基 NCCCOC^烷基且A是C(O)，可以根據圖示13從上述定義之式Ib(iii)化合物製備，經由在合適的溶劑例如二氯曱烷中，在合適的溫度例如-l〇t：至l〇°C，用式OfCXCOCw烷 66 200804352 基]2之酐處理。〇Cwalkylalkyl νη2 Ib(iii) lb Figure 12 Compound of formula Ib(iv), which is a hydrazine compound wherein R2, R3, R4 and R5 are as defined above for the definition of formula Ib(iii), R1 is - Cw alkylene NCCCOC^alkyl and A is C(O), which can be prepared according to Scheme 13 from a compound of formula Ib(iii) as defined above, via a suitable solvent such as dichloromethane at a suitable temperature, for example -l〇t: to l〇 ° C, treated with an anhydride of the formula OfCXCOCw alkane 66 200804352.

0[C(0)Cl-6^S2 Ib(iii)0[C(0)Cl-6^S2 Ib(iii)

lb(iv) 圖示13 式Ic(i)化合物，其係式1A化合物其中r3及r4是根據上述用於式IA之定義，R1是Ci-s烧基，A是C(O)，R5是 Ci-6烧基、Ci-6烯基、_Cl-8伸烧基N(Ci_3烧基)2、-Cw伸烷基-雜環基、-CCCOCu烷基、-C(0)R2a、-Cw伸烷基 nrGcccooCu烷基或-Cu伸烷基NRGCCC^Ck烷基，其中 RG是根據上述用於式IA之定義，或N-酞醯亞胺基-Cw伸烷基-，且R2是OR11其中R11是Cw烯基或-Cw伸烷基Rd，其中Rd是氫、Cy烧基、芳基、雜芳基、雜環基、環烧基、雜％基、CCI3、fl基、-NHC(0)Ci_6 烧基、_NHC(0)0Ci_6 烧基、或CXCOC!-6烷基，可以根據圖示14從式IIIa化合物製備，其中R3及R4是根據上述用於式IA之定義，R1是 Cw烷基，R5是氫且R2是〇Ri〗其中Rii是上述用於Ic(i) 之定義，經由用式R5-C1、R5-Br或R5-OS〇2Y之烧基化劑處理Ilia，其中R5是根據上述用於式Ic(i)之定義且γ是甲基或對-甲苯基，在合適的觸媒例如四丁基硫酸氫銨及視需要選用的碘化鈉存在下，在鹼例如碳酸鉀與氫氧化那隻混 a物存在下，在合適的溶劑例如p苯中，視需要在加溫例 67 200804352 如90-170°C進行。Lb(iv) Figure 13 Compound of formula Ic(i), which is a compound of formula 1A wherein r3 and r4 are as defined above for formula IA, R1 is a Ci-s alkyl group, A is C(O), and R5 is Ci-6 alkyl, Ci-6 alkenyl, _Cl-8 extended alkyl N (Ci_3 alkyl) 2, -Cw alkyl-heterocyclyl, -CCCOCu alkyl, -C(0)R2a, -Cw An alkyl group nrGcccooCu alkyl or -Cu alkylene NRGCCC^Ck alkyl, wherein RG is as defined above for formula IA, or N-quinone imido-Cw alkyl-, and R2 is OR11 R11 is Cw alkenyl or -Cw alkylene Rd, wherein Rd is hydrogen, Cyalkyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, heteropoly, CCI3, fl, -NHC (0 Ci_6 alkyl, _NHC(0)0Ci_6 alkyl, or CXCOC!-6 alkyl, can be prepared according to Figure 14 from the compound of formula IIIa, wherein R3 and R4 are according to the above definition for formula IA, R1 is Cw alkane a group, R5 is hydrogen and R2 is 〇Ri wherein Rii is as defined above for Ic(i), and Ilia is treated via an alkylating agent of formula R5-C1, R5-Br or R5-OS〇2Y, wherein R5 Is based on the above definition for formula Ic(i) and γ is methyl or p-tolyl, in a suitable catalyst such as tetrabutylammonium hydrogen sulfate and as needed In the presence of sodium iodide to be used, in the presence of a base such as potassium carbonate and hydroxide, in a suitable solvent such as p-benzene, if necessary, in warming example 67 200804352, such as 90-170 ° C.

R5-CI ^ R5-Br 或 CN r5-〇s〇2y R3R5-CI ^ R5-Br or CN r5-〇s〇2y R3

cn lc(0 式Id化合物，其係式IA化合物其中R1 r2 r3 r4 及R5是根據上述用於式认之定義，A是卻、可以根據圖示15從式II化合物製備，其中Rl、R3、“及“是根據上述用於式ΙΑ之疋義，經由用磺醯氯r2s〇2Ci處理化合物 II’其中R疋根據上述用於式{之定義，在合適的溶劑例如吼。疋中進行。礦I氯R2s〇2C1是可得自商業化供應或從對應的續酸R2S02〇H製備，經由在合適的溶劑例如甲苯中，在加溫例如9(M70〇C，帛亞磺醯氯處理磺酸。Cn lc (0 formula Id compound, wherein the compound of formula IA wherein R1 r2 r3 r4 and R5 are defined according to the above formula, A is, can be prepared according to the formula 15 from the compound of formula II, wherein Rl, R3, "And" is based on the above-mentioned formula for the treatment of the compound II' by treatment with sulfonium chloride r2s〇2Ci wherein R is carried out in a suitable solvent such as hydrazine. I chloride R2s〇2C1 is commercially available or can be prepared from the corresponding acid R2S02〇H, by heating in a suitable solvent such as toluene, for example 9 (M70〇C, sulfinium chloride treatment of sulfonic acid) .

圖示15 、從事此藝者將可了解在式IA化合物中的R3及R4基可 ^轉4化3成其他r3及R4基以便提供其他式IA化合物。例如，當R4是漠，在峨化銅Ϊ)及雙（三笨基膦）氣化鈀(II)存在下， 200804352 經由*與H-C.C-芳基反應，可將R4轉化成芳基。例如，虽R是溴，在醋酸鈀及合適的鹼例如BINAp及碳酸鉀之混合物存在下’經由與合適的胺H_NHCi3伸烧基_芳基反應，可將R4轉化成NHCi-3伸烧基-芳基。例如，當r4是溴，經由與2,2-二氟-2-(氟礦醯基）醋_旨、六曱基石粦酸醯胺及碘化銅(I)反應’視需要在合適的溫度加熱，例如8〇。。，可將R轉化f CF3。同樣地，可以在化合物m進行轉化，例如，當R3是氯，在合適的溶劑例如甲醇中，經由與曱醇鈉反應，可將R3轉化成甲氧基。從事此藝者很容易理解其他式认化合物可以使用類似於上述方法或簽考在本文提供的實驗中詳細說明的實驗方法製備。 k事此蟄者也可理解在製備式IA化合物或其溶劑化物日π，可此而要及/或想要保護分子或適當中間物中的一或多個敏性基，以防止不要的副反應、。根據本發明使用的合適保護基是從事此藝者所熟知且可以在傳統方式下使用。見例如 T.W· Greene 及 Ρ·αΜ· Wuts 之“pr〇tective 比Figure 15. It will be appreciated by those skilled in the art that the R3 and R4 groups in the compounds of formula IA can be converted to other r3 and R4 groups to provide other compounds of formula IA. For example, when R4 is a desert, in the presence of palladium (II) and bis(triphenylphosphine) gasified palladium (II), 200804352 can be converted to an aryl group via reaction with H-C.C-aryl. For example, although R is bromine, R4 can be converted to NHCi-3 extended alkyl group by reaction with a suitable amine H_NHCi3 extended alkyl group-aryl group in the presence of a mixture of palladium acetate and a suitable base such as BINAp and potassium carbonate. Aryl. For example, when r4 is bromine, it is reacted with 2,2-difluoro-2-(fluoroindolyl) vinegar, hexamethylene phthalate and copper iodide (I) as needed at the appropriate temperature. Heat, for example 8 〇. . , R can be converted to CF3. Similarly, conversion can be carried out at compound m, for example, when R3 is chlorine, and R3 can be converted to a methoxy group by reaction with sodium decoxide in a suitable solvent such as methanol. It is readily understood by those skilled in the art that other formulae compounds can be prepared using experimental procedures similar to those described above or signed in the experiments provided herein. It is also understood that in the preparation of the compound of formula IA or its solvate day π, it is desirable and/or desirable to protect one or more sensitizing groups in the molecule or in the appropriate intermediate to prevent unwanted reaction,. Suitable protecting groups for use in accordance with the present invention are well known to those skilled in the art and can be used in conventional manner. See, for example, T.W. Greene and Ρ·αΜ· Wuts for “pr〇tective ratios”

Organic Synthesis (John Wiley & Sons 1991)或 P.J·Organic Synthesis (John Wiley & Sons 1991) or P.J.

Kocienski 之“Protecting Gr〇ups”（Ge〇rg Thieme 1994)。合適的胺基保護基之實例包括醯基型保護基（見甲醯基、二氟乙醯基、乙醯基）、芳族胺基甲酸乙酯型保護基 (例如卞氧羰基（Cbz)及經取代之Cbz)、脂族胺基甲酸乙酯塑保護基(例如9_苟基鉀氧幾基(Fm〇c)、第三丁氧絲 (Boc)、異丙氧羰基、環己氧羰基)及烷基或芳烷基型保護基 69 200804352 (例如苄基、三苯曱基、氯三苯曱基）。合適的氧保護基之實例可包括例如烧基石夕烧基，例如三甲石夕烧基或第三丁基二曱基矽烷基；烷基醚例如四氳吡喃基或第三丁基；或酯類例如錯酸酯。【實施方式】下列實例說明本發明。這些實例不是要限制本發明之範圍，而是提供指引供從事此藝者製備及使用本發明化合物、組成物及方法。雖然提供特定的具體實施例，從事此藝者將可理解可以進行多種變化及修改而沒有偏離本發明之精神及範圍。中間物中間物1 : 4-[(4-甲基-1-六氫吡畊基）曱基]苯曱酸甲酯Kocienski's "Protecting Gr〇ups" (Ge〇rg Thieme 1994). Examples of suitable amine protecting groups include fluorenyl protecting groups (see formazan, difluoroacetinyl, ethenyl), aromatic urethane-type protecting groups (eg, oxiranylcarbonyl (Cbz) and Substituted Cbz), aliphatic urethane functional protecting group (eg, 9-mercapto potassium oxy (Fm〇c), third butoxide (Boc), isopropoxycarbonyl, cyclohexyloxycarbonyl And an alkyl or aralkyl type protecting group 69 200804352 (e.g., benzyl, triphenylsulfonyl, chlorotriphenyl). Examples of suitable oxygen protecting groups may include, for example, a decyl group, such as a tripotas or a tributyl decyl decyl group; an alkyl ether such as a tetradecylpyranyl or a tert-butyl group; or an ester Classes such as the acid ester. [Embodiment] The following examples illustrate the invention. These examples are not intended to limit the scope of the invention, but rather to provide guidance for the preparation and use of the compositions, compositions and methods of the invention. While the invention has been described with respect to the specific embodiments, it will be understood that various changes and modifications may be made without departing from the spirit and scope of the invention. Intermediate Intermediate 1: 4-[(4-Methyl-1-hexahydropyrryl)indolyl]benzoic acid methyl ester

;'iN-甲基六氳吡啡基(ALDRICH，1.46毫升，13.1毫莫耳）於二甲基曱醯胺（5毫升）中的溶液冷卻至〇°c，且隨後加入碳酸鉀（1.81克，13·1毫莫耳）。將此混合物在〇°c攪拌 30分鐘。然後，加入4-(溴甲基）苯甲酸甲S旨（ALDRICH, 3 克，13.1¾莫耳）。使反應混合物溫熱至室溫並擾掉17小時。將混合物在減壓下濃縮。將殘留物溶解在DCM並用水清洗，將水層用DCM萃取。將有機層合併，用水清洗，經由MgS04乾燥，過濾並在減壓下將溶劑去除，得到標題化合物。巾 NMR (300 MHz，CDC13_d6): 7·97 (d，2H)，7.40 (d， 70 200804352 2H)，3·9〇 (s，3H)，3.55 (s，2H)，2.47 (br. m，8H)，2.28 (s， 3H)。中間物2 : 4-[(4-甲基-1-六氫吡畊基）曱基]苯甲酸A solution of 'iN-methylhexapirinyl (ALDRICH, 1.46 ml, 13.1 mmol) in dimethyl decylamine (5 ml) was cooled to 〇°c, and then potassium carbonate (1.81 g) was added. , 13.1 millimoles). This mixture was stirred at 〇 °c for 30 minutes. Then, 4-(bromomethyl)benzoic acid methyl S was added (ALDRICH, 3 g, 13.13⁄4 mol). The reaction mixture was allowed to warm to room temperature and was taken up for 17 hours. The mixture was concentrated under reduced pressure. The residue was dissolved in DCM and washed with water. The organic layers were combined, washed with water, dried EtOAc mjjjjj NMR (300 MHz, CDC13_d6): 7·97 (d, 2H), 7.40 (d, 70 200804352 2H), 3·9〇(s, 3H), 3.55 (s, 2H), 2.47 (br. m, 8H), 2.28 (s, 3H). Intermediate 2: 4-[(4-Methyl-1-hexahydropyrryl)indenyl]benzoic acid

將氫氧化鋰(ALDRICH, 337毫克，14.1毫莫耳)於H20 (1〇毫升）之溶液添加至中間物1 (1·4克，5·63毫莫耳)於 MeOH (20毫升）之溶液並將混合物迴流2小時。將混合物在減壓下濃縮。將殘留物溶解在DCM並加入2N氫氯酸而得到pH 5。將水層用正丁醇分配(5次）並將洗提液合併，經由MgS04乾燥，過濾並在減壓下蒸發，得到標題化合物之白色固體。1H NMR (300 MHz，DMSO-d6): 12.83 (br· m，1H)， 11.05 (br· m，1H)，7·90 (d，2H), 7·43 (d，2H)，4.36 (m，1H)， 3·60 (s，2H)，3.38-2.80 (br· m，8H)，2.68 (s，3H)。[ES+MS] m/z 235 (MH)+ 〇中間物3 ·· 2-(2-甲基丙基)肼敌酸i，i_二甲基乙酯今丫、1 將胼羧酸ι，ι-二曱基乙酯（ALDRICH，9·2克，7〇毫莫耳）於i-PrOH(50毫升）之溶液在yc用異丁醛(aldrich， 6·4耄升，70耄莫耳）處理經15分鐘並在〇它攪拌2小時，A solution of lithium hydroxide (ALDRICH, 337 mg, 14.1 mmol) in H20 (1 mL) was added to a solution of Intermediate 1 (1·4 g, 5.63 mmol) in MeOH (20 mL) The mixture was refluxed for 2 hours. The mixture was concentrated under reduced pressure. The residue was dissolved in DCM and 2N hydrochloric acid was added to afford pH 5. The aqueous layer was partitioned with n-butanol (5) and EtOAc (EtOAc) 1H NMR (300 MHz, DMSO-d6): 12.83 (br· m, 1H), 11.05 (br· m, 1H), 7·90 (d, 2H), 7·43 (d, 2H), 4.36 (m) , 1H), 3·60 (s, 2H), 3.38-2.80 (br· m, 8H), 2.68 (s, 3H). [ES+MS] m/z 235 (MH)+ 〇Intermediate 3 ·· 2-(2-methylpropyl) oxime acid i,i_dimethylethyl phthalate, 1 胼胼, i-dithiol ethyl ester (ALDRICH, 9 · 2 g, 7 〇 millimol) in i-PrOH (50 ml) solution in yc with isobutyraldehyde (aldrich, 6.4 liters, 70 耄 Mo The ear) was treated for 15 minutes and stirred for 2 hours.

71 200804352 中加入Pt〇2並將懸浮液在室溫及2.6巴氫化48小時。將懸浮液過濾並在減壓下將溶劑蒸發後得到標題化合物。ιΗ NMR (300 MHz，CDC13): 6·02 (br· s，1H)，3.92 (br· s，1H)， 2.66 (d，2H)，1.73 (m，1H)，1·46 (s，9H)，0·93 (d，6H)。 [ES+MS] m/z 189 (ΜΗ)、中間物4 · 2-(5->臭-2_氣-4-¾、咬基)-(2 -曱基丙基)胼叛酸ii_ 二曱基乙酯71 200804352 Pt〇2 was added and the suspension was hydrogenated at room temperature and 2.6 bar for 48 hours. The suspension was filtered and the solvent was evaporated <RTI ID=0.0> Η NMR (300 MHz, CDC13): 6·02 (br·s,1H), 3.92 (br·s,1H), 2.66 (d,2H), 1.73 (m,1H),1·46 (s,9H) ), 0·93 (d, 6H). [ES+MS] m/z 189 (ΜΗ), intermediate 4 · 2-(5-> odor-2_gas-4-3⁄4, bite base)-(2-mercaptopropyl) 胼酸 acid ii_ Dimercaptoethyl ester

在5-溴-2,4_二氣嘧啶(ALDRICH，3·0克，13毫莫耳）及中間物3 (2.5克，13毫莫耳)於KPr〇H (80毫升）之溶液中加入N，N-二異丙基乙基胺（3毫升，17毫莫耳）並將所得的反應混合物迴流5小時。將混合物在減壓下濃縮並將殘留物分配在DCM及1M氯化銨之間。將有機層用水及鹽水清洗並經由無水NajO4乾燥。將殘留物經由快速層析法純化（流提液：Hex/EtOAc 9:1)後得到標題化合物。NMR (300 MHz，CDC13) δ ppm: 8·27 (br· s，1Η)，6·85_6.40 (br· m， 1H)，4·15-3·00 (br· m，2H)，2·06 (m，1H)，1·55-1·30 (br. m， 9H)，0·97 (d，ffi)。[ES+MS] m/z 379 (M)+，[ES-MS] m/z 377 (M-2H)、中間物5 : 2-(5-溴-2-氰基σ定基)-(2-甲基丙基)胼叛酸 1，1-二甲基乙酉旨 72 200804352Add to a solution of 5-bromo-2,4-dioxapyrimidine (ALDRICH, 3.00, 13 mmol) and Intermediate 3 (2.5 g, 13 mmol) in KPr〇H (80 mL) N,N-Diisopropylethylamine (3 mL, 17 mmol) and the obtained mixture was refluxed for 5 hr. The mixture was concentrated under reduced pressure and the residue was partitioned between DCM and 1M ammonium chloride. The organic layer was washed with water and brine and dried over anhydrous Naj. The residue was purified by flash chromatography (EtOAc:EtOAc: NMR (300 MHz, CDC13) δ ppm: 8·27 (br· s, 1Η), 6.85_6.40 (br· m, 1H), 4·15-3·00 (br· m, 2H), 2 · 06 (m, 1H), 1·55-1·30 (br. m, 9H), 0·97 (d, ffi). [ES+MS] m/z 379 (M)+, [ES-MS] m/z 377 (M-2H), Intermediate 5: 2-(5-bromo-2-cyanosyl-s- yl)-(2 -Methylpropyl) 胼Resin 1,1,2-dimethylethyl hydrazine 72 200804352

將氰化鉀(0·9克，13毫莫耳）添加至中間物4(4·1克， π毫莫耳）及DABCO (1.2克，11毫莫耳)於DMS0/H20 9:1 混合物在室溫之懸浮液中。將反應混合物在室溫攪拌3小時後倒入冰水中。將沈澱的乳色固體過濾，用大量水清洗並在空氣下乾燥。將化合物經由快速層析法純化（流提液：Potassium cyanide (0·9 g, 13 mmol) was added to Intermediate 4 (4.1 g, π mmol) and DABCO (1.2 g, 11 mmol) to DMS0/H20 9:1 mixture In a suspension at room temperature. The reaction mixture was stirred at room temperature for 3 hours and then poured into ice water. The precipitated milk solid was filtered, washed with a large amount of water and dried under air. Purification of the compound via flash chromatography (liquid extract:

Hex/EtOAc 19:1)後得到標題化合物。hNMR (300 MHz， CDC13) δ ppm: 8.46 (br· s，1H)，6·85-6·45 (br· m，1H)， 4·15·3·0 (br· m，2H)，2.06 (m，1H)，1.52-1.31 (br· m，9H)， 0.97 (d? 6H) ； lU NMR (300 MHz5 d6-DMSO? 80°C) δ ppm: 9·77 (br· s，1H)，8·59 (s，1H), 3.59 (br. s，2H)，2·04 (m，1H), 1·41 (br· s，9H)，〇·92 (d，6H) ; 13C NMR (90 MHz，d6-DMSO) δ ppm: 160·7, 159.6, 153.6, 140·6, 115.7, 1〇4·7, 80.4, 58.6， 27.7, 25·5, 20·0。[ES+MS] m/z 370 (M)+。中間物6 : 5-溴-4-[l-(2-甲基丙基)肼基]-2-嘧啶腈The title compound was obtained after Hex /EtOAc 19: 1). hNMR (300 MHz, CDC13) δ ppm: 8.46 (br· s,1H),6·85-6·45 (br· m,1H), 4·15·3·0 (br· m,2H),2.06 (m,1H), 1.52-1.31 (br· m,9H), 0.97 (d? 6H) ; lU NMR (300 MHz5 d6-DMSO? 80°C) δ ppm: 9·77 (br·s,1H) ,8·59 (s,1H), 3.59 (br. s,2H),2·04 (m,1H), 1·41 (br· s,9H),〇·92 (d,6H) ; 13C NMR (90 MHz, d6-DMSO) δ ppm: 160·7, 159.6, 153.6, 140·6, 115.7, 1〇4·7, 80.4, 58.6, 27.7, 25·5, 20·0. [ES+MS] m/z 370 (M)+. Intermediate 6 : 5-Bromo-4-[l-(2-methylpropyl)indolyl]-2-pyrimidinenitrile

在中間物5 (3.5克，9.4毫莫耳)於無水乙腈(70毫升）之溶液中加入對-甲苯石黃酸(4.07克，23.6毫莫耳）並將所得的反應混合物在室溫攪拌24小時。然後將混合物在真空濃縮並將殘留物分配在DCM及飽和的碳酸氫鈉之間。將殘留 73 200804352To a solution of Intermediate 5 (3.5 g, 9.4 mmol) in dry EtOAc (EtOAc) (EtOAc) hour. The mixture was then concentrated in vacuo and the residue was partitioned between DCM and sat. Will remain 73 200804352

物經由製備級 HPLC (X-TERRA 19x150 毫米，ACN:H20， 0.1% TFA，梯度10-100%)純化後得到標題化合物。1H NMR (300 MHz，CDC13) δ ppm: 8·39 (s，1H)，3·75 (d，2H)，2.22 (m， 1H)，0.96 (d，6H)。[ES+MS] m/z 270 (M)+。中間物7 : 4-[(4-丙基-1-六氮吡畊基）曱基]苯曱酸〜0""〇y〇h 〇將4-(溴曱基）苯甲酸(ALDRICH，5克，23·2毫莫耳）、 1-Ν-丙基六氫吡畊二溴酸鹽(ALDRICH，6·74克，23.2毫莫耳）及微細粉末化的無水碳酸鉀(ALDRICH，6.4克，46.5 毫莫耳）於無水乙腈（80毫升）之混合物在室溫攪拌17小時。然後加入IN HC1直到pH 2。將混合物在減壓下濃縮。將粗產物經由製備級HPLC (X-TERRA 19x150亳米， ACN:H2〇, 0.1% TFA，梯度0-30%)純化後得到標題化合物。 !H NMR (300 MHz，DMSO，d6) δ ppm: 7·94 (d，2H)，7.49 (d 2H)，3.89 (br，2H)，3·02 (m，2H)，3.70-2.50 (m，8H)，1·62 (m 2H)，0.88 (t，3H)。[ES+MS] m/z 263 (MH)+。中間物8 : 3-[(4-丙基-1-六氫吡畊基）甲基]笨甲酸〇在3-(氣甲基)-苯甲酸(ALDRICH，0·5克，3毫莫耳)於無水乙腈（10毫升）之溶液中加入1-Ν-丙基六氫咄畊二填酸 74 200804352 鹽(ALDRICH，0·86克，3耄莫耳）及碳酸_(〇·83克，6毫Purification by preparative HPLC (X-TERRA 19 <RTI ID=0.0></RTI> </RTI> <RTIgt; 1H NMR (300 MHz, CDC13) δ ppm: 8·39 (s, 1H), 3·75 (d, 2H), 2.22 (m, 1H), 0.96 (d, 6H). [ES+MS] m/z 270 (M)+. Intermediate 7: 4-[(4-propyl-1-hexafluoropyridinyl)indolyl]benzoic acid~0""〇y〇h 4- 4-(bromoindolyl)benzoic acid (ALDRICH, 5 g, 23.2 mmol, 1-Ν-propyl hexahydropyridinium dibromide (ALDRICH, 6.74 g, 23.2 mmol) and finely powdered anhydrous potassium carbonate (ALDRICH, 6.4) A mixture of EtOAc (46.5 mmol) in dry EtOAc (EtOAc) Then IN HC1 was added until pH 2. The mixture was concentrated under reduced pressure. The crude product was purified by EtOAc EtOAc EtOAc (EtOAc: !H NMR (300 MHz, DMSO, d6) δ ppm: 7·94 (d, 2H), 7.49 (d 2H), 3.89 (br, 2H), 3·02 (m, 2H), 3.70-2.50 (m , 8H), 1.62 (m 2H), 0.88 (t, 3H). [ES+MS] m/z 263 (MH)+. Intermediate 8: 3-[(4-propyl-1-hexahydropyrryl)methyl] benzoic acid hydrazine in 3-(gasmethyl)-benzoic acid (ALDRICH, 0.5 gram, 3 mmol) In a solution of anhydrous acetonitrile (10 ml), 1-Ν-propyl hexahydroquinone hydrazine is added to the acid 74 200804352 salt (ALDRICH, 0·86 g, 3 耄mol) and carbonic acid _ (〇·83 g, 6 millimeters

莫耳）並將所得的混合物在室溫攪拌。經22小時後，反應達到完成且因此在真空將溶劑蒸發。將殘留物分配在1 _ 丁醇及1NNHUC1，將合併的有機層用鹽水清洗並經由Na2S〇4 乾燥。在減壓下將溶劑蒸發後得到標題化合物。iHNMR (300 MHz，DMSO-d6) δ ppm: 7·81 (br，1H)，7·79-7·71 (br， 1Η)，7·84-7·21 (br，2Η)，3·81-2·99 (br，6Η)，2·44-2·22 (br， 4H)，2·18 (m，2H)，1·38 (m，2H)，0·82 (m，3H)。[ES+MS] m/z 263 (MH)+，[ES-MS] m/z 261 (M-H)、中間物9 : 2-(2,5-二氣-4-喷咬基)-(2-曱基丙基)胼魏酸i，i_ 二曱基乙酯Mohr) and the resulting mixture was stirred at room temperature. After 22 hours, the reaction was complete and the solvent was evaporated in vacuo. The residue was partitioned between 1 -butanol and 1NNHUC1 and the combined organic layers were washed with brine and dried over Na.sub.2. The solvent was evaporated under reduced pressure to give the title compound. iHNMR (300 MHz, DMSO-d6) δ ppm: 7·81 (br, 1H), 7·79-7·71 (br, 1Η), 7·84-7·21 (br, 2Η), 3·81 -2·99 (br,6Η), 2·44-2·22 (br, 4H), 2·18 (m, 2H), 1.38 (m, 2H), 0·82 (m, 3H). [ES+MS] m/z 263 (MH)+, [ES-MS] m/z 261 (MH), Intermediate 9: 2-(2,5-diox-4-purchase)-(2 -mercaptopropyl) 胼wei acid i,i_didecyl ethyl ester

在2,4,5-三氣嘧啶(LANCASTER, 0.5克，2.7毫莫耳）及中間物3(0.6克，3.1毫莫耳）於i-Pr〇H(15毫升）之溶液中加入N，N-二異丙基乙基胺(0.7毫升，3 ·7毫莫耳）並將所得的反應混合物迴流3小時。將混合物在減壓下濃縮並將殘留物分配在DCM及1Μ氯化銨之間。將有機層用水及鹽水清洗並經由無水NaJO4乾燥。將殘留物經由快速層析法純化（流提液：Hex/EtOAc 19:1)後得到標題化合物。4 NMR (300 MHz，CDC13) δ ppm: 8·11 (br· s，1H)，6·85-6·70 (br. m， 1H)，3·80-3·50 (br. m，2H)，2·06 (m，1H)，1·46 (br· s，9H)， 0.96 (d，6H)。[ES+MS] m/z 335 (MH)+。 75 200804352 中間物10 : 2-(5-氯-2-氰基-4-嘧啶基)-(2-甲基丙基)胼羧酸 U·二甲基乙酯Add N to a solution of 2,4,5-tris-pyrimidine (LANCASTER, 0.5 g, 2.7 mmol) and Intermediate 3 (0.6 g, 3.1 mmol) in i-Pr〇H (15 mL). N-Diisopropylethylamine (0.7 mL, 3 · 7 mmol) and the obtained mixture was refluxed for 3 hr. The mixture was concentrated under reduced pressure and the residue was partitioned between DCM andEtOAc. The organic layer was washed with water and brine and dried over anhydrous Na.sub.4. The residue was purified by flash chromatography (EtOAc:EtOAc: 4 NMR (300 MHz, CDC13) δ ppm: 8·11 (br· s, 1H), 6·85-6·70 (br. m, 1H), 3·80-3·50 (br. m, 2H ), 2·06 (m, 1H), 1.46 (br·s, 9H), 0.96 (d, 6H). [ES+MS] m/z 335 (MH)+. 75 200804352 Intermediate 10: 2-(5-Chloro-2-cyano-4-pyrimidinyl)-(2-methylpropyl)indolecarboxylic acid U·dimethylethyl ester

將氰化鉀(0.2克，2.7毫莫耳）添加至中間物9(0.7克， 2.2 毫莫耳）及 DABCO (1.2 克，11 毫莫耳)於 DMS0/H20 9··1 混合物（20毫升）在室溫之懸浮液中。將反應混合物在室溫攪拌9小時後倒入冰水中。將沈澱的淡黃色固體過濾，用大量水清洗並在空氣下乾燥。將化合物經由快速層析法純化（流提液：Hex/EtOAc混合物19:1至9:1)後得到標題化合物。]Η NMR (300 MHz，d6-DMSO) δ ρρπκ 10·09 (br· s， 1Η)，8·51 (br· s，1Η)，3·98-3·71 (br· m，1Η)，3·30-3·07 (br· m， 1Η), 1.98 (m? 1H)? 1.41 (br. s5 9H)? 0.99-0.79 (br. 6H) ； lU NMR (300 MHz，d6-DMSO, 80°C) δ ρρηκ 9·81 (br· s，1H)， 8.47 (s，1H)，3·80-3·34 (br· m，2H)，2·03 (m，1H)，1.41 (br. s， 9H)，0.93 (d，6H)。[ES+MS] m/z 326 (MH)+。中間物11 · 5-氣-4-[l-(2-甲基丙基)月井基]-2-嘴σ定腈Potassium cyanide (0.2 g, 2.7 mmol) was added to Intermediate 9 (0.7 g, 2.2 mmol) and DABCO (1.2 g, 11 mmol) to DMS0/H20 9··1 mixture (20 ml) ) in a suspension at room temperature. The reaction mixture was stirred at room temperature for 9 hours and then poured into ice water. The precipitated pale yellow solid was filtered, washed with a large amount of water and dried under air. The title compound was obtained after purification by flash chromatography (EtOAc:EtOAc:EtOAc:EtOAc Η NMR (300 MHz, d6-DMSO) δ ρρπκ 10·09 (br· s, 1Η), 8·51 (br· s, 1Η), 3·98-3·71 (br· m, 1Η), 3·30-3·07 (br· m, 1Η), 1.98 (m? 1H)? 1.41 (br. s5 9H)? 0.99-0.79 (br. 6H) ; lU NMR (300 MHz, d6-DMSO, 80 °C) δ ρρηκ 9·81 (br· s,1H), 8.47 (s,1H),3·80-3·34 (br· m,2H),2·03 (m,1H),1.41 (br .s, 9H), 0.93 (d, 6H). [ES+MS] m/z 326 (MH)+. Intermediate 11 · 5-Gas-4-[l-(2-methylpropyl) Moonhole Base]-2-Tip Sigma

在中間物10(0.5克，1.5毫莫耳)於無水乙腈10毫升）之溶液中加入對_甲苯磺酸(0.79克，4.6毫莫耳）並將所得的反應混合物在室溫攪拌20小時。將混合物在真空濃縮並將 76 200804352 殘留物分配在DCM及碳酸氫鈉的飽和溶液之間。將合併的有機層用鹽水處理並經由MgS04乾燥。將殘留物經由快速層析法純化（流提液：Hex/EtOAc 100:0至3:2)純化後得到標題化合物。NMR (300 MHz, d6-DMSO) δ ppm: 8·30 (s， 1Η)，5·09 (br· s，2Η)，3.56 (d，2Η)，2.18 (m，1Η), 0·86 (d， 6H)。[ES+MS] m/z 226 (MH)+。中間物12 : 4-氟-3-曱基苯甲酸甲酯p-Toluenesulfonic acid (0.79 g, 4.6 mmol) was added to a solution of Intermediate 10 (0.5 g, 1.5 mmol) in dry acetonitrile (10 mL) and the obtained mixture was stirred at room temperature for 20 hr. The mixture was concentrated in vacuo and the residue was taken in EtOAc EtOAc EtOAc EtOAc. The combined organic layers were treated with brine and dried over MgSO 4 . The residue was purified by flash chromatography (EtOAc:EtOAc:EtOAc NMR (300 MHz, d6-DMSO) δ ppm: 8·30 (s, 1Η), 5·09 (br· s, 2Η), 3.56 (d, 2Η), 2.18 (m, 1Η), 0·86 ( d, 6H). [ES+MS] m/z 226 (MH)+. Intermediate 12: methyl 4-fluoro-3-indolylbenzoate

將4-氟-3-甲基苯曱酸(ALDRICH, 5.06克，32.8毫莫耳）、碳酸鉀（17.9克，130毫莫耳）及碘化鉀(20.2毫升，324.5 毫莫耳）溶解在無水丙酮(200毫升）。將所得的反應混合物在室溫攪拌5分鐘後加熱至50°C。經16小時後，反應到達完成且因此在真空將溶劑蒸發。經由將殘留物溶解在 DCM將過量的碘化鉀去除，隨後在減壓下將溶劑去除。將殘留物經由快速層析法純化（流提液：Hex/EtOAc 100:0至 3:2)純化後得到標題化合物。iH NMR (300 MHz，CDC13) δ ppm: 7·94_7·82 (m，2Η)，7·08_7·02 (m，1Η)，3·91 (s，3Η)， 2.33-2.32 (m，3H) 〇 J· Org· Chem·，（1996) 61(12)，4062-4072· 中間物13 : 3-(溴甲基)-4-氟苯曱酸曱酯4-Fluoro-3-methylbenzoic acid (ALDRICH, 5.06 g, 32.8 mmol), potassium carbonate (17.9 g, 130 mmol) and potassium iodide (20.2 mL, 324.5 mmol) dissolved in dry acetone (200 ml). The resulting reaction mixture was stirred at room temperature for 5 minutes and then heated to 50 °C. After 16 hours, the reaction was complete and the solvent was evaporated in vacuo. Excess potassium iodide was removed by dissolving the residue in DCM, followed by removal of the solvent under reduced pressure. The residue was purified by flash chromatography (EtOAc:EtOAc:EtOAc iH NMR (300 MHz, CDC13) δ ppm: 7·94_7·82 (m, 2Η), 7·08_7·02 (m, 1Η), 3·91 (s, 3Η), 2.33-2.32 (m, 3H) 〇J· Org·Chem·, (1996) 61(12), 4062-4072· Intermediate 13: 3-(Bromomethyl)-4-fluorobenzoate decyl ester

77 200804352 在氬氣壓下，將中間物12(1克，6毫莫耳）溶解在四氯化碳(25毫升）。在所得的溶液中通入氬氣氣泡數分鐘後加入先前從水再結晶的N-溴代琥珀醯亞胺（ΐ·27克，7.1毫莫耳）及α，α’-偶氮異丁腈(〇·1克，〇·6毫莫耳）。然後將所得的反應混合物在80 C加熱。經3小時後，反應到達完成且因此將固體過濾並在真空將過濾液的溶劑去除。經由快速層析法純化（流提液：Hex/EtOAc 100:0至1:1)純化後得到標題化合物。1H NMR (300 MHz，CDC13) δ ppm: 8·1 (dd，1H)， 8·05-7·98 (m，1Η)，7·18-7·09 (m，1Η)，4·53 (m，2Η)，3·93 (s， 3H)。中間物14 : 4-氟-3-[(4-丙基-1-六氫吼σ井基）甲基]苯曱酸曱酯77 200804352 Intermediate 12 (1 g, 6 mmol) was dissolved in carbon tetrachloride (25 mL) under argon pressure. After the argon bubble was bubbled through the resulting solution for a few minutes, N-bromosinium iodide (ΐ27 g, 7.1 mmol) previously recrystallized from water and α,α'-azoisobutyronitrile were added. (〇·1g, 〇·6 millimoles). The resulting reaction mixture was then heated at 80 C. After 3 hours, the reaction reached completion and the solid was filtered and the solvent of the filtrate was removed in vacuo. Purification by flash chromatography (filtrate: Hex / EtOAc 100:0 to 1:1) afforded the title compound. 1H NMR (300 MHz, CDC13) δ ppm: 8·1 (dd, 1H), 8·05-7·98 (m, 1Η), 7·18-7·09 (m, 1Η), 4·53 ( m, 2Η), 3·93 (s, 3H). Intermediate 14 : 4-fluoro-3-[(4-propyl-1-hexahydroindole σ 井 )) methyl] benzoate oxime ester

在中間物13 (0.7克，2.7毫莫耳)於無水ACN (1〇毫升）之溶液中加入1-Ν-丙基六氩吡畊二溴酸鹽（ALDRICH，0.9 克，3·3毫莫耳）、碳酸鉀(0.8克，5.7毫莫耳）及催化的碘化鈉。然後將所得的反應混合物在室溫攪拌。經16小時後，反應到達完成且因此在真空將溶劑蒸發。將殘留物分配在 DCM及飽和水性氯化銨之間。將水層用DCM萃取並將合併的有機層用鹽水清洗並經由無水流酸納乾燥。在真空將溶劑去除後得到黃色油，然後將其經由快速層析法純化（流提液：Hex/EtOAc 100:0至1:1)純化後得到標題化合物。1η 78 200804352 NMR (300 MHz，CDC13) δ ppm: 8·09_8·03 (dd，1H)， 7.98-7.90 (m，1H)，7·11-7·05 (m，1H)，3·92 (s，3H)，3.63 (m， 2H)，2.68-2.40 (br·，8H)，2·35-2·3〇 (m，2H)，1.58-1.45 (m， 2H)，0.89 (t，3H)。中間物15 : 4-氟-3-[(4-丙基-1-六氫吡畊基）曱基]苯曱酸三氟醋酸鹽Add 1-indole-hexa-hexa-hydropyridyl dibromide (ALD RICH, 0.9 g, 3 · 3 mmol) to a solution of Intermediate 13 (0.7 g, 2.7 mmol) in anhydrous ACN (1 mL) Ear), potassium carbonate (0.8 g, 5.7 mmol) and catalytic sodium iodide. The resulting reaction mixture was then stirred at room temperature. After 16 hours, the reaction reached completion and the solvent was evaporated in vacuo. The residue was partitioned between DCM and saturated aqueous ammonium chloride. The aqueous layer was extracted with DCM and the combined organic layers were washed with brine and dried over anhydrous sodium sulfate. After removal of the solvent in vacuo, EtOAcqqqqqqqqq 1η 78 200804352 NMR (300 MHz, CDC13) δ ppm: 8·09_8·03 (dd,1H), 7.98-7.90 (m,1H),7·11-7·05 (m,1H),3·92 ( s, 3H), 3.63 (m, 2H), 2.68-2.40 (br·, 8H), 2·35-2·3〇 (m, 2H), 1.58-1.45 (m, 2H), 0.89 (t, 3H) ). Intermediate 15 : 4-fluoro-3-[(4-propyl-1-hexahydropyrryl)indenyl]benzoic acid trifluoroacetate

在中間物14 (0.3克，1·0毫莫耳）於5:1 THF-水混合物 (6毫升）之溶液中加入氫氧化鋰單水合物（〇·ΐ3克，3.2毫莫耳）。然後將所得的反應混合物在室溫攪拌。經16小時後，反應到達完成且因此在真空將溶劑蒸發。然後將殘留物溶解在MeOH並經由製備級HPLC (SUNFIRE 19x150毫米， ACN:H2〇,（U%TFA，梯度0-30%)純化後得到標題化合物。 !H NMR (300 MHz, d6-DMSO) δ ppm: 9.64-9.10 (br.? 1H), 8·〇4晒8·〇1 (dd，1H)，7.96-7.89 (m，1H)，7.36-7.30 (m，1H)， 3·72 (s，2H)，3.53-3.32 (br·，2H)，3.16-2.80 (br·，6H)， 2.52-2.29 (br·，2H)，1.69-1.50 (m，2H)，0·87 (t, 3H) 〇中間物16 : 4-氟-3-[(4-丙基-1-六氫吡畊基）甲基]苯甲醯氯To a solution of the intermediate 14 (0.3 g, 1.00 mmol) in a 5:1 THF-water mixture (6 mL), lithium hydroxide monohydrate (3 g, 3.2 mmol) was added. The resulting reaction mixture was then stirred at room temperature. After 16 hours, the reaction reached completion and the solvent was evaporated in vacuo. The residue was then taken up in EtOAc (EtOAc) (EtOAc) δ ppm: 9.64-9.10 (br.? 1H), 8·〇4 drying 8·〇1 (dd,1H), 7.96-7.89 (m,1H), 7.36-7.30 (m,1H), 3·72 ( s, 2H), 3.53-3.32 (br·, 2H), 3.16-2.80 (br·, 6H), 2.52-2.29 (br·, 2H), 1.69-1.50 (m, 2H), 0·87 (t, 3H) 〇Intermediate 16 : 4-fluoro-3-[(4-propyl-1-hexahydropyrryl)methyl]benzhydryl chloride

在氮氣壓下，將中間物15(0·3克，0.9毫莫耳）溶解於 79 200804352 亞硫醢氯（1 〇毫升）並將所得的反應混合物在室溫攪拌。經 16小時後，反應實質上到達完成且因此在真空將溶劑蒸發。經由將殘留物溶解在DCM將過量的亞硫醯氣去除，隨後在減壓下將溶劑去除，得到標題化合物，其不再有任何進一步純化而使用。]HNMR (300 MHz，CDC13) δ ppm: 8·74_8·67 (m，1Η)，8·35-8·24 (m，1Η)，7.42-7.34 (m，1Η)， 4·41 (br· s，2H)，4.29-4.14 (br·, 2H)，4.14-3.96 (br·，2H)， 3·66-3·50 (br·，4H)，3.11-2.99 (br·，2H)，2·0Μ·84 (br·，2H)， 1·08_1·03 (m，3H)。中間物17 : N’-(5-氣-2-氰基-4-嘧啶基)-4-(氣曱基)-N’-(2- 曱基丙基）笨曱醯胼Intermediate 15 (0.3 g, 0.9 mmol) was dissolved in 79 200804352 sulfinium chloride (1 mL) under nitrogen pressure and the resulting mixture was stirred at room temperature. After 16 hours, the reaction essentially reached completion and thus the solvent was evaporated under vacuum. Excess sulphur sulfonium was removed by dissolving the residue in DCM, then the solvent was removed under reduced pressure to give the title compound which was used without further purification. HNMR (300 MHz, CDC13) δ ppm: 8·74_8·67 (m, 1Η), 8·35-8·24 (m, 1Η), 7.42-7.34 (m, 1Η), 4·41 (br· s, 2H), 4.29-4.14 (br·, 2H), 4.14-3.96 (br·, 2H), 3·66-3·50 (br·, 4H), 3.11-2.99 (br·, 2H), 2 ·0Μ·84 (br·, 2H), 1·08_1·03 (m, 3H). Intermediate 17: N'-(5-Gas-2-cyano-4-pyrimidinyl)-4-(azepine)-N'-(2-mercaptopropyl) alum

在中間物11 (2.58克，11毫莫耳)於無水THF (40毫升) 的攪拌溶液中加入4-(氯甲基）苯甲醯氯(ALDRICH, 2.17 克，11毫莫耳）及碳酸鉀(3·35克，24毫莫耳）並將所得的反應混合物在室溫擾拌2·5小時。將混合物過濾並在真空將溶劑蒸發。將粗反應混合物經由快速層析法純化（流提液： Hex/EtOAc從100:0至1:1)純化後得到標題化合物。1H NMR (300 MHz，CDC13) δ ppm: 8.31 (s，1Η)，8.25 (br· s，1Η)，7.8 (d，2H)，7.51 (d，2H)，4.62 (s，2H)，3.79 (br· m，2H)，2.09 (m， 1H)，1.01 (d，6H) 〇 200804352 中間物18 : Ν’-(5_演-2-氰基-4-0密咬基)冰(氣甲基)_n，-(2 曱基丙基）苯曱醯肼Add 4-(chloromethyl)benzimidium chloride (ALDRICH, 2.17 g, 11 mmol) and potassium carbonate to a stirred solution of intermediate 11 (2.58 g, 11 mmol) in dry THF (40 mL) (3. 35 g, 24 mmol) and the resulting reaction mixture was stirred at room temperature for 2.5 hours. The mixture was filtered and the solvent was evaporated in vacuo. The crude reaction mixture was purified by flash chromatography (EtOAc:EtOAc:EtOAc 1H NMR (300 MHz, CDC13) δ ppm: 8.31 (s, 1 Η), 8.25 (br· s, 1 Η), 7.8 (d, 2H), 7.51 (d, 2H), 4.62 (s, 2H), 3.79 ( Br· m,2H),2.09 (m, 1H),1.01 (d,6H) 〇200804352 Intermediate 18 : Ν'-(5_演-2-cyano-4-0 密基基)Ice Base)_n,-(2 mercaptopropyl)benzoquinone

在中間物6 (195毫克，0.72毫莫耳)及K2C03 (200毫克， 1.44毫莫耳）於THF (7毫升）的攪拌混合物中加入4-(氣甲基) 笨曱酿氣(ALDRICH，164毫克，0·87毫莫耳）並將混合物在室溫攪拌15小時。將混合物過濾，將過濾液在真空蒸發至乾，並將所得的殘留物層析（矽膠，己烷/醋酸乙酯20%) 後得到所要的產物。]HNMR (300 MHz，DMSO-d6) δ ppm: 11·38 (s，1Η)，8·63 (s，1Η)，7·92 (m，2Η)，7·59 (m，2Η)，4·83 (s，2H)，4·02 (m，1H)，3·43 (m，1H)，2·07 (m，1H)，0.95 (d， 6H)。[ES+MS] m/z 422 (M)+。 t間物19 : N’_(5-氯-2_氰基-4-嘧啶基)-3-(氯甲基)-N，-(2- 曱基丙基）苯曱醯胼Add 4-(gas methyl) awkward gas (ALDRICH, 164) to a stirred mixture of intermediate 6 (195 mg, 0.72 mmol) and K2C03 (200 mg, 1.44 mmol) in THF (7 mL). Mg, 0. 87 mmoles and the mixture was stirred at room temperature for 15 hours. The mixture was filtered, and the filtrate was evaporated EtOAcjjjjjjjj HNMR (300 MHz, DMSO-d6) δ ppm: 11·38 (s, 1Η), 8·63 (s, 1Η), 7.92 (m, 2Η), 7·59 (m, 2Η), 4 · 83 (s, 2H), 4·02 (m, 1H), 3·43 (m, 1H), 2·07 (m, 1H), 0.95 (d, 6H). [ES+MS] m/z 422 (M)+. T-intermediate 19 : N'_(5-chloro-2-cyano-4-pyrimidinyl)-3-(chloromethyl)-N,-(2-mercaptopropyl)phenylhydrazine

將3-(氣曱基)-苯曱醯氣(aldRICH，0.106克，〇·56毫莫耳）添加至中間物11 (0.13克，0.58毫莫耳）及碳酸鉀 (〇·160克，M6毫莫耳）於無水THF (2毫升）之溶液並將所 81 200804352 得的反應混合物在室溫攪拌。經2小時後，反應完成，將混合物過濾並將溶劑蒸發。將粗產物使用石夕膠純化（洗提液：己烷/醋酸乙酯），得到標題化合物。ES+MS m/z378 (M)+。中間物20 : 1-L-丙基u比略咬3-(Gasyl)-benzoquinone (aldRICH, 0.106 g, 〇·56 mmol) was added to Intermediate 11 (0.13 g, 0.58 mmol) and potassium carbonate (〇·160 g, M6) A solution of the residue in anhydrous THF (2 mL) and EtOAc. After 2 hours, the reaction was completed, the mixture was filtered and solvent evaporated. The crude product was purified using EtOAc (EtOAc:EtOAc) ES+MS m/z378 (M)+. Intermediate 20: 1-L-propylu is slightly bitten

在（s)_(-)-2-(l-吡咯啶基羰基)_1_吡咯啶羧酸苄酯 (ALDRICH，300毫克，1 ·〇毫莫耳)於曱醇/醋酸(30毫升）之溶液中加入Pd/C 10% (30毫克）。將懸浮液在室溫及2.46 巴氫化150分鐘。將懸浮液過濾並將溶劑在減壓下蒸發。粗產物不再進一步純化而用在下一個步驟。[ES+MS] m/z 169 (ΜΗ)、中間物21 : 3-(溴曱基)-4-氟苯曱酸Benzyl (s)-(-)-2-(l-pyrrolidinylcarbonyl)_1-pyrrolidinecarboxylate (ALDRICH, 300 mg, 1 · 〇 mmol) in methanol/acetic acid (30 ml) Pd/C 10% (30 mg) was added to the solution. The suspension was hydrogenated at room temperature and 2.46 bar for 150 minutes. The suspension was filtered and the solvent was evaporated under reduced pressure. The crude product was used in the next step without further purification. [ES+MS] m/z 169 (ΜΗ), intermediate 21 : 3-(bromoindolyl)-4-fluorobenzoic acid

在4-氟-3-曱基笨甲酸(ALDRICH，1克，6.49毫莫耳）於四氯化碳(25毫升）的溶液中，在惰性氣壓下加入N_漠代琥珀醯亞胺(ALDRICH，2.54克，14.27毫莫耳）及過氧化苯曱酸(ALDRICH，111毫克）。將反應混合物迴流2小時並在室溫攪拌過夜。將混合物過濾並在減壓下將溶劑蒸發。將所得的殘留物經由製備級HPLC (LUNA 50x250毫米 82 200804352 ACN:H2〇, 0.1%TFA，梯度30-80%)純化後得到標題化合物。1H NMR (300 MHz，d6-DMSO) δ ppm: 13.18 (br s，1H)， 8·17-8·11 (br· m，1H)，8.00-7.91 (br· m，1H)，7.41-7.31 (br· m, 1H)，4·77 (s，2H)。 ’ 中間物22 : 3_(溴甲基)-4-氟苯曱醯氣Add N-Dime amber quinone imine (ALDRICH) under inert pressure in a solution of 4-fluoro-3-indolyl acid (ALDRICH, 1 g, 6.49 mmol) in carbon tetrachloride (25 ml) , 2.54 g, 14.27 mmol) and benzoic acid (ALDRICH, 111 mg). The reaction mixture was refluxed for 2 hours and stirred at room temperature overnight. The mixture was filtered and the solvent was evaporated under reduced pressure. The residue obtained was purified by preparative EtOAc (EtOAc EtOAc EtOAc EtOAc 1H NMR (300 MHz, d6-DMSO) δ ppm: 13.18 (br s,1H), 8·17-8·11 (br· m,1H), 8.00-7.91 (br· m,1H),7.41-7.31 (br· m, 1H), 4·77 (s, 2H). ' Intermediate 22 : 3_(bromomethyl)-4-fluorophenyl fluorene

在中間物21 (500毫克，2·12毫莫耳)於DCM (10毫升) 之溶液中加入亞硫醯氣(ALDRICH，4毫升）。將反應混合物在室溫攪拌過夜。在減壓下將溶劑蒸發後得到標題化合物◦粗產物不再進一步純化而用在下一個步驟。中間物23 : 3-(溴曱基)-N，-(5-氣-2-氰基-4-嘧啶基氟 -Ν’-(2-曱基丙基）苯甲酿胼Thionite gas (ALDRICH, 4 mL) was added to a solution of intermediate 21 (500 mg, 2.12 mmol) in DCM (10 mL). The reaction mixture was stirred at room temperature overnight. The title compound was obtained after evaporation of the solvent under reduced pressure and crude product was used in the next step without further purification. Intermediate 23: 3-(bromoindolyl)-N,-(5-gas-2-cyano-4-pyrimidinylfluoro-indole-(2-mercaptopropyl)benzazole

在中間物22 (531耄克，2.12毫莫耳)於無水THF (15 毫升）的溶液中加入中間物u (396毫克，176毫莫耳）及 N，N-二異丙基乙基胺(FLUKA，〇·613毫升，3 52毫莫耳）將反應混合物在室溫攪拌過夜後得到標題化合物，其不再Add intermediate u (396 mg, 176 mmol) and N,N-diisopropylethylamine to a solution of intermediate 22 (531 g, 2.12 mmol) in dry THF (15 mL) FLUKA, 613·613 ml, 3 52 mmol. The reaction mixture was stirred at room temperature overnight to give the title compound

83 20080435283 200804352

將5-曱基異口寻唑_3_羧酸乙酯（AVOCADO，1克，6.45 宅莫耳）溶解在CCiU (60宅升）。加入N-溴代琥拍酿亞胺 (ALDRICH，1.717克，9.67毫莫耳）及一刮刀尖的過氧化苯曱醯(ALDRICH)並將所得的溶液迴流3天。將反應混合物過濾，蒸發並將殘留物經由製備級HPLC (LUNA 50x250 毫米，梯度·· 30% ACN，0.1%TFA 至 80% ACN，0.1%TFA) 純化後得到標題化合物。1HNMR(300 MHz，CDCl3)3ppm: 6·72 (s，1H)，4·48 (s，2H)，4·44 (q，2H，>7·2)，1·41 (t，3H， J=7.2)。[ES+MS] m/z 234 (M)+。中間物25 : 5·(溴曱基)-3-異噚唑羧酸The 5-mercaptoisoxazole _3_carboxylic acid ethyl ester (AVOCADO, 1 g, 6.45 house Moule) was dissolved in CCiU (60 house liters). N-bromosuccinimide (ALDRICH, 1.617 g, 9.67 mmol) and a spatula benzoic acid benzoate (ALDRICH) were added and the resulting solution was refluxed for 3 days. The reaction mixture was filtered, evaporated and purified title crystal crystal crystal crystal crystal crystal crystal crystal 1H NMR (300 MHz, CDCl3) 3 ppm: 6·72 (s, 1H), 4·48 (s, 2H), 4·44 (q, 2H, > 7·2), 1·41 (t, 3H, J=7.2). [ES+MS] m/z 234 (M)+. Intermediate 25 : 5 · (bromomethyl)-3-isoxazolecarboxylic acid

在中間物24 (242.7毫克，ΐ·〇4毫莫耳)於THF (5毫升) 之溶液中加入氫氧化鋰單水合物（ALDRICH，62·〇8毫克， 2·59耄莫耳）在水(3毫升）中的溶液。將所得的溶液在室溫攪拌3·5小時。將溶劑蒸發後得到標題化合物，其不再進一步純化而用在下一個步驟。iH NMR (3〇〇 ΜΗζ， CDC13/CD30D) δ ppm: 6·5〇 (S，m)，4.36 (s，2Η)。中間物26 : N’-(5_溴氰基-4-嘧啶基)-5-(氯甲基)_n，-(2-甲基丙基)-3-異今唾卡巴月井 84 200804352Add lithium hydroxide monohydrate (ALDRICH, 62·〇8 mg, 2·59 mmol) in water to a solution of intermediate 24 (242.7 mg, ΐ·〇 4 mmol) in THF (5 mL) Solution in (3 ml). The resulting solution was stirred at room temperature for 3.5 hours. The solvent was evaporated to give the title compound, which was used in the next step without further purification. iH NMR (3〇〇 ΜΗζ, CDC13/CD30D) δ ppm: 6·5〇 (S, m), 4.36 (s, 2Η). Intermediate 26: N'-(5-bromocyano-4-pyrimidinyl)-5-(chloromethyl)_n,-(2-methylpropyl)-3-iso-salt Kabata well 84 200804352

ClCl

CN 相當於…毫莫耳)溶解於㈣，、、、 H，笔升，在二氯甲烷中的2M溶液）。將所得的溶液攪拌24小時，然後蒸發，並將殘留物(418毫克i π 毫莫耳）添加至中間物6(2似7毫克，0·935毫莫耳）及N，N一一異丙基^基胺(FLUKA，〇·65亳升，IN毫莫耳)於無水 ΤΗ^ΙΟ耄升）的溶液（先攪拌15分鐘）。在所得的溶液中加入第二丁醇鉀(ALDRICH，146.9亳克，1.31毫莫耳）。將混合物在室溫攪拌過夜。將溶劑蒸發並將殘留物經由製備級 HPLC (LUNA 50x250 毫米，梯度：4〇% ACN，0.1%TFA 至 80% ACN，0.1°/〇TFA)純化後得到標題化合物。NMR (300 MHz，CDC13) δ ppm: 8·81 (br· s，1H)，8.49 (s，1H)，6.79 (s， iH)，4.67 (s，2Η)，3·77 (m，2Η)，2·1〇 (m，1Η)，1.00 (d，6Η, J二6 Hz)。[ES+MS] m/z 413 (M)+。中間物27 : 7-甲基-1-苯並呋喃-2-叛酸乙酯CN is equivalent to ... millimolar) dissolved in (4),,,, H, pen liter, 2M solution in dichloromethane). The resulting solution was stirred for 24 hours, then evaporated, and the residue (418 mg i π m.) was added to Intermediate 6 (2: 7 mg, 0. 935 mM) and N, N isopropyl A solution of the base amine (FLUKA, 〇·65 liter, IN millimolar) in anhydrous hydrazine (first stirred for 15 minutes). To the resulting solution was added potassium dibutoxide (ALDRICH, 146.9 g, 1.31 mmol). The mixture was stirred at room temperature overnight. The solvent was evaporated and the residue was purified EtOAcjjjjjjjj NMR (300 MHz, CDC13) δ ppm: 8·81 (br·s, 1H), 8.49 (s, 1H), 6.79 (s, iH), 4.67 (s, 2Η), 3·77 (m, 2Η) , 2·1〇 (m, 1Η), 1.00 (d, 6Η, J 2 6 Hz). [ES+MS] m/z 413 (M)+. Intermediate 27: 7-Methyl-1-benzofuran-2-oleic acid ethyl ester

將2_羥基-3_曱基苯甲醛(ALDRICH, 1克，7·34毫莫耳) 及溴丙二酸二乙酯（ALDRICH, 1.82毫升，11.03毫莫耳）在氮氣壓下溶解在2-丁酮(ALDRICH, 9毫升）。加入碳酸 85 200804352 鉀(ALDRICH，2·03克，14·69毫莫耳）並將所得的懸浮液迴流至沒有起始物質（21小時）。將反應混合物冷卻至室溫，將碳酸鉀過濾並用醋酸乙酯稀釋過濾液，用NH4C11N (2x)、飽和的NaHC03 (1χ)及飽和的NaCl (lx)清洗。將合併的有機層用MgS04乾燥，過濾並蒸發至乾。得到3_羥基 -7-曱基-1-苯並呋喃-2,2-(3H)-二羧酸二乙酯並溶解在無水 THF (50毫升）。逐滴加入60%分散在礦物油中的氫化鈉 (ALDRICH，734毫克，18.35毫莫耳）。經1小時後，反應完成。將反應混合物倒入冰中，加入飽和的NaHC03及醋酸乙酯。將液層分離並將有機層用飽和的NaCl清洗，用 MgS04乾燥，過濾並蒸發至乾。將殘留物在矽膠上純化兩次（己烷/AcOEt混合物），得到標題化合物。1HNMR(300 MHz，CDC13) δ ppm: 7·50-7·52 (m，2H)，7·18-7·26 (m，2H)， 4·45 (q，2Η，J=7.2 Ηζ)，2.60 (s，3Η)，1·44 (t，3Η，J二7.0 Hz)。 [ES+MS] m/z 205 (MH)+。中間物28 · 7-(漠甲基苯並吱n南-2-羧酸乙酯2_Hydroxy-3_mercaptobenzaldehyde (ALDRICH, 1 g, 7.34 mmol) and diethyl bromomalonate (ALDRICH, 1.82 ml, 11.03 mmol) dissolved in 2 under nitrogen pressure - Butanone (ALDRICH, 9 ml). Carbonate 85 200804352 potassium (ALDRICH, 2.03 g, 14.69 mmol) was added and the resulting suspension was refluxed to no starting material (21 h). The reaction mixture was cooled to rt. EtOAc (EtOAc)EtOAc. The combined organic layers were dried over MgSO4, filtered and evaporated to dry. 3-Hydroxy-7-mercapto-1-benzofuran-2,2-(3H)-dicarboxylic acid diethyl ester was obtained and dissolved in anhydrous THF (50 mL). 60% sodium hydride (ALDRICH, 734 mg, 18.35 mmol) dispersed in mineral oil was added dropwise. After 1 hour, the reaction was completed. The reaction mixture was poured into ice, and saturated NaHC03 and ethyl acetate were added. The layers were separated and the organic layer was washed with sat. NaCI. The residue was purified twice on EtOAc (hexane /EtOAcEtOAc) 1HNMR (300 MHz, CDC13) δ ppm: 7·50-7·52 (m, 2H), 7·18-7·26 (m, 2H), 4·45 (q, 2Η, J=7.2 Ηζ), 2.60 (s, 3Η), 1.44 (t, 3Η, J 2 7.0 Hz). [ES+MS] m/z 205 (MH)+. Intermediate 28 · 7-(Methyl-methylbenzoindole n-N-2-carboxylic acid ethyl ester

將中間物27 (730毫克，3.57毫莫耳）溶解在四氣化碳 (20毫升）。加入N-溴代琥珀醯亞胺(ALDRICH，763毫克， 4·29毫莫耳）及過氧化苯甲醯(ALDRIch，18毫克，觸媒）並將所得的溶液在迴流加熱至沒有起始物質（22小時）。使反應冷卻，將固體過濾並將過濾液蒸發。將殘留物在矽膠 200804352 純化（己烧/AcOEt混合物），得到標題化合物。1η NMR (300 MHz，CDC13) δ ppm: 7·63_7·66 (m，1H)，7.54 (s，1H), 7·48-7·52 (m，1H)，7·30-7·33 (m，1H)，4.85 (s，2H)，4.46 (q， 2H，J=7.0 Hz)，1.44 (t，3H，J:7.2 Hz)。[ES+MS] m/z 283 (MH)、中間物29 : 7-(溴曱基)_1-苯並呋喃_2_羧酸Intermediate 27 (730 mg, 3.57 mmol) was dissolved in four carbonized carbon (20 mL). Add N-bromosuccinimide (ALDRICH, 763 mg, 4.29 mmol) and benzamidine peroxide (ALDRIch, 18 mg, catalyst) and heat the resulting solution to reflux without starting material (22 hours). The reaction was allowed to cool, the solid was filtered and the filtrate evaporated. The residue was purified in EtOAc (EtOAc/EtOAc) 1η NMR (300 MHz, CDC13) δ ppm: 7·63_7·66 (m, 1H), 7.54 (s, 1H), 7·48-7·52 (m, 1H), 7·30-7·33 ( m, 1H), 4.85 (s, 2H), 4.46 (q, 2H, J = 7.0 Hz), 1.44 (t, 3H, J: 7.2 Hz). [ES+MS] m/z 283 (MH), intermediate 29: 7-(bromomethyl)_1-benzofuran-2-carboxylic acid

將中間物28 (637毫克，2·25毫莫耳）溶解在THF (45 宅升）。加入氫氧化鋰在水中的2N溶液(ALDRICH, 2.8毫升，5.62毫莫耳）並將反應在室溫攪拌24小時。加入醋酸乙醋及水並將液層分離。將水層用2N HC1酸化並用二氯曱烧卒取(4x)。將有機層分離，用MgS04乾燥，過濾並蒸發後得到標題化合物。iHNMRpOOMHz’DMSO-dJSppm: 7·76_7·79 (m，1H)，7.72 (s，1H)，7·58·7·61 (m，1H)，7.32-7.37 (m，1Η)，4·96 (s，2Η)。[ES+MS] m/z 255 (Μ)+。中間物30 : 5-[(4-甲基小六氳吡呼基）甲基]-2-呋喃羧酸乙酯三氟醋酸鹽Intermediate 28 (637 mg, 2.25 mmol) was dissolved in THF (45 liter). A 2N solution of lithium hydroxide in water (ALDRICH, 2.8 mL, 5.62 mmol) was added and the mixture was stirred at room temperature for 24 hours. Ethyl acetate and water were added and the layers were separated. The aqueous layer was acidified with 2N HCl and was then taken from <RTIgt; The organic layer was separated, dried with EtOAc EtOAc EtOAc iHNMRpOOMHz'DMSO-dJSppm: 7·76_7·79 (m,1H), 7.72 (s,1H),7·58·7·61 (m,1H),7.32-7.37 (m,1Η),4·96 ( s, 2Η). [ES+MS] m/z 255 (Μ)+. Intermediate 30: 5-[(4-Methylpiperidine)methyl]-2-furancarboxylate Ethyl trifluoroacetate

將5_(氯甲基）-2-呋喃羧酸乙酯（ALDRICH, 1克，5·32 晕莫耳）溶解在無水ACN (60毫升）。加入碳酸鉀 87 200804352 (ALDRICH，585·9毫克，4.24毫莫耳）、N-甲基-六氫口比，井 (ALDRICH，258微升，2.33毫莫耳成㈣刀尖的蛾化納 (FLUKA)並將所得的懸〉孚液在室溫擾拌過夜。將混合物過濾，蒸發並將殘留物在製備級HPLC(XTERRA管柱 5〇χ25〇耄米，梯度：0% ACN，0.1〇/〇TFA 至 60% ACN， 0.1%TFA)純化後得到標題化合物。iHNmr(300 MHz， CDC13/CD30D) δ ppm: 7.10 (d，1H，>3·4 Ηζ)，6·40 (d，1H， J=3.4 Hz)，4.32 (q，2H，J=7.1 Hz)，3·73 (s，2H)，3.24 (br· m， 3H)，2.79-2.95 (m，8H)，1.34 (t，3H，J=7.1)。[ES+MS] m/z 253 (MH)+ 〇中間物31 : 5-[(4_甲基小六氫吡畊基）甲基]_2吱喃羧酸三氟醋酸鹽Ethyl 5-(chloromethyl)-2-furancarboxylate (ALDRICH, 1 g, 5.32 vaole) was dissolved in anhydrous ACN (60 mL). Add potassium carbonate 87 200804352 (ALDRICH, 585·9 mg, 4.24 mmol), N-methyl-hexahydroport ratio, well (ALDRICH, 258 μl, 2.33 mmol to (four) tip of moth ( FLUKA) and the resulting suspension of the suspension was stirred overnight at room temperature. The mixture was filtered, evaporated and the residue was purified on preparative HPLC (XTERRA column 5 〇χ 25 〇耄, gradient: 0% ACN, 0.1 〇 / The title compound was obtained after purification from 〇TFA to 60% ACN, 0.1%TFA. iHNmr (300 MHz, CDC13/CD30D) δ ppm: 7.10 (d,1H,>3·4 Ηζ),6·40 (d,1H) , J=3.4 Hz), 4.32 (q, 2H, J=7.1 Hz), 3·73 (s, 2H), 3.24 (br· m, 3H), 2.79-2.95 (m, 8H), 1.34 (t, 3H, J=7.1). [ES+MS] m/z 253 (MH) + 〇 intermediate 31 : 5-[(4-methyl hexahydropyranyl)methyl] 2 decyl carboxylic acid trifluoride Acetate

在中間物30 (896.2毫克，3·552毫莫耳)於THF (20毫升）的溶液中加入氫氧化鋰單水合物(ALDRICH, 212.68毫克，8·88毫莫耳)在水（1〇毫升）中的溶液。將所得的溶液在室溫攪拌過夜後將其迴流24小時。使反應混合物冷卻，用 2Ν HC1酸化並濃縮至乾。將殘留物在製備級HPLC (XTERRA 管柱 50x250 毫米，梯度：l〇%ACN，0.1%TFA 至100%ACN，0.1%TFA)純化後得到標題化合物。1HNMR (300 MHz，DMSO-d6) δ ppm: 9·80 (br s，1H)，7·17 (d，1H， J=6 Ηζ)，6,54 (d，1Η，J二6 Hz), 3·68 (s，2Η)，3·35-3·38 (m， 88 200804352 2H)，2·95-3·15 (m，4H)，2.75 (s，3H)，2·30-2·45 (m，2H)。 [ES+MS] m/z 225 (MH)+。中間物32 · 6-[3_(經基甲基）苯基]-3-吼咬缓酸Add lithium hydroxide monohydrate (ALDRICH, 212.68 mg, 8.88 mmol) in water (1 mL) in a solution of intermediate 30 (896.2 mg, 3.552 mmol) in THF (20 mL) The solution in ). The resulting solution was stirred at room temperature overnight and then refluxed for 24 hours. The reaction mixture was cooled, acidified with EtOAc (EtOAc)EtOAc. The residue was purified by preparative EtOAc EtOAc EtOAc EtOAc. 1HNMR (300 MHz, DMSO-d6) δ ppm: 9·80 (br s,1H),7·17 (d,1H, J=6 Ηζ), 6,54 (d,1Η, J 2 6 Hz), 3·68 (s, 2Η), 3·35-3·38 (m, 88 200804352 2H), 2·95-3·15 (m, 4H), 2.75 (s, 3H), 2·30-2· 45 (m, 2H). [ES+MS] m/z 225 (MH)+. Intermediate 32 · 6-[3_(transmethyl)phenyl]-3-anthracene acid

將6-氣菸鹼酸(ALDRICH，300毫克，L90毫莫耳)在氮氣壓下溶解於1,2-二甲氧基乙烷（15毫升；)。加入肆三苯基膦I巴(ALDRICH，440毫克，0.38毫莫耳）並將所得的反應混合物攪拌15分鐘。依序加入碳酸鈉（161毫克，1.52毫莫耳）、水(4毫升）及3-(羥基甲基）苯硼酸(LANCASTER, 404 毫克，2·66毫莫耳）。將所得的反應混合物在95°C攪拌16 小時後冷卻至室溫。經由石夕藻土過滤後，將反應混合物酸化(2N HC1)至pH 4，但是沒有產物可經由DCM萃取。因此，將水層蒸發至乾並經由製備級HPLC (XTERRA管柱 19x150 毫米，ACN:H2O,0.1%TFA，梯度 10_100%)純化後得到標題化合物。1HNMR(300 MHz, DMSO-d6)3ppm: 9.13 (m，1H)，8·358·8·29 (m，1H)，8.16-7.96 (m，3H)，8·02 (m， 1H)，7·51 -7·40 (m，2H)，4·59 (s，2H)。6-gas nicotinic acid (ALDRICH, 300 mg, L90 mmol) was dissolved in 1,2-dimethoxyethane (15 ml;) under nitrogen pressure. Triphenylphosphine I bar (ALDRICH, 440 mg, 0.38 mmol) was added and the resulting reaction mixture was stirred for 15 minutes. Sodium carbonate (161 mg, 1.52 mmol), water (4 ml) and 3-(hydroxymethyl)phenylboronic acid (LANCASTER, 404 mg, 2.66 mmol) were added sequentially. The resulting reaction mixture was stirred at 95 ° C for 16 hours and then cooled to room temperature. After filtration through Shixia, the reaction mixture was acidified (2N HCl) to pH 4, but no product was extracted from DCM. The title compound was obtained after purification from EtOAc EtOAc (EtOAc:EtOAc: 1H NMR (300 MHz, DMSO-d6) 3 ppm: 9.13 (m, 1H), 8·358·8·29 (m, 1H), 8.16-7.96 (m, 3H), 8·02 (m, 1H), 7 · 51 -7·40 (m, 2H), 4·59 (s, 2H).

Synthesis (2003), 551-554. 中間物33 : 6-[3-(經基曱基）苯基]-3-外bσ定石炭酿氯Synthesis (2003), 551-554. Intermediate 33: 6-[3-(via fluorenyl)phenyl]-3-external bσ

89 200804352 將中間物32 (35毫克，〇.15毫莫耳)及亞賴氣 (ALDIUCH’ 4毫升)在室溫授拌22小時後迴流％減壓下將溶劑蒸發後得财間物33。此粗產物不再進一步純化而用於下一個步驟。 ^ 中間物34 : N，_(5-溴_2_氰基如密咬基)·♦(氯甲基）苯基]_Ν’-(2_曱基丙基)_3_u比u定卡巴月井89 200804352 Intermediate 32 (35 mg, 〇15 mmol) and ALDIUCH (4 ml) were mixed at room temperature for 22 hours, and refluxed under reduced pressure. The solvent was evaporated to give the residue 33. This crude product was used in the next step without further purification. ^ Intermediate 34: N, _(5-bromo-2-cyano such as dimethylidene)·♦(chloromethyl)phenyl]_Ν’-(2_mercaptopropyl)_3_u ratio u Dingka Ba Yue

將中間物6 (83耄克，〇·31毫莫耳）及N，N_二異丙基乙基胺(FLUKA，0.107宅升，〇·61毫莫耳)於無水THF (2毫升) 在至溫攪拌30分釦。然後加入中間物33 (4〇毫克，〇15 毫莫耳）於無水THF (4亳升）之溶液。將反應混合物在室溫攪拌17小時。將溶劑蒸發並將粗產物經由製備級Ηριχ 、Sunfire 19x150 毫米，ACN:H20, 0.1%TFA，梯度 20-100% ) 純化後得到標題化合物。1H NMR ραα MHa DMSO_dJ δ ppm: 11·59 (s，1H)，9.17 (m，1H)，8·67 (s，邱，8 41-8 34 (m， 1H)，8.26 (s，1H)，8.21-8.09 (m，2H)，7 6〇_7 55 (m, 2H)，4 88 (s，2H)，4·68-3·19 (br·，2H)，2·1〇 (m，ih)，0.97 (d，6H)。中間物35 : 6-[4_(經基甲基）苯基]_3_吡啶羧酸Intermediate 6 (83 g, 〇 31 mmol) and N,N-diisopropylethylamine (FLUKA, 0.107 house liter, 〇·61 mmol) in anhydrous THF (2 mL) Stir to 30 minutes with warm stirring. A solution of intermediate 33 (4 mg, 〇15 mmol) in dry THF (4 liters) was then added. The reaction mixture was stirred at room temperature for 17 hours. The title compound was obtained after evaporation of EtOAc EtOAc EtOAc. 1H NMR ραα MHa DMSO_dJ δ ppm: 11·59 (s, 1H), 9.17 (m, 1H), 8.67 (s, Qiu, 8 41-8 34 (m, 1H), 8.26 (s, 1H), 8.21-8.09 (m, 2H), 7 6〇_7 55 (m, 2H), 4 88 (s, 2H), 4·68-3·19 (br·, 2H), 2·1〇 (m, Ih), 0.97 (d, 6H). Intermediate 35: 6-[4_(transmethylmethyl)phenyl]_3_pyridinecarboxylic acid

200804352 將6-氣菸鹼酸(ALDRICH，500毫克，2.5毫莫耳)在氮氣壓下溶解於1，2-二曱氧基乙烷(20毫升）。加入肆三苯基膦鈀(ALDRICH，733毫克，0·64毫莫耳）並將所得的反應混合物攪拌15分鐘。依序加入破酸鈉（2·7克，25.4毫莫耳）、水(20毫升）及4-(羥基曱基）苯硼酸(LANCASTER, 674毫克，4.44毫莫耳）。將所得的反應混合物在95。〇攪拌π小時後冷卻至室溫。經由矽藻土過濾後，將反應混合物酸化並在減壓下濃縮，粗產物不再純化而用於下一個步驟。200804352 6-Gas nicotinic acid (ALDRICH, 500 mg, 2.5 mmol) was dissolved in 1,2-dimethoxyethane (20 mL) under nitrogen pressure. Phenyltriphenylphosphine palladium (ALDRICH, 733 mg, 0·64 mmol) was added and the resulting reaction mixture was stirred for 15 minutes. Sodium decarboxylate (2.7 g, 25.4 mmol), water (20 mL) and 4-(hydroxyindenyl)benzeneboronic acid (LANCASTER, 674 mg, 4.44 mmol) were added sequentially. The resulting reaction mixture was at 95. The mixture was stirred for π hours and then cooled to room temperature. After filtration through celite, the reaction mixture was acidified and concentrated under reduced pressure.

Synthesis (2003)，551-554. 中間物36 : 6-[4-(氯甲基）苯基]-3-吡啶碳醯氣Synthesis (2003), 551-554. Intermediate 36: 6-[4-(Chloromethyl)phenyl]-3-pyridine carbon oxime

將中間物35及亞硫醯氯(ALDRICH，20亳升）迴流2小日守後在室溫攪拌過夜。在減壓下將溶劑蒸發後得到中間物 35。此粗產物不再進一步純化而用於下一個步驟。中間物37 : Ν’Ά溴-2-氰基-4-嘧啶基)-6-[4-(氯曱基）苯基]-Ν你甲基丙基)_3•咕啶卡巴肼The intermediate 35 and sulfinium chloride (ALDRICH, 20 liters) were refluxed for 2 hours and kept at room temperature overnight. The solvent was evaporated under reduced pressure to give Intermediate 35. This crude product was used in the next step without further purification. Intermediate 37: Ν'Άbromo-2-cyano-4-pyrimidinyl)-6-[4-(chloroindolyl)phenyl]-oxime methylpropyl)_3• acridine carbazone

將中間物6 (1〇1毫克，〇·37毫莫耳）及Ν，队二異丙基乙 91 200804352 基胺(FLUKA，0.097毫升，0·55毫莫耳)於無水THF (5毫升) 在室溫攪拌30分鐘。然後加入中間物36 (200毫克，0.75 毫莫耳)於無水THF (5毫升）之溶液。將反應混合物在室溫攪拌24小時。將溶劑蒸發ϋ用飽和的NaHC03清洗，經由 MgS04乾燥並在真空濃縮，將粗產物經由製備級HPLC (Sunfire 19x150 毫米，ACN:H20, 0.1%TFA，梯度 30_80〇/〇 ) 純化後得到標題化合物。1HNMR(300 MHz, DMSO-d6)S ppm: 11·58 (s，1H)，9·15 (m，1H)，8·66 (s，1H)，8·40-8·32 (m， 1H)，8·22-8·12 (m，3H)，7·59 (d，2H), 4·84 (s，2H)，4·01 (br·， 1H)，3.33 (br·，1H)，2·10 (m，1H)，0.96 (d，6H)。中間物38 : 5-[4-(羥基曱基）苯基]-3-吡啶羧酸Intermediate 6 (1〇1 mg, 〇·37 mmol) and hydrazine, team diisopropylethyl 91 200804352 amide (FLUKA, 0.097 ml, 0·55 mmol) in anhydrous THF (5 mL) Stir at room temperature for 30 minutes. A solution of intermediate 36 (200 mg, 0.75 mmol) in dry THF (5 mL). The reaction mixture was stirred at room temperature for 24 hours. The solvent was evaporated, washed with EtOAc EtOAc EtOAc (EtOAc m. 1HNMR (300 MHz, DMSO-d6) S ppm: 11·58 (s, 1H), 9·15 (m, 1H), 8.66 (s, 1H), 8·40-8·32 (m, 1H) ),8·22-8·12 (m,3H),7·59 (d,2H), 4·84 (s,2H),4·01 (br·, 1H), 3.33 (br·,1H) , 2·10 (m, 1H), 0.96 (d, 6H). Intermediate 38: 5-[4-(hydroxyindenyl)phenyl]-3-pyridinecarboxylic acid

將5-溴菸鹼酸(FLUKA，500毫克，2.5毫莫耳)在氮氣壓下溶解於1,2-二曱氧基乙烷(25毫升）。加入肆三苯基膦鈀(ALDRICH，572毫克，0·49毫莫耳）並將所得的反應混合物攪拌15分鐘。依序加入碳酸鈉(2.1克，19.8毫莫耳）、水(20毫升）及4-(羥基曱基）苯硼酸(LANCASTER, 525毫克，3.46毫莫耳）。將所得的反應混合物在95°C攪拌16小時後冷卻至室溫。經由矽藻土過濾後，將反應混合物酸化並在減壓下濃縮，粗產物不再純化而用於下一個步驟。1Η NMR (300 MHz，DMSO_d6) δ ppm: 9·32 (m，1Η)，9·12 (m， 1Η)，8·84 (m，1Η)，7.84 (d，2Η)，7·50 (d，2Η)，4·56 (s，2Η)。 92 2008043525-Bromonicotinic acid (FLUKA, 500 mg, 2.5 mmol) was dissolved in 1,2-dimethoxyethane (25 mL) under nitrogen. Triphenylphosphine palladium (ALDRICH, 572 mg, 0. 49 mmol) was added and the resulting reaction mixture was stirred for 15 min. Sodium carbonate (2.1 g, 19.8 mmol), water (20 ml) and 4-(hydroxyindenyl)benzeneboronic acid (LANCASTER, 525 mg, 3.46 mmol) were added sequentially. The resulting reaction mixture was stirred at 95 ° C for 16 hours and then cooled to room temperature. After filtration through celite, the reaction mixture was acidified and concentrated under reduced pressure. 1Η NMR (300 MHz, DMSO_d6) δ ppm: 9·32 (m, 1Η), 9·12 (m, 1Η), 8.84 (m, 1Η), 7.84 (d, 2Η), 7·50 (d , 2Η), 4·56 (s, 2Η). 92 200804352

Synthesis (2003), 551-554. 中間物39 ·· 5_[4_(氯曱基）苯基]-34啶碳醯氯Synthesis (2003), 551-554. Intermediate 39 ·· 5_[4_(Chloromethyl)phenyl]-34 pyridine Carbonium Chloride

將中間物38及亞硫醯氯(ALDRICH, 15毫升）迴流2小時後在室溫攪拌過夜。在減壓下將溶劑蒸發後得到中間物 39。此粗產物不再進一步純化而用於下一個步驟。中間物40 : N’-(5-溴-2-氰基-4-嘧啶基)-5-[4-(氣曱基）苯基]-N’-(2_曱基丙基）-3•吼。定卡巴胼The intermediate 38 and sulfinium chloride (ALDRICH, 15 ml) were refluxed for 2 hours and then stirred at room temperature overnight. The solvent was evaporated under reduced pressure to give Intermediate 39. This crude product was used in the next step without further purification. Intermediate 40: N'-(5-bromo-2-cyano-4-pyrimidinyl)-5-[4-(azepine)phenyl]-N'-(2-mercaptopropyl)-3 •Roar. Kaba

進一步純化而用於下一中間物41 : 羥某將中間物6(100毫克，〇·37毫莫耳）及N，N-二異丙基乙基胺(FLUKA，0.097毫升，〇·55毫莫耳)於無水THF (1〇毫 =)在室溫攪拌20分鐘。然後加入中間物39 (3〇〇毫克，U3 耄莫耳）於無水THF (10毫升）之溶液。將反應混合物在室溫攪拌過夜。在減壓下將溶劑蒸發後得到中間物4〇，其不再一個步驟。 -[3-(羥基曱基）笨基卜3_吡啶羧酸 ΌΗ 93 200804352 將5-溴菸鹼酸(FLUKA，500毫克，2.5毫莫耳)在氮氣壓下溶解於1，2-二曱氧基乙烷(25毫升）。加入肆三苯基膦 !巴(ALDRICH，572毫克，〇·49毫莫耳）並將所得的反應混合物攪拌15分鐘。依序加入碳酸鈉(2·；[克，19.8毫莫耳）、水(20毫升）及4-(經基甲基）苯硼酸(LANCASTER，525毫克，3.46毫莫耳）。將所得的反應混合物在9yc攪拌16小時後冷卻至室溫。經由矽藻土過濾後，將反應混合物酸化並在減壓下濃縮，粗產物不再純化而用於下一個步驟。Further purification for use in the next intermediate 41: Hydroxyl intermediate 6 (100 mg, 〇37 mmol) and N,N-diisopropylethylamine (FLUKA, 0.097 mL, 〇·55 mil The mixture was stirred at room temperature for 20 minutes under anhydrous THF (1 EtOAc). A solution of Intermediate 39 (3 mg, U3 MeOH) in dry THF (10 mL) was then taken. The reaction mixture was stirred at room temperature overnight. Evaporation of the solvent under reduced pressure afforded intermediate 4 s, which was one step. -[3-(Hydroxyfluorenyl) phenylidene 3_pyridinecarboxylate 93 200804352 5-Bromonicotinic acid (FLUKA, 500 mg, 2.5 mmol) dissolved in 1,2-diox under nitrogen pressure Oxyethane (25 ml). Triphenylphosphine! Bar (ALDRICH, 572 mg, 〇·49 mmol) was added and the resulting reaction mixture was stirred for 15 minutes. Sodium carbonate (2·; [g, 19.8 mmol), water (20 ml) and 4-(methylidene)phenylboronic acid (LANCASTER, 525 mg, 3.46 mmol) were added sequentially. The resulting reaction mixture was stirred at 9 ° C for 16 hours and then cooled to room temperature. After filtration through celite, the reaction mixture was acidified and concentrated under reduced pressure.

Synthesis (2003), 551-554· 中間物42 : 5-[3-(氣甲基）苯基]_3_吡啶碳醯氯Synthesis (2003), 551-554· Intermediate 42 : 5-[3-(Gasmethyl)phenyl]_3_pyridine Carbonium Chloride

將中間物41及亞硫醯氯(ALDRICH，15毫升）迴流2小時後在室溫攪拌過夜。在減壓下將溶劑蒸發後得到標題中間物。此粗產物不再進一步純化而用於下一個梦驟。中間物43 ··贝’-(5-溴_2-氰基-4-嘧啶基)-5-[4-(氯甲基）苯基]-N’-(2_甲基丙基)_3^比咬卡巴肼Intermediate 41 and sulfinium chloride (ALDRICH, 15 ml) were refluxed for 2 hours and then stirred at room temperature overnight. The title intermediate was obtained by evaporating the solvent under reduced pressure. This crude product was used in the next dream without further purification. Intermediate 43 ·····(5-Bromo-2-cyano-4-pyrimidinyl)-5-[4-(chloromethyl)phenyl]-N'-(2-methylpropyl)_3 ^Bite Kabbah

將中間物6(1〇〇毫克，〇·37毫莫耳）及N，N_二異丙基乙基胺(FLUKA，0.097毫升，〇·55毫莫耳)於無水THF (1〇毫 94 200804352 升)在室溫攪拌20分鐘。然後加入中間物42 (300毫克，U3 毫莫耳)於無水THF (10毫升）之溶液。將反應混合物在室溫攪拌過夜並將粗產物不再進一步純化而用於下一個步驟。中間物44 ·· 5-甲基-苯並呋喃-2-羧酸乙酯Intermediate 6 (1 mg, 〇37 mmol) and N,N-diisopropylethylamine (FLUKA, 0.097 mL, 〇·55 mmol) in anhydrous THF (1 〇 940 200804352 l) Stir at room temperature for 20 minutes. Then a solution of intermediate 42 (300 mg, U3 mmol) in dry THF (10 mL). The reaction mixture was stirred at room temperature overnight and the crude material was used without further purification. Intermediate 44 · · 5-methyl-benzofuran-2-carboxylic acid ethyl ester

在2-羥基·5·甲基苯甲醛(ALDRICH, 2克，14.7毫莫耳； 1當量）及溴丙二酸二乙酯（ALDRICH，2·37克，9.92毫莫耳；1·5當量）於2_丁酮（ALDRICH，10毫升）之攪拌溶液中加入K2C03 (ALDRICH，4.06克，2當量）並將混合物迴流 2小時。將粗產物過濾，並將過濾液用EtOAc及NH4C1鹽 (兩次）卒取，然後將有機層用飽和的NaHC〇3及鹽水清洗。將合併的有機層乾燥(Na2S04)，過濾並將溶劑蒸發。將NaH (ALDRICH，60%在礦物油中，2.5當量）添加至在50毫升 THF中的粗產物，將反應混合物攪拌1〇分鐘後滴入冰與飽的NaHC〇3之混合物中，用EtOAc萃取數次，並用鹽水清洗。將合併的有機層乾燥(NajO4)並將粗產物經由管柱層析法(矽膠；己烷/EtOAc)純化後得到標題化合物。 NMR (d6-DMSO) δ ppm·· 7·7_7·5 (m，3Η)，7·3 (d，8·5 Ηζ，1Η)， 4·3 (q，7·7 Ηζ，2Η)，2·4 (s，3Η)，1·3 (t，7·7 Ηζ，3Η)。中間物45 : 5-(溴曱基)-1-苯並吱喃-2-叛酸乙酯In 2-hydroxy·5·methylbenzaldehyde (ALDRICH, 2 g, 14.7 mmol; 1 equivalent) and diethyl bromomalonate (ALDRICH, 2.37 g, 9.92 mmol; 1.5 equivalents) K2C03 (ALDRICH, 4.06 g, 2 eq.) was added to a stirred solution of 2-butanone (ALDRICH, 10 mL) and the mixture was refluxed for 2 hr. The crude product was filtered, and the filtrate was filtered with EtOAc EtOAc EtOAc EtOAc The combined organic layers were dried (Na2SO4) filtered and evaporated. Add NaH (ALDRICH, 60% in mineral oil, 2.5 eq.) to EtOAc EtOAc (EtOAc) Wash it several times with salt water. The combined organic layers were dried (EtOAc EtOAcqqqqq NMR (d6-DMSO) δ ppm·· 7·7_7·5 (m, 3Η), 7·3 (d,8·5 Ηζ,1Η), 4·3 (q,7·7 Ηζ, 2Η), 2 · 4 (s, 3Η), 1·3 (t, 7·7 Ηζ, 3Η). Intermediate 45: 5-(bromoindolyl)-1-benzopyran-2-pyruvate ethyl ester

95 200804352 在中間物44(1.3克，6·4毫莫耳；1當量）在氮氣壓下在20毫升CC14之迴流溶液中加入沁溴代琥珀醯亞胺 (ALDRICH，1.36克，7·63毫莫耳；2當量）及1刮刀尖的過氧化苯甲醯(ALDRICH)。將混合物迴流5天，當其到達完成時，將反應混合物冷卻至〇°C，過濾並在矽膠純化（己烷 /EtOAc)後得到產物之混合物。iHNMR(d6_DMSO)5ppm: 7.8-7.4 (m，4H)，4·9 (s，2H)，4·6 (s，0·4Η)，4.36 (q，7·2 Hz， 2Η)，1·35 (t，7·2 Ηζ，3Η) 〇中間物46 : 5-(溴曱基)-1-苯並呋喃_2_羧酸95 200804352 In the intermediate 44 (1.3 g, 6.4 mmol; 1 eq.), under reflux of 20 ml of CC14 in ruthenium bromide (ALDRICH, 1.36 g, 7.63 m) under nitrogen pressure. Mohr; 2 equivalents) and 1 scraper tip of benzophenone peroxide (ALDRICH). The mixture was refluxed for 5 days, and when it was completed, the reaction mixture was cooled to EtOAc, filtered and purified from EtOAc (hexane/EtOAc). iHNMR (d6_DMSO) 5ppm: 7.8-7.4 (m, 4H), 4·9 (s, 2H), 4·6 (s, 0·4Η), 4.36 (q, 7·2 Hz, 2Η), 1.35 (t,7·2 Ηζ,3Η) 〇Intermediate 46 : 5-(bromoindolyl)-1-benzofuran-2-carboxylic acid

在中間物45 (230毫克)於12毫升THF/H20 (5/1)的溶液中加入2N氫氧化鋰(ALDRICH，2.44毫莫耳）。將反應混合物在室溫攪拌3小時。反應完成時(TLC，洗提液： DCM/MeOH9:l)，將溶劑蒸發，加入水及DCM並將水層萃取並酸化至？^!4。將有機層用0€]^及人〇0£1萃取，將合併的有機層乾燥(Na2S04)，過濾並將溶劑蒸發後得到標題化合物，其不再進一步純化而用於下一個步驟。iHNMR (d4-CD3OD) δ ppm: 7·7 (m, 1H)，7·55 (m，2H)，7·47 (m，1H)， 4.7 (s，2H) 〇中間物47 · 5-(氯或漠曱基)-1-苯並咬喃-2-碳酿氯To a solution of intermediate 45 (230 mg) in 12 mL of THF / H.sub.2 (5/1), 2N lithium hydroxide (ALDRICH, 2.44 m.m.). The reaction mixture was stirred at room temperature for 3 hours. Upon completion of the reaction (TLC, eluent: DCM / MeOH 9:1), the solvent was evaporated, water and DCM were added and the aqueous layer was extracted and acidified to ? ^!4. The organic layer was extracted with EtOAc (EtOAc) (EtOAc). iHNMR (d4-CD3OD) δ ppm: 7·7 (m, 1H), 7·55 (m, 2H), 7·47 (m, 1H), 4.7 (s, 2H) 〇 intermediate 47 · 5-( Chlorine or Molybdenum)-1-Benzobenzopyrene-2-carbonic chlorine

X=CI 或 Br 96 200804352 在N2下將中間物46在1毫升S0C12 (ALDRICH)中的攪拌溶液活硫1小時。反應完成後，在減壓下將溶劑蒸發，得到標題化合物，其不再進一步純化而用於下一個步驟。中間物48 : N’_(5-溴-2-氰基-4-嘧啶基)-5-(氣或溴曱基)-N’-(2-甲基丙基)-l-苯並呋喃-2-卡巴胼X = CI or Br 96 200804352 Intermediate 46 was sulphurized in 1 ml of a stirred solution of SOC12 (ALDRICH) for 1 hour under N2. After the reaction was completed, the solvent was evaporated,jjjjjjjjjjjj Intermediate 48: N'-(5-bromo-2-cyano-4-pyrimidinyl)-5-(gas or bromomethyl)-N'-(2-methylpropyl)-l-benzofuran -2- Kabbah

在中間物47於2毫升無水DCM之冷卻溶液中逐滴加入81毫克中間物6 (0·30毫莫耳）與51微升DIPEA (FLUKA，〇·30毫莫耳）之溶液。將反應在Ν2下攪拌過夜並經由HPLC 監視(X-TERRA 4.6x50 毫米，H20:ACN，0.1%TFA，梯度 25-100% )。當反應達成後，將溶劑蒸發並加入h2〇及DCM，將液層分離並將有機層用飽和的NH4C1 (25毫升）清洗，隨後用Na2C〇3 (25毫升）清洗，最後用25毫升鹽水清洗。將合併的有機層乾燥(Na2S04)。將粗產物經由層析法(矽膠，己烷:EtOAc)純化後得到標題化合物混合物。ES+MS m/z 462 (MH)+& 507 (M)+。中間物49 : 5-(溴甲基)-2-噻吩羧酸A solution of 81 mg of Intermediate 6 (0·30 mmol) and 51 μl of DIPEA (FLUKA, 30 mmol) was added dropwise to a cooling solution of Intermediate 47 in 2 mL of dry DCM. The reaction was stirred at Ν2 overnight and was monitored by HPLC (X-TERRA 4.6 x 50 mm, H20: ACN, 0.1% TFA, gradient 25-100%). After the reaction was completed, the solvent was evaporated and EtOAc (EtOAc) was evaporated. EtOAcjjjjjjjjjjjjjjjjjjjjjjj . The combined organic layers were dried (Na 2 SO 4 ). The crude product was purified by chromatography (EtOAc EtOAc) ES+MS m/z 462 (MH)+& 507 (M)+. Intermediate 49 : 5-(Bromomethyl)-2-thiophenecarboxylic acid

在5-甲基-2-噻吩羧酸(ALDRICH, 1克，7.03毫莫耳；1 97 200804352 當量）於60毫升CC14在但氣壓下的迴流溶液中，加入1·5 克（8.44毫莫耳；1·2當量）的Ν-溴代玻珀醯亞胺及催化量的過氧化笨曱醯。將混合物迴流3小時且當其達成反應(HPLC: X-TERRA 4.6x50 毫米，H20:ACN，0.1%TFA，梯度 10-100%; Rt·· 4.2’），在減壓下將溶劑蒸發。將所得的固體經由製備級 HPLC 純化（X-TERRA 50x250 毫米，H20:ACN，0.1%TFA，梯度10-100%)，得到標題化合物。1HNMR(DMSO)5ppm: 7·6 (d，3·81 Hz，2H)，7·26 (d，3·81 Hz，1H)，7 (d，8·31 Hz， 1H)，5 (s，2H)，4.65 (s，2H)。將此產物經由製備級HPLC純化(X_TERRA 50x250 毫米，H2O.ACN，0.1%TFA，梯度 10-100°/。），得到標題化合物。1HNMR (CDC13) δ ppm: 7·8 (d， 3·81 Hz，0.1H)，7·74 (d，3.81 Hz，1H)，7.14 (d，3·81 Hz，1H)， 7.04 (d，3·81 Hz，0·1Η)，4·9 (s，0·3Η)，4·7 (s，2H)。中間物50 ·· 5-(溴或氯甲基)-2-噻吩碳醯氯In 5-methyl-2-thiophenecarboxylic acid (ALDRICH, 1 g, 7.03 mmol; 1 97 200804352 equivalent) in 60 ml of a reflux solution of CC14 at atmospheric pressure, add 1.5 gram (8.44 mmol) ;1·2 equivalents) of Ν-bromo porphyrin and a catalytic amount of abundance of peroxidation. The mixture was refluxed for 3 hours and when it reached a reaction (HPLC: X-TERRA 4.6×50 mm, H20: ACN, 0.1% TFA, gradient 10-100%; Rt 4.2), the solvent was evaporated under reduced pressure. The resulting solid was purified by preparative EtOAc (EtOAc: EtOAc (EtOAc) 1H NMR (DMSO) 5 ppm: 7·6 (d, 3·81 Hz, 2H), 7·26 (d, 3·81 Hz, 1H), 7 (d, 8·31 Hz, 1H), 5 (s, 2H), 4.65 (s, 2H). The product was purified by preparative EtOAc (EtOAc: EtOAc (EtOAc) 1HNMR (CDC13) δ ppm: 7·8 (d, 3·81 Hz, 0.1H), 7.74 (d, 3.81 Hz, 1H), 7.14 (d, 3·81 Hz, 1H), 7.04 (d, 3·81 Hz, 0·1Η), 4·9 (s, 0·3Η), 4·7 (s, 2H). Intermediate 50 ·· 5-(Bromo or chloromethyl)-2-thiophene carbon醯

〇 CI或已「兩種方法用於合成此中間物： a)在N2下將70毫克中間物49(0.317毫莫耳；1當量) 在3毫升無水THF的攪拌溶液中加入草醯氯(〇.475毫莫耳；1.5當量）。將混合物在室溫攪拌並經由HPLC監視 (X-TERRA 4.6x50 毫米，H2〇:ACN，0.1%TFA，梯度 10-100% )。攪拌3小時後，再次加入20微升草醯氯使幾 98 200804352 乎完成反應。在減壓下將溶劑蒸發後得到粗混合物，其不再進一步純化而用於下一個步驟。 b)將在N2下的1〇〇毫克中間物49 (0·452毫莫耳)在1 毫升SOC12的攪拌溶液迴流1小時。在減壓下將溶劑蒸發後得到粗物質，其不再進一步純化而用於下一個步驟。中間物51 : Ν，-(5-溴_2_氰基-4_嘧啶基)-5-(氯或溴甲基)-N’_(2-甲基丙基)-2-噻吩卡巴肼〇CI or "Two methods for the synthesis of this intermediate: a) Add 70 mg of intermediate 49 (0.317 mmol; 1 equivalent) to a stirred solution of 3 ml of anhydrous THF under N2. .475 mmol; 1.5 equivalents. The mixture was stirred at room temperature and monitored by HPLC (X-TERRA 4.6 x 50 mm, H2 〇: ACN, 0.1% TFA, gradient 10-100%). After stirring for 3 hours, again Add 20 μl of chlorophyll chloride to a few 98 200804352 to complete the reaction. The solvent was evaporated under reduced pressure to give a crude mixture which was used in the next step without further purification. b) 1 〇〇 mg under N2 The intermediate 49 (0. 452 mmol) was refluxed for 1 hr. Ν,-(5-Bromo-2-cyano-4-pyrimidinyl)-5-(chloro or bromomethyl)-N'_(2-methylpropyl)-2-thiophenecarbazide

兩種方法用於合成此中間物： a) 將71.36毫克(0.264毫莫耳）的中間物6及150微升 DIPEA在3毫升無水THF之溶液逐滴添加至中間物5〇 a) 且隨後，加入35毫克第三丁醇鉀。將反應混合物在室溫攪拌過夜。在減壓下將溶劑蒸發，加入25毫升DCM及25 毫升飽和的NH4C1。將液層分離，並將有機層用Na2C03(25 毫升）清洗，隨後用25毫升鹽水清洗。將合併的有機層乾燥(Na2S04)。將粗產物經由層析法(矽膠，己烷:EtOAc)純化後得到標題產物(HPLCX-TERRA 4.6x50毫米，H20:ACN， (U%TFA，梯度 10-100%; Rt: 5.2 分鐘）。ES+MS m/z 473 & 428 (ΜΗ)、Two methods were used to synthesize this intermediate: a) 71.36 mg (0.264 mmol) of intermediate 6 and 150 μl of DIPEA in 3 ml of anhydrous THF were added dropwise to the intermediate 5〇a) and subsequently Add 35 mg of potassium t-butoxide. The reaction mixture was stirred at room temperature overnight. The solvent was evaporated under reduced pressure and 25 mL DCM and 25 mL sat. The layers were separated and the organic layer was washed with Na.sub.2 C.sub.3 (25 mL). The combined organic layers were dried (Na 2 SO 4 ). The crude product was purified by EtOAc EtOAc EtOAc (EtOAc (EtOAc) +MS m/z 473 & 428 (ΜΗ),

b) 在中間物50b)於1毫升無水DCM之冷卻溶液中，逐滴加入134毫克中間物6 (0,497毫莫耳）與84微升DIPEA 99 200804352 (〇·497微升）之溶液。將反應攪拌(在&下），經15分鐘後，加入0.249毫莫耳之DIPEA。將混合物在室溫攪拌過夜並由1^1^監視(乂-丁£1^1^入4.6\50毫米，112〇:八〇1^，0.1%丁|7八梯度10-100% )。當反應完成後，加入20毫升DCM並將混合物滴在25毫克冰-水中，將液層分離並將有機層經由飽和的NH4C1 (25毫升）、Na2C03 (25毫升）及25毫升鹽水萃取。將合併的有機層乾燥(NazSO4)。將粗產物經由層析法(矽膠，己烷:Teac)純化後得到標題產物(HPLC X-TERRA 4·6χ50 毫米，H20:ACN，0.1%TFA，梯度 UM00%; Rt: 5.2 分鐘）。ES+MS m/z 428 & 473 (MH)+。在a)與b)部份所得的化合物是混合並在下一個步驟使用。中間物52 : 2-(2,2-二甲基丙基)胼羧酸1，1·二曱基乙酯b) A solution of 134 mg of intermediate 6 (0,497 mmol) and 84 μl of DIPEA 99 200804352 (〇·497 μl) was added dropwise to a cooled solution of intermediate 50b) in 1 mL of dry DCM. The reaction was stirred (under &) and after 15 minutes, 0.249 mmol of DIPEA was added. The mixture was stirred at room temperature overnight and monitored by 1^1^ (乂-丁?1^1^ into 4.6\50 mm, 112 〇: 〇1^, 0.1% butyl | 7-8 gradient 10-100%). After the reaction was completed, 20 ml of DCM was added, and the mixture was applied to 25 ml of ice-water, and the layers were separated, and the organic layer was extracted with saturated NH4C1 (25 ml), Na2CO3 (25 ml) and 25 ml of brine. The combined organic layers were dried (NazSO4). The crude product was purified by chromatography (EtOAc EtOAc:EtOAc) ES+MS m/z 428 & 473 (MH)+. The compounds obtained in parts a) and b) are mixed and used in the next step. Intermediate 52: 1,1·Dimethylethyl 2-(2,2-dimethylpropyl)hydrazinecarboxylate

經由類似於說明用於中間物3的方法製備標題化合物，將異丁醛用三曱基乙醛(ALDRICH)替代。4 NMR (300 MHz，CDC13)3 ppm: 8.19 (s，1H)，3·34 (br· s，1H)，2.46 (d， 2H)，1.37 (s，9H)，0.85 (s，9H)，[ES+MS] m/z 203 (MH)+。中間物53 : 2-(5-溴-2-氯-4-嘧啶基)-2-(2,2-二曱基丙基)肼羧酸1，1-二曱基乙酯 100 200804352 ΒΓ^^ΝThe title compound was prepared via a procedure similar to that described for Intermediate 3, and isobutyraldehyde was replaced with tridecyl acetaldehyde (ALDRICH). 4 NMR (300 MHz, CDC13) 3 ppm: 8.19 (s, 1H), 3·34 (br·s, 1H), 2.46 (d, 2H), 1.37 (s, 9H), 0.85 (s, 9H), [ES+MS] m/z 203 (MH)+. Intermediate 53: 1,1-didecylethyl 2-(5-bromo-2-chloro-4-pyrimidinyl)-2-(2,2-dimercaptopropyl)indolecarboxylate 2008 200804352 ΒΓ^ ^Ν

在5-溴-2,4-二氣嘧啶（15 4克，68毫莫耳）及中間物入 (12.5克，62毫莫耳）於i_PrOH(15〇毫并）厶溶液中Ί典 N，N-二異丙基乙基胺（14毫升，80毫莫耳）旅將所得的心混合物迴流2·5小時，然後在室溫攪拌過夜，並使 · 分配在DCM及1Μ氯化銨之間。將有機層用鹽水處理旅.、由無水MgS04乾燥。將殘留物經由快速層析法（洗权液！己烷/EtOAc混合物95:1至1:1)純化後得刻標題化合物 NMR (300 MHz，CDC13)3 ppm: 8·27 (br.s，1H)，6.85 (br· s， 1H)，4·85_4·63 (br.m·，1H)，2.90-2.65 (br· m，1H)，1·47 (s， 9H)，0·98 (s，9H)。[ES+MS] m/z 393 (M)+。 1間物54:2-(5-溴-2-氰基-4-嘧啶基)_2_(2,2-二甲基丙基）肼羧酸1，1-二曱基乙酯In the solution of 5-bromo-2,4-dioxapyrimidine (15 4 g, 68 mmol) and intermediate (12.5 g, 62 mmol) in a solution of i_PrOH (15 mmol), N-Diisopropylethylamine (14 ml, 80 mmol) was transferred to a mixture of the mixture for 2.5 hours, then stirred at room temperature overnight and partitioned between DCM and 1 EtOAc. . The organic layer was treated with brine and dried over anhydrous MgS04. The residue was purified by flash chromatography (EtOAc: EtOAc/EtOAc EtOAc: EtOAc: EtOAc: EtOAc 1H), 6.85 (br· s, 1H), 4·85_4·63 (br.m·, 1H), 2.90-2.65 (br· m,1H),1·47 (s, 9H), 0·98 ( s, 9H). [ES+MS] m/z 393 (M)+. 1Interstance 54: 2-(5-Bromo-2-cyano-4-pyrimidinyl)_2_(2,2-dimethylpropyl) decanoic acid 1,1-didecylethyl ester

將fl化鉀（1 ·6克，25毫莫耳）添加至中間物(9克， 23笔莫耳）及DABCO (2.6克，23毫莫耳）於DMS〇/H2〇 9:1 10] 200804352 混合物（100毫升）在室溫之懸浮液。將反應混合物在80°c 加熱1·5小時後倒入冰水中。攪拌1.5小時後，將沈澱的黃色產物過濾並用大量的水清洗。將化合物再度溶解在DCM 並將所得的溶液用水(2次）及鹽水清洗並將有機層經由 MgS〇4乾燥。將化合物經由快速層析法（洗提液··己烷 /EtOAc 7:3)純化後得到標題化合物。iHNMR (300 MHz， CDC13)3 ppm: 8·47 (br.s，1H)，6·86 (br· s，1H)，4·85_4·65 (br.m” 1H)，2·90-2·70 (br· m，1H)，1·47 (s，9H)，0.99 (s， 9H)。[ES+MS] m/z 384 (M)+。中間物55 : 5-溴-4_[l-(2,2-二甲基丙基)肼基]-2-嘧啶Add potassium fluoride (1 · 6 g, 25 mmol) to the intermediate (9 g, 23 moles) and DABCO (2.6 g, 23 mmol) to DMS〇/H2〇9:1 10] 200804352 A suspension of the mixture (100 ml) at room temperature. The reaction mixture was heated at 80 ° C for 1.5 hours and poured into ice water. After stirring for 1.5 hours, the precipitated yellow product was filtered and washed with a large amount of water. The compound was dissolved again in DCM and the resulting solution was washed with water (2 times) and brine and dried organic layer The title compound was obtained after purified by flash chromatography eluting elut elut elut iHNMR (300 MHz, CDC13) 3 ppm: 8·47 (br.s, 1H), 6·86 (br·s, 1H), 4·85_4·65 (br.m” 1H), 2·90-2 · 70 (br· m,1H),1·47 (s,9H), 0.99 (s, 9H).[ES+MS] m/z 384 (M)+. Intermediate 55: 5-bromo-4_[ L-(2,2-dimethylpropyl)indolyl]-2-pyrimidine

Br\r^NBr\r^N

Λ 在中間物54 (2克，5.2毫莫耳）於無水乙腈（1〇〇毫升）之溶液中加入對-甲苯磺酸（13毫莫耳）並將所得的反應混合物在室溫攪拌過夜。然後將混合物在真空濃縮，並將殘留物分配在DCM及碳酸氫鈉的飽和溶液之間。將有機層用鹽水清洗並經由無水NaHC03乾燥。將殘留物經由製備級 HPLC (X-TERRA 19x150 毫米，ACN:H20, 0.1%TFA，梯度 10-100%)純化後得到標題化合物。1H NMR (300 MHz， CDC13)3 ppm: 8.39 (s，1H), 3.85 (s，2H)，1.00 (s，9H)。 [ES+MS] m/z 284 (Μ)、 102 200804352 實例1 : N，-(5-溴-2-氰基-4-嘧啶基)-‘[(4-甲基_丨_六氫吡σ 基）曱基]-Ν，·(2-曱基丙基）苯曱醯胼三氟醋酸鹽p-Toluenesulfonic acid (13 mmol) was added to a solution of intermediate 54 (2 g, 5.2 mmol) in dry acetonitrile (1 mL) and the resulting mixture was stirred at room temperature overnight. The mixture was then concentrated in vacuo and the residue was partitioned between DCM and sat. The organic layer was washed with brine and dried over anhydrous NaHC. The residue was purified by preparative EtOAc EtOAc (EtOAc:EtOAc 1H NMR (300 MHz, CDC13) 3 ppm: 8.39 (s, 1H), 3.85 (s, 2H), 1.00 (s, 9H). [ES+MS] m/z 284 (Μ), 102 200804352 Example 1: N,-(5-bromo-2-cyano-4-pyrimidinyl)-'[(4-methyl-indole_hexahydropyridinium σ group) fluorenyl]-Ν,·(2-mercaptopropyl)phenylhydrazine trifluoroacetate

4-[(4-甲基小六氫吡畊基）曱基]笨甲醯氣之製備將中間物2 (500毫克，2.13毫莫耳）溶解在亞硫醯氣(5 毫升）。將反應混合物迴流6小時。在真空將溶劑蒸發並將粗產物不再有任何進一步純化而使用。在中間物6 (200宅克，〇·74笔莫耳）於吼咬（1 〇毫升）之授拌溶液中，加入先前製備的酶基氯(539毫克，2 13毫莫耳）及DIPEA (0.26宅升，1.48毫莫耳）在無水thf (1 〇毫升、) 之混合物並將所得的反應混合物在室溫擾拌2小時。在真純化後得到以=固體經由HPLC (Η20,〇.卿 η 心碭化合物。1HNMR(300 MHz，DMSO)3PPm:Preparation of 4-[(4-methyl hexahydropyranyl) fluorenyl] benzoate oxime Intermediate 2 (500 mg, 2.13 mmol) was dissolved in sulfoxide (5 mL). The reaction mixture was refluxed for 6 hours. The solvent was evaporated in vacuo and the crude material was used without further purification. Add the previously prepared enzyme-based chlorine (539 mg, 2 13 mmol) and DIPEA to the intermediate solution 6 (200 oz, 〇·74 lm) in a bite solution (1 〇 ml). A mixture of 0.26 house liters, 1.48 mmoles in anhydrous thf (1 mL), and the resulting mixture was stirred at room temperature for 2 hours. After true purification, a solid was obtained via HPLC (Η20, 〇. 砀砀砀 compound. 1H NMR (300 MHz, DMSO) 3 ppm:

實例2-5疋經由類似於實例 • S，1Η)，8·64 (s，1H1 7.92 (d，2H)，7·48 (d，2H)，3·98 ，3·38 (m，4H)，3.02 (m，4H)，2·78 (s， 2·〇5 (m，1Η)，0·94 (d，6Η)。[ES+MS] m/z 1說明之方法製備，用表1 103 200804352 所示的中間物及酸/醯基氯替代中間物6及4-[(4-曱基-1-六氫吡畊基）曱基]苯曱醯氣。表1 石列酸或醯灰氣中間物物理數據 2 1 〇 fK 。Ϋ 中間物7 6 1HNMR (300 MHz, DMSO-d6): 11.35 (s,1H), 8.64 (s,1H), 7.92 (d, 2H), 7.49 (d, 2H), 3.73 (s, 2H), 3.42 (m, 2H)，3.00 (m, 8H), 2.05 (m, 1H), 1.60 (m, 2H), 0.94 (d, 6H), 0.89 (t, 3H). [ES+ MS] nn/z514 (M)+. 3 ° V 中間物8 6 [ES+ MS] m/z 514 (M广 ^ 104 200804352 實例結構酸或醯基氯中間物物理數據 1HNMR (300 MHz, DMSO-d6): 11.38 (s, 1H), 8.52 (s, 1H), 7.90 (d, 2H), 7.50 4 ς〕〇 V 中間物7 11 (df 2H),3.75 (s,2H)r 3.55-2.80 (br, 10H), 2.06 (m，1H), 1.60 (mf 2H), 0.95 (d, 6H), 0.89 (t, 3H)· [ES+ MS] m/z 470 (MH)+. 5 〔，。Ϋ Ns +: 中間物8 11 [ES+ MS] m/z 470 實例6 : N’-(5-溴-2_氰基-4·嘧啶基)-4-氟-N’-(2-曱基丙基）_3-[(4-丙基小六氫吡畊基）曱基]苯曱醯胼三氟醋酸鹽Example 2-5 is similar to the example • S,1Η), 8.64 (s,1H1 7.92 (d,2H),7·48 (d,2H),3·98,3·38 (m,4H) , 3.02 (m, 4H), 2·78 (s, 2·〇5 (m, 1Η), 0·94 (d, 6Η). [ES+MS] m/z 1 Description of method preparation, using Table 1 103 200804352 Intermediates and acid/hydrazinyl chloride as shown in place of intermediate 6 and 4-[(4-mercapto-1-hexahydropyrryl)indenyl]phenylhydrazine. Table 1 Stone acid or strontium Physical data of ash intermediates 2 1 〇fK Ϋ Intermediate 7 6 1H NMR (300 MHz, DMSO-d6): 11.35 (s, 1H), 8.64 (s, 1H), 7.92 (d, 2H), 7.49 (d , 2H), 3.73 (s, 2H), 3.42 (m, 2H), 3.00 (m, 8H), 2.05 (m, 1H), 1.60 (m, 2H), 0.94 (d, 6H), 0.89 (t, 3H). [ES+ MS] nn/z514 (M)+. 3 ° V Intermediate 8 6 [ES+ MS] m/z 514 (M Guang ^ 104 200804352 Example Structure Acid or Mercapto Chloride Intermediate Physical Data 1HNMR (300 MHz, DMSO-d6): 11.38 (s, 1H), 8.52 (s, 1H), 7.90 (d, 2H), 7.50 4 ς] 〇V Intermediate 7 11 (df 2H), 3.75 (s, 2H)r 3.55-2.80 (br, 10H), 2.06 (m, 1H), 1.60 (mf 2H), 0.95 (d, 6H), 0.89 (t, 3H)· [ES+ MS] m/z 470 (MH)+. 5 〔, Ϋ Ns +: intermediate 8 11 [ES+ MS] m/z 470 Example 6: N'-(5-bromo-2-cyano-4.pyrimidinyl)-4-fluoro-N'-(2-fluorenyl) Propyl)_3-[(4-propyl hexahydropyranyl) fluorenyl]phenylhydrazine trifluoroacetate

在中間物6 (5) (0.07克，0.3毫莫耳）於無水THF (5毫升）之溶液中，加入N，N-二異丙基乙基胺（0.2毫升，1.2毫莫耳）並將所得的反應混合物在室溫攪拌1〇分鐘。然後，加入中間物16 (0.15克，0·5毫莫耳）及第三丁醇鉀 (ALDRICH, 0.04克，0·4毫莫耳）並將反應混合物在室溫再攪拌16小時。在真空將溶劑去除並將所得的殘留物溶解在 105 200804352In a solution of the intermediate 6 (5) (0.07 g, 0.3 mmol) in anhydrous THF (5 mL) The resulting reaction mixture was stirred at room temperature for 1 Torr. Then, intermediate 16 (0.15 g, 0.55 mmol) and potassium t-butoxide (ALDRICH, 0.04 g, 0.4 mmol) were added and the mixture was stirred at room temperature for additional 16 hours. The solvent was removed in vacuo and the resulting residue was dissolved in 105 200804352

MeOH並經由製備級HPLC (SUNF1RE 19x150毫米， ACN:H20, 0.1%TFA，梯度10-100%)純化後得到標題化合物。1H NMR (300 MHz，CDC13)3 ppm: 9.77 (s，1H)，8·43 (s， 1H)，8.29-8.27 (dd，1H)，8·08-8·02 (m，1H)，7.34-7.28 (m， 1H)，4.24 (s，2H)，3.91-3.72 (br·，2H)，3.66-3.32 (br·，8H)， 3.00-2.94 (m，2H)，2.20-2.07 (m，1H)，1.85-1.72 (m，2H)， 1.05-1.01 (m，9H) 〇 [ES+MS] m/z 532 & 534 (MH)+。實例7 : N’-(5-氣-2_氰基-4-嘧啶基)-4-氟-N’_(2-甲基丙基)-3-[(4-丙基-1-六氫吡畊基）曱基]苯甲醯肼三氟醋酸鹽The title compound was obtained after EtOAc (EtOAc m. 1H NMR (300 MHz, CDC13) 3 ppm: 9.77 (s, 1H), 8.43 (s, 1H), 8.29-8.27 (dd, 1H), 8·08-8·02 (m, 1H), 7.34 -7.28 (m, 1H), 4.24 (s, 2H), 3.91-3.72 (br·, 2H), 3.66-3.32 (br·, 8H), 3.00-2.94 (m, 2H), 2.20-2.07 (m, 1H), 1.85-1.72 (m, 2H), 1.05-1.01 (m, 9H) 〇 [ES+MS] m/z 532 & 534 (MH)+. Example 7: N'-(5-Gas-2-cyano-4-pyrimidinyl)-4-fluoro-N'-(2-methylpropyl)-3-[(4-propyl-1-6) Hydrogen pyridinyl) fluorenyl] benzamidine trifluoroacetate

在中間物11 (39) (0·06克，0.3毫莫耳)於無水THF (5 毫升）之溶液中，加入Ν，Ν-二異丙基乙基胺（0.2毫升，1·2 气类耳）並將所得的反應混合物在室溫攪拌10分鐘。然後，加入中間物16(0.13克，0.44毫莫耳）及第三丁醇鉀 (AU)RICH，0·04克，0·4毫莫耳）並將反應混合物在室溫再攪拌16小時。在真空將溶劑去除並將所得的殘留物溶解在 MeOH並經由製備級HPLC (SUNF1RE 19x150毫米， ACN:H20, 0.1%TFA，梯度ΗΜ00%)純化後得到標題化合物。1H NMR (300 MHz, CDC13)3 ppm: 9.90 (s, 1H)，8.30-8.24 (m，2H)，8.11-8.05 (m，1H)，7.36-7.30 (m，1H)，4.34 (s，2H)， 3.94-3.76 (br·，2H)，3.76-3,44 (br·，8H)，3.04-2.98 (m，2H)， 106 200804352 2.21-2.06 (m，1H)，1.87-1.72 (m，2H)，1·08-0·93 (m，9H); [ES+MS] m/z 488 (MH)+。實例8 : 4-(l，4’-聯六氫吡啶-1，-基曱基)-N，-(5-氣-2-氰基-4-嘧啶基)-N’_(2-曱基丙基）苯曱醯肼三氟醋酸鹽In a solution of the intermediate 11 (39) (0·06 g, 0.3 mmol) in dry THF (5 mL), Ν, Ν-diisopropylethylamine (0.2 ml, 1:1 gas) The resulting reaction mixture was stirred at room temperature for 10 minutes. Then, intermediate 16 (0.13 g, 0.44 mmol) and potassium butoxide (AU) RICH, 0.04 g, 0. 4 mmoles were added and the mixture was stirred at room temperature for a further 16 hours. The solvent was removed in vacuo and the residue was crystalljjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj 1H NMR (300 MHz, CDC13) 3 ppm: 9.90 (s, 1H), 8.30-8.24 (m, 2H), 8.11-8.05 (m, 1H), 7.36-7.30 (m, 1H), 4.34 (s, 2H) ), 3.94-3.76 (br·, 2H), 3.76-3, 44 (br·, 8H), 3.04-2.98 (m, 2H), 106 200804352 2.21-2.06 (m, 1H), 1.87-1.72 (m, 2H), 1·08-0·93 (m, 9H); [ES+MS] m/z 488 (MH)+. Example 8: 4-(l,4'-bipyridinyl-1,-ylindenyl)-N,-(5-aero-2-cyano-4-pyrimidinyl)-N'-(2-oxime Propyl phenyl trifluoroacetate

將中間物17 (54毫克，0.14毫莫耳）、4-六氳批唆基六氫吡啶(ALDRICH，29毫克，0.17毫莫耳）、碳酸鉀(39毫克， 0·29毫莫耳）及碘化鈉溶解在無水ACN (2毫升）。將反應混合物在室溫攪拌過夜。反應完成後，將反應混合物過濾、並在減壓下將溶劑蒸發。將所得的粗殘留物溶解在MeOH，過濾並將所得的粗產物經由製備級HPLC (SUNF1RE 19x150 毫米，ACN:H20, 0.1%TFA，梯度 10_100%)純化後得到標題化合物。1H NMR (300 MHz，CDCl3-d6 + CD3OD，d6)3 ppm·· 8·24 (s，1H)，7·89 (d，2H)，7.56 (d，2H)， 4.23 (s，2H)，3.79-2.72 (br· m，10H)，2·2(Μ·89 (br· m，10H)， 1.41 (m，1H)，0.99 (d，6H); [ES+MS] m/z 510 (MH)+。實例9-37是經由類似於實例8說明之方法製備，用表 2所示的中間物及胺替代中間物π及4-六氫吡啶基六氫吡啶。 107 200804352 表2 實例; 結構胺f 中間物杨理數據’ 9 ΟΓΟγΟίΧ F 0 〇中。Η 丫六氫11比長 (ALDRICH) 18 1H NMR (300 MHz, DMSO-d6) δ ppm: 11.45 (s, 1Η)，9·61 (br.s，1Η)， 8.65 (s，1H)，8.00 (d, 2H)， 7.64 (d，2H), 4.35 (d，2H)， 3.97 (m, 1H)，3.59 (m， 1H), 3.30 (m，2H), 2.90 (m, 2H), 2.06 (m, 1H)， 1.78 (mr 2H), 1.65 (m, 3H)f 1.37 (mf 1H), 0.95 (d, 6H). [ES+· MS】m/z 471 (M)+. 10 中：° γ 吼每啶 (ALDRICH) 18 1H NMR (300 MHz, DMSO-d6) δ ppm: 11.44 (sf 1H)f 10.00 (br.s, 1H)f 8.65 (s，1H)，7.99 (d，2H), 7.66 (d, 2H), 4.43 (d, 2H), 3.98 (mf 1H), 3.63 (m, 1H)f 3.37 (m, 2H), 3.10 (m, 2H), 2.04 (m, 3H), 1.84 (m, 2H), 0.95 (d, 6H). [ES+ MS] m/z 457 (M)+. 11 00CV:1X ρ1Λη 丫一2,6:二—▼墓六氫°比σ定‘· (ALDRICH) 17 1H NMR (300 MHz, CDCI3-d6): 11.55-10.94 (b「· m, 1H), 9.09 (m, 1H), 8.31-7.53 (br. m，5H)，, 4.49-2.96 (m, 6H), 2.17-1.37 (m, 13H)，1.03 (d, 6H). fES+ MSI m/z 455 (MH)' 12 〇<οτν^ F OH 4-六氫吡啶羧酸乙酯 (ALDRICH) 17 1H NMR (300 MHz, CDCI3-d6): 9.00-8.88 (br. m，1H)，8.29 (s, 1H), 7.92 (d, 2H), 7.62 (d, 2H), 4.24-2.05 (br. m, 16H), 1.31-1.22 (m, 3H), 1.02 (d, 6H). 旧S+ MS] m/z 499 (MH)+. 108 200804352 實例結構胺中词物物理數據 13 F OH N-[(3S)-3-吡咯啶1] 乙烤酿胺 (TCI) 17 1H NMR (300 MHz, CDCI3): ):8.57-8.49 (br.s, 1H), 8.32 (s, 1H), 8,18-8.08 (br.s, 1H), 7.90 (d丨 2H), 7.65 (d, 2H), 4.98-4.77 (br”1H)，4.40- 4.10 (AB system, 2H), 4.00-3.71 (br.m, 3H), 3.46-3.29 (br.m, 1H), 3.21-2.85 (br., 2H), 2.62-2.42 (br.,1H), 2.27-2.04 (br.m, 2H),1.94 (s, 3H), 1.03 (d, 6H). [ES+ MSI m/z 470 (MH)' 14 ί 视caN 〇 v F OH 3-(m 氧 It涵基）吡洛咬 (TCI FLUOROCH EM) 17 1H NMR (300 MHz, CDCI3): ): 8.73-8.59 (br.s, 1H)，8.31 (s，1H)，7.89 (d， 2H)，7.62(d，2H)，6.24-5.97 (br.s，1H)，4.70-4.46 (b「” 1H), 4.41- 4.12 (br.， 2H)，3.94- 3.62 (br·, 3H)， 3.53- 3.36 (br., 1H), 3.18-2.77 (br.r 2H), 2.58- 1.92 (br·，3H)，1.41 (s，9H), 1.02 (d,6H). TES+ MSI m/z 528 (MH)". 15 r〇"X)Y%XXN 4<0 F OH 1-(2-(2- M M z7% 基）乙基)_ 六氫°比σ井 (ALDRICH) 17 1H NMR (300 MHz, DMSO): 11.38 (s? 1H),, 8.52 (s, 1H)r 7.9 (d, 2H), 7.5 (d, 2H)f 5.5- 3.87 (br., 6H)f 3.85- 3.64 (br., 4H), 3.59- 2.81 (br., 11H), 2.06 (m, 1H), 0.95 (df6H). [ES+ MS] γπ/ζ516(ΜΗΓ. 109 200804352 實例結構胺申間‘ 物理數據 16 CTCVl 山。。γ F OH 六氫吼咬 (ALDRICH) 17 1H NMR (300 MHz, CDCI3-d6): 11.97 (s, 1H), 8.87 (s, 1H)，8.30 (s, 1H), 7.90 (d，2H)，7.58 (d, 2H)， 4.20 (s, 2H), 3.81 (br. m， 2H), 3.56 (m, 2H), 2.64 (m, 2H), 2.11 (mf 1H), 1.99-1.84 (m, 5H), 1.42 (m, 1H), 1.02 (d, 6H). [ES+MS]m/z427(MH)' 17 ^Oy'XXm 3 V (RH+2-吼嘻σ定甲醇 (ALDRICH) 17 1HNMR (300 MHz, CDCI3):8.94(b「.s, 1H〉， 8.29 (s，1H)，7.89 (d,2H), 7.59 (d，2H), 4.74 (d，1H), 4.11 (d,1H), 3.99-3.46 (br.m, 7H), 3.12-2.85 (b「·， 2H)，2.27-2.00 (br·，3H)， 1.90 (m, 1H)t 1.01 (d, 6H). TES+ MS] m/z 443 (MH)+. 18 f-H〇 q f〇h "cvXl 〇 V °比Φ唆 (ALDRICH) 17 1HNMR.(300 MHz, CDCI3): 9.10 (br.s, 1H), 8.28 (s, 1H), 7.90 (df 2H), 7·60 (d, 2H> 4.26 (br.s, 2H), 3.91-3.58 (br.m, 4H), Z97-2.77 (m, 2H), 2.27- 1.91 (br.m，5H)， , 1.01 (d，6H). [ES+ MSI m/z413(MH)+. 19 Q f1^〇h ° V 3 - ^ (ALDRICH) 17 1H NMR (300 MHz， CDCI3): 9.08 8.28 (br.s, 1H)f 7.92 (m, 2H), 7.67 (m, 2H), 5.90 (br.s, 1H), 4.46-4.19 (br.,3H), 3.95- 3.53 (br.,4H), 2.58-1.96 (br，3H)，1.01 (d, 6H). [ES+ MS] m/z 411 (MH)+. 110 200804352 實例結構胺中間杨 i物理數據 20 。V 2,5-二甲基 -3-吡洛。林 (ALDRICH) 17 1HNMR (300 MHz, DMSO):7.59 (br.s, 1H), 7.20 (d, 2H)f 6.94 (mf 2H), 5.29- 5.01 (br，2H), 4.13- 3.97 (br.,2H), 3.87-3.72 (br.f 4H), 133 (m, ΊΗ), 0-74-0.35 (br”6H), 0.23 (d, 6H). [ES+ MSI m/z 439 (MH)+. 21 从〇·χναΧ4 4/ 0 Υ F OH 1，1 - 二f基乙墓二 1，4-六氫吼$ 胺ΐ甲酸鹽1 (ALDRICH) • 17 [ES+ MS] m/z 542 (MH)+. 22 <。ν F CH 丨1-(3:二〒胺基丙基）六氫吡_ (ALDRICH) 17 1HNMR (300 MHz, CDCI3-d6 + CD30D-d6): 8.14 (st 1H), 7.77 (d, 2H), 7.38 (d, 2H)f 3.46-2.75 (m, 17H)，2.73(br, s，6H), 2.00 (m，3H), 0.90 (d, 6H). [ES+ MS] m/z513(MH+). 23 o 一 9Ά^χ 1-(孓二乙胺基丙基）六氫ϋ比。井 (FLUOROC HEM) 17、 1H NMR (300 MHz, CDCI3-d6 + CD30D-d6): 8·16 (s, 1H), 7·79 (d, 2H), 7.39 (df 2H), 3.85 (m, ^ 6H), 3.20-2.73 (m, 19H), 2.02 (m，3H), 0.92 (d, 6H). fES+ MSI m/z 555 (MH+). 111 200804352 "胥例結¥> 胺中間物物理數據 24 〇一〇νΊ ° V F OH 1 - (3 -嗎福咁基丙基) 六氫σ比啡 (FLUOROC HEM) 17 1H NMR (300 MHz, DMSO-d6): 11.40 (s, 1H〉， 9.38 (br·，1H)，8.52 (s， 1H)，7.92 (d，2H), 7.54 (d, 2H), 3.70-2.72 (mf 20H), 2.06 (m, 1H), 1.92 (m, 2H)f 1.18 (t, 6H), 0.95 (d, 6H). [ES+ MSI m/z 541 _+). 25 二一 F OH 、 1:(3 1脸基丙墓) 六氫σ比得 (FLUOROC HEM) 17 1H NMR (300 MHz, DMSO-d6): 11.40 (s, 1H), 9.41 (br., 1H), 8.52 (s, 1H), 7.92 (dt 2H), 7.53 (df 2H), 4.13-2.73 (m, 20H), 2.06 (m, 1H), 1.94 (m, 2H), 1.61 (m, 4H), .1.00-0.83 (m, 12H). [ES+ MSI m/z 569 (MH+). 26 二一ΟΧνΊ 山。。γ F OH 1-(3-二娣胺六氫吼吩 (FLUOROC HEM) 17 1H NMR (300 MHz, DMSO-d6): 11.41 (s, 1H), 10.08 (br., 1H), 8.52 (s, 1H)f 7.93 (d, 2H), 7.54 (d, 2H), 5.QJ (m, 2H)f 5.55 (m, 4H), 4.102.71 (m, 20H), 2.13-1.88 (m, 3H), 0.96 (d, 6H). fES+ MS] m/z 565 (MH+).， 27 、OXrXV政山。。Υ F 〇H 基-4:六:¾ 吡啶尹基）六氫吡0井 (FLUOROC HEM) 17 1H NMR (300 MHz, DMSO-d6): 11.40 (s，1H)， 9.30 (br·，1H)，8,53 (s， 1H), 7.92 (m, 2H), 7.54 (m, 2H), 3.70-2.72 (m, 23H), 2.06 (m，1H), 1.90 (m, 2H), 1.26 (m, 1H)f 0.95 (d, 6H). [ES+ MS] m/z 539 (MH+). 112 200804352 實例結構 Έ 中間物物理數據 • 1Η NMR (300 MHz, D30D-d6): 8·38 (br. m， 1H), 7.86 (m, 2H), 7.50 (m, 2H), 3.65 (s, 2H)t 3.43 (b「· m, 2H)，3.00-2.48 (m, 16H), 2.22-2.02 (m, 4H), 1.74 (m, 2H), 1.02 (d, 6H). fES+ MS] m/z 525 (MH+). 28 士。。γ F OH 1-(N-曱基4 六氫4咬基六氫AD评 (ALDRICH) > 17 1 29 Fti 9H V-1 V o 1 2-(六氫 0比σ定-4 -基）乙酸乙酯 (FLUOROC HEM) 17 1H NMR(CDCI3) δ ppm : 9.09(s;1H);8.28(s;1H);7.9 0(d;7.91Hz;2H);7.56(d;7.9 1Hz;2H);4.17(s;2H);4.12( q;7.2Hz;2H);3.80(m;2H);3 .55(m;2H);2.67(m;2H);2.2 9(d;6.3HZ;2H);2.11(m;6.4 4Hz;1H);1.96(m;3H);1.75( m;2H);1.24(t;7Hz;3H);1.0 1(d;6.6Hz;6H) ES+MS m/z513(MH)+ 30 A 〜crci/X^ 」士。。Y F OH 1 -二 6 胺基乙基> 六氫°比σ井. (CHEMPUR) 17 1H NMR(CDCI3) δ ppm: 9.1(s; 1H);8.29(s; 1H); 7.86(d; 8.2Hz; 2H); 7.53(d; 8.2Hz; 2H); 4.16(s;2H);3.8(m; 2H); 3.35-2.7(m; 16H); 、 2.11(m;6.6Hz; 1H);1.32(t; 7.3Hz;6H); 1.01(d; 6.6Hz;6H). ES+MS m/z 527(MH)+ 113 200804352 實例_ T结構胺中間物 1物理數據 31 /A 〔N〕F 〇 V 卜(2-二兵丙胺基乙基）六氫°比°井 (FLUOROC HEM) 17 1HNMR (300 MHz, CDCI3): 9.07 (s, 1H), 8.30 (s, 1H), 7.9(d,2H), 7.5 (d，2H), 6.07-5.86 (m, 2H), 5.65- 5.46 (m，4H), 4.16 (s,2H), 3.87- 3.75 (br, 2H), 3.7 (dt 4H), 3.36-3.13 (br.,4H), 3.13-3.00 (br.，2H), 2.94-2.71 (br., 6H), 2.19- 2.02 (m, 1H), 1.02 (d,6H). [ES+ MSI m/z551 (MH+). 32 V 乂认H 〔N〕F 〇 V 1 -(乏-二丙涵基乙基）六氫σ比畊 (FLUOROC HEM) 17 1HNMR (300 MHz, CDCI3):8.99(br.s, 1H), 8.30(s, 1H>，7.9(d，2H〉， 7.5 (d, 2H), 4.18 (s, 2H), 3.82- 3.63 (br., 2H), 3.23-2.89 (br.f 10H), 2.87- 2.66 (br., 6H), 2.19- 2.05 (m, 1H), 1.76- 1.54 (m, 4H), 1.03-0.84 (m, 12H). [ES+ MSI m/z555(MH+). 33 丫、 F 〇H rNT 1 V 2「6-二甲基六氫吼咬 (ALDRICH) 19 1H NMR (300 MHz, DMSO-d6): 10.49 (d, 1H), 9.31-8.99 (br· s, 1H), 8.54 (s, 1H), 8.05-7.94 (m, 2H), 7.83-7.57 (m, 2H),. 4.60(m, 1H)，4.39(m, 1H), 3.55-1.54 (m, 11H), 1.47 (d, 3H), 1.27 (d, 3H), 0.96 (d, 6H)· fES+ MSI m/z 455 (MH+). 114 200804352 實例 :結構 —w 中間物物理數據 34 ν ρΉη 4-六氫吡咬基六氫吼σ定 (ALDRICH) 19 1H NMR (300 MHz, DMSO-d6): 11.50 (s, 1H), 9.98 (br., 1H)t 9.53 (br.t 1H)t 8.54 (s, 1H), 8.07- 7.98 (m，2H), 7.76-7.61 (m, 2H), 4.36 (br.f 2H), 4.08-3.24 (m, 6H), 2.94 (br. m, 4H), 2.20 (br. m, 2H), 2.07 (m, 1H), 1.93-1.53 (m, 8H), 1.40 (mf 1H), 0.96 (d,6H). TES+ MSI m/z510(MH+). 35 n f-h° CV f 〇H 6yd 1 V —N -甲基六氫吡畊 (ALDRICH) 19 1H NMR (300 MHz, DMSO-d6): 11.49 (s, 1H), 9.41 (b「.s, 1H), 8.54 (sf 1H), 8.01 (m, 2H)r 7.76-7.61 (mr 2H), 4.35 (m, 2H), 3.32 (m, 3H), 2.90 (m, 2H), 2.07 (m, 1H), 1.88-1.48 (m, 6H)f 1.37 (m, 1H), 0.96 (dt6H). [ES+ MSI m/z 427 (MH+). 36 f^| C，Y^N ^ ^nv^A^n.nAnAcn +: 。Ϋ 1-(3-二丙胺基丙基）六氫σ比畊 (FLUOROC HEM) 19 1H NMR (300 MHz, CDCI3-d6): 10.10 (s, 1H), 8.24 (m, 2H), 8.03 (m, 1H)，7.61-7.47 (m,2H), 4.16 (s, 2H), 3.90-3.35 (m, 10H)，3.31-2.92 (m, 8H)f 2.81 (m, 2H), 2.21-2.01 (m, 3H), 1.74 (m, 4H), 1.10-0.93 (m, 12H). [ES+ MS〗 m/z 569 (MH+)· 115 200804352 實例 • —*·-·- · -*—--------------- :結構中間物丨丨櫨 37 〇…o為：ιχ 士。0 γ F OH —--__ 1 -(3-二乙胺基丙基）六氫°比11井 (FLUOROC HEM) 19 1HNMR (300 MHz, CDCI3-d6): 10.06 (s, 1H), 8.25 (m，2H)，8.03 (m, 1H)，7.61-7.47 (m, 2H)， 4.17 (s，2H)，3.82 (br.sf 2H)，3.39-2.97 (m, 14 H)， 2.86 (m，2H)，2.20-2.03 (m，3H)，1.33 (t，6H)，1.01 (d, 6H)· fES+ MSI m/z 541 (MH+). 貫例38 :N’-(5-氣-2-氰基-4_嘧啶基）-4-[(4_經基-1-六氫吡啶基）甲基甲基丙基）苯曱醯肼三氟醋酸鹽Intermediate 17 (54 mg, 0.14 mmol), 4-hexamethylene hexahydropyridine (ALDRICH, 29 mg, 0.17 mmol), potassium carbonate (39 mg, 0·29 mmol) and Sodium iodide was dissolved in anhydrous ACN (2 mL). The reaction mixture was stirred at room temperature overnight. After the reaction was completed, the reaction mixture was filtered, and the solvent was evaporated under reduced pressure. The resulting crude residue was taken up in EtOAc EtOAcjHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH 1H NMR (300 MHz, CDCl3-d6 + CD3OD, d6) 3 ppm·· 8·24 (s, 1H), 7·89 (d, 2H), 7.56 (d, 2H), 4.23 (s, 2H), 3.79-2.72 (br· m,10H),2·2 (Μ·89 (br· m,10H), 1.41 (m,1H), 0.99 (d,6H); [ES+MS] m/z 510 ( MH)+. Example 9-37 was prepared via a procedure similar to that described in Example 8, substituting the intermediates and amines shown in Table 2 for the intermediates π and 4-hexahydropyridylhexahydropyridine. 107 200804352 Table 2 Examples; Structural amine f intermediate Yang Yang data ' 9 ΟΓΟ γ Ο Χ Χ F 0 〇 Η 丫丫氢氢 ( ( (ALDRICH) 18 1H NMR (300 MHz, DMSO-d6) δ ppm: 11.45 (s, 1 Η), 9.61 (br.s,1Η), 8.65 (s,1H), 8.00 (d, 2H), 7.64 (d,2H), 4.35 (d,2H), 3.97 (m, 1H), 3.59 (m, 1H), 3.30 (m, 2H), 2.90 (m, 2H), 2.06 (m, 1H), 1.78 (mr 2H), 1.65 (m, 3H)f 1.37 (mf 1H), 0.95 (d, 6H). [ES+· MS]m/z 471 (M)+. 10 Medium: ° γ 吼 per pyridine (ALDRICH) 18 1H NMR (300 MHz, DMSO-d6) δ ppm: 11.44 (sf 1H)f 10.00 (br.s, 1H) f 8.65 (s,1H), 7.99 (d,2H), 7.66 (d, 2H), 4.43 (d, 2H), 3.98 (mf 1H), 3.63 (m, 1H)f 3.37 (m, 2H), 3.10 (m, 2H), 2.04 (m, 3H), 1.84 (m, 2H), 0.95 (d, 6H). [ES+ MS] m/z 457 (M)+. 11 00CV: 1X ρ1Λη 丫一2,6:二—▼ Tomb hexahydrogen ratio σ定'· (ALDRICH) 17 1H NMR (300 MHz, CDCI3-d6): 11.55-10.94 (b “· m, 1H), 9.09 (m , 1H), 8.31-7.53 (br. m, 5H),, 4.49-2.96 (m, 6H), 2.17-1.37 (m, 13H), 1.03 (d, 6H). fES+ MSI m/z 455 (MH) ' 12 〇<οτν^ F OH 4-Ethylhydropyridinecarboxylate (ALDRICH) 17 1H NMR (300 MHz, CDCI3-d6): 9.00-8.88 (br. m,1H), 8.29 (s, 1H) , 7.92 (d, 2H), 7.62 (d, 2H), 4.24-2.05 (br. m, 16H), 1.31-1.22 (m, 3H), 1.02 (d, 6H). Old S+ MS] m/z 499 (MH)+. 108 200804352 Example Structural amines Physical data 13 F OH N-[(3S)-3-pyrrolidine 1] B-broiled amine (TCI) 17 1H NMR (300 MHz, CDCI3): ): 8.57-8.49 (br.s, 1H), 8.32 (s, 1H), 8,18-8.08 (br.s, 1H), 7.90 (d丨2H), 7.65 (d, 2H), 4.98-4.77 (br "1H", 4.40- 4.10 (AB system, 2H), 4.00-3.71 (br.m, 3H), 3.46-3.29 (br.m, 1H), 3.21-2.85 (br., 2H), 2.62-2.42 ( Br.,1H), 2.27-2.04 (br.m, 2H), 1.94 (s, 3H), 1.03 (d, 6H). [ES+ MSI m /z 470 (MH)' 14 ί ca caN 〇v F OH 3-(m oxy It sulphate) pyridine (TCI FLUOROCH EM) 17 1H NMR (300 MHz, CDCI3): ): 8.73-8.59 (br. s, 1H), 8.31 (s, 1H), 7.89 (d, 2H), 7.62 (d, 2H), 6.24-5.97 (br.s, 1H), 4.70-4.46 (b "" 1H), 4.41- 4.12 (br., 2H), 3.94 - 3.62 (br·, 3H), 3.53- 3.36 (br., 1H), 3.18-2.77 (br.r 2H), 2.58- 1.92 (br·, 3H), 1.41 (s , 9H), 1.02 (d,6H). TES+ MSI m/z 528 (MH)". 15 r〇"X)Y%XXN 4<0 F OH 1-(2-(2- MM z7% base Ethyl)_hexahydrogen ratio σ 井 (ALDRICH) 17 1H NMR (300 MHz, DMSO): 11.38 (s? 1H),, 8.52 (s, 1H)r 7.9 (d, 2H), 7.5 (d, 2H)f 5.5- 3.87 (br., 6H)f 3.85- 3.64 (br., 4H), 3.59- 2.81 (br., 11H), 2.06 (m, 1H), 0.95 (df6H). [ES+ MS] γπ /ζ516(ΜΗΓ. 109 200804352 Example structure amine Shenjian' physical data 16 CTCVl mountain. . γ F OH hexahydro sputum (ALDRICH) 17 1H NMR (300 MHz, CDCI3-d6): 11.97 (s, 1H), 8.87 (s, 1H), 8.30 (s, 1H), 7.90 (d, 2H), 7.58 (d, 2H), 4.20 (s, 2H), 3.81 (br. m, 2H), 3.56 (m, 2H), 2.64 (m, 2H), 2.11 (mf 1H), 1.99-1.84 (m, 5H ), 1.42 (m, 1H), 1.02 (d, 6H). [ES+MS]m/z427(MH)' 17 ^Oy'XXm 3 V (RH+2-吼嘻σ定MeOH (ALDRICH) 17 1HNMR (300 MHz, CDCI3): 8.94 (b ".s, 1H>, 8.29 (s, 1H), 7.89 (d, 2H), 7.59 (d, 2H), 4.74 (d, 1H), 4.11 (d, 1H) ), 3.99-3.46 (br.m, 7H), 3.12-2.85 (b"·, 2H), 2.27-2.00 (br·, 3H), 1.90 (m, 1H)t 1.01 (d, 6H). TES+ MS ] m/z 443 (MH)+. 18 fH〇qf〇h "cvXl 〇V ° ratio Φ唆(ALDRICH) 17 1HNMR.(300 MHz, CDCI3): 9.10 (br.s, 1H), 8.28 (s , 1H), 7.90 (df 2H), 7·60 (d, 2H> 4.26 (br.s, 2H), 3.91-3.58 (br.m, 4H), Z97-2.77 (m, 2H), 2.27- 1.91 (br.m,5H), , 1.01 (d,6H). [ES+ MSI m/z413(MH)+. 19 Q f1^〇h ° V 3 - ^ (ALDRICH) 17 1H NMR (300 MHz, CDCI3) : 9.08 8.28 (br.s, 1H)f 7.92 (m, 2H), 7.67 (m, 2H), 5.90 (br.s, 1H), 4.46-4.19 (br.,3H), 3.95 - 3.53 (br., 4H), 2.58-1.96 (br, 3H), 1.01 (d, 6H). [ES+ MS] m/z 411 (MH)+. 110 200804352 Example Structure Amine Intermediate yang i Physical data 20 . V 2,5-dimethyl-3-pyrrol. ALDRICH 17 1HNMR (300 MHz, DMSO): 7.59 (br.s, 1H), 7.20 (d, 2H)f 6.94 (mf 2H), 5.29- 5.01 (br, 2H), 4.13- 3.97 (br. , 2H), 3.87-3.72 (br.f 4H), 133 (m, ΊΗ), 0-74-0.35 (br"6H), 0.23 (d, 6H). [ES+ MSI m/z 439 (MH)+ 21 From 〇·χναΧ4 4/ 0 Υ F OH 1,1 - bis-f-tomb, di-1,4-hexahydroindole, amine carbazate 1 (ALDRICH) • 17 [ES+ MS] m/z 542 ( MH)+. 22 <. ν F CH 丨 1-(3: diammonium propyl) hexahydropyridyl _ (ALDRICH) 17 1HNMR (300 MHz, CDCI3-d6 + CD30D-d6): 8.14 (st 1H ), 7.77 (d, 2H), 7.38 (d, 2H)f 3.46-2.75 (m, 17H), 2.73 (br, s, 6H), 2.00 (m, 3H), 0.90 (d, 6H). [ES+ MS] m/z 513 (MH+). 23 o -9 Ά χ χ 1-(孓 diethylaminopropyl) hexahydropyrene ratio. Well (FLUOROC HEM) 17, 1H NMR (300 MHz, CDCI3-d6 + CD30D- D6): 8·16 (s, 1H), 7·79 (d, 2H), 7.39 (df 2H), 3.85 (m, ^ 6H), 3.20-2.73 (m, 19H), 2.02 (m, 3H) , 0.92 (d, 6H). fES+ MSI m/z 555 (MH+). 111 200804352 "胥例结¥> Amine Intermediate Physical Data 24 〇一〇νΊ ° VF OH 1 - (3 - 福福咁基Propyl) hexahydro σ-pyrene (FLUORO C HEM) 17 1H NMR (300 MHz, DMSO-d6): 11.40 (s, 1H), 9.38 (br., 1H), 8.52 (s, 1H), 7.92 (d, 2H), 7.54 (d, 2H) , 3.70-2.72 (mf 20H), 2.06 (m, 1H), 1.92 (m, 2H)f 1.18 (t, 6H), 0.95 (d, 6H). [ES+ MSI m/z 541 _+). 25 II A F OH , 1: (3 1 face base tomb) hexahydro σ ratio (FLUOROC HEM) 17 1H NMR (300 MHz, DMSO-d6): 11.40 (s, 1H), 9.41 (br., 1H), 8.52 (s, 1H), 7.92 (dt 2H), 7.53 (df 2H), 4.13-2.73 (m, 20H), 2.06 (m, 1H), 1.94 (m, 2H), 1.61 (m, 4H), . 1.00-0.83 (m, 12H). [ES+ MSI m/z 569 (MH+). 26 ΟΧ ΟΧ Ί Ί mountain. . γ F OH 1-(3-Diamine hexahydrophene (FLUOROC HEM) 17 1H NMR (300 MHz, DMSO-d6): 11.41 (s, 1H), 10.08 (br., 1H), 8.52 (s, (H, 2H), 5.54 (d, 2H) , 0.96 (d, 6H). fES+ MS] m/z 565 (MH+)., 27, OXrXV Zhengshan..Υ F 〇H base-4:6:3⁄4 pyridinyl) hexahydropyridinium 0 (FLUOROC HEM 17 1H NMR (300 MHz, DMSO-d6): 11.40 (s, 1H), 9.30 (br·, 1H), 8, 53 (s, 1H), 7.92 (m, 2H), 7.54 (m, 2H) , 3.70-2.72 (m, 23H), 2.06 (m, 1H), 1.90 (m, 2H), 1.26 (m, 1H)f 0.95 (d, 6H). [ES+ MS] m/z 539 (MH+). 112 200804352 Example structure 中间 Intermediate physical data • 1Η NMR (300 MHz, D30D-d6): 8·38 (br. m, 1H), 7.86 (m, 2H), 7.50 (m, 2H), 3.65 (s, 2H)t 3.43 (b"· m, 2H), 3.00-2.48 (m, 16H), 2.22-2.02 (m, 4H), 1.74 (m, 2H), 1.02 (d, 6H). fES+ MS] m/ z 525 (MH+). 28 。 γ F OH 1-(N-fluorenyl 4 hexahydro 4 octyl hexahydrogen AD evaluation (ALDRICH) > 17 1 29 Fti 9H V-1 V o 1 2- (six Hydrogen 0 to sigma-4 -yl) Ethyl acetate (FLUOROC HEM) 17 1H NMR ( CDCI3) δ ppm : 9.09 (s; 1H); 8.28 (s; 1H); 7.9 0 (d; 7.91 Hz; 2H); 7.56 (d; 7.9 1 Hz; 2H); 4.17 (s; 2H); 4.12 (q) ; 7.2 Hz; 2H); 3.80 (m; 2H); 3.55 (m; 2H); 2.67 (m; 2H); 2.2 9 (d; 6.3HZ; 2H); 2.11 (m; 6.4 4 Hz; 1H) ; 1.96 (m; 3H); 1.75 (m; 2H); 1.24 (t; 7 Hz; 3H); 1.0 1 (d; 6.6 Hz; 6H) ES+MS m/z 513 (MH) + 30 A ~crci/X ^"士士. . YF OH 1 -di 6 -aminoethyl > hexahydrogen ratio σ well. (CHEMPUR) 17 1H NMR (CDCI3) δ ppm: 9.1 (s; 1H); 8.29 (s; 1H); 7.86 (d; 8.2 Hz; 2H); 7.53 (d; 8.2 Hz; 2H); 4.16 (s; 2H); 3.8 (m; 2H); 3.35-2.7 (m; 16H);, 2.11 (m; 6.6 Hz; 1H); (t; 7.3 Hz; 6H); 1.01 (d; 6.6 Hz; 6H). ES+MS m/z 527(MH)+ 113 200804352 Example _ T-Structure Amine Intermediate 1 Physical Data 31 /A [N]F 〇 V 卜 (2-two propylaminoethyl) hexahydrogen ratio (FLUOROC HEM) 17 1HNMR (300 MHz, CDCI3): 9.07 (s, 1H), 8.30 (s, 1H), 7.9 (d, 2H) ), 7.5 (d, 2H), 6.07-5.86 (m, 2H), 5.65- 5.46 (m, 4H), 4.16 (s, 2H), 3.87- 3.75 (br, 2H), 3.7 (dt 4H), 3.36 -3.13 (br.,4H), 3.13-3.00 (br.,2H), 2.94-2.71 (br., 6H), 2.19- 2.02 (m, 1H), 1.02 (d,6H). [ES+ MSI m/ Z551 (MH+). 32 V HH 〔N]F 〇V 1 -(l-dipropyl arylethyl) hexahydro sigma ratio (FLUOROC HEM) 17 1HNMR (300 MHz, CDCI3): 8.99 (br. s, 1H), 8.30(s, 1H>, 7.9(d, 2H>, 7.5 (d, 2H), 4.18 (s, 2H), 3.82- 3.63 (br., 2H), 3.23-2.89 (br.f 10H), 2.87- 2.66 (br., 6H), 2.19- 2.05 (m, 1H), 1.76- 1.54 (m, 4H), 1.0 3-0.84 (m, 12H). [ES+ MSI m/z555(MH+). 33 丫, F 〇H rNT 1 V 2 "6-Dimethylhexahydropurine bite (ALDRICH) 19 1H NMR (300 MHz, DMSO -d6): 10.49 (d, 1H), 9.31-8.99 (br· s, 1H), 8.54 (s, 1H), 8.05-7.94 (m, 2H), 7.83-7.57 (m, 2H), 4.60 ( m, 1H), 4.39 (m, 1H), 3.55-1.54 (m, 11H), 1.47 (d, 3H), 1.27 (d, 3H), 0.96 (d, 6H)· fES+ MSI m/z 455 (MH+ 114 200804352 Example: Structure - w Intermediate physical data 34 ν ρΉη 4-hexahydropyridyl hexahydropurine sigma (ALDRICH) 19 1H NMR (300 MHz, DMSO-d6): 11.50 (s, 1H), 9.98 (br., 1H)t 9.53 (br.t 1H)t 8.54 (s, 1H), 8.07- 7.98 (m,2H), 7.76-7.61 (m, 2H), 4.36 (br.f 2H), 4.08 -3.24 (m, 6H), 2.94 (br. m, 4H), 2.20 (br. m, 2H), 2.07 (m, 1H), 1.93-1.53 (m, 8H), 1.40 (mf 1H), 0.96 ( d,6H). TES+ MSI m/z 510(MH+). 35 n fh° CV f 〇H 6yd 1 V —N-methylhexahydropyrazine (ALDRICH) 19 1H NMR (300 MHz, DMSO-d6): 11.49 (s, 1H), 9.41 (b ".s, 1H), 8.54 (sf 1H), 8.01 (m, 2H)r 7.76-7.61 (mr 2H), 4.35 (m, 2H), 3.32 (m, 3H) , 2.90 (m, 2H), 2.07 (m, 1H), 1.88-1.48 (m, 6H)f 1.37 (m, 1 H), 0.96 (dt6H). [ES+ MSI m/z 427 (MH+). 36 f^| C,Y^N ^ ^nv^A^n.nAnAcn +: . Ϋ 1-(3-Dipropylaminopropyl) hexahydro sigma ratio (FLUOROC HEM) 19 1H NMR (300 MHz, CDCI3-d6): 10.10 (s, 1H), 8.24 (m, 2H), 8.03 (m , 1H), 7.61-7.47 (m, 2H), 4.16 (s, 2H), 3.90-3.35 (m, 10H), 3.31-2.92 (m, 8H)f 2.81 (m, 2H), 2.21-2.01 (m , 3H), 1.74 (m, 4H), 1.10-0.93 (m, 12H). [ES+ MS] m/z 569 (MH+)· 115 200804352 Examples • —*·-·- · -*—---- ----------- : Structural intermediates 丨丨栌37 〇...o is: ιχ士士. 0 γ F OH —--__ 1 —(3-diethylaminopropyl) Hexahydrogen ratio 11 Well (FLUOROC HEM) 19 1HNMR (300 MHz, CDCI3-d6): 10.06 (s, 1H), 8.25 ( m, 2H), 8.03 (m, 1H), 7.61-7.47 (m, 2H), 4.17 (s, 2H), 3.82 (br.sf 2H), 3.39-2.97 (m, 14 H), 2.86 (m, 2H), 2.20-2.03 (m, 3H), 1.33 (t, 6H), 1.01 (d, 6H)· fES+ MSI m/z 541 (MH+). Example 38: N'-(5-gas-2- Cyano-4_pyrimidinyl)-4-[(4-alkyl-1-hexahydropyridyl)methylmethylpropyl)phenylhydrazine trifluoroacetate

CNCN

0 將中間物17(54毫克，〇·14毫莫耳）、4-羥基六氫吡啶 vumiCH，17毫克，0·17毫莫耳）、碳酸鉀(39毫克，0.29 毫莫耳）及碘化鈉溶解在無水ACN (2毫升）。將反應混合物在室溫攪拌過夜。反應完成後，將反應混合物過濾並在減壓下將溶劑蒸發。將所得的粗殘留物溶解在MeOH，過濾並將所得的粗產物經由製備級HPLC (SUNFIRE 19x150毫米，ACN:H2〇，0.1%TFA，梯度10-100%)純化後得到標題化合物。NMR (300 MHz，CDCl3-d6): 8.74 (s，1H)，8·30 (s, 1Η)，7·93 (d，2Η)，7·72 (d，2Η)，4.26-4.20 (m，3Η)，3·82 (m， 2H)，3·37-3·14 (br· m，4H)，2·42-1·86 (br· m，5H)，1.03 (d， 116 200804352 6H); [ES+MS] m/z 443 (M)+。實例39 : N’-(5-氯-2-氰基-4-嘧啶基)-4-{[4-(2-羥基乙基)_卜六氫吡啶基]甲基卜N’-(2_T基丙基）苯甲醯胼三氟醋酸鹽0 Intermediate 17 (54 mg, 14 mmol), 4-hydroxyhexahydropyridine vumiCH, 17 mg, 0·17 mmol, potassium carbonate (39 mg, 0.29 mmol) and iodinated Sodium was dissolved in anhydrous ACN (2 mL). The reaction mixture was stirred at room temperature overnight. After the reaction was completed, the reaction mixture was filtered and the solvent was evaporated under reduced pressure. The resulting crude residue was taken up in EtOAc EtOAcjHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH NMR (300 MHz, CDCl3-d6): 8.74 (s, 1H), 8·30 (s, 1Η), 7.93 (d, 2Η), 7·72 (d, 2Η), 4.26-4.20 (m, 3Η), 3·82 (m, 2H), 3·37-3·14 (br· m, 4H), 2·42-1·86 (br· m, 5H), 1.03 (d, 116 200804352 6H) ; [ES+MS] m/z 443 (M)+. Example 39: N'-(5-Chloro-2-cyano-4-pyrimidinyl)-4-{[4-(2-hydroxyethyl)- hexahydropyridyl]methyl b N'-(2_T Propyl benzhydrazine trifluoroacetate

將中間物17 (54毫克，0.14毫莫耳）、4-六氳吡啶乙醇 (ALDRICH，22毫克，0.17毫莫耳）、碳酸鉀(39毫克，〇·29 毫莫耳）及碘化鈉溶解在無水ACN (2毫升）。將反應混合物在室溫攪拌過夜。反應完成後，將反應混合物過濾並在減壓下將溶劑蒸發。將所得的粗殘留物溶解在MeOH，過濾並將所得的粗產物經由製備級HPLC (SUNF1RE 19x150毫米，ACN:H2〇,〇.1%TFA，梯度ΗΜ00%)純化後得到標題化合物。NMR (300 MHz，CDCl3-d6): 8.84 (s，1H)，8.30 (s， 1H)，7.92 (d，2H)，7·67 (d，2H)，4·19 (s，2H)，3·83-3·35 (br· m， 6H)，2.67 (m，2H)，2.17-1.56 (m，8H)，1·〇2 (d，6H); [ES+MS] m/z 471 (MH)+ 〇貫例40 : N’-(5-氯-2-氰基-4-嘧啶基)_4_{[‘(2_羥基乙基)_卜六氫吡畊基]曱基}-Ν，-(2-曱基丙基）苯曱醯胼三氟醋酸鹽Intermediate 17 (54 mg, 0.14 mmol), 4-hexapyridine alcohol (ALDRICH, 22 mg, 0.17 mmol), potassium carbonate (39 mg, 〇·29 mmol) and sodium iodide dissolved In anhydrous ACN (2 ml). The reaction mixture was stirred at room temperature overnight. After the reaction was completed, the reaction mixture was filtered and the solvent was evaporated under reduced pressure. The resulting crude residue was taken up in EtOAc EtOAcjHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH NMR (300 MHz, CDCl3-d6): 8.84 (s, 1H), 8.30 (s, 1H), 7.92 (d, 2H), 7·67 (d, 2H), 4·19 (s, 2H), 3 · 83-3·35 (br· m, 6H), 2.67 (m, 2H), 2.17-1.56 (m, 8H), 1·〇2 (d, 6H); [ES+MS] m/z 471 ( MH)+ 〇 Example 40: N'-(5-chloro-2-cyano-4-pyrimidinyl)_4_{['(2_hydroxyethyl)- hexahydropyranyl] fluorenyl}-Ν ,-(2-mercaptopropyl)phenylhydrazine trifluoroacetate

117 200804352 將中間物17(50毫克，0.13毫莫耳）、1_(2-羥基乙基）六氫吼畊(ALDRICH，〇·〇2毫升，〇·ΐ6毫莫耳）、碳酸鉀（36 毫克，〇·26毫莫耳）及碘化鈉溶解在無水ACN (2毫升）。將反應混合物在室溫攪拌過夜。反應完成後，將反應混合物過濾並在減壓下將溶劑蒸發。將所得的粗殘留物溶解在 MeOH，過濾並將所得的粗產物經由製備級HPLC (SUNFIRE 19x150 毫米，ACN:H2〇, 〇jo/oTfa，梯度 1(M00%) 純化後得到標題化合物。1HNMR(300 MHz，d6-DMSO): 11.39 (s，1H)，8.52 (s，1H)，7.9 (d，2H)，7·5 (d，2H), 5·35-2·5 (br” 17H)，2·06 (m，1H)，〇·95 (d，6H); [ES+MS] m/z 472 (MH)+。實例41 : N’-(5-氣_2-氰基_4_嘧啶基)_4-{[4-(羥基曱基)小六氫吼咬基]曱基卜N，-(2-甲基丙基）苯甲醯胼三氟醋酸鹽117 200804352 Intermediate 17 (50 mg, 0.13 mmol), 1_(2-hydroxyethyl) hexahydroquinone (ALDRICH, 毫升·〇 2 ml, 〇·ΐ 6 mmol), potassium carbonate (36 mg) , 〇·26 mmol) and sodium iodide dissolved in anhydrous ACN (2 mL). The reaction mixture was stirred at room temperature overnight. After the reaction was completed, the reaction mixture was filtered and the solvent was evaporated under reduced pressure. The resulting crude residue was taken up in EtOAc EtOAc (mjHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH 300 MHz, d6-DMSO): 11.39 (s, 1H), 8.52 (s, 1H), 7.9 (d, 2H), 7·5 (d, 2H), 5·35-2·5 (br" 17H) , 2·06 (m, 1H), 〇·95 (d, 6H); [ES+MS] m/z 472 (MH)+. Example 41: N'-(5-gas_2-cyano_4 _[pyrimidinyl)_4-{[4-(hydroxyindenyl) hexahydroindenyl] sulfhydryl N,-(2-methylpropyl)benzimidazole trifluoroacetate

將中間物17 (54毫克，0.14毫莫耳）、4-(羥基曱基）六氫口比咬(ALDRICH，20毫克，〇·π毫莫耳）、碳酸鉀(39毫克， 0.29毫莫耳）及碘化鈉溶解在無水ACN (2毫升）。將反應混合物在室溫攪拌過夜。反應完成後，將反應混合物過濾並在減壓下將溶劑蒸發。將所得的粗殘留物溶解在MeOH，過濾、並將所得的粗產物經由製備級HPLC (SUNFIRE 19x150^ 米，aCN:H2〇,〇1%tfa，梯度 1〇_1〇〇0/心純化，且 118 200804352 隨後經由第二個製備級HPLC (SUNFIRE 19x150毫米， ACN:H20, 0.1%TFA，梯度30-100%)純化後得到標題化合物。1H NMR (300 MHz, CDC13-d6): 8.59 (br·，1H)，8·32 (s， 1H)，7·89 (d，2H)，7·67 (d，2H)，4·22 (br· s，2H), 3·84-3·55 (br· m，6H)，2.69 (m，2H)，2·17·1·95 (br· m，6H)，1·03 (d, 6H); [ES+MS] m/z 457 (MH)+。貫例42 · l-[(4-{[2-(5-氣-2-氰基-4-口密°定基)-2-(2-甲基丙基）胼基]羰基}苯基）甲基]-N，N-二甲基脯胺醯胺三氟醋酸鹽Intermediate 17 (54 mg, 0.14 mmol), 4-(hydroxyindenyl) hexahydro port bite (ALDRICH, 20 mg, 〇·π mmol), potassium carbonate (39 mg, 0.29 mmol) And sodium iodide dissolved in anhydrous ACN (2 ml). The reaction mixture was stirred at room temperature overnight. After the reaction was completed, the reaction mixture was filtered and the solvent was evaporated under reduced pressure. The resulting crude residue was taken up in MeOH, filtered and purified eluting EtOAc EtOAc EtOAc The title compound was obtained after purification from EtOAc (EtOAc): EtOAc (EtOAc: EtOAc, EtOAc, EtOAc ·, 1H), 8·32 (s, 1H), 7·89 (d, 2H), 7·67 (d, 2H), 4·22 (br· s, 2H), 3·84-3·55 (br· m,6H), 2.69 (m,2H),2·17·1·95 (br· m,6H),1·03 (d, 6H); [ES+MS] m/z 457 (MH +) Example 42 · l-[(4-{[2-(5-Gas-2-cyano-4-yloxy)-based 2-(2-methylpropyl)indolyl]carbonyl} Phenyl)methyl]-N,N-dimethyl amidoxime trifluoroacetate

FF

將中間物17 (50毫克，〇·ΐ3毫莫耳）於無水ACN的溶液中加入N，N-一異丙基乙基胺(FLUKA，0.046毫升，0.26 耄莫耳）、碘化鈉及N，N-二曱基-L-脯胺醯胺（BACHEM，23 耄克，0.16¾莫耳）。將溶液在室溫攪拌過夜。過濾後，在減壓下將溶劑蒸發並將殘留物經由快速層析法（洗提液： DCM/MeOH)純化，且I1返後經由製備級hplc (ACN:H2〇， 0.1%TFA，梯度10-100%)純化後得到標題化合物。1hnmr (300 MHz，DMSO-d6)·· 11.45 (s，1Η)，9·71 (br 1H) 8 53 (s 1Η)? 7.94 (d? 2Η), 7.64 (d? 2H)5 4.72-3.18 ^ 6H)? 2.87 (b, 1 3H)，2·68 (br· s，3H)，2.19-1.65 (m，5H)，〇·95 (d 6H)· 119 200804352 [ES+MS] m/z 510 (MH)+。實例43 : 4_(1_吖丁啶基)_；^，_(5_氯_2_氰基_4_嘧啶基)_N，_(2_ 甲基丙基）苯曱醯胼三氟醋酸鹽Add N,N-isopropylethylamine (FLUKA, 0.046 mL, 0.26 mmol), sodium iodide and N to a solution of the intermediate 17 (50 mg, 〇·ΐ 3 mmol) in anhydrous ACN. , N-dimercapto-L-decylamine (BACHEM, 23 grams, 0.163⁄4 mole). The solution was stirred at room temperature overnight. After filtration, the solvent was evaporated <RTI ID=0.0></RTI> and the residue was purified EtOAc EtOAcjjjjjjjjj -100%) After purification, the title compound was obtained. 1hnmr (300 MHz, DMSO-d6)·· 11.45 (s, 1Η), 9·71 (br 1H) 8 53 (s 1Η)? 7.94 (d? 2Η), 7.64 (d? 2H)5 4.72-3.18 ^ 6H)? 2.87 (b, 1 3H), 2·68 (br· s, 3H), 2.19-1.65 (m, 5H), 〇·95 (d 6H)· 119 200804352 [ES+MS] m/z 510 (MH)+. Example 43: 4_(1_吖丁ridyl)_;^,_(5-chloro-2-cyano-4-pyrimidinyl)_N,_(2-methylpropyl)phenylhydrazine trifluoroacetate

在中間物18 (50毫克，0.12毫莫耳)於THF (2毫升）之攪拌溶液中，加入DIPEA(FLUKA，0.042毫升，0.24毫莫耳）及吖丁啶鹽酸鹽（ALDRICH，22毫克，0.24毫莫耳）並將所得的反應混合物在室溫攪拌5天。在真空將溶劑蒸發並將粗反應混合物經由HPLC (H20, 0.1% TFA:ACN)純化後得到標題化合物。1H NMR (300 MHz, DMSO)5 ppmM 1·42 (s，1H)，8.65 (s，1Η)，7·97 (d，2H)，7.58 (d，2H)，4.42 (m，2H)， 4.35-3.81 (m，4H)，2.48-2.31 (m，2H)，2·06 (m，1H)，0.94 (d， 6H); [ES+MS] m/z 443 (MH)'In a stirred solution of intermediate 18 (50 mg, 0.12 mmol) in THF (2 mL), DIPEA (FLUKA, 0.042 mL, 0.24 mmol) and azetoidine hydrochloride (ALDRICH, 22 mg, 0.24 mmoles and the resulting reaction mixture was stirred at room temperature for 5 days. The title compound was obtained after evaporation of EtOAc EtOAc. 1H NMR (300 MHz, DMSO) 5 ppmM 1·42 (s, 1H), 8.65 (s, 1 Η), 7.97 (d, 2H), 7.58 (d, 2H), 4.42 (m, 2H), 4.35 -3.81 (m, 4H), 2.48-2.31 (m, 2H), 2·06 (m, 1H), 0.94 (d, 6H); [ES+MS] m/z 443 (MH)'

實例44 : N’-(5-氣-2-氰基-4-嘧啶基)-N’-(2-甲基丙基:Κ4-{[(23)-2-(1-吡咯啶基羰基)-1-吡咯啶基]甲基}苯曱醯胼三氟醋酸鹽在中間物20 (300毫克，0.79毫莫耳)於無水ACN (5毫 120 200804352 升）的溶液中加入N，N-二異丙基乙基胺(flxjkA，0.382毫升，2.68毫莫耳）、碘化鈉集中尖物17(27〇毫克，16〇毫莫耳）。將、/谷液在室溫攪拌4小時。將殘留物經由層析法（洗提液：己烧/AcOEt)純化後得到標題化合物。iHNMRpOO MHz，DMSO-d6): 11.46 (s，1H)，9.78 (br·，1H)，8.54 (s，1H)， 7.92 (d，2H)，7·64 (d，2H)，4·54_2·85 (m，10H)，2·19]·50 (m， 9H)，〇·95 (d，6H); [ES+MS] m/z 510 (MH)+。實例45 : N’-(5-氯-2-氰基_4-嘧啶基)_N’_(2-曱基丙基）-4- {[4-(4-嗎福咁基)-1 -六氫吡啶基]甲基}苯曱醯胼三氟醋酸鹽Example 44: N'-(5-Gas-2-cyano-4-pyrimidinyl)-N'-(2-methylpropyl: Κ4-{[(23)-2-(1-pyrrolidinylcarbonyl) )-1-pyrrolidinyl]methyl}phenylhydrazine trifluoroacetate is added to a solution of intermediate 20 (300 mg, 0.79 mmol) in anhydrous ACN (5 mM 120 2008 04 352 liters). Diisopropylethylamine (flxjkA, 0.382 ml, 2.68 mmol), sodium iodide concentrate tip 17 (27 mg, 16 mmol). The solution was stirred at room temperature for 4 hours. The residue was purified by EtOAc EtOAc (EtOAc:EtOAc:EtOAc 1H), 7.92 (d, 2H), 7·64 (d, 2H), 4·54_2·85 (m, 10H), 2·19]·50 (m, 9H), 〇·95 (d, 6H) ; [ES+MS] m/z 510 (MH)+. Example 45: N'-(5-Chloro-2-cyano-4-pyrimidinyl)_N'_(2-mercaptopropyl)-4-{[4-(4-)-propenyl)-1 Hexahydropyridyl]methyl}phenylhydrazine trifluoroacetate

在中間物17 (50.5毫克，0.13毫莫耳)於在無水ACN (2 毫升）的混合物中加入4-嗎福4基六氫吼咬(ALDRICH， 35.6毫克，〇·21毫莫耳）、碳酸鉀(FLUKA，41.1毫克，0.26 毫莫耳）及1刮刀尖的碘化鈉。將所得的反應混合物在室溫袢過夜。反應完成後，將反應混合物過濾並在減壓下將溶劑蒸發。將所得的粗殘留物溶解在MeOH，過濾並將所得的粗產物經由製備級HPLC (SUNFIRE 19x150毫米， ACN:H20, 0.1%TFA，梯度10-100%)純化後得到標題化合物。1H NMR (300 MHz，d6-DMSO)3 ppm: 11.5 (s，1H)， 10·7-10·4 (br，1H)，8.5 (s，1H)，7.9 (d，2H)，7·6 (d，2H)， 121 200804352 4.55-2,66 (br· m，16H)，2.35-2.14 (br. m，2H)，2.15-1.95 (m， 2H)，1.96-1.7 (br· m，2H)，0.9 (d，6H); [ES+MS] m/z 512 (MH)+。實例46 : N’-(5-氯-2-氰基-4-嘧啶基)-N’-(2-曱基丙基)-4-({4-[2-(l-六氮批咬基）乙基]-1-六氮吼σ井基}甲基）苯曱醯肼三氟醋酸鹽In the intermediate 17 (50.5 mg, 0.13 mmol) in a mixture of anhydrous ACN (2 mL) was added 4-fosfo-4-ylhexahydropurine (ALDRICH, 35.6 mg, 〇·21 mmol), carbonic acid Potassium (FLUKA, 41.1 mg, 0.26 mmol) and 1 spatula tip sodium iodide. The resulting reaction mixture was stirred at room temperature overnight. After the reaction was completed, the reaction mixture was filtered and the solvent was evaporated under reduced pressure. The resulting crude residue was taken up in EtOAc (mjjHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH 1H NMR (300 MHz, d6-DMSO) 3 ppm: 11.5 (s, 1H), 10·7-10·4 (br, 1H), 8.5 (s, 1H), 7.9 (d, 2H), 7·6 (d,2H), 121 200804352 4.55-2,66 (br· m,16H),2.35-2.14 (br. m,2H),2.15-1.95 (m, 2H), 1.96-1.7 (br· m,2H ), 0.9 (d, 6H); [ES+MS] m/z 512 (MH)+. Example 46: N'-(5-Chloro-2-cyano-4-pyrimidinyl)-N'-(2-mercaptopropyl)-4-({4-[2-(l-hexanitrogen) bite Ethyl]-1-hexanitropurine σ well base}methyl)phenylhydrazine trifluoroacetate

將中間物17(50.0毫克，0.13毫莫耳）、1-(2-六氫吡啶基乙基）-六氫吡畊(FLUOROCHEM，31·0毫克，0.16毫莫耳）、碳酸鉀（36.0毫克，0.26毫莫耳）及1刮刀尖的碘化鈉溶解在無水ACN (3毫升）。將反應混合物在室溫擾拌過夜。反應完成後，將反應混合物過濾並在減壓下將溶劑蒸發。將所得的粗殘留物溶解在MeOH，過濾並將所得的粗產物經由製備級HPLC (SUNFIRE 19x150毫米，ACN:H20, 0,1%TFA，梯度10-100%)純化後得到標題化合物。1HNMR (300 MHz, d6-DMSO)3 ppm: 11.48 (s，1H)，10.07 (br. s，1H)， 8·53 (s，1H)，7·97 (d，2H)，7.63 (d，2H)，4.44-1.37 (br· m， 27H)，0.96 (d，6H); [ES+MS] m/z 539 (MH)+。實例47 : N’-(5-氯-2-氰基-4_嘧啶基)-4-({4-[(l_曱基-3-六氫吡啶基）曱基六氫吡畊基}曱基:)-Ν’-(2-曱基丙基）-苯曱醯胼三氟醋酸鹽 122 200804352Intermediate 17 (50.0 mg, 0.13 mmol), 1-(2-hexahydropyridylethyl)-hexahydropyrazole (FLUOROCHEM, 31·0 mg, 0.16 mmol), potassium carbonate (36.0 mg) , 0.26 millimolar) and 1 scraper tip sodium iodide dissolved in anhydrous ACN (3 ml). The reaction mixture was stirred overnight at room temperature. After the reaction was completed, the reaction mixture was filtered and evaporated under reduced pressure. The resulting crude residue was taken up in EtOAc EtOAcjHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH 1HNMR (300 MHz, d6-DMSO) 3 ppm: 11.48 (s, 1H), 10.07 (br. s, 1H), 8·53 (s, 1H), 7·97 (d, 2H), 7.63 (d, 2H), 4.44-1.37 (br· m, 27H), 0.96 (d, 6H); [ES+MS] m/z 539 (MH)+. Example 47: N'-(5-Chloro-2-cyano-4-pyrimidinyl)-4-({4-[(l-mercapto-3-hexahydropyridinyl)fluorenylhexahydropyranyl} Mercapto:)-Ν'-(2-mercaptopropyl)-phenylhydrazine trifluoroacetate 122 200804352

將中間物17(50.0毫克，〇·13毫莫耳）、1-(N-曱基-3-六氫17比咬基曱基)-六氫吼_(FLUOROCHEM，31 ·0毫克，〇·16毫莫耳）、碳酸鉀(FLUKA，36.0毫克，0.26毫莫耳)及1 刮刀尖的峨化納溶解在無水ACN (3毫升）。將反應混合物在室溫攪拌過夜。反應完成後，將反應混合物過濾並在減壓下將溶劑蒸發。將所得的粗殘留物溶解在MeOH，過濾並將所得的粗產物經由製備級HPLC (SUNFIRE 19x150毫来，ACN:H20,〇.1%TFA，梯度10-100%)純化後得到標題化合物。】H NMR (300 MHz，d6-DMSO)3 ppm: 11.44 (br· s，1H)， 9·38 (br· s，1H)，8.53 (s，1H)，7.95 (d，2H)，7.59 (m，2H)， 4·13]·49 (br. m，27H)，0·96 (d，6H); [ES+MS] m/z 539 (MH)、實例48 : N’-(5_氣I氰基_4_嘧啶基曱基丙基)-4-({4-[3-(卜六氫吡啶基）丙基]_；μ六氩吡畊基}曱基）苯曱醯胼三氟醋酸鹽Intermediate 17 (50.0 mg, 〇·13 mmol), 1-(N-mercapto-3-hexahydro-17-bito-yl)-hexahydroindole_(FLUOROCHEM, 31 · 0 mg, 〇· 16 mmoles, potassium carbonate (FLUKA, 36.0 mg, 0.26 mmol) and 1 scraper tip of sodium hydride were dissolved in anhydrous ACN (3 mL). The reaction mixture was stirred at room temperature overnight. After the reaction was completed, the reaction mixture was filtered and the solvent was evaporated under reduced pressure. The resulting crude residue was taken up in EtOAc EtOAcjHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH H NMR (300 MHz, d6-DMSO) 3 ppm: 11.44 (br·s, 1H), 9·38 (br·s, 1H), 8.53 (s, 1H), 7.95 (d, 2H), 7.59 ( m, 2H), 4·13]·49 (br. m, 27H), 0·96 (d, 6H); [ES+MS] m/z 539 (MH), Example 48: N'-(5_ Gas Icyano-4-methylpyrimidinylpropyl)-4-({4-[3-(b-hexahydropyridinyl)propyl]_; μhexafluoropyranyl}indenyl)phenylhydrazine Trifluoroacetate

將中間物17(50.0毫克，0.13毫莫耳）、ι_(3_六氫吡啶 123 200804352 基丙基）六氫吡畊(FLUOROCHEM，33·0毫克，0.16毫莫耳）碳酸鉀(FLUKA，36,0毫克，0·26毫莫耳）及1刮刀尖的峨化鈉溶解在無水ACN (3毫升）。將反應混合物在室溫授拌過夜。反應完成後，將反應混合物過濾並在減壓下將溶劑蒸發。將所得的粗殘留物溶解在MeOH，過濾並將所得的粗產物經由製備級HPLC (SUNFIRE 19x150毫米，ACN:H2〇 0.1%TFA，梯度10-100%)純化後得到標題化合物。1HMMR (300 MHz，d6_DMSO)3 ppm·· 11.41 (br· s，1H)，9.38 (br· s， 1H)，8·52 (s，1H)，7.92 (d，2H)，7.53 (d，2H)，4.39-1.28 (br· m 29H)，0.96 (d，6H); [ES+MS] m/z 553 (MH)+。實例49 : N’-(5-氯-2-氰基-4-嘧啶基)-4_{[4-(二乙胺基六氫1^比σ定基]甲基}-N’-(2-曱基丙基)-苯甲醯肼三氟醋酸鹽Intermediate 17 (50.0 mg, 0.13 mmol), ι_(3_Hexahydropyridine 123 200804352 propyl) hexahydropyrazine (FLUOROCHEM, 33.0 mg, 0.16 mmol) potassium carbonate (FLUKA, 36 , 0 mg, 0·26 mmol) and 1 scraper tip sodium hydride dissolved in anhydrous ACN (3 mL). The reaction mixture was stirred overnight at room temperature. After the reaction was completed, the reaction mixture was filtered and evaporated under reduced pressure. The resulting crude residue was taken up in EtOAc EtOAcjHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH 1HMMR (300 MHz, d6_DMSO) 3 ppm·· 11.41 (br· s, 1H), 9.38 (br· s, 1H), 8·52 (s, 1H), 7.92 (d, 2H), 7.53 (d, 2H) ), 4.39-1.28 (br· m 29H), 0.96 (d, 6H); [ES+MS] m/z 553 (MH)+. Example 49: N'-(5-Chloro-2-cyano-4-pyrimidinyl)-4_{[4-(diethylamino hexahydro 1 比 σ decyl) methyl}-N'-(2- Mercaptopropyl)-benzamide trifluoroacetate

將中間物17(50.0毫克，0.132毫莫耳）、4-二乙胺基、六氫吡啶(FLUOROCHEM，24.9毫克，0.159毫莫耳）、碳酉楚鉀（FLUKA，36·0毫克，0.26毫莫耳）及1刮刀尖的蛾化鈉溶解在無水ACN (2毫升）。將反應混合物在室溫授拌過夜。反應完成後，將反應混合物過濾並在減壓下將溶劑蒸發。將所得的粗殘留物溶解在MeΟΗ，過遽並將所得的粗產斗分經由製備級 HPLC (SUNFIRE 19x150 毫米，ACN:H2〇 0.1%TFA，梯度10-100%)純化後得到標題化合物。iHnmr 124 200804352 (CI)C13+CD30D)5 ppm: 8.16 (s，1H)，7.83 (d，8.35 Hz，2H)， 7.48 (d，8·35 Hz，2H)，4·17 (s，3H)，3·39 (m，2H)，3.06 (m， 6H)，2.12 (m，4H), 2.01 (m，6·44 Hz，1H), 1.26 (t，7.32 Hz， 6H)，0·91 (d，6·74 Hz，6H); [ES+MS] m/z 498 (MH)+。實例50 : N’-(5-氯-2-氰基_4-嘧啶基)-4-{[4-(4-曱基-1-六氫吡畊基)-1-六氫吡啶基]曱基卜N，-(2-曱基丙基)-苯甲醯胼三氟醋酸鹽Intermediate 17 (50.0 mg, 0.132 mmol), 4-diethylamino, hexahydropyridine (FLUOROCHEM, 24.9 mg, 0.159 mmol), potassium sulphate (FLUKA, 33.0 mg, 0.26 m) Moth) and 1 scraper tip sodium molybdenum dissolved in anhydrous ACN (2 ml). The reaction mixture was stirred overnight at room temperature. After the reaction was completed, the reaction mixture was filtered and the solvent was evaporated under reduced pressure. The resulting crude residue was taken up in EtOAc (EtOAc m.) iHnmr 124 200804352 (CI)C13+CD30D)5 ppm: 8.16 (s,1H), 7.83 (d, 8.35 Hz, 2H), 7.48 (d,8·35 Hz, 2H), 4·17 (s,3H) ,3·39 (m,2H), 3.06 (m, 6H), 2.12 (m,4H), 2.01 (m,6·44 Hz,1H), 1.26 (t,7.32 Hz, 6H),0·91 ( d, 6·74 Hz, 6H); [ES+MS] m/z 498 (MH)+. Example 50: N'-(5-Chloro-2-cyano-4-pyrimidinyl)-4-{[4-(4-mercapto-1-hexahydropyrryl)-1-hexahydropyridinyl] N,-(2-mercaptopropyl)-benzimidazole trifluoroacetate

將中間物17(50.0毫克，0.132毫莫耳）、1-甲基-4-(六氫吡啶_4_基)-六氫吡畊(FLUOROCHEM，27.1毫克，0.152 毫莫耳）、碳酸鉀(FLUKA，36.0毫克，0.26毫莫耳）及1刮刀尖的碘化鈉溶解在無水ACN (2毫升）。將反應混合物在室溫攪拌過夜。反應完成後，將反應混合物過濾並在減壓下將溶劑蒸發。將所得的粗殘留物溶解在MeOH，過濾並將所得的粗產物經由製備級HPLC (SUNFIRE 19x150毫米， ACN:H2〇,（U〇/〇TFA，梯度10-100%)純化後得到標題化合物。1H NMR (CDC13+CD30D)5 ppm: 8.18 (s，1H)，7·84 (d， 8·35 Ηζ，2Η)，7·47 (d，8·35 Ηζ，2Η)，4·16 (s，2Η)，3·42 (m， 3Η)，3·14 (m，3Η)，2·81 (m，5Η)，2·73 (s，4Η)，2·59 (m，2Η)， 2·03 (m，7.03 Ηζ，1Η)，1.92 (m，4Η)，0·93 (d，6.6 Ηζ，6H); 125 200804352 [ES+MS] m/z 525 (ΜΗ疒。實例51 : N’-(5-氣-2-氰基-4-嘧啶基)-N’-(2-曱基丙基)-4-{[4-(4-σ比咬基）-1-六氮°比ϋ井基]曱基}苯曱酿月井三貌醋酸鹽Intermediate 17 (50.0 mg, 0.132 mmol), 1-methyl-4-(hexahydropyridin-4-yl)-hexahydropyrazine (FLUOROCHEM, 27.1 mg, 0.152 mmol), potassium carbonate ( FLUKA, 36.0 mg, 0.26 mmol) and 1 spatula tip sodium iodide dissolved in anhydrous ACN (2 mL). The reaction mixture was stirred at room temperature overnight. After the reaction was completed, the reaction mixture was filtered and the solvent was evaporated under reduced pressure. The resulting crude residue was taken up in EtOAc EtOAc EtOAcjjjjjjj 1H NMR (CDC13+CD30D) 5 ppm: 8.18 (s,1H), 7.84 (d, 8·35 Ηζ, 2Η), 7·47 (d,8·35 Ηζ, 2Η), 4·16 (s , 2Η), 3·42 (m, 3Η), 3·14 (m, 3Η), 2·81 (m, 5Η), 2·73 (s, 4Η), 2·59 (m, 2Η), 2 · 03 (m, 7.03 Ηζ, 1 Η), 1.92 (m, 4 Η), 0·93 (d, 6.6 Ηζ, 6H); 125 200804352 [ES+MS] m/z 525 (ΜΗ疒. Example 51: N' -(5-Gas-2-cyano-4-pyrimidinyl)-N'-(2-mercaptopropyl)-4-{[4-(4-σ ratio)-1-hexanitrogen ratio ϋ井基]曱基}Benzene 曱月月三貌 acetate

將中間物17 (50毫克，0.13毫莫耳）、1-(4-吡啶基)-六氫吡畊(LANCASTER，27·4毫克，0.17毫莫耳）、碳酸鉀 (FLUKA，36.5毫克，0.26毫莫耳）及1刮刀尖的碘化鈉溶解在無水ACN (2毫升）。將反應混合物在室溫攪拌過夜。反應完成後，將反應混合物過濾並在減壓下將溶劑蒸發。將所得的粗殘留物溶解在MeOH，過濾並將所得的粗產物經 a?製備級 HPLC (SUNFIRE 19x150 毫米，ACN:H20， 0.1%TFA，梯度10-100%)純化後得到標題化合物。1HNMR (300 MHz，d6-DMSO)3 ppm: 11·5 (br. s，1H)，8.5 (s，1H)， 8.34 (d，2Η)，7·97 (d，2Η)，7.6 (d，2Η)，7·24 (d，2Η)， 4.59-2.74 (br· M，12H)，2·08 (m，1H)，0·97 (d，6H); [ES+MS] m/z 505 (MH)+ 〇實例52.]^’-(5-獻1-2-鼠基-4-0密17定基）-]^’-(2-曱基丙基）-4-({4-[2-(1-17比洛咬基）乙基]-1-六氮1：7比1：7井基}甲基）苯甲醯胼三氟醋酸鹽 126 200804352Intermediate 17 (50 mg, 0.13 mmol), 1-(4-pyridyl)-hexahydropyridine (LANCASTER, 27.4 mg, 0.17 mmol), potassium carbonate (FLUKA, 36.5 mg, 0.26) Sodium iodide and 1 scraper tip sodium iodide dissolved in anhydrous ACN (2 mL). The reaction mixture was stirred at room temperature overnight. After the reaction was completed, the reaction mixture was filtered and the solvent was evaporated under reduced pressure. The resulting crude residue was taken up in EtOAc (mjHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH 1HNMR (300 MHz, d6-DMSO) 3 ppm: 11·5 (br. s, 1H), 8.5 (s, 1H), 8.34 (d, 2Η), 7.97 (d, 2Η), 7.6 (d, 2Η),7·24 (d,2Η), 4.59-2.74 (br· M,12H),2·08 (m,1H),0·97 (d,6H); [ES+MS] m/z 505 (MH)+ 〇Example 52.]^'-(5- 1-2 1-2-murine-4-0 密17定)-]^'-(2-mercaptopropyl)-4-({4- [2-(1-17 piroxime)ethyl]-1-hexanitrogen 1:7 to 1:7 well base}methyl)benzamide trifluoroacetate 126 200804352

將中間物17(50.0毫克，0.13毫莫耳）、1-(2-吡鳴乙基）六氫吡畊（FLUOROCHEM，29.0毫克，0·16毫莫耳碳酸鉀(FLUKA，36.0毫克，0.26毫莫耳）及1刮刀尖的娜化鈉溶解在無水ACN (3毫升）。將反應混合物在室溫授拌過夜。反應完成後，將反應混合物過濾並在減壓下將溶劑蒸發。將所得的粗產物經由製備級HPLC (SUNHRE 19x150 毫米，ACN:H2O,0.1%TFA，梯度10-100%)純化後得到標題化合物。1HNMR(300 MHz，d6-DMSO)3 ppm: 11.49 (s，1H)， 10·40-9·20 (br· s，1H)，8.53 (s，1H)，7.98 (d，2H)，7.64 (d， 2H)，4·59-1.77 (br· m，25H)，0·96 (d，6H); [ES+MS] m/z 525 (MH)+。實例53 : N’-(5-氣-2-氰基-4-嘧啶基)-4_({4-[2-(二甲胺基）乙基>1-六氫吡畊基}甲基)-N’-(2-曱基丙基)-苯甲醯胼三氟醋酸鹽Intermediate 17 (50.0 mg, 0.13 mmol), 1-(2-pyrrolidyl) hexahydropyrazine (FLUOROCHEM, 29.0 mg, 0. 16 mmol potassium carbonate (FLUKA, 36.0 mg, 0.26 m) The sodium salt of the molar and 1 scraper tip was dissolved in anhydrous ACN (3 ml). The reaction mixture was stirred overnight at room temperature. After the reaction was completed, the reaction mixture was filtered and evaporated under reduced pressure. The crude product was purified by EtOAc EtOAc EtOAc (EtOAc: EtOAc (HHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH 10·40-9·20 (br· s,1H), 8.53 (s,1H), 7.98 (d,2H), 7.64 (d, 2H), 4·59-1.77 (br· m,25H),0 · 96 (d, 6H); [ES+MS] m/z 525 (MH) +. Example 53: N'-(5-Gas-2-cyano-4-pyrimidinyl)-4_({4-[ 2-(dimethylamino)ethyl>1-hexahydropyranyl}methyl)-N'-(2-mercaptopropyl)-benzimidazole trifluoroacetate

將中間物17(50.0毫克，0.132毫莫耳）、1·[2-(二曱胺基）乙基]六氫吡畊(ALDRICH, 25毫克，0.159毫莫耳）、碳 127 200804352 酸|f(FLUKA，36·5毫克，0·26毫莫耳）及1到刀尖的磁化鈉溶解在無水ACN (2毫升）。將反應混合物在室溫攪拌過夜。反應完成後，將反應混合物過濾並在減壓下將溶劑蒸發。將所得的粗產物經由製備級HPLC (SUNFIRE 19x150 毫米，ACN:H20, 0.1%TFA，梯度10-100%)純化後得到標題化合物。1H NMR (CDC13+CD30D)3 ppm: 8.23 (s，1H)，7.86 (d，8.20 Hz，2H)，7.49 (d，8.2 Hz，2H)，4.18 (s，2H)，3·74 (m， 2H)，3.22 (m，3H)，3.14 (t，5.4 Hz，2H)，2.83 (s，7H)，2·74 (t， 6 Hz，4H)，2.09 (m，6.9 Hz，1H)，0.98 (d，6.74 Hz，6H); [ES+MS] m/z 499 (MH)+。實例54 : N’-(5-氯-2-氰基-4-嘧啶基)-N’-(2-甲基丙基)-3-(1- 吡咯啶基甲基）苯甲醯胼三氟醋酸鹽Intermediate 17 (50.0 mg, 0.132 mmol), 1·[2-(diamido)ethyl]hexahydropyridine (ALDRICH, 25 mg, 0.159 mmol), carbon 127 200804352 acid|f (FLUKA, 36.5 mg, 0·26 mmol) and 1 to the tip of the magnetized sodium dissolved in anhydrous ACN (2 mL). The reaction mixture was stirred overnight at room temperature. After the reaction was completed, the reaction mixture was filtered and evaporated under reduced pressure. The crude product was purified by preparative EtOAc (EtOAc) elute 1H NMR (CDC13+CD30D) 3 ppm: 8.23 (s, 1H), 7.86 (d, 8.20 Hz, 2H), 7.49 (d, 8.2 Hz, 2H), 4.18 (s, 2H), 3·74 (m, 2H), 3.22 (m, 3H), 3.14 (t, 5.4 Hz, 2H), 2.83 (s, 7H), 2·74 (t, 6 Hz, 4H), 2.09 (m, 6.9 Hz, 1H), 0.98 (d, 6.74 Hz, 6H); [ES+MS] m/z 499 (MH)+. Example 54: N'-(5-Chloro-2-cyano-4-pyrimidinyl)-N'-(2-methylpropyl)-3-(1-pyrrolidinylmethyl)benzamide III Fluoroacetate

在中間物19 (50.0毫克，0.13毫莫耳）、碳酸鉀(FLUKA， 37·()毫克，0.27毫莫耳）、1刮刀尖的蛾化鈉在無水ACN (2 毫升）的溶液中加入吡洛啶(ALDRICH，13.0毫克，0.19毫莫耳）◦將反應混合物在室溫攪拌過夜。反應完成後，將反應混合物過滤並在減壓下將溶劑蒸發。將所得的粗產物經由製備級 HPLC (SUNFIRE 19x150 毫米，ACN:H20, 0.1 %TFA，梯度10-100%)純化後得到標題化合物。11_^]^11(300]\/11^， CDC13)3 ppm: 8.15 (s，1H)，8·0 (br· m，1H)，7·90-7·85 (br· m， 128 200804352 1H)，7.54-7.42 (br· m，2H)，4·24 (s，2H)，3.48 (br· m，2H)， 3.24 (m，2H)，2.90 (br· M，2H)，2.02 (m, 5H)，〇·91 (d，6H); [ES+MS] m/z 413 (MH)+。實例55 : N’-(5-氯氰基-4-^σ定基)-N’-(2_曱基丙基）-3-{[4-(4-嗎福啉基)-1-六氫吡啶基]曱基}苯曱醯胼三氟醋酸鹽In the intermediate 19 (50.0 mg, 0.13 mmol), potassium carbonate (FLUKA, 37·(mg, 0.27 mmol), 1 scraper tip sodium molybdenum in a solution of anhydrous ACN (2 mL) Loridine (ALDRICH, 13.0 mg, 0.19 mmol). The reaction mixture was stirred at room temperature overnight. After the reaction was completed, the reaction mixture was filtered and the solvent was evaporated under reduced pressure. The resulting crude product was purified by EtOAc EtOAcjjjjjj 11_^]^11(300]\/11^, CDC13)3 ppm: 8.15 (s,1H),8·0 (br· m,1H),7·90-7·85 (br· m, 128 200804352 1H), 7.54-7.42 (br· m, 2H), 4·24 (s, 2H), 3.48 (br· m, 2H), 3.24 (m, 2H), 2.90 (br·M, 2H), 2.02 ( m, 5H), 〇·91 (d, 6H); [ES+MS] m/z 413 (MH)+. Example 55: N'-(5-Cyanocyano-4-[sigma]-N'-(2-mercaptopropyl)-3-{[4-(4-morpholinyl)-1-hexa-6 Hydropyridyl]fluorenyl}phenylhydrazine trifluoroacetate

在中間物19(50.0毫克，0.13毫莫耳）、碳酸鉀(fluKA， 37.0毫克，〇·27毫莫耳）、1刮刀尖的碘化鈉在無水ACN (2 毫升）的溶液中加入4_嗎福啉基六氫吡啶(ALDRICH，32 〇毫克，〇·19毫莫耳）。將反應混合物在室溫攪拌過夜。反應完成後，將反應混合物過濾並在減壓下將溶劑蒸發。將戶w 得的粗產物經由製備級HPLC (SUNFIRE 19xl5〇毫米、 ACN:H20, 0.1%TFA，梯度ΗΜ00%)純化後得到標題化^ 物。1H NMR (300 MHz，d6-DMSO)3 ppm: 11.49 (s ] m 二 5 8.54 (s，1H), 8.04-7.95 (br· m，2H)，7·75_7·59 (br· m，2H)， 4·5(Μ·66 (br· m，22H)，0·96 (d，6H); [ES+MS] m/z 5i2 _广。六氫吡畊基]甲基}-N’-(2-曱基丙基)-苯甲醯肼三實例56 : N’-(5-氣-2-氰基-4_嘧啶基)-3-{[4-(2-羥基乙基）^ 一鼠醋酸鹽 129 200804352In the intermediate 19 (50.0 mg, 0.13 mmol), potassium carbonate (fluKA, 37.0 mg, 〇 · 27 mmol), 1 scraper tip sodium iodide in anhydrous ACN (2 mL) was added 4_ Tropoline-based hexahydropyridine (ALDRICH, 32 mg, 〇19 mmol). The reaction mixture was stirred at room temperature overnight. After the reaction was completed, the reaction mixture was filtered and the solvent was evaporated under reduced pressure. The crude product obtained was purified by preparative HPLC (SUNF </ RTI> <RTIgt; </RTI> <RTIgt; </ RTI> <RTIgt; </ RTI> <RTIgt; </ RTI> <RTIgt; 1H NMR (300 MHz, d6-DMSO) 3 ppm: 11.49 (s) m 2 5 8.54 (s, 1H), 8.04-7.95 (br· m, 2H), 7·75_7·59 (br· m, 2H) , 4·5 (Μ·66 (br· m, 22H), 0·96 (d, 6H); [ES+MS] m/z 5i2 _ wide. Hexahydropyrylene]methyl}-N'- (2-mercaptopropyl)-benzamide III Example 56: N'-(5-Gas-2-cyano-4-pyrimidinyl)-3-{[4-(2-hydroxyethyl)^ One rat acetate 129 200804352

OH F 將中間物19(50.0毫克，0.132毫莫耳）、i_(2_羥基乙基) 六氫吼σ井(ALDRICH，24.0毫克，0.19毫莫耳）、碳酸鉀 (FLUKA，37.0毫克，0·27毫莫耳）及1到刀尖的蜗化納溶解在無水ACN (2毫升）。將反應混合物在室溫攪拌過夜。反應完成後，將反應混合物過濾、並在減壓下將溶劑蒸發。將所得的粗產物經由製備級HPLC (XTERRA 19x150毫米， ACN:H20, 0.1%TFA，梯度10-100%)純化後得到標題化合物。1H NMR (300 MHz，CDC13)3 ppm: 9.78 (s，1H)，8.31 (s， ⑴），8·2了（s，1H)，8.06 (m，1H)，7·64-7·54 (br· m，2H)，4.31 (s，2H)5 4.09-2.83 (br· m，15H)，2·15 (m，1H)，1·02 (d, 6H); [ES+MS] m/z 472 (MH)+。實例57 : N，-(5_氯-2-氰基-4-嘧啶基)-3-{[4_(羥基曱基)-1-六氫吡啶基]甲基}N，-(2-甲基丙基)-苯甲醯肼三氟醋酸鹽OH F intermediate 19 (50.0 mg, 0.132 mmol), i_(2-hydroxyethyl) hexahydroquinone σ well (ALDRICH, 24.0 mg, 0.19 mmol), potassium carbonate (FLUKA, 37.0 mg, 0 • 27 millimoles) and 1 to the tip of the cochlear nanoparticle dissolved in anhydrous ACN (2 ml). The reaction mixture was stirred at room temperature overnight. After the reaction was completed, the reaction mixture was filtered, and the solvent was evaporated under reduced pressure. The crude product obtained was purified by EtOAc EtOAc EtOAc (EtOAc:EtOAc 1H NMR (300 MHz, CDC13) 3 ppm: 9.78 (s, 1H), 8.31 (s, (1)), 8·2 (s, 1H), 8.06 (m, 1H), 7·64-7·54 ( Br· m,2H),4.31 (s,2H)5 4.09-2.83 (br· m,15H),2·15 (m,1H),1·02 (d, 6H); [ES+MS] m/ z 472 (MH)+. Example 57: N,-(5-Chloro-2-cyano-4-pyrimidinyl)-3-{[4-(hydroxyindenyl)-1-hexahydropyridinyl]methyl}N,-(2-A Propyl)-benzamide trifluoroacetate

在中間物19 (50.0毫克，0.13毫莫耳）、碳酸鉀(FLUKA， 37·0亳克，0.27毫莫耳）、1刮刀尖的碘化鈉在無水ACN (2 毫升）的溶液中加入4-(羥基甲基）六氫吡啶(ALDRICH，21 ·0 130 200804352 毫克，〇·19毫莫耳）。將反應混合物在室溫攪拌過夜。反應完成後，將反應混合物過濾並在減壓下將溶劑蒸發。將所得的粗產物經由製備級HPLC (SUNFIRE 19x150毫米， ACN:H20, 0.1%TFA，梯度10-100%)純化後得到標題化合物。1H NMR (300 MHz，CDC13)3 ppm: 11.59 (br· s，1H)， 11.53 (br· s，1H)，8.23 (s，1H)，8.06 (d，2H)，7.61-7.41 (br· m， 2H)，4.29-1.22 (br· M，17H)，1.01 (d，6H); [ES+MS] m/z 457 (MH)、貫例58 : N’-(5-氣-2-氣基定基）-N’-(2-曱基丙基)-3-({4-[3-(l-六氫吼啶基）丙基]-1-六氫批畊基}曱基)-笨曱醯胼三氟醋酸鹽 ^oh 〇 k/ 將中間物19(5〇·0毫克，0·13毫莫耳）、1-(3-六氫吼^定基）六氫吡畊(FLUOROCHEM，39.0毫克，0·19毫莫耳）、石炭酸鉀(FLUKA，37.0毫克，0·27毫莫耳）及1刮刀尖的峨化名内溶解在無水ACN (2毫升）。將反應混合物在室溫攪拌過夜。發。毫米In the intermediate 19 (50.0 mg, 0.13 mmol), potassium carbonate (FLUKA, 37.0 g, 0.27 mmol), 1 scraper tip sodium iodide in anhydrous ACN (2 mL) was added 4 -(Hydroxymethyl)hexahydropyridine (ALDRICH, 21 · 0 130 200804352 mg, 〇 19 mmol). The reaction mixture was stirred at room temperature overnight. After the reaction was completed, the reaction mixture was filtered and the solvent was evaporated under reduced pressure. The crude product was purified by preparative EtOAc (EtOAc) elute 1H NMR (300 MHz, CDC13) 3 ppm: 11.59 (br·s, 1H), 11.53 (br·s, 1H), 8.23 (s, 1H), 8.06 (d, 2H), 7.61-7.41 (br· m , 2H), 4.29-1.22 (br· M, 17H), 1.01 (d, 6H); [ES+MS] m/z 457 (MH), Example 58: N'-(5-gas-2-gas定))-N'-(2-mercaptopropyl)-3-({4-[3-(l-hexahydroacridinyl)propyl]-1-hexahydropropanyl} fluorenyl)- Awkward trifluoroacetate ^oh 〇k/ Intermediate 19 (5〇·0 mg, 0·13 mmol), 1-(3-hexahydropurine) hexahydropyrazine (FLUOROCHEM, 39.0 mg, 0·19 mmol, potassium carbonate (FLUKA, 37.0 mg, 0·27 mmol) and 1 scraper tip were dissolved in anhydrous ACN (2 mL). The reaction mixture was stirred overnight at room temperature. hair. Millimeter

反應完成後，將反應混合物過濾並在減壓下將溶齊,H 將所得的粗產物經由製備級HPLC (XTERRA 19Χ丨5〇，ACN:H2O,0.1%TFA，梯度ΗΜ00%)純化後得到標題化合物。1H NMR (300 MHz，CDC13)3 ppm: 10.14 (s，1H) 131 200804352 8·24 (s，1Η)，8·07_8·01 (m，1H)，7.61-7.47 (br· m，2H)，4·17 (s，2H)，3·89-1·83 (br· m，27H)，1·〇ΐ (d，6H); [ES+MS] m/z 553 (MH)+ 〇實例59 : N’_(5-氯-2-氰基-4-嘧啶基)-3-{[4-(4-曱基小六氫吡畊基）-1-六氫吡啶基]曱基}N，-(2-曱基丙基)-苯曱醯胼三氟醋酸鹽After completion of the reaction, the reaction mixture was filtered and evaporated under reduced pressure, and the obtained crude product was purified by preparative HPLC (XTERRA 19 Χ丨 5 〇, ACN: H 2 O, 0.1% TFA, gradient ΗΜ 00%) Compound. 1H NMR (300 MHz, CDC13) 3 ppm: 10.14 (s, 1H) 131 200804352 8·24 (s,1Η),8·07_8·01 (m,1H), 7.61-7.47 (br· m,2H), 4·17 (s, 2H), 3·89-1·83 (br· m, 27H), 1·〇ΐ (d, 6H); [ES+MS] m/z 553 (MH)+ 〇 Example 59 : N'_(5-Chloro-2-cyano-4-pyrimidinyl)-3-{[4-(4-mercaptosuccinium pyridinyl)-1-hexahydropyridinyl]fluorenyl}N ,-(2-mercaptopropyl)-phenylhydrazine trifluoroacetate

將中間物19(50.0毫克，0.13毫莫耳）、1-曱基-4-(六氫吡啶-4-基）-六氫吡畊(FLUOROCHEM，34.0毫克，0.19毫莫耳）、碳酸鉀(FLUKA，37.0毫克，0.27毫莫耳）及1刮刀尖的碘化鈉溶解在無水ACN (2毫升）。將反應混合物在室溫攪拌過夜。反應完成後，將反應混合物過濾並在減壓下將溶劑蒸發。將所得的粗產物經由製備級HPLC (XTERRA 19x150 毫米，ACN:H2O,0.1%TFA，梯度 10-100%)純化後得到標題化合物。1H NMR (300 MHz, CDC13+CD30D)5 ppm: 8·21 (s，1H), 8·16 (br· s，1H)，8.04-7.99 (m，1Η)，7.57-7.45 (br· m，2H)，4.21 (s，2H)，3·87-1·89 (br· m，23H)，0.99 (d，6H); [ES+MS] m/z 525 (MH)+。貫例60 : N’-(5-氣-2-鼠基-4-口密咬基）-3-{[4-(二乙胺基）-l_ 六氣吼咬基]曱基}-N’-(2-曱基丙基）-苯曱隨耕二氣醋酸鹽 132 200804352Intermediate 19 (50.0 mg, 0.13 mmol), 1-mercapto-4-(hexahydropyridin-4-yl)-hexahydropyrazine (FLUOROCHEM, 34.0 mg, 0.19 mmol), potassium carbonate ( FLUKA, 37.0 mg, 0.27 mmol) and 1 spatula tip sodium iodide dissolved in anhydrous ACN (2 mL). The reaction mixture was stirred at room temperature overnight. After the reaction was completed, the reaction mixture was filtered and the solvent was evaporated under reduced pressure. The crude product was purified by preparative EtOAc (EtOAc:EtOAc:EtOAc 1H NMR (300 MHz, CDC13+CD30D) 5 ppm: 8·21 (s, 1H), 8·16 (br·s, 1H), 8.04-7.99 (m, 1Η), 7.57-7.45 (br·m, 2H), 4.21 (s, 2H), 3·87-1·89 (br· m, 23H), 0.99 (d, 6H); [ES+MS] m/z 525 (MH)+. Example 60: N'-(5-Gas-2-murine-4-mercapto)-3-{[4-(diethylamino)-l_ 六 gas 吼 base] sulfhydryl}-N '-(2-Mercaptopropyl)-benzoquinone with tillage two gas acetate 132 200804352

將中間物19 (50.0毫克，0.13毫莫耳）、 G月女基_ 氫吡啶（FLUOROCHEM，29·0毫克，0.19毫莫与山、今）、叾炭酸物 (FLUKA，37.0毫克，0.27毫莫耳）及1刮刀尖的峨化巧在無水ACN (2毫升）。將反應混合物在室溫授掉過夜’谷解應完成後，將反應混合物過濾並在減壓下將溶劑蒸#。& 所得的粗產物經由製備級HPLC (XTERRA 1知15〇毫米、 ACN:H20, 0.1%TFA，梯度10-100%)純化後得到標題化合物。1H NMR (300 MHz，CDC13)3 ppm: 10·45 (br· s5 1H)，8 41 (br· s，1H)，8·24 (s，1H)，8·12 (m，1H)，7.64-7.39 (br· m ，化)， 4·20 (br· s，2H)，4·10-2·06 (br· m, 18H)，1.42 (m，6H)，！〇1 (d 6H); [ES+MS] m/z 498 (MH)+ 〇實例61 : N’-(5-氣-2-氰基-4-嘧啶基)-3-({4-[2-(二乙胺基）乙基]-1-六氫吡畊基}甲基）-N’-(2-甲基丙基)-苯甲醯月井三t 醋酸鹽Intermediate 19 (50.0 mg, 0.13 mmol), G-moon female-hydropyridine (FLUOROCHEM, 29.0 mg, 0.19 mmol and Yamamoto), decanoic acid (FLUKA, 37.0 mg, 0.27 mmol) The ear and the tip of the scraper are in the anhydrous ACN (2 ml). The reaction mixture was allowed to pass at room temperature overnight. After completion of the solution, the reaction mixture was filtered and solvent was evaporated under reduced pressure. & The crude product obtained was purified by preparative HPLC (EtOAc EtOAc EtOAc EtOAc 1H NMR (300 MHz, CDC13) 3 ppm: 10·45 (br· s5 1H), 8 41 (br· s, 1H), 8·24 (s, 1H), 8·12 (m, 1H), 7.64 -7.39 (br· m , 化), 4·20 (br· s, 2H), 4·10-2·06 (br· m, 18H), 1.42 (m, 6H),! 〇1 (d 6H); [ES+MS] m/z 498 (MH) + 〇 Example 61: N'-(5-Gas-2-cyano-4-pyrimidinyl)-3-({4-[ 2-(diethylamino)ethyl]-1-hexahydropyrryl}methyl)-N'-(2-methylpropyl)-benzamide 醯月三t Acetate

OH 將中間物19(50.0毫克，0.13毫莫耳）、H2-二乙胺義乙基)-六氫吡畊(CHEMPUR，34.0毫克，0·19毫莫耳、二 133 200804352 酸鉀(FLUKA, 37.0毫克，0.27毫莫耳）及1刮刀尖的碘化鈉溶解在無水ACN (2毫升）。將反應混合物在室溫攪拌過夜。反應完成後，將反應混合物過濾並在減壓下將溶劑蒸發。將所得的粗產物經由製備級HPLC (XTERRA 19x150 毫米，ACN:H2〇, 0.1%TFA，梯度ΗΜ00%)純化後得到標題化合物。1H NMR (300 MHz，CDC13)3 ppm: 10.63 (s，1H)， 8.35 (br· s，1H)，8·22 (s，1H)，8·10-8·04 (m，1H)，7·60-7·44 (m，2H)，4·19 (s，2H)，3·94-1·66 (br· m，19H)，1.35 (m，6H)， 1·00 (d，6H); [ES+MS] m/z 527 (MH)+。實例62 : N’-(5-氯-2-氰基-4-嘴°定基)-3-{[4-(l-曱基-4-六氫吡啶基）-1-六氫吡畊基]曱基卜Ν’·(2-曱基丙基)-苯甲醯胼三氟醋酸鹽OH intermediate 19 (50.0 mg, 0.13 mmol), H2-diethylamine ethyl)-hexahydropyrazine (CHEMPUR, 34.0 mg, 0·19 mmol, II 133 200804352 potassium (FLUKA, 37.0 mg, 0.27 mmol, and 1 scraper tip sodium iodide dissolved in anhydrous ACN (2 mL). The reaction mixture was stirred at room temperature overnight. After the reaction was completed, the reaction mixture was filtered and evaporated. The crude product was purified by EtOAc EtOAc EtOAc (EtOAc (EtOAc) ), 8.35 (br· s,1H),8·22 (s,1H),8·10-8·04 (m,1H),7·60-7·44 (m,2H),4·19 ( s, 2H), 3·94-1·66 (br· m, 19H), 1.35 (m, 6H), 1·00 (d, 6H); [ES+MS] m/z 527 (MH)+. Example 62: N'-(5-Chloro-2-cyano-4-indolyl)-3-{[4-(l-indolyl-4-hexahydropyridyl)-1-hexahydropyrrole ]曱基卜Ν'·(2-mercaptopropyl)-benzimidazole trifluoroacetate

:斗〇將中間物19(50.0毫克，0.13毫莫耳）、1-(Ν-甲基-4-六氫吡啶)-六氫吡畊(ALDRICH，34.0毫克，0.19毫莫耳）、碳酸鉀（FLUKA，37.0毫克，0.27毫莫耳）及1刮刀尖的碘化鈉溶解在無水ACN (2毫升）。將反應混合物在室溫攪拌過夜。反應完成後，將反應混合物過濾並在減壓下將溶劑蒸發。將所得的粗產物經由製備級HPLC (XTERRA 19x150 毫米，ACN:H20, 0.1%TFA，梯度ΗΜ00%)純化後得到標題化合物。1H NMR (300 MHz，CDC13+CD30D)5 ppm: 8.21 (s， 134 200804352 1H)，8.06 (br. s，1H)，7.98-7.92 (m，1H)，7.55-7.47 (br. m 2H)，4.11 (br· s，2H)，3.86-1.95 (br· m，23H)，0.98 (d，6H)’； [ES+MS] m/z 525 (MH)+。 ’ 實例63 : N’-(5-氯_2-氰基-4-嘧啶基)-N’-(2-曱基丙基)-3-({4-[3-(4-嗎福ϋ林基）丙基]-1-六氳吼ϋ井基}曱基)_笨^ 醯肼三氟醋酸鹽: 〇〇 intermediate 19 (50.0 mg, 0.13 mmol), 1-(Ν-methyl-4-hexahydropyridine)-hexahydropyrazine (ALDRICH, 34.0 mg, 0.19 mmol), potassium carbonate (FLUKA, 37.0 mg, 0.27 mmol) and 1 spatula tip sodium iodide dissolved in anhydrous ACN (2 mL). The reaction mixture was stirred overnight at room temperature. After the reaction was completed, the reaction mixture was filtered and evaporated under reduced pressure. The crude product obtained was purified by EtOAc EtOAc EtOAc (EtOAc: 1H NMR (300 MHz, CDC13+CD30D) 5 ppm: 8.21 (s, 134 200804352 1H), 8.06 (br. s, 1H), 7.98-7.92 (m, 1H), 7.55-7.47 (br. m 2H), 4.11 (br· s, 2H), 3.86-1.95 (br· m, 23H), 0.98 (d, 6H)'; [ES+MS] m/z 525 (MH)+. Example 63: N'-(5-Chloro-2-cyano-4-pyrimidinyl)-N'-(2-mercaptopropyl)-3-({4-[3-(4-? Linji) propyl]-1-hexafluorene base 曱 base) _ stupid ^ 醯肼 trifluoroacetate

將中間物19(50·0毫克，0.13毫莫耳）、Κ(3-嗎福σ林基丙基）六氫口比口井（FLUOROCHEM，40.0毫克，0.19毫莫耳）碳酸鉀(FLUKA，37.0毫克，0.27毫莫耳）及1刮刀尖的峨化鈉溶解在無水ACN (2毫升）。將反應混合物在室溫攪拌過夜◦反應完成後，將反應混合物過濾並在減壓下將溶劑蒸發。將所得的粗產物經由製備級HPLC (XTERRA 1知15〇毫米，ACN:H20, 0.1%TFA，梯度10-100%)純化後得到標題化合物。1H NMR (300 MHz，CDC13)3 ppm: 10.07 (s，1H)， 8.25 (s，2H)，8.05 (br· s，1H)，7.63-7.48 (m，2H)，4·19 (br· s， 2H)，4.05-3.05 (br· m，20H)，2.82 (m，2H)，2·12 (m，3H)，1·01 (d，6H); [ES+MS] m/z 555 (MH)+。實例64 ·· N，-(5-氯-2_氰基-4_嘧啶基)-N，-(2-曱基丙基）-3-({4-[2-(l-atba各咬基）乙基]-1-六氯u比σ井基}曱基）-本曱醯胼三氟醋酸鹽 135 200804352 αIntermediate 19 (50·0 mg, 0.13 mmol), Κ(3-?福σ林基propyl) hexahydro port ratio well (FLUOROCHEM, 40.0 mg, 0.19 mmol) potassium carbonate (FLUKA, 37.0 mg, 0.27 mmol) and 1 scraper tip sodium hydride dissolved in anhydrous ACN (2 mL). After the reaction mixture was stirred at room temperature overnight, the reaction mixture was filtered and evaporated under reduced pressure. The crude product was purified by preparative EtOAc (EtOAc: EtOAc (EtOAc) 1H NMR (300 MHz, CDC13) 3 ppm: 10.07 (s, 1H), 8.25 (s, 2H), 8.05 (br·s, 1H), 7.63-7.48 (m, 2H), 4·19 (br·s , 2H), 4.05-3.05 (br· m, 20H), 2.82 (m, 2H), 2·12 (m, 3H), 1·01 (d, 6H); [ES+MS] m/z 555 ( MH)+. Example 64 · · N,-(5-chloro-2-cyano-4-pyrimidinyl)-N,-(2-mercaptopropyl)-3-({4-[2-(l-atba) bite Ethyl]-1-hexachlorou ratio σ well base} fluorenyl)-benzine trifluoroacetate 135 200804352 α

OH 將中間物19(50.0毫克，0.13毫莫耳）、1-(2-毗定& 乙基）六氫吡畊（FLUOROCHEM，34.0毫克，〇·ΐ9毫莫耳^ 碳酸鉀（FLUKA，37.0毫克，0.27毫莫耳）及1刮刀尖的鐵化鈉溶解在無水ACN (2毫升）。將反應混合物在室溫授掉過伙。反應完成後，將反應混合物過濾、並在減壓下將溶劑蒸發。將所得的粗產物經由製備級HPLC (XTERRA 19x150 毫米，ACN:H20, 0.1%TFA，梯度10-100%)純化後得到標題化合物。1H NMR (300 MHz，CDC13)3 ppm: 10·51 (s，1H)， 8.32 (s，1H)，8·23 (s, 1H)，8.11-8.02 (m，1H)，7.60-7·43 (m， 2H)，4·18 (br· s，2H)，4.01-2.01 (br. m，23H)，1.00 (d，6H); [ES+MS] m/z 525 (MH)+ 〇實例65 : N、(5-氣-2-氰基-4-嘧啶基)-3-({4-[(l-曱基-4-六氫咐啶基）甲基]-1-六氫吼畊基}甲基)-Ν’-(2-曱基丙基)-苯甲醯胼三氟醋酸鹽OH will be intermediate 19 (50.0 mg, 0.13 mmol), 1-(2-adjacent & ethyl) hexahydropyrazine (FLUOROCHEM, 34.0 mg, 〇·ΐ9 mmoles) potassium carbonate (FLUKA, 37.0 Mg, 0.27 mmol) and 1 scraper tip sodium hydride dissolved in anhydrous ACN (2 mL). The reaction mixture was allowed to pass at room temperature. After the reaction was completed, the reaction mixture was filtered and solvent was evaporated under reduced pressure. Evaporation. The title compound was obtained from EtOAc EtOAc EtOAc EtOAc. (s,1H), 8.32 (s,1H),8·23 (s,1H),8.11-8.02 (m,1H), 7.60-7·43 (m, 2H),4·18 (br· s, 2H), 4.01-2.01 (br. m, 23H), 1.00 (d, 6H); [ES+MS] m/z 525 (MH) + 〇 Example 65: N, (5-Gas-2-cyano- 4-pyrimidinyl)-3-({4-[(l-fluorenyl-4-hexahydroacridinyl)methyl]-1-hexahydroindole)}methyl)-Ν'-(2-曱Propyl)-benzamide trifluoroacetate

將中間物19(50.0毫克，0.13毫莫耳）、1-(N-曱基-4-六氫吡啶基曱基）六氫吡畊（FLUOROCHEM，37.0毫克，〇. 19 136 200804352 毫莫耳）、碳酸鉀(FLUKA，37.0毫克，0·27毫莫耳）及1刮刀尖的碘化鈉溶解在無水ACN (2毫升）。將反應混合物在室溫授拌過夜。反應完成後，將反應混合物過濾並在減壓下將溶劑蒸發。將所得的粗產物經由製備級HPLC (XTERRA 19x150 毫米，ACN:H20, 0.1%TFA，梯度 10-100%) 純化後得到標題化合物。1HNMR(300 MHz，CDCl3)5ppm: 10.23 (s，1H)，8.34 (br. s，1H)，8.24 (s，1H)，8.09-8.02 (m， 1H)，7.61-7.45 (m，2H)，4·18 (br· s，2H)，3.9M.77 (br· m， 27H)，1.01 (d，6H); [ES+MS] m/z 539 (MH)+。實例66 : N’-(5-氯-2-氰基-4-嘧啶基)-N’-(2-曱基丙基）-3-({4<2-(l-六氫吼啶基）乙基]-1-六氫批畊基}甲基）-苯曱醯肼三氟醋酸鹽Intermediate 19 (50.0 mg, 0.13 mmol), 1-(N-mercapto-4-hexahydropyridinyl) hexahydropyrazine (FLUOROCHEM, 37.0 mg, 〇. 19 136 200804352 mM) Potassium carbonate (FLUKA, 37.0 mg, 0. 27 mmol) and 1 spatula tip sodium iodide were dissolved in anhydrous ACN (2 mL). The reaction mixture was stirred overnight at room temperature. After the reaction was completed, the reaction mixture was filtered and the solvent was evaporated under reduced pressure. The crude product was purified by EtOAc EtOAc EtOAc EtOAc: 1H NMR (300 MHz, CDCl3) 5 ppm: 10.23 (s, 1H), 8.34 (br. s, 1H), 8.24 (s, 1H), 8.09-8.02 (m, 1H), 7.61-7.45 (m, 2H), 4·18 (br· s, 2H), 3.9M.77 (br· m, 27H), 1.01 (d, 6H); [ES+MS] m/z 539 (MH)+. Example 66: N'-(5-Chloro-2-cyano-4-pyrimidinyl)-N'-(2-mercaptopropyl)-3-({4<2-(l-hexahydroacridinyl) Ethyl]-1-hexahydrogenated benzyl}methyl)-phenylhydrazine trifluoroacetate

將中間物19(50.0毫克，0.13毫莫耳）、1-(2-六氫吡啶基乙基）六氫吡畊(FLUOROCHEM，37.0毫克，0.19毫莫耳）、碳酸鉀(FLUKA，37.0毫克，0·27毫莫耳）及1刮刀尖的碘化鈉溶解在無水ACN (2毫升）。將反應混合物在室溫攪拌過夜。反應完成後，將反應混合物過濾並在減壓下將溶劑蒸發。將所得的粗產物經由製備級HPLC (XTERRA 19x150 毫米，ACN:H20，（U%TFA，梯度10-100%)純化後得到標題化合物。1H NMR (300 MHz，CDC13)3 ppm: 10.53 (s，1H)， 137 200804352 8·32 (s，1H)，8·22 (s，1H)，8·ΐ〇-8·02 (m，1H)，7.61-7.45 (m， 2H)，4.20 (s，2H)，3.92-1.78 (br· m，25H)，1.00 (d，6H); [ES+MS] m/z 539 (MH)+ 〇實例67 : N’-(5-氯-2-氰基_4_嘧啶基曱基丙基)-3-{[4-(4-嗎福啉基)-Κ六氫吡啶基]曱基}苯曱醯胼三氟醋酸鹽Intermediate 19 (50.0 mg, 0.13 mmol), 1-(2-hexahydropyridylethyl)hexahydropyrazine (FLUOROCHEM, 37.0 mg, 0.19 mmol), potassium carbonate (FLUKA, 37.0 mg, 0. 27 millimoles) and 1 scraper tip sodium iodide dissolved in anhydrous ACN (2 ml). The reaction mixture was stirred overnight at room temperature. After the reaction was completed, the reaction mixture was filtered and evaporated under reduced pressure. The resulting crude product was purified by EtOAc EtOAc EtOAc (EtOAc (EtOAc) 1H), 137 200804352 8·32 (s,1H),8·22 (s,1H),8·ΐ〇-8·02 (m,1H), 7.61-7.45 (m, 2H), 4.20 (s, 2H), 3.92-1.78 (br· m, 25H), 1.00 (d, 6H); [ES+MS] m/z 539 (MH) + 〇 Example 67: N'-(5-chloro-2-cyano _4_pyrimidinylmercaptopropyl)-3-{[4-(4-morpholino)-indolylhexahydropyridinyl]fluorenyl}phenylhydrazine trifluoroacetate

在中間物23 (90·5毫克，0.20毫莫耳）於THF (1.7毫升) 之溶液中加入4-嗎福啡基六氫吡啶(aldrich，7〇〇毫克， 0.41毫莫耳）及無水THF (1毫升）。將反應混合物在室溫攪拌過夜後，在60°C加熱4小時。再度加入4-嗎福咁基六氫吡啶（35.0毫克，0.205毫莫耳）並將反應混合物在6(rc加熱 3小時，然後在室溫攪拌過夜。反應完成後，將反應混合物過濾並在減壓下將溶劑蒸發。將所得的粗產物溶解在 MeOH並經由製備級HPLC (XTERRA 19x150毫米， ACN:H2〇, 0.1%TFA，梯度10-100%)純化後得到標題化合物。1H NMR (300 MHz，CDC13)3 ppm: 10.27 (br· s，1H)，8.58 (br· m，1H)，8.25 (s，1H)，8.11 (br. m，1H)，7.26 (br. m，1H)， 4.33-1 ·22 (br· m，22H)，1·02 (d，6H); [ES+MS] m/z 530 (MH)+ o 實例68 : N’-(5-氣-2-氰基-4-嘧啶基)_‘氟-3-{[4-(羥基曱 138 200804352 基)-1-六氫吼咬基]曱基}·Ν，-(2_甲基丙基)苯曱賴三氣醋酸鹽To a solution of intermediate 23 (90·5 mg, 0.20 mmol) in THF (1.7 mL), EtOAc (EtOAc EtOAc EtOAc (1 ml). After the reaction mixture was stirred at room temperature overnight, it was heated at 60 ° C for 4 hours. 4-Folfosylpiperidine (35.0 mg, 0.205 mmol) was added again and the reaction mixture was heated at 6 (rc for 3 h then stirred at room temperature overnight. After the reaction was completed, the reaction mixture was filtered and reduced The solvent was evaporated under reduced pressure. , CDC13)3 ppm: 10.27 (br· s,1H), 8.58 (br· m,1H), 8.25 (s,1H), 8.11 (br. m,1H), 7.26 (br. m,1H), 4.33 -1 ·22 (br· m,22H),1·02 (d,6H); [ES+MS] m/z 530 (MH)+ o Example 68: N'-(5-Gas-2-cyano 4-pyrimidinyl)_'fluoro-3-{[4-(hydroxyindole 138 200804352 yl)-1-hexahydroindole)] fluorenyl}·Ν,-(2-methylpropyl)benzoquinone Tri-gas acetate

在中間物23 (90.5愛克，〇·2〇亳莫耳)於THF (1·7毫升) 之溶液中加入在無水THF(1毫升）中的4_(羥基曱基）六氫 t定(ALDRICH，47.G毫克，〇·41毫莫耳）。將反應混合物在室溫攪拌過夜後，在60°C加熱4小時。再度加入‘(羥基甲基）/、氫吡啶(23·5毫克，0.20毫莫耳）並將反應混合物在 60X：加熱3小時，然後在室溫攪拌過夜。反應完成後，將反應混合物過濾並在減壓下將溶劑蒸發。將所得的粗產物浴解在MeOH並經由製備級HPLC (XTERRA 19x150毫米， ACN:H2〇, 0.1%TFA，梯度10-100%)純化後得到標題化合物。1HNMR(300 MHz，CDCl3)3ppm: 11.29 (br. s，1H)，10·7 (s, 1Η)，8·55 (br· m，1Η)，8·23 (s，1Η)，8.13 (br· m，1Η)，7,26 (br· m，1H)，4.36-1.47 (br· m，17H)，1.01 (d，6H); [ES+MS] m/z 475 (MH)+ 〇實例69:3-(l，4’-聯六氫吡啶-l，_基曱基)-N’-(5-氣-2-氰基-4-嘧啶基)-4-氟-N’-(2-曱基丙基）苯甲醯胼三氟醋酸鹽Add 4_(hydroxyindenyl)hexahydro-tidine (ALDRICH) in anhydrous THF (1 ml) in a solution of intermediate 23 (90.5 EtOAc, EtOAc). , 47.G mg, 〇·41 millimoles). After the reaction mixture was stirred at room temperature overnight, it was heated at 60 ° C for 4 hours. ‘(Hydroxymethyl)/hydropyridine (23. 5 mg, 0.20 mmol) was added again and the reaction mixture was heated at 60× for 3 hours and then stirred at room temperature overnight. After the reaction was completed, the reaction mixture was filtered and the solvent was evaporated under reduced pressure. The resulting crude product was taken from EtOAc (EtOAc m. 1H NMR (300 MHz, CDCl3) 3 ppm: 11.29 (br. s, 1H), 10·7 (s, 1 Η), 8·55 (br· m, 1 Η), 8·23 (s, 1 Η), 8.13 (br · m,1Η),7,26 (br· m,1H),4.36-1.47 (br· m,17H),1.01 (d,6H); [ES+MS] m/z 475 (MH)+ 〇Example 69: 3-(l,4'-bipyridinyl-l,-ylindenyl)-N'-(5-aero-2-cyano-4-pyrimidinyl)-4-fluoro-N'-( 2-mercaptopropyl)benzimidazole trifluoroacetate

139 200804352139 200804352

60°C加熱3小時，然後在室 )·20毫莫耳）並將反應混合物在毫莫耳）並將反應混合物在 I拌過夜。反應完成後，將 3小時，然後在室溫攪拌過夜。反應混合物過濾並在減壓下將溶劑蒸發。將所得的粗產物溶解在MeOH並經由製備級HPLC (XTERRA 19x150毫米， ACN:H20, 0.1〇/〇TFA，梯度ΗΜ00%)純化後得到標題化合物。1H NMR (300 MHz，CDC13)3 ppm: 10.45 (s，1H)，8.50 (br· m，1H)，8.24 (s，1H)，8.15 (br· m，1H)，7.32 (br· m，1H)，4·27 (s，2H)，3·96-1·82 (br· m，22H)，1·〇1 (d，6H); [ES+MS] m/z 528 (MH)+ 〇實例70 : N’-(5_氣-2-氰基-4-嘧啶基)_4-氟-3-[(4-甲基·1-六氫吼畊基）曱基]-Ν’-(2-曱基丙基）苯曱酿肼Heat at 60 °C for 3 hours, then in the chamber (20 mmol) and the reaction mixture at mM) and mix the reaction mixture at AI overnight. After the reaction was completed, it was allowed to stand for 3 hours and then stirred at room temperature overnight. The reaction mixture was filtered and the solvent was evaporated under reduced pressure. The obtained crude product was dissolved in EtOAc (EtOAc m. 1H NMR (300 MHz, CDC13) 3 ppm: 10.45 (s, 1H), 8.50 (br· m, 1H), 8.24 (s, 1H), 8.15 (br· m, 1H), 7.32 (br· m, 1H) ),4·27 (s,2H),3·96-1·82 (br· m,22H),1·〇1 (d,6H); [ES+MS] m/z 528 (MH)+ 〇 Example 70: N'-(5-Gas-2-cyano-4-pyrimidinyl)-4-fluoro-3-[(4-methyl·1-hexahydroindolyl)indenyl]-Ν'-( 2-mercaptopropyl)benzoquinone

在中間物23 (90.5毫克，0.20毫莫耳）於THF (1.7毫升) 之溶液中加入在無水THF (1毫升）中的Ν-曱基六氫吡畊 (ALDRICH，41·0毫克，0·41毫莫耳）。將反應混合物在室溫攪拌過夜後，在60°C加熱4小時。反應完成後，將反應混合物過濾並在減壓下將溶劑蒸發。將所得的粗產物溶解在 140 200804352To a solution of intermediate 23 (90.5 mg, 0.20 mmol) in THF (1.7 mL) EtOAc (EtOAc) 41 millimoles). After the reaction mixture was stirred at room temperature overnight, it was heated at 60 ° C for 4 hours. After completion of the reaction, the reaction mixture was filtered and the solvent was evaporated under reduced pressure. The resulting crude product was dissolved at 140 200804352

MeOH並經由製備級HPLC (XTERRA 19x150毫米， ACN:H20, 0.1%TFA，梯度10-100%)純化後得到標題化合物。1HNMR(300 MHz，CDCl3)3ppm: 9·67 (s，1H)，8·30_8·19 (br· m，2Η)，8.00 (m，1Η)，7.29 (br· m，1Η)，4.19 (s，2Η)， 3.92-3.36 (br· m，10H)，2·81 (s，3H)，2·14 (m，1H)，1·〇ΐ (d， 6H); [ES+MS] m/z 460 (MH)+。實例71 : N’-(5-溴-2-氰基-4-嘧啶基)-4-{[4-(4-曱基-i-六氫吡畊基)-1-六氫吡啶基]甲基}-N’-(2-甲基丙基）苯甲醯肼三氟醋酸鹽The title compound was obtained after EtOAc (EtOAc m. 1H NMR (300 MHz, CDCl3) 3 ppm: 9·67 (s, 1H), 8·30_8·19 (br· m, 2Η), 8.00 (m, 1Η), 7.29 (br·m, 1Η), 4.19 (s , 2Η), 3.92-3.36 (br· m, 10H), 2·81 (s, 3H), 2·14 (m, 1H), 1·〇ΐ (d, 6H); [ES+MS] m/ z 460 (MH)+. Example 71: N'-(5-Bromo-2-cyano-4-pyrimidinyl)-4-{[4-(4-indolyl-i-hexahydropyramino)-1-hexahydropyridinyl] Methyl}-N'-(2-methylpropyl)benzimidazole trifluoroacetate

將中間物18 (270.0毫克，〇·639毫莫耳）、1-曱基-4-(六氫吡啶-4-基)_六氫吡畊(FLUOROCHEM，183.3毫克，0.766 X莫耳）、N，N-二異丙基乙基胺(ALDRICH, 215微升，1.278 毫莫耳）及1刮刀尖的碘化鈉溶解在無水ACN (10毫升）。將反應混合物在室溫攪拌過夜。反應完成後，將反應混合物過濾並在減壓下將溶劑蒸發。將所得的粗產物經由製備級 HPLC (X-TERRA 50x250 毫米，ACN:H20, 0,1%TFA，梯度25-100%)純化後得到標題化合物。11^1^11(30(^1^， CDC13+CD30D)3 ppm: 8.73 (s，1H)，8.03 (s，1H)，7.99 (d，8·2 Ηζ，2Η)，7·54 (d，8·2 Ηζ，2Η)，4·63 (s，3Η)，4·14 (s，2Η)，3·45 (m，5Η)，2·86 (m，6Η)，2.73 (s，3Η)，2·53 (m，1.9 Ηζ，3Η)，2 141 200804352 (ΜΗ)+。 (m，8H)，1.2 (m，2H)，0.96 (d，6·6 Hz，6H); [ES+MS] m/z 569 貫例72 · N’-(5-溴-2-氰基_4-嘧啶基)-5_[(4_甲基-；1-六氫吡畊基）甲基]-Ν’-(2·甲基丙基)-3-異噚唑卡巴肼三氟醋酸鹽Intermediate 18 (270.0 mg, 639·639 mmol), 1-mercapto-4-(hexahydropyridin-4-yl)-hexahydropyrazine (FLUOROCHEM, 183.3 mg, 0.766 X Moule), N N-diisopropylethylamine (ALDRICH, 215 μl, 1.278 mmol) and 1 spatula tip sodium iodide were dissolved in anhydrous ACN (10 mL). The reaction mixture was stirred at room temperature overnight. After the reaction was completed, the reaction mixture was filtered and the solvent was evaporated under reduced pressure. The crude product obtained was purified by preparative EtOAc (EtOAc:EtOAc:EtOAc 11^1^11(30(^1^, CDC13+CD30D)3 ppm: 8.73 (s,1H),8.03 (s,1H),7.99 (d,8·2 Ηζ,2Η),7·54 (d ,8·2 Ηζ,2Η),4·63 (s,3Η),4·14 (s,2Η),3·45 (m,5Η),2·86 (m,6Η),2.73 (s,3Η) ), 2·53 (m, 1.9 Ηζ, 3Η), 2 141 200804352 (ΜΗ)+. (m, 8H), 1.2 (m, 2H), 0.96 (d, 6·6 Hz, 6H); [ES+ MS] m/z 569 Example 72 · N'-(5-Bromo-2-cyano-4-pyrimidinyl)-5-[(4-methyl-; 1-hexahydropyrryl)methyl]- Ν'-(2·Methylpropyl)-3-isoxazolecarbazide trifluoroacetate

將中間物26 (28.3毫克，〇·〇68毫莫耳）溶解在無水THF (5耄升）。加入N，N-二異丙基乙基胺(FLUKA，15·2微升， 0·137耄莫耳）及ν_曱基六氳吡u井(ALDRICH, 23.8微升 0.137莫耳）並將所得的溶液在室溫攪拌過夜。加入n，n_: 異丙基乙基胺(FLUKA，30·4微升，0.274毫莫耳)及N-曱基 /、氫吼17井(ALDRICH，23.8微升〇·137莫耳）。將溶液在室溫攪拌過夜。再度加入N，N-二異丙基乙基胺(FLUKA，30.4微升，0.274毫莫耳）並將反應再擾拌is小時。將溶劑蒸發並將殘留物經由製備級HPLC (XTERRA管柱19x150毫米，梯度：10% ACN; 0·ΐ〇/。TFA 至 100% ACN，0.1%TFA)純化後得到標題化合物。bNMR (300 MHz，CDC13)3 ppm: 8.88 (br s，1Η)，8.50 (s，1H)，6.70 (s，1H)，3·89 (s，2H)，3.79 (m， 2H)，3·59 (m，2H)，2·97 (m，4H)，2·84 (s，3H)，2·70 (m，2H)， 2.10 (m，1H)，1·02 (d，6H，J=6 Hz); [ES+MS] m/z 477 (M)+。實例73:N’-(5-溴-2-氰基_4-嘧啶基)·7_[(4_甲基小六氫吡畊基）曱基]-Ν’-(2-曱基丙基)小苯並呋喃-2_卡巴胼三氟醋酸 142 200804352Intermediate 26 (28.3 mg, 〇·〇 68 mmol) was dissolved in dry THF (5 liters). Add N,N-diisopropylethylamine (FLUKA, 15.2 μl, 0·137 耄mol) and ν_曱氲氲pyrazine (ALDRICH, 23.8 μl 0.137 m) and The resulting solution was stirred at room temperature overnight. n, n_: isopropylethylamine (FLUKA, 30·4 μl, 0.274 mmol) and N-mercapto/hydroquinone 17 (ALDRICH, 23.8 μl 〇·137 mol) were added. The solution was stirred at room temperature overnight. N,N-Diisopropylethylamine (FLUKA, 30.4 μL, 0.274 mmol) was added again and the reaction was again scrambled for one hour. The solvent was evaporated and the residue was purified EtOAcjjjjjjjjjj bNMR (300 MHz, CDC13) 3 ppm: 8.88 (br s, 1 Η), 8.50 (s, 1H), 6.70 (s, 1H), 3·89 (s, 2H), 3.79 (m, 2H), 3· 59 (m,2H),2·97 (m,4H),2·84 (s,3H),2·70 (m,2H), 2.10 (m,1H),1·02 (d,6H,J =6 Hz); [ES+MS] m/z 477 (M)+. Example 73: N'-(5-Bromo-2-cyano-4-pyrimidinyl)-7-[(4-methylhexahydropyranyl)indolyl]-Ν'-(2-mercaptopropyl) Small benzofuran-2_carbazol trifluoroacetate 142 200804352

將中間物29 (100毫克，〇·39毫莫耳）溶解在無水DCM (6耄升）及無水THF (1.5毫升）。加入無水DMF (11微升）及草醯氣(ALDRICH，38微升，〇·43毫莫耳）。將反應在室溫擾拌1小時45分鐘直到沒有起始物質。將在無水DCM (3.5毫升）中的中間物6 (127毫克，0·47毫莫耳)及二異丙基乙基胺(FLUKA，171微升，0.98毫莫耳）之溶液逐滴添加至反應並將所得的溶液在室溫攪拌20小時。然後，加入 Ν-曱基六氫吡畊（ALDRICH，52微升0·47莫耳）及二異丙基乙基胺(FLUKA，82微升，〇·47毫莫耳）並將反應在室溫攪拌54小時。將溶劑蒸發至乾並將殘留物經由製備級HPLC (XTERRA 管柱 19x150 毫米，梯度：25% ACNj;〇.l%TFA 至100% ACN-水，0.1%TFA)純化後得到標題化合物。1Η NMR (300 MHz，DMSO-d6)3 ppm: 11·57 (s，1Η)，9.33 (br s， 1H)，8.69 (s，1H)，7·82 (s，1H)，7·75·7·79 (m，1H)，7.46-7.50 (m，1H)，7·34-7·40 (m，1H)，3·99 (m，4H)，2·98-3·10 (m，6H)， 2.77 (s，3H)，2·33-2·45 (m，2H)，2·03·2·14 (m，1H)，0·97 (d， 6H，J=6.8 Hz); [ES+MS] m/z 526 (M)+。實例74:>^’-(5-溴-2-氰基-4-嘧啶基)-5-[(4-曱基-1-六氫吡畊基）甲基]-N’-(2-甲基丙基)-2-苯並呋喃卡巴肼（0.75 143 200804352 TFA/0.25 pTsOH 鹽）Intermediate 29 (100 mg, 〇 39 mmol) was dissolved in dry DCM (6 liters) and anhydrous THF (1. Anhydrous DMF (11 μl) and grass cockroach (ALDRICH, 38 μl, 〇·43 mmol) were added. The reaction was stirred at room temperature for 1 hour and 45 minutes until there was no starting material. A solution of Intermediate 6 (127 mg, 0.47 mmol) and diisopropylethylamine (FLUKA, 171 μL, 0.98 mmol) in anhydrous DCM (3.5 mL) was added dropwise. The reaction was allowed to stir at room temperature for 20 hours. Then, Ν-mercaptohexahydropyrazine (ALDRICH, 52 μl 0·47 mol) and diisopropylethylamine (FLUKA, 82 μl, 〇·47 mmol) were added and the reaction was carried out in the chamber. Stir for 54 hours. The solvent was evaporated to dryness <RTI ID=0.0> 1 NMR (300 MHz, DMSO-d6) 3 ppm: 11·57 (s, 1 Η), 9.33 (br s, 1H), 8.69 (s, 1H), 7·82 (s, 1H), 7·75· 7·79 (m,1H), 7.46-7.50 (m,1H),7·34-7·40 (m,1H),3·99 (m,4H),2·98-3·10 (m, 6H), 2.77 (s, 3H), 2·33-2·45 (m, 2H), 2·03·2·14 (m, 1H), 0·97 (d, 6H, J=6.8 Hz); [ES+MS] m/z 526 (M)+. Example 74: >^'-(5-Bromo-2-cyano-4-pyrimidinyl)-5-[(4-mercapto-1-hexahydropyrryl)methyl]-N'-(2 -methylpropyl)-2-benzofurancarbazide (0.75 143 200804352 TFA/0.25 pTsOH salt)

將中間物3i (780·7毫克，3·489毫莫耳）溶解在4〇 DCM。緩慢加入草醯氯(ALDRICH，513 2微升，5·398毫莫耳）並將反應在至溫授拌2小時後將溶劑蒸發。將二異丙基乙基胺(FLUKA，1.25毫升，7.198毫莫耳）添加至中間物ό (486.1毫克，1.799毫莫耳)在無水THF (5毫升）之溶液。將所彳于的溶液攪拌1〇分鐘後逐滴添加至先前得到的殘留物（846·78毫克，3.489毫莫耳）。加入第三丁醇鉀 (ALDRICH，282.7毫克，2.52毫莫耳）並將反應混合物在室溫攪;拌過夜。將反應過濾，蒸發，並將殘留物經由製備級〇々Q//0Intermediate 3i (780·7 mg, 3.489 mmol) was dissolved in 4 〇 DCM. Grass chlorinated chlorine (ALDRICH, 513 2 μl, 5.398 mmol) was slowly added and the reaction was allowed to evaporate after stirring for 2 hours. Diisopropylethylamine (FLUKA, 1.25 mL, 7.198 mmol) was added to a solution of intermediate (486.1 mg, 1.799 mmol) in anhydrous THF (5 mL). The solution was stirred for 1 minute and then added dropwise to the residue obtained previously (846·78 mg, 3.489 mmol). Potassium tert-butoxide (ALDRICH, 282.7 mg, 2.52 mmol) was added and the reaction mixture was stirred at room temperature; The reaction was filtered, evaporated, and the residue was taken to EtOAc EtOAc.

HPLC (LUNA 管柱 50x250 毫米，梯度：20% ACN; 0.1% TFA 至100% ACN，0.1%TFA)純化後得到標題化合物。1H NMR (300 MHz，DMSO-d6)3 ppm: 11.27 (s，1Η)，9.53 (br s，1Η)， 8·65 (s，1H)，7·33 (d，1H，J=3.4 Hz)，6·59 (d，1H，J=3.5 Hz)， 3.73 (s，2H)，3·38 (m，3H)，3.01 (m，5H)，2.78 (s, 3H)，2·39 (m，2H)，2·06 (m，1H)，0.94 (d，6H，J=6.6 Hz); [ES+MS] m/z 476 (M)、實例75 : N’-(5-溴-2-氰基-4-嘧啶基)-6-{3-[(4-甲基-1-六氫吡啡基）甲基]苯基}-N，-(2-甲基丙基)-3^比啶卡巴胼三氟醋酸鹽 144 200804352HPLC (LUNA column 50 x 250 mm, gradient: 20% ACN; 0.1% TFA to 100% ACN, 0.1% TFA) 1H NMR (300 MHz, DMSO-d6) 3 ppm: 11.27 (s, 1 Η), 9.53 (br s, 1 Η), 8·65 (s, 1H), 7·33 (d, 1H, J = 3.4 Hz) ,6·59 (d,1H,J=3.5 Hz), 3.73 (s,2H),3·38 (m,3H),3.01 (m,5H),2.78 (s, 3H),2·39 (m , 2H), 2·06 (m, 1H), 0.94 (d, 6H, J = 6.6 Hz); [ES+MS] m/z 476 (M), Example 75: N'-(5-bromo-2 -cyano-4-pyrimidinyl)-6-{3-[(4-methyl-1-hexahydropyridyl)methyl]phenyl}-N,-(2-methylpropyl)-3 ^Biidine carbazone trifluoroacetate 144 200804352

將N-曱基六氫吡畊(ALDRICH，0.007毫升0·06毫莫耳) 及N，N-«一異丙基乙基胺(FLUK A，0.014毫升，0.08毫莫耳) 在THF (6毫升）中在室溫攪拌5分鐘。加入中間物34 (26 毫克，0.05毫莫耳）並將溶液在室溫攪拌4天後將其迴流4 小時。將減壓下將反應濃縮並將殘留物經由製備級HPLC (XTERRA 19x150 毫米，ACN:H20, 0.1% TFA，梯度 20-80%) 純化後得到標題化合物。1HNMR(300 MHz，DMSO-d6)3 ppm·· 11·59 (s，1Η)，9·39 (br·，1H)，9·15 (m，1H)，8·67 (s，1H)， 8·42_8·33 (m，1Η)，8·18-8·04 (m，3Η)，7·57_7·43 (m，2Η)， 3.76-2.91 (br· m，12Η)，2·76 (s，3Η)，2·10 (m，1Η)，0·97 (d， 6H); [ES+MS] m/z 563 (MH)+。實例76:1^’-(5-漠-2_氰基-4-1[3密咬基)-6-{4-[(4-曱基-1-六氫口比n井基）曱基]苯基}-N’-(2-曱基丙基)-3-ϋ比唆卡巴月井三氟腊酸鹽N-decyl hexahydropyrazine (ALDRICH, 0.007 ml 0. 06 mmol) and N,N-«-isopropylethylamine (FLUK A, 0.014 ml, 0.08 mmol) in THF (6 Stir in room temperature for 5 minutes at room temperature. Intermediate 34 (26 mg, 0.05 mmol) was added and the solution was stirred at room temperature for 4 d and then refluxed for 4 h. The reaction was concentrated under reduced mpqqqqqqqqqqqqQQQQQQQQQQQQQQQQQQQQQQQQ 1H NMR (300 MHz, DMSO-d6) 3 ppm·· 11·59 (s, 1 Η), 9·39 (br·, 1H), 9·15 (m, 1H), 8.67 (s, 1H), 8·42_8·33 (m,1Η),8·18-8·04 (m,3Η),7·57_7·43 (m,2Η), 3.76-2.91 (br· m,12Η),2·76 ( s, 3Η), 2·10 (m, 1Η), 0·97 (d, 6H); [ES+MS] m/z 563 (MH)+. Example 76: 1^'-(5-Moist-2_Cyano-4-1[3 dimethyl)-6-{4-[(4-mercapto-1-hexahydroport ratio n well base) 曱Phenyl]-phenyl}-N'-(2-mercaptopropyl)-3-indole

在中間物37 (37毫克，0·07毫莫耳）於THF (5毫并）之溶液中加入N，N_DIPEA(FLUKA，0.019毫升，0.11毫莫尊) 145 200804352 及N-曱基六氫吡畊(ALDRICH，0.020毫升0.18毫莫耳）。將溶液在室溫攪拌2天後將其迴流7小時。將減壓下將反應濃縮並將殘留物經由製備級HPLC (XTERRA 19x150毫米，ACN:H20,〇.1%TFA，梯度10-100%)純化後得到標題化合物。1HNMR(300 MHz，DMSOd6)δppm:ll·57(s，lH)， 9.42 (br·，1H)，9·15 (m，1H)，8·40·8·30 (m，1H)，8·20-8·08 (m， 3Η)，7·48 (d，2Η)，4·13·2·84 (br· m，12Η)，2·77 (s，3Η)，2·10 (m，1H)，0.97 (d，6H); [ES+MS] m/z 563 (MH)+。實例77 : N’-(5_溴-2-氰基-4-痛淀基)_5_{4-[(4-甲基-1-六氫吡畊基）曱基]苯基卜N，-(2-甲基丙基)-3_吡啶卡巴胼三氟醋酸鹽Add N,N_DIPEA (FLUKA, 0.019 ml, 0.11 mmol) 145 200804352 and N-decyl hexahydropyridin in a solution of intermediate 37 (37 mg, 0. 07 mmol) in THF (5 m) Ploughing (ALDRICH, 0.020 ml 0.18 mmol). The solution was stirred at room temperature for 2 days and then refluxed for 7 hours. The reaction was concentrated under reduced pressure and purified title crystalljjjjlililililililililililililili 1H NMR (300 MHz, DMSOd6) δ ppm: ll·57 (s, lH), 9.42 (br·, 1H), 9·15 (m, 1H), 8·40·8·30 (m, 1H), 8· 20-8·08 (m, 3Η), 7·48 (d, 2Η), 4·13·2·84 (br· m, 12Η), 2·77 (s, 3Η), 2·10 (m, 1H), 0.97 (d, 6H); [ES+MS] m/z 563 (MH)+. Example 77: N'-(5-bromo-2-cyano-4-wandyl)_5_{4-[(4-methyl-1-hexahydropyrryl)indolyl]phenyl b N,- (2-methylpropyl)-3-pyridine carbazone trifluoroacetate

F 在中間物40 (粗產物）於DCM (10毫升）之溶液中加入 N，N-二異丙基乙基胺(Fluka，0.097毫升，〇·55毫莫耳）Ν 甲基六氫吼吨(ALDRICH, 0.049毫升0·44毫莫耳)及峨化Add N,N-diisopropylethylamine (Fluka, 0.097 ml, 〇·55 mmol) to a solution of the intermediate 40 (crude) in DCM (10 mL). (ALDRICH, 0.049 ml 0·44 mmol) and hydrogenation

納。將溶液在室溫擾拌4天。將減壓下將反應濃縮並將殘留物經由製備級HPLC (XTERRA 19x150毫米，Α(：Ν·Η 〇 0.1% TFA，梯度20-80%)純化後得到標題化合物。lH (300 MHz，DMSO-d6)3 ppm: 11.63 (s，1H)，9·12 (m 1H) 9.06 (m，1H)，8·68 (s，1H)，8·50 (s，1H)，7·82 (d，2H)，7 M (d 2H)，4·46-2·88 (m，13H)，2.77 (s，3H)，2.11 (m，1H)，’〇 % (d ’ 146 200804352 6H); [ES+MS] m/z 563 (MH)+。氟醋貫例78 : N’-(5-溴-2-氰基_4-。密°定基甲基q 口比ϋ井基）曱基]苯基}-N’-(2-曱基丙基)_3_峨。定卡巴月井二酸鹽Na. The solution was stirred at room temperature for 4 days. The reaction was concentrated under reduced pressure and purified EtOAc EtOAcjjjjjjjjj D6)3 ppm: 11.63 (s,1H),9·12 (m 1H) 9.06 (m,1H),8·68 (s,1H),8·50 (s,1H),7·82 (d, 2H), 7 M (d 2H), 4·46-2·88 (m, 13H), 2.77 (s, 3H), 2.11 (m, 1H), '〇% (d ' 146 200804352 6H); [ES +MS] m/z 563 (MH)+. Fluorine vinegar Example 78: N'-(5-bromo-2-cyano-4-.-densified methyl group q-port ratio ϋ井基) thiol]benzene }}-N'-(2-mercaptopropyl)_3_峨. 定卡巴月井二二盐

在中間物43 (粗產物）於THF (20毫升）之溶液中力 DIPEA(Fluka，0.097毫升，0.55毫莫耳）、Ν-甲基六氫Ί啡 (ALDRICH，0.049毫升0.44毫莫耳）及碘化鈉。將溶液在室溫攪拌4天。將減壓下將反應濃縮並將殘留物經由製備級 HPLC (XTERRA 19x150 毫米，ACN:H20, 0.1% TFA，梯渡 10-100%)純化後得到標題化合物。hNMR (300 MHz， DMSO-d6)3 ppm: 11.66 (s，1H)，9·12 (m，2H)，8·67 (m，1H)， 8·50 (m，1H)，7.78 (br· s，1H)，7·60-7·41 (m，2H)，4.07 (br·， 1H)，3·84 (br· s，2H)，3·53-2·93 (m，8H)，2·78 (s，3H)，2.11 (m，1H)，0.97 (d，6H); [ES+MS] m/z 563 (MH)+。實例79:Ν’·(5_溴-2_氰基-4-嘧啶基)-5-[(4_甲基小六氫吡畊基）甲基]-Ν’-(2-曱基丙基)-1-苯並吱味卡巴胼DIPEA (Fluka, 0.097 ml, 0.55 mmol), Ν-methyl hexahydromorphine (ALDRICH, 0.049 ml 0.44 mmol) and a solution of intermediate 43 (crude) in THF (20 mL) Sodium iodide. The solution was stirred at room temperature for 4 days. The reaction was concentrated under reduced pressure and purified EtOAcqqqqqqqq hNMR (300 MHz, DMSO-d6) 3 ppm: 11.66 (s, 1H), 9·12 (m, 2H), 8.67 (m, 1H), 8·50 (m, 1H), 7.78 (br· s,1H),7·60-7·41 (m,2H),4.07 (br·, 1H),3·84 (br· s,2H),3·53-2·93 (m,8H), 2·78 (s, 3H), 2.11 (m, 1H), 0.97 (d, 6H); [ES+MS] m/z 563 (MH)+. Example 79: Ν'·(5_Bromo-2-cyano-4-pyrimidinyl)-5-[(4-methyl hexahydropyranyl)methyl]-Ν'-(2-amidinopropyl) Base)-1-benzopyrene

147 200804352 在中間物48 (76毫克)於4毫升無水ACN之溶液中加入DIPEA (Fluka，43微升，0.246毫莫耳）及曱基六氫吡 4(ALDRICH，22微升）。將反應混合物攪拌5小時並在減壓下將溶劑蒸發。將粗產物經由製備級HPLC (X-TERRA 19x150 毫米，ACN:H20, 0.1% TFA，梯度 25_100%)純化後得到標題化合物。1HNMR(DMSO)3Ppm: 8.6 (s，1Η)，7·8 (s， 2Η)，7.7 (d，8·6 Ηζ，1Η)，7.5 (d，8·6 Ηζ，1Η)，4·6·2·9 (m， 12Η)，2·78 (s，3Η)，2.2-2 (m，6.6 Ηζ，1Η)，〇·96 (d，6.6 Ηζ， 6H); ES+MS m/z 526 (ΜΗ)+。實例80:1^’-(5-溴一2-氰基_4』密咬基)-5-[(4_曱基-1-六氫吼口井基）甲基]-Ν’-(2-曱基丙基)-2-嗔吩卡巴肼三氟酷酸鹽147 200804352 DIPEA (Fluka, 43 μl, 0.246 mmol) and mercaptohexahydropyrimidine 4 (ALDRICH, 22 μL) were added to a solution of Intermediate 48 (76 mg) in 4 mL of dry ACN. The reaction mixture was stirred for 5 hours and the solvent was evaporated under reduced pressure. The crude product was purified by preparative EtOAc EtOAc (EtOAc:EtOAc: 1H NMR (DMSO) 3Ppm: 8.6 (s, 1Η), 7·8 (s, 2Η), 7.7 (d, 8·6 Ηζ, 1Η), 7.5 (d, 8·6 Ηζ, 1Η), 4·6· 2·9 (m, 12Η), 2·78 (s, 3Η), 2.2-2 (m, 6.6 Ηζ, 1Η), 〇·96 (d, 6.6 Ηζ, 6H); ES+MS m/z 526 ( ΜΗ)+. Example 80: 1^'-(5-bromo-2-cyano-4"-butyl)-5-[(4-mercapto-1-hexahydropurine)methyl]-Ν'-( 2-mercaptopropyl)-2-nonylcarbazone trifluorocurate

在中間物51 (100毫克，〇·23毫莫耳)於6毫升無水ACN 之溶液中加入61微升（0·350毫莫耳）的DIPEA及31微升的 Ν-曱基六氫吡畊。將反應混合物攪拌4小時並在減壓下將溶劑蒸發。將粗產物經由製備級HPLC (X-TERRA 19x150 毫米，ACN:H2O,0.1%TFA，梯度UMoo%)純化後得到標題化合物。iH NMR (CDC13)5 ppm: 9.38(s，1H)，8.43 (s，1H)， 7·56 (d，3·81 Hz，1H)，7 (d，3·81 Hz，1H)，3·94 (s，2H)， 3·88-3·66 (m，2H)，3.45-3 (m，4H)，2·82 (s，3H)，2·45-2·1 (m， 148 200804352 4H)，2·07 (m，6·6 Hz，1H) 0 qq n < z：，叫，υ·99 (d，6·6 Hz，6H); ES+MS m/z 492 (MH)+ 〇比較實例 81 : 梟；a j + 1 /吴A鼠基_4-噹啶基）-N，-(2,2-二甲基丙基)-4-[(4-曱基]_六氫吼0井基）甲基]苯甲酿月井三說醋酸鹽Add 61 μl (0·350 mmol) of DIPEA and 31 μl of Ν-mercaptohexahydropyridinium to a solution of intermediate 51 (100 mg, 〇 23 mmol) in 6 mL of anhydrous ACN. . The reaction mixture was stirred for 4 hours and the solvent was evaporated under reduced pressure. The crude product was purified by preparative HPLC (EtOAc-EtOAc (EtOAc) iH NMR (CDC13) 5 ppm: 9.38 (s, 1H), 8.43 (s, 1H), 7·56 (d, 3·81 Hz, 1H), 7 (d, 3·81 Hz, 1H), 3· 94 (s, 2H), 3·88-3·66 (m, 2H), 3.45-3 (m, 4H), 2·82 (s, 3H), 2·45-2·1 (m, 148 200804352 4H),2·07 (m,6·6 Hz,1H) 0 qq n < z: ,叫,υ·99 (d,6·6 Hz,6H); ES+MS m/z 492 (MH) + 〇Comparative Example 81: 枭; aj + 1 / wu A murine _4- dinyl)-N,-(2,2-dimethylpropyl)-4-[(4-indolyl)_6 Hydroquinone 0 well base) methyl] benzoate brewed moon well three said acetate

將中間物2 (1克，4.3亳莫耳）溶解在亞硫醯氯毫升將反應混合物在室溫_17小時。在真空將溶劑蒸發並將醯基氯不再進一步純化而使用。在中間物55 (200毫克，〇·70毫莫耳）於吡啶（1毫升）及 DIPEA (5笔升）之攪拌溶液中加入碳酸鉀（193毫克，14〇毫莫耳)及先前得到的醯基氣(443毫克，1.75毫莫耳）並將所得的反應混合物在室溫攪拌17小時。在真空將溶劑蒸發並將粗反應混合物經由快速層析法(矽膠，二氯甲烷：甲醇）純化。將固體經由HPLC (0.1% TFA，H20:ACN)純化後得到標題化合物。lH NMR (300 MHz, DMSO)3 ppm·· 11.33 (s， 1H)，8.64 (s，1H)，7·91 (d，2H)，7·49 (d，2H)，3·72 (s，2H)， 3·37 (m，2H)，3·25-2·81 (br，6H)，2.78 (s，3H)，0.99 (s，9H); [ES+MS] m/z 500 (MH)+。比較實例82 : N，-(5-溴-2-氰基-4-嘧啶基)-N，-異丁基苯曱酿胼 149 200804352Intermediate 2 (1 g, 4.3 Torr) was dissolved in sulphur chlorochloride. The reaction mixture was allowed to stand at room temperature for -17 hours. The solvent was evaporated in vacuo and the hydrazino chloride was used without further purification. Add potassium carbonate (193 mg, 14 mmol) to the stirred solution of intermediate 55 (200 mg, 〇 70 mmol) in pyridine (1 mL) and DIPEA (5 liters) and previously obtained hydrazine Base gas (443 mg, 1.75 mmol) and the resulting mixture was stirred at room temperature for 17 h. The solvent was evaporated in vacuo and the crude reaction mixture was purified eluting with flash chromatography eluting The solid was purified by EtOAc (EtOAc:EtOAc) lH NMR (300 MHz, DMSO) 3 ppm·· 11.33 (s, 1H), 8.64 (s, 1H), 7·91 (d, 2H), 7·49 (d, 2H), 3·72 (s, 2H), 3·37 (m, 2H), 3·25-2·81 (br, 6H), 2.78 (s, 3H), 0.99 (s, 9H); [ES+MS] m/z 500 (MH )+. Comparative Example 82: N,-(5-bromo-2-cyano-4-pyrimidinyl)-N,-isobutylbenzene 曱 149 200804352

標題化合物是經由類似於實例1說明之方法製備，用笨曱醯氣替代中間物2之醯基氯。1H NMR (300 MHz， CDC13)3 ppm: 8.47 (s，1H)，8.18 (s，1H)，7·85-7·80 (m，2H)， 7.67-7.42 (m，3H)，3·90-3·70 (m，2H)，2·20-2·00 (m，1H)， 1·〇3 (d，J=6.6 Hz，6H); [ES+MS] m/z 374 (M)+。生物測試法本發明化合物可以在其中一種生物測試法中測試，用以測定具有特定藥理效應所需的化合物濃度。 1_)測疋錄形木瓜蛋自酶j_、錄形木瓜是·鱼酶、維瓦木瓜蛋 •自酶_2 (vivgpain_2)、組座.蛋电^酶K、Ju歲蛋白酶S、組織蛋白酶L及組織蛋白酶B蛋白水解攀立丄舌性錄形木瓜蛋白酶-2、錄形木瓜蛋白§每j及維瓦木瓜蛋白酶-2之測試法是用寄生的再重組酶進行。組織蛋白酶K、s、 L·及B是用人類的再重組酶進行。用於測定動力學常數之標準測試法條件使用螢光系肽作用物，通常是 H-D-VLR-AFC (鐮形木瓜蛋白酶-2、鐮形木瓜蛋白酶_3、維瓦木瓜蛋白酶-2)、Z_FR-AFC (組織蛋白峰κ l B)或 KQKLR-AMC (組織蛋白酶S)且在100毫莫耳濃度醋酸納， pH 5.5，含10毫莫耳濃度DTT及0.5毫莫耳濃度CHAPS (鐮形木瓜蛋白酶-2、鐮形木瓜蛋白酶-3、維瓦木瓜蛋白酶_2)， 150 200804352 及100耄莫耳濃度醋酸鈉，ρΗ 5·5，含5毫莫耳濃度L_半胱胺酸、1毫莫耳濃度CHAPS及5毫莫耳濃度EDTA (組織蛋白酶K、L·、B)，或50毫莫耳濃度MES，pH 6.5，含0.5 笔莫耳濃度CHAPS、10毫莫耳濃度l-CYS、5毫莫耳濃度 EDTA (組織蛋白酶s)中測定。儲備作用物溶液是在dms〇中在20耄莫耳濃度製備。活性測試法含30微莫耳濃度作用物(鐮形木瓜蛋白酶-2、鐮形木瓜蛋白酶_3、維瓦木瓜蛋白酶-2)、20微莫耳濃度作用物（組織蛋白酶κ)、25微莫耳濃度作用物（組織蛋白酶B)、5微莫耳濃度作用物（組織蛋白酶L)及30微莫耳濃度作用物（組織蛋白酶s)。全部測試法含1% DMSO。獨立的實驗發現此含量的DMS〇對酶活性或動力學常數沒有效應。全部測試法是在環境溫度進行，終點測試法除了組織蛋白酶S是在90分鐘以外，都是在 60分鐘用在1%DMS0中的16.6微莫耳濃度E-64淬滅。產物形成(AFC或AMC)是從螢光測定(AFFC是在405毫微米激發，在530毫微米放射；或AMC是在360毫微米激發，在 460 毫微米放射）並用 LJL Aquest (Molecular Devices)螢光板讀取機監視。在動力學讀取之情形中（在行動研究之機制中使用），反應沒有淬滅而是在板讀取機每3分鐘讀取經 90分鐘。此外，對於鐮形木瓜蛋白酶_2的行動研究之機制使用Z-LR-AMC作為作用物。產物形成是從AMC之螢光測定，用LJL Aquest (Molecular Devices)螢光板讀取機測量 (在360毫微米激發，在460毫微米放射）。抑制作用研究 151 200804352 滅讀取(終點）法評估有價值的抑制劑。測試法式在不同m化合物存在下進行。經由_及作用物添加至含有在i 00% DMS〇中搗碎的抑跑，加入E64將反物使用預先叹疋的套人工具漿劑量回應數據套人心曲線： y = a + (b_a)/(l + (l〇x/l〇c)d) ⑴ 是在特定抑糊濃度x之回應，a是最小回應值，b 疋取大回應值，e是IQg，且曲線之斜率。假設化合物是競爭性抑制，視Κι可以從心計算如^ 所示： ’ icso - appKt (J+[S]/KM) (2) 其中-^是視Kl，S是作用物濃度，&是對於作用物之 Michaehs黏著常數，且&是競爭性抑制劑對於自由態酶的黏著常數。對於Kl及黏著機制之更直接測量，我們進行行動研究之機制，其包括使用動力學讀取之作用物與抑制劑々滴疋。如果各這些動力學測試法之進展曲線是直線，將測量速率(v)套入公式3 : V = ν^/^ΚΜ(1+[υ/Κι) + [3](1+[ϊ]/αΚι)] (3) /、中m疋隶大速率，§疋具有尺从的Michaelis常數之作用，濃度，股抑制劑濃度，^抑制劑對於自由態酶的黏著常數，且是抑制騎於㈣值__仙物複合物的黏著常數。對於進展曲線不是直線的化合物，時間相關性抑制作用特徵是劑活性隨時間下降，進展曲線套人公式4而得到 152 200804352The title compound was prepared via a procedure similar to that described in Example 1, substituting a sulphur gas for the thiol chloride of Intermediate 2. 1H NMR (300 MHz, CDC13) 3 ppm: 8.47 (s, 1H), 8.18 (s, 1H), 7.85-7.80 (m, 2H), 7.67-7.42 (m, 3H), 3.90 -3·70 (m, 2H), 2·20-2·00 (m, 1H), 1·〇3 (d, J=6.6 Hz, 6H); [ES+MS] m/z 374 (M) +. Biological Test Methods The compounds of the invention can be tested in one of the biological assays to determine the concentration of a compound required for a particular pharmacological effect. 1_) 疋疋木木木木木木木木木木木木木木木木木木木木木录木录录录鱼鱼鱼鱼鱼鱼鱼鱼鱼鱼鱼鱼鱼鱼鱼鱼鱼鱼鱼鱼鱼鱼鱼鱼鱼鱼鱼鱼And cathepsin B proteolysis climbing the tongue-shaped papain-2, recorded papaya protein § per j and Viva papain-2 test method is carried out with parasitic recombinase. Cathepsins K, s, L. and B are carried out using human recombinase. Standard test conditions for the determination of kinetic constants use fluorochrome peptides, usually HD-VLR-AFC (镰 papain-2, 镰 papain-3, Viva papain-2), Z_FR -AFC (tissue protein peak κ l B) or KQKLR-AMC (cathepsin S) and sodium acetate at 100 mM, pH 5.5, DTT at 10 mM and CHAPS at 0.5 mM (Papaya papaya) Protease-2, 镰 papain-3, Viva papain_2), 150 200804352 and 100 耄 molar concentration of sodium acetate, ρΗ 5·5, containing 5 millimolar concentration L_cysteine, 1 mM Molar concentration CHAPS and 5 millimolar concentration EDTA (Cathepsin K, L·, B), or 50 millimolar concentration MES, pH 6.5, containing 0.5 molar concentration CHAPS, 10 millimolar concentration l-CYS, Determined in 5 mM concentration of EDTA (Cathepsin s). The stock solution solution was prepared in dms〇 at a concentration of 20 Torr. The activity test method contains 30 micromolar concentration of the substrate (镰 papain-2, 镰 papain-3, Viva papain-2), 20 micromolar concentration (Cathepsin κ), 25 micromolar Ear concentration substrate (Cathepsin B), 5 micromolar concentration substrate (Cathepsin L) and 30 micromolar concentration substrate (Cathepsin s). All tests contained 1% DMSO. Independent experiments have found that this amount of DMS has no effect on enzyme activity or kinetic constant. All tests were performed at ambient temperature and the endpoint test was quenched with 16.6 micromolar E-64 in 1% DMS0 for 60 minutes except for cathepsin S. Product formation (AFC or AMC) is determined by fluorescence (AFFC is excited at 405 nm, emitted at 530 nm; or AMC is excited at 360 nm, at 460 nm) and LJL Aquest (Molecular Devices) Light board reader monitoring. In the case of kinetic reading (used in the mechanism of the action study), the reaction was not quenched but was read every 30 minutes on a plate reader for 90 minutes. Furthermore, the mechanism of action research for scorpion papain-2 uses Z-LR-AMC as a substrate. Product formation was measured by fluorescence from AMC, measured with a LJL Aquest (Molecular Devices) plate reader (excitation at 360 nm, at 460 nm). Inhibition studies 151 200804352 The off-read (end point) method evaluates valuable inhibitors. The test method was carried out in the presence of different m compounds. Add the _ and the substrate to the smash containing the smash in the i 00% DMS ,, and add the E64 to use the pre-sighing set of tool tool slurry dose response data set curve: y = a + (b_a) / ( l + (l〇x/l〇c)d) (1) is the response at a specific paste concentration x, a is the minimum response value, b is the large response value, e is IQg, and the slope of the curve. Assuming that the compound is competitively inhibited, Κι can be calculated from the heart as shown by ^: ' icso - appKt (J+[S]/KM) (2) where -^ is the apparent Kl, S is the concentration of the agent, & The Michaehs adhesion constant of the substrate, and & is the adhesion constant of the competitive inhibitor to the free state enzyme. For a more direct measurement of Kl and adhesion mechanisms, we performed a mechanism for action studies involving the use of kinetic reads of the substrate and the inhibitor sputum. If the progression curve for each of these kinetic tests is a straight line, factor the measurement rate (v) into Equation 3: V = ν^/^ΚΜ(1+[υ/Κι) + [3](1+[ϊ]/ αΚι)] (3) /, medium m疋 ligature rate, § 疋 has the effect of the Michaelis constant of the ruler, concentration, concentration of the inhibitor, ^ inhibitor of the adhesion constant for the free state enzyme, and is inhibited from riding (4) Value __ The adhesion constant of the fairy compound. For a compound whose progression curve is not a straight line, the time-dependent inhibition is characterized by a decrease in activity of the agent over time, and a curve of progress is given by Equation 4 to obtain 152 200804352

Kobs # [AMC] = vst + (v〇- vss) [1 - exp (-kobst)]/kobs (4) 其中[AMC]是隨時間t形成的產物濃度，最初反應速率且〜是最終穩定狀態速率。值套入公式5及6,分別描述單步驟及雙步驟時間相關的黏著機制： k〇bs ^ + [1]/αρρΚι) (5) k〇bs = Kff + Kn ([1](/αρρΚι + [l]) (6) appKt = ^(1+ [S]/KM) (7) 公式7說明競爭性化合物之視K!且取代至公式5及6 而從套入常規產生相關的黏著常數。此外，最初及最終速率套入公式3而進一步定義黏著機制及效應。此動力學處理之完整討論經充分說明（Morrison以a/.，ddv.Kobs # [AMC] = vst + (v〇- vss) [1 - exp (-kobst)]/kobs (4) where [AMC] is the product concentration formed over time t, the initial reaction rate and ~ is the final steady state rate. The values are embedded in Equations 5 and 6, which describe the single-step and two-step time-dependent adhesion mechanisms: k〇bs ^ + [1]/αρρΚι) (5) k〇bs = Kff + Kn ([1](/αρρΚι + [l]) (6) appKt = ^(1+ [S]/KM) (7) Equation 7 illustrates the apparent K of the competing compound and is substituted for Equations 5 and 6 to produce a correlation with the adhesion constant. In addition, the initial and final rates are embedded in Equation 3 to further define the adhesion mechanism and effects. The full discussion of this kinetic treatment is fully explained (Morrison is a/., ddv.

Relat· Areas Mol· Biol·，19SH，61，2QV)。 2)測定對於惡性瘧原蟲寄生蟲之全細胞活性根據 Sijwali S. and Rosenthal P. J·，（2004) Proceedings uf the National Academy of Sciences of the United States of America (PNAS) 101(13)，4384-4389 (見特別是 4385 頁之 “Measurement of Parasite Growth rates and Inhibitor Sensitivity”)揭示的方法，可以評估化合物對抗惡性瘧原蟲寄生蟲之全細胞活性；IC5G值可以根據Singh A. and Rosenthal P. J.5 (2001) Antimicrobial Agents and Chemotherapy 45(3)，949-951 (見特別是 950 頁，第 1 行）之揭示計算；同步的寄生蟲可以根據DivoA.A.etal.，（1985) Protozool· 32, 59-64 之揭示製備。】53 200804352 3)試管内模式評估對抗骨皙轉移之活性使用下面公告的試管内模式，可以評估化合物對抗骨質轉移之活性：大鼠中***癌骨質轉移模式(Liepe K. et al·，（2005) Anticancer Research 25(2A)，1067-1073 及 Neudert M. et al.? (2003) International Journal of Cancer 107(3)，468-477);小鼠中***及乳癌轉移至骨之模式 (Angelucci A. et al.? (2004) International Journal of Oncology 25(6)，1713-1720 及 Sasaki A· et al·，（1995) Cancer Research 55(16)，3551-3557);及在不同物種中用於評估骨質轉移的其他模式(R〇s〇l Τ. λ et al.，（2003) Cancer. 97， 748-757) 〇 3)比較劑化合物使用兩種化合物作為比較劑化合物。比較實例81，其係一種三氟酷酸鹽，及比較實例82其係自由態鹼，是根據上述製備。各這些化合物之自由態鹼是揭示在w〇 2005/103010 A1 (分別是124頁，實例15(2)及130頁，實例 17(4)) 〇比較實例81 ·· N，-(5-溴-2-氰基-4-嘧啶基)-N，-(2,2-二曱基丙基曱基]_六氫吡畊基）甲基]苯曱醯胼三氟醋酸鹽比較貫例82 : 溴-2-氰基-4-嘧啶基）-N，-異丁基苯曱醯胼從事此藝者將可理解在上述酶測試法條件下，對於特定化合物的自由態鹼所得的測試結果預期是與測試該化合物之鹽所得的結果相同。這是因為在測試法中使用的緩衝 154 200804352 液決定化合物測試時的pH，而pH決定自由態鹼與化合物的鹽測試時的相對量。/此可經由本文舉例的一些化合物之自由悲鹼、鹽酸鹽及三氟醋酸鹽之酶測試法之測試證實。測試之結果、Relat· Areas Mol· Biol·, 19SH, 61, 2QV). 2) Determination of whole cell activity against Plasmodium falciparum parasites according to Sijwali S. and Rosenthal P. J., (2004) Proceedings uf the National Academy of Sciences of the United States of America (PNAS) 101 (13), 4384 -4389 (See, in particular, "Measurement of Parasite Growth rates and Inhibitor Sensitivity" on page 4385) to assess the full-cell activity of compounds against Plasmodium falciparum parasites; IC5G values can be based on Singh A. and Rosenthal PJ5 (2001) Antimicrobial Agents and Chemotherapy 45(3), 949-951 (see especially 950 pages, line 1) revealing calculations; synchronized parasites can be based on DivoA.A. et al., (1985) Protozool 32, Preparation of the disclosure of 59-64. 】 53 200804352 3) In-tube model evaluation of activity against osteophyte metastasis The activity of compounds against bone metastases can be assessed using the in-vitro model published below: Lipope K. et al., 2005 Anticancer Research 25 (2A), 1067-1073 and Neudert M. et al. (2003) International Journal of Cancer 107 (3), 468-477); Patterns of metastasis of prostate and breast cancer to bone in mice (Angelucci A Et al.? (2004) International Journal of Oncology 25(6), 1713-1720 and Sasaki A· et al., (1995) Cancer Research 55(16), 3551-3557); and used in different species Other modes of assessing bone metastasis (R〇s〇l Τ. λ et al., (2003) Cancer. 97, 748-757) 〇 3) Comparative Compounds Two compounds were used as comparator compounds. Comparative Example 81, which is a trifluorocurate, and Comparative Example 82, which is a free base, was prepared as described above. The free base of each of these compounds is disclosed in w〇2005/103010 A1 (124 pages, Examples 15(2) and 130, Example 17(4), respectively) 〇Comparative Example 81 ··N,-(5-bromo 2-cyano-4-pyrimidinyl)-N,-(2,2-dimercaptopropylindenyl)-hexahydropyrrole)methyl]phenylhydrazine trifluoroacetate : bromo-2-cyano-4-pyrimidinyl)-N,-isobutyl benzoquinone. Those skilled in the art will understand the test results obtained for the free base of a particular compound under the conditions of the above enzyme test method. It is expected to be the same as the result obtained by testing the salt of the compound. This is because the buffer 154 200804352 used in the test determines the pH of the compound test, and the pH determines the relative amount of the free base and the salt test of the compound. / This can be confirmed by testing of the enzyme test of the free sorrow, hydrochloride and trifluoroacetate salts of some of the compounds exemplified herein. Test results,

組織蛋白酶K 實例 1-32、35-54、57_73、7%77、乃及 8〇是在白酶K的酶測試法中測試。實例33、从、55、％、％及 78沒有在此測試法中測試。在組織蛋白_κ的酶測試法中測试的貫例發現ICS()值小於11毫微莫耳濃度。鐮里本.瓜蛋^酶-3酶測詖全及令鈿胞測試法 '~^ 根據上述方法在鐮形木瓜蛋白酶_2及鐮形木瓜蛋 -3的酶賴法及全細胞賴法巾測試全部舉例的化合 (實例1-80及比較實例81及82)。全部舉例的本發明化合物（實例1-80)及比較實例81 W之鐮形木瓜蛋白酶_2及鐮形木瓜蛋白酶_3的 /、全細胞測試法之結果列在下表。忒法及表；鐮形木瓜蛋自g帛_2及細彡木錢自酶_3 全細胞測試法活性 · ^ Μ法及 155 200804352 爾、實例編—M 鐮形木瓜鐮形木瓜蛋白S§-3 全細胞蛋白酶-2 ° V 3 •kitirk ★ ★★ ^ i/〇〔:〕，札 ^Oy^nXXcn 0 V . 4 i(夤★★ *★★★ N^VNl^ Ns十： 5 -cccv?x 0 V 6 ★ ★★★ ★ ★貪★ ^xocM 十: 0 Ϋ 7 ★★***★* ★ ★禽俞 8 ★★★★*** ★ ★★Hr ★ ★禽貪 V 〇Ί f ο 〇 k/ F~Kh 丫 9 ★★★★★ 权° y 10 ****侖 irk-kit ★ ★女禽 156 200804352 爾、實㈣編號 _果1 要白酶-2 嫌形木瓜蛋白酶-3 i細胞 άΊ Ρ1Λη 丫 11 **★★*★★ (。士。。υ F OH 12 ★★★★ ςΓ〇γ〇αΝ F OH 13 *★*禽 ^〇y%XXn 〇k 0 V "X山0 F OH 14 ★★★★★★ Γ〇η〇ν：ίΧ 、〜〇、H 〇 V" Ffi 15 ★★禽貪★★禽禽禽★★ ΟΑΟΧ 4/。Y . F OH 16 ★禽 r\ F+<〇 (Λ，f oh 〇 V 17 ★★★★ 157 200804352 I 結構實例編蜣 1鐮形木瓜蛋白酶·2 *鐮形木瓜蛋白酶-3 全細皰 0 V 18 ★★★★ Q f-H〇h 〇 ϋ 19 ★ ★★★ f"H° 人乂 f 〇h ° V 20 人又 XTtV:XXN f-H° 〇 Y F OH 21 iciricic 22 V O 一 crt^OX F-H° ° V F OH 23 iciciric 0一〇nXvXicn f-h° ° v F OH 24 ★★★★★★ ieicitic 二一cncvXk 山。〇 V F OH 25 •kirkic 158 結構、實例編號 1鐮形木瓜蛋白酶·2 i鐮形木瓜蛋白酶·3 1 > 全細瓸二一otvS^ 4/ 0 Υ f OH 26 ***★★★* ★★★★★ 、οχττν：ιχ 山。。Y F 〇H 27 α〇Ά〇αΝ 士。。Sr F OH 28 *★★***★ 9NH \〇一 V 29 ★★★★★★* icick'k —0ΝΧνΧ^ ^ 0 v F OH 30 feic'k'k'k \/ / A 〔:〕F ^"Ο^^νΧΛον 0 Ϋ 31 **★* *★*侖 *t V X认H 〔N〕f ^OyCd 0 V 32 itickiciricir iticirk 159 200804352 結構' '實例編號 '嫌形木瓜蛋白酶-2 .1鐮形木瓜蛋白酶-3 L 全細皰 0 V 33 ★★★★★★★ ★★★★ ★ ★★★ CxN〇 7； ν F-Kh 34 〇 f_Kh 35 ****★★★ irkitic ★ ★★★ 十:。Ϋ 36 ★★★***★ τ-〇χν:ϊχΝ 士。。Υ F OH 37 hXTOvOCL 屮： 0 Ϋ 38 Ό^ΧΧγ-'ΧΚ, Ρ_μ° S 0 k/ F OH Η 1 39 icirk-k *★★食 L0.h l y F OH 40 •k'k'kidc'k'k -kiticic icif 食* 160 200804352 結· 1實例編號 '嫌形木Λ' W~^W:2 ^鐮形木瓜蛋白酶-3 「全細皰1 41 irkit'kit'kit irkicic QyQ °iF 八 Nk〇vCaN 0 Ϋ 42 ic'kic'k'k'k-k ★★★★ 〜 ^ 丫、 F □n^〇Yn'nl n^cn °yVf 〇 ohf 43 ★★★★★★★ ★★★★ HO F ^^ΎΝ、Ν 工N 夂 CN 〇 V 44 **★*★★★ ★ 禽 rNdVcX义CN 认H U Ϊ y f 45 it'k'kirk'kic *★★★ f^ioh ο F 46 V 6j〇nH a 〇 F 47 irkicik'k'kie •kicicie 。一 OjO1子Ά 48 'k'kirk F^r0 49 ★ ★★★ 161 200804352 結構' 實例編號鐮形木瓜要白酶-2 /鐮形木瓜蛋白酶-3 全結胞 50 iticieit ί^Ν^Ί^Ίι αγ^Ν 〇rN」4乂人★ 51 irir-kic 〇〜Ο^Ογ%石人 N 52 **** 、〜GnXl^XXn Ρρχ 1 0 Ϋ T 〇 53 ★*★*★★* ieie-kic OXX^Uh 0 V F 54 iticic-k °ΰΌ 為 0 V F 55 ★★★**** *★** 'OACiX，人 0 Ϋ F 56 *★★禽禽禽*★* ***禽 Jli ^x〇v:x义⑶，人 ° y F 57 ★★★★*** irkitic V 〇一〇jVXicn,A 。V, F 58 kicicific ★★貪★ 0O 為 Uh 0 Ϋ F 59 ★*★★*★* ★★★★★ **★禽 162 200804352 結構、實例福說鐮形木瓜蛋白酶—-2 .鐮形木瓜蛋白酶-3 I ...j ϋ田皰i 〇hO^J\：Xxch ρΛ 0 V F 60 ★ ★★irk /χ 〇 OnJ〇yN.nXXcn 0 Ϋ F 61 ★ ★★★★ Oj〇Y%^^CN 〖々Η 62 ★**★*★★ icicirkir 禽〇O^Oj〇V：Xxcn ρΛη 63 ***** irkieit 0 Ϋ F 64 ★★★***★ frkicicic ★★★★ xro為Od人 0 V F 65 ***★★*貪禽 icicitic 0uv：n 入 0 Ϋ F 66 feie-kicic'k'k *★★★★ ★ ★★★ °O：XVU- 〇 V F 67 ickirk itic-kie 0 V 68 'k'kieirk'kic iciQirk ★ ★★* 163 200804352 贪例編號：鐮形木瓜蛋白酶-2 鐮形木瓜蛋白酶-3 O F 0H 69 ★禽 frkicic wCN f-h° & 1γ F 〇H 70 irkic-k rNOTV:IX f。乂j S y T 71 ★★★★★ 〇 y f 72 icicirk -O 0 v 1 73 ★*** 、〇^yf。歹 74 貪★*** 0 BrV^N \yy"Nv’'々 75 fcitieicirk'k V 0 BrV^N - N 人N 人 CN 〇 ^OJXN V -Y 76 ★★***★★ it-kirk .OXl^：XlCN H〇x,; 77 貪★禽★★女斤CN 々 78 ★*★★**★ 164 200804352 實例編號鐮形木瓜蛋舀S|: 2 鐮形木瓜蛋白酶-3 % 全細ιέ 〇 V 79 ^k'k'k'kick'k ★★★★ Ο 乂)yN、NXXCN H々F 0 V 80 idcirk JTXVXL V F OH ' comparative 81 •kicic ★ 〇yn、nXXn ^ V comparative 82 ★★★★★★★ -kit-kit ★ 表之註解 X =在毫微莫耳濃度之IC50 氺氺氺氺氺氺氺 sLf ^1¾ rf· ^J· 氺氺氺* 氺氺氺氺氺 X < 1 1 <X<2.5 2·5<Χ<15 15<Χ<150 150<Χ<250 250<Χ<400 X> 400 * 與先前技藝之比較實例81及82比較，舉例的本發明化合物在全細胞測試法中顯現改良的活性。 165Examples of cathepsin K 1-32, 35-54, 57_73, 7% 77, and 8 〇 were tested in the enzyme assay of white enzyme K. Example 33, slaves, 55, %, %, and 78 were not tested in this test. The example tested in the enzyme protein test for tissue protein_kappa found that the ICS() value was less than 11 nanomolar.镰里本. 瓜蛋^酶-3 enzyme assay 詖及 and 钿 cell test method '~^ According to the above method in the scorpion papain _2 and scorpion papaya egg-3 enzyme Lai method and whole cell Lai towel All exemplified combinations were tested (Example 1-80 and Comparative Examples 81 and 82). The results of the whole-cell test methods of the compounds of the present invention (Example 1-80) and the comparative examples 81 W of the scorpion papain-2 and the scorpion papain _3 are shown in the following table.忒 method and table; 镰 papaya egg from g帛_2 and fine eucalyptus money from enzyme _3 whole cell test method activity · ^ Μ method and 155 200804352 er, example edit - M 镰 papaya 镰 papaya protein S§ -3 Whole cell protease-2 ° V 3 •kitirk ★ ★★ ^ i/〇[:], Zha ^Oy^nXXcn 0 V . 4 i(夤★★ *★★★ N^VNl^ Ns 10: 5 - Cccv?x 0 V 6 ★ ★★★ ★ ★ Greedy ★ ^xocM Ten: 0 Ϋ 7 ★★***★* ★ ★ 禽俞8 ★★★★*** ★ ★★Hr ★ ★ 禽贪V 〇 Ί f ο 〇k/ F~Kh 丫9 ★★★★★ Right ° y 10 **** irk irk-kit ★ ★Female 156 200804352 er, real (four) number _ fruit 1 to white enzyme-2 suspicion papaya Protease-3 i cell άΊ Ρ1Λη 丫11 **★★*★★ (.士..υ F OH 12 ★★★★ ςΓ〇γ〇αΝ F OH 13 *★*禽^〇y%XXn 〇k 0 V "X山0 F OH 14 ★★★★★★ Γ〇η〇ν:ίΧ,~〇,H 〇V" Ffi 15 ★★禽贪★★禽禽鸟★★ ΟΑΟΧ 4/.Y . F OH 16 ★ poultry r\ F+<〇(Λ,f oh 〇V 17 ★★★★ 157 200804352 I Example of structure compilation 1 木 papain · 2 * 镰 papain-3 full blister 0 V 18 ★★★★ Q fH〇h 〇ϋ 19 ★ ★★★ f"H° 人乂f 〇h ° V 20 people and XTtV:XXN fH° 〇YF OH 21 iciricic 22 VO a crt^OX FH° ° VF OH 23 iciciric 0 〇nXvXicn fh° ° v F OH 24 ★★★★★★ ieicitic 二一cncvXk 山. 〇 VF OH 25 • Kirkic 158 Structure, Example No. 1 镰 papain · 2 i 镰 papain · 3 1 > Full 瓸瓸 otvS^ 4/ 0 Υ f OH 26 ***★★★* ★★ ★★★ , οχττν: ιχ 山.. YF 〇H 27 α〇Ά〇αΝ士. . Sr F OH 28 *★★***★ 9NH \〇一V 29 ★★★★★★* icick'k —0ΝΧνΧ^ ^ 0 v F OH 30 feic'k'k'k \/ / A 〔:〕 F ^"Ο^^νΧΛον 0 Ϋ 31 **★* *★* lun*t VX recognizes H [N]f ^OyCd 0 V 32 itickiciricir iticirk 159 200804352 Structure ' 'example number' sinensis papain-2 . 1 木 papain-3 L full blister 0 V 33 ★★★★★★★ ★★★★ ★ ★★★ CxN〇7; ν F-Kh 34 〇f_Kh 35 ****★★★ irkitic ★ ★★★ Ten:. Ϋ 36 ★★★***★ τ-〇χν: ϊχΝ士. . Υ F OH 37 hXTOvOCL 屮: 0 Ϋ 38 Ό^ΧΧγ-'ΧΚ, Ρ_μ° S 0 k/ F OH Η 1 39 icirk-k *★★食L0.hly F OH 40 •k'k'kidc'k' k -kiticic icif 食* 160 200804352 结·1example number '嫌形Λ' W~^W: 2 ^镰 papain-3 "full blister 1 41 irkit'kit'kit irkicic QyQ °iF eight Nk〇 vCaN 0 Ϋ 42 ic'kic'k'k'k-k ★★★★ ~ ^ 丫, F □n^〇Yn'nl n^cn °yVf 〇ohf 43 ★★★★★★★ ★★★★ HO F ^^ΎΝ,Ν工N 夂CN 〇V 44 **★*★★★ ★ Avian rNdVcX meaningCN HUHU Ϊ yf 45 it'k'kirk'kic *★★★ f^ioh ο F 46 V 6j 〇nH a 〇F 47 irkicik'k'kie •kicicie. One OjO1 Ά 48 'k'kirk F^r0 49 ★ ★★★ 161 200804352 Structure' Example number 镰 papaya to white enzyme-2 / 镰 papain -3 全结结50 iticieit ί^Ν^Ί^Ίι αγ^Ν 〇rN"4乂人★ 51 irir-kic 〇~Ο^Ογ% 石人N 52 **** ,~GnXl^XXn Ρρχ 1 0 Ϋ T 〇53 ★*★*★★* ieie-kic OXX^Uh 0 VF 54 iticic-k °ΰΌ is 0 VF 55 ★★★ **** *★** 'OACiX, person 0 Ϋ F 56 *★★ poultry and poultry*★* *** avian Jli ^x〇v:x meaning (3), person ° y F 57 ★★★★** * irkitic V 〇〇 jVXicn, A. V, F 58 kicicific ★★贪★ 0O is Uh 0 Ϋ F 59 ★*★★*★* ★★★★★ **★禽162 200804352 Structure, example Fu said papain-2 - 镰 papaya Protease-3 I ...j ϋ田疱i 〇hO^J\:Xxch ρΛ 0 VF 60 ★ ★★irk /χ 〇OnJ〇yN.nXXcn 0 Ϋ F 61 ★ ★★★★ Oj〇Y%^^ CN 々Η 62 ★**★*★★ icicirkir poultry O^Oj〇V:Xxcn ρΛη 63 ***** irkieit 0 Ϋ F 64 ★★★***★ frkicicic ★★★★ xro for Od 0 VF 65 ***★★*贪禽icicic 0uv:n 入0 Ϋ F 66 feie-kicic'k'k *★★★★ ★ ★★★ °O:XVU- 〇VF 67 ickirk itic-kie 0 V 68 'k'kieirk'kic iciQirk ★ ★★* 163 200804352 Greedy number: 镰 papain-2 镰 papain-3 OF 0H 69 ★ avian frkicic wCN fh° & 1γ F 〇H 70 irkic-k rNOTV :IX f.乂j S y T 71 ★★★★★ 〇 y f 72 icicirk -O 0 v 1 73 ★***, 〇^yf.歹74 Greedy ★*** 0 BrV^N \yy"Nv''々75 fcitieicirk'k V 0 BrV^N - N 人N人CN 〇^OJXN V -Y 76 ★★***★★ it-kirk .OXl^:XlCN H〇x,; 77 greedy ★ avian ★ ★ female jin CN 々78 ★*★★**★ 164 200804352 Example number 镰 papaya egg tart S|: 2 镰 papain-3 % fine έ 〇V 79 ^k'k'k'kick'k ★★★★ Ο 乂)yN, NXXCN H々F 0 V 80 idcirk JTXVXL VF OH 'comparable 81 •kicic ★ 〇yn, nXXn ^ V comparative 82 ★★ ★★★★★ -kit-kit ★ Annotation of the table X = IC50 at nanomolar concentration 氺氺氺氺氺氺氺sLf ^13⁄4 rf· ^J· 氺氺氺* 氺氺氺氺氺X < 1 1 <X<2.5 2·5<Χ<15 15<Χ<150 150<Χ<250 250<Χ<400 X> 400 *Compared with the prior art Comparative Examples 81 and 82, the exemplified compounds of the present invention were Improved activity is exhibited in the whole cell assay. 165

Claims

200804352 十、申請專利範圍·· 1·一種選自式I化合物之至少一種化學實體：200804352 X. Patent application scope · 1. A chemical entity selected from the group consisting of compounds of formula I:

其中： R4代表鹵素； R2代表 1)-苯基-Cw伸烷基-X、_吡啶基-苯基_c“伸烷基汊或_ 基-Cw伸烷基-X_R、其中苯基是視需要經一個 CF3的基取代；或 ®素或 n) _Y_ci-3伸烷基-X或-Y_Cl 3伸烷基_X_R】；，含有-個含有一至四個選自N、〇及s的雜二貝％之芳族基，該環視需要稠合至苯環，· 、、 R代表Z、_Ci-4伸烷基_z或-c(0)z ; χ及z獨立地代表： 0含有一個氮原子之單環4-員飽和烴基，· •u) ^有個氮料之單環5_貞飽和或部份飽和烴基有一或兩個氮原子及視需要-個氧原子之單環免和、部份飽和或芳族煙基；貝其令X及Z是獨立地視需要經a)—個選自烷基、C"烧基0H、Ci 4淀基〇c"貌基〇H、^ . 166 、1 ^ 200804352 烧基烷基、-qcOOCw 烷基、NRERF、-Cm 烷基 NrErF、-NC(〇)Ci-3 烷基、-NCCCOOCw 烷基及-C(0)NReRf 及b)視需要是c1-4烧基的額外基取代； #及RF獨立地代表氳或Cl_4烷基或Cl_4烯基；及其藥學上可接受的衍生物。 2·根據申請專利範圍第！項之至少一種化學實體，其中R4 代表氣、漠或峨。 3 ·根據申凊專利範圍第丨或2項之至少一種化學實體，其中R+代表-笨基-Cm伸烷基-X、-吡啶基-苯基-Ci 3伸烷基或苯基-Cu伸烧基_x_R'其中苯基是視需要經一個選自鹵素或CF3的基取代。 •根據申明專利範圍第丨或2項之至少一種學實 w代表·υ々3#^μ·υ々3狀基體…、 =申1專利範圍第12或4項中任一項之至少一種化 r奸姑由’、中¥代表吱喃、°塞吩、異十坐或苯並吱喃。 6·根據申請專利範圍第1至5頊中膏髀甘士+ 2 主）員中任一項之至少一種化學貫體’其中在R中的伸絲是亞甲美。 »Γ1! t f?^ ，/、中R代表-Cl-3伸烧基-Z。 8·根據申請專利範圍第丨至7項實體，其中χ；?7想、員之至父一種化學要含有 ^- 代表含有一或兩個氮原子且視需要各有一個氧原子之視需要經視而 9·至少一種化學實體，其係選飽和或芳族烴基。戈之早％ 6-貝飽和、部份 167 200804352 N’-(5-溴-2-氰基-4-嘧啶基)-4-[(4-曱基-1-六氫吡畊基）甲基]-N’-(2-曱基丙基）苯曱醯胼； N’- (5->臭-2 -鼠基-4-口密ϋ定基）·Ν’-(2 -曱基丙基）-4-[(4 -丙基-1_ 六氫吡畊基）曱基]苯曱醯胼； Ν’- (5->臭-2 -氣基_4_0密ϋ定基）-N’-(2 -曱基丙基）-3-[(4 -丙基-1-六氫吡畊基）曱基]苯曱醯胼； 1^’-(5-氣-2-氣基_4-,咬基）-]^’-(2-曱基丙基)-4-[(4-丙基-1-六氫吡畊基）曱基]苯曱醯胼； N’-(5^*鼠-2-氣基-4-口密ΐ7定基)-N’-(2-甲基丙基)-3-[(4-丙基-l-六氫吡畊基）甲基]苯曱醯胼； ^!’-(5-〉臭-2-氣基-4-口密咬基）-4-氣-1^’-(2-曱基丙基）-3-[(4-丙基-1-六氫吡畊基）曱基]苯曱醯胼； Ν’-(5-氯-2-氰基-4-嘧啶基)-4-氟-Ν’-(2-曱基丙基)-3-[(4-丙基-1-六氫吡畊基）曱基]苯曱醯胼； 4-( 1，4’-聯六鼠口比咬-1 ’-基曱基）-Ν’- (5·氣-2·氣基-4-口密°定基)-Ν’-(2-曱基丙基）苯曱醯胼； Ν’-(5-溴-2-氰基-4-嘧啶基)-Ν’-(2-曱基丙基)-4-(1-六氫吡啶基甲基）苯甲醯胼； N’-(5-溴-2-氰基-4-嘧啶基）-N’-(2-曱基丙基)-4-(1-吡咯啶基曱基）苯甲醯胼； N’-(5-氣-2-氣基-4-口密ϋ定基）-4-[(2,6-二曱基-1-六氮吼口定基）曱基卜Ν’-(2-曱基丙基）苯曱醯胼； 1-[(4_{[2-(5-氣-2-氣基-4-0密^定基)-2-(2-曱基丙基)月井基]幾基} 苯基）曱基]-4-六氫吡啶羧酸乙酯； 168 200804352 N-{(3R)小[(4-{[2·(5-氣-2·氰基-4-嘧啶基）_2_(2-甲基丙基）胼基]羰基}苯基）曱基]-3-吡咯啶基}乙醯胺； {1-[(4-{[2-(5-氯-2-氰基-4-嘴咬基)_2-(2-甲基丙基)胼基]幾基}苯基）曱基]-3-吡咯啶基}胺基曱酸1，1_二甲基乙酯；氣-2-氰基-4』密咬基)-4-[(4_{2-[(2-經基乙基）氧基]乙基六氫吡畊基）甲基]-N’-(2-曱基丙基）苯曱醯胼； N’_(5·氣-2-氰基密咬基)-N’-(2_曱基丙基)-4-(1-六氫吼^定基甲基）苯甲醯肼； N’-(5-氣-2-氰基-4-嘧啶基）-4_{[(2R)-2-(羥基曱基)小吡略啶基]曱基}-N’-(2-曱基丙基）苯曱醯胼；氰基-4-嘧啶基)-N，-(2-曱基丙基)-4-(1-吡咯咬基甲基）苯曱醯胼； ^-(5-氣-2_氰基-4-嘴咬基)-4-(2,5-二氫-111-吼略_1-基曱基)-N’-(2-甲基丙基）苯甲醯胼；氰基-4-嘧啶基)_4-[(2,5-二曱基-2,5-二氫-1H-吡咯_1_基）曱基]-N，-(2_曱基丙基）苯曱醯胼； {H(M[2_(5_氯_2_氰基_4“密啶基)·2_(2_甲基丙基)胼基]羰基}苯基）曱基]-4-六氫吡啶基}胺基曱酸1，1_二曱基乙酯； Ν’-(5-氣-2-氰基-4-嘧啶基）-4-({4-[3-(二曱胺基）丙基]-1-六氫吼畊基}曱基)_Ν’-〇曱基丙基）苯曱醯肼； NOU-氰基_4_嘧啶基)-Ν，_(孓曱基丙基)_4_({4_[3_(4_嗎福咐基）丙基]-1-六氫吡畊基}曱基）苯曱醯胼三氟乙酸鹽； Ν’-(5ϋ氰基-4-嘧啶基)_4-({4-[3-(二乙胺基）丙基]小六氫°比畊基}曱基)-Ν’-〇曱基丙基）苯甲醯胼； 169 200804352 二-(5-氣-2-氰基嘧啶基)-4-({4-[3-(二丙胺基）丙基]_1_六氫吡畊基}甲基)-N’-(2-曱基丙基）苯曱醯肼； N -(5-氣-2-氰基-4-嘧啶基)-4-({4·[3-(二_2_丙烯-1-基胺基）丙基>1-六氫吡畊基}甲基)-Ν，_(2—甲基丙基）苯甲醯胼； Ν’-(5-氣-2-氰基-4-嘧啶基)-4-({4-[(1-曱基-4-六氫吡啶基）甲基]_1_六氫吼啡基}甲基)_Ν，-(2_曱基丙基）苯甲醯肼； Ν’-(5_氣-2-氰基-4-嘧啶基)-4-{[4-(1-曱基-4-六氫吡啶基Η-六氫吼畊基]曱基}_Ν，_(2_甲基丙基）苯甲醯肼； {1-[(4-{[2-(5-氣-2-氰基_4_嘧啶基)-2-(2-甲基丙基)肼基]羰基}苯基）甲基]-3-六氫吡咬基}乙酸乙酯； N’-(5-氣—2-氰基_4_嘧啶基）-4-({4-[2-(二乙胺基）乙基]小六氫吼畊基}甲基)-N，-(2-曱基丙基）苯曱醯胼； Ν’-(5ϋ氰基-4-嘧啶基)-4-({4-[2-(二-2-丙烯小基胺基）乙基]-1_六氫吡畊基}甲基)-Ν，-(2-曱基丙基）苯甲醯胼； Ν’_(54_2-氰基_4_嘧啶基)斗（{4-[2_(二丙胺基）乙基]小六氫吼畊基}甲基)氺，_(2_曱基丙基）苯曱醯胼； Ν’-(5ϋ氰基-4-嘧啶基)_3-[(2,6-二曱基小六氫吡啶基）曱基]-Ν’-(2-甲基丙基）苯曱醯肼； 3_(ι，4’-聯六氫吡咬_r_基曱基)_Ν，_(5氯_2-氰基冰嘧啶基)-Ν’_(2-曱基丙基）苯甲醯胼； Ν’-(5-氣-2-氰基-4-嘧啶基>ν，-(2-曱基丙基)-3-(1-六氫吡啶基曱基）苯曱醯胼； N’-(5'氣-2-氰基-4-嘧啶基)-3-({4-[3-(二丙胺基）丙基]-1-六氫吼畊基}曱基)-N，-(2_曱基丙基）苯曱醯胼； 170 200804352 N’_(5-氯-2-氰基-4-嘧啶基)-3-({4-[3-(二乙胺基）丙基]-1-六氫吼畊基}甲基)-N，-(2_f基丙基）苯曱醯肼； N’-(5-氣-2-氰基_4_嘧啶基)-4-[(4-羥基小六氫吡啶基）甲基]-N’-(2_曱基丙基）苯甲醯胼； N’-(5-氣-2-氰基-4-嘧啶基)-4-{[4-(2-羥基乙基）-1·六氳吡啶基]甲基卜N’-(2-甲基丙基）苯甲醯胼； N’_(5-氣-2-氰基-4-嘧啶基)_4-{[4_(2-羥基乙基)-1-六氫吡畊基]甲基}-N’_(2-甲基丙基）苯甲醯胼； N’-(5-氣-2-氰基-4-嘧啶基)-4-{[4_(羥基曱基)-1-六氫吡啶基] 甲基卜Ν’-(2-甲基丙基）苯甲酿胼； 1-[(4-{[2-(5-氯-2-氰基-4-嘧啶基)_2-(2_甲基丙基）醯胼基]羰基}苯基）曱基]-N，N-二甲基脯胺醯胺； 4-(1-吖丁啶基甲基)-N’-(5-溴_2_氰基-4-嘧啶基)-N，-(2-曱基丙基）苯甲醯胼； Ν’_(5ϋ氰基-4-嘧啶基)-N’-(2-甲基丙基)_4-{[(2S)-2-(l-吼咯啶基羰基)-1-吡咯啶基]甲基}苯甲醯肼； 1^(5-氣-2-氰基-4-嘧啶基)-：^’-(2-曱基丙基)-4-{[4-(4-嗎福 ϋ林基）_1-0比洛咬基]曱基}苯甲酸胼； Ν’_(5-氣氰基_4_嘧啶基)-N’-〇曱基丙基)-4-({4-[2-(1-六氫吡啶基）乙基]-1-六氫吡畊基}曱基）笨曱醯肼； Ν’-(5-氣-2-氰基-4-嘧啶基)-4-({4-[(1-曱基_3_六氫吡啶基）曱基]-1-六氫吡畊基}曱基)-Ν，-(2-曱基丙基）苯曱醯胼； ΝΆ氣-2-氰基嘧啶基）·Ν’-(2_曱基丙基）_4-({4-[3-(1-六氫呲啶基）丙基]-1_六氫吡畊基}曱基）苯甲醯胼； 171 200804352 Ν’-(5-氯-2-氰基-4-0密咬基)-4-{[4-(二乙胺基)-1 _六氫u比咬基] 曱基}-Ν’-(2-甲基丙基）苯甲醯胼； ^-(5-氣-2-氰1基-4_哺咬基)-4-{[4-(4-曱基-1-六氳吼口井基)-1-六氫吡啶基]曱基}-Ν’-(2-曱基丙基）苯曱醯胼； ^’-(5-氯-2-氰1基-4-^密11定基)-1\[’-(2-甲基丙基)_4-{[4-(4胃吼咬基)-1-六氫吡畊基]甲基}苯甲醯胼； N’-(5-氯-2-氰基-4-嘧啶基)-N’-(2-曱基丙基)-4-({4-[2-(1-吼咯啶基）乙基>1-六氳吡畊基}曱基）苯甲醯胼； N’-(5-氣-2-氰基-4-嘧啶基)-4-({4-[2-(二曱胺基）乙基]-1-六氫吡畊基}曱基）-N’-(2-甲基丙基）苯曱醯胼； N’-(5-氯-2-氰基-4-嘧啶基)-N’-(2-甲基丙基)-3-(1-吡咯啶基曱基）苯曱醯胼；氰基-4-嘧啶基)_N，-(2-曱基丙基)-3-{[4-(4-嗎福唯基:)-1-六氫吡啶基]曱基}苯甲醯肼； N’_(5-氯-2-氰基冬嘧啶基)-3-{[4-(2-羥基乙基）-1-六氫吡畊基]曱基}-N’-(2-曱基丙基）苯曱醯胼； N’_(5-氣-2-氰基-4-嘧啶基)-3-{[4-(羥基曱基)-1-六氫吡畊基] 曱基卜N’-(2-曱基丙基）苯甲醯胼；氰基-4-嘧啶基)-N’-(2-甲基丙基)-3-({4-[3-(1-六氫17比啶基）丙基]-1-六氫吡畊基}曱基）苯曱醯胼； N -(5-氣-2-氰基-4-哺口定基)-3-{[4_(4-曱基-1-六氫口比口井基)-1-六氫吡啶基]曱基}-N，-(2-曱基丙基）苯曱醯胼； N’_(5-氯-2-氰基-4-嘧啶基)-3-{[4-(二乙胺基）-1-六氫吡啶基] 曱基卜N’-(2-甲基丙基）苯甲醯胼； 172 200804352 N’-(5-氣-2-氰基-4-嘧啶基)-3-({4-[2-(二乙胺基）乙基]小六氫吼畊基}曱基)-N，_(2_曱基丙基）苯曱醯胼； N’-(5-氣-2-氰基斗嘧啶基）_3_{[4-(1-曱基-4-六氫吡啶基)-1-六氫吡畊基]曱基}-N，-(2-曱基丙基）苯甲醯胼；氣-2_氰基-4-嘧啶基)-N，-(2-曱基丙基)-3-({4-[3-(4-嗎福咐基）丙基]-1_六氫吡啡基}曱基）苯甲醯胼； N’-(5-氣-2-氰基-4·嘧啶基)-N，-(2-曱基丙基）-3-({4-[2-(1-吡略"定基）乙基>1-六氫吡畊基}甲基）苯曱醯胼； NM5-氣-2-氰基-4-嘧啶基)-3-({4-[(1-曱基-4-六氫吡啶基）曱基l·1·六氫吡畊基}甲基)-N，-(2-曱基丙基）苯甲醯胼；氣_2_氰基_4_嘧啶基)-N，-(2-曱基丙基)-3-({4-[2-(1-六氫吼啶基）乙基>1-六氫吡畊基}曱基）苯甲醯胼； >^(5-氣-2-氰基-4-嘧啶基)-4-氟_，-(2-甲基丙基)-3-{[4-(4-嗎福咁基）-1-六氫吡啶基]曱基}苯曱醯胼； N’-(5-氣-2-氱基-4-嘧啶基)-4-氟-3-{[4-(羥基曱基)-1-六氫吼σ定基]曱基}况_(2_曱基丙基）苯甲醯胼； 3-(Μ、聯六氫吡啶-；!，_基甲基)_Ν，_(5_氯1氰基-4_嘧啶基Μ-氟-N’-(2_f基丙基）苯曱醯胼； NO-氣_2_氰基_4_嘧啶基)_4_氟冬[(4-甲基小六氫吡畊基）甲基]-N’-(2-甲基丙基）苯曱醯胼； N’-(5-演_2_氰基-4“密咬基)-4-{[4-(4-甲基小六氫吡畊基)-1-六氫吼啶基]甲基}-N，-(2-曱基丙基）苯甲醯胼；氰基|嘧啶基)_5_[(4_曱基小六氫吡畊基）曱基]-N -(2-甲基丙基）-3-異。号嗤卡巴胼（carb〇hydrazide); 173 200804352 N、(5备2-氰基-4-♦定基[(心甲基小六氩口比畊基）曱基]-N -(2-曱基丙基)-1_苯並呋喃-2_卡巴肼； N _(5冬2·氰基-4-嘧啶基)_5_[(4_曱基小六氫吡畊基）曱基>Ν’-(2-曱基丙基)_2-呋喃卡巴胼仁曱基苯磺酸鹽； Ν -(5_>臭_2_氰基冰喷啶基)_6]3_[(4_曱基小六氫吡畊基）甲基]苯基卜Ν’-(2_曱基丙基)_3_σ比啶卡巴胼； Ν -(5备2-氰基-4“密口定基)-6」4_[(4_曱基小六氫吼σ井基）甲基]笨基卜Ν’-(2_曱基丙基)_3_吼咬卡巴胼； Ν’-(5-溴-2-氰基-4-嘧啶基y5_{4_[(4_甲基六氫吡畊基）曱基]本基卜Ν’_(2_曱基丙基)_3_^σ定卡巴胼； Ν -(5-溴-2-氰基-4·嘧啶基)-5-{3-[(4-曱基-1-六氫吡u井基）曱基]笨基卜Ν’_(2·甲基丙基)_3-吼咬卡巴胼； Ν -(5-溴-2-氰基-4-嘧啶基)-卜[(4_曱基-1-六氫吡畊基）曱基]-N’-(2-曱基丙基)-1·苯並呋喃卡巴肼； N’_(5U-氰基-4_嘧啶基)-5_[(4_曱基小六氫吡畊基）曱基]-Ν’-(2-曱基丙基)-2-喧吩卡巴胼；及其藥學上可接受的衍生物。 10·至少一種化學實體，其係選自： N’_(5U-氰基-4-嘧啶基)-4-[(4-曱基小六氫吡畊基）曱曱基丙基）苯曱醯肼三氟醋酸鹽； ’-(5-溴-2-氰基-4-嘧啶基)-比_(2-曱基丙基)-4-[(4-丙基-1_ 六氫咄畊基）曱基]苯曱醯胼三氟醋酸鹽； Ν’-(5-;臭-2_氰基-4-嘧啶基)-Ν’-(2-曱基丙基)-3-[(4-丙基小六氫吡畊基）曱基]苯曱醯胼三氟醋酸鹽； 174 200804352 ^’-(5-氣_2-氰基-4-嘧啶基)-Ν’-(2-曱基丙基)-4_[(4-丙基小六氫吡畊基）曱基]苯甲醯肼三氟醋酸鹽； N’-(5-氣-2-氰基斗嘧啶基)_Ν’-(2-曱基丙基)_3_[(4_丙基小六氫吡畊基）甲基]苯曱醯肼三氟醋酸鹽； Ν'(5-演-2-氰基-4-。密σ定基)-4-氣-Ν’-(2-曱基丙基)-3-[(4-丙基-1-六氫吡畊基）甲基]苯曱醯肼三氟醋酸鹽； Ν’-(5-氣_2_氰基-4“密咬基)-4-氟-Ν’-(2-曱基丙基)-3-[(4-丙基-1胃六氫吡畊基）曱基]苯甲醯肼三氟醋酸鹽； 4-(1，4’-聯六氫吡啶-1’-基曱基)-1^’-(5-氣-2-氰基-4-嘧啶基）-N’-(2-曱基丙基）苯甲醯胼三氟醋酸鹽； N’-(5-溴-2-氰基冰嘧啶基)-N’-(2-甲基丙基)-4-(1-六氫吡啶基甲基）苯曱醯胼三氟醋酸鹽； N -(5->臭-2 -泉基-4-口密咬基)-Ν’-(2-曱基丙基)-4-( 1 -。比17各σ定基曱基）苯曱醯肼三氟醋酸鹽；氣-2-氰基_4_哺咬基)·4-[(2,6-二曱基小六氫吡咬基）甲基]-Ν’-(2-曱基丙基）苯曱醯胼三氟醋酸鹽； 1-[(4-{[2-(5-氣-2-氰基-4-嘧啶基)-2-(2-曱基丙基)胼基]羰基} 笨基）曱基]-4-六氫吡啶羧酸乙酯三氟醋酸鹽； N-{(3R)_l_[(4-{[2-(5-氣-2-氰基-4-嘧啶基)-2-(2-甲基丙基）胼基]幾基}苯基）甲基]-3-吡咯啶基}乙醯胺三氟醋酸鹽； {1-[(4-{[2-(5-氯_2-氰基-4-嘧啶基)-2_(2-甲基丙基)胼基]幾基}苯基）甲基]-3-吡咯啶基}胺基甲酸丨，；[_二曱基乙酯三氟醋酸鹽； N’-(5-氣-2-氰基-4_嘧啶基)-4-[(4-{2-[(2_羥基乙基）氧基]乙 175 200804352 基}-1_六氫吡啡基）曱基]-：^，-(2-曱基丙基）苯曱醯胼三氟醋酸鹽； ΝΆ氣氰基-4-嘧啶基)-N，_(2-曱基丙基)-4-(1-六氫呲咬基曱基）苯曱醯胼三IL醋酸鹽； N’-(5-氣-2-氰基-4-嘧啶基)-4-{[(2R)-2-(羥基曱基)小吡略啶基]曱基}况_(2_曱基丙基）苯甲醯胼三氟醋酸鹽； N’-(5-氣-2-氰基-4-嘧啶基)-N’-(2-甲基丙基)-4-(1-吡咯咬基曱基）苯曱醯胼三氟醋酸鹽； N _(5-氣·2·氰基_4_口密唆基)·4-(2,5_二氫-1H-吼咯-1-基曱基)_Ν’_〇曱基丙基）苯曱醯胼三氟醋酸鹽； Ν’_(5-氣-2-氰基 _4_ 嘧啶基)-4-[(2,5-二曱基-2,5·二氫]Η-吡略]•基）曱基]-Ν’-(2_甲基丙基）苯曱醯肼三氟醋酸鹽；氣1氰基_4_嘧啶基)_2_(2_甲基丙基)肼基]羰基}苯基）曱基H-六氫吡啶基}胺基甲酸二甲基乙酯三氟醋酸鹽； N’_(5-氣-2-氰基-4-嘧啶基)_4-({4-[3-(二甲胺基）丙基]_丨_六氫吡畊基}甲基)-N’-(2-甲基丙基）苯甲醯胼三氟醋酸鹽； N、(54_2-氰基_4_嘧啶基)-N，_(2-曱基丙基)-4-({4_[3-(4-嗎褐唯基）丙基]-1-六氫吡畊基}甲基）苯甲醯胼三氟醋酸鹽； =-(5-氣-2-氰基-4-嘧啶基）-4·({4-[3·(二乙胺基）丙基]-卜六氫吡畊基}甲基)-Ν，-(2-曱基丙基）苯甲醯胼三氟醋酸鹽； =气5-氯-2-氰基-4-嘧啶基)_4_({4-[3-(二丙胺基）丙基；μ卜六氫比畊基}甲基)-Ν’-(2-曱基丙基）苯甲醯胼三氟醋酸鹽； Ν-(5-氣-2-氰基嘧啶基)_4_({4-[3_(二_2•丙烯_丨_基胺基） 176 200804352 丙基>1-六氫吼畊基}甲基>N，-(2-曱基丙基）苯甲醯胼三氟醋酸鹽； N’-(5-氣-2-氰基-4-嘧啶基)-4-({4-[(1-曱基-4-六氫吡啶基）曱基]小六氫吡畊基}曱基)…，#-曱基丙基）苯曱醯胼三氟醋酸鹽； N’-(5-氣-2_氰基_4_嘧啶基)_4_{[4-(1-甲基-4-六氫吡啶基)-1-六氫吼畊基]甲基}_N，气曱基丙基）苯曱醯胼三氟醋酸鹽； {1-[(4-{[2-(5-氯-2-氰基-4-嘧啶基)-2-(2-甲基丙基)肼基]羰基}苯基）曱基]-3-六氫吡啶基}乙酸乙酯三氟醋酸鹽； N’-(5-氣-2-氰基-4-嘧啶基）-4-({4-[2-(二乙胺基）乙基]-1-六氫咐。井基}曱基)-N，_(2_f基丙基）苯甲醯胼三氟醋酸鹽； N’-(5-氣_2_氰基-4-嘧啶基)-4-({4-[2-(二-2-丙烯小基胺基）乙基]-1-六氫吡畊基}甲基)-N，-(2-甲基丙基）苯甲醯胼三氟醋酸鹽； N’-(5-氣-2-氰基-4·嘧啶基)-4·({4-[2-(二丙胺基）乙基]-1-六氫吼畊基}甲基)-Ν’-(2-曱基丙基）苯曱醯胼三氟醋酸鹽； Ν’-(5-氣-2-氰基-4-嘧啶基)-3-[(2,6-二甲基-1-六氫吡啶基）甲基>Ν’-(2-曱基丙基）苯甲醯胼三氟醋酸鹽； 3-(1，4、聯六氫吡啶-1’_基甲基)_；^，_(5_氣_2_氰基-4_嘧啶基)-Ν’_(2_甲基丙基）苯甲醯胼三氟醋酸鹽； Ν’-(5-氣-2-氰基-4_嘧唆基)->1’-(2_甲基丙基)-3-(1-六氫吡啶基甲基）苯甲醯肼三氟醋酸鹽； NM5-氣-2-氰基-4-嘧啶基)-3-({4-[3-(二丙胺基）丙基]小六 177 200804352 氫吡畊基}甲基)-N，-(2-甲基丙基）苯曱醯胼三氟醋酸鹽； N’_(5-氣-2-氰基-4-嘧啶基)_3-({4-[3-(二乙胺基）丙基]小六氫吡畊基}甲基)-N，-(2-曱基丙基）苯甲醯胼三氟醋酸鹽； N’-(5-氣-2-氰基-4-嘧啶基)-4·[(4-羥基小六氫吡啶基）曱基]_Ν’-(2-曱基丙基）苯甲醯胼三氟醋酸鹽； Ν’-(5-氣-2-氰基-4-嘧啶基)-4-{[4-(2-羥基乙基)-1-六氫吡啶基]甲基卜N’-(2-曱基丙基）苯曱醯胼三氟醋酸鹽； N (5 -氣-2 -乱基-4-°密咬基）-4-{[4-(2-經基乙基）-1 -六氣批°井基]曱基卜Ν’-(2-曱基丙基）苯曱醯胼三氟醋酸鹽； Ν’-(5-氣-2-氰基—4-嘧啶基)-4-{[4-(羥基曱基）-1-六氫吡啶基] 曱基}-N’-(2-曱基丙基）苯曱醯胼三氟醋酸鹽； 1-[(4-{[2-(5-氯-2-氰基-4-嘧啶基)-2-(2-甲基丙基）醯胼基]羰基}苯基）甲基]-N，N-二曱基-L-脯胺醯胺三氟醋酸鹽；吖丁啶基曱基)-Ν，-(5-溴-2-氰基-4-嘧啶基)-N，-(2-甲基丙基）苯曱醯胼三氟醋酸鹽； >^’-(5-氣_2-氰基》4_嘧啶基)-：^，-(2-甲基丙基)-4-{[(28)-2-(1_ t各咬基羰基）-1-吡π各咬基]曱基}苯甲酿胼三氟醋酸鹽； N’-(5U_氰基-4-嘧啶基)-N’-(2-曱基丙基)-4_{[4-(4-嗎福啉基)-1-吡咯啶基]曱基}苯曱醯胼三氟醋酸鹽； N’-(5-氣-2-氰基-4-嘧啶基)-N，-(2-曱基丙基)-4_({4-[2-(1_六氫吡啶基）乙基]-1-六氫吡畊基}曱基）苯曱醯胼三氟醋酸鹽； N’-(5-氣-2-氰基_4_嘧啶基)-4-({‘[(1-曱基_3_六氫吡啶基）甲基]-1_六氫吼吨基}曱基)-Ν’-(2-曱基丙基）笨曱醯胼三氟 178 200804352 醋酸鹽； N’-(5-氣-2-氰基_4_嘧啶基)-N’-(2-甲基丙基)_4-({4_[3_(l-六氫吡啶基）丙基]-1-六氫吡畊基}曱基）苯曱醯胼三氟醋酸鹽； N’-(5-氯-2-氰基-4-嘧啶基)-4-{[4-(二乙胺基)-1-六氫吡啶基] 甲基卜N’-(2-甲基丙基）苯曱醯胼三氟醋酸鹽； N’-(5-氣-2-氰基-4-嘧啶基)-4-{[4-(4-曱基-1-六氫吡畊基)-1-六氫吡啶基]曱基}-N，-(2-曱基丙基）苯曱醯肼三氟醋酸鹽； N’_(5-氯-2-氰基-4-嘧啶基)-N’-(2-曱基丙基)-4-{[4-(4-吡啶基六氫吡畊基]曱基}苯甲醯胼三氟醋酸鹽； N’-(5-氣_2_氰基-4-嘧啶基)-N，_(2-曱基丙基)-4-({4_[2-(1』比咯啶基）乙基]-1-六氫吡畊基}甲基）苯甲醯肼三氟醋酸鹽； N’-(5-氣-2-氰基-4-嘧啶基)-4-({4-[2-(二曱胺基）乙基]六氫吼畊基}曱基）-N，-(2-甲基丙基）苯甲醯胼三氟醋酸鹽； N (5-氣-2 -氮基-4_唯唆基)-N’-(2-曱基丙基)_3_( 1 -吼略σ定基曱基）苯曱醯胼三氟醋酸鹽； Ν (5 -氟-2 -氣基-4-σ密咬基）-N，-(2 -曱基丙基）-3-{[4-(4-嗎福啡基>1-六氫吡啶基]曱基}苯曱醯肼三氟醋酸鹽； N (5 -氣-2-氣基密σ定基)-3- {[4-(2-經基乙基）-1-六氫u比σ井基]曱基卜Ν，-(2-曱基丙基）苯甲醯肼三氟醋酸鹽； Ν (5-氣-2 -氰基-4一密咬基）-3-{[4-(經基曱基）-1 -六氫。比σ井基] 曱基卜Ν’-(2-曱基丙基）苯甲醯胼三氟醋酸鹽； ΝΜ5-氣-2-氰基-4-嘧啶基)-Ν’-(2-甲基丙基)-3-({4-[3-(1_六 179 200804352 氫吡啶基）丙基：Μ-六氫吡畊基}曱基）苯曱醯肼三氟醋酸鹽；氣_2_氰基-4-嘧啶基)-3-{[4-(4-曱基-1-六氫吡畊基)-1-六氫吡啶基]甲基卜Ν，-(2-曱基丙基）苯甲醯胼三氟醋酸鹽； Ν’_(5-氣-2-氰基+嘧啶基)-3-{[4-(二乙胺基)小六氫吡啶基] 曱基卜Ν’-(2-曱基丙基）苯曱酷胼三氟醋酸鹽； Ν’-(5-氣-2-氰基|嘧啶基)-3-({4-[2-(二乙胺基）乙基]-1-六氫吡畊基}甲基)-Ν，-(2-曱基丙基）苯甲醯胼三氟醋酸鹽； 1^’-(5_氣-2-氰基-4-嘧啶基)-3-{[4-(1-曱基-4-六氫吡啶基)-1-六氫吡畊基]甲基卜Ν，-(2-甲基丙基）苯曱醯胼三氟醋酸鹽； Ν、(5-氣-2-氰基-4-嘧啶基)-Ν’-(2-甲基丙基)-3-({4-[3-(4-嗎福唯基）丙基]-1-六氫吡畊基}曱基）苯曱醯胼三氟醋酸鹽； Ν’_(5-氣-2-氰基-4-嘧啶基)-Ν’_(2-甲基丙基)-3-({4-[2-(1-吡各咬基）乙基]_1_六氫吡畊基}曱基）苯甲醯胼三氟醋酸鹽； Ν (5-氣-2-氧基-4-¾咬基）-3-({4-[(1-甲基_4-六氮口比咬基）曱基六氫吡畊基}曱基)-N，-(2-甲基丙基）苯甲醯胼三氟醋酸鹽； 1^’_(5-氣-2-氰基-4-嘧啶基)-^[，-(2-甲基丙基)-3-({4-[2-(1-六氫口比咬基）乙基]-1-六氫吡畊基}曱基）苯曱醯肼三氟醋酸鹽； N、(5-氣_2_氰基-4-嘧啶基)-4-氟-N，-(2-甲基丙基)_3-{[4-(4-嗎福咁基）-1 -六氫吡啶基]甲基}苯甲醯肼三氟醋酸鹽； 180 200804352 N’_(5-氯·2_氰基-4-嘧啶基)冬氟_3-{[4-(羥基曱基)小六氫吡啶基]曱基}-N’-(2-曱基丙基）苯曱醯胼三氟醋酸鹽； 3 - (1，4 ’ -聯六鼠口比ϋ定-1 ’ -基甲基)-N’ - (5 -氣-2 -氣基-4_口密^定基）-4-氟-N’-(2-曱基丙基）笨曱醯胼三氟醋酸鹽； N’-(5-氣-2_鼠基_4_^ϋ定基)_4_氣-3-[(4-曱基-1-六鼠口比口井基) 曱基]-N’-(2-曱基丙基）苯甲醯胼三氟醋酸鹽； N’-(5_溴-2-氰基-4-嘧啶基)-4-{[4-(4•甲基-1-六氫吡畊基)-1-六氫吨啶基]曱基卜N’-(2-曱基丙基）苯甲醯胼三氟醋酸鹽； N’-(5-溴-2-氰基-4-嘧啶基)-5-[(4-曱基-1-六氫吡畊基）曱基]-N’-(2-曱基丙基)-3-異崎唑卡巴胼三氟醋酸鹽； N’-(5->臭-2-氣基-4-°密咬基)-7-[(4-曱基-1-六氮17比研基）曱基]-N’-(2-甲基丙基)-1_苯並咬喃-2-卡巴耕二氣醋酸鹽； N’-(5->臭-2-鼠基-4-13密咬基)-5-[(4-曱基-1-六氮17比ΰ井基）曱基]-Ν’-(2-曱基丙基)-2-咬喃卡巴耕4_曱基苯石黃酸鹽三氟醋酸鹽； N’-(5->臭-2-鼠基-4-^σ定基)-6-{3-[(4-曱基-1-六氮口比口井基）曱基]苯基卜Ν’-(2-曱基丙基)-3-4(:唆卡巴耕三氟醋酸鹽； N’-(5->臭-2-氣基-4-口密ϋ定基)-6-{4-[(4-曱基-1_六氮吼口井基）曱基]苯基}-N’-(2 -曱基丙基)-3-吼σ定卡巴耕三氟醋酸鹽； Ν -(5-〉臭-2-氣基-4-^σ定基)-5-{4-[(4-曱基_1-六氮口比口井基）曱基]苯基}-Ν’-(2-曱基丙基)-3_ϋ比咬卡巴胼三敦醋酸鹽； Ν’-(5-溴-2_氰基_4_嘧啶基)-5-{3-[(4-曱基-1_六氫吡畊基）曱基]苯基}-Ν’-(2 -甲基丙基)-3-吼0定卡巴耕三氟醋酸鹽； 181 200804352 N’-(5-溴-2-氰基如密咬基)_5|甲基小六氫吼〇井基）甲 = (2_甲基丙基)+苯並π夫喃_2_卡巴駢三氟醋酸鹽；及 =_(512_氰基_4+定基)_5-[(4-甲基小六氫㈣基）甲基]-Ν -(2-甲基丙基)_2“塞吩卡巴耕三敦醋酸鹽。虞申請專利範圍第丨至1〇項中任一項學貫體，其係用於醫療。種化 12. 一種f據申請專利範圍第1至1G項中任-項之至少-介的病情之用途。易又+耽胺酸蛋白酶抑制劑仲 13. -種根據申請專利範圍第1至丨項中任化學實體用於治療癔疾之用途。〉一種 14. -種用於治療罹患易受病情之人類或動物患者之編白甘酶，丨仲介的申請專利範圍第i至1〇項中任之至、已含有效量根據 15·—種用於治療罹自虑广員之至^、一種化學實體。此療惟患癌疾之人類或動物•、者,殺〜丄，其包含有效量根據申請專利範圍第】至1〇::;讀之至少一種化學實體。員中任一項 16·—種醫藥組成物豆句人拍祕士士項t任-項之至少圍第叉的载劑及/或賦形劑。某予上可接 γ.—種用於製備根據申請專物之方法，其係從式η化合物，：範圍第】項中用於式r _ R2^據在申請專利极據在申請專利範圍第⑷用二 182 200804352 圖示反應 h2n、Wherein: R4 represents halogen; R2 represents 1)-phenyl-Cw alkyl-X, _pyridyl-phenyl-c"alkyl hydrazine or _yl-Cw alkyl-X-R, wherein phenyl is regarded as Need to be substituted by a CF3 group; or ® or n) _Y_ci-3 alkyl-X or -Y_Cl 3 alkylene_X_R]; , containing one containing one to four selected from N, 〇 and s The aromatic group of dibe, the ring needs to be fused to the benzene ring, ·, R represents Z, _Ci-4 alkyl-z or -c(0)z; χ and z independently represent: 0 contains one a monocyclic 4-membered saturated hydrocarbon group of a nitrogen atom, · u) ^ a monocyclic 5_贞 saturated or partially saturated hydrocarbon group having one or two nitrogen atoms and optionally a single ring of oxygen atoms Partially saturated or aromatic cigarette base; Beckering X and Z are independently selected as required a) - selected from alkyl, C " burnt base 0H, Ci 4 precipitate base & c " appearance base 〇 H, ^ 166 , 1 ^ 200804352 alkylalkyl, -qcOOCw alkyl, NRERF, -Cm alkyl NrErF, -NC(〇)Ci-3 alkyl, -NCCCOOCw alkyl and -C(0)NReRf and b) Need to be an additional base substitution for c1-4 alkyl; # and RF independently represent hydrazine or Cl_4 alkyl or Cl _4 alkenyl; and pharmaceutically acceptable derivatives thereof 2. According to at least one chemical entity of the scope of the patent application, wherein R4 represents gas, desert or sputum. At least one chemical entity, wherein R+ represents - stupyl-Cm alkyl-X, -pyridyl-phenyl-Ci 3 alkyl or phenyl-Cu extended _x_R' wherein phenyl is optionally a radical substitution selected from halogen or CF3. • According to the at least one of the 丨 or 2 of the scope of the claimed patent, w represents υ々3#^μ·υ々3 matrix..., = 1 patent scope 12 or At least one of the four items of the traitor is represented by ', the middle ¥ represents 吱、, ° 塞、, 异十 sitting or benzo 吱。. 6 · According to the scope of the patent application No. 1 to 5 At least one chemical permeate of any one of the sergeants + 2 main clerk' wherein the stretched wire in R is yammi. » Γ1! tf?^ , /, where R represents -Cl-3 extension base -Z 8. According to the scope of the application for patents 丨 to 7 entities, where χ; 7 think, the father to the father of a chemical to contain ^- represents one or two nitrogen atoms and There is an oxygen atom as needed to observe and at least one chemical entity, which is selected as a saturated or aromatic hydrocarbon group. Gezhi early % 6-bean saturation, part 167 200804352 N'-(5-bromo-2-cyanide 4-pyrimidinyl)-4-[(4-mercapto-1-hexahydropyrryl)methyl]-N'-(2-mercaptopropyl)phenylhydrazine; N'- (5 ->Smell-2-murine-4-mercaptopurine)·Ν'-(2-mercaptopropyl)-4-[(4-propyl-1_hexahydropyrryl)indenyl]benzene Ν; Ν'- (5-> odor-2 - gas group _4_0 dimethyl group)-N'-(2-mercaptopropyl)-3-[(4-propyl-1-hexahydro) Pyridinyl) fluorenyl] phenylhydrazine; 1^'-(5-gas-2-ayl_4-, octyl)-]^'-(2-mercaptopropyl)-4-[( 4-propyl-1-hexahydropyridinyl)indenyl]benzoquinone; N'-(5^*murine-2-ayl-4-mercapto-7)-N'-(2-A Propyl)-3-[(4-propyl-l-hexahydropyrryl)methyl]benzoquinone; ^!'-(5->odor 2 - gas base-4-mouth bite 4-)-1-(1)-(2-mercaptopropyl)-3-[(4-propyl-1-hexahydropyrryl)indenyl]phenylhydrazine; Ν'-(5 -chloro-2-cyano-4-pyrimidinyl)-4-fluoro-indole-(2-mercaptopropyl)-3-[(4-propyl-1-hexahydropyrrole)曱 ] 曱醯胼曱醯胼 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- Stationary)-Ν'-(2-mercaptopropyl)phenylhydrazine; Ν'-(5-bromo-2-cyano-4-pyrimidinyl)-oxime-(2-mercaptopropyl)- 4-(1-hexahydropyridylmethyl)benzimidazole; N'-(5-bromo-2-cyano-4-pyrimidinyl)-N'-(2-mercaptopropyl)-4- (1-pyrrolidinyl fluorenyl)benzhydrazide; N'-(5-Gas-2-Ayl-4-mercapto-based)-4-[(2,6-dimercapto-1-6) Nitrogen sulfhydryl group) 曱基卜Ν '-(2-mercaptopropyl) phenylhydrazine; 1-[(4_{[2-(5-气-2-气基-4-0密定定基) -2-(2-mercaptopropyl) hydroxy]yl]}phenyl)indolyl]-4-hexahydropyridinecarboxylate; 168 200804352 N-{(3R) small [(4-{[ 2·(5-Gas-2·cyano-4-pyrimidinyl)_2_(2-methylpropyl)indolyl]carbonyl}phenyl)indolyl]-3-pyrrolidyl}acetamide; {1 -[(4-{[2-(5-chloro-2-cyano-4-mercapto)_2-(2-methylpropyl)indolyl]yl}phenyl)indolyl]-3- Pyrrolidinyl}amino phthalic acid 1,1-dimethylethyl ester; gas-2-cyano-4 thiophene)-4-[(4_{2-[(2-ylethyl))oxy) Ethyl hexahydropyridinium Methyl]-N'-(2-mercaptopropyl)phenylhydrazine; N'_(5·Ga-2-cyanocarbonate)-N'-(2-mercaptopropyl) 4-(1-hexahydroindoleylmethyl)benzhydryl; N'-(5-Gas-2-cyano-4-pyrimidinyl)-4_{[(2R)-2-(hydroxyindole) ))pyridinyl]mercapto}-N'-(2-mercaptopropyl)phenylhydrazine; cyano-4-pyrimidinyl)-N,-(2-mercaptopropyl)-4 -(1-pyrrolidylmethyl)phenylhydrazine; ^-(5-gas-2_cyano-4-mouthbityl)-4-(2,5-dihydro-111-吼略_1 -N-(2-methylpropyl)benzamide; cyano-4-pyrimidinyl)-4-[(2,5-dimercapto-2,5-dihydro-1H -pyrrole_1_yl)indenyl]-N,-(2-mercaptopropyl)phenylhydrazine; {H(M[2_(5-chloro-2-cyano-4)") 2-(2-methylpropyl)indenyl]carbonyl}phenyl)indolyl]-4-hexahydropyridinyl}amino decanoic acid 1,1-didecylethyl ester; Ν'-(5-gas- 2-cyano-4-pyrimidinyl)-4-({4-[3-(didecylamino)propyl]-1-hexahydroindole]}indolyl)_Ν'-mercaptopropyl) Benzoquinone; NOU-cyano_4_pyrimidinyl)-indole, _(mercaptopropyl)_4_({4_[3_(4_?))]]hexahydropyrene Benzoquinone Trifluoroacetate; Ν'-(5ϋCyano-4-pyrimidinyl)_4-({4-[3-(diethylamino)propyl) hexahydrogen ～耕基}曱基)-Ν' -mercaptopropyl)benzamide; 169 200804352 bis-(5-Gas-2-cyanopyrimidinyl)-4-({4-[3-(dipropylamino)propyl]_1_hexahydro Pyridyl}methyl)-N'-(2-mercaptopropyl)phenylhydrazine; N-(5-Gas-2-cyano-4-pyrimidinyl)-4-({4·[3 -(di-2-propen-1-ylamino)propyl>1-hexahydropyranyl}methyl)-indole, _(2-methylpropyl)benzamide; Ν'-( 5-Gas-2-cyano-4-pyrimidinyl-4-({4-[(1-indolyl-4-hexahydropyridyl)methyl]_1_hexahydroindolyl}methyl)_Ν ,-(2_mercaptopropyl)benzimid; Ν'-(5_Gas-2-cyano-4-pyrimidinyl)-4-{[4-(1-indolyl-4-hexahydro) Pyridyl hydrazine-hexahydroindolyl] fluorenyl}_Ν, _(2-methylpropyl) benzamidine; {1-[(4-{[2-(5-gas-2-cyano)_ 4-(pyrimidinyl)-2-(2-methylpropyl)indolyl]carbonyl}phenyl)methyl]-3-hexahydropyridyl}ethyl acetate; N'-(5-gas-2 Cyano 4-(pyrimidinyl)-4-({4-[2-(diethylamino)ethyl] hexahydroindole) methyl)-N,-(2-mercaptopropyl)benzene曱醯胼; Ν'- (5ϋCyano-4-pyrimidinyl)-4-({4-[2-(di-2-propenylamino)ethyl]-1_hexahydropyrrole}methyl)-Ν,- (2-mercaptopropyl) benzamidine; Ν'_(54_2-cyano-4-pyrimidinyl) bucket ({4-[2_(dipropylamino)ethyl) hexamethylene hydrazine}氺, _(2_mercaptopropyl)phenylhydrazine; Ν'-(5ϋCyano-4-pyrimidinyl)_3-[(2,6-diindenyl hexahydropyridyl) fluorenyl ]-Ν'-(2-methylpropyl)phenylhydrazine; 3_(ι,4'-bi-hexahydropyridyl _r_ylindenyl)_Ν,_(5-chloro-2-cyano-pyrimidine ))-Ν'_(2-mercaptopropyl)benzhydrazide; Ν'-(5-Gas-2-cyano-4-pyrimidinyl) ν,-(2-mercaptopropyl)- 3-(1-hexahydropyridylfluorenyl)phenylhydrazine; N'-(5' gas-2-cyano-4-pyrimidinyl)-3-({4-[3-(dipropylamino)) Propyl]-1-hexahydroindole hydrazine} fluorenyl)-N,-(2-mercaptopropyl)phenylhydrazine; 170 200804352 N'_(5-chloro-2-cyano-4-pyrimidine Benzyl-3-({4-[3-(diethylamino)propyl]-1-hexahydroindolyl}methyl)-N,-(2_f-propyl)phenylhydrazine; N' -(5-Gas-2-cyano-4-imidyl)-4-[(4-hydroxysuccinolimidyl)methyl]-N'-(2-mercaptopropyl)benzene N'-(5-Gas-2-cyano-4-pyrimidinyl)-4-{[4-(2-hydroxyethyl)-1·hexafluoridyl]methyl b N'-( 2-methylpropyl)benzhydryl; N'_(5-Gas-2-cyano-4-pyrimidinyl)_4-{[4_(2-hydroxyethyl)-1-hexahydropyrrole ]methyl}-N'_(2-methylpropyl)benzimid; N'-(5-Gas-2-cyano-4-pyrimidinyl)-4-{[4_(hydroxyindenyl) -1-hexahydropyridyl]methyldip-'-(2-methylpropyl)benzonitrile; 1-[(4-{[2-(5-chloro-2-cyano-4-pyrimidine) 2)(2-(methylpropyl)indenyl]carbonyl}phenyl)indenyl]-N,N-dimethyliminamine; 4-(1-azetidinylmethyl)-N' -(5-bromo-2-cyano-4-pyrimidinyl)-N,-(2-mercaptopropyl)benzhydrazide; Ν'_(5ϋcyano-4-pyrimidinyl)-N'- (2-methylpropyl)_4-{[(2S)-2-(l-fluorenylcarbonyl)-1-pyrrolidinyl]methyl}benzamide; 1^(5-gas-2 -cyano-4-pyrimidinyl)-:^'-(2-mercaptopropyl)-4-{[4-(4-isofolinyl)-1-0 piroxime] fluorenyl}benzene胼'_(5-aerocyano-4-imidyl)-N'-mercaptopropyl)-4-({4-[2-(1-hexahydropyridyl)ethyl]- 1-hexahydropyranyl} 曱 base) clumsy; '-(5-Gas-2-cyano-4-pyrimidinyl)-4-({4-[(1-indolyl_3_hexahydropyridyl)indolyl]-1-hexahydropyrrole} Mercapto)-Ν,-(2-mercaptopropyl)phenylhydrazine; xenon-2-cyanopyrimidinyl)·Ν'-(2_mercaptopropyl)_4-({4-[3 -(1-hexahydroacridinyl)propyl]-1_hexahydropyranyl}indenyl)benzamide; 171 200804352 Ν'-(5-chloro-2-cyano-4-0 bite ))-4-{[4-(diethylamino)-1 _hexahydrou than butyl] fluorenyl}-Ν'-(2-methylpropyl) benzamidine; ^-(5- Gas-2-cyano-1-yl-4_bearing)-4-{[4-(4-mercapto-1-hexafluorenyl)-1-hexahydropyridyl]fluorenyl}-Ν -(2-mercaptopropyl)phenylhydrazine; ^'-(5-chloro-2-cyano-1yl-4-(methyl)11-)-[[-(2-methylpropyl)_4 -{[4-(4-gastrinyl)-1-hexahydropyrryl]methyl}benzamide; N'-(5-chloro-2-cyano-4-pyrimidinyl)-N' -(2-mercaptopropyl)-4-({4-[2-(1-decalyl)ethyl>1-hexapyranyl}indenyl)benzamide; N'- (5-Gas-2-cyano-4-pyrimidinyl)-4-({4-[2-(didecylamino)ethyl]-1-hexahydropyranyl}indenyl)-N'- (2-methylpropyl)phenylhydrazine; N'-(5-chloro-2-cyano-4-pyrimidinyl)-N '-(2-Methylpropyl)-3-(1-pyrrolidinyl)phenylhydrazine; cyano-4-pyrimidinyl)-N,-(2-mercaptopropyl)-3-{ [4-(4-Isofosyl:)-1-hexahydropyridyl]fluorenyl}benzamide; N'_(5-chloro-2-cyanopyrimidinyl)-3-{[4 -(2-hydroxyethyl)-1-hexahydropyranyl]mercapto}-N'-(2-mercaptopropyl)phenylhydrazine; N'_(5-gas-2-cyano- 4-pyrimidinyl)-3-{[4-(hydroxyindenyl)-1-hexahydropyrrole] 曱基卜 N'-(2-mercaptopropyl)benzhydrazide; cyano-4- Pyrimidinyl)-N'-(2-methylpropyl)-3-({4-[3-(1-hexahydro17-pyridyl)propyl]-1-hexahydropyrrole} fluorenyl) Benzoquinone; N-(5-Gas-2-cyano-4-methyl-based)-3-{[4_(4-mercapto-1-hexahydroport) well-1-hexahydro Pyridyl]fluorenyl}-N,-(2-mercaptopropyl)phenylhydrazine; N'_(5-chloro-2-cyano-4-pyrimidinyl)-3-{[4-(two Ethyl)-1-hexahydropyridyl] decyl N'-(2-methylpropyl)benzimid; 172 200804352 N'-(5-Gas-2-cyano-4-pyrimidinyl) )-3-({4-[2-(diethylamino)ethyl) hexahydroindole cultivating base} fluorenyl)-N, _(2-mercaptopropyl) phenylhydrazine; N'- (5-Gas-2-cyanopropylpyrimidinyl) )_3_{[4-(1-mercapto-4-hexahydropyridyl)-1-hexahydropyrryl]mercapto}-N,-(2-mercaptopropyl)benzimid; gas- 2-cyano-4-pyrimidinyl)-N,-(2-mercaptopropyl)-3-({4-[3-(4-)-propenyl)propyl]-1_hexahydropyridin Benzoquinone; N'-(5-aero-2-cyano-4.pyrimidinyl)-N,-(2-mercaptopropyl)-3-({4-[2- (1-pyrrole "deciding)ethyl>1-hexahydropyranyl}methyl)phenylhydrazine; NM5-gas-2-cyano-4-pyrimidinyl)-3-({4- [(1-Mercapto-4-hexahydropyridyl) fluorenyl l·1·hexahydropyrrole}methyl)-N,-(2-mercaptopropyl)benzimid; gas_2_ Cyano-4-pyrimidinyl)-N,-(2-mercaptopropyl)-3-({4-[2-(1-hexahydroacridinyl)ethyl> 1-hexahydropyrrole }曱基)Benzyl hydrazine; >^(5-Gas-2-cyano-4-pyrimidinyl)-4-fluoro-,-(2-methylpropyl)-3-{[4-( 4-orfosyl)-1-hexahydropyridinyl]fluorenyl}phenylhydrazine; N'-(5-Gas-2-mercapto-4-pyrimidinyl)-4-fluoro-3-{[ 4-(hydroxyindenyl)-1-hexahydroindole sigma] fluorenyl} condition_(2_mercaptopropyl)benzhydrazide; 3-(indole, hexahydropyridine-; Base)_Ν,_(5_chloro-1cyano-4-pyrimidinylfluorene-fluoro-N'- (2_f-propyl)phenylhydrazine; NO-gas_2_cyano_4_pyrimidinyl)_4_fluorodong[(4-methylsuccinium pyridinyl)methyl]-N'-( 2-methylpropyl)phenylhydrazine; N'-(5-exemplified 2-cyano-4"-density)-4-{[4-(4-methyl small hexahydropyranyl) -1-hexahydroacridinyl]methyl}-N,-(2-mercaptopropyl)benzhydryl; cyano|pyrimidinyl)_5_[(4_fluorenyl hexahydropyrryl)曱Base]-N-(2-methylpropyl)-3-iso. 〇嗤胼胼 az 〇〇〇〇〇〇〇〇〇〇〇〇〇〇〇〇〇〇〇〇〇〇〇〇〇〇〇〇〇〇〇〇〇〇〇〇〇〇〇〇〇〇〇〇〇〇〇 Propyl)-1_benzofuran-2_carbazide; N _(5 winter 2 · cyano-4-pyrimidinyl)_5_[(4_fluorenyl hexahydropyrryl) sulfhydryl] Ν -(2-mercaptopropyl)_2-furancarbazone benzenesulfonate; Ν -(5_>odor 2_cyano acylpyridyl)_6]3_[(4_fluorenyl hexahydro Pyridinyl)methyl]phenylindole'-(2_mercaptopropyl)_3_σ-pyridylcarbazide; Ν-(5-prepared 2-cyano-4 "densified base"-6"4_[(4 _ 曱小小吼 ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) Pyrimidinyl y5_{4_[(4-methylhexahydropyrryl) fluorenyl]benzib Ν'_(2_mercaptopropyl)_3_^σ定卡巴胼; Ν-(5-bromo-2- Cyano-4.pyrimidinyl)-5-{3-[(4-mercapto-1-hexahydropyridinyl)indolyl] stupid base Ν'_(2·methylpropyl)_3-吼咬-(5-bromo-2-cyano-4-pyrimidinyl)-bu[(4-mercapto-1-hexahydropyrryl)indolyl]-N'-(2-indenyl) Propyl)-1·benzofurancarbazide; N'_(5U-cyano-4_ Pyrimidinyl)-5_[(4-fluorenylhexahydropyranyl)mercapto]-Ν'-(2-mercaptopropyl)-2-nonylcarbazone; and pharmaceutically acceptable derivatives thereof 10. At least one chemical entity selected from the group consisting of: N'_(5U-cyano-4-pyrimidinyl)-4-[(4-indolylhexahydropyranyl)mercaptopropyl)benzene曱醯肼Trifluoroacetate; '-(5-bromo-2-cyano-4-pyrimidinyl)-pyro-(2-mercaptopropyl)-4-[(4-propyl-1_hexahydroindole) Plough base] fluorenyl] phenylhydrazine trifluoroacetate; Ν'-(5-; odor-2-cyano-4-pyrimidinyl)-Ν'-(2-mercaptopropyl)-3-[ (4-propyl hexahydropyridinyl) fluorenyl] phenylhydrazine trifluoroacetate; 174 200804352 ^'-(5-gas 2 -cyano-4-pyrimidinyl)-Ν'-(2 -mercaptopropyl)-4_[(4-propyl hexahydropyranyl) fluorenyl] benzamidine trifluoroacetate; N'-(5-Gas-2-cyanopiperidinyl)_Ν '-(2-Mercaptopropyl)_3_[(4-propyl hexahydropyranyl)methyl]phenylhydrazine trifluoroacetate; Ν'(5-act-2-cyano-4-密σ定基)-4-Gas-Ν'-(2-Mercaptopropyl)-3-[(4-propyl-1-hexahydropyrryl)methyl]phenylhydrazine trifluoroacetate ;Ν'-(5-gas_2_cyano-4" Tertiary)-4-fluoro-Ν'-(2-mercaptopropyl)-3-[(4-propyl-1 gastric hexahydropyranyl) fluorenyl] benzamidine trifluoroacetate; 4 -(1,4'-bipyridinyl-1'-ylindenyl)-1^'-(5-aero-2-cyano-4-pyrimidinyl)-N'-(2-mercaptopropyl Benzoguanidine trifluoroacetate; N'-(5-bromo-2-cyano pralinyl)-N'-(2-methylpropyl)-4-(1-hexahydropyridylmethyl Phenylhydrazine trifluoroacetate; N-(5->Smell-2-mercapto-4-mercapto)-Ν'-(2-mercaptopropyl)-4-(1-. Ratio of 17 σ 曱曱 base) phenyl hydrazine trifluoroacetate; gas-2-cyano _4_ gnach base · · 4-[(2,6-didecyl hexahydropyranyl) A ]]-Ν'-(2-mercaptopropyl)phenylhydrazine trifluoroacetate; 1-[(4-{[2-(5-Gas-2-cyano-4-pyrimidinyl)-2 -(2-mercaptopropyl)indenyl]carbonyl} phenyl)mercapto]-4-hexahydropyridinecarboxylate ethyl ester trifluoroacetate; N-{(3R)_l_[(4-{[2- (5-Gas-2-cyano-4-pyrimidinyl)-2-(2-methylpropyl)indolyl]yl}phenyl)methyl]-3-pyrrolidinyl}acetamidotrifluoro Acetate; {1-[(4-{[2-(5-chloro-2-cyano-4-pyrimidinyl)-2_(2-methylpropyl)indolyl)-yl}phenyl)methyl [-3-pyrrolidyl} guanidinium carbamate, [-didecylethyl ester trifluoroacetate; N'-(5-Gas-2-cyano-4-pyrimidinyl)-4-[(4 -{2-[(2-hydroxyethyl)oxy]ethyl 175 200804352 】}-1 hexahydropyridyl) fluorenyl]-:^,-(2-mercaptopropyl)benzoquinone Fluoroacetate; helium cyano-4-pyrimidinyl)-N,-(2-mercaptopropyl)-4-(1-hexahydroindenyl) phenylhydrazine tri-IL acetate; N '-(5-Gas-2-cyano-4-pyrimidinyl)-4-{[(2R)-2-(hydroxyindenyl)pyrididine曱基} conditions_(2_mercaptopropyl) benzamidine trifluoroacetate; N'-(5-Gas-2-cyano-4-pyrimidinyl)-N'-(2-methyl Propyl)-4-(1-pyrrolyl) phenylhydrazine trifluoroacetate; N _(5-gas·2·cyano_4_mouth thiol)·4-(2,5 _Dihydro-1H-fluoren-1-ylindenyl)-Ν'_mercaptopropyl)phenylhydrazine trifluoroacetate; Ν'_(5-Gas-2-cyano-4-pyrimidinyl) -4-[(2,5-dimercapto-2,5-dihydro]indole-pyrrolidin]-yl)indenyl]-indole-(2-methylpropyl)phenylhydrazinetrifluoroacetic acid Salt; gas 1 cyano-4-pyrimidinyl)_2_(2-methylpropyl)indenyl]carbonyl}phenyl)decyl H-hexahydropyridyl} dimethyl carbamic acid trifluoroacetate ; N'_(5-Gas-2-cyano-4-pyrimidinyl)_4-({4-[3-(dimethylamino)propyl]_丨_hexahydropyranyl}methyl)- N'-(2-methylpropyl)benzimidazole trifluoroacetate; N, (54_2-cyano-4-pyrimidinyl)-N,_(2-mercaptopropyl)-4-({ 4_[3-(4-Mercapto)propyl]-1-hexahydropyrrole}methyl)benzamide trifluoroacetate; =-(5-gas-2-cyano-4- Pyrimidinyl)-4·({4-[3·(diethylamino)propyl]-dihexahydropyrryl}methyl)-Ν -(2-mercaptopropyl)benzimidium trifluoroacetate; = gas 5-chloro-2-cyano-4-pyrimidinyl)_4_({4-[3-(dipropylamino)propyl);卜六六六 } } } methyl}-Ν'-(2-mercaptopropyl) benzamidine trifluoroacetate; Ν-(5-Gas-2-cyanopyrimidinyl)_4_({4 -[3_(di_2•propene_丨_ylamino) 176 200804352 propyl >1-hexahydroindolyl}methyl>N,-(2-mercaptopropyl)benzamide III Fluoroacetate; N'-(5-Gas-2-cyano-4-pyrimidinyl)-4-({4-[(1-indolyl-4-hexahydropyridyl)indolyl] hexahydropyrrolidine耕基}曱基)...,#-mercaptopropyl)phenylhydrazine trifluoroacetate; N'-(5-gas-2-cyano-4-pyrimidinyl)_4_{[4-(1- Methyl-4-hexahydropyridyl)-1-hexahydroindolyl]methyl}_N, gastriyl propyl)phenylhydrazine trifluoroacetate; {1-[(4-{[2- (5-chloro-2-cyano-4-pyrimidinyl)-2-(2-methylpropyl)indenyl]carbonyl}phenyl)indolyl]-3-hexahydropyridinyl}ethyl acetate trifluoro Acetate; N'-(5-Gas-2-cyano-4-pyrimidinyl)-4-({4-[2-(diethylamino)ethyl]-1-hexahydroindole. Well base} fluorenyl)-N, _(2_f-propyl) benzamidine trifluoroacetate; N'-(5-gas_2-cyano-4-pyrimidinyl)-4-({4- [2-(di-2-propenylamino)ethyl]-1-hexahydropyrryl}methyl)-N,-(2-methylpropyl)benzhydrazide trifluoroacetate; N'-(5-Gas-2-cyano-4.pyrimidinyl)-4·({4-[2-(dipropylamino)ethyl]-1-hexahydroindole) methyl)-Ν '-(2-Mercaptopropyl)phenylhydrazine trifluoroacetate; Ν'-(5-Gas-2-cyano-4-pyrimidinyl)-3-[(2,6-dimethyl- 1-hexahydropyridyl)methyl>Ν'-(2-mercaptopropyl)benzhydrazide trifluoroacetate; 3-(1,4,bipiperidin-1'-ylmethyl) _;^,_(5_Gas_2_cyano-4_pyrimidinyl)-Ν'_(2_methylpropyl)benzimidazole trifluoroacetate; Ν'-(5-gas-2 -cyano-4-pyrimidinyl)->1'-(2-methylpropyl)-3-(1-hexahydropyridylmethyl)benzhydrazide trifluoroacetate; NM5-gas- 2-cyano-4-pyrimidinyl)-3-({4-[3-(dipropylamino)propyl) small hexa 177 200804352 Hydrogen pyridinyl}methyl)-N,-(2-methylpropane Benzoquinone trifluoroacetate; N'_(5-gas-2-cyano-4-pyrimidinyl)_3-({4-[3-(diethylamino) Propyl] small hexahydropyranyl}methyl)-N,-(2-mercaptopropyl)benzhydrazide trifluoroacetate; N'-(5-aero-2-cyano-4-pyrimidine )-(5-Gas-2-cyanide; Ν'-(5-Gas-2-cyanide; ('-(2-mercaptopropyl) fluorenyltrifluoroacetate 4-pyrimidinyl)-4-{[4-(2-hydroxyethyl)-1-hexahydropyridyl]methyl b N'-(2-mercaptopropyl)phenylhydrazine trifluoroacetic acid Salt; N (5 - gas - 2 - chaotic - 4 ° dense bite) - 4 {[4-(2-transethyl)-1 - six gas batch ° well base] 曱基卜Ν' -(2-mercaptopropyl)phenylhydrazine trifluoroacetate; Ν'-(5-Gas-2-cyano-4-pyrimidinyl)-4-{[4-(hydroxyindenyl)-1 - hexahydropyridyl] fluorenyl}-N'-(2-mercaptopropyl)phenylhydrazine trifluoroacetate; 1-[(4-{[2-(5-chloro-2-cyano)- 4-pyrimidinyl)-2-(2-methylpropyl)indenyl]carbonyl}phenyl)methyl]-N,N-didecyl-L-indoleamine guanamine trifluoroacetate; azetidinyl Indole, -(5-bromo-2-cyano-4-pyrimidinyl)-N,-(2-methylpropyl)phenylhydrazine trifluoroacetate; >^'-(5 -Gas_2-cyano"4_pyrimidinyl)-:^,-(2-methylpropyl)-4-{[(28)-2-(1_t each bite Carbonyl)-1-pyridyl π each] thiol}benzazole trifluoroacetate; N'-(5U-cyano-4-pyrimidinyl)-N'-(2-mercaptopropyl)- 4_{[4-(4-Morfolinyl)-1-pyrrolidinyl]fluorenyl}phenylhydrazine trifluoroacetate; N'-(5-Gas-2-cyano-4-pyrimidinyl) -N,-(2-mercaptopropyl)-4_({4-[2-(1_hexahydropyridyl)ethyl]-1-hexahydropyrrolidinyl}indenyl)phenylfluorene Acetate; N'-(5-Gas-2-cyano-4-pyrimidinyl)-4-({'[(1-indolyl_3_hexahydropyridinyl)methyl]-1_hexahydroindole Tonsyl}mercapto)-Ν'-(2-mercaptopropyl) alum trifluoride 178 200804352 acetate; N'-(5-Gas-2-cyano-4-pyrimidinyl)-N' -(2-methylpropyl)_4-({4_[3_(l-hexahydropyridyl)propyl]-1-hexahydropyrryl}}yl)phenylhydrazine trifluoroacetate; N' -(5-chloro-2-cyano-4-pyrimidinyl)-4-{[4-(diethylamino)-1-hexahydropyridyl]methyl b N'-(2-methylpropyl Benzoquinone trifluoroacetate; N'-(5-Gas-2-cyano-4-pyrimidinyl)-4-{[4-(4-mercapto-1-hexahydropyrrole)- 1-hexahydropyridyl]fluorenyl}-N,-(2-mercaptopropyl)phenylhydrazine trifluoroacetate; N'_(5-chloro-2-cyanide 4-pyrimidinyl)-N'-(2-mercaptopropyl)-4-{[4-(4-pyridylhexahydropyrrolidinyl)fluorenyl}benzimidium trifluoroacetate; N' -(5-gas_2_cyano-4-pyrimidinyl)-N,-(2-mercaptopropyl)-4-({4_[2-(1′′)pyrryl)ethyl]-1 - hexahydropyranyl}methyl)benzhydrazide trifluoroacetate; N'-(5-Gas-2-cyano-4-pyrimidinyl)-4-({4-[2-(dioxin) Amino)ethyl]hexahydroindolyl}indenyl)-N,-(2-methylpropyl)benzhydrazide trifluoroacetate; N (5-gas-2-nitrogen-4_only唆-)-N'-(2-mercaptopropyl)_3_(1 - 吼 σ 定定曱 )) phenylhydrazine trifluoroacetate; Ν (5-fluoro-2 - gas-based -4- σ dense Oleto)-N,-(2-mercaptopropyl)-3-{[4-(4-norfosyl)>1-hexahydropyridyl]fluorenyl}phenylhydrazine trifluoroacetate; N (5-Gas-2-Gas-based sigma)-3-{[4-(2-P-ethyl)-1-hexahydro-u ratio σ well base] 曱基卜Ν,-(2-曱Propyl) benzamidine trifluoroacetate; hydrazine (5-gas-2-cyano-4-densyl)-3-{[4-(transylhydrazino)-1-hexahydro. Ratio σ well base] 曱基卜Ν '-(2-mercaptopropyl) benzamidine trifluoroacetate; ΝΜ5-gas-2-cyano-4-pyrimidinyl)-Ν'-(2-A Propyl)-3-({4-[3-(1_六179 200804352 hydropyridyl)propyl: Μ-hexahydropyrrole} fluorenyl) phenylhydrazine trifluoroacetate; gas _2 _Cyano-4-pyrimidinyl)-3-{[4-(4-mercapto-1-hexahydropyrrole)-1-hexahydropyridinyl]methyl bromide,-(2-mercaptopropyl Benzopyridinium trifluoroacetate; Ν'_(5-Gas-2-cyano+pyrimidinyl)-3-{[4-(diethylamino) hexahydropyridyl] sulfhydryl '-(2-Mercaptopropyl)benzoquinone hydrazine trifluoroacetate; Ν'-(5-Gas-2-cyano-pyrimidinyl)-3-({4-[2-(diethylamino) Ethyl]-1-hexahydropyranyl}methyl)-indole,-(2-mercaptopropyl)benzamide trifluoroacetate; 1^'-(5_gas-2-cyano 4-pyrimidinyl)-3-{[4-(1-indolyl-4-hexahydropyridinyl)-1-hexahydropyrrole]methyldiphenyl,-(2-methylpropyl)benzene曱醯胼Trifluoroacetate; Ν, (5-Gas-2-cyano-4-pyrimidinyl)-Ν'-(2-methylpropyl)-3-({4-[3-(4-吗福基基)propyl]-1-hexahydropyrrole} fluorenyl) phenylhydrazine trifluoroacetate; Ν'_(5 - gas-2-cyano-4-pyrimidinyl)-indole'_(2-methylpropyl)-3-({4-[2-(1-pyridyl)ethyl]_1_hexahydro Pyridinyl}indenyl)benzamide trifluoroacetate; Ν(5-aero-2-oxo-4-3⁄4 ate)-3-({4-[(1-methyl-4-6) Nitrogen-to-bite base) fluorenyl hexahydropyranyl} fluorenyl)-N,-(2-methylpropyl)benzhydrazide trifluoroacetate; 1^'_(5-gas-2-cyanide 4-pyrimidinyl)-^[,-(2-methylpropyl)-3-({4-[2-(1-hexahydroport))ethyl]-1-hexahydropyrazine Phenylhydrazine trifluoroacetate; N, (5-gas-2_cyano-4-pyrimidinyl)-4-fluoro-N,-(2-methylpropyl)_3-{ [4-(4-Isofosyl)-1 -hexahydropyridyl]methyl}benzhydrazide trifluoroacetate; 180 200804352 N'_(5-chloro-2-cyano-4-pyrimidinyl Winter fluoro_3-{[4-(hydroxyindenyl) hexahydropyridinyl] fluorenyl}-N'-(2-mercaptopropyl)phenylhydrazine trifluoroacetate; 3 - (1, 4 '- 联六鼠口比ϋ定-1 '-ylmethyl)-N' - (5 - gas-2 - gas base-4_ 口密^定基)-4-fluoro-N'-(2- Mercaptopropyl) awkward trifluoroacetate; N'-(5-gas-2_murine_4_^ϋ定基)_4_气-3-[(4-mercapto-1-hexazone) ratio Well base) fluorenyl]-N'-(2-mercaptopropyl) benzamidine trifluoroacetate; N'-(5-bromo-2-cyano-4-pyrimidinyl)-4-{[ 4-(4•Methyl-1-hexahydropyrrole)-1-hexahydrotolylhydrazinyl]indolyl N'-(2-mercaptopropyl)benzhydrazide trifluoroacetate; N' -(5-bromo-2-cyano-4-pyrimidinyl)-5-[(4-mercapto-1-hexahydropyrryl)indenyl]-N'-(2-mercaptopropyl)- 3-isoxazole, carbamazepine trifluoroacetate; N'-(5-> odor-2-yl-4-yl thiol)-7-[(4-mercapto-1-hexanitrogen-17 ratio研基]曱基]-N'-(2-methylpropyl)-1_benzoindole-2-carbamate di-acetate; N'-(5-> odor-2-murine-4 -13-bite base)-5-[(4-mercapto-1-hexanitrogen- 17 ΰ 基 base) fluorenyl]-Ν'-(2-mercaptopropyl)-2-bitankabeng 4_ Mercaptophthalein trifluoroacetate; N'-(5-> odor-2-muryl-4-^σ-based)-6-{3-[(4-mercapto-1-hexanitro)比比 ] ] ] ] ] ] ] ] ] ] - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - -4- ϋ ϋ ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) -吼σ定卡巴耕三氯酸盐Ν -(5->odor 2 - gasyl-4-^σ定基)-5-{4-[(4-mercapto-1 - hexanitroport) sulfhydryl]phenyl}-oxime '-(2-Mercaptopropyl)-3_ϋ is a bite of kappa 胼三敦 acetate; Ν'-(5-bromo-2-cyano-4-pyrimidinyl)-5-{3-[(4-曱-1-1_hexahydropyrrole) fluorenyl]phenyl}-Ν'-(2-methylpropyl)-3-indole 0-carbazone trifluoroacetate; 181 200804352 N'-(5-bromo- 2-cyano group such as dimethyl sulfonate) _5|methyl hexahydropyrene hydrazide) a = (2 - methyl propyl) + benzopyridin 2 - carbazone trifluoroacetate; and = _ (512_Cyano-4+) _5-[(4-Methyl hexahydro(tetra)yl)methyl]-oxime-(2-methylpropyl)_2 "Sentene Kaba Cultivate Sandon Acetate.虞 Apply for any of the scope of the patent range from item 1 to item 1, which is used for medical treatment. Seeding 12. A use of at least the condition of any of the items 1 to 1G of the patent application. Yishen + prolyl protease inhibitors. - 13. The use of chemical entities in the first to third paragraphs of the patent application for the treatment of dysentery. 〉 A kind of glycerol-like enzyme for treating human or animal patients suffering from a disease, 丨介的的的申请申请申请申请申请申请申请申请申请申请申请申请申请申请申请申请申请申请申请申请申请申请申请申请申请申请It is used to treat a self-concerned person to a chemical entity. The treatment of a human or animal suffering from a cancerous disease, which kills ~丄, contains an effective amount according to the scope of the patent application of the first to the first::; read at least one chemical entity. Any one of the members of the pharmacy composition of the medicinal composition. A pre-attachable γ.-type is used to prepare a method according to the application, which is used in the formula η compound, the scope of the formula is used in the formula r _ R2 ^ according to the patent application in the patent application scope (4) Using the two 182 200804352 diagram reaction h2n,

18· —種用於製備根據申請專利範物之方法，其係從對應的式χπ 項疋義的式I化合是根據在申請專利範圍第1項中用於;^月井化合物，其中R4 片τ用於式j之定義且化乂是_ 芳基齒基匕3伸烧基或-雜芳基-芳基_基〇13伸烷基，經由與式XIII化合物，该化合物是雜環基或雜環基_r:，例如化合物XIII是“X，，或“X_RJ，，，其中“X，，及“X_RJ，，是根據在申請專利範圍第1項中用於式I之定義，根據下面圖示反應。18. A method for preparing a method according to the patent application, which is based on the formula χ π 疋是是是是是是是是是是是是是是是 ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ τ is used for the definition of formula j and is _ aryl aryl 匕 3 伸 alkyl or -heteroaryl-aryl yl 〇 13 alkyl, via a compound of formula XIII, the compound is a heterocyclic group or Heterocyclyl-r:, for example, compound XIII is "X," or "X_RJ,, wherein "X,, and "X_RJ," are used according to the definition of Formula I in Item 1 of the scope of the patent application, according to the following The reaction is shown.

_驗 ”x"或"X-RJ" XIII_ test "x" or "X-RJ" XIII

CN 183 200804352 七、指定代表圖： (一）本案指定代表圖為：第（無）圖。 (二）本代表圖之元件符號簡單說明：無八、本案若有化學式時，請揭示最能顯示發明特徵的化學式：CN 183 200804352 VII. Designation of representative representatives: (1) The representative representative of the case is: (No). (2) A brief description of the symbol of the representative figure: None 8. If there is a chemical formula in this case, please disclose the chemical formula that best shows the characteristics of the invention:

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