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      治療神經(jīng)失調(diào)的咪唑并嘧啶和咪唑并吡啶的制作方法

      文檔序號:965879閱讀:347來源:國知局
      專利名稱:治療神經(jīng)失調(diào)的咪唑并嘧啶和咪唑并吡啶的制作方法
      技術(shù)領(lǐng)域
      本發(fā)明領(lǐng)域本發(fā)明涉及新的化合物、組合物和治療精神紊亂和神經(jīng)疾病的方法,這些疾病包括主要的抑郁癥、與焦慮相關(guān)的紊亂、創(chuàng)傷后應(yīng)激紊亂、核上庥痹和飲食紊亂以及治療免疫的、心血管的或與心臟相關(guān)的疾病和與精神病理性障礙和應(yīng)激有關(guān)的腸道超敏反應(yīng)。特別地,本發(fā)明涉及新的咪唑并嘧啶和咪唑并吡啶、含有這樣化合物的藥用組合物和它們在治療精神紊亂、神經(jīng)疾病、免疫學(xué)的、心血管的或與心臟相關(guān)的疾病和與精神病理性障礙和應(yīng)激有關(guān)的腸道超敏反應(yīng)的用途。
      本發(fā)明背景促腎上腺素皮質(zhì)激素釋放因子(在此表示為CRF)為41個氨基酸的肽,它是從垂體前葉腺分泌的阿黑皮素原(proopiomelanocortin)(POMC)-衍生肽的主要生理調(diào)節(jié)劑[J.Rivier等,Proc.Nat.Acad.Sci.(USA)804851(1983);W.Vale等,Science 2131394(1981)]。除了它在前葉腺的內(nèi)分泌作用之外,CRF的免疫組織化學(xué)的定位作用已經(jīng)證實該激素在中樞神經(jīng)系統(tǒng)具有廣泛的下丘腦外的紊亂作用并且產(chǎn)生與在大腦中神經(jīng)遞質(zhì)或神經(jīng)調(diào)節(jié)物質(zhì)的作用相一致的廣譜自律的、電生理的和行為的作用[W.Vale等,Rec.Prog.Horm.Res.39245(1983);G.F.Koob,Persp.Behav.Med.239(1985);E.B.De Souza等,J.Neurosci.53189(1985)]。也有證據(jù)表明CRF在使免疫系統(tǒng)的應(yīng)答結(jié)合到生理的、精神的和免疫學(xué)的應(yīng)激子中起著重要的作用[J.E.Blalock,Physiological Reviews 691(1989);J.E.Morley,Life Sci.41527(1987)]。
      臨床數(shù)據(jù)提供了證據(jù)即CRF在精神紊亂和神經(jīng)疾病包括抑郁癥、與焦慮相關(guān)的紊亂和飲食紊亂方面起著重要的作用。對于CRF的作用已經(jīng)在阿爾滋海默氏病、帕金森氏病、亨廷頓氏病、進(jìn)行性核上麻痹和肌萎縮外側(cè)硬化病的病因?qū)W和病理生理學(xué)中被假定為它們與在中樞神經(jīng)系統(tǒng)中的CRF神經(jīng)元機能紊亂有關(guān)[有關(guān)綜述參見E.B.De Souza,Hosp.Practice 2359(1988)]。
      在情感障礙中或主要的抑郁癥中,在沒有藥物的個體的腦脊液(CSF)中CRF的濃度顯著增加[C.B.Nemeroff等,Science 2261342(1984);C.M.Banki等,Am.J.Psychiatry 144873(1987);R.D.France等,Biol.Psychiatry 2886(1988);M.Arato等,Biol.Psychiatry 25355(1989)]。此外,在自殺犧牲者的前額皮質(zhì)中CRF受體的密度明顯減少,這與CRF的過度分泌相一致[C.B.Nemeroff等,Arch.Gen.Psychiatry 45577(1988)]。另外,在抑郁的患者中觀察到存在對CRF(靜脈給予)的鈍化的促腎上腺素皮質(zhì)激素(ACTH)應(yīng)答[P.W.Gold等,Am.J.Psychiatry 141619(1984);F.Holsboer等,Psychoneuroendocrinology9147(1984);P.W.Gold等,New Eng.J.Med.3141129(1986)]。對于CRF的過度分泌可能涉及到在人抑郁癥中所看到的癥狀的假設(shè),大鼠和非人靈長目的臨床前研究為這種假設(shè)提供了支持[R.M.Sapolsky,Arch.Gen.Psychiatry 461047(1989)]。存在初步的證據(jù)即三環(huán)類抗抑郁藥物能夠改變CRF水平并且由此調(diào)節(jié)CRF受體在大腦中的數(shù)量[Grigoriadis等,Neuropsychopharmacology 253(1989)]。
      也據(jù)此假設(shè)CRF在與焦慮相關(guān)的疾病的病因?qū)W中起作用。CRF在動物中產(chǎn)生焦慮樣效應(yīng)并且在苯并二氮雜/非苯并二氮雜抗焦慮藥物與CRF之間的相互作用已經(jīng)在多種行為焦慮模型上得到證實[D.R.Britton等,Life Sci.31363(1982);C.W.Berridge和A.J.DunnRegul.Peptides 1683(1986)]。使用推測了氨基酸序列的CRF受體拮抗劑a-螺旋ovine CRF(9-41)在多種行為paradigms的初步研究中證實該拮抗劑產(chǎn)生了與苯并二氮雜類性質(zhì)相似的“抗焦慮樣”作用[C.W.Berridge和A.J.Dunn Horm.Behav.21393(1987),Brain ResearchReviews 1571(1990)]。
      神經(jīng)化學(xué)的、內(nèi)分泌的和受體結(jié)合研究已經(jīng)全部證實CRF和苯并二氮雜類抗焦慮藥物之間的相互作用,對于CRF與這些疾病有關(guān)提供了進(jìn)一步的證據(jù)。氯氮(chlordiazepoxide)在兩個沖突的試驗[K.T.Britton等,Psychopharmacology 86170(1985);K.T.Britton等,Psychopharmacology 94306(1988)]中和在大鼠的聽覺驚跳試驗[N.R.Swerdlow等,Psychopharmacology 88147(1986)]中減弱CRF的“焦慮樣”作用。在操作沖突的試驗中單獨無行為活性的苯并二氮雜受體拮抗劑(Ro15-1788)以劑量依賴關(guān)系逆轉(zhuǎn)CRF的作用,而苯并二氮雜反轉(zhuǎn)激動劑(FG7142)則增強CRF的作用[K.T.Britton等,Psychopharmacology 94306(1988)]。
      進(jìn)一步假定CRF在免疫的、心血管或與心臟相關(guān)的疾病如高血壓、心動過速和充血性心力衰竭、中風(fēng)、骨質(zhì)疏松癥、早產(chǎn)、心理侏儒癥、應(yīng)激引起的發(fā)熱、潰瘍、腹瀉、術(shù)后腸梗阻和涉及心理病理學(xué)的紊亂和應(yīng)激有關(guān)的結(jié)腸超敏反應(yīng)中起作用。
      標(biāo)準(zhǔn)抗焦慮藥物和抗抑郁藥物借以產(chǎn)生它們的治療作用的作用機制和位點有待闡明。然而,已經(jīng)假設(shè)它們與抑制在這些失調(diào)中觀察到的CRF的過度分泌有關(guān)。其中特別重要的是在多種行為paradigms中檢測到CRF受體拮抗劑(a-螺旋CRF9-41)的作用的初步研究已經(jīng)證實該CRF拮抗劑產(chǎn)生與苯并二氮雜類性質(zhì)相似的“抗焦慮樣”作用[綜述參見G.F.Koob和K.T.Britton,在Corticotropin-ReleasingFactorBasic and Clinical Studies of a Neuropeptide,E.B.De Souza和C.B.Nemeroff eds.,CRC Press第221頁(1990)]。
      DuPont Merck PCT申請US 94/11050描述了下式的促腎上腺素皮質(zhì)激素釋放因子拮抗劑化合物
      和它們的治療精神紊亂和神經(jīng)疾病的用途。在該說明書中包括了下式稠和的吡啶和嘧啶
      其中V為CR1a或N;Z為CR2或N;A為CR3O或N和D為CR28或N。
      其它所報道的具有如促腎上腺素皮質(zhì)激素釋放因子的活性的化合物在WO 95/33750、WO 95/34563和WO 95/33727中得到公開。
      本發(fā)明概述一方面,本發(fā)明提供了與促腎上腺素皮質(zhì)激素釋放因子受體結(jié)合從而改變CRF分泌的焦慮樣作用的新化合物。本發(fā)明化合物用于在哺乳動物中治療精神紊亂和神經(jīng)疾病、與焦慮相關(guān)的失調(diào)、創(chuàng)傷后應(yīng)激紊亂、核上麻痹和飲食紊亂以及治療免疫的、心血管的或與心臟相關(guān)的疾病和與精神病理性障礙和應(yīng)激有關(guān)的結(jié)腸超敏反應(yīng)。
      另一方面,本發(fā)明提供了用作促腎上腺素皮質(zhì)激素釋放因子拮抗劑的式(I)的新化合物(以下所述)。本發(fā)明化合物作為促腎上腺素皮質(zhì)激素釋放因子拮抗劑呈現(xiàn)活性并且似乎抑制CRF過度分泌。本發(fā)明也包括含有式(I)化合物的藥用組合物和使用這樣的化合物抑制CRF過度分泌和/或治療焦慮樣失調(diào)的方法。
      另一方面,本發(fā)明提供了新的化合物、藥用組合物和可用于治療情感障礙、焦慮、抑郁、應(yīng)激性腸道綜合征、創(chuàng)傷后應(yīng)激紊亂、核上麻痹、免疫抑制、阿爾滋海默氏病、胃腸疾病、神經(jīng)性厭食或其它飲食紊亂、藥物或酒精成癮戒除癥、藥物成癮、炎性疾病、生育問題、紊亂的方法,通過拮抗CRF起作用或促進(jìn)的治療包括(但不局限于)CRF引起或促進(jìn)的疾病或選自炎性疾病如類風(fēng)濕性關(guān)節(jié)炎和骨關(guān)節(jié)炎、疼痛、哮喘、牛皮癬和變態(tài)反應(yīng)的疾病、泛化焦慮失調(diào)、驚恐、恐怖癥、強迫與觀念行為失調(diào)、創(chuàng)傷后應(yīng)激紊亂、緊張引起的睡眠失調(diào)、疼痛知覺如纖維肌痛、情緒紊亂如抑郁、包括主要抑郁、單一發(fā)作抑郁、復(fù)發(fā)性抑郁、抑郁引起的兒童噁習(xí)和產(chǎn)后抑郁、精神抑郁癥、雙相情感障礙、循環(huán)情感性氣質(zhì)、疲勞綜合征、應(yīng)激引起的頭疼、癌癥、人免疫缺陷病毒(HIV)感染、神經(jīng)退化性疾病如阿爾滋海默氏病、帕金森氏病和亨廷頓氏病、胃腸疾病如潰瘍、應(yīng)激性腸道綜合征、節(jié)段性回腸炎、痙攣性結(jié)腸、腹瀉和術(shù)后腸梗阻和與心理病理學(xué)紊亂和應(yīng)激有關(guān)的結(jié)腸超敏反應(yīng)、飲食紊亂如神經(jīng)性厭食和貪食癥、出血性緊張、應(yīng)激引起的精神病發(fā)作、甲狀腺機能患病綜合征、不適宜的止瀉激素(ADH)綜合征、肥胖、不育癥、頭部創(chuàng)傷、脊髓創(chuàng)傷、局部缺血神經(jīng)元損傷(例如大腦局部缺血如腦海馬局部缺血)、興奮毒性神經(jīng)元損傷、癲癇、心血管和與心臟相關(guān)的疾病包括高血壓、心動過速和充血性心力衰竭、中風(fēng)、免疫機能紊亂包括應(yīng)激引起的免疫機能紊亂(例如應(yīng)激引起的發(fā)熱、豬樣應(yīng)激綜合征、牛樣裝船發(fā)熱、馬樣陣發(fā)纖維性顫動和雞樣孵化引起的機能紊亂、羊樣絕對應(yīng)激(sheering stress)或人-動物相互作用有關(guān)的犬樣應(yīng)激)、肌肉痙攣、尿失禁、阿爾滋海默氏型的老年性癡呆、多重梗塞癡呆、肌萎縮外側(cè)硬化病、化學(xué)依賴性和成癮(例如依賴酒精、可卡因、海洛因、苯并二氮雜類或其它的藥物)、藥物和酒精成癮戒除癥、骨質(zhì)疏松癥、心理侏儒癥和哺乳動物中的血糖過少。
      根據(jù)本發(fā)明的另一方面,本發(fā)明提供的化合物(并且特別標(biāo)記為這個發(fā)明的化合物)在測量結(jié)合于該CRF受體的潛在的藥物的能力中也用作標(biāo)準(zhǔn)品和試劑。
      本發(fā)明詳述[1]因此,在第一個實施方案中,本發(fā)明提供了式I的新化合物
      或其立體異構(gòu)體或藥學(xué)上可接受的鹽形式,其中A為N或C-R7;B為N或C-R8;假定基團(tuán)A和B中至少一個為N;D為通過不飽和碳原子連接的芳基或雜芳基基團(tuán);X選自基團(tuán)CH-R9、N-R10、O、S(O)n和鍵;n為0、1或2;R1選自C1-10烷基、C2-10鏈烯基、C2-10炔基、C3-8環(huán)烷基、C3-6環(huán)烷基-C1-6烷基、C1-4烷氧基-C1-4烷基、-SO2-C1-10烷基、-SO2-R1a和-SO2-R1b;R1由0-1個選自基團(tuán)-CN、-S(O)nR14b、-COR13a、-CO2R13a、-NR15aCOR13a、-N(COR13a)2、-NR15aCONR13aR16a、-NR15aCO2R14b、-CONR13aR16a、1-嗎啉基、1-哌啶基、1-哌嗪基和C3-8環(huán)烷基的取代基來取代,其中在C4-8環(huán)烷基中的0-1個碳原子以選自-O-、-S(O)n-、-NR13a-、-NCO2R14b-、-NCOR14b-和-NSO2R14b-的基團(tuán)取代,并且其中在1-哌嗪基中的N4由0-1個選自基團(tuán)R13a、CO2R14b、COR14b和SO2R14b的取代基來取代;R1也由0-3個在每一個情況下獨立選自基團(tuán)R1a、R1b、R1c、C1-6烷基、C2-8鏈烯基、C2-8炔基、Br、Cl、F、I、C1-4鹵代烷基、-OR13a、-NR13aR16a、C1-4烷氧基-C1-4烷基和由0-1個R9取代的C3-8環(huán)烷基的取代基取代并且其中C4-8環(huán)烷基的0-1個碳被-O-替代;前提是R1不是(a)環(huán)己基-(CH2)2-基團(tuán);(b)3-環(huán)丙基-3-甲氧基丙基基團(tuán);(c)不飽和-(烷氧基)甲基基團(tuán);和,(d)1-羥基烷基基團(tuán);另外的前提是當(dāng)R1烷基由OH取代,那么鄰近該環(huán)N的碳不是CH2;R1a為芳基并且選自基團(tuán)苯基、萘基、2,3-二氫化茚基和茚基,每一個R1a由0-1個-OR17和0-5個在每一個情況下獨立選自C1-6烷基、C3-6環(huán)烷基、Br、Cl、F、I、C1-4鹵代烷基、-CN、硝基、SH、-S(O)nR18、-COR17、-OC(O)R18、-NR15aCOR17、-N(COR17)2、-NR15aCONR17aR19a、-NR15aCO2R18、-NR17aR19a和-CONR17aR19a的取代基取代;R1b為雜芳基和選自基團(tuán)吡啶基、嘧啶基、三嗪基、呋喃基、喹啉基、異喹啉基、噻吩基、咪唑基、噻唑基、吲哚基、吡咯基、噁唑基、苯并呋喃基、苯并噻吩基、苯并噻唑基、苯并噁唑基、異噁唑基、吡唑基、三唑基、四唑基、吲唑基、2,3-二氫苯并呋喃基、2,3-二氫苯并噻吩基、2,3-二氫苯并噻吩基-S-氧化物、2,3-二氫苯并噻吩基-S-二氧化物、二氫吲哚基、苯并噁唑啉-2-酮基、苯并二氧戊環(huán)基和苯并二噁烷,每一個雜芳基在0-4個碳原子上由在每一個情況下獨立選自下列的取代基取代C1-6烷基、C3-6環(huán)烷基、Br、Cl、F、I、C1-4鹵代烷基、-CN、硝基、-OR17、SH、-S(O)mR18、-COR17、-OC(O)R18、-NR15aCOR17、-N(COR17)2、-NR15aCONR17aR19a、-NR15aCO2R18、-NR17aR19a和-CONR17aR19a,并且每一個雜芳基在任何氮原子上被0-1個選自基團(tuán)R15a、CO2R14b、COR14b和SO2R14b的取代基取代;R1c為雜芳基并且為飽和的或部分飽和的雜芳基,每個雜芳基在0-4個碳原子上用在每一個情況下獨立選自下列的取代基取代C1-6烷基、C3-6環(huán)烷基、Br、Cl、F、I、C1-4鹵代烷基、-CN、硝基、-OR13a、SH、-S(O)nR14b、-COR13a、-OC(O)R14b、-NR15aCOR13a、-N(COR13a)2、-NR15aCONR13aR16a、-NR15aCO2R14b、-NR13aR16a和-CONR13aR16a,并且每一個雜環(huán)基在任何氮原子上用0-1個選自基團(tuán)R13a、CO2R14b、COR14b和SO2R14b的取代基取代并且其中任何硫原子任選地單氧化或雙氧化;前提是R1不是-(CH2)1-4-芳基、-(CH2)1-4-雜芳基或-(CH2)1-4-雜環(huán),其中該芳基、雜芳基或雜環(huán)基團(tuán)被取代或未取代;R2選自基團(tuán)C1-4烷基、C3-8環(huán)烷基、C2-4鏈烯基和C2-4炔基并且由0-3個選自基團(tuán)-CN、羥基、鹵代和C1-4烷氧基的取代基取代;或者R2在其中X為鍵的情況下選自-CN、CF3和C2F5;R3、R7和R8在每一個情況下獨立選自基團(tuán)H、Br、Cl、F、I、-CN、C1-4烷基、C3-8環(huán)烷基、C1-4烷氧基、C1-4烷基硫代、C1-4烷基亞硫?;?、C1-4烷基磺?;被?、C1-4烷基氨基、(C1-4烷基)2氨基和苯基,每一個苯基由0-3個選自基團(tuán)C1-7烷基、C3-8環(huán)烷基、Br、Cl、F、I、C1-4鹵代烷基、硝基、C1-4烷氧基、C1-4鹵代烷氧基、C1-4烷基硫代、C1-4烷基亞硫?;?、C1-4烷基磺?;?、C1-6烷基氨基和(C1-4烷基)2氨基的取代基來取代;假定R1為不飽和的C1-10烷基,那么R3不是取代的或未取代的苯基;R9和R10在每一個情況下獨立選自基團(tuán)H、C1-4烷基、C3-6環(huán)烷基-C1-4烷基和C3-8環(huán)烷基;R13選自基團(tuán)H、C1-4烷基、C1-4鹵代烷基、C1-4烷氧基-C1-4烷基、C3-6環(huán)烷基、C3-6環(huán)烷基-C1-6烷基、芳基、芳基(C1-4烷基)-、雜芳基和雜芳基(C1-4烷基)-;R13a和R16a在每一個情況下獨立選自基團(tuán)H、C1-4烷基、C1-4鹵代烷基、C1-4烷氧基-C1-4烷基、C3-6環(huán)烷基和C3-6環(huán)烷基-C1-6烷基;R14選自基團(tuán)C1-4烷基、C1-4鹵代烷基、C1-4烷氧基-C1-4烷基、C3-6環(huán)烷基、C3-6環(huán)烷基-C1-6烷基、芳基、芳基(C1-4烷基)-、雜芳基和雜芳基(C1-4烷基)-和芐基,每一個芐基在該芳基部分上由0-1個選自基團(tuán)C1-4烷基、Br、Cl、F、I、C1-4鹵代烷基、硝基、C1-4烷氧基鹵代烷氧基和二甲基氨基的取代基來取代;R14a選自基團(tuán)C1-4烷基、C1-4鹵代烷基、C1-4烷氧基-C1-4烷基、C3-6環(huán)烷基、C3-6環(huán)烷基-C1-6烷基和芐基,每一個芐基在該芳基部分上由0-1個選自基團(tuán)C1-4烷基、Br、Cl、F、I、C1-4鹵代烷基、硝基、C1-4烷氧基、C1-4鹵代烷氧基和二甲基氨基的取代基取代;R14b選自基團(tuán)C1-4烷基、C1-4鹵代烷基、C1-4烷氧基-C1-4烷基、C3-6環(huán)烷基和C3-6環(huán)烷基-C1-6烷基;R15在每一個情況下獨立選自基團(tuán)H、C1-4烷基、C3-7環(huán)烷基、C3-6環(huán)烷基-C1-6烷基、苯基和芐基,每一個苯基或芐基在該芳基部分上以0-3個選自基團(tuán)C1-4烷基、Br、Cl、F、I、C1-4鹵代烷基、硝基、C1-4烷氧基、C1-4鹵代烷氧基和二甲基氨基的基團(tuán)來取代;R15a在每一個情況下獨立選自基團(tuán)H、C1-4烷基、C3-7環(huán)烷基和C3-6環(huán)烷基-C1-6烷基;R17在每一個情況下選自基團(tuán)H、C1-6烷基、C3-10環(huán)烷基、C3-6環(huán)烷基-C1-6烷基、C1-2烷氧基-C1-2烷基、C1-4鹵代烷基、R14S(O)n-C1-4烷基和R17bR19bN-C2-4烷基;R18和R19在每一個情況下獨立選自基團(tuán)H、C1-6烷基、C3-10環(huán)烷基、C3-6環(huán)烷基-C1-6烷基、C1-2烷氧基-C1-2烷基和C1-4鹵代烷基;或者,在NR17R19部分中,R17和R19一起形成1-吡咯烷基、1-嗎啉基、1-哌啶基或1-哌嗪基,其中在1-哌嗪基中的N4由0-1個選自基團(tuán)R13、CO2R14、COR14和SO2R14的取代基來取代;或者,在NR17bR19b部分中,R17b和R19b一起形成1-吡咯烷基、1-嗎啉基、1-哌啶基或1-哌嗪基,其中在1-哌嗪基中的N4由0-1個選自基團(tuán)R13、CO2R14、COR14和SO2R14的取代基來取代;R17a和R19a在每一個情況下獨立選自基團(tuán)H、C1-6烷基、C3-10環(huán)烷基、C3-6環(huán)烷基-C1-6烷基和C1-4鹵代烷基;芳基在每一個情況下獨立選自基團(tuán)苯基、萘基、2,3-二氫化茚基和茚基,每一個芳基由0-5個在每一個情況下獨立選自基團(tuán)C1-6烷基、C3-6環(huán)烷基、亞甲二氧基、C1-4烷氧基-C1-4烷氧基、-OR17、Br、Cl、F、I、C1-4鹵代烷基、-CN、-NO2、SH、-S(O)nR18、-COR17、-CO2R17、-OC(O)R18、-NR15COR17、-N(COR17)2、-NR15CONR17R19、-NR15CO2R18、-NR17R19和-CONR17R19和1個苯基的取代基來取代,每一個苯基取代基由0-4個選自基團(tuán)C1-3烷基、C1-3烷氧基、Br、Cl、F、I、-CN、二甲基氨基、CF3、C2F5、OCF3、SO2Me和乙?;娜〈〈浑s芳基在每一個情況下獨立選自基團(tuán)吡啶基、嘧啶基、三嗪基、呋喃基、喹啉基、異喹啉基、噻吩基、咪唑基、噻唑基、吲哚基、吡咯基、噁唑基、苯并呋喃基、苯并噻吩基、苯并噻唑基、苯并噁唑基、異噁唑基、三唑基、四唑基、吲唑基、2,3-二氫苯并呋喃基、2,3-二氫苯并噻吩基、2,3-二氫苯并噻吩基-S-氧化物、2,3-二氫苯并噻吩基-S-二氧化物、二氫吲哚基、苯并噁唑啉-2-酮基、苯并二氧戊環(huán)基和苯并二噁烷,每一個雜芳基在0-4個碳原子上由在每一個情況下獨立選自基團(tuán)C1-6烷基、C3-6環(huán)烷基、Br、Cl、F、I、C1-4鹵代烷基、-CN、硝基、-OR17、SH、-S(O)mR18、-COR17、-CO2R17、-OC(O)R18、-NR15COR17、-N(COR17)2、-NR15CONR17R19、-NR15CO2R18、-NR17R19和-CONR17R19的取代基取代,并且每一個雜芳基在任何氮原子上以0-1個選自基團(tuán)R15、CO2R14a、COR14b和SO2R14a的取代基取代;和前提是當(dāng)D為咪唑或三唑時,R1不是未取代的C1-6線性的或分枝的烷基或C3-6環(huán)烷基。[2]在一個優(yōu)選的實施方案中,本發(fā)明提供新的式Ia化合物 在一個更優(yōu)選的實施方案中,本發(fā)明提供新的式Ia化合物,其中X選自基團(tuán)O、S(O)n和鍵;n為0、1或2;R1選自基團(tuán)C1-6烷基、C2-6鏈烯基、C2-6炔基和C3-8環(huán)烷基;R1以0-1個選自基團(tuán)-CN、-S(O)nR14b、-COR13a、-CO2R13a和C3-8環(huán)烷基的取代基取代,其中在C4-8環(huán)烷基中的0-1個碳原子以選自基團(tuán)-O-、-S(O)n-、-NR13a-、-NCO2R14b-、-NCOR14b-和-NSO2R14b-的基團(tuán)來替代;R1也以0-2個在每一個情況下獨立選自基團(tuán)R1a、R1b、C1-6烷基、C2-8鏈烯基、C2-8炔基、Br、Cl、F、CF3、CF2CF3、-OR13a、-NR13aR16a、C1-2烷氧基-C1-2烷基和由0-1個R9取代的C3-8環(huán)烷基的取代基來取代并且其中C4-8環(huán)烷基的0-1個碳由-O-替代;前提是R1不是環(huán)己基-(CH2)2-基團(tuán);R1a為芳基并且選自基團(tuán)苯基和2,3-二氫化茚基,每一個R1a以0-1個-OR17和0-5個在每一個情況下獨立選自基團(tuán)C1-4烷基、C3-6環(huán)烷基、Br、Cl、F、C1-4鹵代烷基、-CN、-S(O)nR18、-COR17、-NR17aR19a和-CONR17aR19a的取代基來取代;R1b為雜芳基和選自基團(tuán)吡啶基、嘧啶基、呋喃基、噻吩基、咪唑基、噻唑基、吡咯基、噁唑基、異噁唑基、吡唑基、三唑基、四唑基和吲唑基,每一個雜芳基在0-4個碳原子上用在每一個情況下獨立選自基團(tuán)C1-4烷基、C3-6環(huán)烷基、Br、Cl、F、CF3、-CN、-OR17、-S(O)mR18、-COR17、-NR17aR19a和-CONR17aR19a的取代基來取代,并且每一個雜芳基在任何氮原子上用0-1個選自基團(tuán)R15a、CO2R14b、COR14b和SO2R14b的取代基來取代;前提是R1不是-(CH2)1-4-芳基或-(CH2)1-4-雜芳基,其中該芳基或雜芳基基團(tuán)是取代的或未取代的;R2選自基團(tuán)C1-4烷基、C2-4鏈烯基和C2-4炔基并且用0-1個選自基團(tuán)-CN、OH、Cl、F和C1-4烷氧基的取代基來取代;R3和R8在每一個情況下獨立選自基團(tuán)H、Br、Cl、F、-CN、C1-4烷基、C3-6環(huán)烷基、C1-4烷氧基、NH2、C1-4烷基氨基和(C1-4烷基)2-氨基;R9在每一個情況下獨立選自基團(tuán)H、C1-4烷基和C3-8環(huán)烷基;R13選自基團(tuán)C1-4烷基、C1-2鹵代烷基、C1-2烷氧基-C1-2烷基、C3-6環(huán)烷基-C1-2烷基、芳基(C1-2烷基)-和雜芳基(C1-2烷基)-;R13a和R16a在每一個情況下獨立選自基團(tuán)H、C1-4烷基、C1-4鹵代烷基、C1-4烷氧基-C1-4烷基、C3-6環(huán)烷基和C3-6環(huán)烷基-C1-6烷基;R14選自基團(tuán)C1-4烷基、C1-2鹵代烷基、C1-2烷氧基-C1-2烷基、C3-6環(huán)烷基-C1-2烷基、芳基(C1-2烷基)-和雜芳基(C1-2烷基)-;R14a選自基團(tuán)C1-4烷基、C1-2鹵代烷基、C1-2烷氧基-C1-2烷基和C3-6環(huán)烷基-C1-2烷基;R14b選自基團(tuán)C1-4烷基、C1-2鹵代烷基、C1-2烷氧基-C1-2烷基、C3-6環(huán)烷基和C3-6環(huán)烷基-C1-2烷基;R15在每一個情況下獨立選自基團(tuán)H、C1-4烷基、C3-7環(huán)烷基、C3-6環(huán)烷基-C1-6烷基、苯基和芐基,每一個苯基或芐基在該芳基部分上由0-3個選自基團(tuán)C1-4烷基、Br、Cl、F、C1-4鹵代烷基、C1-4烷氧基、C1-4鹵代烷氧基和二甲基氨基的基團(tuán)來取代;R15a在每一個情況下獨立選自基團(tuán)H、C1-4烷基、C3-7環(huán)烷基和C3-6環(huán)烷基-C1-6烷基;R17、R18和R19在每一個情況下獨立選自基團(tuán)H、C1-6烷基、C3-10環(huán)烷基、C3-6環(huán)烷基-C1-6烷基、C1-2烷氧基-C1-2烷基和C1-4鹵代烷基;或者,在NR17R19部分中,R17和R19一起形成1-吡咯烷基、1-嗎啉基、1-哌啶基或1-哌嗪基,其中在1-哌嗪基中的N4由0-1個選自基團(tuán)R13、CO2R14、COR14和SO2R14的取代基來取代;R17a和R19a在每一個情況下獨立選自基團(tuán)H、C1-6烷基、C3-10環(huán)烷基、C3-6環(huán)烷基-C1-6烷基和C1-4鹵代烷基;芳基為由1-4個在每一個情況下獨立選自基團(tuán)C1-4烷基、C3-6環(huán)烷基、-OR17、Br、Cl、F、C1-4鹵代烷基、-CN、-S(O)nR18、-COR17、-CO2R17、-NR15COR17、-NR15CO2R18、-NR17R19和-CONR17R19的取代基來取代的苯基;和,雜芳基在每一個情況下獨立選自基團(tuán)吡啶基、嘧啶基、三嗪基、呋喃基、喹啉基、異喹啉基、噻吩基、噻唑基、吲哚基、吡咯基、噁唑基、苯并呋喃基、苯并噻吩基、苯并噻唑基、苯并噁唑基、異噁唑基、四唑基、吲唑基、2,3-二氫苯并呋喃基、2,3-二氫苯并噻吩基、2,3-二氫苯并噻吩基-S-氧化物、2,3-二氫苯并噻吩基-S-二氧化物、二氫吲哚基、苯并噁唑啉-2-酮基、苯并二氧戊環(huán)基和苯并二噁烷,每一個雜芳基在1-4個碳原子上以由在每一個情況下獨立地選自基團(tuán)C1-6烷基、C3-6環(huán)烷基、Br、Cl、F、C1-4鹵代烷基、-CN、-OR17、-S(O)mR18、-COR17、-CO2R17、-OC(O)R18、-NR15COR17、-N(COR17)2、-NR15CO2R18、-NR17R19和-CONR17R19的取代基來取代,并且每一個雜芳基在任何氮原子上以0-1個選自基團(tuán)R15、CO2R14a、COR14a和SO2R14a的取代基取代。[2b]在一個甚至更優(yōu)選的實施方案中,本發(fā)明提供了新的式Ia化合物,其中X選自基團(tuán)O、S和鍵;R1為取代的C1-6烷基;R1由0-1個選自基團(tuán)-CN、-CO2R13a和C3-8環(huán)烷基的取代基取代,其中在C4-8環(huán)烷基中的0-1個碳原子由選自基團(tuán)-O-、-S(O)n-、-NR13a-的基團(tuán)替代;R1也由0-2個在每一個情況下獨立選自基團(tuán)R1a、R1b、C1-6烷基、C2-8鏈烯基、C2-8炔基、Br、Cl、F、CF3、-OR13a、-NR13aR16a、C1-2烷氧基-C1-2烷基和由0-1個CH3取代的C3-6環(huán)烷基的取代基取代,并且其中C4-8環(huán)烷基的0-1個碳以-O-替代;前提是R1不是環(huán)己基-(CH2)2-基團(tuán);R1a為芳基和由0-1個選自O(shè)CH3、OCH2CH3、OCH(CH3)2、OCH2CH2CH3和OCF3的取代基和由0-3個在每一個情況下獨立選自CH3、CH2CH3、CH(CH3)2、CH2CH2CH3、環(huán)丙基、Br、Cl、F、CF3、-CN、SCH3、-NH2、-NHCH3、-N(CH3)2、-C(O)NH2、-C(O)NHCH3和-C(O)N(CH3)2的取代基取代的苯基;R1b為雜芳基和選自基團(tuán)呋喃基、噻吩基、咪唑基、噻唑基、噁唑基、異噁唑基、吡唑基、三唑基、四唑基和吲唑基,每一個雜芳基在0-3個碳原子上由在每一個情況下獨立選自基團(tuán)CH3、CH2CH3、CH(CH3)2、CH2CH2CH3、環(huán)丙基、OCH3、OCH2CH3、OCH(CH3)2、OCH2CH2CH3、OCF3、Br、Cl、F、CF3、-CN、SCH3、-NH2、-NHCH3、-N(CH3)2、-C(O)NH2、-C(O)HCH3和-C(O)N(CH3)2的取代基取代,并且每一個雜芳基在任何氮原子上由0-1個選自基團(tuán)CH3、CO2CH3、COCH3和SO2CH3的取代基取代。前提是R1不是-(CH2)1-4-芳基或-(CH2)1-4-雜芳基,其中該芳基或雜芳基基團(tuán)是取代的或未取代的;R2選自基團(tuán)CH3、CH2CH3、CH(CH3)2和CH2CH2CH3;R3和R8在每一個情況下獨立選自基團(tuán)H、CH3、CH2CH3、CH(CH3)2和CH2CH2CH3;芳基為由2-4個在每一個情況下獨立選自基團(tuán)CH3、CH2CH3、CH(CH3)2、CH2CH2CH3、環(huán)丙基、OCH3、OCH2CH3、OCH(CH3)2、OCH2CH2CH3、OCF3、Br、Cl、F、CF3、-CN、SCH3、SO2CH3、-NH2、-NHCH3、-N(CH3)2、-C(O)NH2、-C(O)NHCH3和-C(O)N(CH3)2的取代基取代的苯基;和,雜芳基在每一個情況下獨立選自基團(tuán)吡啶基、吲哚基、苯并噻吩基、2,3-二氫苯并呋喃基、2,3-二氫苯并噻吩基、2,3-二氫苯并噻吩基-S-氧化物、2,3-二氫苯并噻吩基-S-二氧化物、二氫吲哚基和苯并噁唑啉-2-酮-基,每一個雜芳基在2-4個碳原子上由在每一個情況下獨立選自基團(tuán)CH3、CH2CH3、CH(CH3)2、CH2CH2CH3、環(huán)丙基、OCH3、OCH2CH3、OCH(CH3)2、OCH2CH2CH3、OCF3、Br、Cl、F、CF3、-CN、SCH3、SO2CH3、-NH2、-NHCH3、-N(CH3)2、-C(O)NH2、-C(O)NHCH3和-C(O)N(CH3)2的取代基取代,并且每一個雜芳基在任何氮原子上以0-1個選自基團(tuán)CH3、CO2CH3、COCH3和SO2CH3的取代基取代。[2c]在一個仍然更優(yōu)選的實施方案中,本發(fā)明提供了式Ia的新化合物,其中R1為取代的C1;R1由0-1個選自基團(tuán)-CN、-CO2CH3和-CO2CH2CH3的取代基來取代;R1也由0-2個在每一個情況下獨立選自基團(tuán)R1a、R1b、CH3、CH2CH3、CH(CH3)2、CH2CH2CH3、-(CH2)3CH3、-CH=CH2、-CH=CH(CH3)、-CH≡CH、-CH≡C(CH3)、-CH2OCH3、-CH2CH2OCH3、F、CF3、環(huán)丙基、CH3-環(huán)丙基、環(huán)丁基、CH3-環(huán)丁基、環(huán)戊基、CH3-環(huán)戊基的取代基取代;R1a為由0-1個選自O(shè)CH3、OCH2CH3和OCF3的取代基和以0-2個在每一個情況下獨立選自基團(tuán)CH3、CH2CH3、CH(CH3)2、CH2CH2CH3、Br、Cl、F、CF3、-CN和SCH3的取代基取代的苯基R1b為雜芳基并且選自基團(tuán)呋喃基、噻吩基、咪唑基、噻唑基、噁唑基、異噁唑基、吡唑基、三唑基和四唑基,每一個雜芳基在0-3個碳原子上由在每一個情況下獨立選自的基團(tuán)CH3、CH2CH3、CH(CH3)2、CH2CH2CH3、OCH3、OCH2CH3、OCF3、Br、Cl、F、CF3、-CN和SCH3的取代基取代,并且每一個雜芳基在任何氮原子上以0-1個選自基團(tuán)CH3、CO2CH3、COCH3和SO2CH3的取代基取代;前提是R1不是-(CH2)1-4-芳基或-(CH2)1-4-雜芳基,其中該芳基或雜芳基基團(tuán)是取代的或未取代的;R2選自基團(tuán)CH3、CH2CH3和CH(CH3)2;R3和R8在每一個情況下獨立選自基團(tuán)H和CH3;芳基為由2-4個在每一個情況下獨立選自基團(tuán)CH3、CH2CH3、CH(CH3)2、CH2CH2CH3、環(huán)丙基、OCH3、OCH2CH3、OCH(CH3)2、OCH2CH2CH3、OCF3、Br、Cl、F、CF3、-CN、SCH3、SO2CH3、-NH2、-NHCH3、-N(CH3)2、-C(O)NH2、-C(O)NHCH3和-C(O)N(CH3)2的取代基取代的苯基;和,雜芳基為在2-4個碳原子上以在每一個情況下獨立選自基團(tuán)CH3、CH2CH3、CH(CH3)2、CH2CH2CH3、環(huán)丙基、OCH3、OCH2CH3、OCH(CH3)2、OCH2CH2CH3、OCF3、Br、Cl、F、CF3、-CN、SCH3、SO2CH3、-NH2、-NHCH3、-N(CH3)2、-C(O)NH2、-C(O)NHCH3和-C(O)N(CH3)2的取代基取代的吡啶基。[2d]在更優(yōu)選的實施方案中,本發(fā)明提供了式Ia的新化合物,其中R1為取代的(環(huán)丙基)-C1烷基或(環(huán)丁基)-C1烷基;R1由0-1個-CN取代;R1也由0-1個在每一個情況下獨立選自基團(tuán)R1a、R1b、CH3、CH2CH3、CH(CH3)2、CH2CH2CH3、-(CH2)3CH3、-CH=CH2、-CH=CH(CH3)、-CH≡CH、-CH≡C(CH3)、-CH2OCH3、-CH2CH2OCH3、F、CF3、環(huán)丙基和CH3-環(huán)丙基的取代基取代;R1a為由0-1個選自O(shè)CH3、OCH2CH3和OCF3的取代基和由0-2個在每一個情況下獨立選自基團(tuán)CH3、CH2CH3、CH(CH3)2、CH2CH2CH3、Br、Cl、F、CF3、-CN和SCH3的取代基取代的苯基R1b為雜芳基和選自基團(tuán)呋喃基、噻吩基、咪唑基、噻唑基、噁唑基、異噁唑基和吡唑基,每一個雜芳基在0-3個碳原子上由在每一個情況下獨立選自基團(tuán)CH3、CH2CH3、CH(CH3)2、CH2CH2CH3、OCH3、OCH2CH3、OCF3、Br、Cl、F、CF3、-CN和SCH3的取代基取代。[2e]在另一個更優(yōu)選的實施方案中,本發(fā)明提供了新的式Ia化合物,其中R1為在每一個情況下以一個獨立選自基團(tuán)R1a、R1b、CH3、CH2CH3、CH(CH3)2、CH2CH2CH3、-(CH2)3CH3、-CH=CH2、-CH=CH(CH3)、-CH≡CH、-CH≡C(CH3)、-CH2OCH3、-CH2CH2OCH3、F、CF3、環(huán)丙基和CH3-環(huán)丙基的取代基取代的(環(huán)丙基)C1烷基或(環(huán)丁基)-C1烷基;R1a為以0-2個在每一個情況下獨立選自基團(tuán)CH3、CH2CH3、Cl、F和CF3的取代基取代的苯基;R1b為雜芳基并且選自基團(tuán)呋喃基、噻吩基和異噁唑基,每一個雜芳基在0-2個碳原子上以在每一個情況下獨立選自基團(tuán)CH3、OCH3、Cl、F和CF3的取代基取代。[2f]在甚至更優(yōu)選的實施方案中,本發(fā)明提供了新的式Ia化合物,其中R1選自基團(tuán)(環(huán)丙基)CH-CH3、(環(huán)丙基)CH-CH2CH3、(環(huán)丙基)CH-CH2OCH3、(環(huán)丙基)CH-CH2CH2CH3、(環(huán)丙基)CH-CH2CH2OCH3、(環(huán)丙基)2CH、苯基(環(huán)丙基)CH、呋喃基(環(huán)丙基)CH、噻吩基(環(huán)丙基)CH、異噁唑基(環(huán)丙基)CH、(CH3-呋喃基)(環(huán)丙基)CH、(環(huán)丁基)CH-CH3、(環(huán)丁基)CH-CH2CH3、(環(huán)丁基)CH-CH2OCH3、(環(huán)丁基)CH-CH2CH2CH3、(環(huán)丁基)CH-CH2CH2OCH3、(環(huán)丁基)2CH、苯基(環(huán)丁基)CH、呋喃基(環(huán)丁基)CH、噻吩基(環(huán)丁基)CH、異噁唑基(環(huán)丁基)CH和(CH3-呋喃基)(環(huán)丁基)CH;[2g]在另一個更優(yōu)選的實施方案中,本發(fā)明提供了新的式Ia化合物,其中D為以2-4個在每一個情況下獨立選自基團(tuán)CH3、CH2CH3、CH(CH3)2、CH2CH2CH3、環(huán)丙基、OCH3、OCH2CH3、OCH(CH3)2、OCH2CH2CH3、OCF3、Br、Cl、F和CF3的取代基取代的苯基。[2h]在另一個更優(yōu)選的實施方案中,本發(fā)明提供了新的式Ia化合物,其中D為在2-4個碳原子上由在每一個情況下獨立選自基團(tuán)CH3、CH2CH3、CH(CH3)2、CH2CH2CH3、環(huán)丙基、OCH3、OCH2CH3、OCH(CH3)2、OCH2CH2CH3、OCF3、Br、Cl、F和CF3的取代基取代的吡啶基。[2i]在另一個優(yōu)選的實施方案中,本發(fā)明提供了式Ia的新化合物,其中該化合物選自基團(tuán)3-(1-環(huán)丙基丙基)-7-(2,4-二氯苯基)-2-乙基-3H-咪唑并[4,5-b]吡啶;3-(1-環(huán)丙基丙基)-7-(2,4-二氯苯基)-2-甲氧基-3H-咪唑并[4,5-b]吡啶;3-(1-環(huán)丙基丙基)-7-(2,4-二氯苯基)-2-(甲基sulfanyl)-3H-咪唑并[4,5-b]吡啶;7-[2-氯-4-(三氟甲基)苯基]-3-(1-環(huán)丙基丙基)-2-乙基-3H-咪唑并[4,5-b]吡啶;7-[2-氯-4-(三氟甲基)苯基]-3-(1-環(huán)丙基丙基)-2-甲氧基-3H-咪唑并[4,5-b]吡啶;7-[2-氯-4-(三氟甲基)苯基]-3-(1-環(huán)丙基丙基)-2-(甲基sulfanyl)-3H-咪唑并[4,5-b]吡啶;3-(1-環(huán)丙基丙基)-2-乙基-7-[2-甲基-4-(三氟甲基)苯基]-3H-咪唑并[4,5-b]吡啶;7-(2-氯-4-甲氧基苯基)-3-(1-環(huán)丙基丙基)-2-乙基-3H-咪唑并[4,5-b]吡啶;7-(2-氯-4-甲氧基苯基)-3-(1-環(huán)丙基丙基)-2-甲氧基-3H-咪唑并[4,5-b]吡啶;3-(1-環(huán)丙基丙基)-2-乙基-7-(4-甲氧基-2,5-二甲基苯基)-3H-咪唑并[4,5-b]吡啶;3-(1-環(huán)丙基丙基)-2-甲氧基-7-(4-甲氧基-2,5-二甲基苯基)-3H-咪唑并[4,5-b]吡啶;7-(2-氯-4-甲氧基苯基)-3-(1-環(huán)丙基丙基)-2-乙基--3H-咪唑并[4,5-b]吡啶;7-(2-氯-4-甲氧基苯基)-3-(1-環(huán)丙基丙基)-2-甲氧基-3H-咪唑并[4,5-b]吡啶;7-(2-氯-5-氟-4-甲氧基苯基)-3-(1-環(huán)丙基丙基)-2-乙基-3H-咪唑并[4,5-b]吡啶;7-(2-氯-氟-4-甲氧基苯基)-3-(1-環(huán)丙基丙基)-2-甲氧基-3H-咪唑并[4,5-b]吡啶;7-(2-氯-5-氟-4-甲基苯基)-3-(1-環(huán)丙基丙基)-2-乙基-3H-咪唑并[4,5-b]吡啶;7-(2-氯-氟-4-甲基苯基)-3-(1-環(huán)丙基丙基)-2-甲氧基-3H-咪唑并[4,5-b]吡啶;3-(1-環(huán)丙基丙基)-2-乙基-7-(2,4,5-三甲基苯基)-3H-咪唑并[4,5-b]吡啶;3-(1-環(huán)丙基丙基)-2-甲氧基-7-(2,4,5-三甲基苯基)-3H-咪唑并[4,5-b]吡啶;3-(1-環(huán)丙基丙基)-2-乙基-7-(2,5,6-三甲基-3-吡啶基)-3H-咪唑并[4,5-b]吡啶;3-(1-環(huán)丙基丙基)-2-甲氧基-7-(2,5,6-三甲基-3-吡啶基)-3H-咪唑并[4,5-b]吡啶;3-(1-環(huán)丙基丙基)-7-(2,6-二甲基-3-吡啶基)-2-乙基-3H-咪唑并[4,5-b]吡啶;3-(1-環(huán)丙基丙基)-7-(2,6-二甲基-3-吡啶基)-2-甲氧基-3H-咪唑并[4,5-b]吡啶;3-(1-環(huán)丙基丙基)-7-(2,6-二甲氧基-3-吡啶基)-2-乙基-3H-咪唑并[4,5-b]吡啶;7-(2,4-二氯苯基)-2-乙基-3-(1-乙基丙基)-3H-咪唑并[4,5-b]吡啶;7-(2,4-二氯苯基)-3-(1-乙基丙基)-2-甲氧基-3H-咪唑并[4,5-b]吡啶;7-[2-氯-4-(三氟甲基)苯基]-2-乙基-3-(1-乙基丙基)-3H-咪唑并[4,5-b]吡啶;7-[2-氯-4-(三氟甲基)苯基]-3-(1-乙基丙基)-2-甲氧基-3H-咪唑并[4,5-b]吡啶;7-[2-氯-4-(甲基磺?;?苯基]-2-乙基-3-(1-乙基丙基)-3H-咪唑并[4,5-b]吡啶;7-[2-氯-4-(甲基磺酰基)苯基]-3-(1-乙基丙基)-2-甲氧基-3H-咪唑并[4,5-b]吡啶;2-乙基-3-(1-乙基丙基)-7-(4-甲氧基-2,5-二甲基苯基)-3H-咪唑并[4,5-b]吡啶;3-(1-乙基丙基)-2-甲氧基-7-(4-甲氧基-2,5-二甲基苯基)-3H-咪唑并[4,5-b]吡啶;7-(2-氯-4-甲氧基苯基)-2-乙基-3-(1-乙基丙基)-3H-咪唑并[4,5-b]吡啶;7-(2-氯-4-甲氧基苯基)-3-(1-乙基丙基)-2-甲氧基-3H-咪唑并[4,5-b]吡啶;2-乙基-3-(1-乙基丙基)-7-[4-甲氧基-2-(三氟甲基)苯基]-3H-咪唑并[4,5-b]吡啶;3-(1-乙基丙基)-2-甲氧基-7-[4-甲氧基-2-(三氟甲基)苯基]-3H-咪唑并[4,5-b]吡啶;7-(2,6-二甲氧基-3-吡啶基)-2-乙基-3-(1-乙基丙基)-3H-咪唑并[4,5-b]吡啶;7-(2,6-二甲基-3-吡啶基)-2-乙基-3-(1-乙基丙基)-3H-咪唑并[4,5-b]吡啶;2-乙基-3-(1-乙基丙基)-7-(2,5,6-三甲基-3-吡啶基)-3H-咪唑并[4,5-b]吡啶;2-乙基-3-(1-乙基丙基)-7-(5-氟-4-甲氧基-2-甲基苯基)-3H-咪唑并[4,5-b]吡啶;3-(1-乙基丙基)-7-(5-氟-4-甲氧基-2-甲基苯基)-2-甲氧基-3H-咪唑并[4,5-b]吡啶;3-氯-4-[2-乙基-3-(1-乙基丙基)-3H-咪唑并[4,5-b]吡啶-7-基]芐腈;3-氯-4-[3-(1-乙基丙基)-2-甲氧基-3H-咪唑并[4,5-b]吡啶-7-基]芐腈;1-{3-氯-4-[2-乙基-3-(1-乙基丙基)-3H-咪唑并[4,5-b]吡啶-7-基]苯基}-1-乙酮;1-{3-氯-4-[3-(1-乙基丙基)-2-甲氧基-3H-咪唑并[4,5-b]吡啶-7-基]苯基}-1-乙酮;3-(二環(huán)丙基甲基)-2-乙基-7-(5-氟-4-甲氧基-2-甲基苯基)-3H-咪唑并[4,5-b]吡啶;3-(二環(huán)丙基甲基)-7-(5-氟-4-甲氧基-2-甲基苯基)-2-甲氧基-3H-咪唑并[4,5-b]吡啶;7-(2-氯-4-甲氧基苯基)-3-(二環(huán)丙基甲基)-2-乙基-3H-咪唑并[4,5-b]吡啶;7-(2-氯-4-甲氧基苯基)-3-(二環(huán)丙基甲基)-2-甲氧基-3H-咪唑并[4,5-b]吡啶;7-(2,4-二氯苯基)-3-(二環(huán)丙基甲基)-2-乙基-3H-咪唑并[4,5-b]吡啶;7-(2,4-二氯苯基)-3-(二環(huán)丙基甲基)-2-甲氧基-3H-咪唑并[4,5-b]吡啶;7-[2-氯-4-(三氟甲基)苯基]-3-(二環(huán)丙基甲基)-2-乙基-3H-咪唑并[4,5-b]吡啶;7-[2-氯-4-(三氟甲基)苯基]-3-(二環(huán)丙基甲基)-2-甲氧基-3H-咪唑并[4,5-b]吡啶;7-(2,4-二氯苯基)-2-乙基-3-(1-乙基-3-甲氧基丙基)-3H-咪唑并[4,5-b]吡啶;7-(2,4-二氯苯基)-3-(1-乙基-3-甲氧基丙基)-2-甲氧基-3H-咪唑并[4,5-b]吡啶;7-[2-氯-4-(三氟甲基)苯基]-2-乙基-3-(1-乙基-3-甲氧基丙基)-3H-咪唑并[4,5-b]吡啶;7-[2-氯-4-(三氟甲基)苯基]-3-(1-乙基-3-甲氧基丙基)-2-甲氧基-3H-咪唑并[4,5-b]吡啶;7-(2-氯-4-甲氧基苯基)-2-乙基-3-(1-乙基-3-甲氧基丙基)-3H-咪唑并[4,5-b]吡啶;7-(2-氯-4-甲氧基苯基)-3-(1-乙基-3-甲氧基丙基)-2-甲氧基-3H-咪唑并[4,5-b]吡啶;7-(2-氯-5-氟-4-甲氧基苯基)-2-乙基-3-(1-乙基-3-甲氧基丙基)-3H-咪唑并[4,5-b]吡啶;7-(2-氯-5-氟-4-甲氧基苯基)-3-(1-乙基-3-甲氧基丙基)-2-甲氧基-3H-咪唑并[4,5-b]吡啶;2-乙基-3-(1-乙基-3-甲氧基丙基)-7-(4-甲氧基-2,5-二甲基苯基)-3H-咪唑并[4,5-b]吡啶;3-(1-乙基-3-甲氧基丙基)-2-甲氧基-7-(4-甲氧基-2,5-二甲基苯基)-3H-咪唑并[4,5-b]吡啶;2-乙基-3-(1-乙基-3-甲氧基丙基)-7-(5-氟-4-甲氧基-2-甲基苯基)-3H-咪唑并[4,5-b]吡啶;3-(1-乙基-3-甲氧基丙基)-7-(5-氟-4-甲氧基-2-甲基苯基)-2-甲氧基-3H-咪唑并[4,5-b]吡啶;7-(2-氯-5-氟-4-甲基苯基)-2-乙基-3-(1-乙基-3-甲氧基丙基)-3H-咪唑并[4,5-b]吡啶;7-(2-氯-5-氟-4-甲基苯基)-3-(1-乙基-3-甲氧基丙基)-2-甲氧基-3H-咪唑并[4,5-b]吡啶;7-[2-氯-4-(甲基磺?;?苯基]-2-乙基-3-(1-乙基-3-甲氧基丙基)-3H-咪唑并[4,5-b]吡啶;7-[2-氯-4-(甲基磺?;?苯基]-3-(1-乙基-3-甲氧基丙基)-2-甲氧基-3H-咪唑并[4,5-b]吡啶;1-{3-氯-4-[2-乙基-3-(1-乙基-3-甲氧基丙基)-3H-咪唑并[4,5-b]吡啶-7-基]苯基}-1-乙酮;1-{3-氯-4-[3-(1-乙基-3-甲氧基丙基)-2-甲氧基-3H-咪唑并[4,5-b]吡啶-7-基]苯基}-1-乙酮;1-{5-[2-乙基-3-(1-乙基-3-甲氧基丙基)-3H-咪唑并[4,5-b]吡啶-7-基]-6-甲基-2-吡啶基}-1-乙酮;1-{5-[3-(1-乙基-3-甲氧基丙基)-2-甲氧基-3H-咪唑并[4,5-b]吡啶-7-基]-6-甲基-2-吡啶基}-1-乙酮;2-乙基-3-(1-乙基-3-甲氧基丙基)-7-(6-甲氧基-2-甲基-3-吡啶基)-3H-咪唑并[4,5-b]吡啶;3-(1-乙基-3-甲氧基丙基)-2-甲氧基-7-(6-甲氧基-2-甲基-3-吡啶基)-3H-咪唑并[4,5-b]吡啶;7-(2,6-二甲氧基-3-吡啶基)-2-乙基-3-(1-乙基-3-甲氧基丙基)-3H-咪唑并[4,5-b]吡啶;7-(2,6-二甲氧基-3-吡啶基)-3-(1-乙基-3-甲氧基丙基)-2-甲氧基-3H-咪唑并[4,5-b]吡啶;7-(2,6-二甲基-3-吡啶基)-2-乙基-3-(1-乙基-3-甲氧基丙基)-3H-咪唑并[4,5-b]吡啶;7-(2,6-二甲基-3-吡啶基)-3-(1-乙基-3-甲氧基丙基)-2-甲氧基-3H-咪唑并[4,5-b]吡啶;2-乙基-3-(1-乙基-3-甲氧基丙基)-7-(2,5,6-三甲基-3-吡啶基)-3H-咪唑并[4,5-b]吡啶;3-(1-乙基-3-甲氧基丙基)-2-甲氧基-7-(2,5,6-三甲基-3-吡啶基)-3H-咪唑并[4,5-b]吡啶;7-(2,4-二氯苯基)-2-乙基-3-[1-(甲氧基甲基)丙基]-3H-咪唑并[4,5-b]吡啶;7-(2,4-二氯苯基)-2-甲氧基-3-[1-(甲氧基甲基)丙基]-3H-咪唑并[4,5-b]吡啶;7-[2-氯-4-(三氟甲基)苯基]-2-乙基-3-[1-(甲氧基甲基)丙基]-3H-咪唑并[4,5-b]吡啶;7-[2-氯-4-(三氟甲基)苯基]-2-甲氧基-3-[1-(甲氧基甲基)丙基]-3H-咪唑并[4,5-b]吡啶;7-(2-氯-5-氟-4-甲基苯基)-2-乙基-3-[1-(甲氧基甲基)丙基]-3H-咪唑并[4,5-b]吡啶;7-(2-氯-5-氟-4-甲基苯基)-2-甲氧基-3-[1-(甲氧基甲基)丙基]-3H-咪唑并[4,5-b]吡啶;2-乙基-7-(4-甲氧基-2,5-二甲基苯基)-3-[1-(甲氧基甲基)丙基]-3H-咪唑并[4,5-b]吡啶;2-甲氧基-7-(4-甲氧基-2,5-二甲基苯基)-3-[1-(甲氧基甲基)丙基]-3H-咪唑并[4,5-b]吡啶;2-乙基-7-(5-氟-4-甲氧基-2-甲基苯基)-3-[1-(甲氧基甲基)丙基]-3H-咪唑并[4,5-b]吡啶;7-(5-氟-4-甲氧基-2-甲基苯基)-2-甲氧基-3-[1-(甲氧基甲基)丙基]-3H-咪唑并[4,5-b]吡啶;2-乙基-3-[1-(甲氧基甲基)丙基]-7-(6-甲氧基-2-甲基-3-吡啶基)-3H-咪唑并[4,5-b]吡啶;2-甲氧基-3-[1-(甲氧基甲基)丙基]-7-(6-甲氧基-2-甲基-3-吡啶基)-3H-咪唑并[4,5-b]吡啶;7-(2,6-二甲氧基-3-吡啶基)-2-乙基-3-[1-(甲氧基甲基)丙基]-3H-咪唑并[4,5-b]吡啶;7-(2,6-二甲氧基-3-吡啶基)-2-甲氧基-3-[1-(甲氧基甲基)丙基]-3H-咪唑并[4,5-b]吡啶;7-(2,6-二甲基-3-吡啶基)-2-乙基-3-[1-(甲氧基甲基)丙基]-3H-咪唑并[4,5-b]吡啶;7-(2,6-二甲基-3-吡啶基)-2-甲氧基-3-[1-(甲氧基甲基)丙基]-3H-咪唑并[4,5-b]吡啶;2-乙基-3-[1-(甲氧基甲基)丙基]-7-(2,5,6-三甲基-3-吡啶基)-3H-咪唑并[4,5-b]吡啶;2-甲氧基-3-[1-(甲氧基甲基)丙基]-7-(2,5,6-三甲基-3-吡啶基)-3H-咪唑并[4,5-b]吡啶;7-[2-氯-4-(甲基磺?;?苯基]-2-乙基-3-[1-(甲氧基甲基)丙基]-3H-咪唑并[4,5-b]吡啶;和7-[2-氯-4-(甲基磺酰基)苯基]-2-甲氧基-3-[1-(甲氧基甲基)丙基]-3H-咪唑并[4,5-b]吡啶;或其藥學(xué)上可接受的鹽形式。[2j]在另一個更優(yōu)選的實施方案中,本發(fā)明提供了新的式Ia化合物,其中R1為C3-8環(huán)烷基;R1由0-1個選自基團(tuán)-CN、-S(O)nR14b、-COR13a、-CO2R13a、-NR15aCOR13a、-N(COR13a)2、-NR15aCONR13aR16a、-NR15aCO2R14b、-CONR13aR16a、1-嗎啉基、1-哌啶基、1-哌嗪基和C4-8環(huán)烷基的取代基來取代,其中在C4-8環(huán)烷基中的0-1個碳原子由選自基團(tuán)-O-、-S(O)n-、-NR13a-、-NCO2R14b-、-NCOR14b-和-NSO2R14b-的基團(tuán)取代,并且其中在1-哌嗪基中的N4以0-1個選自基團(tuán)R13a、CO2R14b、COR14b和SO2R14b的取代基取代;和,R1也由0-3個在每一個情況下獨立選自基團(tuán)R1a、R1b、R1c、C1-6烷基、C2-8鏈烯基、C2-8炔基、Br、Cl、F、I、C1-4鹵代烷基、-OR13a、C1-2烷氧基-C1-2烷基和-NR13aR16a的取代基取代。[2k]在另一個甚至更優(yōu)選的實施方案中,本發(fā)明提供了新的式Ia化合物,其中X選自基團(tuán)O、S(O)n和鍵;n為0、1或2;R1選自環(huán)丙基、環(huán)丁基和環(huán)戊基;R1由0-1個選自基團(tuán)-CN、-S(O)nR14b、-COR13a、-CO2R13a和C4-8環(huán)烷基的取代基取代,其中在C4-8環(huán)烷基中的一個碳原子由選自-O-、-S(O)n-、-NR13a-、-NCO2R14b-、-NCOR14b-和-NSO2R14b-的基團(tuán)替代;R1也以0-2個在每一個情況下獨立選自基團(tuán)R1a、R1b、C1-6烷基、C2-8鏈烯基、C2-8炔基、Br、Cl、F、CF3、CF2CF3、-OR13a、C1-2烷氧基-C1-2烷基和-NR13aR16a的取代基取代。R1a為芳基和選自基團(tuán)苯基和2,3-二氫化茚基,每一個R1a由0-1個-OR17和0-5個在每一個情況下獨立選自基團(tuán)C1-4烷基、C3-6環(huán)烷基、Br、Cl、F、C1-4鹵代烷基、-CN、-S(O)nR18、-COR17、-NR17aR19a和-CONR17aR19a的取代基來取代;R1b為雜芳基和選自基團(tuán)吡啶基、嘧啶基、呋喃基、噻吩基、咪唑基、噻唑基、吡咯基、噁唑基、異噁唑基、吡唑基、三唑基、四唑基和吲唑基,每一個雜芳基在0-4個碳原子上由在每一個情況下獨立選自基團(tuán)C1-4烷基、C3-6環(huán)烷基、Br、Cl、F、CF3、-CN、-OR17、-S(O)mR18、-COR17、-NR17aR19a和-CONR17aR19a的取代基取代,并且每一個雜芳基在任何氮原子上由0-1個選自基團(tuán)R15a、CO2R14b、COR14b和SO2R14b的取代基取代;R2選自基團(tuán)C1-4烷基、C2-4鏈烯基和C2-4炔基,并且以0-1個選自基團(tuán)-CN、OH、Cl、F和C1-4烷氧基的取代基取代;R9在每一個情況下獨立選自基團(tuán)H、C1-4烷基和C3-8環(huán)烷基;R3和R8在每一個情況下獨立選自基團(tuán)H、Br、Cl、F、-CN、C1-4烷基、C3-6環(huán)烷基、C1-4烷氧基、NH2、C1-4烷基氨基和(C1-4烷基)2-氨基;R13選自基團(tuán)C1-4烷基、C1-2鹵代烷基、C1-2烷氧基-C1-2烷基、C3-6環(huán)烷基-C1-2烷基、芳基(C1-2烷基)-和雜芳基(C1-2烷基)-;R13a和R16a在每一個情況下獨立選自基團(tuán)H、C1-4烷基、C1-4鹵代烷基、C1-4烷氧基-C1-4烷基、C3-6環(huán)烷基和C3-6環(huán)烷基-C1-6烷基;R14選自基團(tuán)C1-4烷基、C1-2鹵代烷基、C1-2烷氧基-C1-2烷基、C3-6環(huán)烷基-C1-2烷基、芳基(C1-2烷基)-和雜芳基(C1-2烷基)-;R14a選自基團(tuán)C1-4烷基、C1-2鹵代烷基、C1-2烷氧基-C1-2烷基和C3-6環(huán)烷基-C1-2烷基;R14b選自基團(tuán)C1-4烷基、C1-2鹵代烷基、C1-2烷氧基-C1-2烷基、C3-6環(huán)烷基和C3-6環(huán)烷基-C1-2烷基;R15在每一個情況下獨立選自基團(tuán)H、C1-4烷基、C3-7環(huán)烷基、C3-6環(huán)烷基-C1-6烷基、苯基和芐基,每一個苯基或芐基在該芳基部分上由0-3個選自基團(tuán)C1-4烷基、Br、Cl、F、C1-4鹵代烷基、C1-4烷氧基、C1-4鹵代烷氧基和二甲基氨基的基團(tuán)取代;R15a在每一個情況下獨立選自基團(tuán)H、C1-4烷基、C3-7環(huán)烷基和C3-6環(huán)烷基-C1-6烷基;R17、R18和R19在每一個情況下獨立選自基團(tuán)H、C1-6烷基、C3-10環(huán)烷基、C3-6環(huán)烷基-C1-6烷基、C1-2烷氧基-C1-2烷基和C1-4鹵代烷基;或者,在NR17R19部分中,R17和R19一起形成1-吡咯烷基、1-嗎啉基、1-哌啶基或1-哌嗪基,其中在1-哌嗪基中的N4由0-1個選自基團(tuán)R13、CO2R14、-COR14和SO2R14的取代基取代;R17a和R19a在每一個情況下獨立選自基團(tuán)H、C1-6烷基、C3-10環(huán)烷基、C3-6環(huán)烷基-C1-6烷基和C1-4鹵代烷基;芳基為由1-4個在每一個情況下獨立選自基團(tuán)C1-4烷基、C3-6環(huán)烷基、-OR17、Br、Cl、F、C1-4鹵代烷基、-CN、-S(O)nR18、-COR17、-CO2R17、-NR15COR17、-NR15CO2R18、-NR17R19和-CONR17R19的取代基取代的苯基;和雜芳基在每一個情況下獨立選自基團(tuán)吡啶基、嘧啶基、三嗪基、呋喃基、喹啉基、異喹啉基、噻吩基、噻唑基、吲哚基、吡咯基、噁唑基、苯并呋喃基、苯并噻吩基、苯并噻唑基、苯并噁唑基、異噁唑基、四唑基、吲唑基、2,3-二氫苯并呋喃基、2,3-二氫苯并噻吩基、2,3-二氫苯并噻吩基-S-氧化物、2,3-二氫苯并噻吩基-S-二氧化物、二氫吲哚基、苯并噁唑啉-2-酮基、苯并二氧戊環(huán)基和苯并二噁烷,每一個雜芳基在1-4個碳原子上由在每一個情況下獨立地選自基團(tuán)C1-6烷基、C3-6環(huán)烷基、Br、Cl、F、C1-4鹵代烷基、-CN、-OR17、-S(O)mR18、-COR17、-CO2R17、-OC(O)R18、-NR15COR17、-N(COR17)2、-NR15CO2R18、-NR17R19和-CONR17R19的取代基取代,并且每一個雜芳基在任何氮原子上由0-1個選自基團(tuán)R15、CO2R14a、COR14a和SO2R14a的取代基取代。[21]在另一個仍然更優(yōu)選的實施方案中,本發(fā)明提供了新的式Ia化合物,其中X選自基團(tuán)O、S和鍵;R1由0-1個選自基團(tuán)-CN、-CO2R13a和C4-8環(huán)烷基的取代基來取代,其中在C4-8環(huán)烷基中的0-1個碳原子由選自基團(tuán)-O-、-S(O)n-和-NR13a-的基團(tuán)來替代;R1也以0-2個在每一個情況下獨立選自基團(tuán)R1a、R1b、C1-6烷基、C2-8鏈烯基、C2-8炔基、Br、Cl、F、CF3、CF3、-OR13a、-OH、-OCH3、-OCH2CH3、-CH2OCH3、-CH2CH2OCH3和-NR13aR16a的取代基取代;R1a為芳基和由0-1個選自O(shè)CH3、OCH2CH3、OCH(CH3)2、OCH2CH2CH3和OCF3的取代基和以0-3個在每一個情況下獨立選自基團(tuán)CH3、CH2CH3、CH(CH3)2、CH2CH2CH3、環(huán)丙基、Br、Cl、F、CF3、-CN、SCH3、-NH2、-NHCH3、-N(CH3)2、-C(O)NH2、-C(O)NHCH3和-C(O)N(CH3)2的取代基取代的苯基;R1b為雜芳基并且選自基團(tuán)呋喃基、噻吩基、咪唑基、噻唑基、噁唑基、異噁唑基、吡唑基、三唑基、四唑基和吲唑基、每一個雜芳基在0-3個碳原子上由在每一個情況下獨立選自基團(tuán)CH3、CH2CH3、CH(CH3)2、CH2CH2CH3、環(huán)丙基、OCH3、OCH2CH3、OCH(CH3)2、OCH2CH2CH3、OCF3、Br、Cl、F、CF3、-CN、SCH3、-NH2、-NHCH3、-N(CH3)2、-C(O)NH2、-C(O)NHCH3和-C(O)N(CH3)2的取代基取代,并且每一個雜芳基在任何氮原子上由0-1個選自基團(tuán)CH3、CO2CH3、COCH3和SO2CH3的取代基取代;R2選自基團(tuán)CH3、CH2CH3、CH(CH3)2和CH2CH2CH3;R3和R8在每一個情況下獨立地選自基團(tuán)H、CH3、CH2CH3、CH(CH3)2和CH2CH2CH3;芳基為在每一個情況下由2-4個獨立選自基團(tuán)CH3、CH2CH3、CH(CH3)2、CH2CH2CH3、環(huán)丙基、OCH3、OCH2CH3、OCH(CH3)2、OCH2CH2CH3、OCF3、Br、Cl、F、CF3、-CN、SCH3、SO2CH3、-NH2、-NHCH3、-N(CH3)2、-C(O)NH2、-C(O)NHCH3和-C(O)N(CH3)2的取代基取代的苯基;和,雜芳基在每一個情況下獨立選自基團(tuán)吡啶基、吲哚基、苯并噻吩基、2,3-二氫苯并呋喃基、2,3-二氫苯并噻吩基、2,3-二氫苯并噻吩基-S-氧化物、2,3-二氫苯并噻吩基-S-二氧化物、二氫吲哚基和苯并噁唑啉-2-酮基,每一個雜芳基在2-4個碳原子上由在每一個情況下獨立地選自基團(tuán)CH3、CH2CH3、CH(CH3)2、CH2CH2CH3、環(huán)丙基、OCH3、OCH2CH3、OCH(CH3)2、OCH2CH2CH3、OCF3、Br、Cl、F、CF3、-CN、SCH3、SO2CH3、-NH2、-NHCH3、-N(CH3)2、-C(O)NH2、-C(O)NHCH3和-C(O)N(CH3)2的取代基取代,并且每一個雜芳基在任何氮原子上由0-1個選自基團(tuán)CH3、CO2CH3、COCH3和SO2CH3的取代基來取代;[2m]在另一個更優(yōu)選的實施方案中,本發(fā)明提供了新的式Ia化合物,其中R1以0-2個在每一個情況下獨立選自基團(tuán)R1a、R1b、CH3、CH2CH3、CH(CH3)2、CH2CH2CH3、-(CH2)3CH3、-CH=CH2、-CH=CH(CH3)、-CH≡CH、-CH≡C(CH3)、-CH2OCH3、-CH2CH2OCH3、F和CF3的取代基取代;R1a為由0-1個選自O(shè)CH3、OCH2CH3、OCH(CH3)2、OCH2CH2CH3和OCF3的取代基和由0-2個在每一個情況下獨立選自基團(tuán)CH3、CH2CH3、CH(CH3)2、CH2CH2CH3、Br、Cl、F、CF3、-CN和SCH3的取代基取代的苯基;R1b為雜芳基和選自基團(tuán)呋喃基、噻吩基、咪唑基、噻唑基、噁唑基、異噁唑基、吡唑基、三唑基和四唑基,每一個雜芳基在0-3個碳原子上由在每一個情況下獨立選自基團(tuán)CH3、CH2CH3、CH(CH3)2、CH2CH2CH3、OCH3、OCH2CH3、OCF3、Br、Cl、F、CF3、-CN和SCH3的取代基取代,并且每一個雜芳基在任何氮原子上以0-1個選自基團(tuán)CH3、CO2CH3、COCH3和SO2CH3的取代基取代;R2選自基團(tuán)CH3、CH2CH3和CH(CH3)2;R3和R8在每一個情況下獨立選自基團(tuán)H和CH3;芳基為在每一個情況下由2-4個獨立選自基團(tuán)CH3、CH2CH3、CH(CH3)2、CH2CH2CH3、環(huán)丙基、OCH3、OCH2CH3、OCH(CH3)2、OCH2CH2CH3、OCF3、Br、Cl、F、CF3、-CN、SCH3、SO2CH3、-NH2、-NHCH3、-N(CH3)2、-C(O)NH2、-C(O)NHCH3和-C(O)N(CH3)2的取代基取代的苯基;和,雜芳基為在2-4個碳原子上由在每一個情況下獨立地選自基團(tuán)CH3、CH2CH3、CH(CH3)2、CH2CH2CH3、環(huán)丙基、OCH3、OCH2CH3、OCH(CH3)2、OCH2CH2CH3、OCF3、Br、Cl、F、CF3、-CN、SCH3、SO2CH3、-NH2、-NHCH3、-N(CH3)2、-C(O)NH2、-C(O)NHCH3和-C(O)N(CH3)2的取代基取代的吡啶基。[2n]在另一個甚至更優(yōu)選的實施方案中,本發(fā)明提供了新的式Ia化合物,其中R1由0-2個在每一個情況下獨立選自基團(tuán)R1a、CH3、CH2CH3、CH(CH3)2、CH2CH2CH3、-(CH2)3CH3、-CH2OCH3、-CH2CH2OCH3、F和CF3的取代基取代;和,R1a為由0-2個在每一個情況下獨立選自基團(tuán)CH3、CH2CH3、CH(CH3)2、CH2CH2CH3、Br、Cl、F、CF3、-CN和SCH3的取代基取代的苯基。[2o]在仍然更優(yōu)選的實施方案中,本發(fā)明提供了新的式Ia化合物,其中D為由2-4個在每一個情況下獨立選自基團(tuán)CH3、CH2CH3、CH(CH3)2、CH2CH2CH3、環(huán)丙基、OCH3、OCH2CH3、OCH(CH3)2、OCH2CH2CH3、OCF3、Br、Cl、F和CF3的取代基取代的苯基;[2p]在另一個仍然更優(yōu)選的實施方案中,本發(fā)明提供了新的式Ia化合物,其中D為在2-4個碳原子上以每一個情況下獨立選自基團(tuán)CH3、CH2CH3、CH(CH3)2、CH2CH2CH3、環(huán)丙基、OCH3、OCH2CH3、OCH(CH3)2、OCH2CH2CH3、OCF3、Br、Cl、F和CF3的取代基來取代的吡啶基;[2q]在另一個更優(yōu)選的實施方案中,本發(fā)明提供了新的式Ia化合物,其中R1選自基團(tuán)C1-10烷基、C2-10鏈烯基、C2-10炔基、C3-8環(huán)烷基、C3-6環(huán)烷基-C1-6烷基和C1-4烷氧基-C1-4烷基;R1由C3-8環(huán)烷基基團(tuán)取代,其中在該C4-8環(huán)烷基基團(tuán)的0-1個碳原子上由選自基團(tuán)-O-、-S(O)n-、-NR13a-、-NCO2R14b-、-NCOR14b-和-NSO2R14b-的基團(tuán)來替代;R1也由0-3個在每一個情況下獨立選自基團(tuán)R1a、R1b、R1c、C1-6烷基、C2-8鏈烯基、C2-8炔基、Br、Cl、F、I、C1-4鹵代烷基、-OR13a、-NR13aR16a、C1-2烷氧基-C1-2烷基和由0-1個R9取代的C3-8環(huán)烷基的取代基取代并且其中C4-8環(huán)烷基的0-1個碳以-O-替代;假定R1不是環(huán)己基-(CH2)2-基團(tuán);R1a為芳基和選自基團(tuán)苯基、萘基、2,3-二氫化茚基和茚基,每一個R1a由0-1個-OR17和0-5個在每一個情況下獨立選自基團(tuán)C1-6烷基、C3-6環(huán)烷基、Br、Cl、F、I、C1-4鹵代烷基、-CN、硝基、SH、-S(O)nR18、-COR17、-OC(O)R18、-NR15aCOR17、-N(COR17)2、-NR15aCONR17aR19a、-NR15aCO2R18、-NR17aR19a和-CONR17aR19a的取代基來取代;R1b為雜芳基并且選自基團(tuán)吡啶基、嘧啶基、三嗪基、呋喃基、喹啉基、異喹啉基、噻吩基、咪唑基、噻唑基、吲哚基、吡咯基、噁唑基、苯并呋喃基、苯并噻吩基、苯并噻唑基、苯并噁唑基、異噁唑基、吡唑基、三唑基、四唑基、吲唑基、2,3-二氫苯并呋喃基、2,3-二氫苯并噻吩基、2,3-二氫苯并噻吩基-S-氧化物、2,3-二氫苯并噻吩基-S-二氧化物、二氫吲哚基、苯并噁唑啉-2-酮基、苯并二氧戊環(huán)基和苯并二噁烷,每一個雜芳基在0-4個碳原子上以在每一個情況下獨立選自基團(tuán)C1-6烷基、C3-6環(huán)烷基、Br、Cl、F、I、C1-4鹵代烷基、-CN、硝基、-OR17、SH、-S(O)mR18、-COR17、-OC(O)R18、-NR15aCOR17、-N(COR17)2、-NR15aCONR17aR19a、-NR15aCO2R18、-NR17aR19a和-CONR17aR19a的取代基取代,并且每一個雜芳基在任何氮原子上以0-1個選自基團(tuán)R15a、CO2R14b、COR14b和SO2R14b的取代基來取代;和,R1c為雜環(huán)基并且為飽和的或部分飽和的雜芳基,每個雜環(huán)基在0-4個碳原子上由在每一個情況下獨立選自基團(tuán)C1-6烷基、C1-6環(huán)烷基、Br、Cl、F、I、C1-4鹵代烷基、-CN、硝基、-OR13a、SH、-S(O)nR14b、-COR13a、-OC(O)R14b、-NR15aCOR13a、-N(COR13a)2、-NR15aCONR13aR16a、-NR15aCO2R14b、-NR13aR16a和-CONR13aR16a的取代基取代,并且每一個雜環(huán)基在任何氮原子上以0-1個選自基團(tuán)R13a、CO2R14b、COR14b和SO2R14b的取代基取代并且其中任何硫原子任選地單氧化或雙氧化。[2r]在另一個甚至更優(yōu)選的實施方案中,本發(fā)明提供了新的式Ia化合物,其中X選自基團(tuán)O、S(O)n和鍵;n為0、1或2;R1選自基團(tuán)C1-6烷基、C2-6鏈烯基、C2-6炔基和C3-8環(huán)烷基;R1由C3-6環(huán)烷基基團(tuán)取代,其中在該C4-6環(huán)烷基基團(tuán)的0-1個碳原子上以選自基團(tuán)-O-、-S(O)n-和-NR13a-的基團(tuán)取代;R1也以0-2個在每一個情況下獨立選自基團(tuán)R1a、R1b、C1-6烷基、C2-8鏈烯基、C2-8炔基、Br、Cl、F、CF3、CF2CF3、-OR13a、-NR13aR16a、C1-2烷氧基-C1-2烷基和由0-1個R9取代的C3-6環(huán)烷基的取代基取代并且其中C4-8環(huán)烷基的0-1個碳以-O-替代;R1a為芳基并且選自基團(tuán)苯基和2,3-二氫化茚基,每一個R1a以0-1個-OR17和0-5個在每一個情況下獨立選自基團(tuán)C1-4烷基、C3-6環(huán)烷基、Br、Cl、F、C1-4鹵代烷基、-CN、-S(O)nR18、-COR17、-NR17aR19a和-CONR17aR19a的取代基取代;R1b為雜芳基和選自基團(tuán)吡啶基、嘧啶基、呋喃基、噻吩基、咪唑基、噻唑基、吡咯基、噁唑基、異噁唑基、吡唑基、三唑基、四唑基和吲唑基,每一個雜芳基在0-4個碳原子上由在每一個情況下獨立選自基團(tuán)C1-4烷基、C3-6環(huán)烷基、Br、Cl、F、CF3、-CN、-OR17、-S(O)mR18、-COR17、-NR17aR19a和-CONR17aR19a的取代基取代,并且每一個雜芳基在任何氮原子上以0-1個選自基團(tuán)R15a、CO2R14b、COR14b和SO2R14b的取代基來取代;R2選自基團(tuán)C1-4烷基、C2-4鏈烯基和C2-4炔基并且以0-1個選自基團(tuán)-CN、OH、Cl、F和C1-4烷氧基的取代基來取代;R9在每一個情況下獨立選自基團(tuán)H、C1-4烷基和C3-8環(huán)烷基;R3和R8在每一個情況下獨立選自基團(tuán)H、Br、Cl、F、-CN、C1-4烷基、C3-6環(huán)烷基、C1-4烷氧基、NH2、C1-4烷基氨基和(C1-4烷基)2-氨基;R13選自基團(tuán)C1-4烷基、C1-2鹵代烷基、C1-2烷氧基-C1-2烷基、C3-6環(huán)烷基-C1-2烷基、芳基(C1-2烷基)-和雜芳基(C1-2烷基)-;R13a和R16a在每一個情況下獨立選自基團(tuán)H、C1-4烷基、C1-4鹵代烷基、C1-4烷氧基-C1-4烷基、C3-6環(huán)烷基和C3-6環(huán)烷基-C1-6烷基;R14選自基團(tuán)C1-4烷基、C1-2鹵代烷基、C1-2烷氧基-C1-2烷基、C3-6環(huán)烷基-C1-2烷基、芳基(C1-2烷基)-和雜芳基(C1-2烷基)-;R14a選自基團(tuán)C1-4烷基、C1-2鹵代烷基、C1-2烷氧基-C1-2烷基和C3-6環(huán)烷基-C1-2烷基;R14b選自基團(tuán)C1-4烷基、C1-2鹵代烷基、C1-2烷氧基-C1-2烷基、C3-6環(huán)烷基和C3-6環(huán)烷基-C1-2烷基;R15在每一個情況下獨立選自基團(tuán)H、C1-4烷基、C3-7環(huán)烷基、C3-6環(huán)烷基-C1-6烷基、苯基和芐基,每一個苯基或芐基在該芳基部分上由0-3個選自基團(tuán)C1-4烷基、Br、Cl、F、C1-4鹵代烷基、C1-4烷氧基、C1-4鹵代烷氧基和二甲基氨基的基團(tuán)來取代;R15a在每一個情況下獨立選自基團(tuán)H、C1-4烷基、C3-7環(huán)烷基和C3-6環(huán)烷基-C1-6烷基;R17、R18和R19在每一個情況下獨立選自基團(tuán)H、C1-6烷基、C3-10環(huán)烷基、C3-6環(huán)烷基-C1-6烷基、C1-2烷氧基-C1-2烷基和C1-4鹵代烷基;或者,在NR17R19部分中,R17和R19一起形成1-吡咯烷基、1-嗎啉基、1-哌啶基或1-哌嗪基,其中在1-哌嗪基中的N4以0-1個選自基團(tuán)R13、CO2R14、COR14和SO2R14的取代基取代;R17a和R19a在每一個情況下獨立選自基團(tuán)H、C1-6烷基、C3-10環(huán)烷基、C3-6環(huán)烷基-C1-6烷基和C1-4鹵代烷基;芳基為由1-4個在每一個情況下獨立選自基團(tuán)C1-4烷基、C3-6環(huán)烷基、-OR17、Br、Cl、F、C1-4鹵代烷基、-CN、-S(O)nR18、-COR17、-CO2R17、-NR15COR17、-NR15CO2R18、-NR17R19和-CONR17R19的取代基取代的苯基;和,雜芳基在每一個情況下獨立選自基團(tuán)吡啶基、嘧啶基、三嗪基、呋喃基、喹啉基、異喹啉基、噻吩基、噻唑基、吲哚基、吡咯基、噁唑基、苯并呋喃基、苯并噻吩基、苯并噻唑基、苯并噁唑基、異噁唑基、四唑基、吲唑基、2,3-二氫苯并呋喃基、2,3-二氫苯并噻吩基、2,3-二氫苯并噻吩基-S-氧化物、2,3-二氫苯并噻吩基-S-二氧化物、二氫吲哚基、苯并噁唑啉-2-酮基、苯并二氧戊環(huán)基和苯并二噁烷,每一個雜芳基在1-4個碳原子上以在每一個情況下獨立地選自基團(tuán)C1-6烷基、C3-6環(huán)烷基、Br、Cl、F、C1-4鹵代烷基、-CN、-OR17、-S(O)mR18、-COR17、-CO2R17、-OC(O)R18、-NR15COR17、-N(COR17)2、-NR15CO2R18、-NR17R19和-CONR17R19的取代基來取代,并且每一個雜芳基在任何氮原子上以0-1個選自基團(tuán)R15、CO2R14a、COR14a和SO2R14a的取代基來取代。[2s]在另一個仍然更優(yōu)選的實施方案中,本發(fā)明提供了式Ia的新化合物,其中X選自基團(tuán)O、S和鍵;R1為C1-6烷基;R1由C3-6環(huán)烷基取代,其中在該C4-6環(huán)烷基的0-1個碳原子上以選自基團(tuán)-O-、-S(O)n-和-NR13a-的基團(tuán)替代;R1也由0-2個在每一個情況下獨立選自基團(tuán)R1a、R1b、C1-6烷基、C2-8鏈烯基、C2-8炔基、F、CF3、-OR13a、-NR13aR16a、-CH2OCH3、-CH2CH2OCH3和由0-1個CH3取代的C3-6環(huán)烷基的取代基取代,并且其中C4-8環(huán)烷基的0-1個碳以-O-替代;前提是R1不是環(huán)己基-(CH2)2-基團(tuán);R1a為芳基和以0-1個選自O(shè)CH3、OCH2CH3、OCH(CH3)2、OCH2CH2CH3和OCF3的取代基和以0-3個在每一個情況下獨立選自基團(tuán)CH3、CH2CH3、CH(CH3)2、CH2CH2CH3、環(huán)丙基、Br、Cl、F、CF3、-CN、SCH3、-NH2、-NHCH3、-N(CH3)2、-C(O)NH2、-C(O)NHCH3和-C(O)N(CH3)2的取代基取代的苯基;R1b為雜芳基和選自基團(tuán)呋喃基、噻吩基、咪唑基、噻唑基、噁唑基、異噁唑基、吡唑基、三唑基、四唑基和吲唑基,每一個雜芳基在0-3個碳原子上由在每一個情況下獨立選自基團(tuán)CH3、CH2CH3、CH(CH3)2、CH2CH2CH3、環(huán)丙基、OCH3、OCH2CH3、OCH(CH3)2、OCH2CH2CH3、OCF3、Br、Cl、F、CF3、-CN、SCH3、-NH2、-NHCH3、-N(CH3)2、-C(O)NH2、-C(O)NHCH3和-C(O)N(CH3)2的取代基取代,并且每一個雜芳基在任何氮原子上以0-1個選自基團(tuán)CH3、CO2CH3、COCH3和SO2CH3的取代基取代。R2選自基團(tuán)CH3、CH2CH3、CH(CH3)2和CH2CH2CH3;R3和R8在每一個情況下獨立選自基團(tuán)H、CH3、CH2CH3、CH(CH3)2和CH2CH2CH3;芳基為在每一個情況下由2-4個獨立選自基團(tuán)CH3、CH2CH3、CH(CH3)2、CH2CH2CH3、環(huán)丙基、OCH3、OCH2CH3、OCH(CH3)2、OCH2CH2CH3、OCF3、Br、Cl、F、CF3、-CN、SCH3、SO2CH3、-NH2、-NHCH3、-N(CH3)2、-C(O)NH2、-C(O)NHCH3和-C(O)N(CH3)2的取代基取代的苯基;和,雜芳基在每一個情況下獨立選自基團(tuán)吡啶基、吲哚基、苯并噻吩基、2,3-二氫苯并呋喃基、2,3-二氫苯并噻吩基、2,3-二氫苯并噻吩基-S-氧化物、2,3-二氫苯并噻吩基-S-二氧化物、二氫吲哚基和苯并噁唑啉-2-酮基,每一個雜芳基在2-4個碳原子上以在每一個情況下獨立地選自基團(tuán)CH3、CH2CH3、CH(CH3)2、CH2CH2CH3、環(huán)丙基、OCH3、OCH2CH3、OCH(CH3)2、OCH2CH2CH3、OCF3、Br、Cl、F、CF3、-CN、SCH3、SO2CH3、-NH2、-NHCH3、-N(CH3)2、-C(O)NH2、-C(O)NHCH3和-C(O)N(CH3)2的取代基取代,并且每一個雜芳基在任何氮原子上由0-1個選自基團(tuán)CH3、CO2CH3、COCH3和SO2CH3的取代基來取代。[2t]在另一個更優(yōu)選的實施方案中,本發(fā)明提供了新的式Ia化合物,其中R1為(環(huán)丙基)C1烷基或(環(huán)丁基)C1烷基;R1由1-2個在每一個情況下獨立選自基團(tuán)R1a、R1b、CH3、CH2CH3、CH(CH3)2、CH2CH2CH3、-(CH2)3CH3、-CH=CH2、-CH=CH(CH3)、-CH≡CH、-CH≡C(CH3)、-CH2OCH3、-CH2CH2OCH3、F、CF3、環(huán)丙基、CH3-環(huán)丙基、環(huán)丁基、CH3-環(huán)丁基、環(huán)戊基、CH3-環(huán)戊基的取代基取代;R1a為以0-1個選自O(shè)CH3、OCH2CH3和OCF3的取代基和以0-2個在每一個情況下獨立選自基團(tuán)CH3、CH2CH3、CH(CH3)2、CH2CH2CH3、Br、C1、F、CF3、-CN和SCH3的取代基取代的苯基;R1b為雜芳基并且選自基團(tuán)呋喃基、噻吩基、咪唑基、噻唑基、噁唑基、異噁唑基、吡唑基、三唑基和四唑基,每一個雜芳基在0-3個碳原子上以在每一個情況下獨立選自基團(tuán)CH3、CH2CH3、CH(CH3)2、CH2CH2CH3、OCH3、OCH2CH3、OCF3、Br、Cl、F、CF3、-CN和SCH3的取代基取代,并且每一個雜芳基在任何氮原子上以0-1個選自基團(tuán)CH3、CO2CH3、COCH3和SO2CH3的取代基取代;R2選自基團(tuán)CH3、CH2CH3和CH(CH3)2;R3和R8在每一個情況下獨立選自基團(tuán)H和CH3;芳基為在每一個情況下由2-4個獨立選自基團(tuán)CH3、CH2CH3、CH(CH3)2、CH2CH2CH3、環(huán)丙基、OCH3、OCH2CH3、OCH(CH3)2、OCH2CH2CH3、OCF3、Br、Cl、F、CF3、-CN、SCH3、SO2CH3、-NH2、-NHCH3、-N(CH3)2、-C(O)NH2、-C(O)NHCH3和-C(O)N(CH3)2的取代基取代的苯基;和,雜芳基為在2-4個碳原子上由每一個情況下獨立選自基團(tuán)CH3、CH2CH3、CH(CH3)2、CH2CH2CH3、環(huán)丙基、OCH3、OCH2CH3、OCH(CH3)2、OCH2CH2CH3、OCF3、Br、Cl、F、CF3、-CN、SCH3、SO2CH3、-NH2、-NHCH3、-N(CH3)2、-C(O)NH2、-C(O)NHCH3和-C(O)N(CH3)2的取代基取代的吡啶基。[2u]在另一個甚至更優(yōu)選的實施方案中,本發(fā)明提供了新的式Ia化合物,其中R1為(環(huán)丙基)C1烷基或(環(huán)丁基)C1烷基;R1由1-2個在每一個情況下獨立選自基團(tuán)R1a、R1b、CH3、CH2CH3、CH(CH3)2、CH2CH2CH3、-(CH2)3CH3、-CH=CH2、-CH=CH(CH3)、-CH≡CH、-CH≡C(CH3)、-CH2OCH3、-CH2CH2OCH3、F、CF3、環(huán)丙基和CH3-環(huán)丙基的取代基來取代;R1a為由0-2個在每一個情況下獨立選自CH3、CH2CH3、CH(CH3)2、CH2CH2CH3、Br、Cl、F、CF3、-CN和SCH3的取代基取代的苯基;R1b為雜芳基并且選自基團(tuán)呋喃基、噻吩基、咪唑基、噻唑基、噁唑基、異噁唑基和吡唑基,每一個雜芳基在0-3個碳原子上由在每一個情況下獨立選自基團(tuán)CH3、CH2CH3、CH(CH3)2、CH2CH2CH3、OCH3、OCH2CH3、OCF3、Br、Cl、F、CF3、-CN和SCH3的取代基取代。[2v]在另一個更優(yōu)選的實施方案中,本發(fā)明提供了新的式Ia化合物,其中D為由2-4個在每一個情況下獨立選自基團(tuán)CH3、CH2CH3、CH(CH3)2、CH2CH2CH3、環(huán)丙基、OCH3、OCH2CH3、OCH(CH3)2、OCH2CH2CH3、OCF3、Br、Cl、F和CF3的取代基取代的苯基。[2w]在另一個更優(yōu)選的實施方案中,本發(fā)明提供了式Ia的新化合物,其中D為在2-4個碳原子上由在每一個情況下獨立選自基團(tuán)CH3、CH2CH3、CH(CH3)2、CH2CH2CH3、環(huán)丙基、OCH3、OCH2CH3、OCH(CH3)2、OCH2CH2CH3、OCF3、Br、Cl、F和CF3的取代基取代的吡啶基。[3]在另一個優(yōu)選的實施方案中,本發(fā)明提供了新的式Ib化合物 在另一個更優(yōu)選的實施方案中,本發(fā)明提供了新的式Ib化合物,其中X選自基團(tuán)O、S(O)n和鍵;n為0、1或2;R1選自基團(tuán)C1-6烷基、C2-6鏈烯基、C2-6炔基和C3-8環(huán)烷基;R1由0-1個選自基團(tuán)-CN、-S(O)nR14b、-COR13a、-CO2R13a和C3-8環(huán)烷基的基團(tuán)來取代,其中在C4-8環(huán)烷基中的0-1個碳原子以選自基團(tuán)-O-、-S(O)n-、-NR13a-、-NCO2R14b-、-NCOR14b-和-NSO2R14b-的基團(tuán)來替代;R1也以0-2個在每一個情況下獨立選自基團(tuán)R1a、R1b、C1-6烷基、C2-8鏈烯基、C2-8炔基、Br、Cl、F、CF3、CF2CF3、-OR13a、-NR13aR16a、C1-2烷氧基-C1-2烷基和以0-1個R9取代的C3-8環(huán)烷基的取代基取代并且其中C4-8環(huán)烷基的0-1個碳由-O-替代;前提是R1不是環(huán)己基-(CH2)2-基團(tuán);R1a為芳基和選自基團(tuán)苯基和2,3-二氫化茚基,每一個R1a以0-1個-OR17和0-5個在每一個情況下獨立選自基團(tuán)C1-4烷基、C3-6環(huán)烷基、Br、Cl、F、C1-4鹵代烷基、-CN、-S(O)nR18、-COR17、-NR17aR19a和-CONR17aR19a的取代基取代;R1b為雜芳基和選自基團(tuán)吡啶基、嘧啶基、呋喃基、噻吩基、咪唑基、噻唑基、吡咯基、噁唑基、異噁唑基、吡唑基、三唑基、四唑基和吲唑基,每一個雜芳基在0-4個碳原子上以在每一個情況下獨立選自基團(tuán)C1-4烷基、C3-6環(huán)烷基、Br、Cl、F、CF3、-CN、-OR17、-S(O)mR18、-COR17、-NR17aR19a和-CONR17aR19a的取代基取代,并且每一個雜芳基在任何氮原子上由0-1個選自基團(tuán)R15a、CO2R14b、COR14b和SO2R14b的取代基取代;假定R1不是-(CH2)1-4-芳基或-(CH2)1-4-雜芳基,其中該芳基或雜芳基基團(tuán)是取代的或未取代的;R2選自基團(tuán)C1-4烷基、C2-4鏈烯基和C2-4炔基并且由0-1個選自基團(tuán)-CN、OH、Cl、F和C1-4烷氧基的取代基來取代;R3和R7在每一個情況下獨立選自基團(tuán)H、Br、Cl、F、-CN、C1-4烷基、C3-6環(huán)烷基、C1-4烷氧基、NH2、C1-4烷基氨基和(C1-4烷基)2-氨基;R9在每一個情況下獨立選自基團(tuán)H、C1-4烷基和C3-8環(huán)烷基;R13選自基團(tuán)C1-4烷基、C1-2鹵代烷基、C1-2烷氧基-C1-2烷基、C3-6環(huán)烷基-C1-2烷基、芳基(C1-2烷基)-和雜芳基(C1-2烷基)-;R13a和R16a在每一個情況下獨立選自基團(tuán)H、C1-4烷基、C1-4鹵代烷基、C1-4烷氧基-C1-4烷基、C3-6環(huán)烷基和C3-6環(huán)烷基-C1-6烷基;R14選自基團(tuán)C1-4烷基、C1-2鹵代烷基、C1-2烷氧基-C1-2烷基、C3-6環(huán)烷基-C1-2烷基、芳基(C1-2烷基)-和雜芳基(C1-2烷基)-;R14a選自基團(tuán)C1-4烷基、C1-2鹵代烷基、C1-2烷氧基-C1-2烷基和C3-6環(huán)烷基-C1-2烷基;R14b選自基團(tuán)C1-4烷基、C1-2鹵代烷基、C1-2烷氧基-C1-2烷基、C3-6環(huán)烷基和C3-6環(huán)烷基-C1-2烷基;R15在每一個情況下獨立選自基團(tuán)H、C1-4烷基、C3-7環(huán)烷基、C3-6環(huán)烷基-C1-6烷基、苯基和芐基,每一個苯基或芐基在該芳基部分上由0-3個選自基團(tuán)C1-4烷基、Br、Cl、F、C1-4鹵代烷基、C1-4烷氧基、C1-4鹵代烷氧基和二甲基氨基的基團(tuán)來取代;R15a在每一個情況下獨立選自基團(tuán)H、C1-4烷基、C3-7環(huán)烷基和C3-6環(huán)烷基-C1-6烷基;R17、R18和R19在每一個情況下獨立選自基團(tuán)H、C1-6烷基、C3-10環(huán)烷基、C3-6環(huán)烷基-C1-6烷基、C1-2烷氧基-C1-2烷基和C1-4鹵代烷基;或者,在NR17R19部分中,R17和R19一起形成1-吡咯烷基、1-嗎啉基、1-哌啶基或1-哌嗪基,其中在1-哌嗪基中的N4由0-1個選自基團(tuán)R13、CO2R14、COR14和SO2R14的取代基取代;R17a和R19a在每一個情況下獨立選自基團(tuán)H、C1-6烷基、C3-10環(huán)烷基、C3-6環(huán)烷基-C1-6烷基和C1-4鹵代烷基;芳基為由1-4個在每一個情況下獨立選自基團(tuán)C1-4烷基、C3-6環(huán)烷基、-OR17、Br、Cl、F、C1-4鹵代烷基、-CN、-S(O)nR18、-COR17、-CO2R17、-NR15COR17、-NR15CO2R18、-NR17R19和-CONR17R19的取代基取代的苯基,;和,雜芳基在每一個情況下獨立選自基團(tuán)吡啶基、嘧啶基、三嗪基、呋喃基、喹啉基、異喹啉基、噻吩基、噻唑基、吲哚基、吡咯基、噁唑基、苯并呋喃基、苯并噻吩基、苯并噻唑基、苯并噁唑基、異噁唑基、四唑基、吲唑基、2,3-二氫苯并呋喃基、2,3-二氫苯并噻吩基、2,3-二氫苯并噻吩基-S-氧化物、2,3-二氫苯并噻吩基-S-二氧化物、二氫吲哚基、苯并噁唑啉-2-酮基、苯并二氧戊環(huán)基和苯并二噁烷,每一個雜芳基在1-4個碳原子上由在每一個情況下獨立地選自基團(tuán)C1-6烷基、C3-6環(huán)烷基、Br、Cl、F、C1-4鹵代烷基、-CN、-OR17、-S(O)mR18、-COR17、-CO2R17、-OC(O)R18、-NR15COR17、-N(COR17)2、-NR15CO2R18、-NR17R19和-CONR17R19的取代基取代,并且每一個雜芳基在任何氮原子上以0-1個選自基團(tuán)R15、CO2R14a、COR14a和SO2R14a的取代基來取代。[3b]在另一個甚至更優(yōu)選的實施方案中,本發(fā)明提供了新的式Ib化合物,其中X選自基團(tuán)O、S和鍵;R1為取代的C1-6烷基;R1由0-1個選自基團(tuán)-CN、-CO2R13a和C3-8環(huán)烷基的取代基來取代,其中在C4-8環(huán)烷基中的0-1個碳原子由選自基團(tuán)-O-、-S(O)n-和-NR13a-的基團(tuán)來替代;R1也以0-2個在每一個情況下獨立選自基團(tuán)R1a、R1b、C1-6烷基、C2-8鏈烯基、C2-8炔基、Br、Cl、F、CF3、-OR13a、-NR13aR16a、C1-2烷氧基-C1-2烷基和由0-1個CH3取代的C3-6環(huán)烷基的取代基取代并且其中C4-8環(huán)烷基的0-1個碳由-O-替代;假定R1不是環(huán)己基-(CH2)2-基團(tuán);R1a為芳基和由0-1個選自O(shè)CH3、OCH2CH3、OCH(CH3)2、OCH2CH2CH3和OCF3的取代基和由0-3個在每一個情況下獨立選自基團(tuán)CH3、CH2CH3、CH(CH3)2、CH2CH2CH3、環(huán)丙基、Br、Cl、F、CF3、-CN、SCH3、-NH2、-NHCH3、-N(CH3)2、-C(O)NH2、-C(O)NHCH3和-C(O)N(CH3)2的取代基取代的苯基;R1b為雜芳基和選自基團(tuán)呋喃基、噻吩基、咪唑基、噻唑基、噁唑基、異噁唑基、吡唑基、三唑基、四唑基和吲唑基,每一個雜芳基在0-3個碳原子上由在每一個情況下獨立選自基團(tuán)CH3、CH2CH3、CH(CH3)2、CH2CH2CH3、環(huán)丙基、OCH3、OCH2CH3、OCH(CH3)2、OCH2CH2CH3、OCF3、Br、Cl、F、CF3、-CN、SCH3、-NH2、-NHCH3、-N(CH3)2、-C(O)NH2、-C(O)NHCH3和-C(O)N(CH3)2的取代基取代,并且每一個雜芳基在任何氮原子上由0-1個選自基團(tuán)CH3、CO2CH3、COCH3和SO2CH3的取代基取代;假定R1不是-(CH2)1-4-芳基或-(CH2)1-4-雜芳基,其中該芳基或雜芳基基團(tuán)是取代的或未取代的;R2選自基團(tuán)CH3、CH2CH3、CH(CH3)2和CH2CH2CH3;R3和R7在每一個情況下獨立選自基團(tuán)H、CH3、CH2CH3、CH(CH3)2和CH2CH2CH3;芳基為在每一個情況下由2-4個獨立選自基團(tuán)CH3、CH2CH3、CH(CH3)2、CH2CH2CH3、環(huán)丙基、OCH3、OCH2CH3、OCH(CH3)2、OCH2CH2CH3、OCF3、Br、Cl、F、CF3、-CN、SCH3、SO2CH3、-NH2、-NHCH3、-N(CH3)2、-C(O)NH2、-C(O)NHCH3和-C(O)N(CH3)2的取代基取代的苯基;和,雜芳基在每一個情況下獨立選自基團(tuán)吡啶基、吲哚基、苯并噻吩基、2,3-二氫苯并呋喃基、2,3-二氫苯并噻吩基、2,3-二氫苯并噻吩基-S-氧化物、2,3-二氫苯并噻吩基-S-二氧化物、二氫吲哚基和苯并噁唑啉-2-酮-基,每一個雜芳基在2-4個碳原子上以在每一個情況下獨立地選自基團(tuán)CH3、CH2CH3、CH(CH3)2、CH2CH2CH3、環(huán)丙基、OCH3、OCH2CH3、OCH(CH3)2、OCH2CH2CH3、OCF3、Br、Cl、F、CF3、-CN、SCH3、SO2CH3、-NH2、-NHCH3、-N(CH3)2、-C(O)NH2、-C(O)NHCH3和-C(O)N(CH3)2的取代基取代,并且每一個雜芳基在任何氮原子上由0-1個選自基團(tuán)CH3、CO2CH3、COCH3和SO2CH3的取代基來取代。[3c]在另一個仍然更優(yōu)選的實施方案中,本發(fā)明提供了新的式Ib化合物,其中R1為取代的C1;R1以0-1個選自基團(tuán)-CN、-CO2CH3和-CO2CH2CH3的取代基取代;R1也以0-2個在每一個情況下獨立選自基團(tuán)R1a、R1b、CH3、CH2CH3、CH(CH3)2、CH2CH2CH3、-(CH2)3CH3、-CH=CH2、-CH=CH(CH3)、-CH≡CH、-CH≡C(CH3)、-CH2OCH3、-CH2CH2OCH3、F、CF3、環(huán)丙基、CH3-環(huán)丙基、環(huán)丁基、CH3-環(huán)丁基、環(huán)戊基、CH3-環(huán)戊基的取代基取代;R1a為由0-1個選自O(shè)CH3、OCH2CH2和OCF3的取代基和由0-2個在每一個情況下獨立選自基團(tuán)CH3、CH2CH3、CH(CH3)2、CH2CH2CH3、Br、Cl、F、CF3、-CN和SCH3的取代基取代的苯基;R1b為雜芳基和選自基團(tuán)呋喃基、噻吩基、咪唑基、噻唑基、噁唑基、異噁唑基、吡唑基、三唑基和四唑基,每一個雜芳基在0-3個碳原子上由在每一個情況下獨立選自基團(tuán)CH3、CH2CH3、CH(CH3)2、CH2CH2CH3、OCH3、OCH2CH3、OCF3、Br、Cl、F、CF3、-CN和SCH3的取代基取代,并且每一個雜芳基在任何氮原子上由0-1個選自基團(tuán)CH3、CO2CH3、COCH3和SO2CH3的取代基取代。前提是R1不是-(CH2)1-4-芳基或-(CH2)1-4-雜芳基,其中該芳基或雜芳基基團(tuán)是取代的或未取代的;R2選自基團(tuán)CH3、CH2CH3和CH(CH3)2;R3和R7在每一個情況下獨立選自基團(tuán)H和CH3;芳基為由2-4個在每一個情況下獨立選自基團(tuán)CH3、CH2CH3、CH(CH3)2、CH2CH2CH3、環(huán)丙基、OCH3、OCH2CH3、OCH(CH3)2、OCH2CH2CH3、OCF3、Br、Cl、F、CF3、-CN、SCH3、SO2CH3、-NH2、-NHCH3、-N(CH3)2、-C(O)NH2、-C(O)NHCH3和-C(O)N(CH3)2的取代基取代的苯基;和,雜芳基為在2-4個碳原子上由每一個情況下獨立選自基團(tuán)CH3、CH2CH3、CH(CH3)2、CH2CH2CH3、環(huán)丙基、OCH3、OCH2CH3、OCH(CH3)2、OCH2CH2CH3、OCF3、Br、Cl、F、CF3、-CN、SCH3、SO2CH3、-NH2、-NHCH3、-N(CH3)2、-C(O)NH2、-C(O)NHCH3和-C(O)N(CH3)2的取代基取代的吡啶基。[3d]在另一個更優(yōu)選的實施方案中,本發(fā)明提供了新的式Ib化合物,其中R1為取代的(環(huán)丙基)-C1烷基或(環(huán)丁基)-C1烷基;R1由0-1個-CN取代;R1也以0-1個在每一個情況下獨立選自基團(tuán)R1a、R1b、CH3、CH2CH3、CH(CH3)2、CH2CH2CH3、-(CH2)3CH3、-CH=CH2、-CH=CH(CH3)、-CH≡CH、-CH≡C(CH3)、Br、Cl、F、CF3、環(huán)丙基和CH3-環(huán)丙基的取代基來取代;R1也以0-1個在每一個情況下獨立選自基團(tuán)R1a、R1b、CH3、CH2CH3、CH(CH3)2、CH2CH2CH3、-(CH2)3CH3、-CH=CH2、-CH=CH(CH3)、-CH≡CH、-CH≡C(CH3)、-CH2OCH3、-CH2CH2OCH3、F、CF3、環(huán)丙基和CH3-環(huán)丙基的取代基取代;R1b為雜芳基和選自基團(tuán)呋喃基、噻吩基、咪唑基、噻唑基、噁唑基、異噁唑基和吡唑基,每一個雜芳基在0-3個碳原子上由在每一個情況下獨立選自基團(tuán)CH3、CH2CH3、CH(CH3)2、CH2CH2CH3、OCH3、OCH2CH3、OCF3、Br、Cl、F、CF3、-CN和SCH3的取代基取代。[3e]在另一個更優(yōu)選的實施方案中,本發(fā)明提供了新的式Ib化合物,其中R1為由一個在每一個情況下獨立選自基團(tuán)R1a、R1b、CH3、CH2CH3、CH(CH3)2、CH2CH2CH3、-(CH2)3CH3、-CH=CH2、-CH=CH(CH3)、-CH≡CH、-CH≡C(CH3)、-CH2OCH3、-CH2CH2OCH3、F、CF3、環(huán)丙基和CH3-環(huán)丙基的取代基取代的(環(huán)丙基)C1烷基或(環(huán)丁基)-C1烷基;R1a為由0-2個在每一個情況下獨立選自基團(tuán)CH3、CH2CH3、Cl、F和CF3的取代基取代的苯基;R1b為雜芳基和選自基團(tuán)呋喃基、噻吩基和異噁唑基,每一個雜芳基在0-2個碳原子上由在每一個情況下獨立選自基團(tuán)CH3、OCH3、Cl、F和CF3的取代基取代。[3f]在一個甚至更優(yōu)選的實施方案中,本發(fā)明提供了新的式Ib化合物,其中R1選自基團(tuán)(環(huán)丙基)CH-CH3、(環(huán)丙基)CH-CH2CH3、(環(huán)丙基)CH-CH2OCH3、(環(huán)丙基)CH-CH2CH2CH3、(環(huán)丙基)CH-CH2CH2OCH3、(環(huán)丙基)2CH、苯基(環(huán)丙基)CH、呋喃基(環(huán)丙基)CH、噻吩基(環(huán)丙基)CH、異噁唑基(環(huán)丙基)CH、(CH3-呋喃基)(環(huán)丙基)CH、(環(huán)丁基)CH-CH3、(環(huán)丁基)CH-CH2CH3、(環(huán)丁基)CH-CH2OCH3、(環(huán)丁基)CH-CH2CH2CH3、(環(huán)丁基)CH-CH2CH2OCH3、(環(huán)丁基)2CH、苯基(環(huán)丁基)CH、呋喃基(環(huán)丁基)CH、噻吩基(環(huán)丁基)CH、異噁唑基(環(huán)丁基)CH和(CH3-呋喃基)(環(huán)丁基)CH;[3g]在另一個更優(yōu)選的實施方案中,本發(fā)明提供了新的式Ib化合物,其中D為由2-4個在每一個情況下獨立選自基團(tuán)CH3、CH2CH3、CH(CH3)2、CH2CH2CH3、環(huán)丙基、OCH3、OCH2CH3、OCH(CH3)2、OCH2CH2CH3、OCF3、Br、Cl、F和CF3的取代基取代的苯基。[3h]在另一個更優(yōu)選的實施方案中,本發(fā)明提供了新的式Ib化合物,其中D為在2-4個碳原子上由在每一個情況下獨立選自基團(tuán)CH3、CH2CH3、CH(CH3)2、CH2CH2CH3、環(huán)丙基、OCH3、OCH2CH3、OCH(CH3)2、OCH2CH2CH3、OCF3、Br、Cl、F和CF3的取代基取代的吡啶基。[3i]在另一個優(yōu)選的實施方案中,本發(fā)明提供了新的式Ib化合物,其中該化合物選自基團(tuán)1-(1-環(huán)丙基丙基)-4-(2,4-二氯苯基)-2-乙基-1H-咪唑并[4,5-c]吡啶;1-(1-環(huán)丙基丙基)-4-(2,4-二氯苯基)-2-甲氧基-1H-咪唑并[4,5-c]吡啶;1-(1-環(huán)丙基丙基)-2-乙基-4-[2-甲基-4-(三氟甲基)苯基]-1H-咪唑并[4,5-c]吡啶;4-[2-氯-4-(三氟甲基)苯基]-1-(1-環(huán)丙基丙基)-2-乙基-1H-咪唑并[4,5-c]吡啶;4-[2-氯-4-(三氟甲基)苯基]-1-(1-環(huán)丙基丙基)-2-甲氧基-1H-咪唑并[4,5-c]吡啶;4-[2-氯-4-(三氟甲基)苯基]-1-(1-環(huán)丙基丙基)-2-(甲基sulfanyl)-1H-咪唑并[4,5-c]吡啶;4-(2-氯-4-甲氧基苯基)-1-(1-環(huán)丙基丙基)-2-乙基-1H-咪唑并[4,5-c]吡啶;4-(2-氯-4-甲氧基苯基)-1-(1-環(huán)丙基丙基)-2-甲氧基-1H-咪唑并[4,5-c]吡啶;1-(1-環(huán)丙基丙基)-2-乙基-4-(4-甲氧基-2,5-二甲基苯基)-1H-咪唑并[4,5-c]吡啶;1-(1-環(huán)丙基丙基)-2-甲氧基-4-(4-甲氧基-2,5-二甲基苯基)-1H-咪唑并[4,5-c]吡啶;4-(2-氯-4-甲氧基苯基)-1-(1-環(huán)丙基丙基)-2-乙基-1H-咪唑并[4,5-c]吡啶;4-(2-氯-4-甲氧基苯基)-1-(1-環(huán)丙基丙基)-2-甲氧基-1H-咪唑并[4,5-c]吡啶;4-(2-氯-5-氟-4-甲氧基苯基)-1-(1-環(huán)丙基丙基)-2-乙基-1H-咪唑并[4,5-c]吡啶;4-(2-氯-氟-4-甲氧基苯基)-1-(1-環(huán)丙基丙基)-2-甲氧基-1H-咪唑并[4,5-c]吡啶;4-(2-氯-5-氟-4-甲基苯基)-1-(1-環(huán)丙基丙基)-2-乙基-1H-咪唑并[4,5-c]吡啶;2.4-(2-氯-氟-4-甲基苯基)-1-(1-環(huán)丙基丙基)-2-甲氧基-1H-咪唑并[4,5-c]吡啶;1-(1-環(huán)丙基丙基)-2-甲氧基-4-(2,4,5-三甲基苯基)-1H-咪唑并[4,5-c]吡啶;1-(1-環(huán)丙基丙基)-2-乙基-4-(2,4,5-三甲基苯基)-1H-咪唑并[4,5-c]吡啶;1-(1-環(huán)丙基丙基)-2-乙基-4-(2,5,6-三甲基-3-吡啶基)-1H-咪唑并[4,5-c]吡啶;1-(1-環(huán)丙基丙基)-2-甲氧基-4-(2,5,6-三甲基-3-吡啶基)-1H-咪唑并[4,5-c]吡啶;1-(1-環(huán)丙基丙基)-4-(2,6-二甲基-3-吡啶基)-2-乙基-1H-咪唑并[4,5-c]吡啶;1-(1-環(huán)丙基丙基)-4-(2,6-二甲基-3-吡啶基)-2-甲氧基-1H-咪唑并[4,5-c]吡啶;1-(1-環(huán)丙基丙基)-4-(2,6-二甲氧基-3-吡啶基)-2-乙基-1H-咪唑并[4,5-c]吡啶;4-(2,4-二氯苯基)-2-乙基-1-(1-乙基丙基)-1H-咪唑并[4,5-c]吡啶;4-(2,4-二氯苯基)-1-(1-乙基丙基)-2-甲氧基-1H-咪唑并[4,5-c]吡啶;4-[2-氯-4-(三氟甲基)苯基]-1-(1-乙基丙基)-2-甲氧基-1H-咪唑并[4,5-c]吡啶;4-[2-氯-4-(三氟甲基)苯基]-2-乙基-1-(1-乙基丙基)-1H-咪唑并[4,5-c]吡啶;4-[2-氯-4-(甲基磺?;?苯基]-2-乙基-1-(1-乙基丙基)-1H-咪唑并[4,5-c]吡啶;4-[2-氯-4-(甲基磺?;?苯基]-1-(1-乙基丙基)-2-甲氧基-1H-咪唑并[4,5-c]吡啶;2-乙基-1-(1-乙基丙基)-4-(4-甲氧基-2,5-二甲基苯基)-1H-咪唑并[4,5-c]吡啶;1-(1-乙基丙基)-2-甲氧基-4-(4-甲氧基-2,5-二甲基苯基)-1H-咪唑并[4,5-c]吡啶;4-(2-氯-4-甲氧基苯基)-2-乙基-1-(1-乙基丙基)-1H-咪唑并[4,5-c]吡啶;4-(2-氯-4-甲氧基苯基)-1-(1-乙基丙基)-2-甲氧基-1H-咪唑并[4,5-c]吡啶;2-乙基-1-(1-乙基丙基)-4-[4-甲氧基-2-(三氟甲基)苯基]-1H-咪唑并[4,5-c]吡啶;1-(1-乙基丙基)-2-甲氧基-4-[4-甲氧基-2-(三氟甲基)苯基]-1H-咪唑并[4,5-c]吡啶;1-(1-乙基丙基)-4-(5-氟-4-甲氧基-2-甲基苯基)-2-甲氧基-1H-咪唑并[4,5-c]吡啶;2-乙基-1-(1-乙基丙基)-4-(5-氟-4-甲氧基-2-甲基苯基)-1H-咪唑并[4,5-c]吡啶;3-氯-4-[1-(1-乙基丙基)-2-甲氧基-1H-咪唑并[4,5-c]吡啶-4-基]芐腈;3-氯-4-[2-乙基-1-(1-乙基丙基)-1H-咪唑并[4,5-c]吡啶-4-基]芐腈;1-{3-氯-4-[2-乙基-1-(1-乙基丙基)-1H-咪唑并[4,5-c]吡啶-4-基]苯基}-1-乙酮;1-{3-氯-4-[1-(1-乙基丙基)-2-甲氧基-1H-咪唑并[4,5-c]吡啶-4-基]苯基}-1-乙酮;1-(二環(huán)丙基甲基)-2-乙基-4-(5-氟-4-甲氧基-2-甲基苯基)-1H-咪唑并[4,5-c]吡啶;1-(二環(huán)丙基甲基)-4-(5-氟-4-甲氧基-2-甲基苯基)-2-甲氧基-1H-咪唑并[4,5-c]吡啶;4-(2-氯-4-甲氧基苯基)-1-(二環(huán)丙基甲基)-2-乙基-1H-咪唑并[4,5-c]吡啶;4-(2-氯-4-甲氧基苯基)-1-(二環(huán)丙基甲基)-2-甲氧基-1H-咪唑并[4,5-c]吡啶;4-(2,4-二氯苯基)-1-(二環(huán)丙基甲基)-2-乙基-1H-咪唑并[4,5-c]吡啶;4-(2,4-二氯苯基)-1-(二環(huán)丙基甲基)-2-甲氧基-1H-咪唑并[4,5-c]吡啶;4-[2-氯-4-(三氟甲基)苯基]-1-(二環(huán)丙基甲基)-2-乙基-1H-咪唑并[4,5-c]吡啶;4-[2-氯-4-(三氟甲基)苯基]-1-(二環(huán)丙基甲基)-2-甲氧基-1H-咪唑并[4,5-c]吡啶;4-(2,4-二氯苯基)-1-(1-乙基-3-甲氧基丙基)-2-甲氧基-1H-咪唑并[4,5-c]吡啶;4-(2,4-二氯苯基)-2-乙基-1-(1-乙基-3-甲氧基丙基)-1H-咪唑并[4,5-c]吡啶;4-[2-氯-4-(三氟甲基)苯基]-1-(1-乙基-3-甲氧基丙基)-2-甲氧基-1H-咪唑并[4,5-c]吡啶;4-[2-氯-4-(三氟甲基)苯基]-2-乙基-1-(1-乙基-3-甲氧基丙基)-1H-咪唑并[4,5-c]吡啶;4-(2-氯-4-甲氧基苯基)-1-(1-乙基-3-甲氧基丙基)-2-甲氧基-1H-咪唑并[4,5-c]吡啶;4-(2-氯-4-甲氧基苯基)-2-乙基-1-(1-乙基-3-甲氧基丙基)-1H-咪唑并[4,5-c]吡啶;4-(2-氯-5-氟-4-甲氧基苯基)-1-(1-乙基-3-甲氧基丙基)-2-甲氧基-1H-咪唑并[4,5-c]吡啶;4-(2-氯-5-氟-4-甲氧基苯基)-2-乙基-1-(1-乙基-3-甲氧基丙基)-1H-咪唑并[4,5-c]吡啶;1-(1-乙基-3-甲氧基丙基)-2-甲氧基-4-(4-甲氧基-2,5-二甲基苯基)-1H-咪唑并[4,5-c]吡啶;2-乙基-1-(1-乙基-3-甲氧基丙基)-4-(4-甲氧基-2,5-二甲基苯基)-1H-咪唑并[4,5-c]吡啶;2-乙基-1-(1-乙基-3-甲氧基丙基)-4-(5-氟-4-甲氧基-2-甲基苯基)-1H-咪唑并[4,5-c]吡啶;1-(1-乙基-3-甲氧基丙基)-4-(5-氟-4-甲氧基-2-甲基苯基)-2-甲氧基-1H-咪唑并[4,5-c]吡啶;4-(2-氯-5-氟-4-甲基苯基)-1-(1-乙基-3-甲氧基丙基)-2-甲氧基-1H-咪唑并[4,5-c]吡啶;4-(2-氯-5-氟-4-甲基苯基)-2-乙基-1-(1-乙基-3-甲氧基丙基)-1H-咪唑并[4,5-c]吡啶;4-[2-氯-4-(甲基磺?;?苯基]-1-(1-乙基-3-甲氧基丙基)-2-甲氧基-1H-咪唑并[4,5-c]吡啶;4-[2-氯-4-(甲基磺?;?苯基]-2-乙基-1-(1-乙基-3-甲氧基丙基)-1H-咪唑并[4,5-c]吡啶;1-{3-氯-4-[1-(1-乙基-3-甲氧基丙基)-2-甲氧基-1H-咪唑并[4,5-c]吡啶-4-基]苯基}-1-乙酮;1-{3-氯-4-[2-乙基-1-(1-乙基-3-甲氧基丙基)-1H-咪唑并[4,5-c]吡啶-4-基]苯基}-1-乙酮;1-{5-[1-(1-乙基-3-甲氧基丙基)-2-甲氧基-1H-咪唑并[4,5-c]吡啶-4-基]-6-甲基-2-吡啶基}-1-乙酮;1-{5-[2-乙基-1-(1-乙基-3-甲氧基丙基)-1H-咪唑并[4,5-c]吡啶-4-基]-6-甲基-2-吡啶基}-1-乙酮;1-(1-乙基-3-甲氧基丙基)-2-甲氧基-4-(6-甲氧基-2-甲基-3-吡啶基)-1H-咪唑并[4,5-c]吡啶;2-乙基-1-(1-乙基-3-甲氧基丙基)-4-(6-甲氧基-2-甲基-3-吡啶基)-1H-咪唑并[4,5-c]吡啶;4-(2,6-二甲氧基-3-吡啶基)-2-乙基-1-(1-乙基-3-甲氧基丙基)-1H-咪唑并[4,5-c]吡啶;4-(2,6-二甲氧基-3-吡啶基)-1-(1-乙基-3-甲氧基丙基)-2-甲氧基-1H-咪唑并[4,5-c]吡啶;4-(2,6-二甲基-3-吡啶基)-1-(1-乙基-3-甲氧基丙基)-2-甲氧基-1H-咪唑并[4,5-c]吡啶;4-(2,6-二甲基-3-吡啶基)-2-乙基-1-(1-乙基-3-甲氧基丙基)-1H-咪唑并[4,5-c]吡啶;2-乙基-1-(1-乙基-3-甲氧基丙基)-4-(2,5,6-三甲基-3-吡啶基)-1H-咪唑并[4,5-c]吡啶;1-(1-乙基-3-甲氧基丙基)-2-甲氧基-4-(2,5,6-三甲基-3-吡啶基)-1H-咪唑并[4,5-c]吡啶;4-(2,4-二氯苯基)-2-乙基-1-[1-(甲氧基甲基)丙基]-1H-咪唑并[4,5-c]吡啶;4-(2,4-二氯苯基)-2-甲氧基-1-[1-(甲氧基甲基)丙基]-1H-咪唑并[4,5-c]吡啶;4-[2-氯-4-(三氟甲基)苯基]-2-乙基-1-[1-(甲氧基甲基)丙基]-1H-咪唑并[4,5-c]吡啶;4-[2-氯-4-(三氟甲基)苯基]-2-甲氧基-1-[1-(甲氧基甲基)丙基]-1H-咪唑并[4,5-c]吡啶;4-(2-氯-5-氟-4-甲基苯基)-2-乙基-1-[1-(甲氧基甲基)丙基]-1H-咪唑并[4,5-c]吡啶;4-(2-氯-5-氟-4-甲基苯基)-2-甲氧基-1-[1-(甲氧基甲基)丙基]-1H-咪唑并[4,5-c]吡啶;2-甲氧基-4-(4-甲氧基-2,5-二甲基苯基)-1-[1-(甲氧基甲基)丙基]-1H-咪唑并[4,5-c]吡啶;2-乙基-4-(4-甲氧基-2,5-二甲基苯基)-1-[1-(甲氧基甲基)丙基]-1H-咪唑并[4,5-c]吡啶;2-乙基-4-(5-氟-4-甲氧基-2-甲基苯基)-1-[1-(甲氧基甲基)丙基]-1H-咪唑并[4,5-c]吡啶;4-(5-氟-4-甲氧基-2-甲基苯基)-2-甲氧基-1-[1-(甲氧基甲基)丙基]-1H-咪唑并[4,5-c]吡啶;2-甲氧基-1-[1-(甲氧基甲基)丙基]-4-(6-甲氧基-2-甲基-3-吡啶基)-1H-咪唑并[4,5-c]吡啶;2-乙基-1-[1-(甲氧基甲基)丙基]-4-(6-甲氧基-2-甲基-3-吡啶基)-1H-咪唑并[4,5-c]吡啶;4-(2,6-二甲氧基-3-吡啶基)-2-乙基-1-[1-(甲氧基甲基)丙基]-1H-咪唑并[4,5-c]吡啶;4-(2,6-二甲氧基-3-吡啶基)-2-甲氧基-1-[1-(甲氧基甲基)丙基]-1H-咪唑并[4,5-c]吡啶;4-(2,6-二甲基-3-吡啶基)-2-乙基-1-[1-(甲氧基甲基)丙基]-1H-咪唑并[4,5-c]吡啶;4-(2,6-二甲基-3-吡啶基)-2-甲氧基-1-[1-(甲氧基甲基)丙基]-1H-咪唑并[4,5-c]吡啶;2-乙基-1-[1-(甲氧基甲基)丙基]-4-(2,5,6-三甲基-3-吡啶基)-1H-咪唑并[4,5-c]吡啶;2-甲氧基-1-[1-(甲氧基甲基)丙基]-4-(2,5,6-三甲基-3-吡啶基)-1H-咪唑并[4,5-c]吡啶;4-[2-氯-4-(甲基磺?;?苯基]-2-乙基-1-[1-(甲氧基甲基)丙基]-1H-咪唑并[4,5-c]吡啶;和4-[2-氯-4-(甲基磺?;?苯基]-2-甲氧基-1-[1-(甲氧基甲基)丙基]-1H-咪唑并[4,5-c]吡啶;或它的藥學(xué)上可接受的鹽形式。[3j]在另一個更優(yōu)選的實施方案中,本發(fā)明提供了新的式Ib化合物,其中R1為C3-8環(huán)烷基;R1由0-1個選自基團(tuán)-CN、-S(O)nR14b、-COR13a、-CO2R13a、-NR15aCOR13a、-N(COR13a)2、-NR15aCONR13aR16a、-NR15aCO2R14b、-CONR13aR16a、1-嗎啉基、1-哌啶基、1-哌嗪基和C4-8環(huán)烷基的取代基取代,其中在C4-8環(huán)烷基中的0-1個碳原子上由選自基團(tuán)-O-、-S(O)n-、-NR13a-、-NCO2R14b-、-NCOR14b-和-NSO2R14b-的基團(tuán)來替代,并且其中在1-哌嗪基中的N4以0-1個選自基團(tuán)R13a、CO2R14b、COR14b和SO2R14b的取代基來取代;和,R1也以0-3個在每一個情況下獨立選自基團(tuán)R1a、R1b、R1c、C1-6烷基、C2-8鏈烯基、C2-8炔基、Br、Cl、F、I、C1-4鹵代烷基、-OR13a、C1-2烷氧基-C1-2烷基和-NR13aR16a的取代基取代。[3k]在另一個甚至更優(yōu)選的實施方案中,本發(fā)明提供了式Ib的新化合物,其中X選自基團(tuán)O、S(O)n和鍵;n為0、1或2;R1選自基團(tuán)環(huán)丙基、環(huán)丁基和環(huán)戊基;R1由0-1個選自基團(tuán)-CN、-S(O)nR14b、-COR13a、-CO2R13a和C4-8環(huán)烷基的取代基取代,其中在C4-8環(huán)烷基中的一個碳原子由選自基團(tuán)-O-、-S(O)n-、-NR13a-、-NCO2R14b-、-NCOR14b-和-NSO2R14b-的基團(tuán)替代;R1也由0-2個在每一個情況下獨立選自基團(tuán)R1a、R1b、C1-6烷基、C2-8鏈烯基、C2-8炔基、Br、Cl、F、CF3、CF2CF3、-OR13a、C1-2烷氧基-C1-2烷基和-NR13aR16a的取代基來取代。R1a為芳基和選自基團(tuán)苯基和2,3-二氫化茚基,每一個R1a以0-1個-OR17和0-5個在每一個情況下獨立選自基團(tuán)C1-4烷基、C3-6環(huán)烷基、Br、Cl、F、C1-4鹵代烷基、-CN、-S(O)nR18、-COR17、-NR17aR19a和-CONR17aR19a的取代基取代;R1b為雜芳基和選自基團(tuán)吡啶基、嘧啶基、呋喃基、噻吩基、咪唑基、噻唑基、吡咯基、噁唑基、異噁唑基、吡唑基、三唑基、四唑基和吲唑基,每一個雜芳基在0-4個碳原子上由在每一個情況下獨立選自基團(tuán)C1-4烷基、C3-6環(huán)烷基、Br、Cl、F、CF3、-CN、-OR17、-S(O)mR18、-COR17、-NR17aR19a和-CONR17aR19a的取代基取代,并且每一個雜芳基在任何氮原子上以0-1個選自基團(tuán)R15a、CO2R14b、COR14b和SO2R14b的取代基取代;R2選自基團(tuán)C1-4烷基、C2-4鏈烯基和C2-4炔基,并且由0-1個選自基團(tuán)-CN、OH、Cl、F和C1-4烷氧基的取代基取代;R9在每一個情況下獨立選自基團(tuán)H、C1-4烷基和C3-8環(huán)烷基;R3和R7在每一個情況下獨立選自基團(tuán)H、Br、Cl、F、-CN、C1-4烷基、C3-6環(huán)烷基、C1-4烷氧基、NH2、C1-4烷基氨基和(C1-4烷基)2-氨基;R13選自基團(tuán)C1-4烷基、C1-2鹵代烷基、C1-2烷氧基-C1-2烷基、C3-6環(huán)烷基-C1-2烷基、芳基(C1-2烷基)-和雜芳基(C1-2烷基)-;R13a和R16a在每一個情況下獨立選自基團(tuán)H、C1-4烷基、C1-4鹵代烷基、C1-4烷氧基-C1-4烷基、C3-6環(huán)烷基和C3-6環(huán)烷基-C1-6烷基;R14選自基團(tuán)C1-4烷基、C1-2鹵代烷基、C1-2烷氧基-C1-2烷基、C3-6環(huán)烷基-C1-2烷基、芳基(C1-2烷基)-和雜芳基(C1-2烷基)-;R14a選自基團(tuán)C1-4烷基、C1-2鹵代烷基、C1-2烷氧基-C1-2烷基和C3-6環(huán)烷基-C1-2烷基;R14b選自基團(tuán)C1-4烷基、C1-2鹵代烷基、C1-2烷氧基-C1-2烷基、C3-6環(huán)烷基和C3-6環(huán)烷基-C1-2烷基;R15在每一個情況下獨立選自基團(tuán)H、C1-4烷基、C3-7環(huán)烷基、C3-6環(huán)烷基-C1-6烷基、苯基和芐基,每一個苯基或芐基在該芳基部分上由0-3個選自C1-4烷基、Br、Cl、F、C1-4鹵代烷基、C1-4烷氧基、C1-4鹵代烷氧基和二甲基氨基的基團(tuán)來取代;R15a在每一個情況下獨立選自基團(tuán)H、C1-4烷基、C3-7環(huán)烷基和C3-6環(huán)烷基-C1-6烷基;R17、R18和R19在每一個情況下獨立選自基團(tuán)H、C1-6烷基、C3-10環(huán)烷基、C3-6環(huán)烷基-C1-6烷基、C1-2烷氧基-C1-2烷基和C1-4鹵代烷基;或者,在NR17R19部分中,R17和R19一起形成1-吡咯烷基、1-嗎啉基、1-哌啶基或1-哌嗪基,其中在1-哌嗪基中的N4由0-1個選自基團(tuán)R13、CO2R14、COR14和SO2R14的取代基取代;R17a和R19a在每一個情況下獨立選自基團(tuán)H、C1-6烷基、C3-10環(huán)烷基、C3-6環(huán)烷基-C1-6烷基和C1-4鹵代烷基;芳基為由1-4個在每一個情況下獨立選自基團(tuán)C1-4烷基、C3-6環(huán)烷基、-OR17、Br、Cl、F、C1-4鹵代烷基、-CN、-S(O)nR18、-COR17、-CO2R17、-NR15COR17、-NR15CO2R18、-NR17R19和-CONR17R19的取代基取代的苯基;和雜芳基在每一個情況下獨立選自基團(tuán)吡啶基、嘧啶基、三嗪基、呋喃基、喹啉基、異喹啉基、噻吩基、噻唑基、吲哚基、吡咯基、噁唑基、苯并呋喃基、苯并噻吩基、苯并噻唑基、苯并噁唑基、異噁唑基、四唑基、吲唑基、2,3-二氫苯并呋喃基、2,3-二氫苯并噻吩基、2,3-二氫苯并噻吩基-S-氧化物、2,3-二氫苯并噻吩基-S-二氧化物、二氫吲哚基、苯并噁唑啉-2-酮基、苯并二氧戊環(huán)基和苯并二噁烷,每一個雜芳基在1-4個碳原子上以在每一個情況下獨立地選自基團(tuán)C1-6烷基、C3-6環(huán)烷基、Br、Cl、F、C1-4鹵代烷基、-CN、-OR17、-S(O)mR18、-COR17、-CO2R17、-OC(O)R18、-NR15COR17、-N(COR17)2、-NR15CO2R18、-NR17R19和-CONR17R19的取代基取代,并且每一個雜芳基在任何氮原子上由0-1個選自基團(tuán)R15、CO2R14a、COR14a和SO2R14a的取代基取代。[31]在另一個仍然更優(yōu)選的實施方案中,本發(fā)明提供了新的式Ib化合物,其中X選自基團(tuán)O、S和鍵;R1由0-1個選自基團(tuán)-CN、-CO2R13a和C4-8環(huán)烷基的取代基取代,其中在C4-8環(huán)烷基中的0-1個碳原子以選自基團(tuán)-O-、-S(O)n-和-NR13a-的基團(tuán)替代;R1也以0-2個在每一個情況下獨立選自基團(tuán)R1a、R1b、C1-6烷基、C2-8鏈烯基、C2-8炔基、Br、Cl、F、CF3、CF3、-OR13a、-OH、-OCH3、-OCH2CH3、-CH2OCH3、-CH2CH2OCH3和-NR13aR16a的取代基取代;R1a為芳基和由0-1個選自O(shè)CH3、OCH2CH3、OCH(CH3)2、OCH2CH2CH3和OCF3的取代基和以0-3個在每一個情況下獨立選自基團(tuán)CH3、CH2CH3、CH(CH3)2、CH2CH2CH3、環(huán)丙基、Br、Cl、F、CF3、-CN、SCH3、-NH2、-NHCH3、-N(CH3)2、-C(O)NH2、-C(O)NHCH3和-C(O)N(CH3)2的取代基取代的苯基;R1b為雜芳基和選自基團(tuán)呋喃基、噻吩基、咪唑基、噻唑基、噁唑基、異噁唑基、吡唑基、三唑基、四唑基和吲唑基,每一個雜芳基在0-3個碳原子上由在每一個情況下獨立選自基團(tuán)CH3、CH2CH3、CH(CH3)2、CH2CH2CH3、環(huán)丙基、OCH3、OCH2CH3、OCH(CH3)2、OCH2CH2CH3、OCF3、Br、Cl、F、CF3、-CN、SCH3、-NH2、-NHCH3、-N(CH3)2、-C(O)NH2、-C(O)NHCH3和-C(O)N(CH3)2的取代基取代,并且每一個雜芳基在任何氮原子上由0-1個選自基團(tuán)CH3、CO2CH3、COCH3和SO2CH3的取代基取代;R2選自基團(tuán)CH3、CH2CH3、CH(CH3)2和CH2CH2CH3;R3和R7在每一個情況下獨立選自基團(tuán)H、CH3、CH2CH3、CH(CH3)2和CH2CH2CH3;芳基為由2-4個在每一個情況下獨立選自基團(tuán)CH3、CH2CH3、CH(CH3)2、CH2CH2CH3、環(huán)丙基、OCH3、OCH2CH3、OCH(CH3)2、OCH2CH2CH3、OCF3、Br、Cl、F、CF3、-CN、SCH3、SO2CH3、-NH2、-NHCH3、-N(CH3)2、-C(O)NH2、-C(O)NHCH3和-C(O)N(CH3)2的取代基取代的苯基;和,雜芳基在每一個情況下獨立選自基團(tuán)吡啶基、吲哚基、苯并噻吩基、2,3-二氫苯并呋喃基、2,3-二氫苯并噻吩基、2,3-二氫苯并噻吩基-S-氧化物、2,3-二氫苯并噻吩基-S-二氧化物、二氫吲哚基和苯并噁唑啉-2-酮基,每一個雜芳基在2-4個碳原子上由在每一個情況下獨立地選自基團(tuán)CH3、CH2CH3、CH(CH3)2、CH2CH2CH3、環(huán)丙基、OCH3、OCH2CH3、OCH(CH3)2、OCH2CH2CH3、OCF3、Br、Cl、F、CF3、-CN、SCH3、SO2CH3、-NH2、-NHCH3、-N(CH3)2、-C(O)NH2、-C(O)NHCH3和-C(O)N(CH3)2的取代基取代,并且每一個雜芳基在任何氮原子上由0-1個選自基團(tuán)CH3、CO2CH3、COCH3和SO2CH3的取代基取代。[3m]在另一個更優(yōu)選的實施方案中,本發(fā)明提供了新的式Ib化合物,其中R1由0-2個在每一個情況下獨立選自基團(tuán)R1a、R1b、CH3、CH2CH3、CH(CH3)2、CH2CH2CH3、-(CH2)3CH3、-CH=CH2、-CH=CH(CH3)、-CH≡CH、-CH≡C(CH3)、-CH2OCH3、-CH2CH2OCH3、F和CF3的取代基取代;R1a為由0-1個選自O(shè)CH3、OCH2CH3、OCH(CH3)2、OCH2CH2CH3和OCF3的取代基和由0-2個在每一個情況下獨立選自基團(tuán)CH3、CH2CH3、CH(CH3)2、CH2CH2CH3、Br、Cl、F、CF3、-CN和SCH3的取代基取代的苯基;R1b為雜芳基和選自基團(tuán)呋喃基、噻吩基、咪唑基、噻唑基、噁唑基、異噁唑基、吡唑基、三唑基和四唑基,每一個雜芳基在0-3個碳原子上由在每一個情況下獨立選自基團(tuán)CH3、CH2CH3、CH(CH3)2、CH2CH2CH3、OCH3、OCH2CH3、OCF3、Br、Cl、F、CF3、-CN和SCH3的取代基取代,并且每一個雜芳基在任何氮原子上由0-1個選自基團(tuán)CH3、CO2CH3、COCH3和SO2CH3的取代基取代;R2選自基團(tuán)CH3、CH2CH3和CH(CH3)2;R3和R7在每一個情況下獨立選自基團(tuán)H和CH3;芳基為由2-4個在每一個情況下獨立選自基團(tuán)CH3、CH2CH3、CH(CH3)2、CH2CH2CH3、環(huán)丙基、OCH3、OCH2CH3、OCH(CH3)2、OCH2CH2CH3、OCF3、Br、Cl、F、CF3、-CN、SCH3、SO2CH3、-NH2、-NHCH3、-N(CH3)2、-C(O)NH2、-C(O)NHCH3和-C(O)N(CH3)2的取代基取代的苯基;和,雜芳基為在2-4個碳原子上由在每一個情況下獨立地選自基團(tuán)CH3、CH2CH3、CH(CH3)2、CH2CH2CH3、環(huán)丙基、OCH3、OCH2CH3、OCH(CH3)2、OCH2CH2CH3、OCF3、Br、Cl、F、CF3、-CN、SCH3、SO2CH3、-NH2、-NHCH3、-N(CH3)2、-C(O)NH2、-C(O)NHCH3和-C(O)N(CH3)2的取代基取代的吡啶基。[3n]在另一個甚至更優(yōu)選的實施方案中,本發(fā)明提供了新的式Ib化合物,其中R1由0-2個在每一個情況下獨立選自基團(tuán)R1a、CH3、CH2CH3、CH(CH3)2、CH2CH2CH3、-(CH2)3CH3、-CH2OCH3、-CH2CH2OCH3、F和CF3的取代基取代;和,R1a為由0-2個在每一個情況下獨立選自基團(tuán)CH3、CH2CH3、CH(CH3)2、CH2CH2CH3、Br、Cl、F、CF3、-CN和SCH3的取代基取代的苯基。[3o]在另一個仍然更優(yōu)選的實施方案中,本發(fā)明提供了新的式Ib化合物,其中D為以2-4個在每一個情況下獨立選自基團(tuán)CH3、CH2CH3、CH(CH3)2、CH2CH2CH3、環(huán)丙基、OCH3、OCH2CH3、-OCH(CH3)2、OCH2CH2CH3、OCF3、Br、Cl、F和CF3的取代基取代的苯基;[3p]在另一個仍然更優(yōu)選的實施方案中,本發(fā)明提供了新的式Ib化合物,其中D為在2-4個碳原子上由每一個情況下獨立選自基團(tuán)CH3、CH2CH3、CH(CH3)2、CH2CH2CH3、環(huán)丙基、OCH3、OCH2CH3、OCH(CH3)2、OCH2CH2CH3、OCF3、Br、Cl、F和CF3的取代基來取代的吡啶基。[3q]在另一個更優(yōu)選的實施方案中,本發(fā)明提供了新的式Ib化合物,其中R1選自基團(tuán)C1-10烷基、C2-10鏈烯基、C2-10炔基、C3-8環(huán)烷基、C3-6環(huán)烷基-C1-6烷基和C1-4烷氧基-C1-4烷基;R1由C3-8環(huán)烷基基團(tuán)取代,其中在該C4-8環(huán)烷基基團(tuán)的0-1個碳原子上由選自基團(tuán)-O-、-S(O)n-、-NR13a-、-NCO2R14b-、-NCOR14b-和-NSO2R14b-的基團(tuán)替代;R1也由0-3個在每一個情況下獨立選自基團(tuán)R1a、R1b、R1c、C1-6烷基、C2-8鏈烯基、C2-8炔基、Br、Cl、F、I、C1-4鹵代烷基、-OR13a、-NR13aR16a、C1-2烷氧基-C1-2烷基和由0-1個R9取代的C3-8環(huán)烷基的取代基來取代并且其中C4-8環(huán)烷基的0-1個碳由-O-替代;前提是R1不是環(huán)己基-(CH2)2-基團(tuán);R1a為芳基和選自基團(tuán)苯基、萘基、2,3-二氫化茚基和茚基,每一個R1a由0-1個-OR17和0-5個在每一個情況下獨立選自基團(tuán)C1-6烷基、C3-6環(huán)烷基、Br、Cl、F、I、C1-4鹵代烷基、-CN、硝基、SH、-S(O)nR18、-COR17、-OC(O)R18、-NR15aCOR17、-N(COR17)2、-NR15aCONR17aR19a、-NR15aCO2R18、-NR17aR19a和-CONR17aR19a的取代基取代;R1b為雜芳基并且選自基團(tuán)吡啶基、嘧啶基、三嗪基、呋喃基、喹啉基、異喹啉基、噻吩基、咪唑基、噻唑基、吲哚基、吡咯基、噁唑基、苯并呋喃基、苯并噻吩基、苯并噻唑基、苯并噁唑基、異噁唑基、吡唑基、三唑基、四唑基、吲唑基、2,3-二氫苯并呋喃基、2,3-二氫苯并噻吩基、2,3-二氫苯并噻吩基-S-氧化物、2,3-二氫苯并噻吩基-S-二氧化物、二氫吲哚基、苯并噁唑啉-2-酮基、苯并二氧戊環(huán)基和苯并二噁烷,每一個雜芳基在0-4個碳原子上由在每一個情況下獨立選自基團(tuán)C1-6烷基、C3-6環(huán)烷基、Br、Cl、F、I、C1-4鹵代烷基、-CN、硝基、-OR17、SH、-S(O)mR18、-COR17、-OC(O)R18、-NR15aCOR17、-N(COR17)2、-NR15aCONR17aR19a、-NR15aCO2R18、-NR17aR19a和-CONR17aR19a的取代基取代,并且每一個雜芳基在任何氮原子上以0-1個選自基團(tuán)R15a、CO2R14b、COR14b和SO2R14b的取代基取代;和,R1c為雜芳基并且為飽和的或部分飽和的雜芳基,每個雜芳基在0-4個碳原子上由在每一個情況下獨立選自基團(tuán)C1-6烷基、C3-6環(huán)烷基、Br、Cl、F、I、C1-4鹵代烷基、-CN、硝基、-OR13a、SH、-S(O)nR14b、-COR13a、-OC(O)R14b、-NR15aCOR13a、-N(COR13a)2、-NR15aCONR13aR16a、-NR15aCO2R14b、-NR13aR16a和-CONR13aR16a的取代基取代,并且每一個雜芳基在任何氮原子上由0-1個選自基團(tuán)R13a、CO2R14b、COR14b和SO2R14b的取代基取代并且其中任何硫原子任選地單氧化或雙氧化;[3r]在另一個甚至更優(yōu)選的實施方案中,本發(fā)明提供了新的式Ib化合物,其中X選自基團(tuán)O、S(O)n和鍵;n為0、1或2;R1選自基團(tuán)C1-6烷基、C2-6鏈烯基、C2-6炔基、C3-8環(huán)烷基;R1由C3-6環(huán)烷基基團(tuán)取代,其中在該C4-6環(huán)烷基基團(tuán)的0-1個碳原子上由選自基團(tuán)-O-、-S(O)n-和-NR13a-的基團(tuán)來替代;R1也由0-2個在每一個情況下獨立選自基團(tuán)R1a、R1b、C1-6烷基、C2-8鏈烯基、C2-8炔基、Br、Cl、F、CF3、CF2CF3、-OR13a、-NR13aR16a、C1-2烷氧基-C1-2烷基和由0-1個R9取代的C3-6環(huán)烷基的取代基取代并且其中C4-8環(huán)烷基的0-1個碳由-O-替代;R1a為芳基和選自基團(tuán)苯基和2,3-二氫化茚基,每一個R1a以0-1個-OR17和0-5個在每一個情況下獨立選自基團(tuán)C1-4烷基、C3-6環(huán)烷基、Br、Cl、F、C1-4鹵代烷基、-CN、-S(O)nR18、-COR17、-NR17aR19a和-CONR17aR19a的取代基來取代;R1b為雜芳基和選自基團(tuán)吡啶基、嘧啶基、呋喃基、噻吩基、咪唑基、噻唑基、吡咯基、噁唑基、異噁唑基、吡唑基、三唑基、四唑基和吲唑基,每一個雜芳基在0-4個碳原子上由在每一個情況下獨立選自基團(tuán)C1-4烷基、C3-6環(huán)烷基、Br、Cl、F、CF3、-CN、-OR17、-S(O)mR18、-COR17、-NR17aR19a和-CONR17aR19a的取代基取代,并且每一個雜芳基在任何氮原子上以0-1個選自基團(tuán)R15a、CO2R14b、COR14b和SO2R14b的取代基取代;R2選自基團(tuán)C1-4烷基、C2-4鏈烯基和C2-4炔基并且由0-1個選自基團(tuán)-CN、OH、Cl、F和C1-4烷氧基的取代基取代;R9在每一個情況下獨立選自基團(tuán)H、C1-4烷基和C3-8環(huán)烷基;R3和R7在每一個情況下獨立選自基團(tuán)H、Br、Cl、F、-CN、C1-4烷基、C3-6環(huán)烷基、C1-4烷氧基、NH2、C1-4烷基氨基和(C1-4烷基)2-氨基;R13選自基團(tuán)C1-4烷基、C1-2鹵代烷基、C1-2烷氧基-C1-2烷基、C3-6環(huán)烷基-C1-2烷基、芳基(C1-2烷基)-和雜芳基(C1-2烷基)-;R13a和R16a在每一個情況下獨立選自基團(tuán)H、C1-4烷基、C1-4鹵代烷基、C1-4烷氧基-C1-4烷基、C3-6環(huán)烷基和C3-6環(huán)烷基-C1-6烷基;R14選自基團(tuán)C1-4烷基、C1-2鹵代烷基、C1-2烷氧基-C1-2烷基、C3-6環(huán)烷基-C1-2烷基、芳基(C1-2烷基)-和雜芳基(C1-2烷基)-;R14a選自基團(tuán)C1-4烷基、C1-2鹵代烷基、C1-2烷氧基-C1-2烷基和C3-6環(huán)烷基-C1-2烷基;R14b選自基團(tuán)C1-4烷基、C1-2鹵代烷基、C1-2烷氧基-C1-2烷基、C3-6環(huán)烷基和C3-6環(huán)烷基-C1-2烷基;R15在每一個情況下獨立選自基團(tuán)H、C1-4烷基、C3-7環(huán)烷基、C3-6環(huán)烷基-C1-6烷基、苯基和芐基,每一個苯基或芐基在該芳基部分上由0-3個選自基團(tuán)C1-4烷基、Br、Cl、F、C1-4鹵代烷基、C1-4烷氧基、C1-4鹵代烷氧基和二甲基氨基的基團(tuán)取代;R15a在每一個情況下獨立選自基團(tuán)H、C1-4烷基、C3-7環(huán)烷基和C3-6環(huán)烷基-C1-6烷基;R17、R18和R19在每一個情況下獨立選自基團(tuán)H、C1-6烷基、C3-10環(huán)烷基、C3-6環(huán)烷基-C1-6烷基、C1-2烷氧基-C1-2烷基和C1-4鹵代烷基;或者,在NR17R19部分中,R17和R19一起形成1-吡咯烷基、1-嗎啉基、1-哌啶基或1-哌嗪基,其中在1-哌嗪基中的N4由0-1個選自基團(tuán)R13、CO2R14、COR14和SO2R14的取代基取代;R17a和R19a在每一個情況下獨立選自基團(tuán)H、C1-6烷基、C3-10環(huán)烷基、C3-6環(huán)烷基-C1-6烷基和C1-4鹵代烷基;芳基為由1-4個在每一個情況下獨立選自基團(tuán)C1-4烷基、C3-6環(huán)烷基、-OR17、Br、Cl、F、C1-4鹵代烷基、-CN、-S(O)nR18、-COR17、-CO2R17、-NR15COR17、-NR15CO2R18、-NR17R19和-CONR17R19的取代基取代的苯基;和雜芳基在每一個情況下獨立選自基團(tuán)吡啶基、嘧啶基、三嗪基、呋喃基、喹啉基、異喹啉基、噻吩基、噻唑基、吲哚基、吡咯基、噁唑基、苯并呋喃基、苯并噻吩基、苯并噻唑基、苯并噁唑基、異噁唑基、四唑基、吲唑基、2,3-二氫苯并呋喃基、2,3-二氫苯并噻吩基、2,3-二氫苯并噻吩基-S-氧化物、2,3-二氫苯并噻吩基-S-二氧化物、二氫吲哚基、苯并噁唑啉-2-酮基、苯并二氧戊環(huán)基和苯并二噁烷,每一個雜芳基在1-4個碳原子上由在每一個情況下獨立地選自基團(tuán)C1-6烷基、C3-6環(huán)烷基、Br、Cl、F、C1-4鹵代烷基、-CN、-OR17、-S(O)mR18、-COR17、-CO2R17、-OC(O)R18、-NR15COR17、-N(COR17)2、-NR15CO2R18、-NR17R19和-CONR17R19的取代基取代,并且每一個雜芳基在任何氮原子上以0-1個選自基團(tuán)R15、CO2R14a、COR14a和SO2R14a的取代基來取代。[3s]在另一個仍然更優(yōu)選的實施方案中,本發(fā)明提供了新的式Ib化合物,其中X選自基團(tuán)O、S和鍵;R1為C1-6烷基;R1由C3-6環(huán)烷基取代,其中在該C4-4環(huán)烷基的0-1個碳原子上由選自基團(tuán)-O-、-S(O)n-和-NR13a-的基團(tuán)來替代;R1也由0-2個在每一個情況下獨立選自基團(tuán)R1a、R1b、C1-6烷基、C2-8鏈烯基、C2-8炔基、F、CF3、-OR13a、-NR13aR16a、-CH2OCH3、-CH2CH2OCH3、和由0-1個CH3取代的C3-6環(huán)烷基的取代基取代并且其中C4-8環(huán)烷基的0-1個碳由-O-替代;前提是R1不是環(huán)己基-(CH2)2-基團(tuán);R1a為芳基和由0-1個選自O(shè)CH3、OCH2CH3、OCH(CH3)2、OCH2CH2CH3和OCF3的取代基和由0-3個在每一個情況下獨立選自基團(tuán)CH3、CH2CH3、CH(CH3)2、CH2CH2CH3、環(huán)丙基、Br、Cl、F、CF3、-CN、SCH3、-NH2、-NHCH3、-N(CH3)2、-C(O)NH2、-C(O)NHCH3和-C(O)N(CH3)2的取代基取代的苯基;R1b為雜芳基和選自基團(tuán)呋喃基、噻吩基、咪唑基、噻唑基、噁唑基、異噁唑基、吡唑基、三唑基、四唑基和吲唑基,每一個雜芳基在0-3個碳原子上由在每一個情況下獨立選自基團(tuán)CH3、CH2CH3、CH(CH3)2、CH2CH2CH3、環(huán)丙基、OCH3、OCH2CH3、OCH(CH3)2、OCH2CH2CH3、OCF3、Br、Cl、F、CF3、-CN、SCH3、-NH2、-NHCH3、-N(CH3)2、-C(O)NH2、-C(O)NHCH3和-C(O)N(CH3)2的取代基取代,并且每一個雜芳基在任何氮原子上由0-1個選自基團(tuán)CH3、CO2CH3、COCH3和SO2CH3的取代基取代;R2選自基團(tuán)CH3、CH2CH3、CH(CH3)2和CH2CH2CH3;R3和R7在每一個情況下獨立選自基團(tuán)H、CH3、CH2CH3、CH(CH3)2和CH2CH2CH3;芳基為由2-4個在每一個情況下獨立選自基團(tuán)CH3、CH2CH3、CH(CH3)2、CH2CH2CH3、環(huán)丙基、OCH3、OCH2CH3、OCH(CH3)2、OCH2CH2CH3、OCF3、Br、Cl、F、CF3、-CN、SCH3、SO2CH3、-NH2、-NHCH3、-N(CH3)2、-C(O)NH2、-C(O)NHCH3和-C(O)N(CH3)2的取代基取代的苯基;和,雜芳基在每一個情況下獨立選自基團(tuán)吡啶基、吲哚基、苯并噻吩基、2,3-二氫苯并呋喃基、2,3-二氫苯并噻吩基、2,3-二氫苯并噻吩基-S-氧化物、2,3-二氫苯并噻吩基-S-二氧化物、二氫吲哚基和苯并噁唑啉-2-酮基,每-個雜芳基在2-4個碳原子上由在每一個情況下獨立地選自基團(tuán)CH3、CH2CH3、CH(CH3)2、CH2CH2CH3、環(huán)丙基、OCH3、OCH2CH3、OCH(CH3)2、OCH2CH2CH3、OCF3、Br、Cl、F、CF3、-CN、SCH3、SO2CH3、-NH2、-NHCH3、-N(CH3)2、-C(O)NH2、-C(O)NHCH3和-C(O)N(CH3)2的取代基取代,并且每一個雜芳基在任何氮原子上由0-1個選自基團(tuán)CH3、CO2CH3、COCH3和SO2CH3的取代基取代。[3t]在另一個更優(yōu)選的實施方案中,本發(fā)明提供了新的式Ib化合物,其中R1為(環(huán)丙基)C1烷基或(環(huán)丁基)C1烷基;R1以1-2個在每一個情況下獨立選自基團(tuán)R1a、R1b、CH3、CH2CH3、CH(CH3)2、CH2CH2CH3、-(CH2)3CH3、-CH=CH2、-CH=CH(CH3)、-CH≡CH、-CH≡C(CH3)、-CH2OCH3、-CH2CH2OCH3、F、CF3、環(huán)丙基、CH3-環(huán)丙基、環(huán)丁基、CH3-環(huán)丁基、環(huán)戊基、CH3-環(huán)戊基的取代基取代;R1a為由0-1個選自O(shè)CH3、OCH2CH3和OCF3的取代基和由0-2個在每一個情況下獨立選自基團(tuán)CH3、CH2CH3、CH(CH3)2、CH2CH2CH3、Br、Cl、F、CF3、-CN和SCH3的取代基取代的苯基;R1b為雜芳基并且選自基團(tuán)呋喃基、噻吩基、咪唑基、噻唑基、噁唑基、異噁唑基、吡唑基、三唑基和四唑基,每一個雜芳基在0-3個碳原子上以在每一個情況下獨立選自基團(tuán)CH3、CH2CH3、CH(CH3)2、CH2CH2CH3、OCH3、OCH2CH3、OCF3、Br、Cl、F、CF3、-CN和SCH3的取代基取代,并且每一個雜芳基在任何氮原子上以0-1個選自基團(tuán)CH3、CO2CH3、COCH3和SO2CH3的取代基取代;R2選自基團(tuán)CH3、CH2CH3和CH(CH3)2;R3和R7在每一個情況下獨立選自基團(tuán)H和CH3;芳基為以2-4個在每一個情況下獨立選自基團(tuán)CH3、CH2CH3、CH(CH3)2、CH2CH2CH3、環(huán)丙基、OCH3、OCH2CH3、OCH(CH3)2、OCH2CH2CH3、OCF3、Br、Cl、F、CF3、-CN、SCH3、SO2CH3、-NH2、-NHCH3、-N(CH3)2、-C(O)NH2、-C(O)NHCH3和-C(O)N(CH3)2的取代基取代的苯基;和,雜芳基為在2-4個碳原子上由在每一個情況下獨立選自基團(tuán)CH3、CH2CH3、CH(CH3)2、CH2CH2CH3、環(huán)丙基、OCH3、OCH2CH3、OCH(CH3)2、OCH2CH2CH3、OCF3、Br、Cl、F、CF3、-CN、SCH3、SO2CH3、-NH2、-NHCH3、-N(CH3)2、-C(O)NH2、-C(O)NHCH3和-C(O)N(CH3)2的取代基取代的吡啶基。[3u]在另一個甚至更優(yōu)選的實施方案中,本發(fā)明提供了新的式Ib化合物,其中R1為(環(huán)丙基)C1烷基或(環(huán)丁基)C1烷基;R1由1-2個在每一個情況下獨立選自基團(tuán)R1a、R1b、CH3、CH2CH3、CH(CH3)2、CH2CH2CH3、-(CH2)3CH3、-CH=CH2、-CH=CH(CH3)、-CH≡CH、-CH≡C(CH3)、-CH2OCH3、-CH2CH2OCH3、F、CF3、環(huán)丙基和CH3-環(huán)丙基的取代基來取代;R1a為由0-2個在每一個情況下獨立選自基團(tuán)CH3、CH2CH3、CH(CH3)2、CH2CH2CH3、Br、Cl、F、CF3、-CN和SCH3的取代基取代的苯基;R1b為雜芳基和選自基團(tuán)呋喃基、噻吩基、咪唑基、噻唑基、噁唑基、異噁唑基和吡唑基,每一個雜芳基在0-3個碳原子上由在每一個情況下獨立選自基團(tuán)CH3、CH2CH3、CH(CH3)2、CH2CH2CH3、OCH3、OCH2CH3、OCF3、Br、Cl、F、CF3、-CN和SCH3的取代基取代。[3v]在另一個更優(yōu)選的實施方案中,本發(fā)明提供了新的式Ib化合物,其中D為由2-4個在每一個情況下獨立選自基團(tuán)CH3、CH2CH3、CH(CH3)2、CH2CH2CH3、環(huán)丙基、OCH3、OCH2CH3、OCH(CH3)2、OCH2CH2CH3、OCF3、Br、Cl、F和CF3的取代基取代的苯基。[3w]在另一個更優(yōu)選的實施方案中,本發(fā)明提供了新的式Ib化合物,其中D為在2-4個碳原子上由在每一個情況下獨立選自基團(tuán)CH3、CH2CH3、CH(CH3)2、CH2CH2CH3、環(huán)丙基、OCH3、OCH2CH3、OCH(CH3)2、OCH2CH2CH3、OCF3、Br、Cl、F和CF3的取代基取代的吡啶基。[4]在另一個優(yōu)選的實施方案中,本發(fā)明提供了新的式Ic化合物, 在另一個更優(yōu)選的實施方案中,本發(fā)明提供了新的式Ic化合物,其中X選自基團(tuán)O、S(O)n和鍵;n為0、1或2;R1選自基團(tuán)C1-6烷基、C2-6鏈烯基、C2-6炔基和C3-8環(huán)烷基;R1由0-1個選自基團(tuán)-CN、-S(O)nR14b、-COR13a、-CO2R13a和C3-8環(huán)烷基的取代基來取代,其中在C4-8環(huán)烷基中的0-1個碳原子上以選自基團(tuán)-O-、-S(O)n-、-NR13a-、-NCO2R14b-、-NCOR14b-和-NSO2R14b-的基團(tuán)來替代;R1也以0-2個在每一個情況下獨立選自基團(tuán)R1a、R1b、C1-6烷基、C2-8鏈烯基、C2-8炔基、Br、Cl、F、CF3、CF2CF3、-OR13a、-NR13aR16a、C1-2烷氧基-C1-2烷基和由0-1個R9取代的C3-8環(huán)烷基的取代基取代并且C4-8環(huán)烷基的0-1個碳由-O-替代;前提是R1不是環(huán)己基-(CH2)2-基團(tuán);R1a為芳基并且選自基團(tuán)苯基和2,3-二氫化茚基,每一個R1a由0-1個-OR17和0-5個在每一個情況下獨立選自基團(tuán)C1-4烷基、C3-6環(huán)烷基、Br、Cl、F、C1-4鹵代烷基、-CN、-S(O)nR18、-COR17、-NR17aR19a和-CONR17aR19a的取代基取代;R1b為雜芳基和選自基團(tuán)吡啶基、嘧啶基、呋喃基、噻吩基、咪唑基、噻唑基、吡咯基、噁唑基、異噁唑基、吡唑基、三唑基、四唑基和吲唑基,每一個雜芳基在0-4個碳原子上由在每一個情況下獨立選自基團(tuán)C1-4烷基、C3-6環(huán)烷基、Br、C1、F、CF3、-CN、-OR17、-S(O)mR18、-COR17、-NR17aR19a和-CONR17aR19a的取代基來取代,并且每一個雜芳基在任何氮原子上以0-1個選自基團(tuán)R15a、CO2R14b、COR14b和SO2R14b的取代基來取代;前提是R1不是-(CH2)1-4-芳基或-(CH2)1-4-雜芳基,其中該芳基或雜芳基基團(tuán)是取代的或未取代的;R2選自基團(tuán)C1-4烷基、C2-4鏈烯基和C2-4炔基并且以0-1個選自基團(tuán)-CN、OH、Cl、F和C1-4烷氧基的取代基取代;R3選自基團(tuán)H、Br、Cl、F、-CN、C1-4烷基、C3-6環(huán)烷基、C1-4烷氧基、NH2、C1-4烷基氨基和(C1-4烷基)2-氨基;R9在每一個情況下獨立選自基團(tuán)H、C1-4烷基和C3-8環(huán)烷基;R13選自基團(tuán)C1-4烷基、C1-2鹵代烷基、C1-2烷氧基-C1-2烷基、C3-6環(huán)烷基-C1-2烷基、芳基(C1-2烷基)-和雜芳基(C1-2烷基)-;R13a和R16a在每一個情況下獨立選自基團(tuán)H、C1-4烷基、C1-4鹵代烷基、C1-4烷氧基-C1-4烷基、C3-6環(huán)烷基和C3-6環(huán)烷基-C1-6烷基;R14選自基團(tuán)C1-4烷基、C1-2鹵代烷基、C1-2烷氧基-C1-2烷基、C3-6環(huán)烷基-C1-2烷基、芳基(C1-2烷基)-和雜芳基(C1-2烷基)-;R14a選自基團(tuán)C1-4烷基、C1-2鹵代烷基、C1-2烷氧基-C1-2烷基和C3-6環(huán)烷基-C1-2烷基;R14b選自基團(tuán)C1-4烷基、C1-2鹵代烷基、C1-2烷氧基-C1-2烷基、C3-6環(huán)烷基和C3-6環(huán)烷基-C1-2烷基;R15在每一個情況下獨立選自基團(tuán)H、C1-4烷基、C3-7環(huán)烷基、C3-6環(huán)烷基-C1-6烷基、苯基和芐基,每一個苯基或芐基在該芳基部分上由0-3個選自基團(tuán)C1-4烷基、Br、Cl、F、C1-4鹵代烷基、C1-4烷氧基、C1-4鹵代烷氧基和二甲基氨基的基團(tuán)取代;R15a在每一個情況下獨立選自基團(tuán)H、C1-4烷基、C3-7環(huán)烷基和C3-6環(huán)烷基-C1-6烷基;R17、R18和R19在每一個情況下獨立選自基團(tuán)H、C1-6烷基、C3-10環(huán)烷基、C3-6環(huán)烷基-C1-6烷基、C1-2烷氧基-C1-2烷基和C1-4鹵代烷基;或者,在NR17R19部分中,R17和R19一起形成1-吡咯烷基、1-嗎啉基、1-哌啶基或1-哌嗪基,其中在1-哌嗪基中的N4由0-1個選自基團(tuán)R13、CO2R14、COR14和SO2R14的取代基取代;R17a和R19a在每一個情況下獨立選自基團(tuán)H、C1-6烷基、C3-10環(huán)烷基、C3-6環(huán)烷基-C1-6烷基和C1-4鹵代烷基;芳基為由1-4個在每一個情況下獨立選自基團(tuán)C1-4烷基、C3-6環(huán)烷基、-OR17、Br、Cl、F、C1-4鹵代烷基、-CN、-S(O)nR18、-COR17、-CO2R17、-NR15COR17、-NR15CO2R18、-NR17R19和-CONR17R19的取代基取代的苯基;和雜芳基在每一個情況下獨立選自基團(tuán)吡啶基、嘧啶基、三嗪基、呋喃基、喹啉基、異喹啉基、噻吩基、噻唑基、吲哚基、吡咯基、噁唑基、苯并呋喃基、苯并噻吩基、苯并噻唑基、苯并噁唑基、異噁唑基、四唑基、吲唑基、2,3-二氫苯并呋喃基、2,3-二氫苯并噻吩基、2,3-二氫苯并噻吩基-S-氧化物、2,3-二氫苯并噻吩基-S-二氧化物、二氫吲哚基、苯并噁唑啉-2-酮基、苯并二氧戊環(huán)基和苯并二噁烷,每一個雜芳基在1-4個碳原子上以在每一個情況下獨立地選自基團(tuán)C1-6烷基、C3-6環(huán)烷基、Br、Cl、F、C1-4鹵代烷基、-CN、-OR17、-S(O)mR18、-COR17、-CO2R17、-OC(O)R18、-NR15COR17、-N(COR17)2、-NR15CO2R18、-NR17R19和-CONR17R19的取代基取代,并且每一個雜芳基在任何氮原子上由0-1個選自基團(tuán)R15、CO2R14a、COR14a和SO2R14a的取代基取代。[4b]在另一個甚至更優(yōu)選的實施方案中,本發(fā)明提供了新的式Ic化合物,其中X選自基團(tuán)O、S和鍵;R1為取代的C1-6烷基;R1由0-1個選自基團(tuán)-CN、-CO2R13a和C3-8環(huán)烷基的取代基取代,其中在C4-8環(huán)烷基中的0-1個碳原子由選自基團(tuán)-O-、-S(O)n-和-NR13a-的基團(tuán)替代;R1也由0-2個在每一個情況下獨立選自基團(tuán)R1a、R1b、C1-6烷基、C2-8鏈烯基、C2-8炔基、Br、Cl、F、CF3、-OR13a、-NR13aR16a、C1-2烷氧基-C1-2烷基和由0-1個CH3取代的C3-6環(huán)烷基的取代基取代并且其中C4-8環(huán)烷基的0-1個碳由-O-替代;前提是R1不是環(huán)己基-(CH2)2-基團(tuán);R1a為芳基和由0-1個選自O(shè)CH3、OCH2CH3、OCH(CH3)2、OCH2CH2CH3和OCF3的取代基和0-3個在每一個情況下獨立選自基團(tuán)CH3、CH2CH3、CH(CH3)2、CH2CH2CH3、環(huán)丙基、Br、Cl、F、CF3、-CN、SCH3、-NH2、-NHCH3、-N(CH3)2、-C(O)NH2、-C(O)NHCH3和-C(O)N(CH3)2的取代基取代的苯基;R1b為雜芳基并且選自基團(tuán)呋喃基、噻吩基、咪唑基、噻唑基、噁唑基、異噁唑基、吡唑基、三唑基、四唑基和吲唑基,每一個雜芳基在0-3個碳原子上由在每一個情況下獨立選自基團(tuán)CH3、CH2CH3、CH(CH3)2、CH2CH2CH3、環(huán)丙基、OCH3、OCH2CH3、OCH(CH3)2、OCH2CH2CH3、OCF3、Br、Cl、F、CF3、-CN、SCH3、-NH2、-NHCH3、-N(CH3)2、-C(O)NH2、-C(O)NHCH3和-C(O)N(CH3)2的取代基取代,并且每一個雜芳基在任何氮原子上以0-1個選自基團(tuán)CH3、CO2CH3、COCH3和SO2CH3的取代基取代;前提是R1不是-(CH2)1-4-芳基或-(CH2)1-4-雜芳基,其中該芳基或雜芳基基團(tuán)是取代的或未取代的;R2選自基團(tuán)CH3、CH2CH3、CH(CH3)2和CH2CH2CH3;R3選自基團(tuán)H、CH3、CH2CH3、CH(CH3)2和CH2CH2CH3;芳基為由2-4個在每一個情況下獨立選自基團(tuán)CH3、CH2CH3、CH(CH3)2、CH2CH2CH3、環(huán)丙基、OCH3、OCH2CH3、OCH(CH3)2、OCH2CH2CH3、OCF3、Br、Cl、F、CF3、-CN、SCH3、SO2CH3、-NH2、-NHCH3、-N(CH3)2、-C(O)NH2、-C(O)NHCH3和-C(O)N(CH3)2的取代基取代的苯基;和,雜芳基在每一個情況下獨立選自基團(tuán)吡啶基、吲哚基、苯并噻吩基、2,3-二氫苯并呋喃基、2,3-二氫苯并噻吩基、2,3-二氫苯并噻吩基-S-氧化物、2,3-二氫苯并噻吩基-S-二氧化物、二氫吲哚基和苯并噁唑啉-2-酮-基,每一個雜芳基在2-4個碳原子上由在每一個情況下獨立地選自基團(tuán)CH3、CH2CH3、CH(CH3)2、CH2CH2CH3、環(huán)丙基、OCH3、OCH2CH3、OCH(CH3)2、OCH2CH2CH3、OCF3、Br、Cl、F、CF3、-CN、SCH3、SO2CH3、-NH2、-NHCH3、-N(CH3)2、-C(O)NH2、-C(O)NHCH3和-C(O)N(CH3)2的取代基取代,并且每一個雜芳基在任何氮原子上由0-1個選自基團(tuán)CH3、CO2CH3、COCH3和SO2CH3的取代基取代;[4c]在另一個仍然更優(yōu)選的實施方案中,本發(fā)明提供了新的式Ic化合物,其中R1為取代的C1;R1由0-1個選自基團(tuán)-CN、-CO2CH3和-CO2CH2CH3的取代基取代;R1也由0-2個在每一個情況下獨立選自基團(tuán)R1a、R1b、CH3、CH2CH3、CH(CH3)2、CH2CH2CH3、-(CH2)3CH3、-CH=CH2、-CH=CH(CH3)、-CH≡CH、-CH≡C(CH3)、-CH2OCH3、-CH2CH2OCH3、F、CF3、環(huán)丙基、CH3-環(huán)丙基、環(huán)丁基、CH3-環(huán)丁基、環(huán)戊基、CH3-環(huán)戊基的取代基取代;R1a為由0-1個選自O(shè)CH3、OCH2CH3、OCF3的取代基和由0-2個在每一個情況下獨立選自基團(tuán)CH3、CH2CH3、CH(CH3)2、CH2CH2CH3、Br、Cl、F、CF3、-CN和SCH3的取代基取代的苯基;R1b為雜芳基和選自基團(tuán)呋喃基、噻吩基、咪唑基、噻唑基、噁唑基、異噁唑基、吡唑基、三唑基和四唑基,每一個雜芳基在0-3個碳原子上以在每一個情況下獨立選自基團(tuán)CH3、CH2CH3、CH(CH3)2、CH2CH2CH3、OCH3、OCH2CH3、OCF3、Br、Cl、F、CF3、-CN和SCH3的取代基取代,并且每一個雜芳基在任何氮原子上以0-1個選自基團(tuán)CH3、CO2CH3、COCH3和SO2CH3的取代基取代;假定R1不是-(CH2)1-4-芳基或-(CH2)1-4-雜芳基,其中該芳基或雜芳基基團(tuán)是取代的或未取代的;R2選自基團(tuán)CH3、CH2CH3和CH(CH3)2;R3選自基團(tuán)H和CH3;芳基為由2-4個在每一個情況下獨立選自基團(tuán)CH3、CH2CH3、CH(CH3)2、CH2CH2CH3、環(huán)丙基、OCH3、OCH2CH3、OCH(CH3)2、OCH2CH2CH3、OCF3、Br、Cl、F、CF3、-CN、SCH3、SO2CH3、-NH2、-NHCH3、-N(CH3)2、-C(O)NH2、-C(O)NHCH3和-C(O)N(CH3)2的取代基取代的苯基;和,雜芳基為在2-4個碳原子上由每一個情況下獨立選自基團(tuán)CH3、CH2CH3、CH(CH3)2、CH2CH2CH3、環(huán)丙基、OCH3、OCH2CH3、OCH(CH3)2、OCH2CH2CH3、OCF3、Br、Cl、F、CF3、-CN、SCH3、SO2CH3、-NH2、-NHCH3、-N(CH3)2、-C(O)NH2、-C(O)NHCH3和-C(O)N(CH3)2的取代基取代的吡啶基。[4d]在另一個更優(yōu)選的實施方案中,本發(fā)明提供了新的式Ic化合物,其中R1為取代的(環(huán)丙基)-C1烷基或(環(huán)丁基)C1烷基;R1以0-1個-CN取代;R1也以0-1個在每一個情況下獨立選自基團(tuán)R1a、R1b、CH3、CH2CH3、CH(CH3)2、CH2CH2CH3、-(CH2)3CH3、-CH=CH2、-CH=CH(CH3)、-CH≡CH、-CH≡C(CH3)、-CH2OCH3、-CH2CH2OCH3、F、CF3、環(huán)丙基和CH3-環(huán)丙基的取代基取代;R1a為由0-1個選自O(shè)CH3、OCH2CH3和OCF3的取代基和由0-2個在每一個情況下獨立選自基團(tuán)CH3、CH2CH3、CH(CH3)2、CH2CH2CH3、Br、Cl、F、CF3、-CN和SCH3的取代基取代的苯基;R1b為雜芳基和選自基團(tuán)呋喃基、噻吩基、咪唑基、噻唑基、噁唑基、異噁唑基和吡唑基,每一個雜芳基在0-3個碳原子上以在每一個情況下獨立選自基團(tuán)CH3、CH2CH3、CH(CH3)2、CH2CH2CH3、OCH3、OCH2CH3、OCF3、Br、Cl、F、CF3、-CN和SCH3的取代基取代。[4e]在另一個更優(yōu)選的實施方案中,本發(fā)明提供了新的式Ic化合物,其中R1為由一個在每一個情況下獨立選自基團(tuán)R1a、R1b、CH3、CH2CH3、CH(CH3)2、CH2CH2CH3、-(CH2)3CH3、-CH=CH2、-CH=CH(CH3)、-CH≡CH、-CH≡C(CH3)、-CH2OCH3、-CH2CH2OCH3、F、CF3、環(huán)丙基和CH3-環(huán)丙基的取代基取代的(環(huán)丙基)C1烷基或(環(huán)丁基)-C1烷基;R1a為由0-2個在每一個情況下獨立選自基團(tuán)CH3、CH2CH3、Cl、F和CF3的取代基取代的苯基;R1b為雜芳基并且選自基團(tuán)呋喃基、噻吩基和異噁唑基,每一個雜芳基在0-2個碳原子上由在每一個情況下獨立選自基團(tuán)CH3、OCH3、Cl、F和CF3的取代基取代。[4f]在一個甚至更優(yōu)選的實施方案中,本發(fā)明提供了新的式Ic化合物,其中R1選自基團(tuán)(環(huán)丙基)CH-CH3、(環(huán)丙基)CH-CH2CH3、(環(huán)丙基)CH-CH2OCH3、(環(huán)丙基)CH-CH2CH2CH3、(環(huán)丙基)CH-CH2CH2OCH3、(環(huán)丙基)2CH、苯基(環(huán)丙基)CH、呋喃基(環(huán)丙基)CH、噻吩基(環(huán)丙基)CH、異噁唑基(環(huán)丙基)CH、(CH3-呋喃基)(環(huán)丙基)CH、(環(huán)丁基)CH-CH3、(環(huán)丁基)CH-CH2CH3、(環(huán)丁基)CH-CH2OCH3、(環(huán)丁基)CH-CH2CH2CH3、(環(huán)丁基)CH-CH2CH2OCH3、(環(huán)丁基)2CH、苯基(環(huán)丁基)CH、呋喃基(環(huán)丁基)CH、噻吩基(環(huán)丁基)CH、異噁唑基(環(huán)丁基)CH和(CH3-呋喃基)(環(huán)丁基)CH;[4g]在另一個更優(yōu)選的實施方案中,本發(fā)明提供了新的式Ic化合物,其中D為由2-4個在每一個情況下獨立選自基團(tuán)CH3、CH2CH3、CH(CH3)2、CH2CH2CH3、環(huán)丙基、OCH3、OCH2CH3、OCH(CH3)2、OCH2CH2CH3、OCF3、Br、Cl、F和CF3的取代基取代的苯基。[4h]在另一個更優(yōu)選的實施方案中,本發(fā)明提供了新的式Ic化合物,其中D為在2-4個碳原子上由在每一個情況下獨立選自基團(tuán)CH3、CH2CH3、CH(CH3)2、CH2CH2CH3、環(huán)丙基、OCH3、OCH2CH3、OCH(CH3)2、OCH2CH2CH3、OCF3、Br、Cl、F和CF3的取代基取代的吡啶基。[4i]在另一個優(yōu)選的實施方案中,本發(fā)明提供了新的式Ic化合物,其中該化合物選自基團(tuán)6-(2,4-雙(三氟甲基)苯基-9-(二環(huán)丙基甲基)-8-乙基-9H-嘌呤;6-(2-氯-4-氰基苯基)-9-(二環(huán)丙基甲基)-8-乙基-9H-嘌呤;6-(2-氯4-甲氧基-5-氯苯基)-9-(二環(huán)丙基甲基)-8-乙基-9H-嘌呤;6-(2-氯-4-甲氧基-5-甲基苯基)-9-(二環(huán)丙基甲基)-8-乙基-9H-嘌呤;6-(2-氯-4-甲氧基苯基)-8-乙基-9-(2-己基)-9H-嘌呤;6-(2-氯-4-甲氧基苯基)-8-乙基-9-(2-戊基)-9H-嘌呤;6-(2-氯-4-甲氧基苯基)-8-乙基-9-(3-庚基)-9H-嘌呤;6-(2-氯-4-甲氧基苯基)-8-乙基-9-(3-己基)-9H-嘌呤;6-(2-氯-4-甲氧基苯基)-8-乙基-9-(4-庚基)-9H-嘌呤;6-(2-氯-4-甲氧基苯基)-9-(1-環(huán)丙基丁基)-8-乙基-9H-嘌呤;6-(2-氯-4-甲氧基苯基)-9-(1-環(huán)丙基丙基)-8-乙基-9H-嘌呤;6-(2-氯-4-甲氧基苯基)-9-(二環(huán)丙基甲基)-8-乙基-9H-嘌呤;6-(2-氯-4-甲氧基苯基)-9-(二環(huán)丙基甲基)-8-甲氧基-9H-嘌呤;6-(2-氯-4-甲基-5-氟苯基)-9-(二環(huán)丙基甲基)-8-乙基-9H-嘌呤;6-(2-氯-4-甲基苯基)-8-乙基-9-(2-戊基)-9H-嘌呤;6-(2-氯-4-甲基苯基)-8-乙基-9-(4-庚基)-9H-嘌呤;6-(2-氯-4-甲基苯基)-9-(1-環(huán)丙基丁基)-8-乙基-9H-嘌呤;6-(2-氯-4-甲基苯基)-9-(二環(huán)丙基甲基)-8-乙基-9H-嘌呤;6-(2-氯-4-三氟甲氧基苯基)-8-乙基-9-(2-戊基)-9H-嘌呤;6-(2-氯-4-三氟甲氧基苯基)-8-乙基-9-(3-己基)-9H-嘌呤;6-(2-氯-4-三氟甲氧基苯基)-9-(1-環(huán)丙基丁基)-8-乙基-9H-嘌呤;6-(2-氯-4-三氟甲氧基苯基)-9-(1-環(huán)丙基丙基)-8-乙基-9H-嘌呤;6-(2-氯-4-三氟甲氧基苯基)-9-(二環(huán)丙基甲基)-8-乙基-9H-嘌呤;6-(2-氯-4-三氟甲基苯基)-8-乙基-9-(1-己炔-3-基)-9H-嘌呤;6-(2-氯-4-三氟甲基苯基)-8-乙基-9-(1-戊炔-3-基)-9H-嘌呤;6-(2-氯-4-三氟甲基苯基)-8-乙基-9-(1-戊炔-4-基)-9H-嘌呤;6-(2-氯-4-三氟甲基苯基)-8-乙基-9-(1-苯基-2-丁炔基)-9H-嘌呤;6-(2-氯-4-三氟甲基苯基)-8-乙基-9-(2-庚炔-4-基)-9H-嘌呤;6-(2-氯-4-三氟甲基苯基)-8-乙基-9-(2-己炔-4-基)-9H-嘌呤;6-(2-氯-4-三氟甲基苯基)-8-乙基-9-(2-戊基)-9H-嘌呤;6-(2-氯-4-三氟甲基苯基)-8-乙基-9-(4-庚基)-9H-嘌呤;6-(2-氯-4-三氟甲基苯基)-8-乙基-9-[(2-呋喃基)環(huán)丙基甲基]-9H-嘌呤;6-(2-氯-4-三氟甲基苯基)-8-乙基-9-[1-(2-呋喃基)丙基]-9H-嘌呤;6-(2-氯-4-三氟甲基苯基)-9-(1-環(huán)丁基乙基)-8-乙基-9H-嘌呤;6-(2-氯-4-三氟甲基苯基)-9-(1-環(huán)丙基-2-丁炔基)-8-乙基-9H-嘌呤;6-(2-氯-4-三氟甲基苯基)-9-(1-環(huán)丙基-2-丙烯基)-8-乙基-9H-嘌呤;6-(2-氯-4-三氟甲基苯基)-9-(1-環(huán)丙基丁基)-8-乙基-9H-嘌呤;6-(2-氯-4-三氟甲基苯基)-9-(1-環(huán)丙基丙基)-8-乙基-9H-嘌呤;6-(2-氯-4-三氟甲基苯基)-9-(二環(huán)丙基甲基)-8-乙基-9H-嘌呤;6-(2-氯-4-三氟甲基苯基)-9-(二環(huán)丙基甲基)-8-甲氧基-9H-嘌呤;6-(2-氯-4-三氟甲基苯基)-9-[1-環(huán)丙基-1-(2-噻吩基)甲基]-8-乙基-9H-嘌呤;9-(1-環(huán)丁基乙基)-6-(2,4-二氯苯基)-8-乙基-9H-嘌呤;9-[1-環(huán)丙基-(3-甲基異噁唑-5-基)甲基]-6-(2,4-二氯苯基)-8-乙基-9H-嘌呤;9-(1-環(huán)丙基-2-丁炔基)-6-(2,4-二氯苯基)-8-乙基-9H-嘌呤;9-(1-環(huán)丙基-2-丁炔基)-6-(2,4-二氯苯基)-8-乙基-9H-嘌呤;9-(1-環(huán)丙基-2-丙烯基)-6-(2,4-二氯-6-甲基苯基)-8-乙基-9H-嘌呤;9-(1-環(huán)丙基-2-丙烯基)-6-(2,4-二氯苯基)-8-乙基-9H-嘌呤;9-(1-環(huán)丙基-2-丙炔基)-8-乙基-6-(2-三氟甲基-4-甲氧基苯基)-9H-嘌呤;9-(1-環(huán)丙基-4’-氟芐基)-6-(2,4-二氯苯基)-8-乙基-9H-嘌呤;9-(1-環(huán)丙基芐基)-6-(2,4-二氯苯基)-8-乙基-9H-嘌呤;9-(1-環(huán)丙基芐基)-8-乙基-6-(2-三氟甲基-4-甲氧基苯基)-9H-嘌呤;9-(1-環(huán)丙基丁基)-6-(2,4-二氯苯基)-8-乙基-9H-嘌呤;9-(1-環(huán)丙基丁基)-8-乙基-6-(2,4,6-三甲基苯基)-9H-嘌呤;9-(1-環(huán)丙基丁基)-8-乙基-6-(2-甲基-4,5-二甲氧基苯基)-9H-嘌呤;9-(1-環(huán)丙基丁基)-8-乙基-6-(2-甲基-4-氯苯基)-9H-嘌呤;9-(1-環(huán)丙基丁基)-8-乙基-6-(2-甲基-4-甲氧基苯基)-9H-嘌呤;9-(1-環(huán)丙基丁基)-8-乙基-6-(2-三氟甲基-4-氯苯基)-9H-嘌呤;9-(1-環(huán)丙基丁基)-8-乙基-6-(2-三氟甲基-4-甲氧基苯基)-9H-嘌呤;9-(1-環(huán)丙基乙基)-6-(2,4-二氯苯基)-8-乙基-9H-嘌呤;9-(1-環(huán)丙基乙基)-8-乙基-6-(2-三氟甲基-4-氯苯基)-9H-嘌呤;9-(1-環(huán)丙基戊基)-8-乙基-6-(2-甲基-4-甲氧基苯基)-9H-嘌呤;9-(1-環(huán)丙基丙基)-6-(2,4-二氯-6-甲基苯基)-8-乙基-9H-嘌呤;9-(1-環(huán)丙基丙基)-6-(2,4-二氯苯基)-8-乙基-9H-嘌呤;9-(1-環(huán)丙基丙基)-8-乙基-6-(2,4,6-三甲基苯基)-9H-嘌呤;9-(1-環(huán)丙基丙基)-8-乙基-6-(2-三氟甲基-4-氯苯基)-9H-嘌呤;6-(2,4-二氯-5-氟苯基)-9-(二環(huán)丙基甲基)-8-乙基-9H-嘌呤;6-(2,4-二氯-6-甲基苯基)-8-乙基-9-(2-戊烯-3-基)-9H-嘌呤;6-(2,4-二氯-6-甲基苯基)-9-(二環(huán)丙基甲基)-8-乙基-9H-嘌呤;6-(2,4-二氯苯基)-8-乙基-9-(1-己炔-3-基)-9H-嘌呤;6-(2,4-二氯苯基)-8-乙基-9-(1-甲氧基羰基丙基)-9H-嘌呤;6-(2,4-二氯苯基)-8-乙基-9-(1-苯基-2-丁炔基)-9H-嘌呤;6-(2,4-二氯苯基)-8-乙基-9-(2-庚炔-4-基)-9H-嘌呤;6-(2,4-二氯苯基)-8-乙基-9-(2-己基)-9H-嘌呤;6-(2,4-二氯苯基)-8-乙基-9-(2-己炔-4-基)-9H-嘌呤;6-(2,4-二氯苯基)-8-乙基-9-(2-戊烯-3-基)-9H-嘌呤;6-(2,4-二氯苯基)-8-乙基-9-(2-戊基)-9H-嘌呤;6-(2,4-二氯苯基)-8-乙基-9-(3-庚基)-9H-嘌呤;6-(2,4-二氯苯基)-8-乙基-9-(3-己基)-9H-嘌呤;6-(2,4-二氯苯基)-8-乙基-9-(3-戊基)-9H-嘌呤;6-(2,4-二氯苯基)-8-乙基-9-(4-庚基)-9H-嘌呤;6-(2,4-二氯苯基)-8-乙基-9-[1-(2-甲基環(huán)丙基)乙基]-9H-嘌呤;6-(2,4-二氯苯基)-9-(二環(huán)丙基甲基)-8-乙基-9H-嘌呤;6-(2,4-二氯苯基)-9-(二環(huán)丙基甲基)-8-乙基-9H-嘌呤;6-(2,4-二氯苯基)-9-(二環(huán)丙基甲基)-8-甲氧基-9H-嘌呤;6-(2,4-二氯苯基)-9-(二苯基甲基)-8-乙基-9H-嘌呤;9-(二環(huán)丙基甲基)-6-(2,4-二甲基苯基)-8-乙基-9H-嘌呤;9-(二環(huán)丙基甲基)-6-(2,4-二甲基苯基)-8-乙基-9H-嘌呤;9-(二環(huán)丙基甲基)-6-(2,6-二甲氧基吡啶-3-基)-8-甲氧基-9H-嘌呤;9-(二環(huán)丙基甲基)-8-乙基-6-(2,4,5-三氯苯基)-9H-嘌呤;9-(二環(huán)丙基甲基)-8-乙基-6-(2-甲氧基-4-三氟甲基苯基)-9H-嘌呤;9-(二環(huán)丙基甲基)-8-乙基-6-(2-甲基-4,5-二甲氧基苯基)-9H-嘌呤;9-(二環(huán)丙基甲基)-8-乙基-6-(2-甲基-4-氯苯基)-9H-嘌呤;9-(二環(huán)丙基甲基)-8-乙基-6-(2-甲基-4-二甲基氨基苯基)-9H-嘌呤;9-(二環(huán)丙基甲基)-8-乙基-6-(2-甲基-4-甲氧基-5-氯苯基)-9H-嘌呤;9-(二環(huán)丙基甲基)-8-乙基-6-(2-甲基-4-甲氧基-5-氟苯基)-9H-嘌呤;9-(二環(huán)丙基甲基)-8-乙基-6-(2-氯-4-甲氧基-5-氟苯基)-9H-嘌呤;9-(二環(huán)丙基甲基)-8-乙基-6-(2-甲基-4-甲氧基苯基)-9H-嘌呤;9-(二環(huán)丙基甲基)-8-乙基-6-(2-三氟甲基-4-氯苯基)-9H-嘌呤;9-(二環(huán)丙基甲基)-8-乙基-6-(2-三氟甲基-4-甲氧基苯基)-9H-嘌呤;9-(二環(huán)丙基甲基)-8-乙基-6-(2-三氟甲基-4-丙氧基苯基)-9H-嘌呤;6-(2,6-二甲氧基吡啶-3-基)-8-乙基-9-(2-戊基)-9H-嘌呤;6-(2,4-二甲基苯基)-8-乙基-9-(2-戊基)-9H-嘌呤;8-乙基-6-(2-甲基-4,5-二甲氧基苯基)-9-(2-戊基)-9H-嘌呤;8-乙基-6-(2-甲基-4,5-二甲氧基苯基)-9-(3-戊基)-9H-嘌呤;8-乙基-9-(1-己烯-3-基)-6-(2-甲基-4,5-二甲氧基苯基)-9H-嘌呤;8-乙基-9-(1-己烯-3-基)-6-(2-三氟甲基-4-甲氧基苯基)-9H-嘌呤;8-乙基-9-(2-己基)-6-(2-三氟甲基-4-甲氧基苯基)-9H-嘌呤;8-乙基-9-(2-戊基)-6-(2-三氟甲基-4-甲氧基苯基)-9H-嘌呤;8-乙基-9-(3-己基)-6-(2-甲基-4-甲氧基苯基)-9H-嘌呤;8-乙基-9-(3-己基)-6-(2-三氟甲基-4-甲氧基苯基)-9H-嘌呤;8-乙基-9-(3-戊基)-6-(2-三氟甲基-4-氯苯基)-9H-嘌呤;8-乙基-9-(4-庚基)-6-(2-甲基-4-氯苯基)-9H-嘌呤;8-乙基-9-(4-庚基)-6-(2-甲基-4-甲氧基苯基)-9H-嘌呤;8-乙基-9-(4-庚基)-6-(2-三氟甲基-4-氯苯基)-9H-嘌呤;8-乙基-9-(4-庚基)-6-(2-三氟甲基-4-甲氧基苯基)-9H-嘌呤;和9-(二環(huán)丙基甲基)-8-乙基-6-(2-甲基-6-甲氧基-3-吡啶基)-9H-嘌呤;或它的藥學(xué)上可接受的鹽形式。[4j]在另一個更優(yōu)選的實施方案中,本發(fā)明提供了新的式Ic化合物,其中R1為C3-8環(huán)烷基;R1由0-1個選自基團(tuán)-CN、-S(O)nR14b、-COR13a、-CO2R13a、-NR15aCOR13a、-N(COR13a)2、-NR15aCONR13aR16a、-NR15aCO2R14b、-CONR13aR16a、1-嗎啉基、1-哌啶基、1-哌嗪基和C4-8環(huán)烷基的取代基來取代,其中在C4-8環(huán)烷基中的0-1個碳原子以選自基團(tuán)-O-、-S(O)n-、-NR13a-、-NCO2R14b-、-NCOR14b-和-NSO2R14b-的基團(tuán)來替代,并且其中在1-哌嗪基中的N4以0-1個選自基團(tuán)R13a、CO2R14b、COR14b和SO2R14b的取代基取代;和,R1也由0-3個在每一個情況下獨立選自基團(tuán)R1a、R1b、R1c、C1-6烷基、C2-8鏈烯基、C2-8炔基、Br、Cl、F、I、C1-4鹵代烷基、-OR13a、C1-2烷氧基-C1-2烷基和-NR13aR16a的取代基來取代。[4k]在另一個甚至更優(yōu)選的實施方案中,本發(fā)明提供了新的式Ic化合物,其中X選自基團(tuán)O、S(O)n和鍵;n為0、1或2;R1選自基團(tuán)環(huán)丙基、環(huán)丁基和環(huán)戊基;R1由0-1個選自基團(tuán)-CN、-S(O)nR14b、-COR13a、-CO2R13a和C4-8環(huán)烷基的取代基取代,其中在C4-8環(huán)烷基中的一個碳原子以選自基團(tuán)-O-、-S(O)n-、-NR13-、-NCO2R14b-、-NCOR14b-和-NSO2R14b-的基團(tuán)替代;R1也以0-2個在每一個情況下獨立選自基團(tuán)R1a、R1b、C1-6烷基、C2-8鏈烯基、C2-8炔基、Br、Cl、F、CF3、CF2CF3、-OR13a、C1-2烷氧基-C1-2烷基和-NR13aR16a的取代基取代。R1a為芳基并且選自基團(tuán)苯基和2,3-二氫化茚基,每一個R1a由0-1個-OR17和0-5個在每一個情況下獨立選自基團(tuán)C1-4烷基、C3-6環(huán)烷基、Br、Cl、F、C1-4鹵代烷基、-CN、-S(O)nR18、-COR17、-NR17aR19a和-CONR17R19a的取代基取代;R1b為雜芳基并且選自基團(tuán)吡啶基、嘧啶基、呋喃基、噻吩基、咪唑基、噻唑基、吡咯基、噁唑基、異噁唑基、吡唑基、三唑基、四唑基和吲唑基,每一個雜芳基在0-4個碳原子上由在每一個情況下獨立選自基團(tuán)C1-4烷基、C3-6環(huán)烷基、Br、Cl、F、CF3、-CN、-OR17、-S(O)mR18、-COR17、-NR17aR19a和-CONR17aR19a的取代基來取代,并且每一個雜芳基在任何氮原子上由0-1個選自基團(tuán)R15a、CO2R14b、COR14b和SO2R14b的取代基取代;R2選自基團(tuán)C1-4烷基、C2-4鏈烯基和C2-4炔基,并且由0-1個選自基團(tuán)-CN、OH、Cl、F和C1-4烷氧基的取代基來取代;R9在每一個情況下獨立選自基團(tuán)H、C1-4烷基和C3-8環(huán)烷基;R3選自基團(tuán)H、Br、Cl、F、-CN、C1-4烷基、C3-6環(huán)烷基、C1-4烷氧基、NH2、C1-4烷基氨基和(C1-4烷基)2-氨基;R13選自基團(tuán)C1-4烷基、C1-2鹵代烷基、C1-2烷氧基-C1-2烷基、C3-6環(huán)烷基-C1-2烷基、芳基(C1-2烷基)-和雜芳基(C1-2烷基)-;R13a和R16a在每一個情況下獨立選自基團(tuán)H、C1-4烷基、C1-4鹵代烷基、C1-4烷氧基-C1-4烷基、C3-6環(huán)烷基和C3-6環(huán)烷基-C1-6烷基;R14選自基團(tuán)C1-4烷基、C1-2鹵代烷基、C1-2烷氧基-C1-2烷基、C3-6環(huán)烷基-C1-2烷基、芳基(C1-2烷基)-和雜芳基(C1-2烷基)-;R14a選自基團(tuán)C1-4烷基、C1-2鹵代烷基、C1-2烷氧基-C1-2烷基和C3-6環(huán)烷基-C1-2烷基;R14b選自基團(tuán)C1-4烷基、C1-2鹵代烷基、C1-2烷氧基-C1-2烷基、C3-6環(huán)烷基和C3-6環(huán)烷基-C1-2烷基;R15在每一個情況下獨立選自基團(tuán)H、C1-4烷基、C3-7環(huán)烷基、C3-6環(huán)烷基-C1-6烷基、苯基和芐基,每一個苯基或芐基在該芳基部分上由0-3個選自基團(tuán)C1-4烷基、Br、Cl、F、C1-4鹵代烷基、C1-4烷氧基、C1-4鹵代烷氧基和二甲基氨基的基團(tuán)來取代;R15a在每一個情況下獨立選自基團(tuán)H、C1-4烷基、C3-7環(huán)烷基和C3-6環(huán)烷基-C1-6烷基;R17、R18和R19在每一個情況下獨立選自基團(tuán)H、C1-6烷基、C3-10環(huán)烷基、C3-6環(huán)烷基-C1-6烷基、C1-2烷氧基-C1-2烷基和C1-4鹵代烷基;或者,在NR17R19部分中,R17和R19一起形成1-吡咯烷基、1-嗎啉基、1-哌啶基或1-哌嗪基,其中在1-哌嗪基中的N4以0-1個選自基團(tuán)R13、CO2R14、COR14和SO2R14的取代基取代;R17a和R19a在每一個情況下獨立選自基團(tuán)H、C1-6烷基、C3-10環(huán)烷基、C3-6環(huán)烷基-C1-6烷基和C1-4鹵代烷基;芳基為由1-4個在每一個情況下獨立選自基團(tuán)C1-4烷基、C3-6環(huán)烷基、-OR17、Br、Cl、F、C1-4鹵代烷基、-CN、-S(O)nR18、-COR17、-CO2R17、-NR15COR17、-NR15CO2R18、-NR17R19和-CONR17R19的取代基取代的苯基;和雜芳基在每一個情況下獨立選自基團(tuán)吡啶基、嘧啶基、三嗪基、呋喃基、喹啉基、異喹啉基、噻吩基、噻唑基、吲哚基、吡咯基、噁唑基、苯并呋喃基、苯并噻吩基、苯并噻唑基、苯并噁唑基、異噁唑基、四唑基、吲唑基、2,3-二氫苯并呋喃基、2,3-二氫苯并噻吩基、2,3-二氫苯并噻吩基-S-氧化物、2,3-二氫苯并噻吩基-S-二氧化物、二氫吲哚基、苯并噁唑啉-2-酮基、苯并二氧戊環(huán)基和苯并二噁烷,每一個雜芳基在1-4個碳原子上由在每一個情況下獨立地選自基團(tuán)C1-6烷基、C3-6環(huán)烷基、Br、Cl、F、C1-4鹵代烷基、-CN、-OR17、-S(O)mR18、-COR17、-CO2R17、-OC(O)R18、-NR15COR17、-N(COR17)2、-NR15CO2R18、-NR17R19和-CONR17R17的取代基取代,并且每一個雜芳基在任何氮原子上以0-1個選自基團(tuán)R15、CO2R14a、COR14a和SO2R14a的取代基來取代;[41]在另一個仍然更優(yōu)選的實施方案中,本發(fā)明提供了新的式Ic化合物,其中X選自基團(tuán)O、S和鍵;R1由0-1個選自基團(tuán)-CN、-CO2R13a和C4-8環(huán)烷基的取代基取代,其中在C4-8環(huán)烷基中的0-1個碳原子以選自基團(tuán)-O-、-S(O)n-和-NR13a-的基團(tuán)替代;R1也以0-2個在每一個情況下獨立選自基團(tuán)R1a、R1b、C1-6烷基、C2-8鏈烯基、C2-8炔基、Br、Cl、F、CF3、CF3、-OR13a、-OH、-OCH3、-OCH2CH3、-CH2OCH3、-CH2CH2OCH3和-NR13aR16a的取代基取代;R1a為芳基和由0-1個選自O(shè)CH3、OCH2CH3、OCH(CH3)2、OCH2CH2CH3和OCF3的取代基和由0-3個在每一個情況下獨立選自基團(tuán)CH3、CH2CH3、CH(CH3)2、CH2CH2CH3、環(huán)丙基、Br、Cl、F、CF3、-CN、SCH3、-NH2、-NHCH3、-N(CH3)2、-C(O)NH2、-C(O)NHCH3和-C(O)N(CH3)2的取代基取代的苯基;R1b為雜芳基并且選自基團(tuán)呋喃基、噻吩基、咪唑基、噻唑基、噁唑基、異噁唑基、吡唑基、三唑基、四唑基和吲唑基,每一個雜芳基在0-3個碳原子上由在每一個情況下獨立選自基團(tuán)CH3、CH2CH3、CH(CH3)2、CH2CH2CH3、環(huán)丙基、OCH3、OCH2CH3、OCH(CH3)2、OCH2CH2CH3、OCF3、Br、Cl、F、CF3、-CN、SCH3、-NH2、-NHCH3、-N(CH3)2、-C(O)NH2、-C(O)NHCH3和-C(O)N(CH3)2的取代基取代,并且每一個雜芳基在任何氮原子上以0-1個選自基團(tuán)CH3、CO2CH3、COCH3和SO2CH3的取代基取代。R2選自基團(tuán)CH3、CH2CH3、CH(CH3)2和CH2CH2CH3;R3選自基團(tuán)H、CH3、CH2CH3、CH(CH3)2和CH2CH2CH3;芳基為由2-4個在每一個情況下獨立選自基團(tuán)CH3、CH2CH3、CH(CH3)2、CH2CH2CH3、環(huán)丙基、OCH3、OCH2CH3、OCH(CH3)2、OCH2CH2CH3、OCF3、Br、Cl、F、CF3、-CN、SCH3、SO2CH3、-NH2、-NHCH3、-N(CH3)2、-C(O)NH2、-C(O)NHCH3和-C(O)N(CH3)2的取代基取代的苯基;和,雜芳基在每一個情況下獨立選自基團(tuán)吡啶基、吲哚基、苯并噻吩基、2,3-二氫苯并呋喃基、2,3-二氫苯并噻吩基、2,3-二氫苯并噻吩基-S-氧化物、2,3-二氫苯并噻吩基-S-二氧化物、二氫吲哚基和苯并噁唑啉-2-酮基,每一個雜芳基在2-4個碳原子上由在每一個情況下獨立地選自基團(tuán)CH3、CH2CH3、CH(CH3)2、CH2CH2CH3、環(huán)丙基、OCH3、OCH2CH3、OCH(CH3)2、OCH2CH2CH3、OCF3、Br、Cl、F、CF3、-CN、SCH3、SO2CH3、-NH2、-NHCH3、-N(CH3)2、-C(O)NH2、-C(O)NHCH3和-C(O)N(CH3)2的取代基取代,并且每一個雜芳基在任何氮原子上以0-1個選自基團(tuán)CH3、CO2CH3、COCH3和SO2CH3的取代基來取代。[4m]在另一個更優(yōu)選的實施方案中,本發(fā)明提供了新的式Ic化合物,其中R1由0-2個在每一個情況下獨立選自基團(tuán)R1a、R1b、CH3、CH2CH3、CH(CH3)2、CH2CH2CH3、-(CH2)3CH3、-CH=CH2、-CH=CH(CH3)、-CH≡CH、-CH≡C(CH3)、-CH2OCH3、-CH2CH2OCH3、F和CF3的取代基取代;R1a為由0-1個選自O(shè)CH3、OCH2CH3、OCH(CH3)2、OCH2CH2CH3和OCF3的取代基和由0-2個在每一個情況下獨立選自基團(tuán)CH3、CH2CH3、CH(CH3)2、CH2CH2CH3、Br、Cl、F、CF3、-CN和SCH3的取代基取代的苯基;R1b為雜芳基并且選自基團(tuán)呋喃基、噻吩基、咪唑基、噻唑基、噁唑基、異噁唑基、吡唑基、三唑基和四唑基,每一個雜芳基在0-3個碳原子上由在每一個情況下獨立選自基團(tuán)CH3、CH2CH3、CH(CH3)2、CH2CH2CH3、OCH3、OCH2CH3、OCF3、Br、Cl、F、CF3、-CN和SCH3的取代基取代,并且每一個雜芳基在任何氮原子上由0-1個選自基團(tuán)CH3、CO2CH3、COCH3和SO2CH3的取代基取代。R2選自基團(tuán)CH3、CH2CH3和CH(CH3)2;R3選自基團(tuán)H和CH3;芳基為由2-4個在每一個情況下獨立選自基團(tuán)CH3、CH2CH3、CH(CH3)2、CH2CH2CH3、環(huán)丙基、OCH3、OCH2CH3、OCH(CH3)2、OCH2CH2CH3、OCF3、Br、Cl、F、CF3、-CN、SCH3、SO2CH3、-NH2、-NHCH3、-N(CH3)2、-C(O)NH2、-C(O)NHCH3和-C(O)N(CH3)2的取代基取代的苯基;和,雜芳基為在2-4個碳原子上由在每一個情況下獨立地選自基團(tuán)CH3、CH2CH3、CH(CH3)2、CH2CH2CH3、環(huán)丙基、OCH3、OCH2CH3、OCH(CH3)2、OCH2CH2CH3、OCF3、Br、Cl、F、CF3、-CN、SCH3、SO2CH3、-NH2、-NHCH3、-N(CH3)2、-C(O)NH2、-C(O)NHCH3和-C(O)N(CH3)2的取代基取代的吡啶基。[4n]在另一個甚至更優(yōu)選的實施方案中,本發(fā)明提供了新的式Ic化合物,其中R1由0-2個在每一個情況下獨立選自基團(tuán)R1a、CH3、CH2CH3、CH(CH3)2、CH2CH2CH3、-(CH2)3CH3、-CH2OCH3、-CH2CH2OCH3、F和CF3的取代基來取代;和,R1a為由0-2個在每一個情況下獨立選自基團(tuán)CH3、CH2CH3、CH(CH3)2、CH2CH2CH3、Br、Cl、F、CF3、-CN和SCH3的取代基取代的苯基。[4o]在另一個仍然更優(yōu)選的實施方案中,本發(fā)明提供了新的式Ic化合物,其中D為由2-4個在每一個情況下獨立選自基團(tuán)CH3、CH2CH3、CH(CH3)2、CH2CH2CH3、環(huán)丙基、OCH3、OCH2CH3、-OCH(CH3)2、OCH2CH2CH3、OCF3、Br、Cl、F和CF3的取代基取代的苯基;[4p]在另一個仍然更優(yōu)選的實施方案中,本發(fā)明提供了新的式Ic化合物,其中D為在2-4個碳原子上由每一個情況下獨立選自基團(tuán)CH3、CH2CH3、CH(CH3)2、CH2CH2CH3、環(huán)丙基、OCH3、OCH2CH3、-OCH(CH3)2、OCH2CH2CH3、OCF3、Br、Cl、F和CF3的取代基取代的吡啶基。[4q]在另一個更優(yōu)選的實施方案中,本發(fā)明提供了新的式Ic化合物,其中R1選自基團(tuán)C1-10烷基、C2-10鏈烯基、C2-10炔基、C3-8環(huán)烷基、C3-6環(huán)烷基-C1-6烷基和C1-4烷氧基-C1-4烷基;R1由C3-8環(huán)烷基基團(tuán)取代,其中在該C4-8環(huán)烷基基團(tuán)的0-1個碳原子由選自基團(tuán)-O-、-S(O)n-、-NR13a-、-NCO2R14b-、-NCOR14b-和-NSO2R14b-的基團(tuán)替代;R1也由0-3個在每一個情況下獨立選自基團(tuán)R1a、R1b、R1c、C1-6烷基、C2-8鏈烯基、C2-8炔基、Br、Cl、F、I、C1-4鹵代烷基、-OR13a、-NR13aR16a、C1-2烷氧基-C1-2烷基和由0-1個R9取代的C3-8環(huán)烷基的取代基取代并且其中C4-8環(huán)烷基的0-1個碳由-O-替代;前提是R1不是環(huán)己基-(CH2)2-基團(tuán);R1a為芳基和選自基團(tuán)苯基、萘基、2,3-二氫化茚基和茚基,每一個R1a以0-1由-OR17和0-5個在每一個情況下獨立選自基團(tuán)C1-6烷基、C3-6環(huán)烷基、Br、Cl、F、I、C1-4鹵代烷基、-CN、硝基、SH、-S(O)nR18、-COR17、-OC(O)R18、-NR15aCOR17、-N(COR17)2、-NR15aCONR17aR19a、-NR15aCO2R18、-NR17aR19a和-CONR17aR19a的取代基來取代;R1b為雜芳基并且選自基團(tuán)吡啶基、嘧啶基、三嗪基、呋喃基、喹啉基、異喹啉基、噻吩基、咪唑基、噻唑基、吲哚基、吡咯基、噁唑基、苯并呋喃基、苯并噻吩基、苯并噻唑基、苯并噁唑基、異噁唑基、吡唑基、三唑基、四唑基、吲唑基、2,3-二氫苯并呋喃基、2,3-二氫苯并噻吩基、2,3-二氫苯并噻吩基-S-氧化物、2,3-二氫苯并噻吩基-S-二氧化物、二氫吲哚基、苯并噁唑啉-2-酮基、苯并二氧戊環(huán)基和苯并二噁烷,每一個雜芳基在0-4個碳原子上由在每一個情況下獨立選自基團(tuán)C1-6烷基、C3-6環(huán)烷基、Br、Cl、F、I、C1-4鹵代烷基、-CN、硝基、-OR17、SH、-S(O)mR18、-COR17、-OC(O)R18、-NR15aCOR17、-N(COR17)2、-NR15aCONR17aR19a、-NR15aCO2R18、-NR17aR19a和-CONR17aR19a的取代基取代,并且每一個雜芳基在任何氮原子上以0-1個選自基團(tuán)R15a、CO2R14b、COR14b和SO2R14b的取代基取代;和,R1c為雜環(huán)基并且為飽和的或部分飽和的雜芳基,每個雜環(huán)基在0-4個碳原子上由在每一個情況下獨立選自基團(tuán)C1-6烷基、C3-6環(huán)烷基、Br、Cl、F、I、C1-4鹵代烷基、-CN、硝基、-OR13a、SH、-S(O)nR14b、-COR13a、-OC(O)R14b、-NR15aCOR13a、-N(COR13a)2、-NR15aCONR13aR16a、-NR15aCO2R14b、-NR13aR16a和-CONR13aR16a的取代基取代,并且每一個雜環(huán)基在任何氮原子上由0-1個選自基團(tuán)R13a、CO2R14b、COR14b和SO2R14b的取代基取代并且其中任何硫原子任選地單氧化或雙氧化;[4r]在另一個甚至更優(yōu)選的實施方案中,本發(fā)明提供了式Ic的新化合物,其中X選自基團(tuán)O、S(O)n和鍵;n為0、1或2;R1選自基團(tuán)C1-6烷基、C2-6鏈烯基、C2-6炔基和C3-8環(huán)烷基;R1由C3-6環(huán)烷基基團(tuán)取代,其中在該C4-6環(huán)烷基基團(tuán)的0-1個碳原子由選自基團(tuán)-O-、-S(O)n-和-NR13a-的基團(tuán)替代;R1也以0-2個在每一個情況下獨立選自基團(tuán)R1a、R1b、C1-6烷基、C2-8鏈烯基、C2-8炔基、Br、Cl、F、CF3、CF2CF3、-OR13a、-NR13aR16a、C1-2烷氧基-C1-2烷基和由0-1個R9取代的C3-6環(huán)烷基的取代基取代并且其中C4-8環(huán)烷基的0-1個碳由-O-替代;R1a為芳基并且選自基團(tuán)苯基和2,3-二氫化茚基,每一個R1a由0-1個-OR17和0-5個在每一個情況下獨立選自基團(tuán)C1-4烷基、C3-6環(huán)烷基、Br、Cl、F、C1-4鹵代烷基、-CN、-S(O)nR18、-COR17、-NR17aR19a和-CONR17aR19a的取代基來取代;R1b為雜芳基并且選自基團(tuán)吡啶基、嘧啶基、呋喃基、噻吩基、咪唑基、噻唑基、吡咯基、噁唑基、異噁唑基、吡唑基、三唑基、四唑基和吲唑基,每一個雜芳基在0-4個碳原子上由在每一個情況下獨立選自基團(tuán)C1-4烷基、C3-6環(huán)烷基、Br、Cl、F、CF3、-CN、-OR17、-S(O)mR18、-COR17、-NR17aR19a和-CONR17aR19a的取代基取代,并且每一個雜芳基在任何氮原子上由0-1個選自基團(tuán)R15a、CO2R14b、COR14b和SO2R14b的取代基來取代;R2選自基團(tuán)C1-4烷基、C2-4鏈烯基和C2-4炔基并且由0-1個選自基團(tuán)-CN、OH、Cl、F和C1-4烷氧基的取代基取代;R9在每一個情況下獨立選自基團(tuán)H、C1-4烷基和C3-8環(huán)烷基;R3選自基團(tuán)H、Br、Cl、F、-CN、C1-4烷基、C3-6環(huán)烷基、C1-4烷氧基、NH2、C1-4烷基氨基和(C1-4烷基)2-氨基;R13選自基團(tuán)C1-4烷基、C1-2鹵代烷基、C1-2烷氧基-C1-2烷基、C3-6環(huán)烷基-C1-2烷基、芳基(C1-2烷基)-和雜芳基(C1-2烷基)-;R13a和R16a在每一個情況下獨立選自基團(tuán)H、C1-4烷基、C1-4鹵代烷基、C1-4烷氧基-C1-4烷基、C3-6環(huán)烷基和C3-6環(huán)烷基-C1-6烷基;R14選自基團(tuán)C1-4烷基、C1-2鹵代烷基、C1-2烷氧基-C1-2烷基、C3-6環(huán)烷基-C1-2烷基、芳基(C1-2烷基)-和雜芳基(C1-2烷基)-;R14a選自基團(tuán)C1-4烷基、C1-2鹵代烷基、C1-2烷氧基-C1-2烷基和C3-6環(huán)烷基-C1-2烷基;R14b選自基團(tuán)C1-4烷基、C1-2鹵代烷基、C1-2烷氧基-C1-2烷基、C3-6環(huán)烷基和C3-6環(huán)烷基-C1-2烷基;R15在每一個情況下獨立選自基團(tuán)H、C1-4烷基、C3-7環(huán)烷基、C3-6環(huán)烷基-C1-6烷基、苯基和芐基,每一個苯基或芐基在該芳基部分上由0-3個選自基團(tuán)C1-4烷基、Br、Cl、F、C1-4鹵代烷基、C1-4烷氧基、C1-4鹵代烷氧基和二甲基氨基的基團(tuán)取代;R15a在每一個情況下獨立選自基團(tuán)H、C1-4烷基、C3-7環(huán)烷基和C3-6環(huán)烷基-C1-6烷基;R17、R18和R19在每一個情況下獨立選自基團(tuán)H、C1-6烷基、C3-10環(huán)烷基、C3-6環(huán)烷基-C1-6烷基、C1-2烷氧基-C1-2烷基和C1-4鹵代烷基;或者,在NR17R19部分中,R17和R19一起形成1-吡咯烷基、1-嗎啉基、1-哌啶基或1-哌嗪基,其中在1-哌嗪基中的N4以0-1個選自基團(tuán)R13、CO2R14、COR14和SO2R14的取代基取代;R17a和R19a在每一個情況下獨立選自基團(tuán)H、C1-6烷基、C3-10環(huán)烷基、C3-6環(huán)烷基-C1-6烷基和C1-4鹵代烷基;芳基為由1-4個在每一個情況下獨立選自基團(tuán)C1-4烷基、C3-6環(huán)烷基、-OR17、Br、Cl、F、C1-4鹵代烷基、-CN、-S(O)nR18、-COR17、-CO2R17、-NR15COR17、-NR15CO2R18、-NR17R19和-CONR17R19的取代基取代的苯基;和雜芳基在每一個情況下獨立選自基團(tuán)吡啶基、嘧啶基、三嗪基、呋喃基、喹啉基、異喹啉基、噻吩基、噻唑基、吲哚基、吡咯基、噁唑基、苯并呋喃基、苯并噻吩基、苯并噻唑基、苯并噁唑基、異噁唑基、四唑基、吲唑基、2,3-二氫苯并呋喃基、2,3-二氫苯并噻吩基、2,3-二氫苯并噻吩基-S-氧化物、2,3-二氫苯并噻吩基-S-二氧化物、二氫吲哚基、苯并噁唑啉-2-酮基、苯并二氧戊環(huán)基和苯并二噁烷,每一個雜芳基在1-4個碳原子上由在每一個情況下獨立地選自基團(tuán)C1-6烷基、C3-6環(huán)烷基、Br、Cl、F、C1-4鹵代烷基、-CN、-OR17、-S(O)mR18、-COR17、-CO2R17、-OC(O)R18、-NR15COR17、-N(COR17)2、-NR15CO2R18、-NR17R19和-CONR17R19的取代基取代,并且每一個雜芳基在任何氮原子上由0-1個選自基團(tuán)R15、CO2R14a、COR14a和SO2R14a的取代基取代;[4s]在另一個仍然更優(yōu)選的實施方案中,本發(fā)明提供了新的式Ic化合物,其中X選自基團(tuán)O、S和鍵;R1為C1-6烷基;R1以C3-6環(huán)烷基取代,其中在該C4-4環(huán)烷基的0-1個碳原子上由選自基團(tuán)-O-、-S(O)n-和-NR13a-的基團(tuán)替代;R1也以0-2個在每一個情況下獨立選自基團(tuán)R1a、R1b、C1-6烷基、C2-8鏈烯基、C2-8炔基、F、CF3、-OR13a、-NR13aR16a、-CH2OCH3、-CH2CH2OCH3、和以0-1個CH3取代的C3-6環(huán)烷基的取代基取代并且其中C4-8環(huán)烷基的0-1個碳由-O-替代;前提是R1不是環(huán)己基-(CH2)2-基團(tuán);R1a為芳基和由0-1個選自O(shè)CH3、OCH2CH3、OCH(CH3)2、OCH2CH2CH3和OCF3的取代基和以0-3個在每一個情況下獨立選自基團(tuán)CH3、CH2CH3、CH(CH3)2、CH2CH2CH3、環(huán)丙基、Br、Cl、F、CF3、-CN、SCH3、-NH2、-NHCH3、-N(CH3)2、-C(O)NH2、-C(O)NHCH3和-C(O)N(CH3)2的取代基取代的苯基;R1b為雜芳基并且選自基團(tuán)呋喃基、噻吩基、咪唑基、噻唑基、噁唑基、異噁唑基、吡唑基、三唑基、四唑基和吲唑基,每一個雜芳基在0-3個碳原子上由在每一個情況下獨立選自基團(tuán)CH3、CH2CH3、CH(CH3)2、CH2CH2CH3、環(huán)丙基、OCH3、OCH2CH3、OCH(CH3)2、OCH2CH2CH3、OCF3、Br、Cl、F、CF3、-CN、SCH3、-NH2、-NHCH3、-N(CH3)2、-C(O)NH2、-C(O)NHCH3和-C(O)N(CH3)2的取代基取代,并且每一個雜芳基在任何氮原子上由0-1個選自基團(tuán)CH3、CO2CH3、COCH3和SO2CH3的取代基取代;R2選自基團(tuán)CH3、CH2CH3、CH(CH3)2和CH2CH2CH3;R3選自基團(tuán)H、CH3、CH2CH3、CH(CH3)2和CH2CH2CH3;芳基為由2-4個在每一個情況下獨立選自基團(tuán)CH3、CH2CH3、CH(CH3)2、CH2CH2CH3、環(huán)丙基、OCH3、OCH2CH3、OCH(CH3)2、OCH2CH2CH3、OCF3、Br、Cl、F、CF3、-CN、SCH3、SO2CH3、-NH2、-NHCH3、-N(CH3)2、-C(O)NH2、-C(O)NHCH3和-C(O)N(CH3)2的取代基取代的苯基;和,雜芳基在每一個情況下獨立選自基團(tuán)吡啶基、吲哚基、苯并噻吩基、2,3-二氫苯并呋喃基、2,3-二氫苯并噻吩基、2,3-二氫苯并噻吩基-S-氧化物、2,3-二氫苯并噻吩基-S-二氧化物、二氫吲哚基和苯并噁唑啉-2-酮基,每一個雜芳基在2-4個碳原子上由在每一個情況下獨立地選自基團(tuán)CH3、CH2CH3、CH(CH3)2、CH2CH2CH3、環(huán)丙基、OCH3、OCH2CH3、OCH(CH3)2、OCH2CH2CH3、OCF3、Br、Cl、F、CF3、-CN、SCH3、SO2CH3、-NH2、-NHCH3、-N(CH3)2、-C(O)NH2、-C(O)NHCH3和-C(O)N(CH3)2的取代基取代,并且每一個雜芳基在任何氮原子上由0-1個選自基團(tuán)CH3、CO2CH3、COCH3和SO2CH3的取代基取代;[4t]在另一個更優(yōu)選的實施方案中,本發(fā)明提供了新的式Ic化合物,其中R1為(環(huán)丙基)C1烷基或(環(huán)丁基)C1烷基;R1由1-2個在每一個情況下獨立選自基團(tuán)R1a、R1b、CH3、CH2CH3、CH(CH3)2、CH2CH2CH3、-(CH2)3CH3、-CH=CH2、-CH=CH(CH3)、-CH≡CH、-CH≡C(CH3)、-CH2OCH3、-CH2CH2OCH3、F、CF3、環(huán)丙基、CH3-環(huán)丙基、環(huán)丁基、CH3-環(huán)丁基、環(huán)戊基、CH3-環(huán)戊基的取代基取代;R1a為由0-1個選自O(shè)CH3、OCH2CH3和OCF3的取代基和以0-2個在每一個情況下獨立選自基團(tuán)CH3、CH2CH3、CH(CH3)2、CH2CH2CH3、Br、Cl、F、CF3、-CN和SCH3的取代基取代的苯基;R1b為雜芳基并且選自基團(tuán)呋喃基、噻吩基、咪唑基、噻唑基、噁唑基、異噁唑基、吡唑基、三唑基和四唑基,每一個雜芳基在0-3個碳原子上由在每一個情況下獨立選自基團(tuán)CH3、CH2CH3、CH(CH3)2、CH2CH2CH3、OCH3、OCH2CH3、OCF3、Br、Cl、F、CF3、-CN和SCH3的取代基取代,并且每一個雜芳基在任何氮原子上以0-1個選自基團(tuán)CH3、CO2CH3、COCH3和SO2CH3的取代基取代;R2選自基團(tuán)CH3、CH2CH3和CH(CH3)2;R3選自基團(tuán)H和CH3;芳基為由2-4個在每一個情況下獨立選自基團(tuán)CH3、CH2CH3、CH(CH3)2、CH2CH2CH3、環(huán)丙基、OCH3、OCH2CH3、OCH(CH3)2、OCH2CH2CH3、OCF3、Br、Cl、F、CF3、-CN、SCH3、SO2CH3、-NH2、-NHCH3、-N(CH3)2、-C(O)NH2、-C(O)NHCH3和-C(O)N(CH3)2的取代基取代的苯基;和,雜芳基為在2-4個碳原子上以在每一個情況下獨立選自基團(tuán)CH3、CH2CH3、CH(CH3)2、CH2CH2CH3、環(huán)丙基、OCH3、OCH2CH3、OCH(CH3)2、OCH2CH2CH3、OCF3、Br、Cl、F、CF3、-CN、SCH3、SO2CH3、-NH2、-NHCH3、-N(CH3)2、-C(O)NH2、-C(O)NHCH3和-C(O)N(CH3)2的取代基取代的吡啶基。[4u]在另一個甚至更優(yōu)選的實施方案中,本發(fā)明提供了新的式Ic化合物,其中R1為(環(huán)丙基)C1烷基或(環(huán)丁基)C1烷基;R1由1-2個在每一個情況下獨立選自基團(tuán)R1a、R1b、CH3、CH2CH3、CH(CH3)2、CH2CH2CH3、-(CH2)3CH3、-CH=CH2、-CH=CH(CH3)、-CH≡CH、-CH≡C(CH3)、-CH2OCH3、-CH2CH2OCH3、F、CF3、環(huán)丙基和CH3-環(huán)丙基的取代基取代;R1a為由0-2個在每一個情況下獨立選自基團(tuán)CH3、CH2CH3、CH(CH3)2、CH2CH2CH3、Br、Cl、F、CF3、-CN和SCH3的取代基取代的苯基;R1b為雜芳基和選自基團(tuán)呋喃基、噻吩基、咪唑基、噻唑基、噁唑基、異噁唑基和吡唑基,每一個雜芳基在0-3個碳原子上由在每一個情況下獨立選自基團(tuán)CH3、CH2CH3、CH(CH3)2、CH2CH2CH3、OCH3、OCH2CH3、OCF3、Br、Cl、F、CF3、-CN和SCH3的取代基取代。[4v]在另一個更優(yōu)選的實施方案中,本發(fā)明提供了新的式Ic化合物,其中D為由2-4個在每一個情況下獨立選自基團(tuán)CH3、CH2CH3、CH(CH3)2、CH2CH2CH3、環(huán)丙基、OCH3、OCH2CH3、OCH(CH3)2、OCH2CH2CH3、OCF3、Br、Cl、F和CF3的取代基取代的苯基。[4w]在另一個更優(yōu)選的實施方案中,本發(fā)明提供了新的式Ic化合物,其中D為在2-4個碳原子上由在每一個情況下獨立選自基團(tuán)CH3、CH2CH3、CH(CH3)2、CH2CH2CH3、環(huán)丙基、OCH3、OCH2CH3、OCH(CH3)2、OCH2CH2CH3、OCF3、Br、Cl、F和CF3的取代基取代的吡啶基。[5]在第三個實施方案中,本發(fā)明提供了新的藥用組合物,包括藥學(xué)上可接受的載體和治療有效量的式(I)化合物
      或它的立體異構(gòu)體或藥學(xué)上可接受的鹽形式,其中A為N或C-R7;B為N或C-R8;前提是基團(tuán)A和B至少一個為N;D為通過不飽和碳原子連接的芳基或雜芳基基團(tuán);X選自基團(tuán)CH-R9、N-R10、O、S(O)n和鍵;n為0、1或2;R1選自基團(tuán)C1-10烷基、C2-10鏈烯基、C2-10炔基、C3-8環(huán)烷基、C3-6環(huán)烷基-C1-6烷基、C1-4烷氧基-C1-4烷基、-SO2-C1-10烷基、-SO2-R1a和-SO2-R1b;R1由0-1個選自基團(tuán)-CN、-S(O)nR14b、-COR13a、-CO2R13a、-NR15aCOR13a、-N(COR13a)2、-NR15aCONR13aR16a、-NR15aCO2R14b、-CONR13aR16a、1-嗎啉基、1-哌啶基、1-哌嗪基和C3-8環(huán)烷基的取代基取代,其中在C4-8環(huán)烷基中的0-1個碳原子由選自基團(tuán)-O-、-S(O)n-、-NR13a-、-NCO2R14b-、-NCOR14b-和-NSO2R14b-的基團(tuán)替代,并且其中在1-哌嗪基中的N4由0-1個選自基團(tuán)R13a、CO2R14b、COR14b和SO2R14b的取代基取代;R1也由0-3個在每一個情況下獨立選自基團(tuán)R1a、R1b、R1c、C1-6烷基、C2-8鏈烯基、C2-8炔基、Br、Cl、F、I、C1-4鹵代烷基、-OR13a、-NR13aR16a和由0-1個R9取代的C3-8環(huán)烷基的取代基取代并且其中C4-8環(huán)烷基的0-1個碳由-O-替代;前提是R1不是(a)3-環(huán)丙基-3-甲氧基丙基;(b)未取代的-(烷氧基)甲基;和,(c)1-羥基烷基;另外的前提是當(dāng)R1烷基由OH取代時,那么鄰近該環(huán)N的碳不是CH2;R1a為芳基并且選自基團(tuán)苯基、萘基、2,3-二氫化茚基和茚基,每一個R1a由0-5個在每一個情況下獨立選自基團(tuán)C1-6烷基、C3-6環(huán)烷基、Br、Cl、F、I、C1-4鹵代烷基、-CN、硝基、-OR17、SH、-S(O)nR18、-COR17、-OC(O)R18、-NR15aCOR17、-N(COR17)2、-NR15aCONR17aR19a、-NR15aCO2R18、-NR17aR19a和-CONR17aR19a的取代基取代;R1b為雜芳基并且選自基團(tuán)吡啶基、嘧啶基、三嗪基、呋喃基、喹啉基、異喹啉基、噻吩基、咪唑基、噻唑基、吲哚基、吡咯基、噁唑基、苯并呋喃基、苯并噻吩基、苯并噻唑基、苯并噁唑基、異噁唑基、吡唑基、三唑基、四唑基、吲唑基、2,3-二氫苯并呋喃基、2,3-二氫苯并噻吩基、2,3-二氫苯并噻吩基-S-氧化物、2,3-二氫苯并噻吩基-S-二氧化物、二氫吲哚基、苯并噁唑啉-2-酮基、苯并二氧戊環(huán)基和苯并二噁烷,每一個雜芳基在0-4個碳原子上由在每一個情況下獨立選自基團(tuán)C1-6烷基、C3-6環(huán)烷基、Br、Cl、F、I、C1-4鹵代烷基、-CN、硝基、-OR17、SH、-S(O)mR18、-COR17、-OC(O)R18、-NR15aCOR17、-N(COR17)2、-NR15aCONR17aR19a、-NR15aCO2R18、-NR17aR19a和-CONR17aR19a的取代基取代,并且每一個雜芳基在任何氮原子上以0-1個選自基團(tuán)R15a、CO2R18b、COR14b和SO2R14b的取代基取代;R1c為雜環(huán)基并且為飽和的或部分飽和的雜芳基,每個雜環(huán)基在0-4個碳原子上由在每一個情況下獨立選自基團(tuán)C1-6烷基、C3-6環(huán)烷基、Br、Cl、F、I、C1-4鹵代烷基、-CN、硝基、-OR13a、SH、-S(O)nR14b、-COR13a、-OC(O)R14b、-NR15aCOR13a、-N(COR13a)2、-NR15aCONR13aR16a、-NR15aCO2R14b、-NR13aR16a和-CONR13aR16a的取代基取代,并且每一個雜環(huán)基在任何氮原子上由0-1個選自基團(tuán)R13a、CO2R14b、COR14b和SO2R14b的取代基取代并且其中任何硫原子任選單氧化或雙氧化;R2選自基團(tuán)C1-4烷基、C3-8環(huán)烷基、C2-4鏈烯基、和C2-4炔基并且由0-3個選自基團(tuán)-CN、羥基、鹵代和C1-4烷氧基的取代基取代;或者在其中X為鍵的情況下,R2選自基團(tuán)-CN、CF3和C2F5;R3、R7和R8在每一個情況下獨立選自基團(tuán)H、Br、Cl、F、I、-CN、C1-4烷基、C3-8環(huán)烷基、C1-4烷氧基、C1-4烷硫基、C1-4烷基亞硫?;1-4烷基磺?;?、氨基、C1-4烷基氨基、(C1-4烷基)2氨基和苯基,每一個苯基由0-3個選自基團(tuán)C1-7烷基、C3-8環(huán)烷基、Br、Cl、F、I、C1-4鹵代烷基、硝基、C1-4烷氧基、C1-4鹵代烷氧基、C1-4烷硫基、C1-4烷基亞硫?;?、C1-4烷基磺?;?、C1-6烷基氨基和(C1-4烷基)2氨基的基團(tuán)取代;前提是R1為不飽和的C1-10烷基,那么R3不是取代的或未取代的苯基;R9和R10在每一個情況下獨立選自基團(tuán)H、C1-4烷基、C3-6環(huán)烷基-C1-4烷基和C3-8環(huán)烷基;R13選自基團(tuán)H、C1-4烷基、C1-4鹵代烷基、C1-4烷氧基-C1-4烷基、C3-6環(huán)烷基、C3-6環(huán)烷基-C1-6烷基、芳基、芳基(C1-4烷基)-雜芳基和雜芳基(C1-4烷基)-;R13a和R16a在每一個情況下獨立選自基團(tuán)H、C1-4烷基、C1-4鹵代烷基、C1-4烷氧基-C1-4烷基、C3-6環(huán)烷基和C3-6環(huán)烷基-C1-6烷基;R14選自基團(tuán)C1-4烷基、C1-4鹵代烷基、C1-4烷氧基-C1-4烷基、C3-6環(huán)烷基、C3-6環(huán)烷基-C1-6烷基、芳基、芳基(C1-4烷基)-、雜芳基和雜芳基(C1-4烷基)-和芐基,每一個芐基在該芳基部分上由0-1個選自基團(tuán)C1-4烷基、Br、Cl、F、I、C1-4鹵代烷基、硝基、C1-4烷氧基、C1-4鹵代烷氧基和二甲基氨基的取代基取代;R14a選自基團(tuán)C1-4烷基、C1-4鹵代烷基、C1-4烷氧基-C1-4烷基、C3-6環(huán)烷基、C3-6環(huán)烷基-C1-6烷基和芐基,每一個芐基在該芳基部分上由0-1個選自基團(tuán)C1-4烷基、Br、Cl、F、I、C1-4鹵代烷基、硝基、C1-4烷氧基、C1-4鹵代烷氧基和二甲基氨基的取代基取代;R14b選自基團(tuán)C1-4烷基、C1-4鹵代烷基、C1-4烷氧基-C1-4烷基、C3-6環(huán)烷基和C3-6環(huán)烷基-C1-6烷基;R15在每一個情況下獨立選自基團(tuán)H、C1-4烷基、C3-7環(huán)烷基、C3-6環(huán)烷基-C1-6烷基、苯基和芐基,每一個苯基或芐基在該芳基部分上由0-3個選自基團(tuán)C1-4烷基、Br、Cl、F、I、C1-4鹵代烷基、硝基、C1-4烷氧基、C1-4鹵代烷氧基和二甲基氨基的基團(tuán)取代;R15a在每一個情況下獨立選自基團(tuán)H、C1-4烷基、C3-7環(huán)烷基和C3-6環(huán)烷基-C1-6烷基;R17在每一個情況下選自基團(tuán)H、C1-6烷基、C3-10環(huán)烷基、C3-6環(huán)烷基-C1-6烷基、C1-2烷氧基-C1-2烷基、C1-4鹵代烷基、R14S(O)n-C1-4烷基和R17bR19bN-C2-4烷基;R18和R19在每一個情況下獨立選自基團(tuán)H、C1-6烷基、C3-10環(huán)烷基、C3-6環(huán)烷基-C1-6烷基、C1-2烷氧基-C1-2烷基和C1-4鹵代烷基;或者,在NR17R19部分中,R17和R19一起形成1-吡咯烷基、1-嗎啉基、1-哌啶基或1-哌嗪基,其中在1-哌嗪基中的N4由0-1個選自基團(tuán)R13、CO2R14、COR14和SO2R14的取代基取代;或者,在NR17bR19b部分中,R17b和R19b一起形成1-吡咯烷基、1-嗎啉基、1-哌啶基或1-哌嗪基,其中在1-哌嗪基中的N4由0-1個選自基團(tuán)R13、CO2R14、COR14和SO2R14的取代基取代;R17a和R19a在每一個情況下獨立選自基團(tuán)H、C1-6烷基、C3-10環(huán)烷基、C3-6環(huán)烷基-C1-6烷基和C1-4鹵代烷基;芳基在每一個情況下獨立選自基團(tuán)苯基、萘基、2,3-二氫化茚基和茚基,每一個芳基由0-5個在每一個情況下獨立選自基團(tuán)C1-6烷基、C3-6環(huán)烷基、亞甲二氧基、C1-4烷氧基-C1-4烷氧基、-OR17、Br、Cl、F、I、C1-4鹵代烷基、-CN、-NO2、SH、-S(O)nR18、-COR17、-CO2R17、-OC(O)R18、-NR15COR17、-N(COR17)2、-NR15CONR17R19、-NR15CO2R18、-NR17R19和-CONR17R19和由一個苯基的取代基取代,每一個苯基取代基由0-4個選自基團(tuán)C1-3烷基、C1-3烷氧基、Br、Cl、F、I、-CN、二甲基氨基、CF3、C2F5、OCF3、SO2Me和乙?;娜〈〈缓碗s芳基在每一個情況下獨立選自基團(tuán)吡啶基、嘧啶基、三嗪基、呋喃基、喹啉基、異喹啉基、噻吩基、咪唑基、噻唑基、吲哚基、吡咯基、噁唑基、苯并呋喃基、苯并噻吩基、苯并噻唑基、苯并噁唑基、異噁唑基、三唑基、四唑基、吲唑基、2,3-二氫苯并呋喃基、2,3-二氫苯并噻吩基、2,3-二氫苯并噻吩基-S-氧化物、2,3-二氫苯并噻吩基-S-二氧化物、二氫吲哚基、苯并噁唑啉-2-酮基、苯并二氧戊環(huán)基和苯并二噁烷,每一個雜芳基在0-4個碳原子上由在每一個情況下獨立選自基團(tuán)C1-6烷基、C3-6環(huán)烷基、Br、Cl、F、I、C1-4鹵代烷基、-CN、硝基、-OR17、SH、-S(O)mR18、-COR17、-CO2R17、-OC(O)R18、-NR15COR17、-N(COR17)2、-NR15CONR17R19、-NR15CO2R18、-NR17R19和-CONR17R19的取代基取代,并且每一個雜芳基在任何氮原子上由0-1個選自基團(tuán)R15、CO2R14a、COR14a和SO2R14a的取代基取代;[6]在第二個實施方案中,本發(fā)明提供了治療情感障礙、焦慮、抑郁、頭疼、過敏性腸道綜合征、突觸后應(yīng)激失調(diào)、核上麻痹、免疫抑制、阿爾滋海默氏病、胃腸道疾病、神經(jīng)性厭食或其它飲食失調(diào)、藥物濫用、藥物或酒精戒斷綜合征、炎性疾病、心血管或與心臟相關(guān)的疾病、生育問題、人免疫缺陷病毒感染、出血應(yīng)激、肥胖癥、不育、頭和脊髓創(chuàng)傷、癲癇、中風(fēng)、潰瘍、肌肉萎縮外側(cè)硬化癥、血糖過少或治療在哺乳動物上能夠通過抑制CRF來影響或促進(jìn)的包括(但不局限于)由CRF介導(dǎo)或促進(jìn)的疾病的新方法,該方法包括給予該哺乳動物治療有效量的式(I)化合物
      或它的立體異構(gòu)體或藥學(xué)上可接受的鹽形式,其中A為N或C-R7;B為N或C-R8;前提是基團(tuán)A和B至少一個為N;D為通過不飽和碳原子連接的芳基或雜芳基基團(tuán);X選自基團(tuán)CH-R9、N-R10、O、S(O)n和鍵;n為0、1或2;R1選自基團(tuán)C1-10烷基、C2-10鏈烯基、C2-10炔基、C3-8環(huán)烷基、C3-6環(huán)烷基-C1-6烷基、C1-4烷氧基-C1-4烷基、-SO2-C1-10烷基、-SO2-R1a和-SO2-R1b;R1由0-1個選自基團(tuán)-CN、-S(O)nR14b、-COR13a、-CO2R13a、-NR15aCOR13a、-N(COR13a)2、-NR15aCONR13aR16a、-NR15aCO2R14b、-CONR13aR16a、1-嗎啉基、1-哌啶基、1-哌嗪基和C3-8環(huán)烷基的取代基取代,其中在C4-8環(huán)烷基中的0-1個碳原子由選自基團(tuán)-O-、-S(O)n-、-NR13a-、-NCO2R14b-、-NCOR14b-和-NSO2R14b-的基團(tuán)替代,并且其中在1-哌嗪基中的N4由0-1個選自基團(tuán)R13a、CO2R14b、COR14b和SO2R14b的取代基取代;R1也由0-3個在每一個情況下獨立選自基團(tuán)R1a、R1b、R1c、C1-6烷基、C2-8鏈烯基、C2-8炔基、Br、Cl、F、I、C1-4鹵代烷基、-OR13a、-NR13aR16a和由0-1個R9取代的C3-8環(huán)烷基的取代基取代并且其中C4-8環(huán)烷基的0-1個碳由-O-替代;前提是R1不是(a)3-環(huán)丙基-3-甲氧基丙基;(b)不飽和-(烷氧基)甲基;和(c)1-羥基烷基;另外的前提是當(dāng)R1烷基由OH取代,那么鄰近該環(huán)N的碳不是CH2;R1a為芳基并且選自基團(tuán)苯基、萘基、2,3-二氫化茚基和茚基,每一個R1a由0-5個在每一個情況下獨立選自基團(tuán)C1-6烷基、C3-6環(huán)烷基、Br、Cl、F、I、C1-4鹵代烷基、-CN、硝基、-OR17、SH、-S(O)nR18、-COR17、-OC(O)R18、-NR15aCOR17、-N(COR17)2、-NR15aCONR17aR19a、-NR15aCO2R18、-NR17aR19a和-CONR17aR19a的取代基取代;R1b為雜芳基并且選自基團(tuán)吡啶基、嘧啶基、三嗪基、呋喃基、喹啉基、異喹啉基、噻吩基、咪唑基、噻唑基、吲哚基、吡咯基、噁唑基、苯并呋喃基、苯并噻吩基、苯并噻唑基、苯并噁唑基、異噁唑基、吡唑基、三唑基、四唑基、吲唑基、2,3-二氫苯并呋喃基、2,3-二氫苯并噻吩基、2,3-二氫苯并噻吩基-S-氧化物、2,3-二氫苯并噻吩基-S-二氧化物、二氫吲哚基、苯并噁唑啉-2-酮基、苯并二氧戊環(huán)基和苯并二噁烷,每一個雜芳基在0-4個碳原子上由在每一個情況下獨立選自基團(tuán)C1-6烷基、C3-6環(huán)烷基、Br、Cl、F、I、C1-4鹵代烷基、-CN、硝基、-OR17、SH、-S(O)mR18、-COR17、-OC(O)R18、-NR15aCOR17、-N(COR17)2、-NR15aCONR17aR19a、-NR15aCO2R18、-NR17aR19a和-CONR17aR19a的取代基取代,并且每一個雜芳基在任何氮原子上由0-1個選自基團(tuán)R15a、CO2R14b、COR14b和SO2R14b的取代基取代;R1c為雜環(huán)基并且為飽和的或部分飽和的雜芳基,每個雜環(huán)基在0-4個碳原子上由在每一個情況下獨立選自基團(tuán)C1-6烷基、C3-6環(huán)烷基、Br、Cl、F、I、C1-4鹵代烷基、-CN、硝基、-OR13a、SH、-S(O)nR14b、-COR13a、-OC(O)R14b、-NR15aCOR13a、-N(COR13a)2、-NR15aCONR13aR16a、-NR15aCO2R14b、-NR13aR16a和-CONR13aR16a的取代基取代,并且每一個雜環(huán)基在任何氮原子上由0-1個選自基團(tuán)R13a、CO2R14b、COR14b和SO2R14b的取代基取代并且其中任何硫原子任選地單氧化或雙氧化;R2選自基團(tuán)C1-4烷基、C3-8環(huán)烷基、C2-4鏈烯基和C2-4炔基并且以0-3個選自基團(tuán)-CN、羥基、鹵代和C1-4烷氧基的取代基取代;或者R2在其中X為鍵的情況下選自基團(tuán)-CN、CF3和C2F5;R3、R7和R8在每一個情況下獨立選自基團(tuán)H、Br、Cl、F、I、-CN、C1-4烷基、C3-8環(huán)烷基、C1-4烷氧基、C1-4烷硫基、C1-4烷基亞硫?;?、C1-4烷基磺?;?、氨基、C1-4烷基氨基、(C1-4烷基)2氨基和苯基,每一個苯基由0-3個選自基團(tuán)C1-7烷基、C3-8環(huán)烷基、Br、Cl、F、I、C1-4鹵代烷基、硝基、C1-4烷氧基、C1-4鹵代烷氧基、C1-4烷硫基、C1-4烷基亞硫酰基、C1-4烷基磺?;?、C1-6烷基氨基和(C1-4烷基)2氨基的取代基取代;前提是當(dāng)R1為未取代的C1-10烷基時,那么R3不是取代的或未取代的苯基;R9和R10在每一個情況下獨立選自基團(tuán)H、C1-4烷基、C3-6環(huán)烷基-C1-4烷基和C3-8環(huán)烷基;R13選自基團(tuán)H、C1-4烷基、C1-4鹵代烷基、C1-4烷氧基-C1-4烷基、C3-6環(huán)烷基、C3-6環(huán)烷基-C1-6烷基、芳基、芳基(C1-4烷基)-、雜芳基和雜芳基(C1-4烷基)-;R13a和R16a在每一個情況下獨立選自基團(tuán)H、C1-4烷基、C1-4鹵代烷基、C1-4烷氧基-C1-4烷基、C3-6環(huán)烷基和C3-6環(huán)烷基-C1-6烷基;R14選自基團(tuán)C1-4烷基、C1-4鹵代烷基、C1-4烷氧基-C1-4烷基、C3-6環(huán)烷基、C3-6環(huán)烷基-C1-6烷基、芳基、芳基(C1-4烷基)-、雜芳基和雜芳基(C1-4烷基)-和芐基,每一個芐基在該芳基部分上由0-1個選自基團(tuán)C1-4烷基、Br、Cl、F、I、C1-4鹵代烷基、硝基、C1-4烷氧基C1-4鹵代烷氧基和二甲基氨基的取代基取代;R14a選自基團(tuán)C1-4烷基、C1-4鹵代烷基、C1-4烷氧基-C1-4烷基、C3-6環(huán)烷基、C3-6環(huán)烷基-C1-6烷基和芐基,每一個芐基在該芳基部分上由0-1個選自基團(tuán)C1-4烷基、Br、Cl、F、I、C1-4鹵代烷基、硝基、C1-4烷氧基、C1-4鹵代烷氧基和二甲基氨基的取代基取代;R14b選自基團(tuán)C1-4烷基、C1-4鹵代烷基、C1-4烷氧基-C1-4烷基、C3-6環(huán)烷基和C3-6環(huán)烷基-C1-6烷基;R15在每一個情況下獨立選自基團(tuán)H、C1-4烷基、C3-7環(huán)烷基、C3-6環(huán)烷基-C1-6烷基、苯基和芐基,每一個苯基或芐基在該芳基部分上由0-3個選自基團(tuán)C1-4烷基、Br、Cl、F、I、C1-4鹵代烷基、硝基、C1-4烷氧基、C1-4鹵代烷氧基和二甲基氨基的取代基取代;R15a在每一個情況下獨立選自基團(tuán)H、C1-4烷基、C3-7環(huán)烷基和C3-6環(huán)烷基-C1-6烷基;R17在每一個情況下選自基團(tuán)H、C1-4烷基、C3-10環(huán)烷基、C3-6環(huán)烷基-C1-6烷基、C1-2烷氧基-C1-2烷基、C1-4鹵代烷基、R14S(O)n-C1-4烷基和R17bR19bN-C2-4烷基;R18和R19在每一個情況下獨立選自基團(tuán)H、C1-6烷基、C3-10環(huán)烷基、C3-6環(huán)烷基-C1-6烷基、C1-2烷氧基-C1-2烷基和C1-4鹵代烷基;或者,在NR17R19部分中,R17和R19一起形成1-吡咯烷基、1-嗎啉基、1-哌啶基或1-哌嗪基,其中在1-哌嗪基中的N4由0-1個選自基團(tuán)R13、CO2R14、COR14和SO2R14的取代基取代;或者,在NR17bR19b部分中,R17b和R19b一起形成1-吡咯烷基、1-嗎啉基、1-哌啶基或1-哌嗪基,其中在1-哌嗪基中的N4由0-1個選自基團(tuán)R13、CO2R14、COR14和SO2R14的取代基取代;R17a和R19a在每一個情況下獨立選自基團(tuán)H、C1-6烷基、C3-10環(huán)烷基、C3-6環(huán)烷基-C1-6烷基和C1-4鹵代烷基;芳基在每一個情況下獨立選自基團(tuán)苯基、萘基、2,3-二氫化茚基和茚基,每一個芳基由0-5個在每一個情況下獨立選自基團(tuán)C1-6烷基、C3-6環(huán)烷基、亞甲二氧基、C1-4烷氧基-C1-4烷氧基、-OR17、Br、Cl、F、I、C1-4鹵代烷基、-CN、-NO2、SH、-S(O)nR18、-COR17、-CO2R17、-OC(O)R18、-NR15COR17、-N(COR17)2、-NR15CONR17R19、-NR15CO2R18、-NR17R19和-CONR17R19和一個苯基的取代基取代,每一個苯基取代基由0-4個選自基團(tuán)C1-3烷基、C1-3烷氧基、Br、Cl、F、I、-CN、二甲基氨基、CF3、C2F5、OCF3、SO2Me和乙?;娜〈〈?;雜芳基在每一個情況下獨立選自基團(tuán)吡啶基、嘧啶基、三嗪基、呋喃基、喹啉基、異喹啉基、噻吩基、咪唑基、噻唑基、吲哚基、吡咯基、噁唑基、苯并呋喃基、苯并噻吩基、苯并噻唑基、苯并噁唑基、異噁唑基、三唑基、四唑基、吲唑基、2,3-二氫苯并呋喃基、2,3-二氫苯并噻吩基、2,3-二氫苯并噻吩基-S-氧化物、2,3-二氫苯并噻吩基-S-二氧化物、二氫吲哚基、苯并噁唑啉-2-酮基、苯并二氧戊環(huán)基和苯并二噁烷,每一個雜芳基在0-4個碳原子上由在每一個情況下獨立選自基團(tuán)C1-6烷基、C3-6環(huán)烷基、Br、Cl、F、I、C1-4鹵代烷基、-CN、硝基、-OR17、SH、-S(O)mR18、-COR17、-CO2R17、-OC(O)R18、-NR15COR17、-N(COR17)2、-NR15CONR17R19、-NR15CO2R18、-NR17R19和-CONR17R19的取代基取代,并且每一個雜芳基在任何氮原子上由0-1個選自基團(tuán)R15、CO2R14a、COR14a和SO2R14a的取代基取代。在另一個優(yōu)選的實施方案中,R1不是環(huán)己基-(CH2)1,2,3,4,5,6,7,8,9或10-基團(tuán)。在另一個優(yōu)選的實施方案中,R1不是芳基-(CH2)1,2,3,4,5,6,7,8,9或10-基團(tuán),其中該芳基基團(tuán)為取代的或未取代的。在另一個優(yōu)選的實施方案中,R1不是雜芳基-(CH2)1,2,3,4,5,6,7,8,9或10-基團(tuán),其中該雜芳基基團(tuán)為取代的或未取代的。在另一個優(yōu)選的實施方案中,R1不是雜環(huán)基-(CH2)1,2,3,4,5,6,7,8,9或10-基團(tuán),其中該雜環(huán)基基團(tuán)為取代的或未取代的。在另一個優(yōu)選的實施方案中,當(dāng)D為咪唑或三唑時,R1不是未取代的C1,2,3,4,5,6,7,8,9或10線性的或分枝的烷基或C3,4,5,6,7或8環(huán)烷基。在另一個優(yōu)選的實施方案中,R1a不被OR17取代。
      本發(fā)明許多化合物具有一個或多個不對稱中心或平面。除非另外指明,所有手性(對映體的或非對映體的)和外消旋形式包括在本發(fā)明中。烯烴、C=N雙鍵等等許多幾何異構(gòu)體也能存在于這些化合物中,并且在本發(fā)明中期待所有這樣穩(wěn)定的異構(gòu)體。這些化合物可以光學(xué)活性或外消旋形式分離。如通過外消旋形式的拆分或通過從光學(xué)活性起始原料的合成來制備旋光活性形式的方法為本領(lǐng)域所熟知。也意指結(jié)構(gòu)的所有手性(對映體的或非對映體的)和外消旋形式和所有的幾何異構(gòu)體形式,除非特別指明該特殊的立體化學(xué)或異構(gòu)體形式。
      術(shù)語“烷基”包括具有特定碳原子數(shù)目的分枝的和直鏈的烷基。“鏈烯基”包括直鏈的或者分枝的構(gòu)型并且一個或多個不飽和碳-碳鍵可發(fā)生在沿著該鏈如乙烯基、丙烯基等等的任何穩(wěn)定的點上的烴鏈?!叭不卑ㄖ辨湹幕蛘叻种Φ臉?gòu)型并且一個或多個碳-碳叁鍵可發(fā)生在沿著該鏈如乙炔基、丙炔基等等的任何穩(wěn)定的點上的烴鏈;“鹵代烷基”意指包括以一個或多個鹵素取代的具有特定碳原子數(shù)目的分枝的和直鏈的烷基;“烷氧基”代表通過一個氧橋連接的指明了碳原子數(shù)目的烷基基團(tuán);“環(huán)烷基”意指包括包含有單-、雙-或多環(huán)體系如環(huán)丙基、環(huán)丁基、環(huán)戊基、環(huán)己基等等的飽和環(huán)基團(tuán);“鹵代”或“鹵素”包括氟代、氯代、溴代和碘代。
      如同在這里所使用的術(shù)語“取代的”意指在指定的原子上的一個或多個氫由選自指定的基團(tuán)置換,前提是所指定的原子的化合價不超過正常值并且該取代作用導(dǎo)致一個穩(wěn)定的化合物。當(dāng)取代基為酮基(即=O),那么在該原子上的2個氫被置換。
      取代基和/或變量的組合僅當(dāng)這樣的組合導(dǎo)致穩(wěn)定的化合物時才是許可的?!胺€(wěn)定的化合物”或“穩(wěn)定的結(jié)構(gòu)”意指足夠強大到從反應(yīng)混合物中經(jīng)過分離而不被破壞以至達(dá)到有用的純度的程度并且配制為有效治療藥物的化合物。
      術(shù)語“藥學(xué)上可接受的鹽”包括式(I)和式(II)化合物的酸或堿鹽。藥學(xué)上可接受的鹽的實例包括(但不局限于)堿性殘基如胺的礦物酸或有機酸鹽;酸性殘基如羧酸等的堿或有機鹽等等。
      本發(fā)明化合物藥學(xué)上可接受的鹽能夠通過使這些化合物的游離酸或堿形式與化學(xué)計算量的適當(dāng)?shù)膲A或酸在水或在有機溶劑或在兩者的混合物中反應(yīng)來制備;一般地,非水介質(zhì)像乙醚、乙酸乙酯、乙醇、異丙醇或乙腈為優(yōu)選的。適宜的鹽的條目在Remington’sPharmaceutical Science,第17版,Mack出版公司,Easton,PA,1985,第1418頁找到,該公開的內(nèi)容通過引用結(jié)合到本文中。
      “前藥”被認(rèn)為是當(dāng)把這樣的前藥給予哺乳動物接受者時在體內(nèi)釋放出式(I)或(II)活性母體藥物的任何共價鍵結(jié)合的載體。式(I)和(II)化合物的前藥通過以這樣的方式,即在途徑控制或在體內(nèi)解離出母體化合物來修飾化合物中的功能基團(tuán)來制備。前藥包括其中結(jié)合到任何基團(tuán)的羥基、胺或巰基基團(tuán)的化合物當(dāng)給予哺乳動物接受者這樣的化合物時,分別解離形成游離的羥基、氨基或巰基基團(tuán)。前藥的實例包括(但不局限于)式(I)和(II)化合物中醇和胺功能基團(tuán)的乙酸基、甲酸基和苯甲酸基衍生物等等。
      術(shù)語“治療有效量”的本發(fā)明化合物意指有效拮抗CRF的異常水平或治療情感障礙、焦慮、抑郁、免疫的、心血管的或與心臟相關(guān)的疾病和與宿主精神紊亂和應(yīng)激有關(guān)的結(jié)腸超敏反應(yīng)癥狀的量。
      合成通過下列合成途徑與流程能夠制備式(I)化合物。這里未提供詳細(xì)的描述,假定有機合成領(lǐng)域的技術(shù)人員將易于理解該含義。
      式(I)化合物的合成可通過在流程1中顯示的反應(yīng)來制備。
      用適當(dāng)?shù)脑噭┛墒故?II)化合物能夠在它的咪唑氮原子上烷基化。該轉(zhuǎn)化典型的條件包括在適宜的溫度(0℃或如果必要的話溫?zé)嶂潦覝?下,于溶劑如四氫呋喃、二甲基甲酰胺或二甲基亞砜中,以堿如氫化鈉、叔丁醇鉀、六甲基乙硅疊氮鈉等,隨后用其中J代表鹵化物(氯化物、溴化物或碘化物)的試劑J-R1或擬鹵化物(甲苯磺酸鹽、甲磺酸鹽、三氟甲磺酸鹽等)處理式(II)化合物?;蛘呖墒褂肕itsunobu條件(Mitsunobu,Synthesis 1981,第1-28頁)實施該反應(yīng)。該化合物(II)用醇化合物R1OH伴隨膦(三苯基、三丁基等)和膦活化試劑如二乙基氮雜二羧酸酯處理。
      可依據(jù)顯示在流程2的途徑制備式(II)化合物。
      隨著元素M-K的消除,式(III)化合物可偶合到式(IV)的芳香化合物上。對于化合物(III)而言,K代表鹵化物、擬鹵化物(如甲磺酸鹽、甲苯磺酸鹽、三氟甲磺酸鹽)或硫代甲基,并且P代表保護(hù)基團(tuán)(如果該反應(yīng)的條件確實保護(hù)了咪唑的N-H;否則P為H)。適宜的P基團(tuán)可包括芐基、4-甲氧基芐基、甲氧基甲基、三甲基甲硅烷基乙氧基甲基、叔丁氧基羰基或芐氧基羰基。對于化合物(IV)而言,M代表基團(tuán)如鋰、溴化鎂、氯化鋅、(二羥基)硼、(二烷氧基)硼、三烷基甲錫烷基等等??稍谶m當(dāng)?shù)拇呋瘎┤缢?三苯基膦)鈀、雙(三苯基膦)鈀二氯化物、[1,3-雙(二苯基膦代)丙烷]鎳二氯化物等存在下實施該偶合反應(yīng)。兩個特別有用的方法包括根據(jù)Negishi等的方法(JOrg.Chem.1977,42,1821)使氯雜環(huán)與就地制備的芳基鋅試劑偶合和根據(jù)Suzuki等的方法(Chem.Letter.1989,1405)使氯雜環(huán)與芳基硼酸酯偶合。對于這類反應(yīng)適當(dāng)?shù)娜軇┮话惆ㄋ臍溥秽?、乙醚、二甲基甲酰胺或二甲基亞砜。典型的溫度范圍從環(huán)境溫度直到該溶劑的沸點。一旦偶合,可除去該P基團(tuán)以得到化合物(II)。除去該保護(hù)基團(tuán)的條件對于有機合成領(lǐng)域的技術(shù)人員是熟知的;如通過氫化除去芐基或芐氧基羰基、通過氟化物源(如四丁基氟化銨)除去甲硅烷基乙氧基甲基和通過酸源(如三氟乙酸)除去叔丁氧基羰基或4-甲氧基芐基等。
      能夠依據(jù)顯示在流程3的計劃制備式(III)化合物。
      式(V)的二胺化合物(在這個情況下,P為基團(tuán)如芐基,它能被引入連接于氮原子,否則P初步代表H和另一個在稍后的步驟中引入的保護(hù)基團(tuán))在環(huán)縮合反應(yīng)中用于制備咪唑環(huán)。當(dāng)然所使用的條件依所選擇的X基團(tuán)而定,并且可包括該化合物(VI)的中間體。形成咪唑反應(yīng)的綜述可在Comprehensive Heterocyclic Chemistry(Pergamon Press,1984)第5卷,第457-498頁中找到。
      其中A和B兩者均為氮原子的式(V)化合物的制備可按照流程4的途徑進(jìn)行。
      特別是對于K=氯代物來說可從商業(yè)來源得到式(VII)化合物??蓮耐ㄟ^以適當(dāng)?shù)幕罨噭┤缬袡C磺酸酐或磺酰氯處理相應(yīng)的二羥基化合物得到帶有擬氯代物K基團(tuán)的化合物。通過或者(i)用化合物P-NH2單烷基化,隨后通過還原硝基基團(tuán);或者(ii)還原硝基基團(tuán)得到式(VIII)的胺化合物,隨后用化合物P-NH2單烷基化;或者(iii)在兩者中任何一種途徑使用氨源(氨氣、氫氧化銨等)隨后通過用基團(tuán)P保護(hù)胺基團(tuán)來轉(zhuǎn)化化合物(VII)為(V)。這類嘧啶化學(xué)在本文獻(xiàn)中得到很好地闡述,并且在Comprehensive Heterocyclic Chemistry第6卷中給出了綜述。用胺化合物使氯嘧啶烷基化可在酸性(如鹽酸或乙酸)或堿性(三烷基胺、叔丁醇鉀等)條件下完成。使用包括催化氫化、二氯化錫、連二亞硫酸鈉、鋅金屬、鐵粉等任何數(shù)量的條件之一能夠?qū)⑦@類化合物中的硝基基團(tuán)還原成氨基基團(tuán)。
      其中A或者B代表氮原子的式(V)化合物的制備顯示在流程5中。
      使用任選如在濃硫酸或乙酸的存在下的濃硫酸或發(fā)煙硝酸的條件硝化式(IX)的羥基吡啶酮化合物得到化合物(X)。該羥基吡啶酮可用K基團(tuán)選擇性單活化得到式(XI)的化合物;這樣做的一個方法包括用三氯氧化磷處理化合物(X)的二環(huán)己基胺鹽得到其中K=Cl的(XI)。或者,在化合物(X)中羥基和吡啶酮基團(tuán)可以同時活化,使用更強烈的條件如三氯氧磷和熱、或過量的甲苯磺酸酐得到化合物(XII)。使用以上對于嘧啶討論的相同的普通途徑,化合物(XI)可轉(zhuǎn)化為保護(hù)的胺化合物(XIII)。使用化合物(XII)選擇性單烷基化也是可能的,但是將可能得到區(qū)域異構(gòu)體產(chǎn)物(XIV)和(XV)的混合物。然后如上討論的那樣還原這些化合物中的硝基基團(tuán)得到其中A或B為氮原子的式(V)化合物。
      流程6顯示了在包括起始步驟中引入R1基團(tuán)的方法的另一條途徑。
      當(dāng)R1代表其中化合物(II)的烷基化是不實用的但是也能用于一般方法的基團(tuán)(如很大R1基團(tuán))時這是特別有用的。這里在以上所描述的酸性或堿性條件下用胺試劑R1-NH2使式(XVI)或(XVII)的化合物(氨基-或硝基-吡啶或嘧啶)烷基化。通過早先描述的硝基還原反應(yīng)可使硝基化合物(XVIII)轉(zhuǎn)化為胺化合物(XIX)。化合物(XIX)能夠環(huán)合為咪唑化合物(XX)。如上所述,該反應(yīng)依X基團(tuán)的選擇而定。例如,對于X=CHR9來說,伴隨在潔凈的溶液中或高沸騰的溶劑中加熱,并且在酸催化劑(如鹽酸或硫酸)的任選存在下,一個技術(shù)人員能使用原酸酯試劑如R2CH(R9)C(OR)3(參見Montgomery和Temple,J.Org.Chem.1960,25,395)。對于X=NR10來說,使用試劑如結(jié)構(gòu)為R2R10N-C(=NH)NH2的胍試劑或其中D代表像OCH3、SCH3或SO2CH3的結(jié)構(gòu)為R2R10N-C(=NH)D的脲衍生的試劑實施該環(huán)合作用。對于X=O來說,使用結(jié)構(gòu)為(R2O)4C的試劑(用乙酸催化)形成該環(huán),條件是一個技術(shù)人員已經(jīng)理解了選擇的R2基團(tuán)的試劑(參見Brown和Lynn,J.Chem.Soc.Perkin Trans.I1974,349)。或者用光氣處理二胺(XIX)隨后通過O-烷基化作用來引入該R2基團(tuán)(如像R2-I或R2-Br的試劑)。對于X=S來說能夠使用相似的方法,它使用硫代光氣或一些相似的試劑,隨后用R2基團(tuán)進(jìn)行S-烷基化作用。這個化合物中的硫原子(和一般貫穿整個分子的硫化物基團(tuán))可被氧化成為亞砜或砜,如果需要的話,通過用適宜的氧化試劑如高錳酸鉀、過氧化單硫酸鉀或間氯過氧苯甲酸處理。最后,化合物(XX)能用于如上所描述的芳基偶合反應(yīng)中,以化合物(I)中所要求的芳基基團(tuán)來代替K基團(tuán)。
      化合物的R1-OH、R1-J和R1-NH2的合成方法是相關(guān)的,其中該醇用于另外兩個化合物的合成中,如在流程7中顯示的那樣。
      例如,使用所指明的試劑(這個途徑不局限于這些J基團(tuán))甲磺酸酯使用甲磺酰氯或酸酐和適宜的堿,甲苯磺酸酯使用甲苯磺酰氯或酸酐和適宜的堿,碘化物使用碘/三苯基膦,溴化物使用三溴化磷或四溴化碳/三苯基膦、或者三氟甲磺酸酯使用三氟甲烷-硫酸酐和適宜的堿可使該羥基基團(tuán)轉(zhuǎn)化為以下的J基團(tuán)。化合物R1-OH和R1-J兩者用于在流程1描述的方法中。將R1-J轉(zhuǎn)化為R1-N3需要使用疊氮化物源如疊氮化鈉和溶劑如二甲基亞砜或二甲基甲酰胺,或水和相轉(zhuǎn)移催化劑(如四丁基硫酸氫銨)。使用試劑如硼氫化鈉或三苯基膦、或氫氣和催化劑(如鈀碳)可完成將該疊氮化合物R1-N3還原成R1-NH2。然后該胺R1-NH2可用于流程6所描述的方法中。
      在這些情況中,其中R1a和R1b與甲醇次甲基基團(tuán)一起組成代表這些結(jié)構(gòu)的包括全部基團(tuán)R1的式(XXI)能夠代表的化合物R1-OH(流程8),該化合物能夠通過加入羰基化合物來制備。
      該途徑特別用于R1a或R1b代表環(huán)烷基基團(tuán)如環(huán)丙基的情況。有機金屬試劑(這里M’代表金屬基團(tuán)如Li、CuCN、CuI、MgCl、MgBr、MgI、ZnCl、CrCl等)與醛試劑反應(yīng)來制備式(XXI)的醇化合物,或者,式(XXII)酮可用還原劑如硼氫化鈉、氫化鋁鋰等處理,它也將產(chǎn)生式(XXI)的醇??墒褂迷谶m宜于制備式(XXII)化合物的酮合成的一般方法,它對于有機合成領(lǐng)域的技術(shù)人員來說將是熟悉的。
      相應(yīng)的方法也可用于醇R1-OH的合成中,包括環(huán)醚化合物與有機金屬試劑的開環(huán)反應(yīng)(流程9)。
      這里,使用了有機金屬試劑R1a-M”,其中M”代表金屬如Mg、Zn或Cu。特別有用的方法描述在Huynh等,Tetrahedron Letters 1979,(17),第1503-1506頁中,其中在碘化亞銅(I)催化下有機鎂試劑與環(huán)醚反應(yīng)。在此方法中使用式(XXIII)的環(huán)氧化物導(dǎo)致合成式(XXIV)的醇化合物,并且使用式(XXV)的氧雜環(huán)丁烷烷化合物生成式(XXVI)的醇?;衔?XXIV)和(XXVI)兩者為R1-OH的變化形式。
      以式(XXVII)合成化合物R1-NH2顯示在流程10中。
      酮(XXII)簡單的還原氨基化將產(chǎn)生胺(XXVII)。在氫和催化劑存在下使用干燥的氨可實施該反應(yīng)。或者,將有機金屬試劑加入到腈化合物中得到亞胺,它用還原試劑(如氰硼氫化鈉)就地處理得到胺(XXVII)。最后,其中Q為任選取代的氧原子(即肟)或氮原子(即腙)的式(XXVIII)化合物可與有機金屬試劑R1b-M反應(yīng)。這里,金屬基團(tuán)M如MgBr、CuCl或CeCl2用于加到肟或腙上。式(XXIX)的中間體加成產(chǎn)物可經(jīng)受還原離去(使用條件如鈉/液氨或催化氫化),它將提供胺(XXVII)。
      氨基酸,無論天然的或合成的,均為合成本發(fā)明化合物的有用起始原料的有效來源。流程11顯示這個方法的一些可能的應(yīng)用。
      式(XXXI)的保護(hù)氨基酸從式(XXX)母體化合物進(jìn)行制備;有用的保護(hù)基團(tuán)(“Prot”)包括叔丁氧基羰基、芐氧基羰基和三苯基甲基。在肽化學(xué)的標(biāo)準(zhǔn)教科書中描述了這種保護(hù)。使用試劑如硼氫化鋰可還原該羧酸基團(tuán),得到醇(XXXII)。如以前所描述的那樣可把該羥基基團(tuán)轉(zhuǎn)化為離去基團(tuán)“J”。用適宜的試劑處理式(XXXIII)化合物可產(chǎn)生包括在本發(fā)明范圍內(nèi)的各種功能基團(tuán)(化合物(XXXIV));用氰化物(這里可使用在溫?zé)岬亩谆柞0分械那杌c)置換J得到腈,用硫醇置換J(在堿如碳酸鉀存在下)得到二硫化物,用仲胺置換J得到叔銨等。
      帶有不飽和R1基團(tuán)的式(I)化合物為包括在本發(fā)明中的化合物的另外的來源。用適當(dāng)?shù)脑噭┰诃h(huán)加成化學(xué)中加入不飽和(雙和叁)鍵(流程12)。式XXXVI的炔化合物與1,3-二烯環(huán)加成得到像式XXXVII的六元環(huán)化合物(一般稱作狄爾斯-阿德爾反應(yīng)),并且與3-原子雙極試劑環(huán)加成得到式XXXVIII的雜環(huán)化合物,這對于有機合成領(lǐng)域的技術(shù)人員來說是熟悉的。這個方法的一個特別的實例為從炔XXXVI和腈氧化物試劑合成式XXXIX的異噁唑化合物。
      在以下流程13中顯示的合成方法可用于制備4,5-b咪唑并吡啶。流程13
      如早先所描述的那樣(Koagel等.Recl.Trav.Chim.Pays-Bas.29,38,67,1948),用HNO3使2,4-二羥基吡啶(XXXX)硝基化,得到相應(yīng)的3-硝基吡啶酮(XXXXI),用有機胺堿如環(huán)庚基胺處理它可選擇性得到相應(yīng)的4-氯吡啶酮(XXXXIII)。這依次在非質(zhì)子傳遞溶劑或質(zhì)子溶劑如CH3CN、DMSO、DMF中與其中R為早先所描述基團(tuán)的伯胺RNH2反應(yīng),或者在有機或無機堿如三烷基胺、K2CO3、Na2CO3等存在下并且在溫度20-200℃范圍內(nèi)與烷基醇反應(yīng)得到4-氨基加成物(XXXXIII)。通過以POCl3處理將吡啶酮(XXXXIII)轉(zhuǎn)化為2-氯吡啶(XXXXIV),并且在鈀催化劑存在下使(XXXXIV)與芳基硼酸ArB(OH)2偶合得到(XXXXV)。通過使用Na2S2O4或Fe、Sn或SnCl2把硝基吡啶(XXXXV)還原為相應(yīng)的氨基吡啶,并且在回流的丙酸中把它轉(zhuǎn)化為咪唑并[4,5-c]吡啶。通過使用腈、imidate、thioimidate或三烷基原丙酸酯能夠影響相同的轉(zhuǎn)化。以下在流程14中顯示的合成方法可用于制備4,5-b咪唑并吡啶。流程14
      如在流程13(Smith A.M等,J.Med.Chem.36,8,1999)中所描述的那樣,在溫度為30-80℃范圍內(nèi),使4-氯吡啶酮(XXXXII)與芳基鹵化物如芐基溴在苯中及在Ag2CO3存在下反應(yīng)得到相應(yīng)2-芐氧基吡啶(XXXXVII)。它與芳基硼酸ArB(OH)2在鈀催化條件下偶合得到(XXXXIX)。通過用強酸如三氟乙酸、三氟甲磺酸(triflic)、硫酸、HCl等處理除去芐氧基,得到吡啶酮(L)。用POX3、PX5或相應(yīng)的三氟甲磺酸鹽、甲苯磺酸酯或甲磺酸酯作用將其轉(zhuǎn)化為2-鹵吡啶,再用伯胺RNH2置換得到(LI)。在流程13中描述的條件下還原該硝基基團(tuán)并且在流程13中描述的條件下將該氨基吡啶環(huán)合為咪唑并[4,5-b]吡啶(LII)。
      提供以下實施例進(jìn)一步詳細(xì)描述本發(fā)明。這些實施例預(yù)期為進(jìn)行本發(fā)明的最佳模式,它們被用來舉例說明而并不對本發(fā)明進(jìn)行限制。
      在以下討論的制備8-乙基-9-(1-乙基戊基)-6-(2,4,6-三甲基苯基)嘌呤(表1,實施例2,結(jié)構(gòu)A)和9-丁基-8-乙基-6-(2,4,6-三甲基苯基)嘌呤(表1,實施例27,結(jié)構(gòu)A)的方法可用來制備所有的包含在表1、表1A和表1B中的結(jié)構(gòu)A的實施例,必要的話對方法稍作修改,并且使用適宜結(jié)構(gòu)的試劑。
      在以下討論的制備3-(1-環(huán)丙基丙基)-7-(2,4-二氯苯基)-2-乙基-3H-咪唑并[4,5-b]吡啶(表1,實施例38,結(jié)構(gòu)B)和1-(1-環(huán)丙基丙基)-4-(2,4-二氯苯基)-2-乙基-1H-咪唑并[4,5-c]吡啶(表1,實施例38,結(jié)構(gòu)C)的方法可用來制備許多的包含在表1、表1A、表1B和表1C中的結(jié)構(gòu)B和C的實施例,必要的話對方法稍作修改,并且使用適宜結(jié)構(gòu)的試劑。
      實施例2制備8-乙基-9-(1-乙基戊基)-6-(2,4,6-三甲基苯基)嘌呤部分A.用芐基胺(7.30mL,67.1mmol)處理5-氨基-4,6-二氟嘧啶(10.0g,61.0mmol)和三乙胺(12.8mL,91.5mmol)在乙醇(100mL)中的溶液并加熱至50℃過夜。冷卻該生成的混合物,并過濾收集生成的結(jié)晶固體。以己烷研磨該固體,再次過濾并真空干燥。從母液收集第二份產(chǎn)物并且像第一份產(chǎn)物一樣純化,總共得到5-氨基-6-芐基氨基-4-氯嘧啶12.67g(48.8mmol,80%)。TLC RF0.10(30∶70乙酸乙酯-己烷)。1H NMR(300MHz,CDCl3)d 7.62(1H,s),7.13-6.97(5H,m),6.61(1H,br t,J=5Hz),4.43(2H,d,J=5.5Hz),4.24(2H,br s)。MS(NH3-CI)m/e 238(4),237(33),236(15),235(100)。部分B.將來自部分A的二胺(10.45g,44.5mmol)和3滴濃鹽酸在三乙基原丙酸酯(70mL)中的溶液加熱至100℃1小時,然后冷卻,傾入水(200mL)中并以乙酸乙酯(2×200mL)提取。該提取物以鹽水(100mL)連續(xù)洗滌,然后合并,以無水硫酸鈉干燥,過濾并蒸發(fā)。經(jīng)柱層析(硅膠,20∶80乙酸乙酯-己烷)分離該殘余物,得到結(jié)晶固體的N-(6-芐基氨基-4-氯嘧啶-5-基)-O-乙基-propionimidate(12.82g,40.2mmol,90%),m.p.85-86℃。TLC RF0.25(20∶80乙酸乙酯-己烷)。1H NMR(300MHz,CDCl3)d 8.19(1H,s),7.35-7.29(5H,m),5.21(1H,br t,J=5Hz),4.70(2H,d,J=5.9Hz),4.29(2H,br),2.15(2H,br q,J=7.3Hz),1.35(3H,t,J=7.0Hz),1.06(3H,t,J=7.3Hz)。MS(NH3-CI)m/e 322(6),321(34),320(20),319(100)。部分C.將在以上部分B中制備的imidate化合物(10.66g,33.4mmol)和對-甲苯磺酸一水合物(100mg)在二苯基醚(10mL)中的溶液加熱至170℃2小時,然后冷卻該生成的混合物并將它傾入50mL水中。以乙酸乙酯(2×50mL)提取。該提取物以鹽水(50mL)連續(xù)洗滌,然后合并,以無水硫酸鈉干燥,過濾并蒸發(fā)。經(jīng)柱層析(硅膠,己烷除去二苯基醚,然后30∶70乙酸乙酯-己烷)分離該殘余物,得到油狀的產(chǎn)物9-芐基-6-氯-8-乙基嘌呤(8.16g,29.9mmol,89%)。TLC RF0.20(30∶70乙酸乙酯-己烷)。1H NMR(300MHz,CDCl3)d 8.72(1H,s),7.37-7.29(3H,m),7.19-7.14(2H,m),5.46(2H,s),2.89(2H,q,J=7.7Hz),1.38(3H,t,J=7.7Hz)。MS(NH3-CI)m/e 276(6),275(36),274(20),273(100)。部分D.在環(huán)境溫度下用乙醚中的2,4,6-三甲苯基溴化鎂(39.1mL,1.0M,39.1mmol)溶液處理在無水新蒸四氫呋喃(50mL)中的氯化鋅(5.32g,39.1mmol)溶液。45分鐘后,用二異丁基氫化鋁(2.6mL,1.0M,2.6mmol)的己烷溶液處理在另一個燒瓶中的雙(三苯基膦)-二氯化鈀(0.92g,1.3mmol)的四氫呋喃(30mL)溶液。將該混合物攪拌15分鐘,然后通過套管滴加2,4,6-三甲苯基氯化鋅溶液進(jìn)行處理。然后,通過注射器加入在10mL四氫呋喃溶液中的氯代嘌呤化合物,并且將該混合物在環(huán)境溫度下攪拌12小時。將它傾入水(150mL)中并滴加1N鹽酸水溶液酸化直到該混合物均勻。用乙酸乙酯(2×150mL)提取,并且用飽和鹽水(100mL)連續(xù)洗滌該提取物,然后合并,以無水硫酸鈉干燥,過濾并蒸發(fā)。經(jīng)柱層析(硅膠,30∶70乙酸乙酯-己烷)分離該殘余物,得到灰白色蠟狀固體產(chǎn)物的9-芐基-8-乙基-6-(2,4,6-三甲基苯基)嘌呤(6.68g,18.7mmol,72%),m.p.121-122℃。1H NMR(300MHz,CDCl3)d 9.00(1H,s),7.38-7.31(3H,m),7.23-7.21(2H,m),6.96(2H,s),5.50(2H,s),2.84(2H,q,J=7.6Hz),2.33(3H,s),2.06(6H,s),1.26(3H,t,J=7.5Hz)。MS(NH3-CI)m/e 359(3),358(26),357(100)。部分E.將來自以上部分D的芐基化合物(5.33g,14.95mmol)的三氟乙酸(320mL)的溶液分份加入到四個Parr燒瓶中,并且每一個用在碳上的20%氫氧化鈀0.8g處理。這些燒瓶每一個在搖床經(jīng)受氫化(50psi)18小時。以氮氣驅(qū)除氣體,然后合并溶液,通過硅藻土過濾并蒸發(fā)。經(jīng)柱層析(硅膠,50∶50乙酸乙酯-己烷)分離該殘余物,得到白色結(jié)晶固體的產(chǎn)物8-乙基-6-(2,4,6-三甲基苯基)嘌呤(3.75g,14.1mmol,94%),m.p.215-217℃。TLC RF0.17(50∶50乙酸乙酯-己烷)。1H NMR(300MHz,CDCl3)d 12.35(1H,br s),9.03(1H,s),6.96(2H,s),3.05(2H,q,J=7.7Hz),2.32(3H,s),2.05(6H,s),1.50(3H,t,J=7.7Hz)。MS(NH3-CI)m/e 269(2),268(19),267(100)。部分F.將來自以上部分E的嘌呤化合物(200mg,0.75mmol)、3-庚醇(0.13mL,0.90mmol)和三苯基膦(0.24g,0.90mmol)在新蒸四氫呋喃(5mL)的溶液冷卻至0℃,并且通過注射器滴加偶氮二羧酸二乙酯(0.14mL,0.90mmol)進(jìn)行處理。攪拌該混合物12小時,然后蒸發(fā)。經(jīng)柱層析(硅膠,15∶85乙酸乙酯-己烷)分離該殘余物,得到白色固體的標(biāo)題產(chǎn)物(0.152g,0.42mmol,56%),m.p.99-100℃。TLC RF0.17(10∶90乙酸乙酯-己烷)。1H NMR(300MHz,CDCl3)d 8.91(1H,s),6.95(2H,s),4.22(1H,br),2.92(2H,q,J=7.7Hz),2.41(2H,br),2.32(3H,s),2.10-1.98(2H,m),2.05(3H,s),2.04(3H,s),1.37(3H,t,J=7.5Hz),1.34-1.23(4H,m),0.84(3H,t,J=7.1Hz),0.81(3H,t,J=7.5Hz)。MS(NH3-CI)m/e 367(3),366(27),365(100)。
      實施例27制備9-丁基-8-乙基-6-(2,4,6-三甲基苯基)嘌呤將8-乙基-6-(2,4,6-三甲基苯基)嘌呤(200mg,0.75mmol)在無水二甲基甲酰胺(5mL)中的溶液冷卻至0℃,然后用分散在礦物油中的氫化鈉(72mg 50%w/w,1.50mmol)處理。1小時后,通過注射器加入溴丁烷(0.10mL,0.90mmol),并且攪拌該混合物12小時。將它傾入到乙酸乙酯(120mL)中并以水(3×120mL)和鹽水(100mL)洗滌。該水層以乙酸乙酯(120mL)連續(xù)回提,并合并該提取液,以無水硫酸鈉干燥,過濾并蒸發(fā)。經(jīng)柱層析(硅膠,20∶80乙酸乙酯-己烷)分離該殘余物,得到粘油狀的標(biāo)題產(chǎn)物(64.2mg,0.20mmol,27%)。TLC RF0.20(30∶70乙酸乙酯-己烷)。1H NMR(300MHz,CDCl3)d 8.96(1H,s),6.95(2H,s),4.25(2H,t,J=7.5Hz),2.93(2H,q,J=7.7Hz),2.32(3H,s),2.04(6H,s),1.91-1.86(2H,m),1.50-1.38(2H,m),1.39(3H,t,J=7.7Hz),1.01(3H,t,J=7.5Hz)。MS(NH3-CI)m/e 325(3),324(23),323(100)。
      實施例35制備6-(2,4-二氯苯基)-8-乙基-9-(1-乙基戊基)嘌呤將2,4-二氯苯硼酸(572mg,3.00mmol)和乙二醇(205mg,3.30mmol)在苯(20mL)中的溶液加熱回流并共沸除水8小時。冷卻生成的溶液并用6-氯-8-乙基-9-(1-乙基戊基)嘌呤(參見以上實施例2的部分C;562mg,2.00mmol)、碳酸鉈(1.03g,2.20mmol)和四(三苯基膦)鈀(116mg,0.10mmol)處理。攪拌下加熱該生成的混合物至回流12小時,然后冷卻,經(jīng)過硅藻土過濾和蒸發(fā)。經(jīng)柱層析(硅膠,10∶90乙酸乙酯-己烷)分離得到的殘余物,得到粘油狀的標(biāo)題化合物(530mg,1.35mmol,68%)。TLC RF0.31(20∶80乙酸乙酯-己烷)。1H NMR(300MHz,CDCl3)d 8.94(1H,s),7.71(1H,d,J=8.4Hz),7.58(1H,d,J=1.8Hz),7.41(1H,dd,J=8.4,1.8Hz),4.27(1H,br),2.95(2H,q,J=7.3Hz),2.41(2H,br),2.11-1.98(2H,br),1.42(3H,t,J=7.3Hz),1.37-1.20(3H,m),1.09-0.99(1H,m),0.84(3H,t,J=7.7Hz),0.82(3H,t,J=7.7Hz)。MS(NH3-CI)m/e C20H25N4Cl2的計算值391.1456,實測值391.1458;395(11),394(14),393(71),392(29),391(100)。
      實施例38制備3-(1-環(huán)丙基丙基)-7-(2,4-二氯苯基)-2-乙基-3H-咪唑并[4,5-b]吡啶部分A.將2,4-二羥基吡啶(15.0g,135mmol)在HNO3(85mL)中于80℃下加熱15-20分鐘,在此期間使它溶于溶液。維持該溫度5分鐘并在冷卻后將它傾入冰/水(~200mL)中。收集該沉淀的固體并干燥(19.0g,90%收率)。1H NMR(300MHz,dmso d6)12.3-12.5(1H,brs),11.75-11.95(1H,brs),7.41(1H,d J=7.3Hz),5.99(1H,d J=7.3,Hz)。部分B.把4-羥基-3-硝基吡啶酮(8.0g,51.25mmol)和環(huán)庚胺(6.8mL,53.4mmol)在甲醇(100mL)中加熱回流15分鐘。解吸溶劑,并以1∶1的EWtOAc/己烷洗滌該殘余固體并真空干燥。該環(huán)庚胺鹽在POCl3(60mL)中攪拌40小時并傾入冰/水(~600mL)中。收集沉淀的產(chǎn)物并真空干燥(7.0g,78%收率)。1H NMR(300MHz,dmso d6)12.8-13.05(1H,brs),7.73(1h,d J=7.0Hz),6.50(1H,d J=7.0Hz)。部分C.將在干燥苯(20mL)中的4-氯-3-硝基-吡啶酮(0.5g,2.86mmol)、Ag2CO3(0.83g,3mmol)和芐基溴(0.36mL,3mmol)在60℃下攪拌5小時。過濾該反應(yīng)混合物并且真空解吸。經(jīng)硅膠柱層析(10%乙酸乙酯/己烷作為洗脫劑)分離該殘余物,得到產(chǎn)物(0.6g,79%)。1HNMR(300MHz,CDCl3)8.15(1H,d J=4.0Hz),7.30-7.42(5H,m),7.04(1H,d J=4.0Hz),5.50(2H,s)。部分D.將2-芐氧基-4-氯-3-硝基吡啶(0.5g,1.9mmol)、2,4-二氯苯基硼酸(0.363g,1.9mmol)、Pd(PPh3)2Cl2(76mg,0.11mmol)和Ba(OH)2·8H2O(0.6g,1.9mmol)在1,2-二甲氧基乙烷(6mL)和水(6mL)中加熱回流5小時。將該混合物在EtOAc(100mL)和水(30mL)中分配并用水、鹽水洗滌EtOAc層,干燥并真空解吸。經(jīng)硅膠柱層析(10%乙酸乙酯/己烷作為洗脫劑)該殘余物,得到產(chǎn)物(370mg,收率52%)。1H NMR(300MHz,CDCl3)8.31(1H,d J=5.1Hz),7.51(1H,d J=2.2Hz),7.30-7.43(6H,m),7.20(1H,d J=8.0Hz),6.91(1H,d J=5.1Hz),5.56(2H,s)。部分E.將2-芐氧基-4-(2,4-二氯苯基)-3-硝基吡啶(1.65g,4.39mmol)在CF3CO2H(25mL)中于25℃下攪拌4小時。真空解吸CF3CO2H,并且該殘余物用20%的EtOAc/己烷洗滌并用于下一步反應(yīng)。1H NMR(300MHz,CDCl3)7.62(1H,d J=7.0Hz),7.53(1H,d J=2.2Hz),7.34(1H,dd J=7.0,2.2Hz),7.22(1H,d J=8.1Hz),6.33(1H,d J=7.0Hz)。部分F.把4-(2,4-二氯苯基)-3-硝基吡啶酮(4.39mmol)在POCl3(5mL)中加熱回流5小時。冷卻后將它傾入冰/水(~60mL)中并以EtOAc(2×100mL)提取。以飽和NaHCO3、鹽水洗滌該EtOAc層,干燥并真空解吸。未進(jìn)行進(jìn)一步純化用于下一步反應(yīng)。1H NMR(300MHz,CDCl3)8.60(1H,d J=5.2Hz),7.54(1H,d J=2.2Hz),7.36(1H,dd J=8.1,2.2Hz),7.20(1H,d J=8.1Hz)。部分G.把2-氯-4-(2,4-二氯苯基)-3-硝基吡啶(0.5g,1.65mmol)、1-環(huán)丙基丙胺鹽酸鹽(461mg,3.4mmol)和二異丙基乙胺(1.26mL,0.72mmol)在CH3CN(10mL)中加熱回流64小時。該混合物在EtOAc(70mL)和水(40mL)中分配。以EtOAc(50mL)提取水層,并且以鹽水洗滌合并的EtOAc提取液,干燥并真空解吸。經(jīng)硅膠柱層析(10%乙酸乙酯/己烷作為洗脫劑)該殘余物,得到產(chǎn)物(310mg,51%收率)。1HNMR(300MHz,CDCl3)8.29(1H,d J=4.7Hz),7.76(1H,brd J=8.0Hz),7.46(1H,d J=2.2Hz),7.32(1H,dd J=8.5,2.2Hz),7.15(1H,d J=8.5Hz),3.72-3.85(1H,m),1.70-1.80(2H,m),0.90-1.08(4H,m),0.30-0.66(4H,m)。部分H.把2-(1-環(huán)丙基)丙基氨基-4-(2,4-二氯苯基)-3-硝基吡啶(310mg,0.85mmol)溶于二氧六環(huán)(8mL)中并先后加入含有濃NH4OH(0.3mL)的水(8mL)和Na2S2O4(1.1g,6.86mmol)。該反應(yīng)在25℃下攪拌4小時,并以EtOAc(100mL)提取。以鹽水洗滌該EtOAc,干燥并真空解吸。經(jīng)硅膠柱層析(25%乙酸乙酯/己烷和~1%濃NH4OH洗脫劑)該殘余物,得到產(chǎn)物(150mg,53%收率)。1H NMR(300MHz,CDCl3)7.73(1H,d J=5.5Hz),7.53(1H,d J=1.8Hz),7.35(1H,dd J=8.1,1.8Hz),7.24(1H,d J=8.1Hz),6.35(1H,d J=5.5Hz),4.3(1H,brs),3.5(1H,brs),3.42-3.55(1H,m),3.04(2H,brs),1.70-1.81(2H,m),0.88-1.08(4H,m),0.3-0.6(4H,m)。部分I.把3-氨基-2-(1-環(huán)丙基)丙基氨基-4-(2,4-二氯苯基)-吡啶(140mg,0.42mmol)在丙酸(5mL)中加熱回流23小時。然后以水(50mL)稀釋該混合物,以固體NaHCO3中和并且以50%NaOH堿化。然后以EtOAc(80mL)提取,干燥并真空解吸該EtOAc。經(jīng)硅膠柱層析(10%和20%乙酸乙酯/己烷作為洗脫劑)該殘余物,得到產(chǎn)物,將其從己烷中結(jié)晶(70mg,45%收率),mp 118-119℃。1H NMR(300MHz,CDCl3)8.31(1H,d J=4.7Hz),7.62(1H,d J=7.2Hz),7.55(1H,d J=1.8Hz),7.37(1H,dd J=7.2,1.8Hz),7.23(1H,d J=4.7Hz),3.50-3.70(1H,brs),2.87-2.96(2H,q),2.36-2.56(1H,m),2.18-2.35(1H,m),1.90-2.05(1H,m),1.38(3H,t),0.86(3H,t),0.75-0.84(1H,m),0.40-0.54(1H,m),0.15-0.25(1H,m)。
      實施例38A制備1-(1-環(huán)丙基丙基)-4-(2,4-二氯苯基)-2-乙基-1H-咪唑并[4,5-c]吡啶部分A.將4-氯-3-硝基-2-吡啶酮(2.0g,11.4mmol)、1-環(huán)丙基丙胺鹽酸鹽(1.5g,11.4mmol)和N,N-二異丙基乙基胺(4.8ml,27.4mmol)在CH3CN(50mL)的混合物中于25℃下攪拌16小時,并且回流4小時。冷卻后使其真空解吸,并且將該殘余物在EtOAc(100mL)和H2O(50mL)之間分配。分離該不溶物,以H2O和EtOAc洗滌,并真空干燥得到1.51g。分離該濾液層,并以EtOAc(2×50mL)提取水層。以鹽水洗滌合并的提取液,經(jīng)過MgSO4干燥,過濾并真空濃縮。以EtOAc(2×)洗滌該殘余物并真空干燥,得到黃色固體0.69g。合并的4-(1-環(huán)丙基丙基)氨基-3-硝基-2-吡啶酮重量為2.2g,收率81%。1H NMR(300MHz,dmso d6)11.19(1H,br),8.94(1H,d J=8.8Hz),7.33(1H,t J=6.9Hz),6.03(1H,d J=7.7Hz),3.18-3.24(1H,m),1.60-1.74(2H,m),1.03-1.11(1H,m),0.91(3H,t),0.40-0.60(1H,m),0.20-0.39(1H,m)。部分B.將4-(1-環(huán)丙基)丙基氨基-3-硝基-2-吡啶酮(2.20g,9.27mmol)在POCl3(15mL)中于25℃下攪拌16小時。然后把它傾入到冰/水(220mL)中并攪拌直到所有的POCl3反應(yīng)完畢。以固體NaHCO3中和該混合物,過濾并且以EtOAc(3×60mL)提取。該合并的有機提取液以鹽水洗滌,經(jīng)MgSO4干燥,過濾并真空解吸。經(jīng)硅膠(100g)柱層析該粗油并用10-20%乙酸乙酯/己烷梯度洗脫,得到2-氯-4-(1-環(huán)丙基丙基)氨基-3-硝基吡啶1.91g,81%收率。1H NMR(300MHz,CDCl3)7.96(1H,d J=6.3Hz),6.58(1H,d J=6.3Hz),6.52(1H,brd J=5.5Hz),2.90-3.00(1H,m),1.61-1.82(2H,m),1.01(3H,t J=7.7Hz),0.90-1.02(1H,m),0.51-0.70(2H,m),0.21-0.34(2H,m)。部分C.在干燥燒瓶中,在N2下把2-氯-4-(1-環(huán)丙基)丙基氨基-3-硝基吡啶(730mg,2.85mmol)、2,4-二氯苯基硼酸(544mg,2.85mmol)、二氯雙(三苯基膦)鈀(III)(114mg,0.17mmol)和氫氧化鋇八水合物(899mg,2.85mmol)在二甲氧基乙烷(8.6mL)和H2O(8.6mL)中的混合物加熱回流1.5小時。冷卻后使其在EtOAc(100mL)和水(20mL)中分配并通過硅藻土過濾。以EtOAc(2×50mL)提取水層。該合并的有機層以鹽水洗滌,經(jīng)MgSO4干燥,過濾并真空解吸。經(jīng)硅膠(40gm)層析該殘余物并用30%EtOAc/己烷洗脫,得到黃色的油1.00g,收率90%。1H NMR(300MHz,CDCl3)8.24(1H,d J=6.2Hz),7.87(1H,brd J=7.3Hz),7.43(1H,s),7.34(2H,s),6.71(1H,d J=6.2Hz),3.00-3.10(1H,m),1.70-1.85(2H,m),0.95-1.15(4H,m),0.50-0.71(2H,m),0.25-0.40(2H,m)。部分D.將來自部分C的產(chǎn)物(0.94g,2.57mmol)溶于二氧六環(huán)(26ml)、H2O(26ml)和濃NH4OH(1.0ml)中,同時加入Na2S2O4并在室溫下攪拌2小時。加入CH2Cl2并提取。以CH2Cl2(2×)提取水層。合并有機層并用鹽水洗滌,經(jīng)MgSO4干燥,過濾并真空濃縮。得到黃色固體1.01g。不經(jīng)純化直接把它用于下一步反應(yīng)。部分E.通過回流8小時使來自部分D的胺(1.01g,3.00mmol)與丙酸(27ml,365.45mmol)環(huán)合。使其冷卻至室溫。然后以1M NaOH和50%NaOH堿化。以EtOAc(2×60mL)和CH2Cl2(60mL)提取。合并的有機層用水、鹽水洗滌,經(jīng)MgSO4干燥,過濾并真空濃縮。經(jīng)硅膠(40g)層析該粗油并以30%EtOAc/己烷洗脫,得到淺黃色的固體520mg(用己烷研磨),收率46%。1H NMR(300MHz,CDCl3)8.43(1H,d J=5.8Hz),7.63(1H,d J=8.1Hz),7.55(1H,d J=1.8Hz),7.46(1H,d J=5.8Hz),7.36(1H,dd J=8.1,1.8Hz),3.40-3.50(1H,m),2.80-2.90(2H,q J=7.7Hz),2.10-2.30(2H,m),1.50-1.64(1H,m),1.37(3H,t J=7.3Hz),0.87(3H,t J=7.3Hz),0.81-0.91(1H,m),0.48-0.58(2H,m),0.18-0.26(1H,m)。C20H21N3Cl2元素的分析計算值C,64.18;H,5.665;N,11.23;實測值C,64.37;H,5.66;N,11.15。
      實施例831制備6-(2-氯-4-甲氧基苯基)-9-二環(huán)丙基甲基-8-乙基嘌呤部分A.把二環(huán)丙基酮(50g)在絕對甲醇(150mL)中的溶液在自動加料管先后與W4蘭尼鎳(12g,洗至無水并在甲醇中呈淤漿狀)和無水氨(17g)接觸。該混合物經(jīng)受120大氣壓的氫在150-160℃下反應(yīng)5小時,然后冷卻并且驅(qū)凈過量氣體。通過硅藻土過濾生成的淤漿,并將濾液蒸發(fā)至原來體積的大約三分之一(大氣壓,Vigreaux(維格羅)柱)。將釜中溶液冷卻至0℃,用3體積乙醚稀釋,并以4N鹽酸的無水二氧六環(huán)溶液處理直到引起沉淀形成。通過過濾收集該固體產(chǎn)物(二環(huán)丙基甲基胺鹽酸鹽),過量乙醚洗滌,真空干燥(45.22g,306mmol,67%)。1H NMR(300MHz,甲醇-d4)d 1.94(1H,t,J=9.3Hz),1.11-0.99(2H,m),0.75-0.59(4H,m),0.48-0.37(4H,m)。MS(NH3-DCI)m/e 114(5),113(100)。部分B.把5-氨基-4,6-二氯嘧啶(5.00g,30.5mmol)和二異丙基乙胺(12.0mL,68.9mmol)在乙醇(100mL)中的溶液用來自部分A的胺(3.81g,25.8mmol)處理,加熱回流72小時。冷卻該生成的混合物并將其傾入水(300mL)中,并以乙酸乙酯(2×300mL)提取。該提取液以鹽水洗滌,合并,經(jīng)硫酸鈉干燥,過濾并蒸發(fā)。經(jīng)柱層析(30∶70乙酸乙酯-己烷)分離該粗油,并以溫?zé)岬囊颐?己烷研磨所需的產(chǎn)物5-氨基-4-氯-6-二環(huán)丙基甲基氨基嘧啶,過濾收集,并真空干燥(3.15g,13.2mmol,43%)。m.p.137-138℃。TLC RF0.17(30∶70乙酸乙酯-己烷)。1HNMR(300MHz,CDCl3)d 8.01(1H,s),4.95(1H,br d,J=7.3Hz),3.45(1H,q,J=7.0Hz),3.37(2H,br s),1.06-0.94(2H,m),0.59-0.32(8H,m)。MS(NH3-CI)m/e 243(1),242(5),241(36),240(16),239(100)。部分C.將來自部分B的二胺溶液(1.80g,7.54mmol)和1滴濃鹽酸在三乙基原丙酸酯(12mL)中的溶液加熱至100℃6小時。通過蒸餾除去過量的原酸酯(部分真空,短途徑),并且使該釜的殘余物固化,得到產(chǎn)物N-(4-氯-6-二環(huán)丙基甲基氨基嘧啶-5-基)-o-乙基-propionimidate。1H NMR(300MHz,CDCl3)d 8.08(1H,s),4.84(1H,brd,J=8.0Hz),4.35(2H,br),3.45(1H,q,J=7.7Hz),2.14(2H,q,J=7.3Hz),1.41(3H,t,J=7.1Hz),1.08(3H,t,J=7.7Hz),1.03-0.93(2H,m),0.58-0.27(8H,m)。MS(NH3-CI)m/e 327(1),326(7),325(36),324(21),323(100)。部分D.將在以上部分C中制備的imidate化合物和對-甲苯磺酸單水合物(50mg)在二苯基醚(10mL)中的溶液加熱至170℃2小時,使生成混合物冷卻,并經(jīng)柱層析(硅膠,己烷除去二苯基醚,然后30∶70乙酸乙酯-己烷)分離該生成的混合物,得到固體產(chǎn)物6-氯-9-二環(huán)丙基甲基-8-乙基嘌呤(1.42g,5.13mmol,C和D兩步驟合計收率68%)。m.p.99-100℃。TLC RF0.26(30∶70乙酸乙酯-己烷)。1H NMR(300MHz,CDCl3)d 8.63(1H,s),2.99(2H,br),1.92(1H,br),1.50(3H,t,J=7.3Hz),0.87-0.78(2H,m),0.50-0.39(4H,m),0.20-0.10(4H,m)。MS(NH3-CI)m/e 280(6),279(36),278(19),277(100)。部分E.將4-氨基-3-氯苯酚鹽酸鹽(18.6g,103mmol)和乙酸鈉(18.6g,227mmol)在冰乙酸(200mL)中的溶液加熱至溫和地回流12小時,然后冷卻并傾進(jìn)4體積水中。分批加入碳酸氫鈉中和,以乙酸乙酯(2×500mL)提取該生成的混合物。該提取液用鹽水洗滌,合并,經(jīng)硫酸鎂干燥,過濾并蒸發(fā)。并以溫?zé)岬囊颐蜒心ド傻墓腆w;過濾并真空干燥,得到4-乙酰氨基-3-氯苯酚(16.1g,86.7mmol,84%)。m.p.128-129℃。TLC RF0.14(50∶50乙酸乙酯-己烷)。1H NMR(300MHz,4∶1 CDCl3·CD3OD)d 7.66(1H,d,J=8.8Hz),6.88(1H,d J=1.7Hz),6.74(1H,dd,J=8.8,1.7Hz),2.19(3H,s)。MS(H2O-GC/MS)m/e 186(100)。部分F.將部分E的苯酚(14.6g,78.8mmol)、碘甲烷(10.0mL,160mmol)和碳酸鈉(10.0g,94.3mmol)在乙腈(200mL)中的溶液加熱回流48小時。冷卻并傾入水(800mL)中。以乙酸乙酯(2×800mL)提取。該提取液以鹽水洗滌,合并,經(jīng)硫酸鎂干燥,過濾并蒸發(fā)。從乙醚-乙酸乙酯重結(jié)晶生成的固體,得到純的產(chǎn)物2-氯-4-甲氧基-N-乙酰苯胺(13.2g,66.3mmol,84%)。m.p.118-119℃(乙醚-乙酸乙酯)。TLC RF0.30(50∶50 乙酸乙酯-己烷)。1H NMR(300MHz,CDCl3)d 8.15(1H,d,J=9.2Hz),7.39(1H,br s),6.92(1H,d J=3.0Hz),6.82(1H,dd,J=9.2,3.0Hz),3.78(3H,s),2.22(3H,s)。MS(NH3-CI)m/e 219(19),217(60),202(40),201(14),200(100)。部分G.將來自部分F的酰胺(10.1g,50.7mmol)和氫氧化鈉(10mL,5N,50mmol)在95%乙醇(200mL)中的溶液加熱至50℃24小時。然后另外加入5mL氫氧化鈉溶液,并將該混合物加熱至充分回流另外48小時。冷卻并蒸發(fā)該溶液,并且該殘余物在乙醚和水中分配。以乙醚第二次提取水相,該提取液以鹽水洗滌,合并,經(jīng)硫酸鈉干燥,過濾并蒸發(fā)。該生成的產(chǎn)物2-氯-4-甲氧基苯胺經(jīng)硅膠短柱層析并以30∶70 乙酸乙酯-己烷洗脫并蒸發(fā)洗脫劑來純化(7.98g,100%)。部分H.把來自部分G的苯胺(7.98g,50mmol)在濃HCl(25mL)中的溶液冷卻至-5℃,并用滴加亞硝酸鈉(3.80g,55.1mmol)的濃水溶液處理。30分鐘后,以15mL的環(huán)己烷和15mL二氯甲烷負(fù)荷該混合物,然后滴加碘化鉀(16.6g,100mmol)的濃水溶液處理。使該混合物攪拌4小時,然后以二氯甲烷(2×100mL)提取。連續(xù)用1N亞硫酸氫鈉水溶液(100mL)和鹽水(60mL)洗滌,然后合并,經(jīng)硫酸鎂干燥,過濾并蒸發(fā),得到足夠純的產(chǎn)物3-氯-4-碘苯甲醚(7.00g,26.1mmol,52%)。TLC RF0.39(5∶95乙酸乙酯-己烷)。1H NMR(300MHz,CDCl3)d 7.69(1H,d,J=8.8Hz),7.03(1H,d,J=3.0Hz),6.57(1H,dd,J=8.8,3.0Hz),3.78(3H,s)。MS(H2O-GC/MS)m/e 269(100)。部分I.把來自部分H的碘化物化合物(7.00g,26.1mmol)在無水四氫呋喃(50mL)中的溶液冷卻至-90℃。并用正丁基鋰(16.5mL,1.6M,26.4mmol)的己烷溶液處理。15分鐘后,以三異丙基硼酸酯(6.10mL,26.4mmol)處理該溶液,使其溫?zé)嶂镰h(huán)境溫度6小時。以6N HCl水溶液(5mL)和水(5mL)處理該生成的混合物,將其攪拌1小時,然后傾入水(100mL)中并以乙酸乙酯(2×100mL)提取。連續(xù)以1N亞硫酸氫鈉水溶液和鹽水(各80mL)洗滌該提取液,合并,經(jīng)硫酸鈉干燥,過濾并蒸發(fā),以1∶1的乙醚-己烷研磨殘余物固體,過濾收集并真空干燥,得到純的產(chǎn)物2-氯-4-甲氧基苯硼酸(3.05g,16.4mmol,63%),m.p.191-195℃。部分J.把來自部分D的氯化物(770mg,2.78mmol)、來自部分I的硼酸(770mg,4.13mmol)、2N的碳酸鈉水溶液(4mL,8mmol)和三苯基膦(164mg,0.625mmol)在DME(20mL)中的溶液通過用短真空泵反復(fù)循環(huán)壓脫氣,隨后以氮氣清洗。向其中加入乙酸鈀(II)(35mg,0.156mmol),然后再次使該混合物脫氣并然后加熱回流14小時。使之冷卻,并傾入水(100mL)中。以乙酸乙酯(2×100mL)提取該混合物,并且該提取液連續(xù)以鹽水(60mL)洗滌,合并,經(jīng)硫酸鈉干燥,過濾并蒸發(fā)。經(jīng)柱層析(硅膠,15∶85乙酸乙酯-己烷)分離該殘余物,得到固體標(biāo)題化合物。它經(jīng)己烷重結(jié)晶純化(791mg,2.07mmol,74%)。m.p.139-140℃(己烷)。TLC RF0.18(30∶70乙酸乙酯-己烷)。1H NMR(300MHz,CDCl3)d 8.93(1H,s),7.74(1H,d,J=8.4,Hz),7.10(1H,d,J=2.6Hz),6.96(1H,dd,J=8.4,2.6Hz),4.20(1H,v br),3.87(3H,s),2.97(2H,v br),2.00(2H,v br),1.44(3H,br t,J=7Hz),0.89-0.79(2H,m),0.62-0.52(2H,m),0.51-0.40(2H,m),0.26-0.16(2H,m).MS(NH3-CI)m/e387(1),386(9),385(41),384(30),383(100)。C21H23ClN4O的分析計算值C,65.87;H,6.05;N,14.63;實測值C,65.77;H,6.03;N,14.57。
      在表1、表1A和表1B中相應(yīng)于結(jié)構(gòu)化合物的熔點除非另外指明。表1
      實施R2XR3R4R5R11R6R1aR1bmp例號 ℃a1 CH3CH2HCH3CH3HCH3C2H5C2H5128-1292 CH3CH2HCH3CH3HCH3C2H5C4H999-1003 CH3CH2HCH3CH3HCH3C2H5CH2OCH3油4 CH3CH2HCH3CH3HCH3C2H5C6H5-5 CH3CH2HCH3CH3HCH3C2H5c-C3H5143-1456 CH3CH2HCH3CH3HCH3C2H5C6H13-7 CH3CH2HCH3CH3HCH3C2H5C3H768-718 CH3CH2HCH3CH3HCH3C2H5(CH2)2OCH3油9 CH3CH2HCH3CH3HCH3C2H5(CH2)2OH 196-19710CH3CH2HCH3CH3HCH3C2H5(CH2)2-(Q1)b油11CH3CH2HCH3CH3HCH3C2H5(CH2)2-(Q2)b油12CH3CH2HCH3CH3HCH3C2H5CH2N(CH3)2-13CH3CH2HCH3CH3HCH3c-C3H5C4H9120-12114CH3CH2HCH3CH3HCH3c-C3H5(CH2)2OH 209-21015CH3CH2HCH3CH3HCH3c-C3H5H140-15016CH3CH2HCH3CH3HCH3c-C3H5c-C3H5186-18717CH3CH2HCH3CH3HCH3HC6H5121-12218CH3CH2HCH3CH3HCH3H 3-(CH3O)-C6H4油19CH3CH2HCH3CH3HCH3H 2-Br-C6H484-8520CH3CH2HCH3CH3HCH3H 4-CH3-C6H448-5021CH3CH2HCH3CH3HCH3H 4-C6H5-C6H4-22CH3CH2HCH3CH3HCH3H 2-(C4H9)-C4H9-23CH3CH2HCH3CH3HCH3H 3-(C4H9)-C5H10-24CH3CH2HCH3CH3HCH3H (CH2)2OCH3-25CH3CH2HCH3CH3HCH3H CH2OCH3-26CH3CH2HCH3CH3HCH3H C2H5120-12327CH3CH2HCH3CH3HCH3H C3H7油28CH3CH2HCH3CH3HCH3H C4H9油29CH3CH2HCH3CH3HCH3CH2OCH3CH2OCH3-30CH3CH2HCH3CH3HCH3C2H5OC2H591-9331CH3CH2HCH3CH3HCH3H (CH3)2CH 120-12132CH3CH2HCH3CH3HCH3H O(CH2)2-OCH3-33CH3CH2HCH3CH3HCH3CH2OCH3C6H5-34CH3CH2HCl Cl HH C2H5C2H5油35CH3CH2HCl Cl HH C2H5C4H9油36CH3CH2HCl Cl HH C2H5CH2OCH3-37CH3CH2HCl Cl HH C2H5C6H5-38CH3CH2HCl Cl HH C2H5c-C3H5油(A)118-119(B)125-126(C)39CH3CH2HCl Cl HH C2H5C6H13-40CH3CH2HCl Cl HH C2H5C3H7油41CH3CH2HCl Cl HH C2H5(CH2)2OCH3-42CH3CH2HCl Cl HH C2H5CH2CN-43CH3CH2HCl Cl HH C2H5(CH2)2-(Q1)b-44CH3CH2HCl Cl HH C2H5(CH2)2-(Q2)c-45CH3CH2HCl Cl HH C2H5CH2N(CH3)2-46CH3CH2HCl Cl HH c-C3H5C4H9-47CH3CH2HCl Cl HH c-C3H5CH2OCH3-48CH3CH2HCl Cl HH c-C3H5C6H5油49CH3CH2HCl Cl HH c-C3H5c-C3H5156-15750CH3CH2HCl Cl HH H C6H5油51CH3CH2HCl Cl HH H 3-(CH3O)-C6H4油52CH3CH2HCl Cl HH H 2-Br-C6H4-53CH3CH2HCl Cl HH H 4-CH3-C6H4114-11554CH3CH2HCl Cl HH H 4-C6H5-C6H4油55CH3CH2HCl Cl HH H 2-(C4H9)-C4H9-56CH3CH2HCl Cl HH H 3-(C4H9)-C5H10-57CH3CH2HCl Cl HH H (CH2)2OCH3-58CH3CH2HCl Cl HH H CH2OCH3-59CH3CH2HCl Cl HH H C2H5-60CH3CH2HCl Cl HH H C3H7-61CH3CH2HCl Cl HH H C4H9-62CH3CH2HCl Cl HH CH2OCH3CH2OCH3-63CH3CH2HCl Cl HH C2H5OC2H5-64CH3CH2HCl Cl HH H OC2H5-65CH3CH2HCl Cl HH H O(CH2)2-OCH3-66CH3CH2HCl Cl HH CH2OCH3C6H5-67CH3CH2HCH3OCH3H CH3C2H5C2H5-68CH3CH2HCH3OCH3H CH3C2H5C4H9油69CH3CH2HCH3OCH3H CH3C2H5CH2OCH3-70CH3CH2HCH3OCH3H CH3C2H5C6H5-71CH3CH2HCH3OCH3H CH3C2H5c-C3H5-72CH3CH2HCH3OCH3H CH3C2H5C6H13-73CH3CH2HCH3OCH3H CH3C2H5C3H7-74CH3CH2HCH3OCH3H CH3C2H5(CH2)2OCH3-75CH3CH2HCH3OCH3H CH3C2H5CH2CN-76CH3CH2HCH3OCH3H CH3C2H5(CH2)2-(Q1)b-77CH3CH2HCH3OCH3H CH3C2H5(CH2)2-(Q2)c-78CH3CH2HCH3OCH3H CH3C2H5CH2N(CH3)2-79CH3CH2HCH3OCH3H CH3c-C3H5C4H9-80CH3CH2HCH3OCH3H CH3c-C3H5CH2OCH3-81CH3CH2HCH3OCH3H CH3c-C3H5C6H5-82CH3CH2HCH3OCH3H CH3c-C3H5c-C3H5167-16983CH3CH2HCH3OCH3H CH3H C6H5134-13584CH3CH2HCH3OCH3H CH3H 3-(CH3O)-C6H4-85CH3CH2HCH3OCH3H CH3H 2-Br-C6H4-86CH3CH2HCH3OCH3H CH3H 4-CH3-C6H4-87CH3CH2HCH3OCH3H CH3H 4-C6H5-C6H4-88CH3CH2HCH3OCH3H CH3H 2-(C4H9)-C4H9-89CH3CH2HCH3OCH3H CH3H 3-(C4H9)-C5H10-90CH3CH2HCH3OCH3H CH3H (CH2)2OCH3-91CH3CH2HCH3OCH3H CH3H CH2OCH3-92CH3CH2HCH3OCH3H CH3H C2H5-93 CH3CH2HCH3OCH3HCH3H C3H7-94 CH3CH2HCH3OCH3HCH3H C4H9-95 CH3CH2HCH3OCH3HCH3CH2OCH3CH2OCH3-96 CH3CH2HCH3OCH3HCH3C2H5OC2H5-97 CH3CH2HCH3OCH3HCH3H OC2H5-98 CH3CH2HCH3OCH3HCH3H O(CH2)2-OCH3-99 CH3CH2HCH3OCH3HCH3CH2OCH3C6H5-100CH3CH2HCH3CH3HCH3H CH3138-140101H CH2HCH3CH3HCH3C2H5C2H5198-199102H CH2HCH3CH3HCH3C2H5C4H9147-148103H CH2HCH3CH3HCH3C2H5CH2OCH3140-142104H CH2HCH3CH3HCH3C2H5C6H5-105H CH2HCH3CH3HCH3C2H5c-C3H5-106H CH2HCH3CH3HCH3C2H5C6H13-107H CH2HCH3CH3HCH3C2H5C3H7-108H CH2HCH3CH3HCH3C2H5(CH2)2OCH3-109H CH2HCH3CH3HCH3C3H5CH2CN-110H CH2HCH3CH3HCH3C2H5(CH2)2-(Q1)b-111H CH2HCH3CH3HCH3C2H5(CH2)2-(Q2)c-112H CH2HCH3CH3HCH3C2H5CH2N(CH3)2-113H CH2HCH3CH3HCH3c-C3H5C4H9-114H CH2HCH3CH3HCH3c-C3H5CH2OCH3-115H CH2HCH3CH3HCH3c-C3H5C6H5-116H CH2HCH3CH3HCH3c-C3H5c-C3H5-117H CH2HCH3CH3HCH3H C6H5-118H CH2HCH3CH3HCH3H 3-(CH3O)-C6H4-119H CH2HCH3CH3HCH3H 2-Br-C6H4-120H CH2HCH3CH3HCH3H 4-CH3-C6H6-121H CH2HCH3CH3HCH3H 4-C6H5-C6H4-122H CH2HCH3CH3HCH3H 3-C7H15油123H CH2HCH3CH3HCH3H 2-(C2H5)-C6H12油124H CH2HCH3CH3HCH3H (CH2)2OCH3-125H CH2HCH3CH3HCH3H CH2OCH3-126H CH2HCH3CH3HCH3H C2H5-127H CH2HCH3CH3HCH3H C3H7-128H CH2HCH3CH3HCH3H C4H9-129H CH2HCH3CH3HCH3CH2OCH3CH2OCH3-130H CH2HCH3CH3HCH3C2H5OC2H5-131H CH2HCH3CH3HCH3H OC2H5-132H CH2HCH3CH3HCH3H O(CH2)2-OCH3-133HCH2HCH3CH3HCH3CH2OCH3C6H5-134HCH2HCl Cl HH C2H5C2H5-135HCH2HCl Cl HH C2H5C4H9-136HCH2HCl Cl HH C2H5CH2OCH3-137HCH2HCl Cl HH C2H5C6H5-138HCH2HCl Cl HH C2H5c-C3H5-139HCH2HCl Cl HH C2H5C6H13-140HCH2HCl Cl HH C2H5C3H7-141HCH2HCl Cl HH C2H5(CH2)2OCH3-142HCH2HCl Cl HH C2H5CH2CN -143HCH2HCl Cl HH C2H5(CH2)2-(Q1)b-144HCH2HCl Cl HH C2H5(CH2)2-(Q2)c-145HCH2HCl Cl HH C2H5CH2N(CH3)2-146HCH2HCl Cl HH c-C3H5C4H9-147HCH2HCl Cl HH c-C3H5CH2OCH3-148HCH2HCl Cl HH c-C3H5C6H5-149HCH2HCl Cl HH c-C3H5c-C3H5-150HCH2HCl Cl HH H C6H5151HCH2HCl Cl HH H 3-(CH3O)-C6H4-152HCH2HCl Cl HH H 2-Br-C6H4-153HCH2HCl Cl HH H 4-CH3-C6H4-154HCH2HCl Cl HH H 4-C6H5-C6H4-155HCH2HCl Cl HH H 2-(C4H9)-C4H9-156HCH2HCl Cl HH H 3-(C4H9)-C5H10-157HCH2HCl Cl HH H (CH2)2OCH3-158HCH2HCl Cl HH H CH2OCH3-159HCH2HCl Cl HH H C2H5-160HCH2HCl Cl HH H C3H7-161HCH2HCl Cl HH H C4H9-162HCH2HCl Cl HH CH2OCH3CH2OCH3-163HCH2HCl Cl HH C2H5OC2H5-164HCH2HCl Cl HH H OC2H5-165HCH2HCl Cl HH H O(CH2)2-OCH3-166HCH2HCl Cl HH CH2OCH3C6H5-167HCH2HCH3OCH3HCH3C2H5C2H5-168HCH2HCH3OCH3HCH3C2H5C4H9-169HCH2HCH3OCH3HCH3C2H5CH2OCH3-170HCH2HCH3OCH3HCH3C2H5C6H5-171HCH2HCH3OCH3HCH3C2H5c-C3H5-172HCH2HCH3OCH3HCH3C2H5C6H13-173H CH2HCH3OCH3HCH3C2H5C3H7-174H CH2HCH3OCH3HCH3C2H5(CH2)2OCH3-175H CH2HCH3OCH3HCH3C2H5CH2CN -176H CH2HCH3OCH3HCH3C2H5(CH2)2-(Q1)b-177H CH2HCH3OCH3HCH3C2H5(CH2)2-(Q2)c-178H CH2HCH3OCH3HCH3C2H5CH2N(CH3)2-179H CH2HCH3OCH3HCH3c-C3H5C4H9-180H CH2HCH3OCH3HCH3c-C3H5CH2OCH3-181H CH2HCH3OCH3HCH3c-C3H5C6H5-182H CH2HCH3OCH3HCH3c-C3H5c-C3H5-183H CH2HCH3OCH3HCH3H C6H5-184H CH2HCH3OCH3HCH3H 3-(CH3O)-C6H4-185H CH2HCH3OCH3HCH3H 2-Br-C6H4-186H CH2HCH3OCH3HCH3H 4-CH3-C6H4-187H CH2HCH3OCH3HCH3H 4-C6H5-C6H4-188H CH2HCH3OCH3HCH3H 2-(C4H9)-C4H9-189H CH2HCH3OCH3HCH3H 3-(C4H9)-C5H10-190H CH2HCH3OCH3HCH3H (CH2)2OCH3-191H CH2HCH3OCH3HCH3H CH2OCH3-192H CH2HCH3OCH3HCH3H C2H5-193H CH2HCH3OCH3HCH3H C3H7-194H CH2HCH3OCH3HCH3H C4H9-195H CH2HCH3OCH3HCH3CH2OCH3CH2OCH3-196H CH2HCH3OCH3HCH3C2H5OC2H5-197H CH2HCH3OCH3HCH3H OC2H5-198H CH2HCH3OCH3HCH3H O(CH2)2-OCH3-199H CH2HCH3OCH3HCH3CH2OCH3C6H5-200CH3CH2HCH3CH3HCH3CH3C2H598-100201CH3O HCH3CH3HCH3C2H5C2H5-202CH3O HCH3CH3HCH3C2H5C4H9油203CH3O HCH3CH3HCH3C2H5CH2OCH3-204CH3O HCH3CH3HCH3C2H5C6H5-205CH3O HCH3CH3HCH3C2H5c-C3H5-206CH3O HCH3CH3HCH3C2H5C6H13-207CH3O HCH3CH3HCH3C2H5C3H7-208CH3O HCH3CH3HCH3C2H5(CH2)2OCH3-209CH3O HCH3CH3HCH3C2H5CH2CN-210CH3O HCH3CH3HCH3C2H5(CH2)2-(Q1)b-211CH3O HCH3CH3HCH3C2H5(CH2)2-(Q2)c-212CH3O HCH3CH3HCH3C2H5CH2N(CH3)2-213CH3OHCH3CH3HCH3c-C3H5C4H9-214CH3OHCH3CH3HCH3c-C3H5CH2OCH3-215CH3OHCH3CH3HCH3c-C3H3C6H5-216CH3OHCH3CH3HCH3c-C3H5c-C3H5-217CH3OHCH3CH3HCH3H C6H5-218CH3OHCH3CH3HCH3H 3-(CH3O)-C6H4-219CH3OHCH3CH3HCH3H 2-Br-C6H4-220CH3OHCH3CH3HCH3H 4-CH3-C6H4-221CH3OHCH3CH3HCH3H 4-C6H5-C6H4-222CH3OHCH3CH3HCH3H 2-(C4H9)-C4H9-223CH3OHCH3CH3HCH3H 3-(C4H9)-C5H10-224CH3OHCH3CH3HCH3H (CH2)2OCH3-225CH3OHCH3CH3HCH3H CH2OCH3-226CH3OHCH3CH3HCH3H C2H5-227CH3OHCH3CH3HCH3H C3H7-228CH3OHCH3CH3HCH3H C4H9-229CH3OHCH3CH3HCH3CH2OCH3CH2OCH3-230CH3OHCH3CH3HCH3C2H5OC2H5-231CH3OHCH3CH3HCH3C3H7OC2H5-232CH3OHCH3CH3HCH3H O(CH2)2-OCH3-233CH3OHCH3CH3HCH3CH2OCH3C6H5-234CH3OHCl Cl HH C2H5C2H5-235CH3OHCl Cl HH C2H5C4H9-236CH3OHCl Cl HH C2H5CH2OCH3-237CH3OHCl Cl HH C2H5C6H5-238CH3OHCl Cl HH C2H5c-C3H5-239CH3OHCl Cl HH C2H5C6H13-240CH3OHCl Cl HH C2H5C3H7-241CH3OHCl Cl HH C2H5(CH2)2OCH3-242CH3OHCl Cl HH C2H5CH2CN -243CH3OHCl Cl HH C2H5(CH2)2-(Q1)b-244CH3OHCl Cl HH C2H5(CH2)2-(Q2)c-245CH3OHCl Cl HH C2H5CH2N(CH3)2-246CH3OHCl Cl HH c-C3H5C4H9-247CH3OHCl Cl HH c-C3H5CH2OCH3-248CH3OHCl Cl HH c-C3H5C6H5-249CH3OHCl Cl HH c-C3H5c-C3H5132-134250CH3OHCl Cl HH H C6H5-251CH3OHCl Cl HH H 3-(CH3O)-C6H4-252CH3OHCl Cl HH H 2-Br-C6H4-253CH3OHCl Cl H H H 4-CH3-C6H4-254CH3OHCl Cl H H H 4-C6H5-C6H4-255CH3OHCl Cl H H H 2-(C4H9)-C4H9-256CH3OHCl Cl H H H 3-(C4H9)-C5H10-257CH3OHCl Cl H H H (CH2)2OCH3-258CH3OHCl Cl H H H CH2OCH3-259CH3OHCl Cl H H H C2H5-260CH3OHCl Cl H H H C3H7-261CH3OHCl Cl H H H C4H9-262CH3OHCl Cl H H CH2OCH3CH2OCH3-263CH3OHCl Cl H H C2H5OC2H5-264CH3OHCl Cl H H H OC2H5-265CH3OHCl Cl H H H O(CH2)2-OCH3-266CH3OHCl Cl H H CH2OCH3C6H5-267CH3OHCH3OCH3HCH3C2H5C2H5-268CH3OHCH3OCH3HCH3C2H5C4H9-269CH3OHCH3OCH3HCH3C2H5CH2OCH3-270CH3OHCH3OCH3HCH3C2H5C6H5-271CH3OHCH3OCH3HCH3C2H5c-C3H5-272CH3OHCH3OCH3HCH3C2H5C6H13-273CH3OHCH3OCH3HCH3C2H5C3H7-274CH3OHCH3OCH3HCH3C2H5(CH2)2OCH3-275CH3OHCH3OCH3HCH3C2H5CH2CN-276CH3OHCH3OCH3HCH3C2H5(CH2)2-(Q1)b-277CH3OHCH3OCH3HCH3C2H5(CH2)2-(Q2)c-278CH3OHCH3OCH3HCH3C2H5CH2N(CH3)2-279CH3OHCH3OCH3HCH3c-C3H5C4H9-280CH3OHCH3OCH3HCH3c-C3H5CH2OCH3-281CH3OHCH3OCH3HCH3c-C3H5C6H5-282CH3OHCH3OCH3HCH3c-C3H5c-C3H5-283CH3OHCH3OCH3HCH3H C6H5-284CH3OHCH3OCH3HCH3H 3-(CH3O)-C6H4-285CH3OHCH3OCH3HCH3H 2-Br-C6H4-286CH3OHCH3OCH3HCH3H 4-CH3-C6H4-287CH3OHCH3OCH3HCH3H 4-C6H5-C6H4-288CH3OHCH3OCH3HCH3H 2-(C4H9)-C4H9-289CH3OHCH3OCH3HCH3H 3-(C4H9)-C5H10-290CH3OHCH3OCH3HCH3H (CH2)2OCH3-291CH3OHCH3OCH3HCH3H CH2OCH3-292CH3OHCH3OCH3HCH3H C2H5-293CH3O H CH3OCH3HCH3H C3H7-294CH3O H CH3OCH3HCH3H C4H9-295CH3O H CH3OCH3HCH3CH2OCH3CH2OCH3-296CH3O H CH3OCH3HCH3C2H5OC2H5-297CH3O H CH3OCH3HCH3H OC2H5-298CH3O H CH3OCH3HCH3H O(CH2)2-OCH3-299CH3O H CH3OCH3HCH3CH2OCH3C6H5-300CH3CH2CH3HCl HH c-C3H5c-C3H5106-109301CH3S H CH3CH3HCH3C2H5C2H5-302CH3S H CH3CH3HCH3C2H5C4H9-303CH3S H CH3CH3HCH3C2H5CH2OCH3-304CH3S H CH3CH3HCH3C2H5C6H5-305CH3S H CH3CH3HCH3C2H5c-C3H5-306CH3S H CH3CH3HCH3C2H5C6H13-307CH3S H CH3CH3HCH3C2H5C3H7-308CH3S H CH3CH3HCH3C2H3(CH2)2OCH3-309CH3S H CH3CH3HCH3C2H5CH2CN-310CH3S H CH3CH3HCH3C2H5(CH2)2-(Q1)b-311CH3S H CH3CH3HCH3C2H5(CH2)2-(Q2)c-312CH3S H CH3CH3HCH3C2H5CH2N(CH3)2-313CH3S H CH3CH3HCH3c-C3H5C4H9-314CH3S H CH3CH3HCH3c-C3H5CH2OCH3-315CH3S H CH3CH3HCH3c-C3H5C6H5-316CH3S H CH3CH3HCH3c-C3H5c-C3H5-317CH3S H CH3CH3HCH3H C6H5-318CH3S H CH3CH3HCH3H 3-(CH3O)-C6H4-319CH3S H CH3CH3HCH3H 2-Br-C6H4-320CH3S H CH3CH3HCH3H 4-CH3-C6H4-321CH3S H CH3CH3HCH3H 4-C6H5-C6H4-322CH3S H CH3CH3HCH3H 2-(C4H9)-C4H9-323CH3S H CH3CH3HCH3H 3-(C4H9)-C5H10-324CH3S H CH3CH3HCH3H (CH2)2OCH3-325CH3S H CH3CH3HCH3H CH2OCH3-326CH3S H CH3CH3HCH3H C2H5-327CH3S H CH3CH3HCH3H C3H7-328CH3S H CH3CH3HCH3H C4H9-329CH3S H CH3CH3HCH3CH2OCH3CH2OCH3-330CH3S H CH3CH3HCH3C2H5OC2H5-331CH3S H CH3CH3HCH3H OC2H5-332CH3S H CH3CH3HCH3H O(CH2)2-OCH3-333CH3S HCH3CH3HCH3CH2OCH3C6H5-334CH3SHCl Cl HH C2H5C2H5-335CH3SHCl Cl HH C2H5C4H9-336CH3SHCl Cl HH C2H5CH2OCH3-337CH3SHCl Cl HH C2H5C6H5-338CH3SHCl Cl HH C2H5c-C3H5-339CH3SHCl Cl HH C2H5C6H13-340CH3SHCl Cl HH C2H5C3H7-341CH3SHCl Cl HH C2H5(CH2)2OCH3-342CH3SHCl Cl HH C2H5CH3CN-343CH3SHCl Cl HH C2H5(CH2)2-(Q1)b-344CH3SHCl Cl HH C2H5(CH2)2-(Q2)c-345CH3SHCl Cl HH C2H5CH2N(CH3)2-346CH3SHCl Cl HH c-C3H5C4H9-347CH3SHCl Cl HH c-C3H5CH2OCH3-348CH3SHCl Cl HH c-C3H5C6H5-349CH3SHCl Cl HH c-C3H5c-C3H5-350CH3SHCl Cl HH H C6H5-351CH3SHCl Cl HH H 3-(CH3O)-C6H4-352CH3SHCl Cl HH H 2-Br-C6H4-353CH3SHCl Cl HH H 4-CH3-C6H4-354CH3SHCl Cl HH H 4-C6H5-C6H4-355CH3SHCl Cl HH H 2-(C4H9)-C4H9-356CH3SHCl Cl HH H 3-(C4H9)-C5H10-357CH3SHCl Cl HH H (CH2)2OCH3-358CH3SHCl Cl HH H CH2OCH3-359CH3SHCl Cl HH H C2H5-360CH3SHCl Cl HH H C3H7-361CH3SHCl Cl HH H C4H9-362CH3SHCl Cl HH CH2OCH3CH2OCH3-363CH3SHCl Cl HH C2H5OC2H5-364CH3SHCl Cl HH H OC2H5-365CH3SHCl Cl HH H O(CH2)2-OCH3-366CH3SHCl Cl HH CH2OCH3C6H5-367CH3SHCH3OCH3HCH3C2H5C2H5-368CH3SHCH3OCH3HCH3C2H5C4H9-369CH3SHCH3OCH3HCH3C2H5CH2OCH3-370CH3SHCH3OCH3HCH3C2H5C6H5-371CH3SHCH3OCH3HCH3C2H5c-C3H5-372CH3SHCH3OCH3HCH3C2H5C6H13-373CH3S H CH3OCH3HCH3C2H5C3H7-374CH3S H CH3OCH3HCH3C2H5(CH2)2OCH3-375CH3S H CH3OCH3HCH3C2H5CH2CN-376CH3S H CH3OCH3HCH3C2H5(CH2)2-(Q1)b-377CH3S H CH3OCH3HCH3C2H5(CH2)2-(Q2)c-378CH3S H CH3OCH3HCH3C2H5CH2N(CH3)2-379CH3S H CH3OCH3HCH3c-C3H5C4H9-380CH3S H CH3OCH3HCH3c-C3H5CH2OCH3-381CH3S H CH3OCH3HCH3c-C3H5C6H5-382CH3S H CH3OCH3HCH3c-C3H5c-C3H5-383CH3S H CH3OCH3HCH3H C6H5-384CH3S H CH3OCH3HCH3H 3-(CH3O)-C6H4-385CH3S H CH3OCH3HCH3H 2-Br-C6H4-386CH3S H CH3OCH3HCH3H 4-CH3-C6H4-387CH3S H CH3OCH3HCH3H 4-C6H5-C6H4-388CH3S H CH3OCH3HCH3H 2-(C4H9)-C4H9-389CH3S H CH3OCH3HCH3H 3-(C4H9)-C5H10-390CH3S H CH3OCH3HCH3H (CH2)2OCH3-391CH3S H CH3OCH3HCH3H CH2OCH3-392CH3S H CH3OCH3HCH3H C2H5-393CH3S H CH3OCH3HCH3H C3H7-394CH3S H CH3OCH3HCH3H C4H9-395CH3S H CH3OCH3HCH3CH2OCH3CH2OCH3-396CH3S H CH3OCH3HCH3C2H5OC2H5-397CH3S H CH3OCH3HCH3H OC2H5-398CH3S H CH3OCH3HCH3H O(CH2)2-OCH3-399CH3S H CH3OCH3HCH3CH2OCH3C6H5-400CH3CH2H Cl Cl HCH3C3H7c-C3H5153-156401CH3CH2CH3CH3CH3HCH3C2H5C2H5-402CH3CH2CH3CH3CH3HCH3c-C3H5C4H9107-108403CH3CH2CH3CH3CH3HCH3c-C3H5c-C3H5187-188404CH3CH2CH3CH3CH3HCH3H C4H9油405CH3CH2CH3CH3CH3HCH3C2H5C4H998-99406CH3CH2CH3CH3CH3HCH3H C6H5149-150407CH3CH2CH3CH3CH3HCH3C2H5(CH2)2OCH3-408CH3CH2CH3CH3CH3HCH3H (CH2)2OCH3-409CH3CH2CH3CH3CH3HCH3CH2OCH3CH2OCH3-410CH3CH3CH3CH3CH3HCH3C2H5CH2OCH3-411CH3CH2H CH3Cl HH C2H5C2H5-412CH3CH2H CH3Cl HH c-C3H5C4H9-413CH3CH2HCH3Cl HH c-C3H5c-C3H5139-140414CH3CH2HCH3Cl HH CH3C3H7油(A,C)415CH3CH2HCH3Cl HH C2H5C4H9油416CH3CH2HCH3Cl HH H C6H5-417CH3CH2HCH3Cl HH C2H5(CH2)2OCH3-418CH3CH2HCH3Cl HH H (CH2)2OCH3-419CH3CH2HCH3Cl HH CH2OCH3CH2OCH3-420CH3CH2HCH3Cl HH C2H5CH2OCH3-421CH3CH2HCl CH3HH C2H5C2H5-422CH3CH2HCl CH3HH c-C3H5C4H9-423CH3CH2HCl CH3HH c-C3H5c-C3H5177-178424CH3CH2HCl CH3HH CH3C3H7油425CH3CH2HCl CH3HH C2H5C4H9-426CH3CH2HCl CH3HH H C6H5-427CH3CH2HCl CH3HH C2H5(CH2)2OCH3-428CH3CH2HCl CH3HH H (CH2)2OCH3-429CH3CH2HCl CH3HH CH2OCH3CH2OCH3-430CH3CH2HCl CH3HH C2H5CH2OCH3-431CH3CH2HCl Cl HOCH3C3H7c-C3H5141-144432CH3CH2HCH3CH3HOCH3C2H5C3H7108-110433CH3CH2HCl Cl HCH3c-C3H5c-C3H5194-195434CH3CH2HCH3CH3HCH3C2H5c-C3H5CH2油435CH3CH2HCH3CH3HCH3C2H5CH2OH 155-157436CH3CH2HCH3OCH3HH C2H5c-C3H5CH2油437CH3CH2HCH3OCH3HH CH3C3H7油438CH3CH2HCH3OCH3HH H 4-(CH3O)-C6H4油439CH3CH2HCH3OCH3HH C2H5c-C3H5油440CH3CH2HCH3OCH3HH CH3C5H11油441CH3CH2HCl NMe2HH C2H5C2H5-442CH3CH2HCl NMe2HH c-C3H5C4H9-443CH3CH2HCl NMe2HH c-C3H5c-C3H5-444CH3CH2HCl NMe2HH H C3H7-445CH3CH2HCl NMe2HH C2H5C4H9-446CH3CH2HCl NMe2HH H C6H5-447CH3CH2HCl NMe2HH C2H5(CH2)2OCH3-448CH3CH2HCl NMe2HH H (CH2)2OCH3-449CH3CH2HCl NMe2HH CH2OCH3CH2OCH3-450CH3CH2HCl NMe2HH C2H5CH2OCH3-451CH3CH2HCH3NMe2HH C2H5C2H5-452CH3CH2H CH3NMe2HH c-C3H5C4H9-453CH3CH2H CH3NMe2HH c-C3H5c-C3H5-454CH3CH2H CH3NMe2HH H C3H7-455CH3CH2H CH3NMe2HH C2H5C4H9-456CH3CH2H CH3NMe2HH H C6H5-457CH3CH2H CH3NMe2HH C2H5(CH2)2OCH3-458CH3CH2H CH3NMe2HH H (CH2)2OCH3-459CH3CH2H CH3NMe2HH CH2OCH3CH2OCH3-460CH3CH2H CH3NMe2HH C2H5CH2OCH3-461CH3CH2NMe2CH3CH3HCH3C2H5C2H5-462CH3CH2NMe2CH3CH3HCH3c-C3H5C4H9-463CH3CH2NMe2CH3CH3HCH3c-C3H5c-C3H5-464CH3CH2NMe2CH3CH3HCH3H C3H5-465CH3CH2NMe2CH3CH3HCH3C2H5C4H9-466CH3CH2NMe2CH3CH3HCH3H C6H5-467CH3CH2NMe2CH3CH3HCH3C2H5(CH2)2OCH3-468CH3CH2NMe2CH3CH3HCH3H (CH2)2OCH3-469CH3CH2NMe2CH3CH3HCH3CH2OCH3CH2OCH3-470CH3CH2NMe2CH3CH3HCH3C2H3CH2OCH3-471C2H5CH2H CH3CH3HCH3C2H5C2H5-472C2H5CH2H CH3CH3HCH3c-C3H5C4H9-473C2H5CH2H CH3CH3HCH3c-C3H5c-C3H5-474C2H5CH2H CH3CH3HCH3H C3H7-475C2H5CH3H CH3CH3HCH3C2H5C4H992-95476C2H5CH2H CH3CH3HCH3H C6H5-477C2H5CH2H CH3CH3HCH3C2H5(CH2)2OCH3-478C2H5CH2H CH3CH3HCH3H (CH2)2OCH3-479C2H5CH2H CH3CH3HCH3CH2OCH3CH2OCH3-480C2H5CH2H CH3CH3HCH3C2H5CH2OCH3-481CH3CHCH3H CH3CH3HCH3C2H5C2H5-482CH3CHCH3H CH3CH3HCH3c-C3H5C4H9-483CH3CHCH3H CH3CH3HCH3c-C3H5c-C3H5-484CH3CHCH3H CH3CH3HCH3H C3H7-485CH3CHCH3H CH3CH3HCH3C2H5C4H9-486CH3CHCH3H CH3CH3HCH3H C6H5-487CH3CHCH3H CH3CH3HCH3C2H5(CH2)2OCH3-488CH3CHCH3H CH3CH3HCH3H (CH2)2OCH3-489CH3CHCH3H CH3CH3HCH3CH2OCH3CH2OCH3-490CH3CHCH3H CH3CH3HCH3C2H5CH2OCH3-491CH3CH2H CH3CH3HH C2H5C2H596-97492CH3CH2HCH3CH3HH c-C3H5C4H9-493CH3CH2HCH3CH3HH c-C3H5c-C3H5149-150494CH3CH2HCH3CH3HH H C3H799-100495CH3CH2HCH3CH3HH C2H5C4H9-496CH3CH2HCH3CH3HH H C6H5-497CH3CH2HCH3CH3HH C2H5(CH2)2OCH3-498CH3CH2HCH3CH3HH H (CH2)2OCH3-499CH3CH2HCH3CH3HH CH2OCH3CH2OCH3-500CH3CH2HCH3CH3HH C2H5CH2OCH3-501CH3CH2HCH3CH3HCH3CH3C3H7-502CH3CH2HCH3CH3HCH3CH3C4H9油503CH3CH2HCH3CH3HCH3CH3C5H11油504CH3CH2HCH3CH3HCH3C2H52-C4H9109-110505CH3CH2HCH3CH3HCH3C2H5CH2OC2H5-506CH3CH2HCl Cl HH CH3C3H7油(A,B,C)507CH3CH2HCl Cl HH CH3C4H9油508CH3CH2HCl Cl HH CH3C5H11-509CH3CH2HCl Cl HH C2H52-C4H9-510CH3CH2HCl Cl HH C2H5CH2OC2H5-511CH3CH2HCl CF3HH C2H5c-C3H5油(A)78-80(B)116-117(C)512CH3CH2HCl CF3HH c-C3H5c-C3H5145-146513CH3CH2HCl CF3HH C2H5C4H9油514CH3CH2HCl CF3HH C2H5C2H5油515CH3CH2HCl CF3HH C2H5CH2OC2H5-516CH3CH2HOCH3Cl HCl C2H5c-C3H5-517CH3CH2HOCH3Cl HCl c-C3H5c-C3H5183-184518CH3CH2HOCH3Cl HCl C2H5C4H9109-110519CH3CH2HOCH3Cl HCl C2H5(CH2)2OCH3-520CH3CH2HOCH3Cl HCl C2H5CH2OC2H5-521CH3CH2HCH3CH3HCH3C3H7C3H7115-120522CH3O HCH3CH3HCH3C3H7C3H7-523CH3CH2HCl Cl HH C3H7C3H799-101524CH3CH2HCH3OCH3HH C3H7C3H7油525CH3CH2HOCH3CH3HCH3C3H7C3H7109-111526CH3CH2HCH3Cl H H C3H7C3H7油527CH3CH2HCH3CH3CH3H C3H7C3H7-528CH3CH2HCl CF3H H C3H7C3H7油529CH3CH2HCl CF3H ClC3H7C3H7-530CH3CH3HOCH3Cl H ClC3H7C3H7129-131531CH3CH2HCH3CH3H CH3CH3(CH3)2CHCH277-85532CH3O HCH3CH3H CH3CH3(CH3)2CHCH2-533CH3CH2HCl Cl H H CH3(CH3)2CHCH2-534CH3CH2HCH3OCH3H H CH3(CH3)2CHCH2-535CH3CH2HOCH3CH3H CH3CH3(CH3)2CHCH2-536CH3CH2HCH3Cl H H CH3(CH3)2CHCH2-537CH3CH2HCH3CH3CH3H CH3(CH3)2CHCH2-538CH3CH2HCl CF3H H C2H5(CH3)2CH 油539CH3CH2HCl CF3H ClCH3(CH3)2CHCH2-540CH3CH2HOCH3Cl H ClCH3(CH3)2CHCH2-541CH3CH2HCH3CH3H CH3CH3c-C3H5118-127542CH3O HCH3CH3H CH3CH3c-C3H5-543CH3CH2HCl Cl H H CH3c-C3H5油544CH3CH2HCH3OCH3H H CH3c-C3H5油545CH3CH2HOCH3CH3H CH3CH3c-C3H5-546CH3CH2HCH3Cl H H CH3c-C3H5-547CH3CH2HCH3CH3CH3H CH3c-C3H5-548CH3CH2HCl CF3H H CH3c-C3H5油549CH3CH2HCl CF3H ClCH3c-C3H5-550CH3CH2HOCH3Cl H ClCH3c-C3H5-551CH3CH2HCH3CH3H CH3CH3CH3油552CH3O HCH3CH3H CH3CH3CH3-553CH3CH2HCl Cl H H CH3CH3-554CH3CH2HCH3OCH3H H CH3CH3-555CH3CH2HOCH3CH3H CH3CH3CH3-556CH3CH2HCH3Cl H H CH3CH3-557CH3CH2HCH3CH3CH3H CH3CH3-558CH3CH2HCl CF3H H CH3C4H9油559CH3CH2HCl CF3H ClCH3CH3-560CH3CH2HOCH3Cl H ClCH3CH3-561CH3CH2HCH3CH3H CH3C2H5C5H11102-103562CH3O HCH3CH3H CH3C2H5C5H11-563CH3CH2HCl Cl H H C2H5C5H11-564CH3CH2HCH3OCH3H H C2H5C4H9油565CH3CH2HOCH3CH3H CH3C2H5C5H11-566CH3CH2HCH3Cl H H C2H5C5H11-567CH3CH2HCH3CH3CH3H C2H5C5H11-568CH3CH2HCl CF3H H C2H5C5H11-569CH3CH2HCl CF3H Cl C2H5C5H11-570CH3CH2HOCH3Cl H Cl C2H5C5H11-571CH3CH2HCH3CH3H CH3C2H5C2H5O(CH2)2油572CH3O HCH3CH3H CH3C2H5C2H5O(CH2)2-573CH3CH2HCl Cl H H C2H5C2H5O(CH2)2-574CH3CH2HCH3OCH3H H C2H5C2H5O(CH2)2-575CH3CH2HOCH3CH3H CH3C2H5C2H5O(CH2)2-576CH3CH2HCH3Cl H H C2H5C2H5O(CH2)2-577CH3CH2HCH3CH3CH3H C2H5C2H5O(CH2)2-578CH3CH2HCl CF3H H C2H5C2H5O(CH2)2-579CH3CH2HCl CF3H Cl C2H5C2H5O(CH2)2-580CH3CH2HOCH3Cl H Cl C2H5C2H5O(CH2)2-581CH3CH2HCH3CH3H CH3C2H5C2H5OCH2油582CH3O HCH3CH3H CH3C2H5C2H5OCH2-583CH3CH2HCl Cl H H C2H5C2H5OCH2-584CH3CH2HCH3OCH3H H C2H5C2H5OCH2-585CH3CH2HOCH3CH3H CH3C2H5C2H5OCH2-586CH3CH2HCH3Cl H H C2H5C2H5OCH2-587CH3CH2HCH3CH3CH3H C2H5C2H5OCH2-588CH3CH2HCl CF3H H C2H5C2H5OCH2-589CH3CH2HCl CF3H Cl C2H5C2H5OCH2-590CH3CH2HOCH3Cl H Cl C2H5C2H5OCH2-591CH3CH2HCH3CH3H CH3H c-C3H5CH(OMe)油(CH2)2592CH3O HCH3CH3H CH3H c-C3H5CH(OMe)-(CH2)2593CH3CH2HCl Cl H H H c-C3H5CH(OMe)-(CH2)2594CH3CH2HCH3OCH3H H H c-C3H5CH(OMe)-(CH2)2595CH3CH2HOCH3CH3H CH3H c-C3H5CH(OMe)-(CH2)2596CH3CH2HCH3Cl H H H c-C3H5CH(OMe)-(CH2)2597CH3CH2HCH3CH3CH3H H c-C3H5CH(OMe)-(CH2)2598CH3CH2HCl CF3H H H c-C3H5CH(OMe)-(CH2)2599CH3CH2H Cl CF3HCl H c-C3H5CH(OMe)-(CH2)2600CH3CH2H OCH3Cl HCl H c-C3H5CH(OMe)-(CH2)2601CH3CH2CH3Cl Cl HH C2H5C2H5-602CH3CH2CH3Cl Cl HH c-C3H5C4H9-603CH3CH2CH3Cl Cl HH c-C3H5c-C3H5155-156604CH3CH2CH3Cl Cl HH H C4H9-605CH3CH2CH3Cl Cl HH C2H5C4H9-606CH3CH2CH3Cl Cl HH H C6H5-607CH3CH2CH3Cl Cl HH C2H5(CH2)2OCH3-608CH3CH2CH3Cl Cl HH CH3C4H9-609CH3CH2CH3Cl Cl HH C3H7C3H7-610CH3CH2CH3Cl Cl HH C2H5C3H7-611CH3CH2CH3OCH3CH3HCH3C2H5C2H5-612CH3CH2CH3OCH3CH3HCH3c-C3H5C4H9-613CH3CH2CH3OCH3CH3HCH3c-C3H5c-C3H5-614CH3CH2CH3OCH3CH3HCH3H C4H9-615CH3CH2CH3OCH3CH3HCH3C2H5C4H9-616CH3CH2CH3OCH3CH3HCH3H C6H5-617CH3CH2CH3OCH3CH3HCH3C2H5(CH2)2OCH3-618CH3CH2CH3OCH3CH3HCH3CH3C4H9-619CH3CH2CH3OCH3CH3HCH3C3H7C3H7-620CH3CH2CH3OCH3CH3HCH3C2H5C3H7-621CH3CH2CH3CH3OCH3HH C2H5C2H5-622CH3CH2CH3CH3OCH3HH c-C3H5C4H9-623CH3CH2CH3CH3OCH3HH c-C3H5c-C3H5-624CH3CH2CH3CH3OCH3HH H C4H9-625CH3CH2CH3CH3OCH3HH C2H5C4H9-626CH3CH2CH3CH3OCH3HH H C6H5-627CH3CH2CH3CH3OCH3HH C2H5(CH2)2OCH3-628CH3CH2CH3CH3OCH3HH CH3C4H9-629CH3CH2CH3CH3CH3HH C3H7C3H7-630CH3CH2CH3CH3OCH3HH C2H5C3H7-631CH3CH2CH3CH3Cl HH C2H5C2H5-632CH3CH2CH3CH3Cl HH c-C3H5C4H9-633CH3CH2CH3CH3Cl HH c-C3H5c-C3H5-634CH3CH2CH3CH3Cl HH H C4H9-635CH3CH2CH3CH3Cl HH C2H5C4H9-636CH3CH2CH3CH3Cl HH H C6H5-637CH3CH2CH3CH3Cl HH C2H5(CH2)2OCH3-638CH3CH2CH3CH3Cl HH CH3C4H9-639CH3CH2CH3CH3Cl HH C3H7C3H7-640CH3CH2CH3CH3Cl HH C2H5C3H7-641CH3CH2CH3Cl CF3HH C2H5C2H5-642CH3CH2CH3Cl CF3HH c-C3H5C4H9-643CH3CH2CH3Cl CF3HH c-C3H5c-C3H5-644CH3CH2CH3Cl CF3HH H C4H9-645CH3CH2CH3Cl CF3HH C2H5C4H9-646CH3CH2CH3Cl CF3HH H C6H5-647CH3CH2CH3Cl CF3HH C2H5(CH2)2OCH3-648CH3CH2CH3Cl CF3HH CH3C4H9-649CH3CH2CH3Cl CF3HH C3H7C3H7-650CH3CH2CH3Cl CF3HH C2H5C3H7-651CH3CH2CH3Cl CF3HClC2H5C2H5-652CH3CH2CH3Cl CF3HClc-C3H5C4H9-653CH3CH2CH3Cl CF3HClc-C3H5c-C3H5-654CH3CH2CH3Cl CF3HClH C4H9-656CH3CH2CH3Cl CF3HClC2H5C4H9-656CH3CH2CH3Cl CF3HClH C6H5-657CH3CH2CH3Cl CF3HClC2H5(CH2)2OCH3-658CH3CH2CH3Cl CF3HClCH3C4H9-659CH3CH2CH3Cl CF3HClC3H7C3H7-660CH3CH2CH3Cl CF3HClC2H5C3H7-661CH3CH2CH3OCH3Cl HClC2H5C2H5-662CH3CH2CH3OCH3Cl HClc-C3H5C4H9-663CH3CH2CH3OCH3Cl HClc-C3H5c-C3H5-664CH3CH2CH3OCH3Cl HClH C4H9-665CH3CH2CH3OCH3Cl HClC2H5C4H9-666CH3CH2CH3OCH3Cl HClH C6H5-667CH3CH2CH3OCH3Cl HClC2H5(CH2)2OCH3-668CH3CH2CH3OCH3Cl HClCH3C4H9-669CH3CH2CH3OCH3Cl HClC3H7C3H7-670CH3CH2CH3OCH3Cl HClC2H5C3H7-671CH3CH2CH3CH3CH3HH C2H5C2H5-672CH3CH2CH3CH3CH3HH c-C3H5C4H9-673CH3CH2CH3CH3CH3HH c-C3H5c-C3H5-674CH3CH2CH3CH3CH3HH H C4H9-675CH3CH2CH3CH3CH3HH C2H5C4H9-676CH3CH2CH3CH3CH3H H H C6H5-677CH3CH2CH3CH3CH3H H C2H5(CH2)2OCH3-678CH3CH2CH3CH3CH3H H CH3C4H9-679CH3CH2CH3CH3CH3H H C3H7C3H7-680CH3CH2CH3CH3CH3H H C2H5C3H7-681CH3CH2H CH3OCH3H H C2H5C4H9-682CH3CH2H OCH3CH3H CH3C2H5C4H9107-109683CH3CH2H Cl CF3H Cl C2H5C4H9-684CH3CH2H CH3CH3CH3H C2H5C4H9-685CH3CH2H CH3OCH3H H c-C3H5c-C3H5101-103686CH3CH2H OCH3CH3H CH3c-C3H5c-C3H5187-188687CH3CH2H Cl CF3H Cl c-C3H5c-C3H5-688CH3CH2H CH3CH3CH3H c-C3H5c-C3H5119-121689CH3CH2H CH3OCH3H H H C6H5108-109690CH3CH2H OCH3CH3H CH3H C6H5油691CH3CH2H Cl CF3H Cl H C6H5-692CH3CH2H CH3CH3CH3H H C6H5油693CH3CH2H CH3OCH3H H c-C3H5C4H9油694CH3CH2H OCH3CH3H CH3c-C3H5C4H9-695CH3CH2H Cl CF3H Cl c-C3H5C4H9-696CH3CH2H CH3CH3CH3H c-C3H5C4H9-697CH3CH2H CH3OCH3H H CH3C4H9油698CH3CH2H OCH3CH3H CH3CH3C4H9-699CH3CH2H Cl CF3H Cl CH3C4H9-700CH3CH2H CH3CH3CH3H CH3C4H9-701CH3O H CH3OCH3H H C2H5C4H9-702CH3O H OCH3CH3H CH3C2H5C4H9-703CH3O H Cl CF3H Cl C2H5C4H9-704CH3O H CH3CH3CH3H C2H5C4H9-705CH3O H CH3OCH3H H C-C3H5c-C3H5-706CH3O H OCH3CH3H CH3c-C3H5c-C3H5-707CH3O H Cl CF3H Cl c-C3H5c-C3H5-708CH3O H CH3CH3CH3H c-C3H5c-C3H5-709CH3O H CH3OCH3H H H C6H5-710CH3O H OCH3CH3H CH3H C6H5-711CH3O H Cl CF3H Cl H C6H5-712CH3O H CH3CH3CH3H H C6H5-713CH3O H CH3OCH3H H c-C3H5C4H9-714CH3O H OCH3CH3H CH3c-C3H5C4H9-715CH3O H Cl CF1H Cl c-C3H5C4H9-716CH3O HCH3CH3CH3H c-C3H5C4H9-717CH3O HCH3OCH3H H CH3C4H9-718CH3O HOCH3CH3H CH3CH3C4H9-719CH3O HCl CF3H Cl CH3C4H9-720CH3O HCH3CH3CH3H CH3C4H9-721CH3CH2HCH3CH3H CH3C2H5CH(CH3)2146-147722CH3CH2HCl Cl H H C2H5CH(CH3)2-723CH3CH2HCl CH3H H C2H5CH(CH3)2-724CH3CH2HC1 OCH3H H C2H5CH(CH3)2油725CH3CH2HCH3OCH3H H C2H5CH(CH3)2油726CH3CH2HCl CF3H H C2H5CH(CH3)2-727CH3CH2HCF3Cl H H C2H5CH(CH3)2油728CH3CH2HCH3Cl H H C2H5CH(CH3)2-729CH3CH2HCF3CF3H H C2H5CH(CH3)2-730CH3CH2HCl CN H H C2H5CH(CH3)2-731CH3CH2HCl Cl F H C2H5CH(CH3)2-732CH3CH2HCl Cl Cl H C2H5CH(CH3)2-733CH3CH2HCH3OCH3F H C2H5CH(CH3)2-734CH3CH2HCH3OCH3Cl H C2H5CH(CH3)2-735CH3CH2HCl CH3F H C2H5CH(CH3)2-736CH3CH2HCl CF3Cl H C2H5CH(CH3)2-737CH3CH2HCl CF3F H C2H5CH(CH3)2-738CH3CH2HCl OCH3Cl H C2H5CH(CH3)2-739CH3CH2HCl OCH3F H C2H5CH(CH3)2-740CH3CH2HCl OCH3CH3H C2H5CH(CH3)2-741CH3CH2HCH3OCH3CH3H C2H5CH(CH3)2-742CH3CH2HCl H Cl H C2H5CH(CH3)2-743CH3CH2HCl Cl OCH3H C2H5CH(CH3)2-744CH3CH2HCl CH3OCH3H C2H5CH(CH3)2-745CH3CH2HCH3Cl OCH3H C2H5CH(CH3)2-746CH3CH2HCH3CH3OCH3H C2H5CH(CH3)2-747CH3CH2HCH3CH3H CH3C3H7c-C3H5140-143748CH3CH2HCl Cl H H C3H7c-C3H5107-108(A)79-82(C)749CH3CH2HCl CH3H H C3H7c-C3H5106-108750CH3CH2HCl OCH3H H C3H7c-C3H5油751CH3CH2HCH3OCH3H H C3H7c-C3H5油752CH3CH2HCl CF3H H C3H7c-C3H5108-109753CH3CH2HCF3Cl H HC3H7c-C3H5油(A)95-97(C)754CH3CH2HCH3Cl H HC3H7c-C3H587-88755CH3CH2HCF3CF3H HC3H7c-C3H5-756CH3CH2HCl CN H HC3H7c-C3H5-757CH3CH2HCl Cl F HC3H7c-C3H5-758CH3CH2HCl Cl Cl HC3H7c-C3H5-759CH3CH2HCH3OCH3F HC3H7c-C3H5-760CH3CH2HCH3OCH3Cl HC3H7c-C3H5-761CH3CH2HCl CH3F HC3H7c-C3H5-762CH3CH2HCl CF3Cl HC3H7c-C3H5-763CH3CH2HCl CF3F HC3H7c-C3H5-764CH3CH2HCl OCH3Cl HC3H7c-C3H5-765CH3CH2HCl OCH3F HC3H7c-C3H5-766CH3CH2HC1 OCH3CH3HC3H7c-C3H5-767CH3CH2HCH3OCH3CH3HC3H7c-C3H5油768CH3CH2HCl H Cl HC3H7c-C3H5-769CH3CH2HCl Cl OCH3HC3H7c-C3H5-770CH3CH2HCl CH3OCH3HC3H7c-C3H5-771CH3CH2HCH3Cl OCH3HC3H7c-C3H5-772CH3CH2HCH3CH3OCH3HC3H7c-C3H5-773CH3CH2HCH3CH3H CH3CH3CH2Cl 109-110774CH3CH2HCl Cl H HC2H5C3H7-775CH3CH2HCl CH3H HC2H5C3H7-776CH3CH2HCl OCH3H HC2H5C3H7油777CH3CH2HCH3OCH3H HC2H5C3H7油778CH3CH2HCl CF3H HC2H5C3H7油779CH3CH2HCF3Cl H HC2H5C3H7油780CH3CH2HCH3Cl H HC2H5C3H7-781CH3CH2HCF3CF3H HC2H5C3H7-782CH3CH2HCl CN H HC2H5C3H7-783CH3CH2HCl Cl F HC2H5C3H7-784CH3CH2HCl Cl Cl HC2H5C3H7-785CH3CH2HCH3OCH3F HC2H5C3H7-786CH3CH2HCH3OCH3Cl HC2H5C3H7-787CH3CH2HCl CH3F HC2H5C3H7-788CH3CH2HCl CF3Cl HC2H5C3H7-789CH3CH2HCl CF3F HC2H5C3H7-790CH3CH2HCl OCH3Cl HC2H5C3H7-791CH3CH2HCl OCH3F HC2H5C3H7-792CH3CH2HCl OCH3CH3HC2H5C3H7-793CH3CH2HCH3OCH3CH3HC2H5C3H7油794CH3CH2HCl H Cl HC2H5C3H7-795CH3CH2HCl Cl OCH3HC2H5C3H7-796CH3CH2HCl CH3OCH3HC2H5C3H7-797CH3CH2HCH3Cl OCH3HC2H5C3H7-798CH3CH2HCH3CH3OCH3HC2H5C3H7-799CH3CH2HCH3CH3CH3HC2H5C3H7油800CH3CH2HCF3Cl H HH 4-CH3O-C6H4138-139801CH3CH2HCF3Cl H Hc-C3H5c-C3H5138-139802CH3CH2HCF3Cl H HC2H5c-C3H5油(A)122-125(C)803CH3CH2HCF3Cl H HCH3c-C3H5油804CH3CH2HCF3Cl H HCH3C3H7油805CH3CH2HCF3Cl H HCH3C4H9油806CH3CH2HCF3Cl H HCH3C5H11-807CH3CH2HCF3Cl H HC2H5C4H9油808CH3CH2HCF3Cl H HC3H7C3H7油809CH3CH2HCF3Cl H HC2H5C2H5油810CH3CH2HCl CN H HH 4-CH3O-C6H4-811CH3CH2HCl CN H Hc-C3H5c-C3H5180-182812CH3CH2HCl CN H HC2H5c-C3H5-813CH3CH2HCl CN H HCH3c-C3H5-814CH3CH2HCl CN H HCH3C3H7-815CH3CH2HCl CN H HCH3C4H9-816CH3CH2HCl CN H HCH3C5H11-817CH3CH2HCl CN H HC2H5C4H9-818CH3CH2HCl CN H HC3H7C3H7-819CH3CH2HCl CN H HC2H5C2H5-820CH3CH2HCF3CF3H HH 4-CH3O-C6H4-821CH3CH2HCF3CF3H Hc-C3H5c-C3H5149-150822CH3CH2HCF3CF3H HC2H5c-C3H5-823CH3CH2HCF3CF3H HCH3c-C3H5-824CH3CH2HCF3CF3H HCH3C3H7油825CH3CH2HCF3CF3H HCH3C4H9-826CH3CH2HCF3CF3H HCH3C5H11-827CH3CH2HCF3CF3H HC2H5C4H9-828CH3CH2HCF3CF3H HC3H7C3H7-829CH3CH2HCF3CF3H HC2H5C2H5-830CH3CH2HCl OCH3H HH 4-CH3O-C6H458-60831CH3CH2HCl OCH3H Hc-C3H5c-C3H5139-140832CH3CH2HCl OCH3H HC2H5c-C3H5油833CH3CH2HCl OCH3H HH c-C3H5油834CH3CH2HCl OCH3H HCH3C3H7油835CH3CH2HCl OCH3H HCH3C4H9油836CH3CH2HCl OCH3H HCH3C5H11油837CH3CH2HCl OCH3H HC2H5C4H9油838CH3CH2HCl OCH3H HC3H7C3H7油839CH3CH2HCl OCH3H HC2H5C2H5油840CH3CH2HCl Cl F HH 4-CH3O-C6H4-841CH3CH3HCl Cl F Hc-C3H5c-C3H5148-149842CH3CH2HCl Cl F HC2H5c-C3H5-843CH3CH2HCl Cl F HCH3c-C3H5-844CH3CH2HCl Cl F HCH3C3H7-845CH3CH2HCl Cl F HCH3C4H9-846CH3CH2HCl Cl F HCH3C5H11-847CH3CH2HCl Cl F HC2H5C4H9-848CH3CH2HCl Cl F HC3H7C3H7-849CH3CH2HCl Cl F HC2H5C2H5-850CH3CH2HCl Cl ClHH 4-CH3O-C6H4-851CH3CH2HCl Cl ClHc-C3H5c-C3H5-852CH3CH2HCl Cl ClHC2H5c-C3H5-853CH3CH2HCl Cl ClHCH3c-C3H5-854CH3CH2HCl Cl ClHCH3C3H7-855CH3CH2HCl Cl ClHCH3C4H9-856CH3CH2HCl Cl ClHCH3C5H11-857CH3CH2HCl Cl ClHC2H5C4H9-858CH3CH2HCl Cl ClHC3H7C3H7-859CH3CH2HCl Cl ClHC2H5C2H5-860CH3CH2HCH3OCH3F HH 4-CH3O-C6H4-861CH3CH2HCH3OCH3F Hc-C3H5c-C3H5128-129862CH3CH2HCH3OCH3F HC2H3c-C3H5-863CH3CH2HCH3OCH3F HCH3c-C3H5-864CH3CH2HCH3OCH3F HCH3C3H7-865CH3CH2HCH3OCH3F HCH3C4H9-866CH3CH2HCH3OCH3F HCH3C5H11-867CH3CH2HCH3OCH3F HC2H5C4H9-868CH3CH2HCH3OCH3F HC3H7C3H7-869CH3CH2HCH3OCH3F HC2H5C2H5-870CH3CH2HCH3OCH3ClHH 4-CH3O-C6H4油871CH3CH2HCH3OCH3ClHc-C3H5c-C3H5179-181872CH3CH2HCH3OCH3ClHC2H5c-C3H5-873CH3CH2HCH3OCH3ClHCH3c-C3H5-874CH3CH2HCH3OCH3ClHCH3C3H7-875CH3CH2HCH3OCH3ClHCH3C4H9-876CH3CH2HCH3OCH3ClHCH3C5H11-877CH3CH2HCH3OCH3ClHC2H5C4H9-878CH3CH2HCH3OCH3ClHC3H7C3H7-879CH3CH2HCH3OCH3ClHC2H5C2H5-880CH3CH2HCl CH3F HH 4-CH3O-C6H4-881CH3CH2HCl CH3F Hc-C3H5c-C3H5130-131882CH3CH2HCl CH3F HC2H5c-C3H5-883CH3CH2HCl CH3F HCH3c-C3H5-884CH3CH2HCl CH3F HCH3C3H9-885CH3CH2HCl CH3F HCH3C4H9-886CH3CH2HCl CH3F HCH3C3H11-887CH3CH2HCl CH3F HC2H5C4H9-888CH3CH2HCl CH3F HC3H7C3H7-889CH3CH2HCl CH3F HC2H5C2H5-890CH3CH2HCl CF3ClHH 4-CH3O-C6H4-891CH3CH2HCl CF3ClHc-C3H5c-C3H5-892CH3CH2HCl CF3ClHC2H5c-C3H5-893CH3CH2HCl CF3ClHCH3c-C3H5-894CH3CH2HCl CF3ClHCH3C3H7-895CH3CH2HCl CF3ClHCH3C4H9-896CH3CH2HCl CF3ClHCH3C5H11-897CH3CH2HCl CF3ClHC2H5C4H9-898CH3CH2HCl CF3ClHC3H7C3H7-899CH3CH2HCl CF3ClHC2H5C2H5-900CH3CH2HCH3OCH3H HH C4H9油901CH3CH2HCH3OCH3H HC2H5C2H569-73902CH3CH2HCl CH3H HC3H7C3H7油903CH3CH2HCl CF3F HH 4-CH3O-C6H4-904CH3CH2HCl CF3F Hc-C3H5c-C3H5-905CH3CH2HCl CF3F HC2H5c-C3H5-906CH3CH2HCl CF3F HCH3c-C3H5-907CH3CH2HClCF3F HCH3C3H7-908CH3CH2HClCF3F HCH3C4H9-909CH3CH2HClCF3F HCH3C5H11-910CH3CH2HClCF3F HC2H5C4H9-911CH3CH2HClCF3F HC3H7C3H7-912CH3CH2HClCF3F HC2H5C2H5-913CH3CH2HClOCH3Cl HH 4-CH3O-C6H4-914CH3CH2HClOCH3Cl Hc-C3H5c-C3H5油915CH3CH2HClOCH3Cl HC2H5c-C3H5-916CH3CH2HClOCH3Cl HCH3c-C3H5-917CH3CH2HClOCH3Cl HCH3C3H7-918CH3CH2HClOCH3Cl HCH3C4H9-919CH3CH2HClOCH3Cl HCH3C5H11-920CH3CH2HClOCH3Cl HC2H5C4H9-921CH3CH2HClOCH3Cl HC3H7C3H7-922CH3CH2HClOCH3Cl HC2H5C2H5-923CH3CH2HClOCH3F HH 4-CH3O-C6H4-924CH3CH2HClOCH3F Hc-C3H5c-C3H5-925CH3CH2HClOCH3F HC2H3c-C3H5-926CH3CH2HClOCH3F HCH3c-C3H5-927CH3CH2HClOCH3F HCH3C3H7-928CH3CH2HClOCH3F HCH3C4H9-929CH3CH2HClOCH3F HCH3C5H11-930CH3CH2HClOCH3F HC2H5C4H9-931CH3CH2HClOCH3F HC3H7C3H7-932CH3CH2HClOCH3F HC2H5C2H5-933CH3CH2HClOCH3CH3HH 4-CH3O-C6H4-934CH3CH2HClOCH3CH3Hc-C3H5c-C3H5150-151935CH3CH2HClOCH3CH3HC2H5c-C3H5-936CH3CH2HClOCH3CH3HCH3c-C3H5-937CH3CH2HClOCH3CH3HCH3C3H7-938CH3CH2HClOCH3CH3HCH3C4H9-939CH3CH2HClOCH3CH3HCH3C5H11-940CH3CH2HClOCH3CH3HC2H5C4H9-941CH3CH2HClOCH3CH3HC3H7C3H7-942CH3CH2HClOCH3CH3HC2H5C2H5-943CH3CH2HCH3OCH3CH3HH 4-CH3O-C6H4-944CH3CH2HCH3OCH3CH3Hc-C3H5c-C3H5148-151945CH3CH2HCH3OCH3CH3HC2H5c-C3H5油946CH3CH2HCH3OCH3CH3HCH3c-C3H5-947CH3CH2HCH3OCH3CH3HCH3C3H7油948CH3CH2HCH3OCH3CH3HCH3C4H9-949CH3CH2HCH3OCH3CH3HCH3C5H11-950CH3CH2HCH3OCH3CH3HC2H5C4H9-951CH3CH2HCH3OCH3CH3HC3H7C3H7油952CH3CH2HCH3OCH3CH3HC2H5C2H5油953CH3CH2HCl H Cl HH 4-CH3O-C6H4-954CH3CH2HCl H Cl Hc-C3H5c-C3H5151-153955CH3CH2HCl H Cl HC2H5c-C3H5-956CH3CH2HCl H Cl HCH3c-C3H5-957CH3CH2HCl H Cl HCH3C3H7-958CH3CH2HCl H Cl HCH3C4H9-959CH3CH2HCl H Cl HCH3C5H11-960CH3CH2HCl H Cl HC2H5C4H9-961CH3CH2HCl H Cl HC3H7C3H7-962CH3CH2HCl H Cl HC2H5C2H5-963CH3CH2HCl Cl OCH3HH 4-CH3O-C6H4-964CH3CH2HCl Cl OCH3Hc-C3H5c-C3H5-965CH3CH2HCl Cl OCH3HC2H5c-C3H5-966CH3CH2HCl Cl OCH3HCH3c-C3H5-967CH3CH2HCl Cl OCH3HCH3C3H7-968CH3CH2HCl Cl OCH3HCH3C4H9-969CH3CH2HCl Cl OCH3HCH3C5H11-970CH3CH2HCl Cl OCH3HC2H5C4H9-971CH3CH2HCl Cl OCH3HC3H7C3H7-972CH3CH2HCl Cl OCH3HC2H5C2H5-973CH3CH2HCl CH3OCH3HH 4-CH3O-C6H4-974CH3CH2HCl CH3OCH3Hc-C3H5c-C3H5-975CH3CH2HCl CH3OCH3HC2H5c-C3H5-976CH3CH2HCl CH3OCH3HCH3c-C3H5-977CH3CH2HCl CH3OCH3HCH3C3H7-978CH3CH2HCl CH3OCH3HCH3C4H9-979CH3CH2HCl CH3OCH3HCH3C5H11-980CH3CH2HCl CH3OCH3HC2H5C4H9-981CH3CH2HCl CH3OCH3HC3H7C3H7-982CH3CH2HCl CH3OCH3HC2H5C2H5-983CH3CH2HCH3Cl OCH3HH 4-CH3O-C6H4-984CH3CH2HCH3Cl OCH3Hc-C3H5c-C3H5-985CH3CH2HCH3Cl OCH3HC2H5c-C3H5-986CH3CH2HCH3Cl OCH3HCH3c-C3H5-987 CH3CH2HCH3Cl OCH3HCH3C3H7-988 CH3CH2HCH3Cl OCH3HCH3C4H9-989 CH3CH2HCH3Cl OCH3HCH3C5H11-990 CH3CH2HCH3Cl OCH3HC2H5C4H9-991 CH3CH2HCH3Cl OCH3HC3H7C3H7-992 CH3CH2HCH3Cl OCH3HC2H5C2H5-993 CH3CH2HCH3CH3OCH3HH 4-CH3O-C6H4-994 CH3CH2HCH3CH3OCH3Hc-C3H5c-C3H5-995 CH3CH2HCH3CH3OCH3HC2H5c-C3H5-996 CH3CH2HCH3CH3OCH3HCH3c-C3H5-997 CH3CH3HCH3CH3OCH3HCH3C3H7-998 CH3CH2HCH3CH3OCH3HCH3C4H9-999 CH3CH2HCH3CH3OCH3HCH3C5H11-1000CH3CH2HCH3CH3OCH3HC2H5C4H9-1001CH3CH2HCH3CH3OCH3HC3H7C3H7-1002CH3CH2HCH3CH3OCH3HC2H5C2H5-1003CH3CH2HCH3OCH3OCH3HH 4-CH3O-C6H4油1004CH3CH2HCH3OCH3OCH3Hc-C3H5c-C3H5138-1401005CH3CH2HCH3OCH3OCH3HC2H5c-C3H5-1006CH3CH2HCH3OCH3OCH3HCH3c-C3H5-1007CH3CH2HCH3OCH3OCH3HCH3C3H7-1008CH3CH2HCH3OCH3OCH3HCH3C4H9-1009CH3CH2HCH3OCH3OCH3HCH3C5H11-1010CH3CH2HCH3OCH3OCH3HC2H5C4H9-1011CH3CH2HCH3OCH3OCH3HC3H7C3H7-1012CH3CH2HCH3OCH3OCH3HC2H5C2H5油1013CH3CH2HC1 OCH3OCH3HH 4-CH3O-C6H4-1014CH3CH2HCl OCH3OCH3Hc-C3H5c-C3H5-1015CH3CH2HCl OCH3OCH3HC2H5c-C3H5-1016CH3CH2HCl OCH3OCH3HCH3c-C3H5-1017CH3CH2HCl OCH3OCH3HCH3C3H7-1018CH3CH2HCl OCH3OCH3HCH3C4H9-1019CH3CH2HCl OCH3OCH3HCH3C5H11-1020CH3CH2HCl OCH3OCH3HC2H5C4H9-1021CH3CH2HCl OCH3OCH3HC3H7C3H7-1022CH3CH2HCl OCH3OCH3HC2H5C2H5-1023CH3CH2HCl OCF3HHH 4-CH3O-C6H4油1024CH3CH2HCl OCF3HHc-C3H5c-C3H5119-1201025CH3CH2HCl OCF3HHC2H5c-C3H5103-1041026CH3CH2HCl OCF3HHCH3c-C3H5-1027CH3CH2HCl OCF3HHCH3C3H7油1028CH3CH2HCl OCF3HHCH3C4H9油1029CH3CH2HCl OCF3HHCH3C5H11-1030CH3CH2HCl OCF3HHC2H5C4H9-1031CH3CH2HCl OCF3HHC3H7C3H7-1032CH3CH2HCl OCF3HHC2H5C2H5油1033CH3CH2HCl SCF3HHH 4-CH3O-C6H4-1034CH3CH2HCl SCF3HHc-C3H5c-C3H5-1035CH3CH2HCl SCF3HHC2H5c-C3H5-1036CH3CH2HCl SCF3HHCH3c-C3H5-1037CH3CH2HCl SCF3HHCH3C3H7-1038CH3CH2HCl SCF3HHCH3C4H9-1039CH3CH2HCl SCF3HHCH3C5H11-1040CH3CH2HCl SCF3HHC2H3C4H9-1041CH3CH2HCl SCF3HHC3H7C3H7-1042CH3CH2HCl SCF3HHC3H5C2H5-1044CH3CH2HCl CF3HHH 4-CH3O-C6H4105-1071045CH3CH2HCF3Q3HHc-C3H5c-C3H5168-1691046CH3CH2HCl Q3HHc-C3H5c-C3H5130-1321047CH3CH2HCF3SCH3HHc-C3H5c-C3H5-1048CH3CH2HCl SCH3HHc-C3H5c-C3H5-1049CH3CH2HCF3COCH3HHc-C3H5c-C3H5-1050CH3CH2HCl COCH3HHc-C3H5c-C3H5-1051CH3CH2HCF3CHCH2HHc-C3H5c-C3H5-1052CH3CH2HCl CHCH2HHc-C3H5c-C3H5-1053CH3CH2HCl CH3HHH 4-CH3O-C6H4113-1151054CH3CH2HOCH3OCH3HHH 4-CH3O-C6H4-1055CH3CH2HOCH3OCH3HHc-C3H5c-C3H5128-1301056CH3CH2HOCH3OCH3HHC2H5c-C3H5-1057CH3CH2HOCH3OCH3HHCH3c-C3H5-1058CH3CH2HOCH3OCH3HHCH3C3H7-1059CH3CH2HOCH3OCH3HHCH3C4H9-1060CH3CH2HOCH3OCH3HHCH3C5H11-1061CH3CH2HOCH3OCH3HHC2H5C4H9-1062CH3CH2HOCH3OCH3HHC3H7C3H7-1063CH3CH2HOCH3OCH3HHC2H5C2H5-1064CH3CH2HOCH3CF3HHH 4-CH3O-C6H4-1065CH3CH2HOCH3CF3HHc-C3H5c-C3H5158-1591066CH3CH2HOCH3CF3HHC2H5c-C3H5-1067CH3CH2HOCH3CF3HHCH3c-C3H5-1068CH3CH2HOCH3CF3H HCH3C3H7-1069CH3CH2HOCH3CF3H HCH3C4H9-1070CH3CH2HOCH3CF3H HCH3C5H11-1071CH3CH2HOCH3CF3H HC2H5C4H9-1072CH3CH2HOCH3CF3H HC3H7C3H7-1073CH3CH2HOCH3CF3H HC2H5C2H5-1074CH3CH2HCF3OCH3H HH 4-CH3O-C6H4油1075CH3CH2HCF3OCH3H Hc-C3H5c-C3H5129-1301076CH3CH2HCF3OCH3H HC2H5c-C3H5119-1221077CH3CH2HCF3OCH3H HCH3c-C3H5-1078CH3CH2HCF3OCH3H HCH3C3H7油1079CH3CH2HCF3OCH3H HCH3C4H9油1080CH3CH2HCF3OCH3H HCH3C5H11-1081CH3CH2HCF3OCH3H HC2H5C4H9-1082CH3CH2HCF3OCH3H HC3H7C3H7油1083CH3CH2HCF3OCH3H HC2H5C2H577-781084CH3CH2HOCH3Cl OCH3HH 4-CH3O-C6H4-1085CH3CH2HOCH3Cl OCH3Hc-C3H5c-C3H5-1086CH3CH2HOCH3Cl OCH3HC2H5c-C3H5-1087CH3CH2HOCH3Cl OCH3HCH3c-C3H5-1088CH3CH2HOCH3Cl OCH3HCH3C3H7-1089CH3CH2HOCH3Cl OCH3HCH3C4H9-1090CH3CH2HOCH3Cl OCH3HCH3C5H11-1091CH3CH2HOCH3Cl OCH3HC2H5C4H9-1092CH3CH2HOCH3Cl OCH3HC3H7C3H7-1093CH3CH2HOCH3Cl OCH3HC2H5C2H5-1094CH3CH2HOCH3CH3OCH3HH 4-CH3O-C6H4-1095CH3CH2HOCH3CH3OCH3Hc-C3H5c-C3H5-1096CH3CH2HOCH3CH3OCH3HC2H5c-C3H5-1097CH3CH2HOCH3CH3OCH3HCH3c-C3H5-1098CH3CH2HOCH3CH3OCH3HCH3C3H7-1099CH3CH2HOCH3CH3OCH3HCH3C4H9-1100CH3CH2HOCH3CH3OCH3HCH3C5H11-1101CH3CH2HOCH3CH3OCH3HC2H5C4H9-1102CH3CH2HOCH3CH3OCH3HC3H7C3H7-1103CH3CH2HOCH3CH3OCH3HC2H5C2H5-1104CH3CH2HOCH3CF3OCH3HH 4-CH3O-C6H4-1105CH3CH2HOCH3CF3OCH3Hc-C3H5c-C3H5-1106CH3CH2HOCH3CF3OCH3HC2H5c-C3H5-1107CH3CH2HOCH3CF3OCH3HCH3c-C3H5-1108CH3CH2HOCH3CF3OCH3HCH3C3H7-1109CH3CH2HOCH3CF3OCH3HCH3C4H9-1110CH3CH2HOCH3CF3OCH3HCH3C5H11-1111CH3CH2HOCH3CF3OCH3HC2H5C4H9-1112CH3CH2HOCH3CF3OCH3HC3H7C3H7-1113CH3CH2HOCH3CF3OCH3HC2H5C2H5-1114CH3CH2HOCH3CN OCH3HH4-CH3O-C6H4-1115CH3CH2HOCH3CN OCH3Hc-C3H5c-C3H5-1116CH3CH2HOCH3CN OCH3HC2H5c-C3H5-1117CH3CH2HOCH3CN OCH3HCH3c-C3H5-1118CH3CH2HOCH3CN OCH3HCH3C3H7-1119CH3CH2HOCH3CN OCH3HCH3C4H9-1120CH3CH2HOCH3CN OCH3HCH3C5H11-1121CH3CH2HOCH3CN OCH3HC2H5C4H9-1122CH3CH2HOCH3CN OCH3HC3H7C3H7-1123CH3CH2HOCH3CN OCH3HC2H5C2H5-1124CH3CH2HOCH3OCH3OCH3HH4-CH3O-C6H4-1125CH3CH2HOCH3OCH3OCH3Hc-C3H5c-C3H5-1126CH3CH2HOCH3OCH3OCH3HC2H5c-C3H5-1127CH3CH2HOCH3OCH3OCH3HCH3c-C3H5-1128CH3CH2HOCH3OCH3OCH3HCH3C3H7-1129CH3CH2HOCH3OCH3OCH3HCH3C4H9-1130CH3CH2HOCH3OCH3OCH3HCH3C5H11-1131CH3CH2HOCH3OCH3OCH3HC2H5C4H9-1132CH3CH2HOCH3OCH3OCH3HC3H7C3H7-1133CH3CH2HOCH3OCH3OCH3HC2H5C2H3-1134CH3CH2HCH3CH3H CH3C2H5CH2OSO2CH3110-1111135CH3CH2HCH3CH3H CH3C2H5CH2SCH3134-1351136CH3CH2HCH3CH3H CH3C2H5CH2Cl140-1411137CH3CH2HCH3CH3H CH3C2H5CH2CN142-1471138CH3CH2HCl Cl H HC2H5CH2OSO2CH3-1139CH3CH2HCl Cl H HC2H5CH2SCH3-1140CH3CH2HCl Cl H HC2H5CH2Cl-1141CH3CH2HCl Cl H HC2H5CH2CN-1142CH3CH2HCl CF3H HC2H5CH2OSO2CH3-1143CH3CH2HCl CF3H HC2H5CH2SCH3-1144CH3CH2HCl CF3H HC2H5CH2Cl-1145CH3CH2HCl CF3H HC2H5CH2CN-1146CH3CH2HCl OCH3H HC2H5CH2OSO2CH3-1147CH3CH2HCl OCH3H HC2H5CH2SCH3-1148CH3CH2HCl OCH3H H C2H5CH2Cl-1149CH3CH2HCl OCH3H H C2H5CH2CN-1150CH3CH2HCF3OCH3H H C3H7c-C3H5油1151CH3CH2HCl CF3H H CH3C3H797-981152CH3CH2HCH3OCH3CH3H C6H5c-C3H5-1153CH3CH2HCl CF3H H C6H5c-C3H5油1154CH3CH2HCl OCH3H H C6H5c-C3H5-1155CH3CH2HCl OCF3H H C6H5c-C3H5油1156CH3CH2HCl CH3H H C6H5c-C3H5119-1201157CH3CH2HCF3OCH3H H C6H5c-C3H5油1158CH3CH2HCl Cl H CH3C6H5c-C3H5油1159CH3CH2HCH3OCH3Cl H C6H5c-C3H5-1160CH3CH2HCH3OCH3F H C6H5c-C3H5-1161CH3CH2HCl Cl H H 4-F-C6H4c-C3H5油1162CH3CH2HCH3OCH3CH3H 4-F-C6H4c-C3H5-1163CH3CH2HCl CF3H H 4-F-C6H4c-C3H5油1164CH3CH2HCl OCH3H H 4-F-C6H4c-C3H5-1165CH3CH2HCl OCF3H H 4-F-C6H4c-C3H5-1166CH3CH2HCl CH3H H 4-F-C6H4c-C3H5-1167CH3CH2HCF3OCH3H H 4-F-C6H4c-C3H5-1168CH3CH2HCl Cl H CH34-F-C6H4c-C3H5-1169CH3CH2HCH3OCH3Cl H 4-F-C6H4c-C3H5-1170CH3CH2HCH3OCH3F H 4-F-C6H4c-C3H5-1171CH3CH2HCl Cl H H CH3c-C4H7109-1101172CH3CH2HCH3OCH3CH3H CH3c-C4H7-1173CH3CH2HCl CF3H H CH3c-C4H7136-1371174CH3CH2HCl OCH3H H CH3c-C4H7-1175CH3CH2HCl OCF3H H CH3c-C4H7-1176CH3CH2HCl CH3H H CH3c-C4H7-1177CH3CH2HCF3OCH3H H CH3c-C4H7-1178CH3CH2HCl Cl H CH3CH3c-C4H7-1179CH3CH2HCH3OCH3Cl H CH3c-C4H7-1180CH3CH2HCH3OCH3F H CH3c-C4H7-1181CH3CH2HCl Cl H H C2H5c-C4H7-1182CH3CH2HCH3OCH3CH3H C2H5c-C4H7-1183CH3CH2HCl CF3H H C2H5c-C4H7-l184CH3CH2HCl OCH3H H C2H5c-C4H7-1185CH3CH2HCl OCF3H H C2H5c-C4H7-1186CH3CH2HCl CH3H H C2H5c-C4H7-1187CH3CH2HCF3OCH3H H C2H5c-C4H7-1188CH3CH2HCl Cl H CH3C2H5c-C4H7-1189CH3CH2HCH3OCH3Cl H C2H5c-C4H7-1l90CH3CH2HCH3OCH3F H C2H5c-C4H7-119lCH3CH2HCl Cl H H C3H7c-C4H7-1192CH3CH2HCH3OCH3CH3H C3H7c-C4H7-1193CH3CH2HCl CF3H H C3H7c-C4H7-1194CH3CH2HCl OCH3H H C3H7c-C4H7-1195CH3CH2HCl OCF3H H C3H7c-C4H7-1196CH3CH2HCl CH3H H C3H7c-C4H7-1197CH3CH2HCF3OCH3H H C3H7c-C4H7-1198CH3CH2HCl Cl H CH3C3H7c-C4H7-1199CH3CH2HCH3OCH3Cl H C3H7c-C4H7-1200CH3CH2HCH3OCH3F H C3H7c-C4H7-1201CH3CH2HCl Cl H H c-C4H7c-C4H7-1202CH3CH2HCH3OCH3CH3H c-C4H7c-C4H7-1203CH3CH2HCl CF3H H c-C4H7c-C4H7-1204CH3CH2HCl OCH3H H c-C4H7c-C4H7-1205CH3CH2HCl OCF3H H c-C4H7c-C4H7-1206CH3CH2HCl CH3H H c-C4H7c-C4H7-1207CH3CH2HCF3OCH3H H c-C4H7c-C4H7-1208CH3CH2HCl Cl H CH3c-C4H7c-C4H7-1209CH3CH2HCH3OCH3Cl H c-C4H7c-C4H7-1210CH5CH2HCH3OCH3F H c-C4H7c-C4H7-1211CH3S HSCH3Cl H Cl C2H5C3H763-651212CH3CH2HOCH3Cl H H c-C3H5c-C3H5152-1541213CH3CH2HOCH3Cl H H C2H5c-C3H5-1214CH3CH2HOCH3Cl H H C3H7c-C3H5-1215CH3CH2HOCH3Cl H H CH3c-C4H7-1216CH3CH2HOCH3Cl H H CH3C3H7-1217CH3CH2HOCH3Cl H H C2H5C3H7-1218CH3CH2HOCH3Cl H H C2H5C2H5-1219CH3CH2HOCH3Cl H H C3H7C3H7-1220CH3CH2HOCH3Cl H H CH3C4H9-1221CH3CH2HOCH3Cl H H H 4-CH3O-C6H4-1222CH3CH2HOCH3CH3H H c-C3H5c-C3H5油1223CH3CH2HOCH3CH3H H C2H5c-C3H5-1224CH3CH2HOCH3CH3H H C3H7c-C3H5-1225CH3CH2HOCH3CH3H H CH3c-C4H7-1226CH3CH2HOCH3CH3H H CH3C3H7-1227CH3CH2HOCH3CH3H H C2H5C3H7-1228CH3CH2HOCH3CH3HHC2H5C2H5-1229CH3CH2HOCH3CH3HHC3H7C3H7-1230CH3CH2HOCH3CH3HHCH3C4H9-1231CH3CH2HOCH3CH3HHH 4-CH3O-C6H4-1232CH3CH2HOCH3OCH3HFc-C3H5c-C3H5176-1781233CH3CH2HOCH3OCH3HFC2H5c-C3H5-1234CH3CH2HOCH3OCH3HFC3H7c-C3H5-1235CH3CH2HOCH3OCH3HFCH3c-C4H7-1236CH3CH2HOCH3OCH3HFCH3C3H7-1237CH3CH2HOCH3OCH3HFC2H5C3H7-1238CH3CH2HOCH3OCH3HFC2H5C2H5-1239CH3CH2HOCH3OCH3HFC3H7C3H7-1240CH3CH2HOCH3OCH3HFCH3C4H9-1241CH3CH2HOCH3OCH3HFH 4-CH3O-C6H4-1242CH3CH2HCF3F HHc-C3H5c-C3H5-1243CH3CH2HCF3F HHC2H5c-C3H5-1244CH3CH2HCF3F HHC3H7c-C3H5115-1181245CH3CH2HCF3F HHCH3c-C4H7-1246CH3CH2HCF3F HHCH3C3H7-1247CH3CH2HCF3F HHC2H5C3H7-1248CH3CH2HCF3F HHC2H5C2H5-1249CH3CH2HCF3F HHC3H7C3H7-1250CH3CH2HCF3F HHCH3C4H9-1251CH3CH2HCF3F HHH 4-CH3O-C6H457-701252CH3CH2HCF3F HHBnOCH2BnOCH2油1253CH3CH2HCF3F HHCH3C6H5119-1201254CH3CH2HCF3F HHC6H5C6H5135-1391255CH3CH2HCl OCF3HHC3H7c-C3H5油1256CH3CH2HCl OCF3HHC2H5C3H7油1257CH3CH2HCl CF3HHH CH2=CH-CH=CH 83-851258CH3CH2HCF3OBn HHc-C3H5c-C3H5163-1651259CH3CH2HCF3OH HHc-C3H5c-C3H5245-2461260CH3CH2HCF3OC3H7HHc-C3H5c-C3H5127-1281261CH3CH2HCF3OC3H7HHC2H5c-C3H5-1262CH3CH2HCF3OC3H7HHC3H7c-C3H5-1263CH3CH2HCF3OC3H7HHCH3c-C4H7-1264CH3CH2HCF3OC3H7HHCH3C3H7-1265CH3CH3HCF3OC3H7HHC2H5C3H7-1266CH3CH2HCF3OC3H7HHC2H5C2H5-1267CH3CH2HCF3OC3H7HHC3H7C3H7-1268CH3CH2HCF3OC3H7H H CH3C4H9-1269CH3CH2HCF3OC3H7H H H 4-CH3O-C6H4-1284CH3CH2HCH3OH F H c-C3H5c-C3H5-1285CH3CH2HCH3OH F H C2H5c-C3H5-1286CH3CH2HCH3OH F H C3H7c-C3H5-1287CH3CH2HCH3OH F H CH3c-C4H7-1288CH3CH2HCH3OH F H CH3C3H7-1289CH3CH2HCH3OH F H C2H5C3H7-1290CH3CH2HCH3OH F H C2H5C2H5-1291CH3CH2HCH3OH F H C3H7C3H7-1292CH3CH2HCH3OH F H CH3C4H9-1293CH3CH2HCH3OH F H H 4-CH3O-C6H4-1294CH3CH2HCH3OCH3OCH3H CH3CH3101-1021295CH3CH2HCH3OCH3OCH3H CH3C2H5油1296CH3CH2HCl Cl H H C2H54-CH3O-C6H4油1297CH3CH2HCl Cl H CH3C2H5C2H5133-1351298CH3CH2HCl Cl H CH3C2H5C3H7123-1251299CH3CH2HCl Cl H CH3C3H7C3H7125-1271300CH3CH2HCl Cl H CH3C2H5c-C3H5157-1591301CH3O HCH3OCH3CH3H c-C3H5c-C3H5-1302CH3O HCl CF3H H c-C3H5c-C3H5149-1501303CH3O HCl OCH3H H c-C3H5c-C3H5124-1251304CH3O HCl OCF3H H c-C3H5c-C3H5-1305CH3O HCl CH3H H c-C3H5c-C3H5-1306CH3O HCF3OCH3H H c-C3H5c-C3H5-1307CH3O HCl Cl H CH3c-C3H5c-C3H5-1308CH3O HCH3OCH3Cl H c-C3H5c-C3H5-1309CH3O HCH3OCH3F H c-C3H5c-C3H5-1310CH3O HCH3OCH3CH3H CH3C3H7-1311CH3O HCl CF3H H CH3C3H7-1312CH3O HCl OCH3H H CH3C3H7-1313CH3O HCl OCF3H H CH3C3H7-1314CH3O HCl CH3H H CH3C3H7-1315CH3O HCF3OCH3H H CH3C3H7-1316CH3O HCl Cl H CH3CH3C3H7-1317CH3O HCH3OCH3Cl H CH3C3H7-1318CH3O HCH3OCH3F H CH3C3H7-1319CH3CH2HCl Cl H H C6H5C6H5油1320CH3CH2HCl Cl H H C6H5CH3油1321CH3CH2HCl Cl H H c-C3H52-CH3-C6H4油1322CH3CH2HCl Cl H H C4H9CH(CH2OH)2油1323CH3CH2HCl Cl H H C6H5CO2C2H5油1324CH3CH2HCl Cl H H C6H5CO2H 油1325CH3CH2HCl Cl H H C6H5CH2OH 油1326CH3CH2HCH3OCH3ClH H 2-Cl-C6H4油1327CH3CH2HCH3OCH3ClH H 3-Cl-C6H4油1328CH3CH2HCH3OCH3ClH H 4-Cl-C6H4油1329CH3CH2HCH3OCH3ClH H 3-CH3O-C6H4油1330CH3CH2HCH3OCH3ClH H 3-CN-C6H4油1331CH3CH2HCH3OCH3ClH H 4-CN-C6H4油1332CH3CH2HCH3OCH3ClH H 4-BnO-C6H4油1333CH3CH2HCH3OCH3ClH H 2,5-(CH3O)-C6H3油1334CH3CH2HCH3OCH3ClH H 2-CH3O-C6H4油1335CH3CH2HCl Cl H H CN c-C3H5油1336CH3CH2HCl Cl H H CH3CH2OC2H596-971337CH3CH2HCl Cl H H H CH(OH)CH2OC6H5油1338CH3CH2HCl Cl H H H CH(OH)CH2C6H5油1339CH3CH2HCl Cl H H H CH(OH)C3H7油1340CH3CH2HCl Cl H H CH(CH3)2C(O)-1-嗎啉基 154-1551341CH3CH2HCl Cl H H C2H5CO2CH3油1342CH3CH2HCl Cl H H CH3CO2CH3油1343CH3CH2HCl Cl H H CH3CN 油1344CH3CH2HCl Cl H H CH3COCH3油1345CH3CH2HCl Cl H H H 2-Cl-C6H4149-1521346CH3CH2HCl Cl H H H 3-Cl-C6H4油1347CH3CH2HCl Cl H H H 4-F-C6H4148-1491348CH3CH2HCl Cl H H H 4-CN-C6H4199-2001349CH3CH2HCl Cl H H H 4-Cl-C6H4183-1841350CH3CH2HCl Cl H H c-C3H5c-C4H7-1351CH3CH2HCH3OCH3CH3H c-C3H5c-C4H7-1352CH3CH2HCl CF3H H c-C3H5c-C4H7-1353CH3CH2HCl OCH3H H c-C3H5c-C4H7-1354CH3CH2HCl OCF3H H c-C3H5c-C4H7-1355CH3CH2HCl CH3H H c-C3H5c-C4H7-1356CH3CH2HCF3OCH3H H c-C3H5c-C4H7-1357CH3CH2HCl Cl H CH3c-C3H5c-C4H7-1358CH3CH2HCH3OCH3ClH c-C3H5c-C4H7-1359CH3CH2HCH3OCH3F H c-C3H5c-C4H7-1360CH3CH2HCl OCH3F Hc-C3H5c-C3H5-1361CH3CH2HCl OCH3F HC2H5c-C3H5-1362CH3CH2HCl OCH3F HC3H7c-C3H5-1363CH3CH2HCl OCH3F HCH3c-C4H7-1364CH3CH2HCl OCH3F HCH3C3H7-1365CH3CH2HCl OCH3F HC2H5C3H7-1366CH3CH2HCl OCH3F HC2H5C2H5-1367CH3CH2HCl OCH3F HC3H7C3H7-1368CH3CH2HCl OCH3F HCH3C4H9-1369CH3CH2HCl OCH3F HH 4-CH3O-C6H4-1370CH3CH2HCF3OCH3H HC2H5C3H7油1371CH3CH2HCl Cl H HCH32-CH3-c-C3H4油1372CH3CH2HCH3OCH3CH3HCH32-CH3-c-C3H4-1373CH3CH2HCl CF3H HCH32-CH3-c-C3H4-1374CH3CH2HCl OCH3H HCH32-CH3-c-C3H4-1375CH3CH2HCl OCF3H HCH32-CH3-c-C3H4-1376CH3CH2HCl CH3H HCH32-CH3-c-C3H4-1377CH3CH2HCF3OCH3H HCH32-CH3-c-C3H4-1378CH3CH2HCl Cl H CH3CH32-CH3-c-C3H4-1379CH3CH2HCH3OCH3Cl HCH32-CH3-c-C3H4-1380CH3O HCl Cl H HCH32-CH3-c-C3H4-1381CH3CH2HCl Cl H HCH32-C6H5-c-C3H4-1382CH3CH2HCH3OCH3CH3HCH32-C6H5-c-C3H4-1383CH3CH2HCl CF3H HCH32-C6H5-c-C3H4-1384CH3CH2HCl OCH3H HCH32-C6H5-c-C3H4-1385CH3CH2HCl OCF3H HCH32-C6H5-c-C3H4-1386CH3CH2HCl CH3H HCH32-C6H5-c-C3H4-1387CH3CH2HCF3OCH3H HCH32-C6H5-c-C3H4-1388CH3CH2HCl Cl H CH3CH32-C6H5-c-C3H4-1389CH3CH2HCH3OCH3Cl HCH32-C6H5-c-C3H4-1390CH3O HCl Cl H HCH32-C6H5-c-C3H4-1391CH3CH2HCl Cl H HCH32-(2-吡啶基)-c-C3H4-1392CH3CH2HCH3OCH3CH3HCH32-(2-吡啶基)-c-C3H4-1393CH3CH2HCl CF3H HCH32-(2-吡啶基)-c-C3H4-1394CH3CH2HCl OCH3H HCH32-(2-吡啶基)-c-C3H4-1395CH3CH2HClOCF3H H CH32-(2-吡啶基)-c-C3H4-1396CH3CH2HClCH3H H CH32-(2-吡啶基)-c-C3H4-1397CH3CH2HCF3OCH3H H CH32-(2-吡啶基)-c-C3H4-1398CH3CH2HClCl H CH3CH32-(2-吡啶基)-c-C3H4-1399CH3CH2HCH3OCH3ClH CH32-(2-吡啶基)-c-C3H4-1400CH3O HClCl H H CH32-(2-吡啶基)-c-C3H4-關(guān)鍵(a)在化合物被表明為“油”的地方,提供數(shù)據(jù)如下實施例3波譜數(shù)據(jù)TLC RF0.27(30∶70乙酸乙酯-己烷)。1HNMR(300MHz,CDCl3)δ8.90(1H,s),6.95(2H,s),4.45(1H,br),4.27-4.17(2H,m),3.85(1H,dd,J=9.5,4.8Hz),3.27(3H,s),2.94(2H,q,J=7.5Hz),2.56-2.46(1H,m),2.32(3H,s),2.06(3H,s),2.03(3H,s),1.37(3H,t,J=7.5Hz),0.85(3H,t,J=7.5Hz)。MS(NH3-CI)m/e355(3),354(25),353(100)。C21H28N4O·1.5H2O的分析計算值C,66.46;H,8.23;N,14.76;實測值C,67.00;H,8.10;N,14.38。
      實施例8波譜數(shù)據(jù)TLC RF0.34(50∶50乙酸乙酯-己烷)。1HNMR(300MHz,CDCl3)δ8.89(1H,s),6.95(2H,s),4.46(1H,br),3.41-3.33(1H,m),3.22(3H,s),2.94(2H,q,J=7.3Hz),2.93-2.85(1H,m),2.84-2.69(2H,m),2.51(1H,br),2.32(3H,s),2.30-2.20(1H,m),2.04(6H,s),1.37(3H,t,J=7.7Hz),0.84(3H,t,J=7.3Hz)。MS(NH3-CI)m/e C22H30N4O的計算值366.2420,實測值366.2400;369(3),368(27),367(100)。
      實施例10波譜數(shù)據(jù)TLC RF0.13(乙酸乙酯)。1H NMR(300MHz,CDCl3)δ8.93(1H,s),8.10(1H,s),7.96(1H,s),6.96(2H,s),4.39(1H,br),4.24-4.14(1H,m),4,12-4.00(1H,m),3.20(1H,br),2.80(2H,q,J=7.0Hz),2.78-2.68(1H,m),2.42(1H,br),2.33(3H,s),2.13-2.04(1H,m),2.06(3H,s),2.03(3H,s),1.33(3H,t,J=7.5Hz),0.80(3H,t,J=7.3Hz)。MS(NH3-CI)m/e C23H30N7的計算值404.2563,實測值404.2556;406(4),405(28),404(100)。
      實施例11波譜數(shù)據(jù)TLC RF0.60(乙酸乙酯)。1H NMR(300MHz,CDCl3)δ8.92(1H,s),8.51(1H,s),6.96(2H,s),4.78-4.68(1H,m),4.57-4.47(1H,m),4,32-4.22(1H,m),3.43(1H,br),2.81(2H,q,J=6.9Hz),2.78(1H,br),2.43(1H,br),2.33(3H,s),2.10-2.00(1H,m),2.07(3H,s),2.03(3H,s),1.32(3H,t,J=7.0Hz),0.78(3H,t,J=7.5Hz)。MS(NH3-CI)m/e C22H29N8的計算值405.2515,實測值405.2509;407(4),406(27),405(100)。
      實施例18波譜數(shù)據(jù)TLC RF0.20(30∶70乙酸乙酯-己烷)。1HNMR(300MHz,CDCl3)δ9.00(1H,s),7.26(1H,模糊的),6.96(2H,s),6.86-6.76(3H,m),5.46(2H,s),3.76(3H,s),2.85(2H,q,J=7.7Hz),2.33(3H,s),2.06(6H,s),1.28(3H,t,J=7.7Hz)。MS(NH3-CI)m/e389(4),388(28),387(100)。C24H26N4O的分析計算值C,74.58;H,6.78;N,14.50;實測值C,74.36;H,6.73;N,13.83。
      實施例27波譜數(shù)據(jù)TLC RF0.20(30∶70乙酸乙酯-己烷)。1HNMR(300MHz,CDCl3)δ8.96(1H,s),6.95(2H,s),4.25(2H,t,J=7.5Hz),2.93(2H,q,J=7.7Hz),2.32(3H,s),2.04(6H,s),1.91-1.86(2H,m),1.50-1.38(2H,m),1.39(3H,t,J=7.7Hz),1.01(3H,t,J=7.5Hz)。MS(NH3-CI)m/e 325(3),324(23),323(100)。
      實施例28波譜數(shù)據(jù)TLC RF0.28(30∶70乙酸乙酯-己烷)。1HNMR(300MHz,CDCl3)δ8.96(1H,s),6.95(2H,s),4.24(2H,t,J=7.9Hz),2.93(2H,q,J=7.6Hz),2.32(3H,s),2.04(6H,s),1.90(2H,m),1.44-1.36(7H,m),0.93(3H,t,J=7.1Hz)。MS(NH3-CI)m/e 339(3),338(25),337(100)。C21H28N4的分析計算值C,74.96;H,8.40;N,16.65;實測值C,74.24;H,8.22;N,16.25。
      實施例34波譜數(shù)據(jù)MS(ESI)m/e 365(M+2),363(M+H+,100%)。
      實施例35波譜數(shù)據(jù)TLC RF0.31(20∶80乙酸乙酯-己烷)。1H NMR(300MHz,CDCl3)δ8.94(1H,s),7.71(1H,d,J=8.4Hz),7.58(1H,d,J=1.8Hz),7.41(1H,dd,J=8.4,1.8Hz),4.27(1H,br),2.95(2H,q,J=7.3Hz),2.41(2H,br),2.11-1.98(2H,br),1.42(3H,t,J=7.3Hz),1.37-1.20(3H,m),1.09-0.99(1H,m),0.84(3H,t,J=7.7Hz),0.82(3H,t,J=7.7Hz)。MS(NH3-CI)m/e C20H25N4Cl2的計算值391.1456,實測值391.1458;395(11),394(14),393(71),392(29),391(100)。
      實施例38波譜數(shù)據(jù)MS(NH3-CI)m/e 375(M+H+,100%)。
      實施例40波譜數(shù)據(jù)MS(NH3-CI)m/e 377(M+H+,100%)。
      實施例48波譜數(shù)據(jù)MS(NH3-CI)m/e 423(M+H+,100%)。
      實施例50波譜數(shù)據(jù)TLC RF0.27(30∶70乙酸乙酯-己烷)。1HNMR(300MHz,CDCl3)δ9.03(1H,s),7.70(1H,d,J=8.0Hz),7.59(1H,d,J=1.8Hz),7.41(1H,dd,J=8.0,1.8Hz),7.36-7.30(2H,m),7.24-7.19(3H,m),5.50(2H,s),2.87(2H,q,J=7.5Hz),1.31(3H,t,J=7.5Hz)。MS(NH3-CI)m/e C20H16N4Cl2的計算值382.0752,實測值382.0746;388(3),387(12),386(16),385(66),384(26),383(100)。
      實施例51波譜數(shù)據(jù)MS(NH3-CI)m/e 413(M+H+,100%)。
      實施例54波譜數(shù)據(jù)MS(NH3-CI)m/e 459(M+H+,100%)。
      實施例68波譜數(shù)據(jù)TLC RF0.28(30∶70乙酸乙酯-己烷)。1HNMR(300MHz,CDCl3)δ8.91(1H,s),6.69(2H,s),4.30-4.19(1H,m),3.82(3H,s),2.92(2H,q,J=7.6Hz),2.41(1H,br),2.08(3H,s),2.07(3H,s),2.06(1H,br),1.38(3H,t,J=7.6Hz),1.36-1.22(4H,m),1.10-0.98(1H,m),0.96-0.87(1H,m),0.84(3H,t,J=7.0Hz),0.81(3H,t,J=6.7Hz)。MS(NH3-CI)m/e 383(4),382(27),381(100)。
      實施例122波譜數(shù)據(jù)TLC RF0.10(20∶80乙酸乙酯-己烷)。1HNMR(300MHz,CDCl3)δ8.97(1H,s),6.94(2H,s),4.14(2H,d,J=7.7Hz),3.48(1H,q,J=7.0Hz),2.63(3H,s),2.31(3H,s),2.01(6H,s),1.43-1.19(8H,m),0.94(3H,t,J=7.3Hz),0.84(3H,t,J=7.0Hz)。MS(NH3-CI)m/e 367(3),366(25),365(100)。
      實施例123波譜數(shù)據(jù)TLC RF0.24(30∶70乙酸乙酯-己烷)。1HNMR(300MHz,CDCl3)δ8.97(1H,s),6.94(2H,s),4.25(2H,t,J=8.1Hz),3.48(1H,q,J=7.1Hz),2.63(3H,s),2.31(3H,s),2.01(6H,s),1.81(2H,m),1.47-1.19(8H,m),0.91(6H,m)。MS(NH3-CI)m/e 381(4),380(27),379(100)。C24H34N4的分析計算值C,76.15;H,9.05;N,14.80;實測值C,76.29;H,9.09;N,14.75。
      實施例202波譜數(shù)據(jù)TLC RF0.20(10∶90乙酸乙酯-己烷)。1HNMR(300MHz,CDCl3)d 8.82(1H,s),6.96(2H,s),4.46-4.38(1H,m),4.13(3H,s),2.34(3H,s),2.28-2.11(2H,m),2.07(6H,s),1.95-1.81(2H,m),1.38-1.17(3H,m),1.14-0.99(1H,m),0.83(3H,t,J=7.7Hz),0.80(3H,t,J=7.7Hz)。MS(NH3-CI)m/e C22H30N4的計算值366.2420,實測值366.2408;369(4),368(26),367(100)。
      實施例404波譜數(shù)據(jù)TLC RF0.20(20∶80乙酸乙酯-己烷)。1HNMR(300MHz,CDCl3)δ6.93(2H,s),4.20(2H,t,J=7.7Hz),2.90(2H,q,J=7.6Hz),2.83(3H,s),2.30(3H,s),2.03(6H,s),1.88(2H,m),1.42-1.34(7H,m),0.93(3H,t,J=6Hz)。MS(NH3-CI)m/e 353(3),352(27),351(100)。
      實施例414波譜數(shù)據(jù)TLC RF0.36(20∶80乙酸乙酯-己烷)。1HNMR(300MHz,CDCl3)δ8.92(1H,s),7.66(1H,d,J=8.1Hz),7.32-7.26(2H,m),4.54(1H,m),2.95(2H,q,J=7.4Hz),2.43(3H,s),2.39(1H,m),2.03(1H,m),1.74(3H,d,J=7.0Hz),1.41(3H,t,J=7.5Hz),1.31(1H,m),1.16(1H,m),0.92(3H,t,J=7.3Hz)。MS(NH3-CI)m/eC19H24N4Cl的計算值343.1690,實測值343.1704;346(7),345(34),344(23),343(100)。
      實施例415波譜數(shù)據(jù)TLC RF0.25(10∶90乙酸乙酯-己烷)。1HNMR(300MHz,CDCl3)δ8.91(1H,s),7.71(1H,d,J=8.1Hz),7.34-7.30(2H,m),4.30-4.20(1H,m),2.94(2H,q,J=7.5Hz),2.50-2.35(2H,m),2.44(3H,s),2.08-1.95(2H,m),1.43(3H,t,J=7.5Hz),1.29(3H,m),1.08-0.98(1H,m),0.84(3H,t,J=7.0Hz),0.81(3H,t,J=7.3Hz)。MS(NH3-CI)m/e 374(7),373(33),372(25),371(100)。C21H27ClN4的分析計算值C,68.00;H,7.35;N,15.10;實測值C,68.25;H,7.30;N,14.85。
      實施例424波譜數(shù)據(jù)TLC RF0.28(5∶95乙酸乙酯-二氯甲烷)。1H NMR(300MHz,CDCl3)δ8.95(1H,s),7.60(1H,d,J=7.7Hz),7.37(1H,d,J=0.8Hz),7.21(1H,dd,J=7.7,0.8Hz),4.58-4.50(1H,m),2.96(2H,dq,J=7.5,2.0Hz),2.46-2.33(1H,m),2.40(3H,s),2.08-1.96(1H,m),1.74(3H,d,J=6.6Hz),1.40(3H,t,J=7.5Hz),1.39-1.22(1H,m),1.20-1.08(1H,m),0.92(3H,t,J=7.3Hz)。MS(NH3-CI)m/eC19H24ClN4的計算值343.1690,實測值343.1697;346(8),345(38),344(25),343(100)。
      實施例434波譜數(shù)據(jù)TLC RF0.78(50∶50乙酸乙酯-己烷)。1HNMR(300MHz,CDCl3)δ8.90(1H,s),6.95(2H,s),2.97(2H,J=7.3Hz),2.60-2.50(1H,m),2.41-2.33(1H,m),2.32(3H,s),2.20-2.10(1H,m),2.05(3H,s),2.02(3H,s),1.85-1.80(1H,m),1.39(3H,t,J=7.5Hz),0.85(3H,t,J=7.5Hz),0.50-0.35(2H,m),0.25-0.15(1H,m),0.10-0.00(1H,m)。MS(NH3-CI)m/e C23H30N4的計算值362.2470,實測值362.2458;365(4),364(27),363(100)。
      實施例436波譜數(shù)據(jù)TLC RF0.31(30∶70乙酸乙酯-己烷)。1HNMR(300MHz,CDCl3)δ8.88(1H,s),7.77(1H,d,J=9.2Hz),6.87(2H,m),4.40-4.25(1H,m),3.86(3H,s),2.99(2H,q,J=7.5Hz),2.60-2.35(2H,m),2.47(3H,s),2.15-2.00(1H,m),1.80-1.70(1H,m),1.45(3H,t,J=7.5Hz),0.84(3H,t,J=7.5Hz),0.50-0.35(2H,m),0.30-0.20(1H,m),0.10-0.00(1H,m),-0.85--0.95(1H,m)。
      實施例437波譜數(shù)據(jù)TLC RF0.25(30∶70乙酸乙酯-己烷)。1HNMR(300MHz,CDCl3)δ8.90(1H,s),7.73(1H,d,J=9.2Hz),6.89-6.86(2H,m),4.58-4.51(1H,m),3.86(3H,s),2.95(2H,dq,J=7.6,1.8Hz),2.47(3H,s),2.45-2.34(1H,m),2.07-1.97(1H,m),1.73(3H,d,J=7.0Hz),1.42(3H,t,J=7.6Hz),1.40-1.27(1H,m),1.20-1.07(1H,m),0.92(3H,t,J=7.4Hz)。MS(NH3-CI)m/e C20H27N4O的計算值339.2185,實測值339.2187;341(3),340(22),339(100)。C20H26N4O的分析計算值C,70.98;H,7.74;N,16.55;實測值C,69.97;H,7.48;N,15.84。
      實施例438波譜數(shù)據(jù)TLC RF0.42(40∶60乙酸乙酯-己烷)。1HNMR(300MHz,CDCl3)δ8.98(1H,s),7.77(1H,d,J=9.1Hz),7.17(2H,d,J=8.8Hz),6.90-6.83(4H,m),5.42(2H,s),3.86(3H,s),3.78(3H,s),2.86(2H,q,J=7.5Hz),2.49(3H,s),1.33(3H,t,J=7.5Hz)。MS(NH3-CI)m/e 391(4),390(26),389(100)。C23H24N4O2的分析計算值C,71.11;H,6.24;N,14.42;實測值C,71.14;H,5.97;N,14.03。
      實施例439波譜數(shù)據(jù)TLC RF0.41(30∶70乙酸乙酯-己烷)。1HNMR(300MHz,CDCl3)δ8.89(1H,s),7.77(1H,d,J=3.1Hz),6.89(2H,m),3.86(3H,s),3.53(1H,m),2.91(2H,q,J=7.5Hz),2.49(3H,s),2.28(1H,m),2.21(1H,m),1.43(3H,t,J=7.3Hz),0.86(3H,t,J=7.3Hz),0.78(2H,m),0.46(2H,m),0.20(1H,m)。
      實施例440波譜數(shù)據(jù)TLC RF0.28(30∶70乙酸乙酯-己烷)。1HNMR(300MHz,CDCl3)δ8.89(1H,s),7.73(1H,d,J=9.1Hz),6.90-6.86(2H,m),4.60-4.40(1H,m),3.86(3H,s),2.95(2H,dq,J=7.7,2.2Hz),2.47(3H,s),2.44-2.36(1H,m),2.05-1.98(1H,m),1.74(3H,d,J=7.0Hz),1.42(3H,t,J=7.5Hz),1.40-1.20(5H,m),1.13-1.05(1H,m),0.830(3H,t,J=6.6Hz)。
      實施例502波譜數(shù)據(jù)TLC RF0.63(50∶50乙酸乙酯-己烷)。1HNMR(300MHz,CDCl3)δ8.92(1H,s),6.95(2H,s),4.60-4.47(1H,m),2.93(2H,q,J=7.7Hz),2.43-2.33(1H,m),2.32(3H,s),2.16-2.06(1H,m),2.05(3H,s),2.03(3H,s),1.76(3H,d,J=7.0Hz),1.36(3H,t,J=7.7Hz),1.36-1.20(4H,m),0.86(3H,t,J=7.2Hz)。MS(NH3-CI)m/eC22H30N4的計算值350.2470,實測值350.2480;353(3),352(28),351(100)。
      實施例503波譜數(shù)據(jù)1H NMR(300MHz,CDCl3)δ8.92(1H,s),6.94(2H,s),4.58-4.48(1H,m),2.93(2H,q,J=7.3Hz),2.32(3H,s),2.05(3H,s),2.02(3H,s),1.76(3H,d,J=6.6Hz),1.36(3H,t,J=7.3Hz),1.34-1.05(8H,m),0.88(3H,t,J=7Hz)。MS(NH3-CI)m/e C23H32N4的計算值365.2705,實測值365.2685;367(3),366(27),365(100)。
      實施例506波譜數(shù)據(jù)TLC RF0.28(20∶80乙酸乙酯-己烷)。1HNMR(300MHz,CDCl3)δ8.95(1H,s),7.67(1H,d,J=8.4Hz),7.57(1H,d,J=1.8Hz),7.42-7.37(1H,m),4.56(1H,六重峰,J=7.1Hz),2.99(2H,q,J=7.5Hz),2.43-2.33(1H,m),2.09-1.97(1H,m),1.74(3H,d,J=7.0Hz),1.41(3H,t,J=7.5Hz),1.35-1.07(2H,m),0.92(3H,t,J=7.3Hz)。MS(NH3-CI)m/e 367(12),366(14),365(67),364(24),363(100)。
      實施例507波譜數(shù)據(jù)MS(NH3-CI)m/e 377(M+H+,100%)。
      實施例511波譜數(shù)據(jù)TLC RF0.51(30∶70乙酸乙酯-己烷)。1HNMR(300MHz,CDCl3)δ8.97(1H,s),7.87(1H,d,J=8.1Hz),7.83(1H,d,J=1.1Hz),7.68(1H,dd,J=8.1,1.1Hz),3.60-3.51(1H,m),2.94(2H,q,J=7.5Hz),2.53-2.39(1H,m),2.36-2.20(1H,m),1.96(1H,br),1.42(3H,t,J=7.5Hz),0.88(3H,t,J=7.3Hz),0.88-0.78(1H,m),0.52-0.44(2H,m),0.24-0.16(1H,m)。MS(NH3-CI)m/e 412(7),411(33),410(23),409(100)。
      實施例513波譜數(shù)據(jù)TLC RF0.62(30∶70乙酸乙酯-己烷)。1HNMR(300MHz,CDCl3)δ8.97(1H,s),7.87(1H,d,J=8.0Hz),7.83(1H,d,J=0.7Hz),7.68(1H,dd,J=8.0,0.7Hz),4.21(1H,br),2.96(2H,q,J=7.5Hz),2.42(2H,br),2.12-1.97(2H,m),1.43(3H,t,J=7.5Hz),1.40-1.20(4H,m),0.85(3H,t,J=7.3Hz),0.83(3H,t,J=7.6Hz)。MS(NH3-CI)m/e 428(8),427(38),426(29),425(100)。
      實施例514波譜數(shù)據(jù)TLC RF0.51(30∶70乙酸乙酯-己烷)。1HNMR(300MHz,CDCl3)δ8.96(1H,s),7.86(1H,d,J=8.1Hz),7.83(1H,d,J=0.8Hz),7.68(1H,dd,J=8.1,0.8Hz),4.20(1H,br),2.97(2H,q,J=7.7Hz),2.54-2.39(2H,m),2.15-2.01(2H,m),1.43(3H,t,J=7.7Hz),0.84(6H,t,J=7.5Hz)。MS(NH3-CI)m/e 400(7),399(37),398(26),397(100)。
      實施例524波譜數(shù)據(jù)TLC RF0.50(30∶70乙酸乙酯-己烷)。1HNMR(300MHz,CDCl3)δ8.89(1H,s),7.76(1H,d,J=9.1Hz),6.90-6.87(2H,m),4.35(1H,v br),3.86(3H,s),2.93(2H,q,J=7.6Hz),2.48(3H,s),2.39(2H,br),2.00-1.90(2H,m),1.43(3H,t,J=7.6Hz),1.38-1.22(2H,m),1.18-1.02(2H,m),0.90(6H,t,J=7.3Hz)。MS(NH3-CI)m/e C22H31N4O的計算值367.2498,實測值367.2506;369(3),368(25),367(100)。
      實施例526波譜數(shù)據(jù)TLC RF0.28(10∶90乙酸乙酯-己烷)。1HNMR(300MHz,CDCl3)δ8.91(1H,s),7.69(1H,d,J=8.1Hz),7.34-7.30(2H,m),4.40-4.35(1H,m),2.93(2H,q,J=7.4Hz),2.44(3H,s),2.38(2H,m),1.96(2H,m),1.43(3H,t,J=7.5Hz),1.35-1.22(2H,m),1.15-1.05(2H,m),0.90(6H,t,J=7.1Hz)。MS(NH3-CI)m/e 374(8),373(35),372(25),371(100)。C21H27N4Cl的分析計算值C,68.00;H,7.35;N,15.10;實測值C,67.89;H,7.38;N,14.94。
      實施例528波譜數(shù)據(jù)TLC RF0.65(30∶70乙酸乙酯-己烷)。1HNMR(300MHz,CDCl3)δ8.97(1H,s),7.86(1H,d,J=8.0Hz),7.82(1H,d,J=1.1Hz),7.67(1H,dd,J=8.0,1.1Hz),4.38(1H,br),2.95(2H,q,J=7.5Hz),2.39(2H,br),2.04-1.92(2H,br),1.42(3H,t,J=7.5Hz),1.40-1.21(3H,m),1.19-1.03(1H,m),0.91(6H,t,J=7.3Hz)。MS(NH3-CI)m/e 428(8),427(37),426(27),425(100)。
      實施例538波譜數(shù)據(jù)TLC RF0.56(30∶70乙酸乙酯-己烷)。1HNMR(300MHz,CDCl3)δ8.96(1H,s),7.88(1H,d,J=8.0Hz),7.83(1H,d,J=0.8Hz),7.68(1H,dd,J=8.0,0.8Hz),3.77(1H,br),2.95(2H,q,J=7.5Hz),2.61(1H,br),2.08(1H,br),1.45(3H,t,J=7.5Hz),1.36-1.25(1H,m),1.17(3H,d,J=6.6Hz),0.71(3H,t,J=7.3Hz),0.69(3H,d,J=7.0Hz)。MS(NH3-CI)m/e 414(7),413(33),412(24),411(100)。
      實施例534波譜數(shù)據(jù)MS(ESI)m/e 363(M+2),361(M+,100%)。
      實施例544波譜數(shù)據(jù)TLC RF0.63(50∶50乙酸乙酯-己烷)。1HNMR(300MHz,CDCl3)δ8.90(1H,s),7.74(1H,d,J=9.1Hz),6.89-6.86(2H,m),3.86(3H,s),3.79-3.73(1H,m),2.93(3H,dq,J=7.7,2.6Hz),2.49(3H,s),2.03-1.99(1H,m),1.81(3H,d,J=6.9Hz),1.41(3H,t,J=7.3Hz),0.84-0.74(2H,m),0.53-0.41(2H,m),0.28-0.21(1H,m)。
      實施例548波譜數(shù)據(jù)TLC RF0.42(30∶70乙酸乙酯-己烷)。1HNMR(300MHz,CDCl3)δ8.99(1H,s),7.84(1H,d,J=7.7Hz),7.82(1H,d,J=0.9Hz),7.68(1H,dd,J=7.7,0.9Hz),3.83-3.70(1H,m),3.00-2.90(2H,m),2.09-1.98(1H,m),1.83(3H,d,J=7.0Hz),1.40(3H,t,J=7.3Hz),0.88-0.78(1H,m),0.57-0.41(2H,m),0.30-0.20(1H,m)。MS(NH3-CI)m/e 398(6),397(31),396(22),395(100)。
      實施例551波譜數(shù)據(jù)TLC RF0.56(50∶50乙酸乙酯-己烷)。1HNMR(300MHz,CDCl3)δ8.93(1H,s),6.94(2H,s),4.75(1H,七重峰,J=7.0Hz),2.95(2H,q,J=7.7Hz),2.32(3H,s),2.04(6H,s),1.80(6H,d,J=7.0Hz),1.36(3H,t,J=7.7Hz)。MS(NH3-CI)m/e 311(4),310(34),309(100)。C19H24N4·0.5H2O的計算值C,71.89;H,7.94;N,17.65;實測值C,71.59;H,7.83;17.41。
      實施例558波譜數(shù)據(jù)TLC RF0.53(30∶70乙酸乙酯-己烷)。1HNMR(300MHz,CDCl3)δ8.98(1H,s),7.86-7.81(2H,m),7.67(1H,dd,J=8.4,1.1Hz),4.60-4.48(1H,m),3.01-2.93(2H,m),2.49-2.35(1H,m),2.13-2.00(1H,m),1.76(3H,d,J=7.0Hz),1.41(3H,t,J=7.5Hz),1.40-1.20(4H,m),0.87(3H,t,J=7.3Hz)。MS(NH3-CI)m/e 414(8),413(38),412(27),411(100)。
      實施例564波譜數(shù)據(jù)TLC RF0.34(30∶70乙酸乙酯-己烷)。1HNMR(300MHz,CDCl3)δ8.89(1H,s),7.77(1H,d,J=9.2Hz),6.89(2H,m),4.30-4.20(1H,m),3.86(3H,s),2.93(2H,q,J=7.5Hz),2.48(3H,s),2.45-2.35(2H,m),2.10-1.95(2H,m),1.44(3H,t,J=7.5Hz),1.40-1.20(3H,m),1.10-0.95(1H,m),0.84(3H,t,J=7.3Hz),0.81(3H,t,J=7.3Hz)。
      實施例571波譜數(shù)據(jù)TLC RF0.40(50∶50乙酸乙酯-己烷)。1HNMR(300MHz,CDCl3)δ8.89(1H,s),6.95(2H,s),4.51(1H,br),3.44-3.24(4H,m),2.96(2H,q,J=7.3Hz),2.95-2.87(1H,m),2.85-2.75(1H,m),2.59-2.49(1H,m),2.32(3H,s),2.27-2.18(1H,m),2.04(3H,s),2.04(3H,s),1.38(3H,t,J=7.7Hz),1.12(3H,t,J=7.0Hz),0.84(3H,t,J=7.3Hz)。MS(NH3-CI)m/e C23H32N4O的計算值380.2576,實測值380.2554。383(4),382(28),381(100)。
      實施例581波譜數(shù)據(jù)TLC RF0.33(30∶70乙酸乙酯-己烷)。1HNMR(300MHz,CDCl3)δ8.89(1H,s),6.95(2H,s),4.49-4.39(1H,m),4.23-4.13(1H,m),3.91(1H,dd,J=9.9,4.8Hz),3.48(1H,dq,J=9.1,7.0Hz),3.30(1H,dq,J=9.1,7.0Hz),2.95(2H,q,J=7.7Hz),2.60-2.47(1H,m),2.32(3H,s),2.15-2.01(1H,m),2.04(3H,s),2.03(3H,s),1.37(3H,t,J=7.5Hz),1.00(3H,t,J=7.0Hz),0.86(3H,t,J=7.3Hz)。MS(NH3-CI)m/e C22H31N4O的計算值367.2498,實測值367.2497;369(4),368(27),367(100)。
      實施例591波譜數(shù)據(jù)TLC RF0.42(50∶50乙酸乙酯-己烷)。1HNMR(300MHz,CDCl3)δ8.91(1H,s),6.95(2H,s),3.76(1H,br),3.47-3.40(1H,m),3.21(3H,s),2.99-2.90(1H,m),2.88(2H,q,J=7.3Hz),2.76(1H,br),2.51-2.41(1H,m),2.32(3H,s),2.09(1H,br),2.08(3H,s),2.04(3H,s),1.35(3H,t,J=7.3Hz),0.84-0.76(1H,m),0.56-0.44(2H,m),0.30-0.21(1H,m)。MS(NH3-CI)m/e C23H31N4O的計算值379.2498,實測值379.2514;381(4),380(27),379(100)。
      實施例690波譜數(shù)據(jù)TLC RF0.12(30∶70乙酸乙酯-己烷)。1HNMR(300MHz,CDCl3)d 9.01(1H,s),7.38-7.22(5H,m),6.75(1H,s),6.69(1H,s),5.48(2H,s),3.70(3H,s),2.84(2H,q,J=7.7Hz),2.37(3H,s),2.05(3H,s),1.26(3H,t,J=7.7Hz)。MS(NH3-CI)m/e 375(4),374(28),373(100)。
      實施例692波譜數(shù)據(jù)TLC RF0.32(30∶70乙酸乙酯-己烷)。1HNMR(300MHz,CDCl3)δ8.98(1H,s),7.48(1H,s),7.37-7.18(5H,m),7.11(1H,s),5.49(2H,s),2.84(2H,q,J=7.3Hz),2.38(3H,s),2.29(6H,s),1.31(3H,t,J=7.3Hz)。MS(H3-CI)m/e C23H24N4的計算值356.2001,實測值356.1978;359(4),358(28),357(100)。
      實施例693波譜數(shù)據(jù)TLC RF0.22(20∶80乙酸乙酯-己烷)。1HNMR(300MHz,CDCl3)δ8.90(1H,s),7.78(1H,d,J=9.5Hz),6.90-6.87(2H,m),3.86(3H,s),3.62(1H,br),2.91(2H,q,J=7.5Hz),2.50(3H,s),2.40(1H,br),2.26-2.13(1H,m),1.92(1H,br),1.58(1H,br),1.43(3H,t,J=7.5Hz),1.35-1.25(1H,m),1.13-1.03(1H,m),0.95-0.75(2H,m),0.85(3H,t,J=7.1Hz),0.54-0.42(2H,m),0.22-0.17(1H,m)。MS(NH3-CI)m/e 381(4),380(25),379(100)。
      實施例697波譜數(shù)據(jù)TLC RF0.28(30∶70乙酸乙酯-己烷)。1HNMR(300MHz,CDCl3)δ8.89(1H,s),7.74(1H,d,J=9.5Hz),6.90-6.86(2H,m),4.58-4.45(1H,m),2.95(2H,dq,J=7.7,2.2Hz),2.48(3H,s),2.45-2.35(1H,m),2.09-1.99(1H,m),1.74(3H,d,J=7.0Hz),1.42(3H,t,J=7.5Hz),1.37-1.23(3H,m),1.11-1.03(1H,m),0.86(3H,t,J=7.0Hz)。
      實施例724波譜數(shù)據(jù)TLC RF0.45(30∶70乙酸乙酯-己烷)。1HNMR(300Mz,CDCl3)δ8.92(1H,s),7.75(1H,d,J=8.4Hz),7.09(1H,d,J=2.6Hz),6.96(1H,dd,J=8.4,2.6Hz),3.87(3H,s),3.76(1H,br),2.94(2H,q,J=7.3Hz),2.61(1H,br),2.09(1H,br),1.45(3H,t,J=7.3Hz),1.36-1.26(1H,m),1.15(3H,d,J=6.6Hz),0.71(3H,t,J=7.3Hz),0.68(3H,d,J=6.6Hz)。MS(NH3-CI)m/e 377(1),376(8),375(38),374(25),373(100)。
      實施例725波譜數(shù)據(jù)TLC RF0.31(30∶70乙酸乙酯-己烷)。1HNMR(300MHz,CDCl3)δ8.88(1H,s),7.80(1H,d,J=9.2Hz),6.89(2H,m),3.86(3H,s),3.75(1H,m),2.92(2H,q,J=7.4Hz),2.60(1H,m),2.48(3H,s),2.05(1H,m),1.46(3H,t,J=7.4Hz),1.16(3H,d,J=7.0Hz),0.70(3H,t,J=7.3Hz),0.67(3H,d,J=6.6Hz)。
      實施例727波譜數(shù)據(jù)TLC RF0.44(30∶70乙酸乙酯-己烷)。1HNMR(300MHz,CDCl3)δ8.90(1H,s),7.84(1H,d,J=2.2Hz),7.74(1H,d,J=8.4Hz),7.65(1H,dd,J=8.4,2.2Hz),3.76(1H,br),2.93(1H,q,J=7.3Hz),2.60(1H,br),2.08(1H,br),1.42(3H,t,J=7.3Hz),1.37-1.27(1H,m),1.16(3H,d,J=7.0Hz),0.69(3H,t,J=7.3Hz),0.67(3H,d,J=7.0Hz)。MS(NH3-CI)m/e 414(7),413(33),412(27),411(100)。
      實施例750波譜數(shù)據(jù)TLC RF0.42(30∶70乙酸乙酯-己烷)。1HNMR(300MHz,CDCl3)δ8.94(1H,s),7.73(1H,d,J=8.4Hz),7.10(1H,d,J=2.6Hz),6.96(1H,dd,J=8.4,2.6Hz),3.87(3H,s),3.63(1H,vbr),2.92(2H,q,J=7.3Hz),2.38(1H,br),2.22-2.10(1H,m),1.94(1H,br),1.42(3H,t,J=7.3Hz),1.41-1.29(1H,m),1.23-1.08(1H,m),0.91(3H,t,J=7.3Hz),0.89-0.79(1H,m),0.51-0.41(2H,m),0.25-0.15(1H,m)。MS(NH3-CI)m/e 388(8),387(34),386(25),385(100)。
      實施例751波譜數(shù)據(jù)TLC RF0.36(40∶60乙酸乙酯-己烷)。1HNMR(300MHz,CDCl3)δ8.89(1H,s),7.77(1H,d,J=9.1Hz),6.90(2H,m),3.86(3H,m),3.62(1H,m),2.84(2H,q,J=7.5Hz),2.49(3H,s),2.40(1H,m),2.19(1H,m),1.90(1H,m),1.43(3H,t,J=7.5Hz),1.38(1H,m),1.19(1H,m),0.91(3H,t,J=7.3Hz),0.80(1H,m),0.49(2H,m),0.21(1H,m)。
      實施例753波譜數(shù)據(jù)TLC RF0.44(30∶70乙酸乙酯-己烷)。1HNMR(300MHz,CDCl3)δ8.92(1H,s),7.84(1H,d,J=1.8Hz),7.73(1H,d,J=8.5Hz),7.65(1H,dd,J=8.5,1.8Hz),3.65(1H,br),2.92(1H,q,J=7.5Hz),2.38(1H,br),2.25-2.14(1H,m),1.94(1H,br),1.43-1.26(1H,m),1.40(3H,t,J=7.5Hz),1.21-1.06(1H,m),0.92(3H,t,J=7.3Hz),0.91-0.79(1H,m),0.52-0.44(2H,m),0.22-0.16(1H,m)。MS(NH3-CI)m/e 426(9),425(42),424(31),423(100)。
      實施例767波譜數(shù)據(jù)MS(NH3-CI)m/e 379(M+H+,100%)。
      實施例776波譜數(shù)據(jù)TLC RF0.41(30∶70乙酸乙酯-己烷)。1HNMR(300MHz,CDCl3)δ8.93(1H,s),7.73(1H,d,J=8.4Hz),7.09(1H,d,J=2.6Hz),6.96(1H,dd,J=8.4,2.6Hz),4.28(1H,br),3.87(3H,s),2.95(2H,q,J=7.3Hz),2.41(2H,br),2.10-1.93(2H,m),1.43(3H,t,J=7.3Hz),1.40-1.23(1H,m),1.18-1.03(1H,m),0.91(3H,t,J=7.3Hz),0.82(3H,t,J=7.5Hz)。MS(NH3-CI)m/e C20H26ClN4O的計算值373.1795,實測值373.1815;376(8),375(35),374(24),373(100)。
      實施例777波譜數(shù)據(jù)TLC RF0.46(30∶70乙酸乙酯-己烷)。1HNMR(300MHz,CDCl3)δ8.89(1H,s),7.76(1H,d,J=9.0Hz),6.90-6.87(2H,m),4.29(1H,br),3.86(3H,s),2.94(2H,q,J=7.4Hz),2.48(3H,s),2.40(2H,br),2.10-1.92(2H,m),1.44(3H,t,J=7.4Hz),1.37-1.22(1H,m),1.18-1.02(1H,m),0.90(3H,t,J=7.3Hz),0.81(3H,t,J=7.3Hz)。MS(NH3-CI)m/e C21H29N4O的計算值353.2341,實測值353.2328;355(3),354(23),353(100)。
      實施例778波譜數(shù)據(jù)TLC RF0.58(30∶70乙酸乙酯-己烷)。1HNMR(300MHz,CDCl3)δ8.97(1H,s),7.86(1H,d,J=8.0Hz),7.83(1H,d,J=0.8Hz),7.68(1H,dd,J=8.0,0.8Hz),4.30(1H,br),2.96(2H,q,J=7.5Hz),2.41(2H,br),2.11-1.95(2H,m),1.43(3H,t,J=7.5Hz),1.42-1.22(2H,m),0.92(3H,t,J=7.3Hz),0.83(3H,t,J=7.3Hz)。MS(NH3-CI)m/e 414(8),413(39),412(28),411(100)。
      實施例779波譜數(shù)據(jù)TLC RF0.44(30∶70乙酸乙酯-己烷)。1HNMR(300MHz,CDCl3)δ8.91(1H,s),7.84(1H,d,J=1.8Hz),7.72(1H,d,J=8.0Hz),7.65(1H,dd,J=8.0,1.8Hz),4.31(1H,br),2.94(1H,q,J=7.5Hz),2.40(2H,br),2.10-1.93(2H,m),1.40(3H,t,J=7.5Hz),1.37-1.21(1H,m),1.19-1.02(1H,m),0.91(3H,t,J=7.3Hz),0.81(3H,t,J=7.3Hz)。MS(NH3-CI)m/e 414(9),413(43),412(31),411(100)。
      實施例793波譜數(shù)據(jù)MS(NH3-CI)m/e 367(M+H+,100%)。
      實施例799波譜數(shù)據(jù)TLC RF0.61(30∶70乙酸乙酯-己烷)。1HNMR(300MHz,CDCl3)δ8.90(1H,s),7.47(1H,s),7.10(1H,s),4.28(1H,br),2.93(2H,q,J=7.3Hz),2.41(1H,br),2.36(3H,s),2.28(6H,s),2.07-1.91(3H,m),1.42(3H,t,J=7.3Hz),1.35-1.21(1H,m),1.19-1.03(1H,m),0.90(3H,t,J=7.2Hz),0.81(3H,t,J=7.3Hz)。MS(NH3-CI)m/e C22H30N4的計算值350.2470,實測值350.2476;353(3),352(24),351(100)。
      實施例802波譜數(shù)據(jù)TLC RF0.38(30∶70乙酸乙酯-己烷)。1HNMR(300MHz,CDCl3)δ8.92(1H,s),7.84(1H,d,J=1.8Hz),7.73(1H,d,J=8.4Hz),7.65(1H,dd,J=8.4,1.8Hz),3.53(1H,br),2.91(1H,q,J=7.4Hz),2.52-2.35(1H,m),2.34-2.20(1H,m),1.95(1H,br),1.40(3H,t,J=7.4Hz),0.89-0.79(1H,m),0.87(3H,t,J=7.3Hz),0.55-0.42(2H,m),0.25-0.15(1H,m)。MS(NH3-CI)m/e 412(8),411(41),410(29),409(100)。
      實施例803波譜數(shù)據(jù)TLC RF0.33(30∶70乙酸乙酯-己烷)。1HNMR(300MHz,CDCl3)δ8.93(1H,s),7.85(1H,d,J=2.2Hz),7.71(1H,d,J=8.4Hz),7.64(1H,dd,J=8.4,2.2Hz),3.77(1H,dq,J=9.9,7.0Hz),2.93(1H,dq,J=7.5,2.0Hz),2.09-1.98(1H,m),1.82(3H,d,J=7.0Hz),1.39(3H,t,J=7.5Hz),0.86-0.78(1H,m),0.59-0.50(1H,m),0.49-0.40(1H,m),0.29-0.20(1H,m)。MS(NH3-CI)m/e 399(2),398(8),397(39),396(24),395(100)。
      實施例804波譜數(shù)據(jù)TLC RF0.31(20∶80乙酸乙酯-己烷)。1HNMR(300MHz,CDCl3)δ8.92(1H,s),7.84(1H,d,J=1.8Hz),7.71-7.62(2H,m),4.55(1H,m),2.95(2H,q,J=7.5Hz),2.43-2.32(1H,m),2.10-1.98(1H,m),1.75(3H,d,J=7.0Hz),1.39(3H,t,J=7.5Hz),1.38-1.27(1H,m),1.19-1.09(1H,m),0.93(3H,t,J=7.1Hz)。MS(NH3-CI)m/e 400(7),399(32),398(22),397(100)。C19H20ClF3N4的分析計算值C,57.51;H,5.08;N,14.12;實測值C,57.55;H,5.06;N,13.95。
      實施例805波譜數(shù)據(jù)TLC RF0.41(30∶70乙酸乙酯-己烷)。1HNMR(300MHz,CDCl3)δ8.92(1H,s),7.84(1H,d,J=1.8Hz),7.70(1H,d,J=8.0Hz),7.64(1H,dd,J=8.0,1.8Hz),4.58-4.49(1H,m),2.95(1H,q,J=7.5Hz),2.45-2.33(1H,m),2.11-2.00(1H,m),1.75(3H,d,J=6.6Hz),1.39(3H,t,J=7.5Hz),1.38-1.21(4H,m),0.86(3H,t,J=7.0Hz)。MS(NH3-CI)m/e 414(8),413(40),412(29),411(100)。
      實施例807波譜數(shù)據(jù)TLC RF0.49(30∶70乙酸乙酯-己烷)。1HNMR(300MHz,CDCl3)δ8.91(1H,s),7.84(1H,d,J=1.8Hz),7.73(1H,d,J=8.4Hz),7.65(1H,dd,J=8.4,1.8Hz),4.38-4.19(1H,m),2.94(1H,q,J=7.5Hz),2.40(2H,br),2.10-1.98(2H,m),1.41(3H,t,J=7.5Hz),1.38-1.20(3H,m),1.09-0.99(1H,m),0.84(3H,t,J=7.0Hz),0.81(3H,t,J=7.5Hz)。MS(NH3-CI)m/e 428(7),427(32),426(25),425(100)。
      實施例808波譜數(shù)據(jù)TLC RF0.51(30∶70乙酸乙酯-己烷)。1HNMR(300MHz,CDCl3)δ8.91(1H,s),7.84(1H,d,J=1.8Hz),7.72(1H,d,J=8.4Hz),7.64(1H,dd,J=8.4,1.8Hz),4.37(1H,br),2.93(1H,q,J=7.5Hz),2.38(2H,br),2.02-1.90(2H,m),1.40(3H,t,J=7.5Hz),1.38-1.20(2H,m),1.18-1.01(2H,m),0.90(6H,t,J=7.3Hz)。MS(NH3-CI)m/e 428(8),427(39),426(30),425(100)。
      實施例809波譜數(shù)據(jù)TLC RF0.40(30∶70乙酸乙酯-己烷)。1HNMR(300MHz,CDCl3)δ8.90(1H,s),7.84(1H,d,J=2.2Hz),7.72(1H,d,J=8.1Hz),7.65(1H,dd,J=8.1,2.2Hz),4.20(1H,br),2.94(1H,q,J=7.5Hz),2.51-2.38(2H,m),2.13-2.00(2H,m),1.41(3H,t,J=7.5Hz),0.82(6H,t,J=7.5Hz)。MS(NH3-CI)m/e 400(7),399(36),398(25),397(100)。
      實施例824波譜數(shù)據(jù)TLC RF0.27(20∶80乙酸乙酯-己烷)。1HNMR(300Mz,CDCl3)δ8.94(1H,s),8.10(1H,s),7.94(1H,d,J=8.8Hz),7.87(1H,d,J=8.1Hz),4.56(1H,m),2.96(2H,q,J=7.5Hz),2.40(1H,m),2.10-2.00(1H,m),1.76(3H,d,J=7.0Hz),1.39(3H,t,J=7.5Hz),1.33-1.10(2H,m),0.93(3H,t,J=7.1Hz)。19F NMR(300MHz,CDCl3)δ-58.2,-63.4。MS(NH3-CI)m/e 433(3),432(24),431(100)。
      實施例832波譜數(shù)據(jù)TLC RF0.34(30∶70乙酸乙酯-己烷)。1HNMR(300MHz,CDCl3)δ8.94(1H,s),7.73(1H,d,J=8.5Hz),7.10(1H,d,J=2.6Hz),6.96(1H,dd,J=8.5,2.6Hz),3.87(3H,s),3.55(1H,br),2.92(2H,q,J=7.3Hz),2.53-2.35(1H,m),2.31-2.18(1H,m),1.96(1H,br),1.42(3H,t,J=7.3Hz),0.87(3H,t,J=7.5Hz),0.87-0.79(1H,m),0.53-0.43(2H,m),0.25-0.15(1H,m)。MS(NH3-CI)m/e 374(8),373(34),372(24),371(100)。
      實施例833波譜數(shù)據(jù)TLC RF0.20(30∶70乙酸乙酯-己烷)。1HNMR(300MHz,CDCl3)δ8.96(1H,s),7.70(1H,d,J=8.4Hz),7.10(1H,d,J=2.5Hz),6.96(1H,dd,J=8.4,2.5Hz),4.16(2H,d,J=7.0Hz),3.87(3H,s),3.01(2H,q,J=7.3Hz),1.46(3H,t,J=7.3Hz),1.37-1.27(1H,m),0.66-0.52(4H,m)。 MS(NH3-CI)m/e 346(6),345(32),344(23),343(100)。
      實施例834波譜數(shù)據(jù)TLC RF0.18(30∶70乙酸乙酯-己烷)。1HNMR(300MHz,CDCl3)δ8.94(1H,s),7.69(1H,d,J=8.4Hz),7.09(1H,d,J=1Hz),6.96(1H,dd,J=8.4,1Hz),4.60-4.50(1H,m),3.87(3H,s),2.97(2H,q,J=7.3Hz),2.49-2.33(1H,m),2.09-1.97(1H,m),1.74(3H,d,J=7.0Hz),1.41(3H,t,J=7.5Hz),1.40-1.22(1H,m),1.21-1.09(1H,m),0.92(3H,t,J=7.1Hz)。MS(NH3-CI)m/e C19H24ClN4O的計算值359.1639,實測值359.1623;362(7),361(33),360(23),359(100)。C19H23ClN4O·0.5H2O的分析計算值C,62.20;H,6.32,N,15.27;實測值C,62.33;H,6.36;N,14.86。
      實施例835波譜數(shù)據(jù)TLC RF0.39(30∶70乙酸乙酯-己烷)。1HNMR(300MHz,CDCl3)δ8.94(1H,s),7.69(1H,d,J=8.4Hz),7.09(1H,d,J=2.5Hz),6.95(1H,dd,J=8.4,2.5Hz),4.53-4.47(1H,m),3.87(3H,s),3.01-2.92(2H,m),2.48-2.35(1H,m),2.11-1.99(1H,m),1.74(3H,d,J=6.9Hz),1.41(3H,t,J=7.5Hz),1.38-1.22(3H,m),1.14-1.00(1H,m),0.86(3H,t,J=7.1Hz)。MS(NH3-CI)m/e 376(7),375(33),374(23),373(100)。
      實施例836波譜數(shù)據(jù)TLC RF0.42(30∶70乙酸乙酯-己烷)。1HNMR(300MHz,CDCl3)δ8.94(1H,s),7.79(1H,d,J=8.8Hz),7.09(1H,d,J=2.5Hz),6.95(1H,dd,J=8.8,2.5Hz),4.55-4.47(1H,m),3.87(3H,s),3.01-2.92(2H,m),2.48-2.35(1H,m),2.10-1.97(1H,m),1.74(3H,d,J=7.0Hz),1.41(3H,t,J=7.5Hz),1.35-1.20(5H,m),1.18-1.02(1H,m),0.84(3H,t,J=7.0Hz)。MS(H3-CI)m/e C21H28ClN4O的計算值387.1952,實測值387.1944;391(1),390(8),389(35),388(25),387(100)。
      實施例837波譜數(shù)據(jù)TLC RF0.45(30∶70乙酸乙酯-己烷)。1HNMR(300MHz,CDCl3)δ8.93(1H,s),7.73(1H,d,J=8.8Hz),7.09(1H,d,J=2.6Hz),6.96(1H,dd,J=8.8,2.6Hz),4.25(1H,br),3.87(3H,s),2.95(2H,q,J=7.3Hz),2.41(2H,br),2.10-2.00(2H,m),1.43(3H,t,J=7.3Hz),1.37-1.20(3H,m),1.12-0.98(1H,m),0.84(3H,t,J=7.3Hz),0.82(3H,t,J=7.4Hz)。MS(NH3-CI)m/e 390(8),389(34),388(25),387(100)。
      實施例838波譜數(shù)據(jù)TLC RF0.48(30∶70乙酸乙酯-己烷)。1HNMR(300MHz,CDCl3)δ8.94(1H,s),7.72(1H,d,J=8.5Hz),7.09(1H,d,J=2.2Hz),6.96(1H,dd,J=8.5,2.2Hz),4.36(1H,v br),3.87(3H,s),2.94(2H,q,J=7.3Hz),2.39(2H,br),2.02-1.90(2H,m),1.42(3H,t,J=7.3Hz),1.39-1.21(2H,m),1.18-1.03(2H,m),0.90(6H,t,J=7.3 Hz)。MS(NH3-CI)m/e C21H29ClN4O的計算值387.1952,實測值387.1958;391(1),390(8),389(34),388(26),387(100)。
      實施例839波譜數(shù)據(jù)TLC RF0.36(30∶70乙酸乙酯-己烷)。1HNMR(300MHz,CDCl3)δ8.93(1H,s),7.73(1H,d,J=8.5Hz),7.09(1H,d,J=2.6Hz),6.96(1H,dd,J=8.5,2.6Hz),4.19(1H,br s),3.87(3H,s),2.96(2H,q,J=7.5Hz),2.52-2.38(2H,m),2.13-1.99(2H,m),1.43(3H,t,J=7.5Hz),0.83(6H,t,J=7.3Hz)。MS(NH3-CI)m/eC19H24ClN4的計算值359.1639,實測值359.1632;362(7),361(34),360(23),359(100)。
      實施例870波譜數(shù)據(jù)MS(NH3-CI)m/e 423(M+H+,100%)。
      實施例900波譜數(shù)據(jù)TLC RF0.38(50∶50乙酸乙酯-己烷)。1HNMR(300MHz,CDCl3)δ8.93(1H,s),7.75(1H,d,J=9.2Hz),6.90-6.86(2H,m),4.23(2H,t,J=7.7Hz),3.86(3H,s),2.95(2H,q,J=7.7Hz),2.48(3H,s),1.93-1.83(2H,m),1.45(3H,t,J=7.6Hz),1.43-1.36(4H,m),0.92(3H,t,J=7.0Hz)。
      實施例902波譜數(shù)據(jù)TLC RF0.28(5∶95乙酸乙酯-二氯甲烷)。1H NMR(300MHz,CDCl3)δ8.94(1H,s),7.63(1H,d,J=8.1Hz),7.37(1H,d,J=1.0Hz),7.21(1H,dd,J=8.1,1.0Hz),4.38(1H,br),2.94(2H,q,J=7.5Hz),2.41(3H,s),2.40(2H,br),2.00-1.90(2H,m),1.42(3H,t,J=7.5Hz),1.35-1.22(2H,m),1.17-1.03(2H,m),0.90(6H,t,J=7.3 Hz)。MS(NH3-CI)m/e C21H28ClN4的計算值371.2002,實測值371.1993;374(8),373(34),372(25),371(100)。
      實施例944波譜數(shù)據(jù)MS(NH3-CI)m/e 377(M+H+,100%)。
      實施例945波譜數(shù)據(jù)MS(NH3-CI)m/e 365(M+H+,100%)。
      實施例947波譜數(shù)據(jù)MS(NH3-CI)m/e 353(M+H+,100%)。
      實施例951波譜數(shù)據(jù)MS(NH3-CI)m/e 381(M+H+,100%)。
      實施例952波譜數(shù)據(jù)MS(NH3-CI)m/e 353(M+H+,100%)。
      實施例1003波譜數(shù)據(jù)TLC RF0.10(30∶70乙酸乙酯-己烷)。1HNMR(300MHz,CDCl3)δ8.99(1H,s),7.43(1H,s),7.19(2H,d,J=8.8Hz),6.86(2H,d,J=8.8Hz),6.84(1H,s),5.42(2H,s),3.94(3H,s),3.91(3H,s),3.78(3H,s),2.86(2H,q,J=7.7Hz),2.45(3H,s),1.35(3H,t,J=7.7Hz)。MS(NH3-CI)m/e 421(4),420(27),419(100)。C24H26N4O3的分析計算值C,68.88;H,6.26;N,13.39;實測值C,68.53;H,6.30;N,12.96。
      實施例1012波譜數(shù)據(jù)m.p.147-148℃。TLC RF0.18(30∶70乙酸乙酯-己烷)。1H NMR(300MHz,CDCl3)δ8.88(1H,s),7.60(1H,s),6.77(1H,s),4.61(2H,t,J=8.6Hz),3.44(1H,v br),3.24(2H,t,J=8.6Hz),2.94(2H,br),2.44(3H,s),2.03(2H,v br),1.45(3H,br t,J=6Hz),0.89-0.79(2H,m),0.58(2H,br),0.50-0.40(2H,m),0.27-0.17(2H,m)。MS(NH3-CI)m/e 377(4),376(27),375(100)。C23H26N4O的分析計算值C,73.77;H,7.01;N,14.96;實測值C,73.69;H,7.08;N,14.40。
      實施例1023波譜數(shù)據(jù)TLC RF0.22(30∶70乙酸乙酯-己烷)。1HNMR(300MHz,CDCl3)δ9.04(1H,s),7.78(1H,d,J=8.4Hz),7.44(1H,d,J=1.1Hz),7.30(1H,dd,J=8.4,1.1Hz),7.20(2H,d,J=8.5Hz),6.87(2H,d,J=8.5Hz),5.44(2H,s),3.79(3H,s),2.90(2H,q,J=7.5Hz),1.32(3H,t,J=7.5Hz)。MS(NH3-CI)m/e 467(1),466(8),465(35),464(27),463(100)。
      實施例1027波譜數(shù)據(jù)TLC RF0.41(25∶75乙酸乙酯-己烷)。1HNMR(300MHz,CDCl3)δ8.96(1H,s),7.76(1H,d,J=8.4Hz),7.45-7.44(1H,m),7.27(1H,dm,J=8Hz),4.61-4.51(1H,m),2.98(2H,dq,J=7.5,1.6Hz),2.48-2.35(1H,m),2.10-1.98(1H,m),1.75(3H,d,J=7.0Hz),1.41(3H,t,J=7.5Hz),1.35-1.22(2H,m),0.93(3H,t,J=7.2Hz)。MS(NH3-CI)m/e C19H21ClF3N4O的計算值413.1349,實測值413.1344;416(8),415(35),414(24),413(100)。
      實施例1028波譜數(shù)據(jù)TLC RF0.45(25∶75乙酸乙酯-己烷)。1HNMR(300MHz,CDCl3)δ8.96(1H,s),7.77(1H,d,J=8.4Hz),7.44(1H,m),7.27(1H,dm,J=8Hz),4.57-4.49(1H,m),2.97(2H,dq,J=7.7,1.7Hz),2.47-2.36(1H,m),2.12-2.02(1H,m),1.75(3H,d,J=7.0Hz),1.41(3H,t,J=7.7Hz),1.33-1.21(4H,m),0.86(3H,t,J=7.3Hz)。MS(NH3-CI)m/e C20H23ClF3N4O的計算值427.1509,實測值427.1507;430(8),429(35),428(25),427(100)。
      實施例1032波譜數(shù)據(jù)TLC RF0.44(25∶75乙酸乙酯-己烷)。1HNMR(300MHz,CDCl3)δ8.95(1H,s),7.80(1H,d,J=8.4Hz),7.45-7.44(1H,m),7.30(1H,dm,J=8Hz),4.23-4.17(1H,m),2.97(2H,q,J=7.6Hz),2.54-2.39(2H,m),2.14-2.00(2H,m),1.43(3H,t,J=7.6Hz),0.84(6H,t,J=7.3Hz)。MS(NH3-CI)m/e C19H21ClF3N4O的計算值413.1368,實測值413.1373;416(8),415(34),414(24),413(100)。
      實施例1150波譜數(shù)據(jù)TLC RF0.23(30∶70乙酸乙酯-己烷)。1HNMR(300MHz,CDCl3)δ8.90(1H,s),7.73(1H,d,J=8.8Hz),7.36(1H,d,J=2.6Hz),7.17(1H,dd,J=8.8,2.6Hz),3.92(3H,s),3.70-3.55(1H,m),2.91(2H,q,J=7.4Hz),2.45-2.35(1H,m),2.25-2.15(1H,m),2.00-1.90(1H,m),1.40(3H,t,J=7.4Hz),1.40-1.30(1H,m),1.20-1.10(1H,m),0.91(3H,t,J=7.2Hz),0.87-0.77(1H,m),0.54-0.44(2H,m),0.25-0.15(1H,m)。MS(NH3-CI)m/e C22H26F3N4O的計算值419.2057,實測值419.2058;421(3),420(25),419(100)。
      實施例1153波譜數(shù)據(jù)TLC RF0.48(30∶70乙酸乙酯-己烷)。1HNMR(300MHz,CDCl3)δ9.00(1H,s),7.89(1H,d,J=8.0Hz),7.84(1H,s),7.69(1H,d,J=8.0Hz),7.40-7.30(5H,m),5.14(1H,d,J=10.2Hz),2.82(1H,dq,J=15.5,7.7Hz),2.68(1H,dq,J=15.5,7.7Hz),2.15(1H,br),1.23(3H,t,J=7.7Hz),1.13-1.03(1H,m),0.78-0.62(2H,m),0.53-0.43(1H,m)。MS(NH3-CI)m/e C24H21ClF3N4的計算值457.1407,實測值457.1389;460(9),459(35),458(29),457(100)。
      實施例1155波譜數(shù)據(jù)TLC RF0.46(25∶75乙酸乙酯-己烷)。1HNMR(300MHz,CDCl3)δ8.98(1H,s),7.83(1H,d,J=8.4Hz),7.46-7.27(7H,m),5.13(1H,d,J=10.7Hz),2.88-2.62(2H,m),2.15(1H,br),1.26(3H,t,J=7.5Hz),1.12-1.02(1H,m),0.78-0.62(2H,m),0.54-0.44(1H,m)。MS(NH3-CI)m/e C24H21ClF3N4O的計算值473.1361,實測值473.1365;476(9),475(36),474(29),473(100)。
      實施例1157波譜數(shù)據(jù)TLC RF0.19(30∶70乙酸乙酯-己烷)。1HNMR(300MHz,CDCl3)δ8.93(1H,s),7.77(1H,d,J=8.8Hz),7.40-7.30(6H,m),7.19(1H,dd,J=8.8,2.2Hz),5.13(1H,d,J=10.6Hz),3.92(3H,s),2.79(1H,dq,J=15,7.7Hz),2.64(1H,dq,J=15,7.7Hz),2.12(1H,br),1.21(3H,t,J=7.7Hz),1.10-1.00(1H,m),0.77-0.62(2H,m),0.55-0.45(1H,m)。MS(NH3-CI)m/e C25H24F3N4O的計算值453.1902,實測值453.1903;455(4),454(28),453(100)。
      實施例1158波譜數(shù)據(jù)TLC RF0.16(20∶80乙酸乙酯-己烷)。1HNMR(300MHz,CDCl3)δ8.98(1H,s),7.46-7.25(7H,m),5.12(1H,br d,J=9Hz),2.85-2.62(2H,m),2.14(1H,br),2.13(3H,d,J=0.7Hz),1.18(3H,dq,J=7.7,4.1Hz),0.75-0.35(4H,m)。MS(NH3-CI)m/eC24H23Cl2N4的計算值437.1300,實測值437.1294;440(19),439(67),438(32),437(100)。
      實施例1161波譜數(shù)據(jù)MS(NH3-CI)m/e 441(M+H+,100%)。
      實施例1163波譜數(shù)據(jù)TLC RF0.44(30∶70乙酸乙酯-己烷)。1HNMR(300MHz,CDCl3)δ9.00(1H,s),7.89(1H,d,J=8.4Hz),7.84(1H,s),7.69(1H,d,J=8.4Hz),7.38(2H,d,J=9Hz),7.05(2H,d,J=9Hz),5.08(1H,d,J=10.2Hz),2.82(1H,dq,J=15.5,7.7Hz),2.68(1H,dq,J=15.5,7.7Hz),2.14(1H,m),1.25(3H,t,J=7.7Hz),1.10-1.01(1H,m),0.74-0.62(2H,m),0.51-0.41(1H,m)。MS(NH3-CI)m/eC24H20ClF4N4的計算值475.1313,實測值475.1307;479(1),478(9),477(35),476(30),475(100)。
      實施例1222波譜數(shù)據(jù)MS(NH3-CI)m/e 363(M+H+,100%)。
      實施例1252波譜數(shù)據(jù)TLC RF0.24(20∶80乙酸乙酯-己烷)。1HNMR(300MHz,CDCl3)δ8.72(1H,s),7.87(1H,dd,J=8.8,5.5Hz),7.46(1H,dd,J=8.8,2.5Hz),7.35-7.26(1H,m),7.24-7.18(6H,m),7.08-7.01(4H,m),4.89-4.79(1H,m),4.49(2H,d,J=12.1Hz),4.37(2H,d,J=12.1Hz),4.27(2H,t,J=9.3Hz),4.01(2H,dd,J=9.9,5.2Hz),2.98(2H,q,J=7.7Hz),1.39(3H,t,J=7.7Hz)。MS(NH3-CI)m/eC31H29F4N4O2的計算值565.2227,實測值565.2226;567(7),566(36),565(100)。
      實施例1255波譜數(shù)據(jù)TLC RF0.50(25∶75乙酸乙酯-己烷)。1HNMR(300MHz,CDCl3)δ8.96(1H,s),7.80(1H,d,J=8.4Hz),7.45-7.43(1H,m),7.31-7.27(1H,dm,J=8Hz),3.80-3.73(1H,m),2.93(2H,q,J=7.3Hz),2.40(1H,br),2.25-2.14(1H,m),1,95(1H,br),1.42(3H,t,J=7.5Hz),1.35-1.10(2H,m),0.92(3H,t,J=7.3Hz),0.91-0.80(1H,m),0.53-0.44(2H,m),0.24-0.14(1H,m)。MS(NH3-CI)m/e C21H23ClF3N4O的計算值439.1519,實測值439.1524;442(8),441(34),440(26),439(100)。
      實施例1256波譜數(shù)據(jù)TLC RF0.48(25∶75乙酸乙酯-己烷)。1HNMR(300MHz,CDCl3)δ8.95(1H,s),7.79(1H,d,J=8.4Hz),7.45-7.43(1H,m),7.27(1H,dm,J=8Hz),4.35-4.25(1H,m),2.96(2H,q,J=7.4Hz),2.42(2H,br),2.12-1.93(2H,m),1.43(3H,t,J=7.4Hz),1.37-1.22(2H,m),0.91(3H,t,J=7.2Hz),0.83(3H,t,J=7.5Hz)。MS(NH3-CI)m/e C20H23ClF3N4O的計算值427.1514,實測值427.1515;430(8),429(34),428(25),427(100)。
      實施例1295波譜數(shù)據(jù)TLC RF0.37(50∶50乙酸乙酯-己烷)。1HNMR(300MHz,CDCl3)δ8.91(1H,s),7.38(1H,s),6.83(1H,s),4.46(1H,m,J=7.3Hz),3.94(3H,s),3.91(3H,s),2.96(2H,q,J=7.6Hz),2.49-2.39(1H,m),2.43(3H,s),2.12-2.02(1H,m),1.75(3H,d,J=6.5Hz),1.44(3H,t,J=7.5Hz),0.86(3H,t,J=7.5Hz)。MS(NH3-CI)m/e C20H27N4O2的計算值355.2134,實測值355.2139;357(3),356(23),355(100)。
      實施例1296波譜數(shù)據(jù)TLC RF0.37(30∶70乙酸乙酯-己烷)。1HNMR(300MHz,CDCl3)δ9.00(1H,s),7.68(1H,d,J=8.4Hz),7.57(1H,d,J=2.2Hz),7.39(1H,dd,J=8.4,2.2Hz),7.27(2H,d,J=8.4Hz),6.89(2H,d,J=8.4Hz),5.56(1H,dd,J=9.7,7.4Hz),3.79(3H,s),2.92-2.75(3H,m),2.65-2.55(1H,m),1.31(3H,t,J=7.5Hz),0.92(3H,t,J=6.6Hz)。MS(NH3-CI)m/e C23H23Cl2N4O的計算值441.1249,實測值441.1247;445(12),444(18),443(67),442(30),441(100)。
      實施例1319波譜數(shù)據(jù)MS(NH3-CI)m/e 459(M+H+,100%)。
      實施例1320波譜數(shù)據(jù)1H NMR(300MHz,CDCl3)δ8.99(s,1H),7.68(d,1H,J=8.4Hz),7.58(d,1H,J=1.9Hz),7.42-7.3(m,6H),6.04(q,1H),2.82,(m,2H),2.16(d,3H,J=7.4Hz),1.27(t,3H,J=7.3,7.7Hz)。
      實施例1321 7906-5波譜數(shù)據(jù)1H NMR(300MHz,CDCl3)δ9.02(1H,s),7.98(d,1H),7.71(d,1H),7.57(d,1H),7.42-7.26(m,3H),7.15(m,1H),5.38(d,1H),2.65(m,1H),2.4(m,1H),1.85(m,1H),1.82(s,3H),0.97(t,3H),0.8(m,2H),0.6(m,2H)。
      實施例1322波譜數(shù)據(jù)MS(NH3-CI)m/e 437(M+H+,100%)。
      實施例1323波譜數(shù)據(jù)MS(NH3-CI)m/e 455(M+H+,100%)。
      實施例1324波譜數(shù)據(jù)MS(ESI)m/e 425(M+H+),381(M+H+-CO2,100%)。
      實施例1325波譜數(shù)據(jù)MS(NH3-CI)m/e 413(M+H+,100%)。
      實施例1326波譜數(shù)據(jù)MS(NH3-CI)m/e 427(M+H+,100%)。
      實施例1327波譜數(shù)據(jù)MS(NH3-CI)m/e 427(M+H+,100%)。
      實施例1328波譜數(shù)據(jù)MS(NH3-CI)m/e 427(M+H+,100%)。
      實施例1329波譜數(shù)據(jù)MS(NH3-CI)m/e 423(M+H+,100%)。
      實施例1330波譜數(shù)據(jù)MS(NH3-CI)m/e 418(M+H+,100%)。
      實施例1331波譜數(shù)據(jù)MS(NH3-CI)m/e 418(M+H+,100%)。
      實施例1332波譜數(shù)據(jù)MS(NH3-CI)m/e 499(M+H+,100%)。
      實施例1333波譜數(shù)據(jù)MS(NH3-CI)m/e 453(M+H+,100%)。
      實施例1334波譜數(shù)據(jù)MS(NH3-CI)m/e 423(M+H+,100%)。
      實施例1335波譜數(shù)據(jù)MS(NH3-CI)m/e 372(M+H+,100%)。
      實施例1337波譜數(shù)據(jù)MS(NH3-CI)m/e 443(M+H+,100%)。
      實施例1338波譜數(shù)據(jù)MS(NH3-CI)m/e 427(M+H+,100%)。
      實施例1339波譜數(shù)據(jù)MS(NH3-CI)m/e 379(M+H+,100%)。
      實施例1341波譜數(shù)據(jù)MS(NH3-CI)m/e 393(M+H+,100%)。
      實施例1342波譜數(shù)據(jù)MS(NH3-CI)m/e 378(M+H+,100%)。
      實施例1343波譜數(shù)據(jù)MS(NH3-CI)m/e 346(M+H+,100%)。
      實施例1344波譜數(shù)據(jù)MS(NH3-CI)m/e 363(M+H+,100%)。
      實施例1346波譜數(shù)據(jù)MS(NH3-CI)m/e 416(M+H+,100%)。
      實施例1370波譜數(shù)據(jù)TLC RF0.23(30∶70乙酸乙酯-己烷)。1HNMR(300MHz,CDCl3)δ8.89(1H,s),7.72(1H,d,J=8.4Hz),7.35(1H,d,J=2.5Hz),7.17(1H,dd,J=8.4,2.5Hz),4.27(1H,br),3.91(3H,s),2.93(2H,q,J=7.7Hz),2.40(2H,br),2.10-1.95(2H,m),1.41(3H,t,J=7.7Hz),1.39-1.27(1H,m),1.20-1.07(1H,m),0.91(3H,t,J=7.3Hz),0.81(3H,t,J=7.5 Hz)。MS(NH3-CI)m/e C21H26F3N4O的計算值407.2058,實測值407.2052;409(3),408(24),407(100)。
      實施例1371波譜數(shù)據(jù)MS(ESI)m/e 377(M+2),375(M+,100%)。
      (b)Q1=2-四唑基(c)Q2=1,2,4-三唑-2-基表1A
      實施R2X R3R4R12R11R6R1aR1bmp,例號 ℃a1043CH3CH2H CH3CH3CH3H CH3C3H7油關(guān)鍵(a)化合物被指明為“油”的地方,提供數(shù)據(jù)如下
      實施例1043波譜數(shù)據(jù)TLC RF0.40(30∶70乙酸乙酯-己烷)。1HNMR(300MHz,CDCl3)d 8.91(1H,s),7.43(1H,s),7.10(1H,s),4.60-4.50(1H,m),2.94(2H,dq,J=7.5,2.0Hz),2.45-2.35(1H,m),2.35(3H,s),2.28(6H,s),2.07-1.97(1H,m),1.73(3H,d,J=6.9Hz),1.41(3H,t,J=7.5Hz),1.40-1.27(1H,m),1.20-1.07(1H,m),0.92(3H,t,J=7.3Hz)。MS(NH3-CI)m/e C21H29N4的計算值337.2392,實測值337.2396;339(3),338(23),337(100)。C21H28N4的分析計算值C,74.96;H,8.40;N,16.65;實測值C,74.28;H,8.02;N,16.37。
      表1B
      實施例號 R2XR4R5R1aR1bmp,℃a1270 CH3CH2CF3O(CH2)2-c-C3H5c-C3H5-OH1271 CH3CH2CF3OCH2CO2-c-C3H5c-C3H5-C2H51272 CH3CH2CF3OCH2CO- c-C3H5c-C3H5-N(CH3)21273 CH3CH2CF3O(CH2)2-c-C3H5c-C3H5-NMe3+Cl-1274 CH3CH2CF3OCH2CH- c-C3H5c-C3H5-(OH)C2H51275 CH3CH2OCH2OCH3CH3CH3C3H777-791276 CH3CH2OH CH3CH3C3H7-1277 CH3CH2OC2H5CH3CH3C3H7-1278 CH3CH2OC3H7CH3CH3C3H7-1279 CH3CH2O(CH2)2-OH CH3CH3C3H7-1280 CH3CH2OCH2CO2-CH3CH3C3H7-C2H51281 CH3CH2OCH2CO- CH3CH3C3H7-N(CH3)21282 CH3CH2O(CH2)2-CH3CH3C3H7-NMe3+Cl-1283 CH3CH2OCH2CH-CH3CH3C3H7-(OH)C2H5表1C
      實施例號 X R4R5R11R1aR1bmp,℃a1501 CH2ClCF3H C3H7OCH376-781502 CH2ClCF3H C2H5C2H4OCH3油1503 CH2ClCl H C2H5C2H4OCH3-1504 CH2ClOCH3H C2H5C2H4OCH3-1505 CH2CF3OCH3H C2H5C2H4OCH3-1506 CH2ClSO2CH3H C2H5C2H4OCH3-1507 CH2ClCOCH3H C2H5C2H4OCH3-1508 CH2CH3OCH3CH3C2H5C2H4OCH3-1509 CH2ClCH3F C2H5C2H4OCH3-1510 CH2CH3OCH3F C2H5C2H4OCH3-1511 CH2CH3CH3CH3C2H5C2H4OCH3-1512 CH2ClCF3H c-C3H5C2H4OCH3-1513 CH2ClCl H c-C3H5C2H4OCH3-1514 CH2ClOCH3H c-C3H5C2H4OCH3-1515 CH2CF3OCH3H c-C3H5C2H4OCH3-1516 CH2ClSO2CH3H c-C3H5C2H4OCH3-1517 CH2ClCOCH3H c-C3H5C2H4OCH3-1518 CH2CH3OCH3CH3c-C3H5C2H4OCH3-1519 CH2ClCH3F c-C3H5C2H4OCH3-1520CH2CH3OCH3F c-C3H5C2H4OCH3-1521CH2CH3CH3CH3c-C3H5C2H4OCH3-1522CH2ClCF3H C2H5CH2OCH3油1523CH2ClCl H C2H5CH2OCH3-1524CH2ClOCH3H C2H5CH2OCH3-1525CH2CF3OCH3H C2H5CH2OCH3-1526CH2ClSO2CH3H C2H5CH2OCH3-1527CH2ClCOCH3H C2H5CH2OCH3 -1528CH2CH3OCH3CH3C2H5CH2OCH3-1529CH2ClCH3F C2H5CH2OCH3-1530CH2CH3OCH3F C2H5CH2OCH3-1531CH2CH3CH3CH3C2H5CH2OCH3-1532CH2ClCF3H c-C3H5CH2OCH3-1533CH2ClCl H c-C3H5CH2OCH3-1534CH2ClOCH3H c-C3H5CH2OCH3-1535CH2CF3OCH3H c-C3H5CH2OCH3-1536CH2ClSO2CH3H c-C3H5CH2OCH31537CH2ClCOCH3H c-C3H5CH2OCH3-1538CH2CH3OCH3CH3c-C3H5CH2OCH3-1539CH2ClCH3F c-C3H5CH2OCH3-1540CH2CH3OCH3F c-C3H5CH2OCH3-1541CH2CH3CH3CH3c-C3H5CH2OCH3-1542O ClCF3H C2H5C2H4OCH3油1543O ClCl H C2H5C2H4OCH3-1544O ClOCH3H C2H5C2H4OCH3-1545O CF3OCH3H C2H5C2H4OCH3-1546O ClSO2CH3H C2H5C2H4OCH3-1547O ClCOCH3H C2H5C2H4OCH3-1548O CH3OCH3CH3C2H5C2H4OCH3-1549O ClCH3F C2H5C2H4OCH3-1550O CH3OCH3F C2H5C2H4OCH3-1551O CH3CH3CH3C2H5C2H4OCH3-1552O ClCF3H c-C3H5C2H4OCH3-1553O ClCl H c-C3H5C2H4OCH3-1554O ClOCH3H c-C3H5C2H4OCH3-1555O CF3OCH3H c-C3H5C2H4OCH3-1556O ClSO2CH3H c-C3H5C2H4OCH3-1557OClCOCH3H c-C3H5C2H4OCH3-1558OCH3OCH3CH3c-C3H5C2H4OCH3-1559OClCH3F c-C3H5C2H4OCH3-1560OCH3OCH3F c-C3H5C2H4OCH3-1561OCH3CH3CH3c-C3H5C2H4OCH3-1562OClCF3H C2H5CH2OCH3油1563OClOCH3H C2H5CH2OCH3-1564OCF3OCH3H C2H5CH2OCH3-1565OClSO2CH3H C2H5CH2OCH3-1566OClCOCH3H C2H5CH2OCH3-1567OCH3OCH3CH3C2H5CH2OCH3-1568OClCH3F C2H5CH2OCH3-1569OCH3OCH3F C2H5CH2OCH3-1570OCH3CH3CH3C2H5CH2OCH3-1571OClCF3H c-C3H5CH2OCH3-1572OClClH c-C3H5CH2OCH3-1573OClOCH3H c-C3H5CH2OCH3-1574OCF3OCH3H c-C3H5CH2OCH3-1575OClSO2CH3H c-C3H5CH2OCH3-1576OClCOCH3H c-C3H5CH2OCH3-1577OCH3OCH3CH3c-C3H5CH2OCH3-1578OClCH3F c-C3H5CH2OCH3-1579OCH3OCH3F c-C3H5CH2OCH3-1580OCH3CH3CH3c-C3H5CH2OCH3-表1D
      實施例號 X R4R5R11R1aR1bmp,℃1601 CH2CH3Cl H C2H5c-C3H5109-1111602 CH2Cl Cl H C2H5C2H4OCH3-1603 CH2Cl OCH3H C2H5C2H4OCH3-1604 CH2CF3OCH3H C2H5C2H4OCH3-1605 CH2Cl SO2CH3H C2H5C2H4OCH3-1606 CH2Cl COCH3H C2H5C2H4OCH3-1607 CH2CH3OCH3CH3C2H5C2H4OCH3-1608 CH2Cl CH3F C2H5C2H4OCH3-1609 CH2CH3OCH3F C2H5C2H4OCH3-1610 CH2CH3CH3CH3C2H5C2H4OCH3-1611 CH2Cl CF3H c-C3H5C2H4OCH3-1612 CH2Cl Cl H c-C3H5C2H4OCH3-1613 CH2Cl OCH3H c-C3H5C2H4OCH3-1614 CH2CF3OCH3H c-C3H5C2H4OCH3-1615 CH2Cl SO2CH3H c-C3H5C2H4OCH3-1616 CH2Cl COCH3H c-C3H5C2H4OCH3-1617 CH2CH3OCH3CH3c-C3H5C2H4OCH3-1618 CH2Cl CH3F c-C3H5C2H4OCH3-1619 CH2CH3OCH3F c-C3H5C2H4OCH3-1620 CH2CH3CH3CH3c-C3H5C2H4OCH3-1621 CH2Cl CF3H C2H5CH2OCH3油1622 CH2Cl Cl H C2H5CH2OCH3-1623 CH2Cl OCH3H C2H5CH2OCH3-1624 CH2CF3OCH3H C2H5CH2OCH3-1625 CH2Cl SO2CH3H C2H5CH2OCH3-1626 CH2Cl COCH3H C2H5CH2OCH3-1627 CH2CH3OCH3CH3C2H5CH2OCH3-1628 CH2Cl CH3F C2H5CH2OCH3-1629 CH2CH3OCH3F C2H5CH2OCH3-1630 CH2CH3CH3CH3C2H5CH2OCH3-1631 CH2Cl CF3H c-C3H5CH2OCH3-1632 CH2Cl Cl H c-C3H5CH2OCH3-1633 CH2Cl OCH3H c-C3H5CH2OCH3-1634 CH2CF3OCH3H c-C3H5CH2OCH3-1635CH2Cl SO2CH3Hc-C3H5CH2OCH3-1636CH2Cl COCH3Hc-C3H5CH2OCH3-1637CH2CH3OCH3CH3c-C3H5CH2OCH3-1638CH2Cl CH3Fc-C3H5CH2OCH3-1639CH2CH3OCH3Fc-C3H5CH2OCH3-1640CH2CH3CH3CH3c-C3H5CH2OCH3-1641O Cl CF3HC2H5C2H4OCH3油1642O Cl Cl HC2H5C2H4OCH3-1643O Cl OCH3HC2H5C2H4OCH3-1644O CF3OCH3HC2H5C2H4OCH3-1645O Cl SO2CH3HC2H5C2H4OCH3-1646O Cl COCH3HC2H5C2H4OCH3-1647O CH3OCH3CH3C2H5C2H4OCH3-1648O Cl CH3FC2H5C2H4OCH3-1649O CH3OCH3FC2H5C2H4OCH3-1650O CH3CH3CH3C2H5C2H4OCH3-1651O Cl CF3Hc-C3H5C2H4OCH3-1652O Cl Cl Hc-C3H5C2H4OCH3-1653O Cl OCH3Hc-C3H5C2H4OCH3-1654O CF3OCH3Hc-C3H5C2H4OCH3-1655O Cl SO2CH3Hc-C3H5C2H4OCH3-1656O Cl COCH3Hc-C3H5C2H4OCH3-1657O CH3OCH3CH3c-C3H5C2H4OCH3-1658O Cl CH3Fc-C3H5C2H4OCH3-1659O CH3OCH3Fc-C3H5C2H4OCH3-1660O CH3CH3CH3c-C3H5C2H4OCH3-1661O Cl CF3HC2H5CH2OCH3油1662O Cl OCH3HC2H5CH2OCH3-1663O CF3OCH3HC2H5CH2OCH3-1664O Cl SO2CH3HC2H5CH2OCH3-1665O Cl COCH3HC2H5CH2OCH3-1666O CH3OCH3CH3C2H5CH2OCH3-1667O Cl CH3FC2H5CH2OCH3-1668O CH3OCH3FC2H5CH2OCH3-1669O CH3CH3CH3C2H5CH2OCH3-1670O Cl CF3Hc-C3H5CH2OCH3-1671 OCl Cl H c-C3H5CH2OCH3-1672 OCl OCH3H c-C3H5CH2OCH3-1673 OCF3OCH3H c-C3H5CH2OCH3-1674 OCl SO2CH3H c-C3H5CH2OCH3-1675 OCl COCH3H c-C3H5CH2OCH3-1676 OCH3OCH3CH3c-C3H5CH2OCH3-1677 OCl CH3F c-C3H5CH2OCH3-1678 OCH3OCH3F c-C3H5CH2OCH3-1679 OCH3CH3CH3c-C3H5CH2OCH3-下述制備1-芐基-6-甲基-4-(2,4,6-三甲基苯基)咪唑并[4,5-c]吡啶(實施例2001,表2,結(jié)構(gòu)A)的方法可用于制備在表2中所包含的結(jié)構(gòu)A的所有實施例,必要的話進(jìn)行微小的方法改進(jìn),并且使用適宜結(jié)構(gòu)的試劑。
      流程13和14的方法可用于制備在表2中所包含的結(jié)構(gòu)B和結(jié)構(gòu)C的許多實施例,必要的話進(jìn)行微小的方法改進(jìn),并且使用適宜結(jié)構(gòu)的試劑。
      實施例2001制備1-芐基-6-甲基-4-(2,4,6-三甲基苯基)咪唑并[4,5-c]吡啶部分A.把4-氯-6-甲基-3-硝基吡啶酮(5.0g,26.5mmol)在乙腈(93mL)中的溶液用芐基胺(2.89mL,26.5mmol)和二異丙基乙胺(5.54mL,31.8mmol)處理。將該混合物加熱回流4小時,然后冷卻至環(huán)境溫度并使之?dāng)嚢?2小時。把該混合物在二氯甲烷和水中分配(各200mL),并以二氯甲烷(200mL)提取水層。連續(xù)以水(200mL)洗滌該提取液,并且合并,過濾收集生成的沉淀。以硫酸鈉干燥濾液,再次過濾并蒸發(fā),得到第二份結(jié)晶產(chǎn)物4-芐基氨基-6-甲基-3-硝基吡啶酮(總共6.74g,26.0mmol,98%)。m.p.246-247℃。TLC RF0.35(10∶90異丙醇-乙酸乙酯)。1H NMR(300MHz,CDCl3)d 10.48(1H,br s),9.69(1H,br s),7.41-7.26(5H,m),5.66(1H,s),4.57(2H,d,J=5.5Hz),2.26(3H,s)。MS(NH3-CI)m/e 261(10),260(70),226(100)。
      部分B.把來自部分A的吡啶酮(6.72g,25.9mmol)在三氯氧磷(52mL,25.5mmol)中的溶液在環(huán)境溫度下攪拌3天。把該反應(yīng)混合物傾入冰(150g)和二氯甲烷(200mL)的混合物中。在冰融化后,加入100mL二氯甲烷,用固體NaHCO3調(diào)節(jié)該混合物的pH至7。分離該混合物,并且以二氯甲烷提取水相。合并提取物,以硫酸鈉干燥,過濾和蒸發(fā),得到亮黃色結(jié)晶固體產(chǎn)物(4-芐基氨基-2-氯-6-甲基-3-硝基吡啶)(6.45g,23.2mmol,90%)。TLC RF0.76(乙酸乙酯)。1H NMR(300MHz,CDCl3)d7.43-7.26(5H,m),7.04(1H,br),6.47(1H,s),4.48(2H,d,J=5.5Hz),2.40(3H,s)。MS(NH3-CI)m/e 281(5),280(35),279(17),278(100)。
      部分C.用鐵粉(13.61g)和冰乙酸(13.6mL)處理來自以上部分B的硝基化合物(6.42g,23.1mmol)在甲醇(162mL)中的溶液。將所生成的混合物加熱回流2小時,然后冷卻,通過硅藻土過濾(以甲醇洗滌),并且蒸發(fā)。將該殘余物質(zhì)溶解于二氯甲烷(231mL)和1N HCl(162mL)水溶液中,并通過加入固體NaHCO3調(diào)節(jié)該混合物的pH至中性。該混合物通過硅藻土過濾,并且分離,以二氯甲烷提取水相。合并該提取液,以Na2SO4干燥,過濾并蒸發(fā),得到固體產(chǎn)物3-氨基-4-芐基氨基-2-氯-6-甲基吡啶(5.59g,22.6mmol,98%)。m.p.177-178℃。TLCRF0.60(乙酸乙酯)。1H NMR(300MHz,CDCl3)d 7.41-7.32(5H,m),6.33(1H,s),4.54(1H,br),4.36(2H,d,J=5.1Hz),3.30(2H,br s),2.35(3H,s)。MS(NH3-CI)m/e 251(6),250(37),249(19),248(100)。
      部分D.以濃HCl(3滴)處理來自以上部分C的二胺(2.15g,8.68mmol)在原丙酸三乙酯(5mL)中的懸浮液并加熱回流1小時,然后冷卻,并真空蒸餾除去過量的正丙酸酯。用乙酸乙酯(120mL)溶解釜中殘余物,以水和鹽水(各100mL)洗滌。以乙酸乙酯連續(xù)回提該水相,合并該提取液,以Na2SO4干燥,過濾并蒸發(fā),得到N-(4-芐基氨基-2-氯-6-甲基吡啶-3-基)丙酰胺O-乙基imidate(2.62g,91%)。TLC RF0.40(30∶70乙酸乙酯-己烷)。1H NMR(300MHz,CDCl3)d 7.39-7.29(5H,m),6.29(1H,s),4.64(1H,br t,J=5.8Hz),4.37(2H,d,J=5.8Hz),4.25(2H,br),2.35(3H,s),2.18-2.11(2H,m),1.36(3H,t,J=7.0Hz),1.06(3H,t,J=7.7Hz)。MS(NH3-CI)m/e 335(7),334(34),333(22),332(100)。
      部分E.把來自部分D的化合物(2.62g,7.90mmol)在苯基醚(10mL)中的溶液加熱至170℃6小時,然后冷卻并傾入乙酸乙酯(150mL)中。以水和鹽水(各100mL)洗滌該混合物。然后以Na2SO4干燥,過濾并蒸發(fā)。經(jīng)過柱層析法(己烷,然后乙酸乙酯)分離該殘余液,得到油狀產(chǎn)物1-芐基-4-氯-2-乙基-6-甲基咪唑并[4,5-c]吡啶(2.16g,96%)。m.p.140-141℃。TLC RF0.06(30∶70乙酸乙酯-己烷)。1H NMR(300MHz,CDCl3)d 7.36-7.32(3H,m),7.02-6.98(2H,m),6.93(1H,s),5.31(2H,s),2.89(2H,q,J=7.3Hz),2.58(3H,s),1.39(3H,t,J=7.3Hz)。MS(NH3-CI)m/e 289(6),288(35),287(20),286(100)。
      部分F.以2-(2,4,6-三甲苯基)溴化鎂(3.95mL,1.0M)的四氫呋喃溶液處理在四氫呋喃(7mL)中的氯化鋅(538mg)溶液,并且攪拌1小時。在另一個燒瓶中,以二異丁基氫化鋁(0.263mL,1.0M)的己烷溶液處理在四氫呋喃(5mL)中的雙(三苯基膦)氯化鈀(93mg,0.132mmol)的溶液,攪拌該溶液20分鐘。然后把該芳基鋅溶液通過加料管加入到含有該鈀催化劑的燒瓶中,隨后加入在部分E中制備氯化物。該混合物加熱回流12小時,然后冷卻,并傾入水(100mL)中。以乙酸乙酯(2×150mL)提取,以鹽水洗滌該提取液,合并,以Na2SO4干燥,過濾并蒸發(fā)。經(jīng)過柱層析法(1∶1乙酸乙酯-己烷)分離該殘余物質(zhì),以乙醚重結(jié)晶純化得到固體標(biāo)題化合物(187mg,29%)。m.p.177-180℃(乙醚)。TLC RF0.27(50∶50乙酸乙酯-己烷)。1H NMR(300MHz,CDCl3)d 7.38-7.32(3H,m),7.10-7.05(2H,m),6.96(1H,s),6.93(2H,s),5.32(2H,s),2.84(2H,q,J=7.3Hz),2.64(3H,s),2.30(3H,s),2.02(6H,s),1.26(3H,t,J=7.3Hz)。MS(NH3-CI)m/e 372(4),371(29),370(100)。對于C25H27N3的分析計算值C,81.26;H,7.38;N,11.37;實測值C,80.70;H,7.26;N,11.20。
      表2
      實施例號XR4R5R11R6R1mp,℃a2001 CH2Cl Cl HH c-C4H7-2002 CH2Cl Cl HH c-C5H9111-1122003 CH2Cl Cl HH c-C6H11油2004 CH2Cl Cl HH c-C7H13128-1302005 CH2Cl Cl HH c-C8H15-2006 CH2Cl Cl HH 2-CH3-c-C5H8油2007 CH2Cl Cl HH 3-CH3-c-C5H8-2008 CH2Cl Cl HH 2-OCH3-c-C5H8-2009 CH2Cl Cl HH 2,5-(CH3)2-c-C5H7-2010 CH2Cl Cl HH 2-(CH3)2CH-5-CH3-c-C6H9-2011 CH2Cl Cl HH 9-芴基 油2012 CH2Cl Cl HH 1-四氫化萘基 油2013 CH2Cl Cl HH 1-(2,3-二氫化茚)基 油2014 CH2Cl Cl HH 4-苯并二氫吡喃基 油2015 CH2Cl Cl HH 2-氧-c-C5H7166-1682016 CH2Cl Cl HH 5-二苯并環(huán)庚烷基 -2017 CH2Cl Cl HH 5-二苯并環(huán)庚烯基 -2018 CH2Cl CF3HH c-C4H7-2019 CH2Cl CF3HH c-C5H9146-1472020 CH2Cl CF3HH c-C6H11油2021 CH2Cl CF3HH c-C7H13129-1302022 CH2Cl CF3HH c-C8H15-2023 CH2Cl CF3HH 2-CH3-c-C5H898-992024 CH2ClCF3H H3-CH3-c-C5H8-2025 CH2ClCF3H H2-OCH3-c-C5H8-2026 CH2ClCF3H H2,5-(CH3)2-c-C5H7-2027 CH2ClCF3H H2-(CH3)2CH-5-CH3-c-C6H9-2028 CH2ClCF3H H9-芴基-2029 CH2ClCF3H H1-四氫化萘基 -2030 CH2ClCF3H H1-(2,3-二氫化茚)基 -2031 CH2ClCF3H H4-苯并二氫吡喃基 -2032 CH2ClCF3H H2-氧-c-C5H7-2033 CH2ClCF3H H5-二苯并環(huán)庚烷基 -2034 CH2ClCF3H H5-二苯并環(huán)庚烯基 -2035 CH2ClOCH3H Hc-C4H7-2036 CH2ClOCH3H Hc-C5H9-2037 CH2ClOCH3H Hc-C6H11-2038 CH2ClOCH3H Hc-C7H13-2039 CH2ClOCH3H Hc-C8H15-2040 CH2ClOCH3H H2-CH3-c-C5H8-2041 CH2ClOCH3H H3-CH3-c-C5H8-2042 CH2ClOCH3H H2-OCH3-c-C5H8-2043 CH2ClOCH3H H2,5-(CH3)2-c-C5H7-2044 CH2ClOCH3H H2-(CH3)2CH-5-CH3-c-C6H9-2045 CH2ClOCH3H H9-芴基-2046 CH2ClOCH3H H1-四氫化萘基 -2047 CH2ClOCH3H H1-(2,3-二氫化茚)基 -2048 CH2ClOCH3H H4-苯并二氫吡喃基 -2049 CH2ClOCH3H H2-氧-c-C5H7-2050 CH2ClOCH3H H5-二苯并環(huán)庚烷基 -2051 CH2ClOCH3H H5-二苯并環(huán)庚烯基 -2052 CH2ClOCF3H Hc-C4H7-2053 CH2ClOCF3H Hc-C5H9油2054 CH2ClOCF3H Hc-C6H11-2055 CH2ClOCF3H Hc-C7H13-2056 CH2ClOCF3H Hc-C8H15-2057 CH2ClOCF3H H2-CH3-c-C5H8-2058 CH2ClOCF3H H3-CH3-c-C5H8-2059 CH2ClOCF3H H2-OCH3-c-C5H8-2060 CH2ClOCF3H H2,5-(CH3)2-c-C5H7-2061 CH2ClOCF3H H2-(CH3)2CH-5-CH3-c-C6H92062 CH2Cl OCF3H H 9-芴基-2063 CH2Cl OCF3H H 1-四氫化萘基 -2064 CH2Cl OCF3H H 1-(2,3-二氫化茚)基 -2065 CH2Cl OCF3H H 4-苯并二氫吡喃基 -2066 CH2Cl OCF3H H 2-氧-c-C5H7-2067 CH2Cl OCF3H H 5-二苯并環(huán)庚烷基 -2068 CH2Cl OCF3H H 5-二苯并環(huán)庚烯基 -2069 CH2Cl CH3H H c-C4H7-2070 CH2Cl CH3H H c-C5H9-2071 CH2Cl CH3H H c-C6H11-2072 CH2Cl CH3H H c-C7H13-2073 CH2Cl CH3H H c-C8H15-2074 CH2Cl CH3H H 2-CH3-c-C5H8-2075 CH2Cl CH3H H 3-CH3-c-C5H8-2076 CH2Cl CH3H H 2-OCH3-c-C5H8-2077 CH2Cl CH3H H 2,5-(CH3)2-c-C5H7-2078 CH2Cl CH3H H 2-(CH3)2CH-5-CH3-c-C6H9-2079 CH2Cl CH3H H 9-芴基-2080 CH2Cl CH3H H 1-四氫化萘基 -2081 CH2Cl CH3H H 1-(2,3-二氫化茚)基 -2082 CH2Cl CH3H H 4-苯并二氫吡喃基 -2083 CH2Cl CH3H H 2-氧-c-C5H7-2084 CH2Cl CH3H H 5-二苯并環(huán)庚烷基 -2085 CH2Cl CH3H H 5-二苯并環(huán)庚烯基 -2086 CH2CF3Cl H H c-C4H7-2087 CH2CF3Cl H H c-C5H9143-1452088 CH2CF3Cl H H c-C6H11-2089 CH2CF3Cl H H c-C7H13-2090 CH2CF3Cl H H c-C8H15-2091 CH2CF3Cl H H 2-CH3-c-C5H8-2092 CH2CF3Cl H H 3-CH3-c-C5H8-2093 CH2CF3Cl H H 2-OCH3-c-C5H8-2094 CH2CF3Cl H H 2,5-(CH3)2-c-C5H7-2095 CH2CF3Cl H H 2-(CH3)2CH-5-CH3-c-C6H9-2096 CH2CF3Cl H H 9-芴基-2097 CH2CF3Cl H H 1-四氫化萘基 -2098 CH2CF3Cl H H 1-(2,3-二氫化茚)基 -2099 CH2CF3Cl H H 4-苯并二氫吡喃基 -2100 CH2CF3Cl H H2-氧-c-C5H7-2101 CH2CF3Cl H H5-二苯并環(huán)庚烷基-2102 CH2CF3Cl H H5-二苯并環(huán)庚烯基-2103 CH2CF3OCH3H Hc-C4H7-2104 CH2CF3OCH3H Hc-C5H9103-1062105 CH2CF3OCH3H Hc-C6H11-2106 CH2CF3OCH3H Hc-C7H13-2107 CH2CF3OCH3H Hc-C8H15-2108 CH2CF3OCH3H H2-CH3-c-C5H8-2109 CH2CF3OCH3H H3-CH3-c-C5H8-2110 CH2CF3OCH3H H2-OCH3-c-C5H8-2111 CH2CF3OCH3H H2,5-(CH3)2-c-C5H7-2112 CH2CF3OCH3H H2-(CH3)2CH-5-CH3-c-C6H9-2113 CH2CF3OCH3H H9-芴基 -2114 CH2CF3OCH3H H1-四氫化萘基-2115 CH2CF3OCH3H H1-(2,3-二氧化茚)基 -2116 CH2CF3OCH3H H4-苯并二氫吡喃基-2117 CH2CF3OCH3H H2-氧-c-C5H7-2118 CH2CF3OCH3H H5-二苯并環(huán)庚烷基-2119 CH2CF3OCH3H H5-二苯并環(huán)庚烯基-2120 CH2CF3F H Hc-C4H7-2121 CH2CF3F H Hc-C5H9-2122 CH2CF3F H Hc-C6H11-2123 CH2CF3F H Hc-C7H13119-1222124 CH2CF3F H Hc-C8H15-2125 CH2CF3F H H2-CH3-c-C5H8-2126 CH2CF3F H H3-CH3-c-C5H8-2127 CH2CF3F H H2-OCH3-c-C5H8-2128 CH2CF3F H H2,5-(CH3)2-c-C5H7-2129 CH2CF3F H H2-(CH3)2CH-5-CH3-c-C6H9155-1562130 CH2CF3F H H9-芴基 184-1852131 CH2CF3F H H1-四氫化萘基-2132 CH2CF3F H H1-(2,3-二氫化茚)基 -2133 CH2CF3F H H4-苯并二氫吡喃基-2134 CH2CF3F H H2-氧-c-C5H7-2135 CH2CF3F H H5-二苯并環(huán)庚烷基-2136 CH2CF3F H H5-二苯并環(huán)庚烯基-2137 CH2CH3OCH3CH3Hc-C4H7-2138 CH2CH3OCH3CH3H c-C5H9-2139 CH2CH3OCH3CH3H c-C6H11-2140 CH2CH3OCH3CH3H c-C7H13-2141 CH2CH3OCH3CH3H c-C8H15-2142 CH2CH3OCH3CH3H 2-CH3-c-C5H8-2143 CH2CH3OCH3CH3H 3-CH3-c-C5H8-2144 CH2CH3OCH3CH3H 2-OCH3-c-C5H8-2145 CH2CH3OCH3CH3H 2,5-(CH3)2-c-C5H7-2146 CH2CH3OCH3CH3H 2-(CH3)2CH-5-CH3-c-C6H9-2147 CH2CH3OCH3CH3H 9-芴基-2148 CH2CH3OCH3CH3H 1-四氫化萘基 -2149 CH2CH3OCH3CH3H 1-(2,3-二氫化茚)基 -2150 CH2CH3OCH3CH3H 4-苯并二氫吡喃基 -2151 CH2CH3OCH3CH3H 2-氧-c-C5H7-2152 CH2CH3OCH3CH3H 5-二苯并環(huán)庚烷基 -2153 CH2CH3OCH3CH3H 5-二苯并環(huán)庚烯基 -2154 CH2CH3OCH3ClH c-C4H7-2155 CH2CH3OCH3ClH c-C5H9115-1162156 CH2CH3OCH3ClH c-C6H11-2157 CH2CH3OCH3ClH c-C7H13-2158 CH2CH3OCH3ClH c-C8H15-2159 CH2CH3OCH3ClH 2-CH3-c-C5H8-2160 CH2CH3OCH3ClH 3-CH3-c-C5H8-2161 CH2CH3OCH3ClH 2-OCH3-c-C5H8-2162 CH2CH3OCH3ClH 2,5-(CH3)2-c-C5H7-2163 CH2CH3OCH3ClH 2-(CH3)2CH-5-CH3-c-C6H9-2164 CH2CH3OCH3ClH 9-芴基-2165 CH2CH3OCH3ClH 1-四氫化萘基 -2166 CH2CH3OCH3ClH 1-(2,3-二氫化茚)基 -2167 CH2CH3OCH3ClH 4-苯并二氫吡喃基 -2168 CH2CH3OCH3ClH 2-氧-c-C5H7-2169 CH2CH3OCH3ClH 5-二苯并環(huán)庚烷基 -2170 CH2CH3OCH3ClH 5-二苯并環(huán)庚烯基 -2171 CH2CH3OCH3F H c-C4H7-2172 CH2CH3OCH3F H c-C5H9-2173 CH2CH3OCH3F H c-C6H11-2174 CH2CH3OCH3F H c-C7H13-2175 CH2CH3OCH3F H c-C8H15-2176 CH2CH3OCH3F H2-CH3-c-C5H8-2177 CH2CH3OCH3F H3-CH3-c-C5H8-2178 CH2CH3OCH3F H2-OCH3-c-C5H8-2179 CH2CH3OCH3F H2,5-(CH3)2-c-C5H7-2180 CH2CH3OCH3F H2-(CH3)2CH-5-CH3-c-C6H9-2181 CH2CH3OCH3F H9-芴基-2182 CH2CH3OCH3F H1-四氫化萘基 -2183 CH2CH3OCH3F H1-(2,3-二氫化茚)基 -2184 CH2CH3OCH3F H4-苯并二氫吡喃基 -2185 CH2CH3OCH3F H2-氧-c-C5H7-2186 CH2CH3OCH3F H5-二苯并環(huán)庚烷基 -2187 CH2CH3OCH3F H5-二苯并環(huán)庚烯基 -2188 CH2CH3CH3H CH3c-C4H7-2189 CH2CH3CH3H CH3c-C5H9-2190 CH2CH3CH3H CH3c-C6H11-2191 CH2CH3CH3H CH3c-C7H13-2192 CH2CH3CH3H CH3c-C8H15-2193 CH2CH3CH3H CH32-CH3-c-C5H8-2194 CH2CH3CH3H CH33-CH3-c-C5H8-2195 CH2CH3CH3H CH32-OCH3-c-C5H8-2196 CH2CH3CH3H CH32,5-(CH3)2-c-C5H7-2197 CH2CH3CH3H CH32-(CH3)2CH-5-CH3-c-C6H9-2198 CH2CH3CH3H CH39-芴基-2199 CH2CH3CH3H CH31-四氫化萘基 -2200 CH2CH3CH3H CH31-(2,3-二氫化茚)基 -2201 CH2CH3CH3H CH34-苯并二氫吡喃基 -2202 CH2CH3CH3H CH32-氧-c-C5H7-2203 CH2CH3CH3H CH35-二苯并環(huán)庚烷基 -2204 CH2CH3CH3H CH35-二苯并環(huán)庚烯基 -2205 CH2Cl Cl H CH3c-C4H7-2206 CH2Cl Cl H CH3c-C5H9-2207 CH2Cl Cl H CH3c-C6H11-2208 CH2Cl Cl H CH3c-C7H13-2209 CH2Cl Cl H CH3c-C8H15-2210 CH2Cl Cl H CH32-CH3-c-C5H8-2211 CH2Cl Cl H CH33-CH3-c-C5H8-2212 CH2Cl Cl H CH32-OCH3-c-C5H8-2213 CH2Cl Cl H CH32,5-(CH3)2-c-C5H7-2214 CH2ClCl H CH32-(CH3)2CH-5-CH3-c-C6H9-2215 CH2ClCl H CH39-芴基 -2216 CH2ClCl H CH31-四氫化萘基 油2217 CH2ClCl H CH31-(2,3-二氫化茚)基 -2218 CH2ClCl H CH34-苯并二氫吡喃基 -2219 CH2ClCl H CH32-氧-c-C5H7-2220 CH2ClCl H CH35-二苯并環(huán)庚烷基 -2221 CH2ClCl H CH35-二苯并環(huán)庚烯基 -2222 CH2CH3OCH3OCH3Hc-C4H7-2223 CH2CH3OCH3OCH3Hc-C5H9油2224 CH2CH3OCH3OCH3Hc-C6H11-2225 CH2CH3OCH3OCH3Hc-C7H13-2226 CH2CH3OCH3OCH3Hc-C8H15-2227 CH2CH3OCH3OCH3H2-CH3-c-C5H8油2228 CH2CH3OCH3OCH3H3-CH3-c-C5H8-2229 CH2CH3OCH3OCH3H2-OCH3-c-C5H8-2230 CH2CH3OCH3OCH3H2,5-(CH3)2-c-C5H7-2231 CH2CH3OCH3OCH3H2-(CH3)2CH-5-CH3-c-C6H9-2232 CH2CH3OCH3OCH3H9-芴基-2233 CH2CH3OCH3OCH3H1-四氫化萘基 -2234 CH2CH3OCH3OCH3H1-(2,3-二氫化茚)基 -2235 CH2CH3OCH3OCH3H4-苯并二氫吡喃基2236 CH2CH3OCH3OCH3H2-氧-c-C5H7-2237 CH2CH3OCH3OCH3H5-二苯并環(huán)庚烷基 -2238 CH2CH3OCH3OCH3H5-二苯并環(huán)庚烯基 -2239 OClCl H Hc-C5H9-2240 OClCF3H Hc-C5H9-2241 OClOCH3H Hc-C5H9-2242 OClOCF3H Hc-C5H9-2243 OClCH3H Hc-C5H9-2244 OCF3Cl H Hc-C5H9-2245 OCF3OCH3H Hc-C5H9-2246 OCH3OCH3CH3Hc-C5H9-2247 OCH3OCH3Cl Hc-C5H9-2248 OCH3OCH3F Hc-C5H9-2249 OCH3CH3H CH3c-C5H9-2250 OClCl H CH3c-C5H9-
      關(guān)鍵(a)在化合物被列為“油”的地方,提供波譜數(shù)據(jù)如下實施例2003波譜數(shù)據(jù)MS(NH3-CI)m/e 374(M+H+,100%)。
      實施例2006波譜數(shù)據(jù)TLC RF0.20(20∶80乙酸乙酯-己烷)。1HNMR(300MHz,CDCl3)δ8.94(1H,s),7.67(1H,d,J=8.1Hz),7.57(1H,d,J=1.8Hz),7.40(1H,dd,J=8.1,1.8Hz),4.83(1H,q,J=8.0Hz),3.20-3.04(1H,m),2.98(2H,q,J=7.3Hz),2.50-2.38(1H,m),2.30-2.15(2H,m),2.03-1.93(2H,m),1.75-1.60(1H,m),1.42(3H,t,J=7.3Hz),0.68(3H,d,J=6.9Hz)。MS(NH3-CI)m/e C19H21Cl2N4的計算值375.1143,實測值375.1149;380(2),379(12),378(15),377(66),376(27),375(100)。
      實施例2011波譜數(shù)據(jù)MS(NH3-CI)m/e 457(M+H+,100%)。
      實施例2012波譜數(shù)據(jù)TLC RF0.38(30∶70乙酸乙酯-己烷)。1HNMR(300MHz,CDCl3)δ8.94(1H,s),7.72(1H,d,J=8.5Hz),7.58(1H,d,J=1.8Hz),7.47-7.40(2H,m),7.24-7.18(1H,m),6.56(1H,d,J=7.7Hz),6.18-6.10(1H,m),4.82-4.76(1H,m),3.15-2.30(5H,m),2.10-1.77(3H,m),1.27(3H,t,J=7.5Hz)。MS(NH3-CI)m/e C23H21Cl2N4的計算值423.1143,實測值423.1142;427(13),426(18),425(67),424(31),423(100)。
      實施例2013波譜數(shù)據(jù)TLC RF0.28(30∶70乙酸乙酯-己烷)。1HNMR(300MHz,CDCl3)δ8.91(1H,s),7.68(1H,d,J=8.5Hz),7.58(1H,d,J=1.8Hz),7.46-7.38(2H,m),7.22-7.15(1H,m),6.91(1H,d,J=7.7Hz),6.42(1H,br t,J=7Hz),5.30-5.22(1H,m),3.43-3.33(1H,m),3.20-3.03(1H,m),2.89-2.76(2H,m),2.56-2.43(1H,m),2.01-1.90(1H,m),1.31(3H,t,J=7.5Hz)。MS(NH3-CI)m/e C22H19Cl2N4的計算值409.0987,實測值409.0987;413(12),412(17),411(67),410(29),409(100)。
      實施例2014波譜數(shù)據(jù)TLC RF0.38(30∶70乙酸乙酯-己烷)。1HNMR(300MHz,CDCl3)δ8.95(1H,s),7.71(1H,d,J=8.4Hz),7.59(1H,d,J=2.2Hz),7.42(1H,dd,J=8.4,2.2Hz),7.26-7.19(1H,m),6.98-6.90(1H,m),6.58(1H,d,J=7.7Hz),6.30-6.22(1H,m),4.60-4.53(1H,m),4.43-4.33(1H,m),4.20(1H,br),2.82-2.72(1H,m),2.69-2.58(1H,m),2.46-2.36(1H,m),2.18-2.08(1H,m),1.29(3H,t,J=7.5Hz)。MS(NH3-CI)m/e C22H19Cl2N4O的計算值425.0936,實測值425.0926;429(12),428(17),427(67),426(30),425(100)。
      實施例2020波譜數(shù)據(jù)TLC RF0.43(30∶70乙酸乙酯-己烷)。1HNMR(300MHz,CDCl3)δ8.98(1H,s),7.81(2H,d,J=8.4Hz),7.67(1H,dd,J=8.0,0.7Hz),4.26(1H,m),3.00(2H,q,J=7.6Hz),2.75-2.66(2H,m),2.06-1.90(4H,m),1.50-1.36(4H,m),1.40(3H,t,J=7.5Hz)。MS(NH3-CI)m/e 412(7),411(34),410(25),409(100)。
      實施例2053波譜數(shù)據(jù)TLC RF0.36(25∶75乙酸乙酯-己烷)。1HNMR(300MHz,CDCl3)δ8.96(1H,s),7.73(1H,d,J=8.4Hz),7.44(1H,d,J=1.1Hz),7.28(1H,dd,J=8.4,1.1Hz),4.79(1H,五重峰,J=8.4Hz),3.01(2H,q,J=7.7Hz),2.62-2.50(2H,m),2.23-2.07(2H,m),1.89-1.77(2H,m),1.66-1.49(2H,m),1.41(3H,t,J=7.7Hz)。MS(NH3-CI)m/e C19H19ClF3N4O的計算值411.1205,實測值411.1208;414(7),413(34),412(24),411(100)。
      實施例2215波譜數(shù)據(jù)TLC RF0.13(20∶80乙酸乙酯-己烷)。1HNMR(300MHz,CDCl3)δ8.94(1H,s),7.48-7.02(5H,m),6.53(1H,dd,J=7.7,1.5Hz),6.18-6.10(1H,m),3.16-2.20(5H,m),2.13(3H,d,J=4.8Hz),2.06-1.70(3H,m),1.23(3H,dt,J=7.4,4.4Hz)。MS(NH3-CI)m/e C24H23C12N4的計算值437.1300,實測值437.1299;439(67),437(100)。
      實施例2223波譜數(shù)據(jù)TLC RF0.36(50∶50乙酸乙酯-己烷)。1HNMR(300MHz,CDCl3)δ8.91(1H,s),7.33(1H,s),6.83(1H,s),4.78(1H,五重峰,J=8.5Hz),3.94(3H,s),3.90(3H,s),2.98(2H,q,J=7.6Hz),2.58-2.48(2H,m),2.42(3H,s),2.19-2.07(2H,m),1.84-1.56(4H,m),1.43(3H,t,J=7.5Hz)。MS(NH3-CI)m/e C21H27N4O2的計算值367.2134,實測值367.2120;369(3),368(24),367(100)。
      實施例2227波譜數(shù)據(jù)TLC RF0.45(50∶50乙酸乙酯-己烷)。1HNMR(300MHz,CDCl3)δ8.90(1H,s),7.37(1H,s),6.83(1H,s),4.85(1H,q,J=8.4Hz),3.94(3H,s),3.91(3H,s),3.19-3.11(1H,m),2.96(2H,dq,J=7.9,1.5Hz),2.41(3H,s),2.24-2.16(2H,m),2.04-1.94(2H,m),1.71-1.62(2H,m),1.44(3H,t,J=7.4Hz),0.69(3H,d,J=6.9Hz)。MS(NH3-CI)m/e C22H29N4O2的計算值381.2290,實測值381.2294;383(4),382(25),381(100)。
      在下列制備3-芐基-5-甲基-7-(2,4,6-三甲基苯基)-咪唑并[4,5-b]吡啶(實施例3001,表3)中所討論的方法可用于制備在表3中所包含的結(jié)構(gòu)A的所有實施例,必要的話稍作方法改變,并且使用適宜結(jié)構(gòu)的試劑。
      流程13和14的方法可用于制備在表3中所包含結(jié)構(gòu)B和結(jié)構(gòu)C的許多實施例,必要的話稍作方法改變,并且使用適宜結(jié)構(gòu)的試劑。
      實施例3001制備3-芐基-5-甲基-7-(2,4,6-三甲基苯基)咪唑并[4,5-b]吡啶部分A.以過量正丁醇處理2,4,6-三甲基苯硼酸在苯(0.5M)中的溶液,在迪恩-斯塔克蒸餾頭下加熱回流該溶液以共沸除水。蒸發(fā)除去溶劑,并且生成的2,4,6-三甲基苯基硼酸二丁酯直接用于部分B。部分B.可在此使用Snieckus等(Fu,J.M.;Zhao,B.P.;Sharp,M.J.;Snieckus,V.Can.J.Chem.1994,72,227-236)的方法。因此,以來自部分A的硼酸酯(1.2當(dāng)量)、三堿基磷酸鉀(2.4當(dāng)量)和[1,1’-雙(二苯基膦基)二茂鐵]二氯化鈀(1.2當(dāng)量)處理在二甲基甲酰胺中的4-氯-6-甲基-3-硝基-2-吡啶酮的溶液(0.1M)。在環(huán)境溫度下攪拌該混合物30小時,然后將其傾入4體積的乙酸乙酯中。以3體積的水、鹽水依次洗滌。以Na2SO4干燥提取液,過濾并蒸發(fā)。層析法分離,得到純的6-甲基-3-硝基-4-(2,4,6-三甲基苯基)-2-吡啶酮。部分C.將來自部分B的吡啶酮懸浮于6當(dāng)量的三氯氧化磷中,并在溫?zé)嵯聰嚢柚钡皆摶衔锶芙?。冷卻該混合物,并傾入冰中。在融化后,以二氯甲烷將該混合物提取兩遍,合并該提取液,以Na2SO4干燥,過濾并蒸發(fā)。通過層析法或重結(jié)晶法純化產(chǎn)物2-氯-6-甲基-3-硝基-4-(2,4,6-三甲基苯基)吡啶。部分D.將來自部分C的氯化物溶解在乙醇中,并且以芐基胺(1.2當(dāng)量)處理。把該混合物加熱回流直到經(jīng)過薄層層析法檢測到該起始原料消耗完全。蒸發(fā)該混合物,在水和乙酸乙酯中分配該殘余物質(zhì)。分離該有機層,鹽水洗滌,以Na2SO4干燥,過濾并蒸發(fā)。通過層析法或重結(jié)晶法純化產(chǎn)物2-芐基氨基-6-甲基-3-硝基-4-(2,4,6-三甲基苯基)吡啶。部分E.把來自部分D的硝基化合物溶解在1∶1的二氧六環(huán)水溶液中,并以濃氫氧化銨水溶液處理。在2小時內(nèi)向其中分幾份加入固體連二亞硫酸鈉。使該混合物繼續(xù)攪拌4小時,然后在水和乙酸乙酯中分配。分離該有機層,鹽水洗滌,以Na2SO4干燥,過濾并蒸發(fā)。通過層析法或重結(jié)晶法純化產(chǎn)物3-氨基-2-芐基氨基-6-甲基-4-(2,4,6-三甲基苯基)吡啶。部分F.以濃HCl處理來自以上部分E的二胺在三乙基原丙酸酯中的懸浮液,并加熱回流1小時,然后冷卻,并且真空蒸餾除去過量的正丙酸酯。該釜殘余物含有足夠純的N-[2-芐基氨基-4-(2,4,6-三甲基苯基)-6-甲基吡啶-3-基]丙酰胺O-乙基imidate。部分G.以催化量的對甲苯磺酸處理來自部分F的化合物在苯基醚中的溶液,并加熱至170℃6小時,然后冷卻。通過柱層析法(己烷,然后乙酸乙酯)分離該殘余液,得到標(biāo)題化合物。表3
      實施例 XR4R5R11R6R1mp,號 ℃a3001 CH2ClCl H H C(=O)OC2H5-3002 CH2ClCl H H C(=O)OC3H790-913003 CH2ClCl H H C(=O)OC4H957-593004 CH2ClCl H H C(=O)OCH(CH3)280-813005 CH2ClCl H H C(=O)OCH2CH(CH3)260-623006 CH2ClCl H H C(=O)N(CH3)2-3007 CH2ClCl H H C(=O)N(C2H5)2120-1233008 CH2ClCl H H C(=O)N[CH(CH3)2]2147-1493009 CH2ClCl H H C(=O)(1-嗎啉基) 158-1593010 CH2ClCl H H SO2C6H5132-1333011 CH2ClCl H H SO2(4-CH3-C6H4) 154-1553012 CH2ClCl H H SO2(4-OCH3-C6H4) 156-1583013 CH2ClCl H H SO2-(2-噻吩基) 176-1783014 CH2ClCl H H SO2CH2C6H5127-1293015 CH2ClCl H H SO2C3H7100-1013016 CH2ClCl H H SO2C4H979-803017 CH2ClCl H H C(=O)-(2-Cl-C6H4) 110-1133018 CH2ClCF3H H C(=O)OC2H5-3019 CH2ClCF3H H C(=O)OC3H7-3020 CH2Cl CF3H H C(=O)OC4H9-3021 CH2Cl CF3H H C(=O)OCH(CH3)2-3022 CH2Cl CF3H H C(=O)OCH2CH(CH3)2-3023 CH2Cl CF3H H C(=O)N(CH3)2-3024 CH2Cl CF3H H C(=O)N(C2H5)2-3025 CH2Cl CF3H H C(=O)N[CH(CH3)2]2-3026 CH2Cl CF3H H C(=O)(1-嗎啉基) -3027 CH2Cl CF3H H SO2C6H5-3028 CH2Cl CF3H H SO2(4-CH3-C6H4) -3029 CH2Cl CF3H H SO2(4-OCH3-C6H4)-3030 CH2Cl CF3H H SO2-(2-噻吩基) -3031 CH2Cl CF3H H SO2CH2C6H5-3032 CH2Cl CF3H H SO2C3H7-3033 CH2Cl CF3H H SO2C4H9-3034 CH2Cl CF3H H C(=O)-(2-Cl-C6H4)-3035 CH2Cl OCH3H H C(=O)OC2H5-3036 CH2Cl OCH3H H C(=O)OC3H7-3037 CH2Cl OCH3H H C(=O)OC4H9-3038 CH2Cl OCH3H H C(=O)OCH(CH3)2-3039 CH2Cl OCH3H H C(=O)OCH2CH(CH3)2-3040 CH2Cl OCH3H H C(=O)N(CH3)2-3041 CH2Cl OCH3H H C(=O)N(C2H5)2-3042 CH2Cl OCH3H H C(=O)N[CH(CH3)2]2-3043 CH2Cl OCH3H H C(=O)(1-嗎啉基) -3044 CH2Cl OCH3H H SO2C6H5-3045 CH2Cl OCH3H H SO2(4-CH3-C6H4) -3046 CH2Cl OCH3H H SO2(4-OCH3-C6H4)-3047 CH2Cl OCH3H H SO2-(2-噻吩基) -3048 CH2Cl OCH3H H SO2CH2C6H5-3049 CH2Cl OCH3H H SO2C3H7-3050 CH2Cl OCH3H H SO2C4H9-3051 CH2Cl OCH3H H C(=O)-(2-Cl-C6H4)-3052 CH2Cl OCF3H H C(=O)OC2H5-3053 CH2Cl OCF3H H C(=O)OC3H7-3054 CH2Cl OCF3H H C(=O)OC4H9-3055 CH2Cl OCF3H H C(=O)OCH(CH3)2-3056 CH2Cl OCF3H H C(=O)OCH2CH(CH3)2-3057 CH2Cl OCF3H H C(=O)N(CH3)2-3058 CH2ClOCF3H HC(=O)N(C2H5)2-3059 CH2ClOCF3H HC(=O)N[CH(CH3)2]2-3060 CH2ClOCF3H HC(=O)(1-嗎啉基)-3061 CH2ClOCF3H HSO2C6H5-3062 CH2ClOCF3H HSO2(4-CH3-C6H4)-3063 CH2ClOCF3H HSO2(4-OCH3-C6H4) -3064 CH2ClOCF3H HSO2-(2-噻吩基)-3065 CH2ClOCF3H HSO2CH2C6H5-3066 CH2ClOCF3H HSO2C3H7-3067 CH2ClOCF3H HSO2C4H9-3068 CH2ClOCF3H HC(=O)-(2-Cl-C6H4) -3069 CH2ClCH3H HC(=O)OC2H5-3070 CH2ClCH3H HC(=O)OC3H7-3071 CH2ClCH3H HC(=O)OC4H9-3072 CH2ClCH3H HC(=O)OCH(CH3)2-3073 CH2ClCH3H HC(=O)OCH2CH(CH3)2-3074 CH2ClCH3H HC(=O)N(CH3)2-3075 CH2ClCH3H HC(=O)N(C2H5)2-3076 CH2ClCH3H HC(=O)N[CH(CH3)2]2-3077 CH2ClCH3H HC(=O)(1-嗎啉基)-3078 CH2ClCH3H HSO2C6H5-3079 CH2ClCH3H HSO2(4-CH3-C6H4)-3080 CH2ClCH3H HSO2(4-OCH3-C6H4) -3081 CH2ClCH3H HSO2-(2-噻吩基)-3082 CH2ClCH3H HSO2CH2C6H5-3083 CH2ClCH3H HSO2C3H7-3084 CH2ClCH3H HSO2C4H9-3085 CH2ClCH3H HC(=O)(2-Cl-C6H4)-3086 CH2CF3Cl H HC(=O)OC2H5-3087 CH2CF3Cl H HC(=O)OC3H7-3088 CH2CF3Cl H HC(=O)OC4H9-3089 CH2CF3Cl H HC(=O)OCH(CH3)2-3090 CH2CF3Cl H HC(=O)OCH2CH(CH3)2-3091 CH2CF3Cl H HC(=O)N(CH3)2-3092 CH2CF3Cl H HC(=O)N(C2H5)2-3093 CH2CF3Cl H HC(=O)N[CH(CH3)2]2-3094 CH2CF3Cl H HC(=O)(1-嗎啉基)-3095 CH2CF3Cl H HSO2C6H5-3096 CH2CF3Cl H H SO2(4-CH3-C6H4)-3097 CH2CF3Cl H H SO2(4-OCH3-C6H4) -3098 CH2CF3Cl H H SO2-(2-噻吩基)-3099 CH2CF3Cl H H SO2CH2C6H5-3100 CH2CF3Cl H H SO2C3H7-3101 CH2CF3Cl H H SO2C4H9-3102 CH2CF3Cl H H C(=O)-(2-Cl-C6H4) -3103 CH2CF3OCH3H H C(=O)OC2H5-3104 CH2CF3OCH3H H C(=O)OC3H7-3105 CH2CF3OCH3H H C(=O)OC4H9-3106 CH2CF3OCH3H H C(=O)OCH(CH3)2-3107 CH2CF3OCH3H H C(=O)OCH2CH(CH3)2-3108 CH2CF3OCH3H H C(=O)N(CH3)2-3109 CH2CF3OCH3H H C(=O)N(C2H5)2-3110 CH2CF3OCH3H H C(=O)N[CH(CH3)2]2-3111 CH2CF3OCH3H H C(=O)(1-嗎啉基)-3112 CH2CF3OCH3H H SO2C6H5-3113 CH2CF3OCH3H H SO2(4-CH3-C6H4)-3114 CH2CF3OCH3H H SO2(4-OCH3-C6H4) -3115 CH2CF3OCH3H H SO2-(2-噻吩基)-3116 CH2CF3OCH3H H SO2CH2C6H5-3117 CH2CF3OCH3H H SO2C3H7-3118 CH2CF3OCH3H H SO2C4H9-3119 CH2CF3OCH3H H C(=O)-(2-Cl-C6H4) -3120 CH2CF3F H H C(=O)OC2H5-3121 CH2CF3F H H C(=O)OC3H7-3122 CH2CF3F H H C(=O)OC4H9-3123 CH2CF3F H H C(=O)OCH(CH3)2-3124 CH2CF3F H H C(=O)OCH2CH(CH3)2-3125 CH2CF3F H H C(=O)N(CH3)2-3126 CH2CF3F H H C(=O)N(C2H5)2-3127 CH2CF3F H H C(=O)N[CH(CH3)2]2-3128 CH2CF3F H H C(=O)(1-嗎啉基) -3129 CH2CF3F H H SO2C6H5-3130 CH2CF3F H H SO2(4-CH3-C6H4)-3131 CH2CF3F H H SO2(4-OCH3-C6H4) -3132 CH2CF3F H H SO2-(2-噻吩基)-3133 CH2CF3F H H SO2CH2C6H5-3134CH2CF3FH HSO2C3H7-3135CH2CF3FH HSO2C4H9-3136CH2CF3FH HC(=O)-(2-Cl-C6H4) -3137CH2CH3OCH3CH3HC(=O)OC2H5-3138CH2CH3OCH3CH3HC(=O)OC3H7-3139CH2CH3OCH3CH3HC(=O)OC4H9-3140CH2CH3OCH3CH3HC(=O)OCH(CH3)2-3141CH2CH3OCH3CH3HC(=O)OCH2CH(CH3)2-3142CH2CH3OCH3CH3HC(=O)N(CH3)2-3143CH2CH3OCH3CH3HC(=O)N(C2H5)2-3144CH2CH3OCH3CH3HC(=O)N[CH(CH3)2]2-3145CH2CH3OCH3CH3HC(=O)(1-嗎啉基)-3146CH2CH3OCH3CH3HSO2C6H5-3147CH2CH3OCH3CH3HSO2(4-CH3-C6H4)-3148CH2CH3OCH3CH3HSO2(4-OCH3-C6H4) -3149CH2CH3OCH3CH3HSO2-(2-噻吩基)-3150CH2CH3OCH3CH3HSO2CH2C6H5-3151CH2CH3OCH3CH3HSO2C3H7-3152CH2CH3OCH3CH3HSO2C4H9-3153CH2CH3OCH3CH3HC(=O)-(2-Cl-C6H4) -3154CH2CH3OCH3Cl HC(=O)OC2H5-3155CH2CH3OCH3Cl HC(=O)OC3H7-3156CH2CH3OCH3Cl HC(=O)OC4H9-3157CH2CH3OCH3Cl HC(=O)OCH(CH3)2-3158CH2CH3OCH3Cl HC(=O)OCH2CH(CH3)2-3159CH2CH3OCH3Cl HC(=O)N(CH3)2-3160CH2CH3OCH3Cl HC(=O)N(C2H5)2-3161CH2CH3OCH3Cl HC(=O)N[CH(CH3)2]2-3162CH2CH3OCH3Cl HC(=O)(1-嗎啉基)-3163CH2CH3OCH3Cl HSO2C6H5-3164CH2CH3OCH3Cl HSO2(4-CH3-C6H4)-3165CH2CH3OCH3Cl HSO2(4-OCH3-C6H4) -3166CH2CH3OCH3Cl HSO2-(2-噻吩基)-3167CH2CH3OCH3Cl HSO2CH2C6H5-3168CH2CH3OCH3Cl HSO2C3H7-3169CH2CH3OCH3Cl HSO2C4H9-3170CH2CH3OCH3Cl HC(=O)-(2-Cl-C6H4) -3171CH2CH3OCH3F HC(=O)OC2H5-3172 CH2CH3OCH3F HC(=O)OC3H7-3173 CH2CH3OCH3F HC(=O)OC4H9-3174 CH2CH3OCH3F HC(=O)OCH(CH3)2-3175 CH2CH3OCH3F HC(=O)OCH2CH(CH3)2-3176 CH2CH3OCH3F HC(=O)N(CH3)2-3177 CH2CH3OCH3F HC(=O)N(C2H5)2-3178 CH2CH3OCH3F HC(=O)N[CH(CH3)2]2-3179 CH2CH3OCH3F HC(=O)(1-嗎啉基) -3180 CH2CH3OCH3F HSO2C6H5-3181 CH2CH3OCH3F HSO2(4-CH3-C6H4) -3182 CH2CH3OCH3F HSO2(4-OCH3-C6H4) -3183 CH2CH3OCH3F HSO2-(2-噻吩基) -3184 CH2CH3OCH3F HSO2CH2C6H5-3185 CH2CH3OCH3F HSO2C3H7-3186 CH2CH3OCH3F HSO2C4H9-3187 CH2CH3OCH3F HC(=O)-(2-Cl-C6H4) -3188 CH2CH3CH3H CH3C(=O)OC2H5-3189 CH2CH3CH3H CH3C(=O)OC3H7-3190 CH2CH3CH3H CH3C(=O)OC4H9-3191 CH2CH3CH3H CH3C(=O)OCH(CH3)2-3192 CH2CH3CH3H CH3C(=O)OCH2CH(CH3)2-3193 CH2CH3CH3H CH3C(=O)N(CH3)2-3194 CH2CH3CH3H CH3C(=O)N(C2H5)2-3195 CH2CH3CH3H CH3C(=O)N[CH(CH3)2]2-3196 CH2CH3CH3H CH3C(=O)(1-嗎啉基) -3197 CH2CH3CH3H CH3SO2C6H5-3198 CH2CH3CH3H CH3SO2(4-CH3-C6H4) -3199 CH2CH3CH3H CH3SO2(4-OCH3-C6H4) -3200 CH2CH3CH3H CH3SO2-(2-噻吩基) -3201 CH2CH3CH3H CH3SO2CH2C6H5-3202 CH2CH3CH3H CH3SO2C3H7-3203 CH2CH3CH3H CH3SO2C4H9-3204 CH2CH3CH3H CH3C(=O)-(2-Cl-C6H4) -3205 CH2Cl Cl H CH3C(=O)OC2H5-3206 CH2Cl Cl H CH3C(=O)OC3H7-3207 CH2Cl Cl H CH3C(=O)OC4H9-3208 CH2Cl Cl H CH3C(=O)OCH(CH3)2-3209 CH2Cl Cl H CH3C(=O)OCH2CH(CH3)2-3210 CH2Cl ClH CH3C(=O)N(CH3)2-3211 CH2Cl ClH CH3C(=O)N(C2H5)2-3212 CH2Cl ClH CH3C(=O)N[CH(CH3)2]2-3213 CH2Cl ClH CH3C(=O)(1-嗎啉基) -3214 CH2Cl ClH CH3SO2C6H5-3215 CH2Cl ClH CH3SO2(4-CH3-C6H4) -3216 CH2Cl ClH CH3SO2(4-OCH3-C6H4)-3217 CH2Cl ClH CH3SO2-(2-噻吩基) -3218 CH2Cl ClH CH3SO2CH2C6H5-3219 CH2Cl ClH CH3SO2C3H7-3220 CH2Cl ClH CH3SO2C4H9-3221 CH2Cl ClH CH3C(=O)-(2-Cl-C6H4)-3222 CH2CH3OCH3OCH3HC(=O)OC2H5-3223 CH2CH3OCH3OCH3HC(=O)OC3H7-3224 CH2CH3OCH3OCH3HC(=O)OC4H9-3225 CH2CH3OCH3OCH3HC(=O)OCH(CH3)2-3226 CH2CH3OCH3OCH3HC(=O)OCH2CH(CH3)2-3227 CH2CH3OCH3OCH3HC(=O)N(CH3)2-3228 CH2CH3OCH3OCH3HC(=O)N(C2H5)2-3229 CH2CH3OCH3OCH3HC(=O)N[CH(CH3)2]2-3230 CH2CH3OCH3OCH3HC(=O)(1-嗎啉基) -3231 CH2CH3OCH3OCH3HSO2C6H5-3232 CH2CH3OCH3OCH3HSO2(4-CH3-C6H4) -3233 CH2CH3OCH3OCH3HSO2(4-OCH3-C6H4)-3234 CH2CH3OCH3OCH3HSO2-(2-噻吩基) -3235 CH2CH3OCH3OCH3HSO2CH2C6H53236 CH2CH3OCH3OCH3HSO2C3H7-3237 CH2CH3OCH3OCH3HSO2C4H9-3238 CH2CH3OCH3OCH3HC(=O)-(2-Cl-C6H4)-3239 O Cl ClH HSO2C3H7-3240 O Cl CF3H HSO2C3H7-3241 O Cl OCH3H HSO2C3H7-3242 O Cl OCF3H HSO2C3H7-3243 O Cl CH3H HSO2C3H7-3244 O CF3ClH HSO2C3H7-3245 O CF3OCH3H HSO2C3H7-3246 O CH3OCH3CH3HSO2C3H7-3247 O CH3OCH3Cl HSO2C3H7-3248 OCH3OCH3F HSO2C3H7-3249 OCH3CH3H CH3SO2C3H7-3250 OCl Cl H CH3SO2C3H7-3251 CH2Cl Cl H HC(=O)-(3-Cl-C6H4)115-118
      制備表1中結(jié)構(gòu)A的化合物所使用的方法可用于制備在表4中結(jié)構(gòu)A的化合物。例如,在鈀-催化芳基交叉偶合方法(參見實施例35或831)中以各種取代的吡啶-和嘧啶硼酸替代苯硼酸將得到6-吡啶基-或6-嘧啶基嘌呤化合物。
      流程13和14的方法可用于制備在表4中所包含的結(jié)構(gòu)B和結(jié)構(gòu)C的實施例,必要的話稍做方法改變,并且使用適宜結(jié)構(gòu)的試劑。表4
      實施 XR4ZR3Y R6R1aR1bmp,例號 ℃a4001 CH2CH3CH N(CH3)2N H c-C3H5c-C3H5-4002 CH2CH3CH N(CH3)2N H CH3c-C3H5-4003 CH2CH3CH N(CH3)2N H C2H5c-C3H5-4004 CH2CH3CH N(CH3)2N H C3H7c-C3H5-4005 CH2CH3CH N(CH3)2N H C4H9c-C3H5-4006 CH2CH3CH N(CH3)2N H CH3C3H7-4007 CH2CH3CH N(CH3)2N H C2H5C3H7-4008 CH2CH3CH N(CH3)2N H C3H7C3H7-4009 CH2CH3CH N(CH3)2N H C2H5C4H9-4010 CH2CH3CH N(CH3)2N H H 4-CH3O-C6H4-4011 O CH3CH N(CH3)2N H c-C3H5c-C3H5-4012 O CH3CH N(CH3)2N H CH3c-C3H5-4013 O CH3CH N(CH3)2N H C2H5c-C3H5-4014 O CH3CH N(CH3)2N H C3H7c-C3H5-4015 O CH3CH N(CH3)2N H C4H9c-C3H5-4016 O CH3CH N(CH3)2N H CH3C3H7-4017 O CH3CH N(CH3)2N H C2H5C3H7-4018 O CH3CH N(CH3)2N H C3H7C3H7-4019 O CH3CH N(CH3)2N H C2H5C4H9-4020 O CH3CH N(CH3)2N H H 4-CH3O-C6H4-4021 CH2CH3CH CH3N CH3c-C3H5c-C3H5-4022 CH2CH3CH CH3N CH3CH3c-C3H5-4023CH2CH3CHCH3NCH3C2H5c-C3H5-4024CH2CH3CHCH3NCH3C3H7c-C3H5-4025CH2CH3CHCH3NCH3C4H9c-C3H5-4026CH2CH3CHCH3NCH3CH3C3H7-4027CH2CH3CHCH3NCH3C2H5C3H7-4028CH2CH3CHCH3NCH3C3H7C3H7-4029CH2CH3CHCH3NCH3C2H5C4H9-4030CH2CH3CHCH3NCH3H 4-CH3O-C6H4-4031O CH3CHCH3NCH3c-C3H5c-C3H5-4032O CH3CHCH3NCH3CH3c-C3H5-4033O CH3CHCH3NCH3C2H5c-C3H5-4034O CH3CHCH3NCH3C3H7c-C3H5-4035O CH3CHCH3NCH3C4H9c-C3H5-4036O CH3CHCH3NCH3CH3C3H7-4037O CH3CHCH3NCH3C2H5C3H7-4038O CH3CHCH3NCH3C3H7C3H7-4039O CH3CHCH3NCH3C2H5C4H9-4040O CH3CHCH3NCH3H 4-CH3O-C6H4-4041CH2CH3CHSCH3NH c-C3H5c-C3H5-4042CH2CH3CHSCH3NH CH3c-C3H5-4043CH2CH3CHSCH3NH C2H5c-C3H5-4044CH2CH3CHSCH3NH C3H7c-C3H5-4045CH2CH3CHSCH3NH C4H9c-C3H5-4046CH2CH3CHSCH3NH CH3C3H7-4047CH2CH3CHSCH3NH C2H5C3H7-4048CH2CH3CHSCH3NH C3H7C3H7-4049CH2CH3CHSCH3NH C2H5C4H9-4050CH2CH3CHSCH3NH H 4-CH3O-C6H4-4051O CH3CHSCH3NH c-C3H5c-C3H5-4052O CH3CHSCH3NH CH3c-C3H5-4053O CH3CHSCH3NH C2H5c-C3H5-4054O CH3CHSCH3NH C3H7c-C3H5-4055O CH3CHSCH3NH C4H9c-C3H5-4056O CH3CHSCH3NH CH3C3H7-4057O CH3CHSCH3NH C2H5C3H7-4058O CH3CHSCH3NH C3H7C3H7-4059O CH3CHSCH3NH C2H5C4H9-4060O CH3CHSCH3NH H 4-CH3O-C6H4-4061CH2SCH3NCH3NSCH3c-C3H5c-C3H5-4062CH2SCH3NCH3NSCH3CH3c-C3H5-4063CH2SCH3NCH3NSCH3C2H5c-C3H5-4064CH2SCH3NCH3NSCH3C3H7c-C3H5-4065CH2SCH3NCH3NSCH3C4H9c-C3H5-4066CH2SCH3NCH3NSCH3CH3C3H7-4067CH2SCH3NCH3NSCH3C2H5C3H7-4068CH2SCH3NCH3NSCH3C3H7C3H7-4069CH2SCH3NCH3NSCH3C2H5C4H9-4070CH2SCH3NCH3NSCH3H 4-CH3O-C6H4-4071O SCH3NCH3NSCH3c-C3H5c-C3H5-4072O SCH3NCH3NSCH3CH3c-C3H5-4073O SCH3NCH3NSCH3C2H5c-C3H5-4074O SCH3NCH3NSCH3C3H7c-C3H5-4075O SCH3NCH3NSCH3C4H9c-C3H5-4076O SCH3NCH3NSCH3CH3C3H7-4077O SCH3NCH3NSCH3C2H5C3H7-4078O SCH3NCH3NSCH3C3H7C3H7-4079O SCH3NCH3NSCH3C2H5C4H9-4080O SCH3NCH3NSCH3H 4-CH3O-C6H4-4081CH2CH3NCH3NCH3c-C3H5c-C3H5-4082CH2CH3NCH3NCH3CH3c-C3H5-4083CH2CH3NCH3NCH3C2H5c-C3H5-4084CH2CH3NCH3NCH3C3H7c-C3H5-4085CH2CH3NCH3NCH3C4H9c-C3H5-4086CH2CH3NCH3NCH3CH3C3H7-4087CH2CH3NCH3NCH3C2H5C3H7-4088CH2CH3NCH3NCH3C3H7C3H7-4089CH2CH3NCH3NCH3C2H5C4H9-4090CH2CH3NCH3NCH3H 4-CH3O-C6H4-4091O CH3NCH3NCH3c-C3H5c-C3H5-4092O CH3NCH3NCH3CH3c-C3H5-4093O CH3NCH3NCH3C2H5c-C3H5-4094O CH3NCH3NCH3C3H7c-C3H5-4095O CH3NCH3NCH3C4H9c-C3H5-4096O CH3NCH3NCH3CH3C3H7-4097O CH3NCH3NCH3C2H5C3H7-4098O CH3NCH3NCH3C3H7C3H7-4099 O CH3N CH3N CH3C2H5C4H9-4100 O CH3N CH3N CH3H 4-CH3O-C6H4-4101 CH2CH3CH CH3N H c-C3H5c-C3H5-4102 CH2CH3CH CH3N H CH3c-C3H5-4103 CH2CH3CH CH3N H C2H5c-C3H5-4104 CH2CH3CH CH3N H C3H7c-C3H5-4105 CH2CH3CH CH3N H C4H9c-C3H5-4106 CH2CH3CH CH3N H CH3C3H7-4107 CH2CH3CH CH3N H C2H5C3H7-4108 CH2CH3CH CH3N H C3H7C3H7-4109 CH2CH3CH CH3N H C2H5C4H9-4110 CH2CH3CH CH3N H H 4-CH3O-C6H4-4111 O CH3CH CH3N H c-C3H5c-C3H5-4112 O CH3CH CH3N H CH3c-C3H5-4113 O CH3CH CH3N H C2H5c-C3H5-4114 O CH3CH CH3N H C3H7c-C3H5-4115 O CH3CH CH3N H C4H9c-C3H5-4116 O CH3CH CH3N H CH3C3H7-4117 O CH3CH CH3N H C2H5C3H7-4118 O CH3CH CH3N H C3H7C3H7-4119 O CH3CH CH3N H C2H5C4H9-4120 O CH3CH CH3N H H 4-CH3O-C6H4-4121 CH2CH3N N(CH3)2CHH c-C3H5c-C3H5-4122 CH2CH3N N(CH3)2CHH CH3c-C3H5-4123 CH2CH3N N(CH3)2CHH C2H5c-C3H5-4124 CH2CH3N N(CH3)2CHH C3H7c-C3H5-4125 CH2CH3N N(CH3)2CHH C4H9c-C3H5-4126 CH2CH3N N(CH3)2CHH CH3C3H7-4127 CH2CH3N N(CH3)2CHH C2H5C3H7-4128 CH2CH3N N(CH3)2CHH C3H7C3H7-4129 CH2CH3N N(CH3)2CHH C2H5C4H9-4130 CH2CH3N N(CH3)2CHH H 4-CH3O-C6H4-4131 O CH3N N(CH3)2CHH c-C3H5c-C3H5-4132 O CH3N N(CH3)2CHH CH3c-C3H5-4133 O CH3N N(CH3)2CHH C2H5c-C3H5-4134 O CH3N N(CH3)2CHH C3H7c-C3H5-4135 O CH3N N(CH3)2CHH C4H9c-C3H5-4136 O CH3N N(CH3)2CHH CH3C3H7-4137 O CH3NN(CH3)2CHH C2H5C3H7-4138 O CH3NN(CH3)2CHH C3H7C3H7-4139 O CH3NN(CH3)2CHH C2H5C4H9-4140 O CH3NN(CH3)2CHH H 4-CH3O-C6H4-4141 CH2CH3NCH3CHH c-C3H5c-C3H5-4142 CH2CH3NCH3CHH CH3c-C3H5-4143 CH2CH3NCH3CHH C2H5c-C3H5-4144 CH2CH3NCH3CHH C3H7c-C3H5-4145 CH2CH3NCH3CHH C4H9c-C3H5-4146 CH2CH3NCH3CHH CH3C3H7-4147 CH2CH3NCH3CHH C2H5C3H7-4148 CH2CH3NCH3CHH C3H7C3H7-4149 CH2CH3NCH3CHH C2H5C4H9-4150 CH2CH3NCH3CHH H 4-CH3O-C6H4-4151 O CH3NCH3CHH c-C3H5c-C3H5-4152 O CH3NCH3CHH CH3c-C3H5-4153 O CH3NCH3CHH C2H5c-C3H5-4154 O CH3NCH3CHH C3H7c-C3H5-4155 O CH3NCH3CHH C4H9c-C3H5-4156 O CH3NCH3CHH CH3C3H7-4157 O CH3NCH3CHH C2H5C3H7-4158 O CH3NCH3CHH C3H7C3H7-4159 O CH3NCH3CHH C2H5C4H9-4160 O CH3NCH3CHH H 4-CH3O-C6H4-4161 CH2OCH3NOCH3CHH c-C3H5c-C3H5120-1214162 CH2OCH3NOCH3CHH CH3c-C3H5-4163 CH2OCH3NOCH3CHH C2H5c-C3H5-4164 CH2OCH3NOCH3CHH C3H7c-C3H5-4165 CH2OCH3NOCH3CHH C4H9c-C3H5-4166 CH2OCH3NOCH3CHH CH3C3H7油4167 CH2OCH3NOCH3CHH C2H5C3H7-4168 CH2OCH3NOCH3CHH C3H7C3H7-4169 CH2OCH3NOCH3CHH C2H5C4H9-4170 CH2OCH3NOCH3CHH H 4-CH3O-C6H4-4171 O OCH3NOCH3CHH c-C3H5c-C3H5油4172 O OCH3NOCH3CHH CH3c-C3H5-4173 O OCH3NOCH3CHH C2H5c-C3H5-4174 O OCH3NOCH3CHH C3H7c-C3H5-4175 O OCH3NOCH3CHH C4H9c-C3H5-4176 O OCH3NOCH3CHH CH3C3H7-4177 O OCH3NOCH3CHH C2H5C3H7-4178 O OCH3NOCH3CHH C3H7C3H7-4179 O OCH3NOCH3CHH C2H5C4H9-4180 O OCH3NOCH3CHH H 4-CH3O-C6H4-4181 CH2OCH3NN(CH3)2CHH c-C3H5c-C3H5-4182 CH2OCH3NN(CH3)2CHH CH3c-C3H5-4183 CH2OCH3NN(CH3)2CHH C2H5c-C3H5-4184 CH2OCH3NN(CH3)2CHH C3H7c-C3H5-4185 CH2OCH3NN(CH3)2CHH C4H9c-C3H5-4186 CH2OCH3NN(CH3)2CHH CH3C3H7-4187 CH2OCH3NN(CH3)2CHH C2H5C3H7-4188 CH2OCH3NN(CH3)2CHH C3H7C3H7-4189 CH2OCH3NN(CH3)2CHH C2H5C4H9-4190 CH2OCH3NN(CH3)2CHH H 4-CH3O-C6H4-4191 O OCH3NN(CH3)2CHH c-C3H5c-C3H5-4192 O OCH3NN(CH3)2CHH CH3c-C3H5-4193 O OCH3NN(CH3)2CHH C2H5c-C3H5-4194 O OCH3NN(CH3)2CHH C3H7c-C3H5-4195 O OCH3NN(CH3)2CHH C4H9c-C3H5-4196 O OCH3NN(CH3)2CHH CH3C3H7-4197 O OCH3NN(CH3)2CHH C2H5C3H7-4198 O OCH3NN(CH3)2CHH C3H7C3H7-4199 O OCH3NN(CH3)2CHH C2H5C4H9-4200 O OCH3NN(CH3)2CHH H 4-CH3O-C6H4-4201 CH2N(CH3)2NOCH3CHH c-C3H5c-C3H5-4202 CH2N(CH3)2NOCH3CHH CH3c-C3H5-4203 CH2N(CH3)2NOCH3CHH C2H5c-C3H5-4204 CH2N(CH3)2NOCH3CHH C3H7c-C3H5-4205 CH2N(CH3)2NOCH3CHH C4H9c-C3H5-4206 CH2N(CH3)2NOCH3CHH CH3C3H7-4207 CH2N(CH3)2NOCH3CHH C2H5C3H7-4208 CH2N(CH3)2NOCH3CHH C3H7C3H7-4209 CH2N(CH3)2NOCH3CHH C2H5C4H9-4210 CH2N(CH3)2NOCH3CHH H 4-CH3O-C6H4-4211 O N(CH3)2NOCH3CHH c-C3H5c-C3H5-4212 O N(CH3)2NOCH3CHH CH3c-C3H5-4213 O N(CH3)2NOCH3CHH C2H5c-C3H5-4214 O N(CH3)2NOCH3CHH C3H7c-C3H5-4215 O N(CH3)2NOCH3CHH C4H9c-C3H5-4216 O N(CH3)2NOCH3CHH CH3C3H7-4217 O N(CH3)2NOCH3CHH C2H5C3H7-4218 O N(CH3)2NOCH3CHH C3H7C3H7-4219 O N(CH3)2NOCH3CHH C2H5C4H9-4220 O N(CH3)2NOCH3CHH H 4-CH3O-C6H4-4221 CH2OCH3NOCH3CHH C2H52-呋喃基 -4222 CH2OCH3NOCH3CHH C3H72-呋喃基 -4223 CH2OCH3NOCH3CHH C2H5b -4224 CH2OCH3NOCH3CHH C3H7b -4225 CH2OCH3NOCH3CHH C6H5b -4226 CH2OCH3NOCH3CHH c-C3H5b -4227 CH2OCH3NOCH3CHH CH3CH=CHCH3-4228 CH2OCH3NOCH3CHH C3H7CH=CH2-4229 CH2OCH3NOCH3CHH CH3C6H5-4230 CH2OCH3NOCH3CHH CH3c-C4H7-關(guān)鍵(a)在化合物被指明為“油”的地方,提供波譜數(shù)據(jù)如下實施例4166元素分析C19H25N5O2的計算值C 64.20,H 7.10,N 19.70;實測值C 64.13,H 6.67,N 19.30。實施例4171元素分析C20H23N5O3的計算值C 62.98,H 6.09,N 18.36;實測值C 62.80,H 6.10,N 18.19。
      b)C≡C-CH3制備表1中化合物所使用方法可用于合成在表5和表5A中的結(jié)構(gòu)A的那些化合物。用于制備帶有苯并呋喃基團(tuán)的類似物的方法在下列實施例中闡明。
      流程13和14的方法可用于制備在表5和表5A中所包含的結(jié)構(gòu)B和結(jié)構(gòu)C的許多實施例,必要的話稍作方法改變,并且使用適宜結(jié)構(gòu)的試劑。
      實施例5001制備9-雙環(huán)丙基甲基-8-乙基-6-(6-甲基-2,3-二氫苯并呋喃-5-基)嘌呤部分A.以己烷洗滌在礦物油中的氫化鈉(5.05g,50%w/w,105mmol)分散體并使之真空干燥。加入DMF(100mL),將該漿狀物冷卻至0℃,并以在DMF(20mL)中的間甲酚(10mL,95.6mmol)溶液處理。使該生成的混合物攪拌1小時,然后通過注射器以氯甲基甲基醚(8.00mL,105mmol)處理它。將該混合物攪拌過夜,然后傾入乙酸乙酯(200mL)中。以水(3×200mL)和鹽水(100mL)洗滌該混合物,并以乙酸乙酯連續(xù)回提該水相,合并提取液,經(jīng)硫酸鎂干燥,過濾并蒸發(fā)。通過硅膠柱以10∶90乙酸乙酯-己烷洗脫純化該油狀產(chǎn)物,然后蒸發(fā)得到油狀純產(chǎn)物3-(甲氧基甲氧基)甲苯(13.93g,91.5mmol,96%)。TLCRF0.46(10∶90乙酸乙酯-己烷)。1H NMR(300MHz,CDCl3)d 7.17(1H,t,J=7.7Hz),6.86-6.81(3H,m),5.17(2H,s),3.48(3H,s),2.33(3H,s)。MS(H2O-GC/MS)m/e 153(60),121(100)。部分B.將3-(甲氧基甲氧基)甲苯(5.00g,32.9mmol)和TMEDA(5.30mL,35.1mmol)在THF(50mL)中的溶液冷卻至0℃,并且以正丁基鋰的己烷溶液(22.0mL,1.6M,35.2mmol)處理。4小時后,把該溶液冷卻至-78℃,并且滴加環(huán)氧乙烷(2.00mL,40mmol,從演示燒瓶通過指形冷凍器進(jìn)入滴液漏斗來縮合)處理。使該混合物攪拌并且溫?zé)嶂镰h(huán)境溫度過夜,然后把它傾入飽和的氯化銨水溶液中(120mL)。以乙酸乙酯(2×120mL)提取,連續(xù)以鹽水洗滌該提取液,合并,經(jīng)硫酸鎂干燥,過濾并蒸發(fā)。通過柱層析法(10∶90乙酸乙酯-己烷)分離該殘余油狀物,得到所要求的泡沫狀液體產(chǎn)物2-[2-(甲氧基甲氧基)-4-甲基苯基]乙醇(2.25g,11.5mmol,35%),同時回收起始原料2.50g。該1H NMR波譜顯示在10∶1過量的區(qū)域選擇性。TLC RF0.09(10∶90乙酸乙酯-己烷)。1H NMR(300MHz,CDCl3)d 7.06(1H,d,J=7.7Hz),6.92(1H,br s),6.78(1H,br d,J=7.7Hz),5.20(2H,s),3.83(2H,q,J=6.4Hz),3.49(3H,s),2.89(2H,t,J=6.6Hz),2.32(3H,s),1.61(1H,t,J=5.9Hz)。MS(NH3-DCI)m/e 214(76),212(100),197(9),182(30),165(38)。部分C.把來自部分B的MOM化合物(1.84g,9.38mmol)溶液溶解于1∶1的THF-異丙醇(20mL)中,并且以在二氧六環(huán)中的HCl(2.5mL,4N,10.0mmol)處理。在環(huán)境溫度下把該反應(yīng)攪拌過夜。水提出后得到足夠純的產(chǎn)物2-(2-羥基-4-甲基苯基)乙醇。部分D.將來自部分C的二醇(ca.9mmol)和三苯基膦(2.83g,10.8mmol)在THF(20mL)中的溶液冷卻至0℃,并經(jīng)過注射器用偶氮二羧酸二乙酯(1.70mL,10.8mmol)處理。將該溶液攪拌過夜,然后蒸發(fā),并經(jīng)過快速柱分離該殘余物,得到6-甲基-2,3-二氫苯并呋喃(780mg,5.81mmol,65%)。TLC RF0.29(2∶98乙酸乙酯-己烷)。1H NMR(300MHz,CDCl3)d 7.07(1H,d,J=7.4Hz),6.66(1H,d,J=7.4Hz),6.62(1H,s),4.54(2H,t,J=8.6Hz),3.16(2H,t,J=8.6Hz),2.30(3H,s)。MS(D2O-GC/MS)m/e 135(100)。部分E.把以上化合物(780mg)和N-溴代琥珀酰亞胺(1.24g,6.97mmol)在二氯乙烷(10mL)中的溶液加熱回流過夜,然后冷卻,過濾并蒸發(fā)。經(jīng)過柱層析法(己烷,然后2∶98乙酸乙酯-己烷)分離首先得到5-溴-6-甲基苯并呋喃(270mg,1.27mmol,22%),然后得到5-溴-6-甲基-2,3-二氫苯并呋喃(923mg,4.33mol,75%),兩者均為固體。對于該二氫產(chǎn)物TLC RF0.35(2∶98乙酸乙酯-己烷)。1H NMR(300MHz,CDCl3)d 7.31(1H,s),6.68(1H,s),4.56(2H,t,J=8.8Hz),3.17(2H,t,J=8.8Hz),2.33(3H,s)。MS(H2O-GC/MS)m/e 215(76),213(100)。部分F.將來自部分E的溴化物(923mg,4.33mmol)在THF(20mL)中的溶液冷卻至-78℃,并且以正丁基鋰的己烷溶液(3.0mL,1.6M,4.8mmol)處理。1小時后,以三異丙基硼酸酯(1.00mL,4.33mmol)處理該反應(yīng)混合物并使該溶液至環(huán)境溫度6小時,然后加入1mL 6N的HCl水溶液和3mL水,并攪拌該生成的混合物1小時。把它傾入水(100mL)中,并以乙酸乙酯(2×100mL)提取,以鹽水(60mL)洗滌該提取液,合并,經(jīng)硫酸鈉干燥,過濾并蒸發(fā)。得到固體,以己烷研磨純化,得到6-甲基-2,3-二氫苯并呋喃-5-硼酸(718mg,4.03mmol,93%)。部分G.把來自部分F的硼酸(298mg,1.67mmol)、6-氯-9-二環(huán)丙基甲基-8-乙基嘌呤(309mg,1.12mmol)、2N的碳酸鈉水溶液(1.7mL,3.4mmol)和三苯基膦(61mg,0.233mmol)在DME(20mL)中的混合物通過用短真空泵反復(fù)循環(huán)壓脫氣,隨后以氮氣清洗。向其中加入乙酸鈀(II)(13mg,0.058mmol),然后再次使該混合物脫氣并然后加熱回流14小時。使之冷卻,并傾入水(100mL)中。以乙酸乙酯(2×100mL)提取該混合物,并且該提取液連續(xù)以鹽水(60mL)洗滌,合并,經(jīng)硫酸鈉干燥,過濾并蒸發(fā)。經(jīng)柱層析(硅膠,20∶80乙酸乙酯-己烷)分離該殘余物,得到固體標(biāo)題化合物。它經(jīng)乙醚重結(jié)晶至純度(253mg,0.77mmol,69%)。m.p.147-148℃。TLC RF0.18(30∶70乙酸乙酯-己烷)。1HNMR(300MHz,CDCl3)d 8.88(1H,s),7.60(1H,s),6.77(1H,s),4.61(2H,t,J=8.6Hz),3.44(1H,v br),3.24(2H,t,J=8.6Hz),2.94(2H,br),2.44(3H,s),2.03(2H,v br),1.45(3H,brt,J=6Hz),0.89-0.79(2H,m),0.58(2H,br),0.50-0.40(2H,m),0.27-0.17(2H,m)。MS(NH3-CI)m/e377(4),376(27),375(100)。C23H26N4O的分析計算值C,73.77;H,7.01;N,14.96;實測值C,73.69;H,7.08;N,14.40。
      實施例5201、5231和5232制備9-二環(huán)丙基甲基-8-乙基-6-(6-甲基苯并呋喃-5-基)嘌呤、6-(2-溴-6-甲基苯并呋喃-5-基)-9-二環(huán)丙基甲基-8-乙基嘌呤和6-(7-溴-6-甲基-2,3二氫苯并呋喃-5-基)-9-二環(huán)丙基甲基-8-乙基嘌呤把實施例5001的化合物(250mg,0.668mmol)和N-溴代琥珀酰亞胺(119mg,0.669mmol)在1,2-二氯乙烷(10mL)中的溶液加熱回流12小時,然后冷卻并蒸發(fā)。將生成的該混合物溶解于乙醚中,過濾并蒸發(fā),經(jīng)過快速層析法(硅膠,20∶80乙酸乙酯-己烷)分離該殘余物,以便得到以下三個產(chǎn)物6-(2-溴-6-甲基苯并呋喃-5-基)-9-二環(huán)丙基甲基-8-乙基嘌呤m.p.177-178℃。TLC RF0.23(20∶80乙酸乙酯-己烷)。1H NMR(300MHz,CDCl3)d 8.92(1H,s),7.85(1H,s),7.42(1H,s),6.74(1H,s),4.15(1H,v br),2.97(2H,v br),2.54(3H,s),2.00(2H,v br),1.44(3H,br t,J=7Hz),0.90-0.80(2H,m),0.63-0.53(2H,m),0.50-0.40(2H,m),0.26-0.16(2H,m)。MS(NH3-CI)m/e C23H24BrN4O的計算值451.1133,實測值451.1132;455(3),454(25),453(99),452(31),451(100)。9-二環(huán)丙基甲基-8-乙基-6-(6-甲基苯并呋喃-5-基)嘌呤m.p.139-141℃。 TLC RF0.16(20∶80乙酸乙酯-己烷)。1H NMR(300MHz,CDCl3)d8.92(1H,s),7.95(1H,s),7.60(1H,d,J=2.2Hz),7.48(1H,d,J=0.7Hz),6.78(1H,dd,J=2.2,0.7Hz),4.40(1H,v br),2.97(2H,v br),2.56(3H,s),2.04(2H,v br),1.44(3H,br t,J=7Hz),0.90-0.80(2H,m),0.62-0.52(2H,m),0.51-0.41(2H,m),0.29-0.18(2H,m)。MS(NH3-CI)m/e C23H25N4O的計算值373.2028,實測值373.2033;375(3),374(26),373(100)。6-(7-溴-6-甲基-2,3二氫苯并呋喃-5-基)-9-二環(huán)丙基甲基-8-乙基嘌呤m.p.179-180℃。TLC RF0.04(20∶80乙酸乙酯-己烷)。1H NMR(300MHz,CDCl3)d 8.89(1H,s),7.47(1H,s),4.73(2H,t,J=8.6Hz),3.80(1H,v br),3.37(2H,t,J=8.6Hz),2.95(2H,v br),2.44(3H,s),1.44(3H,br t,J=7Hz),0.89-0.79(2H,m),0.6 1-0.52(2H,m),0.5 1-0.41(2H,m),0.28-0.18(2H,m)。MS(NH3-CI)m/e C23H26BrN4O的計算值453.1290,實測值453.1285;455(98),453(100)。表5
      實施X R3R4a b cR1aR1bmp,例號 ℃5001CH2H CH3CH2CH2Oc-C3H5c-C3H5147-1485002CH2H CH3CH2CH2OH 4-(CH3O)-C6H4-5003CH2H CH3CH2CH2OCH3c-C3H5-5004CH2H CH3CH2CH2OC2H5c-C3H5-5005CH2H CH3CH2CH2OC3H7c-C3H5-5006CH2HCH3CH2CH2O C4H9c-C3H5-5007CH2HCH3CH2CH2O C2H5C3H7-5008CH2HCH3CH2CH2O C2H5C4H9-5009CH2HCH3CH2CH2O C3H7C3H7-5010CH2HCH3CH2CH2O CH3C3H7-5011CH2HCH3O CH2O c-C3H5c-C3H5168-1695012CH2HCH3O CH2O H 4-(CH3O)-C6H4-5013CH2HCH3O CH2O CH3c-C3H5-5014CH2HCH3O CH2O C2H5c-C3H5-5015CH2HCH3O CH2O C3H7c-C3H5-5016CH2HCH3O CH2O C4H9c-C3H5-5017CH2HCH3O CH2O C2H5C3H7-5018CH2HCH3O CH2O C2H5C4H9-5019CH2HCH3O CH2O C3H7C3H7-5020CH2HCH3O CH2O CH3C3H7-5021CH2HCH3O CH2CH2c-C3H5c-C3H5-5022CH2HCH3O CH2CH2H 4-(CH3O)-C6H4-5023CH2HCH3O CH2CH2CH3c-C3H5-5024CH2HCH3O CH2CH2C2H5c-C3H5-5025CH2HCH3O CH2CH2C3H7c-C3H5-5026CH2HCH3O CH2CH2C4H9c-C3H5-5027CH2HCH3O CH2CH2C2H5C3H7-5028CH2HCH3O CH2CH2C2H5C4H9-5029CH2HCH3O CH2CH2C3H7C3H7-5030CH2HCH3O CH2CH2CH3C3H7-5031CH2HCH3CH2OCH2c-C3H5c-C3H5-5032CH2HCH3CH2OCH2H 4-(CH3O)-C6H4-5033CH2HCH3CH2OCH2CH3c-C3H5-5034CH2HCH3CH2OCH2C2H5c-C3H5-5035CH2HCH3CH2OCH2C3H7c-C3H5-5036CH2HCH3CH2OCH2C4H9c-C3H5-5037CH2HCH3CH2OCH2C2H5C3H7-5038CH2HCH3CH2OCH2C2H5C4H9-5039CH2HCH3CH2OCH2C3H7C3H7-5040CH2HCH3CH2OCH2CH3C3H7-5041CH2HCl CH2CH2O c-C3H5c-C3H5-5042CH2HCl CH2CH2O H 4-(CH3O)-C6H4-5043CH2HCl CH2CH2O CH3c-C3H5-5044CH2H Cl CH2CH2O C2H5c-C3H5-5045CH2H Cl CH2CH2O C3H7c-C3H5-5046CH2H Cl CH2CH2O C4H9c-C3H5-5047CH2H Cl CH2CH2O C2H5C3H7-5048CH2H Cl CH2CH2O C2H5C4H9-5049CH2H Cl CH2CH2O C3H7C3H7-5050CH2H Cl CH2CH2O CH3C3H7-5051CH2H Cl OCH2O c-C3H5c-C3H5-5052CH2H Cl OCH2O H 4-(CH3O)-C6H4-5053CH2H Cl OCH2O CH3c-C3H5-5054CH2H Cl OCH2O C2H5c-C3H5-5055CH2H Cl OCH2O C3H7c-C3H5-5056CH2H Cl OCH2O C4H9c-C3H5-5057CH2H Cl OCH2O C2H5C3H7-5058CH2H Cl OCH2O C2H5C4H9-5059CH2H Cl OCH2O C3H7C3H7-5060CH2H Cl OCH2O CH3C3H7-5061O H CH3CH2CH2O c-C3H5c-C3H5-5062O H CH3CH2CH2O H 4-(CH3O)-C6H4-5063O H CH3CH2CH2O CH3c-C3H5-5064O H CH3CH2CH2O C2H5c-C3H5-5065O H CH3CH2CH2O C3H7c-C3H5-5066O H CH3CH2CH2O C4H9c-C3H5-5067O H CH3CH2CH2O C2H5C3H7-5068O H CH3CH2CH2O C2H5C4H9-5069O H CH3CH2CH2O C3H7C3H7-5070O H CH3CH2CH2O CH3C3H7-5071O H CH3OCH2O c-C3H5c-C3H5-5072O H CH3OCH2O H 4-(CH3O)-C6H4-5073O H CH3OCH2O CH3c-C3H5-5074O H CH3OCH2O C2H5c-C3H5-5075O H CH3OCH2O C3H7c-C3H5-5076O H CH3OCH2O C4H9c-C3H5-5077O H CH3OCH2O C2H5C3H7-5078O H CH3OCH2O C2H5C4H9-5079O H CH3OCH2O C3H7C3H7-5080O H CH3OCH2O CH3C3H7-5081O H Cl CH2CH2O c-C3H5c-C3H5-5082 O H Cl CH2CH2OH 4-(CH3O)-C6H4-5083 O H Cl CH2CH2OCH3c-C3H5-5084 O H Cl CH2CH2OC2H5c-C3H5-5085 O H Cl CH2CH2OC3H7c-C3H5-5086 O H Cl CH2CH2OC4H9c-C3H5-5087 O H Cl CH2CH2OC2H5C3H7-5088 O H Cl CH2CH2OC2H5C4H9-5089 O H Cl CH2CH2OC3H7C3H7-5090 O H Cl CH2CH2OCH3C3H7-5091 O H Cl OCH2Oc-C3H5c-C3H5-5092 O H Cl OCH2OH 4-(CH3O)-C6H4-5093 O H Cl OCH2OCH3c-C3H5-5094 O H Cl OCH2OC2H5c-C3H5-5095 O H Cl OCH2OC3H7c-C3H5-5096 O H Cl OCH2OC4H9c-C3H5-5097 O H Cl OCH2OC2H5C3H7-5098 O H Cl OCH2OC2H5C4H9-5099 O H Cl OCH2OC3H7C3H7-5100 O H Cl OCH2OCH3C3H7-5101 CH2CH3CH3CH2CH2Oc-C3H5c-C3H5-5102 CH2CH3CH3CH2CH2OH 4-(CH3O)-C6H4-5103 CH2CH3CH3CH2CH2OCH3c-C3H5-5104 CH2CH3CH3CH2CH2OC2H5c-C3H5-5105 CH2CH3CH3CH2CH2OC3H7c-C3H5-5106 CH2CH3CH3CH2CH2OC4H9c-C3H5-5107 CH2CH3CH3CH2CH2OC2H5C3H7-5108 CH2CH3CH3CH2CH2OC2H5C4H9-5109 CH2CH3CH3CH2CH2OC3H7C3H7-5110 CH2CH3CH3CH2CH2OCH3C3H7-5111 CH2H Cl OC=O NH c-C3H5c-C3H5-5112 CH2H Cl OC=O NH H 4-(CH3O)-C6H4-5113 CH2H Cl OC=O NH CH3c-C3H5-5114 CH2H Cl OC=O NH C2H5c-C3H5-5115 CH2H Cl OC=O NH C3H7c-C3H5-5116 CH2H Cl OC=O NH C4H9c-C3H5-5117 CH2H Cl OC=O NH C2H5C3H7-5118 CH2H Cl OC=O NH C2H5C4H9-5119 CH2H Cl OC=O NH C3H7C3H7-5120CH2HClO C=ONH CH3C3H7-5121CH2HClO C=ONCH3c-C3H5c-C3H5-5122CH2HClO C=ONCH3H 4-(CH3O)-C6H4-5123CH2HClO C=ONCH3CH3c-C3H5-5124CH2HClO C=ONCH3C2H5c-C3H5-5125CH2HClO C=ONCH3C3H7c-C3H5-5126CH2HClO C=ONCH3C4H9c-C3H5-5127CH2HClO C=ONCH3C2H5C3H7-5128CH2HClO C=ONCH3C2H5C4H9-5129CH2HClO C=ONCH3C3H7C3H7-5130CH2HClO C=ONCH3CH3C3H7-5131CH2HClO CCH3N c-C3H5c-C3H5-5132CH2HClO CCH3N H 4-(CH3O)-C6H4-5133CH2HClO CCH3N CH3c-C3H5-5134CH2HClO CCH3N C2H5c-C3H5-5135CH2HClO CCH3N C3H7c-C3H5-5136CH2HClO CCH3N C4H9c-C3H5-5137CH2HClO CCH3N C2H5C3H7-5138CH2HClO CCH3N C2H5C4H9-5139CH2HClO CCH3N C3H7C3H7-5140CH2HClO CCH3N CH3C3H7-5141CH2HClO C=ONC2H5c-C3H5c-C3H5-5142CH2HClO C=0NC2H5H 4-(CH3O)-C6H4-5143CH2HClO C=ONC2H5CH3c-C3H5-5144CH2HClO C=ONC2H5C2H5c-C3H5-5145CH2HClO C=ONC2H5C3H7c-C3H5-5146CH2HClO C=ONC2H5C4H9c-C3H5-5147CH2HClO C=ONC2H5C2H5C3H7-5148CH2HClO C=ONC2H5C2H5C4H9-5149CH2HClO C=ONC2H5C3H7C3H7-5150CH2HClO C=ONC2H5CH3C3H7-5151CH2HClO C=OO c-C3H5c-C3H5-5152CH2HClO C=OO H 4-(CH3O)-C6H4-5153CH2HClO C=OO CH3c-C3H5-5154CH2HClO C=OO C2H5c-C3H5-5155CH2HClO C=OO C3H7c-C3H5-5156CH2HClO C=OO C4H9c-C3H5-5157CH2HClO C=OO C2H5C3H7-5158 CH2H Cl O C=O O C2H5C4H9-5159 CH2H Cl O C=O O C3H7C3H7-5160 CH2H Cl O C=O O CH3C3H7-5161 CH2H Cl O CH2CH2O c-C3H5c-C3H5-5162 CH2H Cl O CH2CH2O H 4-(CH3O)-C6H4-5163 CH2H Cl O CH2CH2O CH3c-C3H5-5164 CH2H Cl O CH2CH2O C2H5c-C3H5-5165 CH2H Cl O CH2CH2O C3H7c-C3H5-5166 CH2H Cl O CH2CH2O C4H9c-C3H5-5167 CH2H Cl O CH2CH2O C2H5C3H7-5168 CH2H Cl O CH2CH2O C2H5C4H9-5169 CH2H Cl O CH2CH2O C3H7C3H7-5170 CH2H Cl O CH2CH2O CH3C3H7-5171 CH2H CH3O C=O O c-C3H5c-C3H5-5172 CH2H CH3O C=O O H 4-(CH3O)-C6H4-5173 CH2H CH3O C=O O CH3c-C3H5-5174 CH2H CH3O C=O O C2H5c-C3H5-5175 CH2H CH3O C=O O C3H7c-C3H5-5176 CH2H CH3O C=O O C4H9c-C3H5-5177 CH2H CH3O C=O O C2H5C3H7-5178 CH2H CH3O C=O O C2H5C4H9-5179 CH2H CH3O C=O O C3H7C3H7-5180 CH2H CH3O C=O O CH3C3H7-5181 CH2H CH3O CH2CH2O c-C3H5c-C3H5-5182 CH2H CH3O CH2CH2O H 4-(CH3O)-C6H4-5183 CH2H CH3O CH2CH2O CH3c-C3H5-5184 CH2H CH3O CH2CH2O C2H5c-C3H5-5185 CH2H CH3O CH2CH2O C3H7c-C3H5-5186 CH2H CH3O CH2CH2O C4H9c-C3H5-5187 CH2H CH3O CH2CH2O C2H5C3H7-5188 CH2H CH3O CH2CH2O C2H5C4H9-5189 CH2H CH3O CH2CH2O C3H7C3H7-5190 CH2H CH3O CH2CH2O CH3C3H7-5191 CH2H Cl O CH2CH2NCH3c-C3H5c-C3H5-5192 CH2H Cl O CH2CH2NCH3H 4-(CH3O)-C6H4-5193 CH2H Cl O CH2CH2NCH3CH3c-C3H5-5194 CH2H Cl O CH2CH2NCH3C2H5c-C3H5-5195 CH2H Cl O CH2CH2NCH3C3H7c-C3H5-5196CH2HCl O CH2CH2NCH3C4H9c-C3H5-5197CH2HCl O CH2CH2NCH3C2H5C3H7-5198CH2HCl O CH2CH2NCH3C2H5C4H9-5199CH2HCl O CH2CH2NCH3C3H7C3H7-5200CH2HCl O CH2CH2NCH3CH3C3H7-5201CH2HCH3CHCH Oc-C3H5c-C3H5139-1415202CH2HCH3CHCH OH 4-(CH3O)-C6H4-5203CH2HCH3CHCH OCH3c-C3H5-5204CH2HCH3CHCH OC2H5c-C3H5-5205CH2HCH3CHCH OC3H7c-C3H5-5206CH2HCH3CHCH OC4H9c-C3H5-5207CH2HCH3CHCH OC2H5C3H7-5208CH2HCH3CHCH OC2H5C4H9-5209CH2HCH3CHCH OC3H7C3H7-5210CH2HCH3CHCH OCH3C3H7-5211CH2HCl CHCH Oc-C3H5c-C3H5-5212CH2HCl CHCH OH 4-(CH3O)-C6H4-5213CH2HCl CHCH OCH3c-C3H5-5214CH2HCl CHCH OC2H5c-C3H5-5215CH2HCl CHCH OC3H7c-C3H5-5216CH2HCl CHCH OC4H9c-C3H5-5217CH2HCl CHCH OC2H5C3H7-5218CH2HCl CHCH OC2H5C4H9-5219CH2HCl CHCH OC3H7C3H7-5220CH2HCl CHCH OCH3C3H7-5221CH2HCH3CHCHCH CH c-C3H5c-C3H5-5222CH2HCH3CHCHCH CH H 4-(CH3O)-C6H4-5223CH2HCH3CHCHCH CH CH3c-C3H5-5224CH2HCH3CHCHCH CH C2H5c-C3H5-5225CH2HCH3CHCHCH CH C3H7c-C3H5-5226CH2HCH3CHCHCH CH C4H9c-C3H5-5227CH2HCH3CHCHCH CH C2H5C3H7-5228CH2HCH3CHCHCH CH C2H5C4H9-5229CH2HCH3CHCHCH CH C3H7C3H7-5230CH2HCH3CHCHCH CH CH3C3H7-5231CH2HCH3CHCBr Oc-C3H5c-C3H5177-1785232CH2HCH3CH2CH2Oc-C3H5c-C3H5179-1805233CH2HCH3CHCCH3Oc-C3H5c-C3H5-5234CH2HCH3CH2CH2Oc-C3H5c-C3H5-5235CH2HCH3CH CSCH3Oc-C3H5c-C3H5-5236CH2HCH3CH2CH2Oc-C3H5c-C3H5-表5A
      實施例X R12a b cR1aR1bm.p.,號 ℃5232 CH2Br CH2CH2Oc-C3H5c-C3H5179-1805234 CH2CN CH2CH2Oc-C3H5c-C3H5-5236 CH2SCH3CH2CH2Oc-C3H5c-C3H5-
      制備表1中化合物所使用的方法可用于制備表6中結(jié)構(gòu)A的化合物。例如,在鈀-催化芳基交叉偶合方法(參見實施例35或831)中以各種取代的五原子雜芳基硼酸替代苯硼酸將得到所需的6-雜芳基嘌呤化合物。
      流程13和14的方法可用于制備在表6中所包含的結(jié)構(gòu)B和結(jié)構(gòu)C的許多實施例,必要的話對方法稍作改進(jìn),并且使用適宜結(jié)構(gòu)的試劑。表6
      實施XR3a bcdR1aR1bmp,例號 ℃a6001CH2HCCH3NOCCH3c-C3H5c-C3H5油6002CH2HCCH3NOCCH3CH3c-C3H5-6003CH2HCCH3NOCCH3C2H5c-C3H5-6004CH2HCCH3NOCCH3C3H7c-C3H5-6005CH2HCCH3NOCCH3C4H9c-C3H5-6006CH2HCCH3NOCCH3CH3C3H7-6007CH2HCCH3NOCCH3C2H5C3H7-6008CH2HCCH3NOCCH3C3H7C3H7-6009CH2HCCH3NOCCH3C2H5C4H9-6010CH2HCCH3NOCCH3H 4-CH3O-C6H4-6011O HCCH3NOCCH3c-C3H5c-C3H5-6012O HCCH3NOCCH3CH3c-C3H5-6013O HCCH3NOCCH3C2H5c-C3H5-6014O HCCH3N OCCH3C3H7c-C3H5-6015O HCCH3N OCCH3C4H9c-C3H5-6016O HCCH3N OCCH3CH3C3H7-6017O HCCH3N OCCH3C2H5C3H7-6018O HCCH3N OCCH3C3H7C3H7-6019O HCCH3N OCCH3C2H5C4H9-6020O HCCH3N OCCH3H 4-CH3O-C6H4-6021CH2CH3CCH3N OCCH3c-C3H5c-C3H5-6022CH2CH3CCH3N OCCH3CH3c-C3H5-6023CH2CH3CCH3N OCCH3C2H5c-C3H5-6024CH2CH3CCH3N OCCH3C3H7c-C3H5-6025CH2CH3CCH3N OCCH3C4H9c-C3H5-6026CH2CH3CCH3N OCCH3CH3C3H7-6027CH2CH3CCH3N OCCH3C2H5C3H7-6028CH2CH3CCH3N OCCH3C3H7C3H7-6029CH2CH3CCH3N OCCH3C2H5C4H9-6030CH2CH3CCH3N OCCH3H 4-CH3O-C6H4-6031CH2HCCH3N NCH3CCH3c-C3H5c-C3H5-6032CH2HCCH3N NCH3CCH3CH3c-C3H5-6033CH2HCCH3N NCH3CCH3C2H5c-C3H5-6034CH2HCCH3N NCH3CCH3C3H7c-C3H5-6035CH2HCCH3N NCH3CCH3C4H9c-C3H5-6036CH2HCCH3N NCH3CCH3CH3C3H7-6037CH2HCCH3N NCH3CCH3C2H5C3H7-6038CH2HCCH3N NCH3CCH3C3H7C3H7-6039CH2HCCH3N NCH3CCH3C2H5C4H9-6040CH2HCCH3N NCH3CCH3H 4-CH3O-C6H4-6041O HCCH3N NCH3CCH3c-C3H5c-C3H5-6042O HCCH3N NCH3CCH3CH3c-C3H5-6043O HCCH3N NCH3CCH3C2H5c-C3H5-6044O HCCH3N NCH3CCH3C3H7c-C3H5-6045O HCCH3N NCH3CCH3C4H9c-C3H5-6046O HCCH3N NCH3CCH3CH3C3H7-6047O HCCH3N NCH3CCH3C2H5C3H7-6048O HCCH3N NCH3CCH3C3H7C3H7-6049O HCCH3N NCH3CCH3C2H5C4H9-6050O HCCH3N NCH3CCH3H 4-CH3O-C6H4-6051CH2CH3CCH3N NCH3CCH3c-C3H5c-C3H5-6052CH2CH3CCH3NNCH3CCH3CH3c-C3H5-6053CH2CH3CCH3NNCH3CCH3C2H5c-C3H5-6054CH2CH3CCH3NNCH3CCH3C3H7c-C3H5-6055CH2CH3CCH3NNCH3CCH3C4H9c-C3H5-6056CH2CH3CCH3NNCH3CCH3CH3C3H7-6057CH2CH3CCH3NNCH3CCH3C2H5C3H7-6058CH2CH3CCH3NNCH3CCH3C3H7C3H7-6059CH2CH3CCH3NNCH3CCH3C2H5C4H9-6060CH2CH3CCH3NNCH3CCH3H 4-CH3O-C6H4-6061CH2H CCH3NNC2H5CCH3c-C3H5c-C3H5-6062CH2H CCH3NNC2H5CCH3CH3c-C3H5-6063CH2H CCH3NNC2H5CCH3C2H5c-C3H5-6064CH2H CCH3NNC2H5CCH3C3H7c-C3H5-6065CH2H CCH3NNC2H5CCH3C4H9c-C3H5-6066CH2H CCH3NNC2H5CCH3CH3C3H7-6067CH2H CCH3NNC2H5CCH3C2H5C3H7-6068CH2H CCH3NNC2H5CCH3C3H7C3H7-6069CH2H CCH3NNC2H5CCH3C2H5C4H9-6070CH2H CCH3NNC2H5CCH3H 4-CH3O-C6H4-6071O H CCH3NNC2H5CCH3c-C3H5c-C3H5-6072O H CCH3NNC2H5CCH3CH3c-C3H5-6073O H CCH3NNC2H5CCH3C2H5c-C3H5-6074O H CCH3NNC2H5CCH3C3H7c-C3H5-6075O H CCH3NNC2H5CCH3C4H9c-C3H5-6076O H CCH3NNC2H5CCH3CH3C3H7-6077O H CCH3NNC2H5CCH3C2H5C3H7-6078O H CCH3NNC2H5CCH3C3H7C3H7-6079O H CCH3NNC2H5CCH3C2H5C4H9-6080O H CCH3NNC2H5CCH3H 4-CH3O-C6H4-6081CH2CH3CCH3NNC2H5CCH3c-C3H5c-C3H5-6082CH2CH3CCH3NNC2H5CCH3CH3c-C3H5-6083CH2CH3CCH3NNC2H5CCH3C2H5c-C3H5-6084CH2CH3CCH3NNC2H5CCH3C3H7c-C3H5-6085CH2CH3CCH3NNC2H5CCH3C4H9c-C3H5-6086CH2CH3CCH3NNC2H5CCH3CH3C3H7-6087CH2CH3CCH3NNC2H5CCH3C2H5C3H7-6088CH2CH3CCH3NNC2H5CCH3C3H7C3H7-6089CH2CH3CCH3NNC2H5CCH3C2H5C4H9-6090CH2CH3CCH3NNC2H5CCH3H 4-CH3O-C6H4-6091CH2H CCH3NCCH3NCH3c-C3H5c-C3H5-6092CH2H CCH3NCCH3NCH3CH3c-C3H5-6093CH2H CCH3NCCH3NCH3C2H5c-C3H5-6094CH2H CCH3NCCH3NCH3C3H7c-C3H5-6095CH2H CCH3NCCH3NCH3C4H9c-C3H5-6096CH2H CCH3NCCH3NCH3CH3C3H7-6097CH2H CCH3NCCH3NCH3C2H5C3H7-6098CH2H CCH3NCCH3NCH3C3H7C3H7-6099CH2H CCH3NCCH3NCH3C2H5C4H9-6100CH2H CCH3NCCH3NCH3H 4-CH3O-C6H4-6101CH2H CCH3NNC6H5CCH3c-C3H5c-C3H5-6102CH2H CCH3NNC6H5CCH3CH3c-C3H5-6103CH2H CCH3NNC6H5CCH3C2H5c-C3H5-6104CH2H CCH3NNC6H5CCH3C3H7c-C3H5-6105CH2H CCH3NNC6H5CCH3C4H9c-C3H5-6106CH2H CCH3NNC6H5CCH3CH3C3H7-6107CH2H CCH3NNC6H5CCH3C2H5C3H7-6108CH2H CCH3NNC6H5CCH3C3H7C3H7-6109CH2H CCH3NNC6H5CCH3C2H5C4H9-6110CH2H CCH3NNC6H5CCH3H 4-CH3O-C6H4-6111O H CCH3NNC6H5CCH3c-C3H5c-C3H5-6112O H CCH3NNC6H5CCH3CH3c-C3H5-6113O H CCH3NNC6H5CCH3C2H5c-C3H5-6114O H CCH3NNC6H5CCH3C3H7c-C3H5-6115O H CCH3NNC6H5CCH3C4H9c-C3H5-6116O H CCH3NNC6H5CCH3CH3C3H7-6117O H CCH3NNC6H5CCH3C2H5C3H7-6118O H CCH3NNC6H5CCH3C3H7C3H7-6119O H CCH3NNC6H5CCH3C2H5C4H9-6120O H CCH3NNC6H5CCH3H 4-CH3O-C6H4-6121CH2CH3CCH3NNC6H5CCH3c-C3H5c-C3H5-6122CH2CH3CCH3NNC6H5CCH3CH3c-C3H5-6123CH2CH3CCH3NNC6H5CCH3C2H5c-C3H5-6124CH2CH3CCH3NNC6H5CCH3C3H7c-C3H5-6125CH2CH3CCH3NNC6H5CCH3C4H9c-C3H5-6126CH2CH3CCH3NNC6H5CCH3CH3C3H7-6127CH2CH3CCH3NNC6H5CCH3C2H5C3H7-6128CH2CH3CCH3NNC6H5CCH3C3H7C3H7-6129CH2CH3CCH3NNC6H5CCH3C2H5C4H9-6130CH2CH3CCH3NNC6H5CCH3H 4-CH3O-C6H4-關(guān)鍵(a)在化合物被指明為“油”的地方,提供波譜數(shù)據(jù)如下實施例6001波譜數(shù)據(jù)MS(NH3-CI)m/e 338(M+H+,100%)。
      制備表1中化合物所使用的方法可用于制備在表7中結(jié)構(gòu)A的許多化合物。那些衍生于帶有炔基的R1基團(tuán)的化合物環(huán)加成的化合物的制備通過以下實施例闡明。
      流程13和14的方法可用于制備在表7中所包含的結(jié)構(gòu)B和結(jié)構(gòu)C的許多實施例,必要的話對方法稍作改進(jìn),并且使用適宜結(jié)構(gòu)的試劑。
      實施例7409制備9-[1-環(huán)丙基-1-(3-甲基-異噁唑-5-基)甲基]-6-(2,4-二氯苯基)-8-乙基-9H-嘌呤向攪拌著的實施例7241的化合物(90mg,0.24mmol;以類似于實施例2的方法使用6-(2,4-二氯苯基)-8-乙基-9H-嘌呤和3-環(huán)丙基-1-丙炔-3-醇制備)在二氯甲烷(2mL)中的溶液加入氯乙醛肟(25mg,0.27mmol)和三乙胺(0.038mL,0.27mmol)。(先前通過使等摩爾量的乙醛肟與N-氯代琥珀酰亞胺在DMF中反應(yīng),然后將該產(chǎn)物提取到乙醚中并且以水洗滌來制備所使用的氯乙醛肟)。通過TLC檢測該環(huán)加成反應(yīng),并且加入額外量的氯乙醛肟和三乙胺直到所有的起始原料消耗完全。通過直接加入到硅膠柱并使用100%己烷至在己烷中25%的乙酸乙酯的梯度洗脫純化該反應(yīng)混合物。收集72mg的白色泡沫體。MS(NH3-CI)428(M+H+)。HRMSm/e=428.1037(M+H+,C21H20Cl2N5O)。通過反相HPLC的純度>97%。
      實施例7396和7398制備6-(2,4-二氯苯基)-9-[1-(3-乙氧基羰基-異噁唑-5-基)丁基]-8-乙基-9H-嘌呤和9-[1-(4-氰基-3-乙氧基羰基-異噁唑-5-基)丁基]-6-(2,4-二氯苯基)-8-乙基-9H-嘌呤將實施例7259的化合物(120mg,0.321mmol;以類似于實施例2的方法使用6-(2,4-二氯苯基)-8-乙基-9H-嘌呤和1-己炔-3-醇制備)、氯肟基乙酸乙酯(146mg,0.963mmol)和二異丙基乙胺(170μL,0.976mmol)在甲苯(2mL)中的溶液加熱回流20小時,然后冷卻并以20mL乙酸乙酯稀釋。用水(2×20mL)和飽和的鹽水溶液(20mL)洗滌,并且以乙酸乙酯(20mL)連續(xù)回提水相。合并有機提取液,無水硫酸鈉干燥,過濾并蒸發(fā)。通過柱層析法(硅膠,1∶4乙酸乙酯-己烷)分離該殘余物質(zhì),依次得到未反應(yīng)的原料(大約50mg)、然后是實施例7396的化合物(58.7mg,0.120mmol,37%),最后是實施例7398化合物(23.8mg,0.046mmol,14%),后兩個化合物為非晶形固體。實施例7396的波譜數(shù)據(jù)TLC RF0.27(20∶80乙酸乙酯-己烷)。1H NMR(300MHz,CDCl3)δ8.96(1H,s),7.67(1H,d,J=8.1Hz),7.58(1H,d,J=1.8Hz),7.41(1H,dd,J=8.1,1.8Hz),6.86(1H,s),5.83(1H,dd,J=9.9,6.2Hz),4.43(2H,q,J=7.3Hz),2.98(2H.q,J=7.7Hz),2.91-2.78(1H,m),2.63-2.49(1H,m),1.42(3H,t,J=7.7Hz),1.40(3H,t,J=7.3Hz),1.39-1.19(2H,m),1.00(3H,t,J=7.3Hz)。MS(NH3-CI)m/e C23H24Cl2N5O3的計算值488.1256,實測值488.1252;493(3),492(13),491(18),490(68),489(28),488(100)。實施例7398波譜數(shù)據(jù)TLC RF0.11(20∶80乙酸乙酯-己烷)。1H NMR(300MHz,CDCl3)δ8.99(1H,s),7.72(1H,d,J=8.1Hz),7.59(1H,d,J=1.8Hz),7.42(1H,dd,J=8.1,1.8Hz),5.40(1H,dd,J=10.4,5.0Hz),4.42(2H,q,J=7.4Hz),3.00-2.90(2H,m),2.66-2.52(1H,m),2.51-2.38(1H,m),1.46(3H,t,J=7.4Hz),1.41(3H,t,J=7.3Hz),1.40-1.10(2H,m),0.98(3H,t,J=7.2Hz)。MS(NH3-CI)m/eC24H25Cl2N6O4的計算值531.1315,實測值531.1315;531(100)。表7
      實施XR4R5R11R6R1aL Gam.p.,例號℃b7001CH2CH3CH3HCH3CH3鍵 G1-7002CH2CH3CH3HCH3C2H5鍵 G1-7003CH2CH3CH3HCH3C3H7鍵 G1-7004CH2CH3CH3HCH3c-C3H5鍵 G1-7005CH2CH3CH3HCH3CH3鍵 G2-7006CH2CH3CH3HCH3C2H5鍵 G2-7007CH2CH3CH3HCH3C3H7鍵 G2-7008CH2CH3CH3HCH3c-C3H5鍵 G2-7009CH2CH3CH3HCH3CH3鍵 G3-7010CH2CH3CH3HCH3C2H5鍵 G3-7011CH2CH3CH3HCH3C3H7鍵 G3-7012CH2CH3CH3HCH3c-C3H5鍵 G3-7013CH2CH3CH3HCH3CH3CH2G4-7014CH2CH3CH3HCH3C2H5CH2G4-7015CH2CH3CH3HCH3C3H7CH2G4-7016CH2CH3CH3HCH3c-C3H5CH2G4-7017CH2CH3CH3HCH3CH3CH2G5-7018CH2CH3CH3HCH3C2H5CH2G5-7019CH2CH3CH3HCH3C3H7CH2G5-7020CH2CH3CH3HCH3c-C3H5CH2G5-7021CH2CH3CH3HCH3CH3鍵 G6-7022CH2CH3CH3HCH3C2H5鍵 G6-7023CH2CH3CH3HCH3C3H7鍵 G6-7024CH2CH3CH3HCH3c-C3H5鍵 G6-7025CH2CH3CH3HCH3CH2=CH 鍵 G7-7026CH2CH3CH3HCH3CH3鍵 G8-7027CH2CH3CH3HCH3C2H5CH2G1-7028CH2CH3CH3HCH3C3H7CH2G1-7029CH2CH3CH3HCH3C2H5CH2G2-7030CH2CH3CH3HCH3C3H7CH2G2-7031CH2Cl Cl HH CH3鍵 Gl-7032CH2Cl Cl HH C2H5鍵 G1-7033CH2Cl Cl HH C3H7鍵 G1-7034CH2Cl Cl HH c-C3H5鍵 G1-7035CH2Cl Cl HH CH3鍵 G2-7036CH2Cl Cl HH C2H5鍵 G2-7037CH2Cl Cl HH C3H7鍵 G2-7038CH2Cl Cl HH c-C3H5鍵 G2-7039CH2Cl Cl HH CH3鍵 G3-7040CH2Cl Cl HH C2H5鍵 G3-7041CH2Cl Cl HH C3H7鍵 G3-7042CH2Cl Cl HH c-C3H5鍵 G3-7043CH2Cl Cl HH CH3CH2G4-7044CH2Cl Cl HH C2H5CH2G4-7045CH2Cl Cl HH C3H7CH2G4-7046CH2Cl Cl HH c-C3H5CH2G4-7047CH2Cl Cl HH CH3CH2G5-7048CH2Cl Cl HH C2H5CH2G5-7049CH2Cl Cl HH C3H7CH2G5-7050CH2Cl Cl HH c-C3H5CH2G5-7051CH2Cl Cl HH CH3鍵 G6-7052CH2Cl Cl HH C2H5鍵 G6-7053CH2Cl Cl HH C3H7鍵 G6-7054CH2Cl Cl HH c-C3H5鍵 G6-7055CH2Cl Cl HH CH2=CH 鍵 G7-7056CH2Cl Cl HH CH3鍵 G8-7057CH2Cl Cl HH C2H5CH2G1-7058CH2Cl Cl HH C3H7CH2G1-7059CH2Cl Cl HH C2H5CH2G2-7060CH2Cl Cl HH C3H7CH2G2-7061CH2CH3OCH3HH CH3鍵 G1-7062CH2CH3OCH3HH C2H5鍵 G1-7063CH2CH3OCH3HH C3H7鍵 G1-7064CH2CH3OCH3HH c-C3H5鍵 G1-7065CH2CH3OCH3HH CH3鍵 G2-7066CH2CH3OCH3HH C2H5鍵 G2-7067CH2CH3OCH3HH C3H7鍵 G2-7068CH2CH3OCH3HH c-C3H5鍵 G2-7069CH2CH3OCH3HH CH3鍵 G3-7070CH2CH3OCH3HH C2H5鍵 G3-7071CH2CH3OCH3HH C3H7鍵 G3-7072CH2CH3OCH3HH c-C3H5鍵 G3-7073CH2CH3OCH3HH CH3CH2G4-7074CH2CH3OCH3HH C2H5CH2G4-7075CH2CH3OCH3HH C3H7CH2G4-7076CH2CH3OCH3HH c-C3H5CH2G4-7077CH2CH3OCH3HH CH3CH2G5-7078CH2CH3OCH3HH C2H5CH2G5-7079CH2CH3OCH3HH C3H7CH2G5-7080CH2CH3OCH3HH c-C3H5CH2G5-7081CH2CH3OCH3HH CH3鍵 G6-7082CH2CH3OCH3HH C2H5鍵 G6-7083CH2CH3OCH3HH C3H7鍵 G6-7084CH2CH3OCH3HH c-C3H5鍵 G6-7085CH2CH3OCH3HH CH2=CH 鍵 G7-7086CH2CH3OCH3HH CH3鍵 G8油7087CH2CH3OCH3HH C2H5CH2G1-7088CH2CH3OCH3HH C3H7CH2G1-7089CH2CH3OCH3HH C2H5CH2G2-7090CH2CH3OCH3HH C3H7CH2G2-7091CH2ClOCH3HH CH3鍵 G1-7092CH2ClOCH3HH C2H5鍵 G1-7093CH2ClOCH3HH C3H7鍵 G1-7094CH2ClOCH3HH c-C3H5鍵 G1-7095CH2ClOCH3HH CH3鍵 G2-7096CH2ClOCH3HH C2H5鍵 G2-7097CH2ClOCH3HH C3H7鍵 G2-7098CH2ClOCH3HH c-C3H5鍵 G2-7099CH2ClOCH3HH CH3鍵 G3-7100CH2ClOCH3HH C2H5鍵 G3-7101CH2ClOCH3HH C3H7鍵 G3-7102CH2ClOCH3HH c-C3H5鍵 G3-7103CH2ClOCH3HH CH3CH2G4-7104CH2ClOCH3HH C2H5CH2G4-7105CH2ClOCH3HH C3H7CH2G4-7106CH2ClOCH3HH c-C3H5CH2G4-7107CH2ClOCH3HH CH3CH2G5-7108CH2ClOCH3HH C2H5CH2G5-7109CH2ClOCH3HH C3H7CH2G5-7110CH2ClOCH3HH c-C3H5CH2G5-7111CH2ClOCH3HH CH3鍵 G6-7112CH2ClOCH3HH C2H5鍵 G6-7113CH2ClOCH3HH C3H7鍵 G6-7114CH2ClOCH3HH c-C3H5鍵 G6-7115CH2ClOCH3HH CH2=CH 鍵 G7-7116CH2ClOCH3HH CH3鍵 G8油7117CH2ClOCH3HH C2H5CH2G1-7118CH2ClOCH3HH C3H7CH2G1-7119CH2ClOCH3HH C2H5CH2G2-7120CH2ClOCH3HH C3H7CH2G2-7121CH2ClCF3HH CH3鍵 G1-7122CH2ClCF3HH C2H5鍵 G1-7123CH2ClCF3HH C3H7鍵 G1-7124CH2ClCF3HH c-C3H5鍵 G1-7125CH2ClCF3HH CH3鍵 G2-7126CH2Cl CF3HH C2H5鍵 G2-7127CH2Cl CF3HH C3H7鍵 G2-7128CH2Cl CF3HH c-C3H5鍵 G2-7129CH2Cl CF3HH CH3鍵 G3-7130CH2Cl CF3HH C2H5鍵 G3-7131CH2Cl CF3HH C3H7鍵 G3-7132CH2Cl CF3HH c-C3H5鍵 G3-7133CH2Cl CF3HH CH3CH2G4-7134CH2Cl CF3HH C2H5CH2G4-7135CH2Cl CF3HH C3H7CH2G4-7136CH2Cl CF3HH c-C3H5CH2G4-7137CH2Cl CF3HH CH3CH2G5-7138CH2Cl CF3HH C2H5CH2G5-7139CH2Cl CF3HH C3H7CH2G5-7140CH2Cl CF3HH c-C3H5CH2G5-7141CH2Cl CF3HH CH3鍵 G6-7142CH2Cl CF3HH C2H5鍵 G6-7143CH2Cl CF3HH C3H7鍵 G6-7144CH2Cl CF3HH c-C3H5鍵 G6-7145CH2Cl CF3HH CH2=CH鍵 G7-7146CH2Cl CF3HH CH3鍵 G8油7147CH2Cl CF3HH C2H5CH2G1-7148CH2Cl CF3HH C3H7CH2G1-7149CH2Cl CF3HH C2H5CH2G2-7150CH2Cl CF3HH C3H7CH2G2-7151CH2CF3Cl HH CH3鍵 G1-7152CH2CF3Cl HH C2H5鍵 G1-7153CH2CF3Cl HH C3H7鍵 G1-7154CH2CF3Cl HH c-C3H5鍵 G1-7155CH2CF3Cl HH CH3鍵 G2-7156CH2CF3Cl HH C2H5鍵 G2-7157CH2CF3Cl HH C3H7鍵 G2-7158CH2CF3Cl HH c-C3H5鍵 G2-7159CH2CF3Cl HH CH3鍵 G3-7160CH2CF3Cl HH C2H5鍵 G3-7161CH2CF3Cl HH C3H7鍵 G3-7162CH2CF3Cl HH c-C3H5鍵 G3-7163CH2CF3Cl HH CH3CH2G4-7164CH2CF3Cl H HC2H5CH2G4-7165CH2CF3Cl H HC3H7CH2G4-7166CH2CF3Cl H Hc-C3H5CH2G4-7167CH2CF3Cl H HCH3CH2G5-7168CH2CF3Cl H HC2H5CH2G5-7169CH2CF3Cl H HC3H7CH2G5-7170CH2CF3Cl H Hc-C3H5CH2G5-7171CH2CF3Cl H HCH3鍵 G6-7172CH2CF3Cl H HC2H5鍵 G6-7173CH2CF3Cl H HC3H7鍵 G6-7174CH2CF3Cl H Hc-C3H5鍵 G6-7175CH2CF3Cl H HCH2=CH 鍵 G7-7176CH2CF3Cl H HCH3鍵 G8-7177CH2CF3Cl H HC2H5CH2G1-7178CH2CF3Cl H HC3H7CH2G1-7179CH2CF3Cl H HC2H5CH2G2-7180CH2CF3Cl H HC3H7CH2G2-7181CH2CH3OCH3CH3HCH3鍵 G1-7182CH2CH3OCH3CH3HC2H5鍵 G1-7183CH2CH3OCH3CH3HC3H7鍵 G1-7184CH2CH3OCH3CH3Hc-C3H5鍵 G1-7185CH2CH3OCH3CH3HCH3鍵 G2-7186CH2CH3OCH3CH3HC2H5鍵 G2-7187CH2CH3OCH3CH3HC3H7鍵 G2-7188CH2CH3OCH3CH3Hc-C3H5鍵 G2-7189CH2CH3OCH3CH3HCH3鍵 G3-7190CH2CH3OCH3CH3HC2H5鍵 G3-7191CH2CH3OCH3CH3HC3H7鍵 G3-7192CH2CH3OCH3CH3Hc-C3H5鍵 G3-7193CH2CH3OCH3CH3HCH3CH2G4-7194CH2CH3OCH3CH3HC2H5CH2G4-7195CH2CH3OCH3CH3HC3H7CH2G4-7196CH2CH3OCH3CH3Hc-C3H5CH2G4-7197CH2CH3OCH3CH3HCH3CH2G5-7198CH2CH3OCH3CH3HC2H5CH2G5-7199CH2CH3OCH3CH3HC3H7CH2G5-7200CH2CH3OCH3CH3Hc-C3H5CH2G5-7201CH2CH3OCH3CH3HCH3鍵 G6-7202CH2CH3OCH3CH3H C2H5鍵G6-7203CH2CH3OCH3CH3H C3H7鍵G6-7204CH2CH3OCH3CH3H c-C3H5鍵G6-7205CH2CH3OCH3CH3H CH2=CH 鍵G7-7206CH2CH3OCH3CH3H CH3鍵G8-7207CH2CH3OCH3CH3H C2H5CH2G1-7208CH2CH3OCH3CH3H C3H7CH2G1-7209CH2CH3OCH3CH3H C2H5CH2G2-7210CH2CH3OCH3CH3H C3H7CH2G2-7211O ClCF3H H C2H5CH2G1-7212O ClCF3H H C3H7CH2G1-7213O ClCF3H H C2H5鍵G2-7214O ClCF3H H C3H7鍵G2-7215O ClCF3H H C2H5CH2G4-7216CH2ClCF3H H C2H5CH2G1-7217CH2ClCF3H H C3H7CH2G1-7218CH2ClCF3H H C2H5鍵G2-7219CH2ClCF3H H C3H7鍵G2-7220CH2ClCF3H H C2H5CH2G4-7221O CF3Cl H H C2H5CH2G1-7222O CF3Cl H H C3H7CH2G1-7223O CF3Cl H H C2H5鍵G2-7224O CF3Cl H H C3H7鍵G2-7225O CF3Cl H H C2H5CH2G4-7226CH2CF3Cl H H C2H5CH2G1-7227CH2CF3Cl H H C3H7CH2G1-7228CH2CF3Cl H H C2H5鍵G2-7229CH2CF3Cl H H C3H7鍵G2-7230CH2CF3Cl H H C2H5CH2G4-7231CH2CH3CH3H CH3C2H5CH2O G3油7232CH2ClCl H H c-C3H5鍵G9-7233O ClCl H H c-C3H5鍵G9-7234CH2ClCF3H H c-C3H5鍵G9油7235O ClCF3H H c-C3H5鍵G9-7236CH2ClOCH3H H c-C3H5鍵G9-7237CH2ClOCF3H H c-C3H5鍵G9-7238CH2CH3OCH3Cl H c-C3H5鍵G9-7239CH2ClCl H CH3c-C3H5鍵G9-7240CH2CF3OCH3HH c-C3H5鍵G9 -7241CH2ClCl HH c-C3H5鍵G10油7242O ClCl HH c-C3H5鍵G10-7243CH2ClCF3HH c-C3H5鍵G10油7244O ClCF3HH c-C3H5鍵G10-7245CH2ClOCH3HH c-C3H5鍵G10-7246CH2ClOCF3HH c-C3H5鍵G10-7247CH2CH3OCH3Cl H c-C3H5鍵G10-7248CH2ClCl HCH3c-C3H5鍵G10-7249CH2CF3OCH3HH c-C3H5鍵G10油7250CH2ClCl HH C2H5鍵G10油7251O ClCl HH C2H5鍵G10-7252CH2ClCF3HH C2H5鍵G1098-997253O ClCF3HH C2H5鍵G10-7254CH2ClOCH3HH C2H5鍵G10-7255CH2ClOCF3HH C2H5鍵G10-7256CH2CH3OCH3Cl H C2H5鍵G10-7257CH2ClCl HCH3C2H5鍵G10-7258CH2CF3OCH3HH C2H5鍵G10-7259CH2ClCl HH C3H7鍵G10油7260O ClCl HH C3H7鍵G10-7261CH2ClCF3HH C3H7鍵G10油7262O ClCF3HH C3H7鍵G10-7263CH2ClOCH3HH C3H7鍵G10-7264CH2ClOCF3HH C3H7鍵G10-7265CH2CH3OCH3Cl H C3H7鍵G10-7266CH2ClCl HCH3C3H7鍵G10油7267CH2CH3OCH3HH C3H7鍵G10-7268CH2ClCl HH C5H11鍵G10油7269O ClCl HH C5H11鍵G10-7270CH2ClCF3HH C5H11鍵G10油7271O ClCF3HH C5H11鍵G10-7272CH2ClOCH3HH C5H11鍵G10-7273CH2ClOCF3HH C5H11鍵G10-7274CH2CH3OCH3Cl H C5H11鍵G10-7275CH2ClCl HCH3C5H11鍵G10-7276CH2CH3OCH3HH C5H11鍵G10-7277CH2ClCl HH CH3CH2G10-7278O ClCl H H CH3CH2G10-7279CH2ClCF3H H CH3CH2G10油7280O ClCF3H H CH3CH2G10-7281CH2ClOCH3H H CH3CH2G10-7282CH2ClOCF3H H CH3CH2G10-7283CH2CH3OCH3ClH CH3CH2G10-7284CH2ClCl H CH3CH3CH2G10-7285CH2CF3OCH3H H CH3CH2G10-7286CH2ClCl H H c-C3H5鍵G11油7287O ClCl H H c-C3H5鍵G11-7288CH2ClCF3H H c-C3H5鍵G11油7289O ClCF3H H c-C3H5鍵G11-7290CH2ClOCH3H H c-C3H5鍵G11-7291CH2ClOCF3H H c-C3H5鍵G11-7292CH2CH3OCH3ClH c-C3H5鍵G11-7293CH2ClCl H CH3c-C3H5鍵G11-7294CH2CF3OCH3H H c-C3H5鍵G11-7295CH2ClCl H H C2H5鍵G11油7296O ClCl H H C2H5鍵G11-7297CH2ClCF3H H C2H5鍵G11油7298O ClCF3H H C2H5鍵G11-7299CH2ClOCH3H H C2H5鍵G11-7300CH2ClOCF3H H C2H5鍵G11-7301CH2CH3OCH3ClH C2H5鍵G11-7302CH2ClCl H CH3C2H5鍵G11-7303CH2CF3OCH3H H C2H5鍵G11-7304CH2ClCl H H C3H7鍵G1188-897305O ClCl H H C3H7鍵G11-7306CH2ClCF3H H C3H7鍵G11油7307O ClCF3H H C3H7鍵G11-7308CH2ClOCH3H H C3H7鍵G11-7309CH2ClOCF3H H C3H7鍵G11-7310CH2CH3OCH3ClH C3H7鍵G11-7311CH2ClCl H CH3C3H7鍵G11-7312CH2CF3OCH3H H C3H7鍵G11-7313CH2ClCl H H C6H5鍵G11156-1577314O ClCl H H C6H5鍵G11-7315CH2ClCF3H H C6H5鍵G11150-1517316O ClCF3HH C6H5鍵G11-7317CH2ClOCH3HH C6H5鍵G11-7318CH2ClOCF3HH C6H5鍵G11-7319CH2CH3OCH3Cl H C6H5鍵G11-7320CH2ClCl HCH3C6H5鍵G11-7321CH2CF3OCH3HH C6H5鍵G11-7322CH2ClCl HH C2H5鍵G12-7323O ClCl HH C2H5鍵G12-7324CH2ClCF3HH C2H5鍵G12油7325O ClCF3HH C2H5鍵G12-7326CH2ClOCH3HH C2H5鍵G12-7327CH2ClOCF3HH C2H5鍵G12-7328CH2CH3OCH3Cl H C2H5鍵G12-7329CH2ClCl HCH3C2H5鍵G12-7330CH2CF3OCH3HH C2H5鍵G12-7331CH2ClCl HH C3H7鍵G12-7332O ClCl HH C3H7鍵G12-7333CH2ClCF3HH C3H7鍵G12-7334O ClCF3HH C3H7鍵G12-7335CH2ClOCH3HH C3H7鍵G12-7336CH2ClOCF3HH C3H7鍵G12-7337CH2CH3OCH3Cl H C3H7鍵G12-7338CH2ClCl HCH3C3H7鍵G12-7339CH2CF3OCH3HH C3H7鍵G12-7340CH2ClCl HH c-C3H5鍵G12-7341O ClCl HH c-C3H5鍵G12-7342CH2ClCF3HH c-C3H5鍵G12128-1307343O ClCF3HH c-C3H5鍵G12-7344CH2ClOCH3HH c-C3H5鍵G12-7345CH2ClOCF3HH c-C3H5鍵G12-7346CH2CH3OCH3Cl H c-C3H5鍵G12-7347CH2ClCl HCH3c-C3H5鍵G12-7348CH2CF3OCH3HH c-C3H5鍵G12-7349CH2ClCF3HH c-C3H5鍵G13油7350CH2ClCl HH c-C3H5鍵G13-7351CH2ClCF3HH c-C3H5鍵G7 油7352CH2ClCl HH c-C3H5鍵G7 油7353CH2ClCF3HH CH3鍵G7 -7354CH2Cl Cl HH CH3鍵G7-7355CH2CH3OCH3CH3H CH3鍵G7油7356CH2CH3OCH3CH3H C3H7鍵G7油7357CH2CF3OCH3HH C3H7鍵G7油7358CH2CH3OCH3CH3H C4H9鍵G7油7359CH2Cl Cl HCH3c-C3H5鍵G7156-1587360CH2CF3OCH3HH CH3鍵G8油7361CH2CH3OCH3OCH3H C2H5鍵G10 油7362O Cl Cl HH CH3鍵G1-7363O Cl CF3HH CH3鍵G1-7364CH2Cl OCF3HH CH3鍵G1-7365CH2CH3OCH3Cl H CH3鍵G1-7366CH2Cl Cl HCH3CH3鍵G1-7367CH2CF3OCH3HH CH3鍵G1-7368CH2CH3OCH3FH CH3鍵G1-7369O Cl Cl HH C2H5鍵G1-7370O Cl CF3HH C2H5鍵G1-7371CH2Cl OCF3HH C2H5鍵G1-7372CH2CH3OCH3Cl H C2H5鍵G1-7373CH2Cl Cl HCH3C2H5鍵G1-7374CH2CF3OCH3HH C2H5鍵G1-7375CH2CH3OCH3FH C2H5鍵G1-7376O Cl Cl HH C3H7鍵G1-7377O Cl CF3HH C3H7鍵G1-7378CH2Cl OCF3HH C3H7鍵G1-7379CH2CH3OCH3Cl H C3H7鍵G1-7380CH2Cl Cl HCH3C3H7鍵G1-7381CH2CF3OCH3HH C3H7鍵G1-7382CH2CH3OCH3FH C3H7鍵G1-7383O Cl Cl HH c-C3H5鍵G1-7384O Cl CF3HH c-C3H5鍵G1-7385CH2Cl OCF3HH c-C3H5鍵G1-7386CH2CH3OCH3Cl H c-C3H5鍵G1-7387CH2Cl Cl HCH3c-C3H5鍵G1-7388CH2CF3OCH3HH c-C3H5鍵G1-7389CH2CH3OCH3FH c-C3H5鍵G1-7390CH2Cl CF3HH c-C3H5鍵G14 油7391CH2Cl Cl HH c-C3H5鍵G14 -7391CH2ClCF3H H c-C3H5鍵G15 油7392CH2ClCl H H c-C3H5鍵G15 -7393CH2ClCF3H H c-C3H5鍵G16 139-1407394CH2ClCl H H c-C3H5鍵G16 -7395CH2ClCF3H H c-C3H5鍵G17 -7396CH2ClCl H H c-C3H5鍵G17 油7397CH2ClCF3H H c-C3H5鍵G18 -7398CH2ClCl H H c-C3H5鍵G18 油7399CH2ClCl H CH3CH3鍵G8 油7400CH2ClCF3H H c-C3H5鍵G19 -7401CH2ClCl H H c-C3H5鍵G19 油7402CH2ClCl H H c-C3H5鍵G20 油7403CH2ClCF3H H c-C3H5鍵G20 -7404CH2ClCl H H C4H9鍵G1 油7405CH2ClCl H H C6H5C=O C6H5油7406CH2ClCl H H C6H5C=O G21 油7407CH2ClCl H H C6H5C=O G22 油7408CH2ClCl H H 4-F-C=O CH3油C6H4CH27409CH2ClCl H H c-C3H5鍵G23 油關(guān)鍵(a)G基團(tuán)
      (b)在化合物被指明為“油”的地方,提供波譜數(shù)據(jù)如下實施例7056波譜數(shù)據(jù)MS(ESI)m/e 363(M+2),361(M+,100%)。
      實施例7086波譜數(shù)據(jù)TLC RF0.25(30∶70乙酸乙酯-己烷)。1HNMR(300MHz,CDCl3)δ8.91(1H,s),7.72(1H,d,J=9.2Hz),6.90-6.84(2H,m),6.08(1H,ddq,J=15.4Hz,6.6H,1.4Hz),5.67(1H,dqd,J=15.4Hz,6.5H,1.5Hz),5.24(1H,br五重峰,J=7.0Hz),3.85(3H,s),2.96(2H,dq,J=7.5,1.1Hz),2.47(3H,s),1.81(3H,d,J=7.0Hz),1.73(3H,dt,J=6.2,1.3Hz),1.41(3H,t,J=7.5Hz)。MS(NH3-CI)m/e 339(3),338(23),337(100)。
      實施例7116波譜數(shù)據(jù)TLC RF0.15(30∶70乙酸乙酯-己烷)。1HNMR(300MHz,CDCl3)δ8.96(1H,s),7.68(1H,d,J=8.4Hz),7.09(1H,d,J=2.6Hz),6.96(1H,dd,J=8.4,2.6Hz),6.09(1H,ddq,J=15.4Hz,6.6H,1.8Hz),5.67(1H,dqd,J=15.4Hz,6.5H,1.4Hz),5.23(1H,br五重峰,J=6.8Hz),3.87(3H,s),2.98(2H,q,J=7.5Hz),1.82(3H,d,J=7.0Hz),1.73(3H,dt,J=6.6,1.3Hz),1.40(3H,t,J=7.5Hz)。MS(NH3-CI)m/e 360(7),359(33),358(23),357(100)。
      實施例7145波譜數(shù)據(jù)m.p.78-79℃。TLC RF0.52(30∶70乙酸乙酯-己烷)。1H NMR(300MHz,CDCl3)δ9.01(1H,s),7.86-7.81(2H,m),7.68(1H,d,J=8.0Hz),6.38(2H,ddd,J=17.2Hz,10.6H,5.8Hz),5.90-5.83(1H,m),5.40(2H,dd,J=10.6,1.3Hz),5.29(2H,dt,J=17.2,0.9Hz),2.97(2H,q,J=7.6Hz),1.41(3H,t,J=7.6Hz)。MS(NH3-CI)m/e 396(8),395(36),394(25),393(100)。C19H16ClF3N4的分析計算值C,58.10;H,4.12;N,14.26;實測值C,58.14;H,4.28;N,13.74。
      實施例7146波譜數(shù)據(jù)TLC RF0.43(30∶70乙酸乙酯-己烷)。1HNMR(300MHz,CDCl3)δ8.99(1H,s),7.84-7.79(2H,m),7.67(1H,dd,J=8.5,1.1Hz),6.10(1H,ddq,J=15.4Hz,6.8H,1.8Hz),5.70(1H,dqd,J=15.4Hz,6.5H,1.1Hz),5.24(1H,五重峰,J=7.0Hz),2.99(2H,q,J=7.5Hz),1.83(3H,d,J=7.0Hz),1.74(3H,dt,J=6.6,1.3Hz),1.40(3H,t,J=7.5Hz)。MS(NH3-CI)m/e 398(7),397(36),396(25),395(100)。
      實施例7231波譜數(shù)據(jù)m.p.78-88℃。TLC RF0.55(50∶50乙酸乙酯-己烷)。1H NMR(300MHz,CDCl3)較多的異構(gòu)體δ8.90(1H,s),6.95(2H,s),4.68-3.05(6H,m),3.02-2.92(2H,m),2.70-2.55(2H,m),2.32(3H,s),2.20-2.00(2H,m),2.05(3H,s),1.96(3H,s),1,70-1.45(4H,m),1.39(3H,t,J=7.7Hz),0.93(3H,t,J=7.3Hz);較少的異構(gòu)體δ8.89(1H,s),6.95(2H,s),4.68-3.05(6H,m),3.02-2.92(2H,m),2.70-2.55(2H,m),2.32(3H,s),2.20-2.00(2H,m),2.06(3H,s),2.01(3H,s),1.70-1.45(4H,m),1.38(3H,t,J=7.7Hz),0.90(3H,t,J=7.3Hz)。MS(NH3-CI)m/e C25H35N4O2的計算值423.2760,實測值423.2748;425(5),424(29),423(100)。C25H34N4O2·H2O的分析計算值C,68.15;H,8.24;N,12.72;實測值C,67.80;H,7.89;N,12.24。
      實施例7234波譜數(shù)據(jù)TLC RF0.46(30∶70乙酸乙酯-己烷)。1HNMR(300MHz,CDCl3)δ8.99(1H,s),7.87(1H,d,J=8.0Hz),7.83(1H,s),7.68(1H,d,J=8.0Hz),6.50(1H,d,J=3.0Hz),5.99(1H,d,J=3.0Hz),5.10(1H,d,J=10.6Hz),2.99-2.79(2H,m),2.20(3H,s),2.10-2.00(1H,m),1.30(3H,t,J=7.5Hz),1.00-0.90(1H,m),0.71-0.59(2H,m),0.56-0.46(1H,m)。MS(NH3-CI)m/e 463(35),461(100)。
      實施例7241波譜數(shù)據(jù)MS(NH3-CI)m/e 371(M+H+,100%)。
      實施例7243波譜數(shù)據(jù)TLC RF0.43(30∶70乙酸乙酯-己烷)。1HNMR(300MHz,CDCl3)δ9.01(1H,s),7.85(1H,d,J=8.0Hz),7.83(1H,s),7.69(1H,d,J=8.0Hz),5.24(1H,dd,J=8.4,2.5Hz),3.28(1H,dq,J=15.5,7.5Hz),3.14(1H,dq,J=15.5,7.5Hz),2.56(1H,d,J=2.5Hz),1.78-1.67(1H,m),1.48(3H,t,J=7.5Hz),0.92-0.81(2H,m),0.66-0.49(2H,m)。MS(NH3-CI)m/e C20H17ClF3N4的計算值405.1094,實測值405.1098;408(8),407(34),406(25),405(100)。
      實施例7249波譜數(shù)據(jù)TLC RF0.19(30∶70乙酸乙酯-己烷)。1HNMR(300MHz,CDCl3)δ8.93(1H,s),7.72(1H,d,J=8.5Hz),7.37(1H,d,J=2.5Hz),7.18(1H,dd,J=8.5,2.5Hz),5.23(1H,dd,J=8.1,2.6Hz),3.92(3H,s),3.31-3.04(2H,m),2.54(1H,d,J=2.6Hz),1.76-1.64(1H,m),1.47(3H,t,J=7.5Hz),0.90-0.80(2H,m),0.64-0.52(2H,m)。MS(NH3-CI)m/e C21H20F3N4O的計算值401.1603,實測值401.1602;403(6),402(24),401(100)。
      實施例7250波譜數(shù)據(jù)TLC RF0.17(20∶80乙酸乙酯-己烷)。1HNMR(300MHz,CDCl3)δ9.01(1H,s),7.67(1H,d,J=8.5Hz),7.58(1H,d,J=1.8Hz),7.41(1H,dd,J=8.5,1.8Hz),5.53(1H,dt,J=8.0,2.6Hz),3.20(1H,dq,J=15.8,7.5Hz),3.05(1H,dq,J=15.8,7.5Hz),2.55(1H,d,J=2.6Hz),2.42-2.29(1H,m),2.28-2.15(1H,m),1.46(3H,t,J=7.5Hz),1.04(3H,t,J=7.5Hz)。MS(NH3-CI)m/e C18H17Cl2N4的計算值359.0830,實測值359.0835;364(2),363(12),362(14),361(67),360(24),359(100)。
      實施例7259波譜數(shù)據(jù)TLC RF0.22(20∶80乙酸乙酯-己烷)。1HNMR(300MHz,CDCl3)δ9.01(1H,s),7.67(1H,d,J=8.1Hz),7.58(1H,d,J=1.8Hz),7.40(1H,dd,J=8.1,1.8Hz),5.63(1H,dt,J=7.9,2.5Hz),3.20(1H,dq,J=15.7,7.7Hz),3.05(1H,dq,J=15.7,7.7Hz),2.54(1H,d,J=2.5Hz),2.37-2.24(1H,m),2.19-2.06(1H,m),1.60-1.45(1H,m),1.46(3H,t,J=7.7Hz),1.39-1.25(1H,m),0.99(3H,t,J=7.3Hz)。MS(NH3-CI)m/e C19H19Cl2N4的計算值373.0987,實測值373.0984;378(3),377(12),376(15),375(66),374(26),373(100)。
      實施例7261波譜數(shù)據(jù)TLC RF0.52(30∶70乙酸乙酯-己烷)。1HNMR(300MHz,CDCl3)δ9.03(1H,s),7.84(2H,m),7.68(1H,dd,J=7.3,0.7Hz),5.65(1H,dt,J=8.1,2.6Hz),3.24-3.02(2H,m),2.55(1H,d,J=2.6Hz),2.33-2.25(1H,m),2.20-2.12(1H,m),1.46(3H,t,J=7.5Hz),1.00(3H,t,J=7.3Hz)。MS(NH3-CI)m/e C20H19ClF3N4的計算值407.1250,實測值407.1243;410(8),409(36),408(25),407(100)。
      實施例7266波譜數(shù)據(jù)TLC RF0.19(20∶80乙酸乙酯-己烷)。1HNMR(300MHz,CDCl3)δ9.01(1H,d,J=1.5Hz),7.38(1H,d,J=1.8Hz),7.24(1H,d,J=1.8Hz),5.70-5.58(1H,m),3.24-3.00(2H,m),2.55(1H,d,J=2.5Hz),2.40-2.25(1H,m),2.20-2.05(1H,m),2.10(3H,d,J=1.8Hz),1.62-1.47(1H,m),1.43(3H,t,J=7.5Hz),1.42-1.27(1H,m),1.00(3H,t,J=7.3Hz)。MS(NH3-CI)m/e C20H21Cl2N4的計算值387.1143,實測值387.1144;392(3),391(12),390(16),389(66),388(27),387(100)。
      實施例7268波譜數(shù)據(jù)TLC RF0.29(20∶80乙酸乙酯-己烷)。1HNMR(300MHz,CDCl3)δ9.01(1H,s),7.67(1H,d,J=8.5Hz),7.58(1H,d,J=2.2Hz),7.41(1H,dd,J=8.5,2.2Hz),5.60(1H,dt,J=7.9,2.6Hz),3.19(1H,dq,J=15.3,7.3Hz),3.05(1H,dq,J=15.3,7.3Hz),2.54(1H,d,J=2.6Hz),2.38-2.23(1H,m),2.20-2.05(1H,m),1.58-1.44(1H,m),1.46(3H,t,J=7.3Hz),1.40-1.23(5H,m),0.87(3H,t,J=7.0Hz)。MS(NH3-CI)m/e C21H23Cl2N4的計算值401.1300,實測值401.1300;406(3),405(13),404(17),403(69),402(28),401(100)。
      實施例7270波譜數(shù)據(jù)TLC RF0.60(30∶70乙酸乙酯-己烷)。1HNMR(300MHz,CDCl3)δ9.03(1H,s),7.84(2H,m),7.68(1H,dd,J=9.1,0.7Hz),5.62(1H,dt,J=8.1,2.6Hz),3.24-3.02(2H,m),2.55(1H,d,J=2.6Hz),2.34-2.27(1H,m),2.19-2.13(1H,m),1.46(3H,t,J=7.3Hz),1.40-1.25(6H,m),0.88(3H,t,J=7.0Hz)。MS(NH3-CI)m/eC22H23ClF3N4的計算值435.1563,實測值435.1566;438(9),437(36),436(27),435(100)。
      實施例7279波譜數(shù)據(jù)TLC RF0.31(30∶70乙酸乙酯-己烷)。1HNMR(300MHz,CDCl3)δ8.97(1H,s),7.84(2H,m),7.68(1H,d,J=7.7Hz),4.74-4.67(1H,m),3.45-3.36(1H,m),3.03(2H,q,J=7.7Hz),3.00-2.93(1H,m),1.93(1H,t,J=2.7Hz),1.86(3H,d,J=7.0Hz),1.43(3H,t,J=7.5Hz)。MS(NH3-CI)m/e 396(7),395(34),394(24),393(100)。
      實施例7286波譜數(shù)據(jù)TLC RF0.29(20∶80乙酸乙酯-己烷)。1HNMR(300MHz,CDCl3)δ8.97(1H,s),7.68(1H,d,J=8.4Hz),7.58(1H,d,J=1.8Hz),7.41(1H,dd,J=8.4,1.8Hz),5.19(1H,dq,J=8.4,2.6Hz),3.26(1H,dq,J=15.7,7.3Hz),3.14(1H,dq,J=15.7,7.3Hz),1.88(3H,d,J=2.6Hz),1.70-1.60(1H,m),1.47(3H,t,J=7.3Hz),0.89-0.78(2H,m),0.60-0.43(2H,m)。MS(NH3-CI)m/e C20H19Cl2N4的計算值385.0986,實測值385.0992;390(3),389(12),388(15),387(66),386(26),385(100)。
      實施例7288波譜數(shù)據(jù)MS(NH3-CI)m/e 419(M+H+,100%)。
      實施例7295波譜數(shù)據(jù)TLC RF0.19(20∶80乙酸乙酯-己烷)。1HNMR(300MHz,CDCl3)δ8.99(1H,s),7.67(1H,d,J=8.4Hz),7.57(1H,d,J=2.2Hz),7.40(1H,dd,J=8.4,2.2Hz),5.49(1H,tq,J=7.7,2.2Hz),3.19(1H,dq,J=15.3,7.7Hz),3.05(1H,dq,J=15.3,7.7Hz),2.26(1H,dq,J=21.3,7.7Hz),2.13(1H,dq,J=21.3,7.7Hz),1.87(3H,d,J=2.2Hz),1.45(3H,t,J=7.7Hz),1.01(3H,t,J=7.7Hz)。MS(NH3-CI)m/e C19H19Cl2N4的計算值373.0987,實測值373.0987;378(3),377(13),376(15),375(68),374(25),373(100)。
      實施例7297波譜數(shù)據(jù)TLC RF0.48(30∶70乙酸乙酯-己烷)。1HNMR(300MHz,CDCl3)δ9.01(1H,s),7.83(2H,m),7.67(1H,dd,J=7.4,0.8Hz),5.51(1H,dt,J=8.1,2.2Hz),3.25-3.03(2H,m),2.35-2.13(2H,m),1.88(3H,d,J=2.2Hz),1.45(3H,t,J=7.5Hz),1.01(3H,t,J=7.3Hz)。MS(NH3-CI)m/e C20H19ClF3N4的計算值407.1250,實測值407.1267;410(8),409(35),408(25),407(100)。
      實施例7306波譜數(shù)據(jù)MS(NH3-CI)m/e 421(M+H+,100%)。
      實施例7324波譜數(shù)據(jù)TLC RF0.38(30∶70乙酸乙酯-己烷)。1HNMR(300MHz,CDCl3)δ8.99(1H,s),7.84(1H,d,J=8.4Hz),7.83(1H,d,J=1.8Hz),7.68(1H,dd,J=8.4,1.8Hz),7.36(1H,d,J=3Hz),6.51(1H,d,J=5Hz),6.39(1H,dd,J=5,3Hz),5.78(1H,dd,J=9,7Hz),3.00-2.85(2H,m),2.75-2.52(2H,m),1.37(3H,t,J=7.5Hz),0.98(3H,t,J=7.5Hz)。MS(NH3-CI)m/e 439(1),438(8),437(34),436(26),435(100)。
      實施例7349波譜數(shù)據(jù)TLC RF0.20(30∶70乙酸乙酯-己烷)。1HNMR(300MHz,CDCl3)δ9.00(1H,s),7.87(1H,d,J=8.0Hz),7.83(1H,s),7.69(1H,d,J=8.0Hz),5.01(1H,d,J=10.6Hz),2.93(1H,dq,J=15.9,7.5Hz),2.75(1H,dq,J=15.9,7.5Hz),2.58(3H,s),2.04-1.94(1H,m),1.93(3H,s),1.33(3H,t,J=7.5Hz),1.32-1.22(1H,m),1.00-0.87(1H,m),0.74-0.60(3H,m)。MS(NH3-CI)m/e C23H22ClF3N5O的計算值476.1465,實測值476.1469;478(35),476(100)。
      實施例7351波譜數(shù)據(jù)TLC RF0.44(30∶70乙酸乙酯-己烷)。1HNMR(300MHz,CDCl3)δ8.99(1H,s),7.88-7.82(2H,m),7.68(1H,d,J=8.0Hz),6.35(1H,ddd,J=17.2Hz,10.6H,5.1Hz),5.33(1H,br d,J=10.6Hz),5.26(1H,br d,J=17.2Hz),4.43-4.37(1H,m),3.02-2.90(2H,m),1.99-1.89(1H,m),1.41(3H,t,J=7.5Hz),0.94-0.84(1H,m),0.62-0.52(2H,m),0.40-0.30(1H,m)。MS(NH3-CI)m/e 411(1),410(7),409(34),408(25),407(100)。
      實施例7352波譜數(shù)據(jù)TLC RF0.13(20∶80乙酸乙酯-己烷)。1HNMR(300MHz,CDCl3)δ8.96(1H,s),7.69(1H,d,J=8.4Hz),7.58(1H,d,J=2.2Hz),7.41(1H,dd,J=8.8,2.2Hz),6.33(1H,ddd,J=17.2,10.6,5.2Hz),5.35-5.20(2H,m),4.42-4.35(1H,m),3.03-2.88(2H,m),2.00-1.89(1H,m),1.40(3H,t,J=7.6Hz),0.92-0.82(1H,m),0.62-0.52(2H,m),0.40-0.30(1H,m)。MS(NH3-CI)m/e C19H19Cl2N4的計算值373.1000,實測值373.0995;378(3),377(12),376(15),375(66),374(26),373(100)。
      實施例7355波譜數(shù)據(jù)MS(NH3-CI)m/e 337(M+H+,100%)。
      實施例7356波譜數(shù)據(jù)MS(NH3-CI)m/e 365(M+H+,100%)。
      實施例7357波譜數(shù)據(jù)TLC RF0.19(30∶70乙酸乙酯-己烷)。1HNMR(300MHz,CDCl3)δ8.91(1H,s),7.70(1H,d,J=8.4Hz),7.35(1H,d,J=2.6Hz),7.19(1H,dd,J=8.4,2.6Hz),6.42(1H,ddd,J=16.9,10.3,6.6Hz),5.27(1H,d,J=10.2Hz),5.14(1H,d,J=17.3Hz),5.08-4.99(1H,m),3.91(3H,s),2.99-2.90(2H,m),2.42-2.29(1H,m),2.27-2.15(1H,m),1.39(3H,t,J=7.5Hz),1.38-1.10(2H,m),0.95(3H,t,J=7.1Hz)。MS(NH3-CI)m/e C21H23F3N4O的計算值405.1915,實測值405.1923;407(5),406(24),405(100)。C21H23F3N4O的分析計算值C,62.37;H,5.73;N,13.85;實測值C,62.42;H,5.73;N,13.48。
      實施例7358波譜數(shù)據(jù)MS(NH3-CI)m/e 379(M+H+,100%)。
      實施例7360波譜數(shù)據(jù)TLC RF0.13(30∶70乙酸乙酯-己烷)。1HNMR(300MHz,CDCl3)δ8.91(1H,s),7.68(1H,d,J=8.8Hz),7.35(1H,d,J=2.6Hz),7.16(1H,dd,J=8.8,2.6Hz),6.15-6.05(1H,m),5.73-5.63(1H,m),5.28-5.18(1H,m),3.91(3H,s),2.96(2H,q,J=7.4Hz),1.82(3H,d,J=7.3Hz),1.74(3H,dt,J=6.6,1.3Hz),1.39(3H,t,J=7.4Hz)。MS(NH3-CI)m/e C20H22F3N4O的計算值391.1733,實測值391.1736;393(3),392(23),391(100)。
      實施例7361波譜數(shù)據(jù)TLC RF0.43(50∶50乙酸乙酯-己烷)。1HNMR(300MHz,CDCl3)δ8.96(1H,s),7.42(1H,s),6.84(1H,s),5.55(1H,dt,J=5.5,2.2Hz),3.94(3H,s),3.92(3H,s),3.49-2.98(2H,m),2.54(1H,d,J=2.6Hz),2.45(3H,s),2.35-2.16(2H,m),1.48(3H,t,J=7.5Hz),1.03(3H,t,J=7.5Hz)。MS(NH3-CI)m/e C21H25N4O2的計算值365.1978,實測值365.1966;367(6),366(24),365(100)。
      實施例7390波譜數(shù)據(jù)TLC RF0.45(30∶70乙酸乙酯-己烷)。1HNMR(300MHz,CDCl3)δ8.99(1H,s),7.88(1H,d,J=8.0Hz),7.83(1H,s),7.69(1H,d,J=8.0Hz),7.30-7.22(1H,m),7.07-7.01(1H,m),6.99-6.92(1H,m),5.25(1H,d,J=10.2Hz),2.97-2.78(2H,m),2.23(1H,br),1.32(3H,t,J=7.3Hz),1.10-1.00(1H,m),0.81-0.71(1H,m),0.64-0.54(1H,m),0.50-0.40(1H,m)。MS(NH3-CI)m/e C22H19ClF3N4S計算值463.0971,實測值463.0960;467(3),466(10),465(99),464(28),463(100)。
      實施例7392波譜數(shù)據(jù)TLC RF0.44(30∶70乙酸乙酯-己烷)。1HNMR(300MHz,CDCl3)δ8.99(1h,s),7.88(1H,d,J=8.0Hz),7.83(1H,s),7.68(1H,d,J=8.0Hz),7.30(1H,br d,J=4.8Hz),7.18(1H,br d,J=4.8Hz),6.92(1H,m),5.12(1H,d,J=9.9Hz),2.92-2.67(2H,m),2.13(1H,br),1.28(3H,t,J=7.5Hz),1.08-0.99(1H,m),0.79-0.69(1H,m),0.55-0.45(2H,m)。MS(NH3-CI)m/e C22H19ClF3N4S的計算值463.0971,實測值463.0953;467(3),466(10),465(39),464(29),463(100)。
      實施例7396波譜數(shù)據(jù)TLC RF0.27(20∶80乙酸乙酯-己烷)。1HNMR(300MHz,CDCl3)δ8.96(1H,s),7.67(1H,d,J=8.1Hz),7.58(1H,d,J=1.8Hz),7.41(1H,dd,J=8.1,1.8Hz),6.86(1H,s),5.83(1H,dd,J=9.9,6.2Hz),4.43(2H,q,J=7.3Hz),2.98(2H,q,J=7.7Hz),2.91-2.78(1H,m),2.63-2.49(1H,m),1.42(3H,t,J=7.7Hz),1.40(3H,t,J=7.3Hz),1.39-1.19(2H,m),1.00(3H,t,J=7.3Hz)。MS(NH3-CI)m/eC23H24Cl2N5O3的計算值488.1256,實測值488.1252;493(3),492(13),491(18),490(68),489(28),488(100)。
      實施例7398波譜數(shù)據(jù)TLC RF0.11(20∶80乙酸乙酯-己烷)。1HNMR(300MHz,CDCl3)δ8.99(1H,s),7.72(1H,d,J=8.1Hz),7.59(1H,d,J=1.8Hz),7.42(1H,dd,J=8.1,1.8Hz),5.40(1H,dd,J=10.4,5.0Hz),4.42(2H,q,J=7.4Hz),3.00-2.90(2H,m),2.66-2.52(1H,m),2.51-2.38(1H,m),1.46(3H,t,J=7.4Hz),1.41(3H,t,J=7.3Hz),1.40-1.10(2H,m),0.98(3H,t,J=7.2Hz)。MS(NH3-CI)m/e C24H25Cl2N6O4計算值531.1315,實測值531.1315;531(100)。
      實施例7399波譜數(shù)據(jù)TLC RF0.13(20∶80乙酸乙酯-己烷)。1HNMR(300MHz,CDCl3)δ8.98(1H,s),7.38(1H,d,J=1.8Hz),7.23(1H,d,J=1.8Hz),6.15-6.06(1H,m),5.76-5.63(1H,m),5.26-5.20(1H,m),2.96(2H,q,J=7.4Hz),2.10(3H,s),1.83(3H,d,J=7.0Hz),1.74(3H,d,J=6.6Hz),1.37(3H,t,J=7.4Hz)。MS(NH3-CI)m/eC19H21Cl2N4計算值375.1117,實測值375.1123;380(2),379(12),378(15),377(66),376(26),375(100)。
      實施例7401波譜數(shù)據(jù)TLC RF0.20(乙酸乙酯)。1H NMR(300MHz,CDCl3)δ8.99(1H,s),7.71(1H,d,J=8.4Hz),7.58(1H,d,J=1.8Hz),7.41(1H,dd,J=8.4,1.8Hz),7.11(1H,d,J=1.1Hz),6.87(1H,d,J=1.1Hz),5.41(1H,d,J=10.3Hz),3.34(3H,s),3.08(1H,dq,J=15.8,7.7Hz),2.89(1H,dq,J=15.8,7.7Hz),2.39-2.25(1H,m),1.14(3H,t,J=7.7Hz),1.07-0.97(1H,m),0.70-0.58(2H,m),0.52-0.42(1H,m)。MS(NH3-CI)m/e C21H21Cl2N6的計算值427.1205,實測值427.1196;429(66),427(100)。
      實施例7402波譜數(shù)據(jù)MS(NH3-CI)m/e 424(M+H+,100%)。
      實施例7404波譜數(shù)據(jù)MS(NH3-CI)m/e 419(M+H+,100%)。
      實施例7405波譜數(shù)據(jù)MS(NH3-CI)m/e 487(M+H+,100%)。
      實施例7406波譜數(shù)據(jù)MS(NH3-CI)m/e 501(M+H+,100%)。
      實施例7407波譜數(shù)據(jù)MS(NH3-CI)m/e 517(M+H+,100%)。
      實施例7408波譜數(shù)據(jù)MS(NH3-CI)m/e 457(M+H+,100%)。
      實施例7409波譜數(shù)據(jù)MS(NH3-CI)m/e 429(M+H+,100%)。
      用途用于生物學(xué)活性評價的CRF-R1受體結(jié)合試驗以下是分離用于標(biāo)準(zhǔn)結(jié)合試驗的含有克隆的人CRF-R1受體的細(xì)胞膜的描述以及該試驗本身的描述。
      從人海馬中分離出來信使RNA。使用寡(dt)12-18逆轉(zhuǎn)錄該mRNA并且通過PCR從起始到終止密碼子放大的編碼區(qū)。所生成的PCR片段被克隆到pGEMV的EcoRV位點,從那里該插入片段使用XhoI+XbI+復(fù)原,并且將其克隆到pm3ar載體的XhoI+XbaI位點(它含有CMV啟動子、SV40‘t’剪接和早期聚腺苷酸(poly A)信號、埃-巴二氏病毒復(fù)制起點和潮霉素可選擇的標(biāo)記)。所生成的稱作phchCRFR的表達(dá)載體在293EBNA細(xì)胞中轉(zhuǎn)染,并且在400mM潮霉素存在下選擇保持有游離體的細(xì)胞。使選擇在潮霉素中生存4周的細(xì)胞合并,使之適宜于在懸浮液中生長,并用于產(chǎn)生以下所描述的結(jié)合試驗的膜。然后把含有大約1×108的懸浮細(xì)胞的單一的等分試樣離心以形成沉淀并且冷凍。
      對于該結(jié)合試驗來說,將以上描述的含有以hCRFR1受體轉(zhuǎn)染的293EBNA細(xì)胞的冷凍沉淀在10mL的冰冷組織緩沖液(50mMHEPES緩沖液pH 7.0、它含有10mM MgCl2、2mM EGTA、1mg/L抑蛋白酶肽、1mg/mL亮抑蛋白酶肽和1mg/mL抑胃酶肽)中勻漿化。該勻漿在40,000×g轉(zhuǎn)速下離心12分鐘,并且生成的沉淀在10mL的組織緩沖液中再次勻漿化。又一次在40,000×g轉(zhuǎn)速下離心12分鐘之后,該沉淀重新懸浮至蛋白濃度為360mg/mL,以便于在該試驗中使用。
      結(jié)合試驗在96孔板上實施;每一個孔具有300mL的容積。向每一個孔中加入50mL的受試藥物的稀釋液(藥物最終濃度范圍從10-10至10-5M)、100mL的125I-羊-CRF(125I-o-CRF)(最終濃度150pM)和150mL的上述的細(xì)胞勻漿。然后使這些板在室溫下孵育2小時,然后使用適宜的細(xì)胞收集器通過GF/F濾膜(以0.3%聚乙烯亞胺預(yù)先浸泡)過濾該孵育物。以冰冷的試驗緩沖液沖洗該濾液兩次,再移去單個濾膜,并且在伽馬計數(shù)器上評定它們的放射活性。
      在受試藥物的多種稀釋液中的125I-o-CRF結(jié)合于細(xì)胞膜的抑制曲線通過迭合曲線擬合法程序LIGAND來分析[P.J.Munson和D.Rodbard,Anal.Biochem.107220(1980),該方法提供了抑制作用的K1值,然后用于評定生物活性。
      或者,自然表達(dá)CRF受體的組織和細(xì)胞能夠用于與那些以上描述的類似的結(jié)合試驗中。
      如果一個化合物對于抑制CRF具有小于大約10000nM的K1值,就認(rèn)為它是有活性的。CRF刺激的腺苷酸環(huán)化酶活性的抑制作用如同G.Battaglia等.Synapse 1572(1987)所描述的那樣實施CRF刺激的腺苷酸環(huán)化酶活性的抑制作用。簡而言之,試驗于37℃下在200mL的含有100mM Tris-HCl(在37℃下pH7.4)、10mM MgCl2、0.4mM EGTA、0.1%BSA、1mM異丁基甲基黃嘌呤(IBMX)、250單位/mL磷酸肌酸激酶、5mM肌酸磷酸酯、100mM鳥苷5’-三磷酸、100nM oCRF、拮抗劑肽(濃度范圍在10-9至10-6M之間)和0.8mg原濕重組織(大約40-60mg蛋白)的緩沖液中進(jìn)行10分鐘。通過加入1mM ATP/32P]ATP(大約2-4mCi/管)啟動反應(yīng),并且通過加入100mL的50mM Tris-HCl、45mM ATP和2%十二烷基硫酸鈉終止反應(yīng)。為了檢測cAMP的恢復(fù),分離之前在每一個試管中加入1mL的[3H]cAMP(大約40,000dpm)。通過經(jīng)Dowex和氧化鋁柱上連續(xù)洗脫從[32P]ATP中分離[32P]cAMP。體內(nèi)生物活性本發(fā)明化合物的體內(nèi)活性可使用本領(lǐng)域內(nèi)任何一個可以得到的和接受的生物活性試驗進(jìn)行評價。這些試驗的描述包括聽覺驚跳試驗、階梯爬行試驗和慢性給藥試驗。這些和其它的用于本發(fā)明的化合物試驗的模型概述在C.W.Berridge和A.J.Dunn的Brain ResearchReviews 1571(1990)中?;衔锟稍谌魏畏N類的嚙齒動物或小哺乳動物上試驗。
      在患有抑郁癥、情感障礙和/或焦慮癥的患者中,本發(fā)明化合物在治療與促腎上腺皮質(zhì)激素釋放因子異常水平有關(guān)的失衡具有效用。
      借助產(chǎn)生使活性藥物與藥物的作用部位的接觸,本發(fā)明化合物能夠通過給藥來治療這些在哺乳動物體內(nèi)的異常疾病。這些化合物能夠通過任何現(xiàn)有常規(guī)的方式與藥劑聯(lián)同使用,或者作為單獨的藥物或與治療藥物聯(lián)合的方式給藥。它們可單獨給藥,但是一般與根據(jù)選擇了給藥途徑和標(biāo)準(zhǔn)藥物實踐的基礎(chǔ)選擇的藥用載體一起給藥。
      給藥劑量將依用途和已知的因素如具體藥物的藥代動力學(xué)性質(zhì)和它的給藥模式與給藥途徑、接受者的年齡、體重和健康狀況、癥狀性質(zhì)和程度、現(xiàn)行治療的種類、治療頻率和要求的效果而定。對于在治療所述疾病或狀況中的用途來說,本發(fā)明化合物能夠在0.002至200mg/kg的體重的活性成分的劑量下每日口服給藥。一般地,每天一到四次0.01至10mg/kg的分開劑量或者以持續(xù)釋放制劑將在獲得所要求的藥理效果方面是有效的。
      適宜于給藥的劑型(組合物)每單位含有大約1mg至大約100mg的活性成分。在這些藥用組合物中,該活性成分將一般以基于該組合物的總重量的大約0.5至95%(重量)的量存在。
      可以口服給藥的該活性成分為固體劑型如膠囊劑、片劑和散劑,或者為液體形式如酏劑、糖漿劑和/或混懸劑。本發(fā)明化合物也能夠以無菌液體劑量制劑非腸道給藥。
      明膠膠囊能用于裝有該活性成分和適宜的載體如(但不局限于)乳糖、淀粉、硬脂酸鎂、硬脂酸或纖維素衍生物。相似的稀釋劑能夠用于制備壓制片劑。片劑和膠囊劑兩者能夠制備為持續(xù)釋放的產(chǎn)品以在一定的時間區(qū)間內(nèi)連續(xù)釋放藥物。壓制片劑可以用糖包衣或薄膜包衣以掩蔽任何不良味道或用于保護(hù)該活性成分與空氣隔離,或在胃腸道選擇性地崩解該片劑。
      口服給藥的液體劑量形式能含有著色或矯味劑以增加患者的可接受性。
      一般地,水、藥學(xué)上可接受的油、鹽水、右旋糖(葡萄糖)水溶液和有關(guān)的糖溶液和甘油如丙二醇或聚乙二醇為非腸道給藥適宜的載體。非腸道給藥的溶液劑優(yōu)選含有該活性成分的水溶性鹽、適宜的穩(wěn)定劑,并且如果必要的話還有緩沖劑物質(zhì)。抗氧化劑如亞硫酸氫鈉、亞硫酸鈉或抗壞血酸,單獨的或聯(lián)合的,為適宜的穩(wěn)定劑。也使用枸櫞酸和它的鹽和EDTA。另外,非腸道給藥的溶液劑能夠含有防腐劑如benzalkonium氯化物、甲基或丙基對羥基苯甲酸酯和氯丁醇。
      在本領(lǐng)域標(biāo)準(zhǔn)參考文獻(xiàn)“Remington’s Pharmaceutical sciences”,A.Osol中描述了適宜的藥用載體。
      本發(fā)明化合物給藥的有用的藥物劑型闡述如下膠囊劑大量單位膠囊劑通過以100mg的粉末活性成分、150mg乳糖、50mg纖維素和6mg硬脂酸鎂填充每一個標(biāo)準(zhǔn)的兩節(jié)的硬明膠膠囊來制備。
      軟明膠膠囊劑制備并且借助正位移泵注射的在易消化的油如豆油、棉籽油或橄欖油中的活性成分的混合物被泵入明膠以形成含有100mg活性成分的軟明膠膠囊。洗滌和干燥該膠囊。
      片劑大量片劑通過常規(guī)方法制備以至于該劑量單位有100mg活性成分、0.2mg膠態(tài)二氧化硅、5mg硬脂酸鎂、275mg微晶纖維素、11mg淀粉和98.8mg乳糖。適宜的包衣可應(yīng)用于增加口感或延遲吸收。
      本發(fā)明化合物也可用作神經(jīng)功能、機能紊亂和疾病的生化研究的試劑或標(biāo)準(zhǔn)品。
      盡管本發(fā)明已經(jīng)描述和根據(jù)一定的優(yōu)選實施方案舉例說明,其它的實施方案對于那些本領(lǐng)域技術(shù)人員是顯而易見的。因此,本發(fā)明不局限于所描述和舉例說明的特別實施方案,但是能夠改進(jìn)或變化而不脫離本領(lǐng)域的精神實質(zhì),其全部范圍通過附加的權(quán)利要求書加以描述。
      權(quán)利要求
      1.式(I)化合物
      或其立體異構(gòu)體或藥學(xué)上可接受的鹽形式,其中A為N或C-R7;B為N或C-R8;前提是基團(tuán)A和B中至少一個為ND為通過不飽和碳原子連接的芳基或雜芳基;X選自基團(tuán)CH-R9、N-R10、O、S(O)n和鍵;n為0、1或2;R1選自基團(tuán)C1-10烷基、C2-10鏈烯基、C2-10炔基、C3-8環(huán)烷基、C3-6環(huán)烷基-C1-6烷基、C1-4烷氧基-C1-4烷基、-SO2-C1-10烷基、-SO2-R1a和-SO2-R1b;R1由0-1個選自基團(tuán)-CN、-S(O)nR14b、-COR13a、-CO2R13a、-NR15aCOR13a、-N(COR13a)2、-NR15aCONR13aR16a、-NR15aCO2R14b、-CONR13aR16a、1-嗎啉基、1-哌啶基、1-哌嗪基和C3-8環(huán)烷基的取代基取代,其中在C4-8環(huán)烷基中的0-1個碳原子由選自-O-、-S(O)n-、-NR13a-、-NCO2R14b-、-NCOR14b-和-NSO2R14b-的基團(tuán)替代,并且其中在1-哌嗪基中的N4由0-1個選自基團(tuán)R13a、CO2R14b、COR14b和SO2R14b的取代基取代;R1也由0-3個在每一個情況下獨立選自基團(tuán)R1a、R1b、R1c、C1-6烷基、C2-8鏈烯基、C2-8炔基、Br、Cl、F、I、C1-4鹵代烷基、-OR13a、-NR13aR16a、C1-4烷氧基-C1-4烷基和由0-1個R9取代的C3-8環(huán)烷基的取代基取代并且其中C4-8環(huán)烷基的0-1個碳由-O-替代;前提為R1不是(a)環(huán)己基-(CH2)2-基團(tuán);(b)3-環(huán)丙基-3-甲氧基丙基;(c)不飽和-(烷氧基)甲基;和(d)1-羥基烷基;另外的前提是當(dāng)R1烷基由OH取代時,那么鄰近該環(huán)N的碳不是CH2;R1a為芳基并且選自基團(tuán)苯基、萘基、2,3-二氫化茚基和茚基,每一個R1a由0-1個-OR17和0-5個在每一個情況下獨立選自基團(tuán)C1-6烷基、C3-6環(huán)烷基、Br、Cl、F、I、C1-4鹵代烷基、-CN、硝基、SH、-S(O)nR18、-COR17、-OC(O)R18、-NR15aCOR17、-N(COR17)2、-NR15aCONR17aR19a、-NR15aCO2R18、-NR17aR19a和-CONR17aR19a的取代基取代;R1b為雜芳基并且選自基團(tuán)吡啶基、嘧啶基、三嗪基、呋喃基、喹啉基、異喹啉基、噻吩基、咪唑基、噻唑基、吲哚基、吡咯基、噁唑基、苯并呋喃基、苯并噻吩基、苯并噻唑基、苯并噁唑基、異噁唑基、吡唑基、三唑基、四唑基、吲唑基、2,3-二氫苯并呋喃基、2,3-二氫苯并噻吩基、2,3-二氫苯并噻吩基-S-氧化物、2,3-二氫苯并噻吩基-S-二氧化物、二氫吲哚基、苯并噁唑啉-2-酮基、苯并二氧戊環(huán)基和苯并二噁烷,每一個雜芳基在0-4個碳原子上由在每一個情況下獨立選自基團(tuán)C1-6烷基、C3-6環(huán)烷基、Br、Cl、F、I、C1-4鹵代烷基、-CN、硝基、-OR17、SH、-S(O)mR18、-COR17、-OC(O)R18、-NR15aCOR17、-N(COR17)2、-NR15aCONR17aR19a、-NR15aCO2R18、-NR17aR19a和-CONR17aR19a的取代基取代,并且每一個雜芳基在任何氮原子上由0-1個選自基團(tuán)R15a、CO2R14b、COR14b和SO2R14b的取代基取代;R1c為雜環(huán)基并且為飽和的或部分飽和的雜芳基,每個雜環(huán)基在0-4個碳原子上由在每一個情況下獨立選自基團(tuán)C1-6烷基、C3-6環(huán)烷基、Br、Cl、F、I、C1-4鹵代烷基、-CN、硝基、-OR13a、SH、-S(O)nR14b、-COR13a、-OC(O)R14b、-NR15aCOR13a、-N(COR13a)2、-NR15aCONR13aR16a、-NR15aCO2R14b、-NR13aR16a和-CONR13aR16a的取代基取代,并且每一個雜芳基在任何氮原子上由0-1個選自基團(tuán)R13a、CO2R14b、COR14b和SO2R14b的取代基取代并且其中任何硫原子任選地單氧化或雙氧化;前提為R1不是-(CH2)1-4-芳基、-(CH2)1-4-雜芳基或-(CH2)1-4-雜環(huán),其中所述芳基、雜芳基或雜環(huán)基團(tuán)為取代的或未取代的;R2選自基團(tuán)C1-4烷基、C3-8環(huán)烷基、C2-4鏈烯基、和C2-4炔基并且由0-3個選自基團(tuán)-CN、羥基、鹵代和C1-4烷氧基的取代基取代;或者在其中X為鍵的情況下,R2選自基團(tuán)-CN、CF3和C2F5;R3、R7和R8在每一個情況下獨立選自基團(tuán)H、Br、Cl、F、I、-CN、C1-4烷基、C3-8環(huán)烷基、C1-4烷氧基、C1-4烷硫基、C1-4烷基亞硫?;1-4烷基磺?;?、氨基、C1-4烷基氨基、(C1-4烷基)2氨基和苯基,每一個苯基由0-3個選自基團(tuán)C1-7烷基、C3-8環(huán)烷基、Br、Cl、F、I、C1-4鹵代烷基、硝基、C1-4烷氧基、C1-4鹵代烷氧基、C1-4烷硫基、C1-4烷基亞硫酰基、C1-4烷基磺?;?、C1-6烷基氨基和(C1-4烷基)2氨基的取代基取代;前提是R1為未取代的C1-10烷基時,那么R3不是取代的未取代的苯基;R9和R10在每一個情況下獨立選自基團(tuán)H、C1-4烷基、C3-6環(huán)烷基-C1-4烷基和C3-8環(huán)烷基;R13選自基團(tuán)H、C1-4烷基、C1-4鹵代烷基、C1-4烷氧基-C1-4烷基、C3-6環(huán)烷基、C3-6環(huán)烷基-C1-6烷基、芳基、芳基(C1-4烷基)-、雜芳基和雜芳基(C1-4烷基)-;R13a和R16a在每一個情況下獨立選自基團(tuán)H、C1-4烷基、C1-4鹵代烷基、C1-4烷氧基-C1-4烷基、C3-6環(huán)烷基和C3-6環(huán)烷基-C1-6烷基;R14選自基團(tuán)C1-4烷基、C1-4鹵代烷基、C1-4烷氧基-C1-4烷基、C3-6環(huán)烷基、C3-6環(huán)烷基-C1-6烷基、芳基、芳基(C1-4烷基)-、雜芳基和雜芳基(C1-4烷基)-和芐基,每一個芐基在該芳基部分上由0-1個選自基團(tuán)C1-4烷基、Br、Cl、F、I、C1-4鹵代烷基、硝基、C1-4烷氧基C1-4鹵代烷氧基和二甲基氨基的取代基取代;R14a選自基團(tuán)C1-4烷基、C1-4鹵代烷基、C1-4烷氧基-C1-4烷基、C3-6環(huán)烷基、C3-6環(huán)烷基-C1-6烷基和芐基,每一個芐基在該芳基部分上由0-1個選自基團(tuán)C1-4烷基、Br、Cl、F、I、C1-4鹵代烷基、硝基、C1-4烷氧基、C1-4鹵代烷氧基和二甲基氨基的取代基取代;R14b選自基團(tuán)C1-4烷基、C1-4鹵代烷基、C1-4烷氧基-C1-4烷基、C3-6環(huán)烷基和C3-6環(huán)烷基-C1-6烷基;R15在每一個情況下獨立選自基團(tuán)H、C1-4烷基、C3-7環(huán)烷基、C3-6環(huán)烷基-C1-6烷基、苯基和芐基,每一個苯基或芐基在該芳基部分上由0-3個選自C1-4烷基、Br、Cl、F、I、C1-4鹵代烷基、硝基、C1-4烷氧基、C1-4鹵代烷氧基和二甲基氨基的基團(tuán)取代;R15a在每一個情況下獨立選自基團(tuán)H、C1-4烷基、C3-7環(huán)烷基和C3-6環(huán)烷基-C1-6烷基;R17在每一個情況下選自基團(tuán)H、C1-6烷基、C3-10環(huán)烷基、C3-6環(huán)烷基-C1-6烷基、C1-2烷氧基-C1-2烷基、C1-4鹵代烷基、R14S(O)n-C1-4烷基和R17bR19bN-C2-4烷基;R18和R19在每一個情況下獨立選自基團(tuán)H、C1-6烷基、C3-10環(huán)烷基、C3-6環(huán)烷基-C1-6烷基、C1-2烷氧基-C1-2烷基和C1-4鹵代烷基;或者,在NR17R19部分中,R17和R19一起形成1-吡咯烷基、1-嗎啉基、1-哌啶基或1-哌嗪基,其中在1-哌嗪基中的N4由0-1個選自基團(tuán)R13、CO2R14、COR14和SO2R14的取代基取代;或者,在NR17bR19b部分中,R17b和R19b一起形成1-吡咯烷基、1-嗎啉基、1-哌啶基或1-哌嗪基,其中在1-哌嗪基中的N4由0-1個選自基團(tuán)R13、CO2R14、COR14和SO2R14的取代基取代;R17a和R19a在每一個情況下獨立選自基團(tuán)H、C1-6烷基、C3-10環(huán)烷基、C3-6環(huán)烷基-C1-6烷基和C1-4鹵代烷基;芳基在每一個情況下獨立選自基團(tuán)苯基、萘基、2,3-二氫化茚基和茚基,每一個芳基由0-5個在每一個情況下獨立選自基團(tuán)C1-6烷基、C3-6環(huán)烷基、亞甲二氧基、C1-4烷氧基-C1-4烷氧基、-OR17、Br、Cl、F、I、C1-4鹵代烷基、-CN、-NO2、SH、-S(O)nR18、-COR17、-CO2R17、-OC(O)R18、-NR15COR17、-N(COR17)2、-NR15CONR17R19、-NR15CO2R18、-NR17R19和-CONR17R19和一個苯基的取代基取代,每一個苯基取代基由0-4個選自基團(tuán)C1-3烷基、C1-3烷氧基、Br、Cl、F、I、-CN、二甲基氨基、CF3、C2F5、OCF3、SO2Me和乙?;娜〈〈?;雜芳基在每一個情況下獨立選自基團(tuán)吡啶基、嘧啶基、三嗪基、呋喃基、喹啉基、異喹啉基、噻吩基、咪唑基、噻唑基、吲哚基、吡咯基、噁唑基、苯并呋喃基、苯并噻吩基、苯并噻唑基、苯并噁唑基、異噁唑基、三唑基、四唑基、吲唑基、2,3-二氫苯并呋喃基、2,3-二氫苯并噻吩基、2,3-二氫苯并噻吩基-S-氧化物、2,3-二氫苯并噻吩基-S-二氧化物、二氫吲哚基、苯并噁唑啉-2-酮基、苯并二氧戊環(huán)基和苯并二噁烷,每一個雜芳基在0-4個碳原子上由在每一個情況下獨立選自基團(tuán)C1-6烷基、C3-6環(huán)烷基、Br、Cl、F、I、C1-4鹵代烷基、-CN、硝基、-OR17、SH、-S(O)mR18、-COR17、-CO2R17、-OC(O)R18、-NR15COR17、-N(COR17)2、-NR15CONR17R19、-NR15CO2R18、-N17R19和-CONR17R19的取代基取代,并且每一個雜芳基在任何氮原子上由0-1個選自基團(tuán)R15、CO2R14a、COR14a和SO2R14a的取代基取代;和前提是當(dāng)D為咪唑或三唑時,R1不是未取代的C1-6線性的或分枝的烷基或C3-6環(huán)烷基。
      2.權(quán)利要求1的化合物,其中該化合物具有式Ia
      3.權(quán)利要求1的化合物,其中該化合物具有式Ib
      4.權(quán)利要求1的化合物,其中該化合物具有式Ic
      5.藥用組合物,包括藥學(xué)上可接受的載體和治療有效量的式(I)的化合物
      或其立體異構(gòu)體或藥學(xué)上可接受的鹽形式,其中A為N或C-R7;B為N或C-R8;前提是基團(tuán)A和B中至少一個為N;D為通過不飽和碳原子連接的芳基或雜芳基;X選自基團(tuán)CH-R9、N-R10、O、S(O)n和鍵;n為0、1或2;R1選自基團(tuán)C1-10烷基、C2-10鏈烯基、C2-10炔基、C3-8環(huán)烷基、C3-6環(huán)烷基-C1-6烷基、C1-4烷氧基-C1-4烷基、-SO2-C1-10烷基、-SO2-R1a和-SO2-R1b;R1由0-1個選自基團(tuán)-CN、-S(O)nR14b、-COR13a、-CO2R13a、-NR15aCOR13a、-N(COR13a)2、-NR15aCONR13aR16a、-NR15aCO2R14b、-CONR13aR16a、1-嗎啉基、1-哌啶基、1-哌嗪基和C3-8環(huán)烷基的取代基取代,其中在C4-8環(huán)烷基中的0-1個碳原子由選自-O-、-S(O)n-、-NR13a-、-NCO2R14b-、-NCOR14b-和-NSO2R14b-的基團(tuán)來替代,并且其中在1-哌嗪基中的N4由0-1個選自基團(tuán)R13a、CO2R14b、COR14b和SO2R14b的取代基取代;R1也由0-3個在每一個情況下獨立選自基團(tuán)R1a、R1b、R1c、C1-6烷基、C2-8鏈烯基、C2-8炔基、Br、Cl、F、I、C1-4鹵代烷基、-OR13a、-NR13aR16a、C1-4烷氧基-C1-4烷基和由0-1個R9取代的C3-8環(huán)烷基的取代基取代并且其中C4-8環(huán)烷基的0-1個碳由-O-替代;前提為R1不是(a)3-環(huán)丙基-3-甲氧基丙基;(b)未取代的-(烷氧基)甲基;和(c)1-羥基烷基;另外的前提是當(dāng)R1烷基由OH取代時,那么鄰近該環(huán)N的碳不是CH2;R1a為芳基并且選自基團(tuán)苯基、萘基、2,3-二氫化茚基和茚基,每一個R1a由0-5個在每一個情況下獨立選自基團(tuán)C1-6烷基、C3-6環(huán)烷基、Br、Cl、F、I、C1-4鹵代烷基、-CN、硝基、-OR17、SH、-S(O)nR18、-COR17、-OC(O)R18、-NR15aCOR17、-N(COR17)2、-NR15aCONR17aR19a、-NR15aCO2R18、-NR17aR19a和-CONR17aR19a的取代基取代;R1b為雜芳基并且選自基團(tuán)吡啶基、嘧啶基、三嗪基、呋喃基、喹啉基、異喳啉基、噻吩基、咪唑基、噻唑基、吲哚基、吡咯基、噁唑基、苯并呋喃基、苯并噻吩基、苯并噻唑基、苯并噁唑基、異噁唑基、吡唑基、三唑基、四唑基、吲唑基、2,3-二氫苯并呋喃基、2,3-二氫苯并噻吩基、2,3-二氫苯并噻吩基-S-氧化物、2,3-二氫苯并噻吩基-S-二氧化物、二氫吲哚基、苯并噁唑啉-2-酮基、苯并二氧戊環(huán)基和苯并二噁烷,每一個雜芳基在0-4個碳原子上由在每一個情況下獨立選自基團(tuán)C1-6烷基、C3-6環(huán)烷基、Br、Cl、F、I、C1-4鹵代烷基、-CN、硝基、-OR17、SH、-S(O)mR18、-COR17、-OC(O)R18、-NR15aCOR17、-N(COR17)2、-NR15aCONR17aR19a、-NR15aCO2R18、-NR17aR19a和-CONR17aR19a的取代基來取代,并且每一個雜芳基在任何氮原子上由0-1個選自基團(tuán)R15a、CO2R14b、COR14b和SO2R14b的取代基取代;R1c為雜環(huán)基并且為飽和的或部分飽和的雜芳基,每個雜環(huán)基在0-4個碳原子上由在每一個情況下獨立選自基團(tuán)C1-6烷基、C3-6環(huán)烷基、Br、Cl、F、I、C1-4鹵代烷基、-CN、硝基、-OR13a、SH、-S(O)nR14b、-COR13a、-OC(O)R14b、-NR15aCOR13a、-N(COR13a)2、-NR15aCONR13aR16a、-NR15aCO2R14b、-NR13aR16a和-CONR13aR16a的取代基取代,并且每一個雜芳基在任何氮原子上由0-1個選自基團(tuán)R13a、CO2R14b、COR14b和SO2R14b的取代基取代并且其中任何硫原子任選地單氧化或雙氧化;R2選自基團(tuán)C1-4烷基、C3-8環(huán)烷基、C2-4鏈烯基和C2-4炔基并且由0-3個選自基團(tuán)-CN、羥基、鹵代和C1-4烷氧基的取代基取代;或者在其中X為鍵的情況下,R2選自基團(tuán)-CN、CF3和C2F5;R3、R7和R8在每一個情況下獨立選自基團(tuán)H、Br、Cl、F、I、-CN、C1-4烷基、C3-8環(huán)烷基、C1-4烷氧基、C1-4烷硫基、C1-4烷基亞硫?;1-4烷基磺?;?、氨基、C1-4烷基氨基、(C1-4烷基)2氨基和苯基,每一個苯基由0-3個選自C1-7烷基、C3-8環(huán)烷基、Br、Cl、F、I、C1-4鹵代烷基、硝基、C1-4烷氧基、C1-4鹵代烷氧基、C1-4烷硫基、C1-4烷基亞硫?;1-4烷基磺?;1-6烷基氨基和(C1-4烷基)2氨基的取代基取代;前提是當(dāng)R1為未取代的C1-10烷基時,那么R3不是取代的或未取代的苯基;R9和R10在每一個情況下獨立選自基團(tuán)H、C1-4烷基、C3-6環(huán)烷基-C1-4烷基和C3-8環(huán)烷基;R13選自基團(tuán)H、C1-4烷基、C1-4鹵代烷基、C1-4烷氧基-C1-4烷基、C3-6環(huán)烷基、C3-6環(huán)烷基-C1-6烷基、芳基、芳基(C1-4烷基)-、雜芳基和雜芳基(C1-4烷基)-;R13a和R16a在每一個情況下獨立選自基團(tuán)H、C1-4烷基、C1-4鹵代烷基、C1-4烷氧基-C1-4烷基、C3-6環(huán)烷基和C3-6環(huán)烷基-C1-6烷基;R14選自基團(tuán)C1-4烷基、C1-4鹵代烷基、C1-4烷氧基-C1-4烷基、C3-6環(huán)烷基、C3-6環(huán)烷基-C1-6烷基、芳基、芳基(C1-4烷基)-、雜芳基和雜芳基(C1-4烷基)-和芐基,每一個芐基在該芳基部分上由0-1個選自基團(tuán)C1-4烷基、Br、Cl、F、I、C1-4鹵代烷基、硝基、C1-4烷氧基、C1-4鹵代烷氧基和二甲基氨基的取代基取代;R14a選自基團(tuán)C1-4烷基、C1-4鹵代烷基、C1-4烷氧基-C1-4烷基、C3-6環(huán)烷基、C3-6環(huán)烷基-C1-6烷基和芐基,每一個芐基在該芳基部分上由0-1個選自基團(tuán)C1-4烷基、Br、Cl、F、I、C1-4鹵代烷基、硝基、C1-4烷氧基、C1-4鹵代烷氧基和二甲基氨基的取代基取代;R14b選自基團(tuán)C1-4烷基、C1-4鹵代烷基、C1-4烷氧基-C1-4烷基、C3-6環(huán)烷基和C3-6環(huán)烷基-C1-6烷基;R15在每一個情況下獨立選自基團(tuán)H、C1-4烷基、C3-7環(huán)烷基、C3-6環(huán)烷基-C1-6烷基、苯基和芐基,每一個苯基或芐基在該芳基部分上由0-3個選自C1-4烷基、Br、Cl、F、I、C1-4鹵代烷基、硝基、C1-4烷氧基、C1-4鹵代烷氧基和二甲基氨基的基團(tuán)取代;R15a在每一個情況下獨立選自基團(tuán)H、C1-4烷基、C3-7環(huán)烷基和C3-6環(huán)烷基-C1-6烷基;R17在每一個情況下選自基團(tuán)H、C1-6烷基、C3-10環(huán)烷基、C3-6環(huán)烷基-C1-6烷基、C1-2烷氧基-C1-2烷基、C1-4鹵代烷基、R14S(O)n-C1-4烷基和R17bR19bN-C2-4烷基;R18和R19在每一個情況下獨立選自基團(tuán)H、C1-6烷基、C3-10環(huán)烷基、C3-6環(huán)烷基-C1-6烷基、C1-2烷氧基-C1-2烷基和C1-4鹵代烷基;或者,在NR17R19部分中,R17和R19一起形成1-吡咯烷基、1-嗎啉基、1-哌啶基或1-哌嗪基,其中在1-哌嗪基中的N4由0-1個選自基團(tuán)R13、CO2R14、COR14和SO2R14的取代基取代;或者,在NR17bR19b部分中,R17b和R19b一起形成1-吡咯烷基、1-嗎啉基、1-哌啶基或1-哌嗪基,其中在1-哌嗪基中的N4由0-1個選自基團(tuán)R13、CO2R14、COR14和SO2R14的取代基取代;R17a和R19a在每一個情況下獨立選自基團(tuán)H、C1-6烷基、C3-10環(huán)烷基、C3-6環(huán)烷基-C1-6烷基和C1-4鹵代烷基;芳基在每一個情況下獨立選自基團(tuán)苯基、萘基、2,3-二氫化茚基和茚基,每一個芳基由0-5個在每一個情況下獨立選自基團(tuán)C1-6烷基、C3-6環(huán)烷基、亞甲二氧基、C1-4烷氧基-C1-4烷氧基、-OR17、Br、Cl、F、I、C1-4鹵代烷基、-CN、-NO2、SH、-S(O)nR18、-COR17、CO2R17、-OC(O)R18、-NR15COR17、-N(COR17)2、-NR15CONR17R19、-NR15CO2R18、-NR17R19和-CONR17R19和一個苯基的取代基取代,每一個苯基取代基由0-4個選自基團(tuán)C1-3烷基、C1-3烷氧基、Br、Cl、F、I、-CN、二甲基氨基、CF3、C2F5、OCF3、SO2Me和乙?;娜〈〈?;和雜芳基在每一個情況下獨立選自基團(tuán)吡啶基、嘧啶基、三嗪基、呋喃基、喹啉基、異喹啉基、噻吩基、咪唑基、噻唑基、吲哚基、吡咯基、噁唑基、苯并呋喃基、苯并噻吩基、苯并噻唑基、苯并噁唑基、異噁唑基、三唑基、四唑基、吲唑基、2,3-二氫苯并呋喃基、2,3-二氫苯并噻吩基、2,3-二氫苯并噻吩基-S-氧化物、2,3-二氫苯并噻吩基-S-二氧化物、二氫吲哚基、苯并噁唑啉-2-酮基、苯并二氧戊環(huán)基和苯并二噁烷,每一個雜芳基在0-4個碳原子上由在每一個情況下獨立選自基團(tuán)C1-6烷基、C3-6環(huán)烷基、Br、Cl、F、I、C1-4鹵代烷基、-CN、硝基、-OR17a、SH、-S(O)mR18、-COR17、-CO2R17、-OC(O)R18、-NR15COR17、-N(COR17)2、-NR15CONR17R19、-NR15CO2R18、-NR17R19和-CONR17R19的取代基取代,并且每一個雜芳基在任何氮原子上由0-1個選自基團(tuán)R15、CO2R14a、COR14a和SO2R14a的取代基取代。
      6.在哺乳動物中治療情感障礙、焦慮、抑郁、頭疼、過敏性腸道綜合征、突觸后應(yīng)激失調(diào)、核上麻痹、免疫抑制、阿爾滋海默氏病、胃腸道疾病、神經(jīng)性厭食或其它飲食失調(diào)、藥物濫用、藥物或酒精戒癮癥狀、炎性疾病、心血管或與心臟相關(guān)的疾病、生育問題、人免疫缺陷病毒感染、出血性緊張、肥胖癥、不育、頭和脊髓創(chuàng)傷、癲癇、中風(fēng)、潰瘍、肌肉萎縮外側(cè)硬化癥、血糖過少或能夠通過拮抗CRF而影響或促進(jìn)治療的疾病的方法,包括(但不局限于)治療由CRF介導(dǎo)或促進(jìn)的疾病的方法,該方法包括給子所述哺乳動物治療有效量的式(I)化合物
      或其立體異構(gòu)體或藥學(xué)上可接受的鹽形式,其中A為N或C-R7;B為N或C-R8;前提是基團(tuán)A和B中至少一個為N;D為通過不飽和碳原子連接的芳基或雜芳基;X選自基團(tuán)CH-R9、N-R10、O、S(O)n和鍵;n為0、1或2;R1選自基團(tuán)C1-10烷基、C2-10鏈烯基、C2-10炔基、C3-8環(huán)烷基、C3-6環(huán)烷基-C1-6烷基、C1-4烷氧基-C1-4烷基、-SO2-C1-10烷基、-SO2-R1a和-SO2-R1b;R1以0-1個選自基團(tuán)-CN、-S(O)nR14b、-COR13b、-CO2R13a、-NR15aCOR13a、-N(COR13a)2、-NR15aCONR13aR16a、-NR15aCO2R14b、-CONR13aR16a、1-嗎啉基、1-哌啶基、1-哌嗪基和C3-8環(huán)烷基的取代基取代,其中在C4-8環(huán)烷基中的0-1個碳原子由選自-O-、-S(O)n-、-NR13a-、-NCO2R14b-、-NCOR14b-和-NSO2R14b-的基團(tuán)替代,并且其中在1-哌嗪基中的N4由0-1個選自基團(tuán)R13a、CO2R14b、COR14b和SO2R14b的取代基取代;R1也由0-3個在每一個情況下獨立選自基團(tuán)R1a、R1b、R1c、C1-6烷基、C2-8鏈烯基、C2-8炔基、Br、Cl、F、I、C1-4鹵代烷基、-OR13a、-NR13aR16a、C1-4烷氧基-C1-4烷基和由0-1個R9取代的C3-8環(huán)烷基的取代基取代并且其中C4-8環(huán)烷基的0-1個碳由-O-替代;前提為R1不是(a)3-環(huán)丙基-3-甲氧基丙基;(b)未取代的-(烷氧基)甲基;和(c)1-羥基烷基;另外的前提是當(dāng)R1烷基由OH取代時,那么鄰近該環(huán)N的碳不是CH2;R1a為芳基并且選自基團(tuán)苯基、萘基、2,3-二氫化茚基和茚基,每一個R1a由0-5個在每一個情況下獨立選自C1-6烷基、C3-6環(huán)烷基、Br、Cl、F、I、C1-4鹵代烷基、-CN、硝基、-OR17、SH、-S(O)nR18、-COR17、-OC(O)R18、-NR15aCOR17、-N(COR17)2、-NR15aCONR17aR19a、-NR15aCO2R18、-NR17aR19a和-CONR17aR19a的取代基取代;R1b為雜芳基并且選自基團(tuán)吡啶基、嘧啶基、三嗪基、呋喃基、喹啉基、異喹啉基、噻吩基、咪唑基、噻唑基、吲哚基、吡咯基、噁唑基、苯并呋喃基、苯并噻吩基、苯并噻唑基、苯并噁唑基、異噁唑基、吡唑基、三唑基、四唑基、吲唑基、2,3-二氫苯并呋喃基、2,3-二氫苯并噻吩基、2,3-二氫苯并噻吩基-S-氧化物、2,3-二氫苯并噻吩基-S-二氧化物、二氫吲哚基、苯并噁唑啉-2-酮基、苯并二氧戊環(huán)基和苯并二噁烷,每一個雜芳基在0-4個碳原子上由在每一個情況下獨立選自基團(tuán)C1-6烷基、C3-6環(huán)烷基、Br、Cl、F、I、C1-4鹵代烷基、-CN、硝基、-OR17、SH、-S(O)mR18、-COR17、-OC(O)R18、-NR15aCOR17、-N(COR17)2、-NR15aCONR17aR19a、-NR15aCO2R18、-NR17aR19a和-CONR17aR19a的取代基取代,并且每一個雜芳基在任何氮原子上由0-1個選自基團(tuán)R15a、CO2R14b、COR14b和SO2R14b的取代基取代;R1c為雜環(huán)基并且為飽和的或部分飽和的雜芳基,每個雜環(huán)基在0-4個碳原子上由在每一個情況下獨立選自基團(tuán)C1-6烷基、C3-6環(huán)烷基、Br、Cl、F、I、C1-4鹵代烷基、-CN、硝基、-OR13a、SH、-S(O)nR14b、-COR13a、-OC(O)R14b、-NR15aCOR13a、-N(COR13a)2、-NR15aCONR13aR16a、-NR15aCO2R14b、-NR13aR16a和-CONR13aR16a的取代基取代,并且每一個雜芳基在任何氮原子上由0-1個選自基團(tuán)R13a、CO2R14b、COR14b和SO2R14b的取代基取代并且其中任何硫原子任選地單氧化或雙氧化;R2選自基團(tuán)C1-4烷基、C3-8環(huán)烷基、C2-4鏈烯基和C2-4炔基并且由0-3個選自基團(tuán)-CN、羥基、鹵代和C1-4烷氧基的取代基取代;或者在其中X為鍵的情況下,R2選自基團(tuán)-CN、CF3和C2F5;R3、R7和R8在每一個情況下獨立選自基團(tuán)H、Br、Cl、F、I、-CN、C1-4烷基、C3-8環(huán)烷基、C1-4烷氧基、C1-4烷硫基、C1-4烷基亞硫?;?、C1-4烷基磺?;?、氨基、C1-4烷基氨基、(C1-4烷基)2氨基和苯基、每一個苯基由0-3個選自C1-7烷基、C3-8環(huán)烷基、Br、Cl、F、I、C1-4鹵代烷基、硝基、C1-4烷氧基、C1-4鹵代烷氧基、C1-4烷硫基、C1-4烷基亞硫酰基、C1-4烷基磺酰基、C1-6烷基氨基和(C1-4烷基)2氨基的基團(tuán)取代;前提是當(dāng)R1為未取代的C1-10烷基時,那么R3不是取代的或未取代的苯基;R9和R10在每一個情況下獨立選自基團(tuán)H、C1-4烷基、C3-6環(huán)烷基-C1-4烷基和C3-8環(huán)烷基;R13選自基團(tuán)H、C1-4烷基、C1-4鹵代烷基、C1-4烷氧基-C1-4烷基、C3-6環(huán)烷基、C3-6環(huán)烷基-C1-6烷基、芳基、芳基(C1-4烷基)-、雜芳基和雜芳基(C1-4烷基)-;R13a和R16a在每一個情況下獨立選自基團(tuán)H、C1-4烷基、C1-4鹵代烷基、C1-4烷氧基-C1-4烷基、C3-6環(huán)烷基和C3-6環(huán)烷基-C1-6烷基;R14選自基團(tuán)C1-4烷基、C1-4鹵代烷基、C1-4烷氧基-C1-4烷基、C3-6環(huán)烷基、C3-6環(huán)烷基-C1-6烷基、芳基、芳基(C1-4烷基)-、雜芳基和雜芳基(C1-4烷基)-和芐基,每一個芐基在該芳基部分上由0-1個選自基團(tuán)C1-4烷基、Br、Cl、F、I、C1-4鹵代烷基、硝基、C1-4烷氧基、C1-4鹵代烷氧基和二甲基氨基的取代基取代;R14a選自基團(tuán)C1-4烷基、C1-4鹵代烷基、C1-4烷氧基-C1-4烷基、C3-6環(huán)烷基、C3-6環(huán)烷基-C1-6烷基和芐基,每一個芐基在該芳基部分上由0-1個選自基團(tuán)C1-4烷基、Br、Cl、F、I、C1-4鹵代烷基、硝基、C1-4烷氧基、C1-4鹵代烷氧基和二甲基氨基的取代基取代;R14b選自基團(tuán)C1-4烷基、C1-4鹵代烷基、C1-4烷氧基-C1-4烷基、C3-6環(huán)烷基和C3-6環(huán)烷基-C1-6烷基;R15在每一個情況下獨立選自基團(tuán)H、C1-4烷基、C3-7環(huán)烷基、C3-6環(huán)烷基-C1-6烷基、苯基和芐基,每一個苯基或芐基在該芳基部分上由0-3個選自C1-4烷基、Br、Cl、F、I、C1-4鹵代烷基、硝基、C1-4烷氧基、C1-4鹵代烷氧基和二甲基氨基的基團(tuán)來取代;R15a在每一個情況下獨立選自基團(tuán)H、C1-4烷基、C3-7環(huán)烷基和C3-6環(huán)烷基-C1-6烷基;R17在每一個情況下選自基團(tuán)H、C1-6烷基、C3-10環(huán)烷基、C3-6環(huán)烷基-C1-6烷基、C1-2烷氧基-C1-2烷基、C1-4鹵代烷基、R14S(O)n-C1-4烷基和R17bR19bN-C2-4烷基;R18和R19在每一個情況下獨立選自基團(tuán)H、C1-6烷基、C3-10環(huán)烷基、C3-6環(huán)烷基-C1-6烷基、C1-2烷氧基-C1-2烷基和C1-4鹵代烷基;或者,在NR17R19部分中,R17和R19一起形成1-吡咯烷基、1-嗎啉基、1-哌啶基或1-哌嗪基,其中在1-哌嗪基中的N4由0-1個選自基團(tuán)R13、CO2R14、COR14和SO2R14的取代基取代;或者,在NR17bR19b部分中,R17b和R19b一起形成1-吡咯烷基、1-嗎啉基、1-哌啶基或1-哌嗪基,其中在1-哌嗪基中的N4由0-1個選自基團(tuán)R13、CO2R14、COR14和SO2R14的取代基取代;R17a和R19a在每一個情況下獨立選自基團(tuán)H、C1-6烷基、C3-10環(huán)烷基、C3-6環(huán)烷基-C1-6烷基和C1-4鹵代烷基;芳基在每一個情況下獨立選自基團(tuán)苯基、萘基、2,3-二氫化茚基和茚基,每一個芳基由0-5個在每一個情況下獨立選自基團(tuán)C1-6烷基、C3-6環(huán)烷基、亞甲二氧基、C1-4烷氧基-C1-4烷氧基、-OR17、Br、Cl、F、I、C1-4鹵代烷基、-CN、-NO2、SH、-S(O)nR18、-COR17、-CO2R17、-OC(O)R18、-NR15COR17、-N(COR17)2、-NR15CONR17R19、-NR15CO2R18、-NR17R19和-CONR17R19和一個苯基的取代基取代,每一個苯基取代基由0-4個選自基團(tuán)C1-3烷基、C1-3烷氧基、Br、Cl、F、I、-CN、二甲基氨基、CF3、C2F5、OCF3、SO2Me和乙?;娜〈〈?;和雜芳基在每一個情況下獨立選自基團(tuán)吡啶基、嘧啶基、三嗪基、呋喃基、喹啉基、異喹啉基、噻吩基、咪唑基、噻唑基、吲哚基、吡咯基、噁唑基、苯并呋喃基、苯并噻吩基、苯并噻唑基、苯并噁唑基、異噁唑基、三唑基、四唑基、吲唑基、2,3-二氫苯并呋喃基、2,3-二氫苯并噻吩基、2,3-二氫苯并噻吩基-S-氧化物、2,3-二氫苯并噻吩基-S-二氧化物、二氫吲哚基、苯并噁唑啉-2-酮基、苯并二氧戊環(huán)基和苯并二噁烷,每一個雜芳基在0-4個碳原子上由在每一個情況下獨立選自基團(tuán)C1-6烷基、C3-6環(huán)烷基、Br、Cl、F、I、C1-4鹵代烷基、-CN、硝基、-OR17、SH、-S(O)mR18、-COR17、-CO2R17、-OC(O)R18、-NR15COR17、-N(COR17)2、-NR15CONR17R19、-NR15CO2R18、-NR17R19和-CONR17R19的取代基取代,并且每一個雜芳基在任何氮原子上由0-1個選自基團(tuán)R15、CO2R14a、COR14a和SO2R14a的取代基取代。
      全文摘要
      式(Ⅰ)的促腎上腺皮質(zhì)激素釋放因子(CRF)拮抗劑和它們在哺乳動物上治療精神紊亂和神經(jīng)疾病、與焦慮相關(guān)的紊亂、創(chuàng)傷后應(yīng)激紊亂、核上麻痹和飲食紊亂以及治療免疫的、心血管的或與心臟相關(guān)的疾病和與精神病理性障礙和應(yīng)激有關(guān)的腸道超敏反應(yīng)的用途。
      文檔編號A61K31/496GK1268137SQ98808584
      公開日2000年9月27日 申請日期1998年7月2日 優(yōu)先權(quán)日1997年7月3日
      發(fā)明者R·G·懷爾德, R·巴克塔瓦特查拉姆, J·P·貝克, A·G·阿沃尼蒂斯 申請人:杜邦藥品公司
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