CN1390206A - 因子Xa的抑制剂 - Google Patents
因子Xa的抑制剂 Download PDFInfo
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- CN1390206A CN1390206A CN00815757A CN00815757A CN1390206A CN 1390206 A CN1390206 A CN 1390206A CN 00815757 A CN00815757 A CN 00815757A CN 00815757 A CN00815757 A CN 00815757A CN 1390206 A CN1390206 A CN 1390206A
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- WROMPOXWARCANT-UHFFFAOYSA-N tfa trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F.OC(=O)C(F)(F)F WROMPOXWARCANT-UHFFFAOYSA-N 0.000 description 1
- 229960004559 theobromine Drugs 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 125000004627 thianthrenyl group Chemical group C1(=CC=CC=2SC3=CC=CC=C3SC12)* 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
- 229930192474 thiophene Natural products 0.000 description 1
- 230000002537 thrombolytic effect Effects 0.000 description 1
- 229960000187 tissue plasminogen activator Drugs 0.000 description 1
- 238000004448 titration Methods 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- 239000012049 topical pharmaceutical composition Substances 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
- 125000004306 triazinyl group Chemical group 0.000 description 1
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 1
- 125000004385 trihaloalkyl group Chemical group 0.000 description 1
- UORVGPXVDQYIDP-UHFFFAOYSA-N trihydridoboron Substances B UORVGPXVDQYIDP-UHFFFAOYSA-N 0.000 description 1
- YFTHZRPMJXBUME-UHFFFAOYSA-N tripropylamine Chemical compound CCCN(CCC)CCC YFTHZRPMJXBUME-UHFFFAOYSA-N 0.000 description 1
- 125000002221 trityl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C([*])(C1=C(C(=C(C(=C1[H])[H])[H])[H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- 239000012588 trypsin Substances 0.000 description 1
- 229960005356 urokinase Drugs 0.000 description 1
- 230000025033 vasoconstriction Effects 0.000 description 1
- 230000009385 viral infection Effects 0.000 description 1
- 229940046010 vitamin k Drugs 0.000 description 1
- PJVWKTKQMONHTI-UHFFFAOYSA-N warfarin Chemical compound OC=1C2=CC=CC=C2OC(=O)C=1C(CC(=O)C)C1=CC=CC=C1 PJVWKTKQMONHTI-UHFFFAOYSA-N 0.000 description 1
- 229960005080 warfarin Drugs 0.000 description 1
- 125000001834 xanthenyl group Chemical group C1=CC=CC=2OC3=CC=CC=C3C(C12)* 0.000 description 1
- BPICBUSOMSTKRF-UHFFFAOYSA-N xylazine Chemical compound CC1=CC=CC(C)=C1NC1=NCCCS1 BPICBUSOMSTKRF-UHFFFAOYSA-N 0.000 description 1
- 229960001600 xylazine Drugs 0.000 description 1
- 239000008096 xylene Substances 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
Classifications
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/72—Nitrogen atoms
- C07D213/75—Amino or imino radicals, acylated by carboxylic or carbonic acids, or by sulfur or nitrogen analogues thereof, e.g. carbamates
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
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- A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
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- A61P7/04—Antihaemorrhagics; Procoagulants; Haemostatic agents; Antifibrinolytic agents
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- C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
- C07C311/15—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings
- C07C311/16—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the sulfonamide groups bound to hydrogen atoms or to an acyclic carbon atom
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- C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
- C07C311/30—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound nitrogen atoms, not being part of nitro or nitroso groups
- C07C311/45—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound nitrogen atoms, not being part of nitro or nitroso groups at least one of the singly-bound nitrogen atoms being part of any of the groups, X being a hetero atom, Y being any atom, e.g. N-acylaminosulfonamides
- C07C311/46—Y being a hydrogen or a carbon atom
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- C07C317/26—Sulfones; Sulfoxides having sulfone or sulfoxide groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton
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- C07C317/38—Sulfones; Sulfoxides having sulfone or sulfoxide groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton with sulfone or sulfoxide groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton having sulfone or sulfoxide groups and amino groups bound to carbon atoms of six-membered aromatic rings being part of the same non-condensed ring or of a condensed ring system containing that ring with the nitrogen atom of at least one amino group being part of any of the groups, X being a hetero atom, Y being any atom, e.g. N-acylaminosulfones
- C07C317/40—Y being a hydrogen or a carbon atom
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- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
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- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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- C07D213/82—Amides; Imides in position 3
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- C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
- C07D217/22—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the nitrogen-containing ring
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- C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
- C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
- C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
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- C07D333/26—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
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- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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Abstract
本发明公开了具有抗哺乳动物因子Xa的活性的新化合物、它们的盐以及与其有关的组合物。该化合物用于体外或体内预防或治疗凝血疾病。
Description
相关申请的交叉引用
根据35 U.S.C.§119(e),本申请要求1999年9月17日提交的美国临时申请60/154,332的优先权利益,该文献引入本文作参考。
技术领域
本发明涉及新的化合物,所述化合物是分离的或者当被装配在凝血酶原酶复合物中时的因子Xa的有效和高选择性的抑制剂。这些化合物表现出对因子Xa而不是其它凝血蛋白酶(例如凝血酶、fVIIa、fIXa)或血纤维蛋白溶解级联(例如纤溶酶原激活物,纤溶酶)的选择性。另一方面,本发明涉及新的含单脒基的化合物,它们的药物学上可接受的盐,及其药物学上可接受的组合物,它们在哺乳动物中用作有效和特异性的凝血抑制剂。在另一方面,本发明涉及用于哺乳动物中以凝血疾病为特征的疾病状态的使用这些抑制剂作为治疗剂的方法。
背景技术
止血、出血的控制通过外科方法进行,或者通过血管收缩和凝血的生理血性质而进行。本发明特别地涉及凝血和方法,所述方法有助于在损伤、炎症、疾病、先天缺陷、机能障碍或其它破坏后保持哺乳动物循环的完整性。虽然血小板和凝血都与血栓形成有关,但凝血级联的某些成分主要负责在血小板聚集和血纤蛋白沉积中涉及的过程的扩增或加速。
凝血酶是凝血级联和止血中的关键酶。凝血酶通过其催化血纤蛋白原转化成血纤蛋白的能力和通过其有效的血小板活化活性而在血栓形成中起主要作用。直接或间接抑制凝血酶活性已经成为近来各种抗凝策略的焦点,如Claeson,G.,"Synthetic Peptides and Peptidomimetics asSubstrates and Inhibitors of Thrombin and Other Proteases in the BloodCoagulation system(合成肽和肽类似物作为凝血酶与凝血系统中的其它蛋白酶的底物和抑制剂)",Blood Coag.Fibrinol.5,411-436(1994)所综述的。目前在临床中使用的几类抗凝剂直接或间接影响凝血酶(即肝素、低分子量肝素、肝素样化合物和香豆素)。
凝血酶原酶复合物,包括因子Xa(一种丝氨酸蛋白酶,其因子X前体的活化形式,且为钙离子结合、含γ羧谷氨酰基(Gla)的、维生素K依赖性凝血糖蛋白族的一员),将酶原凝血酶原转化为活性促凝剂凝血酶。与作用于各种蛋白质底物和特异性受体的凝血酶不同,因子Xa似乎具有单一的生理学底物,即凝血酶原。由于一分子的因子Xa能产生高达138分子的凝血酶分子(Elodi等,Thromb.Res.15,617-619(1979)),直接抑制因子Xa作为间接抑制凝血酶形成的方法可能是一种有效的抗凝策略。因此,已经提出选择性地抑制因子Xa的化合物可以用作体外诊断试剂,或者用于某种血栓形成疾病的治疗给药,参见例如WO94/13693。
已经报道来自血液寄生生物的多肽,它们是因子Xa的高效和特异性的抑制剂。美国专利4,588,587描述了墨西哥水蛭Haementeria officinalis的唾液中的抗凝活性。Nutt,E.等,"The Amino Acid Sequence ofAntistasin,a Potent Inhibitor of Factor Xa Reveals a Repeated InternalStructure(Antistasin,一种因子Xa的有效的抑制剂的氨基酸序列显示重复的内部结构)",J.Biol.Chem.,
263,10162-10167(1988)证明这种唾液的基本成分是多肽因子Xa抑制剂,antistasin(ATS)。Waxman,L.,等,"Tick Anticoagulant Peptide(TAP)is a Novel Inhibitor of Blood CoagulationFactor Xa(蜱抗凝肽(TAP)是凝血因子Xa的一种新的抑制剂)",Science,248,593-596(1990)报道,已从软蜱Ornithidoros moubata的全体提取物中分离出因子Xa的另一种有效而高特异性的抑制剂,称为蜱抗凝肽(TAP)。
也已经报道了不是大肽型抑制剂的因子Xa抑制化合物,包括:Tidwell,R.R.等,"Strategies for Anticoagulation With Synthetic ProteaseInhibitors.Xa Inhibitors Versus Thrombin Inhibitors(采用合成蛋白酶抑制剂Xa抑制剂而非凝血酶抑制剂的抗凝策略)",Thromb.Res.,
19,339-349(1980);Turner,A.D.等,"p-Amidino Esters as Irreversible Inhibitors of FactorIXa and Xa and Thrombin(p-脒基酯作为因子IXa和Xa以及凝血酶的不可逆抑制剂)",Biochemistry,
25,4929-4935(1986);Hitomi,Y.等,"InhibitoryEffect of New Synthetic Protease Inhibitor(FUT-175)on the CoagulationSystem(新的合成蛋白酶抑制剂(FUT-175)对血凝系统的抑制作用)",Haemostasis,
15,164-168(1985);Sturzebecher,J.等,"Synthetic Inhibitorsof Bovine Factor Xa and Thrombin.Comparison of Their AnticoagulantEfficiency(牛因子Xa和凝血酶的合成抑制剂,它们的抗凝效果比较)",Thromb.Res.,
54,245-252(1989);Kam,C.M.等,"Mechanism BasedIsocoumarin Inhibitors for Trypsin and Blood Coagulation Serine Proteases:New Anticoagulants(基于机理的胰蛋白酶和凝血丝氨酸蛋白酶的异香豆素抑制剂:新的凝血剂)",Biochemistry,
27,2547-2557(1988);Hauptmann,J.等,"Comparison of the Anticoagulant and Antithrombotic Effects ofSynthetic Thrombin and Factor Xa Inhibitors(合成凝血酶和因子Xa抑制剂的抗凝血和抗血栓形成作用的比较)",Thromb.Haemost.,
63,220-223(1990),等等。
其它人已经报道了小分子有机化合物的因子Xa抑制剂,如具有脒基取代基的含氮杂环化合物,其中这些化合物的两个官能团可以结合于因子Xa的两个活性部位上。例如,WO 98/28269描述了具有末端C(=NH)-NH2基团的吡唑化合物;WO 97/21437描述了被碱性基取代的苯并咪唑化合物,所述碱性基通过直链或支链亚烷基、-C(=O)或-S(=O)2桥基连接到萘基上;WO 99/10316描述了具有4-苯基-N-烷基脒基-哌啶基和4-苯氧基-N-烷基脒基-哌啶基的化合物,所述基团通过酰胺基亚烷基氨基桥而连接到3-脒基苯基上;而EP 798295描述了具有4-苯氧基-N-烷基脒基-哌啶基的化合物,所述基团通过取代或未取代的氨磺酰或酰胺桥基连接到脒基萘基基团上。
需要用于调节止血,和用于预防和治疗血栓形成以及其它由凝血酶在脉管系统中诱导的病理过程如再狭窄和炎症的有效治疗剂。具体而言,仍需要选择性地抑制因子Xa或其前体的化合物。需要具有不同于先前发现的化合物的桥基和官能团的组合的化合物,特别是选择性地或优先地结合于因子Xa的化合物。期望比结合于凝血酶更高程度地结合于因子Xa的化合物,特别是具有良好生物利用度和/或其他药理学上所希望的性质的化合物。
发明内容
本发明涉及抑制因子Xa的新化合物,它们的药物学上可接受的异构体、盐、水合物、溶剂化物和前药衍生物,及其药物学上可接受的组合物,它们具有特定的生理学性质并在哺乳动物中用作有效和特定凝血抑制剂。另一方面,本发明涉及用于哺乳动物中以不期望的血栓形成为特征的或具有凝血疾病的疾病状态的使用这些抑制剂作为诊断剂或作为治疗剂的方法,如用于治疗或预防任何血栓形成介导的急性冠脉或脑血管综合征,任何在静脉系统中发生的血栓形成综合征,任何凝血病,和任何与体外循环或器械操作法有关的血栓形成并发症,以及用于抑制生物样品凝固。
在某些实施方案中,本发明涉及新的化合物,所述化合物是分离的或当装配在凝血原酶原复合物时的因子Xa的有效和高选择性的抑制剂。这些化合物表现出对因子Xa而不是对凝血级联的其它蛋白酶(例如凝血酶等)或血纤维蛋白溶解级联的其他蛋白酶选择性,并用作诊断剂和抗血栓形成剂。
在一个实施方案中,本发明提供包含5元杂环结构或者包括该5元杂环的二环环系的化合物,所述杂环结构具有1-4个选自于N、O和S的杂原子,而且该二环环系可具有1-4个选自于N、O和S的杂原子,化合物整体具有基本上中性的pH。优选的是,pH为约5-8,更优选为约6-7.5,并最优选为约7.0。根据本发明的化合物相对于凝血级联的其他蛋白酶(如凝血酶等)或者纤维蛋白溶解级联的其他蛋白酶是强效其且选择性的因子Xa抑制剂,并可用作诊断试剂和抗血栓形成剂。本发明化合物的具体实施方案见以下优选实施方案中所述,并包括所有的药物学上可接受的异构体、盐、水合物、溶剂化物和前药衍生物。
在本发明的某些方面,提供了用作诊断剂的化合物。在另一方面,本发明包括包含药学有效量的本发明的化合物和药物学上可接受的载体的药物组合物。在另一方面,本发明包括使用以上化合物和药物组合物用于以下用途的方法:用于预防或治疗哺乳动物中以不期望的血栓形成或凝血过程疾病为特征的疾病状态,或者用于防止保存的血产品和样品的凝固。任选地,本发明的方法包括将该药物组合物与其它治疗剂如抗血栓形成和/或溶解血栓剂和/或抗凝剂一起给药。
具体实施方式
定义
根据本发明和如本文所用,将以下术语定义为以下含义,除非另外明确说明。
术语“链烯基”指三价直链或支链不饱和脂族基。术语“炔基”指包括至少两个通过叁键连接的碳原子的直链或支链脂族基。如果没有特别指明碳数,则链烯基和炔基分别指具有2-12个碳原子的基团。
术语“烷基”指包括直链、支链和环状基的饱和脂族基,其具有特别指明的碳原子数目,或者如果没有特别指明数目,则具有多至12个碳原子。本文所用的术语“环烷基”指具有3至14个碳原子,优选3至7个碳原子的单、二或三环脂族环。
如本文所用,术语“碳环结构”和“C3-16碳环单、二环或三环结构”等分别意指仅有碳原子作为环原子的稳定环结构,其中环结构为选自以下的取代或未取代的基团:具有6个环原子的芳环(“芳基”)稳定单环;环中具有3至7个环原子的稳定单环非芳环;在两个环中总共具有7至12个环原子的稳定二环结构,其中该二环结构选自以下环结构:其中两个环都为芳环的环结构,其中一个环为芳环的环结构,其中两个都为非芳环的环结构;以及在三个环中总共具有10至16个原子的稳定三环结构,其中该三环结构选自:其中三个环为芳环的环结构,其中两个环为芳环的环结构,和其中三个环都为非芳环的环结构。在各情况中,当非芳环存在于单环、二环或三环结构时,它可以独立地为饱和、部分饱和或完全饱和的。这种碳环结构的实例包括,但不限于环丙基、环丁基、环戊基、环己基、金刚烷基、环辛基、[3.3.0]二环辛烷、[4.3.0]二环壬烷、[4.4.0]二环癸烷(十氢萘),[2.2.2]二环辛烷、芴基、苯基、萘基、2,3-二氢化茚基、金刚烷基或四氢萘基(四氢萘)。而且,本文所述的环结构可以通过任何导致稳定结构的碳原子连接到一个或多个所指明的侧基上。与碳环结构一起使用的术语“取代的”指连接到本文所述的环结构的环碳原子上的氢原子可以被一个或多个对于该结构指明的取代基取代,如果这些取代导致稳定的化合物。
术语“碳环结构”中所包含的术语“芳基”指未取代或取代的芳环,所述取代的芳环被1、2或3个选自以下的取代基取代:低级烷氧基、低级烷基、低级烷基氨基、羟基、卤素、氰基、羟基、巯基、硝基、硫代烷氧基、醛(carboxaldehyde)、羧基、烷氧羰基和酰胺(carboxamide),包括但不限于碳环芳基、杂环芳基和联芳等,所有这些基团可以任选地是取代的。优选的芳基包括苯基、卤代苯基、低级烷基苯基、萘基、联苯、菲基和并四苯基。
术语“碳环芳基”中包含的术语“芳基烷基”指一、二或三个具有指定碳原子数目的芳基,附加于具有指定碳原子数目的烷基上。适宜的芳基烷基包括,但不限于苄基、吡啶甲基、萘基甲基、苯乙基、benzyhydryl、三苯甲基等,所有这些基团可以任选地是取代的。
如本文所用,术语“杂环”或“杂环环系”意指取代或未取代的选自以下的基团:稳定的单环,其本身在环中具有5-7个原子,并具有1至4个选自N、O和S的杂原子;稳定的二环结构,其在两个环中总共具有7至12个原子,其中两个环中的至少一个具有1至4个选自于N、O和S的杂原子,包括其中任何所述稳定单环杂环稠合到己烷或苯环上的二环结构;稳定的三环杂环结构,其在三个环中总共具有10至16个原子,其中三个环中的至少一个具有1至4个选自N、O和S的杂原子。存在于这种杂环结构的杂环中的任何氮和硫原子可以被氧化。除非另外指出,术语“杂环”或“杂环环系”包括芳环、以及非芳环,其可以是饱和、部分饱和或完全饱和的非芳环。而且,除非另外指出,术语“杂环环系”包括其中所有环均含有至少一个杂原子的环结构,以及含有至少一个杂原子的环少于环结构中的所有环的结构,例如,术语“杂环环系”包括这样的二环结构,其中一个环为苯环,而另一环具有一个或多个杂原子;以及这样的二环结构,其中两个环每一个均具有至少一个杂原子。而且,本文所述的环结构可以通过任何导致稳定结构的杂原子或碳原子而连接于一个或多个所指明的侧基上。而且,术语“取代的”指本文所述的环结构中的各环的环碳原子或氮原子上的氢原子可以被一个或多个所指明的取代基代替,如果这种代替导致稳定的化合物。环结构中的氮原子可以被季铵化,但这种化合物是特别指明的或者包含在术语特定化合物的“药物学上可接受的盐”内。当单杂环中的O和S原子的总数大于1时,优选这些原子彼此不相邻。优选地,在给定的杂环结构的同一环中有不超过1个O或S环原子。
单环和二环杂环环系的实例依字母顺序为吖啶基、吖辛因基(azocinyl)、苯并咪唑基、苯并呋喃基、苯并噻吩基(benzothiofuranyl)、苯并噻吩基、苯并噁唑基、苯并噻唑基、苯并三唑基、苯并四唑基、苯并异噁唑基、苯并异噻唑基、苯并咪唑啉基、咔唑基、4aH-咔唑基、咔啉基、苯并二氢吡喃基、色烯基、噌啉基、十氢喹啉基、2H,6H-1,5,2-二噻嗪基、二氢呋喃并[2,3-b]四氢呋喃、呋喃基、呋咱基、咪唑烷基、咪唑啉基、咪唑基、1H-吲唑基、二氢吲哚基、中氮茚基、吲哚基、3H-吲哚基、异苯并呋喃基、异苯并二氢吡喃基、异吲唑基、异二氢吲哚基、异吲哚基、异喹啉基(苯并咪唑基)、异噻唑基、异噁唑基、吗啉基、1,5-二氮杂萘基、八氢异喹啉基、噁二唑基、1,2,3-噁二唑基、1,2,4-噁二唑基、1,2,5-噁二唑基、1,3,4-噁二唑基、噁唑烷基、噁唑基、噁唑烷基、嘧啶基、菲啶基、菲咯啉基、吩嗪基、吩噻嗪基、吩氧硫杂环己二烯基(phenoxathiinyl)、吩噁嗪基、2,3-二氮杂萘基、哌嗪基、哌啶基、蝶啶基、嘌呤基、吡喃基、吡嗪基、吡唑烷基、吡唑啉基、吡唑基、哒嗪基、吡啶并噁唑、吡啶并咪唑、吡啶并噻唑、吡啶烷基(pyridinyl)、吡啶基、嘧啶基、吡咯烷基、吡咯啉基、2H-吡咯基、吡咯基、喹唑啉基、喹啉基、4H-喹嗪基、喹喔啉基、奎宁环基、四氢呋喃基、四氢异喹啉基、四氢喹啉基、6H-1,2,5-噻二嗪基(thiadazinyl)、1,2,3-噻二唑基、1,2,4-噻二唑基、1,2,5-噻二唑基、1,3,4-噻二唑基、噻蒽基、噻唑基、噻吩基、噻吩并噻唑基、噻吩并噁唑基、噻吩并咪唑基、噻吩基、三嗪基、1,2,3-三唑基、1,2,4-三唑基、1,2,5-三唑基、1,3,4-三唑基和呫吨基。优选的杂环结构包括但不限于,吡啶基、呋喃基、噻吩基、吡咯基、吡唑基、吡咯烷基、咪唑基、吲哚基、苯并咪唑基、1H-吲唑基、噁唑啉基或靛红基(isatinoyl)。还包括含有例如以上杂环结构的稠环和螺环化合物。
如本文所用,术语“芳香杂环环系”基本上具有与关于单环和二环系统相同的定义,除了该环系统的至少一个环为芳香杂环之外,或者除了该二环具有稠合到芳香碳环结构上的芳香或非芳香杂环之外。
本文所用的术语“卤素”指Cl、Br、F或I取代基。术语“卤代烷基”等指具有至少一个被Cl、Br、F或I原子代替的氢原子的脂族碳基团,包括被不同卤原子的混合物代替。例如,三卤代烷基包括三氟甲基等优选的基团。
术语“亚甲基”指-CH2-。
术语“药物学上可接受的盐”包括衍生自化合物与有机或无机酸组合的该化合物的盐。这些化合物的游离碱和盐的形式都有用。在实践中,使用盐形式相当于使用碱形式;酸和碱加成盐都在本发明的范围内。
“药物学上可接受的酸加成盐”指这样的盐,它保持游离碱的生物有效性和性质,且不是生物学不期望的,它们由以下物质形成:无机酸如盐酸、氢溴酸、硫酸、硝酸、磷酸等,以及有机酸如乙酸、丙酸、乙醇酸、丙酮酸、草酸、马来酸、丙二酸、琥珀酸、富马酸、酒石酸、柠檬酸、苯甲酸、肉桂酸、扁桃酸、甲磺酸、乙磺酸、对甲苯磺酸、水杨酸等。
“药物学上可接受的碱加成盐”包括衍生自无机碱的盐,如钠、钾、锂、铵、钙、镁、铁、锌、铜、锰、铝盐等。特别优选的是铵、钾、钠、钙和镁盐。衍生自药物学上可接受的有机无毒碱的盐包括以下化合物的盐:伯、仲和叔胺;取代的胺,包括天然存在的取代的胺;环状胺;以及碱性离子交换树脂,如异丙胺、三甲胺、二乙胺、三乙胺、三丙胺、乙醇胺、2-二乙基氨基乙醇、三甲胺、二环己胺、赖氨酸、精氨酸、组氨酸、咖啡因、普鲁卡因、醇胺(hydrabamine)、胆碱、甜菜碱、乙二胺、葡糖胺、甲基葡糖胺、可可碱、嘌呤、哌嗪(piperizine)、哌啶、N-乙基哌啶、聚胺树脂等。特别优选的有机无毒碱是异丙胺、二乙胺、乙醇胺、三甲胺、二环己胺、胆碱和咖啡因。
为本文目的的“生物学性质”意指通过本发明的化合物而直接或间接地进行的体内效应物或抗原功能或活性,其通常在体外试验中证明。效应物功能包括受体或配体结合、任何酶活性或酶调节活性、任何载体结合活性、任何激素活性、任何促进或抑制细胞粘附于细胞外基质或细胞表面分子的活性,或任何结构作用。抗原功能包括拥有能够与由其得到的抗体反应的表位或抗原位点。
在本发明的化合物中,结合于四个不同取代基上的碳原子是不对称的。因此,这些化合物可以以非对映异构体、对映异构体或其混合物存在。本文所述的合成可以采用消旋体、对映异构体或非对映异构体作为起始原料或中间体。由这种合成得到的非对映异构体产物可以通过色谱或结晶方法,或通过本领域已知的其它方法分离。类似地,对映异构体产物混合物可以通过相同的技术,或通过本领域已知的其它方法分离。每个不对称碳原子当存在于本发明的化合物中时,可以是两种构型(R或S)之一,它们均在本发明的范围内。优选实施方案
本发明提供以下式(I)的化合物:
A-Q-D-E-G-J-X其中:A选自于:
(a) C1-C6-烷基;
(b) C3-C8-环烷基;
(c)-N(R2,R3)、-C(=NR2)-R3、-C(=NR2)N(R2,R3)、
-N(R3)-C(=NR2)N(R2,R3)-、以及-N(R2)C(=NR3)-R2
(d)苯基,其独立地被0-2个R1取代基取代;
(e)萘基,其独立地被0-2个R1取代基取代;以及
(f)具有5-10个环原子的单环或者稠合二环杂环系,其中该环
系的1-4个环原子选自于N、O和S,而且该环系可被0-2
个R1取代基取代;R1选自于:
卤素,-CN,-C(=O)-N(R2,R3),-NO2,-SO2N(R2,R3),-SO2R2,
-(CH2)mNR2R3,-(CH2)m-C(=NR3)-R2,-(CH2)m-C(=NR2)-N(R2,R3),
-(CH2)m-N(R2)-C(=NR2)-N(R2,R3),-(CH2)mNR2-C3-6杂环,C1-4烷基,C2-6
烯基,C2-6炔基,C3-8环烷基,C0-4烷基C3-8环烷基,-CF3,-OR2,以及包
含1-4个选自于N、O和S的杂原子的5-6元杂环系,其中该杂
环系时的1-4个氢原子可独立地被选自于以下组中的基团置换:
卤素、C1-4烷基-CN、C1-4烷基、C2-6烯基、C2-6炔基、C3-8环烷基、
C0-4烷基C3-8环烷基以及-NO2;R2和R3独立地选自于以下组中:
-H,-ORa,-N(-Ra,-Rb),-C1-4烷基,-C2-6烯基,-C2-6炔基,-C3-8环烷基,
-C0-4烷基C3-8环烷基,-C0-4烷基苯基,以及-C0-4烷基萘基,其中苯基
和萘基部分上的1-4个氢原子可独立地被选自以下组中的基团置
换:卤素、C1-4烷基-CN、-C1-4烷基、-C2-6烯基、-C2-6炔基、-C3-8
环烷基、-C0-4烷基C3-8环烷基、-CN、以及-NO2;或者R2和R3可一起形成3-8元环烷基或者杂环系,其中杂环系可具有
3-10个环原子,该环系中可有1-2个环,而且可包含1-4个选
自于N、O和S的杂原子,其中杂环系上的1-4个氢原子可独立
地被选自于以下组中的基团置换:卤素、C1-4烷基-CN、-C1-4烷基、-C2-6
烯基、-C2-6炔基、-C3-8环烷基、-C0-4烷基C3-8环烷基,以及-NO2;Ra和Rb独立地选自于以下组中:-C1-4烷基,-C2-6烯基,-C2-6炔基,-C3-8环
烷基,-C0-4烷基C3-8环烷基,或者Ra和Rb可与它们所连接的氮原子
一起形成包含1-4个选自于N、O和S的杂原子的3-8元杂环环
系,其中杂环系上的1-4个氢原子可独立地被选自于以下组中的
基团置换:卤素、-CN、-C1-4烷基、-C2-6烯基、-C2-6炔基、-C3-8环
烷基、-C0-4烷基C3-8环烷基、以及-NO2;M是0-2的整数;Q选自于以下组中:
直接键连,二价-C1-4烷基,二价-C2-4烯基,二价-C2-4炔基,-C(=O)-,
-C(=NH)-,-C(=NMe)-,-N(-R4)-,-N(-R4)-CH2-,-C(=O)-N(-R4)-,
-N(-R4)-C(=O)-,-S(=O)2-,-O-,-S(=O)2-N(-R4)-和-N(-R4)-S(=O)2-,
其中二价C1-4烷基,二价C2-4烯基以及二价C2-4炔基部分上的一个
或者多个氢原子可被-R4基团取代;R4选自于以下组中:
-H,-CF3,-C1-4烷基,-C2-6烯基,-C2-6炔基,-C3-8环烷基,-C0-4烷基C3-8
环烷基,-C0-4烷基苯基和-C0-4烷基萘基,苯基和萘基部分的环原子
上的1-4个氢原子可独立地被选自于以下组中的基团取代:卤
素、-C1-4烷基、-C2-6烯基、-C2-6炔基、-C3-8环烷基、-C0-4烷基C3-8
环烷基、-CN、-CF3,和-NO2;D选自于以下组中:
(a)直接键连;
(b)苯基,其独立地被0-2个R1a取代基取代;
(c)萘基,其独立地被0-2个R1a取代基取代;以及
(d)具有5-10个环原子的单环或者稠合二环杂环系,其中该环
系的1-4个环原子选自于N、O和S,而且该环系可被0-
2个R1a取代基取代;R1a选自于以下组中:
卤素,C1-4烷基,C2-6烯基,C2-6炔基,C3-8环烷基,C0-4烷基C3-8环烷基,
-CN,-NO2,(CH2)nNR2aR3a,SO2NR2aR3a,SO2R2a,CF3,OR2a,以及包
含1-4个选自于N、O和S的杂原子的5-6元芳香杂环环系,其
中该芳香杂环环系的1-4个氢原子可独立地被选自于以下组中的
基团置换:卤素、C1-4烷基、C2-6烯基、C2-6炔基、C3-8环烷基、C0-4
烷基C3-8环烷基、-CN和-NO2;R2a和R3a独立地选自于以下组中:
-H,C1-4烷基,C2-6烯基,C2-6炔基,C3-8环烷基,C0-4烷基C3-8环烷基,C0-4
烷基苯基以及C0-4烷基萘基,其中苯基和萘基部分的环原子上的1
-4个氢原子可独立地被选自于以下组中的基团置换:卤素、C1-4
烷基、C2-6烯基、C2-6炔基、C3-8环烷基、C0-4烷基C3-8环烷基、-CN
和-NO2;n是0-2的整数;E选自于以下组中:
直接键连,-(CH2)q-C(=O)-,-(CH2)q-N(-R5)-C(=O)-(CH2)x-,
-(CH2)q-C(=O)-N(-R5)-(CH2)x-,-(CH2)q-N(-R5)-(CH2)x-,,
-(CH2)q-N(R5)CO-NR6(CH2)x和-SO2-;q和x独立地是0-2的整数;R5和R6独立地选自于以下组中:
H,-C1-6烷基,-C1-6烷基oxy,-C2-6烯基,-C2-6炔基,-C3-8环烷基,-C0-6
烷基C3-8环烷基,-C1-4烷基-C(=O)-OH,-C0-6烷基-(碳环芳基),-C0-4烷
基-(单环杂芳基)和-C1-4烷基-C(=O)-O-C1-4烷基,其中碳环芳基和
单环杂芳基部分的环原子上的0-4个氢原子可独立地被选自于以
下组中的基团置换:卤素、-C1-4烷基、-C2-6烯基、-C2-6炔基、-C3-8
环烷基、-C0-4烷基C3-8环烷基、-S(=O)2-OH、-CN、-CF3、以及-NO2;G选自于以下组中:
苯基,其被0-2个R1b基团取代;以及
包含1-4个选自于N、O和S的杂原子的5-6原芳香及非芳香杂
环,其中该杂环被0-2个R1b基团取代;R1b选自于以下组中:
卤素,-C1-6烷基,-C2-6烯基,-C2-6炔基,-C3-8环烷基,-C0-6烷基C3-8环
烷基,-C1-4烷基-C(=O)-OH,-CN,-COOR2b,-CONR2bR3b,-NO2,
-S(=O)2-OH,-N(-R2b,-R3b),-C(=O)-N(-R2b,-R3b),-S(=O)2-N(-R2b,-R3b),
-S(=O)2-R2b,-CF3,-O-R2b,-O-CH2-CH2-O-R2b,-O-CH2-C(=O)-O-R2b,
-N(-R2b)-CH2-CH2-O-R2b,-N(-CH2-CH2-O-R2b)2,-N(-R2b)-C(=O)-R3b,
-N(-R2b)-S(=O)2-R3b,以及包含1-4个选自于N、O和S的杂原子
的5-6原杂环,其中该杂环被0-4个R1b′基团取代;
或者,当两个R1b出现在G的相邻环原子上时,可组合形成被0-4
个R1b′基团取代苯环或者被0-4个R1b′基团取代的具有1-3个选
自于N、O和S的杂原子的5-6元芳香或非芳香杂环;
或者,G中R1b基团之一可与E中的-N-R5基团成环形成包含1-4
个选自于N、O和S的杂原子的5-7元杂环,该杂环被0-4个R1b′
基团取代,其中连接在相同的环碳原子上的R1b′基团可形成(=O)基
团;R2b和R3b独立地选自于以下组中:
-H,-C1-6烷基,-C1-6烷基oxy,-C2-6烯基,-C2-6炔基,-C3-8环烷基,-C0-6
烷基C3-8环烷基和-C0-6烷基-(碳环芳基),其中碳环芳基部分的环
原子上的0-4个氢原子可独立地被选自于以下组中的基团置换:
卤素、-C1-4烷基、-C2-6烯基、-C2-6炔基、-C3-8环烷基、-C0-4烷基C3-8
环烷基、-S(=O)2-OH、-CN、-CF3和-NO2;R1b′选自于以下组中:
卤素,-C1-6烷基,-C2-6烯基,-C2-6炔基,-C3-8环烷基,-C0-6烷基C3-8环
烷基,-C1-4烷基-C(=O)-OH,-CN,-NO2,-S(=O)2-OH,-N(-R2b′,-R3b′),
-C(=O)-N(-R2b′,-R3b′),-S(=O)2-N(-R2b′,-R3b′),-S(=O)2-R2b′,-CF3,-O-R2b′,
-O-CH2-CH2-O-R2b′,-O-CH2-C(=O)-O-R2b′,-N(-R2b′)-CH2-CH2-O-R2b′,
-N(-CH2-CH2-O-R2b′)2,-N(-R2b′)-C(=O)-R3b′和-N(-R2b′)-S(=O)2-R3b′;R2b’和R3b′独立地选自于以下组中:
-H,-C1-6烷基,-C1-6烷氧基,-C2-6烯基,-C2-6炔基,-C3-8环烷基,-C0-6烷
基C3-8环烷基和-C0-6烷基-(碳环芳基),其中碳环芳基部分的环原
子上的0-4个氢原子可独立地被选自于以下组中的基团置换:卤
素、-C1-4烷基、-C2-6烯基、-C2-6炔基、-C3-8cycloakyl、-C0-4烷基C3-8
环烷基、-S(=O)2-OH、-CN、-CF3和-NO2;J选自于以下组中:
直接键连,-S(=O)2-,-C(=O)-,-N(-R7)-S(=O)2-,-C(=O)-N(-R7)-S(=O)2-,
-C(=O)-N(-R7)-(CH2)y-,-S(=O)2-N(-R7)-(CH2)y-,和
-N(-R7)-C(=O)-(CH2)y-;y是0-2的整数;R7选自于以下组中:
-H,-C2-4烷基,-C2-6烯基,-C2-6炔基,-C3-8环烷基,-C0-6烷基C3-8环烷
基,-C1-6烷基-C(=O)-OH,-C1-6烷基-OH,-C1-6烷基-O-C1-4烷基,-C0-4
烷基-(碳环芳基),-C0-4烷基-(具有0-4个选自于N、O和S的杂原
子的单环或者二环杂环系),-CH2-C(=O)-O-C1-4烷基和-
CH2-C(=O)-O-C1-4烷基-(碳环芳基),其中碳环芳基部分或者杂环系
的环原子上的0-4个氢原子可独立地被选自于以下组中的基团置
换:卤素、-C1-4烷基、-C2-6烯基、-C2-6炔基、-C3-8环烷基、-C0-4烷
基C3-8环烷基、-S(=O)2-OH、-CN、-CF3和-NO2;X选自于以下组中:
苯基,其被0-3个R1c基团取代;
萘基,其被0-3个R1c基团取代;
包含1-2个氮原子的6元杂芳香环,其中该环被0-3个R1c基团
取代;以及
稠合杂二环系,其中该环系包含1-3个选自于N、O和S的杂原
子,而且被0-3个R1c基团取代;R1c选自于以下组中:
卤素,-CF3,-C1-6烷基,-C2-6烯基,-C2-6炔基,-C3-8环烷基,-C0-6烷基C3-8
环烷基,-C1-4烷基-C(=O)-OH,-CF3,-CN,-NO2,-(CH2)z-N(-R2c,-R3c),
-C(=O)-N(-R2c,-R3c),-C(=NH)-N(-R2c,-R3c),-C(=NMe)-N(-R2c,-R3c),
-S(=O)2-N(-R2c,-R3c),-S(=O)2-R2c,-S(=O)2-OH,-CF3,-O-R2c,
-O(-CH2)z-O-R2c,-O(-CH2)z-C(=O)-O-R2c,-N(-R2c),-O(-CH2)z-O-R2c,
-N[(-CH2)z-O-R2c]2,-(CH2)z-N(-R2c)-C(=O)-R3c,
-(CH2)z-N(-R2c)-S(=O)2-R3c,以及包含1-4个选自于N、O和S的
杂原子的5-6元杂环;z是0-4的整数;R2c和R3c独立地选自于以下组中:
-H,-C1-6烷基,-C1-6烷基oxy,-C2-6烯基,-C2-6炔基,-C3-8环烷基,-C0-6
烷基C3-8环烷基和-C0-6烷基-(碳环芳基),其中碳环芳基部分的环
原子上的0-4个氢原子可独立地被选自于以下组中的基团置换:
卤素、-C1-4烷基、-C2-6烯基、-C2-6炔基、-C3-8环烷基、-C0-4烷基C3-8
环烷基、-S(=O)2-OH、-CN、-CF3和-NO2;及其所有的药物学上可接受的异构体、盐、水合物、溶剂化物和前药衍生物。
本发明还提供以下式(I)的化合物:
A-Q-D-E-G-J-X其中:A选自于以下组中:
-C1-6烷基和-C3-8环烷基;
苯基,其被0-2个R1基团取代;
萘基,其被0-2个R1基团取代;以及
可为单环环系或者稠合二环环系的5-10元芳香或非芳香杂环系,
其中该杂环系包含1-4个选自于N、O和S的杂原子并且被0-2
个R1基团取代;R1选自于以下组中:
卤素,-C1-4烷基,-CN,-NO2,-(CH2)m-N(-R2,-R3),-C(=O)-N(-R2,-R3),
-S(=O)2-N(-R2,-R3),-S(=O)2-R2,-(CH2)m-C(=NR3)-R2,
-(CH2)m-C(=NR2)-N(R2,R3),-(CH2)m-N(R2)-C(=NR2)-N(R2,R3),-CF3,
-(CH2)m-O-R2以及包含1-4个选自于N、O和S的杂原子的5-6
元芳香杂环;R2和R3独立地选自于以下组中:
-H,-C1-4烷基,或者R2和R3可一起形成3-8元环烷基或者杂环系,其中杂环系可具有
3-10个环原子,在环系中可有1-2个环,并包含1-4个选自于
N、O和S的杂原子,其中该杂环系上的1-4个氢原子可被选自于
以下组中的基团置换:卤素、C1-C4-烷基-CN、-C1-4烷基、-C2-6烯
基、-C2-6炔基、-C3-8环烷基、-C0-4烷基C3-8环烷基和-NO2;m是0-2的整数;Q选自于以下组中:
直接键连,-C1-4烷基,-C2-4烯基,-C2-4炔基,-C(=O)-,-C(=NH)-,
-C(=NMe)-,-N(-R4)-,-N(-R4)-CH2-,-C(=O)-N(-R4)-,-N(-R4)-C(=O)-,
-S(=O)2-,-O-,-S(=O)2-N(-R4)-和-N(-R4)-S(=O)2-;R4选自于以下组中:
-H,-CF3,-C1-4烷基,D选自于以下组中:
直接键连;
苯基,其被0-2个R1a基团取代;以及
5-10元芳香或非芳香杂环系,该杂环系可以是单环环系或者稠合
二环环系,其中杂环系包含1-4个选自于N、O和S的杂原子,
而且环系被0-2个R1a基团取代;R1a选自于以下组中:
卤素,-C1-4烷基,-CN,-NO2,-(CH2)n-N(-R2a,-R3a),-S(=O)2-N(-R2a,-R3a)
,-S(=O)2-R2a,-CF3,-(CH2)n-OR2a,-C(=O)-O-R2a,-C(=O)-N(-R2a,-R3a)
以及包含1-4个选自于N、O和S的杂原子的5-6元芳香杂
环;n是0-2的整数;R2a和R3a独立地选自于以下组中:
-H,-CF3和-C1-4烷基,E选自于以下组中:
直接键连,-(CH2)q-C(=O)-,-(CH2)q-N(-R5)-C(=O)-(CH2)x-,
-(CH2)q-C(=O)-N(-R5)-(CH2)x-,-(CH2)q-N(-R5)-(CH2)x-,
-(CH2)q-N(R5)CO-NR6(CH2)x-和-SO2-;R5和R6分别是H,-C1-4烷基,-C2-6烯基,-C2-6炔基,-C3-8环烷基,或者-C0-4
烷基C3-8环烷基;Q和x独立地是0-2的整数;G选自于以下组中:
苯基,其独立地被0-2个R1b基团取代;以及
5-6元芳香和非芳香杂环环烯,其包含1-4个选自于O、S和N
的杂原子,其中该杂环被0-2个R1b基团取代;R1b选自于以下组中:
卤素,-C1-4烷基,-CN,-NO2,-N(-R2b,-R3b),-C(=O)-N(-R2b,-R3b),
-S(=O)2-N(-R2b,-R3b),-S(=O)2-R2b,-CF3,-O-R2b,-O-CH2-CH2-O-R2b,
-O-CH2-C(=O)-O-R2b,-N(-R2b)-CH2-CH2-O-R2b,-N(-CH2-CH2-O-R2b)2,
-N(-R2b)-C(=O)-R3b,-N(-R2b)-S(=O)2-R3b,以及5-6元包含1-4个
选自于N、O和S的杂原子的杂环;
或者,当两个R1b出现在G环的相邻环原子上时,可一并形成被0
-4个R1b′基团取代的苯环或者具有1-3个选自于N、O和S的杂
原子并被0-4个R1b′基团取代的5-6元芳香或非芳香杂环;
或者,G中的R1b基团之一可与E中的-N-R5基团成环形成包含1-
4个选自于N、O和S的杂原子的5-7元饱和、不饱和或者部分
不饱和的杂环,该杂环被0-4个R1b′基团取代,其中连接在相同环
碳原子上的两个R1b′基团可形成(=O)基团;R2b和R3b选自于以下组中:
-H,-CF3,-C1-4烷基和-C1-4烷基-(碳环芳基);R1b′选自于以下组中:
卤素,-C1-4烷基,-CN,-NO2,-N(-R2b′,-R3b′),-C(=O)-N(-R2b′,-R3b′),
-S(=O)2-N(-R2b′,-R3b′),-S(=O)2-R2b′,-CF3,-O-R2b′,-O-CH2-CH2-O-R2b′,
-O-CH2-C(=O)-O-R2b′,-N(-R2b′)-CH2-CH2-O-R2b′,-N(-CH2-CH2-O-R2b′)2,
-N(-R2b′)-C(=O)-R3b′,-N(-R2b′)-S(=O)2-R3b′;R2b′和R3b′独立地选自于以下组中:
-H,-C1-4烷基和-C1-4烷基-(碳环芳基);J选自于以下组中:
直接键连,-S(=O)2-,-C(=O)-,-N(-R7)-S(=O)2-,-C(=O)-N(-R7)-S(=O)2-,
-C(=O)-N(-R7)-(CH2)y-,-S(=O)2-N(-R7)-,-(CH2)y-和
-N(-R7)-C(=O)-(CH2)y-;y是0-2的整数;R7选自于以下组中:
-H,-C1-4烷基,-C2-6烯基,-C2-6炔基,-C0-4烷基-(碳环芳基),-C0-4烷
基-(杂环系),-CH2-C(=O)-O-C1-4烷基和-CH2-C(=O)-O-C1-4烷基-(碳
环芳基);X选自于以下组中:
苯基,其被0-3个R1c基团取代;
萘基,其被0-3个R1c基团取代;
包含1-2个氮原子的6元杂芳香环,其中该环被0-3个R1c基团
取代;以及
稠合杂二环环系,其中该环系包含1-3个选自于N、O和S的杂
原子,而且被0-3个R1c基团取代;R1c选自于以下组中:
卤素,-C1-4烷基,-CN,-NO2,-(CH2)z-N(-R2c,-R3c),-C(=O)-N(-R2c,-R3c),
-C(=NH)-N(-R2c,-R3c),-C(=NMe)-N(-R2c,-R3c),-S(=O)2-N(-R2c,-R3c),
-S(=O)2-R2c,-S(=O)2-O-,-CF3,-O-R2c,-O-CH2-CH2-O-R2c,
-O-CH2-C(=O)-O-R2c,-N(-R2c)-CH2-CH2-O-R2c,-N(-CH2-CH2-O-R2c)2,
-(CH2)z-N(-R2c)-C(=O)-R3c,-(CH2)z-N(-R2c)-S(=O)2-R3c,以及包含1-
4个选自于N、O和S的杂原子的5-6元杂环;z是0-2的整数;R2c和R3c独立地选自于以下组中:
-H,-C1-4烷基和-C1-4烷基-(碳环芳基);及其所有的药物学上可接受的异构体、盐、水合物、溶剂化物和前药衍生物。
本发明还提供以下式(I)的化合物:
直接键连,-C(=NH),-C(=NMe)-,-C(=O)-,-CH2-,-NH-,-N(-CH3)-,-O-,
直接键连,-NH-C(=O)-,-N(-CH3)-C(=O)-,-N(-CH2CO2H)-C(=O)-,
-H,-Me,-CF3,-F,-Cl,-Br,-SO2Me,-CN,-CONH2,-CONMe2,-NH2,
-NO2,-NHCOMe,-NHSO2Me,-CH2NH2和-CO2H;J选自于以下组中:
直接键连,-NH-,-O-,-S(=O)2-,-S(=O)2-NH,-NH-S(=O)2-,-C(=O)-,
列于以下53个表中的化合物都是本发明的实施方案:表1R1b选自于以下组中:-H,-CH3和-CF3。表2其中:R1a1和R1a2独立地选自于以下组中:-H,-F,-Cl和-Br;R1b选自于以下组中:-H,-CH3 and CF3;以及R1c2选自于以下组中:-H,-F,-Cl,-Br,-OH,-OCH3和-NH2。表3其中:R1b选自于以下组中:-H,-CH3和-CF3;以及R1c2选自于以下组中:-H,-F,-Cl,-Br,-OH,-OCH3和-NH2。
表4其中:R1a1和R1a2独立地选自于以下组中:-H,-F,-Cl和-Br;R1b选自于以下组中:-H,-CH3和-CF3;以及R1c1选自于以下组中:-F,-Cl,-Br,-CN,-CH2NH2,-CH2OH,-CONH2,
-C(=NH)NH2,-CO2H,-CO2Me,-SO2Me,-SO2NH2,-OH,-NH2,和
-NO2。
表5其中:R1a1和R1a2独立地选自于以下组中:-H,-F,-Cl和-Br;R1b选自于以下组中:-H,-CH3和-CF3;以及R1c3选自于以下组中:-H,-F,-Cl,-Br,-OH,-OCH3和-NH2。表6其中:R1a1和R1a2独立地选自于以下组中:-H,-F,-Cl和-Br;R1b选自于以下组中:-H,-CH3,-CF3,-CH2CH3,-CF2CF3,-CH2NH2,-CONH2,
-SO2CH3,-SO2NH2,-NH2COCH3和-NH2COCF3;R1c1选自于以下组中:-H,-F,-Cl,-Br,-CN,-CH2NH2,-CH2OH,-CONH2,
-C(=NH)NH2,-CO2H,-CO2Me,-SO2Me,-SO2NH2,-OH,-NH2,和-NO2;R1c2选自于以下组中:-H,-F,-Cl,-Br,-OH,-OCH3,和-NH2;以及R1c3选自于以下组中:-H,-F,-Cl,-Br,-OH,-OCH3,和-NH2。表7其中:R1选自于以下组中:-H,-NH2,-SO2NH2,-SO2CH3,-CN,-CONH2,
-CONH(CH3),-CON(CH3)2,CH2NH2,-CH2NH(CH3),-CH2N(CH3)2;R1i选自于以下组中:-H,-NH2,-SO2NH2,-SO2CH3,-CN,-CONH2,
-CONH(CH3),-CON(CH3)2,-CH2NH2,-CH2NH(CH3),-CH2N(CH3)2;R1a1和R1a2独立地选自于以下组中:-H,-F,-Cl和-Br;R1b选自于以下组中:-H,-CH3,-CF3,-CH2CH3,-CF2CF3,-CH2NH2,-CONH2,
-SO2CH3,-SO2NH2,-NH2COCH3和-NH2COCF3;R1c1选自于以下组中:-H,-F,-Cl,-Br,-CN,-CH2NH2,-CH2OH,-CONH2,
-C(=NH)NH2,-CO2H,-CO2Me,-SO2Me,-SO2NH2,-OH,-NH2,和-NO2;R1c2选自于以下组中:-H,-F,-Cl,-Br,-OH,-OCH3,和-NH2;以及R1c3选自于以下组中:-H,-F,-Cl,-Br,-OH,-OCH3,和-NH2。表8其中:R1选自于以下组中:-SO2NH2,-SO2CH3,-CN,-CONH2,-CONH(CH3),
-CON(CH3)2,-CH2NH2,-CH2NH(CH3),-CH2N(CH3)2;R1b选自于以下组中:-H,-CH3和-CF3;R1c1选自于以下组中:-H,-F,-Cl,-Br,-CN,-CH2NH2,-CH2OH,-CONH2,
-C(=NH)NH2,-CO2H,-CO2Me,-SO2Me,-SO2NH2,-OH,-NH2,和-NO2;R1c2选自于以下组中:-H,-F,-Cl,-Br,-OH,-OCH3,和-NH2;以及R1c3选自于以下组中:-H,-F,-Cl,-Br,-OH,-OCH3,和-NH2。表9其中:A选自于以下组中:R1a1和R1a2独立地选自于以下组中:-H,-F,-Cl和-Br;R1b选自于以下组中:-H,-CH3,-CF3,-CH2CH3,-CF2CF3,-CH2NH2,-CONH2,
-SO2CH3,-SO2NH2,-NH2COCH3和-NH2COCF3;R1c1选自于以下组中:-H,-F,-Cl,-Br,-CN,-CH2NH2,-CH2OH,-CONH2,
-C(=NH)NH2,-CO2H,-CO2Me,-SO2Me,-SO2NH2,-OH,-NH2,和-NO2;R1c2选自于以下组中:-H,-F,-Cl,-Br,-OH,-OCH3,和-NH2;以及R1c3选自于以下组中:-H,-F,-Cl,-Br,-OH,-OCH3,和-NH2。
表10其中:A-Q独立地选自于以下组中: R1a1和R1a2独立地选自于以下组中:-H,-F,-Cl和-Br;R1b选自于以下组中:-H,-CH3,-CF3,-CH2CH3,-CF2CF3,-CH2NH2,-CONH2,
-SO2CH3,-SO2NH2,-NH2COCH3和-NH2COCF3;R1c1选自于以下组中:-H,-F,-Cl,-Br,-CN,-CH2NH2,-CH2OH,-CONH2,
-C(=NH)NH2,-CO2H,-CO2Me,-SO2Me,-SO2NH2,-OH,-NH2,和-NO2;R1c2选自于以下组中:-H,-F,-Cl,-Br,-OH,-OCH3,和-NH2;以及R1c3选自于以下组中:-H,-F,-Cl,-Br,-OH,-OCH3,和-NH2。表11其中:R1选自于以下组中:-SO2NH2,-SO2CH3,-CN,-CONH2,-CONH(CH3),
-CON(CH3)2,-CH2NH2,-CH2NH(CH3),-CH2N(CH3)2;R1b选自于以下组中:-H,-CH3和-CF3;R1a1和R1a2独立地选自于以下组中:-H,-F,-Cl和-Br;R1c1选自于以下组中:-H,-F,-Cl,-Br,-CN,-CH2NH2,-CH2OH,-CONH2,
-C(=NH)NH2,-CO2H,-CO2Me,-SO2Me,-SO2NH2,-OH,-NH2,和-NO2;R1c2选自于以下组中:-H,-F,-Cl,-Br,-OH,-OCH3,和-NH2;R1c3选自于以下组中:-H,-F,-Cl,-Br,-OH,-OCH3,和-NH2;以及G选自于以下组中:其中:R1b1选自于以下组中:-H,-CH3和-CF3;R1b2选自于以下组中:-H,-CH3和-CF3;以及R1b3选自于以下组中:-Cl,-NH2,-CH3和-CF3。表12其中:A选自于以下组中:R1b选自于以下组中:-H,-CH3和-CF3;R1a1和R1a2独立地选自于以下组中:-H,-F,-Cl和-Br;R1c1选自于以下组中:-H,-F,-Cl,-Br,-CN,-CH2NH2,-CH2OH,-CONH2,
-C(=NH)NH2,-CO2H,-CO2Me,-SO2Me,-SO2NH2,-OH,-NH2,和-NO2;R1c2选自于以下组中:-H,-F,-Cl,-Br,-OH,-OCH3,和-NH2;R1c3选自于以下组中:-H,-F,-Cl,-Br,-OH,-OCH3,和-NH2;以及G选自于以下组中:其中:R1b1选自于以下组中:-H,-CH3和-CF3;R1b2选自于以下组中:-H,-CH3和-CF3;以及R1b3选自于以下组中:-Cl,-NH2,-CH3和-CF3
表13其中:A-Q独立地选自于以下组中: R1b选自于以下组中:-H,-CH3和-CF3;R1a1和R1a2独立地选自于以下组中:-H,-F,-Cl和-Br;R1c1选自于以下组中:-H,-F,-Cl,-Br,-CN,-CH2NH2,-CH2OH,-CONH2,-C(=NH)NH2,-CO2H,-CO2Me,-SO2Me,-SO2NH2,-OH,-NH2,和-NO2;R1c2选自于以下组中:-H,-F,-Cl,-Br,-OH,-OCH3,和-NH2;R1c3选自于以下组中:-H,-F,-Cl,-Br,-OH,-OCH3,和-NH2;以及G选自于以下组中:其中:R1b1选自于以下组中:-H,-CH3和-CF3;R1b2选自于以下组中:-H,-CH3和-CF3;以及R1b3选自于以下组中:-Cl,-NH2,-CH3和-CF3。
表14其中:R1选自于以下组中:-SO2NH2,-SO2CH3,-CN,-CONH2,-CONH(CH3),
-CON(CH3)2,-CH2NH2,-CH2NH(CH3),-CH2N(CH3)2;R1b选自于以下组中:-H,-CH3,-CF3;R1c1选自于以下组中:-H,-F,-Cl,-Br,-CN,-CH2NH2,-CH2OH,-CONH2,
-C(=NH)NH2,-CO2H,-CO2Me,-SO2Me,-SO2NH2,-OH,-NH2,和-NO2;R1c2选自于以下组中:-H,-F,-Cl,-Br,-OH,-OCH3,和-NH2;以及R1c3选自于以下组中:-H,-F,-Cl,-Br,-OH,-OCH3,和-NH2。表15其中:A选自于以下组中:R1b选自于以下组中:-H,-CH3和-CF3;R1c1选自于以下组中:-H,-F,-Cl,-Br,-CN,-CH2NH2,-CH2OH,-CONH2,-C(=NH)NH2,-CO2H,-CO2Me,-SO2Me,-SO2NH2,-OH,-NH2,和-NO2;R1c2选自于以下组中:-H,-F,-Cl,-Br,-OH,-OCH3,和-NH2;以及R1c3选自于以下组中:-H,-F,-Cl,-Br,-OH,-OCH3,和-NH2。
表16其中:A-Q独立地选自于以下组中: R1b选自于以下组中:-H,-CH3和-CF3;R1c1选自于以下组中:-H,-F,-Cl,-Br,-CN,-CH2NH2,-CH2OH,-CONH2,-C(=NH)NH2,-CO2H,-CO2Me,-SO2Me,-SO2NH2,-OH,-NH2,和-NO2;R1c2选自于以下组中:-H,-F,-Cl,-Br,-OH,-OCH3,和-NH2;以及R1c3选自于以下组中:-H,-F,-Cl,-Br,-OH,-OCH3,和-NH2。表17表17(续)其中:R1选自于以下组中:-SO2NH2,-SO2CH3,-CN,-CONH2,-CONH(CH3),
-CON(CH3)2,-CH2NH2,-CH2NH(CH3),-CH2N(CH3)2;R1a1和R1a2独立地选自于以下组中:-H,-F,-Cl and Br;R1b选自于以下组中:-H,-CH3和-CF3;R1c1选自于以下组中:-H,-F,-Cl,-Br,-CN,-CH2NH2,-CH2OH,-CONH2,
-C(=NH)NH2,-CO2H,-CO2Me,-SO2Me,-SO2NH2,-OH,-NH2,和-NO2;R1c2选自于以下组中:-H,-F,-Cl,-Br,-OH,-OCH3,和-NH2;以及R1c3选自于以下组中:-H,-F,-Cl,-Br,-OH,-OCH3,和-NH2。表18表18(续)其中:A选自于以下组中:R1a1和R1a2独立地选自于以下组中:-H,-F,-Cl and Br;R1b选自于以下组中:-H,-CH3和-CF3;R1c1选自于以下组中:-H,-F,-Cl,-Br,-CN,-CH2NH2,-CH2OH,-CONH2,
-C(=NH)NH2,-CO2H,-CO2Me,-SO2Me,-SO2NH2,-OH,-NH2,和-NO2;R1c2选自于以下组中:-H,-F,-Cl,-Br,-OH,-OCH3,和-NH2;以及R1c3选自于以下组中:-H,-F,-Cl,-Br,-OH,-OCH3,和-NH2。表19表19(续)其中:A-Q独立地选自于以下组中: R1a1和R1a2独立地选自于以下组中:-H,-F,-Cl and Br;R1b选自于以下组中:-H,-CH3和-CF3;R1c1选自于以下组中:-H,-F,-Cl,-Br,-CN,-CH2NH2,-CH2OH,-CONH2,
-C(=NH)NH2,-CO2H,-CO2Me,-SO2Me,-SO2NH2,-OH,-NH2,和-NO2;R1c2选自于以下组中:-H,-F,-Cl,-Br,-OH,-OCH3,和-NH2;以及R1c3选自于以下组中:-H,-F,-Cl,-Br,-OH,-OCH3,和-NH2。
表20其中:R1选自于以下组中:-SO2NH2,-SO2CH3,-CN,-CONH2,-CONH(CH3),
-CON(CH3)2,-CH2NH2,-CH2NH(CH3),-CH2N(CH3)2;R1a1和R1a2独立地选自于以下组中:-H,-F,-Cl和-Br;R1c1选自于以下组中:-H,-F,-Cl,-Br,-CN,-CH2NH2,-CH2OH,-CONH2,
-C(=NH)NH2,-CO2H,-CO2Me,-SO2Me,-SO2NH2,-OH,-NH2,和-NO2;R1c2选自于以下组中:-H,-F,-Cl,-Br,和-OCH3;R1c3选自于以下组中:-H,-F,-Cl,-Br,-OH,-OCH3,-NH2,-CONH2,-CH2NH2,-CH2NHCH3,-CH2N(CH3)2,-C(=NH)NH2;以及G选自于以下组中:其中:R1b1选自于以下组中:-H,-CH3和-CF3;R1b2选自于以下组中:-H,-CH3和-CF3;R1b3选自于以下组中:-Cl,-NH2,-CH3和-CF3。
-CON(CH3)2,-CH2NH2,-CH2NH(CH3),-CH2N(CH3)2;R1a1和R1a2独立地选自于以下组中:-H,-F,-Cl和-Br;R1c1选自于以下组中:-H,-F,-Cl,-Br,-CN,-CH2NH2,-CH2OH,-CONH2,
-C(=NH)NH2,-CO2H,-CO2Me,-SO2Me,-SO2NH2,-OH,-NH2,和-NO2;R1c2选自于以下组中:-CH2-,-O-,-NH-,-N(CH3)-,-CH2CH2-,-O-CH2-,-NH-CH2-,和-N(CH3)-CH2-;R1c3选自于以下组中:-CH2-,-O-,-NH-,-N(CH3)-,和-CH(NH2)-;以及G选自于以下组中:其中:R1b1选自于以下组中:-H,-CH3和-CF3;R1b2选自于以下组中:-H,-CH3和-CF3;以及R1b3选自于以下组中:-Cl,-NH2,-CH3和-CF3。
-CON(CH3)2,-CH2NH2,-CH2NH(CH3),-CH2N(CH3)2;R1a1和R1a2独立地选自于以下组中:-H,-F,-Cl和-Br;R1c1选自于以下组中:-H,-F,-Cl,-Br,-CN,-CH2NH2,-CH2OH,-CONH2,
-C(=NH)NH2,-CO2H,-CO2Me,-SO2Me,-SO2NH2,-OH,-NH2,和-NO2;R1c2选自于以下组中:-H,-F,-Cl,-Br,和-OCH3;R1c3选自于以下组中:-H,-F,-Cl,-Br,-OH,-OCH3,-NH2,-CONH2,
-CH2NH2,-CH2NHCH3,-CH2N(CH3)2,-C(=NH)NH2;以及G选自于以下组中:其中:R1b1选自于以下组中:-H,-CH3和-CF3;R1b2选自于以下组中:-H,-CH3和-CF3;以及R1b3选自于以下组中:-Cl,-NH2,-CH3和-CF3。表23其中:R1选自于以下组中:-SO2NH2,-SO2CH3,-CN,-CONH2,-CONH(CH3),
-CON(CH3)2,-CH2NH2,-CH2NH(CH3),-CH2N(CH3)2;R1a1和R1a2独立地选自于以下组中:-H,-F,-Cl和-Br;R1c1选自于以下组中:-H,-F,-Cl,-Br,-CN,-CH2NH2,-CH2OH,-CONH2,
-C(=NH)NH2,-CO2H,-CO2Me,-SO2Me,-SO2NH2,-OH,-NH2,和-NO2;R1c2和R1c3独立地选自于以下组中:-H,-F,-Cl,-Br,和-OCH3;以及G选自于以下组中:其中:R1b1选自于以下组中:-H,-CH3和-CF3;R1b2选自于以下组中:-H,-CH3和-CF3;以及R1b3选自于以下组中:-Cl,-NH2,-CH3和-CF3。
-CON(CH3)2,-CH2NH2,-CH2NH(CH3),-CH2N(CH3)2;R1a1和R1a2独立地选自于以下组中:-H,-F,-Cl和-Br;R1c1选自于以下组中:-H,-F,-Cl,-Br,-CN,-CH2NH2,-CH2OH,-CONH2,
-C(=NH)NH2,-CO2H,-CO2Me,-SO2Me,-SO2NH2,-OH,-NH2,以及
-NO2;R1c2选自于以下组中:-CH-,和-N-;R1c3选自于以下组中:-NH-,和-O-;以及G选自于以下组中:其中:R1b1选自于以下组中:-H,-CH3和-CF3;R1b2选自于以下组中:-H,-CH3和-CF3;以及R1b3选自于以下组中:-Cl,-NH2,-CH3和-CF3。
表25其中:R1选自于以下组中:-SO2NH2,-SO2CH3,-CN,-CONH2,-CONH(CH3),
-CON(CH3)2,-CH2NH2,-CH2NH(CH3),-CH2N(CH3)2;R1a1和R1a2独立地选自于以下组中:-H,-F,-Cl和-Br;R1c1选自于以下组中:-H,-F,-Cl,-Br,-CN,-CH2NH2,-CH2OH,-CONH2,
-C(=NH)NH2,-CO2H,-CO2Me,-SO2Me,-SO2NH2,-OH,-NH2,和-NO2;R1c2选自于以下组中:-CH2-,-O-和-NH-;R1c3选自于以下组中:-CH-,-C(NH2)-和-N-;以及G选自于以下组中:其中:R1b1选自于以下组中:-H,-CH3和-CF3;R1b2选自于以下组中:-H,-CH3和-CF3;以及R1b3选自于以下组中:-Cl,-NH2,-CH3和-CF3。
表26其中:A选自于以下组中: R1a1和R1a2独立地选自于以下组中:-H,-F,-Cl和-Br;R1c1选自于以下组中:-H,-F,-Cl,-Br,-CN,-CH2NH2,-CH2OH,-CONH2,
-C(=NH)NH2,-CO2H,-CO2Me,-SO2Me,-SO2NH2,-OH,-NH2,和-NO2;R1c2选自于以下组中:-H,-F,-Cl,-Br,和-OCH3;R1c3选自于以下组中:-H,-F,-Cl,-Br,-OH,-OCH3,-NH2,-CONH2,-CH2NH2,-CH2NHCH3,-CH2N(CH3)2,-C(=NH)NH2;以及G选自于以下组中:其中:R1b1选自于以下组中:-H,-CH3和-CF3;R1b2选自于以下组中:-H,-CH3和-CF3;以及R1b3选自于以下组中:-Cl,-NH2,-CH3和-CF3。表27其中:A-Q独立地选自于以下组中: R1a1和R1a2独立地选自于以下组中:-H,-F,-Cl和-Br;R1c1选自于以下组中:-H,-F,-Cl,-Br,-CN,-CH2NH2,-CH2OH,-CONH2,
-C(=NH)NH2,-CO2H,-CO2Me,-SO2Me,-SO2NH2,-OH,-NH2,和-NO2;R1c2选自于以下组中:-H,-F,-Cl,-Br,和-OCH3;R1c3选自于以下组中:-H,-F,-Cl,-Br,-OH,-OCH3,-NH2,-CONH2,
-CH2NH2,-CH2NHCH3,-CH2N(CH3)2,-C(=NH)NH2;以及G选自于以下组中:其中:R1b1选自于以下组中:-H,-CH3和-CF3;R1b2选自于以下组中:-H,-CH3和-CF3;以及R1b3选自于以下组中:-Cl,-NH2,-CH3和-CF3。表28其中:A选自于以下组中:R1a1和R1a2独立地选自于以下组中:-H,-F,-Cl和-Br;R1c1选自于以下组中:-H,-F,-Cl,-Br,-CN,-CH2NH2,-CH2OH,-CONH2,
-C(=NH)NH2,-CO2H,-CO2Me,-SO2Me,-SO2NH2,-OH,-NH2,和-NO2;R1c2选自于以下组中:-H,-F,-Cl,-Br,和-OCH3;R1c3选自于以下组中:-H,-F,-Cl,-Br,-OH,-OCH3,-NH2,-CONH2,
-CH2NH2,-CH2NHCH3,-CH2N(CH3)2,-C(=NH)NH2;G选自于以下组中:其中:R1b1选自于以下组中:-H,-CH3和-CF3;R1b2选自于以下组中:-H,-CH3和-CF3;以及R1b3选自于以下组中:-Cl,-NH2,-CH3和-CF3。
表29其中:A-Q独立地选自于以下组中: R1a1和R1a2独立地选自于以下组中:-H,-F,-Cl和-Br;R1c1选自于以下组中:-H,-F,-Cl,-Br,-CN,-CH2NH2,-CH2OH,-CONH2,-
C(=NH)NH2,-CO2H,-CO2Me,-SO2Me,-SO2NH2,-OH,-NH2,和-NO2;R1c2选自于以下组中:-CH2-,-O-,-NH-,-N(CH3)-,-CH2CH2-,-O-CH2-,
-NH-CH2-,和-N(CH3)-CH2-;R13选自于以下组中:-CH2-,-O-,-NH-,-N(CH3)-,和-CH(NH2)-;以及G选自于以下组中:其中:R1b1选自于以下组中:-H,-CH3和-CF3;R1b2选自于以下组中:-H,-CH3和-CF3;以及R1b3选自于以下组中:-Cl,-NH2,-CH3和-CF3。表30其中:A选自于以下组中:R1a1和R1a2选自于以下组中:-H,-F,-Cl和-Br;R1c1选自于以下组中:-H,-F,-Cl,-Br,-CN,-CH2NH2,-CH2OH,-CONH2,
-C(=NH)NH2,-CO2H,-CO2Me,-SO2Me,-SO2NH2,-OH,-NH2,和-NO2;R1c2选自于以下组中:-H,-F,-Cl,-Br,和-OCH3;R1c3选自于以下组中:-H,-F,-Cl,-Br,-OH,-OCH3,-NH2,-CONH2,
-CH2NH2,-CH2NHCH3,-CH2N(CH3)2,-C(=NH)NH2,-C(=NH)NH(CH3),
-C(=NH)NH(CH3)2;以及G选自于以下组中:其中:R1b1选自于以下组中:-H,-CH3和-CF3;R1b2选自于以下组中:-H,-CH3和-CF3;以及R1b3选自于以下组中:-Cl,-NH2,-CH3和-CF3。
表31其中:A-Q独立地选自于以下组中: R1a1和R1a2独立地选自于以下组中:-H,-F,-Cl和-Br;R1c1选自于以下组中:-H,-F,-Cl,-Br,-CN,-CH2NH2,-CH2OH,-CONH2,
-C(=NH)NH2,-CO2H,-CO2Me,-SO2Me,-SO2NH2,-OH,-NH2,和-NO2;R1c2选自于以下组中:-H,-F,-Cl,-Br,-OH,-OCH3,和-NH2;R1c3选自于以下组中:-H,-F,-Cl,-Br,-OH,-OCH3,和-NH2;以及G选自于以下组中:其中:R1b1选自于以下组中:-H,-CH3和-CF3;R1b2选自于以下组中:-H,-CH3和-CF3;以及R1b3选自于以下组中:-Cl,-NH2,-CH3和-CF3。
表32其中:A选自于以下组中: R1a1和R1a2独立地选自于以下组中:-H,-F,-Cl和-Br;R1c1选自于以下组中:-H,-F,-Cl,-Br,-CN,-CH2NH2,-CH2OH,-CONH2,
-C(=NH)NH2,-CO2H,-CO2Me,-SO2Me,-SO2NH2,-OH,-NH2,和-NO2;R1c2选自于以下组中:-H,-F,-Cl,-Br,和-OCH3;以及G选自于以下组中:其中:R1b1选自于以下组中:-H,-CH3和-CF3;R1b2选自于以下组中:-H,-CH3和-CF3;以及R1b3选自于以下组中:-Cl,-NH2,-CH3和-CF3。表33其中:A选自于以下组中:R1a1和R1a2独立地选自于以下组中:-H,-F,-Cl和-Br;R1c1选自于以下组中:-H,-F,-Cl,-Br,-CN,-CH2NH2,-CH2OH,-CONH2,
-C(=NH)NH2,-CO2H,-CO2Me,-SO2Me,-SO2NH2,-OH,-NH2,和-NO2;R1c2选自于以下组中:-H,-F,-Cl,-Br,和-OCH3;以及G选自于以下组中:其中:R1b1选自于以下组中:-H,-CH3和-CF3;R1b2选自于以下组中:-H,-CH3和-CF3;以及R1b3选自于以下组中:-Cl,-NH2,-CH3和-CF3。
表34其中:A-Q独立地选自于以下组中:R1a1和R1a2独立地选自于以下组中:-H,-F,-Cl和-Br;R1c1选自于以下组中:-H,-F,-Cl,-Br,-CN,-CH2NH2,-CH2OH,-CONH2,
-C(=NH)NH2,-CO2H,-CO2Me,-SO2Me,-SO2NH2,-OH,-NH2,和-NO2;R1c2选自于以下组中:-H,-F,-Cl,-Br,和-OCH3;以及G选自于以下组中:其中:R1b1选自于以下组中:-H,-CH3和-CF3;R1b2选自于以下组中:-H,-CH3和-CF3;以及R1b3选自于以下组中:-Cl,-NH2,-CH3和-CF3。
表35其中:A-Q独立地选自于以下组中: 其中:A选自于以下组中:R1a1和R1a2独立地选自于以下组中:-H,-F,-Cl和-Br;R1c1选自于以下组中:-H,-F,-Cl,-Br,-CN,-CH2NH2,-CH2OH,-CONH2,
-C(=NH)NH2,-CO2H,-CO2Me,-SO2Me,-SO2NH2,-OH,-NH2,和-NO2;R1c2和R1c3独立地选自于以下组中:-H,-F,-Cl,-Br,和-OCH3;以及G选自于以下组中:其中:R1b1选自于以下组中:-H,-CH3和-CF3;R1b2选自于以下组中:-H,-CH3和-CF3;以及R1b3选自于以下组中:-Cl,-NH2,-CH3和-CF3。
表36其中:A-Q独立地选自于以下组中: 其中:A选自于以下组中:R1a1和R1a2独立地选自于以下组中:-H,-F,-Cl和-Br;R1c1选自于以下组中:-H,-F,-Cl,-Br,-CN,-CH2NH2,-CH2OH,-CONH2,
-C(=NH)NH2,-CO2H,-CO2Me,-SO2Me,-SO2NH2,-OH,-NH2,和-NO2;R1c2选自于以下组中:-CH2-,-O-和-NH-;R1c3选自于以下组中:-CH-,-C(NH2)-和-N-;以及G选自于以下组中:其中:R1b1选自于以下组中:-H,-CH3和-CF3;R1b2选自于以下组中:-H,-CH3和-CF3;以及R1b3选自于以下组中:-Cl,-NH2,-CH3和-CF3。
表37其中:R1选自于以下组中:-SO2NH2,-SO2CH3,-CN,-CONH2,-CONH(CH3),
-CON(CH3)2,-CH2NH2,-CH2NH(CH3),-CH2N(CH3)2;R1a选自于以下组中:-H,-F,-Cl和-Br;R1b1选自于以下组中:-H,-CH3和-CF3;R1b2选自于以下组中:-Cl,-NH2,-CH3和-CF3;R1c1选自于以下组中:-H,-F,-Cl,-Br,-CN,-CH2NH2,-CH2OH,-CONH2,
-C(=NH)NH2,-CO2H,-CO2Me,-SO2Me,-SO2NH2,-OH,-NH2,和-NO2;R1c2选自于以下组中:-H,-F,-Cl和-Br;以及R1c3选自于以下组中:-H,-F,-Cl和-Br。
-CON(CH3)2,-CH2NH2,-CH2NH(CH3),-CH2N(CH3)2;R1a选自于以下组中:-H,-F,-Cl和-Br;R1b1选自于以下组中:-H,-CH3和-CF3;R1b2选自于以下组中:-Cl,-NH2,-CH3和-CF3;R1c1选自于以下组中:-H,-F,-Cl,-Br,-CN,-CH2NH2,-CH2OH,-CONH2,
-C(=NH)NH2,-CO2H,-CO2Me,-SO2Me,-SO2NH2,-OH,-NH2,和-NO2;R1c2选自于以下组中:-H,-F,-Cl和-Br;以及R1c3选自于以下组中:-H和-NH2。
表39其中:A-Q独立地选自于以下组中: 其中:A选自于以下组中:R1a选自于以下组中:-H,-F,-Cl和-Br;R1b1选自于以下组中:-H,-CH3和-CF3;R1b2选自于以下组中:-Cl,-NH2,-CH3和-CF3;R1c1选自于以下组中:-H,-F,-Cl,-Br,-CN,-CH2NH2,-CH2OH,-CONH2,-C(=NH)NH2,-CO2H,-CO2Me,-SO2Me,-SO2NH2,-OH,-NH2,和-NO2;R1c2选自于以下组中:-H,-F,-Cl和-Br;以及R1c3选自于以下组中:-H,-F,-Cl和-Br。表40其中:A-Q独立地选自于以下组中: 其中:A选自于以下组中:R1a选自于以下组中:-H,-F,-Cl和-Br;R1b1选自于以下组中:-H,-CH3和-CF3;R1b2选自于以下组中:-Cl,-NH2,-CH3和-CF3;R1c1选自于以下组中:-H,-F,-Cl,-Br,-CN,-CH2NH2,-CH2OH,-CONH2,
-C(=NH)NH2,-CO2H,-CO2Me,-SO2Me,-SO2NH2,-OH,-NH2,和-NO2;R1c2选自于以下组中:-H,-F,-Cl和-Br;以及R1c3选自于以下组中:-H和-NH2。
表41其中:R1选自于以下组中:-SO2NH2,-SO2CH3,-CN,-CONH2,-CONH(CH3),
-CON(CH3)2,-CH2NH2,-CH2NH(CH3),-CH2N(CH3)2;R1a选自于以下组中:-H,-F,-Cl和-Br;R1b1选自于以下组中:-H,-CH3和-CF3;R1b2选自于以下组中:-Cl,-NH2,-CH3和-CF3;R1c1选自于以下组中:-H,-F,-CN,-CH2NH2,-CONH2,-SO2Me,-SO2NH2
和-NO2;R1c2选自于以下组中:-H,-F,-Cl,-Br和-OCH3;以及R1c3选自于以下组中:-H,-F,-Cl,Br,-OCH3,-CH2NH2,-CONH2和
-C(N=H)NH2。
-CON(CH3)2,-CH2NH2,-CH2NH(CH3),-CH2N(CH3)2;R1a选自于以下组中:-H,-F,-Cl和-Br;R1b1选自于以下组中:-H,-CH3和-CF3;R1b2选自于以下组中:-Cl,-NH2,-CH3和-CF3;R1c1选自于以下组中:-H,-F,-CN,-CH2NH2,-CONH2,-SO2Me,-SO2NH2
和-NO2;R1c2选自于以下组中:-H,-F,-Cl,-Br和-OCH3;以及R1c3选自于以下组中:-H,-F,-Cl,Br,-OCH3,-CH2NH2,-CONH2和
-C(N=H)NH2。
表43其中:A-Q独立地选自于以下组中: 其中:A选自于以下组中:R1a选自于以下组中:-H,-F,-Cl和-Br;R1b1选自于以下组中:-H,-CH3和-CF3;R1b2选自于以下组中:-Cl,-NH2,-CH3和-CF3;R1c1选自于以下组中:-H,-F,-CN,-CH2NH2,-CONH2,-SO2Me,-SO2NH2
和-NO2;R1c2选自于以下组中:-H,-F,-Cl,-Br和-OCH3;以及R1c3选自于以下组中:-H,-F,-Cl,Br,-OCH3,-CH2NH2,-CONH2和
-C(N=H)NH2。表44其中:A-Q独立地选自于以下组中: 其中:A选自于以下组中:R1a选自于以下组中:-H,-F,-Cl和-Br;R1b1选自于以下组中:-H,-CH3和-CF3;R1b2选自于以下组中:-Cl,-NH2,-CH3和-CF3;R1c1选自于以下组中:-H,-F,-CN,-CH2NH2,-CONH2,-SO2Me,-SO2NH2
和-NO2;R1c2选自于以下组中:-H,-F,-Cl,-Br和-OCH3;以及R1c3选自于以下组中:-H,-F,-Cl,Br,-OCH3,-CH2NH2,-CONH2和
-C(N=H)NH2。表45其中:R1选自于以下组中:-SO2NH2,-SO2CH3,-CN,-CONH2,-CONH(CH3),
-CON(CH3)2,-CH2NH2,-CH2NH(CH3),-CH2N(CH3)2;R1a1和R1a2独立地选自于以下组中:-H,-F,-Cl和-Br;R1c2和R1c3独立地选自于以下组中:-H,-F,-Cl,-Br,和-OCH3;以及G选自于以下组中:其中:R1b1选自于以下组中:-H,-CH3和-CF3;R1b2选自于以下组中:-H,-CH3和-CF3;以及R1b3选自于以下组中:-Cl,-NH2,-CH3和-CF3。
表46其中:R1选自于以下组中:-SO2NH2,-SO2CH3,-CN,-CONH2,-CONH(CH3),
-CON(CH3)2,-CH2NH2,-CH2NH(CH3),-CH2N(CH3)2;R1a1和R1a2独立地选自于以下组中:-H,-F,-Cl和-Br;R1c2和R1c3独立地选自于以下组中:-H,-F,-Cl,-Br,和-OCH3;以及G选自于以下组中:其中:R1b1选自于以下组中:-H,-CH3和-CF3;R1b2选自于以下组中:-H,-CH3和-CF3;以及R1b3选自于以下组中:-Cl,-NH2,-CH3和-CF3。
表47其中:A-Q独立地选自于以下组中: 其中:A选自于以下组中:R1a1和R1a2独立地选自于以下组中:-H,-F,-Cl和-Br;R1c2和R1c3独立地选自于以下组中:-H,-F,-Cl,-Br,和-OCH3;以及G选自于以下组中:其中:R1b1选自于以下组中:-H,-CH3和-CF3;R1b2选自于以下组中:-H,-CH3和-CF3;以及R1b3选自于以下组中:-Cl,-NH2,-CH3和-CF3。表48其中:A-Q独立地选自于以下组中: 其中:A选自于以下组中: R1a1和R1a2独立地选自于以下组中:-H,-F,-Cl和-Br;R1c2和R1c3独立地选自于以下组中:-H,-F,-Cl,-Br,和-OCH3;以及G选自于以下组中:其中:R1b1选自于以下组中:-H,-CH3和-CF3;R1b2选自于以下组中:-H,-CH3和-CF3;以及R1b3选自于以下组中:-Cl,-NH2,-CH3和-CF3。表49其中:A-Q独立地选自于以下组中: 其中:A选自于以下组中: R1a1和R1a2独立地选自于以下组中:-H,-F,-Cl和-Br;R1c2和R1c3独立地选自于以下组中:-H,-F,-Cl,-Br,和-OCH3;以及G选自于以下组中:其中:R1b1选自于以下组中:-H,-CH3和-CF3;R1b2选自于以下组中:-H,-CH3和-CF3;以及R1b3选自于以下组中:-Cl,-NH2,-CH3和-CF3。表50其中:R1选自于以下组中:-SO2NH2,-SO2CH3,-CN,-CONH2,-CONH(CH3),
-CON(CH3)2,-CH2NH2,-CH2NH(CH3),-CH2N(CH3)2;R1a选自于以下组中:-H,-F,-Cl和-Br;R1b1选自于以下组中:-H,-CH3和-CF3;以及R1c2和R1c3独立地选自于以下组中:-H,-F,-Cl,-Br,和-OCH3。表51其中:R1选自于以下组中:-SO2NH2,-SO2CH3,-CN,-CONH2,-CONH(CH3),
-CON(CH3)2,-CH2NH2,-CH2NH(CH3),-CH2N(CH3)2;R1a选自于以下组中:-H,-F,-Cl和-Br;R1b1选自于以下组中:-H,-CH3和-CF3;以及R1c2和R1c3独立地选自于以下组中:-H,-F,-Cl,-Br,和-OCH3。表52其中:A-Q独立地选自于以下组中: 其中:A选自于以下组中: R1a选自于以下组中:-H,-F,-Cl和-Br;R1b1选自于以下组中:-H,-CH3和-CF3;以及R1c2和R1c3独立地选自于以下组中:-H,-F,-Cl,-Br和-OCH3。
表53其中:A-Q独立地选自于以下组中:其中:A选自于以下组中:R1a选自于以下组中:-H,-F,-Cl和-Br;R1b1选自于以下组中:-H,-CH3和-CF3;以及R1c2和R1c3独立地选自于以下组中:-H,-F,-Cl,-Br和-OCH3。
以下化合物是本发明的实施方案:其中:R1选自于以下组中:
-SO2NH2,-SO2Me,-CH2NH2和-CH2NMe2;R1a选自于以下组中:
-H,-F,-Cl和-Br;R1b选自于以下组中:
-CH3,-CF3,-CH2CH3,-SO2Me,-CONH2和-NHSO2Me;R1c1选自于以下组中:
-H,-F,-Cl,-Br,-NH2,-OH,-SO2Me,-SO2Et,-SO2NH2,-NO2,-CH2NH2,
-CN,-CONH2,-CH2OH;R1c2选自于以下组中:
-H,-F,-Cl和-Br;以及R1c3选自于以下组中:
-H,-F,-Cl和-Br。
以下化合物是本发明的实施方案:其中:R1选自于以下组中:
-SO2NH2,-SO2Me,-CH2NH2和-CH2NMe2;R1a选自于以下组中:
-H,-F,-Cl和-Br;R1b选自于以下组中:
-CH3,-CF3,-CH2CH3,-SO2Me,-CONH2和-NHSO2Me;R1c1选自于以下组中:
-H,-F,-Cl,-Br,-NH2,-OH,-SO2Me,-SO2Et,-SO2NH2,-NO2,-CH2NH2,
-CN,-CONH2,-CH2OH;R1c2选自于以下组中:
-H,-F,-Cl,-Br和-OMe;以及R1c3选自于以下组中:
-H,-F,-Cl,-Br,-OCH3,-NH2,-CH2NH2,-CONH2,-CONHMe,-CONMe2。
-SO2NH2,-SO2CH3,-CN,-CONH2,-CONH(CH3),-CON(CH3)2,
-CH2NH2,-CH2NH(CH3),-CH2N(CH3)2;R1a选自于以下组中:
-H,-F,-Cl和-Br;R1b选自于以下组中:
-CH3和-CF3;R1c1选自于以下组中:
-H,-F,-Cl,-Br,-CN,-CH2NH2,-CH2OH,-CONH2,-C(=NH)NH2,
-CO2H,-CO2Me,-SO2Me,-SO2NH2,-OH,-NH2,和-NO2;R1c2选自于以下组中:
-H,-F,-Cl,-Br,和-OCH3;以及R1c3选自于以下组中:
-H,-F,-Cl,-Br,-OCH3,-NH2,-CH2NH2,-CONH2,-CONHMe,-CONMe2。
-SO2NH2,-SO2Me,-CH2NH2和-CH2NMe2;R1a选自于以下组中:
-H,-F,-Cl和-Br;R1b选自于以下组中:
-CH3,-CF3,-CH2CH3,-SO2Me,-CONH2和-NHSO2Me;以及R1c选自于以下组中:-H,-F,-Cl,-Br,-NH2,-OH,-SO2Me,-SO2Et,-SO2NH2,-NO2,-CH2NH2,-CN,-CONH2,-CH2OH。以下化合物是本发明的实施方案:其中:R1选自于以下组中:
-SO2NH2,-SO2Me,-CH2NH2和-CH2NMe2;R1a选自于以下组中:
-H,-F,-Cl和-Br;R1b选自于以下组中:
-CH3,-CF3,-CH2CH3,-SO2Me,-CONH2和-NHSO2Me;R1c1选自于以下组中:
-H,-F,-Cl,-Br,-NH2,-OH,-SO2Me,-SO2Et,-SO2NH2,-NO2,-CH2NH2,
-CN,-CONH2,-CH2OH;以及R1c2和R1c3独立地选自于以下组中:
-H,-F,-Cl和-Br。
-Me,-CF3,-Et,-SO2Me,-CONH2和-NHSO2Me;R1c1选自于以下组中:
-H,-F,-Cl,-Br,-NH2,-OH,-SO2Me,-SO2Et,-SO2NH2,-NO2,-CH2NH2,
-CN,-CONH2,-CH2OH;R1c2选自于以下组中:
-H,-F,-Cl和-Br;以及R1c3选自于以下组中:
-H,-F,-Cl和-Br。
-H,-F,-Cl和-Br;R1b选自于以下组中:
-CH3,-CF3,-CH2CH3,-SO2Me,-CONH2和-NHSO2Me;R1c1选自于以下组中:
-H,-F,-Cl,-Br,-NH2,-OH,-SO2Me,-SO2Et,-SO2NH2,-NO2,-CH2NH2,
-CN,-CONH2,-CH2OH;R1c2选自于以下组中:
-H,-F,-Cl,-Br和-OMe;以及R1c3选自于以下组中:
-SO2NH2,-SO2CH3,-CN,-CONH2,-CONH(CH3),-CON(CH3)2,
-CH2NH2,-CH2NH(CH3),-CH2N(CH3)2;R1a选自于以下组中:
-H,-F,-Cl and Br;R1b选自于以下组中:
-CH3和-CF3;R1c1选自于以下组中:
-H,-F,-Cl,-Br,-CN,-CH2NH2,-CH2OH,-CONH2,-C(=NH)NH2,
-CO2H,-CO2Me,-SO2Me,-SO2NH2,-OH,-NH2,和-NO2;R1c2选自于以下组中:
-H,-F,-Cl和-Br;以及R1c3选自于以下组中:
-H,-F,-Cl和-Br。以下化合物是本发明的实施方案:其中:R1选自于以下组中:-CN,-CH2NH2,-CONH2,-C(=NH)NH2,,-SO2Me,
-SO2NH2,和-NH2;R1a选自于以下组中:
-H,-F,-Cl和-Br;R1b选自于以下组中:
-CH3,-CF3,-CH2CH3,-SO2Me,-CONH2和-NHSO2Me;R1c1选自于以下组中:
-H,-F,-Cl,-Br,-NH2,-OH,-SO2Me,-SO2Et,-SO2NH2,-NO2,-CH2NH2,
-CN,-CONH2,-CH2OH;R1c2选自于以下组中:
-H,-F,-Cl,-Br和-OCH3;R1c3选自于以下组中:
-H,-F,-Cl,-Br,-OCH3,-NH2,-CH2NH2,-CONH2,-CONHMe,
-CONMe2。
-H,-F,-Cl和-Br;R1b选自于以下组中:
-CH3和-CF3;R1c1选自于以下组中:
-H,-F,-Cl,-Br,-CN,-CH2NH2,-CH2OH,-CONH2,-C(=NH)NH2,
-CO2H,-CO2Me,-SO2Me,-SO2NH2,-OH,-NH2,和-NO2;R1c2选自于以下组中:
-H,-F,-Cl,-Br,和-OCH3;以及R1c3选自于以下组中:
-H,-F,-Cl,-Br,-OCH3,-NH2,-CH2NH2,-CONH2,-CONHMe,-CONMe2。以下化合物是本发明的实施方案:其中:R1选自于以下组中:
-SO2NH2,-SO2CH3,-CN,-CONH2,-CONH(CH3),-CON(CH3)2,
-CH2NH2,-CH2NH(CH3),-CH2N(CH3)2;R1a选自于以下组中:
-H,-F,-Cl和-Br;R1b选自于以下组中:
-H,-CH3和-CF3;R1c1选自于以下组中:
-H,-F,-Cl,-Br,-CN,-CH2NH2,-CH2OH,-CONH2,-C(=NH)NH2,
-CO2H,-CO2Me,-SO2Me,-SO2NH2,-OH,-NH2,和-NO2;R1c2选自于以下组中:
-H,-F,-Cl和-Br;以及R1c3选自于以下组中:
-H,-F,-Cl和-Br。
以下化合物是本发明的实施方案:其中:R1选自于以下组中:
-SO2NH2,-SO2CH3,-CN,-CONH2,-CONH(CH3),-CON(CH3)2,
-CH2NH2,-CH2NH(CH3),-CH2N(CH3)2;R1a选自于以下组中:
-H,-F,-Cl和-Br;R1b选自于以下组中:
-H,-CH3和-CF3;R1c1选自于以下组中:
-H,-F,-CN,-CH2NH2,-CONH2,-SO2Me,-SO2NH2和-NO2;R1c2选自于以下组中:
-H,-F,-Cl,-Br和-OCH3;以及R1c3选自于以下组中:
-H,-F,-Cl,-Br,-OCH3,-NH2,-CH2NH2,-CONH2,-CONHMe,
-H,-F,-Cl和-Br;R1b选自于以下组中:
-H,-CH3和-CF3;R1c1选自于以下组中:
-H,-F,-Cl,-Br,-CN,-CH2NH2,-CH2OH,-CONH2,-C(=NH)NH2,
-CO2H,-CO2Me,-SO2Me,-SO2NH2,-OH,-NH2,和-NO2;R1c2选自于以下组中:
-H,-F,-Cl和-Br;以及R1c3选自于以下组中:
-H,-F,-Cl和-Br;R1b选自于以下组中:
-H,-CH3和-CF3;R1c1选自于以下组中:
-H,-F,-CN,-CH2NH2,-CONH2,-SO2Me,-SO2NH2和-NO2;R1c2选自于以下组中:
-H,-F,-Cl,-Br和-OCH3;以及R1c3选自于以下组中:
-H,-F,-Cl,-Br,-OCH3,-NH2,-CH2NH2,-CONH2,-CONHMe,
-CONMe2。以下化合物是本发明的实施方案:其中:R1选自于以下组中:
-SO2NH2,-SO2Me,-CH2NH2和-CH2NMe2;R1a选自于以下组中:
-H,-F,-Cl和-Br;R1b选自于以下组中:
-CH3,-CF3,-CH2CH3,-SO2Me,-CONH2和-NHSO2Me;R1c2和R1c3选自于以下组中:
-H,-F,-Cl和-Br。以下化合物是本发明的实施方案:其中:R1选自于以下组中:
-SO2NH2,-SO2Me,-CH2NH2和-CH2NMe2;R1a选自于以下组中:
-H,-F,-Cl和-Br;R1b选自于以下组中:
-CH3,-CF3,-CH2CH3,-SO2Me,-CONH2和-NHSO2Me;R1c2和R1c3独立地选自于以下组中:
-H,-F,-Cl和-Br。
本发明还包括式(I)化合物之所有的药物学上可接受的异构体、盐、水合物、溶剂化物以及前药衍生物。另外,式(I)的化合物可以各种异构体或者互变异构体的形式存在,而且所有的此等异构体和互变异构体形式及其药物学上可接受的盐、水合物、溶剂化物以及前药衍生物都包括在本发明的范围内。
本发明的化合物可以游离酸或碱的形式分离,或者转化为各种无机和有机酸及碱的盐。此等盐也在本发明的范围之内。非毒性以及生理相容性盐是特别有用的,但是其他并不特别希望的盐也可用于分离和纯制步骤中。
许多方法都可用于制备如上所述的盐,而且对于本领域技术人员而言也是已知的。例如,游离酸或游离碱形式的本发明化合物可与一或者多摩尔当量的所希望的酸或碱在溶剂或者溶剂混合物中反应,而所述盐则不溶于所述溶剂或者溶剂混合物中,或者诸如水的溶剂能够通过蒸发、蒸馏或者冻干来除去。或者,游离酸或者碱形式的产物可由离子交换树脂中通过,以形成所希望的盐,或者盐形式的产物可使用相同的常规方法转化为其他的盐。化合物的制备
本发明的化合物可通过标准教科书中描述的标准有机化学合成方法来合成。这些方法在本领域中是已知的。例如参见:March,“AdvancedOrganic Chemistry”,John Wiley & Sons,New York,1992;Joule,Mills andSmith,“Heterocyclic Chemistry”,Chapman & Hall,London,1995。
这些方法中所用的起始物可由化学品销售商如Aldrich、Fluka、Lancaster、TCI、Maybridge、Frontier、Fluorochem、Alfa Aesar等处购得,或者可通过已知的方法来合成。
反应可在标准的实验室玻璃仪器和反应容器中于标准温度和压力的反应条件下进行,除非另有说明。
在合成这些化合物期间,取代基的官能团可任选地用保护基进行保护,以防止交叉反应。合适保护基的例子以及它们的应用描述在以下文献中:Kocienski,“Protecting Groups”,Thieme,Stuttgart,1994;Greene andWuts,“Protective Groups in Organic Synthesis”,John Wiley & Sons,NewYork,1999。这些文献的内容在此并入作为参考。
如下直接概括出非限制性的合成路线,而具体的步骤描述在实施例中。反应产物是通过常规方法来分离和纯制的,典型地包括用溶剂萃取至相配适的溶剂中。产物可进一步通过本领域技术人员已知的方法来纯制,如快速柱色谱、用高纯度的水和乙腈进行的反相制备性高效液相色谱(HPLC)、或者其他合适的方法。总的合成方法
在以下合成路线1中概括了具有N-连接G环的化合物的总合成法。在合成路线1中,A′、Q′、D′、E′、J′和X′是经保护的官能结构,其可通过本领域技术人员已知的方法(如脱保护法)分别转化为A、Q、D、E、J和X。在形成N-连接的G环时,合适的芳香胺前体在Joule,Mills andSmith,“Heterocyclic Chemistry”,Chapman & Hall,London,1995,或者其中引用的参考文献,或者在制备部分中描述的条件下处理,形成G环。合成路线1合成路线2
以上所示的合成路线2显示了具有N-连接的吡唑G环的化合物的总合成法。通过还原其重氮盐,经合适保护的芳香胺转化为芳香肼。肼与1,3-二酮缩合,产生吡唑结构。
合成路线3显示了具有N-连接的三唑G环的化合物的总合成法。由其重氮盐,经合适保护的芳香胺转化为芳香叠氮化物。该叠氮化物与炔缩合,产生三唑结构。
合成路线4显示了具有N-连接的四唑G环的化合物的总合成法。经合适保护的芳香胺用氯氧代乙酸乙酯进行酰基化。所得的酰胺可通过本领域已知的方法转化为四唑。例如参考:Journal of Organic Chemistry,56,2395(1991);Synthesis,767(1993);Journal of Organic Chemistry,58,32(1993);Bioorganic & Medicinal Chemistry Letters,6,1015(1996)。
合成路线5显示了具有C-连接的G环的化合物的总合成法。A′、Q′、D′、E′、J′和X′是经保护的官能结构,可分别转化为A、Q、D、E、J和X。在形成C-连接的G环时,合适的芳香醛前体在Joule,Mills andSmith,“Heterocyclic Chemistry”,Chapman & Hall,London,1995,或者其中引用的参考文献,或者在制备部分中描述的条件下处理,形成G环。C-连接的G环也可使用Suzuki交叉偶联法(Chemical Reviews,95,2457(1995))连接在芳香X或者芳香D上。合成路线5
合成路线6显示了具有C-连接的异恶唑G环的化合物的总合成法。经取代的芳香醛与羟胺反应,然后被氯化,形成hydroximinoyl choride(Journal of Organic Chemistry,45,3916(1980))。该化合物用三乙基胺处理,原位产生氧化腈,其与trans-3-甲氧基丙烯酸甲酯或者丙炔酸甲酯反应,形成异恶唑结构(Chemical Letters,1,85,(1987))。合成路线6
合成路线7显示了具有C-连接的噻唑G环的化合物的总合成法。在氯化锡(II)存在下,经取代的芳香醛与叠氮基乙酸乙酯反应,形成β-酮基酯。该酯然后转化为噻唑。合成路线7组合物及制剂
可以将本发明的化合物分离为游离酸或碱,或者将其转化为各种无机和有机酸或碱的盐。这些盐在本发明的范围内。无毒和生理学相容的盐是特别有用的,虽然其它较不理想的盐可以用于分离和纯化过程中。
许多方法用于制备上述盐,并且是本领域技术人员已知的。例如,上述结构的化合物的游离酸或游离碱形式与一或多摩尔当量的期望的酸或碱在盐不溶的溶剂或溶剂混合物中反应,或者在溶剂如水中反应,然后蒸发、蒸馏或冻干除去溶剂。或者将游离酸或碱形式的产物通过离子交换树脂形成期望的盐,或者用同样的常规方法将产物的一种盐形式转化成另一种盐形式。
本发明还包括本文所包含的化合物的前药衍生物。术语“前药”指母药分子的药理学非活性衍生物,它需要在生物体内自发或酶促的生物转化以释放活性药物。前药是本发明的化合物的变体或衍生物,其具有在代谢条件下可裂解的基团。当前药在生理条件下经历溶剂解或经历酶促降解时,它们成为在体内具有药学活性的本发明的化合物。本发明的前药化合物可以被称为单、双、三等,这取决于在生物体内释放活性药物所需的生物转化步骤的数目,并代表在前体型形式中存在的官能团的数目。前药形式通常提供在哺乳动物生物体内的溶解性、组织相容性或延迟释放的优点(参见Bundgard,Design of Prodrugs(前药设计),第7-9、21-24页,Elsevier,Amsterdam 1985和Silverman,The Organic Chemistry ofDrug Design and Drug Action(药物设计的有机化学和药物作用),第352-401页,Academic Press,San Diego,CA,1992)。本领域公知的前药包括本领域技术人员熟知的酸衍生物,例如通过母酸与适宜的醇反应制备的酯,或通过母酸化合物与胺,或与反应形成酰化碱衍生物的碱性基团反应而制备的酰胺。而且,本发明的前药衍生物可以与已知的本文的其它特征组合以提高生物利用度。
本发明的化合物的诊断应用一般采用诸如溶液或混悬液的制剂。在血栓形成疾病的治疗中,本发明的化合物可以以组合物应用,如用于口服给药的片剂、胶囊剂或酏剂,栓剂、无菌溶液或混悬液或注射给药等,或者掺入成形制品中。可以向需要用本发明的化合物治疗的受试者(一般为哺乳动物)给药提供最佳功效的剂量。给药剂量和方法随受试者而变,并取决于如下因素:被治疗的哺乳动物的类型、其性别、体重、饮食、共同药物治疗、整体临床症状、所用的特定化合物、所用化合物的具体用途,以及其它本领域技术人员将认识到的因素。
通过混合具有期望纯度的化合物和生理学可接受的载体、赋形剂、稳定剂等而制得本发明的化合物的制剂,用于储存或给药,其可以以缓释或控释制剂提供。用于治疗用途的可接受的载体或稀释剂在药学领域是已知的,例如在Remington′s Pharmaceutical Sciences,Mack PublishingCo.,(A.R.Gennaro edit.1985)中所述。这些材料在所用的剂量和浓度下对接受者是无毒的,它包括缓冲剂如磷酸盐、柠檬酸盐、醋酸盐和其它有机酸盐,抗氧化剂如抗坏血酸、低分子量(小于约10个残基)肽如聚精氨酸,蛋白质如血清白蛋白,明胶或免疫球蛋白,亲水聚合物如聚乙烯吡咯烷酮,氨基酸如甘氨酸、谷氨酸、天冬氨酸或精氨酸,单糖、二糖,以及其它碳水化合物,包括纤维素或其衍生物、葡萄糖、甘露糖或糊精,螯合剂如EDTA,糖醇如甘露糖醇或山梨糖醇,抗衡离子如钠和/或非离子表面活性剂如Tween、Pluronics或聚乙二醇。
用于治疗给药的本发明的化合物的剂型必须是无菌的。无菌可以容易地通过无菌膜如0.2微米的膜过滤,或通过其它常规方法实现。制剂一般以冻干形式或以水溶液储存。本发明的制剂的pH一般为3-11,更优选为5-9,且最优选为7-8。将会理解用某些前述赋形剂、载体或稳定剂将导致形成环状多肽盐。虽然优选的给药途径是通过注射,但也预期其它给药方法,如静脉内(快速浓注和/或输注)、皮下、肌内、结肠、直肠、鼻或腹膜内给药,使用各种剂型如栓剂、植入丸或小圆柱、气雾剂、口服制剂或局部制剂如软膏、滴剂和皮肤药贴。期望地将本发明的化合物掺入成形制品如植入物中,所述植入物可以采用惰性材料如可生物降解的聚合物或合成聚硅氧烷,例如硅橡胶、硅酮橡胶或其它可商购的聚合物。
本发明的化合物还可以以脂质体给药系统形式给药,如小单层囊泡、大单层囊泡和多层囊泡。可以由各种类脂如胆固醇、硬脂酰胺或卵磷脂形成脂质体。
还可以使用该化合物分子偶合其上的抗体、抗体片断、生长因子、激素或其它靶向部分而给药本发明的化合物。本发明的化合物还可以与适宜的作为靶向药物载体的聚合物偶合。这些聚合物可以包括聚乙烯吡咯烷酮、吡喃共聚物、聚羟基-丙基-甲基丙烯酰胺-酚、聚羟基乙基-天冬酰胺-酚或被棕榈酰残基取代的聚环氧乙烷-多熔素。而且,本发明的因子Xa抑制剂可以偶合到用于实现药物控释的一类可生物降解的聚合物上,例如聚乳酸、聚乙醇酸、聚乳酸和聚乙醇酸的共聚物、聚ε己内酯、聚羟基丁酸、聚原酸酯、聚缩醛、聚二氢吡喃、聚氰基丙烯酸酯和水凝胶的交联或两亲的嵌段共聚物。聚合物和半渗透的聚合物基质可以成形为成形制品,如瓣膜、支架、管、假体等等。
一般将治疗化合物液体制剂置于具有无菌入孔的容器内,例如具有皮下注射针可刺破的塞子的静脉内溶液袋或小瓶。
可以通过体外或体内方法测定治疗有效剂量。对于本发明的各具体化合物,可以进行单个测定以确定所需的最佳剂量。治疗有效剂量的范围受给药途径、治疗目的和患者症状的影响。对于通过皮下针注射而言,可以认为剂量给入体液。对于其它给药途径,必须通过已知的药理学方法单独测定各抑制剂的吸收功效。因此,治疗学家可能需要滴定此剂量并改变给药途径,以得到最佳的治疗效果。有效剂量水平的测定,即实现期望效果所需的剂量水平,将由本领域技术人员容易地测定。通常,化合物的应用起始于低剂量水平,并增大剂量水平直至实现期望的效果。
一般的剂量范围为约0.001mg/kg至约1000mg/kg,优选为约0.01mg/kg至约100mg/kg,更优选为约0.10至约20mg/kg。有利地,本发明的化合物可以每日几次给药,并且也可以使用其它给药方案。
通常,游离酸或碱形式,或者药学可接受的盐的约0.5至500mg的本发明的化合物或化合物的混合物与以下物质复合:生理学可接受的赋形剂(vehicle)、载体、赋形剂(excipient)、粘合剂、防腐剂、稳定剂、染料、调味料等,这些物质是可接受的药学实践需要的。这些组合物中活性成分的量是得到所指明的范围内的适宜剂量的量。
可以掺入片剂、胶囊剂等中的辅剂为粘合剂,如阿拉伯胶、玉米淀粉或明胶;以及赋形剂,如微晶纤维素、崩解剂样玉米淀粉或海藻酸;润滑剂如硬脂酸镁;甜味剂如蔗糖或乳糖;或者调味剂。当剂型为胶囊剂时,除了上述材料之外,它还可以含有液体载体,如水、盐水、脂肪油。各种类型的其它材料可以用作包衣或作为剂量单元物理形式的改性剂。可以根据常规药学实践制剂注射用的无菌组合物。例如,将活性化合物溶解或悬浮在赋形剂如油或合成脂肪赋形剂样油酸乙酯中,或者期望溶解或悬浮于脂质体中。根据公认的药学实践,可以加入缓冲剂、防腐剂、抗氧化剂等。
在实施本发明的方法时,可以单独或组合使用本发明的化合物,或者与其它治疗剂或诊断剂组合使用。在某些优选的实施方案中,本发明的化合物可以与其它医学实践普遍接受的这些症状的常规处方化合物联合给药,所述常规处方化合物如抗凝剂、溶栓剂或其它抗血栓形成剂,包括血小板聚集抑制剂、组织纤溶酶原激活物、尿激酶、前尿激酶、链激酶、肝素、阿斯匹林或华法令。本发明的化合物可以在体内使用,一般用于哺乳动物如灵长类,如人、羊、马、牛、猪、狗、猫、大鼠和小鼠,或在体外使用。
本发明优选的化合物的特征在于它们抑制血栓形成的能力和对与其应用相关的凝血参数、血小板和血小板功能的可接受的影响、可接受的水平的出血并发症。以不期望的血栓形成为特征的症状包括涉及动脉和静脉脉管系统的症状。
就冠状动脉脉管系统而言,异常血栓形成是已形成的动脉粥样硬化斑破裂的特征,它是急性心肌梗死和不稳定型心绞痛的主要原因,它还是由溶栓治疗或经皮透照冠脉血管成形术(PTCA)导致的闭塞性冠脉血栓的形成的特征。
就静脉脉管系统而言,异常血栓形成是在接受下肢或腹部区域的大外科手术的患者中观察到的症状的特征,这些患者经常患有静脉脉管系统中的血栓形成,导致流到受影响肢体的血液减少和肺栓塞的倾向。异常血栓形成还是在败血症性休克、某些病毒感染和癌症期间在两种血管系统中经常发生的播散性血管内凝血的特征,而播散性血管内凝血是这样一种症状,其中发生凝血因子快速消耗和全身性凝血,其导致遍及微脉管系统的危及生命的血栓形成,引起广泛的器官衰竭。
据信本文公开的所选择和使用的本发明的化合物用于预防或治疗以不期望的血栓形成为特征的症状,如(a)治疗或预防任何血栓形成介导的急性冠脉综合征,包括心肌梗死、不稳定型心绞痛、顽固性心绞痛、溶栓治疗后或冠脉血管成形术后发生的闭塞性冠脉血栓;(b)治疗或预防任何血栓形成介导的脑血管综合征,包括栓塞性中风、血栓形成性中风或短暂性脑缺血发作;(c)治疗或预防任何在静脉系统中发生的血栓形成综合征,包括深部静脉血栓形成或者自发地或在恶性肿瘤、外科手术或外伤的环境中发生的肺栓塞;(d)治疗或预防任何凝血病,包括播散性血管内凝血(包括败血症性休克或其它感染、外科手术、妊娠、外伤或恶性肿瘤的环境,以及是否与多器官衰竭有关)、血栓性血小板减少性紫癜、闭塞性血栓血管炎或与肝素诱导的血小板减少有关的血栓形成疾病;(e)治疗或预防与体外循环(如肾透析、心肺动脉分流手术或其它氧合过程、血浆置换)有关的血栓形成并发症;(f)治疗或预防与器械操作法(例如心或其它血管内导管插入、主动脉内囊泵、冠脉支架或心瓣膜)有关的血栓形成并发症,和(g)与假体装置安装有关的治疗或预防。
抗凝治疗还用于防止所储存的全血凝固,并防止其它用于试验和储存的生物样品凝固。因此,可以将本发明的化合物加入到或与任何含有或怀疑含有因子Xa的介质中,其中期望凝血受到抑制,例如当将哺乳动物血液与以下材料接触时:血管移植物、支架、矫形假体、心支架、瓣膜和假体、体外循环系统等。
在没有进一步描述的情况下,相信本领域技术人员可以利用在前的描述和以下的说明性实施例制备和应用本发明的化合物并实施所要求保护的方法。以下实施例仅是具体地指明本发明的优选实施方案,但绝不是对本发明范围的限制。实施例1
步骤1:将2-萘基硼酸(5.00g,29.1mmol)和3-甲基吡唑-5-甲酸乙基酯(4.48g,29.1mmol)溶解在100ml无水二氯甲烷(DCM)中,然后向该溶液中添加吡啶(4.7ml,58.2mmol)和无水乙酸铜(II)粉末(7.94g,43.7mmol)。添加一些经活化的分子筛粉末。所得浆液在氩气中搅拌2天。混合物用DCM稀释。通过celite过滤,蓝色滤液用水洗涤(×2),在硫酸镁上干燥,浓缩,然后用硅胶柱纯制,得到3-甲基-1-(2-萘基)-1H-吡唑-5-甲酸乙基酯及其区域异构体(regioisomer),比例为1∶1,产率为70%。Rf 0.59(1∶2乙酸乙酯∶己烷),M+H281;区域异构体,5-甲基-1-(2-萘基)-1H-吡唑-3-甲酸乙基酯,Rf0.44(1∶2乙酸乙酯∶己烷)。ES-MS:(M+H)+281。
步骤2:将2′-N-叔丁基氨基磺酰基-[1,1′]-联苯基-4-基胺(50mg,0.16mmol)溶解在1ml的DCM中,然后在室温下于氩气中向该溶液中添加三甲基铝(2.0M的己烷溶液,0.41ml,0.82mmol)。搅拌30分钟后,向混合物中添加如上制得的酯(46mg,0.16mmol)在1ml DCM中的溶液。所得混合物搅拌过夜。用5ml饱和的Rochelle盐水溶液使反应停止。用DCM萃取混合物(×3)。有机相合并,干燥,旋转蒸发,然后进行快速柱纯制,得到偶联产物,产率为52%(46mg)。Rf 0.46(1∶1乙酸乙酯∶己烷)。ES-MS:(M+H)+539。
步骤3:如上制得的化合物(42mg,0.078mmol)放置在3ml的三氟乙酸(TFA)中。该溶液在60℃浴中搅拌30分钟。旋转蒸发除去TFA。残留物溶解在甲醇中,并用制备性HPLC纯制,得到标题化合物,产率为95%。ES-MS:(M+H)+483。实施例2
步骤1:搅拌氯化锡(II)(2.08g,10.96mmol)和偶氮基乙酸乙酯(2.76ml,26.28mmol)在50ml DCM中的混合物2小时。添加萘-2-甲醛。在室温下搅拌18小时后,浓缩混合物,溶解在乙酸乙酯中,用水洗涤(×3),干燥,然后蒸发。粗产物进行纯制,得到产物3-(2-萘基)-3-氧代丙酸乙基酯。Rf 0.61(1∶1乙酸乙酯∶己烷)。ES-MS:(M+H)+243。
步骤2:在65℃下将如上制得的酯(240mg,1mmol)溶解在15ml的MeCN中,然后在该溶液中添加羟基(甲苯磺酰氧基)碘苯(430mg,1.1mmol)。搅拌1小时后,在该混合物中添加硫脲(83mg,1.1mmol)。所得混合物在65℃下搅拌过夜。冷却并浓缩该溶液。残留物溶解在乙酸乙酯中,用盐水洗涤,在硫酸镁上干燥,然后蒸发,得到粗的2-甲基-4-(2-萘基)-5-(乙酯基)噻唑。Rf 0.64(1∶3乙酸乙酯∶己烷)。ES-MS:(M+H)+298。
步骤3:将如上制得的产物(148mg,0.50mmol)和2′-N-叔丁基氨基磺酰基-[1,1′]-联苯基-4-基胺(152mg,0.50mmol)溶解在3ml的DCM中,在该溶液中添加三甲基铝(2.0M己烷溶液,0.75ml,1.5mmol),并在室温下搅拌混合物20小时。反应物用4ml的1N盐酸中和,然后用乙酸乙酯萃取。有机层用盐水洗涤,在硫酸镁上干燥,然后浓缩,得到偶联产物(170mg,61%)。Rf 0.25(1∶3乙酸乙酯∶己烷)。ES-MS:(M+H)+556。
步骤4:如上制得的化合物(100mg)放置在3ml的TFA中。该溶液在80℃浴中搅拌60分钟。旋转蒸发除去TFA。残留物溶解在甲醇中,并用制备性HPLC纯制,得到标题化合物,产率为90%以上。ES-MS:(M+H)+500。实施例3
步骤1:将3-氨基-2-萘甲酸(40.4g,216mmol)放入200ml的浓盐酸中。在0℃下,用机械搅拌桨剧烈地搅拌该浆液。向其中添加亚硝酸钠(29.8g,432mmol)在70ml水中的冷溶液。添加完全后,在0℃下搅拌该冷的浆液30分钟。向其中添加冷的四氟硼酸(48重量%的水溶液,56ml,432mmol)。在0℃下搅拌30分钟后,用Buchner漏斗过滤固体。固体饼小心地用冷水(10ml×2)、冷的四氟硼酸(10ml×2)和冷乙醇(5ml×2)淋洗。真空干燥固体。然后放入300ml的二甲苯中,并回流过夜。旋转蒸发除去二甲苯。残留物用盐酸水溶液酸化至pH为1,然后倒入乙酸乙酯中。用盐水洗涤(×2),干燥,蒸发,得到3-氟-2-萘甲酸(32.6g,78%)。ES-MS:(M+H)+191。
步骤2:将如上制得的酸(14.7g,77mmol)溶解在200ml的氯仿中。向其中添加0.5ml的无水DMF。然后在室温下,滴加草酰氯(20ml,232mmol)。搅拌反应溶液过夜。真空除去所有的溶剂。将残留物抽至干燥。将其溶解在150ml的无水二恶烷中,冷却至0℃,然后剧烈搅拌。在冷的温度下,向其中分批添加叠氮化钠(10g,155mmol,在30ml水和15ml二恶烷中)冷溶液。反应物在0℃下放置2小时。真空除去溶剂。残留物倾倒在乙酸乙酯中,用盐水洗涤(×3)。有机相干燥,然后真空蒸发至干,得到3-氟-2-萘甲酰基叠氮化物。Rf 0.83(1∶1乙酸乙酯∶己烷)。将其溶解在80ml的DMF中。向其中添加40ml的水。回流乳状混合物过夜。真空除去溶剂。残留物放入乙酸乙酯中,并用盐水洗涤(×2)。有机相干燥,浓缩,然后通过快速硅胶柱纯制,得到3-氟-2-萘基胺(8.1g,65%)。Rf 0.40(1∶3乙酸乙酯∶己烷)。ES-MS:(M+H)+162。
步骤3:如上制得的化合物(7.5g,46mmol)放入50ml的浓盐酸中。在冰浴中剧烈搅拌该混合物。向其中滴加亚硝酸钠(3.8g,55mmol)在10ml水中的冷溶液。添加完全后,在0℃下搅拌混合物半小时。在0℃下,向其中滴加SnCl2·2H2O(26.3g,116mmol)在20ml浓盐酸中的冷溶液。该浆液在0℃下搅拌半小时,冷却,并通过Buchner漏斗过滤,以分离固体肼。真空干燥,将固体肼溶解在100ml冰乙酸中。向其中添加2-N-(甲氧基)亚氨基-4-氧代戊酸乙酯(10.4g,56mmol,由2,4-二氧代戊酸乙酯和甲氧基胺盐酸盐在乙醇中制得)和50ml的THF。该混合物回流2小时。真空除去溶剂。残留物放入乙酸乙酯中,用盐水和水洗涤。有机相干燥,浓缩,然后用快速硅胶柱纯制,得到3-甲基-1-(3-氟-2-萘基)-1H-吡唑-5-甲酸乙基酯(9.0g,65%)。Rf 0.52(1∶2乙酸乙酯∶己烷)。ES-MS:(M+H)+299。
步骤4:将2′-N-叔丁基氨基磺酰基-[1,1′]-联苯基-4-基胺(77mg,0.25mmol)溶解在1ml的无水DCM中,向其中添加三甲基铝(2.0M的己烷溶液,0.51ml,1.0mmol)。该混合物搅拌20分钟。将如上制得的酯(50mg,0.17mmol)溶解在3ml的无水DCM中,并添加在铝混合物中。反应物在室温下搅拌过夜,用饱和的Rochelle盐水溶液使反应停止。用氯仿萃取(×3)。有机相合并,干燥,浓缩,然后用快速硅胶柱纯制,得到偶联产物(85mg,90%)。Rf 0.45(1∶1乙酸乙酯;己烷)。ES-MS:(M+H)+557。
步骤5:如上制得的化合物放置在3ml的TFA中。该混合物在室温下搅拌过夜。蒸发,溶解在甲醇中,并用制备性HPLC纯制,得到标题化合物,产率为90%以上。ES-MS:(M+H)+501。实施例4
步骤1:与实施例3之步骤3相同地制备3-甲基-1-(3-氟-2-萘基)-1H-吡唑-5-甲酸乙基酯。该酯(13.2g,44mmol)溶解在80ml甲醇中。向其中添加LiOH·H2O(3.7g,49mmol)和40ml的水。混合物在室温下搅拌过夜。真空蒸发除去甲醇。残留物用1N盐酸酸化至pH为1。混合物用乙酸乙酯萃取(×4)。有机萃取物合并,干燥,蒸发,然后抽至干燥,得到3-甲基-1-(3-氟-2-萘基)-1H-吡唑甲酸,产率超过90%。ES-MS:(M+H)+271。
步骤2:如上制得的酸(33mg,0.12mmol)、2′-N-叔丁基氨基磺酰基-3-氟-[1,1′]-联苯基-4-基胺(77mg,0.24mmol)和催化量的DMAP(5mg)溶解在2ml的吡啶中。该溶液在0℃下搅拌,向其中添加POCl3(45μl,0.48mmol)。搅拌该混合物1小时,用冰片使反应停止。向其中添加乙酸乙酯。用盐水洗涤(×2),干燥,然后浓缩。向残留物中添加3ml的TFA。混合物在60℃下搅拌1小时,浓缩,溶解在甲醇中,然后通过制备性HPLC纯制,得到标题化合物,产率为50%(31mg)。ES-MS:(M+H)+519。实施例5
按照与实施例4相同的方法制备该化合物,其中用2′-N-叔丁基氨基磺酰基-3-氯-[1,1′]-联苯基-4-基胺替换2′-N-叔丁基氨基磺酰基-3-氟-[1,1′]-联苯基-4-基胺。ES-MS:(M+H)+535。实施例6
按照与实施例4相同的方法制备该化合物,其中用2′-N-叔丁基氨基磺酰基-3-溴-[1,1′]-联苯基-4-基胺替换2′-N-叔丁基氨基磺酰基-3-氟-[1,1′]-联苯基-4-基胺。ES-MS:(M+H)+579,581(溴取代时)。实施例7
按照与实施例4相同的方法制备该化合物,其中用2-氨基-5-(2-(N-叔丁基氨基磺酰基)苯基)吡啶替换2′-N-叔丁基氨基磺酰基-3-氟-[1,1′]-联苯基-4-基胺。ES-MS:(M+H)+502。实施例8
按照与实施例4相同的方法制备该化合物,其中用2-氨基-5-(2-(N-叔丁基氨基磺酰基)苯基)嘧啶替换2′-N-叔丁基氨基磺酰基-3-氟-[1,1′]-联苯基-4-基胺。ES-MS:(M+H)+503。实施例9
按照与实施例4相同的方法制备该化合物,其中用2′-氰基-[1,1′]-联苯基-4-基胺替换2′-N-叔丁基氨基磺酰基-3-氟-[1,1′]-联苯基-4-基胺,而且不进行TFA处理。ES-MS:(M+H)+447。实施例10
将实施例9的标题化合物(40mg,0.09mmol)溶解在2ml的无水DMF中。在0℃下,向其中添加硼氢化钠(27mg,0.72mmol)和无水氯化钴(II)(23mg,0.18mmol)。该混合物搅拌2小时,然后用1ml乙酸使反应停止。蒸发混合物,溶解在甲醇中,过滤,用制备性HPLC纯制,得到标题化合物,产率60%。ES-MS:(M+H)+451。实施例11
将实施例9的标题化合物(40mg,0.09mmol)溶解在2ml的无水DMF中。在0℃下,向其中添加硼氢化钠(27mg,0.72mmol)和无水氯化钴(II)(23mg,0.18mmol)。该混合物搅拌2小时,向其中添加10ml丙酮。该混合物在室温下搅拌1小时。用1ml乙酸使反应停止。蒸发混合物,溶解在甲醇中,过滤,用制备性HPLC纯制,得到标题化合物,产率60%。ES-MS:(M+H)+493。实施例12
按照与实施例4相同的方法制备该化合物,其中用2′-(N-二甲基氨基)甲基-[1,1′]-联苯基-4-基胺替换2′-N-叔丁基氨基磺酰基-3-氟-[1,1′]-联苯基-4-基胺,而且没有TFA处理。ES-MS:(M+H)+479。实施例13
步骤1:与实施例4之步骤1相同地制备3-甲基-1-(3-氟-2-萘基)-1H-吡唑甲酸。
步骤2:该酸(65mg,0.24mmol)、4-氨基苄腈(57mg,0.48mmol)和DMAP(5mg)溶解在3ml的吡啶中。该溶液在0℃下搅拌,向其中添加POCl3(90μl,0.96mmol)。混合物搅拌1小时。用冰片使反应停止。用乙酸乙酯稀释,有机相用盐水洗涤(×2),干燥,浓缩,然后用快速硅胶柱纯制,得到偶联产物(60mg,68%)。Rf 0.40(1∶1乙酸乙酯己烷)。ES-MS:(M+H)+371。
步骤3:将如上制得的腈溶解在10ml的无水甲醇中。在冰浴中冷却并搅拌。通过长的针向该溶液中吹入氯化氢气体,直至达到饱和(用设置在反应烧瓶顶部的气球指示)。所得溶液搅拌过夜。ES-MS:(M+H)+403。真空除去溶剂。残留物抽至干燥。将固体溶解在5ml的无水甲醇中。向其中添加无水N-甲基亚乙基二胺(0.5ml)。该混合物回流1小时,浓缩,然后用制备性HPLC纯制,得到标题化合物,产率为80%。ES-MS:(M+H)+428。实施例14
按照与实施例13相同的方法制备该化合物,但用哌啶替换N-甲基亚乙基二胺。ES-MS:(M+H)+456。实施例16
按照与实施例13相同的方法制备该化合物,但用二甲基胺(市售的为在THF中的2M溶液)替换N-甲基亚乙基二胺。ES-MS:(M+H)+416。实施例17
步骤1:将2-氟-4-碘苯胺(5.0g,21mmol)溶解在20ml的无水DMF中。向其中添加CuCN(3.8g,42mmol)和催化量的CuI(200mg)。该浆液回流1小时。用乙酸乙酯稀释。用celite过滤。真空浓缩,得到固体4-氨基-3-氟苄腈(2.9g,100%)。ES-MS:(M+H)+137。
步骤2:与实施例4之步骤1相同地制备3-甲基-1-(3-氟-2-萘基)-1H-吡唑甲酸。该酸(270mg,1.0mmol)、4-氨基-3-氟苄腈(272mg,2.0mmol)和DMAP(10mg)溶解在15ml的吡啶中。该溶液在0℃下搅拌。向其中添加POCl3(380μl,4.0mmol)。该混合物搅拌1小时。用冰片使反应停止。用乙酸乙酯稀释。有机相用盐水洗涤(×2)。干燥,浓缩,然后用快速硅胶柱纯制,得到偶联产物(350mg,97%)。Rf 0.77(7∶3乙酸乙酯∶己烷)。ES-MS:(M+H)+389。
步骤3:将如上制得的腈(30mg,0.077mmol)溶解在10ml的无水甲醇中。在冰浴中冷却并搅拌。通过长的针向该溶液中吹入氯化氢气体,直至达到饱和(用设置在反应烧瓶顶部的气球指示)。所得溶液搅拌过夜。ES-MS:(M+H)+421。真空除去溶剂。残留物抽至干燥。将固体溶解在5ml的无水甲醇中。向其中添加无水N-甲基亚乙基二胺(0.5ml)。该混合物回流1小时,浓缩,然后用制备性HPLC纯制,得到标题化合物,产率为80%。ES-MS:(M+H)+446。实施例23
按照与实施例22相同的方法制备该化合物,但用吡咯烷替换N-甲基亚乙基二胺。ES-MS:(M+H)+460。实施例24
按照与实施例22相同的方法制备该化合物,但用六亚甲基亚胺替换N-甲基亚乙基二胺。ES-MS:(M+H)+488。实施例26
按照与实施例22相同的方法制备该化合物,但用吗啉替换N-甲基亚乙基二胺。ES-MS:(M+H)+476。实施例27
步骤1:与实施例4之步骤1相同地制备3-甲基-1-(3-氟-2-萘基)-1H-吡唑甲酸。该酸(50mg,0.18mmol)、4-氨基-2,5-二氟苄腈(57mg,0.36mmol)和DMAP(5mg)溶解在8ml的吡啶中。该溶液在0℃下搅拌。向其中添加POCl3(70μl,0.74mmol)。该混合物搅拌1小时。用冰片使反应停止。用乙酸乙酯稀释。有机相用盐水洗涤(×2)。干燥,浓缩,然后用快速硅胶柱纯制,得到偶联产物(70mg,93%)。Rf 0.69(7∶3乙酸乙酯∶己烷)。ES-MS:(M+H)+407。
步骤2:将如上制得的腈(30mg,0.074mmol)溶解在10ml的无水甲醇中。在冰浴中冷却并搅拌。通过长的针向该溶液中吹入氯化氢气体,直至达到饱和(用设置在反应烧瓶顶部的气球指示)。所得溶液搅拌过夜。ES-MS:(M+H)+439。真空除去溶剂。残留物抽至干燥。将固体溶解在5ml的无水甲醇中。向其中添加无水N-甲基亚乙基二胺(0.5ml)。该混合物回流1小时,浓缩,然后用制备性HPLC纯制,得到标题化合物,产率为80%。ES-MS:(M+H)+464。实施例29
按照与实施例28相同的方法制备该化合物,但用吡咯烷替换N-甲基亚乙基二胺。ES-MS:(M+H)+478。实施例30
按照与实施例28相同的方法制备该化合物,但用乙酸铵替换N-甲基亚乙基二胺。ES-MS:(M+H)+424。实施例31
步骤1:按照与实施例3之步骤3相同的方法合成3-甲基-1-(3-溴-2-萘基)-1H-吡唑-甲酸乙基酯,但用市售的3-溴-2-萘基胺替换3-氟-2-萘基胺。产率为60%。Rf 0.42(1∶3乙酸乙酯∶己烷)。ES-MS:(M+H)+359,361(溴取代时)。
步骤2:将如上制得的溴化物(370mg,1.0mmol)溶解在3ml的无水DMF中。向其中添加CuCN(180mg,2.0mmol)和CuI(20mg)。回流该浆液混合物2小时,用乙酸乙酯稀释,然后由celite过滤。浓缩,并用快速硅胶柱纯制,得到3-甲基-1-(3-氰基-2-萘基)-1H-吡唑-甲酸乙基酯(220mg,70%)。Rf 0.48(1∶2乙酸乙酯∶己烷)。ES-MS:(M+H)+306。
步骤3:将2′-N-叔丁基氨基磺酰基-[1,1′]-联苯基-4-基胺(164mg,0.54mmol)溶解在2ml的无水DCM中,向其中添加三甲基铝(2.0M的己烷溶液,1.1ml,2.2mmol)。该混合物搅拌20分钟。将如上制得的酯(137mg,0.45mmol)溶解在6ml的无水DCM中,并添加在铝混合物中。反应物在室温下搅拌过夜,用饱和的Rochelle盐水溶液使反应停止。用氯仿萃取(×3)。有机相合并,干燥,浓缩,然后用快速硅胶柱纯制,得到3-甲基-1-(3-氰基-2-萘基)-1H-吡唑-5-(N-(2′-N-叔丁基氨基磺酰基-[1,1′]-联苯-4-基))羧酰胺(170mg,67%)。Rf 0.40(1∶1乙酸乙酯;己烷)。ES-MS:(M+H)+564。
步骤4:将如上制得的化合物(30mg,0.05mmol)溶解在5m1的无水DCM中。在0℃下,向其中滴加BF3·OEt2(62μl,0.5mmol)。该混合物搅拌过夜。第二天,在室温下再分批添加额外的1.0mmol的BF3·OEt2。再搅拌过夜,脱保护为约70%完全。该混合物在短的快速硅胶柱上进行分离。用制备性HPLC纯制标题产物(55%产率)。ES-MS:(M+H)+508。实施例35
步骤1:按照与实施例34之步骤3相同的方法合成3-甲基-1-(3-氰基-2-萘基)-1H-吡唑-5-(N-(2′-N-叔丁基氨基磺酰基-[1,1′]-联苯-4-基))羧酰胺。
按照与实施例34相同的方法制备该化合物,其中用2′-N-叔丁基氨基磺酰基-3-氟-[1,1′]-联苯基-4-基胺替换2′-N-叔丁基氨基磺酰基-[1,1′]-联苯基-4-基胺。ES-MS:(M+H)+526。实施例37
按照与实施例35相同的方法制备该化合物,其中用2′-N-叔丁基氨基磺酰基-3-氟-[1,1′]-联苯基-4-基胺替换2′-N-叔丁基氨基磺酰基-[1,1′]-联苯基-4-基胺。ES-MS:(M+H)+544。实施例38
步骤1:按照与实施例34之步骤2相同的方法合成3-甲基-1-(3-氰基-2-萘基)-1H-吡唑-甲酸乙基酯。
步骤2:将如上制得的酯(930mg,3.0mmol)溶解在20ml的甲醇中。向其中添加LiOH·H2O(256mg,6.0mmol)和10ml的水。该混合物在室温下搅拌3小时。真空除去甲醇。残留物小心地用1N盐酸酸化至pH为1。用乙酸乙酯萃取(×4)。有机相合并,干燥,然后真空蒸发至干,得到3-甲基-1-(3-氰基-2-萘基)-1H-吡唑-5-甲酸(720mg,85%)。ES-MS:(M+H)+278。
步骤3:将如上制得的酸(110mg,0.40mmol)、2′-N-叔丁基氨基磺酰基-3-氯-[1,1′]-联苯基-4-基胺(0.21g,0.60mmol)、DMAP(5mg)溶解在5ml的吡啶中,然后在0℃下搅拌。向其中添加POCl3(120μl,1.2mmol)。混合物搅拌2.5小时,然后用冰片使反应停止。用乙酸乙酯稀释,用盐水洗涤(×2),干燥,浓缩,然后用快速硅胶柱纯制,得到3-甲基-1-(3-氰基-2-萘基)-1H-吡唑-5-(N-(2′-N-叔丁基氨基磺酰基-3-氯-[1,1 ′]-联苯-4-基))羧酰胺(240mg,95%)。Rf 0.65(1∶1乙酸乙酯;己烷)。ES-MS:(M+H)+598。
步骤4:将如上制得的化合物(30mg,0.05mmol)溶解在5ml的无水DCM中。在0℃下,向其中滴加BF3·OEt2(62μl,0.5mmol)。该混合物搅拌过夜。第二天,在室温下再分批添加额外的1.0mmol的BF3·OEt2。再搅拌过夜,脱保护为约70%完全。该混合物在短的快速硅胶柱上进行分离。用制备性HPLC纯制标题产物(52%产率)。ES-MS:(M+H)+542。实施例39
步骤1:按照与实施例38之步骤3相同的方法合成3-甲基-1-(3-氰基-2-萘基)-1H-吡唑-5-(N-(2′-N-叔丁基氨基磺酰基-3-氯-[1,1′]-联苯-4-基))羧酰胺。
步骤2:将如上制得的化合物(30mg,0.05mmol)放入3ml的TFA中,然后回流1小时。浓缩后,用制备性HPLC纯制,得到标题化合物(85%)。ES-MS:(M+H)+560。实施例40
按照与实施例38相同的方法制备该化合物,其中用2′-N-叔丁基氨基磺酰基-3-溴-[1,1′]-联苯基-4-基胺替换2′-N-叔丁基氨基磺酰基-3-氯-[1,1′]-联苯基-4-基胺。ES-MS:(M+H)+586,588(溴取代时)。实施例41
按照与实施例39相同的方法制备该化合物,其中用2′-N-叔丁基氨基磺酰基-3-溴-[1,1′]-联苯基-4-基胺替换2′-N-叔丁基氨基磺酰基-3-氯-[1,1′]-联苯基-4-基胺。ES-MS:(M+H)+604,606(溴取代时)。实施例42
按照与实施例38相同的方法制备该化合物,其中用2-氨基-5-(2-(N-叔丁基氨基磺酰基)苯基)吡啶替换2′-N-叔丁基氨基磺酰基-3-氯-[1,1′]-联苯基-4-基胺。ES-MS:(M+H)+509。实施例43
按照与实施例39相同的方法制备该化合物,其中用2-氨基-5-(2-(N-叔丁基氨基磺酰基)苯基)吡啶替换2′-N-叔丁基氨基磺酰基-3-氯-[1,1′]-联苯基-4-基胺。ES-MS:(M+H)+527。实施例44
按照与实施例38相同的方法制备该化合物,其中用2-氨基-5-(2-(N-叔丁基氨基磺酰基)苯基)嘧啶替换2′-N-叔丁基氨基磺酰基-3-氯-[1,1′]-联苯基-4-基胺。ES-MS:(M+H)+510。实施例45 按照与实施例39相同的方法制备该化合物,其中用2-氨基-5-(2-(N-叔丁基氨基磺酰基)苯基)嘧啶替换2′-N-叔丁基氨基磺酰基-3-氯-[1,1′]-联苯基-4-基胺。ES-MS:(M+H)+528。实施例46
步骤1:在0℃下将4-硝基苯胺(1.0g,6.7mmol)溶解在50ml无水乙醇中,然后通过长针向其中吹入氯化氢气体,直至达到饱和。所得溶液搅拌过夜。真空除去溶剂。残留物抽至干燥。将其溶解在50ml的无水乙醇中。向其中添加2ml的N-甲基亚乙基二胺。该混合物回流1小时,然后真空蒸发,得到1-甲基-2-(4-硝基苯基)-2-咪唑啉盐酸盐,产率为90%。ES-MS:(M+H)+206。
步骤2:将如上制得的硝基化合物(500mg,2.4mmol)溶解在4ml的4N盐酸和50ml甲醇中,然后向其中添加10%的Pd/C(50mg)。该混合物在氩气下搅拌2小时。通过celite过滤,然后真空浓缩,得到4-(1-甲基-2-咪唑啉-2-基)苯胺盐酸盐,产率为90%。ES-MS:(M+H)+176。
步骤3:在0℃下将如上制得的胺化合物(40mg,0.22mmol)、3-甲基-1-(3-氰基-2-萘基)-1H-吡唑-5-甲酸(15mg,0.054mmol,见实施例38的步骤2)、DMAP(2mg)溶解在2ml的吡啶中,然后添加POCl3(20μl,0.22mmol)。该混合物搅拌2小时。真空浓缩,用制备性HPLC纯制,得到标题化合物,产率为60%。ES-MS:(M+H)+435。实施例47
将实施例46中制得的标题化合物(10mg)放入TFA中。回流1小时,然后用制备性HPLC纯制,得到标题化合物,产率为85%。ES-MS:(M+H)+453。实施例48
步骤1:在0℃下将2-氟4-硝基苯胺(300mg,2.2mmol)溶解在20ml无水甲醇中,然后通过长针向其中吹入氯化氢气体,直至达到饱和。所得溶液搅拌过夜。真空除去溶剂。残留物抽至干燥。将其溶解在10ml的无水甲醇中。向其中添加1ml的N-甲基亚乙基二胺。该混合物回流1小时,然后真空蒸发,得到1-甲基-2-(2-氟-4-硝基苯基)-2-咪唑啉盐酸盐,产率为90%。ES-MS:(M+H)+224。
步骤2:将如上制得的硝基化合物溶解在2ml的4N盐酸和25ml甲醇中,然后向其中添加10%的Pd/C(20mg)。该混合物在氩气下搅拌2小时。通过celite过滤,然后真空浓缩,得到2-氟-4-(1-甲基-2-咪唑啉-2-基)苯胺盐酸盐,产率为90%。ES-MS:(M+H)+194。
步骤3:在0℃下将如上制得的胺化合物(100mg,0.51mmol)溶解在2ml的DCM中,然后添加三甲基铝(2.0M己烷溶液,2ml,4.0mmol)。该混合物搅拌20分钟。将3-甲基-1-(3-氰基-2-萘基)-1H-吡唑-5-甲酸乙基酯(765mg,0.25mmol,见实施例34的步骤2)溶解在2ml的DCM中,然后添加在反应烧瓶中。该混合物在室温下搅拌2天。用饱和的Rochelle盐水溶液使反应停止,然后用氯仿萃取(×4)。有机相合并,干燥,浓缩,然后用制备性HPLC纯制,得到标题化合物(55%)。ES-MS:(M+H)+453。实施例49
步骤1:按照与实施例34之步骤3相同的方法制备3-甲基-1-(3-氰基-2-萘基)-1H-吡唑-5-(N-(2′-N-叔丁基氨基磺酰基-[1,1′]-联苯基-4-基))羧酰胺。
步骤2:将如上制得的化合物(70mg,0.12mmol)溶解在2ml的无水DMF中。在0℃下,向其中添加硼氢化钠(36mg,0.96mmol)和CoCl2(32mg,0.24mmol)。搅拌2天。用乙酸乙酯稀释,然后搅拌1小时。混合物通过celite过滤。滤液蒸发,得到粗的3-甲基-1-(3-氨甲基-2-萘基)-1H-吡唑-5-(N-(2′-N-叔丁基氨基磺酰基-[1,1′]-联苯基-4-基))羧酰胺。ES-MS:(M+H)+568。
步骤3:如上制得的粗产物放入3ml的TFA中。该混合物在60℃下搅拌1小时。混合物蒸发,然后用制备性HPLC纯制,以分离出标题化合物(35%产率)。ES-MS:(M+H)+512。实施例51
步骤1:按照与实施例34之步骤3相同的方法制备3-甲基-1-(3-氰基-2-萘基)-1H-吡唑-5-(N-(2′-N-叔丁基氨基磺酰基-3-氟-[1,1′]-联苯基-4-基))羧酰胺,但用2′-N-叔丁基氨基磺酰基-3-氟-[1,1′]-联苯基-4-基胺替代2′-N-叔丁基氨基磺酰基-[1,1′]-联苯基-4-基胺。ES-MS:(M+H)+582。
步骤2:在-20℃下将如上制得的化合物(77mg,0.13mmol)溶解在3ml的无水甲醇和3ml的无水乙酸乙酯中,然后通过长针向其中吹入氯化氢气体直至饱和。该混合物搅拌过夜。真空除去溶剂。干燥的残留物溶解在5ml的无水甲醇中。向其中添加50mg的乙酸铵。混合物搅拌2.5小时。用制备性HPLC纯制,以分离标题化合物(55%产率)。ES-MS:(M+H)+543。实施例52
步骤1:将3-氨基-2-萘甲酸(5.8g,31mmol)放入50ml的浓盐酸中。在0℃下剧烈地搅拌该浆液。向其中滴加亚硝酸钠(2.35g,34mmol)在14ml水中的冷溶液。添加完全后,在0℃下搅拌该混合物40分钟。在剧烈搅拌下向其中滴加冷的SnCl2·2H2O溶液(21g,93mmol,在30ml浓盐酸中)。在冰浴中搅拌该混合物30分钟并冷却。用Buchner漏斗收集粗的3-羧基-2-萘基肼,并真空抽至干燥。
步骤2:将如上制得的粗肼放入60ml的冰醋酸和30ml的THF中。向其中添加2-N-(甲氧基)亚氨基-4-氧代戊酸乙基酯(2.6g,14mmol)。该混合物回流过夜。真空除去溶剂。残留物溶解在乙酸乙酯中,并用盐水洗涤(×2)。有机相干燥,浓缩,然后通过快速硅胶柱纯制,得到3-甲基-1-(3-羧基-2-萘基)-1H-吡唑-5-甲酸乙基酯(4.1g,90%)。Rf 0.15(1∶1乙酸乙酯∶己烷)。ES-MS:(M+H)+325。
步骤3:将2′-N-叔丁基氨基磺酰基-[1,1′]-联苯基-4-基胺(36mg,0.12mmol)溶解在1ml的无水DCM中,向其中添加三甲基铝(2.0M的己烷溶液,0.5ml,1.0mmol)。该混合物搅拌20分钟。将如上制得的酯(38mg,0.12mmol)溶解在3ml的无水DCM中,并添加在铝混合物中。反应物在室温下搅拌过夜,用饱和的Rochelle盐水溶液使反应停止。用氯仿萃取(×3)。有机相合并,干燥,浓缩,然后用快速硅胶柱纯制,得到偶联产物(60%)。ES-MS:(M+H)+583。
按照与实施例52相同的方法制备该化合物,但用2′-N-叔丁基氨基磺酰基-3-氟-[1,1′]-联苯基-4-基胺替代2′-N-叔丁基氨基磺酰基-[1,1′]-联苯基-4-基胺。ES-MS:(M+H)+545。
步骤1:将如上制备的粗酸溶解在150ml的无水乙醇中。向其中添加pTSA(3.3g)。该混合物回流4天,直至酯化超过95%。真空除去溶剂。残留物溶解在乙酸乙酯中,用盐水洗涤(×3),干燥,通过短的快速硅胶柱纯制,得到3-甲基-1-(3-甲硫基-2-萘基)-1H-吡唑-5-甲酸乙基酯,产率为80%以上。ES-MS:(M+H)+327。
步骤2:如上制得的酯(4.95g,15mmol)溶解在150ml的DCM中。在0℃下,在20分钟的时间内向剧烈搅拌的溶液中分批地添加MCPBA(11g,38mmol)。反应物放置1小时,然后用氯仿稀释。用碳酸氢钠饱和水溶液洗涤(×3),干燥,浓缩,然后用快速硅胶柱纯制,得到3-甲基-1-(3-甲基磺酰基-2-萘基)-1H-吡唑-5-甲酸乙基酯(3.49g,65%)。Rf 0.52(1∶1乙酸乙酯∶己烷)。ES-MS:(M+H)+359。
步骤3:将2′-N-叔丁基氨基磺酰基-[1,1′]-联苯基-4-基胺(21mg,0.068mmol)溶解在1ml的无水DCM中,向其中添加三甲基铝(2.0M的己烷溶液,0.14ml,0.28mmol)。该混合物搅拌20分钟。将如上制得的酯(16mg,0.045mmol)溶解在4ml的无水DCM中,并添加在铝混合物中。反应物在室温下搅拌过夜,用饱和的Rochelle盐水溶液使反应停止。用氯仿萃取(×3)。有机相合并,干燥,浓缩,然后用快速硅胶柱纯制,得到偶联产物(52%)。Rf 0.17(1∶1乙酸乙酯∶己烷)。ES-MS:(M+H)+617。
步骤1:按照与实施例53之步骤4相同的方法合成3-甲基-1-(3-甲基磺酰基-2-萘基)-1H-吡唑-5-甲酸乙基酯。
步骤2:将如上制得的酯(3.4g,9.7mmol)溶解在20ml甲醇中。向其中添加LiOH·H2O(0.82g,19.5mmol)和10ml的水。该混合物在室温下搅拌过夜。蒸发溶剂。残留物用1N盐酸酸化至pH为1。混合物用乙酸乙酯萃取(×4)。有机相合并,干燥,蒸发至干,得到3-甲基-1-(3-甲磺酰基-2-萘基)-1H-吡唑-5-甲酸(3.24g,99%)。ES-MS:(M+H)+331。
步骤3:将如上制得的酸(102mg,0.31mmol)、2′-N-叔丁基氨基磺酰基-3-氟-[1,1′]-联苯基-4-基胺(150mg,0.46mmol)、DMAP(10mg)溶解在3ml的吡啶中。于0℃下向上述混合物中添加POCl3(87μl,0.93mmol)。该混合物搅拌2小时,然后用冰片使反应停止。用乙酸乙酯稀释,用盐水洗涤(×2),干燥,浓缩,然后通过快速硅胶柱纯制,得到偶联化合物(130mg,66%)。Rf 0.29(1∶1乙酸乙酯∶己烷)。ES-MS:(M+H)+635。
按照与实施例54相同的方法制备该化合物,其中用2′-N-叔丁基氨基磺酰基-3-氯-[1,1′]-联苯基-4-基胺替换2′-N-叔丁基氨基磺酰基-3-氟-[1,1′]-联苯基-4-基胺。ES-MS:(M+H)+595。实施例56
按照与实施例54相同的方法制备该化合物,其中用2′-N-叔丁基氨基磺酰基-3-溴-[1,1′]-联苯基-4-基胺替换2′-N-叔丁基氨基磺酰基-3-氟-[1,1′]-联苯基-4-基胺。ES-MS:(M+H)+639,641(溴取代时)。实施例57
按照与实施例54相同的方法制备该化合物,其中用2-氨基-5-(2-(N-叔丁基氨基磺酰基)-苯基)吡啶替换2′-N-叔丁基氨基磺酰基-3-氟-[1,1′]-联苯基-4-基胺。ES-MS:(M+H)+562。实施例58
按照与实施例54相同的方法制备该化合物,其中用2-氨基-5-(2-(N-叔丁基氨基磺酰基)-苯基)嘧啶替换2′-N-叔丁基氨基磺酰基-3-氟-[1,1′]-联苯基-4-基胺。ES-MS:(M+H)+563。实施例59
按照与实施例54相同的方法制备该化合物,其中用2′-甲基磺酰基-[1,1′]-联苯基-4-基胺替换2′-N-叔丁基氨基磺酰基-3-氟-[1,1′]-联苯基-4-基胺。ES-MS:(M+H)+560。实施例60
按照与实施例54相同的方法制备该化合物,其中用2′-氰基-[1,1′]-联苯基-4-基胺替换2′-N-叔丁基氨基磺酰基-3-氟-[1,1′]-联苯基-4-基胺,而且不进行TFA处理。ES-MS:(M+H)+507。实施例61
将实施例60的标题化合物(55mg,0.11mmol)溶解在2ml的无水DMF中。在0℃下搅拌该溶液,并向其中添加硼氢化钠(33mg,0.88mmol)和CoCl2(30mg,0.22mmol)。反应物放置2小时,然后用乙酸使其停止。蒸发该混合物,用乙酸乙酯稀释,然后用碳酸氢钠水溶液洗涤。有机相干燥,蒸发,然后用制备性HPLC纯制,得到标题化合物,产率为55%。ES-MS:(M+H)+511。实施例62
按照与实施例54相同的方法制备该化合物,其中用2′-(N-二甲基氨基甲基)-[1,1′]-联苯基-4-基胺替换2′-N-叔丁基氨基磺酰基-3-氟-[1,1′]-联苯基-4-基胺,而且不进行TFA处理。ES-MS:(M+H)+539。实施例63
按照与实施例54相同的方法制备该化合物,其中用3′-(N-tert-Boc-氨基甲基)-[1,1′]-联苯基-4-基胺替换2′-N-叔丁基氨基磺酰基-3-氟-[1,1′]-联苯基-4-基胺。ES-MS:(M+H)+511。实施例64
按照与实施例54相同的方法制备该化合物,其中用1-(4-氨基苯基)-4-甲基哌嗪盐酸盐替换2′-N-叔丁基氨基磺酰基-3-氟-[1,1′]-联苯基-4-基胺,而且不进行最终的TFA处理。ES-MS:(M+H)+504。实施例65
按照与实施例54相同的方法制备该化合物,其中用1-(N-甲基哌啶-4-基)-哌嗪替换2′-N-叔丁基氨基磺酰基-3-氟-[1,1′]-联苯基-4-基胺,而且不进行最终的TFA处理。ES-MS:(M+H)+496。实施例66
按照与实施例54相同的方法制备该化合物,其中用1-(4-吡啶基)-哌嗪替换2′-N-叔丁基氨基磺酰基-3-氟-[1,1′]-联苯基-4-基胺,而且不进行最终的TFA处理。ES-MS:(M+H)+476。实施例67 按照与实施例54相同的方法制备该化合物,其中用4-(N-吡咯烷基羰基)-苯胺替换2′-N-叔丁基氨基磺酰基-3-氟-[1,1′]-联苯基-4-基胺,而且不进行最终的TFA处理。ES-MS:(M+H)+503。实施例68
步骤1:按照与实施例54之步骤2相同的方法合成3-甲基-1-(3-甲基磺酰基-2-萘基)-1H-吡唑-5-甲酸。
步骤2:将如上制得的酸(200mg,0.61mmol)、4-氨基苄腈(108mg,0.91mmol)、和DMAP(10mg)溶解在6ml的吡啶中。于0℃下搅拌该溶液。向其中添加POCl3(170μl,1.8mmol)。该混合物搅拌1小时,然后用冰片使反应停止。用乙酸乙酯稀释,用盐水洗涤(×2),干燥,浓缩,然后通过快速硅胶柱纯制,得到偶联化合物(250mg,95%)。Rf 0.20(1∶1乙酸乙酯∶己烷)。ES-MS:(M+H)+431。
步骤3:将如上制得的腈(70mg,0.16mmol)溶解在6ml的无水甲醇中。在冰浴中冷却并搅拌。通过长的针向该溶液中吹入氯化氢气体,直至达到饱和(用设置在反应烧瓶顶部的气球指示)。所得溶液搅拌过夜。ES-MS:(M+H)+463。真空除去溶剂。残留物抽至干燥。将固体溶解在6ml的无水甲醇中。向其中添加无水N-甲基亚乙基二胺(0.5ml)。该混合物回流1小时,浓缩,然后用制备性HPLC纯制,得到标题化合物,产率为80%。ES-MS:(M+H)+488。实施例69
按照与实施例68相同的方法制备该化合物,其中用吡咯烷替换N-甲基亚乙基二胺。ES-MS:(M+H)+502。实施例70
按照与实施例68相同的方法制备该化合物,其中用4-氨基-3-氟苄腈替换4-氨基苄腈,并用N-甲基-1,3-丙烷二胺替换N-甲基亚乙基二胺。ES-MS:(M+H)+520。实施例74 按照与实施例68相同的方法制备该化合物,其中用4-氨基-3-氟苄腈替换4-氨基苄腈,并用吡咯烷替换N-甲基亚乙基二胺。ES-MS:(M+H)+520。实施例75
按照与实施例68相同的方法制备该化合物,其中用4-氨基-3-氟苄腈替换4-氨基苄腈,并用乙酸铵替换N-甲基亚乙基二胺。ES-MS:(M+H)+466。实施例78
步骤1:在-78℃下将2-溴-6-甲氧基萘(2.0g,8.4mmol)溶解在20ml的无水THF中,然后用注射器向该溶液中滴加BuLi(1.6M,7.9ml,12.6mmol)。该混合物搅拌30分钟,然后向其中滴加三异丙基硼烷(2.34ml,10.1mmol)。除去干冰浴。反应混合物温热至室温。15小时后,真空除去THF。向残留物中添加40ml的3M盐酸。该混合物在室温下搅拌8小时。用乙醚萃取产物(×3)。有机相合并,干燥,真空浓缩,然后抽至干燥,得到6-甲氧基-2-萘基硼酸(产率75%),为白色固体。Rf 0.32(1∶1乙酸乙酯∶己烷)。
步骤2:如上制得的硼酸(0.84g,3.2mmol)和3-甲基吡唑-5-甲酸乙基酯(0.49g,3.2mmol)溶解在20ml的无水DCM中,然后向其中添加吡啶(0.77ml,9.5mmol)和无水乙酸铜(II)粉末(1.15g,6.3mmol)。之后添加一些经活化的分子筛。所得浆液在氩气中搅拌4天。混合物用DCM稀释,然后通过celite过滤。蓝色滤液用水洗涤(×2),干燥,浓缩,然后用快速硅胶柱纯制,单独形成3-甲基-1-(6-甲氧基-2-萘基)-1H-吡唑-5-甲酸乙基酯(37%产率,Rf 0.80 (1∶1乙酸乙酯∶己烷),ES-MS:(M+H)+311)以及5-甲基-1-(6-甲氧基-2-萘基)-1H-吡唑-3-甲酸乙基酯(25%产率,Rf 0.69(1∶1乙酸乙酯∶己烷),ES-MS:(M+H)+466),它们的比例为1.5∶1。
步骤3:将2′-N-叔丁基氨基磺酰基-[1,1′]-联苯基-4-基胺(44mg,0.14mmol)溶解在1ml的DCM中,然后在室温下向其中添加三甲基铝(2.0M己烷溶液,0.35ml,0.70mmol)。该混合物搅拌30分钟,然后向其中添加如上制得的3-甲基-1-(6-甲氧基-2-萘基)-1H-吡唑-5-甲酸乙基酯(44mg,0.14mmol)在2ml DCM中的溶液。所得混合物搅拌过夜。用5ml的饱和Rochelle盐溶液使反应停止。混合物用DCM萃取(×3)。有机相合并,干燥,浓缩,然后进行快速硅胶柱纯制,得到偶联产物,产率为84%(67mg)。Rf 0.41(1∶1乙酸乙酯∶己烷)。ES-MS:(M+H)+569。
步骤4:将如上制得的混合物放入3ml的TFA中,然后在65℃下搅拌30分钟。蒸发后,残留物溶解在甲醇中,然后用制备性HPLC纯制,得到标题化合物,产率为95%。ES-MS:(M+H)+513。实施例79
步骤1:按照与实施例83之步骤2相同的方法制备3-甲基-1-(6-甲氧基-2-萘基)-1H-吡唑-5-甲酸乙基酯。
步骤2:将如上制得的化合物(150mg,0.48mmol)溶解在2ml的DCM中。在0℃下,搅拌该溶液,并同时向其中添加三溴化硼(1.0M的DCM溶液,0.72ml,0.72mmol)。该混合物在室温下搅拌过夜。直接进行快速硅胶柱纯制,得到3-甲基-1-(6-羟基-2-萘基)-1H-吡唑-5-甲酸乙基酯(78mg,55%)。Rf 0.73(2∶1乙酸乙酯∶己烷)。ES-MS:(M+H)+297。
步骤3:将2′-N-叔丁基氨基磺酰基-[1,1′]-联苯基-4-基胺(80mg,0.26mmol)溶解在1ml的DCM中,然后在室温下向其中添加三甲基铝(2.0M己烷溶液,0.65ml,1.3mmol)。30分钟后,向该混合物中添加3-甲基-1-(6-羟基-2-萘基)-1H-吡唑-5-甲酸乙基酯(78mg,0.26mmol)在3ml DCM中的溶液。所得混合物搅拌4小时。用5ml的饱和Rochelle盐溶液使反应停止。混合物用DCM萃取(×3)。有机相合并,干燥,浓缩,然后进行快速硅胶柱纯制,得到偶联产物,产率为65%。Rf 0.32(1∶1乙酸乙酯∶己烷)。ES-MS:(M+H)+555。
步骤4:将如上制得的混合物放入3ml的TFA中,然后在70℃下搅拌30分钟。蒸发后,残留物溶解在甲醇中,然后用制备性HPLC纯制,得到标题化合物,产率为95%。ES-MS:(M+H)+499。实施例80
步骤1:6-溴-2-萘甲酸(1.11g,4.4mmol)和2ml亚硫酰氯的混合物回流过夜。真空除去亚硫酰氯。将干燥的酰氯溶解在5ml的二恶烷中。在0℃下,向其中滴加叠氮化钠(0.52g,8.0mmol)在2.5ml水和2.5ml二恶烷中的溶液。该混合物搅拌2小时。真空蒸发除去溶剂后,将残留物溶解在乙酸乙酯中,用盐水洗涤,干燥,真空浓缩,得到叠氮基酮(1.22g,99%)。Rf 0.88(1∶1乙酸乙酯∶己烷)。
步骤2:将如上制得的化合物溶解在20ml的DMF中。向其中添加10ml的水。该混合物回流过夜,然后用500ml的乙酸乙酯稀释,用盐水洗涤(×2),干燥,真空浓缩,得到6-溴-2-萘基胺(1.2g,99%)。Rf 0.73(1∶1乙酸乙酯∶己烷)。ES-MS:(M+H)+222,224(溴取代时)。
步骤3:如上制得的化合物(1.2g,5.4mmol)放入6ml的浓盐酸中。在0℃下,向其中滴加亚硝酸钠(0.37g,5.4mmol)在2ml水中的溶液。搅拌混合物30分钟。在0℃下,向其中滴加SnCl2·2H2O(3.66g,16.2mmol)在6ml浓盐酸中的冷溶液。搅拌10分钟后,将该混合物放置在冷冻机中过夜。通过Buchner漏斗收集固体。用冰冷的盐水(7ml)和冰冷的己烷(7ml)洗涤该固体。将固体饼转移至烧瓶中,并抽至干燥。向其中添加30ml的乙酸、15ml的THF、以及2-N-(甲氧基)亚氨基-4-氧代戊酸乙酯(1.3g,7.0mmol)。所得混合物回流过夜。真空除去溶剂。残留物溶解在乙酸乙酯中,用盐水洗涤(×2),干燥,浓缩,然后用快速硅胶柱纯制,得到3-甲基-1-(6-溴-2-萘基)-1H-吡唑-5-甲酸乙基酯(0.64g,33%)。Rf 0.71(1∶2乙酸乙酯∶己烷)。ES-MS:(M+H)+359,361(溴取代时)。
步骤4:将2′-N-叔丁基氨基磺酰基-[1,1′]-联苯基-4-基胺(93mg,0.31mmol)溶解在1ml的DCM中,然后在室温下向其中添加三甲基铝(2.0M己烷溶液,0.70ml,1.4mmol)。30分钟后,向该混合物中添加如上制得的乙基酯(100mg,0.28mmol)在3ml DCM中的溶液。所得混合物搅拌过夜。用5ml的饱和Rochelle盐溶液使反应停止。混合物用DCM萃取(×3)。有机相合并,干燥,浓缩,然后进行快速硅胶柱纯制,得到偶联产物(146mg,85%)。Rf 0.44(1∶1乙酸乙酯∶己烷)。ES-MS:(M+H)+617,619(溴取代时)。
步骤5:将如上制得的化合物放入3ml的TFA中,然后在65℃下搅拌40分钟。蒸发后,残留物溶解在甲醇中,然后用制备性HPLC纯制,得到标题化合物,产率为95%。ES-MS:(M+H)+561,563(溴取代时)。实施例81
按照与实施例80相同的方法制备该化合物,其中用2′-N-叔丁基氨基磺酰基-3-氟-[1,1′]-联苯基-4-基胺替换2′-N-叔丁基氨基磺酰基-[1,1′]-联苯基-4-基胺。ES-MS:(M+H)+579,581(溴取代时)。实施例82
按照与实施例80相同的方法制备该化合物,其中用2′-N-叔丁基氨基磺酰基-3-氯-[1,1′]-联苯基-4-基胺替换2′-N-叔丁基氨基磺酰基-[1,1′]-联苯基-4-基胺。ES-MS:(M+H)+595,597(溴取代时)。实施例83
按照与实施例80相同的方法制备该化合物,其中用2′-N-叔丁基氨基磺酰基-3-溴-[1,1′]-联苯基-4-基胺替换2′-N-叔丁基氨基磺酰基-[1,1′]-联苯基-4-基胺。ES-MS:(M+H)+640,642,644(2溴取代时)。实施例84
按照与实施例80相同的方法制备该化合物,其中用2′-N-叔丁基氨基磺酰基-5′-氯-[1,1′]-联苯基-4-基胺替换2′-N-叔丁基氨基磺酰基-[1,1′]-联苯基-4-基胺。ES-MS:(M+H)+595,597(溴氯取代时)。实施例85
按照与实施例80相同的方法制备该化合物,其中用5-(2-N-叔丁基氨基磺酰基-1-苯基)-2,3-二氢吲哚替换2′-N-叔丁基氨基磺酰基-[1,1′]-联苯基-4-基胺。ES-MS:(M+H)+587,589(溴取代时)。实施例86
步骤1:按照与实施例80之步骤3相同的方法合成3-甲基-1-(6-溴-2-萘基)-1H-吡唑-5-甲酸乙基酯。
步骤2:将如上制得的乙基酯(1.0g,2.8mmol)溶解在20ml甲醇中。向其中添加LiOH·H2O(350mg,8.3mmol)和10ml的水。该混合物搅拌过夜,然后真空蒸发。残留物用1N盐酸酸化。混合物用乙酸乙酯萃取(×4)。有机相合并,干燥,蒸发至干,得到3-甲基-1-(6-溴-2-萘基)-1H-吡唑-5-甲酸(0.97g,100%)。ES-MS:(M+H)+331,333(溴取代时)。
步骤3:于0℃下将如上制得的酸(33mg,0.10mmol)、2-氨基-5(2-(N-叔丁基氨基磺酰基)苯基)吡啶(61mg,0.20mmol)、DMAP(5mg)溶解在3ml的吡啶中并搅拌。向上述混合物中添加POCl3(55μl,0.6mmol)。该混合物搅拌2小时,然后用冰片使反应停止。用乙酸乙酯稀释,用盐水洗涤(×2),干燥,浓缩,然后通过快速硅胶柱纯制,得到偶联化合物(34mg,55%)。Rf 0.35(1∶1乙酸乙酯∶己烷)。ES-MS:(M+H)+618,620(溴取代时)。
步骤4:将如上制得的混合物放入3ml的TFA中,然后在65℃下搅拌40分钟。蒸发后,残留物溶解在甲醇中,然后用制备性HPLC纯制,得到标题化合物,产率为95%。ES-MS:(M+H)+562,564(溴取代时)。实施例87
按照与实施例86相同的方法制备该化合物,其中用2-氨基-5(2-(N-叔丁基氨基磺酰基)苯基)嘧啶替换2-氨基-5(2-(N-叔丁基氨基磺酰基)苯基)吡啶。ES-MS:(M+H)+563,565(溴取代时)。实施例88
步骤1:按照与实施例86之步骤2相同的方法合成3-甲基-1-(6-溴-2-萘基)-1H-吡唑-5-甲酸。
步骤2:将如上制得的酸(970mg,2.9mmol)、4-氨基苄腈(700mg,5.8mmol)、DMAP(40mg)溶解在15ml的吡啶中,然后在0℃下搅拌。向上述混合物中添加POCl3(1.1ml,12mmol)。该混合物搅拌1小时,然后用冰片使反应停止。用乙酸乙酯稀释,用盐水洗涤(×2),干燥,浓缩,然后通过快速硅胶柱纯制,得到偶联化合物(720mg,58%)。Rf 0.30(1∶1乙酸乙酯∶己烷)。ES-MS:(M+H)+431,433(溴取代时)。
步骤3:将如上制得的腈(40mg,0.09mmol)溶解在6ml的无水甲醇中。在冰浴中冷却并搅拌。通过长的针向该溶液中吹入氯化氢气体,直至达到饱和。所得溶液搅拌过夜。ES-MS:(M+H)+463,465(溴取代时)。真空除去溶剂。残留物抽至干燥。将固体溶解在6ml的无水甲醇中。向其中添加无水N-甲基亚乙基二胺(0.5ml)。该混合物回流1小时,浓缩,然后用制备性HPLC纯制,得到标题化合物,产率为85%。ES-MS:(M+H)+488,490(溴取代时)。实施例89
按照与实施例88相同的方法制备该化合物,其中用N-甲基哌嗪替换N-甲基亚乙基二胺。ES-MS:(M+H)+531,533(溴取代时)。实施例93 按照与实施例88相同的方法制备该化合物,其中用4-氨基-3-氟苄腈替换4-氨基苄腈。ES-MS:(M+H)+506,508(溴取代时)。实施例94
按照与实施例88相同的方法制备该化合物,其中用4-氨基-2,5-二氟苄腈替换4-氨基苄腈。ES-MS:(M+H)+524,526(溴取代时)。实施例95
按照与实施例88相同的方法制备该化合物,其中用4-氨基-3-氯苄腈替换4-氨基苄腈。ES-MS:(M+H)+522,524(溴取代时)。实施例96
按照与实施例88相同的方法制备该化合物,其中用4-氨基-3-氯苄腈替换4-氨基苄腈,并用N-甲基-1,3-丙烷二胺替换N-甲基亚乙基二胺。ES-MS:(M+H)+536,538(溴取代时)。实施例100
按照与实施例88相同的方法制备该化合物,其中用4-氨基-3-氯苄腈替换4-氨基苄腈,并用1,3-丙烷二胺替换N-甲基亚乙基二胺。ES-MS:(M+H)+522,524(溴取代时)。实施例101
按照与实施例88相同的方法制备该化合物,其中用4-氨基-3-氯苄腈替换4-氨基苄腈,并用2-甲基吡咯烷替换N-甲基亚乙基二胺。ES-MS:(M+H)+534,536(溴取代时)。实施例103
按照与实施例88相同的方法制备该化合物,其中用4-氨基-2,5-二氟苄腈替换4-氨基苄腈,并用吡咯烷替换N-甲基亚乙基二胺。ES-MS:(M+H)+538,540(溴取代时)。实施例104
按照与实施例88相同的方法制备该化合物,其中用4-氨基-3-氟苄腈替换4-氨基苄腈,并用乙酸铵替换N-甲基亚乙基二胺。ES-MS:(M+H)+466,468(溴取代时)。实施例108
按照与实施例88相同的方法制备该化合物,其中用4-氨基-2,5-二氟苄腈替换4-氨基苄腈,并用甲基胺(2M的甲醇溶液)替换N-甲基亚乙基二胺。ES-MS:(M+H)+498,500(溴取代时)。实施例109
按照与实施例88相同的方法制备该化合物,其中用4-氨基-3-氯苄腈替换4-氨基苄腈,并用二甲基胺(2M的THF溶液)替换N-甲基亚乙基二胺。ES-MS:(M+H)+510,512(溴氯取代时)。实施例110
步骤1:将6-溴-2-萘甲酸(4.4g,17.5mmol)溶解在50ml的无水DMF中,然后向该溶液中添加CuCl(8.7g,87.5mmol)和CuI(0.2g)。该浆液回流1小时。在室温下,用300ml的乙酸乙酯稀释,然后搅拌2小时。通过celite过滤,然后真空蒸发滤液,得到6-氯-2-萘甲酸(2.7g,75%)。ES-MS:(M+H)+207。
按照与实施例110相同的方法制备该化合物,其中用2′-N-叔丁基氨基磺酰基-3-氟-[1,1′]-联苯基-4-基胺替换2′-N-叔丁基氨基磺酰基-[1,1′]-联苯基-4-基胺。ES-MS:(M+H)+535。实施例112
按照与实施例110相同的方法制备该化合物,其中用2′-甲基磺酰基-3-氟-[1,1′]-联苯基-4-基胺替换2′-N-叔丁基氨基磺酰基-[1,1′]-联苯基-4-基胺。ES-MS:(M+H)+534。实施例113
按照与实施例114相同的方法制备该化合物,其中用哌啶替换N-甲基亚乙基二胺。ES-MS:(M+H)+490。实施例116
按照与实施例114相同的方法制备该化合物,其中用二甲基胺(2M的THF溶液)替换N-甲基亚乙基二胺。ES-MS:(M+H)+450。实施例117
步骤1:按照与实施例34之步骤3相同的方法合成3-甲基-1-(3-氰基-2-萘基)-1H-吡唑-5-(N-(2′-N-叔丁基氨基磺酰基-[1,1′]-联苯-4-基))羧酰胺。
步骤2:在0℃下将如上制得的化合物(30mg)溶解在10ml的无水乙醇中,然后通过长的针向该溶液中吹入氯化氢气体,直至达到饱和。所得溶液搅拌过夜。真空除去溶剂。干的残留物溶解在5ml的无水甲醇中。向其中添加0.5ml的N-甲基亚乙基二胺。该混合物回流2小时。ES-MS:(M+H)+621。真空浓缩。向残留物中添加3ml的THF,并在70℃下搅拌混合物1小时。蒸发后,反应混合物用制备性HPLC纯制,得到标题化合物(产率为20%)。ES-MS:(M+H)+565。实施例118
按照与实施例117相同的方法制备标题化合物,其中用二甲基胺(2M的THF溶液)替换N-甲基亚乙基二胺。ES-MS:(M+H)+553。实施例119
按照与实施例52相同的方法制备标题化合物,其中用市售的2-硝基苯基肼替换3-羧基-2-萘基肼。ES-MS:(M+H)+478。实施例123
步骤1:将4-甲基磺酰基-3-硝基苯甲酸(0.90g,3.7mmol)溶解在10ml的乙醇中。向其中添加肼单水合物(0.46ml,15mmol)以及催化量的10%Pd/C。该混合物回流1.5小时,用甲醇稀释,通过celite过滤,然后真空浓缩,得到3-氨基-4-甲基磺酰基苯甲酸(>70%)。ES-MS:(M+H)+216。
步骤2:在冰浴中,使如上制得的苯胺(2.2g,10mmol)在16ml的浓盐酸中搅拌。向其中滴加亚硝酸钠溶液(1.1g,15mmol,在7ml水中)。添加完全后,该混合物在0℃下搅拌30分钟。向其中滴加SnCl2·2H2O的冷溶液(9.2g,40mmol,在14ml的浓盐酸中)。该混合物搅拌30分钟,然后由Buchner漏斗中过滤。固体粗产物肼收集并干燥。
步骤3:将粗肼溶解在40ml的乙酸中。向其中添加20ml的THF和2-N-(甲氧基)亚氨基-4-氧代戊酸乙基酯(2.8g,15mmol)。混合物回流过夜。真空除去溶剂后,反应混合物残留物溶剂在800ml的醚中。有机溶液用盐水洗涤(×2),干燥,浓缩,然后用快速硅胶柱纯制,得到3-甲基-1-(5-羧基-2-甲基磺酰基苯基)-1H-吡唑-5-甲酸乙基酯(2.1g,60%)。Rf 0.17(纯的乙酸乙酯)。ES-MS:(M+H)+353。
步骤4:将如上制得的酸(2.1g,6.5mmol)溶解在50ml的无水DMF中。向其中顺序添加叔丁基胺(1.4ml,13mmol)、DIEA(9.2ml,52mmol)、和PyBOP(13g,26mmol)。所得混合物在室温下搅拌过夜。真空除去DMF。残留物放入乙酸乙酯中,并用盐水洗涤(×2)。有机相干燥,浓缩,然后用快速硅胶柱纯制,以分离3-甲基-1-(5-N-叔丁基氨基羰基-2-甲基磺酰基苯基)-1H-吡唑-5-甲酸乙基酯(0.74g,30%)。Rf0.70(纯的乙酸乙酯)。ES-MS:(M+H)+408。
步骤5:将2′-N-叔丁基氨基磺酰基-[1,1′]-联苯基-4-基胺(100mg,0.33mmol)溶解在2ml的DCM中,然后在室温下于氩气中向其中添加三甲基铝(2.0M己烷溶液,0.66ml,1.3mmol)。搅拌30分钟后,向该混合物中添加如上制得的乙基酯(90mg,0.22mmol)在10ml DCM中的溶液。所得混合物搅拌过夜。用10ml的饱和Rochelle盐溶液使反应停止。混合物用DCM萃取(×3)。有机相合并,干燥,浓缩,然后进行快速硅胶柱纯制,得到偶联产物(90mg,62%)。Rf 0.10(1∶1乙酸乙酯∶己烷)。ES-MS:(M+H)+666。
步骤6:将如上制得的化合物(20mg)放入5ml的TFA中,然后在70℃下搅拌1小时,蒸发并用制备性HPLC纯制,分离标题化合物(90%)。ES-MS:(M+H)+554。实施例124
步骤1:将4-联苯基硼酸(1.0g,5.1mmol)和3-甲基吡唑-5-甲酸乙基酯(0.78g,5.1mmol)溶解在25ml的DCM中,然后向该溶液中添加吡啶(1.2ml,15mmol)和无水乙酸铜(II)粉末(1.84g,10mmol)。添加-些经活化的分子筛粉末。所得浆液在氩气中回流2天。混合物用DCM稀释,然后通过celite过滤。蓝色滤液用水洗涤(×2),干燥,浓缩,用快速硅胶柱纯制,得到3-甲基-1-(4-苯基苯基)-1H-吡唑-5-甲酸乙基酯(26%),Rf 0.67(1∶2乙酸乙酯∶己烷),ES-MS:(M+H)+307;及其区域异构体,5-甲基-1-(4-苯基苯基)-1H-吡唑-3-甲酸乙基酯(31%),Rf 0.50(1∶2乙酸乙酯∶己烷)。ES-MS:(M+H)+307。
步骤2:将4-氯苯胺(24mg,0.18mmol)溶解在1ml的DCM中,然后在室温下向该溶液中添加三甲基铝(2.0M的己烷溶液,0.43ml,0.86mmol)。30分钟后,向混合物中添加如上制得的3-甲基-1-(4-苯基苯基)-1H-吡唑-5-甲酸乙基酯(52mg,0.17mmol)在3ml DCM中的溶液。所得混合物搅拌过夜。用5ml饱和的Rochelle盐水溶液使反应停止。用DCM萃取混合物(×3)。有机相合并,干燥,浓缩,然后进行快速柱纯制,得到标题化合物(46mg,70%)。Rf 0.46(1∶1乙酸乙酯∶己烷)。ES-MS:(M+H)+388。实施例125
按照与实施例124相同的方法制备标题化合物,其中用4-甲氧基苯胺替换4-氯苯胺。ES-MS:(M+H)+384。实施例126 步骤1:将2′-N-叔丁基氨基磺酰基-[1,1′]-联苯基-4-基胺(1.9g,6.2mmol)放入8ml的浓盐酸中。在0℃下,向搅拌该混合物并向其中滴加亚硝酸钠的冷溶液(0.43g,6.2mmol,在2ml的水中)。30分钟后,向其中添加SnCl2·2H2O的冷溶液(4.2g,18.4mmol,在8ml的水中)。在0℃下搅拌混合物1小时,然后通过Buchner漏斗收集固体。干燥该粗固体肼。
步骤2:如上制得的粗肼溶解在20ml的乙酸中。向其中添加10ml的THF和2-N-(甲氧基)亚氨基-4-氧代戊酸乙基酯(0.93g,5.0mmol)。该混合物回流3小时。真空除去溶剂。残留物放入乙酸乙酯中,用盐水洗涤,干燥,浓缩,然后通过快速硅胶柱纯制,得到3-甲基-1-(4-(2-氨基磺酰基苯基)-苯基)-1H-吡唑-5-甲酸乙基酯(0.95g,40%)。Rf 0.51(1∶1乙酸乙酯∶己烷)。ES-MS:(M+H)+386。
步骤3:将如上制得的乙基酯溶解在20ml的甲醇中。向其中添加LiOH·H2O(0.31g,7.4mmol)和10ml的水。该混合物搅拌3小时,用乙酸酸化至pH为5,然后真空蒸发。残留物用乙腈浸泡,然后倾析多次,以萃取出有机产物。合并有机溶液,然后真空蒸发,得到3-甲基-1-(4-(2-氨基磺酰基苯基)-苯基)-1H-吡唑-5-甲酸(0.81g,92%)。ES-MS:(M+H)+358。该产物进-步通过制备性HPLC纯制。
步骤4:将如上制得的酸(20mg,0.056mmol)溶解在1ml的无水DMF中。向其中顺序地添加4-溴苯胺(10mg,0.056mmol)、DIEA(30μl,0.17mmol)、和PyBOP(58mg,0.12mmol)。反应混合物直接放在制备性HPLC上纯制,得到标题化合物,产率为45%。ES-MS:(M+H)+511,513(溴取代时)。实施例127
按照与实施例126相同的方法制备标题化合物,其中用4-甲氧基苯胺替换4-溴苯胺。ES-MS:(M+H)+463。实施例128
按照与实施例126相同的方法制备标题化合物,其中用6-溴-2-萘基胺替换4-溴苯胺。ES-MS:(M+H)+562,564(溴取代时)。实施例130
步骤1:使4-氰基苯基肼盐酸盐(5.7g,33mmol)、2-N-(甲氧基)亚氨基-4-氧代戊酸乙基酯(7.5g,40mmol)、100ml乙酸和50mlTHF的混合物回流2小时。真空除去溶剂。残留物放入500ml乙酸乙酯中,用盐水洗涤,干燥,然后真空蒸发,得到3-甲基-1-(4-氰基苯基)-1H-吡唑-5-甲酸乙基酯(10g,99%)。ES-MS:(M+H)+256。
步骤2:将如上制得的酯(10g)溶解在100ml的THF中。向其中添加LiOH·H2O(4.2g,100mmol)、100ml甲醇和50ml水。该混合物搅拌1小时。用1N盐酸酸化至pH为1。蒸发除去有机溶剂。残留物用乙酸乙酯萃取(×4)。有机相合并,干燥,然后蒸发至干,得到3-甲基-1-(4-氰基苯基)-1H-吡唑-5-甲酸(95%)。ES-MS:(M+H)+228。
步骤3:将如上制得的酸(1.4g,6.2mmol)溶解在20ml的吡啶中。向其中添加2-氨基-5-溴吡啶(2.2g,13mmol)和DMAP(100mg)。在0℃下,向其中添加POCl3(2.3ml,25mmol)。反应物放置1.5小时,然后用冰片使反应停止。真空蒸发后,残留物放入300ml的乙酸乙酯中,用盐水洗涤,干燥,蒸发,然后通过快速硅胶柱纯制,得到偶联产物(45%)。Rf 0.52(1∶1乙酸乙酯∶己烷)。ES-MS:(M+H)+382,384(溴取代时)。
步骤4:在0℃下将如上制得的腈(30mg)溶解在10ml的无水甲醇中,然后通过长针向其中吹入氯化氢气体,直至达到饱和。该混合物搅拌过夜。真空除去溶剂。干燥的残留物溶解在5ml的无水甲醇中。向其中添加0.5ml的N-甲基亚乙基二胺。混合物回流1小时。蒸发后,反应混合物通过制备性HPLC纯制,以分离标题化合物(产率为80%)。ES-MS:(M+H)+439,441(溴取代时)。实施例135
按照与实施例134相同的方法制备标题化合物,其中用亚乙基二胺替换N-甲基亚乙基二胺。ES-MS:(M+H)+425,427(溴取代时)。实施例136
按照与实施例134相同的方法制备标题化合物,其中用2-甲基吡咯烷替换N-甲基亚乙基二胺。ES-MS:(M+H)+467,469(溴取代时)。实施例138
按照与实施例134相同的方法制备标题化合物,其中用哌啶替换N-甲基亚乙基二胺。ES-MS:(M+H)+467,469(溴取代时)。实施例139
按照与实施例134相同的方法制备标题化合物,其中用硫代吗啉替换N-甲基亚乙基二胺。ES-MS:(M+H)+485,487(溴取代时)。实施例141
按照与实施例134相同的方法制备标题化合物,其中用N-甲基哌嗪替换N-甲基亚乙基二胺。ES-MS:(M+H)+482,484(溴取代时)。实施例142
按照与实施例134相同的方法制备标题化合物,其中用1-甲基高哌嗪替换N-甲基亚乙基二胺。ES-MS:(M+H)+496,498(溴取代时)。实施例144
按照与实施例134相同的方法制备标题化合物,其中用乙酸铵替换N-甲基亚乙基二胺。ES-MS:(M+H)+399,401(溴取代时)。实施例146
将2′-N-叔丁基氨基磺酰基-[1,1′]-联苯基-4-基胺(50mg,0.16mmol)溶解在1ml的无水DCM中。搅拌该溶液,并向其中添加三甲基铝(2.0M的己烷溶液,0.4ml,0.8mmol)。搅拌30分钟后,向混合物中添加市售的1-(6-氯-1,3-苯并噻唑-2-基)-3-甲基-1H-吡唑-5-甲酸乙基酯(50mg,0.16mmol)在2ml DCM中的溶液。所得混合物搅拌4小时。用饱和的Rochelle盐水溶液使反应停止,然后用DCM稀释混合物。该混合物用盐水洗涤(×2),干燥,真空蒸发,然后与3ml的TFA接触。搅拌过夜后,反应混合物蒸发,并通过逆向制备性HPLC纯制,得到标题化合物,产率为55%。ES-MS:(M+H)+524(氯取代时)。生物活性实施例
本发明化合物的评估是通过体外蛋白酶活性分析(见以下所述)和体内研究来进行的,以评估抗血栓形成效力以及对止血和血液学参数的影响。
本发明的化合物溶解在缓冲液中,以形成包含浓缩物的溶液,其中该分析浓缩物的浓度范围是0-100μM。在用于凝血酶、凝血酶原酶和因子Xa的分析中,将一种合成的生色底物添加至包含测试化合物及目标酶的溶液中,然后通过分光光度计测量该酶的残留催化活性。由底物转换测量化合物的IC50。IC50是50%抑制底物转换时的测试化合物浓度。希望本发明的化合物在因子Xa分析中具有低于500nM的IC50,优选低于200nM,更优选为约100nM或更低。在凝血酶原酶分析中,希望本发明的化合物具有低于4.0μM的IC50,优选低于200nM,更优选为约10nM或更低。在凝血酶分析作,希望本发明的化合物具有大于1.0μM的IC50,优选大于10.0μM,更优选大于100.0。用于测定蛋白酶抑制活性的酰胺分解试验
因子Xa和凝血酶试验是于室温下在0.02M的Tris·HCl缓冲液中进行的,pH为7.5,包含0.15M的氯化钠。在酶与抑制剂于室温下预保温5分钟后,使用Softmax 96孔板读数器(Molecular Devices)测量用于因子Xa的对硝基N-酰苯胺底物S-275(Chromogenix)、以及用于凝血酶的底物Chromozym TH(Boehringer Mannheim)的水解率,在405nm处监控,以测量对硝基苯胺随时间的出现。
在无血浆的体系中进行凝血酶原酶抑制试验,该体系用Sinha,U.等人,Thromb.Res.,75,427-436(1994)中描述的方法改进。具体而言,使用对硝基N-酰苯胺底物Chromozym TH测量凝血酶产生的时间过程,由此测定凝血酶原酶复合物的活性。该试验包括以下步骤:20mM的Tris·HCl缓冲液(pH7.5,包含0.15M的氯化钠、5mM的氯化钙、和0.1%的牛血清白蛋白)中预保温(5分钟)作为抑制剂选择的测试化合物以及由因子Xa(0.5nM)、因子Va(2nM)、磷脂酰丝氨酸∶磷脂酰胆碱(25∶75,20μM)。将复合物-抑制剂化合物的等份液添加至凝血酶原(1nM)和Chromozym TH(0.1mM)中。在405nM处监测底物分解率2分钟。分析8种不同浓度的抑制剂,重复进行2次。使用由等量的未经处理的复合物产生的凝血酶标准曲线测定百分抑制作用。在静脉血栓形成的兔模型中的抗血栓形成效力
使用Hollenbach,S.等人,Thromb.Haemost.71,357-362(1994)中描述的兔深部静脉血栓形成模型来测定测试化合物的体内抗血栓形成活性。兔子用I.M.注射氯胺酮、赛拉嗪和乙酰丙嗪的混合物麻醉。标准规程包括在已经麻醉的兔子的腹静脉腔中插入血栓形成性棉线和铜线装置。在中心静脉循环中发展非闭塞性血栓,并使用对血栓生长的抑制作用作为所研究化合物的抗血栓形成活性的量度。通过边缘耳静脉插管给药测试剂和对照盐水。在稳态输入测试化合物之前以及期间,使用股静脉插管采取血样。将棉线装置放入中心静脉循环后,立即开始引发血栓形成。在时间为30分钟-90分钟(此时试验结束)时给药测试化合物。杀死兔子,并通过手术方法取出,然后称重,进行组织学检查。分析血样在血液学和凝集参数方面的变化。化合物在兔静脉血栓形成模型中的作用
在兔静脉血栓形成模型中给药化合物,证实在更高的评估剂量时的抗血栓形成效力。在最高剂量(100μg/kg+2.57μg/kg/min)时,化合物对延长aPTT和PT没有显著的作用。与盐水对照相比,化合物对于血液学参数没有显著的作用。所有的测量都是在稳态给药载体或者D-Arg-Gly-Arg-噻唑后所有样品的平均值。数值以平均值±SD表示。
在没有进一步说明的情况下,认为本领域技术人员可以利用前面的描述和例举性实施例,来制备和使用本发明的化合物,并实施所要求的方法。应该理解前面的讨论和实施例只是介绍某些优选的实施方案的详细说明。对本领域技术人员来说,显然可以在不背离本发明的构思和保护范围的情况下作各种改进和等同替换。以上讨论和引述的所有患者,期刊文章和其它文献引入本文作为参考。
Claims (36)
1、以下式(I)的化合物:
A-Q-D-E-G-J-X (I)其中:A选自于:
(a)C1-C6-烷基;
(b)C3-C8-环烷基;
(c)-N(R2,R3),-C(=NR2)-R3,-C(=NR2)N(R2,R3),-N(R3)-C(=NR2)N(R2,R3)-
,和-N(R2)C(=NR3)-R2
(d)苯基,其独立地被0-2个R1取代基取代;
(e)萘基,其独立地被0-2个R1取代基取代;以及
(f)具有5-10个环原子的单环或者稠合二环杂环系,其中该环系
的1-4个环原子选自于N、O和S,而且该环系可被0-2个R1
取代基取代;R1选自于:
卤素,-CN,-C(=O)-N(R2,R3),-NO2,-SO2N(R2,R3),-SO2R2,
-(CH2)mNR2R3,-(CH2)m-C(=NR3)-R2,-(CH2)m-C(=NR2)-N(R2,R3),
-(CH2)m-N(R2)-C(=NR2)-N(R2,R3),-(CH2)mNR2-C3-6杂环,C1-4烷基,C2-6
烯基,C2-6炔基,C3-8环烷基,C0-4烷基C3-8环烷基,-CF3,-OR2,以及包
含1-4个选自于N、O和S的杂原子的5-6元杂环系,其中该杂
环系上的1-4个氢原子可独立地被选自于以下组中的基团置换:
卤素、C1-4烷基-CN、C1-4烷基、C2-6烯基、C2-6炔基、C3-8环烷基、
C0-4烷基C3-8环烷基和-NO2;R2和R3独立地选自于以下组中:
-H,-ORa,-N(-Ra,-Rb),-C1-4烷基,-C2-6烯基,-C2-6炔基,-C3-8环烷基,
-C0-4烷基C3-8环烷基,-C0-4烷基苯基和-C0-4烷基萘基,其中苯基和
萘基部分的环原子上的1-4个氢原子可独立地被选自于以下组中
的基团置换:卤素、C1-4烷基-CN、-C1-4烷基、-C2-6烯基、-C2-6炔
基、-C3-8环烷基、-C0-4烷基C3-8环烷基、-CN,和-NO2;或者R2和R3一起形成3-8元环烷基或者杂环系,其中该杂环系可具有
3-10个环原子,在环系中具有1-2个环,而且包含1-4个选自
于N、O和S的杂原子,其中杂环系上的1-4个氢原子可独立地
被选自于以下组中的基团置换:卤素、C1-4烷基-CN、-C1-4烷基、-C2-6
烯基、-C2-6炔基、-C3-8环烷基、-C0-4烷基C3-8环烷基和-NO2;Ra和Rb独立地选自于以下组中:-C1-4烷基,-C2-6烯基,-C2-6炔基,-C3-8环
烷基,-C0-4烷基C3-8环烷基,或者Ra和Rb可与它们所连接的氮原子
一起形成包含1-4个选自于N、O和S的杂原子的3-8元杂环环
系,其中该杂环系上的1-4个氢原子可被选自于以下组中的基团
置换:卤素、-CN、-C1-4烷基、-C2-6烯基、-C2-6炔基、-C3-8环烷基、-C0-4
烷基C3-8环烷基和-NO2;M是0-2的整数;Q选自于以下组中:
直接键连,二价-C1-4烷基,二价-C2-4烯基,二价-C2-4炔基,-C(=O)-,
-C(=NH)-,-C(=NMe)-,-N(-R4)-,-N(-R4)-CH2-,-C(=O)-N(-R4)-,
-N(-R4)-C(=O)-,-S(=O)2-,-O-,-S(=O)2-N(-R4)-和-N(-R4)-S(=O)2-,
其中二价C1-4烷基、二价C2-4烯基和二价C2-4炔基部分上的一个或
者多个氢原子都可被-R4基团置换;R4选自于以下组中:
-H,-CF3,-C1-4烷基,-C2-6烯基,-C2-6炔基,-C3-8环烷基,-C0-4烷基C3-8
环烷基,-C0-4烷基苯基和-C0-4烷基萘基,其中苯基和萘基部分的环
原子上的1-4个氢原子可被选自于以下组中的基团置换:卤
素、-C1-4烷基、-C2-6烯基、-C2-6炔基、-C3-8环烷基、-C0-4烷基C3-8
环烷基、-CN、-CF3,和-NO2;D选自于以下组中:
(a)直接键连;
(b)苯基,其独立地被0-2个R1a取代基取代;
(c)萘基,其独立地被0-2个R1a取代基取代;以及
(d)具有5-10个环原子的单环或者稠合二环杂环系,其中该环
系的1-4个环原子选自于N、O和S,而且该环系被0-2
个R1a取代基取代;R1a选自于以下组中:
卤素,C1-4烷基,C2-6烯基,C2-6炔基,C3-8环烷基,C0-4烷基C3-8环烷基,
-CN,-NO2,(CH2)nNR2aR3a,SO2NR2aR3a,SO2R2a,CF3,OR2a,以及包
含1-4个选自于N、O和S的杂原子的5-6元芳香杂环环系,其
中该芳香杂环系上的1-4个氢原子可独立地被选自于以下组中的
基团置换:卤素、C1-4烷基、C2-6烯基、C2-6炔基、C3-8环烷基、C0-4
烷基C3-8环烷基、-CN和-NO2;R2a和R3a独立地选自于以下组中:
-H,C1-4烷基,C2-6烯基,C2-6炔基,C3-8环烷基,C0-4烷基C3-8环烷基,C0-4
烷基苯基和C0-4烷基萘基,其中苯基和萘基部分的环原子上的1-4
个氢原子可独立地被选自于以下组中的基团置换:卤素、C1-4烷基、
C2-6烯基、C2-6炔基、C3-8环烷基、C0-4烷基C3-8环烷基、-CN和-NO2;n是0-2的整数;E选自于以下组中:
直接键连,-(CH2)q-C(=O)-,-(CH2)q-N(-R5)-C(=O)-(CH2)x-,
-(CH2)q-C(=O)-N(-R5)-(CH2)x-,-(CH2)q-N(-R5)-(CH2)x-,,
-(CH2)q-N(R5)CO-NR6(CH2)x和-SO2-;q和x独立地是0-2的整数;R5和R6独立地选自于以下组中:
H,-C1-6烷基,-C1-6烷氧基,-C2-6烯基,-C2-6炔基,-C3-8环烷基,-C0-6烷
基C3-8环烷基,-C1-4烷基-C(=O)-OH,-C0-6烷基-(碳环芳基),-C0-4烷
基-(单环杂芳基)和-C1-4烷基-C(=O)-O-C1-4烷基,其中碳环芳基和
单环杂芳基部分的环原子上的0-4个氢原子可独立地被选自于以
下组中的基团置换:卤素、-C1-4烷基、-C2-6烯基、-C2-6炔基、-C3-8
环烷基、-C0-4烷基C3-8环烷基、-S(=O)2-OH、-CN、-CF3和-NO2;G选自于以下组中:
苯基,其被0-2个R1b基团取代;以及
包含1-4个选自于N、O和S的杂原子的5-6元芳香以及非芳香
杂环,其中该杂环被0-2个R1b基团取代;R1b选自于以下组中:
卤素,-C1-6烷基,-C2-6烯基,-C2-6炔基,-C3-8环烷基,-C0-6烷基C3-8环
烷基,-C1-4烷基-C(=O)-OH,-CN,-COOR2b,-CONR2bR3b,-NO2,
-S(=O)2-OH,-N(-R2b,-R3b),-C(=O)-N(-R2b,-R3b),-S(=O)2-N(-R2b,-R3b),
-S(=O)2-R2b,-CF3,-O-R2b,-O-CH2-CH2-O-R2b,-O-CH2-C(=O)-O-R2b,
-N(-R2b)-CH2-CH2-O-R2b,-N(-CH2-CH2-O-R2b)2,-N(-R2b)-C(=O)-R3b,
-N(-R2b)-S(=O)2-R3b,以及包含1-4个选自于N、O和S的杂原子
并被0-4个R1b′基团取代的5-6元杂环;
或者,当两个R1b出现在G的相邻环原子上时,可组合形成被0-4
个R1b′基团取代的苯环或者被0-4个R1b′基团取代的具有1-3个
选自于N、O和S的杂原子的5-6元芳香或非芳香杂环;
或者,G中R1b基团之一可与E中的-N-R5基团成环形成包含1-4
个选自于N、O和S的杂原子的5-7元杂环,该杂环被0-4个R1b′
基团取代,其中连接在相同的环碳原子上的R1b′基团可形成(=O)基
团;R2b和R3b独立地选自于以下组中:
-H,-C1-6烷基,-C1-6烷氧基,-C2-6烯基,-C2-6炔基,-C3-8环烷基,-C0-6烷
基C3-8环烷基和-C0-6烷基-(碳环芳基),其中碳环芳基部分的环原
子上的0-4个氢原子可独立地被选自于以下组中的基团置换:卤
素、-C1-4烷基、-C2-6烯基、-C2-6炔基、-C3-8环烷基、-C0-4烷基C3-8
环烷基、-S(=O)2-OH、-CN、-CF3和-NO2;R1b′选自于以下组中:
卤素,-C1-6烷基,-C2-6烯基,-C2-6炔基,-C3-8环烷基,-C0-6烷基C3-8环
烷基,-C1-4烷基-C(=O)-OH,-CN,-NO2,-S(=O)2-OH,-N(-R2b′,-R3b′),
-C(=O)-N(-R2b′,-R3b′),-S(=O)2-N(-R2b′,-R3b′),-S(=O)2-R2b′,-CF3,-O-R2b′,
-O-CH2-CH2-O-R2b′,-O-CH2-C(=O)-O-R2b′,-N(-R2b′)-CH2-CH2-O-R2b′,
-N(-CH2-CH2-O-R2b′)2,-N(-R2b′)-C(=O)-R3b′和-N(-R2b′)-S(=O)2-R3b′;R2b′和R3b′独立地选自于以下组中:
-H,-C1-6烷基,-C1-6烷氧基,-C2-6烯基,-C2-6炔基,-C3-8环烷基,-C0-6烷
基C3-8环烷基和-C0-6烷基-(碳环芳基),其中碳环芳基部分的环原
子上的0-4个氢原子可独立地被选自于以下组中的基团置换:卤
素、-C1-4烷基、-C2-6烯基、-C2-6炔基、-C3-8环烷基、-C0-4烷基C3-8
环烷基、-S(=O)2-OH、-CN、-CF3和-NO2;J选自于以下组中:
直接键连,-S(=O)2-,-C(=O)-,-N(-R7)-S(=O)2-,-C(=O)-N(-R7)-S(=O)2-,
-C(=O)-N(-R7)-(CH2)y-,-S(=O)2-N(-R7)-(CH2)y-,和
-N(-R7)-C(=O)-(CH2)y-;y是0-2的整数;R7选自于以下组中:
-H,-C2-4烷基,-C2-6烯基,-C2-6炔基,-C3-8环烷基,-C0-6烷基C3-8环烷
基,-C1-6烷基-C(=O)-OH,-C1-6烷基-OH,-C1-6烷基-O-C1-4烷基,-C0-4
烷基-(碳环芳基),-C0-4烷基-(具有0-4个选自于N、O和S的杂原
子的单环或者二环杂环系),-CH2-C(=O)-O-C1-4烷基和-
CH2-C(=O)-O-C1-4烷基-(碳环芳基),其中碳环芳基或者杂环系部分
的环原子上的0-4个氢原子可独立地被选自于以下组中的基团置
换:卤素、-C1-4烷基、-C2-6烯基、-C2-6炔基、-C3-8环烷基、-C0-4烷
基C3-8环烷基、-S(=O)2-OH、-CN、-CF3和-NO2;X选自于以下组中:
苯基,其被0-3个R1c基团取代;
萘基,其被0-3个R1c基团取代;
包含1-2个氮原子的6元杂芳香环,其中该环被0-3个R1c基团
取代;以及
稠合杂二环环系,其中该环系包含-13个选自于N、O和S的杂原
子并被0-3个R1c基团取代;R1c选自于以下组中:
卤素,-CF3,-C1-6烷基,-C2-6烯基,-C2-6炔基,-C3-8环烷基,-C0-6烷基C3-8
环烷基,-C1-4烷基-C(=O)-OH,-CF3,-CN,-NO2,-(CH2)z-N(-R2c,-R3c),
-C(=O)-N(-R2c,-R3c),-C(=NH)-N(-R2c,-R3c),-C(=NMe)-N(-R2c,-R3c),
-S(=O)2-N(-R2c,-R3c),-S(=O)2-R2c,-S(=O)2-OH,-CF3,-O-R2c,
-O(-CH2)z-O-R2c,-O(-CH2)z-C(=O)-O-R2c,-N(-R2c),-O(-CH2)z-O-R2c,
-N[(-CH2)z-O-R2c]2,-(CH2)z-N(-R2c)-C(=O)-R3c,
-(CH2)z-N(-R2c)-S(=O)2-R3c,以及包含1-4个选自于N、O和S的
杂原子的5-6元杂环;z是0-4的整数;R2c和R3c独立地选自于以下组中:
-H,-C1-6烷基,-C1-6烷氧基,-C2-6烯基,-C2-6炔基,-C3-8环烷基,-C0-6烷
基C3-8环烷基和-C0-6烷基-(碳环芳基),其中碳环芳基部分的环原
子上的0-4个氢原子可独立地被选自于以下组中的基团置换:卤
素、-C1-4烷基、-C2-6烯基、-C2-6炔基、-C3-8环烷基、-C0-4烷基C3-8
环烷基、-S(=O)2-OH、-CN、-CF3和-NO2;及其所有的药物学上可接受的异构体、盐、水合物、溶剂化物和前药衍生物。
2、如权利要求1所述的化合物,其中:A选自于以下组中:
-C1-6烷基和-C3-8环烷基;
苯基,其被0-2个R1基团取代;
萘基,其被0-2个R1基团取代;以及
5-10元芳香或非芳香杂环系,其可为单环或者稠合二环环系,其
中该杂环系包含1-4个选自于N、O和S的杂原子并被0-2个R1
基团取代;R1选自于以下组中:
卤素,-C1-4烷基,-CN,-NO2,-(CH2)m-N(-R2,-R3),-C(=O)-N(-R2,-R3),
-S(=O)2-N(-R2,-R3),-S(=O)2-R2,-(CH2)m-C(=NR3)-R2,
-(CH2)m-C(=NR2)-N(R2,R3),-(CH2)m-N(R2)-C(=NR2)-N(R2,R3),-CF3,
-(CH2)m-O-R2以及包含1-4个选自于N、O和S的杂原子的5-6
元芳香杂环;R2和R3独立地选自于以下组中:
-H,-C1-4烷基,或者R2和R3可一起形成3-8元环烷基或者杂环系,其中该杂环系可包
含3-10个环原子,在该环系中具有1-2个环而且包含1-4个选
自于N、O和S的杂原子,其中该杂环系上的1-4个氢原子可独
立地被选自于以下组中的基团取代:卤素、C1-C4-烷基-CN、-C1-4
烷基、-C2-6烯基、-C2-6炔基、-C3-8环烷基、-C0-4烷基C3-8环烷基和
-NO2;m是0-2的整数;Q选自于以下组中:
直接键连,-C1-4烷基,-C2-4烯基,-C2-4炔基,-C(=O)-,-C(=NH)-,
-C(=NMe)-,-N(-R4)-,-N(-R4)-CH2-,-C(=O)-N(-R4)-,-N(-R4)-C(=O)-,
-S(=O)2-,-O-,-S(=O)2-N(-R4)-和-N(-R4)-S(=O)2-;R4选自于以下组中:
-H,-CF3,-C1-4烷基,D选自于以下组中:
直接键连;
苯基,其被0-2个R1a基团取代;以及
5-10元芳香或者非芳香杂环系,其可为单环或者稠合二环环系,其
中该杂环系包含1-4个选自于N、O和S的杂原子并被0-2个R1a
基团取代;R1a选自于以下组中:
卤素,-C1-4烷基,-CN,-NO2,-(CH2)n-N(-R2a,-R3a),-S(=O)2-N(-R2a,-R3a)
,-S(=O)2-R2a,-CF3,-(CH2)n-OR2a,-C(=O)-O-R2a,-C(=O)-N(-R2a,-R3a)
以及包含1-4个选自于N、O和S的杂原子的5-6元芳香杂
环;n是0-2的整数;R2a和R3a独立地选自于以下组中:
-H,-CF3和-C1-4烷基,E选自于以下组中:
直接键连,-(CH2)q-C(=O)-,-(CH2)q-N(-R5)-C(=O)-(CH2)x-,
-(CH2)q-C(=O)-N(-R5)-(CH2)x-,-(CH2)q-N(-R5)-(CH2)x-,
-(CH2)q-N(R5)CO-NR6(CH2)x-和-SO2-;R5和R6分别是H,-C1-4烷基,-C2-6烯基,-C2-6炔基,-C3-8环烷基,或者-C0-4
烷基C3-8环烷基;Q和x独立地是0-2的整数;G选自于以下组中:
苯基,其被0-2个R1b基团取代;以及
包含1-4个选自于O、S和N的杂原子的5-6元芳香和非芳香杂
环,其中该杂环被0-2个R1b基团取代;R1b选自于以下组中:
卤素,-C1-4烷基,-CN,-NO2,-N(-R2b,-R3b),-C(=O)-N(-R2b,-R3b),
-S(=O)2-N(-R2b,-R3b),-S(=O)2-R2b,-CF3,-O-R2b,-O-CH2-CH2-O-R2b,
-O-CH2-C(=O)-O-R2b,-N(-R2b)-CH2-CH2-O-R2b,-N(-CH2-CH2-O-R2b)2,
-N(-R2b)-C(=O)-R3b,-N(-R2b)-S(=O)2-R3b以及包含1-4个选自于N、
O和S的杂原子的5-6元杂环;
或者,当两个R1b出现在G环的相邻环原子上时,可一并形成被0
-4个R1b′基团取代的苯环或者具有1-3个选自于N、O和S的杂
原子并被0-4个R1b′基团取代的5-6元芳香或非芳香杂环;
或者,G中的R1b基团之一可与E中的-N-R5基团成环形成包含1-
4个选自于N、O和S的杂原子的5-7元饱和、不饱和或者部分
不饱和的杂环,该杂环被0-4个R1b′基团取代,其中连接在相同环
碳原子上的两个R1b′基团可形成(=O)基团;R2b和R3b独立地选自于以下组中:-H,-CF3,-C1-4烷基和-C1-4烷基-(碳环芳基);R1b′选自于以下组中:
卤素,-C1-4烷基,-CN,-NO2,-N(-R2b′,-R3b′),-C(=O)-N(-R2b′,-R3b′),-S(=O)2-N(-R2b′,-R3b′),-S(=O)2-R2b′,-CF3,-O-R2b′,-O-CH2-CH2-O-R2b′,
-O-CH2-C(=O)-O-R2b′,-N(-R2b′)-CH2-CH2-O-R2b′,-N(-CH2-CH2-O-R2b′)2,
-N(-R2b′)-C(=O)-R3b′,-N(-R2b′)-S(=O)2-R3b′;R2b′和R3b′独立地选自于以下组中:
-H,-C1-4烷基和-C1-4烷基-(碳环芳基);J选自于以下组中:
直接键连,-S(=O)2-,-C(=O)-,-N(-R7)-S(=O)2-,-C(=O)-N(-R7)-S(=O)2-,
-C(=O)-N(-R7)-(CH2)y-,-S(=O)2-N(-R7)-,-(CH2)y-和
-N(-R7)-C(=O)-(CH2)y-;y是0-2的整数;R7选自于以下组中:
-H,-C1-4烷基,-C2-6烯基,-C2-6炔基,-C0-4烷基-(碳环芳基),-C0-4烷
基-(杂环系),-CH2-C(=O)-O-C1-4烷基和-CH2-C(=O)-O-C1-4烷基-(碳
环芳基);X选自于以下组中:
苯基,其被0-3个R1c基团取代;
萘基,其被0-3个R1c基团取代;
包含1-2个氮原子的6元杂芳香环,其中该环被0-3个R1c基团
取代;以及
稠合杂二环环系,其中该环系可包含1-3个选自于N、O和S的
杂原子,而且被0-3个R1c基团取代;R1c选自于以下组中:
卤素,-C1-4烷基,-CN,-NO2,-(CH2)z-N(-R2c,-R3c),-C(=O)-N(-R2c,-R3c),
-C(=NH)-N(-R2c,-R3c),-C(=NMe)-N(-R2c,-R3c),-S(=O)2-N(-R2c,-R3c),
-S(=O)2-R2c,-S(=O)2-O-,-CF3,-O-R2c,-O-CH2-CH2-O-R2c,
-O-CH2-C(=O)-O-R2c,-N(-R2c)-CH2-CH2-O-R2c,-N(-CH2-CH2-O-R2c)2,
-(CH2)z-N(-R2c)-C(=O)-R3c,-(CH2)z-N(-R2c)-S(=O)2-R3c,以及包含1-
4个选自于N、O和S的杂原子的5-6元杂环;z是0-2的整数;R2c和R3c独立地选自于以下组中:
-H,-C1-4烷基和-C1-4烷基-(碳环芳基);及其所有的药物学上可接受的异构体、盐、水合物、溶剂化物和前药衍生物。
直接键连,-C(=NH),-C(=NMe)-,-C(=O)-,-CH2-,-NH-,-N(-CH3)-,-O-,
-NH-CH2-,-CH2-NH-,-N(-CH3)-CH2-,和-CH2-N(-CH3)-;D选自于以下组中:E选自于以下组中:
直接键连,-NH-C(=O)-,-N(-CH3)-C(=O)-,-N(-CH2CO2H)-C(=O)-,
-H,-Me,-CF3,-F,-Cl,-Br,-SO2Me,-CN,-CONH2,-CONMe2,-NH2,
-NO2,-NHCOMe,-NHSO2Me,-CH2NH2和-CO2H;J选自于以下组中:
直接键连,-NH-,-O-,-S(=O)2-,-S(=O)2-NH,-NH-S(=O)2-,-C(=O)-,
4、如权利要求1所述的化合物,其中:A选自于以下组中:
苯基,其被0-2个R1基团取代;
萘基,其被1个R1基团取代;以及
5-7元芳香或者非芳香单环杂环,其中该杂环包含1-2个选自于
N、O和S的杂原子并被0-1个R1基团取代;R1选自于以下组中:
-S(=O)2-N(-R2,-R3),-S(=O)2-R2,-CH2N(-R2,-R3),-CN以及卤素。R2和R3独立地选自于以下组中:
-H和-C1-4烷基;Q选自于以下组中:
直接键连,-C(=NH),-C(=NMe)-,-C(=O)-,-CH2-,-NH-,和-N(-CH3)-;D选自于以下组中:
直接键连;
苯基,其被0-2个R1a基团取代;以及
5-6元芳香杂环,其中该杂环包含1-2个选自于N和S的杂原子
并被0-1个R1a基团取代;R1a选自于以下组中:
-H和卤素;E选自于以下组中:
直接键连,-NH-C(=O)-和-C(=O)-NH-;G选自于以下组中:
吡唑、吡唑啉、三唑和四唑,它们被0-2个R1b基团取代;以及
5元芳香杂环,其中该杂环包含2个选自于N、O和S的杂原子并
被0-1个R1b基团取代;R1b选自于以下组中:
-Me,-Et,-CF3,-C(=O)-NH2,-NH2,-NH-C(=O)-Me,-NH-S(=O)2-Me,
-SMe-S(=O)2-Me以及卤素;
或者,当两个R1b基团出现在G的相邻环原子上时,可组合形成苯
环;
或者,G中的R1b基团之一可与E中的NH基团成环形成包含1-2
个氮原子并被0-2个C=O基团取代的5-6元非芳香杂环;J选自于以下组中:
直接键连,-NH-C(=O)-和-C(=O)-NH-;X选自于以下组中:
苯基,其被1-3个R1c基团取代;
萘基,其被1-3个R1c基团取代;
吡啶基,其被1-3个R1c基团取代;以及
9-10元稠合二环芳香环,其中该芳香环包含0-2个选自于N和
O的杂原子并被0-3个R1c基团取代;R1c选自于以下组中:
-H,卤素,-Me,-CF3,-OH,-OMe,-NH2,-CN,-NO2,-CH2-R2c,
-C(=O)-N(-R2c,-R3c),-S(=O)2-R2c,-S(=O)2-N(-R2c,-R3c),-S(=O)2-OH,
-C(=NH)-N(-R2c,-R3c),2-咪唑啉-2-基和1-甲基-2-咪唑啉-2-基;R2c和R3c独立地选自于以下组中:
-H,-OH,-NH2和-C1-4烷基;及其所有的药物学上可接受的异构体、盐、水合物、溶剂化物和前药衍生物。
5、如权利要求1所述的化合物,其选自于以下组中:其中:R1选自于以下组中:
-SO2NH2,-SO2Me,-CH2NH2和-CH2NMe2;R1a选自于以下组中:
-H,-F,-Cl和-Br;R1b选自于以下组中:
-CH3,-CF3,-CH2CH3,-SO2Me,-CONH2和-NHSO2Me;R1c1选自于以下组中:
-H,-F,-Cl,-Br,-NH2,-OH,-SO2Me,-SO2Et,-SO2NH2,-NO2,-CH2NH2,
-CN,-CONH2,-CH2OH;R1c2选自于以下组中:
-H,-F,-Cl和-Br;以及R1c3选自于以下组中:
-H,-F,-Cl和-Br及其所有的药物学上可接受的异构体、盐、水合物、溶剂化物和前药衍生物。
-SO2NH2,-SO2Me,-CH2NH2和-CH2NMe2;R1a选自于以下组中:
-H,-F,-Cl和-Br;R1b选自于以下组中:
-CH3,-CF3,-CH2CH3,-SO2Me,-CONH2和-NHSO2Me;R1c1选自于以下组中:
-H,-F,-Cl,-Br,-NH2,-OH,-SO2Me,-SO2Et,-SO2NH2,-NO2,-CH2NH2,
-CN,-CONH2,-CH2OH;R1c2选自于以下组中:
-H,-F,-Cl,-Br和-OMe;以及R1c3选自于以下组中:
-H,-F,-Cl,-Br,-OCH3,-NH2,-CH2NH2,-CONH2,-CONHMe,
-CONMe2,及其所有的药物学上可接受的异构体、盐、水合物、溶剂化物和前药衍生物。
-SO2NH2,-SO2CH3,-CN,-CONH2,-CONH(CH3),-CON(CH3)2,
-CH2NH2,-CH2NH(CH3),-CH2N(CH3)2;R1a选自于以下组中:
-H,-F,-Cl和-Br;R1b选自于以下组中:
-CH3和-CF3;R1c1选自于以下组中:
-H,-F,-Cl,-Br,-CN,-CH2NH2,-CH2OH,-CONH2,-C(=NH)NH2,
-CO2H,-CO2Me,-SO2Me,-SO2NH2,-OH,-NH2,和-NO2;R1c2选自于以下组中:
-H,-F,-Cl,-Br,和-OCH3;以及R1c3选自于以下组中:
-H,-F,-Cl,-Br,-OCH3,-NH2,-CH2NH2,-CONH2,-CONHMe,
-CONMe2,及其所有的药物学上可接受的异构体、盐、水合物、溶剂化物和前药衍生物。
8、如权利要求1所述的化合物,其选自于以下组中:其中:R1选自于以下组中:
-SO2NH2,-SO2Me,-CH2NH2和-CH2NMe2;R1a选自于以下组中:
-H,-F,-Cl和-Br;R1b选自于以下组中:
-CH3,-CF3,-CH2CH3,-SO2Me,-CONH2和-NHSO2Me;以及R1c选自于以下组中:
-H,-F,-Cl,-Br,-NH2,-OH,-SO2Me,-SO2Et,-SO2NH2,-NO2,-CH2NH2,
-CN,-CONH2,-CH2OH,及其所有的药物学上可接受的异构体、盐、水合物、溶剂化物和前药衍生物。
9、如权利要求1所述的化合物,其选自于以下组中:其中:R1选自于以下组中:
-SO2NH2,-SO2Me,-CH2NH2和-CH2NMe2;R1a选自于以下组中:
-H,-F,-Cl和-Br;R1b选自于以下组中:
-CH3,-CF3,-CH2CH3,-SO2Me,-CONH2和-NHSO2Me;R1c1选自于以下组中:
-H,-F,-Cl,-Br,-NH2,-OH,-SO2Me,-SO2Et,-SO2NH2,-NO2,-CH2NH2,
-CN,-CONH2,-CH2OH;以及R1c2和R1c3独立地选自于以下组中:
-H,-F,-Cl和-Br,及其所有的药物学上可接受的异构体、盐、水合物、溶剂化物和前药衍生物。
其中:
A选自于以下组中: R1a选自于以下组中:-H,-F,-Cl和-Br;R1b选自于以下组中:
-Me,-CF3,-Et,-SO2Me,-CONH2和-NHSO2Me;R1c1选自于以下组中:
-H,-F,-Cl,-Br,-NH2,-OH,-SO2Me,-SO2Et,-SO2NH2,-NO2,-CH2NH2,
-CN,-CONH2,-CH2OH;R1c2选自于以下组中:
-H,-F,-Cl和-Br;以及R1c3选自于以下组中:
-H,-F,-Cl和-Br及其所有的药物学上可接受的异构体、盐、水合物、溶剂化物和前药衍生物。
其中:
A选自于以下组中:R1a选自于以下组中:
-H,-F,-Cl和-Br;R1b选自于以下组中:
-CH3,-CF3,-CH2CH3,-SO2Me,-CONH2和-NHSO2Me;R1c1选自于以下组中:
-H,-F,-Cl,-Br,-NH2,-OH,-SO2Me,-SO2Et,-SO2NH2,-NO2,-CH2NH2,
-CN,-CONH2,-CH2OH;R1c2选自于以下组中:
-H,-F,-Cl,-Br和-OMe;以及R1c3选自于以下组中:
-H,-F,-Cl,-Br,-OH,-OCH3,-NH2,-CONH2,-CH2NH2,及其所有的药物学上可接受的异构体、盐、水合物、溶剂化物和前药衍生物。
-SO2NH2,-SO2CH3,-CN,-CONH2,-CONH(CH3),-CON(CH3)2,
-CH2NH2,-CH2NH(CH3),-CH2N(CH3)2;R1a选自于以下组中:
-H,-F,-Cl和-Br;R1b选自于以下组中:
-CH3和-CF3;R1c1选自于以下组中:
-H,-F,-Cl,-Br,-CN,-CH2NH2,-CH2OH,-CONH2,-C(=NH)NH2,
-CO2H,-CO2Me,-SO2Me,-SO2NH2,-OH,-NH2,和-NO2;R1c2选自于以下组中:
-H,-F,-Cl和-Br;以及R1c3选自于以下组中:
-H,-F,-Cl和-Br,及其所有的药物学上可接受的异构体、盐、水合物、溶剂化物和前药衍生物。
13、如权利要求1所述的化合物,其选自于以下组中:其中:R1选自于以下组中:
-SO2NH2,-SO2CH3,-CN,-CONH2,-CONH(CH3),-CON(CH3)2,
-CH2NH2,-CH2NH(CH3),-CH2N(CH3)2;R1a选自于以下组中:
-H,-F,-Cl和-Br;R1b选自于以下组中:
-CH3,-CF3,-CH2CH3,-SO2Me,-CONH2和-NHSO2Me;R1c1选自于以下组中:
-H,-F,-Cl,-Br,-NH2,-OH,-SO2Me,-SO2Et,-SO2NH2,-NO2,-CH2NH2,
-CN,-CONH2,-CH2OH;R1c2选自于以下组中:
-H,-F,-Cl,-Br和-OCH3;以及R1c3选自于以下组中:
-H,-F,-Cl,-Br,-OCH3,-NH2,-CH2NH2,-CONH2,-CONHMe,
-CONMe2,及其所有的药物学上可接受的异构体、盐、水合物、溶剂化物和前药衍生物。
14、如权利要求1所述的化合物,其选自于以下组中:其中:A-Q独立地选自于以下组中:
其中:
-H,-F,-Cl和-Br;R1b选自于以下组中:
-CH3和-CF3;R1c1选自于以下组中:
-H,-F,-Cl,-Br,-CN,-CH2NH2,-CH2OH,-CONH2,-C(=NH)NH2,
-CO2H,-CO2Me,-SO2Me,-SO2NH2,-OH,-NH2,和-NO2;R1c2选自于以下组中:
-H,-F,-Cl,-Br,和-OCH3;以及R1c3选自于以下组中:
-H,-F,-Cl,-Br,-OCH3,-NH2,-CH2NH2,-CONH2,-CONHMe,
-CONMe2,及其所有的药物学上可接受的异构体、盐、水合物、溶剂化物和前药衍生物。
15、如权利要求1所述的化合物,其选自于以下组中:其中:R1选自于以下组中:
-SO2NH2,-SO2CH3,-CN,-CONH2,-CONH(CH3),-CON(CH3)2,
-CH2NH2,-CH2NH(CH3),-CH2N(CH3)2;R1a选自于以下组中:
-H,-F,-Cl和-Br;R1b选自于以下组中:
-H,-CH3和-CF3;R1c1选自于以下组中:
-H,-F,-Cl,-Br,-CN,-CH2NH2,-CH2OH,-CONH2,-C(=NH)NH2,
-CO2H,-CO2Me,-SO2Me,-SO2NH2,-OH,-NH2,和-NO2;R1c2选自于以下组中:
-H,-F,-Cl和-Br;以及R1c3选自于以下组中:
-H,-F,-Cl和-Br及其所有的药物学上可接受的异构体、盐、水合物、溶剂化物和前药衍生物。
16、如权利要求1所述的化合物,其选自于以下组中:其中:R1选自于以下组中:
-SO2NH2,-SO2CH3,-CN,-CONH2,-CONH(CH3),-CON(CH3)2,
-CH2NH2,-CH2NH(CH3),-CH2N(CH3)2;R1a选自于以下组中:
-H,-F,-Cl和-Br;R1b选自于以下组中:
-H,-CH3和-CF3;R1c1选自于以下组中:
-H,-F,-CN,-CH2NH2,-CONH2,-SO2Me,-SO2NH2和-NO2;R1c2选自于以下组中:
-H,-F,-Cl,-Br和-OCH3;以及R1c3选自于以下组中:
-H,-F,-Cl,-Br,-OCH3,-NH2,-CH2NH2,-CONH2,-CONHMe,
-CONMe2,及其所有的药物学上可接受的异构体、盐、水合物、溶剂化物和前药衍生物。
其中:
-H,-F,-Cl和-Br;R1b选自于以下组中:
-H,-CH3和-CF3;R1c1选自于以下组中:
-H,-F,-Cl,-Br,-CN,-CH2NH2,-CH2OH,-CONH2,-C(=NH)NH2,
-CO2H,-CO2Me,-SO2Me,-SO2NH2,-OH,-NH2,和-NO2;R1c2选自于以下组中:
-H,-F,-Cl和-Br;以及R1c3选自于以下组中:
-H,-F,-Cl和-Br,及其所有的药物学上可接受的异构体、盐、水合物、溶剂化物和前药衍生物。
-H,-F,-Cl和-Br;R1b选自于以下组中:
-H,-CH3和-CF3;R1c1选自于以下组中:
-H,-F,-CN,-CH2NH2,-CONH2,-SO2Me,-SO2NH2和-NO2;R1c2选自于以下组中:
-H,-F,-Cl,-Br和-OCH3;以及R1c3选自于以下组中:
-H,-F,-Cl,-Br,-OCH3,-NH2,-CH2NH2,-CONH2,-CONHMe,
-CONMe2,及其所有的药物学上可接受的异构体、盐、水合物、溶剂化物和前药衍生物。
21、用于预防或者治疗哺乳动物中以非所希望的栓塞形成为特征的病症的药物组合物,其包括药物学上可接受的载体以及治疗有效量的如权利要求1所述的化合物。
22、用于预防或者治疗哺乳动物中以非所希望的栓塞形成为特征的病症的方法,其包括向所述哺乳动物给药治疗有效量的如权利要求1所述的化合物。
23、如权利要求22所述的方法,其中所述病症选自于以下组中:
急性冠脉综合征、心肌梗死、不稳定型心绞痛、顽固性心绞痛、溶栓治疗后或冠脉血管成形术后发生的闭塞性冠脉血栓、血栓形成介导的脑血管综合征、栓塞性中风、血栓形成性中风、短暂性脑缺血发作、静脉血栓形成、深部静脉血栓形成、肺栓塞、凝血病、播散性血管内凝血、血栓性血小板减少性紫癜、闭塞性血栓血管炎、与肝素诱导的血小板减少有关的血栓形成疾病、与体外循环有关的血栓形成并发症、与器械操作法有关的血栓形成并发症以及与假体装置安装有关的血栓形成并发症。
24、用于抑制生物样品凝集的方法,其包括施用如权利要求1所述的化合物的步骤。
25、用于预防或者治疗哺乳动物中以非所希望的栓塞形成为特征的病症的药物组合物,其包括药物学上可接受的载体以及治疗有效量的如权利要求2所述的化合物。
26、用于预防或者治疗哺乳动物中以非所希望的栓塞形成为特征的病症的方法,其包括向所述哺乳动物给药治疗有效量的如权利要求2所述的化合物。
27、如权利要求26所述的方法,其中所述病症选自于以下组中:
急性冠脉综合征、心肌梗死、不稳定型心绞痛、顽固性心绞痛、溶栓治疗后或冠脉血管成形术后发生的闭塞性冠脉血栓、血栓形成介导的脑血管综合征、栓塞性中风、血栓形成性中风、短暂性脑缺血发作、静脉血栓形成、深部静脉血栓形成、肺栓塞、凝血病、播散性血管内凝血、血栓性血小板减少性紫癜、闭塞性血栓血管炎、与肝素诱导的血小板减少有关的血栓形成疾病、与体外循环有关的血栓形成并发症、与器械操作法有关的血栓形成并发症以及与假体装置安装有关的血栓形成并发症。
28、用于抑制生物样品凝集的方法,其包括施用如权利要求2所述的化合物的步骤。
29、用于预防或者治疗哺乳动物中以非所希望的栓塞形成为特征的病症的药物组合物,其包括药物学上可接受的载体以及治疗有效量的如权利要求3所述的化合物。
30、用于预防或者治疗哺乳动物中以非所希望的栓塞形成为特征的病症的方法,其包括向所述哺乳动物给药治疗有效量的如权利要求3所述的化合物。
31、如权利要求30所述的方法,其中所述病症选自于以下组中:
急性冠脉综合征、心肌梗死、不稳定型心绞痛、顽固性心绞痛、溶栓治疗后或冠脉血管成形术后发生的闭塞性冠脉血栓、血栓形成介导的脑血管综合征、栓塞性中风、血栓形成性中风、短暂性脑缺血发作、静脉血栓形成、深部静脉血栓形成、肺栓塞、凝血病、播散性血管内凝血、血栓性血小板减少性紫癜、闭塞性血栓血管炎、与肝素诱导的血小板减少有关的血栓形成疾病、与体外循环有关的血栓形成并发症、与器械操作法有关的血栓形成并发症以及与假体装置安装有关的血栓形成并发症。
32、用于抑制生物样品凝集的方法,其包括施用如权利要求3所述的化合物的步骤。
33、用于预防或者治疗哺乳动物中以非所希望的栓塞形成为特征的病症的药物组合物,其包括药物学上可接受的载体以及治疗有效量的如权利要求4所述的化合物。
34、用于预防或者治疗哺乳动物中以非所希望的栓塞形成为特征的病症的方法,其包括向所述哺乳动物给药治疗有效量的如权利要求4所述的化合物。
35、如权利要求34所述的方法,其中所述病症选自于以下组中:
急性冠脉综合征、心肌梗死、不稳定型心绞痛、顽固性心绞痛、溶栓治疗后或冠脉血管成形术后发生的闭塞性冠脉血栓、血栓形成介导的脑血管综合征、栓塞性中风、血栓形成性中风、短暂性脑缺血发作、静脉血栓形成、深部静脉血栓形成、肺栓塞、凝血病、播散性血管内凝血、血栓性血小板减少性紫癜、闭塞性血栓血管炎、与肝素诱导的血小板减少有关的血栓形成疾病、与体外循环有关的血栓形成并发症、与器械操作法有关的血栓形成并发症以及与假体装置安装有关的血栓形成并发症。
36、用于抑制生物样品凝集的方法,其包括施用如权利要求4所述的化合物的步骤。
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Cited By (4)
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CN101743001B (zh) * | 2007-04-13 | 2013-02-06 | 千年药品公司 | 用起因子xa抑制剂作用的化合物的组合抗凝治疗 |
CN103483242A (zh) * | 2012-06-15 | 2014-01-01 | 上海朴颐化学科技有限公司 | 4-(2’-吡啶基)苄基肼及其中间体的制备方法 |
CN104016944A (zh) * | 2014-06-16 | 2014-09-03 | 山东大学 | N-(2-(胺甲基)苯基)噻唑-4-甲酰胺衍生物及其制备方法与应用 |
CN104016944B (zh) * | 2014-06-16 | 2016-05-18 | 山东大学 | N-(2-(胺甲基)苯基)噻唑-4-甲酰胺衍生物及其制备方法与应用 |
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MXPA02002762A (es) | 2003-10-14 |
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BR0014078A (pt) | 2002-12-31 |
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CA2385589A1 (en) | 2001-03-22 |
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AU781880B2 (en) | 2005-06-16 |
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NO20021230L (no) | 2002-05-21 |
ZA200306490B (en) | 2004-05-26 |
CZ2002959A3 (cs) | 2002-07-17 |
ZA200202117B (en) | 2004-02-25 |
ZA200306488B (en) | 2004-04-28 |
WO2001019798A2 (en) | 2001-03-22 |
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