CN102026970B - 用于治疗肺部和心血管病症的联芳基pde4抑制剂 - Google Patents
用于治疗肺部和心血管病症的联芳基pde4抑制剂 Download PDFInfo
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- CN102026970B CN102026970B CN2008801251832A CN200880125183A CN102026970B CN 102026970 B CN102026970 B CN 102026970B CN 2008801251832 A CN2008801251832 A CN 2008801251832A CN 200880125183 A CN200880125183 A CN 200880125183A CN 102026970 B CN102026970 B CN 102026970B
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- 0 CC(*)(CCC1)*CCCCC1Nc(c(*)c1)c(*)c(-c2ccc(*)c(*)c2)c1O* Chemical compound CC(*)(CCC1)*CCCCC1Nc(c(*)c1)c(*)c(-c2ccc(*)c(*)c2)c1O* 0.000 description 9
- IGRMOMGUKGJIKJ-UHFFFAOYSA-N COc1c(-c2cc(Cl)ccc2)c(F)c(Cc(cc2)cnc2F)cc1 Chemical compound COc1c(-c2cc(Cl)ccc2)c(F)c(Cc(cc2)cnc2F)cc1 IGRMOMGUKGJIKJ-UHFFFAOYSA-N 0.000 description 2
- QCYOIFVBYZNUNW-UHFFFAOYSA-N CC(C(O)=O)N(C)C Chemical compound CC(C(O)=O)N(C)C QCYOIFVBYZNUNW-UHFFFAOYSA-N 0.000 description 1
- HPLZOSFGNRLDPK-UHFFFAOYSA-N CC1(C)OSOC1(C)C Chemical compound CC1(C)OSOC1(C)C HPLZOSFGNRLDPK-UHFFFAOYSA-N 0.000 description 1
- ANNOVYFIHYHFNO-UHFFFAOYSA-N CC1(C)O[B+]OC1(C)C Chemical compound CC1(C)O[B+]OC1(C)C ANNOVYFIHYHFNO-UHFFFAOYSA-N 0.000 description 1
- HQCGQZDUXUDISL-UHFFFAOYSA-N CCOC(CCNC(Nc1ccc(Cc(ccc(OC)c2-c3cc(Br)ccc3)c2F)cc1)=O)=O Chemical compound CCOC(CCNC(Nc1ccc(Cc(ccc(OC)c2-c3cc(Br)ccc3)c2F)cc1)=O)=O HQCGQZDUXUDISL-UHFFFAOYSA-N 0.000 description 1
- TVWVYGAVAMOPPP-UHFFFAOYSA-N CN(CC1)CCN1C(NCSI)=O Chemical compound CN(CC1)CCN1C(NCSI)=O TVWVYGAVAMOPPP-UHFFFAOYSA-N 0.000 description 1
- CWLQUGTUXBXTLF-UHFFFAOYSA-N CN(CCC1)C1C(O)=O Chemical compound CN(CCC1)C1C(O)=O CWLQUGTUXBXTLF-UHFFFAOYSA-N 0.000 description 1
- HIGJWAKKJVCGPH-UHFFFAOYSA-N COC(C1c2cccc(Cl)c2)=CC=C(CC2=CC=C(C=N)NC2)C1F Chemical compound COC(C1c2cccc(Cl)c2)=CC=C(CC2=CC=C(C=N)NC2)C1F HIGJWAKKJVCGPH-UHFFFAOYSA-N 0.000 description 1
- DEXFCBGTTHRGPG-UHFFFAOYSA-N COC(c1ccc(Cc(cc2)cc(-c3cccc(Cl)c3)c2OC)cn1)=O Chemical compound COC(c1ccc(Cc(cc2)cc(-c3cccc(Cl)c3)c2OC)cn1)=O DEXFCBGTTHRGPG-UHFFFAOYSA-N 0.000 description 1
- FPXUKONXRQIPMP-UHFFFAOYSA-N COc(ccc(C(c(cc1)ccc1N)=O)c1)c1-c1cc(Cl)ccc1 Chemical compound COc(ccc(C(c(cc1)ccc1N)=O)c1)c1-c1cc(Cl)ccc1 FPXUKONXRQIPMP-UHFFFAOYSA-N 0.000 description 1
- MDNIWNLPZGCEDH-UHFFFAOYSA-N COc(ccc(C(c(cc1)ccc1NC(NC(N)=O)=O)=O)c1)c1-c1cc(Cl)ccc1 Chemical compound COc(ccc(C(c(cc1)ccc1NC(NC(N)=O)=O)=O)c1)c1-c1cc(Cl)ccc1 MDNIWNLPZGCEDH-UHFFFAOYSA-N 0.000 description 1
- RCBPIVYTUXPNFL-UHFFFAOYSA-N COc(ccc(C(c(cc1)ccc1NC(NC(N)=O)=O)O)c1)c1-c1cc(Cl)ccc1 Chemical compound COc(ccc(C(c(cc1)ccc1NC(NC(N)=O)=O)O)c1)c1-c1cc(Cl)ccc1 RCBPIVYTUXPNFL-UHFFFAOYSA-N 0.000 description 1
- DIOGEPIMKJBVMB-UHFFFAOYSA-N COc(ccc(CBr)c1)c1-c1cc(Cl)ccc1 Chemical compound COc(ccc(CBr)c1)c1-c1cc(Cl)ccc1 DIOGEPIMKJBVMB-UHFFFAOYSA-N 0.000 description 1
- JIAVXICJYRCUTA-UHFFFAOYSA-N COc(ccc(Cc1ccc(C(O)=O)nc1)c1)c1-c1cc(Cl)ccc1 Chemical compound COc(ccc(Cc1ccc(C(O)=O)nc1)c1)c1-c1cc(Cl)ccc1 JIAVXICJYRCUTA-UHFFFAOYSA-N 0.000 description 1
- UNOIKUYNHCHFDG-UHFFFAOYSA-N COc1c(-c2cc(Br)ccc2)c(F)c(Cc(cc2)ccc2NC(NCCC(O)=O)=O)cc1 Chemical compound COc1c(-c2cc(Br)ccc2)c(F)c(Cc(cc2)ccc2NC(NCCC(O)=O)=O)cc1 UNOIKUYNHCHFDG-UHFFFAOYSA-N 0.000 description 1
- BRLCEJXTZZJVBQ-UHFFFAOYSA-N COc1c(-c2cc(Cl)ccc2)c(F)c(CBr)cc1 Chemical compound COc1c(-c2cc(Cl)ccc2)c(F)c(CBr)cc1 BRLCEJXTZZJVBQ-UHFFFAOYSA-N 0.000 description 1
- WDJVLTRRERDOST-IBGZPJMESA-N COc1c(-c2cc(Cl)ccc2)c(F)c(Cc(cc2)cnc2N2[C@H](CO)CC2)cc1 Chemical compound COc1c(-c2cc(Cl)ccc2)c(F)c(Cc(cc2)cnc2N2[C@H](CO)CC2)cc1 WDJVLTRRERDOST-IBGZPJMESA-N 0.000 description 1
- ZJMHKFFAQJYFOC-UHFFFAOYSA-N Cc(cc1)cc(-c2cc([N]3(C=C3)O)ccc2)c1OC Chemical compound Cc(cc1)cc(-c2cc([N]3(C=C3)O)ccc2)c1OC ZJMHKFFAQJYFOC-UHFFFAOYSA-N 0.000 description 1
- QZYHIOPPLUPUJF-UHFFFAOYSA-N Cc1cc([N+]([O-])=O)ccc1 Chemical compound Cc1cc([N+]([O-])=O)ccc1 QZYHIOPPLUPUJF-UHFFFAOYSA-N 0.000 description 1
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- C07C217/80—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having amino groups and etherified hydroxy groups bound to carbon atoms of six-membered aromatic rings of the same carbon skeleton having amino groups and etherified hydroxy groups bound to carbon atoms of non-condensed six-membered aromatic rings
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Abstract
Description
技术领域
本发明涉及作为用于治疗和预防中风、心肌梗塞和心血管炎性疾病及病症的联芳基磷酸二酯酶-4(PDE-4)抑制剂的化学物质。
发明背景
PDE4是在炎性细胞和免疫细胞中发现的主要cAMP-代谢酶。已证实PDE4抑制剂具有特别是在炎性肺病,如哮喘、COPD和鼻炎中作为抗炎药物的潜力。它们抑制细胞因子及其他炎性信号的释放,并抑制活性氧的产生。已开发了大量的PDE4抑制剂用于多种临床适应证(Torphy and Page.2000.TIPS 21,157-159;Burnouf and Pruniaux.2002.Curr.Pharm.Design 8,1255-1296;Lipworth.2005.Lancet 365,167-175)。引用British Journal ofPharmacology中的一篇近期文章,“自80年代起,已开发PDE4抑制剂作为以哮喘和慢性阻塞性肺病(COPD)为主要适应证的新型抗炎疗法。尽管最初是乐观的,但这些治疗剂尚无一种上市。在大多数情况下,包括西洛司特、非明司特、利米司特(lirimilast)、吡拉米司特、妥非司特(tofimilast)等在内的多种结构类型的PDE4抑制剂的开发已由于缺乏疗效而中断。主要问题是这些化合物的低治疗比,其严重地限制了可以给予的剂量。实际上,对于这些化合物中的许多化合物,似乎最高耐受剂量或是亚治疗的,或是处于有效剂量-反应曲线的非常低的位置。因此,挑战是去克服该限制。”[Giembycz,Brit.J.Pharmacol.155,288-290(2008)]。由于呕吐的不良副作用,现有技术的许多PDE4抑制剂尚未上市(Giembycz 2005.Curr.Opin.Pharm.5,238-244)。对所有已知PDE4抑制剂的分析表明,它们与cAMP竞争并在活性位点内结合(Houslay等人,2005.DDT 10,1503-1519);这可以解释它们较窄的治疗比。本发明的化合物是cAMP的非竞争性抑制剂,并同时是基因特异性抑制剂(PDE4D),并且,根据目标原理(target rationale)和体外药效,本领域技术人员会期待所述化合物用作治疗、改善或预防炎性疾病及由此引发的并发症的抗炎剂。
发明概述
本发明涉及表现出PDE4酶抑制的化合物,其具有通式Ia、Ib、Ic或Id:
在这些化合物中,
R1是具有三个或更少个环的任选取代的碳环或任选取代的杂环;
R1a选自
(a)选自
(b)具有三个或更少个环的取代杂环或具有三个或更少个环的取代碳环;以及
(c)本身由具有其它取代基的杂环所取代的杂环;
其中,所述杂环和碳环上的取代基选自羟基、羧基、烷氧羰基、羧基烷基羰基氨基、羧基烷基氨基羰基氨基、胍基、5-四唑基、氨基酸残基以及N-甲基化氨基酸残基;
R2是具有两个或更少个环的任选取代的碳环或任选取代的杂环;
R3选自H、-C(=O)NH2、-(C1-C6)烷基、卤代(C1-C6)烷基、-(C1-C6)烷基-R30、-(C2-C6)烷基-R31以及任选地被甲基取代的饱和4-元或5-元杂环;
R30选自-C(=O)NH2和任选地被甲基取代的4-元或5-元杂环;
R31选自(C1-C4)烷氧基、氨基、羟基、(C1-C6)烷基氨基以及二(C1-C6)烷基氨基;
R4选自H和F;
R6选自H、(C1-C6)烷基和卤素;
X是N、N→O或C-R5;
R5选自H、卤素、OH、(C1-C6)烷基、(C1-C6)烷氧基、CF3、CN、NH2、CH2OH、CH2NH2和C≡CH;以及
M选自直接键、-C(R20)(R21)-、-O-、-NR22-、-S(O)n-、-C(=O)-、-C(R20)(R21)C(R20)(R21)-、-C(R20)=C(R21)-、-C(R20)(R21)-O-、-C(R20)(R21)-NR22-、-C(R20)(R21)-S(O)n-、-C(R20)(R21)-C(=O)-、-O-C(R20)(R21)-、-NR22-C(R20)(R21)-、-S(O)n-C(R20)(R21)-、-C(=O)-C(R20)(R21)-和
本发明还涉及药物组合物,其包含药学可接受的载体和治疗有效量的至少一种上述通式I(即Ia、Ib、Ic或Id)的化合物。当所述化合物以盐的形式存在时,所述盐应当是药学可接受的盐。
在又一方面,本发明涉及治疗或预防由外周(即在CNS之外的)磷酸二酯酶-4介导的疾病或病状的方法。所述方法包括向哺乳动物给药治疗有效量的具有通式I的化合物。本发明的化合物未显示穿过血脑屏障,并因此特别用于在不发生主要副作用如呕吐的情况下治疗外周PDE4介导的疾病。所述疾病或病状可能与过敏性、急性或慢性炎症有关。所述疾病可以是,例如,动脉粥样硬化、血栓形成、中风、急性冠状动脉综合征、稳定型心绞痛、外周血管病、重症下肢缺血(critical leg ischemia)、间歇性跛行、腹主动脉瘤或心肌梗塞。
本发明的选择性PDE4抑制剂还用于治疗哮喘和慢性阻塞性肺病(COPD)。还发现本发明的抑制肿瘤生长和转移的化合物在治疗和预防包括食道癌、脑癌、胰腺癌和结肠癌在内的癌症中的效用。还发现本发明的化合物在治疗和预防骨丢失、膀胱炎、膀胱过度活动或由膀胱炎引发的疼痛中的效用。
结合说明书和所附权利要求,会清楚本发明的这些及其它实施方案。
发明详述
在本说明书全文中,当引入取代基时进行定义并保持它们的定义。
除非另有说明,烷基意图包括直链、支链、或环状的烃结构及其组合。例如组合会是环丙基甲基。低级烷基是指具有1-6个碳原子的烷基。低级烷基的实例包括甲基、乙基、丙基、异丙基、丁基、仲丁基和叔丁基等。优选的烷基是C20或C20以下的烷基;更优选C1-C8烷基。环烷基是烷基的子类,并且包括具有3-8个碳原子的环状烃基。环烷基的实例包括环丙基、环丁基、环戊基、降冰片基(norbomyl)等。
C1-C20烃包括烷基、环烷基、多环烷基、烯基、炔基、芳基及其组合。实例包括苄基、苯乙基、环己基甲基、樟脑酰基和萘乙基。烃是指由作为仅有元素成分的氢和碳组成的任意取代基。
除非另有说明,术语“碳环”意图包括其中的环原子均为除任何氧化态的碳的环体系。因此(C3-C10)碳环既指非芳族体系也指芳族体系,包括诸如环丙烷、苯、环戊烯和环己烯的体系;(C8-C12)碳多环是指诸如降莰烷、十氢化萘、二氢化茚和萘的体系。除非另外限定,碳环是指单环、双环和多环。
烷氧基是指通过氧与母体结构相连的具有1-8个碳原子的直链、支链或环状构型的基团及其组合。实例包括:甲氧基、乙氧基、丙氧基、异丙氧基、环丙氧基、环己氧基等。低级烷氧基是指含有1-4个碳的基团。对于本申请,烷氧基和低级烷氧基包括亚甲二氧基和亚乙二氧基。烷氧基烷基是指通过烷基与母体结构相连的具有3-8个原子的直链、支链、环状构型的醚基团及其组合。实例包括:甲氧基甲基、甲氧基乙基、乙氧基丙基等。烷氧基芳基是指与芳基相连的烷氧基取代基,其中所述芳基与母体结构相连。芳基烷氧基是指与氧相连的芳基取代基,其中所述氧与母体结构相连。取代芳基烷氧基是指与氧相连的取代芳基取代基,其中所述氧与母体结构相连。
氧杂烷基是指其中的一个或多个碳(及它们的结合氢)已被氧替代的烷基残基。实例包括甲氧基丙氧基;3,6,9-三氧杂癸基;2,6,7-三氧杂双环[2.2.2]辛烷等。术语氧杂烷基意图如本领域所理解的[参见Naming and Indexing ofChemical Substances for Chemical Abstracts,由American Chemical Society出版,196,但不包括127(a)的限定],即它是指其中的氧通过单键与其相邻原子结合(形成醚键)的化合物;它不是指如在羰基中发现的双键氧。类似地,硫代烷基和氮杂烷基是指其中的一个或多个碳已分别被硫或氮替代的烷基残基。实例包括乙基氨基乙基和甲硫基丙基。
除非另有说明,酰基是指甲酰基,以及通过羰基官能团与母体结构相连的具有1、2、3、4、5、6、7和8个碳原子的直链、支链、环状构型的,饱和的、不饱和的及芳族的基团及其组合。只要与母体相连的位点仍然保留在所述羰基上,所述酰基残基中的一个或多个碳可以被氮、氧或硫替代。实例包括乙酰基、苯甲酰基、丙酰基、异丁酰基、叔丁氧羰基、苄氧羰基等。低级酰基是指含有1-4个碳的基团。当双键结合的氧本身被称为取代基时,其被称为“氧代”。
芳基和杂芳基意指:(i)苯基(或苯)或者含有1-4个选自O、N或S的杂原子的单环5-元或6-元杂芳环;(ii)含有0-4个选自O、N或S的杂原子的双环9-元或10-元芳环或杂芳环体系;或者(iii)含有0-5个选自O、N或S的杂原子的三环13-元或14-元芳环或杂芳环体系。本文所理解的芳基包括其中的一个或多个环为芳环但不需均为芳环的残基。因此芳族6-元至14-元碳环包括:例如,苯、萘、二氢化茚、四氢化萘和芴,并且5-元至10-元芳族杂环包括:例如,咪唑、吡啶、吲哚、噻吩、苯并吡喃酮、噻唑、呋喃、苯并咪唑、喹啉、异喹啉、喹噁啉、嘧啶、吡嗪、四唑和吡唑。
芳基烷基是指其中的芳基残基通过烷基与母体结构相连的取代基。实例是苄基、苯乙基等。杂芳基烷基是指其中的杂芳基残基通过烷基与母体结构相连的取代基。在一个实施方案中,芳基烷基或杂芳基烷基的烷基是具有1-6个碳的烷基。实例包括:例如,吡啶基甲基、嘧啶基乙基等。
杂环是指其中的1-3个碳被选自N、O和S的杂原子替代的环烷基或芳基碳环残基。氮和硫杂原子可以任选地被氧化,并且氮杂原子可以任选地被季铵化。除非另有说明,杂环可以是非芳族的或芳族的。应注意,杂芳基是杂环的子类,其中所述杂环是芳族的。落在本发明范围内的杂环残基的实例包括:吡唑、吡咯、吲哚、喹啉、异喹啉、四氢异喹啉、苯并呋喃、苯并二噁烷、苯并间二氧杂环戊烯(benzodioxole,当作为取代基出现时,通常被称为亚甲二氧基苯基)、吗啉、噻唑、吡啶(包括2-氧代吡啶)、吡啶N-氧化物、嘧啶、噻吩(即thiene)、呋喃、噁唑、噁唑啉、噁唑烷、异噁唑烷、异噁唑、二噁烷、氮杂环丁烷、哌嗪、哌啶、吡咯烷、哒嗪、氮杂吡唑烷、咪唑、咪唑啉、咪唑烷、咪唑并吡啶、吡嗪、噻唑烷、异噻唑、1,2-噻嗪-1,1-二氧化物、喹核碱、异噻唑烷、苯并咪唑、噻二唑、苯并吡喃、苯并噻唑、苯并***、苯并噁唑、四氢呋喃、四氢吡喃、苯并噻吩、硫吗啉、硫吗啉亚砜、硫吗啉砜、噁二唑、***、四唑、靛红(二氧代吲哚)、邻苯二甲酰亚胺(二氧代异吲哚)、吡咯并吡啶、***并吡啶,以及上述化合物中的全不饱和环体系的二氢和四氢同源物。
氧杂环是环内含有至少一个氧的杂环;它可以含有额外的氧及其它杂原子。见于本发明的实施例的氧杂环包括四氢呋喃、苯并间二氧杂环戊烯、吗啉、异噁唑和2,6,7-三氧杂双环[2.2.2]辛烷。硫杂环是环内含有至少一个硫的杂环;它可以含有额外的硫及其它杂原子。氮杂环是环内含有至少一个氮的杂环;它可以含有额外的氮及其它杂原子。
本文中所用的术语“任选取代的”可与“未取代的或取代的”互换使用。术语“取代的”是指用特定基团替代特定基团中的一个或多个氢原子。例如,取代烷基、芳基、环烷基、杂环基等是指这样的烷基、芳基、环烷基或杂环基,其中在各残基中的至多3个H原子被以下基团取代:卤素、卤代烷基、烷基、酰基、烷氧基烷基、羟烷基、羰基(即氧代)、苯基、杂芳基、苯磺酰基、羟基、烷氧基、卤代烷氧基、氧杂烷基、羧基、羧基烷基、羧基烷氧基、羧基烷硫基、烷氧羰基[-C(=O)O-烷基]、烷氧羰基氨基[-NHC(=O)O-烷基]、烷氧羰基氨基烷基[-烷基-NHC(=O)O-烷基]、羧基烷基羰基氨基[-NHC(=O)-烷基-COOH]、甲酰氨基[-C(=O)NH2]、氨基羰氧基[-OC(=O)NH2]、烷基氨基羰基[-C(=O)NH-烷基]、二烷基氨基羰基[-C(=O)N(烷基)2]、氨基羰基烷基[-烷基-C(=O)NH2]、氰基、乙酰氧基、硝基、氨基、烷基氨基、二烷基氨基、氨基烷基、(烷基)(芳基)氨基烷基、烷基氨基烷基(包括环烷基氨基烷基)、二烷基氨基烷基、二烷基氨基烷氧基、烷基(羟烷基)氨基、杂环基烷氧基、巯基、烷硫基、烷基磺酰基、烷基磺酰氨基、烷基亚磺酰基、烷基磺酰基、芳硫基、芳基磺酰基、芳基磺酰氨基、芳基亚磺酰基、芳基磺酰基、酰氨基烷基、酰氨基烷氧基、酰氨基、脒基、芳基、苄基、杂环基、杂环基烷基、苯氧基、苄氧基、杂芳氧基、杂环基氨基、羟基亚胺基、烷氧基亚胺基、氧杂烷基、氨基磺酰基、三苯甲基、脒基、胍基、脲基、-NHC(=O)NH烷基、-NHC(=O)NH-杂环基、-烷基-NHC(=O)N(烷基)2、杂环基烷基羰基氨基、苄氧基苯基和苄氧基。尽管在被称为以“任选取代的”取代基中包括氧代,本领域的技术人员会理解,由于氧代是二价基团,所以会存在它不适于作为取代基的情况(例如在苯基上)。被认为是所述术语,特别是对于R1的术语的范围内的其它取代基是氨基酸残基、氨基酸酰胺、氨基酸及其酰胺的受保护的残基,以及N-甲基化的(视适合情况,单甲基化或二甲基化的)氨基酸和氨基酸酰胺。
对于R1,取代基烷基、酰基、烷氧基烷基、羟基低级烷基、苯基、杂芳基、苯磺酸基、低级烷氧基、卤代烷氧基、氧杂烷基、烷氧羰基、烷氧羰基氨基、甲酰氨基、烷基氨基羰基、氨基、烷基氨基、(烷基)(芳基)氨基烷基、烷基氨基烷基、杂环基烷氧基、烷硫基、磺酰氨基、烷基亚磺酰基、烷基磺酰基、酰氨基烷基、酰氨基烷氧基、酰氨基、脒基、芳基、苄基、杂环基、杂环基烷基、杂环基烷氧基、苯氧基、苄氧基、杂芳氧基、杂环基氨基、氧杂烷基、氨基磺酰基、脒基、胍基、脲基、苄氧基苯基和苄氧基可进一步地被一个或两个以上所列的取代基取代。被认为是所述术语,特别是对于R1的术语的范围内的取代基是氨基酸残基、氨基酸酰胺和氨基酸及其酰胺的受保护的残基,以及以下特定残基:-CH3、-CH2CF3、-CF3、-CHO、-COOH、-CN、卤素、-OH、-OEt、-C(=O)NH2、-C(=O)NHEt、-C(=O)NMe2、-COOCH3、-COOEt、-CH2NHC(=O)NH2、-CH(CH3)NHC(=O)NH2、-CH2NHC(=O)H、-CH2NHC(=O)CH3、-CH2C(=O)NH2、-CH2COOH、-CH2COOEt、-CH2NHC(=O)OEt、-CH2NHC(=O)O-C6H5、-CH2NHC(=O)C(=O)NH2、-CH2NHC(=O)NHEt、-C(CH3)2OH、-CH2NHC(=O)N(CH3)2、-CH2NHC(=O)NHCH3、-CH2NH2、-CH(CH3)NH2、-C(CH3)2NH2、-CH2OH、-CH2CH2OH、-CH2NHSO2CH3、-CH2OC(=O)NHEt、-OCH(CH3)COOH、-SCH2COOH、-OCH3、-OC(=O)NH2、-OCH2CH2N(CH3)2、-OCH2CH2OCH3、-NHC(=O)NH2、-NHC(=O)NHEt、-NHCH3、-NHEt、-NH(tBoc)、-NHCH2COOH(“甘氨酸残基”)、-N(CH3)CH2COOH(“N-甲基甘氨酸残基”)、-NHC(=O)NHCH2CH2Cl、-NHSO2NH2、-NHEt、-N(CH3)2、-NH2、-NH(CH3)C(=O)NH2、-NHSO2CH3、-N(SO2CH3)2、-NHC(=O)OCH3、-NHC(=O)OtBu、-NHC(=O)CH3、-SO2NH2、-NHC(=O)CH2CH2COOH、-NHC(=O)NHCH2COOH、-CH2NHCHO、-NHC(=O)NHCH2COOEt、-NHC(=O)NH(CH2)3COOEt、-NHC(=O)NH(CH2)2COOEt、-N(CH3)CH2CH2OH、-NHC(=O)OEt、-N(Et)C(=O)OEt、-NHC(=O)NH(CH2)2COOH、-NHC(=O)CH2N(CH3)2、-NHC(=O)NH(CH2)3COOH、-NHC(=O)CH2NH2、-NHC(=O)CH2CH2NH2、-NHC(=O)CH2NH(tBoc)、 以及术语“氨基酸残基、氨基酸酰胺”等是指缺少被认为是母体结构上部分键的官能团的氨基酸等。例如,在下示分子中:
在除去将N-甲基丙氨酸与苯环相连的氢后,剩余的A的结构是:因为缺少在氨基端的氢原子,这并不是严格意义上的N-甲基氨基酸。这种结构以及缺少连接位点上的原子(如NH2的H)的类似结构在本文中被称为其各自母体的“残基”。
术语“卤代烷基”和“卤代烷氧基”分别意指被一个或多个卤素原子取代的烷基或烷氧基。术语“烷基羰基”和“烷氧羰基”分别意指-C(=O)烷基或-C(O)烷氧基。
术语“卤素”意指氟、氯、溴或碘。在一个实施方案中,卤素可以是氟或氯。
通常当引入时定义取代基Rn,并在说明书全文和所有独立权利要求中保持该定义。
在某些取代基的表征中,据述某些取代基可以结合以形成环。除非另有说明,意图这样的环可以表现出不同的不饱和度(从完全饱和至完全不饱和),可以包含杂原子,并且可以被低级烷基或烷氧基取代。
应认识到,本发明的化合物可以以放射标记的形式存在,即所述化合物可以包含一个或多个具有不同于自然界常见原子质量或质量数的原子质量或质量数的原子。氢、碳、磷、氟和氯的放射性同位素分别包括2H、3H、13C、14C、15N、35S、18F和36Cl。含有那些放射性同位素和/或其它原子的其它放射性同位素的化合物落在本发明的范围内。特别优选含氚的(即3H)和碳-14(即14C)放射性同位素,因为它们易于制备和检测。含有同位素11C、13N、15O和18F的化合物非常适合用于正电子发射断层摄影术。本发明的放射性标记的式I化合物及其前药通常可以通过本领域技术人员公知的方法进行制备。可以方便地通过实施实施例和合成路线中所公开的步骤,用易得的放射性标记的试剂取代非放射性标记的试剂来制备这样的放射性标记的化合物。
如本文所用的(特别是在权利要求中)以及如本领域技术人员所理解的,表述“化合物”意图包括所述化合物的盐、溶剂合物、共晶体和包合络合物以及任意立体异构形式,或者所述化合物的任意这样的形式以任意比例的混合物。因此,根据本发明的某些实施方案,以盐的形式提供在药物组合物、治疗方法和化合物本身的上下文中包括的如本文所述的化合物。因此,例如,其中R1是咪唑基的上述表述“式I的化合物”会包括咪唑鎓盐。在具体实施方案中,术语“式I的化合物”是指所述化合物或其药学可接受的盐。
本文所述的化合物可以包含不对称中心,并因此可以引起对映体、非对映体及其它立体异构形式。就绝对立体化学而言,可将各手性中心定义为(R)-或(S)-。本发明意图包括任意比例的、从外消旋形式至光学纯形式的所有这些可能的异构体。可以使用手性合成子或手性试剂制备,或者使用常规技术拆分旋光的(R)-和(S)-异构体。前缀“rac”是指外消旋体。除非另有说明,当本文所述的化合物含有烯属双键或其它几何不对称中心时,所述化合物意图包括E和Z几何异构体。本文中出现的任何碳-碳双键的构型表达仅仅是出于便利而进行选择,并且除非明确指出,其并非意图指明特定的构型。因此,任意描述为E的碳-碳双键可以是Z、E,或者此二者以任意比例的混合物。同样,还意图包括所有互变异构形式。
术语“溶剂合物”是指固态的式I化合物,其中适合的溶剂分子被掺入晶格中。用于治疗性给药的适合溶剂是在给药剂量下生理学上可耐受的。用于治疗性给药的适合溶剂的实例是乙醇和水。当水是溶剂时,所述溶剂合物被称为水合物。通常,通过将化合物溶于适当的溶剂,并经冷却或使用反溶剂使溶剂合物分离来形成溶剂合物。一般在环境条件下将溶剂合物干燥或共沸。在Remington:The Science and Practice of Pharmacy第19版(1995)卷1,176-177页中记载了包合络合物,将其援引加入本文。最常用的包合络合物是那些具有环糊精的包合络合物,并且在权利要求中特别包括了所有天然的和合成的环糊精络合物。
术语“药学可接受的盐”是指由包括无机酸和碱及有机酸和碱在内的药学可接受的无毒酸或碱制备的盐。当本发明的化合物是碱性时,盐可以由包括无机酸和有机酸在内的药学可接受的无毒酸制备。对于本发明的化合物,适合的药学可接受的阴离子包括醋酸根、苯磺酸根(besylate)、苯甲酸根、碳酸氢根、硫酸氢根、碳酸根、樟脑磺酸根、柠檬酸根、乙磺酸根、富马酸根、葡糖酸根、谷氨酸根、羟乙酸根、溴离子(bromide)、氯离子(chloride)、羟乙基磺酸根、乳酸根、马来酸根、苹果酸根、扁桃酸根、甲磺酸根、粘酸根、硝酸根、双羟萘酸根、泛酸根、磷酸根、琥珀酸根、硫酸根、酒石酸根、三氟乙酸根、对甲苯磺酸根、乙酰氨基苯甲酸根、己二酸根、藻酸根、氨基水杨酸根、脱水亚甲基柠檬酸根(anhydromethylenecitrate)、抗坏血酸根、天冬氨酸根、依地酸钙、樟脑酸根、右旋樟脑磺酸根、癸酸根、己酸根、辛酸根、肉桂酸根、环氨酸根、二氯乙酸根、依地酸根(EDTA)、乙二磺酸根、双羟萘酸根、丙酸酯十二烷基硫酸根、乙磺酸根、氟离子(fluoride)、甲酸根、龙胆酸根、葡庚糖酸根、葡糖醛酸根、甘油磷酸根、羟乙酸根、乙醇酰对氨基苯砷酸根(glycollylarsanilate)、己基间苯二酚离子(hexylresorcinate)、马尿酸根、羟基萘甲酸根、碘离子(iodide)、乳糖酸根、丙二酸根、甲磺酸根(mesylate)、萘二磺酸根、萘磺酸根、烟酸根、油酸根、乳清酸根、草酸根、酮戊二酸根、棕榈酸根、果胶酸根(pectinate)、果胶酸酯聚合物(pectinate polymer)、苯乙基巴比妥酸根、苦味酸根、氧脯氨酸根、丙酸根、硫氰酸根(rhodanide)、水杨酸根、癸二酸根、硬脂酸根、鞣酸根、8-氯茶碱(theoclate)、甲苯磺酸根等。通过在季铵盐(quat.)的合成中所得到的任何反荷离子的离子交换可获得所期望的盐。这些方法为本领域技术人员所公知。尽管会优选药学可接受的反荷离子用于制备药物制剂,但是可接受其它阴离子作为合成中间体。当所述化合物含有酸性侧链时,本发明的化合物的适合的药学可接受的碱加成盐包括由铝、钙、锂、镁、钾、钠和锌制备的金属盐,或者由赖氨酸、N,N′-二苄基乙二胺、氯普鲁卡因、胆碱、二乙醇胺、乙二胺、葡甲胺(N-甲基葡糖胺)和普鲁卡因制备的有机盐。
本文所用的外消旋的、双非外消旋的(ambiscalemic)和非外消旋的(scalemic)或对映体纯的化合物的图示采用Maehr J.Chem.Ed.62,114-120(1985)中的表述:实楔形和虚楔形用于表示手性元素的绝对构型;波浪线和单细线表示它代表的键不能产生任何立体化学含义;实粗线和虚粗线是除了表示外消旋特征以外,表示所示相对构型的几何符号;并且楔形轮廓和点线或虚线表示不确定绝对构型的对映体纯的化合物。
在本申请全文中出现与“保护”、“脱保护”和“受保护的”官能团有关的术语。这样的术语为本领域技术人员很好地理解,并且用于涉及用一系列试剂连续处理的方法的上下文中。在这样的上下文中,保护基团是指在方法步骤期间用于掩蔽官能团的基团,否则该官能团会在方法步骤期间发生反应,而该反应是不被期望的。保护基团在该步骤中阻止反应,但是可以随后被除去以暴露原来的官能团。除去或“脱保护”发生在会受到该官能团干扰的一个或多个反应完成之后。因此如在本发明的方法中的,当指定一系列的试剂时,本领域技术人员可以容易地预见那些适于作为“保护基团”的基团。在化学领域的标准教科书,如T.W.Greene的Protective Groups inOrganic Synthesis[John Wiley & Sons,New York,1991]中讨论了适用于该目的的基团,将其援引加入本文。
有机化学家所用缩写的综合列表刊登在Journal of Organic Chemistry的每卷的第1期中。将一般在标题为“Standard List of Abbreviations”的表格中提供的该列表援引加入本文。
一般而言,可以通过例如下述的一般反应路线中所示的方法,或者通过其变形,使用易得的原料、试剂和常规的合成操作,来制备本发明的化合物。在这些反应中,还可能使用本领域已知但未在本文中提及的不同形式。原料或是可商购的,或是按照实施例中所述合成的,或是可以通过本领域技术人员公知的方法得到的。
在临床研究中已证明PDE4抑制剂是有效的治疗剂。例如,向患有哮喘和COPD的患者给药西洛司特和罗氟司特(PDE4抑制剂)表现出初期的优异结果,但是西洛司特的效果在长期试验中消失[Lipworth,Lancet 365,167-175(2005)]。遗传学研究已清楚表明PDE4D与缺血性中风之间的关系(Gretarsdottir等人,2003.Nature Genetics.35,1-8)。选择性PDE4抑制剂(例如咯利普兰)还用于治疗骨丢失[Yao等人,J.Musculoskelet.Neuronal Interact. 7,119-130(2007)]。
此外,证明PDE4抑制剂YM976改善大鼠中实验诱发的间质性膀胱炎的作用,其导致排尿频率降低和每次排尿时尿量增加[Kitta等人,BJU Int. 102,1472-1476(2008)]。在阻塞性膀胱的啮齿动物模型中,证明另一种PDE4抑制剂IC485与市售用于治疗过度活动膀胱的药物酒石酸托特罗定(tolteradine tartrate)具有相同的疗效[Kaiho等人,BJU Int.101,615-20(2008)]。这些发现表明PDE4抑制剂会在治疗膀胱过度活动、发炎和疼痛的症状方面有用。
此外,本发明的化合物、组合物和方法可用于治疗癌症。已证明磷酸二酯酶活性与骨髓恶性肿瘤相关[Lerner等人,Biochem.J.393,21-41(2006);Ogawa等人,Blood 99,3390-3397(2002)]。
此外,特别是当如上所述地进行放射性标记,或者通过本领域公知的方法用荧光标记物和自旋标记物进行标记时,本发明的化合物、组合物和方法可以用作显像剂以及以其它方式用于诊断和/或治疗。另外,将本发明的化合物固定于固体支撑物上可以用于亲和纯化,并且用化学活性基团修饰本发明的化合物可以用于蛋白标记。
对于上述许多效用,将通式I的化合物与以下药剂联合给药是有利的,所述药剂为:胆碱酯酶抑制剂(例如他克林、石杉碱、多奈哌齐);NMDA拮抗剂(例如拉尼西明、瑞马西胺、奈拉美生(neramexane)、美金刚);钙蛋白酶抑制剂(例如CEP-3122);抗氧化剂(例如维生素E、辅酶Q10)和已表现出临床疗效但其机理尚不清楚的药剂(例如dimebon)。
术语“治疗或预防的方法”意指改善、预防或缓解与病症相关的症状和/或作用。本文使用的术语“预防”是指预先将药物给药以预先阻止或缓和急性发作。医学领域(本方法权利要求所涉及的领域)的技术人员认识到,术语“预防”并不是绝对的术语。在医学领域中,该术语被理解为指将药物预防性地给药以基本上降低病状的可能性或严重性,并且这也是在申请人的权利要求中意图表达的含义。如本文所用的,提及对患者的“治疗”意图包括预防。
术语“哺乳动物”以其字典中的含义使用。哺乳动物类中包括人类,并且人类会是所述方法的优选对象。
虽然可以将式I的化合物以化学原料形式给药,但是通常会优选将其作为药物组合物的部分而提供。根据本发明的实施方案,提供了药物组合物,其包含式I的化合物或其药学可接受的盐,以及一种或多种其药物载体,和任选的一种或多种其它治疗成分。在与该制剂中的其它成分可相容以及对其接受者无害的意义上,所述一种或多种载体必须是“可接受的”。此外,当在独立权利要求中提及化合物或其药学可接受的盐时,应理解,引用涉及这样的化合物的独立权利要求的权利要求也包括所述化合物的药学可接受的盐,即使在该从属权利要求中未明确地提及所述盐。
所述制剂包括适合于口服给药、肠胃外(包括皮下、真皮内、肌肉内、静脉内和关节内)给药、直肠给药和局部(包括皮肤、含服、舌下和眼内)给药的那些制剂。最适合的途径可以取决于接受者的病状和病症。所述制剂可以方便地以单位剂量形式提供,并可以通过药学领域公知的任何方法制备。这样的方法包括使式I的化合物或其药学可接受的盐或其溶剂合物(“活性成分”)与构成一种或多种助剂的载体相结合的步骤。一般而言,通过以下方法制备所述制剂:将活性成分与液体载体或细分散的固体载体或其二者均匀且紧密地结合,然后视需要将产物定形成期望的剂型。
适于口服给药的制剂可作为以下形式提供:作为各自包含预定量的活性成分的独立单位,如胶囊剂、扁胶囊剂或片剂;作为散剂或颗粒剂;作为在水性液体或非水性液体中的溶液剂或混悬剂;或者作为水包油液体乳剂或油包水液体乳剂。所述活性成分还可以作为大丸剂(bolus)、煎膏剂(electuary)或糊剂而提供。
可以通过任选地与一种或多种助剂压制或模制来制备片剂。可以通过在适合的机器中压制任选地与粘合剂、润滑剂(lubricant)、惰性稀释剂、润滑剂(lubricating agent)、表面活性剂或分散剂混合的自由流动形式(如粉末或颗粒)的活性成分来制备压制片剂。可以通过在适合的机器中模制用惰性液体稀释剂润湿的粉状化合物的混合物来制备模制片剂。所述片剂可以任选地被包衣或刻痕,并可以将其配制以提供其中的活性成分的持续释放、迟延释放或控制释放。所述药物组合物可以包含“药学可接受的惰性载体”并且此表述意图包括一种或多种惰性赋形剂,其包括淀粉、多元醇、粒化剂、微晶纤维素、稀释剂、润滑剂、粘合剂、崩解剂等。若需要,所公开组合物的片剂可以通过标准水性或非水性技术进行包衣。“药学可接受的载体”也包括控释手段。
药物组合物还可以任选地包含其它治疗成分、抗结剂、防腐剂、甜味剂、着色剂、矫味剂、干燥剂、增塑剂、染料等。任何这样的任选成分必须与式I的化合物相容以保证制剂的稳定性。所述组合物可以视需要包含其它添加剂,其包括:例如乳糖、葡萄糖、果糖、半乳糖、海藻糖、蔗糖、麦芽糖、棉子糖、麦芽糖醇、松三糖、水苏糖、拉克替醇、palatinite、淀粉、木糖醇、甘露糖、肌醇等及其水合物,以及氨基酸例如丙氨酸、甘氨酸和甜菜碱,以及肽和蛋白质例如胚乳。
用作药学可接受的载体和药学可接受的惰性载体以及上述其它成分的赋形剂的实例包括但不限于粘合剂、填充剂、崩解剂、润滑剂、抗微生物剂和包衣剂。
成人的剂量范围通常为口服0.005mg-10g/天。片剂或以独立单位提供的其它给药形式可以方便地包含一定量的式I化合物,其在此剂量下或者在多剂量下有效,例如,含有5mg-500mg,通常约10mg-200mg的单位。向患者给药的化合物的确切量将由主治医师决定。但是,使用的剂量会取决于许多因素,其包括患者的年龄和性别、待治疗的确切病症及其严重性。
剂量单位(例如口服剂量单位)可以包括,例如,1-30mg、1-40mg、1-100mg、1-300mg、1-500mg、2-500mg、3-100mg、5-20mg、5-100mg(例如1mg、2mg、3mg、4mg、5mg、6mg、7mg、8mg、9mg、10mg、11mg、12mg、13mg、14mg、15mg、16mg、17mg、18mg、19mg、20mg、25mg、30mg、35mg、40mg、45mg、50mg、55mg、60mg、65mg、70mg、75mg、80mg、85mg、90mg、95mg、100mg、150mg、200mg、250mg、300mg、350mg、400mg、450mg、500mg)的本文所述的化合物。
关于药物组合物及其制剂的其它信息参见,例如,Remington:TheScience and Practice of Pharmacy,第20版,2000。所述药剂可以通过例如,静脉注射、肌内注射、皮下注射、腹膜内注射、局部、舌下、关节内(在关节内)、真皮内、含服、眼部(包括眼内)、鼻内(包括使用插管)给药,或者通过其它途径给药。所述药剂可作为以下形式口服给药:例如,作为含有预定量的活性成分的片剂或扁胶囊剂、凝胶剂、丸剂、糊剂、糖浆剂、大丸剂、煎膏剂、膏剂(slurry)、胶囊剂、散剂、颗粒剂,作为在水性液体或非水性液体中的溶液剂或混悬剂,作为水包油液体乳剂或油包水液体乳剂,通过胶束剂型(参见,例如WO 97/11682),通过脂质体剂型(参见,例如EP736299、WO 99/59550和WO 97/13500),通过WO 03/094886中所述的剂型或者以某些其它形式。所述药剂还可以透皮给药(即通过储库型(reservoir-type)或骨架型(matrix-type)贴剂、显微操作针、热致孔(thermalporation)、皮下注射针、电离子透入疗法、电致孔、超声或超声促渗的其它形式、快速注射,或者任何上述方法的组合(Prausnitz等人,2004,NatureReviews Drug Discovery 3:115))。所述药剂可以局部给药,例如在受伤部位向受伤的血管局部给药。可以将所述药剂涂敷在支架(stent)上。可以采用U.S.20020061336中所述的水凝胶颗粒制剂,通过高速透皮颗粒注射(high-velocity transdermal particle injection)技术来给药所述药剂。在WO00/45792、WO 00/53160和WO 02/19989中记载了其它颗粒制剂。可以在WO 89/04179中找到含有膏药和促吸收剂二甲基异山梨醇酯的透皮制剂的实例。WO 96/11705提供适合于透皮给药的制剂。可以以栓剂的形式或者通过其它***或直肠手段给药所述药剂。可以如WO 90/07923中所述,以跨膜制剂(transmembrane formulation)给药所述药剂。可以通过U.S.6,485,706中所述的脱水颗粒,无创地给药所述药剂。可以如WO 02/49621中所述,以肠溶包衣药物制剂给药所述药剂。可以采用U.S.5,179,079中所述的制剂鼻内给药所述药剂。在WO 00/62759中记载了适于肠胃外注射的制剂。可以采用U.S.20030206939和WO 00/06108中所述的酪蛋白制剂给药所述药剂。可以采用U.S.20020034536中所述的颗粒制剂给药所述药剂。
可以利用若干技术经肺部途径将所述药剂单独给药或者与其它适合的成分联合给药,所述技术包括但不限于:气管内滴入(通过注射器将溶液递送至肺)、脂质体的气管内递送、吹入法(通过注射器或任何其它类似装置将散剂制剂向肺部给药)和喷雾法。气雾剂(例如喷射雾化器或超声雾化器、定量吸入器(MDI)和干粉吸入器(DPI))也可以用于鼻内施用。气雾剂制剂是固体材料和液滴在气态介质中的稳定的分散体或混悬剂,并且可以置于加压可接受的抛射剂中,所述抛射剂如氢氟烷类(HFAs,即HFA-134a和HFA-227或其混合物)、二氯二氟甲烷(或其它含氯氟烃抛射剂如抛射剂11、12和/或114的混合物)、丙烷、氮气等。肺部制剂可以包含促渗剂如脂肪酸和糖、螯合剂、酶抑制剂(例如蛋白酶抑制剂)、佐剂(例如甘胆酸盐、枯草菌表面活素、span 85和萘莫司他)、防腐剂(例如苯扎氯铵或氯丁醇),以及乙醇(通常至多5重量%,但是可能高达20重量%)。由于乙醇能够改善计量阀的功能并且在某些情况下还能够改善分散体的稳定性,通常将其包含在气雾剂组合物中。肺部制剂还可以包含表面活性剂,其包括但不限于胆汁盐和U.S.6,524,557及其参考文献中所述的那些表面活性剂。在U.S.6,524,557中所述的表面活性剂,例如C8-C16脂肪酸盐、胆汁盐、磷脂或烷基糖(alkylsaccharide)的优点在于:据报道它们中的某些还促进制剂中化合物的吸收。适合于本发明的还有干粉制剂,其包含与适当载体混合的治疗有效量的活性化合物,并且适合与干粉吸入器联用。可以加入本发明的干粉制剂中的促吸收剂包括U.S.6,632,456中记载的那些促吸收剂。WO 02/080884记载了粉末表面改性的新方法。气雾剂制剂可以包括U.S.5,230,884、U.S.5,292,499、WO 017/8694、WO 01/78696、U.S.2003019437、U.S.20030165436和WO 96/40089(其包含植物油)中所记载的制剂。在U.S.20010036481A1、20030232019A1和U.S.20040018243A1以及在WO 01/13891、WO02/067902、WO 03/072080和WO 03/079885中记载了适于吸入的缓释制剂。在WO 03/015750、U.S.20030008013和WO 00/00176中记载了含有微粒的肺部制剂。在U.S.20020141945和U.S.6,309,671中记载了含有稳定的玻璃态粉末的肺部制剂。在EP 1338272A1、WO 90/09781、U.S.5,348,730、U.S.6,436,367、WO 91/04011和U.S.6,294,153中记载了其它气雾剂制剂,并且U.S.6,290,987中记载了可以通过气雾剂或其它手段给药的脂质体基制剂。在U.S.20030053960和WO 01/60341中记载了用于吸入的散剂制剂。如U.S.20010038824中所述,可以将所述药剂鼻内给药。
通常使用在缓冲盐水和类似载体中的药物溶液在雾化器中产生气雾剂。简单的雾化器按照Bernoulli原理运行,并使用空气或氧气流以产生喷雾颗粒。更为复杂的雾化器则利用超声以产生喷雾颗粒。这两种类型均为本领域所公知,并且在标准药学教科书如Sprowls的American Pharmacy和Remington的The Science and Practice of Pharmacy中有所记载。用于产生气雾剂的其它装置利用压缩气体(通常是氢氟烃(hydrofluorocarbons)和含氯氟烃),其与药物和任何需要的赋形剂在加压容器中混合,这些装置同样在诸如Sprowls和Remington的标准教科书中有所记载。
可以将所述药剂掺入脂质体中以改善半衰期。还可以将所述药剂与聚乙二醇(PEG)链结合。可以在Harris和Chess,Nature Reviews Drug Discovery2:214-221及其参考文献中找到聚乙二醇化方法和含有PEG-结合物的其它制剂(即PEG-基水凝胶、PEG改性的脂质体)。可以通过纳米蜗形(nanocochleate)或蜗形(cochleae)递送载体给药所述药剂(BioDeliverySciences International)。可以使用如U.S.5,204,108中所记载的制剂,经粘膜(即透过粘膜表面,如***、眼或鼻)给药所述药剂。如WO 88/01165中所述,可以将所述药剂配制成微胶囊。可以使用U.S.20020055496、WO00/47203和U.S.6,495,120中所记载的制剂口腔内给药所述药剂。可以使用WO 01/91728A2中所记载的纳米乳液制剂递送所述制剂。
一般而言,可以通过例如下述的一般反应路线所示的方法,或者通过其变形,使用易得的原料、试剂和常规合成步骤,来制备式I的化合物。在这些反应中,还可能使用本领域已知但未在本文中提及的不同形式。
本发明涉及表现出PDE4酶抑制的化合物,其具有通式Ia、Ib、Ic或Id:
在某些Ia或Ic的实施方案中,X是N或N→O;在其它实施方案中,X是CR5。在另一实施方案中,M选自直接键、-CH2-、-CH(OH)-、-C[(CH3)(OH)]-、-C[(CH3)(NH2)]-、-C(=O)-、-O-、-NH-、-N(CH3)-、-S(O)n-、-CH2NH-、-CH2CH2-、-CH=CH-、-CH2S(O)n-、-CH2O-和
在一个实施方案中,R1或R1a是取代苯基。在另一实施方案中,R1是未取代杂环。在另一实施方案中,R1或R1a是取代杂环。在这两种杂环的实施方案中,所述杂环可选自吡唑、吡咯、吲哚、喹啉、异喹啉、四氢异喹啉、苯并呋喃、苯并二噁烷、苯并间二氧杂环戊烯、吗啉、噻唑、吡啶、吡啶N-氧化物、嘧啶、噻吩、呋喃、噁唑、噁唑啉、噁唑烷、异噁唑烷、异噁唑、二噁烷、氮杂环丁烷、哌嗪、哌啶、吡咯烷、哒嗪、氮杂吡唑烷、咪唑、咪唑啉、咪唑烷、嘌呤、咪唑并吡啶、吡嗪、噻唑烷、异噻唑、1,2-噻嗪-1,1-二氧化物、2,6,7-三氧杂双环[2.2.2]辛烷、喹核碱、异噻唑烷、苯并咪唑、噻二唑、苯并吡喃、苯并噻唑、苯并***、苯并噁唑、苯并噁二唑、四氢呋喃、四氢吡喃、苯并噻吩、硫吗啉、硫吗啉亚砜、硫吗啉砜、噁二唑、***、四唑、异吲哚、吡咯并吡啶、***并吡啶及其二氢和四氢同源物(无论其是否具体命名)。例如,吲哚的二氢同源物是二氢吲哚(indoline或dihydroindole);吡啶的四氢同源物是哌啶。在另一实施方案中,R1是任选取代的杂环,所述杂环选自吡唑、苯并间二氧杂环戊烯、吗啉、噻唑、吡啶、吡啶N-氧化物、嘧啶、噻吩、噁唑烷、异噁唑、氮杂环丁烷、哌嗪、吡咯烷、咪唑、咪唑烷、咪唑并吡啶、吡嗪、1,2-噻嗪-1,1-二氧化物、苯并咪唑、噻二唑、苯并***、苯并噁唑、噁二唑、***、四唑、异吲哚、吡咯并吡啶、***并吡啶及它们的二氢和四氢同源物。
在一个实施方案中,取代苯基或取代杂环是被以下取代基所取代,所述取代基选自卤素、卤代烷基、烷基、酰基、烷氧基烷基、羟烷基、羰基、苯基、杂芳基、苯磺酰基、羟基、烷氧基、卤代烷氧基、氧杂烷基、羧基、烷氧羰基、烷氧羰基烷基、烷氧羰基氨基、羧基烷基、羧基烷氧基、羧基烷硫基、烷氧羰基氨基烷基、羧基烷基羰基氨基、甲酰胺基、氨基羰氧基、烷基氨基羰基、二烷基氨基羰基、氨基羰基烷基、氰基、乙酰氧基、硝基、氨基、烷基氨基、二烷基氨基、氨基烷基、(烷基)(芳基)氨基烷基、烷基氨基烷基、二烷基氨基烷基、二烷基氨基烷氧基、烷基(羟烷基)氨基、杂环基烷氧基、巯基、烷硫基、烷基磺酰基、烷基磺酰氨基、烷基亚磺酰基、烷基磺酰基、芳硫基、芳基磺酰基、芳基磺酰氨基、芳基亚磺酰基、芳基磺酰基、酰氨基烷基、酰氨基烷氧基、酰氨基、脒基、芳基、苄基、杂环基、杂环基烷基、苯氧基、苄氧基、杂芳氧基、杂环基氨基、羟基亚胺基、烷氧基亚胺基、氧杂烷基、氨基磺酰基、三苯甲基、脒基、胍基、脲基、-NHC(=O)NH烷基、-NHC(=O)NH-杂环基、-烷基-NHC(=O)N(烷基)2、杂环基烷基羰基氨基、苄氧基苯基、苄氧基、氨基酸残基、氨基酸酰胺、受保护的氨基酸残基、受保护的氨基酸酰胺残基、N-甲基化氨基酸和N-甲基化氨基酸酰胺。示例性的氨基酸是甘氨酸、丙氨酸和脯氨酸。示例性的羧基烷氧基和羧基烷硫基分别是乳酸和硫基乙酸。
在另一实施方案中,取代苯基或取代杂环是被以下取代基所取代,所述取代基选自-CH3、-CH2CF3、-CF3、-CHO、-COOH、-CN、卤素、-OH、-OEt、-C(=O)NH2、-C(=O)NHEt、-C(=O)NMe2-COOCH3、-COOEt、-CH2NHC(=O)NH2、-CH(CH3)NHC(=O)NH2、-CH2NHC(=O)H、-CH2NHC(=O)CH3、-CH2C(=O)NH2、-CH2COOH、-CH2COOEt、-CH2NHC(=O)OEt、-CH2NHC(=O)O-C6H5、-CH2NHC(=O)C(=O)NH2、-CH2NHC(=O)NHEt、-C(CH3)2OH、-CH2NHC(=O)N(CH3)2、-CH2NHC(=O)NHCH3、-CH2NH2、-CH(CH3)NH2、-C(CH3)2NH2、-CH2OH、-CH2CH2OH、-CH2NHSO2CH3、-CH2OC(=O)NHEt、-OCH3、-OC(=O)NH2、-OCH2CH2N(CH3)2、-OCH2CH2OCH3、-OCH(CH3)COOH、-SCH2COOH、-NHC(=O)NH2、-NHC(=O)NHEt、-NHCH3、-NHEt、-NH(tBoc)、-NHCH2COOH、-N(CH3)CH2COOH、-NHC(=O)NHCH2CH2Cl、-NHSO2NH2、-NHEt、-N(CH3)2、-NH2、-NH(CH3)C(=O)NH2、-NHSO2CH3、-N(SO2CH3)2、-NHC(=O)OCH3、-NHC(=O)OtBu、-NHC(=O)CH3、-SO2NH2、-NHC(=O)CH2CH2COOH、-NHC(=O)NHCH2COOH、-CH2NHCHO、-NHC(=O)NHCH2COOEt、-NHC(=O)NH(CH2)3COOEt、-NHC(=O)NH(CH2)2COOEt、-N(CH3)CH2CH2OH、-NHC(=O)OEt、-N(Et)C(=O)OEt、-NHC(=O)NH(CH2)2COOH、-NHC(=O)CH2N(CH3)2、-NHC(=O)NH(CH2)3COOH、-NHC(=O)CH2NH2、-NHC(=O)CH2CH2NH2、-NHC(=O)CH2NH(tBoc)、
在式Ia的实施方案中,R1a可以是(1)具有3个或更少个环的取代杂环;(2)与取代单环杂环相连接的单环杂环;(3)具有3个或更少个环的取代碳环。在杂环或碳环上的取代基可选自-COOH、-OH、-COOCH3、-COOEt、-CH2COOH、-CH2COOEt、-CH2NHC(=O)OEt、-CH2NHC(=O)C(=O)NH2、-OCH(CH3)COOH、-SCH2COOH、-NHCH2COOH、-N(CH3)CH2COOH、-NHSO2NH2、-NHC(=O)CH2CH2COOH、-NHC(=O)NHCH2COOH、-NHC(=O)NHCH2COOEt、-NHC(=O)NH(CH2)3COOEt、-NHC(=O)NH(CH2)2COOEt、-NHC(=O)NH(CH2)2COOH、-NHC(=O)NH(CH2)3COOH和5-四唑基。第二类实施方案的实例,即与被羧酸取代的单环杂环相连接的单环杂环是在下文的实施例A053中记载的R1a残基:
在一个实施方案中,R2选自任选取代的苯基、任选取代的单环不饱和杂环、未取代的双环不饱和杂环以及氟代双环不饱和杂环。在另一实施方案中,R2选自任选取代的苯基、吲哚、苯并间二氧杂环戊烯、苯并噁二唑、苯并二噁烷、苯并咪唑、噁二唑、吡唑、吡啶和吡啶N-氧化物。在另一实施方案中,R2选自间位取代的苯基、吲哚、苯并间二氧杂环戊烯、2,2-二氟苯并间二氧杂环戊烯、苯并噁二唑、苯并咪唑、5-(吡啶-4-基)[1,2,4]噁二唑、5-(吡啶-4-基)[1,3,4]噁二唑、苯并二噁烷、4-氯吡唑、4-(吡啶-4-基)吡唑、6-氯吡啶、3-(三氟甲基)吡唑和吡啶N-氧化物。
在另一实施方案中,R2是以下取代苯基:
其中,R7选自氢、卤素、硝基、氰基、卤代(C1-C6)烷基、羟基、(C1-C6)烷氧基、(C1-C6)氧杂烷基、羧基、(C1-C6)烷氧羰基、氨基羰基(-CONH2)、(C1-C6)烷基氨基羰基、酰基、羟基(C1-C6)烷基、卤代(C1-C6)烷氧基、氨基(C1-C6)烷基、氨基、(C1-C6)烷基氨基、二[(C1-C6)烷基]氨基、巯基、(C1-C6)烷硫基、(C1-C6)烷基亚磺酰基、(C1-C6)烷基磺酰基、(C1-C6)烷基磺酰氨基、酰氨基、脒基、苯基、苄基、杂环基、苯氧基、苄氧基和杂芳氧基;并且R8和R13独立地选自H和F。在另一实施方案中,R8和R13是H,并且R7选自氢、氟、氯、溴、硝基、氰基、乙酰基、三氟甲基、甲氧基、三氟甲氧基、噁二唑基、四唑基、甲硫基、甲基亚磺酰基、甲磺酰基、甲磺酰氨基、氨基、甲氧基甲基、羟乙基和吗啉基。
在式Ib和Ic的实施方案中,R1可选自任选取代的苯基、任选取代的5-元杂芳基、任选取代的6-元杂芳基、任选取代的4-7元非芳基杂环以及任选取代的稠合双环。例如,R1可选自任选取代的苯基;任选取代的5-元杂芳基,其选自噻唑、噻二唑、吡唑、噁二唑、异噁唑、***、咪唑、噻吩、四唑和噁唑;任选取代的6-元杂芳基,其选自吡啶、嘧啶、哒嗪酮、嘧啶酮、吡啶酮、吡嗪和二嗪;任选取代的5-元和6-元非芳基杂环,其选自四氢噻吩、哌嗪、噁唑烷酮、咪唑啉酮、吗啉、哌啶、吡咯烷酮、吡咯烷二酮(pyrrolidinedione)、吡咯烷、哌啶酮、哌啶二酮以及三氧杂双环[2.2.2]辛烷;以及任选取代的稠合双环,其选自苯并噁唑酮、吲哚、异二氢吲哚二酮(isoindolinedione)、2H-吡咯并吡啶二酮、嘌呤、二氢吲哚二酮、***并吡啶酮、苯并咪唑、苯并噁二唑、喹啉和喹诺酮;其中所述取代基独立地选自氢、卤素、卤代(C1-C6)烷基、羟基、(C1-C6)烷氧基、羧基、(C1-C6)烷氧羰基、氨基羰基(-CONH2)、(C1-C6)烷基氨基羰基、氰基、羰基(氧代)、酰基、羟基(C1-C6)烷基、卤代(C1-C6)烷氧基、氨基(C1-C6)烷基、(C1-C6)烷氧基(C1-C6)烷基、硝基、氨基、(C1-C6)烷基氨基、二[(C1-C6)烷基]氨基、巯基、(C1-C6)烷硫基、亚砜、砜、磺酸酯、磺酰亚胺、酰氨基、脒基、苯基、苄基、杂环基、苯氧基、苄氧基、杂芳氧基、氨基羰基(C1-C6)烷基、(C1-C6)烷氧羰基(C1-C6)烷基、羧基(C1-C6)烷基、甲酰氨基(C1-C6)烷基、羧基(C1-C6)烷基氨基、-(CH2)p-NR12CO-(CH2)q-NR9R10、-NHSO2R11、-OCH2CH2NR9R10、-NHSO2NR9R10、-SO2NR9R10、-(CH2)p-NHCOR9、OCONR9R10以及NR12COOR11;
R3选自-CH3、-CH2CH3、-CF3、-CHF2以及-CH2F;
R5选自H、-F、-OH、-CH3、-OCH3、-CF3、-CN、-NH2以及-C≡CH;
R2是
(a)苯基,并且R7选自H、卤素、硝基、乙酰基、羟乙基、-NH2、-SCH3、甲氧羰基、-SOCH3、-SO2CH3、-OCH3、-OCF3、-CN、-CF3、-CH2OCH3;或
(b)苯并噁二唑、苯并间二氧杂环戊烯、2,2-二氟苯并间二氧杂环戊烯、苯并噁二唑、苯并二噁烷、苯并咪唑、噁二唑、吡唑、吡啶和吡啶N-氧化物;
R9选自H、(C1-C6)烷基、卤代(C1-C6)烷基、(C1-C6)烷氧羰基、羧基(C1-C6)烷基、(C1-C6)烷氧基羧基(C1-C6)烷基;
R10是H、(C1-C6)烷基,或共同是,或者
R9和R10共同形成任选地被(C1-C6)烷基取代的杂环;
p是0或1,
q是0、1或2,
R11是直链(C1-C6)烷基,
R12是H或(C1-C6)烷基;或者
两个相邻的取代基共同形成任选取代的稠合杂环。
在式Ib和Ic的实施方案中,R1a可选自取代苯基;取代的5-元杂芳基,其选自噻唑、噻二唑、吡唑、噁二唑、异噁唑、***、咪唑、噻吩、四唑和噁唑;取代的6-元杂芳基,其选自吡啶、嘧啶、哒嗪酮、嘧啶酮、吡啶酮、吡嗪和二嗪;取代的5-元和6-元非芳基杂环,其选自四氢噻吩、哌嗪、噁唑烷酮、咪唑啉酮、吗啉、哌啶、吡咯烷酮、吡咯烷二酮、吡咯烷、哌啶酮、哌啶二酮以及三氧杂双环[2.2.2]辛烷;以及取代的稠合双环,其选自苯并噁唑酮、吲哚、异二氢吲哚二酮、2H-吡咯并吡啶二酮、嘌呤、二氢吲哚二酮、***并吡啶酮、苯并咪唑、苯并噁二唑、喹啉和喹诺酮。在这种情况下,所述取代基独立地选自-COOH、-OH、-COOCH3、-COOEt、-CH2COOH、-CH2COOEt、-CH2NHC(=O)OEt、-CH2NHC(=O)C(=O)NH2、-OCH(CH3)COOH、-SCH2COOH、-NHCH2COOH、-N(CH3)CH2COOH、-NHSO2NH2、-NHC(=O)CH2CH2COOH、-NHC(=O)NHCH2COOH、-NHC(=O)NHCH2COOEt、-NHC(=O)NH(CH2)3COOEt、-NHC(=O)NH(CH2)2COOEt、-NHC(=O)NH(CH2)2COOH、-NHC(=O)NH(CH2)3COOH和5-四唑基;
R3选自-CH3、-CH2CH3、-CF3、-CHF2以及-CH2F;
R5选自H、-F、-OH、-CH3、-OCH3、-CF3、-CN、-NH2以及-C≡CH;
R2是
(a)苯基,并且R7选自H、卤素、硝基、乙酰基、羟乙基、-NH2、-SCH3、甲氧羰基、-SOCH3、-SO2CH3、-OCH3、-OCF3、-CN、-CF3、-CH2OCH3;或
(b)苯并噁二唑、苯并间二氧杂环戊烯、2,2-二氟苯并间二氧杂环戊烯、苯并噁二唑、苯并二噁烷、苯并咪唑、噁二唑、吡唑、吡啶和吡啶N-氧化物;
R9选自H、(C1-C6)烷基、卤代(C1-C6)烷基、(C1-C6)烷氧羰基、羧基(C1-C6)烷基、(C1-C6)烷氧基羧基(C1-C6)烷基;
R10是H、(C1-C6)烷基,或共同是,或者
R9和R10共同形成任选地被(C1-C6)烷基取代的杂环;
p是0或1,
q是0、1或2,
R11是直链(C1-C6)烷基,
R12是H或(C1-C6)烷基;或者
两个相邻的取代基共同形成任选取代的稠合杂环。
通类Ia化合物的一个实施方案具有下式:
其中
R1b是苯基、5-元杂芳基、6-元杂芳基、4-7元非芳基杂环或稠合双环;
R14选自-COOH、-OH、-COOCH3、-COOEt、-CH2COOH、-CH2COOEt、-CH2NHC(=O)OEt、-CH2NHC(=O)C(=O)NH2、-OCH(CH3)COOH、-SCH2COOH、-NHCH2COOH、-N(CH3)CH2COOH、-NHSO2NH2、-NHC(=O)CH2CH2COOH、-NHC(=O)NHCH2COOH、-NHC(=O)NHCH2COOEt、-NHC(=O)NH(CH2)3COOEt、-NHC(=O)NH(CH2)2COOEt、-NHC(=O)NH(CH2)2COOH、-NHC(=O)NH(CH2)3COOH、5-四唑基以及被任何前述基团取代的单环杂环;
R27选自氢、卤素、硝基、氰基、卤代(C1-C6)烷基、羟基、(C1-C6)烷氧基、(C1-C6)氧杂烷基、羧基、(C1-C6)烷氧羰基、氨基羰基(-CONH2)、(C1-C6)烷基氨基羰基、酰基、羟基(C1-C6)烷基、卤代(C1-C6)烷氧基、氨基(C1-C6)烷基、氨基、(C1-C6)烷基氨基、二[(C1-C6)烷基]氨基、巯基、(C1-C6)烷硫基、(C1-C6)烷基亚磺酰基、(C1-C6)烷基磺酰基、(C1-C6)烷基磺酰氨基、酰氨基、脒基、苯基、苄基、杂环基、苯氧基、苄氧基和杂芳氧基;
R28选自H和F,或
通类Ib和Ic的实施方案具有下式:
R1c是苯基、5-元杂芳基、6-元杂芳基、4-7元非芳基杂环或稠合双环;
R14选自H、-CH2NHC(=O)NH2、-NHC(=O)NH2、-NHC(=O)NHEt、-CH3、-CH2CF3、-CH2NHC(=O)CH3、-NHCH3、-NHEt、-NH(tBoc)、-CHO、-NHC(=O)NHCH2CH2Cl、-NHSO2NH2、-NHEt、-N(CH3)2、-NH2、-COOH、-OCH(CH3)COOH、-SCH2COOH、-C(=O)NH2、-CH2C(=O)NH2、-CH2COOH、-CH2COOEt、-CN、-OCH3、-OC(=O)NH2、-NH(CH3)C(=O)NH2、卤素、-CH2NHC(=O)OEt、-NHSO2CH3、-N(SO2CH3)2、-NHC(=O)OCH3、-OH、-CH2NHC(=O)N(CH3)2、-CH2NH2、-CH2OH、-CH2CH2OH、-SO2NH2、-NHC(=O)NHCH2COOH、-CH2NHCHO、-NHC(=O)NHCH2COOEt、-COOCH3、-COOEt、-NHC(=O)NH(CH2)3COOEt、-NHC(=O)NH(CH2)2COOEt、-NH(Et)C(=O)OEt、-NHC(=O)NH(CH2)2COOH、-CH2NHSO2CH3、-OEt、-NHC(=O)CH2N(CH3)2、-NHC(=O)NH(CH2)3COOH、-NHC(=O)CH2NH2、-NHC(=O)CH2CH2NH2、-NHC(=O)CH2NH(tBoc)、-OCH2CH2N(CH3)2、-OCH2CH2OCH3、3′-硝基-6-甲氧基联苯-3-基甲基、四氢咪唑-2-酮-1-基、3-甲基四氢咪唑-2-酮-1-基、吡唑-1-基、 以及
R15选自H、NO2、OH、NH2以及-NHSO2NH2;或者
R15与R14共同形成亚甲二氧基;
R27选自氢、卤素、硝基、氰基、卤代(C1-C6)烷基、羟基、(C1-C6)烷氧基、(C1-C6)氧杂烷基、羧基、(C1-C6)烷氧羰基、氨基羰基(-CONH2)、(C1-C6)烷基氨基羰基、酰基、羟基(C1-C6)烷基、卤代(C1-C6)烷氧基、氨基(C1-C6)烷基、氨基、(C1-C6)烷基氨基、二[(C1-C6)烷基]氨基、巯基、(C1-C6)烷硫基、(C1-C6)烷基亚磺酰基、(C1-C6)烷基磺酰基、(C1-C6)烷基磺酰氨基、酰氨基、脒基、苯基、苄基、杂环基、苯氧基、苄氧基和杂芳氧基;
R28选自H和F,或
R27与R28共同形成5-元环。
在另一实施方案中,R27和R28表示在3-位和4-位的稠合杂环,以使由R27和R28与它们连接的苯基共同形成的残基选自:
在其它实施方案中,R27选自卤素、硝基、乙酰基、羟乙基、氨基、甲硫基、三氟甲基、甲氧基甲基、甲氧羰基、三氟甲氧基、氰基和1,3,4-噻二唑-2-基,或R7和R8共同为亚甲二氧基或二氟亚甲二氧基。在前述实施方案中,R1a可选自苯环、***、吡啶或吡啶N-氧化物、吡唑、四氢噻吩、咪唑、嘧啶、噻二唑以及咪唑并吡啶。
在本发明的一个实施方案中,R5是氟、H、CN或OH。在其它实施方案中,R3是甲基或氟甲基。
本发明的另一实施方案具有下式:
其中是通过其氮原子连接的4-7元杂环;R17和R18独立地选自H、(C1-C6)烷基和卤代(C1-C6)烷基;R19选自H、(C1-C6)烷基、卤代(C1-C6)烷基、-[(C1-C6)烷基]COOH以及-[(C1-C6)烷基]COO(C1-C6)烷基;并且R20选自羧酸、甲酰胺、羧酸酯、伯、仲或叔醇以及伯、仲或叔胺。羧酸、甲酰胺、羧酸酯、伯、仲或叔醇以及伯、仲或叔胺的实例包括-COOH、-CONH2、-CONHCH3、-CON(CH3)2、-COOCH3、-CH2OH、-CH(CH3)OH、-C(CH3)2OH、-CH2NH2、-CH(CH3)NH2以及-C(CH3)2NH2。
落在上述母体类Ia、Ib和Ic范围内的化合物作为外周PDE4抑制剂是有用的。在审查时可能发现,由于目前未排除的种类(species)和类属(genera)已被公开,所以它们对本申请的发明人而言是不具有可专利性的。在此情况下,应认为在申请人的权利要求中对种类和类属的排除是专利申请与审查中的人为结果,而非反映发明人的构思或者其发明的描述。在组合物方面,本发明是除了公众所有的那些化合物之外的所有式Ia、Ib和Ic的活性化合物。
一般而言,可以通过例如下述的一般反应路线所示的方法,或者通过其变形,使用易得的原料、试剂和常规合成步骤,来制备式I的化合物。
通常可以由含有期望官能团W(其中W可以是例如CH、N、COH、CF等)的适当地官能化的烷氧基-芳基醚衍生物来制备式I的化合物(途径A,路线A1),其中R2是取代芳基/杂芳基,并且两个联芳基通过C-C键连接。一般可通过Suzuki或Stille偶联首先构建联芳基部分(G1->G2)。在这种情况下,Y=卤素或OSO2R(OTf,ONf),并且另一种试剂是R2-B(OR)2或R2-SnR3’,反之亦然,其中R2-卤素与含有硼酸盐/硼酸或三烷基锡作为Y的G1偶联。当A是碳衍生的取代基,如CH3、CH2OH、CO2R”、CN等时,将这些基团转化以提供中间体G3(其中D是卤素或OTf、ONf或OCOOR”(碳酸酯)),使得通过利用过渡金属催化偶联反应,如Suzuki、Stille或Negishi反应引入取代基(R1)。G4型化合物的可选途径包括基本颠倒R1和R2片段的引入顺序。如在路线A1中突出标记的途径B使得能够形成G6,其中与在G1-G2中所利用的化学作用(如Suzuki、Stille偶联)类似,在顺序的后一阶段引入R2片段。
路线A1
可通过多种连接基团M将R1连接到中心芳环(Ar)上,其中R1可以是芳基、杂环、非环状、脂族的或任何其它期望的官能团种类。中心芳环(Ar)可以是具有已连接的R2基团的联芳环体系,或可在连接R1之后连接R2基团。连接基团M可以是具有一个或多个由C、N、O或S组成的原子的直链。连接基团M还可由以下官能团组成,所述官能团包括但不限于酰胺、磺酰胺、砜或酮。本领域技术人员清楚,许多这些示例性官能团可以以多于一种方式进行连接,例如Ar-CH2-O-R1或Ar-O-CH2-R1。就这些具有M基团,如S或O的化合物而言,杂原子最初可以在Ar或在R1基团中。关于这两种基团随后的连接手段的某些实例是芳族亲核取代、金属-促进偶联及亲核置换(路线A2)。当确定哪一部分(partner)包含连接杂原子以及哪一部分应当作为反应部分(reaction partner)时,当然应当考虑Ar和R1基团的化学反应性。例如,公知在芳环体系中,与离去基团(例如卤素)对位或邻位的吸电子基团使得芳族卤素易于发生亲核置换。因此,含有NO2、CO2R、酮、CN等的Ar1基团使得能够形成芳基-M-芳基(杂芳基)中间体。连接基团M还可进行进一步的处理(elaboration)。例如,可将硫化物氧化为亚砜和砜,并且可使胺进行烷基化或还原胺化。公知的合成转化可用于构建连接基团M,如醚酰胺、磺酰胺等。如上所述,在前体Ar和R1基团中的官能团位置可用于表示连接的性质和类型(例如可选的醚)。
路线A2
(例如A=OH,SH) (例如M=O,S(O)n=0-2)
还可使用非过渡金属催化形成C-C键的偶联反应连接关键片段Ar和R1。当A=H时,可利用Fridele-Crafts酰基化或烷基化以将Ar和R1基团结合。考虑到Ar环上的芳族邻甲氧基的化学反应性,Friedel-Crafts酰基化一般包括适于处理的R1-COCl(酰基氯)基团以形成化合物G10。在这种情况下,J=CO,可将其还原为仲醇(一般用氢化物基的还原剂)。如果使用R’MgX或其它这样的有机金属试剂,可通过同时加入R′基团将J=CO基团转化为叔醇。在另一种变化中,可使用标准操作将J=CO基团转化为亚胺或肟,并且添加R′MgX型试剂产生叔胺衍生物。可以视需要用多种成熟的方法将J=CO基团还原为CH2基团(M)。在另一种变化中,当A=H时,可通过Vilsmeier反应或通过路易斯酸(TiCl4、BF3·OEt2等)介导的反应,用二氯甲基甲基引入醛基。随后可将所述醛官能团转化为适合的过渡金属催化偶联反应部分。或者,可将醛基用于形成烯或CH2CH2键的Wittig反应以引入R1。在又一变化中,取代基“A”可以是多种类型的羰基(醛或酮)或亚胺基。在一个实施例中,将适当处理的有机金属R1基团(例如R1-MgX)加成到醛G9(A=CHO)上会产生G10(J=C(H)OH)。该醇的还原产生G11(M=CH2)。如果G9包含A=酮基或亚胺基,本领域技术人员可利用类似的转化类型。
路线A3
或者,可通过用存在于G12的连接基团M(Scheme G4)中的亲核试剂置换R1上的离去基团以实现在Ar和R1基团之间的C-C键形成反应。可除去活化基团以提供Z=H(Z=CO2R-脱羧,或Z=CN-脱氰),或者可将这些基团进一步转化为其它官能团,例如Z=CH2OH或CH2NH2。当M-Z是CH2-卤化物或CH2-O-磺酸酯时,可通过形成醚键来引入R1片段。这使得R1通过不同长度和组成的间隔基(M)连接到中心芳环上。(路线A4)
路线A4
为了形成杂环或杂芳环,还可以从非环状中间体组成R1基团。这些化学作用的实例包括从酰肼(G16)形成5-元杂芳基,如噁二唑、噻二唑、***;从2-卤代-酮形成噻唑或从烯或乙酰基经偶极环化加成反应以形成5-元杂环或5-元杂芳基(G18)[路线A5]。或者,可以通过Diels-Alder或杂-Diels-Alder化学作用,使用具有亲双烯体或二烯的适当地取代的烷基芳基醚,来形成6-元杂芳基或杂环。可根据前述中间体(例如醛、卤代烷)的路线,通过标准方法合成必要的非环状前体。
路线A5
当R2基团通过杂原子(N)连接到Ar基团上时,可通过有机金属介导的氮杂-偶联反应或其它基于亲核芳族取代的步骤(路线G6)来制备这些联芳基体系。可以从已具有R1基团的中间体G6形成Ar-(N)R2联芳基。或者,可首先将(N)R2环加成到中心Ar环上,可通过多种使用前述路线中所述途径的方法连接R1。(HN)R2杂芳基或杂环的实例包括但不限于咪唑、吡咯、吡唑、吡咯烷或***。在将(N)R2加成到Ar上之前可充分处理R2官能团,或者在形成关键的C-N键之后将其适当地处理。
路线A6
可以通过本领域公知的标准官能团转化来形成存在于R1和R2中的取代基的多种选择。这些标准官能团转化中的一些包括从具有R2、R3或Ar环片段的适合的胺、羧酸、醇或苯酚基团形成酰胺、磺酰胺、脲、咪唑酮、噁唑酮、氨基甲酸酯。特别有用的芳环官能化技术(可利用R2或R1环)是邻-卤代含氮芳环的亲核置换(G20,路线A7)。用于该类转化的环底物(substrate)包括2-卤代-吡啶、2-卤代-嘧啶和2-卤代-咪唑。此外,除卤素(X)之外还可使用其它离去基团,如磺酸酯(Otf、ONf)。这些置换反应可以用碱或叔胺碱进行,或者可以通过使用有机金属试剂如钯或铝试剂来介导。用于该类转化的亲核试剂(R”)的实例包括能够进行亲核置换的胺(伯胺、仲胺、叔胺;非环状或环状的胺)、醇、苯酚或含有HN的杂环基团(咪唑或吡唑)。
路线A7
当R1基团包含许多在之前的化学作用期间已被掩蔽或保护的其它官能团,如胺、酯/酸/醇时,可将这些官能团用于进一步的官能团处理。可以使用成熟的合成步骤来实现R1官能团的多种修饰,所述合成步骤包括但不限于:烷基化、还原胺化、亲核置换、环化、皂化以及氧化/还原。此外,与这些官能团处理类似,可将Ar1单环进一步转化为双环。这样的环转化的实例可以以将吡啶衍生物处理为咪唑并[1,2-a]吡啶和咪唑并[1,5-a]吡啶为代表。可以在引入R2或进行其他合成转化之前或之后,在任何化学适合的位点实现这些官能团的处理和双环的处理。
可以从在中心Ar环中包含或不包含氟取代基的烷基化苯酚进行这些上述转化。这些途径中的几种还可以适用于3-烷氧基吡啶作为Ar环原料的情况。意图在下文路线中所述的非限制性的具体实施例作为可能的反应的宽范围的实例。类似地,可以通过以下类似的化学作用(路线A1-A7)衍生出W=CH2OH、COOH、CN、CONH2等(或被适当保护的前体)的类似物,并且这些官能团可以衍生自酯或酰胺衍生的原料。
制备了下列化合物实施例。
表1
实施例序号 | X | R3 | M | Rb | Ra |
A-001 | C-H | CH3 | CH2 | 3-NO2 | 7-(糖精) |
A-008 | C-F | CH3 | CH2 | 3-Cl | 4-(NHSO2NH2)苯基 |
A-011 | C-F | CH3 | CH2 | 3-Cl | (3-OH,4-NHSO2NH2)苯基 |
A-016 | C-F | CH3 | CH2 | 3-COCH3 | 4-(NHSO2NH2)苯基 |
A-018 | C-F | CH3 | CH2 | 3-COCH3 | 4-(COOCH3)苯基 |
A-019 | C-F | CH3 | CH2 | 3-COCH3 | 4-(COOH)苯基 |
A-022 | C-F | CH3 | CH2 | 3-Br | 4-(NHCONHCH2COOH)苯基 |
A-023 | C-F | CH3 | CH2 | 3-Br | 4-(NHCONHCH2CH2COOH)苯基 |
A-039 | C-F | CH3 | CH2 | 3-Cl | 6-{咪唑并[1,2-a]吡啶-2-羧酸乙酯} |
A-043 | C-F | CH3 | CH2 | 3-Cl | 6-{咪唑并[1,2-a]吡啶-2-羧酸} |
A-051 | C-F | CH3 | CH2 | 3-Cl | 6-{咪唑并[1,5-a]吡啶-2-羧酸} |
A-062 | SO3-Na+ | CH3 | CH2 | CH2 | 4-(NHCONH2)苯基 |
A-064 | C-H | CH3 | CO | 3-Cl | 4-(NHCONHCONH2)苯基 |
A-065 | C-H | CH3 | CD(OH) | 3-Cl | 4-(NHCONHCONH2)苯基 |
实施例序号 | X | R3 | M | Rb | Ra |
B-080 | N-O | CH3 | CH2 | 3-NO2 | 4-F-苯基 |
B-084 | CH | CH3 | CH2 | * | 4-F-苯基 |
*Rb-苯基被3-吡啶N-氧化物取代
表2.
实施例序号 | X | R3 | M | Rb | P | Q | U | V | W | Ra |
A-010 | C-F | CH3 | CH2 | 3-Cl | CH | CH | N | CH | C | (W)-NHSO2NH2 |
A-012 | C-F | CH3 | CH2 | 3-Cl | CH | CH | N | N | C | (W)-NHSO2NH2 |
A-013 | C-F | CH3 | CH2 | 3-COCH3 | CH | CH | N | CH | C | (W)-NHSO2NH2 |
A-014 | C-F | CH3 | CH2 | 3-Cl | CH | CH | CH | N-O | C | (W)-NHCONH2 |
A-015 | C-F | CH3 | CH2 | 3-Cl | CH | CH | N | N-O | C | (W)-NHCONH2 |
A-017 | C-F | CH3 | CH2 | 3-COCH3 | CH | CH | N | N | C | (W)-NHSO2NH2 |
A-020 | C-F | CH3 | CH2 | 3-COCH3 | CH | CH | N | CH | C | (W)-CO2CH3 |
A-021 | C-F | CH3 | CH2 | 3-COCH3 | CH | CH | N | CH | C | (W)-CO2H |
A-028 | C-F | CH3 | CH2 | 3-Cl | CH | CH | N | CH | C | (W)-NHCONHCH2CO2H |
A-029 | C-F | CH3 | CH2 | 3-Cl | CH | CH | N | CH | C | (W)-NHCONHCH2CH2CO2Et |
A-032 | C-F | CH3 | CH2 | 3-Cl | CH | CH | N | CH | C | (W)-NHCONHCH2CH2CO2H |
A-033 | C-F | CH3 | CH2 | 3-Cl | CH | CH | N | CH | C | (W)-CO-N(哌啶-4-CO2Et) |
A-034 | C-F | CH3 | CH2 | 3-Cl | CH | CH | N | CH | C | (W)-CO-N(哌啶-4-COOH) |
A-035 | C-F | CH3 | CH2 | 3-Cl | CH | CH | N | CH | C | (W)-NHCH2CO2H |
A-036 | C-F | CH3 | CH2 | 3-Cl | CH | CH | N | CH | C | (W)-OH |
实施例序号 | X | R3 | M | Rb | P | Q | U | V | W | Ra |
A-037 | C-F | CH3 | CH2 | 3-Cl | CH | CH | N | CH | C | (W)-N(COCH3)CH2CO2H |
A-038 | C-F | CH3 | CH2 | 3-Cl | CH | CH | N | CH | C | (W)-CO-1N-吡咯烷-3-CO2H) |
A-040 | C-F | CH3 | CH2 | 3-Cl | CH | CH | N | N | C | (W)-1N-(S)-脯氨酸 |
A-041 | C-F | CH3 | CH2 | 3-Cl | CH | CH | N | N | C | (W)-1N-(哌啶-3-CO2H) |
A-042 | C-F | CH3 | CH2 | 3-Cl | CH | CH | N | CH | C | (W)-1H-5-四唑 |
A-044 | C-F | CH3 | CH2 | 3-Cl | CH | CH | N | N | C | (W)-1N-(吡咯烷-3-CO2H) |
A-045 | C-F | CH3 | CH2 | 3-Cl | CH | CH | N | N | C | (W)-1N-(吡咯烷-3-CO2Me |
A-047 | C-F | CH3 | CH2 | 3-Cl | CH | CH | N | N | C | (W)-肌氨酸 |
A-048 | C-F | CH3 | CH2 | 3-Cl | CH | CH | CH | N | C | (W)-CH2NHCOCO2Et |
A-049 | C-F | CH3 | CH2 | 3-Cl | CH | CH | N | N | C | (W)-N(氮杂环丁烷-(W)-COOH) |
A-050 | C-F | CH3 | CH2 | 3-Cl | CH | CH | CH | N | C | (W)-CONHSO2CH3 |
A-053 | C-F | CH3 | CH2 | 3-Cl | CH | CH | N | N | C | (W)-N(氮杂环丁烷-4-COOH) |
A-054 | C-F | CH3 | CH2 | 3-Cl | CH | CH | CH | N | C | (W)-N(氮杂环丁烷-2-COOH) |
A-056 | C-F | CH3 | CH2 | 3-Cl | CH | CH | CH | N | C | (W)-N(CH2-COOH)-CONHEt |
A-057 | C-F | CH3 | CH2 | 3-Cl | CH | CH | CH | N | C | (W)-N(CH2-COOH)-CONH2 |
A-061 | C-F | CH3 | CH2 | 3-Cl | CH | CH | CH | N | C | (W)-N(氮杂环丁烷-(S)-2-COOH) |
A-063 | C-F | CH3 | CH2 | 3-Cl | CH | CH | CH | N | C | (W)-N(R)-脯氨酸 |
A-066 | C-F | CH3 | CH2 | 3-Cl | CH | CH | CH | N | C | (W)-N(氮杂环丁烷-(R)-2-COOH) |
实施例序号 | X | R3 | M | Rb | P | Q | U | V | W | Ra |
A-067 | C-H | CH3 | CH2 | 3-Cl | CH | CH | CH | N | C | (W)-N(氮杂环丁烷-2-COOH) |
A-068 | C-H | CH3 | CH2 | 3-Cl | CH | CH | CH | N | C | (W)-N(R)-脯氨酸 |
A-069 | C-F | CH3 | CH2 | 3-Cl | CH | CH | CH | N | C | (W)-N(R)-脯氨酸甲酯 |
A-070 | C-F | CH3 | CH2 | 3-Cl | CH | CH | CH | N | C | (W)-N(3-哌可酸) |
A-071 | C-H | CH3 | CH2 | 3-Cl | CH | CH | CH | N | C | (W)-COOH |
A-072 | C-F | CH3 | CH2 | 3-Cl | CH | CH | CH | N | C | (W)-N(S)-脯氨酸 |
A-073 | C-H | CH3 | CH2 | 3-Cl | CH | CH | CH | N | C | (W)-COOCH3 |
A-074 | C-F | CH3 | CH2 | 3-Cl | CH | CH | CH | N | C | (W)-N(CH3)-CH2COOH |
A-075 | C-H | CF2H | CH2 | 3-Cl | CH | CH | CH | N | C | (W)-COOCH3 |
A-076 | C-H | CF2H | CH2 | 3-Cl | CH | CH | CH | N | C | (W)-四唑 |
A-077 | C-H | CH3 | CH2 | 3-Cl | CH | CH | CH | N | C | (W)-N(CH3)-CH2COOH |
A-078 | C-H | CF2H | CH2 | 3-Cl | CH | CH | CH | N | C | (W)-N(CH3)-CH2COOH |
A-079 | C-H | CF2H | CH2 | 3-Cl | CH | CH | CH | N | C | (W)-N(CH3)-[S]CH(CH3)-COOH |
B-081 | CF | CH3 | CH2 | 3-Cl | CH | CH | N-O | CH | C | (W)-NHCONHEt |
B-082 | CF | CH3 | CH2 | 3-Cl | CH | CH | N-O | CH | C | (W)-CH2-NHCONHEt |
B-083 | CF | CH3 | CH2 | 3-Cl | CH | CH | N-O | CH | C | (W)-CH2-(1-咪唑烷-2-酮) |
表3.
实施例序号 | 中心 | R3 | M | Rb | P | Q | U | V | Ra |
A-006 | C-H | CH3 | CH2 | 3-NO2 | C(CH3) | C(CH3) | N | N | (U)-CH2COOH |
A-024 | C-F | CH3 | CH2 | 3-Cl | S | N | C | N | (U)-NHCONHCH2COOCH2CH3 |
A-025 | C-F | CH3 | CH2 | 3-Cl | S | N | C | N | (U)-NHCONHCH2CH2COOCH2CH3 |
A-026 | C-F | CH3 | CH2 | 3-Cl | S | N | C | N | (U)-NHCONHCH2COOH |
A-027 | C-F | CH3 | CH2 | 3-Cl | S | N | C | N | (U)-NHCONHCH2CH2COOH |
A-030 | C-F | CH3 | CH2 | 3-Cl | S | N | C | N | (U)-NHCONH(CH2)3COOCH2CH3 |
A-031 | C-F | CH3 | CH2 | 3-Cl | S | N | C | N | (U)-NHCONH(CH2)3COOH |
A-058 | C-F | CH3 | CH2 | 3-Cl | N | NH | N | N | - |
表4.
实施例序号 | X | M | Rb | N(Rc) |
A-002 | C-H | CH2 | 3-NO2 | N-糖精 |
A-003 | C-H | CH2 | 3-NO2 | 9N-2-氨基-6-氯嘌呤 |
A-004 | C-H | CH2 | 3-NO2 | 9N-鸟嘌呤 |
A-005 | C-H | CH2 | 3-NO2 | N-L-4-羟脯氨酸甲酯 |
A-007 | C-H | CH2 | 3-NO2 | 1N-吡啶-2-酮-4-羧酸 |
A-059 | C-F | CH2 | 3-Cl | 1N-咪唑-4-羧酸 |
A-060 | C-F | CH2 | 3-Cl | 1N-咪唑-5-羧酸 |
PDE4酶的体外测定。用实时酶偶联分光光度测定法测量PDE4酶的体外活性和本发明所述治疗剂的体外功效。通过使用三种不同的偶联酶,将PDE4反应产物偶联到还原形式β-烟酰胺腺嘌呤二核苷酸(NADH)的氧化上,可以在340nM经分光光度法监测其消失。
测定说明。准备含有50mM Tris(pH 8.0)、16mM MgCl2和80nM KCl的缓冲液A,并在室温下贮藏。准备含有50mM Tris(pH 8.0)的缓冲液B并在室温下贮藏。在缓冲液B中准备以下试剂的储备溶液并在-20℃贮藏:5’-三磷酸腺苷(ATP)、5’-环单磷酸腺苷(cAMP)、磷酸烯醇丙酮酸(PEP)和NADH。通过将缓冲液A、三氯乙基膦(trichloroethylphosphine,TCEP)、ATP、PEP、NADH、肌激酶(MK)、丙酮酸激酶(PK)、乳酸脱氢酶(LDH)和PDE4混合至最终体积为20mL(足以用于单个96-孔测定板)来准备测定混合物。将在1∶1DMSO/H2O混合物中的测定混合物(180μL)和检品(10μL)在室温下预孵育10min。通过加入cAMP(10μL)引发酶反应。在测定(200μL/孔)中所有组分的最终浓度如下:10mM MgCl2、50mM KCl、5mM TCEP、2.5%DMSO、0.4mM NADH、1mM PEP、0.04mM ATP、5单位MK、1单位PK、1单位LDH和适量的PDE4。在能够在340nM下测量吸光度的读板器中监测反应进程曲线。在340nm的吸光度降低是由于NADH的氧化。在每个测定板上包含不含检品的阳性对照和不含检品及cAMP的阴性对照。从该进程曲线的线性部分的斜率测定反应速率。将所有数据相对于对照进行百分比归一化,并以抑制百分比的形式表示。
以下在表A和表B中显示了代表性物质的测定结果。将活性规定为A=<5μM,B=5-20μM,C=20-40μM。
表A
化合物序号 | hPDE4D | 化合物序号 | hPDE4D | 化合物序号 | hPDE4D | ||
A-001 | A | A-026 | A | A-051 | A | ||
A-002 | B | A-027 | A | A-053 | A | ||
A-003 | A | A-028 | A | A-054 | A | ||
A-004 | B | A-029 | A | A-056 | A | ||
A-005 | C | A-030 | A | A-057 | A | ||
A-006 | A | A-031 | A | A-058 | B | ||
A-007 | B | A-032 | A | A-059 | A | ||
A-008 | A | A-033 | A | A-060 | A | ||
A-010 | A | A-034 | A | A-061 | A | ||
A-011 | A | A-035 | A | A-062 | A | ||
A-012 | A | A-036 | A | A-063 | A | ||
A-013 | A | A-037 | A | A-064 | B | ||
A-014 | A | A-038 | A | A-065 | A | ||
A-015 | A | A-039 | A | A-066 | A | ||
A-016 | A | A-040 | A | A-067 | A | ||
A-017 | A | A-041 | A | A-068 | A | ||
A-018 | A | A-042 | A | A-069 | A | ||
A-019 | A | A-043 | A | A-070 | A | ||
A-020 | A | A-044 | A | A-071 | A | ||
A-021 | B | A-045 | A | A-072 | A |
A-022 | A | A-047 | A | A-073 | A | ||
A-023 | A | A-048 | A | A-074 | A | ||
A-024 | A | A-049 | A | A-075 | A | ||
A-025 | A | A-050 | A | A-076 | A | ||
A-077 | A | A-078 | A | A-079 | A | ||
B-080 | A | B-081 | A | B-082 | A | ||
B-083 | A | B-084 | B |
表B
化合物序号 | hPDE4B | 化合物序号 | hPDE4B | 化合物序号 | hPDE4B | ||
A-001 | C | A-028 | A | A-052 | A | ||
A-003 | B | A-030 | B | A-053 | B | ||
A-004 | C | A-031 | B | A-054 | A | ||
A-006 | B | A-032 | B | A-055 | A | ||
A-007 | B | A-034 | C | A-057 | A | ||
A-008 | A | A-035 | A | A-058 | C | ||
A-010 | A | A-036 | A | A-059 | B | ||
A-011 | B | A-037 | A | A-060 | B | ||
A-012 | A | A-038 | A | A-061 | B | ||
A-013 | A | A-040 | A | A-063 | A | ||
A-014 | B | A-041 | B | A-064 | B | ||
A-015 | A | A-042 | A | A-065 | B | ||
A-016 | A | A-043 | B | A-066 | A | ||
A-017 | A | A-044 | C | A-067 | B | ||
A-018 | C | A-047 | A | A-068 | A | ||
A-019 | B | A-048 | A | A-070 | B | ||
A-020 | A | A-049 | A | A-073 | A | ||
A-021 | B | A-050 | A | A-074 | A | ||
A-027 | C | A-051 | A | A-075 | A | ||
A-076 | A | B-080 | A | B-081 | A | ||
B-082 | A | B-083 | A |
还利用离体测定来测量本发明所述的PDE4抑制剂的活性,所述离体测定测量在Sephadex刺激后人类全血中的白三烯E4(LTE4)。本发明的治疗剂的抗炎活性由如通过人类全血中受葡聚糖凝胶珠(sephadex beads)刺激的LTE4生成而测量的对嗜酸性粒细胞激活的抑制来表示。对于每个样品,将356μl的肝素化人类全血(Vacutainer真空采血管#6480)加入96孔板的孔中。然后,重复三次加入4μl的一系列化合物稀释液(在DMSO中),混合悬浮液,并在温和振摇下在37℃下孵育15min。其后,通过加入40μLSephadex G-15珠(Sigma-Aldrich,瑞典)来刺激血样。将所述珠预溶于PBS(0.16g/mL PBS)中。混合后,将悬浮液在37℃下孵育90min。然后,将8μL的15%EDTA/PBS加入各样品中,混合,并在21℃及115×g下板式离心5min,并取上清液。在各板中,使用含有DMSO而非化合物溶液的10个阳性对照和10个阴性对照。如在样品部分中所述,用Sephadex刺激阳性对照,而在阴性对照(未经刺激)中,则由PBS替代Sephadex溶液。根据制造商的说明书,用商品酶联免疫测定(Cayman Chemical Company,AnnArbor,MI)来测定所得血浆样品中的LTE4水平。在该离体测定中,实施例A-008、A-016、A-035、A-037、A-054、A-066和B-080显示出IC50<1μM,而A-028和A-055则给出IC50>1μM。本领域技术人员相信,在PDE4模型中的阳性结果预测了上述治疗效用。
以下显示了本发明的合成实施例:
2-甲氧基-5-甲基-3′-硝基-联苯(INT-1):
将2-甲氧基-5-甲基苯基硼酸(5g,30.3mmol)、3-硝基-碘苯(7.5g,30.3mmol)、K2CO3(8.36g,60.6mmol)、Pd(OAc)2(339mg,1.52mmol)在甲醇(150ml)和水(30ml)中的反应混合物在室温下搅拌20小时。将反应混合物用乙酸乙酯(600ml)稀释,用稀NaHSO3水溶液、水、盐水洗涤,并用Na2SO4干燥。除去溶剂后,得到6.7g INT-1粗产物。收率:91%。
5-溴甲基-2-甲氧基-3′-硝基-联苯(INT-2):
在室温下,向INT-1化合物(6.95g,28.5mmol)在四氯化碳(350ml)中的混合物中加入溴(1.54ml,29.9mmol)。在N2保护下,在日光灯下,在80℃下搅拌反应混合物。在除去溶剂后,将残余物用乙酸乙酯/己烷作为洗脱剂经150g硅胶柱色谱进行纯化,以得到5.6g产物INT-2。收率:61%。
A-003.合成6-氯-9-(6-甲氧基-3′-硝基-联苯-3-基甲基)-9H-嘌呤-2-基胺
将INT-2(322mg,1.00mmol)、2-氨基-6-氯嘌呤(169mg,1.00mmol)和固体碳酸钾(276mg,2.00mmol)在二甲基甲酰胺(10mL)中的悬浮液在室温下搅拌18h。将反应混合物倒入水(100mL)中,搅拌10min,并收集所得沉淀物。将粗品溶于乙酸乙酯(30mL)中,用硫酸钠干燥,过滤,真空除去溶剂。将粗品残余物通过在己烷/乙酸乙酯(100mL∶30mL)中研磨数次进行纯化,以得到作为黄色固体的A-003(58.5mg,收率14%)。
1H NMR(400MHz,DMSO-d6)δppm 3.78(s,3H)5.27(s,2H)6.93(s,2H)7.15(d,J=8.45Hz,1H)7.29-7.43(m,1H)7.47(d,J=2.15Hz,1H)7.62-7.83(m,1H)7.92(d,J=7.65Hz,1H)8.13-8.41(m,3H)。
A-004.合成2-氨基-9-(6-甲氧基-3′-硝基-联苯-3-基甲基)-1,9-二氢-嘌呤-6-酮
在室温下,将A-003(60mg,0.15mmol)和无水氢氧化钠(1.2g,30mmol)在水(6mL)和二甲基甲酰胺(6mL)中的溶液搅拌5min。通过加入水(50mL)使黄色溶液终止反应。通过过滤收集所得沉淀,将其溶于乙酸乙酯(10mL),用硫酸钠干燥,过滤,并真空除去溶剂,以得到作为黄色固体的A-004(29.9mg,收率51%)。
1H NMR(400MHz,DMSO-d6)δ3.77(s,3H)5.19(s,2H)5.82(s,2H)6.91(br.s.,1H)7.14(d,J=8.59Hz,1H)7.30(dd,J=8.45,2.01Hz,1H)7.42(d,J=2.01Hz,1H)7.71(t,J=7.98Hz,1H)7.83(s,1H)7.91(d,J=7.78Hz,1H)8.16-8.23(m,1H)8.27(d,J=1.61Hz,1H)。
A-005 MCLS1363-018-1
(2R,4S)-4-羟基-1-(6-甲氧基-3′-硝基-联苯-3-基甲基)-吡咯烷-2-羧酸甲酯
向配有搅拌棒的20ml小瓶中加入Int-2(0.30g,0.93mmol)、(2R,4S)-4-羟基-吡咯烷-2-羧酸甲酯盐酸盐(0.62mmol)、Cs2CO3(0.20g,0.62mmol)和DMF(2mL)。将反应在室温下搅拌4天,然后加入10ml水。用乙酸乙酯(3×10mL)萃取产物,并将有机相合并并浓缩。将残余物用0-5%甲醇/二氯甲烷经快速柱色谱纯化,以得到36mg(8%)A-005。1H NMR(400MHz,氯仿-d)ppm 2.03-2.15(m,1H)2.27(dt,J=13.8,7.1Hz,1H)2.51(dd,J=10.2,3.6Hz,1H)3.37(dd,J=10.1,5.6Hz,1H)3.57-3.73(m,5H)3.83(s,3H)3.90(d,J=12.9Hz,1H)4.48(br.s.,1H)6.96(d,J=8.3Hz,1H)7.29(d,J=2.0Hz,1H)7.33(dd,J=8.3,2.0Hz,1H)7.56(t,J=8.0Hz,1H)7.86(d,J=7.7Hz,1H)8.17(dd,J=8.2,1.3Hz,1H)8.37-8.44(m,1H)。LC/MS=93.7%,387.1,(APCI+)。
A-006A[MCLS1354-035-2]
Int-3 MCLS1354-034-2
合成3-(6-甲氧基-3′-硝基-联苯-3-基甲基)-戊烷-2,4-二酮
向2,4-戊二酮在二甲氧基乙烷(5mL)中的溶液中加入NaH(80mg,1.2mmol)。30分钟后,在室温下加入Int-2(322mg,1.0mmol),并将反应在室温下搅拌过夜。向反应中加入30mL水,并用2×30mL EtOAc萃取产物,用盐水洗涤,用Na2SO4干燥并浓缩。将残余物用2∶1己烷∶EtOAc洗脱,经快速柱色谱纯化,以得到标题化合物(106mg,31%)。
合成[4-(6-甲氧基-3′-硝基-联苯-3-基甲基)-3,5-二甲基-吡唑-1-基]-乙酸乙酯
向INT-3(102mg,0.300mmol)在1,2-二甲氧基乙烷(5mL)中的溶液中加入肼基乙酸乙酯盐酸盐(93mg,0.60mmol)和4埃分子筛(200mg),并将反应在回流下搅拌3h。将热悬浮液过滤,并真空除去溶剂。将残余物溶于二氯甲烷(10mL),并用水(30mL)洗涤。用二氯甲烷(2×30mL)萃取洗涤水液,并合并萃取物。将有机溶液用盐水洗涤,用硫酸钠干燥,过滤,并真空除去溶剂。将粗品经硅胶柱色谱(2∶1己烷∶乙酸乙酯)纯化以得到A-006A(97.1mg,收率76%)。
1H NMR(氯仿-d)d:8.38(t,J=1.9Hz,1H),8.15(dd,J=8.2,2.3Hz,1H),7.79-7.82(m,1H),7.53-7.56(m,1H),7.07-7.10(m,2H),6.90(d,J=9.1Hz,1H),4.79(s,2H),4.21(q,J=7.1Hz,2H),3.80(s,3H),3.74(s,2H),2.13(s,3H),2.13(s,3H),1.26(t,J=7.1Hz,3H)。LCMS:98.7%纯度。
A-006.
合成[4-(6-甲氧基-3′-硝基-联苯-3-基甲基)-3,5-二甲基-吡唑-1-基]-乙酸
向A-006A(105mg,0.25mmol)在乙醇(1mL)中的溶液中加入2M氢氧化钠水溶液(0.625mL,1.25mmol),并将反应在50℃下搅拌3h。用10%氯化氢水溶液将反应酸化至pH 6。用***(5mL)萃取悬浮液,用硫酸钠干燥,并真空浓缩。将粗品经硅胶柱色谱(10%甲醇/二氯甲烷)纯化以得到作为白色粉末的A-006(33.1mg,收率34%)。1H NMR(氯仿-d)d:8.32-8.39(m,1H),8.11-8.19(m,1H),7.80(d,J=7.7Hz,1H),7.49-7.58(m,1H),7.02-7.10(m,1H),6.90(d,J=9.1Hz,1H),4.77(s,2H),3.80(s,3H),3.73(s,2H),2.16(s,3H),2.15(s,3H)。LCMS=97.6%纯度。
Int-3 MCLS1363-200-1
1-(6-甲氧基-3′-硝基-联苯-3-基甲基)-2-氧代-1,2-二氢-吡啶-4-腈
向配有搅拌棒的100ml RBF中加入Int-2(2.76g,8.55mmol)、2-羟基-异烟腈(934mg,7.78mmol)、K2CO3(2.36g,17.11mmol)和DME(30mL)。将悬浮液在80℃下搅拌18小时,并随后在室温下搅拌2天。将反应过滤,将滤液浓缩,并用***研磨所得固体,以得到2.12g(75%)作为黄色固体的Int-3。1H NMR(400MHz,DMSO-d6)=8.29(s,1H),8.20(dd,J=1.3,8.3Hz,1H),8.12(d,J=7.1Hz,1H),7.93(d,J=7.8Hz,1H),7.73(t,J=8.0Hz,1H),7.49(d,J=2.0Hz,1H),7.43(dd,J=1.9,8.5Hz,1H),7.16(d,J=8.6Hz,1H),7.04(d,J=1.3Hz,1H),6.56(dd,J=1.7,7.0Hz,1H),5.12(s,2H),3.79(s,3H)。LC/MS=96.1%,361.0(APCI-)。
A-007 MCLS1404-010-1
1-(6-甲氧基-3′-硝基-联苯-3-基甲基)-2-氧代-1,2-二氢-吡啶-4-羧酸
向配有搅拌棒的20mL小瓶中加入Int-3(480mg,1.33mmol)、3mL乙醇和3mL 1N NaOH(aq)。在80℃下将溶液搅拌1小时,然后将其冷却至室温。蒸发约一半体积的溶剂,并将溶液用DCM洗涤两次。将剩余的水相部分加入6N HCl溶液中,并搅拌1小时,随后过滤出固体,并用水洗涤。将固体在真空干燥器中干燥3天,以得到366mg(72%)作为淡黄色固体的A-007。1H NMR(400MHz,DMSO-d6)=8.28(d,J=1.6Hz,1H),8.20(dd,J=1.5,8.1Hz,1H),7.99(d,J=7.0Hz,1H),7.93(d,J=7.8Hz,1H),7.72(t,J=7.9Hz,1H),7.48(d,J=2.0Hz,1H),7.42(dd,J=2.0,8.5Hz,1H),7.16(d,J=8.5Hz,1H),6.87(d,J=1.6Hz,1H),6.57(dd,J=1.7,7.0Hz,1H),5.13(s,2H),3.79(s,3H)。LC/MS=95.9%。
合成A-016
(Int-4)[MCLS1374-115-1]合成3-溴-2-氟-4-甲氧基-苯甲醛:
在配有氮气管路和搅拌棒的250mL三颈圆底烧瓶中加入2-溴-1-氟-3-甲氧基-苯(2.0g,9.75mmol)和二氯甲烷(48mL)。将溶液在冰水浴中冷却15分钟,然后加入四氯化钛(5.02mL,45.8mmol)和二氯甲基甲醚(1.32mL,14.6mmol),使反应混合物升温至室温,并反应2小时。将反应混合物缓慢加入冰水(250mL)中,并用二氯甲烷(2×100mL)萃取。将有机部分合并,用饱和碳酸氢钠溶液(75mL)、水(75mL)和盐水(75mL)洗涤,干燥(MgSO4)并浓缩。将粗品用己烷(15mL)研磨,以74%的收率得到1.67g作为灰白色固体的Int-4。
MS(ESI+):233.2(M+)。
(Int-5)[MCLS1374-119-1]合成(3-溴-2-氟-4-甲氧基-苯基)-甲醇:
在配有搅拌棒的100mL圆底烧瓶中加入Int-4(1.67g,7.17mmol)、甲烷(12mL)、二氯甲烷(12mL)和硼氢化钠。将反应混合物在室温下搅拌17小时,用水(10mL)和1M HCl(5mL)终止反应,并用二氯甲烷(2×30mL)萃取。将有机部分合并,用盐水(30mL)洗涤,干燥(MgSO4)并浓缩。将粗品用己烷(15mL)研磨,以57%的收率得到955mg作为白色固体的Int-5。
(Int-6)[MCLS1374-121-2]合成1-(2′-氟-3′-羟甲基-6′-甲氧基-联苯-3-基)-乙酮:
在配有搅拌棒的40mL小瓶中加入Int-5(950mg,4.04mmol)、3-乙酰基苯基硼酸(729mg,4.44mmol)、碳酸钾(1.68g,12.1mmol)、三苯基膦(318mg,1.21mmol)、1,4-二噁烷(8mL)、50%乙醇水溶液(8mL),随后加入乙酸钯(II)(90.7mg,0.404mmol)。将混合物在68℃下加热72小时,然后冷却至室温。通过硅藻土过滤除去钯催化剂。向滤液中加入1M HCl(30mL)和水(30mL)。用乙酸乙酯(2×30mL)萃取水相部分,合并有机部分,用盐水(30mL)洗涤,干燥(MgSO4)并浓缩。将粗品用50%EtOAc/己烷作为洗脱剂经柱色谱纯化,以55%的收率得到614mg作为灰白色固体的Int-6。
(Int-7)[MCLS1374-123-2]合成碳酸-3′-乙酰基-2-氟-6-甲氧基-联苯-3-基甲酯:
在配有搅拌棒的18mL小瓶中加入Int-6(400mg,1.46mmol)、无水四氢呋喃(4.9mL)和吡啶(154μL,1.90mmol)。将所得澄清溶液在冰水浴中冷却10分钟,随后加入氯甲酸甲酯(124μL,1.61mmol),将反应混合物缓慢升温至室温,并反应17小时。另外加入吡啶(154μL,1.90mmol)和氯甲酸甲酯(124μL,1.61mmol),并将反应混合物在室温下再搅拌17小时。用1M HCl将反应酸化至pH 1,加入水(30mL),随后用二氯甲烷(2×30mL)萃取。将有机部分合并,用盐水(30mL)洗涤,干燥(MgSO4)并浓缩。将粗品用40%EtOAc/己烷作为洗脱剂,经柱色谱纯化,以71%的收率得到346mg作为无色粘性油状物的Int-7。
(Int-8)[MCLS1374-131-1]合成[4-(3′-乙酰基-2-氟-6-甲氧基-联苯-3-基甲基)-苯基]-氨基甲酸叔丁酯:
在配有搅拌棒的18mL小瓶中加入Int-7(295mg,0.888mmol)、4-[(叔丁氧羰基)氨基]-苯基硼酸(232mg,0.977mmol)、碳酸钾(270mg,1.95mmol)、1,5-双(二苯基膦基)戊烷(39.1mg,0.0888mmol)、氯化烯丙基钯(II)二聚体(16.2mg,0.0444mmol)和二甲基甲酰胺(1.5mL)。将反应混合物在80℃下加热17小时。为了消耗残余的Int-7,另外加入氯化烯丙基钯(II)二聚体(32.5mg,0.0888mmol)和1,5-双(二苯基膦基)戊烷(78.2mg,0.178mmol),并使反应混合物在80℃下搅拌17小时。通过硅藻土过滤反应混合物,并向滤液中加入水(30mL)和饱和氯化铵溶液(40mL)。用乙酸乙酯(2×50mL)萃取,将有机部分合并,用盐水(50mL)洗涤、干燥(MgSO4)并浓缩。将粗品用30%EtOAc/己烷作为洗脱剂经柱色谱纯化,以91%的收率得到365mg作为淡黄色固体的Int-8。
(Int-9)[MCLS1374-135-1]合成1-[3′-(4-氨基-苄基)-2′-氟-6′-甲氧基-联苯-3-基]-乙酮盐酸盐:
在配有搅拌棒的8mL小瓶中加入Int-8(265mg,0.590mmol)、二氯甲烷(2.0ml)和三氟乙酸(438μL,5.90mmol)。将反应混合物在室温下搅拌4小时,然后用饱和碳酸氢钠溶液终止反应至pH 7。加入水(30mL),并用二氯甲烷(2×30mL)萃取,将有机部分合并,用盐水(30mL)洗涤,干燥(MgSO4)并浓缩。将粗品用***(3mL)和在***(1mL)中的2.0M HCl处理,并在室温下搅拌2小时。收集固体,并用***(3×2mL)洗涤,以61%的收率得到139mg作为浅橙色粉末的Int-9。
A-016[MCLS1374-173-2]
1-[3′-(4-氨基-苄基)-2′-氟-6′-甲氧基-联苯-3-基]-乙酮盐酸盐的氨磺酰化(Sulfamoylation):
在配有搅拌棒的8mL小瓶中加入二氯甲烷(400μL)和氯磺酰异氰酸酯(13.5μL,0.155mmol)。将溶液在冰水浴中冷却5分钟,然后加入叔丁醇(15.9μL,0.167mmol),并将反应混合物升温至室温25分钟。然后加入Int-9(46mg,0.119mmol)、吡啶(106μL,0.131mmol)和二氯甲烷(300μL)的溶液,并将反应混合物在室温下搅拌17小时。用水(30mL)终止反应,并用二氯甲烷(2×30mL)萃取。将有机部分合并,用1M HCl(30mL)和盐水(30mL)洗涤,干燥(MgSO4)并浓缩。向该Boc保护的中间体中加入1,4-二噁烷(600μL)和在1,4-二噁烷(400μL)中的4.0M HCl。将混合物在室温下搅拌17小时,然后用水(30mL)终止反应,并用二氯甲烷(2×30mL)萃取。将有机部分合并,用饱和碳酸氢钠溶液(30mL)和盐水(30mL)洗涤,干燥(MgSO4)并浓缩,以24%的收率得到12mg作为橙色粘性油状物的A-016。
1H NMR(400MHz,CDCl3)δ2.62(s,3H),3.76(s,3H),3.95(s,2H),4.63(bs,2H),6.34(bs,1H),6.73(d,J=8Hz,1H),7.10-7.24(m,5H),7.52(t,J=8Hz,1H),7.60(d,J=6Hz,1H),7.94(d,J=8Hz,1H),7.99(bs,1H)。
合成A-017
(Int-10)[MCLS1374-155-1]合成1-[3′-(2-氨基-嘧啶-5-基甲基)-2′-氟-6′-甲氧基-联苯-3-基]-乙酮盐酸盐:
在配有搅拌棒的18mL小瓶中加入Int-7(704mg,2.12mmol)、5-(4,4,5,5-四甲基-[1,3,2]二氧杂环戊硼烷-2-基)-嘧啶-2-基胺(515mg,2.33mmol)、碳酸钾(879mg,6.36mmol)、1,5-双(二苯基膦基)戊烷(280mg,0.636mmol)、氯化烯丙基钯(II)二聚体(116mg,0.318mmol)和二甲基甲酰胺(4.2mL)。将反应混合物在70℃下加热65小时。通过硅藻土过滤反应混合物,并向滤液中加入水(30mL)和饱和氯化铵溶液(40mL)。用乙酸乙酯(2×50mL)萃取,将有机部分合并,用盐水(50mL)洗涤,干燥(MgSO4)并浓缩。将粗品用20%丙酮/DCM(增至30%,然后40%丙酮/DCM的梯度洗脱)作为洗脱剂经柱色谱纯化,以46%的收率得到341mg作为灰白色固体的Int-10(游离碱)。然后用1,4-二噁烷(1mL)处理Int-10(游离碱)(20mg,0.0569mmol),并将混合物加热以形成溶液。向该溶液中加入在1,4-二噁烷(1mL)中的4.0M HCl,并将混合物在室温下搅拌3小时。通过氮气流除去溶剂,并将所得固体用***(1mL)研磨,通过抽滤收集,并用***(3×1mL)洗涤,以55%的收率得到12mg作为浅黄色固体的Int-10。
A-017.[MCLS1374-175-3]1-[3′-(2-氨基-嘧啶-5-基甲基)-2′-氟-6′-甲氧基-联苯-3-基]-乙酮的氨磺酰化:
在配有搅拌棒的8mL小瓶中加入二氯甲烷(500μL)和氯磺酰异氰酸酯(32.2μL,0.371mmol)。将溶液在冰水浴中冷却5分钟,然后加入叔丁醇(38.2μL,0.399mmol),并将反应混合物升温至室温25分钟。然后加入Int-10(游离碱)(100mg,0.285mmol)、吡啶(254μL,3.14mmol)和二氯甲烷(500μL)的溶液,并将反应混合物在室温下搅拌3小时。用水(30mL)终止反应,并用二氯甲烷(2×30mL)萃取。将有机部分合并,用1M HCl(30mL)和盐水(30mL)洗涤,干燥(MgSO4)并浓缩。向该Boc保护的中间体中加入1,4-二噁烷(1.5mL)和在1,4-二噁烷(1.0mL)中的4.0M HCl。将混合物在50℃下搅拌2小时,然后用水(30mL)终止反应,并用二氯甲烷(2×30mL)萃取。将有机部分合并,用饱和碳酸氢钠溶液(30mL)和盐水(30mL)洗涤,干燥(MgSO4)并浓缩。将粗品用20%丙酮/DCM研磨,以8%的收率得到9.5mg作为白色固体的A-017。
1H NMR(400MHz,DMSO-d6)δ2.59(s,3H),3.73(s,3H),3.91(bs,2H),6.97(d,J=8Hz,1H),7.08(bs,2H),7.36(t,J=9Hz,1H),7.57-7.58(m,2H),7.87(s,1H),7.94-7.96(m,1H),8.46(s,2H),10.96(bs,1H).MS(APCI+):431.1(M+1),LC-MS:97%。
A-018.合成4-(3′-乙酰基-2-氟-6-甲氧基-联苯-3-基甲基)-苯甲酸甲酯
A-018
将Int-7(300mg,0.928mmol)、4-甲氧羰基苄基硼酸(184mg,1.02mmol)和碳酸钾(385mg,2.78mmol)在二甲基甲酰胺(2mL)中的悬浮液用氮气吹扫,并加入氯化烯丙基钯二聚体(50.9mg,0.139mmol)和双(二苯基膦基)戊烷(123mg,0.278mmol)。将反应加热至65℃过夜。在该反应中加入乙酸乙酯(5mL)和水(5mL),将所得层通过硅藻土过滤,用乙酸乙酯(15mL)和水(15mL)洗涤硅藻土,并分离各层。将水层用乙酸乙酯(2×50mL)萃取,合并有机萃取物,并用盐水(100mL)洗涤。用硫酸镁干燥有机溶液,过滤,并真空除去溶剂以得到粗产物。将产物先后经快速硅胶柱色谱(25%乙酸乙酯/己烷)和制备硅胶TLC板(用25%乙酸乙酯/己烷洗脱)纯化,并在***(5mL)中研磨,以得到作为白色粉末的A-018(72.4mg,收率20%)。
1H NMR(400MHz CDCl3)d:7.991-7.939(m,4H),7.586-7.583(m,1H),7.517(t,J=7.80Hz,1H),7.299(d,J=8.80Hz,2H),7.107(t,J=8.60Hz,1H),6.742-6.720(m,1H),4.027(s,2H),3.899(s,3H),3.758(s,3H),2.619(s,3H).
LCMS=96.6%纯度。MS(APCI+)=394.1(M+2)。
A-020.(PR162)[MCLS1376-184-4]合成5-(3′-乙酰基-2-氟-6-甲氧基-联苯-3-基甲基)-吡啶-2-羧酸甲酯
在氮气流下将Int-7(500mg,1.50mmol)、2-甲基羧基吡啶-5-硼酸频哪醇酯(435mg,1.65mmol)和碳酸钾(624mg,4.51mmol)在二甲基甲酰胺(3.5mL)中的悬浮液脱气15min。向该溶液中加入双(二甲基膦基)戊烷(199mg,0.451mmol)和氯化烯丙基钯二聚体(82.7mg,0.226mmol)。将反应在65℃下加热50h。用乙酸乙酯(50mL)稀释反应,并通过硅藻土过滤。向滤液中加入水(50mL),并分离各层。用乙酸乙酯(2×50mL)萃取水洗液,将所有三种有机萃取物合并,并用盐水(100mL)洗涤。用硫酸镁干燥有机溶液,过滤,并真空除去溶剂。将残余物经快速硅胶柱色谱(5%丙酮/二氯甲烷)纯化,并在***(15mL)中研磨,过滤,并用***(5mL)洗涤,以得到作为白色粉末的A-020(190.6mg,收率32%)。1H NMR(400MHz CDCl3)d:8.656(d,J=2.00Hz,1H),8.062(d,J=8.00Hz,1H),7.973-7.940(m,2H),7.665(dd,J=8.20Hz,2.20Hz,1H),7.574(dd,J=7.60Hz,1.60Hz,H),7.518(t,J=7.60Hz,1H),7.125(t,J=8.60Hz,1H),6.747(d,J=8.80Hz,1H),4.053(s,2H),3.996(s,3H),3.765(s,3H),2.618(s,3H)。LCMS=100.0%纯度。MS(APCI+)=394.1(M+1)。
合成A-019和A-021
A-018X=C A-019X=C
A-020X=N A-021X=N
A-019(PR164)[MCLS1376-188-1]合成4-(3′-乙酰基-2-氟-6-甲氧基-联苯-3-基甲基)-苯甲酸
将A-018(65.0mg,0.166mmol)在甲醇(750μL)、水(750μL)和1N氢氧化钠水溶液(231μL,0.231mmol)中的溶液在室温下搅拌过夜。将所得白色悬浮液用四氢呋喃(1mL)溶解,并在室温下搅拌2h。通过硅胶TLC(在50%乙酸乙酯/己烷中的Rf=0.07)显示反应完成。真空除去四氢呋喃和甲醇,并加入1N盐酸水溶液(2mL)。用乙酸乙酯(2×25mL)萃取水性悬浮液,合并有机萃取物,并用已用1N盐酸水溶液(3mL)酸化的盐水(10mL)洗涤,用硫酸钠干燥,过滤并真空除去溶剂,以得到作为白色粉末的A-019(42.6mg,收率68%)。
1HNMR(400MHz d6-DMSO)d:12.81(s,1H),7.962-7.935(m,1H),7.880-7.860(m,3H),7.577(d,J=5.20Hz,2H),7.366-7.322(m,3H),6.965(d,J=8.80Hz,1H),4.030(s,2H),3.729(s,3H),2.600(s,3H)。LCMS=100.0%纯度。MS(APCI-)=377.0(M-1)。
A-021.(PR165)[MCLS1376-192-2]合成5-(3′-乙酰基-2-氟-6-甲氧基-联苯-3-基甲基)-吡啶-2-羧酸
将A-020(150mg,0.381mmol)在四氢呋喃(1mL)、甲醇(1mL)、水(1mL)和1N氢氧化钠水溶液(0.763mL)中的溶液在室温下搅拌18h。真空除去大约一半的溶剂。通过加入冰醋酸将剩余的溶液调节至pH 3。用二氯甲烷(10mL)萃取悬浮液,将水(5mL)加入洗涤液,并另外用二氯甲烷(2×10mL)萃取水洗涤液。将所有三种有机萃取物合并,用硫酸镁干燥,过滤,并真空除去溶剂,并将残余物在高真空下干燥24h。所得的浅褐色糖浆由于具有乙酸乙酯和乙酸而不纯,所以将残余物在***(5mL)中结晶,搅拌30min,过滤,并用己烷(2×2mL)洗涤,以得到作为白色粉末的A-021(90.6mg,收率63%)。
1H NMR(400MHz d6-DMSO)d:8.622(d,J=2.00Hz,1H),7.989-7.936(m,2H),7.869(s,1H),7.779(dd,J=7.80Hz,2.20Hz,1H),7.576(d,J=5.20Hz,2H),7.387(t,J=8.80Hz,1H),6.982(d,J=8.40Hz,1H),4.081(s,2H),3.732(s,3H),2.588(s,3H)。
LCMS=100.0%纯度(APCI+)。MS(APCI+)=380.0(M+1)。
合成A-022
(Int-11)[MCLS1277-195-01]合成3′-溴-6-氟-2-甲氧基-联苯
向2-氟-5-甲氧基苯基硼酸(1g,5.9mmol,1eq.)、Pd(PPh3)4(340mg,0.3mmol,0.05eq.)的混合物中加入甲苯(48ml)和EtOH(12ml),然后加入1-溴-3-碘苯(2g,7.1mmol,1.2eq.)和2N Na2CO3水溶液(6ml,2eq.)。将混合物在90℃下搅拌3小时。冷却至室温,分离水层,并将有机层用MgSO4干燥。减压除去溶剂得到残余物,将其先后用己烷和己烷/EtOAc(20∶1)作为洗脱剂,经硅胶色谱纯化,以83%的收率得到1.37g作为无色油状物的期望产物Int-11。
(Int-12)[MCLS1277-197-01]合成N-[4-(3′-溴-2-氟-6-甲氧基-联苯-3-羰基)-苯基]-乙酰胺
在室温下向AlCl3(400mg,3.3mmol,3eq.)中加入硝基苯(2ml)。将混合物在室温下搅拌1小时。然后一次性加入4-乙酰氨基-苯甲酰氯(200mg,1mmol,1eq.),随后加入Int-11在DCM(2ml)中的溶液。在室温下搅拌所得混合物,直至酸氯化物在3小时内耗尽。将混合物加入水中,并随后用乙酸乙酯萃取。分离有机层,并干燥。将溶剂蒸发得到残余物,将其用EtOAc/己烷(1∶1其后2∶1)作为洗脱剂经硅胶色谱纯化,以50%的收率得到221mg期望产物Int-12。
(Int-13)[MCLS1277-200-01]合成N-[4-(3′-溴-2-氟-6-甲氧基-联苯-3-基甲基)-苯基]-乙酰胺
向Int-12(170mg,0.38mmol,1eq.)在三氟乙酸(1ml)中的溶液中加入三乙基硅烷(0.5ml)。将混合物在室温下搅拌4小时。然后减压除去挥发性物质以得到残余物,将其用DCM/己烷(1∶2)研磨。将固体过滤并用己烷洗涤。干燥后,以定量收率得到190mg Int-13。
(Int-14)[MCLS1277-201-01]合成4-(3′-溴-2-氟-6-甲氧基-联苯-3-基甲基)-苯基胺
在40ml的小瓶中加入Int-13(230mg,0.54mmol,1eq.)、浓HCl(8ml)和EtOH(8ml)。将混合物在85℃下搅拌5小时。冷却至室温后,加入水,随后加入NaHCO3水溶液。用EtOAc萃取混合物。将有机层分离并干燥。除去溶剂,在未进行进一步的纯化的情况下得到176mg期望产物Int-14(收率85%)。
(Int-15)[MCLS1435-055-1]合成{3-[4-(3′-溴-2-氟-6-甲氧基-联苯-3-基甲基)-苯基]-脲基}-乙酸乙酯
向含有Int-14(108mg,0.280mmol)的8mL小瓶中加入磁搅拌棒和吡啶(0.5mL)。在15s内向该处于搅拌中的溶液中滴加异氰酰乙酸乙酯(62μL,72mg,0.56mmol)。将溶液在室温下搅拌过夜。用水(5mL)稀释反应混合物,并在室温下快速搅拌2h。将所得固体过滤,用水(2×3mL)洗涤,并干燥以得到120mg(83%)固体Int-15。1H NMR(400MHz,DMSO-d6)1.19(t,J=7.2Hz,3H),3.71(s,3H),3.84(m,4H),4.10(q,J=7.2Hz,2H),6.38(t,J=5.6Hz,1H),6.91(d,J=8.0Hz,1H)7.08(m,2H),7.26,t,J=8.8Hz,1H),7.30(m,3H),7.38(dd,明显的三重峰,J=8.0,7.6Hz,1H),7.49(s,1H),7.55(m,1H)。
A-022[MCLS1435-059-1]合成{3-[4-(3′-溴-2-氟-6-甲氧基-联苯-3-基甲基)-苯基]-脲基}-乙酸
向含有Int-15(70mg,0.136mmol)和磁搅拌棒的8mL小瓶中先后加入无水四氢呋喃(2mL)和1M无水氢氧化锂(408μL,0.408mmol)。在1h后,在氮气流下将反应混合物浓缩至最终体积为约0.4mL,然后用水稀释至总体积为3mL。在搅拌下,在约1min内滴加2N HCl水溶液(250μL,0.5mmol),得到成块固体。将混合物在室温下搅拌30min,得到自由流动的固体,将其过滤并干燥,以得到50mg(76%)A-022。
1H NMR(400MHz,DMSO-d6)3.71(s,3H),3.77(d,J=5.6Hz,2H),3.84(s,2H)6.30(t,H=5.6Hz,1H),6.91(d,J=8.4Hz,1H),7.25(dd,明显的三重峰,J=9.2,8.4Hz,1H),7.30(m,3H),7.38(dd,明显的三重峰,J=8.0,7.6Hz,1H),7.49(m,1H),7.55(m,1H),8.68(s,1H),12.53(br s,1H).MS(APCI+):487.0(M+),489(M++2);LC-MS:98.0%。
A-023[MCLS1435-063-1]合成3-{3-[4-(3′-溴-2-氟-6-甲氧基-联苯-3-基甲基)-苯基]-脲基}-丙酸
[MCLS1435-056-1]合成3-{3-[4-(3′-溴-2-氟-6-甲氧基-联苯-3-基甲基)-苯基]-脲基}-丙酸乙酯
以与化合物Int-15的合成所述方式类似的方式,使用Int-14(101mg,0.26mmol)和异氰酰丙酸乙酯(替代异氰酰乙酸乙酯)合成化合物Int-16,以得到117mg(85%)作为灰白色固体的Int-16。
1H NMR(400MHz,DMSO-d6)1.19(t,J=7.6Hz,3H),2.47(t,J=6.4Hz,2H),3.29(dd,J=6.4,5.6Hz,2H),3.72(s,3H),3.84(s,2H),4.07(q,J=7.6Hz,2H),6.17(t,H=5.6Hz,1H),6.91(d,J=8.8Hz,1H),7.06(m,2H),7.25(dd,明显的三重峰,J=8.4Hz,1H),7.30(m,3H),7.38(dd,明显的三重峰,J=8.0,7.6Hz,1H),7.49(m,1H),7.55(m,1H)。
以与化合物A-022的合成所述方式类似的方式,使用化合物Int-16(73mg,0.26mmol)合成化合物A-023,以得到46mg(67%)固体A-023。
1H NMR(400MHz,DMSO-d6)δ2.40(t,J=6.4Hz,2H),3.26(dd,J=6.4,5.6Hz,2H),3.71(s,3H),3.83(s,2H),6.16(t,H=5.6Hz,1H),6.91(d,J=8.4Hz,1H),7.06(m,2H),7.27(m,3H),7.32(m,1H),7.38(dd,明显的三重峰,J=8.0,7.6Hz,1H),7.49(m,1H),7.55(m,1H),8.47(s,1H),12.25(br s,1H)。MS(APCI+):501.0(M+),503(M++2);LC-MS:97.8%。
合成A-024、A-025、A-026、A-027:
(Int-17)[MCLS1379-166-1]使用氯化钛(IV)合成3-溴-2-氟-4-甲氧基-苯甲醛。
将2-溴-3-氟苯甲醚(5.00g,24.3mmol)在二氯甲烷(120mL)中的溶液在盐冰浴中冷却至0℃,并用氮气吹扫。在氮气中将反应搅拌15min。向反应中加入氯化钛(IV)(23.1g,122mmol),随后在0℃下,在氮气中加入a,a-二氯甲基-甲醚(4.21g,36.6mmol)。将反应升温至室温,并搅拌22h。将红色溶液倒入冰水(600mL)中,并萃取到二氯甲烷(3×200mL)中。合并有机萃取物,用饱和碳酸氢钠水溶液(2×400mL)、水(2×400mL)和盐水(400mL)洗涤,用硫酸钠干燥,过滤,并真空除去溶剂以得到湿产物。在80℃下,将产物在真空箱中干燥过夜以得到Int-17(5.75g,定量收率)。
1H NMR(400MHz CDCl3)δ10.22(s,1H),7.86(dd,J=8.8Hz,7.6Hz,1H),6.82(d,J=8.4Hz,1H),4.01(s,3H)。
(Int-18)[MCLS1489-130-1]合成3′-氯-2-氟-6-甲氧基-联苯-3-醛
将Int-17(2.0g,7.98mmol)、3-氯苯基硼酸(1.4g,8.76mmol)和碳酸铯(5.2g,15.9mmol)在二甲基甲酰胺(20mL)中的混合物用氮气流脱气4min。向反应中加入乙酸钯(II)(89mg,0.398mmol),并将反应在50℃下搅拌2h,并在室温下搅拌16h。另外加入乙酸钯(II)(89mg,0.398mmol),并将反应在50℃下搅拌2h。将反应冷却,通过硅藻土过滤,并用乙酸乙酯洗涤。将反应用乙酸乙酯(100mL)和水(100mL)进行分配,并加入盐水(20mL)。将水层用乙酸乙酯(2×75mL)萃取,并用5%氯化锂水溶液(50mL)、0.5N盐酸水溶液(50mL)、水(2×50mL)和盐水(50mL)洗涤合并的萃取物。用硫酸镁干燥溶液,过滤,并真空除去溶剂,以得到粗品Int-18(2.2g,收率98%),将其在未进一步的纯化的情况下用于下一步骤。
(Int-19)[MCLS1489-132]合成(3′-氯-2-氟-6-甲氧基-联苯-3-基)-甲醇
将Int-18(2.00g,6.8mmol)在四氢呋喃(18mL)和水(6mL)中的溶液在冰水浴中冷却至0℃。向溶液中加入硼氢化钠(388mg,10mmol)。将反应搅拌10分钟,并在反应完成时用水(10mL)和饱和氯化铵水溶液(40mL)稀释。用乙酸乙酯(50mL,100mL)萃取反应,并用水(2×50mL)和盐水(50mL)洗涤合并的萃取物。用硫酸镁干燥溶液,过滤,并真空除去溶剂以得到Int-19(2.1g),将其在未进一步的纯化的情况下用于下一步骤。
(Int-20)[MCLS1426-103-1]合成3-溴甲基-3′-氯-2-氟-6-甲氧基-联苯:
将Int-19(5.44mmol;1.0eq.)和三苯基膦(5.98mmol;1.1eq.)的溶液冷却至0-5℃,并加入N-溴代琥珀酰亚胺(5.98mmol;1.1eq.)。将混合物搅拌,并升温至室温h小时。另外加入N-溴代琥珀酰亚胺(0.54mmol;0.1eq.)和三苯基膦(0.54mmol;0.1eq.),并将反应再搅拌1小时。然后用水稀释反应,并分离各层。依次用水和盐水洗涤有机部分,用硫酸钠干燥,并通过一层硅胶而过滤。将滤液浓缩,并将残余物用1%丙酮/己烷作为洗脱剂,经硅胶短柱过滤(silica gel plug filtration)进行纯化,以78%的收率得到作为白色针状物的标题化合物。1HNMR,CDCl3;400MHz):δ3.79(s,3H),4.55(s,2H),6.76(dd,J=8.8,1.2Hz,1H),7.28(m,1H),7.34-7.38(M,3H),7.39(m,1H)。
(Int-21)合成碳酸-3′-氯-2-氟-6-甲氧基-联苯-3-基甲酯
将(3′-氯-2-氟-6-甲氧基-联苯-3-基)-甲醇(Int-19)(3.00g,11.3mmol)在吡啶(2.31g,29.3mmol)和四氢呋喃(40mL)中的溶液在冰水浴中冷却至0℃。用氮气吹扫反应容器,并加入氯甲酸甲酯(2.34g,24.8mmol)。移除冰水浴,并将反应在室温下搅拌过夜。通过加入1N盐酸水溶液(约25mL)将白色悬浮液调节至pH 2,并用二氯甲烷(200mL)和水(150mL)稀释黄色两相溶液。分离各层,并用二氯甲烷(2×100mL)萃取水层。将二氯甲烷萃取物合并,用水(2×200mL)和盐水(200mL)洗涤,用硫酸钠干燥,过滤,并真空除去溶剂以得到Int-21(3.84g,定量收率)。1H NMR(400MHz CDCl3)d:7.41-7.32(m,4H),7.29-7.27(m,1H),6.77(dd,J=8.4Hz,0.8Hz,1H),5.20(s,2H),3.80(s,3H),3.80(s,3H)。LCMS=98.2%纯度。MS(APCI+)=249.0(M-78),MS(APCI-)=249.0(M-78)。
(Int-22)[MCLS1426-077-1]合成(3′-氯-2-氟-6-甲氧基-联苯-3-基)-乙腈
将Int-20(15.2mmol;1.0eq.)和***(22.8mmol;1.5eq.)在含水异丙醇中的悬浮液回流1小时。将反应冷却至室温,并浓缩以除去异丙醇。用2份乙酸乙酯萃取所得水层,并依次用水和盐水洗涤有机层,并用硫酸镁干燥。将残余物用10%丙酮/己烷作为洗脱剂,经硅胶快速色谱纯化,以57%的收率得到作为白色固体的标题化合物(Int-22)。(1HNMR,CDCl3;400MHz):δ3.80(s,3H),3.93(s,2H),6.80(dd,J=8.8,1.6Hz,1H),7.26(m,1H),7.35-7.41(M,4H)。
合成Int-23:
Int-23[MCLS1426-108-1]合成5-(3′-氯-2-氟-6-甲氧基-联苯-3-基甲基)-[1,3,4]噻二唑-2-基胺:
将Int-22(0.91mmol;1.0eq.)和氨基硫脲(1.03mmol;1.1eq.)在三氟乙酸中的混合物在60℃下加热6小时,并将其冷却至室温。将混合物加入冰水中,搅拌1小时并过滤。将滤饼用水洗涤,然后在45-50℃下真空干燥5小时,以99%的收率得到标题化合物。
A-024[MCLS1426-127-1]合成{3-[5-(3′-氯-2-氟-6-甲氧基-联苯-3-基甲基)-[1,3,4]噻二唑-2-基]-脲基}-乙酸乙酯:
在室温下向Int-23在吡啶中的溶液中加入异氰酸酯。在室温下将所得混合物搅拌3天,并将其加入水中。将所得悬浮液搅拌1小时,过滤,并用水洗涤。将固体在乙酸乙酯蒸气中真空干燥,以67%的收率得到作为白色固体的期望产物。
(1HNMR,DMSO-d6;400MHz):δ1.17(t,J=7.2Hz,3H),3.34(d,J=6.4Hz,2H),3,75(s,3H),4.06(q,J=7.2Hz,2H),4.27(s,2H),6.69(bs 1H),6.99(d,J=8.8Hz,1H),7.29(d,J=6.8Hz,1H),7.37(s,1H),7.40-7.48(M,4H),10.79(s,1H)。
LC/MS(90.7%)APCI+实测值:479.0;计算值:478.9m/z。
A-025.[MCLS1426-128-1]合成3-{3-[5-(3′-氯-2-氟-6-甲氧基-联苯-3-基甲基)-[1,3,4]噻二唑-2-基]-脲基}-丙酸乙酯:
以与A-024类似的制备方式制备该化合物,收率51%。
(1HNMR,DMSO-d6;400MHz):1.19(t,J=7.2Hz,3H),3.75(s,3H),3.90(d,J=6.0Hz,2H),4.05-4.13(M,2H),4.27(s,2H),6.51(dd,J=6.0Hz,1H),6.99(d,J=8.4Hz,1H),7.29(d,J=6.8Hz,1H),7.37(s,1H),7.40-7.48(M,4H),11.11(s,1H)。
A-026.[MCLS1426-130-1]合成{3-[5-(3′-氯-2-氟-6-甲氧基-联苯-3-基甲基)-[1,3,4]噻二唑-2-基]-脲基}-乙酸:
向原料酯在THF中的溶液中加入过量的1M氢氧化锂水溶液。在室温下搅拌两相混合物,直至TLC显示原料完全耗尽。用氮气流除去THF,并将所得水溶液用3N盐酸酸化至pH 1-2。将所得固体过滤,用水洗涤,并在乙酸乙酯蒸气中真空干燥,以70%的收率得到作为白色固体的期望产物。
(1HNMR,DMSO-d6;400MHz):δ3.75(s,3H),3.83(d,J=5.6Hz,2H),4.27(s,2H),6.83(m,1H),6.99(d,J=8.4Hz,1H),7.29(d,J=7.2Hz,1H),7.38(s,1H),7.40-7.48(M,4H),11.06s,1H),12.70(s,1H)。LC/MS(91.7%)APCI-实测值:449.0(M-1);计算值:450.9m/z。
A-027.[MCLS1426-131-1]合成3-{3-[5-(3′-氯-2-氟-6-甲氧基-联苯-3-基甲基)-[1,3,4]噻二唑-2-基]-脲基}-丙酸:
以与A-026类似的制备方式制备该化合物,收率68%。
(1HNMR,DMSO-d6;400MHz):δ2.42(t,J=6.4Hz,2H),3.32(t,J=6.4Hz,2H),3.75(s,3H),4.26(s,2H),6.71(m,1H),6.99(d,J=8.4Hz,1H),7.29(d,J=6.8Hz,1H),7.38(s,1H),7.40-7.46(M,4H),10.80(s,1H),12.32(s,1H)。
LC/MS(91.7%)APCI-实测值:463.0(M-1);计算值:464.9m/z。
合成A-033和A-034
(Int-22)[MCLS1458-041-3]合成5-(3′-氯-2-氟-6-甲氧基-联苯-3-基甲基)-吡啶-2-羧酸甲酯
使用与A-020相同的步骤,从Int-21(516mg,1.59mmol)和2-甲基羧基吡啶-5-硼酸频哪醇酯(460mg,1.75mmol)合成Int-22。将粗品经快速硅胶柱色谱(0-5%丙酮/二氯甲烷)纯化,以得到作为橙色糖浆状物的Int-22(381.4mg,收率62%)。
1H NMR(400MHz CDCl3)δ8.65(d,J=2.4Hz,1H),8.06(d,J=8.0Hz,1H),7.66(dd,J=8.0Hz,2.0Hz,1H),7.37-7.39(m,3H),7.26-7.24(m,1H),7.11(t,J=8.6Hz,1H),6.78(dd,J=8.6Hz,1.0Hz,1H),4.04(s,2H),4.00(s,3H),3.77(s,3H)。LCMS=96.8%纯度。MS(APCI+)=386.0(M+1)。
(Int-23)[MCLS1458-043-2]合成5-(3′-氯-2-氟-6-甲氧基-联苯-3-基甲基)-吡啶-2-羧酸
向Int-22(317mg,0.822mmol)在四氢呋喃(2.2mL)、甲醇(2.2mL)和水(2.2mL)中的溶液中加入1N氢氧化钠水溶液(1.64mL,1.64mmol)。将所得溶液在室温下搅拌23h。用冰醋酸将pH调节至4。真空除去约3/4的溶剂,并用水(10mL)稀释剩余的悬浮液。用二氯甲烷(3×10mL)萃取悬浮液,并用硫酸镁干燥合并的萃取物,过滤,并真空除去溶液,以得到作为浅褐色固体的粗品Int-23(250.8mg,收率82%)。
1H NMR(400MHz CDCl3)δ8.50(m,1H),8.13(d,J=7.6Hz,1H),7.76-7.71(m,1H),7.37-7.32(m,3H),7.26-7.24(m,1H),7.13(t,J=8.6Hz,1H),6.74(d,J=8.8Hz,1H),4.05(s,2H),3.77(s,3H)。
A-033[MCLS1458-057-2]合成1-[5-(3′-氯-2-氟-6-甲氧基-联苯-3-基甲基)-吡啶-2-羰基]-哌啶-4-羧酸乙酯
将Int-23(75.0mg,0.202mmol)、哌啶-4-羧酸乙酯(34.9mg,0.222mmol)、EDCI(42.6mg,0.222mol)和HOBt(30.0mg,0.222mmol)在四氢呋喃(2mL)中的溶液在室温下搅拌16h。真空除去溶剂,并将残余物悬浮在乙酸乙酯(20mL)中。用1∶1饱和碳酸氢钠水溶液和水(20mL)洗涤有机悬浮液,并用乙酸乙酯(20mL)萃取洗涤液。合并有机萃取物,并用水(20mL)、盐水(20mL)洗涤,用硫酸钠干燥,过滤并真空除去溶剂,以得到作为黄色油脂的粗产物。将产物经硅胶制备薄层色谱(10%甲醇/二氯甲烷)纯化以得到A-033(88.3mg,收率86%)。
1H NMR(400mHz CDCl3)δ:8.47(s,1H),7.63-7.54(m,3H),7.39-7.28(m,3H),7.12(t,J=8.6Hz,1H),6.73(d,J=8.4Hz,1H),4.55-4.52(m,1H),4.15(q,J=14.0Hz,2H),3.95(m,1H),3.77(s,3H),3.21-3.01(m,2H),2.61-2.55(m,1H),2.51-2.02(m,1H),1.86-1.80(m,3H),1.26(t,J=7.0Hz,3H)。LCMS=97.4%。MS(APCI+)=511.0(M+1)。
A-034.[MCLS1458-073-1]合成1-[5-(3′-氯-2-氟-6-甲氧基-联苯-3-基甲基)-吡啶-2-羰基]-哌啶-4-羧酸。
将A-033(60.0mg,0.117mmol)在四氢呋喃(2mL)、水(2mL)和1N氢氧化钠水溶液(0.176mL,0.176mmol)中的溶液在室温下搅拌3h。真空除去四氢呋喃,并加入冰醋酸(0.5mL)。用二氯甲烷(5mL)萃取水混悬液,然后用水(10mL)稀释,并用二氯甲烷(10mL)萃取。合并有机萃取物,用盐水(15mL)洗涤,用硫酸镁干燥,过滤,并真空除去溶剂,以得到作为树胶状物质的产物。在室温下,将树胶状固体在高真空下干燥1h以得到A-034(43.7mg,收率77%)。
1H NMR(400MHz CDCl3)δ:8.55(d,J=2.0Hz,1H),7.65(dd,J=8.0Hz,2.0Hz,1H),7.56-7.46(m,2H),7.39-7.27(m,3H),7.13(t,J=8.6Hz,1H),6.73(d,J=7.6Hz,1H),4.56-4.53(m,1H),4.01(s,1H),3.88-3.85(m,1H),3.77(s,3H),3.16-3.02(m,2H),2.65-2.60(m,1H),2.06(brs 1H),1.89(brs,3H)。LCMS=98.1%纯度。MS(APCI-)=481.1(M-1)。
合成A-038
(Int-24)[MCLS 1458-081-2]合成1-[5-(3′-氯-2-氟-6-甲氧基-联苯-3-基甲基)-吡啶-2-羰基]-吡咯烷-3-羧酸甲酯
向Int-23(100mg,0.269mmol)和吡咯烷-3-羧酸甲酯(49.0mg,0.296mmol)在四氢呋喃(3mL)中的溶液中加入HOBt(40.0mg,0.296mmol)和EDCI(56.7mg,0.296mmol)。加入二甲基甲酰胺(1mL),并将反应在室温下搅拌过夜。另外加入吡咯烷-3-羧酸甲酯(25.0mg),并将反应在室温下搅拌过夜。真空除去溶剂,并加入二氯甲烷(10mL)和水(10mL)。分离各层,并用二氯甲烷(10mL)萃取水层。合并有机萃取物,用水(20mL)、饱和碳酸氢钠水溶液(20mL)和盐水(20mL)洗涤,用硫酸镁干燥,过滤,并真空除去溶剂以得到粗产物。将粗品经硅胶制备薄层色谱(用10%丙酮/二氯甲烷洗脱)纯化,以得到作为澄清油状物的Int-24(28.4mg,收率22%)。
A-038.[MCLS1458-091-1]合成1-[5-(3′-氯-2-氟-6-甲氧基-联苯-3-基甲基)-吡啶-2-羰基]-吡咯烷-3-羧酸
将Int-24(25.0mg,0.0518mmol)和1N氢氧化钠水溶液(77.7μL,0.0777mmol)在四氢呋喃(1mL)和水(1mL)中的溶液在室温下搅拌3h。真空除去溶剂,并用10滴冰醋酸中和残余物。将粗品溶于水(5mL)和二氯甲烷(5mL)中,并将两层分离。用二氯甲烷(5mL)萃取水溶液,并用水(5mL)和盐水(5mL)洗涤合并的二氯甲烷层,用硫酸镁干燥,过滤,并在氮气流中除去溶剂,以得到作为浅褐色粉末的粗产物。将产品经硅胶制备薄层色谱(用25%丙酮/二氯甲烷洗脱,展开3次)纯化,以得到A-038(11.6mg,收率48%)。
1H NMR(400MHz d6-DMSO)δ:8.51(d,J=7.6Hz,1H),7.74-7.66(m,2H),7.45-7.28(m,5H),6.96(d,J=8.4Hz,1H),4.03(s,2H),3.76-3.64(m,7H),2.95(s,1H),2.02(m,2H)。LCMS=98.1%纯度。MS(APCI-)=467.1(M-1)。
Int-25[MCLS1471-064-1]5-(3′-氯-2-氟-6-甲氧基-联苯-3-基甲基)-吡啶-2-基胺
向250mL圆底烧瓶中加入Int-21(8.04g,24.76mmol)、5-(4,4,5,5-四甲基-[1,3,2]二氧杂环戊硼烷-2-基)-吡啶-2-基胺(4.09g,18.57mmol)、K2CO3(10.27g,74.27mmol)和DMF(100mL)。用N2脱气20分钟,加入氯化烯丙基钯(II)二聚体(1.36g,3.71mmol)和1,5-双(二苯基膦基)戊烷(3.27g,7.43mmol),并将反应在80℃下搅拌18小时,并在室温下搅拌2天。加入水,并用EtOAc萃取产物。浓缩有机物,然后将残余物经快速柱色谱(0-5%MeOH/DCM)纯化,以得到作为红色油状物的Int-25(4.1g,48%)。将该化合物用于下一步反应中。
A-039 MCLS1471-072-2
6-(3′-氯-2-氟-6-甲氧基-联苯-3-基甲基)-咪唑并[1,2-a]吡啶-2-羧酸乙酯
向18mL小瓶中加入Int-25(565mg,1.65mmol)、3-溴-2-氧代-丙酸乙酯(0.52mL,4.12mmol)和二甲氧基乙烷(DME,5mL)。将反应在室温下搅拌18小时。加入饱和NaHCO3(aq),并用EtOAc萃取产物。浓缩有机物,并经快速柱色谱(5%丙酮/DCM)纯化,以得到棕褐色固体。用***研磨固体,以得到作为灰白色固体的A-039(198mg,26%)。1H-NMR(400MHz,CDCl3):8.51(s,1H),8.39(s,1H),7.56(d,J=9.4Hz,1H),7.49-7.35(m,4H),7.30(d,J=6.7Hz,1H),7.25(dd,J=1.3,9.4Hz,1H),6.97(d,J=8.6Hz,1H),4.29(q,J=7.1Hz,2H),3.96(s,2H),3.74(s,3H),1.31(t,J=7.0Hz,3H)。
A-043 MCLS1471-078-1
6-(3′-氯-2-氟-6-甲氧基-联苯-3-基甲基)-咪唑并[1,2-a]吡啶-2-羧酸
向8mL小瓶中加入A-039(39mg,0.089mmol)、1N NaOH(1mL)和1mL EtOH。将反应在室温下搅拌18小时,然后在60℃下搅拌1小时。用1N HCl将pH调节至约为5,并形成浅色沉淀。将固体过滤,用水洗涤,并在高真空下干燥,以得到作为灰白色固体的A-043(22.2mg,61%)。1H-NMR(400MHz,DMSO-d6):8.36(s,1H),8.14(s,1H),7.39(m,6H),7.14(dd,1H,J=9.2,2.0Hz),6.96(d,1H,J=8.4Hz),3.93(s,2H),3.73(s,3H)。LC/MS=94.6%,411.0(APCI+)。
Int-26 MCLS1430-173-1
5-(4,4,5,5-四甲基-[1,3,2]二氧杂环戊硼烷-2-基)-吡啶-2-腈
向250mL RBF加入3.0g 5-溴-吡啶-2-腈(3.0g,16.39mmol)、双戊酰二硼(Bis(pinacolato)diboron,4.58g,18.03mmol)、KOAc(5.47g,55.74mmol)和DMSO(100mL)。脱气20分钟,加入PdCl2dppf-CH2Cl2(1.39g,1.64mmol),并将溶液在80℃下搅拌24小时,然后在室温下搅拌3天。加入50mL水,并用乙酸乙酯萃取产物。用盐水洗涤合并的有机层,用Na2SO4干燥并浓缩。将深色残余物用20%丙酮/己烷洗脱,经FCC纯化以得到红色固体。用己烷研磨固体,以得到1.72g(46%)作为浅粉色固体的Int-26。
Int-27 MCLS1430-126-1
[5-(3′-氯-2-氟-6-甲氧基-联苯-3-基甲基)-吡啶-2-基甲基]-氨基甲酸叔丁酯
向20mL小瓶中加入Int-26(401mg,1.22mmol)、Int-20(336mg,1.46mmol)、K2CO3(504mg,3.65mmol)、DME(5mL)、水(0.5mL)、乙醇(0.5mL),并将悬浮液脱气15分钟。加入Pd(PPh3)4(141mg,0.12mmol),并将反应在80℃下搅拌16小时。用水稀释反应,并用乙酸乙酯萃取。浓缩有机物,并将其用15-20%乙酸乙酯/己烷洗脱,经FCC纯化以得到作为浅黄色油状物的Int-27(64mg,15%)。1H NMR(400MHz,CHLOROFORM-d)δ=8.62(br.s.,1H),7.68-7.56(m,2H),7.40-7.30(m,3H),7.26-7.21(m,1H),7.13(t,J=8.4Hz,1H),6.75(d,J=8.3Hz,1H),4.03(br.s.,2H),3.78(s,3H)。LC/MS=98.5%,353.0(APCI+)。
A-042 MCLS1471-075-4(Ex-428)
5-(3′-氯-2-氟-6-甲氧基-联苯-3-基甲基)-2-(1H-四唑-5-基)-吡啶
向20mL小瓶中加入Int-27(129mg,0.37mmol)、NH4Cl(137mg,2.56mmol)、NaN3(119mg,1.83mmol)和DMF(3mL)。将反应在80℃下搅拌18小时,然后过滤并浓缩。将残余物先后用25-75%丙酮/DCM和10%甲醇/DCM洗脱,经FCC纯化以得到无色油状物。用***处理油状物,以得到作为棕褐色固体的A-042(13mg,9%)。1H NMR(400MHz,DMSO-d6)δ=8.49(br.s.,1H),7.95(br.s.,1H),7.66(br.s.,1H),7.49-7.33(m,4H),7.32-7.25(m,1H),6.96(d,J=8.6Hz,1H),4.00(br.s.,2H),3.73(s,3H)。LC/MS=100.0%,396.0(APCI+)。
合成A-047
(Int-28)[MCLS1448-146-1]合成2-氯-嘧啶-5-硼酸
在氮气中将5-溴-2-氯嘧啶(30mmol,5.79g)、甲苯(48mL)、THF(12mL)和硼酸三异丙酯(36mmol,8.4mL)加入200mL圆底烧瓶中。在-70℃下搅拌混合物,并缓慢加入(1.5h期间)正丁基锂(2.5M己烷溶液,36mmol,14.4mL)在-70℃下搅拌2h,将反应升温至-20℃,然后加入2N HCl(30mL)。在添加HCl时,反应混合物从浅色均匀溶液变为白色两相溶液。当混合物达到室温时,将其转移入分液漏斗并分离各层。用1N NaOH将水层中和至pH=7,然后用THF(3×150mL)萃取。用Na2SO4干燥合并的有机层并浓缩。将粗品溶于THF(5mL)中,并加入***(100mL)。析出黄色固体。收集固体并干燥,以得到作为浅黄色固体的Int-28(3.79g)。
(Int-29)[MCLS1226-099-1]合成3′-氯-2-氟-3-(4-碘-苄基)-6-甲氧基-联苯:
将Int-20(2.5mmol,824mg)和Int-28(2.5mmol,400mg)溶于甲苯(10mL)和乙醇(2.5mL)中。先后加入Pd(PPh3)4(144mg,0.125mmol)和Na2CO3水溶液(2M,5mL,2.5mmol)。将反应混合物在85℃下加热过夜。用EtOAc(25mL)稀释所得混合物,用水和盐水洗涤,然后用Na2SO4干燥。将有机溶液过滤并减压浓缩。将粗品用己烷/EtOAc(9∶1)洗脱,经硅胶(40g)柱(直径1/2英寸)色谱纯化,以得到作为浅黄色固体的标题化合物(297.4mg)。
A-047[MCLS1457-144-1]合成{[5-(3′-氯-2-氟-6-甲氧基-联苯-3-基甲基)-嘧啶-2-基]-甲基-氨基}-乙酸:
在配有搅拌棒的8mL小瓶中加入Int-29(120mg,0.330mmol)、N-甲基甘氨酸(44.1mg,0.495mmol)、异丙醇(1.5mL)和二异丙基乙胺(172μL,0.990mmol)。将反应混合物在80℃下加热18小时。将该物质与20mg规模的相同反应进程的反应混合物合并。用饱和碳酸氢钠溶液(60mL)、水(30mL)将混合物处理为pH 8,并用乙酸乙酯(2×50mL)萃取以除去有机杂质。合并有机部分,用饱和碳酸氢钠溶液(75mL)洗涤,随后合并所有的水相部分,用3M盐酸将其酸化至pH 1。用乙酸乙酯(3×75mL)萃取水相部分,并合并有机部分,用盐水(100mL)洗涤,干燥(硫酸镁)并浓缩,以27%的收率得到44mg作为白色粉末的A-047。
1H NMR(400MHz,DMSO-d6)δ3.11(s,3H),3.72(s,3H),3.77(s,2H),4.24(s,2H),6.93(d,J=9Hz,1H),7.284-7.328(m,2H),7.38(s,1H),7.43-7.46(m,2H),8.25(bs,2H)。
Int-30 MCLS1430-114-3
C-[5-(3′-氯-2-氟-6-甲氧基-联苯-3-基甲基)-吡啶-2-基]-甲胺
向100mL RBF中加入Int-27(0.55g,1.56mmol)、甲醇(20mL)、浓HCl(0.65mL,7.79mmol)和10%Pd/C(100mg)。在H2气球下将悬浮液搅拌18小时,然后通过硅藻土过滤。浓缩滤液。向固体中加入1N NaOH,并用DCM萃取产物。浓缩DCM,并将其用5-10%甲醇/DCM洗脱,经FCC纯化,以得到无色油状的Int-30(89mg,16%)。1H NMR(400MHz,DMSO-d6)δ=8.55(d,J=1.2Hz,1H),8.32(br.s.,3H),7.71(dd,J=1.9,7.9Hz,1H),7.50-7.37(m,3H),7.36(d,J=5.4Hz,2H),7.27(d,J=6.6Hz,1H),6.96(d,J=8.6Hz,1H),4.75(br.s.,2H),4.14(q,J=5.8Hz,2H),4.01(s,2H),3.73(s,3H)。LC/MS=95.1%,357.1(APCI+)。
A-048 MCLS1471-115-2
N-[5-(3′-氯-2-氟-6-甲氧基-联苯-3-基甲基)-吡啶-2-基甲基]-草酰酸乙酯
向18mL小瓶中加入Int-30(152mg,0.43mmol)、TEA(0.11mL,0.85mmol)和DCM(4mL)。将溶液冷却至0℃,并加入草酰氯单乙酯(ethylchlorooxoacetate,71μL,0.64mmoL)。20分钟后,将反应在室温下用盐水洗涤,并将有机物浓缩。用1∶1***∶EtOAc研磨半固体,过滤,并用EtOAc洗涤,以得到作为灰蓝色固体的标题化合物(69mg,35%)。1H NMR(400MHz,DMSO-d6)δ=9.38(t,J=6.0Hz,1H),8.41(s,1H),7.59(dd,J=4.0,8.0Hz,2H),7.48-7.25(m,8H),7.22(d,J=8.1Hz,2H),6.94(d,J=8.6Hz,2H),4.39(d,J=6.0Hz,2H),4.32-4.18(m,2H),3.94(s,2H),3.72(s,3H),1.27(t,J=7.1Hz,3H)。LC/MS=97.9%,457.0(APCI+)。
A-050 MCLS1471-143-2
N-[5-(3′-氯-2-氟-6-甲氧基-联苯-3-基甲基)-吡啶-2-羰基]-甲磺酰胺
向8mL小瓶中加入Int-23(85mg,0.23mmol)、甲磺酰胺(26mg,0.27mmoL)、EDCI(88mg,0.46mmol)、DMAP(56mg,0.46mmol)、DCM(2mL)和0.5mL DMSO。在室温下搅拌3天,加入2mL水,并分离各层。用2×2mL NH4Cl饱和溶液洗涤有机层,然后浓缩。将残余物用50%丙酮/DCM洗脱经快速柱色谱纯化。用***研磨该物质,以得到作为白色固体的标题化合物(27.2mg,26%)。1H NMR(400MHz,DMSO-d6)δ=8.66(br.s.,1H),7.98(d,J=7.9Hz,1H),7.72(d,J=7.5Hz,1H),7.50-7.32(m,4H),7.28(d,J=6.4Hz,1H),6.96(d,J=8.6Hz,1H),4.05(s,2H),3.73(s,3H),2.95(s,3H)。LC/MS=100.0%,449.0(APCI+)。
Int-31 MCLS1471-127-1
6-(3′-氯-2-氟-6-甲氧基-联苯-3-基甲基)-咪唑并[1,5-a]吡啶-3-羧酸乙酯
向4mL小瓶中加入A-048(44mg,0.096mmol)、DCM(1mL)、吡啶(31μL,0.48mmol)和POCl3(13μL,0.14mmol)。将反应在室温下搅拌18小时,之后加入2mL水。分离各层,并用2mL DCM萃取产物。将有机物合并,浓缩,并将其用20%丙酮/己烷洗脱,经快速柱色谱纯化以得到浅黄色半固体。用己烷研磨残余物得到固体,将其过滤,用己烷洗涤并干燥。得到作为棕褐色固体的标题化合物(8.2mg,19%)。
A-051 MCLS1471-140-1
6-(3′-氯-2-氟-6-甲氧基-联苯-3-基甲基)-咪唑并[1,5-a]吡啶-3-羧酸盐酸盐
向8mL小瓶中加入Int-31(42mg,0.14mmol)、EtOH(1mL)和1NNaOH(1mL)。将反应在60℃下搅拌1小时。冷却至室温后,通过尼龙过滤器过滤除去某些不溶物。蒸发EtOH,并使用1N HCl将剩余的水相的pH调节至1。过滤所形成的固体,用水洗涤,真空干燥以得到作为黄色固体的标题化合物(A-051)(14.2mg,23%)。1H NMR(400MHz,DMSO-d6)δ=9.15(s,1H),7.79(d,J=9.3Hz,1H),7.65(s,1H),7.51-7.34(m,4H),7.33-7.25(m,1H),7.10(s,1H),6.97(d,J=8.6Hz,1H),4.02(s,2H),3.74(s,3H)。
合成A-052
A-052 MCLS1471-075-4
5-(3′-氯-2-氟-6-甲氧基-联苯-3-基甲基)-2-(1H-四唑-5-基)-吡啶
向20mL小瓶中加入Int-27(129mg,0.37mmol)、NH4C1(137mg,2.56mmol)、NaN3(119mg,1.83mmol)和DMF(3mL)。将反应在80℃下搅拌18小时,然后过滤并浓缩。将残余物先后用25-75%丙酮/DCM和10%甲醇/DCM洗脱,经FCC纯化以得到无色油状物。用***处理该油状物以得到作为棕褐色固体的A-052(13mg,9%)。1H NMR(400MHz,DMSO-d6)δ=8.49(br.s.,1H),7.95(br.s.,1H),7.66(br.s.,1H),7.49-7.33(m,4H),7.32-7.25(m,1H),6.96(d,J=8.6Hz,1H),4.00(br.s.,2H),3.73(s,3H)。LC/MS=100.0%,396.0(APCI+)。
合成A-055
Int-32[MCLS1448-171-1]合成5-(3′-氯-2-氟-6-甲氧基-联苯-3-基甲基)-2-氟-吡啶
在高压氮气气氛中,将Int-20(824mg,2.50mmol)、2-氟代吡啶-5-硼酸(352mg,2.50mmol)、2M碳酸钠水溶液(2.5mL,5.00mmol)和四(三苯基膦)钯(0)(144mg,0.125mmol)在甲苯(10mL)和乙醇(2.5mL)中的悬浮液在80℃下搅拌过夜。将反应冷却至室温。用水(10mL)稀释,并用乙酸乙酯(2×20mL)萃取。用硫酸钠干燥合并的萃取物,过滤,并真空浓缩。将残余物经硅胶柱色谱(4∶1己烷/乙酸乙酯)纯化,以得到作为白色固体的Int-32(694.7mg,收率78%)。
A-055[MCLS1486-102-1]合成1-[5-(3′-氯-2-氟-6-甲氧基-联苯-3-基甲基))-吡啶-2-基]-氮杂环丁烷-2-羧酸:
向5-(3′-氯-2-氟-6-甲氧基-联苯-3-基甲基)-2-氟-吡啶(Int-32)(0.2g,0.58mmol)和氮杂环丁烷-2-羧酸(2)(0.18g,1.74mmol)中加入1,8-二氮杂双环[5.4.0]十一-7-烯(DBU)(0.44g,2.89mmol)。将反应混合物搅拌,并在160℃下加热20min。冷却至室温,用二氯甲烷(8mL)稀释,用0.5N HCl(2×4mL)洗涤,用Na2SO4干燥,过滤并浓缩。将残余物用3%甲醇/二氯甲烷经硅胶柱色谱纯化,以得到0.19g(77%)作为灰白色固体的A-055。1H NMR(DMSO-d6,400MHz):7.87(d,J=2.0Hz,1H),7.4-7.47(m,2H),7.37(s,1H),7.2-7.3(m,3H),6.91(d,J=8.4Hz,1H),6.55(d,J=8.8Hz,1H),4.08(dd,J=9.0,6.8Hz,1H),3.62-3.74(m,2H),3.74(s,2H),3.71(s,3H),2.18-2.3(m,2H);MS(APCI+):427.1(M+1),LC-MS:97.1%;HPLC 95.2%。
合成A-062
Int-33 MCLS1435-080-1
合成[4-(3-溴-4-甲氧基-苄基)-苯基]-脲(Int-33)
向配有特氟龙螺纹盖和磁搅拌棒的40mL小瓶中加入2-溴-4-溴甲基-1-甲氧基苯(649mg,2.32mmol)、[4-(4,4,5,5-四甲基-[1,3,2]二氧杂环戊硼烷-2-基)-苯基]-脲(577mg,2.20mmol)和磷酸钾(933mg,4.40mmol)。然后向该小瓶中加入二甲氧基乙烷(15mL)、乙醇(3.7mL)和水(3.7mL)。向该搅拌中的溶液中加入四(三苯基膦)钯(127mg,0.11mmol),并通过向溶液中通入N2气而将溶液脱气20min。将小瓶封盖,放入油浴中,并在65℃下搅拌12.5h。将冷却的反应混合物在N2气流中浓缩至总体积为约5mL,然后用乙酸乙酯(20mL)和水(10mL)稀释。在振摇时析出白色固体。将该固体过滤并干燥,以得到272mg(34%)作为白色固体的化合物Int-33。
1H NMR(400MHz,DMSO-d6)3.78(s,2H),3.80(s,3H),5.77(br s,2H),7.01(d,J=8.4Hz,1H),7.05(m,2H),7.17(dd,J=8.4,2.0Hz,1H),7.29(m,2H),7.37(d,J=2.0Hz,1H),8.43(br s,1H)。MS(APCI+):335.0(M+);337.0(M++2),LC-MS:99.3%。
Int-34 MCLS1435-084-1
合成[4-(3′-氯-6-甲氧基-联苯-3-基甲基)-苯基]-脲
向配有磁搅拌棒和螺纹盖的20mL小瓶中加入化合物Int-33(250mg,0.746mmol)、二甲氧基乙烷(5mL)、乙醇(1mL)和水(1mL)。向该混合物中加入3-氯苯基硼酸(140mg,0.895mmol)、磷酸钾(316mg,1.49mmol)和四(三苯基膦)钯(30mg,0.0254mmol)。通过向溶液中通入N2气而将搅拌中的溶液脱气10min。将小瓶封盖,放入油浴中,并在80℃下搅拌16h。将冷却的反应混合物浓缩至干,然后用水(5mL)和乙酸乙酯(15mL)稀释。用乙酸乙酯(2×5mL)萃取水层,并干燥(Na2SO4)合并的有机萃取物,过滤并在N2气流中浓缩。将残余物用9∶1二氯甲烷/丙酮作为洗脱剂,经快速硅胶(35g)色谱纯化。合并TCL纯的部分并浓缩,以得到139mg(51%)作为灰白色固体的Int-34。1H NMR(400MHz,DMSO-d6)3.74(s,3H),3.83(s,2H),5.75(br s,2H),7.03(d,J=8.4Hz,1H),7.08(m,2H),7.15(d,J=2.4Hz,1H),7.18(dd,J=8.4,2.4Hz,1H),7.28(m,2H),7.36-7.41(m,3H),7.48(m,1H),8.40(br s,1H)。MS(APCI+):367.0(M++1);LC-MS:95.9%。
Int-35 MCLS1489-012-1
在-70℃下,在5分钟内向Int-34(2.2mmol,1.0eq.)在二氯甲烷中的悬浮液中加入三溴化硼在二氯甲烷(6.6mmol,3eq.)中的1.0M溶液。将反应混合物搅拌,并升温至环境温度,然后搅拌20分钟。将反应倒入冰水(100mL)中,搅拌30分钟,过滤,并依次用水和己烷洗涤滤饼。将固体在乙酸乙酯蒸气中真空干燥4小时,以得到标题化合物,将其直接用于后续反应。将一部分标题化合物进一步用丙酮/二氯甲烷作为洗脱剂,经硅胶色谱纯化,然后用二氯甲烷研磨以得到作为白色固体的标题化合物。(1HNMR,DMSO-d6;400MHz):3.78(s,2H),5.75(s,2H),6.86(d,J=8.0Hz,1H),7.00(dd,J=8.4,2.4Hz,1H),7.07(d,J=8.4Hz,2H),7.12(d,J=2.4Hz,1H),7.28(d,J=8.4Hz,2H),7.4(m,1H),7.41(dd,J=8.0,7.6Hz,1H),4.47(m,1H),7.56(m,1H),8.40(s,1H),9.50(s,1H)。LC/MS(100%)APCI+实测值:353.0,计算值352.8m/z。
A-062[MCLS1457-189-4]合成[4-(3′-氯-6-羟基-联苯-3-基甲基)-苯基]-脲的硫酸钠盐:
在氮气气氛中,在配有搅拌棒的18mL小瓶中加入Int-35(250mg,0.709mmol)、吡啶(2.5mL)和三氧化硫-吡啶络合物(226mg,1.42mmol)。将混合物在室温下搅拌18小时。另外加入三氧化硫-吡啶络合物(100mg),并将反应混合物在70℃下加热4小时。用氮气流浓缩反应混合物,加入甲醇(2.5mL),然后加入1M NaOH以达到pH 8。通过抽滤除去形成的白色固体。将滤液浓缩,并加入***(3mL),得到黄色半固体。收集该固体,并在35℃下在高真空箱中干燥5小时,得到灰白色粉末。通过将粗品溶解在水(4mL,通过加入数滴浓氢氧化胺制成碱性)中,并用乙酸乙酯(3×4mL)洗涤。将水相部分冻干过夜,以17%的收率得到56mg作为松散白色固体的A-062。
1H NMR(400MHz,DMSO-d6)δ3.83(s,2H),5.88(s,2H),6.95(d,J=6Hz,1H),7.08-7.13(m,3H),7.31(d,J=9Hz,2H),7.34-7.36(m,1H),7.40(t,J=8Hz,1H),7.48-7.50(m,1H),7.56(d,J=8Hz,1H),7.64(t,J=2Hz,1H),8.74(bs,1H)。
LC-MS:98%。
合成A-064和A-065
Int-37[MCLS1475-078-2]合成(4-氨基-苯基)-(3′-氯-6-甲氧基-联苯-3-基)-甲酮
在室温下向在EtOH-H2O(1∶1,15mL)中含有(3′-氯-6-甲氧基-联苯-3-基)-(4-硝基-苯基)-甲酮(Int-36(以与Int-12类似的方式制备),500mg,1.3mmol)的25mL小瓶中在室温下先后加入NH4Cl(200mg,4mmol)和Fe(150mg,3mmole)。将反应混合物在室温下搅拌72h。将混合物倒入50mL水中,用乙酸乙酯(3×30mL)萃取,用水(20mL)、盐水(30mL)洗涤,用Na2SO4干燥。真空除去溶液,以85%的收率得到420mg(4-氨基-苯基)-(3′-氯-6-甲氧基-联苯-3-基)-甲酮(Int-37)。1H NMR(DMSO-d6,400MHz):δ=7.70(dd,J=8.4,2.4Hz,1H),7.40-7.57(m,7H),7.25(d,J=8.8Hz,1H),6.61(d,J=8.8Hz,2H),6.09(s,2H),3.88(s,3H)。
A-064[MCLS1475-079-3]合成1-乙酰氨基-3-[4-(3′-氯-6-甲氧基-联苯-3-羰基)-苯基]-脲
在室温下向在吡啶(2mL)和THF(8mL)中含有(4-氨基-苯基)-(3′-氯-6-甲氧基-联苯-3-基)-甲酮(Int-37,420mg,1.3mmol)的25mL小瓶中加入TMS-异氰酸酯(1.7mL,过量)。将混合物在室温下搅拌100h。将混合物倒入25mL冰水溶液中,加入5mL饱和NaHCO3,并将所形成的混合物在室温下搅拌2h。用乙酸乙酯(3×30mL)萃取混合物,用水(20mL)、盐水(30mL)洗涤,并用Na2SO4干燥。除去溶剂以得到粗产物,将其用乙酸乙酯-己烷作为洗脱剂,经硅胶柱色谱分离,以48.4%的收率得到250mg 1-乙酰氨基-3-[4-(3′-氯-6-甲氧基-联苯-3-羰基)-苯基]-脲(A-064)。1H NMR(DMSO-d6,400MHz):δ=10.6(br,s,1H),9.37(br.s.,1H),7.40-7.81(m.,7H),7.30(d,J=8.4Hz,1H),6.84-7.10(m,2H),3.90(s,3H)。LC/MSCalc.423.86;APCI+(M+1):424.1,95%。
A-065[MCLS1475-080-1J合成1-乙酰氨基-3-{4-[(3′-氯-2-氟-6-甲氧基-联苯-3-基)-羟基-氘代-甲基]-苯基}-脲
在0℃下,向在THF(7mL)和D2O(3mL)中含有1-乙酰氨基-3-[4-(3′-氯-6-甲氧基-联苯-3-羰基)-苯基]-脲(A-064,100mg,0.3mmol)的50mL小瓶中加入NaBD4(130mg,0.7mmol)。将反应混合物升温至室温,并在室温下搅拌24小时。将反应混合物倒入40mL冰水中,用NH4Cl(饱和,4mL)中和,用乙酸乙酯(3×30mL)萃取,用水(20mL)、盐水(20mL)洗涤,并用Na2SO4干燥。除去溶剂后,将残余物用乙酸乙酯/己烷作为洗脱剂,经硅胶柱色谱分离,以26%的收率得到70mg 1-乙酰氨基-3-{4-[(3′-氯-2-氟-6-甲氧基-联苯-3-基)-羟基-氘代-甲基]-苯基}-脲。1H NMR(DMSO-d6,400MHz):δ=9.89(s,1H),8.80(s,1H),7.47(br,s,1H),7.42(d,J=6.8Hz,1H),7.28-7.39(m,7H),7.05(d,J=7.2Hz,1H),5.75(s,1H),3.74(s,3H)。LC/MS计算值426.87;APCI+(M-OH):309.1,98%。
合成A-035、A-056、A-037和A-057
(Int-38)[MCLS1316-161-4]合成5-(3′-氯-2-氟-6-甲氧基-联苯-3-基甲基)-吡啶-2-基胺
在氮气中向Int-20(0.3g,0.91mmol)和2-氨基吡啶-5-硼酸频哪醇酯(0.24g,1.1mmol)在DME/EtOH/H2O(4/1/1,12ml)中的混合物中加入磷酸钾(0.39g,1.82mmol)和四(三苯基膦)钯(0)(53mg,0.046mmol)。将反应混合物在80℃下加热2h。用水稀释反应,用乙酸乙酯萃取,用水和盐水洗涤,并用Na2SO4干燥。将其真空浓缩后,将残余物经硅胶色谱纯化以得到期望产物,将其转化为其HCl盐Int-38(0.165g,50%)。
(Int-39)[MCLS1325-188-1]合成N-[5-(3′-氯-2-氟-6-甲氧基-联苯-3-基甲基)-吡啶-2-基]-乙酰胺
在0℃下,向含有5-(3′-氯-2-氟-6-甲氧基-联苯-3-基甲基)-吡啶-2-基胺(Int-38,420mg,1.2mmol)在吡啶(2mL)中的混合物的20mL小瓶中加入Ac2O(2mL,过量)。将混合物升温至室温,并在室温下搅拌16h,随后将其倒入50mL冰水溶液中。将所形成的固体滤出,用水(3×15mL)洗涤,风干以得到360mg(收率85%)的标题产物(Int-39)。
(Int-40)[MCLS1325-201-2]合成{乙酰基-[5-(3′-氯-2-氟-6-甲氧基-联苯-3-基甲基)-吡啶-2-基]-氨基}-乙酸甲酯
在0℃下,向在DMF(2mL)中含有NaH(40%在矿物油中,40mg,1mmol)的25mL小瓶中加入N-[5-(3′-氯-2-氟-6-甲氧基-联苯-3-基甲基)-吡啶-2-基]-乙酰胺(Int-39,77mg,0.2mmol)。将反应升温至室温,并在室温下搅拌1h,冷却至0℃,加入溴代乙酸甲酯(153mg,1.0mmol)。将混合物升温至室温,并在室温下搅拌16h,然后将其倒入25mL冰水溶液中,将其用乙酸乙酯(3×20mL)萃取,用水(3×20mL),盐水(20mL)洗涤,并用Na2SO4干燥。除去溶剂后,将残余物用乙酸乙酯-己烷作为洗脱剂,经硅胶柱色谱纯化,以74%的收率得到68mg标题化合物。
A-035.[MCLS1325-207-1]合成[5-(3′-氯-2-氟-6-甲氧基-联苯-3-基甲基)-吡啶-2-基氨基]-乙酸
在室温下,向在MeOH(2mL)中含有Int-40(37mg,0.08mmol)的20mL小瓶中加入LiOH(1N在水中,2mL,2mmol)。将反应混合物在室温下搅拌48h。将混合物倒入25mL冰水溶液中,通过加入2N HCl将其酸化至pH=1-2,然后用乙酸乙酯(3×20mL)萃取,用水(3×20mL)、盐水(20mL)洗涤,并用Na2SO4干燥。除去溶剂后,通过将粗产物溶于丙酮,加入30mL1∶9乙酸乙酯-己烷,然后缓慢除去丙酮进行纯化,以得到从水层中分离出的半固体,将其真空干燥以60%的收率得到20mg A-035。
1H NMR(DMSO-d6,400MHz):δ=7.85(br,s,1H),7.68-7.80(m,2H),7.28-7.46(m,5H),7.07-7.10(m,1H),6.96(d,J=8.8Hz,1H),4.18(s,2H),3.88(s,2H),3.73(s,3H)。计算值400.8;APCI+(M+1):401.0。
A-056[MCLS1475-056-3]合成{1-[5-(3′-氯-2-氟-6-甲氧基-联苯-3-基甲基)-吡啶-2-基]-3-乙基-脲基}-乙酸
在室温下,向在吡啶(2mL)中含有A-035(18mg,0.05mmol)的20mL小瓶中加入异氰酸乙酯(0.2mL,过量)。将混合物在室温下搅拌48h。将混合物倒入20mL冰水溶液中,并将所形成的固体滤出,用水(20mL)洗涤,并溶于二噁烷-H2O(1∶1,10mL)中。在室温下向该溶液中加入250mg KOH。将混合物在室温下搅拌16h,然后通过加入2N HCl将该溶液调节至pH=1,用乙酸乙酯(3×20mL)萃取,用水(20mL)、盐水(20mL)洗涤,并用Na2SO4干燥。除去溶剂后,将粗品用乙酸乙酯-己烷作为洗脱剂,经硅胶色谱进行分离,以50%的收率得到17mg A-056。
1H NMR(氯仿-d,400MHz):δ=8.20(br,s,1H),8.15(d,J=8.8Hz,1H),7.57(dd,J=8.8,2.4Hz,1H),7.25-7.39(m,4H),7.09(t,J=8.4Hz,1H),6.71(d,J=8.4Hz,1H),4.50(s,2H),3.93(s,2H),3.74(s,3H),3.66(q,J=7.6Hz,2H),1.27(t,J=7.6Hz,3H),).LC/MS计算值:471.9;APCI+(M-OH):454.1,100%。
A-057[MCLS1475-62-2]合成{1-[5-(3′-氯-2-氟-6-甲氧基-联苯-3-基甲基)-吡啶-2-基]-脲基}-乙酸
在室温下向在吡啶(5mL)中含有A-035(80mg,0.2mmol)的20mL小瓶中加入TMS-异氰酸酯(0.5mL,过量)。将混合物在室温下搅拌48h。将混合物倒入20mL冰水溶液中,并将所形成的固体滤出,用水(20mL)洗涤,并溶于二噁烷-5%NaHCO3(1∶1,10mL)中。将混合物在室温下搅拌24h。通过加入2N HCl将该溶液调节至pH=1,将所形成的固体滤出,用水(20mL)洗涤,风干以22%的收率得到20mg期望的A-057。
1H NMR(DMSO-d6,400MHz):δ=11.26(s,1H),8.24(d,J=2.0Hz,1H),8.05(d,J=8.4Hz,1H),7.67(dd,J=8.8,2.4Hz,1H),7.25-7.49(m,5H),6.93(d,J=8.8Hz,1H),4.43(s,2H),3.92(s,2H),3.72(s,3H),3.57(s,3H).LC/MS计算值:443.9;APCI+(M-OH):426.1,100%。
A-037[MCLS1475-013-1]合成{乙酰基-[5-(3′-氯-2-氟-6-甲氧基-联苯-3-基甲基)-吡啶-2-基]-氨基}-乙酸
在0℃下,向在MeOH(2mL)中含有Int-40(150mg,0.34mmol)的20mL小瓶中加入KOH(1N在水中,2mL,2mmol)。将反应混合物升温至室温,并在室温下搅拌24h。将混合物冷却至0℃,通过加入2N HCl将其酸化至pH=1-2,然后加入20mL水。用CH2Cl2-MeOH(20∶1,5×20mL)萃取混合物。用盐水(20mL)洗涤合并的有机层,并用Na2SO4干燥。真空除去溶剂,以77%的收率得到120mg标题化合物(A-037)。1H NMR(DMSO-d6,400MHz):δ=8.33(s,1H),7.85(br,s,1H),7.78-7.80(m,2H),7.28-7.46(m,4H),6.95(d,J=8.0Hz,1H),4.44(s,2H),3.97(s,2H),3.73(s,3H),2.07(s,3H)。
合成A-061
A-061[MCLS1486-111-1]合成(R)-1-[5-(3′-氯-2-氟-6-甲氧基-联苯-3-基甲基)-吡啶-2-基]-氮杂环丁烷-2-羧酸
向5-(3′-氯-2-氟-6-甲氧基-联苯-3-基甲基)-2-氟-吡啶(Int-32)(0.2g,0.58mmol)和D-氮杂环丁烷-2-羧酸(2)(0.18g,1.74mmol)中加入1,8-二氮杂双环[5.4.0]十一-7-烯(DBU)(0.44g,2.89mmol)。将反应搅拌,并在160℃下加热20min。冷却至室温,用二氯甲烷(8mL)稀释,用0.5N HCl(2×4mL)洗涤,用Na2SO4干燥,过滤并浓缩。将残余物用3%甲醇/二氯甲烷经硅胶柱色谱纯化,以得到0.1g(40%)作为灰白色固体的A-061。1H NMR(DMSO-d6,400MHz):7.98(d,J=2.0Hz,1H),7.4-7.47(m,3H),7.37(s,1H),7.24-7.3(m,2H),6.92(d,J=8.4Hz,1H),6.41(d,J=8.8Hz,1H),4.08(dd,J=8.8,7.2Hz,1H),3.7-3.792(m,2H),3.8(s,2H),3.72(s,3H),2.3-2.56(m,2H);MS(APCI+):427.1(M+1),LC-MS:90.1%。
合成A-063
A-063[MCLS1486-137-1]合成(S)-1-[5-(3′-氯-2-氟-6-甲氧基-联苯-3-基甲基)-吡啶-2-基]-吡咯烷-2-羧酸
向5-(3′-氯-2-氟-6-甲氧基-联苯-3-基甲基)-2-氟-吡啶(Int-32)(0.15g,0.43mmol)和(S)-吡咯烷-2-羧酸(2)(0.15g,1.3mmol)中加入1,8-二氮杂双环[5.4.0]十一-7-烯(DBU)(0.33g,2.17mmol)。将反应混合物搅拌,并在160℃下加热20min。冷却至室温,用二氯甲烷(8mL)稀释,用0.5N HCl(2×4mL)洗涤,用Na2SO4干燥,过滤并浓缩。将残余物用5%甲醇/二氯甲烷经硅胶柱色谱纯化,以得到0.04g(21%)作为灰白色固体的A-063。1H NMR(DMSO-d6,400MHz):7.93(d,J=2.4Hz,1H),7.4-7.65(m,2H),7.34-7.38(m,2H),7.23-7.3(m,2H),6.92(d,J=8.4Hz,1H),6.4(d,J=8.4Hz,1H),4.6-4.68(m,1H),3.77(s,2H),3.71(s,3H),3.26-3.48(m,2H),2.16-2.25(m,1H),1.9-2.03(m,3H);MS(APCI+):441.1(M+1),LC-MS:97.8%.
合成A-066
A-066[MCLS1486-130-2]合成(S)-1-[5-(3′-氯-2-氟-6-甲氧基-联苯-3-基甲基)-吡啶-2-基]-氮杂环丁烷-2-羧酸:
向5-(3′-氯-2-氟-6-甲氧基-联苯-3-基甲基)-2-氟-吡啶(Int-32)(0.2g,0.58mmol)和L-氮杂环丁烷-2-羧酸(2)(0.18g,1.74mmol)中加入1,8-二氮杂双环[5.4.0]十一-7-烯(DBU)(0.44g,2.89mmol)。将反应混合物搅拌,并在160℃下加热20min。冷却至室温,用二氯甲烷(8mL)稀释,用0.5N HCl(2×4mL)洗涤,用Na2SO4干燥,过滤并浓缩。将残余物用5%甲醇/二氯甲烷经硅胶柱色谱纯化,以得到0.042g(17%)作为灰白色固体的A-066。1HNMR(DMSO-d6,400MHz):7.98(d,J=2.0Hz,1H),7.39-7.48(m,3H),7.37(s,1H),7.24-7.3(m,2H),6.92(d,J=8.4Hz,1H),6.4(d,J=8.4Hz,1H),4.58(dd,J=9.2,6.4Hz,1H),3.7-3.9(m,2H),3.8(s,2H),3.72(s,3H),2.3-2.55(m,2H);MS(APCI+):427.1(M+1),LC-MS:100%。
合成A-067
A-067[MCLS1486-143-1]合成1-[5-(3′-氯-6-甲氧基-联苯-3-基甲基)-吡啶-2-基]-氮杂环丁烷-2-羧酸乙酸盐:
向5-(3′-氯-6-甲氧基-联苯-3-基甲基)-2-氟-吡啶(Int-41,以与Int-32类似的方式制备)(0.27g,0.82mmol)和氮杂环丁烷-2-羧酸(2)(0.12g,1.24mmol)中加入1,8-二氮杂双环[5.4.0]十一-7-烯(DBU)(0.63g,4.12mmol)。将反应混合物搅拌,并在160℃下加热30min。冷却至室温,用二氯甲烷(8mL)稀释,用0.5N HCl(2×4mL)洗涤,用Na2SO4干燥,过滤并浓缩。将残余物用5%甲醇/二氯甲烷经硅胶柱色谱纯化,以得到0.1g灰白色固体。将固体溶于乙酸(5mL)中,冻干以得到0.102g(30%)作为灰白色固体的A-067。1H NMR(DMSO-d6,400MHz):8.02(d,J=2.0Hz,1H),7.36-7.5(m,5H),7.14-7.22(m,2H),7.04(d,J=8.4Hz,1H),6.38(d,J=8.4Hz,1H),4.58(dd,J=8.8,6.8Hz,1H),3.7-3.9(m,2H),3.79(s,2H),3.73(s,3H),2.3-2.55(m,2H),1.91(s,3H);MS(APCI+):409.1(M+1),LC-MS:100%。
合成A-068
A-068[MCLS1486-147-2]合成(S)-1-[5-(3′-氯-6-甲氧基-联苯-3-基甲基)-吡啶-2-基]-吡咯烷-2-羧酸:
向5-(3′-氯-6-甲氧基-联苯-3-基甲基)-2-氟-吡啶(Int-41)(0.15g,0.46mmol)和(S)-吡咯烷-2-羧酸(2)(0.11g,0.92mmol)中加入1,8-二氮杂双环[5.4.0]十一-7-烯(DBU)(0.35g,2.29mmol)。将反应混合物搅拌,并在160℃下加热20min。冷却至室温,用二氯甲烷(8mL)稀释,用0.5N HCl(2×4mL)洗涤,用Na2SO4干燥,过滤并浓缩以得到0.19g(98%)作为浅黄色固体的A-068。1H NMR(DMSO-d6,400MHz):7.96(d,J=1.2Hz,1H),7.78(br s,1H),7.36-7.54(m,4H),7.24-7.27(m,2H),7.06(d,J=8.8Hz,1H),6.84(br s,1H),4.65-4.7(m,1H),3.86(s,2H),3.76(s,3H),3.45-3.65(m,2H),1.85-2.3(m,4H);MS(APCI+):423.2(M+1),LC-MS:95.8%。
合成A-069
A-069.[MCLS1486-144-1]合成(S)-1-[5-(3′-氯-2-氟-6-甲氧基-联苯-3-基甲基)-吡啶-2-基]-吡咯烷-2-羧酸甲酯:
向在甲醇(2.5mL)中的A-063(0.1g,0.22mmol)中加入浓硫酸(0.1mL)。将反应混合物搅拌,并在60℃下加热2h。冷却至室温,浓缩。加入水(5mL),并用二氯甲烷(2×6mL)萃取产物,用盐水(4mL)洗涤,用Na2SO4干燥,过滤并浓缩,以得到0.088g(90%)作为白色固体的A-069。1H NMR(DMSO-d6,400MHz):7.91(d,J=2.0Hz,1H),7.75(br s,1H),7.41-7.48(m,2H),7.26-7.38(m,3H),6.95(d,J=8.8Hz,1H),6.9(br s,1H),4.7-4.8(m,1H),3.89(s,2H),3.73(s,3H),3.66(s,3H),3.45-3.65(m,2H),1.85-2.35(m,4H);MS(APCI+):455.1(M+1),LC-MS:94.1%。
合成A-072
A-072.[MCLS1486-184-1]合成(R)-1-[5-(3′-氯-2-氟-6-甲氧基-联苯-3-基甲基)-吡啶-2-基]-吡咯烷-2-羧酸:
向5-(3′-氯-2-氟-6-甲氧基-联苯-3-基甲基)-2-氟-吡啶(Int-32)(0.15g,0.43mmol)和(R)-吡咯烷-2-羧酸(2)(0.1g,0.87mmol)中加入1,8-二氮杂双环[5.4.0]十一-7-烯(DBU)(0.33g,2.17mmol)。将反应混合物搅拌,并在160℃下加热20min。冷却至室温,用二氯甲烷(8mL)稀释,用0.5N HCl(2×4mL)洗涤,用Na2SO4干燥,过滤并浓缩。将残余物用5%甲醇/二氯甲烷经硅胶柱色谱纯化,以得到0.14g(73%)作为白色固体的A-072。1H NMR(DMSO-d6,400MHz):7.93(d,J=2.4Hz,1H),7.34-7.46(m,4H),7.26-7.3(m,2H),6.91(d,J=8.4Hz,1H),6.4(d,J=8.8Hz,1H),4.35(dd,J=9.2,2.8Hz,1H),3.77(s,2H),3.72(s,3H),3.3-3.48(m,2H),2.15-2.25(m,1H),1.9-2.06(m,3H);MS(APCI+):441.1(M+1),LC-MS:98.0%。
合成A-074
A-074[MCLS1621-033-2]合成{[5-(3′-氯-2-氟-6-甲氧基-联苯-3-基甲基)-吡啶-2-基]-甲基-氨基}-乙酸:
向5-(3′-氯-2-氟-6-甲氧基-联苯-3-基甲基)-2-氟-吡啶(Int-32)(0.15g,0.43mmol)和肌氨酸(2)(0.08g,0.87mmol)中加入1,8-二氮杂双环[5.4.0]十一-7-烯(DBU)(0.33g,2.17mmol)。将反应混合物搅拌,并在160℃下加热35min。冷却至室温,用二氯甲烷(8mL)稀释,用0.5N HCl(2×4mL)洗涤,用Na2SO4干燥,过滤并浓缩。将残余物用5-10%甲醇/二氯甲烷经硅胶柱色谱纯化,以得到0.09g(50%)作为灰白色固体的A-074。1H NMR(DMSO-d6,400MHz):7.94(d,J=2.4Hz,1H),7.24-7.48(m,6H),6.91(d,J=8.8Hz,1H),6.56(d,J=8.4Hz,1H),4.16(s,2H),3.77(s,2H),3.71(s,3H),2.99(s,3H);MS(APCI+):416.6(M+1),LC-MS:100%。
合成A-077
A-077[MCLS1621-059-1]合成{[5-(3′-氯-6-甲氧基-联苯-3-基甲基)-吡啶-2-基]-甲基-氨基}-乙酸:
向5-(3′-氯-6-甲氧基-联苯-3-基甲基)-2-氟-吡啶(Int-41)(0.12g,0.37mmol)和肌氨酸(2)(0.07g,0.73mmol)中加入1,8-二氮杂双环[5.4.0]十一-7-烯(DBU)(0.283g,1.8mmol)。将反应混合物搅拌,并在150℃下加热40min。冷却至室温,用二氯甲烷(8mL)稀释,用0.5N HCl(2×4mL)洗涤,用Na2SO4干燥,过滤并浓缩。将残余物用5-10%甲醇/二氯甲烷经硅胶柱色谱纯化,以得到0.11g(74%)作为浅绿色固体的A-077。1H NMR(DMSO-d6,400MHz):7.9(d,J=2.0Hz,1H),7.36-7.5(m,5H),7.18-7.22(m 2H),7.03(d,J=8.4Hz,1H),6.56(d,J=8.8Hz,1H),4.2(s,2H),3.77(s,2H),3.73(s,3H),2.99(s,3H);MS(APCI+):397.1(M+1),LC-MS:100%。
合成A-070
A-070[MCLS1546-013-2]合成5′-(3′-氯-2-氟-6-甲氧基-联苯-3-基甲基)-3,4,5,6-四氢-2H-[1,2′]联吡啶-3-羧酸:
在配有搅拌棒的8mL小瓶中加入Int-32(200mg,0.578mmol)、哌啶-3-羧酸(224mg,1.73mmol)和1,8-二氮杂双环[5.4.0]十一-7-烯(DBU)(407μL,2.89mmol)。将混合物在160℃下加热1小时,然后冷却至室温。将反应混合物用水(4mL)和1M HCl(6mL)处理。用二氯甲烷(2×30mL)萃取水相部分,将有机部分合并,用盐水(15mL)洗涤,干燥(MgSO4)并浓缩。将粗品用10%异丙醇/DCM作为洗脱剂,经硅胶柱色谱纯化,以38%的收率得到100mg作为浅黄色粘性油状物的A-070。1H NMR(400MHz,DMSO-d6)δ1.04(d,J=6Hz,2H),1.58-1.67(m,1H),1.91-1.95(m,1H),2.35-2.42(m,1H),2.87-2.98(m,2H),3.72(s,3H),3.78(s,2H),3.95(bd,J=12Hz,1H),4.26(dd,J=13,4Hz,1H),6.78(d,J=9Hz,1H),6.92(d,J=8Hz,1H),7.26-7.30(m,2H),7.35(d,J=3Hz,1H),7.37(s,1H),7.41-7.47(m,2H),8.00(d,J=2Hz,1H),12.27(bs,1H).MS(APCI+):455.2(M+1),LC-MS:97%。
合成A-075
(Int-42)[MCLS1544-032-4]
3-溴-4-二氟甲氧基-苯甲醛
向配有机械搅拌器和加热套的5L圆底烧瓶中加入3-溴4-羟基苯甲醛(100.5g,0.50mol)、Cs2CO3(244.4g,0.75mol)、一氯二氟乙酸钠(190.6g,1.25mol)和DMF(1L)。将反应在65℃下搅拌1小时,然后冷却至约35℃。在10分钟内通过分液漏斗将反应混合物加入12L冰水中。将混合物搅拌1小时,然后通过玻璃粉(glass frit)过滤固体。用2×500mL水洗涤滤饼,然后在40℃下真空干燥18小时,之后在真空干燥器中干燥5天。得到作为棕褐色固体的标题产物(65.7g,52%)。
1H NMR(400MHz,DMSO-d6)δ=9.96(s,1H),8.26(d,J=1.7Hz,1H),8.00(dd,J=1.9,8.5Hz,1H),7.54(d,J=8.5Hz,1H),7.49(t,J=72.6Hz,1H)。
(Int-43)[MCLS1544-058-1]
3′-氯-6-二氟甲氧基-联苯-3-醛
向5L三颈圆底烧瓶中加入Int-42(58.4g,232.6mmol)、3-氯苯基硼酸(40.0g,255.9mmol)、DMF(1.17L)和2M Cs2CO3水溶液(233mL,464.2mmol)。通过通入N2气将悬浮液脱气30min,然后加入Pd(OAc)2(5.3g,23.3mmol)。在1小时内将混合物缓慢升温至50℃,冷却至室温,然后通过硅藻土过滤,用DMF洗涤。向滤液中加入2L水,并用4×750mL EtOAc萃取产物。用1L盐水洗涤合并的有机相,用Na2SO4干燥,然后浓缩。将残余物通过200g SiO2短柱(用15%丙酮/己烷洗脱),然后浓缩以得到作为红色油状物的标题化合物,将其直接使用。
(Int-44)[MCLS1544-063-1和MCLS1544-063-2]
(3′-氯-6-二氟甲氧基-联苯-3-基)-甲醇
在配有磁搅拌棒的3L圆底烧瓶中加入Int-43(78.1g,276.5mmol)、THF(500mL)和水(500mL)。将浑浊溶液冷却至0℃,然后在15分钟内分四批加入NaBH4(15.7g,414.8mmol)。再搅拌15分钟后,分离各层。用2×500mL EtOAc萃取水层,将有机层合并,用盐水洗涤,并浓缩。将残余物用5-20%丙酮/己烷洗脱,经快速柱色谱纯化,以得到作为接近无色油状物的标题化合物(43.3g,65%,2步)。1H NMR(400MHz,DMSO-d6)=7.56-7.38(m,6H),7.27(d,J=9.0Hz,1H),7.14(t,J=73.9Hz,1H),5.28(t,J=5.8Hz,1H),4.54(d,J=5.6Hz,2H)。
(Int-45)[MCLS1546-097-1]合成碳酸-3′-氯-6-二氟甲氧基-联苯-3-基甲酯
按照与Int-21所述相同的步骤。以75%的收率分离出1.55g作为白色固体的Int-45。
A-075[MCLS1546-083-1]合成5-(3′-氯-6-二氟甲氧基-联苯-3-基甲基)-吡啶-2-羧酸甲酯:
在配有搅拌棒的40mL小瓶中加入Int-45(700mg,2.04mmol)、5-(4,4,5,5-四甲基-[1,3,2]二氧杂环戊硼烷-2-基)-吡啶-2-羧酸甲酯(590mg,2.24mmol)、碳酸钾(846mg,6.12mmol)、1,5-双(二苯基膦基)戊烷(270mg,0.612mmol)和DMF(10mL)。通过吹入氮气将反应混合物脱气15分钟,然后加入氯化烯丙基钯(II)二聚体(112mg,0.306mmol)。将反应混合物在85℃下加热4小时。向反应混合物中加入水(40mL)和乙酸乙酯(40mL),并通过硅藻土过滤混合物。将滤液层分离,并用乙酸乙酯(40mL)萃取水相部分。合并有机部分,用盐水(40mL)洗涤,干燥(MgSO4)并浓缩。将粗产物用12-100%乙酸乙酯/己烷梯度洗脱,经50克硅胶SNAP柱(Biotage SP4FlashChromatography仪器)纯化,以56%的收率得到458mg作为黄色粘性固体的A-075。
1H NMR(400MHz,DMSO-d6)δ3.86(s,3H),4.12(s,2H),7.13(t,J=74Hz,1H),7.25(d,J=8Hz,1H),7.37(dd,J=8,2Hz,1H),7.57(dt,J=7,2Hz,1H),7.44-7.52(m,4H),7.88(dd,J=8,2Hz,1H),7.99(d,J=8Hz,1H),8.71(s,1H)。
MS(APCI+):404.5(M+1)LC/MS:98%。
合成A-076
(Int-46)[MCLS2544-064-1]
5-溴甲基-3′-氯-2-二氟甲氧基-联苯
向配有磁搅拌棒的2L圆底烧瓶中加入Int-44(39.6g,139.1mmol)、DCM(500mL),并将溶液冷却至0℃。加入PPh3(73.0g,278.2mmol)和NBS(49.5g,278.2mmo1),并将溶液搅拌30分钟。用2×500mL水、500mL盐水洗涤溶液,用Na2SO4干燥,并浓缩。经快速柱色谱(15%丙酮/己烷)纯化,得到作为无色油状物的标题化合物(43.5g,90%)。1H NMR(400MHz,DMSO-d6)=7.62-7.38(m,5H),7.37(s,1H),7.31(d,J=8.3Hz,1H),7.21(t,J=73.7Hz,1H),4.77(s,2H)。
(Int-47)[MCLS1546-052-2]合成5-(3′-氯-6-二氟甲氧基-联苯-3-基甲基)-吡啶-2-腈:
在配有搅拌棒的40mL小瓶中加入Int-46(1.0g,2.88mmol)、5-(4,4,5,5-四甲基-[1,3,2]二氧杂环戊硼烷-2-基)-吡啶-2-腈(729mg,3.17mmol)、四(三苯基膦)钯(166mg,0.144mmol)、乙醇(4.4mL)和甲苯(17.6mL)。搅拌5分钟后,加入2M碳酸钠水溶液(2.88mL),并通过在混合物中通入氮气将反应混合物脱气。在80℃下加热2.5小时后,通过硅藻土将反应过滤,并将滤液用水(40mL)稀释,并且用乙酸乙酯(2×60mL)萃取。将有机部分合并,干燥(MgSO4),浓缩,并用40%乙酸乙酯/己烷作为洗脱剂经硅胶柱色谱纯化,以80%的收率得到859mg作为黄色粘性油状物的Int-47。
A-076[MCLS1546-084-2]合成5-(3′-氯-6-二氟甲氧基-联苯-3-基甲基)-2-(1H-四唑-5-基)-吡啶盐酸盐:
在配有搅拌棒的8mL小瓶中加入Int-47(150mg,0405mmol)、叠氮化钠(29.0mg,0.466mmol)、氯化铵(23.9mg,,0.466mmol)和二甲基甲酰胺(700μL)。将溶液在100℃下加热5小时,然后将无机盐滤除。将反应混合物浓缩,加入水(3mL)和1M HCl(3mL)。收集半固体并干燥,以定量收率得到167mg作为灰白色固体的A-076(游离碱)。向A-076(游离碱)(140mg,0.341mmol)中加入***(3mL)和在***(800μL)中的2M HCl。将混合物在室温下搅拌10分钟,浓缩并干燥,以86%的收率得到131mg作为白色固体的A-076。
1H NMR(400MHz,DMSO-d6)δ4.15(s,2H),7.13(t,J=74Hz,1H),7.27(d,J=8Hz,1H),7.40-7.53(m,6H),7.98(dd,J=8,2Hz,1H),8.16(d,J=8Hz,1H),8.81(D,J=2Hz,1H)。
合成A-078和A-079
(Int-48)[MCLS1546-091-1]合成5-(3′-氯-6-二氟甲氧基-联苯-3-基甲基)-2-氟-吡啶
以与A-075类似的方式制备。以70%的收率分离出372mg略带暗黄色的作为粘性油状物的Int-48。
A-078[MCLS1546-096-1]合成{[5-(3′-氯-6-二氟甲氧基-联苯-3-基甲基)-吡啶-2-基]-甲基-氨基}-乙酸:
在配有搅拌棒的8mL小瓶中加入Int-48(190mg,0.522mmol)、N-甲基甘氨酸(140mg,1.57mmol)和1,8-二氮杂二环[5.4.0]十一-7-烯(368μL,2.61mmol)。将混合物在160℃下加热35分钟,然后用DCM(15mL)洗脱。用0.5M HCl(3×10mL)洗涤有机部分,合并水洗液,并用DCM(15mL)萃取。合并有机部分,干燥(MgSO4)并浓缩。将粗品用10%异丙醇/DCM(含有1%AcOH)作为洗脱剂,经硅胶柱色谱纯化,以8%的收率得到17mg作为浅绿色固体的A-078。
1H NMR(400MHz,DMSO-d6)δ2.99(s,3H),3.83(s,2H),4.20(s,2H),6.58(d,J=8Hz,1H),7.10(t,J=74Hz,1H),7.21(d,J=8Hz,1H),7.30(dd,J=9,2Hz,1H),7.37(d,J=2Hz,1H),7.40-7.51(m,5H),8.01(d,J=2Hz,1H),12.37(s,1H)。
MS(ESI+):435.0(M+2),LC/MS:97%。
A-079[MCLS1546-101-1]合成(R)-2-{[5-(3′-氯-6-二氟甲氧基-联苯-3-基甲基)-吡啶-2-基]-甲基-氨基}-丙酸:
在配有搅拌棒的8mL小瓶中加入Int-48(173mg,0.476mmol)、N-α-甲基-D-丙氨酸HCl(199mg,1.43mmol)和1,8-二氮杂二环[5.4.0]十一-7-烯(403μL,2.86mmol)。将混合物在160℃下加热35分钟,然后用DCM(15mL)洗脱。用0.5M HCl(3×10mL)洗涤有机部分,合并水洗液,并用DCM(15mL)萃取。合并有机部分,干燥(MgSO4)并浓缩。将粗品用10%异丙醇/DCM(含有1%AcOH)作为洗脱剂,经硅胶柱色谱纯化,以得到56mg仍含有杂质的黄色固体。将不纯品用10%异丙醇/DCM作为洗脱剂,经制备TLC(20×20cm,1500微米)纯化,以4%的收率得到18mg作为黄色固体的A-078。
1H NMR(400MHz,DMSO-d6)δ1.35(t,J=8Hz,3H),2.84(s,3H),3.84(s,2H),3.94(q,J=7Hz,1H),6.59(d,J=9Hz,1H),7.10(t,J=74Hz,1H),7.21(d,J=8Hz,1H),7.29-7.32(m,2H),7.37(d,J=2Hz,1H),7.40-7.51(m,4H),8.01(d,J=2Hz,1H),12.37(bs,1H)。MS(APCI+):447.1(M+1)。
合成A-073
A-073[MCLS1475-133-2]合成5-(3′-氯-6-甲氧基-联苯-3-基甲基)-吡啶-2-羧酸甲酯
在氮气中,向在DME(30mL)中含有碳酸-3′-氯-6-甲氧基-联苯-3-基甲酯(Int-49,以与Int-021类似的方式制备,2.0g,6.6mmol)和5-(4,4,5,5-四甲基-[1,3,2]二氧杂环戊硼烷-2-基)-吡啶-2-羧酸甲酯(1.6g,6mmol)的250mL烧瓶中在室温下加入K2CO3(2.5g,18mmol)、[Pd(y3C3H5Cl)]2(300mg,0.8mmol)和DPPPent(800mg,1.9mmol)。将反应混合物在85℃下加热,并在85℃下搅拌16h。将反应混合物冷却至室温,倒入冰水(200mL)中,将所形成的半固体从水层中分离以得到粗产物,将其用二氯甲烷-丙酮作为洗脱剂经硅胶色谱纯化,以得到标题化合物(1200mg,50%)。1H NMR(氯仿-d,400MHz):δ=8.64(s,1H),8.05(d,J=8.0Hz,1H),7.62(d,J=8.0Hz,1H),7.47(s,1H),7.29-7.36(m,2H),7.11(d,J=8.0Hz,1H),7.09(d,J=2.0Hz,1H),6.93(d,J=8.4Hz,1H),4.04(s,2H),3.99(s,3H),3.80(s,3H)。LC/MS:计算值367.84;APCI+(M+1):368.1,99%。
合成A-058
Int-50[MCLS1426-077-1]合成(3′-氯-2-氟-6-甲氧基-联苯-3-基)-乙腈:
将Int-20(15.2mmol;1.0eq.)和***(22.8mmol;1.5eq.)在含水异丙醇中的悬浮液回流1小时。将反应冷却至室温,并浓缩以除去异丙醇。用2份乙酸乙酯萃取所得的水层,并依次用水和盐水洗涤有机物,并用硫酸镁干燥。将残余物用10%丙酮/己烷作为洗脱剂经快速硅胶色谱纯化,以57%的收率得到作为白色固体的标题化合物。
(1HNMR,CDCl3;400MHz):3.80(s,3H),3.93(s,2H),6.80(dd,J=8.8,1.6Hz,1H),7.26(m,1H),7.35-7.41(M,4H)。
A-058MCLS1471-166-1
5-(3′-氯-2-氟-6-甲氧基-联苯-3-基甲基)-1H-四唑
向18mL小瓶中加入Int-50(138mg,0.50mmol)、NH4Cl(187mg,3.50mmol)、NaN3(65mg,1.00mmol)和DMF(4mL)。将反应在80℃下搅拌4小时,然后在100℃下搅拌18小时。通过玻璃粉及SiO2短柱过滤悬浮液,然后浓缩。将残余物用25-50%丙酮/己烷洗脱,经快速柱色谱纯化。将固体在50℃的真空箱中干燥8小时,在室温下干燥18小时。得到作为棕褐色固体的标题化合物(25mg,16%)。1H NMR(400MHz,DMSO-d6)δ=16.19(br.s.,1H),7.50-7.40(m,2H),7.40-7.33(m,2H),7.29(d,J=6.6Hz,1H),6.99(d,J=8.6Hz,1H),4.27(s,2H),3.75(s,3H)。LC/MS=98.7%,317.0(APCI+)。
合成A-071
Int-52 MCLS1544-062-1
5-(3′-氯-6-甲氧基-联苯-3-基甲基)-吡啶-2-羧酸甲酯
向250mL圆底烧瓶中加入5-溴甲基-3′-氯-2-甲氧基-联苯(Int-51,以与Int-20类似的方式制备,4.89g,15.69mmol)、5-(1,5-二甲基-2,4-二氧杂-3-硼杂-二环[3.1.0]己-3-基)-吡啶-2-羧酸甲酯(4.52g,17.26mmol)、甲苯(120mL)、EtOH(20mL)、水(20mL)和K3PO4(6.66g,31.38mmol)。用N2将悬浮液脱气15分钟,然后加入Pd(PPh3)4(1.81g,1.57mmol),并在80℃下将反应搅拌1小时。分离各层,并用50mL EtOAc萃取水层。合并有机物,并用50mL盐水洗涤,用Na2SO4干燥,并浓缩。将残余物用10%丙酮/己烷洗脱,经快速柱色谱纯化,以得到作为浅黄色油状物的标题化合物(0.89g,15%)。
A-071 MCLS1544-068-1
5-(3′-氯-6-甲氧基-联苯-3-基甲基)-吡啶-2-羧酸
向18mL小瓶中加入Int-52(185mg,0.50mmol)、EtOH(4mL)和1NNaOH(4mL)。在室温下搅拌1小时后,将EtOH蒸发。用浓HCl将pH调节至约为4,将所得固体过滤,并在50℃真空箱中干燥4小时。得到作为白色固体的标题化合物(99mg,56%)。1H NMR(400MHz,DMSO-d6)δ=8.66(d,J=1.6Hz,1H),7.96(d,J=7.9Hz,1H),7.82(dd,J=1.9,7.9Hz,1H),7.50(s,1H),7.46-7.34(m,3H),7.31-7.22(m,2H),7.12-7.03(m,1H),4.05(s,2H),3.75(s,3H)。
合成A-059和A-060
Int-53和Int-54
(Int-53)1-(3′-氯-2-氟-6-甲氧基-联苯-3-基甲基)-1H-咪唑-4-羧酸甲酯
(Int-54)1-(3′-氯-2-氟-6-甲氧基-联苯-3-基甲基)-1H-咪唑-2-羧酸甲酯
向18mL小瓶中加入4-咪唑羧酸甲酯(113mg,0.90mmol)、DMF(3mL)和NaH(43mg,1.08mmol)。20分钟后,在室温下加入Int-20(295mg,0.90mmol)。将反应在室温下搅拌2小时,然后加入水。用EtOAc萃取产物,并浓缩有机物。将残余物用6%-10%丙酮/DCM洗脱,经快速柱色谱纯化,以分离位置异构体。得到作为无色油状物的4-取代酯(Int-53,67mg,20%)和2-取代酯(Int-54,79mg,23%)。
A-059
1-(3′-氯-2-氟-6-甲氧基-联苯-3-基甲基)-1H-咪唑-4-羧酸
在8mL小瓶中加入Int-53(31mg,0.08mmol)、EtOH(1mL)和2NNaOH(1mL)。在室温下搅拌2小时,将EtOH蒸发。用浓HCl将pH调节至约为5,产生白色沉淀。将固体过滤并在50℃真空箱中干燥2小时,以得到作为白色固体的标题化合物(6mg,20%)。1H NMR(400MHz,DMSO-d6)δ=7.80(s,2H),7.50-7.36(m,4H),7.29(d,J=6.2Hz,1H),7.02(d,J=8.7Hz,1H),5.26(s,2H),3.75(s,3H)。MS=361.1(APCI+)。
A-060 MCLS1471-180-1
3-(3′-氯-2-氟-6-甲氧基-联苯-3-基甲基)-3H-咪唑-4-羧酸
向8mL小瓶中加入Int-54(38mg,0.10mmol)、EtOH(1mL)和2NNaOH(1mL)。在室温下搅拌2小时,将EtOH蒸发。用浓HCl将pH调节至约为5,产生白色沉淀。将固体过滤并在50℃真空箱中干燥2小时,以得到作为白色固体的标题化合物(17mg,47%)。1H NMR(400MHz,DMSO-d6)δ=12.87(br.s.,1H),7.97(s,1H),7.61(s,1H),7.50-7.42(m,2H),7.39(s,1H),7.30(d,J=6.4Hz,1H),7.08-6.99(m,1H),6.98-6.91(m,1H),5.55(s,2H),3.73(s,3H)。LC/MS=361.1(APCI+).
合成A-030和A-031
Int-55.[MCLS1426-108-1]合成5-(3′-氯-2-氟-6-甲氧基-联苯-3-基甲基)-[1,3,4]噻二唑-2-基胺
将Int-50(0.998mmol,1.0eq.)和氨基硫脲(2.99mmol,3eq.)在过量三氯氧磷中的混合物在120℃下加热45分钟,并将其冷却至室温。将所得混合物加入水中,并用2份乙酸乙酯萃取。将有机物用盐水洗涤,并用硫酸钠干燥。将残余物用在5%(MeOH中的1N NH3)/二氯甲烷作为洗脱剂,经快速色谱纯化,以39%的收率得到标题化合物。
(1HNMR,DMSO-d6;400MHz):3.75(s,3H),4.17(s,2H),6.98(d,J=8.0Hz,1H),7.29(d,J=6.4Hz,1H),7.37-7.41(M,2H),7.43-7.49(M,2H),7.58-7.76(bs,2H)。
A-030 MCLS1430-143-1
4-{3-[5-(3′-氯-2-氟-6-甲氧基-联苯-3-基甲基)-[1,3,4]噻二唑-2-基]-脲基}-丁酸乙酯
在室温下,向Int-55(125mg,0.36mmol)在吡啶(0.5mL)中的溶液中加入4-异氰酸酯基-丁酸乙酯(136μL,0.89mmol)。将所得溶液在室温下搅拌18小时,然后在50℃下搅拌24小时。向该溶液中加入10mL水,并将产物用3×15mL EtOAc萃取,并用Na2SO4干燥合并的有机物,然后浓缩。向黄色油状物中加入5mL***,并将溶液在室温下静置18小时。将所得固体过滤,用***洗涤并干燥,以得到作为白色固体的标题化合物(66mg,36%)。1H NMR(400MHz,氯仿-d)δ10.72(s,1H),7.48-7.37(m,4H),7.30-7.28(m,1H),6.99(d,J=8.4Hz,1H),6.91(bs,1H),4.26(s,2H),4.03(q,J=7.1Hz,2H),3.75(s,3H),3.12(q,J=6.0Hz,2H),2.28(t,J=7.6Hz,2H),1.66(quin,J=7.6Hz,2H),1.15(t,J=7.0Hz,3H)。LC/MS=91.1%,507.0(APCI+)。
A-031 MCLS1430-150-1
4-{3-[5-(3′-氯-2-氟-6-甲氧基-联苯-3-基甲基)-[1,3,4]噻二唑-2-基]-脲基}-丁酸
向A-030(35mg,0.069mmol)在THF(0.5mL)中的溶液中加入1M氢氧化锂水溶液(345μL,0.35mmol)。将反应在室温下搅拌1小时。用氮气流除去THF,并用6N HCl将所得的水溶液酸化至pH 1-2。在室温下搅拌30分钟,将所得固体过滤,用水洗涤,并在50℃的真空箱中干燥4小时。得到作为棕褐色固体的标题化合物(19.8mg,60%)。1H NMR(400MHz,氯仿-d)δ10.78(bs,1H),7.48-7.38(m,3H),7.30-7.28(m,1H),6.99(d,J=8.0Hz,1H),6.94(bs,1H),4.26(s,2H),3.75(s,3H),3.12(q,J=6.7Hz,2H),2.21(t,J=7.4Hz,2H),1.65(t,quin=7.0Hz,2H)。
合成A-002
A-002[MCLS1226-178-1]合成2-(6-甲氧基-3′-硝基-联苯-3-基甲基)-1,1-二氧代-1,2-二氢-1λ*6*-苯并[d]异噻唑-3-酮
在-78℃下,向Int-02(161mg,0.500mmol)和糖精(183mg,1.00mmol)在二甲基甲酰胺(1.5mL)中的溶液中加入氢化钠(60重量%分散体,40mg,1.00mmol)。在氢气逸出结束后,将反应在120℃下搅拌过夜。将反应混合物过滤,并减压浓缩滤液。用乙酸乙酯(15mL)稀释残余物,用水、盐水洗涤,用硫酸钠干燥,过滤,并真空除去溶剂。将产物通过用己烷(50mL)和乙酸乙酯(5mL)研磨进行纯化,以得到A-002(190mg,收率90%)。1H NMR(400MHz,氯仿-d)δ3.83(s,3H)4.92(s,2H)6.99(d,J=8.45Hz,1H)7.46-7.61(m,3H)7.78-7.98(m,4H)8.06(d,J=7.11Hz,1H)8.17(dd,J=8.25,1.41Hz,1H)8.42(t,J=1.74Hz,1H)。
LCMS=94%纯度。
合成A-040
A-040[MCLS1448-152-1]合成1-[5-(3′-氯-2-氟-6-甲氧基-联苯-3-基甲基)-嘧啶-2-基]-吡咯烷-2-羧酸
将Int-29(100mg,0.28mmol)、吡咯烷-2-羧酸叔丁酯(72mg,0.42mmol)和二异丙基乙胺(0.15mL,0.84mmol)在2-甲基-1-丙醇(1mL)中的溶液在80℃下搅拌4天。将反应冷却至室温,并真空浓缩。向粗品中加入四氢呋喃(5mL)和1M氢氧化锂水溶液(0.56mL,0.56mmol),并将该溶液在80℃下加热过夜。将反应冷却至室温,并用2N盐酸水溶液酸化至pH 3。向反应中加入三氟乙酸(0.84mmol),并将反应在80℃下加热过夜。将反应冷却至室温,并真空浓缩,并将残余物经硅胶柱色谱(2∶1己烷/乙酸乙酯)纯化,以得到作为白色固体的A-040(49.1mg,收率35%)。1H NMR(400MHz,氯仿-d)=8.32(br.s.,2H),7.40-7.30(m,3H),7.14(t,J=8.6Hz,1H),6.74(d,J=8.5Hz,1H),4.59-4.51(m,1H),3.83(s,2H),3.77(s,3H),3.75-3.66(m,1H),3.65-3.55(m,1H),2.13-2.02(m,4H)。LC/MS=95%,442.0(APCI+)。
合成A-044
A-041[MCLS1448.155-3]合成1-[5-(3′-氯-2-氟-6-甲氧基-联苯-3-基甲基)-嘧啶-2-基]-哌啶-2-羧酸
将Int-29(100mg,0.28mmol)、哌啶酸(54mg,0.42mmol)和二异丙基乙胺(0.15mL,0.84mmol)在2-甲基-1-丙醇(1mL)中的溶液在80℃下搅拌过夜。将反应冷却至室温,并真空浓缩。将粗产物经硅胶柱色谱(20∶1二氯甲烷/甲醇)纯化,在二氯甲烷/己烷中研磨,以得到作为乳膏状无色固体的A-041(36.5mg,收率29%)。
1H NMR(400MHz,氯仿-d)δppm 1.56(br.s.,1H)1.71-1.87(m,2H)2.17(s,2H)2.50-2.68(m,1H)3.05-3.15(m,1H)3.26(dd,J=13.28,10.06Hz,1H)3.71-3.80(m,5H)4.45(d,J=13.15Hz,1H)4.69(dd,J=13.35,3.56Hz,1H)6.70(d,J=8.45Hz,1H)7.10(t,J=8.52Hz,1H)7.29-7.41(m,3H)8.22(s,2H)。LCMS=97%。
合成A-044
A-045[MCLS1448-154-4]合成1-[5-(3′-氯-2-氟-6-甲氧基-联苯-3-基甲基)-嘧啶-2-基]-吡咯烷-3-羧酸甲酯
将Int-29(100mg,0.28mmol)、吡咯烷-2-羧酸甲酯(70mg,0.42mmol)和二异丙基乙胺(0.15mL,0.84mmol)在2-甲基-1丙醇(1mL)中的混合物在80℃下搅拌过夜。将反应冷却,并真空除去溶剂。将粗产物经硅胶柱色谱(4∶1己烷/乙酸乙酯,2∶1己烷/乙酸乙酯)纯化2次,以得到A-045(44.7mg,收率35%)。1H NMR(400MHz,氯仿-d)=8.21(s,2H),7.40-7.29(m,3H),7.08(t,J=8.6Hz,1H),6.69(d,J=8.5Hz,1H),3.88-3.74(m,3H),3.76(s,2H),3.75(s,3H),3.72(s,3H),3.63-3.53(m,1H),3.19(quin,J=7.4Hz,1H),2.33-2.22(m,2H)。LC/MS=94.7%,456.1(APCI+)。
A-044[MCLS1448-162-1]合成1-[5-(3′-氯-2-氟-6-甲氧基-联苯-3-基甲基)-嘧啶-2-基]-吡咯烷-3-羧酸
将Int-29(35mg,0.075mmol)和三氟乙酸(85mg,0.75mmol)在水(0.5mL)和二氯甲烷(2mL)中的混合物在室温下搅拌过夜。将反应在80℃下加热3天。用二氯甲烷(2mL)和水(1mL)稀释反应,分离,并用二氯甲烷(2×2mL)萃取水相部分。用硫酸钠干燥合并的有机萃取物,过滤并浓缩。将残余物经硅胶柱色谱(40∶1二氯甲烷/甲醇)纯化,以得到A-044(30.7mg,收率93%)。
1H NMR(400MHz,DMSO-d6)=8.26(s,2H),7.48-7.40(m,2H),7.37(s,1H),7.33-7.25(m,2H),6.93(d,J=8.6Hz,1H),3.77(s,2H),3.72(s,3H),3.67-3.60(m,2H),3.55-3.43(m,2H),3.15(quin,J=7.0Hz,1H),2.23-2.04(m,2H)。LC/MS=93.6%,442.0(APCI+)。
合成A-053
A-053[MCLS1448-159-4]合成1-[5-(3′-氯-2-氟-6-甲氧基-联苯-3-基甲基)-嘧啶-2-基]-氮杂环丁烷-3-羧酸
将Int-29(100mg,0.28mmol)、氮杂环丁烷-3-羧酸(42mg,0.42mmol)和二异丙基乙胺(0.15mL,0.84mmol)在2-甲基-1丙醇(1mL)中的混合物在80℃下搅拌过夜。将反应冷却,并真空除去溶剂。粗产物经硅胶柱色谱(18∶己烷/乙酸乙酯)纯化2次,用***/二氯甲烷研磨,并经硅胶制备薄层色谱(9∶1二氯甲烷/甲醇)纯化,以得到A-053(11.5mg,收率9.6%)。
1H NMR(400MHz,DMSO-d6)δ2.03-2.24(m,2H)3.15(t,J=6.98Hz,1H)3.25(s,1H)3.44-3.55(m,1H)3.64(t,J=6.91Hz,1H)3.72(s,2H)3.77(s,2H)6.93(d,J=8.59Hz,1H)7.25-7.34(m,2H)7.37(s,1H)7.40-7.47(m,2H)8.19-8.28(m,2H)。
合成A-049
A-049[MCLS1448-180-1]合成1-[5-(3′-氯-2-氟-6-甲氧基-联苯-3-基甲基)-嘧啶-2-基]-氮杂环丁烷-2-羧酸
将氮杂环丁烷-2-羧酸(56mg,0.56mmol)和氢化钠(60重量%分散体,33mg,0.84mmol)在二甲基甲酰胺(1mL)中的混合物搅拌至不再逸出气体。再搅拌2min后,加入Int-29(102mg,0.28mmol),并将反应在120℃下加热过夜。将反应冷却至室温,用水(15mL)稀释,并用乙酸乙酯(3×5mL)萃取。将合并的萃取物用硫酸钠干燥,过滤,并真空除去溶剂。将残余物经硅胶柱色谱(9∶1二氯甲烷/甲醇)纯化,以得到作为乳膏状固体的A-049(65.3mg,收率58%)。
1H NMR(400MHz,DMSO-d6)δ2.17-2.28(m,1H)2.55-2.67(m,1H)3.72(s,3H)3.78(s,2H)3.87-4.05(m,2H)4.63(dd,J=9.12,5.77Hz,1H)6.93(d,J=8.59Hz,1H)7.25-7.36(m,2H)7.38(s,1H)7.41-7.47(m,2H)8.25(s,2H)12.64(br.s.,1H)。LCMS=95.0%。
制备B-080
合成2-碘-3-甲氧基-6-甲基-吡啶(I-95)
向在丙酮(20mL)中的2-碘-6-甲基-吡啶-3-醇(1.0g,4.25mmol)和K2CO3(1.18g,8.51mmol)中加入MeI(0.91g,6.38mmol)。将反应在N2中,在45℃下搅拌20h。将反应冷却至室温并浓缩。将残余物用二氯甲烷经硅胶柱色谱纯化,以得到1.04g(98%)作为浅黄色固体的I-95。
合成3-甲氧基-6-甲基-2-(3-硝基-苯基)-吡啶(I-113)
向I-95(0.5g,2.0mmol)、3-硝基苯基硼酸(0.5g,3.06mmol)、三苯基膦(0.11g,0.4mmol)、K2CO3(0.83g,6.0mmol)和乙酸钯(II)(0.045g,0.2mmol)中加入DME(16mL)和EtOH-H2O(1∶1,4mL)。向搅拌中的溶液中通入氩气5分钟。在氩气下,将反应在60℃下搅拌18h。将反应冷却至室温,浓缩,并加入H2O和二氯甲烷(各40mL)。分离有机层,并用二氯甲烷(2×25mL)萃取水层。将合并的有机萃取物用Na2SO4干燥,过滤并浓缩。将残余物先后用1∶1二氯甲烷-己烷和二氯甲烷经硅胶柱色谱纯化,以得到0.22g(44%)作为浅黄色固体的I-113。
合成6-溴甲基-3-甲氧基-2-(3-硝基-苯基)-吡啶(I-114)
向在CCl4(10mL)中的I-113(0.21g,0.86mmol)和NBS(0.17g,0.95mmol)中加入过氧化苯甲酰(0.02g,0.08mmol)。在N2中,将反应在60℃下搅拌18h。将反应冷却至室温并浓缩。将残余物溶于二氯甲烷和己烷的混合物(1∶1,8mL)中,并先后用1∶1二氯甲烷-己烷和二氯甲烷经硅胶柱色谱纯化,以得到0.15g(55%)作为浅棕色固体的I-114。
合成6-(4-氟-苄基)-3-甲氧基-2-(3-硝基-苯基)-吡啶(P-023)
向I-114(0.05g,0.15mmol)、3-氟苯基硼酸(1)(0.032g,0.23mmol)、三苯基膦(0.004g,0.015mmol)、K3PO4(0.066g,0.31mmol)和乙酸钯(II)(0.002g,0.008mmol)中加入DME(1.8mL)和EtOH-H2O(1∶1,0.6mL)。使用Biotage-60Microwave Synthsizer将反应在160℃下搅拌5min。将反应冷却至室温并浓缩。将残余物先后用1∶1二氯甲烷-己烷和二氯甲烷经硅胶柱色谱纯化,以得到0.024g(46%)作为浅棕色粘性液体的P-023。1H NMR(CDCl3,400MHz):8.89(dd,J=2.0,1.6Hz,1H),8.32-8.36(m,1H),8.2-8.24(m,1H),7.59(t,J=8.4Hz,1H),7.22-7.3(m,3H),7.07(d,J=8.4Hz,1H),6.96-7.04(m,2H),4.14(s,2H),3.88(s,3H);MS(APCI+):339.1(M+1),LC-MS:100%。
6-(4-氟-苄基)-3-甲氧基-2-(3-硝基-苯基)-吡啶1-氧化物(B-080)
将化合物P-023(100mg,0.3mmole)和3-氯过氧苯甲酸(101mg,0.45mmol)在DCM(10ml)中的反应混合物在室温下搅拌过夜。将反应混合物用饱和NaHCO3(3×6ml)、水(2×8ml)洗涤,用Na2SO4干燥。除去溶剂后,用***(5ml)/己烷(5ml)洗涤残余物,以得到66mg产物B-080,收率:62%;1H-NMR(400MHz,DMSO-d6);MS(APCI+):355.1(M+1);LC-MS:97%.1HNMR(CDCl3,400MHz):d=3.79(3H,s),4.19(2H,s),6.90(1H,d,J=9.2Hz),6.98(1H,d,J=8.8Hz),7.04(2H,m),7.27(2H,m),7.64(1H,dd,J=8 and 8Hz),7.89(1H,m),8.28(1H,m),8.39(1H,m)。
合成B-081
合成1-[5-(3′-氯-2-氟-6-甲氧基-联苯-3-基甲基)-1-氧-吡啶-2-基]-3-乙基-脲(P-397)
在室温下,将P-356(82.7mg,0.200mmol)在***(5mL)中的溶液与过氧乙酸(32重量%,0.06mL,0.300mmol)搅拌3h。浓缩混合物,并将残余物用硅胶柱色谱(19∶1二氯甲烷/甲醇)纯化,以得到P-397(27.6mg,收率32%)。1H NMR(400MHz,CDCl3):1.12(t,3H)3.17-3.35(m,2H),3.72-3.80(m,3H),3.87(s,2H),6.64-6.78(m,1H),6.86(br s,1H),7.02-7.17(m,1H),7.22(s,1H),7.29-7.43(m,3H),7.93(s,1H),8.36(d,J=8.9Hz,1H),9.73(s,1H)ppm。LCMS=100%纯度。APCI(-)=428.1(M-2)。
合成B-082
合成3-溴-2-氟-4-甲氧基-苯甲醛(I-30)
在配有氮气管路和搅拌棒的250mL三颈圆底烧瓶中加入2-溴-1氟-3-甲氧基-苯(I-29,2.0g,9.75mmol)和二氯甲烷(48mL)。将溶液在冰水浴中冷却15分钟,然后加入四氯化钛(5.02mL,45.8mmol)和二氯甲基甲醚(1.32mL,14.6mmol),并将反应混合物升温至室温,反应2小时。将反应混合物缓慢加入冰水(250mL)中,并用二氯甲烷(2×100mL)萃取。将有机部分合并,用饱和碳酸氢钠溶液(75mL)、水(75mL)和盐水(75mL)洗涤,干燥(MgSO4)并浓缩。用己烷(15mL)研磨粗品,以74%的收率得到1.67g作为灰白色固体的3-溴-2-氟-4-甲氧基-苯甲醛(I-30)。MS(ESI+):233.2(M+)。
合成(3-溴-2-氟-4-甲氧基-苯基)-甲醇(I-31)
在配有搅拌棒的100mL圆底烧瓶中加入3-溴-2-氟-4-甲氧基-苯甲醛(I-30,1.67g,7.17mmol)、甲醇(12mL)、二氯甲烷(12mL)和硼氢化钠。将反应混合物在室温下搅拌17小时,用水(10mL)和1M HCl(5mL)终止反应,并用二氯甲烷(2×30mL)萃取。合并有机部分,用盐水(30mL)洗涤,干燥(MgSO4)并浓缩。用己烷(15mL)研磨粗品,以得到955mg(57%)作为白色固体的(3-溴-2-氟-4-甲氧基-苯基)-甲醇(I-31)。
合成(3′-氯-2-氟-6-甲氧基-联苯-3-基)-甲醇(I-32)
向100mL圆底烧瓶中加入(3-溴-2-氟-4-甲氧基-苯基)-甲醇(I-31,1.04g,4.0mmol)、3-氯苯基硼酸(0.76g,4.8mmol)、Pd(PPh3)4(0.45g,0.41mmol)、Na2CO3(6mL,2M水溶液)、甲苯(32mL)和EtOH(11mL)。用N2将反应脱气,然后在80℃下搅拌24小时。加入水,并用乙酸乙酯萃取产物。将合并的有机物浓缩,并通过SiO2短柱过滤(用50%乙酸乙酯/己烷洗脱)。将固体用***研磨并过滤。浓缩滤液,用***研磨并过滤。将滤饼合并,并用20%丙酮/己烷洗脱,经快速柱色谱纯化,以得到作为白色固体的(3′-氯-2-氟-6-甲氧基-联苯-3-基)-甲醇(I-32,0.79g,67%)
合成3-溴甲基-3′-氯-2-氟-6-甲氧基-联苯(I-33)
向250mL圆底烧瓶中加入如上合成的(3′-氯-2-氟-6-甲氧基-联苯-3-基)-甲醇(1.21g,4.54mmol)、二氯甲烷(20mL)、PPh3(1.19g,4.54mmol),并将溶液冷却至0℃。加入NBS(0.81g,4.54mmol),并将反应在0℃下搅拌2小时。用水洗涤有机物并浓缩。将残余物用8%乙酸乙酯/己烷洗脱,经快速柱色谱纯化,以得到作为灰白色固体的3-溴甲基-3′-氯-2-氟-6-甲氧基-联苯(I-33,956mg,64%)。
合成5-(4,4,5,5-四甲基-[1,3,2]二氧杂环戊硼烷-2-基)-吡啶-2-腈(I-238)
向250mL圆底烧瓶中加入3.0g 5-溴-吡啶-2-腈(3.0g,16.39mmol)、双戊酰二硼(4.58g,18.03mmol)、KOAc(5.47g,55.74mmol)和DMSO(100mL)。脱气20分钟,加入PdCl2dppf-CH2Cl2(1.39g,1.64mmol),并将溶液在80℃下搅拌24小时,然后在室温下搅拌3天。加入50mL水,并用乙酸乙酯萃取产物。用盐水洗涤合并的有机物,用Na2SO4干燥并浓缩。将深色残余物用20%丙酮/己烷经快速柱色谱纯化,以得到1.72g(46%)作为浅粉色固体的I-238。
合成5-(3′-氯-2-氟-6-甲氧基-联苯-3-基甲基)-吡啶-2-基甲基]-氨基甲酸叔丁酯(P-355)
向20mL小瓶中加入I-33(401mg,1.22mmol)、I-238(336mg,1.46mmol)、K2CO3(504mg,3.65mmol)、DME(5mL)、水(0.5mL)、乙醇(0.5mL),并将悬浮液脱气15分钟。加入四(三苯基膦)钯(0)(141mg,0.12mmol),并将反应在80℃下搅拌16小时。将反应用水稀释,并用乙酸乙酯萃取。将有机物浓缩,并用15-20%乙酸乙酯/己烷洗脱,经快速柱色谱纯化,以得到作为浅黄色油状物的P-355(64mg,15%)。1H NMR(400MHz,CDCl3)δ8.62(brs,1H),7.68-7.56(m,2H),7.40-7.30(m,3H),7.26-7.21(m,1H),7.13(t,J=8.4Hz,1H),6.75(d,J=8.3Hz,1H),4.03(br s,2H),3.78(s,3H)ppm。LC/MS=98.5%,353.0(APCI+)。
合成C-[5-(3′-氯-2-氟-6-甲氧基-联苯-3-基甲基)-吡啶-2-基]-甲胺(P-344)
向100mL圆底烧瓶中加入P-355(0.55g,1.56mmol)、甲醇(20mL)、浓HCl(0.65mL,7.79mmol)和10%Pd/C(100mg)。在H2气球下将悬浮液搅拌18小时,然后通过硅藻土过滤。将滤液浓缩。向固体中加入1N NaOH水溶液,并用二氯甲烷萃取产物。将二氯甲烷浓缩,并用5-10%甲醇/二氯甲烷洗脱,经快速柱色谱纯化,以得到作为无色油状物的P-344(89mg,16%)。1H NMR(400MHz,DMSO-d6)8.55(d,J=1.2Hz,1H),8.32(br s,3H),7.71(dd,J=1.9,7.9Hz,1H),7.50-7.37(m,3H),7.36(d,J=5.4Hz,2H),7.27(d,J=6.6Hz,1H),6.96(d,J=8.6Hz,1H),4.75(br s,2H),4.14(q,J=5.8Hz,2H),4.01(s,2H),3.73(s,3H)ppm。LC/MS=95.1%,357.1(APCI+)。
合成C-[5-(3′-氯-2-氟-6-甲氧基-联苯-3-基甲基)-吡啶-2-基]-甲胺(P-344)
向100mL圆底烧瓶中加入P-355(0.55g,1.56mmol)、甲醇(20mL)、浓HCl(0.65mL,7.79mmol)和10%Pd/C(100mg)。在H2气球下将悬浮液搅拌18小时,然后通过硅藻土过滤。将滤液浓缩。向固体中加入1N NaOH水溶液,并用二氯甲烷萃取产物。将二氯甲烷浓缩,并用5-10%甲醇/二氯甲烷洗脱,经快速柱色谱纯化,以得到作为无色油状物的P-344(89mg,16%)。1H NMR(400MHz,DMSO-d6)8.55(d,J=1.2Hz,1H),8.32(br s,3H),7.71(dd,J=1.9,7.9Hz,1H),7.50-7.37(m,3H),7.36(d,J=5.4Hz,2H),7.27(d,J=6.6Hz,1H),6.96(d,J=8.6Hz,1H),4.75(br s,2H),4.14(q,J=5.8Hz,2H),4.01(s,2H),3.73(s,3H)ppm。LC/MS=95.1%,357.1(APCI+)。
合成1-[5-(3′-氯-2-氟-6-甲氧基-联苯-3-基甲基)-吡啶-2-基甲基]-3-乙基-脲(P-372)
向8mL小瓶中加入P-344(23mg,0.064mmol)、二氯甲烷(1.5mL),并将溶液冷却至室温。加入异氰酸乙酯(8μL,0.097mmol),并将反应在室温下搅拌18小时,然后浓缩。向所得固体中加入4.0M HCl/二噁烷,并将溶液在室温下搅拌18小时,然后浓缩。将所得的油状物用***处理以形成固体,将其过滤以得到作为白色固体的P-372(15.1mg,50%)。1HNMR(400MHz,DMSO-d6)8.63(s,1H),8.14(d,J=8.3Hz,1H),7.63(d,J=8.2Hz,1H),7.51-7.33(m,4H),7.28(d,J=6.3Hz,1H),6.98(d,J=8.6Hz,1H),6.62(br s,1H),6.31(br s,1H),4.42(s,2H),4.10(s,2H),3.74(s,3H),3.01(q,J=7.1Hz,2H),0.99(t,J=7.1Hz,3H)ppm。MS:428.1(APCI+)。
1-[5-(3′-氯-2-氟-6-甲氧基-联苯-3-基甲基)-1-氧-吡啶-2-基甲基]-3-乙基-脲(B-082)
向18mL小瓶中加入P-372(66mg,0.15mmol)、二氯甲烷(4mL),并将溶液冷却至0℃。加入mCPBA(69mg,0.31mmol),并将反应在室温下搅拌1小时,然后加入5mL饱和NaHCO3水溶液。分离各层,并依次用各5mL的饱和NaHCO3水溶液、H2O和盐水洗涤有机层。然后用1N NaOH(2×5mL)、水(5mL)和盐水(5mL)洗涤残余物。用Na2SO4干燥产物,过滤并浓缩,以得到作为白色固体的B-082(14.8mg,22%)。1H NMR(400MHz,DMSO-d6)8.19(s,1H),7.53-7.34(m,4H),7.29(d,J=6.6Hz,1H),7.25-7.16(m,2H),6.96(d,J=8.6Hz,1H),6.38(t,J=6.0Hz,1H),6.17(t,J=5.4Hz,1H),4.22(d,J=6.2Hz,2H),3.91(s,2H),3.73(s,3H),3.09-2.91(m,2H),0.97(t,J=7.2Hz,3H)ppm。LC/MS=100.0%,444.1(APCI+)。
合成B-083
合成1-(2-氯-乙基)-3-[5-(3′-氯-2-氟-6-甲氧基-联苯-3-基甲基)-吡啶-2-基甲基]-脲(I-239)
向8mL小瓶中加入P-344(63mg,0.177mmol)、二氯甲烷(2mL),并将反应冷却至0℃。加入异氰酸氯乙酯(19mg,0.177mmol),并将反应在室温下搅拌1小时,然后浓缩以得到I-239,将其直接使用。
合成1-[5-(3′-氯-2-氟-6-甲氧基-联苯-3-基甲基)-吡啶-2-基甲基]-咪唑烷-2-酮(P-374)
向8mL小瓶中加入I-239(82mg,0.177mmol)、THF(2mL),并将悬浮液冷却至0℃。加入氢化钠(8mg,0.212mmol),并将反应在室温下搅拌3天。另外加入4mg氢化钠,并将反应在50℃下搅拌1小时。加入水,并用乙酸乙酯萃取产物。将有机物浓缩,并用25-50%丙酮/二氯甲烷洗脱,经快速柱色谱纯化,以得到作为白色固体的P-374(35mg,47%,2步)。1H NMR(400MHz,DMSO-d6)8.42(d,J=1.5Hz,1H),7.60(dd,J=1.9,7.9Hz,1H),7.49-7.39(m,2H),7.37(s,1H),7.34(t,J=8.7Hz,1H),7.28(d,J=6.7Hz,1H),7.19(d,J=7.9Hz,1H),6.94(d,J=8.6Hz,1H),6.41(s,1H),4.28(s,2H),3.95(s,2H),3.72(s,3H),3.31-3.19(m,4H)ppm。LC/MS=100.0%,426.1(APCI+)。
1-[5-(3′-氯-2-氟-6-甲氧基-联苯-3-基甲基)-1-氧-吡啶-2-基甲基]-咪唑烷-2-酮(B-083)。
向18mL小瓶中加入P-374(62mg,0.15mmol)、二氯甲烷(4mL),并将溶液冷却至0℃。加入mCPBA(82mg,0.36mmol),并将反应在室温下搅拌1小时,然后加入5mL 1N NaOH水溶液。分离各层,并用二氯甲烷(2×3mL)萃取水层。将有机物合并,并用水(5mL)和盐水(5mL)洗涤,然后浓缩。将残余物溶于5mL EtOAc,并用5mL盐水洗涤,用Na2SO4干燥,并浓缩至固体。将残余物用***研磨以得到作为白色固体的B-083(23.5mg,35%)。1H NMR(400MHz,DMSO-d6)8.23(s,1H),7.49-7.34(m,4H),7.32-7.16(m,3H),6.96(d,J=8.6Hz,1H),6.56(s,1H),4.31(s,2H),3.93(s,2H),3.73(s,3H),3.45-3.36(m,2H),3.32-3.25(m,2H)ppm。LC/MS=93.4%,442.0(APCI+)。
合成B-084
合成3-[5-(4-氟-苄基)-2-甲氧基-苯基]-吡啶(P-474)
在搅拌下,将I-168(158mg,0.53mmol)、3-吡啶硼酸(61.5mg,0.50mmol)、双(二亚苄基丙酮)钯(0)(14.4mg,0.025mmol)和三苯基膦(13.1mg,0.050mmol)在二甲基甲酰胺(5mL)和1M碳酸钠水溶液(1.5mL,1.5mmol)中的悬浮液在85℃下加热过夜。真空除去溶剂,并将残余物悬浮于乙酸乙酯(15mL)中。将有机悬浮液用水(3×15mL)和盐水洗涤,用硫酸钠干燥,并真空除去溶剂以得到粗材料。将残余物经硅胶制备薄层色谱纯化以得到69.1mg(47%)P-474。
合成3-[5-(4-氟-苄基)-2-甲氧基-苯基]-吡啶1-氧化物(B-084)
向小瓶中加入P-474(60mg,0.20mmol)、甲基钌氧化物(2.5mg,0.010mmol)、30%过氧化氢水溶液(0.5mL)和二氯甲烷(1.0mL)。将反应在室温下搅拌3天。用催化量的二氧化锰(1.7mg,0.02mmol)处理两相混合物,并仔细搅拌,直至氧气不再逸出(1h)。将不同相分离,用二氯甲烷(2×1mL)萃取水层,将有机层合并,用硫酸钠干燥,并真空除去溶剂,以34%的收率得到20.9mg B-084。1H NMR(400MHz,CDCl3)3.82(s,3H)3.94(s,2H)6.89-7.24(m,8H)7.41(d,J=8.1Hz,1H)8.16(d,J=6.3Hz,1H)8.44(s,1H)ppm。LCMS=92.0%纯度。
通过与上述类似的方法制备下列化合物。
1HNMR数据表:
PCTUS实施例序号 | 1H NMR数据 | LCMS |
A-001 | 1H NMR(400MHz,氯仿-d)δppm 3.85(s,3H)4.55(s,2H)6.98(d,J=8.45Hz,1H)7.31(d,J=7.78Hz,1H)7.38(d,J=2.28Hz,1H)7.43(dd,J=8.45,2.28Hz,1H)7.48-7.68(m,3H)7.77(s,1H)7.85(d,J=7.65Hz,1H)8.19(dd,J=8.18,1.34Hz,1H)8.40(t,J=1.81Hz,1H) | |
A-008 | 1H NMR(氯仿-d,400MHz):δ=7.29-7.41(m,7H),7.19-7.29(m,12H),7.07-7.18(m,7H),6.71(s,2H),6.38(br.s.,2H),4.64(br.s.,4H),3.94(s,5H),3.75(s,7H),2.14(s,1H),1.26(s,3H),0.89ppm(s,1H) | |
A-010 | 1HNMR(400MHz,氯仿-d)δppm 7.94(br.s.,1H)7.65(dd,J=9.1,1.9Hz,1H)7.30-7.40(m,3H)7.23-7.29(m,2H)7.12(t,J=8.5Hz,1H)6.73(d,J=8.6Hz,1H)3.87(s,2H)3.77(s,3H) | |
A-011 | 1H NMR(400MHz,DMSO,d-6)3.72(3H,s),3.82(2H,s),6.64-6.68(2H,m)6.91-6.94(3H,m),7.20(1H,d,J=8Hz),7.26-7.31(2H,m),7.37(1H,br),7.41-7.48(2H,m),7.70(1H,s). | |
A-012 | 1HNMR(400MHz,DMSO-d6)δppm 10.95(s,1H)8.45(s,2H)7.19-7.54(m,5H)7.07(s,2H)6.96(d,J=8.6Hz,1H)3.89(s,2H)3.74(s,3H) | |
A-013 | 1HNMR(400MHz,氯仿-d)δppm 7.89-8.04(m,2H)7.54-7.63(m,1H)7.53(d,J=7.6Hz,1H)725-7.34(m,7H)7.09(t,J=8.6Hz,1H)6.71(d,J=8.5Hz,1H)6.46(d,J=8.5Hz,1H)3.83(s,3H)3.75(s,3H)2.62(s,3H) | |
A-014 | 1HNMR(400MHz,氯仿-d)δppm 7.98(s,1H)7.26-7.46(m,5H)7.05-7.17(m,3H)7.00(s,1H)6.70(s,1H)5.47(br.s.,1H)3.81(br.s.,2H)3.76(s,3H) | |
A-015 | 1HNMR(400MHz,氯仿-d)δppm 7.98(s,1H)7.29-7.44(m,3H)7.06-7.15(m,2H)7.00(s,1H)6.70(s,1H)5.47(br.s.,1H)3.81(br.s.,2H)3.76(s,3H) | |
A-028 | 1H NMR(400MHz,DMSO-d6)δ=8.09(s,1H),7.63(br.s.,1H),7.48-7.40(m,3H),7.37(s,1H),7.32-7.25(m,4H),6.94(d,J=8.6Hz,1H),3.89(s,2H),3.87(s,2H),3.73(s,3H) | |
A-029 | 1H NMR(400MHz,氯仿-d)δppm 1.24(t,3H)2.63(t,J=6.37Hz,2H)3.64(q,J=6.31Hz,2H)3.76(s,3H)3.87(s,2H)4.15(q,J=7.20Hz,2H)6.57(d,J=8.45Hz,1H)6.71(d,J=8.45Hz,1H)6.92(s,1H)7.09(t,J=8.52Hz,1H)7.29-7.40(m,3H)7.44(dd,J=8.32,2.15Hz,1H)8.07(d,J=1.74Hz,1H)9.52(br.s.,1H) | |
A-032 | 1H NMR(400MHz,DMSO-d6)δ=9.37(br.s.,1H),8.15(br.s.,1H),8.04(s,1H),7.59(d,J=7.6Hz,1H),7.49-7.23(m,6H),6.94(d,J=8.6Hz,1H),3.87(s,2H),3.73(s,3H),2.57-2.53(m,2H),2.47-2.41(m,2H) | |
A-036 | 1HNMR(氯仿-d,400MHz):δ=8.06(s,1H),7.25-7.39(m,5H),7.07(t,J=8.6Hz,1H),6.67(d,J=8.5Hz,1H),6.47(d,J=8.7Hz,1H),3.80(s,2H),3.74(s,3H). | 计算值:343.8;APCl+(M+CHO):371.1,97.6% |
A-054 | 1H NMR(400MHz,DMSO-d6)δppm 3.72(s,3H)3.75-3.94(m,3H)4.56(br.s.,1H)6.40(d,J=8.45Hz,1H)6.92(d,J=8.59Hz,1H)7.21.7.47(m,5H)7.97(s,1H) |
Claims (32)
1.式Ia的化合物或其盐:
其中
R1a选自
(a)选自
(b)具有三个或更少个环的取代杂环或具有三个或更少个环的取代碳环;以及
(c)本身由具有其它取代基的杂环所取代的杂环;
其中,所述杂环和碳环上的取代基选自羟基、羧基、烷氧羰基、羧基烷基羰基氨基、羧基烷基、羧基烷氧基、羧基烷硫基、羧基烷基氨基羰基氨基、胍基、氨基酸残基以及N-甲基化氨基酸残基;
R2是具有两个或更少个环的任选取代的碳环或任选取代的杂环;
R3选自-C(=O)NH2、-(C1-C6)烷基、卤代(C1-C6)烷基、-(C1-C6)烷基-R30、-(C2-C6)烷基-R31以及任选地被甲基取代的饱和4-元或5-元杂环;
R30选自-C(=O)NH2和任选地被甲基取代的4-元或5-元杂环;
R31选自(C1-C4)烷氧基、氨基、羟基、(C1-C6)烷基氨基以及二(C1-C6)烷基氨基;
R4选自H和F;
R6选自H、(C1-C6)烷基和卤素;
X是N、N→O或C-R5;
R5选自H、卤素、OH、(C1-C6)烷基、(C1-C6)烷氧基、CF3、CN、NH2、CH2OH、CH2NH2和C≡CH;以及
M选自直接键、-C(R20)(R21)-、-O-、-NR22-、-S(O)n-、-C(=O)-、-C(R20)(R21)C(R20)(R21)-、-C(R20)=C(R21)-、-C(R20)(R21)-O-、-C(R20)(R21)-NR22-、-C(R20)(R21)-S(O)n-、-C(R20)(R21)-C(=O)-、-O-C(R20)(R21)-、-NR22-C(R20)(R21)-、-S(O)n-C(R20)(R21)-、-C(=O)-C(R20)(R21)-和
是任选地被甲基取代的5-元或6-元环;
n是0、1或2;并且
R20、R21和R22在每次出现时独立地选自H和(C1-C4)烷基,
条件是当R3为甲基、R2为苯基且R1a为羟基苯基时,M不能是-C(=O)-,并且
其中所述任选取代的是指未取代的或一个或多个氢原子被以下基团取代:卤素、卤代烷基、烷基、酰基、烷氧基烷基、羟烷基、羰基(即氧代)、苯基、杂芳基、苯磺酰基、羟基、烷氧基、卤代烷氧基、氧杂烷基、羧基、羧基烷基、羧基烷氧基、羧基烷硫基、烷氧羰基[-C(=O)O-烷基]、烷氧羰基氨基[-NHC(=O)O-烷基]、烷氧羰基氨基烷基[-烷基-NHC(=O)O-烷基]、羧基烷基羰基氨基[-NHC(=O)-烷基-COOH]、甲酰氨基[-C(=O)NH2]、氨基羰氧基[-OC(=O)NH2]、烷基氨基羰基[-C(=O)NH-烷基]、二烷基氨基羰基[-C(=O)N(烷基)2]、氨基羰基烷基[-烷基-C(=O)NH2]、氰基、乙酰氧基、硝基、氨基、烷基氨基、二烷基氨基、氨基烷基、(烷基)(芳基)氨基烷基、烷基氨基烷基(包括环烷基氨基烷基)、二烷基氨基烷基、二烷基氨基烷氧基、烷基(羟烷基)氨基、杂环基烷氧基、巯基、烷硫基、烷基磺酰基、烷基磺酰氨基、烷基亚磺酰基、烷基磺酰基、芳硫基、芳基磺酰基、芳基磺酰氨基、芳基亚磺酰基、芳基磺酰基、酰氨基烷基、酰氨基烷氧基、酰氨基、脒基、芳基、苄基、杂环基、杂环基烷基、苯氧基、苄氧基、杂芳氧基、杂环基氨基、羟基亚胺基、烷氧基亚胺基、氧杂烷基、氨基磺酰基、三苯甲基、脒基、胍基、脲基、-NHC(=O)NH烷基、-NHC(=O)NH-杂环基、-烷基-NHC(=O)N(烷基)2、杂环基烷基羰基氨基、苄氧基苯基和苄氧基;
所述烷基包括直链、支链、或环状的烃结构及其组合;
所述碳环包括其中的环原子均为除任何氧化态的碳的环体系;
所述杂环是指其中的1-3个碳被选自N、O和S的杂原子替代的环烷基或芳基碳环残基,其中氮和硫杂原子可以任选地被氧化,并且氮杂原子可以任选地被季铵化;并且
所述氨基酸残基是指缺少被认为是母体结构上部分键的官能团的氨基酸。
2.如权利要求1所述的式Ia的化合物或盐,其中X是N或N→O。
3.如权利要求1所述的式Ia的化合物或盐,其中X是CR5。
5.如权利要求1、2或3中任意一项所述的化合物或盐,其中R1a是取代苯基。
6.如权利要求1、2或3中任意一项所述的化合物或盐,其中R1a是任选取代的杂环,所述杂环选自吡唑、吡咯、吲哚、喹啉、异喹啉、四氢异喹啉、苯并呋喃、苯并二噁烷、苯并间二氧杂环戊烯、吗啉、噻唑、吡啶、吡啶N-氧化物、嘧啶、噻吩、呋喃、噁唑、噁唑啉、噁唑烷、异噁唑烷、异噁唑、二噁烷、氮杂环丁烷、哌嗪、哌啶、吡咯烷、哒嗪、氮杂、吡唑烷、咪唑、咪唑啉、咪唑烷、嘌呤、咪唑并吡啶、吡嗪、噻唑烷、异噻唑、1,2-噻嗪-1,1-二氧化物、2,6,7-三氧杂双环[2.2.2]辛烷、喹核碱、异噻唑烷、苯并咪唑、噻二唑、苯并吡喃、苯并噻唑、苯并***、苯并噁唑、苯并噁二唑、四氢呋喃、四氢吡喃、苯并噻吩、硫吗啉、硫吗啉亚砜、硫吗啉砜、噁二唑、***、四唑、异吲哚、吡咯并吡啶、***并吡啶及它们的二氢和四氢同源物。
7.如权利要求6所述的化合物或盐,其中R1a是任选取代的杂环,所述杂环选自吡唑、苯并间二氧杂环戊烯、吗啉、噻唑、吡啶、吡啶N-氧化物、嘧啶、噻吩、噁唑烷、异噁唑、氮杂环丁烷、哌嗪、吡咯烷、咪唑、咪唑烷、咪唑并吡啶、吡嗪、1,2-噻嗪-1,1-二氧化物、苯并咪唑、噻二唑、苯并***、苯并噁唑、噁二唑、***、四唑、异吲哚、吡咯并吡啶、***并吡啶及它们的二氢和四氢同源物。
8.式Ia的化合物或盐,
其中
R1a选自:
具有三个或更少个环的取代杂环;
与取代单环杂环相连接的单环杂环;和
具有三个或更少个环的取代碳环
其中所述杂环或碳环上的取代基选自-COOH、-OH、-COOCH3、-COOEt、-CH2COOH、-CH2COOEt、-CH2NHC(=O)OEt、-CH2NHC(=O)C(=O)NH2、-OCH(CH3)COOH、-SCH2COOH、-NHCH2COOH、-N(CH3)CH2COOH、-NHSO2NH2、-NHC(=O)CH2CH2COOH、-NHC(=O)NHCH2COOH、-NHC(=O)NHCH2COOEt、-NHC(=O)NH(CH2)3COOEt、-NHC(=O)NH(CH2)2COOEt、-NHC(=O)NH(CH2)2COOH、-NHC(=O)NH(CH2)3COOH和5-四唑基;
R2是具有两个或更少个环的任选取代的碳环或任选取代的杂环;
R3选自-C(=O)NH2、-(C1-C6)烷基、卤代(C1-C6)烷基、-(C1-C6)烷基-R30、-(C2-C6)烷基-R31以及任选地被甲基取代的饱和4-元或5-元杂环;
R30选自-C(=O)NH2和任选地被甲基取代的4-元或5-元杂环;
R31选自(C1-C4)烷氧基、氨基、羟基、(C1-C6)烷基氨基以及二(C1-C6)烷基氨基;
R4选自H和F;
R6选自H、(C1-C6)烷基和卤素;
X是N、N→O或C-R5;
R5选自H、卤素、OH、(C1-C6)烷基、(C1-C6)烷氧基、CF3、CN、NH2、CH2OH、CH2NH2和C≡CH;以及
M选自直接键、-C(R20)(R21)-、-O-、-NR22-、-S(O)n-、-C(=O)-、-C(R20)(R21)C(R20)(R21)-、-C(R20)=C(R21)-、-C(R20)(R21)-O-、-C(R20)(R21)-NR22-、-C(R20)(R21)-S(O)n-、-C(R20)(R21)-C(=O)-、-O-C(R20)(R21)-、-NR22-C(R20)(R21)-、-S(O)n-C(R20)(R21)-、-C(=O)-C(R20)(R21)-和
是任选地被甲基取代的5-元或6-元环;
n是0、1或2;并且
R20、R21和R22在每次出现时独立地选自H和(C1-C4)烷基。
9.如权利要求1、2或3中任意一项所述的化合物或盐,其中R2选自任选取代的苯基、任选取代的单环不饱和杂环、未取代的双环不饱和杂环以及氟代双环不饱和杂环。
10.如权利要求9所述的化合物或盐,其中R2选自任选取代的苯基、吲哚、苯并间二氧杂环戊烯、苯并噁二唑、苯并二噁烷、苯并咪唑、噁二唑、吡唑、吡啶和吡啶N-氧化物。
11.如权利要求10所述的化合物或盐,其中R2选自间位取代的苯基、吲哚、苯并间二氧杂环戊烯、2,2-二氟苯并间二氧杂环戊烯、苯并噁二唑、苯并咪唑、5-(吡啶-4-基)[1,2,4]噁二唑、5-(吡啶-4-基)[1,3,4]噁二唑、苯并二噁烷、4-氯吡唑、4-(吡啶-4-基)吡唑、6-氯吡啶、3-(三氟甲基)吡唑和吡啶N-氧化物。
12.如权利要求10所述的化合物或盐,其中R2是以下取代苯基:
其中,R7选自氢、卤素、硝基、氰基、卤代(C1-C6)烷基、羟基、(C1-C6)烷氧基、(C1-C6)氧杂烷基、羧基、(C1-C6)烷氧羰基、氨基羰基(-CONH2)、(C1-C6)烷基氨基羰基、酰基、羟基(C1-C6)烷基、卤代(C1-C6)烷氧基、氨基(C1-C6)烷基、氨基、(C1-C6)烷基氨基、二[(C1-C6)烷基]氨基、巯基、(C1-C6)烷硫基、(C1-C6)烷基亚磺酰基、(C1-C6)烷基磺酰基、(C1-C6)烷基磺酰氨基、酰氨基、脒基、苯基、苄基、杂环基、苯氧基、苄氧基和杂芳氧基;并且
R8和R13独立地选自H和F。
13.如权利要求12所述的化合物或盐,其中R8和R13是H,并且R7选自氢、氟、氯、溴、硝基、氰基、乙酰基、三氟甲基、甲氧基、三氟甲氧基、噁二唑基、四唑基、甲硫基、甲基亚磺酰基、甲磺酰基、甲磺酰氨基、氨基、甲氧基甲基、羟乙基和吗啉基。
14.如权利要求8所述的式Ia的化合物或盐,其中R1a选自:取代苯基;取代5-元杂芳基,其选自噻唑、噻二唑、吡唑、噁二唑、异噁唑、***、咪唑、噻吩、四唑和噁唑;取代6-元杂芳基,其选自吡啶、嘧啶、哒嗪酮、嘧啶酮、吡啶酮、吡嗪和二嗪;取代5-元和6-元非芳基杂环,其选自四氢噻吩、哌嗪、噁唑烷酮、咪唑啉酮、吗啉、哌啶、吡咯烷酮、吡咯烷二酮、吡咯烷、哌啶酮、哌啶二酮以及三氧杂双环[2.2.2]辛烷;取代稠合双环,其选自苯并噁唑酮、吲哚、异二氢吲哚二酮、2H-吡咯并吡啶二酮、嘌呤、二氢吲哚二酮、***并吡啶酮、苯并咪唑、苯并噁二唑、喹啉和喹诺酮;以及取代杂环基杂环,其选自氮杂环丁基嘧啶、吡咯烷基嘧啶、哌啶基嘧啶、氮杂环丁基吡啶、吡咯烷基吡啶和哌啶基吡啶;其中所述取代基独立地选自-COOH、-OH、-COOCH3、-COOEt、-CH2COOH、-CH2COOEt、-CH2NHC(=O)OEt、-CH2NHC(=O)C(=O)NH2、-OCH(CH3)COOH、-SCH2COOH、-NHCH2COOH、-N(CH3)CH2COOH、-NHSO2NH2、-NHC(=O)CH2CH2COOH、-NHC(=O)NHCH2COOH、-NHC(=O)NHCH2COOEt、-NHC(=O)NH(CH2)3COOEt、-NHC(=O)NH(CH2)2COOEt、-NHC(=O)NH(CH2)2COOH、-NHC(=O)NH(CH2)3COOH和5-四唑基;
R3选自-CH3、-CH2CH3、-CF3、-CHF2以及-CH2F;
R5选自H、-F、-OH、-CH3、-OCH3、-CF3、-CN、–NH2以及–C≡CH;
R2是
(a)在间位被选自H、卤素、硝基、乙酰基、羟乙基、-NH2、-SCH3、甲氧羰基、-SOCH3、-SO2CH3、-OCH3、-OCF3、-CN、-CF3、-CH2OCH3的取代基取代的苯基;或
(b)苯并噁二唑、苯并间二氧杂环戊烯、2,2-二氟苯并间二氧杂环戊烯、苯并二噁烷、苯并咪唑、噁二唑、吡唑、吡啶和吡啶N-氧化物;
R9选自H、(C1-C6)烷基、卤代(C1-C6)烷基、(C1-C6)烷氧羰基、羧基(C1-C6)烷基、(C1-C6)烷氧基羧基(C1-C6)烷基;
R10是H、(C1-C6)烷基,或共同是,或
R9和R10共同形成任选地被(C1-C6)烷基取代的杂环;
p是0或1,
q是0、1或2,
R11是直链(C1-C6)烷基,
R12是H或(C1-C6)烷基;或两个相邻的取代基共同形成任选取代的稠合杂环。
15.如权利要求1所述的下式的化合物或盐
其中
R1b是苯基、5-元杂芳基、6-元杂芳基、4-7元非芳基杂环或稠合双环;
R14选自-COOH、-OH、-COOCH3、-COOEt、-CH2COOH、-CH2COOEt、-CH2NHC(=O)OEt、-CH2NHC(=O)C(=O)NH2、-OCH(CH3)COOH、-SCH2COOH、-NHCH2COOH、-N(CH3)CH2COOH、-NHSO2NH2、-NHC(=O)CH2CH2COOH、-NHC(=O)NHCH2COOH、-NHC(=O)NHCH2COOEt、-NHC(=O)NH(CH2)3COOEt、-NHC(=O)NH(CH2)2COOEt、-NHC(=O)NH(CH2)2COOH、-NHC(=O)NH(CH2)3COOH、5-四唑基以及被任何前述基团取代的单环杂环;
R27选自氢、卤素、硝基、氰基、卤代(C1-C6)烷基、羟基、(C1-C6)烷氧基、(C1-C6)氧杂烷基、羧基、(C1-C6)烷氧羰基、氨基羰基(-CONH2)、(C1-C6)烷基氨基羰基、酰基、羟基(C1-C6)烷基、卤代(C1-C6)烷氧基、氨基(C1-C6)烷基、氨基、(C1-C6)烷基氨基、二[(C1-C6)烷基]氨基、巯基、(C1-C6)烷硫基、(C1-C6)烷基亚磺酰基、(C1-C6)烷基磺酰基、(C1-C6)烷基磺酰氨基、酰氨基、脒基、苯基、苄基、杂环基、苯氧基、苄氧基和杂芳氧基;
R28选自H和F,或
R27与R28形成5-元环。
16.如权利要求1所述的下式的化合物或盐
或
其中
R1c是苯基、5-元杂芳基、6-元杂芳基、4-7元非芳基杂环或稠合双环;
R14选自H、-CH2NHC(=O)NH2、-NHC(=O)NH2、-NHC(=O)NHEt、-CH3、-CH2CF3、-CH2NHC(=O)CH3、-NHCH3、-NHEt、-NH(tBoc)、-CHO、-NHC(=O)NHCH2CH2Cl、-NHSO2NH2、-NHEt、-N(CH3)2、-NH2、-COOH、-C(=O)NH2、-CH2C(=O)NH2、-CH2COOH、-CH2COOEt、-CN、-OCH3、-OC(=O)NH2、-NH(CH3)C(=O)NH2、卤素、-CH2NHC(=O)OEt、-NHSO2CH3、-N(SO2CH3)2、-NHC(=O)OCH3、-OH、-CH2NHC(=O)N(CH3)2、-CH2NH2、-CH2OH、-CH2CH2OH、-SO2NH2、-NHC(=O)NHCH2COOH、-CH2NHCHO、-NHC(=O)NHCH2COOEt、-COOCH3、-COOEt、-NHC(=O)NH(CH2)3COOEt、-NHC(=O)NH(CH2)2COOEt、-OCH(CH3)COOH、-SCH2COOH、-NH(Et)C(=O)OEt、-NHC(=O)NH(CH2)2COOH、-CH2NHSO2CH3、-OEt、-NHC(=O)CH2N(CH3)2、-NHC(=O)NH(CH2)3COOH、-NHC(=O)CH2NH2、-NHC(=O)CH2CH2NH2、-NHC(=O)CH2NH(tBoc)、-OCH2CH2N(CH3)2、-OCH2CH2OCH3、3′-硝基-6-甲氧基联苯-3-基甲基、四氢咪唑-2-酮-1-基、3-甲基四氢咪唑-2-酮-1-基、吡唑-1-基、以及
R15选自H、NO2、OH、NH2以及-NHSO2NH2;或
R15与R14共同形成亚甲二氧基;
R27选自氢、卤素、硝基、氰基、卤代(C1-C6)烷基、羟基、(C1-C6)烷氧基、(C1-C6)氧杂烷基、羧基、(C1-C6)烷氧羰基、氨基羰基(-CONH2)、(C1-C6)烷基氨基羰基、酰基、羟基(C1-C6)烷基、卤代(C1-C6)烷氧基、氨基(C1-C6)烷基、氨基、(C1-C6)烷基氨基、二[(C1-C6)烷基]氨基、巯基、(C1-C6)烷硫基、(C1-C6)烷基亚磺酰基、(C1-C6)烷基磺酰基、(C1-C6)烷基磺酰氨基、酰氨基、脒基、苯基、苄基、杂环基、苯氧基、苄氧基和杂芳氧基;
R28选自H和F,或
R27与R28共同形成5-元环。
18.如权利要求15或16所述的化合物或盐,其中R27选自卤素、硝基、乙酰基、羟乙基、氨基、甲硫基、三氟甲基、甲氧基甲基、甲氧羰基、三氟甲氧基、氰基和1,3,4-噻二唑-2-基,或R7和R8共同是亚甲二氧基或二氟亚甲二氧基。
19.如权利要求18所述的化合物或盐,其中R1b或R1c选自苯环、***、吡啶或吡啶N-氧化物、吡唑、四氢噻吩、咪唑、嘧啶、噻二唑以及咪唑并吡啶。
20.如权利要求1至3中任意一项所述的化合物或盐,其中R5是氟、H、CN或OH。
21.如权利要求1至3中任意一项所述的化合物或盐,其中R3是甲基或氟甲基。
23.如权利要求1至3中任意一项所述的化合物的盐,其中所述盐是药学可接受的盐。
24.药物组合物,其包含药学可接受的载体和如权利要求1至3中任意一项所述的化合物或药学可接受的盐。
25.药物组合物,其包含
(a)药学可接受的载体;
(b)如权利要求1至3中任意一项所述的化合物或药学可接受的盐;以及
(c)选自胆碱酯酶抑制剂、NMDA拮抗剂、钙蛋白酶抑制剂和抗氧化剂的另一种药剂。
26.如权利要求25所述的药物组合物,其中所述另一种药剂选自他克林、石杉碱、多奈哌齐、拉尼西明、瑞马西胺、奈拉美生、美金刚、维生素E和辅酶Q10。
27.如权利要求1至3中任意一项所述的化合物在制备用于治疗或预防由外周磷酸二酯酶-4介导的疾病或病症的药物中的用途。
28.如权利要求27所述的用途,其中所述疾病或病症选自中风、心肌梗塞和心血管炎性病症。
29.如权利要求27所述的用途,其中所述疾病或病症是癌症。
30.如权利要求27所述的用途,其中所述疾病或病症选自哮喘和COPD。
31.如权利要求1至3中任意一项所述的化合物在制备用于治疗或预防骨丢失的药物中的用途。
32.如权利要求1至3中任意一项所述的化合物在制备用于治疗膀胱炎症、膀胱过度活动或由膀胱炎症引发的疼痛的药物中的用途。
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- 2008-11-20 AU AU2008326309A patent/AU2008326309C1/en not_active Ceased
- 2008-11-20 KR KR1020107013786A patent/KR20100108346A/ko not_active Application Discontinuation
- 2008-11-20 CN CN201310270697XA patent/CN103351390A/zh active Pending
- 2008-11-20 WO PCT/US2008/084230 patent/WO2009067621A1/en active Application Filing
- 2008-11-20 JP JP2010535073A patent/JP2011504505A/ja active Pending
- 2008-11-20 EP EP13000709.9A patent/EP2628727A3/en not_active Withdrawn
- 2008-11-20 US US12/275,163 patent/US20090324569A1/en not_active Abandoned
- 2008-11-20 EP EP08852110A patent/EP2222639A1/en not_active Withdrawn
- 2008-11-20 US US12/275,152 patent/US20090136473A1/en not_active Abandoned
- 2008-11-20 CN CN2008801251832A patent/CN102026970B/zh not_active Expired - Fee Related
- 2008-11-20 CA CA2722611A patent/CA2722611A1/en not_active Abandoned
- 2008-11-20 KR KR1020107013784A patent/KR20100098653A/ko not_active Application Discontinuation
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2010
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2012
- 2012-03-26 US US13/430,164 patent/US8791267B2/en not_active Expired - Fee Related
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2014
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- 2014-06-23 US US14/311,728 patent/US20140301999A1/en not_active Abandoned
- 2014-10-10 JP JP2014209336A patent/JP2015044829A/ja not_active Withdrawn
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Also Published As
Publication number | Publication date |
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CN103351390A (zh) | 2013-10-16 |
US20140301999A1 (en) | 2014-10-09 |
AU2008326309C1 (en) | 2015-03-12 |
AU2008326309A1 (en) | 2009-05-28 |
US20120183522A1 (en) | 2012-07-19 |
EP2628727A3 (en) | 2013-12-25 |
AU2008326309B2 (en) | 2014-10-02 |
CA2722611A1 (en) | 2009-05-28 |
EP2222639A1 (en) | 2010-09-01 |
IL205882A0 (en) | 2010-11-30 |
WO2009067621A1 (en) | 2009-05-28 |
KR20100098653A (ko) | 2010-09-08 |
JP2015044829A (ja) | 2015-03-12 |
US20120213758A1 (en) | 2012-08-23 |
EP2628727A2 (en) | 2013-08-21 |
JP2011504505A (ja) | 2011-02-10 |
EP2674417A3 (en) | 2014-04-09 |
US20090136473A1 (en) | 2009-05-28 |
US8791267B2 (en) | 2014-07-29 |
JP2014185149A (ja) | 2014-10-02 |
US20090324569A1 (en) | 2009-12-31 |
KR20100108346A (ko) | 2010-10-06 |
CN102026970A (zh) | 2011-04-20 |
EP2674417A2 (en) | 2013-12-18 |
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