CN103764658B - 化合物、其药物组合物及其作为用于治疗癌症的idh1突变体抑制剂的用途 - Google Patents
化合物、其药物组合物及其作为用于治疗癌症的idh1突变体抑制剂的用途 Download PDFInfo
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- CN103764658B CN103764658B CN201280037490.1A CN201280037490A CN103764658B CN 103764658 B CN103764658 B CN 103764658B CN 201280037490 A CN201280037490 A CN 201280037490A CN 103764658 B CN103764658 B CN 103764658B
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- alkylidene
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Classifications
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- C07D491/044—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
- C07D491/052—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring the oxygen-containing ring being six-membered
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- A61K31/551—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep
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Abstract
提供了具有化学式(I)的化合物,其中X、Y、Z、W、V、R2、R3以及m如在说明书中所定义。还提供了它们的药物组合物及其作为用于治疗癌症的IDHl突变体抑制剂的用途。
Description
优先权要求
本申请要求于2011年6月17日提交的中国专利申请号CN 201110172357.4、于2011年7月18日提交的U.S.S.N.61/509,084以及于2012年1月6日提交的U.S.S.N.61/584,209的优先权,其中的每个通过引用以其全文而结合。
发明背景
异柠檬酸脱氢酶(IDH)催化异柠檬酸氧化脱羧为2-氧化戊二酸(即,α-酮戊二酸)。这些酶属于两种不同的亚类,其中之一利用NAD(+)作为电子受体并且另一种利用NADP(+)作为电子受体。已经报道了五种异柠檬酸脱氢酶:三种集中于粒线体基质的NAD(+)依赖性异柠檬酸脱氢酶;以及两种NADP(+)依赖性异柠檬酸脱氢酶,其中之一是粒线体的并且另一种主要是细胞溶质的。每种NADP(+)依赖性同工酶都是一个同型二聚体。
IDH1(异柠檬酸脱氢酶1(NADP+),细胞溶质的)也称为IDH;IDP;IDCD;IDPC或PICD。由这种基因编码的蛋白质是发现于细胞质和过氧化物酶体中的NADP(+)依赖性异柠檬酸脱氢酶。它包含PTS-1过氧化物酶体靶向信号序列。过氧化物酶体中这种酶的存在表明了在以下方面中的作用:针对内部过氧化物酶体减少的NADPH的再生,例如2,4-二烯酰基-CoA向3-烯酰基-CoA的转化,以及消耗2-氧化戊二酸的过氧化物酶体反应(即植烷酸的α-羟化)。这种胞质酶在细胞质NADPH生产中发挥重要作用。
人类IDH1基因编码一种具有414个氨基酸的蛋白质。人类IDH1的核苷酸序列和氨基酸序列可以分别发现为GenBank条目NM_005896.2和NP_005887.2。IDH1的核苷酸序列和氨基酸序列还描述于例如Nekrutenko(耐克鲁唐克)等人,Mol.Biol.Evol.(《分子生物学与进化》)15:1674-1684(1998);Geisbrecht(盖斯布莱特)等人,J.Biol.Chem.(《生物化学杂志》)274:30527-30533(1999);Wiemann(维买恩)等人,Genome Res.(《基因组研究》)11:422-435(2001);MGC项目团队,Genome Res.(《基因组研究》)14:2121-2127(2004);Lubec(卢贝克)等人,递交(DEC-2008)至UniProtKB;Kullmann(库曼恩)等人,递交(JUN-1996)至EMBL/GenBank/DDBJ数据库;以及Sjoeblom(斯犹布鲁姆)等人,Science(《科学》)314:268-274(2006)中。
非突变型(例如,野生型)IDH1催化异柠檬酸氧化脱羧为α-酮戊二酸,由此将NAD+(NADP+)还原为NADP(NADPH),例如在正反应中:
异柠檬酸+NAD+(NADP+)→α-KG+CO2+NADH(NADPH)+H+。
已经发现存在于某些癌细胞中的IDH1的突变导致这种酶催化α-酮戊二酸依赖于NAPH地还原为R(-)-2-羟基戊二酸(2HG)的新的能力。2HG不是由野生型IDH1形成。据称2HG的产生有助于癌症的形成和进展(Dang,L(丹格L)等人,Nature(《自然》)2009,462:739-44)。
所以,突变型IDH1及其新活性的抑制是用于癌症的一种潜在的治疗疗法。因此,对具有α羟基新活性的IDH1突变体的抑制剂存在持续需求。
发明概述
在此描述的是具有结构式I的化合物:
或其药学上可接受的盐,其中:
X是CR4或N;
Y是-N(R5)-或-CH(R5)-;
Z是-O-、-S-、-C(R)2-或N(R7);
W是C(R1)(R1)或N(R7);其条件是Z和W两者不同时为N(R7);
V是N或C(R);
每个R独立地选自氢、甲基或CF3;
每个R1独立地选自氢、烷氧基、或可任选地被OH或SH取代的烷基;
或两个R1与它们所结合的碳原子一起形成一个3-7元环烷基、或4-7元饱和杂环基环,其中所述环烷基或杂环基可任选地被甲基、卤素或CF3取代;
R2选自苯基、3-7元环烷基、C2-C4烷基、或CF3,其中该苯基或环烷基可任选地被一个选自甲基、CF3或氟的单个取代基取代;
每个R3独立地选自-(C1-C4亚烷基)-O-(C1-C4烷基)、-C1-C4氟代烷基、-C(O)-O-(C1-C4烷基)、-苯基、-杂芳基、C3-C7环烷基、-CH2-N(C1-C4烷基)2、C(O)-N-(C1-C4烷基)2、-C(O)-NH-(C1-C4烷基)、可任选地被卤素或–OH取代的-C1-C4烷基,或两个R3一起形成一个3-8元饱和环或稠合苯基,其中所述饱和环或稠合苯基可任选地被1至2个甲基取代;
R4选自氢、-CN、卤素、C1-C4烷氧基、-CH2NH(C1-C4烷基)、C2-C4烯基、C2-C4炔基、-(C1-C4烷基)-O-(C1-C4烷基)、C1-C4氟代烷基、C(O)-N-(C1-C4烷基)2、-C(O)-NH-(C1-C4烷基)、-S(O)2-(C1-C4烷基)、或5元杂芳基;
R5选自:C1-C4烷基、-C(O)-(C1-C4烷基)、-C(O)-(C0-C2亚烷基)-Q、-C(O)-(C0-C2亚烷基)-N(R6)-(C0-C2亚烷基)-Q、-C(O)-O-(C0-C2亚烷基)-Q、-C(O)-(C1-C2亚烷基)-O-(C0-C2亚烷基)-Q、-C(O)-C(O)-Q、-S(O)2-Q、-C(O)-(C1-C4亚烷基)-O-C(O)-(C1-C4烷基)、-C(O)-(C1-C4亚烷基)-C(O)-O-(C1-C4烷基)、-C(O)-N(R6)-(C1-C4亚烷基)-O-C(O)-(C1-C4烷基)、-C(O)-N(R6)-(C1-C4亚烷基)-C(O)-O-(C1-C4烷基)、-C(O)-(C0-C2亚烷基)-N(R6)-(C1-C6烷基)、-C(O)-(C0-C2亚烷基)-C(O)N(R6)-(C1-C6烷基)、-C(O)-(C0-C2亚烷基)-C(O)-(C1-C6烷基)、-C(O)-(C0-C2亚烷基)-N(R6)C(O)O-(C1-C6烷基)、-C(O)-(C0-C2亚烷基)N(R6)-(C2-C6炔基)、-C(O)-(C0-C2亚烷基)-N(R6)-(C2-C6烯基)、C(O)-(C0-C2亚烷基)-N(R6)-(C0-C2亚烷基)-O-(C1-C4烷基)、-C(O)-(C1-C4亚烷基)-O-(C1-C4烷基)、-C(O)-(C1-C2亚烷基)-C(O)C(O)N(R)(C1-C4烷基)、-C(O)-O-(C1-C4亚烷基)-O-(C1-C4烷基)、-(C0-C4亚烷基)-O-C(O)-(C1-C4烷基)、-(C0-C4亚烷基)-C(O)-O-(C1-C4烷基)、-(C0-C4亚烷基)-O-(C1-C4烷基)、-C(O)-(C1-C2亚烷基)-S(O)0-2-(C1-C4烷基)、-S(O)2-(C1-C4烷基)、-C(O)-(C1-C4亚烷基)-C(O)C(O)N(R6)(C1-C6烷基)、-C(O)-(C1-C4亚烷基)-N(R6)S(O)2-(C1-C6烷基)、或-C(O)-(C1-C4亚烷基)-N(R6)S(O)2Q,其中
R5中存在的任何亚烷基部分可任选地被OH或F取代;
R5中存在的任何末端甲基部分可任选地被-CH2OH、CF3、-CH2F、-CH2Cl、C(O)CH3、C(O)CF3、CN、-OH或CO2H替代;
每个R6独立地选自氢和甲基;
Q选自芳基、杂芳基、碳环基以及杂环基;并且Q可任选地被高达3个独立地选自以下项的取代基取代:可任选地被-OH取代的C1-C4烷基,C1-C4烷氧基,-(C1-C4亚烷基)-OC(O)O-(C1-C4烷基),-C(O)O-(C1-C4烷基),-CN,氟,氯,以及溴;
每个R7独立地是-G-L-M;
G是一个键或二价的C1-C6饱和的或不饱和的、直链的或支链的烃链,其中可任选地,该烃链的一个、两个或三个亚甲基单位独立地被-NR8-、-O-、-C(O)-、-OC(O)-、-C(O)O-、-S-、-SO-、-SO2-、-C(=S)-、-C(=NR8)-、-N=N-、或-C(=N2)-替代;
L是一个共价键或二价的C1-8饱和的或不饱和的、直链的或支链的烃链,其中L的一个、两个、或三个亚甲基单位可任选地并且独立地被环丙烯、-NR8-、-N(R8)C(O)-、-C(O)N(R8)-、-N(R8)SO2-、SO2N(R8)-、-O-、-C(O)-、-OC(O)-、-C(O)O-、-S-、-SO-、-SO2-、-C(=S)-、-C(=NR8)-、-N=N-、或-C(=N2)-替代;
M是E或3-10元单环的或二环的、饱和的、部分不饱和的、或芳香族的环,具有0-3个独立地选自氮、氧、或硫的杂原子,并且其中所述环被1-4个独立地选自以下项的基团取代:-D-E、氧、NO2、卤素、CN、C1-C6烷基、C2-C6烯基、或C2-C6炔基;
D是一个共价键或二价的C1-C6饱和的或不饱和的、直链的或支链的烃链,其中D的一个或两个亚甲基单位可任选地并且独立地被-NR8-、-S-、-O-、-C(O)-、-SO-、或-SO2-替代;
E是氢、C1-C6烷基、C2-C6烯基、或C2-C6炔基,其中所述烷基、烯基或炔基可任选地被氧、卤素、或CN取代;
每个R8独立地是氢、C1-C6烷基、C2-C6烯基、C2-C6炔基,或选自以下项的可任选经取代的基团:苯基,具有1-2个独立地选自氮、氧、或硫的杂原子的4-7元杂环基,或具有1-4个独立地选自氮、氧、或硫的杂原子的5-6元单环的杂芳环;并且
m是0、1、2或3。
具有化学式I的化合物抑制突变体IDH1,特别是具有α羟基新活性的突变体IDH1。在此还描述了包括具有化学式I的化合物的药物组合物以及使用此类组合物对特征在于突变型IDH1的存在的癌症进行治疗的方法。
发明详细说明
本发明在其申请中并不局限于在以下说明书中列举或在附图中说明的构造的细节以及组分的安排。本发明能够具有其他实施例并且能够以不同方式被实践或被进行。而且,在此使用的词组和术语是出于说明的目的并且不应当被视为是限制性的。在此使用的“包括(including)”、“包括(comprising)”、或“具有(having)”、“含有(containing)”、“涉及(involving)”及其变体意在涵盖其后列出的项及其等效物,连同额外的项。
定义:
术语“卤素(halo或halogen)”是指氟、氯、溴或碘的任何基团。
术语“烷基”是指可以是包含指定数目的碳原子的直链或支链的烃链。例如,C1-C12烷基表示其中可以具有从1至12(包括两端)个碳原子的基团。术语“卤烷基”是指其中一个或多个氢原子被卤素替代的烷基,并且包括其中所有氢已经被卤素替代的烷基部分(例如,全氟烷基)。术语“芳基烷基”或“芳烷基”是指烷基部分,其中烷基氢原子被芳基替代。芳烷基包括其中多于一个氢原子已经被芳基替代的基团。“芳基烷基”或“芳烷基”的实例包括苄基,2-苯基乙基,3-苯基丙基,9-芴基,二苯甲基和三苯甲基。
术语“亚烷基”是指二价的烷基,例如-CH2-、-CH2CH2-、-CH2CH2CH2-以及-CH2CH(CH3)CH2-。
术语“烯基”是指包含2-12个碳原子并且具有一个或多个双键的直链或支链的烃链。烯基的实例包括但不局限于,烯丙基,丙烯基,2-丁烯基,3-己烯基和3-辛烯基。双键碳中的一个可以任选地是烯基取代基的附接点。
术语“炔基”是指含有2-12个碳原子并且其特征在于具有一个或多个三键的直链或支链的烃链。炔基的实例包括但不局限于乙炔基、炔丙基和3-己炔基。三键碳中的一个可以任选地是炔基取代基的附接点。
术语“烷氧基”是指-O-烷基基团。术语“卤代烷氧基”是指其中一个或多个氢原子被卤素替代的烷氧基,并且包括其中所有氢已经被卤素替代的烷氧基部分(例如,全氟烷氧基)。
术语“芳基”是指完全芳香族的单环、双环或三环的烃环系统。芳基部分的实例是苯基、萘基、以及蒽基。除非另外说明,芳基中的任何环原子可以被一个或多个取代基取代。
术语“碳环基”是指非芳香族的、单环、双环或三环的烃环系统。碳环基包括完全饱和的环系统(例如,环烷基),以及部分饱和的环系统。
如在此使用的,术语“环烷基”包括具有3至12个碳的饱和环,双环,三环或多环烃基。任何环原子可以被取代(例如,被一个或多个取代基取代)。环烷基部分的实例包括但不局限于环丙基,环己基,甲基环己基,金刚烷基和降冰片基。
术语“杂芳基”是指全芳香族5-8元单环,8-12元双环或11-14元三环的环系统,如果是单环具有1-3个杂原子,如果是双环具有1-6个杂原子,或如果是三环具有1-9个杂原子,所述杂原子选自O、N或S(或氧化形式,例如N+-O-、S(O)以及S(O)2)。
术语“杂环基”是指非芳香族的3-10元单环,8-12元双环或11-14元三环的环系统,如果是单环具有1-3个杂原子,如果是双环具有1-6个杂原子,或如果是三环具有1-9个杂原子,所述杂原子选自O、N或S(或氧化形式,例如N+-O-、S(O)以及S(O)2)。该杂原子可以任选地是杂环基取代基的附接点。杂环基的实例包括但不局限于四氢呋喃基,四氢吡喃基,哌啶基,吗啉代,吡咯啉基,嘧啶基,和吡咯烷基。杂环基基团包括完全饱和的环系统,以及部分饱和的环系统。
含有一个或多个杂原子的双环和三环的环系统以及其中该环系统至该分子的其余部分的附着点是经由一个非芳香环的芳香环和非芳香环两者都被认为是杂环基基团。其中一个芳基或杂芳基被融合至碳环基或杂环基并且该环系统至该分子的其余部分的附着点是经由一个芳香环的双环或三环的环系统被认为是芳基或杂芳基基团。
单独的亦或作为一个基团的一部分(例如,芳烷基基团的芳基部分)的芳基、杂芳基、碳环基(包括环烷基)、以及杂环基基团在一个或多个可取代的原子处可任选地被独立地选自以下项的取代基取代(除非另外说明):卤素、-C≡N、C1-C4烷基、=O、-ORb、-ORb’、-SRb、-SRb’、-(C1-C4烷基)-N(Rb)(Rb)、-(C1-C4烷基)-N(Rb)(Rb’)、-N(Rb)(Rb)、-N(Rb)(Rb’)、-O-(C1-C4烷基)-N(Rb)(Rb)、-O-(C1-C4烷基)-N(Rb)(Rb’)、-(C1-C4烷基)-O-(C1-C4烷基)-N(Rb)(Rb)、-(C1-C4烷基)-O-(C1-C4烷基)-N(Rb)(Rb’)、-C(O)-N(Rb)(Rb)、-(C1-C4烷基)-C(O)-N(Rb)(Rb)、-(C1-C4烷基)-C(O)-N(Rb)(Rb’)、-ORb’、Rb’、-C(O)(C1-C4烷基)、-C(O)Rb’、-C(O)N(Rb’)(Rb)、-N(Rb)C(O)(Rb)、-N(Rb)C(O)(Rb’)、-N(Rb)SO2(Rb)、-SO2N(Rb)(Rb)、-N(Rb)SO2(Rb’)、以及-SO2N(Rb)(Rb’),其中任何烷基取代基可任选地进一步被-OH、-O-(C1-C4烷基)、卤素、-NH2、-NH(C1-C4烷基)、或-N(C1-C4烷基)2中的一个或多个取代;
每个Rb独立地选自氢和-C1-C4烷基;或
两个Rb与它们结合到其上的氮原子一起形成一个4-至8-元杂环,该杂环可任选地包括一个选自N、S、以及O的额外的杂原子;并且
每个Rb’独立地选自C3-C7碳环基、苯基、杂芳基、以及杂环基,其中在所述苯基、环烷基、杂芳基或杂环取代基上的一个或多个可取代的位置可任选地进一步被-(C1-C4烷基)、-(C1-C4氟代烷基)、-OH、-O-(C1-C4烷基)、-O-(C1-C4氟代烷基)、卤素、-NH2、-NH(C1-C4烷基)、或-N(C1-C4烷基)2中的一个或多个取代。
单独的亦或作为一个基团的部分,杂环基基团在一个或多个任何可取代的氮原子处可任选地被氧、-C1-C4烷基、或氟取代的C1-C4烷基取代。
术语“取代的”是指被另一个基团替代氢原子。
如在此使用的,术语“2HG的提高的水平”意指比不携带突变体IDH1等位基因的受试者中存在的2HG高10%、20%30%、50%、75%、100%、200%、500%或更多。术语“2HG的提高的水平”可以指细胞中的、肿瘤中的、包括肿瘤的器官中的、或体液中的2HG的量。
术语“体液”包括以下中的一种或多种:围绕胎儿的羊水,眼房水,血液(例如,血浆),血清,脑脊髓液,耵聍,食糜,库珀氏液(Cowper'sfluid),女性喷射液,间质液,淋巴,母乳,粘液(例如,鼻腔排液或痰),胸膜液,脓液,唾液,皮脂,精液,血清,汗,眼泪,尿液,阴道分泌物,或呕吐物。
如在此使用的,术语“抑制”或“预防”包括完全和部分抑制以及预防两者。抑制剂可以完全或部分地抑制预期靶标。
术语“治疗”意指降低(decrease)、抑制(suppress)、弱化、减少(diminish)、阻止(arrest)、或稳定一种疾病/失调(例如,癌症)的发展或进展,减轻该疾病/失调(例如,癌症)的严重性或改善与该疾病/失调(例如,癌症)相关联的症状。
如在此使用的,有效治疗紊乱的化合物的量,或“治疗有效量”是指在向受试者给予单一或多个剂量后,在处理细胞,或治疗、减轻、缓解或改善患病的受试者至超过没有进行这种治疗所预期的水平方面有效的化合物的量。
如在此使用的,术语“受试者”旨在包括人类和非人类动物。示例性人类受试者包括患有失调(例如在此所描述的失调)的人类患者(称作一位患者)或正常受试者。本发明的术语“非人类动物”包括所有脊椎动物,例如非哺乳动物(例如鸡、两栖动物、爬行动物)和哺乳动物,例如非人灵长类动物、家养动物和/或农业有用的动物,例如羊、狗、猫、牛、猪、等。
化合物
提供的是一种具有结构式I的化合物:
或其药学上可接受的盐,其中:
X是CR4或N;
Y是-N(R5)-或-CH(R5)-;
Z是-O-、-S-、-C(R)2-或N(R7);
W是C(R1)(R1)或N(R7);其条件是Z和W两者不同时为N(R7);
V是N或C(R);
每个R独立地选自氢、甲基或CF3;
每个R1独立地选自氢、烷氧基、或可任选地被OH或SH取代的烷基;
或两个R1与它们所结合的碳原子一起形成一个3-7元环烷基、或4-7元饱和杂环基环,其中所述环烷基或杂环基可任选地被甲基、卤素或CF3取代;
R2选自苯基、3-7元环烷基、C2-C4烷基、或CF3,其中该苯基或环烷基可任选地被一个选自甲基、CF3或氟的单个取代基取代;
每个R3独立地选自-(C1-C4亚烷基)-O-(C1-C4烷基)、-C1-C4氟代烷基、-C(O)-O-(C1-C4烷基)、-苯基、-杂芳基、C3-C7环烷基、-CH2-N(C1-C4烷基)2、C(O)-N-(C1-C4烷基)2、-C(O)-NH-(C1-C4烷基)、可任选地被卤素或-OH取代的-C1-C4烷基,或两个R3一起形成一个3-8元饱和环或稠合苯基,其中所述饱和环或稠合苯基可任选地被1至2个甲基取代;
R4选自氢、-CN、卤素、C1-C4烷氧基、-CH2NH(C1-C4烷基)、C2-C4烯基、C2-C4炔基、-(C1-C4烷基)-O-(C1-C4烷基)、C1-C4氟代烷基、C(O)-N-(C1-C4烷基)2、-C(O)-NH-(C1-C4烷基)、-S(O)2-(C1-C4烷基)、或5元杂芳基;
R5选自:C1-C4烷基、-C(O)-(C1-C4烷基)、-C(O)-(C0-C2亚烷基)-Q、-C(O)-(C0-C2亚烷基)-N(R6)-(C0-C2亚烷基)-Q、-C(O)-O-(C0-C2亚烷基)-Q、-C(O)-(C1-C2亚烷基)-O-(C0-C2亚烷基)-Q、-C(O)-C(O)-Q、-S(O)2-Q、-C(O)-(C1-C4亚烷基)-O-C(O)-(C1-C4烷基)、-C(O)-(C1-C4亚烷基)-C(O)-O-(C1-C4烷基)、-C(O)-N(R6)-(C1-C4亚烷基)-O-C(O)-(C1-C4烷基)、-C(O)-N(R6)-(C1-C4亚烷基)-C(O)-O-(C1-C4烷基)、-C(O)-(C0-C2亚烷基)-N(R6)-(C1-C6烷基)、-C(O)-(C0-C2亚烷基)-C(O)N(R6)-(C1-C6烷基)、-C(O)-(C0-C2亚烷基)-C(O)-(C1-C6烷基)、-C(O)-(C0-C2亚烷基)-N(R6)C(O)O-(C1-C6烷基)、-C(O)-(C0-C2亚烷基)N(R6)-(C2-C6炔基)、-C(O)-(C0-C2亚烷基)-N(R6)-(C2-C6烯基)、C(O)-(C0-C2亚烷基)-N(R6)-(C0-C2亚烷基)-O-(C1-C4烷基)、-C(O)-(C1-C4亚烷基)-O-(C1-C4烷基)、-C(O)-(C1-C2亚烷基)-C(O)C(O)N(R)(C1-C4烷基)、-C(O)-O-(C1-C4亚烷基)-O-(C1-C4烷基)、-(C0-C4亚烷基)-O-C(O)-(C1-C4烷基)、-(C0-C4亚烷基)-C(O)-O-(C1-C4烷基)、-(C0-C4亚烷基)-O-(C1-C4烷基)、-C(O)-(C1-C2亚烷基)-S(O)0-2-(C1-C4烷基)、-S(O)2-(C1-C4烷基)、-C(O)-(C1-C4亚烷基)-C(O)C(O)N(R6)(C1-C6烷基)、-C(O)-(C1-C4亚烷基)-N(R6)S(O)2-(C1-C6烷基)、或-C(O)-(C1-C4亚烷基)-N(R6)S(O)2Q,其中:
R5中存在的任何亚烷基部分可任选地被OH或F取代;
R5中存在的任何末端甲基部分可任选地被-CH2OH、CF3、-CH2F、-CH2Cl、C(O)CH3、C(O)CF3、CN、-OH或CO2H替代;
每个R6独立地选自氢和甲基;
Q选自芳基、杂芳基、碳环基以及杂环基;并且Q可任选地被高达3个独立地选自以下项的取代基取代:可任选地被-OH取代的C1-C4烷基,C1-C4烷氧基,-(C1-C4亚烷基)-OC(O)O-(C1-C4烷基),-C(O)O-(C1-C4烷基),-CN,氟,氯,以及溴;
每个R7独立地是-G-L-M;
G是一个键或二价的C1-C6饱和的或不饱和的、直链的或支链的烃链,其中可任选地,该烃链的一个、两个或三个亚甲基单位独立地被-NR8-、-O-、-C(O)-、-OC(O)-、-C(O)O-、-S-、-SO-、-SO2-、-C(=S)-、-C(=NR8)-、-N=N-、或-C(=N2)-替代;
L是一个共价键或二价的C1-8饱和的或不饱和的、直链的或支链的烃链,其中L的一个、两个、或三个亚甲基单位可任选地并且独立地被环丙烯、-NR8-、-N(R8)C(O)-、-C(O)N(R8)-、-N(R8)SO2-、SO2N(R8)-、-O-、-C(O)-、-OC(O)-、-C(O)O-、-S-、-SO-、-SO2-、-C(=S)-、-C(=NR8)-、-N=N-、或-C(=N2)-替代;
M是E或3-10元单环的或二环的、饱和的、部分不饱和的、或芳香族的环,具有0-3个独立地选自氮、氧、或硫的杂原子,并且其中所述环被1-4个独立地选自以下项的基团取代:-D-E、氧、NO2、卤素、CN、C1-C6烷基、C2-C6烯基、或C2-C6炔基;
D是一个共价键或二价的C1-C6饱和的或不饱和的、直链的或支链的烃链,其中D的一个或两个亚甲基单位可任选地并且独立地被-NR8-、-S-、-O-、-C(O)-、-SO-、或-SO2-替代;
E是氢、C1-C6烷基、C2-C6烯基、或C2-C6炔基,其中所述烷基、烯基或炔基可任选地被氧、卤素、或CN取代;
每个R8独立地是氢、C1-C6烷基、C2-C6烯基、C2-C6炔基,或选自以下项的可任选经取代的基团:苯基,具有1-2个独立地选自氮、氧、或硫的杂原子的4-7元杂环基,或具有1-4个独立地选自氮、氧、或硫的杂原子的5-6元单环的杂芳环;并且
m是0、1、2或3。
在一些实施例中,提供的是一种具有结构式I的化合物:
或其药学上可接受的盐,其中:
X是CR4或N;
Y是-N(R5)-或-CH(R5)-;
Z是-O-、-S-、-C(R)2-或N(R7);
W是C(R1)(R1)或N(R7);其条件是(1)当Z是-C(R)2-时,那么W不是C(R1)(R1);并且(2)Z和W两者不同时是N(R7);
V是N或C(R);
每个R独立地选自氢、甲基或CF3;
每个R1独立地选自氢、烷氧基、或可任选地被OH或SH取代的烷基;
或两个R1与它们所结合的碳原子一起形成一个3-7元环烷基、或4-7元饱和杂环基环,其中所述环烷基或杂环基可任选地被甲基、卤素或CF3取代;
R2选自苯基、3-7元环烷基、或C2-C4烷基,其中该苯基或环烷基可任选地被一个选自甲基、CF3或氟的单个取代基取代;
每个R3独立地选自可任选地被卤素取代的-C1-C4烷基,-(C1-C4烷基)-O-(C1-C4烷基),-C1-C4氟代烷基,-C(O)-O-(C1-C4烷基),-苯基,-杂芳基,C3-C7环烷基,-CH2-N(C1-C4烷基)2,C(O)-N-(C1-C4烷基)2,-C(O)-NH-(C1-C4烷基),或两个R3一起形成一个3-8元饱和环或稠合苯基,其中所述饱和环或稠合苯基可任选地被1至2个甲基取代;
R4选自氢、-CN、卤素、C1-C4烷氧基、-CH2NH(C1-C4烷基)、C2-C4烯基、C2-C4炔基、-(C1-C4烷基)-O-(C1-C4烷基)、C1-C4氟代烷基、C(O)-N-(C1-C4烷基)2、-C(O)-NH-(C1-C4烷基)、-S(O)2-(C1-C4烷基)、以及5元杂芳基;
R5选自:-C(O)-(C1-C4烷基)、-C(O)-(C0-C2亚烷基)-Q、-C(O)-(C0-C2亚烷基)-N(R6)-(C0-C2亚烷基)-Q、-C(O)-O-(C1-C2亚烷基)-Q、-C(O)-(C1-C2亚烷基)-O-(C0-C2亚烷基)-Q、-C(O)-C(O)-Q、-S(O)2-Q、-C(O)-(C1-C4亚烷基)-O-C(O)-(C1-C4烷基)、-C(O)-(C1-C4亚烷基)-C(O)-O-(C1-C4烷基)、-C(O)-N(R6)-(C1-C4亚烷基)-O-C(O)-(C1-C4烷基)、-C(O)-N(R6)-(C1-C4亚烷基)-C(O)-O-(C1-C4烷基)、-C(O)-(C0-C2亚烷基)-N(R6)-(C1-C6烷基)、-C(O)-(C0-C2亚烷基)N(R6)-(C2-C6炔基)、-C(O)-(C0-C2亚烷基)-N(R6)-(C2-C6烯基)、-C(O)-(C0-C2亚烷基)-N(R6)-(C0-C2亚烷基)-O-(C1-C4烷基)、-C(O)-(C1-C2亚烷基)-O-(C1-C4烷基)、-C(O)-(C1-C2亚烷基)-C(O)C(O)N(R)(C1-C4烷基)、-C(O)-O-(C1-C4亚烷基)-O-(C1-C4烷基)、-(C0-C4亚烷基)-O-C(O)-(C1-C4烷基)、-(C0-C4亚烷基)-C(O)-O-(C1-C4烷基)、-(C0-C4亚烷基)-O-(C1-C4烷基)、-C(O)-(C1-C2亚烷基)-S(O)0-2-(C1-C4烷基)、-S(O)2-(C1-C4烷基)、)、-C(O)-(C1-C4亚烷基)-C(O)C(O)N(R6)(C1-C6烷基)、-C(O)-(C1-C4亚烷基)-N(R6)S(O)2-(C1-C6烷基)、以及-C(O)-(C1-C4亚烷基)-N(R6)S(O)2Q,其中:
R5中存在的任何亚烷基部分可任选地被OH或F取代;
R5中存在的任何末端甲基部分可任选地被-CH2OH、CF3、-CH2F、-CH2Cl、C(O)CH3、或C(O)CF3替代;
每个R6独立地选自氢和甲基;
Q选自芳基、杂芳基、碳环基以及杂环基;并且Q可任选地被高达3个独立地选自以下项的取代基取代:C1-C4烷基、C1-C4烷氧基、-CN、氟、氯、以及溴;
每个R7独立地是-G-L-M;
G是一个键或二价的C1-C6饱和的或不饱和的、直链的或支链的烃链,其中可任选地,该烃链的一个、两个或三个亚甲基单位独立地被-NR8-、-O-、-C(O)-、-OC(O)-、-C(O)O-、-S-、-SO-、-SO2-、-C(=S)-、-C(=NR8)-、-N=N-、或-C(=N2)-替代;
L是一个共价键或二价的C1-8饱和的或不饱和的、直链的或支链的烃链,其中L的一个、两个、或三个亚甲基单位可任选地并且独立地被环丙烯、-NR8-、-N(R8)C(O)-、-C(O)N(R8)-、-N(R8)SO2-、SO2N(R8)-、-O-、-C(O)-、-OC(O)-、-C(O)O-、-S-、-SO-、-SO2-、-C(=S)-、-C(=NR8)-、-N=N-、或-C(=N2)-替代;
M是E或3-10元单环的或二环的、饱和的、部分不饱和的、或芳香族的环,具有0-3个独立地选自氮、氧、或硫的杂原子,并且其中所述环被1-4个独立地选自以下项的基团取代:-D-E、氧、NO2、卤素、CN、C1-C6烷基、C2-C6烯基、或C2-C6炔基;
D是一个共价键或二价的C1-C6饱和的或不饱和的、直链的或支链的烃链,其中D的一个或两个亚甲基单位可任选地并且独立地被-NR8-、-S-、-O-、-C(O)-、-SO-、或-SO2-替代;
E是氢、C1-C6烷基、C2-C6烯基、或C2-C6炔基,其中所述烷基、烯基或炔基可任选地被氧、卤素、或CN取代;
每个R8独立地是氢、C1-C6烷基、C2-C6烯基、C2-C6炔基,或选自以下项的可任选经取代的基团:苯基,具有1-2个独立地选自氮、氧、或硫的杂原子的4-7元杂环基,或具有1-4个独立地选自氮、氧、或硫的杂原子的5-6元单环的杂芳环;并且
m是0、1、2或3。
在一些实施例中,当X是-C(CN)-,Y是-N(R5)-,m是0,R2是苯基或C2-C4烷基,并且Z是-O-或-S-时,那么每个R1不同时是甲基;并且当X是-C(CN)-,Y是-N(R5)-,m是0,R2是苯基或C2-C4烷基,Z是-CH2-并且W是C(R1)(R1)时,那么每个R1不同时是氢。
在一些实施例中,X是-C(CN)-。
在一些实施例中,每个R1都是相同的并且选自甲基和氢。在这些实施例的一个方面中,Z是-O-。在这些实施例的一个替代性方面中,Z是-N(R7)-。在这些实施例的一个替代性方面中,Z是-C(CH3)2-并且每个R1是氢。在这些实施例的再另一个方面中,Z是-CH2-。
在一些实施例中,Y是-N(R5)-。
在一些实施例中,R2选自可任选地被单个的氟或单个的甲基取代的苯基,可任选地被单个的甲基取代的环己基、环戊基、环丁基、环丙基,异丙基,乙基以及甲基。在这一实施例的一个方面中,R2选自环己基、环丁基、环丙基、乙基以及异丙基。在这些实施例的一个方面中,R2是环己基,Z是-O-并且每个R1都是氢。在这些实施例的另一个方面中,R2选自环丙基和异丙基,Z是-O-并且每个R1是甲基。
在一些实施例中,每个R3独立地选自氢、甲基、乙基、异丁基、异丙基、苯基、-C(O)-O-CH2CH3、-C(O)-O-CH3、以及-CH2-O-CH3。
R3c选自氢和甲基;
R3d选自氢、苯基和甲基
在一些实施例中,R4选自:
在一些实施例中,R5选自-C(O)-(C1-C4烷基)、-C(O)-(CH2)0-2-Q、-C(O)-(CH2)1-2-O-(CH2)0-2-Q、-C(O)-(C1-C4亚烷基)-C(O)-O-(C1-C4烷基)、-C(O)-N(R6)-(C1-C4亚烷基)-C(O)-O-(C1-C4烷基)、-C(O)-(CH2)0-2-N(R6)-(C2-C6烯基)、-C(O)-(CH2)1-2-O-(C1-C4烷基)、-C(O)-O-(C1-C4亚烷基)-O-(C1-C4烷基)、-(CH2)0-4-C(O)-O-(C1-C4烷基)、以及-C(O)-(CH2)1-2-S-(C1-C4烷基)。
在一些实施例中,每个R7独立地选自:
-C(O)-CH3、-SO2CH3、-CH2CH2OH、-(CH2)1-4-SH、或-(CH2)1-4-OH。
在一些实施例中,该化合物由结构式II描绘;
其中:
每个R1是相同的并且选自氢和甲基;
R2选自可任选地被单个的氟或单个的甲基取代的苯基,可任选地被单个的甲基取代的环己基、环戊基、环丁基、环丙基,异丙基以及甲基;
R3a选自氢和甲基;
R3b选自氢、甲基、乙基、异丁基、异丙基、环丙基、苯基、-C(O)-O-CH2CH3、-C(O)-O-CH3、以及-CH2-O-CH3,其中甲基、乙基、异丁基、以及异丙基中的每一个可任选地被氟取代;
R3c选自氢和甲基;
R3d选自氢、苯基和甲基;并且
R5是如对于结构式I所定义的。
在结构式II的某些实施例中,每个R1是甲基;并且R2选自乙基、异丙基、环丙基以及环丁基。在这些实施例的一个方面中,R3a、R3c和R3d同时是氢;并且R3b选自(R)-甲基、(R)-乙基、(R)-异丙基、以及C(O)-O-CH2CH3。在一些实施例中,结构式II的哌啶环中或R3a、R3b、R3c、或R3d中的一个或多个氢是氘同位素。
在结构式II的某些实施例中,每个R1是甲基;并且R2是环丙基。在这些实施例的一个方面中,R3a、R3c和R3d同时是氢;并且R3b选自(R)-甲基、(R)-乙基、(R)-异丙基、(R)-环丙基、以及C(O)-O-CH2CH3。在一些实施例中,结构式II的哌啶环中或R3a、R3b、R3c、或R3d中的一个或多个氢是氘同位素。
在结构式II的一个替代性实施例中,每个R1是氢;并且R2是环己基。在这些实施例的一个方面中,R3a、R3c和R3d同时是氢;并且R3b是(R)-甲基。
在结构式I或II的一些实施例中,R5选自-C(O)-(C1-C4烷基)、-C(O)-(CH2)0-2-Q、-C(O)-(CH2)1-2-O-(CH2)0-2-Q、-C(O)-(CH2)0-2-Q-C(O)-(C1-C2烷基)、-C(O)-(CH2)0-2-Q-(C1-C4烷基)、-C(O)-(CH2)0-2-Q-OC(O)O-(C1-C4烷基)、-C(O)-(C1-C4亚烷基)-C(O)-O-(C1-C4烷基)、-C(O)-N(R6)-(C1-C4亚烷基)-C(O)-O-(C1-C4烷基)、-C(O)-(CH2)0-2-N(R6)-(C2-C6烯基)、-C(O)-(CH2)1-2-O-(C1-C4烷基)、-C(O)-O-(C1-C4亚烷基)-O-(C1-C4烷基)、-(CH2)0-4-C(O)-O-(C1-C4烷基)、以及-C(O)-(CH2)1-2-S-(C1-C4烷基)。在这些实施例的一个方面中,R5选自-C(O)-(CH2)0-3-OCH3、-C(O)-(CH2)0-3-OCH2CH3、-C(O)-呋喃基、-C(O)-NH-CH2-CH=CH2、-C(O)-(CH2)1-4-C(O)-OCH3、C(O)-(CH2)2-C(O)-OC2-C3烷基、-C(O)-(CH2)2C(O)CH3、C(O)-(CH2)2-C(O)-OC(CH2)2OH、-C(O)-(CH2)1-2-SCH3、-C(O)-环丙基、-C(O)-异噁唑基、-C(O)-CH2-环丙基、-C(O)-CH2CH3、-C(O)-(CH2)2CH3、-C(O)-CH2Cl、-C(O)-NH-CH3、-C(O)-CH2-噻吩基、-C(O)-NH-(CH2)2-C(O)-OCH3、-C(O)-CH2-吡啶基、-C(O)-(CH2)2-O-苯基、-C(O)-CH2-吡唑基、-C(O)-CH2-噁二唑基、-C(O)-噁唑基、-C(O)CH2CF3、C(O)(CH2)2-3OH、-C(O)(CH2)C(O)CH3、-C(O)CH2CH(OH)CH3、-C(O)CH2CH2F、-C(O)环丙基-C(O)O-C1-C2烷基、-C(O)环丙基-CH2-OC(O)O-C1-C2烷基、以及C(O)环丙基-CH2OH。
在另一个实施例中,该化合物选自列举于下表1中的任何一种化合物。
在一些实施例中,该化合物由结构式III描绘;
其中:
W或Z中之一是N(R7)并且W或Z中的另一个是C(R1)(R1)
每个R1都是相同的并且选自氢和甲基;
R2选自可任选地被单个的氟或单个的甲基取代的苯基,可任选地被单个的甲基取代的环己基、环戊基、环丁基、环丙基,异丙基以及甲基;
R3a选自氢和甲基;
R3b选自氢、甲基、乙基、异丁基、异丙基、苯基、C3-C7环烷基、-C(O)-O-CH2CH3、-C(O)-O-CH3、以及-CH2-O-CH3;
R3c选自氢和甲基;
R3d选自氢、苯基和甲基;并且
R5选自:-C(O)-(C1-C4烷基)、-C(O)-(C0-C2亚烷基)-Q、-C(O)-(C1-C4亚烷基)-O-C(O)-(C1-C4烷基)、-C(O)-(C1-C4亚烷基)-C(O)-O-(C1-C4烷基)、-C(O)-(C1-C2亚烷基)-O-(C1-C4烷基)、-C(O)-O-(C1-C4亚烷基)-O-(C1-C4烷基)、-(C0-C4亚烷基)-O-C(O)-(C1-C4烷基)、-(C0-C4亚烷基)-C(O)-O-(C1-C4烷基)、以及-(C0-C4亚烷基)-O-(C1-C4烷基),其中:
R5中存在的任何亚烷基部分可任选地被OH或F取代;
R5中存在的任何末端甲基部分可任选地被-CH2OH、CF3、-CH2F、-CH2Cl、C(O)CH3、或C(O)CF3替代;
Q选自芳基、杂芳基、碳环基以及杂环基;并且Q可任选地被高达3个独立地选自以下项的取代基取代:C1-C4烷基、C1-C4烷氧基、-CN、氟、氯、以及溴;并且
R7是如对于结构式I所定义的。
在一些实施例中,每个R1是H。
在一些实施例中,Z是N(R7)并且W是CH2。在一些实施例中,R7是这样的,使得与G-L-M一起形成C(O)C1-C4烷基,例如C(O)CH3;C(O)C2-C4烯基,例如C(O)CHCH2;或C(O)C2-C4炔基,例如C(O)CCH,在一些实施例中,R7是这样的,使得与G-L-M一起形成S(O)2C1-C4烷基(例如S(O)2CH3)或S(O)2C2-C4烯基。在一些实施例中,R7是这样的,使得与G-L-M一起形成-C1-C4-OH,例如-CH2CH2OH。
在一些实施例中,W是N(R7)并且Z是CH2。在一些实施例中,R7是这样的,使得与G-L-M一起形成C(O)C1-C4烷基,例如C(O)CH3;C(O)C2-C4烯基,例如C(O)CHCH2;或C(O)C2-C4炔基,例如C(O)CCH。在一些实施例中,R7是这样的,使得与G-L-M一起形成S(O)2C1-C4烷基(例如S(O)2CH3)或S(O)2C2-C4烯基。在一些实施例中,C(O)C2-C4烷基被氟取代,例如形成C(O)CFCH2。
在一些实施例中,R2选自可任选地被单个的甲基取代的环己基、环戊基、环丁基、或环丙基,异丙基以及甲基。在一些实施例中,R2选自环丙基。
在一些实施例中,R3a是氢并且R3b选自甲基、乙基、异丁基、异丙基、以及C3-C7环烷基。在一些实施例中,R3b是C3-C7环烷基,例如环丙基,像(R)环丙基。
在一些实施例中,R3a和R3b具有在化学式(II)的化合物中的以下立体构型:
在一些实施例中,R3c是氢。在一些实施例中,R3d是氢。在一些实施例中,R3c和R3d两者都是氢。
在一些实施例中,R5选自:-C(O)-(C1-C4烷基)、-C(O)-(C0-C2亚烷基)-Q、-C(O)-(C1-C2亚烷基)-O-(C1-C4烷基),其中:R5中存在的任何亚烷基部分可任选地被OH或F取代;并且R5中存在的任何末端甲基部分可任选地被-CH2OH、CF3、-CH2F、-CH2Cl、C(O)CH3、或C(O)CF3替代。在一些实施例中,R5是:-C(O)-(C1-C4烷基),其中R5中存在的任何末端甲基部分可任选地被-CH2OH、CF3、-CH2F、-CH2Cl、C(O)CH3、或C(O)CF3,例如CH2CF3替代。在一些实施例中,R5是C(O)-(C0-C2亚烷基)-Q,其中Q是碳环基,例如环丙基。在一些实施例中,R5是-C(O)环丙基。在一些实施例中,R5是-C(O)-(C1-C2亚烷基)-O-(C1-C4烷基)。在一些实施例中,R5是-C(O)CH2CH2OCH3。
示例性化合物提供于下表4中:
表4
本发明的化合物可以含有一个或多个不对称中心并且因此作为消旋体、消旋混合物、非消旋混合物(scalemic mixture)、以及非对映异构体混合物、连同基本上不含另一种可能的对映体或立体异构体的单一对映异构体或单独的立体异构体而出现。如在此使用的,术语“基本上不含其他立体异构体”意指富含这样一种化合物的制剂,该化合物在一个或多个所选择的立体中心处具有至少约60%、65%、70%、75%、80%、85%、90%、95%、96%、97%、98%、或99%的所选择的立体化学性。术语“富含”意指至少指定百分比的制剂是在一个或多个选择的立构中心处具有所选择的立体化学性的化合物。获得或合成给定的化合物的单独的对映异构体或立体异构体的方法在本领域中是已知的并且可以切实可行的应用至最终化合物或起始材料或中间体。
在一个实施例中,当m是2并且两个不同的R3基团结合至同一碳上时,具有化学式I的化合物富含在两个R3基团结合的碳原子处具有所选择的立体化学性的一种或多种结构。在一个实施例中,在那个碳原子处的所选择的立体化学性是R。在另一个实施例中,在那个碳原子处的所选择的立体化学性是S。例如,该化合物以至少约60%、65%、70%、75%、80%、85%、90%、95%、96%、97%、98%、或99%富含特定的立体异构体。
具有化学式I的化合物还可以包括一个或多个同位素置换。例如,H可以处于任何同位素形式,包括1H,2H(D或氘)以及3H(T或氚);C可以处于任何同位素形式,包括12C,13C,以及14C;O可以处于任何同位素形式,包括16O以及18O;等。
除非另外指明,当一种披露的化合物通过未指明立体化学性的结构来命名或描绘且具有一个或多个手性中心时,应理解为表示该化合物的所有可能的立体异构体。
本发明的这些化合物还可表示为多种互变异构形式,在这类情况下,本发明清楚地包括在此描述的这些化合物的所有互变异构形式,即使仅仅单一互变异构形式可被表示(例如,环系统的烷基化可导致多个位点的烷基化,本发明清楚地包括所有此类反应产物)。本发明中清楚地包括此类化合物的所有此类异构体形式。本发明清楚地包括在此描述的这些化合物的所有晶形。
可以方便的或令人希望的制备、纯化、和/或处理该活性化合物的对应的盐,例如药学上可接受的盐。药学上可接受的盐的实例讨论于Berge(贝尔热)等人,1977,“Pharmaceutically Acceptable Salts(药学上可接受的盐),”J.Pharm.Sci.(《药学科学杂志》)第66卷,第1-19页中。
例如,如果这种化合物是阴离子的,或具有可以是阴离子的官能团(例如,-COOH可以是-COO-),那么可以与一种适合的阳离子形成盐。适合的无机阳离子的实例包括,但不限于:碱金属离子,例如Na+和K+;碱土金属阳离子,例如Ca2+和Mg2+;以及其他阳离子,例如Al3+。适合的有机阳离子的实例包括,但不限于:铵离子(即,NH4 +)以及经取代的铵离子(例如,NH3R+、NH2R2+、NHR3+、NR4+)。一些适合的经取代的铵离子的实例是衍生自以下的那些:乙胺,二乙胺,二环己胺,三乙胺,丁胺,乙二胺,乙醇胺,二乙醇胺,哌嗪,苄胺,苯基苄胺,胆碱,葡甲胺,以及氨丁三醇,连同氨基酸(例如赖氨酸和精氨酸)。常见的季铵离子的一个实例是N(CH3)4 +。
如果这种化合物是阳离子的,或具有可以是阳离子的官能团(例如,-NH2可以是-NH3 +),那么可以与一种适合的阴离子形成盐。适合的无机阴离子的实例包括,但不限于衍生自以下无机酸的那些:盐酸,氢溴酸,氢碘酸,硫酸,亚硫酸,硝酸,亚硝酸,磷酸,以及亚磷酸。
适合的有机阴离子的实例包括,但不限于衍生自以下有机酸的那些:2-乙酰氧基苯甲酸,乙酸,抗坏血酸,天冬氨酸,苯甲酸,樟脑磺酸,肉桂酸,柠檬酸,依地酸,乙烷二磺酸,乙烷磺酸,富马酸,葡庚糖酸,葡糖酸,谷氨酸,乙醇酸,羟基马来酸,羟基萘羧酸,羟乙基磺酸,乳酸,乳糖酸,月桂酸,马来酸,苹果酸,甲烷磺酸,粘酸,油酸,草酸,棕榈的酸,扑酸,泛酸,苯乙酸,苯磺酸,丙酸,丙酮酸,水杨酸,硬脂酸,琥珀酸,磺胺酸,酒石酸,甲基苯磺酸,以及缬草酸。适合的聚合有机阴离子的实例包括,但不限于衍生自以下聚合酸的那些:鞣酸,羧甲基纤维素。
除非另外说明,一种具体化合物的提及也包括其盐。
组合物和给予途径
在向一位受试者给予之前,可以将在此处所描述的方法中利用的化合物与一种药学上可接受的载体或佐剂一起配制为药学上可接受的组合物。在另一个实施例中,此类药学上可接受的组合物进一步包括处于有效实现疾病或疾病症状(包括在此所描述的那些)的调节的量的额外治疗剂。
术语“药学上可接受的载体或佐剂”是指可以与本发明的化合物一起被给予给一位受试者,且不破坏其药理活性,并且当按足以递送该化合物的治疗量的剂量给予时为无毒的载体或佐剂。
可用于本发明的药物组合物的药学上可接受的载体、佐剂和媒介物包括但不限于离子交换剂、氧化铝、硬脂酸铝、卵磷脂、自乳化药物递送系统(SEDDS)例如d-α-生育酚聚乙二醇1000琥珀酸酯、用于药物剂型例如吐温或其他类似聚合物递送基质的表面活性剂、血清蛋白例如人血清蛋白、缓冲物质例如磷酸盐、甘氨酸、山梨酸、山梨酸钾、饱和的植物脂肪酸的偏甘油酯混合物、水、盐或电解质例如硫酸鱼精蛋白、磷酸氢二钠、磷酸氢钾、氯化钠、锌盐、胶体硅、三硅酸镁、聚乙烯吡咯烷酮、基于纤维素的物质、聚乙二醇、羧甲基纤维素钠、聚丙烯酸酯、蜡、聚乙烯-聚氧丙烯-嵌段聚合物、聚乙二醇和羊毛脂。环糊精例如α-、β-和γ-环糊精、或化学修饰的衍生物,例如羟基烷基环糊精(包括2-和3-羟基丙基-β-环糊精)、或其他可溶性衍生物也可以有利地用于增强具有在此描述的化学式的化合物的递送。
本发明的药物组合物可经口服、胃肠外、吸入喷雾、局部、直肠、鼻、口腔、阴道或经由植入式储药器的形式给予,优选地通过口服给予或通过注射给予。本发明的药物组合物可以含有任何无毒的常规药学上可接受的载体、佐剂或媒介物。在一些情况下,可用药学上可接受的酸、碱或缓冲液调节该配制品的pH以增强所配制的化合物或其递送形式的稳定性。如在此使用的,术语胃肠外包括皮下的,皮内的,静脉内的,肌内的,关节内的,动脉内的,滑膜内的,胸骨内的,鞘内的,病灶内的和颅内的注射或输注技术。
这些药物组合物可以处于无菌可注射制剂的形式,例如,为无菌可注射水性或油性的悬浮液的形式。这种悬浮液可以根据本领域中已知技术,使用适合的分散剂或润湿剂(例如像,吐温80)和助悬剂进行配制。该无菌可注射制剂也可以是在一种无毒的胃肠外可接受的稀释液或溶剂中的无菌可注射溶液或悬浮液,例如,为一种在1,3-丁二醇中的溶液。可能用到的可接受的媒介物和溶剂之中,有甘露醇、水、林格氏溶液和等渗氯化钠溶液。此外,无菌性非挥发油通常用作溶剂或悬浮介质。为此目的,可使用任何温和的非挥发油,包括合成的单甘油酯或二甘油酯。脂肪酸,例如油酸及其甘油酯衍生物在血管注射剂的制备中是有用的,天然的药学上可接受的油(例如橄榄油或蓖麻油,尤其处于其聚氧乙烯化形态)也是有用的。这些油溶液或悬浮液还可以包含长链醇稀释液或分散剂,或羧甲基纤维素或通常用于配制药学上可接受剂型(例如乳剂和或悬浮液)的类似分散剂。出于配制的目的,还可使用其他常用的表面活性剂例如吐温或司盘和/或其他常用于制造药学上可接受的固体、液体或其他剂型的类似乳化剂或生物利用度增强剂。
本发明的药物组合物能以任何口服可接受剂型口服给予,这些剂型包括但不局限于,胶囊,片剂,乳剂和水性悬浮液,分散体和溶液。在口服使用的片剂的情况下,常用的载体包括乳糖和玉米淀粉。通常也添加润滑剂,如硬脂酸镁。对胶囊形式的口服给予有用的稀释剂包括乳糖和干燥玉米淀粉。当口服给予水性悬浮液和/或乳剂时,可悬浮或溶解于油相中的活性成分与乳化剂和/或助悬剂结合。如果希望的话,可以添加某些甜味剂和/或调味剂和/或着色剂。
本发明的药物组合物还能以用于直肠给予的栓剂形式给予。这些组合物可以通过混合本发明的化合物与适合的无刺激性的赋形剂来制备,该赋形剂在室温时是固体,但在直肠温度时是液体,并且因此将在直肠中熔融以释放这些活性组分。此类物质包括但不局限于可可脂、蜂蜡和聚乙二醇。
当所希望的治疗涉及通过局部应用容易接近的区域或器官时,本发明的药物组合物的局部给予是有用的。对于局部应用于皮肤,该药物组合物应该用合适的、含有悬浮或溶解在载体中的活性组分的软膏进行配制。用于本发明的这些化合物的局部给予的载体包括但不限于:矿物油,液态石油,白凡士林,丙二醇,聚氧乙烯聚氧丙烯化合物,乳化蜡和水。可替代地,该药物组合物可以与适合的洗剂和乳膏进行配制,该洗剂和乳膏含有悬浮或溶解于载体(具有适合的乳化剂)中的活性化合物。适合的载体包括但不限于:矿物油、脱水山梨糖醇单硬脂酸酯、聚山梨醇酯60、十六烷基酯蜡、鲸蜡硬脂醇、2-辛基十二烷醇、苯甲醇和水。本发明的药物组合物还可以通过直肠栓剂配制品或以适合的灌肠剂配制品形式局部应用于低位肠道。本发明还包括局部透皮贴剂。
本发明的药物组合物可以通过鼻气溶胶或吸入给予。根据药物配制品领域中熟知的技术制备此类组合物并且可以采用苯甲醇或其他适合的防腐剂、用以增强生物利用度的吸收促进剂、碳氟化合物、和/或其他本领域中己知的增溶剂或分散剂将其制备为盐水溶液。
当本发明的组合物包括具有在此描述的化学式的化合物与一种或多种额外治疗剂或预防剂的组合时,该化合物与该额外的药剂两者应以正常给予单一疗法方案中的剂量的约1%至100%之间,并且更优选约5%至95%之间的剂量水平存在。这些额外的药剂可以作为多剂量方案的一部分,与本发明的这些化合物分开给予。可替代地,那些药剂可以是单一剂型的部分,与本发明的这些化合物一起混合在单一组合物中。
在此描述的这些化合物可以,例如,通过静脉内、动脉内、经皮下(subdermally)、腹膜内、肌内或皮下地(subcutaneously)注射给予;或通过口服、经颊、经鼻、经粘膜、局部、在眼用制剂中或通过吸入给予,剂量范围为从约0.5至约100mg/kg体重,可替代地剂量在1mg与1000mg/剂量之间,每4至120小时给予一次,或根据具体药物的需要。在此的这些方法预期给予有效量的化合物或化合物组合物以实现所希望的或所述的作用。典型地,将从每天约1次至约6次或可替代地以连续输注形式给予本发明的这些药物组合物。此类给予可用作慢性或急性疗法。可与载体材料组合以产生单一剂型的活性成分的量将根据待治疗的宿主和具体的给予模式而变化。典型的制剂将包含从约5%至约95%的活性化合物(w/w)。可替代地,此类制剂包含从约20%至约80%的活性化合物。
可能需要低于或高于上述量的剂量。针对任何特定受试者的具体剂量和治疗方案将取决于多种因素,这些因素包括所用的具体化合物的活性,年龄,体重,总体健康状况,性别,饮食,给予时间,排泄速率,药物组合,该疾病、病症或症状的严重性和进程,受试者易患该疾病、病症或症状,以及治疗医生的判断。
受试者的病症经改善之后,如果必要的话,可以给予维持剂量的本发明的化合物、组合物或组合。随后,给予的剂量或频率或两者,作为这些症状的函数,可减至当这些症状已被减轻至所希望水平时保持经改善的病症的水平。然而,一旦疾病症状有任何复发,则受试者就需要基于长期的间歇治疗。
包括具有结构式I或II的化合物或在此处的任一实施例中描述的化合物的药物组合物可以进一步包括另一种用于治疗癌症的治疗剂。
使用方法
提供了一种用于抑制突变型IDH1活性的方法,该方法包括使对其有需要的受试者与具有结构式I或II的化合物、在此处的任一实施例中描述的化合物、或其药学上可接受的盐进行接触。在一个实施例中,有待治疗的癌症的特征在于IDH1的突变型等位基因,其中IDH1突变导致一位受试者中这种酶催化α-酮戊二酸依赖于NAPH地还原为R(-)-2-羟基戊二酸的新的能力。在这个实施例的一个方面中,这种突变型IDH1具有R132X突变。在这个实施例的一个方面中,该R132X突变选自R132H、R132C、R132L、R132V、R132S以及R132G。在另一个方面中,该R132X突变是R132H或R132C。在又另一个方面中,该R132X突变是R132H。
还提供了对特征在于IDH1的突变型等位基因的存在的癌症进行治疗的方法,这些方法包括以下步骤:向对其有需要的受试者给予(a)具有结构式I或II的化合物,在此处的任一实施例中描述的化合物,或其药学上可接受的盐;或(b)包括(a)以及药学上可接受的载体的药物组合物。
在一个实施例中,有待治疗的癌症的特征在于IDH1的突变型等位基因,其中IDH1突变导致一位患者中这种酶催化α-酮戊二酸依赖于NAPH地还原为R(-)-2-羟基戊二酸的新的能力。在这个实施例的一个方面中,该IDH1突变是R132X突变。在这个实施例的另一个方面中,该R132X突变选自R132H、R132C、R132L、R132V、R132S以及R132G。在另一个方面中,该R132X突变是R132H。可以通过对细胞样品进行测序以确定在IDH1的氨基酸132处的突变(例如,存在于氨基酸132处的改变的氨基酸)的存在及其特定性质来分析一种癌症。
不被理论所束缚,申请人认为IDH1的突变型等位基因(其中IDH1突变导致这种酶催化α-酮戊二酸依赖于NAPH地还原为R(-)-2-羟基戊二酸的新的能力),并且特别是IDH1的R132H突变,不论其细胞性质或在体内的位置,可表征所有类型的癌症的子集。本发明的这些化合物和方法对于治疗其特征在于以下方面的任何类型的癌症是有用的:存在赋予这种活性的IDH1的突变型等位基因并且特别是IDH1R132H突变的存在。
在这个实施例的一个方面中,通过测量这位受试者中2HG的水平来监测癌症治疗的疗效。典型地,在治疗之前测量2HG的水平,其中升高的水平指示使用具有化学式I的化合物治疗这种癌症。一旦确立升高的水平,就在治疗的过程中和/或治疗结束之后确定2HG的水平以确立疗效。在某些实施例中,仅在治疗的过程中和/或治疗结束之后确定2HG的水平。在治疗的过程中以及治疗之后2HG水平的减少指示有疗效。类似地,在治疗的过程中或治疗之后2HG水平不升高的测定也指示有疗效。典型地,这些2HG测量将与癌症治疗的疗效的其他熟知的测定一起被利用,例如肿瘤和/或其他癌症相关病灶的数目和大小的减少、受试者的总体健康的改善、以及其他与癌症治疗疗效相关的生物标记的改变。
样品中的2HG可以通过LC/MS检测。将该样品与甲醇以80:20混合,并且在4℃下、在3,000rpm离心20分钟。在LC-MS/MS之前,可以收集生成的上清液并且将其储存在-80℃下,以评价2-羟基戊二酸水平。可以使用多种不同的液相色谱(LC)分离方法。可以通过负电喷射电离(ESI,-3.0kV)将每种方法与以多重反应监测(MRM)模式操作的三重四极质谱仪连接,其中MS参数基于注入的代谢物标准溶液进行优化。根据以前报道的方法(Luo(罗)等人JChromatogr A(《色谱法A杂志》)1147,153-64,2007)的变体,可以通过反相色谱法使用10mM三丁基胺作为水性流动相中的离子对试剂来分离代谢物。一种方法允许TCA代谢物的拆分:t=0,50%B;t=5,95%B;t=7,95%B;t=8,0%B,其中B是指100%甲醇的有机流动相。另一种方法特异性针对2-羟基戊二酸,在5分钟内从50%-95%B(如上所述的缓冲液)跑快速线性梯度。如上所述,可以将Synergi Hydro-RP,100mm×2mm,2.1μm颗粒大小(Phenomonex)用作柱。可以通过在已知浓度处将峰面积与纯的代谢物标准品的峰面积进行比较来对代谢物进行定量。可以如描述于例如Munger(孟格)等人Nat Biotechnol(《自然生物技术》)26,1179-86,2008中的从13C-谷氨酰胺进行代谢流研究。
在一个实施例中,直接评估2HG。
在另一个实施例中,对在进行分析方法的过程中形成的2HG的衍生物进行评估。通过举例,这样的一种衍生物可以是在MS分析中形成的衍生物。衍生物可以包括盐加合物(例如Na加合物),水合变体,或也是盐加合物的水合变体(例如在如MS分析中形成的Na加合物)。
在另一个实施例中,对2HG的代谢衍生物进行评估。实例包括作为2HG的存在的结果而积累或升高、或减少的种类,例如将与2HG(例如R-2HG)相关的戊二酸或谷氨酸。
示例性2HG衍生物包括脱水衍生物,例如以下提供的这些化合物或其盐加合物:
在一个实施例中,这种癌症是一种肿瘤,其中在诊断或治疗时,至少30%、40%、50%、60%、70%、80%或90%的肿瘤细胞携带IDH1突变,并且特别是IDH1R132H突变。
已知IDH1R132X突变发生于如在下表2中所表明的某些类型的癌症中。
表2.与某些癌症相关的IDH突变
已经在恶性胶质瘤、急性骨髓性白血病、肉瘤、黑色素瘤、非小细胞肺癌、胆管癌、软骨肉瘤、骨髓增生异常综合征(MDS)、骨髓增生性肿瘤(MPN)、结肠癌、以及血管免疫母细胞非何杰金氏淋巴瘤(NHL)中鉴定出IDH1R132H突变。因此,在一个实施例中,使用在此所描述的这些方法治疗患者的神经胶质瘤(glioblastoma)、急性骨髓性白血病、肉瘤、黑色素瘤、非小细胞肺癌(NSCLC)或胆管癌、软骨肉瘤、骨髓增生异常综合征(MDS)、骨髓增生性肿瘤(MPN)或结肠癌。
因此,在一个实施例中,这种癌症是一种选自表2中列出的任一癌症类型的癌症,并且IDH R132X突变是针对那种具体的癌症类型而列于表2中的IDH R132X突变中的一种或多种。
在用具有结构式I或II的化合物或在此处的任一实施例中描述的化合物治疗之前和/或之后,在此描述的治疗方法可以额外地包括不同的评估步骤。
在一个实施例中,在用具有结构式I或II的化合物或在此处的任一实施例中描述的化合物治疗之前和/或之后,该方法进一步包括评估癌症的生长、大小、重量、侵袭性、阶段和/或其他表型的步骤。
在一个实施例中,在用具有化学式I或I-a的化合物或在此处的任一实施例中描述的化合物治疗之前和/或之后,该方法进一步包括评估这种癌症的IDH1基因型的步骤。这可以通过本领域中普通的方法实现,例如DNA测序,免疫分析,和/或2HG的存在、分布或水平的评估。
在一个实施例中,在用具有化学式I或I-a的化合物或在此处的任一实施例中描述的化合物治疗之前和/或之后,该方法进一步包括确定受试者中的2HG水平的步骤。这可以通过以下实现:光谱分析,例如基于磁共振的分析,例如MRI和/或MRS测量;体液的样品分析,例如血清或脊髓液分析;或通过手术材料的分析,例如通过质谱法。
组合疗法
在一些实施例中,在此所描述的这些方法包括向对其有需要的受试者共给予一种第二疗法的额外步骤,例如一种额外的癌症治疗剂或额外的癌症治疗。示例性的额外的癌症治疗剂包括例如化学疗法、靶向疗法、抗体疗法、免疫疗法、以及激素疗法。额外的癌症治疗包括例如:手术,以及放射治疗。以下提供了这些治疗中的每个的实例。
如在此使用的,相对于一种额外的癌症治疗剂,术语“共给予”意指可以将这种额外的癌症治疗剂作为单一剂型(例如本发明的组合物,包括一种本发明的化合物以及一种如上所述的第二治疗剂)的一部分或作为分开的多个剂型与本发明的化合物一起给予。可替代地,这种额外的癌症治疗剂可以在本发明的化合物的给予之前、相继地、或之后给予。在此类组合疗法治疗中,本发明的化合物和一种或多种第二治疗剂两者都是通过常规方法给予。向一位受试者给予包括一种本发明的化合物以及一种第二治疗剂两者的本发明的组合物不排除在治疗过程中,在另一时间向所述受试者分开给予同一治疗剂、任何其他的第二治疗剂或本发明的任何化合物。如在此使用的,相对于一种额外的癌症治疗,术语“共给予”意指这种额外的癌症治疗可以在本发明的化合物的给予之前、相继地、同时地或之后发生。
在一些实施例中,这种额外的癌症治疗剂是一种化疗剂。用于癌症疗法的化疗剂的实例包括例如,抗代谢物(例如,叶酸、嘌呤和嘧啶衍生物),烷基化剂(例如,氮芥、亚硝基脲、铂、烷基磺酸酯、肼、三氮烯、氮丙啶、纺锤体毒剂、细胞毒剂、拓扑异构酶抑制剂以及其他)以及低甲基化剂(例如,地西他滨(5-氮杂-脱氧胞苷)、泽布拉恩(zebularine)、异硫氰酸酯、阿扎胞苷(5-氮杂胞苷)、5-氟-2'-脱氧胞苷、5,6-二氢-5-氮杂胞苷以及其他)。示例性药剂包括阿克拉霉素、放线菌素、阿利维A酸、六甲蜜胺、氨基蝶呤、氨基乙酰丙酸、氨柔比星、安吖啶、阿那格雷、三氧化二砷、天冬酰胺酶、阿曲生坦、贝洛替康、蓓萨罗丁、苯达莫司汀、博莱霉素、硼替佐米、白消安、喜树碱、卡培他滨、卡铂、卡波醌、卡莫氟、卡莫司汀、塞来昔布、苯丁酸氮芥、氮芥、顺铂、克拉屈滨、氯法拉滨、菊欧文氏酶(Crisantaspase)、环磷酰胺、阿糖胞苷、达卡巴嗪、更生霉素、柔红霉素、地西他滨、地美可辛、多西紫杉醇、阿霉素、乙丙昔罗、伊利司莫、依沙芦星、依诺他滨、表柔比星、雌氮芥、依托格鲁、依托泊苷、氟尿苷、氟达拉滨、氟脲嘧啶(5FU)、福替目丁、吉西他滨、卡氮芥糯米纸胶囊剂植入物、羟基脲(Hydroxycarbamide)、羟基脲(Hydroxyurea)、去甲氧柔红霉素、异环磷酰胺、伊立替康、伊罗夫文、伊沙匹隆、Larotaxel、亚叶酸、脂质体阿霉素、脂质体柔红霉素、氯尼达明、洛莫司汀、硫蒽酮、甘露舒凡、马索罗酚、美法仑、巯基嘌呤、美司那、甲氨蝶呤、氨基酮戊酸甲酯、二溴甘露醇、米托胍腙、米托坦、丝裂霉素、米托蒽醌、奈达铂、嘧啶亚硝脲、奥利莫森(Oblimersen)、Omacetaxine、奥他赛(Ortataxel)、奥沙利铂、紫杉醇、培门冬酶、培美曲塞、喷司他丁、吡柔比星、匹杉琼(Pixantrone)、光辉霉素、卟吩姆钠、泼尼莫司汀、丙卡巴肼、雷替曲塞、雷莫司汀、卢比替康、Sapacitabine、司莫司汀、腺病毒载体定位码基因(Sitimageneceradenovec)、沙铂、链佐星、他拉泊芬、替加氟-尿嘧啶、替莫泊芬、替莫唑胺、替尼泊苷、Tesetaxel、睾内脂、四硝酸酯、噻替派、噻唑呋林、硫鸟嘌呤、替吡法尼(Tipifarnib)、托泊替康、曲贝替定、三乙撑亚胺苯醌、曲他胺、Triplatin、维甲酸、苏消安、曲洛磷胺、尿嘧啶氮芥、戊柔比星、维替泊芬、长春花碱、长春新碱、长春地辛、长春氟宁、长春瑞滨、伏立诺他、佐柔比星、以及在此描述的其他细胞抑制剂或细胞毒素剂。
由于一些药物联用优于单独时的情况,因此通常同时给出两种或更多种药物。通常,两种或更多种化疗剂用作组合化疗。
在一些实施例中,这种额外的癌症治疗剂是一种分化剂。
此类分化剂包括维甲酸(例如全反式维甲酸(ATRA),9-顺式维甲酸,13-反式-维甲酸(13-cRA)以及4-羟基-苯基维甲酰胺(phenretinamide)(4-HPR));三氧化二砷;组蛋白脱乙酰酶抑制剂HDAC(例如氮杂胞苷(Vidaza)以及丁酸盐(例如,苯基丁酸钠));混合极性化合物(例如六亚甲基二乙酰胺((HMBA));维生素D;以及细胞因子(例如集落刺激因子(包括G-CSF和GM-CSF),以及干扰素类)。
在一些实施例中,这种额外的癌症治疗剂是一种靶向疗法药剂。靶向疗法包括对癌细胞的失调蛋白具有特异性的药剂的使用。小分子靶向疗法药物通常是在癌细胞内的突变蛋白、过表达蛋白或在其他方面关键的蛋白上的酶结构域的抑制剂。最突出的实例是酪氨酸激酶抑制剂,例如阿西替尼、博舒替尼、西地尼布、达沙替尼、埃罗替尼、伊马替尼、吉非替尼、拉帕替尼、来他替尼、尼罗替尼、司马沙尼(Semaxanib)、索拉非尼、舒尼替尼和凡德他尼;并且还是细胞周期蛋白依赖性激酶抑制剂,例如Alvocidib和Seliciclib。单克隆抗体疗法是另一种策略,其中治疗剂为特异性结合在癌细胞表面上的蛋白质的抗体。实例包括典型地用于乳腺癌的抗-HER2/neu抗体曲妥珠单抗以及典型地用于多种B细胞恶性肿瘤的抗-CD20抗体利妥昔单抗和托西莫单抗。其他示例性抗体包括西妥昔单抗、帕尼单抗、曲妥珠单抗、阿伦珠单抗、贝伐珠单抗、依决洛单抗、以及吉姆单抗。示例性融合蛋白包括阿柏西普和地尼白介素-毒素连接物(Denileukin diftitox)。在一些实施例中,靶向疗法可以与在此所描述的化合物组合使用,例如双胍,例如二甲双胍或苯乙双胍,优选苯乙双胍。
靶向疗法也可包括可结合细胞表面受体或肿瘤周围受侵袭的细胞外基质上的、作为“归巢装置”的小肽。与这些肽(例如,RGD)附接的放射性核素最终杀死癌细胞(如果核素在细胞附近衰变的话)。此类疗法的一个实例包括
在一些实施例中,这种额外的癌症治疗剂是一种免疫疗法药剂。癌症免疫疗法是指被设计为诱导受试者自身免疫系统与肿瘤斗争的一组不同的治疗策略。用于产生对抗肿瘤的免疫反应的现代方法包括浅表性膀胱癌的囊内BCG免疫疗法,以及使用干扰素和其他细胞因子以在肾细胞癌和黑素瘤受试者中诱导免疫反应。
异源造血干细胞移植可以被认为是一种免疫疗法的形式,因为供体的免疫细胞通常将以移植体-对-肿瘤作用来攻击肿瘤。在一些实施例中,免疫治疗剂可以与在此描述的化合物或组合物组合使用。
在一些实施例中,这种额外的癌症治疗剂是一种激素治疗剂。一些癌症的生长可通过提供或阻断某些激素来抑制。激素-敏感性肿瘤的常见实例包括某些类型的乳腺癌和前列腺癌。除去或阻断雌激素或睾丸素通常是重要的额外疗法。在某些癌症中,激素促效剂例如孕激素类的给予可以具有治疗上的益处。在一些实施例中,激素治疗剂可以与在此描述的化合物或组合物组合使用。
其他可能的额外的治疗形式包括伊马替尼,基因疗法,肽和树突细胞疫苗,合成氯毒索,以及放射性标记药物和抗体。
实例
缩写
anhy.-无水的
aq.-水性的
min-分钟
mL-毫升
mmol-毫摩尔
mol-摩尔
MS-质谱法
NMR-核磁共振
TLC-薄层色谱分析法
HPLC-高效液相色谱法
Hz-赫兹
δ-化学位移
J-偶合常数
s-单峰
D-双峰
t-三重峰
q-四重峰
m-多重峰
br-宽峰
qd-双峰的四重峰
dquin-五重峰的双峰
dd-双峰的双峰
dt-三重峰的双峰
CHCl3-氯仿
DCM-二氯甲烷
DMF-二甲基甲酰胺
Et2O-二乙醚
EtOH-乙醇
EtOAc-乙酸乙酯
MeOH-甲醇
MeCN-乙腈
PE-石油醚
THF-四氢呋喃
AcOH-乙酸
HCl-盐酸
H2SO4-硫酸
NH4Cl-氯化铵
KOH-氢氧化钾
NaOH-氢氧化钠
K2CO3-碳酸钾
Na2CO3-碳酸钠
TFA-三氟乙酸
Na2SO4-硫酸钠
NaBH4-硼氢化钠
NaHCO3-碳酸氢钠
LiHMDS-六甲基二硅基胺基锂
NaHMDS-六甲基二硅基胺基钠
LAH-氢化铝锂
NaBH4-硼氢化钠
LDA-二异丙基氨基锂
Et3N-三乙胺
DMAP-4-(二甲氨基)吡啶
DIPEA-N,N-甲二异丙基乙胺
NH4OH-氢氧化铵
EDCI-1-乙基-3-(3-二甲基氨基丙基)碳二亚胺
HOBt-1-羟基苯并三唑
HATU-O-(7-氮杂苯并三唑-1-基)-N,N,N',N'-四-甲基脲
BINAP-2,2’-双(二苯基膦基)-1,1’-联萘基
在以下实例中,试剂购自商业来源(包括Alfa公司,Acros公司,Sigma Aldrich(西格玛奥德里奇公司),TCI公司以及Shanghai Chemical Reagent Company(上海化学试剂公司)),并且不用进一步纯化而使用。在Ez提纯器III上,使用具有200-300筛目的硅胶颗粒的柱进行快速色谱。分析型和制备型薄层色谱法平板(TLC)是HSGF 254(0.15-0.2mm厚度,中国上海安邦公司(Shanghai Anbang Company,China))。在Brucker AMX-400NMR(布鲁克尔公司(Brucker),瑞士)上获得核磁共振(NMR)光谱。化学位移报道为从四甲基硅烷起低场的百万分之几(ppm,δ)。用来自Waters LCT TOF质谱仪(沃特斯公司(Waters),USA)的电喷射电离(ESI)跑质谱。在安捷伦(Agilent)1200液相色谱上记录HPLC色谱(Agilent(安捷伦),USA,柱:Ultimate 4.6mm×50mm,5μm,流动相A:水中的0.1%甲酸;流动相B:乙腈)。在Initiator 2.5微波合成仪(Initiator 2.5Microwave Synthesizer)(Biotage,瑞典)上运行微波反应。
对于在本节中披露的示例性化合物而言,立体异构体(例如,(R)或(S)立体异构体)的说明指示那种化合物的制备,这样使得该化合物在特定的立构中心处以至少90%、95%、96%、97%、98%、或99%富集。
实例1.可任选经取代的二甲基-环丙基吡喃并吡啶(5)的合成。
在制备具有结构式I和II的化合物的过程中,可任选经取代的二甲基-环丙基吡喃并吡啶5被用作常见合成中间体并且其本身根据以下方案1合成。
方案1.
步骤A:5-(环丙烷羰基)-2,2-二甲基二氢-2H-吡喃-4(3H)-酮(2)。将500mL配备有搅拌棒的三颈圆底烧瓶填充上2,2-二甲基二氢-2H-吡喃-4(3H)-酮(6g,46.8mmol)和120mL的干甲苯。将该溶液用氮气进行吹扫并且冷却至0℃。在搅拌下,逐滴添加LDA(在THF/正庚烷中的2M溶液,24.5mL,15.6mmol)溶液,并且允许将该反应混合物在0℃下继续搅拌5min,之后在剧烈搅拌下添加环丙烷碳酰氯(2.8mL,31.2mmol)。在0℃下再搅拌20min之后,将该反应混合物用1N HCl淬灭至PH<7。在H2O与二氯甲烷之间进行分配之后,进而将合并的有机层用盐水进行洗涤,用无水Na2SO4干燥并且在真空中进行浓缩。快速柱色谱法(10%乙酸乙酯/石油醚)给出6g呈淡黄色油状物的粗品标题化合物。MS(ES)M+H预期是197.1,发现是197.3。
步骤B:8-环丙基-6-羟基-3,3-二甲基-3,4-二氢-1H-吡喃并[3,4-c]吡啶-5-腈(3)。向在70mL EtOH中的5-(环丙烷羰基)-2,2-二甲基二氢-2H-吡喃-4(3H)-酮(2;6g,30.6mmol)和2-氰基乙酰胺(4.1g,49.0mmol)的溶液中添加二乙胺(2.1mL,20.4mmol)。将该反应混合物在室温下搅拌72小时,直到LC-MS指示完成形成产物。然后,将该反应混合物加热至回流并且添加足够的EtOH,以制备澄清溶液。在冷却回至室温以后,将产物从EtOH溶液中沉淀出并且在真空过滤和风干以后获得3.3g呈白色固体的标题化合物。MS(ES)M+H预期是245.1,发现是245。1H NMR(氯仿-d)δ4.74(s,2H),2.82(s,2H),1.68-1.78(m,1H),1.34(s,6H),1.30-1.32(m,2H),1.24-1.26(m,2H)。
步骤C1:5-氰基-8-环丙基-3,3-二甲基-3,4-二氢-1H-吡喃并[3,4-c]吡啶-6基三氟甲烷-磺酸酯(4,Ra=OTf)。将250mL圆底烧瓶填充上8-环丙基-6-羟基-3,3-二甲基-3,4-二氢-1H-吡喃并[3,4-c]吡啶-5-腈(3;3.7g,15.16mmol)、DMAP(185mg,1.52mmol)、三乙胺(2.74mL,19.7mmol)以及150mL的二氯甲烷。在将该反应混合物在干冰-丙酮浴中冷却至0℃以后,经由注射器逐滴添加三氟甲磺酸酐(3.3mL,19.7mmol)。将生成的混合物在0℃下搅拌30min,之后允许将其加温至室温,并且再搅拌2小时。在TLC指示起始材料完全转化为产物以后,将该反应混合物在真空中进行浓缩并且通过快速柱色谱法(1:10乙酸乙酯/石油醚)纯化,以给出4.9g呈白色固体的标题化合物。1H NMR(氯仿-d)δ4.91(s,2H),2.88(s,2H),1.73-1.84(m,1H),1.34(s,6H),1.23-1.27(m,2H),1.17-1.22(m,2H)。
步骤C2:6-氯-8-环丙基-3,3-二甲基-3,4-二氢-1H-吡喃并[3,4-c]吡啶-5-腈(4,Ra=Cl)。将8-环丙基-6-羟基-3,3-二甲基-3,4-二氢-1H-吡喃并[3,4-c]吡啶-5-腈(3;5g,20.5mmol)、20mL的磷酰三氯以及一滴DMF的混合物加热至回流过夜,直到LC-MS指示完全转化为产物。在减压下蒸发掉过量的磷酰三氯之后,将残余物重溶于二氯甲烷中并且小心地用10%水性KOH中和并且随后用1N HCl和盐水进行洗涤。将合并的有机层用无水Na2SO4干燥并且在真空中进行浓缩。然后,快速柱色谱法分离(1:10乙酸乙酯/石油醚)给出1g呈淡黄色固体的标题化合物。MS(ES)M+H预期是263.1,发现是263。
步骤D:(R)-8-环丙基-6-(3-异丙基哌嗪-1-基)-3,3-二甲基-3,4-二氢-1H-吡喃并[3,4-c]吡啶-5-腈(5;R3=3-(R)-异丙基;m=1)。将密封试管填充上来自步骤的C1的4(600mg,1.60mmol)、(R)-2-异丙基哌嗪(170mg,1.33mmol)、以及2mL EtOH中的三乙胺(0.24mL,1.73mmol)。在回流温度下,将该反应混合物加热过夜。在减压下浓缩之后,通过快速柱色谱法(1:10甲醇/二氯甲烷)纯化该反应混合物,以给出428mg的标题化合物。MS(ES)M+H预期是355.2,发现是355.2。1H NMR(氯仿-d)δ4.84(s,2H),4.33(d,J=13.1Hz,1H),4.19(d,J=14.3Hz,1H),3.47-3.55(m,1H),3.35-3.47(m,1H),2.94-3.21(m,3H),2.77(s,2H),1.98-2.14(m,1H),1.64-1.77(m,1H),1.31(s,6H),1.14-1.21(m,3H),1.08-1.14(m,5H),0.98-1.07(m,2H)。
可替代地,将来自步骤C1的4(200mg,0.53mmol)、(R)-2-异丙基哌嗪(135mg,1.06mmol)、以及悬浮于0.8mL乙腈中的三乙胺(0.2mL,1.59mmol)合并在一起并且使该混合物在175℃下经受45min微波反应来形成(R)-8-环丙基-6-(3-异丙基哌嗪-1-基)-3,3-二甲基-3,4-二氢-1H-吡喃并[3,4-c]吡啶-5-腈。在将该反应混合物在真空中浓缩以后,将残余物通过快速柱色谱法进行纯化,以给出189mg呈淡黄色油状物的标题化合物。
实例2.具有化学式II的化合物的制备。
根据以下方案2,从中间体5制备具有化学式II的不同化合物,其中每个R1是甲基并且R2是环丙基。
方案2:
以下详细地描述在本发明的化合物的合成中的最终的一个或多个步骤。
步骤E1:(R)-8-环丙基-6-(4-(呋喃-3-羰基)-3-异丙基哌嗪-1-基)-3,3-二甲基-3,4-二氢-1H-吡喃并[3,4-c]吡啶-5-腈(化合物180)。在一个5-mL的琥珀玻璃小瓶中放置5(30mg,0.08mmol),呋喃-3-羧酸(38mg,0.34mmol),EDCI(68.8mg,0.36mmol),HOBt(48.6mg,0.36mmol),三乙胺(36.8mg,0.36mmol)以及1mL的二氯甲烷。将生成的反应混合物在室温下搅拌过夜。将该混合物用1N HCl水溶液淬灭,用EtOAc萃取三次。将合并的有机层用饱和NaHCO3和盐水进行洗涤,用无水Na2SO4干燥并且在真空中进行浓缩。通过制备型TLC(DCM:丙酮/70:1)来纯化粗产物,以给出29mg呈白色固体的标题化合物。MS(ES)M+H预期是449.3,发现是449.1。1H NMR(氯仿-d)δ7.71(br.s.,1H),7.45(t,J=1.8Hz,1H),6.55(s,1H),4.75-4.91(m,2H),3.49-4.48(m,5H),2.93-3.11(m,2H),2.77(s,2H),2.14-2.34(m,1H),1.68-1.77(m,1H),1.32(d,J=2.0Hz,6H),1.00-1.16(m,6H),0.81-0.94(m,4H)。
步骤E2:(R)-6-(4-(2-氯乙酰基)-3-异丙基哌嗪-1-基)-8-环丙基-3,3-二甲基-3,4-二氢-1H-吡喃并[3,4-c]吡啶-5-腈(化合物317)。向在1.5mL二氯甲烷和三乙胺(0.02mL,0.16mmol)中的5(30mg,0.08mmol)的溶液中缓慢添加氯乙酰氯(2滴,0.16mmol)。允许将生成的反应混合物在室温下搅拌过夜。然后将该反应混合物用盐水淬灭并且分离。将有机层用无水Na2SO4干燥并且在真空中进行浓缩。通过制备型TLC(DCM:丙酮/70:1)来纯化粗产物,以给出23mg呈淡黄色油状物的标题化合物。MS(ES)M+H预期是431.2,发现是431.0。1H NMR(氯仿-d)δ4.77-4.89(m,2H),4.54-4.57(m,0.5H),4.04-4.38(m,4.5H),3.75(d,J=13.6Hz,0.5H),3.55(td,J=12.9,3.1Hz,0.5H),4.42-4.45(m,0.5H),2.95-3.17(m,2.5H),2.77(s,2H),2.10-2.30(m,1H),1.67-1.77(m,1H),1.32(d,J=2.5Hz,6H),1.07-1.19(m,2H),0.98-1.06(m,5H),0.81-0.93(m,3H)。
步骤E3:(R)-6-(4-(2-(1H-吡唑-1-基)乙酰基)-3-异丙基哌嗪-1-基)-8-环丙基-3,3-二甲基-3,4-二氢-1H-吡喃并[3,4-c]吡啶-5-腈(化合物325)。向在1mLMeCN中的1H-吡唑(10mg,0.14mmol)和K2CO3(20mg,0.14mmol,在一些情况下,Cs2CO3被用作替代性碱)的溶液中添加5(30mg,0.07mmol)。将生成的反应混合物在室温下搅拌过夜。在用二氯甲烷稀释以后,将该混合物用盐水进行洗涤。将有机层用无水Na2SO4干燥并且在真空中进行浓缩。通过制备型TLC分离(DCM:丙酮/70:1)来纯化粗产物,以给出10mg呈白色固体的标题化合物。MS(ES)M+H预期是463.3,发现是463.1。1HNMR(氯仿-d)δ7.45-7.63(m,2H),6.33(d,J=2.0Hz,1H),4.90-5.20(m,2H),4.74-4.89(m,2H),4.55-4.58(m,0.5H),4.22-4.40(m,1.5H),4.07-4.21(m,1H),3.88(d,J=13.6Hz,0.5H),3.59-3.61(m,0.5H),3.36-3.49(m,0.5H),2.81-3.10(m,2.5H),2.76(s,2H),2.07-2.36(m,1H),1.64-1.79(m,1H),1.31(d,J=2.8Hz,6H),0.94-1.19(m,7H),0.86-0.93(m,1.5H),0.74-0.84(m,1.5H)。
步骤E4:(R)-8-环丙基-6-(3-异丙基-4-(2-甲氧基乙酰基)哌嗪-1-基)-3,3-二甲基-3,4-二氢-1H-吡喃并[3,4-c]吡啶-5-腈(化合物347)。向5(30mg,0.07mmol)的1.5mLMeCN溶液中添加MeOH(0.3mL)和DIPEA(0.04mL,0.21mmol)。将生成的反应混合物在65℃下加热过夜。在用5mL的二氯甲烷稀释以后,将该反应混合物用盐水进行洗涤。然后,将有机层用无水Na2SO4干燥并且在真空中进行浓缩。通过制备型TLC(DCM:丙酮/60:1)来纯化粗产物,以给出14mg呈无色油状物的标题化合物。MS(ES)M+H预期是427.6,发现是427.3。1H NMR(氯仿-d)δ4.77-4.90(m,2H),4.56-4.58(m,0.5H),3.99-4.36(m,4.5H),3.79(d,J=13.6Hz,0.5H),3.37-3.52(m,4H),2.91-3.11(m,2.5H),2.70-2.82(m,2H),2.08-2.33(m,1H),1.64-1.77(m,1H),1.31(d,J=2.5Hz,6H),0.96-1.19(m,7H),0.80-0.93(m,3H)。
步骤E5:(R)-8-环丙基-6-(4-(2-(环丙基氨基)乙酰基)-3异丙基哌嗪-1-基)-3,3-二甲基-3,4-二氢-1H-吡喃并[3,4-c]吡啶-5-腈(化合物372)。向5(30mg,0.07mmol)的1.5mL MeCN溶液中添加环丙胺(12mg,0.21mmol)。将生成的反应混合物在65℃下加热过夜。在用5mL的二氯甲烷稀释以后,将该反应混合物用盐水进行洗涤。然后,将有机层用无水Na2SO4干燥并且在真空中进行浓缩。通过制备型TLC(DCM:丙酮/30:1)来纯化粗产物,以给出11mg呈无色油状物的标题化合物。MS(ES)M+H预期是452.3,发现是452.4。1H NMR(氯仿-d)δ4.78-4.90(m,2H),4.52-4.74(m,0.5H),4.28-4.45(m,1.5H),4.11-4.23(m,1H),3.49-3.71(m,2.5H),3.30-3.49(m,1H),2.93-3.11(m,3H),2.72-2.80(m,2H),2.20-2.33(m,1.5H),1.98-2.18(m,1H),1.67-1.75(m,1H),1.31(d,J=2.5Hz,7H),1.06-1.17(m,2H),0.97-1.05(m,5H),0.86-0.93(m,1.5H),0.82(d,J=6.8Hz,1.5H),0.43-0.56(m,3H)。
步骤E6:(R)-6-(4-(2-(1H-吲唑-1-基)乙酰基)-3-异丙基哌嗪-1-基)-8-环丙基-3,3-二甲基-3,4-二氢-1H-吡喃并[3,4-c]吡啶-5-腈(化合物405)。在一个密封试管中放置1H-吲唑(25mg,0.21mmol)和Cs2CO3(68mg,0.21mmol,在一些情况下K2CO3被用作替代性碱)、5(30mg,0.07mmol)、以及1.5mL MeCN的混合物。将生成的反应混合物在60℃下搅拌过夜。在用二氯甲烷稀释以后,将该混合物用盐水进行洗涤。将有机层用无水Na2SO4干燥并且在真空中进行浓缩。通过制备型TLC(DCM:丙酮/70:1)来纯化粗产物,以给出15mg呈无色油状物的标题化合物。MS(ES)M+H预期是513.3,发现是513.2。1H NMRδ8.06(d,J=6.3Hz,1H),7.74(dd,J=8.2,4.1Hz,1H),7.34-7.57(m,2H),7.11-7.22(m,1H),5.15-5.45(m,2H),4.81(br.s.,2H),4.52-4.56(m,0.5H),4.19-4.38(m,1.5H),3.97-4.18(m,1.5H),3.71-4.73(m,0.5H),3.38-4.45(m,0.5H),2.98-3.06(m,0.5H),2.82-2.95(m,1H),2.63-2.80(m,3H),2.04-2.32(m,1H),1.65-1.74(m,1H),1.29-1.33(m,6H),0.87-1.17(m,8.5H),0.74(d,J=6.8Hz,1.5H)。
步骤F1:(R)-甲基4-(5-氰基-8-环丙基-3,3-二甲基-3,4-二氢-1H-吡喃并[3,4-c]吡啶-6-基)-2-异丙基哌嗪-1-羧酸酯(化合物346)。向在1.5mL二氯甲烷中的5(30mg,0.08mmol)的溶液中添加三乙胺(0.02mL,0.16mmol)和氯甲酸甲酯(15mg,0.16mmol)。允许将生成的反应混合物在室温下搅拌过夜。在用DCM稀释以后,将该混合物用盐水进行洗涤。将有机层用无水Na2SO4干燥并且在真空中进行浓缩。通过制备型TLC(DCM:丙酮/70:1)来纯化粗产物,以给出12mg呈淡黄色油状物的标题化合物。MS(ES)M+H预期是413.3,发现是413.2。1H NMR(氯仿-d)δ4.74-4.89(m,2H),4.28(d,J=13.3Hz,1H),4.13(d,J=12.3Hz,2H),3.76-3.86(m,1H),3.69-3.74(m,3H),3.18(t,J=11.8Hz,1H),2.96-3.09(m,2H),2.76(s,2H),2.11(dquin,J=10.3,6.6Hz,1H),1.65-1.74(m,1H),1.31(d,J=2.3Hz,6H),0.93-1.18(m,7H),0.82-0.90(m,3H)。步骤F2:(R)-2-羟乙基4-(5-氰基-8-环丙基-3,3-二甲基-3,4-二氢-1H-吡喃并[3,4-c]吡啶-6-基)-2-异丙基哌嗪-1-羧酸酯(化合物368)。在0℃下,向在2mL乙腈中的5(30mg,0.08mmol)的溶液中添加吡啶(12.7mg,0.16mmol),随后添加三光气(15mg,0.16mmol)。在添加额外的过量的乙烷-1,2-二醇之前,将生成的反应混合物在0℃下搅拌5min。将产生的反应混合物加温至室温并且然后在60℃下加热过夜。在用二氯甲烷稀释以后,将该反应混合物用盐水进行洗涤并且将有机层用无水Na2SO4干燥并且在真空中进行浓缩。通过制备型TLC(DCM/丙酮:10:1)来纯化粗产物,以给出16mg呈淡黄色油状物的标题化合物。MS(ES)M+H预期是443.3,发现是443.4。1H NMR(氯仿-d)δ4.76-4.90(m,2H),4.22-4.39(m,3H),4.00-4.21(m,2H),3.73-3.96(m,3H),3.21(br.s.,1H),2.99-3.11(m,2H),2.66-2.84(m,2H),2.09-2.20(m,1H),1.66-1.76(m,1H),1.31(d,J=2.8Hz,6H),1.06-1.17(m,2H),0.94-1.05(m,5H),0.82-0.92(m,3H)。
步骤F3:(R)-叔丁基4-(5-氰基-8-环丙基-3,3-二甲基-3,4-二氢-1H-吡喃并[3,4-c]吡啶-6-基)-2-异丙基哌嗪-1-羧酸酯(化合物306)。向在1.5mL二氯甲烷中的5(30mg,0.08mmol)的溶液中添加三乙胺(0.02mL,0.16mmol)和二碳酸二叔丁酯(35mg,0.16mmol)。允许将生成的反应混合物在室温下搅拌过夜。将该反应混合物用DCM稀释,用盐水洗涤。将有机层用无水Na2SO4干燥并且在真空中进行浓缩。通过制备型TLC(DCM/丙酮:70:1)来纯化粗产物,以给出18mg呈无色油状物的标题化合物。MS(ES)M+H预期是455.3,发现是399.1。1HNMRδ4.75-4.88(m,2H),4.29(d,J=12.8Hz,1H),3.95-4.19(m,2H),3.68-3.88(m,1H),2.94-3.19(m,3H),2.71-2.80(m,2H),2.09(dq,J=17.1,6.6Hz,1H),1.66-1.76(m,1H),1.47(s,9H),1.29-1.35(m,6H),1.06-1.20(m,2H),0.92-1.03(m,5H),0.82-0.89(m,3H)。
步骤G1:(R)-N-烯丙基-4-(5-氰基-8-环丙基-3,3-二甲基-3,4-二氢-1H-吡喃并[3,4-c]吡啶-6-基)-2-异丙基哌嗪-1-羧酰胺(化合物304)。向在3mL二氯甲烷中的5(100mg,0.282mmol)的溶液中添加异氰酸烯丙酯(35.2mg,0.424mmol)。将生成的反应混合物在室温下搅拌过夜。向该反应混合物中添加乙烷-1,2-二胺,以通过在室温下搅拌5min来破坏过量的异氰酸酯。将该反应混合物用DCM稀释并且然后用盐水洗涤。将有机层用无水Na2SO4干燥并且在真空中进行浓缩。通过制备型TLC(DCM/丙酮:60:1)来纯化粗产物,以给出41.4mg呈白色固体的标题化合物。MS(ES)M+H预期是438.3,发现是438.3。1H NMR(氯仿-d)δ5.82-5.98(m,1H),5.07-5.24(m,2H),4.74-4.90(m,2H),4.43(br.s.,1H),4.24(d,J=13.1Hz,1H),4.12(d,J=11.5Hz,1H),3.81-4.02(m,3H),3.68(br.s.,1H),3.04-3.34(m,3H),2.71-2.83(m,2H),2.12-2.22(m,1H),1.69(td,J=8.0,3.9Hz,1H),1.28-1.37(m,6H),0.94-1.19(m,7H),0.90(d,J=6.8Hz,3H)。
步骤G2:(R)-4-(5-氰基-8-环丙基-3,3-二甲基-3,4-二氢-1H-吡喃并[3,4-c]吡啶-6-基)-2-异丙基-N-丙基哌嗪-1-羧酰胺(化合物350)。在0℃下,向在3mL二氯甲烷中的5(30mg,0.08mmol)的溶液中添加三乙胺(0.03mL,0.16mmol),随后添加三光气(47mg,0.16mmol)。搅拌5min之后,向该反应混合物中缓慢添加0.5mL的丙胺。在0℃下再搅拌30min之后,将该反应混合物加温至室温并且搅拌过夜。将该反应混合物用DCM稀释并且然后用盐水洗涤。将有机层用无水Na2SO4干燥并且在真空中进行浓缩。通过制备型TLC(DCM/丙酮:40:1)来纯化粗产物,以给出20mg呈无色油状物的标题化合物。MS(ES)M+H预期是440.3,发现是440.3。1H NMRδ4.75-4.89(m,2H),4.39(br.s.,1H),4.23(d,J=13.3Hz,1H),4.12(d,J=11.8Hz,1H),3.92(d,J=12.8Hz,1H),3.64(d,J=9.5Hz,1H),3.04-3.30(m,5H),2.70-2.80(m,2H),2.10-2.19(m,1H),1.65-1.74(m,1H),1.53(sxt,J=7.3Hz,2H),1.31(d,J=2.5Hz,6H),1.06-1.17(m,2H),0.96-1.03(m,5H),0.86-0.95(m,6H)。
步骤H:(R)-8-环丙基-6-(4-(乙磺酰基)-3-异丙基哌嗪-1-基)-3,3-二甲基-3,4-二氢-1H-吡喃并[3,4-c]吡啶-5-腈(化合物391)。向在1.5mL二氯甲烷中的5(30mg,0.08mmol)的溶液中添加三乙胺(0.02mL,0.16mmol)和乙磺酰氯(20mg,0.16mmol)。将生成的反应混合物在室温下搅拌过夜。将该反应混合物用DCM稀释并且然后用盐水洗涤。将有机层用无水Na2SO4干燥并且在真空中进行浓缩。通过制备型TLC(DCM/丙酮:70:1)来纯化粗产物,以给出11mg呈无色油状物的标题化合物。MS(ES)M+H预期是447.2,发现是447.1。1H NMR(氯仿-d)δ4.75-4.89(m,2H),4.31(d,J=13.6Hz,1H),4.04-4.18(m,1H),3.73(dt,J=14.2,1.5Hz,1H),3.51(d,J=10.0Hz,1H),3.28-3.43(m,1H),2.95-3.17(m,4H),2.76(s,2H),2.11-2.27(m,1H),1.65-1.75(m,1H),1.39(t,J=7.4Hz,3H),1.28-1.35(m,6H),1.05-1.17(m,2H),0.92-1.03(m,8H)。
步骤I1-1:(R)-8-环丙基-6-(4-(2-羟乙基)-3-异丙基哌嗪-1-基)-3,3-二甲基-3,4-二氢-1H-吡喃并[3,4-c]吡啶-5-腈(化合物420)。在一个20mL密封试管中放置5(200mg,0.565mmol)、3-溴丙-1-醇(157.1mg,1.13mmol)、和K2CO3(171.5mg,1.243mmol)、以及5mL的MeCN。在175℃下,使该反应混合物经受30min微波反应。在蒸发掉溶剂之后,将残余物溶解于二氯甲烷中并且用盐水洗涤。将有机层用无水Na2SO4干燥并且在真空中进行浓缩。通过快速柱色谱法(DCM/丙酮:4:1)来纯化粗产物,以给出170mg呈无色油状物的标题化合物。MS(ES)M+H预期是412.3,发现是413.1。1HNMR(氯仿-d)δ4.75-4.89(m,2H),4.21-4.34(m,1H),4.09-4.18(m,1H),3.97-4.05(m,1H),3.79-3.88(m,2H),3.33(d,J=12.0Hz,1H),3.08-3.25(m,2H),2.84-3.02(m,1H),2.69-2.81(m,2H),2.41(d,J=12.5Hz,1H),2.20-2.36(m,3H),1.95-2.09(m,1H),1.65-1.73(m,1H),1.31(s,6H),0.94-1.18(m,10H)。
步骤I1-2:(R)-2-(4-(5-氰基-8-环丙基-3,3-二甲基-3,4-二氢-1H-吡喃并[3,4-c]吡啶-6-基)-2-异丙基哌嗪-1-基)乙酸乙酯(化合物322)。向在1.5mL二氯甲烷中的化合物420(30mg,0.073mmol)的溶液中添加三乙胺(0.02mL,0.15mmol)和乙酰氯(11.2mg,0.15mmol)。将生成的反应混合物在室温下搅拌过夜。将该反应混合物用DCM稀释并且然后用盐水洗涤。将有机层用无水Na2SO4干燥并且在真空中进行浓缩。通过制备型TLC(DCM/丙酮:10:1)来纯化粗产物,以给出17mg呈无色油状物的标题化合物。MS(ES)M+H预期是455.3,发现是455.3。1H NMR(氯仿-d)δ4.72-4.89(m,2H),4.07-4.18(m,3H),4.03(dd,J=12.8,2.3Hz,1H),3.15(t,J=10.0Hz,1H),2.94-3.03(m,1H),2.89(t,J=9.9Hz,2H),2.71-2.78(m,2H),2.35-2.48(m,2H),2.24-2.32(m,1H),2.10-2.20(m,1H),2.06(s,3H),1.81(d,J=6.0Hz,2H),1.65-1.73(m,1H),1.31(s,6H),1.10-1.19(m,2H),1.03(d,J=6.8Hz,3H),0.99(dd,J=7.9,1.9Hz,2H),0.87-0.94(m,3H)。
步骤I2:(R)-甲基2-(4-(5-氰基-8-环丙基-3,3-二甲基-3,4-二氢-1H-吡喃并[3,4-c]吡啶-6-基)-2-异丙基哌嗪-1-基)乙酸酯(化合物397)。向在1.5mL乙腈和K2CO3(33mg,0.24mmol)中的5(30mg,0.073mmol)的溶液中添加2-溴乙酸甲酯(37mg,0.24mmol),并且将生成的反应混合物在室温下搅拌过夜。将该反应混合物用DCM稀释并且然后用盐水洗涤。将有机层用无水Na2SO4干燥并且在真空中进行浓缩。通过制备型TLC(DCM/丙酮:70:1)来纯化粗产物,以给出15mg呈无色油状物的标题化合物。MS(ES)M+H预期是427.3,发现是427.4。1HNMR(氯仿-d)δ4.75-4.89(m,2H),4.20(d,J=12.5Hz,1H),4.08(dd,J=12.9,2.4Hz,1H),3.71(s,3H),3.34-3.58(m,2H),3.17(br.s.,1H),2.82-3.01(m,3H),2.75(s,2H),2.69(d,J=10.3Hz,1H),2.02-2.15(m,1H),1.65-1.74(m,1H),1.31(s,6H),1.09-1.16(m,2H),1.03-1.08(m,3H),0.96-1.01(m,2H),0.89-0.96(m,3H)。
实例3.8-取代的-6-羟基-3,4-二氢-1H-吡喃并[3,4-c]吡啶-5-腈中间体的制备。
具有以下通式的不同的8-取代的-6-羟基-3,4-二氢-1H-吡喃并[3,4-c]吡啶-5-腈中间体:如下所述地进行制备。这些中间体被用作方案1中的8-环丙基-6-羟基-3,3-二甲基-3,4-二氢-1H-吡喃并[3,4-c]吡啶-5-腈(3)的替代物,以生产另外的具有化学式I和II的化合物。
6-羟基-8-环丙基-3,3-二甲基-3,4-二氢-1H-吡喃并[3,4-c]吡啶-5-腈。
根据描述于实例1,步骤A和B中的方法,从异丁酸氯化物和2,2-二甲基二氢-2H-吡喃-4(3H)-酮制备MS(ES)M+H预期是247.1,发现是247.0。1H NMRδ4.64(s,2H),2.89(quin,J=7.0Hz,1H),2.84(s,2H),1.38-1.45(m,6H),1.33(s,6H)。
8-乙基-6-羟基-3,3-二甲基-3,4-二氢-1H-吡喃并[3,4-c]吡啶-5-腈。
根据描述于二甲基-环丙基吡喃并吡啶的实验程序(步骤A和B)中的方法,从丙酰氯和2,2-二甲基二氢-2H-吡喃-4(3H)-酮制备MS(ES)M+H预期是233.1,发现是233.1。根据描述于实例1,步骤A和B中的方法,从1-甲基环丙烷碳酰氯和2,2-二甲基二氢-2H-吡喃-4(3H)-酮制备6-羟基-3,3-二甲基-8-(1-甲基环丙基)-3,4-二氢-1H-吡喃并[3,4-c]吡啶-5-腈。MS(ES)M+H预期是259.1,发现是259.1。1H NMRδ4.73(s,2H),2.81(s,2H),1.34(s,3H),1.31(s,6H),0.83-0.98(m,4H)。
8-环丁基-6-羟基-3,3-二甲基-3,4-二氢-1H-吡喃并[3,4-c]吡啶-5-腈。
根据描述于实例1,步骤A和B中的方法,从环丁烷碳酰氯和2,2-二甲基二氢-2H-吡喃-4(3H)-酮制备MS(ES)M+H预期是259.1,发现是259.2。1H NMR(氯仿-d).δ4.54(s,2H),3.43-3.55(m,1H),2.80(s,2H),2.46-2.62(m,2H),2.30-2.42(m,2H),2.03-2.18(m,2H),1.30(s,6H)。
8-环戊基-6-羟基-3,3-二甲基-3,4-二氢-1H-吡喃并[3,4-c]吡啶-5-腈。
根据描述于实例1,步骤A和B中的方法,从环戊烷碳酰氯和2,2-二甲基二氢-2H-吡喃-4(3H)-酮制备MS(ES)M+H预期是273.1,发现是273.1。
8-环己基-6-羟基-3,3-二甲基-3,4-二氢-1H-吡喃并[3,4-c]吡啶-5-腈。
根据描述于实例1,步骤A和B中的方法,从环己烷碳酰氯和2,2-二甲基二氢-2H-吡喃-4(3H)-酮制备MS(ES)M+H预期是287.2,发现是287.0。1H NMR(氯仿-d)δ4.64(s,2H),2.84(s,2H),2.42-2.57(m,1H),1.86-2.02(m,4H),1.80(d,J=13.3Hz,1H),1.71(d,J=12.0Hz,2H),1.54-1.65(m,1H),1.34-1.41(m,2H),1.33(s,6H)。
8-(3-氟苯基)-6-羟基-3,3-二甲基-3,4-二氢-1H-吡喃并[3,4-c]吡啶-5-腈。
根据描述于实例1,步骤A和B中的方法,从3-氟苯甲酰基和2,2-二甲基二氢-2H-吡喃-4(3H)-酮制备MS(ES)M+H预期是299.1,发现是299.0。
8-环己基-6-羟基-3,4-二氢-1H-吡喃并[3,4-c]吡啶-5-腈。
根据描述于实例1,步骤A和B中的方法,从环己烷碳酰氯和二氢-2H-吡喃-4(3H)-酮制备MS(ES)M+H预期是259.1,发现是258.9。1H NMR(氯仿-d)δ12.97(br.s.,1H),4.63(s,2H),3.94(t,J=5.8Hz,2H),2.99(t,J=5.8Hz,2H),2.31-2.54(m,1H),1.87-2.04(m,4H),1.79(d,J=13.1Hz,1H),1.70(d,J=11.0Hz,2H),1.54-1.66(m,1H),1.24-1.43(m,2H)。
8-环戊基-6-羟基-3,4-二氢-1H-吡喃并[3,4-c]吡啶-5-腈。
根据描述于实例1,步骤A和B中的方法,从环戊烷碳酰氯和二氢-2H-吡喃-4(3H)-酮制备MS(ES)M+H预期是245.1,发现是245.1。1HNMRδ4.641-4.68(m,2H),3.90-3.98(m,2H),2.98(t,J=5.8Hz,2H),2.79-2.91(m,1H),2.10-2.19(m,2H),1.96-2.06(m,2H),1.86-1.95(m,2H),1.78-1.85(m,2H)。
6-羟基-8-异丙基-3,4-二氢-1H-吡喃并[3,4-c]吡啶-5-腈。
根据描述于实例1,步骤A和B中的方法,从异丁酰氯和二氢-2H-吡喃-4(3H)-酮制备MS(ES)M+H预期是219.1,发现是219.1。1H NMRδ4.642(s,2H),3.90-3.98(m,2H),2.98(t,J=5.8Hz,2H),2.86(spt,J=6.9Hz,1H),1.39(d,J=6.8Hz,6H)。
6-羟基-8-对甲苯基-3,4-二氢-1H-吡喃并[3,4-c]吡啶-5-腈。
根据描述于实例1,步骤A和B中的方法,从4-甲基苯甲酰氯和二氢-2H-吡喃-4(3H)-酮制备MS(ES)M+H预期是267.1,发现是267.1。1H NMR(DMSO-d6)δ7.34(s,4H),4.31(s,2H),3.87(t,J=5.9Hz,2H),2.91(t,J=5.9Hz,2H),2.38(s,3H)。
实例4.3-羟基-1-异丙基-5,6,7,8-四氢异喹啉-4-腈中间体的制备。
根据方案3制备3-羟基-1-异丙基-5,6,7,8-四氢异喹啉-4-腈中间体。这些中间体也被用作方案1中的8-环丙基-6-羟基-3,3-二甲基-3,4-二氢-1H-吡喃并[3,4-c]吡啶-5-腈(3)的替代物,以生产本发明的另外的化合物。
方案3:
步骤J:2-异丁酰环己酮(12;R=R=H)。将250mL配备有搅拌棒的三颈圆底烧瓶填充上环己酮(4.91g,50mmol)和87mL的干甲苯。将该溶液用氮气进行吹扫并且冷却至0℃。在搅拌下,逐滴添加LiHMDS(在甲基叔丁基醚中的1.0M溶液,52.5mL,52.5mmol)溶液,并且允许将该反应混合物在0℃下搅拌2min,之后在剧烈搅拌下添加异丁酰氯(2.66g,25mmol)。在0℃下再经2min之后,移除冷水浴并且5min之后,将该反应混合物用乙酸(20mL,50%AcOH/H2O)淬灭。在H2O与醚之间进行分配之后,将有机层用盐水进行洗涤,用无水Na2SO4干燥并且在真空中进行浓缩。快速柱色谱法(30%乙酸乙酯/石油醚)给出4.4g呈淡黄色油状物的标题化合物。MS(ES)M+H预期是169.1,发现是169.1。1H NMR(DMSO-d6)δ16.36(s,1H),2.85-2.96(m,1H),2.38(qd,J=6.4,1.1Hz,4H),1.69-1.73(m,4H),1.13(s,3H),1.11(s,3H)。
步骤K:3-羟基-1-异丙基-5,6,7,8-四氢异喹啉-4-腈(13;R=R=H)。向在26mLEtOH中的2-异丁酰环己酮(12;4.33g,25.76mmol)和2-氰基乙酰胺(2.17g,25.76mmol)的溶液中添加二乙胺(2.7mL,25.76mmol)。将该反应混合物在室温下搅拌72小时,直到LC-MS指示完成形成产物。然后,将该反应混合物加热至回流并且添加足够的EtOH,以制备澄清溶液。在冷却回至室温以后,将所希望的产物及其区域异构体(regioisomer)从EtOH溶液中沉淀出。在冷却回至室温以后,获得作为白色固体的混合物的4.1g的标题化合物连同它的区域异构体,并且不用进一步纯化而用于下一个步骤中。MS(ES)M+H预期是217.1,发现是217.1。
3-羟基-1-异丙基-7,7-二甲基-5,6,7,8-四氢异喹啉-4-腈(13;R=R=CH3)。
根据描述于以上的步骤J和K中的方法,从异丁酰氯和4,4-二甲基环己酮制备作为两种区域异构的产物的混合物的标题化合物。MS(ES)M+H预期是245.2,发现是245.0。
实例5.不同的经取代的哌嗪中间体的制备
使用作为方案1的步骤D中的(R)-2-异丙基哌嗪的替代物有用的、不同的经取代的哌嗪中间体来合成其他具有化学式I和II的化合物。
根据方案4A制备这些取代的哌嗪中间体23中的一种。
方案4A:
步骤L:1,4-二苄基哌嗪-2-羧酸乙酯22。在80℃下,向在甲苯(30mL)中的N,N’-二苄基乙烷-1,2-二胺(21;7.2g,30mmol)和Et3N(10mL)的搅拌溶液中逐滴添加甲苯(30mL)中的2,3-二溴丙酸乙酯(8g,31mmol)。添加之后,将该反应混合物在80℃下搅拌3小时,直到TLC指示完全形成产物。将生成的混合物冷却至室温并且将固体进行过滤。将滤液用饱和水性NaHCO3(20mL)进行洗涤。将该有机相用无水Na2SO4干燥并且在真空中进行浓缩。快速柱色谱法(5%乙酸乙酯/石油醚)给出7.5g呈苍白色油状物的标题化合物。MS(ES)M+H预期是339.2,发现是339。
步骤M:哌嗪-2-羧酸乙酯23。在40℃下,在H2气氛下,将在EtOH(30mL)中的1,4-二苄基哌嗪-2-羧酸乙酯(22;4g,12mmol)和10%Pd/C(60mg)的混合物搅拌24小时,直到TLC指示起始材料完全消耗。将生成的混合物冷却至室温并且将固体进行过滤。将滤液进行浓缩,以给出2g呈白色固体的标题化合物。1H NMR(DMSO-d6)d:4.07(q,J=7.1Hz,2H),3.31(dd,J=8.3,3.0Hz,2H),2.29-2.32(m,2H),2.76-2.92(m,2H),2.63(d,J=8.0Hz,2H),2.52(s,1H),1.18(t,J=7.0Hz,3H)。
根据方案4B制备另外的经取代的哌嗪中间体29和30。
方案4B:
步骤N:1,4-双(叔丁氧基羰基)哌嗪-2-羧酸25。在室温下,向Na2CO3(40g,380mmol,在200mL的水中)的水溶液中添加哌嗪-2-羧酸二盐酸化物(对映异构体的混合物亦或特定的立体异构体)(24;10g,50mmol),随后添加四氢呋喃(200mL)中的二碳酸二叔丁酯(41g,183mmol)。将该反应混合物在室温下搅拌20小时并且然后在减压下除去挥发物。然后,将生成的混合物用二乙醚(100mL)萃取。用3.0M HCl处理水层,直到它呈轻微酸性(pH=4)并且然后用乙酸乙酯(150mL)萃取。将有机层用盐水洗涤,用无水Na2SO4干燥,过滤,并且浓缩,以给出16g呈白色固体的标题化合物。
步骤O:
1,4-二叔丁基2-甲基哌嗪-1,2,4-三羧酸酯(26;R b=Me)。向在DMF(10mL)中的1,4-双(叔丁氧基羰基)-哌嗪-2-羧酸(25;3.6g,11mmol)混合物中添加K2CO3(2g,18mmol)。将生成的悬浮液冷却至0℃并且用碘甲烷(1.5mL,12mmol)进行处理。然后,允许将该混合物加温至室温,搅拌6小时。在用水(200mL)淬灭以后,将该混合物用乙酸乙酯(100mL)萃取,并且将有机层用盐水进行洗涤,用无水Na2SO4干燥,过滤,并且在真空中浓缩,以给出3.6g呈白色固体的标题化合物。
1,4-二叔丁基2-乙基哌嗪-1,2,4-三羧酸酯(26;R b=乙基)。向在10mL的DMF中的1,4-双(叔丁氧基羰基)-哌嗪-2-羧酸(对映异构体的混合物亦或特定的立体异构体)(25;0.5g,1.38mmol)混合物中添加K2CO3(0.6g,4.4mmol)。将生成的悬浮液冷却至0℃并且用溴乙烷(1mL,9.34mmol)进行处理。允许将该反应混合物加温至室温,搅拌24小时。在用水(10mL)淬灭以后,将该混合物用乙酸乙酯(20mL)萃取,并且将有机层用盐水进行洗涤,用无水Na2SO4干燥,过滤,并且在真空中浓缩,以给出0.48g呈白色固体的标题化合物。
步骤P:二叔丁基2-(羟甲基)哌嗪-1,4-二羧酸酯27。在0℃下,向在乙醇(10mL)中的1,4-二叔丁基2-甲基哌嗪-1,2,4-三羧酸酯(26;2g,56mmol)的溶液中添加CaCl2(5g,45mmol),随后以两部分添加NaBH4(1.1g,28mmol)。将该反应混合物加温室温并且搅拌1.5h。在冷却至0℃以后,将该混合物用柠檬酸水溶液(50mL的水中的6g柠檬酸)淬灭。然后,将生成的混合物用乙酸乙酯(200mL)萃取,并且将有机层用盐水进行洗涤,用无水Na2SO4干燥,过滤,并且在真空中浓缩,以给出1.8g呈白色固体的标题化合物。
步骤Q:二叔丁基2-(甲氧基甲基)哌嗪-1,4-二羧酸酯28。在-20℃下,在氮气氛下,向在无水THF中的二叔丁基2-(羟甲基)哌嗪-1,4-二羧酸酯(27;1.5g,4.74mmol)的溶液中分部分地添加NaH(210mg,矿物油中的60%分散体)。在搅拌5min以后,然后添加碘甲烷并且将该混合物在室温下搅拌3小时并且倾倒进水(20mL)中。然后,将该混合物用乙酸乙酯(2×100mL)萃取,将合并的有机萃取物用盐水进行洗涤,用无水Na2SO4干燥,过滤,并且在真空中浓缩,以给出1.6g呈白色固体的标题化合物。
步骤R:2-(甲氧基甲基)哌嗪29。在室温下,向在甲醇(5mL)中的二叔丁基2-(甲氧基甲基)哌嗪-1,4-二羧酸酯(28;1.5g,4.5mmol)的溶液中添加HCl溶液(在EtOAc中,10mL,4.0M)。将该反应混合物在室温下搅拌过夜并且然后在真空中浓缩,以给出1.2g作为盐酸盐的2-(甲氧基甲基)哌嗪,将其不用进一步纯化而用于下一个步骤中。
步骤S:哌嗪-2-羧酸乙酯30(Rb=乙基)。在室温下,向在甲醇(4mL)中的1,4-二叔丁基2-乙基哌嗪-1,2,4-三羧酸酯(26,Rb=乙基;1.2g,4.5mmol)的溶液中添加HCl溶液(在EtOAc中,5mL,4.0M)。将该反应混合物在室温下搅拌过夜并且然后浓缩,以给出1g作为盐酸盐的2-(甲氧基甲基)哌嗪,将其不用进一步纯化而用于下一个步骤中。
分别进行26的(S)-异构体和(R)-异构体两者的这一反应,以生产29的对应的异构体。
根据方案4c制备仍其他的取代的哌嗪中间体35。
方案4c:
步骤T:2-氨基-2-苯乙酰胺32。向在5mL的水中的2-氨基-2-苯乙酸甲酯盐酸化物(对映异构体的或特定的立体异构体)(31;5.0g,25mmol)中添加氨水(25mL,28%)并且将该混合物在室温下搅拌18小时。在TLC指示该反应完成以后,将该混合物蒸发至干燥。在水与二氯甲烷之间进行分配以后,将有机层分离,用无水MgSO4干燥,并且在真空中进行浓缩,以给出2.34g呈白色固体的标题化合物。MS(ES)M+H预期是151.1,发现是151。
步骤U:1-苯乙烷-1,2-二胺33。向在50mL的无水THF中的32(2.34g,15.6mmol)的悬浮液中分部分地添加冰水浴中的LiAlH4(1.78g,46.8mmol)。允许将生成的混合物加温至室温并且然后加热至回流温度,持续4小时。在冷却至0℃以后,通过缓慢添加8mL的10%KOH溶液,伴随剧烈搅拌来分解过量的LAH。通过过滤除去固体。将滤液蒸发至干燥,以给出2g呈淡黄色油状物的33。MS(ES)M+H预期是137.1,发现是137。
步骤V:
5-苯基哌嗪-2,3-二酮34。向在200mL EtOH中的33(1.9g,14mmol)的溶液中添加草酸二乙酯(2.04g,14mmol)。在回流下,将生成的混合物搅拌2小时。在冷却至室温以后,将该混合物用盐水淬灭,用EtOAc萃取。将有机层在真空中浓缩,以给出2.15g呈淡黄色油状物的34。MS(ES)M+H预期是191.1,发现是191。
根据描述于步骤V中的方法,从2-甲基丙烷-1,2-二胺制备5,5-二甲基哌嗪-2,3-二酮。MS(ES)M+H预期是143.1,发现是143。
步骤W:2-苯基哌嗪35。向在50mL无水THF中的34(2.15g,11mmol)的悬浮液中分部分地添加冰水浴中的LiAlH4(2.58g,68mmol)。允许将生成的混合物加温至室温并且然后加热至回流,持续4小时。在冷却至0℃以后,通过缓慢添加8mL的10%KOH溶液,伴随剧烈搅拌来分解过量的LAH。通过过滤除去固体。将滤液蒸发至干燥,以给出1.65g呈淡黄色油状物的35。MS(ES)M+H预期是163.1,发现是163。
根据描述于步骤W中的方法,从5,5-二甲基哌嗪-2,3-二酮制备2,2-二甲基哌嗪。MS(ES)M+H预期是115.1,发现是115。
如列举于方案4d中的来制备用于具有化学式I的化合物39的合成中的再另一些经取代的哌嗪中间体。
方案4d:
步骤X:呋喃-2-碳酰氯37。在0℃下,向在5mL DCM中的呋喃-2-羧酸(36;0.5g,4.5mmol)的溶液中缓慢添加在冰水浴中的草酰二氯(0.5mL),随后添加一滴DMF。将生成的混合物在室温下搅拌30min并且然后缓慢地加温至回流温度,持续1小时。在将该混合物冷却至室温以后,将它在真空中浓缩,以给出0.59g的粗品标题化合物。
步骤Y:呋喃-2-基(3-甲基哌嗪-1-基)甲酮39。在0℃下,向在5mL H2O和2.5mL丙酮中的2-甲基哌嗪(对映异构体的混合物亦或特定的立体异构体)(38;0.41g,4.1mmol)和NaHCO3(1.56g,18.5mmol)的混合物中缓慢添加1.5mL丙酮中的呋喃-2-碳酰氯(37;0.59g,4.5mmol)。允许将生成的混合物加温至室温并且搅拌2小时。将该混合物用盐水淬灭,用EtOAc萃取。将有机层干燥并且在真空中浓缩。将残余物通过快速柱色谱法(25%石油醚/乙酸乙酯)进行纯化,以给出0.32g的标题化合物。MS(ES)M+H预期是195.1,发现是195。
根据描述于步骤Y中的方法,从2-苯基哌嗪(对映异构体的混合物亦或特定的立体异构体)制备呋喃-2-基(3苯基哌嗪-1-基)甲酮。MS(ES)M+H预期是257.1,发现是257。
实例6.根据方案2,步骤E1产生的另外的具有化学式I的化合物。
使用适当的吡喃并吡啶和经取代的哌嗪中间体,按照与使用方案2的步骤E1制备的化合物等效的方式制备本发明的以下化合物。
3-(4-(呋喃-2-羰基)-3-甲基哌嗪-1-基)-1-异丙基-5,6,7,8-四氢异喹啉-4-腈(化合物125)。
1H NMRδ7.45-7.59(m,1H),7.03(d,J=3.5Hz,1H),6.51(dd,J=3.5,1.8Hz,1H),4.86(br.s.,1H),4.48(d,J=13.6Hz,1H),4.15-4.24(m,1H),4.11(dt,J=13.1,2.0Hz,1H),3.55(br.s.,1H),3.28(dd,J=13.1,3.8Hz,1H),3.06-3.23(m,2H),2.84-2.96(m,2H),2.58-2.74(m,2H),1.78-1.87(m,4H),1.44-1.53(m,3H),1.15-1.23(m,6H)。LC-MS:m/z 393.0(M+H)+。
3-(4-(呋喃-2-羰基)哌嗪-1-基)-1-异丙基-7,7-二甲基-5,6,7,8-四氢异喹啉-4-腈(化合物116)。
1H NMRδ7.53(dd,J=1.8,0.8Hz,1H),7.06(dd,J=3.4,0.9Hz,1H),6.52(dd,J=3.5,1.8Hz,1H),3.98(br.s.,4H),3.61-3.78(m,4H),3.08-3.23(m,1H),2.92(t,J=6.8Hz,2H),2.42(s,2H),1.56-1.62(m,2H),1.16-1.22(m,6H),0.98-1.05(m,6H)。LC-MS:m/z 406.9(M+H)+。
(R)-8-环己基-6-(3-甲基-4-(5-甲基异噁唑-4-羰基)哌嗪-1-基)-3,4-二氢-1H-吡喃并[3,4-c]吡啶-5-腈(化合物187)。
1H NMRδ8.23(s,1H),4.71(s,2H),4.13-4.25(m,2H),3.94(t,J=5.8Hz,2H),3.51(br.s.,1H),3.22(dd,J=13.1,3.5Hz,1H),3.05(td,J=12.5,3.3Hz,1H),2.94(t,J=5.8Hz,2H),2.57(s,3H),2.42(tt,J=11.2,3.6Hz,1H),1.81-1.88(m,2H),1.75(d,J=11.0Hz,1H),1.62-1.71(m,3H),1.43(d,J=6.8Hz,3H),1.26-1.40(m,4H)。LC-MS:m/z450.1(M+H)+。
(R)-8-环己基-6-(4-(呋喃-3-羰基)-3-甲基哌嗪-1-基)-3,4-二氢-1H-吡喃并[3,4-c]吡啶-5-腈(化合物160)。
1H NMRδ7.75(s,1H),7.47(s,1H),6.55-6.64(m,1H),4.72(s,3H),4.14-4.41(m,3H),3.95(t,J=5.6Hz,2H),3.49(br.s.,1H),3.26(dd,J=13.1,3.3Hz,1H),3.09(td,J=12.5,3.3Hz,1H),2.95(t,J=5.5Hz,2H),2.33-2.51(m,1H),1.85(d,J=12.5Hz,2H),1.77(d,J=10.8Hz,1H),1.65-1.72(m,2H),1.60(d,J=12.0Hz,2H),1.44(d,J=6.8Hz,3H),1.30-1.39(m,3H)。LC-MS:m/z 435.1(M+H)+。
(R)-8-环己基-6-(4-(3-甲氧基丙酰基)-3-甲基哌嗪-1-基)-3,4-二氢-1H-吡喃并[3,4-c]吡啶-5-腈(化合物240)。
1H NMR(氯仿-d).δ4.89(br.s.,1H),4.69(s,2H),4.12-4.26(m,2H),3.90-3.97(m,2H),3.66-3.83(m,3H),3.47-3.66(m,1H),3.33-3.41(m,3H),2.99-3.28(m,2H),2.92(t,J=5.6Hz,2H),2.63-2.80(m,1H),2.52-2.63(m,1H),2.41(tt,J=11.1,3.7Hz,1H),1.84(d,J=12.8Hz,2H),1.75(d,J=10.5Hz,1H),1.62-1.71(m,3H),1.26-1.41(m,7H)。LC-MS:m/z 427.2(M+H)+。
(R)-8-环己基-6-(4-(呋喃-3-羰基)-3-异丙基哌嗪-1-基)-3,4-二氢-1H-吡喃并[3,4-c]吡啶-5-腈(化合物183)。
1H NMRδ7.72(br.s.,1H),7.40-7.49(m,1H),6.51-6.66(m,1H),4.70(s,2H),4.45-4.64(m,2H),4.27(br.s.,1H),3.87-4.16(m,3H),3.54-3.75(m,1H),3.11(dd,J=13.3,3.0Hz,2H),2.92(t,J=5.6Hz,2H),2.41(tt,J=11.1,3.5Hz,1H),2.17-2.34(m,1H),1.84(d,J=12.5Hz,2H),1.70-1.77(m,2H),1.54-1.65(m,3H),1.29-1.39(m,3H),0.84-1.07(m,4H)。LC-MS:m/z 463.2(M+H)+。
8-环己基-6-(4-(呋喃-3-羰基)-3-甲基哌嗪-1-基)-3,4-二氢-1H-吡喃并[3,4-c]吡啶-5-腈(化合物133)。
1H NMRδ7.70-7.80(m,1H),7.39-7.54(m,1H),6.60(s,1H),4.72(s,3H),4.13-4.42(m,3H),3.95(t,J=5.6Hz,2H),3.50(br.s.,1H),3.26(d,J=12.5Hz,1H),3.04-3.17(m,1H),2.95(t,J=5.5Hz,2H),2.43(t,J=11.2Hz,1H),1.85(d,J=12.3Hz,2H),1.56-1.80(m,5H),1.44(d,J=6.8Hz,3H),1.25-1.37(m,3H)。LC-MS:m/z 435.1(M+H)+。
4-(5-氰基-8-环己基-3,4-二氢-1H-吡喃并[3,4-c]吡啶-6-基)-1-(3-(甲硫基)-丙酰基)哌嗪-2-羧酸乙酯(化合物313)。
1H NMRδ5.21-5.32(m,1H),4.72-4.84(m,1H),4.69(s,2H),4.11-4.28(m,2H),4.02-4.09(m,1H),3.78-4.01(m,4H),3.32(dd,J=13.6,4.5Hz,1H),3.02-3.18(m,1H),2.82-2.97(m,4H),2.69-2.79(m,2H),2.36-2.46(m,1H),2.13-2.20(m,3H),1.85(d,J=11.8Hz,2H),1.76(d,J=9.5Hz,1H),1.66(br.s.,1H),1.60(d,J=11.8Hz,2H),1.27-1.41(m,4H),1.14-1.22(m,3H)。LC-MS:m/z 501.0(M+H)+。
(R)-8-环己基-6-(3-甲基-4-(2-(苯硫-2-基)乙酰基)哌嗪-1-基)-3,4-二氢-1H-吡喃并[3,4-c]吡啶-5-腈(化合物185)。
1H NMRδ7.21(dd,J=5.1,1.1Hz,1H),6.87-6.99(m,2H),4.91(br.s.,1H),4.69(s,2H),4.22(d,J=13.6Hz,1H),4.13(d,J=13.3Hz,1H),3.86-3.98(m,4H),3.77(d,J=13.3Hz,1H),3.50-3.67(m,1H),3.11-3.23(m,1H),2.88-3.05(m,3H),2.33-2.48(m,1H),1.84(d,J=12.3Hz,2H),1.75(d,J=10.3Hz,1H),1.62-1.69(m,3H),1.26-1.38(m,7H)。LC-MS:m/z 465.1(M+H)+。
4-(5-氰基-8-环己基-3,4-二氢-1H-吡喃并[3,4-c]吡啶-6-基)-1-(呋喃-3-羰基)哌嗪-2-羧酸乙酯(化合物258)。
1H NMRδ7.79(br.s.,1H),7.40-7.52(m,1H),6.49-6.70(m,1H),5.39(br.s.,0.5H),4.79(br.s.,0.5H),4.65-4.74(m,2H),4.21(dq,J=10.7,7.1Hz,2H),4.03-4.16(m,2H),3.81-4.03(m,3H),3.39(d,J=11.5Hz,1H),3.03-3.17(m,1H),2.92(t,J=5.6Hz,2H),2.34-2.47(m,1H),1.50-1.84(m,10H),1.09-1.39(m,3H)。LC-MS:m/z 493.2(M+H)+。
8-环己基-6-(4-(呋喃-3-羰基)哌嗪-1-基)-3,4-二氢-1H-吡喃并[3,4-c]吡啶-5-腈(化合物120)。
1H NMR(氯仿-d).δ7.77(s,1H),7.47(s,1H),6.60(s,1H),4.72(s,2H),3.96(t,J=5.6Hz,2H),3.87(br.s.,4H),3.69(br.s.,4H),2.95(t,J=5.4Hz,2H),2.44(t,J=10.9Hz,1H),1.86(d,J=12.5Hz,2H),1.57-1.81(m,5H),1.31-1.42(m,3H)。LC-MS:m/z420.9(M+H)+。
8-环己基-6-(3-乙基-4-(呋喃-3-羰基)哌嗪-1-基)-3,4-二氢-1H-吡喃并[3,4-c]吡啶-5-腈(化合物175)。
1H NMRδ7.74(s,1H),7.45-7.54(m,1H),6.54-6.64(m,1H),4.53-5.02(m,2H),4.11-4.41(m,3H),3.89-4.08(m,2H),3.51(m,1H),3.21(dd,J=13.1,3.5Hz,1H),3.01-3.15(m,1H),2.94(t,J=5.8Hz,2H),2.43(tt,J=11.1,3.5Hz,1H),1.73-1.96(m,6H),1.53-1.65(m,2H),1.29-1.43(m,4H),0.85-1.03(m,3H)。LC-MS:m/z 449.2(M+H)+。
4-(5-氰基-8-环己基-3,4-二氢-1H-吡喃并[3,4-c]吡啶-6-基)-1-(呋喃-2-羰基)哌嗪-2-羧酸乙酯(化合物314)。
1H NMRδ7.52(br.s.,1H),7.11(d,J=3.5Hz,1H),6.51(br.s.,1H),5.34(br.s.,1H),4.70(s,3H),4.53(d,J=13.6Hz,1H),4.16-4.31(m,2H),4.12(d,J=7.0Hz,1H),3.86-4.05(m,3H),3.50(d,J=10.0Hz,1H),3.23(br.s.,1H),2.93(t,J=5.5Hz,2H),2.41(br.s.,1H),1.84(d,J=11.5Hz,2H),1.75(d,J=9.5Hz,1H),1.65(br.s.,3H),1.29-1.38(m,4H),1.20(t,J=7.2Hz,3H)。LC-MS:m/z 495.2(M+H)+。
4-(5-氰基-8-环己基-3,4-二氢-1H-吡喃并[3,4-c]吡啶-6-基)-1-(2-甲基呋喃-3-羰基)哌嗪-2-羧酸乙酯(化合物277)。
1H NMRδ7.69(br.s.,1H),7.46-7.51(m,1H),5.39(br.s.,0.5H),4.80(br.s.,0.5H),4.72(d,J=3.5Hz,2H),4.25(dq,J=9.7,7.3Hz,2H),4.01-4.15(m,2H),3.93(br.s.,1H),3.40(d,J=11.8Hz,1H),3.03-3.18(m,1H),2.92(t,J=5.6Hz,2H),2.54-2.57(s,3H),2.34-2.47(m,1H),1.50-1.84(m,10H),1.09-1.39(m,3H)。LC-MS:m/z 507.2(M+H)+。
(R)-8-环己基-6-(3-甲基-4-(噻吩-3-羰基)哌嗪-1-基)-3,4-二氢-1H-吡喃并[3,4-c]吡啶-5-腈(化合物242)。
1H NMR7.53(d,J=2.8Hz,1H),7.36(dd,J=4.9,2.9Hz,1H),7.20(d,J=5.0Hz,1H),4.59-4.83(m,3H),4.08-4.38(m,3H),3.88-3.99(m,2H),3.46(br.s.,1H),3.23(d,J=10.8Hz,1H),3.07(td,J=12.5,3.4Hz,1H),2.87-2.97(m,2H),2.41(tt,J=11.0,3.5Hz,1H),1.83(d,J=12.8Hz,2H),1.74(d,J=11.0Hz,1H),1.68(br.s.,1H),1.53-1.61(m,2H),1.41(d,J=6.8Hz,3H),1.27-1.39(m,4H)。LC-MS:m/z 451.0(M+H)+。
8-环己基-6-(3-乙基-4-(呋喃-2-羰基)哌嗪-1-基)-3,4-二氢-1H-吡喃并[3,4-c]吡啶-5-腈(化合物174)。
1H NMRδ7.44-7.59(m,1H),7.05(d,J=3.3Hz,1H),6.52(dd,J=3.3,1.8Hz,1H),4.72(s,3H),4.48(br.s.,1H),4.23-4.38(m,2H),3.87-4.04(m,2H),3.47(br.s.,1H),3.30(dd,J=13.2,3.6Hz,1H),3.16(td,J=12.4,3.3Hz,1H),2.95(t,J=5.6Hz,2H),2.43(tt,J=10.9,3.6Hz,1H),1.89-2.08(m,1H),1.74-1.88(m,4H),1.52-1.64(m,2H),1.21-1.44(m,5H),0.83-1.04(m,3H)。LC-MS:m/z 449.1(M+H)+。
(R)-8-环己基-6-(3-甲基-4-(2-(吡啶-2-基)乙酰基)哌嗪-1-基)-3,4-二氢-1H-吡喃并[3,4-c]吡啶-5-腈(化合物238)。
1H NMRδ8.57(dd,J=5.0,0.8Hz,1H),7.70(t,J=7.2Hz,1H),7.39(dd,J=14.1,7.8Hz,1H),7.22(d,J=6.8Hz,1H),4.89(br.s.,0.5H),4.69(s,2H),4.53(d,J=13.8Hz,0.5H),4.09-4.24(m,2.5H),3.89-4.07(m,3H),3.54(t,J=11.0Hz,1H),3.09-3.23(m,1H),2.78-3.05(m,2.5H),2.29-2.47(m,1H),1.83(d,J=12.5Hz,4H),1.75(d,J=10.0Hz,2H),1.62-1.70(m,2H),1.46-1.62(m,2H),1.12-1.40(m,3H)。LC-MS:m/z 460.1(M+H)+。
(R)-8-环己基-6-(3-甲基-4-(4-甲基噁唑-5-羰基)哌嗪-1-基)-3,4-二氢-1H-吡喃并[3,4-c]吡啶-5-腈(化合物225)。
1H NMRδ7.83(s,1H),4.70(s,3H),4.12-4.32(m,3H),3.85-3.99(m,2H),3.53(br.s.,1H),3.30(dd,J=13.1,3.5Hz,1H),3.14(td,J=12.5,3.5Hz,1H),2.93(t,J=5.6Hz,2H),2.36-2.47(m,4H),1.80-1.89(m,2H),1.75(d,J=11.3Hz,1H),1.53-1.63(m,2H),1.45(d,J=6.8Hz,3H),1.26-1.41(m,5H)。LC-MS:m/z 450.2(M+H)+。
(R)-8-环己基-6-(3-甲基-4-(2-甲基呋喃-3-羰基)哌嗪-1-基)-3,4-二氢-1H-吡喃并[3,4-c]吡啶-5-腈(化合物184)。
1H NMRδ7.28(d,J=1.8Hz,1H),6.36(d,J=1.8Hz,1H),4.70(s,2H),4.14-4.25(m,2H),3.93(t,J=5.8Hz,2H),3.44(br.s.,1H),3.22(d,J=10.8Hz,1H),3.00-3.09(m,1H),2.93(t,J=5.6Hz,2H),2.35-2.47(m,4H),1.84(d,J=12.8Hz,2H),1.75(d,J=11.3Hz,1H),1.63-1.70(m,3H),1.39(d,J=6.8Hz,3H),1.27-1.35(m,4H)。LC-MS:m/z449.1(M+H)+。
8-环己基-6-((3R)-3-甲基-4-(四氢呋喃-3-羰基)哌嗪-1-基)-3,4-二氢-1H-吡喃并[3,4-c]吡啶-5-腈(化合物263)。
1H NMRδ4.89(br.s.,1H),4.70(s,2H),4.13-4.27(m,2H),3.80-4.08(m,7H),3.42-3.67(m,1H),3.12-3.42(m,2H),2.99-3.10(m,1H),2.93(t,J=5.6Hz,2H),2.42(tt,J=11.0,3.6Hz,1H),1.98-2.24(m,2H),1.84(d,J=12.5Hz,2H),1.75(d,J=10.5Hz,1H),1.63-1.70(m,3H),1.28-1.43(m,7H)。LC-MS:m/z 439.1(M+H)+。
(R)-8-环己基-6-(4-(2-(2-甲氧苯基)乙酰基)-3-甲基哌嗪-1-基)-3,4-二氢-1H-吡喃并[3,4-c]吡啶-5-腈(化合物224)。
1H NMRδ7.19-7.26(m,2H),6.86-6.95(m,2H),4.92(br.s.,1H),4.69(s,2H),4.22(d,J=10.8Hz,1H),4.11(d,J=12.8Hz,1H),3.81-4.03(m,4H),3.71-3.81(m,2H),3.34-3.51(m,1H),3.09-3.34(m,1H),2.87-3.04(m,3H),2.40(tt,J=11.0,3.6Hz,1H),1.83(d,J=12.5Hz,2H),1.74(d,J=14.6Hz,2H),1.59-1.68(m,3H),1.26-1.37(m,5H)。LC-MS:m/z 489.1(M+H)+。
(R)-8-环己基-6-(4-(2-(3-甲氧苯基)乙酰基)-3-甲基哌嗪-1-基)-3,4-二氢-1H-吡喃并[3,4-c]吡啶-5-腈(化合物189)。
1H NMRδ7.24(t,J=8.0Hz,1H),6.73-6.89(m,3H),4.91(br.s.,1H),4.68(s,2H),4.21(d,J=13.8Hz,1H),4.10(d,J=12.3Hz,2H),3.92(t,J=5.0Hz,2H),3.72-3.83(m,4H),3.44(t,J=11.2Hz,1H),3.07-3.23(m,1H),2.96-3.07(m,1H),2.90(t,J=5.5Hz,2H),2.39(tt,J=11.0,3.5Hz,1H),1.72-1.86(m,4H),1.61-1.67(m,2H),1.51-1.61(m,2H),1.25-1.34(m,5H)。LC-MS:m/z 489.1(M+H)+。
(R)-8-环己基-6-(4-(呋喃-2-羰基)-3-甲基哌嗪-1-基)-3,4-二氢-1H-吡喃并[3,4-c]吡啶-5-腈(化合物162)。
1H NMRδ7.52(dd,J=1.8,0.8Hz,1H),7.05(dd,J=3.5,0.8Hz,1H),6.51(dd,J=3.5,1.8Hz,1H),4.88(br.s.,1H),4.71(s,2H),4.49(d,J=13.1Hz,1H),4.27(d,J=12.0Hz,1H),4.18(dt,J=13.1,2.1Hz,1H),3.87-4.05(m,2H),3.55(br.s.,1H),3.34(dd,J=13.1,3.8Hz,1H),3.17(td,J=12.5,3.4Hz,1H),2.94(t,J=5.6Hz,2H),2.43(tt,J=11.1,3.7Hz,1H),1.85(d,J=12.8Hz,2H),1.54-1.79(m,5H),1.46(d,J=6.8Hz,3H),1.31-1.42(m,3H)。LC-MS:m/z435.2(M+H)+。
(R)-8-环己基-6-(3-甲基-4-(3-(甲硫基)丙酰基)哌嗪-1-基)-3,4-二氢-1H-吡喃并[3,4-c]吡啶-5-腈(化合物264)。
1H NMRδ4.88(br.s.,1H),4.70(s,2H),4.52(d,J=13.6Hz,1H),4.23(d,J=13.1Hz,1H),3.90-3.97(m,2H),3.52-3.82(m,1H),3.00-3.30(m,3H),2.80-2.97(m,4H),2.56-2.78(m,2H),2.37-2.46(m,1H),2.11-2.21(m,3H),1.84(d,J=12.8Hz,2H),1.75(d,J=14.6Hz,2H),1.52-1.63(m,2H),1.26-1.42(m,7H)。LC-MS:m/z 443.2(M+H)+。
(R)-8-环己基-6-(3-甲基-4-(噻吩-2-羰基)哌嗪-1-基)-3,4-二氢-1H-吡喃并[3,4-c]吡啶-5-腈(化合物241)。
1H NMRδ7.46(dd,J=5.0,1.0Hz,1H),7.32(dd,J=3.6,1.1Hz,1H),7.06(dd,J=5.0,3.8Hz,1H),4.77(br.s.,1H),4.70(s,2H),4.37(d,J=13.6Hz,1H),4.12-4.28(m,2H),3.91-3.98(m,2H),3.53(t,J=11.4Hz,1H),3.28(dd,J=13.1,3.5Hz,1H),3.12(td,J=12.5,3.3Hz,1H),2.93(t,J=5.6Hz,2H),2.41(tt,J=11.1,3.6Hz,1H),1.83(d,J=12.8Hz,2H),1.75(d,J=10.8Hz,1H),1.68(br.s.,1H),1.55-1.59(m,1H),1.45(d,J=6.8Hz,3H),1.27-1.40(m,5H)。LC-MS:m/z 451.0(M+H)+。
(R)-8-环己基-6-(3-甲基-4-(2-甲基咪唑并[1,2-a]吡啶-3-羰基)哌嗪-1-基)-3,4-二氢-1H-吡喃并[3,4-c]吡啶-5-腈(化合物190)。
1H NMRδ8.47(d,J=6.8Hz,1H),7.60(d,J=8.5Hz,1H),7.31(t,J=7.4Hz,1H),6.89(t,J=6.0Hz,1H),4.60-4.87(m,3H),4.23(d,J=12.8Hz,2H),3.88-4.08(m,3H),3.55-3.76(m,1H),3.32(d,J=11.3Hz,1H),3.08(br.s.,1H),2.94(t,J=5.6Hz,2H),2.54(s,3H),2.42(tt,J=11.0,3.6Hz,1H),1.83(d,J=12.8Hz,2H),1.57-1.79(m,5H),1.45(d,J=5.3Hz,3H),1.27-1.38(m,3H)。LC-MS:m/z 499.1(M+H)+。
8-环己基-6-((3S,5R)-4-(呋喃-2-羰基)-3,5-二甲基哌嗪-1-基)-3,4-二氢-1H-吡喃并[3,4-c]吡啶-5-腈(化合物128)。
1H NMRδ7.47-7.56(m,1H),7.07(d,J=3.3Hz,1H),6.52(dd,J=3.3,1.8Hz,1H),4.87(br.s.,2H),4.73(s,2H),4.31(d,J=13.1Hz,2H),3.96(t,J=5.8Hz,2H),3.23(dd,J=12.9,4.1Hz,2H),2.96(t,J=5.6Hz,2H),2.39-2.52(m,1H),1.86(d,J=12.8Hz,2H),1.60-1.80(m,5H),1.57(d,J=6.8Hz,6H),1.30-1.43(m,3H)。LC-MS:m/z449.2(M+H)+。
(R)-8-环己基-6-(3-甲基-4-(1-甲基-1H-咪唑-2-羰基)哌嗪-1-基)-3,4-二氢-1H-吡喃并[3,4-c]吡啶-5-腈(化合物262)。
1H NMRδ7.79(br.s.,1H),7.32(br.s.,1H),4.79(br.s.,1H),4.71(s,2H),4.35(d,J=6.5Hz,1H),4.11-4.27(m,2H),3.91-3.99(m,2H),3.86(s,3H),3.55(br.s.,1H),3.21-3.28(m,1H),3.03-3.14(m,1H),2.94(t,J=5.6Hz,2H),2.42(tt,J=11.0,3.6Hz,1H),1.75(d,J=10.3Hz,2H),1.69(br.s.,1H),1.54-1.62(m,2H),1.45(d,J=6.5Hz,3H),1.27-1.41(m,5H)。LC-MS:m/z 449.1(M+H)+。
8-环己基-6-(4-(呋喃-2-羰基)哌嗪-1-基)-3,4-二氢-1H-吡喃并[3,4-c]吡啶-5-腈(化合物110)。
1H NMRδ7.47-7.57(m,1H),7.05(d,J=3.5Hz,1H),6.50(dd,J=3.5,1.8Hz,1H),4.70(s,2H),3.87-4.11(m,6H),3.66-3.78(m,4H),2.93(t,J=5.8Hz,2H),2.42(tt,J=11.0,3.6Hz,1H),1.80-1.89(m,2H),1.53-1.78(m,5H),1.27-1.41(m,3H)。LC-MS:m/z 421.0(M+H)+。
(R)-8-环己基-6-(3-甲基-4-(2-(吡啶-3-基)乙酰基)哌嗪-1-基)-3,4-二氢-1H-吡喃并[3,4-c]吡啶-5-腈(化合物260)。
1H NMRδ8.54(br.s.,2H),7.72(br.s.,1H),7.34(dd,J=7.7,4.9Hz,1H),4.89(br.s.,1H),4.69(s,3H),4.53(d,J=14.3Hz,1H),4.02-4.31(m,3H),3.89-3.97(m,2H),3.72-3.80(m,3H),3.37-3.63(m,1H),3.17(t,J=13.7Hz,2H),2.89-3.05(m,3H),2.41(tt,J=11.1,3.5Hz,1H),1.28-1.37(m,7H)。LC-MS:m/z 480.1(M+H)+。
(R)-8-环己基-6-(4-(呋喃-2-羰基)-3-异丙基哌嗪-1-基)-3,4-二氢-1H-吡喃并[3,4-c]吡啶-5-腈(化合物182)。
1H NMRδ7.44-7.59(m,1H),7.03(br.s.,1H),6.50(dd,J=3.3,1.8Hz,1H),4.70(s,2H),4.21–4.58(m,4H),3.85-4.04(m,2H),3.60(br.s.,1H),3.08-3.28(m,2H),2.92(t,J=5.6Hz,2H),2.41(tt,J=11.0,3.7Hz,1H),2.18-2.32(m,1H),1.84(d,J=12.5Hz,2H),1.54-1.75(m,5H),1.06(br.s.,3H),0.80-0.95(m,3H)。LC-MS:m/z 463.1(M+H)+。
8-环己基-6-(4-(呋喃-2-羰基)-3-甲基哌嗪-1-基)-3,4-二氢-1H-吡喃并[3,4-c]吡啶-5-腈(化合物132)。
1H NMRδ7.52(s,1H),7.05(d,J=3.5Hz,1H),6.46-6.58(m,1H),4.88(br.s.,1H),4.72(s,2H),4.50(d,J=13.1Hz,1H),4.28(d,J=12.5Hz,1H),4.19(d,J=12.8Hz,1H),3.95(t,J=5.6Hz,2H),3.56(br.s.,1H),3.34(dd,J=13.2,3.6Hz,1H),3.10-3.26(m,1H),2.95(t,J=5.6Hz,2H),2.43(t,J=11.3Hz,1H),1.85(d,J=12.3Hz,2H),1.55-1.77(m,5H),1.47(d,J=6.8Hz,3H),1.31-1.42(m,3H)。LC-MS:m/z 435.1(M+H)+。
6-(4-(1H-吲哚-5-羰基)-3-甲基哌嗪-1-基)-8-环己基-3,4-二氢-1H-吡喃并[3,4-c]吡啶-5-腈(化合物134)。
1H NMRδ8.88(br.s.,1H),7.74(s,1H),7.36(d,J=8.5Hz,1H),7.22-7.28(m,2H),6.59(br.s.,1H),4.72(s,3H),4.08-4.37(m,3H),3.95(t,J=5.6Hz,2H),3.50(t,J=11.4Hz,1H),3.29(d,J=11.5Hz,1H),3.04-3.18(m,1H),2.94(t,J=5.6Hz,2H),2.42(tt,J=11.0,3.5Hz,1H),1.85(d,J=12.5Hz,2H),1.55-1.79(m,5H),1.43(d,J=6.5Hz,3H),1.30-1.39(m,3H)。LC-MS:m/z 484.1(M+H)+。
8-环己基-6-(4-(2,5-二甲基呋喃-3-羰基)哌嗪-1-基)-3,4-二氢-1H-吡喃并[3,4-c]吡啶-5-腈(化合物121)。
1H NMRδ5.97(s,1H),4.72(s,2H),3.95(t,J=5.8Hz,2H),3.80(br.s.,4H),3.67(br.s.,4H),2.95(t,J=5.6Hz,2H),2.40-2.48(m,1H),2.37(s,3H),2.27(s,3H),1.85(d,J=12.5Hz,2H),1.61-1.76(m,5H),1.30-1.42(m,3H)。LC-MS:m/z 448.9(M+H)+。
6-(4-(1H-吲哚-4-羰基)哌嗪-1-基)-8-环己基-3,4-二氢-1H-吡喃并[3,4-c]吡啶-5-腈(化合物119)。
1H NMRδ8.87(br.s.,1H),7.42(d,J=7.3Hz,1H),7.14-7.27(m,3H),6.55(br.s.,1H),4.72(s,2H),4.06(br.s.,2H),3.94(t,J=5.6Hz,2H),3.80(br.s.,2H),3.56(br.s.,4H),2.93(t,J=5.6Hz,2H),2.36-2.48(m,1H),1.80-1.89(m,2H),1.53-1.79(m,5H),1.29-1.41(m,3H)。LC-MS:m/z 469.9(M+H)+。
(R)-8-环己基-6-(3-甲基-4-(噻唑-4-羰基)哌嗪-1-基)-3,4-二氢-1H-吡喃并[3,4-c]吡啶-5-腈(化合物239)。
1H NMRδ8.81(d,J=1.8Hz,1H),8.01(d,J=2.0Hz,1H),4.88-5.04(m,1H),4.70(s,2H),4.57(br.s.,1H),4.13-4.41(m,2H),3.89-3.97(m,2H),3.55-3.77(m,1H),3.36(br.s.,1H),3.18(br.s.,1H),2.93(t,J=5.8Hz,2H),2.41(tt,J=11.1,3.7Hz,1H),1.80-1.91(m,2H),1.74(d,J=10.8Hz,1H),1.63-1.68(m,2H),1.41-1.45(m,3H),1.26-1.40(m,5H)。LC-MS:m/z 452.1(M+H)+。
(S)-8-环己基-6-(4-(呋喃-2-羰基)-2-甲基哌嗪-1-基)-3,4-二氢-1H-吡喃并[3,4-c]吡啶-5-腈(化合物201)。
1H NMRδ7.47-7.54(m,1H),7.04-7.09(m,1H),6.51(dd,J=3.5,1.8Hz,1H),4.66-4.76(m,2H),4.58(br.s.,1H),4.46(d,J=12.0Hz,1H),4.27(dd,J=13.3,1.5Hz,1H),4.05(d,J=13.3Hz,1H),3.94(t,J=5.6Hz,2H),3.36-3.59(m,3H),2.93(t,J=5.6Hz,2H),2.41(tt,J=11.2,3.5Hz,1H),1.84(d,J=12.5Hz,2H),1.52-1.79(m,5H),1.29(d,J=6.5Hz,6H)。LC-MS:m/z 435.2(M+H)+。
(R)-6-(4-(苯并[b]噻吩-3-羰基)-3-甲基哌嗪-1-基)-8-环己基-3,4-二氢-1H-吡喃并[3,4-c]吡啶-5-腈(化合物243)。
1H NMRδ7.87-7.94(m,1H),7.77-7.84(m,1H),7.53-7.60(m,1H),7.37-7.46(m,2H),5.26-5.38(m,1H),4.69(s,2H),4.17(d,J=14.1Hz,3H),3.90-3.96(m,2H),3.49(t,J=11.7Hz,1H),3.28(d,J=11.8Hz,1H),3.08(t,J=11.5Hz,1H),2.88-2.96(m,2H),2.40(tt,J=11.0,3.6Hz,1H),1.82(d,J=12.8Hz,2H),1.73(d,J=11.3Hz,1H),1.60-1.69(m,3H),1.56(br.s.,1H),1.43(dd,J=3.9,1.9Hz,3H),1.28-1.36(m,3H)。LC-MS:m/z501.1(M+H)+。
4-(5-氰基-8-环己基-3,4-二氢-1H-吡喃并[3,4-c]吡啶-6-基)-1-(3-甲氧基丙酰基)哌嗪-2-羧酸乙酯(化合物278)。
1H NMRδ5.29(d,J=2.0Hz,0.5H),4.76(s,0.5H),4.71(s,2H),4.15(d,J=7.0Hz,2H),4.06(d,J=7.0Hz,1H),3.83-4.00(m,2H),3.72-3.83(m,2H),3.63-3.71(m,4H),3.36-3.41(m,3H),3.25-3.36(m,2H),2.92(t,J=5.6Hz,2H),2.58-2.74(m,3H),1.85(d,J=11.8Hz,3H),1.47-1.75(m,4H),1.27-1.42(m,3H),1.18(t,J=7.2Hz,3H)。LC-MS:m/z 485.1(M+H)+。
(R)-8-环己基-6-(4-(2-(3-氟苯基)乙酰基)-3-甲基哌嗪-1-基)-3,4-二氢-1H-吡喃并[3,4-c]吡啶-5-腈(化合物191)。
1H NMRδ7.27-7.35(m,1H),6.93-7.08(m,3H),4.69(s,2H),4.55(d,J=13.6Hz,1H),4.22(d,J=12.8Hz,1H),4.02-4.17(m,2H),3.93(t,J=5.8Hz,2H),3.75(br.s.,2H),3.12-3.35(m,1H),3.02-3.12(m,1H),2.91(t,J=5.6Hz,3H),2.33-2.47(m,1H),1.83(d,J=12.8Hz,2H),1.75(d,J=10.5Hz,1H),1.67(br.s.,1H),1.50-1.61(m,2H),1.26-1.40(m,7H)。LC-MS:m/z 477.1(M+H)+。
(R)-8-环己基-6-(4-(咪唑并[1,2-a]吡啶-3-羰基)-3-甲基哌嗪-1-基)-3,4-二氢-1H-吡喃并[3,4-c]吡啶-5-腈(化合物227)。
1H NMRδ9.02(d,J=6.8Hz,1H),7.94(s,1H),7.77(d,J=8.0Hz,1H),7.40(t,J=7.7Hz,1H),7.00(t,J=6.9Hz,1H),4.93(br.s.,1H),4.71(s,2H),4.49(d,J=13.1Hz,1H),4.14-4.32(m,2H),3.87-4.00(m,2H),3.65(br.s.,1H),3.32(dd,J=13.1,3.5Hz,1H),3.17(td,J=12.5,3.4Hz,1H),2.94(t,J=5.6Hz,2H),2.42(tt,J=11.0,3.7Hz,1H),1.84(d,J=12.3Hz,2H),1.75(d,J=9.8Hz,1H),1.56-1.62(m,2H),1.53(d,J=6.8Hz,3H),1.28-1.42(m,5H)。LC-MS:m/z385.1(M+H)+。
(R)-8-环己基-6-(3-甲基-4-(3-甲基呋喃-2-羰基)哌嗪-1-基)-3,4-二氢-1H-吡喃并[3,4-c]吡啶-5-腈(化合物186)。
1H NMRδ7.34(d,J=1.5Hz,1H),6.34(d,J=1.5Hz,1H),4.62-4.85(m,3H),4.13-4.42(m,3H),3.94(t,J=5.8Hz,2H),3.51(br.s.,1H),3.32(d,J=10.0Hz,1H),3.06-3.21(m,1H),2.93(t,J=5.6Hz,2H),2.42(t,J=11.3Hz,1H),2.29(s,3H),1.84(d,J=12.5Hz,2H),1.75(d,J=10.5Hz,3H),1.43(d,J=6.5Hz,3H),1.27-1.38(m,5H)。LC-MS:m/z 449.0(M+H)+。
6-(4-(1H-吲哚-5-羰基)哌嗪-1-基)-8-环己基-3,4-二氢-1H-吡喃并[3,4-c]吡啶-5-腈(化合物122)。
1H NMRδ8.74(br.s.,1H),7.78(s,1H),7.36-7.43(m,1H),7.25-7.32(m,2H),6.51-6.67(m,1H),4.72(s,2H),3.95(t,J=5.8Hz,3H),3.84(br.s.,2H),3.70(br.s.,5H),2.94(t,J=5.6Hz,2H),2.43(tt,J=11.0,3.6Hz,1H),1.81-1.89(m,2H),1.55-1.81(m,5H),1.30-1.41(m,3H)。LC-MS:m/z 470.2(M+H)+。
6-(4-(1H-吲哚-5-羰基)哌嗪-1-基)-8-环己基-3,4-二氢-1H-吡喃并[3,4-c]吡啶-3-腈(化合物118)。
1H NMRδ8.78(br.s.,1H),7.72(d,J=7.3Hz,1H),7.58(d,J=2.3Hz,1H),7.39-7.47(m,1H),7.20-7.26(m,2H),4.71(s,2H),3.94(t,J=5.8Hz,2H),3.88(br.s.,4H),3.69(br.s.,4H),2.93(t,J=5.6Hz,2H),2.34-2.48(m,1H),1.83(d,J=12.8Hz,2H),1.74(d,J=10.8Hz,1H),1.67(br.s.,2H),1.53-1.60(m,2H),1.28-1.38(m,3H)。LC-MS:m/z469.9(M+H)+。
8-环己基-6-(4-(3-甲基呋喃-2-羰基)哌嗪-1-基)-3,4-二氢-1H-吡喃并[3,4-c]吡啶-5-腈(化合物129)。
1H NMRδ7.38(d,J=1.5Hz,1H),6.36(d,J=1.5Hz,1H),4.72(s,2H),3.96(t,J=5.8Hz,2H),3.85-3.93(m,4H),3.68-3.81(m,4H),2.95(t,J=5.6Hz,2H),2.38-2.50(m,1H),2.32(s,3H),1.86(d,J=12.3Hz,2H),1.56-1.81(m,5H),1.29-1.44(m,3H)。LC-MS:m/z 435.1(M+H)+。
(R)-8-环己基-6-(4-(2-(2-氟苯基)乙酰基)-3-甲基哌嗪-1-基)-3,4-二氢-1H-吡喃并[3,4-c]吡啶-5-腈(化合物188)。
1H NMRδ7.27-7.37(m,1H),7.21-7.26(m,1H),7.03-7.15(m,2H),4.91(br.s.,1H),4.69(s,2H),4.18-4.27(m,1H),4.14(d,J=13.3Hz,1H),3.86-4.04(m,2H),3.71-3.86(m,3H),3.53(t,J=11.2Hz,1H),3.17(t,J=14.7Hz,1H),2.87-3.04(m,3H),2.40(tt,J=11.1,3.7Hz,1H),1.84(d,J=12.5Hz,2H),1.75(d,J=10.0Hz,1H),1.65(br.s.,4H),1.27-1.37(m,6H)。LC-MS:m/z477.1(M+H)+。
6-(4-(1H-吲哚-5-羰基)哌嗪-1-基)-8-环己基-3,4-二氢-1H-吡喃并[3,4-c]吡啶-6-腈(化合物123)。
1H NMRδ8.54(br.s.,1H),7.68(d,J=8.0Hz,1H),7.60(br.s.,1H),7.34(d,J=2.5Hz,1H),7.21(d,J=8.0Hz,1H),6.61(d,J=2.8Hz,1H),4.72(s,2H),3.70–3.97(m,10H),2.95(t,J=5.6Hz,2H),2.38-2.52(m,1H),1.85(d,J=12.5Hz,2H),1.55-1.80(m,5H),1.30-1.41(m,3H)。LC-MS:m/z 469.9(M+H)+。
(R)-8-环己基-6-(3-甲基-4-(吡唑并[1,5-a]嘧啶-3-羰基)哌嗪-1-基)-3,4-二氢-1H-吡喃并[3,4-c]吡啶-5-腈(化合物261)。
1H NMRδ8.71-8.79(m,1H),8.64(dd,J=4.0,1.8Hz,1H),8.43(s,1H),6.96(dd,J=6.9,4.1Hz,1H),4.70(s,3H),4.11-4.41(m,3H),3.88-3.98(m,2H),3.57(br.s.,1H),3.43(dd,J=13.1,3.5Hz,1H),3.26(t,J=11.5Hz,1H),2.86-2.98(m,2H),2.41(tt,J=11.0,3.7Hz,1H),1.83(d,J=12.8Hz,2H),1.74(d,J=11.3Hz,1H),1.69(br.s.,1H),1.54-1.63(m,2H),1.43(d,J=6.8Hz,3H),1.26-1.38(m,4H)。LC-MS:m/z486.2(M+H)+。
(R)-8-环己基-6-(3-甲基-4-(噁唑-4-羰基)哌嗪-1-基)-3,4-二氢-1H-吡喃并[3,4-c]吡啶-5-腈(化合物226)。
1H NMRδ8.20-8.26(m,1H),7.86-7.93(m,1H),4.81-5.04(m,1H),4.70(s,3H),4.15-4.34(m,2H),3.87-3.97(m,2H),3.55-3.76(m,1H),3.30-3.37(m,1H),3.09-3.24(m,1H),2.93(t,J=5.6Hz,2H),2.41(tt,J=11.0,3.7Hz,1H),1.81-1.87(m,2H),1.75(d,J=10.8Hz,2H),1.54-1.63(m,2H),1.43(d,J=6.5Hz,3H),1.27-1.38(m,4H)。LC-MS:m/z436.1(M+H)+。
8-环戊基-6-(4-(呋喃-2-羰基)哌嗪-1-基)-3,4-二氢-1H-吡喃并[3,4-c]吡啶-5-腈(化合物124)。
1H NMRδ7.48-7.60(m,1H),7.07(d,J=3.5Hz,1H),6.52(dd,J=3.3,1.8Hz,1H),4.74(s,2H),3.85-4.14(m,6H),3.67-3.83(m,4H),2.87-3.06(m,3H),1.76-1.99(m,5H),1.62-1.75(m,3H)。LC-MS:m/z 406.9(M+H)+。
8-环戊基-6-((3S,5R)-4-(呋喃-2-羰基)-3,5-二甲基哌嗪-1-基)-3,4-二氢-1H-吡喃并[3,4-c]吡啶-5-腈(化合物126)。
1H NMRδ7.52(d,J=1.0Hz,1H),7.07(d,J=3.3Hz,1H),6.52(dd,J=3.5,1.8Hz,1H),4.87(br.s.,2H),4.74(s,2H),4.28(d,J=12.8Hz,2H),3.97(t,J=5.8Hz,2H),3.22(dd,J=12.9,4.4Hz,2H),2.91-3.03(m,3H),1.80-1.96(m,5H),1.56(d,J=6.8Hz,6H),1.33(br.s.,3H)。LC-MS:m/z 435.1(M+H)+。
(R)-6-(4-(呋喃-3-羰基)-3-甲基哌嗪-1-基)-8-异丙基-3,4-二氢-1H-吡喃并[3,4-c]吡啶-5-腈(化合物140)。
1H NMRδ7.71-7.80(m,1H),7.47(t,J=1.6Hz,1H),6.54-6.67(m,1H),4.72(s,3H),4.14-4.42(m,3H),3.89-4.01(m,2H),3.50(br.s.,1H),3.27(dd,J=12.9,3.4Hz,1H),3.10(td,J=12.5,3.5Hz,1H),2.95(t,J=5.6Hz,2H),2.83(dt,J=13.3,6.7Hz,1H),1.44(d,J=6.8Hz,3H),1.15-1.24(m,6H)。LC-MS:m/z 395.0(M+H)+。
8-异丙基-6-(4-(2-甲基呋喃-3-羰基)-2-苯基哌嗪-1-基)-3,4-二氢-1H-吡喃并[3,4-c]吡啶-5-腈(化合物177)。
1H NMRδ7.38(br.s.,1H),7.22-7.33(m,5H),7.18(d,J=6.5Hz,1H),5.26(br.s.,1H),4.58-4.76(m,2H),4.15(br.s.,1H),3.86-4.05(m,3H),3.78(br.s.,3H),3.47-3.61(m,1H),2.88-3.03(m,2H),2.62-2.77(m,1H),2.30-2.43(m,3H),1.16(d,J=6.5Hz,3H),0.85(br.s.,3H)。LC-MS:m/z 471.1(M+H)+。
6-(4-(1H-吲哚-5-羰基)哌嗪-1-基)-8-异丙基-3,4-二氢-1H-吡喃并[3,4-c]吡啶-3-腈(化合物104)。
1H NMRδ9.18(br.s.,1H),7.76(d,J=7.5Hz,1H),7.36-7.50(m,2H),7.14-7.34(m,2H),4.74(s,2H),3.83-4.01(m,6H),3.73(br.s.,4H),2.96(br.s.,2H),2.75-2.89(m,1H),1.21(d,J=6.5Hz,6H)。LC-MS:m/z 430.4(M+H)+。
6-(4-(呋喃-2-羰基)-2-苯基哌嗪-1-基)-8-异丙基-3,4-二氢-1H-吡喃并[3,4-c]吡啶-5-腈(化合物111)。
1H NMRδ7.51(dd,J=1.8,0.8Hz,1H),7.37(br.s.,2H),7.25(t,J=7.4Hz,2H),7.13-7.20(m,1H),7.06(d,J=3.5Hz,1H),6.51(dd,J=3.5,1.8Hz,1H),5.20(br.s.,1H),4.55-4.74(m,2H),4.31(br.s.,2H),3.78-4.08(m,5H),3.61(br.s.,1H),2.89-3.01(m,2H),2.57-2.77(m,1H),1.09-1.19(m,3H),0.81(d,J=6.3Hz,3H)。LC-MS:m/z456.9(M+H)+。
6-(4-(3,4-二氯苯甲酰基)哌嗪-1-基)-8-异丙基-3,4-二氢-1H-吡喃并[3,4-c]吡啶-5-腈(化合物105)。
1H NMRδ7.48-7.63(m,2H),7.29-7.33(m,1H),4.73(s,2H),3.96(t,J=5.8Hz,4H),3.62–3.74(m,6H),2.96(t,J=5.8Hz,2H),2.83(dt,J=13.4,6.5Hz,1H),1.21(d,J=6.5Hz,6H)。LC-MS:m/z 459.1(M+H)+。
6-(4-(2,4-二氯苯甲酰基)哌嗪-1-基)-8-异丙基-3,4-二氢-1H-吡喃并[3,4-c]吡啶-5-腈(化合物106)。
1H NMRδ7.47(d,J=1.8Hz,1H),7.33-7.38(m,1H),7.26-7.31(m,1H),4.72(s,2H),3.99-4.09(m,1H),3.86-3.98(m,3H),3.70-3.81(m,2H),3.56-3.70(m,2H),3.43-3.52(m,1H),3.33-3.42(m,1H),2.95(t,J=5.6Hz,2H),2.83(dt,J=13.3,6.7Hz,1H),1.20(d,J=6.8Hz,6H)。LC-MS:m/z 459.1(M+H)+。
6-(4-(呋喃-2-羰基)-2,5-二甲基哌嗪-1-基)-8-异丙基-3,4-二氢-1H-吡喃并[3,4-c]吡啶-5-腈(化合物114)。
1H NMRδ7.50(s,1H),7.05(d,J=3.0Hz,1H),6.50(br.s.,1H),4.65-4.95(m,4H),4.29(br.s.,1H),4.17(d,J=13.6Hz,1H),3.94(t,J=5.6Hz,2H),3.59(dd,J=13.6,3.3Hz,2H),2.92(t,J=5.5Hz,2H),2.81(dt,J=13.4,6.6Hz,1H),1.43(br.s.,3H),1.31(d,J=6.5Hz,3H),1.18(d,J=6.5Hz,3H),1.19(d,J=6.5Hz,3H)。LC-MS:m/z 408.9(M+H)+。
(R)-6-(4-(呋喃-2-羰基)-3-甲基哌嗪-1-基)-8-异丙基-3,4-二氢-1H-吡喃并[3,4-c]吡啶-5-腈(化合物139)。
1H NMRδ7.52(dd,J=1.8,0.8Hz,1H),7.05(d,J=3.5Hz,1H),6.51(dd,J=3.5,1.8Hz,1H),4.88(br.s.,1H),4.72(s,2H),4.49(d,J=13.3Hz,1H),4.29(d,J=12.0Hz,1H),4.14-4.24(m,1H),3.92-4.03(m,2H),3.55(br.s.,1H),3.35(dd,J=13.1,3.8Hz,1H),3.19(td,J=12.4,3.5Hz,1H),2.95(t,J=5.6Hz,2H),2.72-2.88(m,1H),1.46(d,J=6.8Hz,3H),1.15-1.25(m,6H)。LC-MS:m/z 395.0(M+H)+。
8-异丙基-6-(4-(2-甲基呋喃-3-羰基)哌嗪-1-基)-3,4-二氢-1H-吡喃并[3,4-c]吡啶-5-腈(化合物113)。
1H NMRδ7.25-7.34(m,1H),6.39(d,J=1.8Hz,1H),4.72(s,2H),3.95(t,J=5.8Hz,2H),3.80(br.s.,4H),3.68(br.s.,4H),2.95(t,J=5.6Hz,2H),2.82(dt,J=13.4,6.7Hz,1H),2.42(s,3H),1.16-1.25(m,6H)。LC-MS:m/z 394.9(M+H)+。
6-(4-(呋喃-2-羰基)-3,5-二甲基哌嗪-1-基)-8-对甲苯基异色满-5-腈(化合物112)。
1H NMRδ7.52-7.58(m,1H),7.37-7.44(m,2H),7.24-7.35(m,2H),7.07(dd,J=3.5,0.8Hz,1H),6.52(dd,J=3.5,1.8Hz,1H),4.88(br.s.,2H),4.70(s,2H),4.31(d,J=13.1Hz,2H),4.05(t,J=5.9Hz,2H),3.25(dd,J=12.9,4.1Hz,2H),3.07(t,J=5.9Hz,2H),2.44(s,3H),1.59(d,J=7.0Hz,6H)。LC-MS:m/z456.9(M+H)+。
(R)-8-环丙基-6-(3-异丙基-4-(3-甲氧基丙酰基)哌嗪-1-基)-3,3-二甲基-3,4-二氢-1H-吡喃并[3,4-c]吡啶-5-腈(化合物270)。
1H NMRδ4.77-4.89(m,2H),4.65(d,J=10.3Hz,0.5H),4.40(d,J=10.3Hz,0.5H),4.27-4.36(m,1H),4.07-4.26(m,1H),3.64-3.87(m,2.5H),3.39-3.58(m,1H),3.36(d,J=3.8Hz,3H),2.90-3.09(m,2.5H),2.76(s,2H),2.52-2.74(m,2H),2.19-2.30(m,0.5H),2.10(dt,J=10.4,6.7Hz,0.5H),1.67-1.74(m,1H),1.31(d,J=2.5Hz,6H),1.05-1.17(m,2H),0.97-1.04(m,5H),0.84-0.92(d,J=6.8Hz,1.5H),0.82(d,J=6.8Hz,1.5H)。LC-MS:m/z 441.2(M+H)+。
(R)-8-环丙基-6-(3-乙基-4-(3-甲氧基丙酰基)哌嗪-1-基)-3,3-二甲基-3,4-二氢-1H-吡喃并[3,4-c]吡啶-5-腈(化合物297)。
1H NMRδ4.83(s,2H),4.69(br.s.,0.5H),4.58(d,J=12.8Hz,0.5H),4.05-4.22(m,2H),3.90(br.s.,0.5H),3.67-3.81(m,2.5H),3.42-3.54(m,0.5H),3.36(s,3H),2.88-3.18(m,2.5H),2.76(s,2H),2.51-2.74(m,2H),1.66-1.80(m,3H),1.31(d,J=1.5Hz,6H),1.09-1.17(m,2H),0.99-1.04(m,2H),0.90(dt,J=18.1,7.5Hz,3H)。LC-MS:m/z427.0(M+H)+。
(R)-8-环丙基-6-(3-异丙基-4-(3-(甲硫基)丙酰基)哌嗪-1-基)-3,3-二甲基-3,4-二氢-1H-吡喃并[3,4-c]吡啶-5-腈(化合物269)。
1H NMRδ4.76-4.89(m,2H),4.64(d,J=9.2Hz,0.5H),4.39(d,J=10.3Hz,0.5H),4.32(d,J=13.6Hz,1H),4.10-4.24(m,1H),3.74(d,J=13.6Hz,0.5H),3.39-3.54(m,1H),2.90-3.08(m,2.5H),2.80-2.89(m,2H),2.76(s,2H),2.59-2.72(m,2H),2.20-2.33(m,0.5H),2.04-2.13(m,0.5H),1.67-1.75(m,1H),1.31(d,J=2.3Hz,6H),1.05-1.19(m,2H),0.96-1.05(m,5H),0.88(d,J=6.8Hz,1.5H),0.82(d,J=6.8Hz,1.5H)。LC-MS:m/z457.2(M+H)+。
(R)-8-环丙基-6-(4-(2-环丙基乙酰基)-3-异丙基哌嗪-1-基)-3,3-二甲基-3,4-二氢-1H-吡喃并[3,4-c]吡啶-5-腈(化合物382)。
1H NMRδ4.76-4.89(m,2H),4.66-4.68(m,0.5H),4.32-4.43(m,1.5H),4.18(t,J=9.0Hz,1H),3.73(d,J=13.3Hz,0.5H),3.38-3.51(m,1H),2.89-3.12(m,2.5H),2.76(s,2H),2.10-2.43(m,3H),1.64-1.75(m,1H),1.31(d,J=2.3Hz,6H),1.06-1.18(m,3H),0.96-1.05(m,5H),0.79-0.91(m,3H),0.59(d,J=7.5Hz,2H),0.13-0.29(m,2H)。LC-MS:m/z 437.3(M+H)+。
(R)-8-环丙基-6-(3-乙基-4-(2-甲基呋喃-3-羰基)哌嗪-1-基)-3,3-二甲基-3,4-二氢-1H-吡喃并[3,4-c]吡啶-5-腈(化合物237)。
1H NMRδ7.28(d,J=2.0Hz,1H),6.32-6.40(m,1H),4.83(s,2H),3.85-4.82(m,4H),3.34(br.s.,1H),3.13(dd,J=13.2,3.6Hz,1H),2.90-3.04(m,1H),2.77(s,2H),2.37-2.40(m,3H),1.83-1.96(m,1H),1.66-1.79(m,2H),1.29-1.35(m,6H),1.08-1.15(m,2H),0.98-1.04(m,2H),0.84-0.94(m,3H)。LC-MS:m/z 449.1(M+H)+。
(R)-8-环丙基-6-(3-乙基-4-(2-(苯硫-2-基)乙酰基)哌嗪-1-基)-3,3-二甲基异色满-5-腈(化合物236)。
1H NMR(氯仿-d)δ7.20(dd,J=5.1,1.1Hz,1H),6.87-6.99(m,2H),4.82(s,2H),4.69(br.s.,0.5H),4.46-4.64(m,0.5H),4.01-4.17(m,2H),3.87-3.94(m,1H),3.77(d,J=13.1Hz,1H),3.39-3.56(m,1H),3.01-3.14(m,1H),2.81-3.01(m,2H),2.72-2.79(m,2H),1.66-1.84(m,3H),1.30(d,J=2.5Hz,6H),1.10(d,J=4.0Hz,2H),0.98-1.05(m,2H),0.82-0.94(m,3H)。LC-MS:m/z 465.1(M+H)+。
(R)-8-环丙基-6-(3-异丙基-4-(2-(苯硫-2-基)乙酰基)哌嗪-1-基)-3,3-二甲基异色满-5-腈(化合物194)。
1H NMR(氯仿-d)δ7.16-7.26(m,1H),6.85-6.99(m,2H),4.75-4.88(m,2H),4.64-4.65(m,0.5H),4.40(d,J=10.5Hz,0.51H),4.24-4.33(m,1H),4.08-4.18(m,1H),3.79-4.05(m,3H),3.32-3.50(m,1H),2.92-3.04(m,1H),2.78-2.90(m,1H),2.75(s,2H),2.06-2.275(m,1H),1.62-1.71(m,1H),1.31(d,J=3.0Hz,6H),0.93-1.19(m,7H),0.76-0.90(m,3H)。LC-MS:m/z 479.1(M+H)+。
(R)-8-环丙基-6-(3-异丙基-4-(2-甲基呋喃-3-羰基)哌嗪-1-基)-3,3-二甲基异色满-5-腈(化合物181)。
1H NMR(氯仿-d)δ7.24-7.34(m,1H),6.35(br.s.,1H),4.78-4.92(m,2H),4.13-4.56(m,3H),3.87(d,J=12.3Hz,0.5H),3.46-3.54(m,1H),2.92-3.16(m,2.5H),2.78(s,2H),2.35-2.48(m,3H),2.18-2.32(m,1H),1.69-1.77(m,1H),1.33(d,J=2.3Hz,6H),1.00-1.21(m,6H),0.79-0.98(m,4H)。LC-MS:m/z 463.1(M+H)+。
(R)-8-环丙基-6-(3-乙基-4-(呋喃-3-羰基)哌嗪-1-基)-3,3-二甲基异色满-5-腈(化合物235)。
1H NMRδ7.65-7.76(m,1H),7.40-7.48(m,1H),6.46-6.60(m,1H),4.83(s,2H),3.98-4.52(m,4H),3.98(br.s.,1H),3.40(br.s.,1H),3.13(dd,J=13.1,3.8Hz,1H),2.92-3.05(m,1H),2.77(s,2H),1.66-1.96(m,3H),1.29-1.38(m,6H),1.08-1.15(m,2H),0.98-1.04(m,2H),0.85-0.96(m,3H)。LC-MS:m/z 435.2(M+H)+。
(R)-8-环丙基-6-(3-异丙基-4-(2-(吡啶-3-基)乙酰基)哌嗪-1-基)-3,3-二甲基异色满-5-腈(化合物265)。
1H NMR(氯仿-d)δ8.46-8.57(m,2H),7.67(d,J=7.5Hz,1H),7.27-7.32(m,1H),4.82(s,2H),4.63-4.65(m,0.5H),4.40(d,J=10.3Hz,0.5H),4.23-4.34(m,1H),4.09-4.19(m,1H),3.72-3.80(m,2.5H),3.39-3.55(m,1H),2.92-3.04(m,1H),2.79-2.91(m,1.5H),2.75(s,2H),2.07-2.30(m,1H),1.66-1.73(m,1H),1.29-1.33(m,6H),0.96-1.16(m,7H),0.88(d,J=6.8Hz,1.5H),0.79(d,J=6.8Hz,1.5H)。LC-MS:m/z 474.2(M+H)+。
(R)-8-环丙基-3,3-二甲基-6-(3-甲基-4-(2-甲基呋喃-3-羰基)哌嗪-1-基)异色满-5-腈(化合物230)。
1H NMR(氯仿-d)δ7.27(d,J=2.5Hz,1H),6.35(d,J=2.0Hz,1H),4.52-5.22(m,3H),3.98-4.28(m,3H),3.41(br.s.,1H),3.15(dd,J=12.9,3.4Hz,1H),2.97(td,J=12.5,3.5Hz,1H),2.77(s,2H),2.35-2.45(m,3H),1.66-1.75(m,1H),1.38(d,J=6.8Hz,3H),1.31(s,6H),1.09-1.15(m,2H),0.98-1.04(m,2H)。LC-MS:m/z 435.1(M+H)+。
(R)-8-环丙基-3,3-二甲基-6-(3-甲基-4-(2-(苯硫-2-基)乙酰基)哌嗪-1-基)异色满-5-腈(化合物231)。
1H NMRδ7.16-7.24(m,1H),6.85-6.99(m,2H),4.89(br.s.,0.5H),4.82(s,2H),4.51-4.54(m,0.5H),4.10-4.22(m,0.5H),3.97-4.12(m,2H),3.88-3.97(m,2H),3.74(d,J=13.3Hz,0.5H),3.52(t,J=11.9Hz,0.5H),2.99-3.22(m,1.5H),2.82-2.96(m,1H),2.76(s,2H),1.68-1.75(m,1H),1.26-1.36(m,9H),1.07-1.15(m,2H),0.95-1.04(m,2H)。LC-MS:m/z 451.1(M+H)+。(R)-8-环丙基-6-(3-异丙基-4-(3-苯氧基丙酰基)哌嗪-1-基)-3,3-二甲基异色满-5-腈(化合物366)。
1H NMRδ7.25-7.32(m,2H),6.84-7.02(m,3H),4.76-4.89(m,2H),4.67(d,J=10.5Hz,0.5H),4.42(d,J=10.5Hz,0.5H),4.29-4.38(m,3H),4.10-4.25(m,1H),3.87(d,J=13.6Hz,0.5H),3.59(d,J=10.3Hz,0.5H),3.48(td,J=12.8,3.0Hz,0.5H),2.84-3.10(m,4.5H),2.71-2.79(m,2H),2.29(dt,J=10.3,6.7Hz,0.5H),2.05-2.18(m,0.5H),1.67-1.76(m,1H),1.32(d,J=2.3Hz,6H),1.07-1.18(m,2H),0.96-1.05(m,5H),0.89-0.96(m,1.5H),0.83(d,J=6.8Hz,1.5H)。LC-MS:m/z 503.2(M+H)+。
(R)-8-环丙基-6-(3-异丙基-4-(2-(吡啶-2-基)乙酰基)哌嗪-1-基)-3,3-二甲基异色满-5-腈(化合物211)。
1H NMRδ8.46-8.62(m,1H),7.66(t,J=7.7Hz,1H),7.39(t,J=7.4Hz,1H),7.19(dd,J=6.9,4.4Hz,1H),4.76-4.92(m,2H),4.61-4.64(m,0.5H),4.37(d,J=10.5Hz,0.5H),4.24-4.34(m,1H),4.02-4.19(m,2H),3.99(d,J=5.3Hz,1H),3.79-3.95(m,1H),3.31-3.43(m,0.5H),2.87-3.02(m,1.5H),2.82(dd,J=12.9,3.4Hz,1H),2.72-2.78(m,2H),1.99-2.27(m,2H),1.64-1.75(m,1H),1.31(d,J=3.0Hz,6H),0.95-1.18(m,7H),0.79(dd,J=12.8,6.8Hz,3H)。LC-MS:m/z 474.3(M+H)+。
(R)-8-环丙基-6-(3-异丙基-4-(噁唑-4-羰基)哌嗪-1-基)-3,3-二甲基异色满-5-腈(化合物209)。
1H NMRδ8.23(d,J=9.0Hz,1H),7.89(s,1H),4.76-4.96(m,3H),4.61-4.64(m,0.5H),4.36-4.51(m,1.5H),4.15-4.32(m,1H),3.44-3.60(m,0.5H),3.02-3.20(m,2.5H),2.77(s,2H),2.19-2.34(m,1H),1.66-1.74(m,1H),1.29-1.35(m,6H),0.82-1.18(m,10H)。LC-MS:m/z 450.2(M+H)+。
(S)-8-环丙基-6-(4-(呋喃-2-羰基)-3-苯基哌嗪-1-基)-3,3-二甲基异色满-5-腈(化合物273)。
1H NMRδ7.48(s,1H),7.37-7.44(m,2H),7.30-7.36(m,2H),7.27(br.s.,1H),7.23-7.26(m,1H),6.99(br.s.,1H),6.41-6.49(m,1H),5.87(t,J=4.1Hz,1H),4.76-4.88(m,2H),4.59(d,J=13.1Hz,1H),4.47(d,J=11.0Hz,1H),4.20(d,J=12.0Hz,1H),3.85(dd,J=13.8,4.5Hz,1H),3.60(br.s.,1H),3.42-3.52(m,1H),2.75(s,2H),1.67-1.75(m,1H),1.31(d,J=1.8Hz,6H),1.06-1.20(m,2H),1.02(dd,J=8.0,3.5Hz,2H)。LC-MS:m/z483.1(M+H)+。
8-环丙基-6-((3R)-3-异丙基-4-(四氢呋喃-3-羰基)哌嗪-1-基)-3,3-二甲基异色满-5-腈(化合物266)。
1H NMRδ4.78-4.90(m,2H),4.28-4.46(m,1.5H),4.12-4.24(m,1H),3.81-4.09(m,4.5H),3.40-3.60(m,1H),3.24-3.36(m,1H),2.92-3.07(m,2H),2.76(s,2H),2.22-2.34(m,1H),1.98-2.21(m,3H),1.69-1.76(m,1H),1.31(d,J=2.3Hz,6H),0.95-1.19(m,6H),0.77-0.92(m,4H)。LC-MS:m/z 453.3(M+H)+。
(R)-8-环丙基-6-(3-异丙基-4-(噻吩-3-羰基)哌嗪-1-基)-3,3-二甲基异色满-5-腈(化合物255)。
1H NMRδ7.45-7.60(m,1H),7.37(dd,J=5.0,3.0Hz,1H),7.11-7.22(m,1H),4.77-4.90(m,2H),4.10-4.55(m,3H),3.85(d,J=10.8Hz,0.5H),3.50(br.s.,1H),3.07(d,J=11.0Hz,2H),2.87-3.03(m,0.5H),2.76(s,2H),2.20-2.33(m,1H),1.65-1.77(m,1H),1.31(d,J=2.0Hz,6H),0.93-1.18(m,8H),0.78-0.93(m,2H)。LC-MS:m/z 465.2(M+H)+。
(R)-8-环丙基-6-(3-乙基-4-(噻吩-3-羰基)哌嗪-1-基)-3,3-二甲基异色满-5-腈(化合物292)。
1H NMR(氯仿-d)δ7.47-7.53(m,1H),7.36(dd,J=4.9,2.9Hz,1H),7.18(dd,J=5.0,1.0Hz,1H),4.83(s,2H),4.16(d,J=12.5Hz,3H),3.42(br.s.,1H),3.14(d,J=11.0Hz,1H),2.92-3.05(m,1H),2.77(s,2H),1.64-2.02(m,4H),1.29-1.35(m,6H),1.07-1.15(m,2H),0.98-1.05(m,2H),0.77-0.98(m,3H)。LC-MS:m/z 451.1(M+H)+。
4-(5-氰基-8-环丙基-3,3-二甲基异色满-6-基)-1-(呋喃-3-羰基)哌嗪-2-羧酸甲酯(化合物387)。
1H NMRδ7.79(br.s.,1H),7.46(s,1H),6.63(br.s.,1H),5.39(br.s.,1H),4.83(s,2H),4.66(d,J=11.5Hz,1H),4.01-4.21(m,3H),3.73(s,3H),3.28(d,J=11.0Hz,1H),3.03(td,J=12.3,3.5Hz,1H),2.77(s,2H),1.63-1.80(m,1H),1.29-1.39(m,6H),1.14(dd,J=8.0,4.0Hz,2H),1.03(dt,J=5.1,2.7Hz,2H)。LC-MS:m/z 465.2(M+H)+。
(R)-8-环丙基-6-(3-异丙基-4-(2-(2-甲氧苯基)乙酰基)哌嗪-1-基)-3,3-二甲基异色满-5-腈(化合物208)。
1H NMRδ7.18-7.27(m,2H),6.79-6.96(m,2H),4.76-4.88(m,2H),4.64-4.66(m,0.5H),4.41(d,J=10.5Hz,0.5H),4.20-4.34(m,1H),4.03-4.17(m,1H),3.81-3.91(m,3.5H),3.71-3.81(m,1.5H),3.51-3.71(m,1H),3.29-3.42(m,0.5H),2.89-3.01(m,1.5H),2.71-2.84(m,3H),2.06-2.25(m,1H),1.66-1.71(m,1H),1.30(d,J=2.8Hz,6H),0.95-1.18(m,7H),0.84(dd,J=16.6,6.8Hz,3H)。LC-MS:m/z 503.2(M+H)+。
(R)-8-环丙基-6-(4-(呋喃-2-羰基)-3-苯基哌嗪-1-基)-3,3-二甲基异色满-5-腈(化合物272)。
1H NMRδ7.45-7.51(m,1H),7.37-7.44(m,2H),7.33(t,J=7.5Hz,2H),7.20-7.27(m,2H),6.99(br.s.,1H),6.46(br.s.,1H),5.87(br.s.,1H),4.75-4.89(m,2H),4.60(d,J=13.1Hz,1H),4.47(d,J=11.5Hz,1H),4.20(d,J=11.8Hz,1H),3.85(dd,J=13.8,4.3Hz,1H),3.60(br.s.,1H),3.38-3.52(m,1H),2.70-2.81(m,2H),1.68-1.73(m,1H),1.29-1.33(m,6H),1.07-1.19(m,2H),1.02(dd,J=7.9,3.4Hz,2H)。LC-MS:m/z 483.1(M+H)+。
(R)-8-环丙基-6-(3-乙基-4-(2-(吡啶-3-基)乙酰基)哌嗪-1-基)-3,3-二甲基异色满-5-腈(化合物294)。
1H NMRδ8.46-8.61(m,2H),7.62-7.73(m,1H),7.28-7.33(m,1H),4.82(s,2H),4.70(d,J=11.8Hz,0.5H),4.58(d,J=13.3Hz,0.5H),4.01-4.21(m,2H),3.68-3.88(m,3H),3.38-3.59(m,0.5H),2.81-3.11(m,2.5H),2.76(s,2H),1.66-1.92(m,3H),1.29-1.35(m,6H),1.06-1.16(m,2H),0.97-1.05(m,2H),0.80-0.97(m,3H)。LC-MS:m/z 460.1(M+H)+。
(R)-8-环丙基-6-(3-乙基-4-(噁唑-4-羰基)哌嗪-1-基)-3,3-二甲基异色满-5-腈(化合物291)。
1H NMRδ8.24(s,1H),7.89(s,1H),5.13(br.s.,0.5H),4.80-4.98(m,3H),4.49-4.69(m,0.5H),4.20(d,J=13.1Hz,2H),3.49-3.56(m,0.5H),3.22(dd,J=13.3,3.8Hz,1.5H),2.99-3.12(m,1H),2.77(s,2H),1.60-1.87(m,3H),1.32(s,6H),1.10-1.17(m,2H),0.99-1.05(m,2H),0.80-0.98(m,3H)。LC-MS:m/z 436.1(M+H)+。
(R)-8-环丙基-6-(3-乙基-4-(2-(3-甲氧苯基)乙酰基)哌嗪-1-基)-3,3-二甲基异色满-5-腈(化合物296)。
1H NMRδ7.22-7.28(m,1H),6.78-6.89(m,3H),4.83(s,2H),4.73(br.s.,0.5H),4.60-4.63(m,0.5H),3.96-4.16(m,2H),3.87(br.s.,0.5H),3.81(d,J=2.3Hz,3H),3.77(s,2H),3.68-3.75(m,1H),3.31-3.46(m,0.5H),2.97-3.15(m,1H),2.79-2.95(m,1H),2.76(s,2H),1.66-1.81(m,3H),1.28-1.36(m,6H),1.11(d,J=2.5Hz,2H),0.96-1.04(m,2H),0.88(td,J=7.3,3.1Hz,3H)。LC-MS:m/z 489.2(M+H)+。
(R)-8-环丙基-6-(3-异丙基-4-(2-(3-甲氧苯基)乙酰基)哌嗪-1-基)-3,3-二甲基异色满-5-腈(化合物254)。
1H NMRδ7.18-7.28(m,1H),6.71-6.88(m,3H),4.73-4.89(m,2H),4.41(d,J=10.3Hz,0.5H),4.40-4.42(m,0.5H),4.02-4.30(m,2H),3.69-3.87(m,6H),3.48-3.51(m,0.5H),3.33(t,J=11.7Hz,0.5H),2.88-3.00(m,1H),2.64-2.81(m,3H),2.04-2.22(m,1H),1.64-1.75(m,1H),1.30(d,J=3.5Hz,6H),0.94-1.16(m,7H),0.75-0.88(m,3H)。LC-MS:m/z 503.2(M+H)+。
(R)-8-环丙基-6-(3-乙基-4-(2-(2-甲氧苯基)乙酰基)哌嗪-1-基)-3,3-二甲基异色满-5-腈(化合物295)。
1H NMRδ7.20-7.26(m,2H),6.81-6.96(m,2H),4.82(s,2H),4.71(br.s.,0.5H),4.60(d,J=13.1Hz,0.5H),3.97-4.18(m,2H),3.81-3.92(m,4H),3.69-3.79(m,2H),3.33-3.47(m,0.5H),2.97-3.12(m,1H),2.79-2.96(m,1.5H),2.71-2.78(m,2H),1.63-1.81(m,3H),1.30(d,J=2.8Hz,6H),1.06-1.14(m,2H),0.96-1.03(m,2H),0.83-0.92(m,3H)。LC-MS:m/z 489.2(M+H)+。
(R)-8-环丙基-6-(3-异丙基-4-(4-甲基噁唑-5-羰基)哌嗪-1-基)-3,3-二甲基异色满-5-腈(化合物210)。
1H NMRδ7.84(s,1H),4.77-4.89(m,2H),4.14-4.45(m,3H),3.99(d,J=12.5Hz,0.5H),3.43-3.77(m,1H),2.99-3.22(m,2.5H),2.77(s,2H),2.37-2.47(m,3H),2.20-2.31(m,1H),1.66-1.75(m,1H),1.32(d,J=2.3Hz,6H),0.96-1.18(m,7H),0.77-0.96(m,3H)。LC-MS:m/z 464.1(M+H)+。
4-(5-氰基-8-环丙基-3,3-二甲基异色满-6-基)-1-(3-甲氧基丙酰基)-哌嗪-2-羧酸甲酯(化合物388)。
1H NMRδ5.16-5.35(m,1H),4.83(s,2H),4.62(dt,J=13.6,2.0Hz,1H),4.11(dd,J=12.7,2.1Hz,1H),3.71-3.91(m,3H),3.61-3.70(m,2H),3.34-3.41(m,3H),3.27(br.s.,1H),3.21(dd,J=13.4,4.4Hz,1H),3.04(td,J=12.0,3.5Hz,1H),2.72-2.79(m,3H),2.60-2.71(m,1H),1.57-1.78(m,1H),1.27-1.39(m,6H),1.10-1.18(m,2H),0.96-1.10(m,2H)。LC-MS:m/z 457.3(M+H)+。
(R)-8-环丙基-6-(4-(呋喃-3-羰基)-3-甲基哌嗪-1-基)-3,3-二甲基异色满-5-腈(化合物164)。
1H NMRδ7.71-7.80(m,1H),7.41-7.52(m,1H),6.59(dd,J=1.9,0.9Hz,1H),4.85(s,2H),4.69(br.s.,1H),4.30(br.s.,1H),4.00-4.17(m,2H),3.47(br.s.,1H),3.18(dd,J=13.1,3.5Hz,1H),3.01(td,J=12.5,3.4Hz,1H),2.79(s,2H),1.69-1.77(m,1H),1.40-1.50(m,3H),1.33(s,6H),1.08-1.19(m,2H),0.98-1.07(m,2H)。LC-MS:m/z421.2(M+H)+。
(R)-8-环丙基-6-(3-乙基-4-(2-(吡啶-2-基)乙酰基)哌嗪-1-基)-3,3-二甲基异色满-5-腈(化合物290)。
1H NMR(氯仿-d)δ8.44-8.63(m,1H),7.67(td,J=7.7,1.5Hz,1H),7.39(t,J=8.4Hz,1H),7.16-7.25(m,1H),4.82(s,2H),4.68(br.s.,0.5H),4.57(d,J=13.3Hz,0.5H),3.85-4.18(m,5H),3.32-3.52(m,0.5H),2.95-3.09(m,1H),2.78-2.93(m,1.5H),2.75(s,2H),1.62-1.82(m,3H),1.28-1.34(m,6H),1.05-1.13(m,2H),0.94-1.03(m,2H),0.81-0.92(m,3H)。LC-MS:m/z 460.1(M+H)+。
(R)-8-环丙基-6-(3-异丙基-4-(1-甲基环丙烷羰基)哌嗪-1-基)-3,3-二甲基异色满-5-腈(化合物377)。
1H NMRδ4.83(s,2H),4.17-4.41(m,4H),3.38-3.51(m,1H),2.87-3.06(m,2H),2.77(s,2H),2.13(dt,J=10.5,6.5Hz,1H),1.65-1.74(m,1H),1.28-1.39(m,9H),1.06-1.19(m,2H),0.96-1.06(m,6H),0.84-0.94(m,2H),0.79(d,J=6.8Hz,4H),0.54-0.68(m,2H)。LC-MS:m/z 481.2(M+H)+。
(R)-8-环丙基-6-(3-异丙基-4-烟酰哌嗪-1-基)-3,3-二甲基异色满-5-腈(化合物271)。
1H NMRδ8.71(br.s.,2H),7.80(d,J=7.5Hz,1H),7.38-7.51(m,1H),4.77-4.92(m,2H),4.07–4.65(m,3H),3.55-3.67(m,1H),2.95–3.34(m,3H),2.77(s,2H),2.21-2.38(m,1H),1.65-1.76(m,1H),1.31(s,6H),0.95-1.16(m,8H),0.80(br.s.,2H)。LC-MS:m/z 460.2(M+H)+。
8-环丙基-6-(4-(呋喃-3-羰基)-3-苯基哌嗪-1-基)-3,3-二甲基异色满-5-腈(化合物156)。
1H NMRδ7.63(br.s.,1H),7.34-7.45(m,5H),7.29-7.32(m,1H),6.53(br.s.,1H),4.74-4.90(m,2H),4.46(br.s.,2H),4.18(d,J=11.3Hz,1H),3.83(d,J=13.1Hz,1H),3.58(br.s.,1H),3.43(br.s.,1H),2.76(s,2H),1.70–1.72(m,1H),1.33(d,J=3.5Hz,6H),1.15(dd,J=7.8,4.5Hz,1H),1.03(d,J=7.8Hz,3H)。LC-MS:m/z 483.3(M+H)+。
8-环丙基-6-((3S,5R)-4-(3-甲氧基丙酰基)-3,5-二甲基哌嗪-1-基)-3,3-二甲基异色满-5-腈(化合物356)。
1H NMRδ4.84(s,2H),4.78(br.s.,1H),4.13(d,J=12.5Hz,3H),3.75(t,J=6.4Hz,2H),3.33-3.43(m,3H),3.01(br.s.,2H),2.78(s,2H),2.49-2.74(m,2H),1.67-1.82(m,1H),1.36-1.52(m,6H),1.32(s,6H),1.09-1.18(m,2H),0.99-1.05(m,2H)。LC-MS:m/z 427.2(M+H)+。
(R)-8-环丙基-6-(4-(2-(2-氟苯基)乙酰基)-3-异丙基哌嗪-1-基)-3,3-二甲基异色满-5-腈(化合物228)。
1H NMRδ7.30-7.37(m,1H),7.19-7.26(m,1H),6.99-7.15(m,2H),4.75-4.88(m,2H),4.64(d,J=10.5Hz,0.5H),4.40(d,J=10.3Hz,0.5H),4.22-4.34(m,1H),4.06-4.21(m,1H),3.71-3.80(m,2H),3.50-3.54(m,0.5H),3.32-3.46(m,1.5H),2.93-3.01(m,1H),2.81-2.89(m,1H),2.75(s,2H),2.24(dt,J=9.7,6.6Hz,0.5H),2.10(dt,J=10.4,6.7Hz,0.5H),1.66-1.72(m,1H),1.31(d,J=3.0Hz,6H),1.06-1.19(m,2H),0.94-1.05(m,5H),0.87(d,J=6.8Hz,1.5H),0.80(d,J=6.8Hz,1.5H)。LC-MS:m/z 491.3(M+H)+。
8-环丙基-6-(4-(呋喃-3-羰基)-3-甲基哌嗪-1-基)-3,3-二甲基异色满-5-腈(化合物136)。
1H NMRδ7.75(s,1H),7.42-7.53(m,1H),6.59(dd,J=1.8,0.8Hz,1H),4.85(s,2H),4.68(br.s.,1H),4.28(br.s.,1H),4.01-4.16(m,2H),3.46(br.s.,1H),3.18(dd,J=12.9,3.4Hz,1H),3.01(td,J=12.5,3.4Hz,1H),2.79(s,2H),1.68-1.80(m,1H),1.39-1.49(m,3H),1.33(s,6H),1.09-1.18(m,2H),0.99-1.07(m,2H)。LC-MS:m/z 421.1(M+H)+。
(R)-6-(4-(呋喃-3-羰基)-3-异丙基哌嗪-1-基)-3,3-二甲基-8-(1-甲基环丙基)异色满-5-腈(化合物386)。
1H NMRδ7.71(br.s.,1H),7.45(t,J=1.6Hz,1H),6.40-6.64(m,1H),4.86(s,2H),4.53-4.56(m,2H),4.27(s,1H),3.48(s,1H),3.00-3.24(m,3H),2.78(s,2H),2.24(m,1H),1.26-1.36(m,9H),1.04-1.16(m,2H),0.79-0.98(m,6H),0.63-0.79(m,2H)。LC-MS:m/z 463.2(M+H)+。
(R)-8-环丙基-6-(4-(呋喃-2-羰基)-3-异丙基哌嗪-1-基)-3,3-二甲基异色满-5-腈(化合物192)。
1H NMRδ7.50(d,J=1.3Hz,1H),7.02(br.s.,1H),6.50(dd,J=3.3,1.8Hz,1H),4.77-4.89(m,2H),4.20-4.54(m,4H),3.58(br.s.,1H),3.00-3.21(m,2H),2.77(s,2H),2.18-2.34(m,1H),1.65-1.76(m,1H),1.32(d,J=1.8Hz,6H),0.92-1.19(m,8H),0.79-0.92(m,2H)。LC-MS:m/z 449.2(M+H)+。
(R)-6-(3-异丙基-4-(3-甲氧基丙酰基)哌嗪-1-基)-3,3-二甲基-8-(1-甲基环丙基)异色满-5-腈(化合物385)。
1H NMRδ4.87(s,2H),4.55(d,J=13.6Hz,2H),4.28(dd,J=12.9,1.9Hz,1H),3.64-3.91(m,3H),3.39(d,J=4.3Hz,3H),2.88-3.18(m,3H),2.79(s,2H),2.47-2.76(m,1H),1.28-1.37(m,6H),1.07(d,J=6.5Hz,3H),0.86-0.92(m,3H),0.78-0.86(m,2H),0.65-0.76(m,2H)。LC-MS:m/z 455.2(M+H)+。
8-环丙基-6-((2S,5R)-2,5-二甲基-4-(2-(苯硫-2-基)乙酰基)哌嗪-1-基)-3,3-二甲基异色满-5-腈(化合物309)。
1H NMRδ7.21(br.s.,1H),6.90-6.96(m,2H),4.90(br.s.,0.5H),4.81(br.s.,2H),4.59(br.s.,1H),4.34(d,J=13.3Hz,0.5H),4.20(br.s.,0.5H),3.81-4.07(m,3H),3.64(d,J=11.5Hz,1H),3.33-3.58(m,1H),3.21(d,J=11.3Hz,0.5H),2.75(br.s.,2H),1.69(br.s.,1H),1.25-1.43(m,8H),0.99-1.17(m,8H)。LC-MS:m/z 465.0(M+H)+。
(S)-8-环丙基-6-(3-异丁基-4-(3-甲氧基丙酰基)哌嗪-1-基)-3,3-二甲基异色满-5-腈(化合物389)。
1H NMR(氯仿-d)δ4.87(br.s.,0.5H),4.83(s,2H),4.55-4.58(m,0.5H),3.98-4.18(m,2.5H),3.65-3.81(m,2.5H),3.42-3.57(m,1H),3.36(s,3H),2.90-3.20(m,2.5H),2.73-2.81(m,2H),2.49-2.73(m,2H),1.47-1.74(m,4H),1.31(s,6H),1.07-1.16(m,2H),0.99-1.04(m,2H),0.89-0.97(m,6H)。LC-MS:m/z 455.4(M+H)+。
(R)-8-环丙基-6-(3-异丙基-4-(四氢-2H-吡喃-4-羰基)哌嗪-1-基)-3,3-二甲基异色满-5-腈(化合物305)。
1H NMRδ4.78-4.88(m,2H),4.62-4.64(m,0.5H),4.30-4.47(m,1.5H),4.13-4.26(m,1H),3.96-4.09(m,2H),3.79(d,J=13.3Hz,0.5H),3.39-3.55(m,3H),2.88-3.08(m,2.5H),2.71-2.82(m,3H),2.08-2.34(m,2H),1.77-2.06(m,2H),1.67-1.74(m,1H),1.63(m,1H),1.31(d,J=2.0Hz,6H),1.07-1.18(m,2H),0.97-1.05(m,5H),0.84-0.90(m,1.5H),0.79(d,J=6.8Hz,1.5H)。LC-MS:m/z 467.1(M+H)+。
(R)-8-环丙基-6-(3-乙基-4-(噻唑-4-羰基)哌嗪-1-基)-3,3-二甲基异色满-5-腈(化合物293)。
1H NMR(氯仿-d)δ8.81(d,J=2.3Hz,1H),8.00(d,J=2.0Hz,1H),4.44–4.83(m,4H),4.09-4.24(m,2H),3.54–3.56(m,0.5H),3.25(dd,J=13.2,3.6Hz,1.5H),3.09(td,J=12.4,3.3Hz,1H),2.77(s,2H),1.89-2.05(m,1H),1.65-1.75(m,2H),1.31(s,6H),1.08-1.18(m,2H),0.95-1.04(m,4H),0.79(br.s.,1H)。LC-MS:m/z 452.1(M+H)+。
(R)-8-环丙基-6-(4-(2,5-二甲基呋喃-3-羰基)-3-甲基哌嗪-1-基)-3,3-二甲基异色满-5-腈(化合物244)。
1H NMRδ5.88-5.96(m,1H),4.83(s,2H),4.65(br.s.,1H),3.99-4.29(m,3H),3.39(br.s.,1H),3.14(dd,J=12.9,3.4Hz,1H),2.96(td,J=12.5,3.4Hz,1H),2.77(s,2H),2.31-2.37(m,3H),2.22-2.28(m,3H),1.64-1.75(m,1H),1.37(d,J=6.8Hz,3H),1.31(s,6H),1.09-1.16(m,2H),0.97-1.04(m,2H)。LC-MS:m/z 449.1(M+H)+。
(R)-8-环丙基-6-(3-异丙基-4-(3-甲基呋喃-2-羰基)哌嗪-1-基)-3,3-二甲基异色满-5-腈(化合物193)。
1H NMRδ7.34(d,J=1.5Hz,1H),6.30-6.37(m,1H),4.75-4.92(m,2H),3.40-4.42(m,5H),3.00-3.21(m,2H),2.69-2.82(m,2H),2.17-2.33(m,4H),1.67-1.76(m,1H),1.32(d,J=1.8Hz,6H),0.72-1.19(m,10H)。LC-MS:m/z 463.2(M+H)+。
(S)-8-环丙基-6-(4-(呋喃-3-羰基)-3-苯基哌嗪-1-基)-3,3-二甲基异色满-5-腈(化合物275)。
1H NMRδ7.57-7.69(m,1H),7.32-7.42(m,5H),7.27-7.31(m,1H),6.51(br.s.,1H),5.67(br.s.,1H),4.73-4.88(m,2H),4.43(br.s.,2H),4.16(d,J=11.8Hz,1H),3.80(d,J=11.3Hz,1H),3.50-3.63(m,1H),3.40(br.s.,1H),2.68-2.81(m,2H),1.66-1.74(m,1H),1.30(d,J=3.8Hz,6H),1.03-1.17(m,2H),1.01(m,2H)。LC-MS:m/z 483.1(M+H)+。
8-环丙基-6-(3,3-二甲基-4-(2-甲基呋喃-3-羰基)哌嗪-1-基)-3,3-二甲基异色满-5-腈(化合物321)。
1H NMRδ7.24(d,J=1.8Hz,1H),6.33(d,J=2.0Hz,1H),4.82(s,2H),3.79-3.84(m,2H),3.74-3.79(m,4H),2.70-2.82(m,2H),2.40(s,3H),1.70(td,J=8.2,4.0Hz,1H),1.60(s,6H),1.31(s,6H),1.12(dt,J=7.3,3.7Hz,2H),0.97-1.03(m,2H)。LC-MS:m/z 449.0(M+H)+。
(R)-8-环丙基-6-(4-(呋喃-2-羰基)-3-甲基哌嗪-1-基)-3,3-二甲基异色满-5-腈(化合物167)。
1H NMRδ7.51(d,J=1.0Hz,1H),7.03(d,J=3.5Hz,1H),6.50(dd,J=3.4,1.9Hz,1H),4.84(s,3H),4.46(d,J=12.8Hz,1H),4.00-4.22(m,2H),3.50(d,J=10.8Hz,1H),3.25(dd,J=13.1,3.5Hz,1H),3.09(td,J=12.4,3.5Hz,1H),2.78(s,2H),1.67-1.77(m,1H),1.41-1.50(m,3H),1.26-1.38(m,6H),1.13(dd,J=6.3,4.3Hz,2H),0.97-1.06(m,2H)。LC-MS:m/z 421.3(M+H)+。
8-环丙基-6-(4-(呋喃-2-羰基)-3,3-二甲基哌嗪-1-基)-3,3-二甲基异色满-5-腈(化合物319)。
1H NMRδ7.45-7.53(m,1H),6.95(dd,J=3.4,0.6Hz,1H),6.47(dd,J=3.5,1.8Hz,1H),4.82(s,2H),3.95-4.04(m,2H),3.87-3.95(m,2H),3.82(s,2H),2.76(s,2H),1.68-1.76(m,1H),1.59(s,6H),1.32(s,6H),1.09-1.15(m,2H),0.97-1.03(m,2H)。LC-MS:m/z 435.0(M+H)+。
8-环丙基-6-(4-(呋喃-2-羰基)-3-甲基哌嗪-1-基)-3,3-二甲基-3,4-二氢-1H-吡喃并[3,4-c]吡啶-5-腈(化合物135)。
1H NMRδ7.52(d,J=1.3Hz,1H),7.05(d,J=3.3Hz,1H),6.52(dd,J=3.5,1.8Hz,1H),4.85(s,3H),4.48(d,J=13.8Hz,1H),4.15(d,J=12.8Hz,1H),4.08(dt,J=13.1,2.0Hz,1H),3.53(br.s.,1H),3.26(dd,J=12.9,3.6Hz,1H),3.10(td,J=12.4,3.5Hz,1H),2.79(s,2H),1.70-1.77(m,1H),1.47(d,J=6.8Hz,3H),1.34(s,6H),1.11-1.18(m,2H),0.97-1.07(m,2H)。LC-MS:m/z 421.1(M+H)+。
4-(5-氰基-8-环丙基-3,3-二甲基-3,4-二氢-1H-吡喃并[3,4-c]吡啶-6-基)-1-(呋喃-3-羰基)哌嗪-2-羧酸乙酯(化合物259)。
1H NMRδ7.80(br.s.,1H),7.37-7.51(m,1H),6.64(br.s.,1H),5.38(br.s.,1H),4.78-4.89(m,2H),4.69(br.s.,1H),4.00-4.27(m,4H),3.29(br.s.,1H),3.03(td,J=12.2,3.4Hz,1H),2.68-2.86(m,2H),1.64-1.79(m,1H),1.18-1.35(m,9H),1.14(br.s.,2H),0.94-1.08(m,2H)。LC-MS:m/z 479.1(M+H)+。
(R)-8-环丙基-6-(4-(呋喃-3-羰基)-3-苯基哌嗪-1-基)-3,3-二甲基-3,4-二氢-1H-吡喃并[3,4-c]吡啶-5-腈(化合物274)。
1H NMRδ7.54-7.72(m,1H),7.33-7.44(m,5H),7.27-7.29(m,1H),6.51(br.s.,1H),5.67(br.s.,1H),4.74-4.87(m,2H),4.43(br.s.,2H),4.16(d,J=12.0Hz,1H),3.72-3.87(m,1H),3.50-3.64(m,1H),3.33-3.46(m,1H),2.68-2.79(m,2H),1.68-1.75(m,1H),1.30(d,J=3.5Hz,6H),1.03-1.17(m,2H),0.98-1.02(m,2H)。LC-MS:m/z 483.1(M+H)+。
(R)-8-环丙基-6-(3-异丙基-4-(2-甲基中氮茚-3-羰基)哌嗪-1-基)-3,3-二甲基-3,4-二氢-1H-吡喃并[3,4-c]吡啶-5-腈(化合物229)。
1H NMRδ8.39(br.s.,1H),7.58(br.s.,1H),7.27-7.40(m,1H),6.88(br.s.,1H),4.77-4.89(m,2H),4.10-4.55(m,3H),3.52–3.85(m,1H),3.21(br.s.,2H),2.77(s,2H),2.54(s,3H),2.21-2.35(m,2H),1.67-1.78(m,1H),1.29-1.38(m,6H),0.67-1.20(m,10H)。LC-MS:m/z 513.3(M+H)+。
8-环丙基-6-(4-(呋喃-2-羰基)哌嗪-1-基)-3,3-二甲基-3,4-二氢-1H-吡喃并[3,4-c]吡啶-5-腈(化合物142)。
1H NMRδ7.45-7.55(m,1H),7.05(d,J=3.5Hz,1H),6.51(dd,J=3.5,1.8Hz,1H),4.84(s,2H),3.95(br.s.,4H),3.60-3.70(m,4H),2.79(s,2H),1.68-1.77(m,1H),1.32(s,6H),1.14(quin,J=3.7Hz,2H),0.98-1.06(m,2H)。LC-MS:m/z 407.2(M+H)+。
8-环丙基-6-((2S,5R)-4-(3-甲氧基丙酰基)-2,5-二甲基哌嗪-1-基)-3,3-二甲基-3,4-二氢-1H-吡喃并[3,4-c]吡啶-5-腈(化合物310)。
1H NMRδ4.85-4.96(m,0.5H),4.82(s,2H),4.53-4.65(m,1H),4.32(d,J=13.6Hz,0.5H),4.18(br.s.,0.5H),3.88-4.07(m,1H),3.69-3.77(m,2H),3.65(dd,J=13.4,3.6Hz,0.5H),3.40-3.55(m,1.5H),3.34-3.39(m,3H),3.20(dd,J=13.4,3.6Hz,0.5H),2.72-2.85(m,2.5H),2.53-2.64(m,1.5H),1.66-1.74(m,1H),1.51-1.58(m,1H),1.41-1.48(m,1H),1.31(d,J=2.8Hz,6H),1.19-1.27(m,3H),1.16(d,J=6.5Hz,1H),1.10(dd,J=9.5,5.0Hz,2H),0.97-1.03(m,2H)。LC-MS:m/z 427.0(M+H)+。
(R)-8-环丙基-6-(3-异丙基-4-(5-甲基烟酰基)哌嗪-1-基)-3,3-二甲基-3,4-二氢-1H-吡喃并[3,4-c]吡啶-5-腈(化合物245)。
1H NMRδ8.47(s,1H),8.52(s,1H),7.57(s,1H),4.76-4.92(m,2H),4.28-4.54(m,2H),4.02-4.16(m,1H),3.50–3.61(m,1H),2.90-3.15(m,2H),2.76(s,2H),2.41(s,3H),2.19-2.33(m,1H),1.92-2.06(m,1H),1.67-1.78(m,1H),1.29-1.38(m,6H),0.96-1.18(m,8H),0.81-0.91(m,2H)。LC-MS:m/z474.2(M+H)+。
8-环丙基-6-(3,3-二甲基-4-(3-(甲硫基)丙酰基)哌嗪-1-基)-3,3-二甲基-3,4-二氢-1H-吡喃并[3,4-c]吡啶-5-腈(化合物320)。
1H NMRδ4.82(s,2H),3.85-3.94(m,2H),3.76(s,2H),3.69-3.75(m,2H),2.77-2.85(m,2H),2.76(s,2H),2.56-2.67(m,2H),2.15(s,3H),1.68-1.74(m,1H),1.51(s,6H),1.31(s,6H),1.08-1.14(m,2H),0.96-1.03(m,2H)。LC-MS:m/z 443.0(M+H)+。
(S)-8-环丙基-6-(4-(呋喃-2-羰基)-2-甲基哌嗪-1-基)-3,3-二甲基-3,4-二氢-1H-吡喃并[3,4-c]吡啶-5-腈(化合物203)。
1H NMRδ7.50(s,1H),7.03-7.10(m,1H),6.50(dd,J=3.5,1.8Hz,1H),4.84(s,2H),4.38-4.56(m,2H),4.23-4.32(m,1H),3.89-3.98(m,1H),3.54(d,J=8.8Hz,1H),3.33-3.50(m,2H),2.78(s,2H),1.92-2.10(m,1H),1.32(s,6H),1.25(s,3H),1.09-1.17(m,2H),0.99-1.03(m,2H)。LC-MS:m/z 422.9(M+H)+。
8-环丙基-6-((2S,5R)-4-(呋喃-3-羰基)-2,5-二甲基哌嗪-1-基)-3,3-二甲基-3,4-二氢-1H-吡喃并[3,4-c]吡啶-5-腈(化合物308)。
1H NMRδ7.62-7.82(m,1H),7.38-7.50(m,1H),6.56(s,1H),4.76-5.04(m,2.5H),4.31-4.60(m,2H),3.97(d,J=13.6Hz,1H),3.37-3.51(m,2.5H),2.76(s,2H),1.65-1.79(m,1H),1.31(d,J=3.5Hz,6H),1.20-1.28(m,6H),1.05-1.15(m,2H),0.96-1.04(m,2H)。LC-MS:m/z 435.0(M+H)+。
8-环丙基-6-(4-(呋喃-3-羰基)-3,3-二甲基哌嗪-1-基)-3,3-二甲基-3,4-二氢-1H-吡喃并[3,4-c]吡啶-5-腈(化合物318)。
1H NMRδ7.69-7.74(m,1H),7.43(t,J=1.6Hz,1H),6.52-6.56(m,1H),4.82(s,2H),3.87-3.92(m,2H),3.83-3.87(m,2H),3.80(s,2H),2.76(s,2H),2.22(t,J=7.7Hz,1H),1.59(s,6H),1.32(s,6H),1.12(quin,J=3.7Hz,2H),0.98-1.05(m,2H)。LC-MS:m/z 435.1(M+H)+。
(R)-8-环丙基-6-(4-(呋喃-2-羰基)-2-甲基哌嗪-1-基)-3,3-二甲基-3,4-二氢-1H-吡喃并[3,4-c]吡啶-5-腈(化合物204)。
1H NMRδ7.47-7.53(m,1H),7.02-7.09(m,1H),6.50(dd,J=3.4,1.9Hz,1H),4.83(s,2H),4.38-4.56(m,2H),4.22-4.31(m,1H),3.88-3.98(m,1H),3.34-3.61(m,3H),2.77(s,2H),1.67-1.76(m,1H),1.32(s,6H),1.25(s,3H),1.08-1.14(m,2H),0.98-1.04(m,2H)。LC-MS:m/z 421.2(M+H)+。
(R)-8-环丙基-6-(3-异丙基-4-(吡唑并[1,5-a]嘧啶-3-羰基)哌嗪-1-基)-3,3-二甲基-3,4-二氢-1H-吡喃并[3,4-c]吡啶-5-腈(化合物232)。
1H NMRδ8.73(d,J=3.8Hz,1H),8.64(br.s.,1H),8.43(s,1H),6.87-7.04(m,1H),4.78-4.90(m,2H),4.35–4.62(m,2.5H),4.16(d,J=12.5Hz,0.5H),3.55-3.97(m,2H),3.06-3.29(m,2H),2.76(s,2H),2.21-2.38(m,1H),1.64-1.75(m,1H),1.28-1.36(m,6H),0.96-1.21(m,8H),0.69-0.84(m,2H)。LC-MS:m/z 500.1(M+H)+。
(R)-6-(4-(呋喃-2-羰基)-3-异丙基哌嗪-1-基)-8-异丙基-3,3-二甲基-3,4-二氢-1H-吡喃并[3,4-c]吡啶-5-腈(化合物171)。
1H NMRδ7.52(s,1H),7.04(br.s.,1H),6.52(dd,J=3.4,1.6Hz,1H),4.68-4.81(m,2H),4.37-4.68(m,4H),3.63(br.s.,1H),3.10-3.32(m,2H),2.83-2.91(m,1H),2.80(s,2H),1.72(br.s.,1H),1.30-1.36(m,6H),1.16-1.25(m,6H),1.06(br.s.,3H),0.91(br.s.,3H)。LC-MS:m/z 451.2(M+H)+。
(R)-6-(3-乙基-4-(2-甲基呋喃-3-羰基)哌嗪-1-基)-8-异丙基-3,3-二甲基-3,4-二氢-1H-吡喃并[3,4-c]吡啶-5-腈(化合物207)。
1H NMRδ7.28(d,J=2.0Hz,1H),6.28-6.42(m,1H),4.72(s,3H),3.93-4.37(m,3H),3.43(br.s.,1H),3.20(dd,J=13.1,3.5Hz,1H),2.96-3.10(m,1H),2.80-2.89(m,1H),2.78(s,2H),2.40(s,3H),1.84-1.98(m,1H),1.76(dt,J=14.2,7.0Hz,1H),1.30(s,6H),1.15-1.23(m,6H),0.85-0.95(m,3H)。LC-MS:m/z 451.2(M+H)+。
(R)-6-(4-(呋喃-3-羰基)-3-异丙基哌嗪-1-基)-8-异丙基-3,3-二甲基-3,4-二氢-1H-吡喃并[3,4-c]吡啶-5-腈(化合物165)。
1H NMRδ7.74(br.s.,1H),7.47(t,J=1.8Hz,1H),6.47-6.68(m,1H),4.69-4.79(m,2H),4.30-4.58(m,3H),3.50-4.03(m,2H),3.14(dd,J=13.3,3.3Hz,2H),2.83-2.90(m,1H),2.80(s,2H),2.26(br.s.,1H),1.28-1.34(m,6H),1.17-1.25(m,6H),1.07(br.s.,2H),0.91(br.s.,4H)。LC-MS:m/z 451.2(M+H)+。
(R)-6-(3-乙基-4-(2-(苯硫-2-基)乙酰基)哌嗪-1-基)-8-异丙基-3,3-二甲基-3,4-二氢-1H-吡喃并[3,4-c]吡啶-5-腈(化合物206)。
1H NMRδ7.21(dd,J=5.0,1.3Hz,1H),6.89-6.99(m,2H),4.70(s,2.5H),4.61(d,J=12.5Hz,0.5H),4.13-4.34(m,2H),3.78-4.07(m,3H),3.39-3.60(m,0.5H),2.88-3.18(m,2.5H),2.74-2.87(m,3H),1.77-1.86(m,1H),1.72(dd,J=14.9,7.7Hz,1H),1.29(d,J=2.5Hz,6H),1.16-1.21(m,6H),0.83-0.96(m,3H)。LC-MS:m/z 467.1(M+H)+。
(R)-6-(3-乙基-4-(呋喃-3-羰基)哌嗪-1-基)-8-异丙基-3,3-二甲基-3,4-二氢-1H-吡喃并[3,4-c]吡啶-5-腈(化合物205)。
1H NMRδ7.72(s,1H),7.46(t,J=1.8Hz,1H),6.57(d,J=1.0Hz,1H),4.72(s,3H),4.10-4.39(m,3H),3.29-3.58(m,1H),3.20(dd,J=13.2,3.4Hz,1H),3.07(td,J=12.4,3.0Hz,1H),2.74-2.88(m,3H),1.75-1.97(m,2H),1.30(s,6H),1.16-1.23(m,6H),0.86-0.99(m,3H)。LC-MS:m/z 437.2(M+H)+。
(R)-8-异丙基-6-(3-异丙基-4-(2-(苯硫-2-基)乙酰基)哌嗪-1-基)-3,3-二甲基-3,4-二氢-1H-吡喃并[3,4-c]吡啶-5-腈(化合物195)。
1H NMRδ7.17-7.24(m,1H),6.83-7.04(m,2H),4.67-4.75(m,2H),4.38-4.57(m,1.5H),4.17-4.32(m,1H),3.81-4.10(m,3H),3.46-3.47(m,1H),2.79-3.53(m,3.5H),2.76(s,2H),2.10-2.30(m,1H),1.29(d,J=2.3Hz,6H),1.13-1.22(m,6H),0.97-1.08(m,3H),0.79-0.91(m,3H)。LC-MS:m/z 481.2(M+H)+。
(R)-8-异丙基-6-(3-异丙基-4-(2-甲基呋喃-3-羰基)哌嗪-1-基)-3,3-二甲基-3,4-二氢-1H-吡喃并[3,4-c]吡啶-5-腈(化合物176)。
1H NMRδ7.30(d,J=2.0Hz,1H),6.37(br.s.,1H),4.69-4.79(m,2H),4.26-4.67(m,3H),3.90(d,J=9.8Hz,0.5H),3.52(br.s.,1H),2.99-3.22(m,2.5H),2.86(quin,J=6.7Hz,1H),2.80(s,2H),2.42(s,3H),2.20-2.33(m,1H),1.31-1.36(m,6H),1.15-1.26(m,6H),1.09(br.s.,2H),0.84-1.02(m,4H)。LC-MS:m/z 465.2(M+H)+。
4-(5-氰基-8-异丙基-3,3-二甲基-3,4-二氢-1H-吡喃并[3,4-c]吡啶-6-基)-1-(2-(苯硫-2-基)乙酰基)哌嗪-2-羧酸乙酯(化合物332)。
1H NMRδ7.19-7.25(m,1H),6.89-7.01(m,2H),5.24-5.40(m,1H),4.63-4.82(m,3H),3.98-4.24(m,5H),3.77-3.93(m,2H),3.25-3.36(m,1H),2.94-3.10(m,1H),2.74-2.89(m,3H),1.29(d,J=4.8Hz,6H),1.14-1.22(m,9H)。LC-MS:m/z 511.4(M+H)+。
4-(5-氰基-8-异丙基-3,3-二甲基-3,4-二氢-1H-吡喃并[3,4-c]吡啶-6-基)-1-(呋喃-3-羰基)哌嗪-2-羧酸乙酯(化合物276)。
1H NMRδ7.79(br.s.,1H),7.46(s,1H),6.63(br.s.,1H),5.39(br.s.,0.5H),4.80(br.s.,0.5H),4.72(d,J=3.5Hz,2H),4.21(dq,J=10.7,7.1Hz,2H),4.01-4.15(m,2H),3.93(br.s.,1H),3.40(d,J=11.8Hz,1H),3.03-3.18(m,1H),2.76-2.89(m,3H),1.11-1.34(m,15H)。LC-MS:m/z 481.2(M+H)+。
(R)-8-异丙基-3,3-二甲基-6-(3-甲基-4-(2-甲基呋喃-3-羰基)哌嗪-1-基)-3,4-二氢-1H-吡喃并[3,4-c]吡啶-5-腈(化合物163)。
1H NMRδ7.30(d,J=2.0Hz,1H),6.38(d,J=2.0Hz,1H),4.56-4.83(m,3H),4.03-4.32(m,3H),3.47(br.s.,1H),3.18-3.31(m,1H),3.07(td,J=12.6,3.1Hz,1H),2.83-2.92(m,1H),2.81(s,2H),2.36-2.46(m,3H),1.38-1.46(m,3H),1.30-1.37(m,6H),1.21(d,J=6.5Hz,6H)。LC-MS:m/z 437.2(M+H)+。
(R)-8-异丙基-3,3-二甲基-6-(3-甲基-4-(5-甲基异噁唑-4-羰基)哌嗪-1-基)-3,4-二氢-1H-吡喃并[3,4-c]吡啶-5-腈(化合物217)。
1H NMRδ8.24(s,1H),4.73(s,2H),4.12-4.29(m,2H),3.49(s,1H),3.23(dd,J=13.1,3.5Hz,1H),3.01-3.14(m,1H),2.77-2.91(m,3H),2.57(s,3H),1.44(d,J=6.8Hz,3H),1.31(s,6H),1.16-1.23(m,6H)。LC-MS:m/z438.1(M+H)+。
(R)-8-异丙基-6-(3-异丙基-4-(噁唑-4-羰基)哌嗪-1-基)-3,3-二甲基-3,4-二氢-1H-吡喃并[3,4-c]吡啶-5-腈(化合物212)。
1H NMRδ8.25(d,J=7.0Hz,1H),7.93(d,J=10.8Hz,1H),4.84(d,J=12.0Hz,1H),4.71(s,2H),4.66(d,J=9.8Hz,0.5H),4.60(d,J=14.1Hz,1H),4.49(d,J=10.3Hz,0.5H),4.33(d,J=12.8Hz,1H),3.57(t,J=11.7Hz,1H),3.12-3.32(m,2H),2.81-2.89(m,1H),2.74-2.81(m,2H),2.19-2.34(m,1H),1.30(s,6H),1.18(d,J=6.8Hz,3H),1.21(d,J=6.8Hz,3H),1.00-1.09(m,3H),0.80-0.94(m,3H)。LC-MS:m/z 452.2(M+H)+。
(R)-8-异丙基-3,3-二甲基-6-(3-甲基-4-(3-(甲硫基)丙酰基)哌嗪-1-基)-3,4-二氢-1H-吡喃并[3,4-c]吡啶-5-腈(化合物267)。
1H NMRδ4.89(br.s.,0.5H),4.72(s,2H),4.52(d,J=12.0Hz,0.5H),4.02-4.32(m,2.5H),3.74(d,J=13.1Hz,0.5H),3.59(t,J=11.3Hz,0.5H),3.01-3.30(m,2.5H),2.84(quin,J=6.6Hz,3H),2.79(s,2H),2.56-2.73(m,2H),2.16(s,3H),1.30-1.44(m,9H),1.20(d,J=6.3Hz,6H)。LC-MS:m/z 431.2(M+H)+。
(R)-8-异丙基-6-(3-异丙基-4-(2-(吡啶-3-基)乙酰基)哌嗪-1-基)-3,3-二甲基-3,4-二氢-1H-吡喃并[3,4-c]吡啶-5-腈(化合物250)。
1H NMRδ8.55(d,J=5.0Hz,2H),7.73(d,J=6.5Hz,1H),7.33(dd,J=7.5,5.0Hz,1H),4.62-4.75(m,2.5H),4.37-4.57(m,1.5H),4.16-4.33(m,1H),3.72-3.87(m,2.5H),3.42-3.61(m,1H),2.91-3.12(m,2.5H),2.83(dt,J=13.3,6.7Hz,1H),2.77(s,2H),2.08-2.37(m,1H),1.30(d,J=2.3Hz,6H),1.15-1.24(m,6H),1.03(dd,J=13.4,6.4Hz,3H),0.89(dd,J=10.3,6.8Hz,1.5H),0.80(d,J=6.8Hz,1.5H)。LC-MS:m/z 476.2(M+H)+。
(R)-8-异丙基-6-(3-异丙基-4-(2-(吡啶-2-基)乙酰基)哌嗪-1-基)-3,3-二甲基-3,4-二氢-1H-吡喃并[3,4-c]吡啶-5-腈(化合物214)。
1H NMRδ8.54(d,J=2.8Hz,1H),7.61-7.77(m,1H),7.41(t,J=8.4Hz,1H),7.15-7.24(m,1H),4.58-4.74(m,2.5H),4.49(dt,J=13.6,2.0Hz,1H),4.40(d,J=10.3Hz,0.5H),4.18-4.34(m,1H),3.87-4.15(m,3H),3.33-3.51(m,0.5H),2.96-3.06(m,1.5H),2.85-2.94(m,1H),2.82(quin,J=6.7Hz,1H),2.76(s,2H),2.09-2.30(m,1H),1.29(d,J=2.3Hz,6H),1.17(dd,J=10.4,6.7Hz,6H),1.01(dd,J=9.9,6.7Hz,3H),0.80(dd,J=12.7,6.9Hz,3H)。LC-MS:m/z 476.2(M+H)+。
(R)-8-异丙基-6-(4-(3-甲氧基丙酰基)-3-甲基哌嗪-1-基)-3,3-二甲基-3,4-二氢-1H-吡喃并[3,4-c]吡啶-5-腈(化合物268)。
1H NMRδ4.89(br.s.,0.5H),4.71(s,2H),4.53(d,J=12.8Hz,0.5H),4.09-4.31(m,2.5H),3.66-3.82(m,2.5H),3.50-3.63(m,0.5H),3.37(s,3H),3.01-3.29(m,2.5H),2.81-2.88(m,1H),2.76-2.81(m,2H),2.53-2.74(m,2H),1.30-1.44(m,9H),1.19(d,J=6.5Hz,6H)。LC-MS:m/z 415.2(M+H)+。
(R)-8-异丙基-3,3-二甲基-6-(3-甲基-4-(2-(苯硫-2-基)乙酰基)哌嗪-1-基)-3,4-二氢-1H-吡喃并[3,4-c]吡啶-5-腈(化合物158)。
1H NMRδ7.23(dd,J=5.0,1.3Hz,1H),6.86-7.07(m,2H),4.93(br.s.,0.5H),4.73(s,2H),4.57(d,J=13.3Hz,0.5H),4.09-4.35(m,2.5H),3.90-4.05(m,2H),3.79(d,J=12.8Hz,0.5H),3.57(t,J=12.0Hz,0.5H),3.13-3.32(m,1.5H),3.00(q,J=11.7Hz,1H),2.82-2.88(m,1H),2.75-2.82(m,2H),1.28-1.39(m,9H),1.14-1.24(m,6H)。LC-MS:m/z 453.0(M+H)+。
4-(5-氰基-8-异丙基-3,3-二甲基-3,4-二氢-1H-吡喃并[3,4-c]吡啶-6-基)-1-(3-甲氧基丙酰基)哌嗪-2-羧酸乙酯(化合物311)。
1H NMRδ5.29(dd,J=4.3,2.0Hz,1H),4.74-4.86(m,1H),4.63-4.74(m,2H),4.25(dd,J=12.8,2.0Hz,3H),3.97-4.21(m,2H),3.62-3.89(m,3H),3.37-3.40(m,2H),3.33-3.37(m,1H),3.11(ddd,J=12.9,10.7,4.5Hz,1H),2.76-2.87(m,3H),2.60-2.71(m,1H),1.29(d,J=3.5Hz,6H),1.09-1.23(m,9H)。LC-MS:m/z 473.3(M+H)+。
(S)-6-(4-(呋喃-2-羰基)-3-苯基哌嗪-1-基)-8-异丙基-3,3-二甲基-3,4-二氢-1H-吡喃并[3,4-c]吡啶-5-腈(化合物223)。
1H NMR(氯仿-d)δ7.46(s,1H),7.43(d,J=7.5Hz,2H),7.29-7.35(m,2H),7.22-7.25(m,1H),6.95-7.02(m,1H),6.45(br.s.,1H),5.91(t,J=4.4Hz,1H),4.68-4.75(m,2H),4.57-4.67(m,2H),4.27(d,J=10.5Hz,1H),3.96(dd,J=13.8,4.5Hz,1H),3.56-3.67(m,1H),3.50-3.56(m,1H),2.83(dt,J=13.2,6.6Hz,1H),2.76(s,2H),1.29(s,6H),1.21(d,J=6.5Hz,3H),1.13-1.19(m,3H)。LC-MS:m/z 485.1(M+H)+。
6-(4-(呋喃-2-羰基)-3-苯基哌嗪-1-基)-8-异丙基-3,3-二甲基-3,4-二氢-1H-吡喃并[3,4-c]吡啶-5-腈(化合物154)。
1H NMRδ7.42-7.51(m,3H),7.31-7.38(m,2H),7.24-7.28(m,1H),7.00(br.s.,1H),6.47(br.s.,1H),5.94(t,J=4.4Hz,1H),4.72(d,J=6.3Hz,2H),4.58-4.69(m,2H),4.30(d,J=10.3Hz,1H),3.98(dd,J=13.9,4.1Hz,1H),3.46-3.73(m,2H),2.81-2.90(m,1H),2.78(s,2H),1.32(s,6H),1.23(d,J=6.8Hz,3H),1.19(d,J=6.5Hz,3H)。LC-MS:m/z 485.3(M+H)+。
4-(5-氰基-8-异丙基-3,3-二甲基-3,4-二氢-1H-吡喃并[3,4-c]吡啶-6-基)-1-(呋喃-2-羰基)哌嗪-2-羧酸乙酯(化合物298)。
1H NMRδ7.52(br.s.,1H),7.12(d,J=3.5Hz,1H),6.52(br.s.,1H),5.34(t,J=3.1Hz,1H),4.76(s,1H),4.72(d,J=3.8Hz,2H),4.53(d,J=13.3Hz,1H),4.15-4.34(m,2H),3.42-3.57(m,1H),3.23(br.s.,1H),2.75-2.91(m,3H),1.30(d,J=4.5Hz,6H),1.10-1.23(m,6H)。
(R)-6-(4-(呋喃-3-羰基)-3-甲基哌嗪-1-基)-8-异丙基-3,3-二甲基-3,4-二氢-1H-吡喃并[3,4-c]吡啶-5-腈(化合物149)。
1H NMRδ7.75(s,1H),7.47(t,J=1.8Hz,1H),6.55-6.64(m,1H),4.74(s,3H),4.12-4.42(m,3H),3.49(br.s.,1H),3.26(dd,J=12.9,3.9Hz,1H),3.10(td,J=12.5,3.4Hz,1H),2.86(quin,J=6.7Hz,1H),2.81(s,2H),1.45(d,J=6.8Hz,3H),1.32(s,6H),1.21(d,J=6.5Hz,6H)。LC-MS:m/z 423.1(M+H)+。
(R)-8-异丙基-6-(3-异丙基-4-(4-甲基噁唑-5-羰基)哌嗪-1-基)-3,3-二甲基-3,4-二氢-1H-吡喃并[3,4-c]吡啶-5-腈(化合物213)。
1H NMRδ7.97(s,1H),4.72(s,2H),4.51-4.66(m,1.5H),4.29-4.49(m,2H),3.99(d,J=14.1Hz,0.5H),3.62-3.77(m,1H),3.08-3.28(m,2H),2.81-2.93(m,1H),2.79(s,2H),2.41-2.49(m,3H),2.20-2.32(m,1H),1.28-1.36(m,6H),1.18-1.22(m,6H),0.83-1.08(m,6H)。LC-MS:m/z 466.2(M+H)+。
(R)-8-异丙基-6-(4-(2-(3-甲氧苯基)乙酰基)-3-甲基哌嗪-1-基)-3,3-二甲基-3,4-二氢-1H-吡喃并[3,4-c]吡啶-5-腈(化合物221)。
1H NMRδ7.24(dd,J=8.5,7.8Hz,1H),6.77-6.88(m,3H),4.92(br.s.,1H),4.70(s,2H),4.16-4.24(m,1H),4.09(t,J=11.9Hz,1H),3.80(s,3H),3.56-3.76(m,2H),3.44(br.s.,1H),3.19(dd,J=13.3,3.3Hz,1H),2.92-3.10(m,1H),2.70-2.92(m,4H),1.29(d,J=1.8Hz,9H),1.17(d,J=6.8Hz,6H)。LC-MS:m/z 477.1(M+H)+。
(R)-8-异丙基-3,3-二甲基-6-(3-甲基-4-(2-甲基咪唑并[1,2-a]吡啶-3-羰基)哌嗪-1-基)-3,4-二氢-1H-吡喃并[3,4-c]吡啶-5-腈(化合物220)。
1H NMRδ8.47(d,J=6.5Hz,1H),7.58(br.s.,1H),7.30(br.s.,1H),6.89(br.s.,1H),4.62-4.92(m,3H),4.23(d,J=12.8Hz,2H),3.99(br.s.,1H),3.65(br.s.,1H),3.32(d,J=11.8Hz,1H),3.08(br.s.,1H),2.75-2.91(m,3H),2.53(br.s.,3H),1.41-1.51(m,3H),1.31(s,6H),1.19(dd,J=6.7,1.6Hz,6H)。LC-MS:m/z487.1(M+H)+。
(R)-8-异丙基-6-(3-异丙基-4-(2-(2-甲氧苯基)乙酰基)哌嗪-1-基)-3,3-二甲基-3,4-二氢-1H-吡喃并[3,4-c]吡啶-5-腈(化合物216)。
1H NMRδ7.27-7.30(m,1H),7.20-7.25(m,1H),6.85-6.96(m,2H),4.60-4.79(m,2.5H),4.37-4.57(m,1.5H),4.17-4.28(m,1H),3.57-3.92(m,6H),3.38(t,J=11.4Hz,0.5H),2.77-3.07(m,3.5H),2.76(d,J=2.5Hz,2H),2.09-2.27(m,1H),1.29(d,J=1.8Hz,6H),1.13-1.22(m,6H),1.01(dd,J=6.4,1.6Hz,3H),0.85(dd,J=17.1,6.8Hz,3H)。LC-MS:m/z 505.2(M+H)+。
(R)-8-异丙基-3,3-二甲基-6-(3-甲基-4-(噻吩-2-羰基)哌嗪-1-基)-3,4-二氢-1H-吡喃并[3,4-c]吡啶-5-腈(化合物246)。
1H NMRδ7.46(dd,J=5.0,1.0Hz,1H),7.33(dd,J=3.8,1.0Hz,1H),7.07(dd,J=5.0,3.8Hz,1H),4.78(br.s.,1H),4.72(s,2H),4.38(d,J=13.1Hz,1H),4.07-4.28(m,2H),3.43-3.63(m,1H),3.28(dd,J=13.1,3.5Hz,1H),3.12(td,J=12.5,3.5Hz,1H),2.84(dt,J=13.3,6.7Hz,1H),2.79(s,2H),1.42-1.51(m,3H),1.30(s,6H),1.15-1.22(m,6H)。LC-MS:m/z 439.1(M+H)+。
(S)-6-(4-(呋喃-3-羰基)-3-苯基哌嗪-1-基)-8-异丙基-3,3-二甲基-3,4-二氢-1H-吡喃并[3,4-c]吡啶-5-腈(化合物257)。
1H NMRδ7.61(br.s.,1H),7.39(br.s.,3H),7.34(t,J=7.5Hz,3H),6.51(br.s.,1H),5.71(br.s.,1H),4.52-4.74(m,4H),4.24(d,J=10.8Hz,1H),3.92(d,J=11.3Hz,1H),3.56(d,J=11.8Hz,1H),3.50(d,J=10.0Hz,1H),2.81(dt,J=13.3,6.7Hz,1H),2.75(s,2H),1.27-1.31(m,6H),1.19(d,J=6.5Hz,3H),1.13(d,J=6.0Hz,3H)。LC-MS:m/z 485.1(M+H)+。
6-(4-(呋喃-3-羰基)-3-苯基哌嗪-1-基)-8-异丙基-3,3-二甲基-3,4-二氢-1H-吡喃并[3,4-c]吡啶-5-腈(化合物155)。
1H NMRδ7.63(br.s.,1H),7.32-7.46(m,5H),7.25-7.31(m,1H),6.53(br.s.,1H),5.73(br.s.,1H),4.60-4.81(m,4H),4.26(d,J=11.0Hz,1H),3.94(d,J=12.0Hz,1H),3.41-3.70(m,2H),2.83(dt,J=13.3,6.7Hz,1H),2.77(s,2H),1.31(d,J=2.0Hz,6H),1.19-1.24(m,3H),1.16(d,J=6.5Hz,3H)。LC-MS:m/z 485.4(M+H)+。
(R)-8-异丙基-3,3-二甲基-6-(3-甲基-4-(噻吩-3-羰基)哌嗪-1-基)-3,4-二氢-1H-吡喃并[3,4-c]吡啶-5-腈(化合物251)。
1H NMRδ7.51-7.58(m,1H),7.37(dd,J=4.9,2.9Hz,1H),7.18-7.23(m,1H),4.59-4.87(m,3H),4.09-4.39(m,3H),3.48(br.s.,1H),3.24(d,J=12.0Hz,1H),3.07(td,J=12.5,3.3Hz,1H),2.84(dt,J=13.3,6.7Hz,1H),2.79(s,2H),1.43(d,J=6.8Hz,3H),1.30(s,6H),1.19(d,J=6.8Hz,6H)。LC-MS:m/z 439.1(M+H)+。
(R)-6-(4-(2-(2-氟苯基)乙酰基)-3-异丙基哌嗪-1-基)-8-异丙基-3,3-二甲基-3,4-二氢-1H-吡喃并[3,4-c]吡啶-5-腈(化合物215)。
1H NMRδ7.30-7.38(m,1H),7.20-7.30(m,1H),7.03-7.14(m,2H),4.62-4.78(m,2H),4.40-4.56(m,1.5H),4.20-4.32(m,1H),3.55-3.92(m,3H),3.32-3.47(m,1H),2.88-3.10(m,2H),2.83(dt,J=13.3,6.7Hz,1H),2.76(s,2H),2.10-2.32(m,1.5H),1.30(d,J=2.5Hz,6H),1.14-1.23(m,6H),1.02(dd,J=9.0,6.5Hz,3H),0.88(dd,J=6.9,4.9Hz,1.5H),0.81(d,J=6.8Hz,1.5H)。LC-MS:m/z 493.2(M+H)+。
6-(4-(呋喃-3-羰基)-3-甲基哌嗪-1-基)-8-异丙基-3,3-二甲基-3,4-二氢-1H-吡喃并[3,4-c]吡啶-5-腈(化合物138)。
1H NMRδ7.76(s,1H),7.47(s,1H),6.60(d,J=1.0Hz,1H),4.74(s,3H),4.13-4.42(m,3H),3.50(br.s.,1H),3.26(dd,J=13.1,3.0Hz,1H),3.10(td,J=12.4,3.3Hz,1H),2.86(quin,J=6.7Hz,1H),2.81(s,2H),1.45(d,J=6.8Hz,3H),1.32(s,6H),1.21(d,J=6.5Hz,6H)。LC-MS:m/z 423.0(M+H)+。
(R)-6-(4-(2-(3-氟苯基)乙酰基)-3-异丙基哌嗪-1-基)-8-异丙基-3,3-二甲基-3,4-二氢-1H-吡喃并[3,4-c]吡啶-5-腈(化合物234)。
1H NMRδ7.28-7.33(m,1H),6.91-7.09(m,3H),4.62-4.79(m,2.5H),4.37-4.55(m,1.5H),4.12-4.32(m,1H),3.66-3.84(m,3H),3.33-3.47(m,1H),2.96-3.11(m,1H),2.78-2.91(m,2H),2.76(d,J=3.3Hz,2H),2.06-2.28(m,1H),1.29(d,J=2.3Hz,6H),1.15-1.22(m,6H),1.01(dd,J=6.4,2.1Hz,3H),0.85(d,J=7.0Hz,1.5H),0.80(d,J=6.8Hz,1.5H)。LC-MS:m/z 493.3(M+H)+。
(R)-8-异丙基-3,3-二甲基-6-(3-甲基-4-(3-甲基呋喃-2-羰基)哌嗪-1-基)-3,4-二氢-1H-吡喃并[3,4-c]吡啶-5-腈(化合物173)。
1H NMRδ7.36(s,1H),6.35(s,1H),4.73(s,3H),4.14-4.44(m,3H),3.43-3.63(m,1H),3.33(dd,J=13.1,3.5Hz,1H),3.17(td,J=12.3,3.3Hz,1H),2.76-2.92(m,3H),2.30(s,3H),1.45(d,J=6.8Hz,3H),1.32(s,7H),1.21(d,J=6.8Hz,6H)。LC-MS:m/z437.1(M+H)+。
(R)-6-(4-(2-(2-氟苯基)乙酰基)-3-甲基哌嗪-1-基)-8-异丙基-3,3-二甲基-3,4-二氢-1H-吡喃并[3,4-c]吡啶-5-腈(化合物219)。
1H NMRδ7.28-7.36(m,1H),7.21-7.26(m,1H),7.03-7.14(m,2H),4.71(s,3H),4.01-4.26(m,2H),3.70-3.95(m,3H),3.10-3.37(m,2H),2.98(d,J=13.6Hz,1H),2.75-2.88(m,3H),1.27-1.33(m,9H),1.18(d,J=6.8Hz,6H)。LC-MS:m/z 465.1(M+H)+。
(R)-8-异丙基-6-(3-异丙基-4-(2-(3-甲氧苯基)乙酰基)哌嗪-1-基)-3,3-二甲基-3,4-二氢-1H-吡喃并[3,4-c]吡啶-5-腈(化合物233)。
1H NMRδ7.24(t,J=7.8Hz,1H),6.82-6.88(m,2H),6.76-6.82(m,1H),4.61-4.78(m,2.5H),4.35-4.54(m,1.5H),4.14–4.28(m,1H),3.72-3.86(m,5.5H),3.31-3.54(m,1H),2.95-3.08(m,1.5H),2.71-2.86(m,4H),2.07-2.30(m,1H),1.29(d,J=2.5Hz,6H),1.14-1.22(m,6H),1.00(dd,J=6.5,2.0Hz,3H),0.75-0.87(m,3H)。LC-MS:m/z 505.3(M+H)+。
(R)-6-(4-(2-(3,5-二氟苯基)乙酰基)-3-甲基哌嗪-1-基)-8-异丙基-3,3-二甲基-3,4-二氢-1H-吡喃并[3,4-c]吡啶-5-腈(化合物159)。
1H NMRδ6.79-6.89(m,2H),6.69-6.78(m,1H),4.92(br.s.,0.5H),4.73(s,2H),4.57(d,J=13.8Hz,0.5H),4.05-4.30(m,2.5H),3.63-3.86(m,2.5H),3.46-3.62(m,0.5H),3.11-3.26(m,1.5H),2.92-3.08(m,1H),2.85(quin,J=6.7Hz,1H),2.80(s,2H),1.29-1.38(m,9H),1.20(d,J=6.8Hz,6H)。LC-MS:m/z 483.0(M+H)+。
6-(4-(呋喃-2-羰基)-3-甲基哌嗪-1-基)-8-异丙基-3,3-二甲基-3,4-二氢-1H-吡喃并[3,4-c]吡啶-5-腈(化合物137)。
1H NMRδ7.52(d,J=1.0Hz,1H),7.05(d,J=3.0Hz,1H),6.52(dd,J=3.5,1.8Hz,1H),4.88(br.s.,1H),4.74(s,2H),4.50(d,J=13.6Hz,1H),4.27(d,J=13.1Hz,1H),4.19(dd,J=13.1,2.0Hz,1H),3.56(br.s.,1H),3.35(dd,J=13.1,3.8Hz,1H),3.18(td,J=12.4,3.5Hz,1H),2.79-2.90(m,3H),1.48(d,J=6.8Hz,3H),1.32(s,6H),1.18-1.23(m,6H)。LC-MS:m/z 423.0(M+H)+。
(R)-8-异丙基-3,3-二甲基-6-(3-甲基-4-(2-氧代-2-苯乙酰基)哌嗪-1-基)-3,4-二氢-1H-吡喃并[3,4-c]吡啶-5-腈(化合物157)。
1H NMRδ7.95-8.03(m,2H),7.65-7.73(m,1H),7.51-7.59(m,2H),4.95-5.08(m,0.5H),4.74(s,2H),4.64(d,J=13.6Hz,0.5H),4.35(d,J=13.1Hz,0.5H),4.25(d,J=13.3Hz,0.5H),4.08-4.19(m,1H),3.92(br.s.,0.5H),3.64(td,J=12.8,3.3Hz,0.5H),3.49(d,J=13.3Hz,0.5H),3.30-3.43(m,1H),3.03-3.27(m,1.5H),2.76-2.92(m,3H),1.51(d,J=6.8Hz,1.5H),1.43(d,J=6.8Hz,1.5H),1.32(s,6H),1.16-1.24(m,6H)。LC-MS:m/z461.1(M+H)+。
(R)-8-异丙基-6-(4-(2-(2-甲氧苯基)乙酰基)-3-甲基哌嗪-1-基)-3,3-二甲基-3,4-二氢-1H-吡喃并[3,4-c]吡啶-5-腈(化合物199)。
1H NMRδ7.17-7.29(m,2H),6.83-7.00(m,2H),4.93(br.s.,0.5H),4.71(s,2H),4.57(d,J=13.3Hz,0.5H),4.22(d,J=10.3Hz,1H),4.11(d,J=12.8Hz,1.5H),3.81-3.89(m,3H),3.67-3.78(m,2.5H),3.46(t,J=11.7Hz,0.5H),3.07-3.26(m,1.5H),2.88-3.05(m,1H),2.73-2.87(m,3H),1.30(s,9H),1.18(d,J=6.8Hz,6H)。LC-MS:m/z477.3(M+H)+。
6-(3-乙基-4-(呋喃-3-羰基)哌嗪-1-基)-8-异丙基-3,3-二甲基-3,4-二氢-1H-吡喃并[3,4-c]吡啶-5-腈(化合物172)。
1H NMRδ7.73(s,1H),7.41-7.54(m,1H),6.58(s,1H),4.73(s,3H),4.12-4.41(m,3H),3.50(br.s.,1H),3.22(dd,J=13.2,3.4Hz,1H),3.04-3.15(m,1H),2.75-2.93(m,3H),1.78-2.02(m,2H),1.32(s,6H),1.15-1.24(m,6H),0.87-1.03(m,3H)。LC-MS:m/z437.3(M+H)+。
(R)-6-(4-(苯并[b]噻吩-3-羰基)-3-甲基哌嗪-1-基)-8-异丙基-3,3-二甲基-3,4-二氢-1H-吡喃并[3,4-c]吡啶-5-腈(化合物247)。
1H NMRδ7.86-7.95(m,1H),7.82(dd,J=6.5,2.3Hz,1H),7.57(s,1H),7.36-7.48(m,2H),4.71(s,3H),4.15–4.20(m,3H),3.49(t,J=11.7Hz,1H),3.29(d,J=12.0Hz,1H),3.09(t,J=11.3Hz,1H),2.73-2.91(m,3H),1.44(d,J=6.0Hz,3H),1.28-1.35(m,6H),1.16-1.19(m,6H)。LC-MS:m/z 489.1(M+H)+。
(R)-8-异丙基-3,3-二甲基-6-(3-甲基-4-烟酰哌嗪-1-基)-3,4-二氢-1H-吡喃并[3,4-c]吡啶-5-腈(化合物249)。
1H NMRδ8.70(br.s.,2H),7.79(d,J=7.8Hz,1H),7.41(dd,J=7.4,4.9Hz,1H),4.72(s,3H),4.03-4.33(m,3H),3.50(br.s.,1H),3.25(d,J=10.3Hz,1H),3.09(t,J=12.2Hz,1H),2.73-2.93(m,3H),1.45(d,J=6.5Hz,3H),1.30(s,6H),1.19(d,J=6.5Hz,6H)。LC-MS:m/z 434.2(M+H)+。
(R)-6-(4-(2-(3-氯苯基)乙酰基)-3-甲基哌嗪-1-基)-8-异丙基-3,3-二甲基-3,4-二氢-1H-吡喃并[3,4-c]吡啶-5-腈(化合物161)。
1H NMRδ7.21-7.35(m,3H),7.12-7.21(m,1H),4.93(br.s.,0.5H),4.73(s,2H),4.57(d,J=12.8Hz,0.5H),4.11–4.25(m,2.5H),3.67-3.84(m,3H),3.51(t,J=11.3Hz,0.5H),3.09-3.25(m,1.5H),2.89-3.06(m,1H),2.75-2.88(m,3H),1.30-1.34(m,9H),1.20(d,J=6.8Hz,6H)。LC-MS:m/z 481.2(M+H)+。
(R)-8-异丙基-3,3-二甲基-6-(3-甲基-4-(噁唑-4-羰基)哌嗪-1-基)-3,4-二氢-1H-吡喃并[3,4-c]吡啶-5-腈(化合物198)。
1H NMR(氯仿-d)δ8.24(s,1H),7.93(s,1H),4.62–5.21(m,4H),4.27(br.s.,1H),4.19(d,J=13.1Hz,1H),3.34-3.66(m,2H),3.18(br.s.,1H),2.73-2.92(m,3H),1.39-1.50(m,3H),1.31(s,6H),1.19(d,J=6.8Hz,6H)。LC-MS:m/z 424.2(M+H)+。
(R)-6-(4-(咪唑并[1,2-a]吡啶-3-羰基)-3-甲基哌嗪-1-基)-8-异丙基-3,3-二甲基-3,4-二氢-1H-吡喃并[3,4-c]吡啶-5-腈(化合物222)。
1H NMRδ9.03(d,J=7.0Hz,1H),7.98(br.s.,1H),7.84(br.s.,1H),7.44(t,J=7.8Hz,1H),6.98-7.08(m,1H),4.94(br.s.,1H),4.73(s,2H),4.49(d,J=11.5Hz,1H),4.16-4.32(m,2H),3.66(br.s.,1H),3.32(dd,J=13.1,3.3Hz,1H),3.17(td,J=12.4,3.3Hz,1H),2.71-2.93(m,3H),1.54(d,J=6.8Hz,3H),1.31(s,6H),1.17-1.21(m,6H)。LC-MS:m/z 473.0(M+H)+。
(R)-6-(4-(呋喃-2-羰基)-3-甲基哌嗪-1-基)-8-异丙基-3,3-二甲基-3,4-二氢-1H-吡喃并[3,4-c]吡啶-5-腈(化合物148)。
1H NMRδ7.47-7.57(m,1H),7.05(d,J=3.5Hz,1H),6.47-6.59(m,1H),4.88(br.s.,1H),4.73(s,2H),4.50(d,J=13.1Hz,1H),4.27(d,J=13.8Hz,1H),4.19(d,J=13.3Hz,1H),3.56(br.s.,1H),3.35(dd,J=13.2,3.6Hz,1H),3.18(td,J=12.5,3.4Hz,1H),2.74-2.94(m,3H),1.42-1.54(m,3H),1.30-1.37(m,6H),1.17-1.24(m,6H)。LC-MS:m/z423.1(M+H)+。
(R)-8-异丙基-3,3-二甲基-6-(3-甲基-4-(4-甲基噁唑-5-羰基)哌嗪-1-基)-3,4-二氢-1H-吡喃并[3,4-c]吡啶-5-腈(化合物197)。
1H NMRδ7.94(s,1H),4.72(s,3H),4.12-4.41(m,3H),3.50(br.s.,1H),3.31(dd,J=12.9,3.1Hz,1H),3.15(td,J=12.4,3.0Hz,1H),2.71-2.93(m,3H),2.45(s,3H),1.47(d,J=6.8Hz,3H),1.28-1.38(m,6H),1.20(d,J=6.5Hz,6H)。LC-MS:m/z 438.1(M+H)+。
(R)-8-异丙基-3,3-二甲基-6-(3-甲基-4-(噻唑-4-羰基)哌嗪-1-基)-3,4-二氢-1H-吡喃并[3,4-c]吡啶-5-腈(化合物252)。
1H NMRδ8.82(s,1H),8.01(s,1H),4.96(br.s.,1H),4.72(s,2H),4.56(br.s.,1H),4.19(d,J=13.1Hz,2H),3.64(br.s.,1H),3.38(br.s.,1H),3.19(br.s.,1H),2.71-2.91(m,3H),1.45(d,J=6.8Hz,3H),1.30(s,6H),1.19(d,J=6.5Hz,6H)。LC-MS:m/z440.1(M+H)+。
(R)-6-(4-(2,5-二甲基呋喃-3-羰基)-3-甲基哌嗪-1-基)-8-异丙基-3,3-二甲基-3,4-二氢-1H-吡喃并[3,4-c]吡啶-5-腈(化合物196)。
1H NMRδ5.94(s,1H),4.55-4.84(m,3H),4.12-4.31(m,3H),3.42(br.s.,1H),3.17-3.29(m,1H),2.98-3.11(m,1H),2.73-2.89(m,3H),2.31-2.39(m,3H),2.22-2.30(m,3H),1.35-1.42(m,3H),1.30(s,6H),1.19(d,J=6.8Hz,6H)。LC-MS:m/z 451.2(M+H)+。
(R)-6-(4-(呋喃-2-羰基)-3-苯基哌嗪-1-基)-8-异丙基-3,3-二甲基-3,4-二氢-1H-吡喃并[3,4-c]吡啶-5-腈(化合物200)。
1H NMRδ7.47(s,1H),7.43(d,J=7.5Hz,2H),7.28-7.36(m,2H),7.21-7.26(m,1H),6.98(br.s.,1H),6.46(br.s.,1H),5.92(t,J=4.4Hz,1H),4.70(d,J=6.3Hz,2H),4.55-4.67(m,2H),4.27(d,J=10.0Hz,1H),3.96(dd,J=13.8,4.0Hz,1H),3.48-3.74(m,2H),2.83(dt,J=13.3,6.7Hz,1H),2.76(s,2H),1.30(s,6H),1.21(d,J=6.8Hz,3H),1.17(d,J=6.5Hz,3H)。LC-MS:m/z 485.1(M+H)+。
(R)-6-(4-(2,4-二氯苯甲酰基)-3-甲基哌嗪-1-基)-8-异丙基-3,3-二甲基-3,4-二氢-1H-吡喃并[3,4-c]吡啶-5-腈(化合物166)。
1H NMRδ7.46(dd,J=8.8,1.8Hz,1H),7.32-7.38(m,1H),7.20-7.30(m,1H),5.07(d,J=4.0Hz,0.5H),4.65-4.80(m,2.5H),4.21-4.38(m,1H),4.06-4.21(m,1H),3.68(td,J=12.8,3.3Hz,1H),3.23-3.41(m,2H),3.07-3.23(m,1H),2.75-2.91(m,3H),1.44-1.50(m,1.5H),1.32(s,7.5H),1.21(dt,J=6.7,3.2Hz,6H)。LC-MS:m/z 501.2(M+H)+。
(R)-8-异丙基-3,3-二甲基-6-(3-甲基-4-(2-(吡啶-3-基)乙酰基)哌嗪-1-基)-3,4-二氢-1H-吡喃并[3,4-c]吡啶-5-腈(化合物248)。
1H NMRδ8.48-8.61(m,2H),7.70(br.s.,1H),7.32(dd,J=7.8,5.0Hz,1H),4.89(br.s.,0.5H),4.71(s,2H),4.53(d,J=13.1Hz,0.5H),4.05-4.31(m,2.5H),3.68-3.87(m,2.5H),3.57(t,J=11.3Hz,0.5H),3.17(t,J=13.2Hz,1.5H),2.92-3.09(m,1H),2.71-2.89(m,3H),1.37(d,J=6.0Hz,1.5H),1.30(s,7.5H),1.19(d,J=6.8Hz,6H)。LC-MS:m/z 448.1(M+H)+。
8-异丙基-3,3-二甲基-6-(4-(2-甲基呋喃-3-羰基)-2-苯基哌嗪-1-基)-3,4-二氢-1H-吡喃并[3,4-c]吡啶-5-腈(化合物179)。
1H NMRδ7.71(br.s.,1H),7.39-7.49(m,2H),7.36(d,J=9.3Hz,1H),7.25(br.s.,2H),7.19(d,J=7.5Hz,1H),6.52-6.62(m,1H),5.37(br.s.,1H),4.91-5.16(m,1H),4.59-4.73(m,2H),4.21(br.s.,2H),3.82(br.s.,2H),3.57(br.s.,1H),2.77-2.87(m,2H),2.67-2.77(m,1H),1.29-1.30(m,6H),1.16(d,J=6.5Hz,3H),0.83(br.s.,3H)。LC-MS:m/z 499.1(M+H)+。
(R)-6-(4-(呋喃-3-羰基)-3-苯基哌嗪-1-基)-8-异丙基-3,3-二甲基-3,4-二氢-1H-吡喃并[3,4-c]吡啶-5-腈(化合物256)。
1H NMRδ7.61(br.s.,1H),7.44(br.s.,1H),7.39(br.s.,2H),7.27-7.36(m,3H),6.51(br.s.,1H),5.71-5.79(br.s.,1H),4.45-4.74(m,4H),4.24(d,J=10.8Hz,1H),3.91(d,J=10.3Hz,1H),3.56(d,J=11.8Hz,1H),3.50(d,J=9.8Hz,1H),2.81(dt,J=13.2,6.6Hz,1H),2.75(s,2H),1.29(s,6H),1.19(d,J=6.5Hz,3H),1.13(d,J=5.8Hz,3H)。LC-MS:m/z 485.1(M+H)+。
6-(4-(呋喃-3-羰基)-2-苯基哌嗪-1-基)-8-异丙基-3,3-二甲基-3,4-二氢-1H-吡喃并[3,4-c]吡啶-5-腈(化合物178)。
1H NMRδ7.38-7.54(m,2H),7.22-7.28(m,3H),7.18(d,J=6.5Hz,1H),6.36(d,J=1.5Hz,1H),5.37(br.s.,1H),4.91-5.14(m,1H),4.60-4.73(m,2H),4.05(br.s.,2H),3.79(br.s.,2H),3.58(br.s.,1H),2.77-2.86(m,2H),2.68-2.77(m,1H),2.37(s,3H),1.29-1.31(m,6H),1.17(d,J=6.5Hz,3H),0.89-0.92(m,3H)。LC-MS:m/z 485.1(M+H)+。
(R)-8-异丙基-3,3-二甲基-6-(3-甲基-4-(2-(吡啶-2-基)乙酰基)哌嗪-1-基)-3,4-二氢-1H-吡喃并[3,4-c]吡啶-5-腈(化合物218)。
1H NMRδ8.57(d,J=4.8Hz,1H),7.65-7.76(m,1H),7.40(dd,J=14.4,7.9Hz,1H),7.23(dd,J=6.8,5.3Hz,1H),4.71(s,2H),4.52(br.s.,1H),3.94-4.24(m,5H),3.06-3.27(m,2H),2.95(dd,J=13.1,3.0Hz,1H),2.73-2.90(m,3H),1.29(s,9H),1.18(d,J=6.5Hz,6H)。LC-MS:m/z 448.1(M+H)+。
8-异丙基-3,3-二甲基-6-((3R)-3-甲基-4-(四氢呋喃-3-羰基)哌嗪-1-基)-3,4-二氢-1H-吡喃并[3,4-c]吡啶-5-腈(化合物253)。
1H NMRδ4.90(br.s.,0.5H),4.72(s,2H),4.54(d,J=13.1Hz,0.5H),4.12-4.37(m,2.5H),3.81-4.08(m,4.5H),3.59(q,J=11.5Hz,0.5H),3.12-3.35(m,2.5H),2.95-3.10(m,1H),2.76-2.90(m,3H),2.04-2.25(m,2H),1.39-1.48(m,1.5H),1.30(s,7.5H),1.20(d,J=6.8Hz,6H)。LC-MS:m/z 427.2(M+H)+。
8-异丙基-3,3-二甲基-6-(4-(2-(苯硫-2-基)乙酰基)哌嗪-1-基)-3,4-二氢-1H-吡喃并[3,4-c]吡啶-5-腈(化合物145)。
1H NMR(氯仿-d)δ7.24(d,J=5.0Hz,1H),6.99(dd,J=5.3,3.5Hz,1H),6.95(br.s.,1H),4.73(s,2H),3.98(s,2H),3.83(br.s.,2H),3.68(d,J=18.3Hz,4H),3.60(d,J=4.8Hz,2H),2.75-2.90(m,3H),1.32(s,6H),1.21(d,J=6.5Hz,6H)。LC-MS:m/z 439.2(M+H)+。
6-(4-(呋喃-2-羰基)哌嗪-1-基)-8-异丙基-3,3-二甲基-3,4-二氢-1H-吡喃并[3,4-c]吡啶-5-腈(化合物145)。
1H NMRδ7.48-7.57(m,1H),7.07(d,J=3.5Hz,1H),6.52(dd,J=3.5,1.8Hz,1H),4.74(s,2H),3.99(br.s.,4H),3.69-3.85(m,4H),2.77-2.96(m,3H),1.32(s,6H),1.22(d,J=6.5Hz,6H)。LC-MS:m/z 409.1(M+H)+。
(S)-6-(4-(呋喃-2-羰基)-2-甲基哌嗪-1-基)-8-异丙基-3,3-二甲基-3,4-二氢-1H-吡喃并[3,4-c]吡啶-5-腈(化合物202)。
1H NMRδ7.51(s,1H),7.07(dd,J=3.4,0.6Hz,1H),6.51(dd,J=3.5,1.8Hz,1H),4.72(s,2H),4.60(br.s.,1H),4.47(d,J=11.3Hz,1H),4.29(dt,J=13.2,1.4Hz,1H),4.07(d,J=13.1Hz,1H),3.51(t,J=10.8Hz,2H),2.84(dt,J=13.3,6.7Hz,1H),2.79(s,2H),2.20-2.25(m,1H),1.31(s,6H),1.20(d,J=2.5Hz,3H),1.18(d,J=2.5Hz,3H)。LC-MS:m/z 423.2(M+H)+。
(R)-8-环己基-6-(4-(呋喃-3-羰基)-3-甲基哌嗪-1-基)-3,3-二甲基-3,4-二氢-1H-吡喃并[3,4-c]吡啶-5-腈(化合物151)。
1H NMRδ7.69-7.83(m,1H),7.39-7.52(m,1H),6.59(dd,J=1.8,0.8Hz,1H),4.73(s,3H),4.13-4.42(m,3H),3.50(d,J=6.8Hz,1H),3.25(dd,J=13.2,3.4Hz,1H),3.08(td,J=12.5,3.5Hz,1H),2.80(s,2H),2.46(tt,J=11.2,3.6Hz,1H),1.82-1.90(m,2H),1.56-1.79(m,6H),1.43-1.48(m,3H),1.29-1.39(m,8H)。LC-MS:m/z 463.1(M+H)+。
8-环己基-6-(4-(呋喃-3-羰基)-3-甲基哌嗪-1-基)-3,3-二甲基-3,4-二氢-1H-吡喃并[3,4-c]吡啶-5-腈(化合物169)。
1H NMRδ7.76(s,1H),7.41-7.52(m,1H),6.60(d,J=1.3Hz,1H),4.73(s,3H),4.13-4.43(m,3H),3.51(br.s.,1H),3.25(dd,J=12.8,3.0Hz,1H),3.09(td,J=12.5,3.4Hz,1H),2.75-2.85(m,2H),2.46(tt,J=11.1,3.7Hz,1H),1.86(d,J=12.8Hz,2H),1.59-1.73(m,6H),1.45(d,J=6.8Hz,3H),1.29-1.40(m,8H)。LC-MS:m/z 463.2(M+H)+。
(R)-8-环己基-6-(4-(3-甲氧基丙酰基)-3-甲基哌嗪-1-基)-3,3-二甲基-3,4-二氢-1H-吡喃并[3,4-c]吡啶-5-腈(化合物312)。
1H NMRδ4.90(br.s.,0.5H),4.71(s,2H),4.53(d,J=12.5Hz,0.5H),4.04-4.33(m,2.5H),3.68-3.84(m,2.5H),3.49-3.64(m,0.5H),3.38(s,3H),2.99-3.27(m,2.5H),2.64-2.84(m,3H),2.52-2.62(m,1H),2.44(tt,J=11.0,3.5Hz,1H),1.84(d,J=12.8Hz,2H),1.75(d,J=10.5Hz,1H),1.60-1.68(m,4H),1.38(d,J=6.8Hz,3H),1.29(s,9H)。LC-MS:m/z 455.1(M+H)+。
(R)-8-环己基-3,3-二甲基-6-(3-甲基-4-(2-(苯硫-2-基)乙酰基)哌嗪-1-基)-3,4-二氢-1H-吡喃并[3,4-c]吡啶-5-腈(化合物153)。
1H NMRδ7.19-7.26(m,1H),6.87-7.04(m,2H),4.94(br.s.,0.5H),4.72(s,2H),4.57(d,J=12.8Hz,0.5H),4.09-4.34(m,2.5H),3.88-3.99(m,2H),3.79(d,J=12.0Hz,0.5H),3.51-3.67(m,0.5H),3.11-3.31(m,1.5H),2.91-3.08(m,1H),2.79(s,2H),2.45(tt,J=11.1,3.6Hz,1H),1.86(d,J=12.8Hz,2H),1.77(d,J=10.3Hz,1H),1.54-1.72(m,6H),1.30-1.36(m,10H)。LC-MS:m/z493.1(M+H)+。
8-环己基-6-(4-(呋喃-3-羰基)-3-苯基哌嗪-1-基)-3,3-二甲基-3,4-二氢-1H-吡喃并[3,4-c]吡啶-5-腈(化合物143)。
1H NMRδ7.64(br.s.,1H),7.39-7.47(m,3H),7.36(t,J=7.7Hz,2H),7.25-7.32(m,1H),6.53(br.s.,1H),5.76(br.s.,1H),4.45-4.75(m,4H),4.25(d,J=11.3Hz,1H),3.90(d,J=13.8Hz,1H),3.39-3.66(m,2H),2.71-2.81(m,2H),2.44(t,J=11.0Hz,1H),1.74-1.91(m,3H),1.67(d,J=8.5Hz,2H),1.29-1.43(m,11H)。LC-MS:m/z525.0(M+H)+。
(R)-8-环己基-6-(4-(呋喃-2-羰基)-3-甲基哌嗪-1-基)-3,3-二甲基-3,4-二氢-1H-吡喃并[3,4-c]吡啶-5-腈(化合物150)。
1H NMRδ7.52(s,1H),7.05(d,J=3.3Hz,1H),6.46-6.63(m,1H),4.89(br.s.,1H),4.73(s,2H),4.50(d,J=13.1Hz,1H),4.26(d,J=13.3Hz,1H),4.18(d,J=13.1Hz,1H),3.56(br.s.,1H),3.34(dd,J=12.8,3.0Hz,1H),3.12-3.24(m,1H),2.80(s,2H),2.37-2.55(m,1H),1.86(d,J=11.8Hz,2H),1.56-1.77(m,6H),1.48(d,J=6.5Hz,3H),1.34-1.42(m,2H),1.32(s,6H)。LC-MS:m/z463.1(M+H)+。
8-环己基-6-(4-(呋喃-2-羰基)-3-甲基哌嗪-1-基)-3,3-二甲基-3,4-二氢-1H-吡喃并[3,4-c]吡啶-5-腈(化合物168)。
1H NMRδ7.45-7.58(m,1H),7.04(d,J=3.5Hz,1H),6.50(dd,J=3.3,1.8Hz,1H),4.87(br.s.,1H),4.71(s,2H),4.49(d,J=13.8Hz,1H),4.25(d,J=13.8Hz,1H),4.17(dd,J=13.1,2.0Hz,1H),3.54(br.s.,1H),3.32(dd,J=13.1,3.8Hz,1H),3.16(td,J=12.4,3.5Hz,1H),2.79(s,2H),2.45(tt,J=11.0,3.8Hz,1H),1.79-1.91(m,3H),1.54-1.79(m,5H),1.43-1.52(m,3H),1.27-1.36(m,8H)。LC-MS:m/z 463.2(M+H)+。
8-环己基-6-(4-(呋喃-2-羰基)哌嗪-1-基)-3,3-二甲基-3,4-二氢-1H-吡喃并[3,4-c]吡啶-5-腈(化合物117)。
1H NMRδ7.53(dd,J=1.6,0.9Hz,1H),7.07(dd,J=3.4,0.6Hz,1H),6.52(dd,J=3.5,1.8Hz,1H),4.73(s,2H),3.99(br.s.,4H),3.61-3.80(m,4H),2.81(s,2H),2.39-2.53(m,1H),1.82-1.90(m,2H),1.55-1.80(m,6H),1.34-1.45(m,2H),1.30-1.33(m,6H)。LC-MS:m/z 448.9(M+H)+。
8-(3-氟苯基)-6-(4-(呋喃-3-羰基)-3-甲基哌嗪-1-基)-3,3-二甲基-3,4-二氢-1H-吡喃并[3,4-c]吡啶-5-腈(化合物130)。
1H NMRδ7.73-7.84(m,1H),7.39-7.54(m,2H),7.13-7.26(m,3H),6.53-6.66(m,1H),4.75(br.s.,1H),4.68(s,2H),4.18–4.41(m,3H),3.52(br.s.,1H),3.30(dd,J=12.9,3.6Hz,1H),3.12(td,J=12.5,3.4Hz,1H),2.90(s,2H),1.44-1.53(m,3H),1.37(s,6H)。LC-MS:m/z 475.1(M+H)+。
(R)-8-环丁基-6-(4-(呋喃-3-羰基)-3-异丙基哌嗪-1-基)-3,3-二甲基-3,4-二氢-1H-吡喃并[3,4-c]吡啶-5-腈(化合物288)。
1H NMRδ7.72(br.s.,1H),7.44-7.51(m,1H),6.52-6.61(m,1H),4.46-4.70(m,4H),4.31(br.s.,1H),4.04(br.s.,0.5H),3.81(br.s.,0.5H),3.57(br.s.,0.5H),3.46(quin,J=8.2Hz,1H),3.03-3.26(m,2H),2.71-2.83(m,2H),2.32-2.46(m,2H),2.21-2.31(m,3H),1.98-2.12(m,1H),1.84-1.95(m,1H),1.29(d,J=2.0Hz,6H),0.99-1.14(m,2H),0.85-0.99(m,4H)。LC-MS:m/z 463.2(M+H)+。
(R)-8-环丁基-6-(3-异丙基-4-(2-(苯硫-2-基)乙酰基)哌嗪-1-基)-3,3-二甲基-3,4-二氢-1H-吡喃并[3,4-c]吡啶-5-腈(化合物289)。
1H NMRδ7.20(d,J=5.0Hz,1H),6.88-7.01(m,2H),4.41-4.65(m,4H),4.19-4.35(m,1H),3.83-4.07(m,2.5H),3.38-3.61(m,2H),2.87-3.17(m,2.5H),2.68-2.83(m,2H),2.30-2.48(m,2H),2.19-2.29(m,2H),1.98-2.16(m,1H),1.23-1.30(m,6H),0.99-1.11(m,3H),0.85(dd,J=19.6,6.8Hz,3H)。LC-MS:m/z 493.2(M+H)+。
8-环戊基-6-((3S,5R)-4-(呋喃-3-羰基)-3,5-二甲基哌嗪-1-基)-3,3-二甲基-3,4-二氢-1H-吡喃并[3,4-c]吡啶-5-腈(化合物146)。
1H NMRδ7.70-7.80(m,1H),7.47(t,J=1.6Hz,1H),6.64(dd,J=1.8,0.8Hz,1H),4.75(s,4H),4.22(d,J=13.1Hz,2H),3.16(dd,J=13.1,4.3Hz,2H),2.93-3.08(m,1H),2.81(s,2H),1.89-1.98(m,2H),1.80-1.87(m,3H),1.54(d,J=7.0Hz,6H),1.33(s,6H),1.26-1.31(m,3H)。LC-MS:m/z 463.1(M+H)+。
8-环戊基-6-(4-(呋喃-2-羰基)-3-甲基哌嗪-1-基)-3,3-二甲基-3,4-二氢-1H-吡喃并[3,4-c]吡啶-5-腈(化合物147)。
1H NMRδ7.47-7.58(m,1H),7.01-7.10(m,1H),6.51(dd,J=3.3,1.8Hz,1H),4.88(br.s.,1H),4.74(s,2H),4.49(d,J=13.3Hz,1H),4.24(d,J=13.8Hz,1H),4.11-4.18(m,1H),3.55(br.s.,1H),3.32(dd,J=13.1,3.8Hz,1H),3.16(td,J=12.4,3.5Hz,1H),2.95-3.05(m,1H),2.80(s,2H),1.87-1.96(m,2H),1.77-1.86(m,4H),1.63-1.74(m,2H),1.44-1.51(m,3H),1.30-1.36(m,6H)。LC-MS:m/z 449.1(M+H)+。
(R)-8-乙基-6-(4-(呋喃-3-羰基)-3-异丙基哌嗪-1-基)-3,3-二甲基-3,4-二氢-1H-吡喃并[3,4-c]吡啶-5-腈(化合物414)。
1H NMR(DMSO-d6)δ7.72(br.s.,1H),7.39-7.55(m,1H),6.55(s,1H),4.45-4.74(m,4H),4.27(br.s.,1H),4.02(d,J=12.0Hz,0.5H),3.55(br.s.,1H),3.12(dd,J=13.4,3.4Hz,2.5H),2.71-2.82(m,2H),2.55(q,J=7.5Hz,2H),2.11-2.39(m,1H),1.27-1.32(m,6H),1.23(t,J=7.4Hz,3H),1.06(br.s.,2H),0.82-0.98(m,4H)。LC-MS:m/z 437.3(M+H)+。
(R)-8-乙基-6-(3-异丙基-4-(3-甲氧基丙酰基)哌嗪-1-基)-3,3-二甲基-3,4-二氢-1H-吡喃并[3,4-c]吡啶-5-腈(化合物413)。
1H NMRδ4.61-4.75(m,2.5H),4.52(d,J=13.3Hz,1H),4.44(d,J=10.3Hz,0.5H),4.25-4.36(m,1H),3.79-3.89(m,0.5H),3.69-3.78(m,2H),3.56(d,J=9.8Hz,0.5H),3.41-3.52(m,0.5H),3.34-3.40(m,3H),2.92-3.18(m,2.5H),2.51-2.81(m,6H),2.03-2.32(m,1H),1.31(d,J=2.0Hz,6H),1.25(t,J=7.4Hz,3H),1.04(d,J=6.5Hz,3H),0.90(d,J=6.8Hz,1.5H),0.84(d,J=6.8Hz,1.5H)。
(S)-乙基4-(5-氰基-8-环丙基-3,3-二甲基-3,4-二氢-1H-吡喃并[3,4-c]吡啶-6-基)-1-(呋喃-3-羰基)哌嗪-2-羧酸酯(化合物411)。
1H NMRδ7.79(br.s.,1H),7.46(s,1H),6.63(br.s.,1H),5.39(br.s.,0.5H),4.80(br.s.,0.5H),4.72(d,J=3.5Hz,2H),4.21(dq,J=10.7,7.1Hz,2H),4.01-4.15(m,2H),3.93(br.s.,1H),3.40(d,J=11.8Hz,1H),3.03-3.18(m,1H),2.76-2.89(m,3H),1.11-1.34(m,15H)。LC-MS:m/z 481.4(M+H)+。
(R)-乙基4-(5-氰基-8-环丙基-3,3-二甲基-3,4-二氢-1H-吡喃并[3,4-c]吡啶-6-基)-1-(呋喃-3-羰基)哌嗪-2-羧酸酯(化合物410)。
1H NMRδ7.79(br.s.,1H),7.46(s,1H),6.63(br.s.,1H),5.39(br.s.,0.5H),4.80(br.s.,0.5H),4.72(d,J=3.5Hz,2H),4.21(dq,J=10.7,7.1Hz,2H),4.01-4.15(m,2H),3.93(br.s.,1H),3.40(d,J=11.8Hz,1H),3.03-3.18(m,1H),2.76-2.89(m,3H),1.11-1.34(m,15H)。LC-MS:m/z 481.2(M+H)+。
8-环丙基-6-(3-(甲氧基甲基)-4-(3-甲氧基丙酰基)哌嗪-1-基)-3,3-二甲基-3,4-二氢-1H-吡喃并[3,4-c]吡啶-5-腈(化合物403)。
1H NMRδ4.91(s,0.5H),4.83(s,2H),4.56(d,J=13.6Hz,0.5H),4.18(d,J=13.3Hz,2H),4.07(d,J=11.0Hz,1H),3.58-3.84(m,5H),3.54(d,J=6.5Hz,1H),3.33-3.41(m,4H),3.30(s,3H),2.99-3.20(m,2H),2.94(d,J=11.0Hz,1H),1.62-1.76(m,1H),1.31(s,6H),1.13(br.s.,2H),0.94-1.08(m,2H)。LC-MS:m/z 443.2(M+H)+。
8-环丙基-6-(4-(呋喃-3-羰基)-3-(甲氧基甲基)哌嗪-1-基)-3,3-二甲基-3,4-二氢-1H-吡喃并[3,4-c]吡啶-5-腈(化合物402)。
1H NMRδ7.82(br.s.,1H),7.43(t,J=1.5Hz,1H),6.65(br.s.,1H),4.84(s,2H),4.07(d,J=12.5Hz,3H),3.77(br.s.,1H),3.59-3.73(m,1H),3.35(s,4H),3.01(td,J=12.5,3.3Hz,2H),2.68-2.84(m,3H),1.70(td,J=8.2,3.9Hz,1H),1.27-1.37(m,6H),1.08-1.17(m,2H),0.95-1.08(m,2H)。LC-MS:m/z 451.1(M+H)+。
(R)-8-环丁基-6-(3-异丙基-4-(3-甲氧基丙酰基)哌嗪-1-基)-3,3-二甲基-3,4-二氢-1H-吡喃并[3,4-c]吡啶-5-腈(化合物395)。
1H NMRδ4.50-4.75(m,3.5H),4.39-4.50(m,0.5H),4.24-4.37(m,1H),3.84(d,J=13.6Hz,0.5H),3.68-3.79(m,2H),3.53-3.62(m,0.5H),3.40-3.52(m,1.5H),3.37(d,J=3.3Hz,3H),2.95-3.22(m,2.5H),2.53-2.83(m,4H),2.32-2.48(m,2H),2.19-2.31(m,2H),1.99-2.19(m,2H),1.85-1.96(m,1H),1.29(d,J=2.5Hz,6H),1.00-1.11(m,3H),0.87-0.94(m,1.5H),0.80-0.87(m,1.5H)。LC-MS:m/z 455.4(M+H)+。
4-(5-氰基-8-环丙基-3,3-二甲基-3,4-二氢-1H-吡喃并[3,4-c]吡啶-6-基)-1-(2-甲基呋喃-3-羰基)哌嗪-2-羧酸甲酯(化合物394)。
1H NMRδ7.17-7.37(m,2H),6.43(br.s.,0.5H),5.40(br.s.,0.5H),4.83(s,2H),4.67(d,J=13.1Hz,1H),4.05(d,J=11.0Hz,1H),3.84-3.98(m,1H),3.81(d,J=13.8Hz,1H),3.72(s,3H),3.27(d,J=11.5Hz,1H),2.90-3.07(m,1H),2.77(s,2H),2.43(br.s.,3H),1.64-1.79(m,1H),1.31(d,J=2.8Hz,6H),1.14(dd,J=8.0,3.8Hz,2H),0.92-1.08(m,2H)。LC-MS:m/z 479.4(M+H)+。
4-(5-氰基-8-异丙基-3,3-二甲基-3,4-二氢-1H-吡喃并[3,4-c]吡啶-6-基)-1-(呋喃-3-羰基)哌嗪-2-羧酸甲酯(化合物393)。
1H NMRδ7.80(br.s.,1H),7.46(s,1H),6.64(br.s.,1H),5.42(br.s.,1H),4.64-4.86(m,3H),4.19(d,J=10.3Hz,2H),3.73(s,3H),3.38(d,J=11.3Hz,1H),3.06-3.22(m,2H),2.70-2.92(m,3H),1.24-1.34(m,6H),1.20(d,J=6.5Hz,6H)。LC-MS:m/z467.4(M+H)+。
实例7.根据方案2,步骤E2产生的另外的具有化学式I的化合物。
使用适当的吡喃并吡啶和经取代的哌嗪中间体,按照与使用方案2的步骤E2制备的化合物等效的方式制备本发明的以下化合物。
(R)-6-(4-(2-氯乙酰基)-3-甲基哌嗪-1-基)-8-环己基-3,4-二氢-1H-吡喃并[3,4-c]吡啶-5-腈(化合物340)。
1H NMRδ4.82(br.s.,1H),4.70(s,2H),4.23(d,J=19.3Hz,2H),3.99-4.18(m,3H),3.90-3.97(m,2H),3.59-3.80(m,1H),3.08-3.30(m,2H),2.93(t,J=5.6Hz,2H),2.37-2.48(m,1H),1.84(d,J=12.5Hz,2H),1.75(d,J=10.5Hz,1H),1.69(br.s.,1H),1.55-1.64(m,3H),1.46(d,J=6.0Hz,1H),1.35-1.41(m,1H),1.32(d,J=7.8Hz,3H),1.27-1.29(m,1H)。LC-MS:m/z 417.0(M+H)+。
(R)-8-环己基-6-(3-甲基-4-丙酰基哌嗪-1-基)-3,4-二氢-1H-吡喃并[3,4-c]吡啶-5-腈(化合物363)。
1H NMRδ4.88(br.s.,0.5H),4.65-4.75(m,2H),4.50(d,J=13.1Hz,0.5H),4.06-4.29(m,2.5H),3.88-3.99(m,2H),3.52-3.78(m,1H),3.00-3.29(m,2.5H),2.93(t,J=5.8Hz,2H),2.33-2.48(m,1H),2.10-2.18(m,3H),1.79-1.89(m,2H),1.55-1.76(m,5H),1.35-1.41(m,2H),1.24-1.34(m,6H)。LC-MS:m/z 397.2(M+H)+。
(R)-8-环己基-6-(4-(环丙烷羰基)-3-甲基哌嗪-1-基)-3,4-二氢-1H-吡喃并[3,4-c]吡啶-5-腈(化合物375)。
1H NMRδ4.70(s,2H),4.45(d,J=11.8Hz,1H),4.24(br.s.,1H),4.05-4.21(m,2H),3.89-3.98(m,2H),3.56-3.81(m,1H),3.39(d,J=10.5Hz,1H),3.21(br.s.,1H),3.00-3.16(m,1H),2.86-2.97(m,2H),2.41(tt,J=11.1,3.6Hz,1H),1.80-1.89(m,2H),1.54-1.79(m,6H),1.40-1.45(m,1H),1.27-1.38(m,4H),0.95-1.08(m,2H),0.73-0.85(m,2H)。LC-MS:m/z 409.2(M+H)+。
8-环己基-6-(4-(2-苯乙酰基)哌嗪-1-基)-3,4-二氢-1H-吡喃并[3,4-c]吡啶-5-腈(化合物131)。
1H NMRδ7.32-7.39(m,2H),7.24-7.32(m,3H),4.71(s,2H),3.94(t,J=5.8Hz,2H),3.77-3.86(m,4H),3.57-3.67(m,4H),3.46-3.53(m,2H),2.92(t,J=5.6Hz,2H),2.42(tt,J=11.1,3.5Hz,1H),1.85(d,J=12.5Hz,2H),1.76(d,J=14.8Hz,2H),1.61-1.69(m,2H),1.58(d,J=12.0Hz,1H),1.24-1.42(m,3H)。LC-MS:m/z 445.1(M+H)+。
(R)-8-环己基-6-(4-(3-甲氧基丙酰基)-3-甲基哌嗪-1-基)-3,4-二氢-1H-吡喃并[3,4-c]吡啶-5-腈(化合物341)。
1H NMRδ5.27-5.53(m,1H),4.70(s,3H),4.23(br.s.,4H),4.16(br.s.,2H),3.93(t,J=5.4Hz,1H),3.48(br.s.,3H),3.24(br.s.,1H),3.08(br.s.,1H),2.93(t,J=5.4Hz,2H),2.42(br.s.,1H),1.84(d,J=11.0Hz,2H),1.75(d,J=10.0Hz,1H),1.66(br.s.,4H),1.30-1.39(m,6H)。LC-MS:m/z 413.2(M+H)+。
(R)-6-(4-乙酰基-3-甲基哌嗪-1-基)-8-环己基-3,4-二氢-1H-吡喃并[3,4-c]吡啶-5-腈(化合物362)。
1H NMRδ4.81-4.96(m,0.5H),4.66-4.75(m,2H),4.50(d,J=13.6Hz,0.5H),4.06-4.33(m,2.5H),3.87-4.03(m,2H),3.51-3.79(m,1H),2.96-3.23(m,2.5H),2.86-2.95(m,2H),2.41(tt,J=11.1,3.6Hz,1H),2.14(d,J=9.5Hz,3H),1.80-1.89(m,2H),1.54-1.75(m,5H),1.32-1.41(m,3H),1.25-1.31(m,3H)。LC-MS:m/z 383.2(M+H)+。
8-环己基-6-(4-(环丙烷羰基)哌嗪-1-基)-3,4-二氢-1H-吡喃并[3,4-c]吡啶-5-腈(化合物141)。
1H NMRδ4.71(s,2H),9.95(t,J=5.8Hz,2H),3.85(br.s.,2H),3.80(br.s.,2H),3.73(br.s.,2H),3.66(br.s.,2H),2.94(t,J=5.6Hz,2H),2.43(tt,J=11.1,3.7Hz,1H),1.73-1.90(m,3H),1.55-1.72(m,4H),1.23-1.43(m,4H),1.00-1.07(m,2H),0.76-0.84(m,2H)。LC-MS:m/z 395.2(M+H)+。
(R)-6-(4-丁酰基-3-甲基哌嗪-1-基)-8-环己基-3,4-二氢-1H-吡喃并[3,4-c]吡啶-5-腈(化合物379)。
1H NMRδ4.89(br.s.,1H),4.70(s,2H),4.12-4.25(m,2H),3.89-3.98(m,2H),3.74(d,J=12.8Hz,1H),2.98-3.28(m,2H),2.88-2.97(m,2H),2.20-2.48(m,3H),1.80-1.88(m,2H),1.60-1.77(m,6H),1.26-1.42(m,6H),0.99(t,J=7.4Hz,3H)。LC-MS:m/z411.2(M+H)+。
(R)-6-(4-(环丙烷羰基)-3-异丙基哌嗪-1-基)-8-环丙基-3,3-二甲基-3,4-二氢-1H-吡喃并[3,4-c]吡啶-5-腈(化合物376)。
1H NMRδ4.83(s,2H),4.60(d,J=908Hz,1H),4.28-4.49(m,1H),4.04-4.28(m,1H),3.84(d,J=9.8Hz,1H),3.12(td,J=13.2,3.0Hz,1H),2.91-3.05(m,2H),2.77(s,2H),2.12-2.29(m,1H),1.64-1.82(m,2H),1.32(d,J=2.3Hz,6H),1.06-1.19(m,2H),0.96-1.05(m,8H),0.87-0.94(m,2H),0.71-0.84(m,2H)。LC-MS:m/z 423.2(M+H)+。
(R)-8-环丙基-6-(3-异丙基-4-丙酰基哌嗪-1-基)-3,3-二甲基-3,4-二氢-1H-吡喃并[3,4-c]吡啶-5-腈(化合物354)。
1H NMRδ4.83(s,2H),4.40(d,J=10.3Hz,1H),4.33(d,j=13.1Hz,1H),4.10-4.24(m,1H),3.73(d,J=13.3Hz,1H),3.28-3.58(m,1H),2.84-3.10(m,2H),2.76(s,2H),2.40(d,J=7.3Hz,1H),1.70(td,J=7.9,4.0Hz,2H),1.31(d,J=2.3Hz,6H),1.18(t,J=7.3Hz,3H),0.93-1.06(m,6H),0.64-0.92(m,4H)。LC-MS:m/z 411.2(M+H)+。
(R)-6-(4-丁酰基-3-异丙基哌嗪1-基)-8-环丙基-3,3-二甲基异色满-5-腈(化合物383)。
1H NMRδ4.76-4.89(m,2H),4.64-4.67(m,0.5H),4.41(d,J=10.5Hz,0.5H),4.33(dd,J=13.3,1.8Hz,1H),4.14-4.24(m,1H),3.74(d,J=13.6Hz,0.5H),3.36-3.55(m,1H),2.90-3.07(m,2.5H),2.76(s,2H),2.29-2.43(m,2.5H),2.08-2.20(m,0.5H),1.64-1.76(m,3H),1.31(d,J=2.5Hz,6H),0.95-1.18(m,10H),0.87(d,J=6.8Hz,1.5H),0.81(d,J=6.8Hz,1.5H)。LC-MS:m/z425.3(M+H)+。
(R)-6-(4-乙酰基-3-异丙基哌嗪1-基)-8-环丙基-3,3-二甲基异色满-5-腈(化合物352)。
1H NMRδ4.83(s,2H),4.38(d,J=10.3Hz,1H),4.32(d,J=13.3Hz,1H),4.03-4.25(m,1H),3.69(d,J=13.3Hz,1H),3.35-3.58(m,1H),2.86-3.12(m,2H),2.76(s,2H),2.24(d,J=7.3Hz,1H),2.09-2.18(m,3H),1.67-1.76(m,1H),1.31(d,J=2.5Hz,6H),0.94-1.06(m,6H),0.86-0.94(m,2H),0.83(d,J=6.8Hz,2H)。LC-MS:m/z 397.2(M+H)+。
8-异丙基-3,3-二甲基-6-(4-(2-苯乙酰基)哌嗪-1-基)-3,4-二氢-1H-吡喃并[3,4-c]吡啶-5-腈(化合物144)。
1H NMRδ7.33-7.39(m,2H),7.26-7.31(m,3H),4.72(s,2H),3.77-3.86(m,4H),3.57-3.68(m,4H),3.43-3.54(m,2H),2.74-2.92(m,3H),1.31(s,6H),1.19(d,J=6.8Hz,6H)。LC-MS:m/z 433.2(M+H)+。
(R)-8-环己基-3,3-二甲基-6-(3-甲基-4-(2-苯乙酰基)哌嗪-1-基)-3,4-二氢-1H-吡喃并[3,4-c]吡啶-5-腈(化合物152)。
1H NMRδ7.23-7.42(m,5H),4.95(br.s.,0.5H),4.71(s,2H),4.59(d,J=13.3Hz,0.5H),4.20-4.23(m,1H),4.08-4.23(m,1.5H),3.80(br.s.,2H),3.72(d,J=13.6Hz,0.5H),3.48(t,J=10.9Hz,0.5H),3.13-3.21(m,1H),2.92-3.08(m,1H),2.86(t,J=11.2Hz,0.5H),2.77(s,2H),2.39-2.53(m,1H),1.85(d,J=12.3Hz,2H),1.54-1.63(m,6H),1.29-1.43(m,11H)。LC-MS:m/z 487.1(M+H)+。
(R)-3-(4-(5-氰基-8-环丙基-3,3-二甲基-3,4-二氢-1H-吡喃并[3,4-c]吡啶-6-基)-2-异丙基哌嗪-1-基)-2,2-二甲基-3-氧代丙基乙酸酯(化合物419)。
1H NMRδ4.83(s,2H),4.31-4.45(m,2H),4.16-4.27(m,3H),4.09(d,J=8.5Hz,1H),3.40(br.s.,1H),2.90-3.08(m,2H),2.76(s,2H),2.12-2.28(m,1H),2.03-2.10(m,3H),1.67-1.76(m,1H),1.33(dd,J=11.7,1.4Hz,12H),1.07-1.18(m,2H),0.97-1.06(m,5H),0.82(d,J=6.8Hz,3H)。LC-MS:m/z 497.5(M+H)+。
(R)-甲基4-(4-(5-氰基-8-环丙基-3,3-二甲基-3,4-二氢-1H-吡喃并[3,4-c]吡啶-6-基)-2-异丙基哌嗪-1-基)-4-氧代丁酸酯(化合物412)。
1H NMRδ4.78-4.91(m,2H),4.62-4.65(m,0.5H),4.29-4.44(m,1.5H),4.10-4.26(m,1H),3.79(d,J=13.8Hz,0.5H),3.68-3.74(m,3H),3.40-3.58(m,1H),2.91-3.15(m,2.5H),2.78(s,2H),2.64-2.74(m,4H),2.07-2.34(m,1H),1.69-1.76(m,1H),1.33(d,J=2.5Hz,6H),1.07-1.20(m,2H),0.99-1.06(m,5H),0.89-0.95(m,1.5H),0.82(d,J=7.0Hz,1.5H)。LC-MS:m/z 469.4(M+H)+。
(R)-4-(4-(5-氰基-8-环丙基-3,3-二甲基-3,4-二氢-1H-吡喃并[3,4-c]吡啶-6-基)-2-异丙基哌嗪-1-基)-4-氧代丁酸(化合物416)。
标题化合物制备自化合物412的LiOH/methanol-H2O水解。1H NMR(甲醇-d4.)δ4.80-4.92(m,2H),4.50-4.53(m,0.5H),4.23-4.45(m,1.5H),4.10-4.22(m,1H),3.97(d,J=14.1Hz,0.5H),3.42-3.55(m,0.5H),2.91-3.20(m,2.5H),2.58-2.87(m,6H),2.07-2.32(m,1H),1.81-1.92(m,1H),1.26-1.38(m,6H),1.09-1.17(m,2H),1.02-1.09(m,3H),1.00(d,J=6.5Hz,2H),0.92(d,J=6.8Hz,1H),0.82(d,J=6.8Hz,2H)。LC-MS:m/z 455.4(M+H)+。
(R)-甲基3-(4-(5-氰基-8-环丙基-3,3-二甲基-3,4-二氢-1H-吡喃并[3,4-c]吡啶-6-基)-2-异丙基哌嗪-1-基)-3-氧代丙酸酯(化合物409)。
1H NMRδ4.75-4.90(m,2H),4.63-4.68(m,0.5H),4.29-4.44(m,1.5H),4.11-4.27(m,1H),3.71-3.83(m,3H),3.42-3.67(m,4H),2.93-3.15(m,2H),2.71-2.84(m,2H),2.06-2.33(m,1H),1.66-1.78(m,1H),1.32(d,J=2.5Hz,6H),1.06-1.18(m,2H),0.97-1.05(m,5H),0.81-0.94(m,3H)。LC-MS:m/z 455.3(M+H)+。
(R)-3-(4-(5-氰基-8-环丙基-3,3-二甲基-3,4-二氢-1H-吡喃并[3,4-c]吡啶-6-基)-2-异丙基哌嗪-1-基)-3-氧代丙酸(化合物418)。
标题化合物制备自化合物409的LiOH/甲醇-H2O水解。1H NMR(甲醇-d4)δ4.82-4.90(m,2H),4.25-4.46(m,2H),4.10-4.25(m,1H),3.85(d,J=14.1Hz,1H),3.39-3.65(m,2H),2.93-3.22(m,3H),2.78(s,2H),2.09-2.21(m,1H),1.82-1.90(m,1H),1.32(s,6H),0.97-1.17(m,7H),0.84-0.94(m,3H)。LC-MS:m/z 441.5(M+H)+。
(R)-8-环丁基-6-(4-(环丙烷羰基)-3-乙磺酰-1-基)-3,3-二甲基-3,4-二氢-1H-吡喃并[3,4-c]吡啶-5-腈(化合物396)。
1H NMRδ4.52-4.69(m,3.5H),4.26-4.49(m,1.5H),4.16(d,J=12.5Hz,0.5H),3.90(d,J=10.0Hz,0.5H),3.37-3.66(m,2H),2.99-3.29(m,2.5H),2.70-2.83(m,2H),2.37(dt,J=19.6,10.1Hz,2H),2.20-2.31(m,2.5H),1.98-2.11(m,1H),1.84-1.96(m,1H),1.73-1.83(m,1H),1.29(d,J=2.3Hz,6H),0.89-1.11(m,7H),0.77-0.87(m,3H)。LC-MS:m/z 437.3(M+H)+。
实例8.根据方案2,步骤E3产生的另外的具有化学式I的化合物。
使用适当的吡喃并吡啶和经取代的哌嗪中间体,按照与使用方案2的步骤E3制备的化合物等效的方式制备本发明的以下化合物。
(R)-8-环丙基-6-(3-异丙基-4-(2-(甲氧基(甲基)氨基)乙酰基)哌嗪-1-基)-3,3-二甲基异色满-5-腈(化合物338)。
1H NMRδ4.77-4.89(m,2H),4.51-4.68(m,0.5H),4.28-4.43(m,1.5H),4.21(d,J=11.0Hz,1H),4.00(d,J=13.6Hz,0.5H),3.66-3.83(m,1H),3.52-3.64(m,3.5H),3.38-3.50(m,1H),2.91-3.21(m,2.5H),2.73-2.80(m,2H),2.64-2.71(m,2H),1.97-2.29(m,2H),1.67-1.75(m,1H),1.31(d,J=2.0Hz,6H),0.98-1.20(m,7H),0.81-0.91(m,3H)。LC-MS:m/z 456.1(M+H)+。
(R)-6-(4-(2-(1H-咪唑-1-基)乙酰基)-3-异丙基哌嗪-1-基)-8-环丙基-3,3-二甲基-3,4-二氢-1H-吡喃并[3,4-c]吡啶-5-腈(化合物374)。
1H NMRδ7.83(d,J=10.0Hz,1H),7.12(s,1H),7.04(s,1H),5.06(dd,J=16.3,7.8Hz,1H),4.86-4.97(m,1H),4.79-4.85(m,2H),4.53-4.56(m,0.5H),4.26-4.41(m,1.5H),4.12-4.24(m,1H),3.70(d,J=13.3Hz,0.5H),3.40-3.58(m,1H),2.95-3.16(m,2.5H),2.76(s,2H),2.09-2.27(m,1H),1.67-1.75(m,1H),1.31(d,J=2.8Hz,6H),0.90-1.19(m,8.5H),0.82(d,J=6.8Hz,1.5H)。LC-MS:m/z 463.2(M+H)+。
(R)-8-环丙基-6-(3-异丙基-4-(2-(2-甲基-1H-咪唑-1-基)乙酰基)哌嗪-1-基)-3,3-二甲基-3,4-二氢-1H-吡喃并[3,4-c]吡啶-5-腈(化合物380)。
1H NMRδ6.93-7.16(m,1H),6.86(s,1H),4.73-5.03(m,4H),4.12-4.42(m,3H),3.82(br.s.,0.5H),3.50-3.65(m,1H),2.95-3.19(m,2.5H),2.68-2.82(m,2H),2.32-2.43(m,3H),2.12-2.25(m,1H),1.67-1.78(m,1H),1.32(d,J=2.8Hz,6H),1.07-1.19(m,3.5H),0.92-1.05(m,5H),0.82(d,J=6.8Hz,1.5H)。LC-MS:m/z 477.3(M+H)+。
(R)-6-(4-(2-(1H-1,2,4-三唑-1-基)乙酰基)-3-异丙基哌嗪-1-基)-8-环丙基-3,3-二甲基-3,4-二氢-1H-吡喃并[3,4-c]吡啶-5-腈(化合物324)。
1H NMRδ8.28(br.s.,1H),7.98(br.s.,1H),4.99-5.22(m,2H),4.75-4.92(m,2H),4.57(d,J=12.8Hz,0.5H),4.26-4.44(m,1.5H),4.19(dd,J=19.1,13.3Hz,1H),3.79(d,J=13.3Hz,0.5H),3.45-3.65(m,1H),2.92-3.16(m,2.5H),2.70-2.85(m,2H),2.11-2.41(m,1H),1.67-1.80(m,1H),1.32(d,J=2.8Hz,6H),0.90-1.19(m,8.5H),0.82(d,J=6.5Hz,1.5H)。LC-MS:m/z 464.0(M+H)+。
实例9.根据方案2,步骤E4产生的另外的具有化学式I的化合物。
使用适当的吡喃并吡啶和经取代的哌嗪中间体,按照与使用方案2的步骤E4制备的化合物等效的方式制备本发明的以下化合物。
(R)-8-环丙基-6-(4-(2-(2-羟基乙氧基)乙酰基)-3-异丙基哌嗪-1-基)-3,3-二甲基异色满-5-腈(化合物348)。
1H NMRδ4.78-4.90(m,2H),4.58-4.60(m,0.5H),4.11-4.41(m,4.5H),3.73(dd,J=18.6,4.3Hz,4H),3.60(d,J=13.6Hz,1H),3.35-3.52(m,0.5H),3.27-3.29(m,0.5H),2.92-3.10(m,2H),2.76(s,2H),2.22-2.35(m,0.5H),2.13(dt,J=10.8,6.5Hz,0.5H),1.66-1.75(m,1H),1.32(d,J=2.8Hz,6H),0.97-1.18(m,7H),0.88-0.92(m,1.5H),0.84(d,J=6.8Hz,1.5H)。LC-MS:m/z 457.3(M+H)+。
实例10.根据方案2,步骤E5产生的另外的具有化学式I的化合物。
使用适当的吡喃并吡啶和经取代的哌嗪中间体,按照与使用方案2的步骤E5制备的化合物等效的方式制备本发明的以下化合物。
(R)-8-环丙基-6-(3-异丙基-4-(2-(丙-2-炔基氨基)乙酰基)哌嗪-1-基)-3,3-二甲基-3,4-二氢-1H-吡喃并[3,4-c]吡啶-5-腈(化合物373)。
1H NMRδ4.76-4.90(m,2H),4.61(d,J=10.3Hz,0.5H),4.27-4.42(m,1.5H),4.09-4.23(m,1H),3.34-3.70(m,6H),2.93-3.11(m,3H),2.76(s,2H),2.20-2.33(m,2H),1.67-1.75(m,1H),1.31(d,J=2.3Hz,6H),1.07-1.17(m,2H),0.98-1.05(m,5H),0.88-0.92(m,1.5H),0.83(d,J=6.8Hz,1.5H)。LC-MS:m/z 450.4(M+H)+。
实例11.根据方案2,步骤E6产生的另外的具有化学式I的化合物。
使用适当的吡喃并吡啶和经取代的哌嗪中间体,按照与使用方案2的步骤E6制备的化合物等效的方式制备本发明的以下化合物。
(R)-8-环丙基-6-(4-(2-乙氧基乙酰基)-3-异丙基哌嗪-1-基)-3,3-二甲基异色满-5-腈(化合物345)。
1H NMRδ4.75-4.90(m,2H),4.54-4.57(m,0.5H),4.25-4.41(m,2H),4.05-4.23(m,2.5H),3.87(d,J=13.6Hz,0.5H),3.58(q,J=6.9Hz,2H),3.42(t,J=11.7Hz,1H),2.90-3.11(m,2.5H),2.76(s,2H),2.07-2.33(m,1H),1.66-1.75(m,1H),1.31(d,J=2.0Hz,6H),1.20-1.28(m,3H),0.97-1.19(m,7H),0.79-0.93(m,3H)。LC-MS:m/z 441.3(M+H)+。
(R)-8-环丙基-6-(4-(2-(环丙基甲氧基)乙酰基)-3-异丙基哌嗪-1-基)-3,3-二甲基异色满-5-腈(化合物390)。
1H NMRδ4.77-4.89(m,2H),4.53-4.56(m,0.5H),4.28-4.41(m,2H),4.10-4.28(m,2.5H),3.89(d,J=13.6Hz,0.5H),3.58-3.60(m,0.5H),3.31-3.49(m,2.5H),2.92-3.12(m,2.5H),2.70-2.84(m,2H),2.10-2.31(m,1H),1.65-1.77(m,1H),1.31(d,J=2.0Hz,6H),0.95-1.17(m,8H),0.79-0.92(m,3H),0.50-0.64(m,2H),0.18-0.31(m,2H)。LC-MS:m/z467.4(M+H)+。
(R)-8-环丙基-6-(3-异丙基-4-(2-丙氧基乙酰基)哌嗪-1-基)-3,3-二甲基异色满-5-腈(化合物381)。
1H NMRδ4.76-4.89(m,2H),4.54-4.56(m,0.5H),4.25-4.40(m,2H),4.04-4.24(m,2.5H),3.89(d,J=13.6Hz,0.5H),3.36-3.62(m,3H),2.89-3.10(m,2.5H),2.72-2.81(m,2H),2.08-2.30(m,1H),1.60-1.70(m,3H),1.31(d,J=2.5Hz,6H),1.05-1.18(m,2H),0.98-1.04(m,5H),0.91-0.97(m,3H),0.82-0.90(m,3H)。LC-MS:m/z 455.4(M+H)+。
8-环丙基-6-((3R)-3-异丙基-4-(2-(四氢呋喃-3-基氧基)乙酰基)哌嗪-1-基)-3,3-二甲基-3,4-二氢-1H-吡喃并[3,4-c]吡啶-5-腈(化合物417)。
1H NMRδ4.79-4.91(m,2H),4.55-4.57(m,0.5H),4.11-4.40(m,5.5H),3.76-3.97(m,4.5H),3.44(t,J=12.5Hz,1H),2.92-3.14(m,2.5H),2.73-2.82(m,2H),2.13-2.31(m,1H),2.00-2.11(m,2H),1.68-1.78(m,1H),1.33(d,J=2.5Hz,6H),1.08-1.19(m,2H),0.98-1.07(m,5H),0.83-0.95(m,3H)。LC-MS:m/z 483.5(M+H)+。
(R)-8-环丙基-6-(4-(2-(呋喃-2-基甲氧基)乙酰基)-3异丙基哌嗪-1-基)-3,3-二甲基-3,4-二氢-1H-吡喃并[3,4-c]吡啶-5-腈(化合物404)。
1H NMRδ7.43(s,1H),6.30-6.49(m,2H),4.76-4.91(m,2H),4.48-4.67(m,2.5H),4.08-4.38(m,4.5H),3.76(d,J=13.3Hz,0.5H),3.30-3.58(m,1H),2.87-3.16(m,2.5H),2.67-2.84(m,2H),2.07-2.33(m,1H),1.62-1.79(m,1H),1.31(d,J=1.5Hz,6H),1.06-1.18(m,2H),0.93-1.06(m,5H),0.80-0.90(m,3H)。LC-MS:m/z 493.4(M+H)+。
(R)-8-环丙基-6-(4-(2-(3-氟苯氧基)乙酰基)-3-异丙基哌嗪-1-基)-3,3-二甲基异色满-5-腈(化合物384)。
1H NMRδ7.11-7.26(m,1H),6.66-6.77(m,2.5H),6.56-6.65(m,0.5H),4.83(s,2H),4.67-4.78(m,2H),4.53-4.57(m,0.5H),4.26-4.40(m,1.5H),4.07-4.25(m,1H),3.89(d,J=13.6Hz,0.5H),3.51-3.60(m,0.5H),3.42-3.49(m,0.5H),2.86-3.14(m,2.5H),2.76(s,2H),2.05-2.23(m,1H),1.64-1.78(m,1H),1.31(d,J=3.5Hz,6H),0.95-1.18(m,7H),0.83-0.95(m,1.5H),0.76(d,J=6.8Hz,1.5H)。LC-MS:m/z 507.4(M+H)+。
(R)-8-环丙基-6-(3-异丙基-4-(2-(吡啶-3-基氧基)乙酰基)哌嗪-1-基)-3,3-二甲基-3,4-二氢-1H-吡喃并[3,4-c]吡啶-5-腈(化合物399)。
1H NMRδ8.38(br.s.,1H),8.28(br.s.,1H),7.19-7.46(m,2H),4.72-4.98(m,4H),4.54-4.57(m,0.5H),4.26-4.42(m,1.5H),4.12-4.25(m,1H),3.85(d,J=13.3Hz,0.5H),3.45-3.62(m,1H),2.90-3.17(m,2.5H),2.72-2.82(m,2H),2.09-2.35(m,1H),1.66-1.76(m,1H),1.32(d,J=3.8Hz,6H),0.91-1.19(m,8.5H),0.76(d,J=6.8Hz,1.5H)。LC-MS:m/z 490.4(M+H)+。
(R)-6-(4-(2-(4-溴代-1H-吡唑-1-基)乙酰基)-3-异丙基哌嗪-1-基)-8-环丙基-3,3-二甲基-3,4-二氢-1H-吡喃并[3,4-c]吡啶-5-腈(化合物415)。
1H NMRδ7.60(d,J=7.8Hz,1H),7.51(s,1H),4.90-5.13(m,2H),4.80-4.90(m,2H),4.56-4.59(m,0.5H),4.27-4.40(m,1.5H),4.18(d,J=12.8Hz,1H),3.82(d,J=13.3Hz,0.5H),3.41-3.63(m,1H),2.89-3.12(m,2.5H),2.78(s,2H),2.08-2.34(m,1H),1.65-1.81(m,1H),1.33(d,J=3.0Hz,6H),0.96-1.19(m,7H),0.88-0.95(m,1.5H),0.82(d,J=6.8Hz,1.5H)。LC-MS:m/z 541.2(M+H)+。
(R)-6-(4-(2-(1H-1,2,3-三唑-1-基)乙酰基)-3-异丙基哌嗪-1-基)-8-环丙基-3,3-二甲基-3,4-二氢-1H-吡喃并[3,4-c]吡啶-5-腈(化合物408)。
1H NMRδ7.70-7.87(m,2H),5.19-5.47(m,2H),4.76-4.91(m,2H),4.55-4.58(m,0.5H),4.26-4.43(m,1.5H),4.18(t,J=13.1Hz,1H),3.84(d,J=13.6Hz,0.5H),3.43-3.67(m,1H),2.90-3.16(m,2.5H),2.77(s,2H),2.16(td,J=6.8,3.5Hz,1H),1.67-1.78(m,1H),1.32(d,J=2.5Hz,6H),0.97-1.19(m,7H),0.89-0.96(m,1.5H),0.80(d,J=6.8Hz,1.5H)。LC-MS:m/z 464.4(M+H)+。
(R)-6-(4-(2-(2H-1,2,3-三唑-2-基)乙酰基)-3-异丙基哌嗪-1-基)-8-环丙基-3,3-二甲基-3,4-二氢-1H-吡喃并[3,4-c]吡啶-5-腈(化合物407)。
1H NMRδ7.62-7.74(m,2H),5.32-5.50(m,2H),4.75-4.91(m,2H),4.56–4.59(m,0.5H),4.32(t,J=11.3Hz,1.5H),4.17(d,J=10.8Hz,1H),3.69(d,J=13.8Hz,0.5H),3.35-3.58(m,1H),2.92-3.14(m,2.5H),2.70-2.83(m,2H),2.08-2.26(m,1H),1.71(dd,J=7.5,4.5Hz,1H),1.31(d,J=2.8Hz,6H),0.94-1.18(m,8.5H),0.78-0.91(m,1.5H)。LC-MS:m/z 464.4(M+H)+。
(R)-6-(4-(2-(1H-吲哚-1-基)乙酰基)-3-异丙基哌嗪-1-基)-8-环丙基-3,3-二甲基-3,4-二氢-1H-吡喃并[3,4-c]吡啶-5-腈(化合物406)。
1H NMRδ7.62(d,J=7.8Hz,1H),7.17-7.30(m,2H),7.05-7.14(m,2H),6.57(br.s.,1H),4.85-5.00(m,2H),4.81(br.s.,2H),4.57(d,J=10.0Hz,0.5H),4.34(d,J=10.0Hz,0.5H),4.23(dd,J=18.9,13.7Hz,1H),4.13(d,J=12.5Hz,0.5H),4.03(d,J=12.5Hz,0.5H),3.63(d,J=13.6Hz,0.5H),3.31-3.52(m,1H),2.89-3.08(m,1.5H),2.62-2.86(m,3H),2.06-2.32(m,1H),1.66-1.75(m,1H),1.30(d,J=3.5Hz,6H),0.91-1.16(m,8.5H),0.82(d,J=6.8Hz,1.5H)。LC-MS:m/z 512.4(M+H)+。
(R)-8-环丙基-6-(3-异丙基-4-(2-(4-甲基-1H-吡唑-1-基)乙酰基)哌嗪-1-基)-3,3-二甲基-3,4-二氢-1H-吡喃并[3,4-c]吡啶-5-腈(化合物401)。
1H NMRδ7.30-7.38(m,2H),4.79-5.11(m,4H),4.55-4.58(m,0.5H),4.23-4.39(m,1.5H),4.15(dd,J=9.9,7.7Hz,1H),3.87(d,J=13.6Hz,0.5H),3.58-4.61(m,0.5H),3.35-3.52(m,0.5H),2.83-3.12(m,2.5H),2.71-2.82(m,2H),2.04-2.15(m,4H),1.66-1.75(m,1H),1.31(d,J=2.8Hz,6H),0.96-1.16(m,7H),0.85-0.93(m,1.5H),0.80(d,J=6.8Hz,1.5H)。LC-MS:m/z 477.5(M+H)+。
(R)-8-环丙基-6-(3-异丙基-4-(2-(3-甲基-1H-吡唑-1-基)乙酰基)哌嗪-1-基)-3,3-二甲基-3,4-二氢-1H-吡喃并[3,4-c]吡啶-5-腈(化合物400)。
1H NMRδ7.42(dd,J=7.0,2.3Hz,1H),6.10(t,J=2.5Hz,1H),4.76–5.15(m,3H),4.55–4.58(m,0.5H),4.29(t,J=14.3Hz,1.5H),4.14(t,J=10.3Hz,1H),3.85(d,J=13.6Hz,0.5H),3.56-3.58(m,0.5H),3.33-3.50(m,0.5H),2.83-3.12(m,2.5H),2.69-2.81(m,2H),2.26-2.35(m,3H),2.08-2.25(m,1H),1.65-1.75(m,1H),1.31(d,J=2.8Hz,6H),0.94-1.20(m,7H),0.88(d,J=6.8Hz,1.5H),0.81(d,J=6.8Hz,1.5H)。LC-MS:m/z477.5(M+H)+。
实例11.根据方案2,步骤F1产生的另外的具有化学式I的化合物。
使用适当的吡喃并吡啶和经取代的哌嗪中间体,按照与使用方案2的步骤F1制备的化合物等效的方式制备本发明的以下化合物。
2-乙基-1-(2-甲氧基乙基)4-(5-氰基-8-环己基-3,4-二氢-1H-吡喃并[3,4-c]吡啶-6-基)-哌嗪-1,2-二羧酸酯(化合物315)。
1H NMRδ4.68-4.91(m,4H),4.06-4.34(m,6H),3.87-4.00(m,2H),3.58-3.69(m,3H),3.37-3.45(m,4H),3.09(t,J=12.5Hz,1H),2.93(t,J=5.6Hz,2H),2.38-2.48(m,1H),1.86(d,J=11.5Hz,2H),1.77(d,J=9.0Hz,1H),1.63-1.70(m,3H),1.29-1.44(m,4H),1.20(t,J=7.2Hz,3H)。LC-MS:m/z501.0(M+H)+。
(R)-乙基4-(5-氰基-8-环己基-3,4-二氢-1H-吡喃并[3,4-c]吡啶-6-基)-2-甲基哌嗪-2-羧酸酯(化合物358)。
1H NMRδ4.69(s,2H),4.41(br.s.,1H),4.08-4.25(m,4H),4.01(d,J=13.3Hz,1H),3.93(td,J=5.8,1.0Hz,2H),3.18-3.40(m,2H),3.05(td,J=12.4,3.5Hz,1H),2.92(t,J=5.6Hz,2H),2.35-2.46(m,1H),1.79-1.89(m,2H),1.75(d,J=10.3Hz,1H),1.54-1.70(m,4H),1.31-1.41(m,2H),1.30(d,J=3.0Hz,3H),1.27-1.29(m,3H),1.23-1.26(m,1H)。LC-MS:m/z 413.3(M+H)+。
(R)-丙基4-(5-氰基-8-环己基-3,4-二氢-1H-吡喃并[3,4-c]吡啶-6-基)-2-甲基哌嗪-2-羧酸酯(化合物359)。
1H NMRδ4.69(s,2H),4.41(br.s.,1H),3.97-4.25(m,5H),3.88-3.96(m,2H),3.20-3.41(m,2H),3.06(td,J=12.4,3.8Hz,1H),2.92(t,J=5.6Hz,2H),2.41(tt,J=10.9,3.9Hz,1H),1.84(d,J=12.8Hz,2H),1.71-1.77(m,1H),1.53-1.71(m,6H),1.26-1.41(m,6H),0.97(t,J=7.4Hz,3H)。LC-MS:m/z 427.3(M+H)+。
(R)-苄基4-(5-氰基-8-环己基-3,4-二氢-1H-吡喃并[3,4-c]吡啶-6-基)-2-甲基哌嗪-2-羧酸酯(化合物343)。
1H NMRδ7.30-7.43(m,6H),5.11-5.22(m,2H),4.63-4.73(m,2H),4.45(br.s.,1H),4.09-4.27(m,2H),4.04(d,J=13.3Hz,1H),3.93(td,J=5.8,1.0Hz,2H),3.36(td,J=12.7,3.3Hz,1H),3.25(dd,J=13.1,3.8Hz,1H),3.05(td,J=12.4,3.5Hz,1H),2.91(t,J=5.8Hz,2H),2.33-2.49(m,1H),1.78-1.88(m,2H),1.74(d,J=10.5Hz,1H),1.48-1.70(m,6H),1.25-1.40(m,7H)。LC-MS:m/z 475.3(M+H)+。
4-甲氧苯基4-(5-氰基-8-异丙基-3,4-二氢-1H-吡喃并[3,4-c]吡啶-6基)哌嗪-1-羧酸酯(化合物103)。
1H NMRδ7.04-7.16(m,2H),6.86-6.98(m,2H),4.74(s,2H),3.92-4.03(m,2H),3.82(s,5H),3.69-3.79(m,6H),2.97(t,J=5.6Hz,2H),2.84(dt,J=13.3,6.7Hz,1H),1.22(d,J=6.5Hz,6H)。LC-MS:m/z 437.3(M+H)+。
(R)-2-甲氧基乙基4-(5-氰基-8-环丙基-3,3-二甲基异色满-6-基)-2-异丙基-哌嗪-1-羧酸酯(化合物307)。
1H NMRδ4.74-4.90(m,2H),4.20-4.33(m,3H),4.14(d,J=12.0Hz,2H),3.85(br.s.,1H),3.55-3.65(m,2H),3.39(s,3H),3.20(d,J=6.3Hz,1H),2.97-3.11(m,2H),2.76(s,2H),2.12(dt,J=10.4,6.6Hz,1H),1.68-1.74(m,1H),1.31(d,J=2.3Hz,6H),0.94-1.17(m,7H),0.86(d,J=6.8Hz,3H)。LC-MS:m/z 457.0(M+H)+。
(R)-乙基4-(5-氰基-8-环丙基-3,3-二甲基异色满-6-基)-2-异丙基-哌嗪-1-羧酸酯(化合物367)。
1H NMRδ4.77-4.88(m,2H),4.29(d,J=13.3Hz,1H),4.14(d,J=13.3Hz,4H),3.83(br.s.,1H),3.11-3.24(m,1H),2.95-3.10(m,2H),2.72-2.81(m,2H),2.11(dq,J=17.1,6.7Hz,1H),1.65-1.73(m,1H),1.31(d,J=2.5Hz,6H),1.27(t,J=7.0Hz,3H),1.05-1.17(m,2H),0.94-1.04(m,5H),0.83-0.88(m,3H)。LC-MS:m/z 427.2(M+H)+。
(R)-丙基4-(5-氰基-8-环丙基-3,3-二甲基异色满-6-基)-2-异丙基哌嗪-1-羧酸酯(化合物371)。
1H NMRδ4.77-4.89(m,2H),4.29(d,J=13.1Hz,1H),4.01-4.16(m,4H),3.82(br.s.,1H),3.10-3.26(m,1H),2.93-3.10(m,2H),2.73-2.81(m,2H),2.07-2.18(m,1H),1.62-1.74(m,3H),1.31(d,J=2.5Hz,6H),1.05-1.19(m,2H),0.93-1.03(m,8H),0.82-0.89(m,3H)。LC-MS:m/z 441.3(M+H)+。
(R)-4-甲氧苯基4-(5-氰基-8-环丙基-3,3-二甲基-3,4-二氢-1H-吡喃并[3,4-c]-吡啶-6-基)-2-异丙基哌嗪-1-羧酸酯(化合物337)。
1H NMRδ6.98-7.05(m,2H),6.84-6.91(m,2H),4.78-4.89(m,2H),4.35(d,J=13.6Hz,1H),4.20(d,J=11.8Hz,2H),3.91-4.03(m,1H),3.80(s,3H),3.40(dt,J=12.9,6.7Hz,1H),3.15(d,J=12.8Hz,2H),2.77(s,2H),2.18-2.27(m,1H),1.68-1.77(m,1H),1.32(d,J=2.5Hz,6H),1.09-1.22(m,2H),0.92-1.06(m,8H)。LC-MS:m/z 505.0(M+H)+。
(R)-异丁基4-(5-氰基-8-环丙基-3,3-二甲基-3,4-二氢-1H-吡喃并[3,4-c]吡啶-6-基)-2-异丙基-哌嗪-1-羧酸酯(化合物339)。
1H NMRδ4.76-4.90(m,2H),4.30(d,J=13.3Hz,1H),4.15(d,J=12.5Hz,2H),3.78-3.97(m,3H),3.17(d,J=11.5Hz,1H),2.97-3.10(m,2H),2.76(s,2H),2.12(dt,J=10.3,6.7Hz,1H),1.95(dt,J=13.3,6.7Hz,1H),1.66-1.74(m,1H),1.31(d,J=2.3Hz,6H),1.07-1.18(m,2H),0.92-1.03(m,11H),0.86(d,J=6.8Hz,3H)。LC-MS:m/z 455.0(M+H)+。
2-乙基1-甲基4-(5-氰基-8-异丙基-3,3-二甲基-3,4-二氢-1H-吡喃并[3,4-c]吡啶-6-基)哌嗪-1,2-二羧酸酯(化合物333)。
1H NMRδ4.87(br.s.,1H),4.68-4.84(m,3H),4.12-4.29(m,2H),3.92-4.12(m,2H),3.69-3.82(m,3H),3.48-3.68(m,1H),3.35(td,J=13.6,4.3Hz,1H),3.00-3.14(m,1H),2.75-2.88(m,3H),1.29(d,J=3.5Hz,6H),1.19(td,J=7.0,4.0Hz,9H)。LC-MS:m/z 477.1(M+H)+。
2-乙基1-(2-甲氧基乙基)4-(5-氰基-8-异丙基-3,3-二甲基-3,4-二氢-1H-吡喃并[3,4-c]吡啶-6-基)哌嗪-1,2-二羧酸酯(化合物329)。
1H NMRδ4.73-4.88(m,2H),4.71(d,J=3.8Hz,2H),4.14-4.39(m,4H),3.97-4.13(m,2H),3.50-3.69(m,3H),3.42(s,1.5H),3.31-3.37(m,1.5H),3.08(t,J=12.2Hz,1H),2.75-2.91(m,3H),1.24-1.36(m,9H),1.13-1.23(m,6H)。LC-MS:m/z 489.0(M+H)+。
2-乙基1-丙基4-(5-氰基-8-异丙基-3,3-二甲基-3,4-二氢-1H-吡喃并[3,4-c]吡啶-6-基)哌嗪-1,2-二羧酸酯(化合物364)。
1H NMRδ4.72-4.92(m,2H),4.71(d,J=3.5Hz,2H),4.00-4.27(m,6H),3.60(d,J=13.1Hz,1H),3.28-3.47(m,1H),3.08(d,J=11.5Hz,1H),2.80-2.88(m,1H),2.75-2.80(m,2H),1.62-1.75(m,2H),1.29(d,J=4.0Hz,7H),1.14-1.22(m,10H)。LC-MS:m/z 473.3(M+H)+。
实例12.根据方案2,步骤F2产生的另外的具有化学式I的化合物。
使用适当的吡喃并吡啶和经取代的哌嗪中间体,按照与使用方案2的步骤F2制备的化合物等效的方式制备本发明的以下化合物。
(R)-环丙基甲基4-(5-氰基-8-环丙基-3,3-二甲基-3,4-二氢-1H-吡喃并[3,4-c]-吡啶-6-基)-2-异丙基哌嗪-1-羧酸酯(化合物370)。
1H NMRδ4.75-4.91(m,2H),4.30(d,J=12.5Hz,1H),4.07-4.21(m,2H),3.80-3.98(m,3H),3.18(br.s.,1H),2.96-3.10(m,2H),2.76(s,2H),2.11(dt,J=10.4,6.5Hz,1H),1.67-1.73(m,1H),1.31(d,J=2.5Hz,6H),1.07-1.20(m,3H),0.94-1.05(m,5H),0.87(d,J=6.8Hz,3H),0.50-0.63(m,2H),0.28(q,J=4.7Hz,2H)。LC-MS:m/z 453.4(M+H)+。
实例13.根据方案2,步骤G1产生的另外的具有化学式I的化合物。
使用适当的吡喃并吡啶和经取代的哌嗪中间体,按照与使用方案2的步骤G1制备的化合物等效的方式制备本发明的以下化合物。
4-(4-氰基-1-异丙基-5,6,7,8-四氢异喹啉-3-基)-N-环己基哌嗪-1-羧酰胺(化合物115)。
1H NMRδ4.32(d,J=7.5Hz,1H),3.67-3.75(m,1H),3.61-3.67(m,4H),3.49-3.55(m,4H),3.17(quin,J=6.7Hz,1H),2.89(d,J=6.3Hz,2H),2.64(d,J=6.0Hz,2H),1.93-2.04(m,2H),1.79-1.85(m,4H),1.61-1.76(m,4H),1.33-1.47(m,2H),1.19(d,J=6.8Hz,6H),1.08-1.17(m,2H)。LC-MS:m/z410.0(M+H)+。
(2S,6R)-4-(4-氰基-1-异丙基-5,6,7,8-四氢异喹啉-3-基)-N-环己基-2,6-二甲基哌嗪-1-羧酰胺(化合物109)。
1H NMRδ4.29(d,J=6.8Hz,1H),4.17(d,J=12.5Hz,4H),3.74(br.s.,1H),3.07-3.27(m,3H),2.89(br.s.,2H),2.66(br.s.,2H),2.00(d,J=10.5Hz,2H),1.71(br.s.,7H),1.34-1.49(m,8H),1.08-1.26(m,9H)。LC-MS:m/z 438.0(M+H)+。
(R)-4-(5-氰基-8-环己基-3,4-二氢-1H-吡喃并[3,4-c]吡啶-6-基)-N-(4-氟苯基)-2-甲基哌嗪-1-羧酰胺(化合物281)。
1H NMRδ7.30-7.36(m,2H),6.97-7.02(m,2H),6.40(s,1H),4.70(s,2H),4.36(dt,J=6.5,3.2Hz,1H),4.13-4.31(m,2H),3.85-4.01(m,3H),3.31-3.51(m,2H),3.17(td,J=12.3,3.5Hz,1H),2.93(t,J=5.6Hz,2H),2.42(tt,J=11.1,3.7Hz,1H),1.80-1.88(m,2H),1.76(d,J=10.8Hz,1H),1.65-1.71(m,2H),1.53-1.62(m,2H),1.37(d,J=6.5Hz,3H),1.26-1.35(m,3H)。LC-MS:m/z 478.2(M+H)+。
1-(烯丙基氨基甲酰基)-4-(5-氰基-8-环己基-3,4-二氢-1H-吡喃并[3,4-c]吡啶-6-基)-哌嗪-2-羧酸乙酯(化合物330)。
1H NMRδ5.90(ddt,J=17.1,10.5,5.4Hz,1H),5.23(dq,J=17.1,1.6Hz,1H),5.14(dd,J=10.3,1.3Hz,1H),4.99(dd,J=4.0,2.3Hz,1H),4.79(dt,J=13.6,2.0Hz,1H),4.65-4.74(m,3H),4.22-4.30(m,1H),3.86-4.19(m,6H),3.64-3.75(m,1H),3.50-3.60(m,1H),3.37(dd,J=13.4,4.4Hz,1H),3.09-3.20(m,1H),2.91(t,J=5.8Hz,2H),2.35-2.45(m,1H),1.84(d,J=12.0Hz,2H),1.75(d,J=9.5Hz,1H),1.64-1.72(m,2H),1.54-1.60(m,1H),1.28-1.41(m,4H),1.17(t,J=7.2Hz,3H)。LC-MS:m/z 482.4(M+H)+。
(R)-4-(5-氰基-8-环己基-3,4-二氢-1H-吡喃并[3,4-c]吡啶-6-基)-N-乙基-2-甲基哌嗪-1-羧酰胺(化合物335)。
1H NMRδ4.69(s,2H),4.16-4.27(m,2H),4.12(d,J=12.8Hz,1H),3.88-3.97(m,2H),3.81(d,J=12.5Hz,1H),3.28-3.41(m,4H),3.15(br.s.,1H),2.92(t,J=5.6Hz,2H),2.40(tt,J=11.1,3.5Hz,1H),1.84(d,J=12.5Hz,2H),1.75(d,J=10.3Hz,1H),1.68(br.s.,1H),1.53-1.62(m,2H),1.27-1.37(m,7H),1.15-1.19(m,3H)。LC-MS:m/z412.2(M+H)+。
(R)-N-烯丙基-4-(5-氰基-8-环己基-3,4-二氢-1H-吡喃并[3,4-c]吡啶-6-基)-2-甲基哌嗪-1-羧酰胺(化合物334)。
1H NMRδ5.91(ddt,J=17.1,10.4,5.6Hz,1H),5.09-5.25(m,2H),4.69(s,2H),4.51(br.s.,1H),4.17-4.26(m,2H),4.13(d,J=13.1Hz,1H),3.89-3.98(m,4H),3.78-3.89(m,1H),3.28-3.39(m,2H),3.04-3.22(m,1H),2.92(t,J=5.8Hz,2H),2.40(tt,J=11.1,3.7Hz,1H),1.84(d,J=12.5Hz,2H),1.75(d,J=10.3Hz,1H),1.63-1.70(m,3H),1.52-1.63(m,2H),1.32-1.42(m,2H),1.30(d,J=6.8Hz,3H)。LC-MS:m/z 424.3(M+H)+。
(R)-4-(5-氰基-8-环己基-3,4-二氢-1H-吡喃并[3,4-c]吡啶-6-基)-N-(2-氟苯基)-2-甲基哌嗪-1-羧酰胺(化合物300)。
1H NMRδ8.07-8.16(m,1H),6.93-7.16(m,3H),6.63(d,J=3.8Hz,1H),4.70(s,2H),4.33-4.44(m,1H),4.27(d,J=13.3Hz,1H),4.17(d,J=13.1Hz,1H),3.88-4.03(m,3H),3.35-3.54(m,2H),3.13-3.27(m,1H),2.93(t,J=5.6Hz,2H),2.34-2.49(m,1H),1.85(d,J=12.5Hz,2H),1.76(d,J=10.0Hz,1H),1.54-1.64(m,3H),1.40(d,J=6.5Hz,3H),1.27-1.38(m,4H)。LC-MS:m/z 477.9(M+H)+。
(R)-4-(5-氰基-8-环己基-3,4-二氢-1H-吡喃并[3,4-c]吡啶-6-基)-2-甲基-N-对甲苯基哌嗪-1-羧酰胺(化合物280)。
1H NMRδ7.25(s,1H),7.10(d,J=8.3Hz,2H),6.34(br.s.,1H),4.70(s,2H),4.36(dd,J=6.4,3.1Hz,1H),4.11-4.31(m,2H),3.87-4.02(m,3H),3.31-3.51(m,2H),3.17(td,J=12.2,3.5Hz,1H),2.93(t,J=5.8Hz,2H),2.41(tt,J=11.1,3.6Hz,1H),2.30(s,3H),1.84(d,J=12.8Hz,2H),1.75(d,J=10.3Hz,1H),1.64-1.71(m,3H),1.54-1.60(m,1H),1.36(d,J=6.5Hz,3H),1.26-1.34(m,3H)。LC-MS:m/z 474.2(M+H)+。
(R)-4-(5-氰基-8-环己基-3,4-二氢-1H-吡喃并[3,4-c]吡啶-6-基)-2-甲基-N-邻甲苯基哌嗪-1-羧酰胺(化合物279)。
1H NMRδ7.09-7.22(m,2H),6.87(d,J=7.3Hz,1H),6.32(s,1H),4.70(s,2H),4.37(dt,J=6.5,3.2Hz,1H),4.14-4.31(m,2H),3.93(td,J=5.8,1.3Hz,3H),3.33-3.51(m,2H),3.18(td,J=12.3,3.8Hz,1H),2.93(t,J=5.8Hz,2H),2.37-2.47(m,1H),2.33(s,3H),1.85(d,J=12.5Hz,2H),1.76(d,J=10.3Hz,1H),1.60-1.72(m,4H),1.37(d,J=6.8Hz,3H),1.26-1.35(m,3H)。LC-MS:m/z 474.2(M+H)+。
(R)-4-(5-氰基-8-环己基-3,4-二氢-1H-吡喃并[3,4-c]吡啶-6-基)-N-(4-甲氧苯基)-2-甲基哌嗪-1-羧酰胺(化合物299)。
1H NMRδ7.27(br.s.,1H),7.25(br.s.,1H),6.85(d,J=8.8Hz,2H),6.35(br.s.,1H),4.70(s,2H),4.35(br.s.,1H),4.10-4.31(m,2H),3.87-4.00(m,3H),3.79(s,3H),3.31-3.50(m,2H),3.18(br.s.,1H),2.93(t,J=5.6Hz,2H),2.37-2.46(m,1H),1.84(d,J=12.5Hz,2H),1.75(d,J=10.3Hz,1H),1.69(br.s.,1H),1.54-1.63(m,2H),1.36(d,J=6.5Hz,3H),1.26-1.35(m,4H)。LC-MS:m/z490.0(M+H)+。
(2S,6R)-4-(5-氰基-8-环戊基-3,4-二氢-1H-吡喃并[3,4-c]吡啶-6-基)-N-环己基-2,6-二甲基哌嗪-1-羧酰胺(化合物127)。
1H NMRδ4.72(s,2H),4.31(d,J=7.8Hz,1H),4.14-4.28(m,4H),3.95(t,J=5.6Hz,2H),3.72(dtd,J=10.7,7.1,3.6Hz,1H),3.15(dd,J=12.7,4.1Hz,2H),2.89-3.02(m,3H),1.94-2.04(m,2H),1.77-1.93(m,7H),1.60-1.76(m,5H),1.40(d,J=6.8Hz,7H),1.09-1.23(m,3H)。LC-MS:m/z 466.2(M+H)+。
4-(5-氰基-8-异丙基-3,4-二氢-1H-吡喃并[3,4-c]吡啶-6-基)-N-环己基-2,6-二甲基哌嗪-1-羧酰胺(化合物108)。
1H NMRδ4.67-4.75(m,2H),4.28(d,J=12.8Hz,3H),4.13-4.23(m,2H),3.94(t,J=5.6Hz,2H),3.63-3.84(m,1H),3.17(dd,J=12.7,4.1Hz,2H),2.93(t,J=5.5Hz,2H),2.81(dt,J=13.4,6.7Hz,1H),1.90-2.05(m,3H),1.67-1.76(m,3H),1.34-1.43(m,8H),1.15-1.23(m,8H).。LC-MS:m/z 439.9(M+H)+。
4-(5-氰基-8-异丙基-3,4-二氢-1H-吡喃并[3,4-c]吡啶-6-基)-N-环己基哌嗪-1-羧酰胺(化合物107)。
1H NMRδ4.72(s,2H),4.34(d,J=7.3Hz,1H),3.95(t,J=5.6Hz,2H),3.64-3.85(m,5H),3.54(d,J=5.0Hz,4H),2.95(t,J=5.4Hz,2H),2.82(dt,J=13.1,6.4Hz,1H),1.99(d,J=9.8Hz,2H),1.70-1.77(m,2H),1.31-1.50(m,3H),1.27(br.s.,1H),1.08-1.24(m,8H)。LC-MS:m/z 412.2(M+H)+。
4-(5-氰基-8-异丙基-3,4-二氢-1H-吡喃并[3,4-c]吡啶-6-基)N-(4-氟苯基)哌嗪-1-羧酰胺(化合物102)。
1H NMRδ7.32-7.41(m,2H),6.97-7.10(m,2H),6.43(s,1H),4.73(s,2H),3.97(t,J=5.8Hz,2H),3.74-3.81(m,4H),3.64-3.73(m,4H),2.96(t,J=5.6Hz,2H),2.84(dt,J=13.3,6.7Hz,1H),1.22(d,J=6.8Hz,6H)。LC-MS:m/z424.3(M+H)+。
(R)-乙基3-(4-(5-氰基-8-环丙基-3,3-二甲基异色满-6-基)-2-异丙基哌嗪-1-羧酰胺基)丙酸酯(化合物392)。
1H NMRδ5.17(br.s.,1H),4.75-4.89(m,2H),4.24(d,J=13.3Hz,1H),4.08-4.20(m,3H),3.94(d,J=11.0Hz,1H),3.59(br.s.,1H),3.52(br.s.,2H),3.01-3.30(m,3H),2.71-2.80(m,2H),2.55(br.s.,2H),2.14(m,1H),1.65-1.74(m,1H),1.31(d,J=2.5Hz,6H),1.27(t,J=7.2Hz,3H),0.94-1.18(m,7H),0.81-0.91(m,3H)。LC-MS:m/z 498.3(M+H)+。
(R)-4-(5-氰基-8-环丙基-3,3-二甲基异色满-6-基)-N-乙基-2-异丙基哌嗪-1-羧酰胺(化合物326)。
1H NMR(氯仿-d)δ4.76-4.89(m,2H),4.36(br.s.,1H),4.24(d,J=13.1Hz,1H),4.12(d,J=11.5Hz,1H),3.92(d,J=11.0Hz,1H),3.58-3.76(m,1H),3.30(br.s.,2H),3.22(br.s.,1H),3.03-3.19(m,2H),2.70-2.82(m,2H),2.09-2.19(m,1H),1.66-1.74(m,1H),1.31(d,J=2.3Hz,6H),1.07-1.20(m,5H),0.95-1.04(m,5H),0.89(d,J=6.5Hz,3H)。LC-MS:m/z 426.2(M+H)+。
(R)-4-(5-氰基-8-环丙基-3,3-二甲基异色满-6-基)-2-异丙基-N-戊基哌嗪-1-羧酰胺(化合物327)。
1H NMRδ4.76-4.89(m,2H),4.38(br.s.,1H),4.24(d,J=13.3Hz,1H),4.12(d,J=11.8Hz,1H),3.91(d,J=12.5Hz,1H),3.64(d,J=9.5Hz,1H),3.04-3.32(m,5H),2.75(s,2H),2.08-2.20(m,1H),1.66-1.73(m,1H),1.48-1.56(m,2H),1.28-1.37(m,10H),1.05-1.17(m,2H),0.95-1.02(m,5H),0.85-0.93(m,6H)。LC-MS:m/z 468.5(M+H)+。
(R)-N-苄基-4-(5-氰基-8-环丙基-3,3-二甲基异色满-6-基)-2-异丙基哌嗪-1-羧酰胺(化合物328)。
1H NMRδ7.22-7.40(m,5H),4.76-4.91(m,2H),4.69(br.s.,1H),4.45(br.s.,2H),4.24(d,J=13.1Hz,1H),4.11(d,J=12.0Hz,1H),3.94(d,J=11.8Hz,1H),3.58-3.77(m,1H),3.04-3.33(m,3H),2.69-2.82(m,2H),2.10-2.17(m,1H),1.65-1.76(m,1H),1.31(d,J=3.3Hz,6H),1.05-1.17(m,2H),0.93-1.02(m,5H),0.83-0.93(m,3H)。LC-MS:m/z 488.5(M+H)+。
(R)-4-(5-氰基-8-环丙基-3,3-二甲基异色满-6-基)-N-(4-氟苯基)-2-异丙基哌嗪-1-羧酰胺(化合物283)。
1H NMRδ7.22-7.36(m,2H),6.91-7.07(m,2H),6.44(s,1H),4.73-4.92(m,2H),4.29(d,J=13.3Hz,1H),4.16(d,J=12.5Hz,1H),4.00(d,J=12.5Hz,1H),3.80(d,J=9.0Hz,1H),3.31(td,J=12.5,3.1Hz,1H),3.07-3.24(m,2H),2.76(s,2H),2.18-2.29(m,1H),1.67-1.74(m,1H),1.32(d,J=2.3Hz,6H),1.05-1.18(m,2H),0.98-1.04(m,5H),0.94(d,J=6.8Hz,3H)。LC-MS:m/z492.2(M+H)+。
(R)-4-(5-氰基-8-环丙基-3,3-二甲基异色满-6-基)-N,2-二异丙基哌嗪-1-羧酰胺(化合物287)。
1H NMRδ4.74-4.89(m,2H),4.24(d,J=13.3Hz,1H),4.07-4.19(m,2H),3.94-4.06(m,1H),3.88(d,J=12.5Hz,1H),3.58-3.72(m,1H),3.03-3.28(m,3H),2.70-2.80(m,2H),2.09-2.18(m,1H),1.65-1.73(m,1H),1.31(d,J=1.8Hz,6H),1.15(dd,J=6.4,3.1Hz,6H),1.07-1.13(m,2H),0.94-1.03(m,5H),0.83-0.92(m,3H)。LC-MS:m/z 440.2(M+H)+。
(R)-4-(5-氰基-8-环丙基-3,3-二甲基异色满-6-基)-2-异丙基-N-苯乙基哌嗪-1-羧酰胺(化合物286)。
1H NMRδ7.28-7.34(m,2H),7.17-7.25(m,3H),4.73-4.88(m,2H),4.36(br.s.,1H),4.19(d,J=13.3Hz,1H),4.08(d,J=11.5Hz,1H),3.85(d,J=12.3Hz,1H),3.44-3.59(m,3H),3.01-3.21(m,3H),2.84(t,J=6.8Hz,2H),2.75(s,2H),2.04-2.12(m,1H),1.65-1.73(m,1H),1.31(d,J=2.5Hz,6H),1.04-1.17(m,2H),0.97-1.02(m,2H),0.90-0.95(m,3H),0.74-0.82(m,3H)。LC-MS:m/z 502.2(M+H)+。
(R)-4-(5-氰基-8-环丙基-3,3-二甲基-3,4-二氢-1H-吡喃并[3,4-c]吡啶-6-基)-N-(4-氰基苯基)-2-异丙基哌嗪-1-羧酰胺(化合物303)。
1H NMRδ7.44-7.63(m,4H),6.78(br.s.,1H),4.74-4.91(m,2H),4.30(d,J=13.3Hz,1H),4.17(d,J=12.0Hz,1H),4.01(d,J=12.0Hz,1H),3.84(d,J=8.3Hz,1H),3.35(t,J=11.5Hz,1H),3.05-3.24(m,2H),2.76(s,2H),2.20-2.32(m,1H),1.63-1.76(m,1H),1.32(d,J=2.3Hz,6H),1.07-1.15(m,2H),0.99-1.05(m,5H),0.93(d,J=6.8Hz,3H)。LC-MS:m/z 499.1(M+H)+。
(R)-4-(5-氰基-8-环丙基-3,3-二甲基-3,4-二氢-1H-吡喃并[3,4-c]吡啶-6-基)-N-(4-乙氧基苯基)-2-异丙基哌嗪-1-羧酰胺(化合物282)。
1H NMRδ7.20-7.26(m,2H),6.80-6.86(m,2H),6.29(s,1H),4.75-4.90(m,2H),4.28(d,J=13.3Hz,1H),4.16(d,J=12.3Hz,1H),3.99(q,J=6.9Hz,3H),3.78(d,J=9.3Hz,1H),3.29(td,J=12.5,3.1Hz,1H),3.09-3.23(m,2H),2.73-2.80(m,2H),2.16-2.23(m,1H),1.67-1.73(m,1H),1.37-1.43(m,3H),1.31(d,J=2.5Hz,6H),1.06-1.18(m,2H),0.98-1.04(m,5H),0.95(d,J=6.8Hz,3H)。LC-MS:m/z 518.2(M+H)+。
(R)-4-(5-氰基-8-环丙基-3,3-二甲基-3,4-二氢-1H-吡喃并[3,4-c]吡啶-6-基)-2-异丙基-N-对甲苯基哌嗪-1-羧酰胺(化合物301)。
1H NMRδ7.21-7.26(m,J=8.5Hz,2H),7.03-7.15(m,J=8.0Hz,2H),6.29-6.46(m,1H),4.74-4.91(m,2H),4.28(d,J=13.3Hz,1H),4.11-4.20(m,1H),4.01(d,J=12.8Hz,1H),3.80(d,J=9.5Hz,1H),3.29(td,J=12.5,3.1Hz,1H),3.08-3.22(m,2H),2.76(s,2H),2.29(s,3H),2.16-2.23(m,1H),1.66-1.72(m,1H),1.31(d,J=2.3Hz,6H),1.07-1.18(m,2H),0.98-1.03(m,5H),0.94(d,J=6.8Hz,3H)。LC-MS:m/z 488.0(M+H)+。
(R)-4-(5-氰基-8-环丙基-3,3-二甲基-3,4-二氢-1H-吡喃并[3,4-c]吡啶-6-基)-2-异丙基-N-(4-甲氧苯基)哌嗪-1-羧酰胺(化合物316)。
1H NMRδ7.25(d,J=8.8Hz,2H),6.84(d,J=8.5Hz,2H),6.30(br.s.,1H),4.75-4.89(m,2H),4.28(d,J=13.1Hz,1H),4.16(d,J=12.0Hz,1H),4.01(d,J=12.5Hz,1H),3.78(s,4H),3.25-3.35(m,1H),3.09-3.24(m,2H),2.72-2.81(m,2H),2.18-2.26(m,1H),1.67-1.76(m,1H),1.31(d,J=2.0Hz,6H),1.07-1.19(m,2H),1.01(d,J=6.3Hz,5H),0.95(d,J=6.8Hz,3H)。LC-MS:m/z 503.9(M+H)+。
1-(烯丙基氨基甲酰基)-4-(5-氰基-8-环己基-3,3-二甲基-3,4-二氢-1H-吡喃并[3,4-c]吡啶-6-基)哌嗪-2-羧酸乙酯(化合物331)。
1H NMRδ5.81-5.98(m,1H),5.23(dd,J=17.1,1.3Hz,1H),5.14(dd,J=10.3,1.3Hz,1H),4.99(br.s.,1H),4.65-4.84(m,4H),4.22-4.30(m,1H),4.01-4.18(m,2H),3.92(t,J=5.3Hz,2H),3.63-3.77(m,1H),3.56(d,J=11.3Hz,1H),3.39(dd,J=13.4,4.1Hz,1H),3.09-3.22(m,1H),2.75-2.87(m,3H),1.29(d,J=2.8Hz,6H),1.15-1.22(m,9H)。LC-MS:m/z 470.4(M+H)+。
实例14.根据方案2,步骤G2产生的另外的具有化学式I的化合物。
使用适当的吡喃并吡啶和经取代的哌嗪中间体,按照与使用方案2的步骤G2制备的化合物等效的方式制备本发明的以下化合物。
(R)-4-(5-氰基-8-环己基-3,4-二氢-1H-吡喃并[3,4-c]吡啶-6-基)-N,2-二甲基哌嗪-1-羧酰胺(化合物357)。
1H NMRδ4.69(s,2H),4.38-4.61(m,1H),4.17-4.29(m,2H),4.13(d,J=13.1Hz,1H),3.89-4.00(m,2H),3.77-3.87(m,1H),3.20-3.40(m,2H),3.04-3.19(m,1H),2.92(t,J=5.6Hz,2H),2.81-2.88(m,3H),2.40(tt,J=11.0,3.6Hz,1H),1.84(d,J=12.8Hz,2H),1.52-1.75(m,5H),1.24-1.41(m,6H)。LC-MS:m/z 398.3(M+H)+。
(R)-4-(5-氰基-8-环己基-3,4-二氢-1H-吡喃并[3,4-c]吡啶-6-基)-2-甲基-N-(丙-2-炔基)哌嗪-1-羧酰胺(化合物361)。
1H NMRδ4.70(s,3H),4.10-4.28(m,3H),4.07(br.s.,2H),3.89-3.97(m,2H),3.84(dt,J=12.8,2.9Hz,1H),3.27-3.40(m,2H),3.11(td,J=12.2,3.6Hz,1H),2.88-2.95(m,2H),2.41(tt,J=11.1,3.7Hz,1H),2.25(t,J=2.5Hz,1H),1.81-1.88(m,2H),1.75(d,J=10.3Hz,1H),1.63-1.71(m,2H),1.52-1.63(m,2H),1.27-1.44(m,6H)。LC-MS:m/z422.4(M+H)+。
(R)-4-(5-氰基-8-环己基-3,4-二氢-1H-吡喃并[3,4-c]吡啶-6-基)-N-环丙基-2-甲基哌嗪-1-羧酰胺(化合物360)。
1H NMRδ4.69(s,3H),4.05-4.29(m,3H),3.93(td,J=5.8,1.3Hz,2H),3.69-3.86(m,1H),3.31(td,J=12.1,3.4Hz,2H),3.11(br.s.,1H),2.85-2.95(m,2H),2.68(dt,J=7.0,3.4Hz,1H),2.33-2.46(m,1H),1.80-1.87(m,2H),1.75(d,J=10.5Hz,1H),1.63-1.70(m,2H),1.58(d,J=12.0Hz,2H),1.29-1.41(m,3H),1.28(d,J=6.5Hz,3H),0.69-0.80(m,2H),0.42-0.57(m,2H)。LC-MS:m/z424.4(M+H)+。
(R)-4-(5-氰基-8-环己基-3,4-二氢-1H-吡喃并[3,4-c]吡啶-6-基)-2-甲基-N-丙基哌嗪-1-羧酰胺(化合物378)。
1H NMRδ4.70(s,2H),4.53(br.s.,1H),4.07-4.27(m,3H),3.88-3.98(m,2H),3.78-3.86(m,1H),3.17-3.38(m,4H),3.12(t,J=10.9Hz,1H),2.92(t,J=5.6Hz,2H),2.40(tt,J=11.0,3.6Hz,1H),1.80-1.88(m,2H),1.75(d,J=10.5Hz,1H),1.45-1.70(m,6H),1.26-1.41(m,6H),0.91-0.96(m,3H)。LC-MS:m/z 426.2(M+H)+。
(R)-4-(5-氰基-8-环丙基-3,3-二甲基异色满-6-基)-2-异丙基-N-甲基哌嗪-1-羧酰胺(化合物344)。
1H NMRδ4.75-4.90(m,2H),4.45(br.s.,1H),4.23(d,J=13.3Hz,1H),4.11(d,J=11.5Hz,1H),3.92(d,J=12.8Hz,1H),3.65(d,J=9.8Hz,1H),3.03-3.31(m,3H),2.83(s,3H),2.75(s,2H),2.09-2.22(m,1H),1.66-1.74(m,1H),1.31(d,J=2.8Hz,6H),0.95-1.18(m,7H),0.88(d,J=6.8Hz,3H)。LC-MS:m/z 412.3(M+H)+。
(R)-4-(5-氰基-8-环丙基-3,3-二甲基异色满-6-基)-2-异丙基-N-(丙-2-炔基)哌嗪-1-羧酰胺(化合物355)。
1H NMRδ4.72-4.90(m,2H),4.55(br.s.,1H),4.25(d,J=13.3Hz,1H),4.13(d,J=12.3Hz,1H),4.05(br.s.,2H),3.93(d,J=12.8Hz,1H),3.64(d,J=8.5Hz,1H),3.18-3.33(m,1H),3.02-3.18(m,2H),2.76(s,2H),2.20-2.28(m,1H),2.15(dt,J=10.0,6.7Hz,1H),1.31(d,J=3.0Hz,6H),0.97-1.06(m,6H),0.84-0.96(m,4H)。LC-MS:m/z 436.2(M+H)+。
(R)-4-(5-氰基-8-环丙基-3,3-二甲基异色满-6-基)-2-异丙基-N-(2-甲氧基乙基)哌嗪-1-羧酰胺(化合物353)。
1H NMRδ4.74-4.86(m,3H),4.26(d,J=13.3Hz,1H),4.13(d,J=12.3Hz,1H),3.93(d,J=12.3Hz,1H),3.65(d,J=8.8Hz,1H),3.41-3.50(m,2H),3.33-3.40(m,3H),3.01-3.29(m,4H),2.76(s,2H),2.08-2.19(m,1H),1.64-1.74(m,1H),1.28-1.36(m,6H),0.95-1.03(m,6H),0.88(d,J=7.0Hz,4H)。LC-MS:m/z 456.2(M+H)+。
(R)-4-(5-氰基-8-环丙基-3,3-二甲基异色满-6-基)-N-(2-羟乙基)-2-异丙基哌嗪-1-羧酰胺(化合物349)。
1H NMRδ4.96(br.s.,1H),4.76-4.88(m,2H),4.25(d,J=13.3Hz,1H),4.12(d,J=12.0Hz,1H),3.91(d,J=12.0Hz,1H),3.61-3.79(m,3H),3.43(br.s.,2H),3.18-3.31(m,1H),3.03-3.18(m,2H),2.70-2.81(m,2H),2.12-2.23(m,1H),1.66-1.74(m,1H),1.31(d,J=2.8Hz,6H),1.07-1.18(m,2H),0.95-1.05(m,5H),0.89(d,J=6.8Hz,3H)。LC-MS:m/z 442.3(M+H)+。
(R)-4-(5-氰基-8-环丙基-3,3-二甲基异色满-6-基)-2-异丙基-N,N-二甲基哌嗪-1-羧酰胺(化合物351)。
1H NMRδ4.76-4.88(m,2H),4.29(d,J=13.3Hz,1H),4.11(d,J=12.8Hz,1H),3.49-3.71(m,2H),3.37(td,J=12.6,3.1Hz,1H),3.16(dd,J=13.3,3.5Hz,1H),3.02(td,J=12.2,3.4Hz,1H),2.82(s,6H),2.76(s,2H),2.08-2.24(m,1H),1.63-1.73(m,1H),1.31(s,6H),1.06-1.19(m,2H),0.97-1.04(m,2H),0.93(d,J=6.5Hz,3H),0.87(d,J=6.8Hz,3H)。LC-MS:m/z 426.3(M+H)+。
(R)-4-(5-氰基-8-环丙基-3,3-二甲基异色满-6-基)-N-(环丙基甲基)-2-异丙基哌嗪-1-羧酰胺(化合物365)。
1H NMRδ4.74-4.92(m,2H),4.47(br.s.,1H),4.25(d,J=13.3Hz,1H),4.13(d,J=11.8Hz,1H),3.93(d,J=12.8Hz,1H),3.67(d,J=9.5Hz,1H),3.03-3.28(m,5H),2.69-2.80(m,2H),2.08-2.18(m,1H),1.82(br.s.,1H),1.66-1.74(m,1H),1.31(d,J=2.5Hz,6H),1.06-1.19(m,2H),0.94-1.02(m,5H),0.85-0.93(m,3H),0.43-0.55(m,2H),0.19(q,J=4.8Hz,2H)。LC-MS:m/z 452.2(M+H)+。
(R)-4-(5-氰基-8-环丙基-3,3-二甲基-3,4-二氢-1H-吡喃并[3,4-c]吡啶-6-基)-N-环丙基-2-异丙基哌嗪-1-羧酰胺(化合物398)。
1H NMRδ4.76-4.88(m,2H),4.66(br.s.,1H),4.23(d,J=13.3Hz,1H),4.11(d,J=11.5Hz,1H),3.88(d,J=12.0Hz,1H),3.54-3.75(m,1H),2.97-3.25(m,3H),2.75(s,2H),2.66(tt,J=7.0,3.6Hz,1H),2.09-2.18(m,1H),1.66-1.75(m,1H),1.31(d,J=2.8Hz,6H),1.00-1.18(m,4H),0.97(d,J=6.5Hz,3H),0.82-0.90(m,3H),0.69-0.78(m,2H),0.42-0.54(m,2H)。LC-MS:m/z 438.4(M+H)+。
实例15.根据方案2,步骤H产生的另外的具有化学式I的化合物。
使用适当的吡喃并吡啶和经取代的哌嗪中间体,按照与使用方案2的步骤H制备的化合物等效的方式制备本发明的以下化合物。
(R)-8-环己基-6-(3-甲基-4-(甲磺酰基)哌嗪-1-基)-3,4-二氢-1H-吡喃并[3,4-c]吡啶-5-腈(化合物336)。
1H NMRδ4.70(s,2H),4.09-4.25(m,3H),3.94(t,J=5.9Hz,2H),3.70(d,J=12.8Hz,1H),3.43(t,J=12.0Hz,1H),3.28(d,J=12.0Hz,1H),3.14(t,J=10.8Hz,1H),2.89-2.95(m,5H),2.42(t,J=10.7Hz,1H),1.84(d,J=12.3Hz,2H),1.75(d,J=10.0Hz,1H),1.68(br.s.,1H),1.59(d,J=12.3Hz,2H),1.41(d,J=6.8Hz,3H),1.28-1.37(m,4H)。LC-MS:m/z 419.2(M+H)+。
(R)-8-异丙基-6-(3-甲基-4-(苯硫-2-基磺酰基)哌嗪-1-基)-3,4-二氢-1H-吡喃并[3,4-c]吡啶-5-腈(化合物101)。
1H NMRδ7.66(d,J=5.0Hz,1H),7.59(d,J=3.0Hz,1H),7.18(t,J=4.3Hz,1H),4.71(s,2H),3.94(t,J=5.6Hz,2H),3.73-3.83(m,4H),3.18-3.33(m,4H),2.92(t,J=5.5Hz,2H),2.81(dt,J=13.2,6.6Hz,1H),1.18(d,J=6.5Hz,6H)。LC-MS:m/z 433.1(M+H)+。
(R)-8-环丙基-6-(3-异丙基-4-(苯硫-2-基磺酰基)哌嗪-1-基)-3,3-二甲基-3,4-二氢-1H-吡喃并[3,4-c]吡啶-5-腈(化合物284)。
1H NMRδ7.58(dd,J=3.8,1.3Hz,1H),7.53(dd,J=5.0,1.3Hz,1H),7.04(dd,J=5.0,3.8Hz,1H),4.73-4.88(m,2H),4.15(d,J=13.6Hz,1H),3.86-4.03(m,2H),3.61-3.73(m,1H),3.37-3.50(m,1H),2.99(dd,J=13.8,4.0Hz,1H),2.89(td,J=12.5,3.8Hz,1H),2.64-2.78(m,2H),2.04-2.15(m,1H),1.64-1.72(m,1H),1.30(d,J=6.3Hz,6H),0.92-1.12(m,10H)。LC-MS:m/z 501.2(M+H)+。
(R)-8-环丙基-6-(3-异丙基-4-甲苯磺酰基哌嗪-1-基)-3,3-二甲基-3,4-二氢-1H-吡喃并[3,4-c]吡啶-5-腈(化合物302)。
1H NMRδ7.72(d,J=8.3Hz,2H),7.19-7.31(m,2H),4.71-4.87(m,2H),4.05-4.18(m,1H),3.79-3.95(m,2H),3.63(dt,J=9.7,3.0Hz,1H),3.29-3.45(m,1H),2.96(dd,J=13.7,3.9Hz,1H),2.73-2.85(m,1H),2.70(d,J=3.3Hz,2H),2.40(s,3H),2.07(dq,J=9.8,6.7Hz,1H),1.65-1.71(m,1H),1.29(d,J=7.8Hz,6H),1.05-1.13(m,1H),0.97-1.04(m,3H),0.94(d,J=6.5Hz,6H)。LC-MS:m/z 509.0(M+H)+。
(R)-6-(4-(5-氯苯硫-2-基磺酰基)-3-异丙基哌嗪-1-基)-8-环丙基-3,3-二甲基-3,4-二氢-1H-吡喃并o[3,4-c]吡啶-5-腈(化合物285)。
1H NMRδ7.35(d,J=4.0Hz,1H),6.86(d,J=4.0Hz,1H),4.74-4.89(m,2H),4.05-4.16(m,1H),3.97(dt,J=12.8,1.6Hz,1H),3.79-3.91(m,1H),3.64(dt,J=9.3,3.5Hz,1H),3.37-3.49(m,1H),3.12(dd,J=13.8,4.0Hz,1H),3.00(td,J=12.5,4.0Hz,1H),2.66-2.81(m,2H),2.06-2.15(m,1H),1.64-1.72(m,1H),1.30(d,J=8.5Hz,6H),1.08-1.16(m,1H),1.00-1.07(m,3H),0.97(d,J=3.0Hz,3H),0.97(d,J=10.5Hz,3H)。LC-MS:m/z535.0(M+H)+。
(R)-8-环丙基-6-(3-异丙基-4-(甲磺酰基)哌嗪-1-基)-3,3-二甲基-3,4-二氢-1H-吡喃并[3,4-c]吡啶-5-腈(化合物323)。
1H NMRδ4.77-4.90(m,2H),4.22-4.33(m,1H),4.04-4.14(m,1H),3.80(dt,J=14.3,1.6Hz,1H),3.56(d,J=10.3Hz,1H),3.32-3.44(m,1H),3.09-3.19(m,2H),2.90-2.98(m,3H),2.76(s,2H),2.14-2.20(m,1H),1.68-1.76(m,1H),1.32(d,J=3.8Hz,6H),1.01-1.17(m,4H),0.97(d,J=3.8Hz,3H),0.99(d,J=4.0Hz,3H)。LC-MS:m/z 433.4(M+H)+。
(R)-8-异丙基-3,3-二甲基-6-(3-甲基-4-(苯硫-2-基磺酰基)哌嗪-1-基)-3,4-二氢-1H-吡喃并[3,4-c]吡啶-5-腈(化合物170)。
1H NMRδ7.60(ddd,J=9.3,4.3,1.4Hz,2H),7.10(dd,J=5.0,3.8Hz,1H),4.72(s,2H),4.27-4.41(m,1H),4.16(d,J=12.8Hz,1H),4.06(dd,J=13.2,2.1Hz,1H),3.77-3.89(m,1H),3.45(td,J=12.3,3.3Hz,1H),3.28(dd,J=13.1,3.5Hz,1H),3.14(td,J=12.3,3.5Hz,1H),2.85(quin,J=6.7Hz,1H),2.78(s,2H),1.31(d,J=3.0Hz,6H),1.26(d,J=6.8Hz,3H),1.19(d,J=4.0Hz,3H),1.21(d,J=4.0Hz,3H)。LC-MS:m/z 475.2(M+H)+。
实例16.根据方案2,步骤I1-1产生的另外的具有化学式I的化合物。
使用适当的吡喃并吡啶和经取代的哌嗪中间体,按照与使用方案2的步骤I1-1制备的化合物等效的方式制备本发明的以下化合物。
(R)-8-环丙基-6-(3-异丙基-4-(2-甲氧基乙基)哌嗪-1-基)-3,3-二甲基-3,4-二氢-1H-吡喃并[3,4-c]吡啶-5-腈(化合物369)。
1H NMRδ4.76-4.88(m,2H),4.13(dd,J=12.8,2.3Hz,1H),3.97-4.07(m,1H),3.45-3.62(m,2H),3.36(s,3H),3.12-3.24(m,1H),2.98-3.10(m,2H),2.89(t,J=11.3Hz,1H),2.75(s,2H),2.51(dd,J=11.5,8.0Hz,2H),2.28-2.37(m,1H),2.12-2.25(m,1H),1.64-1.72(m,1H),1.30(s,6H),1.09-1.17(m,2H),1.01-1.06(m,3H),0.96-1.00(m,2H),0.93(d,J=7.0Hz,3H)。LC-MS:m/z413.3(M+H)+。
实例17.根据方案2,步骤I2产生的另外的具有化学式I的化合物。
使用适当的吡喃并吡啶和经取代的哌嗪中间体,按照与使用方案2的步骤I2制备的化合物等效的方式制备本发明的以下化合物。
(R)-甲基2-(4-(5-氰基-8-环己基-3,4-二氢-1H-吡喃并[3,4-c]吡啶-6-基)-2-甲基-哌嗪-1-基)乙酸酯(化合物342)。
1H NMR(氯仿-d)δ4.70(s,2H),4.09-4.24(m,2H),3.94(t,J=5.8Hz,2H),3.68-3.83(m,3H),3.45-3.59(m,1H),3.39(br.s.,2H),3.07(br.s.,1H),2.73-3.02(m,5H),2.41(tt,J=11.1,3.6Hz,1H),1.86(d,J=12.5Hz,2H),1.76(d,J=10.0Hz,1H),1.70(br.s.,1H),1.54-1.64(m,2H),1.29-1.42(m,4H),1.10-1.24(m,3H)。LC-MS:m/z 412.6(M+H)+。
实例18:IDH1R132H抑制剂的测定。
如下在一个标准384孔平板中,在76μl体积的测定缓冲液(150mM NaCl,10mMMgCl2,20mM Tris pH 7.5,0.03%牛血清白蛋白)中进行测定:向25ul的底物混合物(8uMNADPH,2mM aKG)中添加DMSO中的1μl的测试化合物。将该平板短暂离心,并且然后添加25μl的酶混合物(0.2μg/ml IDH1 R132H),随后是短暂离心并且在100RPM下振荡。将该反应在室温下孵育50分钟,然后添加25μl的检测混合物(30μM刃天青,36μg/ml)并且将该混合物在室温下进一步孵育5分钟。在Ex544 Em590c/o 590处,通过荧光光谱检测刃天青向试卤灵的转化。
在这一测定中测试了列举于表1中的具有化学式I的化合物并且将结果列举于下表2中。如在表2中所使用,“A”是指针对IDH1 R132H的抑制活性IC50≤0.5μM;“B”是指针对IDH1 R132H的抑制活性IC50大于0.5μM并且≤1μM;“C”是指针对IDH1 R132H的抑制活性IC50大于1μM并且≤10μM;“D”针对IDH1 R132H的抑制活性IC50大于10μM。
如在表3中所使用,“A”是指针对IDH1 R132H的抑制活性IC50≤0.5μM或抑制2-HG的产生的IC50≤0.5μM;“B”是指针对IDH1 R132H的抑制活性IC50大于0.5μM并且≤1μM或2-HG的产生的IC50产生大于0.5μM并且≤1μM;“C”是指针对IDH1 R132H的抑制活性IC50大于1μM并且≤10μM或2-HG的产生的IC50大于1μM并且≤10μM;并且“D”是指针对IDH1 R132H的抑制活性IC50大于10μM或2-HG的产生的IC50大于10μM。
表2.通过具有化学式I的化合物抑制IDH1 R132H
表3
在一些实施例中,本发明提供了一种选自化合物编号165、171、176、180、181、194、195、205、206、207、211、230、231、235、236、237、265、269、270、288、289、297、304、307、317、340、344、345、346、347、354、366、376、382、383、392、395、401、409、412、以及413中的任一个的化合物。
实例19:IDH1m(R132H或R132C)抑制剂的细胞测定。
使细胞(例如,HT1080或U87MG)生长于T125烧瓶中的DMEM中,DMEM包含10%FBS、1×青霉素/链霉素和500ug/mL G418。通过胰蛋白酶收获它们并且将其以5000细胞/孔的密度以100ul/孔接种于96孔白底平板中的具有10%FBS的DMEM中。在第1列和第12列中不放细胞。将细胞在37℃下,在5%CO2中孵育过夜。第二天,制备2×浓度的化合物并且向每孔细胞中添加100ul。DMSO的终浓度是0.2%并且将DMSO对照孔放置在G行。然后,将这些平板放置在培养箱中48小时。在第48小时时,从每孔中除去100μl的培养基,并且通过LC-MS针对2-HG浓度进行分析。将细胞平板放回至培养箱中,再持续24小时。在添加化合物之后72小时时,解冻10mL/平板的Promega Cell Titer Glo试剂并且混合。将细胞平板从该培养箱中取出并且允许将其平衡至室温。然后,向每孔的培养基中添加100ul的试剂。然后,将细胞平板放置在定轨摇床上10分钟并且然后允许将其在室温下静置20分钟。然后,以500ms的积分时间针对发光对平板进行读取。
针对具有化学式I的不同化合物,在这两个细胞系中抑制2-HG产生的IC50(与对照相比,测试化合物用以减少50%的2HG的产生时的浓度)列举于上表3中。
实例20:程序(二甲基-环丙基吡喃并吡啶)
核心1合成,由以下针对5的来举例说明:
步骤A1:5-(环丙烷羰基)-2,2-二甲基二氢-2H-吡喃-4(3H)-酮(2)
将500mL配备有搅拌棒的三颈圆底烧瓶填充上2,2-二甲基二氢-2H吡喃-4(3H)-酮(6g,46.8mmol)和120mL的干甲苯。将该溶液用氮气进行吹扫并且冷却至0℃。在搅拌下,逐滴添加LDA(在THF/正庚烷中的2M溶液,24.5mL,15.6mmol)溶液,并且允许将该反应混合物在0℃下继续搅拌5min,之后添加环丙烷碳酰氯(2.8mL,31.2mmol)。在0℃下再搅拌20min之后,将该反应混合物用1N HCl淬灭,直到pH高于7。在H2O与二氯甲烷之间进行分配之后,然后将有机层用盐水进行洗涤,用无水Na2SO4干燥并且在真空下进行浓缩。快速柱色谱法(10%乙酸乙酯/石油醚)给出6g呈淡黄色油状物的粗品标题化合物,将其不用进一步纯化而直接用于下一个步骤中。MS(ES)M+H预期是197.1,发现是197.3。
步骤A2:8-环丙基-6-羟基-3,3-二甲基-3,4-二氢-1H-吡喃并[3,4-c]吡啶-5-腈(3)
向在70mL EtOH中的5-(环丙烷羰基)-2,2-二甲基二氢-2H-吡喃-4(3H)-酮(2)(6g,30.6mmol)和2-氰基乙酰胺(4.1g,49.0mmol)的溶液中添加二乙胺(2.1mL,20.4mmol)。将该反应混合物在室温下搅拌72小时,直到LC-MS指示完成形成产物。然后,将该反应混合物加热至回流温度,在这期间添加足够的EtOH,以制备澄清溶液。在冷却回至室温以后,将产物从EtOH溶液中沉淀出并且在真空过滤和风干以后获得3.3g呈白色固体的标题化合物。MS(ES)M+H预期是245.1,发现是245。1H NMR(氯仿-d)δ4.74(s,2H),2.82(s,2H),1.68-1.78(m,1H),1.34(s,6H),1.30-1.32(m,2H),1.24-1.26(m,2H)
步骤A3:5-氰基-8-环丙基-3,3-二甲基-3,4-二氢-1H-吡喃并[3,4-c]吡啶-6基三氟甲烷-磺酸酯(4)
将250mL圆底烧瓶填充上8-环丙基-6-羟基-3,3-二甲基-3,4-二氢-1H-吡喃并[3,4-c]吡啶-5-腈(3)(3.7g,15.16mmol)、DMAP(185mg,1.52mmol)、三乙胺(2.74mL,19.7mmol)以及150mL的二氯甲烷。在将该反应混合物在干冰-丙酮浴中冷却至0℃以后,经由注射器逐滴添加三氟甲磺酸酐(3.3mL,19.7mmol)。将生成的混合物在0℃下搅拌30min,之后允许将其加温至室温,并且再搅拌2小时。在TLC指示起始材料完全转化为产物以后,将该反应混合物在真空下进行浓缩并且通过快速柱色谱法(1:10乙酸乙酯/石油醚)纯化,以给出4.9g呈白色固体的标题化合物。1H NMR(氯仿-d)δ4.91(s,2H),2.88(s,2H),1.73-1.84(m,1H),1.34(s,6H),1.23-1.27(m,2H),1.17-1.22(m,2H)
步骤A4:(R)-8-环丙基-6-(3-异丙基哌嗪-1-基)-3,3-二甲基-3,4-二氢-1H-吡喃并[3,4-c]吡啶-5-腈(化合物A2)
将密封试管填充上在2mL EtOH中的5-氰基-8-环丙基-3,3-二甲基-3,4-二氢-1H-吡喃并[3,4-c]吡啶-6基三氟甲烷-磺酸酯(600mg,1.60mmol)、(R)-2-异丙基哌嗪(170mg,1.33mmol)、以及三乙胺(0.24mL,1.73mmol)。在回流温度下,将该反应混合物加热过夜。在将它减压下浓缩之后,通过快速柱色谱法(1:10甲醇/二氯甲烷)纯化该反应混合物,以给出428mg的标题化合物。MS(ES)M+H预期是355.2,发现是355.2。1H NMR(氯仿-d)δ4.84(s,2H),4.33(d,J=13.1Hz,1H),4.19(d,J=14.3Hz,1H),3.47-3.55(m,1H),3.35-3.47(m,1H),2.94-3.21(m,3H),2.77(s,2H),1.98-2.14(m,1H),1.64-1.77(m,1H),1.31(s,6H),1.14-1.21(m,3H),1.08-1.14(m,5H),0.98-1.07(m,2H)
可替代地,它可以通过以下方法制备。
使悬浮于0.8mL乙腈中的4(200mg,0.53mmol)、(R)-2-异丙基哌嗪(135mg,1.06mmol)、以及三乙胺(0.2mL,1.59mmol)的混合物在175℃下,经受45min微波反应。在将该反应混合物在真空下浓缩以后,将残余物通过快速柱色谱法进行纯化,以给出189mg呈淡黄色油状物的标题化合物。
酰胺偶联实例
步骤B:4-(5-氰基-8-环丙基-3,3-二甲基-3,4-二氢-1H-吡喃并[3,4-c]吡啶-6-基)-1-(2-(苯硫-2-基)乙酰基)哌嗪-2-羧酸乙酯
化合物#421
向一个5-mL的琥珀玻璃小瓶中添加4-(5-氰基-8-环丙基-3,3-二甲基-3,4-二氢-1H-吡喃并[3,4-c]吡啶-6-基)哌嗪-2-羧酸乙酯(31mg,0.08mmol)、2-(苯硫-2-基)乙酸(48mg,0.34mmol)、EDCI(68.8mg,0.36mmol)、HOBt(48.6mg,0.36mmol)、三乙胺(36.8mg,0.36mmol)以及1mL的二氯甲烷。将生成的反应混合物在室温下搅拌过夜。将该混合物用1NHCl水溶液淬灭,用EtOAc萃取三次。将合并的有机层用饱和NaHCO3和盐水进行洗涤,用无水Na2SO4干燥并且在真空下进行浓缩。通过制备型TLC分离(DCM:丙酮/70:1)来纯化粗产物,以给出21mg呈白色固体的标题化合物。MS(ES)M+H预期是509.2,发现是509.3。1H NMR(氯仿-d)δ:7.22-7.26(m,1H),6.89-7.01(m,2H),5.24-5.38(m,0.5H),4.79-4.89(m,2H),4.61-4.73(m,1H),4.00-4.28(m,4.5H),3.74-3.93(m,2H),3.19-3.29(m,1H),2.92-3.05(m,1H),2.72-2.85(m,2H),1.68-1.78(m,1H),1.29-1.36(m,6H),1.12-1.23(m,5H),0.99-1.08(m,2H)
步骤C:(R)-甲基3-(4-(5-氰基-8-环丙基-3,3-二甲基-3,4-二氢-1H-吡喃并[3,4-c]吡啶-6-基)-2-环丙基哌嗪-1-基)-3-氧代丙酸酯
化合物#440
向在15mL二氯甲烷中的(R)-8-环丙基-6-(3-环丙基哌嗪-1-基)-3,3-二甲基-3,4-二氢-1H-吡喃并[3,4-c]吡啶-5-腈(250mg,0.7mmol)的溶液中添加三乙胺(0.2mL,1.4mmol)和3-氯-3-氧代丙酸甲酯(191mg,1.4mmol)。允许将生成的反应混合物在室温下搅拌过夜。将该反应混合物用DCM稀释并且然后用盐水洗涤。将有机层用无水Na2SO4干燥并且在真空下进行浓缩。通过制备型TLC分离(DCM/丙酮:70:1)来纯化粗产物,以给出200mg呈黄色油状物的标题化合物。1H NMR(氯仿-d)δ4.83(s,2H),4.62-4.65(m,0.5H),4.26(d,J=13.1Hz,1H),4.16(d,J=12.5Hz,1H),4.03(d,J=9.3Hz,0.5H),3.71-3.85(m,3.5H),3.60-3.70(m,0.5H),2.93-3.58(m,5H),2.78(s,2H),1.66-1.75(m,1H),1.36-1.44(m,1H),1.32(d,J=3.0Hz,6H),1.13(t,J=3.6Hz,2H),0.97-1.07(m,2H),0.31-0.64(m,4H)
LC-MS:m/z 453.2(M+H)+
结构单元合成
结构单元1的合成:(R)-2-异丙基哌嗪
步骤D:(R)-2-异丙基哌嗪
向一个烧瓶中添加THF(5mL)中的(R)-3-异丙基哌嗪-2,5-二酮(154mg,1mmol),并且在0℃下、在N2下逐滴添加LAH(THF中的2.5M溶液)(2.5mL,6mmol)。将生成的混合物加热至65℃并且允许搅拌过夜。然后将该反应混合物冷却至室温,随后添加0.23mL H2O、0.23mL10%NaOH以及0.46mL H2O。将该反应混合物进行过滤并且将滤饼用EtOAc进行洗涤。将有机相进行浓缩,以给出呈固体的粗产物(86mg):1H NMR(氯仿-d)0.93(d,3H,J=6.6Hz),1.48-1.57(m,1H),1.75(br,2H),2.31-2.45(m,2H),2.67-2.83(m,2H),2.90(d,1H,J=11.5Hz),2.99-3.02(m,2H)
结构单元2的合成:(R)-2-环丙基哌嗪
步骤1:在室温下,向在水(1250ml)中的(R)-6-环丙基-2-(4-(3-甲氧基丙酰基)-3-甲基哌嗪-1-基)-5-(2-乙烯基喹唑啉-5-基)烟腈(100g,0.87mol)的溶液中添加NaHCO3(175g,2.08mol),随后添加THF(1250mL)中的(Boc)2O溶液。将生成的混合物加热至回流过夜。在搅拌过夜之后,将该反应混合物进行浓缩,以在减压下除去THF。向残余物中添加EtOAc(1250mL)并且将生成的混合物冷却至5℃并且然后用饱和水性NaHSO4调节至pH3。分离这些层并且用EtOAc(1000mL×3)萃取水层。将合并的EtOAc层用水和盐水进行洗涤,用Na2SO4干燥并且在减压下浓缩,以给出(R)-2-(叔丁氧基羰基氨基)-2-环丙基乙酸(165g,收率88%,ee>99%)。1H NMRδ3.16-3.14(d,J=8.8,1H),1.11(s,9H),0.73-0.78(m,1H),0.28-0.2(m,3H),0.18-0.15(m,1H)
步骤2:在0℃-5℃下,向在DCM(1000mL)中的(R)-2-(叔丁氧基羰基氨基)-2-环丙基乙酸(129g,0.6moL)和Et3N(67g,0.66moL)的搅拌混合物中经1小时添加氯甲酸异丁酯(81.6g,0.6moL)并且将该反应混合物在0℃-5℃下搅拌1小时。在一个分离烧瓶中,将甘氨酸甲酯盐酸化物(82.8g,0.66moL)、Et3N(73g,0.72moL)以及DCM(1000mL)的混合物搅拌1小时并且然后向该烧瓶中经2小时添加该混合物。在添加完成之后,将该混合物在室温下搅拌40小时并且然后用水和盐水进行洗涤,用Na2SO4干燥,在减压下浓缩,并且将残余物通过柱色谱法进行纯化,以给出呈白色固体的(R)-甲基2-(2-(叔丁氧基羰基氨基)-2-环丙基乙酰氨基)乙酸酯(100g,收率58%,ee>99%)。1H NMRδ8.2-8.16(t,J=5.6,1H),6.66-6.86(d,J=8.8,9H),3.71-3.92(m,2H),3.62(s,3H),3.46-3.51(t,J=8.4,1H),1.36(s,9H),0.97-1.01(m,1H),0.38-0.44(m,3H),0.25-0.28(m,1H)
步骤3:在0℃下,向在DCM(1740mL)中的(R)-甲基2-(2-(叔丁氧基羰基氨基)-2-环丙基乙酰氨基)乙酸酯(290g,1.014mol)的溶液中逐滴添加TFA(870mL)。将反应溶液在室温下搅拌过夜。将生成的溶液在减压下进行浓缩,以给出(R)-甲基2-(2-氨基-2-环丙基乙酰氨基)乙酸酯(511g粗品。)
步骤4:在0℃下,向在MeOH(1250ml)中的(R)-甲基2-(2-氨基-2-环丙基乙酰氨基)乙酸酯(255.5g粗品,0.507mol)的溶液中逐滴添加Et3N(750ml,10.78mol)。然后,将该反应混合物在室温下搅拌两天。将生成的混合物过滤并且用MTBE洗涤沉淀物并且通过高真空干燥,以给出(R)-3-环丙基哌嗪-2,5-二酮(60g,收率76.9%)。1H NMR TH03840-082-1(DMSO400MHz)7.98(s,1H),7.74(s,1H),3.68-6.64(d,J=17.6,1H),3.30-3.36(m,1H),2.9-2.93(dd,J=3.2,1H),0.87-0.92(m,1H),0.21-0.27(m,3H),0.18-0.21(m,1H)
步骤5:在0℃下,向在THF(1000mL)中的(R)-3-环丙基哌嗪-2,5-二酮(30g,0.195mmol)悬浮混合物中经1.5小时分部分地添加AlLiH4(45g,1.184mol)。然后,将该反应混合物加热至70℃过夜。冷却之后,在0℃下逐滴添加水(45mL)并且然后在0℃下逐滴添加KOH(45mL,1%)溶液。将生成的混合物过滤并且将残余物用EtOAc和MeOH(3:1)进行洗涤,并且将滤液在减压下进行浓缩,以给出粗产物。然后,将该粗产物用DCM进行洗涤,并且将滤液在减压下进行浓缩,以给出(R)-2-环丙基哌嗪(18.5g,收率75.5%,ee>99%)。1H NMR(MeOD400MHz)2.9-2.96(m,1H),2.8-2.88(m,1H),2.7-2.8(m,1H),2.55-2.68(m,2H),2.4-2.5(q,J=10.4,1H),1.65-1.73(m,1H),0.55-0.67(m,1H),0.35-0.45(m,2H),0.05-0.25(m,2H)
结构单元3的合成:2-环丙基哌嗪
步骤F1:2-环丙基吡嗪
在-40℃下,向在20mL无水THF中的2-氯吡嗪(1.14g,10mmol)和50mg Fe(acac)3的溶液中经1min添加环丙基氯化镁(10mL,1M)。然后,将该溶液在-40℃下搅拌0.5h并且加温至0℃。通过减压除去THF并且添加100mL水和100mL EA。将EA层用水(两次)和盐水进行洗涤,以在通过快速柱色谱法(EA:PE=1:10)纯化以后给出产物(0.8g)。1H NMR(氯仿-d)δ8.48(d,J=2.5Hz,1H),8.37(br.s.,1H),8.29(t,J=3.0Hz,1H),2.05(dt,J=6.2,3.0Hz,1H),0.95-1.19(m,4H)。
步骤F2:2-环丙基哌嗪
向在50mL甲醇中的2-环丙基吡嗪(0.8g)溶液中添加5mL AcOH和50mg Pd/C。在室温下,在H2(60psi)下,将该反应混合物搅拌过夜。将该混合物过滤并且将滤液浓缩至干燥,以获得产物(0.85g),将其不用进一步纯化而使用。1H NMR(DMSO)δ:3.53(dd,J=13.9,3.1Hz,1H),3.32-3.48(m,2H),2.99-3.18(m,3H),2.38-2.62(m,1H),0.73-0.89(m,1H),0.50-0.63(m,2H),0.23-0.42(m,2H)
结构单元4的合成:2-(2,2,2-三氟乙基)哌嗪
步骤G1:2-(叔丁氧基羰基氨基)-4,4,4-三氟丁酸
向在5mL H2O和5mL THF中的2-氨基-4,4,4-三氟丁酸(450mg,3mmol)的溶液中添加NaHCO3(504mg,mmol),随后添加在THF(3mL)中的二碳酸二叔丁酯(650mg,3mmol)的溶液。将生成的混合物在80℃下搅拌过夜。在除去THF之后,将该混合物倾倒进水中并且用二氯甲烷萃取。将合并的有机层用无水Na2SO4干燥并且在真空下进行浓缩。获得723mg作为粗产物的标题化合物并且不用进一步纯化而用于随后反应中。MS(ES)M+H预期是201.1,发现是201.3。1H NMR(氯仿-d)4.40-4.67(m,1H),2.60-2.90(m,2H),1.46(s,9H)。
步骤G2:2-(2-(叔丁氧基羰基氨基)-4,4,4-三氟丁酰氨基)乙酸甲酯
向25mL的圆底烧瓶中添加在5mL二氯甲烷中的2-(叔丁氧基羰基氨基)-4,4,4-三氟丁酸(723mg,2.8mmol)、Et3N(560mg,5.6mmol)、氯甲酸异丁酯(isobutylcarbonochloridate)(380mg,2.8mmol)。将生成的反应混合物在0℃下搅拌0.5小时。然后添加2-氨基乙酸甲酯(352mg,2.8mmol),并且将生成的混合物在室温下搅拌过夜。在用饱和NaHCO3、盐水洗涤以后,将合并的有机层用无水Na2SO4干燥并且在真空下进行浓缩。获得900mg作为粗产物的标题化合物,并且将其不用进一步纯化而用于随后反应中。MS(ES)M+H预期是272.1,发现是272.0。1H NMR(氯仿-d)δ7.11(br.s.,1H),5.28(br.s.,1H),4.44-4.67(m,1H),3.84-4.07(m,2H),3.69-3.83(s,3H),2.72-2.95(m,1H),2.42-2.64(m,1H),1.38-1.50(m,9H)
步骤G3:3-(2,2,2-三氟乙基)哌嗪-2,5-二酮
将在5mL 1,2-二氯苯中的2-(2-(叔丁氧基羰基氨基)-4,4,4-三氟丁酰氨基)乙酸甲酯(900mg,2.7mmol)的混合物加热至180℃过夜。将该混合物冷却下来并且添加MTBE(5mL)。形成棕淡黄色沉淀。用MTBE洗涤该滤饼并且风干,以给出200mg的标题化合物。1HNMR(DMSO-d6)δ8.28(d,J=9.3Hz,2H),4.00-4.26(m,1H),3.68-3.87(m,2H),2.66-2.88(m,2H)。
步骤G4:2-(2,2,2-三氟乙基)哌嗪
向一个烧瓶中添加THF(5mL)中的3-(2,2,2-三氟乙基)哌嗪-2,5-二酮(200mg,1mmol),并且在0℃下、在N2下逐滴添加LAH(2.5mL,6mmol,(THF中的2.5M溶液)),并且然后将该混合物加热至65℃过夜。在反应完成以后,将该混合物冷却下来,并且添加0.23mLH2O,随后添加0.23mL 10%NaOH和0.46mL H2O。将该混合物进行过滤并且将滤饼用EtOAc进行洗涤。将有机相进行浓缩,以给出粗产物(140mg固体)。1H NMR(氯仿-d)δ2.75-3.02(m,7H),2.52(dd,J=11.7,9.9Hz,1H),2.10-2.17(m,2H)。
结构单元5的合成:2-甲基-1,4-二氮杂卓
根据描述于Hidaka,Hiroyoshi;EP1074545;(2001);(A1)中的程序
结构单元6的合成:哌嗪-2-羧酸乙酯
步骤H1:1,4-双(叔丁氧基羰基)哌嗪-2-羧酸
在室温下,向Na2CO3(40g,380mmol,在200mL的水中)的水溶液中添加哌嗪-2-羧酸二盐酸化物(10g,50mmol),随后添加四氢呋喃(200mL)中的二碳酸二叔丁酯(41g,183mmol)。将该反应混合物在室温下搅拌20小时并且然后在减压下除去挥发物。然后,将生成的混合物用二乙醚(100mL)萃取。用3.0M HCl处理水层,直到它呈轻微酸性(pH=4)并且然后用乙酸乙酯(150mL)萃取。将有机层用盐水洗涤,用无水Na2SO4干燥,过滤,并且浓缩,以给出16g呈白色固体的标题化合物。1H NMR(氯仿-d)δ12.9(1H,s),,2.70-4.50(m,7H),1.33(m,18H)。
(S)-1,4-双(叔丁氧基羰基)哌嗪-2-羧酸
根据描述于步骤H1中的方法,从(S)-哌嗪-2-羧酸二盐酸化物制备该标题化合物。
步骤H2:(S)-1,4-二叔丁基2-乙基哌嗪-1,2,4-三羧酸酯
向在10mL的DMF中的(S)-1,4-双(叔丁氧基羰基)哌嗪-2-羧酸(0.5g,1.38mmol)混合物中添加K2CO3(0.6g,4.4mmol)。将生成的悬浮液冷却至0℃并且用溴乙烷(1mL,9.34mmol)进行处理。允许将该反应混合物加温至室温,搅拌24小时。在用水(10mL)淬灭以后,将该混合物用乙酸乙酯(20mL)萃取,并且将有机层用盐水进行洗涤,用无水Na2SO4干燥,过滤,并且在真空下浓缩,以给出0.48g呈白色固体的标题化合物,将其不用进一步纯化而直接用于下一个步骤中。
步骤H3:(S)-乙基哌嗪-2-羧酸酯
在室温下,向在甲醇(4mL)中的(S)-1,4-二叔丁基2-乙基哌嗪-1,2,4-三羧酸酯(1.2g,4.5mmol)的溶液中添加HCl溶液(在EtOAc中,5mL,4.0M)。将该反应混合物在室温下搅拌过夜并且然后浓缩,以给出1g作为盐酸盐的2-(甲氧基甲基)哌嗪,将其不用进一步纯化而用于下一个步骤中。1H NMR(氯仿-d)δ4.18(m,2H),3.43(dd,1H),3.13(dd,1H),2.96(m,1H),2.70(m,4H),1.27(t,3H)。
结构单元7的合成:2-(二氟甲基)哌嗪
步骤I:2-(二氟甲基)哌嗪
向在40mL EtOH中的1,4-二苄基-2-(二氟甲基)哌嗪(根据描述于SyntheticCommunications(《合成通讯》),2011,第41卷,#14,p.2031-2035中的程序合成)(80mg,0.253mmol)的溶液中添加Pd(OH)2/C(15mg)。将生成的混合物在50Psi下、在室温下氢化两天。将该反应混合物过滤,并且将滤液进行浓缩,以给出标题化合物(不用进一步纯化而直接使用)。1H NMR(氯仿-d)δ5.67(td,1H),2.62-3.13(m,7H)。
结构单元8的合成:(6-氟-2-甲基-1,4-二氮杂卓)
步骤J1:6-氟-2-甲基-1,4-二甲苯磺酰基-1,4-二氮杂卓
根据描述于Synthesis(《合成》),2003,2,p.223-226中的程序制备2-甲基-1,4-二甲苯磺酰基-1,4-二氮杂卓-6-醇、和6-氟-2-甲基-1,4-二甲苯磺酰基-1,4-二氮杂卓。1HNMR(氯仿-d)7.30-7.37(m,4H),5.00-4.84(m,1H),4.09-4.37(m,2H),3.73-3.95(m,1H),3.37-3.62(m,2H),3.12-3.32(m,1H),3.05(ddd,J=13.6,7.2,4.0Hz,1H),2.43-2.46(m,6H),1.05-1.14(m,3H)
步骤J2:6-氟-2-甲基-1,4-二氮杂卓
使用微波辐射,将在压力管中的HOAc–HBr(3mL,30wt%)中的6-氟-2-甲基-1,4-二甲苯磺酰基-1,4-二氮杂卓(84mg,0.19mmol)悬浮液加热至100℃,持续3min。在真空中除去溶剂并且将残余物用Et2O进行研磨,用Et2O进行洗涤,以给出标题化合物,不用进一步纯化而直接使用。
结构单元9的合成:(R)-2-氘核-2-(全氘丙-2-基)哌嗪
步骤K1:(R)-2-(叔丁氧基羰基氨基)-2,3,4,4,4-五氘-3-(三氘甲基)丁酸
向在水(6.4mL)中的D-缬氨酸(d8)(500mg,4.27mmol)的溶液中添加NaHCO3(717mg,8.53mmol),随后添加在THF(6.4mL)中的二碳酸二叔丁酯(932mg)的溶液。将该混合物在回流下搅拌并加热16h,并且然后在真空下浓缩,以除去THF。然后添加EtOAc(EtOAc),并且将该混合物冷却至10℃,并且然后用饱和水性NaHSO4(3.3mL)调节至pH 3。分离这些层,并且用EtOAc(4mL×3)萃取水层。将合并的EtOAc层用水(2mL×1)和盐水进行洗涤,用MgSO4干燥,并且在真空下浓缩,以给出所希望的化合物(924mg,99%)。
1H NMR(氯仿-d)δ:5.00(br.s.,1H),1.45(s,9H)
步骤K2:(R)-甲基2-(2-(叔丁氧基羰基氨基)-2,3,4,4,4-五氘-3(三氘甲基)丁-氨基)乙酸酯
在5℃下,向在CH2Cl2(12.3mL)中的(R)-2-(叔丁氧基羰基氨基)-2,3,4,4,4-五氘-3-(三氘甲基)丁酸(924g,4.25mol)和Et3N(430mg,4.25mmol)的搅拌混合物中经30min添加氯甲酸异丁酯(580mg,4.25mmol)。当添加完成时,将该混合物在0℃-5℃下搅拌30min。在一个分离烧瓶中,将甘氨酸甲酯盐酸化物(534mg,4.25mmol)、Et3N(430mg,4.25mmol)以及CH2Cl2(12.3mL)的混合物搅拌30min并且然后向该混合物中经0.5h添加以上的混合物。在添加完成之后,将该混合物在室温下搅拌16h并且然后用水(3×15mL)和盐水进行洗涤,干燥,并且在真空下浓缩,以给出产物(1.12g,91%)。
步骤K3:(R)-3-氘核-3-(全氘丙-2-基)哌嗪-2,5-二酮
在175℃-180℃下,将在1,2-二氯苯(9mL)中的(R)-甲基2-(2-(叔丁氧基羰基氨基)-2,3,4,4,4-五氘-3-(三氘甲基)丁-氨基)乙酸酯(999mg,3.46mmol)溶液加热18h,允许通过蒸馏除去形成的任何MeOH。在大气压下伴随氮流的协助,通过蒸馏除去6mL的溶剂之后,将该混合物冷却至50℃并且谨慎地添加MTBE(5mL)。将该混合物冷却至十五年并且过滤。用MTBE(0.2mL)洗涤生成的固体并且在100℃下、在真空下干燥,以给出产物(320mg,59%)。1H NMR(DMSO-d6)δ:8.18(br.s.,1H),8.01(br.s.,1H),3.81(d,J=17.8Hz,1H),3.61(dd,J=17.8,3.0Hz,1H)
步骤K4:(R)-2-氘核-2-(全氘丙-2-基)哌嗪
向在干THF(5mL)中的(R)-3-氘核-3-(全氘丙-2-基)哌嗪-2,5-二酮(160mg,1mmol)的溶液中添加LiAlH4(228mg,6mmol)。在回流下,将该混合物搅拌12h。在冷却至0℃后,小心地添加水(0.5mL),并且将该混合物在室温下搅拌30min。滤出固体并且将滤液在真空下浓缩,以给出产物(120mg,88%),将其不用进一步纯化而直接用于下一个步骤中。
(R)-2,2,3,5,5-五氘-3-(全氘丙-2-基)哌嗪
根据描述于K4中的方法,用LiAlD4从(R)-3-氘核-3-(全氘丙-2-基)哌嗪-2,5-二酮制备该标题化合物。
(R)-甲基-2-(2-(叔丁氧基羰基氨基)-2,3,4,4,4-五氘-3-(三氘甲基)丁-酰氨基)-2,2-二氘乙酸酯
根据描述于步骤K2中的方法,用甘氨酸甲酯盐酸化物(d2)从(R)-2-(叔丁氧基羰基氨基)-2,3,4,4,4-五氘-3-(三氘甲基)丁酸制备该标题化合物。
(R)-3,3,6-三氘-6-(全氘丙-2-基)哌嗪-2,5-二酮
根据描述于步骤K3中的方法,从(R)-甲基2-(2-(叔丁氧基羰基氨基)-2,3,4,4,4-五氘-3-(三氘甲基)丁-酰氨基)-2,2-二氘乙酸酯制备该标题化合物。
(R)-2,2,5-三氘-5-(全氘丙-2-基)哌嗪
根据描述于K4中的方法,从(R)-3,3,6-三氘-6-(全氘丙-2-基)哌嗪-2,5-二酮制备该标题化合物。
(R)-2,2,3,3,5,5,6-七氘-6-(全氘丙-2-基)哌嗪
根据描述于K4中的方法,用LiAlD4从(R)-3,3,6-三氘-6-(全氘丙-2-基)哌嗪-2,5-二酮制备该标题化合物。
结构单元10的合成:2-(氧杂环丁-3-基)乙酸锂
步骤L1:2-(氧杂环丁-3-亚基)乙酸甲酯
根据描述于US 20100075983中的程序合成该标题化合物。1H NMR(400MHz,CDCl3)δ=5.66(dd,J=4.7,2.3Hz,1H),5.51(dd,J=6.5,2.9Hz,2H),5.31(dt,J=5.2,2.7Hz,2H),3.72(s,3H)。
步骤L2:2-(氧杂环丁-3-基)乙酸甲酯
在室温下,向在甲醇(25mL)中的2-(氧杂环丁-3-亚基)乙酸甲酯(641.0mg,5mmol)的溶液中添加25mg的Pd/C(10%)并且将生成的混合物在H2气氛下搅拌过夜。在经由硅藻土衬垫除去Pd/C之后,将残余物在减压下干燥,并且然后使其经受硅胶柱色谱法,使用乙酸乙酯/石油醚(1:1,V/V)作为洗脱液,以给出浅黄色液体。收率:586.1mg(90.1%)。1H NMR(400MHz,CDCl3)δ=4.94-4.78(m,2H),4.42(t,J=6.3Hz,2H),3.67(s,3H),3.44-3.29(m,1H),2.74(d,J=7.9Hz,2H)。
步骤L3:2-(氧杂环丁-3-基)乙酸锂
在-10℃下,使用干冰-丙酮浴,向在四氢呋喃(10mL)与水(3mL)的混合物中的2-(氧杂环丁-3-基)乙酸甲酯(130.1mg,1.00mmol)的溶液中添加一水合氢氧化锂(44.1mg,1.05mmol)。允许将生成的溶液加温至室温并且搅拌过夜。在除去四氢呋喃和水之后,将获得的白色固体不用进一步纯化而直接用于下一个反应步骤中。收率:121.4mg(99.5%)。1HNMR(400MHz,D2O)δ4.83–4.73(m,1H),4.33(t,J=6.4Hz,1H),4.33(t,J=6.4Hz,1H),3.18(dt,J=14.7,7.3Hz,1H),2.48(d,J=8.0Hz,1H)。
结构单元11的合成:2-(氧杂环丁-2-基)乙酸
步骤M1:((丁-3-烯-1-基氧基)甲基)苯
将3-丁烯-1-醇(5.00g)、三乙胺(0.46g)、氢氧化钠(4.10g)和己烷(50mL)的混合物在50℃下搅拌0.5h并且然后在低于60℃下向该混合物中添加溴化苄(12.9g)。允许将该混合物加温至回流并且回流3h。将该混合物倾倒进冰冷水中并且将该混合物用己烷萃取。将有机层用水、盐水进行洗涤,用Na2SO4干燥并且在真空下进行浓缩。将残余物通过硅胶色谱法(石油醚至石油醚:乙酸乙酯=10:1)进行纯化,以给出呈油状物的标题化合物(6g)。1HNMR(氯仿-δ)d:7.30-7.43(m,5H),5.78-5.95(m,1H),5.03-5.19(m,2H),4.56(s,2H),3.57(t,J=6.8Hz,2H),2.42(qt,J=6.7,1.3Hz,2H)
步骤M2:2-(2-(苄氧基)乙基)氧杂环丙烷
在冰冷却下,向在甲苯(200mL)中的[(丁-3-烯-1-基氧基)甲基]苯(10.6g)的溶液中添加具有水(69%-75%,20.0g)的间氯过苯甲酸,并且然后允许将该混合物加温至室温。在室温下搅拌18h之后,将该混合物进行过滤。将滤液用己烷进行稀释,用在5%碳酸氢钠水溶液(200mL)中的五水合硫代硫酸钠(8.1g)溶液、碳酸氢钠水溶液(200mL)、水(200mL)、盐水进行洗涤,用Na2SO4干燥并且在真空下浓缩。将残余物通过硅胶色谱法(己烷:乙酸乙酯=20:1至4:1)进行纯化,以给出呈油状物的标题化合物(10.2g)。1H NMR(氯仿-d)δ:7.31-7.42(m,5H),4.56(s,2H),3.60-3.69(m,2H),3.10(td,J=4.5,1.9Hz,1H),2.77-2.85(m,1H),2.56(dd,J=5.0,2.8Hz,1H),1.88-2.00(m,1H),1.74-1.86(m,1H)
参照US 2010/94000。
步骤M3:2-(2-(苄氧基)乙基)氧杂环丁烷
在50℃下,将在干t-BuOH(13mL)中的KOBu-t(1.12g,10mmol)和三甲基氧代碘化锍(2.2g,10mmol)的混合物磁力搅拌1h。然后逐滴添加在干t-BuOH(10mL)中的2-(2-(苄氧基)乙基)氧杂环丙烷(0.9g,5mmol)的溶液并且搅拌3天。在减压下小心蒸发掉溶剂,并且向残留悬浮液中添加水(30mL)。将该混合物用正己烷萃取,用无水MgSO4干燥,并且浓缩,以给出粗产物,通过柱色谱法纯化该粗产物,以给出呈无色油状物的产物(0.4g)。1H NMR(氯仿-d)δ:7.29-7.45(m,5H),5.03(dd,J=7.2,5.6Hz,1H),4.70(td,J=8.0,5.8Hz,1H),4.47-4.61(m,3H),3.48-3.63(m,2H),2.64-2.77(m,1H),2.35-2.49(m,1H),2.09-2.22(m,1H),1.93-2.09(m,1H)
参照Journal of Organic Chemistry(《有机化学杂志》),2000,67(26),9488-9491
步骤M4:2-(氧杂环丁-2-基)乙醇
向在MeOH(15mL)中的2-(2-(苄氧基)乙基)氧杂环丁烷(0.3g,14.2mmol)的溶液中添加10%Pd/C(20mg)。将该反应混合物用氢气吹扫并且在氢气氛下搅拌2d。使黑色悬浮液通过用MeOH洗脱的硅藻土塞子,然后将有机层进行浓缩,以产生呈无色油状物的所希望的产物(0.10g,62%)。1H NMR(氯仿-d)d:5.12(qd,J=7.3,4.6Hz,1H),4.72(td,J=8.0,6.0Hz,1H),4.60(dt,J=9.1,6.0Hz,1H),3.88(ddd,J=11.0,7.0,4.5Hz,1H),3.79(ddd,J=11.0,6.7,4.6Hz,1H),2.66-2.80(m,1H),2.56(br.s.,1H),2.40-2.52(m,1H),2.07(dtd,J=14.4,7.2,4.5Hz,1H),1.93(ddt,J=14.4,7.2,4.5Hz,1H)。
步骤M5:2-(氧杂环丁-2-基)乙酸
当冰冷却时,向水(3mL)中的氧化铬(VI)的溶液中依次添加硫酸(1mL)和水(3mL)。将该溶液逐滴添加至丙酮(10mL)中的2-羟甲基氧杂环丁烷(40mg)的溶液中,同时在冰冷却下,将内部温度保持在20℃以下,并且将该混合物在室温下搅拌2小时。然后,添加2-丙醇来淬灭该反应,并且将该溶液用乙酸乙酯进行稀释并且通过硅藻土过滤。将滤液用盐水进行洗涤并且将水层用乙酸乙酯萃取两次。在将有机层合并在一起并且用无水硫酸镁干燥之后,将溶剂蒸发,以给出产物,将其不用进一步纯化而用于下一个步骤中(30mg)。1H NMR(400MHz,甲醇-d4)δ5.26–5.15(m,1H),4.69(ddd,J=8.3,7.8,5.9Hz,1H),4.58(dt,J=9.2,5.9Hz,1H),2.88–2.70(m,3H),2.51(ddt,J=11.2,9.1,7.3Hz,1H)。
结构单元12的合成:2-(甲氧羰基氨基)乙酸
步骤N:2-(甲氧羰基氨基)乙酸
向在H2O(1mL)中的2-氨基乙酸(2.0g,26.2mmol)的溶液中分部分地添加氯甲酸甲酯(1.6g,16.6mmol)和NaOH(2.6mL,10N)。15min后,在继续搅拌下添加Na2CO3(1.3g)。然后,将该溶液用4mL的浓盐酸酸化并且用乙酸乙酯萃取,用Na2SO4干燥并浓缩。将残余物用乙酸乙酯进行稀释并且在室温下搅拌过夜。将该混合物过滤,以获得331mg白色固体,将其不用进一步纯化而直接用于下一个步骤中。
实例:
化合物#422
(R)-3-(4-(5-氰基-8-环丙基-3,3-二甲基-3,4-二氢-1H-吡喃并[3,4-c]吡啶-6-基)-2-异丙基哌嗪-1-基)-N-甲基-3-氧代丙酰胺
在30℃下,将在NH3/MeOH(1.5mL,1M)中的(R)-甲基3-(4-(5-氰基-8-环丙基-3,3-二甲基-3,4-二氢-1H-吡喃并[3,4-c]吡啶-6-基)-2-环丙基哌嗪-1-基)-3-氧代丙酸酯(40mg,0.09mmol)的溶液搅拌过夜。然后,将该反应混合物进行浓缩并且通过制备型TLC分离(DCM/甲醇:20:1)纯化,以给出33mg呈无色油状物的标题化合物。1H NMR(氯仿-d)δ7.68(br.s.,0.5H),7.50(br.s.,0.5H),4.76-4.91(m,2H),4.53-4.71(m,0.5H),4.26-4.46(m,1.5H),4.17(d,J=11.5Hz,1H),3.88(d,J=13.8Hz,0.5H),3.61(d,J=10.5Hz,0.5H),3.27-3.53(m,2.5H),2.90-3.15(m,2.5H),2.80-2.87(m,3H),2.77(s,2H),2.05-2.35(m,1H),1.66-1.78(m,1H),1.32(d,J=3.0Hz,6H),0.95-1.16(m,7H),0.75-0.92(m,3H)
LC-MS:m/z 454.4(M+H)+
化合物#429
(R)-8-环丙基-6-(4-(3-羟基丙酰基)-3-异丙基哌嗪-1-基)-3,3-二甲基-3,4-二氢-1H-吡喃并[3,4-c]吡啶-5-腈
向在10mL四氢呋喃中的(R)-甲基3-(4-(5-氰基-8-环丙基-3,3-二甲基-3,4-二氢-1H-吡喃并[3,4-c]吡啶-6-基)-2-环丙基哌嗪-1-基)-3-氧代丙酸酯(43mg,0.09mmol)和NaBH4(7mg,0.18mmol)的溶液中逐滴添加BF3.OEt2(0.02mL,0.18mmol)。然后,将该混合物在室温下搅拌过夜。将该溶液用水和盐水进行洗涤。将有机层用无水Na2SO4干燥并且在真空下进行浓缩。通过制备型TLC(DCM/丙酮:70:1)来纯化粗产物,以给出14mg呈无色油状物的标题化合物。1H NMR(氯仿-d)δ4.77-4.91(m,2H),4.64(d,J=10.0Hz,0.5H),4.28-4.46(m,1.5H),4.10-4.26(m,1H),3.90(br.s.,2H),3.63-3.83(m,1H),3.37-3.54(m,1H),2.91-3.11(m,2H),2.72-2.88(m,2H),2.56-2.66(m,2H),2.11-2.36(m,1H),1.67-1.77(m,1H),1.32(d,J=2.3Hz,6H),0.95-1.18(m,7H),0.78-0.93(m,3H)
LC-MS:m/z 427.1(M+H)+
化合物#437
(R)-8-环丙基-6-(4-(3-氟代丙酰基)-3-异丙基哌嗪-1-基)-3,3-二甲基-3,4-二氢-1H-吡喃并[3,4-c]吡啶-5-腈
在-78℃下,向在干DCM(10mL)中的(R)-8-环丙基-6-(4-(3-羟基丙酰基)-3-异丙基哌嗪-1-基)-3,3-二甲基-3,4-二氢-1H-吡喃并[3,4-c]吡啶-5-腈(106mg,0.4mmol)的溶液中添加DAST。将该混合物在这一温度下搅拌2h,并且然后用水(0.5mL)淬灭。将有机相用1N HCl(2×5mL)、盐水洗涤,用无水Na2SO4干燥并且在真空下浓缩。通过制备型TLC(PE/EA:5:1)来纯化粗产物,以给出75mg呈无色油状物的标题化合物。1H NMRδ4.80-4.93(m,3H),4.71-4.80(m,1H),4.66(d,J=10.3Hz,0.5H),4.41(d,J=10.3Hz,0.5H),4.33(d,J=13.6Hz,1H),4.12-4.25(m,1H),3.75(d,J=13.6Hz,0.5H),3.39-3.52(m,1H),2.96-3.08(m,2H),2.95(s,0.5H),2.81-2.87(m,1H),2.62-2.81(m,3H),2.20-2.35(m,0.5H),2.05-2.20(m,0.5H),1.66-1.76(m,1H),1.32(d,J=2.5Hz,6H),1.08-1.18(m,2H),0.95-1.06(m,5H),0.89(d,J=6.8Hz,2H),0.82(d,J=6.8Hz,2H)
LC-MS:m/z 429.5(M+H)
化合物#456
(R)-乙基-4-(4-(5-氰基-8-环丙基-3,3-二甲基-3,4-二氢-1H-吡喃并[3,4-c]吡啶-6-基)-2-异丙基哌嗪-1-基)-4-氧代丁酸酯
向在20mL二氯甲烷中的(R)-8-环丙基-6-(3-异丙基哌嗪-1-基)-3,3-二甲基-3,4-二氢-1H-吡喃并[3,4-c]吡啶-5-腈(500mg,1.4mmol)的溶液中添加三乙胺(0.4mL,2.8mmol)和4-氯-4-氧代丁酸甲酯(0.35mL,2.8mmol)。将生成的反应混合物在室温下搅拌过夜。将该反应混合物用DCM稀释并且然后用盐水洗涤。将有机层用无水Na2SO4干燥并且在真空下进行浓缩。通过快速柱色谱法(DCM/丙酮:70:1)纯化粗产物,以给出368mg呈浅黄色油状物的(R)-甲基4-(4-(5-氰基-8-环丙基-3,3-二甲基-3,4-二氢-1H-吡喃并[3,4-c]吡啶-6-基)-2-异丙基哌嗪-1-基)-4-氧代丁酸酯。H NMR(氯仿-d)δ4.83(s,2H),4.28-4.50(m,2H),4.02-4.28(m,1H),3.70-3.84(m,3H),3.40-3.70(m,4H),2.91-3.18(m,2H),2.76(s,2H),2.05-2.32(m,1H),1.61-1.81(m,1H),1.32(d,J=2.5Hz,6H),0.95-1.18(m,7H),0.78-0.95(m,3H)
将在10mL MeOH/H2O(9:1)中的(R)-甲基-4-(4-(5-氰基-8-环丙基-3,3-二甲基-3,4-二氢-1H-吡喃并[3,4-c]吡啶-6-基)-2-异丙基哌嗪-1-基)-4-氧代丁酸酯冷却至0℃并且添加(84mg,2.0mmol)LiOH,然后将该溶液在室温下搅拌24h。向该混合物中添加水,并且然后用1N HCl将pH调节至~3。然后,将它用DCM萃取,用N2SO4干燥,浓缩并且通过快速柱色谱法纯化,以获得331mg呈黄色固体的(R)-4-(4-(5-氰基-8-环丙基-3,3-二甲基-3,4-二氢-1H-吡喃并[3,4-c]吡啶-6-基)-2-异丙基哌嗪-1-基)-4-氧代丁酸。LC-MS:m/z 455.2(M+H)+
向在2mL DMF中的(R)-4-(4-(5-氰基-8-环丙基-3,3-二甲基-3,4-二氢-1H-吡喃并[3,4-c]吡啶-6-基)-2-异丙基哌嗪-1-基)-4-氧代丁酸(50mg,0.1mmol)的溶液中添加Cs2CO3(72mg,0.2mmol)和溴乙烷(0.02mL,0.3mmol)。在55℃下,将生成的反应混合物在密封试管中搅拌过夜。将该反应混合物用水稀释,用DCM萃取并且然后用盐水洗涤。将有机层用无水Na2SO4干燥并且在真空下进行浓缩。通过制备型TLC(DCM/丙酮:70:1)来纯化粗产物,以给出18mg标题化合物。1H NMR(氯仿-d)δ4.74-4.91(m,2H),4.43-4.72(m,0.5H),4.29-4.40(m,1.5H),4.09-4.23(m,3H),3.79(d,J=13.6Hz,0.5H),3.36-3.57(m,1H),2.90-3.14(m,2.5H),2.76(s,2H),2.60-2.72(m,4H),2.07-2.33(m,1H),1.67-1.74(m,1H),1.31(d,J=2.3Hz,6H),1.27(td,J=7.1,2.1Hz,3H),0.96-1.19(m,7H),0.77-0.94(m,3H)。LC-MS:m/z483.5(M+H)+
化合物#448
(R)-6-(4-(3-(1,3,4-噁二唑-2-基)丙酰基)-3-异丙基哌嗪-1-基)-8-环丙基-3,3-二甲基-3,4-二氢-1H-吡喃并[3,4-c]吡啶-5-腈
向在5mL无水乙醇中的(R)-甲基4-(4-(5-氰基-8-环丙基-3,3-二甲基-3,4-二氢-1H-吡喃并[3,4-c]吡啶-6-基)-2-异丙基哌嗪-1-基)-4-氧代丁酸酯(40mg,0.1mmol)的溶液中添加水合肼(10mg,0.2mmol)。将生成的混合物加热至回流4小时。在TLC显示反应完成以后,将该混合物在减压下蒸发。在回流下,将获得的残余物、原甲酸三甲酯(11mg)、4-甲苯磺酸(5mg)和MeOH(5mL)的混合物加热过夜。在LC-MS显示反应完成以后,将该混合物蒸发。将残余物通过制备型TLC分离(DCM/丙酮:70:1)进行纯化,以给出该标题化合物。1H NMR(400MHz,氯仿-d)4.83(s,2H),4.62(d,J=10.2Hz,0.5H),4.27-4.39(m,1.5H),4.11-4.23(m,1H),3.78(d,J=14.6Hz,0.5H),3.43-3.55(m,1H),3.27(t,J=7.2Hz,2H),2.98-3.07(m,2H),2.89-2.98(m,2.5H),2.77(s,2H),2.12(m,1H),1.65-1.75(m,1H),1.32(d,J=2.6Hz,6H),0.96-1.04(m,6H),0.87-0.93(m,2H),0.79(d,J=6.8Hz,2H)
LC-MS:m/z 479.3(M+H)+
化合物#462
8-环丙基-6-((R)-4-((1R,2R)-2-(羟甲基)环丙烷羰基)-3-异丙基哌嗪-1-基)-3,3-二甲基-3,4-二氢-1H-吡喃并[3,4-c]吡啶-5-腈
向在MeOH/THF(5mL/5mL)中的反式-甲基2-((R)-4-(5-氰基-8-环丙基-3,3-二甲基-3,4-二氢-1H-吡喃并[3,4-c]吡啶-6-基)-2-异丙基哌嗪-1-羰基)环丙烷羧酸酯(120mg,0.4mmol)的溶液中以若干部分的形式添加LiBH4(53mg,2.4mmol)。将该混合物在室温下搅拌2h。添加水(0.5mL)以淬灭该反应,并且然后添加EA(20mL)。将该有机相用水、盐水进行洗涤,用无水Na2SO4干燥并且在真空下进行浓缩。通过制备型TLC(PE/EA:2:1)来纯化粗产物,以给出66mg呈无色油状物的标题化合物。1H NMRδ4.69-4.97(m,2H),4.58(d,J=10.0Hz,0.5H),4.27-4.47(m,1.5H),4.00-4.27(m,1.5H),3.61-3.91(m,1.5H),3.35-3.61(m,1.5H),2.89-3.18(m,2.5H),2.78(d,J=17.3Hz,2H),2.27(ddd,J=13.2,6.7,3.4Hz,0.5H),2.12(dt,J=6.7,3.3Hz,0.5H),1.62-1.92(m,2H),1.19-1.38(m,6H),0.96-1.17(m,7H),0.69-0.96(m,4H)
LC-MS:m/z 453.6(M+H)+
化合物#472
((1R,2R)-2-((R)-4-(5-氰基-8-环丙基-3,3-二甲基-3,4-二氢-1H-吡喃并[3,4-c]吡啶-6-基)-2-异丙基哌嗪-1-羰基)环丙基)甲基碳酸甲酯
在0℃下,向在DMF(4mL)中的8-环丙基-6-((R)-4-((1R,2R)-2-(羟甲基)环丙烷羰基)-3-异丙基哌嗪-1-基)-3,3-二甲基-3,4-二氢-1H-吡喃并[3,4-c]吡啶-5-腈(100mg,0.22mmol)的溶液中添加NaH(16.3mg,65%,0.44mmol)。在0℃下,将该混合物搅拌30min。添加碳酸二甲酯(30mg,0.33mmol)。将生成的混合物在室温下搅拌2h。小心地添加水(20mL)以淬灭该反应。将水相用DCM(3×10mL)萃取。将合并的有机相用水、盐水进行洗涤,用无水Na2SO4干燥并且在真空下进行浓缩。通过制备型TLC(PE/EA:3:1)来纯化粗产物,以给出30mg呈无色油状物的标题化合物。
1H NMRδ4.74-4.94(m,2H),4.57(dd,J=10.2,4.4Hz,0.5H),4.13-4.42(m,4H),3.84-4.01(m,1H),3.74-3.84(m,3.5H),3.38-3.61(m,0.5H),2.92-3.13(m,2.5H),2.77(s,2H),2.27(dt,J=10.7,5.5Hz,0.5H),2.13(dt,J=10.5,6.5Hz,0.5H),1.65-1.93(m,4H),1.32(d,J=2.5Hz,6H),0.97-1.19(m,7H),0.76-0.94(m,4H)
LC-MS:m/z 511.6(M+H)
化合物#421
4-(5-氰基-8-环丙基-3,3-二甲基-3,4-二氢-1H-吡喃并[3,4-c]吡啶-6-基)-1-(2-(苯硫-2-基)乙酰基)哌嗪-2-羧酸乙酯
1H NMR(氯仿-d)d:7.22-7.26(m,1H),6.89-7.01(m,2H),5.24-5.38(m,0.5H),4.79-4.89(m,2H),4.61-4.73(m,1H),4.00-4.28(m,4.5H),3.74-3.93(m,2H),3.19-3.29(m,1H),2.92-3.05(m,1H),2.72-2.85(m,2H),1.68-1.78(m,1H),1.29-1.36(m,6H),1.12-1.23(m,5H),0.99-1.08(m,2H)
化合物#423
(R)-8-环丙基-6-(3-异丙基-4-(3,3,3-三氟丙酰基)哌嗪-1-基)-3,3-二甲基-3,4-二氢-1H-吡喃并[3,4-c]吡啶-5-腈(步骤B)
1H NMR(氯仿-d)δ4.76-4.91(m,2H),4.65-4.68(m,0.5H),4.42(d,J=10.5Hz,0.5H),4.34(d,J=13.6Hz,1H),4.12-4.27(m,1H),3.61-3.75(m,0.5H),3.44-3.60(m,0.5H),3.14-3.43(m,2.5H),2.94-3.10(m,2.5H),2.77(s,2H),2.14(dq,J=17.2,6.7Hz,1H),1.67-1.75(m,1H),1.32(d,J=2.8Hz,6H),0.96-1.18(m,7H),0.77-0.92(m,3H)
LC-MS:m/z 465.2(M+H)+
化合物#424
(R)-8-环丙基-6-(3-异丙基-4-(4-甲氧基丁酰基)哌嗪-1-基)-3,3-二甲基-3,4-二氢-1H-吡喃并[3,4-c]吡啶-5-腈(步骤B)
1H NMR(氯仿-d)δ4.75-4.90(m,2H),4.64-4.66(m,0.5H),4.40(d,J=10.3Hz,0.5H),4.33(d,J=13.6Hz,1H),4.07-4.25(m,1H),3.78(d,J=13.6Hz,0.5H),3.38-3.57(m,3H),3.34(s,3H),2.89-3.07(m,2.5H),2.69-2.82(m,2H),2.35-2.54(m,2H),2.10-2.31(m,1H),1.87-2.04(m,2H),1.66-1.75(m,1H),1.31(d,J=2.5Hz,6H),0.96-1.16(m,7H),0.75-0.92(m,3H)
LC-MS:m/z 455.2(M+H)+
化合物#425
8-环丙基-6-(3-环丙基-4-(3-甲氧基丙酰基)哌嗪-1-基)-3,3-二甲基-3,4-二氢-1H-吡喃并[3,4-c]吡啶-5-腈(结构单元3,步骤B)
1H NMR(氯仿-d)δ4.78-4.91(m,2H),4.25(d,J=12.8Hz,1H),4.15(d,J=12.5Hz,1H),3.69-4.10(m,4H),3.61-3.75(m,3H),2.50-3.24(m,7H),1.67-1.76(m,1H),1.31(d,J=2.8Hz,6H),1.20(d,J=6.8Hz,1H),1.09-1.17(m,2H),0.96-1.05(m,2H),0.29-0.64(m,4H)
LC-MS:m/z 439.2(M+H)+
化合物#426
8-环丙基-6-(3-环丙基-4-(呋喃-3-羰基)哌嗪-1-基)-3,3-二甲基-3,4-二氢-1H-吡喃并[3,4-c]吡啶-5-腈(结构单元3,步骤B)
1H NMR(氯仿-d)δ7.64-7.77(m,1H),7.37-7.50(m,1H),6.55(s,1H),4.84(s,2H),4.14-4.30(m,3H),3.67-4.00(m,21H),3.15(dd,J=12.8,3.5Hz,1H),2.98(td,J=12.5,3.3Hz,1H),2.78(s,2H),1.67-1.79(m,1H),1.41-1.57(m,1H),1.32(d,J=2.3Hz,6H),1.10-1.19(m,2H),0.95-1.06(m,2H),0.60(td,J=8.5,3.8Hz,1H),0.42-0.54(m,1H),0.38(br.s.,1H)
LC-MS:m/z 447.2(M+H)+
化合物#427
(R)-8-环丙基-6-(3-异丙基-4-(异噁唑-3-羰基)哌嗪-1-基)-3,3-二甲基-3,4-二氢-1H-吡喃并[3,4-c]吡啶-5-腈(步骤B)
1H NMR(400MHz,氯仿-d)δ8.48(d,J=1.5Hz,1H),6.69(d,J=1.5Hz,1H),4.83(s,2H),4.68(d,J=13.0Hz,0.5H),4.33-4.53(m,2H),4.12-4.32(m,1.5H),3.53(td,J=12.9,3.2Hz,0.5H),3.01-3.22(m,2.5H),2.77(d,J=3.0Hz,2H),2.16-2.36(m,1H),1.64-1.77(m,1H),1.32(s,6H),1.04-1.15(m,3H),1.02(dd,J=7.9,2.6Hz,2H),0.93(t,J=6.4Hz,3H),0.81(d,J=6.7Hz,2H)
LC-MS:m/z 450.2(M+H)+
化合物#428
(R)-8-环丙基-6-(3-异丙基-4-(4-氧代戊酰基)哌嗪-1-基)-3,3-二甲基-3,4-二氢-1H-吡喃并[3,4-c]吡啶-5-腈(步骤B)
1H NMR(400MHz,氯仿-d)δ4.75-4.89(m,2H),4.46-4.69(m,0.5H),4.24-4.40(m,2H),4.06-4.23(m,1H),3.81(d,J=13.8Hz,0.5H),3.52-3.60(m,0.5H),3.37-3.51(m,1H),2.89-3.12(m,2.5H),2.79-2.84(m,2H),2.76(s,2H),2.55-2.71(m,2H),2.23(s,3H),1.64-1.77(m,1H),1.27-1.37(s,6H),1.06-1.19(m,2H),0.94-1.05(m,4H),0.85-0.94(m,2H),0.80(d,J=6.8Hz,2H)
LC-MS:m/z 453.0(M+H)+
化合物#430
8-环丙基-6-(3-环丙基-4-(3,3,3-三氟丙酰基)哌嗪-1-基)-3,3-二甲基-3,4-二氢-1H-吡喃并[3,4-c]吡啶-5-腈(结构单元3,步骤B)
1H NMR(氯仿-d)δ4.78-4.90(m,2H),4.66(br.s.,0.5H),4.26(d,J=12.8Hz,1H),4.17(d,J=12.5Hz,1H),4.07(d,J=8.5Hz,0.5H),3.67–3.84(m,1.5H),3.30(q,J=9.8Hz,2H),3.03-3.15(m,1.5H),2.90-3.03(m,1H),2.71-2.84(m,2H),1.68-1.78(m,1H),1.37-1.47(m,1H),1.32(d,J=3.0Hz,6H),1.10-1.19(m,2H),0.98-1.07(m,2H),0.28-0.71(m,4H)
LC-MS:m/z 463.1(M+H)+
化合物#431
(R)-甲基3-(4-(5-氰基-8-环丙基-3,3-二甲基-3,4-二氢-1H-吡喃并[3,4-c]吡啶-6-基)-2-异丙基哌嗪-1-基)-3-氧代丙基氨基甲酸酯(结构单元12,步骤B)
1H NMR(氯仿-d)δ5.50(br.s.,1H),4.75-4.91(m,2H),4.60-4.65(m,0.5H),4.24-4.41(m,1.5H),4.08-4.22(m,1H),3.60-3.80(m,3.5H),3.33-3.50(m,3H),2.91-3.04(m,2.5H),2.70-2.82(m,2H),2.50-2.63(m,2H),2.05-2.34(m,1H),1.65-1.78(m,1H),1.31(d,J=2.8Hz,6H),0.95-1.19(m,7H),0.70-0.91(m,3H)
LC-MS:m/z 484.1(M+H)+
化合物#432
(R)-8-环丙基-6-(4-(3-甲氧基丙酰基)-3-甲基哌嗪-1-基)-3,3-二甲基-3,4-二氢-1H-吡喃并[3,4-c]吡啶-5-腈(步骤B)
1H NMR(氯仿-d)δ4.76-4.96(m,2.5H),4.51(d,J=13.6Hz,0.5H),4.20(br.s.,0.5H),3.93-4.14(m,2H),3.65-3.83(m,2.5H),3.46-3.65(m,0.5H),3.37(s,3H),3.06-3.24(m,1.5H),2.88-3.06(m,1H),2.55-2.80(m,4H),1.66-1.76(m,1H),1.24-1.39(m,9H),1.09-1.19(m,2H),0.97-1.05(m,2H)
LC-MS:m/z 413.2(M+H)+
化合物#433
8-环丙基-6-((3R)-4-(3-羟基丁酰基)-3-异丙基哌嗪-1-基)-3,3-二甲基-3,4-二氢-1H-吡喃并[3,4-c]吡啶-5-腈(步骤B)
1H NMR(400MHz,氯仿-d)δ4.83(s,2H)4.63(m,0.5H),4.28-4.47(m,2H),4.04-4.28(m,2H),3.63-3.78(m,0.5H),3.43(td,J=8.2,3.4Hz,1H),2.90-3.08(m,2.5H),2.76(s,2H),2.44-2.62(m,1H),2.21-2.43(m,1.5H),1.58-1.78(m,1H),1.28-1.38(m,6H),1.18-1.28(m,5H),0.94-1.07(m,4H),0.88(t,J=6.2Hz,2H),0.74-0.84(m,2H)
LC-MS:m/z 441.2(M+H)+
化合物#434
(R)-8-环丙基-6-(3-环丙基-4-(3-甲氧基丙酰基)哌嗪-1-基)-3,3-二甲基-3,4-二氢-1H-吡喃并[3,4-c]吡啶-5-腈(结构单元2,步骤B)
1H NMR(氯仿-d)δ4.83(s,2H),4.63–4.65(m,0.5H),4.24(d,J=12.5Hz,1H),4.15(d,J=12.5Hz,1H),4.05(d,J=8.8Hz,0.5H),3.69-3.88(m,3H),3.36(s,3H),2.94–3.24(m,3H),2.75-2.82(m,2H),2.50-2.67(m,2H),1.66-1.76(m,1H),1.31(d,J=3.0Hz,7H),1.10-1.18(m,2H),0.98-1.06(m,2H),0.33-0.63(m,4H)
LC-MS:m/z 439.1(M+H)+
化合物#435
(R)-8-环丙基-6-(3-环丙基-4-(3,3,3-三氟丙酰基)哌嗪-1-基)-3,3-二甲基-3,4-二氢-1H-吡喃并[3,4-c]吡啶-5-腈(结构单元2,步骤B)
1H NMR(氯仿-d)δ4.84(s,2H),4.66(br.s.,0.5H),4.26(d,J=12.8Hz,1H),4.17(d,J=12.8Hz,1H),4.07(d,J=8.5Hz,0.5H),3.67-3.92(m,1.5H),3.21-3.38(m,2H),3.06-3.18(m,1.5H),2.94-3.01(m,1H),2.78(s,2H),1.68-1.80(m,1H),1.38-1.49(m,1H),1.32(d,J=3.3Hz,6H),1.10-1.20(m,2H),0.99-1.08(m,2H),0.27-0.79(m,4H)
LC-MS:m/z 463.0(M+H)+
化合物#436
((R)-8-环丙基-6-(3-氘-4-(3-甲氧基丙酰基)-3-(全氘丙-2-基)哌嗪-1-基)-3,3-二甲基-3,4-二氢-1H-吡喃并[3,4-c]吡啶-5-腈(结构单元9,步骤B)
1H NMRδ4.75-4.91(m,2H),4.65(d,J=11.3Hz,0.5H),4.32(ddd,J=13.3,5.3,1.5Hz,1H),4.18(d,J=14.1Hz,1H),3.62-3.85(m,3H),3.27-3.48(m,4.5H),2.90-3.04(m,2H),2.73-2.79(m,2H),2.52-2.70(m,2H),1.64-1.76(m,1H),1.31(d,J=2.3Hz,6H),1.08-1.16(m,2H),0.95-1.05(m,2H)
LC-MS:m/z 449.6(M+H)+
化合物#438
(R)-8-环丙基-3,3-二甲基-6-(2,2,3,5,5-五氘-4-(3-甲氧基丙酰基)-3-(全氘丙-2-基)哌嗪-1-基)-3,4-二氢-1H-吡喃并[3,4-c]吡啶-5-腈(结构单元9,步骤B)
1H NMRδ4.76-4.89(m,2H),4.16(dd,J=12.7,7.4Hz,1H),3.64-3.80(m,2H),3.36(d,J=3.5Hz,3H),2.88-3.05(m,1H),2.76(s,2H),2.49-2.74(m,2H),1.64-1.76(m,1H),1.31(d,J=2.5Hz,6H),0.96-1.18ppm(m,4H)
LC-MS:m/z 453.6(M+H)+
化合物#439
5-((R)-4-(5-氰基-8-环丙基-3,3-二甲基-3,4-二氢-1H-吡喃并[3,4-c]吡啶-6-基)-2-异丙基哌嗪-1-基)-2-甲基-5-氧代戊酸甲酯
1H NMR(氯仿-d)δ4.77-4.91(m,2H),4.62-4.70(m,0.5H),4.28-4.49(m,1.5H),4.07-4.25(m,1H),3.63-3.79(m,3.5H),3.34-3.54(m,1H),2.88-3.11(m,2.5H),2.72-2.83(m,2H),2.49-2.62(m,1H),2.33-2.46(m,1H),2.19-2.30(m,1H),1.81–1.98(m,2H),1.64-1.78(m,1H),1.29-1.37(m,6H),1.21(d,J=7.0Hz,3H),0.95-1.17(m,7H),0.76-0.89(m,3H)
LC-MS:m/z 497.2(M+H)+
化合物#441
(R)-8-环丙基-6-(2,2,3,3,5,6,6-七氘-4-(3-甲氧基丙酰基)-5-(全氘丙-2-基)哌嗪-1-基)-3,3-二甲基-3,4-二氢-1H-吡喃并[3,4-c]吡啶-5-腈(结构单元9,步骤B)
1H NMRδ4.82(s,2H),3.65-3.80(m,2H),3.36(d,J=3.5Hz,3H),2.74-2.80(m,2H),2.49-2.74(m,2H),1.63-1.74(m,1H),1.31(d,J=2.5Hz,6H),0.96-1.20(m,4H)
LC-MS:m/z 454.6(M+H)+
化合物#444
(R)-8-环丙基-3,3-二甲基-6-(2,2,5-三氘-4-(3-甲氧基丙酰基)-5-(全氘丙-2-基)哌嗪-1-基)-3,4-二氢-1H-吡喃并[3,4-c]吡啶-5-腈(结构单元9,步骤B)
1H NMRδ4.83(s,2H),4.64(d,J=13.8Hz,0.5H),4.25-4.38(m,1H),3.66-3.84(m,2.5H),3.31-3.40(m,3H),2.86-3.08(m,2H),2.73-2.80(m,2H),2.49-2.73(m,2H),1.64-1.75(m,1H),1.31(d,J=2.3Hz,6H),0.96-1.19(m,4H)
LC-MS:m/z 451.6(M+H)+
化合物#451
(R)-8-环丙基-6-(3-氘-3-(全氘丙-2-基)-4-(3,3,3-三氟丙酰基)哌嗪-1-基)-3,3-二甲基-3,4-二氢-1H-吡喃并[3,4-c]吡啶-5-腈(结构单元9,步骤B)
1H NMRδ4.83(s,2H),4.32(d,J=13.1Hz,0.5H),4.19(br.s.,2H),3.64(br.s.,1.5H),3.32(d,J=9.8Hz,2H),2.94-3.05(m,2H),2.77(s,2H),1.66-1.77(m,1H),1.32(d,J=2.8Hz,6H),0.97-1.19(m,4H)
LC-MS:m/z 473.6(M+H)+
化合物#449
(R)-甲基4-(4-(5-氰基-8-环丙基-3,3-二甲基-3,4-二氢-1H-吡喃并[3,4-c]吡啶-6-基)-2-氘-2-(全氘丙-2-基)哌嗪-1-基)-4-氧代丁酸酯(结构单元9,步骤B)
1H NMRδ4.83(s,2H),4.62(d,J=10.8Hz,0.5H),4.31(dd,J=12.7,6.7Hz,1H),4.11-4.24(m,1H),3.78(d,J=13.6Hz,0.5H),3.70(d,J=3.8Hz,3H),3.45(m.,0.5H),2.88-3.11(m,2.5H),2.76(s,2H),2.60-2.74(m,4H),1.65-1.76(m,1H),1.32(d,J=2.5Hz,6H),0.99-1.17(m,4H)
LC-MS:m/z 477.6(M+H)+
化合物#449
(R)-甲基4-(4-(5-氰基-8-环丙基-3,3-二甲基-3,4-二氢-1H-吡喃并[3,4-c]吡啶-6-基)-2,2,3,3,5,5,6-七氘-6-(全氘丙-2-基)哌嗪-1-基)-4-氧代丁酸酯(结构单元9,步骤B)
1H NMRδ4.82(s,2H),3.70(d,J=3.5Hz,3H),2.76(s,2H),2.57-2.74(m,4H),1.66-1.76(m,1H),1.31(d,J=2.5Hz,6H),0.96-1.18(m,4H)
LC-MS:m/z 483.7(M+H)+
化合物#452
(R)-8-环丙基-6-(2,2,3,3,5,6,6-七氘-5-(全氘丙-2-基)-4-(3,3,3-三氟丙酰基)哌嗪-1-基)-3,3-二甲基-3,4-二氢-1H-吡喃并[3,4-c]吡啶-5-腈(结构单元9,步骤B)
1H NMRδ4.83(s,2H),3.14-3.42(m,2H),2.77(s,2H),1.68-1.76(m,1H),1.32(d,J=2.8Hz,6H),0.97-1.18(m,4H)
LC-MS:m/z 479.7(M+H)+
化合物#476
(R)-8-环丙基-3,3-二甲基-6-(2,2,3,5,5-五氘-3-(1,1,1,3,3,3-六氘丙-2-基)-4-(3,3,3-三氟丙酰基)哌嗪-1-基)-3,4-二氢-1H-吡喃并[3,4-c]吡啶-5-腈(结构单元11,步骤B)
1H NMRδ4.75-4.93(m,2H),4.10-4.27(m,1H),3.22-3.47(m,2H),2.90-3.07(m,1H),2.77(s,2H),1.72(dt,J=8.0,3.9Hz,1H),1.32(d,J=2.8Hz,6H),0.98-1.20(m,4H)
LC-MS:m/z 477.6(M+H)+
化合物#477
(R)-8-环丙基-3,3-二甲基-6-(2,2,3,5,5-五氘-3-(1,1,1,3,3,3-六氘丙-2-基)-4-(3,3,3-三氟丙酰基)哌嗪-1-基)-3,4-二氢-1H-吡喃并[3,4-c]吡啶-5-腈(结构单元9,步骤B)
1H NMRδ4.74-4.94(m,2H),3.15-3.43(m,2H),2.78(s,2H),1.69-1.76(m,1H),1.33(d,J=2.8Hz,6H),0.99-1.20(m,4H)
LC-MS:m/z 479.6(M+H)+
化合物#442
8-环丙基-6-((3R)-3-环丙基-4-(3-羟基丁酰基)哌嗪-1-基)-3,3-二甲基-3,4-二氢-1H-吡喃并[3,4-c]吡啶-5-腈(结构单元2,步骤B)
1H NMR(氯仿-d)δ4.84(s,2H),4.62-4.65(m,0.5H),4.13-4.35(m,3H),4.03(d,J=8.3Hz,0.5H),3.61-3.83(m,1H),2.91-3.19(m,3H),2.78(s,2H),2.30-2.58(m,2H),1.67-1.77(m,1H),1.29-1.35(m,7H),1.19-1.27(m,3H),1.13(m,2H),0.98-1.07(m,2H),0.38-0.68(m,4H)
LC-MS:m/z 439.0(M+H)+
化合物#445
(R)-8-环丙基-6-(3-异丙基-4-(2-(甲硫基)乙酰基)哌嗪-1-基)-3,3-二甲基-3,4-二氢-1H-吡喃并[3,4-c]吡啶-5-腈(步骤B)
1H NMR(氯仿-d)δ4.76-4.90(m,2H),4.58-4.61(m,0.5H),4.28-4.43(m,1.5H),4.20(d,J=11.5Hz,1H),3.73(d,J=13.6Hz,0.5H),3.27-3.53(m,3H),3.07-3.13(m,1H),2.89-3.04(m,1H),2.69-2.84(m,2H),2.05-2.33(m,4H),1.65-1.73(m,1H),1.32(d,J=2.5Hz,6H),0.95-1.19(m,7H),0.77-0.93(m,3H)
LC-MS:m/z 443.5(M+H)+
化合物#446
(R)-8-环丙基-6-(3-异丙基-4-(2-(甲磺酰基)乙酰基)哌嗪-1-基)-3,3-二甲基-3,4-二氢-1H-吡喃并[3,4-c]吡啶-5-腈(步骤B)
1H NMR(氯仿-d)δ4.76-4.90(m,2H),4.62-4.65(m,0.5H),4.27-4.45(m,2H),4.12-4.26(m,2H),3.81-4.10(m,1H),3.51-3.66(m,1H),3.11-3.20(m,4H),2.99-3.11(m,1.5H),2.68-2.86(m,2H),2.10-2.37(m,1H),1.71(dddd,J=10.0,7.6,5.1,2.4Hz,1H),1.32(d,J=3.0Hz,6H),0.97-1.18(m,7H),0.87(dd,J=6.7,3.6Hz,3H)
LC-MS:m/z 475.6(M+H)+
化合物#447
(R)-8-环丙基-6-(4-(3-(呋喃-2-基)丙酰基)-3-异丙基哌嗪-1-基)-3,3-二甲基-3,4-二氢-1H-吡喃并[3,4-c]吡啶-5-腈(步骤B)
1H NMR(400MHz,氯仿-d)6.82(d,J=3.01Hz,1H),6.04(d,J=3.0Hz,1H),4.82(s,2H),4.64(m,0.5H),4.40(d,J=10.3Hz,0.5H),4.30(t,J=13.9Hz,1H)4.09-4.19(m,1H),3.73(d,J=13.5Hz,0.5H),3.35-3.51(m,1H),2.97-3.07(m,2.5H),2.88-2.97(m,2H),2.76(S,2H),2.68-2.74(m,1H),2.09(m,1H),1.70(tt,J=7.9,4.1Hz,2H),1.31(d,J=2.2Hz,6H),0.95-1.18(m,6H),0.86(d,J=6.8Hz,2H),0.79(d,J=6.8Hz,2H)
LC-MS:m/z 477.3(M+H)+
化合物#453
8-环丙基-6-((3R)-3-异丙基-4-(2-(甲基亚磺酰基)乙酰基)哌嗪-1-基)-3,3-二甲基-3,4-二氢-1H-吡喃并[3,4-c]吡啶-5-腈(步骤B)
1H NMR(400MHz,氯仿-d)4.50-4.67(m,0.5H),4.26-4.45(m,1.5H),4.04-4.25(m,1.5H),3.71-3.85(m,0.5H),3.58-3.71(m,0.5H),3.40-3.58(m,0.5H),2.92-3.17(m,3H),2.71-2.85(m,5H),2.22-2.37(m,1H),2.13(dd,J=10.8,5.2Hz,1H),1.61-1.77(m,1H),1.27-1.41(m,6H),1.05-1.16(m,3H),0.95-1.05(m,4H),0.75-0.94(m,3H)
LC-MS:m/z 459.3(M+H)+
化合物#454
(1R,2R)-甲基2-((R)-4-(5-氰基-8-环丙基-3,3-二甲基-3,4-二氢-1H-吡喃并[3,4-c]吡啶-6-基)-2-异丙基哌嗪-1-羰基)环丙烷羧酸酯)(步骤B)
1H NMRδ4.83(s,2H),4.57(d,J=10.0Hz,0.5H),4.27-4.40(m,1.5H),4.13-4.25(m,1.5H),3.76-3.84(m,0.5H),3.67-3.76(m,3H),3.52(d,J=1.8Hz,0.5H),2.93-3.18(m,2.5H),2.77(s,2H),2.31-2.40(m,1H),2.17-2.27(m,1H),1.65-1.76(m,1H),1.43-1.50(m,1H),1.27-1.37(m,6H),1.08-1.19(m,2H),0.97-1.06(m,5H),0.84-0.94(m,2H),0.80(dd,J=6.7,4.6Hz,1H)
LC-MS:m/z 481.6(M+H)+
化合物#455
(R)-6-(4-(2-(1,3,4-噁二唑-2-基)乙酰基)-3-异丙基哌嗪-1-基)-8-环丙基-3,3-二甲基-3,4-二氢-1H-吡喃并[3,4-c]吡啶-5-腈(步骤B)
1H NMR(400MHz,氯仿-d)4.73-4.93(m,2H),4.60(d,J=11.8Hz,0.5H),4.26-4.41(m,1.5H),3.96-4.25(m,3H),3.78(d,J=13.5Hz,0.5H),3.43-3.61(m,1H),2.89-3.17(m,2.5H),2.77(s,2H),2.06-2.25(m,1H),1.63-1.77(m,1H),1.32(d,J=3.0Hz,6H),0.95-1.11(m,6H),0.72-0.95(m,4H)
LC-MS:m/z 465.5(M+H)+
化合物#459
(R)-8-环丙基-6-(4-(3-乙氧基丙酰基)-3-异丙基哌嗪-1-基)-3,3-二甲基-3,4-二氢-1H-吡喃并[3,4-c]吡啶-5-腈(步骤B)
1H NMRδ4.84(s,2H),4.66(d,J=9.8Hz,0.5H),4.41(d,J=10.5Hz,0.5H),4.34(d,J=13.3Hz,1H),4.11-4.23(m,1H),3.70-3.89(m,3H),3.48-3.63(m,3H),3.28-3.48(m,1H),2.92-3.13(m,2H),2.82(s,3H),2.74-2.80(m,2H),2.56-2.73(m,2H),2.19(dt,2H),1.71(dt,J=7.8,3.6Hz,1H),1.33(d,J=2.0Hz,6H),1.24-1.30(m,3H),0.97-1.08(m,4H),0.79-0.92(m,4H)
LC-MS:m/z 455.6(M+H)+
化合物#464
6-(4-(环丙烷羰基)-3-(二氟甲基)哌嗪-1-基)-8-环丙基-3,3-二甲基-3,4-二氢-1H-吡喃并[3,4-c]吡啶-5-腈(结构单元7,步骤B)
1H NMR(氯仿-d)4.90-5.04(m,0.5H),4.76-4.90(m,2H),4.68(d,J=13.3Hz,0.5H),4.16-4.34(m,1.5H),4.04-4.16(m,1H),3.91(d,J=13.3Hz,0.5H),3.55-3.82(m,2.5H),3.28-3.45(m,3.5H),3.01-3.22(m,1.5H),2.89-3.01(m,0.5H),2.68-2.89(m,3H),2.56-2.68(m,1H),1.67-1.76(m,1H),1.32(d,J=4.3Hz,6H),1.09-1.18(m,2H),0.96-1.09(m,2H)
LC-MS:m/z 449.2(M+H)+
化合物#465
(1R,2R)-乙基2-((R)-4-(5-氰基-8-环丙基-3,3-二甲基-3,4-二氢-1H-吡喃并[3,4-c]吡啶-6-基)-2-异丙基哌嗪-1-羰基)环丙烷羧酸酯(步骤B)
1H NMRδ4.77-4.89(m,2H),4.57(d,J=10.3Hz,0.5H),4.28-4.41(m,1.5H),4.14-4.22(m,3H),3.95-4.12(m,0.5H),3.77(t,J=10.2Hz,0.5H),3.44-3.60(m,1H),3.05-3.14(m,1H),2.96-3.05(m,0.5H),2.77(s,2H),2.08-2.38(m,3H),1.67-1.77(m,1H),1.46(ddd,J=8.9,5.9,3.3Hz,1H),1.35-1.43(m,1H),1.27-1.34(m,9H),1.09-1.18(m,2H),0.95-1.06(m,5H),0.76-0.93(m,4H)
LC-MS:m/z 495.6(M+H)+
化合物#466
(R)-8-环丙基-6-(3-环丙基-4-(2-(氧杂环丁-3-基)乙酰基)哌嗪-1-基)-3,3-二甲基-3,4-二氢-1H-吡喃并[3,4-c]吡啶-5-腈(结构单元10,步骤B)
1H NMR(400MHz,CDCl3)δ=4.91(ddd,J=8.0,6.3,1.9Hz,2H),4.83(s,2H),4.40(dd,J=7.9,4.5Hz,2H),4.24(d,J=12.8Hz,1H),4.16(d,J=7.2Hz,1H),3.97(s,1H),3.71(t,J=10.0Hz,2H),3.41(dt,J=14.0,6.3Hz,1H),3.32-2.87(m,3H),2.79(d,J=11.3Hz,4H),1.77-1.57(m,2H),1.38-1.28(m,6H),1.14(dd,J=7.1,3.8Hz,2H),1.02(ddd,J=9.4,6.6,2.8Hz,2H),0.58(s,1H),0.40(d,J=4.9Hz,2H)。
LC-MS:m/z 451.6(M+H)+
化合物#467
(R)-N-丁基-5-(4-(5-氰基-8-环丙基-3,3-二甲基-3,4-二氢-1H-吡喃并[3,4-c]吡啶-6-基)-2-异丙基哌嗪-1-基)-2,5-二氧代戊酰胺(步骤B)
1H NMR(400MHz,氯仿-d)δ6.81-6.95(m,1H),4.83(s,2H),4.56(m,0.5H),4.24-4.38(m,1.5H),4.07-4.24(m,1H),3.77(d,J=13.3Hz,0.5H),3.39-3.56(m,1H),3.30(qd,J=6.8,3.6Hz,2H),3.15-3.26(m,2H),2.98-3.10(m,1.5H),2.91-2.98(m,1H),2.70-2.80(m,4H),2.00-2.15(m,1H),1.65-1.76(m,1H),1.48-1.57(m,2H),1.31-1.42(m,6H),1.25-1.31(m,3H),0.88-1.05(m,10H),0.80(d,J=6.8Hz,2H)
LC-MS:m/z 538.5(M+H)+
化合物#469
8-环丙基-6-(4-(3-甲氧基丙酰基)-3-(2,2,2-三氟乙基)哌嗪-1-基)-3,3-二甲基-3,4-二氢-1H-吡喃并[3,4-c]吡啶-5-腈(结构单元4,步骤B)
1H NMR(氯仿-d)δ5.24(br.s.,0.5H),4.69-4.73(m,0.5H),4.51(br,0.5H),3.96-4.15(m,2H),3.88(d,J=13.8Hz,0.5H),3.64-3.83(m,2H),3.46-3.58(m,0.5H),2.88-3.17(m,2.5H),2.56-2.80(m,5H),1.73(br.s.,1H),1.33(s,6H),1.02-1.16(m,4H)
LC-MS:m/z 481.6(M+H)+
化合物#470
8-环丙基-3,3-二甲基-6-(3-(2,2,2-三氟乙基)-4-(3,3,3-三氟丙酰基)哌嗪-1-基)-3,4-二氢-1H-吡喃并[3,4-c]吡啶-5-腈(结构单元4,步骤B)
1H NMR(氯仿-d)δ5.28(br.s.,0.5H),4.71-4.75(m,0.5H),4.32(br,0.5H),3.95-4.16(m,2H),3.75(d,J=13.3Hz,0.5H),3.55-3.70(m,0.5H),3.16-3.35(m,2H),2.88-3.16(m,3H),2.66-2.86(m,3H),1.73(dd,J=8.4,3.9Hz,1H),1.32-1.39(m,6H),1.03-1.17(m,4H)
LC-MS:m/z 505.5(M+H)+
化合物#473
8-环丙基-6-((3R)-3-异丙基-4-(2-(氧杂环丁-2-基)乙酰基)哌嗪-1-基)-3,3-二甲基-3,4-二氢-1H-吡喃并[3,4-c]吡啶-5-腈(结构单元11,步骤B)
1H NMR(400MHz,氯仿-d)4.78-4.90(m,2H),4.67-4.78(m,1H),4.48-4.62(m,0.5H),4.29-4.47(m,1.5H),4.08-4.26(m,1H),3.84(d,J=15.6Hz,0.5H),3.39-3.61(m,1H),2.91-3.10(m,3.5H),2.81-2.91(m,1.5H),2.72-2.81(m,2.5H),2.40-2.64(m,1H),1.91-2.15(m,2H),1.72(m,1H),1.33(m,6H),0.96-1.17(m,6H),0.76-0.96(m,4H)
LC-MS:m/z 453.3(M+H)+
化合物#461
(R)-6-(4-(环丙烷羰基)-3-环丙基哌嗪-1-基)-8-环丙基-3,3-二甲基-3,4-二氢-1H-吡喃并[3,4-c]吡啶-5-腈(结构单元2,步骤C)
1H NMR(氯仿-d)δ4.84(s,2H),3.49-4.54(m,5H),2.99-3.17(m,2H),2.78(s,2H),1.66-1.78(m,2H),1.32(d,J=2.5Hz,6H),1.11-1.19(m,2H),0.89-1.09(m,6H),0.72-0.82(m,2H),0.61(br.s.,1H),0.34-0.54(m,3H)
LC-MS:m/z 421.4(M+H)+
化合物#463
6-(4-(环丙烷羰基)-3-(二氟甲基)哌嗪-1-基)-8-环丙基-3,3-二甲基-3,4-二氢-1H-吡喃并[3,4-c]吡啶-5-腈(结构单元7,步骤C)
1H NMR4.94(d,J=15.6Hz,0.5H),4.76-4.88(m,2H),4.63(d,J=13.6Hz,0.5H),4.51(br,0.5H),4.13-4.33(m,2H),4.01-4.13(m,0.5H),3.73(t,J=11.0Hz,0.5H),3.35(d,J=13.8Hz,0.5H),3.06-3.30(m,1.5H),2.99(t,J=12.0Hz,0.5H),2.78(s,2H),1.74-1.83(m,1H),1.67-1.74(m,1H),1.32(d,J=4.3Hz,6H),1.11-1.18(m,2H),0.94-1.11(m,4H),0.82-0.90(m,2H)
LC-MS:m/z 431.2(M+H)+
化合物#468
(S)-乙基1-乙酰基-4-(5-氰基-8-环丙基-3,3-二甲基-3,4-二氢-1H-吡喃并[3,4-c]吡啶-6-基)哌嗪-2-羧酸酯(结构单元6,步骤C)
1H NMR(氯仿-d)δ5.24(dd,J=4.1,1.9Hz,0.5H),4.77-4.91(m,2H),4.67(dt,J=13.4,2.0Hz,1H),4.42-4.50(m,0.5H),4.11-4.27(m,2H),4.01-4.10(m,0.5H),3.69-3.90(m,1.5H),3.19-3.45(m,1.5H),2.95-3.11(m,1H),2.68-2.84(m,2H),2.05-2.32(m,3.5H),1.66-1.75(m,1H),1.31(d,J=3.3Hz,6H),1.12-1.23(m,5H),0.97-1.07(m,2H)
LC-MS:m/z 427.5(M+H)+
化合物#471
6-(4-(环丙烷羰基)-3-(2,2,2-三氟乙基)哌嗪-1-基)-8-环丙基-3,3-二甲基-3,4-二氢-1H-吡喃并[3,4-c]吡啶-5-腈(结构单元4,步骤C)
1H NMR(氯仿-d)δ5.20(br.s.,0.5H),4.85(s,2H),4.64(d,J=13.3Hz,1H),4.19(d,J=13.3Hz,0.5H),3.94-4.14(m,2H),3.32-3.64(m,2H),2.92-3.22(m,3H),2.68-2.88(m,3H),2.54-2.68(m,0.5H),1.69-1.74(m,1H),1.33(s,6H),1.11-1.15(m,2H),1.01-1.08(m,4H),0.84(br.s.,2H)
LC-MS:m/z 463.3(M+H)+
化合物#474
6-(4-(环丙烷羰基)-6-氟-3-甲基-1,4-二氮杂卓-1-基)-8-环丙基-3,3-二甲基-3,4-二氢-1H-吡喃并[3,4-c]吡啶-5-腈(结构单元8,步骤C)
1H NMR(氯仿-d)δ4.87(s,2H),4.42-4.83(m,4H),4.29(m,1H),4.11(br.s.,1H),3.04-3.15(m,2H),2.80(s,2H),1.71-1.76(m,1H),1.65-1.63(m,1H),1.34(s,6H),1.27(m,1.5H),1.17-1.20(m,1.5H),1.03-1.09(m,4H),0.80-0.98(m,4H)LC-MS:m/z 427.3(M+H)+
化合物#475
6-(4-(环丙烷羰基)-5-甲基-1,4-二氮杂卓-1-基)-8-环丙基-3,3-二甲基-3,4-二氢-1H-吡喃并[3,4-c]吡啶-5-腈(结构单元5,步骤C)
1H NMR(氯仿-d)δ4.76-4.91(m,2H),4.67(dt,J=10.1,6.5Hz,0.5H),4.16-4.42(m,3.5H),3.35-3.52(m,1H),3.05-3.30(m,1.5H),2.90-3.05(m,0.5H),2.71-2.84(m,2H),2.19-2.49(m,1H),1.62-1.92(m,4H),1.21-1.42(m,8H),1.06-1.21(m,4H),0.88-1.06(m,3H),0.73-0.88(m,2H)
LC-MS:m/z 409.2(M+H)+
化合物#443
(R)-8-环丙基-6-(4-(4-羟基丁酰基)-3-异丙基哌嗪-1-基)-3,3-二甲基-3,4-二氢-1H-吡喃并[3,4-c]吡啶-5-腈(步骤B)
1H NMR(氯仿-d)δ4.77-4.91(m,2H),4.65(d,J=10.8Hz,0.5H),4.36-4.48(m,0.5H),4.32(dd,J=13.3,1.8Hz,1H),4.10-4.24(m,1H),3.65-3.84(m,2.5H),3.36-3.58(m,1H),2.89-3.11(m,2.5H),2.69-2.83(m,2H),2.47-2.63(m,2H),2.21-2.34(m,1H),1.90-1.98(m,1H),1.66-1.76(m,1H),1.32(d,J=2.8Hz,6H),0.95-1.17(m,7H),0.75-0.93(m,3H)
LC-MS:m/z 441.2(M+H)+
化合物#460
(R)-8-环丙基-6-(3-环丙基-4-(3-羟基丙酰基)哌嗪-1-基)-3,3-二甲基-3,4-二氢-1H-吡喃并[3,4-c]吡啶-5-腈
1H NMR(氯仿-d)δ4.85(s,2H),4.63-4.67(m,0.5H),4.26(d,J=12.8Hz,1H),4.17(dd,J=12.7,2.1Hz,1H),4.05(d,J=9.0Hz,0.5H),3.91(br.s.,2H),3.74(br.s.,1H),2.90-3.38(m,3H),2.79(s,2H),2.47-2.66(m,2H),1.69-1.78(m,1H),1.33-1.41(m,7H),1.10-1.19(m,2H),0.98-1.09(m,2H),0.44-0.69(m,4H)
LC-MS:m/z 425.4(M+H)+
化合物#457
(R)-异丙基4-(4-(5-氰基-8-环丙基-3,3-二甲基-3,4-二氢-1H-吡喃并[3,4-c]吡啶-6-基)-2-异丙基哌嗪-1-基)-4-氧代丁酸酯(步骤B)
1H NMR(氯仿-d)δ5.02(dq,J=12.4,6.2Hz,1H),4.75-4.91(m,2H),4.62(d,J=11.3Hz,0.5H),4.26-4.43(m,1.5H),4.07-4.26(m,1H),3.79(d,J=13.6Hz,0.5H),3.38-3.60(m,1H),2.91-3.13(m,2.5H),2.71-2.81(m,2H),2.56-2.71(m,4H),2.07-2.39(m,1H),1.66-1.77(m,1H),1.31(d,J=2.5Hz,6H),1.21-1.27(m,6H),0.97-1.18(m,7H),0.74-0.94(m,3H)
LC-MS:m/z 497.3(M+H)+
化合物#458
(R)-2-羟乙基4-(4-(5-氰基-8-环丙基-3,3-二甲基-3,4-二氢-1H-吡喃并[3,4-c]吡啶-6-基)-2-异丙基哌嗪-1-基)-4-氧代丁酸酯(步骤B)
1H NMR(氯仿-d)δ4.76-4.90(m,2H),4.59(d,J=10.8Hz,0.5H),4.09-4.38(m,4.5H),3.68-3.90(m,2.5H),3.36-3.60(m,1H),2.89-3.15(m,2.5H),2.63-2.83(m,6H),2.07-2.36(m,1H),1.67-1.74(m,1H),1.31(d,J=2.5Hz,6H),0.95-1.16(m,7H),0.86-0.94(m,1.5H),0.80(d,J=6.8Hz,1.5H)
LC-MS:m/z 449.7(M+H)+
化合物#440
(R)-甲基3-(4-(5-氰基-8-环丙基-3,3-二甲基-3,4-二氢-1H-吡喃并[3,4-c]吡啶-6-基)-2-环丙基哌嗪-1-基)-3-氧代丙酸酯(结构单元2,步骤C)
1H NMR(氯仿-d)δ4.83(s,2H),4.62–4.65(m,0.5H),4.26(d,J=13.1Hz,1H),4.16(d,J=12.5Hz,1H),4.03(d,J=9.3Hz,0.5H),3.71-3.85(m,3.5H),3.60-3.70(m,0.5H),2.93-3.58(m,5H),2.78(s,2H),1.66-1.75(m,1H),1.36-1.44(m,1H),1.32(d,J=3.0Hz,6H),1.13(t,J=3.6Hz,2H),0.97-1.07(m,2H),0.31-0.64(m,4H)
LC-MS:m/z 453.2(M+H)+
实例21用于6-哌啶并吡啶和7-哌啶并吡啶核心的程序
核心合成1:
步骤A:3-(环丙烷羰基)-4-氧代哌啶-1-羧酸叔丁酯
将500mL配备有搅拌棒的三颈圆底烧瓶填充上4-氧代哌啶-1-羧酸叔丁酯(9.3g,46.8mmol)和120mL的干甲苯。将该溶液用氮气进行吹扫并且冷却至0℃。在搅拌下,逐滴添加LDA(在THF/正庚烷中的2M溶液,24.5mL,15.6mmol)溶液,并且允许将该反应混合物在0℃下继续搅拌5min,之后在剧烈搅拌下添加环丙烷碳酰氯(2.8mL,31.2mmol)。在0℃下再搅拌20min之后,将该反应混合物用1N HCl淬灭直到PH<7。在H2O与二氯甲烷之间进行分配之后,然后将合并的有机层用盐水进行洗涤,用无水Na2SO4干燥并且在真空中进行浓缩。快速柱色谱法(10%乙酸乙酯/石油醚)给出9g呈淡黄色油状物的标题化合物,将其不用进一步纯化而直接用于下一个步骤中。LC-MS:m/z 268.3(M+H)。
步骤B:5-氰基-8-环丙基-6-羟基-3,4-二氢-2,7-萘啶-2(1H)-羧酸叔丁酯
向在70mL EtOH中的3-(环丙烷羰基)-4-氧代哌啶-1-羧酸叔丁酯(8.2g,30.6mmol)和2-氰基乙酰胺(4.1g,49.0mmol)的溶液中添加二乙胺(2.1mL,20.4mmol)。将该反应混合物在室温下搅拌72小时,直到LC-MS指示完成产物的形成。然后,将该反应混合物加热至回流温度;在此期间添加足够的EtOH,以制备澄清溶液。在冷却回至室温以后,将产物从EtOH溶液中沉淀出并且在真空过滤和风干以后获得5.3g呈白色固体的标题化合物,将其不用进一步纯化而直接用于下一个步骤中。LC-MS:m/z 316.5(M+H)。
步骤C:5-氰基-8-环丙基-6-羟基-3,4-二氢-2,7-萘啶-2(1H)-羧酸叔丁酯
将250mL圆底烧瓶填充上8-环丙基-6-羟基-3,3-二甲基-3,4-二氢-1H-吡喃并[3,4-c]吡啶-5-腈(4.8g,15.2mmol)、DMAP(185mg,1.52mmol)、三乙胺(2.74mL,19.7mmol)以及150mL的二氯甲烷。在将该反应混合物在干冰-丙酮浴中冷却至0℃以后,经由注射器逐滴添加三氟甲磺酸酐(3.3mL,19.7mmol)。将生成的混合物在0℃下搅拌30min,之后允许将其加温至室温,并且再搅拌2小时。在TLC指示起始材料完全转化为产物以后,将该反应混合物在真空中进行浓缩并且通过快速柱色谱法(1:10乙酸乙酯/石油醚)纯化,以给出6.5g呈灰白色固体的标题化合物。1H NMR(氯仿-d)δ4.74(br.s.,2H),3.72(t,J=5.9Hz,2H),3.04(t,J=5.8Hz,2H),1.96(br.s.,1H),1.51(s,9H),1.16-1.28(m,4H)
步骤D:(R)-叔丁基5-氰基-8-环丙基-6-(3-环丙基哌嗪-1-基)-3,4-二氢-2,7-萘啶-2(1H)-羧酸酯
将一个密封试管填充上以上的5-氰基-8-环丙基-6-羟基-3,4-二氢-2,7-萘啶-2(1H)-羧酸叔丁酯(715mg,1.60mmol)、(R)-2-环丙基哌嗪(202mg,1.60mmol)、以及在2mL的CH3CN中的二乙胺(0.24mL,1.73mmol)。在回流下,将该反应混合物加热过夜。在将它减压下浓缩之后,通过快速柱色谱法(1:10甲醇/二氯甲烷)纯化该反应混合物,以给出610mg的标题化合物。MS(ES)M+H预期是424.5,发现是424.5。1H NMR(氯仿-d)δ4.62(br.s.,2H),4.25(d,J=13.1Hz,1H),4.05-4.15(m,1H),3.58-3.72(m,2H),3.24-3.38(m,2H),3.16(dd,J=13.3,10.5Hz,1H),3.00(td,J=12.0,3.1Hz,1H),2.91(t,J=5.5Hz,2H),2.26(td,J=9.8,2.8Hz,1H),1.88(br.s.,1H),1.50(s,9H),1.08-1.16(m,2H),1.04(d,J=6.5Hz,2H),0.60-0.67(m,2H),0.47-0.57(m,1H),0.36-0.46(m,1H)
步骤E1:(R)-叔丁基5-氰基-8-环丙基-6-(3-环丙基-4-(3-甲氧基丙酰基)哌嗪-1-基)-3,4-二氢-2,7-萘啶-2(1H)-羧酸酯
向在二氯甲烷(30mL)中的(R)-叔丁基5-氰基-8-环丙基-6-(3-环丙基哌嗪-1-基)-3,4-二氢-2,7-萘啶-2(1H)-羧酸酯(30mg,0.08mmol)、3-甲氧基丙酸(4.23g,10mmol)和DIPEA(2.6g,20mmol)的溶液中添加HATU(4.18g,11mmol)。将该反应混合物在室温下搅拌2h。将有机相用1NHCl水溶液(1×20mL)、饱和NaHCO3以及盐水洗涤,用无水Na2SO4干燥,并且在真空中浓缩。通过制备型HPLC(PE:EA/80:20)来纯化粗产物,以给出4.5g呈白色固体的标题化合物。MS(ES)M+H预期是510.6,发现是510.5,1H NMR(氯仿-d)δ4.55-4.73(m,2H),4.27(d,J=12.8Hz,1H),4.17(d,J=12.5Hz,1H),4.06(d,J=7.5Hz,0.5H),3.83(d,J=12.3Hz,0.5H),3.57-3.77(m,5H),3.38(s,3H),3.20-3.33(m,1H),3.08(d,J=12.8Hz,1H),2.89-3.04(m,3H),2.69(br.s.,1H),2.64(br.s.,1H),1.90(br.s.,1H),1.71(br.s.,1H),1.47-1.57(m,9H),1.10-1.19(m,2H),1.05(d,J=7.0Hz,2H),0.58(br.s.,1H),0.51(br.s.,1H),0.34-0.47(m,2H)
步骤E2:(R)-叔丁基5-氰基-6-(4-(环丙烷羰基)-3-环丙基哌嗪-1-基)-8-环丙基-3,4-二氢-2,7-萘啶-2(1H)-羧酸酯
向在二氯甲烷(30mL)中的(R)-叔丁基5-氰基-8-环丙基-6-(3-环丙基哌嗪-1-基)-3,4-二氢-2,7-萘啶-2(1H)-羧酸酯(4.23g,10mmol)和DIPEA(2.6g,20mmol)的溶液中添加环丙烷碳酰氯(1.76g,15mmol)。将该反应混合物在室温下搅拌0.5h。将有机相用1NHCl水溶液(1×20mL)、饱和NaHCO3以及盐水洗涤,用无水Na2SO4干燥,并且在真空中浓缩。通过制备型HPLC(PE:EA/80:20)来纯化粗产物,以给出4.1g呈白色固体的标题化合物。MS(ES)M+H预期是492.6,发现是492.5。1H NMR(氯仿-d)δ4.55-4.73(m,2H),4.28(d,J=12.5Hz,1H),4.18(d,J=12.3Hz,1H),4.02(br.s.,1H),3.59-3.72(m,3H),3.36-3.58(m,0.5H),3.16(br.s.,1.5H),3.00(br.s.,1H),2.93(t,J=5.6Hz,2H),1.89(br.s.,1H),1.65-1.77(m,1H),1.44-1.55(m,9H),1.14(br.s.,2H),0.95-1.09(m,4H),0.85-0.95(m,1H),0.70-0.83(m,2H),0.60(br.s.,1H),0.31-0.54(m,3H)
(R)-叔丁基5-氰基-8-环丙基-6-(3-环丙基-4-(3,3,3-三氟丙酰基)哌嗪-1-基)-3,4-二氢-2,7-萘啶-2(1H)-羧酸酯
使用方法E1,从3,3,3-三氟丙酸制备该标题化合物。MS(ES)M+H预期是534.6,发现是534.6。1H NMR(氯仿-d)δ4.54-4.73(m,2H),4.26(d,J=12.8Hz,1H),4.17(d,J=12.5Hz,1H),4.06(d,J=8.0Hz,1H),3.75-3.87(m,1H),3.57-3.75(m,2.5H),3.29(q,J=9.3Hz,2H),3.07(d,J=11.8Hz,1.5H),2.86-3.02(m,3H),1.89(br.s.,1H),1.46-1.56(m,9H),1.36-1.44(m,1H),1.13(br.s.,2H),1.05(d,J=6.8Hz,2H),0.60(br.s.,1H),0.52(br.s.,1H),0.36-0.48(m,2H)
(R)-叔丁基5-氰基-8-环丙基-6-(3-环丙基-4-(3-羟基丙酰基)哌嗪-1-基)-3,4-二氢-2,7-萘啶-2(1H)-羧酸酯
使用方法E1,从3-羟基丙酸钠制备该标题化合物。LC-MS:m/z 496.6(M+H)。
步骤F1:(R)-1-环丙基-3-(3-环丙基-4-(3-甲氧基丙酰基)哌嗪-1-基)-5,6,7,8-四氢-2,7-萘啶-4-腈(HCl盐)
向在MeOH(10mL)中的(R)-叔丁基5-氰基-8-环丙基-6-(3-环丙基-4-(3-甲氧基丙酰基)哌嗪-1-基)-3,4-二氢-2,7-萘啶-2(1H)-羧酸酯(2.55g,5mmol)的溶液中添加1NHCl/MeOH溶液(50mL)。将该混合物在室温下搅拌,直到反应完成。在真空中除去溶剂,以给出呈浅黄色油状物的粗产物(2.3g),将其不用进一步纯化而用于下一个步骤中。LC-MS:m/z410.6(M+H)。(R)-3-(4-(环丙烷羰基)-3-环丙基哌嗪-1-基)-1-环丙基-5,6,7,8-四氢-2,7-萘啶-4-腈(HCl盐)
使用方法F1,从(R)-叔丁基5-氰基-6-(4-(环丙烷羰基)-3-环丙基哌嗪-1-基)-8-环丙基-3,4-二氢-2,7-萘啶-2(1H)-羧酸酯制备该标题化合物。LC-MS:m/z392.6(M+H)。
(R)-1-环丙基-3-(3-环丙基-4-(3,3,3-三氟丙酰基)哌嗪-1-基)-5,6,7,8-四氢-2,7-萘啶-4-腈(HCl盐)
使用方法F1,从(R)-叔丁基5-氰基-8-环丙基-6-(3-环丙基-4-(3,3,3-三氟丙酰基)哌嗪-1-基)-3,4-二氢-2,7-萘啶-2(1H)-羧酸酯制备该标题化合物。LC-MS:m/z 434.5(M+H)。
(R)-1-环丙基-3-(3-环丙基-4-(3-羟基丙酰基)哌嗪-1-基)-5,6,7,8-四氢-2,7-萘啶-4-腈(HCl盐)
使用方法F1,从(R)-叔丁基5-氰基-8-环丙基-6-(3-环丙基-4-(3-羟基丙酰基)哌嗪-1-基)-3,4-二氢-2,7-萘啶-2(1H)-羧酸酯制备该标题化合物。LC-MS:m/z396.6(M+H)。
步骤G1:(R)-7-乙酰基-1-环丙基-3-(3-环丙基-4-(3-甲氧基丙酰基)哌嗪-1-基)-5,6,7,8-四氢-2,7-萘啶-4-腈
化合物#478
向在二氯甲烷(10mL)中的(R)-1-环丙基-3-(3-环丙基-4-(3-甲氧基丙酰基)哌嗪-1-基)-5,6,7,8-四氢-2,7-萘啶-4-腈(111mg,0.25mmol)和Et3N(0.1mL,0.75mmol)的溶液中添加乙酰氯(30mg,0.375mmol)。将该混合物在室温下搅拌1h。在TLC指示起始材料完全转化为产物之后,将该反应混合物用1N HCl水溶液(1×20mL)、饱和NaHCO3以及盐水洗涤,用无水Na2SO4干燥,并且在真空中浓缩。通过制备型HPLC(PE:EA/80:20)来纯化该粗品,以给出78mg呈灰白色固体的标题化合物。
1H NMR(氯仿-d)δ4.70-4.89(m,4H),4.29(d,J=13.1Hz,1H),4.18(d,J=12.5Hz,1H),3.78-3.93(m,1H),3.59-3.77(m,4H),3.36(s,3H),3.19-3.31(m,1H),3.09(d,J=12.8Hz,1H),2.86-3.04(m,3H),2.56-2.74(m,2H),2.17-2.27(m,3H),1.89-2.07(m,2H),1.43(d,J=3.5Hz,0.5H),1.32(br.s.,0.5H),0.99-1.23(m,4H),0.56(br.s.,1H),0.50(br.s.,1H),0.28-0.46(m,2H);LC-MS:m/z 452.6(M+H)
步骤G2:(R)-1-环丙基-3-(3-环丙基-4-(3-甲氧基丙酰基)哌嗪-1-基)-7-丙炔酰基-5,6,7,8-四氢-2,7-萘啶-4-腈
化合物#488
向在二氯甲烷(10mL)中的(R)-1-环丙基-3-(3-环丙基-4-(3-甲氧基丙酰基)哌嗪-1-基)-5,6,7,8-四氢-2,7-萘啶-4-腈(111mg,0.25mmol)、丙炔酸(26mg,0.375mmol)和DIPEA(97mg,0.75mmol)的溶液中添加HATU(142mg,0.375mmol)。将该反应混合物在室温下搅拌2h。将有机相用1N HCl水溶液(1×20mL)、饱和NaHCO3以及盐水洗涤,用无水Na2SO4干燥,并且在真空中浓缩。通过制备型HPLC(PE:EA/80:20)来纯化粗产物,以给出55mg呈白色油状物的标题化合物。
1H NMR(氯仿-d)δ4.98(s,1H),4.73-4.93(m,1H),4.32(d,J=12.8Hz,1H),4.22(d,J=12.8Hz,1H),3.97-4.15(m,2H),3.80-3.97(m,1H),3.62-3.80(m,3H),3.38(s,3H),3.20-3.32(m,1H),2.88-3.17(m,4H),2.69(br.s.,1H),2.44-2.66(m,1H),1.83-1.97(m,1H),1.39(d,J=7.0Hz,1H),0.99-1.24(m,4H),0.58(br.s.,1H),0.52(br.s.,1H),0.42(br.s.,2H);LC-MS:m/z 461.2(M+H)
(R)-1-环丙基-3-(3-环丙基-4-(3-甲氧基丙酰基)哌嗪-1-基)-7-(甲磺酰基)-5,6,7,8-四氢-2,7-萘啶-4-腈
化合物#479
使用方法G1,从(R)-1-环丙基-3-(3-环丙基-4-(3-甲氧基丙酰基)哌嗪-1-基)-5,6,7,8-四氢-2,7-萘啶-4-腈和甲磺酰氯制备该标题化合物。
1H NMR(氯仿-d)δ4.40-4.56(m,2H),4.31(d,J=12.8Hz,1H),4.21(d,J=12.5Hz,1H),4.05(d,J=8.0Hz,1H),3.81(br.s.,1H),3.70(t,J=5.9Hz,2H),3.47-3.62(m,2H),3.36(s,3H),3.27(s,1H),3.03-3.21(m,3H),2.99(d,J=11.8Hz,1H),2.93(s,3H),2.55-2.77(m,2H),1.78-1.90(m,1H),1.29-1.46(m,1H),1.10-1.21(m,2H),0.99-1.10(m,2H),0.56(br.s.,1H),0.50(br.s.,1H),0.29-0.48(m,2H);LC-MS:m/z 488.6(M+H)
(R)-1-环丙基-3-(3-环丙基-4-(3-甲氧基丙酰基)哌嗪-1-基)-7-(2-羟乙基)-5,6,7,8-四氢-2,7-萘啶-4-腈
化合物#484
使用方法G1,从(R)-1-环丙基-3-(3-环丙基-4-(3-甲氧基丙酰基)哌嗪-1-基)-5,6,7,8-四氢-2,7-萘啶-4-腈和2-氯乙醇制备该标题化合物。
1H NMRδ4.62-4.65(d,J=8.3Hz,1H),4.24(d,J=13.1Hz,1H),4.14(d,J=12.5Hz,1H),4.04(d,J=8.3Hz,0.5H),3.60-3.90(m,7H),3.36(s,3H),3.23(br.s.,1H),3.06(d,J=12.8Hz,1H),2.89-3.02(m,3H),2.74-2.89(m,4H),2.43-2.73(m,3H),1.78-1.89(m,1H),1.34(br.s.,1H),1.08-1.19(m,2H),0.93-1.06(m,2H),0.56(br.s.,1H),0.49(br.s.,1H),0.40(d,J=5.5Hz,2H);LC-MS:m/z 454.6(M+H)
化合物#485
(R)-7-丙烯酰基-1-环丙基-3-(3-环丙基-4-(3-甲氧基丙酰基)哌嗪-1-基)-5,6,7,8-四氢-2,7-萘啶-4-腈
使用方法G1,从(R)-1-环丙基-3-(3-环丙基-4-(3-甲氧基丙酰基)哌嗪-1-基)-5,6,7,8-四氢-2,7-萘啶-4-腈和丙烯酰氯制备该标题化合物。
1H NMR(氯仿-d)δ6.67(dd,J=16.7,10.7Hz,1H),6.38(d,J=16.8Hz,1H),5.80(d,J=10.5Hz,1H),4.75-5.05(m,2H),4.30(d,J=12.8Hz,0.5H),4.20(d,J=12.5Hz,1H),4.00-4.13(m,1H),3.80(d,J=11.0Hz,4H),3.55-3.75(m,2H),3.37(s,3H),3.10(d,J=12.0Hz,1H),3.01(br.s.,3H),2.69(br.s.,1H),2.64(br.s.,1H),1.99(br.s.,1H),1.83(br.s.,1H),0.95-1.19(m,4H),0.57(br.s.,2H),0.51(br.s.,1H),0.41(br.s.,1H);LC-MS:m/z 464.6(M+H)
(R)-7-丙烯酰基-1-环丙基-3-(3-环丙基-4-(3-羟基丙酰基)哌嗪-1-基)-5,6,7,8-四氢-2,7-萘啶-4-腈
化合物#498
使用方法G1,从(R)-1-环丙基-3-(3-环丙基-4-(3-羟基丙酰基)哌嗪-1-基)-5,6,7,8-四氢-2,7-萘啶-4-腈和丙烯酰氯制备该标题化合物。
1H NMRδ6.67(dd,J=16.7,10.7Hz,1H),6.37(dd,J=16.8,1.8Hz,1H),5.80(dd,J=10.5,1.5Hz,1H),4.71-4.96(m,2H),4.29(d,J=12.8Hz,1H),4.19(d,J=12.5Hz,1H),3.90(br.s.,3H),3.76-3.87(m,1H),3.62-3.76(m,1H),3.49(br.s.,1H),3.20-3.33(m,1H),3.06-3.20(m,1H),2.85-3.06(m,3H),2.41-2.66(m,2H),1.88(br.s.,1H),1.34(br.s.,1H),0.98-1.18(m,4H),0.59(br.s.,1H),0.50(br.s.,1H),0.43(d,J=6.3Hz,2H);LC-MS:m/z 450.6(M+H)
(R)-1-环丙基-3-(3-环丙基-4-(3-羟基丙酰基)哌嗪-1-基)-7-丙炔酰基-5,6,7,8-四氢-2,7-萘啶-4-腈
化合物#500
使用方法G2,从(R)-1-环丙基-3-(3-环丙基-4-(3-羟基丙酰基)哌嗪-1-基)-5,6,7,8-四氢-2,7-萘啶-4-腈和丙炔酸制备该标题化合物。
1H NMR(氯仿-d)δ4.98(s,1H),4.72-4.94(m,1H),4.28-4.39(m,1H),4.21(d,J=12.8Hz,1H),3.98-4.15(m,2H),3.82-3.98(m,2H),3.61-3.82(m,2H),3.37-3.53(m,1H),3.09-3.35(m,2H),2.90-3.08(m,3H),2.41-2.69(m,2H),1.82-1.96(m,1H),1.72(br.s.,1H),1.30-1.40(m,1H),1.01-1.24(m,4H),0.60(br.s.,1H),0.52(br.s.,1H),0.44(d,J=6.0Hz,2H);LC-MS:m/z 448.5(M+H)
(R)-1-环丙基-3-(3-环丙基-4-(3-甲氧基丙酰基)哌嗪-1-基)-7-甲基丙烯酰基-5,6,7,8-四氢-2,7-萘啶-4-腈
化合物#502
使用方法G2,从(R)-1-环丙基-3-(3-环丙基-4-(3-甲氧基丙酰基)哌嗪-1-基)-5,6,7,8-四氢-2,7-萘啶-4-腈和甲基丙烯酸制备该标题化合物。
1H NMR(氯仿-d)δ5.26(s,1H),5.09(s,1H),4.67-4.86(m,2H),4.25(d,J=12.8Hz,1H),4.15(d,J=12.8Hz,1H),4.01(d,J=8.3Hz,1H),3.58-3.72(m,5H),3.32(s,3H),3.23(br.s.,1H),3.02-3.16(m,1H),2.83-3.02(m,3H),2.51-2.73(m,2H),1.86-2.07(m,4H),1.30(br.s.,1H),0.94-1.17(m,4H),0.53(br.s.,1H),0.46(br.s.,1H),0.21-0.42(m,2H);LC-MS:m/z 478.6(M+H)
(R)-1-环丙基-3-(3-环丙基-4-(3-甲氧基丙酰基)哌嗪-1-基)-7-(3-羟基丙酰基)-5,6,7,8-四氢-2,7-萘啶-4-腈
化合物#501
使用方法G2,从(R)-1-环丙基-3-(3-环丙基-4-(3-甲氧基丙酰基)哌嗪-1-基)-5,6,7,8-四氢-2,7-萘啶-4-腈和3-羟基丙酸钠制备该标题化合物。
1H NMR(氯仿-d)δ4.70-4.91(m,1H),4.65(s,1H),4.30(d,J=12.8Hz,1H),4.19(d,J=12.5Hz,1H),4.00-4.11(m,1H),3.87-3.96(m,2H),3.65-3.86(m,5H),3.36(s,3H),3.26(br.s.,1H),3.04-3.19(m,1H),2.89-3.04(m,3H),2.45-2.74(m,5H),1.89-2.01(m,1H),1.31(br.s.,1H),0.98-1.21(m,4H),0.53-0.74(m,1H),0.50(br.s.,1H),0.17-0.46(m,2H);LC-MS:m/z 482.6(M+H)
(R)-7-乙酰基-3-(4-(环丙烷羰基)-3-环丙基哌嗪-1-基)-1-环丙基-5,6,7,8-四氢-2,7-萘啶-4-腈
化合物#480
使用方法G1,从(R)-3-(4-(环丙烷羰基)-3-环丙基哌嗪-1-基)-1-环丙基-5,6,7,8-四氢-2,7-萘啶-4-腈和乙酰氯制备该标题化合物。
1H NMRδ4.77(q,J=16.9Hz,2H),4.66(s,0.5H),4.30(d,J=12.8Hz,1H),4.20(d,J=12.3Hz,1.5H),3.76-3.91(m,1H),3.62-3.76(m,2H),3.23-3.31(m,0.5H),3.17(dd,J=11.3,6.5Hz,1.5H),2.88-3.07(m,3H),2.15-2.26(m,4H),1.89-2.00(m,1H),1.77-1.89(m,1H),1.30-1.55(m,1H),1.10-1.20(m,2H),0.89-1.10(m,4H),0.69-0.82(m,2H),0.59(br.s.,1H),0.24-0.54(m,3H);LC-MS:m/z 434.6(M+H)
(R)-3-(4-(环丙烷羰基)-3-环丙基哌嗪-1-基)-1-环丙基-7-(甲磺酰基)-5,6,7,8-四氢-2,7-萘啶-4-腈
化合物#481
使用方法G1,从(R)-3-(4-(环丙烷羰基)-3-环丙基哌嗪-1-基)-1-环丙基-5,6,7,8-四氢-2,7-萘啶-4-腈和甲磺酰氯制备该标题化合物。
1H NMR(氯仿-d)δ4.48(d,J=2.8Hz,2H),4.33(d,J=12.5Hz,1H),4.22(d,J=12.3Hz,1H),3.95–4.12(m,1H),3.43-3.64(m,3H),3.27(d,J=7.3Hz,1H),3.15(s,1H),2.98-3.12(m,3H),2.92(s,3H),1.88-1.97(m,1H),1.79-1.87(m,1H),1.20-1.27(m,1H),1.12-1.18(m,2H),0.91-1.08(m,4H),0.71-0.84(m,2H),0.35-0.65(m,4H);LC-MS:m/z470.6(M+H)
(R)-7-丙烯酰基-3-(4-(环丙烷羰基)-3-环丙基哌嗪-1-基)-1-环丙基-5,6,7,8-四氢-2,7-萘啶-4-腈
化合物#489
使用方法G1,从(R)-3-(4-(环丙烷羰基)-3-环丙基哌嗪-1-基)-1-环丙基-5,6,7,8-四氢-2,7-萘啶-4-腈和丙烯酰氯制备该标题化合物。
1H NMRδ6.67(dd,J=16.4,10.7Hz,1H),6.28-6.48(m,1H),5.80(d,J=10.5Hz,1H),4.72-5.02(m,2H),4.46(d,J=6.3Hz,1H),4.33(d,J=12.8Hz,1H),4.23(d,J=12.5Hz,1H),3.74-4.03(m,3H),3.19(br.s.,2H),3.02(br.s.,3H),2.00(br.s.,1H),1.70(br.s.,1H),1.37-1.52(m,1H),1.16(br.s.,2H),0.93-1.11(m,4H),0.72-0.87(m,2H),0.62(br.s.,1H),0.45-0.55(m,2H),0.29-0.45(m,1H);LC-MS:m/z 446.6(M+H)
(R)-3-(4-(环丙烷羰基)-3-环丙基哌嗪-1-基)-1-环丙基-7-丙炔酰基-5,6,7,8-四氢-2,7-萘啶-4-腈
化合物#491
使用方法G2,从(R)-3-(4-(环丙烷羰基)-3-环丙基哌嗪-1-基)-1-环丙基-5,6,7,8-四氢-2,7-萘啶-4-腈和丙炔酸制备该标题化合物。
1H NMR(氯仿-d)δ4.98(s,0.5H),4.71-4.91(m,1.5H),4.53(br.s.,1H),4.34(d,J=12.5Hz,1H),4.24(d,J=12.3Hz,1H),3.97-4.16(m,2H),3.81-3.97(m,1H),3.55-3.78(m,1H),3.14-3.35(m,2H),2.90-3.13(m,3H),1.86-1.99(m,1H),1.30-1.58(m,2H),1.13-1.23(m,2H),1.03-1.13(m,3H),1.00(br.s.,1H),0.71-0.84(m,2H),0.61(br.s.,1H),0.45-0.55(m,2H),0.22-0.45(m,1H);LC-MS:m/z 444.5(M+H)
(R)-3-(4-(环丙烷羰基)-3-环丙基哌嗪-1-基)-1-环丙基-7-(乙烯基磺酰基)-5,6,7,8-四氢-2,7-萘啶-4-腈
化合物#493
使用方法G1,从(R)-3-(4-(环丙烷羰基)-3-环丙基哌嗪-1-基)-1-环丙基-5,6,7,8-四氢-2,7-萘啶-4-腈和2-氯乙磺酰氯制备该标题化合物。
1H NMR(氯仿-d)δ6.52(dd,J=16.6,9.8Hz,1H),6.38(d,J=16.6Hz,1H),6.11(d,J=9.8Hz,1H),4.39-4.50(m,3H),4.34(d,J=12.8Hz,1H),4.24(d,J=12.3Hz,1H),3.58-3.85(m,1H),3.51(dtd,J=18.9,12.5,5.8Hz,2.5H),3.13-3.38(m,1.5H),3.07(t,J=5.8Hz,3H),1.77-1.88(m,1H),1.31-1.50(m,2H),1.13-1.22(m,2H),0.95-1.11(m,4H),0.76-0.86(m,2H),0.62(br.s.,1H),0.29-0.56(m,3H);LC-MS:m/z 482.6(M+H)
(R)-甲基5-氰基-6-(4-(环丙烷羰基)-3-环丙基哌嗪-1-基)-8-环丙基-3,4-二氢-2,7-萘啶-2(1H)-羧酸酯
化合物#494
使用方法G1,从(R)-3-(4-(环丙烷羰基)-3-环丙基哌嗪-1-基)-1-环丙基-5,6,7,8-四氢-2,7-萘啶-4-腈和氯甲酸甲酯制备该标题化合物。
1H NMR(氯仿-d)δ4.61-4.77(m,2H),4.50(br.s.,0.5H),4.30(d,J=12.8Hz,1H),4.21(d,J=12.5Hz,1H),3.86-4.06(m,0.5H),3.78(s,3H),3.63-3.77(m,3H),3.50(br.s.,1H),3.18(br.s.,1H),2.84-3.09(m,3H),1.91(br.s.,1H),1.36-1.51(m,1H),1.22-1.35(m,1H),1.12-1.20(m,2H),0.94-1.10(m,4H),0.73-0.85(m,2H),0.62(br.s.,1H),0.33-0.56(m,3H);LC-MS:m/z 450.6(M+H)
(R)-7-(2-氰乙酰基)-3-(4-(环丙烷羰基)-3-环丙基哌嗪-1-基)-1-环丙基-5,6,7,8-四氢-2,7-萘啶-4-腈
化合物#497
使用方法G2,从(R)-3-(4-(环丙烷羰基)-3-环丙基哌嗪-1-基)-1-环丙基-5,6,7,8-四氢-2,7-萘啶-4-腈和2-氰乙酸制备该标题化合物
1H NMR(氯仿-d)δ4.70-4.91(m,1H),4.67(s,1H),4.33(d,J=12.5Hz,1H),4.22(d,J=11.5Hz,1H),3.94-4.15(m,0.5H),3.70-3.94(m,2.5H),3.60-3.69(m,1H),3.43-3.60(m,1H),3.12-3.34(m,1H),2.99-3.12(m,2H),2.89-2.99(m,1H),1.87-1.96(m,2H),1.69(br.s.,1H),1.12-1.22(m,2H),0.91-1.11(m,4H),0.71-0.83(m,2H),0.59(br.s.,1H),0.29-0.54(m,3H);LC-MS:m/z 459.6(M+H)
(R,E)-7-丁-2-烯酰-3-(4-(环丙烷羰基)-3-环丙基哌嗪-1-基)-1-环丙基-5,6,7,8-四氢-2,7-萘啶-4-腈
化合物#499
使用方法G2,从(R)-3-(4-(环丙烷羰基)-3-环丙基哌嗪-1-基)-1-环丙基-5,6,7,8-四氢-2,7-萘啶-4-腈和(E)-丁-2-烯酸制备该标题化合物
1H NMRδ6.85-7.03(m,1H),6.23-6.43(m,1H),4.70-4.99(m,2H),4.53(br.s.,1H),4.26-4.37(m,1H),4.20(d,J=12.5Hz,1H),3.90-4.06(m,1H),3.68-3.90(m,2H),3.39-3.66(m,1H),3.09-3.39(m,1H),2.99(br.s.,3H),1.84-2.03(m,4H),1.61-1.79(m,1H),1.36-1.51(m,1H),1.10-1.20(m,2H),0.92-1.10(m,4H),0.74-0.85(m,2H),0.60(br.s.,1H),0.27-0.54(m,3H);LC-MS:m/z 460.6(M+H)
(R)-7-丙烯酰基-1-环丙基-3-(3-环丙基-4-(3,3,3-三氟丙酰基)哌嗪-1-基)-5,6,7,8-四氢-2,7-萘啶-4-腈
化合物#490
使用方法G1,从(R)-1-环丙基-3-(3-环丙基-4-(3,3,3-三氟丙酰基)哌嗪-1-基)-5,6,7,8-四氢-2,7-萘啶-4-腈和丙烯酰氯制备该标题化合物
1H NMRδ6.66(dd,J=16.1,10.8Hz,1H),6.37(d,J=16.8Hz,1H),5.68-5.97(m,1H),4.72-5.01(m,2H),4.44(t,J=6.1Hz,1H),4.31(d,J=12.8Hz,1H),4.21(d,J=12.3Hz,1H),3.76-3.98(m,3H),3.72(br.s.,1H),3.30(d,J=8.8Hz,2H),3.05-3.20(m,2H),3.01(br.s.,2H),1.99(br.s.,1H),1.37(br.s.,1H),0.95-1.24(m,4H),0.60(br.s.,1H),0.52(br.s.,1H),0.36-0.48(m,2H);LC-MS:m/z 488.5(M+H)
步骤H:5-氰基-8-环丙基-6-(2-氟-4-(甲氧羰基)苯基)-3,4-二氢-2,7-萘啶-2(1H)-羧酸叔丁酯
向在DMF(150mL)中的2-氟-4-(甲氧羰基)苯基硼酸(400mg,2mmol)的溶液中添加5-氰基-8-环丙基-6-(三氟甲基磺酰基氧基)-3,4-二氢-2,7-萘啶-2(1H)-羧酸叔丁酯(896mg,2mmol)、二氯-双(三苯基膦)钯(II)(140mg,0.2mmol)和碳酸钾(420mg,6mmol),并且将该混合物在90℃下,在氮气下搅拌10小时。将该混合物用乙酸乙酯和水进行稀释。将有机层分离,用盐水进行洗涤,用硫酸镁干燥并且在真空中浓缩。快速柱色谱法(10%乙酸乙酯/石油醚)给出呈灰白色固体的标题化合物(780mg),将其不用进一步纯化而直接用于下一个步骤中。LC-MS:m/z 352.5(M+H)
步骤J:4-(4-氰基-1-环丙基-5,6,7,8-四氢-2,7-萘啶-3-基)-3-氟苯甲酸甲酯盐酸化物
向在MeOH(5mL)中的5-氰基-8-环丙基-6-(2-氟-4-(甲氧羰基)苯基)-3,4-二氢-2,7-萘啶-2(1H)-羧酸叔丁酯(270mg,0.5mmol)的溶液中添加1NHCl/MeOH溶液(20mL)。将该混合物在室温下搅拌,直到反应完成。在真空中除去溶剂,以给出呈浅黄色油状物的粗产物(240mg),将其不用进一步纯化而用于下一个步骤中。LC-MS:m/z 352.5(M+H)
化合物#496
向在二氯甲烷(10mL)中的4-(4-氰基-1-环丙基-5,6,7,8-四氢-2,7-萘啶-3-基)-3-氟苯甲酸甲酯盐酸化物(97mg,0.25mmol)和Et3N(0.1mL,0.75mmol)的溶液中添加2-氯乙磺酰氯(62mg,0.375mmol)。将该混合物在室温下搅拌3h。在TLC指示起始材料完全转化为产物之后,将该反应混合物用1N HCl水溶液(1×20mL)、饱和NaHCO3以及盐水洗涤,用无水Na2SO4干燥,并且在真空中浓缩。通过制备型HPLC分离(PE:EA/80:20)来纯化该粗品,以给出55mg呈灰白色固体的标题化合物。
1H NMR(氯仿-d)δ7.95(dd,J=8.0,1.5Hz,1H),7.87(dd,J=10.4,1.4Hz,1H),7.58(t,J=7.5Hz,1H),6.55(dd,J=16.6,9.8Hz,1H),6.41(d,J=16.6Hz,1H),6.15(d,J=9.5Hz,1H),4.59(s,2H),3.97(s,3H),3.59(t,J=5.9Hz,2H),3.20(t,J=5.8Hz,2H),1.88-2.01(m,1H),1.24-1.31(m,2H),1.08-1.18(m,2H);LC-MS:m/z 442.5(M+H)
化合物#495
向在二氯甲烷(10mL)中的4-(4-氰基-1-环丙基-5,6,7,8-四氢-2,7-萘啶-3-基)-3-氟苯甲酸甲酯盐酸化物(97mg,0.25mmol)、丙炔酸(26mg,0.375mmol)和DIPEA(97mg,0.75mmol)的溶液中添加HATU(142mg,0.375mmol)。将该反应混合物在室温下搅拌2h。将有机相用1N HCl水溶液(1×20mL)、饱和NaHCO3以及盐水洗涤,用无水Na2SO4干燥,并且在真空中浓缩。通过制备型HPLC(PE:EA/80:20)来纯化粗产物,以给出52mg呈灰白色油状物的标题化合物。
1H NMR(氯仿-d)δ7.95(d,J=8.0Hz,1H),7.87(d,J=10.5Hz,1H),7.58(t,J=7.5Hz,1H),5.14(s,0.5H),4.98(s,1.5H),4.14(t,J=5.8Hz,1.5H),3.86-4.06(m,3.5H),3.28(s,1H),3.03-3.24(m,2H),2.02-2.12(m,1H),1.21-1.29(m,2H),1.10-1.19(m,2H);LC-MS:m/z 404.4(M+H)
化合物#503
1H NMR(氯仿-d)δ.6.50(dd,J=16.6,9.8Hz,1H),6.36(d,J=16.6Hz,1H),6.09(d,J=9.8Hz,1H),4.41(s,2H),3.62-3.76(m,4H),3.49(t,J=5.9Hz,2H),3.02(t,J=5.9Hz,2H),2.46-2.66(m,4H),2.36(s,3H),1.65-1.86(m,1H),1.09-1.20(m,2H)。LC-MS:m/z 388.2(M+H)
核心合成2:
步骤A:4-(环丙烷羰基)-3-氧代哌啶-1-羧酸叔丁酯
在-70℃下,向在THF(20mL)中的3-氧代哌啶-1-羧酸叔丁酯(5.5g,27.6mmol)的溶液中缓慢添加LDA(11mL,16.8mmol)。将该混合物在-70℃下搅拌20min之后,添加环丙烷碳酰氯(1.58ml,16.2mmol)。将生成的混合物再搅拌10min,允许加温至0℃,并且然后用水(10mL)中的饱和NH4Cl淬灭。然后添加EA(30mL)并且将有机相分离、干燥并浓缩,以给出苍白色油状物,用快柱(PE:EA=5:1)纯化该油状物,以获得4g的标题化合物11,将其不用进一步纯化而直接用于下一个步骤中。
步骤B:8-氰基-5-环丙基-7-羟基-3,4-二氢-2,6-萘啶-2(1H)-羧酸叔丁酯
向在EtOH(7ml)中的化合物11(3g,11.6mmol)的溶液中添加Et2NH(1mL)和2-氰基乙酰胺(1.47g,17.5mmol)。将该混合物在室温下搅拌2天。将生成的沉淀进行过滤并干燥,以给出1g的标题化合物12,将其不用进一步纯化而用于下一个步骤中。1H NMR(氯仿-d)δ:4.58(br.s.,2H),3.66(t,J=5.6Hz,2H),2.76(br.s.,2H),1.49(s,9H),0.92-1.05(m,4H)。
步骤C:8-氰基-5-环丙基-7-(((三氟甲基)磺酰基)氧基)-3,4-二氢-2,6-萘啶-2(1H)-羧酸叔丁酯
在-40℃下,向在DCM(10ml)中的12的溶液中缓慢添加Et3N。然后在相同温度下添加三氟甲磺酸酐。在从-30℃至0℃下,将该反应再搅拌3h。使用TLC来监测起始材料的完全消耗。然后向该反应中添加水(10mL)并且将有机相分离、浓缩并且用PTLC(EA:PE=1:2)纯化,以给出600mg的标题化合物13。1H NMR(氯仿-d)δ4.78(br.s.,2H),3.75(t,J=5.6Hz,2H),3.06(t,J=5.8Hz,2H),2.01(br.s.,1H),1.51(s,9H),1.19-1.31(m,4H)。
步骤D:(R)-叔丁基8-氰基-5-环丙基-7-(3-环丙基哌嗪-1-基)-3,4-二氢-2,6-萘啶-2(1H)-羧酸酯
将在密封试管中的化合物13(100mg,0.223mmol)和环丙基哌嗪(170mg,1.35mmol)的溶液加热至80℃并且在相同温度下再搅拌12小时。将生成的溶液进行浓缩并且通过PTLC(EA:PE=1:1)进行纯化,以给出80mg的标题化合物14。1H NMR(氯仿-d)δ4.62(br.s.,2H),4.28(d,1H),4.07-4.18(m,1H),3.58-3.72(m,2H),3.24-3.38(m,2H),3.16(dd,10.5Hz,1H),3.00(td,J=12.0,3.1Hz,1H),2.89(t,J=5.3Hz,2H),2.26(td,J=9.8,2.8Hz,1H),1.88(br.s.,1H),1.52(s,9H),1.08-1.16(m,2H),1.04(d,J=6.5Hz,2H),0.65-0.69(m,2H),0.49-0.59(m,1H),0.38-0.47(m,1H)。
步骤E:(R)-叔丁基8-氰基-5-环丙基-7-(3-环丙基-4-(3-甲氧基丙酰基)哌嗪-1-基)-3,4-二氢-2,6-萘啶-2(1H)-羧酸酯
在室温下,将在DCM(2mL)中的14(60mg,0.141mmol)、3-甲氧基丙酸(22mg,0.17mmol)、HATU(8mg)的溶液搅拌2小时。将该反应用水进行洗涤,浓缩并且通过PTLC(EA:PE=2:3)进行纯化,以给出50mg的标题化合物15。1H NMR(氯仿-d)δ:4.65(br.s.,2H),3.99-4.29(m,3H),3.58-3.88(m,4H),3.32-3.48(m,3H),2.84(t,J=5.3Hz,2H),2.58(t,J=6.3Hz,2H),2.01(br.s.,1H),1.81(m,1H),1.47-1.54(m,9H),1.06-1.15(m,2H),1.02(dt,J=7.7,2.9Hz,2H)
步骤F:(R)-6-丙烯酰基-1-环丙基-3-(3-环丙基-4-(3-甲氧基丙酰基)哌嗪-1-基)-5,6,7,8-四氢-2,6-萘啶-4-腈
将在HCl.MTBE(1N,5mL)中的5(50mg)的溶液搅拌2小时。将生成的溶液进行浓缩,以给出黏稠油状物,将其溶解于DCM(2mL)中并且用丙烯酰氯(17mg)和Et3N(20mg)进行处理并且再搅拌10min。使用PTLC(PE:EA=1:1),从该反应中分离出该标题化合物,以给出10mg的化合物#483。1H NMR(氯仿-d)δ6.68(dd,J=16.8,10.5Hz,1H),6.38(d,J=16.8Hz,1H),5.80(d,J=10.8Hz,1H),4.91(br.s.,1H),4.78(br.s.,1H),4.29(d,J=11.8Hz,1H),4.18(d,J=12.3Hz,2H),3.84(br.s.,2H),3.53-3.79(m,3H),3.37(s,3H),2.91(br.s.,3H),2.63(d,J=6.5Hz,2H),2.01(br.m,H),1.08-1.20(m,2H),1.04(br.s.,2H),0.58(br.s.,2H),0.41(br.s.,2H);LC-MS:m/z 464.8(M+H)+
化合物#483
(R)-6-丙烯酰基-1-环丙基-3-(3-环丙基-4-(3-甲氧基丙酰基)哌嗪-1-基)-5,6,7,8-四氢-2,6-萘啶-4-腈
1H NMRδ6.68(dd,J=16.8,10.5Hz,1H),6.38(d,J=16.8Hz,1H),5.80(d,J=10.8Hz,1H),4.91(br.s.,1H),4.78(br.s.,1H),4.29(d,J=11.8Hz,1H),4.18(d,J=12.3Hz,2H),3.84(br.s.,2H),3.53-3.79(m,3H),3.37(s,3H),2.91(br.s.,3H),2.63(d,J=6.5Hz,2H),2.01(br.m,H),1.08-1.20(m,2H),1.04(br.s.,2H),0.58(br.s.,2H),0.41(br.s.,2H);LC-MS:m/z 464.8(M+H)+
化合物#482
(R)-6-丙烯酰基-3-(4-(环丙烷羰基)-3-环丙基哌嗪-1-基)-1-环丙基-5,6,7,8-四氢-2,6-萘啶-4-腈
使用与化合物#483相同的程序合成该标题化合物,不同的是用环丙烷碳酰氯代替3-甲氧基丙酸(步骤E)。
1H NMRδ6.69(dd,J=16.8,10.5Hz,1H),6.39(d,J=16.6Hz,1H),5.81(d,J=11.0Hz,1H),4.92(br.s.,1H),4.79(br.s.,1H),4.32(d,J=12.8Hz,1H),4.22(d,J=12.3Hz,2H),3.85(br.s.,4H),2.92(br.s.,2H),2.02(br.s.,2H),1.23-1.38(m,4H),1.11-1.23(m,2H),0.97-1.10(m,4H),0.73-0.97(m,4H),0.31-0.60(m,2H).LC-MS:m/z446.9(M+H)+
化合物#487
(R)-1-环丙基-3-(3-环丙基-4-(3-甲氧基丙酰基)哌嗪-1-基)-6-(甲磺酰基)-5,6,7,8-四氢-2,6-萘啶-4-腈
1H NMRδ4.51(s,2H),4.30(d,J=12.8Hz,1H),4.21(d,J=12.5Hz,1H),3.73(t,J=5.8Hz,3H),3.61(br.m.,5H),3.38(s,3H),2.86-3.05(m,6H),2.65(m,2H),1.87-2.11(m,2H),1.04-1.23(m,4H),0.37-0.64(m,4H).LC-MS:m/z 462.9(M+H)+
化合物#486
(R)-1-环丙基-3-(3-环丙基-4-(3-甲氧基丙酰基)哌嗪-1-基)-6-丙炔酰基-5,6,7,8-四氢-2,6-萘啶-4-腈
使用与化合物#483相同的程序合成该标题化合物,不同的是用丙炔酸代替丙烯酰氯(步骤F)。
1H NMRδ5.00(d,J=4.0Hz,1H),4.86(s,1H),4.25-4.50(m,1H),4.20(d,J=12.8Hz,1H),4.02-4.15(m,2H),3.78-4.02(m,2H),3.57-3.78(m,3H),3.33-3.41(m,3H),3.10-3.19(m,1H),2.85-3.10(m,3H),2.46-2.75(m,2H),2.11-2.26(m,1H),1.87-2.11(m,1H),0.97-1.24(m,4H),0.59(br.s.,1H),0.52(br.s.,1H),0.22-0.48(m,2H)。LC-MS:m/z 462.7(M+H)+
化合物#492
(R)-叔丁基8-氰基-5-环丙基-7-(3-环丙基-4-(3-甲氧基丙酰基)哌嗪-1-基)-3,4-二氢-2,6-萘啶-2(1H)-羧酸酯
1H NMR(氯仿-d)δ:5.45(d,J=3.3Hz,1H),5.29-5.40(m,1H),5.24(dd,J=16.6,3.0Hz,1H),4.82(s,2H),4.29(d,J=12.5Hz,1H),4.19(d,J=12.5Hz,1H),4.06(br.s.,1H),3.86(br.s.,2H),3.57-3.79(m,3H),3.32-3.48(m,3H),3.27(br.s.,1H),3.10(d,J=13.6Hz,1H),2.86-3.05(m,3H),2.69(br.s.,1H),2.64(br.s.,1H),2.01(dd,J=7.5,3.8Hz,1H),1.58-1.84(m,2H),1.38-1.51(m,1H),1.30-1.38(m,2H),1.27(br.s.,2H),0.97-1.20(m,4H),0.89(t,J=6.5Hz,1H),0.58(br.s.,1H),0.52(br.s.,1H),0.42(br.s.,2H)。LC-MS:m/z 482.2(M+H)+
尽管已经描述了本发明的若干实施例的若干方面,应理解,本领域技术人员将容易想到不同变更、修饰和改进。此类变更、修饰和改进旨在为本披露的一部分,并且旨在本发明的精神和范围之内。
Claims (43)
1.一种具有结构式I的化合物
或其药学上可接受的盐,其中:
X是CR4;
Y是-N(R5)-或-CH(R5)-;
Z是-O-、-S-、-C(R)2-或N(R7);
W是C(R1)(R1)或N(R7);其条件是Z和W两者不同时为N(R7);
V是N或C(R);
每个R独立地选自氢、甲基以及CF3;
每个R1独立地选自氢、C1-C12烷氧基、以及可任选地被OH或SH取代的C1-C12烷基;
或两个R1与它们所结合的碳原子一起形成一个3-7元环烷基、或4-7元饱和杂环基环,其中所述环烷基或杂环基可任选地被甲基、卤素或CF3取代;
R2选自苯基、3-7元环烷基、C2-C4烷基、以及CF3,其中该苯基或环烷基可任选地被一个选自甲基、CF3或氟的单个取代基取代;
每个R3独立地选自-(C1-C4亚烷基)-O-(C1-C4烷基)、-C1-C4氟代烷基、-C(O)-O-(C1-C4烷基)、-苯基、-杂芳基、C3-C7环烷基、-CH2-N(C1-C4烷基)2、C(O)-N-(C1-C4烷基)2、-C(O)-NH-(C1-C4烷基)、可任选地被卤素以及-OH取代的-C1-C4烷基,或两个R3一起形成一个3-8元饱和环或稠合苯基,其中所述饱和环或稠合苯基可任选地被1至2个甲基取代;
R4选自氢、-CN、卤素、C1-C4烷氧基、-CH2NH(C1-C4烷基)、C2-C4烯基、C2-C4炔基、-(C1-C4烷基)-O-(C1-C4烷基)、C1-C4氟代烷基、C(O)-N-(C1-C4烷基)2、-C(O)-NH-(C1-C4烷基)、-S(O)2-(C1-C4烷基)、以及5元杂芳基;
R5选自:C1-C4烷基、-C(O)-(C1-C4烷基)、-C(O)-(C0-C2亚烷基)-Q、-C(O)-(C0-C2亚烷基)-N(R6)-(C0-C2亚烷基)-Q、-C(O)-O-(C0-C2亚烷基)-Q、-C(O)-(C1-C2亚烷基)-O-(C0-C2亚烷基)-Q、-C(O)-C(O)-Q、-S(O)2-Q、-C(O)-(C1-C4亚烷基)-O-C(O)-(C1-C4烷基)、-C(O)-(C1-C4亚烷基)-C(O)-O-(C1-C4烷基)、-C(O)-N(R6)-(C1-C4亚烷基)-O-C(O)-(C1-C4烷基)、-C(O)-N(R6)-(C1-C4亚烷基)-C(O)-O-(C1-C4烷基)、-C(O)-(C0-C2亚烷基)-N(R6)-(C1-C6烷基)、-C(O)-(C0-C2亚烷基)-C(O)N(R6)-(C1-C6烷基)、-C(O)-(C0-C2亚烷基)-C(O)-(C1-C6烷基)、-C(O)-(C0-C2亚烷基)-N(R6)C(O)O-(C1-C6烷基)、-C(O)-(C0-C2亚烷基)N(R6)-(C2-C6炔基)、-C(O)-(C0-C2亚烷基)-N(R6)-(C2-C6烯基)、C(O)-(C0-C2亚烷基)-N(R6)-(C0-C2亚烷基)-O-(C1-C4烷基)、-C(O)-(C1-C4亚烷基)-O-(C1-C4烷基)、-C(O)-(C1-C2亚烷基)-C(O)C(O)N(R)(C1-C4烷基)、-C(O)-O-(C1-C4亚烷基)-O-(C1-C4烷基)、-(C0-C4亚烷基)-O-C(O)-(C1-C4烷基)、-(C0-C4亚烷基)-C(O)-O-(C1-C4烷基)、-(C0-C4亚烷基)-O-(C1-C4烷基)、-C(O)-(C1-C2亚烷基)-S(O)0-2-(C1-C4烷基)、-S(O)2-(C1-C4烷基)、-C(O)-(C1-C4亚烷基)-C(O)C(O)N(R6)(C1-C6烷基)、-C(O)-(C1-C4亚烷基)-N(R6)S(O)2-(C1-C6烷基)、以及-C(O)-(C1-C4亚烷基)-N(R6)S(O)2Q,其中:
R5中存在的任何亚烷基部分可任选地被OH或F取代;
R5中存在的任何末端甲基部分可任选地被-CH2OH、CF3、-CH2F、-CH2Cl、C(O)CH3、C(O)CF3、CN、-OH或CO2H替代;
每个R6独立地选自氢和甲基;
Q选自芳基、杂芳基、碳环基以及杂环基;并且Q可任选地被高达3个独立地选自以下项的取代基取代:可任选地被-OH取代的C1-C4烷基,C1-C4烷氧基,-(C1-C4亚烷基)-OC(O)O-(C1-C4烷基),-C(O)O-(C1-C4烷基),-CN,氟,氯,以及溴;
每个R7独立地是-G-L-M;
G是一个键或二价的C1-C6饱和的或不饱和的、直链的或支链的烃链,其中可任选地,该烃链的一个、两个或三个亚甲基单位独立地被-NR8-、-O-、-C(O)-、-OC(O)-、-C(O)O-、-S-、-SO-、-SO2-、-C(=S)-、-C(=NR8)-、-N=N-、或-C(=N2)-替代;
L是一个共价键或二价的C1-8饱和的或不饱和的、直链的或支链的烃链,其中L的一个、两个、或三个亚甲基单位可任选地并且独立地被环丙烯、-NR8-、-N(R8)C(O)-、-C(O)N(R8)-、-N(R8)SO2-、SO2N(R8)-、-O-、-C(O)-、-OC(O)-、-C(O)O-、-S-、-SO-、-SO2-、-C(=S)-、-C(=NR8)-、-N=N-、或-C(=N2)-替代;
M是E或3-10元单环的或二环的、饱和的、部分不饱和的、或芳香族的环,具有0-3个独立地选自氮、氧、或硫的杂原子,并且其中所述环被1-4个独立地选自以下项的基团取代:-D-E、氧、NO2、卤素、CN、C1-C6烷基、C2-C6烯基、或C2-C6炔基;
D是一个共价键或二价的C1-C6饱和的或不饱和的、直链的或支链的烃链,其中D的一个或两个亚甲基单位可任选地并且独立地被-NR8-、-S-、-O-、-C(O)-、-SO-、或-SO2-替代;
E是氢、C1-C6烷基、C2-C6烯基、或C2-C6炔基,其中所述烷基、烯基或炔基可任选地被氧、卤素、或CN取代;
每个R8独立地是氢、C1-C6烷基、C2-C6烯基、C2-C6炔基,或选自以下项的可任选经取代的基团:苯基,具有1-2个独立地选自氮、氧、或硫的杂原子的4-7元杂环基,或具有1-4个独立地选自氮、氧、或硫的杂原子的5-6元单环的杂芳环;并且
m是0、1、2或3;
其条件是:
当X是-C(CN)-,Y是-N(R5)-,m是0,R2是苯基或C2-C4烷基,并且Z是-O-或-S-时,那么每个R1不同时是甲基;并且
当X是-C(CN)-,Y是-N(R5)-,m是0,R2是苯基或C2-C4烷基,Z是-CH2-,并且W是C(R1)(R1)时,那么每个R1不同时是氢;以及其中
“芳基”是指完全芳香族的苯基、萘基或蒽基;
“杂芳基”是指全芳香族5-8元单环或8-12元双环的环系统,如果是单环具有1-3个杂原子,如果是双环具有1-6个杂原子,所述杂原子选自O、N、S或其氧化形式;
““碳环基”是指非芳香族的C3-C12单环、双环或三环的烃环系统;以及
“杂环基”是指非芳香族的3-10元单环,8-12元双环的环系统,如果是单环具有1-3个杂原子,如果是双环具有1-6个杂原子,所述杂原子选自O、N、S或其氧化形式。
2.如权利要求1所述的化合物,其中:
X是CR4;
Y是-N(R5)-或-CH(R5)-;
Z是-O-、-S-、-C(R)2-或N(R7);
W是C(R1)(R1)或N(R7);其条件是(1)当Z是-C(R)2-时,那么W不是C(R1)(R1);并且(2)Z和W两者不同时是N(R7);
V是N或C(R);
每个R独立地选自氢、甲基和CF3;
每个R1独立地选自氢、烷氧基、或可任选地被OH以及SH取代的烷基;
或两个R1与它们所结合的碳原子一起形成一个3-7元环烷基、或4-7元饱和杂环基环,其中所述环烷基或杂环基可任选地被甲基、卤素或CF3取代;
R2选自苯基、3-7元环烷基、和C2-C4烷基,其中该苯基或环烷基可任选地被一个选自甲基、CF3或氟的单个取代基取代;
每个R3独立地选自可任选地被卤素取代的-C1-C4烷基,-(C1-C4烷基)-O-(C1-C4烷基),-C1-C4氟代烷基,-C(O)-O-(C1-C4烷基),-苯基,-杂芳基,C3-C7环烷基,-CH2-N(C1-C4烷基)2,C(O)-N-(C1-C4烷基)2,以及-C(O)-NH-(C1-C4烷基),或两个R3一起形成一个3-8元饱和环或稠合苯基,其中所述饱和环或稠合苯基可任选地被1至2个甲基取代;
R4选自氢、-CN、卤素、C1-C4烷氧基、-CH2NH(C1-C4烷基)、C2-C4烯基、C2-C4炔基、-(C1-C4烷基)-O-(C1-C4烷基)、C1-C4氟代烷基、C(O)-N-(C1-C4烷基)2、-C(O)-NH-(C1-C4烷基)、-S(O)2-(C1-C4烷基)、和5元杂芳基;
R5选自:-C(O)-(C1-C4烷基)、-C(O)-(C0-C2亚烷基)-Q、-C(O)-(C0-C2亚烷基)-N(R6)-(C0-C2亚烷基)-Q、-C(O)-O-(C1-C2亚烷基)-Q、-C(O)-(C1-C2亚烷基)-O-(C0-C2亚烷基)-Q、-C(O)-C(O)-Q、-S(O)2-Q、-C(O)-(C1-C4亚烷基)-O-C(O)-(C1-C4烷基)、-C(O)-(C1-C4亚烷基)-C(O)-O-(C1-C4烷基)、-C(O)-N(R6)-(C1-C4亚烷基)-O-C(O)-(C1-C4烷基)、-C(O)-N(R6)-(C1-C4亚烷基)-C(O)-O-(C1-C4烷基)、-C(O)-(C0-C2亚烷基)-N(R6)-(C1-C6烷基)、-C(O)-(C0-C2亚烷基)N(R6)-(C2-C6炔基)、-C(O)-(C0-C2亚烷基)-N(R6)-(C2-C6烯基)、-C(O)-(C0-C2亚烷基)-N(R6)-(C0-C2亚烷基)-O-(C1-C4烷基)、-C(O)-(C1-C2亚烷基)-O-(C1-C4烷基)、-C(O)-(C1-C2亚烷基)-C(O)C(O)N(R)(C1-C4烷基)、-C(O)-O-(C1-C4亚烷基)-O-(C1-C4烷基)、-(C0-C4亚烷基)-O-C(O)-(C1-C4烷基)、-(C0-C4亚烷基)-C(O)-O-(C1-C4烷基)、-(C0-C4亚烷基)-O-(C1-C4烷基)、-C(O)-(C1-C2亚烷基)-S(O)0-2-(C1-C4烷基)、-S(O)2-(C1-C4烷基)、)、-C(O)-(C1-C4亚烷基)-C(O)C(O)N(R6)(C1-C6烷基)、-C(O)-(C1-C4亚烷基)-N(R6)S(O)2-(C1-C6烷基)、和-C(O)-(C1-C4亚烷基)-N(R6)S(O)2Q,其中:
R5中存在的任何亚烷基部分可任选地被OH或F取代;
R5中存在的任何末端甲基部分可任选地被-CH2OH、CF3、-CH2F、-CH2Cl、C(O)CH3、或C(O)CF3替代;
每个R6独立地选自氢和甲基;
Q选自芳基、杂芳基、碳环基以及杂环基;并且Q可任选地被高达3个独立地选自以下项的取代基取代:C1-C4烷基、C1-C4烷氧基、-CN、氟、氯、以及溴;
每个R7独立地是-G-L-M;
G是一个键或二价的C1-C6饱和的或不饱和的、直链的或支链的烃链,其中可任选地,该烃链的一个、两个或三个亚甲基单位独立地被-NR8-、-O-、-C(O)-、-OC(O)-、-C(O)O-、-S-、-SO-、-SO2-、-C(=S)-、-C(=NR8)-、-N=N-、或-C(=N2)-替代;
L是一个共价键或二价的C1-8饱和的或不饱和的、直链的或支链的烃链,其中L的一个、两个、或三个亚甲基单位可任选地并且独立地被环丙烯、-NR8-、-N(R8)C(O)-、-C(O)N(R8)-、-N(R8)SO2-、SO2N(R8)-、-O-、-C(O)-、-OC(O)-、-C(O)O-、-S-、-SO-、-SO2-、-C(=S)-、-C(=NR8)-、-N=N-、或-C(=N2)-替代;
M是E或3-10元单环的或二环的、饱和的、部分不饱和的、或芳香族的环,具有0-3个独立地选自氮、氧、或硫的杂原子,并且其中所述环被1-4个独立地选自以下项的基团取代:-D-E、氧、NO2、卤素、CN、C1-C6烷基、C2-C6烯基、或C2-C6炔基;
D是一个共价键或二价的C1-C6饱和的或不饱和的、直链的或支链的烃链,其中D的一个或两个亚甲基单位可任选地并且独立地被-NR8-、-S-、-O-、-C(O)-、-SO-、或-SO2-替代;
E是氢、C1-C6烷基、C2-C6烯基、或C2-C6炔基,其中所述烷基、烯基或炔基可任选地被氧、卤素、或CN取代;
每个R8独立地是氢、C1-C6烷基、C2-C6烯基、C2-C6炔基,或选自以下项的可任选经取代的基团:苯基,具有1-2个独立地选自氮、氧、或硫的杂原子的4-7元杂环基,或具有1-4个独立地选自氮、氧、或硫的杂原子的5-6元单环的杂芳环;并且
m是0、1、2或3;
其条件是:
当X是-C(CN)-,Y是-N(R5)-,m是0,R2是苯基或C2-C4烷基,并且Z是-O-或-S-时,那么每个R1不同时是甲基;并且
当X是-C(CN)-,Y是-N(R5)-,m是0,R2是苯基或C2-C4烷基,并且Z是-CH2-时,那么每个R1不同时是氢。
3.如权利要求1所述的化合物或其药学上可接受的盐,其中X是-C(CN)-。
4.如权利要求1或2所述的化合物或其药学上可接受的盐,其中每个R1是相同的并且选自甲基和氢。
5.如权利要求3所述的化合物或其药学上可接受的盐,其中Z是-O-。
6.如权利要求3所述的化合物或其药学上可接受的盐,其中Z是-C(CH3)2-并且每个R1是氢。
7.如权利要求3所述的化合物或其药学上可接受的盐,其中Z是-CH2-。
8.如权利要求3所述的化合物或其药学上可接受的盐,其中Z是-N(R7)-。
9.如权利要求1-3或5-8中任一项所述的化合物或其药学上可接受的盐,其中Y是-N(R5)-。
10.如权利要求1所述的化合物或其药学上可接受的盐,其中R2选自可任选地被单个的氟或单个的甲基取代的苯基,可任选地被单个的甲基取代的环己基、环戊基、环丁基、环丙基,异丙基,乙基以及甲基。
11.如权利要求10所述的化合物或其药学上可接受的盐,其中R2选自环己基、环丁基、环丙基、乙基以及异丙基。
12.如权利要求11所述的化合物或其药学上可接受的盐,其中R2是环己基;Z是-O-;并且每个R1是氢。
13.如权利要求11所述的化合物或其药学上可接受的盐,其中R2选自环丁基,环丙基,乙基和异丙基;Z是-O-;并且每个R1是甲基。
14.如权利要求1所述的化合物或其药学上可接受的盐,其中R5选自-C(O)-(C1-C4烷基)、-C(O)-(CH2)0-2-Q、-C(O)-(CH2)1-2-O-(CH2)0-2-Q、-C(O)-(C1-C4亚烷基)-C(O)-O-(C1-C4烷基)、-C(O)-N(R6)-(C1-C4亚烷基)-C(O)-O-(C1-C4烷基)、-C(O)-(CH2)0-2-N(R6)-(C2-C6烯基)、-C(O)-(CH2)1-2-O-(C1-C4烷基)、-C(O)-O-(C1-C4亚烷基)-O-(C1-C4烷基)、-(CH2)0-4-C(O)-O-(C1-C4烷基)、以及-C(O)-(CH2)1-2-S-(C1-C4烷基)。
15.如权利要求1所述的化合物或其药学上可接受的盐,其中R5是-C(O)-(C0-C2亚烷基)-C(O)N(R6)-(C1-C6烷基)、-C(O)-(C0-C2亚烷基)-C(O)-(C1-C6烷基)、-C(O)-(C0-C2亚烷基)-N(R6)C(O)O-(C1-C6烷基)。
16.如权利要求1所述的化合物或其药学上可接受的盐,其中每个R7独立地选自:
以及-(CH2)1-4-SH。
17.如权利要求1所述的化合物或其药学上可接受的盐,其中R7独立地选自-C(O)-CH3、-SO2CH3以及-CH2CH2OH。
18.如权利要求1所述的化合物或其药学上可接受的盐,具有结构式II:
其中:
每个R1都是相同的并且选自氢和甲基;
R2选自可任选地被单个的氟或单个的甲基取代的苯基,可任选地被单个的甲基取代的环己基、环戊基、环丁基、环丙基,异丙基以及甲基;
R3a选自氢和甲基;
R3b选自氢、甲基、乙基、异丁基、异丙基、苯基、-C(O)-O-CH2CH3、-C(O)-O-CH3、以及-CH2-O-CH3;
R3c选自氢和甲基;
R3d选自氢、苯基和甲基;并且
R5是如在权利要求1中所定义的。
19.如权利要求18所述的化合物或其药学上可接受的盐,其中:
每个R1是甲基;并且
R2选自异丙基、环丙基以及环丁基。
20.如权利要求19所述的化合物或其药学上可接受的盐,其中:
R3a、R3c和R3d同时是氢;并且
R3b选自(R)-甲基、(R)-乙基、(R)-异丙基、以及C(O)-O-CH2CH3。
21.如权利要求18所述的化合物或其药学上可接受的盐,其中:
每个R1是氢;并且
R2是环己基。
22.如权利要求20所述的化合物或其药学上可接受的盐,其中
R3a、R3c和R3d同时是氢;并且
R3b是(R)-甲基。
23.如权利要求18-22中任一项所述的化合物或其药学上可接受的盐,其中R5选自-C(O)-(CH2)0-2-OCH3、-C(O)-CH2-OCH2CH3、-C(O)-呋喃基、-C(O)-NH-CH2-CH=CH2、-C(O)-(CH2)1-2-C(O)-OCH3、-C(O)-(CH2)2-SCH3、-C(O)-环丙基、-C(O)-CH2-环丙基、-C(O)-CH2CH3、-C(O)-(CH2)2CH3、-C(O)-CH2Cl、-C(O)-NH-CH3、-C(O)-CH2-噻吩基、-C(O)-NH-(CH2)2-C(O)-OCH3、-C(O)-CH2-吡啶基、-C(O)-(CH2)2-O-苯基、-C(O)-CH2-吡唑基、以及-C(O)-噁唑基。
24.如权利要求1所述的化合物或其药学上可接受的盐,具有结构式(III):
其中:
W或Z中之一是N(R7)并且W或Z中的另一个是C(R1)(R1);
每个R1是相同的并且选自氢和甲基;
R2选自可任选地被单个的氟或单个的甲基取代的苯基,可任选地被单个的甲基取代的环己基、环戊基、环丁基、环丙基,异丙基以及甲基;
R3a选自氢和甲基;
R3b选自氢、甲基、乙基、异丁基、异丙基、苯基、C3-C7环烷基、-C(O)-O-CH2CH3、-C(O)-O-CH3、以及-CH2-O-CH3;
R3c选自氢和甲基;
R3d选自氢、苯基和甲基;并且
R5选自:-C(O)-(C1-C4烷基)、-C(O)-(C0-C2亚烷基)-Q、-C(O)-(C1-C4亚烷基)-O-C(O)-(C1-C4烷基)、-C(O)-(C1-C4亚烷基)-C(O)-O-(C1-C4烷基)、-C(O)-(C1-C2亚烷基)-O-(C1-C4烷基)、-C(O)-O-(C1-C4亚烷基)-O-(C1-C4烷基)、-(C0-C4亚烷基)-O-C(O)-(C1-C4烷基)、-(C0-C4亚烷基)-C(O)-O-(C1-C4烷基)、以及-(C0-C4亚烷基)-O-(C1-C4烷基),其中:
R5中存在的任何亚烷基部分可任选地被OH或F取代;
R5中存在的任何末端甲基部分可任选地被-CH2OH、CF3、-CH2F、-CH2Cl、C(O)CH3、或C(O)CF3替代;
Q选自芳基、杂芳基、碳环基以及杂环基;并且Q可任选地被高达3个独立地选自以下项的取代基取代:C1-C4烷基、C1-C4烷氧基、-CN、氟、氯、以及溴;并且
R7是如对于结构式I所定义的。
25.如权利要求24所述的化合物或其药学上可接受的盐,其中Z是N(R7)并且W是CH2。
26.如权利要求24所述的化合物或其药学上可接受的盐,其中W是N(R7)并且Z是CH2。
27.如权利要求24-26中任一项所述的化合物或其药学上可接受的盐,其中R7是C(O)C1-C4烷基、C(O)C2-C4烯基、C(O)C2-C4炔基、S(O)2C1-C4烷基或S(O)2C2-C4烯基。
28.如权利要求1所述的化合物或其药学上可接受的盐,具有在化学式(II)的化合物中的以下立体构型:
其中:
R3a选自氢和甲基所组成的组中;
R3b选自氢、甲基、乙基、异丁基、异丙基、环丙基、苯基、C(O)OCH2CH3,C(O)OCH3,和CH2OCH3所组成的组中,其中甲基、乙基,异丁基和异丙基中的每一个可任选被氟取代;
R3c选自氢和甲基;以及
R3d选自氢、苯基和甲基。
29.如权利要求24-26或28中任一项所述的化合物或其药学上可接受的盐,其中R5选自:-C(O)-(C1-C4烷基)、-C(O)-(C0-C2亚烷基)-Q、以及-C(O)-(C1-C2亚烷基)-O-(C1-C4烷基)。
30.如权利要求1所述的化合物或其药学上可接受的盐,其中所述化合物选自:
31.如权利要求1所述的化合物或其药学上可接受的盐,其具有如下结构式:
32.如权利要求1所述的化合物或其药学上可接受的盐,其具有如下结构式:
33.如权利要求1所述的化合物或其药学上可接受的盐,其具有如下结构式:
34.如权利要求1所述的化合物或其药学上可接受的盐,其具有如下结构式:
35.如权利要求1所述的化合物或其药学上可接受的盐,其具有如下结构式:
36.一种药物组合物,包括如权利要求1所述的化合物或其药学上可接受的盐,以及一种药学上可接受的载体。
37.如权利要求36所述的药物组合物,进一步包括一种第二治疗剂。
38.权利要求36所述的药物组合物在制备用于治疗一种对特征在于IDH1突变的存在的癌症的药物中的应用,其中该IDH1突变导致一位患者中该酶催化α-酮戊二酸还原为R(-)-2-羟基戊二酸的新的能力。
39.如权利要求38所述的应用,其中该IDH1突变是IDH1 R132H或IDH1R132C突变。
40.如权利要求39所述的应用,其中该癌症选自神经胶质瘤、急性骨髓性白血病、肉瘤、黑色素瘤、非小细胞肺癌、胆管癌、骨髓增生异常综合征、骨髓增生性肿瘤、或结肠癌。
41.如权利要求40所述的应用,其中所述神经胶质瘤是恶性胶质瘤。
42.如权利要求40所述的应用,其中所述肉瘤是软骨肉瘤。
43.如权利要求38-42中任一项所述的应用,其中所述治疗进一步包括一种第二治疗剂。
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PCT/CN2012/077096 WO2012171506A1 (en) | 2011-06-17 | 2012-06-18 | Compounds, their pharmaceutical compositions and their uses as idh1 mutants inhibitors for treating cancers |
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- 2011-06-17 CN CN2011101723574A patent/CN102827170A/zh active Pending
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EP2721033A4 (en) | 2014-11-05 |
CA2839616A1 (en) | 2012-12-20 |
ES2618637T3 (es) | 2017-06-21 |
AU2012269473B2 (en) | 2017-04-20 |
AU2012269473A1 (en) | 2014-01-09 |
JP2014517017A (ja) | 2014-07-17 |
CN103764658A (zh) | 2014-04-30 |
US9662327B2 (en) | 2017-05-30 |
CA2839616C (en) | 2019-08-06 |
JP6196615B2 (ja) | 2017-09-13 |
US20140206673A1 (en) | 2014-07-24 |
EP2721033B1 (en) | 2016-12-07 |
EP2721033A1 (en) | 2014-04-23 |
WO2012171506A1 (en) | 2012-12-20 |
JP2017178968A (ja) | 2017-10-05 |
US20170210749A1 (en) | 2017-07-27 |
CN102827170A (zh) | 2012-12-19 |
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