CN108779096A - 一类氟取代的环丙胺类化合物及其制备方法、药物组合物和用途 - Google Patents

一类氟取代的环丙胺类化合物及其制备方法、药物组合物和用途 Download PDF

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CN108779096A
CN108779096A CN201780017669.3A CN201780017669A CN108779096A CN 108779096 A CN108779096 A CN 108779096A CN 201780017669 A CN201780017669 A CN 201780017669A CN 108779096 A CN108779096 A CN 108779096A
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CN108779096B (zh
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柳红
李佳
王江
苏明波
王姝妮
周宇波
朱未
徐威
李淳朴
蒋华良
陈凯先
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Shanghai Institute of Materia Medica of CAS
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Abstract

提供通式I化合物,其外消旋体、R‑异构体、S‑异构体、可药用盐及它们的混合物,其制备方法、含此类化合物的药物组合物及作为赖氨酸特异性脱甲基酶1(LSD1)抑制剂的用途。提供氟取代的环丙肢类通式I化合物在治疗癌症中的用途。

Description

一类氟取代的环丙胺类化合物及其制备方法、药物组合物和用途 技术领域
本发明涉及药物化学和药物治疗学领域,具体涉及一类氟取代的环丙胺类化合物、其制备方法、含此类化合物的药物组合物及作为赖氨酸特异性脱甲基酶1(LSD1)抑制剂,特别是制备用于治疗癌症、白血病等疾病的药物的用途。
背景技术
表观遗传学是研究基因的DNA序列不发生变化的前提下,通过对核苷酸或染色体的可逆性修饰使基因表达可遗传的变化的遗传学分支学科。表观遗传学的调控机制主要包括DNA甲基化、组蛋白修饰、非编码RNA作用等。大多数情况下,表观遗传信息通过改变胞嘧啶和组蛋白的化学修饰而储存起来,这些化学结构的改变调控染色质的结构。正常的表观遗传过程对于胚胎发育、细胞分化等生命活动有着重要作用。研究证明,很多疾病的发生与表观遗传修饰的异常相关,近年来表观遗传学成为生物学、医学等领域内的研究热点,表观遗传学的相关研究在人类许多疾病的防治过程中具有的重要意义。
LSD1(又称为BHC110、p110b和NPAO)由Shi课题组于2004年所确认11,其结构从酵母到人类均高度保守。在细胞中,LSD1的去甲基化能力具有基因、底物专和环境高度专一性,对不同基因位点的基因表达产生出不同(甚至相反)的功效。研究发现LSD1在促进正常细胞分化中起到了重要的作用,但LSD1也被发现会被异常的招募对致白血病的基因受损的下游异常基因目标产生不当的抑制作用(如MLL-AF9)。在这种情况下,LSD1会维持初始损伤赋予白血病干细胞(LSC)的活性,LSD1下游的细胞效应也显著区别于正常的细胞状态。在正常的造血过程中,在最原始造血干细胞(HSC)水平上并未发现基因表达的变化,这与由完全相反的LSD1消耗诱导的血球减少的观察结果相一致。因此,LSD1若能对正常造血细胞产生可控可逆的毒性,可作为潜在治疗白血病的药物作用靶点。
开发结构新颖的小分子LSD1抑制剂,对于治疗恶性肿瘤和白血病等疾病的研究具有重要的研究意义。
发明内容
本发明的一个目的在于提供一种通式I所示的氟取代的环丙胺类化合物、其可药用的盐、外消旋体、R-异构体、S-异构体或它们的混合物。
本发明的另一个目的在于提供一种上述通式I所示的氟取代的环丙胺类化合物的制备方法。
本发明的再一个目的在于提供一种药物组合物,其包含治疗有效量的选自上述通式I所示的氟取代的环丙胺类化合物、其可药用的盐、外消旋体、R-异构体、S-异构体或它们的混合物中的一种或多种。
本发明的又一个目的在于提供一种赖氨酸特异性脱甲基酶1(LSD1)抑制剂,其包含选自上述通式I所示的氟取代的环丙胺类化合物、其可药用的盐、外消旋体、R-异构体、S-异构体或它们的混合物中的一种或多种。
本发明的又一个目的在于提供上述通式I所示的氟取代的环丙胺类化合物、其可药用的盐、外消旋体、R-异构体、S-异构体或它们的混合物在制备用于治疗与赖氨酸 特异性脱甲基酶1(LSD1)抑制剂相关的恶性肿瘤疾病,例如癌症、白血病等疾病的药物中的用途。
本发明的又一个目的在于提供一种治疗与赖氨酸特异性脱甲基酶1(LSD1)抑制剂相关的恶性肿瘤疾病,例如癌症、白血病等疾病药物的方法,其包括向需要该治疗的患者给药选自上述通式I所示的氟取代的环丙胺类化合物、其可药用的盐、外消旋体、R-异构体、S-异构体或它们的混合物中的一种或多种。
基于上述目的,本发明提供了一种具有如下通式I所示结构的氟取代的环丙胺类化合物,及其外消旋体、R-异构体、S-异构体、药学上可接受的盐或它们混合物:
其中:
A选自:取代或未取代的苯环或者取代或未取代的含有1~4个选自氧、硫和氮中的杂原子的C5-C12的芳香杂环,其中所述的取代的苯环或取代的芳香杂环,每个环上包括1~3个取代基;
其中,所述取代的苯环或取代的芳香杂环上的取代基为氢、氢的同位素、卤素、未取代或由1-3个卤素取代的C1-C12直链或支链的烷基、未取代或由1-3个卤素或苯基取代的C1-C12直链或支链的烷氧基、未取代或由1-3个卤素取代的C2-C12直链或支链的不饱和烃基、未取代或由1-3个卤素取代的C3-C6环烷基、由C1-C6烷氧基取代的C1-C6直链或支链的烷基、由C3-C6环烷基取代的C1-C6直链或支链的烷基、羟基、氰基、硝基、C1-C6直链或支链的羟烷基或巯基;
或者,所述取代的苯环或取代的芳香杂环上任意两个取代基可以与其相邻的碳原子或杂原子一起连接成含有1至3个选自N、O和S中的杂原子的5-7元杂环,所述5-7元杂环非必须地被选自如下基团的取代基所取代:氢、氢的同位素、卤素、未取代或由1-3个卤素取代的C1-C6直链或支链的烷基、未取代或由1-3个卤素取代的C1-C6直链或支链的烷氧基、或羟基;
各R1独立地选自:取代的或未取代的芳基、取代的或未取代的杂芳基、氢、取代的或未取代的C1-C6烷基、-SO2Ra、-NC(O)Ra、-CH2C(O)ORa、-C(O)ORa、-C(O)Ra、-C(O)NRaRb、-NRcRd、取代的或未取代的氨基、脲、酰胺、磺酰胺、取代的或未取代的芳烷基和取代的或未取代的杂芳烷基;
各Ra独立地为氢、苯基、苯基甲基、3,5-二甲基异噁唑-4-基、1,2-二甲基-1H-咪唑-4-基、C3-C7环烷基、C1-C6烷基、C1-C4烷氧基、C1-C3烷基氨基或-NHPh;
Rb为氢或C1-C3烷基,或当连接至相同原子时,
Ra和Rb一起形成5-或6-元杂环烷基环;
Rc、Rd各自独立地选自氢、C1~C3直链或支链烷基、C3~C5环烷基、C1~C3烷氧基、4~6元杂环基、C1~C3烷基酰基、C5~C7芳基酰基、苄基、C5~C7芳基;所述C1~C3直链或支链烷基非必须地被一个或多个选自甲磺基、C1~C3烷氧基、C1~C3烷氧基羰基中的基团所取代;所述杂环基含有1个选自氧、硫和氮中的杂原子;
R2为氢或COOH;
R3为C1-C4烷基、酰基、-C(O)CF3或氢;
W为-(CH2)1-4或-CH(Re)(CH2)0-3,其中Re为CN或C1-C4烷基;
Y为N或C;
X为N或C;
Z为O或(CH2)q,其中q为0-2,当q为0时,Z表示键;
n为0-3;
条件是当Z为O时,Y为N且X为C;
而且,条件是当X为C时,至少一个连接至X的R1基团不为氢。
在另一优选例中,当X为N时,仅有一个R1与X相连。
在另一优选例中,W为-CH2-。
在另一优选例中,Z为(CH2)q,其中q为1。
在另一优选例中,X为C,且至少一个连接至X的R1为-NRcRd,Rc、和Rd各自独立地选自氢、C1-C3直链或支链烷基、C3-C5环烷基、C1-C3烷氧基、4-6元杂环基、C1-C3烷基酰基、C5-C7芳基酰基、苄基、C5-C7芳基;所述C1-C3直链或支链烷基非必须地被一个或多个选自甲磺基、C1-C3烷氧基、C1-C3烷氧基羰基中的基团所取代;所述杂环基含有1个选自氧、硫和氮中的杂原子。
在另一优选例中,X为N,且至少一个连接至X的R1选自取代的或未取代的:芳基、杂芳基、芳烷基、和杂芳烷基。
在另一优选例中,X为N,且至少一个连接至的R1选自取代的或未取代的:芳基C1~C4烷基、和杂芳基C1~C4烷基。
在另一优选例中,所述化合物的结构如通式(1R,2S)-Ia或通式(1S,2R)-Ib所示:
在本发明中,所述卤素为F、Cl、Br或I。
在本发明中,除非特别指出,所用术语具有本领域技术人员公知的一般含义。
在本发明中,术语“C1-C6烷基”是指具有1至6个碳原子的直链或支链烷基,非限制性地包括甲基、乙基、丙基、异丙基、丁基、异丁基、仲丁基、叔丁基、戊基和已基等;优选乙基、丙基、异丙基、丁基、异丁基、仲丁基和叔丁基。
在本发明中,术语“C1-C6烷氧基”是指具有1至6个碳原子的直链或支链烷氧基,非限制性地包括甲氧基、乙氧基、丙氧基、异丙氧基和丁氧基等。
在本发明中,术语“C2-C6烯基”是指具有2至6个碳原子的含有一个双键的直链或支链烯基,非限制性地包括乙烯基、丙烯基、丁烯基、异丁烯基、戊烯基和己烯基等。
在本发明中,术语“C2-C6炔基”是指具有2至6个碳原子的含有一个三键的直链或支链炔基,非限制性地包括乙炔基、丙炔基、丁炔基、异丁炔基、戊炔基和己炔基等。
在本发明中,术语“C3-C10环烷基”是指在环上具有3至10个碳原子的环状烷基,非限制性地包括环丙基、环丁基、环戊基、环己基、环庚基、环辛基和环癸基等。术语“C3-C8环烷基”、“C3-C7环烷基”、和“C3-C6环烷基”具有类似的含义。
在本发明中,术语“C3-C10环烯基”是指在环上具有3至10个碳原子的环状烯基,非限制性地包括环丙烯基、环丁烯基、环戊烯基、环己烯基、环庚烯基、环辛烯基和环癸基烯等。术语“C3-C7环烯基”具有类似的含义。
在本发明中,术语“芳环”或“芳基”具有相同的含义,优选地“芳基”为“C6-C12芳基”或“C6-C10芳基”。术语“C6-C12芳基”是指在环上不含杂原子的具有6至12个碳原子的芳香族环基,如苯基、萘基等。术语“C6-C10芳基”具有类似的含义。
在本发明中,术语“芳香杂环”或“杂芳基”具有相同的含义,指包含一个到多个杂原子的杂芳族基团。这里所指的杂原子包括氧、硫和氮。例如呋喃基、噻吩基、吡啶基、吡唑基、吡咯基、N-烷基吡咯基、嘧啶基、吡嗪基、咪唑基、四唑基等。所 述杂芳基环可以稠合于芳基、杂环基或环烷基环上,其中与母体结构连接在一起的环为杂芳基环。杂芳基可以是任选取代的或未取代的。
在本发明中,术语“3-12元杂环基”是指在环上含有1~3个选自氧、硫和氮中的杂原子的饱和或不饱和的3-12元环基,例如二氧杂环戊基等。术语“3-7元杂环基”具有类似的含义。
在本发明中,术语“取代”指特定的基团上的一个或多个氢原子被特定的取代基所取代。特定的取代基为在前文中相应描述的取代基,或各实施例中所出现的取代基。除非特别说明,某个取代的基团可以在该基团的任何可取代的位点上具有一个选自特定组的取代基,所述的取代基在各个位置上可以是相同或不同的。环状取代基,例如杂环烷基,可以与另一个环相连,例如环烷基,从而形成螺二环系,例如,两个环具有一个共用碳原子。本领域技术人员应理解,本发明所预期的取代基的组合是那些稳定的或化学上可实现的组合。所述取代基例如(但并不限于):C1-8烷基、C2-8烯基、C2-8炔基、C3-8环烷基、3-至12-元杂环基,芳基、杂芳基、卤素、羟基、羧基(-COOH)、C1-8醛基、C2-10酰基、C2-10酯基、氨基、烷氧基、C1-10磺酰基等。
在本发明更优选的实施方案中,本发明的通式(I)的化合物优选为如下具体化合物:
本发明的化合物具有不对称中心、手性轴和手性平面,并且可以以外消旋体、R-异构体或S-异构体的形式存在。本领域技术人员能够采用常规技术手段由外消旋体拆分获得R-异构体和/或S-异构体。
本发明提供了通式I化合物的可药用的盐,具体地为通式I化合物与无机酸或有机酸反应形成常规的可药用盐。例如,常规的可药用盐可通过通式I化合物与无机酸或有机酸反应制得,所述无机酸包括盐酸、氢溴酸、硫酸、硝酸、胺基磺酸和磷酸等,以及所述有机酸包括柠檬酸、酒石酸、乳酸、丙酮酸、乙酸、苯磺酸、对甲苯磺酸、甲磺酸、萘磺酸、乙磺酸、萘二磺酸、马来酸、苹果酸、丙二酸、富马酸、琥珀酸、丙酸、草酸、三氟乙酸、硬酯酸、扑酸、羟基马来酸、苯乙酸、苯甲酸、水杨酸、谷氨酸、抗坏血酸、对胺基苯磺酸、2-乙酰氧基苯甲酸和羟乙磺酸等;或者通式I化合物与无机碱形成的钠盐、钾盐、钙盐、铝盐或铵盐;或者通式I化合物与有机碱形成的甲胺盐、乙胺盐或乙醇胺盐。
本发明另一方面提供了一种通式I表示的化合物的制备方法,该制备方法按照如下方案1、方案2或方案3进行。
式(I)化合物可以通过以下方案1所示的方法制备
以下方案中使用的结构式和R基团标号仅在本部分使用。式(II)和(III)化合物可市场上获得或可使用本领域的常规技术合成。本领域技术人员理解,当HCl用于制备的最后步骤时,下面例示的化合物可以以盐酸盐的形式存在。
式(II)和(III)化合物可以在常规的还原胺化条件下反应,得到式(I)化合物。加成反应通常在极性溶剂(例如甲醇)和酸(例如乙酸)的存在下进行。所述酸通常以相对于式(I)100mol%的量存在。还原剂通常为硼氢化物(例如氰基硼氢化钠)。
方案1
其中,A、W、X、Y、Z、R1、R2、R3分别如上所述,R4选自下组:H、或甲基,V为-CH2-W-或-W-CH2-。
式(I)化合物可以方便地通过方案2所示的方法制备,起始于合成的环丙基胺(IV)和合适地保护的醛(V)。胺(IV)与醛(V)通过还原胺化得到式(VI)中间体。然后可将胺基保护。然后脱去X或Y基团的保护基得到式(VII)化合物,以便于合适的R1取代基进行官能团化,得到式(VIII)化合物。然后,胺可以脱保护基并用R3基团官能团化;
方案2
其中,A、W、X、Y、Z、R1、R2、R3分别如上所述,R4选自下组:H、或甲基,V为-CH2-W-或-W-CH2-。
式(II)和(IV)化合物可以如方案3所示合成。起始于肉桂酸(IX),在缩合剂(例如HATU)和碱(例如DIPEA)的存在下,与二甲羟胺缩合得到酰胺(X)。然后在标准条件(例如三甲基碘化亚砜及氢化钠)的存在下进行环丙基化,反应得到式(XI)化合物。然后该酰胺水解得到式(XII)酸。然后将其在标准的Curtius重排条件下反应,得到所需式(IV)化合物。式(IV)化合物可以在标准条件下转化为式(II)化合物。
方案3
式(1R,2S)-I与(1S,2R)-I化合物可分别通过方案4与方案5所述制备方法得到,具体操作步骤同方案2。
方案4
方案5
本发明的另一方面提供了一种药物组合物,其含有治疗有效量的选自上述通式(Ⅰ)的化合物、其可药用的盐、对映异构体、非对映异构体或外消旋体中的一种或多种,以及任选地,一种或多种可药用的载体、赋形剂、佐剂、辅料和/或稀释剂。所述辅料例如为气味剂、香味剂、甜味剂等。
本发明所提供的药物组合物优选含有重量比为1-99%的活性成份,其优选的比例是,通式I化合物作为活性成分占总重量的65wt%~99wt%,其余部分为药学可接受的载体、稀释液或溶液或盐溶液。
本发明所提供的化合物和药物组合物可以是多种形式,如片剂、胶囊、粉剂、糖浆、溶液状、悬浮液和气雾剂等,并可以存在于适宜的固体或液体的载体或稀释液中和适宜的用于注射或滴注的消毒器具中。
本发明的药物组合物的各种剂型可按照药学领域的常规制备方法制备。其制剂配方的单位计量中包含0.05-200mg通式I化合物,优选地,制剂配方的单位计量中包含0.1mg-100mg通式I化合物。
本发明的化合物和药物组合物可对哺乳动物临床使用,包括人和动物,可以通过口、鼻、皮肤、肺或者胃肠道等的给药途径。最优选为口服。最优选日剂量为0.01-200mg/kg体重,一次性服用,或0.01-100mg/kg体重分次服用。不管用何种服用方法,个人的最佳剂量应依据具体的治疗而定。通常情况下是从小剂量开始,逐渐增加剂量一直到找到最适合的剂量。
本发明的又一方面提供了一种赖氨酸特异性脱甲基酶1(LSD1)抑制剂,其包含选自上述通式I所示的化合物、其可药用的盐、外消旋体、R-异构体、S-异构体或它 们的混合物中的一种或多种,以及任选地一种或多种可药用的载体、赋形剂、佐剂、辅料和/或稀释剂。
本发明的化合物和组合物用于治疗和预防与赖氨酸特异性脱甲基酶1(LSD1)抑制剂相关的恶性肿瘤疾病,所述疾病包括,但不限于,癌症、白血病等疾病。
因此,本发明的又一方面提供了上述通式I所示的化合物、其可药用的盐、外消旋体、R-异构体、S-异构体或它们的混合物在制备用于治疗与赖氨酸特异性脱甲基酶1(LSD1)抑制剂相关的恶性肿瘤疾病,例如癌症、白血病等疾病的药物中的用途。
本发明的又一个方面提供了一种治疗与治疗与赖氨酸特异性脱甲基酶1(LSD1)抑制剂相关的恶性肿瘤疾病,例如癌症、白血病等疾病的方法,其包括向需要该治疗的患者给药选自上述通式I所示的化合物、其可药用的盐、外消旋体、R-异构体、S-异构体或它们的混合物中的一种或多种。
具体实施方式
活性成分
本发明提供了一种具有如下通式I所示结构的氟取代的环丙胺类化合物,或者其外消旋体、R-异构体、S-异构体、药学上可接受的盐或它们的混合物:
其中,
A选自:取代或未取代的芳环(优选地为苯环)或者取代或未取代的含有1~4个选自氧、硫和氮中的杂原子的5-12元的芳香杂环,其中所述的取代的苯环或取代的芳香杂环,每个环上包括1~3个取代基;
其中,所述取代的芳环或取代的芳香杂环上的取代基独立地选自下组:氢、氢的同位素、卤素、未取代或取代的C1-C12直链或支链的烷基、未取代或取代的C1-C12直链或支链的烷氧基、未取代或取代的C2-C12直链或支链的不饱和烃基、未取代或取代的C3-C6环烷基、由C1-C6烷氧基取代的C1-C6直链或支链的烷基、由C3-C6环烷基取代的C1-C6直链或支链的烷基、羟基、氰基、硝基、C1-C6直链或支链的羟烷基或巯基、氧(=O)、未取代的或取代的C6-C12芳基(如苯基、萘基)、未取代的或取代的C6-C12芳基氧基(如苯基、萘基)、取代的或取代的苯基氧基、羧基、酰基(如乙酰基)、和磺酰基(包括苯磺酰基、烷基磺酰基),优选地所述取代基选自下组:卤素、C1-C4直链或支链的烷基、卤素取代的C1-C4直链或支链的烷基、C1-C4烷基氧基、氰基取代的苯基;
或者,所述取代的芳环或取代的芳香杂环上任意两个取代基可以与其相邻的碳原子或杂原子一起连接成含有1至3个选自N、O和S中的杂原子的5-7元杂环,所述5-7元杂环任选地被选自下组的的取代基所取代:氢、氢的同位素、卤素、未取代或由1-3个卤素取代的C1-C6直链或支链的烷基、未取代或由1-3个卤素取代的C1-C6直链或支链的烷氧基、和羟基;
各R1独立地选自:取代的或未取代的芳基、取代的或未取代的杂芳基、氢、取代的或未取代的C1-C6烷基、-SO2Ra、-NC(O)Ra、-(CH2)mC(O)ORa、-C(O)O(CH2)m Ra、-C(O)ORa、-C(O)Ra、-(CH2)mORa、-C(O)NRaRb、-C(S)NRaRb、-CORa、-NRcRd、取代的或未取代的氨基、取代的或未取代的脲、取代的或未取代的酰胺、取代的或未取代的磺酰胺、取代的或未取代的芳基烷基和取代的或未取代的杂芳基烷基,其中m 为1-3的整数,优选地所述取代基选自下组:卤素、羟基、羧基、氰基、氨基、C1-C4烷基、卤素取代的C1-C4烷基、C1-C4烷基酯基、C1-C4烷基磺酰基、氨基苯基酰胺基芳基烷基、和芳基;
各Ra独立地为氢、取代的或未取代的苯基、取代的或未取代的苯基甲基、3,5-二甲基异噁唑-4-基、1,2-二甲基-1H-咪唑-4-基、取代的或未取代的C3-C7环烷基、取代的或未取代的C3-C7杂环基、取代的或未取代的C3-C7杂环基烷基、取代的或未取代的C1-C6烷基、取代的或未取代的C1-C6烯基、取代的或未取代的C1-C4烷氧基、取代的或未取代的C1-C3烷基氨基、-NHPh、或取代的或未取代的5-10元杂芳基、取代的或未取代的芳基烷基和取代的或未取代的杂芳基烷基,优选地所述取代基选自下组:C1-C4烷基、卤素取代的C1-C4烷基、苯基取代的C1-C4烷基、C1-C4烷基酯基、C3-C7环基、C3-C7环基烷基、C3-C7杂环基、苄基取代的C3-C7杂环烷基、芳基、卤素、C1-C4烷氧基、C1-C4卤代烷基、羧基、和羧基取代的苄基;
Rb为氢或C1-C3烷基,或当连接至相同原子时,
Ra和Rb一起形成5-或6-元杂环烷基环;
Rc、Rd各自独立地选自氢、取代的或未取代的C1-C3直链或支链烷基、取代的或未取代的C3-C5环烷基、取代的或未取代的C1-C3烷氧基、取代的或未取代的4-6元杂环基、取代的或未取代的C1-C3烷基酰基、取代的或未取代的芳基酰基、取代的或未取代的芳基磺酰基、取代的或未取代的苄基、取代的或未取代的芳基;所述C1-C3直链或支链烷基非必须地被一个或多个选自甲磺基、C1~C3烷氧基、C1~C3烷氧基羰基、芳基中的基团所取代;所述杂环基含有1个选自氧、硫和氮中的杂原子;
R2为氢或COOH;
R3为C1-C4烷基、酰基、-C(O)CF3或氢;
W为-(CH2)1-4或-CH(Re)(CH2)0-3,其中Re为CN或C1-C4烷基;
Y为N、C或无;
X为N或C;
Z为O或(CH2)q,其中q为0-2,当q为0时,Z表示键;
n为0-3;
条件是当Z为O时,Y为N且X为C。
在本发明的一个优选地实施方式中,A为取代或未取代的苯环或者取代或未取代的含有1~4个选自氧、硫和氮中的杂原子的5-12元的芳香杂环,其中所述的取代的苯环或取代的芳香杂环,每个环上包括1~3个取代基;
其中,所述取代的芳环或取代的芳香杂环上的取代基独立地选自下组:氢、氢的同位素、卤素、羧基、硝基、C1-C4烷基、C1-C4烷酰基、C1-C4烷氧基、氰基、氧(=O)、磺酰基。
在本发明的一个优选地实施方式中,各R1独立地选自:取代的或未取代的芳基、取代的或未取代的杂芳基、氢、取代的或未取代的C1-C4烷基、-SO2Ra、-NC(O)Ra、-(CH2)mC(O)ORa、-C(O)ORa、-C(O)Ra、-(CH2)mORa、-C(O)NRaRb、-NRcRd、取代的或未取代的芳烷基和取代的或未取代的杂芳烷基,其中m为1-3的整数;
各Ra独立地为氢、取代的或未取代的苯基、取代的或未取代的苯基甲基、取代的或未取代的C3-C7环烷基、取代的或未取代的C1-C4烷基、取代的或未取代的C1-C4烯基、取代的或未取代的C1-C4烷氧基、取代的或未取代的C1-C3烷基氨基、-NHPh、或取代的或未取代的5-10元杂芳基;
Rb为氢或C1-C3烷基;
Rc、Rd各自独立地选自氢、C1-C3直链或支链烷基、取代的或未取代的C3-C5环 烷基、取代的或未取代的C1-C3烷氧基、取代的或未取代的4-6元杂环基、取代的或未取代的C1-C3烷基酰基、取代的或未取代的芳基酰基、取代的或未取代的芳基磺酰基、取代的或未取代的苄基、取代的或未取代的芳基;所述杂环基含有1个选自氧、硫和氮中的杂原子;
所述取代基选自下组:C1-C8烷基、C2-C8烯基、C2-C8炔基、C3-C8环烷基、3-至12-元杂环基、芳基、杂芳基、卤素、羟基、羧基(-COOH)、C1-C8醛基、C2-C10酰基、C2-C10酯基、氨基、和烷氧基。
在本发明的另一个优选地实施方式中,X为N,且连接至X的R1选自:取代的或未取代的:芳基、杂芳基、芳烷基、和杂芳烷基,其中所述取代基选自下组:C1-C8烷基、C2-C8烯基、C2-C8炔基、C3-C8环烷基、3-至12-元杂环基、芳基、杂芳基、卤素、羟基、羧基(-COOH)、C1-C8醛基、C2-C10酰基、C2-C10酯基、氨基、和烷氧基。
在本发明的一个优选地实施方式中,X为N,且连接至的R1选自取代的或未取代的:芳基C1~C4烷基、和杂芳基C1~C4烷基,其中所述取代基选自下组:C1-C8烷基、C2-C8烯基、C2-C8炔基、C3-C8环烷基、3-至12-元杂环基、芳基、杂芳基、卤素、羟基、羧基(-COOH)、C1-C8醛基、C2-C10酰基、C2-C10酯基、氨基、和烷氧基。
在本发明的一个优选地实施方式中,W为-(CH2)1-2
在本发明的一个优选地实施方式中,所述化合物的结构如通式(1R,2S)-Ia或通式(1S,2R)-Ib所示:
制备方法
根据本发明的作为活性成分的氟取代的环胺化合物的制备方法可以选用如下方案1、或方案2:
方案1
式(II)和(III)化合物还原胺化条件下反应,得到式(I)化合物
方案2
式(IV)化合物和式(V)化合物反应得到式(VI)化合物,然后可将胺基保护再脱去X和/或Y基团的保护基得到式(VII)化合物,使用R1取代基对式(VII)化合物进行官能团化得到式(VIII)化合物,脱去胺基脱保护基并用R3基团对式(VIII)化合物官能团化从而获得式(I)化合物;
其中,A、W、X、Y、Z、R1、R2、R3分别如上所述,R4选自下组:H、或甲基,V为-CH2-W-或-W-CH2-。在本发明的一个优选地实施方式中,所述式(II)化合物的制备方法包括步骤:
将肉桂酸式(IX)化合物,在缩合剂和碱的存在下,与二甲羟胺缩合得到酰胺式(X)化合物;然后进行环丙基化,反应得到式(XI)化合物;然后式(XI)化合物水解得到式(XII)化合物;然后将其在Curtius重排条件下反应,得到式(IV)化合物,将用R3基团对式(IV)化合物官能团化从而获得式(II)化合物;
式(1R,2S)-I与(1S,2R)-I化合物可分别通过方案4与方案5所述制备方法得到,具体操作步骤同方案2。
方案4
方案5
在以下的实施例中将进一步举例说明本发明。这些实施例仅用于说明本发明,但不以任何方式限制本发明。
实施例1 4-氟-4-(((反式-2-苯基环丙基)氨基)甲基)哌啶-1-甲酸苄酯(A1)
向100mL茄形瓶中加入20mL无水甲醇,称取反式-2-苯基环丙胺167mg及4-氟-4-甲酰基哌啶-1-甲酸苄酯300mg加入到甲醇溶液中,再向体系中加入72μl乙酸,氮气保护下加热回流10分钟,然后冷却至室温,再向溶液中加入142mg氰基硼氢化钠,室温搅拌5小时,用薄层层析(TLC)监测反应。反应结束旋干甲醇,加入50mL水,二氯甲烷50mL萃取3次,有机层旋干,二氯甲烷:甲醇=50:1柱层析得到目标产物A1(310mg,产率72%)。1H NMR(600MHz,MeOD)δ7.41–7.34(m,4H),7.36–7.30(m,3H),7.27–7.24(m,1H),7.22–7.19(m,2H),5.15(s,2H),4.14–4.08(m,2H),3.54(d,J=20.1Hz,2H),3.27–3.14(m,2H),3.07(dt,J=8.0,4.1Hz,1H),2.60(ddd,J=10.3,6.6,3.6Hz,1H),2.02–1.95(m,2H),1.87–1.72(m,2H),1.60(ddd,J=10.4,6.8,4.4Hz,1H),1.41(dt,J=7.8,6.7Hz,1H);LRMS(ESI):383.21[M+H]+
实施例2N-((4-氟哌啶-4-基)甲基)-反式-2-苯基环丙胺(A2)
2.1 4-氟-4-(((反式-2-苯基环丙基)氨基)甲基)哌啶-1-甲酸叔丁酯的合成
将4-氟-4-甲酰基哌啶-1-甲酸苄酯替换为4-氟-4-甲酰基哌啶-1-甲酸叔丁酯,其余所需原料、试剂及制备方法同实施例1,得到4-氟-4-(((反式-2-苯基环丙基)氨基)甲基)哌啶-1-甲酸叔丁酯(产率75%)。
2.2终产物A2的合成
将3.5g 4-氟-4-(((反式-2-苯基环丙基)氨基)甲基)哌啶-1-甲酸叔丁酯溶于30mL2M盐酸1,4-二氧六环中,常温搅拌10小时,反应完毕,旋干溶剂得白色固体。将固体溶于少量甲醇,加入大量乙酸乙酯,超声析出白色固体,抽滤后取滤饼干燥,得到目标产物A2的二盐酸盐4.4g(产率97%)。1H NMR(400MHz,D2O)δ7.30(t,J=7.4Hz,2H),7.22(t,J=7.3Hz,1H),7.14(d,J=7.5Hz,2H),3.55(d,J=20.3Hz,2H),3.38(dd,J=13.4,4.7Hz,2H),3.21(td,J=13.2,3.1Hz,2H),2.97(dt,J=8.0,4.1Hz,1H),2.52(ddd,J=10.4,6.7,3.6Hz,1H),2.25–2.10(m,2H),1.96(dtd,J=37.8,14.7,4.9Hz,2H),1.50(ddd,J=10.9,7.1,4.4Hz,1H),1.36(q,J=7.2Hz,1H);LRMS(ESI):249.17[M+H]+
实施例3 4-((4-氟-4-(((反式-2-苯基环丙基)氨基)甲基)哌啶-1-基)甲基)苯甲酸甲酯(A3)
将4-氟-4-甲酰基哌啶-1-甲酸苄酯替换为4-((4-氟-4-甲酰基哌啶-1-基)甲基)苯甲酸甲酯,其余所需原料、试剂及制备方法同实施例1,得产物A3(产率63%)。1H NMR(400MHz,D2O)δ7.95(d,J=8.3Hz,2H),7.48(d,J=8.2Hz,2H),7.27–7.18(m,2H),7.18–7.12(m,1H),7.08–7.04(m,2H),4.31(s,2H),3.79(s,3H),3.48(d,J=20.2Hz,2H),3.39(d,J=12.5Hz,2H),3.23(t,J=12.2Hz,2H),2.90(dt,J=7.9,4.0Hz,1H),2.44(ddd,J=10.4,6.7,3.6Hz,1H),2.21–2.07(m,2H),2.04–1.81(m,2H),1.43(ddd,J=10.9,7.2,4.4Hz,1H),1.29(q,J=7.3Hz,1H);LRMS(ESI):397.22[M+H]+
实施例4(1s,4s)-4-氟-4-(((反式-2-苯基环丙基)氨基)甲基)环己胺(A4)
将4-氟-4-甲酰基哌啶-1-甲酸叔丁酯替换为((1s,4s)-4-氟-4-甲酰基环己基)氨基甲酸叔丁酯,其余所需原料、试剂及制备方法同实施例2,得产物A4(产率70%)。1H NMR(400MHz,DMSO-d6)δ7.33–7.27(m,2H),7.25–7.16(m,3H),3.51(d,J=19.8Hz,2H),3.28–3.18(m,1H),3.05(dt,J=7.9,4.1Hz,1H),2.61(ddd,J=10.3,6.6,3.6Hz,1H),2.21–2.10(m,2H),2.08–1.97(m,2H),1.87–1.66(m,4H),1.60(ddd,J=10.5,6.8,4.4Hz,1H),1.38(dt,J=7.9,6.7Hz,1H);LRMS(ESI):263.18[M+H]+
实施例5 4-((4-氟-4-(((反式-2-苯基环丙基)氨基)甲基)哌啶-1-基)甲基)苯甲酸(A5)
5.1 4-氟-4-((2,2,2-三氟-N-(反式-2-苯基环丙基)乙酰胺基)甲基)哌啶-1-甲酸叔丁 酯的合成
将实施例2.1所得产物4-氟-4-(((反式-2-苯基环丙基)氨基)甲基)哌啶-1-甲酸叔丁酯210mg溶于15ml氯仿,加入1.2ml三乙胺后,向溶液中缓缓滴加0.44ml三氟乙酸酐,室温搅拌30分钟后加入1M碳酸钠溶液6ml淬灭反应,分离得有机层,水层用5ml二氯甲烷萃取两次,合并有机层后旋干溶剂,柱层析分离(石油醚:乙酸乙酯=10:1)得黄色油状物1.09g,为4-氟-4-((2,2,2-三氟-N-(反式-2-苯基环丙基)乙酰胺基)甲基)哌啶-1-甲酸叔丁酯(产率85%)。
5.22,2,2-三氟-N-((4-氟哌啶-4-基)甲基)-N-(反式-2-苯基环丙基)乙酰胺盐酸盐的合成
将4-氟-4-((2,2,2-三氟-N-(反式-2-苯基环丙基)乙酰胺基)甲基)哌啶-1-甲酸叔丁酯1.09g溶于15ml 2M盐酸1,4-二氧六环中,常温搅拌4小时,反应完毕,旋干溶剂后得到黄色固体为2,2,2-三氟-N-((4-氟哌啶-4-基)甲基)-N-(反式-2-苯基环丙基)乙酰胺盐酸盐(产率99%)。
5.34-((4-氟-4-((2,2,2-三氟-N-(反式-2-苯基环丙基)乙酰氨基)甲基)哌啶-1-基甲基)苯甲酸叔丁酯的合成
将2,2,2-三氟-N-((4-氟哌啶-4-基)甲基)-N-(反式-2-苯基环丙基)乙酰胺盐酸盐1.1g溶于20ml乙腈中,向体系中依次加入784mg 4-溴甲基苯甲酸叔丁酯及1.2g碳酸钾后加热回流2小时,用薄层层析(TLC)监测反应。反应结束后将乙腈旋干,再加入30mL水,二氯甲烷20mL萃取3次,有机层旋干,柱层析分离(石油醚:乙酸乙酯=2:1)得到4-((4-氟-4-((2,2,2-三氟-N-(2-苯基环丙基)乙酰氨基)甲基)哌啶1-基甲基)苯甲酸叔丁酯720mg(产率47%)。
5.4终产物A5的合成
将4-((4-氟-4-((2,2,2-三氟-N-(2-苯基环丙基)乙酰氨基)甲基)哌啶1-基甲基)苯甲酸叔丁酯720mg溶于20ml乙醇,加入1M氢氧化钠溶液10ml,加热回流2小时后停止加热,冷却至室温,旋干溶剂,加入30mL水,二氯甲烷20mL萃取3次,有机层用无水硫酸钠干燥后旋干,将得到的淡黄色油状体溶于1M盐酸溶液中,90℃加热1小时后停止反应,将反应液置于冰浴中搅拌1小时后析出固体,抽滤,将滤饼干燥得到白色固体为目标产物A5的二盐酸盐540mg(产率88%)。1H NMR(400MHz,DMSO-d6)δ8.00–7.93(m,2H),7.44(dt,J=7.4,1.2Hz,2H),7.26–7.11(m,5H),3.54(d,J=1.5Hz,2H),3.11(dt,J=12.6,7.2Hz,2H),2.76–2.64(m,2H),2.62–2.49(m,3H),2.05–1.85(m,3H),1.45(ddt,J=25.1,13.2,7.2Hz,2H),0.95(td,J=7.0,4.9Hz,1H),0.71(td,J=7.0,5.0Hz,1H);LRMS(ESI):383.21[M+H]+
实施例6N-((1-苄基-4-氟哌啶-4-基)甲基)-反式-2-苯基环丙胺(A6)
6.1N-((1-苄基-4-氟哌啶-4-基)甲基)-2,2,2-三氟-N-(反式-2-苯基环丙基)乙酰胺的合成
将4-溴甲基苯甲酸叔丁酯替换为溴甲基苯,其余所需原料、试剂及制备方法同实施例5.3,得到产物N-((1-苄基-4-氟哌啶-4-基)甲基)-2,2,2-三氟-N-(2-苯基环丙基)乙酰胺210mg(产率70%)。
6.2终产物A6的合成
将210mg N-((1-苄基-4-氟哌啶-4-基)甲基)-2,2,2-三氟-N-(2-苯基环丙基)乙酰胺溶于10ml乙醇,加入1M氢氧化钠溶液5ml,加热回流2小时后停止加热,冷却至室温,旋干溶剂,加入30mL水,二氯甲烷20mL萃取3次,有机层旋干,柱层析分离(二氯甲烷:甲醇=40:1)得到目标产物A6 149mg(产率91%)。1H NMR(500MHz,D2O)δ7.50–7.41(m,5H),7.35–7.28(m,2H),7.27–7.22(m,1H),7.18–7.12(m,2H),4.32(s,2H),3.54(d,J=20.3Hz,2H),3.47(d,J=8.3Hz,2H),3.28(t,J=12.7Hz,2H),2.97(dt,J=8.0,4.1Hz,1H),2.52(ddd,J=10.4,6.7,3.6Hz,1H),2.22(dd,J=15.3,8.4Hz,2H),2.11–1.86(m,2H),1.50(ddd,J=10.9,7.2,4.4Hz,1H),1.37(q,J=7.2Hz,1H);LRMS(ESI):339.22[M+H]+
实施例7 3-(4-氟-4-(((反式-2-苯基环丙基)氨基)甲基)哌啶-1-基)-丙酸甲酯(A7)
将4-氟-4-甲酰基哌啶-1-甲酸苄酯替换为3-(4-氟-4-甲酰基哌啶-1-基)-丙酸甲酯,其余所需原料、试剂及制备方法同实施例1,得产物A7(产率57%)。1H NMR(500MHz,D2O)δ7.32(t,J=7.5Hz,2H),7.25(t,J=7.4Hz,1H),7.16(d,J=7.5Hz,2H),3.68(s,3H),3.61–3.54(m,4H),3.46(t,J=7.0Hz,2H),3.32–3.23(m,2H),3.00(dt,J=8.0,4.1Hz,1H),2.93–2.85(m,2H),2.55(ddd,J=10.4,6.7,3.6Hz,1H),2.30–2.20(m,2H),2.16–1.94(m,2H),1.52(ddd,J=11.1,7.2,4.4Hz,1H),1.38(q,J=7.3Hz,1H);LRMS(ESI):335.21[M+H]+
实施例8 1-(4-氟-4-(((反式-2-苯基环丙基)氨基)甲基)哌啶-1-基)-3-苯基-1-丙酮(A8)
8.1 2,2,2-三氟-N-((4-氟-1-(3-苯基丙酰基)哌啶-4-基)甲基)-N-(反式-2-苯基环丙基)乙酰胺的合成
取实施例5.2产物2,2,2-三氟-N-((4-氟哌啶-4-基)甲基)-N-(反式-2-苯基环丙基)乙酰胺盐酸盐200mg溶于10ml干燥二氯甲烷中,加入0.22ml三乙胺,冰浴下逐滴加入已溶于二氯甲烷的3-苯基丙酰氯106mg,滴加完毕后室温搅拌2h,反应结束加入15ml水和15ml二氯甲烷萃取,收集有机层旋干后得无色油状体为2,2,2-三氟-N-((4-氟-1-(3-苯基丙酰基)哌啶-4-基)甲基)-N-(反式-2-苯基环丙基)乙酰胺粗品。
8.2终产物A8的合成
将N-((1-苄基-4-氟哌啶-4-基)甲基)-2,2,2-三氟-N-(2-苯基环丙基)乙酰胺替换为2,2,2-三氟-N-((4-氟-1-(3-苯基丙酰基)哌啶-4-基)甲基)-N-(反式-2-苯基环丙基)乙酰胺, 其余所需原料、试剂及制备方法同实施例6.2,得产物A8(产率72%)。1H NMR(400MHz,D2O)δ7.28–7.12(m,5H),7.14–7.04(m,5H),4.14(d,J=13.5Hz,1H),3.61(d,J=14.1Hz,1H),3.21(d,J=20.3Hz,2H),3.06(t,J=13.2Hz,1H),2.90–2.62(m,5H),2.57–2.47(m,1H),2.46–2.37(m,1H),1.78(t,J=12.4Hz,1H),1.62(t,J=12.5Hz,1H),1.48–1.21(m,3H),0.81(dt,J=39.9,13.9Hz,1H);LRMS(ESI):381.23[M+H]+
实施例9 4-氟-4-(((反式-2-苯基环丙基)氨基)甲基)哌啶-1-甲酸苯酯(A9)
将4-氟-4-甲酰基哌啶-1-甲酸苄酯替换为4-氟-4-甲酰基哌啶-1-甲酸苯酯,其余所需原料、试剂及制备方法同实施例1,得产物A9(产率79%)。1H NMR(400MHz,D2O)δ7.30(t,J=7.4Hz,2H),7.24(t,J=7.2Hz,2H),7.16(t,J=7.1Hz,2H),7.08(d,J=7.4Hz,2H),6.98(d,J=7.6Hz,2H),4.11(d,J=13.8Hz,1H),3.87(d,J=13.6Hz,1H),3.41(d,J=20.4Hz,2H),3.23(t,J=12.7Hz,1H),3.10(t,J=12.9Hz,1H),2.94–2.85(m,1H),2.49–2.40(m,1H),1.94–1.83(m,2H),1.83–1.58(m,2H),1.43(ddd,J=10.8,7.1,4.0Hz,1H),1.35–1.22(m,1H).;LRMS(ESI):369.19[M+H]+
实施例10 3-环己基-1-(4-氟-4-(((反式-2-苯基环丙基)氨基)甲基)哌啶-1-基)-1-丙酮(A10)
将3-苯基丙酰氯替换为3-环己基丙酰氯,其余所需原料、试剂及制备方法同实施例8,得产物A10(产率54%)。1H NMR(400MHz,DMSO)δ7.34–7.27(m,2H),7.25–7.16(m,3H),4.48–4.41(m,1H),3.95–3.88(m,1H),3.53(d,J=20.1Hz,2H),3.40(ddd,J=14.2,12.4,2.9Hz,1H),3.05(dt,J=7.9,4.1Hz,1H),2.96(td,J=12.8,3.0Hz,1H),2.58(ddd,J=10.3,6.5,3.5Hz,1H),2.42(td,J=7.5,3.6Hz,2H),2.11–1.93(m,2H),1.93–1.54(m,8H),1.53–1.34(m,3H),1.33–1.09(m,4H),1.01–0.82(m,2H);LRMS(ESI):387.27[M+H]+
实施例11 4-氟-N-甲基-4-(((反式-2-苯基环丙基)氨基)甲基)环己烷-1-胺(A11)
11.1N-((4-氨基-1-氟环己基)甲基)-2,2,2-三氟-N-(反式-2-苯基环丙基)乙酰胺盐酸盐的合成
将4-氟-4-甲酰基哌啶-1-甲酸苄酯替换为(4-氟-4-甲酰基环己基)氨基甲酸叔丁酯,其余所需原料、试剂及制备方法同实施例1,5.1及5.2,得产物N-((4-氨基-1-氟环己基)甲基)-2,2,2-三氟-N-(反式-2-苯基环丙基)乙酰胺盐酸盐(产率39%)。
11.2终产物A11的合成
将4-氟-4-甲酰基哌啶-1-甲酸苄酯替换为甲醛溶液(含8%-14%甲醇),将反式-2-苯基环丙基-1-胺替换为N-((4-氨基-1-氟环己基)甲基)-2,2,2-三氟-N-(反式-2-苯基环丙基)乙酰胺,其余所需原料、试剂及制备方法同实施例1及6.2,得产物A11(产率64%)。1H NMR(400MHz,D2O)δ7.24–7.17(m,2H),7.16–7.10(m,1H),7.07–7.02(m,2H), 3.34(d,J=20.4Hz,2H),3.06–2.9D2O 5(m,1H),2.85(dt,J=8.0,4.1Hz,1H),2.54(s,3H),2.41(ddd,J=10.4,6.7,3.6Hz,1H),2.01–1.89(m,4H),1.64–1.43(m,4H),1.39(ddd,J=10.5,7.2,4.4Hz,1H),1.30–1.19(m,1H);LRMS(ESI):277.20[M+H]+
实施例12N-((4-氟-1-(3-苯基丙基)哌啶-4-基)甲基)-反式-2-苯基环丙胺(A12)
将溴甲基苯替换为溴丙基苯,其余所需原料、试剂及制备方法同实施例6,得产物A12(产率75%)。1H NMR(400MHz,D2O)δ7.45–7.39(m,4H),7.38–7.31(m,4H),7.28–7.23(m,2H),3.71–3.58(m,4H),3.33–3.16(m,4H),3.09(dt,J=8.0,4.1Hz,1H),2.77(t,J=7.4Hz,2H),2.64(ddd,J=10.4,6.7,3.6Hz,1H),2.38–2.26(m,2H),2.22–2.01(m,4H),1.62(ddd,J=10.5,7.2,4.4Hz,1H),1.48(q,J=7.2Hz,1H);LRMS(ESI):367.25[M+H]+
实施例13N-((1-([1,1'-联苯]-4-甲基)-4-氟哌啶-4-基)甲基)-反式-2-苯基环丙胺(A13)
将溴甲基苯替换为4-溴甲基-1,1'-联苯,其余所需原料、试剂及制备方法同实施例6,得产物A13(产率80%)。1H NMR(400MHz,MeOD)δ7.78(d,J=8.1Hz,2H),7.74–7.64(m,4H),7.49(t,J=7.6Hz,2H),7.44–7.38(m,1H),7.33(t,J=7.4Hz,2H),7.29–7.14(m,3H),4.48(s,2H),3.72–3.54(m,4H),3.38(d,J=13.2Hz,2H),3.09(t,J=4.6Hz,1H),2.64(t,J=9.6Hz,1H),2.40–2.13(m,4H),1.67–1.59(m,1H),1.42(q,J=7.0Hz,1H);LRMS(ESI):415.27[M+H]+
实施例14N-((1-(3-环己基丙基)-4-氟哌啶-4-基)甲基)-反式-2-苯基环丙胺(A14)
将溴甲基苯替换为溴丙基环己烷,其余所需原料、试剂及制备方法同实施例6,得产物A14(产率74%)。1H NMR(400MHz,D2O)δ7.45–7.39(m,2H),7.38–7.32(m,1H),7.28–7.23(m,2H),3.73–3.58(m,4H),3.29(td,J=13.2,2.9Hz,2H),3.22–3.15(m,2H),3.10(dt,J=8.0,4.0Hz,1H),2.64(ddd,J=10.5,6.9,3.7Hz,1H),2.41–2.30(m,2H),2.25–2.02(m,2H),1.86–1.55(m,8H),1.49(q,J=7.3Hz,1H),1.35–1.04(m,6H),0.99–0.82(m,2H);LRMS(ESI):373.29[M+H]+
实施例15N-((4-氟-1-甲基哌啶-4-基)甲基)-反式-2-苯基环丙胺(A15)
将(4-氟-4-甲酰环己基)氨基甲酸叔丁酯替换为4-氟-4-甲酰基哌啶-1-甲酸叔丁酯,其余所需原料、试剂及制备方法同实施例11,得产物A15(产率34%)。1H NMR(400MHz,D2O)δ7.30–7.24(m,2H),7.22–7.17(m,1H),7.11(dd,J=7.1,1.8Hz,2H),3.52(d,J=20.3Hz,2H),3.43(dd,J=12.7,4.5Hz,2H),3.20(td,J=13.2,3.1Hz,2H),2.94(dt,J=8.0,4.1Hz,1H),2.81(s,3H),2.49(ddd,J=10.4,6.7,3.6Hz,1H),2.19(dd,J=15.1,8.6Hz,2H),2.03(td,J=15.1,14.7,4.9Hz,1H),1.93(td,J=14.5,4.8Hz,1H),1.47(ddd,J=10.5,7.2,4.4Hz,1H),1.33(q,J=7.2Hz,1H);LRMS(ESI):263.18[M+H]+
实施例16N-((4-氟-1-(4-(甲磺酰基)苄基)哌啶-4-基)甲基)-反式-2-苯基环丙胺(A16)
将溴甲基苯替换为1-溴甲基-4-甲磺酰基苯,其余所需原料、试剂及制备方法同实施例6,得产物A16(产率72%)。1H NMR(400MHz,MeOD)δ8.10–8.06(m,2H),7.92–7.87(m,2H),7.33–7.28(m,2H),7.25–7.16(m,3H),4.53(s,2H),3.65(d,J=20.1Hz,2H),3.53(d,J=12.5Hz,2H),3.42–3.30(m,2H),3.16(s,3H),3.10–3.05(m,1H),2.66–2.56(m,1H),2.37–2.16(m,4H),1.61(dt,J=11.0,6.2Hz,1H),1.40(q,J=7.1Hz,1H);LRMS(ESI):417.19[M+H]+
实施例17N-((4-氟-1-(萘基-2-甲基)哌啶-4-基)甲基)-反式-2-苯基环丙胺(A17)
将溴甲基苯替换为2-溴甲基萘,其余所需原料、试剂及制备方法同实施例6,得产物A17(产率60%)。1H NMR(400MHz,DMSO-d6)δ7.95–7.77(m,3H),7.69(d,J=1.5Hz,1H),7.61–7.47(m,3H),7.26–7.11(m,5H),3.66(s,2H),3.00(dt,J=12.6,7.2Hz,2H),2.66(s,1H),2.60(s,1H),2.46(dt,J=12.6,7.2Hz,2H),1.93(ddt,J=25.1,14.2,7.2Hz,3H),1.53(ddt,J=25.1,13.1,7.0Hz,2H),0.95(td,J=7.0,5.1Hz,1H),0.70(td,J=7.0,5.1Hz,1H);LRMS(ESI):389.23[M+H]+
实施例18N-((1-氟环己基)甲基)-反式-2-苯基环丙胺(A18)
将4-氟-4-甲酰基哌啶-1-甲酸苄酯替换为1-氟环己烷-1-甲醛,其余所需原料、试剂及制备方法同实施例1,得产物A18(产率82%)。1H NMR(400MHz,MeOD)δ7.36–7.30(m,2H),7.28–7.24(m,1H),7.22(tt,J=5.9,1.2Hz,2H),3.47(d,J=20.0Hz,2H),3.06(dt,J=8.0,4.1Hz,1H),2.59(ddd,J=10.3,6.6,3.6Hz,1H),1.99–1.88(m,2H),1.74–1.62(m,6H),1.59(ddd,J=10.3,6.8,4.4Hz,2H),1.40(dt,J=7.9,6.7Hz,2H);LRMS(ESI):248.17[M+H]+
实施例19(4-氟-4-(((反式-2-苯基环丙基)氨基)甲基)环己基)氨基甲酸苄酯(A19)
将4-氟-4-甲酰基哌啶-1-甲酸苄酯替换为(4-氟-4-甲酰基环己基)氨基甲酸苄酯,其余所需原料、试剂及制备方法同实施例1,得产物A19(产率64%)。1H NMR(400MHz,DMSO-d6)δ7.39–7.26(m,5H),7.26–7.11(m,5H),5.02(s,2H),4.11(p,J=7.0Hz,1H),2.73–2.64(m,2H),1.94–1.72(m,5H),1.65–1.50(m,2H),1.54–1.43(m,2H),0.99(td,J=6.9,5.0Hz,1H),0.67(td,J=7.0,5.0Hz,1H);LRMS(ESI):397.22[M+H]+
实施例20N-((4-氟-1-苯基哌啶-4-基)甲基)-反式-2-苯基环丙胺(A20)
将溴甲基苯替换为溴苯,其余所需原料、试剂及制备方法同实施例6,得产物A20(产率41%)。1H NMR(400MHz,DMSO-d6)δ7.30–7.11(m,7H),7.07–6.99(m,2H),6.80(tt,J=7.4,2.0Hz,1H),4.00(dt,J=12.6,7.2Hz,2H),3.33(dt,J=12.4,7.0Hz,2H),2.77–2.64(m,2H),2.60(s,1H),2.06–1.84(m,3H),1.50(ddt,J=25.2,13.2,7.1Hz,2H),0.97(td,J=7.0,5.1Hz,1H),0.69(td,J=7.0,5.0Hz,1H);LRMS(ESI):325.20[M+H]+
实施例21环己基甲基4-氟-4-(((反式-2-苯基环丙基)氨基)甲基)哌啶-1-甲酸酯(A21)
将3-苯基丙酰氯替换为环己基甲基氯甲酸酯,其余所需原料、试剂及制备方法同实施例8,得产物A21(产率63%)。1H NMR(400MHz,DMSO-d6)δ7.26–7.11(m,5H),4.02(dt,J=12.4,7.1Hz,2H),3.91–3.85(m,2H),3.27(dt,J=12.4,7.1Hz,2H),2.76–2.64(m,2H),2.04–1.85(m,3H),1.77–1.65(m,2H),1.70–1.56(m,4H),1.60–1.42(m,2H),1.34–1.12(m,6H),0.95(td,J=7.0,5.0Hz,1H),0.71(td,J=6.9,5.0Hz,1H);LRMS(ESI):389.25[M+H]+
实施例22吡啶-4-基甲基4-氟-4-(((反式-2-苯基环丙基)氨基)甲基)哌啶-1-甲酸酯(A22)
将3-苯基丙酰氯替换为吡啶-4-基甲基氯甲酸酯,其余所需原料、试剂及制备方法同实施例8,得产物A22(产率53%)。1H NMR(400MHz,DMSO-d6)δ8.58(d,J=5.1Hz,2H),7.70(d,J=5.1Hz,2H),7.26–7.11(m,5H),5.80(s,2H),4.17(dt,J=12.6,7.2Hz,2H),3.10(dt,J=12.5,7.0Hz,2H),2.75–2.64(m,2H),2.04–1.83(m,3H),1.63(ddt,J=25.2,13.2,7.1Hz,2H),0.92(td,J=6.9,5.0Hz,1H),0.70(td,J=7.0,5.0Hz,1H);LRMS(ESI):384.20[M+H]+
实施例23 4-氟-4-(((反式-2-苯基环丙基)氨基)甲基)哌啶-1-甲酸苯乙酯(A23)
将3-苯基丙酰氯替换为氯甲酸苯乙酯,其余所需原料、试剂及制备方法同实施例8,得产物A23(产率60%)。1H NMR(400MHz,DMSO-d6)δ7.27–7.11(m,10H),4.41(t,J=7.5Hz,2H),4.05(dt,J=12.4,7.0Hz,2H),3.30(dt,J=12.6,7.2Hz,2H),2.86(t,J=7.5Hz,2H),2.78–2.64(m,2H),2.05–1.86(m,3H),1.65(ddt,J=25.2,13.2,7.1Hz,2H),0.96(td,J=7.0,5.0Hz,1H),0.71(td,J=7.0,5.0Hz,1H);LRMS(ESI):397.22[M+H]+
实施例24 4-氟-4-(((反式-2-苯基环丙基)氨基)甲基)哌啶-1-甲酸乙酯(A24)
将3-苯基丙酰氯替换为氯甲酸乙酯,其余所需原料、试剂及制备方法同实施例8,得产物A24(产率74%)。1H NMR(400MHz,DMSO-d6)δ7.26–7.11(m,5H),4.10–3.98(m,4H),3.25(dt,J=12.5,7.1Hz,2H),2.77–2.64(m,2H),2.60(s,1H),2.00–1.82(m,3H),1.64(ddt,J=25.2,13.2,7.1Hz,2H),1.17(t,J=8.0Hz,3H),0.94(td,J=7.0,5.0Hz,1H),0.71(td,J=6.9,5.0Hz,1H);LRMS(ESI):321.19[M+H]+
实施例25(1H-吲哚-5-基)甲基4-氟-4-(((反式-2-苯基环丙基)氨基)甲基)哌啶-1-甲酸酯(A25)
将3-苯基丙酰氯替换为(1H-吲哚-5-基)甲基氯甲酸酯,其余所需原料、试剂及制备方法同实施例8,得产物A25(产率36%)。1H NMR(400MHz,DMSO-d6)δ11.53(s,1H),8.06(t,J=1.5Hz,1H),7.61(d,J=7.5Hz,1H),7.50–7.40(m,2H),7.26–7.11(m,5H),6.65(dd,J=7.6,1.5Hz,1H),5.02(s,2H),4.04(dt,J=12.4,7.1Hz,2H),3.30(dt,J=12.6,7.2Hz,2H),2.76–2.64(m,2H),2.60(s,1H),2.05–1.86(m,3H),1.64(ddt,J=25.2,13.2,7.1Hz,2H),0.95(td,J=7.0,5.0Hz,1H),0.71(td,J=7.0,5.0Hz,1H);LRMS(ESI):422.22[M+H]+
实施例26 1-(4-氟-4-(((反式-2-苯基环丙基)氨基)甲基)吡啶-1-基)-1-乙酮(A26)
将3-苯基丙酰氯替换为乙酰氯,其余所需原料、试剂及制备方法同实施例8,得产物A26(产率76%)。1H NMR(400MHz,DMSO-d6)δ7.26–7.11(m,5H),3.96(dt,J=12.5,7.1Hz,2H),2.93(dt,J=12.5,7.1Hz,2H),2.71–2.61(m,2H),2.60(s,1H),2.10(s,3H),2.00–1.82(m,3H),1.63(ddt,J=25.3,13.2,7.2Hz,2H),0.99(td,J=7.0,5.0Hz,1H),0.66(td,J=7.0,5.1Hz,1H);LRMS(ESI):291.18[M+H]+
实施例27噻吩-2基甲基4-氟-4-(((反式-2-苯基环丙基)氨基)甲基)哌啶-1-甲酸酯(A27)
将3-苯基丙酰氯替换为噻吩-2基甲基氯甲酸酯,其余所需原料、试剂及制备方法同实施例8,得产物A27(产率70%)。1H NMR(400MHz,DMSO-d6)δ7.30(dd,J=6.4,2.5Hz,1H),7.26–7.11(m,5H),7.05–6.96(m,2H),5.61(s,2H),4.19(dt,J=12.5,7.1Hz,2H),3.11(dt,J=12.5,7.1Hz,2H),2.75–2.64(m,2H),2.08–1.82(m,3H),1.73–1.55(m,2H),0.95(td,J=7.0,5.0Hz,1H),0.70(td,J=7.0,5.1Hz,1H);LRMS(ESI):389.16[M+H]+
实施例28呋喃-2基甲基4-氟-4-(((反式-2-苯基环丙基)氨基)甲基)哌啶-1-甲酸酯(A28)
将3-苯基丙酰氯替换为呋喃-2基甲基氯甲酸酯,其余所需原料、试剂及制备方法同实施例8,得产物A28(产率76%)。1H NMR(400MHz,DMSO-d6)δ7.45(dd,J=7.0,1.9Hz,1H),7.26–7.11(m,5H),6.44–6.32(m,2H),5.09(s,2H),4.06(dt,J=12.5,7.1 Hz,2H),3.31(dt,J=12.5,7.2Hz,2H),2.76–2.64(m,2H),2.60(s,1H),1.99(dt,J=10.9,6.0Hz,1H),1.98–1.86(m,2H),1.65(ddt,J=25.3,13.3,7.1Hz,2H),0.95(td,J=7.0,5.0Hz,1H),0.71(td,J=7.0,5.0Hz,1H);LRMS(ESI):373.18[M+H]+
实施例29 4-氟苄基4-氟-4-(((反式-2-苯基环丙基)氨基)甲基)哌啶-1-甲酸酯(A29)
将3-苯基丙酰氯替换为4-氟苄基氯甲酸酯,其余所需原料、试剂及制备方法同实施例8,得产物A29(产率74%)。1H NMR(400MHz,DMSO-d6)δ7.35(dd,J=7.2,5.7Hz,2H),7.26–7.11(m,7H),5.21–5.15(m,2H),4.03(dt,J=12.5,7.1Hz,2H),3.25(dt,J=12.5,7.1Hz,2H),2.75–2.64(m,2H),2.00–1.82(m,3H),1.64(ddt,J=25.1,13.2,7.0Hz,2H),0.94(td,J=7.0,5.0Hz,1H),0.71(td,J=7.0,5.0Hz,1H);LRMS(ESI):401.20[M+H]+
实施例30 4-氯苄基4-氟-4-(((反式-2-苯基环丙基)氨基)甲基)哌啶-1-甲酸酯(A30)
将3-苯基丙酰氯替换为4-氯苄基氯甲酸酯,其余所需原料、试剂及制备方法同实施例8,得产物A30(产率75%)。1H NMR(400MHz,DMSO-d6)δ7.39(d,J=7.5Hz,2H),7.34–7.26(m,2H),7.26–7.11(m,5H),5.18(s,1H),4.04(dt,J=12.5,7.1Hz,2H),3.25(dt,J=12.5,7.1Hz,2H),2.75–2.64(m,2H),2.60(s,1H),2.00–1.82(m,3H),1.64(ddt,J=25.3,13.2,7.2Hz,2H),0.94(td,J=6.9,5.0Hz,1H),0.71(td,J=7.0,5.0Hz,1H);LRMS(ESI):417.17[M+H]+
实施例31 4-溴苄基4-氟-4-(((反式-2-苯基环丙基)氨基)甲基)哌啶-1-甲酸酯(A31)
将3-苯基丙酰氯替换为4-溴苄基氯甲酸酯,其余所需原料、试剂及制备方法同实施例8,得产物A31(产率70%)。1H NMR(400MHz,DMSO-d6)δ7.58(d,J=7.6Hz,2H),7.29–7.22(m,2H),7.27–7.11(m,5H),5.18(s,1H),4.02(dt,J=12.5,7.1Hz,2H),3.28(dt,J=12.5,7.1Hz,2H),2.75–2.64(m,2H),2.60(s,1H),2.04–1.86(m,3H),1.63(ddt,J=25.3,13.2,7.2Hz,2H),0.95(td,J=7.0,4.9Hz,1H),0.71(td,J=7.0,5.0Hz,1H);LRMS(ESI):461.12[M+H]+
实施例32 4-甲氧基苄基4-氟-4-(((反式-2-苯基环丙基)氨基)甲基)哌啶-1-甲酸酯(A32)
将3-苯基丙酰氯替换为4-甲氧基苄基氯甲酸酯,其余所需原料、试剂及制备方法同实施例8,得产物A32(产率76%)。1H NMR(400MHz,DMSO-d6)δ7.26–7.11(m,5H),7.03–6.96(m,2H),6.94–6.87(m,2H),5.18(s,1H),4.03(dt,J=12.5,7.1Hz,2H),3.79(s,3H),3.28(dt,J=12.5,7.1Hz,2H),2.76–2.64(m,2H),2.60(s,1H),2.04–1.85(m,3H),1.72–1.54(m,2H),0.95(td,J=7.0,5.0Hz,1H),0.71(td,J=7.0,5.1Hz, 1H);LRMS(ESI):413.22[M+H]+
实施例33 4-三氟甲基苄基4-氟-4-(((反式-2-苯基环丙基)氨基)甲基)哌啶-1-甲酸酯(A33)
将3-苯基丙酰氯替换为4-三氟甲基苄基氯甲酸酯,其余所需原料、试剂及制备方法同实施例8,得产物A33(产率68%)。1H NMR(400MHz,DMSO-d6)δ7.69(d,J=7.2Hz,2H),7.58–7.52(m,2H),7.26–7.11(m,5H),5.18(s,1H),4.03(dt,J=12.5,7.2Hz,2H),3.27(dt,J=12.5,7.1Hz,2H),2.74–2.64(m,2H),2.60(s,1H),1.94(ddt,J=25.0,14.1,7.1Hz,3H),1.73–1.54(m,2H),0.96(td,J=7.0,5.0Hz,1H),0.70(td,J=7.0,5.0Hz,1H);LRMS(ESI):451.19[M+H]+
实施例34 3,5-二甲氧基苄基4-氟-4-(((反式-2-苯基环丙基)氨基)甲基)哌啶-1-甲酸酯(A34)
将3-苯基丙酰氯替换为3,5-二甲氧基苄基氯甲酸酯,其余所需原料、试剂及制备方法同实施例8,得产物A34(产率77%)。1H NMR(400MHz,DMSO-d6)δ7.26–7.11(m,5H),6.59(dt,J=2.2,1.0Hz,2H),6.33(t,J=2.0Hz,1H),5.02(d,J=1.2Hz,2H),4.16(dt,J=12.6,7.2Hz,2H),3.66(s,6H),3.09(dt,J=12.5,7.1Hz,2H),2.77–2.64(m,2H),2.60(s,1H),2.05–1.81(m,3H),1.61(ddt,J=25.1,13.2,7.2Hz,2H),0.94(td,J=7.0,5.0Hz,1H),0.69(td,J=7.0,5.0Hz,1H);LRMS(ESI):443.23[M+H]+
实施例35 4-((4-氟-4-(((反式-2-苯基环丙基)氨基)甲基)哌啶-1-羰氧基)甲基)苯甲酸(A35)
35.1 4-(叔丁氧羰基)苄基4-氟-4-((2,2,2-三氟-N-(反式-2-苯基环丙基)乙酰氨基)甲基)哌啶-1-甲酸酯的合成
将3-苯基丙酰氯替换为4-((氯甲酰氧基)甲基)苯甲酸叔丁酯,其余所需原料、试剂及制备方法同实施例8.1,得4-(叔丁氧羰基)苄基4-氟-4-((2,2,2-三氟-N-(反式-2-苯基环丙基)乙酰氨基)甲基)哌啶-1-甲酸酯(产率77%)。
35.2终产物A35的合成
将4-((4-氟-4-((2,2,2-三氟-N-(2-苯基环丙基)乙酰氨基)甲基)哌啶1-基甲基)苯甲酸叔丁酯替换为4-(叔丁氧羰基)苄基4-氟-4-((2,2,2-三氟-N-(反式-2-苯基环丙基)乙酰氨基)甲基)哌啶-1-甲酸酯,其余所需原料、试剂及制备方法同实施例5.4,得产物A35的盐酸盐(产率85%)。1H NMR(400MHz,DMSO-d6)δ12.91(s,1H),7.93–7.86(m,2H),7.46–7.39(m,2H),7.26–7.11(m,5H),5.18(s,1H),4.03(dt,J=12.6,7.2Hz,2H),3.29(dt,J=12.5,7.2Hz,2H),2.76–2.64(m,2H),2.60(s,1H),2.05–1.86(m,3H),1.63(ddt,J=25.3,13.2,7.2Hz,2H),0.95(td,J=7.0,5.1Hz,1H),0.71(td,J=7.0,5.0Hz,1H);LRMS(ESI):427.20[M+H]+
实施例36(E)-1-(4-氟-4-(((反式-2-苯基环丙基)氨基)甲基)哌啶-1-基)-3-苯基-2-烯-1-丙酮(A36)
将3-苯基丙酰氯替换为肉桂酰氯,其余所需原料、试剂及制备方法同实施例8,得产物A36(产率88%)。1H NMR(400MHz,CD3OD)δ7.66–7.54(m,3H),7.43–7.34(m,3H),7.31(tt,J=6.9,1.0Hz,2H),7.25–7.16(m,4H),4.56(d,J=12.8Hz,1H),4.27(d,J=13.3Hz,1H),3.61–3.45(m,3H),3.17–3.09(m,1H),3.06(dt,J=7.9,4.0Hz,1H),2.58(ddd,J=10.3,6.6,3.6Hz,1H),2.07(q,J=12.6,11.4Hz,2H),1.85(tt,J=25.7,13.1Hz,2H),1.58(ddd,J=10.6,6.8,4.4Hz,1H),1.40(dt,J=7.9,6.7Hz,1H);LRMS(ESI):379.21[M+H]+
实施例37N-苄基-4-氟-4-(((反式-2-苯基环丙基)氨基)甲基)哌啶-1-硫代酰胺(A37)
将3-苯基丙酰氯替换为苄基异硫氰酸酯,其余所需原料、试剂及制备方法同实施例8,得产物A37(产率58%)。1H NMR(400MHz,DMSO-d6)δ7.36–7.13(m,10H),7.13(s,1H),4.75(s,2H),3.97(dt,J=12.5,7.1Hz,2H),2.82(q,J=7.0Hz,1H),2.66(s,1H),2.60(s,1H),2.47(dt,J=12.5,7.0Hz,2H),1.89(q,J=7.0Hz,1H),1.77(ddt,J=25.3,13.2,7.2Hz,2H),1.47(ddt,J=25.3,13.2,7.2Hz,2H),0.97(td,J=7.0,5.0Hz,1H),0.71(td,J=7.0,5.0Hz,1H);LRMS(ESI):398.20[M+H]+
实施例38N-苄基-4-氟-4-(((反式-2-苯基环丙基)氨基)甲基)哌啶-1-甲酰胺(A38)
将3-苯基丙酰氯替换为苄基异氰酸苄酯,其余所需原料、试剂及制备方法同实施例8,得产物A38(产率52%)。1H NMR(400MHz,DMSO-d6)δ7.30(s,3H),7.34–7.23(m,2H),7.27–7.11(m,5H),4.27(s,2H),4.11(dt,J=12.5,7.1Hz,2H),3.09(dt,J=12.5,7.1Hz,2H),2.72–2.57(m,3H),2.04–1.85(m,3H),1.59(ddt,J=25.1,13.2,7.1Hz,2H),0.94(td,J=7.0,5.0Hz,1H),0.68(td,J=7.0,4.9Hz,1H);LRMS(ESI):382.22[M+H]+
实施例39N-((1-((苄氧基)甲基)-4-氟哌啶-4-基)甲基)-反式-2-苯基环丙胺(A39)
将溴甲基苯替换为苄基氯甲基醚,其余所需原料、试剂及制备方法同实施例6,得产物A39(产率64%)。1H NMR(400MHz,DMSO-d6)δ7.37–7.25(m,5H),7.29–7.11(m,5H),4.68(s,1H),4.44(s,2H),3.06(dt,J=12.5,7.2Hz,2H),2.75–2.64(m,2H),2.63–2.51(m,3H),1.96–1.78(m,3H),1.47(ddt,J=25.3,13.3,7.1Hz,2H),0.94(td,J=7.0,4.9Hz,1H),0.69(td,J=7.0,5.0Hz,1H);LRMS(ESI):369.23[M+H]+
实施例40 4-氟-4-(((反式-2-苯基环丙基)氨基)甲基)环己烷-1-甲酸苄酯(A40)
将4-氟-4-甲酰基哌啶-1-甲酸苄酯替换为4-氟-4-甲酰基环己烷-1-甲酸苄酯,其余所需原料、试剂及制备方法同实施例1,得产物A40(产率74%)。1H NMR(400MHz,DMSO-d6)δ7.38–7.26(m,5H),7.26–7.11(m,5H),5.11(s,2H),2.74–2.64(m,2H),2.27(p,J=6.9Hz,1H),2.18–2.05(m,2H),1.98–1.74(m,6H),1.61–1.42(m,2H),0.95(td,J=7.0,5.0Hz,1H),0.68(td,J=7.0,5.0Hz,1H);LRMS(ESI):382.21[M+H]+
实施例41环戊基甲基4-氟-4-(((反式-2-苯基环丙基)氨基)甲基)哌啶-1-甲酸酯(A41)
将3-苯基丙酰氯替换为环戊基甲基氯甲酸酯,其余所需原料、试剂及制备方法同实施例8,得产物A41(产率69%)。1H NMR(400MHz,DMSO-d6)δ7.26–7.11(m,5H),4.04(dt,J=12.5,7.1Hz,2H),3.88(s,2H),3.28(dt,J=12.6,7.2Hz,2H),2.72(s,1H),2.66(s,1H),2.60(s,1H),1.96(ddt,J=25.1,13.2,7.0Hz,2H),1.86(s,1H),1.71–1.42(m,7H),1.07(tdd,J=7.8,4.8,1.5Hz,2H),0.94(s,1H),0.69(s,1H);LRMS(ESI):375.24[M+H]+
实施例42环丁基甲基4-氟-4-(((反式-2-苯基环丙基)氨基)甲基)哌啶-1-甲酸酯(A42)
将3-苯基丙酰氯替换为环丁基甲基氯甲酸酯,其余所需原料、试剂及制备方法同实施例8,得产物A42(产率71%)。1H NMR(400MHz,DMSO-d6)δ7.26–7.11(m,5H),4.13(dt,J=12.5,7.1Hz,2H),3.88(d,J=7.0Hz,2H),3.11(dt,J=12.5,7.0Hz,2H),2.90(q,J=6.9Hz,1H),2.62–2.47(m,2H),2.14–1.96(m,4H),1.90–1.77(m,2H),1.80–1.68(m,2H),1.71–1.58(m,4H),0.93(td,J=6.9,5.0Hz,1H),0.71(td,J=7.0,5.1Hz,1H);LRMS(ESI):361.22[M+H]+
实施例43哌啶-4-基甲基4-氟-4-(((反式-2-苯基环丙基)氨基)甲基)哌啶-1-甲酸酯(A43)
将3-苯基丙酰氯替换为4-((氯甲酰氧基)甲基)哌啶-1-甲酸叔丁酯,其余所需原料、试剂及制备方法同实施例8.1及5.4,得产物A43的二盐酸盐(产率61%)。1H NMR(400MHz,DMSO-d6)δ7.26–7.11(m,5H),4.03(dt,J=12.5,7.1Hz,2H),3.88(s,2H),3.27(dt,J=12.6,7.2Hz,2H),3.04(dt,J=12.5,7.2Hz,2H),2.75–2.57(m,5H),2.44(s,1H),2.04–1.86(m,2H),1.91(s,1H),1.66(s,1H),1.64(ddt,J=25.3,13.7,7.1Hz,2H),1.45(dt,J=13.1,7.1Hz,2H),1.18(dt,J=13.3,7.2Hz,2H),0.95(s,1H),0.71(s,1H);LRMS(ESI):390.25[M+H]+
实施例44 3-氯苄基4-氟-4-(((反式-2-苯基环丙基)氨基)甲基)哌啶-1-甲酸酯(A44)
将3-苯基丙酰氯替换为3-氯苄基氯甲酸酯,其余所需原料、试剂及制备方法同实施例8,得产物A44(产率74%)。1H NMR(400MHz,DMSO-d6)δ7.51–7.45(m,1H),7.39–7.26(m,3H),7.26–7.11(m,5H),5.02(s,2H),4.04(dt,J=12.5,7.1Hz,2H),3.26(dt,J=12.5,7.0Hz,2H),2.76–2.64(m,2H),2.01–1.83(m,3H),1.64(ddt,J=25.1,13.2,7.0Hz,2H),0.93(td,J=7.0,5.1Hz,1H),0.71(td,J=7.0,5.0Hz,1H);LRMS(ESI):417.17[M+H]+
实施例45 2-氯苄基4-氟-4-(((反式-2-苯基环丙基)氨基)甲基)哌啶-1-甲酸酯(A45)
将3-苯基丙酰氯替换为2-氯苄基氯甲酸酯,其余所需原料、试剂及制备方法同实施例8,得产物A45(产率70%)。1H NMR(400MHz,DMSO-d6)δ7.45–7.31(m,2H),7.26–7.05(m,7H),5.09(d,J=0.9Hz,2H),4.03(dt,J=12.5,7.1Hz,2H),3.26(dt,J=12.5,7.0Hz,2H),2.75–2.64(m,2H),2.00–1.82(m,3H),1.73–1.55(m,2H),0.94(td,J=7.0,5.0Hz,1H),0.71(td,J=7.0,5.1Hz,1H);LRMS(ESI):417.17[M+H]+
实施例46(4-氟-4-(((反式-2-苯基环丙基)氨基)甲基)哌啶-1-基)(苯基)甲酮(A46)
将3-苯基丙酰氯替换为苯甲酰氯,其余所需原料、试剂及制备方法同实施例8,得产物A46(产率66%)。1H NMR(400MHz,DMSO-d6)δ7.59(tt,J=7.2,2.2Hz,1H),7.50–7.36(m,4H),7.26–7.11(m,5H),3.75(dt,J=12.5,7.1Hz,2H),3.13(dt,J=12.6,7.2Hz,2H),2.76–2.64(m,2H),2.60(s,1H),1.98–1.86(m,2H),1.90–1.80(m,1H),1.63(ddt,J=25.1,13.2,7.0Hz,2H),0.96(td,J=6.9,5.0Hz,1H),0.70(td,J=7.0,5.0Hz,1H);LRMS(ESI):353.20[M+H]+
实施例47 4-叔丁基苄基4-氟-4-(((反式-2-苯基环丙基)氨基)甲基)哌啶-1-甲酸酯(A47)
将3-苯基丙酰氯替换为4-叔丁基苄基氯甲酸酯,其余所需原料、试剂及制备方法同实施例8,得产物A47(产率69%)。1H NMR(400MHz,DMSO-d6)δ7.39(t,J=6.3Hz,4H),7.26–7.11(m,5H),5.18(d,J=1.2Hz,2H),4.04(dt,J=12.6,7.2Hz,2H),3.25(dt,J=12.5,7.1Hz,2H),2.77–2.64(m,2H),2.00–1.82(m,3H),1.64(ddt,J=25.1,13.2,7.2Hz,2H),1.31(s,9H),0.94(td,J=7.0,5.1Hz,1H),0.70(td,J=7.0,5.1Hz,1H);LRMS(ESI):439.27[M+H]+
实施例48 4-氟-2-甲基-4-(((反式-2-苯基环丙基)氨基)甲基)哌啶-1-甲酸苄酯(A48)
将4-氟-4-甲酰基哌啶-1-甲酸苄酯替换为4-氟-2-甲基-4-甲酰基哌啶-1-甲酸苄酯,其余所需原料、试剂及制备方法同实施例1,得产物A48(产率68%)。1H NMR(400MHz,DMSO-d6)δ7.39–7.26(m,5H),7.26–7.11(m,5H),5.50(d,J=12.3Hz,1H),5.31(d,J=12.4Hz,1H),4.16(dt,J=12.4,7.1Hz,1H),3.79(h,J=6.8Hz,1H),3.21(dt,J=12.4,7.1Hz,1H),3.04(dd,J=25.2,12.4Hz,1H),2.90–2.66(m,2H),2.12–1.60(m,4H),1.46(ddd,J=25.3,13.1,7.0Hz,1H),1.25(d,J=6.8Hz,3H),0.94(td,J=7.0,5.0Hz,1H),0.69(td,J=7.0,4.9Hz,1H).LRMS(ESI):397.22[M+H]+
实施例49 4-氟-2,6-二甲基-4-(((反式-2-苯基环丙基)氨基)甲基)哌啶-1-甲酸苄酯(A49)
将4-氟-4-甲酰基哌啶-1-甲酸苄酯替换为4-氟-2,6-二甲基-4-甲酰基哌啶-1-甲酸苄酯,其余所需原料、试剂及制备方法同实施例1,得产物A49(产率74%)。1H NMR(400MHz,DMSO-d6)δ7.39–7.26(m,5H),7.26–7.11(m,5H),5.35(d,J=12.4Hz,1H),3.88(q,J=6.9Hz,2H),2.74–2.64(m,2H),2.60(s,1H),1.94–1.78(m,3H),1.51(ddd,J=25.3,13.2,7.0Hz,2H),1.25(d,J=6.8Hz,6H),0.95(td,J=7.0,5.0Hz,1H),0.69(td,J=7.0,5.0Hz,1H);LRMS(ESI):411.24[M+H]+
实施例50 4-氟-4-(((反式-2-(萘-2-基)环丙基)氨基)甲基)哌啶-1-甲酸苄酯(A50)
将反式-2-苯基环丙胺替换为反式-2-(萘-2-基)环丙胺,其余所需原料、试剂及制备方法同实施例1,得产物A50(产率60%)。1H NMR(400MHz,DMSO-d6)δ7.94–7.81(m,3H),7.57–7.39(m,4H),7.39–7.26(m,5H),5.22(s,2H),4.04(dt,J=12.4,7.2Hz,2H),3.30(dt,J=12.5,7.1Hz,2H),2.76(q,J=7.0Hz,1H),2.66(s,1H),2.60(s,1H),2.05–1.87(m,3H),1.64(ddt,J=25.1,13.2,7.2Hz,2H),0.99(td,J=7.0,5.0Hz,1H),0.75(td,J=7.0,5.0Hz,1H);LRMS(ESI):433.22[M+H]+
实施例51 4-氟-4-(((反式-2-(苯并噻吩-5-基)环丙基)氨基)甲基)哌啶-1-甲酸苄酯(A51)
将反式-2-苯基环丙胺替换为反式-2-(苯并噻吩-5-基)环丙胺,其余所需原料、试剂及制备方法同实施例1,得产物A51(产率55%)。1H NMR(400MHz,DMSO-d6)δ7.96(d,J=7.5Hz,1H),7.68(s,1H),7.55–7.44(m,2H),7.32(dtd,J=8.9,7.4,2.3Hz,6H),5.22(s,2H),4.03(dt,J=12.6,7.2Hz,2H),3.30(dt,J=12.5,7.0Hz,2H),2.77(q,J=7.0Hz,1H),2.66(s,1H),2.60(s,1H),2.05–1.87(m,3H),1.73–1.55(m,2H),0.99(td,J=7.0,4.9Hz,1H),0.77(td,J=7.0,4.9Hz,1H);LRMS(ESI):439.18[M+H]+
实施例52 4-氟-4-(((反式-2-(吡啶-4-基)环丙基)氨基)甲基)哌啶-1-甲酸苄酯(A52)
将反式-2-苯基环丙胺替换为反式-2-(吡啶-4-基)环丙胺,其余所需原料、试剂及制备方法同实施例1,得产物A52(产率65%)。1H NMR(400MHz,DMSO-d6)δ8.50(d,J=5.1Hz,2H),7.39–7.26(m,5H),7.22(d,J=5.2Hz,2H),5.22(s,2H),4.02(dt,J=12.5,7.0Hz,2H),3.34–3.13(m,3H),2.66(s,1H),2.60(s,1H),1.94(ddt,J=25.3,13.9,7.1Hz,2H),1.79–1.54(m,3H),0.86(td,J=7.0,4.9Hz,1H),0.61(td,J=7.0,5.0Hz,1H);LRMS(ESI):384.20[M+H]+
实施例53 4-氟-4-(((反式-2-(1H-吲哚-5-基)环丙基)氨基)甲基)哌啶-1-甲酸苄酯(A53)
将反式-2-苯基环丙胺替换为反式-2-(1H-吲哚-5-基)环丙胺,其余所需原料、试剂及制备方法同实施例1,得产物A53(产率57%)。1H NMR(400MHz,DMSO-d6)δ11.53(s,1H),7.82(s,1H),7.56(d,J=7.5Hz,1H),7.43(d,J=7.5Hz,1H),7.39–7.24(m,6H),6.64(dd,J=7.4,1.4Hz,1H),5.22(s,2H),4.03(dt,J=12.5,7.1Hz,2H),3.29(dt,J=12.5,7.1Hz,2H),2.76(q,J=7.0Hz,1H),2.66(s,1H),2.60(s,1H),2.05–1.87(m,3H),1.64(ddt,J=25.1,13.2,7.2Hz,2H),0.99(td,J=7.0,4.9Hz,1H),0.76(td,J=6.9,5.0Hz,1H);LRMS(ESI):422.22[M+H]+
实施例54 4-氟-4-(((反式-2-(1-甲基-1H-吲哚-5-基)环丙基)氨基)甲基)哌啶-1-甲酸苄酯(A54)
将反式-2-苯基环丙胺替换为反式-2-(1-甲基-1H-吲哚-5-基)环丙胺,其余所需原料、试剂及制备方法同实施例1,得产物A54(产率67%)。1H NMR(400MHz,DMSO-d6)δ7.66(t,J=1.5Hz,1H),7.52(d,J=7.5Hz,1H),7.39–7.26(m,5H),7.17(d,J=7.5Hz,1H),7.02(dd,J=7.5,1.5Hz,1H),6.53(dd,J=7.5,1.6Hz,1H),5.22(s,2H),4.12(dt,J=12.5,7.1Hz,2H),3.79(s,3H),3.12(dt,J=12.5,7.1Hz,2H),2.75(q,J=6.9Hz,1H),2.66(s,1H),2.60(s,1H),2.02–1.84(m,3H),1.65(ddt,J=25.1,13.2,7.2Hz,2H),0.96(td,J=7.0,5.0Hz,1H),0.72(td,J=7.0,5.0Hz,1H);LRMS(ESI):436.23[M+H]+
实施例55 4-氟-4-(((反式-2-(吲哚啉-5-基)环丙基)氨基)甲基)哌啶-1-甲酸苄酯(A55)
将反式-2-苯基环丙胺替换为反式-2-(吲哚啉-5-基)环丙胺,其余所需原料、试剂及制备方法同实施例1,得产物A55(产率55%)。1H NMR(400MHz,DMSO-d6)δ7.39–7.26(m,5H),6.95(d,J=2.0Hz,1H),6.69(dd,J=7.4,2.0Hz,1H),6.47(d,J=7.5Hz,1H),5.83(s,1H),5.22(s,2H),4.02(dt,J=12.5,7.2Hz,2H),3.65–3.43(m,2H),3.28(dt,J=12.5,7.1Hz,2H),2.88(ddd,J=18.5,10.3,8.0Hz,1H),2.77–2.57(m,4H),2.04–1.82(m,3H),1.63(ddt,J=25.1,13.2,7.1Hz,2H),0.95(td,J=7.0,5.1Hz,1H),0.71(td,J=7.0,5.0Hz,1H);LRMS(ESI):424.23[M+H]+
实施例56 4-氟-4-(((反式-2-(1-(苯磺酰基)吲哚啉-5-基)环丙基)氨基)甲基)哌啶-1-甲酸苄酯(A56)
将反式-2-苯基环丙胺替换为式-2-(1-(苯磺酰基)吲哚啉-5-基)环丙胺,其余所需原料、试剂及制备方法同实施例1,得产物A56(产率70%)。1H NMR(400MHz,DMSO-d6)δ7.68–7.51(m,5H),7.39–7.26(m,5H),7.17(d,J=2.0Hz,1H),6.75(dd,J=7.5,1.9Hz,1H),6.63(d,J=7.5Hz,1H),5.22(s,2H),4.43–4.22(m,2H),4.19–4.09(m,1H),3.99(dt,J=12.5,7.1Hz,1H),3.32(dt,J=12.5,7.1Hz,1H),3.08(dt,J=12.5,7.1Hz,1H),2.97(q,J=6.9Hz,1H),2.92–2.83(m,2H),2.66(s,1H),2.60(s,1H),2.09–1.72(m,4H),1.63(ddt,J=25.1,13.2,7.1Hz,1H),0.90(td,J=7.0,5.0Hz,1H),0.69(td,J=7.0,5.0Hz,1H);LRMS(ESI):564.23[M+H]+
实施例57 4-氟-4-(((反式-2-(1H-吲哚-3-基)环丙基)氨基)甲基)哌啶-1-甲酸苄酯(A57)
将反式-2-苯基环丙胺替换为反式-2-(1H-吲哚-3-基)环丙胺,其余所需原料、试剂及制备方法同实施例1,得产物A57(产率61%)。1H NMR(400MHz,DMSO-d6)δ10.75(s,1H),7.58(dd,J=7.4,1.5Hz,1H),7.39–7.26(m,3H),7.32(s,3H),7.17(s,1H),7.02(dtd,J=32.8,7.4,1.5Hz,2H),5.22(s,2H),3.89–3.71(m,3H),2.89(dt,J=12.5,7.2Hz,2H),2.66(s,1H),2.60(s,1H),1.88(ddt,J=25.1,12.3,7.1Hz,2H),1.72–1.46(m,3H),0.71(td,J=6.9,5.0Hz,1H),0.46(td,J=7.0,5.1Hz,1H);LRMS(ESI):422.22[M+H]+
实施例58 4-氟-4-(((反式-2-(咪唑并[1,2-α]吡啶-3-基)环丙基)氨基)甲基)哌啶-1-甲酸苄酯(A58)
将反式-2-苯基环丙胺替换为反式-2-(咪唑并[1,2-α]吡啶-3-基)环丙胺,其余所需原料、试剂及制备方法同实施例1,得产物A58(产率51%)。1H NMR(400MHz,DMSO-d6)δ8.47(dd,J=7.4,1.5Hz,1H),7.89(s,1H),7.47(dd,J=7.5,1.6Hz,1H),7.39–7.26(m,5H),7.21(td,J=7.5,1.5Hz,1H),6.85(td,J=7.4,1.4Hz,1H),5.22(s,2H),3.83(dt,J=12.4,7.2Hz,2H),3.76(q,J=7.0Hz,1H),2.89(dt,J=12.5,7.2Hz,2H),2.66(s,1H),2.60(s,1H),1.88(ddt,J=25.1,12.3,7.1Hz,2H),1.72–1.46(m,3H),0.82(td,J=7.0,4.9Hz,1H),0.57(td,J=7.0,5.0Hz,1H);LRMS(ESI):422.21[M+H]+
实施例59 4-氟-4-(((反式-2-(2,3-二氢苯并呋喃-5-基)环丙基)氨基)甲基)哌啶-1-甲酸苄酯(A59)
将反式-2-苯基环丙胺替换为反式-2-(2,3-二氢苯并呋喃-5-基)环丙胺,其余所需原料、试剂及制备方法同实施例1,得产物A59(产率65%)。1H NMR(400MHz,DMSO-d6)δ7.39–7.26(m,5H),7.05(d,J=2.0Hz,1H),6.96(dd,J=7.5,2.1Hz,1H),6.78(d,J=7.5Hz,1H),5.22(s,2H),4.47–4.37(m,2H),4.03(dt,J=12.5,7.1Hz,2H),3.29(dt,J =12.5,7.1Hz,2H),2.99(ddd,J=18.6,6.2,2.5Hz,1H),2.77–2.57(m,4H),2.04–1.84(m,3H),1.63(ddt,J=25.1,13.2,7.1Hz,2H),0.95(td,J=7.0,5.0Hz,1H),0.71(td,J=7.0,5.1Hz,1H);LRMS(ESI):425.22[M+H]+
实施例60 4-氟-4-(((反式-2-(色满-6-基)环丙基)氨基)甲基)哌啶-1-甲酸苄酯(A60)
将反式-2-苯基环丙胺替换为反式-2-(色满-6-基)环丙胺,其余所需原料、试剂及制备方法同实施例1,得产物A60(产率66%)。1H NMR(400MHz,DMSO-d6)δ7.39–7.26(m,5H),7.04–6.98(m,1H),6.96–6.89(m,1H),6.77(d,J=7.4Hz,1H),5.22(s,2H),4.08–3.91(m,3H),3.94–3.84(m,1H),3.28(dt,J=12.5,7.1Hz,2H),2.77–2.64(m,3H),2.60(s,1H),2.50–2.36(m,1H),2.04–1.74(m,5H),1.73–1.54(m,2H),0.95(td,J=7.0,5.0Hz,1H),0.71(td,J=7.0,4.9Hz,1H);LRMS(ESI):439.23[M+H]+
实施例61 4-氟-4-(((反式-2-(2-氧代-1,2,3,4-四氢喹啉-6-基)环丙基)氨基)甲基)哌啶-1-甲酸苄酯(A61)
将反式-2-苯基环丙胺替换为反式-2-(2-氧代-1,2,3,4-四氢喹啉-6-基)环丙胺,其余所需原料、试剂及制备方法同实施例1,得产物A61(产率69%)。1H NMR(400MHz,DMSO-d6)δ10.01(s,1H),7.39–7.26(m,5H),7.20(d,J=2.1Hz,1H),7.11(dd,J=7.5,1.9Hz,1H),6.98(d,J=7.5Hz,1H),5.22(s,2H),4.14(dt,J=12.5,7.1Hz,2H),3.31–3.07(m,4H),2.89–2.70(m,2H),2.66(s,1H),2.60(s,1H),2.48(ddd,J=15.2,4.4,1.7Hz,1H),2.11(ddt,J=25.1,13.2,7.2Hz,2H),1.89(q,J=7.0Hz,1H),1.67(ddt,J=25.3,13.2,7.2Hz,2H),0.96(td,J=6.9,5.0Hz,1H),0.72(td,J=7.0,5.0Hz,1H);LRMS(ESI):452.23[M+H]+
实施例62 4-氟-4-(((反式-2-(噻吩-3-基)环丙基)氨基)甲基)哌啶-1-甲酸苄酯(A62)
将反式-2-苯基环丙胺替换为反式-2-(噻吩-3-基)环丙胺,其余所需原料、试剂及制备方法同实施例1,得产物A62(产率75%)。1H NMR(400MHz,DMSO-d6)δ7.39–7.26(m,5H),7.22(d,J=7.5Hz,1H),6.95–6.86(m,2H),5.22(s,2H),3.83(dt,J=12.4,7.2Hz,2H),3.76(q,J=7.0Hz,1H),2.89(dt,J=12.5,7.2Hz,2H),2.66(s,1H),2.60(s,1H),1.88(ddt,J=25.1,12.3,7.1Hz,2H),1.63(ddt,J=25.3,12.5,7.1Hz,2H),1.51(q,J=7.0Hz,1H),0.69(td,J=6.9,5.0Hz,1H),0.44(td,J=7.0,5.0Hz,1H);LRMS(ESI):389.16[M+H]+
实施例63 4-氟-4-(((反式-2-(呋喃-3-基)环丙基)氨基)甲基)哌啶-1-甲酸苄酯(A63)
将反式-2-苯基环丙胺替换为反式-2-(呋喃-3-基)环丙胺,其余所需原料、试剂及制备方法同实施例1,得产物A63(产率75%)。1H NMR(400MHz,DMSO-d6)δ7.39– 7.26(m,6H),7.11(d,J=1.5Hz,1H),6.13(dd,J=7.5,1.5Hz,1H),5.22(s,2H),3.83(dt,J=12.5,7.2Hz,2H),3.76(q,J=7.0Hz,1H),2.89(dt,J=12.4,7.2Hz,2H),2.66(s,1H),2.60(s,1H),1.88(ddt,J=25.1,12.3,7.1Hz,2H),1.63(ddt,J=25.3,12.5,7.1Hz,2H),1.51(q,J=7.0Hz,1H),0.78(td,J=7.0,5.0Hz,1H),0.53(td,J=6.9,5.0Hz,1H);LRMS(ESI):373.18[M+H]+
实施例64 4-氟-4-(((反式-2-(噻唑-2-基)环丙基)氨基)甲基)哌啶-1-甲酸苄酯(A64)
将反式-2-苯基环丙胺替换为反式-2-(噻唑-2-基)环丙胺,其余所需原料、试剂及制备方法同实施例1,得产物A64(产率70%)。1H NMR(400MHz,DMSO-d6)δ7.69(d,J=7.5Hz,1H),7.58(d,J=7.5Hz,1H),7.39–7.26(m,5H),5.22(s,2H),3.83(dt,J=12.4,7.2Hz,2H),3.76(q,J=7.0Hz,1H),2.89(dt,J=12.5,7.2Hz,2H),2.66(s,1H),2.60(s,1H),1.88(ddt,J=25.1,12.3,7.1Hz,2H),1.63(ddt,J=25.3,12.5,7.1Hz,2H),1.51(q,J=7.0Hz,1H),0.78(td,J=7.0,4.9Hz,1H),0.53(td,J=6.9,5.0Hz,1H);LRMS(ESI):390.16[M+H]+
实施例65 4-氟-4-(((反式-2-(4-氟苯基)环丙基)氨基)甲基)哌啶-1-甲酸苄酯(A65)
将反式-2-苯基环丙胺替换为反式-2-(4-氟苯基)环丙胺,其余所需原料、试剂及制备方法同实施例1,得产物A65(产率78%)。1H NMR(400MHz,DMSO-d6)δ7.39–7.26(m,5H),7.16(ddd,J=7.0,5.8,1.1Hz,2H),7.12–7.03(m,2H),5.22(s,2H),4.04(dt,J=12.5,7.1Hz,2H),3.25(dt,J=12.5,7.1Hz,2H),2.75–2.64(m,2H),2.00–1.82(m,3H),1.64(ddt,J=25.1,13.2,7.2Hz,2H),0.95(td,J=7.0,4.9Hz,1H),0.71(td,J=7.0,5.1Hz,1H);LRMS(ESI):401.20[M+H]+
实施例66 4-氟-4-(((反式-2-(4-氰基苯基)环丙基)氨基)甲基)哌啶-1-甲酸苄酯(A66)
将反式-2-苯基环丙胺替换为反式-2-(4-氰基苯基)环丙胺,其余所需原料、试剂及制备方法同实施例1,得产物A66(产率72%)。1H NMR(400MHz,DMSO-d6)δ7.73–7.66(m,2H),7.33(tdd,J=8.7,4.2,2.8Hz,7H),5.22(s,2H),4.09(dt,J=12.4,7.1Hz,2H),3.23(dt,J=12.4,7.1Hz,2H),2.73–2.64(m,2H),2.01–1.83(m,3H),1.67(ddt,J=25.3,13.2,7.2Hz,2H),0.95(td,J=7.0,4.9Hz,1H),0.69(td,J=7.0,5.0Hz,1H);LRMS(ESI):408.20[M+H]+
实施例67 4-氟-4-(((反式-2-(4-甲氧基苯基)环丙基)氨基)甲基)哌啶-1-甲酸苄酯(A67)
将反式-2-苯基环丙胺替换为反式-2-(4-甲氧基苯基)环丙胺,其余所需原料、试剂及制备方法同实施例1,得产物A67(产率70%)。1H NMR(400MHz,DMSO-d6)δ7.39 –7.26(m,5H),7.10–7.03(m,2H),6.95–6.88(m,2H),5.22(s,2H),4.03(dt,J=12.5,7.1Hz,2H),3.79(s,3H),3.28(dt,J=12.5,7.2Hz,2H),2.77–2.64(m,2H),2.04–1.82(m,3H),1.63(ddt,J=25.1,13.2,7.1Hz,2H),0.95(td,J=7.0,5.1Hz,1H),0.71(td,J=7.0,5.0Hz,1H);LRMS(ESI):413.22[M+H]+
实施例68 4-氟-4-(((反式-2-(2-乙酰基苯基)环丙基)氨基)甲基)哌啶-1-甲酸苄酯(A68)
将反式-2-苯基环丙胺替换为反式-2-(2-乙酰基苯基)环丙胺,其余所需原料、试剂及制备方法同实施例1,得产物A68(产率70%)。1H NMR(400MHz,DMSO-d6)δ7.66(dd,J=7.5,2.0Hz,1H),7.46(td,J=7.5,2.1Hz,1H),7.39–7.26(m,5H),7.27–7.12(m,2H),5.22(s,2H),4.04(dt,J=12.6,7.2Hz,2H),3.24(dt,J=12.5,7.0Hz,2H),2.73–2.64(m,2H),2.60(s,1H),2.50(s,3H),2.08–1.82(m,3H),1.72–1.54(m,2H),0.85(td,J=7.0,5.0Hz,1H),0.53(td,J=7.0,5.0Hz,1H).LRMS(ESI):425.22[M+H]+
实施例69 4-氟-4-(((反式-2-([1,1'-联苯]-4-基)环丙基)氨基)甲基)哌啶-1-甲酸苄酯(A69)
将反式-2-苯基环丙胺替换为反式-2-([1,1'-联苯]-4-基)环丙胺,其余所需原料、试剂及制备方法同实施例1,得产物A69(产率68%)。1H NMR(400MHz,DMSO-d6)δ7.70(dd,J=7.6,2.0Hz,2H),7.54–7.37(m,5H),7.37–7.26(m,7H),5.22(s,2H),4.04(dt,J=12.4,7.1Hz,2H),3.29(dt,J=12.5,7.1Hz,2H),2.75(q,J=6.9Hz,1H),2.66(s,1H),2.60(s,1H),2.04–1.85(m,3H),1.73–1.55(m,2H),0.96(td,J=7.0,4.9Hz,1H),0.72(td,J=7.0,5.1Hz,1H);LRMS(ESI):459.24[M+H]+
实施例70 4-氟-4-(((反式-2-(4-甲基苯基)环丙基)氨基)甲基)哌啶-1-甲酸苄酯(A70)
将反式-2-苯基环丙胺替换为反式-2-(4-甲基苯基)环丙胺,其余所需原料、试剂及制备方法同实施例1,得产物A70(产率75%)。1H NMR(400MHz,DMSO-d6)δ7.39–7.26(m,5H),7.12–7.04(m,2H),7.06–6.98(m,2H),5.22(s,2H),4.03(dt,J=12.6,7.2Hz,2H),3.29(dt,J=12.5,7.1Hz,2H),2.77–2.64(m,2H),2.21(s,3H),2.04–1.84(m,3H),1.63(ddt,J=25.1,13.2,7.0Hz,2H),0.95(td,J=7.0,5.0Hz,1H),0.71(td,J=7.0,5.1Hz,1H);LRMS(ESI):397.22[M+H]+
实施例71 4-氟-4-(((反式-2-(4-硝基苯基)环丙基)氨基)甲基)哌啶-1-甲酸苄酯(A71)
将反式-2-苯基环丙胺替换为反式-2-(4-硝基苯基)环丙胺,其余所需原料、试剂及制备方法同实施例1,得产物A71(产率72%)。1H NMR(400MHz,DMSO-d6)δ8.22–8.13(m,2H),7.39–7.26(m,7H),5.22(s,2H),3.95(dt,J=12.6,7.2Hz,2H),3.19(dt,J=12.4,7.1Hz,2H),2.81(q,J=7.0Hz,1H),2.66(s,1H),2.60(s,1H),1.96–1.72(m, 3H),1.56(ddt,J=25.3,13.7,7.1Hz,2H),0.95(td,J=7.0,4.9Hz,1H),0.70(td,J=7.0,5.0Hz,1H);LRMS(ESI):428.19[M+H]+
实施例72 4-(反式-2-(((1-((苄氧基)羰基)-4-氟哌啶-4-基)甲基)氨基)环丙基)苯甲酸(A72)
将反式-2-苯基环丙胺替换为4-(反式-2-氨基环丙基)苯甲酸,其余所需原料、试剂及制备方法同实施例1,得产物A72(产率60%)。1H NMR(400MHz,DMSO-d6)δ12.91(s,1H),7.87–7.81(m,2H),7.39–7.26(m,5H),7.22(dd,J=7.4,1.1Hz,2H),5.22(s,2H),4.03(dt,J=12.4,7.1Hz,2H),3.29(dt,J=12.5,7.1Hz,2H),2.77–2.64(m,2H),2.60(s,1H),2.04–1.86(m,3H),1.64(ddt,J=25.1,13.2,7.1Hz,2H),0.97(td,J=7.0,4.9Hz,1H),0.72(td,J=7.0,5.1Hz,1H);LRMS(ESI):427.20[M+H]+
实施例73 4-氟-4-(((反式-2-(3,4-二氟苯基)环丙基)氨基)甲基)哌啶-1-甲酸苄酯(A73)
将反式-2-苯基环丙胺替换为反式-2-(3,4-二氟苯基)环丙胺,其余所需原料、试剂及制备方法同实施例1,得产物A73(产率75%)。1H NMR(400MHz,DMSO-d6)δ7.39–7.22(m,6H),7.01–6.88(m,2H),5.22(s,2H),4.03(dt,J=12.4,7.0Hz,2H),3.29(dt,J=12.6,7.2Hz,2H),2.77–2.64(m,2H),2.03–1.85(m,3H),1.64(ddt,J=25.3,13.7,7.1Hz,2H),0.98(td,J=6.9,5.0Hz,1H),0.72(td,J=7.0,5.0Hz,1H);LRMS(ESI):419.19[M+H]+
实施例74 4-氟-4-((2,2,2-三氟-N-(反式-2-苯基环丙基)乙酰胺基)甲基)哌啶-1-甲酸苄酯
(A74)
将4-氟-4-(((反式-2-苯基环丙基)氨基)甲基)哌啶-1-甲酸叔丁酯替换为实施例1所得产物A1,其余所需原料、试剂及制备方法同实施例5.1,得产物A74(产率80%)。1H NMR(400MHz,DMSO-d6)δ7.39–7.26(m,5H),7.26–7.11(m,5H),5.22(s,2H),3.99(dt,J=12.4,7.1Hz,2H),3.31(s,1H),3.25(s,1H),3.16(dt,J=12.5,7.1Hz,2H),2.85(q,J=7.0Hz,1H),2.10–1.86(m,3H),1.67–1.48(m,2H),1.04(td,J=7.0,4.9Hz,1H),0.76(td,J=7.0,5.0Hz,1H);LRMS(ESI):479.19[M+H]+
实施例75 4-氟-4-((甲基(反式-2-苯基环丙基)氨基)甲基)哌啶-1-甲酸苄酯(A75)
将反式-2-苯基环丙胺替换为N-甲基-反式-2-苯基环丙胺,其余所需原料、试剂及制备方法同实施例1,得产物A75(产率74%)。1H NMR(400MHz,DMSO-d6)δ7.39–7.26(m,5H),7.26–7.11(m,5H),5.22(s,2H),4.02(dt,J=12.5,7.1Hz,2H),3.24(dt,J=12.5,7.1Hz,2H),2.67(q,J=7.0Hz,1H),2.40(d,J=6.3Hz,4H),1.99–1.80(m,3H),1.62(ddt,J=25.1,13.2,7.0Hz,2H),0.94(td,J=6.9,5.0Hz,1H),0.70(td,J=7.0,5.0Hz,1H);LRMS(ESI):397.22[M+H]+
实施例76 4-氟-4-(1-((反式-2-苯基环丙基)氨基)乙基)哌啶-1-甲酸苄酯(A76)
将4-氟-4-甲酰基哌啶-1-甲酸苄酯替换为4-乙酰基-4-氟哌啶-1-甲酸苄酯,其余所需原料、试剂及制备方法同实施例1,得产物A76(产率48%)。1H NMR(400MHz,DMSO-d6)δ7.39–7.26(m,5H),7.26–7.11(m,5H),5.22(s,2H),4.02(dt,J=12.5,7.1Hz,2H),3.30(dt,J=12.5,7.1Hz,2H),3.02(dq,J=25.1,6.8Hz,1H),2.80(q,J=7.0Hz,1H),2.11(s,1H),2.07–1.86(m,3H),1.65(ddt,J=25.1,13.2,7.0Hz,2H),1.10(d,J=6.7Hz,3H),0.96(td,J=7.0,5.0Hz,1H),0.71(td,J=7.0,5.1Hz,1H);LRMS(ESI):397.22[M+H]+
实施例77 4-氟-4-((N-(反式-2-苯基环丙基)乙酰氨基)甲基)哌啶-1-甲酸苄酯(A77)
将4-氟-4-(((反式-2-苯基环丙基)氨基)甲基)哌啶-1-甲酸叔丁酯替换为实施例1所得产物A1,三氟乙酸酐替换为乙酸酐,其余所需原料、试剂及制备方法同实施例5.1,得产物A77(产率84%)。1H NMR(400MHz,DMSO-d6)δ7.39–7.26(m,5H),7.26–7.11(m,5H),5.22(s,2H),4.09(dt,J=12.6,7.2Hz,2H),3.42–3.29(m,3H),3.25(s,1H),2.78(q,J=7.0Hz,1H),2.08(s,3H),1.96–1.70(m,3H),1.55(ddt,J=25.1,13.2,7.1Hz,2H),0.99(td,J=7.0,5.0Hz,1H),0.69(td,J=7.0,5.0Hz,1H);LRMS(ESI):425.22[M+H]+
实施例78 3-氟-3-(((反式2-苯基环丙基)氨基)甲基)氮杂环丁烷-1-甲酸苄酯(A78)
将4-氟-4-甲酰基哌啶-1-甲酸苄酯替换为3-氟-3-甲酰基氮杂环丁烷-1-甲酸苄酯,其余所需原料、试剂及制备方法同实施例1,得产物A78(产率68%)。1H NMR(400MHz,DMSO-d6)δ7.39–7.26(m,5H),7.26–7.11(m,5H),5.22(s,2H),4.16(d,J=11.3Hz,1H),4.09(d,J=11.1Hz,1H),3.85(d,J=11.1Hz,1H),3.79(d,J=11.2Hz,1H),2.90(q,J=7.0Hz,1H),2.66(s,1H),2.60(s,1H),1.91(q,J=6.9Hz,1H),0.95(td,J=7.0,5.0Hz,1H),0.72(td,J=7.0,5.0Hz,1H);LRMS(ESI):355.17[M+H]+
实施例79 2-氟-2-(((反式-2-苯基环丙基)氨基)甲基)吗啉-4-甲酸苄酯(A79)
将4-氟-4-甲酰基哌啶-1-甲酸苄酯替换为2-氟-2-甲酰基吗啉-4-甲酸苄酯,其余所需原料、试剂及制备方法同实施例1,得产物A79(产率60%)。1H NMR(400MHz,DMSO-d6)δ7.39–7.26(m,5H),7.26–7.11(m,5H),5.41(d,J=1.2Hz,2H),4.10(dd,J=25.2,12.6Hz,1H),3.86–3.72(m,1H),3.74–3.61(m,2H),3.51–3.36(m,2H),3.15(dd,J=25.2,12.4Hz,1H),2.88(dd,J=25.1,12.5Hz,1H),2.78(q,J=7.0Hz,1H),1.88(q,J=7.0Hz,1H),1.55(s,1H),0.95(td,J=7.0,5.0Hz,1H),0.69(td,J=7.0,4.9Hz,1H);LRMS(ESI):385.18[M+H]+
实施例80 4-氟-4-(2-((反式-2-苯基环丙基)氨基)乙基)哌啶-1-甲酸苄酯(A80)
将4-氟-4-甲酰基哌啶-1-甲酸苄酯替换为4-氟-4-(2-氧乙基)哌啶-1-甲酸苄酯,其余所需原料、试剂及制备方法同实施例1,得产物A80(产率78%)。1H NMR(400MHz,DMSO-d6)δ7.39–7.26(m,5H),7.26–7.11(m,5H),5.22(s,2H),4.11(dt,J=12.4,7.0Hz,2H),3.11(tt,J=12.0,7.4Hz,3H),2.97(dt,J=12.3,7.8Hz,1H),2.71(q,J=7.0Hz,1H),1.96–1.77(m,3H),1.72–1.41(m,4H),0.89(td,J=7.0,4.9Hz,1H),0.64(td,J=7.0,4.9Hz,1H);LRMS(ESI):397.22[M+H]+
实施例81 3-氟-3-(((反式-2-苯基环丙基)氨基)甲基)哌啶-1-甲酸苄酯(A81)
将4-氟-4-甲酰基哌啶-1-甲酸苄酯替换为3-氟-3-甲酰基哌啶-1-甲酸苄酯,其余所需原料、试剂及制备方法同实施例1,得产物A81(产率77%)。1H NMR(400MHz,DMSO-d6)δ7.32(dq,J=6.0,3.2Hz,5H),7.26–7.11(m,5H),6.44(d,J=12.3Hz,1H),4.63(d,J=12.5Hz,1H),4.11(dd,J=25.1,12.5Hz,1H),3.76(d,J=12.5Hz,1H),3.38–3.18(m,2H),3.02(dd,J=25.2,12.4Hz,1H),2.75(dd,J=25.3,12.5Hz,1H),2.74(s,1H),1.98–1.80(m,3H),1.70(d,J=13.2Hz,1H),1.57(dd,J=25.1,13.2Hz,1H),0.94(s,1H),0.70(s,1H);LRMS(ESI):383.21[M+H]+
实施例82N-((4-氟-1-(苯磺酰基)哌啶-4-基)甲基)-反式-2-苯基环丙胺(A82)
将3-苯基丙酰氯替换为苯磺酰氯,其余所需原料、试剂及制备方法同实施例8,得产物A82(产率74%)。1H NMR(400MHz,DMSO-d6)δ7.92–7.84(m,2H),7.63(hept,J=2.5Hz,3H),7.26–7.11(m,5H),3.79(dt,J=12.4,7.1Hz,2H),3.35(dt,J=12.4,7.2Hz,2H),2.72–2.64(m,2H),1.75(ddt,J=25.1,13.1,7.0Hz,2H),1.67–1.49(m,3H),0.89(td,J=7.0,5.0Hz,1H),0.63(td,J=6.9,5.0Hz,1H);LRMS(ESI):389.16[M+H]+
实施例83 2-(4-氟-4-(((反式-2-苯基环己基)氨基)甲基)哌啶-1-基)乙醇(A83)
将溴甲基苯替换为2-溴乙醇,其余所需原料、试剂及制备方法同实施例6,得产物A83(产率55%)。1H NMR(400MHz,DMSO-d6)δ7.26–7.11(m,5H),4.25(t,J=5.0Hz,1H),3.53(td,J=7.2,5.0Hz,2H),3.08(dt,J=12.5,7.2Hz,2H),2.74–2.64(m,2H),2.60(s,1H),2.49(dt,J=12.2,7.2Hz,4H),2.00–1.89(m,1H),1.94–1.82(m,2H),1.42(ddt,J=25.1,13.2,7.0Hz,2H),0.95(td,J=6.9,5.0Hz,1H),0.68(td,J=7.0,5.0Hz,1H);LRMS(ESI):293.20[M+H]+
实施例84N-(4-氟-4-(((反式-2-苯基环丙基)氨基)甲基)环己基)乙酰胺(A84)
将4-氟-4-甲酰基哌啶-1-甲酸苄酯替换为N-(4-氟-4-甲酰基环己基)乙酰胺,其余所需原料、试剂及制备方法同实施例1,得到产物A84(产率65%)。1H NMR(400MHz, DMSO-d6)δ7.26–7.11(m,5H),5.49(s,1H),3.44(p,J=7.0Hz,1H),2.72–2.61(m,2H),2.60(s,1H),2.33–2.18(m,2H),1.99(s,3H),1.95–1.75(m,3H),1.77–1.66(m,2H),1.67(dd,J=5.8,4.3Hz,1H),1.61(dt,J=12.3,6.8Hz,1H),0.99(td,J=7.0,5.0Hz,1H),0.66(td,J=7.0,5.0Hz,1H);LRMS(ESI):305.21[M+H]+
实施例85N-苄基-4-氟-4-(((反式-2-苯基环丙基)氨基)甲基)环己胺(A85)
将4-氟-4-甲酰基哌啶-1-甲酸苄酯替换为4-(苄氨基)-1-氟环己烷-1-甲醛,其余所需原料、试剂及制备方法同实施例1,得到产物A85(产率72%)。1H NMR(400MHz,DMSO-d6)δ7.37–7.11(m,10H),4.09(s,2H),2.72–2.57(m,3H),2.09–1.98(m,2H),1.98–1.83(m,5H),1.67–1.49(m,4H),0.99(td,J=7.0,4.9Hz,1H),0.66(td,J=6.9,5.0Hz,1H);LRMS(ESI):353.23[M+H]+
实施例86N-(4-氟-4-(((反式-2-苯基环丙基)氨基)甲基)环己基)苯胺(A86)
将4-氟-4-甲酰基哌啶-1-甲酸苄酯替换为1-氟-4-(苯胺基)环己烷-1-甲醛,其余所需原料、试剂及制备方法同实施例1,得到产物A86(产率64%)。1H NMR(400MHz,DMSO-d6)δ7.26–7.12(m,5H),7.17–7.03(m,2H),6.74–6.60(m,3H),6.26(s,1H),3.06(p,J=7.0Hz,1H),2.76–2.64(m,2H),2.60(s,1H),1.97–1.71(m,5H),1.53(ddt,J=25.3,11.6,6.4Hz,2H),1.42(dq,J=12.7,6.9Hz,2H),0.95(td,J=6.9,5.0Hz,1H),0.68(td,J=7.0,5.0Hz,1H);LRMS(ESI):339.22[M+H]+
实施例87N-(4-氟-4-(((反式-2-苯基环丙基)氨基)甲基)环己基)苯磺酰胺(A87)
将4-氟-4-甲酰基哌啶-1-甲酸苄酯替换为N-(4-氟-4-甲酰基环己基)苯磺酰胺,其余所需原料、试剂及制备方法同实施例1,产物A87(产率68%)。1H NMR(400MHz,DMSO-d6)δ7.86–7.77(m,2H),7.68–7.55(m,4H),7.26–7.11(m,5H),3.05(p,J=7.0Hz,1H),2.75(q,J=7.0Hz,1H),2.66(s,1H),2.60(s,1H),1.93–1.74(m,5H),1.68–1.57(m,1H),1.62–1.44(m,3H),0.94(td,J=7.0,5.1Hz,1H),0.67(td,J=6.9,5.0Hz,1H);LRMS(ESI):403.18[M+H]+
实施例88(1r,4r)-4-氟-4-(((反式-2-苯基环丙基)氨基)甲基)环己胺(A88)
将4-氟-4-甲酰基哌啶-1-甲酸叔丁酯替换为((1r,4r)-4-氟-4-甲酰基环己基)氨基甲酸叔丁酯,其余所需原料、试剂及制备方法同实施例2,得产物A88(产率72%)。1H NMR(400MHz,DMSO-d6)δ7.26–7.11(m,5H),2.83(p,J=7.0Hz,1H),2.76–2.64(m,2H),2.60(s,1H),1.91–1.69(m,5H),1.62–1.44(m,2H),1.47–1.32(m,2H),1.30(s,2H),0.90(td,J=6.9,5.0Hz,1H),0.67(td,J=7.0,5.0Hz,1H);LRMS(ESI):263.18[M+H]+
实施例89(1-甲基哌啶-4-基)甲基4-氟-4-(((反式-2-苯基环丙基)氨基)甲基)哌啶-1-甲酸酯(A89)
将3-苯基丙酰氯替换为(1-甲基哌啶-4-基)甲基氯甲酸酯,其余所需原料、试剂及制备方法同实施例8.1及5.4,得产物A89的二盐酸盐(产率66%)。1H NMR(400MHz,MeOD)δ7.33(tt,J=7.9,1.5Hz,2H),7.30–7.22(m,1H),7.26–7.19(m,2H),4.08(d,J=15.2Hz,4H),3.62–3.51(m,4H),3.29–3.14(m,2H),3.08(p,J=4.2Hz,2H),3.03(dd,J=13.0,2.5Hz,1H),2.88(s,3H),2.64(ddd,J=10.3,6.6,3.6Hz,1H),2.09–1.95(m,5H),1.94–1.76(m,2H),1.76–1.58(m,3H),1.41(dt,J=7.9,6.7Hz,1H);LRMS(ESI):404.26[M+H]+
实施例90(1-苄基哌啶-4-基)甲基4-氟-4-(((反式-2-苯基环丙基)氨基)甲基)哌啶-1-甲酸酯(A90)
将3-苯基丙酰氯替换为(1-苄基哌啶-4-基)甲基氯甲酸酯,其余所需原料、试剂及制备方法同实施例8.1及5.4,得产物A90的二盐酸盐(产率57%)。1H NMR(400MHz,MeOD)δ7.57(dd,J=6.7,2.9Hz,2H),7.52–7.46(m,3H),7.31(tt,J=8.3,1.6Hz,2H),7.26–7.22(m,1H),7.22–7.17(m,2H),4.32(s,2H),4.06(d,J=16.2Hz,4H),3.56(s,1H),3.54–3.45(m,3H),3.28–2.95(m,5H),2.61(ddd,J=10.3,6.6,3.6Hz,1H),2.04–1.92(m,5H),1.91–1.75(m,2H),1.74–1.64(m,2H),1.60(ddd,J=10.4,6.8,4.4Hz,1H),1.39(dt,J=7.8,6.7Hz,1H);LRMS(ESI):478.29[M+H]+
实施例91 4-((4-(((4-氟-4-(((反式-2-苯基环丙基)氨基)甲基)哌啶-1-羰基)氧代)甲基)哌啶-1-基)甲基)苯甲酸(A91)
将4-氟-4-(((反式-2-苯基环丙基)氨基)甲基)哌啶-1-甲酸叔丁酯替换为(1-(叔丁氧羰基)哌啶-4-基)甲基4-氟-4-(((反式-2-苯基环丙基)氨基)甲基)哌啶-1-甲酸酯,其余所需原料、试剂及制备方法同实施例5,得产物A91的二盐酸盐(产率35%)。1H NMR(500MHz,D2O)δ7.98(d,J=8.2Hz,2H),7.51(d,J=8.1Hz,2H),7.28(t,J=7.5Hz,2H),7.24–7.19(m,1H),7.12(d,J=7.2Hz,2H),4.27(s,2H),3.91–3.88(m,4H),3.48–3.39(m,4H),3.15–3.03(m,2H),3.00–2.90(m,3H),2.50(ddd,J=10.4,6.7,3.6Hz,1H),1.99–1.81(m,5H),1.69(td,J=13.3,5.0Hz,1H),1.62(td,J=13.3,5.1Hz,1H),1.48(ddd,J=11.0,7.0,4.4Hz,1H),1.45–1.37(m,2H),1.34(q,J=7.2Hz,1H);LRMS(ESI):524.28[M+H]+
实施例92N-((4-氟-1-(哌啶-4-基甲基)磺酰基)哌啶-4-基)甲基)-反式-2-苯基环丙胺(A92)
将3-苯基丙酰氯替换为叔丁基4-((氯磺酰基)甲基)哌啶-1-羧酸,其余所需原料、试剂及制备方法同实施例8.1及5.4,得产物A92的二盐酸盐(产率68%)。1H NMR(500MHz,MeOD)δ7.31(t,J=7.5Hz,2H),7.24(d,J=7.5Hz,1H),7.20(d,J=7.3Hz,2H),3.79–3.71(m,2H),3.58(d,J=20.1Hz,2H),3.51(dt,J=12.6,3.4Hz,3H),3.36–3.23(m,4H),3.16–2.99(m,3H),2.62(ddd,J=10.3,6.6,3.6Hz,1H),2.30(dd,J=14.7,3.7 Hz,2H),2.10–1.86(m,6H),1.61(ddd,J=10.8,6.8,4.4Hz,1H),1.39(q,J=7.0Hz,1H);LRMS(ESI):410.22[M+H]+
实施例93N-((4-氟-1-(甲基磺酰基)哌啶-4-基)甲基)-反式-2-苯基环丙胺(A93)
将3-苯基丙酰氯替换为甲基磺酰氯,其余所需原料、试剂及制备方法同实施例8.1及5.4,得产物A93的二盐酸盐(产率80%)。1H NMR(400MHz,DMSO-d6)δ9.71(s,2H),7.33–7.28(m,2H),7.25–7.21(m,1H),7.21–7.17(m,2H),3.54–3.42(m,4H),2.99–2.93(m,3H),2.92(s,3H),2.64(ddd,J=10.1,6.4,3.5Hz,1H),2.14–2.04(m,2H),1.97–1.87(m,1H),1.87–1.77(m,1H),1.66(ddd,J=10.4,6.1,4.4Hz,1H),1.27(dt,J=7.7,6.3Hz,1H);LRMS(ESI):327.15[M+H]+
实施例94氮杂环丁烷-3-基甲基4-氟-4-(((反式-2-苯基环丙基)氨基)甲基)哌啶-1-甲酸酯(A94)
将3-苯基丙酰氯替换为叔丁基3-(((氯甲酰基)氧代)甲基)氮杂环丁烷-1-羧酸,其余所需原料、试剂及制备方法同实施例8.1及5.4,得产物A94的二盐酸盐(产率70%)。1H NMR(400MHz,DMSO-d6)δ7.27–7.10(m,5H),4.13(dt,J=12.5,7.1Hz,2H),3.88(d,J=7.0Hz,2H),3.43(dd,J=11.1,7.0Hz,2H),3.15–3.02(m,4H),2.71–2.56(m,4H),2.01–1.86(m,3H),1.75–1.58(m,2H),0.99(td,J=7.0,5.1Hz,1H),0.67(td,J=7.0,5.0Hz,1H).;LRMS(ESI):362.22[M+H]+
实施例95哌啶-4-基4-氟-4-(((反式-2-苯基环丙基)氨基)甲基)哌啶-1-甲酸酯(A95)
将3-苯基丙酰氯替换为叔丁基4-((氯甲酰基)氧代)哌啶-1-羧酸,其余所需原料、试剂及制备方法同实施例8.1及5.4,得产物A95的二盐酸盐(产率65%)。1H NMR(400MHz,DMSO-d6)δ7.26–7.11(m,5H),4.82(p,J=7.0Hz,1H),4.13(dt,J=12.5,7.1Hz,2H),3.11(dt,J=12.5,7.1Hz,2H),2.90(dt,J=12.4,7.1Hz,2H),2.72–2.56(m,5H),2.02–1.84(m,3H),1.77–1.53(m,4H),1.29(dq,J=13.9,7.1Hz,2H),0.99(td,J=7.0,5.0Hz,1H),0.67(td,J=7.0,5.0Hz,1H);LRMS(ESI):376.23[M+H]+
实施例96 4-((4-氟-4-(((反式-2-苯基环丙基)氨基)甲基)哌啶-1-基)甲基)苯甲腈(A96)
将溴甲基苯替换为4-(溴甲基)苯甲腈,其余所需原料、试剂及制备方法同实施例6,得产物A96(产率62%)。1H NMR(400MHz,MeOD)δ7.91–7.83(m,4H),7.35–7.30(m,2H),7.28–7.24(m,1H),7.24–7.19(m,2H),4.52(s,2H),3.67(d,J=20.1Hz,2H),3.54(d,J=12.4Hz,2H),3.44–3.34(m,2H),3.10(dt,J=7.8,4.0Hz,1H),2.70–2.60(m,1H),2.40–2.20(m,4H),1.64(dt,J=11.0,6.0Hz,1H),1.42(dt,J=7.8,6.8Hz,1H);LRMS(ESI):364.21[M+H]+
实施例97N-((4-氟-1-(哌啶-4-基甲基)哌啶-4-基)甲基)-反式-2-苯基环丙胺(A97)
将溴甲基苯替换为4-(溴甲基)哌啶,其余所需原料、试剂及制备方法同实施例6,得产物A97(产率73%)。1H NMR(400MHz,DMSO-d6)δ8.46(d,J=5.1Hz,2H),7.40(d,J=5.1Hz,2H),7.26–7.11(m,5H),4.33(s,2H),2.97(dt,J=12.5,7.1Hz,2H),2.72–2.57(m,3H),2.33(dt,J=12.5,7.1Hz,2H),1.95–1.73(m,3H),1.56(ddt,J=25.1,13.2,7.2Hz,2H),0.99(td,J=7.0,5.0Hz,1H),0.67(td,J=7.0,5.0Hz,1H);LRMS(ESI):340.21[M+H]+
实施例98N-((4-氟-1-(噻吩-3-基甲基)哌啶-4-基)甲基)-反式-2-苯基环丙胺(A98)
将溴甲基苯替换为3-(溴甲基)噻吩,其余所需原料、试剂及制备方法同实施例6,得产物A98(产率75%)。1H NMR(400MHz,DMSO-d6)δ7.31–7.11(m,6H),6.96–6.87(m,2H),3.69(s,2H),3.04(dt,J=12.5,7.1Hz,2H),2.72–2.57(m,3H),2.34(dt,J=12.5,7.2Hz,2H),1.95–1.74(m,3H),1.56(ddt,J=25.1,13.2,7.0Hz,2H),0.99(td,J=7.0,5.0Hz,1H),0.67(td,J=7.0,5.0Hz,1H);LRMS(ESI):345.17[M+H]+
实施例99(1-(环丙基甲基)哌啶-4-基)甲基4-氟-4-(((反式-2-苯基环丙基)氨基)甲基)哌啶-1-甲酸酯(A99)
将3-苯基丙酰氯替换为(1-(环丙基甲基)哌啶-4-基)甲基氯甲酸酯,其余所需原料、试剂及制备方法同实施例8.1及5.4,得产物A99的二盐酸盐(产率60%)。1H NMR(400MHz,MeOD)δ7.34–7.28(m,2H),7.26–7.22(m,1H),7.22–7.17(m,2H),4.15–3.98(m,4H),3.78–3.66(m,2H),3.55(d,J=20.2Hz,2H),3.25–3.10(m,2H),3.10–2.96(m,5H),2.61(ddd,J=10.3,6.6,3.6Hz,1H),2.09–1.94(m,5H),1.92–1.65(m,4H),1.61(ddd,J=10.5,6.8,4.4Hz,1H),1.39(dt,J=7.9,6.7Hz,1H),1.16(ddtd,J=12.4,9.7,7.3,4.5Hz,1H),0.80–0.74(m,2H),0.46(dt,J=6.3,4.7Hz,2H);LRMS(ESI):404.26[M+H]+
实施例100N-(2-氨基苯基)-4-((4-氟-4-(((反式-2-苯基环丙基)氨基)甲基)哌啶-1-基)甲基)苯甲酰胺(A100)
将溴甲基苯替换为叔丁基(2-(4-(溴甲基)苯甲酰胺基)苯基)氨基甲酸酯,其余所需原料、试剂及制备方法同实施例6,得产物A100(产率45%)。1H NMR(400MHz,MeOD)δ8.21(d,J=7.9Hz,2H),7.86(d,J=8.0Hz,2H),7.60–7.46(m,4H),7.33(t,J=7.4Hz,2H),7.24(dd,J=14.2,7.2Hz,3H),4.55(s,2H),3.68(d,J=20.0Hz,2H),3.57(d,J=10.4Hz,2H),3.47–3.36(m,2H),3.14–3.06(m,1H),2.71–2.64(m,1H),2.45–2.21(m,4H),1.70–1.62(m,1H),1.43(dd,J=13.9,7.0Hz,1H);LRMS(ESI):473.26[M+H]+
实施例101叔丁基4-((4-(((2-(5-溴噻吩-2-基)环丙基)氨基)甲基)-4-氟哌啶-1-基)甲基)苯酸酯(A101)
将反式-2-苯基环丙胺替换成反式-2-(5-溴噻吩-2-基)环丙胺,将4-氟-4-甲酰基哌啶-1-甲酸苄酯替换为4-((4-氟-4-甲酰基哌啶-1-基)甲基)苯甲酸叔丁酯,其余所需原料、试剂及制备方法同实施例1,得产物A101(产率61%)。1H NMR(400MHz,DMSO-d6)δ7.96–7.90(m,2H),7.34(dt,J=8.4,1.1Hz,2H),7.00(d,J=8.4Hz,1H),6.77(d,J=8.4Hz,1H),3.57(t,J=1.0Hz,2H),3.18(ddd,J=25.1,14.5,4.9Hz,1H),3.04(dt,J=7.5,4.9Hz,1H),2.96(ddd,J=25.1,14.6,4.9Hz,1H),2.87(ddd,J=12.1,6.2,4.3Hz,2H),2.81(dtd,J=7.5,6.4,5.7Hz,1H),2.59–2.49(m,3H),2.11–1.93(m,4H),1.89(td,J=6.4,1.3Hz,2H),1.55(s,6H).LRMS(ESI):523.14[M+H]+
实施例102 4-((4-(((2-(5-溴噻吩-2-基)环丙基)氨基)甲基)-4-氟哌啶-1-基)甲基)苯甲酸(A102)
将反式-2-苯基环丙胺替换成反式-2-(5-溴噻吩-2-基)环丙胺,其余所需原料、试剂及制备方法同实施例5,得产物A102(产率73%)。1H NMR(400MHz,DMSO-d6)δ7.99–7.93(m,2H),7.37(dt,J=8.4,1.1Hz,2H),7.02(d,J=8.4Hz,1H),6.71(d,J=8.4Hz,1H),3.55(t,J=1.0Hz,2H),3.16(ddd,J=25.1,14.4,5.0Hz,1H),3.08(dt,J=7.3,4.9Hz,1H),3.01(ddd,J=25.1,14.4,4.9Hz,1H),2.91–2.78(m,3H),2.61(ddd,J=12.3,6.4,4.1Hz,2H),2.48(td,J=6.4,5.6Hz,1H),2.11–1.85(m,6H).LRMS(ESI):467.07[M+H]+
实施例103甲基4-((4-(((2-(5-溴噻吩-2-基)环丙基)氨基)甲基)-4-氟哌啶-1-基)甲基)苯酸酯(A103)
将反式-2-苯基环丙胺替换成反式-2-(5-溴噻吩-2-基)环丙胺,其余所需原料、试剂及制备方法同实施例3,得产物A103(产率67%)。1H NMR(400MHz,DMSO-d6)δ7.96–7.90(m,2H),7.34(dt,J=8.4,1.1Hz,2H),7.03(d,J=8.4Hz,1H),6.68(d,J=8.4Hz,1H),3.89(s,2H),3.55(t,J=1.0Hz,2H),3.16(ddd,J=25.1,14.4,5.0Hz,1H),3.08(dt,J=7.3,4.9Hz,1H),3.01(ddd,J=25.1,14.4,5.0Hz,1H),2.91–2.78(m,3H),2.61(ddd,J=12.1,6.4,4.2Hz,2H),2.48(td,J=6.4,5.6Hz,1H),2.11–1.85(m,6H).LRMS(ESI):481.09[M+H]+
实施例104乙基4-((4-(((2-(5-溴噻吩-2-基)环丙基)氨基)甲基)-4-氟哌啶-1-基)甲基)苯酸酯(A104)
将反式-2-苯基环丙胺替换成反式-2-(5-溴噻吩-2-基)环丙胺,将4-氟-4-甲酰基哌啶-1-甲酸苄酯替换为4-((4-氟-4-甲酰基哌啶-1-基)甲基)苯甲酸乙酯,其余所需原料、试剂及制备方法同实施例1,得产物A104(产率75%)。1H NMR(400MHz,DMSO-d6)δ7.96–7.89(m,2H),7.35(dt,J=8.4,1.1Hz,2H),7.03(d,J=8.4Hz,1H),6.68(d,J=8.4Hz,1H),4.44–4.27(m,2H),3.58(dt,J=12.8,1.1Hz,1H),3.52(dt,J=12.8,1.1Hz,1H),3.22(ddd,J=25.3,14.6,4.9Hz,1H),3.07(dt,J=7.3,4.8Hz,1H),3.02–2.88(m,1H),2.91–2.82(m,3H),2.59(ddd,J=12.3,6.1,4.5Hz,2H),2.53(td,J=6.4,5.6Hz,1H),2.11–1.93(m,4H),1.89(td,J=6.4,1.3Hz,2H),1.39(t,J=7.0Hz,3H)..LRMS(ESI):495.10[M+H]+
实施例105叔丁基4-((4-氟-4-(((2-(5-(4-氟苯基)噻吩-2-基)环丙基)氨基)甲基)哌啶-1-基)甲基)苯酸酯(A105)
将反式-2-苯基环丙胺替换成反式-2-(5-(4-氟苯基)噻吩-2-基)环丙胺,其余所需原料、试剂及制备方法同实施例101,得产物A105(产率71%)。1H NMR(400MHz,DMSO-d6)δ7.96–7.90(m,2H),7.63–7.55(m,2H),7.31(dt,J=8.5,1.0Hz,2H),7.21–7.13(m,3H),6.73(d,J=8.4Hz,1H),3.57(t,J=1.0Hz,2H),3.20(ddd,J=25.1,14.6,4.8Hz,1H),3.01(dt,J=7.3,4.9Hz,1H),2.97–2.78(m,4H),2.58(ddd,J=12.3,6.3,4.2Hz,2H),2.28(td,J=6.4,5.6Hz,1H),2.07(ddd,J=13.6,6.4,4.2Hz,1H),2.02(dd,J=13.5,4.2Hz,1H),2.02–1.94(m,1H),1.98–1.89(m,2H),1.92–1.85(m,1H),1.55(s,7H).LRMS(ESI):539.25[M+H]+
实施例106叔丁基4-((4-(((2-(5-(4-氯苯基)噻吩-2-基)环丙基)氨基)甲基)-4-氟哌啶-1-基)甲基)苯酸酯(A106)
将反式-2-苯基环丙胺替换成反式-2-(5-(4-氯苯基)噻吩-2-基)环丙胺,其余所需原料、试剂及制备方法同实施例106,得产物A106(产率77%)。1H NMR(400MHz,DMSO-d6)δ7.96–7.90(m,2H),7.54–7.47(m,2H),7.42–7.36(m,2H),7.31(dt,J=8.4,1.0Hz,2H),7.19(d,J=8.4Hz,1H),6.74(d,J=8.4Hz,1H),3.57(t,J=1.0Hz,2H),3.20(ddd,J=25.1,14.7,4.9Hz,1H),3.01(dt,J=7.3,4.8Hz,1H),2.97–2.78(m,4H),2.58(ddd,J=12.1,6.4,4.2Hz,2H),2.28(td,J=6.4,5.6Hz,1H),2.11–1.86(m,6H),1.55(s,7H).LRMS(ESI):555.22[M+H]+
实施例107叔丁基4-((4-氟-4-(((2-(5-(4-(三氟甲基)苯基)噻吩-2-基)环丙基)氨基)甲基)哌啶-1-基)甲基)苯酸酯(A107)
将反式-2-苯基环丙胺替换成反式-2-(5-(4-三氟甲基苯基)噻吩-2-基)环丙胺,其余所需原料、试剂及制备方法同实施例101,得产物A107(产率66%)。1H NMR(400MHz,DMSO-d6)δ7.97–7.90(m,2H),7.77–7.70(m,2H),7.64–7.58(m,2H),7.37–7.28(m,3H),6.91(d,J=8.4Hz,1H),3.59(dt,J=12.6,0.9Hz,1H),3.53(dt,J=12.6,1.0Hz,1H),3.23–3.10(m,1H),3.08–2.82(m,5H),2.49(ddd,J=12.3,6.3,4.4Hz,2H),2.29(td,J=6.5,5.6Hz,1H),2.11–1.93(m,5H),1.89(t,J=6.4Hz,2H),1.55(s,7H).LRMS(ESI):589.24[M+H]+
实施例108叔丁基4-((4-氟-4-(((2-(5-苯基噻吩-2-基)环丙基)氨基)甲基)哌啶-1-基)甲基)苯酸酯(A108)
将反式-2-苯基环丙胺替换成反式-2-(5-苯基噻吩-2-基)环丙胺,其余所需原料、试剂及制备方法同实施例108,得产物A108(产率73%)。1H NMR(400MHz,DMSO-d6)δ7.96–7.90(m,2H),7.78–7.70(m,2H),7.49–7.40(m,3H),7.32(dd,J=8.4,1.5Hz,3H),6.88(d,J=8.4Hz,1H),3.59(dt,J=12.6,0.9Hz,1H),3.53(dt,J=12.6,1.0Hz,1H),3.18(ddd,J=25.3,14.5,5.1Hz,1H),3.07–2.95(m,1H),2.99–2.92(m,1H),2.91–2.79(m,3H),2.53– 2.42(m,3H),2.11–1.90(m,4H),1.89(t,J=6.4Hz,2H),1.55(s,7H).LRMS(ESI):521.26[M+H]+
实施例109叔丁基4-((4-氟-4-(((2-(5-(萘-1-基)噻吩-2-基)环丙基)氨基)甲基)哌啶-1-基)甲基)苯酸酯(A109)
将反式-2-苯基环丙胺替换成反式-2-(5-(萘-1-基)噻吩-2-基)环丙胺,其余所需原料、试剂及制备方法同实施例101,得产物A109(产率77%)。1H NMR(400MHz,DMSO-d6)δ8.06–7.99(m,1H),7.98–7.89(m,4H),7.69(dd,J=7.9,0.8Hz,1H),7.61(t,J=7.8Hz,1H),7.52(pd,J=7.4,1.5Hz,2H),7.37–7.28(m,3H),6.88(d,J=8.4Hz,1H),3.59(dt,J=12.6,0.9Hz,1H),3.53(dt,J=12.6,1.0Hz,1H),3.17(ddd,J=25.1,14.3,5.1Hz,1H),3.10–2.95(m,2H),2.94(ddd,J=12.1,6.2,4.3Hz,2H),2.85(dtd,J=7.3,6.3,5.6Hz,1H),2.59(ddd,J=12.1,6.1,4.4Hz,2H),2.29(td,J=6.4,5.6Hz,1H),2.11–1.96(m,4H),1.99–1.87(m,2H),1.55(s,7H).LRMS(ESI):571.27[M+H]+
实施例110哌啶-4-基甲基4-氟-4-(((2-(5-(4-(三氟甲基)苯基)噻吩-2-基)环丙基)氨基)甲基)哌啶-1-羧酸酯(A110)
将反式-2-苯基环丙胺替换成反式-2-(5-(4-三氟甲基苯基)噻吩-2-基)环丙胺,其余所需原料、试剂及制备方法同实施例43,得产物A110(产率55%)。1H NMR(400MHz,DMSO-d6)δ7.68–7.62(m,2H),7.57–7.51(m,2H),7.30(d,J=8.4Hz,1H),6.81(d,J=8.4Hz,1H),4.23(dd,J=10.6,6.2Hz,1H),4.02(ddd,J=12.1,6.5,4.1Hz,2H),3.83(dd,J=10.4,6.2Hz,1H),3.70(ddd,J=11.9,6.4,4.0Hz,2H),3.35(p,J=4.1Hz,1H),3.20(ddd,J=25.3,14.6,4.9Hz,1H),3.08(dt,J=7.5,4.9Hz,1H),3.04–2.95(m,1H),2.99–2.91(m,2H),2.84(dtd,J=7.5,6.3,5.6Hz,1H),2.75(ddt,J=14.5,6.4,4.1Hz,2H),2.46(td,J=6.4,5.6Hz,1H),2.06(dddd,J=25.1,13.6,6.4,4.1Hz,2H),2.00–1.81(m,5H),1.63–1.53(m,2H),1.51–1.41(m,2H).LRMS(ESI):540.22[M+H]+
实施例111哌啶-4-基甲基4-(((2-(5-溴噻吩-2-基)环丙基)氨基)甲基)-4-氟哌啶-1-羧酸酯(A111)
将反式-2-苯基环丙胺替换成反式-2-(5-溴噻吩-2-基)环丙胺,其余所需原料、试剂及制备方法同实施例43,得产物A111(产率65%)。1H NMR(400MHz,DMSO-d6)δ7.02(d,J=8.4Hz,1H),6.72(d,J=8.4Hz,1H),4.25(dd,J=10.4,6.2Hz,1H),4.02(ddd,J=12.1,6.5,4.1Hz,2H),3.83(dd,J=10.4,6.2Hz,1H),3.69(ddd,J=12.1,6.4,4.0Hz,2H),3.35(p,J=4.1Hz,1H),3.15(ddd,J=25.3,14.5,5.0Hz,1H),3.09–2.97(m,1H),3.01–2.92(m,3H),2.85–2.71(m,3H),2.48(td,J=6.4,5.6Hz,1H),2.06(dddd,J=25.3,13.6,6.4,4.1Hz,2H),1.99–1.80(m,5H),1.64–1.54(m,2H),1.50–1.40(m,2H).LRMS(ESI):474.11[M+H]+
实施例112哌啶-4-基甲基4-氟-4-(((2-(6-(4-甲氧苯基)吡啶-3-基)环丙基)氨基)甲基)哌啶-1-羧酸酯(A112)
将反式-2-苯基环丙胺替换成反式-2-(6-(4-甲氧苯基)吡啶-3-基)环丙胺,其余所需原料、试剂及制备方法同实施例43,得产物A112(产率63%)。1H NMR(400MHz,DMSO-d6)δ8.40(d,J=1.8Hz,1H),7.83–7.76(m,2H),7.66(d,J=8.5Hz,1H),7.41(dd,J=8.4,1.8Hz,1H),7.03–6.97(m,2H),4.08(dd,J=10.6,6.2Hz,1H),4.06–3.96(m,3H),3.83(s,2H),3.68(ddd,J=12.1,6.4,4.0Hz,2H),3.37(p,J=4.1Hz,1H),3.18(ddd,J=25.1,14.7,4.8Hz,1H),3.11–2.97(m,2H),3.00–2.92(m,2H),2.76(ddt,J=14.5,6.4,4.1Hz,2H),2.40(td,J=6.4,5.6Hz,1H),2.09(dddd,J=25.3,13.6,6.4,4.1Hz,2H),2.01–1.78(m,6H),1.65–1.55(m,2H),1.52–1.42(m,2H).LRMS(ESI):497.28[M+H]+
实施例113哌啶-4-基甲基4-(((2-(5-环丙基噻吩-2-基)环丙基)氨基)甲基)-4-氟哌啶-1-羧酸酯(A113)
将反式-2-苯基环丙胺替换成反式-2-(5-环丙基噻吩-2-基)环丙胺,其余所需原料、试剂及制备方法同实施例43,得产物A113(产率67%)。1H NMR(400MHz,DMSO-d6)δ6.75(q,J=8.4Hz,2H),4.25(dd,J=10.5,6.3Hz,1H),4.02(ddd,J=12.1,6.4,4.0Hz,2H),3.83(dd,J=10.6,6.2Hz,1H),3.69(ddd,J=12.1,6.5,4.1Hz,2H),3.22–3.11(m,1H),3.14–3.08(m,1H),3.09–2.92(m,4H),2.85–2.71(m,3H),2.38(td,J=6.4,5.5Hz,1H),2.32(p,J=5.8Hz,1H),2.06(dddd,J=25.3,13.6,6.4,4.1Hz,2H),1.99–1.87(m,2H),1.91–1.80(m,3H),1.63–1.53(m,6H),1.49–1.39(m,2H).LRMS(ESI):436.24[M+H]+
实施例114哌啶-4-基甲基4-(((2-(5-((4-氰基苯基)乙炔基)噻吩-2-基)环丙基)氨基)甲基)-4-氟哌啶-1-羧酸酯(A114)
将反式-2-苯基环丙胺替换成反式-4-((5-(2-氨基环丙基)噻吩-2-基)乙炔基)苯甲腈,其余所需原料、试剂及制备方法同实施例43,得产物A114(产率51%)。1H NMR(400MHz,DMSO-d6)δ7.65–7.59(m,2H),7.59–7.53(m,2H),7.24(d,J=8.4Hz,1H),6.85(d,J=8.4Hz,1H),4.08(dd,J=10.5,6.3Hz,1H),4.07–3.97(m,3H),3.68(ddd,J=12.1,6.5,4.1Hz,2H),3.37(p,J=4.1Hz,1H),3.18(ddd,J=25.1,14.1,5.2Hz,1H),3.11–2.98(m,2H),3.01–2.88(m,3H),2.76(ddt,J=14.5,6.4,4.1Hz,2H),2.39(td,J=6.4,5.6Hz,1H),2.09(dddd,J=25.3,13.6,6.6,4.2Hz,2H),2.01–1.80(m,5H),1.60(dtd,J=13.4,6.4,4.2Hz,2H),1.47(dtd,J=13.4,6.3,4.2Hz,2H).LRMS(ESI):521.23[M+H]+
实施例115哌啶-4-基甲基4-氟-4-(((2-(6-苯基吡啶-3-基)环丙基)氨基)甲基)哌啶-1-羧酸酯(A115)
将反式-2-苯基环丙胺替换成反式-2-(6-苯基吡啶-3-基)环丙胺,其余所需原料、试剂及制备方法同实施例43,得产物A115(产率68%)。1H NMR(400MHz,DMSO-d6)δ8.45(d,J=1.9Hz,1H),8.02–7.94(m,2H),7.69(d,J=8.4Hz,1H),7.45(dd,J=8.4,2.0Hz,1H),7.44–7.34(m,3H),4.15(dd,J=10.4,6.2Hz,1H),4.03(ddd,J=12.0,6.5,4.1Hz,2H),3.93 (dd,J=10.5,6.3Hz,1H),3.69(ddd,J=12.1,6.4,4.2Hz,2H),3.36(p,J=4.1Hz,1H),3.27–3.19(m,1H),3.23–3.10(m,1H),3.05(ddd,J=25.3,14.7,4.9Hz,1H),2.98(dt,J=6.3,4.1Hz,1H),2.98–2.92(m,1H),2.77(ddt,J=14.5,6.4,4.1Hz,2H),2.40(td,J=6.4,5.6Hz,1H),2.09(dddd,J=25.1,13.4,6.4,4.1Hz,2H),2.03–1.92(m,2H),1.95–1.79(m,4H),1.59(dtd,J=12.8,6.3,4.1Hz,2H),1.46(dtd,J=13.2,6.2,4.0Hz,2H).LRMS(ESI):467.27[M+H]+
实施例116哌啶-4-基甲基4-(((2-(6-(4-乙基苯氧基)吡啶-3-基)环丙基)氨基)甲基)-4-氟哌啶-1-羧酸酯(A116)
将反式-2-苯基环丙胺替换成反式-2-(6-(4-乙基苯氧基)吡啶-3-基)环丙胺,其余所需原料、试剂及制备方法同实施例43,得产物A116(产率64%)。1H NMR(400MHz,DMSO-d6)δ7.97(d,J=1.9Hz,1H),7.61–7.55(m,2H),7.36(dd,J=8.4,1.8Hz,1H),7.12(dt,J=8.4,1.1Hz,2H),7.01(d,J=8.4Hz,1H),4.23(dd,J=10.4,6.2Hz,1H),4.03(ddd,J=12.1,6.4,4.2Hz,2H),3.82(dd,J=10.5,6.3Hz,1H),3.69(ddd,J=12.1,6.5,4.1Hz,2H),3.35(p,J=4.1Hz,1H),3.28–3.12(m,2H),3.06(ddd,J=25.3,14.7,4.8Hz,1H),2.96(ddt,J=14.6,6.4,4.1Hz,2H),2.80–2.63(m,3H),2.59–2.48(m,1H),2.40(td,J=6.4,5.6Hz,1H),2.09(dddd,J=25.3,13.6,6.4,4.1Hz,2H),2.03–1.81(m,6H),1.64–1.54(m,2H),1.46(dtd,J=13.4,6.3,4.2Hz,2H),1.24(t,J=7.2Hz,3H).LRMS(ESI):511.30[M+H]+
实施例117哌啶-4-基甲基4-氟-4-(((2-(6-(3-(三氟甲基)苯基)吡啶-3-基)环丙基)氨基)甲
基)哌啶-1-羧酸酯(A117)
将反式-2-苯基环丙胺替换成反式-2-(6-(3-(三氟甲基)苯基)吡啶-3-基)环丙胺,其余所需原料、试剂及制备方法同实施例43,得产物A117(产率71%)。1H NMR(400MHz,DMSO-d6)δ8.46(d,J=1.9Hz,1H),8.34(t,J=2.2Hz,1H),7.86(ddd,J=7.7,2.2,1.2Hz,1H),7.77(ddd,J=7.9,2.2,1.3Hz,1H),7.72–7.63(m,2H),7.47(dd,J=8.4,2.0Hz,1H),4.08(dd,J=10.4,6.2Hz,1H),4.08–3.97(m,3H),3.68(ddd,J=12.1,6.5,4.2Hz,2H),3.37(p,J=4.1Hz,1H),3.18(ddd,J=25.1,14.7,4.8Hz,1H),3.06(dtd,J=7.5,6.4,5.6Hz,1H),3.04–2.91(m,3H),2.76(ddt,J=14.5,6.4,4.1Hz,2H),2.20(td,J=6.5,5.7Hz,1H),2.08(dddd,J=25.3,13.6,6.4,4.1Hz,2H),2.00–1.78(m,6H),1.65–1.55(m,2H),1.47(dtd,J=13.2,6.2,4.0Hz,2H).LRMS(ESI):535.26[M+H]+
实施例118哌啶-4-基甲基4-氟-4-(((2-(6-(4-氟苯基)吡啶-3-基)环丙基)氨基)甲基)哌啶-1-羧酸酯(A118)
将反式-2-苯基环丙胺替换成反式-2-(6-(4-氟苯基)吡啶-3-基)环丙胺,其余所需原料、试剂及制备方法同实施例43,得产物A118(产率75%)。1H NMR(400MHz,DMSO-d6)δ8.41(d,J=1.8Hz,1H),8.18–8.11(m,2H),7.66(d,J=8.5Hz,1H),7.42(dd,J=8.4,1.8Hz,1H),7.20–7.12(m,2H),4.14(dd,J=10.6,6.2Hz,1H),4.03(ddd,J=12.1,6.4,4.0Hz,2H),3.83(dd,J=10.4,6.2Hz,1H),3.69(ddd,J=12.1,6.5,4.1Hz,2H),3.35(p,J=4.1Hz,1H),3.16(ddd,J=25.3,14.7,4.9Hz,1H),3.09–2.96(m,1H),3.00–2.90(m,3H),2.75(ddt,J= 14.5,6.4,4.1Hz,2H),2.40(td,J=6.4,5.6Hz,1H),2.07(dddd,J=25.1,13.5,6.4,4.0Hz,2H),1.97(ddd,J=13.4,6.4,4.0Hz,1H),1.96–1.86(m,3H),1.89–1.81(m,2H),1.64–1.54(m,2H),1.45(dtd,J=13.2,6.3,4.0Hz,2H).LRMS(ESI):485.26[M+H]+
实施例119哌啶-4-基甲基4-(((2-(6-(4-氯苯基)吡啶-3-基)环丙基)氨基)甲基)-4-氟哌啶-1-羧酸酯(A119)
将反式-2-苯基环丙胺替换成反式-2-(6-(4-氯苯基)吡啶-3-基)环丙胺,其余所需原料、试剂及制备方法同实施例43,得产物A119(产率71%)。1H NMR(400MHz,DMSO-d6)δ8.41(d,J=1.9Hz,1H),7.85–7.79(m,2H),7.68(d,J=8.4Hz,1H),7.46–7.35(m,3H),4.14(dd,J=10.4,6.2Hz,1H),4.02(ddd,J=12.1,6.4,4.2Hz,2H),3.82(dd,J=10.4,6.2Hz,1H),3.69(ddd,J=12.1,6.4,4.0Hz,2H),3.35(p,J=4.1Hz,1H),3.15(ddd,J=25.3,14.7,4.9Hz,1H),3.09–2.90(m,4H),2.75(ddt,J=14.5,6.4,4.1Hz,2H),2.40(td,J=6.4,5.6Hz,1H),2.07(dddd,J=25.1,13.5,6.4,4.1Hz,2H),2.01–1.88(m,2H),1.92–1.85(m,2H),1.89–1.81(m,2H),1.58(dtd,J=12.8,6.3,4.0Hz,2H),1.45(dtd,J=13.4,6.3,4.2Hz,2H).LRMS(ESI):501.24[M+H]+
实施例120哌啶-4-基甲基4-(((2-(6-(3,5-二甲氧苯基)吡啶-3-基)环丙基)氨基)甲基)-4-氟哌啶-1-羧酸酯(A120)
将反式-2-苯基环丙胺替换成反式-2-(6-(3,5-二甲氧苯基)吡啶-3-基)环丙胺,其余所需原料、试剂及制备方法同实施例43,得产物A120(产率61%)。1H NMR(400MHz,DMSO-d6)δ8.40(d,J=1.9Hz,1H),7.68(d,J=8.4Hz,1H),7.34(dd,J=8.4,2.0Hz,1H),7.19(d,J=2.0Hz,2H),6.58(t,J=2.2Hz,1H),4.23(dd,J=10.4,6.2Hz,1H),4.04(ddd,J=12.1,6.4,4.0Hz,2H),3.86–3.80(m,1H),3.81(s,5H),3.68(ddd,J=12.1,6.5,4.1Hz,2H),3.35(p,J=4.1Hz,1H),3.18(ddd,J=25.3,14.7,4.9Hz,1H),3.06(dtd,J=7.3,6.2,5.4Hz,1H),3.04–2.95(m,1H),2.99–2.91(m,2H),2.75(ddt,J=14.5,6.4,4.1Hz,2H),2.21(td,J=6.5,5.7Hz,1H),2.09(dddd,J=25.3,13.6,6.4,4.1Hz,2H),2.00–1.78(m,6H),1.59(dtd,J=13.4,6.3,4.0Hz,2H),1.45(dtd,J=13.4,6.3,4.1Hz,2H).LRMS(ESI):527.30[M+H]+
实施例121哌啶-4-基甲基4-(((2-(6-溴吡啶-3-基)环丙基)氨基)甲基)-4-氟哌啶-1-羧酸酯(A121)
将反式-2-苯基环丙胺替换成反式2-(6-溴吡啶-2-基)环丙胺,其余所需原料、试剂及制备方法同实施例43,得产物A121(产率62%)。1H NMR(400MHz,DMSO-d6)δ8.18(d,J=1.8Hz,1H),7.49(d,J=8.4Hz,1H),7.34(dd,J=8.4,1.8Hz,1H),4.25(dd,J=10.4,6.2Hz,1H),4.02(ddd,J=12.1,6.4,4.2Hz,2H),3.82(dd,J=10.6,6.2Hz,1H),3.68(ddd,J=12.1,6.4,4.2Hz,2H),3.35(p,J=4.1Hz,1H),3.15(ddd,J=25.1,14.7,4.9Hz,1H),3.08–2.94(m,2H),2.98–2.89(m,2H),2.76(ddt,J=14.5,6.4,4.1Hz,2H),2.23(td,J=6.4,5.6Hz,1H),2.06(dddd,J=25.1,13.4,6.4,4.1Hz,2H),2.01–1.89(m,2H),1.90(dd,J=6.4,4.1Hz,0H),1.90(s,1H),1.91–1.80(m,3H),1.64–1.54(m,2H),1.45(dtd,J=13.4,6.3,4.1Hz,2H). LRMS(ESI):469.15[M+H]+
实施例122哌啶-4-基甲基4-(((2-(2-氯噻唑-5-基)环丙基)氨基)甲基)-4-氟哌啶-1-羧酸酯(A122)
将反式-2-苯基环丙胺替换成反式-2-(2-氯噻唑-5-基)环丙胺,其余所需原料、试剂及制备方法同实施例43,得产物A122(产率65%)。1H NMR(400MHzDMSO-d6)δ7.35(s1H),4.16(dd,J=10.6,6.2Hz,1H),4.04(ddd,J=12.1,6.4,4.2Hz,2H),3.94(dd,J=10.4,6.2Hz,1H),3.69(ddd,J=12.1,6.4,4.2Hz,2H),3.20–3.07(m,2H),3.10–2.87(m,5H),2.82–2.72(m,3H),2.16–1.88(m,6H),1.84(hept,J=6.2Hz,1H),1.64–1.54(m,2H),1.50–1.40(m,2H).LRMS(ESI):431.16[M+H]+
实施例123哌啶-4-基甲基4-氟-4-(((2-(2-(4-氟苯基)噻唑-5-基)环丙基)氨基)甲基)哌啶-1-羧酸酯(A123)
将反式-2-苯基环丙胺替换成反式-2-(2-(4-氟苯基)噻唑-5-基)环丙胺,其余所需原料、试剂及制备方法同实施例43,得产物A123(产率70%)。1H NMR(400MHz,DMSO-d6)δ7.70–7.62(m,2H),7.58(s,1H),7.26–7.18(m,2H),4.13(dd,J=10.5,6.3Hz,1H),4.03(ddd,J=12.1,6.4,4.0Hz,2H),3.82(dd,J=10.5,6.3Hz,1H),3.69(ddd,J=12.1,6.5,4.1Hz,2H),3.35(p,J=4.1Hz,1H),3.16(ddd,J=25.1,14.6,4.9Hz,1H),3.09–2.97(m,1H),3.00–2.90(m,4H),2.93–2.85(m,1H),2.75(ddt,J=14.5,6.4,4.1Hz,2H),2.09(ddd,J=13.4,6.4,4.0Hz,1H),2.08–1.97(m,3H),2.00–1.81(m,3H),1.64–1.54(m,2H),1.45(dtd,J=13.4,6.3,4.2Hz,2H).LRMS(ESI):491.22[M+H]+
实施例124哌啶-4-基甲基4-(((2-(2-(4-氯苯基)噻唑-5-基)环丙基)氨基)甲基)-4-氟哌啶-1-羧酸酯(A124)
将反式-2-苯基环丙胺替换成反式-2-(2-(4-氯苯基)噻唑-5-基)环丙胺,其余所需原料、试剂及制备方法同实施例43,得产物A124(产率71%)。1H NMR(400MHz,DMSO-d6)δ8.05–7.99(m,2H),7.60–7.50(m,3H),4.13(dd,J=10.4,6.2Hz,1H),4.02(ddd,J=12.1,6.4,4.2Hz,2H),3.82(dd,J=10.6,6.2Hz,1H),3.69(ddd,J=12.1,6.5,4.1Hz,2H),3.35(p,J=4.1Hz,1H),3.16(ddd,J=25.1,14.5,5.1Hz,1H),3.09–2.97(m,1H),3.01–2.94(m,2H),2.97–2.90(m,2H),2.93–2.85(m,1H),2.75(ddt,J=14.5,6.4,4.1Hz,2H),2.09(ddd,J=13.4,6.4,4.0Hz,1H),2.08–1.99(m,3H),2.02–1.81(m,3H),1.64–1.54(m,2H),1.45(dtd,J=13.4,6.3,4.2Hz,2H).LRMS(ESI):507.19[M+H]+
实施例125哌啶-4-基甲基4-氟-4-(((2-(2-苯基噻唑-5-基)环丙基)氨基)甲基)哌啶-1-羧酸酯(A125)
将反式-2-苯基环丙胺替换成反式-2-(2-苯基噻唑-5-基)环丙胺,其余所需原料、试剂及制备方法同实施例43,得产物A125(产率69%)。1H NMR(400MHz,DMSO-d6)δ7.96–7.90(m,2H),7.58(s,1H),7.53–7.41(m,3H),4.14(dd,J=10.4,6.2Hz,1H),4.03(ddd,J=12.1,6.5,4.1Hz,2H),3.83(dd,J=10.4,6.2Hz,1H),3.70(ddd,J=11.9,6.4,4.0Hz,2H),3.35(p,J=4.1Hz,1H),3.16(ddd,J=25.1,14.4,5.0Hz,1H),3.09–2.97(m,1H),3.01–2.94(m,2H),2.97–2.90(m,2H),2.93–2.85(m,1H),2.76(ddt,J=14.5,6.4,4.1Hz,2H),2.09(ddd,J=13.5,6.5,4.1Hz,1H),2.08–1.99(m,3H),2.01–1.81(m,3H),1.64–1.54(m,2H),1.45(dtd,J=13.2,6.3,4.0Hz,2H).LRMS(ESI):473.23[M+H]+
实施例126哌啶-4-基甲基4-氟-4-(((2-(2-(4-甲氧苯基)噻唑-5-基)环丙基)氨基)甲基)哌啶-1-羧酸酯(A126)
将反式-2-苯基环丙胺替换成反式-2-(2-(4-甲氧基苯基)噻唑-5-基)环丙胺,其余所需原料、试剂及制备方法同实施例43,得产物A126(产率67%)。1H NMR(400MHz,DMSO-d6)δ8.11–8.05(m,2H),7.57(s,1H),7.25–7.19(m,2H),4.15(dd,J=10.5,6.3Hz,1H),4.02(ddd,J=12.1,6.5,4.1Hz,2H),3.86–3.80(m,1H),3.81(s,3H),3.69(ddd,J=12.1,6.4,4.0Hz,2H),3.36(p,J=4.1Hz,1H),3.16(ddd,J=25.1,14.6,4.9Hz,1H),3.09–2.85(m,6H),2.75(ddt,J=14.5,6.4,4.1Hz,2H),2.09(ddd,J=13.6,6.5,4.2Hz,1H),2.08–2.00(m,2H),2.03–1.92(m,2H),1.96–1.80(m,2H),1.63–1.53(m,2H),1.50–1.40(m,2H).LRMS(ESI):503.24[M+H]+
实施例127哌啶-4-基甲基4-(((2-(2-(3,5-二甲氧苯基)噻唑-5-基)环丙基)氨基)甲基)-4-氟哌啶-1-羧酸酯(A127)
将反式-2-苯基环丙胺替换成反式-2-(2-(3,5-二甲氧苯基)噻唑-5-基)环丙胺,其余所需原料、试剂及制备方法同实施例43,得产物A127(产率59%)。1H NMR(400MHz,DMSO-d6)δ7.56(s,1H),7.10(d,J=2.2Hz,2H),6.59(t,J=2.2Hz,1H),4.13(dd,J=10.4,6.2Hz,1H),4.03(ddd,J=12.1,6.4,4.2Hz,2H),3.86–3.80(m,1H),3.81(s,4H),3.69(ddd,J=12.1,6.5,4.1Hz,2H),3.35(p,J=4.1Hz,1H),3.16(ddd,J=25.1,14.2,5.2Hz,1H),3.09–2.85(m,6H),2.75(ddt,J=14.5,6.4,4.1Hz,2H),2.09(ddd,J=13.6,6.4,4.0Hz,1H),2.08–1.96(m,3H),1.95(ddd,J=13.6,6.5,4.2Hz,1H),1.95–1.81(m,2H),1.64–1.54(m,2H),1.50–1.40(m,2H).LRMS(ESI):533.25[M+H]+
实施例128哌啶-4-基甲基4-氟-4-((((1R,2S)-2-苯基环丙基)氨基)甲基)哌啶-1-羧酸酯((1R,2S)-A43)
将反式-2-苯基环丙胺替换成(1R,2S)-2-苯基环丙胺,其余所需原料、试剂及制备方法同实施例43,得产物(1R,2S)-A43(产率49%)。1H NMR(400MHz,D2O)δ7.32(t,J=7.4Hz,2H),7.24(t,J=7.3Hz,1H),7.16(d,J=7.3Hz,2H),3.95(d,J=6.0Hz,4H),3.47(d,J=20.5Hz,2H),3.38(d,J=13.0Hz,2H),3.12(t,J=12.0Hz,2H),3.01–2.87(m,3H),2.53(ddd,J=10.3,6.6,3.5Hz,1H),2.04–1.85(m,5H),1.79–1.70(m,1H),1.65(td,J=13.7,5.1Hz,1H),1.55–1.33(m,4H);LRMS(ESI):390.25[M+H]+
实施例129哌啶-4-基甲基4-氟-4-((((1S,2R)-2-苯基环丙基)氨基)甲基)哌啶-1-羧酸酯((1S,2R)-A43)
将反式-2-苯基环丙胺替换成(1S,2R)-2-苯基环丙胺,其余所需原料、试剂及制备方法同实施例43,得产物(1S,2R)-A43(产率52%)。1H NMR(400MHz,D2O)δ7.31(t,J=7.4Hz,2H),7.24(t,J=7.3Hz,1H),7.15(d,J=7.2Hz,2H),3.94(d,J=5.9Hz,4H),3.47(d,J=20.5Hz,2H),3.38(d,J=12.8Hz,2H),3.12(t,J=12.4Hz,2H),2.95(ddd,J=19.8,10.5,7.1Hz,3H),2.52(ddd,J=10.3,6.7,3.6Hz,1H),2.04–1.86(m,5H),1.74(td,J=13.3,5.0Hz,1H),1.64(td,J=13.7,5.2Hz,1H),1.55–1.33(m,4H);LRMS(ESI):390.25[M+H]+
实施例130(1-苄基哌啶-4-基)甲基4-氟-4-((((1R,2S)-2-苯基环丙基)氨基)甲基)哌啶-1-羧酸酯((1R,2S)-A90)
将反式-2-苯基环丙胺替换成(1R,2S)-2-苯基环丙胺,其余所需原料、试剂及制备方法同实施例90,得产物(1R,2S)-A90(产率44%)。1H NMR(500MHz,MeOD)δ7.58(dd,J=6.6,2.8Hz,2H),7.51–7.45(m,3H),7.31(t,J=7.4Hz,2H),7.25–7.21(m,1H),7.21–7.18(m,2H),4.31(s,2H),4.05(d,J=13.7Hz,4H),3.58–3.46(m,4H),3.24–3.13(m,2H),3.09–2.99(m,3H),2.62(ddd,J=10.3,6.6,3.6Hz,1H),2.08–1.77(m,7H),1.69(td,J=15.0,3.5Hz,2H),1.64–1.58(m,1H),1.39(dd,J=14.5,6.8Hz,1H);LRMS(ESI):478.29[M+H]+
实施例131 4-((4-氟-4-((((1R,2S)-2-苯基环丙基)氨基)甲基)哌啶-1-基)甲基)苯甲酸((1R,2S)-A5)
将反式-2-苯基环丙胺替换成(1R,2S)-2-苯基环丙胺,其余所需原料、试剂及制备方法同实施例5,得产物(1R,2S)-A5(产率22%)。1H NMR(400MHz,DMSO-d6)δ8.02–7.93(m,2H),7.50(dt,J=7.4,1.2Hz,2H),7.26–7.10(m,5H),3.54(d,J=1.5Hz,2H),3.11(dt,J=12.6,7.2Hz,2H),2.76–2.62(m,2H),2.62–2.49(m,3H),2.05–1.82(m,3H),1.45(ddt,J=25.1,13.2,7.1Hz,2H),0.95(td,J=7.0,4.9Hz,1H),0.71(td,J=7.0,5.0Hz,1H);LRMS(ESI):383.21[M+H]+
实施例132 4-((4-氟-4-((((1S,2R)-2-苯基环丙基)氨基)甲基)哌啶-1-基)甲基)苯甲酸((1S,2R)-A5)
将反式-2-苯基环丙胺替换成(1S,2R)-2-苯基环丙胺,其余所需原料、试剂及制备方法同实施例90,得产物(1S,2R)-A5(产率24%)。1H NMR(400MHz,DMSO-d6)δ8.00–7.93 (m,2H),7.44(dt,J=7.4,1.2Hz,2H),7.26–7.11(m,5H),3.54(d,J=1.5Hz,2H),3.11(dt,J=12.6,7.2Hz,2H),2.76–2.64(m,2H),2.62–2.49(m,3H),2.05–1.85(m,3H),1.45(ddt,J=25.1,13.2,7.2Hz,2H),0.95(td,J=7.0,4.9Hz,1H),0.71(td,J=7.0,5.0Hz,1H);LRMS(ESI):383.21[M+H]+
药理活性试验实施例
实施例1、分子水平活性测试:
1.LSD1体外活性实验
筛选方法:赖氨酸特异性脱甲基酶1(LSD1)活性筛选
仪器:酶标仪EnvisionTM(PerkinElmer,USA)。
材料:人源重组LSD1,本实验室利用大肠杆菌表达系统表达并纯化获得的融合GST的LSD1蛋白片断(aa158-end);
LSD1活性检测试剂盒LANCE Ultra LSD1Histone H3-Lysine 4Demethylase Assay,购自Perkin Elmer公司;
H3多肽底物ARTK(me1)QTARKSTGGKAPRKQLA-GG-K(Biotin)-NH2由吉尔生化公司合成。
原理:LSD1能够特异性去除H3多肽底物上K4位赖氨酸上的甲基化修饰,使其变成无甲基化修饰的底物。本方法采用组蛋白H3甲基化多肽(1-24)作为底物,在底物的C段引入生物素标记。当LSD1在FAD的参与下,启动反应,能够去除底物H3K4上的甲基化修饰。在Eu标记的H3K4本底抗体就能够与底物通过抗原抗体反应而结合在一起,同时链霉亲和素标记的受体通过链霉亲和素与生物素的特异性相互作用而结合在一起。从而使得Eu标记的供体能够与链霉亲和素标记的受体相互作用。在荧光共振能量转移中,当由于生物分子相互作用导致两个荧光基团接近时,在激发时被穴状化合物捕获的部分能量将被释放,发射波长为620nm;另一部分能量转移到受体(acceptor)上,发射波长665nm。665nm的发射光仅由供体(donor)引起的FRET产生。所以,当生物分子相互作用时,有两个激发光620nm和665nm;当不存在相互作用时,只有620nm一个激发光。通过检测665nm和620nm两个发射波长的荧光信号比值能反应LSD1去甲基化活性。同时设置空白对照来判定酶活性的强弱。实验采用ORY-1001、GSK-2879552作为阳性抑制剂。
样品处理:样品用DMSO溶解,低温保存,DMSO在最终体系中的浓度控制在不影响检测活性的范围之内。
初筛选择单浓度条件下,例如20μM,对样品的活性进行测试。对于在一定条件下表现出活性的样品,例如抑制率%Inhibition大于50,测试活性剂量依赖关系,即IC50值,通过样品活性对样品浓度进行非线性拟和得到,计算所用软件为Graphpad Prism5,拟合所使用的模型为sigmoidal dose-response(varible slope),对于大多数抑制剂筛选模型,将拟合曲线底部和顶部设定为0和100。
实验结果:
2.MAOA和MAOB体外活性实验
筛选方法:单胺氧化酶MAOA和MAOB活性筛选
仪器:酶标仪EnvisionTM(PerkinElmer,USA)。
材料:人源重组MAOA,购自Promega公司;人源重组MAOB,购自Sigma公司;
MAOA和MAOB活性检测试剂盒MAO-Glo购自Promega公司。
原理:本方法采用特异性的一种特性萤光素衍生物作为底物,MAOA或MAOB能够催化底物变为萤光素甲酯,其产物萤光素甲酯在萤光素酶的作用下能够差生萤光,从而能够通过萤光信号的强弱来反应MAOA或MAOB的活性。同时设置空白对照来判定酶活性的强弱。实验采用Tranylcypromine(TCP)作为阳性抑制剂。
样品处理:样品用DMSO溶解,低温保存,DMSO在最终体系中的浓度控制在不影响检测活性的范围之内。
初筛选择单浓度条件下,例如100μM,对样品的活性进行测试。对于在一定条件下表现出活性的样品,例如抑制率%Inhibition大于50,测试活性剂量依赖关系,即IC50值,通过样品活性对样品浓度进行非线性拟和得到,计算所用软件为Graphpad Prism 5,拟合所使用的模型为sigmoidal dose-response(varible slope),对于大多数抑制剂筛选模型,将拟合曲线底部和顶部设定为0和100。
实验结果:
实施例2、细胞水平活性测试:
1.CD86基因表达激活测试:
实验原理:实时荧光定量PCR(Quantitative Real-time PCR)是一种在DNA扩增反应中,以荧光化学物质测每次聚合酶链式反应(PCR)循环后产物总量的方法。通过内参或者外参法对待测样品中的特定DNA序列进行定量分析的方法。由于在PCR扩增的指数时期,模板的Ct值和该模板的起始拷贝数存在线性关系,所以成为定量的依据。
材料:白血病细胞株MV4-11:小儿急性淋巴髓细胞白血病,免疫双表型,AF4-MLL融合性t(4,11),是LSD1抑制剂激活CD86表达的敏感细胞株(Analytical Biochemistry 442(2013)104–106)。
实验方法:
1.精确计数MV4-11细胞350w/mL,12孔板中,每孔900μL。
2.将待测化合物或阳性化合物3μL加入147μL培养基中,混匀,取100μL加入铺有细胞的12孔板,混匀,恒温箱中37℃,5%CO2孵育24h。
3.收样至1.5mL EP管,2000rpm,离心3min,去上清,加入500mL trizol裂解,静置3min。
4.加入100μL三氯甲烷,剧烈摇晃EP管15s,静置3min,12000rpm,15min。
5.吸取上清至一个新的EP管中,加入200μL异丙醇,置于-20℃冰箱15min,12000rpm,10min。
6.去上清,加入500μL 4°75%乙醇,混匀,7500rpm,10min。
7.去上清,将EP管置于通风橱中风干,加入20-30μL灭过RNA酶的去离子水,混匀,检测RNA浓度。
8.将所有样品统一调成750ng/8μL,加入RT-kit酶与底物,42°反转录15min,85°灭活酶2min。
9.向EP管中加入100μL去离子水,混匀。
10.按照7.6μL样品+0.65μL正向引物+0.65μL反向引物+11.1μLSYBR的比例配置QPCR样品至八连管中,1500rpm,离心1min,开始QPCR。
11.整理数据,采用什么2^(-ΔΔct)方法进行激活倍数的计算(BLOOD,8AUGUST 2013VOLUME 122,NUMBER 6)。
实验结果:
2.MTS方法测试化合物对细胞生长抑制活性
实验原理:MTS法检测受试化合物对白血病细胞MV(4:11)的生长抑制作用,其原理是活细胞内的线粒体中琥珀酸脱氢酶能使外源性的噻唑蓝还原为难溶的蓝色结晶Formazan。
材料:白血病细胞株MV4-11:小儿急性淋巴髓细胞白血病,免疫双表型,AF4-MLL融合性t(4,11),是LSD1抑制剂细胞生长抑制敏感细胞株(Cancer cell.2012,17;21(4):473-487)。
实验方法:
1.取处于对数生长期的MV4-11细胞,精确计数16000cells/mL,将稀释好的细胞液加入96孔板,每孔90μL。
2.取新鲜的培养基,依次加入铺有细胞液的96孔板,每孔90μL。
3.在化合物板中,取浓度为10mM的待测化合物与阳性化合物ORY-1001和GSK2879552,用DMSO依次做3倍浓度梯度稀释,各8个点。
4.分别取稀释好的化合物2μL,分别加入盛有98μL的空白培养基96孔板中,DMSO组以2μLDMSO加入98μL的空白培养基,混匀待用。
5.将用培养基混匀的化合物分别加入铺有细胞的96孔板中,三副孔,每孔20μL,混匀。空白组加入IMDM培养基200μL,DMSO组以用培养基稀释好的DMSO加入180μL含细胞培养基。
6.恒温箱中37℃,5%CO2孵育10天;
7.10天后,加入MTS,孵育2.5h后读值。
实验结果:
实施例3、动物水平慢性药效评价:
LSD1抑制剂对人急性髓系白血病MV4-11裸小鼠皮下移植瘤的生长抑制作用
配制方法:准确称取药物,加入生理盐水,配成0.3mg/ml,给药容积10ml/kg
动物:Balb/c裸小鼠,雌性,体重17-20g,购自北京维通利华实验动物技术有限公司,每组动物数:5只。细胞株:用MV4-11细胞株接种裸小鼠右侧腋窝皮下,细胞接种量为5×106/只,形成移植瘤后即可开始实验。
实验方法:
雌性裸小鼠,体重20±3g,接种MV4-11细胞株接种裸小鼠右侧腋窝皮下,细胞接种量为5×106/只,待成瘤后,用游标卡尺测量移植瘤直径,肿瘤长至100-300mm3,将动物按体重和肿瘤体积分为模型对照组和给药组,每组5只,模型对照组则给等量空白溶剂。分组后每天口服灌胃给药,持续21天。
瘤重抑制率%=(Wc-WT)/Wc×100%
注:Wc:对照组瘤重,WT:治疗组瘤重。
数据处理:数据以均值±标准差表示,统计方法采用T-TEST双尾分析进行显著性分析。
实验结果:
实施例4:小鼠药代动力学实验
实验方法:
GSK2879552取血浆样品15μL于离心管中,加入60μL甲醇:乙腈(1:1,v/v),涡流1min,离心(11000rpm)5min,取上清液20μL加水80μL,涡流混匀后进样分析。GSK2879552的线性范围为0.3~12500ng/mL。
A1取血浆样品15μL于离心管中,加入60μL甲醇:乙腈(1:1,v/v),涡流1min,离心(11000rpm)5min,取上清液20μL加水80μL,涡流混匀后进样分析。A1的线性范围为3.0~25000ng/mL。
A2取血浆样品15μL于离心管中,加入60μL甲醇:乙腈(1:1,v/v),涡流1min,离心(11000rpm)5min,取上清液20μL加水40μL,涡流混匀后进样分析。A2的线性范围为0.3~5000ng/mL。
A4取血浆样品15μL于离心管中,加入60μL甲醇:乙腈(1:1,v/v),涡流1min,离心(11000rpm)5min,取上清液20μL加水40μL,涡流混匀后进样分析。A4的线性范围为1.0~5000ng/mL。
A43、A90、(1R,2S)-A43和(1R,2S)-A90的实验方法同A1。
实验结果:
GSK2879552、A1、A2、A4、A43、A90、(1R,2S)-A43和(1R,2S)-A90的药代动力学参数总表
在本发明提及的所有文献都在本申请中引用作为参考,就如同每一篇文献被单独引用作为参考那样。此外应理解,在阅读了本发明的上述讲授内容之后,本领域技术人员可以对本发明作各种改动或修改,这些等价形式同样落于本申请所附权利要求书所限定的范围。

Claims (15)

  1. 一种具有如下通式I所示结构的氟取代的环丙胺类化合物,或者其外消旋体、R-异构体、S-异构体、药学上可接受的盐或它们的混合物:
    其中:
    A选自:取代或未取代的芳环(优选地为苯环)或者取代或未取代的含有1~4个选自氧、硫和氮中的杂原子的5-12元的芳香杂环,其中所述的取代的苯环或取代的芳香杂环,每个环上包括1~3个取代基;
    其中,所述取代的芳环或取代的芳香杂环上的取代基独立地选自下组:氢、氢的同位素、卤素、未取代或取代的C1-C12直链或支链的烷基、未取代或取代的C1-C12直链或支链的烷氧基、未取代或取代的C2-C12直链或支链的不饱和烃基、未取代或取代的C3-C6环烷基、由C1-C6烷氧基取代的C1-C6直链或支链的烷基、由C3-C6环烷基取代的C1-C6直链或支链的烷基、羟基、氰基、硝基、C1-C6直链或支链的羟烷基或巯基、氧(=O)、未取代的或取代的C6-C12芳基(如苯基、萘基)、未取代的或取代的C6-C12芳基氧基(如苯基、萘基)、取代的或取代的苯基氧基、羧基、酰基(如乙酰基)、和磺酰基(包括苯磺酰基、烷基磺酰基),优选地所述取代基选自下组:卤素、C1-C4直链或支链的烷基、卤素取代的C1-C4直链或支链的烷基、C1-C4烷基氧基、氰基取代的苯基;
    或者,所述取代的芳环或取代的芳香杂环上任意两个取代基可以与其相邻的碳原子或杂原子一起连接成含有1至3个选自N、O和S中的杂原子的5-7元杂环,所述5-7元杂环任选地被选自下组的的取代基所取代:氢、氢的同位素、卤素、未取代或由1-3个卤素取代的C1-C6直链或支链的烷基、未取代或由1-3个卤素取代的C1-C6直链或支链的烷氧基、和羟基;
    各R1独立地选自:取代的或未取代的芳基、取代的或未取代的杂芳基、氢、取代的或未取代的C1-C6烷基、-SO2Ra、-NC(O)Ra、-(CH2)mC(O)ORa、-C(O)O(CH2)m Ra、-C(O)ORa、-C(O)Ra、-(CH2)mORa、-C(O)NRaRb、-C(S)NRaRb、-CORa、-NRcRd、取代的或未取代的氨基、取代的或未取代的脲、取代的或未取代的酰胺、取代的或未取代的磺酰胺、取代的或未取代的芳基烷基和取代的或未取代的杂芳基烷基,其中m为1-3的整数,优选地所述取代基选自下组:卤素、羟基、羧基、氰基、氨基、C1-C4烷基、卤素取代的C1-C4烷基、C1-C4烷基酯基、C1-C4烷基磺酰基、氨基苯基酰胺基芳基烷基、和芳基;
    各Ra独立地为氢、取代的或未取代的苯基、取代的或未取代的苯基甲基、3,5-二甲基异噁唑-4-基、1,2-二甲基-1H-咪唑-4-基、取代的或未取代的C3-C7环烷基、取代的或未取代的C3-C7杂环基、取代的或未取代的C3-C7杂环基烷基、取代的或未取代的C1-C6烷基、取代的或未取代的C1-C6烯基、取代的或未取代的C1-C4烷氧基、取代的或未取代的C1-C3烷基氨基、-NHPh、或取代的或未取代的5-10元杂芳基、取代的或未取代的芳基烷基和取代的或未取代的杂芳基烷基,优选地所述取代基选自下组: C1-C4烷基、卤素取代的C1-C4烷基、苯基取代的C1-C4烷基、C1-C4烷基酯基、C3-C7环基、C3-C7环基烷基、C3-C7杂环基、苄基取代的C3-C7杂环烷基、芳基、卤素、C1-C4烷氧基、C1-C4卤代烷基、羧基、和羧基取代的苄基;
    Rb为氢或C1-C3烷基,或当连接至相同原子时,
    Ra和Rb一起形成5-或6-元杂环烷基环;
    Rc、Rd各自独立地选自氢、取代的或未取代的C1-C3直链或支链烷基、取代的或未取代的C3-C5环烷基、取代的或未取代的C1-C3烷氧基、取代的或未取代的4-6元杂环基、取代的或未取代的C1-C3烷基酰基、取代的或未取代的芳基酰基、取代的或未取代的芳基磺酰基、取代的或未取代的苄基、取代的或未取代的芳基;所述C1-C3直链或支链烷基非必须地被一个或多个选自甲磺基、C1~C3烷氧基、C1~C3烷氧基羰基、芳基中的基团所取代;所述杂环基含有1个选自氧、硫和氮中的杂原子;
    R2为氢或COOH;
    R3为C1-C4烷基、酰基、-C(O)CF3或氢;
    W为-(CH2)1-4或-CH(Re)(CH2)0-3,其中Re为CN或C1-C4烷基;
    Y为N、C或无;
    X为N或C;
    Z为O或(CH2)q,其中q为0-2,当q为0时,Z表示键;
    n为0-3;
    条件是当Z为O时,Y为N且X为C。
  2. 根据权利要求1所述的氟取代的环胺化合物或者其外消旋体、R-异构体、S-异构体、可药用盐或它们的混合物,其中,A为取代或未取代的苯环或者取代或未取代的含有1~4个选自氧、硫和氮中的杂原子的5-12元的芳香杂环,其中所述的取代的苯环或取代的芳香杂环,每个环上包括1~3个取代基;
    其中,所述取代的芳环或取代的芳香杂环上的取代基独立地选自下组:氢、氢的同位素、卤素、羧基、硝基、C1-C4烷基、C1-C4烷酰基、C1-C4烷氧基、氰基、氧(=O)、磺酰基。
  3. 根据权利要求1所述的氟取代的环胺化合物或者其外消旋体、R-异构体、S-异构体、可药用盐或它们的混合物,其中,各R1独立地选自:取代的或未取代的芳基、取代的或未取代的杂芳基、氢、取代的或未取代的C1-C4烷基、-SO2Ra、-NC(O)Ra、-(CH2)mC(O)ORa、-C(O)ORa、-C(O)Ra、-(CH2)mORa、-C(O)NRaRb、-NRcRd、取代的或未取代的芳烷基和取代的或未取代的杂芳烷基,其中m为1-3的整数;
    各Ra独立地为氢、取代的或未取代的苯基、取代的或未取代的苯基甲基、取代的或未取代的C3-C7环烷基、取代的或未取代的C1-C4烷基、取代的或未取代的C1-C4烯基、取代的或未取代的C1-C4烷氧基、取代的或未取代的C1-C3烷基氨基、-NHPh、或取代的或未取代的5-10元杂芳基;
    Rb为氢或C1-C3烷基;
    Rc、Rd各自独立地选自氢、C1-C3直链或支链烷基、取代的或未取代的C3-C5环烷基、取代的或未取代的C1-C3烷氧基、取代的或未取代的4-6元杂环基、取代的或未取代的C1-C3烷基酰基、取代的或未取代的芳基酰基、取代的或未取代的芳基磺酰基、取代的或未取代的苄基、取代的或未取代的芳基;所述杂环基含有1个选自氧、硫和氮中的杂原子;
    所述取代基选自下组:C1-C8烷基、C2-C8烯基、C2-C8炔基、C3-C8环烷基、3-至12-元杂环基、芳基、杂芳基、卤素、羟基、羧基(-COOH)、C1-C8醛基、C2-C10酰基、C2-C10酯基、氨基、和烷氧基。
  4. 根据权利要求1所述的氟取代的环胺化合物或者其外消旋体、R-异构体、S-异构体、可药用盐或它们的混合物,其中,X为N,且连接至X的R1选自:取代的或 未取代的:芳基、杂芳基、芳烷基、和杂芳烷基,其中所述取代基选自下组:C1-C8烷基、C2-C8烯基、C2-C8炔基、C3-C8环烷基、3-至12-元杂环基、芳基、杂芳基、卤素、羟基、羧基(-COOH)、C1-C8醛基、C2-C10酰基、C2-C10酯基、氨基、和烷氧基。
  5. 根据权利要求1所述的氟取代的环胺化合物或者其外消旋体、R-异构体、S-异构体、可药用盐或它们的混合物,其中,X为N,且连接至的R1选自取代的或未取代的:芳基C1~C4烷基、和杂芳基C1~C4烷基,其中所述取代基选自下组:C1-C8烷基、C2-C8烯基、C2-C8炔基、C3-C8环烷基、3-至12-元杂环基、芳基、杂芳基、卤素、羟基、羧基(-COOH)、C1-C8醛基、C2-C10酰基、C2-C10酯基、氨基、和烷氧基。
  6. 根据权利要求1所述的氟取代的环胺化合物或者其外消旋体、R-异构体、S-异构体、可药用盐或它们的混合物,其中,W为-(CH2)1-2
  7. 根据权利要求1所述的氟取代的环胺化合物或者其外消旋体、R-异构体、S-异构体、可药用盐或它们的混合物,其中,所述化合物的结构如通式(1R,2S)-Ia或通式(1S,2R)-Ib所示:
  8. 根据权利要求1所述的氟取代的环胺化合物或者其外消旋体、R-异构体、S-异构体、可药用盐或它们的混合物,其中,所述氟取代的环胺化合物选自如下化合物:
  9. 根据权利要求1所述的氟取代的环胺类化合物或者其外消旋体、R-异构体、S-异构体、药学上可接受的盐或它们的混合物,其中,
    所述可药用盐为所述氟取代的环胺类化合物与无机酸或有机酸反应制得,所述无机酸为盐酸、氢溴酸、硫酸、硝酸、胺基磺酸或磷酸,所述有机酸为柠檬酸、酒石酸、乳酸、丙酮酸、乙酸、苯磺酸、对甲苯磺酸、甲磺酸、萘磺酸、乙磺酸、萘二磺酸、马来酸、苹果酸、丙二酸、富马酸、琥珀酸、丙酸、草酸、三氟乙酸、硬酯酸、扑酸、羟基马来酸、苯乙酸、苯甲酸、水杨酸、谷氨酸、抗坏血酸、对胺基苯磺酸、2-乙酰氧基苯甲酸或羟乙磺酸;或者通式I化合物与无机碱形成的钠盐、钾盐、钙盐、铝盐或铵盐;或者通式I化合物与有机碱形成的甲胺盐、乙胺盐或乙醇胺盐。
  10. 一种如权利要求1所述的氟取代的环胺化合物的制备方法,其中所述制备方法选自如下方案1、或方案2:
    方案1
    式(II)和(III)化合物还原胺化条件下反应,得到式(I)化合物
    方案2
    式(IV)化合物和式(V)化合物反应得到式(VI)化合物,然后可将胺基保护再脱去X和/或Y基团的保护基得到式(VII)化合物,使用R1取代基对式(VII)化合物进行官能团化得到式(VIII)化合物,脱去胺基脱保护基并用R3基团对式(VIII)化合物官能团化从而获得式(I)化合物;
    其中,A、W、X、Y、Z、R1、R2、R3分别如上所述,R4选自下组:H、或甲基,V为-CH2-W-或-W-CH2-。
  11. 如权利要求10所述的方法,其特征在于,所述式(II)化合物的制备方法包括步骤:
    将肉桂酸式(IX)化合物,在缩合剂和碱的存在下,与二甲羟胺缩合得到酰胺式(X)化合物;然后进行环丙基化,反应得到式(XI)化合物;然后式(XI)化合物水解得到式(XII)化合物;然后将其在Curtius重排条件下反应,得到式(IV)化合物,将用R3基团对式(IV)化合物官能团化从而获得式(II)化合物;
    方案3
  12. 一种药物组合物,其含有治疗有效量的选自权利要求1所述的氟取代的环胺化合物、其可药用的盐、外消旋体、R-异构体和S-异构体中的一种或多种,以及任选地,一种或多种可药用的载体、赋形剂、佐剂、辅料和/或稀释剂。
  13. 一种赖氨酸特异性脱甲基酶1(LSD1)抑制剂,其含有治疗有效量的选自权利要求1所述的氟取代的环丙胺化合物、其可药用的盐、外消旋体、R-异构体和S-异构体中的一种或多种。
  14. 如权利要求1所述的氟取代的环胺化合物、其外消旋体、R-异构体、S-异构体或可药用盐在制备治疗或预防与赖氨酸特异性脱甲基酶1(LSD1)相关的恶性肿瘤疾病的药物中的用途;优选地,所述疾病为与赖氨酸特异性脱甲基酶1(LSD1)相关的癌症,其中所述癌症选自:脑癌(胶质瘤)、成胶质细胞瘤、白血病、班-佐综合征、考登病、小脑发育不良性神经节细胞瘤、乳腺癌、炎性乳腺癌、维尔姆斯瘤、尤因肉瘤、横纹肌肉瘤、室管膜瘤、髓母细胞瘤、结肠癌、头颈癌、肾癌、肺癌、肝癌、 黑素瘤、肾癌、卵巢癌、胰腺癌、前列腺癌、肉瘤、骨肉瘤、骨和甲状腺的巨细胞瘤。
  15. 一种治疗肿瘤的方法,其特征在于,所述方法包括步骤:给需要的对象施用治疗有效量的权利要求1所述的氟取代的环胺化合物、其外消旋体、R-异构体、S-异构体或可药用盐。
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