CN108026098B - 作为ido和tdo抑制剂的杂环化合物 - Google Patents
作为ido和tdo抑制剂的杂环化合物 Download PDFInfo
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- CN108026098B CN108026098B CN201680033890.3A CN201680033890A CN108026098B CN 108026098 B CN108026098 B CN 108026098B CN 201680033890 A CN201680033890 A CN 201680033890A CN 108026098 B CN108026098 B CN 108026098B
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- 125000003386 piperidinyl group Chemical group 0.000 description 1
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- 229910052700 potassium Inorganic materials 0.000 description 1
- LJCNRYVRMXRIQR-OLXYHTOASA-L potassium sodium L-tartrate Chemical compound [Na+].[K+].[O-]C(=O)[C@H](O)[C@@H](O)C([O-])=O LJCNRYVRMXRIQR-OLXYHTOASA-L 0.000 description 1
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 1
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- 102000004169 proteins and genes Human genes 0.000 description 1
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- DVWOYOSIEJRHKW-UIRZNSHLSA-M sodium (2S)-2-[[(2S)-2-[[(4,4-difluorocyclohexyl)-phenylmethoxy]carbonylamino]-4-methylpentanoyl]amino]-1-hydroxy-3-[(3S)-2-oxopyrrolidin-3-yl]propane-1-sulfonate Chemical compound FC1(CCC(CC1)C(OC(=O)N[C@H](C(=O)N[C@H](C(S(=O)(=O)[O-])O)C[C@H]1C(NCC1)=O)CC(C)C)C1=CC=CC=C1)F.[Na+] DVWOYOSIEJRHKW-UIRZNSHLSA-M 0.000 description 1
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- UAEJRRZPRZCUBE-UHFFFAOYSA-N trimethoxyalumane Chemical compound [Al+3].[O-]C.[O-]C.[O-]C UAEJRRZPRZCUBE-UHFFFAOYSA-N 0.000 description 1
- 125000000430 tryptophan group Chemical group [H]N([H])C(C(=O)O*)C([H])([H])C1=C([H])N([H])C2=C([H])C([H])=C([H])C([H])=C12 0.000 description 1
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- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
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- A61P35/00—Antineoplastic agents
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Abstract
提供了如下所示的用于治疗由IDO和/或TDO介导的疾病或病症的式(I)化合物,药物组合物和其制备方法。
Description
相关申请的交叉引用
本申请要求于2016年1月2日提交的申请号为62274292和2015年4月12日提交的申请号为62146340的美国临时申请的优先权和利益,其全部内容通过引用纳入本文。
发明领域
本发明尤其提供了新型杂环化合物,其合成以及应用,例如,作为IDO的抑制剂(吲哚胺-2,3-双加氧酶)和/或TDO的抑制剂(色氨酸2,3-双加氧酶)。
发明背景
IDO(吲哚胺2,3-双加氧酶)和/或TDO(色氨酸2,3-双加氧酶)是含有血红素的氧化还原酶,其催化将必需氨基酸L-色氨酸降解成N-甲酰基犬尿氨酸的初始步骤和限速步骤。TDO以肝组织表达为主,并负责调节全身的色氨酸水平。IDO包含两种相关酶IDO同工酶(IDO1,IDO2),在许多细胞,如神经元、星形胶质细胞、小胶质细胞,尤其是抗原呈递细胞(巨噬细胞和树突状细胞)中高水平广泛表达。IDO也在多种不同类型的人类肿瘤中过表达,促进恶性肿瘤从免疫监视中逃脱并促进肿瘤生长。对于IDO-犬尿氨酸路径已经提出了三种免疫抑制机制:1.色氨酸的消耗直接抑制效应T细胞的激活和增殖;2.有毒犬尿氨酸的积累,犬尿氨酸与芳烃受体的结合增强了免疫耐受性;3.TReg细胞的诱导。色氨酸代谢对于细胞增殖、炎症和免疫调节是至关重要的。色氨酸的加速分解有利于肿瘤免疫逃逸。因此IDO可能代表一种在癌症免疫治疗中有吸引力的治疗靶点。
也有越来越多的证据表明IDO抑制剂在许多其他疾病中具有潜在的治疗应用,如治疗传染病、炎症、白内障、子宫内膜异位症、疼痛、动脉粥样硬化、神经或神经精神疾病如抑郁症、肌萎缩侧索硬化、亨廷顿病、阿尔茨海默病、多发性硬化症、帕金森病等。
小分子IDO抑制剂正在被开发用来治疗由IDO酶介导的疾病,并且可以单独或与化疗或免疫治疗(PD-1,CTLA-4,PD-L1等)联合施用。
发明内容
本发明尤其提供了新的杂环化合物及其用途,例如作为IDO(吲哚胺2,3-双加氧酶)和/或TDO(色氨酸2,3-双加氧酶)的抑制剂。
一方面,本发明提供了式(I)化合物或其药学上可接受的盐、前药、氘化衍生物、水合物或溶剂合物:
式(I)中:
环A是5元芳族环,其中T和U各自独立地为N或C;
当γ键是单键时,Z是CR3或N;或者当γ键是双键时,Z是C;
R1和R2各自独立地为氢、卤素、C1-4烷基、C2-4烯基、C2-4炔基、环烷基、C1-4卤代烷基、杂环基、CN、OR5、或N(R5)2;
或者,R1和R2与它们所连接的碳原子一起形成含有0-2个各自独立地为N、O或S的杂原子的3至8元环;
w为0、1、2、3或4;
m和n各自独立地为0、1、2、3或4;
R3为氢、氟或C1-4烷基;
R4各自为氢、卤素、C1-4烷基、C2-4烯基、C2-4炔基、环烷基、C1-4卤代烷基、杂环基、芳基、杂芳基、CN、NO2、OR5、N(R5)2、SR5、C(O)OR5、C(O)N(R5)2、C(O)R5、S(O)2R5、S(O)2N(R5)2、OC(O)R5、OC(O)OR5、OC(O)N(R5)2、N(R5)C(O)R5、或N(R5)C(O)N(R5)2;
R5各自独立地为氢、C1-4烷基、环烷基、杂环基、芳基、或杂芳基;
R为氢、卤素、C1-8烷基、C2-8烯基、C2-8炔基、环烷基、杂环基、芳基、杂芳基、ORA、C(O)RA、C(ORB)(RA)(RC)、C(NHRB)(RA)(RC)、C(=N-ORC)RA、或N(ORC)(RA),其中
RA为氢、C1-8烷基、C2-8烯基、C2-8炔基、芳基、杂芳基、环烷基、环烯基、杂环基、芳基-杂环基、杂芳基-杂环基、环烷基-杂环基、杂环基-杂环基、或杂环基-芳基,各自任选地被取代,
其中,
所述的C1-8烷基、C2-8烯基、C2-8炔基、环烷基、环烯基、杂环基、芳基-杂环基、杂芳基-杂环基、环烷基-杂环基、杂环基-杂环基、或杂环基-芳基各自任选地被一个或两个=RA2基团取代以及各自任选地被一个至三个RA1基团取代;
所述的芳基和杂芳基各自任选地被一个至三个RA1基团取代;
其中
RA1各自独立地为氢、卤素、C1-4烷基、C2-4烯基、C2-4炔基、C1-4卤代烷基、芳基、杂芳基、环烷基、环烯基、杂环基、CN、NO2、N-氧化物、OR5、N(R5)2、SR5、C(O)OR5、C(O)N(R5)2、C(O)N(OH)R5、C(O)R5、C(NR6)R5、C(NR6)N(R6)R5、S(O)R5、S(O)OR5、S(O)N(R5)2、S(O)2R5、S(O)2OR5、S(O)2N(R5)2、OC(O)R5、OC(O)OR5、OC(O)N(R5)2、N(R5)C(O)R5、N(R5)C(O)OR5、或N(R5)C(O)N(R5)2;
=RA2为=O、=S、=N(R5)、=N(OR5)、=C(RA3)2、=(螺环环烷基)、或=(螺环杂环基),其中,RA3各自独立地为氢、卤素、CN、C1-4烷基、环烷基、或杂环基;或者两个RA3与和它们两个连接的原子一起形成单环环烷基或单环杂环基;
RB为氢、C1-4烷基、C(O)RA、C(O)N(H)RA、C(O)(CH2)1-4COOR5、C(O)(CH2)1-4(NR5)COOR5、C(O)CH(NH2)RA、CH2-OP(O)2(OR5)2、或P(O)(ORA)2;
RC为氢或C1-4烷基;
R6各自独立地为氢或C1-4烷基;
上述的烷基、烯基、炔基、环烷基、杂环基、芳基和杂芳基各自任选地被一个至三个选自下组的取代基取代:卤素、C1-4烷基、C2-4烯基、C2-4炔基、环烷基、杂环基、芳基、杂芳基、CN、NO2、OR5、SR5、N(R5)2、C(O)R5、C(O)OR5、C(O)N(R5)2和S(O)2R5;
附带条件是当T和U各自独立地为N或C,R1为H,R2为H,Z为CH,γ为单键,m为0、1、2或3,n为0、1、2、或3,则R为C(ORB)(RA)(RC)以及RA为桥环C7-C16环烷基、芳基-杂环基、环烷基-杂环基、杂环基-杂环基、或杂环基-芳基。
在一优选例中,γ键为单键。
在一优选例中,T和U各自独立地为N或C而Z为CR3或N。
在一优选例中,式(II)
其中:
各处的R4各自独立地为卤素、C1-4烷基、C1-4卤代烷基、CN、NO2、OR5、N(R5)2、SR5,其定义如上;
w为0、1、或2
表示式(II)与式(I)分子的其余部分连接点;
“*”表示手性中心。
在一优选例中,T为C,U为N而Z为CH。
在一优选例中,R1和R2与和它们连接的碳原子一起形成含有0-1个N或O杂原子的3至8元环。
在一优选例中,R1和R2与和它们连接的碳原子一起形成C3-6环烷基。
在一优选例中,R1和R2各自独立地为H或F。
在一优选例中,R1和R2都为H或F。
在一优选例中,m和n各自独立地为0或1。
在一优选例中,R为环烷基、杂环基、芳基、杂芳基、ORA、C(ORB)(RA)(RC)、或N(OR)(RA)。
在一优选例中,R为C(ORB)(RA)(RC)。
在一优选例中,R为C(OH)(RA)(RC)。
在一优选例中,R为CH(OH)(RA)。
在一优选例中,RA为芳基-杂环基、环烷基-杂环基、杂环基-杂环基、或杂环基-芳基。
在一优选例中,RA为C6-10芳基-(5-8元杂环基)、C3-6环烷基-(5-8元杂环基)、(5-8元杂环基)-(5-8元杂环基)、或(5-8元杂环基)-C6-10芳基。
在一优选例中,所述5-8元杂环基包含1或2个氮原子以及任选的1个氧原子(优选1个氮原子和没有氧原子)和其余环原子为C。
在一优选例中,芳基-杂环基,环烷基-杂环基,杂环基-杂环基和杂环基-芳基中两个部分通过N-C键连接。
在一优选例中,RA为桥环C7-C16环烷基,优选桥环C7-C14环烷基,更优选桥环C8-C12环烷基。
在一优选例中,RA为未取代或取代的金刚烷基,未取代或取代的双环[2.2.2]辛基;优选地,术语“取代的”是指含有1-3个选自下组的取代基:卤素、C1-4烷基、–OH、C1-4烷氧基、C1-4卤代烷基、C3-6环烷基、CN、N(C1-4烷基)2、C(O)OC1-4烷基、C(O)N(C1-4烷基)2和C(O)C1-4烷基;
在一优选例中,所述杂环基本身或作为其他取代基的一部分为3-10元杂环基,其任选地被一个或两个=RA2基团取代以及任选地被一个至三个RA1基团取代。
在一优选例中,芳基和杂芳基本身或作为其他取代基的一部分为各自任选地被取代一个至三个RA1基团。
在一优选例中,RA1各自独立地为氢、卤素、C1-4烷基、C1-4卤代烷基、C3-6环烷基、CN、NO2、OR5、N(R5)2、C(O)OR5、C(O)N(R5)2、C(O)N(OH)R5、或C(O)R5。
在一优选例中,各个=RA2为=O。
在另一优选例中,C(ORB)(RA)(RC)为
k=0,1,2,3,4;k1=0,1,2,3;k2=0,1,2,3.
RF=氢,烷基,等
RA1定义如上
在一优选例中,所述化合物特征为式(III):
其中:
R为C(ORB)(RA)(RC);
n为0、1、或2;
R1和R2各自独立地为氢或卤素;
w为0、1、2、或3;
各处的R4各自独立地为卤素、C1-4烷基、C1-4卤代烷基、CN、NO2、OR5、N(R5)2、SR5;和
各处的R5各自独立地为氢或C1-4烷基。
在一优选例中,所述化合物,其中n为0,进一步特征为式(IV):
其中R为具有选自下组结构的C(ORB)(RA)(RC):
k=0,1,2,3,4;k1=0,1,2,3;k2=0,1,2,3.
RF=氢,烷基,等
RA1定义如上
在一优选例中,所述化合物,其中n为0和RC为氢,进一步特征为式(V):
其中:
RA为芳基、杂芳基、环烷基、杂环基、芳基-杂环基、杂芳基-杂环基、环烷基-杂环基、杂环基-杂环基、或杂环基-芳基,各自任选地被取代;和
RB为氢、C1-4烷基、C(O)RA2、或P(O)(ORA2)2,其中RA2为氢或C1-4烷基。
在一优选例中,RA为金刚烷基,二环[2,2,2]辛基,环己基,哌啶基或苯基,各自任选地被取代;和RB为氢或C1-4烷基。
在一优选例中,RA选自下组:
其中:
各个i独立地为0、1、2、或3;
各处的RA1各自独立地为卤素或OH;和
RF选自苯基、C3-C6环烷基和4至6元杂环基,各自任选地被取代。
在一优选例中,w为0、1、或2;R4为卤素;R1和R2各自为氢或氟;RB和RC各自为氢;和RA选自下组:
其中各处的i为0、1、或2;各处的RA1为OH;和RF为任选地被一个或两个选自NO2和CF3的取代基取代的苯基。
在另一优选例中,式(I)化合物选自下组:
在另一优选例中,式(I)化合物为
在另一优选例中,本发明第一方面的化合物的药学上可接受的盐是酸性/阴离子或碱性/阳离子盐。
本发明第二方面提供了一种制备药物组合物的方法,其包含将本发明第一方面的化合物,或其晶型、药学上可接受的盐、水合物或溶剂合物和药学上可接受的载体混合形成药物组合物。
本发明第三方面提供了一种药物组合物,其包含如上所述的本发明的化合物,或其晶型、药学上可接受的盐、水合物或溶剂合物和药学上可接受的载体或赋形剂。
在一实施例中,所述组合物是注射剂,胶囊剂,片剂,丸剂,粉剂或颗粒剂。
在第四方面中,本发明提供了本发明第一方面所述的化合物,或其晶型、药学上可接受的盐、水合物或溶剂合物的用途,其作为IDO(吲哚胺2,3-双加氧酶)和/或TDO(色氨酸2,3-双加氧酶)抑制剂用于生产治疗通过抑制IDO和/或TDO而获益的医学病症的药物。
在一实施例中,IDO为IDO1和/或IDO2。
在一实施例中,IDO为IDO1。
在一实施例中,所述的IDO和/或TDO介导的医学病症包括但不限于癌症,传染病,
炎症,白内障,子宫内膜异位,疼痛,动脉粥样硬化,神经病学或神经精神病症。
在一实施例中,所述神经病学和神经精神病症是抑郁症,肌萎缩性侧索硬化症,亨廷顿病,阿尔茨海默病,多发性硬化症,帕金森病等。
在一实施例中,所述传染病是由丙型肝炎病毒(HCV),人乳头瘤病毒(HPV),人免疫缺陷病毒(HIV),巨细胞病毒(CMV)引起的病毒感染。
在一实施例中,所述癌症为乳腺癌,淋巴癌,白血病,肺癌,卵巢癌,宫颈癌,睾丸癌,肝癌,黑素瘤,结肠癌,直肠癌,肾细胞癌,小肠癌和食道癌,头颈癌,膀胱癌,前列腺癌,胰腺癌或咽癌。
在第五方面中,本发明提供了本发明第一方面所述的化合物,或其晶型、药学上可接受的盐、水合物或溶剂合物的用途,其作为IDO(吲哚胺2,3-双加氧酶)和/或TDO(色氨酸2,3-双加氧酶)抑制,用于生产刺激T细胞增殖或逆转无反应性或免疫抑制的免疫状态的药物。
在一实施例中,所述的无反应性或免疫抑制是由吲哚胺2,3-双加氧酶的表达引起的。
在一实施例中,所述的无反应性或免疫抑制是由色氨酸2,3-双加氧酶的表达引起的。
在第六方面中,本发明提供了一种治疗受试者中由IDO和/或TDO介导的免疫抑制的方法,包含向需要的受试者施用治疗有效量的本发明的第一方面的化合物或本发明第三方面的组合物。
在一实施例中,所述免疫抑制与感染性疾病或癌症有关。
在另一优选例中,所述免疫抑制与感染性疾病有关且传染病是由丙型肝炎病毒(HCV),人乳头瘤病毒(HPV),人免疫缺陷病毒(HIV),巨细胞病毒(CMV)引起的病毒感染。
在另一优选例中,所述免疫抑制与人免疫缺陷病毒(HIV)有关。
在一实施例中,所述免疫抑制与癌症有关。
在另一优选例中,所述免疫抑制为与癌症相关的肿瘤特异性免疫抑制。
在另一优选例中,所述癌症为乳腺癌,淋巴癌,白血病,肺癌,卵巢癌,宫颈癌,睾丸癌,肝癌,黑素瘤,结肠癌,直肠癌,肾细胞癌,小肠癌和食道癌,头颈癌,膀胱癌,前列腺癌,胰腺癌或咽癌。
第七方面中,本发明提供了一种制备本发明第一方面的式(A7)化合物的方法,包括步骤:
(i)在惰性溶剂中,将化合物A5和酸反应,形成化合物A6,
(ii)用还原剂还原化合物A6,和任选地,如果G存在保护基的话,除去保护基形成化合物A7,
P1为保护基或H
RF为苯基、5至10元杂芳基、C3-6环烷基、以及4至6元杂环基,各自任选地被取代。
应理解,在本发明中,上下文(例如实施例)具体描述的技术特征可以相互组合,从而构成新的或者优选的技术方案,其不需要特别指定。
发明的详细说明
定义
如本文所用,除非另外明确指出,否则术语“一”,“一个”等是指一个或多个。
如本文所用,词语“或”具有“或”和“和”的含义,并且等同于“和/或”-除非另外具体限于“或”。
如本文所用,除非另有说明,否则本发明中的化合物的手性碳原子(或手性中心)任选为R构型,S构型或其组合。
如本文所用,除非另有说明,术语“烷基”本身或作为另一取代基(其可包括“烷”的简短形式,例如烷氧基)的一部分是指直链(即非支链),支链或环状烃基,或其组合,其可以是完全饱和的,单不饱和或多不饱和的,并且可以包括二价和多价基团。当烷基前面有碳数的修饰词,例如C1-10时,其意为该烷基包含1-10个碳原子。例如,C1-8烷基的实例可包括具有1-8个碳原子的直链或支链烷基,例如甲基,乙基,丙基,异丙基,丁基,异丁基,仲丁基和叔丁基。
如本文所用,术语“烯基”本身或作为另一取代基的一部分是指具有至少一个碳-碳双键的直链或支链烃链。具有一个双键的烯基可以表示为-CnH2n-1或具有两个双键的-CnH2n-1或具有两个双键的烯基可以表示为-CnH2n-3。当烯基前面有碳数的修饰词,例如C2-8时,其意为该烯基包含2-8个碳原子。例如,C2-8链烯基的实例可包括乙烯基,烯丙基,1,2-丁烯基,2,3-丁烯基和丁二烯基。
如本文所用,术语“炔基”本身或作为另一取代基的一部分是指具有至少一个碳-碳三键的脂族烃基。炔基可以是直链或支链,或其组合。在一些实施方案中,其可以包含2至12(例如2至8,2至6或2至4)个碳原子。当炔基前面有碳数的修饰词,例如C2-8时,其意为该炔基含有2-8个碳原子。炔基(例如C2-8炔基)的实例可以包括乙炔基,丙炔基,异丙炔基,1-丁炔基,异丁炔基和仲丁炔基。
如本文所用,术语“环烷基”本身或作为另一取代基的一部分是指饱和或部分饱和的单环,双环或三环(稠合或桥或螺)碳环环系。它可以含有3至12(例如3至10,或5至10)个碳原子。当环烷基前面有碳数的修饰词,例如C3-10时,其意为该环烷基包含3至10个碳原子。在一些实施方案中,术语“C3-10环烷基”可以指含有3至10个碳原子的饱和或部分饱和的单环或双环烷基环系,例如环丙基,环丁基,环戊基,环己基,环庚基,金刚烷基和双环[2,2,2]辛基。
如本文所用,术语“烷氧基”或“烷基氧基”是指由氧原子连接的烷基(即-O-烷基),其中烷基如上所定义。“烷氧基”的具体实例包括但不限于甲氧基,乙氧基,正丙氧基,异丙氧基,正丁氧基,异丁氧基,仲丁氧基,叔丁氧基,环己氧基和环戊氧基。烷氧基可以任选地被一个或多个合适的取代基如卤素,氨基,氰基或羟基取代。烷氧基可以是直链或支链的。当烷氧基基团前面有碳数的修饰词,例如C1-8时,其意为该烷氧基基团含有1-8个碳原子。
如本文所用,术语“卤代”或“卤素”本身或作为另一取代基(例如卤代烷基)的一部分可指包括F,Cl,Br和/或I。
如本文所用,术语“烷氧基羰基”是指直链或支链的烷氧基羰基部分。它可以含有1至8个碳原子。当烷氧基羰基前面有碳数的修饰词,例如C1-8时,其意为该烷氧基羰基含有1-8个碳原子。例如,C1-8烷氧基羰基可指具有C1-8烷氧基C(=O)-结构的基团,例如甲氧基羰基,乙氧基羰基和叔丁氧基羰基。
如本文所用,“羰基”基团是指-C(O)-或-C(=O)-。
如本文所用,术语“芳基”本身或作为另一取代基的一部分是指并包括单环,双环或多环芳族烃基。芳基可以被取代或未被取代。当芳基前面有碳数的修饰词,例如C6-12时,其意为该芳基含有6-12个碳原子。芳基的实例包括但不限于苯基和萘基。
如本文所用,术语“杂芳基”本身或作为另一个取代基的一部分是指具有指定的环碳原子数的(例如,C4-10是指4至10环碳原子)并且含有至少一个或多个相同或不同的各自独立地为N,O或S的杂原子的单环或多环芳族烃基。每个碳原子可以任选被取代。杂芳基可以是含有1至4个各自独立地为N,O或S的杂原子的5至15元芳香基团。杂芳基可以包括含氮杂芳基,含氧杂芳基,含硫杂芳基。
如本文所用,术语“含氮杂芳基”是指在环中具有一个或多个氮原子的芳香基团。优选为C4-10含氮杂芳基,其为具有4至10个碳原子且环中具有1个或多个氮原子的芳香基团。具体实例包括但不限于取代或未取代的吡啶基,嘧啶基和吡咯基。
如本文所用,术语“含氧杂芳基”是指在环中具有一个或多个氧原子的芳香基团。优选为C4-10含氧杂芳基,其为具有4至10个碳原子且环中具有1个或多个氧原子的芳香基团。例如任选取代的呋喃基和苯并呋喃基。
如本文所用,术语“含硫杂芳基”是指在环中具有一个或多个硫原子的芳香基团。优选为C4-10含硫杂芳基,其为具有4至10个碳原子且环中具有1个或多个硫原子的芳香基团。例如任选取代的噻吩基。
如本文所用,术语“杂环基”本身或作为另一取代基(例如在芳基-杂环基,杂芳基-杂环基,环烷基-杂环基,杂环基-杂环基或杂环基-芳基中)的一部分是指可以是饱和的,部分饱和的或完全不饱和的单环或多环基团,其具有指定的环碳原子数(例如,C3-11是指3至11个环碳原子)并且含有至少一个或多个相同或不同的各自独立地为N,S或O的杂原子。杂环基可以是含有1至4个各自独立地为N,O或S杂原子的3至15元基团。杂芳基可以包含含氮杂环基,含氧杂环基和含硫杂环基,含氮和氧的杂环基,含氮和硫的杂环基,含硫和氧的杂环基等。
如本文所用,术语“任选地”(例如,在“任选地被取代”中)是指所述部分是取代的或未取代的,并且取代仅在化学上可行时发生。例如,H不能被取代基取代且共价键或-C(=O)-基团不能被取代基取代。
如本文所用,“氧代”或“氧化物”基团是指=O。
如本文所用,除非另有说明,否则术语“药学上可接受的盐”是指适用于与受试者(例如人)的组织接触而没有过度不利影响的盐。在一些实施方案中,药学上可接受的盐包括具有酸性基团(例如,钾盐,钠盐,镁盐,钙盐)或碱性基团(例如硫酸盐,盐酸盐,磷酸盐,硝酸盐,碳酸盐)的本发明化合物的盐。
如本文所用,术语“取代的”,无论前面是否冠有术语“任选”的,是指用特定取代基置换给定结构中的氢自由基。特定取代基在上面的定义和下面的化合物及其实施例的记载中被描述。除非另有说明,任选取代的基团可以在基团的每个可取代位置上具有取代基,并且在任何给定结构中,当一个以上的位置可以被选自特定基团的一个以上的取代基取代时,取代基在每个位置可以相同或不同。环取代基,如杂环烷基可以与另一个环,例如环烷基结合形成螺-双环体系,例如两个环共享一个共同的原子。如本领域普通技术人员所认识到的,本发明所设想的取代基的组合是致使形成稳定的或化学上可行的化合物的那些组合。取代基的实例包括但不限于C1-8烷基,C2-8烯基,C2-8炔基,C3-10环烷基,C1-8烷氧基,卤素,羟基,羧基(-COOH),C1-8醛,C2-10酰基,C2-10酯,氨基,酰氨基,苯基。例如,苯基可任选被1-3个取代基取代,所述取代基各自独立地为卤素,C1-10烷基,氰基,OH,硝基,C3-10环状烃基,C1-8烷氧基或氨基。
除非另外定义,否则本文使用的所有术语具有本领域技术人员已知的共同含义。
在一个优选的实施方案中,式(I)化合物选自上述图2中所示的化合物。
在一个优选的实施方案中,式(I)中的R,R1,R2,R3,R4,R5,R6,RA,RB,RC,RA1和RA2各自独立地选自实施例中制备的具体化合物所包含的相应基团。
应该理解,式(I)化合物的富含氘的衍生物或不同晶型也落入本发明的范围。
本发明化合物的一般合成方案
通常,反应在惰性溶剂中,在-40至回流温度(例如100或120℃)下进行,反应时间为1分钟至72小时,优选0.1至24小时或0.2-12小时。示例性溶剂和温度为实施例中所使用的那些。
方案A阐明了化合物A7的一般合成。
方案A
P1为保护基或H
RF如上所定义
方案B阐明了化合物B3的一般合成。
方案B
RF=氢、烷基 等
RA1如上所定义
方案C阐明了化合物C8的一般合成。
方案C
方案D阐明了化合物D11的替代合成。
方案D
方案E阐明了化合物E7的替代合成。
方案E
在上述方案中,R4,RA1和w如上所定义。
药物组合物及其施用
本发明提供的化合物可用作IDO(吲哚胺2,3-双加氧酶)和/或TDO(色氨酸2,3-双加氧酶)的抑制剂。因此,这些化合物可以用于治疗癌症,感染性疾病,炎症,白内障,子宫内膜异位症,疼痛,动脉粥样硬化,神经病学或神经精神病症。
本发明的药物组合物包括(i)安全有效量的本发明化合物或其药学上可接受的盐和(ii)药学上可接受的赋形剂或载体。如本文所用,术语“安全有效量”是指足以改善患者病症并且不会引起任何严重副作用的化合物的量。通常,药物组合物含有0.01-500mg本发明化合物/剂,优选0.10-100mg本发明化合物/剂。在一些实施方案中,“一剂”是指胶囊或片剂。
“药学上可接受的载体”是指适用于人的一种或多种相容的固体或液体填充剂或凝胶材料,并且通常必须具有足够的纯度和足够低的毒性。如本文所用,术语“相容性”是指组合物的组分可以与本发明的化合物或彼此共混,并且不会显着降低化合物的功效。药学上可接受的载体的实例包括但不限于纤维素及其衍生物(如羧甲基纤维素钠,乙基纤维素钠,醋酸纤维素等),明胶,滑石,固体润滑剂(如硬脂酸和硬脂酸镁),硫酸钙,植物油(如大豆油,芝麻油,花生油,橄榄油等),多元醇(如丙二醇,甘油,甘露糖醇,山梨糖醇等),乳化剂(如吐温),润湿剂(如十二烷基硫酸钠),着色剂,调味剂,稳定剂,抗氧化剂,防腐剂和去热原的水。
对于本发明的化合物或药物组合物的施用途径没有特别的限制。代表性的给药途径包括但不限于:口服,肠胃外(静脉内,肌内或皮下)和局部给药。
用于口服给药的固体剂型包括胶囊剂,片剂,丸剂,粉剂和颗粒剂。在这些固体剂型中,将活性化合物与至少一种常规的惰性赋形剂(或载体)混合,如柠檬酸钠或磷酸二钙,或混合使用以下组分:(a)填充剂或增容剂,例如淀粉,乳糖,蔗糖,葡萄糖,甘露糖醇和硅酸;(b)粘合剂,例如羟甲基纤维素,藻酸盐,明胶,聚乙烯吡咯烷酮,蔗糖和阿拉伯胶;(c)保湿剂,如甘油;(d)崩解剂如琼脂,碳酸钙,马铃薯淀粉或木薯淀粉,海藻酸,某些复合硅酸盐和碳酸钠;(e)溶解阻滞剂,例如石蜡;(f)吸收促进剂,例如季铵化合物;(g)润湿剂,如十六烷醇和单一甘油基硬脂酸酯;(h)吸附剂,例如高岭土;和(i)润滑剂如滑石,硬脂酸钙,硬脂酸镁,固体聚乙二醇,月桂基硫酸钠或其混合物。在胶囊,片剂和丸剂中,剂型还可以含有缓冲剂。
固体剂型如片剂,糖丸,胶囊剂,丸剂和颗粒剂可以通过使用包衣和壳材料(例如肠溶衣和本领域已知的其它材料)来制备。它们可以含有不透明的试剂,并且在这样的组合物中可以延迟活性化合物或化合物在消化道的某些部分的释放。嵌入组分的实例可以是聚合物和蜡。如果需要,可将活性化合物和一种或多种上述赋形剂制成微胶囊。
用于口服给药的液体剂型包括药学上可接受的乳剂,溶液剂,混悬剂,糖浆剂或酊剂。除了活性化合物以外,液体剂型还可以含有本领域已知的常规惰性稀释剂,例如水或其它溶剂,增溶剂和乳化剂,例如乙醇,异丙醇,碳酸乙酯,乙酸乙酯,丙二醇,1,3-丁二醇,二甲基甲酰胺以及油,特别是棉籽油,花生油,玉米胚芽油,橄榄油,蓖麻油和芝麻油,或其混合物等。
除了惰性稀释剂外,组合物还可以含有添加剂如润湿剂,乳化剂和悬浮剂,甜味剂,调味剂和香料。
除了活性化合物之外,悬浮液还可以含有悬浮剂,例如乙氧基化异十八醇,聚氧乙烯山梨糖醇和脱水山梨糖醇酯,微晶纤维素,甲醇铝和琼脂,或其混合物等。
用于肠胃外注射的组合物可包含生理上可接受的无菌水溶液或无水溶液,分散液,混悬液或乳液,以及可重新溶解于无菌注射液或分散液中的无菌粉末。合适的水性和非水性载体,稀释剂,溶剂或赋形剂包括水,乙醇,多元醇及其合适的混合物。
用于局部给药的本发明化合物的剂型包括软膏剂,粉剂,贴剂,气雾剂和吸入剂。在无菌条件下,将活性成分与生理上可接受的载体和任何防腐剂,缓冲剂或推进剂(如果需要)混合。
本发明的化合物可以单独施用,或者与其他药学上可接受的化合物组合施用。
当使用药物组合物时,将安全有效量的本发明化合物给药或递送至有需要的哺乳动物(例如人),其中给药剂量为药学有效量。对于体重约60kg的人,日剂量通常为1-2000mg,优选20-500mg。当然,具体剂量也应该取决于其他因素,例如施用途径,患者健康状况等,这些都在熟练医师的技术范围内。
本发明的化合物和药物组合物可用于治疗癌症,感染性疾病,炎症,白内障,子宫内膜异位,疼痛,动脉粥样硬化,神经病学或神经精神病症。如本文所用,术语“癌症”意指包括所有类型的癌性生长或致癌过程,转移性组织或恶性转化的细胞,组织或器官,而不管组织病理学类型或侵入阶段如何。癌性疾病的实例包括,但不限于实体瘤,软组织肿瘤和转移性病变。实体瘤的例子包括恶性肿瘤,例如,肉瘤和那些影响前列腺,肺,乳腺,淋巴,胃肠(例如结肠)和泌尿生殖道(例如肾,尿道上皮细胞),咽的各种器官系统的腺瘤和癌症。腺癌包括恶性肿瘤,如大多数结肠癌,直肠癌,肾细胞癌,肝癌,非小细胞肺癌,小肠癌和食管癌。上述癌症的转移灶也可以使用本发明的方法和组合物治疗或预防。本发明方法可用于治疗例如那些影响肺,乳腺,淋巴,胃肠(例如结肠),膀胱,泌尿生殖道(例如前列腺),咽的各种器官系统的恶性肿瘤,以及包括例如大多数结肠癌,肾细胞癌,前列腺癌和/或睾丸肿瘤,非小细胞肺癌,小肠癌和食道癌的恶性肿瘤的腺癌。癌症的例子包括但不限于乳腺癌,淋巴癌,肺癌,卵巢癌,肝癌,黑色素瘤,结肠癌,直肠癌,肾细胞癌,小肠癌和食管癌,膀胱癌,前列腺癌或咽癌等。如本文所用,术语“感染性疾病”是指包括由丙型肝炎病毒(HCV),人乳头瘤病毒(HPV),人免疫缺陷病毒(HIV)和/或巨细胞病毒(CMV)引起的所有类型的病毒感染。
本发明的主要优点至少包括以下内容:
(1)本发明提供了可用作IDO(吲哚胺2,3-双加氧酶)和/或TDO(色氨酸2,3-双加氧酶)抑制剂的新型杂环化合物。
(2)本发明揭示了这些新型的式(I)杂环化合物具有显着的抑制IDO和TDO的活性效果。
下面将参照具体实施例进一步说明本发明。应该理解的是,这些实施例仅仅是为了说明本发明,而不是为了限制本发明的范围。除非另有说明,份数和百分比按重量计算。
实施例1.制备2-(5H-咪唑并[5,1-a]异吲哚-5-基)-1-(1-苯基哌啶-4-基)乙醇(化合物1)
向1a(100mg,0.26mmol)的DCM(4.0mL)溶液中添加TFA(2.0mL)。溶液在室温下搅拌1小时。真空除去溶剂,残余物溶解于DCM(30mL)。有机溶剂用K2CO3(a.q,1M,5.0mL)和盐水(5.0mL)洗涤,干燥和浓缩得到60mg粗产品1b,为黄色油状物,其直接用于下一步。MS 282.2(M+H)+.
向1b(60mg,0.21mmol)的DCM(4.0mL)溶液中添加TEA(0.2mL),Cu(OAc)2(76mg,0.42mmol)和苯基硼酸(51mg,0.42mmol)。混合物在室温下搅拌24小时,然后过滤。添加DCM(10mL)和MeOH(10mL)来洗涤固体。滤液浓缩至干得到1c,为浅绿色油状物,其直接用于下一步。MS 358.3(M+H)+.
向粗1c的MeOH(4.0mL)溶液中分批添加NaBH4(32mg,0.84mmol)。混合物在室温下搅拌2小时。将HCl(2M,0.5mL)添至溶液中,所得混合物浓缩至干。残余物用硅胶柱(DCM:MeOH=40:1,含有0.5%氨水(28%w/w))纯化。所得粗产品进一步用制备型TLC(DCM:MeOH=12:1,含有0.5%氨水(28%w/w))纯化得到21mg的化合物1,为黄色固体。1H NMR(非对映异构体的混合物,CD3OD,400Hz):δ7.88和7.84(两个s,1H),7.50(d,J=7.6Hz,1H),7.45和7.37(两个d,J=8.0Hz,1H),7.29(t,J=7.6Hz,1H),7.31-7.27(m,1H),7.12-7.08(m,2H),7.05和7.02(两个s,1H),6.86(d,J=8.0Hz,2H),6.71(t,J=7.2Hz,1H),5.41和5.35(d和t,J=10.0Hz和J=5.6Hz,1H),3.69-3.55(m,3H),2.55-2.48(m,2H),2.23-2.00(m,2H),1.90-1.84(m,1H),1.62-1.59(m,1H),1.42-1.37(m,3H);MS 360.2(M+H)+.
实施例2.制备2-(5H-咪唑并[5,1-a]异吲哚-5-基)-1-(1-(吡啶-4-基)哌啶-4-基)乙醇(化合物2)
向2a(200mg,0.63mmol)的DMF(2.0mL)溶液中添加DIEA(542mg,4.2mmol)和4-氯吡啶盐酸盐(2b,190mg,1.26mmol)。混合物在微波反应器中加热至140℃并140℃在下搅拌30min。反应混合物浓缩至干。残余物用硅胶柱(DCM:MeOH=20:1含有0.5%氨水溶液(28%w/w))纯化。所得产品进一步用制备型TLC(DCM:MeOH=10:1含有0.5%氨水溶液(28%w/w))纯化得到24mg的化合物2。1H-NMR(非对映异构体的混合物,CD3OD,400MHz):δ8.05(d,J=6.4Hz,2H),7.97和7.92(两个s,1H),7.59(d,J=7.6Hz,1H),7.53和7.46(两个d,J=8.0Hz和J=7.6Hz,1H),7.39(t,J=7.6Hz,1H),7.32-7.28(m,1H),7.15和7.12(两个s,1H),6.78(d,J=6.4Hz,2H),5.49和5.42(dd和t,J=10.0Hz,2.8Hz和J=6.4Hz,1H),4.06-3.97(m,2H),3.77-3.69(m,1H),2.82(td,J=12.8Hz,2.4Hz,2H),2.33-1.91(m,2H),1.77-1.36(m,5H);MS 361.2(M+H)+.
实施例3.制备1-(1-环丙基哌啶-4-基)-2-(5H-咪唑并[5,1-a]异吲哚-5-基)乙醇(化合物3)
向2a(200mg,0.63mmol)的MeOH(5.0mL)溶液中添加TEA(0.2mL)。溶液在室温下搅拌15分钟。添加HOAc(1.0mL)和(1-乙氧基环丙氧基)三甲基硅烷(3a,220mg,1.26mmol),溶液继续搅拌15分钟。然后分批加入NaBH3CN(80mg,1.26mmol),随后加入无水硫酸镁(200mg)。反应混合物回流30小时。根据LCMS确定反应结束后,过滤混合物并添加MeOH(10mL)来洗涤固体。浓缩滤液,残余物用硅胶柱(DCM:MeOH=40:1含有0.5%氨水溶液(28%w/w))纯化。所得产品进一步用制备型TLC(DCM:MeOH=20:1含有0.5%氨水溶液(28%w/w))纯化,得到25mg的化合物3,为白色固体。1H-NMR(非对映异构体的混合物,CD3OD,400MHz):δ7.95和7.90(两个s,1H),7.55(d,J=7.6Hz,1H),7.49和7.41(两个d,J=7.6Hz,1H),7.35(t,J=7.6Hz,1H),7.28-7.24(m,1H),7.13和7.10(两个s,1H),5.44和5.36(dd和t,J=10.4Hz,2.4Hz和t,J=6.4Hz,1H),3.72-3.65(m,1H),3.08-3.00(m,2H),2.26-1.96(m,4H),1.87-1.81(m,1H),1.68-1.53(m,2H),1.32-1.22(m,3H),0.45-0.32(m,4H);MS 324.4(M+H)+.
实施例4.制备2-(5H-咪唑并[5,1-a]异吲哚-5-基)-1-(1-(环氧丙烷-3-基)哌啶-4-基)乙醇(化合物4)
向2a(100mg,0.31mmol)的DCM(2.0mL)混合物中添加TEA(42mg,0.42mmol)。混合物在室温下搅拌10分钟。然后添加环氧丙烷-3-酮(4a,30mg,0.42mmol)和HOAc(0.2mL)。混合物在室温下搅拌30分钟。然后分批添加三乙酰氧基硼氢化钠(89mg,0.42mmol)。混合物在室温下搅拌16小时。真空除去溶剂。残余物用硅胶柱(DCM:MeOH=25:1含有0.5%氨水溶液(28%w/w))纯化。所得产品进一步用制备型TLC(DCM:MeOH=15:1含有0.5%氨水溶液(28%w/w))纯化,得到13mg的化合物4。1H-NMR(非对映异构体的混合物,CD3OD,400MHz):δ7.97和7.93(两个s,1H),7.60(d,J=7.6Hz,1H),7.54和7.45(两个d,J=7.6Hz,1H),7.39(t,J=7.6Hz,1H),7.30(td,J=7.6Hz,0.8Hz,1H),7.15和7.12(两个s,1H),5.50和5.42(dd和t,J=10.0Hz,2.8Hz和J=6.4Hz,1H),4.68-4.64(m,2H),4.60-4.55(m,2H),3.77-3.72(m,1H),3.47-3.41(m,J=6.4Hz,1H),2.86-2.78(m,2H),2.16-2.02(m,2H),1.89-1.75(m,3H),1.63-1.60(m,1H),1.42-1.25(m,3H);MS 340.2(M+H)+.
实施例5.制备4-(4-(1-羟基-2-(5H-咪唑并[5,1-a]异吲哚-5-基)乙基)哌啶-1-基)环己醇(化合物5)
2a(180mg,0.56mmol)和4-羟基环己酮(5a,64mg,0.56mmol)的DCM(2mL)混合物,室温下用TEA(0.12mL,0.87mmol)处理20min。然后添加NaBH(OAc)3(354mg,1.68mmol),反应混合物室温下搅拌4小时。反应用饱和碳酸氢钠和DCM淬灭。合并的有机层用无水Na2SO4干燥,过滤并浓缩得到粗产品,通过硅胶柱色谱(DCM:MeOH=5:1含有0.5%氨水溶液(28%w/w))纯化。分离到的产品进一步用制备型TLC(DCM:MeOH=5:1含有0.5%氨水溶液(28%w/w))纯化,得到化合物5,为浅黄色固体(40mg)。1H NMR(非对映异构体的混合物,CD3OD,400Hz):δ7.97和7.93(两个s,1H),7.61(d,J=7.6Hz,1H),7.55和7.47(两个d,J=7.6Hz,1H),7.40(t,J=7.6Hz,1H),7.33-7.29(m,1H),7.16和7.13(两个s,1H),5.51和5.44(d和t,J=8.0Hz和J=5.6Hz,1H),3.81-3.78(m,1H),3.43-3.38(m,1H),3.02-2.72(m,3H),2.19-2.13(m,1H),2.09-2.02(m,4H),1.94-1.78(m,5H),1.64-1.46(m,5H);MS 382.3(M+H)+.
实施例6.制备5-(2-环己基-2,2-二氟乙基)-5H-咪唑并[5,1-a]异吲哚(化合物6)
在0℃下,向6a(100mg,0.36mmol)的DCM(2ml)溶液中滴加二乙基氨基三氟化硫(DAST,287mg,1.785mmol)。然后反应混合物在室温下搅拌40h。将混合物缓慢地添加至冰水中,用DCM萃取两次。有机层用Na2SO4干燥,过滤并真空浓缩。所得粗产品用制备型TLC(DCM:MeOH=70:1)纯化并且后用制备型HPLC(柱,Waters X-Select Prep C18 5μm 30*100mm;流速(ml/min):20;注射体积(μL):500;流动相A:ACN;流动相B:H2O(10mmol NH4HCO3);梯度:B9.60min内从45%至25%,1.00min内从25%至5%,以及维持5%3.05min,0.20min内从5%至45%,并维持45%4.15min)纯化,得到化合物6,为浅黄色固体(5mg)。1H NMR(CD3OD,400Hz):δ7.86(s,1H),7.60(d,J=7.6Hz,1H),7.50(d,J=7.6Hz,1H),7.41(t,J=7.6Hz,1H),7.33(td,J=7.6Hz,1.2Hz,1H),7.14(s,1H),5.59(dd,J=8.4Hz,2.4Hz,1H),2.82-2.68(m,1H),2.44-2.29(m,1H),1.92-1.89(m,2H),1.85-1.82(m,2H),1.72-1.70(m,1H),1.35-1.18(m,6H);MS 303.2(M+H)+.
实施例7.制备2-(5H-咪唑并[5,1-a]异吲哚-5-基)-1-(1-(2-硝基苯基)哌啶-4-基)乙醇(化合物7)
2a(60mg,0.212mmol),7a(60mg,0.425mmol)和DIPEA(90mg,0.698mmol)的DMF(2mL)混合物在微波辐射下60℃下搅拌0.5h。混合物冷却至室温,用水(10mL)稀释和用EtOAc(10mL x 3)萃取。合并的有机层用盐水(10mL)洗涤,无水Na2SO4干燥,过滤并浓缩得到残余物,其用制备型TLC(CH2Cl2:MeOH=15:1)纯化,得到化合物7(15mg,17%收率),为黄色固体。1HNMR(非对映异构体的混合物,CD3OD,400MHz,)δ8.02和7.98(两个s,1H),7.72(dd,J=8.0Hz,1.6Hz,1H),7.65-7.25(m,6H),7.18和7.16(两个s,1H),7.08(t,J=8.0Hz,1H),5.56-5.46(m,1H),3.84-3.75(m,1H),3.39-3.23(m,2H),2.86-2.79(m,2H),2.34-2.22(m,2H),1.98-1.90(m,1H),1.72-1.43(m,4H);MS 405.3[M+H]+.
实施例8.制备2-(5H-咪唑并[5,1-a]异吲哚-5-基)-1-(1-(4-(三氟甲基)苯基)哌啶-4-基)乙醇(化合物8)
化合物1b(56mg,0.199mmol),化合物8a(57mg,0.300mmol),Cu(OAc)2(36mg,0.198mmol)和Et3N(60mg0.594mmol)的CH2Cl2(2mL)混合物,在O2气氛下和室温下搅拌24h。过滤反应混合物并用CH2Cl2(10mL x 3)洗涤。真空浓缩滤液得到残余物,其用制备型TLC(CH2Cl2:MeOH=20:1)纯化,得到化合物8b(25mg,30%收率),为黄色固体。MS 426.2[M+H]+.
0℃下,向化合物8b(36mg,0.085mmol)的THF(1mL)搅拌溶液中添加NaBH4(10mg,0.263mmol)。然后混合物在室温下搅拌30min。混合物用冰冷的NH4Cl溶液(10mL)淬灭和用EtOAc(10mL x 3)萃取。合并的有机层用盐水(10mL)洗涤,无水Na2SO4干燥,过滤并真空浓缩得到残余物,其用制备型TLC(CH2Cl2:MeOH=15:1)纯化和然后用制备型TLC(CH2Cl2:CH3CN=1:1)纯化,得到化合物8(4.7mg,13%收率),为黄色固体。1HNMR(非对映异构体的混合物,CD3OD,400Hz)δ8.00和7.95(两个s,1H),7.61(d,J=7.2Hz,1H),7.55(d,J=7.6Hz,1H),7.49-7.37(m,3H),7.34-7.28(m,1H),7.14(s,1H),7.01(d,J=8.8Hz,2H),5.48-5.42(m,1H),3.96-3.83(m,2H),3.81-3.74(m,1H),2.80-2.70(m,2H),2.21-2.06(m,2H),2.00-1.92(m,1H),1.76-1.67(m,1H),1.59-1.40(m,3H);MS 428.2[M+H]+.
实施例9.制备2-(5H-咪唑并[5,1-a]异吲哚-5-基)-1-(1-(2-硝基-4-(三氟甲基)苯基)哌啶-4-基)乙醇(化合物9)
向化合物1a(150mg,0.393mmol)的CH2Cl2(1.5mL)搅拌溶液中,缓慢添加TFA(0.5mL)。混合物在室温下搅拌2h并减压浓缩至干。残余物用DMF(2mL)稀释,然后加入K2CO3(215mg,1.556mmol)以及随后加入化合物9a(123mg,0.588mmol)。混合物在室温下搅拌16h并用水(6mL)淬灭和用EtOAc(6mL x 3)萃取。合并的有机层用盐水(6mL)洗涤,无水Na2SO4干燥,过滤并真空浓缩得到残余物,其用制备型TLC(石油醚:EtOAc=1:1)纯化得到化合物9b(30mg,16%两步收率),为黄色固体。MS 471.1[M+H]+.
0℃下向化合物9b(30mg,0.085mmol)的THF(1mL)搅拌溶液中添加NaBH4(5mg,0.132mmol)。然后混合物在室温下搅拌20min。混合物用冰冷的NH4Cl水溶液(10mL)淬灭和用EtOAc(10mL x 3)萃取。合并的有机层用盐水(10mL)洗涤,无水Na2SO4干燥,过滤并真空浓缩得到残余物,其用制备型TLC(CH2Cl2:MeOH=15:1)纯化,得到化合物9(15mg,50%收率),为黄色固体。1HNMR(非对映异构体的混合物,CD3OD,400Hz)δ8.07-7.95(m,2H),7.72(dd,J=8.8Hz,2.0Hz,1H),7.61(d,J=7.6Hz,1H),7.56(d,J=7.6Hz,1H),7.43-7.29(m,3H),7.16和7.14(两个s,1H),5.55-5.42(m,1H),3.82-3.73(m,1H),3.49-3.31(m,2H),2.96-2.88(m,2H),2.20-2.07(m,2H),1.97-1.88(m,1H),1.72-1.64(m,1H),1.60-1.44(m,3H);MS 473.2[M+H]+.
实施例10.制备1-((3r,5r,7r)-金钢烷-1-基)-2-(5H-咪唑并[5,1-a]异吲哚-5-基)乙醇(化合物10)
室温下向化合物10a(97mg,0.234mmol)和化合物10b(42mg,0.234mmol)的无水THF(10mL)搅拌混合物中,滴加EtONa溶液(21%,EtOH中,98mg,0.304mmol)。反应混合物在室温下搅拌2h并减压浓缩至干。残余物用NH4Cl溶液(10mL)稀释和用EtOAc(10mL x 3)萃取。合并的有机层用盐水(10mL)洗涤,无水Na2SO4干燥,过滤并真空浓缩得到残余物,其溶解于MeOH(8mL)。向这个溶液中添加HOAc(2mL),反应混合物在90℃下搅拌3h。真空浓缩混合物得到残余物,其用NaHCO3饱和溶液(10mL)稀释和用EtOAc(10mL x 3)萃取。合并的有机层用盐水(10mL)洗涤,无水Na2SO4干燥,过滤并真空浓缩得到残余物,其用制备型TLC(CH2Cl2:MeOH=50:1)纯化,得到化合物10c(62mg,79%收率),为灰色固体。MS 333.1[M+H]+.
室温下向化合物10c(62mg,0.187mmol)的MeOH(10mL)搅拌溶液中,添加NaBH4(21mg,0.560mmol)。然后混合物在室温下搅拌1h。混合物用冰冷的NH4Cl水溶液淬灭并用EtOAc(10mL x 3)萃取。合并的有机层用盐水(10mL)洗涤,无水Na2SO4干燥,过滤并真空浓缩得到残余物,其用制备型TLC(CH2Cl2:MeOH=15:1)纯化,得到化合物10(54mg,87%收率),为黄色固体。1H NMR(非对映异构体的混合物,DMSO-d6,400Hz):δ7.95(s,1H),7.61-7.56(m,2H),7.40-7.36(m,1H),7.30-7.25(m,1H),7.11(s,1H),5.37-5.34(m,1H),4.86(d,J=6.4Hz,1H),3.38-3.31(m,1H),2.11-2.03(m,1H),1.98-1.89(m,3H),1.80-1.73(m,1H),1.69-1.40(m,12H);MS 335.2[M+H]+.
实施例11.制备2-(5H-咪唑并[5,1-a]异吲哚-5-基)-1-(4-吗啉-3-硝基苯基)乙醇(化合物11)
1-(4-氟-3-硝基苯基)乙酮(0.20g,1.09mmol)和吗啉(1.5mL)的混合物在90℃下搅拌3h。反应混合物冷却至室温,倒入2N HCl溶液(10mL)中,并用EtOAc(10mL x 3)萃取。合并的有机层用盐水(10mL)洗涤,无水Na2SO4干燥,过滤并真空浓缩得到残余物,其用石油醚和EtOAc(1:1)溶液研磨。所得固体通过过滤收集并真空干燥得到化合物11b(0.24g,88%收率),为棕色固体,其未经进一步纯化用于下一步。MS 251.2[M+H]+.
室温下向化合物11b(0.18g,0.73mmol)和化合物K1-3(0.30g,0.73mmol)的无水THF(15mL)搅拌混合物中滴加EtONa溶液(21%,EtOH中,0.31g,0.94mmol)。反应混合物室温下搅拌2h并减压浓缩至干。残余物用NH4Cl溶液(5mL)稀释和用EtOAc(10mL x 3)萃取。合并的有机层用盐水(10mL x 2)洗涤,无水Na2SO4干燥,过滤并真空浓缩得到残余物,其溶解于MeOH(15mL)。向这个溶液中添加HOAc(3mL),反应混合物在90℃下搅拌3h。混合物真空浓缩得到残余物,其用饱和NaHCO3溶液(10mL)稀释和用EtOAc(10mL x 3)萃取。合并的有机层用盐水(10mL)洗涤,无水Na2SO4干燥,过滤并真空浓缩得到残余物,其用制备型TLC(CH2Cl2:MeOH=20:1)纯化得到化合物11c(0.15g,52%收率),为黄色固体。MS 405.2[M+H]+.
0℃下向化合物11c(0.15g,0.37mmol)的MeOH(10mL)搅拌溶液中添加NaBH4(0.04g,1.11mmol)。然后混合物在室温下搅拌1h。混合物用冰冷的NH4Cl水溶液(15mL)淬灭和用EtOAc(10mL x 3)萃取。合并的有机层用盐水(10mL x 2)洗涤,无水Na2SO4干燥,过滤并真空浓缩得到残余物,其用制备型TLC(CH2Cl2:MeOH=15:1)纯化,得到两种异构体的化合物11:异构体-1(偏上的点,32.44mg,22%收率),为黄色固体,以及异构体-2(偏下的点,22.30mg,15%收率),为黄色固体。异构体-1:1H NMR(CD3OD,400MHz):δ7.79(s,1H),7.61-7.57(m,2H),7.55(d,J=2.0Hz,1H),7.43-7.39(m,2H),7.37-7.32(m,1H),7.19(d,J=8.4Hz,1H),7.01(s,1H),5.48(t,J=5.2Hz,1H),4.82(dd,J=7.6Hz,J=6.4Hz,1H),3.78(t,J=4.8Hz,4H),3.00(t,J=4.8Hz,4H),2.58-2.41(m,2H);MS 407.1[M+H]+.异构体-2:1HNMR(CD3OD,400MHz):δ8.06(s,1H),7.71(d,J=2.0Hz,1H),7.58(d,J=7.6Hz,1H),7.49(dd,J=8.0Hz,J=1.6Hz,1H),7.40-7.33(m,2H),7.27-7.22(m,2H),7.20(s,1H),5.56(dd,J=8.4Hz,J=3.6Hz,1H),4.93-4.89(m,1H),3.79(t,J=4.8Hz,4H),3.04-2.98(m,4H),2.68-2.59(m,1H),2.14-2.06(m,1H);MS 407.2[M+H]+.
实施例12.制备4-(4-(1-羟基-2-(5H-咪唑并[5,1-a]异吲哚-5-基)乙基)苯基)吗啉-3-酮(化合物12)
室温下向化合物10a(500mg,1.21mmol)和化合物1-(4-溴苯基)乙酮(240mg,1.21mmol)的无水THF(20mL)搅拌混合物中,滴加EtONa溶液(21%,EtOH中,508mg,1.57mmol)。反应混合物室温下搅拌2h并减压浓缩至干。残余物用NH4Cl溶液(20mL)稀释和用EtOAc(20mL x 3)萃取。合并的有机层用盐水(20mL)洗涤,无水Na2SO4干燥,过滤并真空浓缩得到残余物,其溶解于MeOH(16mL)。向这个溶液中添加HOAc(4mL),反应混合物在90℃下搅拌3h。混合物真空浓缩得到残余物,其用NaHCO3饱和溶液(20mL)稀释和用EtOAc(20mL x3)萃取。合并的有机层用盐水(20mL)洗涤,无水Na2SO4干燥,过滤并真空浓缩得到残余物,其用制备型TLC(CH2Cl2:MeOH=50:1)纯化得到化合物12b(220mg,52%收率),为黄色固体。MS353.1[M+H]+,355.1[M+H]+.
0℃下向化合物12b(140mg,0.398mmol)的无水THF(5mL)搅拌溶液中添加NaBH4(23mg,0.596mmol)。混合物在0℃下搅拌2h。混合物用冰冷的NH4Cl水溶液(5mL)淬灭和用EtOAc(5mL x 3)萃取。合并的有机层用盐水(5mL)洗涤,无水Na2SO4干燥,过滤并真空浓缩得到残余物,其用制备型TLC(CH2Cl2:MeOH=20:1)纯化,得到化合物12c(60mg,43%收率),为浅棕色油状物。MS 355.0[M+H]+,357.0[M+H]+.
化合物12c(60mg,0.169mmol),吗啉-3-酮(17mg,0.169mmol),N1,N2-二甲基乙烷-1,2-二胺(6mg,0.068mmol),CuI(13mg,0.068mmol)和K2CO3(47mg,0.338mmol)的1,4-二氧六环(1.2mL)混合物,在氩气下100℃下搅拌16h。过滤反应混合物并真空浓缩滤液得到残余物,其用制备型TLC(DCM:MeOH=15:1,含有0.08%氨水溶液(28%w/w))纯化和然后用制备型TLC(丙酮:CH3CN=40:1)纯化,得到化合物12(4.96mg,8%收率),为浅黄色固体。1H NMR(非对映异构体的混合物,CD3OD,400Hz):δ8.05和7.85(两个s,1H),7.62-7.58(m,1H),7.50-7.23(m,7H),7.19和7.09(两个s,1H),5.57-5.52和5.48-5.43(两个m,1H),5.05-4.97(m,1H),4.27(s,2H),4.09-4.01(m,2H),3.79-3.73(m,2H),2.62-2.53,2.45-2.37和2.03-1.94(三个m,2H);MS 376.2[M+H]+.
实施例13.制备(1-(5H-咪唑并[5,1-a]异吲哚-5-基)环丙基)(环己基)甲醇(化合物13)
-78℃下在氮气下向13a(52mg,0.363mmol)的无水THF(5mL)溶液中滴加LDA(2M,THF中,0.2mL,0.40mmol)。反应混合物在-78℃下搅拌1h,滴加10a(100mg,0.242mmol)的无水THF(1mL)溶液。所得反应混合物缓慢升温至室温并继续搅拌3h。反应混合物用水淬灭并用EtOAc(5mL x 3)萃取。合并的有机层用盐水(10mL)洗涤,无水Na2SO4干燥,过滤并真空浓缩得到残余物,其用制备型TLC(石油醚:EtOAc=4:1)纯化得到化合物13b(70mg,52%收率),为白色固体。1H NMR(CD3OD,400MHz):δ7.62-7.55(m,3H),7.45-7.36(m,9H),7.32-7.20(m,8H),7.15(s,1H),5.65(s,1H),1.15(s,9H),1.01-0.87(m,3H),0.54-0.47(m,1H);MS557.3[M+H]+.
60℃下化合物13b(300mg,0.539mmol),甲磺酰氯(123mg,1.079mmol)和TEA(218mg,2.158mmol)的1,2-二氯乙烷(5mL)混合物搅拌16h。反应混合物用水(10mL)淬灭和用EtOAc(5mL x 3)萃取。合并的有机层用盐水(10mL)洗涤,无水Na2SO4干燥,过滤并真空浓缩得到残余物,其用制备型TLC(CH2Cl2:MeOH=15:1)纯化,得到化合物13c(75mg,47%收率),为浅黄色固体。1H NMR(CD3OD,400MHz):δ8.01(br s,1H),7.61(d,J=7.6Hz,1H),7.51(d,J=7.6Hz,1H),7.45-7.39(m,1H),7.35-7.29(m,1H),7.22(br s,1H),4.95(br s,1H),1.50-1.25(m,4H),0.98(s,9H);MS 297.1[M+H]+.
13c(30mg,0.101mmol)的无水THF(3mL)溶液冷却至-78℃。DIBAL-H(1M,甲苯中,0.3mL,0.303mmol)滴加至混合物中。反应混合物在-78℃下搅拌2h。反应混合物-78℃下用MeOH(0.1mL)和酒石酸钾钠饱和溶液(3mL)淬灭,然后用EtOAc(3mL x 3)萃取。合并的有机层用盐水(3mL)洗涤,无水Na2SO4干燥,过滤并真空浓缩得到粗化合物13d(20mg,87%收率),为浅黄色固体,其未经进一步纯化用于下一步。MS 227.2[M+H]+.
化合物13d(20mg,0.088mmol),戴斯马丁氧化剂(Dess Martin periodinane)(37mg,0.088mmol)的CH2Cl2(1mL)混合物室温下搅拌1h。反应混合物直接用制备型TLC(CH2Cl2:MeOH=15:1)纯化得到化合物13e(20mg,99%收率),为白色固体。1H NMR(CDCl3,400MHz):δ8.81(s,1H),7.76(s,1H),7.55(d,J=7.2Hz,1H),7.44-7.37(m,1H),7.31-7.22(m,2H),7.20(s,1H),5.74(s,1H),1.46-1.33(m,3H),0.85-0.76(m,1H);MS 225.2[M+H]+.
0℃下向13e(20mg,0.0.088mmol)的无水THF(3mL)搅拌溶液中缓慢添加环己基溴化镁(1M,THF中,0.35mL,0.358mmol)。混合物在室温下搅拌1h。反应混合物用NH4Cl饱和溶液(3mL)淬灭和用EtOAc(3mL x 3)萃取。合并的有机层用盐水(5mL)洗涤,无水Na2SO4干燥,过滤并真空浓缩得到残余物,其用制备型TLC(CH2Cl2:MeOH=15:1)纯化,得到化合物13(5.53mg,20%收率),为浅棕色固体。1H NMR(非对映异构体的混合物,CD3OD,400MHz):δ8.12和7.99(两个s,1H),7.62-7.57(m,1.2H),7.47-7.28(m,2.8H),7.17和7.13(两个s,1H),5.29和4.93(两个s,1H),3.10和2.78(两个d,J=7.6Hz,4.0Hz,1H),2.00-1.96(m,0.8H),1.80-1.44(m,4.2H),1.30-0.63(m,10H);MS 309.3[M+H]+.
实施例14.制备(1s,3r,5R,7S)-3-(1-羟基-2-(5H-咪唑并[5,1-a]异吲哚-5-基)乙基)金钢烷-1-醇(化合物14f)和(1R,3S,5r,7r)-5-(1-羟基-2-(5H-咪唑并[5,1-a]异吲哚-5-基)乙基)金钢烷-1,3-二醇(化合物14g)
10b(210mg,1.180mmol),2-羟基异吲哚啉-1,3-二酮(38mg,0.233mmol),双(乙酰丙酮根)合钴(30mg,0.117mmol)的HOAc(5mL)混合物在氧气气氛下75℃下搅拌6h。反应混合物减压浓缩至干。残余物用EtOAc(10mL)稀释,滤除不溶固体。真空浓缩滤液得到14b和14c的粗混合物(160mg),为浅棕色油状物,其未经进一步纯化用于下一步。
室温下向化合物10a(150mg,0.362mmol)和化合物14b和14c(70mg,0.362mmol)的无水THF(10mL)搅拌混合物中滴加EtONa溶液(21%,EtOH中,152mg,0.471mmol)。反应混合物室温下搅拌1.5h。混合物减压浓缩至干后,残余物用NH4Cl溶液(10mL)稀释和用EtOAc(10mL x 3)萃取。合并的有机层用盐水(10mL)洗涤,无水Na2SO4干燥,过滤并真空浓缩得到残余物,其溶解于MeOH(8mL)。向这个溶液中添加HOAc(2mL),反应混合物在60℃下搅拌2h。混合物真空浓缩得到残余物,其用NaHCO3饱和溶液(10mL)稀释和用EtOAc(10mL x 3)萃取。合并的有机层用盐水(10mL)洗涤,无水Na2SO4干燥,过滤并真空浓缩得到残余物,其用制备型TLC(EtOAc)纯化,得到化合物14d(70mg,55%收率),MS 349.2[M+H]+和14e(40mg,31%收率),为浅黄色固体,MS实测365.2[M+H]+.
0℃下向化合物14d(66mg,0.189mmol)的无水THF(5mL)搅拌溶液中添加NaBH4(22mg,0.567mmol)。然后搅拌混合物并2h内升温至室温。混合物用冰冷的NH4Cl水溶液(5mL)淬灭和用EtOAc(5mL x 3)萃取。合并的有机层用盐水(5mL)洗涤,无水Na2SO4干燥,过滤并真空浓缩得到残余物,其用制备型TLC(CH2Cl2:MeOH=20:1)纯化得到化合物14f(23.6mg,36%收率),为浅黄色固体。1H NMR(非对映异构体的混合物,DMSO-d6,400MHz,):δ7.95和7.92(两个s,1H),7.60(d,J=7.6Hz,1H),7.57(d,J=7.6Hz,1H),7.38(dd,J=7.6Hz,7.2Hz,1H),7.27(dd,J=7.6Hz,7.6Hz,1H),7.14和7.11(两个s,1H),5.41-5.33(m,1H),4.97和4.92(两个d,J=6.4Hz和J=6.4Hz,1H),4.31(s,1H),3.44-3.38(m,1H),2.17-2.02(m,3H),1.79-1.71(m,1H),1.55-1.31(m,12H);MS 351.2[M+H]+.
通过沃特斯制备型SFC-80在以下条件下分离14f得到四个对映体化合物14f-1,14f-2,14f-3和14f-4:CHIRALCEL OD柱,30x 250mm,5μm;流动相:溶剂A为CO2,共溶剂B为含有0.1%DEA的15%MeOH;检测波长:272nm;柱温:35℃。分析手性SFC条件:CHIRALCEL OD柱,4.6x 100mm,3μm;流动相:溶剂A为CO2,共溶剂B为含有0.1%DEA的18%MeOH;检测波长:270nm;柱温:35℃。化合物14f-1:MS 351.2[M+H]+,RT=3.23min.化合物14f-2:MS 351.2[M+H]+,RT=3.76min.化合物14f-3:1H NMR(CDCl3,400MHz):δ7.82(s,1H),7.55(d,J=7.6Hz,1H),7.42(d,J=7.6Hz,1H),7.38(dd,J=7.6Hz,7.6Hz,1H),7.25(dd,J=7.2Hz,7.2Hz,1H),7.18(s,1H),5.36(t,J=5.6Hz,1H),3.46-3.41(m,1H),2.24(br s,2H),2.16-2.10(m,2H),1.74-1.40(m,12H);MS 351.2[M+H]+,RT=4.14min.化合物14f-4:1H NMR(CDCl3,400MHz):δ7.83(s,1H),7.55(d,J=8.0Hz,1H),7.42(d,J=7.6Hz,1H),7.38(dd,J=7.6Hz,7.6Hz,1H),7.25(dd,J=8.0Hz,8.0Hz,1H),7.18(s,1H),5.36(t,J=5.6Hz,1H),3.46-3.40(m,1H),2.24(br s,2H),2.17-2.10(m,2H),1.74-1.40(m,12H);MS 351.2[M+H]+,RT=4.72min.
0℃下向化合物14e(40mg,0.110mmol)的无水THF(5mL)搅拌溶液中添加NaBH4(13mg,0.330mmol)。混合物升温至室温并搅拌2h。混合物用冰冷的NH4Cl水溶液(5mL)淬灭和用EtOAc(5mL x 3)萃取。合并的有机层用盐水(5mL)洗涤,无水Na2SO4干燥,过滤并真空浓缩得到残余物,其用制备型TLC(CH2Cl2:MeOH=15:1)纯化得到化合物14g(21.9mg,54%收率),为浅黄色固体。1H NMR(非对映异构体的混合物,DMSO-d6,400MHz):δ7.95和7.93(两个s,1H),7.60(d,J=7.6Hz,1H),7.57(d,J=7.6Hz,1H),7.38(dd,J=7.6Hz,7.2Hz,1H),7.27(ddd,J=7.6Hz,7.6Hz,0.8Hz,1H),7.14和7.12(两个s,1H),5.42-5.33(m,1H),5.02和4.98(两个d,J=6.4Hz和J=6.4Hz,1H),4.41(s,2H),3.50-3.43(m,1H),2.14(s,1H),2.10-2.00(m,1H),1.78-1.72(m,1H),1.48-1.17(m,12H);MS367.3[M+H]+.
实施例15.制备(1s,3r,5R,7S)-3-(2-(6-氟-5H-咪唑并[5,1-a]异吲哚-5-基)-1-羟基乙基)金钢烷-1-醇(化合物15d)和1-((3r,5r,7r)-金钢烷-1-基)-2-(6-氟-5H-咪唑并[5,1-a]异吲哚-5-基)乙醇(化合物15e)
10b(200mg,1.124mmol),2-羟基异吲哚啉-1,3-二酮(73mg,0.449mmol),双(乙酰丙酮根)合钴(58mg,0.225mmol)的HOAc(5mL)混合物在O2气氛中在75℃下搅拌6h。反应混合物减压浓缩。残余物用EtOAc(20mL)稀释并过滤混合物。真空浓缩滤液得到10b和14b的粗混合物(140mg),为浅黄色油状物,其未经进一步纯化用于下一步。
室温下向化合物15a(97mg,0.224mmol)和化合物14b和10b(43mg,0.224mmol)的无水THF(10mL)搅拌混合物中,滴加EtONa溶液(21%,EtOH中,94mg,0.291mmol)。反应混合物室温下搅拌0.5h。混合物减压浓缩至干,残余物用NH4Cl溶液稀释并用EtOAc(10mL x 3)萃取。合并的有机层用盐水(10mL)洗涤,无水Na2SO4干燥,过滤并真空浓缩得到残余物,其溶解于MeOH(15mL)。向这个溶液中添加HOAc(3mL),反应混合物在60℃下搅拌1.5h。混合物真空浓缩得到残余物,其溶解于NaHCO3饱和溶液并用EtOAc(10mL x 3)萃取。合并的有机层用盐水(10mL)洗涤,无水Na2SO4干燥,过滤并真空浓缩得到残余物,其用制备型TLC(EtOAc)纯化得到化合物15b(27mg,33%收率)(MS实测:367.2[M+H]+)以及15c(18mg,22%收率),为白色固体,MS实测:351.2[M+H]+.
0℃下向化合物15b(27mg,0.074mmol)的无水THF(5mL)搅拌溶液中添加NaBH4(8.4mg,0.221mmol)。混合物升温至室温并搅拌2.5h。混合物用冰冷的NH4Cl水溶液(10mL)淬灭和用EtOAc(5mL x 3)萃取。合并的有机层用盐水(10mL)洗涤,无水Na2SO4干燥,过滤并真空浓缩得到残余物,其用制备型TLC(EtOAc)纯化得到化合物15d(6mg,22%收率),为白色固体。1H NMR(非对映异构体的混合物,CD3OD,400MHz):δ8.01(s,1H),7.47-7.38(m,2H),7.16(s,1H),7.07-6.98(m,1H),5.56(t,J=4.8Hz,1H),3.20(d,J=10.0Hz,1H),2.51-2.43(m,1H),2.17(s,2H),2.04-1.94(m,1H),1.72-1.52(m,6H),1.50-1.40(m,6H),MS 369.2[M+H]+.
0℃下向化合物15c(18mg,0.051mmol)的THF(5mL)搅拌溶液中添加NaBH4(5.9mg,0.154mmol)。混合物升温至室温并搅拌2h。混合物用冰冷的NH4Cl水溶液(10mL)淬灭和用EtOAc(5mL x 3)萃取。合并的有机层用盐水(10mL)洗涤,无水Na2SO4干燥,过滤并真空浓缩得到残余物,其用制备型TLC(EtOAc)纯化得到化合物15e(6.8mg,38%收率),为白色固体。1H NMR(非对映异构体的混合物,DMSO-d6,400MHz):δ7.95(s,1H),7.44-7.38(m,2H),7.15(s,1H),7.10-7.04(m,1H),5.55(t,J=4.8Hz,1H),4.54(d,J=6.4Hz,1H),3.04-2.98(m,,1H),2.38-2.31(m,1H),1.91(s,3H),1.87-1.77(m,1H),1.68-1.40(m,12H);MS 353.2[M+H]+.
对映体化合物15d-1,15d-2,15d-3和15d-4通过在沃特斯制备型SFC-80上采用如下条件分离15d获得:CHIRALPAK AD柱,大赛璐(Daicel),30x 250mm,5μm;流动相:溶剂A为CO2,共溶剂B为含有0.1%DEA的30%EtOH;检测波长:273nm;柱温:35℃。分析手性SFC条件:CHIRALPAK AD柱,大赛璐,4.6x 100mm,3μm;流动相:溶剂A为CO2,共溶剂B为含有0.1%DEA的30%EtOH;检测波长:273nm;柱温:35℃。化合物15d-1:1H NMR(CDCl3,400MHz):δ7.85(s,1H),7.40-7.30(m,2H),7.21(s,1H),6.95(dd,J=8.4Hz,8.4Hz,1H),5.64(d,J=8.4Hz,1H),3.49(d,J=11.6Hz,1H),2.50-2.40(m,1H),2.25(br s,2H),1.80-1.39(m,13H);MS369.2[M+H]+;RT=3.95min.化合物15d-2:1H NMR(CDCl3,400MHz):δ7.86(s,1H),7.38-7.30(m,2H),7.19(s,1H),6.96-6.91(m,1H),5.47(t,J=4.4Hz,1H),3.34(d,J=10.0Hz,1H),2.41-2.35(m,1H),2.24(brs,2H),2.13-2.05(m,1H),1.71-1.40(m,12H);MS 369.2[M+H]+;RT=4.42min.化合物15d-3:1H NMR(CDCl3,400MHz):δ7.86(s,1H),7.38-7.30(m,2H),7.18(s,1H),6.96-6.91(m,1H),5.47(t,J=4.8Hz,1H),3.34(d,J=9.6Hz,1H),2.42-2.35(m,1H),2.24(brs,2H),2.13-2.05(m,1H),1.71-1.40(m,12H);MS 369.2[M+H]+;RT=5.07min.化合物15d-4:1H NMR(CDCl3,400MHz):δ7.87(s,1H),7.40-7.30(m,2H),7.21(s,1H),6.95(dd,J=8.8Hz,8.4Hz,1H),5.64(d,J=8.4Hz,1H),3.49(d,J=11.2Hz,1H),2.50-2.40(m,1H),2.24(br s,2H),1.80-1.39(m,13H);MS 369.2[M+H]+;RT=6.18min.
实施例16.制备4-(2-(6-氟-5H-咪唑并[5,1-a]异吲哚-5-基)-1-羟基乙基)双环[2.2.2]辛-1-醇(化合物16)
向化合物16a(1.2g,7.05mmol)和K2CO3(1.5g,10.85mmol)的DMF(20mL)混合物中经5min滴加MeI(1.5g,10.57mmol)。混合物在室温下搅拌过夜,用水(20mL)淬灭和用EtOAc(30mL x 3)萃取。合并的有机层用盐水(30mL)洗涤,无水Na2SO4干燥,过滤并真空浓缩得到粗化合物16b(1.2g,92%收率),为黄色固体,其未经进一步纯化用于下一步。1H NMR(DMSO-d6,400MHz):δ4.34(s,1H),3.55(s,3H),1.81-1.75(m,6H),1.53-1.48(m,6H).
向化合物16b(1.2g,6.51mmol)和2,6-二甲基吡啶(2.1g,19.60mmol)的DMF(15mL)混合物中添加TBSOTf(5.2g,19.67mmol)。混合物在室温下搅拌过夜,用水(20mL)淬灭和用EtOAc(30mL x 3)萃取。合并的有机层用盐水(30mL)洗涤,无水Na2SO4干燥,过滤并真空浓缩得到残余物,其用柱色谱法(石油醚:EtOAc=50:1)纯化得到化合物16c(1.5g,77%收率),为黄色油状物。1H NMR(CDCl3,400MHz):δ3.62(s,3H),1.90-1.85(m,6H),1.68-1.62(m,6H),0.82(s,9H),0.04(s,6H).
-78℃下向甲基膦酸二甲酯(209mg,1.68mmol)的THF(6mL)溶液中滴加n-BuLi(2.5M,己烷中,0.84mL,2.10mmol),然后混合物在-78℃下搅拌40min。-78℃下向所得混合物中添加化合物16c(250mg,0.84mmol)的THF(1mL)溶液。混合物在-78℃下搅拌2h,然后用NH4Cl水溶液(10mL)淬灭和用EtOAc(20mL x 3)萃取。合并的有机层用盐水(20mL)洗涤,无水Na2SO4干燥,过滤并真空浓缩得到粗化合物16d(300mg,92%收率),为黄色油状物,其未经进一步纯化用于下一步。1H NMR(CDCl3,400MHz):δ3.79(s,3H),3.77(s,3H),3.14(s,1H),3.08(s,1H),1.87-1.81(m,6H),1.71-1.65(m,6H),0.83(s,9H),0.04(s,6H).
0℃下向化合物16d(300mg,0.77mmol)的THF(6mL)溶液中添加NaH(60%,矿物油中,62mg,1.55mmol)。然后混合物在室温下搅拌20min。向上述混合物中经5min缓慢添加化合物K-3-2(332mg,0.77mmol),并且混合物的温度维持在5℃下。混合物在室温下搅拌过夜,用冰NH4Cl水溶液(20mL)淬灭和用EtOAc(25mL x 3)萃取。合并的有机层用盐水(20mL)洗涤,无水Na2SO4干燥,过滤并真空浓缩得到残余物,其用柱色谱法(石油醚:EtOAc=8:1)纯化,得到化合物16e(400mg,74%收率),为黄色固体。1H NMR(CDCl3,400MHz):δ7.72(d,J=12.0Hz,1H),7.57(d,J=8.0Hz,1H),7.50(s,1H),7.39-7.26(m,10H),7.20-7.16(m,6H),7.10-6.97(m,2H),6.88(s,1H).1.84-1.78(m,6H),1.71-1.65(m,6H),0.83(s,9H),0.06(s,6H).
化合物16e(400mg,0.57mmol)的MeOH(10mL)和AcOH(2.5mL)溶液在60℃下搅拌2h。反应混合物冷却至室温,真空浓缩至干。残余物用Na2CO3水溶液(30mL)稀释和用EtOAc(30mLx 3)萃取。合并的有机层用盐水(30mL)洗涤,无水Na2SO4干燥,过滤并真空浓缩得到残余物,其用柱色谱法(石油醚:EtOAc=8:1)纯化,得到粗化合物16f(220mg,84%收率),为黄色固体。MS 455.2[M+H]+.
化合物16f(172mg,0.375mmol)的CH2Cl2(4mL)和TFA(1mL)混合物在室温下搅拌过夜。反应混合物冷却至室温,真空浓缩除去溶剂。残余物用Na2CO3水溶液(20mL)稀释和用EtOAc(20mL x 3)萃取。合并的有机层用盐水(20mL)洗涤,无水Na2SO4干燥,过滤并真空浓缩得到残余物,其用制备型TLC(CH2Cl2/MeOH=15/1)纯化得到化合物16g(75mg,59%收率),为黄色固体。1H NMR(CDCl3,400MHz):δ7.55(s,1H),7.40-7.28(m,2H),7.18(s,1H),6.94(dd,J=9.2Hz,8.4Hz,1H),5.74(d,J=9.6Hz,1H),3.49(s,1H),3.43(dd,J=18.8Hz,2.0Hz,1H),2.80(dd,J=18.4Hz,10.4Hz,1H),1.91-1.82(m,6H),1.72-1.66(m,6H);MS 341.2[M+H]+.
0℃下向化合物16g(46mg,0.135mmol)的MeOH(3mL)溶液中添加NaBH4(16mg,0.423mmol)。混合物在0℃下搅拌8min。用NH4Cl水溶液(10mL)淬灭和用EtOAc(10mL x 3)萃取。合并的有机层用洗涤盐水(10mL),无水Na2SO4干燥,过滤并真空浓缩得到残余物,其用制备型TLC(CH2Cl2:MeOH=10:1)纯化,得到化合物16(34mg,73%收率),为白色固体。1H NMR(DMSO-d6,400MHz):δ7.97和7.95(两个s,1H),7.47-7.37(m,2H),7.21和7.17(两个s,1H),7.13-7.04(m,1H),5.63-5.57和5.55-5.50(两个m,1H),4.95和4.51(两个d,J=6.4Hz,1H),4.17(s,1H),3.18-3.08(m,1H),2.35-2.20(m,1H),1.83-1.73(m,1H),1.50-1.31(m,12H);MS 343.2[M+H]+.
四个对映体化合物16-1,16-2,16-3和16-4在沃特斯制备型SFC-80上通过如下条件分离化合物16获得:CHIRALCEL OJ柱,大赛璐,30x 250mm,5μm;流动相:溶剂A为CO2,共溶剂B为含有0.1%DEA的15%EtOH;检测波长:272nm;柱温:35℃。分析手性SFC条件:CHIRALCEL OJ柱,大赛璐,4.6x 100mm,3μm;流动相:溶剂A为CO2,共溶剂B为含有0.1%DEA的20%EtOH;检测波长:273nm;柱温:35℃。化合物16-1:1H NMR(CDCl3,400MHz):δ7.82(s,1H),7.38-7.29(m,2H),7.20(s,1H),6.95-6.90(m,1H),5.61(d,J=8.8Hz,1H),3.53(d,J=10.8Hz,1H),2.43-2.33(m,1H),2.10-1.97(m,1H),1.74-1.45(m,12H);MS343.2[M+H]+;RT=2.16min.化合物16-2:1H NMR(CDCl3,400MHz):δ7.83(s,1H),7.37-7.29(m,2H),7.18(s,1H),6.96-6.90(m,1H),5.44(t,J=4.8Hz,1H),3.41(d,J=10.4Hz,1H),2.35-2.27(m,1H),2.06-1.97(m,1H),1.74-1.43(m,12H);MS 343.2[M+H]+;RT=2.89min.化合物16-3:1H NMR(CDCl3,400MHz):δ7.86(s,1H),7.39-7.29(m,2H),7.18(s,1H),6.95-6.90(m,1H),5.44(t,J=4.8Hz,1H),3.42(d,J=9.6Hz,1H),2.35-2.27(m,1H),2.06-1.97(m,1H),1.76-1.43(m,12H);MS 343.2[M+H]+;RT=3.31min.化合物16-4:1H NMR(CDCl3,400MHz):δ7.82(s,1H),7.39-7.30(m,2H),7.20(s,1H),6.94(dd,J=9.2Hz,8.4Hz,1H),5.61(d,J=8.4Hz,1H),3.53(d,J=10.8Hz,1H),2.43-2.33(m,1H),2.10-1.97(m,1H),1.73-1.46(m,12H);MS343.2[M+H]+;RT=4.46min.
实施例17.制备(1R,2s,3S,5s,7s)-5-(2-(6-氟-5H-咪唑并[5,1-a]异吲哚-5-基)-1-羟基乙基)金钢烷-2-醇(化合物17)
con.=浓缩的
室温下向化合物17a(1.0g,5.15mmol)和K2CO3(1.1g,7.96mmol)的DMF(10mL)混合物添加MeI(1.1g,7.75mmol)。混合物在室温下搅拌过夜,用水(30mL)稀释和用EtOAc(30mLx 3)萃取。合并的有机层用盐水(30mL)洗涤,无水Na2SO4干燥,过滤并真空浓缩得到化合物17b(1.05g,98%收率),为黄色固体,其未经进一步纯化用于下一步。1H NMR(CDCl3,400MHz):δ3.69(s,3H),2.64-2.55(m,2H),2.25-2.16(m,5H),2.15-1.93(m,
6H).
室温下向化合物17b(400mg,1.92mmol)和乙二醇(653mg,10.52mmol)的甲苯(6mL)混合物中添加硫酸(38mg,0.38mmol)。混合物在105℃下搅拌2h,冷却至室温,用Na2CO3水溶液(20mL)淬灭和用EtOAc(20mL x 3)萃取。合并的有机层用盐水(20mL)洗涤,无水Na2SO4干燥,过滤并真空浓缩得到化合物17c(390mg,81%收率),为黄色油状物,其未经进一步纯化用于下一步。1H NMR(CDCl3,400MHz):δ3.95(s,4H),3.64(s,3H),2.21-2.14(m,2H),2.00-1.95(m,3H),1.90-1.78(m,6H),1.66-1.59(m,2H).
-78℃下向甲基膦酸二甲酯(385mg,3.10mmol)的THF(6mL)溶液中滴加n-BuLi(2.5M,己烷中,1.6mL,4.00mmol),然后混合物在-78℃下搅拌40min。-78℃下向上述混合物中添加化合物17c(390mg,1.55mmol)的THF(1mL)溶液。然后混合物在-78℃下搅拌2h,然后用NH4Cl水溶液(20mL)淬灭和用EtOAc(20mL x 3)萃取。合并的有机层用盐水(20mL)洗涤,无水Na2SO4干燥,过滤并真空浓缩得到粗化合物17d(430mg,81%收率),为黄色油状物,其未经进一步纯化用于下一步。1H NMR(CDCl3,400MHz):δ3.98-3.92(m,4H),3.80(s,3H),3.78(s,3H),3.80(s,3H),3.18(s,1H),3.12(s,1H),2.17-2.09(m,2H),2.03-1.59(m,11H).
0℃下向化合物17d(400mg,1.16mmol)的THF(10mL)溶液中添加NaH(60%,矿物油中,93mg,2.33mmol)。混合物在室温下搅拌20min。向上述混合物中经5min缓慢添加化合物15a(501mg,1.16mmol),并且混合物的温度维持在5℃下。混合物在室温下搅拌过夜,用冰NH4Cl水溶液(20mL)淬灭和用EtOAc(30mL x 3)萃取。合并的有机层用盐水(30mL)洗涤,无水Na2SO4干燥,过滤并真空浓缩得到残余物,其用柱色谱法(CH2Cl2:EtOAc=6:1)纯化,得到化合物17e(600mg,79%收率),为灰色固体。1H NMR(CDCl3,400MHz):δ7.74和7.70(两个s,1H),7.61(d,J=8.0Hz,1H),7.51(d,J=1.2Hz,1H),7.39-7.30(m,10H),7.24-7.15(m,7H),7.05-6.98(m,1H),6.91-6.86(m,1H),3.97(s,4H),2.15-2.10(m,2H),2.02-1.97(m,3H),1.93-1.88(m,2H),1.79-1.75(m,2H),1.73-1.60(m,4H).
化合物17e(350mg,0.54mmol)的MeOH:AcOH(10mL:2.5mL)溶液在60℃下搅拌2h,然后混合物真空浓缩至干。残余物用Na2CO3水溶液(30mL)稀释和用EtOAc(30mL x 3)萃取。合并的有机层用盐水(30mL)洗涤,无水Na2SO4干燥,过滤并真空浓缩得到粗化合物17f(190mg,87%收率),为黄色固体,其未经进一步纯化用于下一步。MS 409.3[M+H]+.
向化合物17f(100mg,0.24mmol)的THF(3mL)溶液中添加2N HCl(3mL)。混合物在室温下搅拌过夜和真空浓缩至干。残余物用Na2CO3水溶液(20mL)稀释和用EtOAc(15mL x 3)萃取。合并的有机层用盐水(20mL)洗涤,无水Na2SO4干燥,过滤并真空浓缩得到残余物,其用制备型TLC(CH2Cl2:MeOH=20:1)纯化得到化合物17g(75mg,88%收率),为黄色固体。1H NMR(CDCl3,400MHz):δ7.57(s,1H),7.42-7.31(m,2H),7.19(s,1H),6.94(ddd,J=8.8Hz,8.8Hz,0.8Hz,1H),5.77(d,J=9.6Hz,1H),3.52-3.44(m,1H),2.85(dd,J=18.4Hz,10.6Hz,1H),2.66-2.62(m,2H),2.26-2.22(m,1H),2.20-2.14(m,4H),2.06-1.98(m,6H).MS 365.3[M+H]+.
0℃向化合物17g(75mg,0.21mmol)的THF(2mL)溶液中分批添加NaBH4(47mg,1.24mmol)。然后混合物在0℃下搅拌1h,用NH4Cl水溶液(10mL)淬灭和用EtOAc(10mL x 3)萃取。合并的有机层用盐水(20mL)洗涤,无水Na2SO4干燥,过滤并真空浓缩得到残余物,其用制备型TLC(CH2Cl2:MeOH=10:1)纯化得到化合物17(30mg,38%收率),为白色固体。1H NMR(DMSO-d6,400MHz):δ7.94(s,1H),7.51-7.36(m,2H),7.20和7.15(两个s,1H),7.11-7.02(m,1H),5.64-5.62和5.56-5.50(两个m,1H),4.99,4.92和4.56(三个d,J=6.0Hz,1H),4.53-4.42(m,1H),3.59-3.53(m,1H),3.06-2.96(m,1H),2.36-2.30(m,1H),2.04-1.95(m,1H),1.86-1.70(m,5H),1.65-1.30(m,6H),1.27-1.20(m,1H),1.18-1.08(m,1H);MS 369.2[M+H]+.
实施例18.制备(1s,3R,5S,7s)-4-(2-(6-氟-5H-咪唑并[5,1-a]异吲哚-5-基)-1-羟基乙基)金钢烷-1-醇(化合物18k-1,18k-2)
向化合物18a(2.5g,15.04mmol)和甲苯磺酰甲基异氰化物(3.8g,19.46mmol)的DME/EtOH(125mL/4mL)混合物中分批添加t-BuOK(4.2g,37.43mmol),维持温度在10℃下。混合物在室温下搅拌30min并在40℃搅拌2h。过滤反应混合物,滤液真空浓缩得到残余物,其用快速柱色谱法(石油醚/EtOAc=3/1)纯化,得到化合物18c-1(1.1g,41%收率),为灰色固体,以及化合物18c-2(970mg,36%收率),为灰色固体。化合物18c-1:1H NMR(DMSO-d6,400MHz):δ4.63(s,1H),3.02-2.98(m,1H),2.29-2.23(m,2H),2.05-1.99(m,1H),1.87-1.81(m,2H),1.59-1.50(m,8H).化合物18c-2:1H NMR(400MHz,DMSO-d6):δ4.57(s,1H),3.04-2.99(m,1H),2.27-2.20(m,2H),2.11-2.07(m,1H),1.83-1.75(m,2H),1.65-1.55(m,6H),1.55-1.49(m,2H).
向化合物18c-1(1.1g,6.21mmol)的水(22mL)溶液中添加NaOH(992mg,24.80mmol)。然后混合物在100℃下搅拌过夜。混合物冷却至室温,并用3N盐酸酸化至pH=3。混合物用EtOAc(20mL x 4)萃取。合并的有机层真空浓缩,得到粗化合物18d(1.0g,82%收率),为黄色固体,其未经进一步纯化用于下一步。
向化合物18d(1.0g,5.10mmol)和K2CO3(1.1g,7.96mmol)的DMF(15mL)混合物中经5min滴加碘甲烷(1.1g,7.75mmol)。然后混合物在室温下搅拌过夜。混合物用水淬灭并用EtOAc(30mL x 3)萃取。合并的有机层用盐水洗涤,Na2SO4干燥,过滤并浓缩得到粗化合物18e(700mg,65%收率),为黄色固体,其未经进一步纯化用于下一步。1H NMR(DMSO-d6,400MHz):δ4.44,4.38(2s,1H),3.61(s,3H),2.59-2.32(m,3H),2.07-1.93(m,1H),1.63-1.45(m,8H),1.43-1.34(m,2H).
向化合物18e(700mg,3.33mmol)和2,6-二甲基吡啶(1.1g,10.27mmol)的DMF(15mL)混合物中滴加三氟甲磺酸叔丁基二甲基甲硅烷基酯(2.6g,9.84mmol)。然后混合物在室温下搅拌过夜。混合物用水淬灭并用EtOAc(20mL x 3)萃取。合并的有机层用盐水洗涤,无水Na2SO4干燥,过滤并浓缩得到残余物,其用快速柱色谱法(石油醚/EtOAc=60/1)纯化得到化合物18f(1.0g,93%收率),为黄色油状物。1H NMR(DMSO-d6,400MHz):δ3.62(s,3H),2.63-2.50(m,1H),2.46-2.36(m,2H),2.10-1.98(m,1H),1.77-1.51(m,9H),1.44-1.39(m,1H),0.83,0.81(两个s,9H),0.08,0.05(两个s,6H).
-78℃下向甲基膦酸二甲酯(305mg,2.46mmol)的THF(5mL)溶液中滴加n-BuLi(2.5M,己烷中,1.23mL,3.08mmol),然后混合物在-78℃下搅拌40min。在-78℃下向所得混合物中添加化合物18f(400mg,1.23mmol)的THF(1mL)溶液。然后混合物在-78℃下搅拌2h。反应混合物用NH4Cl水溶液淬灭并用EtOAc(20mL x 3)萃取。合并的有机层用盐水(20mL)洗涤,无水Na2SO4干燥,过滤并真空浓缩得到粗化合物18g(400mg,78%收率),为黄色油状物,其未经进一步纯化用于下一步。1H NMR(DMSO-d6,400MHz):δ3.66,3.62(两个s,6H),3.40-3.29(m,2H),2.69-2.63,2.57-2.55(两个m,1H),2.50-2.42(m,2H),2.10-1.97(m,1H),1.76-1.50(m,9H),1.47-1.41(m,1H),0.83,0.82(两个s,9H),0.08,0.05(两个s,6H).
0℃下向化合物18g(300mg,0.72mmol)的THF(6mL)溶液中添加NaH(60%,矿物油中,60mg,1.50mmol)。然后混合物在室温下搅拌20min。向所得混合物中经5min缓慢添加化合物15a(311mg,0.72mmol),不允许混合物的温度上升至5℃以上。然后混合物在室温下搅拌2h。混合物用冰NH4Cl水溶液(10mL)淬灭和用EtOAc(25mL x 3)萃取。合并的有机层用盐水(20mL)洗涤,无水Na2SO4干燥,过滤并真空浓缩得到粗化合物18h,为黄色固体,其未经进一步纯化用于下一步。
粗化合物18h的MeOH/AcOH(12mL/3mL)溶液在60℃下搅拌2h。减压除去溶剂。残余物用Na2CO3水溶液(10mL)稀释和用EtOAc(25mL x 3)萃取。合并的有机层用盐水(20mL)洗涤,无水Na2SO4干燥,过滤并真空浓缩得到残余物,其用快速柱色谱法(石油醚/EtOAc=6/1)纯化得到化合物18i(190mg,55%两步收率),为黄色固体。MS 481.3[M+H]+.
化合物18i(190mg,0.40mmol)的CH2Cl2/TFA(4mL/1mL)混合物,在室温下搅拌2h。减压除去溶剂。残余物用Na2CO3水溶液(20mL)稀释和用EtOAc(20mL x 3)萃取。合并的有机层用盐水(20mL)洗涤,无水Na2SO4干燥,过滤并真空浓缩得到化合物18j(140mg,95.5%收率)。80mg的18j用制备型HPLC纯化,得到两个位置异构体化合物18j-1(10mg,为黄色固体)以及化合物18j-2(12mg,为黄色固体)。化合物18j-1:1H NMR(CDCl3,400MHz):δ7.74(s,1H),7.42-7.31(m,2H),7.23(s,1H),6.96(dd,J=8.8Hz,8.4Hz,1H),5.81(d,J=9.6Hz,1H),3.52(dd,J=18.4Hz,1.6Hz,1H),2.83(dd,J=18.4Hz,10.4Hz,1H),2.63-2.51(m,3H),2.19-2.14(m,1H),1.85-1.41(m,10H);MS 367.2[M+H]+.化合物18j-2:1H NMR(CDCl3,400MHz):δ7.70(s,1H),7.41-7.31(m,2H),7.21(s,1H),6.95(dd,J=8.8Hz,8.4Hz,1H),5.80(d,J=9.6Hz,1H),3.49(dd,J=18.4Hz,2.0Hz,1H),2.81(dd,J=18.4Hz,10.4Hz,1H),2.67-2.58(m,2H),2.44(s,1H),2.23-2.17(m,1H),1.87-1.44(m,10H);MS 367.3[M+H]+.
0℃下向化合物18j-1(10mg,0.027mmol)的MeOH(0.5mL)溶液中添加NaBH4(6mg,0.159mmol)。然后混合物在室温下搅拌1h。混合物用NH4Cl水溶液(5mL)淬灭和用EtOAc(3mLx 3)萃取。合并的有机层用盐水(5mL)洗涤,无水Na2SO4干燥,过滤并真空浓缩得到残余物,其用制备型TLC(CH2Cl2/MeOH=10/1)纯化得到化合物18k-1(6mg,60%收率),为白色固体。1H NMR(非对映异构体的混合物,DMSO-d6,400MHz):δ7.99,7.94(两个s,1H),7.50-7.38(m,2H),7.20,7.16(两个s,1H),7.14-7.04(m,2H),5.74-5.66,5.64-5.57(两个m,1H),5.06,4.65(两个d,J=7.2Hz,1H),4.30,4.29(两个s,1H),4.03-3.93,3.81-3.70(两个m,1H),2.43-2.10(m,2H),1.99-1.91(m,1H),1.89-1.15(m,13H);MS 369.2[M+H]+.
0℃下向化合物18j-2(12mg,0.033mmol)的MeOH(0.5mL)溶液中添加NaBH4(7mg,0.185mmol)。然后混合物在室温下搅拌1h。混合物用NH4Cl水溶液(5mL)淬灭和用EtOAc(3mLx 3)萃取。合并的有机层用盐水(5mL)洗涤,无水Na2SO4干燥,过滤并真空浓缩得到残余物,其用制备型TLC(CH2Cl2/MeOH=10/1)纯化得到化合物18k-2(8mg,66%收率),为白色固体。1H NMR(非对映异构体的混合物,DMSO-d6,400MHz):δ7.94(s,1H),7.48-7.37(m,2H),7.22,7.16(两个s,1H),7.13-7.05(m,1H),5.73-5.67,5.63-5.57(两个m,1H),5.13,4.67(两个d,J=7.2Hz,1H),4.30,4.33(两个s,1H),3.99-3.90,3.79-3.69(两个m,1H),2.45-2.30(m,2H),2.03-1.96(m,1H),1.91-1.16(m,13H);MS 369.2[M+H]+.
实施例19:生物测试
1.IDO1酶测试:
在pH6.5的50mM MES缓冲液,200nM人IDO酶,150μM L-色氨酸,2250单位/mL过氧化氢酶,20mM抗坏血酸和10μM亚甲基蓝的混合物中,测定体外IDO1酶活性。化合物最初在DMSO中以10mM制备,然后用MES缓冲液稀释至所需浓度。将25μL化合物加入到96孔板中,然后在每个孔中加入25μL33.68ng/μL IDO1。将混合物离心1分钟,然后室温下预温育30分钟。通过加入300μM L-色氨酸、50mM pH6.5的MES缓冲液中的4500单位/mL过氧化氢酶和20μM亚甲蓝和0.405M pH 8.0的Tris HCl缓冲液中的40mM抗坏血酸的50μL混合物,开始反应。所得反应混合物在25℃下孵育40分钟。加入50μl 30%(w/v)三氯乙酸终止反应。将样品在60℃进一步温育30分钟,并以2000rpm离心5分钟以除去沉淀的蛋白质。将上清液与等体积的Ehrlich试剂(2%w/v对二甲氨基苯甲醛的冰醋酸溶液)混合,然后混合物在室温下温育10分钟。在分光光度计中读取490nm的OD值。化合物的抑制率按下式计算:
%抑制率=100-100×(样品信号-低对照)/(高对照-低对照)
其中,高对照=无化合物;低对照=无酶以及无化合物。
通过用Xlfit excel加载版本4.3.1拟合剂量-反应曲线来计算IC 50值。结果列于下表1中。
表1
化合物 | IDO1(IC<sub>50</sub>,nM) | IDO1(500nM下的抑制率%) |
1 | >50 | |
6 | >50 | |
7 | >50 | |
8 | >50 | |
9 | <500 | |
10 | <500 | |
14f | <100 | |
15d | <100 | |
15d-1 | >500 | |
15d-2 | >500 | |
15d-3 | <100 | |
15d-4 | >500 | |
15e | <100 | |
16 | <100 | |
17 | <100 | |
18k-1 | <500 | |
18k-2 | <100 |
2.TDO酶测试:
在pH6.5的50mM磷酸钾缓冲液,200nM人TDO酶,300μM L-色氨酸,0.2mg/mL过氧化氢酶,20mM抗坏血酸和20μM亚甲基蓝的混合物中,测定体外TDO酶活性。在DMSO中从1mM开始制备100X化合物,然后稀释3倍,总共8个剂量。将2μL化合物加入到96孔板中,然后在每个孔中加入100μL 400nM TDO和0.4mg/ml过氧化氢酶。将混合物离心1分钟,然后室温下预温育10分钟,加入在pH6.5的50mM磷酸钾缓冲液中的600μM L-色氨酸、40μM亚甲基蓝和40mM抗坏血酸的100μL混合物,开始反应。所得反应混合物摇动30秒,并在室温下在SpectraMax 384中在OD321nm下动态读板20分钟。从Synergy程序复制斜率数据,并将斜率值转换为抑制值。
抑制百分数=(最大-转化)/(最大-最小)*100。“最大”代表高对照;“min”代表低对照。将数据填入GraphPad Prism5.0以获得IC50值。使用的等式是:Y=底部+(顶部-底部)/(1+10^((LogIC50-X)*HillSlope)。
表2
本发明的其他实施例
上面已经参照特定实施例和实施方式描述了本发明,但是不以任何方式来限制本发明的范围。可以理解的是,在不脱离本发明的实质的情况下,可以对所公开的具体示例和实施例进行各种修改和添加,并且这样的修改和添加被预期为本发明的一部分。
Claims (11)
1.一种选自下组的化合物:
。
2.如权利要求1所述的化合物,其特征在于,所述的化合物为
或其对映异构体。
3.如权利要求1所述的化合物,其特征在于,所述的化合物为
。
4.一种制备药物组合物的方法,包括将权利要求1至3任一项所述的化合物,或其药学上可接受的盐与药学上可接受的载体混合,以形成药物组合物。
5.一种药物组合物,含有权利要求1至3任一项所述的化合物,或其药学上可接受的盐,和药学上可接受的载体或赋形剂。
6.权利要求1所述的化合物,或其药学上可接受的盐的用途,其作为IDO(吲哚胺2,3-双加氧酶)和/或TDO(色氨酸2,3-双加氧酶)抑制剂用于生产刺激T细胞增殖或逆转无反应性或免疫抑制的免疫状态的药物。
7.权利要求1至3任一项所述的化合物,或其药学上可接受的盐的用途,其作为IDO(吲哚胺2,3-双加氧酶)和/或TDO(色氨酸2,3-双加氧酶)抑制剂用于生产治疗IDO和/或TDO介导的医学病症的药物。
8.如权利要求7所述的用途,其特征在于,所述的IDO和/或TDO介导的医学病症选自下组:癌症、传染病、炎症、白内障、子宫内膜异位、疼痛、动脉粥样硬化、神经病学或神经精神病症。
9.如权利要求8所述的用途,其特征在于,所述神经病学和神经精神病症选自下组:抑郁症、肌萎缩性侧索硬化症、亨廷顿病、阿尔茨海默病、多发性硬化症、帕金森病。
10.如权利要求8所述的用途,其特征在于,所述传染病是由丙型肝炎病毒(HCV)、人乳头瘤病毒(HPV)、人免疫缺陷病毒(HIV)、或巨细胞病毒(CMV)引起的病毒感染。
11.如权利要求8所述的用途,其特征在于,所述癌症为乳腺癌、淋巴癌、白血病、肺癌、卵巢癌、宫颈癌、睾丸癌、肝癌、黑素瘤、结肠癌、直肠癌、肾细胞癌、小肠癌、食道癌、头颈癌、膀胱癌、前列腺癌、胰腺癌、或咽癌。
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RU2717577C2 (ru) * | 2015-04-21 | 2020-03-24 | Цзянсу Хэнжуй Медицин Ко., Лтд. | Производное имидазоизоиндола, способ его получения и медицинское применение |
US10800780B2 (en) | 2015-12-24 | 2020-10-13 | Genentech, Inc. | TDO2 Inhibitors |
CN107056785B (zh) * | 2016-01-02 | 2021-06-22 | 杭州英创医药科技有限公司 | 作为ido和tdo抑制剂的杂环化合物 |
WO2017198159A1 (zh) * | 2016-05-16 | 2017-11-23 | 鲁南制药集团股份有限公司 | 含桥环的咪唑衍生物 |
CN107556316B (zh) * | 2016-06-30 | 2021-11-12 | 鲁南制药集团股份有限公司 | 含桥环的咪唑衍生物 |
CN107698594A (zh) * | 2016-08-09 | 2018-02-16 | 苏州国匡医药科技有限公司 | 吲哚胺2,3‑双加氧酶抑制剂及其在药学中的用途 |
TW201815766A (zh) | 2016-09-22 | 2018-05-01 | 美商普雷辛肯公司 | 用於ido及tdo調節之化合物及方法以及其適應症 |
GB201701332D0 (en) * | 2017-01-26 | 2017-03-15 | Tc Biopharm Ltd | Immune cells with modified metabolism and their use thereof |
JOP20180040A1 (ar) * | 2017-04-20 | 2019-01-30 | Gilead Sciences Inc | مثبطات pd-1/pd-l1 |
CN107176956B (zh) * | 2017-05-31 | 2019-11-12 | 成都海博锐药业有限公司 | 一种ido抑制剂化合物、药用组合物、用途 |
US11603373B2 (en) | 2017-06-28 | 2023-03-14 | Genentech, Inc. | TDO2 and IDO1 inhibitors |
US11827639B2 (en) | 2017-06-28 | 2023-11-28 | Genentech, Inc. | TDO2 and IDO1 inhibitors |
CN107501272B (zh) * | 2017-09-05 | 2020-03-31 | 中国药科大学 | 咪唑并异吲哚类ido1抑制剂、其制备方法及应用 |
CN108424414A (zh) * | 2017-12-08 | 2018-08-21 | 苏州国匡医药科技有限公司 | 一类含杂环的吲哚胺2,3-双加氧酶调节化合物及其在药学中的用途 |
US11149011B2 (en) | 2018-03-20 | 2021-10-19 | Plexxikon Inc. | Compounds and methods for IDO and TDO modulation, and indications therefor |
US11352320B2 (en) | 2018-05-31 | 2022-06-07 | Merck Sharp & Dohme Corp. | Substituted [1.1.1] bicyclo compounds as indoleamine 2,3-dioxygenase inhibitors |
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