CN104540823A - 用于治疗癌症的α-咔啉 - Google Patents
用于治疗癌症的α-咔啉 Download PDFInfo
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- CN104540823A CN104540823A CN201380024132.1A CN201380024132A CN104540823A CN 104540823 A CN104540823 A CN 104540823A CN 201380024132 A CN201380024132 A CN 201380024132A CN 104540823 A CN104540823 A CN 104540823A
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- Prior art keywords
- phenyl
- indoles
- pyrido
- methylpiperazine
- base
- Prior art date
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- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 81
- -1 methyl Chemical group 0.000 claims description 46
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- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
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- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
- C07F7/02—Silicon compounds
- C07F7/08—Compounds having one or more C—Si linkages
- C07F7/0803—Compounds with Si-C or Si-Si linkages
- C07F7/081—Compounds with Si-C or Si-Si linkages comprising at least one atom selected from the elements N, O, halogen, S, Se or Te
- C07F7/0812—Compounds with Si-C or Si-Si linkages comprising at least one atom selected from the elements N, O, halogen, S, Se or Te comprising a heterocyclic ring
Landscapes
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- Medicinal Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Abstract
本发明涉及本文所述的式(I)的致癌蛋白激酶ALK的抑制剂及其药物组合物,以及其合成的关键中间体。式(I)的化合物可用于制备药物,特别是用于治疗癌症的药物。
Description
本发明涉及具有ALK激酶抑制活性的α-咔啉衍生物、其制药用途及其关键中间体。
该抑制剂可用于治疗过度增殖性疾病例如癌症,特别是用于治疗ALK融合蛋白阳性的癌症例如间变性大细胞淋巴瘤(ALCL)、弥漫性大B细胞淋巴瘤、炎性肌纤维母细胞瘤、非小细胞肺癌(NSCLC)、食管鳞状细胞癌、肾髓质癌、髓性白血病、乳癌和结肠直肠癌。
发明背景
癌症是由控制细胞的正常生长、定位和死亡的过程被破坏所引起的。这种正常控制机制的丢失起因于导致该过程的正常调节中所涉及的蛋白质的致癌性激活的突变。
蛋白激酶是催化磷酸根从5’-三磷酸腺苷(ATP)转移到许多蛋白的特定氨基酸残基上的酶。通常,蛋白的磷酸化会改变其功能,在一些情况中从无活性的变为有活性的,在另一些情况中从有活性的变为无活性的。因此,蛋白激酶参与细胞功能许多方面的调节,因为大部分控制细胞生长、存活、分化和死亡的信号转导途径都是通过磷酸化介导的。已证实蛋白激酶的异常活性与多种癌症以及其它疾病有关。人类基因组编码至少518种激酶,其中有大约90种特异性地磷酸化酪氨酸残基的酚羟基。酪氨酸激酶尤其涉及细胞增殖和存活过程,它们的异常激活极有可能导致致癌性转化。
例如,由染色体重排t(2q23;5q35)引起的ALK结构改变产生了与ALCL相关的NPM/ALK致癌融合蛋白(Rabbitss,T.H.Nature,1994,.372,143)。
大细胞淋巴瘤占所有非-霍奇金氏淋巴瘤的约25%;这些肿瘤的约三分之一是间变性大细胞淋巴瘤(ALCL)。其中,又有大部分的ALCL患者(60-80%)具有染色体易位,该染色体易位导致核磷蛋白(NPM)基因的5’部分与编码ALK激酶的催化域的序列的符合读框的并列。所形成的嵌合基因在强NPM启动子的控制下驱动NPM/ALK致癌融合蛋白的表达。另有10%的ALCL患者携带有其它的ALK融合蛋白。迄今,已经描绘了11种ALK融合体。在所有情况中,ALK激酶结构域序列融合至在靶细胞中高表达的蛋白质的氨基端蛋白-蛋白相互作用结构域。因此,所述融合配偶体提供组成型表达(通过其启动子)和活化(通过寡聚化)。另外,ALK融合蛋白表现出反常的细胞定位。例如,NPM/ALK主要发现于细胞质和核中。相反,野生型ALK是被严格调控的膜内在蛋白质,其仅在特定胞外配体存在下被活化。
约5-8%的NSCLC患者携带有EML4/ALK融合体。与NPM/ALK一样,5’融合配偶体EML4提供了ALK激酶的高度表达和活化。据估计,ALK+NSCLC患者群(尽管其只占全部NSCLC患者的少数)每年新增病例约50-70,000。除融合蛋白外,还描绘了ALK的活化点突变并在家族性(占90%)和散发的(~10%)神经母细胞瘤以及甲状腺未分化癌(10%的患者)中得到了证实。
ALK在胚胎发育期间的神经系统中正常表达,并在出生时急剧下调,在成人组织中降至几乎检测不到的水平。已经广泛证明组成型活化的NPM/ALK是具有转化和致肿瘤性质的强的癌基因(Morris等人,Science,1994,263,1281-1284)。
此外,ALK激酶的重排是肿瘤形成中的极早出现的事件,并且对变异细胞的存活而言是必需的。NPM/ALK和其它ALK融合蛋白变体在淋巴瘤细胞中的高水平表达和它们在淋巴瘤生成中的直接作用以及正常ALK在人体内以低水平表达的事实,表明ALK可能是用于治疗的理想靶点。
目前在临床上只有一种药物可用于治疗ALK-阳性的癌症。克唑替尼(Crizotinib)是一种最近被批准用于ALK+NSCLC的双重MET/ALK抑制剂。其可有效抑制ALK磷酸化并诱导ALK+癌细胞的细胞凋亡。最初的临床试验在晚期NSCLC患者中显示出极佳的活性和患者耐受性(Shaw等人,Lancet Oncol 2011;12:1004-12)。然而,在相当一部分的患者中出现了临床耐药性(Choi等人,N Engl J Med 2010;363:1734-9)。至少有一半的患者显示出ALK基因的扩增或出现导致ALK对克唑替尼不敏感的继发突变。特别是,看门人突变体(gatekeeper mutant)L1196M显示出对克唑替尼的高度耐药性。因此,迫切需要具有更高的效力和选择性、能够抑制克唑替尼耐药性突变体和避开临床耐药性的第二代化合物。此外,还希望开发出非-ATP竞争性的化合物。
同属于本申请人的EP2161271公开了NMP-ALK、RET和Bcr-Abl的α-咔啉衍生物抑制剂。
附图说明
图:在NPM/ALK+Karpas299原位小鼠模型中,用和未用本发明化合物治疗的肿瘤生长曲线的比较。
发明详述
在本发明的第一个方面,提供了式(I)的化合物
其中:
R1是H或C1-C3烷基
R2是卤素或
X是CH或N
R3是C1-C3烷基或(1-甲基哌啶-4-基)
Rx和Ry是H或硝基
Rz和Rz'是H、OH或氧代
Rt和R't可以相同或不同并且是H或C1-C3烷氧基
Ra是H或F
Rb是H、C1-C3烷氧基、三氟甲基或卤素
Re是H或卤素
Rf是H、C1-C3烷基或三氟甲基
Rg是H或F
Rk是H、卤素、三氟甲基、C1-C3烷氧基、C1-C3烷基磺酰氨基
Rl是H或F
Rm是H、C1-C3烷氧基、F或三氟甲基
Rn是H、C1-C3烷基或5-至6-元芳香族或杂芳族环
Rp是C1-C3烷基或5-至6-元芳香族或杂芳族环
Rq是H或三(C1-C4)烷基硅烷基
Rs是三(C1-C4)烷基硅烷基
Rh是H、C1-C3烷氧基或C1-C3烷基羰基氨基
Ru是H或F
Rv是C1-C3烷基
Rw和Rw'可以相同或不同并且是羟基或C1-C3烷氧基
L和L’是O、S、SO或SO2;
Z是C或N
在一个实施方案(实施方案A1)中,提供了式I的化合物,其中:
R1是H或甲基
R2是Cl或
X是CH或N
R3是甲基或1-甲基哌啶-4-基
Rx和Ry是H或硝基
Rz是H、OH或氧代
Rt和R't可以相同或不同并且可以是H或甲氧基
Ra是H或F
Rb是H、甲氧基、三氟甲基、F或Cl
Re是H或Cl
Rf是H、甲基或三氟甲基
Rg是H或F
Rk是H、Cl、F、三氟甲基、甲氧基、甲基磺酰氨基
Rl是H或F
Rm是H、甲氧基、F或三氟甲基
Rn是H、甲基、乙基或苯基
Rp是乙基或苯基
Rq是H或三异丙基硅烷基
Rs是三异丙基硅烷基。
在另一个实施方案(实施方案A2)中,提供了式(I)的化合物,其中:
R1是H或甲基
R2是Cl或
Rz'是H
Ru是F
Rv是甲基
Rw和Rw'分别是羟基和甲氧基,或者同时是甲氧基
Z是C或N
L是O且Rh是H
L'是S且Rh是甲氧基。
在另一个实施方案(实施方案A3)中,提供了实施方案A1和A2的化合物。
在另一个实施方案(实施方案B1)中,提供了式I的化合物,其中:
R1是H
R2是
X是CH
并且R3、Ra、Rb、Re、Rf、Rg、Rk、Rl、Rm、Rn、Rz、Rt、R't和Rp如式(I)或实施方案A1中所定义。
在另一个实施方案(实施方案B2)中,提供了式I的化合物,其中R2选自
并且R1、R3、X、Ra、Rb、Re、Rf、Rg、Rk、Rl、Rm、Rn、Rz、Rt和R't如式(I)或实施方案A1中所定义。
在另一个实施方案(实施方案B3)中,提供了式(I)的化合物,其中R2选自
并且其中Z、Rw、Rw’和Rz如式(I)或实施方案A2或实施方案A3中所定义。
在另一个实施方案(实施方案B4)中,提供了实施方案B2和B3的化合物。
在式(I)、实施方案A1或实施方案B1或实施方案B2、实施方案B4的一个特定的方面(实施方案C1),当R2是
时,Rk、Rl和Rm中有两个是H,第三个如式(I)、实施方案A1、实施方案B1、实施方案B2或实施方案B4中所定义。
在实施方案C1的一个特定的方面(实施方案C2),Rn是H。
在实施方案B1、B2、B4、C1或C2的一个特定的方面(实施方案D),R2是
并且Rk、Rl、Rm、Rn和Rp如实施方案B1、B2、B4、C1或C2中所定义。
在一个特定的方面,R3是甲基并且R1、R2、X、L、L'、Z、Rx、Ry、Ra、Rb、Re、Rf、Rg、Rh、Rk、Rl、Rm、Rn、Rp、Rq、Rs、Rz、Rz'、Rt、R't、Ru、Rv、Rw和Rw'如式(I)、实施方案A1、实施方案A2、实施方案B1、实施方案B2、实施方案B3、实施方案B4、实施方案C1、实施方案C2或实施方案D中所定义。
在另一个特定的方面,R3是(1-甲基哌啶-4-基)并且R1、R2、X、L、L'、Z、Rx、Ry、Ra、Rb、Re、Rf、Rg、Rh、Rk、Rl、Rm、Rn、Rp、Rq、Rs、Rz、Rz'、Rt、R't、Ru、Rv、Rw和Rw'如式(I)、实施方案A1、实施方案A2、实施方案B1、实施方案B2、实施方案B3、实施方案B4、实施方案C1、实施方案C2或实施方案D中所定义。
在另一个实施方案(实施方案G1)中,提供了选自下列的化合物:
■(E)-6-[4-(4-甲基哌嗪-1-基)苯基]-4-(2-苯基乙烯基)-9H-吡啶并[2,3-b]吲哚(R500a);
■(E)-6-[6-(4-甲基哌嗪-1-基)-吡啶-3-基]-4-(2-苯基乙烯基)-9H-吡啶并[2,3-b]吲哚(R505);
■4-联苯-4-基-6-[4-(4-甲基哌嗪-1-基)苯基]-9H-吡啶并[2,3-b]吲哚(R510a);
■(E)-4-[2-(3-氟苯基)乙烯基]-6-[4-(4-甲基哌嗪-1-基)苯基]-9H-吡啶并[2,3-b]吲哚(R511);
■(E)-4-[2-(4-甲氧基苯基)乙烯基]-6-[4-(4-甲基哌嗪-1-基)苯基]-9H-吡啶并[2,3-b]吲哚(R517);
■4-(4-苄氧基苯基)-6-[4-(4-甲基哌嗪-1-基)苯基]-9H-吡啶并[2,3-b]吲哚(R518);
■6-[4-(4-甲基哌嗪-1-基)苯基]-4-[4-(3-(三氟甲基)-苯氧基甲基)苯基]-9H-吡啶并[2,3-b]吲哚(R519);
■(E)-4-(2-(2-甲氧基苯基)乙烯基))-6-(4-(4-甲基哌嗪-1-基)苯基)-9H-吡啶并[2,3-b]吲哚(R520);
■(E)-6-(4-(4-甲基哌嗪-1-基)苯基)-4-(2-(2-(三氟甲基)苯基)乙烯基)-9H-吡啶并[2,3-b]吲哚(R521);
■4-[4-(4-氯-3-甲基-苯氧基甲基)苯基]-6-[4-(4-甲基哌嗪-1-基)苯基]-9H-吡啶并[2,3-b]吲哚(R522);
■6-[4-(4-甲基哌嗪-1-基)苯基]-4-苯基乙炔基-9H-吡啶并[2,3-b]吲哚(R523);
■(E)-4-(2-(4-氟苯基)乙烯基))-6-(4-(4-甲基哌嗪-1-基)苯基)-9H-吡啶并[2,3-b]吲哚(R527);
■(E)-6-(4-(4-甲基哌嗪-1-基)苯基)-4-(2-(4-(三氟甲基)苯基)乙烯基))-9H-吡啶并[2,3-b]吲哚(R528);
■4-(3-氟联苯-4-基)-6-[4-(4-甲基哌嗪-1-基)苯基]-9H-吡啶并[2,3-b]吲哚(R532);
■4-(4-苄基苯基)-6-[4-(4-甲基哌嗪-1-基)苯基]-9H-吡啶并[2,3-b]吲哚(R533);
■4-联苯-3-基-6-[4-(4-甲基哌嗪-1-基)苯基]-9H-吡啶并[2,3-b]吲哚(R534);
■4-((2-甲氧基苯基)乙炔基)-6-[4-(4-甲基哌嗪-1-基)苯基]-9H-吡啶并[2,3-b]吲哚(R538);
■6-[4-(4-甲基哌嗪-1-基)苯基]-4-((2-(三氟甲基)苯基)乙炔基)-9H-吡啶并[2,3-b]吲哚(R539);
■4-((4-氟苯基)乙炔基)-6-[4-(4-甲基哌嗪-1-基)苯基]-9H-吡啶并[2,3-b]吲哚(R540);
■4-((2-氟苯基)乙炔基)-6-[4-(4-甲基哌嗪-1-基)苯基]-9H-吡啶并[2,3-b]吲哚(R541);
■(E)-4-(2-(2-氟苯基)乙烯基))-6-(4-(4-甲基哌嗪-1-基)苯基)-9H-吡啶并[2,3-b]吲哚(R542);
■(E)-4-(2-(2-氯苯基)乙烯基))-6-(4-(4-甲基哌嗪-1-基)苯基)-9H-吡啶并[2,3-b]吲哚(R543);
■6-(4-(4-甲基哌嗪-1-基)苯基)-N-(3-硝基苯基)-9H-吡啶并[2,3-b]吲哚-4-胺(R547);
■6-(4-(4-甲基哌嗪-1-基)苯基]-N-(2-硝基苯基)-9H-吡啶并[2,3-b]吲哚-4-胺(R548);
■4-((2-氯苯基)乙炔基)-6-[4-(4-甲基哌嗪-1-基)苯基]-9H-吡啶并[2,3-b]吲哚(R549);
■4-((2-甲氧基苯基)乙炔基)-9-甲基-6-[4-(4-甲基哌嗪-1-基)苯基]-9H-吡啶并[2,3-b]吲哚(R555);
■4,6-双-[4-(4-甲基哌嗪-1-基)苯基]-9H-吡啶并[2,3-b]吲哚(R556);
■4-(4-苄基苯基)-6-(4-(4-(1-甲基哌啶-4-基)哌嗪-1-基)苯基)-9H-吡啶并[2,3-b]吲哚(R559);
■(E)-6-(4-(4-(1-甲基哌啶-4-基)哌嗪-1-基)苯基)-4-(2-(2-(三氟甲基)苯基)乙烯基))-9H-吡啶并[2,3-b]吲哚(R566);
■6-(4-(4-(1-甲基哌啶-4-基)哌嗪-1-基)苯基)-N-(2-硝基苯基)-9H-吡啶并[2,3-b]吲哚-4-胺(R567);
■(E)-6-(4-(4-甲基哌嗪-1-基)苯基)-4-(1-苯基丙-1-烯-2-基)-9H-吡啶并[2,3-b]吲哚(R569);
■(4-{6-[4-(4-甲基哌嗪-1-基)苯基]-9H-吡啶并[2,3-b]吲哚-4-基}-苯基)苯基-甲醇(R570);
■(4-{6-[4-(4-甲基哌嗪-1-基)苯基]-9H-吡啶并[2,3-b]吲哚-4-基}-苯基)苯基-甲酮(R571);
■4-氯-6-[4-(4-甲基哌嗪-1-基)苯基]-9H-吡啶并[2,3-b]吲哚(R588);
■(E)-N-[2-(2-{6-[4-(4-甲基哌嗪-1-基)苯基]-9H-吡啶并[2,3-b]吲哚-4-基}-乙烯基)苯基]-甲磺酰胺(R589);
■6-[4-(4-甲基哌嗪-1-基)苯基]-4-(4-萘-1-基-苯基)-9H-吡啶并[2,3-b]吲哚(R590);
■(E)-4-(1,2-二苯基乙烯基)-6-[4-(4-甲基哌嗪-1-基)苯基]-9H-吡啶并[2,3-b]吲哚(R593);
■(E)-6-[4-(4-甲基哌嗪-1-基)苯基]-4-(1-苯基-丁-1-烯基)-9H-吡啶并[2,3-b]吲哚(R594);
■(E)-6-(4-(4-甲基哌嗪-1-基)苯基)-4-(1-苯基丁-1-烯-2-基)-9H-吡啶并[2,3-b]吲哚;
■4-[4-(2,4-二甲氧基苄基)苯基]-6-[4-(4-甲基哌嗪-1-基)苯基]-9H-吡啶并[2,3-b]吲哚(R596);
■(E)-4-[1-(2-甲氧基苯基)-丙-1-烯-2-基]-6-[4-(4-甲基哌嗪-1-基)苯基]-9H-吡啶并[2,3-b]吲哚(R604);
■(E)-6-[4-(4-甲基哌嗪-1-基)-苯基]-4-[1-(2-(三氟甲基)苯基)-丙-1-烯-2-基]-9H-吡啶并[2,3-b]吲哚(R605);
■6-(4-(4-甲基哌嗪-1-基)苯基)-4-((三异丙基硅烷基)乙炔基)-9H-吡啶并[2,3-b]吲哚(R606);
■(E)和/或(Z)-6-(4-(4-甲基哌嗪-1-基)苯基)-4-(2-(三异丙基硅烷基)乙烯基)-9H-吡啶并[2,3-b]吲哚R(607)和
■4-乙炔基-6-(4-(4-甲基哌嗪-1-基)苯基)-9H-吡啶并[2,3-b]吲哚R(608)。
在又一个实施方案(实施方案G2)中,提供了选自下列的化合物:
■4-(4-甲氧基-苯硫基)-6-[4-(4-甲基-哌嗪-1-基)-苯基]-9H-吡啶并[2,3-b]吲哚(R619);
■4-(1-(4-甲基苄基)-1H-1,2,3-三唑-4-基)-6-(4-(4-甲基哌嗪-1-基)苯基)-9H-吡啶并[2,3-b]吲哚(R620);
■6-(4-(4-甲基哌嗪-1-基)苯基)-4-(4-苯氧基苯基)-9H-吡啶并[2,3-b]吲哚(R621);
■4-(6-(4-氟苯基)吡啶-3-基)-6-(4-(4-甲基哌嗪-1-基)苯基)-9H-吡啶并[2,3-b]吲哚(R650);
■(2,5-二甲氧基-4-(6-(4-(4-甲基哌嗪-1-基)苯基)-9H-吡啶并[2,3-b]吲哚-4-基)苯基)(苯基)甲酮(R654);
■(2-羟基-5-甲氧基-4-(6-(4-(4-甲基哌嗪-1-基)苯基)-9H-吡啶并[2,3-b]吲哚-4-基)苯基)(苯基)甲酮(R656);
■4-(4-苄基-2,5-二甲氧基苯基)-6-(4-(4-甲基哌嗪-1-基)苯基)-9H-吡啶并[2,3-b]吲哚(R666);
■2-苄基-4-甲氧基-5-(6-(4-(4-甲基哌嗪-1-基)苯基)-9H-吡啶并[2,3-b]吲哚-4-基)苯酚(R667);
■4-(4-苄基-3-(三氟甲基)苯基)-6-(4-(4-甲基哌嗪-1-基)苯基)-9H-吡啶并[2,3-b]吲哚(R686);
■4-(4-苄基-2-(三氟甲基)苯基)-6-(4-(4-甲基哌嗪-1-基)苯基)-9H-吡啶并[2,3-b]吲哚(R687);
■4-(4-苄基-3,5-二甲氧基苯基)-6-(4-(4-甲基哌嗪-1-基)苯基)-9H-吡啶并[2,3-b]吲哚(R696);
■(2,5-二甲氧基-4-(6-(4-(4-甲基哌嗪-1-基)苯基)-9H-吡啶并[2,3-b]吲哚-4-基)苯基)(苯基)甲醇(R655);
■4-(4-苄基哌啶-1-基)-6-(4-(4-甲基哌嗪-1-基)苯基)-9H-吡啶并[2,3-b]吲哚(R664)和
■4-(4-苄基哌嗪-1-基)-6-(4-(4-甲基哌嗪-1-基)苯基)-9H-吡啶并[2,3-b]吲哚(R665)。
在又一个实施方案(实施方案G3)中,提供了选自下列的化合物:
■4-(1-(4-甲基苄基)-1H-1,2,3-三唑-4-基)-6-(4-(4-甲基哌嗪-1-基)苯基)-9H-吡啶并[2,3-b]吲哚(R620);
■6-(4-(4-甲基哌嗪-1-基)苯基)-4-(4-苯氧基苯基)-9H-吡啶并[2,3-b]吲哚(R621);
■4-(6-(4-氟苯基)吡啶-3-基)-6-(4-(4-甲基哌嗪-1-基)苯基)-9H-吡啶并[2,3-b]吲哚(R650);
■(2,5-二甲氧基-4-(6-(4-(4-甲基哌嗪-1-基)苯基)-9H-吡啶并[2,3-b]吲哚-4-基)苯基)(苯基)甲酮(R654);
■(2-羟基-5-甲氧基-4-(6-(4-(4-甲基哌嗪-1-基)苯基)-9H-吡啶并[2,3-b]吲哚-4-基)苯基)(苯基)甲酮(R656);
■4-(4-苄基-2,5-二甲氧基苯基)-6-(4-(4-甲基哌嗪-1-基)苯基)-9H-吡啶并[2,3-b]吲哚(R666);
■2-苄基-4-甲氧基-5-(6-(4-(4-甲基哌嗪-1-基)苯基)-9H-吡啶并[2,3-b]吲哚-4-基)苯酚(R667);
■4-(4-苄基-3-(三氟甲基)苯基)-6-(4-(4-甲基哌嗪-1-基)苯基)-9H-吡啶并[2,3-b]吲哚(R686);
■4-(4-苄基-2-(三氟甲基)苯基)-6-(4-(4-甲基哌嗪-1-基)苯基)-9H-吡啶并[2,3-b]吲哚(R687);
■4-(4-苄基-3,5-二甲氧基苯基)-6-(4-(4-甲基哌嗪-1-基)苯基)-9H-吡啶并[2,3-b]吲哚(R696);
■(2,5-二甲氧基-4-(6-(4-(4-甲基哌嗪-1-基)苯基)-9H-吡啶并[2,3-b]吲哚-4-基)苯基)(苯基)甲醇(R655);
■4-(4-苄基哌啶-1-基)-6-(4-(4-甲基哌嗪-1-基)苯基)-9H-吡啶并[2,3-b]吲哚(R664)和
■4-(4-苄基哌嗪-1-基)-6-(4-(4-甲基哌嗪-1-基)苯基)-9H-吡啶并[2,3-b]吲哚(R665)。
在又一个实施方案(实施方案G4)中,提供了选自下列的化合物:
■4-联苯-4-基-6-[4-(4-甲基哌嗪-1-基)苯基]-9H-吡啶并[2,3-b]吲哚(R510a);
■(E)-4-(2-(2-甲氧基苯基)乙烯基))-6-(4-(4-甲基哌嗪-1-基)苯基)-9H-吡啶并[2,3-b]吲哚(R520);
■(E)-6-(4-(4-甲基哌嗪-1-基)苯基)-4-(2-(2-(三氟甲基)苯基)乙烯基)-9H-吡啶并[2,3-b]吲哚(R521);
■4-[4-(4-氯-3-甲基苯氧基甲基)苯基]-6-[4-(4-甲基哌嗪-1-基)苯基]-9H-吡啶并[2,3-b]吲哚(R522);
■(E)-4-(2-(4-氟苯基)乙烯基))-6-(4-(4-甲基哌嗪-1-基)苯基)-9H-吡啶并[2,3-b]吲哚(R527);
■4-(4-苄基苯基)-6-[4-(4-甲基哌嗪-1-基)苯基]-9H-吡啶并[2,3-b]吲哚(R533);
■4-联苯-3-基-6-[4-(4-甲基哌嗪-1-基)苯基]-9H-吡啶并[2,3-b]吲哚(R534);
■4-((2-甲氧基苯基)乙炔基)-6-[4-(4-甲基哌嗪-1-基)苯基]-9H-吡啶并[2,3-b]吲哚(R538);
■6-(4-(4-甲基哌嗪-1-基)苯基)-N-(3-硝基苯基)-9H-吡啶并[2,3-b]吲哚-4-胺(R547);
■(4-{6-[4-(4-甲基哌嗪-1-基)苯基]-9H-吡啶并[2,3-b]吲哚-4-基}-苯基)苯基-甲醇(R570);
■(4-{6-[4-(4-甲基哌嗪-1-基)苯基]-9H-吡啶并[2,3-b]吲哚-4-基}-苯基)苯基-甲酮(R571);
■6-[4-(4-甲基哌嗪-1-基)苯基]-4-(4-萘-1-基-苯基)-9H-吡啶并[2,3-b]吲哚(R590)。
在又一个实施方案(实施方案G5)中,提供了选自下列的化合物:
■4-(4-苄基哌啶-1-基)-6-(4-(4-甲基哌嗪-1-基)苯基)-9H-吡啶并[2,3-b]吲哚(R664);
■4-(4-苄基哌嗪-1-基)-6-(4-(4-甲基哌嗪-1-基)苯基)-9H-吡啶并[2,3-b]吲哚(R665)和
■4-(4-苄基-2,5-二甲氧基苯基)-6-(4-(4-甲基哌嗪-1-基)苯基)-9H-吡啶并[2,3-b]吲哚(R666)。
在又一个实施方案中,提供了选自实施方案G4和G5的化合物。
在一个特定的实施方案(实施方案G6)中,提供了选自下列的化合物:
4-((4-甲氧基苯基)硫基)-6-(4-(4-甲基哌嗪-1-基)苯基)-9H-吡啶并[2,3-b]吲哚(R619)。
在式(I)或实施方案A1的一个特定的实施方案中,R2选自
并且Rp如式(I)或实施方案A1中所定义。
在式(I)或实施方案A1的一个特定的实施方案中,R2选自
并且Rs如式(I)或实施方案A1中所定义。
在式(I)或实施方案A1的一个特定的实施方案中,R2选自
并且Rs如式(I)或实施方案A1中所定义。
在式(I)、实施方案A1、实施方案C1或实施方案C2的一个特定方面,R2选自
并且Rk、Rl、Rm和Rn如式(I)、实施方案A1或实施方案C1或实施方案C2中所定义。
在式(I)的一个特定的实施方案(实施方案E)中,-R2选自
并且L和Rh如式(I)中所定义。
在实施方案E的一个特定方面,L选自S、SO和SO2。
在实施方案E的一个特定方面,L是O。
在式(I)的一个特定的实施方案(实施方案F)中,R2选自
并且L'和Rh如式(I)中所定义。
在实施方案F的一个特定方面,L'选自S、SO和SO2。
在实施方案F的一个特定方面,L'是O。
在本发明的另一方面,提供了式(II)的化合物,其中R3和X如以上式(I)或实施方案A或实施方案B中所定义,该化合物是合成式(I)化合物的有用的中间体。
在式(II)的一个特定的实施方案中,提供了选自下列的化合物:
■9-苯磺酰基-4-氯-6-[4-(4-甲基哌嗪-1-基)-苯基]-9H-吡啶并[2,3-b]吲哚(结构模块A);
■9-苯磺酰基-4-氯-6-[4-(6-甲基哌嗪-1-基)-吡啶-3-基]-9H-吡啶并[2,3-b]吲哚(结构模块B);
■9-苯磺酰基-4-氯-6-(4-(4-(1-甲基哌啶-4-基)哌嗪-1-基)苯基)-9H-吡啶并[2,3-b]吲哚(结构模块C)。
所有的实施方案可以进行组合。
在以上实施方案中,当R2是
时,波浪键表示包括E-立体异构体、Z-立体异构体及其混合物。
合成本发明化合物的一般路线
本发明化合物可以从如下中间体X制得,该中间体的合成记载于EP2161271。
然后可将中间体X通过如下概述的Suzuki偶联转化成结构模块Y(将在下文中更详细的说明)。
其中R2是
的化合物可以通过铜催化的叠氮化物-炔烃环加成用其中R2是乙炔基的化合物制得。
在所有其它情况下,可以通过Pd催化的偶联反应引入R2以生成如下中间体Z。
当R2是
并且L'是S时,其可以通过Buchwald偶联或通过亲核取代来引入。
当R2是
时,其可以通过Sonogashira偶联来引入。该化合物还可以通过其中Rq是H的化合物的Sonogashira偶联来获得。
在所有其它情况下,可以通过Suzuki偶联引入R2。
随后将中间体Z在标准条件下脱除苯磺酰基保护得到其中R1=H的化合物。可将其用适宜的标准条件进一步烷基化。
其中L或L'是SO或SO2的化合物还可以通过将其中L或L'是S的相应的硫醚氧化来获得。
其中Rz和Rz’是羟基的化合物可以通过将其中Rz或Rz’是氧代的化合物还原来获得。
其它路线
当R2是
时,以上描述的方法可能生成区域异构体和立体异构体的混合物。
这些化合物的区域选择性路线可能涉及烯化反应例如立体选择性的改良Julia反应(Julia-Kocienski vs Julia-Charette),如以下关于Rp或Rn是乙基时所述。
还可以通过热力学平衡来控制立体化学。
这些化合物的立体选择性路线可以通过对α-烷氧基酮在Felkin-Ahn或Cram螯合物选择性和反式消除反应条件下进行加成来完成,如以下关于Rp或Rn是乙基时所述。
生物学评估
本发明的化合物可以在相关的动物模型或在如下试验中进行测试。
基于ELISA的体外激酶试验
用pBacPAK杆状病毒载体系统(Clontech)在Sf9昆虫细胞中表达GST标记的重组野生型或L1196M突变的ALK激酶(rALK)并用GlutathioneSepharose 4B亲和珠(GE Healthcare)纯化。用重组3C蛋白酶除去GST标记。用纯化的ALK在ELISA激酶试验中筛选抑制剂,方法如下:将Nunc-Immuno 96孔板在30℃下与在PBS中包含2μg特异性ALK肽底物(ARDIYRASFFRKGGCAMLPVK)的涂层液一起培养过夜。然后将各孔用200μL洗涤缓冲液(PBS-Tween 0.05%)洗涤并与4%BSA的PBS溶液在30℃下培养至少2小时。在50mM Tris pH7.5、5mM MnCl2、5mMMgCl2、0.3mM ATP和纯化的rALK的存在下进行激酶反应,总体积为100μL/孔,在30℃下进行15分钟。对于抑制剂试验,将反应混合物与抑制剂或溶媒一起在室温下预培养10分钟,然后转移到ELISA板上。反应后,将各孔用200uL洗涤缓冲液洗涤5次。用100μL/孔在PBS+4%BSA中以1:2000稀释的小鼠抗磷酸酪氨酸单克隆抗体(克隆4G10 UpstateBiotechLtd)检测磷酸化的肽。在室温下培养30分钟后,除去抗体并将各孔按如上描述进行洗涤。向各孔中加入100μL以1:1000在PBS+4%BSA中稀释的二抗(抗小鼠IgG,辣根过氧化物酶联全抗体,Amersham PharmaciaBiotech)并将平板再在室温下培养30分钟,然后按照如上描述进行洗涤。将平板用100μL/孔TMB底物溶液(Pierce)显色并通过加入等体积的1MH2SO4终止反应。最后,用ELISA平板读数器(Bio-Rad)在450nm读取吸光度。将与对照相比显示出50%抑制的抑制剂浓度表示为IC50(μM)。
氚标记的胸苷摄取细胞增殖试验
以下步骤采用未转化的亲本BaF3细胞、用致癌融合蛋白NPM/ALK转化的BaF3细胞、用携带有L1196M替换的突变的致癌融合蛋白NPM/ALK转化的BaF3细胞、人NPM/ALK-阳性SUDHL-1和Karpas-299细胞、人ALK-阴性U937和HL-60白血病细胞。将未转化的亲本BaF3细胞和ALK-阴性细胞用作对照。将细胞以10 000细胞/孔以100μL的体积接种在U型底96孔板中的补充培养基中。在未转化的亲本BaF3细胞的情况下,在培养基中添加IL-3。向适宜的孔中加入抑制剂的系列稀释液并将体积调至200μL。对照单独用等体积的溶媒DMSO处理。将平板在37℃培养72小时。加入3[H]-胸苷(1μCi/孔)进行最后8小时的培养。将细胞收获在滤纸上并用β闪烁计数器(1430MicroBeta,Wallac,Turku,芬兰)测定3[H]-胸苷掺入量。将与对照相比使3[H]-胸苷摄取降低50%的抑制剂的浓度定义为50%抑制浓度(IC50),以μM表示。
制剂和给药
优选将式I化合物与可药用载体、赋形剂等混合制成制剂。通常,优选以口服给药的形式施用药物组合物,但某些制剂可以通过胃肠外、静脉内、肌肉内、经皮、含服、皮下、栓剂、经鼻或其它途径给药。本领域技术人员可以根据本说明书的教导对制剂进行改动以提供多种用于特定给药途径的制剂而不会使本发明的组合物不稳定或降低其治疗活性。具体地讲,对本发明的化合物进行修饰以使其在水或其它溶媒中更易溶可以容易地通过小的修饰(成盐、酯化等)来完成,这些是本领域普通技术人员熟知的。对特定化合物的给药途径和剂量方案进行改动以控制本发明化合物的药物动力学,从而在患者中获得最大有益效果也是本领域技术人员熟知的。在某些药物剂型中,化合物的前药形式、尤其包括酯和醚衍生物,以及本发明化合物的各种盐形式是优选的。本领域普通技术人员知晓如何容易地将本发明化合物修饰为前药形式以促进活性化合物向宿主生物或患者体内目标部位的递送。当适宜时,技术人员还可以利用前药的有利的药物动力学参数,以将本发明化合物递送至宿主生物或患者体内的目标部位以使化合物的预期效果达到最大。制备所述剂型的实用方法是本领域技术人员已知的或对其是显而易见的;例如,参见Remington’s Pharmaceutical Sciences,Mack Publishing Company,Easton,Pennsylvania,第15版,1975。在任何情况下,待给药的组合物或制剂均含有可以有效缓解所治疗个体症状的量的活性化合物。虽然本发明化合物在人类中的剂量水平仍需进行优化,但通常,每日剂量为约0.05mg/kg至约100mg/kg体重。当然,活性化合物的给药量取决于所治疗的个体和疾病状态、病患的严重程度、给药的方式和方案以及处方医师的判断。对于本发明的目的而言,本发明组合物的预防有效量(即,明显降低患者死于疾病或病症的风险或疾病或病症恶化的风险的量)在以上关于治疗有效量所列出的相同的浓度范围内并且通常与治疗有效量是相同的。在本发明的某些实施方案中,将一种或多种式(I)化合物与一种或多种其它药物活性剂组合给药。本文所用的短语“组合”指的是向个体同时给药的多种药剂。应当理解,当个体同时暴露于两种(或多种)药剂时,这两种或多种药剂被认为是“组合”给药的。两种或多种药剂中的每一种可以根据不同的方案进行给药;不需要将不同药剂的每一种在同一时间给药或在同一组合物中给药。只要在个体体内存有两种(或多种)药剂,它们就被认为是“组合”给药的。
实施例
结构模块A、B和C的合成
结构模块A:9-苯磺酰基-4-氯-6-[4-(4-甲基哌嗪-1-基)-苯基]-9H-吡啶并
[2,3-b]吲哚
在室温及惰性气氛下,向0.03M9-苯磺酰基-6-溴-4-氯-9H-吡啶并[2,3-b]吲哚的THF溶液中加入Pd(PPh3)4(0.15当量)、K2CO3(3当量)和硼酸频哪醇酯(1.1当量)。将混合物加热至70℃并加入脱气的H2O mQ(所用THF体积的25%)。在70℃搅拌4小时后,将反应混合物冷却至室温,用EtOAc(1体积)稀释然后用硅藻土过滤。将硅藻土垫用EtOAc洗涤并将滤液蒸发至干。将残余物溶于EtOAc并用H2O mQ洗涤两次。将有机层用MgSO4干燥,过滤并蒸发至干。将残余物悬浮在最小体积的甲醇中,研磨并过滤,将固体用甲醇洗涤得到所需化合物
经研磨得到黄色固体状所需产物,77%收率。1H-NMR(300MHz,CDCl3)δ=8.57(d,J=1.6Hz,1H),8.54(d,J=8.8Hz,1H),8.43(d,J=5.4Hz,1H),8.20-8.12(m,2H),7.82(dd,J=8.8,1.9Hz,1H),7.60(d,J=8.8Hz,2H),7.58-7.49(m,1H),7.43(t,J=7.6Hz,2H),7.30(d,J=5.4Hz,1H),7.05(d,J=8.8Hz,2H),3.41-3.29(m,4H),2.77-2.64(m,4H),2.44(s,3H)。13C-NMR(75MHz,CDCl3)δ=151.88(CH),150.80(Cq),146.75(CH),138.54(Cq),138.48(Cq),137.44(Cq),136.49(Cq),134.25(CH),131.60(Cq),129.11(2 CH),128.06(2 CH),127.80(CH),127.72(2 CH),122.42(Cq),120.96(CH),120.36(CH),116.86(Cq),116.27(2 CH),114.96(Cq),55.15(2 CH2),48.93(2 CH2),46.28(CH3)。ESI-MS:517.1m/z[M+H]+。
结构模块B:9-苯磺酰基-4-氯-6-[6-(4-甲基哌嗪-1-基)-吡啶-3-基]-9H-吡啶并
[2,3-b]吲哚
按照与以上关于结构模块A所述类似的方法,经研磨得到黄色固体状所需产物,73%收率。1H NMR(400MHz,CDCl3)δ8.60-8.51(m,3H),8.44(d,J=5.3Hz,1H),8.19-8.13(m,2H),7.81(dd,J=8.8,2.5Hz,1H),7.77(dd,J=8.8,1.9Hz,1H),7.58-7.51(m,1H),7.47-7.40(m,2H),7.30(d,J=5.4Hz,1H),6.78(d,J=8.8Hz,1H),3.74-3.64(m,4H),2.69-2.59(m,4H),2.43(s,J=6.4Hz,3H)。13C-NMR(101MHz,CDCl3)δ=158.7(C),151.9(C),147.0(CH),146.5(CH),138.6(C),136.7(C),136.5(CH),134.8(C),134.3(CH),129.2(2 CH),128.5(C),127.8(2 CH),127.4(CH),126.0(C),122.6(C),120.8(CH),120.4(CH),116.7(C),115.3(CH),107.1(CH),54.9(2 CH2),46.2(CH3),45.1(2 CH2)。ESI-MS:518.2m/z[M+H]+。
结构模块C:9-苯磺酰基-4-氯-6-(4-(4-(1-甲基哌啶-4-基)哌嗪-1-基)苯
基)-9H-吡啶并[2,3-b]吲哚
方法A:
9-苯磺酰基-4-氯-6-(4-(哌嗪-1-基)苯基)-9H-吡啶并[2,3-b]吲哚
在Schlenk管中,在室温及惰性气氛下,将Pd(Ph3)4(0.1eq)、K2CO3(3eq)和硼酸(1.3eq)加入到0.04M 9-苯磺酰基-6-溴-4-氯-9H-吡啶并[2,3-b]吲哚在THF/H2O 4:1混合物中的悬浮液中。将该溶液在70℃搅拌15小时。冷却至室温并用EtOAc稀释后,将混合物用垫过滤。减压蒸除溶剂。将粗产物在MeOH中研磨并过滤。然后,将剩余的固体通过硅胶快速色谱纯化(DCM/MeOH 90:10)得到白色固体状所需化合物,38%收率。
1H NMR(300MHz,CDCl3)δ8.57(d,J=1.8Hz,1H),8.54(d,J=8.9Hz,1H),8.43(d,J=5.4Hz,1H),8.19-8.12(m,2H),7.81(dd,J=8.8,1.9Hz,1H),7.59(d,J=8.7Hz,2H),7.53(t,J=7.4Hz,1H),7.42(t,J=7.6Hz,2H),7.28(d,J=5.4Hz,1H),7.03(d,J=8.8Hz,2H),3.23(dd,J=6.2,3.7Hz,4H),3.08(dd,J=6.1,3.7Hz,4H),2.25(s,1H);13C NMR(75MHz,CDCl3)δ151.9(C),151.3(C),146.8(CH),138.6(C),138.5(C),137.4(C),136.5(C),134.2(CH),131.7(C),129.1(CH),128.0(CH),127.8(CH),127.7(CH),122.4(C),120.9(CH),120.4(CH),116.8(C),116.4(CH),115.0(CH),50.1(CH2),46.1(CH2);MS(ESI)m/z:503.1[M+H]+。
9-苯磺酰基-4-氯-6-(4-(4-(1-甲基哌啶-4-基)哌嗪-1-基)苯基)-9H-吡啶并[2,3-b]吲哚
在惰性气氛下,将9-苯磺酰基-4-氯-6-(4-(哌嗪-1-基)苯基)-9H-吡啶并[2,3-b]吲哚(30mg,0.0596mmol)溶于无水DCM(1.2mL,c=0.05M)。加入N-甲基-4-哌啶酮(22μL,3eq),然后加入两滴冰乙酸。将混合物在室温下搅拌1小时15分钟,然后冷却至0℃。分批加入三乙酰氧基硼氢化钠(38mg,3eq)并将得到的混合物升温至室温,然后搅拌22小时。然后将反应混合物用水和饱和碳酸氢钠水溶液终止反应。将水层用EtOAc(3×7mL)萃取。将合并的有机层用盐水洗涤,用MgSO4干燥,过滤并真空浓缩得到白色固体状所需化合物(33mg,93%),其不经进一步纯化直接使用。
方法B:在Schlenk管中,在室温及惰性气氛下,将Pd(Ph3)4(0.1eq)、K2CO3(3eq)和1-(1-甲基哌啶-4-基)-4-(4-(4,4,5,5-四甲基-1,3,2-二氧硼戊环-2-基)苯基)哌嗪(1.3eq)加入到0.04M 9-苯磺酰基-6-溴-4-氯-9H-吡啶并[2,3-b]吲哚在THF/H2O 6:1混合物中的悬浮液中。将该溶液在70℃搅拌15小时。冷却至室温并用EtOAc稀释后,将混合物用垫过滤。真空除去溶剂。将粗产物在甲醇中研磨并过滤后,以74%的收率得到白色固体。
1H NMR(400MHz,CDCl3)δ8.56(d,J=1.8Hz,1H),8.53(d,J=8.8Hz,1H),8.42(d,J=5.4Hz,1H),8.15(d,J=7.6Hz,2H),7.80(dd,J=8.8,1.8Hz,1H),7.58(d,J=8.7Hz,2H),7.52(t,J=7.4Hz,1H),7.42(t,J=7.8Hz,2H),7.28(d,J=5.4Hz,1H),7.02(d,J=8.7Hz,2H),3.33-3.21(m,4H),2.98(d,J=11.7Hz,2H),2.79-2.71(m,4H),2.32(s,4H),2.06(t,J=10.8Hz,2H),1.88(d,J=12.1Hz,2H),1.70(dd,J=20.6,11.3Hz,2H);13CNMR(101MHz,CDCl3)δ151.9(C),150.9(C),146.7(CH),138.6(C),138.5(C),137.4(C),136.5(C),134.2(CH),131.5(C),129.1(CH),128.0(CH),127.8(CH),127.7(CH),122.4(C),120.9(CH),120.3(CH),116.8(C),116.2(CH),114.9(CH),61.2(CH),55.5,55.2(CH2),49.3(CH2),49.2(CH2),46.0,45.6(NCH3),27.9(CH2);MS(ESI)m/z:600.2[M+H]+,1198.9[2M+H]+。
典型方法A:脱除苯磺酰基保护
在室温及惰性气氛下,向0.11M 4,6-取代的α-咔啉的THF溶液中加入MeOH(7:4MeOH/THF比)和NaOMe(15当量)。将反应混合物用回流冷凝器在65℃下搅拌1.6小时。然后,将反应混合物冷却至室温并用H2O(1mL)终止反应。将混合物用CH2Cl2(20mL)稀释并用H2O(20mL)洗涤两次。将有机层用MgSO4干燥,过滤并蒸发至干。将残余物悬浮在最少量的甲醇中,研磨并过滤,将固体用甲醇洗涤得到所需的最终化合物。当研磨无法获得所需的纯度时,通过硅胶快速色谱纯化所需化合物。
典型方法B:Suzuki偶联
在室温及惰性气氛下,向0.1M 9-苯磺酰基-6-取代的-4-氯-9H-吡啶并[2,3-b]吲哚在二氧六环中的溶液中加入Pd(PPh3)4(0.15当量)、K2CO3(3当量)、硼酸或频哪醇酯(2当量)以及脱气的H2O mQ(二氧六环体积的20%)。放置油浴并将混合物加热至100℃。在100℃下搅拌过夜后,将反应混合物冷却至室温,用EtOAc(3体积)稀释然后用Celite过滤。将Celite垫用EtOAc洗涤并将滤液用H2O mQ洗涤两次。将有机层用MgSO4干燥,过滤并蒸发至干。将残余物悬浮在最少量的甲醇中,研磨并过滤,将固体用甲醇洗涤。
实施例1:4-氯-6-[4-(4-甲基哌嗪-1-基)-苯基]-9H-吡啶并[2,3-b]吲哚(R588)
将结构模块A按照典型方法A脱保护。
通过硅胶快速色谱纯化(CH2Cl2/MeOH 95:5)得到黄色固体状所需产物,57%收率。1H-NMR(300MHz,CDCl3/MeOD 5:2)δ=8.56(d,J=1.3Hz,1H),8.22(d,J=5.5Hz,1H),7.72(dd,J=8.5,1.8Hz,1H),7.59(d,J=8.8Hz,3H),7.17(d,J=5.5Hz,1H),7.04(d,J=8.8Hz,2H),3.30-3.24(m,4H),2.75-2.67(m,4H),2.41(s,3H)。13C-NMR(101MHz,CDCl3/MeOD5:2)δ=153.38(Cq),150.33(Cq),145.83(CH),139.15(Cq),138.79(Cq),134.48(Cq),134.23(Cq),128.46(2 CH),127.21(CH),121.36(CH),120.97(Cq),117.42(2 CH),116.49(CH),115.28(Cq),112.09(CH),55.22(2 CH2),49.27(2 CH2),45.70(CH3)。HRMS(ESI):计算值:C22H22N4Cl:377.1528;实测值:377.1518。
实施例2:(E)-6-[4-(4-甲基哌嗪-1-基)-苯基]-4-(2-苯基乙烯基)-9H-吡啶并
[2,3-b]吲哚(R500a)
9-苯磺酰基-6-[4-(4-甲基哌嗪-1-基)-苯基]-4-(2-苯基乙烯基)-9H-吡啶并
[2,3-b]吲哚
将结构模块A按照典型方法B处理得到黄色固体状所需化合物,73%收率。
1H-NMR(300MHz,CDCl3)δ=8.58(d,J=8.8Hz,1H),8.52(d,J=5.2Hz,1H),8.24(d,J=1.4Hz,1H),8.20-8.13(m,2H),7.85(d,J=16.2Hz,1H),7.76(dd,J=8.8,1.8Hz,1H),7.65-7.55(m,4H),7.56-7.49(m,1H),7.48-7.35(m,6H),7.36(d,J=16.4Hz,1H),7.04(d,J=8.7Hz,2H),3.36-3.23(m,4H),2.67-2.56(m,4H),2.38(s,3H)。13C-NMR(75MHz,CDCl3)δ=151.98(C),150.77(C),146.66(CH),141.64(C),138.93(C),137.31(C),136.74(C),136.33(C),135.78(CH),134.01(CH),132.00(C),129.20(3 CH),129.02(2 CH),128.03(2 CH),127.76(2 CH),127.31(2 CH),127.01(CH),124.08(C),123.49(CH),120.98(CH),116.37(2 CH),116.05(C),116.01(CH),115.27(CH),55.22(22),48.99(2 CH2),46.33(CH3)。ESI-MS:585.2m/z
(E)-6-[4-(4-甲基哌嗪-1-基)-苯基]-4-(2-苯基乙烯基)-9H-吡啶并[2,3-b]吲哚
将9-苯磺酰基-6-[4-(4-甲基哌嗪-1-基)-苯基]-4-(2-苯基乙烯基)-9H-吡啶并[2,3-b]吲哚按照典型方法A处理得到黄色固体状所需化合物,74%收率。
1H-NMR(300MHz,DMSO)δ=11.89(s,1H),8.39(d,J=5.2Hz,1H),8.35(d,J=1.6Hz,1H),8.16(d,J=16.2Hz,1H),7.87-7.79(m,2H),7.70(dd,J=8.5,1.6Hz,1H),7.67-7.53(m,4H),7.53-7.46(m,3H),7.39(t,J=7.3Hz,1H),7.05(d,J=8.8Hz,2H),3.23-3.14(m,4H),2.49-2.43(m,4H),2.24(s,3H)。13C-NMR(126MHz,DMSO)δ=153.02(Cq),149.90(Cq),146.01(CH),140.26(Cq),138.06(Cq),136.48(Cq),134.67(CH),132.33(Cq),131.75(Cq),129.06(2 CH),128.79(CH),127.31(4 CH),125.18(CH),124.21(CH),121.05(Cq),120.30(CH),115.83(2 CH),112.51(Cq),111.66(CH),111.43(CH),54.65(2 CH2),48.08(2 CH2),45.82(CH3)。HRMS(ESI):计算值:C30H29N4:445.2387;实测值:445.2378。
实施例3-32按照与实施例2类似的方式,相应地从结构模块A、B或C合成。
实施例3:(E)-6-[4-(4-甲基哌嗪-1-基)-苯基]-4-[1-(2-(三氟甲基)苯基)丙-1-烯
-2-基]-9H-吡啶并[2,3-b]吲哚(R605)
将粗产物在甲醇中研磨并过滤后,以89%的收率得到黄色固体。1HNMR(500MHz,CDCl3)δ10.07(s,1H),8.51(d,J=4.9Hz,1H),8.28(s,1H),7.77(d,J=7.9Hz,1H),7.70(dd,J=8.4,1.2Hz,1H),7.68-7.62(m,2H),7.59(d,J=8.4Hz,1H),7.53(d,J=8.6Hz,2H),7.47(t,J=7.4Hz,1H),7.11(d,J=5.0Hz,1H),7.01(s,1H),7.00(d,J=8.5Hz,2H),3.41-3.23(m,4H),2.78-2.61(m,4H),2.44(s,3H),2.25(s,3H);13C NMR(75MHz,CDCl3)δ152.9(C),150.0(C),148.2(C),146.0(CH),138.7(C),137.8(C),136.3(d,J=1.8Hz,C),133.7(C),133.5(C),131.8(CH),131.1(CH),129.1(q,29.5Hz,C),128.0(CH),127.4(CH),127.1(CH),126.3(q,J=5.4Hz,CH),126.0(CH),124.4(q,J=274.0Hz,C),121.3(C),121.0(CH),116.6(CH),115.3(CH),113.5(C),111.4(CH),55.1(2CH2),49.0(2CH2),46.1(NCH3),18.8(CH3);HRMS计算值:C32H30F3N4[M+H]+527.2417实测值:527.2402。
实施例4:(E)-6-[6-(4-甲基哌嗪-1-基)-吡啶-3-基]-4-(2-苯基乙烯基)-9H-吡啶
并[2,3-b]吲哚(R505)
经研磨步骤以61%的收率得到棕色固体状所需产物。1H-NMR(300MHz,DMSO)δ=11.92(s,1H),8.54(d,J=2.4Hz,1H),8.40(d,J=5.2Hz,1H),8.36(d,J=1.0Hz,1H),8.17(d,J=16.3Hz,1H),7.95(dd,J=8.8,2.6Hz,1H),7.85(d,J=7.3Hz,2H),7.70(dd,J=8.5,1.5Hz,1H),7.63(d,J=16.3Hz,1H),7.58(d,J=8.4Hz,1H),7.53-7.44(m,3H),7.38(t,J=7.3Hz,1H),6.96(d,J=8.8Hz,1H),3.60-3.48(m,4H),2.46-2.37(m,4H),2.23(s,3H)。13C-NMR(75MHz,DMSO)δ=157.98(Cq),152.99(Cq),146.05(CH),145.51(CH),140.32(Cq),138.16(Cq),136.44(Cq),136.03(CH),134.78(CH),129.62(Cq),128.97(2 CH),128.74(CH),127.39(2 CH),126.33(Cq),124.97(CH),124.13(CH),121.08(Cq),120.30(CH),112.37(Cq),111.73(CH),111.40(CH),107.18(CH),54.44(2 CH2),45.87(CH3),44.78(2 CH2)。HRMS(ESI):计算值:C29H28N5:446.2339;实测值:446.2323。
实施例5:4-联苯-4-基-6-[4-(4-甲基哌嗪-1-基)-苯基]-9H-吡啶并[2,3-b]吲哚
(R510a)
经研磨步骤以88%的收率得到米色固体状所需产物。1H NMR(500MHz,DMSO)δ12.01(s,1H),8.48(d,J=3.9Hz,1H),7.96(d,J=7.3Hz,2H),7.90-7.76(m,5H),7.66(d,J=7.6Hz,1H),7.60-7.50(m,3H),7.48-7.41(m,1H),7.34(d,J=7.6Hz,2H),7.17(d,J=4.1Hz,1H),6.93(d,J=8.0Hz,2H),3.19-3.05(m,4H),2.45-2.39(m,4H),2.20(s,3H)。13C-NMR(126MHz,DMSO)δ=152.77(Cq),149.75(Cq),146.18(CH),143.90(Cq),140.57(Cq),139.56(Cq),138.00(Cq),137.48(Cq),131.65(Cq),131.34(Cq),129.24(2 CH),129.11(2 CH),127.82(CH),127.01(2 CH),126.85(2CH),126.82(2 CH),125.22(CH),120.37(Cq),119.08(CH),115.81(CH),115.64(2 CH),112.29(Cq),111.70(CH),54.54(2 CH2),47.91(2 CH2),45.74(CH3)。HRMS(ESI):计算值:C34H31N4:495.2543;实测值:495.2543。
实施例6:(E)-4-[2-(3-氟苯基)乙烯基]-6-[4-(4-甲基哌嗪-1-基)-苯基]-9H-吡
啶并[2,3-b]吲哚(R511)
经研磨步骤以81%的收率得到黄色固体状所需产物。1H-NMR(500MHz,DMSO)δ=11.90(s,1H),8.40(d,J=5.2Hz,1H),8.36(d,J=1.6Hz,1H),8.23(d,J=16.3Hz,1H),7.74(m 1H),7.70(dd,J=8.4,1.6Hz,1H),7.66(d,J=7.8Hz,1H),7.64-7.61(m,2H),7.61(d,J=15.9Hz,1H),7.56(d,J=8.4Hz,1H),7.52(dt,J=14.2,7.1Hz,1H),7.47(d,J=5.2Hz,1H),7.21(td,J=8.5,2.2Hz,1H),7.04(d,J=8.8Hz,2H),3.22-3.15(m,4H),2.49-2.43(m,4H),2.24(s,3H)。13C-NMR(126MHz,DMSO)δ=162.65(d,J=243.3Hz,Cq),152.95(Cq),149.84(Cq),145.96(CH),139.86(Cq),139.09(d,J=8.0Hz,Cq),138.02(Cq),133.41(d,J=2.4Hz,CH),132.27(Cq),131.72(Cq),130.84(d,J=8.4Hz,CH),127.31(2 CH),125.89(CH),125.21(CH),123.64(d,J=2.2Hz,CH),120.89(Cq),120.45(CH),115.72(2CH),115.31(d,J=21.5Hz,CH),113.51(d,J=21.9Hz,CH),112.56(Cq),111.54(CH),111.53(CH),54.58(2 CH2),48.03(2 CH2),45.75(CH3)。HRMS(ESI):计算值:C30H28FN4:463.2293;实测值:463.2282。
实施例7:(E)-4-[2-(4-甲氧基苯基)乙烯基]-6-[4-(4-甲基哌嗪-1-基)-苯
基]-9H-吡啶并[2,3-b]吲哚(R517)
在甲醇中研磨,随后再在CH2Cl2中进行同样的操作,以66%的收率得到黄色固体状所需产物。1H-NMR(500MHz,DMSO)δ=11.85(s,1H),8.36(d,J=5.2Hz,1H),8.34(d,J=1.5Hz,1H),7.98(d,J=16.2Hz,1H),7.77(d,J=8.7Hz,2H),7.68(dd,J=8.4,1.5Hz,1H),7.64-7.53(m,4H),7.46(d,J=5.3Hz,1H),7.42(d,J=8.7Hz,1H),7.05(d,J=8.0Hz,4H),6.94-6.88(m,1H),3.23-3.14(m,4H),2.49-2.43(m,4H),2.23(s,3H)。13C-NMR(126MHz,DMSO)δ=159.85(Cq),153.03(Cq),149.82(Cq),145.87(CH),140.59(Cq),137.94(Cq),134.29(CH),132.22(Cq),131.75(Cq),129.08(Cq),128.75(2 CH),127.44(CH),127.27(2 CH),121.66(CH),121.12(Cq),120.21(CH),115.78(2 CH),114.48(2 CH),114.21(CH),112.25(Cq),111.05(CH),55.28(CH3),54.62(2 CH2),48.05(2 CH2),45.78(CH3)。HRMS(ESI):计算值:C31H31N4O:475.2492;实测值:475.2475。
实施例8:4-(4-苄氧基苯基)-6-[4-(4-甲基哌嗪-1-基)-苯基]-9H-吡啶并[2,3-b]
吲哚(R518)
在甲醇中研磨,随后再在甲苯中进行同样的操作,以32%的收率得到棕色固体状所需产物。1H-NMR(500MHz,DMSO)δ=11.94(s,1H),8.42(d,J=5.0Hz,1H),7.81(d,J=1.3Hz,1H),7.70(d,J=8.6Hz,2H),7.65(dd,J=8.4,1.7Hz,1H),7.56-7.50(m,3H),7.44-7.39(m,2H),7.38-7.32(m,3H),7.28(d,J=8.7Hz,2H),7.08(d,J=5.0Hz,1H),6.97(d,J=8.8Hz,2H),5.25(s,2H),3.19-3.11(m,4H),2.47-2.41(m,4H),2.22(s,3H)。13C-NMR(126MHz,DMSO)δ=158.89(Cq),152.80(Cq),149.73(Cq),146.08(CH),144.12(Cq),137.91(Cq),136.98(Cq),131.55(Cq),131.43(Cq),130.79(Cq),129.98(2 CH),128.46(2 CH),127.86(CH),127.71(2CH),126.87(2 CH),125.05(CH),120.50(Cq),119.07(CH),115.88(CH),115.69(2 CH),115.08(2 CH),112.30(Cq),111.61(CH),69.43(CH2),54.57(2 CH2),47.97(2 CH2),45.75(CH3)。HRMS(ESI):计算值:C35H33N4O:525.5649;实测值:525.2640。
实施例9:6-[4-(4-甲基哌嗪-1-基)-苯基]-4-[4-(3-三氟甲基-苯氧基甲基)-苯
基]-9H-吡啶并[2,3-b]吲哚(R519)
在甲醇中研磨得到深绿色固体状所需产物,87%收率。1H-NMR(400MHz,DMSO)δ=12.00(s,1H),8.46(d,J=5.0Hz,1H),7.82-7.69(m,5H),7.65(dd,J=8.5,1.6Hz,1H),7.59-7.50(m,2H),7.43-7.36(m,2H),7.35-7.28(m,3H),7.13(d,J=5.0Hz,1H),6.92(d,J=8.8Hz,2H),5.35(s,2H),3.16-3.05(m,4H),2.47-2.39(m,4H),2.21(s,3H)。13C-NMR(101MHz,DMSO)δ=158.78(Cq),152.81(Cq),149.80(Cq),146.28(CH),144.08(Cq),138.12(d,J=7.5Hz,Cq),137.33(Cq),131.69(Cq),131.42(Cq),130.87(CH),130.64(Cq),130.33(Cq),128.90(2 CH),128.24(2 CH),126.94(2CH),125.30(CH),122.75(Cq),120.42(Cq),119.13(d,J=5.3Hz,CH),117.49(d,J=7.3Hz,CH),115.95(CH),115.74(2 CH),114.99(CH),112.40(Cq),111.83(CH),111.54(d,J=4.0Hz,CH),69.54(CH2),54.61(2 CH2),48.00(2 CH2),45.82(CH3)。HRMS(ESI):计算值:C36H32F3N4O:593.2523;实测值:593.2526。
实施例10:(E)-4-(2-(2-甲氧基苯基)乙烯基)-6-(4-(4-甲基哌嗪-1-基)苯
基)-9H-吡啶并[2,3-b]吲哚(R520)
将粗产物在甲醇中研磨并过滤后,以66%的收率得到黄色固体。
1H NMR(400MHz,DMSO)δ11.88(s,NH),8.38(d,J=5.2Hz,1H),8.36(s,1H),8.32(d,J=16.3Hz,1H),7.78(dd,J=7.6,1.4Hz,1H),7.72(d,J=16.5Hz,1H),7.69(dd,J=8.7Hz,1H),7.59(d,J=8.7Hz,2H),7.56(d,J=8.5Hz,1H),7.48(d,J=5.3Hz,1H),7.41-7.35(m,1H),7.15(d,J=8.2Hz,1H),7.07(t,J=7.3Hz,1H),7.05(d,J=8.8Hz,2H),3.94(s,3H),3.22-3.14(m,4H),2.49-2.44(m,4H),2.23(s,3H);13C NMR(101MHz,DMSO)δ157.6(C),153.1(C),149.9(C),146.0(CH),140.7(C),138.0(C),132.3(C),131.7(C),130.5(CH),130.0(CH),129.4(CH),127.3(CH),125.4(CH),125.1(CH),124.6(C),121.1(C),120.9(CH),120.0(CH),115.7(CH),112.3(C),111.7(CH),111.6(CH),110.8(CH),55.8(CH3),54.6(CH2),48.0(CH2),45.8(CH3);HRMS计算值:C31H31N4O[M+H]+475.2492实测值:475.2499。
实施例11:(E)-6-(4-(4-甲基哌嗪-1-基)苯基)-4-(2-(2-(三氟甲基)苯基)乙烯基)
-9H-吡啶并[2,3-b]吲哚(R521)
将粗产物在甲醇中研磨并过滤后,以78%的收率得到黄色固体。
1H NMR(400MHz,DMSO)δ11.96(s,NH),8.44(d,J=5.2Hz,1H),8.31(s,1H),8.28(d,J=8.4Hz,1H),8.24(d,J=16.2Hz,1H),7.87-7.80(m,2H),7.74-7.66(m,2H),7.65-7.55(m,4H),7.41(d,J=5.2Hz,1H),7.03(d,J=8.8Hz,2H),3.21-3.14(m,4H),2.48-2.44(m,4H),2.23(s,3H);13C NMR(101MHz,DMSO)δ152.9(C),149.9(C),146.3(CH),139.4(C),138.1(C),134.9(d,J=1.6Hz,C),133.2(CH),132.3(C),131.6(C),129.2(CH),129.1(q,J=2.8Hz,CH),128.8(CH),128.2(CH),127.3(CH),126.4(q,J=29.2Hz,C),126.1(q,J=6.1Hz,CH),125.4(CH),124.4(q,J=274.2Hz,C),120.7(C),120.3(CH),115.7(CH),112.6(C),111.7(CH),111.4(CH),54.6(CH2),48.0(CH2),45.8(CH3);HRMS计算值:C31H28F3N4O[M+H]+513.2261实测值:513.2273。
实施例12:4-[4-(4-氯-3-甲基-苯氧基甲基)-苯基]-6-[4-(4-甲基哌嗪-1-基)-苯
基]-9H-吡啶并[2,3-b]吲哚(R522)
在MeOH中研磨得到黄色固体状所需产物,66%收率。1H-NMR(400MHz,DMSO)δ=12.00(s,1H),8.46(d,J=5.0Hz,1H),7.77(d,J=8.0Hz,2H),7.73-7.67(m,3H),7.65(dd,J=8.7,1.2Hz,1H),7.55(d,J=8.4Hz,1H),7.34-7.27(m,3H),7.13(d,J=5.0Hz,1H),7.10(d,J=2.9Hz,1H),6.93(m,3H),5.25(s,2H),3.16-3.08(m,4H),2.47-2.40(m,4H),2.30(s,3H),2.22(s,3H)。13C-NMR(101MHz,DMSO)δ=157.16(Cq),152.75(Cq),149.77(Cq),146.19(CH),144.03(Cq),138.01(Cq),137.95(Cq),137.65(Cq),136.58(Cq),131.61(Cq),131.37(Cq),129.52(2CH),128.80(2CH),127.99(2 CH),126.87(2 CH),125.20(CH),124.83(Cq),120.36(Cq),119.06(CH),117.76(2 CH),115.68(2 CH),113.92(CH),112.35(Cq),69.25(CH2),54.60(2 CH2),47.98(2 CH2),45.80(CH3),19.84(CH3)。HRMS(ESI):计算值:C36H34ClN4O:573.2416;实测值:573.2424。
实施例13:(E)-4-(2-(4-氟苯基)乙烯基)-6-(4-(4-甲基哌嗪-1-基)苯基)-9H-吡
啶并[2,3-b]吲哚(R527)
将粗产物在甲醇中研磨并过滤后,以74%的收率得到黄色固体。1HNMR(300MHz,DMSO)δ11.88(s,NH),8.39(d,J=5.2Hz,1H),8.35(s,1H),8.11(d,J=16.3Hz,1H),7.90(dd,J=8.7,5.7Hz,2H),7.70(dd,J=8.5,1.6Hz,1H),7.62(d,J=16.1Hz,1H),7.62(d,J=8.8Hz,2H),7.56(d,J=8.4Hz,1H),7.47(d,J=5.2Hz,1H),7.33(t,J=8.9Hz,2H),7.05(d,J=8.8Hz,2H),3.24-3.14(m,4H),2.49-2.44(m,4H),2.24(s,3H);13C NMR(126MHz,DMSO)δ162.3(d,J=246.4Hz,C),153.0(C),149.8(C),145.9(CH),140.2(C),138.0(C),133.4(CH),133.1(d,J=3.0Hz,C),132.2(C),131.7(C),129.3(d,J=8.3Hz,CH),127.3(CH),125.1(CH),124.1(d,J=2.3Hz,CH),121.0(C),120.3(CH),115.9(d,J=21.7Hz,CH),115.8(CH),112.4(C),111.5(CH),111.3(CH),54.6(CH2),48.1(CH2),45.8(CH3);HRMS计算值:C30H28FN4[M+H]+463.2293实测值:463.2282。
实施例14:(E)-6-(4-(4-甲基哌嗪-1-基)苯基)-4-(2-(4-(三氟甲基)苯基)乙烯
基)-9H-吡啶并[2,3-b]吲哚(R528)
将粗产物在甲醇中研磨并过滤后,以83%的收率得到棕色固体。1HNMR(500MHz,DMSO)δ11.92(s,NH),8.42(d,J=5.1Hz,1H),8.36(s,1H),8.31(d,J=16.3Hz,1H),8.05(d,J=8.0Hz,2H),7.83(d,J=8.1Hz,2H),7.71(d,J=15.9Hz,1H),7.71(d,J=8.7Hz,1H),7.62(d,J=8.7Hz,2H),7.57(d,J=8.4Hz,1H),7.52(d,J=5.2Hz,1H),7.05(d,J=8.7Hz,2H),3.22-3.15(m,4H),2.49-2.45(m,4H),2.23(s,3H);13C NMR(126MHz,DMSO)δ153.0(C),149.8(C),146.0(CH),140.5(C),139.6(C),138.1(C),133.0(CH),132.3(C),131.6(C),128.4(q,J=31.3Hz,C),127.9(CH),127.3(CH),127.0(CH),125.8(q,J=3.5Hz,CH),125.3(CH),124.3(q,J=271.8Hz,C),120.8(C),120.4(CH),115.8(CH),112.6(C),111.6(q,J=10.0Hz,CH),54.6(CH2),48.0(CH2),45.8(CH3);HRMS计算值:C31H28F3N4O[M+H]+513.2261实测值:513.2248。
实施例15:4-(3-氟-联苯-4-基)-6-[4-(4-甲基哌嗪-1-基)-苯基]-9H-吡啶并
[2,3-b]吲哚(R532)
在MeOH中研磨得到深黄色固体状所需产物,89%收率。1H-NMR(400MHz,DMSO)δ=12.06(s,1H),8.50(d,J=5.0Hz,1H),7.84-7.76(m,2H),7.76-7.65(m,4H),7.65-7.52(m,3H),7.52-7.41(m,2H),7.36(d,J=8.7Hz,2H),7.21(d,J=5.0Hz,1H),6.95(d,J=8.8Hz,2H),3.16-3.09(m,4H),2.46-2.39(m,4H),2.20(s,3H)。13C-NMR(101MHz,DMSO)δ=159.17(d,J=247.4Hz,Cq),152.78(Cq),149.84(Cq),146.29(CH),142.50(Cq),139.84(Cq),139.72(d,J=8.0Hz,Cq)138.11(Cq),134.66(Cq),131.77(Cq),131.31(Cq),131.17(d,J=3.9Hz,CH),128.96(CH),128.93(CH),128.86(2 CH),128.79(CH),128.76(CH),128.74(CH),128.25(2 CH),126.87(CH),125.39(d,J=5.7Hz,CH),120.16(Cq),119.04(CH),115.73(CH),115.69(CH),112.23(Cq),111.88(CH),54.58(2 CH2),47.93(2 CH2),45.78(CH3)。HRMS(ESI):计算值:C34H30FN4:513.2449;实测值:513.2435
实施例16:4-(4-苄基苯基)-6-[4-(4-甲基哌嗪-1-基)-苯基]-9H-吡啶并[2,3-b]
吲哚(R533)
在MeOH中研磨得到黄色固体状所需产物,78%收率。1H-NMR(400MHz,DMSO)δ=11.95(s,1H),8.43(d,J=5.0Hz,1H),7.71(s,1H),7.68-7.62(m,3H),7.53(d,J=8.5Hz,1H),7.50(d,J=8.0Hz,2H),7.35-7.25(m,6H),7.24-7.18(m,1H),7.09(d,J=5.0Hz,1H),6.91(d,J=8.7Hz,2H),4.09(s,2H),3.20-3.12(m,4H),2.49-2.43(m,4H),2.23(s,3H)。13C-NMR(101MHz,DMSO)δ=152.75(Cq),149.67(Cq),146.13(CH),144.30(Cq),142.04(Cq),141.28(Cq),137.96(Cq),136.06(Cq),131.37(Cq),131.23(Cq),129.13(2 CH),128.73(3 CH),128.51(3 CH),126.68(2 CH),125.97(CH),124.93(CH),120.44(Cq),119.03(CH),115.72(CH),115.66(2 CH),112.40(Cq),111.65(CH),54.59(2 CH2),48.01(2 CH2),45.79(CH3),40.92(CH2)。HRMS(ESI):计算值:C35H33N4:509.2700;实测值:509.2688。
实施例17:4-联苯-3-基-6-[4-(4-甲基哌嗪-1-基)-苯基]-9H-吡啶并[2,3-b]吲哚
(R534)
在MeOH中研磨得到米色固体状所需产物,60%收率。1H-NMR(400MHz,DMSO)δ=12.01(s,1H),8.49(d,J=5.0Hz,1H),8.09(d,J=1.6Hz,1H),7.91-7.85(m,1H),7.81-7.75(m,3H),7.73(m,2H),7.62(dd,J=8.5,1.6Hz,1H),7.55(d,J=8.4Hz,1H),7.52-7.46(m,2H),7.41(m,1H),7.24(d,J=5.0Hz,1H),7.12(d,J=8.7Hz,2H),6.78(d,J=8.8Hz,2H),3.15-3.02(m,4H),2.47-2.39(m,4H),2.21(s,3H)。13C-NMR(101MHz,DMSO)δ=152.86(Cq),149.67(Cq),146.32(CH),144.13(Cq),140.63(Cq),139.79(Cq),138.87(Cq),138.06(Cq),131.59(Cq),131.16(Cq),129.71(CH),129.07(2 CH),127.83(CH),127.67(CH),127.36(CH),127.19(CH),126.96(2 CH),126.76(2 CH),125.12(CH),120.36(Cq),119.17(CH),115.80(CH),115.59(2 CH),112.31(Cq),111.77(CH),54.55(2 CH2),47.96(2 CH2),45.78(CH3)。HRMS(ESI):计算值:C34H31N4:495.2543;实测值:495.2540。
实施例18:(E)-4-(2-(2-氟苯基)乙烯基)-6-(4-(4-甲基哌嗪-1-基)苯基)-9H-吡
啶并[2,3-b]吲哚(R542)
将粗产物在甲醇中研磨并过滤后,以74%的收率得到黄色固体。1HNMR(300MHz,DMSO)δ11.93(s,NH),8.41(d,J=5.2Hz,1H),8.34(s,1H),8.28(d,J=16.4Hz,1H),7.97(t,J=7.7Hz,1H),7.71(dd,J=8.5,1.1Hz,1H),7.65(d,J=16.6Hz,1H),7.62-7.51(m,4H),7.47-7.40(m,1H),7.40-7.30(m,2H),7.05(d,J=8.7Hz,2H),3.22-3.14(m,4H),2.48-2.43(m,4H),2.23(s,3H);13C NMR(101MHz,DMSO)δ160.4(d,J=249.5Hz,C),153.0(C),149.9(C),146.1(CH),139.8(C),138.1(C),132.3(C),131.6(C),130.4(d,J=8.6Hz,CH),129.4(d,J=3.5Hz,CH),127.3(d,J=7.5Hz,CH),127.2(CH),125.2(CH),125.1(d,J=2.9Hz,CH),124.0(d,J=11.2Hz,C),120.9(C),120.0(CH),116.2(d,J=21.4Hz),115.8(CH),112.5(C),111.7(CH),111.1(CH),54.6(CH2),48.0(CH2),45.8(CH3);HRMS计算值:C30H28FN4[M+H]+463.2293实测值:463.2275。
实施例19:(E)-4-(2-(2-氯苯基)乙烯基)-6-(4-(4-甲基哌嗪-1-基)苯基)-9H-吡
啶并[2,3-b]吲哚(R543)
将粗产物在甲醇中研磨并过滤后,以77%的收率得到黄色固体。1HNMR(400MHz,DMSO)δ11.95(s,NH),8.42(d,J=5.2Hz,1H),8.34(s,1H),8.24(d,J=16.2Hz,1H),8.15(dd,J=7.8,1.3Hz,1H),7.78(d,J=16.1Hz,1H),7.70(dd,J=8.4,1.4Hz,1H),7.62-7.54(m,4H),7.53-7.46(m,2H),7.42(td,J=7.8,1.4Hz,1H),7.03(d,J=8.8Hz,2H),3.20-3.14(m,4H),2.48-2.44(m,4H),2.23(s,3H);13C NMR(101MHz,DMSO)δ153.0(C),149.9(C),146.2(CH),139.7(C),138.1(C),134.1(C),132.7(C),132.3(C),131.6(C),130.2(CH),130.0(CH),129.9(CH),128.1(CH),127.9(CH),127.8(CH),127.3(CH),125.3(CH),120.8(C),120.3(CH),115.7(CH),112.6(C),111.7(CH),111.6(CH),54.6(CH2),48.0(CH2),45.8(CH3);HRMS计算值:C30H28ClN4[M+H]+479.1997实测值:479.1983。
实施例20:4,6-双-[4-(4-甲基哌嗪-1-基)-苯基]-9H-吡啶并[2,3-b]吲哚(R556)
经研磨步骤得到黄色固体状所需产物,76%收率。1H-NMR(300MHz,DMSO)δ=11.90(s,1H),8.39(d,J=5.0Hz,1H),7.89(d,J=1.2Hz,1H),7.64(dd,J=8.2,1.7Hz,1H),7.62(d,J=8.5Hz,2H),7.53(d,J=8.4Hz,1H),7.36(d,J=8.7Hz,2H),7.17(d,J=8.8Hz,2H),7.06(d,J=5.0Hz,1H),6.97(d,J=8.8Hz,2H),3.33-3.26(m,8H),3.20-3.09(m,4H),2.47-2.41(m,4H),2.24(s,3H),2.22(s,3H)。13C-NMR(101MHz,DMSO)δ=152.79(Cq),151.09(Cq),149.56(Cq),145.80(CH),144.45(Cq),137.76(Cq),131.38(Cq),131.29(Cq),129.20(2 CH),127.87(Cq),126.70(2 CH),124.61(CH),120.59(Cq),119.06(CH),115.50(2 CH),115.45(CH),114.71(2 CH),112.21(Cq),111.30(CH),54.39(2 CH2),54.26(2 CH2),47.88(2CH2),47.58(2 CH2),45.55(CH3),45.53(CH3)。HRMS(ESI):计算值:C33H37N6:517.3074;实测值:517.3058。
实施例21:4-(4-苄基苯基)-6-(4-(4-(1-甲基哌啶-4-基)哌嗪-1-基)苯基)-9H-吡
啶并[2,3-b]吲哚(R559)
将粗产物在甲醇中研磨并过滤后,以77%的收率得到白色固体。1HNMR(500MHz,DMSO)δ11.79(s,1H),8.43(d,J=5.0Hz,1H),7.70(s,1H),7.65(d,J=7.9Hz,3H),7.54(d,J=8.5Hz,1H),7.50(d,J=7.8Hz,2H),7.36-7.26(m,J=17.6,7.7Hz,6H),7.22(t,J=6.5Hz,1H),7.08(d,J=4.9Hz,1H),6.90(d,J=8.6Hz,2H),4.11(s,2H),3.21-3.17(m,4H),2.81(d,J=11.4Hz,2H),2.71-2.61(m,4H),2.17(s,4H),1.91(t,J=11.2Hz,2H),1.77(d,J=11.6Hz,2H),1.48(ddd,J=14.6,11.9,3.1Hz,2H);13CNMR(126MHz,DMSO)δ152.6(C),149.5(C),145.8(CH),144.1(C),141.7(C),140.9(C),137.8(C),135.9(C),131.2(C),131.0(C),128.8(CH),128.4(CH),128.4(CH),128.2(CH),126.4(CH),125.7(CH),124.6(CH),120.3(C),118.8(CH),115.4(CH),115.3(CH),112.3(C),111.3(CH),60.4(CH),54.5(2CH2),48.5(2CH2),48.4(2CH2),45.5(NCH3),40.7(CH2),27.7(2CH2);HRMS计算值:C40H42N5[M+H]+592.3435实测值:592.3418。
实施例22:(E)-6-(4-(4-(1-甲基哌啶-4-基)哌嗪-1-基)苯基)-4-(2-(2-(三氟甲基)
苯基)乙烯基)-9H-吡啶并[2,3-b]吲哚(R566)
将粗产物在甲醇中研磨并过滤后,以73%的收率得到黄色固体。1HNMR(500MHz,DMSO)δ11.62(s,1H),8.43(d,J=5.1Hz,1H),8.31(d,J=1.2Hz,1H),8.18(d,J=8.0Hz,1H),8.12(d,J=16.0Hz,1H),7.84-7.79(m,2H),7.73(dd,J=16.2,1.9Hz,1H),7.70(dd,J=8.5,1.6Hz,1H),7.63-7.58(m,2H),7.56(d,J=8.7Hz,2H),7.37(d,J=5.2Hz,1H),7.00(d,J=8.7Hz,2H),3.23-3.16(m,4H),2.80(d,J=11.7Hz,2H),2.69-2.63(m,4H),2.22(dt,1H),2.17(s,3H),1.92(td,J=11.6,2.0Hz,2H),1.76(d,J=12.0Hz,2H),1.49(ddd,J=15.1,11.9,3.6Hz,2H);13C NMR(126MHz,DMSO)δ152.7(C),149.5(C),145.7(CH),139.0(C),137.8(C),134.7(d,J=1.6Hz,C),132.4(CH),132.1(C),131.2(C),128.9(d,J=2.1Hz,CH),128.9(CH),128.2(CH),127.7(CH),126.7(CH),126.2(q,J=29.1Hz,C),125.6(q,J=5.3Hz,CH),124.8(CH),124.0(q,J=274.0Hz,C),120.5(C),119.6(CH),115.2(CH),112.3(C),111.2(CH),111.1(CH),60.3(CH),54.3(2CH2),48.3(2CH2),48.3(2CH2),45.2(NCH3),27.6(2CH2);HRMS计算值:C36H37F3N5[M+H]+596.2996实测值:596.2977。
实施例23:(4-{6-[4-(4-甲基哌嗪-1-基)-苯基]-9H-吡啶并[2,3-b]吲哚-4-基}-
苯基)-苯基-甲酮(R571)
经研磨步骤得到黄色固体状所需产物,54%收率。1H-NMR(300MHz,CDCl3)δ=8.34(d,J=5.1Hz,1H),7.94(d,J=8.1Hz,2H),7.84-7.71(m,5H),7.63-7.53(m,2H),7.52-7.40(m,3H),7.31(d,J=8.6Hz,2H),7.06(d,J=5.1Hz,1H),6.89(d,J=8.7Hz,2H),3.26-3.10(m,4H),2.87-2.49(m,4H),2.35(s,3H)。13C-NMR(75MHz,CDCl3)δ=197.58(CO),152.79(Cq),150.16(Cq),145.49(CH),144.97(Cq),143.65(Cq),138.90(Cq),138.03(Cq),137.80(Cq),134.02(Cq),133.38(CH),133.33(Cq),130.96(2 CH),130.60(2 CH),129.30(2 CH),128.96(2 CH),128.01(2 CH),126.66(CH),121.09(Cq),120.62(CH),117.13(2 CH),116.37(CH),114.52(Cq),112.11(CH),55.22(2 CH2),49.57(2 CH2),45.95(CH3)。HRMS(ESI):计算值:C35H31N4O:523.2492;实测值:523.2490。
实施例24:6-[4-(4-甲基哌嗪-1-基)-苯基]-4-(4-萘-1-基-苯基)-9H-吡啶并
[2,3-b]吲哚(R590)
将化合物通过硅胶快速色谱纯化(CH2Cl2/MeOH 99:1梯度至95:5)得到黄色固体,40%收率。1H-NMR(400MHz,CDCl3)δ=8.14(d,J=5.1Hz,1H),7.75-7.62(m,4H),7.56(d,J=8.0Hz,2H),7.46-7.39(m,3H),7.34-7.22(m,3H),7.19-7.11(m,3H),6.94(d,J=5.1Hz,1H),6.67(d,J=8.7Hz,2H),3.00-2.90(m,4H),2.42-2.34(m,4H),2.11(s,3H)。13C-NMR(101MHz,CDCl3)δ=152.00(Cq),149.22(Cq),145.45(Cq),144.55(CH),141.05(Cq),139.29(Cq),138.05(Cq),137.38(Cq),133.63(Cq),133.32(Cq),132.27(Cq),131.27(Cq),130.00(2 CH),128.30(2 CH),128.04(CH),127.62(CH),127.09(2 CH),126.68(CH),125.97(CH),125.44(2 CH),125.38(CH),125.04(CH),120.69(Cq),119.99(CH),116.39(2 CH),115.73(CH),114.17(Cq),111.16(CH),54.40(2 CH2),48.42(2 CH2),45.06(CH3)。HRMS(ESI):计算值:C38H33N4:545.2700;实测值:545.2690。
实施例25:(E)-4-(1,2-二苯基乙烯基)-6-[4-(4-甲基哌嗪-1-基)-苯基]-9H-吡啶
并[2,3-b]吲哚(R593)
将粗产物通过硅胶快速柱色谱纯化(DCM/MeOH 97:3至90:10)得到黄色固体状所需产物,74%收率。1H NMR(400MHz,CDCl3)δ11.33(s,NH),8.48(d,J=5.1Hz,1H),8.35(d,J=1.4Hz,1H),7.67(dd,J=8.4,1.7Hz,1H),7.58(d,J=8.4Hz,1H),7.39-7.33(m,2H),7.33-7.26(m,10H),7.20(s,1H),7.01(d,J=5.1Hz,1H),6.83(d,J=8.8Hz,2H),3.25-3.18(m,4H),2.64-2.57(m,4H),2.38(s,3H);13C NMR(101MHz,CDCl3)δ153.5(C),145.0(C),148.2(C),145.1(CH),139.2(C),139.0(C),138.2(C),136.8(C),133.1(C),132.8(C),132.6(CH),130.2(CH),129.8(CH),128.7(CH),128.5(CH),128.1(CH),127.7(CH),127.7(CH),125.6(CH),121.6(C),121.1(CH),116.9(CH),116.3(CH),114.8(C),111.4(CH),55.2(CH2),49.1(CH2),46.2(CH3);HRMS计算值:C36H33N4[M+H]+521.2700实测值:521.2690。
实施例26:4-[4-(2,4-二甲氧基苄基)苯基]-6-[4-(4-甲基哌嗪-1-基)-苯基]-9H-
吡啶并[2,3-b]吲哚(R596)
经研磨步骤得到黄色固体状所需产物,70%收率。1H-NMR(300MHz,CDCl3)δ=9.58(s,1H),8.48(d,J=5.1Hz,1H),7.99-7.90(m,1H),7.71-7.60(m,3H),7.53(d,J=8.4Hz,1H),7.40(d,J=8.4Hz,4H),7.11(d,J=5.1Hz,1H),7.05(d,J=8.2Hz,1H),6.95(d,J=8.7Hz,2H),6.51(d,J=2.3Hz,1H),6.44(dd,J=8.3,2.4Hz,1H),4.03(s,2H),3.81(s,6H),3.40-3.24(m,4H),2.81-2.62(m,4H),2.44(s,3H)。13C-NMR(75MHz,CDCl3)δ=159.62(Cq),158.37(Cq),153.07(Cq),149.71(Cq),146.01(Cq),145.44(CH),142.39(Cq),137.93(Cq),136.28(Cq),133.45(Cq),132.67(Cq),130.63(CH),129.28(2 CH),128.82(2 CH),127.69(2 CH),125.78(CH),122.08(Cq),121.53(Cq),120.67(CH),116.75(CH),116.61(2 CH),114.17(Cq),111.37(CH),104.31(CH),98.69(CH),55.56(CH3),55.54(CH3),54.99(2 CH2),48.80(2 CH2),45.88(CH3),35.31(CH2)。HRMS(ESI):计算值:C37H37N4O2:569.2911;实测值:569.2912。
实施例27:(E)-4-[1-(2-甲氧基苯基)-丙-1-烯-2-基]-6-[4-(4-甲基哌嗪-1-基)-
苯基]-9H-吡啶并[2,3-b]吲哚(R604)
将粗产物在甲醇中研磨并过滤后,以46%的收率得到浅黄色固体。1HNMR(400MHz,CDCl3)δ11.01(s,1H),8.58(d,J=1.1Hz,1H),8.51(d,J=5.0Hz,1H),7.70(dd,J=8.4,1.6Hz,1H),7.59(d,J=8.4Hz,1H),7.55(d,J=7.8Hz,1H),7.52(d,J=8.7Hz,2H),7.36-7.30(m,1H),7.15(d,J=5.1Hz,1H),7.09-7.02(m,2H),6.96(d,J=8.7Hz,2H),6.92(d,J=8.2Hz,1H),3.61(s,3H),3.34-3.20(m,4H),2.65(d,J=4.5Hz,4H),2.41(d,J=1.1Hz,3H),2.40(s,3H);13C NMR(101MHz,CDCl3)δ157.7(C),153.4(C),150.1(C),149.7(C),145.3(CH),138.0(C),135.2(C),133.7(C),133.0(C),130.3(CH),128.7(CH),128.0(CH),126.8(CH),126.2(C),125.7(CH),121.7(C),121.4(CH),120.2(CH),116.5(CH),115.0(CH),113.6(C),111.3(CH),110.6(CH),55.2(OCH3),55.2(2CH2),49.3(2CH2),46.2(NCH3),19.1(CH3);HRMS计算值:C32H33N4O[M+H]+489.2649实测值:489.2635。
实施例28:(E)-6-(4-(4-甲基哌嗪-1-基)苯基)-4-(1-苯基丙-1-烯-2-基)-9H-吡
啶并[2,3-b]吲哚(R569)
将粗品残余物通过硅胶快速色谱纯化(DCM/MeOH 98:2至95:5),然后在MeOH中研磨得到无色无定形固体状所需的区域异构体,64%收率。1H NMR(400MHz,CDCl3)δ10.48(s,1H),8.50(d,J=5.1Hz,1H),8.36(s,1H),7.70(dd,J=8.4,1.5Hz,1H),7.58(d,J=8.4Hz,1H),7.55-7.41(m,6H),7.33(t,J=7.2Hz,1H),7.12(d,J=5.1Hz,1H),6.95(d,J=8.9Hz,2H),6.94(s,1H),3.29-3.21(m,4H),2.65-2.56(m,4H),2.48(s,3H),2.38(s,3H);13C NMR(101MHz,CDCl3)δ153.24(C),150.20(C),149.55(C),145.62(CH),137.88(C),137.40(C),135.60(C),133.19(C),133.17(C),130.81(CH),129.26(CH),128.60(CH),127.84(CH),127.26(CH),125.74(CH),121.52(C),120.98(CH),116.41(CH),115.07(CH),113.47(C),111.42(CH),55.27(CH2),49.22(CH2),46.33(NCH3),19.03(CH3);HRMS计算值:C31H31N4[M+H]+459.2543实测值:459.2522。
实施例29:N-[(E)-2-(2-{6-[4-(4-甲基哌嗪-1-基)-苯基]-9H-吡啶并[2,3-b]吲
哚-4-基}-乙烯基)-苯基]-甲磺酰胺(R589)
经研磨步骤得到黄色固体状所需产物,43%收率。1H-NMR(300MHz,CDCl3/MeOD 7:2)δ=8.16(d,J=5.2Hz,2H),7.93-7.71(m,4H),7.56-7.50(m,1H),7.48-7.39(m,4H),7.34(m,2H),6.91(d,J=8.6Hz,2H),3.16-3.07(m,4H),2.84(s,3H),2.64-2.46(m,4H),2.26(s,3H)。HRMS(ESI):计算值:C31H32N5O2S:538.2271;实测值:538.2270。
实施例30:(E)-6-[4-(4-甲基哌嗪-1-基)-苯基]-4-(1-苯基-丁-1-烯基)-9H-吡啶
并[2,3-b]吲哚(R594)
混合物A:4,4,5,5-四甲基-2-(1-苯基-丁-1-烯基)-[1,3,2]二氧硼戊环和2-(1-亚
苄基-丙基)-4,4,5,5-四甲基-[1,3,2]二氧硼戊环
在密封管中加入芳香族炔烃(150mg,1eq)和频哪醇硼烷(2.5eq)。将管在100℃搅拌65小时。冷却至室温后,将反应混合物用20mL EtOAc稀释。然后,将有机相用1/1盐水/水混合物(2×20mL)洗涤,用MgSO4干燥,过滤并真空蒸发。将油状粗品残余物通过硅胶柱色谱纯化(PE/DCM 75:25)得到无色油状的52:48区域异构体的混合物,80%收率。主要的化合物(由52:48混合物推定);1H NMR(500MHz,CDCl3)δ7.34-7.28(m,3H),7.22-7.19(m,1H),7.16-7.13(m,1H),6.57(t,J=7.3Hz,1H),2.16(p,J=7.5Hz,2H),1.27(s,12H),1.00(t,J=7.5Hz,3H);13C NMR(126MHz,CDCl3)δ150.0(CH),140.3(C),129.1(CH),128.2(CH),126.0(CH),83.6(C),24.9(CH3),22.8(CH2),14.0(CH3);次要的化合物(由52:48混合物推定);1HNMR(500MHz,CDCl3)δ7.34-7.28(m,3H),7.26(s,1H),7.22-7.19(m,1H),7.16-7.13(m,1H),2.39(q,J=7.1Hz,2H),1.32(s,12H),1.10(t,J=7.5Hz,3H);13C NMR(126MHz,CDCl3)δ141.5(CH),138.0(C),129.1(CH),127.9(CH),127.2(CH),83.5(C),24.9(CH3),23.4(CH2),14.8(CH3);MS(ESI)m/z:259.0[M+H]+,281.0[M+Na]+。
(E)-6-[4-(4-甲基哌嗪-1-基)-苯基]-4-(1-苯基-丁-1-烯基)-9H-吡啶并[2,3-b]吲
哚
将上述的混合物A通过典型方法B处理。将粗产物通过硅胶快速柱色谱纯化(DCM/MeOH 97:3至90:10)得到白色固体状的区域异构体的混合物,59%化学收率。按照典型方法A脱保护,然后将白色固体在甲醇中研磨并过滤得到所需的纯净区域异构体。
1H NMR(400MHz,CDCl3)δ10.39(s,1H),8.41(d,J=5.1Hz,1H),8.20(d,J=1.4Hz,1H),7.64(dd,J=8.4,1.7Hz,1H),7.54(d,J=8.4Hz,1H),7.45(d,J=8.7Hz,2H),7.36(d,J=4.3Hz,4H),7.32-7.27(m,1H),7.00(d,J=8.8Hz,2H),6.94(d,J=5.1Hz,1H),6.20(t,J=7.5Hz,1H),3.35-3.24(m,4H),2.70-2.60(m,4H),2.53(p,J=7.5Hz,2H),2.40(s,3H),1.19(t,J=7.5Hz,3H);13C NMR(101MHz,CDCl3)δ153.3(s),150.0(s),148.1(s),145.3(CH),139.1(s),138.1(s),137.8(s),136.1(CH),133.6(s),133.1(s),129.7(CH),128.4(CH),128.0(CH),127.5(CH),125.8(CH),121.7(s),121.3(CH),117.5(CH),116.4(CH),114.4(s),111.2(CH),55.2(CH2),49.1(CH2),46.2(CH3),23.3(CH2),14.5(CH3);HRMS计算值:C32H33N4[M+H]+473.2700实测值:473.2709。
实施例31:(E)-6-(4-(4-甲基哌嗪-1-基)苯基)-4-(1-苯基丁-1-烯-2-基)-9H-吡
啶并[2,3-b]吲哚和(E)-6-(4-(4-甲基哌嗪-1-基)苯基)-4-(1-苯基丁-1-烯-1-
基)-9H-吡啶并[2,3-b]吲哚(R595)的62:38混合物
将实施例30的混合物研磨后,将甲醇相蒸发至干。1H NMR(400MHz,CDCl3)δ10.59(s,1.02H),8.50(d,J=5.1Hz,0.51H),8.43-8.39(m,0.91H),8.21(d,J=1.4Hz,0.37H),7.70(dd,J=8.4,1.8Hz,0.62H),7.65(dd,J=8.4,1.8Hz,0.43H),7.59(d,J=8.4Hz,0.64H),7.55(d,J=8.3Hz,0.50H),7.51-7.42(m,4.32H),7.36(d,J=4.4Hz,1.96H),7.11(d,J=5.1Hz,0.61H),7.01(d,J=8.9Hz,0.83H),6.98-6.92(m,1.93H),6.87(s,0.61H),6.20(t,J=7.5Hz,0.35H),3.37-3.22(m,4.06H),2.94(q,J=7.5Hz,1.19H),2.72-2.60(m,4.21H),2.53(qu,J=7.5Hz,0.82H),2.41(s,3.15H),1.19(t,J=7.5Hz,1.19H),1.08(t,J=327.5Hz,1.80H)。
将1.11ppm和1.00ppm(CH3质子)的信号以及6.20ppm和6.87ppm(乙烯基质子)的信号的积分比平均后测得62/38的比例。区域异构体组成通过1H NMR测定。
实施例32:(E)和(Z)-6-(4-(4-甲基哌嗪-1-基)苯基)-4-(2-(三异丙基硅烷基)乙
烯基)-9H-吡啶并[2,3-b]吲哚R(607)
将粗产物通过硅胶快速色谱纯化(DCM/MeOH 98:2至94:6),以45%的收率得到E/Z异构体的74:26比例的混合物,为黄色无定形固体。主要的化合物(由74:26混合物推定)1H NMR(300MHz,CDCl3)δ10.92(s,1H),8.49(d,J=5.5Hz,1H),8.35(d,J=1.2Hz,1H),7.99(d,J=19.4Hz,1H),7.72(dd,J=8.5,1.5Hz,1H),7.64-7.55(m,3H),7.36(d,J=5.3Hz,1H),7.04(d,J=8.8Hz,2H),6.85(d,J=19.3Hz,1H),3.38-3.23(m,4H),2.75-2.59(m,4H),2.42(s,3H),1.38-1.26(m,3H),1.20(d,J=6.6Hz,18H);13CNMR(101MHz,CDCl3)δ153.5(C),150.1(C),145.4(CH),142.7(C),141.9(CH),138.1(C),133.4(C),133.4(C),132.6(CH),127.9(CH),125.7(CH),121.9(C),121.4(CH),116.5(CH),113.7(C),111.9(CH),111.6(CH),55.2(2CH2),49.1(2CH2),46.2(NCH3),19.0(6CH3),11.2(3CH)。
次要的化合物(由74:26混合物推定)1H NMR(300MHz,CDCl3)δ10.92(s,1H),8.47(d,J=6.0Hz,1H),8.27(d,J=1.2Hz,1H),8.07(d,J=16.0Hz,1H),7.69(dd,J=7.2,1.6Hz,1H),7.64-7.55(m,3H),7.13(s,1H),7.05(d,J=8.9Hz,2H),6.24(d,J=16.0Hz,1H),3.41-3.21(m,4H),2.77-2.58(m,4H),2.42(s,3H),1.11-1.00(m,3H),0.96(d,J=6.3Hz,18H);13CNMR(101MHz,CDCl3)δ152.6(C),150.1(C),145.0(CH),144.5(C),144.2(CH),137.9(C),133.6(C),133.6(C),132.2(CH),128.1(CH),125.9(CH),122.1(C),121.5(CH),116.5(CH),114.9(CH),114.3(C),111.3(CH),55.2(2CH2),49.1(2CH2),46.2(NCH3),19.0(6CH3),12.4(3CH);HRMS计算值:C33H45N4Si[M+H]+525.3408实测值:525.3390。
实施例33:(4-{6-[4-(4-甲基哌嗪-1-基)-苯基]-9H-吡啶并[2,3-b]吲哚-4-基}-
苯基)-苯基-甲醇(R570)
向R571(实施例23)(12mg,0.023mmol)在CH2Cl2/MeOH 5:2(0.7mL)中的溶液中加入NaBH4(2mg,0.046mmol)。在室温下搅拌1小时后,将反应混合物用饱和NH4Cl水溶液(0.3mL)终止反应,用CH2Cl2(20mL)稀释并用水(20mL)洗涤。收集有机层并将水层用CH2Cl2(20mL)洗涤两次。将合并的有机层用MgSO4干燥,过滤并蒸发至干得到黄色固体状所需化合物(12mg,定量)。1H-NMR(300MHz,CDCl3)δ=8.20(d,J=5.2Hz,1H),7.71(d,J=1.4Hz,1H),7.55(d,J=8.3Hz,2H),7.51(dd,J=8.5,1.7Hz,1H),7.47(d,J=8.2Hz,2H),7.39(d,J=8.4Hz,1H),7.34-7.28(m,2H),7.24-7.17(m,4H),7.17-7.09(m,1H),6.93(d,J=5.2Hz,1H),6.79(d,J=8.8Hz,2H),5.80(s,1H),3.18-3.03(m,4H),2.58-2.45(m,4H),2.25(s,3H)。13C-NMR(101MHz,CDCl3)δ=152.76(Cq),149.98(Cq),146.34(Cq),145.65(Cq),145.25(CH),144.77(Cq),138.74(Cq),138.04(Cq),134.06(Cq),132.94(Cq),129.15(2 CH),128.87(2 CH),127.83(2 CH),127.75(CH),127.31(4 CH),126.20(CH),121.41(Cq),120.65(CH),117.18(2 CH),116.67(CH),114.73(Cq),111.89(CH),75.97(CH),55.21(2 CH2),49.29(2CH2),45.89(CH3)。HRMS(ESI):计算值:C35H33N4O:525.2649;实测值:525.2653。
实施例34:{6-[4-(4-甲基哌嗪-1-基)-苯基]-9H-吡啶并[2,3-b]吲哚-4-基}-(2-
硝基-苯基)-胺(R548)
9-苯磺酰基-6-(4-(4-甲基哌嗪-1-基)苯基)-N-(2-硝基苯基)-9H-吡啶并[2,3-b]
吲哚-4-胺
在配有搅拌棒的Schlenk管中,加入6-取代的-咔啉(1eq)、K2CO3(3eq)、2-硝基-苯胺(1.3eq)、X-phos(0.16eq)和Pd2(dba)3(0.08eq)。将管排空并用氩气回填(将其再重复3次)。然后加入t-BuOH得到0.05M的悬浮液(使用脱气的溶剂)。将反应混合物在100℃搅拌15小时。冷却至室温并用EtOAc稀释后,将混合物用垫过滤。减压除去滤液中的溶剂。将粗产物在甲醇中研磨并过滤后,以69%的收率得到黄色固体。1H NMR(300MHz,CDCl3)δ10.10(s,1H),8.56(d,J=8.8Hz,1H),8.46(d,J=5.6Hz,1H),8.26(dd,J=8.5,1.3Hz,1H),8.22(d,J=1.5Hz,1H),8.18(d,J=7.3Hz,2H),7.78(dd,J=8.8,1.6Hz,1H),7.63-7.49(m,5H),7.43(t,J=7.6Hz,2H),7.32(d,J=5.6Hz,1H),7.06(dd,J=8.4,1.2Hz,1H),7.01(d,J=8.6Hz,2H),3.35-3.19(m,4H),2.68-2.53(m,4H),2.37(s,3H);13CNMR(75MHz,CDCl3)δ153.1(C),150.7(C),147.7(CH),142.5(C),138.8(C),138.5(C),137.5(C),136.3(C),135.9(C),135.8(CH),134.1(CH),131.4(C),129.1(CH),127.9(CH),127.8(CH),127.0(CH),126.7(CH),122.5(C),121.1(CH),119.4(CH),118.5(CH),116.4(CH),115.2(CH),110.0(C),109.0(CH),55.1(CH2),48.9(CH2),46.2(CH3);MS(ESI)m/z:310.1[M+2H]2+,619.2[M+H]+。
{6-[4-(4-甲基哌嗪-1-基)-苯基]-9H-吡啶并[2,3-b]吲哚-4-基}-(2-硝基-苯基)-
胺(R548)
将9-苯磺酰基-6-(4-(4-甲基哌嗪-1-基)苯基)-N-(2-硝基苯基)-9H-吡啶并[2,3-b]吲哚-4-胺按照上述典型方法A进行处理。
经研磨步骤得到棕色固体状所需产物,69%收率。1H-NMR(300MHz,DMSO)δ=11.92(s,1H),9.75(s,1H),8.31(d,J=5.5Hz,1H),8.26(dd,J=8.4,1.4Hz,1H),7.96(d,J=0.8Hz,1H),7.67(dd,J=8.5,1.5Hz,1H),7.67-7.60(m,1H),7.54(d,J=8.5Hz,1H),7.50-7.45(m,1H),7.42(d,J=8.7Hz,2H),7.24-7.16(m,1H),7.10(d,J=5.5Hz,1H),6.98(d,J=8.8Hz,2H),3.22-3.12(m,4H),2.48-2.41(m,4H),2.22(s,3H)。13C NMR(101MHz,DMSO)δ154.0(C),149.8(C),147.1(CH),142.5(C),138.1(C),137.2(C),137.1(C),135.8(CH),131.9(C),131.2(C),127.0(CH),126.3(CH),124.4(CH),121.3(CH),120.4(CH),119.8(C),119.0(CH),115.6(CH),111.3(CH),106.1(C),105.8(CH),54.6(CH2),48.0(CH2),45.8(CH3)。HRMS(ESI):计算值:C28H27N6O2:479.2195;实测值:479.2137。
实施例35和36按照与实施例34类似的方式,相应地从结构模块A或C合成。
实施例35:6-(4-(4-甲基哌嗪-1-基)苯基)-N-(3-硝基苯基)-9H-吡啶并[2,3-b]
吲哚-4-胺(R547)
将粗产物在甲醇中研磨并过滤后,以57%的收率得到亮黄色固体。
1H NMR(300MHz,DMSO)δ11.80(s,NH),9.20(s,NH),8.22(d,J=5.5Hz,1H),8.13(s,1H),8.07(ft,J=1.9Hz,1H),7.86(d,J=7.9Hz,1H),7.70(d,J=8.4Hz,1H),7.66-7.58(m,J=8.1Hz,2H),7.50(d,J=8.2Hz,1H),7.48(d,J=8.5Hz,2H),6.98(d,J=8.2Hz,2H),6.96(d,J=5.2Hz,1H),3.21-3.06(m,4H),2.48-2.41(m,4H),2.22(s,3H);13C NMR(75MHz,DMSO)δ154.2(C),149.7(C),148.6(C),147.0(CH),144.5(C),143.5(C),136.9(C),131.6(C),131.5(C),130.5(CH),127.1(CH),125.5(CH),123.9(CH),120.3(CH),120.2(C),116.0(CH),115.6(CH),113.5(CH),110.9(CH),104.9(C),103.5(CH),54.6(CH2),48.1(CH2),45.8(CH3);HRMS计算值:C28H27N6O2[M+H]+479.2190实测值:479.2182。
实施例36:6-(4-(4-(1-甲基哌啶-4-基)哌嗪-1-基)苯基)-N-(2-硝基苯基)-9H-
吡啶并[2,3-b]吲哚-4-胺(R567)
将粗产物在甲醇中研磨并过滤后,以91%的收率得到深红色固体。1HNMR(400MHz,DMSO)δ11.92(s,1H),9.75(s,1H),8.31(d,J=5.5Hz,1H),8.26(dd,J=8.5,1.5Hz,1H),7.97(d,J=1.2Hz,1H),7.69-7.60(m,2H),7.54(d,J=8.5Hz,1H),7.49(dd,J=8.4,1.0Hz,1H),7.42(d,J=8.8Hz,2H),7.19(ddd,J=8.3,7.2,1.2Hz,1H),7.10(d,J=5.6Hz,1H),6.96(d,J=8.9Hz,2H),3.18-3.10(m,4H),2.81(d,J=11.7Hz,2H),2.65-2.57(m,4H),2.15(s,4H),1.86(t,J=10.9Hz,2H),1.75(d,J=12.4Hz,2H),1.43(ddd,J=15.3,11.8,3.1Hz,2H);13C NMR(101MHz,DMSO)δ154.03(s),149.84(s),147.14(CH),142.49(s),138.11(s),137.20(s),137.09(s),135.77(CH),131.93(s),131.23(s),126.98(CH),126.33(CH),124.37(CH),121.33(CH),120.48(CH),119.82(s),119.04(CH),115.54(CH),111.34(CH),106.03(s),105.70(CH),60.62(CH),54.74(2CH2),48.76(2CH2),48.49(2CH2),45.76(NCH3),27.87(2CH2);HRMS计算值:C33H37N7O2[M+2H]2+281.6499实测值:281.6496。
实施例37:6-[4-(4-甲基哌嗪-1-基)-苯基]-4-苯基乙炔基-9H-吡啶并[2,3-b]吲
哚(R523)
9-苯磺酰基-6-[4-(4-甲基哌嗪-1-基)-苯基]-4-苯基乙炔基-9H-吡啶并[2,3-b]
吲哚
将结构模块A置于Schlenk管中,然后加入PdCl2(CH3CN)2(0.08当量)、2-二环己基膦-2',4',6'-三异丙基联苯(0.16当量)和Cs2CO3(2.6当量)。将管排空并用氩气回填(将其再重复三次)。加入无水乙腈(使1的浓度为0.08M)然后注射炔(1.3当量)。将反应混合物在90℃搅拌过夜。然后将反应混合物冷却至室温并用H2O mQ(1mL)终止反应。将其用EtOAc(3体积)稀释然后用Celite过滤,将Celite垫用EtOAc(10mL)洗涤5次。将滤液用H2O/盐水1:1(50mL)洗涤两次,用Mg2SO4干燥并蒸发至干。将残余物悬浮在最少量的甲醇中,研磨并过滤,将固体用甲醇洗涤,以82%的收率得到棕色固体状所需化合物。1H-NMR(300MHz,CDCl3)δ=8.82(d,J=1.6Hz,1H),8.61-8.48(m,2H),8.16(d,J=7.7Hz,2H),7.82(dd,J=8.8,1.8Hz,1H),7.71-7.57(m,4H),7.53(t,J=7.4Hz,1H),7.48-7.35(m,6H),7.01(d,J=8.7Hz,2H),3.44-3.26(m,4H),2.83-2.65(m,4H),2.46(s,3H)。13C-NMR(75MHz,CDCl3)δ=150.76(Cq),146.33(CH),138.75(Cq),137.04(Cq),136.67(Cq),134.09(CH),132.07(Cq,2 CH),131.81(Cq),129.72(CH),129.06(2 CH),128.78(2 CH),127.92(2 CH),127.64(2 CH),127.42(CH),124.96(Cq),123.55(Cq),122.06(Cq),121.64(CH),120.20(CH),118.41(Cq),116.27(2 CH),115.03(CH),98.92(Cq),85.93(Cq),55.12(2 CH2),48.94(2 CH2),46.22(CH3)。ESI-MS:583.2m/z
6-[4-(4-甲基哌嗪-1-基)-苯基]-4-苯基乙炔基-9H-吡啶并[2,3-b]吲哚
将9-苯磺酰基-6-[4-(4-甲基哌嗪-1-基)-苯基]-4-苯基乙炔基-9H-吡啶并[2,3-b]吲哚按照典型方法A进行处理。在MeOH中研磨后以81%的收率得到棕色固体状所需产物。1H-NMR(300MHz,DMSO)δ=12.07(s,1H),8.69(d,J=2.2Hz,1H),8.46(d,J=5.1Hz,1H),7.82-7.74(m,3H),7.63-7.54(m,6H),7.34(d,J=5.1Hz,1H),7.04(d,J=8.7Hz,2H),3.23-3.14(m,4H),2.49-2.44(m,4H),2.24(s,3H)。13C-NMR(101MHz,DMSO)δ=152.27(Cq),149.85(Cq),145.83(CH),137.99(Cq),132.28(Cq),131.46(2CH),131.23(Cq),129.68(CH),128.97(2 CH),126.94(2 CH),125.66(CH),122.62(Cq),121.43(Cq),120.52(Cq),118.69(CH),116.77(CH),115.58(2CH),114.46(Cq),111.68(CH),96.75(Cq),86.54(Cq),54.42(2 CH2),47.87(2 CH2),45.54(CH3)。HRMS(ESI):计算值:C30H27N4:443.2230;实测值:443.2247。
按照与实施例37类似的方式合成如下实施例38至43。
实施例38:4-(2-甲氧基苯基乙炔基)-6-[4-(4-甲基哌嗪-1-基)-苯基]-9H-吡啶
并[2,3-b]吲哚(R538)
经研磨步骤得到棕色粉末状所需产物,79%收率。1H-NMR(400MHz,DMSO)δ=12.04(s,1H),8.83(d,J=1.1Hz,1H),8.43(d,J=5.1Hz,1H),7.73(dd,J=8.5,1.6Hz,1H),7.68(dd,J=7.5,1.4Hz,1H),7.58(d,J=8.4Hz,1H),7.56-7.47(m,3H),7.31(d,J=5.1Hz,1H),7.18(d,J=8.4Hz,1H),7.08(t,J=7.5Hz,1H),7.01(d,J=8.7Hz,2H),3.69(s,3H),3.20-3.13(m,4H),2.48-2.42(m,4H),2.22(s,3H)。13C-NMR(101MHz,DMSO)δ=160.11(Cq),152.41(Cq),149.97(Cq),145.92(CH),137.99(Cq),133.52(CH),132.58(Cq),131.66(Cq),131.61(CH),127.30(2 CH),126.06(CH),123.21(Cq),120.80(CH),120.66(Cq),119.08(CH),117.11(CH),115.74(2CH),114.35(Cq),111.64(2 CH),110.46(Cq),94.13(Cq),90.28(Cq),55.86(CH3),54.61(2 CH2),48.10(2 CH2),45.84(CH3)。HRMS(ESI):计算值:C31H29N4O:473.2336;实测值:473.2332。
实施例39:6-[4-(4-甲基哌嗪-1-基)-苯基]-4-(2-三氟甲基-苯基乙炔基)-9H-吡
啶并[2,3-b]吲哚(R539)
经研磨步骤得到橙色固体状所需产物,71%收率。1H-NMR(400MHz,DMSO)δ=11.98(s,1H),8.61(d,J=1.4Hz,1H),8.48(d,J=5.0Hz,1H),8.03(d,J=7.6Hz,1H),7.92(d,J=7.9Hz,1H),7.85(t,J=7.6Hz,1H),7.76(dd,J=8.4,1.7Hz,2H),7.76-7.70(m,J=7.8Hz,2H),7.61(d,J=8.5Hz,1H),7.53(d,J=8.7Hz,2H),7.34(d,J=5.0Hz,1H),6.98(d,J=8.7Hz,2H),3.20-3.15(m,5H),2.49-2.44(m,4H),2.24(s,3H)。13C-NMR(101MHz,DMSO)δ=152.29(Cq),149.80(Cq),145.76(CH),138.04(Cq),134.38(CH),132.69(CH),132.47(Cq),131.14(Cq),129.95(CH),129.66(Cq),126.97(2 CH),126.25(d,J=5.0Hz,CH),126.00(CH),123.43(d,J=273.4Hz,Cq),121.70(Cq),120.22(Cq),119.22(Cq),118.57(CH),117.34(CH),115.43(2 CH),114.18(Cq),111.69(CH),91.96(Cq),91.45(Cq),54.43(2 CH2),47.87(2 CH2),45.56(CH3)。HRMS(ESI):计算值:C31H26F3N4:511.2104;实测值:511.2091
实施例40:4-((4-氟苯基)乙炔基)-6-[4-(4-甲基哌嗪-1-基)-苯基]-9H-吡啶并
[2,3-b]吲哚(R540)
经研磨步骤得到黄色固体状所需产物,86%收率。1H-NMR(500MHz,DMSO)δ=11.91(s,1H),8.66(d,J=1.3Hz,1H),8.45(d,J=5.0Hz,1H),7.85-7.80(m,2H),7.77(dd,J=8.4,1.3Hz,1H),7.61(d,J=8.4Hz,1H),7.56(d,J=8.6Hz,2H),7.41(t,J=8.8Hz,2H),7.32(d,J=5.0Hz,1H),7.03(d,J=8.6Hz,2H),3.25-3.20(m,4H),2.49-2.44(m,4H),2.25(s,3H)。13C-NMR(126MHz,DMSO)δ=162.48(d,J=249.4Hz,Cq),152.21(Cq),149.79(Cq),145.69(CH),137.91(Cq),133.80(CH),133.73(CH),132.19(Cq),131.09(Cq),126.78(2 CH),125.54(CH),122.40(Cq),120.41(Cq),118.56(CH),117.86(d,J=3.4Hz,Cq),116.67(CH),116.29(CH),116.11(CH),115.49(2 CH),114.36(Cq),111.56(CH),95.56(Cq),86.25(Cq),54.38(2 CH2),47.83(2 CH2),45.49(CH3)。HRMS(ESI):计算值:C30H26FN4:461.2136;实测值:461.2138。
实施例41:4-((2-氟苯基)乙炔基)-6-[4-(4-甲基哌嗪-1-基)-苯基]-9H-吡啶并
[2,3-b]吲哚(R541)
经研磨步骤得到棕色固体状所需产物,71%收率。1H-NMR(400MHz,DMSO)δ=12.13(s,1H),8.72(s,1H),8.47(d,J=5.0Hz,1H),7.84(t,J=7.0Hz,1H),7.78(d,J=8.1Hz,1H),7.66-7.46(m,5H),7.41(d,J=7.3Hz,1H),7.37(d,J=4.9Hz,1H),7.03(d,J=8.6Hz,2H),3.24-3.10(m,4H),2.48-2.41(m,4H),2.23(s,3H)。13C-NMR(101MHz,DMSO)δ=162.16(d,J=250.7Hz,Cq),152.38(Cq),149.99(Cq),146.03(CH),138.11(Cq),133.76(CH),132.48(Cq),132.32(d,J=7.0Hz,CH),131.21(Cq),127.12(2CH),126.11(CH),125.26(d,J=3.3Hz,CH),122.12(Cq),120.45(Cq),118.64(CH),117.22(CH),116.18(d,J=20.4Hz,CH),115.66(2 CH),114.37(Cq),111.88(CH),109.95(d,J=15.4Hz,Cq),91.47(Cq),90.08(Cq),54.65(2 CH2),48.00(2 CH2),45.84(CH3)。HRMS(ESI):计算值:C30H26FN4:461.2136;实测值:461.2129。
实施例42:4-((2-氯苯基)乙炔基)-6-[4-(4-甲基哌嗪-1-基)-苯基]-9H-吡啶并
[2,3-b]吲哚(R549)
研磨操作无法纯化所需化合物,将其通过硅胶快速色谱纯化(CH2Cl2/EtOH 85:15),以26%的收率得到黄色固体。1H-NMR(300MHz,CDCl3)δ=9.82(s,1H),8.90(s,1H),8.46(d,J=4.9Hz,1H),7.74(d,J=8.5Hz,2H),7.63(d,J=8.4Hz,2H),7.56(d,J=8.2Hz,1H),7.51(d,J=7.8Hz,1H),7.40-7.30(m,3H),7.03(d,J=8.5Hz,2H),3.33-3.25(m,4H),2.69-2.58(m,4H),2.39(s,3H)。13C-NMR(101MHz,CDCl3)δ=152.68(Cq),150.33(Cq),145.21(CH),137.78(Cq),136.31(Cq),134.14(CH),133.98(Cq),133.28(Cq),130.38(CH),129.72(CH),128.17(2 CH),126.84(2 CH),124.11(Cq),122.79(Cq),121.65(Cq),120.79(CH),118.69(CH),116.43(2CH),116.26(Cq),111.25(CH),94.14(Cq),91.68(Cq),55.30(2 CH2),49.29(2 CH2),46.33(CH3)。HRMS(ESI):计算值:C30H26ClN4:477.1825;实测值:477.1817。
实施例43:6-(4-(4-甲基哌嗪-1-基)苯基)-4-((三异丙基硅烷基)乙炔基)-9H-
吡啶并[2,3-b]吲哚(R606)
将粗产物通过硅胶快速柱色谱纯化(DCM/MeOH 100:0至95:5),以37%的化学收率得到深黄色无定形固体状所需产物。1H NMR(400MHz,CDCl3)δ9.70(s,1H),8.75(d,J=1.6Hz,1H),8.41(d,J=5.1Hz,1H),7.71(dd,J=8.4,1.8Hz,1H),7.59(d,J=8.7Hz,2H),7.55(d,J=8.4Hz,1H),7.27(d,J=6.5Hz,1H),7.00(d,J=8.7Hz,2H),3.45-3.27(m,4H),2.87-2.70(m,4H),2.50(s,3H),1.30-1.21(m,3H),1.19(d,J=6.0Hz,18H);13CNMR(101MHz,CDCl3)δ152.6(C),149.9(C),145.2(CH),137.7(C),133.9(C),133.8(C),128.3(CH),126.8(CH),124.7(C),121.7(C),120.8(CH),119.4(CH),116.6(CH),116.2(C),111.2(CH),103.9(C),100.9(C),54.9(2CH2),48.9(2CH2),45.7(NCH3),18.9(6CH3),11.5(3CH);HRMS计算值:C33H43N4Si[M+H]+523.3252实测值:523.3232。
实施例44:4-乙炔基-6-(4-(4-甲基哌嗪-1-基)苯基)-9H-吡啶并[2,3-b]吲哚
R(608)
将实施例43所用的前体9-苯磺酰基-6-(4-(4-甲基哌嗪-1-基)苯基)-4-((三异丙基硅烷基)乙炔基)-9H-吡啶并[2,3-b]吲哚(按照与实施例37类似的方式获得)用如下方法同时脱除苯磺酰基和三异丙基硅烷基保护基。在惰性气氛下,向9-苯磺酰基-6-(4-(4-甲基哌嗪-1-基)苯基)-4-((三异丙基硅烷基)乙炔基)-9H-吡啶并[2,3-b]吲哚(73.8mg,0.111mmol)的无水THF溶液(2.8mL,0.05M)中滴加TBAF溶液(1M的THF溶液,3eq,330μL)。将反应液在70℃搅拌2.5小时。冷却至室温后,将混合物小心地用水和盐水终止反应。将水层用DCM(3×40mL)萃取。将合并的有机层用盐水洗涤,用MgSO4干燥,过滤并减压浓缩。将粗产物首先通过硅胶快速色谱纯化(DCM/MeOH 95:5至94:6)得到含有TBAF杂质的所需产物。将该混合物在甲醇中研磨、然后在DCM中研磨并过滤,重复两次,以41%的收率得到浅黄色固体。1H NMR(300MHz,DMSO)δ12.07(s,1H),8.59(d,J=1.1Hz,1H),8.42(d,J=5.0Hz,1H),7.76(dd,J=8.5,1.7Hz,1H),7.59(d,J=8.7Hz,1H),7.55(d,J=8.8Hz,2H),7.28(d,J=5.0Hz,1H),7.06(d,J=8.8Hz,2H),5.09(s,1H),3.25-3.09(m,8H),2.24(s,3H);13C NMR(101MHz,DMSO)δ152.29(C),149.93(C),145.94(CH),138.04(C),132.39(C),131.36(C),127.13(CH),126.07(CH),122.20(C),120.33(C),118.66(CH),117.79(CH),115.81(CH),114.71(C),111.80(CH),89.04(C),80.61(CH),54.55(2CH2),47.96(2CH2),45.75(NCH3);HRMS计算值:C24H23N4[M+H]+367.1917实测值:367.1914。
实施例45:4-(2-甲氧基苯基乙炔基)-9-甲基-6-[4-(4-甲基哌嗪-1-基)-苯
基]-9H-吡啶并[2,3-b]吲哚(R555)
在0℃及惰性气氛下,向0.04M的R538(实施例38)的DMF溶液中加入NaH(60%矿物油分散液,2当量)。在0℃下搅拌0.33小时后,缓慢加入CH3I(1当量)。除去冰浴并将反应液在室温下搅拌1小时。然后用H2O(0.1mL)终止反应,用CH2Cl2(20mL)稀释并用H2O/盐水1:1(20mL)洗涤两次。将有机层用MgSO4干燥,过滤并蒸发至干。通过硅胶快速色谱纯化(CH2Cl2/EtOH 95:5)得到黄色固体状所需产物,76%收率。1H-NMR(300MHz,CDCl3)δ=9.06(d,J=1.6Hz,1H),8.45(d,J=5.1Hz,1H),7.75(dd,J=8.5,1.8Hz,1H),7.66(dd,J=7.6,1.7Hz,1H),7.62(d,J=8.7Hz,2H),7.48(d,J=8.5Hz,1H),7.39(ddd,J=8.5,7.6,1.7Hz,1H),7.28(d,J=5.1Hz,1H),7.04-6.96(m,3H),6.92(d,J=8.3Hz,1H),3.98(s,3H),3.64(s,3H),3.32-3.23(m,4H),2.70-2.60(m,4H),2.40(s,3H)。13C-NMR(75MHz,CDCl3)δ=160.63(Cq),152.33(Cq),150.15(Cq),145.31(CH),139.48(Cq),134.01(CH),133.91(Cq),133.55(Cq),130.90(CH),128.27(2CH),126.40(CH),124.64(Cq),121.05(Cq),120.97(CH),120.67(CH),117.65(CH),116.52(2 CH),115.80(Cq),111.98(Cq),110.81(CH),108.95(CH),94.31(Cq),90.92(Cq),55.79(CH3),55.16(2 CH2),49.31(2 CH2),46.20(CH3),27.92(CH3)。HRMS(ESI):计算值:C32H31N4O:487.2492;实测值:487.2475。
实施例46:4-(4-甲氧基-苯硫基)-6-[4-(4-甲基-哌嗪-1-基)-苯基]-9H-吡啶并
[2,3-b]吲哚(R619)
9-苯磺酰基-4-(4-甲氧基-苯硫基)-6-[4-(4-甲基-哌嗪-1-基)-苯基]-9H-吡啶并
[2,3-b]吲哚
在氩气氛下,向9-苯磺酰基-4-氯-6-[4-(4-甲基-哌嗪-1-基)-苯基]-9H-吡啶并[2,3-b]吲哚(结构模块A)(60mg)的DMF(1.2mL)悬浮液中加入K2CO3(56mg,3.5当量)和4-甲氧基苯硫酚(0.029mL,2当量)。在室温下搅拌0.5小时后,将反应混合物用AcOEt(20mL)稀释,用饱和NH4Cl水溶液(20mL)和盐水(20mL)洗涤。将有机层用MgSO4干燥,过滤并蒸发至干。经研磨步骤得到米色固体状所需产物,72%收率。1H-NMR(300MHz,CDCl3)δ=8.55(d,J=8.8Hz,1H),8.48(d,J=1.6Hz,1H),8.21(d,J=5.4Hz,1H),8.18-8.09(m,2H),7.77(dd,J=8.8,1.9Hz,1H),7.65(d,J=8.7Hz,2H),7.57-7.48(m,3H),7.45-7.35(m,2H),7.04(d,J=7.8Hz,2H),7.01(d,J=8.7Hz,2H),6.53(d,J=5.5Hz,1H),3.88(s,3H),3.47-3.33(m,4H),2.90-2.74(m,4H),2.51(s,3H)。13C-NMR(75MHz,CDCl3)δ=161.4(C),150.7(C),150.6(C),147.7(C),146.0(CH),138.8(C),137.7(2 CH),137.1(C),136.0(C),134.0(CH),131.9(C),129.0(2 CH),128.0(2 CH),127.6(2 CH),126.5(CH),123.8(C),121.5(CH),118.2(C),116.3(2 CH),115.8(2 CH),115.1(CH),114.8(CH),114.6(C),55.5(CH3),55.1(2 CH2),48.8(2 CH2),46.2(CH3)。ESI-MS:m/z621.2[M+H]+。
4-(4-甲氧基-苯硫基)-6-[4-(4-甲基-哌嗪-1-基)-苯基]-9H-吡啶并[2,3-b]吲哚
将9-苯磺酰基-4-(4-甲氧基-苯硫基)-6-[4-(4-甲基-哌嗪-1-基)-苯基]-9H-吡啶并[2,3-b]吲哚按照典型方法A脱保护后,经研磨步骤得到橙色固体状所需产物,95%收率。1H-NMR(300MHz,CDCl3)δ=10.04(s,1H),8.55(s,1H),8.16(d,J=5.4Hz,1H),7.75-7.51(m,6H),7.10-7.00(m,4H),6.47(d,J=5.4Hz,1H),3.89(s,3H),3.38-3.26(m,4H),2.76-2.64(m,4H),2.43(s,3H)。13C-NMR(101MHz,CDCl3)δ=159.7(C),150.7(C),148.5(C),144.4(CH),144.3(C),136.4(C),136.0(2 CH),131.5(C),131.2(C),126.3(2 CH),123.6(CH),120.1(C),119.6(CH),117.5(C),114.9(2 CH),114.4(2 CH),110.4(C),110.1(CH),109.7(CH),54.2(CH3),53.4(2 CH2),47.1(2 CH2),44.4(CH3)。HRMS(ESI):计算值:C29H29N4OS:481.2057;实测值:481.2045。
实施例47:4-(1-(4-甲基苄基)-1H-1,2,3-三唑-4-基)-6-(4-(4-甲基哌嗪-1-基)苯
基)-9H-吡啶并[2,3-b]吲哚(R620)
向4-乙炔基-6-(4-(4-甲基哌嗪-1-基)苯基)-9H-吡啶并[2,3-b]吲哚(实施例44,26.1mg,0.071mmol)的1.4mL无水DMF溶液(C=0.05M)中加入CuI(2mg,0.15eq)和185μL0.5M 1-(叠氮基甲基)-4-甲基苯(1.3eq)溶液。然后加入二异丙基乙基胺(82μL,7eq)。将反应混合物在室温下搅拌15小时。然后将混合物用水(30mL)进行水解。将水层用AcOEt(4×15mL)萃取。将合并的有机层用盐水洗涤两次,用MgSO4干燥,过滤并减压浓缩。将粗产物在甲醇中研磨并过滤后,以66%的收率(24.2mg)得到淡棕色固体。1HNMR(500MHz,DMSO)δ11.99(s,1H),9.01-8.92(m,2H),8.47(s,1H),7.70(dd,J=8.4,1.6Hz,1H),7.55(d,J=8.4Hz,1H),7.49(d,J=8.7Hz,2H),7.41(d,J=3.6Hz,1H),7.34(d,J=7.9Hz,2H),7.19(d,J=7.8Hz,2H),7.02(d,J=8.7Hz,2H),5.73(s,2H),3.19(s,4H),2.29(s,3H),2.25(s,3H);13C NMR(126MHz,DMSO)δ153.1(s),149.5(s),145.5(CH),144.9(s),137.9(s),137.3(s),132.8(s),132.6(s),131.6(s),131.5(s),129.1(CH),127.7(CH),126.7(CH),125.0(CH),124.4(CH),121.5(CH),120.5(s),115.5(CH),110.9(CH),54.4(2CH2),52.8(CH2),47.9(2CH2),45.4(NCH3),20.4(CH3);HRMS计算值:C32H32N7[M+H]+514.2714实测值:514.2699。
按照与实施例2类似的方式,用结构模块A作为原料合成如下实施例48-56。
实施例48:6-(4-(4-甲基哌嗪-1-基)苯基)-4-(4-苯氧基苯基)-9H-吡啶并[2,3-b]
吲哚(R621)
将粗产物在甲醇中研磨并过滤后,以62%的收率得到白色固体。1HNMR(400MHz,DMSO)δ11.99(s,1H),8.45(d,J=5.0Hz,1H),7.77(d,J=6.3Hz,2H),7.76(d,J=2.3Hz,1H),7.66(dd,J=8.5,1.7Hz,1H),7.55(d,J=8.4Hz,1H),7.44(ft,J=8.4,7.6Hz,2H),7.36(d,J=8.7Hz,2H),7.26(d,J=8.6Hz,2H),7.20(t,J=7.4Hz,1H),7.14(d,J=7.6Hz,2H),7.13(d,J=4.9Hz,1H),6.97(d,J=8.8Hz,2H),3.24-3.15(m,4H),2.64-2.53(m,4H),2.31(s,3H);13C NMR(101MHz,DMSO)δ157.2(C),156.6(C),152.8(C),149.5(C),146.2(CH),143.7(C),138.0(C),133.4(C),131.6(C),131.6(C),130.5(CH),130.2(CH),126.9(CH),125.1(CH),123.8(CH),120.4(C),119.1(CH),118.9(CH),115.8(CH),112.4(C),111.7(CH),54.3(CH2),47.6(CH2),45.3(CH3);HRMS计算值:C34H31N4O[M+H]+511.2492实测值:511.2473。
实施例49:4-(6-(4-氟苯基)吡啶-3-基)-6-(4-(4-甲基哌嗪-1-基)苯基)-9H-吡啶
并[2,3-b]吲哚(R650)
将粗产物通过硅胶快速色谱纯化(DCM/MeOH 100:0至95:5)得到白色固体状所需产物,80%收率。1H NMR(300MHz,DMSO)δ12.09(s,1H),9.02(d,J=2.1Hz,1H),8.52(d,J=5.0Hz,1H),8.35-8.23(m,4H),7.70(s,1H),7.68(dd,J=8.6Hz,1.7Hz,1H),7.58(d,J=8.3Hz,1H),7.40(t,J=8.8Hz,2H),7.33(d,J=8.7Hz,2H),7.24(d,J=5.0Hz,1H),6.92(d,J=8.8Hz,2H),3.13(t,J=4.9Hz,4H),2.48(t,J=4.9Hz,4H),2.25(s,3H);13CNMR(75MHz,DMSO)δ163.1(d,J=246.8Hz,C),155.2(C),152.7(C),149.7(C),149.0(CH),146.3(CH),140.5(C),138.1(C),137.4(CH),134.7(C),134.6(C),132.7(C),131.9(C),131.4(C),128.9(d,J=8.6Hz,CH),126.9(CH),125.5(CH),120.2(C),119.3(d,J=76.5Hz,CH),116.0(CH),115.7(CH),112.4(CH),111.9(CH),107.0(CH),54.4(CH2),47.7(CH2),45.5(NCH3);MS(ESI)m/z:514.3[M+H]+;1027.7[2M+H]+;HRMS计算值:C34H29N5F[M+H]+514.2401实测值:514.2390。
实施例50:(2,5-二甲氧基-4-(6-(4-(4-甲基哌嗪-1-基)苯基)-9H-吡啶并[2,3-b]
吲哚-4-基)苯基)(苯基)甲酮(R654)
将粗产物通过硅胶快速色谱纯化(DCM/MeOH 98:2至94:6)得到黄色固体状所需产物,70%收率。1H NMR(300MHz,CDCl3)δ11.97(s,1H),8.65(d,J=5.1Hz,1H),7.94(d,J=8.5Hz,2H),7.72-7.67(m,2H),7.62(d,J=8.8Hz,1H),7.59(t,J=7.3Hz,1H),7.45(t,J=7.7Hz,2H),7.43(d,J=8.7Hz,2H),7.24(d,J=5.1Hz,1H),7.21(s,1H),7.18(s,1H),6.94(d,J=8.8Hz,2H),3.70(s,3H),3.65(s,3H),3.26(t,J=5.0Hz,4H),2.64(t,J=5.0Hz,4H),2.40(s,3H);13C NMR(75MHz,CDCl3)δ196.0(C=O),153.1(C),151.4(C),150.8(C),149.9(C),144.9(CH),141.2(C),138.3(C),137.8(C),133.1(CH),132.9(C),132.8(C),130.8(C),129.9(CH),129.5(C),128.5(CH),127.4(CH),125.8(CH),121.5(C),120.1(CH),116.7(CH),116.4(CH),115.1(C),114.7(CH),112.7(CH),111.5(CH),56.5(OCH3),56.4(OCH3),55.1(2CH2),48.9(2CH2),46.1(NCH3);MS(ESI)m/z:583.2[M+H]+;1165.8[2M+H]+;HRMS计算值:C37H35N4O3[M+H]+583.2703实测值:583.2689。
该合成中所用的硼酸频哪醇酯(2,5-二甲氧基-4-(4,4,5,5-四甲基-1,3,2-二氧硼戊环-2-基)苯基)(苯基)甲酮按照如下方法获得:
(4-溴-2,5-二甲氧基苯基)(苯基)甲酮
在0℃下,向2-溴-1,4-二(甲氧基)苯(2.0g,9.21mmol)和苯甲酰氯(1.229mL,10.596mmol,1.15eq)的DCM(9.5mL,C=1.0M)溶液中于5分钟内加入三氟甲磺酸(0.815mL,9.21mmol)。将反应混合物升温至室温(40分钟)然后缓慢加热至温和地回流(油浴,42℃)并搅拌48小时。将反应混合物冷却至室温,然后加入MeOH(0.3mL)并继续搅拌30分钟。将反应混合物倒入80mL冰冷的水中。将水层用1M NaOH溶液中和。将各层分离。将水层用DCM萃取两次(2×20mL)。将合并的有机相用1/1水/盐水混合物(2×30mL)洗涤两次,用MgSO4干燥,过滤并真空浓缩得到棕橙色的油。然后,加入MTBE(7mL)并将混合物在超声浴中搅拌。将形成的固体过滤,用1:1MTBE/己烷混合物冲洗并晾干得到白色固体状[4-溴-2,5-二(甲氧基)苯基](苯基)甲酮,76%收率(2.258g)。1H NMR(300MHz,DMSO)δ7.72(d,J=8.5Hz,1H),7.65(t,J=7.4Hz,1H),7.51(t,J=7.6Hz,1H),7.45(s,1H),7.10(s,1H),3.81(s,2H),3.63(s,2H),13C NMR(75MHz,DMSO)δ194.5(C=O),150.7(C),149.7(C),136.7(C),133.5(CH),129.3(2CH),128.6(2CH),128.2(C),117.3(CH),113.3(C),112.5(CH),56.7(OCH3),56.5(OCH3);MS(ESI)m/z:321.1,323.0[M+H,79Br,81Br]+;243.1,245.0[M-Ph,79Br,81Br]+。
(2,5-二甲氧基-4-(4,4,5,5-四甲基-1,3,2-二氧硼戊环-2-基)苯基)(苯基)甲酮
在装配有搅拌棒的Schlenk管内,加入(4-溴-2-羟基-5-甲氧基苯基)-(苯基)甲酮(200mg,0.623mmol)、乙酸钾AcOK(183mg,3eq)、联硼酸频哪醇酯(237mg,1.5eq)和PdCl2(dppf)(45mg,0.1eq)。将管排空并用氮气回填(将其再重复三次)。然后,加入9mL脱气的1,4-二氧六环(C=0.07M)。将反应混合物在100℃下搅拌14小时30分钟。冷却至室温并用AcOEt稀释后,将混合物用垫过滤。真空除去溶剂。将粗产物通过硅胶快速色谱纯化(DCM/MeOH 100:0至98.5:1.5)得到无色无定形固体状所需化合物,95%收率(281mg,主要含有联硼酸频哪醇酯杂质)。1H NMR(300MHz,CDCl3)δ7.78(d,J=8.5Hz,2H),7.53(t,J=7.4Hz,1H),7.40(t,J=7.5Hz,2H),7.27(s,1H),6.86(s,1H),3.78(s,3H),3.68(s,3H),1.37(s,12H);13C NMR(75MHz,CDCl3)δ196.4(C=O),158.3(C),150.9(C),137.6(C),133.1(CH),132.1(C),129.9(CH),128.3(CH),119.7(CH),111.9(CH),84.0(C),56.8(OCH3),56.5(OCH3),24.9(4CH3);MS(ESI)m/z:369.1[M+H]+;291.1[M-Ph]+。
实施例51:(2-羟基-5-甲氧基-4-(6-(4-(4-甲基哌嗪-1-基)苯基)-9H-吡啶并
[2,3-b]吲哚-4-基)苯基)(苯基)甲酮(R656)
将粗产物通过硅胶快速色谱纯化(DCM/MeOH 100:0至95:5)得到黄色固体状所需产物,68%收率。1H NMR(300MHz,CDCl3)δ11.76(s,1H),11.00(s,1H),8.58(d,J=5.1Hz,1H),7.83(d,J=8.5Hz,2H),7.70-7.61(m,3H),7.62-7.50(m,3H),7.44(d,J=8.7Hz,2H),7.28(s,1H),7.24(s,1H),7.16(d,J=5.0Hz,1H),6.98(d,J=8.7Hz,2H),3.52(s,3H),3.35-3.17(m,4H),2.67-2.55(m,4H),2.38(s,3H);13C NMR(75MHz,CDCl3)δ200.9(C=O),157.7(C),152.8(C),150.1(C),149.1(C),145.2(CH),140.2(C),138.1(C),138.0(C),137.2(C),133.2(C),133.1(C),132.4(CH),129.4(CH),128.7(CH),127.7(CH),126.1(CH),121.4(C),120.8(CH),120.5(CH),118.8(C),116.4(CH),116.3(CH),114.8(C),114.4(CH),111.4(CH),56.4(OCH3),55.2(2CH2),49.1(2CH2),46.2(NCH3);MS(ESI)m/z:569.3[M+H]+;1137.7[2M+H]+;HRMS计算值:C36H33N4O3[M+H]+569.2547实测值:569.2549。
该合成中所用的硼酸频哪醇酯(2-羟基-5-甲氧基-4-(4,4,5,5-四甲基-1,3,2-二氧硼戊环-2-基)苯基)(苯基)甲酮按照如下方法获得:
(4-溴-2-羟基-5-甲氧基苯基)(苯基)甲酮
将[4-溴-2,5-二(甲氧基)苯基](苯基)甲酮(400mg,1.245mmol)的DCM溶液(2.1mL,C=0.6M)滴加到搅拌中的1M BCl3的DCM溶液(1.55mL,1.25eq)中并同时保持反应温度在0℃。将反应混合物在0℃搅拌35分钟,然后通过在10℃下在15分钟内缓慢加入MeOH(0.7mL)终止反应。然后在室温下在15分钟内加入2N HCl溶液(1.4mL)。分层,将有机相通过旋转蒸发浓缩至干。将黄色的油状产物通过硅胶快速柱色谱纯化(用纯DCM洗脱)得到黄色固体状[4-溴-2-羟基-5-(甲氧基)苯基](苯基)甲酮,90%收率(344mg)。1H NMR(300MHz,CDCl3)δ11.67(s,1H),7.67(d,J=8.5Hz,2H),7.60(t,J=7.3Hz,1H),7.51(t,J=7.2Hz,2H),7.29(s,1H),7.02(s,1H),3.70(s,3H);13C NMR(75MHz,CDCl3)δ200.4(C=O),157.5(C),148.3(C),137.6(C),132.3(CH),129.0(CH),128.5(CH),123.2(CH),121.9(C),117.8(C),114.7(CH),56.8(OCH3);MS(ESI)m/z:307.4,309.1[M+H,79Br,81Br]+;229.1,231.0[M-Ph,79Br,81Br]+。
(2-羟基-5-甲氧基-4-(4,4,5,5-四甲基-1,3,2-二氧硼戊环-2-基)苯基)(苯基)甲酮
在装配有搅拌棒的Schlenk管内,加入(4-溴-2-羟基-5-甲氧基苯基)-(苯基)甲酮(200mg,0.651mmol)、乙酸钾AcOK(192mg,3eq)、联硼酸频哪醇酯(215mg,1.3eq)和PdCl2(dppf)(47mg,0.1eq)。将管排空并用氮气回填(将其再重复三次)。然后,加入9.3mL脱气的1,4-二氧六环(C=0.07M)。将反应混合物在100℃下搅拌15小时。冷却至室温并用AcOEt稀释后,将混合物用垫过滤。真空除去溶剂。将粗产物通过硅胶快速色谱纯化(DCM/MeOH 100:0至98.5:1.5),以定量收率得到红色油状所需化合物(267mg,主要含有联硼酸频哪醇酯杂)。1H NMR(300MHz,CDCl3)δ11.35(s,1H),7.70(dd,J=8.3,1.4Hz,2H),7.66-7.53(m,1H),7.50(t,J=7.3Hz,2H),7.36(s,1H),6.97(s,1H),3.67(s,3H),1.36(s,12H);13C NMR(75MHz,CDCl3)δ201.1(C=O),156.8(C),155.5(C),138.1(C),132.2(CH),129.3(CH),128.5(CH),126.1(CH),120.2(C),113.8(CH),84.3(C),56.8(OCH3),24.9(4CH3);MS(ESI)m/z:355.1[M+H]+;709.3[2M+H]+。
实施例52:4-(4-苄基-2,5-二甲氧基苯基)-6-(4-(4-甲基哌嗪-1-基)苯基)-9H-
吡啶并[2,3-b]吲哚(R666)
将粗产物在甲醇中研磨并过滤后,以57%的收率得到橙色固体。1HNMR(300MHz,CDCl3)δ9.94(s,1H),8.52(d,J=5.1Hz,1H),7.68(dd,J=7.1,1.8Hz,1H),7.65(d,J=1.8Hz,1H),7.53(d,J=9.1Hz,1H),7.38(d,J=8.7Hz,2H),7.33-7.28(m,4H),7.25-7.20(m,1H),7.17(d,J=5.1Hz,1H),7.02(s,1H),6.93(d,J=8.8Hz,2H),6.89(s,1H),4.18(d,J=15.2Hz,1H),4.08(d,J=15.2Hz,1H),3.77(s,3H),3.60(s,3H),3.32-3.22(m,4H),2.68-2.57(m,4H),2.39(s,3H);13C NMR(75MHz,CDCl3)δ152.8(C),151.7(C),150.7(C),145.0(C),145.5(CH),142.2(C),141.0(C),137.7(C),132.9(C),132.8(C),131.1(C),128.9(CH),128.6(CH),127.4(CH),126.0(CH),126.0(C),125.6(CH),122.0(C),120.5(CH),117.4(CH),116.4(CH),115.2(C),114.5(CH),113.5(CH),111.1(CH),56.4(OCH3),56.3(OCH3),55.3(2CH2),49.1(2CH2),46.3(NCH3),36.3(CH2Bn);MS(ESI)m/z:569.0[M+H]+;1137.8[2M+H]+;539.3[M-OCH3+2H]+;HRMS计算值:C37H37N4O2[M+H]+569.2911实测值:569.2924。
该合成中所用的硼酸频哪醇酯2-(4-苄基-2,5-二甲氧基苯基)-4,4,5,5-四甲基-1,3,2-二氧硼戊环按照如下方法获得:
1-苄基-4-溴-2,5-二甲氧基苯
向(4-溴-2,5-二甲氧基苯基)(苯基)甲酮(100mg,0.311mmol)的0.2mL无水DCM溶液(C=1.5M)中,依次滴加三氟乙酸(0.24mL,10eq)和三乙基硅烷(0.2mL,4eq)。在室温下搅拌16小时后,将反应混合物用饱和的NH4Cl溶液(5mL)水解。用20mL DCM和20mL水稀释然后分离各层。将水层用DCM(2×10mL)萃取两次。将合并的有机相用饱和NaHCO3溶液(2×20mL)、盐水(2×20mL)洗涤两次,用MgSO4干燥,过滤并真空浓缩。以98%(93.4mg)的收率得到产物,其纯度足以进行下一步反应。1H NMR(300MHz,CDCl3)δ7.34-7.25(m,2H),7.24-7.17(m,3H),7.08(s,1H),6.69(s,1H),3.95(s,2H),3.78(s,3H),3.78(s,3H);13C NMR(75MHz,CDCl3)δ151.9(C),150.1(C),140.4(C),129.9(C),128.9(CH),128.5(CH),126.1(CH),116.1(CH),115.0(CH),109.1(C),57.0(OCH3),56.3(OCH3),35.9(CH2Bn);MS(ESI)m/z:324.5,326.1[M+NH4,79Br,81Br]+;630.3,632.0,634.2[2M+NH4,79Br,81Br]+。
2-(4-苄基-2,5-二甲氧基苯基)-4,4,5,5-四甲基-1,3,2-二氧硼戊环
在装配有搅拌棒的Schlenk管内,加入1-苄基-4-溴-2,5-二甲氧基苯(93mg,0.303mmol)、乙酸钾AcOK(89mg,3eq)、联硼酸频哪醇酯(100mg,1.3eq)和PdCl2(dppf)(22mg,0.1eq)。将管排空并用氮气回填(将其再重复三次)。然后,加入4.3mL脱气的1,4-二氧六环(C=0.07M)。将反应混合物在100℃下搅拌14小时。冷却至室温并用AcOEt稀释后,将混合物用垫过滤。真空除去溶剂。将粗产物通过硅胶快速色谱纯化(PE/AcOEt 100:0至80:20)得到白色固体状所需化合物,62%收率(68.2mg)。1H NMR(300MHz,CDCl3)δ7.31-7.23(m,2H),7.21(s,1H),7.23-7.13(m,3H),6.66(s,1H),4.00(s,2H),3.82(s,3H),3.74(s,3H),1.37(s,12H);13C NMR(75MHz,CDCl3)δ158.8(C),151.4(C),140.8(C),134.1(C),128.9(CH),128.3(CH),125.9(CH),118.5(CH),114.4(CH),83.5(C),57.0(OCH3),56.2(OCH3),36.4(CH2),24.9(4CH3);MS(ESI)m/z:355.4[M+H]+;340.4[M-CH3+H]+;325.3[M-OCH3+2H]。
实施例53:2-苄基-4-甲氧基-5-(6-(4-(4-甲基哌嗪-1-基)苯基)-9H-吡啶并
[2,3-b]吲哚-4-基)苯酚(R667)
将粗产物通过硅胶快速色谱纯化(DCM/MeOH 94:6至90:10)得到白色固体状所需产物,77%收率。1H NMR(300MHz,70CDCl3/30CD3OD)δ8.17(d,J=5.1Hz,1H),7.52(d,J=1.3Hz,1H),7.47(dd,J=8.5,1.8Hz,1H),7.34(d,J=8.5Hz,1H),7.24(d,J=8.8Hz,2H),7.20-7.08(m,4H),7.04(t,J=7.0Hz,1H),6.95(d,J=5.2Hz,1H),6.80(s,1H),6.76(d,J=8.8Hz,2H),6.68(s,1H),4.04(d,J=15.3Hz,1H),3.93(d,J=15.3Hz,1H),3.39(s,3H),3.17-3.06(m,4H),2.66-2.55(m,4H),2.28(s,3H).13C NMR(75MHz,CDCl3)δ151.7(C),149.7(C),149.0(C),148.7(C),144.2(CH),142.5(C),140.8(C),137.8(C),133.5(C),132.1(C),129.0(C),128.6(CH),128.2(CH),127.1(CH),125.7(C),125.6(CH),125.3(CH),121.3(C),120.1(CH),117.0(CH),116.7(CH),116.6(CH),115.4(C),114.0(CH),111.0(CH),56.0(OCH3),54.3(2CH2),48.3(2CH2),44.9(NCH3),35.8(CH2Bn);MS(ESI)m/z:555.2[M+H]+;1109.6[2M+H]+;HRMS计算值:C36H35N4O2[M+H]+555.2754实测值:555.2750。
该合成中所用的硼酸频哪醇酯2-苄基-4-甲氧基-5-(4,4,5,5-四甲基-1,3,2-二氧硼戊环-2-基)苯酚按照如下方法获得:
2-苄基-5-溴-4-甲氧基苯酚
向(4-溴-2-羟基-5-甲氧基苯基)(苯基)甲酮(100mg,0.325mmol)的0.22mL无水DCM溶液(C=1.5M)中依次滴加三氟乙酸(0.25mL,10eq)和三乙基硅烷(0.21mL,4eq)。在室温下搅拌17小时后,将反应混合物用饱和NH4Cl溶液(5mL)水解。用20mL DCM和20mL水稀释,然后分离各层。将水层用DCM(2×5mL)萃取两次。将合并的有机相用饱和NaHCO3溶液(2×20mL)、盐水(20mL)洗涤两次,用MgSO4干燥,过滤并真空浓缩。将粗产物通过硅胶快速色谱纯化(环己烷/AcOEt 97:3),以72%的收率(68.5mg)得到无色油状所需产物。1H NMR(300MHz,CDCl3)δ7.36-7.28(m,2H),7.28-7.20(m,3H),7.01(s,1H),6.70(s,1H),4.89(s,1H),3.96(s,2H),3.80(s,3H);13C NMR(75MHz,CDCl3)δ150.3(C),148.1(C),139.4(C),128.8(CH),128.7(CH),127.5(C),126.6(CH),120.7(CH),115.0(CH),109.4(C),57.0(OCH3),36.4(CH2Bn);MS(ESI)m/z:310.1,312.1[M+NH4,79Br,81Br]+;602.0,604.3,606.1[2M+NH4,79Br,81Br]+。
2-苄基-4-甲氧基-5-(4,4,5,5-四甲基-1,3,2-二氧硼戊环-2-基)苯酚
在装配有搅拌棒的Schlenk管内,加入1-苄基-4-溴-2,5-二甲氧基苯(68.5mg,0.233mmol)、乙酸钾AcOK(69mg,3eq)、联硼酸频哪醇酯(83mg,1.4eq)和PdCl2(dppf)(17mg,0.1eq)。将管排空并用氮气回填(将其再重复三次)。然后,加入3.3mL脱气的1,4-二氧六环(C=0.07M)。将反应混合物在100℃下搅拌15小时。冷却至室温并用AcOEt稀释后,将混合物用垫过滤。真空除去溶剂。将粗产物通过硅胶快速色谱纯化(PE/AcOEt100:0至70:30)得到黄色油状所需化合物,87%收率(69mg)。1H NMR(300MHz,CDCl3)δ7.33-7.12(m,6H),6.63(s,1H),5.96(s,1H),4.00(s,2H),3.71(s,3H),1.33(s,12H);13C NMR(75MHz,CDCl3)δ158.4(C),147.7(C),140.3(C),131.7(C),128.8(CH),128.4(CH),126.1(CH),123.4(CH),114.0(CH),83.5(C),56.7(OCH3),36.6(CH2),24.9(4CH3);MS(ESI)m/z:341.1[M+H]+;698.8[2M+NH4]+。
实施例54:4-(4-苄基-3-(三氟甲基)苯基)-6-(4-(4-甲基哌嗪-1-基)苯基)-9H-
吡啶并[2,3-b]吲哚(R686)
将粗产物在甲醇中研磨并过滤后,以48%的收率得到黄色固体。1HNMR(300MHz,CDCl3)δ9.82(s,1H),8.53(d,J=5.1Hz,1H),8.15(s,1H),7.81(s,1H),7.77(d,J=8.6Hz,1H),7.68(dd,J=8.4,1.5Hz,1H),7.57(d,J=8.5Hz,1H),7.41(d,J=8.6Hz,2H),7.39-7.21(m,6H),7.12(d,J=5.1Hz,1H),6.95(d,J=8.7Hz,2H),4.33(s,2H),3.49-3.28(m,4H),2.92-2.73(m,4H),2.53(s,3H);13C NMR(75MHz,CDCl3)δ152.9(C),149.7(C),149.6(C),146.2(C),146.0(C),143.9(C),140.3(d,J=1.7Hz,C),139.7(C),137.8(C),137.0(C),133.5(C),133.3(C),132.6(CH),132.2(CH),129.3(CH),128.8(CH),127.8(CH),126.6(CH),126.5(q,J=9.8Hz,CH),126.3(CH),124.7(q,J=296.5Hz,C),121.1,120.5(CH),116.8(CH),116.6(CH),111.6(CH),54.8(2CH2),48.5(2CH2),45.6(NCH3),37.9(q,J=1.4Hz,CH2Bn);MS(ESI)m/z:577.3[M+H]+。
该合成中所用的硼酸频哪醇酯2-(4-苄基-3-(三氟甲基)苯基)-4,4,5,5-四甲基-1,3,2-二氧硼戊环按照如下方法获得:
(4-溴-2-(三氟甲基)苯基)(苯基)甲醇
向1,4-二溴-2-(三氟甲基)苯(300mg,0.987mmol)的2mL Et2O溶液(C=0.5M)中在-78℃下滴加1.6M BuLi的己烷溶液(650μL,1.05eq)。搅拌25分钟后,缓慢加入苯甲醛(120μL,1.2eq)。将混合物在-78℃搅拌2小时,然后升温至室温过夜。然后,将反应混合物用水水解并用1M HCl溶液酸化。将各层分离。将水层用DCM(3×10mL)萃取。将合并的有机层用盐水洗涤,用MgSO4干燥,过滤并真空除去溶剂。将粗品残余物通过硅胶快速色谱纯化(环己烷/AcOEt 95:5)得到无色油状所需产物,90%收率(295mg)。1H NMR(300MHz,CDCl3)δ7.80(d,J=2.1Hz,1H),7.67(dd,J=8.4,2.1Hz,1H),7.54(d,J=8.5Hz,1H),7.39-7.27(m,5H),6.24(s,1H),2.44(s,OH);13C NMR(75MHz,CDCl3)δ142.3(C),141.4(q,J=1.4Hz,C),135.5(CH),131.5(CH),129.3(q,J=30.9Hz,C),128.8(q,J=6.1Hz,CH),128.7(CH),128.0(CH),126.5(CH),123.5(q,J=274.6Hz,C),121.7(C),70.6(q,J=2.1Hz,CH);MS(ESI)m/z:375.0,377.0[M-H+HCO2H,79Br,81Br]-;705.2,707.2[2M-2H+HCO2H,79Br,81Br]-。
1-苄基-4-溴-2-(三氟甲基)苯
方法A:向1,4-二溴-2-(三氟甲基)苯(300mg,0.987mmol)的2mL Et2O溶液(C=0.5M)中在-65℃下滴加1.6M BuLi的己烷溶液(650μL,1.05eq)。搅拌15分钟后,缓慢加入苄基溴(141μL,1.2eq)。使混合物缓慢升温至室温达20小时。然后,将反应混合物用1M HCl溶液水解。将有机层稀释(DCM)并分离。将水层用DCM(3×10mL)萃取。将合并的有机层用盐水洗涤,用MgSO4干燥,过滤并真空除去溶剂。将粗品残余物通过硅胶快速色谱纯化(环己烷)得到无色油状所需产物,74%收率(229mg)。
方法B:向(4-溴-2-(三氟甲基)苯基)(苯基)甲醇(101.4mg,0.306mmol)的0.2mL无水DCM溶液(C=1.5M)中依次滴加三氟乙酸(120μL,5eq)和三乙基硅烷(146μL,3eq)。在室温下搅拌1小时45分钟后,将反应混合物用饱和NH4Cl溶液(5mL)水解。用20mL DCM和20mL水稀释然后分离各层。将水层用DCM(3×10mL)萃取。将合并的有机相用饱和NaHCO3溶液(20mL)、盐水(20mL)洗涤,用MgSO4干燥,过滤并真空浓缩。将粗品残余物通过硅胶快速色谱纯化(石油醚)得到无色油状所需产物,65%收率(63.2mg)。
1H NMR(300MHz,CDCl3)δ7.81(d,J=2.1Hz,1H),7.54(dd,J=8.4,2.2Hz,1H),7.37-7.26(m,2H),7.28-7.23(m,1H),7.13(d,J=8.7Hz,2H),7.04(d,J=8.3Hz,1H),4.13(s,2H);13C NMR(75MHz,CDCl3)δ139.3(C),138.8(q,J=1.5Hz,C),134.9(CH),133.5(CH),130.5(q,J=30.4Hz,C),129.2(CH),129.1(q,J=6.1Hz,CH),128.8(CH),126.7(CH),123.7(q,J=274.4Hz,C),120.0(C),37.4(q,J=2.1Hz,CH2)。
2-(4-苄基-3-(三氟甲基)苯基)-4,4,5,5-四甲基-1,3,2-二氧硼戊环
在装配有搅拌棒的Schlenk管内,加入1-苄基-4-溴-2-(三氟甲基)苯(89mg,0.282mmol)、乙酸钾AcOK(83mg,3eq)、联硼酸频哪醇酯(93mg,1.3eq)和PdCl2(dppf)(21mg,0.1eq)。将管排空并用氮气回填(将其再重复三次)。然后,加入4mL脱气的1,4-二氧六环(C=0.07M)。将反应混合物在100℃下搅拌15小时。冷却至室温并用AcOEt稀释后,将混合物用垫过滤。真空除去溶剂。将粗产物通过硅胶快速色谱纯化(PE/DCM 100:0至70:30)得到无色油状所需化合物,82%收率(84mg)。1H NMR(300MHz,CDCl3)δ8.13(s,1H),7.87(d,J=7.7Hz,1H),7.30(tt,J=7.9,1.8Hz,2H),7.26-7.22(m,1H),7.21(d,J=7.6Hz,1H),7.15(d,J=8.4Hz,1H),4.22(s,2H),1.36(s,12H);13C NMR(75MHz,CDCl3)δ142.6(q,J=1.6Hz,C),139.9(C),138.1(CH),132.3(q,J=5.5Hz,CH),131.3(CH),129.2(CH),128.6(CH),128.4(q,J=29.7Hz,C),126.4(CH),124.8(q,J=274.2Hz,C),84.3(2C),38.1(d,J=1.9Hz,CH2),25.0(4CH3);MS(ESI)m/z:380.1[M+NH4]+;742.2[2M+NH4]+。
实施例55:4-(4-苄基-2-(三氟甲基)苯基)-6-(4-(4-甲基哌嗪-1-基)苯基)-9H-
吡啶并[2,3-b]吲哚(R687)
将粗产物通过硅胶快速色谱纯化(DCM/MeOH 100:0至95:5)得到浅黄色固体状所需产物,51%收率。1H NMR(300MHz,DMSO)δ12.01(s,1H),8.46(d,J=5.0Hz,1H),7.92(s,1H),7.73(d,J=8.2Hz,1H),7.62(d,J=8.3Hz,1H),7.52(d,J=8.1Hz,2H),7.41-7.17(m,5H),7.14(d,J=8.6Hz,2H),7.08(d,J=5.0Hz,1H),6.91(d,J=8.7Hz,2H),6.78(s,1H),4.22(s,2H),3.25-3.10(m,4H),2.65-2.52(m,4H),2.30(s,3H);13C NMR(75MHz,DMSO)δ152.1(C),149.5(C),145.5(CH),142.8(C),141.1(C),140.6(C),137.9(C),134.6(d,J=1.4Hz,C),133.1(CH),131.6(C),131.5(d,J=10.1Hz,CH),131.4(CH),131.2(C),128.8(CH),128.7(CH),126.9(d,J=29.7Hz,C),126.6(CH),126.2(CH),125.2(CH),123.9(d,J=274.5Hz,C),120.4(C),118.4(CH),115.9(CH),115.8(CH),113.7(C),111.8(CH),54.3(2CH2),47.7(2CH2),45.4(NCH3),40.3(CH2Bn);MS(ESI)m/z:577.0[M+H]+。
该合成中所用的硼酸频哪醇酯2-(4-苄基-2-(三氟甲基)苯基)-4,4,5,5-四甲基-1,3,2-二氧硼戊环按照如下方法获得:
1-溴-4-碘-2-(三氟甲基)苯
将通过将4-溴-3-(三氟甲基)苯胺(500mg,2.08mmol)加入到温热的浓H2SO437%w/w(0.51mL,4.6eq)和水(2.3mL,C=3.4M)的混合物中制得的溶液在剧烈搅拌下冷却至-10℃(冰盐浴)。苯胺硫酸氢盐的浆液形成沉淀。然后,滴加NaNO2(158mg,1.1eq)的1.06mL水溶液(C=2.15M)。将混合物在-8℃搅拌40分钟,然后加入KI(495mg,1.43eq)的水溶液(0.4mL,C=8M)和铜粉(4mg)。移走冰浴,使棕色反应混合物升温至室温,搅拌30分钟,然后将反应物加热回流(102℃)1小时。冷却至室温并用水稀释后,将水层用DCM(3×20mL)萃取。将萃取液用饱和Na2S2O3溶液(20mL)、盐水(20mL)洗涤,用MgSO4干燥,过滤并真空蒸发。将粗品残余物进行色谱纯化(己烷)得到橙色固体状碘代的化合物,93%收率(679mg)。1H NMR(300MHz,CDCl3)δ7.98(d,J=2.3Hz,1H),7.69(dd,J=8.4,2.1Hz,1H),7.42(d,J=8.4Hz,1H);13C NMR(75MHz,CDCl3)δ142.1(CH),136.7(q,J=5.6Hz,CH),136.6(CH),132.0(q,J=31.7Hz,C),121.9(q,J=274.2Hz,C),120.0(q,J=1.7Hz,C),91.8(C)。
(4-溴-3-(三氟甲基)苯基)(苯基)甲醇
向1-溴-4-碘-2-(三氟甲基)苯(246mg,0.701mmol)的1.4mL Et2O溶液(C=0.5M)中在-78℃下滴加1.6M BuLi的己烷溶液(460μL,1.05eq)。搅拌15分钟后,缓慢加入苯甲醛(86μL,1.2eq)。将混合物在-75℃搅拌4小时,然后用水水解并用1M HCl溶液酸化。将各层分离。将水层用DCM(3×10mL)萃取。将合并的有机层用盐水洗涤,用MgSO4干燥,过滤并真空除去溶剂。将粗品残余物通过硅胶快速色谱纯化(环己烷/AcOEt 93:7至90:10)得到无色油状所需产物,76%收率(176mg)。1H NMR(300MHz,CDCl3)δ7.76(d,J=2.2Hz,1H),7.65(d,J=8.3Hz,1H),7.41-7.27(m,6H),5.81(s,1H),2.36(s,OH);13C NMR(75MHz,CDCl3)δ143.5(C),142.8(C),135.1(d,J=2.0Hz,CH),131.0(CH),130.2(q,J=31.3Hz,C),129.0(CH),128.5(CH),126.7(CH),125.9(q,J=5.4Hz,CH),123.0(q,J=273.6Hz,C),118.9(q,J=2.0Hz,C),75.4(CH);MS(ESI)m/z:313.0,315.0[M-OH,79Br,81Br]+;348.0,350.0[M+NH4,79Br,81Br]+;680.0[2M+NH4,79Br,81Br]+。
4-苄基-1-溴-2-(三氟甲基)苯
向(4-溴-3-(三氟甲基)苯基)(苯基)甲醇(168mg,0.507mmol)的0.34mL无水DCM溶液(C=1.5M)中依次滴加三氟乙酸(195μL,5eq)和三乙基硅烷(243μL,3eq)。在室温下搅拌1小时45分钟后,将反应混合物用饱和NH4Cl溶液(5mL)水解。用20mL DCM和20mL水稀释然后分离各层。将水层用DCM(3×10mL)萃取。将合并的有机相用饱和NaHCO3溶液(20mL)、盐水(20mL)洗涤,用MgSO4干燥,过滤并真空浓缩。将粗品残余物通过硅胶快速色谱纯化(环己烷)得到无色油状所需产物,84%收率(135mg)。1H NMR(300MHz,CDCl3)δ7.62(d,J=8.2Hz,1H),7.54(d,J=2.0Hz,1H),7.34(tt,J=7.9,1.8Hz,2H),7.26(t,J=7.3Hz,1H),7.22-7.15(m,3H),4.00(s,2H);13C NMR(75MHz,CDCl3)δ141.0(C),139.5(C),135.1(CH),133.6(CH),130.2(q,J=31.3Hz,C),129.0(CH),128.9(CH),128.4(q,J=5.4Hz,CH),126.8(CH),123.1(q,J=273.4Hz,C),117.5(q,J=1.9Hz,C),41.3(CH2)。
2-(4-苄基-2-(三氟甲基)苯基)-4,4,5,5-四甲基-1,3,2-二氧硼戊环
在装配有搅拌棒的Schlenk管内,加入4-苄基-1-溴-2-(三氟甲基)苯(135mg,0.428mmol)、乙酸钾AcOK(126mg,3eq)、联硼酸频哪醇酯(141mg,1.3eq)和PdCl2(dppf)(31mg,0.1eq)。将管排空并用氮气回填(将其再重复三次)。然后加入6.1mL脱气的1,4-二氧六环(C=0.07M)。将反应混合物在100℃下搅拌14小时30分钟。冷却至室温并用AcOEt稀释后,将混合物用垫过滤。真空除去溶剂。将粗产物通过硅胶快速色谱纯化(PE/DCM 100:0至80:20)得到无色油状所需化合物,68%收率(105.5mg)。1H NMR(300MHz,CDCl3)δ7.68(d,J=7.6Hz,1H),7.52(s,1H),7.35(d,J=7.6Hz,1H),7.33-7.27(m,2H),7.23(t,J=7.2Hz,1H),7.15(d,J=8.2Hz,2H),4.04(s,2H),1.38(s,12H);13C NMR(75MHz,CDCl3)δ143.5(C),140.1(C),135.3(CH),134.2(d,J=31.2Hz,C),131.4(CH),129.0(CH),128.7(CH),126.5(CH),126.0(q,J=4.7Hz,CH),124.5(q,J=273.5Hz,C),84.5(2C),41.8(CH2),24.7(4CH3);MS(ESI)m/z:393.1[M-H+MeOH]-;420.9[M-H+HCOOH]-。
实施例56:4-(4-苄基-3,5-二甲氧基苯基)-6-(4-(4-甲基哌嗪-1-基)苯基)-9H-
吡啶并[2,3-b]吲哚(R696)
将粗产物通过硅胶快速色谱纯化(DCM/MeOH 95:5)得到黄色固体状所需产物,82%收率。1H NMR(300MHz,CDCl3)δ11.59(s,1H),8.53(d,J=5.1Hz,1H),8.07(d,J=1.4Hz,1H),7.71(dd,J=8.5,1.7Hz,1H),7.60(d,J=8.5Hz,1H),7.41(d,J=8.7Hz,2H),7.36(d,J=7.3Hz,2H),7.26(t,J=7.4Hz,2H),7.18(t,J=7.2Hz,1H),7.13(d,J=5.1Hz,1H),6.97-6.89(m,4H),4.17(s,2H),3.80(s,6H),3.36-3.22(m,4H),2.74-2.61(m,4H),2.43(s,3H);13C NMR(75MHz,CDCl3)δ158.5(2C),153.2(C),149.9(C),146.2(C),145.1(CH),141.7(C),138.2(C),138.1(C),132.8(C),132.5(C),128.7(CH),128.2(CH),127.3(CH),125.6(CH),125.5(CH),121.3(C),120.5(CH),118.0(C),116.4(CH),116.2(CH),114.1(C),111.5(CH),104.5(CH),56.0(2OCH3),55.1(NCH2),48.9(NCH2),46.1(NCH3),28.9(CH2);MS(ESI)m/z:569.3[M+H]+;1137.7[2M+H]+。
该合成中所用的硼酸频哪醇酯2-(4-苄基-3,5-二甲氧基苯基)-4,4,5,5-四甲基-1,3,2-二氧硼戊环按照如下方法获得:
(4-溴-2,6-二甲氧基苯基)(苯基)甲酮
向冷却至0℃的AlCl3(150mg,1.2eq)的2mL无水DCM悬浮液中滴加苯甲酰氯(120μL,1.1eq)。在混合物变清澈后(15分钟),于0℃下缓慢加入溶于1mL DCM的1-溴-3,5-二甲氧基苯(208mg,0.958mmol)。在低温下搅拌1小时15分钟后,将黄色的反应混合物用饱和NH4Cl溶液(6mL)水解。将水层用水和饱和NaHCO3溶液稀释并用DCM(3×12mL)萃取。将合并的萃取液用NaHCO3水溶液(20mL)、盐水(20mL)洗涤,用MgSO4干燥并真空除去溶剂。将粗产物通过硅胶快速色谱纯化(环己烷/AcOEt 100:0至93:7),从而以95%的化学收率分离出(2-溴-4,6-二甲氧基苯基)(苯基)甲酮(264mg)和(4-溴-2,6-二甲氧基苯基)(苯基)甲酮(29.4mg)(90/10比例)。1HNMR(300MHz,CDCl3)δ7.82(d,J=8.5Hz,2H),7.56(t,J=7.4Hz,1H),7.43(t,J=7.5Hz,2H),6.79(s,2H),3.70(s,6H);13C NMR(75MHz,CDCl3)δ194.4(C=O),158.1(C),137.4(C),133.6(CH),129.5(2CH),128.6(2CH),124.2(C),116.9(C),108.0(2CH),56.3(2OCH3);MS(ESI)m/z:321.0,322.9[M+H,79Br,81Br]+;243.1,244.9[M-Ph,79Br,81Br]+。
2-苄基-5-溴-1,3-二甲氧基苯
将(4-溴-2,6-二甲氧基苯基)(苯基)甲酮(87mg,0.271mmol)溶于三氟乙酸(250μL,12eq)和三乙基硅烷(260μL,6eq)的混合物并加热至80℃搅拌15小时。冷却至室温后,向反应混合物中加入20mL DCM。将有机层用饱和NaHCO3溶液(2×20mL)、盐水洗涤,用MgSO4干燥,过滤并真空浓缩。将粗品残余物通过硅胶快速色谱纯化(环己烷/AcOEt 95:5)得到白色固体状还原了的化合物,98%收率(81.4mg)。1H NMR(300MHz,CDCl3)δ7.28-7.21(m,4H),7.20-7.12(m,1H),6.73(s,2H),3.98(s,2H),3.81(s,6H);13C NMR(75MHz,CDCl3)δ158.77(2C),141.23(C),128.57(2CH),128.14(2CH),125.63(CH),120.45(C),116.86(C),107.71(2CH),56.04(2OCH3),28.58(CH2);MS(ESI)m/z:307.4,309.0[M+H,79Br,81Br]+;324.1,326.1[M+NH4,79Br,81Br]+。
2-(4-苄基-3,5-二甲氧基苯基)-4,4,5,5-四甲基-1,3,2-二氧硼戊环
在装配有搅拌棒的Schlenk管内,加入2-苄基-5-溴-1,3-二甲氧基苯(81.6mg,0.266mmol)、乙酸钾AcOK(78mg,3eq)、联硼酸频哪醇酯(88mg,1.3eq)和PdCl2(dppf)(19.5mg,0.1eq)。将管排空并用氮气回填(将其再重复三次)。然后,加入3.8mL脱气的1,4-二氧六环(C=0.07M)。将反应混合物在100℃下搅拌14小时30分钟。冷却至室温并用AcOEt(10mL)稀释后,将混合物用垫过滤。真空除去溶剂。将粗产物通过硅胶快速色谱纯化(PE/AcOEt 100:0至93:7)得到白色固体状所需化合物,82%收率(76.9mg)。1H NMR(300MHz,CDCl3)δ7.29-7.18(m,4H),7.19-7.07(m,1H),7.05(s,2H),4.08(s,2H),3.88(s,6H),1.38(s,12H);13C NMR(75MHz,CDCl3)δ157.9(2C),141.6(C),128.7(2CH),128.0(2CH),125.4(CH),121.3(C),109.8(2CH),83.9(2C),56.0(2OCH3),29.0(CH2),25.0(4CH3);MS(ESI)m/z:355.3[M+H]+;372.5[M+NH4]+;726.5[2M+NH4]+。
实施例57:(2,5-二甲氧基-4-(6-(4-(4-甲基哌嗪-1-基)苯基)-9H-吡啶并[2,3-b]
吲哚-4-基)苯基)(苯基)甲醇(R655)
向(2,5-二甲氧基-4-(6-(4-(4-甲基哌嗪-1-基)苯基)-9H-吡啶并[2,3-b]吲哚-4-基)苯基)(苯基)甲酮(实施例50,39.8mg,0.0683mmol)的CH2Cl2/MeOH 5:2(2mL)溶液中加入NaBH4(6mg,2.3eq)。在室温下搅拌1小时20分钟后,将反应混合物用饱和NH4Cl水溶液(5mL)终止反应,用CH2Cl2(25mL)稀释并用水(30mL)洗涤。收集有机层并将水层用CH2Cl2(20mL)洗涤四次。将合并的有机层用盐水洗涤并用MgSO4干燥,过滤并蒸发至干。将粗产物在DCM中研磨并过滤后,以66%的收率(26.3mg)得到白色固体。1H NMR(300MHz,DMSO,80℃)δ11.61(s,1H),8.41(d,J=5.0Hz,1H),7.63(dd,J=8.4,1.9Hz,1H),7.51(d,J=8.4Hz,1H),7.49-7.41(m,4H),7.35-7.15(m,5H),7.08(d,J=5.0Hz,1H),7.02(s,1H),6.98-6.79(m,2H),6.11(d,J=4.9Hz,1H),5.67(d,J=5.4Hz,1H),3.69(s,3H),3.62(s,3H),3.24-3.14(m,4H),2.54-2.47(m,4H),2.27(s,3H);13C NMR(75MHz,DMSO,80℃)δ152.2(C),150.2(C),149.6(C),149.2(C),145.2(CH),144.8(C),140.6(C),137.6(C),135.1(C),131.0(C),131.0(C),127.5(CH),126.3(CH),126.2(CH),126.1(CH),125.9(C),124.3(CH),121.8(C),120.7(C),118.6(CH),116.1(CH),115.3(CH),113.4(CH),111.0(CH),110.6(CH),68.1(CH),55.9(OCH3),55.8(OCH3),54.3(2CH2),47.8(2CH2),45.3(NCH3);MS(ESI)m/z:585.5[M+H]+;1170.1[2M+H]+;567.3[M-OH]+;HRMS计算值:C37H37N4O3[M+H]+585.2860实测值:585.2868。
实施例58:4-(4-苄基哌啶-1-基)-6-(4-(4-甲基哌嗪-1-基)苯基)-9H-吡啶并
[2,3-b]吲哚(R664)
4-(4-苄基哌啶-1-基)-6-(4-(4-甲基哌嗪-1-基)苯基)-9-(苯基磺酰基)-9H-吡啶
并[2,3-b]吲哚
将9-苯磺酰基-4-氯-6-[4-(4-甲基-哌嗪-1-基)-苯基]-9H-吡啶并[2,3-b]吲哚(结构模块A)60mg,0.116mmol)和4-苄基哌啶(0.25mL,12eq)于150℃加热5小时30分钟。冷却至室温后,将反应混合物用DCM(20mL)稀释,用水洗涤3次(3×10mL)并用盐水(10mL)洗涤。将有机层用MgSO4干燥,过滤并蒸发至干。将粗产物通过硅胶快速色谱纯化(DCM/MeOH 98:2至97:3)得到无色无定形固体状所需产物,67%(50.8mg)收率。1H NMR(300MHz,CDCl3)δ8.53(d,J=8.8Hz,1H),8.38(d,J=5.6Hz,1H),8.17(d,J=8.9Hz,2H),8.06(d,J=1.6Hz,1H),7.73(dd,J=8.7,1.8Hz,1H),7.62(d,J=8.7Hz,2H),7.52-7.46(m,2H),7.40(d,J=7.9Hz,2H),7.36-7.18(m,4H),7.10(d,J=8.8Hz,2H),6.80(d,J=5.7Hz,1H),3.62(d,J=12.1Hz,2H),3.39-3.31(m,4H),2.78(t,J=12.0Hz,2H),2.71-2.62(m,6H),2.40(s,3H),1.89(d,J=12.2Hz,2H),1.79(dt,J=10.4,3.4Hz,1H),1.64(t,J=11.8Hz,2H);13C NMR(75MHz,CDCl3)δ155.79(C),152.9(C),150.6(C),147.8(CH),140.2(C),138.9(C),136.8(C),135.5(C),133.8(CH),132.3(C),129.2(CH),128.9(CH),128.4(CH),128.0(CH),127.6(CH),126.2(CH),125.6(CH),123.4(C),120.7(CH),116.3(CH),114.6(CH),110.3(C),108.5(CH),55.2(2CH2),51.2(2CH2),49.0(2CH2),46.2(NCH3),43.2(CH2Bn),37.7(CH),32.2(CH2);MS(ESI)m/z:656.5[M+H]+;1312.3[2M+H]+;515.2[M-SO2Ph+H]+。
4-(4-苄基哌啶-1-基)-6-(4-(4-甲基哌嗪-1-基)苯基)-9H-吡啶并[2,3-b]吲哚
将4-(4-苄基哌啶-1-基)-6-(4-(4-甲基哌嗪-1-基)苯基)-9-(苯基磺酰基)-9H-吡啶并[2,3-b]吲哚按照典型方法A的操作脱保护,将粗产物在甲醇中研磨并过滤后,以60%的收率得到白色固体。1H NMR(300MHz,CDCl3)δ10.21(s,1H),8.33(d,J=5.6Hz,1H),8.11(d,J=1.6Hz,1H),7.67(dd,J=8.4,1.6Hz,1H),7.63(d,J=8.7Hz,2H),7.54(d,J=8.4Hz,1H),7.37-7.29(m,2H),7.28-7.19(m,3H),7.09(d,J=8.8Hz,2H),6.71(d,J=5.7Hz,1H),3.85(d,J=12.1Hz,2H),3.41-3.24(m,4H),2.85(t,J=11.6Hz,2H),2.71(d,J=6.5Hz,2H),2.69-2.62(m,4H),2.40(s,3H),1.92(d,J=12.7Hz,2H),1.87-1.78(m,1H),1.77-1.64(m,2H);13C NMR(75MHz,CDCl3)δ155.9(C),154.2(C),150.1(C),147.0(CH),140.5(C),136.6(C),133.8(C),133.3(C),129.3(CH),128.4(CH),128.0(CH),126.2(CH),124.5(CH),121.5(C),121.1(CH),116.6(CH),110.9(CH),107.6(C),104.8(CH),55.3(2CH2),51.0(2CH2),49.2(2CH2),46.3(NCH3),43.3(CH2Bn),38.1(CH),32.4(2CH2);MS(ESI)m/z:516.3[M+H]+;1031.8[2M+H]+;HRMS计算值:C34H38N5[M+H]+516.3121实测值:516.3124。
实施例59:4-(4-苄基哌嗪-1-基)-6-(4-(4-甲基哌嗪-1-基)苯基)-9H-吡啶并
[2,3-b]吲哚(R665)
4-(4-苄基哌嗪-1-基)-6-(4-(4-甲基哌嗪-1-基)苯基)-9-(苯基磺酰基)-9H-吡啶
并[2,3-b]吲哚
将9-苯磺酰基-4-氯-6-[4-(4-甲基-哌嗪-1-基)-苯基]-9H-吡啶并[2,3-b]吲哚(结构模块A,50mg,0.0967mmol)和苄基哌嗪(0.21mL,12.5eq)在150℃下加热7小时。冷却至室温后,将反应混合物用DCM(20mL)稀释,用水洗涤3次(3×10mL)并用盐水(10mL)洗涤。将有机层用MgSO4干燥,过滤并蒸发至干。将粗产物通过硅胶快速色谱纯化(DCM/MeOH 100:0至98:2)得到无色无定形固体状所需产物,57%收率(36.1mg)。1H NMR(300MHz,CDCl3)δ8.52(d,J=8.7Hz,1H),8.40(d,J=5.6Hz,1H),8.16(d,J=8.8Hz,2H),8.07(d,J=1.9Hz,1H),7.71(dd,J=8.8,1.9Hz,1H),7.58(d,J=8.7Hz,2H),7.49(t,J=7.4Hz,1H),7.40(d,J=8.0Hz,2H),7.38-7.27(m,5H),7.07(d,J=8.8Hz,2H),6.82(d,J=5.6Hz,1H),3.64(s,2H),3.36-3.31(m,4H),3.30-3.18(m,4H),2.88-2.68(m,4H),2.68-2.60(m,4H),2.40(s,3H);13C NMR(75MHz,CDCl3)δ155.3(C),152.9(C),150.6(C),147.9(CH),138.9(C),137.8(C),136.8(C),135.6(C),133.8(CH),132.2(C),129.2(CH),128.9(CH),128.5(CH),127.9(CH),127.7(CH),127.4(CH),125.8(CH),123.1(C),120.7(CH),116.3(CH),114.7(CH),110.4(C),108.5(CH),63.1(CH2),55.2(2CH2),53.0(2CH2),50.6(2CH2),49.0(2CH2),46.3(NCH3);MS(ESI)m/z:657.3[M+H]+;1314.7[2M+H]+;516.5[M-SO2Ph+H]+。
4-(4-苄基哌嗪-1-基)-6-(4-(4-甲基哌嗪-1-基)苯基)-9H-吡啶并[2,3-b]吲哚
将4-(4-苄基哌嗪-1-基)-6-(4-(4-甲基哌嗪-1-基)苯基)-9-(苯基磺酰基)-9H-吡啶并[2,3-b]吲哚按照典型方法A的操作脱保护,将粗产物通过硅胶快速色谱纯化(DCM/MeOH 94:6)得到白色固体状所需产物,42%收率。1H NMR(300MHz,CDCl3)δ10.59(s,1H),8.36(br s,1H),8.12(d,J=1.7Hz,1H),7.66(dd,J=8.4,1.7Hz,1H),7.61(d,J=8.7Hz,2H),7.55(d,J=8.4Hz,1H),7.44-7.27(m,5H),7.08(d,J=8.8Hz,2H),6.74(d,J=5.4Hz,1H),3.68(s,2H),3.42(br s,4H),3.36-3.26(m,4H),2.83(br s,4H),2.69-2.60(m,4H),2.40(s,3H);13C NMR(75MHz,CDCl3)δ155.5(C),154.4(C),150.2(C),146.9(CH),138.1(C),136.9(C),133.8(C),133.3(C),129.4(CH),128.6(CH),128.0(CH),127.5(CH),124.7(CH),121.2(C),121.2(CH),116.6(CH),111.2(CH),107.8(C),104.7(CH),63.3(CH2),55.4(2CH2),53.3(2CH2),50.5(2CH2),49.3(2CH2),46.4(NCH3);MS(ESI)m/z:517.5[M+H]+;1033.8[2M+H]+;HRMS计算值:C33H37N6[M+H]+517.3074实测值:517.3054。
除非另有说明,以上实施例1至59所用的所有硼酸频哪醇酯或者是可以购买到的,或者可以通过本领域技术人员已知的方法制得。
实施例1至59代表了本发明的单独的实施方案。
生物学活性
生物化学和细胞试验
在以上所述的基于ELISA的体外激酶试验和在BAF3细胞中进行的氚标记的胸苷摄取细胞增殖试验中测试了本发明的化合物并在下表中进行了列表。
(续)
(续)
体内活性
体内研究得到了意大利研究部门以及大学内部伦理委员会的批准,并且按照指南进行以减轻动物的痛苦。将10,000,000个NPM/ALK+Karpas299细胞皮下注射到SCID小鼠的右侧腹。10天后,当肿瘤大小的平均值达到100mm3时,将小鼠随机分配到对照组、仅接受溶媒的组(0.5%羧甲基纤维素和0.1%Tween80)或治疗组(口头强喂化合物R533,150mg/kg,每天两次)。通过卡尺每两周测定一次肿瘤体积。通过监测体重减轻、通过目测任何紧张或痛苦的迹象(包括闭眼或眼睛凸出、皮毛起皱/灰暗、活动减少、瞌睡、腹泻)来评估一般毒性。研究结果如附图所示,其显示了明显的效果。
Claims (15)
1.式(I)的化合物及其可药用盐
其中:
R1是H或C1-C3烷基
R2是卤素或
X是CH或N
R3是C1-C3烷基或(1-甲基哌啶-4-基)
Rx和Ry是H或硝基
Rz和Rz'是H、OH或氧代
Rt和R't可以相同或不同并且是H或C1-C3烷氧基
Ra是H或F
Rb是H、C1-C3烷氧基、三氟甲基或卤素
Re是H或卤素
Rf是H、C1-C3烷基或三氟甲基
Rg是H或F
Rk是H、卤素、三氟甲基、C1-C3烷氧基、C1-C3烷基磺酰氨基
Rl是H或F
Rm是H、C1-C3烷氧基、F或三氟甲基
Rn是H、C1-C3烷基或5-至6-元芳香族或杂芳族环
Rp是C1-C3烷基或5-至6-元芳香族或杂芳族环
Rq是H或三(C1-C4)烷基硅烷基
Rs是三(C1-C4)烷基硅烷基
Rh是H、C1-C3烷氧基或C1-C3烷基羰基氨基
Ru是H或F
Rv是C1-C3烷基
Rw和Rw'可以相同或不同并且是羟基或C1-C3烷氧基
L和L’是O、S、SO或SO2;
Z是C或N。
2.权利要求1的化合物,其中
R1是H或甲基
R2如权利要求1中所定义
X是CH或N
R3是甲基或1-甲基哌啶-4-基
Rx和Ry是H或硝基
Rz是H、OH或氧代
Rz'是H
Rt和R't可以相同或不同并且可以是H或甲氧基
Ra是H或F
Rb是H、甲氧基、三氟甲基、F或Cl
Re是H或Cl
Rf是H、甲基或三氟甲基
Rg是H或F
Rk是H、Cl、F、三氟甲基、甲氧基、甲基磺酰氨基
Rl是H或F
Rm是H、甲氧基、F或三氟甲基
Rn是H、甲基、乙基或苯基
Rp是乙基或苯基
Rq是H或三异丙基硅烷基
Rs是三异丙基硅烷基
Ru是F
Rv是甲基
Rw和Rw'分别是羟基和甲氧基,或者同时是甲氧基
Z是C或N
L是O且Rh是H
L'是S且Rh是甲氧基。
3.权利要求1或2的化合物,其中:
R1是H
R2是
X是CH
并且其中R3、Ra、Rb、Re、Rf、Rg、Rk、Rl、Rm、Rn、Rz、Rt、R't、Rp、Z、Rw和Rw'如权利要求1或2所定义。
4.权利要求1-3的化合物,其中R1、R2、R3、X、L、L'、Z、Rx、Ry、Ra、Rb、Re、Rf、Rg、Rh、Rk、Rl、Rm、Rp、Rq、Rs、Rz、Rz'、Rt、R't、Ru、Rv、Rw和Rw'如权利要求1-3所定义,并且其中当R2是
时,Rk、Rl和Rm中有两个是H,第三个如权利要求1-3中所定义。
5.权利要求3或4的化合物,其中R2选自:
并且Rk、Rl、Rm、Rn和Rp如权利要求3或4中所定义。
6.权利要求1-5的化合物,其中R3是甲基并且其中的R1、R2、X、L、L'、Z、Rx、Ry、Ra、Rb、Re、Rf、Rg、Rh、Rk、Rl、Rm、Rn、Rp、Rq、Rs、Rz、Rz'、Rt、R't、Ru、Rv、Rw和Rw'如权利要求1-5所定义。
7.权利要求1-5的化合物,其中R3是(1-甲基哌啶-4-基),R1、R2、X、L、L'、Z、Rx、Ry、Ra、Rb、Re、Rf、Rg、Rh、Rk、Rl、Rm、Rn、Rp、Rq、Rs、Rz、Rz'、Rt、R't、Ru、Rv、Rw和Rw'如权利要求1-5所定义。
8.权利要求1或2的化合物,选自:
■(E)-6-[4-(4-甲基哌嗪-1-基)苯基]-4-(2-苯基乙烯基)-9H-吡啶并[2,3-b]吲哚;
■(E)-6-[6-(4-甲基哌嗪-1-基)-吡啶-3-基]-4-(2-苯基乙烯基)-9H-吡啶并[2,3-b]吲哚;
■4-联苯-4-基-6-[4-(4-甲基哌嗪-1-基)苯基]-9H-吡啶并[2,3-b]吲哚;
■(E)-4-[2-(3-氟苯基)乙烯基]-6-[4-(4-甲基哌嗪-1-基)苯基]-9H-吡啶并[2,3-b]吲哚;
■(E)-4-[2-(4-甲氧基苯基)乙烯基]-6-[4-(4-甲基哌嗪-1-基)苯基]-9H-吡啶并[2,3-b]吲哚;
■4-(4-苄氧基苯基)-6-[4-(4-甲基哌嗪-1-基)苯基]-9H-吡啶并[2,3-b]吲哚;
■6-[4-(4-甲基哌嗪-1-基)苯基]-4-[4-(3-(三氟甲基)苯氧基甲基)苯基]-9H-吡啶并[2,3-b]吲哚;
■(E)-4-(2-(2-甲氧基苯基)乙烯基))-6-(4-(4-甲基哌嗪-1-基)苯基)-9H-吡啶并[2,3-b]吲哚;
■(E)-6-(4-(4-甲基哌嗪-1-基)苯基)-4-(2-(2-(三氟甲基)苯基)乙烯基)-9H-吡啶并[2,3-b]吲哚;
■4-[4-(4-氯-3-甲基-苯氧基甲基)苯基]-6-[4-(4-甲基哌嗪-1-基)苯基]-9H-吡啶并[2,3-b]吲哚;
■6-[4-(4-甲基哌嗪-1-基)苯基]-4-苯基乙炔基-9H-吡啶并[2,3-b]吲哚;
■(E)-4-(2-(4-氟苯基)乙烯基))-6-(4-(4-甲基哌嗪-1-基)苯基)-9H-吡啶并[2,3-b]吲哚;
■(E)-6-(4-(4-甲基哌嗪-1-基)苯基)-4-(2-(4-(三氟甲基)苯基)乙烯基))-9H-吡啶并[2,3-b]吲哚;
■4-(3-氟联苯-4-基)-6-[4-(4-甲基哌嗪-1-基)苯基]-9H-吡啶并[2,3-b]吲哚;
■4-(4-苄基苯基)-6-[4-(4-甲基哌嗪-1-基)苯基]-9H-吡啶并[2,3-b]吲哚;
■4-联苯-3-基-6-[4-(4-甲基哌嗪-1-基)苯基]-9H-吡啶并[2,3-b]吲哚;
■4-((2-甲氧基苯基)乙炔基)-6-[4-(4-甲基哌嗪-1-基)苯基]-9H-吡啶并[2,3-b]吲哚;
■6-[4-(4-甲基哌嗪-1-基)苯基]-4-((2-(三氟甲基)苯基)乙炔基)-9H-吡啶并[2,3-b]吲哚;
■4-((4-氟苯基)乙炔基)-6-[4-(4-甲基哌嗪-1-基)苯基]-9H-吡啶并[2,3-b]吲哚;
■4-((2-氟苯基)乙炔基)-6-[4-(4-甲基哌嗪-1-基)苯基]-9H-吡啶并[2,3-b]吲哚;
■(E)-4-(2-(2-氟苯基)乙烯基))-6-(4-(4-甲基哌嗪-1-基)苯基)-9H-吡啶并[2,3-b]吲哚;
■(E)-4-(2-(2-氯苯基)乙烯基))-6-(4-(4-甲基哌嗪-1-基)苯基)-9H-吡啶并[2,3-b]吲哚;
■6-(4-(4-甲基哌嗪-1-基)苯基)-N-(3-硝基苯基)-9H-吡啶并[2,3-b]吲哚-4-胺;
■6-(4-(4-甲基哌嗪-1-基)苯基]-N-(2-硝基苯基)-9H-吡啶并[2,3-b]吲哚-4-胺;
■4-((2-氯苯基)乙炔基)-6-[4-(4-甲基哌嗪-1-基)苯基]-9H-吡啶并[2,3-b]吲哚;
■4-((2-甲氧基苯基)乙炔基)-9-甲基-6-[4-(4-甲基哌嗪-1-基)苯基]-9H-吡啶并[2,3-b]吲哚;
■4,6-双-[4-(4-甲基哌嗪-1-基)苯基]-9H-吡啶并[2,3-b]吲哚;
■4-(4-苄基苯基)-6-(4-(4-(1-甲基哌啶-4-基)哌嗪-1-基)苯基)-9H-吡啶并[2,3-b]吲哚;
■(E)-6-(4-(4-(1-甲基哌啶-4-基)哌嗪-1-基)苯基)-4-(2-(2-(三氟甲基)苯基)乙烯基))-9H-吡啶并[2,3-b]吲哚;
■6-(4-(4-(1-甲基哌啶-4-基)哌嗪-1-基)苯基)-N-(2-硝基苯基)-9H-吡啶并[2,3-b]吲哚-4-胺;
■(E)-6-(4-(4-甲基哌嗪-1-基)苯基)-4-(1-苯基丙-1-烯-2-基)-9H-吡啶并[2,3-b]吲哚;
■(4-{6-[4-(4-甲基哌嗪-1-基)苯基]-9H-吡啶并[2,3-b]吲哚-4-基}-苯基)苯基-甲醇;
■(4-{6-[4-(4-甲基哌嗪-1-基)苯基]-9H-吡啶并[2,3-b]吲哚-4-基}-苯基)苯基-甲酮;
■4-氯-6-[4-(4-甲基哌嗪-1-基)苯基]-9H-吡啶并[2,3-b]吲哚;
■(E)-N-[2-(2-{6-[4-(4-甲基哌嗪-1-基)苯基]-9H-吡啶并[2,3-b]吲哚-4-基}-乙烯基)苯基]-甲磺酰胺;
■6-[4-(4-甲基哌嗪-1-基)苯基]-4-(4-萘-1-基-苯基)-9H-吡啶并[2,3-b]吲哚;
■(E)-4-(1,2-二苯基乙烯基)-6-[4-(4-甲基哌嗪-1-基)苯基]-9H-吡啶并[2,3-b]吲哚;
■(E)-6-[4-(4-甲基哌嗪-1-基)苯基]-4-(1-苯基-丁-1-烯基)-9H-吡啶并[2,3-b]吲哚;
■(E)-6-(4-(4-甲基哌嗪-1-基)苯基)-4-(1-苯基丁-1-烯-2-基)-9H-吡啶并[2,3-b]吲哚;
■4-[4-(2,4-二甲氧基苄基)苯基]-6-[4-(4-甲基哌嗪-1-基)苯基]-9H-吡啶并[2,3-b]吲哚;
■(E)-4-[1-(2-甲氧基苯基)-丙-1-烯-2-基]-6-[4-(4-甲基哌嗪-1-基)苯基]-9H-吡啶并[2,3-b]吲哚;
■(E)-6-[4-(4-甲基哌嗪-1-基)-苯基]-4-[1-(2-(三氟甲基)苯基)-丙-1-烯-2-基]-9H-吡啶并[2,3-b]吲哚;
■6-(4-(4-甲基哌嗪-1-基)苯基)-4-((三异丙基硅烷基)乙炔基)-9H-吡啶并[2,3-b]吲哚;
■(E)和/或(Z)-6-(4-(4-甲基哌嗪-1-基)苯基)-4-(2-(三异丙基硅烷基)乙烯基)-9H-吡啶并[2,3-b]吲哚;和
■4-乙炔基-6-(4-(4-甲基哌嗪-1-基)苯基)-9H-吡啶并[2,3-b]吲哚。
9.权利要求1或2的化合物,选自:
■4-(4-甲氧基-苯硫基)-6-[4-(4-甲基-哌嗪-1-基)-苯基]-9H-吡啶并[2,3-b]吲哚;
■4-(1-(4-甲基苄基)-1H-1,2,3-三唑-4-基)-6-(4-(4-甲基哌嗪-1-基)苯基)-9H-吡啶并[2,3-b]吲哚;
■6-(4-(4-甲基哌嗪-1-基)苯基)-4-(4-苯氧基苯基)-9H-吡啶并[2,3-b]吲哚;
■4-(6-(4-氟苯基)吡啶-3-基)-6-(4-(4-甲基哌嗪-1-基)苯基)-9H-吡啶并[2,3-b]吲哚;
■(2,5-二甲氧基-4-(6-(4-(4-甲基哌嗪-1-基)苯基)-9H-吡啶并[2,3-b]吲哚-4-基)苯基)(苯基)甲酮;
■(2-羟基-5-甲氧基-4-(6-(4-(4-甲基哌嗪-1-基)苯基)-9H-吡啶并[2,3-b]吲哚-4-基)苯基)(苯基)甲酮;
■4-(4-苄基-2,5-二甲氧基苯基)-6-(4-(4-甲基哌嗪-1-基)苯基)-9H-吡啶并[2,3-b]吲哚;
■2-苄基-4-甲氧基-5-(6-(4-(4-甲基哌嗪-1-基)苯基)-9H-吡啶并[2,3-b]吲哚-4-基)苯酚;
■4-(4-苄基-3-(三氟甲基)苯基)-6-(4-(4-甲基哌嗪-1-基)苯基)-9H-吡啶并[2,3-b]吲哚;
■4-(4-苄基-2-(三氟甲基)苯基)-6-(4-(4-甲基哌嗪-1-基)苯基)-9H-吡啶并[2,3-b]吲哚;
■4-(4-苄基-3,5-二甲氧基苯基)-6-(4-(4-甲基哌嗪-1-基)苯基)-9H-吡啶并[2,3-b]吲哚;
■(2,5-二甲氧基-4-(6-(4-(4-甲基哌嗪-1-基)苯基)-9H-吡啶并[2,3-b]吲哚-4-基)苯基)(苯基)甲醇;
■4-(4-苄基哌啶-1-基)-6-(4-(4-甲基哌嗪-1-基)苯基)-9H-吡啶并[2,3-b]吲哚;和
■4-(4-苄基哌嗪-1-基)-6-(4-(4-甲基哌嗪-1-基)苯基)-9H-吡啶并[2,3-b]吲哚。
10.权利要求2的化合物,选自:
■4-联苯-4-基-6-[4-(4-甲基哌嗪-1-基)苯基]-9H-吡啶并[2,3-b]吲哚(R510a);
■(E)-4-(2-(2-甲氧基苯基)乙烯基))-6-(4-(4-甲基哌嗪-1-基)苯基)-9H-吡啶并[2,3-b]吲哚;
■(E)-6-(4-(4-甲基哌嗪-1-基)苯基)-4-(2-(2-(三氟甲基)苯基)乙烯基)-9H-吡啶并[2,3-b]吲哚;
■4-[4-(4-氯-3-甲基苯氧基甲基)苯基]-6-[4-(4-甲基哌嗪-1-基)苯基]-9H-吡啶并[2,3-b]吲哚;
■(E)-4-(2-(4-氟苯基)乙烯基))-6-(4-(4-甲基哌嗪-1-基)苯基)-9H-吡啶并[2,3-b]吲哚;
■4-(4-苄基苯基)-6-[4-(4-甲基哌嗪-1-基)苯基]-9H-吡啶并[2,3-b]吲哚;
■4-联苯-3-基-6-[4-(4-甲基哌嗪-1-基)苯基]-9H-吡啶并[2,3-b]吲哚;
■4-((2-甲氧基苯基)乙炔基)-6-[4-(4-甲基哌嗪-1-基)苯基]-9H-吡啶并[2,3-b]吲哚;
■6-(4-(4-甲基哌嗪-1-基)苯基)-N-(3-硝基苯基)-9H-吡啶并[2,3-b]吲哚-4-胺;
■(4-{6-[4-(4-甲基哌嗪-1-基)苯基]-9H-吡啶并[2,3-b]吲哚-4-基}-苯基)苯基-甲醇;
■(4-{6-[4-(4-甲基哌嗪-1-基)苯基]-9H-吡啶并[2,3-b]吲哚-4-基}-苯基)苯基-甲酮;
■6-[4-(4-甲基哌嗪-1-基)苯基]-4-(4-萘-1-基-苯基)-9H-吡啶并[2,3-b]吲哚;
■4-(4-苄基哌啶-1-基)-6-(4-(4-甲基哌嗪-1-基)苯基)-9H-吡啶并[2,3-b]吲哚;
■4-(4-苄基哌嗪-1-基)-6-(4-(4-甲基哌嗪-1-基)苯基)-9H-吡啶并[2,3-b]吲哚;和
■4-(4-苄基-2,5-二甲氧基苯基)-6-(4-(4-甲基哌嗪-1-基)苯基)-9H-吡啶并[2,3-b]吲哚。
11.用作用于治疗癌症的药物的权利要求1-10的化合物。
12.用作用于治疗选自间变性大细胞淋巴瘤(ALCL)、弥漫性大B细胞淋巴瘤、炎性肌纤维母细胞瘤、非小细胞肺癌(NSCLC)、食管鳞状细胞癌、肾髓质癌、髓性白血病、乳癌和结肠直肠癌的癌症的权利要求1-10的化合物。
13.式(II)的化合物
其中R3和X如权利要求1-3中所定义。
14.权利要求13的化合物,选自:
■9-苯磺酰基-4-氯-6-[4-(4-甲基哌嗪-1-基)-苯基]-9H-吡啶并[2,3-b]吲哚(结构模块A);
■9-苯磺酰基-4-氯-6-[4-(6-甲基哌嗪-1-基)-吡啶-3-基]-9H-吡啶并[2,3-b]吲哚(结构模块B);和
■9-苯磺酰基-4-氯-6-(4-(4-(1-甲基哌啶-4-基)哌嗪-1-基)苯基)-9H-吡啶并[2,3-b]吲哚(结构模块C)。
15.权利要求13或14的化合物在制备权利要求1-10的化合物中的应用。
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EP20120167755 EP2662372A1 (en) | 2012-05-11 | 2012-05-11 | Alpha-carbolines for the treatment of cancer |
PCT/EP2013/059721 WO2013167730A1 (en) | 2012-05-11 | 2013-05-10 | Alpha-carbolines for the treatment of cancer |
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EP (2) | EP2662372A1 (zh) |
CN (1) | CN104540823B (zh) |
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EP3655406A1 (en) | 2017-07-18 | 2020-05-27 | Bayer Pharma Aktiengesellschaft | Substituted pyrrolopyridine-derivatives |
WO2021057696A1 (zh) * | 2019-09-27 | 2021-04-01 | 隆泰申医药科技(南京)有限公司 | 一种杂芳基类化合物及其应用 |
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WO2006131552A1 (de) * | 2005-06-09 | 2006-12-14 | Boehringer Ingelheim International Gmbh | Alpha-carboline als cdk-1 inhibitoren |
CN102203092A (zh) * | 2008-09-08 | 2011-09-28 | 米兰-比科卡大学 | NPM-ALK、RET和BCR-ABL的α-咔啉抑制剂 |
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FR2876377B1 (fr) * | 2004-10-11 | 2007-03-16 | Univ Claude Bernard Lyon | Nouveaux derives de 9h-pyrido[2,3-b]indole, leur procede de preparation, ainsi que les compositions pharmaceutiques contenant de tels composes |
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2012
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2013
- 2013-05-10 ES ES13726442.0T patent/ES2641816T3/es active Active
- 2013-05-10 EP EP13726442.0A patent/EP2855475B1/en not_active Not-in-force
- 2013-05-10 PL PL13726442T patent/PL2855475T3/pl unknown
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- 2013-05-10 WO PCT/EP2013/059721 patent/WO2013167730A1/en active Application Filing
- 2013-05-10 CN CN201380024132.1A patent/CN104540823B/zh not_active Expired - Fee Related
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WO2006131552A1 (de) * | 2005-06-09 | 2006-12-14 | Boehringer Ingelheim International Gmbh | Alpha-carboline als cdk-1 inhibitoren |
CN102203092A (zh) * | 2008-09-08 | 2011-09-28 | 米兰-比科卡大学 | NPM-ALK、RET和BCR-ABL的α-咔啉抑制剂 |
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US9428500B2 (en) | 2016-08-30 |
CN104540823B (zh) | 2017-02-22 |
PL2855475T3 (pl) | 2018-02-28 |
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