CN107793411A - 异喹啉酮类化合物及作为抗病毒药物的应用 - Google Patents
异喹啉酮类化合物及作为抗病毒药物的应用 Download PDFInfo
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- CN107793411A CN107793411A CN201710627422.5A CN201710627422A CN107793411A CN 107793411 A CN107793411 A CN 107793411A CN 201710627422 A CN201710627422 A CN 201710627422A CN 107793411 A CN107793411 A CN 107793411A
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- alkyl
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- cycloalkyl
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- YZCKVEUIGOORGS-OUBTZVSYSA-N Deuterium Chemical compound [2H] YZCKVEUIGOORGS-OUBTZVSYSA-N 0.000 claims description 24
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- 125000005843 halogen group Chemical group 0.000 claims description 7
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- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 claims description 5
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 5
- 229920006395 saturated elastomer Polymers 0.000 claims description 5
- 125000006625 (C3-C8) cycloalkyloxy group Chemical group 0.000 claims description 4
- 108091030071 RNAI Proteins 0.000 claims description 4
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 4
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- 239000012024 dehydrating agents Substances 0.000 claims description 2
- 125000005448 ethoxyethyl group Chemical group [H]C([H])([H])C([H])([H])OC([H])([H])C([H])([H])* 0.000 claims description 2
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Abstract
本发明属于医药化学抗病毒领域,涉及一种式(I)所示的异喹啉酮类化合物或其立体异构体、可药用盐、溶剂化物或结晶及其制备和其用作治疗或预防乙肝病毒(HBV)等病毒感染性疾病的药物的用途,特别是作为乙肝表面抗原抑制剂(HBV Surface antigen inhibitors)和乙肝DNA抑制剂(HBV DNA production inhibitors)药物的应用。本发明的化合物具有显著的抑制乙肝表面抗原和乙肝DNA的活性,将来和核苷类药物或其他药物联合用药,有可能显著提高治愈乙肝的几率,有极好的临床应用前景。
Description
技术领域
本发明属于医药化学领域,具体涉及一类新型异喹啉酮类化合物或其立体异构体,含有前述异喹啉酮类化合物或其立体异构体的药物组合物以及它们作为抗病毒药物的用途,特别是作为乙肝表面抗原抑制剂(HBV Surface antigen inhibitors)和乙肝DNA抑制剂(HBV DNA production inhibitors)的药物用于治疗和/或预防感染乙肝病毒的用途,特别是指这类化合物和TLR7抑制剂以及核苷类药物可以作为治愈乙肝的药物组合物的用途。
背景技术
慢性乙型肝炎在全球大约有3.5亿感染,在2011年有78万人因为乙型肝炎死亡,其中中国的乙肝患者占全球乙肝患者总数的约三分之一。中国目前每年用于乙肝治疗的费用超过1000亿,是全球最大的乙肝药物市场。尽管乙肝疫苗已经广泛应用,中国的乙肝病人仍以每年平均250万人左右的速度迅速增长,美国的乙肝病人也以15.4%的速度快速增长。乙肝病毒的携带者大约有25%的病人转变为慢性乙肝,10-30%的慢性乙肝发展为肝硬化或肝癌。慢性乙肝是导致肝硬化的主要因素之一。
目前FDA批准的治疗乙肝的药物有7个,他们分别是干扰素-α,聚乙二醇化干扰素-α,拉米夫定,恩替卡韦,替比夫定,阿德福韦酯和替诺福韦酯。TAF(tenofovir alafenamidefumarate,替诺福韦艾拉酚胺富马酸)已经完成三期临床,等待FDA批准。所有的这些药物都不能有效的治愈乙肝,需要长期服药。干扰素类药物通过刺激人体的免疫系统抑制病毒的DNA和RNA,使用干扰素耐药性较少,有一定的乙肝表面抗原消失和血清转换,缺点是应答率低,需要注射和严重的副作用。拉米夫定和替比夫定容易产生耐药性,不能长期服用。例如服用拉米夫定在第一年有20%的病人产生耐药性,第二年有70%的病人产生耐药性。阿德福韦酯由于耐受性和不良反应逐渐退出一线药物。目前WHO推荐治疗乙肝的一线药物为替诺福韦酯(TDF)和恩替卡韦。特别是替诺福韦酯在连续服用5年没有发现耐药性,并且病毒清除率达95%-100%,副作用小。所有这些核苷类药物都是通过抑制病毒DNA的合成来降低乙肝病毒,对于病毒的RNA没有作用。核苷类药物也不能治愈乙肝,只能压制乙肝病毒的复制。因此需要同时抑制病毒DNA和RNA的全新作用机理的药物治愈乙肝。最新开发的核心蛋白抑制剂可以同时抑制病毒的DNA和RNA,单独用药可以达到和恩替卡韦相似的治疗效果。其中NVR-3-778是一种有效的衣壳抑制剂,但是没有乙肝表面抗原(HBsAg)消失的数据。从现有的数据分析,衣壳抑制剂也不能治愈乙肝,因为这类化合物不能有效的作用于乙肝的cccDNA,也没有数据支持衣壳抑制剂可以缩短cccDNA的半衰期,二期临床研究的衣壳抑制剂需要和核苷类药物或干扰素合用。
以治愈乙肝为目的的新药设计,新设计化合物的机理要求和干扰素一样,需要重新激活人体自身的免疫系统,依靠自身的免疫系统识别和清除感染的肝细胞,从而彻底治愈乙肝。慢性乙肝病人的肝细胞分泌的乙肝表面抗原和其他病毒抗原,通过信号转导系统,干扰免疫系统,阻断免疫细胞对病毒的识别和进一步限制其发挥抗病毒功能。另外持续和过多的乙肝表面抗原可以使免疫系统钝化,T-细胞缺失和进行功能损伤。乙肝表面抗原还可以直接压制免疫细胞对病毒的清除功能。基于以上的原因,开发针对抑制乙肝表面抗原分泌的药物可以有效的恢复免疫细胞的功能,减轻免疫系统的压力,使免疫系统识别并清除感染的肝细胞,达到直接治愈乙肝的目的。
另外,乙肝表面抗原减少也是慢性乙肝好转的生物指标,乙肝表面抗原消失和血清转换表明乙肝已经功能性治愈。目前核苷类药物不能减少乙肝表面抗原,必需设计新的作用机理的药物,和强效的核苷类药物联用,同时有效的清除乙肝表面抗原和血液中的病毒DNA,激活并恢复自身的免疫功能,从而最终可能治愈乙肝。
发明内容
本发明的目的在于提供新型的异喹啉酮类化合物,该类化合物有极强的抑制乙肝DNA的活性,并具有强效的抑制乙肝表面抗原的活性。此外,该类化合物的结构将阻断P450氧化的途径,提高化合物的生物利用度,降低化合物的毒性。这些高活性的化合物将和核苷类化合物以及TLR7激动剂联合用药,在临床上可能显著提高乙肝的治疗效果和治愈率。
为实现上述目的,本发明采用如下技术方案:
一种式(I)所示的异喹啉酮类化合物或其立体异构体、可药用盐、溶剂化物或结晶,
其中:
(1)R1选自H、氘、C1-6烷基、氰基、卤素、羧基、酯基、C3-6环烷基、C4-8杂环烷基、卤代C1-6烷基或C6-10芳基;
(2)R2选自卤素、C1-3烷氧基、氘代C1-3烷氧基、C1-6烷基、C3-6环烷基、C3-6环烷基氧基、C4-8环杂烷基C1-6烷基、卤代C1-3烷基氧基、卤代C3-6环烷基、C3-6环烷基C1-6烷基或R2和R3以碳原子连接形成环;
(3)R3为(a)具有环结构和/或不饱和键的C4-12烃基,该C4-12烃基的氢原子未被取代,或为选自氘、卤素、氰基、羟基、巯基中的一个或多个取代基取代,且该C4-12烃基未被杂原子间断,或被O,S,NH,C=O,C=S,O=S=O中的一个或多个所间断,所述杂原子选自氧、硫或氮;或者,(b)R2和R3以碳原子连接形成环;
(4)R4选自氢、氘、卤素、氰基、酯基或C1-3烷基;
(5)R5,R5′独立的选自氢、氘、卤素、甲基、甲氧基或R5,R5′形成碳环或杂环;或R5,R6形成碳环或杂环;
(6)M为CH或N;
(7)R6选自C1-6烷基、C1-6烷氧C1-6烷基、羟基C1-6烷基、芳基、卤代C1-6烷基或C3-6环烷基C1-6烷基;
(8)W为N或CR7,其中R7选自氢、氘、羟基、卤素、C1-3烷基、C1-6烷氧基、C3-6环烷基氧基、酯基、羧基或氰基;
(9)R8选自羧基、酯基、C1-6烷基、C3-6环烷基、C1-6烷基炔基或C3-6环烷基炔基,其中所述酯基的烷基部分选自C1-6烷基、C3-8环烷基、C3-8环烷基炔基、C1-6烷基炔基、苄基、C1-6烷基C(O)O-C1-3烷基、C1-6烷基-OC(O)O-C1-3烷基。
根据本发明,所述被O,S,NH,C=O,C=S,O=S=O中的一个或多个所间断的烃基是指烃基的相邻接的二个碳原子或该烃基与其所连接的碳原子之间被这些原子或基团所间断,在满足有机化合物的成键规则的前提下,对于间断的位置没有特别限制,被多个原子间断时,这些间隔原子或基团可以是相邻位置或间隔开的,当间隔原子或基团为多个时,它们可以是多个相同的原子或基团,也可以是不同的原子或基团,当间隔原子为多个不同的原子或基团且它们处于相邻位置时,可形成新的间隔基团,例如COO(酯基)、酰胺基(CONH)、SO2NH(磺酰胺基)等。例如,被O,S,NH,C=O,C=S,O=S=O中的一个所间断的丙基可以是例如OCH2CH2CH3;CH2OCH2CH3;CH2SCH2CH3;CH2NHCH2CH3,CH2COCH2CH3,CH2COCH2CH3,CH2SO2CH2CH3;例如被O,S,NH,C=O,C=S,O=S=O中的二个所间断的丙基可以是例如CH2COOCH2CH3,CH2COCH2OCH3,CH2CONHCH2CH3,CH2C=OCHNHCH3,CH2SO2NHCH2CH3等。
进一步地,所述(a)中,所述环结构优选为3~8元环,更优选为3~6元环;所述不饱和键可以为双键或三键。
优选地,所述(a)中,所述的环结构为饱和环。
优选地,所述(a)中,所述环结构、不饱和键的个数分别为1~2个。
优选地,所述(a)具有一个3~8元饱和碳环或3~8元饱和杂环、至少一个杂原子或至少一个双键或三键。
进一步优选地,所述(a)中,所述环结构、不饱和键以及杂原子中的至少二者同时存在。
根据本发明的一个具体且优选方面,所述(a)为满足如下任意一项所述条件的基团:
a1)同时具有所述的环结构和碳碳不饱和键,且环结构和碳碳不饱和键分别有且只有一个;
a2)同时具有所述的环结构和1~3个杂原子,且所述杂原子中至少一个为氧,且该氧原子通过单键与式(I)中苯环连接;
a3)同时具有不饱和键和1~3个杂原子,其中不饱和键为碳碳双键,碳碳三键或者碳氧双键。优选地,不饱和键为碳碳双键,碳碳三键时,它们的一端通过单键与式(I)中苯环连接。
根据本发明的一个具体方面,R3为C5-11双环烷基;C3-6环烷基炔基;C3-6环烷基烯基;C1-3烷氧C1-6烷基炔基;C1-3烷氧C1-6烷基烯基;C4-8环杂烷基;或者,
R3为RA-O-,其中RA选自C3-8环烷基;C5-11双环烷基;氘代C1-6烷基;C4-8环杂烷基;C1-6烷基羰基C1-6烷基;氘代C1-3烷氧基C1-6烷基;C1-3烷氧基C3-8环烷基;C1-3烷氧基C3-8环烷基C1-6烷基;C3-8杂环烷基;C1-3烷氧基C1-6烷基,其中烷基被C3-8环烷烃或C4-8杂环烷烃取代,杂环烷烃的杂原子选自氧、硫或氮;当RA选自C1-3烷氧基C1-6烷基时,R5、R5′独立选自氘、氟、氯、羟基、氰基,且W为N或CR7,其中R7选自氘、氟、氯、羟基、氰基。
根据本发明的一个优选方面,所述R3选自C3-8环烷氧基、C3-8杂环烷氧基、C1-3烷氧C3-8环烷氧基、C1-3烷氧C3-8环烷基C1-6烷氧基、C3-8杂环烷基、C1-3烷氧C2-9烯基、C1-3烷氧C2-9炔基、C3-8环烷基C2-9烯基、C3-8环烷基C2-9炔基。
根据本发明,所述R2优选为选自C1-3烷氧基、卤素、C3-6环烷基、苄基。
根据本发明的一个具体方面,R6选自甲基、乙基、异丙基、丁基、异丁基、甲氧基甲基、甲氧基乙基、甲氧基异丙基、甲氧基丁基、甲氧基异丁基、乙氧基甲基、乙氧基乙基、乙氧基异丙基、乙氧基丁基、乙氧基异丁基、羟基甲基、羟基乙基、羟基异丙基、羟基丁基、羟基异丁基。
根据本发明,除去活泼氢之外,其余所有的氢原子都可以分别独立地被氘取代。
根据本发明,典型的异喹啉酮类化合物如下列化合物:
本发明还提供一种制备本发明所述的式(I)所示的异喹啉酮类化合物、其立体异构体、可药用盐、溶剂化物或结晶的中间体,该中间体如下式(II)所示:
式(II)中,所述R1、R2、R4、R5、R5’、R6、R8、W和N的定义同前。根据本发明的一个具体优选方面,式(II)所示的中间体为化合物10或其异构体或消旋体
本发明还进一步提供一种本发明所述的式(I)所示的异喹啉酮类化合物、其立体异构体、可药用盐、溶剂化物或结晶(以下统称本发明化合物)的制备方法,其采用如下式(II)所示的中间体:
式(II)中,所述R1、R2、R4、R5、R5’、R6、R8、W和N的定义同前。进一步地,所述方法包括使式(II)所示的中间体与RAOH、RAOMs或RABr反应,其中,当反应物为RAOH,所述反应采用Mitsunobu反应,在脱水剂为三苯基膦和/或偶氮二甲酸二乙酯存在下进行;当反应物为RAOMs或RABr,所述反应为SN2反应,在碱为碳酸钾和/或碳酸铯以及催化量KI存在下进行。
根据本发明的一个具体方面,式(II)所示的中间体为化合物10或其异构体或消旋体
本发明还提供一种药物组合物,其含有本发明所述的式(I)所示的异喹啉酮类化合物、其立体异构体、可药用盐、溶剂化物或结晶,以及药学上可接受的载体或赋形剂。
优选地,所述药物组合物为抗病毒药物组合物,其中还包含一种或多种治疗剂,所述治疗剂治选自以下组成的群:核苷类药物、利巴韦林、干扰素、HBV衣壳抑制剂(capsidinhibitor)、cccDNA形成抑制剂、cccDNA表观遗传修饰剂或乙肝RNAi药物、TLR7激动剂。
本发明还涉及本发明所述的式(I)所示的异喹啉酮类化合物、其立体异构体、可药用盐、溶剂化物或结晶或其与一种或多种选自核苷类药物、利巴韦林、干扰素、HBV衣壳抑制剂(capsid inhibitor)、cccDNA形成抑制剂、cccDNA表观遗传修饰剂或乙肝RNAi药物、TLR7激动剂的治疗剂的组合在制备预防和/或治疗病毒感染疾病药物,和/或乙肝表面抗原抑制剂(HBV Surface antigen inhibitors)和乙肝DNA抑制剂(HBV DNA productioninhibitors)药物中的应用,所述病毒感染包括HBV或HDV的感染。
本发明同时还提供所述药物组合物在制备用于治疗或预防乙肝和乙肝病毒感染药物中的应用以及采用所述药物组合物预防或减缓乙肝和乙肝病毒感染患者疾病的方法。
根据本发明的药物组合物,其中本发明所述化合物优选以治疗有效量存在。
上述药物组合物中药学上可接受的载体,如药学上可接受的稀释剂、赋型剂、填充剂、粘合剂、崩解剂、吸收促进剂、表面活性剂、润滑剂、香味剂、甜味剂等。
以本发明化合物为活性成分制备的药物可以是片剂、粉剂、胶囊、粒剂、口服液以及注射制剂等多种形式。药物组合物的剂型优选为片剂、胶囊或针剂。
上述各种剂型的药物均可以按药学领域的常规方法制备。
本发明还提供本发明化合物在制备预防或治疗病毒感染疾病中的用途,优选其中病毒感染疾病为HBV病毒感染。
本发明的药物组合物组成可以由下配比构成:
由于以上技术方案的实施,本发明与现有技术相比存在如下优势:
本发明提供了新型的异喹啉酮类化合物,该类化合物有极强的抑制乙肝DNA的活性,EC50可低于5纳摩尔,并具有强效的抑制乙肝表面抗原的活性,EC50在10纳摩尔左右。此外,该类化合物具有优异的药代动力学特性。
进一步地,本发明化合物将阻断P450氧化的途径,提高化合物的生物利用度,降低化合物的毒性。这些高活性的化合物将和核苷类化合物以及TLR7激动剂联合用药,在临床上可能显著提高乙肝的治疗效果和治愈率。
术语定义
除非另外定义,本文使用的所有技术和科学术语具有与本发明所属领域的普通技术人员通常理解的相同的含义。
术语“立体异构体”是指由分子中原子在空间上排列方式不同所产生的异构体。包括顺反异构体、对映异构体和构象异构体。所有立体异构体均属于本发明的范围。本发明的化合物可以为单独立体异构体或其它异构体的混合例如外消旋体,或者所有其它立体异构体的混合。
术语“盐”是指本发明所述的化合物与酸形成的药学上可接受的盐,所述的酸可以是有机酸或无机酸,具体可选自:磷酸、硫酸、盐酸、氢溴酸、柠檬酸、马来酸、丙二酸、扁桃酸、琥珀酸、富马酸、醋酸、乳酸、硝酸、磺酸、对甲苯磺酸、苹果酸、甲烷磺酸或其类似物。
术语“溶剂化物”是指通过与溶剂分子配位形成固态或液态的配合物的本发明化合物的形式。水合物是溶剂合物的特殊形式,其中与水发生配位。在本发明范围内,溶剂合物优选是水合物。
术语“结晶”是指本发明所述的化合物形成的各种固体形态,包括晶型、无定形。
术语“烃基”是指直链、支链或环状的饱和或不饱和主要由碳和氢构成的取代基。优选1-20个碳原子,更优选1-12个碳原子。术语“烷基”是指直链、支链或环状的饱和烃基。烷基具体包括甲基、乙基、正丙基、异丙基、环丙基、正丁基、异丁基、叔丁基、环丁基、正戊基、异戊基、新戊基、环己基、正己基、异己基、2,2,-甲基丁基和2,3-二甲基丁基、16-烷基、18-烷基。术语“C1-20烷基”是指含有1-20个碳原子的直链、支链或环状的饱和烃基。烷基包括取代的和没有取代的烷基。当烷基被取代时,取代基可以在任何可使用的连接点上取代,取代基可以是单取代或多取代。取代基独立的选自烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、氘、卤素、硫醇、羟基、硝基、羧基、酯基、氰基,环烷基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷硫基、氧代,在命名时取代基通常置于烷基之前,例如C1-3烷氧基C3-8环烷基C1-6烷基指C1-6烷基,其被C3-8环烷基取代,而该C3-8环烷基又为C1-3烷氧基取代,举例:甲氧基环丁基甲基的结构式为:
术语“烯基”和“炔基”分别是指直链、支链或环状的含有双键和三键的不饱和烃基,优选2-20个碳原子,更优选2-12个碳原子。烯基、炔基包括取代的和没有取代的烯基、炔基。当被取代时,取代基可以在任何可使用的连接点上取代,取代基可以是单取代或多取代。取代基独立的选自烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、氘、卤素、硫醇、羟基、硝基、羧基、酯基、氰基,环烷基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷硫基、氧代,在命名时取代基通常置于烯基、炔基之前。
术语“环烷基”指饱和和/或部分不饱和单环或多环环烃基。单环可包括3-10个碳原子。单环环烷烃基的非限制实例包括环丙基、环丁基、环戊基、环戊烯基、环己基、环己烯基、环己二烯基、环庚基等。多环环烷基包括螺环、稠环和桥环的环烷基。环烷基包括无取代基和含有取代基。取代基选自一个或多个取代基团,包括但不仅限于以下基团,独立的选自烷基、环烷基、烷氧基、卤素、羧基、酯基、氨基、酰胺基、羟基、氰基、硝基、芳基、杂芳基。
术语“芳基”指6-10元全碳单环或多环的芳香基团,包括苯基,奈基,联苯基等。芳基可以是取代的和未取代的。取代基独立的选自烷基、环烷基(环丙烷基、环丁烷基和环戊烷基等)、烯基、炔基、叠氮、氨基、氘、烷氧基、烷硫基、烷基氨基,卤素、硫醇、羟基,硝基、杂环烷基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷硫基、杂环烷硫基、烷基硅基等。
术语“杂芳基”指包含1-10个杂原子的杂芳香体系的基团。杂原子包括氧,硫,氮,磷等。其中单杂环基包括但不限于呋喃、噻吩、吡咯、噻唑、咪唑、1,2,3-三氮唑、1,2,4-三氮唑、1,2,3-噻二唑,噁唑、1,2,4-噁二唑、1,3,4-噁二唑、吡啶、嘧啶、哒嗪、吡嗪、四氢呋喃、四氢吡咯、哌啶、哌嗪、吗啉、异噁唑啉等。稠杂环基包括但不限于喹啉、异喹啉、吲哚、苯并呋喃、苯并噻吩、嘌呤、吖啶、咔唑、芴、色烯酮、芴酮、喹喔啉、3,4-二氢萘酮、二苯并呋喃、氢化二苯并呋喃、苯并噁唑基等。杂芳基可以是取代的和未取代的。取代基独立的选自取代基独立的选自烷基、环烷基(环丙烷基、环丁烷基和环戊烷基等)、烯基、炔基、叠氮、氨基、氘、烷氧基、烷硫基、烷基氨基,卤素、硫醇、羟基,硝基、杂环烷基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷硫基、杂环烷硫基、烷基硅基等。
术语“卤素”是指氟、氯、溴、碘,优选为氟、氯、溴。
术语“氘”是氢的同位素,原子质量是后者的2倍,与碳的结合更强。氘化“和”氘“表示氢在指定位置被替换为氘。一个“氘化的取代基”是取代基,其中至少一个氢被以指定的百分比富集的氘取代。
术语“卤代烷基”是指至少被一个卤素原子取代的烷基。
术语“杂环基”是指至少含有一个杂原子的环状基团,其中杂原子为氮、氧、硫、硫等。杂环基包括单杂环基和多杂环基。
具体实施方式
以下实施例可以使本专业技术人员更全面地理解本发明,但不以任何方式限制本发明。所有化合物的结构均经1H NMR或MS所确定。
实施例中用到的化合物名称缩写如下:
DCM:二氯甲烷
EtOAc:乙酸乙酯
THF:四氢呋喃
DME:乙二醇二甲醚
Dioxane:1,4-二氧六环
Pd2(dba)3:三(二亚苄基丙酮)二钯
Xantphos:4,5-双二苯基膦-9,9-二甲基氧杂葸
tBuONa:叔丁醇钠
POCl3:三氯氧磷
NH4OAc:醋酸铵
NaBH3CN:氰基硼氢化钠
p-chloranil:四氯苯醌
MsCl:甲基磺酰氯
Et3N:三乙胺
BnBr:苄溴
DIBAL-H:二异丁基氢化铝
PPh3:三苯基膦
DEAD:偶氮二甲酸二乙酯
PhN(OTf)2:N-苯基双(三氟甲烷磺酸亚胺)
B(OMe)3:硼酸三甲酯
nBuLi:正丁基锂
Pd(dppf)Cl2:[1,1'-双(二苯基膦基)二茂铁]二氯化钯
下面结合具体实施例,对本发明做进一步的说明:
化合物10的制备:
化合物2的制备:在氮气保护下,化合物1(350g,1.72mol),苄溴(352g,2.06mol)和碳酸钾(368g,2.66mol)的混合物在乙腈(4.5L)和丙酮(4.3L)的混合溶剂中回流18小时。反应液冷却,过滤,滤液浓缩后残余物加入乙酸乙酯稀释,有机相依次用水和饱和食盐水洗涤,无水硫酸钠干燥,过滤,浓缩,柱层析纯化得到化合物2(437g,86.4%)。1H NMR(CDCl3,300MHz)δ:7.33-7.48(m,5H),7.04-7.08(m,2H),7.77(s,1H),5.12(s,2H),3.86(s,3H)。
化合物3的制备:化合物2(330g,1.12mol)溶于四氢呋喃(2.8L),然后加入3-甲基-2-丁酮(145g,1.69mol),Pd2(dba)3(三(二亚苄基丙酮)二钯,10g,11.2mmol),Xantphos(4,5-双二苯基膦-9,9-二甲基氧杂葸,19g,33.6mmol)和叔丁醇钠(162g,1.69mol)。反应体系用氮气置换三次,然后在氮气保护下于55℃反应6小时。旋干,剩余物中加入水(800mL)和乙酸乙酯(1000mL)并搅拌30分钟。静置分层,水相用乙酸乙酯(500mL×2)萃取。合并有机相,用饱和食盐水洗涤。无水硫酸钠干燥,过滤,滤液旋干后柱层析纯化得到化合物3(187g,55.6%)。1H NMR(CDCl3,300MHz)δ:7.46-7.28(m,5H),6.88-6.76(m,3H),5.15(s,2H),3.89(s,3H),3.63(s,2H),2.68-2.63(m,1H),1.05(d,J=6.9Hz,6H)。
化合物4的制备:往甲醇(1.4L)中加入化合物3(180g,0.6mol)和醋酸铵(465g,6.0mol)并用冰水浴冷却,然后往里面分批加入氰基硼氢化钠(30g,0.48mol),于室温下搅拌10分钟,然后50℃搅拌21小时。冷却后加入水(490mL)和10N氢氧化钠溶液(120mL,1.2mol),室温下搅拌1小时。然后用二氯甲烷(500mL×3)萃取,合并有机相,用饱和食盐水洗涤,无水硫酸钠干燥后旋干得到化合物4(176g,97.4%)。1H NMR(CDCl3,300MHz)δ:7.46-7.28(m,5H),6.86-6.76(m,3H),5.16(s,2H),3.88(s,3H),2.76-2.72(m,2H),2.37-2.29(m,1H),1.63-1.54(m,3H),0.94(d,J=6.9Hz,6H)。
化合物5的制备:化合物4(3.0g,10mmol)在乙腈(84mL)中搅拌30分钟,然后加入R-扁桃酸(0.84g,5.5mmol)并在55℃搅拌过夜。冷至室温,过滤,固体用乙腈(16mL)洗涤后干燥,得1.6g。重新加到水(8mL)中,加入1M碳酸钾水溶液(4.2mL,4.2mmol),在室温下搅拌2小时至澄清。往体系中加入二氯甲烷(15mL)和食盐固体(0.4g),分出有机相,饱和食盐水洗,干燥,旋干后得到化合物5(0.80g,26.6%,98%ee)。
化合物6的制备:甲酸(86.2g,1.87mol)加入到化合物5(75g,0.25mol)的甲基四氢呋喃(670mL)溶液中,回流12小时。冷却后浓缩,剩余物溶于乙酸乙酯,然后用水洗,饱和食盐水洗,无水硫酸钠干燥,旋干得到化合物6粗品(70g),直接进行下一步反应。
化合物7的制备:化合物6(70g,0.21mol)溶于乙腈(622mL)中,加入三氯氧磷(41g,0.27mol),然后在90℃搅拌2小时。反应结束后冷却,在冰水浴下加入水淬灭反应,浓缩,加入1N氢氧化钠调节至pH=10,然后用二氯甲烷萃取(200mL×3),有机相合并,饱和食盐水洗涤,干燥浓缩后经柱层析纯化得到化合物7(57g,86.1%)。1H NMR(CDCl3,300MHz)δ:8.39(s,1H),7.47-7.34(m,5H),6.92(s,1H),6.74(s,1H),5.22(s,2H),3.93(s,3H),3.42-3.39(m,1H),2.67-2.63(m,2H),2.11-2.09(m,1H),1.11-1.01(m,6H);ESI-MS m/z 310.2(M+H)+。
化合物8的制备:化合物7(12.5g,40.5mmol),2-乙氧基甲基乙酰乙酸乙酯(22.7g,0.12mol)加入到水(118mL)中,于85℃搅拌29小时。反应结束后,冷至室温,用乙酸乙酯萃取,合并有机相,饱和食盐水洗,干燥,浓缩得到24.5g粗产物。
化合物9的制备:化合物8(50g,0.11mol)和四氯苯醌(27.6g,0.11mol)加入到乙二醇二甲醚(470mL)中,于70℃搅拌3小时。反应结束后过滤,滤液浓缩,然后倒入水中,二氯甲烷萃取(200mL×3)。有机相合并,饱和食盐水洗,干燥浓缩后粗产品经柱层析纯化得到化合物9(23.1g,46.2%)。1H NMR(CDCl3,300MHz)δ:8.17(s,1H),7.46-7.34(m,5H),7.20(s,1H),6.92(s,1H),6.72(s,1H),5.22(s,2H),4.41(q,2H),3.94(s,3H),3.72-2.69(m,1H),3.29-3.23(m,1H),2.98-2.93(m,1H),1.80-1.72(m,1H),1.41(m,3H),0.89-0.78(m,6H)。
化合物10的制备:Pd/C(6g)加入到化合物9(23.0g,51.4mmol)的乙醇溶液(250mL)中,反应在氢气下搅拌15小时。过滤,滤液旋干,然后用二氯甲烷重结晶得到化合物10(10.0g,54.0%)。1H NMR(CDCl3,300MHz):δ8.28(s,1H),7.17(s,1H),7.07(s,1H),6.87(s,1H),4.41(q,J=6.9Hz,2H),3.94(s,3H),3.85-3.81(m,1H),3.33-3.26(m,1H),3.04-2.97(m,1H),1.84-1.76(m,1H),1.41(t,J=6.9Hz,3H),0.94-0.92(m,3H),0.84-0.82(m,3H);ESI-MS m/z 358.1(M+H)+。
用同样的方法,消旋的化合物7-rac和10-rac可以用未拆分的原料制得。
实施例1.制备6-异丙基-10-甲氧基-2-氧代-9-(((S)-四氢呋喃-3-基)氧基)-6,7-二氢-2H-吡啶并[2,1-α]异喹啉-3-羧酸(I-1-rac)
化合物1b的制备:化合物1a(0.20g,2.27mmol)溶于6mL二氯甲烷,并在冰水浴中冷却,加入三乙胺(1mL,7.19mmol),缓慢加入甲磺酰氯(0.39g,3.42mmol),混合物于室温搅拌3小时,旋干,粗品溶于乙酸乙酯(60mL),水洗,饱和碳酸钠洗,饱和食盐水洗,无水硫酸钠干燥,过滤,滤液旋干,得粗产品0.36g。
化合物1c-rac的制备:化合物10-rac(100mg,0.28mmol),化合物1b(93mg,0.56mmol)和碳酸钾(116mg,0.84mmol)加入5mL N,N-二甲基甲酰胺中,然后于90℃搅拌18小时。反应结束后倒入水中,乙酸乙酯(40mL×3)萃取,合并有机相,依次用水洗和饱和食盐水洗,无水硫酸钠干燥,过滤,滤液旋干,得到粗品0.128g。
化合物I-1-rac的制备:往化合物1c-rac(0.128g,0.30mmol)的四氢呋喃(5mL)溶液中加入1N的氢氧化钠水溶液(1.8mL,1.80mmol),于室温反应18小时。反应结束后加入1N盐酸调至pH=1-2,二氯甲烷萃取(30mL×3),合并有机层,无水硫酸钠干燥,过滤,滤液旋干,粗品用乙酸乙酯与甲基叔丁基醚重结晶得到化合物I-1-rac(34mg,28.3%)。1H NMR(400MHz,CDCl3)δ:8.44(s,1H),7.19(s,1H),7.05(s,1H),6.70-6.67(m,1H),5.06-5.00(m,1H),4.06-4.00(m,3H),3.97-3.92(m,1H),3.91(s,3H),3.88-3.84(m,1H),3.36-3.31(m,1H),3.21(s,3H),3.08-3.06(m,1H),3.04(s,1H),3.03-3.02(m,1H),2.27-2.18(m,2H),1.86-1.77(m,1H),0.94-0.93(d,J=6.4Hz,3H),0.84-0.82(d,J=6.8Hz,3H);ESI-MS m/z400.2(M+H)+。
实施例2.制备(S)-6-异丙基-10-甲氧基-2-氧代-9-(((R)-四氢呋喃-3-基)氧基)-6,7-二氢-2H-吡啶并[2,1-α]异喹啉-3-羧酸(I-2)
化合物2b的制备:化合物2a(0.20g,2.27mmol)溶于二氯甲烷(5mL)中,加入三乙胺(1mL,7.19mmol),缓慢加入甲磺酰氯(0.39g,3.41mmol),混合物于室温搅拌3小时,旋干,粗品溶于乙酸乙酯(50mL),然后依次用水,饱和碳酸钠溶液和饱和食盐水洗,无水硫酸钠干燥,过滤,滤液旋干得到化合物2b粗品(0.36g)。
化合物2c的制备:化合物10(0.16g,0.45mmol),化合物2b(0.149g,0.90mmol)溶于3mL N,N-二甲基甲酰胺,加入碳酸钾(0.186g,1.34mmol),在90℃反应18小时。反应结束后倒入水中,乙酸乙酯萃取(40ml×3),合并乙酸乙酯层,依次用水洗和饱和食盐水洗,无水硫酸钠干燥,过滤,滤液真空浓缩,得到化合物2c粗品(0.287g)。
化合物I-2的制备:化合物2c(0.287g,0.67mmol)溶于5mL四氢呋喃中,加入1N氢氧化钠水溶液(4.0mL,4.0mmol),于室温反应18小时。反应结束后加入1N盐酸调节至pH=1-2,二氯甲烷萃取(30ml×3),合并有机层,无水硫酸钠干燥,过滤,滤液旋干,粗品用乙酸乙酯与甲基叔丁基醚重结晶得到化合物I-2(0.113g,63.4%)。1H NMR(400MHz,CDCl3)δ:8.47(s,1H),7.20(s,1H),7.07(s,1H),6.69(s,1H),5.09-5.01(m,1H),4.10-3.99(m,3H),3.92(s,3H),3.85-3.40(m,2H),3.36(dd,J1=16.4Hz,J2=5.6Hz,1H),3.11-3.04(m,1H),2.29-2.23(m,2H),1.87-1.78(m,1H),0.95(d,J=6.8Hz,3H),0.85(d,J=6.8Hz,3H);ESI-MS m/z400.2(M+H)+。
实施例3.制备6-异丙基-10-甲氧基-2-氧代-9-(((R)-四氢呋喃-3-基)氧基)-6,7-二氢-2H-吡啶并[2,1-α]异喹啉-3-羧酸(I-2-rac)
按照实施例2的方法,得到I-2-rac,1H NMR(400MHz,CDCl3)δ:8.47(s,1H),7.20(s,1H),7.07(s,1H),6.69(s,1H),5.09-5.01(m,1H),4.10-3.99(m,3H),3.92(s,3H),3.85-3.40(m,2H),3.36(dd,J1=16.4Hz,J2=5.6Hz,1H),3.11-3.04(m,1H),2.29-2.23(m,2H),1.87-1.78(m,1H),0.95(d,J=6.8Hz,3H),0.85(d,J=6.8Hz,3H);ESI-MS m/z 400.2(M+H)+。
实施例4.制备6-异丙基-10-甲氧基-2-氧代-9-((四氢-2H-吡喃-4-基)氧基)-6,7-二氢-2H-吡啶并[2,1-α]异喹啉-3-羧酸(I-3-rac)
化合物3a-rac的制备:化合物10-rac(100mg,0.28mmol)和4-溴四氢吡喃(94mg,0.56mmol)溶于5mL N,N二甲基甲酰胺,加入碳酸钾(78mg,0.56mmol),然后在90℃反应40小时。反应结束后倒入水中,乙酸乙酯萃取(40mL×3),合并乙酸乙酯层,依次用水洗和饱和食盐水洗,无水硫酸钠干燥,过滤,滤液真空浓缩,粗产品经制备板纯化得化合物3a-rac(65mg,56.1%)。
化合物I-3-rac的制备:化合物3a-rac(65mg,0.15mmol)溶于四氢呋喃(5mL)中,加入1N氢氧化钠水溶液(1.0mL,1.0mmol),于室温反应18小时。反应结束后加入1N盐酸调节至pH=1-2,二氯甲烷萃取(30ml×3),合并有机层,无水硫酸钠干燥,过滤,滤液旋干,粗品经制备板纯化得化合物I-3-rac(2mg,3.2%)。1H NMR(400MHz,CDCl3)δ:15.94(s,1H),8.44(s,1H),7.19(s,1H),7.06(s,1H),6.77(s,1H),4.57(m,2H),4.03-4.02(m,2H),3.92(s,3H),3.87-3.84(m,1H),3.61-3.55(m,2H),3.35-3.30(m,1H),3.07-3.03(m,1H),2.07-2.04(m,1H),1.81-1.93(m,4H),0.94-0.93(d,J=6.4Hz,3H),0.84-0.82(d,J=6.8Hz,3H);ESI-MSm/z 414.2(M+H)+。
实施例5.制备6-异丙基-10-甲氧基-9-(氧杂环丁烷-3-基氧基)-2-氧代-6,7-二氢-2H-吡啶并[2,1-a]异喹啉-3-羧酸(I-4-rac)
化合物4a-rac的制备:化合物10-rac(100mg,0.28mmol)和3-溴氧杂环丁烷(75mg,0.56mmol)溶于N,N-二甲基甲酰胺(5mL),加入碳酸钾(78mg,0.56mmol),在90℃搅拌40小时。反应结束后倒入水中,乙酸乙酯萃取(40mL×3),合并乙酸乙酯层,依次用水洗和饱和食盐水洗,无水硫酸钠干燥,过滤,滤液旋干,粗品经制备板分离得到化合物4a-rac(51mg,42.9%)。
化合物I-4-rac的制备:化合物4a-rac(50mg,0.12mmol)溶于四氢呋喃(5mL),加入1N氢氧化钠水溶液(1.0mL,1.0mmol),于室温反应18小时。反应结束后加入1N盐酸调节至pH=1-2,二氯甲烷萃取(30ml×3),合并有机层,无水硫酸钠干燥,过滤,滤液旋干,粗品经制备板纯化得化合物I-4-rac(7mg,15.1%)。1H NMR(400MHz,CDCl3)δ:15.87(s,1H),8.45(s,1H),7.21(s,1H),7.06(s 1H),6.33(s,1H),4.98(s,2H),4.82(s,2H),3.94(s,5H),3.30(s,1H),3.03(s,1H),1.78(s,1H),0.92(s,3H),0.82(s,3H);ESI-MS m/z 386.2(M+H)+。
实施例6.制备(S)-6-异丙基-10-甲氧基-9-((1R,3S)-3-甲氧基环丁氧基)-2-氧代-6,7-二氢-2H-吡啶并[2,1-α]异喹啉-3-羧酸(I-5)
化合物5b的制备:化合物5a(0.70g,3.64mmol)溶于100mL甲醇,加入Pd/C(0.12g)和1滴浓盐酸,氢气置换3次,室温加氢18小时,过滤,滤液旋干得到化合物5b粗品0.43g。
化合物5c的制备:化合物5b(0.43g,4.22mmol)溶于8mL二氯甲烷中,加入三乙胺(1.5mL,8.63mmol),缓慢加入甲磺酰氯(0.72g,6.32mmol),混合物于室温搅拌3小时,旋干,粗品溶于乙酸乙酯(50mL),然后依次用水,饱和碳酸钠溶液和饱和食盐水洗,无水硫酸钠干燥,过滤,滤液旋干得到化合物5c粗品0.70g。
化合物5d的制备:化合物10(0.160g,0.45mmol)和化合物5c(0.161g,0.90mmol)溶于N,N-二甲基甲酰胺(5mL),加入碳酸钾(0.185g,1.34mmol),在90℃搅拌18小时,倒入水中,乙酸乙酯萃取(30mL×4),合并乙酸乙酯层,水洗,饱和食盐水洗,无水硫酸钠干燥,过滤,滤液旋干得到油状物0.21g,为化合物5d。
化合物I-5的制备:化合物5d(0.210g,0.48mmol)溶于四氢呋喃(5mL),加入1N氢氧化钠水溶液(2.85mL,2.85mmol),室温反应18小时。反应结束后加入1N盐酸调节至pH=1-2,二氯甲烷萃取(30ml×3),合并有机层,无水硫酸钠干燥,过滤,滤液旋干,粗品经制备板纯化得化合物I-5(64mg,32.2%)。1H NMR(400MHz,CDCl3)δ:8.46(s,1H),7.18(s,1H),7.07(s,1H),6.54(s,1H),5.00-4.90(m,1H),4.20-4.13(m,1H),3.94(s,3H),3.91-3.84(m,1H),3.52-3.34(m,1H),3.31(s,3H),2.59-2.46(m,1H),2.59-2.48(m,4H),1.88-1.78(m,1H),0.95(d,J=6.8Hz,3H),0.84(d,J=6.8Hz,3H);ESI-MS m/z 414.2(M+H)+。
实施例7.制备6-异丙基-10-甲氧基-9-((1R,3S)-3-甲氧基环丁氧基)-2-氧代-6,7-二氢-2H-吡啶并[2,1-α]异喹啉-3-羧酸(I-5-rac)
按照实施例6的方法,得到化合物I-5-rac,1H NMR(400MHz,CDCl3)δ:8.46(s,1H),7.18(s,1H),7.07(s,1H),6.54(s,1H),5.00-4.90(m,1H),4.20-4.13(m,1H),3.94(s,3H),3.91-3.84(m,1H),3.52-3.34(m,1H),3.31(s,3H),2.59-2.46(m,1H),2.59-2.48(m,4H),1.88-1.78(m,1H),0.95(d,J=6.8Hz,3H),0.84(d,J=6.8Hz,3H);ESI-MS m/z 414.2(M+H)+。
实施例8制备(S)-6-异丙基-10-甲氧基-9-((1-(甲氧基甲基)环丙基)甲氧基)-2-氧代-6,7-二氢-2H-吡啶并[2,1-α]异喹啉-3-羧酸(I-6)
化合物6b的制备:化合物6a(0.50g,4.9mmol),碳酸钾(1.02g,7.4mmol),碘甲烷(1.04g,7.4mmol)和4-氟苯硼酸(69mg,0.49mmol)在N,N-二甲基甲酰胺(5mL)中室温搅拌16小时。往反应液中加入30mL水,然后用乙酸乙酯萃取(30ml×3)。有机相合并,用饱和食盐水洗一次,无水硫酸钠干燥,旋干后得到200mg化合物6b的粗品。直接用于下一步反应。1H NMR(400MHz,CDCl3)δ:3.54(d,J=5.2Hz,2H),3.38(s,2H),3.37(s,3H),2.51(t,J=5.2Hz,1H),0.50-0.55(m,4H)。
化合物6c的制备:化合物6b(0.20g,1.72mmol)溶于10mL二氯甲烷并用冰水浴冷却。然后依次加入三乙胺(0.35g,3.44mmol)和甲基磺酰氯(0.30g,2.59mmol)。在室温下反应2小时后,加入二氯甲烷(20mL)稀释,并用1N稀盐酸(10mL)洗涤。水相用二氯甲烷(20mL×2)萃取。合并有机相,饱和食盐水洗涤,无水硫酸钠干燥之后旋干得到0.30g黄色油状物,为化合物6c。
化合物6d的制备:化合物10(0.15g,0.42mmol),化合物6c(0.30g,1.54mmol)和无水碳酸钾(0.12g,0.84mmol)在5mL N,N-二甲基甲酰胺中于90℃搅拌16小时。反应结束后冷至室温,加入30mL水稀释,并用乙酸乙酯萃取(20mL×2)。合并有机相,饱和食盐水洗,无水硫酸钠干燥后浓缩得到0.18g化合物6d的粗品,直接用于下一步反应。
化合物I-6的制备:往化合物6d(0.18g,0.40mmol)的甲醇(10mL)溶液中加入1N氢氧化钠水溶液(1.6mL,1.60mmol),于50℃反应1.5小时。反应结束后加入1N盐酸调节至pH=1-2,二氯甲烷萃取(20mL×3),合并有机层,无水硫酸钠干燥,过滤,滤液旋干,粗品经制备板纯化得产物化合物I-6(26mg,15.2%)。1H NMR(400MHz,CDCl3)δ:8.47(s,1H),7.17(s,1H),7.07(s,1H),6.76(s,1H),3.98(m,2H),3.91(s,3H),3.88(m,1H),3.40(m,2H),3.35(s,3H),3.29-3.34(m,1H),3.02-3.06(m,1H),1.82(m,1H),0.92(d,J=6.8Hz,3H),0.81(d,J=6.8Hz,3H),0.67(m,2H),0.64(m,2H);ESI-MS m/z428.2(M+H)+。
实施例9.制备6-异丙基-10-甲氧基-9-((1-(甲氧基甲基)环丙基)甲氧基)-2-氧代-6,7-二氢-2H-吡啶并[2,1-α]异喹啉-3-羧酸(I-6-rac)
按照实施例8的方法,得到化合物I-6-rac,1H NMR(400MHz,CDCl3)δ:8.47(s,1H),7.17(s,1H),7.07(s,1H),6.76(s,1H),3.98(m,2H),3.91(s,3H),3.88(m,1H),3.40(m,2H),3.35(s,3H),3.29-3.34(m,1H),3.02-3.06(m,1H),1.82(m,1H),0.92(d,J=6.8Hz,3H),0.81(d,J=6.8Hz,3H),0.67(m,2H),0.64(m,2H);ESI-MS m/z 428.2(M+H)+。
实施例10.制备(S)-6-异丙基-10-甲氧基-9-((3-(甲氧基甲基)氧杂环丁烷-3-基)甲氧基)-2-氧代-6,7-二氢-2H-吡啶并[2,1-α]异喹啉-3-羧酸(I-7)
化合物7b的制备:化合物7a(0.27g,2.3mmol),无水碳酸钾(0.48g,3.5mmol),苄溴(0.59g,3.5mmol)和4-氟苯硼酸(32mg,0.23mmol)在2mL N,N-二甲基甲酰胺中室温搅拌两天。往反应液中加入20mL水,然后用乙酸乙酯萃取(20mL×3)。有机相合并,用饱和食盐水洗,然后用无水硫酸钠干燥后旋干。粗品用柱层析分离得到0.28g油状产物,即为化合物7b。1H NMR(400MHz,CDCl3)δ:7.31-7.36(m,5H),4.56(s,2H),4.48(d,J=6.4Hz,2H),4.42(d,J=6.0Hz,2H),3.93(d,J=4.4Hz,2H),3.80(s,2H),2.34(t,J=5.2Hz,1H)。
化合物7c的制备:化合物7b(0.28g,1.35mmol)溶于干燥的N,N-二甲基甲酰胺(5mL)并用冰水浴冷却。往此溶液中加入NaH(65mg,2.7mmol)并在冰水浴中搅拌40分钟。然后加入碘甲烷(0.48g,3.38mmol)并在冰水浴中搅拌5小时。往反应液中加入30mL水淬灭,然后用乙酸乙酯萃取(20mL×3)。合并有机相,饱和食盐水洗,无水硫酸钠干燥之后旋干。粗品用柱层析分离得到无色油状物化合物7c(0.18g,60.1%)。1H NMR(400MHz,CDCl3)δ:7.29-7.36(m,5H),4.56(s,2H),4.48(m,4H),3.67(s,2H),3.62(s,2H),3.38(s,3H)。
化合物7d的制备:化合物7c(0.18g,0.81mmol)溶于10mL甲醇,加入Pd/C(18mg)。反应在氢气气氛中反应16小时。然后加入1滴浓盐酸,继续在氢气气氛中反应4小时。过滤,滤液旋干,并用柱层析分离得到无色液体,即为化合物7d(0.11g,100%)。1H NMR(400MHz,CDCl3)δ:4.49(d,J=6.4Hz,2H),4.43(d,J=6.0Hz,2H),3.94(m,2H),3.74(s,2H),3.40(s,3H)。
化合物7e的制备:化合物7d(0.11g,0.83mmol)溶于10mL二氯甲烷并用冰水浴冷却。然后依次加入三乙胺(0.168g,1.66mmol)和甲基磺酰氯(0.143g,1.25mmol)。在室温下反应2小时后,加入10mL二氯甲烷稀释,并用1N稀盐酸洗涤。水相用二氯甲烷萃取(20mL×3)。合并有机相,饱和食盐水洗涤,无水硫酸钠干燥之后旋干得到0.13g黄色油状物,即为化合物7e。
化合物7f的制备:化合物10(0.15g,0.42mmol),化合物7e(0.13g,0.63mmol)和无水碳酸钾(0.12g,0.84mmol)在5mL DMF中于90℃搅拌16小时。反应结束后冷至室温,加入30mL水稀释,并用乙酸乙酯萃取(20mL×3)。合并有机相,饱和食盐水洗,无水硫酸钠干燥后浓缩。粗产品经薄层层析分离后得到白色固体,为化合物7f(0.16g,76.2%)。
化合物I-7的制备:往化合物7f(0.16g,0.32mmol)的甲醇(10mL)溶液中加入1N氢氧化钠水溶液(1.3mL,1.30mmol),于50℃反应2小时。反应结束后加入1N盐酸调节至pH=1-2,二氯甲烷萃取(20mL×3),合并有机层,无水硫酸钠干燥,过滤,滤液旋干得到白色固体化合物I-7(94mg,66.2%)。1H NMR(400MHz,CDCl3)δ:8.45(s,1H),7.18(s,1H),7.06(s,1H),6.82(s,1H),4.56-4.63(m,4H),4.28(m,2H),3.90(s,3H),3.86(m,1H),3.77(m,2H),3.40(s,3H),3.32-3.36(m,1H),3.05-3.09(m,1H),1.84(m,1H),0.95(d,J=6.8Hz,3H),0.83(d,J=6.8Hz,3H);ESI-MS m/z 444.2(M+H)+。
实施例11.制备6-异丙基-10-甲氧基-9-((3-(甲氧基甲基)氧杂环丁烷-3-基)甲氧基)-2-氧代-6,7-二氢-2H-吡啶并[2,1-α]异喹啉-3-羧酸(I-7-rac)
按照实施例10的方法,得到I-7-rac。1H NMR(400MHz,CDCl3)δ:8.45(s,1H),7.18(s,1H),7.06(s,1H),6.82(s,1H),4.56-4.63(m,4H),4.28(m,2H),3.90(s,3H),3.86(m,1H),3.77(m,2H),3.40(s,3H),3.32-3.36(m,1H),3.05-3.09(m,1H),1.84(m,1H),0.95(d,J=6.8Hz,3H),0.83(d,J=6.8Hz,3H);ESI-MS m/z 444.2(M+H)+。
实施例12.制备(S)-6-异丙基-10-甲氧基-9-((3-甲氧基环丁基)甲氧基)-2-氧代-6,7-二氢-2H-吡啶并[2,1-a]异喹啉-3-羧酸(I-8)
化合物8b的制备:将化合物8a(5.0g,38mmol)溶于50mL四氢呋喃中,冰浴条件下分批次加入氢化钠(1.84g,76mmol),加毕继续搅拌反应30分钟,缓慢滴加碘甲烷(2.87mL,46mmol)。滴毕室温搅拌反应3小时,TLC监测原料反应完毕。将反应液倒入饱和氯化铵溶液中淬灭,乙酸乙酯萃取(30mL×3)。合并有机相,无水硫酸钠干燥,硅胶柱层析(乙酸乙酯:石油醚=1:5)得化合物8b(1.90g,34.2%)。1H NMR(400MHz,CDCl3)δ:3.81-3.73(m,1H),3.66(s,3H),3.21(s,3H),2.66-2.58(m,1H),2.51-2.45(m,2H),2.21-2.13(m,2H)。
化合物8c的制备:将化合物8b(1.90g,13mmol)溶于20mL无水四氢呋喃中,冰浴条件下,氮气置换气3次,缓慢滴加1.5M DIBAL-H的四氢呋喃溶液(26.4mL,39mmol)。滴毕继续搅拌反应过夜,TLC监测反应完毕,加入2N盐酸(20mL)淬灭反应,乙酸乙酯(30mL×3)萃取,合并有机相,饱和食盐水洗涤,无水硫酸钠干燥,浓缩蒸干硅胶柱层析(乙酸乙酯:石油醚=1:3)得化合物8c(1.00g,66.2%)。1H NMR(400MHz,CDCl3)δ:3.80-3.73(m,1H),3.62-3.57(m,2H),3.21(s,3H),2.37-2.30(m,2H),2.08-2.02(m,1H),1.67-1.60(m,2H)。
化合物8d的制备:将化合物8c(1.00g,8.61mmol)溶于15mL二氯甲烷中,加入三乙胺(2.61g,25.83mmol),冰浴条件下缓慢滴加甲磺酰氯(1.48g,12.92mmol),滴毕,搅拌2小时,TLC监测反应完毕,加入50mL饱和碳酸氢钠溶液,二氯甲烷萃取(30mL×3),合并有机相,饱和食盐水洗涤,无水硫酸钠干燥,浓缩蒸干备用。
化合物8e的制备:将化合物10(0.46g,1.29mmol),化合物8d(0.50g,2.58mmol)和碳酸钾(0.53g,3.87mmol)加入10mL无水N,N-二甲基甲酰胺中,加热至90℃反应5小时。TLC监测反应完毕,将反应液倒入水中,乙酸乙酯(30mL×3)萃取,合并有机相,饱和食盐水洗涤,无水硫酸钠干燥,浓缩蒸干得化合物8e粗品0.50g。
化合物I-8的制备:将化合物8e(0.50g,1.10mmol)溶于15mL四氢呋喃中,加入1N氢氧化钠水溶液(6.6mL,6.60mmol),在35℃条件下反应3小时,TLC监测反应完毕。用1N盐酸调至pH=1-2,有固体析出,过滤,用乙醚和乙醇重结晶得化合物I-8产品(270mg,57.3%)。1HNMR(400MHz,CDCl3)δ:8.44(s,1H),7.17(s,1H),7.05(s,1H),6.72(s,1H),4.07-4.05(m,2H),3.91(s,3H),3.88-3.82(m,2H),3.36-3.31(dd,J1=6Hz,J2=16.8Hz,1H),3.25(s,3H),3.08-3.03(m,1H),2.53-2.48(m,2H),2.42-2.38(m,1H),1.83-1.77(m,3H),0.94(d,J=6.4Hz,3H),0.82(d,J=6.8Hz,3H);ESI-MS m/z 428.2(M+H)+。
实施例13.制备6-异丙基-10-甲氧基-9-((3-甲氧基环丁基)甲氧基)-2-氧代-6,7-二氢-2H-吡啶并[2,1-a]异喹啉-3-羧酸(I-8-rac)
按照实施例12的方法,得到化合物I-8-rac.1H NMR(400MHz,CDCl3)δ:8.44(s,1H),7.17(s,1H),7.05(s,1H),6.72(s,1H),4.07-4.05(m,2H),3.91(s,3H),3.88-3.82(m,2H),3.36-3.31(dd,J1=6Hz,J2=16.8Hz,1H),3.25(s,3H),3.08-3.03(m,1H),2.53-2.48(m,2H),2.42-2.38(m,1H),1.83-1.77(m,3H),0.94(d,J=6.4Hz,3H),0.82(d,J=6.8Hz,3H);ESI-MS m/z 428.2(M+H)+。
实施例14.制备(S)-6-异丙基-10-甲氧基-2-氧代-9-((4-氧代戊基)氧基)-6,7-二氢-2H-吡啶并[2,1-a]异喹啉-3-羧酸(I-9)
化合物9a的制备:将化合物10(0.36g,1.0mmol)溶于10mL四氢呋喃中,加入5-羟基-2-戊酮(0.20g,2.0mmol)和三苯基膦(0.53g,2.0mmol)。氮气置换4次,置于冰水浴中搅拌30分钟,将偶氮二甲酸二乙酯(0.35g,2.0mmol)滴入上述体系中,室温搅拌16小时。加入硅胶拌样,柱层析纯化得产物(0.25g,57.0%)。
化合物I-9的制备:将化合物9a(0.25g,0.57mmol)溶于10mL四氢呋喃和5mL水中,加入1N氢氧化钠水溶液(2.3mL,2.3mmol),在35℃条件下反应3小时,TLC监测反应完毕。用1N盐酸调至pH=1-2,加入20mL二氯甲烷,分液,水层用二氯甲烷萃取(30mL×2),合并有机层,用饱和氯化钠洗,无水硫酸钠干燥,过滤后浓缩得粗品300mg。将该粗品溶于2mL乙醇中,加热回流20分钟后冷却至室温,加入30mL乙醚,搅拌30分钟。产品抽滤烘干,即得化合物I-9(130mg,55.1%)。1H NMR(400MHz,CDCl3)δ:16.01(s,1H),8.45(s,1H),7.16(s,1H),7.05(s,1H),6.76(s,1H),4.08-4.14(m,2H),3.91(s,3H),3.85-3.89(m,1H),3.30-3.36(m,1H),3.06(d,J=15.6Hz,1H),2.69(t,J=6.8Hz,2H),2.78(s,3H),2.10-2.15(m,2H),1.81(m,1H),2.27(m,2H),1.58(m,2H),0.94(d,J=6.4Hz,3H),0.81(d,J=6.4Hz,3H);ESI-MS m/z414.2(M+H)+。
实施例15.制备-6-异丙基-10-甲氧基-2-氧代-9-((4-氧代戊基)氧基)-6,7-二氢-2H-吡啶并[2,1-a]异喹啉-3-羧酸(I-9-rac)
按照实施例14的方法,得到化合物I-9-rac。1H NMR(400MHz,CDCl3)δ:16.01(s,1H),8.45(s,1H),7.16(s,1H),7.05(s,1H),6.76(s,1H),4.08-4.14(m,2H),3.91(s,3H),3.85-3.89(m,1H),3.30-3.36(m,1H),3.06(d,J=15.6Hz,1H),2.69(t,J=6.8Hz,2H),2.78(s,3H),2.10-2.15(m,2H),1.81(m,1H),2.27(m,2H),1.58(m,2H),0.94(d,J=6.4Hz,3H),0.81(d,J=6.4Hz,3H);ESI-MS m/z 414.2(M+H)+。
实施例16.制备(S)-9-(环戊氧基)-6-异丙基-10-甲氧基-2-氧代-6,7-二氢-2H-吡啶并[2,1-a]异喹啉-3-羧酸(I-10)
化合物10a的制备:将化合物10(180mg,0.50mmol)溶于20mL N,N-二甲基甲酰胺中,加入溴代环戊烷(100mg,1.5mmol)和碳酸钾(138mg,1.0mmol)。在85℃条件下反应3小时,冷却至室温,加入60mL水和50mL乙酸乙酯,分液,水层用乙酸乙酯萃取(30mL×3),合并有机层,用饱和氯化钠洗一次,浓缩得化合物10a粗品300mg,直接用于下一步反应。
化合物I-10的制备:将化合物10a(300mg,0.71mmol)溶于10mL四氢呋喃和5mL水中,加入1N氢氧化钠水溶液(2.8mL,2.8mmol),室温搅拌16小时,TLC监测反应完毕。用1N盐酸调至pH=1-2,加入20mL二氯甲烷,分液,水层用二氯甲烷萃取(30mL×2),合并有机层,用饱和氯化钠洗,无水硫酸钠干燥,过滤后浓缩得粗品300mg。将该粗品溶于2mL乙醇中,加热回流20分钟后冷却至室温,加入30mL乙醚,搅拌30分钟。抽滤,烘干得化合物I-10(110mg,39.4%)。1H NMR(400MHz,CDCl3)δ:8.44(s,1H),7.15(s,1H),7.04(s,1H),6.72(s,1H),4.82-4.87(m,1H),3.90(s,3H),3.84-3.89(m,1H),3.31-3.36(m,1H),3.03-3.07(d,J=16Hz,1H),1.81-2.00(m,6H),1.61-1.67(m,4H),0.94(d,J=6.8Hz,3H),0.82(d,J=6.8Hz,3H);ESI-MS m/z 398.2(M+H)+。
实施例17.制备9-(环戊氧基)-6-异丙基-10-甲氧基-2-氧代-6,7-二氢-2H-吡啶并[2,1-a]异喹啉-3-羧酸(I-10-rac)
按照实施例16的方法,得到I-10-rac。1HNMR(400MHz,CDCl3)δ:8.44(s,1H),7.15(s,1H),7.04(s,1H),6.72(s,1H),4.82-4.87(m,1H),3.90(s,3H),3.84-3.89(m,1H),3.31-3.36(m,1H),3.03-3.07(d,J=16Hz,1H),1.81-2.00(m,6H),1.61-1.67(m,4H),0.94(d,J=6.8Hz,3H),0.82(d,J=6.8Hz,3H);ESI-MSm/z 398.2(M+H)+。
实施例18.制备(S)-9-(环丙基乙炔基)-6-异丙基-10-甲氧基-2-氧代-6,7-二氢-2H-吡啶并[2,1-a]异喹啉-3-羧酸(I-11)
化合物11a的制备:化合物10(0.50g,1.40mmol)溶于10mL二氯甲烷,加入三乙胺(0.42g,4.2mmol),滴加N-苯基双(三氟甲烷磺酸亚胺)(0.75g,2.1mmol)的二氯甲烷溶液(6mL),约3分钟滴完,在0℃搅拌30分钟后回到室温,在室温下搅拌2小时,真空浓缩,粗品经过柱层析纯化得到化合物11a(0.60g,87.6%)。
化合物11c的制备:化合物11b(1.32g,20mmol)溶于40mL无水四氢呋喃中,氮气置换3次,冷却至-78℃,搅拌1小时,加入硼酸三甲酯(4.67g,45mmol),在-78℃搅拌1小时后回到-20℃,在-20℃搅拌1小时,加入饱和氟氢化钾饱和溶液(14.06g,0.18mol),剧烈搅拌1小时,回到室温搅拌1小时后,溶剂在减压条件除去,得到白色固体,真空干燥,产品溶于40mL热丙酮,过滤,滤液旋干,固体溶于5mL丙酮,加热至回流,加入50mL乙醚,冷却至0℃,过滤,滤饼真空干燥得到化合物11c(1.72g,50%)。
化合物11d的制备:将化合物11a(0.25g,0.51mmol),化合物11c(0.12g,0.66mmol),Pd(dppf)Cl2(37mg,0.051mmol)和碳酸钠(0.11g,1.02mmol)加入到12mL甲基叔丁基醚和3mL水的混合溶剂中,氮气置换3次,加热至100℃反应3小时,TLC显示反应完全,反应液直接柱层析得到化合物11d(98mg,47.1%)。
化合物I-11的制备:化合物11d(98mg,0.24mmol)溶于3mL四氢呋喃,加入1N氢氧化钠水溶液(1.3mL,1.3mmol),室温反应18小时。加入1N盐酸调节至pH=1-2,然后二氯甲烷萃取(30mL×2),合并有机层,无水硫酸钠干燥,过滤,滤液旋干,粗品用乙酸乙酯与甲基叔丁基醚重结晶得到化合物I-11(32mg,35.3%)。1H NMR(400MHz,CDCl3)δ:8.46(s,1H),7.25(s,1H),7.16-7.11(m,2H),3.93(s,3H),3.88-3.82(m,1H),3.51-3.44(m,1H),3.30-3.21(m,1H),3.10-3.03(m,1H),1.57-1.49(m,1H),1.29-1.23(m,1H),0.96-0.78(m,10H);ESI-MSm/z 378.2(M+H)+。
实施例19.制备9-(环丙基乙炔基)-6-异丙基-10-甲氧基-2-氧代-6,7-二氢-2H-吡啶并[2,1-a]异喹啉-3-羧酸(I-11-rac)
按照实施例18的方法,得到化合物I-11-rac。1H NMR(400MHz,CDCl3)δ:8.46(s,1H),7.25(s,1H),7.16-7.11(m,2H),3.93(s,3H),3.88-3.82(m,1H),3.51-3.44(m,1H),3.30-3.21(m,1H),3.10-3.03(m,1H),1.57-1.49(m,1H),1.29-1.23(m,1H),0.96-0.78(m,10H);ESI-MS m/z 378.2(M+H)+。
实施例20.制备(S)-6-异丙基-10-甲氧基-9-(4-甲氧基丁-1-炔-1-基)-2-氧代-6,7-二氢-2H-吡啶并[2,1-α]异喹啉-3-羧酸(I-12)
化合物12b的制备:化合物12a(1.30g,15.0mmol)溶于30mL无水四氢呋喃中,氮气置换3次,冷却至-78℃,搅拌1小时,加入硼酸三甲酯(2.34g,22.0mmol),在-78℃搅拌1小时后回到-20℃,在-20℃搅拌1小时,加入氟氢化钾饱和溶液(7.03g,90.0mmol),剧烈搅拌1小时,回到室温搅拌1小时后,溶剂在减压条件去除,得到白色固体,真空干燥,产品溶于40mL热丙酮,过滤,滤液旋干,固体溶于5mL丙酮,加热至回流,加入50mL乙醚,冷却至0℃,过滤,滤饼真空干燥得到固体(0.32g,11.2%),即为化合物12b。
化合物12c的制备:将化合物11a(120mg,0.25mmol),化合物12b(71mg,0.37mmol),Pd(dppf)Cl2(18mg,0.025mmol),碳酸钠(78mg,0.74mmol)加入到9mL乙二醇二甲醚和2mL水中,氮气置换3次,加热至100℃,反应3小时,TLC显示反应完全,反应液直接柱层析得到化合物12c(55mg,52.0%)。
化合物I-12的制备:往化合物12c(55mg,0.13mmol)的THF(3mL)溶液中加入1N氢氧化钠水溶液(1.28mL,1.28mmol),室温反应18小时。加入1N盐酸调节至pH=1-2,二氯甲烷萃取(30mL×2),合并有机层,无水硫酸钠干燥,过滤,滤液旋干,粗品用制备色谱纯化得到化合物I-12(11mg,21.4%)。1H NMR(400MHz,CDCl3)δ:8.49-8.48(m,1H),7.33(s,1H),7.18-7.17(m,2H),3.96(s,3H),3.92-3.85(m,1H),3.64(t,J=7.2Hz,2H),3.44(s,3H),3.32-3.25(m,1H),3.14-3.07(m,1H),2.80(t,J=6.4Hz,2H),0.95(d,J=6.4Hz,3H),0.91(d,J=6.4Hz,3H);ESI-MS m/z 396.2(M+H)+。
实施例21.制备(S)-6-异丙基-10-甲氧基-9-((1s,3R)-3-甲氧基环丁氧基)-2-氧代-6,7-二氢-2H-吡啶并[2,1-α]异喹啉-3-羧酸(I-19)
化合物19b:化合物19a(1.60g,8.99mmol),对硝基苯甲酸(1.50g,8.99mmol)和三苯基膦(4.24g,16.18mmol)混合溶于10mL无水THF,氮气置换3次后,冰水浴下滴加偶氮二甲酸二乙酯(2.35g,13.48mmol)到体系中,室温搅拌19小时,旋干得到粗品,直接柱层析(PE→PE:EA=50:1)得到固体2.43g,收率:83.0%。
化合物19c:化合物31b(2.43g,7.43mmol)溶于THF(3ml)和甲醇(1ml),加入氢氧化锂(1.873g,44.6mmol)的水溶液(10mL),室温搅拌4小时,减压浓缩有机溶剂,乙酸乙酯萃取(100ml×3),合并乙酸乙酯层,依次用水和饱和食盐水洗,无水硫酸钠干燥,过滤,滤液真空浓缩得到粗产品1.11g。
化合物19d:化合物3c(1.11g,6.21mmol)溶于15mL无水THF,加入氢化钠(0.30g,12.42mmol),搅拌0.5小时后,加入碘甲烷(1.15g,8.07mmol),加料完毕后,室温搅拌2小时,然后加入10mL水淬灭,加入乙酸乙酯萃取(30ml×3),合并乙酸乙酯层,无水硫酸钠干燥,滤液直接拌硅胶柱层析(PE:EA=30:1)得到1.10g化合物。收率:92.1%。
化合物19e:化合物31d(1.10g,5.72mmol)溶于10mL甲醇,加入Pd/C(0.325g),加入1滴浓盐酸,氢气真空置换3次,室温加氢18小时,过滤,滤液真空浓缩得到产品0.56g。收率:95.9%。
化合物19f:化合物31e(0.560g,5.49mmol)溶于8mL二氯甲烷中,加入三乙胺(1.39g,13.72mmol),冰水浴下缓慢加入甲磺酰氯(0.94g,8.23mmol),混合物室温搅拌2小时,旋干,加入30mL水,乙酸乙酯萃取(50ml×2),有机相合并,依次用水洗和饱和食盐水洗,无水硫酸钠干燥,滤液旋干,得到粗产品0.910g。
化合物19g:化合物10(0.30g,0.84mmol)和化合物19f(0.23g,1.26mmol)溶于6mLDMF中,加入碳酸钾(0.35g,2.52mmol),在90℃反应18小时。反应结束后倒入水中,乙酸乙酯萃取(50ml×4),合并乙酸乙酯层,依次用水洗和饱和食盐水洗,无水硫酸钠干燥,过滤,滤液真空浓缩,得到粗产品0.42g。
化合物I-19:化合物19g(0.42g,0.95mmol)溶于5mL THF中,加入10%氢氧化钠水溶液(0.30g,7.50mmol),反应18小时,用1N盐酸将pH调至1-2,用二氯甲烷萃取(40mL×2),合并有机层,用饱和氯化钠洗,干燥浓缩后,粗品用乙酸乙酯与甲基叔丁基醚重结晶得到产品0.170g。1HNMR(400MHz,CDCl3)δ:8.47(s,1H),7.18(s,1H),7.07(s,1H),6.59(s,1H),4.46-4.37(m,1H),3.91-3.85(m,1H),3.75-3.66(m,1H),3.37-3.31(m,1H),3.29(s,3H),3.07(d,J=15.6Hz,1H),2.98-2.91(m,2H),2.32-2.20(m,2H),1.87-1.79(m,1H),0.95(d,J=6.4Hz,3H),0.84(d,J=6.8Hz,3H).ESI-MS m/z 414.2(M+H)+
实施例22.制备(S)-9-环丁氧基-6-异丙基-10-甲氧基-2-氧代-6,7-二氢-2H-吡啶并[2,1-a]异喹啉-3-羧酸(I-20)
化合物20a:化合物10(0.100g,0.28mmol)和溴代环丁烷(0.075g,0.56mmol)溶于DMF(4ml),加入碳酸钾(0.116g,0.84mmol),在90℃反应18小时。反应结束后倒入水中,乙酸乙酯萃取(50ml×4),合并乙酸乙酯层,依次用水洗和饱和食盐水洗,无水硫酸钠干燥,过滤,滤液真空浓缩,得到粗产品63mg。Yield:54.6%。
化合物I-20:化合物20a(0.063g,0.15mmol)溶于3mL THF,加入10%氢氧化钠水溶液(0.200g,5mmol),室温反应18小时,用1N盐酸将pH调至1-2,用二氯甲烷萃取(40mL×2),合并有机层,用饱和氯化钠洗,干燥浓缩后,粗品用乙酸乙酯与甲基叔丁基醚重结晶得到产品15mg。收率:25.5%。1HNMR(400MHz,CDCl3)δ:8.50(d,J=0.8Hz,1H),7.16(s,1H),7.06(s,1H),6.57(s,1H),4.77-4.67(m,1H),4.64-4.48(m,2H),3.92(s,3H),3.41-3.26(m,1H),3.09-2.98(m,1H),2.56-2.44(m,2H),2.37-3.20(m,2H),1.97-1.85(m,2H),1.75-1.68(m,1H),0.93(d,J=6.4Hz,3H),0.81(d,J=6.4Hz,3H).ESI-MS m/z 384.2(M+H)+
实施例23.制备10-氯-6-异丙基-2-氧代-9-(((R)-四氢呋喃-3-基)氧基)-6,7-二氢-2H-吡啶并[2,1-α]异喹啉-3-羧酸(I-22-rac)
化合物22b:将化合物1(2.07g,10mmol0溶于20mL乙腈中,加入苄溴(2.05g,12mmol)和碳酸钾(2.76g,20mmol)。于80℃加热搅拌16小时,反应结束后加入50mL水和50mL乙酸乙酯,分液,水层用50mL乙酸乙酯萃取,合并有机层,用饱和食盐水洗,干燥后浓缩,柱层析纯化得产物3.00g。收率:100%。
化合物22c:将化合物22b(3.00g,10mmol)溶于50mLTHF中,加入Pd2(dba)3(185mg,0.2mmol),Xantphos(234mg,0.4mmol)和叔丁醇钠(1.55g,16.2mmol)。氮气置换3次,加入4-甲基2-丁酮(1.74g,20.2mmol),于60℃加热搅拌6小时。加入硅胶拌样,色谱柱纯化得产物2.70g。收率:89.4%。
化合物22d-rac:将化合物22c(2.70g,8.94mmol)溶于50mL甲醇中,加入醋酸铵(6.90g,89.4mmol)和氰基硼氢化钠(1.12g,17.88mmol),室温搅拌16小时。浓缩甲醇,加入NaOH水溶液(1.40g氢氧化钠溶于60mL水)和50mLDCM,搅拌20分钟。分液,水层用DCM萃取(50mL×2),合并有机层,用饱和氯化钠洗,无水硫酸钠干燥,浓缩得粗产品2.70g,直接用于下一步反应。
化合物22e-rac:将化合物22d-rac(2.70g,8.94mmol)溶于30mL二氧六环中,加入甲酸(3.50g,44.7mmol),加热回流3小时。冷却至室温,加入50mL饱和碳酸氢钠水溶液和50mL乙酸乙酯,分液,水层用乙酸乙酯萃取(50mL×2),合并有机层,用饱和氯化钠洗,无水硫酸钠干燥,浓缩得粗品3.20g,直接用于下一步反应。
化合物22f-rac:将化合物22e-rac(3.20g,8.86mmol)溶于50mL乙腈中,加入三氯氧磷(1.63g,10.64mmol),室温搅拌16小时。将反应液缓慢倒入50mL水中,浓缩乙腈,用氨水将pH调至8-9,加入50mLDCM,分液,水层用DCM萃取(50mL×2),合并有机层,用饱和氯化钠洗,浓缩,加入硅胶拌样,色谱柱纯化得产物1.80g。收率:64.8%。
化合物22g-rac:将化合物22f-rac(1.80g,5.74mmol)溶于20mL乙醇和3mL水中,加入2-乙氧亚甲基乙酰乙酸乙酯(3.20g,17.2mmol),于80℃加热搅拌4小时。浓缩乙醇和水得粗品3.60g,直接用于下一步反应。
化合物22h-rac:将化合物22g-rac(3.60g,7.96mmol)溶于40mL乙二醇二甲醚中,加入四氯苯醌(1.96g,7.96mmol),置于55℃加热搅拌3小时。加入硅胶拌样,色谱柱纯化得产品2.20g。收率:61.2%。
化合物22i-rac:将化合物22h-rac(2.10g,4.65mmol)溶于30mL干燥的二氯甲烷中,置于冰水浴中冷却,缓慢滴加三溴化硼(2.33g,9.29mmol),冷却搅拌2小时。将反应液缓慢倒入50mL冰水中,加入50mL二氯甲烷,分液,水层用二氯甲烷萃取(50mL×2),合并有机层,依次用饱和碳酸氢钠和饱和食盐水洗。干燥后浓缩得粗品900mg,直接用于下一步反应。
化合物22j-rac:将化合物22i-rac(218mg,0.60mmol)溶于20mLDMF中,加入中间体2b(100mg,0.60mmol)和碳酸钾(166mg,1.20mmol)。于85℃加热搅拌3小时,冷却至室温,加入60mL水和50mL乙酸乙酯,分液,水层用乙酸乙酯萃取(50mL×2),合并有机层,用饱和氯化钠洗,干燥后浓缩得粗品300mg,直接用于下一步反应。
化合物I-22-rac:将化合物22j-rac(200mg,0.46mmol)溶于10mL四氢呋喃和5mL水中,加入氢氧化钠(74mg,1.85mmol),室温搅拌16小时。用1N盐酸将pH调至1到2,加入20mL二氯甲烷,分液,水层用二氯甲烷萃取(30mL×2),合并有机层,用饱和氯化钠洗一次,干燥后浓缩,粗品经制备板纯化得产物34mg。收率:18.3%.1H NMR(400MHz,CDCl3)δ:8.47(s,1H),7.77(s,1H),7.04(s,1H),6.74-6.76(d,J=6.0Hz,1H),5.05(s,1H),3.91-4.10(m,4H),3.34-3.40(m,1H),3.11-3.15(d,J=15.6Hz,1H),2.21-2.31(m,2H),1.72-1.82(m,2H),1.25(s,1H),0.94-0.95(d,J=6.4Hz,3H),0.82-0.84(d,J=6.8Hz,3H).ESI-MS m/z 404.1(M+H)+.
实施例24.制备10-氯-6-异丙基-9-((1R,3R)-3-甲氧基环丁氧基)-2-氧代-6,7-二氢-2H-吡啶并[2,1-a]异喹啉-3-羧酸(I-23-rac)
化合物23a-rac:将化合物22i-rac(80mg,0.25mmol)溶于5mLDMF中,加入中间体5c(90mg,0.50mmol)和碳酸钾(166mg,1.20mmol)。于85℃加热搅拌3小时,冷却至室温,加入60mL水和50mL乙酸乙酯,分液,水层用乙酸乙酯萃取(50mL×2),合并有机层,用饱和氯化钠洗,干燥后浓缩得粗品100mg,直接用于下一步反应。
化合物I-23-rac:将化合物23a-rac(100mg,0.22mmol)溶于10mL四氢呋喃和5mL水中,加入氢氧化钠(40mg,1.00mmol),室温搅拌16小时。用1N盐酸将pH调至1到2,加入20mL二氯甲烷,分液,水层用二氯甲烷萃取(30mL×2),合并有机层,用饱和氯化钠洗一次,干燥后浓缩,粗品经制备板纯化得产物17mg。收率:18.5%.1H NMR(400MHz,CDCl3)δ:8.47(s,1H),7.75(s,1H),7.04(s,1H),6.89(s,1H),4.95(m,1H),4.15(m,1H),3.90(m,1H),3.33(m,4H,overlap),3.13(m,1H),2.50(m,4H),1.77(m,1H),0.95(d,J=6.8Hz,3H),0.84(d,J=6.8Hz,3H);ESI-MS m/z 418.2(M+H)+.
实施例25.制备10-氯-6-异丙基-9-((1-(甲氧基甲基)环丙基)甲氧基)-2-氧代-6,7-二氢-2H-吡啶并[2,1-a]异喹啉-3-羧酸(I-24-rac)
化合物24a-rac:将化合物22i-rac(80mg,0.25mmol)溶于5mLDMF中,加入中间体6c(90mg,0.50mmol)和碳酸钾(138mg,1.00mmol)。于85℃加热搅拌3小时,冷却至室温,加入60mL水和50mL乙酸乙酯,分液,水层用乙酸乙酯萃取(50mL×2),合并有机层,用饱和氯化钠洗,干燥后浓缩得粗品110mg,直接用于下一步反应。
化合物I-24-rac:将化合物24a-rac(110mg,0.24mmol)溶于10mL四氢呋喃和5mL水中,加入氢氧化钠(40mg,1.00mmol),室温搅拌16小时。用1N盐酸将pH调至1到2,加入20mL二氯甲烷,分液,水层用二氯甲烷萃取(30mL×2),合并有机层,用饱和氯化钠洗一次,干燥后浓缩,粗品经制备板纯化得产物23mg。收率:22.2%.1H NMR(400MHz,CDCl3)δ:8.45(s,1H),7.75(s,1H),7.03(s,1H),6.81(s,1H),4.04(m,2H),3.90(m,1H),3.42(m,2H),3.37(s,3H),3.33(m,1H),3.13-3.09(m,1H),1.77(m,1H),0.95(d,J=6.8Hz,3H),0.82(d,J=6.4Hz,3H),0.72(m,2H),0.66(m,2H);ESI-MSm/z 432.1(M+H)+.
实施例26.制备10-氯-6-异丙基-9-((3-(甲氧基甲基)氧杂环丁烷-3-基)甲氧基)-2-氧代-6,7-二氢-2H-吡啶并[2,1-α]异喹啉-3-羧酸(I-25-rac)
化合物25a-rac:将化合物22i-rac(80mg,0.25mmol)溶于5mLDMF中,加入中间体7e(105mg,0.50mmol)和碳酸钾(136mg,1.00mmol)。于85℃加热搅拌3小时,冷却至室温,加入60mL水和50mL乙酸乙酯,分液,水层用乙酸乙酯萃取(50mL×2),合并有机层,用饱和氯化钠洗,干燥后浓缩得粗品105mg,直接用于下一步反应。
化合物I-25-rac:将化合物25a-rac(105mg,0.22mmol)溶于10mL四氢呋喃和5mL水中,加入氢氧化钠(40mg,1.00mmol),室温搅拌16小时。用1N盐酸将pH调至1到2,加入20mL二氯甲烷,分液,水层用二氯甲烷萃取(30mL×2),合并有机层,用饱和氯化钠洗一次,干燥后浓缩,粗品经制备板纯化得产物21mg。收率:21.3%.1H NMR(400MHz,CDCl3)δ:8.48(s,1H),7.76(s,1H),7.04(s,1H),6.89(s,1H),4.62(m,2H),4.55(m,2H),4.30(q,J=8.8Hz,2H),3.95(m,1H),3.79(m,2H),3.65(s,3H),3.37(m,1H),3.13(m,1H),1.70(m,1H),0.95(d,J=6.4Hz,3H),0.82(d,J=6.8Hz,3H).ESI-MS m/z 448.1(M+H)+.
实施例27.制备10-氯-6-异丙基-9-((3-甲氧基环丁基)甲氧基)-2-氧代-6,7-二氢-2H-吡啶并[2,1-a]异喹啉-3-羧酸(I-26-rac)
化合物26a-rac:将化合物22i-rac(186mg,0.52mmol)溶于20mLDMF中,加入中间体8d(100mg,0.52mmol)和碳酸钾(142mg,1.04mmol)。于85℃加热搅拌3小时,冷却至室温,加入60mL水,然后用乙酸乙酯萃取(50mL×3),合并有机层,用饱和氯化钠洗一次,干燥后浓缩得粗品200mg,直接用于下一步反应。
化合物I-26-rac:将化合物26a-rac(200mg,0.44mmol)溶于10mLTHF和5mL水中,加入氢氧化钠(70mg,1.74mmol),室温搅拌16小时。浓缩THF,用1N盐酸将pH调至1到2,用DCM萃取(30mL×3),合并有机层,用饱和氯化钠洗一次,干燥后浓缩。粗产品经制备板纯化得产物12mg。收率:6.32%。1H NMR(400MHz,CDCl3)δ8.47(s,1H),7.74(s,1H),7.02(s,1H),6.79(s,1H),4.06-4.10(m,2H),3.92-3.95(m,1H),3.83-3.87(m,1H),3.34-3.39(m,1H),3.25(s,1H),3.10-3.14(d,J=16.4Hz,1H),2.37-2.52(m,3H),1.80-1.89(m,2H),1.21(s,1H),0.94-0.95(d,J=6.4Hz,3H),0.81-0.83(d,J=6.8Hz,3H).ESI-MS m/z 432.2(M+H)+。
实施例28.制备6-(叔丁基)-10-甲氧基-2-氧代-9-(((R)-四氢呋喃-3-基)氧基)-6,7-二氢-2H-吡啶并[2,1-α]异喹啉-3-羧酸(I-28-rac)
化合物28a:将化合物2(4.40g,15mmol)溶于四氢呋喃(50mL)中,加入Pd2(dba)3(275mg,0.3mmol),Xantphos(347mg,0.6mmol)和叔丁醇钠(2.30g,24mmol)。氮气置换3次,加入频哪酮(3.00g,15mmol),于60℃加热搅拌6小时。加入硅胶拌样,柱纯化得产物3.30g。收率:70.7%。
化合物28b-rac:将化合物28a(3.30g,10.6mmol)溶于50mL甲醇中,加入醋酸铵(8.14g,0.11mol)和氰基硼氢化钠(995mg,15.8mmol),温搅拌16小时。浓缩甲醇,加入NaOH水溶液(1.40g氢氧化钠溶于60mL水)和50mLDCM,搅拌20分钟。分液,水层用DCM萃取(50mL×2),合并有机层,用饱和氯化钠洗一次,无水硫酸钠干燥,浓缩得粗产品3.40g,直接用于下一步反应。
化合物28c-rac:将化合物28b-rac(3.40g,10.9mmol)溶于50mL二氧六环中,加入甲酸(2.51g,54.5mmol),加热回流3小时。冷却至室温,加入50mL饱和碳酸氢钠水溶液,然后用乙酸乙酯萃取(50mL×3),合并有机层,用饱和氯化钠洗一次,无水硫酸钠干燥,浓缩得粗品3.40g,直接用于下一步反应。
化合物28d-rac:将化合物28c-rac(3.40g,10mmol)溶于50mL乙腈中,加入三氯氧磷(1.85g,12mmol),室温搅拌16小时。将反应液缓慢倒入50mL水中,浓缩乙腈,用氨水将pH调至8-9,然后用DCM萃取(50mL×3),合并有机层,用饱和氯化钠洗,无水硫酸钠干燥,浓缩得粗品3.20g,直接用于下一步反应。
化合物28e-rac:将化合物28d-rac(3.20g,9.9mmol)溶于40mL乙醇和5mL水中,加入2-乙氧亚甲基乙酰乙酸乙酯(5.50g,29.7mmol),于80℃加热搅拌4小时。浓缩乙醇和水得粗品6.40g,直接用于下一步反应。
化合物28f-rac:将化合物28e-rac(6.40g,13.8mmol)溶于40mL乙二醇二甲醚中,加入四氯苯醌(3.40g,13.8mmol),于55℃加热搅拌3小时。加入硅胶拌样,柱层析纯化得产品3.20g。收率:50.2%。
化合物28g-rac:将化合物28f-rac(3.2g,6.9mmol)溶于50mL甲醇中,加入200mgPd/C。氢气置换4次,室温搅拌16小时。垫硅藻土抽滤,浓缩得粗产品2.40g。
化合物28h-rac:将化合物28g-rac(223mg,0.60mmol)溶于20mL DMF中,加入中间体2b(100mg,0.60mmol)和碳酸钾(166mg,1.20mmol)。于85℃加热搅拌3小时,冷却至室温,加入60mL水和50mL乙酸乙酯,分液,水层用50mL乙酸乙酯萃取,合并有机层,用饱和氯化钠洗一次,浓缩得粗品300mg,直接用于下一步反应。
化合物I-28-rac:将化合物28h-rac(300mg,0.68mmol)溶于10mL THF和5mL水中,加入氢氧化钠(109mg,2.72mmol),室温搅拌16小时。用1N盐酸将pH调至1到2,用DCM萃取(30mL×3),合并有机层,用饱和氯化钠洗一次,干燥后浓缩,粗产品经制备板纯化得产物100mg。收率:35.5%。1H NMR(400MHz,CDCl3)δ:8.47(s,1H),7.16(s,1H),7.07(s,1H),6.65-6.66(d,J=4.8Hz,1H),5.04(s,1H),4.01-4.06(m,4H),3.91(s,3H),3.39-3.45(m,1H),3.14-3.18(d,J=16.8Hz,1H),2.21-2.26(m,2H),1.25(s,1H),0.81(s,9H).ESI-MS m/z414.2(M+H)+.
实施例29.制备6-(叔丁基)-10-甲氧基-9-((1R,3R)-3-甲氧基环丁氧基)-2-氧代-6,7-二氢-2H-吡啶并[2,1-α]异喹啉-3-羧酸(I-29-rac)
化合物29a-rac:将化合物28g-rac(65mg,0.18mmol),化合物5c(47mg,0.26mmol)和碳酸钾(50mg,0.36mmol)加入到5mL DMF中,置换氮气3次,于90℃加热搅拌反应3小时。反应完毕后加水稀释,用乙酸乙酯萃取(20mL×3),合并有机相,无水硫酸钠干燥,浓缩得粗品75mg。
化合物I-29-rac:将化合物29a-rac(75mg,0.16mmol)溶于4mL四氢呋喃中,加入氢氧化钠45mg和水1mL,于50℃搅拌反应3小时。反应完毕后用1N盐酸调pH至2-3左右,二氯甲烷萃取(20mL×3),合并有机相,无水硫酸钠干燥,浓缩后薄层层析得产品10mg。收率:14.6%。1H-NMR(CDCl3,400MHz)δ:8.45(s,1H),7.14(s,1H),7.05(s,1H),6.51(s,1H),4.94(m,1H),4.16(m,1H),4.01(m,1H),3.92(s,3H),3.37-3.43(m,1H),3.29(s,3H),3.16(m,1H),2.48-2.56(m,3H),0.82(s,9H);ESI-MS m/z 428.2(M+H)+
实施例30.制备6-(叔丁基)-10-甲氧基-9-((1-(甲氧基甲基)环丙基)甲氧基)-2-氧代-6,7-二氢-2H-吡啶并[2,1-α]异喹啉-3-羧酸(I-30-rac)
化合物30a-rac:将化合物28g-rac(85mg,0.23mmol),化合物6c(89mg,0.46mmol)和碳酸钾(63mg,0.46mmol)加入到5mL DMF中,置换氮气3次,于90℃加热搅拌反应3小时。反应完毕后加水稀释,用乙酸乙酯萃取(20mL×3),合并有机相,无水硫酸钠干燥,浓缩得粗品97mg。
化合物I-30-rac:将化合物29a-rac(97mg,0.21mmol)溶于4mL四氢呋喃中,加入氢氧化钠45mg和水1mL,于50℃搅拌反应3小时。反应完毕后用1N盐酸调pH至2-3左右,二氯甲烷萃取(20mL×3),合并有机相,无水硫酸钠干燥,浓缩后薄层层析得产品26mg。收率:28.1%。1H-NMR(CDCl3,400MHz)δ:8.45(s,1H),7.13(s,1H),7.05(s,1H),6.74(s,1H),4.00(m,3H),3.91(s,3H),3.41(s,2H),3.36(s,3H),3.15(m,1H),2.92(m,1H),0.82(s,9H),0.69-0.65(m,4H);ESI-MS m/z 442.2(M+H)+。
实施例31.制备6-(叔丁基)-10-甲氧基-9-((3-(甲氧基甲基)氧杂环丁烷-3-基)甲氧基)-2-氧代-6,7-二氢-2H-吡啶并[2,1-α]异喹啉-3-羧酸(I-31-rac)
化合物31a-rac:将化合物28g-rac(65mg,0.18mmol),化合物7e(55mg,0.26mmol)和碳酸钾(50mg,0.36mmol)加入到5mL DMF中,置换氮气3次,于90℃加热搅拌反应3小时。反应完毕后加水稀释,用乙酸乙酯萃取(20mL×3),合并有机相,无水硫酸钠干燥,浓缩得粗品87mg。
化合物I-31-rac:将化合物31a-rac(87mg,0.18mmol)溶于4mL四氢呋喃中,加入氢氧化钠45mg和水1mL,于50℃搅拌反应3小时。反应完毕后用1N盐酸调pH至2-3左右,二氯甲烷萃取(20mL×3),合并有机相,无水硫酸钠干燥,浓缩后薄层层析得产品10mg。收率:12.1%。1H-NMR(CDCl3,400MHz)δ:8.46(s,1H),7.15(s,1H),7.07(s,1H),6.79(s,1H),4.61(m,4H),4.27(m,2H),4.01(m,1H),3.89(s,3H),3.78(m,2H),3.41(s,3H),3.33(m,1H),3.16(m,1H),0.83(s,9H);ESI-MS m/z458.2(M+H)+。
实施例32.制备6-(叔丁基)-10-甲氧基-9-((3-甲氧基环丁基)甲氧基)-2-氧代-6,7-二氢-2H-吡啶并[2,1-a]异喹啉-3-羧酸(I-32-rac)
化合物32a-rac:将化合物28g-rac(191mg,0.52mmol),化合物8d(100mg,0.52mmol)和碳酸钾(142mg,1.03mmol)加入到10mL DMF中,置换氮气3次,于90℃加热搅拌反应5小时。反应完毕后加水稀释,用乙酸乙酯萃取(50mL×3),合并有机相,无水硫酸钠干燥,浓缩后得粗产品200mg。
化合物I-32-rac:将化合物32a-rac(200mg,0.43mmo)溶于10mL四氢呋喃中,加入氢氧化钠102mg和水5mL,于35℃搅拌反应2小时。反应完毕后用1N盐酸调pH至2-3左右,二氯甲烷萃取(20mL×3),合并有机相,无水硫酸钠干燥,浓缩后薄层层析得产品70mg。收率:36.8%。1H-NMR(CDCl3,400MHz)δ:8.48(s,1H),7.15(s,1H),7.07(s,1H),6.71(s,1H),4.03-4.08(m,3H),3.92(s,3H),3.40-3.46(m,1H),3.15-3.19(d,J=15.2Hz,1H),2.22-2.55(m,3H),1.78-1.82(m,2H),1.26(s,1H),0.82(s,9H).ESI-MS m/z 442.2(M+H)+.
实施例33.制备10-甲氧基-6-(1-甲氧基-2-甲基丙-2-基)-2-氧代-9-(((R)-四氢呋喃-3-基)氧基)-6,7-二氢-2H-吡啶并[2,1-a]异喹啉-3-羧酸(I-52-rac)
化合物52b:将化合物52a(10.0g,0.12mol)溶于18mL三氟乙酸中,加入3.48g多聚甲醛,80℃条件下搅拌反应7小时,冷却后加入500mL饱和碳酸氢钠水溶液搅拌反应6小时。然后二氯甲烷萃取(100mL×5),合并有机相,无水硫酸钠干燥,浓缩拌样,硅胶柱层析(PE:EA=5:1)得产品5.0g。收率:35.8%。
化合物52c:往化合物52b(5.0g,0.043mol)中加入硫酸二甲酯5.5mL,然后加入20N氢氧化钠水溶液3mL,40℃搅拌反应16小时。TLC监测原料反应完毕,用乙醚萃取(30mL×3),合并有机相,无水硫酸钠干燥,浓缩蒸干得1.00g粗产品。
化合物52d:将化合物2(1.00g,3.41mmol),化合物52c(0.89g,6.82mmol),醋酸钯(12mg,1.5%mol),Xphos(2-二环己基磷-2’,4’,6’-三异丙基联苯,49mg,3%mol)和1MLiHMDS(10.2mL,10.2mmol)溶于10mL二氧六环中,氮气保护下置换气3次,70℃条件下加热反应3小时,反应完毕后旋干反应溶剂,硅胶柱层析PE:EA=5:1得产品0.62g。收率:53.4%。
化合物52e:将化合物52d(0.62g,1.82mmol)溶于5mL甲醇中,加入醋酸铵(1.40g,18.2mmol)搅拌反应30分钟,加入氰基硼氢化钠(0.23g,3.64mmol),于60℃搅拌反应16小时。反应完毕后加入2N氢氧化钠溶液50mL,二氯甲烷萃取(30mL×3),合并有机相,无水硫酸钠干燥,浓缩蒸干得0.63g粗产品。
化合物52f-rac:将化合物52e(0.63g,1.84mmol)溶于5mL二氧六环中,加入1.0mL甲酸,0.5mL原甲酸三乙酯,加热回流搅拌反应48小时。反应结束后旋干反应溶剂,二氯甲烷萃取(20mL×3),合并有机相,无水硫酸钠干燥,浓缩蒸干得0.60g粗产品。
化合物52g-rac:将化合物52f-rac(0.60g,1.62mmol)溶于5mL乙腈中,冰浴条件下缓慢滴加三氯氧磷(0.30mL,3.24mmol),滴毕油浴60℃反应1小时。反应完毕后旋干反应溶剂,二氯甲烷萃取(20mL×3),有机相合并,饱和碳酸氢钠溶液洗,无水硫酸钠干燥,浓缩得到0.58g粗产品。
化合物52h-rac:将化合物52g-rac(0.58g,1.64mmol)和2-乙氧亚甲基乙酰乙酸乙酯(0.92g,4.92mmol)溶于6mL乙醇中,加入2mL水,加热回流搅拌反应48小时,反应完毕后旋干反应溶剂得1.17g粗产品。
化合物52i-rac:将化合物52h-rac(1.17g,2.36mmol)和四氯苯醌(0.35g,1.42mmol)溶于15mL乙二醇二甲醚中,加热回流搅拌反应3小时,反应完毕后旋干反应溶剂,硅胶柱层析得产品475mg。收率:40.9%。
化合物52j-rac:将化合物52i-rac(475mg,0.97mmol)溶于15mL甲醇中,加入钯碳50mg,氢气保护下置换气3次。室温过夜搅拌反应,TLC监测反应完毕,抽滤,滤液蒸干得产品300mg。收率:77.3%。1H-NMR(CDCl3,400MHz):δ:8.35(d,1H,J=13.6Hz),7.11(s,1H),6.91(s,1H),6.80(s,1H),4.37(d,2H,J=6.4Hz),3.90(s,3H),3.86(s,1H),3.34(s,3H),3.33-3.28(m,1H),3.03(s,1H),2.99-2.94(m,1H),2.88-2.85(m,1H),1.38-1.24(m,3H),0.95(d,3H,J=4Hz),0.39(d,3H,J=6.8Hz)
化合物52k-rac:将化合物52j-rac(100mg,0.25mmol),化合物2b(83mg,0.50mmol)和碳酸钾(103mg,0.75mmol)加入到5mL DMF中,置换氮气3次,于90℃加热搅拌反应5小时。反应完毕后加水稀释,用乙酸乙酯萃取(20mL×3),合并有机相,无水硫酸钠干燥,薄层层析得产品75mg。收率:40.0%。
化合物I-52-rac:将化合物52k-rac(75mg,0.1mmol)溶于3mL四氢呋喃中,加入氢氧化钠32mg和水1mL,于35℃搅拌反应2小时。反应完毕后用1N盐酸调pH至2-3左右,二氯甲烷萃取(20mL×3),合并有机相,无水硫酸钠干燥,浓缩后薄层层析得产品30mg。收率:67.5%。1H-NMR(CDCl3,400MHz)δ:8.58(s,1H),7.15(s,1H),7.06(s,1H),6.66(s,1H),5.05-5.03(m,1H),4.52-4.51(m,1H),4.05-4.01(m,3H),3.96-3.92(m,1H),3.90(s,3H),3.44-3.37(m,1H),3.35(s,3H),3.11-3.06(m,1H),2.91(s,2H),2.24-2.23(m,2H),0.97(s,3H),0.42(s,3H)。ESI-MS m/z 444.2(M+H)+
实施例34.制备10-甲氧基-6-(1-甲氧基-2-甲基丙-2-基)-9-((1R,3R)-3-甲氧基环丁氧基)-2-氧代-6,7-二氢-2H-吡啶并[2,1-a]异喹啉-3-羧酸(I-53-rac)
化合物53a-rac:将化合物52j-rac(100mg,0.25mmol),化合物5c(90mg,0.50mmol)和碳酸钾(103mg,0.75mmol)加入到5mL DMF中,置换氮气3次,于90℃加热搅拌反应5小时。反应完毕后加水稀释,用乙酸乙酯萃取(20mL×3),合并有机相,无水硫酸钠干燥,浓缩得粗产品120mg。
化合物I-53-rac:将化合物53a-rac(120mg,0.25mmol)溶于3mL四氢呋喃中,加入氢氧化钠32mg和水1mL,于35℃搅拌反应2小时。反应完毕后用1N盐酸调pH至2-3左右,二氯甲烷萃取(20mL×3),合并有机相,无水硫酸钠干燥,浓缩后薄层层析得产品20mg。收率:17.5%。1H-NMR(CDCl3,400MHz)δ:8.58(s,1H),7.15(s,1H),7.06(s,1H),6.52(s,1H),5.00-4.90(m,1H),4.52-4.50(m,1H),4.20(m,1H),3.97(m,1H),3.93(s,3H),3.64(m,1H),3.36(s,3H),3.31(s,3H),3.08(m,1H),2.91(m,2H),2.59(m,4H),0.88(s,3H),0.41(s,3H)。ESI-MS m/z 458.2(M+H)+
实施例35.制备10-甲氧基-6-(1-甲氧基-2-甲基丙-2-基)-9-((1-(甲氧基甲基)环丙基)甲氧基)-2-氧代-6,7-二氢-2H-吡啶并[2,1-a]异喹啉-3-羧酸(I-54-rac)
化合物54a-rac:将化合物52j-rac(100mg,0.25mmol),化合物6c(97mg,0.50mmol)和碳酸钾(103mg,0.75mmol)加入到5mL DMF中,置换氮气3次,于90℃加热搅拌反应5小时。反应完毕后加水稀释,用乙酸乙酯萃取(20mL×3),合并有机相,无水硫酸钠干燥,浓缩得粗产品110mg。
化合物I-54-rac:将化合物54a-rac(110mg,0.22mmol)溶于3mL四氢呋喃中,加入氢氧化钠40mg和水1mL,于35℃搅拌反应2小时。反应完毕后用1N盐酸调pH至2-3左右,二氯甲烷萃取(20mL×3),合并有机相,无水硫酸钠干燥,浓缩后薄层层析得产品27mg。收率:26.1%。1H-NMR(CDCl3,400MHz)δ:8.57(s,1H),7.13(s,1H),7.05(s,1H),6.74(s,1H),4.49(d,J=6.8Hz,1H),3.99(s,2H),3.95(d,J=9.2Hz,1H),3.90(s,3H),3.41(s,2H),3.36(d,J=4.8Hz,6H),3.07(d,J=17.6Hz,1H),2.91(s,2H),0.97(s,3H),0.71-0.63(m,4H),0.43(s,3H);ESI-MS m/z 472.2(M+H)+
实施例36.制备10-甲氧基-6-(1-甲氧基-2-甲基丙-2-基)-9-((3-(甲氧基甲基)氧杂环丁烷-3-基)甲氧基)-2-氧代-6,7-二氢-2H-吡啶并[2,1-a]异喹啉-3-羧酸(I-55-rac)
化合物55a-rac:将化合物67j-rac(54mg,0.13mmol),化合物7e(56mg,0.26mmol)和碳酸钾(56mg,0.39mmol)加入到5mL DMF中,置换氮气3次,于90℃加热搅拌反应5小时。反应完毕后加水稀释,用乙酸乙酯萃取(20mL×3),合并有机相,无水硫酸钠干燥,浓缩得粗品100mg。
化合物I-55-rac:将化合物55a-rac(100mg,0.19mmol)溶于4mL四氢呋喃中,加入氢氧化钠46mg和水1mL,于35℃搅拌反应2小时。反应完毕后用1N盐酸调pH至2-3左右,二氯甲烷萃取(20mL×3),合并有机相,无水硫酸钠干燥,浓缩后薄层层析得产品10mg。收率:10.8%。1H-NMR(CDCl3,400MHz)δ:8.58(s,1H),7.15(s,1H),7.05(s,1H),6.79(s,1H),4.64-4.51(m,5H),4.30-4.24(m,2H),3.89(s,3H),3.81-3.74(m,2H),3.39(d,7H,J=18.8Hz),3.12-3.08(m,1H),2.92(s,2H),0.98(s,3H),0.43(s,3H)。ESI-MS m/z 488.2(M+H)+
实施例37.制备10-甲氧基-6-(1-甲氧基-2-甲基丙-2-基)-9-((3-甲氧基环丁基)甲氧基)-2-氧代-6,7-二氢-2H-吡啶并[2,1-a]异喹啉-3-羧酸(I-56-rac)
化合物56a-rac:将化合物52j-rac(100mg,0.25mmol),化合物8d(96mg,0.50mmol)和碳酸钾(103mg,0.75mmol)加入到5mL DMF中,置换氮气3次,于90℃加热搅拌反应5小时。反应完毕后加水稀释,用乙酸乙酯萃取(20mL×3),合并有机相,无水硫酸钠干燥,浓缩后薄层层析得产品60mg。收率:40.0%。
化合物I-56-rac:将化合物56a-rac(60mg,0.1mmol)溶于4mL四氢呋喃中,加入氢氧化钠25mg和水1mL,于35℃搅拌反应2小时。反应完毕后用1N盐酸调pH至2-3左右,二氯甲烷萃取(20mL×3),合并有机相,无水硫酸钠干燥,浓缩后薄层层析得产品40mg。收率:84.7%。1H-NMR(CDCl3,400MHz)δ:8.57(s,1H),7.13(s,1H),7.04(s,1H),6.70(s,1H),4.51-4.50(m,1H),4.07-4.05(m,2H),3.90(s,3H),3.84(t,J=7.2Hz,1H),3.36(s,3H),3.25(s,3H),3.06(m,1H),2.91(s,2H),2.53-2.48(m,1H),2.42-2.38(m,1H),2.25-2.21(m,1H),1.82-1.77(m,2H),0.98(s,3H),0.42(s,3H);ESI-MS m/z 472.2(M+H)+
实施例38.体外生物活性研究
待测化合物:
本发明的化合物:化合物I-2、化合物I-5、化合物I-6、化合物I-7、化合物I-8、化合物I-9、化合物I-10、化合物I-11、化合物I-12、化合物I-19、化合物I-20、化合物I-1-rac、化合物I-2-rac、化合物I-3-rac、化合物I-4-rac、化合物I-5-rac、化合物I-6-rac、化合物I-7-rac、化合物I-8-rac、化合物I-9-rac、化合物I-10-rac、化合物I-11-rac、化合物I-22-rac、化合物I-23-rac、化合物I-24-rac、化合物I-25-rac、化合物I-26-rac、化合物I-28-rac、化合物I-29-rac、化合物I-30-rac、化合物I-31-rac、化合物I-32-rac、化合物I-52-rac、化合物I-53-rac、化合物I-54-rac、化合物I-55-rac、化合物I-56-rac;对照化合物:A、A-rac(结构式如下所示):
试验方法:在96孔板内,将HepG2.2.15细胞系按照1.5×104个细胞/孔铺板。第二天加入化合物处理细胞,待测化合物3倍稀释,8个浓度点,平行测定2复孔。培养液中DMSO的终浓度为0.5%。第五天更换新的含化合物的培养液,第八天收集上清,用ELISA法检测细胞上清中HBsAg。相对空白对照计算抑制百分率。结果参见表1。
表1.化合物对于HBsAg的抑制活性
化合物 | EC50(nM) | 化合物 | EC50(nM) | 化合物 | EC50(nM) | 化合物 | EC50(nM) |
I-2 | 1.82 | I-1-rac | 5.74 | I-22-rac | 5.46 | I-53-rac | 6.65 |
I-5 | 1.61 | I-2-rac | 3.26 | I-23-rac | 6.83 | I-54-rac | 5.34 |
I-6 | 3.15 | I-3-rac | 7.04 | I-24-rac | 5.78 | I-55-rac | 7.23 |
I-7 | 3.82 | I-4-rac | 3.62 | I-25-rac | 6.97 | I-56-rac | 5.95 |
I-8 | 1.54 | I-5-rac | 3.56 | I-26-rac | 7.56 | A | 4.06 |
I-9 | 3.26 | I-6-rac | 4.12 | I-28-rac | 5.78 | A-rac | 8.21 |
I-10 | 3.01 | I-7-rac | 4.68 | I-29-rac | 6.45 | ||
I-11 | 2.57 | I-8-rac | 5.59 | I-30-rac | 6.74 | ||
I-12 | 3.83 | I-9-rac | 3.71 | I-31-rac | 5.98 | ||
I-19 | 2.89 | I-10-rac | 3.78 | I-32-rac | 7.31 | ||
I-20 | 2.56 | I-11-rac | 2.61 | I-52-rac | 7.57 |
结论:大多数合成的化合物具有优秀的抑制HBsAg的活性,活性低于10nM。
实施例39.大鼠PK研究
静脉注射给药制剂配制:准确称量样品2~3mg,加入适量N,N-二甲基乙酰胺(DMA),涡旋振荡使固体物质完全溶解;再加入适量体积的30%solutol HS-15水溶液,涡旋振荡后再加入saline,使得DMA:30%solutol HS-15:saline=20:20:60(v/v/v),涡旋振荡使液体混合均匀,并过滤,得浓度为0.4mg·mL-1的给药制剂。
口服给药制剂配制:准确称量样品10mg,加入适量体积的0.5%CMC-Na水溶液,涡旋振荡后超声至混合均匀,得浓度为1mg·mL-1的给药制剂。
给药制剂均于给药当天新鲜配制,并进行留样,对留样进行给药制剂实际浓度的测定。
A组S-D大鼠分别单次静脉注射(IV)给予2mg·kg-1的给药制剂;B组S-D大鼠单次灌胃(PO)
给予10mg·kg-1的给药制剂。分别于给药前及给药后5分钟(仅静脉注射组)、15分钟、30分钟、1小时、2小时、4小时、8小时、12小时和24小时,由颈静脉采血0.15mL,置于EDTA-K2抗凝血管中。所有全血样品离心(5500转/分)10分钟后分离血浆,保存在-30~-10℃的冰箱中。
利用LC-MS/MS分析方法,测定S-D大鼠血浆中待测化合物的浓度。采用PharsightPhoenix 7.0中的非房室模型计算相应的药代动力学参数。结果参见表2a和2b。
表2a.测试化合物的PK参数(静脉注射)
表2b测试化合物的PK参数(灌胃)
结论:综合静脉注射和灌胃给药的PK数据,本发明化合物(尤其是I-2,I-5,I-6,I-8)具有良好的PK特性,显示很好的开发前景。可能是由于在化学结构上侧链的环化改善了化合物的内在代谢稳定性。
以上实施例的说明只是用于帮助理解本发明的方法及其核心思想。应当指出,对于本技术领域的普通技术人员来说,在不脱离本发明原理的前提下,还可以对本发明进行若干改进和修饰,这些改进和修饰也落入本发明权利要求的保护范围内。
Claims (19)
1.一种式(I)所示的异喹啉酮类化合物或其立体异构体、可药用盐、溶剂化物或结晶,
其中:
(1)R1选自H、氘、C1-6烷基、氰基、卤素、羧基、酯基、C3-6环烷基、C4-8杂环烷基、卤代C1-6烷基或C6-10芳基;
(2)R2选自卤素、C1-3烷氧基、氘代C1-3烷氧基、C1-6烷基、C3-6环烷基、C3-6环烷基氧基、C4-8环杂烷基C1-6烷基、卤代C1-3烷基氧基、卤代C3-6环烷基、C3-6环烷基C1-6烷基或R2和R3以碳原子连接形成环;
(3)R3为(a)具有环结构和/或不饱和键的C4-12烃基,该C4-12烃基的氢原子未被取代,或为选自氘、卤素、氰基、羟基、巯基中的一个或多个取代基取代,且该C4-12烃基未被杂原子间断,或被O,S,NH,C=O,C=S,O=S=O中的一个或多个所间断,所述杂原子选自氧、硫或氮;或者,(b)R2和R3以碳原子连接形成环;
(4)R4选自氢、氘、卤素、氰基、酯基或C1-3烷基;
(5)R5,R5′独立的选自氢、氘、卤素、甲基、甲氧基或R5,R5′形成碳环或杂环;或R5,R6形成碳环或杂环;
(6)M为CH或N;
(7)R6选自C1-6烷基、C1-6烷氧C1-6烷基、羟基C1-6烷基、芳基、卤代C1-6烷基或C3-6环烷基C1-6烷基;
(8)W为N或CR7,其中R7选自氢、氘、羟基、卤素、C1-3烷基、C1-6烷氧基、C3-6环烷基氧基、酯基、羧基或氰基;
(9)R8选自羧基、酯基、C1-6烷基、C3-6环烷基、C1-6烷基炔基或C3-6环烷基炔基,其中所述酯基的烷基部分选自C1-6烷基、C3-8环烷基、C3-8环烷基炔基、C1-6烷基炔基、苄基、C1-6烷基C(O)O-C1-3烷基、C1-6烷基-OC(O)O-C1-3烷基。
2.根据权利要求1所述的异喹啉酮类化合物或其立体异构体、可药用盐、溶剂化物或结晶,其特征在于,所述(a)中,所述环结构为3~8元环;所述不饱和键为双键或三键。
3.根据权利要求1所述的异喹啉酮类化合物或其立体异构体、可药用盐、溶剂化物或结晶,其特征在于,所述(a)中,所述的环结构为饱和环。
4.根据权利要求1所述的异喹啉酮类化合物或其立体异构体、可药用盐、溶剂化物或结晶,其特征在于,所述(a)中,所述环结构、不饱和键的个数分别为1~2个。
5.根据权利要求1所述的异喹啉酮类化合物或其立体异构体、可药用盐、溶剂化物或结晶,其特征在于,所述(a)具有一个3~8元饱和碳环或3~8元饱和杂环、至少一个杂原子或至少一个双键或三键。
6.根据权利要求1至5中任一项权利要求所述的异喹啉酮类化合物或其立体异构体、可药用盐、溶剂化物或结晶,其特征在于,所述(a)中,所述环结构、不饱和键以及杂原子中的至少二者同时存在。
7.根据权利要求6所述的异喹啉酮类化合物或其立体异构体、可药用盐、溶剂化物或结晶,其特征在于,所述(a)为满足如下任意一项所述条件的基团:
a1)同时具有所述的环结构和碳碳不饱和键,且环结构和碳碳不饱和键分别有且只有一个;
a2)同时具有所述的环结构和1~3个杂原子,且所述杂原子中至少一个为氧,且该氧原子通过单键与式(I)中苯环连接;
a3)同时具有不饱和键和1~3个杂原子,其中不饱和键为碳碳双键,碳碳三键或者碳氧双键,当不饱和键为碳碳双键或碳碳三键时,它们的一端优选通过单键与式(I)中苯环连接。
8.根据权利要求1所述的异喹啉酮类化合物或其立体异构体、可药用盐、溶剂化物或结晶,其特征在于,R3为C5-11双环烷基;C3-6环烷基炔基;C3-6环烷基烯基;C1-3烷氧C1-6烷基炔基;C1-3烷氧C1-6烷基烯基;C4-8环杂烷基;或者,
R3为RA-O-,其中RA选自C3-8环烷基;C5-11双环烷基;氘代C1-6烷基;C4-8环杂烷基;C1-6烷基羰基C1-6烷基;氘代C1-3烷氧基C1-6烷基;C1-3烷氧基C3-8环烷基;C1-3烷氧基C3-8环烷基C1-6烷基;C3-8杂环烷基;C1-3烷氧基C1-6烷基,其中烷基被C3-8环烷烃或C4-8杂环烷烃取代,杂环烷烃的杂原子选自氧、硫或氮;当RA选自C1-3烷氧基C1-6烷基时,R5、R5′独立选自氘、氟、氯、羟基、氰基,且W为N或CR7,其中R7选自氘、氟、氯、羟基、氰基。
9.根据权利要求1所述的异喹啉酮类化合物或其立体异构体、可药用盐、溶剂化物或结晶,其特征在于,所述R3选自C3-8环烷氧基、C3-8杂环烷氧基、C1-3烷氧C3-8环烷氧基、C1-3烷氧C3-8环烷基C1-6烷氧基、C3-8杂环烷基、C1-3烷氧C2-9烯基、C1-3烷氧C2-9炔基、C3-8环烷基C2-9烯基、C3-8环烷基C2-9炔基。
10.根据权利要求1所述的异喹啉酮类化合物或其立体异构体、可药用盐、溶剂化物或结晶,其特征在于,所述R2选自C1-3烷氧基、卤素、C3-6环烷基、苄基。
11.根据权利要求1所述的异喹啉酮类化合物或其立体异构体、可药用盐、溶剂化物或结晶,其特征在于,R6选自甲基、乙基、异丙基、丁基、异丁基、甲氧基甲基、甲氧基乙基、甲氧基异丙基、甲氧基丁基、甲氧基异丁基、乙氧基甲基、乙氧基乙基、乙氧基异丙基、乙氧基丁基、乙氧基异丁基、羟基甲基、羟基乙基、羟基异丙基、羟基丁基、羟基异丁基。
12.根据权利要求1所述的异喹啉酮类化合物或其立体异构体、可药用盐、溶剂化物或结晶,其特征在于,除去活泼氢之外,其余所有的氢原子都可以分别独立地被氘取代。
13.根据权利要求1所述的异喹啉酮类化合物或其立体异构体、可药用盐、溶剂化物或结晶,其特征在于,所述的异喹啉酮类化合物选自如下化合物:
14.一种药物组合物,其特征在于:含有如权利要求1至13中任一项权利要求所述的式(I)所示的异喹啉酮类化合物、其立体异构体、可药用盐、溶剂化物或结晶,以及药学上可接受的载体或赋形剂,药物组合物的剂型优选为片剂、胶囊或针剂。
15.根据权利要求14所述的药物组合物,其特征在于:所述药物组合物为抗病毒药物组合物,其中还包含一种或多种治疗剂,所述治疗剂治选自以下组成的群:核苷类药物、利巴韦林、干扰素、HBV衣壳抑制剂(capsid inhibitor)、cccDNA形成抑制剂、cccDNA表观遗传修饰剂或乙肝RNAi药物、TLR7激动剂。
16.如权利要求1至13中任一项权利要求所述的式(I)所示的异喹啉酮类化合物、其立体异构体、可药用盐、溶剂化物或结晶或其与一种或多种选自核苷类药物、利巴韦林、干扰素、HBV衣壳抑制剂(capsid inhibitor)、cccDNA形成抑制剂、cccDNA表观遗传修饰剂或乙肝RNAi药物、TLR7激动剂的治疗剂的组合在制备预防和/或治疗病毒感染疾病药物,和/或乙肝表面抗原抑制剂(HBV Surface antigen inhibitors)和乙肝DNA抑制剂(HBV DNAproduction inhibitors)药物中的应用,所述病毒感染包括HBV或HDV的感染。
17.一种制备权利要求1至13中任一项权利要求所述的式(I)所示的异喹啉酮类化合物、其立体异构体、可药用盐、溶剂化物或结晶的中间体,其特征在于:所述中间体如下式(II)所示:式(II)中,所述R1、R2、R4、R5、R5’、R6、R8、W和N的定义同前述权利要求。
18.根据权利要求17所述的中间体,其特征在于:式(II)所示的中间体为化合物10或其异构体或消旋体
19.一种制备权利要求1至13中任一项权利要求所述的式(I)所示的异喹啉酮类化合物、其立体异构体、可药用盐、溶剂化物或结晶的制备方法,其特征在于:所述方法包括采取如权利要求17或18所述的式(II)所示的中间体,并使式(II)所示的中间体与RAOH、RAOMs或RABr反应,其中,当反应物为RAOH,所述反应采用Mitsunobu反应,在脱水剂为三苯基磷和/或偶氮二甲酸二异丙酯存在下进行;当反应物为RAOMs或RABr,所述反应为SN2反应,在碱为碳酸钾和/或碳酸铯以及催化量KI存在下进行。
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