CN108558842A - 嘧啶衍生物类间变性淋巴瘤激酶抑制剂 - Google Patents
嘧啶衍生物类间变性淋巴瘤激酶抑制剂 Download PDFInfo
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- CN108558842A CN108558842A CN201810442695.7A CN201810442695A CN108558842A CN 108558842 A CN108558842 A CN 108558842A CN 201810442695 A CN201810442695 A CN 201810442695A CN 108558842 A CN108558842 A CN 108558842A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
- C07D491/04—Ortho-condensed systems
- C07D491/056—Ortho-condensed systems with two or more oxygen atoms as ring hetero atoms in the oxygen-containing ring
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
本发明属于医药技术领域，具体涉及通式(Ⅰ)所示的嘧啶衍生物类间变性淋巴瘤激酶抑制剂或其立体异构体、或者其药学上可接受的盐、酯或溶剂化物，其中R1、R2、R3、R4、R5和A环如说明书中所定义。本发明还涉及这些化合物的制备方法，含有这些化合物的药物制剂和药物组合物，以及该化合物或其立体异构体、或者其药学上可接受的盐、酯或溶剂化物在制备治疗和/或预防由间变性淋巴瘤激酶介导的癌症相关疾病的药物中的应用。
Description
本申请是申请日为2014年3月6日、申请号为201410079234.X、发明名称为“嘧啶衍生物类间变性淋巴瘤激酶抑制剂”的申请的分案申请。
技术领域
本发明属于医药技术领域，具体涉及嘧啶衍生物类间变性淋巴瘤激酶抑制剂或其立体异构体、或者其药学上可接受的盐、酯或溶剂化物，这些化合物的制备方法，含有这些化合物的药物制剂和药物组合物，以及该化合物或其立体异构体、或者其药学上可接受的盐、酯或溶剂化物在制备治疗和/或预防由间变性淋巴瘤激酶介导的癌症相关疾病的药物中的应用。
背景技术
间变性淋巴瘤激酶(Anaplastic lymphoma kinase，ALK)是受体酪氨酸激酶家族成员，可通过自身磷酸化募集下游蛋白，进而表达特定的基因，调节细胞代谢和生长。间变性淋巴瘤激酶最早发现于间变性大细胞淋巴瘤(Anaplastic large cell lymphoma，ALCL)中，后来发现在非小细胞肺癌(NSCLC)中亦有高表达。
ALK的小分子抑制剂可以影响肿瘤细胞的生长，起到抗肿瘤的作用，但已有大量临床证明一代ALK抑制剂Crizotinib，容易产生耐药性，因此，设计并筛选对Crizotinib产生耐药的患者也有良好的疗效的二代ALK抑制剂，具有显著的临床意义。
目前已知的ALK抑制剂包括crizotinib(辉瑞公司)、CH5424802(Roche)、LDK378(Novartis)、AZD-3463(AstraZeneca)。
因此，通过化合物结构修饰寻找新的化合物结构，努力改善化合物的理化性质，提高成药性，如提高化合物的生物利用度，来寻找对ALK突变有活性的小分子抑制剂，对于临床上因ALK突变引起的疾病的治疗，具有重要的意义。
发明内容
本发明以开发针对ALK的小分子抑制剂为目标，发明了对治疗和/或预防ALK介导的癌症相关疾病具有良好效果的嘧啶衍生物类间变性淋巴瘤激酶抑制剂。具体的技术方案为如下：
1.通式(Ⅰ)所示的化合物或其立体异构体、或者其药学上可接受的盐、酯或溶剂化物：
其中，
R1选自氢、羟基、氨基、氰基、硝基、卤素原子、C1-6烷基、羟基C1-6烷基、卤代C1-6烷基、C1-6烷氧基、羟基C1-6烷氧基、卤代C1-6烷氧基、C2-8烯基、C2-8炔基、C1-6烷基氨基、(C1-6烷基)2氨基、磺酰基C1-6烷基或3～8元环烷基；
R2和R3分别独立地选自氢、羟基、氨基、氰基、硝基、卤素原子、C1-6烷基、羟基C1-6烷基、氨基C1-6烷基、卤代C1-6烷基、C1-6烷基氨基、C1-6烷基羰基、C1-6烷基硫基、C1-6烷基磺酰氨基、C1-6烷基氨基磺酰基、(C1-6烷基)2氨基磺酰基、C1-6烷基氨基C1-6烷基磺酰基、(C1-6烷基)2氨基C1-6烷基磺酰基、C1-6烷氧基、卤代C1-6烷氧基、C1-6烷氧基C1-6烷氧基、羟基C1-6烷氧基、C2-8烯基、羧基C2-8烯基、羟基C2-8烯基、C2-8炔基、羧基C2-8炔基、羟基C2-8炔基、羧基C2-8炔基或3～8元杂环基，所述的3～8元杂环基可任选被1～3个q1取代，
或者R2和R3连同与之相连的苯环形成苯并3～8元杂环基，所述的3～8元杂环基可任选被1～3个q1取代；
R4选自氢或C1-6烷基；
R5选自氢、羟基、羧基、氨基、氰基、硝基、C1-6烷基、C1-6烷氧基、卤代C1-6烷基、卤代C1-6烷氧基、C2-8烯基、C2-8炔基、C1-6烷基氨基或(C1-6烷基)2氨基；
A环连同与之相连的苯环形成苯并3～8元杂环基，所述的3～8元杂环基可任选被1～3个q1取代；
q1选自羟基、氨基、羧基、氰基、硝基、卤素原子、C1-6烷基、C1-6烷氧基、C1-6烷基氨基、(C1-6烷基)2氨基、卤代C1-6烷基、卤代C1-6烷氧基、C1-6烷氧基C1-6烷基、C2-8烯基、C2-8炔基或3～8元杂环基。
2.如技术方案1所述的化合物或其立体异构体、或者其药学上可接受的盐、酯或溶剂化物，其中，
R1选自氢、羟基、氨基、氰基、硝基、卤素原子、C1-4烷基、羟基C1-4烷基、卤代C1-4烷基、C1-4烷氧基、羟基C1-4烷氧基、卤代C1-4烷氧基、C2-6烯基、C2-6炔基、C1-4烷基氨基、(C1-4烷基)2氨基、磺酰基C1-4烷基或3～6元环烷基；
R2和R3分别独立地选自氢、羟基、氨基、氰基、硝基、卤素原子、C1-4烷基、羟基C1-4烷基、氨基C1-4烷基、卤代C1-4烷基、C1-4烷基氨基、C1-4烷基羰基、C1-4烷基硫基、C1-4烷基磺酰氨基、C1-4烷基氨基磺酰基、(C1-4烷基)2氨基磺酰基、C1-4烷基氨基C1-4烷基磺酰基、(C1-4烷基)2氨基C1-4烷基磺酰基、C1-4烷氧基、卤代C1-4烷氧基、C1-4烷氧基C1-4烷氧基、羟基C1-4烷氧基、C2-6烯基、羧基C2-6烯基、羟基C2-6烯基、C2-6炔基、羧基C2-6炔基、羟基C2-6炔基、羧基C2-6炔基或3～8元杂环基，所述的3～8元杂环基可任选被1～3个q1取代，
或者R2和R3连同与之相连的苯环形成苯并3～8元杂环基，所述的3～8元杂环基可任选被1～2个q1取代；
R4选自氢或C1-4烷基；
R5选自氢、羟基、羧基、氨基、氰基、硝基、C1-4烷基、C1-4烷氧基、卤代C1-4烷基、卤代C1-4烷氧基、C2-6烯基、C2-6炔基、C1-4烷基氨基或(C1-4烷基)2氨基；
A环连同与之相连的苯环形成苯并3～8元杂环基，所述的3～8元杂环基可任选被1～2个q1取代；
q1选自羟基、氨基、羧基、氰基、硝基、卤素原子、C1-4烷基、C1-4烷氧基、C1-4烷基氨基、(C1-4烷基)2氨基、卤代C1-4烷基、卤代C1-4烷氧基、C1-4烷氧基C1-4烷基、C2-6烯基、C2-6炔基或3～6元杂环基。
3.如技术方案2所述的化合物或其立体异构体、或者其药学上可接受的盐、酯或溶剂化物，其中，
R1选自氢、羟基、氰基、卤素原子或C1-4烷基；
R2选自氢或C1-4烷基；
R3选自4～7元杂环基，所述的4～7元杂环基可任选被1～2个q1取代；
A环连同与之相连的苯环形成苯并4～7元杂环基，所述的4～7元杂环基可任选被1～2个q1；
q1选自C1-4烷基。
4.如技术方案3所述的化合物或其立体异构体、或者其药学上可接受的盐、酯或溶剂化物，其中，
R3选自5～6元杂环基；
A环连同与之相连的苯环形成以下基团：
5.如技术方案2所述的化合物或其立体异构体、或者其药学上可接受的盐、酯或溶剂化物，其中，
R1选自氢、羟基、氰基、卤素原子或C1-4烷基；
R2和R3连同与之相连的苯环形成苯并4～7元杂环基，所述的4～7元杂环基可任选被1～2个q1；
R5选自氢或C1-4烷基；
A环连同与之相连的苯环形成苯并4～7元杂环基，所述的4～7元杂环基可任选被1～2个q1；
q1选自C1-4烷基。
6.如技术方案5所述的化合物或其立体异构体、或者其药学上可接受的盐、酯或溶剂化物，其中，
R1选自氢、羟基、氰基、卤素原子或C1-4烷基；
R2和R3连同与之相连的苯环形成苯并5～6元杂环基；
R5选自氢或C1-4烷基；
A环连同与之相连的苯环形成苯并5～6元杂环基。
7.如技术方案6所述的化合物或其立体异构体、或者其药学上可接受的盐、酯或溶剂化物，其中，
R2和R3连同与之相连的苯环形成以下基团：
8.如技术方案7所述的化合物或其立体异构体、或者其药学上可接受的盐、酯或溶剂化物，其中，
A环连同与之相连的苯环形成以下基团：
9.如技术方案1所述的化合物或其立体异构体、或者其药学上可接受的盐、酯或溶剂化物，所述化合物选自：
10.如技术方案1-9任一项所述的化合物或其立体异构体、或者其药学上可接受的盐、酯或溶剂化物与一种或多种药用载体和/或稀释剂的药物组合物，可以制成药学上可接受的任一剂型。
11.如技术方案10所述的药物组合物，其特征在于还可含有一种或多种抗肿瘤剂和免疫抑制剂，所述的抗肿瘤剂和免疫抑制剂选自甲氨蝶呤、卡培他滨、吉西他滨、去氧氟尿苷、培美曲塞二钠、帕唑帕尼、伊马替尼、埃罗替尼、拉帕替尼、吉非替尼、凡德他尼、赫赛汀、贝伐单抗、利妥昔单抗、曲妥珠单抗、紫杉醇、长春瑞滨、多西他赛、多柔比星、羟基喜树碱、丝裂霉素、表柔比星、吡柔比星、博来霉素、来曲唑、他莫西芬、氟维司群、曲谱瑞林、氟他胺、亮丙瑞林、阿那曲唑、异环磷酰胺、白消安、环磷酰胺、卡莫司汀、尼莫司汀、司莫司汀、氮芥、马法兰、瘤可宁、卡铂、顺铂、奥沙利铂、络铂、拓扑特肯、喜树碱、拓扑替康、依维莫司、西罗莫斯、特癌适、6-巯基嘌呤、6-硫鸟嘌呤、硫唑嘌呤、菌素D、柔红霉素、阿霉素、米托蒽醌、争光霉素、普卡霉素或氨鲁米特。
12.如技术方案1-9任一项所述的化合物或其立体异构体、或者其药学上可接受的盐、酯或溶剂化物在制备用于治疗和/或预防ALK介导的增生性疾病或癌症相关疾病的药物中的应用，所述癌症相关的疾病选自脑瘤、非小细胞性肺癌、鳞状上皮细胞癌、膀胱癌、胃癌、卵巢癌、腹膜癌、胰腺癌、乳腺癌、头颈癌、子宫颈癌、子宫内膜癌、直肠癌、肝癌、肝母细胞瘤、乳头状肾细胞瘤、头颈部鳞状细胞瘤、肾母细胞瘤、肾癌、食管腺癌、食管鳞状细胞癌、雌性生殖道癌、原位癌、淋巴瘤、成神经细胞瘤、神经纤维瘤病、甲状腺癌、骨癌、皮肤癌、结肠癌、睾丸癌、小细胞肺癌、胃肠道间质瘤、前列腺肿瘤、肥大细胞肿瘤、多发性骨髓瘤、黑色素瘤或神经胶质瘤。
本发明的部分化合物
发明详述
本发明所述的“卤素原子”包括氟原子、氯原子、溴原子和碘原子等。
本发明所述的“C1-6烷基”表示直链或支链的含有1-6个碳原子的烷基，包括例如“C1-4烷基”、“C1-3烷基”等，具体实例包括但不限于：甲基、乙基、正丙基、异丙基、正丁基、2-甲基丙基、1-甲基丙基、1,1-二甲基乙基、正戊基、3-甲基丁基、2-甲基丁基、1-甲基丁基、1-乙基丙基、正己基、4-甲基戊基、3-甲基戊基、2-甲基戊基、1-甲基戊基、3,3-二甲基丁基、2,2-二甲基丁基、1,1-二甲基丁基、1,2-二甲基丁基、1,3-二甲基丁基、2,3-二甲基丁基、2-乙基丁基、1,2-二甲基丙基等。
本发明所述的“C2-8烯基”是指含有至少一个双键的碳原子数为2-8的直链或支链或环状的烯基，包括例如“C2-6烯基”、“C2-4烯基”、“C2-3烯基”、“C3-6环烯基”等，具体实例包括但不限于：乙烯基、1-丙烯基、2-丙烯基、2-丁烯基、3-丁烯基、2-甲基-1-丙烯基、1-甲基-2-丙烯基、1-戊烯基、2-戊烯基、3-戊烯基、2-甲基-1-丁烯基、3-甲基-1-丁烯基、2-甲基-3-丁烯基、1,1-二甲基-2-丙烯基、1-乙基-2-丙烯基、2-己烯基、3-己烯基、2-甲基-1-戊烯基、3-甲基-1-戊烯基、1-甲基-2-戊烯基、3-甲基-2-戊烯基、2-甲基-3-戊烯基、1-甲基-4-戊烯基、3-甲基-4-戊烯基、1,1-二甲基-3-丁烯基、1,2-二甲基-3-丁烯基、1,3-二甲基-2-丁烯基、2,2-二甲基-3-丁烯基、2,3-二甲基-2-丁烯基、2,3-二甲基-1-丁烯基、2-乙基-1-丁烯基、2-乙基-3-丁烯基、2-庚烯基、3-庚烯基、4-庚烯基、1-辛烯基、3-辛烯基、4-辛烯基、1,3-丁二烯基、2,4-戊二烯基、1,4-己二烯基、2,4-己二烯基、1,5-庚二烯基、2,5-庚二烯基、2,6-辛二烯基、环戊烯基、1,3-环戊二烯基、环己烯基、1,4-环己二烯基、环庚烯基、1,4-环庚二烯基、环辛烯基等。
本发明所述的“C2-8炔基”是指含有三键的碳原子数为2-8的直链或支链的炔基，其中包括例如“C2-6炔基”、“C2-4炔基”、“C2-3炔基”等，具体实例包括但不限于：乙炔基、1-丙炔基、2-丁炔基、1-甲基-2-丙炔基、2-戊炔基、3-戊炔基、1-甲基-2-丁炔基、2-甲基-3-丁炔基、1,1-二甲基-2-丙炔基、1-乙基-2-丙炔基、2-己炔基、3-己炔基、1-甲基-2-戊炔基、1-甲基-3-戊炔基、2-甲基-3-戊炔基、1,1-二甲基-3-丁炔基、2-乙基-3-丁炔基、2-庚炔基、3-庚炔基、4-甲基-2-己炔基、5-甲基-2-己炔基、2-甲基-3-己炔基、5-甲基-3-己炔基、2-甲基-4-己炔基4-甲基-5-己炔基、2-辛炔基、3-辛炔基、4-辛炔基、4-甲基-2-庚炔基、5-甲基-3-庚炔基、6-甲基-3-庚炔基、2-甲基-4-庚炔基、2-甲基-5-庚炔基、3-甲基-6-庚炔基等。
本发明所述的“C1-6烷氧基、C1-6烷基氨基、(C1-6烷基)2氨基、C1-6烷基硫基、C1-6烷基羰基、C1-6烷基磺酰氨基、C1-6烷基氨基磺酰基、(C1-6烷基)2氨基磺酰基、C1-6烷基磺酰基”是指以C1-6烷基-O-、C1-6烷基-NH-、(C1-6烷基)2-N-、C1-6烷基-S-、C1-6烷基-C(O)-、C1-6烷基-SO2NH-、C1-6烷基-NHSO2-、(C1-6烷基)2-NHSO2-、C1-6烷基-SO2-方式形成的基团，其中“C1-6烷基”的定义如前文所述。
本发明所述的“C1-4烷氧基、C1-4烷基氨基、(C1-4烷基)2氨基、C1-4烷基硫基、C1-4烷基羰基、C1-4烷基磺酰氨基、C1-4烷基氨基磺酰基、(C1-4烷基)2氨基磺酰基、C1-4烷基磺酰基”是指以C1-4烷基-O-、C1-4烷基-NH-、(C1-4烷基)2-N-、C1-4烷基-S-、C1-4烷基-C(O)-、C1-4烷基-SO2NH-、C1-4烷基-NHSO2-、(C1-4烷基)2-NHSO2-、C1-4烷基-SO2-方式形成的基团，其中“C1-4烷基”的定义如前文所述。
本发明所述的“卤代C1-6烷基、羟基C1-6烷基、氨基C1-6烷基、磺酰基C1-6烷基、C1-6烷氧基C1-6烷基、羟基C2-8烯基、羧基C2-8烯基、羟基C2-8炔基、羧基C2-8炔基、卤代C1-6烷氧基、羟基C1-6烷氧基、C1-6烷氧基C1-6烷氧基、羟基C1-6烷基氨基”是指一至多个，例如1～4个、1～3个、1～2个卤素原子、羟基、氨基、磺酰基、羧基、C1-6烷氧基分别取代C1-6烷基、C2-8烯基、C2-8炔基、C1-6烷氧基、C1-6烷基氨基中的氢原子所形成的基团。
本发明所述的“卤代C1-4烷基、羟基C1-4烷基、氨基C1-4烷基、磺酰基C1-4烷基、C1-4烷氧基C1-4烷基、羟基C2-6烯基、羧基C2-6烯基、羟基C2-6炔基、羧基C2-6炔基、卤代C1-4烷氧基、羟基C1-4烷基、羟基C1-4烷氧基、C1-4烷氧基C1-4烷氧基、羟基C1-4烷基氨基”是指一至多个，例如1～4个、1～3个、1～2个卤素原子、羟基、氨基、磺酰基、羧基、C1-4烷氧基分别取代C1-4烷基、C2-6烯基、C2-6炔基、C1-4烷氧基、C1-4烷基氨基中的氢原子所形成的基团。
本发明所述的“C1-6烷基氨基C1-6烷基磺酰基、(C1-6烷基)2氨基C1-6烷基磺酰基”是指C1-6烷基氨基或(C1-6烷基)2氨基取代C1-6烷基磺酰基中的氢原子所形成的基团。
“3～8元环烷基”，是指3～8个碳原子的烷烃部分去除一个氢原子衍生的单环环状烷基，包括例如“3～6元环烷基”、“4～6元环烷基”等。其实例包括但不限于：环丙烷基、环丁烷基、环戊烷基、环己烷基、环庚烷基、环辛烷基、甲基环丙烷基、二甲基环丙烷基、甲基环丁烷基、二甲基环丁烷基、甲基环戊烷基、二甲基环戊烷基、甲基环己烷基、二甲基环己烷基等。
本发明所述的“杂原子”是指N、O、C(O)、S、SO和/或SO2等，优选N、O、S，更优选N、O。
“3～8元杂环基”是指含有3～8个环原子、且含有至少一个杂原子(例如1、2、3、4或5个杂原子)的非芳杂环化合物的单环杂环化合物除去一个氢原子得到的基团，包括例如“3～7元杂环基”、“3～6元杂环基”、“4～7元杂环基”、“4～6元杂环基”、“5～6元杂环基”等。具体实例包括但不仅限于：氮杂环丙烷基、2H-氮杂环丙烷基、二氮杂环丙烷基、3H-二氮杂环丙烯基、氮杂环丁烷基、1,4-二氧杂环己烷基、1,3-二氧杂环己烷基、1,3-二氧杂环戊烷基、1,4-二氧杂环己二烯基、四氢呋喃基、二氢吡咯基、吡咯烷基、咪唑烷基、4,5-二氢咪唑基、吡唑烷基、4,5-二氢吡唑基、2,5-二氢噻吩基、四氢噻吩基、4,5-二氢噻唑基、哌啶基、哌嗪基、吗啉基、4,5-二氢噁唑基、4,5-二氢异噁唑基、2,3-二氢异噁唑基、2H-1,2-噁嗪基、6H-1,3-噁嗪基、4H-1,3-噻嗪基、6H-1,3-噻嗪基、2H-吡喃基、2H-吡喃-2-酮基、3,4-二氢-2H-吡喃基等，优选为“5-6元杂环基”。
本发明还提供了上述化合物的两个制备方法，但不仅限于以下方法，反应方程式如下：
中间体8的制备方法参考专利201410072908.3。
步骤1中间体1的制备
分别购买或制备中间体1。
步骤2中间体2的制备
中间体1溶于适当溶剂(例如N,N-二甲基甲酰胺)，加入适量(例如2当量)N-溴代琥珀酰亚胺，加热(例如55℃)搅拌过夜，降温至室温，加水淬灭反应，有机溶剂(例如乙酸乙酯)萃取，浓缩，经适当方法(例如硅胶柱层析)纯化得到中间体2。
步骤3中间体3的制备
将中间体2溶于适当溶剂(例如乙醇)，加入乙酸，(例如70℃下)分批加入还原铁粉，加热(例如80℃)搅拌(例如3小时)，滤除固体，加水淬灭反应，有机溶剂(例如乙酸乙酯)萃取，浓缩，经适当方法(例如硅胶柱层析)纯化得到中间体3。
步骤4中间体4的制备
将中间体3溶于甲苯和乙酸中，室温下加入适量(例如1.5当量)N-碘代琥珀酰亚胺，搅拌(例如2小时)，加水淬灭反应，有机溶剂(例如乙酸乙酯)萃取，浓缩，经适当方法(例如硅胶柱层析)纯化得到中间体4。
步骤5中间体5的制备
将中间体4和R3-硼酸溶于溶剂(例如二氧六环)，加入金属钯催化剂(例如[1,1'-双(二苯基膦)二茂铁]二氯化钯)，加入适量(例如1.5当量)无机碱(例如碳酸钾)，氮气保护下加热(例如80℃)过夜，抽滤，滤液用有机溶剂(例如乙酸乙酯)萃取，合并的有机相经适当方法(例如硅胶柱层析)纯化得到中间体5。
步骤6中间体6的制备
将中间体5溶于适当溶剂(例如甲醇)，加入钯碳(10％)，室温下通入氢气，搅拌过夜，过滤，滤液浓缩得到中间体6。
步骤8中间体8的制备
中间体8的制备方法参考专利201410072908.3。
步骤7中间体7的制备
将中间体6溶于适当溶剂，加入碱(例如钠氢)，室温下加入R4-X，室温或加热搅拌，加水淬灭反应，有机溶剂(例如乙酸乙酯)萃取，浓缩，经适当方法(硅胶柱层析)纯化得到中间体7。
步骤8本发明通式(I)化合物的制备
将中间体7和中间体8溶于溶剂(例如二氧六环)，加入金属钯催化剂(例如[1,1'-双(二苯基膦)二茂铁]二氯化钯)，加入适量(例如1.5当量)无机碱(例如碳酸铯)，氮气保护下加热(例如90℃)过夜，抽滤，滤液用有机溶剂(例如乙酸乙酯)萃取，合并的有机相经适当方法(例如硅胶柱层析)纯化得到本发明通式(I)化合物。
反应方程式中，R1、R2、R3、R4、R5和A环如前文所定义，X代表氟原子、氯原子、溴原子和碘原子。
本发明式(I)化合物的“立体异构体”是指当式(I)化合物存在不对称碳原子时，会产生对映异构体，当化合物存在碳碳双键或环状结构时，会产生顺反异构体，当化合物存在酮或肟时，会产生互变异构体，所有式(I)化合物的对映异构体、非对映异构体、消旋异构体、顺反异构体、互变异构体、几何异构体、差向异构体及其混合物，均包括在本发明范围中。
本发明的通式(I)所示的任一化合物合成得到的若是消旋体，所需要的对映体纯的化合物可以通过手性拆分的方法得到：可以通过具有手性固定相的色谱法(像高压制备液相色谱、超临界流体色谱)。手性填料包括但不限于：Chiralcel OJ-H,Chiralpak AD-H，Chiralpak IA，Chiralpak AS-H。
本发明的通式(I)所示的任一化合物药学上可接受的盐是指由药学上可接受的、非毒性碱或酸制备的盐，包括有机酸盐、无机酸盐、有机碱盐、无机碱盐。
有机酸盐包括甲酸、乙酸、三氟乙酸盐、苯磺酸、苯甲酸、对甲苯磺酸、樟脑磺酸、柠檬酸、甲磺酸、乙磺酸、丙磺酸、富马酸、葡糖酸、谷氨酸、羟乙磺酸、乳酸、马来酸、苹果酸、扁桃酸、粘酸、双羟萘酸、泛酸、琥珀酸、酒石酸等的盐。
无机酸盐包括氢溴酸、氢氯酸、硝酸、硫酸、磷酸等的盐。
有机碱盐包括伯、仲和叔胺，被取代胺包括天然存在的取代胺、环胺和碱离子交换树脂，选自甜菜碱、咖啡因、胆碱、N,N’-二苄基乙二胺、二乙胺、2-二乙胺基乙醇、2-二甲胺基乙醇、乙醇胺、乙二胺、N-乙基-吗啉、N-乙基哌啶、葡甲胺、氨基葡萄糖、海巴明、异丙基胺、甲基葡糖胺、吗啉、哌嗪、哌啶、普鲁卡因、嘌呤、可可碱、三乙胺、三甲胺、三丙胺、氨丁三醇等的盐。天然氨基酸盐如甘氨酸、丙氨酸、缬氨酸、亮氨酸、异亮氨酸、正亮氨酸、酪氨酸、胱氨酸、半胱氨酸、蛋氨酸、脯氨酸、羟基脯氨酸、组氨酸、鸟氨酸、赖氨酸、精氨酸、丝氨酸等的盐。
无机碱盐包括铵以及锂、钠、钾、钙、镁、锌、钡、铝、铁、酮、亚铁、锰、二价锰等的盐。
本发明式(I)化合物的“酯”是指，当式(I)化合物存在羧基时，可以与醇发生酯化反应而形成的酯，当式(I)化合物存在羟基时，可以有机酸、无机酸、有机酸盐等发生酯化反应而形成的酯。酯在酸或者碱存在的条件下，可以发生水解反应生成相应的酸或醇。
通式(Ⅰ)所示的化合物、其药学上可接受的盐、其立体异构体或其酯可以是溶剂化物形式。若溶剂化物是水合物的情况下，水合作用可以在制备过程中完成或者可以利用原始无水产物的吸湿性逐渐进行。
本发明进一步要求保护包括上述的式(I)所示的任一化合物、其药学上可接受的盐、其立体异构体、其酯或其溶剂化物与一种或多种药用载体和/或稀释剂的药物组合物，可以制成药学上可接受的任一剂型。以口服、肠胃外、直肠或经肺给药等方式施用于需要这种治疗的患者。用于口服给药时，可制成常规的固体制剂，如片剂、胶囊剂、丸剂、颗粒剂等；也可制成口服液体制剂，如口服溶液剂、口服混悬剂、糖浆剂等。制成口服制剂时，可以加入适宜的填充剂、粘合剂、崩解剂、润滑剂等。用于肠胃外给药时，可制成注射剂，包括注射液、注射用无菌粉末与注射用浓溶液。制成注射剂时，可采用现有制药领域中的常规方法生产，配制注射剂时，可以不加入附加剂，也可根据药物的性质加入适宜的附加剂。用于直肠给药时，可制成栓剂等。用于经肺给药时，可制成吸入剂或喷雾剂等。
本发明进一步要求保护包括上面所述的式(I)任一化合物、其药学上可接受的盐、其立体异构体、其酯或其溶剂化物与其它一种或多种抗肿瘤剂和免疫抑制剂的药物组合物。所述的抗肿瘤剂和免疫抑制剂，包括但不限于甲氨蝶呤、卡培他滨、吉西他滨、去氧氟尿苷、培美曲塞二钠、帕唑帕尼、伊马替尼、埃罗替尼、拉帕替尼、吉非替尼、凡德他尼、赫赛汀、贝伐单抗、利妥昔单抗、曲妥珠单抗、紫杉醇、长春瑞滨、多西他赛、多柔比星、羟基喜树碱、丝裂霉素、表柔比星、吡柔比星、博来霉素、来曲唑、他莫西芬、氟维司群、曲谱瑞林、氟他胺、亮丙瑞林、阿那曲唑、异环磷酰胺、白消安、环磷酰胺、卡莫司汀、尼莫司汀、司莫司汀、氮芥、马法兰、瘤可宁、卡铂、顺铂、奥沙利铂、络铂、拓扑特肯、喜树碱、拓扑替康、依维莫司、西罗莫斯、特癌适、6-巯基嘌呤、6-硫鸟嘌呤、硫唑嘌呤、菌素D、柔红霉素、阿霉素、米托蒽醌、争光霉素、普卡霉素或氨鲁米特。
本发明还提供了本发明式(I)所示的化合物、其药学上可接受的盐、其立体异构体、其酯或其溶剂化物在制备治疗和/或预防ALK介导的癌症相关疾病的药物中的应用，所述癌症相关的疾病选自脑瘤、非小细胞性肺癌、鳞状上皮细胞癌、膀胱癌、胃癌、卵巢癌、腹膜癌、胰腺癌、乳腺癌、头颈癌、子宫颈癌、子宫内膜癌、直肠癌、肝癌、肝母细胞瘤、乳头状肾细胞瘤、头颈部鳞状细胞瘤、肾母细胞瘤、肾癌、食管腺癌、食管鳞状细胞癌、雌性生殖道癌、原位癌、淋巴瘤、成神经细胞瘤、神经纤维瘤病、甲状腺癌、骨癌、皮肤癌、脑癌、结肠癌、睾丸癌、小细胞肺癌、胃肠道间质瘤、前列腺肿瘤、肥大细胞肿瘤、多发性骨髓瘤、黑色素瘤或神经胶质瘤。
本发明化合物具有以下优点：
(1)本发明式(I)化合物或其立体异构体、或者其药学上可接受的盐、酯或溶剂化物具有优异的ALK抑制活性；
(2)本发明式(I)化合物或其立体异构体、或者其药学上可接受的盐、酯或溶剂化物显示出良好的生物稳定性，作用更持久，生物利用度高；
(3)本发明化合物制备工艺简单，药品纯度高，质量稳定，易于进行大规模工业生产。
以下通过体外酶学抑制活性实验进一步阐述本发明化合物有益效果，但不应将此理解为本发明化合物仅具有下列有益效果。
实验例1本发明化合物的体外酶学活性实验
供试品：本发明化合物1的三氟乙酸盐,其化学名称和制备方法见化合物1三氟乙酸盐的制备实施例。
对照药：LDK378，自制(参考专利WO2008/073687A2制备方法制备)。
下述中实验的缩写所代表的含义如下：
DMSO：二甲基亚砜
DTT：二硫苏糖醇
SEB：酶催化剂缓冲溶液
ATP：腺嘌呤核苷三磷酸
ALK：间变性淋巴瘤激酶
SA-XL665：链霉亲和素标记的供体
2.5×、5×、10×其中的“×”：倍
实验方法：
ALK激酶缓冲液配制：
分别取20μL母液浓度为1000mM的MgCl2、40μL母液浓度为2500nM的SEB、40μL母液浓度为100mM的DTT、800μL的5×酶缓冲液，加入到3100μL的超纯水中，混匀。
2.5×供试品溶液配制：
对照药的1mM储备液配制：称取对照药1.48mg，加入适量DMSO溶解，混匀，备用。
化合物1的1mM储备液配制：称取化合物1三氟乙酸盐1.54mg，加入适量DMSO溶解，混匀，备用。
分别取1mM储备液，用DMSO稀释制成浓度为200μM的溶液，作为母液。用DMSO将上述母液三倍逐级稀释制成一系列浓度的溶液，然后每个浓度分别用ALK激酶缓冲液稀释80倍，制成各2.5×供试品溶液，浓度分别为：2500nM、833.33nM、277.78nM、92.59nM、30.86nM、10.29nM、3.43nM、1.14nM、0.38nM、0.13nM、0.04nM。
各种其他试剂配制：
用ALK激酶缓冲液分别配制所需要的5×ALK激酶溶液、5×底物溶液、5×ATP溶液，备用。
ALK酶学反应：
1)384孔板中相对应的孔中分别加入4μL配制好的2.5×供试品溶液、2μL配制好的5×ALK激酶溶液，25℃孵育10分钟。
2)相对应的孔中再分别加入2μL配制好的5×底物溶液和2μL配制好的5×ATP溶液，启动酶反应，25℃孵育30分钟。
酶学检测：
用检测缓冲液(detection buffer)配制所需浓度的SA-XL665，然后和等体积的酪氨酸激酶抗体混匀，相对应的孔中分别加入10μL配制好的此抗体溶液，终止反应。25℃孵育1h。
酶标仪665nm/615nm读板。
IC50：计算抑制率(％)＝(最大值－样本比值)/(最大值－最小值)×100，采用Graph prisim软件进行曲线拟合，得出IC50值。
最大值：不加化合物的阳性对照，最小值：不加酶的阴性对照。
实验结果和结论：
表1.本发明化合物的体外酶学抑制活性
由表1可见，与对照药相比，本发明化合物对ALK激酶具有更好的抑制活性，可用于治疗与激酶相关的疾病，特别是ALK激酶介导的病症或病况，具有显著的临床意义。
实验例2本发明化合物的体外细胞活性实验
供试品：本发明化合物1的三氟乙酸盐,其化学名称和制备方法见化合物1的三氟乙酸盐的制备实施例。
对照药1LDK-378，自制(参考专利WO2008/073687A2制备方法制备)，其结构式如背景技术所述。
对照药2CH5424802，自制(参考专利CN102459172A制备方法制备)，其结构式如背景技术所述。
下述中实验的缩写所代表的含义如下：
rpm：转每分钟
DMSO：二甲基亚砜
MTS：溴化噻唑蓝四氮唑
RPMI1640：1640培养基(RPMI:Roswell Park Memorial Institute)
500×、1000×、10×其中的“×”：倍
实验方法：
(一)NCI-H3122、Karpas-299细胞：
(1)细胞制备：
用含10％胎牛血清、100U/ml青霉素、100mg/ml链霉素的RPMI-1640培养基，在5％CO2、37℃条件的培养箱中，培养细胞至80％融合，备用。
(2)接种细胞：
用胰酶消化细胞，1000rpm离心4min，去除上清液，用含2.5％胎牛血清的RPMI-1640培养基重新混悬，调整细胞密度，取该细胞混悬液90μL接种到96孔板中，获得最终细胞密度为3000个/孔；然后在5％CO2、37℃培养箱中培养24h。
(3)加入供试品：
(3.1)供试品溶液配制
对照药1溶液：称取对照药3.02mg，加入适量DMSO溶解并分别用DMSO梯度稀释制成一系列浓度的母液(1000×对照药溶液)，再分别用培养基稀释该母液100倍得到10×对照药溶液，分别取该溶液10μL，加入到96孔板相应的孔中，得到对照药溶液最终浓度为：10μM、2.5μM、625nM、156nM、39nM、9.8nM、2.5nM。
化合物1溶液：称取化合物1的三氟乙酸盐2.09mg，加入适量DMSO溶解并分别用DMSO梯度稀释制成一系列浓度的母液(1000×化合物1溶液)，再分别用培养基稀释该母液100倍得到10×化合物1溶液，分别取该溶液10μL，加入到96孔板相应的孔中，得到化合物1溶液最终浓度为：10μM、2.5μM、625nM、156nM、39nM、9.8nM、2.5nM。
(3.2)对照孔设置：
溶媒对照：0.1％DMSO。
培养基对照：只接种细胞，不加化合物。
空白对照：培养基，仪器调零。
(3.3)将96孔板放37℃、5％CO2培养箱中培养72h。
(4)检测:
MTS检测方法：
①将CellTiter单溶液96孔细胞增殖检测试剂盒室温放置90min。
②向96孔板的每个试验孔中加入CellTiterAQueous单溶液试剂20μL。
③将96孔板放5％CO2、37℃培养箱中培养40min。
④设置酶标仪检测波长490nm，读取结果。
(5)IC50计算：细胞存活率(％)＝(样本值－空白值)/(最大值－空白值)×100，采用Graph prisim软件进行曲线拟合，得出IC50值。
最大值：不加化合物只加溶媒的的细胞对照，空白值：空白对照值。
(二)NCI-H2228细胞：
(1)细胞制备：
用含10％胎牛血清的RPMI-1640培养基，在5％CO2、37℃条件的培养箱中，培养细胞至80％融合，备用。(2)接种细胞：
用胰酶消化细胞，1000rpm离心4min，去除上清液，用含2.5％胎牛血清的RPMI-1640培养基重新混悬，调整细胞密度2×104个/mL，取该细胞混悬液100μL接种到96孔板中，获得最终细胞密度为：2000个细胞/孔。
(3)加入供试品：
(3.1)供试品溶液配制：
化合物1溶液配制：称取化合物1的三氟乙酸盐2.01mg，加入适量DMSO，溶解，混匀，将溶液用DMSO梯度稀释，得到一系列浓度的溶液，备用。
对照药2溶液配制：称取对照药3.21mg，加入适量DMSO，溶解，混匀，将溶液用DMSO梯度稀释，得到一系列浓度的溶液，备用。
接种细胞6h后，取99μL完全培养基分别加入到96孔板每一孔中，然后取上述配制好的不同浓度的溶液1μL加入到对应的孔中，使得化合物1的最终浓度为：10000nM、2500nM、625nM、156.25nM、39.06nM、9.77nM、2.44nM、0.61nM、0.15nM。对照药的最终浓度为：9800nM、2450nM、612.5nM、153.1nM、38.28nM、9.57nM、2.39nM、0.60nM、0.15nM。
(3.2)对照孔设置：
溶媒对照：0.5％DMSO。
培养基对照：只接种细胞，不加化合物。
空白对照：培养基，仪器调零。
(3.3)将此96孔板放5％CO2、37℃条件的培养箱中培养96h。
(4)检测：
CTG检测方法：
①将96孔板每孔中培养基移除80μL，室温平衡30min。
②向96孔板的每个试验孔中加入试剂60μL。
③96孔板用微孔板振荡器避光振荡混匀2min，使细胞裂解。
④将96孔板避光室温孵育10min，使产生的光信号值稳定。
⑤酶标仪在luminescence模式下读取结果。
(5)结果处理：
IC50计算：细胞抑制率(％)＝(OD溶媒－OD化合物)/(OD溶媒－ODpositive)×100，采用Graphprisim软件进行曲线拟合，得出IC50值。
OD溶媒：不加化合物只加溶媒的的细胞对照，ODpositive：加入1000nM紫杉醇的细胞对照。
实验结果和结论：
表2.本发明化合物的细胞抑制活性
由表2可见，与对照药相比，本发明化合物对细胞NCI-H3122、Karpas-299和NCI-H2228均具有更好的抑制活性，可用于治疗ALK激酶介导的病症或病况，具有显著的临床意义。
具体实施方式
以下通过实施例形式的具体实施方式，对本发明的上述内容作进一步的详细说明。但不应将此理解为本发明上述主题的范围仅限于以下实施例。凡基于本发明上述内容所实现的技术均属于本发明的范围。
下述缩写所代表的定义如下：
DMF：N,N-二甲基甲酰胺
NBS：N-溴代丁二酰亚胺
实施例15-氯-4-(1H-吲哚-3-基)-N-(7-甲基-8-(哌啶-4-基)-2,3-二氢苯并[b]
[1,4]二噁英-5-基)嘧啶-2-胺(化合物1)三氟乙酸盐的制备
(1)2-甲氧基-4-甲基-6-硝基苯酚的制备
氮气保护下，将2-甲氧基-4-甲基苯酚(11g,79.62mmol)溶于氯仿(200mL)，冰浴条件下，滴加发烟硝酸的乙酸溶液(31mL,79.62mmol)，冰浴条件下搅拌2分钟，反应液浓缩，再用甲醇重结晶，得到产物(7g,产率48％)。
(2)5-甲基-3-硝基-1,2-苯二酚的制备
氮气保护下，将2-甲氧基-4-甲基-6-硝基苯酚(4.5g,24.57mmol)溶于HBr溶液(48％)(80mL)，加入催化剂甲基三辛基氯化铵(4.5g,11.13mmol)，反应液于110℃搅拌4小时，LC-MS显示反应完全，冷却至室温，加水淬灭，乙酸乙酯萃取(3×100mL)，取有机相用饱和氯化钠水溶液洗涤(3×300mL)，无水硫酸钠干燥，减压浓缩得到粗产物(3g,产率72％)。
(3)7-甲基-5-硝基-2,3-二氢苯并[b][1,4]二噁英的制备
氮气保护下，将5-甲基-3-硝基-1,2-苯二酚(4.5g,26.61mmol)溶于DMF(180mL)，1,2-二溴乙烷(10g,53.23mmol)和碳酸钾(11g,79.59mmol)加入三口瓶中，55℃搅拌过夜，冷却至室温，搅拌过夜，LC-MS显示反应完全，冷却至室温，加水淬灭，乙酸乙酯萃取(3×200mL)，取有机相用饱和氯化钠水溶液洗涤(3×300mL)，无水硫酸钠干燥，减压浓缩，剩余物用硅胶柱层析纯化(乙酸乙酯：石油醚＝1:5)得到产物(4g,产率77％)。
(4)6-溴-7-甲基-5-硝基-2,3-二氢苯并[b][1,4]二噁英的制备的制备
氮气保护下，将7-甲基-5-硝基-2,3-二氢苯并[b][1,4]二噁英(4g,20.49mmol)溶于N,N-二甲基甲酰胺(160mL)，加入NBS(7.3g,41.02mmol)，55℃搅拌过夜，冷却至室温，加水淬灭，乙酸乙酯萃取(3×200mL)，取有机相用饱和氯化钠水溶液洗涤(3×300mL)，无水硫酸钠干燥，减压浓缩后，剩余物经硅胶柱层析纯化(乙酸乙酯：石油醚＝1:5)得到产物(3.5g,产率62％)。
(5)6-溴-7-甲基-2,3-二氢苯并[b][1,4]二噁英-5-胺的制备
氮气保护下，将6-溴-7-甲基-5-硝基-2,3-二氢苯并[b][1,4]二噁英(3.5g,12.77mmol)溶于乙醇(70mL)，加入乙酸(14mL)，70℃下分批加入还原铁粉(10.8g,192.3mmol)后，80℃搅拌3小时，滤除固体，滤液加水淬灭反应，乙酸乙酯萃取(2×200mL)，取有机相用饱和氯化钠水溶液洗涤(3×300mL)，无水硫酸钠干燥，减压浓缩后，剩余物经硅胶柱层析纯化(乙酸乙酯：石油醚＝1:2)得到产物(2.0g,产率64％)。
(6)6-溴-8-碘-7-甲基-2,3-二氢苯并[b][1,4]二噁英-5-胺的制备
氮气保护下，将6-溴-7-甲基-2,3-二氢-1,4-苯并[b][1,4]二噁英-5-胺(2g,8.19mmol)溶于甲苯(20mL)和乙酸(0.5mL)中，室温下，加入NIS(2.8g,12.45mmol)，室温搅拌2小时，加水淬灭，乙酸乙酯萃取(3×200mL)，有机相依次用亚硫酸氢钠(2×200mL)、饱和氯化钠水溶液(3×300mL)洗涤，无水硫酸钠干燥，减压浓缩后，剩余物经硅胶柱层析(乙酸乙酯：石油醚＝1:2)纯化得到产物(1.6g,产率53％)。
(7)叔丁基4-(8-氨基-7-溴-6-甲基-2,3-二氢苯并[b][1,4]二噁英-5-基)-5,6-二氢吡啶-1(2H)-甲酸酯的制备
氮气保护下，将6-溴-8-碘-7-甲基-2,3-二氢苯并[b][1,4]二噁英-5-胺(1.6g,4.32mmol)溶于1,4-二氧六环(30mL)中，再加入溶有叔丁酯4-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼-2-基)-5,6-二氢吡啶-1(2H)-甲酸酯(1.2g,3.88mmol)的水(6mL)溶液中，加入[1,1'-二(二苯膦基)二茂铁]二氯化钯(II)(640mg,0.87mmol)和碳酸钾(1.8g,13.02mmol)，83℃反应2小时，冷却至室温，加水淬灭，二氯甲烷萃取(3×100mL)，有机相浓缩后，剩余物经硅胶柱层析纯化(乙酸乙酯：石油醚＝1:5)得到产物(900mg,产率55％)。
(8)叔丁基4-(8-氨基-6-甲基-2,3-二氢苯并[b][1,4]二噁英-5基)-哌啶-1-甲酸酯的制备
氮气保护下，将叔丁基4-(8-氨基-7-溴-6-甲基-2,3-二氢苯并[b][1,4]二噁英-5-基)-5,6-二氢吡啶-1(2H)-甲酸酯(900mg,2.12mmol)溶于甲醇(30mL)，再加入钯碳(1g)，通入氢气，室温搅拌过夜，滤除固体，滤液减压浓缩得到产物(300mg,产率41％)。
(9)叔丁基3-(2-((8-(1-(叔丁氧羰基)哌啶-4-基)-7-甲基-2,3-二氢苯并[b][1,4]二噁英-5-基)氨基)-5-氯嘧啶-4-基)-1H-吲哚-1-甲酸酯的制备
将叔丁基4-(8-氨基-6-甲基-2,3-二氢苯并[b][1,4]二噁英-5-基)-哌啶-1-甲酸酯(80mg,0.23mmol)溶于1,4-二氧六环(2mL)，加入叔丁基3-(2,5-二氯嘧啶-4-基)-1H-吲哚-1-甲酸酯(100mg,0.27mmol，其制备方法参考专利CN201410072908.3)、[1,1'-二(二苯膦基)二茂铁]二氯化钯(II)(50mg,0.06mmol)和碳酸铯(300mg,0.92mmol)氮气保护下90℃搅拌2小时，冷却时室温，滤除固体，滤液浓缩，剩余物经制备高效液相纯化得到产物(30mg,产率19％)。
(10)5-氯-4-(1H-吲哚-3-基)-N-(7-甲基-8-(哌啶-4-基)-2,3-二氢苯并[b][1,4]二噁英-5-基)嘧啶-2-胺三氟乙酸盐的制备
将叔丁基2-(2-((8-(1-(叔丁氧羰基)哌啶-4-基)-7-甲基-2,3-二氢苯并[b][1,4]二噁英-5-基)氨基)-5-氯嘧啶-4-基)-1H-吲哚-1-甲酸酯(30mg,0.04mmol)溶于二氯甲烷(10mL)，加入三氟乙酸(3mL)，室温搅拌3小时，浓缩后，剩余物经制备高效液相得到标题化合物(19.3mg,产率74％)。
分子式：C28H27ClF3N5O4 分子量：590.00 LC-MS(m/z):476(M+H+)
1H-NMR(300MHz,CD3OD)δ:8.51(s,1H),8.46-8.49(d,1H,J＝7.8Hz),8.34(s,1H),7.69(s,1H),7.47-7.49(d,1H,J＝8.1Hz),7.20-7.25(m,1H),7.07-7.13(m,1H),4.30-4.33(m,4H),3.51-3.56(m,2H),3.08-3.18(m,3H),2.66-2.73(m,2H),2.29(s,3H),1.84-1.88(m,2H).
Claims (7)
1.通式(Ⅱ)、(Ⅲ)、(Ⅳ)、(Ⅴ)、(Ⅵ)、(Ⅶ)所示的化合物、其立体异构体或其药学上可接受的盐、酯或溶剂化物，
其中，
R2选自氢或C1-4烷基；
R3选自4～7元杂环基，所述的4～7元杂环基可任选被1～2个q1取代；
R4选自氢或C1-4烷基；
A环连同与之相连的苯环形成以下结构：
q1选自C1-4烷基；
X代表卤素原子。
2.如权利要求1所述的化合物，分别具有如下(Ⅱ)-1、(Ⅲ)-1、(Ⅳ)-1、(Ⅴ)-1、(Ⅵ)-1、(Ⅶ)-1所示的结构，
3.如权利要求1或2所述化合物的制备方法，其特征在于，
由化合物制备得到化合物(Ⅶ)-1。
4.如权利要求3所述的制备方法，其特征在于，
由化合物制备得到化合物(Ⅵ)-1。
5.如权利要求4所述的制备方法，其特征在于，
由化合物制备得到化合物(Ⅴ)-1。
6.如权利要求5所述的制备方法，其特征在于，
由化合物制备得到化合物(Ⅳ)-1。
7.如权利要求6所述的制备方法，其特征在于，
由化合物制备得到化合物(Ⅲ)-1。
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