CN113574057A - 杂芳基衍生物及包含其作为活性成分的药物组合物 - Google Patents
杂芳基衍生物及包含其作为活性成分的药物组合物 Download PDFInfo
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- CN113574057A CN113574057A CN202080020325.XA CN202080020325A CN113574057A CN 113574057 A CN113574057 A CN 113574057A CN 202080020325 A CN202080020325 A CN 202080020325A CN 113574057 A CN113574057 A CN 113574057A
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Classifications
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- C—CHEMISTRY; METALLURGY
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
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- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
- A23L29/00—Foods or foodstuffs containing additives; Preparation or treatment thereof
- A23L29/03—Organic compounds
- A23L29/045—Organic compounds containing nitrogen as heteroatom
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- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
- A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
- A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
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- 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
- A61K31/4353—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 ortho- or peri-condensed with heterocyclic ring systems
- A61K31/437—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 ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
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- A—HUMAN NECESSITIES
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- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
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- A—HUMAN NECESSITIES
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
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- C—CHEMISTRY; METALLURGY
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- C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
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- C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
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Abstract
本发明涉及一种杂芳基衍生物和一种包含其作为活性成分的用于预防或治疗癌症的药物组合物,以及根据本发明一个方面的化合物、其立体异构体、其水合物或其药学上可接受的盐抑制激酶,特别是TTK激酶,从而可显著抑制癌细胞的增殖,并因此,可有效地用作预防或治疗癌症的药物组合物。
Description
技术领域
本发明涉及杂芳基衍生物和包含其作为活性成分的用于预防或治疗癌症的药物组合物。
背景技术
在用于癌症治疗的治疗剂中,有紫杉烷类和长春花生物碱作用于微管以稳定或破坏微管的作用。它们干扰正常有丝分裂纺锤体的作用,以防止染色体正确附着并诱导有丝分裂停滞。这种停滞是由纺锤体组装检查点强制执行的,并防止姐妹染色单体分离形成两个子细胞。长时间的有丝分裂停滞迫使细胞在没有任何胞质分裂的情况下退出有丝分裂,或驱使细胞进入有丝分裂灾难,从而导致细胞凋亡。尽管有丝分裂诱导剂已被广泛用于治疗实体瘤,但由于这类制剂的副作用和许多类型的肿瘤对现有治疗方法的抗性,有必要开发一种新的药物组合物来治疗癌症。在正常发育过程中参与纺锤体组装检查点的基因的作用,以及该基因在癌症等疾病中的潜在作用已被广泛研究。许多成分在有丝分裂过程中被磷酸化。在这些成分中,有一些激酶。在这种情况下,其中一种激酶是一种双特异性激酶(即酪氨酸苏氨酸激酶(TTK))。
TTK表达与高度增殖的细胞和组织有关,因为在许多癌细胞系和肿瘤类型中观察到TTK被过度表达。在某些物种中,TTK的沉默可防止细胞因纺锤体毒素而发生有丝分裂停滞,这表明TTK在纺锤体组装信号传导中的基本功能。
同时,Mps-1(TTK)是一种双特异性的Ser/Thr激酶,在有丝分裂检查点(也称为“纺锤体检查点”或“纺锤体组装检查点”)的激活中发挥重要作用,从而确保有丝分裂期间染色体的正确分离(Abrieu A等人,Cell,2001,106,83-93)。每个分裂细胞都必须确保复制的染色体平等地分离到两个子细胞中。进入有丝分裂后,染色体在其动粒处与纺锤体的微管相连。有丝分裂检查点是一种监视机制,只要有未连接的动粒存在,它就会活跃,并防止有丝分裂细胞进入后期,从而完成带有未连接染色体的细胞分裂。一旦所有动粒都以正确的两性(即双极)方式与有丝分裂纺锤体连接,检查点得到满足,细胞进入后期,有丝分裂继续进行。有丝分裂检查点由许多必须蛋白的复杂网络组成,包括MAD(有丝分裂停滞缺陷,MAD 1-3)和Bub(发育不受苯并咪唑抑制,Bub 1-3)家族的成员、马达蛋白CENP-E、Mps-1激酶以及其他成分,其中许多在增殖细胞(例如癌细胞)和组织中过度表达。
因此,通过药物抑制Mps-1激酶或有丝分裂检查点的其他成分来消除有丝分裂检查点,提示了一种治疗增殖性疾病的新方法,包括实体瘤,如癌和肉瘤以及白血病和淋巴性恶性肿瘤,或其他与不受控制的细胞增殖有关的疾病。
发明内容
[技术问题]
根据本发明的一方面,本发明旨在提供一种化合物,其表现出激酶抑制作用,特别是TTK激酶抑制作用,并且因此可用于预防或治疗激酶相关疾病或癌症,或其立体异构体、水合物或其药学上可接受的盐。
根据本发明的另一方面,本发明旨在提供一种预防或治疗激酶相关疾病的药物组合物,其含有所述化合物,或其立体异构体,其水合物,或其药学上可接受的盐作为活性成分。
根据本发明的又一方面,本发明旨在提供一种用于预防或治疗癌症的药物组合物,其含有所述化合物或其立体异构体、其水合物或其药学上可接受的盐作为活性成分。
根据本发明的又一方面,本发明旨在提供一种治疗癌症的方法,其包括将所述化合物或其立体异构体、其水合物或其药学上可接受的盐施用于有需要的个体或受试者。
根据本发明的又一方面,本发明旨在提供用于治疗癌症的化合物、或其立体异构体、其水合物或其药学上可接受的盐。
根据本发明的又一方面,本发明旨在提供所述化合物或其立体异构体、其水合物或其药学上可接受的盐用于在制备治疗癌症的药物中的用途。
[技术方案]
根据本发明的一个方面,提供了一种由下式1代表的化合物,或其立体异构体,其水合物,或其药学上可接受的盐:
[式1]
(其中
X是CH或N;
R1是-H、卤素、氰基或卤代烷基;
R2是C3-10环烷基、C3-10环烯基、-NHA1或-OA2;其中A1是C1-10直链或支链烷基、C3-10环烷基,或包含一个或多个选自由N、O和S组成的组的杂原子的3至9元杂环烷基,其中所述烷基、环烷基和杂环烷基各自独立地未被取代或被一个或多个选自由如下组成的组的非氢取代基取代:卤素、C1-5直链或支链烷基、C3-10环烷基、C1-4直链或支链烷基磺酰基、C1-4烷基氨基磺酰基和C1-5直链或支链烷氧基;并且A2是C3-10环烷基,其中所述环烷基未被取代或被一个或多个选自C1-3直链或支链烷基和羟基的非氢取代基取代,
R3是-H、C1-6直链或支链烷氧基或丙烯酰胺,其中所述C1-6直链或支链烷氧基未被取代或被卤代烷基取代,并且R4是-H或C1-6直链或支链烷氧基,或
R3和R4与包含它们所键合的碳原子的苯环一起形成包含一个或多个选自由N、O和S组成的组的杂原子的9-至10-元双环,
R5是-H、C1-6烷基氨基羰基、未取代或取代的苯基、氧代噁唑烷基、二氧化噻唑烷基、氧代吡咯烷基、二氧化噻嗪基、氧代吗啉基或选自由吡唑基、三唑基、噻唑基、噁唑基、吡啶基和咪唑基组成的组的杂芳基,其中所述杂芳基可以未被取代或被一个或多个选自下组的非氢取代基取代:C1-5烷基、卤素和包含一个或多个选自由N、O和S组成的组的杂原子的3至7元杂环烷基,或可与C3-10环烷基稠合形成双环,并且所述取代苯基被羟基取代,或依次被C1-5烷基、包含一个或多个选自由N、O和S组成的组中的杂原子的3至7元杂环烷基和C3-10环烷基或烷基羰基取代;
R6是-H、卤素或C1-10直链或支链烷基。
根据本发明的另一方面,提供了一种用于预防或治疗与一种或多种蛋白激酶相关的疾病的药物组合物,所述蛋白激酶选自由如下组成的组:TTK、JAK2、SNARK、YSK4、PRKCE、CAMKK1、JNK3、TYK2、RSK2、CAMKK2、ULK3、ULK1、RSK4、TRKB、AAK1、GAK、SBK1、TYK2、CAMK2D、MAP3K2、KIT、FLT3、LRRK2、CSNK1D、CSNK1E、MEK4、RIOK1、DYRK1B、JPKN2、JRRK2、LNK2、LPK3、FLT3、JNK2、RIPK5、MEK3、ABL1、MAPKAPK2、GRK4和SRPK3,所述药物组合物含有所述化合物或其立体异构体、其水合物或其药学上可接受的盐作为活性成分。
根据本发明的另一方面,提供了一种用于预防或治疗癌症的药物组合物,其含有所述化合物或其立体异构体、其水合物或其药学上可接受的盐作为活性成分。
根据本发明的又一方面,提供了一种治疗癌症的方法,其包括将所述化合物或其立体异构体、其水合物或其药学上可接受的盐施用于有需要的个体或受试者。
根据本发明的又一方面,提供了用于治疗癌症的化合物或其立体异构体、其水合物或其药学上可接受的盐。
根据本发明的又一方面,提供了所述化合物或其立体异构体、其水合物或其药学上可接受的盐用于在制备治疗癌症的药物中的用途。
[有益效果]
根据本发明的一个方面提供的化合物或其立体异构体、其水合物或其药学上可接受的盐可以抑制激酶(特别是TTK激酶)以显着抑制癌细胞的增殖,因此可以有效地用作用于预防或治疗癌症的药物组合物。
[最佳实施方式]
在下文中,将详细描述本发明。
同时,应当理解,本发明的示例性实施方案可以以各种形式实施,并且不旨在限制本发明的范围。此外,提供本发明的示例性实施方案是为了向本领域的普通技术人员更完整地描述本发明。在本发明的整个说明书中,当一个要素被称为“包括”另一要素时,这也意味着其还可以包括其他要素,除非另有特别说明,否则不排除其他要素。
在本说明书中,术语“卤素”可以是氟、氯、溴或碘。
在本说明书中,术语“卤代烷基”可以指具有被一个或多个卤原子取代的碳原子的直链或支链烷基(烃)。卤代烷基的实施例包括甲基、乙基、丙基、异丙基、异丁基和N-丁基,它们独立地被一个或多个卤原子取代,例如F、Cl、Br和I,但本发明不限于此。
在本说明书中,术语“烷基”可以指由碳原子组成的直链或支链的无环饱和烃。代表性的-(C1-8烷基)包括-甲基、-乙基、-N-丙基、-N-丁基、-N-戊基、-N-己基、-N-庚基和-N-辛基;支链饱和烷基可包括-异丙基、-仲丁基、-异丁基、-叔丁基、-异戊基、2-甲基戊基、3-甲基戊基、4-甲基戊基、2,3-二甲基丁基等。-(C1-8烷基)也可以是取代的或未取代的。例如,C1-8烷基可以被苯基取代以形成苄基。
在本说明书中,术语“环烷基”可以指非芳族的、饱和的或不饱和的碳环。代表性的环烷基包括环丙基、环丁基、环戊基、环戊二烯基、环己基、环己烯基、1,3-环己二烯基、1,4-环己二烯基、环庚基、1,3-环庚二烯基、1,3,5-环庚三烯基、和环丁二烯基,但本发明不限于此。环烷基可以被取代或未被取代。根据一个实施方案,该环烷基可以是C3-8环烷基。C7以上的环烷基可以具有两个以上的环状结构,C7以上的环烷基的一个具体实施例可以是双环烷基。更具体地,双环庚烷可用于本发明。
在本说明书中,术语“芳基”可以指通过从芳烃环上去除一个氢原子而衍生的任何官能团或取代基。芳基可以是单环芳基或多环芳基。芳基可具有5个以上且30个以下、5个以上且20个以下、或5个以上且15个以下的成环碳原子。芳基的实例可包括苯基、萘基、芴基、蒽基、菲基、联苯基、三联苯基、四联苯基、五联苯基、六联苯基、三亚苯基、芘基、苯并荧蒽基、苯并菲基等,但本发明不限于此。
在本说明书中,术语“杂芳基”可以指包含选自O、N、P、Si和S中的一种或多种作为杂原子的芳环基团。杂芳基可具有2个以上且30个以下、或2个以上且20个以下的成环碳原子。杂芳基可以是单环杂芳基或多环杂芳基。例如,多环杂芳基可以具有双环或三环结构。杂芳基的实例可包括噻吩基、噻吩、呋喃基、吡咯基、吡唑基、咪唑基、噻唑基、噁唑基、异噻唑基、噁二唑基、三唑基、吡啶基、联吡啶基、嘧啶基、三嗪基、三唑基、丙烯基、哒嗪基、吡嗪基、喹啉基、喹唑啉、喹喔啉基、苯噁唑基、酞嗪基、嘧啶基、吡啶并嘧啶基、吡啶并吡嗪基、吡嗪并吡嗪基、异喹啉、吲哚、咔唑、咪唑并哒嗪基、咪唑并吡啶基、咪唑并嘧啶基、吡唑并嘧啶基、咪唑并吡嗪基或吡唑并吡啶基、N-芳基咔唑、N-杂芳基咔唑、N-烷基咔唑基、苯并噁唑、苯并咪唑、苯并噻唑、苯并咔唑、苯并噻吩、二苯并噻吩基、噻吩并噻吩、苯并呋喃基、菲咯啉、异噁唑基、噁二唑基、噻二唑基、苯并噻唑基、四唑基、吩噻嗪基、二苯甲硅烷基、二苯并呋喃基等,但本发明不限于此。根据本发明的一个实施方案,所述杂芳基还可包括双环杂环芳基,其包括稠合至杂环烷基环的芳环或稠合至环烷基环的杂芳基。
上述同质或异质取代基中的一个或多个可以在相同或不同的位置被取代,也可以依次被取代。表述“依次”是指在式中一个残基被一个取代基取代,然后该取代基被另一个取代基连续取代。例如,当一个残基被烷基取代时,该烷基被环烷基取代,并且环烷基依次被羰基取代,可命名为“羰基环烷基烷基”,表示该残基依次被所述取代基取代。
本发明一方面提供了由下式1表示的化合物或其立体异构体、其水合物或其药学上可接受的盐:
[式1]
(其中
X是CH或N;
R1是-H、卤素、氰基或卤代烷基;
R2是C3-10环烷基、C3-10环烯基、-NHA1或-OA2;
其中A1是C1-10直链或支链烷基、C3-10环烷基,或包含一个或多个选自由N、O和S组成的组的杂原子的3-至9-元杂环烷基,其中所述烷基、环烷基和杂环烷基各自独立地未被取代或被一个或多个选自由如下组成的组的非氢取代基取代:卤素、C1-5直链或支链烷基、C3-10环烷基、C1-4直链或支链烷基磺酰基、C1-4烷基氨基磺酰基和C1-5直链或支链烷氧基,
A2是C3-10环烷基,其中所述环烷基未被取代或被一个或多个选自C1-3直链或支链烷基和羟基的非氢取代基取代;
R3是-H、C1-6直链或支链烷氧基或丙烯酰胺,其中所述C1-6直链或支链烷氧基未被取代或被卤代烷基取代,并且R4是-H或C1-6直链或支链烷氧基,或
R3和R4与包含它们所键合的碳原子的苯环一起形成包含一个或多个选自由N、O和S组成的组的杂原子的9-至10-元双环;
R5是-H、C1-6烷基氨基羰基、未取代或取代的苯基、氧代噁唑烷基、二氧化噻唑烷基、氧代吡咯烷基、二氧化噻嗪基、氧代吗啉基或选自由吡唑基、三唑基、噻唑基、噁唑基、吡啶基和咪唑基组成的组的杂芳基,其中所述杂芳基可以未被取代或被一个或多个选自由如下组成的组的非氢取代基取代:C1-5烷基、卤素和包含一个或多个选自由N、O和S组成的组的杂原子的3-至7-元杂环烷基,或可与C3-10环烷基稠合形成双环,并且所述取代的苯基被羟基取代,或依次被C1-5烷基、包含一个或多个选自由N、O和S组成的组的杂原子的3-至7-元杂环烷基和C3-10环烷基或烷基羰基取代;并且
R6是-H、卤素或C1-10直链或支链烷基)。
根据一个具体实施方案,R2是C3-8环烷基、C3-6环烯基、-NHA1或-OA2,其中A1是C1-6直链或支链烷基、C3-7环烷基或包含一个或多个O原子的3-至6-元杂环烷基;
其中,当A1是C1-6直链或支链烷基时,所述烷基未被取代或被一个或多个选自由如下组成的组的非氢取代基取代:C3-6环烷基、C1-3直链或支链烷基磺酰基、C1-3烷基氨基磺酰基和C1-3直链或支链烷氧基,
当A1是C3-7环烷基时,所述环烷基未被取代或被一个或多个氟部分取代,
当A1是包含一个或多个O原子的3-至6-元杂环烷基时,所述杂环烷基未被取代或被一个或多个C1-3直链烷基部分取代,并且
A2是C3-6环烷基,其中所述环烷基未被取代或被一个或多个选自C1-3直链或支链烷基和羟基的非氢取代基取代。
根据一个更具体的实施方案,
根据一个具体实施方案,R3是-H、C1-4直链或支链烷氧基,或丙烯酰胺,其中所述C1-4直链烷氧基未被取代或被三氟甲基取代,并且R4是-H或C1-3直链烷氧基,或
R3和R4与包含它们所键合的碳原子的苯环一起可形成9-至10-元双环。更具体地,9-至10-元双环可以是二氢苯并二噁英或二氢苯并呋喃基。
根据一个具体实施方案,R5是-H、C1-3烷基氨基羰基、未取代或取代的苯基、氧代噁唑烷基、二氧化噻唑烷基、氧代吡咯烷基、二氧化噻嗪基、氧代吗啉基或选自由吡唑基、三唑基、噻唑基、噁唑基、吡啶基和咪唑基组成的组的杂芳基,其中所述杂芳基可以未被取代或被一个或多个选自由如下组成的组的非氢取代基取代:C1-3烷基、氟和包含一个或多个O原子的4-至6-元杂环烷基,或可与C3-5环烷基稠合形成双环,并且所述的取代的苯基被羟基或C1-3烷基取代,其中C1-3烷基被乙酰哌嗪或C3-6环烷基哌嗪取代。
根据另一方面,在式1表示的化合物中,
当X是N时,
R1是-H、氯、氟、溴、碘、氰基或三氟甲基,
R2是C3-7环烷基、环己烯基、-NHA1或-OA2,
A1是C1-6直链或支链烷基、C3-7环烷基或包含一个或多个O原子的3至6元杂环烷基,
其中,当A1是C1-6直链或支链烷基时,所述烷基未被取代或被一个或多个非氢取代基取代,所述一个或多个非氢取代基选自C3-6环烷基、C1-3直链或支链烷基磺酰基、C1-3烷基氨基磺酰基和C1-3直链或支链烷氧基,
当A1是C3-7环烷基时,所述环烷基未被取代或被一个或多个氟部分取代,并且
当A1是包含一个或多个O原子的3-至6-元杂环烷基时,所述杂环烷基未被取代或被一个或多个C1-3直链烷基部分取代,
A2是C3-6环烷基,其中所述环烷基未被取代或被一个或多个选自C1-3直链或支链烷基和羟基的非氢取代基取代,
R3是-H、C1-4直链或支链烷氧基或丙烯酰胺,其中所述C1-4直链烷氧基未被取代或被三氟甲基取代,并且R4是-H或C1-3直链烷氧基,或
R3和R4与包含它们所键合的碳原子的苯环一起形成包含一个或多个O原子的9-至10-元双环,
R5是-H、C1-3烷基氨基羰基、未取代或取代的苯基、氧代噁唑烷基、二氧化噻唑烷基、氧代吡咯烷基、二氧化噻嗪基、氧代吗啉基、或选自由吡唑基、三唑基、噻唑基、噁唑基、吡啶基和咪唑基组成的组的杂芳基,其中所述杂芳基可以未被取代或被一个或多个选自由如下组成的组的非氢取代基取代:C1-3烷基、氟和包含一个或多个O原子的4-至6-元杂环烷基,或可与C3-5环烷基稠合形成双环,并且所述的取代的苯基被羟基或C1-3烷基取代,其中C1-3烷基被乙酰哌嗪或C3-6环烷基哌嗪取代,并且
R6可以是-H、卤素或C1-3直链烷基。
根据一个具体实施方案,在式1表示的化合物中,
当X是N时,
R1是-H、氯、氰基或三氟甲基,
R3是-H、C1-4直链或支链烷氧基或丙烯酰胺,其中C1-4直链烷氧基未被取代或被三氟甲基取代,R4是-H或C1-3直链烷氧基,或
R3和R4与包含它们所键合的碳原子的苯环一起形成包含一个或多个O原子的9-至10-元双环,并且所述9-至10-元双环是二氢苯并二噁英或二氢苯并呋喃,R5是-H,
R6可以是-H、卤素或C1-3直链烷基。
根据又一方面,在式1表示的化合物中,
当X是N时,R3和R4与包含它们所键合的碳原子的苯环一起形成二氢苯并二噁英或二氢苯并呋喃的双环,
R1是-H、氯、氰基或三氟甲基,
R2是
R6可以是-H。
根据又一方面,在式1表示的化合物中,
当X是N,R3是-H、C1-4直链或支链烷氧基或丙烯酰胺,其中所述C1-4直链烷氧基未取代或被三氟甲基取代,并且
当R4是-H或C1-3直链烷氧基时,
R1是-H、氯、氰基或三氟甲基,
R5是-H,
R6可以是-H、卤素或C1-3直链烷基。
根据又一方面,
当X时CH时,
R1是氰基或三氟甲基;
R2是-NHA1,其中A1是C3-7环烷基,
R3是C1-6直链或支链烷氧基,R4是-H,或R3和R4与包含它们所键合的碳原子的苯环一起形成包含一个或多个O原子的9-元和10-元双环,
R5是氧代吡咯烷基,并且
R6可以是-H。
根据又一方面,
根据本发明的由式1表示的化合物或其药学上可接受的盐的实施例可包括下表1中列出的实施例1至177的化合物或其药学上可接受的盐。
根据本发明的由式1表示的化合物可以以药学上可接受的盐的形式使用,并且由药学上可接受的游离酸形成的酸加成盐用作盐是有用的。所述酸加成盐得自无机酸,如盐酸、硝酸、磷酸、硫酸、氢溴酸、氢碘酸、亚硝酸、亚磷酸等;无毒有机酸,如脂肪族单羧酸盐和二羧酸盐、苯基取代的链烷酸酯、羟基链烷酸酯和链烷二酸酯、芳族酸以及脂族和芳族磺酸;或有机酸,如三氟乙酸、乙酸、苯甲酸、柠檬酸、乳酸、马来酸、葡萄糖酸、甲磺酸、4-甲苯磺酸、酒石酸和富马酸。这种药学上无毒盐的类型包括硫酸盐、焦硫酸盐、硫酸氢盐、亚硫酸盐、亚硫酸氢盐、硝酸盐、磷酸盐、磷酸一氢盐、磷酸二氢盐、甲基磷酸盐、焦磷酸盐氯化物、溴化物、碘化物、氟化物、醋酸盐、丙酸盐、癸酸盐、辛酸盐、丙烯酸盐、甲酸盐、异丁酸盐、癸酸盐、庚酸盐、丙酸盐、丙二酸盐、丙二酸盐、草酸、辛二酸盐、癸二酸盐、富马酸盐、马来酸盐、丁炔-1,4-二酸盐、己烷-1,6-二酸盐、苯甲酸盐、氯苯甲酸盐、苯甲酸甲盐、二硝基苯甲酸盐、羟基苯甲酸盐、甲氧基苯甲酸盐、邻苯二甲酸盐、对苯二甲酸盐、苯磺酸盐、甲苯磺酸盐、氯苯磺酸盐、苯乙酸盐、苯丙酸盐、苯丁酸盐、柠檬酸盐、乳酸盐、β-羟基丁酸盐、乙醇酸盐、马来酸盐、酒石酸盐、甲磺酸盐、丙磺酸盐、萘-1-磺酸盐、萘-2-磺酸盐和扁桃酸盐等。
本发明的酸加成盐可以使用常规方法制备,并且,例如,通过将式1的衍生物溶解于有机溶剂如甲醇、乙醇、丙酮、二氯甲烷或乙腈中,并过滤和干燥通过向其中加入有机酸或无机酸而产生的沉淀物,或者可以通过减压蒸馏溶剂和过量酸,然后在有机溶剂下干燥和结晶来制备。
此外,可使用碱制备药学上可接受的金属盐。碱金属或碱土金属盐例如通过将化合物溶解于过量的碱金属氢氧化物或碱土金属氢氧化物溶液中,过滤未溶解的化合物盐,将滤液蒸发干燥而得到。在这种情况下,金属盐在药学上适用于制备钠盐、钾盐或钙盐。此外,对应于金属盐的盐是通过使碱金属或碱土金属盐与合适的银盐(例如硝酸银)反应而获得的。
此外,本发明包括所有类型的由式1表示的化合物或其药学上可接受的盐,以及可由其制备的溶剂化物、旋光异构体、水合物等。
在本说明书中,“水合物”可以指含有通过非共价分子间力键合的化学计量或非化学计量量的水的本公开的化合物或其盐。由式1表示的化合物的水合物可以包含通过非共价分子间力键合的化学计量或非化学计量量的水。水合物可含有1当量或更多,优选约1当量至约5当量的水。这种水合物可以通过将本公开的式1表示的化合物、其异构体或其药学上可接受的盐从水或含水溶剂中结晶来制备。
在本说明书中,“溶剂化物”可以指含有通过非共价分子间力键合的化学计量或非化学计量量的溶剂的本公开的化合物或其盐。其合适的溶剂包括挥发性溶剂、无毒溶剂和/或适合施用于人类的溶剂。
在本说明书中,“异构体”可以指具有相同化学式或分子式但在结构或空间上不同的本公开的化合物或其盐。这种异构体包括结构异构体如互变异构体、具有不对称碳中心的R或S异构体、立体异构体如几何异构体(反式或顺式)和旋光异构体(对映异构体)。所有这些异构体及其混合物也落入本公开的范围内。
如下方案A所示,本发明另一方面提供了一种制备式1所示化合物的方法,包括:
将R1引入式00表示的化合物中以制备式AA表示的化合物(步骤1);
将SEM保护基连接到式AA表示的化合物上以制备式BB表示的化合物(步骤2);
将式BB表示的化合物与式CC表示的化合物反应制备式2表示的化合物(步骤3);
将式2表示的化合物与式3表示的化合物反应制备式4表示的化合物(步骤4);以及
将上一步制备的式4所示化合物的SEM保护基去除,制备式1化合物(步骤5)。
[方案A]
(其中,
X和R1至R6如式1中所定义;
Hal是卤素;并且
SEM是保护基)。
在下文中,将描述根据本发明的由式1表示的化合物的制备方法。
在制备式1表示的化合物的方法中,
步骤1是将R1引入式00表示的化合物以制备式AA表示的化合物的步骤。本步骤中,反应可以在DMF溶剂中进行。在这种情况下,反应可以在大约0至25℃的反应温度下进行大约30分钟至4小时的反应时间,但是该反应可以不受任何反应条件的限制进行,只要反应可以顺利进行即可。
步骤2是在式AA表示的化合物中引入SEM保护基以制备式BB表示的化合物的步骤。本步骤中,反应可以在DMF溶剂中进行。在这种情况下,反应可以在大约0至25℃的反应温度下进行大约30分钟至4小时的反应时间,但是该反应可以不受任何反应条件的限制进行,只要反应可以顺利进行即可。
步骤3为将R2引入式BB表示的化合物制备式2表示的化合物的步骤。本步骤中,反应可以在醇类溶剂中进行。在这种情况下,反应可以在大约80℃的反应温度下进行大约12至24小时的反应时间,但是该反应可以不受任何反应条件的限制进行,只要反应可以顺利进行即可。
步骤4是将式2表示的化合物与式3表示的化合物反应制备式4表示的化合物的步骤。本步骤中,反应可以在醇类溶剂中进行。在这种情况下,反应可以在大约60至120℃的反应温度下进行大约30分钟至90分钟的反应时间,但是该反应可以不受任何反应条件的限制进行,只要反应可以顺利进行即可。
步骤5为将步骤4中制备的式4所示化合物脱去保护基(-SEM)制备式1所示化合物。因为该步骤是为了去除保护基团(-SEM),所以该步骤可以使用去除保护基团的已知方法进行,这取决于保护基团的类型。保护基团的实例可包括2-(三甲基硅烷基)乙氧基甲基、三甲基硅烷基(TMS)基团、苄基、乙酰基等。
本发明的另一方面提供了一种用于预防或治疗与一种或多种选自由如下组成的组的蛋白激酶相关的疾病的药物组合物:JAK2、SNARK、TTK、YSK4、JNK1、FLT3、PRKCE、CAMKK1、JNK3、TYK2、RSK2、CAMKK2、ULK3、ULK1、RSK4、TRKB、LRRK2、JNK3、AAK1、GAK、SBK1、TYK2、CAMK2D、MAP3K2、KIT、CSNK1D、CSNK1E、MEK4、RIOK1、DYRK1B、PKN2、FLT3、JNK2、RIPK5、MEK3、ABL1、MAPKAPK2、GRK4和SRPK3,其含有所述化合物或其立体异构体、其水合物或其药学上可接受的盐作为活性成分。所述激酶可以是野生型或突变型。
本发明的又一方面提供一种用于预防或治疗癌症的药物组合物,其包含式1表示的化合物或其立体异构体、其水合物或其药学上可接受的盐作为活性成分。在这种情况下,所述化合物可表现出对TTK激酶的抑制活性以预防或改善癌症。
本发明的另一方面提供了一种预防或治疗蛋白激酶相关疾病,特别是癌症的方法,其包括将式1表示的化合物或其立体异构体、其水合物或其药学上可接受的盐或包含其作为活性成分的药物组合物施用于有需要的受试者。
癌症治疗可以不受任何限制地应用,只要它是本领域已知的癌症,但癌症的一些具体实例可包括选自由如下组成的组的一种或多种:假粘液瘤、肝内胆管癌、肝母细胞瘤、肝癌、甲状腺癌、结肠癌、睾丸癌、骨髓增生异常综合征、胶质母细胞瘤、口腔癌、唇癌、蕈样真菌病、急性髓系白血病、急性淋巴细胞白血病、基底细胞癌、卵巢上皮癌、卵巢生殖细胞癌、男性乳腺癌、脑癌、垂体腺瘤、多发性骨髓瘤、胆囊癌、胆管癌、结直肠癌、慢性粒细胞白血病、慢性淋巴细胞白血病、视网膜母细胞瘤、脉络膜黑色素瘤、壶腹癌、膀胱癌、腹膜癌、甲状旁腺癌、肾上腺癌、鼻和鼻窦癌、非小细胞肺癌、舌癌、星形细胞瘤、小细胞肺癌、儿童脑癌、小儿淋巴瘤、小儿白血病、小肠癌、脑膜瘤、食道癌、神经胶质瘤、肾盂癌、肾癌、心脏癌、十二指肠癌、恶性软组织癌、恶性骨癌、恶性淋巴瘤、恶性间皮瘤、恶性黑色素瘤、眼癌、外阴癌、输尿管癌、尿道癌、原发部位不明的癌症、胃淋巴瘤、胃癌、胃类癌、胃肠道间质瘤、肾母细胞瘤、乳腺癌、肉瘤、阴茎癌、咽癌、妊娠滋养细胞疾病、宫颈癌、子宫内膜癌、子宫肉瘤、前列腺癌、转移性骨癌、转移性脑癌、纵隔癌、直肠癌、直肠类癌、阴道癌、脊髓癌、听神经瘤、胰腺癌、唾液腺癌、卡波西肉瘤、佩吉特病、扁桃体癌、鳞状细胞癌、肺腺癌、肺癌、肺鳞状细胞癌、皮肤癌、肛门癌、横纹肌肉瘤、喉癌、胸膜癌、血癌和胸腺癌。
临床施用时,式1表示的化合物或其药学上可接受的盐可以以各种口服和肠胃外制剂的形式施用。当配制组合物时,可以使用常用的稀释剂或赋形剂例如填充剂、增量剂、粘合剂、润湿剂、崩解剂、表面活性剂等来制备组合物。用于口服施用的固体制剂的实例包括片剂、丸剂、粉剂、颗粒剂、胶囊剂等,并且这些固体制剂可以通过将一种或多种化合物与一种或多种赋形剂例如淀粉、碳酸钙、蔗糖、乳糖或明胶混合来配制。除了简单的赋形剂外,制剂还可以使用润滑剂,例如硬脂酸镁和滑石粉。用于口服施用的液体制剂的实例包括混悬剂、内服液体、乳剂、糖浆剂等,并且这些液体制剂除了简单的常用稀释剂(如水和液体石蜡)之外还可以包括各种类型的赋形剂,例如,润湿剂、甜味剂、调味剂、防腐剂等。肠胃外施用制剂包括无菌水溶液、非水溶剂、悬浮液、乳剂等。非水溶剂和悬浮液的非限制性实例包括丙二醇、聚乙二醇、植物油(例如橄榄油)和可注射酯(例如油酸乙酯)。
一种药物组合物,其包括由式1所表示的化合物或其在药物上可接受的盐作为活性成分,可以肠胃外施用,并且肠胃外施用采用皮下注射、静脉注射、肌肉注射、或者胸腔内注射的方法进行。就此而言,为了配制肠胃外施用的制剂,所述药物组合物可以通过将式1表示的化合物或其药学上可接受的盐与稳定剂或缓冲剂在水中混合制成溶液或悬浮液,然后制备成安瓿或小瓶单位剂型来制备。所述组合物可以被灭菌和/或包括佐剂,例如防腐剂、稳定剂、润湿剂或乳化促进剂、用于控制渗透压的盐和/或缓冲剂,和其他治疗有效的材料,并且可以使用一般方法配制,例如混合、造粒或包衣。
例如,用于口服施用的剂型包括片剂、丸剂、硬/软胶囊、液体、悬浮剂、乳化剂、糖浆剂、颗粒剂、酏剂、锭剂等。在这种情况下,除了活性成分之外,这些制剂还包含稀释剂(例如,乳糖、右旋糖、蔗糖、甘露醇、山梨糖醇、纤维素和/或甘氨酸)和润滑剂(例如,二氧化硅、滑石、硬脂酸及其镁盐或钙盐,和/或聚乙二醇)。片剂可含有粘合剂,例如硅酸镁铝、淀粉糊、明胶、甲基纤维素、羧甲基纤维素钠和/或聚乙烯吡咯烷酮,并且在需要时可以含有崩解剂(淀粉、琼脂、藻酸或其钠盐等)或沸腾混合物和/或吸收剂、着色剂、调味剂和甜味剂。
含有由式1表示的化合物或其旋光异构体或其药学上可接受的盐作为活性成分的用于预防或治疗癌症的药物组合物可以作为单独的治疗剂施用,或与其他抗癌药物联合使用。
本发明的又一方面提供用于治疗癌症的化合物或其立体异构体、其水合物或其药学上可接受的盐。
本发明的又一方面提供了该化合物或其立体异构体、其水合物或其药学上可接受的盐在制备治疗癌症的药物中的用途。
蛋白激酶和与蛋白激酶相关的疾病如上所述,因此将省略其具体描述以避免冗余。
在下文中,将参考如下所述的实施例和实验例详细描述本发明。
然而,应当理解,下面描述的实施例和实验例是为了说明本发明的目的而给出的,并不旨在限制本发明的范围。
<分析和纯化条件>
本发明的实施例中合成的化合物使用以下方法进行纯化和结构分析。
1.制备型中压液相色谱(MPLC)
CombiFlash Rf+UV(TELEEDYNE ISCO Inc.)用于中压液相色谱。
2.分析HPLC条件(ACQUITY UPLC H-级系统)
使用配备有由Waters制造的质量QDA检测器的由Waters制造的UPLC系统(ACQUITYUPLC PDA检测器)。使用的色谱柱为来自Waters的ACQUITYBEH C18(1.7μm,2.1x50mm),并且柱温为30℃。
以含0.1%甲酸的水为流动相A,以含0.1%甲酸的乙腈为流动相B。
梯度条件(10-100%B持续3分钟,流速=0.6ml/min)
3.用于纯化的制备液相色谱质谱(Prep-LCMS)
使用配备有由Waters制造的质量QDA检测器的由Waters制造的自动纯化HPLC系统(2767样品管理器、2545二元梯度模块、2998光电二极管阵列检测器)。所用色谱柱为可从Waters获得的Prep C18 OBDTM(5μm,19x50mm),并且柱温为室温。
流动相A采用含0.035%三氟乙酸的水,流动相B采用含0.035%三氟乙酸的甲醇。
梯度条件(15-100%B持续10分钟,流速=25ml/min)
4.用于纯化的制备型液相色谱UV光谱法(Prep-150 LC系统)
使用由Waters制造的Prep 150LC系统(2545四元梯度模块,2998光电二极管阵列检测器,馏分收集器Ⅲ)。所用色谱柱为可从Waters获得的Prep RP18 OBDTM(10μm,30x300mm),并且柱温为室温。
5.NMR分析
NMR分析使用Bruker制造的AVANCE III 400或AVANCE III 400HD进行,数据以百万分之几(ppm)(δ)表示。
使用市售试剂而无需进一步纯化。本发明中,室温是指20~25℃左右的温度。使用旋转蒸发器进行减压浓缩或通过蒸馏除去溶剂。
<制备例1-1>2-氯-N-环己基-7-((2-(三甲基硅烷基)乙氧基)甲基)-7H-吡咯并[2,3-d]嘧啶-4-胺的制备
标题化合物按照以下方案1中描述的方式制备。
[方案1]
步骤1:将2,4-二氯-7H-吡咯并[2,3-d]嘧啶(1.0当量)在氮气下溶解于DMF(0.62M)中,然后在0℃下向其中缓慢加入NaH(1.2当量)。反应混合物在15℃下反应1小时,并在0℃下进一步向其中加入(2-(氯甲氧基)乙基)三甲基硅烷(1.3当量),然后在相同温度下搅拌1.5小时。向所得反应产物中加入蒸馏水,然后用EtOAc(x 2)萃取有机物。用盐水洗涤收集的有机层后,用Na2SO4除去剩余的水,减压浓缩有机层。浓缩的混合物通过柱层析(SiO2;PE:EA)纯化,得到黄色液体的目标化合物(产率:84%)。
步骤2:将2,4-二氯-7-((2-(三甲基硅烷基)乙氧基)甲基)-7H-吡咯并[2,3-d]嘧啶(1.0当量)、DIPEA(2.9当量)和环己胺(1.5当量)溶解于EtOH(0.32M)中,然后将反应混合物在80℃下搅拌16小时。反应终止后,减压浓缩除去有机溶剂。将1N HCl水溶液(12.5当量)加入到所得反应产物中,然后用EtOAc(x3)萃取有机物。收集的有机层用饱和NaHCO3水溶液和盐水洗涤,然后用Na2SO4除去剩余的水。然后,将有机层在减压下浓缩以获得呈白色固体的目标化合物(产率:95%)。
<制备例2-1>3,6-二氯-N-环己基-7-((2-(三甲基硅烷基)乙氧基)甲基)-7H-吡咯并[2,3-d]嘧啶-4-胺的制备
标题化合物按照以下方案2中描述的方式制备。
[方案2]
步骤1:将2,4-二氯-7H-吡咯并[2,3-d]嘧啶(1.0当量)在氮气下溶解于DMF(0.5M)中,然后在0℃下向其中缓慢加入NCS(1.1当量)。反应混合物在0℃反应10分钟,室温搅拌4小时。向所得反应产物中加入冰水,过滤形成的固体目标化合物(产率:65%)。
步骤2:将2,4,5-三氯-7H-吡咯并[2,3-d]嘧啶(1.0当量)在氮气下溶解于DMF(1.1M)中,然后在0℃下向其中缓慢加入NaH(1.5当量)。反应混合物在0℃反应30分钟,再加入(2-(氯甲氧基)乙基)三甲基硅烷(1.2当量),20℃搅拌4小时。向所得反应产物中加入蒸馏水,然后用乙酸乙酯(x3)萃取有机物。用盐水洗涤收集的有机层后,用Na2SO4除去剩余的水,减压浓缩有机层。浓缩的混合物通过MPLC(EtOAc:Hex)纯化,得到白色固体的目标化合物(产率:59%)。
步骤3:2,4,5-三氯-7-((2-(三甲基硅烷基)乙氧基)甲基)-7H-吡咯并[2,3-d]嘧啶(1.0当量)在氮气下溶解于NMP(1.0M)中,并向其中缓慢加入环己胺(1.2当量)。将反应混合物在80℃下搅拌16小时。向所得反应产物中加入蒸馏水,然后用EtOAc(x3)萃取有机物。用盐水洗涤收集的有机层后,用Na2SO4除去剩余的水,减压浓缩有机层。浓缩的混合物通过MPLC(EtOAc:Hex)纯化,得到白色固体的目标化合物(产率:.98%)。
<制备例3-1>2-氯-N-环己基-5-(三氟甲基)-7-((2-(三甲基硅烷基)乙氧基)甲基)-7H-吡咯并[2,3-d]嘧啶-4-胺的制备
标题化合物按照以下方案3中描述的方式制备。
[方案3]
步骤1:在接近真空的减压下将CuI(5.0当量)和KF(5.0当量)在150℃的温度下保持2小时,同时除去水分。将所得反应产物冷却至室温,然后在氮气下将TMS-CF3(5.0当量)溶解于NMP(1.12M)中,并通过注射器缓慢加入反应产物中。反应混合物在室温下反应一个小时,在氮气下将2,4-二氯-5-碘-7-((2-(三甲基硅烷基)乙氧基)甲基)-7H-吡咯并[2,3-d]嘧啶(1.0当量)进一步溶于NMP(0.45M)中,然后通过注射器慢慢加入。将所得反应混合物在50℃下搅拌12小时。反应终止后,将反应产物冷却至室温。然后,将蒸馏水加入到反应产物中,然后用EtOAc(x3)萃取有机物。用盐水洗涤收集的有机层后,用Na2SO4除去剩余的水,减压浓缩有机层。通过柱色谱法(SiO2;PE:EA)纯化浓缩的混合物,得到黄色液体的目标化合物(产率:.62%)。
第2步:2,4-二氯-5-(三氟甲基)-7-((2-(三甲基硅烷基)乙氧基)甲基)-7H-吡咯并[2,3-d]嘧啶(1.0当量)、DIPEA(2.9当量)和环己胺(1.5当量)溶解于乙醇(0.25M)中,然后将反应混合物在80℃下搅拌16小时。反应终止后,减压浓缩除去有机溶剂。将所得反应产物溶解于EtOAc中,然后用1N HCl水溶液和盐水洗涤。然后,使用Na2SO4去除剩余的水,并将反应产物在减压下浓缩以获得呈棕色固体状的目标化合物(产率:71%)。
<制备例4-1>2-氯-4-(甲基氨基)-7-((2-(三甲基硅烷基)乙氧基)甲基)-7H-吡咯并[2,3-d]嘧啶-5-腈的制备
标题化合物按照以下方案4中描述的方式制备。
[方案4]
步骤1:将2,4-二氯-7H-吡咯并[2,3-d]嘧啶(1.0当量)在氮气下溶解于DCM(0.5M)中,然后在0℃下缓慢加入NIS(1.6当量)。反应混合物在室温下搅拌12小时。反应终止后,过滤形成的固体目标化合物。过滤后的目标化合物用蒸馏水洗涤,得到黄色固体的目标化合物。
步骤2:将2,4-二氯-5-碘-7H-吡咯并[2,3-d]嘧啶(1.0当量)在氮气下溶解于DMF(0.5M)中,然后在0℃下缓慢加入NaH(1.3当量)。反应混合物在0℃反应30分钟,再加入(2-(氯甲氧基)乙基)三甲基硅烷(1.1当量),20℃搅拌1小时。向所得反应产物中加入蒸馏水,然后用EA(x3)萃取有机物。用盐水洗涤收集的有机层后,用Na2SO4除去剩余的水,减压浓缩有机层。浓缩的混合物通过柱色谱法(SiO2;PE:EA)纯化,得到白色固体的目标化合物(产率:94%)。
步骤3:将2,4-二氯-5-碘-7-((2-(三甲基硅烷基)乙氧基)甲基)-7H-吡咯并[2,3-d]嘧啶(1.0当量)溶解于NMP(0.2M)中,然后在0℃下向其中缓慢加入CuCN(2.0当量)。反应混合物在120℃搅拌6小时。将冷蒸馏水和EA加入到所得反应产物中,然后将所得混合物通过硅藻土过滤器过滤。将所得滤液分离为有机层和水层,然后用EtOAc(x2)萃取水层。用盐水洗涤收集的有机层后,用Na2SO4除去剩余的水,减压浓缩有机层。浓缩的混合物通过柱色谱法(SiO2;PE:EA)纯化,得到黄色固体的目标化合物(产率:94%)。
步骤4:2,4-二氯-7-((2-(三甲基硅烷基)乙氧基)甲基)-7H-吡咯并[2,3-d]嘧啶-5-腈(1.0当量)、DIPEA(2.9当量)和甲胺(1.5当量)溶解于EtOH(0.25M)中,然后将反应混合物在80℃下搅拌16小时。反应终止后,减压浓缩除去有机溶剂。将所得反应产物溶解于EtOAc中,然后用1N HCl水溶液和盐水洗涤。然后,使用Na2SO4去除剩余的水,并将反应产物在减压下浓缩以获得呈黄色固体状的目标化合物(产率:90%)。
<制备例4-2>4-(丁基氨基)-2-氯-7-((2-(三甲基硅烷基)乙氧基)甲基)-7H-吡咯并[2,3-d]嘧啶-5-腈的制备
以与制备例4-1相同的方式制备标题化合物(产率:51%)。
<制备例4-3>(S)-4-(仲丁基)-2-氯-7-((2-(三甲基硅烷基)乙氧基)甲基)-7H-吡咯并[2,3-d]嘧啶-5-腈的制备
以与制备例4-1相同的方式制备标题化合物(产率:85%)。
<制备例4-4>2-氯-4-((环戊基甲基)氨基)-7-((2-(三甲基硅烷基)乙氧基)甲基)-7H-吡咯并[2,3-d]嘧啶-5-腈的制备
以与制备例4-1相同的方式制备标题化合物(产率:78%)。
<制备例4-5>2-氯-4-((2-甲氧基乙基)氨基)-7-((2-(三甲基硅烷基)乙氧基)甲基)-7H-吡咯并[2,3-d]嘧啶-5-腈的制备
以与制备例4-1相同的方式制备标题化合物(产率:97%)。
<制备例4-6>2-氯-4-((2-(甲基磺酰基)乙基)氨基)-7-((2-(三甲基硅烷基)乙氧基)甲基)-7H-吡咯并[2,3-d]嘧啶-5-腈的制备
以与制备例4-1相同的方式制备标题化合物(产率:53%)。
<制备例4-7>2-氯-4-((四氢-2H-吡喃-4-基)氨基)-7-((2-(三甲基硅烷基)乙氧基)甲基)-7H-吡咯并[2,3-d]嘧啶-5-腈的制备
以与制备例4-1相同的方式制备标题化合物(产率:86%)。
<制备例4-8>2-氯-4-(环戊基氨基)-7-((2-(三甲基硅烷基)乙氧基)甲基)-7H-吡咯并[2,3-d]嘧啶-5-腈的制备
以与制备例4-1相同的方式制备标题化合物(产率:87%)。
<制备例4-9>2-氯-4-(环己基氨基)-7-((2-(三甲基硅烷基)乙氧基)甲基)-7H-吡咯并[2,3-d]嘧啶-5-腈的制备
以与制备例4-1相同的方式制备标题化合物(产率:90%)。
<制备例4-10>2-氯-4-(环己氧基)-7-((2-(三甲基硅烷基)乙氧基)甲基)-7H-吡咯并[2,3-d]嘧啶-5-腈的制备。
以与制备例4-1相同的方式制备标题化合物(产率:62%)。
<制备例4-11>2-氯-4-(新戊基氨基)-7-((2-(三甲基硅烷基)乙氧基)甲基)-7H-吡咯并[2,3-d]嘧啶-5-腈的制备
以与制备例2-1相同的方式制备标题化合物(产率:70%)。
<制备例5-1>2-氯-4-环丙基-7-((2-(三甲基硅烷基)乙氧基)甲基)-7H-吡咯并[2,3-b]嘧啶-5-腈的制备
标题化合物以如下方案5中描述的方式制备。
[方案5]
步骤1:将2,4-二氯-7-((2-(三甲基硅烷基)乙氧基)甲基)-7H-吡咯并[2,3-b]嘧啶-5-腈(1.0当量),环丙基硼酸(1.5当量)和K3PO4(3.0当量)溶解于1,4-二噁烷(0.20M)中,并将所得混合物通过超声处理脱气1分钟。在氮气下向其中加入Pd(dppf)Cl2(0.1当量)和Ag2O(0.5当量),并且将混合物在90℃下反应16小时。通过硅藻土过滤器过滤反应混合物,并用DCM洗涤数次。将所得滤液浓缩,然后通过MPLC(EtOAc:Hex)纯化,得到目标化合物(产率:65%)。<制备例6-1>6-氯-N-环己基-1-((2-(三甲基硅烷基)乙氧基)甲基)-1H-吡咯并[2,3-b]吡啶-4-胺的制备
标题化合物以如下方案6中描述的方式制备。
[方案6]
步骤1:将4,6-二氯-1H-吡咯并[2,3-b]吡啶(1.0当量)在氮气下溶解于DMF(0.7M)中,然后在0℃下向其中缓慢加入NaH(1.5当量)。反应混合物在0℃反应30分钟,再加入(2-(氯甲氧基)乙基)三甲基硅烷(1.2当量),25℃搅拌2小时。向所得反应产物中加入蒸馏水,然后用乙酸乙酯(x3)萃取有机物。用盐水洗涤收集的有机层后,用Na2SO4除去剩余的水,减压浓缩有机层。浓缩的混合物通过MPLC(EtOAc:Hex)纯化,得到白色固体的目标化合物(产率:88%)。
步骤2:4,6-二氯-1-((2-(三甲基硅烷基)乙氧基)甲基)-1H-吡咯并[2,3-b]吡啶(1.0当量)在氮气下溶解于NMP(1.0M)中,然后向其中缓慢加入环己胺(2.0当量)。反应混合物在100℃搅拌16小时。向所得反应产物中加入蒸馏水,然后用EtOAc(x3)萃取有机物。用盐水洗涤收集的有机层后,用Na2SO4除去剩余的水,减压浓缩有机层。浓缩的混合物通过MPLC(EtOAc:Hex)纯化,得到白色固体的目标化合物(产率:58.4%)。
<制备例7-1>6-氯-N-环己基-1-((2-(三甲基硅烷基)乙氧基)甲基)-1H-吡咯并[2,3-b]吡啶-4-胺的制备
标题化合物以如下方案7中描述的方式制备。
[方案7]
步骤1:将4,6-二氯-1H-吡咯并[2,3-b]吡啶(1.0当量)在氮气下溶解于DMF(0.5M)中,然后在0℃下向其中缓慢加入NCS(1.1当量)。反应混合物在0℃下反应10分钟,并在室温下搅拌4小时。向所得反应产物中加入冰水,过滤形成的固体目标化合物(产率:63%)。
步骤2:将3,4,6-三氯-1H-吡咯并[2,3-b]吡啶(1.0当量)在氮气下溶解于DMF(1.1M)中,然后在0℃下缓慢加入NaH(1.5当量)。反应混合物在0℃反应30分钟,再加入(2-(氯甲氧基)乙基)三甲基硅烷(1.2当量),20℃搅拌4小时。向所得反应产物中加入蒸馏水,然后用乙酸乙酯(x3)萃取有机物。用盐水洗涤收集的有机层后,用Na2SO4除去剩余的水,减压浓缩有机层。浓缩的混合物通过MPLC(EtOAc:Hex)纯化,得到白色固体的目标化合物(产率:59%)。
步骤3:将3,4,6-三氯-1-((2-(三甲基硅烷基)乙氧基)甲基)-1H-吡咯并[2,3-b]吡啶(1.0当量)在氮气下溶解于NMP(1.0M)中,然后向其中缓慢加入环己胺(2.0当量)。反应混合物在100℃搅拌16小时。向所得反应产物中加入蒸馏水,然后用EtOAc(x3)萃取有机物。用盐水洗涤收集的有机层后,用Na2SO4除去剩余的水,减压浓缩有机层。浓缩的混合物通过MPLC(EtOAc:Hex)纯化,得到白色固体的目标化合物(产率:53%)。
<制备例8-1>6-氯-N-环己基-3-(三氟甲基)-1-((2-(三甲基硅烷基)乙氧基)甲基)-1H-吡咯并[2,3-b]吡啶-4-胺的制备
标题化合物以如下方案8中描述的方式制备。
[方案8]
步骤1:在接近真空的减压下将CuI(5.0当量)和KF(5.0当量)在200℃的温度下保持2小时,同时除去水分。将所得反应产物冷却至室温,然后将TMS-CF3(5.0当量)在氮气下溶解于DMF和NMP(1:1比例;共0.2M)中,并通过注射器缓慢加入到反应产物中。反应混合物在室温下反应一个小时,将4,6-二氯-3-碘-1-((2-(三甲基硅烷基)乙氧基)甲基)-1H-吡咯并[2,3-b]吡啶(1.0当量)进一步在氮气下溶解于DMF和NMP(比例为1:1;总共0.2M)中,然后通过注射器慢慢加入。反应混合物在50℃搅拌16小时。向所得反应产物中加入蒸馏水,然后用乙醚(x3)萃取有机物。用盐水洗涤收集的有机层后,用Na2SO4除去剩余的水,减压浓缩有机层。浓缩的混合物通过MPLC(EtOAc:Hex)纯化,得到白色固体的目标化合物(产率:74%)。
步骤2:4,6-二氯-3-(三氟甲基)-1-((2-(三甲基硅烷基)乙氧基)甲基)-1H-吡咯并[2,3-b]吡啶(1.0当量)在氮气下溶解于DMSO(1.0M)中,然后向其中缓慢加入K2CO3(3.0当量)和环己胺(2.0当量)。反应混合物在100℃搅拌16小时。向所得反应产物中加入蒸馏水,然后用EtOAc(x3)萃取有机物。用盐水洗涤收集的有机层后,用Na2SO4除去剩余的水,减压浓缩有机层。浓缩的混合物通过MPLC(EtOAc:Hex)纯化,得到白色固体的目标化合物(产率:58%)。
<制备例9-1>6-氯-4-(环己基氨基)-1-((2-(三甲基硅烷基)乙氧基)甲基)-1H-吡咯并[2,3-b]吡啶-3-腈的制备
标题化合物以如下方案9中描述的方式制备。
[方案9]
步骤1:将4,6-二氯-1H-吡咯并[2,3-b]吡啶(1.0当量)在氮气下溶解于DCM(0.3M)中,然后在0℃下向其中缓慢加入NIS(1.5当量)。反应混合物在0℃下反应10分钟,并在室温下搅拌4小时。向所得反应产物中加入冰水,然后过滤形成的固体目标化合物。过滤后的目标化合物用正己烷洗涤,得到浅褐色固体的目标化合物(产率:91%)。
步骤2:将4,6-二氯-3-碘-1H-吡咯并[2,3-b]吡啶(1.0当量)在氮气下溶解于DMF(0.5M)中,然后在0℃下缓慢加入NaH(1.5当量)。反应混合物在0℃反应30分钟,再加入(2-(2-(氯甲氧基)乙基)三甲基硅烷(1.2当量),然后在20℃搅拌4小时。向所得反应产物中加入蒸馏水,然后用乙醚(x3)萃取有机物。用盐水洗涤收集的有机层后,用Na2SO4除去剩余的水,减压浓缩有机层。浓缩的混合物通过MPLC(EtOAc:Hex)纯化,得到白色固体的目标化合物(产率:65%)。
步骤3:将4,6-二氯-3-碘-1-((2-(三甲基硅烷基)乙氧基)甲基)-1H-吡咯并[2,3-b]吡啶(1.0当量)溶解于EtOH(2.0M)中,然后向其中缓慢加入环己胺(2.0当量)。反应混合物在100℃搅拌16小时。向所得反应产物中加入蒸馏水,然后用乙醚(x3)萃取有机物。用盐水洗涤收集的有机层后,用Na2SO4除去剩余的水,减压浓缩有机层。浓缩的混合物通过MPLC(EtOAc:Hex)纯化,得到白色固体的目标化合物(产率:44%)。
步骤4:将6-氯-N-环己基-3-碘-1-((2-(三甲基硅烷基)乙氧基)甲基)-1H-吡咯并[2,3-b]吡啶-4-胺(1.0当量)溶解于DMF(0.25M)中,然后向其中缓慢加入CuI(0.7当量)和CuCN(2.0当量)。在氮气下于50℃时加入Pd(PPh3)4(0.5当量),80℃搅拌16小时。向所得反应产物中加入蒸馏水,然后用EtOAc(x3)萃取有机物。用盐水洗涤收集的有机层后,用Na2SO4除去剩余的水,减压浓缩有机层。浓缩的混合物通过MPLC(EtOAc:Hex)纯化,得到白色固体的目标化合物(产率:74%)。
<制备例10-1>2-甲氧基-4-(1-甲基-1H-吡唑-3-基)苯胺的制备
标题化合物以如下方案10中描述的方式制备。
[方案10]
将1M Na2CO3(0.1M)添加到溶解了4-溴-2-甲氧基苯胺(1当量)和1-甲基-5-(4,4,5,5-四甲基-1,3,2-二氧硼烷-2-基)-1H-吡唑(1当量)的1,4-二噁烷(0.3M)的混合溶液中,将所得混合物进行超声处理,同时让氮气流动10分钟。将Pd(PPh3)4(0.1当量)加入到反应混合物中,并将反应混合物在95℃下搅拌3小时。当反应完全终止时,反应混合物用乙酸乙酯和水萃取。收集的有机层用盐水洗涤,无水硫酸钠干燥,减压浓缩,然后用MPLC(EtOAc/己烷)纯化,得到目标化合物(产率73%)。
MS(m/z):204.2[M+H]+,UPLC r.t.(min):0.94
1H NMR(400MHz,DMSO)δ7.38(d,J=1.8Hz,1H),6.88(d,J=1.8Hz,1H),6.82(dd,J=8.0,1.8Hz,1H),6.70(d,J=8.0Hz,1H),6.24(d,J=1.8Hz,1H),4.99(s,2H),3.81(d,J=1.4Hz,6H)。
<制备例10-2>4-(1-甲基-1H-吡唑-3-基)苯胺的制备
以与制备例10-1类似的方式制备标题化合物。
<制备例10-3>5-(1-甲基-1H-吡唑-3-基)吡啶-2-胺的制备
以与制备例10-1类似的方式制备标题化合物。
<制备例10-4>2-乙氧基-4-(1-甲基-1H-吡唑-3-基)苯胺的制备
以与制备例10-1类似的方式制备标题化合物。
<制备例10-5>4-(3,5-二甲基异噁唑-4-基)-2-甲氧基苯胺的制备
以与以下方案10-1类似的方式制备标题化合物。
<制备例10-6>4-(6-氟吡啶-3-基)-2-甲氧基苯胺的制备
以与制备例10-1类似的方式制备标题化合物。
<制备例10-7>1-(4-((4'-氨基-3'-甲氧基-[1,1'-联苯基]-4-基)甲基)哌嗪-1-基)乙烷-1-酮的制备
以与制备例10-1类似的方式制备标题化合物。
<制备例10-8>2-甲氧基-4-(1-甲基-1H-吡唑-4-基)苯胺的制备
以与以下方案10-8相同的方式制备标题化合物。
[方案10-8]
步骤1:将4-溴-2-甲氧基-1-硝基-苯(1当量)和4,4,5,5-四甲基-2-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)-1,3,2-二氧杂环戊硼烷(1.1当量)溶解于1,4-二噁烷中,然后在室温和氮气下向其中加入AcOK(2.5当量)和Pd(dppf)Cl2·CH2Cl2(0.06当量)。反应溶液在90℃反应12小时。反应后,将反应溶液通过硅藻土过滤器过滤,并用EA洗涤。洗涤后的有机溶剂减压浓缩,然后进行硅胶层析(石油醚/乙酸乙酯=10/1至5/1),得到白色目标化合物(产率:87.29%)。
MS:m/z 198.0[M-82]+
1H NMR(400MHz,氯仿-d)δ=7.81-7.76(m,1H),7.51-7.48(m,1H),7.47-7.43(m,1H),4.02-3.99(m,3H),1.39-1.36(m,12H)
步骤2:将制备例10-8的步骤1中得到的2-(3-甲氧基-4-硝基-苯基)-4,4,5,5-四甲基-1,3,2-二氧硼烷(1当量),和4-碘-1-甲基-吡唑(1.2当量)在氮气下溶解于1,4-二噁烷(0.3M)和H2O(0.1M)溶剂中,再加入K2CO3(2.0当量)和Pd(dppf)Cl2·CH2Cl2(0.01当量)。然后,反应溶剂在90℃下反应12小时。反应后,反应溶剂通过硅藻土过滤器过滤,并用EA洗涤。将洗涤后的有机溶剂减压浓缩,然后硅胶层析纯化得到黄色目标化合物(产率34.40%)。
MS:m/z 234.2[M+H]+
1H NMR(400MHz,氯仿-d)δ=8.17-8.13(m,1H),7.99-7.96(m,1H),7.88-7.84(m,1H),7.42-7.39(m,1H),7.29-7.23(m,1H),4.03-3.99(m,3H),3.97-3.93(m,3H)
步骤3:将制备例10-8的步骤2中得到的4-(3-甲氧基-4-硝基-苯基)-1-甲基-吡唑(1当量)和Fe(5当量)溶解于EtOH(0.3M)和H2O(0.03M)中,并且向其中加入NH4Cl(5当量)。反应溶剂在80℃反应12小时。反应后,反应溶剂通过硅藻土过滤器过滤,并用EA洗涤。将洗涤后的有机溶剂减压浓缩,水洗后过滤,得到深褐色目标化合物(产率:91.80%)。
MS:m/z 204.2[M+H]+
1H NMR(400MHz,甲醇-d4)δ=7.86-7.80(m,1H),7.75-7.66(m,1H),7.07-6.91(m,2H),6.79(br d,J=7.7Hz,1H),3.90(s,6H)
<制备例10-9>2-甲氧基-4-(1-甲基-1H-1,2,3-三唑-4-基)苯胺的制备
以与制备例10-8类似的方式制备标题化合物。
<制备例10-10>2-甲氧基-4-(1-甲基-1H-1,2,4-三唑-3-基)苯胺的制备
以与制备例10-8类似的方式制备标题化合物。
<制备例10-11>2-甲氧基-4-(1-甲基-1H-1,2,4-三唑-5-基)苯胺的制备
以与制备例10-8类似的方式制备标题化合物。
<制备例10-12>2-乙氧基-4-(1-甲基-1H-1,2,4-三唑-3-基)苯胺的制备
以与制备例10-8类似的方式制备标题化合物。
<制备例10-13>1-(4-((4'-氨基-[1,1'-联苯基]-4-基)甲基)哌嗪-1-基)乙烷-1-酮的制备
以与制备例10-8类似的方式制备标题化合物。
<制备例10-14>4'-((4-环丙基哌嗪-1-基)甲基)-[1,1'-联苯]-4-胺的制备
以与制备例10-8类似的方式制备标题化合物。
<制备例10-15>2-甲氧基-4-(1-(氧杂环丁烷-3-基)-1H-吡唑-4-基)苯胺的制备
以与制备例10-8类似的方式制备标题化合物。
MS:m/z 246.1[M+H]+
1H NMR(400MHz,甲醇-d4)δ=8.02(s,1H),7.87-7.84(m,1H),7.07-7.03(m,1H),7.00-6.95(m,1H),6.82-6.75(m,1H),5.61-5.50(m,1H),5.09-5.03(m,4H),3.94-3.87(m,3H)
<制备例10-16>2-甲氧基-4-(1-(四氢-2H-吡喃-4-基)-1H-吡唑-4-基)苯胺的制备
以与制备例10-8类似的方式制备标题化合物。
MS:m/z 274.1[M+H]+
1H NMR(400MHz,DMSO-d6)δ=8.09-8.03(m,1H),7.75-7.68(m,1H),7.02-6.97(m,1H),6.93-6.87(m,1H),6.63-6.56(m,1H),4.67-4.61(m,1H),4.01-3.91(m,2H),3.84-3.77(m,3H),3.52-3.42(m,2H),2.03-1.88(m,4H)
<制备例10-17>4-(4-(4-氨基-3-甲氧基苯基)-1H-吡唑-1-基)哌啶-1-羧酸叔丁酯的制备
以与制备例10-8类似的方式制备标题化合物。
MS:m/z 373.2[M+H]+
1H NMR(400MHz,甲醇-d4)δ=7.95-7.89(m,1H),7.76-7.72(m,1H),7.05-7.01(m,1H),6.99-6.92(m,1H),6.79-6.71(m,1H),4.40-4.29(m,1H),4.26-4.18(m,2H),3.93-3.85(m,3H),3.04-2.87(m,2H),2.15-2.05(m,2H),2.01-1.88(m,2H),1.53-1.46(m,9H)
<制备例10-18>2-甲氧基-4-(4-甲基-4H-1,2,4-三唑-3-基)苯胺的制备
以与以下方案10-18相同的方式制备标题化合物。
[方案10-18]
步骤1:将3-羟基-4-硝基-苯甲酸酯(1当量)放入圆烧瓶中,溶解于DMF(0.3M)中,再加入K2CO3(3当量)。然后,将碘甲烷(2当量)滴加到反应溶剂中,反应溶剂在室温下反应15小时。反应结束后,向反应溶剂中加入水,使反应溶剂沉淀,过滤,得到淡黄色的目标化合物(产率:87.76%)。
MS:m/z 212.1[M+H]+
1H NMR(400MHz,氯仿-d)δ=7.83(d,J=8.4Hz,1H),7.76(s,1H),7.69(d,J=6.8Hz,1H),4.02(s,3H),3.97(s,3H)
步骤2:将3-甲氧基-4-硝基-苯甲酸甲酯(1当量)放入圆烧瓶中,溶解于MeOH(0.3M)中,然后加入NH2NH2·H2O溶液(3当量)。将反应溶液在80℃反应12小时。反应结束后,将反应溶液冷却至室温,过滤析出的固体,得到淡黄色目标化合物(产率:95.74%)。
MS:m/z 212.2[M+H]+
1H NMR(400MHz,氯仿-d)δ=10.07(s,1H),7.95(d,J=8.4Hz,1H),7.71(s,1H),7.52(d,J=6.8Hz,1H),4.62(br,2H),3.98(s,3H)
步骤3:将3-甲氧基-4-硝基-苯甲酰肼(1当量)放入圆烧瓶中,溶解于THF(0.3M)溶剂中,然后将甲基亚氨基(硫代)甲烷(1当量)加入到反应溶剂中。反应溶液在70℃反应2小时,冷却至室温,然后在室温反应10小时。过滤反应溶液,并用石油醚洗涤。然后将固体干燥,得到黄色目标化合物(产率:83.19%)。
MS:m/z 285.2[M+H]+
1H NMR(400MHz,DMSO-d6)δ=9.43(br,1H),8.00(d,J=8.4Hz,1H),7.79(s,1H),7.62(d,J=6.8Hz,1H),3.99(s,3H),2.90(s,3H)
步骤4:将1-[(3-甲氧基-4-硝基-苯甲酰基)氨基]-3-甲基-硫脲(1当量)加入圆烧瓶中的1M NaHCO3(2.54当量)中,反应溶液在100℃反应4小时。反应结束后,将反应溶液冷却至室温,过滤固体,水洗。过滤后的固体减压干燥,得到淡黄色目标化合物(产率:87.7%)。
MS:m/z 267.2[M+H]+
1H NMR(400MHz,DMSO-d6)δ=14.1(s,1H),8.05(d,J=8.4,1H),7.67(s,1H),7.46(d,J=8.4,1H),3.98(s,3H),3.34(s,3H)
步骤5:将3-(3-甲氧基-4-硝基-苯基)-4-甲基-1H-1,2,4-三唑-5-硫酮溶解于DCM(0.3M)中,然后在0℃下滴加过氧化氢-AcOH溶液(3当量)。加入后,所得混合物在室温下反应12小时。反应完成后,用Na2SO3水溶液终止反应,将NaOH饱和溶液加入到反应溶液中,使混合物的pH值调至10。然后,将反应溶液用水稀释,乙酸乙酯萃取,减压浓缩,得到棕色固体的目标化合物(产率:81.56%)。
步骤6:将制备例10-18的步骤5中得到的3-(3-甲氧基-4-硝基-苯基)-4-甲基-1,2,4-三唑(1当量),和Fe(5当量)溶解于EtOH(0.3M)和H2O(0.03M)中,再加入NH4Cl(5当量)。反应溶剂在80℃反应12小时。反应后,反应溶剂通过硅藻土过滤器过滤,并用EA洗涤。将洗涤后的有机溶剂减压浓缩,水洗后过滤,得浅灰色目标化合物(产率:94.3%)。
MS:m/z 205.2[M+H]+
1H NMR(400MHz,MeOD)δ=8.52(s,1H),7.13(s,1H),7.06(d,J=9.6Hz,1H),6.83(d,J=8.0Hz,1H),3.89(s,3H),3.84(s,3H)
<制备例10-19>2-乙氧基-4-(4-甲基-4H-1,2,4-三唑-3-基)苯胺的制备
以与制备例10-18类似的方式制备标题化合物。
MS:m/z 219.3[M+H]+
1H NMR(400MHz,甲醇-d4)δ=8.46(s,1H),7.16-7.10(m,1H),7.09-7.04(m,1H),6.88-6.83(m,1H),4.18-4.09(m,2H),3.78(s,3H),1.50-1.41(m,3H)
<制备例10-20>4-(6,7-二氢-5H-吡咯并[2,1-c][1,2,4]三唑-3-基)-2-甲氧基苯胺的制备
以与以下方案10-20中相同的方式制备标题化合物。
[方案10-20]
步骤1:将制备例10-18的步骤2中得到的3-甲氧基-4-硝基-苯甲酰肼(1当量)溶解于MeOH(0.3M)中,再加入5-甲氧基-3,4-二氢-2H-吡咯(1当量)。反应溶液在室温下反应48小时。过滤所得固体,然后减压干燥,得到黄色目标化合物(产率:66.4%)。
MS:m/z 279.2[M+H]+
1H NMR(400MHz,DMSO-d6)δ=7.85-7.67(m,3H),3.97(s,3H),3.70-3.59(m,2H),2.67-2.64(m,2H),2.33-2.04(m,2H)
步骤2:将(E)-3-甲氧基-4-硝基-N’-(吡咯烷-2-亚基)苯甲酰肼(1当量)加入圆烧瓶中的1M NaHCO3(2.54当量)中,反应溶液在100℃反应12小时。反应结束后,将反应溶液冷却至0℃,过滤固体,水洗。过滤后的固体减压干燥,得到淡黄色目标化合物(产率:.33.6%)
MS:m/z 261.2[M+H]+
1H NMR(400MHz,CDCl3)δ=7.95(d,J=8.4Hz,1H),7.85(s,1H),7.27(d,J=8.4Hz,1H),4.30-4.26(m,2H),4.05(s,3H),3.09-3.06(m,2H),2.90-2.88(m,2H)
步骤3:将制备例10-20步骤2中得到的3-(3-甲氧基-4-硝基苯基)-6,7-二氢-5H-吡咯并[2,1-c][1,2,4]三唑(1当量),和Fe(5当量)溶解于EtOH(0.3M)和H2O(0.03M)中,再加入NH4Cl(5当量)。反应溶剂在80℃反应12小时。反应后,反应溶剂通过硅藻土过滤器过滤,并用EA洗涤。将洗涤后的有机溶剂减压浓缩,水洗后过滤,得浅灰色目标化合物(产率:82.2%)。
MS:m/z 231.2[M+H]+
1H NMR(400MHz,MeOD)δ=7.30(s,1H),7.15(d,J=7.6Hz,1H),6.78(d,J=8.4Hz,1H),4.24-4.20(m,2H),3.91(s,3H),2.96-2.93(m,2H),2.83-2.78(m,2H)
<制备例10-21>4-(6,7-二氢-5H-吡咯并[2,1-c][1,2,4]三唑-3-基)-2-乙氧基苯胺的制备
以与制备例10-20类似的方式制备标题化合物。
MS:m/z 245.3[M+H]+
1H NMR(400MHz,DMSO-d6)δ=7.23(s,1H),7.15-7.07(m,1H),6.73-6.68(m,1H),5.10(br d,2H),4.20-4.12(m,2H),4.10-4.02(m,2H),2.85-2.78(m,2H),2.72-2.61(m,2H),1.37(m,3H)
<制备例10-22>4-(2,4-二甲基-1H-咪唑-1-基)-2-甲氧基苯胺的制备
以与以下方案10-22中相同的方式制备标题化合物。
[方案10-22]
步骤1:将4-氟-2-甲氧基-1-硝基-苯(1当量)和2,4-二甲基-1H-咪唑(1当量)溶解于DMF(0.1M)中,并向其中加入K2CO3(2当量)。反应溶液在70℃反应52小时。当反应完成时,反应溶液用水稀释,然后有机物用EtOAc(x2)萃取。用盐水洗涤收集的有机层后,用Na2SO4除去剩余的水,并减压浓缩。干燥浓缩的固体混合物,得到白色固体的1-(3-甲氧基-4-硝基-苯基)-2,4-二甲基-咪唑(产率:57.68%)。
1H NMR(400MHz,DMSO-d6)δ8.02(d,J=8.4Hz,1H),7.38(d,J=2.4Hz,1H),7.17(dd,J=8.4,2.4Hz,1H),7.13(d,J=0.8Hz,1H),3.98(s,3H),2.34(s,3H),2.10(d,J=0.8Hz,3H)。
步骤2:将制备例10-20的步骤1中得到的1-(3-甲氧基-4-硝基-苯基)-2,4-二甲基-咪唑(1当量)溶解于EtOH(0.1M)中,再加入Pd/C(10%纯度)。将反应烧瓶减压后,将所得混合物在室温下在氢气下反应10小时。反应后,将反应溶液通过硅藻土过滤器过滤以除去Pd/C,然后用EtOAc洗涤。在减压下浓缩过滤的有机层以获得呈白色固体的4-(2,4-二甲基-1H-咪唑-1-基)-2-甲氧基苯胺(产率:89.74%)。
MS:m/z:218.2[M+H+];
1H NMR(DMSO-d6,400MHz)δ6.81(d,1H,J=0.8Hz),6.77(d,1H,J=1.6Hz),6.6-6.7(m,2H),4.93(s,2H),3.78(s,3H),2.16(s,3H),2.06(d,3H,J=0.8Hz)<实施例1>根据本发明的化合物的制备
根据本发明的吡咯并吡啶和吡咯并嘧啶衍生物化合物以如下方案11中描述的方式制备。
[方案11]
步骤1:将制备例6-1制备的化合物6-氯-N-环己基-1-((2-(三甲基硅烷基)乙氧基)甲基)-1H-吡咯并[2,3-b]吡啶-4-胺(1.0当量),制备例10-1中制备的2-甲氧基-4-(1-甲基-1H-吡唑-3-基)苯胺(1.2当量)和K2CO3(5.0当量)加入并溶解于sec-BuOH(0.1M)中,然后通过超声处理脱气一分钟。在80℃氮气下将Pd2(dba)3(0.1当量)和Xphos(0.1当量)加入反应混合物中,然后在100℃搅拌2小时。通过硅藻土过滤器过滤反应混合物,并用乙酸乙酯洗涤。将所得滤液浓缩,所得液体混合物不经任何进一步纯化即用于下一步骤(产率:100%)。
步骤2:将N4-环己基-N6-(2-甲氧基-4-(1-甲基-1H-吡唑-3-基)苯基)-1-((2-(三甲基硅烷基)乙氧基)甲基)-1H-吡咯并[2,3-b]吡啶-4,6-二胺(1.0当量)溶解于CH2Cl2(0.1M)中,然后在室温下向其中加入TFA(70当量)。反应2小时后,除去溶剂。将浓缩的混合物再次溶解于1,4-二噁烷(0.1M)中,然后向其中加入NH4OH(0.1M)。然后,混合物在室温下反应2小时。反应后,减压浓缩除去溶剂。浓缩的混合物通过Pre-HPLC纯化,得到固体目标化合物(产率:51%)。
以与实施例1类似的方式制备实施例2至177的化合物。实施例1至177的化合物的化学结构、化合物名称以及NMR和质量分析结果总结并列于下表1中。
[表1]
<实验例1>本发明化合物对酶的抑制活性的评估
为评估根据本发明化合物对TTK(MPS1)的抑制活性,进行如下实验。
1)TTK酶活性
使用如下所述的方法使每个实施例化合物与纯化的人TTK(SignalChem#T20-10G)酶反应以评估抑制酶的能力。40mM Tris-HCl(pH 7.4)、20mM MgCl2、0.5mg/mL BSA 和50μMDTT的组合物用作反应缓冲液,测试物质的所有反应均在反应缓冲液中进行。使用连续稀释方法将化合物从10mM DMSO储备液开始稀释12倍,并在最终化合物浓度为50、10、2、0.4、0.08、0.016、0.0032、0.00064、0.000128、0.0000256、0.00000512和0.000001024μM时测量酶活性。在测试中,将纯化的ATP(10μM)和酶底物(0.2μg)与人TTK(25ng)酶在25℃反应2小时,并使用体外ADP-GloTM激酶测定法(Promega)测定酶活性。酶活反应溶液、ADP-Glo反应溶液和酶能力检测溶液以2:2:1的比例反应,用发光测定酶活性的抑制程度。基于未用化合物处理的溶剂对照的酶活性的荧光计算根据每种化合物的处理浓度对酶活性的抑制程度。在这种情况下,将抑制50%酶活性的每种化合物的浓度确定为IC50(nM)值,并使用Prism(5.01版;GraphPad)软件计算。结果列于下表2中。
在下表中,以下符号用于评估对酶的抑制能力。
0-50nM=A;50-200nM=B;200-1,000nM=C;>1,000nM=D
[表2]
如表2所示,证实本发明的实施例化合物有效抑制TTK激酶。因此,本发明的实施例化合物可以有效地用于预防或治疗与TTK激酶相关的疾病的药物组合物中。
<实验例2>对三阴性乳腺细胞(TNBC)和癌细胞增殖的抑制活性的评估
为评估本发明式1所示化合物对三阴性乳腺癌的治疗效果,进行如下实验。结果列于表3中。
具体而言,为了评估本发明的化合物对三阴性乳腺癌细胞(TNBC)的细胞增殖的抑制活性,进行了以下试验。
为了检查抑制两种三阴性乳腺癌细胞系中(MDA-MB-231)细胞生长的能力,进行了如下试验。根据各细胞的生长能力,将细胞以2,000~3,000个细胞/孔的密度接种于白色透明底96孔板(Corning)中的180μL培养液中,然后在5%CO2和37℃的条件下培养24小时。此后,通过用100%DMSO将10mM储备溶液稀释三倍,总共12个浓度来制备化合物,使得化合物的峰值浓度在10mM至0.05μM的范围内,然后将稀释的化合物在每种细胞培养基中稀释,使得化合物的终浓度在100μM至0.5nM的范围内。将20μL用培养基稀释的稀释液加入前一天接种到96孔板的细胞液中,使稀释液的终浓度在10μM至0.05nM范围内。每个细胞培养5天。为检测细胞活力,将发光细胞活力测定试剂盒(Promega)提供的混合物加入到各个培养的细胞培养基中,在37℃条件下再培养10分钟。然后,测量发光度(荧光)。基于未用化合物处理的溶剂对照细胞的荧光计算根据每种化合物的处理浓度的细胞生长抑制程度。在这种情况下,将抑制50%细胞生长的每种化合物的浓度确定为GI50(nM)值,并使用Prism(7.01版;GraphPad)软件计算。
在下表中,以下符号用于评估细胞增殖抑制活性。
0-100nM=A;100-1,000nM=B;>1,000nM=C;
[表3]
如表3所示,可以看出,本发明的实施例化合物抑制了三阴性乳腺癌细胞的增殖。
然后,以与上述类似的方式评估实施例化合物对除TNBC之外的各种类型的癌的活性。结果列于下表4中。在下表中,以下活性值范围(GI50(nM))用于评估细胞增殖抑制活性。
0-100nM=A;100-1,000nM=B;>1,000nM=C;
[表4]
如表4所示,证实了根据本发明的实施例化合物对除上述TNBC以外的各种实体癌具有活性,并且由于TTK参与细胞中的细胞分裂周期,因此可以预期根据本发明的实施例化合物抑制血癌、脑癌等中各种细胞的增殖。
<实验例3>对小细胞肺癌细胞(SCLC)和癌细胞增殖抑制活性的评估
为了评估根据本发明的式1表示的化合物对SCLC的治疗效果,进行如下实验。结果列于表5中。
具体地,进行以下试验以评估根据本发明的化合物对SCLC细胞中的细胞增殖的抑制活性。
为了检查一种SCLC细胞系中细胞生长的抑制能力,进行如下试验。根据各细胞的生长能力,将细胞以2,000~3,000个细胞/孔的密度接种于白色透明底96孔板(Corning)中的180μL培养液中,然后在5%CO2和37℃的条件下培养24小时。此后,通过用100%DMSO将10mM储备溶液稀释三倍,总共12个浓度来制备化合物,使得化合物的峰值浓度在10mM至0.05μM的范围内,并且将稀释的化合物在每种细胞培养基中稀释,使得化合物的终浓度在100μM至0.5nM的范围内。将20μL用培养基稀释的稀释液加入前一天接种到96孔板的细胞液中,使稀释液的终浓度在10μM至0.05nM范围内。每个细胞培养5天。为了检查细胞活力,将发光细胞活力测定试剂盒(Promega)提供的混合物加入到每种培养的细胞培养基中,并在37℃的条件下再培养10分钟。然后,测量发光度(荧光)。基于未用化合物处理的溶剂对照细胞的荧光计算根据每种化合物的处理浓度的细胞生长抑制程度。在这种情况下,将抑制50%细胞生长的每种化合物的浓度确定为GI50(nM)值,并使用Prism(7.01版;GraphPad)软件计算。
在下表中,以下符号用于评估细胞增殖抑制活性。
0-100nM=A;100-1,000nM=B;>1000nM=C;
[表5]
如表5所示,可以看出本发明的实施例化合物抑制了SCLC细胞的增殖。
<实验例4>本发明化合物对各种激酶的抑制活性的评估
为了评估本发明化合物对更多酶的抑制活性,进行如下实验。
具体地,选自本发明实施例化合物中实施例7的化合物的酶(激酶)的选择性是通过委托DiscoverX公司测量的,并且使用用于ScanMAXTM激酶分析的面板进行了实验。
在这种情况下,用酶处理的药物在DMSO中的浓度设置为1μM,并以与以下表达式1中相同的方式定义对照百分比(对照%)。结果列于下表6中。
[表达式1]
(实施例化合物-阳性对照)/(阴性对照-阳性对照)X 100
其中阳性对照代表在DMSO中具有0%对照百分比的化合物,而阴性对照代表在DMSO中具有100%对照百分比的化合物。对于本发明的酶选择性,当每种酶的对照百分比<30%(即小于30%)时,也判断该化合物具有针对相应酶的活性。
[表6]
此外,为了评估本发明化合物对更多酶的抑制活性,进行了如下实验。具体地,选自本发明实施例化合物实施例64的化合物的酶(激酶)的选择性是通过委托DiscoverX公司测量的,并且使用用于ScanMAXTM激酶分析的面板进行了实验。在这种情况下,用酶处理的药物在DMSO中的浓度设置为1μM,并以与以下表达式1中相同的方式定义对照百分比(对照%)。结果列于下表7中。
[表达式1]
(实施例化合物-阳性对照)/(阴性对照-阳性对照)X 100
其中阳性对照代表在DMSO中具有0%对照百分比的化合物,而阴性对照代表在DMSO中具有100%对照百分比的化合物。对于本发明的酶选择性,当每种酶的对照百分比<35%(即小于35%)时,也判断该化合物具有针对相应酶的活性。
[表7]
<实验例5>基于实验例3的一些激酶活性的测量
为了评价根据本发明的化合物对LRRK2和JNKs的抑制活性,如下进行实验。
1)LRRK2酶活性
使用如下所述的方法使实施例7的化合物与纯化的人LRRK2(Invitrogen#PR8604B)酶反应以评价实施例7的化合物抑制酶的能力。40mM Tris-HCl(pH 7.4)、20mMMgCl2、0.5mg/mL BSA和50μM DTT的组合物用作反应缓冲液,测试物质的所有反应均在反应缓冲液中进行。使用连续稀释方法将化合物从10mM DMSO储备液开始稀释12倍,并在最终化合物浓度为50、10、2、0.4、0.08、0.016、0.0032、0.00064、0.000128、0.0000256、0.00000512和0.000001024μM时测量酶活性。在测试中,纯化的ATP(10μM)和酶底物(0.2μg)与人LRRK2(25ng)酶在25℃下反应2小时,然后使用体外ADP-GloTM激酶测定法(Promega)确定酶活性。酶活反应溶液、ADP-Glo反应溶液和酶能力检测溶液以2:2:1的比例反应,用发光测定酶活性的抑制程度。基于未用化合物处理的溶剂对照的酶活性的荧光计算根据每种化合物的处理浓度对酶活性的抑制程度。在这种情况下,将抑制50%酶活性的每种化合物的浓度确定为IC50(nM)值,并使用Prism(5.01版;GraphPad)软件计算。结果列于下表8中。
2)JNK1、2和3酶活性
使用激酶HotSpot服务(Reaction Biology Corporation)测量实施例7的化合物对酶的IC50值,并在10μM的ATP浓度下在相同条件下进行测试。从10mM的峰值浓度开始,以3倍浓度梯度测量化合物的浓度。
所有实验方法均按照激酶HotSpot客户协议(http://www.reactionbiology.com//Kinase_Assay_Protocol)中提供的方法进行。实验结果列于下表8中。
[表8]
酶 | 活性 |
LRRK2 | <1,000nM |
JNK1 | <100nM |
JNK2 | <100nM |
JNK3 | <100nM |
虽然已经参考优选的制备例、实施例和实验例详细描述了本发明,但本公开的范围不限于具体实施例并且应当由所附权利要求解释。此外,本领域普通技术人员将理解,在不脱离本发明的范围的情况下,可以以各种方式进行改变和修改。
Claims (17)
1.一种由下式1表示的化合物,或其异构体、其溶剂化物、其水合物或其药学上可接受的盐:
[式1]
(其中,
X是CH或N;
R1是-H、卤素、氰基或卤代烷基;
R2是C3-10环烷基、C3-10环烯基、-NHA1或-OA2;
其中A1是C1-10直链或支链烷基、C3-10环烷基,或包含一个或多个选自由N、O和S组成的组的杂原子的3-至9-元杂环烷基,其中所述烷基、环烷基和杂环烷基各自独立地未被取代或被一个或多个选自由如下组成的组的非氢取代基取代:卤素、C1-5直链或支链烷基、C3-10环烷基、C1-4直链或支链烷基磺酰基、C1-4烷基氨基磺酰基和C1-5直链或支链烷氧基;
A2是C3-10环烷基,其中所述环烷基未被取代或被一个或多个选自C1-3直链或支链烷基和羟基的非氢取代基取代;
R3是-H、C1-6直链或支链烷氧基或丙烯酰胺,其中所述C1-6直链或支链烷氧基未被取代或被卤代烷基取代,并且R4是-H或C1-6直链或支链烷氧基,或
R3和R4与包含它们所键合的碳原子的苯环一起形成包含一个或多个选自由N、O和S组成的组的杂原子的9-至10-元双环;
R5是-H、C1-6烷基氨基羰基、未取代或取代的苯基、氧代噁唑烷基、二氧化噻唑烷基、氧代吡咯烷基、二氧化噻嗪基、氧代吗啉基或选自由吡唑基、三唑基、噻唑基、噁唑基、吡啶基和咪唑基组成的组的杂芳基,其中所述杂芳基可以未被取代或被一个或多个选自由如下组成的组的非氢取代基取代:C1-5烷基、卤素和包含一个或多个选自由N、O和S组成的组的杂原子的3-至7-元杂环烷基,或可与C3-10环烷基稠合形成双环,并且所述取代的苯基被羟基取代,或依次被C1-5烷基、包含一个或多个选自由N、O和S组成的组中的杂原子的3-至7-元杂环烷基和C3-10环烷基或烷基羰基取代;并且
R6是-H、卤素或C1-10直链或支链烷基。
2.如权利要求1所述的式1的化合物或其异构体、其溶剂化物、其水合物或其药学上可接受的盐,其中R2是C3-8环烷基、C3-6环烯基、-NHA1或-OA2,
A1是C1-6直链或支链烷基、C3-7环烷基或包含一个或多个O原子的3-至6-元杂环烷基,
其中,当A1是C1-6直链或支链烷基时,所述烷基未被取代或被一个或多个选自由如下组成的组的非氢取代基取代:C3-6环烷基、C1-3直链或支链烷基磺酰基、C1-3烷基氨基磺酰基和C1-3直链或支链烷氧基,
当A1是C3-7环烷基时,所述环烷基未被取代或被一个或多个氟部分取代,并且
当A1是包含一个或多个O原子的3-至6-元杂环烷基时,所述杂环烷基未被取代或被一个或多个C1-3直链烷基部分取代,并且
A2是C3-6环烷基,其中所述环烷基未被取代或被一个或多个选自C1-3直链或支链烷基和羟基的非氢取代基取代。
4.如权利要求1所述的式1的化合物或其异构体、其溶剂化物、其水合物或其药学上可接受的盐,其中R3是-H、C1-4直链或支链烷氧基或丙烯酰胺,其中C1-4直链烷氧基未被取代或被三氟甲基取代,并且R4是-H或C1-3直链烷氧基,或
R3和R4与包含它们所键合的碳原子的苯环一起形成包含一个或多个O原子的9-元和10-元双环。
5.如权利要求4所述的式1的化合物或其异构体、其溶剂化物、其水合物或其药学上可接受的盐,其中R3和R4与包含它们所键合的碳原子的苯环一起形成包含一个或多个O原子的9-和10-元双环,并且9-至10-元双环是二氢苯并二噁英或二氢苯并呋喃。
6.如权利要求1所述的式1的化合物或其异构体、其溶剂化物、其水合物或其药学上可接受的盐,其中R5是-H、C1-3烷基氨基羰基、未取代的或取代的苯基、氧代噁唑烷基、二氧化噻唑烷基、氧代吡咯烷基、二氧化噻嗪基、氧代吗啉基或选自由吡唑基、三唑基、噻唑基、噁唑基、吡啶基和咪唑基组成的组的杂芳基,其中所述杂芳基可以未被取代或被一个或多个选自由如下组成的组的非氢取代基取代:C1-3烷基、氟和包含一个或多个O原子的4-至6-元杂环烷基,或可与C3-5环烷基稠合形成双环,并且所述的取代的苯基被羟基或C1-3烷基取代,其中所述C1-3烷基被乙酰哌嗪或C3-6环烷基哌嗪取代。
8.如权利要求1所述的式1的化合物或其异构体、其溶剂化物、其水合物或其药学上可接受的盐,其中,当X是CH时,
R1是氰基或三氟甲基;
R2是-NHA1,其中A1为C3-7环烷基;
R3是C1-6直链或支链烷氧基,并且R4是-H,或R3和R4与包含它们所键合的碳原子的苯环一起形成包含一个或多个O原子的9-元和10-元双环;
R5是氧代吡咯烷基;并且
R6是-H。
9.如权利要求1所述的式1的化合物或其异构体、其溶剂化物、其水合物或其药学上可接受的盐,其中,当X是N时,
R1是-H、氯、氟、溴、碘、氰基或三氟甲基,
R2是C3-7环烷基、环己烯基、-NHA1或-OA2,
A1是C1-6直链或支链烷基、C3-7环烷基或包含一个或多个O原子的3至6元杂环烷基,
其中,当A1是C1-6直链或支链烷基时,所述烷基未被取代或被一个或多个选自由如下组成的组的非氢取代基取代:C3-6环烷基、C1-3直链或支链烷基磺酰基、C1-3烷基氨基磺酰基和C1-3直链或支链烷氧基,
当A1是C3-7环烷基时,所述环烷基未被取代或被一个或多个氟部分取代,并且
当A1是包含一个或多个O原子的3-至6-元杂环烷基时,所述杂环烷基未被取代或被一个或多个C1-3直链烷基部分取代,
A2是C3-6环烷基,其中所述环烷基未被取代或被一个或多个选自C1-3直链或支链烷基和羟基的非氢取代基取代,
R3是-H、C1-4直链或支链烷氧基或丙烯酰胺,其中所述C1-4直链烷氧基未被取代或被三氟甲基取代,并且R4是-H或C1-3直链烷氧基,或
R3和R4与包含它们所键合的碳原子的苯环一起形成包含一个或多个O原子的9-至10-元双环,
R5是-H、C1-3烷基氨基羰基、未取代的或取代的苯基、氧代噁唑烷基、二氧化噻唑烷基、氧代吡咯烷基、二氧化噻嗪基、氧代吗啉基、或选自由吡唑基、三唑基、噻唑基、噁唑基、吡啶基和咪唑基组成的组的杂芳基,其中所述杂芳基可以未被取代或被一个或多个选自由如下组成的组的非氢取代基取代:C1-3烷基、氟和包含一个或多个O原子的4-至6-元杂环烷基,或可与C3-5环烷基稠合形成双环,并且所述取代的苯基被羟基或C1-3烷基取代,其中C1-3烷基被乙酰哌嗪或C3-6环烷基哌嗪取代,并且
R6是-H、卤素或C1-3直链烷基。
13.如权利要求1所述的式1的化合物或其异构体、其溶剂化物、其水合物或其药学上可接受的盐,其中式1表示的化合物包括选自由下列化合物组成的组中的任一种:
(1)(S)-4-(仲丁氨基)-2-((2-甲氧基-4-(1-甲基-1H-吡唑-5-基)苯基)氨基)-7H-吡咯并[2,3-d]嘧啶-5-腈;
(2)4-(环戊基氨基)-2-((2-甲氧基-4-(1-甲基-1H-吡唑-3-基)苯基)氨基)-7H-吡咯并[2,3-d]嘧啶-5-腈;
(3)4-(环己基氨基)-2-((2-甲氧基-4-(2-氧代噁唑烷-3-基)苯基)氨基)-7H-吡咯并[2,3-d]嘧啶-5-腈;
(4)N4-环己基-N2-(2-甲氧基-4-(1-甲基-1H-吡唑-5-基)苯基)-7H-吡咯并[2,3-d]嘧啶-2,4-二胺;
(5)5-氯-N4-环己基-N2-(2-甲氧基-4-(1-甲基-1H-吡唑-5-基)苯基)-7H-吡咯并[2,3-d]嘧啶-2,4-二胺;
(6)N4-环己基-N2-(2-甲氧基-4-(1-甲基-1H-吡唑-5-基)苯基)-5-(三氟甲基)-7H-吡咯并[2,3-d]嘧啶-2,4-二胺;
(7)4-(环己基氨基)-2-((2-甲氧基-4-(1-甲基-1H-吡唑-5-基)苯基)氨基)-7H-吡咯并[2,3-d]嘧啶-5-腈;
(8)4-((环戊基甲基)氨基)-2-((2-甲氧基-4-(1-甲基-1H-吡唑-5-基)苯基)氨基)-7H-吡咯并[2,3-d]嘧啶-5-腈;
(9)2-((2-甲氧基-4-(1-甲基-1H-吡唑-5-基)苯基)氨基)-4-(甲氨基)-7H-吡咯并[2,3-d]嘧啶-5-腈;
(10)(R)-4-(仲丁氨基)-2-((2-甲氧基-4-(1-甲基-1H-吡唑-5-基)苯基)氨基)-7H-吡咯并[2,3-d]嘧啶-5-腈;
(11)4-(丁基氨基)-2-((2-乙氧基-4-(4-甲基-4H-1,2,4-三唑-3-基)苯基)氨基)-7H-吡咯并[2,3-d]嘧啶-5-腈;
(12)2-((2-甲氧基-4-(1-甲基-1H-吡唑-5-基)苯基)氨基)-4-(新戊基氨基)-7H-吡咯并[2,3-d]嘧啶-5-腈;
(13)2-((2-甲氧基-4-(1-甲基-1H-吡唑-5-基)苯基)氨基)-4-((2-甲氧基乙基)氨基)-7H-吡咯并[2,3-d]嘧啶-5-腈;
(14)2-((2-乙氧基-4-(4-甲基-4H-1,2,4-三唑-3-基)苯基)氨基)-4-((2-(甲基磺酰基)乙基)氨基)-7H-吡咯并[2,3-d]嘧啶-5-腈;
(15)2-((2-甲氧基-4-(1-甲基-1H-吡唑-5-基)苯基)氨基)-4-((四氢-2H-吡喃-4-基)氨基)-7H-吡咯并[2,3-d]嘧啶-5-腈;
(16)4-(环戊基氨基)-2-((2-甲氧基-4-(1-甲基-1H-吡唑-5-基)苯基)氨基)-7H-吡咯并[2,3-d]嘧啶-5-腈;
(17)4-(环戊基氨基)-2-((2-甲氧基-4-(噻唑-2-基)苯基)氨基)-7H-吡咯并[2,3-d]嘧啶-5-腈;
(18)4-(环己基氨基)-2-((4-(3,5-二甲基异噁唑-4-基)-2-甲氧基苯基)氨基)-7H-吡咯并[2,3-d]嘧啶-5-腈;
(19)4-(环己基氨基)-2-((2-甲氧基-4-(1-(四氢-2H-吡喃-4-基)-1H-吡唑-4-基)苯基)氨基)-7H-吡咯并[2,3-d]嘧啶-5-腈;
(20)4-(环己基氨基)-2-((2-甲氧基-4-(1-(氧杂环丁-3-基)-1H-吡唑-4-基)苯基)氨基)-7H-吡咯并[2,3-d]嘧啶-5-腈;
(21)2-((4'-((4-乙酰哌嗪-1-基)甲基)-[1,1'-联苯]-4-基)氨基)-4-(环己基氨基)-7H-吡咯并[2,3-d]嘧啶-5-腈;
(22)4-(环己基氨基)-2-((4'-((4-环丙基哌嗪-1-基)甲基)-[1,1'-联苯]-4-基)氨基)-7H-吡咯并[2,3-d]嘧啶-5-腈;
(23)2-((4'-((4-乙酰哌嗪-1-基)甲基)-3-甲氧基-[1,1'-联苯]-4-基)氨基)-4-(环己基氨基)-7H-吡咯并[2,3-d]嘧啶-5-腈;
(24)4-(环己基氨基)-2-((4-(6-氟吡啶-3-基)-2-甲氧基苯基)氨基)-7H-吡咯并[2,3-d]嘧啶-5-腈;
(25)4-(环己基氨基)-2-((2-甲氧基-4-(1-甲基-1H-1,2,3-三唑-4-基)苯基)氨基)-7H-吡咯并[2,3-d]嘧啶-5-腈;
(26)4-(环己基氨基)-2-((2-甲氧基-4-(1-甲基-1H-1,2,4-三唑-5-基)苯基)氨基)-7H-吡咯并[2,3-d]嘧啶-5-腈;
(27)4-(环己基氨基)-2-((2-甲氧基-4-(1-甲基-1H-1,2,4-三唑-3-基)苯基)氨基)-7H-吡咯并[2,3-d]嘧啶-5-腈;
(28)4-(环戊基氨基)-2-((2-异丁氧基-4-(2-氧代吡咯烷-1-基)苯基)氨基)-7H-吡咯并[2,3-d]嘧啶-5-腈;
(29)2-((4-(1,1-二氧化异噻唑烷-2-基)-3-氟苯基)氨基)-4-((四氢-2H-吡喃-4-基)氨基)-7H-吡咯并[2,3-d]嘧啶-5-腈;
(30)4-(环戊基氨基)-2-((2-甲氧基-4-(1-甲基-1H-咪唑-5-基)苯基)氨基)-7H-吡咯并[2,3-d]嘧啶-5-腈;
(31)4-(环己基氨基)-2-((4-(6,7-二氢-5H-吡咯并[2,1-c][1,2,4]三唑-3-基)-2-甲氧基苯基)氨基)-7H-吡咯并[2,3-d]嘧啶-5-腈;
(32)4-(((1s,4s)-4-羟基-4-甲基环己基)氧)-2-((2-甲氧基-4-(2-氧代吡咯烷-1-基)苯基)氨基)-7H-吡咯并[2,3-d]嘧啶-5-腈;
(33)4-(环戊基氨基)-2-((4-(1-甲基-1H-吡唑-5-基)-2,3-二氢苯并呋喃-7-基)氨基)-7H-吡咯并[2,3-d]嘧啶-5-腈;
(34)4-(环己基氨基)-2-((4-(2,4-二甲基-1H-咪唑-1-基)-2-甲氧基苯基)氨基)-7H-吡咯并[2,3-d]嘧啶-5-腈;
(35)4-(环戊基氨基)-2-((2-甲氧基-5-甲基-4-(1-甲基-1H-吡唑-5-基)苯基)氨基)-7H-吡咯并[2,3-d]嘧啶-5-腈;
(36)4-(环己基氨基)-2-((2-乙氧基-4-(1-甲基-1H-吡唑-5-基)苯基)氨基)-7H-吡咯并[2,3-d]嘧啶-5-腈;
(37)4-(环己基氨基)-2-((4-(1-甲基-1H-吡唑-5-基)苯基)氨基)-7H-吡咯并[2,3-d]嘧啶-5-腈;
(38)4-(环戊基氨基)-2-((8-(1-甲基-1H-吡唑-5-基)-2,3-二氢苯并[b][1,4]二噁英-5-基)氨基)-7H-吡咯并[2,3-d]嘧啶-5-腈;
(39)4-(环己基氨基)-2-((8-(1-甲基-1H-吡唑-5-基)-2,3-二氢苯并[b][1,4]二噁英-5-基)氨基)-7H-吡咯并[2,3-d]嘧啶-5-腈;
(40)2-((8-(1-甲基-1H-吡唑-5-基)-2,3-二氢苯并[b][1,4]二噁英-5-基)氨基)-4-((四氢-2H-吡喃-4-基)氨基)-7H-吡咯并[2,3-d]嘧啶-5-腈;
(41)2-((4'-((4-乙酰哌嗪-1-基)甲基)-3-甲氧基-[1,1'-联苯]-4-基)氨基)-4-(环戊基氨基)-7H-吡咯并[2,3-d]嘧啶-5-腈;
(42)4-(环戊基氨基)-2-((4-(6-氟吡啶-3-基)-2-甲氧基苯基)氨基)-7H-吡咯并[2,3-d]嘧啶-5-腈;
(43)4-(环戊基氨基)-2-((2-甲氧基-4-(1-甲基-1H-吡唑-4-基)苯基)氨基)-7H-吡咯并[2,3-d]嘧啶-5-腈;
(44)4-(环戊基氨基)-2-((4-(3,5-二甲基异噁唑-4-基)-2-甲氧基苯基)氨基)-7H-吡咯并[2,3-d]嘧啶-5-腈;
(45)4-(环己氧基)-2-((2-甲氧基-4-(1-甲基-1H-吡唑-5-基)苯基)氨基)-7H-吡咯并[2,3-d]嘧啶-5-腈;
(46)4-环丙基-2-((2-乙氧基-4-(4-甲基-4H-1,2,4-三唑-3-基)苯基)氨基)-7H-吡咯并[2,3-d]嘧啶-5-腈;
(47)1-(4-((4-(环戊基氨基)-7H-吡咯并[2,3-d]嘧啶-2-基)氨基)-3-甲氧基苯基)吡咯烷-2-酮;
(48)1-(4-((4-(环己基氨基)-7H-吡咯并[2,3-d]嘧啶-2-基)氨基)-3-甲氧基苯基)吡咯烷-2-酮;
(49)4-((2-甲氧基乙基)氨基)-2-((8-(1-甲基-1H-吡唑-5-基)-2,3-二氢苯并[b][1,4]二噁英-5-基)氨基)-7H-吡咯并[2,3-d]嘧啶-5-腈;
(50)4-((环戊基甲基)氨基)-2-((8-(1-甲基-1H-吡唑-5-基)-2,3-二氢苯并[b][1,4]二噁英-5-基)氨基)-7H-吡咯并[2,3-d]嘧啶-5-腈;
(51)1-(3-甲氧基-4-((4-(甲氨基)-5-(三氟甲基)-7H-吡咯并[2,3-d]嘧啶-2-基)氨基)苯基)吡咯烷-2-酮;
(52)1-(4-((4-(环戊基氨基)-5-(三氟甲基)-7H-吡咯并[2,3-d]嘧啶-2-基)氨基)-3-甲氧基苯基)吡咯烷-2-酮;
(53)1-(4-((4-(环己基氨基)-5-(三氟甲基)-7H-吡咯并[2,3-d]嘧啶-2-基)氨基)-3-甲氧基苯基)吡咯烷-2-酮;
(54)2-((2-甲氧基-4-(2-氧代吡咯烷-1-基)苯基)氨基)-4-(甲氨基)-7H-吡咯并[2,3-d]嘧啶-5-腈;
(55)4-(环戊基氨基)-2-((2-甲氧基-4-(2-氧代吡咯烷-1-基)苯基)氨基)-7H-吡咯并[2,3-d]嘧啶-5-腈;
(56)4-(环己基氨基)-2-((2-甲氧基-4-(2-氧代吡咯烷-1-基)苯基)氨基)-7H-吡咯并[2,3-d]嘧啶-5-腈;
(57)4-(环戊基氨基)-2-((4-(1,1-二氧化-1,2-噻嗪烷-2-基)-3-氟苯基)氨基)-7H-吡咯并[2,3-d]嘧啶-5-腈;
(58)2-((4-(1,1-二氧化-1,2-噻嗪烷-2-基)-3-氟苯基)氨基)-4-((四氢-2H-吡喃-4-基)氨基)-7H-吡咯并[2,3-d]嘧啶-5-腈;
(59)4-(环庚基氨基)-2-((8-(1-甲基-1H-吡唑-5-基)-2,3-二氢苯并[b][1,4]二噁英-5-基)氨基)-7H-吡咯并[2,3-d]嘧啶-5-腈;
(60)2-((8-(1-甲基-1H-吡唑-5-基)-2,3-二氢苯并[b][1,4]二噁英-5-基)氨基)-4-(新戊基氨基)-7H-吡咯并[2,3-d]嘧啶-5-腈;
(61)4-(((1R,4S)-二环[2.2.1]庚烷-2-基)氨基)-2-((8-(1-甲基-1H-吡唑-5-基)-2,3-二氢苯并[b][1,4]二噁英-5-基)氨基)-7H-吡咯并[2,3-d]嘧啶-5-腈;
(62)1-(4-((4-(环己基氨基)-3-(三氟甲基)-1H-吡咯并[2,3-b]吡啶-6-基)氨基)-3-甲氧基苯基)吡咯烷-2-酮;
(63)4-(环戊基氨基)-6-((2-甲氧基-4-(2-氧代吡咯烷-1-基)苯基)氨基)-1H-吡咯并[2,3-b]吡啶-3-腈;
(64)4-(环己基氨基)-6-((2-甲氧基-4-(2-氧代吡咯烷-1-基)苯基)氨基)-1H-吡咯并[2,3-b]吡啶-3-腈;
(65)4-(异丙基氨基)-2-((2-甲氧基-4-(2-氧代吡咯烷-1-基)苯基)氨基)-7H-吡咯并[2,3-d]嘧啶-5-腈;
(66)4-(异丁基氨基)-2-((2-甲氧基-4-(2-氧代吡咯烷-1-基)苯基)氨基)-7H-吡咯并[2,3-d]嘧啶-5-腈;
(67)4-(丁基氨基)-2-((2-甲氧基-4-(2-氧代吡咯烷-1-基)苯基)氨基)-7H-吡咯并[2,3-d]嘧啶-5-腈;
(68)(S)-4-(仲丁氨基)-2-((2-甲氧基-4-(2-氧代吡咯烷-1-基)苯基)氨基)-7H-吡咯并[2,3-d]嘧啶-5-腈;
(69)4-(环丁基氨基)-2-((2-甲氧基-4-(2-氧代吡咯烷-1-基)苯基)氨基)-7H-吡咯并[2,3-d]嘧啶-5-腈;
(70)4-((环丁基甲基)氨基)-2-((2-甲氧基-4-(2-氧代吡咯烷-1-基)苯基)氨基)-7H-吡咯并[2,3-d]嘧啶-5-腈;
(71)4-((环戊基甲基)氨基)-2-((2-甲氧基-4-(2-氧代吡咯烷-1-基)苯基)氨基)-7H-吡咯并[2,3-d]嘧啶-5-腈;
(72)4-((1-甲氧基-2-甲基丙烷-2-基)氨基)-2-((2-甲氧基-4-(2-氧代吡咯烷-1-基)苯基)氨基)-7H-吡咯并[2,3-d]嘧啶-5-腈;
(73)2-((2-甲氧基-4-(2-氧代吡咯烷-1-基)苯基)氨基)-4-(氧杂环丁-3-基氨基)-7H-吡咯并[2,3-d]嘧啶-5-腈;
(74)2-((2-甲氧基-4-(2-氧代吡咯烷-1-基)苯基)氨基)-4-((四氢-2H-吡喃-4-基)氨基)-7H-吡咯并[2,3-d]嘧啶-5-腈;
(75)2-((8-(1-甲基-1H-吡唑-5-基)-2,3-二氢苯并[b][1,4]二噁英-5-基)氨基)-4-(甲氨基)-7H-吡咯并[2,3-d]嘧啶-5-腈;
(76)4-(异丙基氨基)-2-((8-(1-甲基-1H-吡唑-5-基)-2,3-二氢苯并[b][1,4]二噁英-5-基)氨基)-7H-吡咯并[2,3-d]嘧啶-5-腈;
(77)2-((2-甲氧基-4-(2-氧代吡咯烷-1-基)苯基)氨基)-4-(新戊基氨基)-7H-吡咯并[2,3-d]嘧啶-5-腈;
(78)4-(环己基氨基)-2-((2-乙氧基-4-(2-氧代吡咯烷-1-基)苯基)氨基)-7H-吡咯并[2,3-d]嘧啶-5-腈;
(79)4-(环己基氨基)-2-((8-(2-氧代吡咯烷-1-基)-2,3-二氢苯并[b][1,4]二噁英-5-基)氨基)-7H-吡咯并[2,3-d]嘧啶-5-腈;
(80)4-(环己基氨基)-2-((4-(2-氧代吡咯烷-1-基)苯基)氨基)-7H-吡咯并[2,3-d]嘧啶-5-腈;
(81)4-(环己基氨基)-2-((2-甲氧基-4-(3-氧代吗啉基)苯基)氨基)-7H-吡咯并[2,3-d]嘧啶-5-腈;
(82)4-(环丁基氨基)-2-((8-(1-甲基-1H-吡唑-5-基)-2,3-二氢苯并[b][1,4]二噁英-5-基)氨基)-7H-吡咯并[2,3-d]嘧啶-5-腈;
(83)4-((2-(环丙基磺酰基)乙基)氨基)-2-((8-(1-甲基-1H-吡唑-5-基)-2,3-二氢苯并[b][1,4]二噁英-5-基)氨基)-7H-吡咯并[2,3-d]嘧啶-5-腈;
(84)2-((8-(1-甲基-1H-吡唑-5-基)-2,3-二氢苯并[b][1,4]二噁英-5-基)氨基)-4-((2-(甲基磺酰基)乙基)氨基)-7H-吡咯并[2,3-d]嘧啶-5-腈;
(85)2-((5-氰基-2-((8-(1-甲基-1H-吡唑-5-基)-2,3-二氢苯并[b][1,4]二噁英-5-基)氨基)-7H-吡咯并[2,3-d]嘧啶-4-基)氨基)-N,N-二甲基乙烷-1-磺酰胺;
(86)4-((5-氯-4-(((1s,4S)-4-羟基-4-甲基环己基)氧)-7H-吡咯并[2,3-d]嘧啶-2-基)氨基)-N,N-二甲基-3-(((R)-1,1,1-三氟丙烷-2-基)氧)苯甲酰胺;
(87)4-(环戊基氨基)-6-((2-甲氧基-4-(1-甲基-1H-吡唑-5-基)苯基)氨基)-1H-吡咯并[2,3-b]吡啶-3-腈;
(88)4-(环戊基氨基)-6-((8-(1-甲基-1H-吡唑-5-基)-2,3-二氢苯并[b][1,4]二噁英-5-基)氨基)-1H-吡咯并[2,3-b]吡啶-3-腈;
(89)2-((8-(1-甲基-1H-吡唑-4-基)-2,3-二氢苯并[b][1,4]二噁英-5-基)氨基)-4-((四氢-2H-吡喃-4-基)氨基)-7H-吡咯并[2,3-d]嘧啶-5-腈;
(90)2-((2-甲氧基-4-(4-甲基-4H-1,2,4-三唑-3-基)苯基)氨基)-4-((四氢-2H-吡喃-4-基)氨基)-7H-吡咯并[2,3-d]嘧啶-5-腈;
(91)2-((4-(3,5-二甲基异噁唑-4-基)-2-甲氧基苯基)氨基)-4-((四氢-2H-吡喃-4-基)氨基)-7H-吡咯并[2,3-d]嘧啶-5-腈;
(92)2-((2-甲氧基-4-(1-甲基-1H-吡唑-4-基)苯基)氨基)-4-((四氢-2H-吡喃-4-基)氨基)-7H-吡咯并[2,3-d]嘧啶-5-腈;
(93)2-((2-甲氧基-4-(2-甲基-1H-咪唑-1-基)苯基)氨基)-4-((四氢-2H-吡喃-4-基)氨基)-7H-吡咯并[2,3-d]嘧啶-5-腈;
(94)4-((2-甲氧基乙基)氨基)-2-((8-(1-甲基-1H-吡唑-4-基)-2,3-二氢苯并[b][1,4]二噁英-5-基)氨基)-7H-吡咯并[2,3-d]嘧啶-5-腈;
(95)2-((2-甲氧基-4-(4-甲基-4H-1,2,4-三唑-3-基)苯基)氨基)-4-((2-甲氧基乙基)氨基)-7H-吡咯并[2,3-d]嘧啶-5-腈;
(96)2-((4-(3,5-二甲基异噁唑-4-基)-2-甲氧基苯基)氨基)-4-((2-甲氧基乙基)氨基)-7H-吡咯并[2,3-d]嘧啶-5-腈;
(97)2-((2-甲氧基-4-(1-甲基-1H-吡唑-4-基)苯基)氨基)-4-((2-甲氧基乙基)氨基)-7H-吡咯并[2,3-d]嘧啶-5-腈;
(98)2-((2-甲氧基-4-(2-甲基-1H-咪唑-1-基)苯基)氨基)-4-((2-甲氧基乙基)氨基)-7H-吡咯并[2,3-d]嘧啶-5-腈;
(99)4-(环丙基氨基)-2-((8-(1-甲基-1H-吡唑-5-基)-2,3-二氢苯并[b][1,4]二噁英-5-基)氨基)-7H-吡咯并[2,3-d]嘧啶-5-腈;
(100)4-((环丁基甲基)氨基)-2-((8-(1-甲基-1H-吡唑-5-基)-2,3-二氢苯并[b][1,4]二噁英-5-基)氨基)-7H-吡咯并[2,3-d]嘧啶-5-腈;
(101)(R)-4-((1-甲氧基丙烷-2-基)氨基)-2-((8-(1-甲基-1H-吡唑-5-基)-2,3-二氢苯并[b][1,4]二噁英-5-基)氨基)-7H-吡咯并[2,3-d]嘧啶-5-腈;
(102)2-((4-(3,5-二甲基异噁唑-4-基)-5-氟-2-甲氧基苯基)氨基)-4-((四氢-2H-吡喃-4-基)氨基)-7H-吡咯并[2,3-d]嘧啶-5-腈;
(103)4-(环戊基氨基)-2-((5-氟-2-甲氧基-4-(1-甲基-1H-吡唑-5-基)苯基)氨基)-7H-吡咯并[2,3-d]嘧啶-5-腈;
(104)4-(环戊基氨基)-2-((4-(3,5-二甲基异噁唑-4-基)-5-氟-2-甲氧基苯基)氨基)-7H-吡咯并[2,3-d]嘧啶-5-腈;
(105)4-(环己基氨基)-2-((5-氟-2-甲氧基-4-(1-甲基-1H-吡唑-5-基)苯基)氨基)-7H-吡咯并[2,3-d]嘧啶-5-腈;
(106)N2-(2-甲氧基-4-(1-甲基-1H-吡唑-5-基)苯基)-N4-(四氢-2H-吡喃-4-基)-5-(三氟甲基)-7H-吡咯并[2,3-d]嘧啶-2,4-二胺;
(107)N2-(8-(1-甲基-1H-吡唑-5-基)-2,3-二氢苯并[b][1,4]二噁英-5-基)-N4-(四氢-2H-吡喃-4-基)-5-(三氟甲基)-7H-吡咯并[2,3-d]嘧啶-2,4-二胺;
(108)1-(8-((4-((四氢-2H-吡喃-4-基)氨基)-5-(三氟甲基)-7H-吡咯并[2,3-d]嘧啶-2-基)氨基)-2,3-二氢苯并[b][1,4]二噁英-5-基)吡咯烷-2-酮;
(109)4-((2,2-二甲基四氢-2H-吡喃-4-基)氨基)-2-((8-(1-甲基-1H-吡唑-5-基)-2,3-二氢苯并[b][1,4]二噁英-5-基)氨基)-7H-吡咯并[2,3-d]嘧啶-5-腈;
(110)4-((3,3-二氟环戊基)氨基)-2-((2-甲氧基-4-(1-甲基-1H-吡唑-5-基)苯基)氨基)-7H-吡咯并[2,3-d]嘧啶-5-腈;
(111)4-环丙基-2-((2-甲氧基-4-(1-甲基-1H-吡唑-5-基)苯基)氨基)-7H-吡咯并[2,3-d]嘧啶-5-腈;
(112)4-环丙基-2-((8-(1-甲基-1H-吡唑-5-基)-2,3-二氢苯并[b][1,4]二噁英-5-基)氨基)-7H-吡咯并[2,3-d]嘧啶-5-腈;
(113)N4-环戊基-N2-(2-甲氧基-4-(1-甲基-1H-吡唑-5-基)苯基)-7H-吡咯并[2,3-d]嘧啶-2,4-二胺;
(114)N4-环戊基-N2-(8-(1-甲基-1H-吡唑-5-基)-2,3-二氢苯并[b][1,4]二噁英-5-基)-7H-吡咯并[2,3-d]嘧啶-2,4-二胺;
(115)4-((2,2-二甲基四氢-2H-吡喃-4-基)氨基)-2-((2-甲氧基-4-(1-甲基-1H-吡唑-5-基)苯基)氨基)-7H-吡咯并[2,3-d]嘧啶-5-腈;
(116)4-((3,3-二氟环戊基)氨基)-2-((8-(1-甲基-1H-吡唑-5-基)-2,3-二氢苯并[b][1,4]二噁英-5-基)氨基)-7H-吡咯并[2,3-d]嘧啶-5-腈;
(117)N2-(2-甲氧基-4-(4-甲基-4H-1,2,4-三唑-3-基)苯基)-N4-(四氢-2H-吡喃-4-基)-5-(三氟甲基)-7H-吡咯并[2,3-d]嘧啶-2,4-二胺;
(118)N2-(2-甲氧基-4-(1-甲基-1H-吡唑-4-基)苯基)-N4-(四氢-2H-吡喃-4-基)-5-(三氟甲基)-7H-吡咯并[2,3-d]嘧啶-2,4-二胺;
(119)2-((3-甲氧基-4-(1-甲基-1H-吡唑-5-基)苯基)氨基)-4-((四氢-2H-吡喃-4-基)氨基)-7H-吡咯并[2,3-d]嘧啶-5-腈;
(120)4-(环戊基氨基)-2-((3-甲氧基-4-(1-甲基-1H-吡唑-5-基)苯基)氨基)-7H-吡咯并[2,3-d]嘧啶-5-腈;
(121)4-(环己基氨基)-2-((3-甲氧基-4-(1-甲基-1H-吡唑-5-基)苯基)氨基)-7H-吡咯并[2,3-d]嘧啶-5-腈;
(122)2-((5-氟-2-甲氧基-4-(1-甲基-1H-吡唑-5-基)苯基)氨基)-4-((四氢-2H-吡喃-4-基)氨基)-7H-吡咯并[2,3-d]嘧啶-5-腈;
(123)4-(环己基氨基)-2-((4-(3,5-二甲基异噁唑-4-基)-5-氟-2-甲氧基苯基)氨基)-7H-吡咯并[2,3-d]嘧啶-5-腈;
(124)2-((5-氟-2-甲氧基-4-(1-甲基-1H-吡唑-4-基)苯基)氨基)-4-((四氢-2H-吡喃-4-基)氨基)-7H-吡咯并[2,3-d]嘧啶-5-腈;
(125)4-(环戊基氨基)-2-((5-氟-2-甲氧基-4-(1-甲基-1H-吡唑-4-基)苯基)氨基)-7H-吡咯并[2,3-d]嘧啶-5-腈;
(126)4-(环己基氨基)-2-((5-氟-2-甲氧基-4-(1-甲基-1H-吡唑-4-基)苯基)氨基)-7H-吡咯并[2,3-d]嘧啶-5-腈;
(127)5-氯-N4-环戊基-N2-(2-甲氧基-4-(1-甲基-1H-吡唑-5-基)苯基)-7H-吡咯并[2,3-d]嘧啶-2,4-二胺;
(128)5-氯-N4-环戊基-N2-(8-(1-甲基-1H-吡唑-5-基)-2,3-二氢苯并[b][1,4]二噁英-5-基)-7H-吡咯并[2,3-d]嘧啶-2,4-二胺;
(129)4-(环己-1-烯-1-基)-2-((2-甲氧基-4-(1-甲基-1H-吡唑-5-基)苯基)氨基)-7H-吡咯并[2,3-d]嘧啶-5-腈;
(130)4-(环己-1-烯-1-基)-2-((8-(1-甲基-1H-吡唑-5-基)-2,3-二氢苯并[b][1,4]二噁英-5-基)氨基)-7H-吡咯并[2,3-d]嘧啶-5-腈;
(131)N2-(4-(3,5-二甲基异噁唑-4-基)-2-甲氧基苯基)-N4-(四氢-2H-吡喃-4-基)-5-(三氟甲基)-7H-吡咯并[2,3-d]嘧啶-2,4-二胺;
(132)N4-环戊基-N2-(2-甲氧基-4-(1-甲基-1H-吡唑-5-基)苯基)-5-(三氟甲基)-7H-吡咯并[2,3-d]嘧啶-2,4-二胺;
(133)N4-环戊基-N2-(8-(1-甲基-1H-吡唑-5-基)-2,3-二氢苯并[b][1,4]二噁英-5-基)-5-(三氟甲基)-7H-吡咯并[2,3-d]嘧啶-2,4-二胺;
(134)2-((3-甲氧基-[1,1'-联苯]-4-基)氨基)-4-((四氢-2H-吡喃-4-基)氨基)-7H-吡咯并[2,3-d]嘧啶-5-腈;
(135)2-((3-甲氧基-4-(1-甲基-1H-吡唑-4-基)苯基)氨基)-4-((四氢-2H-吡喃-4-基)氨基)-7H-吡咯并[2,3-d]嘧啶-5-腈;
(136)4-(环戊基氨基)-2-((3-甲氧基-4-(1-甲基-1H-吡唑-4-基)苯基)氨基)-7H-吡咯并[2,3-d]嘧啶-5-腈;
(137)4-(环己基氨基)-2-((3-甲氧基-4-(1-甲基-1H-吡唑-4-基)苯基)氨基)-7H-吡咯并[2,3-d]嘧啶-5-腈;
(138)2-((4-(3,5-二甲基异噁唑-4-基)-3-甲氧基苯基)氨基)-4-((四氢-2H-吡喃-4-基)氨基)-7H-吡咯并[2,3-d]嘧啶-5-腈;
(139)4-(环戊基氨基)-2-((4-(3,5-二甲基异噁唑-4-基)-3-甲氧基苯基)氨基)-7H-吡咯并[2,3-d]嘧啶-5-腈;
(140)4-(环己基氨基)-2-((4-(3,5-二甲基异噁唑-4-基)-3-甲氧基苯基)氨基)-7H-吡咯并[2,3-d]嘧啶-5-腈;
(141)2-((3'-羟基-3-甲氧基-[1,1'-联苯]-4-基)氨基)-4-((四氢-2H-吡喃-4-基)氨基)-7H-吡咯并[2,3-d]嘧啶-5-腈;
(142)N-(2-((5-氰基-4-(环戊基氨基)-7H-吡咯并[2,3-d]嘧啶-2-基)氨基)-5-(1-甲基-1H-吡唑-5-基)苯基)丙烯酰胺;
(143)4-((2,2-二甲基四氢-2H-吡喃-4-基)氨基)-2-((2-甲氧基-4-(4-甲基-4H-1,2,4-三唑-3-基)苯基)氨基)-7H-吡咯并[2,3-d]嘧啶-5-腈;
(144)4-((2,2-二甲基四氢-2H-吡喃-4-基)氨基)-2-((2-甲氧基-4-(1-甲基-1H-吡唑-4-基)苯基)氨基)-7H-吡咯并[2,3-d]嘧啶-5-腈;
(145)4-((2,2-二甲基四氢-2H-吡喃-4-基)氨基)-2-((8-(1-甲基-1H-吡唑-4-基)-2,3-二氢苯并[b][1,4]二噁英-5-基)氨基)-7H-吡咯并[2,3-d]嘧啶-5-腈;
(146)4-(((1R,4S)-二环[2.2.1]庚烷-2-基)氨基)-2-((4-(3,5-二甲基异噁唑-4-基)-2-甲氧基苯基)氨基)-7H-吡咯并[2,3-d]嘧啶-5-腈;
(147)4-(((1R,4S)-二环[2.2.1]庚烷-2-基)氨基)-2-((8-(1-甲基-1H-吡唑-4-基)-2,3-二氢苯并[b][1,4]二噁英-5-基)氨基)-7H-吡咯并[2,3-d]嘧啶-5-腈;
(148)4-(((1R,4S)-二环[2.2.1]庚烷-2-基)氨基)-2-((8-(2-氧代吡咯烷-1-基)-2,3-二氢苯并[b][1,4]二噁英-5-基)氨基)-7H-吡咯并[2,3-d]嘧啶-5-腈;
(149)4-(环庚基氨基)-2-((4-(3,5-二甲基异噁唑-4-基)-2-甲氧基苯基)氨基)-7H-吡咯并[2,3-d]嘧啶-5-腈;
(150)4-(环庚基氨基)-2-((8-(1-甲基-1H-吡唑-4-基)-2,3-二氢苯并[b][1,4]二噁英-5-基)氨基)-7H-吡咯并[2,3-d]嘧啶-5-腈;
(151)4-(环庚基氨基)-2-((8-(2-氧代吡咯烷-1-基)-2,3-二氢苯并[b][1,4]二噁英-5-基)氨基)-7H-吡咯并[2,3-d]嘧啶-5-腈;
(152)4-((3,3-二氟环己基)氨基)-2-((2-甲氧基-4-(1-甲基-1H-吡唑-5-基)苯基)氨基)-7H-吡咯并[2,3-d]嘧啶-5-腈;
(153)4-((3,3-二氟环己基)氨基)-2-((8-(1-甲基-1H-吡唑-5-基)-2,3-二氢苯并[b][1,4]二噁英-5-基)氨基)-7H-吡咯并[2,3-d]嘧啶-5-腈;
(154)4-((3,3-二氟环己基)氨基)-2-((2-甲氧基-4-(4-甲基-4H-1,2,4-三唑-3-基)苯基)氨基)-7H-吡咯并[2,3-d]嘧啶-5-腈;
(155)4-(环戊基氨基)-2-((4-(1,1-二氧化-1,2-噻嗪烷-2-基)-2-甲氧基苯基)氨基)-7H-吡咯并[2,3-d]嘧啶-5-腈;
(156)4-(环戊基氨基)-2-((4-(1,1-二氧化-1,2-噻嗪烷-2-基)苯基)氨基)-7H-吡咯并[2,3-d]嘧啶-5-腈;
(157)4-(环戊基氨基)-2-((4-(1,1-二氧化异噻唑烷-2-基)-2-甲氧基苯基)氨基)-7H-吡咯并[2,3-d]嘧啶-5-腈;
(158)4-(环戊基氨基)-2-((4-(1,1-二氧化异噻唑烷-2-基)苯基)氨基)-7H-吡咯并[2,3-d]嘧啶-5-腈;
(159)4-((3,3-二氟环戊基)氨基)-2-((8-(1-甲基-1H-吡唑-4-基)-2,3-二氢苯并[b][1,4]二噁英-5-基)氨基)-7H-吡咯并[2,3-d]嘧啶-5-腈;
(160)2-((8-(1-甲基-1H-吡唑-5-基)-2,3-二氢苯并[b][1,4]二噁英-5-基)氨基)-4-(氧杂环丁-3-基氨基)-7H-吡咯并[2,3-d]嘧啶-5-腈;
(161)2-((2-甲氧基-4-(1-甲基-1H-吡唑-5-基)苯基)氨基)-4-(氧杂环丁-3-基氨基)-7H-吡咯并[2,3-d]嘧啶-5-腈;
(162)4-((2,2-二甲基四氢-2H-吡喃-4-基)氨基)-2-((3-甲氧基-4-(1-甲基-1H-吡唑-5-基)苯基)氨基)-7H-吡咯并[2,3-d]嘧啶-5-腈;
(163)2-((4-(1,1-二氧化-1,2-噻嗪烷-2-基)-2-甲氧基苯基)氨基)-4-((四氢-2H-吡喃-4-基)氨基)-7H-吡咯并[2,3-d]嘧啶-5-腈;
(164)2-((4-(1,1-二氧化-1,2-噻嗪烷-2-基)苯基)氨基)-4-((四氢-2H-吡喃-4-基)氨基)-7H-吡咯并[2,3-d]嘧啶-5-腈;
(165)2-((4-(1,1-二氧化异噻唑烷-2-基)-2-甲氧基苯基)氨基)-4-((四氢-2H-吡喃-4-基)氨基)-7H-吡咯并[2,3-d]嘧啶-5-腈;
(166)2-((4-(1,1-二氧化异噻唑烷-2-基)苯基)氨基)-4-((四氢-2H-吡喃-4-基)氨基)-7H-吡咯并[2,3-d]嘧啶-5-腈;
(167)(R)-2-((2-甲氧基-4-(2-甲基-1H-咪唑-1-基)苯基)氨基)-4-((1-甲氧基丙烷-2-基)氨基)-7H-吡咯并[2,3-d]嘧啶-5-腈;
(168)(R)-2-((2-甲氧基-4-(1-甲基-1H-吡唑-5-基)苯基)氨基)-4-((1-甲氧基丙烷-2-基)氨基)-7H-吡咯并[2,3-d]嘧啶-5-腈;
(169)(R)-4-((1-甲氧基丙烷-2-基)氨基)-2-((8-(1-甲基-1H-吡唑-4-基)-2,3-二氢苯并[b][1,4]二噁英-5-基)氨基)-7H-吡咯并[2,3-d]嘧啶-5-腈;
(170)2-((2,3-二氢苯并[b][1,4]二噁英-5-基)氨基)-4-((四氢-2H-吡喃-4-基)氨基)-7H-吡咯并[2,3-d]嘧啶-5-腈;
(171)2-((2,3-二氢苯并[b][1,4]二噁英-5-基)氨基)-4-((2,2-二甲基四氢-2H-吡喃-4-基)氨基)-7H-吡咯并[2,3-d]嘧啶-5-腈;
(172)N4-(2,2-二甲基四氢-2H-吡喃-4-基)-N2-(8-(1-甲基-1H-吡唑-5-基)-2,3-二氢苯并[b][1,4]二噁英-5-基)-5-(三氟甲基)-7H-吡咯并[2,3-d]嘧啶-2,4-二胺;
(173)4-(环戊基氨基)-2-((4-(1,1-二氧化异噻唑烷-2-基)-3-氟苯基)氨基)-7H-吡咯并[2,3-d]嘧啶-5-腈;
(174)2-(3-甲氧基-4-((4-((四氢-2H-吡喃-4-基)氨基)-5-(三氟甲基)-7H-吡咯并[2,3-d]嘧啶-2-基)氨基)苯基)异噻唑烷1,1-二氧化物;
(175)2-(3-甲氧基-4-((4-((四氢-2H-吡喃-4-基)氨基)-5-(三氟甲基)-7H-吡咯并[2,3-d]嘧啶-2-基)氨基)苯基)-1,2-噻嗪烷1,1-二氧化物;
(176)2-(4-((4-(环戊基氨基)-5-(三氟甲基)-7H-吡咯并[2,3-d]嘧啶-2-基)氨基)-3-甲氧基苯基)异噻唑烷1,1-二氧化物;
(177)2-(4-((4-(环戊基氨基)-5-(三氟甲基)-7H-吡咯并[2,3-d]嘧啶-2-基)氨基)-3-甲氧基苯基)-1,2-噻嗪烷1,1-二氧化物。
14.一种用于预防或治疗癌症的药物组合物,其包含作为活性成分的权利要求1中限定的式1表示的化合物,或其立体异构体、其水合物、或其药学上可接受的盐。
15.如权利要求14所述的药物组合物,其中所述化合物对一种或多种选自由如下组成的组的蛋白激酶表现出抑制活性:JAK2、SNARK、TTK、YSK4、JNK1、FLT3、PRKCE、CAMKK1、JNK3、TYK2、RSK2、CAMKK2、ULK3、ULK1、RSK4、TRKB、LRRK2、JNK3、AAK1、GAK、SBK1、TYK2、CAMK2D、MAP3K2、KIT、CSNK1D、CSNK1E、MEK4,RIOK1、DYRK1B、PKN2、FLT3、JNK2,RIPK5,MEK3,ABL1、MAPKAPK2、GRK4和SRPK3。
16.如权利要求14所述的药物组合物,其中所述化合物表现出针对TTK激酶的抑制活性。
17.如权利要求14所述的药物组合物,其中所述癌症包含选自由如下组成的组的一种或多种:假粘液瘤、肝内胆管癌、肝母细胞瘤、肝癌、甲状腺癌、结肠癌、睾丸癌、骨髓增生异常综合征、胶质母细胞瘤、口腔癌、唇癌、蕈样真菌病、急性髓系白血病、急性淋巴细胞白血病、基底细胞癌、卵巢上皮癌、卵巢生殖细胞癌、男性乳腺癌、脑癌、垂体腺瘤、多发性骨髓瘤、胆囊癌、胆管癌、结直肠癌、慢性粒细胞白血病、慢性淋巴细胞白血病、视网膜母细胞瘤、脉络膜黑色素瘤、壶腹癌、膀胱癌、腹膜癌、甲状旁腺癌、肾上腺癌、鼻和鼻窦癌、非小细胞肺癌、舌癌、星形细胞瘤、小细胞肺癌、儿童脑癌、小儿淋巴瘤、小儿白血病、小肠癌、脑膜瘤、食道癌、神经胶质瘤、肾盂癌、肾癌、心脏癌、十二指肠癌、恶性软组织癌、恶性骨癌、恶性淋巴瘤、恶性间皮瘤、恶性黑色素瘤、眼癌、外阴癌、输尿管癌、尿道癌、原发部位不明的癌症、胃淋巴瘤、胃癌、胃类癌、胃肠道间质瘤、肾母细胞瘤、乳腺癌、肉瘤、阴茎癌、咽癌、妊娠滋养细胞疾病、宫颈癌、子宫内膜癌、子宫肉瘤、前列腺癌、转移性骨癌、转移性脑癌、纵隔癌、直肠癌、直肠类癌、阴道癌、脊髓癌、听神经瘤、胰腺癌、唾液腺癌、卡波西肉瘤、佩吉特病、扁桃体癌、鳞状细胞癌、肺腺癌、肺癌、肺鳞状细胞癌、皮肤癌、肛门癌、横纹肌肉瘤、喉癌、胸膜癌、血癌和胸腺癌。
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Citations (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2011123937A1 (en) * | 2010-04-06 | 2011-10-13 | University Health Network | Kinase inhibitors and method of treating cancer with same |
CN103517903A (zh) * | 2011-03-14 | 2014-01-15 | 癌症研究科技有限公司 | 作为mps1抑制剂的吡咯并吡啶氨基衍生物 |
WO2016073771A2 (en) * | 2014-11-06 | 2016-05-12 | Ohio State Innovation Foundation | Pyrrolopyrimidine derivatives as mps1/ttk kinase inhibitors |
CN106459035A (zh) * | 2014-02-28 | 2017-02-22 | 癌症研究科技有限公司 | N2‑苯基‑吡啶并[3,4‑d]嘧啶‑2,8‑二胺衍生物及其作为mps1抑制剂的用途 |
CN106715427A (zh) * | 2014-07-14 | 2017-05-24 | 西格诺药品有限公司 | 利用取代的吡咯并嘧啶化合物、其组合物治疗癌症的方法 |
WO2018155916A2 (ko) * | 2017-02-22 | 2018-08-30 | 재단법인 대구경북첨단의료산업진흥재단 | 피롤로-피리미딘 유도체 화합물, 이의 제조방법 및 이를 유효성분으로 함유하는 단백질 키나아제 관련 질환의 예방 또는 치료용 약학적 조성물 |
WO2018174650A1 (ko) * | 2017-03-23 | 2018-09-27 | 재단법인 대구경북첨단의료산업진흥재단 | 피롤로-피리딘 유도체 화합물, 이의 제조방법 및 이를 유효성분으로 함유하는 단백질 키나아제 관련 질환의 예방 또는 치료용 약학적 조성물 |
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2020
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- 2020-03-13 JP JP2021548167A patent/JP2022523351A/ja active Pending
- 2020-03-13 WO PCT/KR2020/003558 patent/WO2020185044A1/ko unknown
- 2020-03-13 US US17/438,341 patent/US20230183243A1/en active Pending
- 2020-03-13 BR BR112021017829A patent/BR112021017829A2/pt unknown
- 2020-03-13 MX MX2021010970A patent/MX2021010970A/es unknown
- 2020-03-13 EP EP20768933.2A patent/EP3915986A4/en not_active Withdrawn
- 2020-03-13 CA CA3130478A patent/CA3130478A1/en active Pending
- 2020-03-13 CN CN202080020325.XA patent/CN113574057A/zh active Pending
- 2020-03-13 AU AU2020236300A patent/AU2020236300A1/en not_active Abandoned
Patent Citations (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2011123937A1 (en) * | 2010-04-06 | 2011-10-13 | University Health Network | Kinase inhibitors and method of treating cancer with same |
CN103517903A (zh) * | 2011-03-14 | 2014-01-15 | 癌症研究科技有限公司 | 作为mps1抑制剂的吡咯并吡啶氨基衍生物 |
CN106459035A (zh) * | 2014-02-28 | 2017-02-22 | 癌症研究科技有限公司 | N2‑苯基‑吡啶并[3,4‑d]嘧啶‑2,8‑二胺衍生物及其作为mps1抑制剂的用途 |
CN106715427A (zh) * | 2014-07-14 | 2017-05-24 | 西格诺药品有限公司 | 利用取代的吡咯并嘧啶化合物、其组合物治疗癌症的方法 |
WO2016073771A2 (en) * | 2014-11-06 | 2016-05-12 | Ohio State Innovation Foundation | Pyrrolopyrimidine derivatives as mps1/ttk kinase inhibitors |
WO2018155916A2 (ko) * | 2017-02-22 | 2018-08-30 | 재단법인 대구경북첨단의료산업진흥재단 | 피롤로-피리미딘 유도체 화합물, 이의 제조방법 및 이를 유효성분으로 함유하는 단백질 키나아제 관련 질환의 예방 또는 치료용 약학적 조성물 |
WO2018174650A1 (ko) * | 2017-03-23 | 2018-09-27 | 재단법인 대구경북첨단의료산업진흥재단 | 피롤로-피리딘 유도체 화합물, 이의 제조방법 및 이를 유효성분으로 함유하는 단백질 키나아제 관련 질환의 예방 또는 치료용 약학적 조성물 |
Non-Patent Citations (1)
Title |
---|
JENNIFER R. RIGGS 等: "Design and Optimization Leading to an Orally Active TTK Protein Kinase Inhibitor with Robust Single Agent Efficacy", JOURNAL OF MEDICINAL CHEMISTRY, vol. 62, pages 4403 * |
Also Published As
Publication number | Publication date |
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EP3915986A4 (en) | 2023-01-25 |
US20230183243A1 (en) | 2023-06-15 |
JP2022523351A (ja) | 2022-04-22 |
WO2020185044A1 (ko) | 2020-09-17 |
MX2021010970A (es) | 2021-10-13 |
AU2020236300A1 (en) | 2021-09-16 |
CA3130478A1 (en) | 2020-09-17 |
KR20200110250A (ko) | 2020-09-23 |
EP3915986A1 (en) | 2021-12-01 |
BR112021017829A2 (pt) | 2021-11-30 |
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