CN114929675A - 作为粘着斑激酶抑制剂的新型金刚烷衍生物 - Google Patents
作为粘着斑激酶抑制剂的新型金刚烷衍生物 Download PDFInfo
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- CN114929675A CN114929675A CN202080082764.3A CN202080082764A CN114929675A CN 114929675 A CN114929675 A CN 114929675A CN 202080082764 A CN202080082764 A CN 202080082764A CN 114929675 A CN114929675 A CN 114929675A
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- amino
- pyrimidin
- trifluoromethyl
- cancer
- adamantan
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Images
Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
- C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
- C07D239/48—Two nitrogen atoms
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—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
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—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
- A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
Abstract
本发明提供作为粘着斑激酶抑制剂的新型金刚烷衍生物、其药学上可接受的盐、其立体异构体、其水合物或溶剂化物和包含其的药物组合物。
Description
技术领域
本发明涉及作为粘着斑激酶抑制剂的新型金刚烷衍生物、其药学上可接受的盐、其立体异构体、其水合物或溶剂化物和包含其的药物组合物。
背景技术
癌症被称为最可怕的不治之症,尽管癌症作为一种高死亡率的疾病在世界范围内的发病率不断上升,但现代医学尚未开发出合适的治疗方法。目前开发的抗癌药物主要与抑制细胞生长或诱导细胞凋亡的机制有关,但由于其不仅影响癌细胞,而且影响正常细胞,因此具有副作用(如细胞毒性)。随着近年医学生物学和分子生物学技术的发展,已经揭示了癌细胞的独特特性,并且通过基因组序列分析发现了许多涉及这些特性的新分子水平靶点,从而开发针对这些靶点的抗癌药物。
一般来说,存在于细胞中的信号转导系统是彼此有机联系在一起的,形成一个复杂的机制,从而调节细胞的增殖、生长、转移和死亡。在信号转导系统中,蛋白质酪氨酸激酶在细胞内调节功能中发挥重要作用。许多疾病与蛋白酪氨酸激酶引发的异常细胞反应有关。这些疾病包括自身免疫性疾病、炎性疾病、骨病、代谢性疾病、神经和神经变性疾病、癌症、心血管疾病、过敏和哮喘、阿尔茨海默病、病毒性疾病和激素相关疾病。特别地,在癌细胞中经常观察到蛋白酪氨酸激酶的异常表达和突变,因此在药物化学中正在进行许多研究,以开发有效的蛋白酪氨酸激酶抑制剂作为抗癌治疗剂。
粘着斑激酶(Focal adhesion kinase,FAK)是一种由PTK2基因编码的蛋白质,是一种存在于细胞质中的非受体酪氨酸激酶,已知接收来自整合素和生长因子受体的信号,并在调节癌症干细胞的细胞生长、增殖、粘附、迁移、侵袭和自我繁殖中发挥重要作用。FAK通过Y397的自磷酸化调节和活化,并通过Src蛋白(另一种酪氨酸激酶)的SH2结构域与自磷酸化的Y397结合,Src蛋白使FAK的Y925磷酸化,从而吸引衔接蛋白Grb2并诱导参与调节细胞增殖的ras和MAP激酶通路的活化。
在正常细胞中,经由FAK的信号转导受到严格的调控,但是在转化为肿瘤的细胞中,FAK过度表达并活化,从而导致恶性肿瘤的各种性质。已知FAK的过度表达通过促进肿瘤细胞增殖、侵袭和转移、抑制癌细胞死亡和增加血管生成来在致癌过程(肿瘤形成、侵袭、转移等)中发挥关键作用。作为确认FAK在该过程中的关联的研究结果,观察到在FAK活性被FAK反义寡核苷酸抑制的肿瘤细胞中,正常细胞粘附被抑制,从而经历细胞凋亡过程。据报道,在FAK表达缺陷的成纤维细胞中,与正常细胞相比,细胞形状从纺锤形变为圆形,细胞迁移因趋化信号而被抑制,还确认了这种现象通过FAK的重新表达恢复到原始状态。
已确认FAK蛋白和mRNA在各种实体癌(如乳腺癌、结直肠癌、肺癌、卵巢癌、前列腺癌等)和血液癌(如急性髓性白血病)中过表达,与正常组织相比,恶性组织中显示活性的磷酸化FAK增加。特别地,FAK活性越高,癌症患者的预后越差。因此,认为FAK的活性在人类癌症的进展或转移中发挥重要作用。
此外,富含脯氨酸的酪氨酸激酶2(proline-rich tyrosine kinase 2,PYK2)是FAK的唯一亚型,在神经元中分布最为广泛,最近已确认具有作为开发用于小细胞肺癌、前列腺癌、肝细胞癌、神经胶质瘤等的抗癌药物的分子靶点的价值。
如此,期待通过抑制FAK活性的抗癌作用,因此,全世界有约20种抑制FAK活性的小分子化合物正在开发中。在它们当中,TAE226通过单独施用或与多西他赛(docetaxel)联合施用,在由紫杉烷敏感细胞系(taxane-sensitive cell line)(HeyA8、SKOV3ip)和紫杉烷抗性细胞系(taxane-resistant cell line)(HeyA8-MDR)形成的三种乳腺癌动物模型中显示出优异的疗效,使肿瘤尺寸缩小87%至90%,但发现其抑制胰岛素受体并引起严重的副作用,如意外抑制葡萄糖代谢、降低血液浓度等,因此在临床前研究中失败。反而,PF-04554878和GSK2256098正处于临床阶段研究中。
[相关技术参考]
(非专利文献1)Cancer Res.2007,67:10976-10983
(非专利文献2)Expert Opin.Investing.Drugs,2010,19:777-788
发明内容
技术问题
为了解决上述问题,本发明的一个目的在于提供作为粘着斑激酶抑制剂的新型金刚烷衍生物、其药学上可接受的盐、其立体异构体、其水合物或溶剂化物。
本发明的另一个目的在于提供一种药物组合物,所述药物组合物包含作为粘着斑激酶抑制剂的新型金刚烷衍生物、其药学上可接受的盐、其立体异构体、其水合物或溶剂化物作为活性成分。
本发明的另一个目的在于提供一种用于预防或治疗FAK相关疾病的药物组合物,所述药物组合物包含作为粘着斑激酶抑制剂的新型金刚烷衍生物、其药学上可接受的盐、其立体异构体、其水合物或溶剂化物作为活性成分。
本发明的另一个目的在于提供一种用于预防或治疗FAK活性相关疾病的方法,所述方法包括向个体施用治疗有效量的作为粘着斑激酶抑制剂的新型金刚烷衍生物、其药学上可接受的盐、其立体异构体、其水合物或溶剂化物。
本发明的另一个目的在于提供作为粘着斑激酶抑制剂的新型金刚烷衍生物、其药学上可接受的盐、其立体异构体、其水合物或溶剂化物用于预防或治疗FAK活性相关疾病的用途。
本发明的另一个目的在于提供作为粘着斑激酶抑制剂的新型金刚烷衍生物、其药学上可接受的盐、其立体异构体、其水合物或溶剂化物在制备用于预防或治疗FAK活性相关疾病的药物中的用途。
技术方案
根据本发明,作为粘着斑激酶抑制剂的新型金刚烷衍生物、其药学上可接受的盐、其立体异构体、其水合物或溶剂化物由下式1表示:
[式1]
其中在上式1中,
L1和L2各自独立地为单键、C1-10亚烷基、C2-10亚烯基、C2-10亚炔基、-N(Ra)-、-C(=O)-N(Ra)-、-N(Ra)-C(=O)-、-C(=O)-、-O-、-C(=O)-O-、-N(Ra)-C(=O)-O-、-N(Ra)-S(=O)-、-N(Ra)-S(=O)2-、-S(=O)(=N-Ra)-或-S-;
R1和R2各自独立地为C1-10亚杂环烷基、C3-10亚环烷基、C5-16亚芳基或C4-10亚杂芳基;
R3为H、C1-10烷基、C2-10烯基、-O-Ra、=O、-NH-Ra、-NH(C=O)-Ra或C1-10杂环烷基;
R4为-O-Ra;
R5和R6各自独立地为H或C1-10烷基;
R7为-CF3或卤素原子;
Ra为H、-CF3或C1-10烷基;和
m、n、p和q各自独立地为0或1。
W1、W2和W3可以各自独立地为CH或N;
W4可以为CH2、NH或O;
Ra可以为H、-CF3或C1-10烷基;和
a、b、c和d可以各自独立地为1、2或3。
Ra可以为H、-CF3或C1-10烷基。
在一个实施方案中,上式1表示的化合物可以为下式2表示的化合物:
[式2]
其中在上式2中,
L1为-N(Ra)-、-C(=O)-N(Ra)-或-O-;
L2为-N(Ra)-、-C(=O)-N(Ra)-、-N(Ra)-C(=O)-、-C(=O)-或-C(=O)-O-;
R6为H或C1-10烷基;
R7为-CF3或Cl;
Ra为H、-CF3或C1-10烷基;和
m、n、p和q各自独立地为0或1。
有利作用
本发明的作为粘着斑激酶抑制剂的新型金刚烷衍生物、其药学上可接受的盐、其立体异构体、其水合物或溶剂化物可以在不抑制胰岛素受体(Ins-R)活性的情况下表现出作用效果,同时选择性抑制FAK和Pyk2(FAK2)的活性。
根据本发明的金刚烷衍生物、其药学上可接受的盐、其立体异构体、其水合物或溶剂化物可以抑制FAK的异常活性。通过抑制FAK的异常活性,它们可以有利地用于预防和治疗诱导的异常细胞生长疾病。
附图说明
图1显示了用于分析本发明的金刚烷衍生物化合物对癌细胞球状体的生长抑制程度的3D球状体测定(3D spheroid assay)的结果。
图2显示了本发明的金刚烷衍生物化合物对人三阴性乳腺癌细胞系MDA-MB-231的3D侵袭抑制程度的显微镜分析结果。
图3显示了本发明的金刚烷衍生物化合物对人三阴性乳腺癌细胞系MDA-MB-231的3D侵袭抑制程度的分析结果。
图4显示了在三阴性乳腺癌异种移植小鼠模型中本发明的金刚烷衍生物化合物对肿瘤生长的抑制程度的分析结果。
具体实施方式
在下文中,本申请中使用的术语仅用于描述某个示例性实施方案,并不旨在限制本发明。除非另有说明,单数形式的术语可以包括复数形式。在本申请中,术语如“包括”、“具有”等应旨在指定本文描述的特征、步骤、操作、组件、部件或其组合的存在,不应被解释为预先排除一个或多个其他特征、步骤、操作、组件、部件或其组合的可能的存在或加入。
除非另有定义,本文使用的所有术语,包括技术或科学术语,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。除非在本申请中明确定义,在通用词典中定义的术语应被解释为具有与相关技术中的上下文含义相同的含义,而不应被解释为具有完美的或过度正式的含义。
金刚烷衍生物、其药学上可接受的盐、其立体异构体、其水合物或溶剂化物
在本发明中,在官能团的表述“Cx”中,x可以表示碳(C)的数目,Cx-y可以表示具有x以上y以下个碳的官能团。
在本发明中,术语“取代的”可以表示具有取代基的部分,所述取代基替代了主链的碳上的至少一个氢。“取代”或“被……取代”可以定义为包括隐含条件,其中取代遵循取代原子和取代基的允许化合价,并产生通过取代稳定的化合物,例如,未被重排、环化、去除等天然修饰的化合物。
在本发明中,“单键”是指与L1或L2相邻的原子或原子团直接彼此键合的情况。
在本发明中,“亚烷基”可以指由如上定义的烷基衍生的二价官能团。
在本发明中,“烯基”可以指包含至少一个碳间双键的不饱和烃基,“炔基”可以指包含至少一个碳间三键的不饱和烃基。
在本发明中,“亚烯基”可以指由如上定义的烯基衍生的二价官能团,“亚炔基”可以指由如上定义的炔基衍生的二价官能团。
在本发明中,“卤素原子”可以指F、Cl、Br或I。
在本发明中,“芳基”可以包括单环芳香族结构或多环芳香族结构,以及饱和烃环稠合到单环芳香族或多环芳香族结构中的结构。芳基可以包括苯基、联苯基、萘基、四氢萘基、蒽基、菲基、芘基等,但不限于此。
在本发明中,“杂芳基”可以指单环或多环杂环,其中芳基中的至少一个或多个碳原子被氮(N)、氧(O)或硫(S)取代。杂芳基可以包括吡啶基、噻吩基、三唑基、四唑基、苯并二氧戊环基、苯并噻唑基、苯并噻吩基、喹啉基、吲哚基、异吲哚基、苯并呋喃基、苯并吡咯基、呋喃基、吡咯基、噻唑基、异噻唑基、咪唑基、吡唑基、噁唑基、异噁唑基、吡嗪基、哒嗪基、嘧啶基、异喹啉基、咔唑基、苯并噁唑基、苯并二噁唑基、苯并二噁英基、苯并咪唑基、二氢苯并噻吩基、二氢苯并呋喃基、嘌呤基、中氮茚基、色满基、色烯基、二氢苯并二噁英基等,但不限于此。
在本发明中,“环烷基”可以指通常具有特定碳原子数的含有环的饱和烃环,饱和烃环可以统一指单环和多环结构,以及至少两个环共享至少一对碳原子的环结构。环烷基可以包括环己基、环庚基、环辛基、四氢萘基、金刚烷基等,但不限于此。
在本发明中,“杂环烷基”可以指包含1至4个独立地选自氮(N)、氧(O)和硫(S)的杂原子的饱和单环和多环杂环,或环结构,其中至少两个环共享至少一对碳原子。杂环烷基可以包括环氧乙烷基、氧杂环丁烷基、吗啉基 、硫杂环丁烷基、吡咯烷基、哌啶基、哌嗪基、四氢呋喃基、四氢噻吩基、四氢吡喃基、四氢噻喃基、6-氮杂双环[3.2.1]辛基等,但不限于此。
根据本发明的由式1表示的金刚烷衍生物可以为选自下表1中所示的化合物中的任何一个化合物。
在本发明中,“立体异构体”可以包括非对映异构体和旋光异构体,其中旋光异构体不仅可以包括对映异构体,还可以包括对映异构体的混合物,甚至外消旋体。
在本发明中,“药学上可接受的盐”可以指制药工业中常规使用的盐,例如,由钙、钾、钠、镁等制备的无机离子盐,由盐酸、硝酸、磷酸、溴酸、碘酸、高氯酸、氢碘酸、硫酸等制备的无机酸盐,由乙酸、三氟乙酸、柠檬酸、马来酸、琥珀酸、草酸、苯甲酸、酒石酸、富马酸、扁桃酸、丙酸、乳酸、乙醇酸、葡萄糖酸、半乳糖醛酸、谷氨酸、戊二酸、葡萄糖醛酸、天冬氨酸、抗坏血酸、碳酸、香草酸等制备的有机酸盐,由甲磺酸、乙磺酸、苯磺酸、对甲苯磺酸、萘磺酸等制备的磺酸盐,由甘氨酸、精氨酸、赖氨酸等制备的氨基酸盐,由三甲胺、三乙胺、氨、吡啶、甲基吡啶等制备的胺盐等,但是本发明中所指的盐的类型不限于那些列出的盐。
本发明的“水合物”可以指金刚烷衍生物、其异构体或其药学上可接受的盐与水通过非共价分子间力结合形成的物质,其可以包含化学计量或非化学计量的量的水。特别地,基于1摩尔活性成分,水合物可以以约0.25摩尔至约10摩尔,更特别地约0.5摩尔、约1摩尔、约1.5摩尔、约2摩尔、约2.5摩尔、3摩尔、约5摩尔等的摩尔比例来含有水。
本发明的“溶剂化物”可以指金刚烷衍生物、其异构体或其药学上可接受的盐与水以外的溶剂通过分子间力结合形成的物质,其可以包含化学计量或非化学计量的量的溶剂。特别地,基于1摩尔活性成分,溶剂化物可以以约0.25摩尔至约10摩尔,更特别地约0.5摩尔、约1摩尔、约1.5摩尔、约2摩尔、约2.5摩尔、约3摩尔、约5摩尔等的摩尔比例来含有溶剂分子。
在本发明中,“抑制剂”可以指阻断或降低酶活性的化合物。抑制剂能够进行可逆或不可逆的结合,因此该术语可以包括消灭酶底物的化合物。抑制剂可以修饰酶活性位点上或附近的一个或多个位点,或可以导致酶上其他部位的构象变化。
包含金刚烷衍生物化合物的组合物、其用途和使用其的治疗方法
本发明提供一种药物组合物,所述药物组合物包含金刚烷衍生物、其药学上可接受的盐、其立体异构体、其水合物或溶剂化物作为活性成分。
本发明提供一种用于预防或治疗FAK活性相关疾病的药物组合物,所述药物组合物包含金刚烷衍生物、其药学上可接受的盐、其立体异构体、其水合物或溶剂化物作为活性成分。
此外,根据本发明的金刚烷衍生物、其立体异构体或其药学上可接受的盐可以抑制FAK和Pyk2(FAK2)中的至少一种的活性。
FAK活性相关疾病可以为由FAK的异常活性诱导的异常细胞生长疾病,其可以为选自自身免疫性疾病、炎性疾病、骨病、代谢性疾病、神经和神经变性疾病、癌症、心血管疾病、过敏和哮喘、阿尔茨海默病、病毒性疾病和激素相关疾病的至少一种,优选为选自实体癌和血液癌的任意一种,所述实体癌包括胃癌、肺癌、肝癌、结直肠癌、小肠癌、胰腺癌、脑癌、骨癌、黑素瘤、乳腺癌、子宫癌、宫颈癌、卵巢癌、头颈癌、甲状腺癌、甲状旁腺癌、肾癌、前列腺癌、尿道癌、膀胱癌、间皮瘤等,所述血液癌包括白血病、多发性骨髓瘤、淋巴瘤等。更优选地,由FAK的异常活性诱导的异常细胞生长疾病可以为选自高侵袭性和转移性三阴性乳腺癌、结直肠癌、肺癌和恶性间皮瘤的任意一种。此外,上述疾病可以包括与FAK功能异常有关的症状或疾病。
本发明提供根据本发明的金刚烷衍生物、其药学上可接受的盐、其立体异构体、其水合物或溶剂化物用于预防或治疗FAK活性相关疾病的用途。
此外,本发明提供一种用于预防或治疗FAK活性相关疾病的方法,所述方法包括向个体施用治疗有效量的金刚烷衍生物、其药学上可接受的盐、其立体异构体、其水合物或溶剂化物。
如本文所使用,术语“预防”是指通过施用根据本发明的化合物来抑制FAK活性相关疾病或延迟其发生的所有行为。
如本文所使用,术语“治疗”是指通过施用根据本发明的化合物使FAK活性相关疾病的症状得到改善或好转的所有行为。
此外,本发明提供一种用于抑制FAK和Pyk2(FAK2)活性的方法,所述方法包括向个体施用金刚烷衍生物、其立体异构体或其药学上可接受的盐。
根据本发明的用于预防或治疗FAK活性相关疾病的方法通过施用金刚烷衍生物化合物、其药学上可接受的盐、其立体异构体、其水合物或溶剂化物不仅包括在症状表现之前处理疾病本身,还包括抑制或避免这些症状。在控制疾病时,某种活性成分的预防或治疗剂量可以根据疾病或病症的性质和严重程度以及活性成分的施用途径而变化。其剂量和频率可以根据个体患者的年龄、体重和反应而变化。考虑到这些因素,本领域技术人员可以容易地选择合适的剂量和用法。此外,根据本发明的用于预防或治疗FAK活性相关疾病的方法可以进一步包括施用治疗有效量的有助于治疗疾病的另外的活性剂,连同金刚烷衍生物、其药学上可接受的盐、其立体异构体、其水合物或溶剂化物,所述另外的活性剂可以与金刚烷衍生物、其药学上可接受的盐、其立体异构体、其水合物或溶剂化物一起表现出协同作用或辅助作用。
本发明还提供金刚烷衍生物、其药学上可接受的盐、其立体异构体、其水合物或溶剂化物在制备用于预防或治疗FAK活性相关疾病的药物中的用途。在制备药物时,可以将金刚烷衍生物、其药学上可接受的盐、其立体异构体、其水合物或溶剂化物与可接受的佐剂、稀释剂、载体等组合,可以将其与其他活性剂一起制成复合制剂,从而具有活性成分的协同作用。
本发明的药物组合物可以进一步包含药学上可接受的载体。
在这种情况下,药学上可接受的载体可以为通常用于配制制剂的载体,包括但不限于乳糖、葡萄糖、蔗糖、山梨糖醇、甘露糖醇、淀粉、阿拉伯胶、磷酸钙、藻酸盐、明胶、硅酸钙、微晶纤维素、聚乙烯吡咯烷酮、纤维素、水、糖浆、甲基纤维素、羟基苯甲酸甲酯、羟基苯甲酸丙酯、滑石、硬脂酸镁、矿物油等。此外,本发明的药物组合物除上述成分外,可以进一步包含润滑剂、保湿剂、甜味剂、矫味剂、乳化剂、混悬剂、防腐剂等。
此外,本发明的药物组合物可以进一步包含药物,所述药物选自细胞信号转导抑制剂、有丝分裂抑制剂、烷化剂、抗代谢物、抗生素、生长因子抑制剂、细胞周期抑制剂、拓扑异构酶抑制剂、生物反应调节剂、抗激素剂、抗雄激素、细胞分化/增殖/存活抑制剂和细胞凋亡诱导剂,本发明的药物组合物可以与以上进一步包含的药物组合使用,或者可以在配制成药物时配制成复合药物。
可以根据预期的方法口服或肠胃外施用(例如,静脉内、皮下、腹膜内或局部应用)本发明的药物组合物,其中其剂量根据患者的情况和体重、疾病程度、药物形式、施用途径和时间而变化,但可以由本领域技术人员适当地选择。
以治疗有效量施用本发明的药物组合物。
在本发明中,“治疗有效量”可以指足以以适用于医学治疗的合理收益/风险比来治疗疾病的量,可以根据包括患者疾病的类型、严重程度、药物活性、对药物的敏感性、施用时间、施用途径和排泄率、治疗时间和同时使用的药物在内的因素以及医学领域熟知的其他因素来确定有效剂量的水平。根据本发明的药物组合物可以作为单独的治疗剂施用或与其他治疗剂组合施用,可以与常规治疗剂顺序或同时施用,并且可以以单一或多种方式施用。考虑到上述所有因素,重要的是以一定的量进行施用,其中可以通过最小的量实现最大的效果且不产生副作用,其中该量可以由本领域技术人员容易地确定。
具体地,本发明的药物组合物的有效量可以根据患者的年龄、性别、病情和体重、活性成分在体内的吸收程度、失活率和排泄率、疾病类型和同时使用的药物而变化,一般可以按每1kg体重0.001至160mg,优选0.01至100mg的量施用,可以每天或隔天施用,或者通过将组合物的每日剂量分开以每天1次至3次施用。然而,有效量可以根据施用途径、肥胖的严重程度、性别、体重、年龄等而增加或减少,因此该剂量不旨在以任何方式限制本发明的范围。
在本发明中,“个体”可以指需要预防或治疗疾病的受试者,更具体地可以指哺乳动物,如人、猴、小鼠、狗、猫、马、牛等,但不限于此。
本发明的用途、组合物和治疗方法中提及的事项如果不相互矛盾,则可以同等适用。此外,除非另有定义,本说明书中使用的术语和缩写词均具有其原始含义。
在下文中,为了更好地理解本发明,将通过实施例详细描述本发明。然而,以下提供的实施例仅用于阐明本发明的目的,因此本发明的范围不限于此。提供本发明的实施例是为了向本领域普通技术人员更完整地描述本发明。
实施例
<实施例1>2-((2-((4-(((反式)-5-羟基金刚烷-2-基)氨基)-2-甲氧基苯基)氨基)-5-(三氟甲基)嘧啶-4-基)氨基)-N,3-二甲基苯甲酰胺(化合物1)的制备
[步骤1](反式)-4-((3-甲氧基-4-硝基苯基)氨基)金刚烷-1-醇的制备
将反式-4-氨基金刚烷-1-醇、4-氟-2-甲氧基-1-硝基苯、碳酸钾和二甲亚砜加热至120℃持续5小时,同时充分搅拌。冷却至室温后,将水加入至反应溶液中以沉淀,同时充分搅拌,通过过滤获得沉淀的固体。将所得的固体通过柱色谱法纯化,以获得标题化合物。
[步骤2](反式)-4-((4-氨基-3-甲氧基苯基)氨基)金刚烷-1-醇的制备
将在上述步骤1中制备的(反式)-4-((3-甲氧基-4-硝基苯基)氨基)金刚烷-1-醇溶解在乙醇中,然后向其中加入10%钯/碳催化剂,在氢气压力下搅拌15小时。反应完成后,将所得的溶液通过硅藻土过滤,将滤液减压浓缩,立即用于下一步而不进行进一步的纯化。
[步骤3](反式)-4-((4-((4-氯-5-(三氟甲基)嘧啶-2-基)氨基)-3-甲氧基苯基)氨基)金刚烷-1-醇的制备
将2,4-二氯-5-(三氟甲基)嘧啶溶解在1,2-二氯乙烷和叔丁醇(1:1)的混合溶剂中,然后加入二氯化锌,在室温搅拌30分钟。冷却至0℃后,将在上述步骤2中制备的(反式)-4-((4-氨基-3-甲氧基苯基)氨基)金刚烷-1-醇溶解在1,2-二氯乙烷和叔丁醇(1:1)的混合溶剂中,并缓慢加入。在0℃搅拌1小时后,加入二异丙胺并在室温搅拌15小时。向反应液中倒入冰水,用二氯甲烷萃取,经无水硫酸镁干燥,过滤,然后将滤液浓缩,通过柱层析法纯化,以获得标题化合物。
[步骤4]2-((2-((4-(((反式)-5-羟基金刚烷-2-基)氨基)-2-甲氧基苯基)氨基)-5-(三氟甲基)嘧啶-4-基)氨基)-N,3-二甲基苯甲酰胺的制备
将在上述步骤3中制备的(反式)-4-((4-((4-氯-5-(三氟甲基)嘧啶-2-基)氨基)-3-甲氧基苯基)氨基)金刚烷-1-醇和2-氨基-N,3-二甲基苯甲酰胺溶解在2-丁醇中,然后加入三氟乙酸并在回流下搅拌5小时。冷却至室温后,向反应溶液中加入蒸馏水,然后用乙酸乙酯萃取。将所得的溶液经无水硫酸镁干燥,过滤,然后将滤液浓缩,通过柱层析法纯化,以获得标题化合物。
1H NMR(400MHz,CDCl3):δ8.24(s,1H),8.19(s,1H),7.38(d,J=7.4Hz,1H),7.34(d,J=7.5Hz,1H),7.27–7.22(m,1H),6.12(d,J=1.8Hz,1H),6.04(s,1H),5.76(s,1H),3.78(s,3H),3.44(s,1H),2.83(d,J=4.6Hz,3H),2.22–2.11(m,5H),1.92–1.69(m,8H),1.60–1.40(m,3H)
<实施例2>2-((2-((4-(金刚烷-2-基氨基)-2-甲氧基苯基)氨基)-5-(三氟甲基)嘧啶-4-基)氨基)-N,3-二甲基苯甲酰胺(化合物2)的制备
[步骤1]N-(3-甲氧基-4-硝基苯基)金刚烷-2-胺的制备
通过使用金刚烷-2-胺代替实施例1步骤1中的反式-4-氨基金刚烷-1-醇,以与实施例1相同的方式合成标题化合物。
[步骤2]N-(金刚烷-2-基)-3-甲氧基苯-1,4-二胺的制备
通过使用N-(3-甲氧基-4-硝基苯基)金刚烷-2-胺代替实施例1步骤2中的(反式)-4-((3-甲氧基-4-硝基苯基)氨基)金刚烷-1-醇,以与实施例1相同的方式合成标题化合物。
[步骤3]N-(金刚烷-2-基)-N-(4-氯-5-(三氟甲基)嘧啶-2-基)-2-甲氧基苯-1,4-二胺的制备
通过使用N-(金刚烷-2-基)-3-甲氧基苯-1,4-二胺代替实施例1步骤3中的(反式)-4-((4-氨基-3-甲氧基苯基)氨基)金刚烷-1-醇,以与实施例1相同的方式合成标题化合物。
[步骤4]2-((2-((4-(金刚烷-2-基)氨基)-2-甲氧基苯基)氨基)-5-(三氟甲基)嘧啶-4-基)氨基)-N,3-二甲基苯甲酰胺的制备
通过使用N-(金刚烷-2-基)-N-(4-氯-5-(三氟甲基)嘧啶-2-基)-2-甲氧基苯-1,4-二胺代替实施例1步骤4中的(反式)-4-((4-((4-氯-5-(三氟甲基)嘧啶-2-基)氨基)-3-甲氧基苯基)氨基)金刚烷-1-醇,以与实施例1相同的方式合成标题化合物。
1H NMR(400MHz,DMSO-d6):δ9.10(s,1H),8.30–8.25(m,1H),8.20(s,1H),7.91(s,1H),7.39(d,J=7.7Hz,1H),7.34(d,J=6.9Hz,1H),7.25–7.20(m,1H),7.01(br s,1H),6.32(s,1H),5.40(br s,1H),3.63(s,3H),3.43–3.38(m,1H),2.69(d,J=4.5Hz,3H),2.15–2.00(m,5H),1.94–1.69(m,9H),1.51–1.45(m,2H)
<实施例3>2-((2-((4-(4-(金刚烷-2-基)哌嗪-1-基)-2-甲氧基苯基)氨基)-5-(三氟甲基)嘧啶-4-基)氨基)-N,3-二甲基苯甲酰胺(化合物3)的制备
[步骤1]1-(3-甲氧基-4-硝基苯基)哌嗪的制备
通过使用哌嗪代替实施例1步骤1中的反式-4-氨基金刚烷-1-醇,以与实施例1相同的方式合成标题化合物。
[步骤2]1-(金刚烷-2-基)-4-(3-甲氧基-4-硝基苯基)哌嗪的制备
将在上述步骤1中制备的1-(3-甲氧基-4-硝基苯基)哌嗪、金刚烷-2-酮、三乙酰氧基硼氢化钠、四氢呋喃和乙酸在室温搅拌15小时。向反应液中倒入冰水,用乙酸乙酯萃取,经无水硫酸镁干燥,过滤,然后将滤液浓缩,通过柱层析法纯化,以获得标题化合物。
[步骤3]4-(4-(金刚烷-2-基)哌嗪-1-基)-2-甲氧基苯胺的制备
通过使用1-(金刚烷-2-基)-4-(3-甲氧基-4-硝基苯基)哌嗪代替实施例1步骤2中的(反式)-4-((3-甲氧基-4-硝基苯基)氨基)金刚烷-1-醇,以与实施例1相同的方式合成标题化合物。
[步骤4]N-(4-(4-(金刚烷-2-基)哌嗪-1-基)-2-甲氧基苯基-4-氯-5-(三氟甲基)嘧啶-2-胺的制备
通过使用4-(4-(金刚烷-2-基)哌嗪-1-基)-2-甲氧基苯胺代替实施例1步骤3中的(反式)-4-((4-氨基-3-甲氧基苯基)氨基)金刚烷-1-醇,以与实施例1相同的方式合成标题化合物。
[步骤5]2-((2-((4-(4-(金刚烷-2-基)哌嗪-1-基)-2-甲氧基苯基)氨基)-5-(三氟甲基)嘧啶-4-基)氨基)-N,3-二甲基苯甲酰胺的制备
通过使用N-(4-(4-(金刚烷-2-基)哌嗪-1-基)-2-甲氧基苯基-4-氯-5-(三氟甲基)嘧啶-2-胺代替实施例1步骤4中的(反式)-4-((4-((4-氯-5-(三氟甲基)嘧啶-2-基)氨基)-3-甲氧基苯基)氨基)金刚烷-1-醇,以与实施例1相同的方式合成标题化合物。
1H NMR(400MHz,CDCl3):δ8.26(s,2H,overlapped),7.41(d,J=7.3Hz,1H),7.34(d,J=7.5Hz,1H),7.31–7.26(m,1H),6.47(d,J=2.0Hz,1H),6.09(br s,1H),6.00(s,1H),3.82(s,3H),3.09(m,4H),2.84(d,J=4.8Hz,3H),2.61(m,4H),2.21(s,3H),2.19–2.10(m,2H),1.96–1.82(m,4H),1.76–1.65(m,5H),1.54–1.39(m,2H)
<实施例4>2-((2-((4-(4-((反式)-5-羟基金刚烷-2-基)哌嗪-1-基)-2-甲氧基苯基)氨基)-5-(三氟甲基)嘧啶-4-基)氨基)-N,3-二甲基苯甲酰胺(化合物4)的制备
[步骤1](反式)-4-(4-(3-甲氧基-4-硝基苯基)哌嗪-1-基)金刚烷-1-醇的制备
通过使用5-羟基金刚烷-2-酮代替实施例3步骤2中的金刚烷-2-酮,以与实施例3相同的方式合成标题化合物。
[步骤2](反式)-4-(4-(4-氨基-3-甲氧基苯基)哌嗪-1-基)金刚烷-1-醇的制备
通过使用(反式)-4-(4-(3-甲氧基-4-硝基苯基)哌嗪-1-基)金刚烷-1-醇代替实施例1步骤2中的(反式)-4-((3-甲氧基-4-硝基苯基)氨基)金刚烷-1-醇,以与实施例1相同的方式合成标题化合物。
[步骤3](反式)-4-(4-(4-((4-氯-5-(三氟甲基)嘧啶-2-基)氨基)-3-甲氧基苯基)哌嗪-1-基)金刚烷-1-醇的制备
通过使用(反式)-4-(4-(4-氨基-3-甲氧基苯基)哌嗪-1-基)金刚烷-1-醇代替实施例1步骤3中的(反式)-4-((4-氨基-3-甲氧基苯基)氨基)金刚烷-1-醇,以与实施例1相同的方式合成标题化合物。
[步骤4]2-((2-((4-(4-((反式)-5-羟基金刚烷-2-基)哌嗪-1-基)-2-甲氧基苯基)氨基)-5-(三氟甲基)嘧啶-4-基)氨基)-N,3-二甲基苯甲酰胺的制备
通过使用(反式)-4-(4-(4-((4-氯-5-(三氟甲基)嘧啶-2-基)氨基)-3-甲氧基苯基)哌嗪-1-基)金刚烷-1-醇代替实施例1步骤4中的(反式)-4-((4-((4-氯-5-(三氟甲基)嘧啶-2-基)氨基)-3-甲氧基苯基)氨基)金刚烷-1-醇,以与实施例1相同的方式合成标题化合物。
1H NMR(400MHz,CDCl3):δ8.26(s,2H,重叠),7.41(d,J=7.3Hz,1H),7.34(d,J=7.5Hz,1H),7.31–7.26(m,1H),6.47(d,J=2.0Hz,1H),6.09(br s,1H),6.00(s,1H),3.82(s,3H),3.09(m,4H),2.84(d,J=4.8Hz,3H),2.61(m,4H),2.32–2.26(m,1H),2.21(s,3H),2.14–1.98(m,4H),1.81–1.59(m,6H),1.42–1.24(m,3H)
<实施例5>2-((2-((4-(4-((顺式)-5-羟基金刚烷-2-基)哌嗪-1-基)-2-甲氧基苯基)氨基)-5-(三氟甲基)嘧啶-4-基)氨基)-N,3-二甲基苯甲酰胺(化合物5)的制备
[步骤1](顺式)-4-(4-(3-甲氧基-4-硝基苯基)哌嗪-1-基)金刚烷-1-醇的制备
通过使用5-羟基金刚烷-2-酮代替实施例3步骤2中的金刚烷-2-酮,以与实施例3相同的方式合成标题化合物。
[步骤2](顺式)-4-(4-(4-氨基-3-甲氧基苯基)哌嗪-1-基)金刚烷-1-醇的制备
通过使用(顺式)-4-(4-(3-甲氧基-4-硝基苯基)哌嗪-1-基)金刚烷-1-醇代替实施例1步骤2中的(反式)-4-((3-甲氧基-4-硝基苯基)氨基)金刚烷-1-醇,以与实施例1相同的方式合成标题化合物。
[步骤3](顺式)-4-(4-(4-((4-氯-5-(三氟甲基)嘧啶-2-基)氨基)-3-甲氧基苯基)哌嗪-1-基)金刚烷-1-醇的制备
通过使用(顺式)-4-(4-(4-氨基-3-甲氧基苯基)哌嗪-1-基)金刚烷-1-醇代替实施例1步骤3中的(反式)-4-((4-氨基-3-甲氧基苯基)氨基)金刚烷-1-醇,以与实施例1相同的方式合成标题化合物。
[步骤4]2-((2-((4-(4-((顺式)-5-羟基金刚烷-2-基)哌嗪-1-基)-2-甲氧基苯基)氨基)-5-(三氟甲基)嘧啶-4-基)氨基)-N,3-二甲基苯甲酰胺的制备
通过使用(顺式)-4-(4-(4-((4-氯-5-(三氟甲基)嘧啶-2-基)氨基)-3-甲氧基苯基)哌嗪-1-基)金刚烷-1-醇代替实施例1步骤4中的(反式)-4-((4-((4-氯-5-(三氟甲基)嘧啶-2-基)氨基)-3-甲氧基苯基)氨基)金刚烷-1-醇,以与实施例1相同的方式合成标题化合物。
1H NMR(400MHz,CDCl3):δ8.26(s,2H,重叠),7.41(d,J=7.3Hz,1H),7.34(d,J=7.5Hz,1H),7.31–7.26(m,1H),6.47(d,J=2.0Hz,1H),6.09(br s,1H),6.00(s,1H),3.82(s,3H),3.09(m,4H),2.84(d,J=4.8Hz,3H),2.61(m,4H),2.33–2.25(m,1H),2.21(s,3H),2.13–1.97(m,4H),1.82–1.60(m,5H),1.41–1.23(m,3H)
<实施例6>2-((2-((4-((1-(金刚烷-2-基)哌啶-4-基)氨基)-2-甲氧基苯基)氨基)-5-(三氟甲基)嘧啶-4-基)氨基)-N,3-二甲基苯甲酰胺(化合物6)的制备
[步骤1]4-((3-甲氧基-4-硝基苯基)氨基)哌啶-1-羧酸叔丁酯的制备
通过使用4-氨基哌啶-1-羧酸叔丁酯代替实施例1步骤1中的反式-4-氨基金刚烷-1-醇,以与实施例1相同的方式合成标题化合物。
[步骤2]N-(3-甲氧基-4-硝基苯基)哌啶-4-胺的制备
将在上述步骤1中制备的4-((3-甲氧基-4-硝基苯基)氨基)哌啶-1-羧酸叔丁酯溶解于二氯甲烷中,然后加入三氟乙酸,室温搅拌3小时。反应结束后,向反应溶液中加入蒸馏水,然后用二氯甲烷萃取。将所得的溶液经无水硫酸镁干燥,过滤,然后将滤液浓缩,通过柱层析法纯化,以获得标题化合物。
[步骤3]1-(金刚烷-2-基)-N-(3-甲氧基-4-硝基苯基)哌啶-4-胺的制备
通过使用N-(3-甲氧基-4-硝基苯基)哌啶-4-胺代替实施例3步骤2中的1-(3-甲氧基-4-硝基苯基)哌嗪,以与实施例3相同的方式合成标题化合物。
[步骤4]N-(1-(金刚烷-2-基)哌啶-4-基)-3-甲氧基苯-1,4-二胺的制备
通过使用1-(金刚烷-2-基)-N-(3-甲氧基-4-硝基苯基)哌啶-4-胺代替实施例1步骤2中的(反式)-4-((3-甲氧基-4-硝基苯基)氨基)金刚烷-1-醇,以与实施例1相同的方式合成标题化合物。
[步骤5]N-(1-(金刚烷-2-基)哌啶-4-基)-N-(4-氯-5-(三氟甲基)嘧啶-2-基)-2-甲氧基苯-1,4-二胺的制备
通过使用N-(1-(金刚烷-2-基)哌啶-4-基)-3-甲氧基苯-1,4-二胺代替实施例1步骤3中的(反式)-4-((4-氨基-3-甲氧基苯基)氨基)金刚烷-1-醇,以与实施例1相同的方式合成标题化合物。
[步骤6]2-((2-((4-((1-(金刚烷-2-基)哌啶-4-基)氨基)-2-甲氧基苯基)氨基)-5-(三氟甲基)嘧啶-4-基)氨基)-N,3-二甲基苯甲酰胺的制备
通过使用N-(1-(金刚烷-2-基)哌啶-4-基)-N-(4-氯-5-(三氟甲基)嘧啶-2-基)-2-甲氧基苯-1,4-二胺代替实施例1步骤4中的(反式)-4-((4-((4-氯-5-(三氟甲基)嘧啶-2-基)氨基)-3-甲氧基苯基)氨基)金刚烷-1-醇,以与实施例1相同的方式合成标题化合物。
1H NMR(400MHz,CDCl3):δ8.25(s,1H),8.13(br s,1H),7.41–7.32(m,2H),7.29–7.24(m,1H),6.13(d,J=2.3Hz,1H),5.97(br s,1H),3.78(s,3H),3.06–2.95(m,2H),2.84(d,J=4.8Hz,3H),2.21(s,3H),2.12–1.92(m,8H),1.90–1.75(m,5H),1.74–1.62(m,5H),1.47–1.35(m,4H)
<实施例7>2-((2-((4-((1-((反式)-5-羟基金刚烷-2-基)哌啶-4-基)氨基)-2-甲氧基苯基)氨基)-5-(三氟甲基)嘧啶-4-基)氨基)-N,3-二甲基苯甲酰胺(化合物7)的制备
[步骤1](反式)-4-(4-((3-甲氧基-4-硝基苯基)氨基)哌啶-1-基)金刚烷-1-醇的制备
通过使用5-羟基金刚烷-2-酮代替实施例6步骤3中的金刚烷-2-酮,以与实施例6相同的方式合成标题化合物。
[步骤2](反式)-4-(4-((4-氨基-3-甲氧基苯基)氨基)哌啶-1-基)金刚烷-1-醇的制备
通过使用(反式)-4-(4-((3-甲氧基-4-硝基苯基)氨基)哌啶-1-基)金刚烷-1-醇代替实施例1步骤2中的(反式)-4-((3-甲氧基-4-硝基苯基)氨基)金刚烷-1-醇,以与实施例1相同的方式合成标题化合物。
[步骤3](反式)-4-(4-((4-((4-氯-5-(三氟甲基)嘧啶-2-基)氨基)-3-甲氧基苯基)氨基)哌啶-1-基)金刚烷-1-醇的制备
通过使用(反式)-4-(4-((4-氨基-3-甲氧基苯基)氨基)哌啶-1-基)金刚烷-1-醇代替实施例1步骤3中的(反式)-4-((4-氨基-3-甲氧基苯基)氨基)金刚烷-1-醇,以与实施例1相同的方式合成标题化合物。
[步骤4]2-((2-((4-((1-((反式)-5-羟基金刚烷-2-基)哌啶-4-基)氨基)-2-甲氧基苯基)氨基)-5-(三氟甲基)嘧啶-4-基)氨基)-N,3-二甲基苯甲酰胺的制备
通过使用(反式)-4-(4-((4-((4-氯-5-(三氟甲基)嘧啶-2-基)氨基)-3-甲氧基苯基)氨基)哌啶-1-基)金刚烷-1-醇代替实施例1步骤4中的(反式)-4-((4-((4-氯-5-(三氟甲基)嘧啶-2-基)氨基)-3-甲氧基苯基)氨基)金刚烷-1-醇,以与实施例1相同的方式合成标题化合物。
1H NMR(400MHz,CDCl3):δ8.25(s,1H),8.15(s,1H),7.41–7.32(m,2H),7.31–7.24(m,2H),6.13(d,J=2.3Hz,1H),5.97(s,1H),5.76(s,1H),3.78(s,3H),3.25–3.14(m,1H),3.05–2.91(m,2H),2.84(d,J=4.8Hz,3H),2.39–2.31(m,2H),2.21(s,3H),2.15–1.95(m,7H),1.77–1.66(m,5H),1.56(m,2H),1.40(m,4H)。
<实施例8>2-((2-((4-((1-((顺式)-5-羟基金刚烷-2-基)哌啶-4-基)氨基)-2-甲氧基苯基)氨基)-5-(三氟甲基)嘧啶-4-基)氨基)-N,3-二甲基苯甲酰胺(化合物8)的制备
[步骤1](顺式)-4-(4-((3-甲氧基-4-硝基苯基)氨基)哌啶-1-基)金刚烷-1-醇的制备
通过使用5-羟基金刚烷-2-酮代替实施例6步骤3中的金刚烷-2-酮,以与实施例6相同的方式合成标题化合物。
[步骤2](顺式)-4-(4-((4-氨基-4-甲氧基苯基)氨基)哌啶-1-基)金刚烷-1-醇的制备
通过使用(顺式)-4-(4-((3-甲氧基-4-硝基苯基)氨基)哌啶-1-基)金刚烷-1-醇代替实施例1步骤2中的(反式)-4-((3-甲氧基-4-硝基苯基)氨基)金刚烷-1-醇,以与实施例1相同的方式合成标题化合物。
[步骤3](顺式)-4-(4-((4-((4-氯-5-(三氟甲基)嘧啶-2-基)氨基)-3-甲氧基苯基)氨基)哌啶-1-基)金刚烷-1-醇的制备
通过使用(顺式)-4-(4-((4-氨基-3-甲氧基苯基)氨基)哌啶-1-基)金刚烷-1-醇代替实施例1步骤3中的(反式)-4-((4-氨基-3-甲氧基苯基)氨基)金刚烷-1-醇,以与实施例1相同的方式合成标题化合物。
[步骤4]2-((2-((4-((1-((顺式)-5-羟基金刚烷-2-基)哌啶-4-基)氨基)-2-甲氧基苯基)氨基)-5-(三氟甲基)嘧啶-4-基)氨基)-N,3-二甲基苯甲酰胺的制备
通过使用(顺式)-4-(4-((4-((4-氯-5-(三氟甲基)嘧啶-2-基)氨基)-3-甲氧基苯基)氨基)哌啶-1-基)金刚烷-1-醇代替实施例1步骤4中的(反式)-4-((4-((4-氯-5-(三氟甲基)嘧啶-2-基)氨基)-3-甲氧基苯基)氨基)金刚烷-1-醇,以与实施例1相同的方式合成标题化合物。
1H NMR(400MHz,CDCl3):δ8.25(s,1H),8.15(s,1H),7.41–7.32(m,2H),7.31–7.24(m,2H),6.13(d,J=2.3Hz,1H),5.97(s,1H),5.76(s,1H),3.78(s,3H),3.25–3.14(m,1H),3.05–2.91(m,2H),2.84(d,J=4.8Hz,3H),2.39–2.31(m,2H),2.21(s,3H),2.15–1.95(m,7H),1.77–1.66(m,5H),1.56(m,2H),1.40(m,4H)。
<实施例9>2-((2-((4-((1-(金刚烷-2-基)哌啶-4-基)氧基)-2-甲氧基苯基)氨基)-5-(三氟甲基)嘧啶-4-基)氨基)-N,3-二甲基苯甲酰胺(化合物9)的制备
[步骤1]4-((3-甲氧基-4-硝基苯基)氧基)哌啶-1-羧酸叔丁酯的制备
通过使用4-羟基哌啶-1-羧酸叔丁酯代替实施例1步骤1中的反式-4-氨基金刚烷-1-醇,以与实施例1相同的方式合成标题化合物。
[步骤2]4-(3-甲氧基-4-硝基苯氧基)哌啶的制备
通过使用4-((3-甲氧基-4-硝基苯基)氧基)哌啶-1-羧酸叔丁酯代替实施例6步骤2中的4-((3-甲氧基-4-硝基苯基)氨基)哌啶-1-羧酸叔丁酯,以与实施例6相同的方式合成标题化合物。
[步骤3]1-(金刚烷-2-基)-4-(3-甲氧基-4-硝基苯氧基)哌啶的制备
通过使用4-(3-甲氧基-4-硝基苯氧基)哌啶代替实施例3步骤2中的1-(3-甲氧基-4-硝基苯基)哌嗪,以与实施例3相同的方式合成标题化合物。
[步骤4]4-((1-(金刚烷-2-基)哌啶-4-基)氧基)-2-甲氧基苯胺的制备
通过使用1-(金刚烷-2-基)-4-(3-甲氧基-4-硝基苯氧基)哌啶代替实施例1步骤2中的(反式)-4-((3-甲氧基-4-硝基苯基)氨基)金刚烷-1-醇,以与实施例1相同的方式合成标题化合物。
[步骤5]N-(4-((1-(金刚烷-2-基)哌啶-4-基)氧基)-2-甲氧基苯基)-4-氯-5-(三氟甲基)嘧啶-2-胺的制备
通过使用4-((1-(金刚烷-2-基)哌啶-4-基)氧基)-2-甲氧基苯胺代替实施例1步骤3中的(反式)-4-((4-氨基-3-甲氧基苯基)氨基)金刚烷-1-醇,以与实施例1相同的方式合成标题化合物。
[步骤6]2-((2-((4-((1-(金刚烷-2-基)哌啶-4-基)氧基)-2-甲氧基苯基)氨基)-5-(三氟甲基)嘧啶-4-基)氨基)-N,3-二甲基苯甲酰胺的制备
通过使用N-(4-((1-(金刚烷-2-基)哌啶-4-基)氧基)-2-甲氧基苯基)-4-氯-5-(三氟甲基)嘧啶-2-胺代替实施例1步骤4中的(反式)-4-((4-((4-氯-5-(三氟甲基)嘧啶-2-基)氨基)-3-甲氧基苯基)氨基)金刚烷-1-醇,以与实施例1相同的方式合成标题化合物。
1H NMR(400MHz,CDCl3):δ8.31(br s,1H),8.27(s,1H),7.42–7.34(m,2H),7.28(t,J=7.5Hz,1H),6.44(d,J=1.9Hz,1H),6.08(br s,1H),5.98(s,1H),4.16(br s,1H),3.81(s,3H),2.92–2.81(m,4H),2.20(s,3H),2.18–1.92(m,8H),1.92–1.75(m,5H),1.75–1.57(m,6H),1.49–1.33(m,3H)。
<实施例10>2-((2-((2-甲氧基-4-((4-氧代金刚烷-1-基)氧基)苯基)氨基)-5-(三氟甲基)嘧啶-4-基)氨基)-N,3-二甲基苯甲酰胺(化合物10)的制备
[步骤1]5-(3-甲氧基-4-硝基苯氧基)金刚烷-2-酮的制备
通过使用5-羟基金刚烷-2-酮代替实施例1步骤1中的反式-4-氨基金刚烷-1-醇,以与实施例1相同的方式合成标题化合物。
[步骤2]5-(4-氨基-3-甲氧基苯氧基)金刚烷-2-酮的制备
通过使用5-(3-甲氧基-4-硝基苯氧基)金刚烷-2-酮代替实施例1步骤2中的(反式)-4-((3-甲氧基-4-硝基苯基)氨基)金刚烷-1-醇,以与实施例1相同的方式合成标题化合物。
[步骤3]5-(4-((4-氯-5-(三氟甲基)嘧啶-2-基)氨基)-3-甲氧基苯氧基)金刚烷-2-酮的制备
通过使用5-(4-氨基-3-甲氧基苯氧基)金刚烷-2-酮代替实施例1步骤3中的(反式)-4-((4-氨基-3-甲氧基苯基)氨基)金刚烷-1-醇,以与实施例1相同的方式合成标题化合物。
[步骤6]2-((2-((2-甲氧基-4-((4-氧代金刚烷-1-基)氧基)苯基)氨基)-5-(三氟甲基)嘧啶-4-基)氨基)-N,3-二甲基苯甲酰胺的制备
通过使用N-(4-((1-(金刚烷-2-基)哌啶-4-基)氧基)-2-甲氧基苯基)-4-氯-5-(三氟甲基)嘧啶-2-胺代替实施例1步骤4中的(反式)-4-((4-((4-氯-5-(三氟甲基)嘧啶-2-基)氨基)-3-甲氧基苯基)氨基)金刚烷-1-醇,以与实施例1相同的方式合成标题化合物。
1H NMR(400MHz,CDCl3):δ8.46(s,1H),8.29(s,1H),7.42–7.35(m,2H),7.28(t,J=7.6Hz,1H),6.45(d,J=2.4Hz,1H),6.17(br s,1H),6.02–5.96(m,1H),3.81(s,3H),2.88(d,J=4.9Hz,3H),2.67–2.62(m,2H),2.40–2.34(m,1H),2.20(s,3H),2.19–2.01(m,6H),1.96–1.92(m,4H)
<实施例11>2-((2-((4-((4-羟基金刚烷-1-基)氧基)-2-甲氧基苯基)氨基)-5-(三氟甲基)嘧啶-4-基)氨基)-N,3-二甲基苯甲酰胺(化合物11)的制备
[步骤1]2-((2-((4-((4-羟基金刚烷-1-基)氧基)-2-甲氧基苯基)氨基)-5-(三氟甲基)嘧啶-4-基)氨基)-N,3-二甲基苯甲酰胺的制备
将在上述实施例10中制备的2-((2-((2-甲氧基-4-((4-氧代金刚烷-1-基)氧基)苯基)氨基)-5-(三氟甲基)嘧啶-4-基)氨基)-N,3-二甲基苯甲酰胺、三乙酰氧基硼氢化钠、四氢呋喃和乙酸在室温搅拌15小时。向反应液中倒入冰水,用乙酸乙酯萃取,经无水硫酸镁干燥,过滤,然后将滤液浓缩,通过柱层析法纯化,以获得标题化合物。
1H NMR(400MHz,DMSO-d6):δ9.15(s,1H),8.30(s,1H),8.29–8.25(m,1H),8.06(s,1H),7.42(d,J=7.4Hz,1H),7.38(d,J=7.2Hz,1H),7.32–7.24(m,2H),6.51(d,J=1.8Hz,1H),6.21(br s,1H),4.66(d,J=3.1Hz,1H),3.70(s,3H),3.69–3.66(m,1H),2.69(d,J=4.6,3H),2.10(s,3H),2.05–1.91(m,5H),1.84–1.71(m,6H),1.26–1.23(m,2H)
<实施例12>2-((2-((2-甲氧基-4-((4-吗啉代金刚烷-1-基)氧基)苯基)氨基)-5-(三氟甲基)嘧啶-4-基)氨基)-N,3-二甲基苯甲酰胺(化合物12)的制备
[步骤1]2-((2-((2-甲氧基-4-((4-吗啉代金刚烷-1-基)氧基)苯基)氨基)-5-(三氟甲基)嘧啶-4-基)氨基)-N,3-二甲基苯甲酰胺的制备
将在上述实施例10中制备的2-((2-((2-甲氧基-4-((4-氧代金刚烷-1-基)氧基)苯基)氨基)-5-(三氟甲基)嘧啶-4-基)氨基)-N,3-二甲基苯甲酰胺、吗啉、三乙酰氧基硼氢化钠、四氢呋喃和乙酸在室温搅拌15小时。向反应液中倒入冰水,用乙酸乙酯萃取,经无水硫酸镁干燥,过滤,然后将滤液浓缩,通过柱层析法纯化,以获得标题化合物。
1H NMR(400MHz,DMSO-d6):δ9.07(s,1H),8.24(s,1H),8.23–8.17(m,1H),8.01(s,1H),7.38–7.30(m,2H),7.26–7.19(m,2H),6.46(s,1H),6.15(br s,1H),3.65(s,3H),3.54(br s,4H),3.27(s,3H),2.63(d,J=4.5Hz,3H),2.45(br s,4H),2.34–2.15(m,5H),2.04(s,3H),1.92–1.64(m,7H),1.21–1.11(m,2H)
<实施例13>2-((2-((2-甲氧基-4-((4-(4-甲基哌嗪-1-基)金刚烷-1-基)氧基)苯基)氨基)-5-(三氟甲基)嘧啶-4-基)氨基)-N,3-二甲基苯甲酰胺(化合物13)的制备
[步骤1]2-((2-((2-甲氧基-4-((4-(4-甲基哌嗪-1-基)金刚烷-1-基)氧基)苯基)氨基)-5-(三氟甲基)嘧啶-4-基)氨基)-N,3-二甲基苯甲酰胺的制备
通过使用4-甲基哌嗪代替实施例12步骤1中的吗啉,以与实施例12相同的方式合成标题化合物。
1H NMR(400MHz,CDCl3):δ8.50(s,1H),8.26(s,1H),7.42–7.36(m,2H),7.28(t,J=7.5Hz,1H),6.45(d,J=2.3Hz,1H),6.21–6.08(m,2H),3.80(s,3H),3.50–3.40(m,2H),3.15–2.65(m,12H),2.28–2.22(m,1H),2.20(s,3H),2.16–1.64(m,11H),1.32–1.22(m,2H)
<实施例14>2-((2-((4-(((反式)-4-((S)-3-乙酰氨基吡咯烷-1-基)金刚烷-1-基)氧基)-2-甲氧基苯基)氨基)-5-(三氟甲基)嘧啶-4-基)氨基)-N,3-二甲基苯甲酰胺(化合物14)的制备
[步骤1]2-((2-((4-(((反式)-4-((S)-3-乙酰氨基吡咯烷-1-基)金刚烷-1-基)氧基)-2-甲氧基苯基)氨基)-5-(三氟甲基)嘧啶-4-基)氨基)-N,3-二甲基苯甲酰胺的制备
通过使用(S)-N-(吡咯烷-3-基)乙酰胺代替实施例12步骤1中的吗啉,以与实施例12相同的方式合成标题化合物。
1H NMR(400MHz,DMSO-d6):δ9.14(s,1H),8.29(s,1H),8.28–8.24(m,1H),8.04(s,1H),7.95(d,J=6.6Hz,1H),7.42(d,J=7.5Hz,1H),7.38(d,J=7.1Hz,1H),7.32–7.24(m,2H),6.50(d,J=1.7Hz,1H),6.20(br s,1H),5.75(s,1H),4.19–4.08(m,1H),3.70(s,3H),2.77–2.62(m,4H),2.55(m,1H),2.43(m,1H),2.24(m,1H),2.21–1.90(m,10H),1.78(s,3H),1.71(m,2H),1.56–1.43(m,7H)
<实施例15>2-((2-((4-(((顺式)-4-((S)-3-乙酰氨基吡咯烷-1-基)金刚烷-1-基)氧基)-2-甲氧基苯基)氨基)-5-(三氟甲基)嘧啶-4-基)氨基)-N,3-二甲基苯甲酰胺(化合物15)的制备
[步骤1]2-((2-((4-(((顺式)-4-((S)-3-乙酰氨基吡咯烷-1-基)金刚烷-1-基)氧基)-2-甲氧基苯基)氨基)-5-(三氟甲基)嘧啶-4-基)氨基)-N,3-二甲基苯甲酰胺的制备
通过使用(S)-N-(吡咯烷-3-基)乙酰胺代替实施例12步骤1中的吗啉,以与实施例12相同的方式合成标题化合物。
1H NMR(400MHz,DMSO-d6):δ9.13(s,1H),8.30(s,1H),8.29–8.23(m,1H),8.05(s,1H),7.93(d,J=4.9Hz,1H),7.41(d,J=7.5Hz,1H),7.38(d,J=7.1Hz,1H),7.32–7.24(m,2H),6.52(d,J=1.2Hz,1H),6.21(br s,1H),5.75(s,1H),4.19–4.08(m,1H),3.70(s,3H),2.81–2.54(m,4H),2.50(m,1H),2.44–2.20(m,2H),2.20–1.87(m,8H),1.87–1.64(m,7H),1.64–1.38(m,2H),1.38–1.04(m,5H)。
<实施例16>4-(3-甲氧基-4-((4-((2-甲基-6-(甲基氨基甲酰基)苯基)氨基)-5-(三氟甲基)嘧啶-2-基)氨基)苯氧基)金刚烷-1-羧酸甲酯(化合物16)的制备
[步骤1]4-(3-甲氧基-4-硝基苯氧基)金刚烷-1-羧酸甲酯的制备
通过使用4-羟基金刚烷-1-羧酸甲酯代替实施例1步骤1中的反式-4-氨基金刚烷-1-醇,以与实施例1相同的方式合成标题化合物。
[步骤2]4-(4-氨基-3-甲氧基苯氧基)金刚烷-1-羧酸甲酯的制备
通过使用4-(3-甲氧基-4-硝基苯氧基)金刚烷-1-羧酸甲酯代替实施例1步骤2中的(反式)-4-((3-甲氧基-4-硝基苯基)氨基)金刚烷-1-醇,以与实施例1相同的方式合成标题化合物。
[步骤3]4-(4-((4-氯-5-(三氟甲基)嘧啶-2-基)氨基)-3-甲氧基苯氧基)金刚烷-1-羧酸甲酯的制备
通过使用4-(4-氨基-3-甲氧基苯氧基)金刚烷-1-羧酸甲酯代替实施例1步骤3中的(反式)-4-((4-氨基-3-甲氧基苯基)氨基)金刚烷-1-醇,以与实施例1相同的方式合成标题化合物。
[步骤4]4-(3-甲氧基-4-((4-((2-甲基-6-(甲基氨基甲酰基)苯基)氨基)-5-(三氟甲基)嘧啶-2-基)氨基)苯氧基)金刚烷-1-羧酸甲酯的制备
通过使用4-(4-((4-氯-5-(三氟甲基)嘧啶-2-基)氨基)-3-甲氧基苯氧基)金刚烷-1-羧酸甲酯代替实施例1步骤4中的(反式)-4-((4-((4-氯-5-(三氟甲基)嘧啶-2-基)氨基)-3-甲氧基苯基)氨基)金刚烷-1-醇,以与实施例1相同的方式合成标题化合物。
1H NMR(400MHz,CDCl3):δ8.40(s,1H),8.26(s,1H),7.51(s,2H),7.30(m,3H),6.44(s,1H),6.11(m,2H),4.25(m,1H),3.79(s,3H),3.66(m,3H),2.82(d,J=4.9Hz,3H),2.32–2.10(m,6H),2.06–1.80(m,7H),1.77–1.65(m,2H),1.48(m,1H)
<实施例17>4-(3-甲氧基-4-((4-((2-甲基-6-(甲基氨基甲酰基)苯基)氨基)-5-(三氟甲基)嘧啶-2-基)氨基)苯氧基)金刚烷1-羧酸(化合物17)的制备
[步骤1]4-(3-甲氧基-4-((4-((2-甲基-6-(甲基氨基甲酰基)苯基)氨基)-5-(三氟甲基)嘧啶-2-基)氨基)苯氧基)金刚烷1-羧酸的制备
将盐酸水溶液加入到在上述实施例16中制备的4-(3-甲氧基-4-((4-((2-甲基-6-(甲基氨基甲酰基)苯基)氨基)-5-(三氟甲基)嘧啶-2-基)氨基)苯氧基)金刚烷-1-羧酸甲酯中,并在回流下搅拌5小时。反应结束后,向反应溶液中加入蒸馏水,然后用二氯甲烷萃取。将所得的溶液经无水硫酸镁干燥,过滤,然后将滤液浓缩,通过柱层析法纯化,以获得标题化合物。
1H NMR(400MHz,CDCl3):δ8.16(s,1H),7.43–7.28(m,4H),6.43(m,1H),6.02(s,2H),4.28(m,1H),3.82(m,3H),2.90(d,J=4.2Hz,3H),2.61(m,1H),2.27(m,3H),2.16(s,3H),2.11–1.84(m,5H),1.79–1.70(m,3H),1.52(m,1H)
<实施例18>4-(3-甲氧基-4-((4-((2-甲基-6-(甲基氨基甲酰基)苯基)氨基)-5-(三氟甲基)嘧啶-2-基)氨基)苯氧基)-N-甲基金刚烷-1-甲酰胺(化合物18)的制备
[步骤1]4-(3-甲氧基-4-((4-((2-甲基-6-(甲基氨基甲酰基)苯基)氨基)-5-(三氟甲基)嘧啶-2-基)氨基)苯氧基)-N-甲基金刚烷-1-甲酰胺的制备
将在上述实施例16中制备的4-(3-甲氧基-4-((4-((2-甲基-6-(甲基氨基甲酰基)苯基)氨基)-5-(三氟甲基)嘧啶-2-基)氨基)苯氧基)金刚烷-1-羧酸、甲胺盐酸盐、1-[双(二甲基氨基)亚甲基]-1H-1,2,3-三唑并[4,5-b]吡啶鎓3-氧化物六氟磷酸盐溶解在N,N-二甲基甲酰胺中,然后加入三乙胺并在室温搅拌5小时。反应结束后,向反应溶液中加入蒸馏水,然后用乙酸乙酯萃取。将所得的溶液经无水硫酸镁干燥,过滤,然后将滤液浓缩,通过柱层析法纯化,以获得标题化合物。
1H NMR(400MHz,CDCl3):δ8.33(s,1H),8.28(s,1H),7.52(s,2H),7.38(m,2H),7.33–7.18(m,1H),6.46(s,1H),6.03(m,2H),5.63(s,1H),4.28(m,1H),3.82(s,3H),2.91–2.72(m,6H),2.30–2.12(m,6H),2.09–1.82(m,6H),1.79–1.63(m,2H),1.53–1.43(m,2H)
<实施例19>2-((2-((2-甲氧基-4-((5-(吗啉-4-羰基)金刚烷-2-基)氧基)苯基)氨基)-5-(三氟甲基)嘧啶-4-基)氨基)-N,3-二甲基苯甲酰胺(化合物19)的制备
[步骤1]2-((2-((2-甲氧基-4-((5-(吗啉-4-羰基)金刚烷-2-基)氧基)苯基)氨基)-5-(三氟甲基)嘧啶-4-基)氨基)-N,3-二甲基苯甲酰胺的制备
通过使用吗啉代替实施例18步骤1中的甲胺盐酸盐,以与实施例18相同的方式合成标题化合物。
1H NMR(400MHz,CDCl3):δ8.36(m,1H),8.28(s,1H),7.52(s,2H),7.38(m,2H),7.34–7.26(m,1H),6.43(m,1H),6.01(m,2H),4.28(s,1H),3.81(m,3H),3.78–3.65(m,6H),2.87(m,3H),2.41(m,1H),2.31–2.13(m,6H),2.12–1.95(m,3H),1.92–1.81(m,1H),1.80–1.67(m,2H),1.65–1.45(m,2H)
<实施例20>2-((2-((2-甲氧基-4-((5-(4-甲基哌嗪-1-羰基)金刚烷-2-基)氧基)苯基)氨基)-5-(三氟甲基)嘧啶-4-基)氨基)-N,3-二甲基苯甲酰胺(化合物20)的制备
[步骤1]2-((2-((2-甲氧基-4-((5-(4-甲基哌嗪-1-羰基)金刚烷-2-基)氧基)苯基)氨基)-5-(三氟甲基)嘧啶-4-基)氨基)-N,3-二甲基苯甲酰胺的制备
通过使用1-甲基哌嗪代替实施例18步骤1中的甲胺盐酸盐,以与实施例18相同的方式合成标题化合物。
1H NMR(400MHz,CDCl3):δ8.35(s,1H),8.27(s,1H),7.51(s,2H),7.38(m,2H),7.32–7.26(m,1H),6.50–6.38(m,1H),6.02(s,2H),4.28(m,1H),3.81(m,3H),3.74(m,4H),2.86(d,J=4.7Hz,3H),2.41(s,5H),2.31(s,3H),2.29–2.12(m,6H),2.01(m,4H),1.87(m,2H),1.71(m,2H),1.51(m,1H)
<实施例21>2-((2-((2-甲氧基-4-((5-((S)-3-乙酰氨基吡咯烷-1-羰基)金刚烷-2-基)氧基)苯基)氨基)-5-(三氟甲基)嘧啶-4-基)氨基)-N,3-二甲基苯甲酰胺(化合物21)的制备
[步骤1]2-((2-((2-甲氧基-4-((5-((S)-3-乙酰氨基吡咯烷-1-羰基)金刚烷-2-基)氧基)苯基)氨基)-5-(三氟甲基)嘧啶-4-基)氨基)-N,3-二甲基苯甲酰胺的制备
通过使用(S)-N-(吡咯烷-3-基)乙酰胺代替实施例18步骤1中的甲胺盐酸盐,以与实施例18相同的方式合成标题化合物。
1H NMR(400MHz,CDCl3):δ8.37(m,1H),8.27(s,1H),7.50(s,2H),7.43–7.34(m,2H),7.29(m,1H),6.46(m,1H),6.10(m,2H),5.58(m,1H),4.45(m,1H),4.27(m,1H),3.82(s,3H),3.75–3.52(m,3H),2.86(d,J=4.7Hz,3H),2.38(m,1H),2.29–2.11(m,7H),2.01(m,6H),1.90–1.80(m,2H),1.77–1.68(m,2H),1.59(br s,2H),1.50(m,1H)
<实施例22>2-((2-((2-甲氧基-4-((5-(吗啉-4-羰基)金刚烷-2-基)氨基)苯基)氨基)-5-(三氟甲基)嘧啶-4-基)氨基)-N,3-二甲基苯甲酰胺(化合物22)的制备
[步骤1]4-((3-甲氧基-4-硝基苯基)氨基)金刚烷-1-羧酸甲酯的制备
通过使用4-氨基金刚烷-1-羧酸甲酯代替实施例1步骤1中的反式-4-氨基金刚烷-1-醇,以与实施例1相同的方式合成标题化合物。
[步骤2]4-((4-氨基-3-甲氧基苯基)氨基)金刚烷-1-羧酸甲酯的制备
通过使用4-((3-甲氧基-4-硝基苯基)氨基)金刚烷-1-羧酸甲酯代替实施例1步骤2中的(反式)-4-((3-甲氧基-4-硝基苯基)氨基)金刚烷-1-醇,以与实施例1相同的方式合成标题化合物。
[步骤3]4-((4-((4-氯-5-(三氟甲基)嘧啶-2-基)氨基)-3-甲氧基苯基)氨基)金刚烷-1-羧酸甲酯的制备
通过使用4-((4-氨基-3-甲氧基苯基)氨基)金刚烷-1-羧酸甲酯代替实施例1步骤3中的(反式)-4-((4-氨基-3-甲氧基苯基)氨基)金刚烷-1-醇,以与实施例1相同的方式合成标题化合物。
[步骤4]4-((3-甲氧基-4-((4-((2-甲基-6-(甲基氨基甲酰基)苯基)氨基)-5-(三氟甲基)嘧啶-2-基)氨基)苯基)氨基)金刚烷-1-羧酸甲酯的制备
通过使用4-((4-((4-氯-5-(三氟甲基)嘧啶-2-基)氨基)-3-甲氧基苯基)氨基)金刚烷-1-羧酸甲酯代替实施例1步骤4中的(反式)-4-((4-((4-氯-5-(三氟甲基)嘧啶-2-基)氨基)-3-甲氧基苯基)氨基)金刚烷-1-醇,以与实施例1相同的方式合成标题化合物。
[步骤5]4-((3-甲氧基-4-((4-((2-甲基-6-(甲基氨基甲酰基)苯基)氨基)-5-(三氟甲基)嘧啶-2-基)氨基)苯基)氨基)金刚烷-1-羧酸的制备
通过使用4-((3-甲氧基-4-((4-((2-甲基-6-(甲基氨基甲酰基)苯基)氨基)-5-(三氟甲基)嘧啶-2-基)氨基)苯基)氨基)金刚烷-1-羧酸甲酯代替实施例17步骤1中的4-(3-甲氧基-4-((4-((2-甲基-6-(甲基氨基甲酰基)苯基)氨基)-5-(三氟甲基)嘧啶-2-基)氨基)苯氧基)金刚烷-1-羧酸甲酯,以与实施例17相同的方式合成标题化合物。
[步骤6]2-((2-((2-甲氧基-4-((5-(吗啉-4-羰基)金刚烷-2-基)氨基)苯基)氨基)-5-(三氟甲基)嘧啶-4-基)氨基)-N,3-二甲基苯甲酰胺的制备
通过使用4-((3-甲氧基-4-((4-((2-甲基-6-(甲基氨基甲酰基)苯基)氨基)-5-(三氟甲基)嘧啶-2-基)氨基)苯基)氨基)金刚烷-1-羧酸代替实施例19步骤1中的4-(3-甲氧基-4-((4-((2-甲基-6-(甲基氨基甲酰基)苯基)氨基)-5-(三氟甲基)嘧啶-2-基)氨基)苯氧基)金刚烷1-羧酸,以与实施例19相同的方式合成标题化合物。
1H NMR(400MHz,CDCl3):δ8.24(s,1H),8.19(s,1H),7.62–7.32(m,3H),7.32–7.26(m,2H),6.11(d,J=2.0Hz,1H),6.03(s,1H),5.73(s,1H),3.77(s,3H),3.68(m,8H),3.41(s,1H),2.84(d,J=4.7Hz,3H),2.20(s,3H),2.18–2.05(m,6H),2.00(s,2H),1.90–1.79(m,6H)
<实施例23>2-((2-((2-甲氧基-4-((5-(4-甲基哌嗪-1-羰基)金刚烷-2-基)氨基)苯基)氨基)-5-(三氟甲基)嘧啶-4-基)氨基)-N,3-二甲基苯甲酰胺(化合物23)的制备
[步骤1]2-((2-((2-甲氧基-4-((5-(4-甲基哌嗪-1-羰基)金刚烷-2-基)氨基)苯基)氨基)-5-(三氟甲基)嘧啶-4-基)氨基)-N,3-二甲基苯甲酰胺的制备
通过使用1-甲基哌嗪代替实施例22步骤6中的吗啉,以与实施例22相同的方式合成标题化合物。
1H NMR(400MHz,CDCl3):δ8.24(s,1H),8.15(s,1H),7.37(m,3H),7.31–7.25(m,1H),6.11(d,J=1.6Hz,1H),6.03(s,1H),5.72(s,1H),3.77(s,3H),3.71(s,4H),3.41(s,1H),2.83(d,J=4.6Hz,3H),2.48–2.32(m,4H),2.29(s,3H),2.20(s,3H),2.17–1.96(m,7H),1.94–1.77(m,6H)
<实施例24>2-((2-((2-甲氧基-4-((5-((S)-3-乙酰氨基吡咯烷-1-羰基)金刚烷-2-基)氨基)苯基)氨基)-5-(三氟甲基)嘧啶-4-基)氨基)-N,3-二甲基苯甲酰胺(化合物24)的制备
[步骤1]2-((2-((2-甲氧基-4-((5-((S)-3-乙酰氨基吡咯烷-1-羰基)金刚烷-2-基)氨基)苯基)氨基)-5-(三氟甲基)嘧啶-4-基)氨基)-N,3-二甲基苯甲酰胺的制备
通过使用(S)-N-(吡咯烷-3-基)乙酰胺代替实施例22步骤6中的吗啉,以与实施例22相同的方式合成标题化合物。
1H NMR(400MHz,CDCl3):δ8.24(s,1H),8.14(s,1H),7.45–7.32(m,3H),7.32–7.26(m,1H),6.13(d,J=2.2Hz,1H),6.07(s,1H),5.74(s,1H),5.62(m,1H),4.42(m,1H),3.86(s,1H),3.78(s,3H),3.63(m,3H),3.41(s,1H),2.83(d,J=4.5Hz,3H),2.21(s,3H),2.18–2.03(m,8H),1.98(m,4H),1.83(m,6H)
<实施例25>N-(3-甲氧基-4-((4-((2-甲基-6-(甲基氨基甲酰基)苯基)氨基)-5-(三氟甲基)嘧啶-2-基)氨基)苯基)-4-吗啉代金刚烷-1-甲酰胺(化合物25)的制备
[步骤1]N-(3-甲氧基-4-硝基苯基)-4-氧代金刚烷-1-甲酰胺的制备
将4-氧代金刚烷-1-羧酸、3-甲氧基-4-硝基苯胺和1-[双(二甲基氨基)亚甲基]-1H-1,2,3-三唑并[4,5-b]吡啶鎓3-氧化物六氟磷酸盐溶解在N,N-二甲基甲酰胺中,然后加入三乙胺并在室温搅拌5小时。反应结束后,向反应溶液中加入蒸馏水,然后用乙酸乙酯萃取。将所得的溶液经无水硫酸镁干燥,过滤,然后将滤液浓缩,通过柱层析法纯化,以获得标题化合物。
[步骤2]N-(4-氨基-3-甲氧基苯基)-4-氧代金刚烷-1-甲酰胺的制备
通过使用N-(3-甲氧基-4-硝基苯基)-4-氧代金刚烷-1-甲酰胺代替实施例1步骤2中的(反式)-4-((3-甲氧基-4-硝基苯基)氨基)金刚烷-1-醇,以与实施例1相同的方式合成标题化合物。
[步骤3]N-(4-((4-氯-5-(三氟甲基)嘧啶-2-基)氨基)-3-甲氧基苯基)-4-氧代金刚烷-1-甲酰胺的制备
通过使用N-(4-氨基-3-甲氧基苯基)-4-氧代金刚烷-1-甲酰胺代替实施例1步骤3中的(反式)-4-((4-氨基-3-甲氧基苯基)氨基)金刚烷-1-醇,以与实施例1相同的方式合成标题化合物。
[步骤4]N-(3-甲氧基-4-((4-((2-甲基-6-(甲基氨基甲酰基)苯基)氨基)-5-(三氟甲基)嘧啶-2-基)氨基)苯基)-4-氧代金刚烷-1-甲酰胺的制备
通过使用N-(4-((4-氯-5-(三氟甲基)嘧啶-2-基)氨基)-3-甲氧基苯基)-4-氧代金刚烷-1-甲酰胺代替实施例1步骤4中的(反式)-4-((4-((4-氯-5-(三氟甲基)嘧啶-2-基)氨基)-3-甲氧基苯基)氨基)金刚烷-1-醇,以与实施例1相同的方式合成标题化合物。
[步骤5]N-(3-甲氧基-4-((4-((2-甲基-6-(甲基氨基甲酰基)苯基)氨基)-5-(三氟甲基)嘧啶-2-基)氨基)苯基)-4-吗啉代金刚烷-1-甲酰胺的制备
通过使用N-(3-甲氧基-4-((4-((2-甲基-6-(甲基氨基甲酰基)苯基)氨基)-5-(三氟甲基)嘧啶-2-基)氨基)苯基)-4-氧代金刚烷-1-甲酰胺代替实施例12步骤1中的2-((2-((2-甲氧基-4-((4-氧代金刚烷-1-基)氧基)苯基)氨基)-5-(三氟甲基)嘧啶-4-基)氨基)-N,3-二甲基苯甲酰胺,以与实施例12相同的方式合成标题化合物。
1H NMR(400MHz,CDCl3):δ8.40(s,1H),8.29(s,1H),7.69(s,1H),7.53(s,1H),7.41(m,2H),7.32(t,J=7.9Hz,1H),7.19(s,1H),6.34(s,1H),6.01(s,1H),3.86(s,3H),3.75(m,4H),2.88(m,3H),2.45(s,3H),2.21(s,3H),2.16–2.01(m,6H),1.93(m,4H),1.58(s,3H),1.40(m,2H)
<实施例26>N-(3-甲氧基-4-((4-((2-甲基-6-(甲基氨基甲酰基)苯基)氨基)-5-(三氟甲基)嘧啶-2-基)氨基)苯基)-4-(4-甲基哌嗪-1-基)金刚烷-1-甲酰胺(化合物26)的制备
[步骤1]N-(3-甲氧基-4-((4-((2-甲基-6-(甲基氨基甲酰基)苯基)氨基)-5-(三氟甲基)嘧啶-2-基)氨基)苯基)-4-(4-甲基哌嗪-1-基)金刚烷-1-甲酰胺的制备
通过使用4-甲基哌嗪代替实施例25步骤5中的吗啉,以与实施例25相同的方式合成标题化合物。
1H NMR(400MHz,CDCl3):δ8.39(s,1H),8.29(s,1H),7.69(s,1H),7.53(s,1H),7.40(m,2H),7.35–7.29(m,1H),7.18(s,1H),6.34(s,1H),6.00(s,1H),3.86(s,3H),2.87(d,J=4.8Hz,3H),2.48(s,4H),2.30(s,3H),2.24(s,1H),2.21(s,3H),2.07(m,5H),1.92(m,3H),1.68(s,7H),1.38(m,2H)
<实施例27>(反式)-4-((S)-3-乙酰氨基吡咯烷-1-基)-N-(3-甲氧基-4-((4-((2-甲基-6-(甲基氨基甲酰基)苯基)氨基)-5-(三氟甲基)嘧啶-2-基)氨基)苯基)金刚烷-1-甲酰胺(化合物27)的制备
[步骤1](反式)-4-((S)-3-乙酰氨基吡咯烷-1-基)-N-(3-甲氧基-4-((4-((2-甲基-6-(甲基氨基甲酰基)苯基)氨基)-5-(三氟甲基)嘧啶-2-基)氨基)苯基)金刚烷-1-甲酰胺的制备
通过使用(S)-N-(吡咯烷-3-基)乙酰胺代替实施例25步骤5中的吗啉,以与实施例25相同的方式合成标题化合物。
1H NMR(400MHz,CDCl3):δ8.45(s,1H),8.28(s,1H),7.69(s,1H),7.52(s,1H),7.46–7.28(m,4H),6.23(s,1H),6.06(s,1H),4.59(s,1H),3.85(s,3H),2.85(d,J=4.7Hz,3H),2.46(m,4H),2.26–2.08(m,6H),2.09–1.83(m,12H),1.71(m,5H)
<实施例28>(顺式)-4-((S)-3-乙酰氨基吡咯烷-1-基)-N-(3-甲氧基-4-((4-((2-甲基-6-(甲基氨基甲酰基)苯基)氨基)-5-(三氟甲基)嘧啶-2-基)氨基)苯基)金刚烷-1-甲酰胺(化合物28)的制备
[步骤1](顺式)-4-((S)-3-乙酰氨基吡咯烷-1-基)-N-(3-甲氧基-4-((4-((2-甲基-6-(甲基氨基甲酰基)苯基)氨基)-5-(三氟甲基)嘧啶-2-基)氨基)苯基)金刚烷-1-甲酰胺的制备
通过使用(S)-N-(吡咯烷-3-基)乙酰胺代替实施例25步骤5中的吗啉,以与实施例25相同的方式合成标题化合物。
1H NMR(400MHz,CDCl3):δ8.43(s,1H),8.29(s,1H),7.69(s,1H),7.50(s,1H),7.40(m,2H),7.31(t,J=7.4Hz,1H),7.20(s,1H),6.35(s,1H),6.07(d,J=5.0Hz,1H),4.49(s,1H),3.86(s,3H),2.87(d,J=4.9Hz,3H),2.55(s,1H),2.29(s,1H),2.24–1.87(m,17H),1.70(s,6H),1.45(d,2H)
<实施例29>4-羟基-N-(3-甲氧基-4-((4-((2-甲基-6-(甲基氨基甲酰基)苯基)氨基)-5-(三氟甲基)嘧啶-2-基)氨基)苯基)金刚烷-1-甲酰胺(化合物29)的制备
[步骤1]4-羟基-N-(3-甲氧基-4-((4-((2-甲基-6-(甲基氨基甲酰基)苯基)氨基)-5-(三氟甲基)嘧啶-2-基)氨基)苯基)金刚烷-1-甲酰胺的制备
通过使用N-(3-甲氧基-4-((4-((2-甲基-6-(甲基氨基甲酰基)苯基)氨基)-5-(三氟甲基)嘧啶-2-基)氨基)苯基)-4-氧代金刚烷-1-甲酰胺代替实施例11步骤1中的2-((2-((2-甲氧基-4-((4-氧代金刚烷-1-基)氧基)苯基)氨基)-5-(三氟甲基)嘧啶-4-基)氨基)-N,3-二甲基苯甲酰胺,以与实施例11相同的方式合成标题化合物。
1H NMR(400MHz,DMSO-d6):δ9.10(s,1H),8.96–8.85(m,1H),8.27–8.20(m,2H),7.90(s,1H),7.41–7.23(m,5H),6.86(br s,1H),4.59(m,1H),3.69(s,3H),3.68–3.54(m,1H),2.63(d,J=4.5,3H),2.15–1.96(m,5H),1.88–1.74(m,7H),1.68(m,1H),1.56(m,1H),1.35–1.27(m,2H)
<实施例30>(反式)-4-((S)-3-氨基吡咯烷-1-基)-N-(3-甲氧基-4-((4-((2-甲基-6-(甲基氨基甲酰基)苯基)氨基)-5-(三氟甲基)嘧啶-2-基)氨基)苯基)金刚烷-1-甲酰胺(化合物30)的制备
[步骤1]((3S)-1-((反式)-5-((3-甲氧基-4-((4-((2-甲基-6-(甲基氨基甲酰基)苯基)氨基)-5-(三氟甲基)嘧啶-2-基)氨基)苯基)氨基甲酰基)金刚烷-2-基)吡咯烷-3-基)氨基甲酸叔丁酯的制备
通过使用(S)-吡咯烷-3-基氨基甲酸叔丁酯代替实施例25步骤5中的吗啉,以与实施例25相同的方式合成标题化合物。
[步骤2](反式)-4-((S)-3-氨基吡咯烷-1-基)-N-(3-甲氧基-4-((4-((2-甲基-6-(甲基氨基甲酰基)苯基)氨基)-5-(三氟甲基)嘧啶-2-基)氨基)苯基)金刚烷-1-甲酰胺的制备
将在上述步骤1中制备的((3S)-1-((反式)-5-((3-甲氧基-4-((4-((2-甲基-6-(甲基氨基甲酰基)苯基)氨基)-5-(三氟甲基)嘧啶-2-基)氨基)苯基)氨基甲酰基)金刚烷-2-基)吡咯烷-3-基)氨基甲酸叔丁酯溶解在4M盐酸二氧六环溶液中并在室温搅拌。通过TLC确认反应结束后,向反应溶液中加入饱和NaHCO3水溶液,然后用乙酸乙酯萃取。将所得的溶液经无水硫酸镁干燥,过滤,然后将滤液浓缩,通过柱层析法纯化,以获得标题化合物。
1H NMR(400MHz,CDCl3):δ8.46(s,1H),8.30(s,1H),7.70(s,1H),7.53(s,1H),7.46–7.20(m,4H),6.37(m,1H),6.14(m,1H),3.52(s,1H),3.86(s,3H),2.87(d,J=4.8Hz,3H),2.85–1.25(m,24H)
<实施例31>(顺式)-4-((S)-3-氨基吡咯烷-1-基)-N-(3-甲氧基-4-((4-((2-甲基-6-(甲基氨基甲酰基)苯基)氨基)-5-(三氟甲基)嘧啶-2-基)氨基)苯基)金刚烷-1-甲酰胺(化合物31)的制备
[步骤1]((3S)-1-((反式)-5-((3-甲氧基-4-((4-((2-甲基-6-(甲基氨基甲酰基)苯基)氨基)-5-(三氟甲基)嘧啶-2-基)氨基)苯基)氨基甲酰基)金刚烷-2-基)吡咯烷-3-基)氨基甲酸叔丁酯的制备
通过使用(S)-吡咯烷-3-基氨基甲酸叔丁酯代替实施例25步骤5中的吗啉,以与实施例25相同的方式合成标题化合物。
[步骤2](顺式)-4-((S)-3-氨基吡咯烷-1-基)-N-(3-甲氧基-4-((4-((2-甲基-6-(甲基氨基甲酰基)苯基)氨基)-5-(三氟甲基)嘧啶-2-基)氨基)苯基)金刚烷-1-甲酰胺的制备
将在上述步骤1中制备的((3S)-1-((顺式)-5-((3-甲氧基-4-((4-((2-甲基-6-(甲基氨基甲酰基)苯基)氨基)-5-(三氟甲基)嘧啶-2-基)氨基)苯基)氨基甲酰基)金刚烷-2-基)吡咯烷-3-基)氨基甲酸叔丁酯溶解在4M盐酸二氧六环溶液中并在室温搅拌。通过TLC确认反应结束后,向反应溶液中加入饱和NaHCO3水溶液,然后用乙酸乙酯萃取。将所得的溶液经无水硫酸镁干燥,过滤,然后将滤液浓缩,通过柱层析法纯化,以获得标题化合物。
1H NMR(400MHz,CDCl3):δ8.45(s,1H),8.29(s,1H),7.70(s,1H),7.53(s,1H),7.46–7.20(m,4H),6.36(m,1H),6.14(m,1H),3.52(s,1H),3.86(s,3H),2.87(d,J=4.8Hz,3H),2.85–1.25(m,24H)
<实施例32>2-((2-((4-(1-((反式)-5-羟基金刚烷-2-基)哌啶-4-基)-2-甲氧基苯基)氨基)-5-(三氟甲基)嘧啶-4-基)氨基)-N,3-二甲基苯甲酰胺(化合物32)的制备
[步骤1]2-((2-((4-(1-((反式)-5-羟基金刚烷-2-基)哌啶-4-基)-2-甲氧基苯基)氨基)-5-(三氟甲基)嘧啶-4-基)氨基)-N,3-二甲基苯甲酰胺的制备
通过使用(反式)-4-(4-(4-((4-氯-5-(三氟甲基)嘧啶-2-基)氨基)-3-甲氧基苯基)哌啶-1-基)金刚烷-1-醇代替实施例1步骤4中的(反式)-4-((4-((4-氯-5-(三氟甲基)嘧啶-2-基)氨基)-3-甲氧基苯基)氨基)金刚烷-1-醇,以与实施例1相同的方式合成标题化合物。
1H NMR(400MHz,CDCl3):δ8.38(s,1H),8.29(s,1H),7.69(br s,1H),7.46–7.28(m,3H),6.70(d,J=7.0Hz,1H),6.41(br s,1H),6.06(br s,1H),5.98(s,1H),3.85(s,3H),3.09(m,2H),2.89(m,2H),2.86(d,J=4.9Hz,3H),2.72–2.59(m,2H),2.53(m,1H),2.37(m,1H),2.31(m,1H),2.24(m,1H),2.22(s,3H),2.13–1.20(m,13H)
<实施例33>2-((2-((4-(1-((顺式)-5-羟基金刚烷-2-基)哌啶-4-基)-2-甲氧基苯基)氨基)-5-(三氟甲基)嘧啶-4-基)氨基)-N,3-二甲基苯甲酰胺(化合物33)的制备
[步骤1]2-((2-((4-(1-((顺式)-5-羟基金刚烷-2-基)哌啶-4-基)-2-甲氧基苯基)氨基)-5-(三氟甲基)嘧啶-4-基)氨基)-N,3-二甲基苯甲酰胺的制备
通过使用(顺式)-4-(4-(4-((4-氯-5-(三氟甲基)嘧啶-2-基)氨基)-3-甲氧基苯基)哌啶-1-基)金刚烷-1-醇代替实施例1步骤4中的(反式)-4-((4-((4-氯-5-(三氟甲基)嘧啶-2-基)氨基)-3-甲氧基苯基)氨基)金刚烷-1-醇,以与实施例1相同的方式合成标题化合物。
1H NMR(400MHz,CDCl3):δ8.38(s,1H),8.29(s,1H),7.69(br s,1H),7.46–7.28(m,3H),6.70(d,J=7.0Hz,1H),6.41(br s,1H),6.06(br s,1H),5.99(s,1H),3.85(s,3H),3.09(m,2H),2.89(m,2H),2.87(d,J=4.9Hz,3H),2.72–2.59(m,2H),2.53(m,1H),2.38(m,1H),2.31(m,1H),2.24(m,1H),2.21(s,3H),2.13–1.20(m,13H)
<实施例34>2-((2-((4-(1-((反式)-5-羟基金刚烷-2-基)哌啶-4-基)-2-甲氧基苯基)氨基)-5-(三氟甲基)嘧啶-4-基)氨基)-3-甲基苯甲酰胺(化合物34)的制备
[步骤1]2-((2-((4-(1-((反式)-5-羟基金刚烷-2-基)哌啶-4-基)-2-甲氧基苯基)氨基)-5-(三氟甲基)嘧啶-4-基)氨基)-3-甲基苯甲酰胺的制备
通过使用2-氨基-3-甲基苯甲酰胺代替实施例32步骤1中的2-氨基-N,3-二甲基苯甲酰胺,以与实施例32相同的方式合成标题化合物。
1H NMR(400MHz,CDCl3):δ8.39(s,1H),8.30(s,1H),7.70(br s,1H),7.54–7.43(m,2H),7.35(m,1H),6.70(s,1H),6.41(br s,1H),6.04(br s,1H),5.57(s,1H),3.85(s,3H),3.09(m,2H),2.87(m,2H),2.63(m,2H),2.53(m,1H),2.37(m,1H),2.31(m,1H),2.23(s,3H),2.13–1.20(m,14H)
<实施例35>2-((2-((4-(1-((顺式)-5-羟基金刚烷-2-基)哌啶-4-基)-2-甲氧基苯基)氨基)-5-(三氟甲基)嘧啶-4-基)氨基)-3-甲基苯甲酰胺(化合物35)的制备
[步骤1]2-((2-((4-(1-((顺式)-5-羟基金刚烷-2-基)哌啶-4-基)-2-甲氧基苯基)氨基)-5-(三氟甲基)嘧啶-4-基)氨基)-3-甲基苯甲酰胺的制备
通过使用2-氨基-3-甲基苯甲酰胺代替实施例33步骤1中的2-氨基-N,3-二甲基苯甲酰胺,以与实施例33相同的方式合成标题化合物。
1H NMR(400MHz,CDCl3):δ8.41(s,1H),8.30(s,1H),7.70(br s,1H),7.53–7.44(m,2H),7.35(t,J=7.6Hz,1H),6.69(s,1H),6.41(br s,1H),6.03(br s,1H),5.59(s,1H),3.85(s,3H),3.09(m,2H),2.87(m,2H),2.63(m,2H),2.53(m,1H),2.37(m,1H),2.31(m,1H),2.23(s,3H),2.13–1.20(m,14H)
<实施例36>2-((5-氯-2-((4-(4-((反式)-5-羟基金刚烷-2-基)哌嗪-1-基)-2-甲氧基苯基)氨基)-嘧啶-4-基)氨基)-N,3-二甲基苯甲酰胺(化合物36)的制备
[步骤1]2-((2,5-二氯嘧啶-4-基)氨基)-N,3-二甲基苯甲酰胺的制备
将2-氨基-N,3-二甲基苯甲酰胺和NaHCO3溶解在乙醇中,然后加入2,4,5-三氯嘧啶并在80℃搅拌。通过TLC确认反应结束后,浓缩溶剂,将所得的固体溶解在乙酸乙酯中并用蒸馏水提取。将所得的溶液经无水硫酸镁干燥,过滤,然后浓缩滤液,用乙腈:蒸馏水=20:1重结晶,以获得标题化合物。
[步骤2]2-((5-氯-2-((4-(4-((反式)-5-羟基金刚烷-2-基)哌嗪-1-基)-2-甲氧基苯基)氨基)-嘧啶-4-基)氨基)-N,3-二甲基苯甲酰胺的制备
将4-(4-(4-氨基-3-甲氧基苯基)哌嗪-1-基)金刚烷-1-醇和在上述步骤1中制备的2-((2,5-二氯嘧啶-4-基)氨基)-N,3-二甲基苯甲酰胺溶解在2-丁醇中,然后加入甲磺酸并在120℃搅拌。反应结束后,向反应溶液中加入蒸馏水,然后用乙酸乙酯萃取。将所得的溶液经无水硫酸镁干燥,过滤,然后将滤液浓缩,通过柱层析法纯化,以获得标题化合物。
1H NMR(400MHz,CDCl3):δ8.66(s,1H),8.01(s,1H),7.67(m,2H),7.45–7.16(m,5H),6.48(m,2H),6.18(m,1H),6.07(br s,1H),3.81(s,3H),3.09(m,4H),2.87(d,J=4.8Hz,3H),2.62(m,4H),2.34–2.26(m,1H),2.22(s,3H),2.14–1.98(m,4H),1.83–1.61(m,5H),1.42–1.24(m,3H)
<实施例37>(反式)-4-(4-(3-甲氧基-4-((4-((2-甲基-6-(甲基氨基甲酰基)苯基)氨基)-5-(三氟甲基)嘧啶-2-基)氨基)苯基)哌嗪-1-基)金刚烷-1-羧酸甲酯(化合物37)的制备
[步骤1](反式)-4-(4-(4-((4-氯-5-(三氟甲基)嘧啶-2-基)氨基)-3-甲氧基苯基)哌嗪-1-基)金刚烷-1-羧酸甲酯的制备
通过使用(反式)-4-(4-(4-氨基-3-甲氧基苯基)哌嗪-1-基)金刚烷-1-羧酸甲酯代替实施例1步骤3中的(反式)-4-((4-氨基-3-甲氧基苯基)氨基)金刚烷-1-醇,以与实施例1相同的方式合成标题化合物。
[步骤2](反式)-4-(4-(3-甲氧基-4-((4-((2-甲基-6-(甲基氨基甲酰基)苯基)氨基)-5-(三氟甲基)嘧啶-2-基)氨基)苯基)哌嗪-1-基)金刚烷-1-羧酸甲酯的制备
通过使用(反式)-4-(4-(4-((4-氯-5-(三氟甲基)嘧啶-2-基)氨基)-3-甲氧基苯基)哌嗪-1-基)金刚烷-1-羧酸甲酯代替实施例1步骤4中的(反式)-4-((4-((4-氯-5-(三氟甲基)嘧啶-2-基)氨基)-3-甲氧基苯基)氨基)金刚烷-1-醇,以与实施例1相同的方式合成标题化合物。
1H NMR(400MHz,CDCl3):δ8.28(s,1H),8.26(s,1H),7.40(d,J=7.3Hz,1H),7.36(d,J=7.5Hz,1H),7.31–7.26(m,1H),6.47(d,J=2.0Hz,1H),6.15–5.95(m,2H),3.82(s,3H),3.66(s,3H),3.09(m,4H),2.84(d,J=4.8Hz,3H),2.60(m,4H),2.25–2.14(m,4H),2.13–2.05(m,2H),2.04–1.92(m,2H),1.91–1.82(m,3H),1.73–1.62(m,2H),1.40–1.33(m,2H),1.31–1.20(m,2H)
<实施例38>(顺式s)-4-(4-(3-甲氧基-4-((4-((2-甲基-6-(甲基氨基甲酰基)苯基)氨基)-5-(三氟甲基)嘧啶-2-基)氨基)苯基)哌嗪-1-基)金刚烷-1-羧酸甲酯(化合物38)的制备
[步骤1](顺式)-4-(4-(4-((4-氯-5-(三氟甲基)嘧啶-2-基)氨基)-3-甲氧基苯基)哌嗪-1-基)金刚烷-1-羧酸甲酯的制备
通过使用(顺式)-4-(4-(4-氨基-3-甲氧基苯基)哌嗪-1-基)金刚烷-1-羧酸甲酯代替实施例1步骤3中的(反式)-4-((4-氨基-3-甲氧基苯基)氨基)金刚烷-1-醇,以与实施例1相同的方式合成标题化合物。
[步骤2](顺式)-4-(4-(3-甲氧基-4-((4-((2-甲基-6-(甲基氨基甲酰基)苯基)氨基)-5-(三氟甲基)嘧啶-2-基)氨基)苯基)哌嗪-1-基)金刚烷-1-羧酸甲酯的制备
通过使用(顺式)-4-(4-(4-((4-氯-5-(三氟甲基)嘧啶-2-基)氨基)-3-甲氧基苯基)哌嗪-1-基)金刚烷-1-羧酸甲酯代替实施例1步骤4中的(反式)-4-((4-((4-氯-5-(三氟甲基)嘧啶-2-基)氨基)-3-甲氧基苯基)氨基)金刚烷-1-醇,以与实施例1相同的方式合成标题化合物。
1H NMR(400MHz,CDCl3):δ8.27(s,1H),8.26(s,1H),7.41(d,J=7.3Hz,1H),7.37(d,J=7.5Hz,1H),7.31–7.26(m,1H),6.47(d,J=2.0Hz,1H),6.15–5.95(m,2H),3.82(s,3H),3.66(s,3H),3.09(m,4H),2.84(d,J=4.8Hz,3H),2.60(m,4H),2.28–2.13(m,5H),2.07(m,1H),1.98(m,1H),1.90–1.77(m,4H),1.75–1.48(m,6H)
<实施例39>(反式)-4-(4-(3-甲氧基-4-((4-((2-甲基-6-(甲基氨基甲酰基)苯基)氨基)-5-(三氟甲基)嘧啶-2-基)氨基)苯基)哌嗪-1-基)金刚烷-1-羧酸(化合物39)的制备
[步骤1](反式)-4-(4-(3-甲氧基-4-((4-((2-甲基-6-(甲基氨基甲酰基)苯基)氨基)-5-(三氟甲基)嘧啶-2-基)氨基)苯基)哌嗪-1-基)金刚烷-1-羧酸的制备
通过使用(反式)-4-(4-(3-甲氧基-4-((4-((2-甲基-6-(甲基氨基甲酰基)苯基)氨基)-5-(三氟甲基)嘧啶-2-基)氨基)苯基)哌嗪-1-基)金刚烷-1-羧酸甲酯代替实施例17步骤1中的4-(3-甲氧基-4-((4-((2-甲基-6-(甲基氨基甲酰基)苯基)氨基)-5-(三氟甲基)嘧啶-2-基)氨基)苯氧基)金刚烷-1-羧酸甲酯,以与实施例17相同的方式合成标题化合物。
1H NMR(400MHz,CD3OD):δ8.20(s,1H),7.48–7.32(m,3H),6.56(d,J=2.4Hz,1H),6.12(m,2H),3.83(s,3H),3.13(m,4H),2.79(s,3H),2.71(m,4H),2.30–2.22(m,3H),2.21(s,3H),2.15–2.08(m,2H),2.06–1.99(m,2H),1.96–1.84(m,5H),1.48–1.40(m,2H)
<实施例40>(顺式)-4-(4-(3-甲氧基-4-((4-((2-甲基-6-(甲基氨基甲酰基)苯基)氨基)-5-(三氟甲基)嘧啶-2-基)氨基)苯基)哌嗪-1-基)金刚烷-1-羧酸(化合物40)的制备
[步骤1](顺式)-4-(4-(3-甲氧基-4-((4-((2-甲基-6-(甲基氨基甲酰基)苯基)氨基)-5-(三氟甲基)嘧啶-2-基)氨基)苯基)哌嗪-1-基)金刚烷-1-羧酸的制备
通过使用(顺式)-4-(4-(3-甲氧基-4-((4-((2-甲基-6-(甲基氨基甲酰基)苯基)氨基)-5-(三氟甲基)嘧啶-2-基)氨基)苯基)哌嗪-1-基)金刚烷-1-羧酸甲酯代替实施例17步骤1中的4-(3-甲氧基-4-((4-((2-甲基-6-(甲基氨基甲酰基)苯基)氨基)-5-(三氟甲基)嘧啶-2-基)氨基)苯氧基)金刚烷-1-羧酸甲酯,以与实施例17相同的方式合成标题化合物。
1H NMR(400MHz,CD3OD):δ8.21(s,1H),7.49–7.33(m,3H),6.57(d,J=2.4Hz,1H),6.13(m,2H),3.84(s,3H),3.14(m,4H),2.80(s,3H),2.72(m,4H),2.31–2.23(m,3H),2.22(s,3H),2.16–2.09(m,2H),2.07–2.00(m,2H),1.97–1.85(m,5H),1.49–1.41(m,2H)
<实施例41>4-(4-(3-甲氧基-4-((4-((2-甲基-6-(甲基氨基甲酰基)苯基)氨基)-5-(三氟甲基)嘧啶-2-基)氨基)苯基)哌嗪-1-基)-N-甲基金刚烷-1-甲酰胺(化合物41)的制备
[步骤1]4-(4-(3-甲氧基-4-((4-((2-甲基-6-(甲基氨基甲酰基)苯基)氨基)-5-(三氟甲基)嘧啶-2-基)氨基)苯基)哌嗪-1-基)-N-甲基金刚烷-1-甲酰胺的制备
通过使用4-(4-(3-甲氧基-4-((4-((2-甲基-6-(甲基氨基甲酰基)苯基)氨基)-5-(三氟甲基)嘧啶-2-基)氨基)苯基)哌嗪-1-基)金刚烷-1-羧酸代替实施例18步骤1中的4-(3-甲氧基-4-((4-((2-甲基-6-(甲基氨基甲酰基)苯基)氨基)-5-(三氟甲基)嘧啶-2-基)氨基)苯氧基)金刚烷1-羧酸,以与实施例18相同的方式合成标题化合物。
1H NMR(400MHz,CD3OD):δ8.19(s,1H),7.47–7.31(m,3H),6.55(d,J=2.4Hz,1H),6.11(m,2H),3.82(s,3H),3.12(m,4H),2.80(s,3H),2.78(s,3H),2.70(m,4H),2.29–2.21(m,3H),2.20(s,3H),2.14–2.07(m,2H),2.05–1.98(m,2H),1.95–1.83(m,5H),1.47–1.39(m,2H)
<实施例42>4-(4-(3-甲氧基-4-((4-((2-甲基-6-(甲基氨基甲酰基)苯基)氨基)-5-(三氟甲基)嘧啶-2-基)氨基)苯基)哌嗪-1-基)金刚烷-1-甲酰胺(化合物42)的制备
[步骤1]4-(4-(3-甲氧基-4-((4-((2-甲基-6-(甲基氨基甲酰基)苯基)氨基)-5-(三氟甲基)嘧啶-2-基)氨基)苯基)哌嗪-1-基)金刚烷-1-甲酰胺的制备
通过使用氯化铵代替实施例41步骤1中的甲胺盐酸盐,以与实施例41相同的方式合成标题化合物。
1H NMR(400MHz,CD3OD):δ8.19(s,1H),7.47–7.31(m,3H),6.55(d,J=2.4Hz,1H),6.11(m,2H),3.82(s,3H),3.12(m,4H),2.78(s,3H),2.70(m,4H),2.29–2.21(m,3H),2.20(s,3H),2.14–2.07(m,2H),2.05–1.98(m,2H),1.95–1.83(m,5H),1.47–1.39(m,2H)
<实施例43>4-(4-(3-甲氧基-4-((4-((2-甲基-6-(甲基氨基甲酰基)苯基)氨基)-5-(三氟甲基)嘧啶-2-基)氨基)苯基)哌嗪-1-基)-N,N-二甲基金刚烷-1-甲酰胺(化合物43)的制备
[步骤1]4-(4-(3-甲氧基-4-((4-((2-甲基-6-(甲基氨基甲酰基)苯基)氨基)-5-(三氟甲基)嘧啶-2-基)氨基)苯基)哌嗪-1-基)-N,N-金刚烷-1-甲酰胺的制备
通过使用二甲胺盐酸盐代替实施例41步骤1中的甲胺盐酸盐,以与实施例41相同的方式合成标题化合物。
1H NMR(400MHz,CD3OD):δ8.19(s,1H),7.47–7.31(m,3H),6.55(d,J=2.4Hz,1H),6.11(m,2H),3.82(s,3H),3.12(m,4H),2.98,(s,3H),2.78(s,3H),2.70(m,4H),2.29–2.21(m,3H),2.20(s,3H),2.14–2.07(m,2H),2.05–1.98(m,2H),1.95–1.83(m,5H),1.47–1.39(m,2H)
<实施例44>2-((2-((4-(4-(5-氨基金刚烷)-2-基)哌嗪-1-基)-2-甲氧基苯基)氨基)-5-(三氟甲基)嘧啶-4-基)氨基)-N,3-二甲基苯甲酰胺(化合物44)的制备
[步骤1](4-(4-(4-((4-氯-5-(三氟甲基)嘧啶-2-基)氨基)-3-甲氧基苯基)哌嗪-1-基)金刚烷-1-基)氨基甲酸(9H-芴-9-基)甲酯的制备
通过使用(4-(4-(4-氨基-3-甲氧基苯基)哌嗪-1-基)金刚烷-1-基)氨基甲酸(9H-芴-9-基)甲酯代替实施例1步骤3中的(反式)-4-((4-氨基-3-甲氧基苯基)氨基)金刚烷-1-醇,以与实施例1相同的方式合成标题化合物。
[步骤2](4-(4-(3-甲氧基-4-((4-((2-甲基-6-(甲基氨基甲酰基)苯基)氨基)-5-(三氟甲基)嘧啶-2-基)氨基)苯基)哌嗪-1-基)金刚烷-1-基)氨基甲酸(9H-芴-9-基)甲酯的制备
通过使用(反式)-4-(4-(4-((4-氯-5-(三氟甲基)嘧啶-2-基)氨基)-3-甲氧基苯基)哌嗪-1-基)金刚烷-1-羧酸甲酯代替实施例1步骤4中的(反式)-4-((4-((4-氯-5-(三氟甲基)嘧啶-2-基)氨基)-3-甲氧基苯基)氨基)金刚烷-1-醇,以与实施例1相同的方式合成标题化合物。
[步骤3]2-((2-((4-(4-(5-氨基金刚烷-2-基)哌嗪-1-基)-2-甲氧基苯基)氨基)-5-(三氟甲基)嘧啶-4-基)氨基)-N,3-二甲基苯甲酰胺的制备
将在上述步骤2中制备的(4-(4-(3-甲氧基-4-((4-((2-甲基-6-(甲基氨基甲酰基)苯基)氨基)-5-(三氟甲基)嘧啶-2-基)氨基)苯基)哌嗪-1-基)金刚烷-1-基)氨基甲酸(9H-芴-9-基)甲酯溶解在乙腈中并在冰浴中冷却。缓慢滴加二乙胺。将所得的溶液在0℃搅拌1小时,在室温搅拌15小时。减压浓缩溶剂,通过柱层析法纯化,以获得标题化合物。
1H NMR(400MHz,CDCl3):δ8.27(s,2H,重叠),7.42(d,J=7.3Hz,1H),7.35(d,J=7.5Hz,1H),7.32–7.27(m,1H),6.48(d,J=2.0Hz,1H),6.10(br s,1H),6.01(s,1H),3.83(s,3H),3.10(m,4H),2.85(d,J=4.8Hz,3H),2.62(m,4H),2.34–2.26(m,1H),2.22(s,3H),2.14–1.98(m,4H),1.83–1.61(m,5H),1.42–1.24(m,3H)
<实施例45>2-((2-((4-(4-(5-(甲基氨基金刚烷)-2-基)哌嗪-1-基)-2-甲氧基苯基)氨基)-5-(三氟甲基)嘧啶-4-基)氨基)-N,3-二甲基苯甲酰胺(化合物45)的制备
[步骤1]2-((2-((4-(4-(5-甲基氨基金刚烷-2-基)哌嗪-1-基)-2-甲氧基苯基)氨基)-5-(三氟甲基)嘧啶-4-基)氨基)-N,3-二甲基苯甲酰胺的制备
将在上述实施例44中制备的2-((2-((4-(4-(5-氨基金刚烷)-2-基)哌嗪-1-基)-2-甲氧基苯基)氨基)-5-(三氟甲基)嘧啶-4-基)氨基)-N,3-二甲基苯甲酰胺溶解在氯仿中,然后加入碳酸钾并搅拌。缓慢加入1当量碘甲烷并在室温搅拌。减压浓缩溶剂,通过柱层析法纯化,以获得标题化合物。
1H NMR(400MHz,CDCl3):δ8.27(s,2H,重叠),7.42(d,J=7.3Hz,1H),7.35(d,J=7.5Hz,1H),7.32–7.27(m,1H),6.48(d,J=2.0Hz,1H),6.10(br s,1H),6.01(s,1H),3.83(s,3H),3.10(m,4H),2.85(d,J=4.8Hz,3H),2.62(m,4H),2.55(s,3H),2.34–2.26(m,1H),2.22(s,3H),2.14–1.98(m,4H),1.83–1.61(m,5H),1.42–1.24(m,3H)
<实施例46>2-((2-((4-(4-(5-二甲基氨基金刚烷)-2-基)哌嗪-1-基)-2-甲氧基苯基)氨基)-5-(三氟甲基)嘧啶-4-基)氨基)-N,3-二甲基苯甲酰胺(化合物46)的制备
[步骤1]2-((2-((4-(4-(5-二甲基氨基金刚烷-2-基)哌嗪-1-基)-2-甲氧基苯基)氨基)-5-(三氟甲基)嘧啶-4-基)氨基)-N,3-二甲基苯甲酰胺的制备
将在上述实施例44中制备的2-((2-((4-(4-(5-氨基金刚烷)-2-基)哌嗪-1-基)-2-甲氧基苯基)氨基)-5-(三氟甲基)嘧啶-4-基)氨基)-N,3-二甲基苯甲酰胺溶解在氯仿中,然后加入碳酸钾并搅拌。缓慢加入碘甲烷(2当量)并在室温搅拌。减压浓缩溶剂,通过柱层析法纯化,以获得标题化合物。
1H NMR(400MHz,CDCl3):δ8.27(s,2H,重叠),7.42(d,J=7.3Hz,1H),7.35(d,J=7.5Hz,1H),7.32–7.27(m,1H),6.48(d,J=2.0Hz,1H),6.10(br s,1H),6.01(s,1H),3.83(s,3H),3.10(m,4H),2.85(d,J=4.8Hz,3H),2.62(m,4H),2.34–2.26(m,1H),2.24(s,6H),2.22(s,3H),2.14–1.98(m,4H),1.83–1.61(m,5H),1.42–1.24(m,3H)
<实施例47>2-((2-((4-(4-(5-丙烯酰氨基金刚烷)-2-基)哌嗪-1-基)-2-甲氧基苯基)氨基)-5-(三氟甲基)嘧啶-4-基)氨基)-N,3-二甲基苯甲酰胺(化合物47)的制备
[步骤1]2-((2-((4-(4-(5-丙烯酰氨基金刚烷-2-基)哌嗪-1-基)-2-甲氧基苯基)氨基)-5-(三氟甲基)嘧啶-4-基)氨基)-N,3-二甲基苯甲酰胺的制备
将在上述实施例44中制备的2-((2-((4-(4-(5-氨基金刚烷)-2-基)哌嗪-1-基)-2-甲氧基苯基)氨基)-5-(三氟甲基)嘧啶-4-基)氨基)-N,3-二甲基苯甲酰胺溶解在氯仿中,然后加入碳酸钾并搅拌。缓慢加入丙烯酰氯并在室温搅拌。减压浓缩溶剂,通过柱层析法纯化,以获得标题化合物。
1H NMR(400MHz,CDCl3):δ8.27(s,2H,重叠),7.42(d,J=7.3Hz,1H),7.35(d,J=7.5Hz,1H),7.32–7.27(m,1H),6.52(m,1H),6.48(d,J=2.0Hz,1H),6.10(br s,1H),6.06(m,1H),6.01(s,1H),5.74(m,1H),3.83(s,3H),3.10(m,4H),2.85(d,J=4.8Hz,3H),2.62(m,4H),2.34–2.26(m,1H),2.22(s,3H),2.14–1.98(m,4H),1.83–1.61(m,5H),1.42–1.24(m,3H)
测试实施例
<实验实施例1>化合物的FAK、Pyk2和InsR抑制活性的测定
通过生化激酶分析确认本发明的金刚烷衍生物化合物对FAK、Pyk2和InsR的抑制活性,下表1显示了每种化合物的每种激酶抑制活性的IC50值。简而言之,通过使用Promega的含有每种激酶的ADP-GloTM激酶检测试剂盒(FAK,Promega,V1971;Pyk2,Promega,V4083;InsR,Promega,V9401)处理本发明的金刚烷衍生物化合物,然后根据制造商的说明进行激酶测试并进行量化。
[表1]
化合物# | FAK IC<sub>50</sub>(nM) | Pyk2 IC<sub>50</sub>(nM) | InsR IC<sub>50</sub>(nM) |
1 | 82.9 | 124.5 | >10,000 |
2 | 205.5 | - | >10,000 |
3 | 154.2 | 255.9 | >10,000 |
4 | 46.2 | 150.5 | 5,666 |
5 | 69.9 | - | 4,685 |
6 | 96.5 | 157.0 | >10,000 |
7 | 46.9 | 108.1 | 6,148 |
8 | 53.3 | - | >10,000 |
9 | 98.1 | - | >10,000 |
10 | 96.7 | - | >10,000 |
11 | 65.1 | 231.0 | >10,000 |
14 | 57.0 | - | - |
18 | 92.9 | - | - |
19 | 126.8 | - | - |
20 | 98.9 | - | - |
22 | 57.0 | - | - |
23 | 77.5 | - | - |
25 | 45.5 | 90.6 | >10,000 |
27 | 39.5 | 81.4 | >10,000 |
28 | 29.0 | 64.5 | >10,000 |
30 | - | 18.2 | 3,804 |
32 | - | 153.6 | 2,153 |
33 | - | 100.6 | 2,054 |
34 | - | 427.0 | 1,636 |
35 | - | 417.6 | 1,437 |
36 | 61.4 | - | - |
37 | 43.6 | - | - |
38 | 70.0 | - | - |
39 | 58.0 | - | - |
40 | 58.3 | - | - |
由上表1可知,根据本发明的金刚烷衍生物对FAK和Pyk2(FAK2)具有优异的抑制活性。此外,可以看出,金刚烷衍生物不抑制胰岛素受体(Ins-R)的活性,而选择性地抑制FAK和Pyk2(FAK2)的活性。
<实验实施例2>化合物在人三阴性乳腺癌细胞系MDA-MB-231中的FAK抑制活性的测定
为了在体外测定本发明的金刚烷衍生物化合物对FAK的抑制活性,在人三阴性乳腺癌细胞系MDA-MB-231中进行FAK[pY397]酶联免疫吸附测定试验,下表2显示了每种化合物的IC50值。简而言之,将1×106MDA-MB-231细胞分配到6孔板的每个孔中,诱导细胞稳定持续24小时,用每种化合物以不同浓度(0、1、5、10、50、100、500、1000nM)处理一小时,然后通过使用FAK(磷酸化)[pY397]人ELISA试剂盒(FAK(Phospho)[pY397]Human ELISA Kit,Thermo Fisher Scientific,KH00441)根据制造商的说明进行酶联免疫吸附测定试验。
[表2]
化合物# | FAK抑制活性(IC<sub>50</sub>,nM) |
1 | 83 |
2 | 111 |
3 | 92 |
4 | 34 |
5 | 32 |
6 | 118 |
7 | 38 |
8 | 121 |
10 | 382 |
11 | 118 |
20 | 153 |
23 | 234 |
25 | 27 |
27 | 55 |
由上表2可知,根据本发明的金刚烷衍生物在人三阴性乳腺癌细胞系MDA-MB-231中具有优异的FAK抑制活性。
<实验实施例3>各种人三阴性乳腺癌细胞系中FAK抑制活性的测定
通过上面描述的FAK[pY397]酶联免疫吸附测定,在多种三阴性乳腺癌细胞系中确认化合物4(其为本发明的金刚烷衍生物化合物)在体外对FAK的抑制活性,下表3显示了每个细胞系的IC50值。
[表3]
本发明的化合物4对各种激酶的抑制活性能力如下。
从通过欧陆集团(Eurofins)进行的激酶筛选和分析的结果中获得这种激酶活性抑制的数据,下表4显示了化合物在单一浓度(1μM)抑制至少70%的107种筛选激酶的相应激酶的抑制活性程度(%抑制率)和IC50值。
[表4]
激酶 | FAK | Pyk2 | Met | ALK |
%抑制率(在1μM时) | 97 | 96 | 79 | 72 |
IC<sub>50</sub>[nM] | 78 | 301 | 542 | 802 |
由上表3可知,根据本发明的金刚烷衍生物在多种三阴性乳腺癌细胞系MDA-MB-231、MDA-MB-453、HCC70、BT-20、BT-549和Hs578T中具有优异的FAK抑制活性。
<实验实施例4>各种人三阴性乳腺癌细胞系中生长抑制活性的测定
进行3D球状体测定作为在三维(3D)培养条件下测量癌细胞生长的方法。简而言之,通过使用MammoCultTM人介质试剂盒(MammoCultTMHuman Medium Kit,StemcellTechnologies,#05620)将96孔平板每孔中的5×103个三阴性乳腺癌细胞三维培养三天,将所形成的癌细胞球状体用不同浓度(0、0.2、0.5、1、2、5、10、20μM)的化合物4处理96小时。通过使用CellTiter-Glo3D细胞活力检测试剂盒(CellTiter-Glo3D Cell ViabilityAssay Kit,Promega,G9681)根据制造商的说明量化化合物的癌细胞生长抑制作用。
图1显示了通过在MDA-MB-231细胞中用不同浓度的化合物处理对癌细胞球状体的生长抑制程度,作为3D球状体测定的代表性示例。
下表5显示了化合物4(本发明的金刚烷衍生物化合物)在包括MDA-MB-231在内的多种三阴性乳腺癌细胞系中的癌细胞球状体生长抑制活性的IC50值。
[表5]
由图1可知,根据本发明的金刚烷衍生物在所有浓度下都具有优异的癌细胞球状体抑制活性。此外,由上表5可知,根据本发明的金刚烷衍生物在多种三阴性乳腺癌细胞系MDA-MB-231、MDA-MB-453、HCC70、BT-20、BT-549和Hs578T中都具有优异的癌细胞球状体生长抑制活性。
<实验实施例5>在人三阴性乳腺癌细胞系MDA-MB-231中的3D侵袭抑制作用
根据3D侵袭试验进行细胞侵袭试验并进行量化。简而言之,将MDA-MB-231细胞在96孔圆板(5×103个/孔)中培养三天以形成癌细胞球状体,然后固定在半固体基质胶和I型胶原蛋白的混合物中,然后用不同浓度(1、5μM)的化合物4处理。72小时后使用显微镜(参见图2)和成像软件ImageJ分析浸润程度,基于下面的方程式(等式1)量化所得的面积值,并显示在图表中(参见图3)。
[等式1]
相对侵袭=(化合物处理组的总面积-化合物处理组的球状体面积)/(对照的总面积-对照的球状体面积)
由图2和图3可知,根据本发明的金刚烷衍生物在人三阴性乳腺癌细胞系MDA-MB-231中具有优异的侵袭抑制活性。
<实验实施例6>在三阴性乳腺癌异种移植小鼠模型中的肿瘤生长抑制作用
在5周龄雄性裸小鼠适应1周后,将1×106个MDA-MB-231细胞皮下接种到小鼠中,观察14天后肿瘤体积达到约100mm3。为了确认衍生候选材料在三阴性乳腺癌异种移植小鼠模型中的肿瘤生长抑制作用,将每组8只小鼠分为对照组和三个不同浓度(4-20mg/kg、4-40mg/kg和4-80mg/kg)的实验组,每种化合物每天处理一次。每周3次隔天测量小鼠的肿瘤体积,在细胞接种后第29天处死小鼠。图4为显示肿瘤体积的图,以药物处理的开始日期为第1天,基于下面的方程式(等式2)计算所述肿瘤体积。
[等式2]
肿瘤体积(mm3)=[(肿瘤短径2×肿瘤长径)/2]
下表6显示了通过基于下面的方程式(等式3)计算肿瘤生长抑制率(%TGI),各化合物处理组的平均肿瘤生长与对照组的平均肿瘤生长的比较。
[等式3]
%TGI=100×[1-(TV最终处理-TV初始处理)/(TV最终对照-TV初始对照)]
[表6]
由图4和图6可知,根据本发明的金刚烷衍生物在三阴性乳腺癌异种移植小鼠模型中具有优异的肿瘤生长抑制活性。
由上述实验实施例1至6的结果可知,根据本发明的金刚烷衍生物对FAK活性相关疾病具有优异的治疗作用。
已经参照本文的优选示例性实施方案描述了本发明,但是本领域技术人员将理解,本发明可以在不脱离本发明的精神和领域的情况下进行各种改变和修改,如随附的专利权利要求的范围中所描述。
Claims (12)
1.由下式1表示的金刚烷衍生物、其药学上可接受的盐、其立体异构体、其水合物或溶剂化物:
[式1]
其中在上式1中,
L1和L2各自独立地为单键、C1-10亚烷基、C2-10亚烯基、C2-10亚炔基、-N(Ra)-、-C(=O)-N(Ra)-、-N(Ra)-C(=O)-、-C(=O)-、-O-、-C(=O)-O-、-N(Ra)-C(=O)-O-、-N(Ra)-S(=O)-、-N(Ra)-S(=O)2-、-S(=O)(=N-Ra)-或-S-;
R1和R2各自独立地为C1-10亚杂环烷基、C3-10亚环烷基、C5-16亚芳基或C4-10亚杂芳基;
R3为H、C1-10烷基、C2-10烯基、-O-Ra、=O、-NH-Ra、-NH(C=O)-Ra或C1-10杂环烷基;
R4为-O-Ra;
R5和R6各自独立地为H或C1-10烷基;
R7为-CF3或卤素原子;
Ra为H、-CF3或C1-10烷基;和
m、n、p和q各自独立地为0或1。
4.根据权利要求1所述的金刚烷衍生物、其药学上可接受的盐、其立体异构体、其水合物或溶剂化物,其中上式1表示的化合物为下式2表示的化合物:
[式2]
其中在上式2中,
L1为-N(Ra)-、-C(=O)-N(Ra)-或-O-;
L2为-N(Ra)-、-C(=O)-N(Ra)-、-N(Ra)-C(=O)-、-C(=O)-或-C(=O)-O-;
R3为H、C1-10烷基、C2-10烯基、-O-Ra、=O、-NH-Ra、-NH(C=O)-Ra或吗啉基;
R6为H或C1-10烷基;
R7为-CF3或Cl;
Ra为H、-CF3或C1-10烷基;和
m、n、p和q各自独立地为0或1。
6.一种药物组合物,其包含根据权利要求1至5中任一项所述的金刚烷衍生物、其药学上可接受的盐、其立体异构体、其水合物或溶剂化物作为活性成分。
7.根据权利要求6所述的药物组合物,其中所述药物组合物用于预防或治疗FAK活性相关疾病。
8.根据权利要求7所述的药物组合物,其中所述FAK活性相关疾病为选自实体癌和血液癌的至少一种,所述实体癌包括胃癌、肺癌、肝癌、结直肠癌、小肠癌、胰腺癌、脑癌、骨癌、黑素瘤、乳腺癌、子宫癌、宫颈癌、卵巢癌、头颈癌、甲状腺癌、甲状旁腺癌、肾癌、前列腺癌、尿道癌、膀胱癌、间皮瘤等,所述血液癌包括白血病、多发性骨髓瘤和淋巴瘤。
9.根据权利要求6所述的药物组合物,其中所述金刚烷衍生物、其药学上可接受的盐、其立体异构体、其水合物或溶剂化物抑制FAK和Pyk2(FAK2)的至少任何一种激酶。
10.一种用于预防或治疗FAK活性相关疾病的方法,其包括向个体施用治疗有效量的根据权利要求1至5中任一项所述的金刚烷衍生物、其药学上可接受的盐、其立体异构体、其水合物或溶剂化物。
11.根据权利要求1至5中任一项所述的金刚烷衍生物、其药学上可接受的盐、其立体异构体、其水合物或溶剂化物用于预防或治疗FAK活性相关疾病的用途。
12.根据权利要求1至5中任一项所述的金刚烷衍生物、其药学上可接受的盐、其立体异构体、其水合物或溶剂化物在制备用于预防或治疗FAK活性相关疾病的药物中的用途。
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KR20210069585A (ko) | 2021-06-11 |
JP2023504468A (ja) | 2023-02-03 |
US20230049557A1 (en) | 2023-02-16 |
CN114929675B (zh) | 2024-02-13 |
WO2021111311A2 (ko) | 2021-06-10 |
WO2021111311A3 (ko) | 2021-07-22 |
KR102472103B1 (ko) | 2022-11-29 |
EP4074697A2 (en) | 2022-10-19 |
JP7390487B2 (ja) | 2023-12-01 |
EP4074697A4 (en) | 2024-01-03 |
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