CN117396463A - 用于预防或治疗癌症的苯甲酰胺衍生物、其制备方法和含有其作为活性成分的药物组合物 - Google Patents
用于预防或治疗癌症的苯甲酰胺衍生物、其制备方法和含有其作为活性成分的药物组合物 Download PDFInfo
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- CN117396463A CN117396463A CN202280035706.4A CN202280035706A CN117396463A CN 117396463 A CN117396463 A CN 117396463A CN 202280035706 A CN202280035706 A CN 202280035706A CN 117396463 A CN117396463 A CN 117396463A
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- methyl
- fluoro
- indol
- hydroxyphenyl
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- 238000000034 method Methods 0.000 title claims abstract description 108
- 206010028980 Neoplasm Diseases 0.000 title claims abstract description 40
- 201000011510 cancer Diseases 0.000 title claims abstract description 37
- 239000004480 active ingredient Substances 0.000 title claims abstract description 20
- 239000008194 pharmaceutical composition Substances 0.000 title claims abstract description 15
- 150000003936 benzamides Chemical class 0.000 title abstract description 11
- 230000035772 mutation Effects 0.000 claims abstract description 29
- 229960005395 cetuximab Drugs 0.000 claims abstract description 5
- -1 cyano, amino Chemical group 0.000 claims description 117
- 150000001875 compounds Chemical class 0.000 claims description 74
- 229910052736 halogen Inorganic materials 0.000 claims description 71
- 150000002367 halogens Chemical class 0.000 claims description 71
- 125000000217 alkyl group Chemical group 0.000 claims description 64
- 238000002360 preparation method Methods 0.000 claims description 57
- 150000003839 salts Chemical class 0.000 claims description 48
- 125000000592 heterocycloalkyl group Chemical group 0.000 claims description 41
- 102000001301 EGF receptor Human genes 0.000 claims description 37
- 108060006698 EGF receptor Proteins 0.000 claims description 37
- 125000003545 alkoxy group Chemical group 0.000 claims description 33
- 239000000203 mixture Substances 0.000 claims description 25
- 230000003287 optical effect Effects 0.000 claims description 25
- 239000012453 solvate Substances 0.000 claims description 25
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 23
- 125000003118 aryl group Chemical group 0.000 claims description 22
- 229910052799 carbon Inorganic materials 0.000 claims description 17
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- 125000001072 heteroaryl group Chemical group 0.000 claims description 10
- 238000011282 treatment Methods 0.000 claims description 10
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Abstract
本发明涉及一种用于预防或治疗癌症的苯甲酰胺衍生物、其制备方法和含有其作为活性成分的药物组合物。本发明一方面提供的苯甲酰胺衍生物可通过抑制EGFR突变用于预防或治疗癌症,并且可有效地用作抗癌剂,因为当与EGFR拮抗剂如西妥昔单抗共同给药时,其表现出显著的协同作用。
Description
技术领域
本发明涉及一种用于预防或治疗癌症的苯甲酰胺衍生物、其制备方法和含有其作为活性成分的药物组合物。
发明背景
癌症的发病与各种环境因素有关,包括化学品、辐射和病毒,以及癌基因、肿瘤抑制基因和与凋亡和DNA修复有关的基因的变化。最近对癌症分子机制的了解使得靶向抗癌疗法成为可能,这是一种新的治疗方法。
靶向制剂通常被制成靶向癌细胞特征性地必须显示其有效性的分子。分子靶标是与癌细胞信号转导途径、血管生成、基质、细胞周期调节因子和凋亡相关的基因。目前,包括酪氨酸激酶抑制剂和“血管生成抑制剂”的“信号转导途径抑制剂”在癌症治疗中用作重要的靶向剂。
已知蛋白酪氨酸激酶在许多恶性肿瘤中起重要作用。特别是,表皮生长因子受体(EGFR)——一种erbB家族的受体酪氨酸激酶,在许多上皮细胞肿瘤中异常激活,包括非小细胞肺癌(NSCLC)、乳腺癌、神经胶质瘤、头颈部鳞状细胞癌、结肠癌、直肠癌、头颈部癌、胃癌和前列腺癌,并且已知EGFR酪氨酸激酶的激活引起连续的细胞增殖、周围组织的侵袭、远处转移、血管形成,并增加细胞存活。
特别地,EGFR是ErbB酪氨酸激酶受体家族(EGFR、HER-2、ErbB-3、ErbB-4)之一,并且是具有包括细胞外配体结合结构域和酪氨酸激酶结构域的细胞内结构域的跨膜酪氨酸激酶。当配体与形成同二聚体或异二聚体的受体结合时,细胞内酪氨酸激酶被激活,EGFR刺激的信号激活磷脂酰肌醇3-激酶(PI3K/AKT/mTOR、RAS/RAF/MAPK、JAK/STAT)信号传导途径(非专利参考文献1,Nat Rev Cancer 2007;7:169-81。Epidermal growth factorreceptor mutations in lung cancer)。
特别是,EGFR在超过一半的非小细胞肺癌(NSCLC)中过表达,并且已经对EGFR作为治疗的靶标进行了许多研究。已经开发出抑制EGFR酪氨酸激酶活性的EGFR TKI(酪氨酸激酶抑制剂),代表性药物包括吉非替尼(IRESSATM)、厄洛替尼(TARCEVATM)和拉帕替尼(TYKERBTM,TYVERBTM)。
另一方面,2004年,报道EGFR的激活突变与对非小细胞肺癌(NSCLC)中对吉非替尼治疗的反应相关。特别是,EGFR突变主要分为致敏突变和耐药突变,外显子19的缺失和外显子21的L858R点突变是最重要的致敏突变,约占85-90%,已知外显子19突变对TKI有较好的敏感性。另一方面,外显子20的T790M点突变是最重要的耐药突变,已知在50%以上的获得性耐药患者中发现。
迄今为止鉴定的体细胞突变包括外显子19中的框内缺失或外显子20中的插入,以及其中在表达的蛋白质中修饰单个核酸残基的点突变(例如,L858R、G719S、G719C、G719A和L861Q)。
尽管吉非替尼/厄洛替尼对具有EGFR突变的NSCLC患者的有最初临床作用,但在用这些药物治疗期间,大多数患者最终发展晚期癌症。复发样品的早期研究鉴定了继发性EGFR突变T790M,使得吉非替尼(zepithinib)和厄洛替尼(erlotinib)成为无效的EGFR激酶活性抑制剂。在随后的研究中证实,在对吉非替尼或厄洛替尼获得耐药的患者的大约50%(24/48)肿瘤中发现EGFR T790M突变。这种继发性基因改变(secondary geneticmodification)发生在与用激酶抑制剂治疗的患者中的‘看门人’残基和与其相关的继发耐药等位基因(例如,伊马替尼耐药CML患者ABL中的T315I)相似的位置。
EGFR突变EGFR_del19或EGFR_L858R是非小细胞肺癌和头颈癌的主要原因早就被人们知晓,并且已经开发了它们的治疗药物易瑞沙(Iressa)和Taseba,并且目前用于临床试验。然而,当这些药物用于患者时,观察到获得性耐药,导致基于药物结构的EGFR继发突变,并且还发现这是实际药物耐药的主要原因。当使用第一代EGFR抑制剂平均10个月时,获得性耐药,即EGFR激酶看门人中的T790M突变发生,第一代EGFR抑制剂无效。即,EGFR_del19_T790M或EGFR_L858R_T790M双突变发生,常规治疗剂不显示功效。
基于这些事实,出现了开发具有优异的药物功效和新结构的二代和三代药物的需要。
在过去10年中,发现对EGFR T790M的双突变有作用的各种三代新候选药物,临床研究正在进行,其中最先进的是跨国制药公司阿斯利康的AZD9291。然而,已报道对AZD9291的耐药性在约10个月内发生,导致AZD9291药效丧失,特别是,已报道对包括C797S在内的三重突变的耐药性。
因此,需要开发对WT EGFR的抑制作用相对较低,而对特异性激活或抗性的EGFR突变形式的抑制作用较高的抑制剂。
发明简述
本发明的一个目的是提供能够通过抑制EGFR突变来预防或治疗癌症的苯甲酰胺衍生物。
本发明的另一个目的是提供一种用于预防或治疗癌症的药物组合物,其包含所述苯甲酰胺衍生物作为活性成分。
本发明的另一个目的是提供一种用于预防或改善癌症的保健功能性食品,其包含所述苯甲酰胺衍生物作为活性成分。
本发明的另一个目的是提供一种用于预防或治疗癌症的组合制剂,其包含所述苯甲酰胺衍生物作为活性成分。
为了实现上述目的,在本发明的一个方面,本发明提供由式1表示的化合物、其光学异构体、其溶剂化物、其水合物或其药学上可接受的盐。
[式1]
在式1中,
X、Y和Z独立地为碳或氮原子;
R1为-H、-OH、卤素、未取代或被一个或多个卤素取代的C1-10烷基、未取代或被一个或多个卤素取代的C1-10烷氧基、硝基、C1-10烷基硫烷基、氰基、氨基、C1-10烷基氨基或5-6元杂芳基;
R2为取代的C6-10芳基或取代的5-10元杂芳基,
其中所述取代的C6-10芳基或取代的5-10元杂芳基独立地是被选自以下的一个或多个取代基取代的芳基或杂芳基:卤素、未取代的或取代的C1-10烷基和未取代的或取代的4-10元完全或部分饱和的杂环烷基,
其中所述取代的C1-10烷基是被5-6元杂环烷基取代,其中1或2个C1-5烷基被取代氨基取代,
所述取代的4-10元完全或部分饱和的杂环烷基是被选自以下的一个或多个取代基取代的4-10元杂环烷基:-OH、卤素、未取代的或被一个或多个卤素取代的C1-5烷基、被5-6元杂环烷基取代的C1-5烷基、未取代的或被一个或多个卤素取代的C1-5烷氧基、硝基、C1-5烷基硫烷基、氰基、未取代的或被1或2个C1-5烷基取代的氨基、未取代的或被C1-5烷基取代的5-6元杂环烷基、C1-5烷氧基羰基、5-6元杂芳基、C6-10芳基氨基羰基和C1-5烷氧基-C1-5烷氧基-C6-10芳基;
R3为卤素;
R4为-OH、卤素或C1-15烷氧基;
R5为-H、-OH、卤素、C1-4烷基或C1-4烷氧基;以及
R6为-H、-OH、卤素、C1-4烷基或C1-4烷氧基。
在本发明的另一个方面,本发明提供一种用于预防或治疗癌症的药物组合物,其包含由式1表示的化合物、其光学异构体、其溶剂化物、其水合物或其药学上可接受的盐作为活性成分。
在本发明的另一个方面,本发明提供一种用于预防或改善癌症的保健功能性食品组合物,其包含由式1表示的化合物、其光学异构体、其溶剂化物、其水合物或其药学上可接受的盐作为活性成分。
在本发明的另一个方面,本发明提供一种用于预防或改善癌症的组合制剂,其包含由式1表示的化合物、其光学异构体、其溶剂化物、其水合物或其药学上可接受的盐作为活性成分。
有益效果
本发明一方面提供的苯甲酰胺衍生物可通过抑制EGFR突变而用于预防或治疗癌症,并且由于当与EGFR拮抗剂如西妥昔单抗共同给药时其表现出显著的协同效应,因此可有效地用作抗癌剂。
发明详述
以下,将详细描述本发明。
本发明的实施例可以以各种其它形式修改,并且本发明的范围不限于下面描述的实施例。本领域的普通技术人员应当理解,给出本发明的实施例是为了更精确地解释本发明。
此外,除非另外特别说明,在整个说明书中,元素“包括”不排除其它元素,而是可以包括其它元素。
除非另有说明,术语“亚烷基”、“烯基”或“烷基”包括直链或支链饱和烃基残基。例如,“C1-6烷基”是指具有1-6个碳原子骨架的烷基,具体地,C1-6烷基可包括甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、正戊基、异戊基、叔戊基、仲戊基、新戊基、己基等。
除非另有说明,术语“环烷基”包括含有碳原子的碳环基团。例如,“C3-8环烷基”是指具有3至8个碳的骨架的环烷基。具体地,C3-8环烷基可以包括环丙基、环丁基、环戊基、环己基等。
除非另有说明,术语“杂环烷基”包括由1至3个含有1、2、3或4个选自N、O或S的杂原子的环组成的一价饱和残基。两个或三个环可以包括桥连的、稠合的或螺杂环烷基。
除非另有说明,术语“杂芳基”可以包括具有单环或两个或三个稠环的芳族基团,所述稠环具有一个或多个包含1、2、3或4个选自N、O或S的环杂原子的芳环。
在本发明的一个方面,本发明提供由式1表示的化合物、其光学异构体、其溶剂化物、其水合物或其药学上可接受的盐。
[式1]
在式1中,
X、Y和Z独立地为碳或氮原子;
R1为-H、-OH、卤素、未取代的或被一个或多个卤素取代的C1-10烷基、未取代的或被一个或多个卤素取代的C1-10烷氧基、硝基、C1-10烷基硫烷基、氰基、氨基、C1-10烷基氨基或5-6元杂芳基;
R2为取代的C6-10芳基或取代的5-10元杂芳基,
其中所述取代的C6-10芳基或取代的5-10元杂芳基独立地为被一个或多个选自以下的取代基取代的芳基或杂芳基:卤素、未取代的或取代的C1-10烷基和未取代的或取代的4-10元完全或部分饱和的杂环烷基,
其中所述取代的C1-10烷基被5-6元杂环烷基取代,其中1或2个C1-5烷基被取代氨基取代,
所述取代的4-10元完全或部分饱和的杂环烷基是被一个或多个选自以下的取代基取代的4-10元杂环烷基:-OH、卤素、未取代的或被一个或多个卤素取代的C1-5烷基、被5-6元杂环烷基取代的C1-5烷基、未取代的或被一个或多个卤素取代的C1-5烷氧基、硝基、C1-5烷基硫烷基、氰基、未取代的或被1或2个C1-5烷基取代的氨基、未取代的或被C1-5烷基取代的5-6元杂环烷基、C1-5烷氧基羰基、5-6元杂芳基、C6-10芳基氨基羰基和C1-5烷氧基-C1-5-烷氧基-C6-10芳基;
R3为卤素;
R4为-OH、卤素或C1-15烷氧基;
R5为-H、-OH、卤素、C1-4烷基或C1-4烷氧基;以及
R6为-H、-OH、卤素、C1-4烷基或C1-4烷氧基。
在另一个方面,
X、Y和Z独立地为碳或氮原子;
R1为-H、-OH、卤素、未取代的或被一个或多个卤素取代的C1-5烷基、未取代的或被一个或多个卤素取代的C1-5烷氧基、硝基、C1-5烷基硫烷基、氰基、氨基、C1-5烷基氨基或5-6元杂芳基;
R2为取代的C6-10芳基或取代的5-6元杂芳基,
其中所述取代的C6-10芳基或取代的5-6元杂芳基独立地为被一个或多个选自以下的取代基取代的芳基或杂芳基:卤素、未取代或取代的C1-5烷基和未取代或取代的含有至少一个N的4-8元完全或部分饱和的杂环烷基,
其中所述取代的C1-5烷基被6元杂环烷基取代,其中2个C1-5烷基被取代氨基取代,
所述取代的4-8元完全或部分饱和的杂环烷基是被一个或多个选自以下的取代基取代的4-8元杂环烷基:-OH、卤素、未取代的或被一个或多个卤素取代的C1-5烷基、被5-6元杂环烷基取代的C1-5烷基、未取代的或被一个或多个卤素取代的C1-5烷氧基、硝基、C1-5烷基硫烷基、氰基、未取代的或被1个或2个C1-5烷基取代的氨基、未取代的或被C1-5烷基取代的5-6元杂环烷基、C1-5烷氧基羰基、5-6元杂芳基、C6-10芳基氨基羰基和C1-5烷氧基-C1-5烷氧基-C6-10芳基;
R3为卤素;
R4为-OH、卤素或C1-10烷氧基;
R5为-H、-OH或卤素;以及
R6为-H、卤素、C1-4烷基或C1-4烷氧基。
在另一个方面,
X、Y和Z独立地为碳或氮原子;
R1为-H、-OH、卤素、未取代的或被一个或多个卤素取代的C1-5烷基、未取代的或被一个或多个卤素取代的C1-5烷氧基、硝基、C1-5烷基硫烷基、氰基、氨基、C1-5烷基氨基、或含有至少一个N的5元杂芳基;
R2为取代的苯基,或含有至少一个N的取代的6元杂芳基,
其中所述取代的苯基或取代的6元杂芳基独立地为被一个或多个选自以下的取代基取代的苯基或杂芳基:卤素、未取代的或取代的C1-3烷基和未取代的或取代的4-8元完全或部分饱和的含有至少一个N的杂环烷基,
其中所述取代的C1-3烷基被6元杂环烷基取代,其中2个C1-3烷基被取代氨基取代,
所述取代的4-8元杂环烷基是被一个或多个选自以下的取代基取代的4-8元杂环烷基:-OH、未被取代或被5-6元杂环烷基取代的C1-3烷基、未被取代或被1个或2个C1-3烷基取代的氨基、未被取代或被C1-3烷基取代的5-6元杂环烷基、C1-4烷氧基羰基、含有至少一个N的5元杂芳基、苯基氨基羰基和C1-3烷氧基-C1-3烷氧基-苯基;
R3为卤素;
R4为-OH、卤素或C1-5烷氧基;
R5为-H、-OH或卤素;以及
R6为-H、卤素、C1-4烷基或C1-4烷氧基。
在另一个方面,
X、Y和Z独立地为碳或氮原子;
R1为-H、-F、-Cl、-OH、-CH3、-CF3、-OCH3、-OCF3、异丙基、叔丁基、-SCH3、-NO2、-CN或咪唑,
R2是
R3为-F或-Cl;
R4为-OH或-OCH3;
R5为-H、-OH、-F、-Cl、C1-4直链或支链烷基或C1-4直链或支链烷氧基;以及
R6为-H、-OH、-F、-Cl、C1-4直链或支链烷基或C1-4直链或支链烷氧基。
优选地,
X是碳或氮原子;
Y和Z是碳原子;
R1为-H、-F、-Cl、-OH、-CH3、-CF3、-OCH3、-OCF3、异丙基、叔丁基、-SCH3、-NO2、-CN或咪唑,
R2为
R3为-F;
R4为-OH或-OCH3;
R5为-H;以及
R6为-H、-F或-Cl。
优选地,由式1表示的化合物可以是由下式2表示的化合物。
[式2]
在式2中,X、Y、Z、R1、R2、R3、R4、R5和R6独立地如上式1中所定义。
在另一个方面,
X是碳或氮原子;
Y和Z是碳原子;
R1为-H、-F、-Cl、-OH、-CH3、-CF3、-OCH3、-OCF3、异丙基、叔丁基、-SCH3、-NO2、-CN或咪唑;
R2为 />
/>
R3为-F;
R4为-OH或-OCH3;
R5为-H;以及
R6为-H、-F或-Cl。
最优选地,由式1表示的化合物可以是选自以下化合物中的任何一种化合物。
(1)(R)-4'-(4-氨基哌啶-1-基)-N-((5-氟-2-羟基苯基)(1H-吲哚-2-基)甲基)-5-甲基-[1,1'-联苯]-3-甲酰胺;
(2)(R)-4'-(4-氨基哌啶-1-基)-N-((5-氟-2-羟基苯基)(1H-吲哚-2-基)甲基)-5-异丙基-[1,1'-联苯]-3-甲酰胺;
(3)(R)-4'-(4-氨基哌啶-1-基)-N-((5-氟-2-羟基苯基)(1H-吲哚-2-基)甲基)-5-甲氧基-[1,1'-联苯]-3-甲酰胺;
(4)(R)-4'-(4-氨基哌啶-1-基)-5-(叔丁基)-N-((5-氟-2-羟基苯基)(1H-吲哚-2-基)甲基)-[1,1'-联苯]-3-甲酰胺;
(5)(R)-4'-(4-氨基哌啶-1-基)-5-氟-N-((5-氟-2-羟基苯基)(1H-吲哚-2-基)甲基)-[1,1'-联苯]-3-甲酰胺;
(6)(R)-4'-(4-氨基哌啶-1-基)-N-((5-氟-2-羟基苯基)(1H-吲哚-2-基)甲基)-5-(三氟甲基)-[1,1'-联苯]-3-甲酰胺;
(7)(R)-4'-(4-氨基哌啶-1-基)-N-((5-氟-2-羟基苯基)(1H-吲哚-2-基)甲基)-5-硝基-[1,1'-联苯]-3-甲酰胺;
(8)(R)-4'-(4-氨基哌啶-1-基)-N-((5-氟-2-羟基苯基)(1H-吲哚-2-基)甲基)-5-(甲硫基)-[1,1'-联苯]-3-甲酰胺;
(9)(R)-4'-(4-氨基哌啶-1-基)-5-氰基-N-((5-氟-2-羟基苯基)(1H-吲哚-2-基)甲基)-[1,1'-联苯]-3-甲酰胺;
(10)(R)-4'-(4-氨基哌啶-1-基)-5-氯-N-((5-氟-2-羟基苯基)(1H-吲哚-2-基)甲基)-[1,1'-联苯]-3-甲酰胺;
(11)(R)-4'-(4-氨基哌啶-1-基)-N-((5-氟-2-羟基苯基)(1H-吲哚-2-基)甲基)-5-(三氟甲氧基)-[1,1'-联苯]-3-甲酰胺;
(12)(R)-4'-(4-氨基哌啶-1-基)-N-((5-氟-2-甲氧基苯基)(1H-吲哚-2-基)甲基)-5-(三氟甲氧基)-[1,1'-联苯]-3-甲酰胺;
(13)(R)-4'-(4-氨基哌啶-1-基)-N-((5-氟-2-羟基苯基)(1H-吲哚-2-基)甲基)-5-(1H-咪唑-1-基)-[1,1'-联苯]-3-甲酰胺;
(14)(R)-2-(4-(4-氨基哌啶-1-基)苯基)-N-((5-氟-2-羟基苯基)(1H-吲哚-2-基)甲基)异烟酰胺;
(15)(R)-2-(4-(4-氨基哌啶-1-基)苯基)-N-((5-氟-2-甲氧基苯基)(1H-吲哚-2-基)甲基)异烟酰胺;
(16)(R)-3-(2-(4-氨基哌啶-1-基)嘧啶-5-基)-N-((5-氟-2-羟基苯基)(1H-吲哚-2-基)甲基)-5-甲基苯甲酰胺;
(17)(R)-3-(5-(4-氨基哌啶-1-基)吡啶-2-基)-N-((5-氟-2-羟基苯基)(1H-吲哚-2-基)甲基)-5-甲基苯甲酰胺;
(18)(R)-3-(5-(4-氨基哌啶-1-基)吡嗪-2-基)-N-((5-氟-2-羟基苯基)(1H-吲哚-2-基)甲基)-5-甲基苯甲酰胺;
(19)(R)-3-(6-(4-氨基哌啶-1-基)吡啶-3-基)-N-((5-氟-2-羟基苯基)(1H-吲哚-2-基)甲基)-5-甲基苯甲酰胺;
(20)(R)-3-(6-(4-氨基哌啶-1-基)哒嗪-3-基)-N-((5-氟-2-羟基苯基)(1H-吲哚-2-基)甲基)-5-甲基苯甲酰胺;
(21)(R)-3-(5-(4-氨基哌啶-1-基)嘧啶-2-基)-N-((5-氟-2-羟基苯基)(1H-吲哚-2-基)甲基)-5-甲基苯甲酰胺;
(22)(R)-4'-(4-氨基哌啶-1-基)-3'-氟-N-((5-氟-2-羟基苯基)(1H-吲哚-2-基)甲基)-5-甲基-[1,1'-联苯]-3-甲酰胺;
(23)(R)-4'-(4-氨基哌啶-1-基)-N-((5-氟-2-羟基苯基)(1H-吲哚-2-基)甲基)-2',5-二甲基-[1,1'-联苯]-3-甲酰胺;
(24)(R)-4'-(4-氨基哌啶-1-基)-2'-氟-N-((5-氟-2-羟基苯基)(1H-吲哚-2-基)甲基)-5-甲基-[1,1'-联苯]-3-甲酰胺;
(25)(R)-4'-(4-氨基哌啶-1-基)-N-((5-氟-2-羟基苯基)(1H-吲哚-2-基)甲基)-3',5-二甲基-[1,1'-联苯]-3-甲酰胺;
(26)(R)-4'-(4-氨基哌啶-1-基)-N-((6-氟-1H-吲哚-2-基)(5-氟-2-羟基苯基)甲基)-5-甲基-[1,1'-联苯]-3-甲酰胺;
(27)(R)-4'-(4-氨基哌啶-1-基)-N-((6-氯-1H-吲哚-2-基)(5-氟-2-羟基苯基)甲基)-5-甲基-[1,1'-联苯]-3-甲酰胺;
(28)(R)-4'-(4-氨基哌啶-1-基)-N-((5-氟-2-羟基苯基)(1H-吲哚-2-基)甲基)-6-甲基-[1,1'-联苯]-3-甲酰胺;
(29)(R)-4'-(4-氨基哌啶-1-基)-N-((5-氟-2-羟基苯基)(1H-吲哚-2-基)甲基)-4-甲基-[1,1'-联苯]-3-甲酰胺;
(30)(R)-4'-(4-氨基哌啶-1-基)-N-((5-氟-2-羟基苯基)(1H-吲哚-2-基)甲基)-2-甲基-[1,1'-联苯]-3-甲酰胺;
(31)(S)-4'-(4-氨基哌啶-1-基)-N-((5-氟-2-羟基苯基)(1H-吲哚-2-基)甲基)-5-甲基-[1,1'-联苯]-3-甲酰胺;
(32)4'-(4-氨基哌啶-1-基)-N-((5-氟-2-羟基苯基)(1H-吲哚-2-基)甲基)-5-甲基-[1,1'-联苯]-3-甲酰胺;
(33)(R)-3-(5-(4-氨基哌啶-1-基)-4-甲基吡啶-2-基)-N-((5-氟-2-羟基苯基)(1H-吲哚-2-基)甲基)-5-甲基苯甲酰胺;
(34)(R)-3-(2-(4-氨基哌啶-1-基)-4-甲基嘧啶-5-基)-N-((5-氟-2-羟基苯基)(1H-吲哚-2-基)甲基)-5-甲基苯甲酰胺;
(35)(R)-4-(2-(3-(((5-氟-2-羟基苯基)(1H-吲哚-2-基)甲基)氨基甲酰基)-5-甲基苯基)嘧啶-5-基)哌嗪-1-甲酸叔丁酯;
(36)(R)-N-((5-氟-2-羟基苯基)(1H-吲哚-2-基)甲基)-3-甲基-5-(5-(哌嗪-1-基)嘧啶-2-基)苯甲酰胺;
(37)(R)-N-((5-氟-2-羟基苯基)(1H-吲哚-2-基)甲基)-3-甲基-5-(5-(4-甲基哌嗪-1-基)嘧啶-2-基)苯甲酰胺;
(38)N-[(R)-(5-氟-2-羟基-苯基)-(1H-吲哚-2-基)甲基]-3-甲基-5-[5-(4-丙基-1-哌啶基)嘧啶-2-基]苯甲酰胺;
(39)3-[5-[4-(二甲基氨基)-1-哌啶基]嘧啶-2-基]-N-[(R)-(5-氟-2-羟基-苯基)-(1H-吲哚-2-基)甲基]-5-甲基-苯甲酰胺;
(40)N-[(R)-(5-氟-2-羟基-苯基)-(1H-吲哚-2-基)甲基]-3-甲基-5-[5-(1-哌啶基)嘧啶-2-基]苯甲酰胺;
(41)N-[(R)-(5-氟-2-羟基-苯基)-(1H-吲哚-2-基)甲基]-3-甲基-5-[5-[4-(1-甲基-4-哌啶基)哌嗪-1-基]嘧啶-2-基]苯甲酰胺;
(42)(R)-3-(5-((4-(二甲基氨基)哌啶-1-基)甲基)吡啶-2-基)-N-((5-氟-2-羟基苯基)(1H-吲哚-2-基))甲基)-5-甲基苯甲酰胺;
(43)(R)-3-(6-((4-(二甲基氨基)哌啶-1-基)甲基)吡啶-3-基)-N-((5-氟-2-羟基苯基)(1H-吲哚-2-基))甲基)-5-甲基苯甲酰胺;
(44)3-[5-[(3R)-3-氨基吡咯烷-1-基]嘧啶-2-基]-N-[(R)-(5-氟-2-羟基-苯基)-(1H-吲哚-2-基)甲基]-5-甲基-苯甲酰胺;
(45)(R)-3-(5-(4-(二乙基氨基)哌啶-1-基)嘧啶-2-基)-N-((5-氟-2-羟基苯基)(1H-吲哚-2-基)甲基)-5-甲基苯甲酰胺;
(46)N-((R)-(5-氟-2-羟基苯基)(1H-吲哚-2-基)甲基)-3-甲基-5-(5-(3-甲基-3,8-二氮杂双环[3.2.1]辛烷-8-基)嘧啶-2-基)苯甲酰胺;
(47)(R)-3-(5-(4-(1H-吡咯-1-基)哌啶-1-基)嘧啶-2-基)-N-((5-氟-2-羟基苯基)(1H-吲哚-2-基)甲基)-5-甲基苯甲酰胺;
(48)(R)-3-(5-(4-(1H-1,2,4-三唑-1-基)哌啶-1-基)嘧啶-2-基)-N-((5-氟-2-羟基苯基)(1H-吲哚-2-基)甲基)-5-甲基苯甲酰胺;
(49)(R)-N-((5-氟-2-羟基苯基)(1H-吲哚-2-基)甲基)-3-(5-(4-羟基哌啶-1-基)嘧啶-2-基)-5-甲基苯甲酰胺;
(50)(R)-3-(5-([1,4'-联哌啶]-1'-基)嘧啶-2-基)-N-((5-氟-2-羟基苯基)(1H-吲哚-2-基)甲基)-5-甲基苯甲酰胺;
(51)(R)-N-((5-氟-2-羟基苯基)(1H-吲哚-2-基)甲基)-3-甲基-5-(5-(4-(吗啉代甲基)哌啶-1-基)嘧啶-2-基)苯甲酰胺;
(52)(R)-N-((5-氟-2-羟基苯基)(1H-吲哚-2-基)甲基)-3-甲基-5-(5-(4-(吡咯烷-1-基甲基)哌啶-1-基)嘧啶-2-基)苯甲酰胺;
(53)3-[5-[(3R)-3-(二甲基氨基)吡咯烷-1-基]嘧啶-2-基]-N-[(R)-(5-氟-2-羟基-苯基)-(1H-吲哚-2-基)甲基]-5-甲基-苯甲酰胺;
(54)(R)-N-((5-氟-2-羟基苯基)(1H-吲哚-2-基)甲基)-3-甲基-5-(5-(4-(甲基氨基)哌啶-1-基)嘧啶-2-基)苯甲酰胺;
(55)(R)-1-(2-(3-(((5-氟-2-羟基苯基)(1H-吲哚-2-基)甲基)氨基甲酰基)-5-甲基苯基)嘧啶-5-基)-N-苯基哌啶-4-甲酰胺;
(56)(R)-N-((5-氟-2-羟基苯基)(1H-吲哚-2-基)甲基)-3-(5-(4-(4-(2-甲氧基乙氧基)苯基)哌嗪-1-基)嘧啶-2-基)-5-甲基苯甲酰胺;
(57)(R)-N-((5-氟-2-羟基苯基)(1H-吲哚-2-基)甲基)-3-甲基-5-(5-(1,2,3,6-四氢吡啶-4-基)嘧啶-2-基)苯甲酰胺;
(58)(R)-N-((5-氟-2-羟基苯基)(1H-吲哚-2-基)甲基)-3-甲基-5-(5-(哌啶-4-基)嘧啶-2-基)苯甲酰胺;
(59)(R)-3-(5-(3-氨基氮杂环丁烷-1-基)嘧啶-2-基)-N-((5-氟-2-羟基苯基)(1H-吲哚-2-基)甲基)-5-甲基苯甲酰胺;
(60)3-(5-((S)-3-(二甲基氨基)吡咯烷-1-基)嘧啶-2-基)-N-((R)-(5-氟-2-羟基苯基)(1H-吲哚-2-基)甲基)-5-甲基苯甲酰胺;
(61)3-(5-((S)-3-氨基吡咯烷-1-基)嘧啶-2-基)-N-((R)-(5-氟-2-羟基苯基)(1H-吲哚-2-基)甲基)-5-甲基苯甲酰胺;以及
(62)(R)-3-(5-(氮杂环丁烷-3-基)嘧啶-2-基)-N-((5-氟-2-羟基苯基)(1H-吲哚-2-基)甲基)-5-甲基苯甲酰胺。
本发明的式1表示的化合物可以以药学上可接受的盐的形式使用,其中所述盐优选为由药学上可接受的游离酸形成的酸加成盐。本文中的酸加成盐可以从无机酸,例如盐酸、硝酸、磷酸、硫酸、氢溴酸、氢碘酸、亚硝酸和亚磷酸;无毒有机酸,例如脂族单/二羧酸酯、苯基取代的链烷酸酯、羟基链烷酸酯、芳族酸和脂族/芳族磺酸;或有机酸,例如三氟乙酸、乙酸盐、苯甲酸、柠檬酸、乳酸、马来酸、葡糖酸、甲磺酸、4-甲苯磺酸、酒石酸和富马酸获得。药学上无毒的盐的例子有硫酸盐、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、偏磷酸盐、焦磷酸盐、氯化物、溴化物、碘化物、氟化物、乙酸盐、丙酸盐、癸酸盐、辛酸盐、丙烯酸盐、甲酸盐、异丁酸盐、辛酸盐、庚酸盐、丙炔酸盐、草酸盐、丙二酸盐、琥珀酸盐、辛二酸盐、卡巴酸盐、富马酸盐、苹果酸盐、丁炔-1,4-二酸盐、己烷-1,6-二酸盐、苯甲酸盐、氯苯甲酸盐、甲基苯甲酸盐、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、二甲苯磺酸盐、苯乙酸盐、苯基丙酸盐、苯基丁酸盐、柠檬酸盐、乳酸盐、羟基丁酸盐、羟乙酸盐、苹果酸盐、酒石酸盐、甲磺酸盐、丙磺酸盐、萘-1-磺酸盐、萘-2-磺酸盐、扁桃酸盐等。
本发明的酸加成盐可通过本领域技术人员已知的常规方法制备。例如,将式1所示的衍生物溶解在有机溶剂如甲醇、乙醇、丙酮、二氯甲烷和乙腈中,向其中加入有机酸或无机酸以诱导沉淀。然后,过滤沉淀并干燥,得到盐。或者将溶剂和过量的酸减压蒸馏,干燥,得到盐。或者在有机溶剂中结晶沉淀物,以得到相同的产物。
使用碱可制备药学上可接受的金属盐。通过以下方法获得碱金属或碱土金属盐:将化合物溶于过量的碱金属氢氧化物或碱土金属氢氧化物溶液中;过滤不溶性复合盐;蒸发剩余溶液并干燥。此时,优选将金属盐制备成药学上合适的钠盐、钾盐或钙盐形式。通过碱金属或碱土金属盐与适当的银盐(例如硝酸银)反应制备相应的银盐。
另外,本发明不仅包括由式1表示的化合物,还包括其药学上可接受的盐,以及可能由其产生的溶剂化物、光学异构体或水合物。
术语“水合物”是指含有通过非共价分子间力结合的化学计量或非化学计量的水的本发明的化合物或其盐。本发明的式1表示的化合物的水合物可以含有通过非共价分子间力结合的化学计量或非化学计量的水。水合物可以含有1当量或更多的水,优选1-5当量的水。该水合物可以通过从水或含水溶剂中结晶式1表示的化合物、其异构体或其药学上可接受的盐来制备。
术语“溶剂化物”是指含有通过非共价分子间力结合的化学计量或非化学计量的溶剂的本发明的化合物或其盐。因此,优选的溶剂包括挥发性、无毒和/或适于给予人的溶剂。
术语“异构体”是指具有相同化学式或分子式,但结构或空间上不同的本发明化合物或其盐。这些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、顺式)和光学异构体(对映体)。所有这些异构体及其混合物也包括在本发明的范围内。
式1表示的化合物可以通过以下通式来制备,对应于实施例1的化合物的制备方法的通式1和2如下所示。
通式1:
方案1。试剂和条件:(a)(S)-2-甲基丙烷-2-亚磺酰胺,乙醇钛(IV),THF,室温(rt),17h;(b)1-(苯磺酰基)-1H-吲哚,正丁基锂(n-BuLi),THF,-78℃至室温,3h;(c)5NNaOH,MeOH,回流,过夜;(d)将4N HCl溶解在二噁烷、MeOH中,室温下1小时。
通式2:
方案2。试剂和条件:(a)3-溴-5-甲基苯甲酸甲酯,4-羟基苯基硼酸,[1,1'-双(二苯基膦基)二茂铁]二氯化钯(II),碳酸钾,二噁烷,水,-78℃,1.5h(b)三氟甲磺酸酐,吡啶,二氯甲烷,室温,3h;(c)哌啶-4-基氨基甲酸叔丁酯,Ruphos Pd G1,Cs2CO3,二噁烷,110℃,过夜;(d)NaOH,二噁烷,110℃,过夜;(e)1-乙基-3-(3-二甲基氨基丙基)碳二亚胺,羟基苯并三唑,三乙胺,CH2Cl2、室温、过夜;(f)将1M BBr3溶解于CH2Cl2,0℃至室温,30分钟。
在本发明的另一个方面,本发明提供一种用于预防或治疗癌症的药物组合物,其包含由式1表示的化合物、其光学异构体、其溶剂化物、其水合物或其药学上可接受的盐作为活性成分。
其中,该化合物可抑制EGFR(表皮生长因子受体)突变,从而预防或治疗癌症。此时,EGFR突变为选自EGFR L858R/T790M和EGFR L858R/T790M/C797S中的至少一种。
本发明的式1表示的化合物或其药学上可接受的盐可以口服或肠胃外给药,并且可以以药物制剂的一般形式使用。也就是说,该化合物或其药学上可接受的盐可以通过与常用的稀释剂或赋形剂如填充剂、增量剂、粘合剂、润湿剂、崩解剂和表面活性剂混合来制备用于口服或肠胃外给药。用于口服给药的固体制剂是片剂、丸剂、粉剂、颗粒剂和胶囊。这些固体制剂通过将一种或多种化合物与一种或多种合适的赋形剂如淀粉、碳酸钙、蔗糖或乳糖、明胶等混合来制备。除了简单的赋形剂之外,可以使用润滑剂,例如硬脂酸镁、滑石等。用于口服给药的液体制剂是混悬液、溶液、乳液和糖浆,并且除了通常使用的简单稀释剂如水和液体石蜡外,上述制剂还可以含有各种赋形剂,如润湿剂、甜味剂、芳香剂和防腐剂。用于肠胃外给药的制剂是无菌水溶液、水不溶性赋形剂、悬浮液和乳液。除了活性化合物之外,水不溶性赋形剂和混悬液可以含有丙二醇、聚乙二醇、植物油如橄榄油、可注射的酯如油酸乙酯等。
包含式1所示化合物或其药学上可接受的盐作为活性成分的药物组合物可以通过肠胃外给药,所述肠胃外给药包括皮下注射、静脉内注射、肌肉内注射或胸内注射。
此时,为了式1所示的化合物或其药学上可接受的盐制备成用于肠胃外给药的制剂,将式1所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以制备溶液或悬浮液,然后将其配制为安瓿或小瓶。本文的组合物可以是无菌的,并且另外含有防腐剂、稳定剂、可湿性粉剂或乳化剂、用于调节渗透压的盐和/或缓冲剂、和其它治疗上有用的物质,并且组合物可以通过常规混合、制粒或包衣方法配制。
用于口服给药的制剂的例子有片剂、丸剂、硬/软胶囊、溶液、悬浮液、乳液、糖浆、颗粒、酏剂和锭剂等。这些制剂除了活性成分之外还可以包括稀释剂(例如,乳糖、葡萄糖、蔗糖、甘露醇、山梨醇、纤维素和/或甘氨酸)和润滑剂(例如,二氧化硅、滑石、硬脂酸盐及其镁盐或钙盐和/或聚乙二醇)。片剂可以包括粘合剂,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,并且如果需要,还可以包括崩解剂,例如淀粉、琼脂糖、海藻酸或其钠盐或共沸混合物和/或吸收剂、着色剂、香料和甜味剂。
本发明的药物组合物以药学有效剂量施用。
术语“药学有效剂量”意指足以以适用于医学治疗或改善的合理的效益/风险比治疗疾病的量。有效剂量水平取决于包括受试者类型和严重程度、年龄、性别、药物活性、对药物的敏感性、施用时间、施用途径和排泄速率、治疗持续时间、伴随药物和医学领域中公知的其它因素在内的因素。例如,有效剂量中包含0.001mg/kg至100mg/kg、0.01mg/kg至10mg/kg或0.1mg/kg至1mg/kg。本发明的药物组合物的剂量的上限可以由本领域技术人员在适当的范围内选择。
在本发明的另一个方面,本发明提供一种用于预防或改善癌症的健康功能性食品组合物,其包含由式1表示的化合物、其光学异构体、其溶剂化物、其水合物或其药学上可接受的盐作为活性成分。
本发明的式1表示的化合物可以直接加入,或者按照常规方法与其它食品成分混合加入。活性成分的混合比例可以根据使用目的(预防或改善)进行调节。通常,本发明的化合物优选以食品总重量的0.1~90重量份加入到食品或饮料中。然而,如果健康和卫生或调节健康状况需要长期给药,则含量可以低于上述含量,但也可以接受更高的含量,因为已经证明本发明的化合物是非常安全的。
此外,与其它饮料一样,本发明的保健饮料组合物可另外包括各种香料或天然碳水化合物等。上述天然碳水化合物可以是单糖如葡萄糖和果糖中的一种;二糖,例如麦芽糖和蔗糖;多糖如糊精和环糊精;以及糖醇如木糖醇、山梨糖醇和赤藓糖醇。此外,天然甜味剂(奇异果甜蛋白、甜叶菊提取物,例如莱鲍迪甙A、甘草甜素等)和合成甜味剂(糖精、阿斯巴甜等)可以作为甜味剂包括在内。在100g本发明的组合物中,天然碳水化合物的含量优选为1~20g,更优选为5~12g。
除了上述成分之外,本发明的式1表示的化合物可以包括各种营养素、维生素、矿物质(电解质)、香料(包括天然香料和合成香料)、着色剂和增量剂(奶酪、巧克力等)、果胶酸及其盐、海藻酸及其盐、有机酸、保护性胶体增粘剂、pH调节剂、稳定剂、防腐剂、甘油、醇、过去常用于加入苏打中的碳酸盐等。此外,本发明的式1表示的化合物可以包含天然果汁和果肉,用于生产果汁饮料和蔬菜饮料。
在本发明的另一个方面,本发明提供一种用于预防或治疗癌症的组合制剂,其包含由式1表示的化合物、其光学异构体、其溶剂化物、其水合物或其药学上可接受的盐作为活性成分。
此时,所述组合制剂是将选自下述组分中的至少一种与式1表示的化合物组合给药的制剂。
此外,本文所述的抗癌治疗可以作为单一疗法应用,或者除了本发明的化合物之外,可以包括常规的手术、放射疗法、化学疗法或免疫疗法。这样的化学疗法可以与使用本发明化合物的治疗同时、依次或分开进行,其中下列类别的抗癌剂中的一种或多种可以用于化学疗法。
(i)用于医学肿瘤学的抗增殖/抗肿瘤药物及其组合,例如烷化剂(例如顺铂、奥沙利铂、卡铂、环磷酰胺、氮芥、美法仑、苯丁酸氮芥、白消安、替莫唑胺和亚硝基脲);抗代谢药(例如吉西他滨和抗叶酸药,例如氟嘧啶,例如5-氟尿嘧啶和替加氟、雷替曲塞、甲氨蝶呤、阿糖胞苷和羟基脲);抗肿瘤抗生素(例如蒽环类,如阿霉素、博来霉素、多柔比星、道诺霉素、表柔比星、伊达比星、丝裂霉素C、更生霉素(dactinomycin)和光辉霉素(mithramycin));有丝分裂抑制剂(例如,长春花生物碱如长春新碱、长春碱、长春地辛和长春瑞滨,紫杉烷类如紫杉醇和泰索帝,和polo样激酶抑制剂(polokinase inhibitors));和拓扑异构酶抑制剂(例如,表鬼臼毒素如依托泊苷和替尼泊苷、安吖啶、拓扑替康和喜树碱);
(ii)细胞增殖抑制剂,例如抗雌激素药(例如他莫昔芬、氟维司群、托瑞米芬、雷洛昔芬、屈洛昔芬和碘昔芬)、抗雄激素药(例如比卡鲁胺、氟他胺、尼鲁米特和醋酸环丙孕酮)、LHRH拮抗剂或LHRH激动剂(例如戈舍瑞林、亮丙瑞林和布舍瑞林)、孕酮(例如醋酸甲地孕酮)、芳香酶抑制剂(例如阿那曲唑、来曲唑、伏立唑和依西美坦(eximestane))和5α-还原酶抑制剂如非那雄胺;
(iii)侵入抑制剂[例如,c-Src激酶抑制剂,如4-(6-氯-2,3-亚甲基二氧基苯胺基)-7-[2-(4-甲基哌嗪-1-基)乙氧基]-5-四氢吡喃-4-基氧基喹唑啉[AZD0530(沙拉替尼);WO 01/94341]、N-(2-氯-6-甲基苯基)-2-{6-[4-(2-羟乙基)哌嗪-1-基]-2-甲基嘧啶-4-基氨基}噻唑-5-甲酰胺(达沙替尼,BMS-354825;J.Med.Chem.,2004,47,6658-6661)和博舒替尼(SKI-606),以及金属蛋白酶抑制剂,例如marimastat、尿激酶纤溶酶原激活物受体抑制剂或抗肝素的抗体];
(iv)生长因子抑制剂(例如,生长因子抗体和生长因子受体抗体如抗erbB2抗体曲妥单抗[HerceptinTM]、抗EGFR抗体帕尼单抗、抗erbB1抗体西妥昔单抗[Erbitux,C225]和文献[Stern等人.Critical reviews in oncology/haematology,2005,Vol.54,pp11-29]中公开的任何生长因子或生长因子受体抗体;酪氨酸激酶抑制剂,如表皮生长因子抑制剂(例如,EGFR酪氨酸激酶抑制剂,如N-(3-氯-4-氟苯基)-7-甲氧基-6-(3-吗啉代丙氧基)-喹唑啉-4-胺(吉非替尼,ZD1839)、N-(3-乙炔基苯基)-6,7-双(2-甲氧基乙氧基)喹唑啉-4-胺(厄洛替尼,OSI-774)和6-丙烯酰氨基-N-(3-氯-4-氟苯基)-7-(3-吗啉代丙氧基)-喹唑啉-4-胺(CI 1033),N-(2-[2-二甲基氨基乙基-甲基氨基]-5-{[4-(1H-吲哚-3-基)嘧啶-2-基]氨基}-4-甲氧基苯基)丙-2-烯酰胺(奥希替尼(Osimertinib),AZD9291),erbB2酪氨酸激酶抑制剂,如拉帕替尼);肝细胞生长因子抑制剂;胰岛素生长因子抑制剂;血小板衍生生长因子抑制剂,例如伊马替尼和/或尼罗替尼(AMN107);丝氨酸/苏氨酸激酶抑制剂(例如,Ras/Raf信号传递抑制剂,例如法尼基转移酶抑制剂,例如索拉非尼(BAY 43-9006)、替比法尼(tipifarnib,R115777)和洛那法尼(lonafarnib,SCH66336))、经由MEK和/或AKT激酶的细胞信号传递抑制剂、c-kit抑制剂、abl激酶抑制剂、PI3激酶抑制剂、Plt3激酶抑制剂、CSF-1R激酶抑制剂、IGF受体(胰岛素样生长因子)激酶抑制剂;极光激酶抑制剂(例如AZD1152、PH739358、VX-680、MLN8054、R763、MP235、MP529、VX-528和AX39459)和细胞周期蛋白依赖性激酶抑制剂如CDK2和/或CDK4抑制剂);
(v)血管生成抑制剂,例如抑制血管内皮生长因子作用的那些[例如,抗血管内皮细胞生长因子抗体贝伐单抗(AvastinTM),和VEGF受体酪氨酸激酶抑制剂,例如凡德他尼(vandetanib,ZD93)、伐他拉尼(vatalanib,PTK787)、舒尼替尼(sunitinib,SU11248)、阿昔替尼(axitinib,AG-013736)、帕唑帕尼(pazopanib,GW786034)和4-(4-氟-2-甲基吲哚-5-基氧基)-6-甲氧基-7-(3-吡咯烷-1-基丙氧基)喹唑啉(AZD2171;WO00/47212的实施例240),例如在WO 97/22596、WO 97/30035、WO 97/32856和WO 98/13354中公开的化合物,和通过其它机制起作用的化合物(例如,linomid、整联蛋白αvβ3抑制剂和血管抑制素)];
(vi)血管损伤剂,例如考布他汀A4和在WO 99/02166、WO 00/40529、WO 00/41669、WO 01/92224、WO 02/04434和WO 02/08213中公开的化合物;
(vii)内分泌素受体拮抗剂,如zivotentan(ZD4054)或阿曲生坦;
(viii)反义疗法,例如针对上文所列靶标的那些,例如ISIS2503和抗ras反义疗法;
(ix)基因治疗方法(例如,置换异常基因如异常p53或异常BRCA1或BRCA2的方法,GDEPT(基因导向酶前药治疗)方法,如使用胞嘧啶脱氨酶、胸苷激酶或细菌硝基还原酶的方法,和增加患者对化疗或放疗的抗性的方法,如多药抗性基因治疗);以及
(x)免疫治疗方法(例如,体外和体内增加患者肿瘤细胞免疫原性的方法,例如使用细胞因子如白介素2、白介素4或粒细胞巨噬细胞集落刺激因子转染的方法,降低T细胞无反应性的方法,使用转染的免疫细胞(如用细胞因子转染的树突细胞)的方法,使用以细胞因子转染的肿瘤细胞系的方法,使用抗独特型抗体的方法,降低免疫抑制细胞如调节性T细胞、髓源性抑制细胞或表达IDO(吲哚胺2,3-脱氧酶)的树突细胞的作用的方法,和使用由衍生自肿瘤相关抗原,如NY-ESO-1、MAGE-3、WT1或Her2/neu的蛋白或肽组成的癌症疫苗的方法)。
因此,在本发明的另一个方面,提供一种用于联合治疗癌症的药物产品,其包含如上定义的式(I)化合物和如上定义的其它抗肿瘤剂。
在本发明的这一方面,提供一种用于联合治疗癌症的药物产品,其包含如上定义的式(I)化合物或其药学上可接受的盐,以及如上定义的其它抗肿瘤剂。
在本说明书中,当术语“联合治疗”用于指联合治疗时,应当理解其可以指同时、分别或顺序给药。“联合给药”的含义应与“联合治疗”类似地解释。在本发明的一个方面,“联合治疗”是指同时给药。在本发明的另一个方面,“联合治疗”是指分开给药。在本发明的另一方面,“联合治疗”是指顺序给药。如果给药是顺序的或分开的,则第二种组分的给药延迟应该使得由使用该组合产生的效果的益处不丧失。因此,在一个实施方案中,顺序治疗包括在11天的时间内施用组合的各组分。在另一个实施方案中,所述时间段是10天。在另一个实施方案中,所述时间段是9天。在另一个实施方案中,所述时间段是8天。在另一个实施方案中,所述时间段是7天。在另一个实施方案中,所述时间段在6天内。在另一个实施方案中,所述时间段在5天内。在另一个实施方案中,所述时间段在4天内。在另一个实施方案中,所述时间段在3天内。在另一个实施方案中,所述时间段在2天内。在另一个实施方案中,所述时间段在24小时内。在另一个实施方案中,所述时间段在12天内。
在本发明的另一个方面,本发明提供一种治疗癌症的方法,该方法包括向有需要的受试者施用包含由式1表示的化合物、其光学异构体、其溶剂化物、其水合物或其药学上可接受的盐作为活性成分的药物组合物或保健功能性食品组合物的步骤。
在本发明的另一个方面,本发明提供由式1表示的化合物、其光学异构体、其溶剂化物、其水合物或其药学上可接受的盐用于预防或治疗癌症。
在本发明的另一个方面,本发明提供由式1表示的化合物、其光学异构体、其溶剂化物、其水合物或其药学上可接受的盐在制备用于预防或治疗癌症的药物中的用途。
本发明一方面提供的苯甲酰胺衍生物可通过抑制EGFR突变用于预防或治疗癌症,并且当与EGFR拮抗剂如西妥昔单抗联合施用时,对抗癌活性显示出显著的协同作用,因此其可有效地用作抗癌剂。上述情况得到后面描述的实施例和实验例的支持。
在所述方法或应用中,可以应用上述药物组合物的详细描述。
以下,通过实施例和实验例对本发明进行详细说明。然而,以下实施例和实验例仅用于说明本发明,本发明的内容不限于此。
通式1:
方案1.试剂和条件:(a)(S)-2-甲基丙烷-2-亚磺酰胺,乙醇钛(IV),THF,室温(rt),17h;(b)1-(苯磺酰基)-1H-吲哚,正丁基锂(n-BuLi),THF,-78℃至rt,3h;(c)5NNaOH,MeOH,回流,过夜;(d)将4N HCl溶解在二噁烷、MeOH中,室温,1h。
[制备实施例1]
(S,E)-N-(5-氟-2-甲氧基亚苄基)-2-甲基丙烷-2-亚磺酰胺
将5-氟-2-甲氧基苯甲醛(26.7g,173mmol)和(S)-2-甲基丙烷-2-亚磺酰胺(20.0g,165mmol)的混合物溶解在乙醇钛(IV)(75.3g,330mmol)的四氢呋喃(4mL)中。用隔膜密封反应烧瓶,并将反应混合物在室温下搅拌24小时。反应混合物用乙酸乙酯和水萃取。收集乙酸乙酯层,用无水硫酸镁干燥并过滤,减压蒸发除去溶剂。残余物通过填充有硅胶的快速柱色谱(己烷/EtOAc,10:1)纯化,得到(S,E)-N-(5-氟-2-甲氧基亚苄基)-2-甲基丙烷-2-亚磺酰胺(40.6g)。
95%收率:1H NMR(500MHz,氯仿-d)δ9.03(d,J=2.4Hz,1H),7.69(dd,J=8.8,3.2Hz,1H),7.19(dd,J=9.1,7.7,3.2Hz,1H),6.94(dd,J=9.1,4.1Hz,1H),3.90(s,3H),1.29(s,9H);LC-MS:274.3[M+H+]。
[制备实施例2]
(S)-N-((R)-(5-氟-2-甲氧基苯基)(1-(苯磺酰基)-1H-吲哚-2-基)甲基)-2-甲基丙烷-2-亚磺酰胺
在-78℃,将正丁基锂滴加到1-(苯磺酰基)-1H-吲哚(56.0g,218mmol)溶于四氢呋喃(200mL)的溶液中。在-78℃下反应1小时后,向其中加入(S,E)-N-(5-氟-2-甲氧基亚苄基)-2-甲基丙烷-2-亚磺酰胺[制备实施例1](40.0g,155mmol)的THF(200mL)溶液,在-78℃下搅拌2小时。通过向混合物中加入饱和NH4Cl水溶液,然后用乙酸乙酯萃取来终止反应。收集乙酸乙酯层,用无水硫酸镁干燥并过滤。减压蒸发除去溶剂。残余物通过填充有硅胶的快速柱色谱(CH2Cl2/EtOAc,10:1)纯化,得到(S)-N-((R)-(5-氟-2-甲氧基苯基)(1-(苯磺酰基)-1H-吲哚-2-基)甲基)-2-甲基丙烷-2-亚磺酰胺[制备实施例2],其为白色固体(79.0g,98%)。
1H NMR(300MHz,氯仿-d)δ8.15(dd,J=8.3,1.1Hz,1H),7.76-7.69(m,2H),7.53-7.47(m,2H),7.42-7.30(m,3H),6.98(ddd,J=8.9,7.7,3.0Hz,1H),6.90(dd,J=9.0,4.5Hz,1H),6.80(d,J=5.8Hz,1H),6.76(d,J=0.9Hz,1H),6.72(dd,J=9.1,3.0Hz,1H),3.92(s,3H),1.26(s,9H);LC-MS:531.6[M+H+].
[制备实施例3]
(S)-N-((R)-(5-氟-2-甲氧基苯基)(1H-吲哚-2-基)甲基)-2-甲基丙烷-2-亚磺酰胺
将溶解于水(8N,69.6g,768mmol,96.0mL)中的NaOH加入到溶解于甲醇(700mL)中的(S)-N-((R)-(5-氟-2-甲氧基苯基)(1-(苯磺酰基)-1H-吲哚-2-基)甲基)-2-甲基丙烷-2-亚磺酰胺(79.0g,154mmol)的溶液中,并将该混合物回流过夜。将混合物在80℃搅拌24小时,然后在室温下冷却。向其中加入水溶液。将混合物减压浓缩。残余物用水和MeOH洗涤并干燥,得到(S)-N-((R)-(5-氟-2-甲氧基苯基)(1H-吲哚-2-基)甲基)-2-甲基丙烷-2-亚磺酰胺[制备实施例3],其为白色固体(50.5g,87%)。
1H NMR(400MHz,DMSO-d6)δ8.83(d,J=2.50Hz,1H),7.62(dd,J=3.31,8.94Hz,1H),7.45(dt,J=3.38,8.63Hz,1H),7.24(dd,J=4.25,9.26Hz,1H),3.91(s,3H),1.17(s,9H).
[制备实施例4]
(R)-(5-氟-2-甲氧基苯基)(1H-吲哚-2-基)甲胺
在室温下,将溶解于二噁烷(0.16mL,0.32mmol)中的4N HCl加入到溶解于甲醇(500mL)中的(S)-N-((R)-(5-氟-2-甲氧基苯基)(1H-吲哚-2-基)甲基)-2-甲基丙烷-2-亚磺酰胺[制备实施例3](51.0g,135mmol)的溶液中。将混合物减压浓缩。将残余物用乙醚固化并过滤,得到(R)-(5-氟-2-甲氧基苯基)(1H-吲哚-2-基)甲烷胺[制备实施例4](黄色固体),产率为97%。
1H NMR(300MHz,甲醇-d4)δ7.59(dt,J=7.8,1.1Hz,1H),7.40-7.35(m,1H),7.26-7.13(m,3H),7.07(ddd,J=8.1,7.1,1.1Hz,1H),6.99(dd,J=8.9,2.7Hz,1H),6.62(t,J=0.9Hz,1H),6.01(s,1H),3.97(s,3H),3.68(s,3H);LC-MS:391.4[M+H+].
通式2:
方案2.试剂和条件:(a)3-溴-5-甲基苯甲酸甲酯、4-羟基苯基硼酸、[1,1'-双(二苯基膦基)二茂铁]二氯化钯(II)、碳酸钾、二噁烷、水、-78℃、1.5h;(b)三氟甲磺酸酐、吡啶、二氯甲烷、rt、3h;(c)叔丁基哌啶-4-基氨基甲酸酯、Ruphos Pd G1、Cs2CO3、二噁烷、110℃、过夜;(d)NaOH、二噁烷、110℃、过夜;(e)1-乙基-3-(3-二甲基氨基丙基)碳二亚胺、羟基苯并三唑、三乙胺、CH2Cl2、rt、过夜;(f)将1M BBr3溶解于CH2Cl2,0℃至室温,30分钟。
[制备实施例5]
4'-羟基-5-甲基-[1,1'-联苯]-3-甲酸甲酯
将4-羟基苯基硼酸(108mg,0.79mmol)、3-溴-5-甲基苯甲酸甲酯(150mg,0.65mmol)、[1,1'-双(二苯基膦基)二茂铁]二氯化钯(II)(48mg,0.066mmol)和碳酸钾(181mg,1.3mmol)在二噁烷/H2O(2.5/0.5mL)中脱气10分钟。将搅拌的悬浮液加热至100℃1.5小时,用乙酸乙酯稀释,并用水和盐水洗涤。有机层用硫酸镁干燥,然后浓缩。残余物通过MPLC纯化,得到4'-羟基-5-甲基-[1,1'-联苯]-3-羧酸酯[制备实施例5],其为黄色固体(120mg,75%)。
1H NMR(400MHz,氯仿-d)δ8.07(s,1H),7.82(s,1H),7.57(s,1H),7.52-7.50(m,2H),6.99-6.96(m,2H),5.94(br s,1H),3.98(s,3H),2.47(s,3H);LC-MS:243.2[M+H+].
[制备实施例6]
5-甲基-4'-(((三氟甲基)磺酰基)氧基)-[1,1'-联苯]-3-羧酸甲酯
在室温下,将吡啶(0.052ml,0.64mmol)加入到4'-羟基-5-甲基-[1,1'-联苯]-3-甲酸甲酯(100mg,0.41mmol)和三氟甲磺酸酐(128mg,0.45mmol)溶解于无水二氯甲烷的溶液中。将混合物搅拌3小时。残余物用水和碳酸氢钠萃取,用盐水洗涤。有机层经硫酸镁干燥,过滤并浓缩。通过MPLC纯化该粗制化合物,得到5-甲基-4'-((三氟甲基)磺酰基)氧基)-[1,1'-联苯]-3-羧酸甲酯[制备实施例6],其为黄色固体(102mg,66%)。
1H NMR(400MHz,氯仿-d)δ8.06(s,1H),7.90(s,1H),7.69-7.67(m,2H),7.57(s,1H),7.38-7.36(m,2H),3.96(s,3H),2.49(s,3H);LC-MS:375.3[M+H+].
[制备实施例7]
4'-(4-((叔丁氧羰基)氨基)哌啶-1-基)-5-甲基-[1,1'-联苯]-3-甲酸甲酯
将4-(叔丁氧羰基氨基)哌啶(61.1mg,0.31mmol)、5-甲基-4'-((三氟甲基)磺酰基)氧基)-[1,1'-联苯基]-3-羧酸甲酯[制备实施例6](104mg,0.28mmol)、Ruphos Pd G1(22.7mg,0.028mmol)和碳酸铯(81.4mg,0.025mmol)在无水1,4-二噁烷(2.5mL)中脱气10分钟。将搅拌的悬浮液在110℃加热过夜,用乙酸乙酯稀释,并用水和盐水洗涤。将有机层用硫酸镁干燥并浓缩,得到4'-(4-((叔丁氧基羰基)氨基)哌啶-1-基)-5-甲基-[1,1'-联苯]-3-羧酸甲酯[制备实施例7](黄色固体),其不经进一步纯化而用于下一步骤。(65mg,55%)
1H NMR(400MHz,氯仿-d)δ8.06(s,1H),7.90(s,1H),7.58(s,1H),7.56-7.53(m,2H),7.03-7.00(m,2H),4.57-4.47(m,1H),3.95(s,3H),3.77-3.67(m,2H),2.96-2.89(m,2H),2.47(s,3H),2.11-2.07(m,2H),1.63-1.53(m,2H),1.49(s,9H);LC-MS:425.5[M+H+].
[制备实施例8]
4'-(4-((叔丁氧羰基)氨基)哌啶-1-基)-5-甲基-[1,1'-联苯]-3-羧酸
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在室温下,将NaOH(5.6mg,0.14mmol)加入到溶于二噁烷的4'-(4-((叔丁氧基羰基)氨基)哌啶-1-基)-5-甲基-[1,1'-联苯]-3-甲酸甲酯(58.9mg,0.14mmol)溶液中。将混合物在110℃加热并搅拌12小时。加入1N盐酸直到混合物的pH值为2,过滤所得固体并干燥,得到4'-(4-((叔丁氧基羰基)氨基)哌啶-1-基)-5-甲基-[1,1'-联苯]-3-羧酸[制备实施例8],其为黄色固体(45mg,79%)。
[制备实施例9]
(R)-(1-(3'-(((5-氟-2-甲氧基苯基)(1H-吲哚-2-基)甲基)氨基甲酰基)-5'-甲基-[1,1'-联苯基]-4-基)哌啶-4-基)氨基甲酸叔丁酯
在室温下,将三乙胺(0.017ml,0.12mmol)加入到溶解于CH2Cl2中的(R)-(5-氟-2-甲氧基苯基)(1H-吲哚-2-基)甲烷胺[制备实施例4](30mg,0.11mmol)、4'-(4-((叔丁氧基羰基)氨基)哌啶-1-基)-5-甲基-[1,1'-联苯]-3-羧酸[制备实施例8](45mg,0.11mmol)、1-乙基-3-(3-二甲基氨基丙基)碳二亚胺(17mg,0.11mmol)和羟基苯并三唑(15mg,0.11mmol)的溶液中。将混合物搅拌过夜。残余物用水和碳酸氢钠萃取,用盐水洗涤。有机层用硫酸镁干燥,然后浓缩。通过MPLC纯化粗制化合物,得到(R)-(1-(3'-(((5-氟-2-甲氧基苯基)(1H-吲哚-2-基)甲基)氨基甲酰基)-5'-甲基-[1,1'-联苯基]-4-基)哌啶-4-基)氨基甲酸叔丁酯[制备实施例9],为黄色固体。(48mg,66%)
1H NMR(400MHz,氯仿-d)δ8.87(s,1H),7.79(s,1H),7.73(d,J=8.4Hz,1H),7.54-7.36(m,5H),7.34(d,J=8.0Hz,1H),7.20-6.99(m,7H),6.72(d,J=8.0Hz,1H),6.06(s,1H),4.50(m,1H),3.90(s,3H),3.72-3.66(m,2H),2.95-2.89(m,2H),2.47(s,3H),2.11-2.08(m,2H),1.49(s,9H);LC-MS:663.8[M+H+].
[实施例1]
(R)-4'-(4-氨基哌啶-1-基)-N-((5-氟-2-羟基苯基)(1H-吲哚-2-基)甲基)-5-甲基-[1,1'-联苯]-3-甲酰胺
在0℃下,将溶解于二氯甲烷(0.20ml)中的1M三溴化硼缓慢加入到(R)-(1-(3'-(((5-氟-2-甲氧基苯基)(1H-吲哚-2-基)甲基)氨基甲酰基)-5'-甲基-[1,1'-联苯基]-4-基)哌啶-4-基)氨基甲酸叔丁酯[制备实施例9](45mg,0.068mmol)中。将反应混合物在室温下搅拌过夜,在0℃下向其中加入碳酸氢钠以终止反应。将四氢呋喃与盐水一起加入其中。收集的有机层经MgSO4干燥,过滤并浓缩。将残余物用PTLC纯化,得到(R)-4'-(4-氨基哌啶-1-基)-N-((5-氟-2-羟基苯基)(1H-吲哚-2-基)甲基)-5-甲基-[1,1'-联苯]-3-甲酰胺[实施例1](11mg,30%),为白色固体。
1H NMR(400MHz,DMSO-d6)δ11.12(br s,1H),9.27(br d,J=8.38Hz,1H),7.97(s,1H),7.66(s,1H),7.55-7.62(m,3H),7.43(d,J=7.88Hz,1H),7.33(d,J=8.00Hz,1H),7.21(dd,J=3.13,9.76Hz,1H),6.90-7.06(m,5H),6.87-6.87(m,1H),6.78-6.88(m,1H),5.99(s,1H),3.67-3.73(m,2H),2.74-2.81(m,2H),2.65-2.71(m,1H),2.46(br s,1H),2.41(s,3H),1.71-1.83(m,2H),1.23-1.37(m,2H);LC-MS:549.6[M+H+].
[实施例2]
(R)-4'-(4-氨基哌啶-1-基)-N-((5-氟-2-羟基苯基)(1H-吲哚-2-基)甲基)-5-异丙基-[1,1'-联苯]-3-甲酰胺
(R)-4'-(4-氨基哌啶-1-基)-N-((5-氟-2-羟基苯基)(1H-吲哚-2-基)甲基)-5-异丙基-[1,1'-联苯]-3-甲酰胺[实施例2](34%)通过与[实施例1]中所述方法相似的方法制备;LC-MS:577.7[M+H+]。
[实施例3]
(R)-4'-(4-氨基哌啶-1-基)-N-((5-氟-2-羟基苯基)(1H-吲哚-2-基)甲基)-5-甲氧基-[1,1'-联苯]-3-甲酰胺
(R)-4'-(4-氨基哌啶-1-基)-N-((5-氟-2-羟基苯基)(1H-吲哚-2-基)甲基)-5-甲氧基-[1,1'-联苯]-3-甲酰胺[实施例3](53%)通过与[实施例1]中所述方法同样的方法制备。
1H NMR(400MHz,DMSO-d6)δ11.16(s,1H),9.28(d,J=8.4Hz,1H),7.63(s,1H),7.53(d,J=8.8Hz,2H),7.41(d,J=8.0Hz,1H),7.36-7.31(m,2H),7.24(s,1H),7.18-6.99(m,6H),6.96 -6.92(m,1H),6.85(d,J=8.4Hz,1H),5.92(s,1H),3.80(s,3H),3.72-3.70(m,2H),2.80-2.74(m,3H),1.81-1.78(m,2H),1.38-1.30(m,2H);LC-MS:565.6[M+H+].
[实施例4]
(R)-4'-(4-氨基哌啶-1-基)-5-(叔丁基)-N-((5-氟-2-羟基苯基)(1H-吲哚-2-基)甲基)-[1,1'-联苯]-3-甲酰胺
(R)-4'-(4-氨基哌啶-1-基)-5-(叔丁基)-N-((5-氟-2-羟基苯基)(1H-吲哚-2-基)甲基)-[1,1'-联苯]-3-甲酰胺[实施例4](16%)通过与[实施例1]中所述方法类似的方法制备;LC-MS:591.7[M+H+]。
[实施例5]
(R)-4'-(4-氨基哌啶-1-基)-5-氟-N-((5-氟-2-羟基苯基)(1H-吲哚-2-基)甲基)-[1,1'-联苯]-3-甲酰胺
(R)-4'-(4-氨基哌啶-1-基)-5-氟-N-((5-氟-2-羟基苯基)(1H-吲哚-2-基)甲基)-[1,1'-联苯]-3-甲酰胺[实施例5](22%)通过与[实施例1]中所述方法类似的方法制备。
1H NMR(400MHz,DMSO-d6)δ11.16(s,1H),9.41(d,J=8.0Hz,1H),8.07(s,1H),7.66-7.60(m,5H),7.43(d,J=7.6Hz,1H),7.32(d,J=8.0Hz,1H),7.20(dd,J=3.2,9.6Hz,1H),7.06-6.92(m,6H),6.88-6.81(m,3H),5.97(s,1H),3.77-3.74(m,2H),2.83-2.77(m,3H),1.82-1.79(m,2H),1.36-1.30(m,2H);LC-MS:553.6[M+H+].
[实施例6]
4'-(4-氨基哌啶-1-基)-N-((5-氟-2-羟基苯基)(1H-吲哚-2-基)甲基)-5-(三氟甲基)-[1,1'-联苯]-3-甲酰胺
4'-(4-氨基哌啶-1-基)-N-((5-氟-2-羟基苯基)(1H-吲哚-2-基)甲基)-5-(三氟甲基)-[1,1'-联苯]-3-甲酰胺[实施例6](2%)通过与[实施例1]中所述方法类似的方法制备。
1H NMR(400MHz,DMSO-d6)δ11.07-11.21(m,1H),9.51-9.62(m,1H),8.33-8.45(m,1H),8.10-8.15(m,1H),8.00-8.06(m,1H),7.64-7.70(m,2H),7.40-7.44(m,1H),7.30-7.34(m,2H),7.12-7.16(m,1H),7.04-7.08(m,1H),7.05(s,2H),6.94-6.97(m,1H),6.83-6.88(m,1H),6.78-6.82(m,1H),6.62-6.69(m,1H),5.96-6.00(m,1H),5.29-5.32(m,2H),1.99-2.04(m,1H),1.93-1.98(m,2H),1.82-1.91(m,2H),1.42-1.46(m,4H),0.83(s,2H);LC-MS:603.6[M+H+].
[实施例7]
4'-(4-氨基哌啶-1-基)-N-((5-氟-2-羟基苯基)(1H-吲哚-2-基)甲基)-5-硝基-[1,1'-联苯]-3-甲酰胺
4'-(4-氨基哌啶-1-基)-N-((5-氟-2-羟基苯基)(1H-吲哚-2-基)甲基)-5-硝基-[1,1'-联苯]-3-甲酰胺[实施例7](3%)通过与[实施例1]中所述方法类似的方法制备。
1H NMR(400MHz,DMSO-d6)δ11.08-11.25(m,1H),9.60-9.75(m,1H),8.58-8.65(m,2H),8.48-8.56(m,1H),7.70-7.75(m,1H),7.73(d,J=9.01Hz,1H),7.41-7.46(m,1H),7.30-7.37(m,1H),7.15-7.22(m,1H),6.92-7.10(m,5H),6.82-6.90(m,2H),5.91-6.01(m,1H),3.75-3.82(m,2H),2.76-2.91(m,3H),2.41-2.47(m,1H),1.75-1.88(m,2H),1.32-1.43(m,2H),1.24(s,2H);LC-MS:580.6[M+H+].
[实施例8]
4'-(4-氨基哌啶-1-基)-N-((5-氟-2-羟基苯基)(1H-吲哚-2-基)甲基)-5-(甲硫基)-[1,1'-联苯]-3-甲酰胺
4'-(4-氨基哌啶-1-基)-N-((5-氟-2-羟基苯基)(1H-吲哚-2-基)甲基)-5-(甲硫基)-[1,1'-联苯]-3-甲酰胺[实施例8](2%)通过与[实施例1]中所述方法类似的方法制备。
1H NMR(400MHz,DMSO-d6)δ11.04-11.16(m,1H),9.22-9.39(m,1H),7.92(t,J=1.44Hz,1H),7.69(d,J=1.50Hz,1H),7.56-7.64(m,3H),7.42(d,J=7.88Hz,1H),7.33(dd,J=0.69,8.07Hz,1H),7.19(dd,J=3.13,9.76Hz,1H),7.00-7.08(m,3H),6.91-6.99(m,2H),6.79-6.88(m,2H),5.96(s,1H),3.74(br d,J=12.76Hz,2H),3.70-3.71(m,1H),2.75-2.86(m,3H),2.75-2.76(m,1H),2.57(s,3H),2.44(s,1H),1.74-1.86(m,2H),1.33-1.40(m,2H),1.24(s,2H);LC-MS:581.7[M+H+].
[实施例9]
4'-(4-氨基哌啶-1-基)-5-氰基-N-((5-氟-2-羟基苯基)(1H-吲哚-2-基)甲基)-[1,1'-联苯]-3-甲酰胺
4'-(4-氨基哌啶-1-基)-5-氰基-N-((5-氟-2-羟基苯基)(1H-吲哚-2-基)甲基)-[1,1'-联苯]-3-甲酰胺[实施例9](2%)通过与[实施例1]中所述方法类似的方法制备。
1H NMR(400MHz,DMSO-d6)δ11.04-11.24(m,1H),9.39-9.61(m,1H),8.43-8.46(m,1H),8.21-8.30(m,2H),7.65-7.73(m,2H),7.40-7.46(m,1H),7.29-7.36(m,1H),7.14-7.21(m,1H),6.92-7.09(m,5H),6.84-6.89(m,1H),6.81(d,J=8.25Hz,1H),5.98(s,1H),3.80-3.85(m,2H),2.96-3.07(m,1H),2.79-2.89(m,2H),1.96-2.03(m,1H),1.81-1.89(m,2H),1.41-1.51(m,2H),0.81-0.90(m,2H);LC-MS:660.6[M+H+].
[实施例10]
(R)-4'-(4-氨基哌啶-1-基)-5-氯-N-((5-氟-2-羟基苯基)(1H-吲哚-2-基)甲基)-[1,1'-联苯]-3-甲酰胺
(R)-4'-(4-氨基哌啶-1-基)-5-氯-N-((5-氟-2-羟基苯基)(1H-吲哚-2-基)甲基)-[1,1'-联苯]-3-甲酰胺[实施例10](15%)通过与[实施例1]中所述方法类似的方法制备。
1H NMR(400MHz,DMSO-d6)δ11.16(br s,1H),9.46(br d,J=8.00Hz,1H),8.13(t,J=1.50Hz,1H),7.81-7.86(m,2H),7.63(d,J=9.01Hz,2H),7.40-7.47(m,1H),7.33(t,J=1.00Hz,1H),7.18(dd,J=3.19,9.69Hz,1H),7.00-7.06(m,3H),6.92-6.99(m,2H),6.83-6.88(m,1H),6.80(d,J=1.00Hz,1H),5.97(s,1H),3.73(br d,J=12.76Hz,2H),2.70-2.83(m,3H),1.77(br dd,J=2.94,12.57Hz,2H),1.24-1.36(m,2H);LC-MS:570.0[M+H+].
[实施例11]
(R)-4'-(4-氨基哌啶-1-基)-N-((5-氟-2-羟基苯基)(1H-吲哚-2-基)甲基)-5-(三氟甲氧基)-[1,1'-联苯]-3-甲酰胺
(R)-4'-(4-氨基哌啶-1-基)-N-((5-氟-2-羟基苯基)(1H-吲哚-2-基)甲基)-5-(三氟甲氧基)-[1,1'-联苯]-3-甲酰胺[实施例11](8%)通过与[实施例1]中所述方法类似的方法制备。
1H NMR(400MHz,DMSO-d6)δ11.18(br s,1H),9.53(br d,J=8.00Hz,1H),8.26(t,J=1.00Hz,1H),7.74(d,J=1.00Hz,2H),7.66(d,J=8.88Hz,2H),7.43(d,J=7.88Hz,1H),7.32(t,J=7.74Hz,1H),7.18(dd,J=3.19,9.69Hz,1H),7.00-7.07(m,3H),6.92-6.99(m,2H),6.80-6.89(m,2H),5.96(s,1H),3.73(br q,J=13.01Hz,1H),2.72-2.84(m,3H),1.77(br d,J=9.88Hz,2H),1.27-1.36(m,2H);LC-MS:619.6[M+H+].
[实施例12]
(R)-4'-(4-氨基哌啶-1-基)-N-((5-氟-2-甲氧基苯基)(1H-吲哚-2-基)甲基)-5-(三氟甲氧基)-[1,1'-联苯]-3-甲酰胺
用与[实施例1]所述方法类似的方法制备中间体后,作为[实施例11]的副产物得到(R)-4'-(4-氨基哌啶-1-基)-N-((5-氟-2-甲氧基苯基)(1H-吲哚-2-基)甲基)-5-(三氟甲氧基)-[1,1'-联苯]-3-甲酰胺[实施例12](8%)。
1H NMR(400MHz,DMSO-d6)δ11.22(s,1H),9.58(d,J=8.26Hz,1H),8.26(t,J=1.44Hz,1H),7.75(s,2H),7.66(d,J=9.01Hz,2H),7.43(d,J=7.75Hz,1H),7.28-7.34(m,2H),7.17(q,J=1.00Hz,1H),7.08-7.12(m,1H),7.02-7.08(m,3H),6.92-6.97(m,1H),6.86(d,J=8.13Hz,1H),5.90-5.92(m,1H),3.80(s,3H),3.70-3.76(m,J=12.76Hz,2H),2.75-2.84(m,3H),1.74-1.81(m,2H),1.27-1.35(m,2H);LC-MS:633.6[M+H+].
[实施例13]
(R)-4'-(4-氨基哌啶-1-基)-N-((5-氟-2-羟基苯基)(1H-吲哚-2-基)甲基)-5-(1H-咪唑-1-基)-[1,1'-联苯]-3-甲酰胺
(R)-4'-(4-氨基哌啶-1-基)-N-((5-氟-2-羟基苯基)(1H-吲哚-2-基)甲基)
-5-(1H-咪唑-1-基)-[1,1'-联苯]-3-甲酰胺[实施例13](44%)通过与[实施例1]中所述方法类似的方法制备。
1H NMR(400MHz,DMSO-d6)δ11.17(br s,1H),9.44(br d,J=7.38Hz,1H),8.42(t,J=1.00Hz,1H),8.14(s,1H),8.02(t,J=1.38Hz,1H),8.00(t,J=1.63Hz,1H),7.91(t,J=1.25Hz,1H),7.72(d,J=8.88Hz,2H),7.43(d,J=7.75Hz,1H),7.33(t,J=1.00Hz,1H),7.18(dd,J=3.13,9.63Hz,1H),7.14(t,J=1.00Hz,1H),7.02-7.07(m,3H),6.92-7.02(m,2H),6.81-6.89(m,2H),6.00(s,1H),3.71-3.77(m,2H),2.69-2.88(m,3H),1.74-1.82(m,2H),1.25-1.39(m,2H);LC-MS:601.6[M+H+].
[实施例14]
(R)-2-(4-(4-氨基哌啶-1-基)苯基)-N-((5-氟-2-羟基苯基)(1H-吲哚-2-基)甲基)异烟酰胺
(R)-2-(4-(4-氨基哌啶-1-基)苯基)-N-((5-氟-2-羟基苯基)(1H-吲哚-2-基)甲基)异烟酰胺[实施例14](12%)按照与[实施例1]所述的方法相似的方法制备。
1H NMR(400MHz,DMSO-d6)δ11.19(br s,1H),9.60(br d,J=7.75Hz,1H),8.71(d,J=5.00Hz,1H),8.30(s,1H),8.01(d,J=9.00Hz,2H),7.65(dd,J=1.50,5.13Hz,1H),7.44(d,J=7.75Hz,1H),7.38(br d,J=4.75Hz,1H),7.30-7.36(m,1H),7.19(dd,J=3.13,9.63Hz,1H),7.00-7.07(m,4H),6.92-7.00(m,2H),6.80-6.89(m,2H),5.99(s,1H),3.76(brd,J=12.76Hz,2H),2.71-2.86(m,3H),1.78(br d,J=10.26Hz,2H),1.26-1.37(m,2H);LC-MS:536.6[M+H+].
[实施例15]
(R)-2-(4-(4-氨基哌啶-1-基)苯基)-N-((5-氟-2-甲氧基苯基)(1H-吲哚-2-基)甲基)异烟酰胺
(R)-2-(4-(4-氨基哌啶-1-基)苯基)-N-((5-氟-2-甲氧基苯基)(1H-吲哚-2-基)甲基)异烟酰胺[实施例15](16%)通过与[实施例1]所述相似的方法制备。
1H NMR(400MHz,DMSO-d6)δ11.22(s,1H),9.64(d,J=8.26Hz,1H),8.71(d,J=5.12Hz,1H),8.30(s,1H),8.01(d,J=9.01Hz,2H),7.62-7.68(m,1H),7.43(d,J=7.88Hz,1H),7.28-7.36(m,2H),7.14-7.20(m,1H),7.02-7.12(m,4H),6.93-6.98(m,1H),6.86(d,J=8.13Hz,1H),5.92-5.95(m,1H),3.81(s,3H),3.76(br d,J=12.88Hz,2H),2.70-2.86(m,3H),1.74-1.82(m,2H),1.27-1.36(m,2H);LC-MS:550.6[M+H+].
[实施例16]
(R)-3-(2-(4-氨基哌啶-1-基)嘧啶-5-基)-N-((5-氟-2-羟基苯基)(1H-吲哚-2-基)甲基)-5-甲基苯甲酰胺
(R)-3-(2-(4-氨基哌啶-1-基)嘧啶-5-基)-N-((5-氟-2-羟基苯基)(1H-吲哚-2-基)甲基)-5-甲基苯甲酰胺[实施例16](31%)通过与[实施例1]中所述的方法相似的方法制备。
1H NMR(400MHz,DMSO-d6)δ11.13(br s,1H),9.21(br d,J=8.50Hz,1H),8.72-8.79(m,2H),8.01(s,1H),7.72(s,1H),7.64(s,1H),7.43(d,J=7.75Hz,1H),7.33(dd,J=0.75,8.00Hz,1H),7.20(dd,J=3.19,9.69Hz,1H),7.03(dt,J=1.25,7.57Hz,1H),6.91-7.01(m,2H),6.85(dd,J=4.88,8.88Hz,1H),6.81(d,J=8.13Hz,1H),5.99(s,1H),4.50-4.61(m,2H),3.01-3.10(m,2H),2.81-2.91(m,1H),2.42(s,3H),1.74-1.81(m,2H),1.12-1.22(m,2H);
LC-MS:550.6[M+H+].
[实施例17]
(R)-3-(5-(4-氨基哌啶-1-基)吡啶-2-基)-N-((5-氟-2-羟基苯基)(1H-吲哚-2-基)甲基)-5-甲基苯甲酰胺
(R)-3-(5-(4-氨基哌啶-1-基)吡啶-2-基)-N-((5-氟-2-羟基苯基)(1H-吲哚-2-基)甲基)-5-甲基苯甲酰胺[实施例17](16%)通过与[实施例1]所述方法相似的方法制备。
1H NMR(400MHz,DMSO-d6)δ11.13(br s,1H),9.27(br d,J=8.38Hz,1H),8.38(d,J=2.75Hz,1H),8.32(s,1H),8.30(br s,1H),7.99(s,1H),7.84(d,J=8.88Hz,1H),7.71(s,1H),7.39-7.44(m,2H),7.33(dd,J=0.69,8.07Hz,1H),7.23(dd,J=3.25,9.76Hz,1H),7.04(dt,J=1.19,7.60Hz,1H),6.91-7.00(m,2H),6.80-6.87(m,2H),6.00(s,1H),3.76(brd,J=12.63Hz,2H),2.80-2.87(m,2H),2.71-2.79(m,1H),2.43(s,3H),1.76-1.83(m,2H),1.30-1.38(m,2H);LC-MS:550.6[M+H+].
[实施例18]
(R)-3-(5-(4-氨基哌啶-1-基)吡嗪-2-基)-N-((5-氟-2-羟基苯基)(1H-吲哚-2-基)甲基)-5-甲基苯甲酰胺
(R)-3-(5-(4-氨基哌啶-1-基)吡嗪-2-基)-N-((5-氟-2-羟基苯基)(1H-吲哚-2-基)甲基)-5-甲基苯甲酰胺[实施例18](46%)通过与[实施例1]中所述方法相似的方法制备。
1H NMR(400MHz,DMSO-d6)δ11.12(br s,1H),9.24(br d,J=8.38Hz,1H),8.70-8.75(m,1H),8.41(t,J=1.00Hz,1H),8.27-8.34(m,1H),7.92-7.97(m,1H),7.73(s,1H),7.43(d,J=7.75Hz,1H),7.33(t,J=8.13Hz,1H),7.23(dd,J=3.25,9.76Hz,1H),7.04(dt,J=1.25,7.57Hz,1H),6.91-7.00(m,2H),6.85(dd,J=4.82,8.82Hz,1H),6.81(d,J=8.38Hz,1H),6.00(s,1H),4.20-4.35(m,2H),2.95-3.09(m,2H),2.79-2.88(m,1H),2.43(s,3H),1.62-1.85(m,2H),1.17-1.33(m,2H);LC-MS:551.6[M+H+].
[实施例19]
(R)-3-(6-(4-氨基哌啶-1-基)吡啶-3-基)-N-((5-氟-2-羟基苯基)(1H-吲哚-2-基)甲基)-5-甲基苯甲酰胺
(R)-3-(6-(4-氨基哌啶-1-基)吡啶-3-基)-N-((5-氟-2-羟基苯基)(1H-吲哚-2-基)甲基)-5-甲基苯甲酰胺[实施例19](83%)通过与[实施例1]所述方法相似的方法制备。
1H NMR(400MHz,DMSO-d6)δ11.14(br s,1H),9.25(br s,1H),8.50(d,J=2.50Hz,1H),7.98(s,1H),7.88(dd,J=2.56,8.94Hz,1H),7.68(s,1H),7.61(s,1H),7.42(d,J=7.75Hz,1H),7.33(t,J=8.00Hz,1H),7.20(dd,J=3.06,9.69Hz,1H),7.00-7.06(m,1H),6.90-7.00(m,3H),6.78-6.87(m,2H),5.99(s,1H),4.23(br d,J=12.76Hz,2H),2.88-2.98(m,2H),2.75-2.85(m,1H),2.41(s,3H),1.75(br d,J=12.38Hz,2H),1.15-1.24(m,2H);LC-MS:550.6[M+H+].
[实施例20]
(R)-3-(6-(4-氨基哌啶-1-基)哒嗪-3-基)-N-((5-氟-2-羟基苯基)(1H-吲哚-2-基)甲基)-5-甲基苯甲酰胺
(R)-3-(6-(4-氨基哌啶-1-基)哒嗪-3-基)-N-((5-氟-2-羟基苯基)(1H-吲哚-2-基)甲基)-5-甲基苯甲酰胺[实施例20](72%)通过与[实施例1]中所述方法类似的方法制备。
1H NMR(400MHz,DMSO-d6)δppm 11.08-11.21(m,1H),,9.25-9.45(m,1H)8.00-8.11(m,1H),8.37(s,1H),7.96(d,J=9.76Hz,1H),7.80(s,1H),7.30-7.45(m,3H),7.18-7.26(m,1H),6.95(br d,J=6.88Hz,3H),6.83(s,2H),6.00(s,1H),5.97-5.97(m,1H),4.24-4.40(m,2H),3.00-3.13(m,2H),,2.80-2.89(m,1H),2.42-2.46(m,3H),1.74-1.84(m,2H),1.20-1.29(m,2H);LC-MS:551.6[M+H+].
[实施例21]
(R)-3-(5-(4-氨基哌啶-1-基)嘧啶-2-基)-N-((5-氟-2-羟基苯基)(1H-吲哚-2-基)甲基)-5-甲基苯甲酰胺
(R)-3-(5-(4-氨基哌啶-1-基)嘧啶-2-基)-N-((5-氟-2-羟基苯基)(1H-吲哚-2-基)甲基)-5-甲基苯甲酰胺[实施例21](24%)通过与[实施例1]中所述方法类似的方法制备。
1H NMR(400MHz,DMSO-d6)δ11.11(br s,1H),9.29(br d,J=8.63Hz,1H),8.57-8.61(m,3H),8.24(s,1H),7.80(s,1H),7.43(d,J=7.88Hz,1H),7.33(d,J=7.96Hz,1H),7.25(dd,J=3.19,9.82Hz,1H),7.04(dt,J=1.25,7.57Hz,1H),6.92-7.00(m,2H),6.79-6.87(m,2H),6.00(s,1H),3.82(br d,J=13.01Hz,2H),2.86-2.92(m,2H),2.75-2.81(m,1H),2.44(s,3H),1.76-1.85(m,2H),1.28-1.36(m,2H);LC-MS:551.6[M+H+].
[实施例22]
(R)-4'-(4-氨基哌啶-1-基)-3'-氟-N-((5-氟-2-羟基苯基)(1H-吲哚-2-基)甲基)-5-甲基-[1,1'-联苯]-3-甲酰胺
(R)-4'-(4-氨基哌啶-1-基)-3'-氟-N-((5-氟-2-羟基苯基)(1H-吲哚-2-基)甲基)-5-甲基-[1,1'-联苯]-3-甲酰胺[实施例22](59%)通过与[实施例1]中所述方法类似的方法制备。
1H NMR(400MHz,DMSO-d6)δ11.13(br s,1H),9.27(br d,J=8.50Hz,1H),8.00(s,1H),7.71(s,1H),7.65(s,1H),7.47-7.58(m,2H),7.43(d,J=7.75Hz,1H),7.32(t,J=7.72Hz,1H),7.19(dd,J=3.13,9.63Hz,1H),7.11(t,J=8.94Hz,1H),7.04(dt,J=1.13,7.57Hz,1H),6.91-7.01(m,2H),6.79-6.89(m,2H),5.98(s,1H),3.37-3.41(m,2H),2.79-2.90(m,1H),2.69-2.76(m,2H),2.42(s,3H),1.77-1.84(m,2H),1.34-1.49(m,2H);LC-MS:567.6[M+H+].
[实施例23]
(R)-4'-(4-氨基哌啶-1-基)-N-((5-氟-2-羟基苯基)(1H-吲哚-2-基)甲基)-2',5-二甲基-[1,1'-联苯]-3-甲酰胺
(R)-4'-(4-氨基哌啶-1-基)-N-((5-氟-2-羟基苯基)(1H-吲哚-2-基)甲基)-2',5-二甲基-[1,1'-联苯]-3-甲酰胺[实施例23](56%)通过与[实施例1]中所述方法类似的方法制备。
1H NMR(400MHz,DMSO-d6)δ11.09(br s,1H),9.18(br d,J=8.50Hz,1H),7.71(s,1H),7.68(s,1H),7.41(d,J=7.63Hz,1H),7.31(dd,J=0.75,8.13Hz,1H),7.28(s,1H),7.20(dd,J=3.25,9.76Hz,1H),7.07(d,J=8.38Hz,1H),7.02(dt,J=1.19,7.54Hz,1H),6.91-6.99(m,2H),6.78-6.87(m,4H),5.97(s,1H),3.66(br d,J=12.76Hz,2H),2.72-2.77(m,2H),2.67-2.71(m,1H),2.40(s,3H),2.20(s,3H),1.72-1.80(m,2H),1.26-1.36(m,1H);LC-MS:563.6[M+H+].
[实施例24]
(R)-4'-(4-氨基哌啶-1-基)-2'-氟-N-((5-氟-2-羟基苯基)(1H-吲哚-2-基)甲基)-5-甲基-[1,1'-联苯]-3-甲酰胺
(R)-4'-(4-氨基哌啶-1-基)-2'-氟-N-((5-氟-2-羟基苯基)(1H-吲哚-2-基)甲基)-5-甲基-[1,1'-联苯]-3-甲酰胺[实施例24](55%)通过与[实施例1]中所述方法类似的方法制备。
1H NMR(400MHz,DMSO-d6)δ11.11(br s,1H),9.22(br d,J=8.00Hz,1H),7.85(s,1H),7.71(s,1H),7.47(s,1H),7.37-7.44(m,2H),7.32(t,J=8.01Hz,1H),7.20(dd,J=3.19,9.69Hz,1H),7.03(dt,J=1.13,7.57Hz,1H),6.91-7.00(m,2H),6.78-6.87(m,4H),5.98(s,1H),3.73(br d,J=12.88Hz,2H),2.77-2.86(m,2H),2.71-2.77(m,1H),2.41(s,3H),1.76(br d,J=13.13Hz,2H),1.23-1.33(m,2H);LC-MS:567.6[M+H+].
[实施例25]
(R)-4'-(4-氨基哌啶-1-基)-N-((5-氟-2-羟基苯基)(1H-吲哚-2-基)甲基)-3',5-二甲基-[1,1'-联苯]-3-甲酰胺
(R)-4'-(4-氨基哌啶-1-基)-N-((5-氟-2-羟基苯基)(1H-吲哚-2-基)甲基)-3',5-二甲基-[1,1'-联苯]-3-甲酰胺[实施例25](50%)通过与[实施例1]中所述方法类似的方法制备。
1H NMR(400MHz,DMSO-d6)δ11.12(br s,1H),9.25(br d,J=8.13Hz,1H),7.96(s,1H),7.70(s,1H),7.60(s,1H),7.40-7.53(m,3H),7.32(t,J=7.73Hz,1H),7.21(dd,J=3.19,9.69Hz,1H),7.09(d,J=8.25Hz,1H),7.03(dt,J=1.13,7.57Hz,1H),6.91-7.00(m,2H),6.79-6.88(m,2H),5.98(s,1H),3.05(br d,J=12.13Hz,2H),2.59-2.69(m,3H),2.42(s,3H),2.30(s,3H),1.77-1.84(m,2H),1.36-1.48(m,2H);LC-MS:563.6[M+H+].
[实施例26]
(R)-4'-(4-氨基哌啶-1-基)-N-((6-氟-1H-吲哚-2-基)(5-氟-2-羟基苯基)甲基)-5-甲基-[1,1'-联苯]-3-甲酰胺
(R)-4'-(4-氨基哌啶-1-基)-N-((6-氟-1H-吲哚-2-基)(5-氟-2-羟基苯基)甲基)-5-甲基-[1,1'-联苯]-3-甲酰胺[实施例26](47%)通过与[实施例1]所述方法类似的方法制备。
1H NMR(400MHz,DMSO-d6)δ11.21(br s,1H),9.27(br d,J=8.38Hz,1H),7.96(s,1H),7.65(s,1H),7.56-7.60(m,3H),7.42(dd,J=5.50,8.63Hz,1H),7.22(dd,J=3.13,9.76Hz,1H),7.08(dd,J=2.31,10.07Hz,1H),7.01(d,J=9.01Hz,2H),6.93-6.98(m,1H),6.77-6.88(m,3H),5.98(s,1H),3.70(br d,J=12.76Hz,2H),2.67-2.81(m,3H),2.41(s,3H),1.74-1.82(m,2H),1.23-1.37(m,2H);LC-MS:567.6[M+H+].
[实施例27]
(R)-4'-(4-氨基哌啶-1-基)-N-((6-氯-1H-吲哚-2-基)(5-氟-2-羟基苯基)甲基)-5-甲基-[1,1'-联苯]-3-甲酰胺
/>
(R)-4'-(4-氨基哌啶-1-基)-N-((6-氯-1H-吲哚-2-基)(5-氟-2-羟基苯基)甲基)-5-甲基-[1,1'-联苯]-3-甲酰胺[实施例27](45%)通过与[实施例1]中所述方法类似的方法制备。
1H NMR(400MHz,DMSO-d6)δ11.31(br s,1H),9.29(br d,J=8.63Hz,1H),7.96(s,1H),7.66(s,1H),7.59(br d,J=8.50Hz,3H),7.44(d,J=8.38Hz,1H),7.32-7.37(m,1H),7.22(br dd,J=3.13,9.76Hz,1H),6.92-7.07(m,5H),6.78-6.92(m,2H),6.01(s,1H),3.78-3.80(m,2H),2.78-2.81(m,2H),2.41(s,3H),1.85-1.91(m,2H),1.44-1.51(m,2H);LC-MS:584.0[M+H+].
[实施例28]
(R)-4'-(4-氨基哌啶-1-基)-N-((5-氟-2-羟基苯基)(1H-吲哚-2-基)甲基)-6-甲基-[1,1'-联苯]-3-甲酰胺
(R)-4'-(4-氨基哌啶-1-基)-N-((5-氟-2-羟基苯基)(1H-吲哚-2-基)甲基)-6-甲基-[1,1'-联苯]-3-甲酰胺[实施例28](3%)通过与[实施例1]中所述方法类似的方法制备。
1H NMR(400MHz,DMSO-d6)δ10.50-11.24(m,1H),8.93-9.33(m,1H),7.42(d,J=7.75Hz,1H),7.24-7.35(m,3H),7.19-7.24(m,1H),7.09-7.16(m,3H),7.00-7.06(m,1H),6.91-7.00(m,4H),6.78-6.86(m,1H),6.68-6.76(m,1H),5.96-6.14(m,1H),3.93-4.08(m,2H),3.40(s,1H),2.62-2.77(m,3H),2.15(s,3H),1.72-1.86(m,2H),1.25-1.43(m,2H);LC-MS:549.6[M+H+].
[实施例29]
(R)-4'-(4-氨基哌啶-1-基)-N-((5-氟-2-羟基苯基)(1H-吲哚-2-基)甲基)-4-甲基-[1,1'-联苯]-3-甲酰胺
(R)-4'-(4-氨基哌啶-1-基)-N-((5-氟-2-羟基苯基)(1H-吲哚-2-基)甲基)-4-甲基-[1,1'-联苯]-3-甲酰胺[实施例29](4%)通过与[实施例1]中所述方法类似的方法制备。
1H NMR(400MHz,DMSO-d6)δ10.77-11.21(m,1H),9.07-9.28(m,1H),7.61(d,J=1.88Hz,1H),7.51(d,J=8.75Hz,3H),7.39-7.45(m,1H),7.32-7.37(m,1H),7.27(s,1H),7.10-7.18(m,1H),7.04(s,1H),7.00(d,J=9.01Hz,2H),6.95(br d,J=8.00Hz,2H),6.79-6.88(m,1H),6.67-6.77(m,1H),6.03(s,1H),3.87-4.06(m,2H),3.38-3.41(m,1H),2.65-2.75(m,3H),2.30(s,3H),1.69-1.85(m,2H),1.22-1.39(m,2H);LC-MS:549.6[M+H+].
[实施例30]
(R)-4'-(4-氨基哌啶-1-基)-N-((5-氟-2-羟基苯基)(1H-吲哚-2-基)甲基)-2-甲基-[1,1'-联苯]-3-甲酰胺
(R)-4'-(4-氨基哌啶-1-基)-N-((5-氟-2-羟基苯基)(1H-吲哚-2-基)甲基)-2-甲基-[1,1'-联苯]-3-甲酰胺[实施例30](9%)通过与[实施例1]中所述方法类似的方法制备。
1H NMR(400MHz,DMSO-d6)δ10.83-11.27(m,1H),9.04-9.32(m,1H),7.76-7.83(m,2H),7.29-7.43(m,3H),7.23(d,J=8.63Hz,3H),7.01(s,5H),6.76-6.87(m,2H),5.97(s,1H),5.76(s,1H),3.68(br d,J=12.63Hz,2H),3.37-3.42(m,1H),2.64-2.81(m,3H),2.30(s,3H),1.73-1.81(m,2H),1.26-1.39(m,2H);LC-MS:549.6[M+H+].
[实施例31]
(S)-4'-(4-氨基哌啶-1-基)-N-((5-氟-2-羟基苯基)(1H-吲哚-2-基)甲基)-5-甲基-[1,1'-联苯]-3-甲酰胺
(S)-4'-(4-氨基哌啶-1-基)-N-((5-氟-2-羟基苯基)(1H-吲哚-2-基)甲基)-5-甲基-[1,1'-联苯]-3-甲酰胺[实施例31](53%)通过与[实施例1]中所述方法类似的方法制备。
1H NMR(400MHz,DMSO-d6)δ11.11(br s,1H),9.25(br d,J=8.51Hz,1H),7.97(s,1H),7.66(s,1H),7.54-7.62(m,3H),7.42(d,J=7.75Hz,1H),7.33(dd,J=0.81,8.07Hz,1H),7.21(dd,J=3.13,9.76Hz,1H),6.91-7.06(m,6H),6.79-6.87(m,2H),5.98(s,1H),3.65-3.74(m,2H),2.69-2.81(m,3H),2.41(s,3H),1.73-1.83(m,2H),1.25-1.37(m,2H);LC-MS:549.6[M+H+].
[实施例32]
4'-(4-氨基哌啶-1-基)-N-((5-氟-2-羟基苯基)(1H-吲哚-2-基)甲基)-5-甲基-[1,1'-联苯]-3-甲酰胺
4'-(4-氨基哌啶-1-基)-N-((5-氟-2-羟基苯基)(1H-吲哚-2-基)甲基)-5-甲基-[1,1'-联苯]-3-甲酰胺[实施例32](31%)通过与[实施例1]中所述方法类似的方法制备。
1H NMR(400MHz,DMSO-d6)δ11.12(br s,1H),9.26(br d,J=8.50Hz,1H),7.96(s,1H),7.65(s,1H),7.54-7.63(m,3H),7.42(d,J=7.88Hz,1H),7.32(d,J=8.76Hz,1H),7.21(dd,J=3.19,9.69Hz,1H),6.91-7.05(m,5H),6.79-6.87(m,2H),5.98(s,1H),3.69(br d,J=12.63Hz,2H),2.70-2.80(m,3H),2.41(s,3H),1.74-1.82(m,2H),1.24-1.37(m,2H);LC-MS:549.6[M+H+].
[实施例33]
(R)-3-(5-(4-氨基哌啶-1-基)-4-甲基吡啶-2-基)-N-((5-氟-2-羟基苯基)(1H-吲哚-2-基)甲基)-5-甲基苯甲酰胺;
(R)-3-(5-(4-氨基哌啶-1-基)-4-甲基吡啶-2-基)-N-((5-氟-2-羟基苯基)(1H-吲哚-2-基)甲基)-5-甲基苯甲酰胺[实施例33](23%)通过与[实施例1]中所述方法相似的方法制备。
1H NMR(400MHz,DMSO-d6)δ11.12(br s,1H),9.26(br d,J=8.38Hz,1H),8.35(s,1H),8.30(s,1H),8.00(s,1H),7.80(s,1H),7.77(s,1H),7.43(d,J=7.75Hz,1H),7.33(d,J=8.13Hz,1H),7.23(dd,J=3.13,9.76Hz,1H),7.01-7.08(m,1H),6.90-6.99(m,2H),6.80-6.88(m,2H),6.00(s,1H),3.14(br d,J=12.01Hz,2H),2.69-2.79(m,3H),2.44(s,3H),2.32(s,3H),1.83(br d,J=10.88Hz,2H),1.35-1.48(m,2H);LC-MS:564.6[M+H+].
[实施例34]
(R)-3-(2-(4-氨基哌啶-1-基)-4-甲基嘧啶-5-基)-N-((5-氟-2-羟基苯基)(1H-吲哚-2-基)甲基)-5-甲基苯甲酰胺
/>
(R)-3-(2-(4-氨基哌啶-1-基)-4-甲基嘧啶-5-基)-N-((5-氟-2-羟基苯基)(1H-吲哚-2-基)甲基)-5-甲基苯甲酰胺[实施例34](13%)通过与[实施例1]中所述方法类似的方法制备。
1H NMR(400MHz,DMSO-d6)δ10.91-11.23(m,1H),9.05-9.28(m,1H),8.20(s,1H),7.65-7.89(m,2H),7.39-7.45(m,1H),7.36(s,1H),7.31(br d,J=0.75Hz,1H),7.18(dd,J=3.13,9.76Hz,1H),7.03(br d,J=1.00Hz,1H),6.91-6.99(m,2H),6.85(br d,J=4.88Hz,1H),6.80(s,1H),5.95-6.04(m,1H),4.51-4.60(m,2H),2.96-3.03(m,2H),2.78-2.88(m,1H),2.37-2.43(m,3H),2.29(s,3H),1.70-1.80(m,2H),1.10-1.20(m,2H);LC-MS:565.6[M+H+].
[实施例35]
(R)-4-(2-(3-(((5-氟-2-羟基苯基)(1H-吲哚-2-基)甲基)氨基甲酰基)-5-甲基苯基)嘧啶-5-基)哌嗪-1-甲酸叔丁酯
(R)-4-(2-(3-(((5-氟-2-羟基苯基)(1H-吲哚-2-基)甲基)氨基甲酰基)-5-甲基苯基)嘧啶-5-基)哌嗪-1-甲酸叔丁酯[实施例35](82%)通过与[制备实施例9]中所述方法类似的方法制备。
1H NMR(400MHz,DMSO-d6)δ11.08-11.13(m,1H),9.65(s,1H),9.29(d,J=8.63Hz,1H),8.62(s,3H),8.25(s,1H),7.82(s,1H),7.43(d,J=8.00Hz,1H),7.33(d,J=7.67Hz,1H),7.25(dd,J=3.19,9.82Hz,1H),7.04(dt,J=1.13,7.57Hz,1H),6.92-7.01(m,2H),6.80-6.88(m,2H),6.00(t,J=1.00Hz,1H),3.46-3.53(m,4H),3.28-3.32(m,4H),2.44(s,3H),1.43(s,9H);LC-MS:637.7[M+H+].
[实施例36]
(R)-N-((5-氟-2-羟基苯基)(1H-吲哚-2-基)甲基)-3-甲基-5-(5-(哌嗪-1-基)嘧啶-2-基)苯甲酰胺
(R)-N-((5-氟-2-羟基苯基)(1H-吲哚-2-基)甲基)-3-甲基-5-(5-(哌嗪-1-基)嘧啶-2-基)苯甲酰胺[实施例36](11%)通过与[实施例1]中所述方法类似的方法制备。
1H NMR(400MHz,DMSO-d6)δ11.10(s,1H),9.65(br s,1H),9.28(d,J=8.63Hz,1H),8.55-8.63(m,3H),8.23-8.26(m,1H),7.80(s,1H),7.43(d,J=7.88Hz,1H),7.33(dd,J=0.75,8.13Hz,1H),7.25(dd,J=3.13,9.76Hz,1H),7.04(dt,J=1.19,7.60Hz,1H),6.91-7.01(m,2H),6.79-6.88(m,2H),6.00(t,J=1.00Hz,1H),3.19-3.25(m,4H),2.81-2.89(m,4H),2.43-2.46(m,3H);
LC-MS:537.7[M+H+].
[实施例37]
(R)-N-((5-氟-2-羟基苯基)(1H-吲哚-2-基)甲基)-3-甲基-5-(5-(4-甲基哌嗪-1-基)嘧啶-2-基)苯甲酰胺
(R)-N-((5-氟-2-羟基苯基)(1H-吲哚-2-基)甲基)-3-甲基-5-(5-(4-甲基哌嗪-1-基)嘧啶-2-基)苯甲酰胺[实施例37](54%)通过与[实施例1]中所述方法类似的方法制备。
1H NMR(400MHz,DMSO-d6)δ11.11(s,1H),9.67(s,1H),9.28(d,J=8.63Hz,1H),8.58-8.66(m,3H),8.22-8.26(m,1H),7.82(s,1H),7.43(d,J=7.88Hz,1H),7.31-7.36(m,1H),7.26(dd,J=3.13,9.76Hz,1H),7.02-7.08(m,1H),6.92-7.01(m,2H),6.80-6.89(m,2H),5.99-6.02(m,1H),4.02(br d,J=12.26Hz,2H),2.78-2.94(m,5H),2.44(s,3H),1.92(br s,2H),1.64(br d,J=10.13Hz,2H),1.05-1.16(m,6H);LC-MS:551.6[M+H+].
[实施例38]
N-[(R)-(5-氟-2-羟基-苯基)-(1H-吲哚-2-基)甲基]-3-甲基-5-[5-(4-丙基-1-哌啶基)嘧啶-2-基]苯甲酰胺
N-[(R)-(5-氟-2-羟基-苯基)-(1H-吲哚-2-基)甲基]-3-甲基-5-[5-(4-丙基-1-哌啶基)嘧啶-2-基]苯甲酰胺[实施例38](18%)通过与[制备实施例9]中所述方法类似的方法制备。
1H NMR(400MHz,DMSO-d6)δ11.07-11.15(m,1H),9.59-9.76(m,1H),9.22-9.31(m,1H),8.60(s,1H),8.58(s,2H),8.24(s,1H),7.96(s,1H),7.80(s,1H),7.43(d,J=7.75Hz,1H),7.32(s,1H),7.25(dd,J=3.13,9.76Hz,1H),6.91-7.07(m,4H),6.84-6.88(m,1H),6.83(s,1H),5.98-6.03(m,1H),2.75-2.83(m,4H),2.42-2.45(m,3H),1.72-1.80(m,2H),1.39-1.47(m,1H),1.33(br s,2H),1.23(br t,J=7.44Hz,4H),0.91-0.92(m,1H),0.89(t,J=7.13Hz,3H));LC-MS:557.7[M+H+].
[实施例39]
3-[5-[4-(二甲基氨基)-1-哌啶基]嘧啶-2-基]-N-[(R)-(5-氟-2-羟基-苯基)-(1H-吲哚-2-基)甲基]-5-甲基-苯甲酰胺
3-[5-[4-(二甲基氨基)-1-哌啶基]嘧啶-2-基]-N-[(R)-(5-氟-2-羟基-苯基)-(1H-吲哚-2-基)甲基]-5-甲基-苯甲酰胺[实施例39](7%)通过与[制备实施例9]中所述方法相似的方法制备。
1H NMR(400MHz,CHLOROFORM-d)δ9.38(br s,1H),8.61(br d,J=8.00Hz,1H),8.44(s,1H),8.12-8.19(m,3H),7.66(s,1H),7.52(d,J=7.75Hz,1H),7.26-7.31(m,2H),7.12(t,J=7.16Hz,1H),7.04-7.10(m,1H),6.97(dd,J=2.81,8.82Hz,1H),6.81-6.92(m,2H),6.70(br d,J=7.13Hz,1H),6.34(s,1H),3.62(br d,J=12.63Hz,1H),3.45-3.54(m,2H),2.60-2.74(m,2H),2.35(s,3H),2.33(s,6H),2.26(ddd,J=4.00,7.72,14.66Hz,1H),1.88(br d,J=12.13Hz,1H),1.78(br d,J=12.63Hz,1H),1.52-1.65(m,1H),1.39-1.50(m,1H),1.28(br s,1H);LC-MS:578.7[M+H+].
[实施例40]
N-[(R)-(5-氟-2-羟基-苯基)-(1H-吲哚-2-基)甲基]-3-甲基-5-[5-(1-哌啶基)嘧啶-2-基]苯甲酰胺
N-[(R)-(5-氟-2-羟基-苯基)-(1H-吲哚-2-基)甲基]-3-甲基-5-[5-(1-哌啶基)嘧啶-2-基]苯甲酰胺[实施例40](24%)通过与[制备实施例9]中所述方法类似的方法制备。
1H NMR(400MHz,DMSO-d6)δ11.10(s,1H),9.65(s,1H),9.28(d,J=8.63Hz,1H),8.56-8.63(m,3H),8.24(s,1H),7.80(s,1H),7.43(d,J=7.75Hz,1H),7.34(d,J=8.00Hz,1H),7.26(dd,J=2.94,9.69Hz,1H),7.01-7.08(m,1H),6.90-7.00(m,2H),6.80-6.89(m,2H),6.00(s,1H),2.44(s,3H),1.40-1.81(m,7H);LC-MS:536.61[M+H+].
[实施例41]
N-[(R)-(5-氟-2-羟基-苯基)-(1H-吲哚-2-基)甲基]-3-甲基-5-[5-[4-(1-甲基-4-哌啶基)哌嗪-1-基]嘧啶-2-基]苯甲酰胺
N-[(R)-(5-氟-2-羟基-苯基)-(1H-吲哚-2-基)甲基]-3-甲基-5-[5-[4-(1-甲基-4-哌啶基)哌嗪-1-基]嘧啶-2-基]苯甲酰胺[实施例41](10%)通过与[制备实施例9]中所述方法类似的方法制备。
1H NMR(400MHz,DMSO-d6)δ11.11(s,1H),9.68(br s,1H),9.28(d,J=8.51Hz,1H),8.56-8.64(m,3H),8.24(s,1H),7.81(s,1H),7.43(d,J=7.75Hz,1H),7.33(d,J=8.13Hz,1H),7.25(dd,J=3.13,9.76Hz,1H),7.01-7.07(m,1H),6.91-7.00(m,2H),6.79-6.88(m,2H),6.00(s,1H),3.29(br s,2H),3.08(s,2H),2.79(br d,J=11.51Hz,2H),2.67(br dd,J=1.88,3.63Hz,1H),2.62-2.66(m,3H),2.44(s,3H),2.17-2.23(m,1H),2.14(s,3H),1.80-1.90(m,2H),1.74(br d,J=11.51Hz,2H),1.37-1.50(m,2H);LC-MS:634.76[M+H+].
[实施例42]
(R)-3-(5-((4-(二甲基氨基)哌啶-1-基)甲基)吡啶-2-基)-N-((5-氟-2-羟基苯基)(1H-吲哚-2-基))甲基)-5-甲基苯甲酰胺
(R)-3-(5-((4-(二甲基氨基)哌啶-1-基)甲基)吡啶-2-基)-N-((5-氟-2-羟基苯基)(1H-吲哚-2-基))甲基)-5-甲基苯甲酰胺[实施例42](84%)通过与[制备实施例9]中所述方法类似的方法制备。
1H NMR(400MHz,DMSO-d6)δ11.12(s,1H),9.66(br s,1H),9.29(d,J=8.51Hz,1H),8.54-8.60(m,1H),8.42(s,1H),8.07(s,1H),7.94-8.05(m,1H),7.78-7.86(m,2H),7.43(d,J=7.75Hz,1H),7.33(d,J=8.00Hz,1H),7.23(dd,J=3.13,9.63Hz,1H),7.01-7.08(m,1H),6.91-7.01(m,2H),6.81-6.91(m,2H),6.00(s,1H),3.47-3.54(m,2H),2.83(brd,J=11.38Hz,2H),2.43-2.48(m,3H),2.16(s,6H),2.00-2.10(m,1H),1.96(br t,J=10.82Hz,2H),1.71(br d,J=12.01Hz,2H),1.30-1.47(m,2H);LC-MS:592.7[M+H+].
[实施例43]
(R)-3-(6-((4-(二甲基氨基)哌啶-1-基)甲基)吡啶-3-基)-N-((5-氟-2-羟基苯基)(1H-吲哚-2-基))甲基)-5-甲基苯甲酰胺
(R)-3-(6-((4-(二甲基氨基)哌啶-1-基)甲基)吡啶-3-基)-N-((5-氟-2-羟基苯基)(1H-吲哚-2-基))甲基)-5-甲基苯甲酰胺[实施例43](90%)通过与[制备实施例9]中所述方法类似的方法制备。
1H NMR(400MHz,DMSO-d6)δ11.12(s,1H),9.66(br s,1H),9.29(d,J=8.51Hz,1H),8.54-8.60(m,1H),8.42(s,1H),8.07(s,1H),7.94-8.05(m,1H),7.78-7.86(m,2H),7.43(d,J=7.75Hz,1H),7.33(d,J=8.00Hz,1H),7.23(dd,J=3.13,9.63Hz,1H),7.01-7.08(m,1H),6.91-7.01(m,2H),6.81-6.91(m,2H),6.00(s,1H),3.47-3.54(m,2H),2.83(brd,J=11.38Hz,2H),2.43-2.48(m,3H),2.16(s,6H),2.00-2.10(m,1H),1.96(br t,J=10.82Hz,2H),1.71(br d,J=12.01Hz,2H),1.30-1.47(m,2H);LC-MS:592.7[M+H+].
[实施例44]
3-[5-[(3R)-3-氨基吡咯烷-1-基]嘧啶-2-基]-N-[(R)-(5-氟-2-羟基-苯基)-(1H-吲哚-2-基)甲基]-5-甲基-苯甲酰胺
3-[5-[(3R)-3-氨基吡咯烷-1-基]嘧啶-2-基]-N-[(R)-(5-氟-2-羟基-苯基)-(1H-吲哚-2-基)甲基]-5-甲基-苯甲酰胺[实施例44](86%)通过与[实施例1]中所述方法类似的方法制备。
1H NMR(400MHz,DMSO-d6)δ11.14(br s,1H),9.31(br d,J=8.13Hz,1H),8.58(s,1H),8.17-8.24(m,3H),7.76(s,1H),7.43(d,J=7.75Hz,1H),7.34(d,J=8.00Hz,1H),7.25(dd,J=2.69,9.69Hz,1H),7.01-7.08(m,1H),6.91-7.00(m,2H),6.78-6.87(m,2H),6.02(s,1H),3.58-3.64(m,1H),3.45-3.53(m,3H),3.00(br dd,J=4.25,9.63Hz,1H),2.43(s,3H),2.03-2.13(m,1H),1.74(qd,J=6.05,12.12Hz,1H);LC-MS:537.6[M+H+].
[实施例45]
(R)-3-(5-(4-(二乙基氨基)哌啶-1-基)嘧啶-2-基)-N-((5-氟-2-羟基苯基)(1H-吲哚-2-基)甲基)-5-甲基苯甲酰胺
(R)-3-(5-(4-(二乙基氨基)哌啶-1-基)嘧啶-2-基)-N-((5-氟-2-羟基苯基)(1H-吲哚-2-基)甲基)-5-甲基苯甲酰胺[实施例45](96%)通过与[制备实施例9]中所述的方法类似的方法制备。
1H NMR(400MHz,DMSO-d6)δ11.11(s,1H),9.67(s,1H),9.28(d,J=8.63Hz,1H),8.58-8.66(m,3H),8.22-8.26(m,1H),7.82(s,1H),7.43(d,J=7.88Hz,1H),7.31-7.36(m,1H),7.26(dd,J=3.13,9.76Hz,1H),7.02-7.08(m,1H),6.92-7.01(m,2H),6.80-6.89(m,2H),5.99-6.02(m,1H),4.02(br d,J=12.26Hz,2H),2.78-2.94(m,5H),2.44(s,3H),1.92(br s,2H),1.64(br d,J=10.13Hz,2H),1.05-1.16(m,6H);LC-MS:607.7[M+H+].
[实施例46]
N-((R)-(5-氟-2-羟基苯基)(1H-吲哚-2-基)甲基)-3-甲基-5-(5-(3-甲基-3,8-二氮杂双环[3.2.1]辛烷-8-基)嘧啶-2-基)苯甲酰胺
N-((R)-(5-氟-2-羟基苯基)(1H-吲哚-2-基)甲基)-3-甲基-5-(5-(3-甲基-3,8-二氮杂双环[3.2.1]辛烷-8-基)嘧啶-2-基)苯甲酰胺[实施例46](91%)通过与[制备实施例9]中所述的方法类似的方法制备。
1H NMR(400MHz,DMSO-d6)δ11.10(s,1H),9.65(s,1H),9.26(d,J=8.63Hz,1H),8.66-8.67(m,1H),8.65-8.66(m,1H),8.58(s,1H),8.44-8.45(m,1H),8.42-8.43(m,1H),8.38(s,2H),8.19-8.24(m,1H),7.78(s,1H),7.41-7.45(m,1H),7.33(dd,J=0.75,8.00Hz,1H),7.26(dd,J=3.19,9.82Hz,1H),7.04(dt,J=1.13,7.57Hz,1H),6.92-7.01(m,2H),6.79-6.88(m,2H),5.99-6.02(m,1H),3.35-3.43(m,3H),3.07(br s,2H),2.53(br s,6H),2.44(s,3H),2.09(br s,1H),1.90(br d,J=11.63Hz,1H),1.75-1.86(m,1H),1.72(br d,J=11.51Hz,1H);
LC-MS:577.6[M+H+].
[实施例47]
(R)-3-(5-(4-(1H-吡咯-1-基)哌啶-1-基)嘧啶-2-基)-N-((5-氟-2-羟基苯基)(1H-吲哚-2-基)甲基)-5-甲基苯甲酰胺
(R)-3-(5-(4-(1H-吡咯-1-基)哌啶-1-基)嘧啶-2-基)-N-((5-氟-2-羟基苯基)(1H-吲哚-2-基)甲基)-5-甲基苯甲酰胺[实施例47](86%)通过与[制备实施例9]中所述方法类似的方法制备。
1H NMR(400MHz,DMSO-d6)δ11.10(s,1H),9.65(s,1H),9.26(d,J=8.63Hz,1H),8.66-8.67(m,1H),8.65-8.66(m,1H),8.58(s,1H),8.44-8.45(m,1H),8.42-8.43(m,1H),8.38(s,2H),8.19-8.24(m,1H),7.78(s,1H),7.41-7.45(m,1H),7.33(dd,J=0.75,8.00Hz,1H),7.26(dd,J=3.19,9.82Hz,1H),7.04(dt,J=1.13,7.57Hz,1H),6.92-7.01(m,2H),6.79-6.88(m,2H),5.99-6.02(m,1H),3.35-3.43(m,3H),3.07(br s,2H),2.53(br s,6H),2.44(s,3H),2.09(br s,1H),1.90(br d,J=11.63Hz,1H),1.75-1.86(m,1H),1.72(br d,J=11.51Hz,1H);
LC-MS:601.6[M+H+].
[实施例48]
(R)-3-(5-(4-(1H-1,2,4-三唑-1-基)哌啶-1-基)嘧啶-2-基)-N-((5-氟-2-羟基苯基)(1H-吲哚-2-基)甲基)-5-甲基苯甲酰胺
(R)-3-(5-(4-(1H-1,2,4-三唑-1-基)哌啶-1-基)嘧啶-2-基)-N-((5-氟-2-羟基苯基)(1H-吲哚-2-基)甲基)-5-甲基苯甲酰胺[实施例48](78%)通过与[制备实施例9]中所述的方法类似的方法制备。
1H NMR(400MHz,DMSO-d6)δ11.10(s,1H),9.65(s,1H),9.26(d,J=8.63Hz,1H),8.66-8.67(m,1H),8.65-8.66(m,1H),8.58(s,1H),8.44-8.45(m,1H),8.42-8.43(m,1H),8.38(s,2H),8.19-8.24(m,1H),7.78(s,1H),7.41-7.45(m,1H),7.33(dd,J=0.75,8.00Hz,1H),7.26(dd,J=3.19,9.82Hz,1H),7.04(dt,J=1.13,7.57Hz,1H),6.92-7.01(m,2H),6.79-6.88(m,2H),5.99-6.02(m,1H),3.35-3.43(m,3H),3.07(br s,2H),2.53(br s,6H),2.44(s,3H),2.09(br s,1H),1.90(br d,J=11.63Hz,1H),1.75-1.86(m,1H),1.72(br d,J=11.51Hz,1H);
LC-MS:603.6[M+H+].
[实施例49]
(R)-N-((5-氟-2-羟基苯基)(1H-吲哚-2-基)甲基)-3-(5-(4-羟基哌啶-1-基)嘧啶-2-基)-5-甲基苯甲酰胺
(R)-N-((5-氟-2-羟基苯基)(1H-吲哚-2-基)甲基)-3-(5-(4-羟基哌啶-1-基)嘧啶-2-基)-5-甲基苯甲酰胺[实施例49](15%)通过与[制备实施例9]中所述方法相似的方法制备。
1H NMR(400MHz,DMSO-d6)δ11.10(s,1H),9.65(s,1H),9.26(d,J=8.63Hz,1H),8.66-8.67(m,1H),8.65-8.66(m,1H),8.58(s,1H),8.44-8.45(m,1H),8.42-8.43(m,1H),8.38(s,2H),8.19-8.24(m,1H),7.78(s,1H),7.41-7.45(m,1H),7.33(dd,J=0.75,8.00Hz,1H),7.26(dd,J=3.19,9.82Hz,1H),7.04(dt,J=1.13,7.57Hz,1H),6.92-7.01(m,2H),6.79-6.88(m,2H),5.99-6.02(m,1H),3.35-3.43(m,3H),3.07(br s,2H),2.53(br s,6H),2.44(s,3H),2.09(br s,1H),1.90(br d,J=11.63Hz,1H),1.75-1.86(m,1H),1.72(br d,J=11.51Hz,1H);
LC-MS:552.6[M+H+].
[实施例50]
(R)-3-(5-([1,4'-联哌啶]-1'-基)嘧啶-2-基)-N-((5-氟-2-羟基苯基)(1H-吲哚-2-基)甲基)-5-甲基苯甲酰胺
(R)-3-(5-([1,4'-联哌啶]-1'-基)嘧啶-2-基)-N-((5-氟-2-羟基苯基)(1H-吲哚-2-基)甲基)-5-甲基苯甲酰胺[实施例50](26%)通过与[制备实施例9]中所述方法相似的方法制备。
1H NMR(400MHz,DMSO-d6)δ11.11(br s,1H),9.66(br s,1H),9.29(br d,J=8.38Hz,1H),8.56-8.63(m,3H),8.23-8.25(m,1H),7.80(s,1H),7.43(d,J=7.75Hz,1H),7.33(dd,J=0.69,8.07Hz,1H),7.25(dd,J=3.19,9.82Hz,1H),7.04(dt,J=1.13,7.57Hz,1H),6.92-7.01(m,2H),6.79-6.87(m,2H),6.00(s,1H),3.94(br d,J=12.76Hz,2H),2.74-2.85(m,2H),2.47(br d,J=2.75Hz,4H),2.44(s,3H),2.37-2.42(m,1H),1.82(br d,J=11.38Hz,2H),1.51-1.60(m,2H),1.48(br d,J=4.88Hz,4H),1.38(br d,J=5.13Hz,2H);LC-MS:619.7[M+H+].
[实施例51]
(R)-N-((5-氟-2-羟基苯基)(1H-吲哚-2-基)甲基)-3-甲基-5-(5-(4-(吗啉代甲基)哌啶-1-基)嘧啶-2-基)苯甲酰胺
(R)-N-((5-氟-2-羟基苯基)(1H-吲哚-2-基)甲基)-3-甲基-5-(5-(4-(吗啉代甲基)哌啶-1-基)嘧啶-2-基)苯甲酰胺[实施例51](100%)通过与[制备实施例9]中所述的方法类似的方法制备。
1H NMR(400MHz,DMSO-d6)δ11.11(br s,1H),9.66(br s,1H),9.29(br d,J=8.38Hz,1H),8.56-8.63(m,3H),8.23-8.25(m,1H),7.80(s,1H),7.43(d,J=7.75Hz,1H),7.33(dd,J=0.69,8.07Hz,1H),7.25(dd,J=3.19,9.82Hz,1H),7.04(dt,J=1.13,7.57Hz,1H),6.92-7.01(m,2H),6.79-6.87(m,2H),6.00(s,1H),3.94(br d,J=12.76Hz,2H),2.74-2.85(m,2H),2.47(br d,J=2.75Hz,4H),2.44(s,3H),2.37-2.42(m,1H),1.82(br d,J=11.38Hz,2H),1.51-1.60(m,2H),1.48(br d,J=4.88Hz,4H),1.38(br d,J=5.13Hz,2H);LC-MS:635.7[M+H+].
[实施例52]
(R)-N-((5-氟-2-羟基苯基)(1H-吲哚-2-基)甲基)-3-甲基-5-(5-(4-(吡咯烷-1-基甲基)哌啶-1-基)嘧啶-2-基)苯甲酰胺
(R)-N-((5-氟-2-羟基苯基)(1H-吲哚-2-基)甲基)-3-甲基-5-(5-(4-(吡咯烷-1-基甲基)哌啶-1-基)嘧啶-2-基)苯甲酰胺[实施例52](11%)通过与[制备实施例9]中所述方法类似的方法制备。
1H NMR(400MHz,DMSO-d6)δ11.11(br s,1H),9.66(br s,1H),9.29(br d,J=8.38Hz,1H),8.56-8.63(m,3H),8.23-8.25(m,1H),7.80(s,1H),7.43(d,J=7.75Hz,1H),7.33(dd,J=0.69,8.07Hz,1H),7.25(dd,J=3.19,9.82Hz,1H),7.04(dt,J=1.13,7.57Hz,1H),6.92-7.01(m,2H),6.79-6.87(m,2H),6.00(s,1H),3.94(br d,J=12.76Hz,2H),2.74-2.85(m,2H),2.47(br d,J=2.75Hz,4H),2.44(s,3H),2.37-2.42(m,1H),1.82(br d,J=11.38Hz,2H),1.51-1.60(m,2H),1.48(br d,J=4.88Hz,4H),1.38(br d,J=5.13Hz,2H);LC-MS:619.7[M+H+].
[实施例53]
3-[5-[(3R)-3-(二甲基氨基)吡咯烷-1-基]嘧啶-2-基]-N-[(R)-(5-氟-2-羟基-苯基)-(1H-吲哚-2-基)甲基]-5-甲基-苯甲酰胺
3-[5-[(3R)-3-(二甲基氨基)吡咯烷-1-基]嘧啶-2-基]-N-[(R)-(5-氟-2-羟基-苯基)-(1H-吲哚-2-基)甲基]-5-甲基-苯甲酰胺[实施例53](33%)按照与[制备实施例9]所述方法类似的方法制备。
1H NMR(400MHz,DMSO-d6)δ11.11(s,1H),9.67(br d,J=0.75Hz,1H),9.28(d,J=8.63Hz,1H),8.58(s,1H),8.21-8.26(m,3H),7.76(d,J=0.63Hz,1H),7.43(d,J=7.88Hz,1H),7.34(dd,J=0.75,8.13Hz,1H),7.26(dd,J=3.19,9.82Hz,1H),7.04(ddd,J=1.19,7.00,8.07Hz,1H),6.89-6.99(m,2H),6.78-6.89(m,2H),6.01(s,1H),3.58(dd,J=7.19,9.57Hz,1H),3.48-3.55(m,1H),3.34-3.39(m,1H),3.10-3.17(m,1H),3.08(s,1H),2.78-2.88(m,1H),2.44(s,3H),2.22(s,6H),2.14-2.20(m,1H),1.83(qd,J=9.32,12.07Hz,1H);LC-MS:565.65[M+H+].
[实施例54]
(R)-N-((5-氟-2-羟基苯基)(1H-吲哚-2-基)甲基)-3-甲基-5-(5-(4-(甲基氨基)哌啶-1-基)嘧啶-2-基)苯甲酰胺
(R)-N-((5-氟-2-羟基苯基)(1H-吲哚-2-基)甲基)-3-甲基-5-(5-(4-(甲基氨基)哌啶-1-基)嘧啶-2-基)苯甲酰胺[实施例54](10%)通过与[实施例1]中所述的方法类似的方法制备。
1H NMR(400MHz,DMSO-d6)δ11.10(s,1H),9.61-9.73(m,1H),9.21-9.39(m,1H),8.64(s,3H),8.23-8.26(m,1H),7.83(s,1H),7.41-7.45(m,1H),7.31-7.35(m,1H),7.22-7.28(m,1H),7.02-7.07(m,1H),6.92-7.00(m,2H),6.80-6.88(m,2H),5.98-6.03(m,1H),4.01(br d,J=12.88Hz,1H),3.98-4.05(m,1H),3.17(d,J=5.25Hz,1H),2.90(br s,2H),2.58-2.59(m,2H),2.45(s,4H),2.32-2.35(m,2H),2.03-2.10(m,3H),1.53-1.62(m,2H);LC-MS:565.6[M+H+].
[实施例55]
(R)-1-(2-(3-(((5-氟-2-羟基苯基)(1H-吲哚-2-基)甲基)氨基甲酰基)-5-甲基苯基)嘧啶-5-基)-N-苯基哌啶-4-甲酰胺
(R)-1-(2-(3-(((5-氟-2-羟基苯基)(1H-吲哚-2-基)甲基)氨基甲酰基)-5-甲基苯基)嘧啶-5-基)-N-苯基哌啶-4-甲酰胺[实施例55](10%)通过与[制备实施例9]中所述的方法相似的方法制备。
1H NMR(400MHz,DMSO-d6)δ11.11(d,J=1.63Hz,1H),9.95(s,1H),9.67(s,1H),9.29(d,J=8.63Hz,1H),8.58-8.66(m,3H),8.26(d,J=0.63Hz,1H),7.96(s,1H),7.81(s,1H),7.58-7.65(m,2H),7.43(d,J=7.88Hz,1H),7.23-7.37(m,4H),6.91-7.08(m,4H),6.77-6.89(m,2H),5.96-6.04(m,1H),3.96-4.04(m,2H),3.18(d,J=5.00Hz,1H),2.89(s,2H),2.45(s,3H),1.92(br s,2H),
1.71-1.83(m,2H);LC-MS:656.7[M+H+].
[实施例56]
(R)-N-((5-氟-2-羟基苯基)(1H-吲哚-2-基)甲基)-3-(5-(4-(4-(2-甲氧基乙氧基)苯基)哌嗪-1-基)嘧啶-2-基)-5-甲基苯甲酰胺
(R)-N-((5-氟-2-羟基苯基)(1H-吲哚-2-基)甲基)-3-(5-(4-(4-(2-甲氧基乙氧基)苯基)哌嗪-1-基)嘧啶-2-基)-5-甲基苯甲酰胺[实施例56](10%)通过与[制备实施例9]中所述的方法类似的方法制备。
1H NMR(400MHz,DMSO-d6)δ11.11(d,J=1.63Hz,1H),9.67(s,1H),9.30(d,J=8.50Hz,1H),8.62-8.68(m,3H),8.27(d,J=0.63Hz,1H),7.83(s,1H),7.44(d,J=7.88Hz,1H),7.34(dd,J=0.81,8.07Hz,1H),7.27(dd,J=3.19,9.82Hz,1H),7.04(ddd,J=1.19,7.10,8.10Hz,1H),6.95-6.99(m,3H),6.94-6.95(m,1H),6.81-6.89(m,4H),5.99-6.03(m,1H),4.00-4.07(m,1H),4.03(q,J=7.05Hz,5H),3.60-3.66(m,2H),3.45-3.51(m,4H),3.30(s,3H),3.19(br d,J=4.88Hz,4H),2.87-2.91(m,1H),2.45(s,3H),1.99(s,6H),1.18(t,J=7.13Hz,6H);
LC-MS:687.7[M+H+].
[实施例57]
(R)-N-((5-氟-2-羟基苯基)(1H-吲哚-2-基)甲基)-3-甲基-5-(5-(1,2,3,6-四氢吡啶-4-基)嘧啶-2-基)苯甲酰胺
(R)-N-((5-氟-2-羟基苯基)(1H-吲哚-2-基)甲基)-3-甲基-5-(5-(1,2,3,6-四氢吡啶-4-基)嘧啶-2-基)苯甲酰胺[实施例57](81%)通过与[实施例1]中所述的方法类似的方法制备。
1H NMR(400MHz,DMSO-d6)δ11.13(s,1H),9.35(d,J=8.51Hz,1H),8.94-9.07(m,2H),8.74(s,1H),8.37(s,1H),7.92(s,1H),7.43(d,J=7.88Hz,1H),7.34(d,J=8.00Hz,1H),7.25(dd,J=3.13,9.76Hz,1H),6.92-7.07(m,3H),6.80-6.88(m,2H),6.53(br s,1H),6.01(s,1H),3.40-3.44(m,2H),2.95(t,J=5.50Hz,2H),2.46-2.48(m,3H),2.38-2.44(m,2H);LC-MS:534.6[M+H+].
[实施例58]
(R)-N-((5-氟-2-羟基苯基)(1H-吲哚-2-基)甲基)-3-甲基-5-(5-(哌啶-4-基)嘧啶-2-基)苯甲酰胺
将(R)-N-((5-氟-2-羟基苯基)(1H-吲哚-2-基)甲基)-3-甲基-5-(5-(1,2,3,6-四氢吡啶-4-基)嘧啶-2-基)苯甲酰胺[实施例57](150mg,0.28mmol)和10%钯/碳(15mg,0.14mmol)在甲醇和二氯甲烷(1:1)中在氢气下于室温搅拌24小时。将反应溶液用硅藻土过滤,然后浓缩滤液。残余物通过MPLC纯化,得到(R)-N-((5-氟-2-羟基苯基)(1H-吲哚-2-基)甲基)-3-甲基-5-(5-(哌啶-4-基)嘧啶-2-基)苯甲酰胺[实施例58](70mg,46%),为白色固体。
1H NMR(400MHz,DMSO-d6)δ11.13(s,1H),9.35(d,J=8.51Hz,1H),8.94-9.07(m,2H),8.74(s,1H),8.37(s,1H),7.92(s,1H),7.43(d,J=7.88Hz,1H),7.34(d,J=8.00Hz,1H),7.25(dd,J=3.13,9.76Hz,1H),6.92-7.07(m,3H),6.80-6.88(m,2H),6.53(br s,1H),6.01(s,1H),3.40-3.44(m,2H),2.95(t,J=5.50Hz,2H),2.46-2.48(m,3H),2.38-2.44(m,2H);LC-MS:536.6[M+H+].
[实施例59]
3-[5-(3-氨基氮杂环丁烷-1-基)嘧啶-2-基]-N-[(R)-(5-氟-2-羟基-苯基)-(1H-吲哚-2-基)甲基]-5-甲基-苯甲酰胺
3-[5-(3-氨基氮杂环丁烷-1-基)嘧啶-2-基]-N-[(R)-(5-氟-2-羟基-苯基)-(1H-吲哚-2-基)甲基]-5-甲基-苯甲酰胺[实施例59](54%)通过与[实施例1]中所述的方法类似的方法制备。
1H NMR(400MHz,DMSO-d6)δ11.10(s,1H),8.58(s,1H),8.17-8.25(m,1H),8.13(s,2H),7.79(s,1H),7.43(d,J=7.88Hz,1H),7.33(dd,J=0.75,8.13Hz,1H),7.25(dd,J=3.13,9.76Hz,1H),6.91-7.07(m,3H),6.79-6.88(m,2H),5.99-6.02(m,1H),4.20(t,J=7.44Hz,2H),3.89(quin,J=6.50Hz,1H),3.54-3.61(m,2H),2.43(s,3H));LC-MS:523.58[M+H+].
[实施例60]
3-[5-[(3S)-3-(二甲基氨基)吡咯烷-1-基]嘧啶-2-基]-N-[(R)-(5-氟-2-羟基-苯基)-(1H-吲哚-2-基)甲基]-5-甲基-苯甲酰胺
3-[5-[(3S)-3-(二甲基氨基)吡咯烷-1-基]嘧啶-2-基]-N-[(R)-(5-氟-2-羟基-苯基)-(1H-吲哚-2-基)甲基]-5-甲基-苯甲酰胺[实施例60](28%)通常与[制备实施例9]所述方法类似的方法制备。
1H NMR(400MHz,DMSO-d6)δ11.13(br s,1H),9.31(br d,J=8.76Hz,1H),8.58(s,1H),8.17-8.29(m,3H),7.76(s,1H),7.43(d,J=7.75Hz,1H),7.33(dd,J=0.81,8.07Hz,1H),7.25(dd,J=3.25,9.76Hz,1H),7.04(ddd,J=1.13,7.04,8.10Hz,1H),6.91-7.00(m,2H),6.78-6.87(m,2H),6.01(s,1H),3.50-3.62(m,2H),3.10-3.17(m,1H),3.08(s,3H),2.43(s,3H),2.22(s,6H),2.14-2.20(m,1H),1.78-1.89(m,1H);LC-MS:565.65[M+H+].
[实施例61]
3-[5-[(3S)-3-氨基吡咯烷-1-基]嘧啶-2-基]-N-[(R)-(5-氟-2-羟基-苯基)-(1H-吲哚-2-基)甲基]-5-甲基-苯甲酰胺
3-[5-[(3S)-3-氨基吡咯烷-1-基]嘧啶-2-基]-N-[(R)-(5-氟-2-羟基-苯基)-(1H-吲哚-2-基)甲基]-5-甲基-苯甲酰胺[实施例61](21%)通过与[实施例1]中所述的方法类似的方法制备。
1H NMR(400MHz,DMSO-d6)δ11.10(d,J=1.25Hz,1H),9.26(d,J=8.63Hz,1H),8.58(s,1H),8.17-8.26(m,3H),7.76(s,1H),7.43(d,J=7.75Hz,1H),7.30-7.38(m,1H),7.26(dd,J=3.13,9.76Hz,1H),7.04(dt,J=1.13,7.57Hz,1H),6.91-7.01(m,2H),6.79-6.88(m,2H),6.01(s,1H),3.66(br d,J=5.25Hz,1H),3.47-3.56(m,3H),3.07(br dd,J=4.25,9.88Hz,1H),2.53(br s,1H),2.44(s,3H),2.08-2.15(m,1H),1.75-1.84(m,1H);LC-MS:537.61[M+H+].
[实施例62]
(R)-3-(5-(氮杂环丁烷-3-基)嘧啶-2-基)-N-((5-氟-2-羟基苯基)(1H-吲哚-2-基)甲基)-5-甲基苯甲酰胺
(R)-3-(5-(氮杂环丁烷-3-基)嘧啶-2-基)-N-((5-氟-2-羟基苯基)(1H-吲哚-2-基)甲基)-5-甲基苯甲酰胺[实施例62](5%)通过与[实施例1]中所述的方法类似的方法制备。
1H NMR(400MHz,Methanol-d4)δ10.53(br s,1H),9.18(d,J=8.4Hz,1H),8.94(s,1H),8.76(s,1H),8.46(s,1H),7.89(s,1H),7.46(d,J=8.0Hz,1H),7.35(d,J=7.2Hz,1H),7.09-7.06(m,1H),7.00-6.85(m,4H),6.21(s,1H),4.47-4.38(m,5H),2.53(s,3H);LC-MS:508.35[M+H+]
实施例1-62中制备的化合物的结构总结并示于下表1中。
[表1]
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<实验例1>评价过表达野生型(WT)和EGFR突变体的BaF3细胞中细胞生长抑制能力
为了证实本发明一方面提供的式1化合物作为WT和EGFR突变体的变构抑制剂,在过表达WT和EGFR突变体的BaF3细胞中评价了细胞生长抑制作用。
更具体地,使用Promega的CellTiter 96水相非放射性细胞增殖分析系统(CellTiter 96AQueous Non-Radioactive Cell Proliferation Assay system)如下评价本发明化合物对过度表达WT和EGFR突变体的Ba/F3细胞系的细胞生长抑制能力。水相非放射性细胞增殖分析系统是一种通过测定显色程度来确定细胞生长抑制能力的方法,所述显色是通过细胞培养状态下活细胞中存在的线粒体分泌的还原酶将MTS(3-(4,5-二甲基噻唑-2-基)-5-(3-羧甲氧基苯基)-2-(4-磺苯基)-2H-四唑)还原成甲(Formazan)来实现的。本发明中使用的Ba/F3 EGFR WT和Ba/F3 EGFR del19/T790M/C797S(DTC)、Ba/F3 EGFRL858R(L)、Ba/F3 EGFR L858R/T790M(LT)和Ba/F3 EGFR L858R/T790M/C797S(LTC)突变细胞系购自Yonsei大学的Byung-Cheol Cho教授的实验室。所有细胞系均在37℃下,在5%CO2培养箱中,在添加10% FBS、1%青霉素-链霉素和1μg/ml嘌呤霉素的RPMI中培养。
通过以下分析方法分析根据每个EGFR突变的化合物的细胞存活抑制作用。
将BaF3细胞以2000~10000个细胞/100μL/孔的密度分配在96孔细胞培养板中,培养24小时。此后,将本发明一方面提供的式1表示的化合物的浓度制备为0.1nM、1nM、10nM、100nM、1000nM和10000nM的终浓度的两倍,并将该化合物处理至平板上(100μL/孔)。将平板在37℃的培养箱中反应72小时。然后,将MTS处理到平板上(20μL/孔),并将平板在37℃孵育2-4小时。最后,用酶标仪测定490nM处的吸光度后,获得与0nM相比的相对值(%对照),以证实该化合物的细胞生长抑制能力。使用Prism程序(版本8.0,Graphpad软件公司)分析测量值,并计算作为化合物的细胞生长抑制能力的指标的IC50值(抑制浓度50)。
结果示于下表2中。
[表2]
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如表2所示,发现本发明的化合物针对EGFR L858R/T790M和L858R/T790M/C797S突变表现出优异活性。
如上所述,通过优选的制备实施例、实施例和实验例详细描述了本发明,但是本发明的范围不限于具体的实施例,并且应该由所附的权利要求解释。此外,本领域的普通技术人员应当理解,在不背离本发明的范围的情况下,许多修改和变化是可能的。
Claims (15)
1.一种由下式1表示的化合物、其光学异构体、其溶剂化物、其水合物或其药学上可接受的盐:
[式1]
(在式1中,
X、Y和Z独立地为碳或氮原子;
R1为-H、-OH、卤素、未取代的或被一个或多个卤素取代的C1-10烷基、未取代的或被一个或多个卤素取代的C1-10烷氧基、硝基、C1-10烷基硫烷基、氰基、氨基、C1-10烷基氨基或5-6元杂芳基;
R2为取代的C6-10芳基或取代的5-10元杂芳基,
其中所述取代的C6-10芳基或取代的5-10元杂芳基独立地为被一个或多个选自以下的取代基取代的芳基或杂芳基:卤素、未取代的或取代的C1-10烷基和未取代的或取代的4-10元完全或部分饱和的杂环烷基,
其中所述取代的C1-10烷基被5-6元杂环烷基取代,其中1或2个C1-5烷基被取代氨基取代,
所述取代的4-10元完全或部分饱和的杂环烷基是被一个或多个选自以下的取代基取代的4-10元杂环烷基:-OH、卤素、未取代的或被一个或多个卤素取代的C1-5烷基、被5-6元杂环烷基取代的C1-5烷基、未取代的或被一个或多个卤素取代的C1-5烷氧基、硝基、C1-5烷基硫烷基、氰基、未取代的或被1或2个C1-5烷基取代的氨基、未取代的或被C1-5烷基取代的5-6元杂环烷基、C1-5烷氧基羰基、5-6元杂芳基、C6-10芳基氨基羰基和C1-5烷氧基-C1-5烷氧基-C6-10芳基;
R3为卤素;
R4为-OH、卤素或C1-15烷氧基;
R5为-H、-OH、卤素、C1-4烷基或C1-4烷氧基;以及
R6为-H、-OH、卤素、C1-4烷基或C1-4烷氧基)。
2.根据权利要求1所述的化合物、其光学异构体、其溶剂化物、其水合物或其药学上可接受的盐,其中:
X、Y和Z独立地为碳或氮原子;
R1为-H、-OH、卤素、未取代的或被一个或多个卤素取代的C1-5烷基、未取代的或被一个或多个卤素取代的C1-5烷氧基、硝基、C1-5烷基硫烷基、氰基、氨基、C1-5烷基氨基或5-6元杂芳基;
R2为取代的C6-10芳基或取代的5-6元杂芳基,
其中所述取代的C6-10芳基或取代的5-6元杂芳基独立地为被一个或多个选自以下的取代基取代的芳基或杂芳基:卤素、未取代或取代的C1-5烷基和未取代或取代的含有至少一个N的4-8元完全或部分饱和的杂环烷基,
其中所述取代的C1-5烷基被6元杂环烷基取代,其中2个C1-5烷基被取代氨基取代,
所述取代的4-8元完全或部分饱和的杂环烷基是被一个或多个选自以下的取代基取代的4-8元杂环烷基:-OH、卤素、未取代的或被一个或多个卤素取代的C1-5烷基、被5-6元杂环烷基取代的C1-5烷基、未取代的或被一个或多个卤素取代的C1-5烷氧基、硝基、C1-5烷基硫烷基、氰基、未取代的或被1个或2个C1-5烷基取代的氨基、未取代的或被C1-5烷基取代的5-6元杂环烷基、C1-5烷氧基羰基、5-6元杂芳基、C6-10芳基氨基羰基和C1-5烷氧基-C1-5烷氧基-C6-10芳基;
R3为卤素;
R4为-OH、卤素或C1-10烷氧基;
R5为-H、-OH或卤素;以及
R6为-H、卤素、C1-4烷基或C1-4烷氧基。
3.根据权利要求1所述的化合物、其光学异构体、其溶剂化物、其水合物或其药学上可接受的盐,其中:
X、Y和Z独立地为碳或氮原子;
R1为-H、-OH、卤素、未取代的或被一个或多个卤素取代的C1-5烷基、未取代的或被一个或多个卤素取代的C1-5烷氧基、硝基、C1-5烷基硫烷基、氰基、氨基、C1-5烷基氨基、或含有至少一个N的5元杂芳基;
R2为取代的苯基,或含有至少一个N的取代的6元杂芳基,
其中所述取代的苯基或取代的6元杂芳基独立地为被一个或多个选自以下的取代基取代的苯基或杂芳基:卤素、未取代的或取代的C1-3烷基和未取代的或取代的4-8元完全或部分饱和的含有至少一个N的杂环烷基,
其中所述取代的C1-3烷基被6元杂环烷基取代,其中2个C1-3烷基被取代氨基取代,
所述取代的4-8元杂环烷基是被一个或多个选自以下的取代基取代的4-8元杂环烷基:-OH、未被取代或被5-6元杂环烷基取代的C1-3烷基、未被取代或被1或2个C1-3烷基取代的氨基、未被取代或被C1-3烷基取代的5-6元杂环烷基、C1-4烷氧基羰基、含有至少一个N的5元杂芳基、苯基氨基羰基和C1-3烷氧基-C1-3烷氧基-苯基;
R3为卤素;
R4为-OH、卤素或C1-5烷氧基;
R5为-H、-OH或卤素;以及
R6为-H、卤素、C1-4烷基或C1-4烷氧基。
4.根据权利要求1所述的化合物、其光学异构体、其溶剂化物、其水合物或其药学上可接受的盐,其中:
X、Y和Z独立地为碳或氮原子;
R1为-H、-F、-Cl、-OH、-CH3、-CF3、-OCH3、-OCF3、异丙基、叔丁基、-SCH3、-NO2、-CN或咪唑,
R2为
R3为-F或-Cl;
R4为-OH或-OCH3;
R5为-H、-OH、-F、-Cl、C1-4烷基或C1-4烷氧基;以及
R6为-H、-OH、-F、-Cl、C1-4烷基或C1-4烷氧基。
5.根据权利要求1所述的化合物、其光学异构体、其溶剂化物、其水合物或其可药用的盐,其中由式1表示的化合物是由下式2表示的化合物:
[式2]
(在式2中,X、Y、Z、R1、R2、R3、R4、R5和R6独立地如权利要求1的式1中所定义)。
6.根据权利要求1所述的化合物、其光学异构体、其溶剂化物、其水合物或其药学上可接受的盐,其中:
X是碳或氮原子;
Y和Z是碳原子;
R1为-H、-F、-Cl、-OH、-CH3、-CF3、-OCH3、-OCF3、异丙基、叔丁基、-SCH3、-NO2、-CN或咪唑,
R2为
R3为-F;
R4为-OH或-OCH3;
R5为-H;以及
R6为-H、-F或-Cl。
7.根据权利要求1所述的化合物、其光学异构体、其溶剂化物、其水合物或其药学上可接受的盐,其中由式1表示的化合物选自以下化合物:
(1)(R)-4'-(4-氨基哌啶-1-基)-N-((5-氟-2-羟基苯基)(1H-吲哚-2-基)甲基)-5-甲基-[1,1'-联苯]-3-甲酰胺;
(2)(R)-4'-(4-氨基哌啶-1-基)-N-((5-氟-2-羟基苯基)(1H-吲哚-2-基)甲基)-5-异丙基-[1,1'-联苯]-3-甲酰胺;
(3)(R)-4'-(4-氨基哌啶-1-基)-N-((5-氟-2-羟基苯基)(1H-吲哚-2-基)甲基)-5-甲氧基-[1,1'-联苯]-3-甲酰胺;
(4)(R)-4'-(4-氨基哌啶-1-基)-5-(叔丁基)-N-((5-氟-2-羟基苯基)(1H-吲哚-2-基)甲基)-[1,1'-联苯]-3-甲酰胺;
(5)(R)-4'-(4-氨基哌啶-1-基)-5-氟-N-((5-氟-2-羟基苯基)(1H-吲哚-2-基)甲基)-[1,1'-联苯]-3-甲酰胺;
(6)(R)-4'-(4-氨基哌啶-1-基)-N-((5-氟-2-羟基苯基)(1H-吲哚-2-基)甲基)-5-(三氟甲基)-[1,1'-联苯]-3-甲酰胺;
(7)(R)-4'-(4-氨基哌啶-1-基)-N-((5-氟-2-羟基苯基)(1H-吲哚-2-基)甲基)-5-硝基-[1,1'-联苯]-3-甲酰胺;
(8)(R)-4'-(4-氨基哌啶-1-基)-N-((5-氟-2-羟基苯基)(1H-吲哚-2-基)甲基)-5-(甲硫基)-[1,1'-联苯]-3-甲酰胺;
(9)(R)-4'-(4-氨基哌啶-1-基)-5-氰基-N-((5-氟-2-羟基苯基)(1H-吲哚-2-基)甲基)-[1,1'-联苯]-3-甲酰胺;
(10)(R)-4'-(4-氨基哌啶-1-基)-5-氯-N-((5-氟-2-羟基苯基)(1H-吲哚-2-基)甲基)-[1,1'-联苯]-3-甲酰胺;
(11)(R)-4'-(4-氨基哌啶-1-基)-N-((5-氟-2-羟基苯基)(1H-吲哚-2-基)甲基)-5-(三氟甲氧基)-[1,1'-联苯]-3-甲酰胺;
(12)(R)-4'-(4-氨基哌啶-1-基)-N-((5-氟-2-甲氧基苯基)(1H-吲哚-2-基)甲基)-5-(三氟甲氧基)-[1,1'-联苯]-3-甲酰胺;
(13)(R)-4'-(4-氨基哌啶-1-基)-N-((5-氟-2-羟基苯基)(1H-吲哚-2-基)甲基)-5-(1H-咪唑-1-基)-[1,1'-联苯]-3-甲酰胺;
(14)(R)-2-(4-(4-氨基哌啶-1-基)苯基)-N-((5-氟-2-羟基苯基)(1H-吲哚-2-基)甲基)异烟酰胺;
(15)(R)-2-(4-(4-氨基哌啶-1-基)苯基)-N-((5-氟-2-甲氧基苯基)(1H-吲哚-2-基)甲基)异烟酰胺;
(16)(R)-3-(2-(4-氨基哌啶-1-基)嘧啶-5-基)-N-((5-氟-2-羟基苯基)(1H-吲哚-2-基)甲基)-5-甲基苯甲酰胺;
(17)(R)-3-(5-(4-氨基哌啶-1-基)吡啶-2-基)-N-((5-氟-2-羟基苯基)(1H-吲哚-2-基)甲基)-5-甲基苯甲酰胺;
(18)(R)-3-(5-(4-氨基哌啶-1-基)吡嗪-2-基)-N-((5-氟-2-羟基苯基)(1H-吲哚-2-基)甲基)-5-甲基苯甲酰胺;
(19)(R)-3-(6-(4-氨基哌啶-1-基)吡啶-3-基)-N-((5-氟-2-羟基苯基)(1H-吲哚-2-基)甲基)-5-甲基苯甲酰胺;
(20)(R)-3-(6-(4-氨基哌啶-1-基)哒嗪-3-基)-N-((5-氟-2-羟基苯基)(1H-吲哚-2-基)甲基)-5-甲基苯甲酰胺;
(21)(R)-3-(5-(4-氨基哌啶-1-基)嘧啶-2-基)-N-((5-氟-2-羟基苯基)(1H-吲哚-2-基)甲基)-5-甲基苯甲酰胺;
(22)(R)-4'-(4-氨基哌啶-1-基)-3'-氟-N-((5-氟-2-羟基苯基)(1H-吲哚-2-基)甲基)-5-甲基-[1,1'-联苯]-3-甲酰胺;
(23)(R)-4'-(4-氨基哌啶-1-基)-N-((5-氟-2-羟基苯基)(1H-吲哚-2-基)甲基)-2',5-二甲基-[1,1'-联苯]-3-甲酰胺;
(24)(R)-4'-(4-氨基哌啶-1-基)-2'-氟-N-((5-氟-2-羟基苯基)(1H-吲哚-2-基)甲基)-5-甲基-[1,1'-联苯]-3-甲酰胺;
(25)(R)-4'-(4-氨基哌啶-1-基)-N-((5-氟-2-羟基苯基)(1H-吲哚-2-基)甲基)-3',5-二甲基-[1,1'-联苯]-3-甲酰胺;
(26)(R)-4'-(4-氨基哌啶-1-基)-N-((6-氟-1H-吲哚-2-基)(5-氟-2-羟基苯基)甲基)-5-甲基-[1,1'-联苯]-3-甲酰胺;
(27)(R)-4'-(4-氨基哌啶-1-基)-N-((6-氯-1H-吲哚-2-基)(5-氟-2-羟基苯基)甲基)-5-甲基-[1,1'-联苯]-3-甲酰胺;
(28)(R)-4'-(4-氨基哌啶-1-基)-N-((5-氟-2-羟基苯基)(1H-吲哚-2-基)甲基)-6-甲基-[1,1'-联苯]-3-甲酰胺;
(29)(R)-4'-(4-氨基哌啶-1-基)-N-((5-氟-2-羟基苯基)(1H-吲哚-2-基)甲基)-4-甲基-[1,1'-联苯]-3-甲酰胺;
(30)(R)-4'-(4-氨基哌啶-1-基)-N-((5-氟-2-羟基苯基)(1H-吲哚-2-基)甲基)-2-甲基-[1,1'-联苯]-3-甲酰胺;
(31)(S)-4'-(4-氨基哌啶-1-基)-N-((5-氟-2-羟基苯基)(1H-吲哚-2-基)甲基)-5-甲基-[1,1'-联苯]-3-甲酰胺;
(32)4'-(4-氨基哌啶-1-基)-N-((5-氟-2-羟基苯基)(1H-吲哚-2-基)甲基)-5-甲基-[1,1'-联苯]-3-甲酰胺;
(33)(R)-3-(5-(4-氨基哌啶-1-基)-4-甲基吡啶-2-基)-N-((5-氟-2-羟基苯基)(1H-吲哚-2-基)甲基)-5-甲基苯甲酰胺;
(34)(R)-3-(2-(4-氨基哌啶-1-基)-4-甲基嘧啶-5-基)-N-((5-氟-2-羟基苯基)(1H-吲哚-2-基)甲基)-5-甲基苯甲酰胺;
(35)(R)-4-(2-(3-(((5-氟-2-羟基苯基)(1H-吲哚-2-基)甲基)氨基甲酰基)-5-甲基苯基)嘧啶-5-基)哌嗪-1-甲酸叔丁酯;
(36)(R)-N-((5-氟-2-羟基苯基)(1H-吲哚-2-基)甲基)-3-甲基-5-(5-(哌嗪-1-基)嘧啶-2-基)苯甲酰胺;
(37)(R)-N-((5-氟-2-羟基苯基)(1H-吲哚-2-基)甲基)-3-甲基-5-(5-(4-甲基哌嗪-1-基)嘧啶-2-基)苯甲酰胺;
(38)N-[(R)-(5-氟-2-羟基-苯基)-(1H-吲哚-2-基)甲基]-3-甲基-5-[5-(4-丙基-1-哌啶基)嘧啶-2-基]苯甲酰胺;
(39)3-[5-[4-(二甲基氨基)-1-哌啶基]嘧啶-2-基]-N-[(R)-(5-氟-2-羟基-苯基)-(1H-吲哚-2-基)甲基]-5-甲基-苯甲酰胺;
(40)N-[(R)-(5-氟-2-羟基-苯基)-(1H-吲哚-2-基)甲基]-3-甲基-5-[5-(1-哌啶基)嘧啶-2-基]苯甲酰胺;
(41)N-[(R)-(5-氟-2-羟基-苯基)-(1H-吲哚-2-基)甲基]-3-甲基-5-[5-[4-(1-甲基-4-哌啶基)哌嗪-1-基]嘧啶-2-基]苯甲酰胺;
(42)(R)-3-(5-((4-(二甲基氨基)哌啶-1-基)甲基)吡啶-2-基)-N-((5-氟-2-羟基苯基)(1H-吲哚-2-基))甲基)-5-甲基苯甲酰胺;
(43)(R)-3-(6-((4-(二甲基氨基)哌啶-1-基)甲基)吡啶-3-基)-N-((5-氟-2-羟基苯基)(1H-吲哚-2-基))甲基)-5-甲基苯甲酰胺;
(44)3-[5-[(3R)-3-氨基吡咯烷-1-基]嘧啶-2-基]-N-[(R)-(5-氟-2-羟基-苯基)-(1H-吲哚-2-基)甲基]-5-甲基-苯甲酰胺;
(45)(R)-3-(5-(4-(二乙基氨基)哌啶-1-基)嘧啶-2-基)-N-((5-氟-2-羟基苯基)(1H-吲哚-2-基)甲基)-5-甲基苯甲酰胺;
(46)N-((R)-(5-氟-2-羟基苯基)(1H-吲哚-2-基)甲基)-3-甲基-5-(5-(3-甲基-3,8-二氮杂双环[3.2.1]辛烷-8-基)嘧啶-2-基)苯甲酰胺;
(47)(R)-3-(5-(4-(1H-吡咯-1-基)哌啶-1-基)嘧啶-2-基)-N-((5-氟-2-羟基苯基)(1H-吲哚-2-基)甲基)-5-甲基苯甲酰胺;
(48)(R)-3-(5-(4-(1H-1,2,4-三唑-1-基)哌啶-1-基)嘧啶-2-基)-N-((5-氟-2-羟基苯基)(1H-吲哚-2-基)甲基)-5-甲基苯甲酰胺;
(49)(R)-N-((5-氟-2-羟基苯基)(1H-吲哚-2-基)甲基)-3-(5-(4-羟基哌啶-1-基)嘧啶-2-基)-5-甲基苯甲酰胺;
(50)(R)-3-(5-([1,4'-联哌啶]-1'-基)嘧啶-2-基)-N-((5-氟-2-羟基苯基)(1H-吲哚-2-基)甲基)-5-甲基苯甲酰胺;
(51)(R)-N-((5-氟-2-羟基苯基)(1H-吲哚-2-基)甲基)-3-甲基-5-(5-(4-(吗啉代甲基)哌啶-1-基)嘧啶-2-基)苯甲酰胺;
(52)(R)-N-((5-氟-2-羟基苯基)(1H-吲哚-2-基)甲基)-3-甲基-5-(5-(4-(吡咯烷-1-基甲基)哌啶-1-基)嘧啶-2-基)苯甲酰胺;
(53)3-[5-[(3R)-3-(二甲基氨基)吡咯烷-1-基]嘧啶-2-基]-N-[(R)-(5-氟-2-羟基-苯基)-(1H-吲哚-2-基)甲基]-5-甲基-苯甲酰胺;
(54)(R)-N-((5-氟-2-羟基苯基)(1H-吲哚-2-基)甲基)-3-甲基-5-(5-(4-(甲基氨基)哌啶-1-基)嘧啶-2-基)苯甲酰胺;
(55)(R)-1-(2-(3-(((5-氟-2-羟基苯基)(1H-吲哚-2-基)甲基)氨基甲酰基)-5-甲基苯基)嘧啶-5-基)-N-苯基哌啶-4-甲酰胺;
(56)(R)-N-((5-氟-2-羟基苯基)(1H-吲哚-2-基)甲基)-3-(5-(4-(4-(2-甲氧基乙氧基)苯基)哌嗪-1-基)嘧啶-2-基)-5-甲基苯甲酰胺;
(57)(R)-N-((5-氟-2-羟基苯基)(1H-吲哚-2-基)甲基)-3-甲基-5-(5-(1,2,3,6-四氢吡啶-4-基)嘧啶-2-基)苯甲酰胺;
(58)(R)-N-((5-氟-2-羟基苯基)(1H-吲哚-2-基)甲基)-3-甲基-5-(5-(哌啶-4-基)嘧啶-2-基)苯甲酰胺;
(59)(R)-3-(5-(3-氨基氮杂环丁烷-1-基)嘧啶-2-基)-N-((5-氟-2-羟基苯基)(1H-吲哚-2-基)甲基)-5-甲基苯甲酰胺;
(60)3-(5-((S)-3-(二甲基氨基)吡咯烷-1-基)嘧啶-2-基)-N-((R)-(5-氟-2-羟基苯基)(1H-吲哚-2-基)甲基)-5-甲基苯甲酰胺;
(61)3-(5-((S)-3-氨基吡咯烷-1-基)嘧啶-2-基)-N-((R)-(5-氟-2-羟基苯基)(1H-吲哚-2-基)甲基)-5-甲基苯甲酰胺;以及
(62)(R)-3-(5-(氮杂环丁烷-3-基)嘧啶-2-基)-N-((5-氟-2-羟基苯基)(1H-吲哚-2-基)甲基)-5-甲基苯甲酰胺。
8.一种用于预防或治疗癌症的药物组合物,其包含权利要求1的式1表示的化合物、其光学异构体、其溶剂化物、其水合物或其药学上可接受的盐作为活性成分。
9.根据权利要求8所述的药物组合物,其中所述化合物抑制EGFR(表皮生长因子受体)突变以预防或治疗癌症。
10.根据权利要求9所述的药物组合物,其中所述EGFR(表皮生长因子受体)突变是选自EGFR L858R/T790M和EGFR L858R/T790M/C797S中的至少一种。
11.一种用于预防或改善癌症的健康功能性食品组合物,其包含权利要求1的式1表示的化合物、其光学异构体、其溶剂化物、其水合物或其药学上可接受的盐作为活性成分。
12.一种用于预防或治疗癌症的组合制剂,其包含权利要求1的式1表示的化合物、其光学异构体、其溶剂化物、其水合物或其药学上可接受的盐作为活性成分。
13.根据权利要求12所述的组合制剂,其中所述组合制剂与选自以下的至少一种组合施用:
顺铂、奥沙利铂、卡铂、环磷酰胺、氮芥、美法仑、苯丁酸氮芥、白消安、替莫唑胺、亚硝基脲、吉西他滨、抗叶酸剂、5-氟尿嘧啶、替加氟、雷替曲塞、甲氨蝶呤、阿糖胞苷、羟基脲、阿霉素、博来霉素、多柔比星、柔红霉素、表柔比星、伊达比星、丝裂霉素C、放线菌素、光辉霉素、长春新碱、长春碱、长春地辛、长春瑞滨、紫杉醇、泰索帝、依托泊苷、替尼泊苷、安吖啶、拓扑替康、喜树碱、他莫昔芬、氟维司群(fulvestrant)、托瑞米芬、雷洛昔芬、屈洛昔芬、碘氧芬、比卡鲁胺、氟他胺(flotamide)、尼鲁胺(nilutamide)、醋酸环丙孕酮、戈舍瑞林、亮丙瑞林、布舍瑞林(buserellin)、醋酸甲地孕酮、阿那曲唑、来曲唑(letrozole)、硼唑、依西美坦、非那雄胺、塞卡替尼(saracatinib)、达沙替尼、博舒替尼、marimastat、西妥昔单抗、吉非替尼、埃罗替尼、帕尼单抗、奥西默替尼、拉帕替尼、伊马替尼、尼罗替尼、索拉菲尼、替匹法尼、洛那法尼、贝伐单抗、凡德替尼、瓦他拉尼、舒尼替尼、阿西替尼、帕唑帕尼、4-(4-氟-2-甲基吲哚-5-基氧基)-6-甲氧基-7-(3-吡咯烷-1-基丙氧基)喹唑啉、考布他汀A4、齐泊坦和阿曲生坦。
14.一种预防或治疗癌症的方法,该方法包括向有需要的受试者施用权利要求1的式1表示的化合物、其光学异构体、其溶剂化物、其水合物或其药学上可接受的盐的步骤。
15.权利要求1的式1表示的化合物、其光学异构体、其溶剂化物、其水合物或其可药用盐在制备用于预防或治疗癌症的药物中的用途。
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CA3220146A1 (en) | 2022-11-24 |
AU2022276958A1 (en) | 2023-12-07 |
IL308518A (en) | 2024-01-01 |
TW202306568A (zh) | 2023-02-16 |
JP2024519054A (ja) | 2024-05-08 |
EP4342882A1 (en) | 2024-03-27 |
WO2022245061A1 (ko) | 2022-11-24 |
BR112023024040A2 (pt) | 2024-02-06 |
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