CN117500805A - 作为ron抑制剂的新型脲衍生化合物 - Google Patents
作为ron抑制剂的新型脲衍生化合物 Download PDFInfo
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- CN117500805A CN117500805A CN202280042920.2A CN202280042920A CN117500805A CN 117500805 A CN117500805 A CN 117500805A CN 202280042920 A CN202280042920 A CN 202280042920A CN 117500805 A CN117500805 A CN 117500805A
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- Prior art keywords
- phenyl
- pyridin
- imidazo
- dihydro
- oxy
- Prior art date
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- 229910052736 halogen Inorganic materials 0.000 claims description 25
- 150000002367 halogens Chemical group 0.000 claims description 25
- 229910052739 hydrogen Inorganic materials 0.000 claims description 23
- 239000001257 hydrogen Substances 0.000 claims description 23
- 125000003118 aryl group Chemical group 0.000 claims description 22
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 22
- 125000001424 substituent group Chemical group 0.000 claims description 17
- 150000002431 hydrogen Chemical group 0.000 claims description 15
- 125000000592 heterocycloalkyl group Chemical group 0.000 claims description 13
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- 125000000217 alkyl group Chemical group 0.000 claims description 9
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 9
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- UCPYLLCMEDAXFR-UHFFFAOYSA-N triphosgene Chemical compound ClC(Cl)(Cl)OC(=O)OC(Cl)(Cl)Cl UCPYLLCMEDAXFR-UHFFFAOYSA-N 0.000 description 1
- NQPDZGIKBAWPEJ-UHFFFAOYSA-N valeric acid Chemical compound CCCCC(O)=O NQPDZGIKBAWPEJ-UHFFFAOYSA-N 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
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Abstract
本发明涉及一种作为蛋白激酶抑制剂、特别是RON抑制剂的新型化合物。
Description
技术领域
与相关申请的交叉引用
本申请要求2021年6月24日在韩国知识产权局提交的韩国专利申请第10-2021-0082700号的利益,所述申请的公开内容整体通过引用并入本文。
技术领域
本发明涉及一种作为蛋白激酶抑制剂的新型化合物。具体来说,本发明涉及一种作为RON抑制剂的新型化合物。
背景技术
已知至少有400种蛋白激酶催化从三磷酸腺苷(ATP)到蛋白质底物的磷酸转移反应。在磷酸基团被转移到的靶蛋白中,具体的氨基酸是酪氨酸、丝氨酸或苏氨酸,因此蛋白激酶通常被称为蛋白酪氨酸激酶(PTK)或丝氨酸/苏氨酸激酶(STK)。
蛋白激酶构成了一个结构相关组的大家族,负责控制细胞内广泛种类的信号传导通路。信号传导通路包括通过磷酸基团转移到靶蛋白的许多其他信号传导通路。这些磷酸化事件充当分子开/关开关,可以调节靶蛋白或蛋白复合物的生物功能。信号传导通路中适合的蛋白激酶功能是激活或失活代谢酶、调节蛋白、受体、细胞骨架蛋白、离子通道和泵、转录因子等。由于蛋白质磷酸化控制缺陷而导致的不受控制的信号传导与许多疾病有关,包括炎症、癌症、过敏/哮喘、免疫系统疾病、中枢神经系统疾病、血管生成等。
几乎所有的激酶都包括类似的250-300个氨基酸的催化结构域。激酶可以根据其磷酸化的底物进行分类,并且已经鉴定出通常与这些激酶家族中的每一者相对应的序列基序。
同时,作为酪氨酸蛋白激酶受体之一的RON(receptor originated from nantes)也被称为巨噬细胞刺激因子1受体(MST1R),并已被报道促进癌细胞的侵袭和转移。RON的过表达也已知出现在各种肿瘤类型中。
肿瘤细胞中酪氨酸蛋白激酶例如RON的激活增加了肿瘤细胞的增殖、侵袭和转移,并且提高了肿瘤细胞对细胞凋亡和细胞毒性疗法的抗性。因此,预期靶向酪氨酸蛋白激酶例如RON的选择性小分子激酶调节剂具有治疗其中RON受体等的激活在原发性肿瘤和继发性转移的发生和进展中起到关键作用的癌症的治疗潜力。因此,正在对用于选择性抑制作为酪氨酸蛋白之一的RON的激酶活性的各种抑制剂进行持续的研究。
发明内容
技术问题
本发明的一个方面提供了一种具有蛋白激酶抑制活性的新型化合物。
本发明的另一方面提供了一种可用于预防或治疗癌症的化合物。
本发明的又一方面提供了一种可用于预防或治疗免疫相关疾病的化合物。
本发明的又一方面提供了一种可用作RON抑制剂的化合物。
技术解决方案
为了实现上述目的,根据本发明的一个方面,提供了一种下式1的吡啶衍生化合物或其药学上可接受的盐。
[式1]
在式1中,
上述X是O,
上述Y是氢、卤素、C1-C6烷基或C3-C6环烷基,
上述R1是氢、C1-C6烷基、C3-C12环烷基或C2-C11杂环烷基,
上述R2是氢或C1-C6烷基,
上述A是-Ar或-(CH2)n-Ar,其中Ar是取代或未取代的C6-C10芳基或取代或未取代的包括1至4个选自氮、硫和氧的杂环原子的5元杂芳基,其中取代基是选自卤素、胺、C1-C6烷基、C3-C12环烷基、卤素取代的C1-C6烷基、C6-C10芳基、C1-C6烷氧基、C1-C6烷硫基、羟基、羧酸、C1-C6烷基羰基、C1-C6烷氧基羰基、C1-C6烷基羰基氧基、硝基、氰基、氨甲酰基、脲、巯基和NR3R4的一者或多者,并且上述n是1至3的整数,
上述R3和R4各自独立地是氢或C1-C6烷基,
上述B是氢、C1-C6烷基、取代的C1-C6烷基、C3-C12环烷基、取代的C3-C12环烷基、C3-C11杂环烷基、取代的C3-C11杂环烷基、C6-C20芳基、取代的C6-C20芳基,其中取代基是卤素、C1-C6烷基、C3-C7环烷基、卤素取代的C1-C6烷基、C1-C6烷氧基、C3-C11杂环烯基或C6-C10芳基,
其中所述卤素选自F、Cl、Br和I。
根据本发明的另一方面,提供了一种药物组合物,其包括上式1的化合物或其药学上可接受的盐和药学上可接受的载体。
有利效果
根据本发明提供了一种新型化合物或其药学上可接受的盐,它们可以通过抑制蛋白激酶、特别是RON受体的蛋白激酶活性,有效地用于治疗各种免疫相关疾病,包括作为抗癌药剂,但本发明不限于此。
具体实施方式
根据一个方面,本发明提供了一种如上所定义的式1的新型脲衍生化合物或其药学上可接受的盐。
在本发明中,所述化合物包括但不限于式1的化合物、其立体异构体例如对映异构体和非对映异构体、溶剂化物和前体药物。
[式1]
在式1中,
上述X是O,
上述Y是氢、卤素、C1-C6烷基或C3-C6环烷基,
上述R1是氢、C1-C6烷基、C3-C12环烷基或C2-C11杂环烷基,
上述R2是氢或C1-C6烷基,
上述A是-Ar或-(CH2)n-Ar,其中Ar是取代或未取代的C6-C10芳基或取代或未取代的包括1至4个选自氮、硫和氧的杂环原子的5元杂芳基,其中取代基是选自卤素、胺、C1-C6烷基、C3-C12环烷基、卤素取代的C1-C6烷基、C6-C10芳基、C1-C6烷氧基、C1-C6烷硫基、羟基、羧酸、C1-C6烷基羰基、C1-C6烷氧基羰基、C1-C6烷基羰基氧基、硝基、氰基、氨甲酰基、脲、巯基和NR3R4的一者或多者,并且上述n是1至3的整数,
上述R3和R4各自独立地是氢或C1-C6烷基,
上述B是氢、C1-C6烷基、取代的C1-C6烷基、C3-C12环烷基、取代的C3-C12环烷基、C3-C11杂环烷基、取代的C3-C11杂环烷基、C6-C20芳基、取代的C6-C20芳基,其中取代基是卤素、C1-C6烷基、C3-C7环烷基、卤素取代的C1-C6烷基、C1-C6烷氧基、C3-C11杂环烯基或C6-C10芳基,
其中所述卤素选自F、Cl、Br和I。
在本说明书中,术语“取代”意味着结构中与碳原子键合的氢原子被改变成另一个取代基,并且取代发生的位置不受限制,只要它是被取代的氢原子所在的位置、即可以用取代基取代的位置即可,并且当在两个或更多个位置处取代时,两个或更多个取代基可以彼此相同或不同。
在本说明书中,除非另有定义,否则“取代基”可以是选自氘、卤素、羟基、C1-C10烷基、C3-C12环烷基、C1-C10烷氧基、C5-C12芳氧基、C1-C10烷基硫氧基、C5-C12芳基硫氧基、C1-C10烷基亚砜基、C5-C12芳基亚砜基、C1-C10卤代烷基、C2-C20烯基、C0-C10胺、腈、硝基、酰亚胺、酰胺、酮基、羰基、羧酸、氨甲酰基、酯、C5-C12芳基和C5-C12杂芳基的一者或多者。
在本说明书中,除非另有定义,否则“烷基”可以是直链或支链,并优选地具有1至20个碳原子。其实例可以包括甲基、乙基、丙基、正丙基、异丙基、丁基、正丁基、异丁基、叔丁基、仲丁基、1-甲基丁基、乙基丁基、戊基、正戊基、异戊基、新戊基、叔戊基、己基、正己基、甲基戊基、2-甲基戊基、4-甲基-2-戊基、3,3-二甲基丁基、2-乙基丁基、庚基、正庚基、1-甲基己基、环戊基甲基、环己基甲基、辛基、正辛基、叔辛基、1-甲基庚基、2-乙基己基、2-丙基戊基、正壬基、2,2-二甲基庚基、1-乙基丙基、二甲基丙基、异己基、2-甲基戊基、4-甲基己基、5-甲基己基等,但不限于此。
在本说明书中,除非另有定义,否则“环烷基”可以意味着环状饱和烃,并优选地具有3至20个碳原子。其实例可以包括环丙基、环丁基、环戊基、3-甲基环戊基、2,3-二甲基环戊基、环己基、3-甲基环己基、4-甲基环己基、2,3-二甲基环己基、3,4,5-三甲基环己基、4-叔丁基环己基、环庚基、环辛基等,但不限于此。
在本说明书中,除非另有定义,否则“烷氧基”可以是直链、支链或环状的,并优选地具有1至20个碳原子。其实例可以包括甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、异丁氧基、叔丁氧基、仲丁氧基、正戊氧基、新戊氧基、异戊氧基、正己氧基、3,3-二甲基丁氧基、2-乙基丁氧基、正辛氧基、正壬氧基、正癸氧基、苯甲氧基、对甲基苯甲氧基等,但不限于此。
在本说明书中,除非另有定义,否则“烯基”可以是直链或支链,并优选地具有2至20个碳原子。其实例可以包括乙烯基、1-丙烯基、异丙烯基、1-丁烯基、2-丁烯基、3-丁烯基、1-戊烯基、2-戊烯基、3-戊烯基、3-甲基-1-丁烯基、1,3-丁二烯基、烯丙基、1-苯基乙烯基-1-基、2-苯基乙烯基-1-基、2,2-二苯基乙烯基-1-基、2-苯基-2-(萘-1-基)乙烯基-1-基、2,2-双(二苯基-1-基)乙烯基-1-基、二苯乙烯基、苯乙烯基等,但不限于此。
在本说明书中,除非另有定义,否则“芳基”可以是单芳基、二芳基或三个或更多个环的多环芳基,并且当包括两个或更多个环状结构时,每个环可以被稠合或以螺形式被包括,并优选地具有5至12个碳原子。其实例可以包括苯基、联苯基、三联苯基、萘基、蒽基、菲基、芘基、苝基等,但不限于此。
在本说明书中,“杂环原子”意味着包含在环中的非碳原子。除非另有定义,否则杂环原子可以包括选自氧、氮、硒和硫的一种或多种原子。
在本说明书中,除非另有定义,否则“杂环烷基”可以意味着包含杂环原子的环状饱和烃,并优选地具有2至20个碳原子。
在本说明书中,“杂芳基”可以意味着包含杂环原子的芳香烃。除非另有定义,否则杂芳基可以是单环或多环的,并且当包括两个或更多个环状结构时,每个环可以被稠合或以螺形式被包括,并优选地具有5至12个碳原子。其实例可以包括噻吩基、呋喃基、吡咯基、咪唑基、噻唑基、唑基、/>二唑基、吡啶基、联吡啶基、嘧啶基、三嗪基、三唑基、吖啶基、哒嗪基、吡嗪基、喹啉基、喹唑啉基、喹喔啉基、酞嗪基、吡啶并嘧啶基、吡啶并吡嗪基、吡嗪并吡嗪基、异喹啉基、吲哚基、咔唑基、苯并/>唑基、苯并咪唑基、苯并噻唑基等,但不限于此。
根据一个实施方式,本发明提供了一种下式2的新型脲衍生化合物或其药学上可接受的盐。
[式2]
所述取代基与式1中所定义的相同。
根据一个实施方式,在上式1中,上述A可以是-Ar或-(CH2)n-Ar,其中上述Ar可以是取代或未取代的C6-C10芳基或取代或未取代的5元杂芳基。此时,对于结构A而言,术语“芳基”不仅仅意味着其中A是单价官能团的结构,即其中在上式1中B是氢的结构,并且当上述B具有氢之外的结构时,上述Ar可以是取代或未取代的C6-C10亚芳基或取代或未取代的5元亚杂芳基。
根据一个实施方式,在上式1中,上述A可以是取代或未取代的5元杂芳基,并且具体来说可以包括至少两个杂环原子。此时所包含的杂环原子可以彼此相同或不同,但不限于此。
根据另一个实施方式,在上式1中,上述Ar可以包括至少一个氮原子作为杂环原子,并且可以进一步包括至少一个选自氮和硫的杂环原子。
根据另一个实施方式,上述Ar可以包括一个或两个选自吡唑、咪唑和噻唑的杂芳基,其中所述杂芳基可以是取代或未取代的,并且取代的杂芳基具有的取代基可以是卤素、胺、C1-C6烷基、卤素取代的C1-C6烷基、C6-C10芳基、C1-C6烷氧基、C1-C6烷硫基、羟基、羧酸、C1-C6烷基羰基、C1-C6烷氧基羰基、C1-C6烷基羰基氧基、硝基、氰基、氨甲酰基、脲、巯基和NR3R4。此时,上述R3和R4如上所定义。
根据另一个实施方式,在上式1中,上述A可以是取代或未取代的C6-C10芳基,具体来说可以是取代或未取代的苯基。此时,取代的苯基具有的取代基可以是选自卤素和卤素取代的C1-C6烷基的一者或多者。更具体而言,取代的苯基具有的取代基可以是选自氟、溴和三氟甲基的一者或多者。
根据另一个实施方式,在上式1中,A可以是-(CH2)n-Ar,其中n可以是1至3的整数,例如n可以是1。
根据一个实施方式,在上式1中,上述B可以是氢、C1-C6烷基、取代的C1-C6烷基、C3-C7环烷基、苯基、取代的苯基、苯甲基、萘、四氢吡喃、哌啶或取代的哌啶,其中取代基可以是卤素、C1-C3烷基、卤化C1-C3烷基、C3-C5环烷基或C1-C3烷氧基。
根据一个实施方式,在上式1中,上述Y是氟。
根据一个实施方式,在上式1中,上述R1是C1-C6烷基、C3-C6环烷基或C4-C6杂环烷基。
根据另一个实施方式,在上式1中,上述R1是氢、甲基、乙基、异丙基、环戊基或四氢呋喃基。
根据一个实施方式,在上式1中,上述R2是氢。
根据一个实施方式,上式1的化合物可以选自:
N-(3-氟-4-((2-酮基-2,3-二氢-1H-咪唑并[4,5-b]吡啶-7-基)氧基)苯基)-1-苯基-5-(三氟甲基)-1H-咪唑-4-甲酰胺,
N-(3-氟-4-((2-酮基-2,3-二氢-1H-咪唑并[4,5-b]吡啶-7-基)氧基)苯基)-1-苯基-5-(三氟甲基)-1H-吡唑-4-甲酰胺,
N-(4-((1-乙基-2-酮基-2,3-二氢-1H-咪唑并[4,5-b]吡啶-7-基)氧基)-3-氟苯基)-1-苯基-5-(三氟甲基)-1H-咪唑-4-甲酰胺,
N-(4-((1-乙基-2-酮基-2,3-二氢-1H-咪唑并[4,5-b]吡啶-7-基)氧基)-3-氟苯基)-1-苯基-5-(三氟甲基)-1H-吡唑-4-甲酰胺,
N-(3-氟-4-((1-甲基-2-酮基-2,3-二氢-1H-咪唑并[4,5-b]吡啶-7-基)氧基)苯基)-1-苯基-5-(三氟甲基)-1H-咪唑-4-甲酰胺,
N-(3-氟-4-((1-甲基-2-酮基-2,3-二氢-1H-咪唑并[4,5-b]吡啶-7-基)氧基)苯基)-1-苯基-5-(三氟甲基)-1H-吡唑-4-甲酰胺,
N-(3-氟-4-((1-异丙基-2-酮基-2,3-二氢-1H-咪唑并[4,5-b]吡啶-7-基)氧基)苯基)-1-苯基-5-(三氟甲基)-1H-吡唑-4-甲酰胺,
N-(3-氟-4-((1-异丙基-2-酮基-2,3-二氢-1H-咪唑并[4,5-b]吡啶-7-基)氧基)苯基)-1-苯基-5-(三氟甲基)-1H-咪唑-4-甲酰胺,
5-乙基-N-(3-氟-4-((2-酮基-2,3-二氢-1H-咪唑并[4,5-b]吡啶-7-基)氧基)苯基)-1-苯基-1H-吡唑-4-甲酰胺,
5-乙基-N-(3-氟-4-((1-异丙基-2-酮基-2,3-二氢-1H-咪唑并[4,5-b]吡啶-7-基)氧基)苯基)-1-苯基-1H-吡唑-4-甲酰胺,
N-(3-氟-4-((2-酮基-1-(四氢-2H-吡喃-4-基)-2,3-二氢-1H-咪唑并[4,5-b]吡啶-7-基)氧基)苯基)-1-苯基-5-(三氟甲基)-1H-咪唑-4-甲酰胺,
N-(3-氟-4-((2-酮基-2,3-二氢-1H-咪唑并[4,5-b]吡啶-7-基)氧基)苯基)-3,5-二甲基-1-苯基-1H-吡唑-4-甲酰胺,
N-(3-氟-4-((1-异丙基-2-酮基-2,3-二氢-1H-咪唑并[4,5-b]吡啶-7-基)氧基)苯基)-3,5-二甲基-1-苯基-1H-吡唑-4-甲酰胺,
N-(3-氟-4-((1-异丙基-2-酮基-2,3-二氢-1H-咪唑并[4,5-b]吡啶-7-基)氧基)苯基)-5-甲基-1-苯基-1H-吡唑-4-甲酰胺,
N-(3-氟-4-((1-异丙基-2-酮基-2,3-二氢-1H-咪唑并[4,5-b]吡啶-7-基)氧基)苯基)-2-苯基噻唑-5-甲酰胺,
N-(3-氟-4-((1-异丙基-2-酮基-2,3-二氢-1H-咪唑并[4,5-b]吡啶-7-基)氧基)苯基)-5-苯基噻唑-2-甲酰胺,
N-(3-氟-4-((1-异丙基-2-酮基-2,3-二氢-1H-咪唑并[4,5-b]吡啶-7-基)氧基)苯基)-1-(对甲苯基)-5-(三氟甲基)-1H-吡唑-4-甲酰胺,
N-(3-氟-4-((1-异丙基-2-酮基-2,3-二氢-1H-咪唑并[4,5-b]吡啶-7-基)氧基)苯基)-1-(2-甲氧基苯基)-5-(三氟甲基)-1H-吡唑-4-甲酰胺,
N-(3-氟-4-((1-异丙基-2-酮基-2,3-二氢-1H-咪唑并[4,5-b]吡啶-7-基)氧基)苯基)-1,5-二苯基-1H-吡唑-4-甲酰胺,
N-(3-氟-4-((1-异丙基-2-酮基-2,3-二氢-1H-咪唑并[4,5-b]吡啶-7-基)氧基)苯基)-1-(四氢-2H-吡喃-3-基)-5-(三氟甲基)-1H-吡唑-4-甲酰胺,
N-(4-((1-环戊基-2-酮基-2,3-二氢-1H-咪唑并[4,5-b]吡啶-7-基)氧基)-3-氟苯基)-1-苯基-5-(三氟甲基)-1H-咪唑-4-甲酰胺,
N-(4-((1-环戊基-2-酮基-2,3-二氢-1H-咪唑并[4,5-b]吡啶-7-基)氧基)-3-氟苯基)-1-苯基-5-(三氟甲基)-1H-吡唑-4-甲酰胺,
N-(4-((1-环戊基-2-酮基-2,3-二氢-1H-咪唑并[4,5-b]吡啶-7-基)氧基)-3-氟苯基)-5-乙基-1-苯基-1H-吡唑-4-甲酰胺,
N-(3-氟-4-((1-异丙基-2-酮基-2,3-二氢-1H-咪唑并[4,5-b]吡啶-7-基)氧基)苯基)-2-(三氟甲基)苯甲酰胺,
4-溴-N-(3-氟-4-((1-异丙基-2-酮基-2,3-二氢-1H-咪唑并[4,5-b]吡啶-7-基)氧基)苯基)-2-(三氟甲基)苯甲酰胺,
N-(3-氟-4-((1-异丙基-2-酮基-2,3-二氢-1H-咪唑并[4,5-b]吡啶-7-基)氧基)苯基)-1-(萘-1-基)-5-(三氟甲基)-1H-吡唑-4-甲酰胺,
3-溴-N-(3-氟-4-((1-异丙基-2-酮基-2,3-二氢-1H-咪唑并[4,5-b]吡啶-7-基)氧基)苯基)-2-(三氟甲基)苯甲酰胺,
1-环己基-N-(3-氟-4-((1-异丙基-2-酮基-2,3-二氢-1H-咪唑并[4,5-b]吡啶-7-基)氧基)苯基)-5-(三氟甲基)-1H-吡唑-4-甲酰胺,
N-(3-氟-4-((1-异丙基-2-酮基-2,3-二氢-1H-咪唑并[4,5-b]吡啶-7-基)氧基)苯基)-1-(四氢-2H-吡喃-4-基)-5-(三氟甲基)-1H-吡唑-4-甲酰胺,
1-(叔丁基)-N-(3-氟-4-((1-异丙基-2-酮基-2,3-二氢-1H-咪唑并[4,5-b]吡啶-7-基)氧基)苯基)-5-(三氟甲基)-1H-吡唑-4-甲酰胺,
1-环庚基-N-(3-氟-4-((1-异丙基-2-酮基-2,3-二氢-1H-咪唑并[4,5-b]吡啶-7-基)氧基)苯基)-5-(三氟甲基)-1H-吡唑-4-甲酰胺,
N-(3-氟-4-((1-异丙基-2-酮基-2,3-二氢-1H-咪唑并[4,5-b]吡啶-7-基)氧基)苯基)-2-(1-苯基-5-(三氟甲基)-1H-吡唑-4-基)乙酰胺,
N-(3-氟-4-((1-异丙基-2-酮基-2,3-二氢-1H-咪唑并[4,5-b]吡啶-7-基)氧基)苯基)-1-(1-甲基哌啶-3-基)-5-(三氟甲基)-1H-吡唑-4-甲酰胺,
N-(3-氟-4-((1-异丙基-2-酮基-2,3-二氢-1H-咪唑并[4,5-b]吡啶-7-基)氧基)苯基)-1-(2氟苯基)-5-(三氟甲基)-1H-吡唑-4-甲酰胺,
1-(2-氯苯基)-N-(3-氟-4-((1-异丙基-2-酮基-2,3-二氢-1H-咪唑并[4,5-b]吡啶-7-基)氧基)苯基)-5-(三氟甲基)-1H-吡唑-4-甲酰胺,
1-(2,6-二氟苯基)-N-(3-氟-4-((1-异丙基-2-酮基-2,3-二氢-1H-咪唑并[4,5-b]吡啶-7-基)氧基)苯基)-5-(三氟甲基)-1H-吡唑-4-甲酰胺,
N-(3-氟-4-((2-酮基-1-(四氢-2H-吡喃-4-基)-2,3-二氢-1H-咪唑并[4,5-b]吡啶-7-基)氧基)苯基)-1-苯基-5-(三氟甲基)-1H-吡唑-4-甲酰胺,
N-(3-氟-4-((2-酮基-1-(四氢呋喃-3-基)-2,3-二氢-1H-咪唑并[4,5-b]吡啶-7-基)氧基)苯基)-1-苯基-5-(三氟甲基)-1H-吡唑-4-甲酰胺,
N-(3-氟-4-((1-(1-甲基哌啶-4-基)-2-酮基-2,3-二氢-1H-咪唑并[4,5-b]吡啶-7-基)氧基)苯基)-1-苯基-5-(三氟甲基)-1H-吡唑-4-甲酰胺,
N-(3-氟-4-((1-异丙基-2-酮基-2,3-二氢-1H-咪唑并[4,5-b]吡啶-7-基)氧基)苯基)-1-苯基-1H-吡唑-3-甲酰胺,
N-(3-氟-4-((1-异丙基-2-酮基-2,3-二氢-1H-咪唑并[4,5-b]吡啶-7-基)氧基)苯基)-1-苯基-1H-1,2,3-三唑-4-甲酰胺,
N-(3-氟-4-((1-异丙基-2-酮基-2,3-二氢-1H-咪唑并[4,5-b]吡啶-7-基)氧基)苯基)-5-甲基-1-苯基-1H-1,2,3-三唑-4-甲酰胺,和
N-(3-氟-4-((1-异丙基-2-酮基-2,3-二氢-1H-咪唑并[4,5-b]吡啶-7-基)氧基)苯基)-1-(2-氟苯基)-1H-1,2,3-三唑-4-甲酰胺,
并且其结构如下表1中所示。
[表1]
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在本发明中,“药学上可接受的盐”包括通常用于形成碱金属盐和形成游离酸或游离碱的加成盐的盐。此类盐的性质并不重要,但所述盐应该是药学上可接受的。适合于式1的化合物的药学上可接受的酸加成盐可以由无机酸或有机酸制备。所述无机酸的实例可以包括盐酸、氢溴酸、氢碘酸、硝酸、碳酸、硫酸和磷酸。适合的有机酸可以选自脂族、环脂族、芳香族、芳基脂族、杂环族、羧酸和磺酸类别的有机酸,并且其实例可以包括甲酸、乙酸、己二酸、丁酸、丙酸、琥珀酸、乙醇酸、葡萄糖酸、乳酸、苹果酸、酒石酸、柠檬酸、抗坏血酸、葡萄糖醛酸、马来酸、富马酸、丙酮酸、天冬氨酸、谷氨酸、苯甲酸、邻氨基苯甲酸、甲磺酸、4-羟基苯甲酸、苯乙酸、扁桃酸、扑酸(帕莫酸)、甲磺酸、乙磺酸、乙二磺酸、苯磺酸、泛酸、2-羟基乙磺酸、甲苯磺酸、磺胺酸、环己基氨基磺酸、樟脑酸、樟脑磺酸、二葡萄糖酸、环戊烷丙酸、十二烷基磺酸、葡庚糖酸、甘油膦酸、庚酸、己酸、2-羟基乙磺酸、烟酸、2-萘磺酸、草酸、棕榈酸、果胶酸、过硫酸、2-苯基丙酸、苦味酸、新戊酸、丙酸、琥珀酸、酒石酸、硫氰酸、甲磺酸、十一烷酸、硬脂酸、海藻酸、β-羟基丁酸、水杨酸、半乳糖二酸和半乳糖醛酸。适合于式1的化合物的药学上可接受的碱加成盐可以是金属盐,例如由铝、钙、锂、镁、钾、钠或锌制成的盐,或由有机碱制成的盐,所述有机碱包括取代的胺(包括伯胺、仲胺或叔胺)和环状胺例如咖啡因、精氨酸、二乙胺、N-乙基哌啶、组氨酸、葡萄糖胺、异丙胺、赖氨酸、吗啉、N-乙基吗啉、哌嗪、哌啶、三乙胺或三甲胺。这些盐可以从本发明的相应化合物通过典型方法例如将适合的酸或碱与式1的化合物反应来制备。当碱性基团和酸性基团存在于同一分子中时,式1的化合物也可以形成内盐。在本发明中,“溶剂化物”可以包括水合物以及与有机溶剂的溶剂化物,所述有机溶剂例如甲醇、乙醇、2-丙醇、1,2-丙二醇、1,3-丙二醇、正丁醇、1,4-丁二醇、叔丁醇、乙酸、丙酮、乙酸丁酯、乙酸甲酯、乙酸乙酯、乙酸丙酯、乙酸叔丁酯、乙酸异丁酯、甲基乙基酮、2-戊酮、四氢呋喃、乙腈、氯仿、甲苯及其混合物。
根据另一方面,本发明提供了一种药物组合物,其包括上文定义的式1的新型化合物或其药学上可接受的盐以及药学上可接受的载体。
所述药物组合物可用于预防或治疗蛋白激酶介导的疾病,但本发明的用途不限于这些疾病。
在一个实施方式中,所述药物组合物可用于预防或治疗RON介导的疾病。
根据本发明的药物组合物包括治疗有效量的上式1的化合物或其药学上可接受的盐。
在一个实施方式中,所述疾病可以是选自肺癌、乳腺癌、结肠直肠癌、肾癌、胰腺癌、头部癌症、宫颈癌、遗传性乳头状肾细胞癌、儿童肝细胞癌和胃癌的癌症,但不限于此。
在另一个实施方式中,所述疾病可以是选自炎性障碍、心血管疾病、病毒诱导的疾病、循环系统疾病、纤维增殖性疾病和痛觉的免疫疾病,但不限于此。
为了治疗上述疾病,可以将所述药物组合物给药到需要预防或治疗上述疾病的受试者。
在本说明书中,术语“预防”意指降低发生疾病或障碍的风险,并且它意味着在暴露于疾病或对疾病易感但尚未患有所述疾病或表现出所述疾病的症状的受试者中,通过阻止所述疾病的超过一种临床症状的进展而抑制或延迟疾病发作的任何行动。
在本说明书中,术语“治疗”意指减轻疾病或障碍,并且它意味着通过停止或减少疾病或其一种或多种临床症状的进展来减轻或有益地改变所述疾病的症状的任何行动。
在本说明书中,术语“载体”意指促进将化合物引入到细胞或组织中的化合物。药物组合物可以通过使用药学上可接受的载体配制而以单位剂量形式制备,或者可以通过引入到多剂量容器中而制备。此时,制剂可以采取在油或水性介质中的溶液、悬液或乳液的形式,或者可以采取提取物、粉剂、颗粒剂、片剂、胶囊或凝胶(例如水凝胶)的形式,并且可以另外包括分散剂或稳定剂。
此外,包含在药物组合物中的由式1表示的化合物或其药学上可接受的盐可以在药学上可接收的载体中运载,所述载体例如胶体悬液、粉末、盐水溶液、脂质、脂质体、微球或纳米球形粒子。它们可以与运输工具形成复合物或与复合物结合,并且可以使用本领域中已知的运输系统在体内运载,所述运输系统例如脂质、脂质体、微粒、金、纳米粒子、聚合物、缩合反应器、多糖、聚氨基酸、树状大分子、皂苷、吸附增强物质或脂肪酸。
此外,药学上可接受的载体可以包括通常在制剂中使用的乳糖、右旋糖、蔗糖、山梨糖醇、甘露糖醇、淀粉、阿拉伯胶、橡胶、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,但不限于此。此外,除了上述组分之外,可以另外包括润滑剂、润湿剂、甜味剂、调味剂、乳化剂、悬浮剂、防腐剂等。
根据本发明的药物组合物可以在临床给药时口服或肠胃外给药,并且可以以通用药物制剂的形式使用。也就是说,本发明的药物组合物可以在实际临床给药时在口服和肠胃外的各种制剂中给药,并且在配制时,使用常用的稀释剂或赋形剂如填充剂、增量剂、黏合剂、润湿剂、崩解剂、表面活性剂等来制备。用于口服给药的固体制剂包括片剂、丸剂、粉剂、颗粒剂、胶囊等,并且此类固体制剂通过将至少一种赋形剂例如淀粉、碳酸钙、蔗糖或乳糖、明胶等在草药提取物或草药发酵产物中混合来制备。此外,除了简单的赋形剂之外,还使用润滑剂例如硬脂酸镁和滑石。用于口服给药的液体制剂可以包括悬液、内服液体、乳液、糖浆等,并且除了作为常用的简单稀释剂的水和液体石蜡之外,还可以包括各种赋形剂例如润湿剂、甜味剂、调味剂、香料、防腐剂等。用于胃肠外给药的制剂包括无菌水溶液、非水性溶剂、悬浮剂、乳液、冻干制剂和栓剂。非水性溶剂和悬液的实例可以包括丙二醇、聚乙二醇、植物油例如橄榄油和可注射的酯例如油酸乙酯。作为栓剂的基料,可以使用witepsol、聚乙二醇、Tween 61、可可脂、月桂精脂肪、甘油、明胶等。
当药物组合物用于临床目的给药时,式1的化合物或其药学上可接受的盐的有效剂量可随着多种因素而变,例如制剂方法、给药方式、患者的年龄、体重、性别、病理状况和饮食、给药时间、给药途径、排泄率、药物混合和响应敏感性,但通常药物组合物可以以每1kg成年患者体重0.01至20mg/天、优选地1至10mg/天给药,并且可以根据医生或药剂师的斟酌以规则的时间间隔,每天几次、优选地每天2至3次分期给药。
另一方面,本发明提供了一种治疗蛋白激酶介导的疾病、特别是RON介导的疾病的方法,所述方法包括向受试者给药治疗有效量的上式1的化合物或其药学上可接受的盐。
另一方面,本发明提供了一种抑制RON受体活性的方法,所述方法包括向受试者给药治疗有效量的上式1的化合物或其药学上可接受的盐。
在本说明书中,术语“治疗有效量”意指每种制剂在通过所述每种制剂自身治疗的过程中实现降低疾病严重程度及其发作频率的目的,但避免通常与其他疗法相关的有害副作用的量。例如,用于肿瘤治疗的有效药剂有效地延长患者生存期、抑制与肿瘤相关的快速增殖细胞的生长或使肿瘤消退。
在下文中,可以根据下述方法制备本发明的示例性化合物,但本发明的化合物不限于所述制备方法。
制备例1. 7-(4-氨基-2-氟苯氧基)-1-异丙基-1,3-二氢-2H-咪唑并[4,5-b]吡啶-2-酮
在下文中,根据下述反应式1制备了制备例1的化合物。
反应式1.
步骤1)(3-氟-4-羟基苯基)氨基甲酸叔丁酯
将4-氨基-2-氟苯酚(10g,79mmol)溶解在THF(100mmol)中,然后向其添加Boc酸酐(34.3g,158mmol),并将混合物在室温下搅拌12小时。将反应混合物浓缩,并将残留物通过柱层析进行纯化,得到标题化合物(13g,得率:72%)。
MS m/z:228[M+H]。
步骤2)(4-((2-氨基-3-硝基吡啶-4-基)氧基)-3-氟苯基)氨基甲酸叔丁酯
将在上述步骤1中得到的化合物(3-氟-4-羟基苯基)氨基甲酸叔丁酯(12.5g,55mmol)和4-氯-3-硝基吡啶-2-胺(9.55g,55mmol)溶解在60mL DMSO中,然后在0℃下向其添加NaH(2.64g,66mmol),并将混合物在100℃下搅拌12小时。将反应混合物用乙酸乙酯稀释,用水和盐水洗涤,然后浓缩。将残留物通过柱层析进行纯化,得到标题化合物(15g,得率:75%)。
MS m/z:365[M+H]。
步骤3)(4-((2,3-二氨基吡啶-4-基)氧基)-3-氟苯基)氨基甲酸叔丁酯
将在上述步骤2中得到的化合物(4-((2-氨基-3-硝基吡啶-4-基)氧基)-3-氟苯基)氨基甲酸叔丁酯在室温下溶解在甲醇/THF混合溶剂中,然后向其添加Pd/C,并将混合物在氢气条件下搅拌12小时。将反应混合物通过硅藻土滤器过滤,然后浓缩。将残留物通过柱层析进行纯化,得到标题化合物(11.5g,得率:84%)。
MS m/z:335[M+H]。
步骤4)(4-((2-氨基-3-((乙氧基羰基)氨基)吡啶-4-基)氧基)-3-氟苯基)氨基甲酸叔丁酯
将在上述步骤3中得到的化合物(4-((2,3-二氨基吡啶-4-基)氧基)-3-氟苯基)氨基甲酸叔丁酯(10g,29.9mmol)和吡啶(4.73g,59.8mmol)溶解在THF中,然后在0℃下向其缓慢添加氯甲酸乙酯(3.57g,32.9mmol)。将混合物搅拌12小时,然后将反应混合物用乙酸乙酯稀释,用水和盐水洗涤,然后浓缩。将残留物通过柱层析进行纯化,得到标题化合物(4.5g,得率:37%)。
MS m/z:407[M+H]。
步骤5)(2-氨基-4-(4-氨基-2-氟苯氧基)吡啶-3-基)氨基甲酸乙酯
将在上述步骤4中获得的化合物(4-((2-氨基-3-((乙氧基羰基)氨基)吡啶-4-基)氧基)-3-氟苯基)氨基甲酸叔丁酯(3.5g,8.61mmol)溶解在TFA/DCM 1:5混合溶剂中,并在室温下搅拌5小时。将反应混合物用乙酸乙酯稀释,用水和盐水洗涤,并通过柱层析进行纯化,得到标题化合物(1.9g,得率:72%)。
MS m/z:307[M+H]。
步骤6)(2-氨基-4-(4-氨基-2-氟苯氧基)吡啶-3-基)(异丙基)氨基甲酸乙酯
将在上述步骤5中得到的化合物(2-氨基-4-(4-氨基-2-氟苯氧基)吡啶-3-基)氨基甲酸乙酯(1.9g,6.2mmol)溶解在DMF中,然后在0℃下向其添加NaH(0.273g,6.82mmol),然后向其缓慢添加2-溴丙烷(0.84g,6.82mmol)。将混合物搅拌12小时,然后将反应混合物用乙酸乙酯稀释,用水和盐水洗涤,然后浓缩。将残留物通过柱层析进行纯化,得到标题化合物(1.25g,得率:58%)。
MS m/z:349[M+H]。
步骤7)7-(4-氨基-2-氟苯氧基)-1-异丙基-1,3-二氢-2H-咪唑并[4,5-b]吡啶-2-酮
将在上述步骤6中得到的化合物(2-氨基-4-(4-氨基-2-氟苯氧基)吡啶-3-基)(异丙基)氨基甲酸乙酯(1.25g,3.59mmol)和乙醇钠(0.488g,7.18mmol)溶解在乙醇中,并将混合物在微波条件和120℃下搅拌4小时。向反应混合物添加水以结晶所述混合物,由此得到标题化合物(1.0g,得率:92%)。
1H NMR(500MHz,MeOH-d4)δ7.76(d,1H),7.03(t,1H),6.62(dd,1H),6.57(dd,1H),6.33(d,1H),5.02(m,1H),1.58(s,3H),1.07(s,3H);MS m/z:303[M+H]
制备例2. 7-(4-氨基-2-氟苯氧基)-1-乙基-1,3-二氢-2H-咪唑并[4,5-b]吡啶-2-酮
以与制备例1相似的方式,通过使用碘乙烷代替制备例1的步骤6中的2-溴丙烷,得到标题化合物(63mg,得率:56%)。
MS m/z:289[M+H]。
制备例3. 7-(4-氨基-2-氟苯氧基)-1-甲基-1,3-二氢-2H-咪唑并[4,5-b]吡啶-2-酮
以与制备例1相似的方式,通过使用碘甲烷代替制备例1的步骤6中的2-溴丙烷,得到标题化合物(90mg,得率:74%)。
MS m/z:275[M+H]。
制备例4. 7-(4-氨基-2-氟苯氧基)-1-环戊基-1,3-二氢-2H-咪唑并[4,5-b]吡啶-2-酮
以与制备例1相似的方式,通过使用环戊基溴代替制备例1的步骤6中的2-溴丙烷,得到标题化合物(150mg,得率:86%)。
MS m/z:329[M+H]。
制备例5. 7-(4-氨基-2-氟苯氧基)-1,3-二氢-2H-咪唑并[4,5-b]吡啶-2-酮
在下文中,按照下述反应式2制备了制备例5的化合物。
反应式2.
步骤1)(3-氟-4-((2-酮基-2,3-二氢-1H-咪唑并[4,5-b]吡啶-7-基)氧基)苯基)氨基甲酸叔丁酯
将(4-((2,3-二氨基吡啶-4-基)氧基)-3-氟苯基)氨基甲酸叔丁酯(250mg,0.75mmol)溶解在THF中,并将混合物冷却至0℃。向其添加三光气(225mg,0.75mmol),并将混合物在0℃下搅拌30分钟。向其添加饱和NaHCO3,并将混合物用乙酸乙酯萃取3次。将有机层用盐水洗涤并浓缩,并将残留物通过柱层析进行纯化,得到标题化合物(85mg,得率:32%)。
MS m/z:361[M+H]。
步骤2)7-(4-氨基-2-氟苯氧基)-1,3-二氢-2H-咪唑并[4,5-b]吡啶-2-酮
将在上述步骤1中得到的化合物(3-氟-4-((2-酮基-2,3-二氢-1H-咪唑并[4,5-b]吡啶-7-基)氧基)苯基)氨基甲酸叔丁酯(80mg,0.22mmol)溶解在3ml DCM中,并向其添加1.5ml TFA。将反应混合物在室温下搅拌2小时。将反应混合物浓缩,用乙酸乙酯稀释,并用饱和NaHCO3洗涤。将有机层用盐水洗涤并浓缩,得到标题化合物(40mg,得率:69%)。
MS m/z:261[M+H]。
制备例6. 1-(2-氟苯基)-5-(三氟甲基)-1H-吡唑-4-甲酸
在下文中,按照下述反应式3制备了制备例6的化合物。
反应式3.
步骤1)2-(乙氧基亚甲基)-4,4,4-三氟-3-酮基丁酸乙酯
将4,4,4-三氟-3-酮基丁酸乙酯(2.0g,10.9mmol)和三乙氧基甲烷(2.0g,14.1mmol)溶解在乙酸酐(3.3g,32.6mmol)中,并将混合物在130℃下搅拌4小时。将反应混合物浓缩,得到标题化合物(2.0g,得率:77%)。
MS m/z:241[M+H]。
步骤2)1-(2-氟苯基)-5-(三氟甲基)-1H-吡唑-4-甲酸乙酯
将在上述步骤1中得到的化合物2-(乙氧基亚甲基)-4,4,4-三氟-3-酮基丁酸乙酯(0.5g,2.1mmol)和(2-氟苯基)肼(0.263g,2.1mmol)溶解在7ml乙醇中,并将混合物在70℃下搅拌4小时。将反应混合物用乙酸乙酯和水萃取并浓缩。将残留物通过柱层析进行纯化,得到标题化合物(0.38g,得率:60%)。
MS m/z:303[M+H]。
步骤3)1-(2-氟苯基)-5-(三氟甲基)-1H-吡唑-4-甲酸
将在上述步骤2中得到的化合物1-(2-氟苯基)-5-(三氟甲基)-1H-吡唑-4-甲酸乙酯(0.38g,1.3mmol)溶解在4ml乙醇中,然后在室温下向其添加2ml 6N氢氧化钠溶液,并将混合物搅拌1小时。将通过向反应产物添加冰水形成的固体过滤出来,得到标题化合物(0.18g,得率:52%)。
MS m/z:275[M+H]。
实施例1.N-(3-氟-4-((2-酮基-2,3-二氢-1H-咪唑并[4,5-b]吡啶-7-基)氧基)苯基)-1-苯基-5-(三氟甲基)-1H-咪唑-4-甲酰胺
在下文中,按照下述反应式4制备实施例1的化合物。
反应式4
将在上述制备例5中得到的化合物7-(4-氨基-2-氟苯氧基)-1H-1,3-二氢-2H-咪唑并[4,5-b]吡啶-2-酮(20mg,0.07mmol)、1-苯基-5-(三氟甲基)-1H-咪唑-4-甲酸(20mg,0.08mmol)和HATU(40mg,0.10mmol)溶解在2mL DMF中,然后向其添加DIPEA(17μl,0.10mmol),并将混合物在室温下搅拌12小时。将反应混合物用乙酸乙酯稀释,用水和盐水洗涤,然后浓缩。将残留物通过制备型HPLC进行纯化(0.1%甲酸水溶液/乙腈),得到标题化合物(11mg,得率:30%)。
1H NMR(500MHz,DMSO-d6)δ11.30(brs,1H),10.77(s,1H),8.35(s,1H),8.04(m,1H),7.78(d,1H),7.72(m,1H),7.60(m,3H),7.39(t,1H),6.37(d,1H);MS m/z:499[M+H]
实施例2.N-(3-氟-4-((2-酮基-2,3-二氢-1H-咪唑并[4,5-b]吡啶-7-基)氧基)苯基)-1-苯基-5-(三氟甲基)-1H-吡唑-4-甲酰胺
以与实施例1相似的方式,通过使用1-苯基-5-(三氟甲基)-1H-吡唑-4-甲酸代替根据实施例1的1-苯基-5-(三氟甲基)-1H-咪唑-4-甲酸,得到标题化合物(9mg,得率:28%)。
1H NMR(500MHz,DMSO-d6)δ10.84(s,1H),8.34(s,1H),7.93(dd,1H),7.78(d,1H),7.64(m,3H),7.56(m,3H),7.40(t,1H),6.38(d,1H);MS m/z:499[M+H]
实施例3.N-(4-((1-乙基-2-酮基-2,3-二氢-1H-咪唑并[4,5-b]吡啶-7-基)氧基)-3-氟苯基)-1-苯基-5-(三氟甲基)-1H-咪唑-4-甲酰胺
以与实施例1相似的方式,通过使用在制备例2中得到的7-(4-氨基-2-氟苯氧基)-1-乙基-1,3-二氢-2H-咪唑并[4,5-b]吡啶-2-酮代替根据实施例1的7-(4-氨基-2-氟苯氧基)-1H-1,3-二氢-2H-咪唑并[4,5-b]吡啶-2-酮,得到标题化合物(35mg,得率:64%)。
1H NMR(500MHz,DMSO-d6)δ11.64(brs,1H),10.74(s,1H),8.31(s,1H),8.01(d,1H),7.98(d,1H),7.75(m,1H),7.59(m,5H),7.41(t,1H),6.36(d,1H),3.97(q,2H),1.26(t,3H);MS m/z:527[M+H]。
实施例4.N-(4-((1-乙基-2-酮基-2,3-二氢-1H-咪唑并[4,5-b]吡啶-7-基)氧基)-3-氟苯基)-1-苯基-5-(三氟甲基)-1H-吡唑-4-甲酰胺
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以与实施例3相似的方式,通过使用1-苯基-5-(三氟甲基)-1H-吡唑-4-甲酸代替根据实施例3的1-苯基-5-(三氟甲基)-1H-咪唑-4-甲酸,得到标题化合物(33mg,得率:60%)。
1H NMR(500MHz,DMSO-d6)δ11.62(brs,1H),10.81(s,1H),8.30(s,1H),7.90(d,1H),7.77(d,1H),7.59(m,3H),7.52(m,3H),7.43(t,1H),6.37(d,1H),3.97(q,2H),1.26(t,3H);MS m/z:527[M+H]。
实施例5.N-(3-氟-4-((1-甲基-2-酮基-2,3-二氢-1H-咪唑并[4,5-b]吡啶-7-基)氧基)苯基)-1-苯基-5-(三氟甲基)-1H-咪唑-4-甲酰胺
以与实施例1相似的方式,通过使用在制备例3中得到的7-(4-氨基-2-氟苯氧基)-1-甲基-1,3-二氢-2H-咪唑并[4,5-b]吡啶-2-酮代替根据实施例1的7-(4-氨基-2-氟苯氧基)-1-H-1,3-二氢-2H-咪唑并[4,5-b]吡啶-2-酮,得到标题化合物(15mg,得率:26%)。
1H NMR(500MHz,DMSO-d6)δ11.63(brs,1H),10.73(s,1H),8.31(s,1H),7.97(d,1H),7.76(d,1H),7.63(m,1H),7.48(m,5H),7.38(t,1H),6.38(d,1H),3.47(s,3H);MS m/z:513[M+H]。
实施例6.N-(3-氟-4-((1-甲基-2-酮基-2,3-二氢-1H-咪唑并[4,5-b]吡啶-7-基)氧基)苯基)-1-苯基-5-(三氟甲基)-1H-吡唑-4-甲酰胺
以与实施例5相似的方式,通过使用1-苯基-5-(三氟甲基)-1H-吡唑-4-甲酸代替根据实施例5的1-苯基-5-(三氟甲基)-1H-咪唑-4-甲酸,得到标题化合物(15mg,得率:21%)。
1H NMR(500MHz,DMSO-d6)δ11.64(brs,1H),10.80(s,1H),8.30(s,1H),7.88(d,1H),7.76(d,1H),7.59(m,3H),7.50(m,3H),7.40(t,1H),6.38(d,1H),3.46(s,3H);MS m/z:513[M+H]。
实施例7.N-(3-氟-4-((1-异丙基-2-酮基-2,3-二氢-1H-咪唑并[4,5-b]吡啶-7-基)氧基)苯基)-1-苯基-5-(三氟甲基)-1H-吡唑-4-甲酰胺
以与实施例1相似的方式,通过使用在制备例1中得到的7-(4-氨基-2-氟苯氧基)-1-异丙基-1,3-二氢-2H-咪唑并[4,5-b]吡啶-2-酮代替根据实施例1的7-(4-氨基-2-氟苯氧基)-1-H-1,3-二氢-2H-咪唑并[4,5-b]吡啶-2-酮,得到标题化合物(10mg,得率:11%)。
1H NMR(500MHz,MeOH-d4)δ8.13(s,1H),7.89(m,2H),7.58(m,6H),7.36(t,1H),6.45(d,1H),5.01(m,1H),1.57(d,6H);MS m/z:541[M+H]。
实施例8.N-(3-氟-4-((1-异丙基-2-酮基-2,3-二氢-1H-咪唑并[4,5-b]吡啶-7-基)氧基)苯基)-1-苯基-5-(三氟甲基)-1H-咪唑-4-甲酰胺
以与实施例7相似的方式,通过使用1-苯基-5-(三氟甲基)-1H-咪唑-4-甲酸代替根据实施例7的1-苯基-5-(三氟甲基)-1H-吡唑-4-甲酸,得到标题化合物(36mg,得率:50%)。
1H NMR(500MHz,DMSO-d6)δ11.68(brs,1H),10.78(s,1H),8.35(s,1H),8.06(m,1H),7.81(d,1H),7.76(m,1H),7.62(m,5H),7.42(t,1H),6.42(d,1H),4.90(m,1H),1.49(d,6H),1.47(s,3H);MS m/z:541[M+H]。
实施例9. 5-乙基-N-(3-氟-4-((2-酮基-2,3-二氢-1H-咪唑并[4,5-b]吡啶-7-基)氧基)苯基)-1-苯基-1H-吡唑-4-甲酰胺
以与实施例1相似的方式,通过使用5-乙基-1-苯基-1H-吡唑-4-甲酸代替根据实施例1的1-苯基-5-(三氟甲基)-1H-咪唑-4-甲酸,得到标题化合物(26mg,得率:53%)。
1H NMR(500MHz,DMSO-d6)δ11.41(brs,1H),11.23(brs,1H),10.14(s,1H),8.32(s,1H),7.98(d,1H),7.78(d,1H),7.62(m,4H),7.51(m,2H),7.38(t,1H),6.36(d,1H),2.98(q,2H),1.08(t,3H);MS m/z:459[M+H]
实施例10. 5-乙基-N-(3-氟-4-((1-异丙基-2-酮基-2,3-二氢-1H-咪唑并[4,5-b]吡啶-7-基)氧基)苯基)-1-苯基-1H-吡唑-4-甲酰胺
以与实施例7相似的方式,通过使用5-乙基-1-苯基-1H-吡唑-4-甲酸代替根据实施例7的1-苯基-5-(三氟甲基)-1H-吡唑-4-甲酸,得到标题化合物(26mg,得率:53%)。
1H NMR(500MHz,DMSO-d6)δ11.68(brs,1H),10.15(s,1H),8.34(s,1H),8.01(d,1H),7.82(d,1H),7.60(m,3H),7.51(m,3H),7.45(t,1H),6.41(d,1H),4.90(m,1H),2.99(q,2H),1.09(t,3H);MS m/z:501[M+H]
实施例11.N-(3-氟-4-((2-酮基-1-(四氢-2H-吡喃-4-基)-2,3-二氢-1H-咪唑并[4,5-b]吡啶-7-基)氧基)苯基)-1-苯基-5-(三氟甲基)-1H-咪唑-4-甲酰胺
以与实施例1相似的方式,通过使用7-(4-氨基-2-氟苯氧基)-1-(四氢-2H-吡喃-4-基)-1,3-二氢-2H-咪唑并[4,5-b]吡啶-2-酮代替根据实施例1的7-(4-氨基-2-氟苯氧基)-1-H-1,3-二氢-2H-咪唑并[4,5-b]吡啶-2-酮,得到标题化合物(1.4mg,得率:12%)。
MS m/z:583[M+H]。
实施例12.N-(3-氟-4-((2-酮基-2,3-二氢-1H-咪唑并[4,5-b]吡啶-7-基)氧基)苯基)-3,5-二甲基-1-苯基-1H-吡唑-4-甲酰胺
以与实施例1相似的方式,通过使用3,5-二甲基-1-苯基-1H-吡唑-4-甲酸代替根据实施例1的1-苯基-5-(三氟甲基)-1H-咪唑-4-甲酸,得到标题化合物(25mg,得率:48%)。
1H NMR(500MHz,DMSO-d6)δ11.41(brs,1H),11.27(brs,1H),10.14(s,1H),7.93(d,1H),7.77(d,1H),7.57(m,2H),7.52(m,4H),7.34(t,1H),6.35(d,1H),2.43(s,3H),2.38(s,3H);MS m/z:459[M+H]
实施例13.N-(3-氟-4-((1-异丙基-2-酮基-2,3-二氢-1H-咪唑并[4,5-b]吡啶-7-基)氧基)苯基)-3,5-二甲基-1-苯基-1H-吡唑-4-甲酰胺
以与实施例7相似的方式,通过使用3,5-二甲基-1-苯基-1H-吡唑-4-甲酸代替根据实施例7的1-苯基-5-(三氟甲基)-1H-吡唑-4-甲酸,得到标题化合物(9mg,得率:22%)。
1H NMR(500MHz,MeOH-d4)δ7.92(d,1H),7.86(d,1H),7.61(m,2H),7.49(m,4H),7.37(t,1H),6.49(d,1H),5.08(m,1H),2.48(s,3H),2.46(s,3H),1.62(d,6H);MS m/z:501[M+H]
实施例14.N-(3-氟-4-((1-异丙基-2-酮基-2,3-二氢-1H-咪唑并[4,5-b]吡啶-7-基)氧基)苯基)-5-甲基-1-苯基-1H-吡唑-4-甲酰胺
以与实施例7相似的方式,通过使用5-甲基-1-苯基-1H-吡唑-4-甲酸代替根据实施例7的1-苯基-5-(三氟甲基)-1H-吡唑-4-甲酸,得到标题化合物(15mg,得率:23%)。
1H NMR(500MHz,DMSO-d6)δ10.15(s,1H),8.34(s,1H),7.98(dd,1s),7.87(d,1H),7.61-7.51(m,6H),7.43(t,1H),6.40(d,1H),4.88(m,1H),2.57(s,3H),1.50(1s,3H),1.49(1s,3H);MS m/z:487[M+H]
实施例15.N-(3-氟-4-((1-异丙基-2-酮基-2,3-二氢-1H-咪唑并[4,5-b]吡啶-7-基)氧基)苯基)-2-苯基噻唑-5-甲酰胺
以与实施例7相似的方式,通过使用2-苯基噻唑-5-甲酸代替根据实施例7的1-苯基-5-(三氟甲基)-1H-吡唑-4-甲酸,得到标题化合物(20mg,得率:31%)。
1H NMR(500MHz,DMSO-d6)δ11.70(s,1H),10.77(s,1H),8.71(s,1H),8.06-8.05(m,2H),7.95(dd,1H),7.82(d,1H),7.62-7.56(m,4H),7.47(t,1H),6.41(d,1H),4.87(m,1H),1.49(s,3H),1.48(s,3H);MS m/z:490[M+H]。
实施例16.N-(3-氟-4-((1-异丙基-2-酮基-2,3-二氢-1H-咪唑并[4,5-b]吡啶-7-基)氧基)苯基)-5-苯基噻唑-2-甲酰胺
以与实施例7相似的方式,通过使用5-苯基噻唑-5-甲酸代替根据实施例7的1-苯基-5-(三氟甲基)-1H-吡唑-4-甲酸,得到标题化合物(10mg,得率:18%)。
1H NMR(500MHz,DMSO-d6)δ11.69(s,1H),11.17(s,1H),8.56(s,1H),8.06(dd,1H),7.86-7.80(m,4H),7.54-7.44(m,4H),6.41(d,1H),4.87(m,1H),1.49(s,3H),1.47(s,3H);MS m/z:490[M+H]。
实施例17.N-(3-氟-4-((1-异丙基-2-酮基-2,3-二氢-1H-咪唑并[4,5-b]吡啶-7-基)氧基)苯基)-1-(对甲苯基)-5-(三氟甲基)-1H-吡唑-4-甲酰胺
以与实施例7相似的方式,通过使用1-(对甲苯基)-5-(三氟甲基)-1H-吡唑-4-甲酸代替根据实施例7的1-苯基-5-(三氟甲基)-1H-吡唑-4-甲酸,得到标题化合物(15mg,得率:20%)。
1H NMR(400MHz,DMSO-d6)δ11.65(s,1H),10.80(s,1H),8.27(s,1H),7.88(dd,1H),7.76(d,1H),7.52(d,1H),7.46-7.35(m,5H),6.36(d,1H),4.83(m,1H),2.31(s,3H),1.45(s,3H),1.43(s,3H);MS m/z:555[M+H]。
实施例18.N-(3-氟-4-((1-异丙基-2-酮基-2,3-二氢-1H-咪唑并[4,5-b]吡啶-7-基)氧基)苯基)-1-(2-甲氧基苯基)-5-(三氟甲基)-1H-吡唑-4-甲酰胺
以与实施例7相似的方式,通过使用1-(2-甲氧基苯基)-5-(三氟甲基)-1H-吡唑-4-甲酸代替根据实施例7的1-苯基-5-(三氟甲基)-1H-吡唑-4-甲酸,得到标题化合物(30mg,得率:40%)。
1H NMR(400MHz,DMSO-d6)δ11.55(brs,1H),10.73(s,1H),8.30(s,1H),7.89(dd,1H),7.76(d,1H),7.58-7.53(m,2H),7.43-7.38(m,2H),7.25(d,1H),7.10(t,1H),6.36(d,1H),4.83(m,1H),3.75(s,3H),1.44(s,3H),1.43(s,3H);MS m/z:571[M+H]。
实施例19.N-(3-氟-4-((1-异丙基-2-酮基-2,3-二氢-1H-咪唑并[4,5-b]吡啶-7-基)氧基)苯基)-1,5-二苯基-1H-吡唑-4-甲酰胺
以与实施例7相似的方式,通过使用1,5-二苯基-1H-吡唑-4-甲酸代替根据实施例7的1-苯基-5-(三氟甲基)-1H-吡唑-4-甲酸,得到标题化合物(14mg,得率:19%)。
1H NMR(400MHz,DMSO-d6)δ10.23(s,1H),8.35(s,1H),7.83(dd,1H),7.74(d,1H),7.46(d,1H),7.36-7.26(m,9H),7.19(dd,2H),6.31(d,1H),4.81(m,1H),1.43(s,3H),1.42(s,3H);MS m/z:549[M+H]。
实施例20.N-(3-氟-4-((1-异丙基-2-酮基-2,3-二氢-1H-咪唑并[4,5-b]吡啶-7-基)氧基)苯基)-1-(四氢-2H-吡喃-3-基)-5-(三氟甲基)-1H-吡唑-4-甲酰胺
以与实施例7相似的方式,通过使用1-(四氢-2H-吡喃-3-基)-5-(三氟甲基)-1H-吡唑-4-甲酸代替根据实施例7的1-苯基-5-(三氟甲基)-1H-吡唑-4-甲酸,得到标题化合物(24mg,得率:33%)。
MS m/z:549[M+H]。
实施例21.N-(4-((1-环戊基-2-酮基-2,3-二氢-1H-咪唑并[4,5-b]吡啶-7-基)氧基)-3-氟苯基)-1-苯基-5-(三氟甲基)-1H-咪唑-4-甲酰胺
以与实施例1相似的方式,通过使用在制备例4中得到的7-(4-氨基-2-氟苯氧基)-1-环戊基-1,3-二氢-2H-咪唑并[4,5-b]吡啶-2-酮代替根据实施例1的7-(4-氨基-2-氟苯氧基)-1-H-1,3-二氢-2H-咪唑并[4,5-b]吡啶-2-酮,得到标题化合物(35mg,得率:64%)。
1H NMR(400MHz,DMSO-d6)δ11.68(s,1H),10.74(s,1H),8.31(s,1H),7.99(dd,1H),7.77(d,1H),7.71(d,1H),7.59-7.54(m,5H),7.39(t,1H),6.36(d,1H),4.94(m,1H),2.08-1.99(m,2H),1.94-1.87(m,2H),1.71-1.69(m,2H),1.59-1.54(m,2H);MS m/z:567[M+H]。
实施例22.N-(4-((1-环戊基-2-酮基-2,3-二氢-1H-咪唑并[4,5-b]吡啶-7-基)氧基)-3-氟苯基)-1-苯基-5-(三氟甲基)-1H-吡唑-4-甲酰胺
以与实施例21相似的方式,通过使用1-苯基-5-(三氟甲基)-1H-吡唑-4-甲酸代替根据实施例21的1-苯基-5-(三氟甲基)-1H-咪唑-4-甲酸,得到标题化合物(20mg,得率:29%)。
1H NMR(400MHz,DMSO-d6)δ11.72(s,1H),10.85(s,1H),8.34(s,1H),7.92(dd,1H),7.82(d,1H),7.64-7.63(m,3H),7.57-7.55(m,3H),7.46(t,1H),6.41(d,1H),2.09-2.05(m,2H),1.98-1.97(m,2H),1.76-1.75(m,2H),1.61-1.60(m,2H);MS m/z:567[M+H]。
实施例23.N-(4-((1-环戊基-2-酮基-2,3-二氢-1H-咪唑并[4,5-b]吡啶-7-基)氧基)-3-氟苯基)-5-乙基-1-苯基-1H-吡唑-4-甲酰胺
以与实施例21相似的方式,通过使用5-乙基-1-苯基-1H-吡唑-4-甲酸代替根据实施例21的1-苯基-5-(三氟甲基)-1H-咪唑-4-甲酸,得到标题化合物(22mg,得率:36%)。
1H NMR(400MHz,DMSO-d6)δ11.68(s,1H),10.11(s,1H),8.29(s,1H),7.94(dd,1H),7.78(d,1H),7.58-7.46(m,6H),7.38(t,1H),6.36(d,1H),4.95(m,1H),2.92(q,2H),2.05-2.00(m,2H),1.94-1.90(m,2H),1.71-1.69(m,2H),1.56-1.55(m,2H),1.03(t,3H);MS m/z:527[M+H]。
实施例24.N-(3-氟-4-((1-异丙基-2-酮基-2,3-二氢-1H-咪唑并[4,5-b]吡啶-7-基)氧基)苯基)-2-(三氟甲基)苯甲酰胺
以与实施例7相似的方式,通过使用2-(三氟甲基)苯甲酸代替根据实施例7的1-苯基-5-(三氟甲基)-1H-吡唑-4-甲酸,得到标题化合物(32mg,得率:51%)。
1H NMR(500MHz,DMSO-d6)δ11.68(s,1H),10.90(s,1H),7.91-7.74(m,6H),7.53(d,1H),7.44(t,1H),6.42(d,1H),4.87(m,1H),1.49(s,3H),1.47(s,3H);MS m/z:475[M+H]。
实施例25. 4-溴-N-(3-氟-4-((1-异丙基-2-酮基-2,3-二氢-1H-咪唑并[4,5-b]吡啶-7-基)氧基)苯基)-2-(三氟甲基)苯甲酰胺
以与实施例7相似的方式,通过使用4-溴-2-(三氟甲基)苯甲酸代替根据实施例7的1-苯基-5-(三氟甲基)-1H-吡唑-4-甲酸,得到标题化合物(27mg,得率:37%)。
1H NMR(500MHz,DMSO-d6)δ11.69(s,1H),10.94(s,1H),8.11(s,1H),8.07(d,1H),7.87(dd,1H),7.81(d,1H),7.73(d,1H),7.50(d,1H),7.45(t,1H),6.41(d,1H),4.87(m,1H),1.48(s,3H),1.47(s,3H);MS m/z:553[M],555[M+2]。
实施例26.N-(3-氟-4-((1-异丙基-2-酮基-2,3-二氢-1H-咪唑并[4,5-b]吡啶-7-基)氧基)苯基)-1-(萘-1-基)-5-(三氟甲基)-1H-吡唑-4-甲酰胺
以与实施例7相似的方式,通过使用1-(萘-1-基)-5-(三氟甲基)-1H-吡唑-4-甲酸代替根据实施例7的1-苯基-5-(三氟甲基)-1H-吡唑-4-甲酸,得到标题化合物(45mg,得率:58%)。
1H NMR(500MHz,DMSO-d6)δ11.69(s,1H),10.90(s,1H),8.49(s,1H),8.25(d,1H),8.15(d,1H),7.95(dd,1H),7.81(d,1H),7.78(d,1H),7.77-7.59(m,4H),7.48(t,1H),7.13(d,1H),6.43(d,1H),4.88(m,1H),1.50(s,3H),1.48(s,1H);MS m/z:591[M+H]。
实施例27. 3-溴-N-(3-氟-4-((1-异丙基-2-酮基-2,3-二氢-1H-咪唑并[4,5-b]吡啶-7-基)氧基)苯基)-2-(三氟甲基)苯甲酰胺
以与实施例7相似的方式,通过使用3-溴-2-(三氟甲基)苯甲酸代替根据实施例7的1-苯基-5-(三氟甲基)-1H-吡唑-4-甲酸,得到标题化合物(100mg,得率:27%)。
1H NMR(500MHz,DMSO-d6)δ11.69(s,1H),10.96(s,1H),8.05(d,1H),7.86-7.73(m,2H),7.70(m,2H),7.49-7.43(m,2H),6.41(d,1H),4.87(m,1H),1.48(s,3H),1.47(s,3H);MSm/z:553[M],555[M+2]。
实施例28. 1-环己基-N-(3-氟-4-((1-异丙基-2-酮基-2,3-二氢-1H-咪唑并[4,5-b]吡啶-7-基)氧基)苯基)-5-(三氟甲基)-1H-吡唑-4-甲酰胺
以与实施例7相似的方式,通过使用1-环己基-5-(三氟甲基)-1H-吡唑-4-甲酸代替根据实施例7的1-苯基-5-(三氟甲基)-1H-吡唑-4-甲酸,得到标题化合物(24mg,得率:33%)。
1H NMR(500MHz,DMSO-d6)δ11.70(s,1H),10.76(s,1H),8.07(s,1H),7.88(d,1H),7.80(d,1H),7.51(d,1H),7.43(t,1H),6.39(d,1H),1.94-1.85(m,6H),1.70-1.68(m,1H),1.48(s,3H),1.47(s,3H),1.43-1.40(m,1H),1.28-1.20(m,2H);MS m/z:547[M+H]。
实施例29.N-(3-氟-4-((1-异丙基-2-酮基-2,3-二氢-1H-咪唑并[4,5-b]吡啶-7-基)氧基)苯基)-1-(四氢-2H-吡喃-4-基)-5-(三氟甲基)-1H-吡唑-4-甲酰胺
以与实施例7相似的方式,通过使用1-(四氢-2H-吡喃-4-基)-5-(三氟甲基)-1H-吡唑-4-甲酸代替根据实施例7的1-苯基-5-(三氟甲基)-1H-吡唑-4-甲酸,得到标题化合物(41mg,得率:57%)。
1H NMR(500MHz,DMSO-d6)δ11.70(s,1H),10.78(s,1H),8.11(s,1H),7.88(dd,1H),7.80(d,1H),7.51(d,1H),7.43(t,1H),6.39(d,1H),4.78(m,1H),4.62(m,1H),3.99(dd,2H),3.54(t,2H),2.15(m,2H),1.90(dd,2H),1.48(s,3H),1.47(s,3H);MS m/z:549[M+H]。
实施例30. 1-(叔丁基)-N-(3-氟-4-((1-异丙基-2-酮基-2,3-二氢-1H-咪唑并[4,5-b]吡啶-7-基)氧基)苯基)-5-(三氟甲基)-1H-吡唑-4-甲酰胺
以与实施例7相似的方式,通过使用1-(叔丁基)-5-(三氟甲基)-1H-吡唑-4-甲酸代替根据实施例7的1-苯基-5-(三氟甲基)-1H-吡唑-4-甲酸,得到标题化合物(30mg,得率:44%)。
1H NMR(500MHz,DMSO-d6)δ11.70(s,1H),10.82(s,1H),7.96(s,1H),7.88(dd,1H),7.50(d,1H),7.43(t,1H),6.39(d,1H),4.86(m,1H),1.67(s,9H),1.48(s,3H),1.47(s,3H);MS m/z:520[M+H]。
实施例31.1-环庚基-N-(3-氟-4-((1-异丙基-2-酮基-2,3-二氢-1H-咪唑并[4,5-b]吡啶-7-基)氧基)苯基)-5-(三氟甲基)-1H-吡唑-4-甲酰胺
以与实施例7相似的方式,通过使用1-环庚基-5-(三氟甲基)-1H-吡唑-4-甲酸代替根据实施例7的1-苯基-5-(三氟甲基)-1H-吡唑-4-甲酸,得到标题化合物(28mg,得率:38%)。
1H NMR(500MHz,DMSO-d6)δ11.69(s,1H),10.76(s,1H),8.06(s,1H),7.88(d,1H),7.80(d,1H),7.51(d,1H),7.43(t,1H),6.39(d,1H),4.86(m,1H),4.52(m,1H),2.10-1.99(m,4H),1.81(m,1H),1.62-1.53(m,6H),1.48(s,3H),1.47(s,3H);MS m/z:561[M+H]。
实施例32.N-(3-氟-4-((1-异丙基-2-酮基-2,3-二氢-1H-咪唑并[4,5-b]吡啶-7-基)氧基)苯基)-2-(1-苯基-5-(三氟甲基)-1H-吡唑-4-基)乙酰胺
以与实施例7相似的方式,通过使用2-(1-苯基-5-(三氟甲基)-1H-吡唑-4-基)乙酸代替根据实施例7的1-苯基-5-(三氟甲基)-1H-吡唑-4-甲酸,得到标题化合物(16mg,得率:22%)。
1H NMR(500MHz,DMSO-d6)δ10.90(s,1H),8.90(d,1H),8.39(s,1H),7.90(d,1H),7.77(d,1H),7.68(d,1H),7.53(d,1H),7.38(t,1H),6.43(s,2H),5.96(d,1H),2.61(s,3H),2.55(s,3H);MS m/z:555[M+H]。
实施例33.N-(3-氟-4-((1-异丙基-2-酮基-2,3-二氢-1H-咪唑并[4,5-b]吡啶-7-基)氧基)苯基)-1-(1-甲基哌啶-3-基)-5-(三氟甲基)-1H-吡唑-4-甲酰胺
以与实施例7相似的方式,通过使用1-(1-甲基哌啶-3-基)-5-(三氟甲基)-1H-吡唑-4-甲酸代替根据实施例7的1-苯基-5-(三氟甲基)-1H-吡唑-4-甲酸,得到标题化合物(2mg,得率:4%)。
MS m/z:562[M+H]。
实施例34.N-(3-氟-4-((1-异丙基-2-酮基-2,3-二氢-1H-咪唑并[4,5-b]吡啶-7-基)氧基)苯基)-1-(2-氟苯基)-5-(三氟甲基)-1H-吡唑-4-甲酰胺
以与实施例7相似的方式,通过使用在制备例6中得到的化合物1-(2-氟苯基)-5-(三氟甲基)-1H-吡唑-4-甲酸代替根据实施例7的1-苯基-5-(三氟甲基)-1H-吡唑-4-甲酸,得到标题化合物(25mg,得率:45%)。
1H NMR(500MHz,DMSO-d6)δ11.70(s,1H),10.87(s,1H),8.44(s,1H),7.93(dd,1H),7.81(d,1H),7.73(m,2H),7.58(m,2H),7.76(m,2H),6.41(d,1H),4.87(m,1H),1.49(s,3H),1.48(s,3H);MS m/z:559[M+H]。
实施例35. 1-(2-氯苯基)-N-(3-氟-4-((1-异丙基-2-酮基-2,3-二氢-1H-咪唑并[4,5-b]吡啶-7-基)氧基)苯基)-5-(三氟甲基)-1H-吡唑-4-甲酰胺
以与实施例7相似的方式,通过使用1-(2-氯苯基)-5-(三氟甲基)-1H-吡唑-4-甲酸代替根据实施例7的1-苯基-5-(三氟甲基)-1H-吡唑-4-甲酸,得到标题化合物(12mg,得率:21%)。
1H NMR(500MHz,DMSO-d6)δ11.69(s,1H),10.84(s,1H),8.45(s,1H),7.94(d,1H),7.80(m,2H),7.71(m,2H),7.60(m,2H),7.46(t,1H),6.41(d,1H),4.87(m,1H),1.49(s,3H),1.48(s,3H);MS m/z:575[M+H]。
实施例36. 1-(2,6-二氟苯基)-N-(3-氟-4-((1-异丙基-2-酮基-2,3-二氢-1H-咪唑并[4,5-b]吡啶-7-基)氧基)苯基)-5-(三氟甲基)-1H-吡唑-4-甲酰胺
以与实施例7相似的方式,通过使用1-(2,6-二氟苯基)-5-(三氟甲基)-1H-吡唑-4-甲酸代替根据实施例7的1-苯基-5-(三氟甲基)-1H-吡唑-4-甲酸,得到标题化合物(22mg,得率:39%)。
1H NMR(500MHz,DMSO-d6)δ11.68(s,1H),10.93(s,1H),8.52(s,1H),7.92(d,1H),7.87-7.81(m,2H),7.57-7.51(m,3H),7.46(t,1H),6.41(d,1H),4.87(m,1H),1.49(s,3H),1.48(s,3H);MS m/z:577[M+H]
实施例37.N-(3-氟-4-((2-酮基-1-(四氢-2H-吡喃-4-基)-2,3-二氢-1H-咪唑并[4,5-b]吡啶-7-基)氧基)苯基)-1-苯基-5-(三氟甲基)-1H-吡唑-4-甲酰胺
以与实施例7相似的方式,通过使用7-(4-氨基-2-氟苯氧基)-1-(四氢-2H-吡喃-4-基)-1,3-二氢-2H-咪唑并[4,5-b]吡啶-2-酮代替根据实施例7的7-(4-氨基-2-氟苯氧基)-1-异丙基-1,3-二氢-2H-咪唑并[4,5-b]吡啶-2-酮,得到标题化合物(30mg,得率:59%)。
1H NMR(500MHz,DMSO-d6)δ11.78(brs,1H),10.86(s,1H),8.35(s,1H),7.94(d,1H),7.83(d,1H),7.63(m,3H),7.57(m,3H),7.47(m,1H),6.43(d,1H),4.71(m,1H),3.97(m,2H),3.43(m,2H),2.43(m,2H),1.73(m,2H);MS m/z:583[M+H]
实施例38.N-(3-氟-4-((2-酮基-1-(四氢呋喃-3-基)-2,3-二氢-1H-咪唑并[4,5-b]吡啶-7-基)氧基)苯基)-1-苯基-5-(三氟甲基)-1H-吡唑-4-甲酰胺
以与实施例7相似的方式,通过使用7-(4-氨基-2-氟苯氧基)-1-(四氢呋喃-3-基)-1,3-二氢-2H-咪唑并[4,5-b]吡啶-2-酮代替根据实施例7的7-(4-氨基-2-氟苯氧基)-1-异丙基-1,3-二氢-2H-咪唑并[4,5-b]吡啶-2-酮,得到标题化合物(25mg,得率:49%)。
1H NMR(500MHz,DMSO-d6)δ11.81(s,1H),10.85(s,1H),8.35(s,1H),7.94(d,1H),7.84(m,1H),7.63(m,3H),7.58(m,3H),7.47(m,1H),6.43(d,1H),5.29(m,1H),4.03(m,1H),3.93(m,3H),2.43(m,1H),2.29(m,1H);MS m/z:569[M+H]
实施例39.N-(3-氟-4-((1-(1-甲基哌啶-4-基)-2-酮基-2,3-二氢-1H-咪唑并[4,5-b]吡啶-7-基)氧基)苯基)-1-苯基-5-(三氟甲基)-1H-吡唑-4-甲酰胺
以与实施例7相似的方式,通过使用7-(4-氨基-2-氟苯氧基)-1-(1-甲基哌啶-4-基)-1,3-二氢-2H-咪唑并[4,5-b]吡啶-2-酮代替根据实施例7的7-(4-氨基-2-氟苯氧基)-1-异丙基-1,3-二氢-2H-咪唑并[4,5-b]吡啶-2-酮,得到标题化合物(0.7mg,得率:4%)。
MS m/z:596[M+H]
实施例40.N-(3-氟-4-((1-异丙基-2-酮基-2,3-二氢-1H-咪唑并[4,5-b]吡啶-7-基)氧基)苯基)-1-苯基-1H-吡唑-3-甲酰胺
以与实施例7相似的方式,通过使用1-苯基-1H-吡唑-3-甲酸代替根据实施例7的1-苯基-5-(三氟甲基)-1H-吡唑-4-甲酸,得到标题化合物(27mg,得率:48%)。
1H NMR(500MHz,DMSO-d6)δ11.67(s,1H),10.47(s,1H),8.68(s,1H),8.12(d,1H),8.07(m,2H),7.81(m,2H),7.60(m,2H),7.43(m,2H),7.08(s,1H),6.41(d,1H),4.86(m,1H),1.49(d,6H)。
实施例41.N-(3-氟-4-((1-异丙基-2-酮基-2,3-二氢-1H-咪唑并[4,5-b]吡啶-7-基)氧基)苯基)-1-苯基-1H-1,2,3-三唑-4-甲酰胺
以与实施例7相似的方式,通过使用1-苯基-1H-1,2,3-三唑-4-甲酸代替根据实施例7的1-苯基-5-(三氟甲基)-1H-吡唑-4-甲酸,得到标题化合物(27mg,得率:48%)。
1H NMR(500MHz,DMSO-d6)δ11.69(s,1H),10.97(s,1H),9.50(s,1H),8.09(m,3H),7.81(s,2H),7.67(m,2H),7.58(m,1H),7.47(m,1H),6.41(d,1H),4.86(m,1H),1.49(d,6H)。
实施例42.N-(3-氟-4-((1-异丙基-2-酮基-2,3-二氢-1H-咪唑并[4,5-b]吡啶-7-基)氧基)苯基)-5-甲基-1-苯基-1H-1,2,3-三唑-4-甲酰胺
以与实施例7相似的方式,通过使用5-甲基-1-苯基-1H-1,2,3-三唑-4-甲酸代替根据实施例7的1-苯基-5-(三氟甲基)-1H-吡唑-4-甲酸,得到标题化合物(35mg,得率:61%)。
1H NMR(500MHz,DMSO-d6)δ11.68(s,1H),10.90(s,1H),8.10(d,1H),7.84(t,2H),7.68(m,5H),7.45(t,1H),6.41(d,1H),4.86(m,1H),2.60(s,3H),1.49(d,6H)。
实施例43.N-(3-氟-4-((1-异丙基-2-酮基-2,3-二氢-1H-咪唑并[4,5-b]吡啶-7-基)氧基)苯基)-1-(2-氟苯基)-1H-1,2,3-三唑-4-甲酰胺
以与实施例7相似的方式,通过使用1-(2-氟苯基)-5-甲基-1H-1,2,3-三唑-4-甲酸代替根据实施例7的1-苯基-5-(三氟甲基)-1H-吡唑-4-甲酸,得到标题化合物(38mg,得率:64%)。
1H NMR(500MHz,DMSO-d6)δ11.69(s,1H),10.94(s,1H),8.09(d,1H),7.84(m,4H),7.65(m,1H),7.54(m,1H),7.46(m,1H),6.41(d,1H),4.86(m,1H),2.50(s,3H),1.49(d,6H)。
实验例1.对RON和MET的抑制活性的评估
[1-1]对RON的抑制活性的评估
为了测量每种实施例化合物对RON的抑制活性,使用时间分辨荧光能量转移化学(TR-FRET)测量了每种化合物的IC50。
具体来说,将所述化合物用100% DMSO制备成1mM的浓度,并通过3倍稀释以逐步方式稀释10次。将2ul所述以逐步方式稀释的化合物添加到含有48ul 1x激酶反应缓冲液(50mM HEPES(pH 7.4),0.01% Tween-20,5mM DTT,0.5mM Na3VO4,2mM EGTA,10mM MgCl2)的96孔板中。
使用RON储存缓冲液(50mM Tris-HCl(pH 7.5),150mM NaCl,0.5mM EDTA,0.02%Triton X-100)将RON蛋白稀释至49.3nM的浓度,然后使用1x激酶反应缓冲液再次稀释至0.4nM的浓度。作为底物混合物,以最终反应浓度的2倍的浓度制备RON特异性底物混合物(40uM ULight标记的Poly GT,100nM ATP)。
然后,制备384孔板,将2.5μl的每种稀释的实施例化合物添加到实验组孔的相应孔中,并将2.5μl 4% DMSO溶液分配到高对照孔和低对照孔中。
然后,将2.5μL的0.4nM RON分配到高对照孔和实验组孔中,将2.5μL的1x激酶反应缓冲液添加到低对照孔中,并将RON和反应缓冲液在室温下以1000RPM离心40秒,然后在室温下温育20至30分钟。然后,将5uL的底物混合物(2x)分配到所有孔中,在室温下以1000RPM离心40秒,然后在室温下温育60分钟。然后,将5uL的30mM EDTA添加到所有孔中以终止反应,然后再次在室温下温育5分钟。然后,将5uL含有铕的4x磷酸酪氨酸抗体(Perkin-Elmer)添加到所有孔中,然后在室温下温育60分钟。在温育后,用Vison读板器读取384孔板。此时,激发波长为340nm,发射波长为620nm和665nm。每种实施例化合物的IC50值使用GraphPdPrism7程序推衍。[1-2]对MET的抑制活性的评估
此外,为了测量对cMET的酶活性抑制,以与RON的酶活性抑制测量实验相同的方式进行了评估。
具体来说,将所述化合物用100% DMSO制备成1mM的浓度,并通过3倍稀释以逐步方式稀释10次。将2ul所述以逐步方式稀释的化合物添加到含有48ul 1x激酶反应缓冲液(50mM HEPES(pH 7.4),0.05% BSA,0.005%Tween-20,1mM DTT,0.5mM MnCl2,20mM MgCl2)的96孔板中。
使用cMET储存缓冲液(50mM Tris-HCl(pH 7.5),150mM NaCl,0.05% Brij35,1mMDTT,10%甘油)将cMET蛋白稀释到263nM的浓度,然后使用1x激酶反应缓冲液再次稀释至2nM的浓度。作为底物混合物,以最终反应浓度的2倍的浓度制备MET特异性底物混合物(5uMTK肽,10mM ATP)。
然后,制备384孔板,将2.5μl的每种稀释的实施例化合物添加到实验组孔的相应孔中,并将2.5μl 4% DMSO溶液分配到高对照孔和低对照孔中。
然后,将2.5μL的2nM cMET分配到高对照孔和实验组孔中,将2.5μL的1x激酶反应缓冲液添加到低对照孔中,并将RON和反应缓冲液在室温下以1000RPM离心40秒,然后在室温下温育20至30分钟。然后,将5uL的底物混合物(2x)分配到所有孔中,在室温下以1000RPM离心40秒,然后在室温下温育60分钟。然后,将5uL的90mM EDTA添加到所有孔中以终止反应,然后再次在室温下温育5分钟。然后,将5uL含有铕的4x磷酸酪氨酸抗体(Perkin-Elmer)添加到所有孔中,然后在室温下温育60分钟。在温育后,用Vison读板器读取384孔板。此时,激发波长为340nm,发射波长为620nm和665nm。每种实施例化合物的IC50值使用GraphPdPrism7程序推衍。
实施例化合物的抑制活性的评估结果如下表2中所示。
(A:<50nM,B:50至500nM,C:500至5000nM,D:>5,000nM)
[表2]
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Claims (9)
1.一种下式1的脲衍生化合物或其药学上可接受的盐:
[式1]
其中在上式1中,
上述X是氧,
上述Y是氢、卤素、C1-C6烷基或C3-C6环烷基,
上述R1是氢、C1-C6烷基、C3-C12环烷基或C2-C11杂环烷基,
上述R2是氢或C1-C6烷基,
上述A是-Ar或-(CH2)n-Ar,其中Ar是取代或未取代的C6-C10芳基或取代或未取代的包括1至4个选自氮、硫和氧的杂环原子的5元杂芳基,其中取代基是选自卤素、胺、C1-C6烷基、C3-C12环烷基、卤素取代的C1-C6烷基、C6-C10芳基、C1-C6烷氧基、C1-C6烷硫基、羟基、羧酸、C1-C6烷基羰基、C1-C6烷氧基羰基、C1-C6烷基羰基氧基、硝基、氰基、氨甲酰基、脲、巯基和NR3R4的一者或多者,并且上述n是1至3的整数,
上述R3和R4各自独立地是氢或C1-C6烷基,
上述B是氢、C1-C6烷基、取代的C1-C6烷基、C3-C12环烷基、取代的C3-C12环烷基、C3-C11杂环烷基、取代的C3-C11杂环烷基、C6-C20芳基、取代的C6-C20芳基,其中取代基是卤素、C1-C6烷基、C3-C7环烷基、卤素取代的C1-C6烷基、C1-C6烷氧基、C3-C11杂环烷基、C3-C11杂环烯基或C6-C10芳基,
其中所述卤素选自F、Cl、Br和I。
2.根据权利要求1所述的脲衍生化合物或其药学上可接受的盐,其中所述化合物由下式2表示:
[式2]
其中取代基与式1中所定义的相同。
3.根据权利要求1所述的脲衍生化合物或其药学上可接受的盐,其中上述A是取代或未取代的5元杂芳基化合物。
4.根据权利要求1所述的脲衍生化合物或其药学上可接受的盐,其中上述B是氢、C1-C6烷基、取代的C1-C6烷基、C3-C7环烷基、苯基、取代的苯基、苯甲基或萘、四氢吡喃、哌啶或取代的哌啶,其中取代基是卤素、C1-C3烷基、卤素取代的C1-C3烷基、C3-C5环烷基或C1-C3烷氧基。
5.根据权利要求1所述的脲衍生化合物或其药学上可接受的盐,其中上述Y是氟。
6.根据权利要求1所述的脲衍生化合物或其药学上可接受的盐,其中上述R1是氢、C1-C6烷基、C3-C6环烷基或C4-C6杂环烷基。
7.根据权利要求1所述的脲衍生化合物或其药学上可接受的盐,其中上述R2是氢。
8.根据权利要求1所述的脲衍生化合物或其药学上可接受的盐,其中所述化合物是选自下述的化合物:
N-(3-氟-4-((2-酮基-2,3-二氢-1H-咪唑并[4,5-b]吡啶-7-基)氧基)苯基)-1-苯基-5-(三氟甲基)-1H-咪唑-4-甲酰胺,
N-(3-氟-4-((2-酮基-2,3-二氢-1H-咪唑并[4,5-b]吡啶-7-基)氧基)苯基)-1-苯基-5-(三氟甲基)-1H-吡唑-4-甲酰胺,
N-(4-((1-乙基-2-酮基-2,3-二氢-1H-咪唑并[4,5-b]吡啶-7-基)氧基)-3-氟苯基)-1-苯基-5-(三氟甲基)-1H-咪唑-4-甲酰胺,
N-(4-((1-乙基-2-酮基-2,3-二氢-1H-咪唑并[4,5-b]吡啶-7-基)氧基)-3-氟苯基)-1-苯基-5-(三氟甲基)-1H-吡唑-4-甲酰胺,
N-(3-氟-4-((1-甲基-2-酮基-2,3-二氢-1H-咪唑并[4,5-b]吡啶-7-基)氧基)苯基)-1-苯基-5-(三氟甲基)-1H-咪唑-4-甲酰胺,
N-(3-氟-4-((1-甲基-2-酮基-2,3-二氢-1H-咪唑并[4,5-b]吡啶-7-基)氧基)苯基)-1-苯基-5-(三氟甲基)-1H-吡唑-4-甲酰胺,
N-(3-氟-4-((1-异丙基-2-酮基-2,3-二氢-1H-咪唑并[4,5-b]吡啶-7-基)氧基)苯基)-1-苯基-5-(三氟甲基)-1H-吡唑-4-甲酰胺,
N-(3-氟-4-((1-异丙基-2-酮基-2,3-二氢-1H-咪唑并[4,5-b]吡啶-7-基)氧基)苯基)-1-苯基-5-(三氟甲基)-1H-咪唑-4-甲酰胺,
5-乙基-N-(3-氟-4-((2-酮基-2,3-二氢-1H-咪唑并[4,5-b]吡啶-7-基)氧基)苯基)-1-苯基-1H-吡唑-4-甲酰胺,
5-乙基-N-(3-氟-4-((1-异丙基-2-酮基-2,3-二氢-1H-咪唑并[4,5-b]吡啶-7-基)氧基)苯基)-1-苯基-1H-吡唑-4-甲酰胺,
N-(3-氟-4-((2-酮基-1-(四氢-2H-吡喃-4-基)-2,3-二氢-1H-咪唑并[4,5-b]吡啶-7-基)氧基)苯基)-1-苯基-5-(三氟甲基)-1H-咪唑-4-甲酰胺,
N-(3-氟-4-((2-酮基-2,3-二氢-1H-咪唑并[4,5-b]吡啶-7-基)氧基)苯基)-3,5-二甲基-1-苯基-1H-吡唑-4-甲酰胺,
N-(3-氟-4-((1-异丙基-2-酮基-2,3-二氢-1H-咪唑并[4,5-b]吡啶-7-基)氧基)苯基)-3,5-二甲基-1-苯基-1H-吡唑-4-甲酰胺,
N-(3-氟-4-((1-异丙基-2-酮基-2,3-二氢-1H-咪唑并[4,5-b]吡啶-7-基)氧基)苯基)-5-甲基-1-苯基-1H-吡唑-4-甲酰胺,
N-(3-氟-4-((1-异丙基-2-酮基-2,3-二氢-1H-咪唑并[4,5-b]吡啶-7-基)氧基)苯基)-2-苯基噻唑-5-甲酰胺,
N-(3-氟-4-((1-异丙基-2-酮基-2,3-二氢-1H-咪唑并[4,5-b]吡啶-7-基)氧基)苯基)-5-苯基噻唑-2-甲酰胺,
N-(3-氟-4-((1-异丙基-2-酮基-2,3-二氢-1H-咪唑并[4,5-b]吡啶-7-基)氧基)苯基)-1-(对甲苯基)-5-(三氟甲基)-1H-吡唑-4-甲酰胺,
N-(3-氟-4-((1-异丙基-2-酮基-2,3-二氢-1H-咪唑并[4,5-b]吡啶-7-基)氧基)苯基)-1-(2-甲氧基苯基)-5-(三氟甲基)-1H-吡唑-4-甲酰胺,
N-(3-氟-4-((1-异丙基-2-酮基-2,3-二氢-1H-咪唑并[4,5-b]吡啶-7-基)氧基)苯基)-1,5-二苯基-1H-吡唑-4-甲酰胺,
N-(3-氟-4-((1-异丙基-2-酮基-2,3-二氢-1H-咪唑并[4,5-b]吡啶-7-基)氧基)苯基)-1-(四氢-2H-吡喃-3-基)-5-(三氟甲基)-1H-吡唑-4-甲酰胺,
N-(4-((1-环戊基-2-酮基-2,3-二氢-1H-咪唑并[4,5-b]吡啶-7-基)氧基)-3-氟苯基)-1-苯基-5-(三氟甲基)-1H-咪唑-4-甲酰胺,
N-(4-((1-环戊基-2-酮基-2,3-二氢-1H-咪唑并[4,5-b]吡啶-7-基)氧基)-3-氟苯基)-1-苯基-5-(三氟甲基)-1H-吡唑-4-甲酰胺,
N-(4-((1-环戊基-2-酮基-2,3-二氢-1H-咪唑并[4,5-b]吡啶-7-基)氧基)-3-氟苯基)-5-乙基-1-苯基-1H-吡唑-4-甲酰胺,
N-(3-氟-4-((1-异丙基-2-酮基-2,3-二氢-1H-咪唑并[4,5-b]吡啶-7-基)氧基)苯基)-2-(三氟甲基)苯甲酰胺,
4-溴-N-(3-氟-4-((1-异丙基-2-酮基-2,3-二氢-1H-咪唑并[4,5-b]吡啶-7-基)氧基)苯基)-2-(三氟甲基)苯甲酰胺,
N-(3-氟-4-((1-异丙基-2-酮基-2,3-二氢-1H-咪唑并[4,5-b]吡啶-7-基)氧基)苯基)-1-(萘-1-基)-5-(三氟甲基)-1H-吡唑-4-甲酰胺,
3-溴-N-(3-氟-4-((1-异丙基-2-酮基-2,3-二氢-1H-咪唑并[4,5-b]吡啶-7-基)氧基)苯基)-2-(三氟甲基)苯甲酰胺,
1-环己基-N-(3-氟-4-((1-异丙基-2-酮基-2,3-二氢-1H-咪唑并[4,5-b]吡啶-7-基)氧基)苯基)-5-(三氟甲基)-1H-吡唑-4-甲酰胺,
N-(3-氟-4-((1-异丙基-2-酮基-2,3-二氢-1H-咪唑并[4,5-b]吡啶-7-基)氧基)苯基)-1-(四氢-2H-吡喃-4-基)-5-(三氟甲基)-1H-吡唑-4-甲酰胺,
1-(叔丁基)-N-(3-氟-4-((1-异丙基-2-酮基-2,3-二氢-1H-咪唑并[4,5-b]吡啶-7-基)氧基)苯基)-5-(三氟甲基)-1H-吡唑-4-甲酰胺,
1-环庚基-N-(3-氟-4-((1-异丙基-2-酮基-2,3-二氢-1H-咪唑并[4,5-b]吡啶-7-基)氧基)苯基)-5-(三氟甲基)-1H-吡唑-4-甲酰胺,
N-(3-氟-4-((1-异丙基-2-酮基-2,3-二氢-1H-咪唑并[4,5-b]吡啶-7-基)氧基)苯基)-2-(1-苯基-5-(三氟甲基)-1H-吡唑-4-基)乙酰胺,
N-(3-氟-4-((1-异丙基-2-酮基-2,3-二氢-1H-咪唑并[4,5-b]吡啶-7-基)氧基)苯基)-1-(1-甲基哌啶-3-基)-5-(三氟甲基)-1H-吡唑-4-甲酰胺,
N-(3-氟-4-((1-异丙基-2-酮基-2,3-二氢-1H-咪唑并[4,5-b]吡啶-7-基)氧基)苯基)-1-(2氟苯基)-5-(三氟甲基)-1H-吡唑-4-甲酰胺,
1-(2-氯苯基)-N-(3-氟-4-((1-异丙基-2-酮基-2,3-二氢-1H-咪唑并[4,5-b]吡啶-7-基)氧基)苯基)-5-(三氟甲基)-1H-吡唑-4-甲酰胺,
1-(2,6-二氟苯基)-N-(3-氟-4-((1-异丙基-2-酮基-2,3-二氢-1H-咪唑并[4,5-b]吡啶-7-基)氧基)苯基)-5-(三氟甲基)-1H-吡唑-4-甲酰胺,
N-(3-氟-4-((2-酮基-1-(四氢-2H-吡喃-4-基)-2,3-二氢-1H-咪唑并[4,5-b]吡啶-7-基)氧基)苯基)-1-苯基-5-(三氟甲基)-1H-吡唑-4-甲酰胺,
N-(3-氟-4-((2-酮基-1-(四氢呋喃-3-基)-2,3-二氢-1H-咪唑并[4,5-b]吡啶-7-基)氧基)苯基)-1-苯基-5-(三氟甲基)-1H-吡唑-4-甲酰胺,
N-(3-氟-4-((1-(1-甲基哌啶-4-基)-2-酮基-2,3-二氢-1H-咪唑并[4,5-b]吡啶-7-基)氧基)苯基)-1-苯基-5-(三氟甲基)-1H-吡唑-4-甲酰胺,
N-(3-氟-4-((1-异丙基-2-酮基-2,3-二氢-1H-咪唑并[4,5-b]吡啶-7-基)氧基)苯基)-1-苯基-1H-吡唑-3-甲酰胺,
N-(3-氟-4-((1-异丙基-2-酮基-2,3-二氢-1H-咪唑并[4,5-b]吡啶-7-基)氧基)苯基)-1-苯基-1H-1,2,3-三唑-4-甲酰胺,
N-(3-氟-4-((1-异丙基-2-酮基-2,3-二氢-1H-咪唑并[4,5-b]吡啶-7-基)氧基)苯基)-5-甲基-1-苯基-1H-1,2,3-三唑-4-甲酰胺,和
N-(3-氟-4-((1-异丙基-2-酮基-2,3-二氢-1H-咪唑并[4,5-b]吡啶-7-基)氧基)苯基)-1-(2-氟苯基)-1H-1,2,3-三唑-4-甲酰胺。
9.一种药物组合物,其包含根据权利要求1至8中任一项所述的化合物或其药学上可接受的盐和药学上可接受的载体。
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