CN117355533A - 作为蛋白激酶抑制剂的新型化合物 - Google Patents
作为蛋白激酶抑制剂的新型化合物 Download PDFInfo
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- CN117355533A CN117355533A CN202280036900.4A CN202280036900A CN117355533A CN 117355533 A CN117355533 A CN 117355533A CN 202280036900 A CN202280036900 A CN 202280036900A CN 117355533 A CN117355533 A CN 117355533A
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- CN
- China
- Prior art keywords
- fluorophenyl
- carboxamide
- keto
- dihydropyridine
- methyl
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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- 150000001875 compounds Chemical class 0.000 title claims abstract description 142
- 239000003909 protein kinase inhibitor Substances 0.000 title abstract description 4
- 229940045988 antineoplastic drug protein kinase inhibitors Drugs 0.000 title description 2
- -1 3-fluoro-4- (1H-indazol-5-yl) phenyl Chemical group 0.000 claims description 68
- 125000001072 heteroaryl group Chemical group 0.000 claims description 34
- 229910052736 halogen Inorganic materials 0.000 claims description 27
- 150000002367 halogens Chemical class 0.000 claims description 27
- 150000003839 salts Chemical class 0.000 claims description 26
- 229910052739 hydrogen Inorganic materials 0.000 claims description 19
- 239000001257 hydrogen Substances 0.000 claims description 19
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 17
- 125000001424 substituent group Chemical group 0.000 claims description 16
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 15
- XTTOEOZCZCIDFY-UHFFFAOYSA-N 1-(4-fluorophenyl)-6-methyl-2-oxopyridine-3-carboxamide Chemical compound CC1=CC=C(C(N)=O)C(=O)N1C1=CC=C(F)C=C1 XTTOEOZCZCIDFY-UHFFFAOYSA-N 0.000 claims description 14
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 13
- 125000003118 aryl group Chemical group 0.000 claims description 13
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- 229910052757 nitrogen Inorganic materials 0.000 claims description 12
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 11
- 125000005842 heteroatom Chemical group 0.000 claims description 11
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 11
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- 125000000468 ketone group Chemical group 0.000 claims description 10
- 229910052717 sulfur Inorganic materials 0.000 claims description 10
- 125000000217 alkyl group Chemical group 0.000 claims description 9
- 150000001412 amines Chemical class 0.000 claims description 9
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- 125000000753 cycloalkyl group Chemical group 0.000 claims description 6
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- 125000006367 bivalent amino carbonyl group Chemical group [H]N([*:1])C([*:2])=O 0.000 claims description 5
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- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims description 5
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 4
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- 125000005431 alkyl carboxamide group Chemical group 0.000 claims description 3
- 125000005392 carboxamide group Chemical group NC(=O)* 0.000 claims description 3
- 125000005843 halogen group Chemical group 0.000 claims description 3
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- C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
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Abstract
本发明涉及一种作为蛋白激酶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22日提交的韩国专利申请第10-2021-0080516号的优先权利益,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C-MET和/或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酶的大家族,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。
几乎所有的激酶都含有类似的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,间充质-上皮转化因子(c-MET)也被称为酪氨酸蛋白激酶受体或肝细胞生长因子受体,并在内皮细胞、上皮细胞和间充质细胞中表达。已报道c-MET与某些肿瘤的进展有关,并且已知c-MET的过表达发生在包括结肠、乳腺、肾、肺、血管瘤、鳞状细胞髓系白血病、黑素瘤、成胶质细胞瘤和星形细胞瘤的多种肿瘤类型中。
此外,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c-MET和RON的激活增加了肿瘤细胞的增殖、侵袭和转移,也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c-MET和RON的选择性小分子激酶调节剂具有治疗其中c-MET受体和/或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,正在对用于抑制酪氨酸蛋白激酶例如c-MET受体和/或RON的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c-MET和/或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的化合物或其药学上可接受的盐。
[式1]
在上式1中,
上述X是直接连键、O、NR3或NHCO,
上述A是5至15元取代或未取代的含有1至5个选自氮、硫和氧的杂环原子的杂芳基,其中取代的杂芳基的取代基是C1-C6烷基、卤素、胺、酮基或C2-C6环烷基甲酰胺基,
上述A是上面定义的取代或未取代的杂芳基的单环或其中所述取代或未取代的杂芳基的两个或更多个环被稠合或通过碳(sp2)-碳(sp2)键连接的多环,
上述B是5至7元取代或未取代的含有酮基并含有1至5个选自氮、硫和氧的杂环原子的杂芳基,其中取代的杂芳基的取代基是C1-C6烷基、羟基或卤素取代的C1-C6烷基、C1-C6烷氧基、5至12元芳基或卤素取代的5至12元芳基,
上述R1是氢、C1-C6烷基或卤素,
上述R2是氢或C1-C6烷基,
上述R3是氢或C1-C6烷基,并且
所述卤素各自独立地选自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
本发明可以提供一种新型化合物或其药学上可接受的盐,它们可以通过抑制受体例如c-MET和/或RON的蛋白激酶的活性有效地用于治疗各种免疫相关疾病、作为抗癌药物,但本发明的效果不限于此。
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的新型化合物或其药学上可接受的盐。
在本发明中,除非另有陈述,否则所述化合物旨在包括式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、前体药物等。
[式1]
在上式1中,
上述X是直接连键、O、NR3或NHCO,
上述A是5至15元取代或未取代的含有1至5个选自氮、硫和氧的杂环原子的杂芳基,其中取代的杂芳基的取代基是C1-C6烷基、卤素、胺、酮基或C2-C6环烷基甲酰胺基,
上述A是上面定义的取代或未取代的杂芳基的单环或其中所述取代或未取代的杂芳基的两个或更多个环被稠合或通过碳(sp2)-碳(sp2)键连接的多环,
上述B是5至7元取代或未取代的含有酮基并含有1至5个选自氮、硫和氧的杂环原子的杂芳基,其中取代的杂芳基的取代基是卤素、C1-C6烷基、羟基取代的C1-C6烷基、卤素取代的C1-C6烷基、C1-C6烷基取代的C1-C6烷基、C1-C6烷氧基、5至12元芳基或卤素取代的5至12元芳基,
上述R1是氢、C1-C6烷基或卤素,
上述R2是氢或C1-C6烷基或取代的C1-C6烷基,其中所述取代的C1-C6烷基的取代基选自C1-C6烷基、C6-C10芳基、卤素、C1-C6卤代烷基、C1-C6烷氧基、C1-C6烷硫基、羟基、-COOH、C1-C6烷基羰基、C1-C6烷氧基羰基、C1-C6烷基羰基氧基、-NH2、氨甲酰基、脲和-SH,
上述R3是氢或C1-C6烷基,并且
所述卤素各自独立地选自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另一个取代基代替,并且取代的位置不受限制,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,并且当两个或更多个位置处的氢原子被取代时,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”可以是直链或支链的,并优选地具有1至20个碳原子,烷基的实例包括甲基、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。环烷基的实例包括环丙基、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。烷氧基的实例包括甲氧基、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”可以是直链或支链的,并优选地具有2至20个碳原子。烯基的实例包括乙烯基、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、二芳基或具有三个或更多个环的多环芳基,并且当芳基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,并且芳基优选地具有5至12个碳原子。芳基的实例包括苯基、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,“杂芳基”含有至少一个碳之外的杂原子,并且具体来说,所述杂原子可以包括选自O、N、Se和S的至少一个杂原子。除非另有定义,否则杂芳基可以是单环或多环的,并且当杂芳基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,并且杂芳基优选地具有5至12个碳原子。杂芳基的实例包括噻吩基、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,在上式1中,上述A是5至12元取代或未取代的含有1至3个选自氮和硫的杂环原子的杂芳基,其中取代的杂芳基的取代基是卤素、胺、酮基或C2-C6环烷基甲酰胺基。
根据另一个实施方式,上述A是5至12元取代或未取代的含有1至3个选自氮和硫的杂环原子的杂芳基,并且是单环或其中两个杂芳基被稠合或两个杂芳基通过碳(sp2)-碳(sp2)键偶联的双环,其中取代的杂芳基的取代基是C1-C6烷基、卤素、胺、酮基或C2-C6环烷基甲酰胺基。
根据另一个实施方式,上述A是吡啶、嘧啶、吡唑、取代的吡啶、取代的嘧啶或取代的吡唑,其中所述取代基是选自甲基(-CH3)、胺基(-NH2)、氯基团(-Cl)、溴基团(-Br)和环丙烷甲酰胺基的至少一者。
根据另一个实施方式,上述A是9至12元杂芳基或取代的9至12元杂芳基,其中所述取代基是胺基或酮基。
根据另一个实施方式,上述A具有下述结构。
根据一个实施方式,在上式1中,上述B具有式2或式3的结构。
[式2]
[式3]
在上述式2或式3中,
上述Y、Z和W各自独立地是选自氮、硫和氧的杂原子,
上述R4、R6和R7各自独立地是氢、C1-C6烷基、卤素、羟基取代的C1-C6烷基、卤素取代的C1-C6烷基、C1-C6烷基取代的C1-C6烷基或C1-C6烷氧基,
上述R5和R8各自独立地是氢或卤素。
根据另一个实施方式,在上述式2或式3中,
上述Y、Z和W是氮原子,
上述R4、R6和R7各自独立地是氢、甲基、卤素、乙氧基或丁氧基,
上述R5和R8各自独立地是氢或卤素。
根据一个实施方式,在上式1中,上述X是直接连键、O、NH或NHCO。
根据另一个实施方式,在上式1中,上述R1是氢、甲基或氟。
根据另一个实施方式,在上式1中,上述R2是氢或甲基。
根据一个实施方式,上式1的化合物可以选自:
N-(4-(2-氨基噻唑并[5,4-b]吡啶-5-基)-3-甲基苯基)-4-乙氧基-1-(4-氟苯基)-2-酮基-1,2-二氢吡啶-3-甲酰胺,
N-(4-(2-氨基噻唑并[5,4-b]吡啶-5-基)-3-氟苯基)-4-乙氧基-1-(4-氟苯基)-2-酮基-1,2-二氢吡啶-3-甲酰胺,
N-(4-((2-氨基噻唑并[5,4-b]吡啶-5-基)氨基)-3-氟苯基)-4-乙氧基-1-(4-氟苯基)-2-酮基-1,2-二氢吡啶-3-甲酰胺,
N-(4-(2-氨基咪唑并[1,2-b]哒嗪-6-基)-3-氟苯基)-4-乙氧基-1-(4-氟苯基)-2-酮基-1,2-二氢吡啶-3-甲酰胺,
N-(4-((6-氯咪唑并[1,2-b]哒嗪-8-基)氧基)-3-氟苯基)-4-乙氧基-1-(4-氟苯基)-2-酮基-1,2-二氢吡啶-3-甲酰胺,
N-(4-((6-氯咪唑并[1,2-b]哒嗪-8-基)氧基)-3-氟苯基)-1-(4-氟苯基)-6-甲基-2-酮基-1,2-二氢吡啶-3-甲酰胺,
N-(3-(6-氨基吡啶-3-基)-4-甲基苯基)-4-乙氧基-1-(4-氟苯基)-2-酮基-1,2-二氢吡啶-3-甲酰胺,
N-(3-(2-氨基嘧啶-5-基)-4-甲基苯基)-4-乙氧基-1-(4-氟苯基)-2-酮基-1,2-二氢吡啶-3-甲酰胺,
N-(3-(2-氨基吡啶-4-基)-4-甲基苯基)-4-乙氧基-1-(4-氟苯基)-2-酮基-1,2-二氢吡啶-3-甲酰胺,
N-(3-(2-氨基吡啶-3-基)-4-甲基苯基)-4-乙氧基-1-(4-氟苯基)-2-酮基-1,2-二氢吡啶-3-甲酰胺,
4-乙氧基-1-(4-氟苯基)-N-(4-甲基-3-(喹啉-6-基)苯基)-2-酮基-1,2-二氢吡啶-3-甲酰胺,
4-乙氧基-1-(4-氟苯基)-N-(3-(异喹啉-6-基)-4-甲基苯基)-2-酮基-1,2-二氢吡啶-3-甲酰胺,
4-乙氧基-1-(4-氟苯基)-N-(4-甲基-3-(1H-吡咯并[2,3-b]吡啶-4-基)苯基)-2-酮基-1,2-二氢吡啶-3-甲酰胺,
N-(4-((3-溴咪唑并[1,2-b]哒嗪-6-基)氧基)-2-氟苯基)-4-乙氧基-1-(4-氟苯基)-2-酮基-1,2-二氢吡啶-3-甲酰胺,
N-(4-(2-(2-氨基嘧啶-4-基)吡啶-4-基)-3-氟苯基)-1-(4-氟苯基)-4-甲氧基-2-酮基-1,2-二氢吡啶-3-甲酰胺,
N-(4-(2-(2-氨基嘧啶-4-基)吡啶-4-基)-3-氟苯基)-1-(4-氟苯基)-6-甲基-2-酮基-1,2-二氢吡啶-3-甲酰胺,
N-(4-(2-(2-氨基嘧啶-4-基)吡啶-4-基)-3-氟苯基)-5-溴-1-(4-氟苯基)-2-酮基-1,2-二氢吡啶-3-甲酰胺,
N-(4-(3-氨基-1H-吲唑-6-基)-3-氟苯基)-4-乙氧基-1-(4-氟苯基)-2-酮基-1,2-二氢吡啶-3-甲酰胺,
4-乙氧基-N-(3-氟-4-(1H-吲唑-5-基)苯基)-1-4-氟苯基)-2-酮基-1,2-二氢吡啶-3-甲酰胺,
4-乙氧基-N-(3-氟-4-(2-酮基吲哚啉-5-基)苯基)-1-(4-氟苯基)-2-酮基-1,2-二氢吡啶-3-甲酰胺,
N-(4-(3-氨基苯并[d]异噻唑-5-基)-3-氟苯基)-4-乙氧基-1-(4-氟苯基)-2-酮基-1,2-二氢吡啶-3-甲酰胺,
N-(4-(3-氨基-1H-吲唑-6-基)-3-氟苯基)-1-(2-羟基-2-甲基丙基)-5-甲基-3-酮基-2-苯基-2,3-二氢-1H-吡唑-4-甲酰胺,
N-(4-(3-氨基-1H-吲唑-6-基)-3-氟苯基)-1-(4-氟苯基)-6-甲基-2-酮基-1,2-二氢吡啶-3-甲酰胺,
N-(4-((2-氨基-3-氯吡啶-4-基)氧基)-3-氟苯基)-1,5-二甲基-3-酮基-2-苯基-2,3-二氢-1H-吡唑-4-甲酰胺,
N-(4-((2-氨基-3-氯吡啶-4-基)氧基)-3-氟苯基)-1-(4-氟苯基)-6-甲基-2-酮基-1,2-二氢吡啶-3-甲酰胺,
N-(4-((2-氨基-3-氯吡啶-4-基)氧基)-3-氟苯基)-1-(4-氟苯基)-6-(羟基甲基)-2-酮基-1,2-二氢吡啶-3-甲酰胺,
N-(4-((2-氨基-3-氯吡啶-4-基)氧基)-3-氟苯基)-5-环丙基-1-(4-氟苯基)-2-酮基-1,2-二氢吡啶-3-甲酰胺,
N-(4-((2-氨基-3-氯吡啶-4-基)氧基)-3-氟苯基)-1-(4-氟苯基)-2-酮基-6-(三氟甲基)-1,2-二氢吡啶-3-甲酰胺,
N-(4-((2-氨基-3-氯吡啶-4-基)氧基)-3-氟苯基)-1-(2-羟基-2-甲基丙基)-5-甲基-3-酮基-2-苯基-2,3-二氢-1H-吡唑-4-甲酰胺,
N-(4-((3-氯-2-(环丙烷甲酰胺基)吡啶-4-基)氧基)-3-氟苯基)-1-(4-氟苯基)-6-甲基-2-酮基-1,2-二氢吡啶-3-甲酰胺,
N-(4-((3-氯-2-(N-(环丙烷羰基)环丙烷甲酰胺基)吡啶-4-基)氧基)-3-氟苯基)-1-(4-氟苯基)-6-甲基-2-酮基-1,2-二氢吡啶-3-甲酰胺,
2-氨基-5-溴-N-(2-氟-4-(1-(4-氟苯基)-6-甲基-2-酮基-1,2-二氢吡啶-3-甲酰胺基)苯基)烟酰胺,
3-氨基-6-溴-N-(2-氟-4-(1-(4-氟苯基)-6-甲基-2-酮基-1,2-二氢吡啶-3-甲酰胺基)苯基)吡嗪-2-甲酰胺,
2-氨基-N-(2-氟-4-(1-(4-氟苯基)-6-甲基-2-酮基-1,2-二氢吡啶-3-甲酰胺基)苯基)-5-(1-甲基-1H-吡唑-4-基)烟酰胺,
3-氨基-N-(2-氟-4-(1-(4-氟苯基)-6-甲基-2-酮基-1,2-二氢吡啶-3-甲酰胺基)苯基)-6-(1-甲基-1H-吡唑-4-基)吡嗪-2-甲酰胺,和
N-(4-((6-氨基-5-氯嘧啶-4-基)氧基)-3-氟苯基)-1-(4-氟苯基)-6-甲基-2-酮基-1,2-二氢吡啶-3-甲酰胺,并且其结构示出在下面的表1中。
[表1]
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在本公开中,“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。这些盐的性质并不重要,但应该是药学上可接受的。式1的化合物的适合的药学上可接受的酸加成盐可以由无机酸或有机酸制备。此类无机酸的实例包括盐酸、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、脂环族、芳香族、芳基脂族、杂环族、羧酸和磺酸组的有机酸,并且有机酸的实例包括甲酸、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。式1的化合物的适合的药学上可接受的碱加成盐包括金属盐,例如由铝、钙、锂、镁、钾、钠和锌制成的盐,或由包括伯胺、仲胺和叔胺的有机碱、包括环状胺的取代胺例如咖啡因、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、三乙胺和三甲胺制成的盐。所有这些盐都可以通过常规方法从本发明的相应化合物通过将例如适合的酸或碱与式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c-MET或RON介导的疾病。
在另一个实施方式中,所述药物组合物可用于预防或治疗c-MET和RON双重介导的疾病。
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、颈部癌症、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敏化的免疫疾病,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”是指降低发生疾病或障碍的风险,并且是指在容易暴露于疾病或对疾病易感但尚未经历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一种或多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”是指减轻疾病或障碍,并且是指通过阻止或减少疾病或其一种或多种临床症状的进展来改善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”是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,或者可以通过并入到多剂量容器中而制备。在这种情况下,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递送,所述载体例如胶体悬液、粉末、盐水、脂质、脂质体或微球或纳米球形粒子。它们可以与介质复合或结合,并且可以使用本领域中已知的递送系统在体内递送,所述递送系统例如脂质、脂质体、微粒、金、纳米粒子、聚合物、缩合试剂、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,还可以包括润滑剂、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给药的各种制剂中给药,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、崩解剂和表面活性剂来制备。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草药提取物或草药发酵产物与至少一种赋形剂例如淀粉、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,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包括悬液、口服液、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、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、悬液、乳液、冻干制剂和栓剂。对于非水性溶液和悬液来说,可以使用丙二醇、聚乙二醇、植物油例如橄榄油、可注射的酯例如油酸乙酯等。作为栓剂的基料,可以使用WitepsolTM、聚乙二醇、TweenTM61、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,上式1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、给药方法、患者的年龄、体重、性别、状况和饮食、给药时间、给药途径、排泄率,药物组合和响应的敏感性,但通常可以是每1kg成年患者体重0.01mg/天至20mg/天,优选地1mg/天至10mg/天,并且可以根据医生或药剂师的决定以规则的时间间隔,以分剂量每天几次、优选地每天2至3次给药。
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c-MET和/或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”是指每种制剂在通过所述每种制剂自身治疗的过程中实现改善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不良反应的量。例如,有效的肿瘤治疗剂表现出延长患者生存期、抑制与肿瘤相关的细胞的增殖或使肿瘤消退的效果。
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. 4-乙氧基-1-(4-氟苯基)-2-酮基-1,2-二氢吡啶-3-甲酸
在下文中,按照下述反应方案1制备了制备例1的化合物。
反应方案1.
步骤1)4-乙氧基-2-酮基-1,2-二氢吡啶-3-甲酸乙酯
向氰基乙酸乙酯(6g,53mmol)添加原乙酸三乙酯(17.21g,106mmol)和50mL乙酸,将混合物在120℃下搅拌12小时。将反应混合物的溶剂浓缩,并添加7.1mL(53mmol)DMF-DEA(N,N-二甲基甲酰胺二乙缩醛)。将反应混合物在70℃下搅拌2小时。向反应混合物添加50mL乙酸和6mL蒸馏水,并将混合物回流12小时。将反应混合物的溶剂浓缩,并用水稀释。使用饱和碳酸氢钠水溶液将反应混合物调节到pH 9-10,然后用DCM萃取三次。将有机层用盐水洗涤并浓缩。将残留物通过柱层析进行纯化,得到标题化合物(3.6g,得率:32%)。
1H NMR(400MHz,CDCl3)δ13.42(brs,1H),7.47(d,1H),6.18(d,1H),4.34(q,2H),4.20(q,2H),1.36(m,6H);MS m/z:212[M+H]
步骤2)4-乙氧基-1-(4-氟苯基)-2-酮基-1,2-二氢吡啶-3-甲酸乙酯
将在上述步骤1中得到的化合物4-乙氧基-2-酮基-1,2-二氢吡啶-3-甲酸乙酯(1.2g,5.68mmol)溶解在50mL DCM中,然后向其添加(4-氟苯基)硼酸(1.59g,11.4mmol)、Cu(OAc)2(1.75g,9.66mmol)和吡啶(1.35g,17.04mmol),然后在室温下搅拌12小时。将反应混合物通过硅藻土过滤,并用水洗涤固体。将滤液用DCM萃取两次,浓缩,并且不需纯化过程即可用于下述步骤3。
MS m/z:306[M+H]
步骤3)4-乙氧基-1-(4-氟苯基)-2-酮基-1,2-二氢吡啶-3-甲酸
将在上述步骤2中得到的化合物4-乙氧基-1-(4-氟苯基)-2-酮基-1,2-二氢吡啶-3-甲酸乙酯溶解在乙醇/水(2:1)混合溶液中,然后向其添加LiOH(0.41g,17.04mmol),然后在室温下搅拌12小时。将反应混合物浓缩,用水稀释,并用乙酸乙酯洗涤。使用3N盐酸水溶液将所述水性溶液调节到pH 2,并用DCM萃取三次。将有机溶液用盐水洗涤并浓缩。向残留物添加乙醚,将产生的固体过滤并干燥,得到标题化合物(1.3g,83%)。
MS m/z:278[M+H]
制备例2. 4-甲氧基-1-(4-氟苯基)-2-酮基-1,2-二氢吡啶-3-甲酸
在下文中,按照下述反应方案2制备了制备例2的化合物。
反应方案2.
步骤1)1-(4-氟苯基)-4-甲氧基-2-酮基-1,2-二氢吡啶-3-甲酸甲酯
将在制备例1的步骤2中得到的化合物4-乙氧基-1-(4-氟苯基)-2-酮基-1,2-二氢吡啶-3-甲酸乙酯(0.5g,1.64mmol)用28% NaOMe溶液处理,然后在室温下搅拌10分钟。将反应混合物浓缩,得到标题化合物(0.36g,79%)。
MS m/z:278[M+H]
步骤2)4-甲氧基-1-(4-氟苯基)-2-酮基-1,2-二氢吡啶-3-甲酸
将在上述步骤1中得到的化合物1-(4-氟苯基)-4-甲氧基-2-酮基-1,2-二氢吡啶-3-甲酸甲酯(0.36g,1.29mmol)溶解在5mL乙醇中,然后在室温下向其添加5mL 3N盐酸溶液。将反应溶液在60℃下搅拌4小时,然后将产生的固体过滤,得到标题化合物(0.23g,68%)。
MS m/z:264[M+H]
实施例1.N-(4-(2-氨基噻唑并[5,4-b]吡啶-5-基)-3-甲基苯基)-4-乙氧基-1-(4-氟苯基)-2-酮基-1,2-二氢吡啶-3-甲酰胺
在下文中,按照下述反应方案3制备实施例1的化合物。
反应方案3.
步骤1. 6-氯吡啶-3-胺
将2-氯-5-硝基吡啶(5g,31.5mmol)溶解在50mL乙酸中,向其添加铁粉(8.8g,158mmol),然后在80℃下搅拌2小时。将反应混合物通过硅藻土过滤,并将滤液在真空下干燥。将残留物溶解在DCM中,用饱和NaHCO3水溶液中和,然后用DCM萃取5次。将有机层用盐水洗涤并浓缩,得到标题化合物(3.8g,得率:94%)。
MS m/z:129[M+H]
步骤2. 5-氯噻唑并[5,4-b]吡啶-2-胺
将在上述步骤1中得到的化合物6-氯吡啶-3-胺(3.8g,29.5mmol)和KSCN(3.06g,31.5mmol)在乙酸溶液中混合,向其缓慢添加溴(1.6ml,31.5mmol),然后在室温下搅拌12小时。将反应混合物通过硅藻土过滤并在真空下干燥,使得滤液的体积为1/3。使用氨水溶液将残留物调节到pH 6,并过滤出沉淀物,得到作为黄色固体的标题化合物(3.6g,得率:66%)。
MS m/z:186[M+H]
步骤3.(5-氯噻唑并[5,4-b]吡啶-2-基)氨基甲酸二叔丁酯
将在上述步骤2中得到的化合物5-氯噻唑并[5,4-b]吡啶-2-胺(2g,10.7mmol)溶解在50mL THF中,向其添加Boc酸酐(5.0ml,21.4mmol)和DMAP(65mg,0.54mmol),然后在室温下搅拌12小时。反应完成,然后将反应溶液用水稀释,用乙酸乙酯萃取三次并浓缩。将残留物通过硅胶柱层析进行纯化,得到标题化合物(3.7g,得率:90%)。
MS m/z:386[M+H]
步骤4.(5-(4-氨基-2-甲基苯基)噻唑并[5,4-b]吡啶-2-基)氨基甲酸二叔丁酯
将在上述步骤3中得到的化合物(5-氯噻唑并[5,4-b]吡啶-2-基)氨基甲酸二叔丁酯(50mg,0.13mmol)溶解在2mL 1,4-二烷中,然后向其加入3-甲基-4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊-2-基)苯胺(37mg,0.16mmol)、饱和NaHCO3水溶液(1.5ml,0.07mmol),和PdCl2(dppf)DCM加成物(5.3mg,0.007mmol),随后在130℃下搅拌2小时。反应混合物通过硅藻土过滤,并将滤液在真空下干燥。将残留物通过硅胶柱层析进行纯化,得到标题化合物(20mg,得率:34%)。
MS m/z:457[M+H]
步骤5.二叔丁基-N-(4-(2-氨基噻唑并[5,4-b]吡啶-5-基)-3-甲基苯基)-4-乙氧基-1-(4-氟苯基)-2-酮基-1,2-二氢吡啶-3-甲酰胺
将在上述步骤4中得到的化合物(5-(4-氨基-2-甲基苯基)噻唑并[5,4-b]吡啶-2-基)氨基甲酸二叔丁酯(20mg,0.04mmol)溶解在2mL THF中,然后向其添加4-乙氧基-1-(4-氟苯基)-2-酮基-1,2-二氢吡啶-3-甲酸(15mg,0.05mmol)、HATU(25mg,0.07mmol)和DIPEA(12μL,0.07mmol),然后在室温下搅拌12小时。将反应溶液用水稀释,然后用乙酸乙酯萃取三次并浓缩。将残留物通过硅胶柱层析进行纯化,得到标题化合物(15mg,48%)。
MS m/z:715[M+H]
步骤6.N-(4-(2-氨基噻唑并[5,4-b]吡啶-5-基)-3-甲基苯基)-4-乙氧基-1-(4-氟苯基)-2-酮基-1,2-二氢吡啶-3-甲酰胺
将在上述步骤5中得到的化合物二叔丁基-N-(4-(2-氨基噻唑并[5,4-b]吡啶-5-基)-3-甲基苯基)-4-乙氧基-1-(4-氟苯基)-2-酮基-1,2-二氢吡啶-3-甲酰胺(15mg,0.02mmol)溶解在1.5mL DCM中,然后向其添加1.5mL TFA,然后在室温下搅拌2小时。将反应溶液在真空下干燥。将残留物溶解在DCM中,然后用饱和NaHCO3水溶液中和,用DCM萃取三次并浓缩。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(10mg,得率:93%)。
1H NMR(400MHz,DMSO-d6)δ7.78(d,1H),7.74(d,1H),7.63(m,2H),7.47(m,2H),7.38(m,2H),7.31(t,2H),6.60(d,1H),4.35(q,2H),2.36(s,3H),1.47(t,3H);MS m/z:516[M+H]
实施例2.N-(4-(2-氨基噻唑并[5,4-b]吡啶-5-基)-3-氟苯基)-4-乙氧基-1-(4-氟苯基)-2-酮基-1,2-二氢吡啶-3-甲酰胺
以与实施例1相似的方式,使用3-氟-4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊-2-基)苯胺代替3-甲基-4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊-2-基)苯胺,按照实施例1的步骤4得到标题化合物(4mg,得率:71%)。
1H NMR(400MHz,DMSO-d6)δ10.6(s,1H),7.91(m,3H),7.79(d,1H),7.69(m,2H),7.45(m,2H),7.36(m,2H),6.52(m,1H),4.25(q,2H),1.30(t,3H);MS m/z:520[M+H]
实施例3.N-(4-((2-氨基噻唑并[5,4-b]吡啶-5-基)氨基)-3-氟苯基)-4-乙氧基-1-(4-氟苯基)-2-酮基-1,2-二氢吡啶-3-甲酰胺
以与实施例1相似的方式,使用(4-氨基-3-氟苯基)氨基甲酸叔丁酯和Pd2(dba)3、Xphos和Cs2CO3,按照实施例1的步骤4得到标题化合物(10mg,得率:36%)。
1H NMR(400MHz,DMSO-d6)δ7.98(t,1H),7.76(m,2H),7.53(d,1H),7.46(m,2H),7.29(m,3H),6.82(d,1H),6.58(m,1H),4.34(q,2H),1.46(t,3H);MS m/z:535[M+H]
实施例4.N-(4-(2-氨基咪唑并[1,2-b]哒嗪-6-基)-3-氟苯基)-4-乙氧基-1-(4-氟苯基)-2-酮基-1,2-二氢吡啶-3-甲酰胺
以与实施例1相似的方式,使用(6-氯咪唑并[1,2-b]哒嗪-2-基)氨基甲酸酯代替(5-氯噻唑并[5,4-b]吡啶-2-基)氨基甲酸二叔丁基酯,按照实施例1的步骤4得到标题化合物(1mg,得率:20%)。
1H NMR(400MHz,DMSO-d6)δ7.96(m,2H),7.82(d,1H),7.68(d,2H),7.48(m,4H),7.28(m,2H),6.64(d,1H),4.36(q,2H),1.42(t,3H);MS m/z:503[M+H]
实施例5.N-(4-((6-氯咪唑并[1,2-b]哒嗪-8-基)氧基)-3-氟苯基)-4-乙氧基-1-(4-氟苯基)-2-酮基-1,2-二氢吡啶-3-甲酰胺
在下文中,按照下述反应方案4制备实施例5的化合物。
反应方案4.
步骤1)4-((6-氯咪唑并[1,2-b]哒嗪-8-基)氧基)-3-氟苯胺
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将8-溴-6-氯咪唑并[1,2-b]哒嗪(600mg,2.58mmol)溶解在12mL乙腈中,并向其添加Cs2CO3(1.0g,3.10mmol)和4-氨基-2-氟苯酚(361mg,2.84mmol),然后在室温下搅拌12小时。将反应混合物用水稀释并用乙酸乙酯萃取三次。将有机层用盐水洗涤并浓缩。将残留物通过硅胶柱层析进行纯化,得到标题化合物(435mg,得率:61%)。
MS m/z:279[M+H]
步骤2)N-(4-((6-氯咪唑并[1,2-b]哒嗪-8-基)氧基)-3-氟苯基)-4-乙氧基-1-(4-氟苯基)-2-酮基-1,2-二氢吡啶-3-甲酰胺
以与实施例1相似的方式,使用在上述步骤1中得到的化合物4-((6-氯咪唑并[1,2-b]哒嗪-8-基)氧基)-3-氟苯胺(200mg,0.72mmol)和4-乙氧基-1-(4-氟苯基)-2-酮基-1,2-二氢吡啶-3-甲酸(240mg,0.86mmol),得到标题化合物(210mg,得率:54%)。
1H NMR(400MHz,CDCl3)δ11.73(s,1H),8.03(m,1H),7.94(s,1H),7.58(s,1H),7.40(d,1H),7.38(m,3H),7.28-7.20(m,4H),6.40(d,1H),4.41(q,2H),1.62(t,3H);MS m/z:538[M+H]
实施例6.N-(4-((6-氯咪唑并[1,2-b]哒嗪-8-基)氧基)-3-氟苯基)-1-(4-氟苯基)-6-甲基-2-酮基-1,2-二氢吡啶-3-甲酰胺
以与实施例5相似的方式,使用1-(4-氟苯基)-6-甲基-2-酮基-1,2-二氢吡啶-3-甲酸代替4-乙氧基-1-(4-氟苯基)-2-酮基-1,2-二氢吡啶-3-甲酸,按照实施例5的步骤2得到标题化合物(21mg,得率:57%)。
1H NMR(400MHz,CDCl3)δ11.99(s,1H),8.66(m,1H),8.04(d,1H),7.94(s,1H),7.76(s,1H),7.37(m,3H),7.28(m,3H),6.54(d,1H),6.18(s,1H),2.15(s,3H);MS m/z:508[M+H]
实施例7.N-(3-(6-氨基吡啶-3-基)-4-甲基苯基)-4-乙氧基-1-(4-氟苯基)-2-酮基-1,2-二氢吡啶-3-甲酰胺
在下文中,按照下述反应方案5制备实施例7的化合物。
反应方案5.
步骤1)N-(3-溴-4-甲基苯基)-4-乙氧基-1-(4-氟苯基)-2-酮基-1,2-二氢吡啶-3-甲酰胺
以与实施例1相似的方式,通过将3-溴-4-甲基苯胺(500mg,2.69mmol)溶解在10mLTHF中并使用4-乙氧基-1-(4-氟苯基)-2-酮基-1,2-二氢吡啶-3-甲酸(894mg,3.22mmol),得到标题化合物(700mg,得率:59%)。
MS m/z:445[M],447[M+2]
步骤2)N-(3-(6-氨基吡啶-3-基)-4-甲基苯基)-4-乙氧基-1-(4-氟苯基)-2-酮基-1,2-二氢吡啶-3-甲酰胺
将在上述步骤1中得到的化合物N-(3-溴-4-甲基苯基)-4-乙氧基-1-(4-氟苯基)-2-酮基-1,2-二氢吡啶-3-甲酰胺(25mg,0.056mmol)溶解在2mL DME中,并向其添加(6-氨基吡啶-3-基)硼酸(9mg,0.062mmol)、2M Na2CO3和Pd(PPh3)4,然后在95℃下搅拌12小时。将反应混合物用水稀释,用DCM萃取三次,用盐水洗涤并浓缩。将残留物通过硅胶柱层析进行纯化,得到标题化合物(8mg,得率:30%)。
1H NMR(400MHz,MeOH-d4)δ7.94(s,1H),7.82(m,1H),7.70(d,1H),7.55(m,2H),7.46(m,2H),7.29(m,3H),6.69(d,1H),6.59(d,1H),4.33(q,2H),2.26(s,3H),1.45(t,3H);MS m/z:459[M+H]
实施例8.N-(3-(2-氨基嘧啶-5-基)-4-甲基苯基)-4-乙氧基-1-(4-氟苯基)-2-酮基-1,2-二氢吡啶-3-甲酰胺
以与实施例7相似的方式,使用(2-氨基嘧啶-5-基)硼酸代替(6-氨基吡啶-3-基)硼酸,按照实施例7的步骤2得到标题化合物(12mg,得率:32%)。
1H NMR(400MHz,MeOH-d4)δ8.30(s,2H),7.76(m,1H),7.57(m,2H),7.44(m,2H),7.29(m,3H),6.59(d,1H),4.31(q,2H),2.28(s,3H),1.44(t,3H);MS m/z:460[M+H]
实施例9.N-(3-(2-氨基吡啶-4-基)-4-甲基苯基)-4-乙氧基-1-(4-氟苯基)-2-酮基-1,2-二氢吡啶-3-甲酰胺
以与实施例7相似的方式,使用4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊-2-基)吡啶-2-胺代替(6-氨基吡啶-3-基)硼酸,按照实施例7的步骤2得到标题化合物(2mg,得率:5%)。
1H NMR(400MHz,MeOH-d4)δ7.92(brs,1H),7.78(d,1H),7.59(m,2H),7.45(m,2H),7.28(m,3H),6.60(m,3H),4.34(q,2H),2.26(s,3H),1.45(t,3H);MS m/z:459[M+H]
实施例10.N-(3-(2-氨基吡啶-3-基)-4-甲基苯基)-4-乙氧基-1-(4-氟苯基)-2-酮基-1,2-二氢吡啶-3-甲酰胺
以与实施例7相似的方式,使用3-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊-2-基)吡啶-2-胺代替(6-氨基吡啶-3-基)硼酸,按照实施例7的步骤2得到标题化合物(12mg,得率:38%)。
1H NMR(400MHz,MeOH-d4)δ7.90(brs,2H),7.77(d,1H),7.62(d,1H),7.50(m,2H),7.45(m,2H),7.35(m,4H),6.77(m,1H),6.59(d,1H),4.33(q,2H),2.14(s,3H),1.44(t,3H);MS m/z:459[M+H]
实施例11. 4-乙氧基-1-(4-氟苯基)-N-(4-甲基-3-(喹啉-6-基)苯基)-2-酮基-1,2-二氢吡啶-3-甲酰胺
以与实施例7相似的方式,使用喹啉-6-基-硼酸代替(6-氨基吡啶-3-基)硼酸,按照实施例7的步骤2得到标题化合物(13mg,得率:40%)。
1H NMR(400MHz,MeOH-d4)δ8.89(brs,1H),8.42(m,1H),8.09(m,1H),7.91(s,1H),7.81(m,2H),7.70(m,1H),7.60(t,2H),7.45(m,2H),7.30(m,3H),6.58(d,1H),4.33(q,2H),2.28(s,3H),1.44(t,3H);MS m/z:494[M+H]
实施例12. 4-乙氧基-1-(4-氟苯基)-N-(3-(异喹啉-6-基)-4-甲基苯基)-2-酮基-1,2-二氢吡啶-3-甲酰胺
以与实施例7相似的方式,使用异喹啉-6-基-硼酸代替(6-氨基吡啶-3-基)硼酸,按照实施例7的步骤2得到标题化合物(9mg,得率:27%)。
1H NMR(400MHz,MeOH-d4)δ9.30(s,1H),8.50(m,1H),8.18(d,1H),7.87(m,2H),7.73(m,2H),7.70(m,1H),7.60(m,1H),7.45(m,2H),7.36(m,3H),6.59(d,1H),4.33(q,2H),2.27(s,3H),1.45(t,3H);MS m/z:494[M+H]
实施例13. 4-乙氧基-1-(4-氟苯基)-N-(4-甲基-3-(1H-吡咯并[2,3-b]吡啶-4-基)苯基)-2-酮基-1,2-二氢吡啶-3-甲酰胺
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以与实施例7相似的方式,使用4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊-2-基)-1H-吡咯并[2,3-b]吡啶代替(6-氨基吡啶-3-基)硼酸,按照实施例7的步骤2得到标题化合物(6mg,得率:18%)。
1H NMR(400MHz,MeOH-d4)δ8.24(d,1H),7.91(s,1H),7.72(m,1H),7.67(m,2H),7.45(m,3H),7.34(d,1H),7.29(m,2H),7.04(d,1H),6.58(d,1H),6.28(d,1H),4.32(q,2H),2.17(s,3H),1.44(t,3H);MS m/z:483[M+H]
实施例14.N-(4-((3-溴咪唑并[1,2-b]哒嗪-6-基)氧基)-2-氟苯基)-4-乙氧基-1-(4-氟苯基)-2-酮基-1,2-二氢吡啶-3-甲酰胺
以与实施例5相似的方式,使用4-(3-溴咪唑并[1,2-b]哒嗪-6-基)氧基)-2-氟苯胺代替化合物4-(6-氯咪唑并[1,2-b]哒嗪-8-基)-3-氟苯胺,按照实施例5的步骤2得到标题化合物(10mg,得率:39.0%)。
MS m/z:582[M],584[M+2]
实施例15.N-(4-(2-(2-氨基嘧啶-4-基)吡啶-4-基)-3-氟苯基)-1-(4-氟苯基)-4-甲氧基-2-酮基-1,2-二氢吡啶-3-甲酰胺
在下文中,按照下述反应方案6制备实施例15的化合物。
反应方案6.
步骤1.(E)-1-(4-氯吡啶-2-基)-3-(二甲基氨基)丙-2-烯-1-酮
将1-(4-氯吡啶-2-基)乙-1-酮(200mg,1.29mmol)和N,N'-二甲基甲酰胺二乙缩醛(1.5ml,9.0mmol)混合,并在120℃下回流搅拌12小时。反应完成,然后将反应溶液浓缩,得到标题化合物(250mg,得率:93%)。
MS m/z:211[M+H]
步骤2. 4-(4-氯吡啶-2-基)嘧啶-2-胺
将在上述步骤1中得到的化合物((E)-1-(4-氯吡啶-2-基)-3-(二甲基氨基)丙-2-烯-1-酮(250mg,1.18mmol)溶解在7mL乙醇中,然后向其添加盐酸胍(147mg,1.54mmol)和K2CO3(355mg,2.57mmol),然后在回流下搅拌12小时。反应完成,然后将反应溶液用水稀释,用DCM萃取三次并浓缩。将残留物通过硅胶柱层析进行纯化,得到标题化合物(170mg,得率:70%)。
MS m/z:207[M+H]
步骤3. 4-(4-(4-氨基-2-氟苯基)吡啶-2-基)嘧啶-2-胺
将在上述步骤2中得到的化合物4-(4-氯吡啶-2-基)嘧啶-2-胺(90mg,0.43mmol)溶解在3mL DME中,然后向其添加3-氟-4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊-2-基)苯胺(124mg,0.52mmol)、2NNa2CO3水溶液(0.54ml,1.09mmol)和Pd(PPh3)4(10mg,0.01mmol),然后在95℃下搅拌12小时。将溶液冷却,用水稀释,然后用DCM萃取三次并浓缩。将残留物通过硅胶柱层析进行纯化,得到标题化合物(100mg,得率:82%)。
MS m/z:281[M+H]
步骤4.N-(4-(2-(2-氨基嘧啶-4-基)吡啶-4-基)-3-氟苯基)-1-(4-氟苯基)-4-甲氧基-2-酮基-1,2-二氢吡啶-3-甲酰胺
将在上述步骤3中得到的化合物4-(4-(4-氨基-2-氟苯基)吡啶-2-基)嘧啶-2-胺(30mg,0.11mmol)溶解在3mL THF中,然后向其添加1-(4-氟苯基)-4-甲氧基-2-酮基-1,2-二氢吡啶-3-甲酸(34mg,0.13mmol)、HATU(61mg,0.07mmol)和DIPEA(37μL,0.21mmol),然后在室温下搅拌12小时。将反应溶液用水稀释,然后用乙酸乙酯萃取三次并浓缩。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(21mg,37%)。
1H NMR(400MHz,DMSO-d6)δ11.76(s,1H),8.78(d,1H),8.52(d,1H),8.43(m,1),7.91(m,2H),7.71(m,2H),7.55(m,2H),7.46(m,2H),7.37(m,2H),6.87(brs,2H),6.56(d,1H),3.93(s,3H);MS m/z:527[M+H]
实施例16.N-(4-(2-(2-氨基嘧啶-4-基)吡啶-4-基)-3-氟苯基)-1-(4-氟苯基)-6-甲基-2-酮基-1,2-二氢吡啶-3-甲酰胺
以与实施例15相似的方式,使用1-(4-氟苯基)-6-甲基-2-酮基-1,2-二氢吡啶-3-甲酸代替1-(4-氟苯基)-4-甲氧基-2-酮基-1,2-二氢吡啶-3-甲酸,按照实施例15的步骤4得到标题化合物(6mg,得率:11%)。
1H NMR(400MHz,DMSO-d6)δ12.18(s,1H),8.77(d,1H),8.52(m,2H),8.42(m,1),7.99(m,1H),7.72(m,2H),7.57-7.43(m,6H),6.78(brs,2H),6.74(d,1H),2.09(s,3H);MSm/z:511[M+H]
实施例17.N-(4-(2-(2-氨基嘧啶-4-基)吡啶-4-基)-3-氟苯基)-5-溴-1-(4-氟苯基)-2-酮基-1,2-二氢吡啶-3-甲酰胺
以与实施例15相似的方式,使用5-溴-1-(4-氟苯基)-2-酮基-1,2-二氢吡啶-3-甲酸代替1-(4-氟苯基)-4-甲氧基-2-酮基-1,2-二氢吡啶-3-甲酸,按照实施例15的步骤4得到标题化合物(6mg,得率:7%)。
1H NMR(400MHz,DMSO-d6)δ12.08(s,1H),8.89(s,1H),8.56(m,3H),8.40(m,1),8.02(m,1H),7.74(m,2H),7.56(m,3H),7.45(m,1H),7.38(m,2H),6.79(brs,2H);MS m/z:575[M],577[M+2]
实施例18.N-(4-(3-氨基-1H-吲唑-6-基)-3-氟苯基)-4-乙氧基-1-(4-氟苯基)-2-酮基-1,2-二氢吡啶-3-甲酰胺
在下文中,按照下述反应方案7制备实施例18的化合物。
反应方案7.
步骤1. 4-乙氧基-N-(3-氟-4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊-2-基)苯基-1-(4-氟苯基)-2-酮基-1,2-二氢吡啶-3-甲酰胺
将3-氟-4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊-2-基)苯胺(500mg,2.11mmol)溶解在10mL THF中,然后向其添加4-乙氧基-1-(4-氟苯基)-2-酮基-1,2-二氢吡啶-3-甲酸(702mg,2.53mmol)、HATU(1200mg,3.16mmol)和DIPEA(553μL,3.16mmol),然后在室温下搅拌12小时。将反应溶液用水稀释,然后用乙酸乙酯萃取三次并浓缩。将残留物通过硅胶柱层析进行纯化,得到标题化合物(450mg,43%)。
MS m/z:497[M+H]
步骤2.N-(4-(3-氨基-1H-吲唑-6-基)-3-氟苯基)-4-乙氧基-1-(4-氟苯基)-2-酮基-1,2-二氢吡啶-3-甲酰胺
将在上述步骤1中得到的化合物4-乙氧基-N-(3-氟-4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊-2-基)苯基-1-(4-氟苯基)-2-酮基-1,2-二氢吡啶-3-甲酰胺(77mg,0.16mmol)溶解在2mL 1,4-二烷中,然后向其添加6-溴-1H-吲唑-3-胺(30mg,0.14mmol)、饱和Na2CO3水溶液(0.14ml,0.28mmol)、PdCl2(dppf)DCM加成物(12mg,0.014mmol),然后在90℃下搅拌12小时。将反应混合物通过硅藻土过滤,并将滤液在真空下干燥。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(17mg,得率:24%)。
1H NMR(400MHz,DMSO-d6)δ11.43(s,1H),10.53(s,1H),7.87(m,1H),7.79(m,2H),7.55(m,4H),7.39(m,3H),7.07(m,1H),6.53(d,1H),5.37(brs,2H),4.28(q,2H),1.32(t,3H);MS m/z:502[M+H]
实施例19. 4-乙氧基-N-(3-氟-4-(1H-吲唑-5-基)苯基)-1-4-氟苯基)-2-酮基-1,2-二氢吡啶-3-甲酰胺
以与实施例18相似的方式,使用5-溴-1H-吲唑代替6-溴-1H-吲唑-3-胺,按照实施例18的步骤2得到标题化合物(17mg,得率:23%)。
1H NMR(400MHz,DMSO-d6)δ10.52(s,1H),8.13(s,1H),7.91(d,1H),7.85(d,1H),7.76(m,1H),7.54(m,1H),7.49(m,5H),7.36(m,2H),6.52(d,1H),4.28(q,2H),1.32(t,3H);MS m/z:487[M+H]
实施例20. 4-乙氧基-N-(3-氟-4-(2-酮基吲哚啉-5-基)苯基)-1-(4-氟苯基)-2-酮基-1,2-二氢吡啶-3-甲酰胺
以与实施例18相似的方式,使用5-溴吲哚啉-2-酮代替6-溴-1H-吲唑-3-胺,按照实施例18的步骤2得到标题化合物(20mg,得率:29%)。
1H NMR(400MHz,DMSO-d6)δ10.49(d,1H),10.46(d,1H),7.86(d,1H),7.75(d,1H),7.48(m,4H),7.39(m,4H),6.91(d,1H),6.52(d,1H),4.27(q,2H),3.54(s,2H),1.31(t,3H);MS m/z:502[M+H]
实施例21.N-(4-(3-氨基苯并[d]异噻唑-5-基)-3-氟苯基)-4-乙氧基-1-(4-氟苯基)-2-酮基-1,2-二氢吡啶-3-甲酰胺
以与实施例18相似的方式,使用5-溴苯并[d]异噻唑-3-胺代替6-溴-1H-吲唑-3-胺,按照实施例18的步骤2得到标题化合物(36mg,得率:52%)。
1H NMR(400MHz,DMSO-d6)δ10.57(s,1H),8.29(s,1H),8.01(m,1H),7.87(d,1H),7.65(m,1H),7.47(m,4H),7.39(m,2H),6.86(brs,2H),6.53(d,1H),4.29(q,2H),1.32(t,3H);MS m/z:519[M+H]
实施例22.N-(4-(3-氨基-1H-吲唑-6-基)-3-氟苯基)-1-(2-羟基-2-甲基丙基)-5-甲基-3-酮基-2-苯基-2,3-二氢-1H-吡唑-4-甲酰胺
在下文中,按照下述反应方案8制备实施例22的化合物。
反应方案8.
步骤1.Boc保护的6-溴吲唑胺
将6-溴-1H-吲唑-3-胺(500mg,2.36mmol)溶解在15mL乙腈中,向其添加Boc酸酐(2.74ml,11.8mmol)和DMAP(14mg,0.12mmol),然后在90℃下搅拌3小时。反应完成,然后将反应溶液用水稀释,用EA萃取三次并浓缩。将残留物通过硅胶柱层析进行纯化,得到标题化合物(900mg,得率:75%)。
MS m/z:512[M],514[M+2]
步骤2. 3-((二叔丁氧基羰基)氨基)-1H-吲唑-1-甲酸叔丁酯
将在上述步骤1中得到的化合物Boc保护的6-溴吲唑胺(900mg,1.76mmol)溶解在10mL DME中,然后向其添加3-氟-4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊-2-基)苯胺(500mg,2.11mmol)、2N Na2CO3水溶液(2.2ml,4.39mmol)和Pd(PPh3)4(41mg,0.035mmol),然后在95℃下搅拌12小时。将反应混合物用水稀释并用DCM萃取三次。将有机层用盐水洗涤并浓缩。将残留物通过硅胶柱层析进行纯化,得到标题化合物(900mg,得率:94%)。
MS m/z:543[M+H]
步骤3. 3-((二叔丁氧基羰基)氨基)-6-(2-氟-4-(1-苯基-5-甲基-3-酮基-2-苯基-2,3-二氢-1H-吡唑-4-甲酰胺基)-吲唑-1-甲酸叔丁酯
将在上述步骤2中得到的化合物3-((二叔丁氧基羰基)氨基)-1H-吲唑-1-甲酸叔丁酯(90mg,0.16mmol)溶解在2mL THF中,然后向其添加1-(2-羟基-2-甲基丙基)-5-甲基-3-酮基-2-苯基-2,3-二氢-1H-吡唑-4-甲酸(51mg,0.20mmol)、HATU(95mg,0.25mmol)和DIPEA(43μL,0.25mmol),然后在室温下搅拌12小时。将反应溶液用水稀释,然后用EA萃取三次并浓缩。将残留物通过硅胶柱层析进行纯化,得到标题化合物(90mg,70%)。
MS m/z:815[M+H]
步骤4.N-(4-(3-氨基-1H-吲唑-6-基)-3-氟苯基)-1-(2-羟基-2-甲基丙基)-5-甲基-3-酮基-2-苯基-2,3-二氢-1H-吡唑-4-甲酰胺
将在步骤3中得到的化合物3-((二叔丁氧基羰基)氨基)-6-(2-氟-4-(1-苯基-5-甲基-3-酮基-2-苯基-2,3-二氢-1H-吡唑-4-甲酰胺基)-吲唑-1-甲酸叔丁酯(90mg,0.11mmol)溶解在1.5mL DCM中,向其添加1.5mL TFA,然后在室温下搅拌2小时。将反应溶液在真空下干燥。将残留物溶解在DCM中,然后用饱和NaHCO3水溶液中和,用DCM萃取三次并浓缩。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(31mg,得率:55%)。
1H NMR(400MHz,DMSO-d6)δ11.46(s,1H),10.87(s,1H),7.82(m,1H),7.74(m,1H),7.59(m,2H),7.45(m,2H),7.33(m,3H),7.28(m,1H),7.02(m,1H),5.36(brs,2H),4.80(s,1H),3.84(brs,2H),2.79(s,3H),0.98(s,6H);MS m/z:515[M+H]
实施例23.N-(4-(3-氨基-1H-吲唑-6-基)-3-氟苯基)-1-(4-氟苯基)-6-甲基-2-酮基-1,2-二氢吡啶-3-甲酰胺
以与实施例22相似的方式,使用1-(4-氟苯基)-6-甲基-2-酮基-1,2-二氢吡啶-3-甲酸代替1-苯基-5-(三氟甲基)-1H-咪唑-4-甲酸,按照实施例22的步骤3得到标题化合物(30mg,得率:55%)。
1H NMR(400MHz,DMSO-d6)δ12.07(s,1H),11.45(s,1H),8.52(d,1H),7.91(d,1H),7.75(d,1H),7.53(m,3H),7.44(m,3H),7.35(s,1H),7.07(d,1H),6.73(d,1H),5.37(brs,2H),2.09(s,3H);MS m/z:472[M+H]
实施例24.N-(4-((2-氨基-3-氯吡啶-4-基)氧基)-3-氟苯基)-1,5-二甲基-3-酮基-2-苯基-2,3-二氢-1H-吡唑-4-甲酰胺
在下文中,按照下述反应方案9制备实施例24的化合物。
反应方案9.
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步骤1)N-(3-氯吡啶-2-基)-1,1-二苯基甲亚胺
将2,3-二氯吡啶(21g,142mmol)(21g,142mmol)溶解在甲基叔丁基醚(MTBE)中,然后向其添加Pd(OAc)2(318mg,1.42mmol)、rac-BINAP(1.4g,2.13mmol)、Cs2CO3(0.9g,2.84mmol)和二苯甲酮亚胺(26g,142mmol)。将反应混合物在70℃下回流搅拌12小时。将反应混合物冷却至室温,并将得到的固体用硅藻土过滤以浓缩溶剂。将残留物通过柱层析进行纯化,得到标题化合物(20g,得率:48%)。
MS m/z:293[M+H]
步骤2)N-(3-氯吡啶-2-基)-1,1-二苯基甲亚胺
将在上述步骤1中得到的化合物N-(3-氯吡啶-2-基)-1,1-二苯基甲亚胺(20g,68.3mmol)溶解在THF 100mL中,并向其添加硼酸三异丙基酯(19.3g,102mmol),然后冷却至0℃。在0℃下向反应混合物缓慢添加二异丙基酰胺锂(11mL,88.8mmol)。将反应混合物在0℃下搅拌2小时,向其添加水(100ml),然后向其添加过碳酸钠(16g,102mmol),然后在室温下进一步搅拌3小时。向反应混合物缓慢添加50ml饱和NaHSO3,并用EA萃取三次。将有机层浓缩,并且不需纯化过程即可用于下面的步骤3中。
MS m/z:309[M+H]
步骤3)N-(3-氯-4-(2-氟-4-硝基苯氧基)吡啶-2-基-1,1-二苯基甲亚胺
将化合物N-(3-氯吡啶-2-基)-1,1-二苯基甲亚胺(20g,65mmol)溶解在DMF中,然后向其添加3,4-二氟硝基苯(9.3mL,84.5mmol)和Cs2CO3(27.5g,84.5mmol),然后在90℃下搅拌1小时。将反应混合物冷却至室温,用水稀释,并用EA萃取三次。将有机溶液用盐水洗涤并浓缩。将残留物通过柱层析进行纯化,得到标题化合物(21g,得率:72%)。
MS m/z:448[M+H]
步骤4)4-((3-氯-2-(二苯基亚甲基)氨基)吡啶-4-基)氧基-3-氟苯胺
将在上述步骤3中获得的化合物N-(3-氯-4-(2-氟-4-硝基苯氧基)吡啶-2-基-1,1-二苯基甲亚胺(20g,44.6mmol)溶解在异丙醇中,向其添加硫化铵(30.4mL,446mmol),然后在室温下搅拌1小时。然后将反应混合物在70℃下再次搅拌3小时。在反应完成后,向其添加水,并将反应混合物冷却至室温。通过过滤获得产生的固体,向其添加乙酸丁酯,在80℃下加热并溶解,向其添加庚烷,并将反应混合物冷却至室温。在将反应混合物冷却至室温后,将产生的固体过滤并干燥,得到标题化合物(14g,75%)。
MS m/z:418[M+H]
步骤5)4-(4-氨基-2-氟苯氧基)-3-氯吡啶-2-胺
将在上述步骤4中获得的化合物4-((3-氯-2-(二苯基亚甲基)氨基)吡啶-4-基)氧基-3-氟苯胺(14g,33mmol)溶解在THF中,向其添加1M HCl(14ml),然后在室温下搅拌2小时。将反应混合物浓缩,然后向其添加饱和NaHCO3,并将反应混合物用EA萃取三次。将有机溶液用盐水洗涤并浓缩。将残留物通过柱层析进行纯化,得到标题化合物(7.1g,得率:84%)。
MS m/z:254[M+H]
步骤6)N-(4-((2-氨基-3-氯吡啶-4-基)氧基)-3-氟苯基)-1,5-二甲基-3-酮基-2-苯基-2,3-二氢-1H-吡唑-4-甲酰胺
将在上述步骤5中得到的化合物4-(4-氨基-2-氟苯氧基)-3-氯吡啶-2-胺(70mg,0.28mmol)溶解在3mL THF中,然后向其添加1,5-二甲基-3-酮基-2-苯基-2,3-二氢-1H-吡唑-4-甲酸(77mg,0.33mmol)、HATU(156mg,0.41mmol)和DIPEA(70μL,0.41mmol),然后在室温下搅拌12小时。将反应溶液用水稀释,然后用EA萃取三次并浓缩。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(74mg,57%)。
1H NMR(400MHz,DMSO-d6)δ10.93(s,1H),7.94(d,1H),7.76(d,1H),7.61(m,2H),7.58(m,1H),7.45(m,2H),7.29(m,2H),6.40(brs,2H),5.94(d,1H),3.37(s,3H),2.71(s,3H);MS m/z:468[M+H]
实施例25.N-(4-((2-氨基-3-氯吡啶-4-基)氧基)-3-氟苯基)-1-(4-氟苯基)-6-甲基-2-酮基-1,2-二氢吡啶-3-甲酰胺
以与实施例24相似的方式,使用1-(4-氟苯基)-6-甲基-2-酮基-1,2-二氢吡啶-3-甲酸代替1,5-二甲基-3-酮基-2-苯基-2,3-二氢-1H-吡唑-4-甲酸,按照实施例24的步骤6得到标题化合物(39mg,得率:75%)。
1H NMR(400MHz,DMSO-d6)δ12.05(s,1H),8.51(d,1H),8.00(m,1H),7.76(d,1H),7.49(m,5H),7.29(t,1H),6.73(d,1H),6.40(brs,2H),5.94(d,1H),2.09(s,3H);MS m/z:483[M+H]
实施例26.N-(4-((2-氨基-3-氯吡啶-4-基)氧基)-3-氟苯基)-1-(4-氟苯基)-6-(羟基甲基)-2-酮基-1,2-二氢吡啶-3-甲酰胺
以与实施例24相似的方式,使用1-(4-氟苯基)-6-(羟基甲基)-2-酮基-1,2-二氢吡啶-3-甲酸代替1,5-二甲基-3-酮基-2-苯基-2,3-二氢-1H-吡唑-4-甲酸,按照实施例24的步骤6得到标题化合物(24mg,得率:45%)。
1H NMR(400MHz,DMSO-d6)δ12.04(s,1H),8.63(d,1H),8.01(m,1H),7.76(d,1H),7.47(m,5H),7.32(t,1H),6.89(d,1H),6.41(brs,2H),5.95(d,1H),4.02(s,2H);MS m/z:499[M+H]
实施例27.N-(4-((2-氨基-3-氯吡啶-4-基)氧基)-3-氟苯基)-5-环丙基-1-(4-氟苯基)-2-酮基-1,2-二氢吡啶-3-甲酰胺
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以与实施例24相似的方式,使用5-环丙基-1-(4-(氟苯基)-2-酮基-1,2-二氢吡啶-3-甲酸代替1,5-二甲基-3-酮基-2-苯基-2,3-二氢-1H-吡唑-4-甲酸,按照实施例24的步骤6得到标题化合物(30mg,得率:80%)。
1H NMR(400MHz,DMSO-d6)δ12.20(s,1H),8.30(d,1H),8.01(m,2H),7.77(d,1H),7.60(m,2H),7.42(m,3H),7.31(m,1H),6.73(d,1H),6.41(brs,2H),5.96(d,1H),2.00(m,1H),0.93(m,2H),0.72(m,2H);MS m/z:509[M+H]
实施例28.N-(4-((2-氨基-3-氯吡啶-4-基)氧基)-3-氟苯基)-1-(4-氟苯基)-2-酮基-6-(三氟甲基)-1,2-二氢吡啶-3-甲酰胺
以与实施例24相似的方式,使用1-(4-氟苯基)-2-酮基-6-(三氟甲基)-1,2-二氢吡啶-3-甲酸代替1,5-二甲基-3-酮基-2-苯基-2,3-二氢-1H-吡唑-4-甲酸,按照实施例24的步骤6得到标题化合物(48mg,得率:89%)。
1H NMR(400MHz,DMSO-d6)δ11.71(s,1H),8.65(d,1H),8.01(m,1H),7.70(d,1H),7.58(m,3H),7.42(m,2H),7.31(t,2H),6.41(brs,2H),5.95(d,1H);MS m/z:537[M+H]
实施例29.N-(4-((2-氨基-3-氯吡啶-4-基)氧基)-3-氟苯基)-1-(2-羟基-2-甲基丙基)-5-甲基-3-酮基-2-苯基-2,3-二氢-1H-吡唑-4-甲酰胺
以与实施例24相似的方式,使用1-(2-羟基-2-甲基丙基)-5-甲基-3-酮基-2-苯基-2,3-二氢-1H-吡唑-4-甲酸代替1,5-二甲基-3-酮基-2-苯基-2,3-二氢-1H-吡唑-4-甲酸,按照实施例24的步骤6得到标题化合物(39mg,得率:79%)。
1H NMR(400MHz,MeOH-d4)δ8.16(d,1H),7.91(d,1H),7.73(d,1H),7.62(m,2H),7.58(m,1H),7.39(m,2H),7.28(m,1H),7.18(m,1H),6.01(d,1H),3.97(brs,2H),2.87(s,3H),1.07(s,6H);MS m/z:526[M+H]
实施例30.N-(4-((3-氯-2-(环丙烷甲酰胺基)吡啶-4-基)氧基)-3-氟苯基)-1-(4-氟苯基)-6-甲基-2-酮基-1,2-二氢吡啶-3-甲酰胺
在下文中,按照下述反应方案10制备实施例30的化合物。
反应方案10.
将实施例25的化合物N-(4-((2-氨基-3-氯吡啶-4-基)氧基)-3-氟苯基)-1-(4-氟苯基)-6-甲基-2-酮基-1,2-二氢吡啶-3-甲酰胺(30mg,0.06mmol)溶解在吡啶中,并在0℃下向其缓慢添加环丙烷羰基氯(7μL,0.07mmol)。将反应混合物在0℃下搅拌1小时,用EA稀释,并用盐水洗涤。将有机层浓缩,然后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(17mg,得率:49%)。
1H NMR(400MHz,DMSO-d6)δ12.09(s,1H),10.47(s,1H),8.51(d,1H),8.21(d,1H),8.06(d,1H),7.52(m,3H),7.46(m,3H),6.73(m,1H),6.67(d,1H),2.09(s,3H),1.92(m,1H),0.80(m,4H);MS m/z:551[M+H]
实施例31.N-(4-((3-氯-2-(N-(环丙烷羰基)环丙烷甲酰胺基)吡啶-4-基)氧基)-3-氟苯基)-1-(4-氟苯基)-6-甲基-2-酮基-1,2-二氢吡啶-3-甲酰胺
作为实施例26的副产物得到标题化合物(7mg,得率:18%)。
1H NMR(400MHz,DMSO-d6)δ12.11(s,1H),8.51(d,1H),8.37(d,1H),8.09(d,1H),7.53(m,3H),7.47(m,3H),6.96(m,1H),6.74(d,1H),2.09(s,3H),1.99(m,2H),1.01(m,8H);MS m/z:620[M+H]
实施例32. 2-氨基-5-溴-N-(2-氟-4-(1-(4-氟苯基)-6-甲基-2-酮基-1,2-二氢吡啶-3-甲酰胺基)苯基)烟酰胺
在下文中,按照下述反应方案11制备实施例32的化合物。
反应方案11.
将2-氨基-5-溴烟酸(88mg,0.41mmol)溶解在DMF中,并向其添加N-(4-氨基-3-氟苯基)-4'-氟-6-甲基-2-酮基-1,2-二氢-[1,1'-联苯基]-3-甲酰胺(120mg,0.34mmol)、HATU(193mg,0.51mmol)和DIPEA(90μL,0.51mmol)。将反应混合物在室温下搅拌约12小时。将反应溶液用水稀释,然后用EA萃取三次并浓缩。将残留物通过硅胶柱层析进行纯化,得到标题化合物(175mg,93%)。
MS m/z:553[M],555[M+2]
实施例33. 3-氨基-6-溴-N-(2-氟-4-(1-(4-氟苯基)-6-甲基-2-酮基-1,2-二氢吡啶-3-甲酰胺基)苯基)吡嗪-2-甲酰胺
以与实施例32相似的方式,使用3-氨基-6-溴吡嗪-2-甲酸代替2-氨基-5-溴烟酸按照实施例32得到标题化合物(135mg,得率:72%)。
MS m/z:554[M],556[M+2]
实施例34. 2-氨基-N-(2-氟-4-(1-(4-氟苯基)-6-甲基-2-酮基-1,2-二氢吡啶-3-甲酰胺基)苯基)-5-(1-甲基-1H-吡唑-4-基)烟酰胺
在下文中,按照下述反应方案12制备实施例34的化合物。
反应方案12.
将实施例32的化合物2-氨基-5-溴-N-(2-氟-4-(1-(4-氟苯基)-6-甲基-2-酮基-1,2-二氢吡啶-3-甲酰胺基)苯基)烟酰胺(40mg,0.072mmol)溶解在1,4-二烷/水(3:1)中,并向其添加1-甲基-4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊-2-基)-1H-吡唑(45mg,0.22mmol)、K2CO3(30mg,0.22mmol)、Pd(PPh3)4(25mg,0.02mmol),然后在100℃下搅拌12小时。将反应混合物用水稀释,用DCM萃取三次,用盐水洗涤并浓缩。将残留物通过硅胶柱层析进行纯化,得到标题化合物(14mg,得率:34%)。
1H NMR(400MHz,DMSO-d6)δ12.03(s,1H),10.04(s,1H),8.51(d,1H),8.41(s,1H),8.29(s,1H),8.06(d,1H),7.83(d,1H),7.72(s,1H),7.49(m,5H),7.39(m,1H),7.03(brs,2H),6.73(d,1H),3.87(s,3H),2.09(s,3H);MS m/z:556[M+H]
实施例35. 3-氨基-N-(2-氟-4-(1-(4-氟苯基)-6-甲基-2-酮基-1,2-二氢吡啶-3-甲酰胺基)苯基)-6-(1-甲基-1H-吡唑-4-基)吡嗪-2-甲酰胺
以与实施例34相似的方式,使用实施例33的化合物3-氨基-6-溴-N-(2-氟-4-(1-(4-氟苯基)-6-甲基-2-酮基-1,2-二氢吡啶-3-甲酰胺基)苯基)吡嗪-2-甲酰胺代替实施例34的2-氨基-5-溴-N-(2-氟-4-(1-(4-氟苯基)-6-甲基-2-酮基-1,2-二氢吡啶-3-甲酰胺基)苯基)烟酰胺,得到标题化合物(9mg,得率:21%)。
1H NMR(400MHz,DMSO-d6)δ12.05(s,1H),10.26(s,1H),8.67(s,1H),8.50(m,1H),8.38(s,1H),8.12(s,1H),7.96(d,1H),7.76(m,1H),7.52(m,6H),6.73(d,2H),3.90(s,3H),2.09(s,3H);MS m/z:557[M+H]
实施例36.N-(4-((6-氨基-5-氯嘧啶-4-基)氧基)-3-氟苯基)-1-(4-氟苯基)-6-甲基-2-酮基-1,2-二氢吡啶-3-甲酰胺
以与实施例25相似的方式,使用6-(4-氨基-2-氟苯氧基)-5-氯嘧啶-4-胺代替4-(4-氨基-3-氟苯氧基)-3-氯吡啶-2-胺,按照实施例25得到标题化合物(32mg,得率:42%)。
1H NMR(400MHz,DMSO-d6)δ12.01(s,1H),8.50(d,1H),7.96(s,1H),7.93(d,1H),7.52(m,2H),7.46(m,5H),7.29(t,1H),6.72(d,1H),2.08(s,3H);MS m/z:484[M+H]
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(TR-FRET)测量了每种化合物的IC50。
具体来说,将所述化合物在100% DMSO中制备成1mM的浓度,并通过3倍稀释以逐步方式稀释10次。将所述以逐步方式稀释的化合物(2μL)添加到含有48μL 1x激酶反应缓冲液(50mM HEPES(pH 7.4),0.01% Tween-20,5mM DTT,0.5mM Na3VO4,2mM EGTA,10mMMgCl2)的96孔板中。
将RON蛋白在RON储存缓冲液(50mM Tris-HCl(pH 7.5),150mM NaCl,0.5mM EDTA,0.02% Triton X-100)中稀释至49.3nM的浓度,然后在1x激酶反应缓冲液中再次稀释至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特异性底物混合溶液(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分配到每个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,并将所有孔在室温下以1,000RPM离心40秒,然后在室温下温育20-30分钟。然后,将5μL的底物混合物(2x)分配到每个孔中,并将所有孔在室温下以1,000RPM离心40秒,然后在室温下温育60分钟。然后,将5μL的30mM EDTA添加到每个孔中以终止反应,然后将所有孔再次在室温下温育5分钟。然后,将5μL含有铕的4x磷酸酪氨酸抗体(Perkin-Elmer)添加到每个孔中,然后将所有孔在室温下温育60分钟。在温育后,用Vison读板器读取384孔板。在这种情况下,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GraphPd Prism7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评估。
具体来说,将所述化合物在100% DMSO中制备成1mM的浓度,并通过3倍稀释以逐步方式稀释10次。将所述以逐步方式稀释的化合物(2μL)添加到含有48μL 1x激酶反应缓冲液(50mM HEPES(pH 7.4),0.05% BSA,0.005%Tween-20,1mM DTT,0.5mM MnCl2,20mMMgCl2)的96孔板中。
将cMET蛋白在cMET储存缓冲液(50mM Tris-HCl(pH 7.5),150mM NaCl,0.05%Brij35,1mM DTT,10%甘油)中稀释到263nM的浓度,然后在1x激酶反应缓冲液中再次稀释至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特异性底物混合溶液(5μM TK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分配到每个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,并将所有孔在室温下以1,000RPM离心40秒,然后在室温下温育20-30分钟。然后,将5μL的底物混合物(2x)分配到每个孔中,并将所有孔在室温下以1,000RPM离心40秒,然后在室温下温育60分钟。然后,将5μL的90mM EDTA添加到每个孔中以终止反应,然后将所有孔再次在室温下温育5分钟。然后,将5μL含有铕的4x磷酸酪氨酸抗体(Perkin-Elmer)添加到每个孔中,然后将所有孔在室温下温育60分钟。在温育后,用Vison读板器读取384孔板。在这种情况下,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GraphPd Prism7程序推衍。
实施例化合物对RON或cMET的抑制活性的评估结果如下表2中所示。
[表2]
RON(IC50,nM) | MET(IC50,nM) | |
实施例1 | 5,120 | 5,230 |
实施例3 | - | 6,720 |
实施例6 | - | 8,270 |
实施例15 | - | 4,857 |
实施例16 | - | 1,486 |
实施例18 | 467 | 496 |
实施例19 | - | 6,543 |
实施例21 | - | 6,033 |
实施例24 | 44 | 11 |
实施例25 | 1 | 2 |
实施例26 | 3 | 3 |
实施例27 | 2 | 6 |
实施例28 | 8 | 18 |
实施例29 | 82 | 54 |
实施例30 | 25 | 12 |
实施例31 | - | 3,551 |
实施例32 | - | 1,692 |
实施例34 | 7,880 | 1,559 |
实施例36 | 7 | 14 |
Claims (9)
1.一种下式1的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是直接连键、O、NR3或NHCO,
上述A是5至15元取代或未取代的含有1至5个选自氮、硫和氧的杂环原子的杂芳基,其中取代的杂芳基的取代基是C1-C6烷基、卤素、胺、酮基或C2-C6环烷基甲酰胺基,
上述A是上面定义的取代或未取代的杂芳基的单环或其中所述取代或未取代的杂芳基的两个或更多个环被稠合或通过碳(sp2)-碳(sp2)键连接的多环,
上述B是5至7元取代或未取代的含有酮基并含有1至5个选自氮、硫和氧的杂环原子的杂芳基,其中取代的杂芳基的取代基是卤素、C1-C6烷基、羟基取代的C1-C6烷基、卤素取代的C1-C6烷基、C1-C6烷基取代的C1-C6烷基、C1-C6烷氧基、5至12元芳基或卤素取代的5至12元芳基,
上述R1是氢、C1-C6烷基或卤素,
上述R2是氢或C1-C6烷基,
上述R3是氢或C1-C6烷基,并且
所述卤素各自独立地选自F、Cl、Br和I。
2.根据权利要求1所述的化合物或其药学上可接受的盐,其中上述A是5至12元取代或未取代的含有1至3个选自氮和硫的杂环原子的杂芳基,其中取代的杂芳基的取代基是甲基、卤素、胺、酮基或C2-C6环丙烷甲酰胺基。
3.根据权利要求1所述的化合物或其药学上可接受的盐,其中上述A具有下述结构:
4.根据权利要求1所述的化合物或其药学上可接受的盐,其中上述B具有下式2或下式3的结构:
[式2]
[式3]
其中在上述式2或式3中,
上述Y、Z和W各自独立地是选自氮、硫和氧的杂原子,
上述R4、R6和R7各自独立地是氢、C1-C6烷基、卤素、羟基或卤素取代的C1-C6烷基或C1-C6烷氧基,
上述R5和R8各自独立地是氢或卤素。
5.根据权利要求1所述的化合物或其药学上可接受的盐,其中上述X是直接连键、O、NH或NHCO。
6.根据权利要求1所述的化合物或其药学上可接受的盐,其中上述R1是氢、甲基或氟。
7.根据权利要求1所述的化合物或其药学上可接受的盐,其中上述R2是氢或甲基。
8.根据权利要求1所述的化合物或其药学上可接受的盐,其中所述化合物选自:
N-(4-(2-氨基噻唑并[5,4-b]吡啶-5-基)-3-甲基苯基)-4-乙氧基-1-(4-氟苯基)-2-酮基-1,2-二氢吡啶-3-甲酰胺,
N-(4-(2-氨基噻唑并[5,4-b]吡啶-5-基)-3-氟苯基)-4-乙氧基-1-(4-氟苯基)-2-酮基-1,2-二氢吡啶-3-甲酰胺,
N-(4-((2-氨基噻唑并[5,4-b]吡啶-5-基)氨基)-3-氟苯基)-4-乙氧基-1-(4-氟苯基)-2-酮基-1,2-二氢吡啶-3-甲酰胺,
N-(4-(2-氨基咪唑并[1,2-b]哒嗪-6-基)-3-氟苯基)-4-乙氧基-1-(4-氟苯基)-2-酮基-1,2-二氢吡啶-3-甲酰胺,
N-(4-((6-氯咪唑并[1,2-b]哒嗪-8-基)氧基)-3-氟苯基)-4-乙氧基-1-(4-氟苯基)-2-酮基-1,2-二氢吡啶-3-甲酰胺,
N-(4-((6-氯咪唑并[1,2-b]哒嗪-8-基)氧基)-3-氟苯基)-1-(4-氟苯基)-6-甲基-2-酮基-1,2-二氢吡啶-3-甲酰胺,
N-(3-(6-氨基吡啶-3-基)-4-甲基苯基)-4-乙氧基-1-(4-氟苯基)-2-酮基-1,2-二氢吡啶-3-甲酰胺,
N-(3-(2-氨基嘧啶-5-基)-4-甲基苯基)-4-乙氧基-1-(4-氟苯基)-2-酮基-1,2-二氢吡啶-3-甲酰胺,
N-(3-(2-氨基吡啶-4-基)-4-甲基苯基)-4-乙氧基-1-(4-氟苯基)-2-酮基-1,2-二氢吡啶-3-甲酰胺,
N-(3-(2-氨基吡啶-3-基)-4-甲基苯基)-4-乙氧基-1-(4-氟苯基)-2-酮基-1,2-二氢吡啶-3-甲酰胺,
4-乙氧基-1-(4-氟苯基)-N-(4-甲基-3-(喹啉-6-基)苯基)-2-酮基-1,2-二氢吡啶-3-甲酰胺,
4-乙氧基-1-(4-氟苯基)-N-(3-(异喹啉-6-基)-4-甲基苯基)-2-酮基-1,2-二氢吡啶-3-甲酰胺,
4-乙氧基-1-(4-氟苯基)-N-(4-甲基-3-(1H-吡咯并[2,3-b]吡啶-4-基)苯基)-2-酮基-1,2-二氢吡啶-3-甲酰胺,
N-(4-((3-溴咪唑并[1,2-b]哒嗪-6-基)氧基)-2-氟苯基)-4-乙氧基-1-(4-氟苯基)-2-酮基-1,2-二氢吡啶-3-甲酰胺,
N-(4-(2-(2-氨基嘧啶-4-基)吡啶-4-基)-3-氟苯基)-1-(4-氟苯基)-4-甲氧基-2-酮基-1,2-二氢吡啶-3-甲酰胺,
N-(4-(2-(2-氨基嘧啶-4-基)吡啶-4-基)-3-氟苯基)-1-(4-氟苯基)-6-甲基-2-酮基-1,2-二氢吡啶-3-甲酰胺,
N-(4-(2-(2-氨基嘧啶-4-基)吡啶-4-基)-3-氟苯基)-5-溴-1-(4-氟苯基)-2-酮基-1,2-二氢吡啶-3-甲酰胺,
N-(4-(3-氨基-1H-吲唑-6-基)-3-氟苯基)-4-乙氧基-1-(4-氟苯基)-2-酮基-1,2-二氢吡啶-3-甲酰胺,
4-乙氧基-N-(3-氟-4-(1H-吲唑-5-基)苯基)-1-4-氟苯基)-2-酮基-1,2-二氢吡啶-3-甲酰胺,
4-乙氧基-N-(3-氟-4-(2-酮基吲哚啉-5-基)苯基)-1-(4-氟苯基)-2-酮基-1,2-二氢吡啶-3-甲酰胺,
N-(4-(3-氨基苯并[d]异噻唑-5-基)-3-氟苯基)-4-乙氧基-1-(4-氟苯基)-2-酮基-1,2-二氢吡啶-3-甲酰胺,
N-(4-(3-氨基-1H-吲唑-6-基)-3-氟苯基)-1-(2-羟基-2-甲基丙基)-5-甲基-3-酮基-2-苯基-2,3-二氢-1H-吡唑-4-甲酰胺,
N-(4-(3-氨基-1H-吲唑-6-基)-3-氟苯基)-1-(4-氟苯基)-6-甲基-2-酮基-1,2-二氢吡啶-3-甲酰胺,
N-(4-((2-氨基-3-氯吡啶-4-基)氧基)-3-氟苯基)-1,5-二甲基-3-酮基-2-苯基-2,3-二氢-1H-吡唑-4-甲酰胺,
N-(4-((2-氨基-3-氯吡啶-4-基)氧基)-3-氟苯基)-1-(4-氟苯基)-6-甲基-2-酮基-1,2-二氢吡啶-3-甲酰胺,
N-(4-((2-氨基-3-氯吡啶-4-基)氧基)-3-氟苯基)-1-(4-氟苯基)-6-(羟基甲基)-2-酮基-1,2-二氢吡啶-3-甲酰胺,
N-(4-((2-氨基-3-氯吡啶-4-基)氧基)-3-氟苯基)-5-环丙基-1-(4-氟苯基)-2-酮基-1,2-二氢吡啶-3-甲酰胺,
N-(4-((2-氨基-3-氯吡啶-4-基)氧基)-3-氟苯基)-1-(4-氟苯基)-2-酮基-6-(三氟甲基)-1,2-二氢吡啶-3-甲酰胺,
N-(4-((2-氨基-3-氯吡啶-4-基)氧基)-3-氟苯基)-1-(2-羟基-2-甲基丙基)-5-甲基-3-酮基-2-苯基-2,3-二氢-1H-吡唑-4-甲酰胺,
N-(4-((3-氯-2-(环丙烷甲酰胺基)吡啶-4-基)氧基)-3-氟苯基)-1-(4-氟苯基)-6-甲基-2-酮基-1,2-二氢吡啶-3-甲酰胺,
N-(4-((3-氯-2-(N-(环丙烷羰基)环丙烷甲酰胺基)吡啶-4-基)氧基)-3-氟苯基)-1-(4-氟苯基)-6-甲基-2-酮基-1,2-二氢吡啶-3-甲酰胺,
2-氨基-5-溴-N-(2-氟-4-(1-(4-氟苯基)-6-甲基-2-酮基-1,2-二氢吡啶-3-甲酰胺基)苯基)烟酰胺,
3-氨基-6-溴-N-(2-氟-4-(1-(4-氟苯基)-6-甲基-2-酮基-1,2-二氢吡啶-3-甲酰胺基)苯基)吡嗪-2-甲酰胺,
2-氨基-N-(2-氟-4-(1-(4-氟苯基)-6-甲基-2-酮基-1,2-二氢吡啶-3-甲酰胺基)苯基)-5-(1-甲基-1H-吡唑-4-基)烟酰胺,
3-氨基-N-(2-氟-4-(1-(4-氟苯基)-6-甲基-2-酮基-1,2-二氢吡啶-3-甲酰胺基)苯基)-6-(1-甲基-1H-吡唑-4-基)吡嗪-2-甲酰胺,和
N-(4-((6-氨基-5-氯嘧啶-4-基)氧基)-3-氟苯基)-1-(4-氟苯基)-6-甲基-2-酮基-1,2-二氢吡啶-3-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;以及药学上可接受的载体。
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