CN101687867B - 具有免疫调节性质的咪唑并喹啉 - Google Patents
具有免疫调节性质的咪唑并喹啉 Download PDFInfo
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- CN101687867B CN101687867B CN2008800240506A CN200880024050A CN101687867B CN 101687867 B CN101687867 B CN 101687867B CN 2008800240506 A CN2008800240506 A CN 2008800240506A CN 200880024050 A CN200880024050 A CN 200880024050A CN 101687867 B CN101687867 B CN 101687867B
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- Prior art keywords
- methyl
- amino
- imidazo
- quinoline
- phenyl
- 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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- RHKWIGHJGOEUSM-UHFFFAOYSA-N 3h-imidazo[4,5-h]quinoline Chemical class C1=CN=C2C(N=CN3)=C3C=CC2=C1 RHKWIGHJGOEUSM-UHFFFAOYSA-N 0.000 title description 3
- 230000002519 immonomodulatory effect Effects 0.000 title description 3
- 150000001875 compounds Chemical class 0.000 claims abstract description 357
- 238000000034 method Methods 0.000 claims abstract description 110
- 150000003839 salts Chemical class 0.000 claims abstract description 53
- 238000002360 preparation method Methods 0.000 claims abstract description 41
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 10
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 322
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 319
- KXKVLQRXCPHEJC-UHFFFAOYSA-N acetic acid trimethyl ester Natural products COC(C)=O KXKVLQRXCPHEJC-UHFFFAOYSA-N 0.000 claims description 317
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 claims description 314
- ODFJOVXVLFUVNQ-UHFFFAOYSA-N acetarsol Chemical compound CC(=O)NC1=CC([As](O)(O)=O)=CC=C1O ODFJOVXVLFUVNQ-UHFFFAOYSA-N 0.000 claims description 241
- -1 pyrrolidyl Chemical group 0.000 claims description 183
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 61
- 238000006243 chemical reaction Methods 0.000 claims description 49
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 41
- 238000011282 treatment Methods 0.000 claims description 32
- 239000003814 drug Substances 0.000 claims description 28
- 229910052736 halogen Inorganic materials 0.000 claims description 24
- 150000002367 halogens Chemical class 0.000 claims description 24
- 125000000623 heterocyclic group Chemical group 0.000 claims description 24
- 239000001257 hydrogen Substances 0.000 claims description 24
- 229910052739 hydrogen Inorganic materials 0.000 claims description 24
- 229910052760 oxygen Inorganic materials 0.000 claims description 24
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 23
- 229910052757 nitrogen Inorganic materials 0.000 claims description 21
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 19
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 18
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 17
- 125000006239 protecting group Chemical group 0.000 claims description 17
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- 201000010099 disease Diseases 0.000 claims description 15
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 14
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 14
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 13
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 13
- 239000001301 oxygen Substances 0.000 claims description 13
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 12
- 125000005843 halogen group Chemical group 0.000 claims description 12
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 11
- 150000002431 hydrogen Chemical class 0.000 claims description 10
- 206010028980 Neoplasm Diseases 0.000 claims description 9
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 9
- CVHZOJJKTDOEJC-UHFFFAOYSA-N saccharin Chemical class C1=CC=C2C(=O)NS(=O)(=O)C2=C1 CVHZOJJKTDOEJC-UHFFFAOYSA-N 0.000 claims description 8
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 7
- 125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 claims description 6
- 201000011510 cancer Diseases 0.000 claims description 6
- 150000001721 carbon Chemical group 0.000 claims description 6
- 229910052799 carbon Inorganic materials 0.000 claims description 6
- 125000000714 pyrimidinyl group Chemical group 0.000 claims description 6
- 241000894006 Bacteria Species 0.000 claims description 5
- 239000012752 auxiliary agent Substances 0.000 claims description 5
- UBUCGEQKZOBBLK-UHFFFAOYSA-N ethyl formate;piperazine Chemical compound CCOC=O.C1CNCCN1 UBUCGEQKZOBBLK-UHFFFAOYSA-N 0.000 claims description 5
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 4
- 241000700605 Viruses Species 0.000 claims description 4
- 125000001118 alkylidene group Chemical group 0.000 claims description 4
- 208000026935 allergic disease Diseases 0.000 claims description 4
- 125000004482 piperidin-4-yl group Chemical group N1CCC(CC1)* 0.000 claims description 4
- 125000005936 piperidyl group Chemical group 0.000 claims description 4
- SJJCQDRGABAVBB-UHFFFAOYSA-N 1-hydroxy-2-naphthoic acid Chemical class C1=CC=CC2=C(O)C(C(=O)O)=CC=C21 SJJCQDRGABAVBB-UHFFFAOYSA-N 0.000 claims description 3
- BQEBXZIJQLNRLJ-UHFFFAOYSA-N CS(=O)(=O)O.CS(=O)(=O)O.C(C)(=O)OC Chemical compound CS(=O)(=O)O.CS(=O)(=O)O.C(C)(=O)OC BQEBXZIJQLNRLJ-UHFFFAOYSA-N 0.000 claims description 3
- 206010012438 Dermatitis atopic Diseases 0.000 claims description 3
- LPQOADBMXVRBNX-UHFFFAOYSA-N ac1ldcw0 Chemical compound Cl.C1CN(C)CCN1C1=C(F)C=C2C(=O)C(C(O)=O)=CN3CCSC1=C32 LPQOADBMXVRBNX-UHFFFAOYSA-N 0.000 claims description 3
- 125000003545 alkoxy group Chemical group 0.000 claims description 3
- 201000008937 atopic dermatitis Diseases 0.000 claims description 3
- 239000004305 biphenyl Substances 0.000 claims description 3
- 235000010290 biphenyl Nutrition 0.000 claims description 3
- 239000003638 chemical reducing agent Substances 0.000 claims description 3
- IWYDHOAUDWTVEP-UHFFFAOYSA-M mandelate Chemical compound [O-]C(=O)C(O)C1=CC=CC=C1 IWYDHOAUDWTVEP-UHFFFAOYSA-M 0.000 claims description 3
- 125000002757 morpholinyl group Chemical group 0.000 claims description 3
- 230000000414 obstructive effect Effects 0.000 claims description 3
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N phenylbenzene Natural products C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 claims description 3
- RNGASVAXHHSNIQ-UHFFFAOYSA-N C(C=CC(=O)O)(=O)O.C(C)(=O)OC Chemical compound C(C=CC(=O)O)(=O)O.C(C)(=O)OC RNGASVAXHHSNIQ-UHFFFAOYSA-N 0.000 claims description 2
- 125000003601 C2-C6 alkynyl group Chemical group 0.000 claims description 2
- 206010020751 Hypersensitivity Diseases 0.000 claims description 2
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- 125000006267 biphenyl group Chemical group 0.000 claims description 2
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims description 2
- 125000004193 piperazinyl group Chemical group 0.000 claims description 2
- 208000023504 respiratory system disease Diseases 0.000 claims description 2
- BDHFUVZGWQCTTF-UHFFFAOYSA-M sulfonate Chemical compound [O-]S(=O)=O BDHFUVZGWQCTTF-UHFFFAOYSA-M 0.000 claims description 2
- 125000003386 piperidinyl group Chemical group 0.000 claims 3
- 125000002393 azetidinyl group Chemical group 0.000 claims 1
- 238000002560 therapeutic procedure Methods 0.000 abstract description 3
- 239000000047 product Substances 0.000 description 146
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 114
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 104
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 66
- 239000007787 solid Substances 0.000 description 65
- 238000005160 1H NMR spectroscopy Methods 0.000 description 64
- 239000000203 mixture Substances 0.000 description 60
- 239000000243 solution Substances 0.000 description 56
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 46
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 44
- 239000002585 base Substances 0.000 description 44
- 238000003756 stirring Methods 0.000 description 43
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 42
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 39
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 37
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 32
- 239000003112 inhibitor Substances 0.000 description 32
- 235000015110 jellies Nutrition 0.000 description 31
- 239000008274 jelly Substances 0.000 description 31
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 28
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 28
- 239000011541 reaction mixture Substances 0.000 description 27
- 239000002904 solvent Substances 0.000 description 27
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 24
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- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 23
- 239000003795 chemical substances by application Substances 0.000 description 22
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 22
- 239000003513 alkali Substances 0.000 description 19
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- FVAUCKIRQBBSSJ-UHFFFAOYSA-M sodium iodide Chemical compound [Na+].[I-] FVAUCKIRQBBSSJ-UHFFFAOYSA-M 0.000 description 12
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Abstract
本发明披露了式(I)化合物及其药用盐,和它们的制备方法、含有它们的药物组合物和它们在治疗中的用途,其中Ra、R1、R2、R3、X1、Y1、Z1、A、n和m如在说明书中所定义。
Description
技术领域
本发明涉及咪唑并喹啉衍生物,它们的制备方法、含有它们的药物组合物和它们在治疗中的用途。
背景技术
免疫系统由先天免疫和获得性免疫构成,这两种免疫协作工作以保护宿主免受微生物感染。已经证明,先天免疫可通过表达在免疫细胞的细胞表面上的toll-样受体(TLRs)识别保守的病原体相关性分子图式(conservedpathogen-associated molecular patterns)。识别侵入性病原体,然后触发细胞因子产生(包括干扰素α(IFNα))和上调吞噬细胞上的共刺激分子,导致T细胞功能的调节。因此,先天免疫与获得性免疫紧密联系,并可影响获得性应答的发展和调节。
TLRs是I型跨膜受体家族,所述家族的特征为NH2-末端细胞外富亮氨酸重复结构域(LRR)和COOH-末端细胞内尾部(tail)(含有保守的区域,称作Toll/IL-1受体(TIR)同源结构域)。所述细胞外结构域含有不同数目的LRR,这些不同数目的LRR被认为牵涉在配体结合中。目前已经在人类和小鼠中描述了十一种TLRs。它们彼此之间在配体特异性、表达方式(expressionpattern)和它们能够诱导的靶基因方面不同。
已经开发出通过TLRs(也称为免疫应答修饰因子(immune responsemodifier,IRMS)起作用的配体,例如在美国专利4689338中描述的咪唑并喹啉衍生物,其包括用于治疗生殖器疣的产物Imiquimod,和在WO 98/01448和WO 99/28321中描述的腺嘌呤衍生物。
本专利申请描述了具有免疫调节性质的、通过TLR7起作用的一类咪唑并喹啉化合物,其用于治疗病毒性疾病或变应性疾病和癌症(viral orallergic diseases and cancers)。
发明内容
根据本发明,其因此提供式(I)化合物或其药用盐,
其中
R1表示直链C1-C6烷基,所述直链C1-C6烷基任选被一个或多个独立选自卤素、氰基、羟基和C1-C3烷氧基的取代基取代;
Z1表示C2-C6亚烷基或C3-C8亚环烷基;
X1表示NR5、>N-COR5、CONR5、NR5CO、SO2NR5、>N-SO2R5、NR5SO2、NR5CONR6、NR6CONR5、S(O)p或O;
Y1表示单键或C1-C6亚烷基;
每个R2独立地选自卤素、氰基、羟基、巯基(thiol)、C1-C3烷基、羟基C1-C3烷基、卤代C1-C3烷基、C1-C3烷氧基、卤代C1-C3烷氧基、C1-3烷基硫基、C1-3烷基磺酰基和C1-3烷基亚磺酰基;
R3表示C1-6烷基,所述C1-6烷基任选被C1-6烷氧基取代;
每个Ra独立地选自卤素、氰基、羟基、巯基、C1-C3烷基、羟基C1-C3烷基、卤代C1-C3烷基、C1-C3烷氧基、卤代C1-C3烷氧基、C1-3烷基硫基、C1-3烷基磺酰基和C1-3烷基亚磺酰基;
R5表示氢、含有环成员O、S(O)p或NR10的3-至8-元饱和杂环基团、C1-C6烷基或C3-C6环烷基,其中所述C1-C6烷基或C3-C6环烷基任选被一个或多个独立选自NR7R8或R9的取代基取代,
或者,R5为C1-C6亚烷基,所述C1-C6亚烷基可与C2-C6亚烷基团Z1中的碳原子相连,从而形成饱和的4-7元含氮环;
条件是,当X1为>N-SO2R5时,R5不表示氢;
R7和R8各自独立地表示氢、含有环成员O、S(O)p或NR10a的3-至8-元饱和杂环基团、C1-C6烷基或C3-C6环烷基,所述C1-C6烷基或C3-C6环烷基任选被一个或多个独立选自如下的基团取代,所述基团为:卤素、氰基、S(O)qR11、OR12、CO2R12、OC(O)R12、SO2NR12R13、CONR12R13、NR12R13、NR12SO2R14、NR12COR13或含有环成员O、S(O)p或NR10b的3-至8-元饱和杂环基团,
或者,R7和R8与它们所连接的氮原子一起形成含有环氮原子和任选一个或多个独立选自氮、氧、硫和磺酰基的额外杂原子的3-至8-元饱和杂环基团,所述杂环基任选被一个或多个独立选自如下的取代基取代,所述取代基为:卤素、氰基、S(O)qR15、OR15、CO2R15、COR15、OC(O)R15、SO2NR15R16、CONR15R16、NR15R16、NR15SO2R17、NR15COR16、NR15CO2R16、杂芳基、卤代C1-C6烷基、C3-C8环烷基和C1-C6烷基,其中所述C3-C8环烷基和C1-C6烷基任选被一个或多个独立选自氰基、S(O)qR18、OR18、CO2R18、SO2NR18R19、CONR18R19或NR18R19的基团取代;
R9表示卤素、氰基、CO2R20、S(O)qR20、OR20、SO2NR20R22、CONR20R22、NR20SO2R21、NR20CO2R21、NR20COR22或含有环成员NR10c的3-至8-元饱和杂环基团;
R10、R10a、R10b和R10c独立表示氢、CO2R23、S(O)qR23、COR24、或C1-C6烷基、C2-C6烯基、C2-C6炔基或C3-C8环烷基,这些基团各自可任选被一个或多个独立选自卤素、氰基、OR25或NR25R26的取代基取代;
R6、R11、R12、R13、R15、R16、R18、R19、R20、R22、R24、R25和R26各自独立地表示氢、C1-C6烷基或C3-C6环烷基;
R14、R17、R21和R23各自独立地表示C1-C6烷基或C3-C6环烷基;
m、n、p和q各自独立地表示整数0、1或2;以及
A表示单环C6-C10芳基或二环C6-C10芳基或含有1-3个杂原子的单环C5-C12杂芳基或含有1-3个杂原子的二环C5-C12杂芳基。
在本发明说明书的上下文中,除非另有说明,取代基中的烷基取代基或烷基部分可以是直链的或支链的。它们可以例如含有1至6个碳原子。C1-C6烷基/部分的例子包括甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、正戊基和正己基。类似地,亚烷基/部分可以是直链的或支链的。C1-C6亚烷基/部分的实例包括亚甲基、亚乙基、亚正丙基(n-propylene)、亚正丁基、亚正戊基、亚正己基、1-甲基亚乙基、2-甲基亚乙基、1,2-二甲基亚乙基、1-乙基亚乙基、2-乙基亚乙基、1-、2-或3-甲基亚丙基和1-,2-或3-乙基亚丙基。烯基或炔基是不饱和的直链或直链基团,含有例如2至6个碳原子。应当理解的是,在式(I)中,如果不止一个基团含有基团或部分即S(O)p或S(O)q,或者如果取代基含有两个或多个S(O)p或S(O)q,则每个“p”或每个“q”独立表示整数0、1或2。例如,如果R7表示被两个基团S(O)qR11取代的C3-C6环烷基,则每个“q”可以相同或不同。同样,当有不止一个“R11”时,每个“R11”可以相同或不同。
环烷基或碳环基是含有例如3至8个碳原子并且为饱和的环基团。
杂环基是如下所述的环基团,所述环基团可以是饱和的、部分不饱和的或不饱和的,并且含有3至20个原子,至少一个原子并且合适地1至4个原子为选自氧、硫和氮的杂原子。环可以是单环杂环体系、稠合杂环体系、桥接杂环体系或螺二环杂环体系。单环杂环在环中含有约3至12个环原子,且具有1至5个选自N、O和S的杂原子,并且合适地为3至7元原子。二环杂环在环中含有7至17元原子,合适地含有7至12元原子。二环杂环含有约7至约17个环原子,合适地含有7至12个环原子。二环杂环可以是稠合的环系、螺环系或桥接环系。
饱和或部分饱和的杂环基的实例包括环醚(环氧烷类(oxirane))例如环氧乙烷、四氢呋喃、二噁烷和饱和的环醚。含氮杂环包括例如,氮杂环丁烷、吡咯烷、哌啶、哌嗪、四氢三嗪、四氢吡唑等。典型的含硫杂环包括四氢噻吩、二氢-1,3-二硫杂环戊二烯-2-基(dihydro-1,3-dithiol-2-yl)和六氢噻庚英-4-基(hcxahydrothiepin-4-yl)。其它杂环包括二氢-氧杂硫杂环戊二烯-4-基(dihydro-oxathiol-4-yl)、四氢-噁唑基、四氢-噁二唑基、四氢二噁唑基、四氢-噁噻唑基、六氢三嗪基、四氢-噁嗪基、吗啉基、硫吗啉基、四氢嘧啶基、二氧杂环戊二烯基(dioxolinyl)、八氢苯并呋喃基、八氢苯并咪唑基和八氢苯并咪噻唑基。对于含硫杂环,也包括含有SO或SO2基团的氧化硫杂环。实例包括四氢噻吩的亚砜形式和砜形式。对于带有1或2个氧代或硫酮(thioxo)取代基的杂环,合适的基团为例如,2-氧代吡咯烷基、2-硫酮吡咯烷基、2-氧代咪唑烷基、2-硫酮咪唑烷基、2-氧代哌啶基、2,5-二氧代吡咯烷基、2,5-二氧代咪唑烷基或2,6-二氧代哌啶基。
性质上为芳香性的杂环基团指的是“杂芳基”基团。这些基团是含有一个或多个(例如,1-4个)选自N、O和S杂原子的芳族单-、二-或多环杂环。术语杂芳基即包括单价种类又包括二价种类。杂芳基的实例包括呋喃基、吡咯基、噻吩基、噁唑基、异噁唑基、咪唑基、吡唑基、噻唑基、异噻唑基、噁二唑基、噻二唑基、三唑基、四唑基、吡啶基、哒嗪基、嘧啶基、吡嗪基、1,3,5-三氮烯基、苯并呋喃基、吲哚基、异吲哚基、苯并噻吩基、苯并噁唑基、苯并咪唑基、苯并噻唑基、苯并噻唑基、吲唑基、嘌呤基、苯并呋咱基、喹啉基、异喹啉基、喹唑啉基、喹喔啉基、噌啉基、蝶啶基、二氮杂萘基、咔唑基、吩嗪基、苯并异喹啉基、吡啶并吡嗪基、噻吩并[2,3-b]呋喃基、2H-呋喃并[3,2-b]-吡喃基、5H-吡啶并[2,3-d]-o-噁嗪基、1H-吡唑并[4,3-d]-噁唑基、4H-咪唑并[4,5-d]噻唑基、吡嗪并[2,3-d]哒嗪基、咪唑并[2,1-b]噻唑基、咪唑并[1,2-b][1,2,4]三嗪基。“杂芳基”也包括其中至少一个环是含有1个或多个选自O、S和N杂原子的芳族环的环系,并且其它环中的一个或多个是任选含有一个或多个选自O、S和N的杂原子的非芳族的、饱和的或部分不饱和的环,例如1,2,3,4-四氢-1,8-二氮杂萘基、1,2,3,4-四氢吡啶并[2,3-b]吡嗪基和3,4-二氢-2H-吡啶并[3,2-b][1,4]噁嗪基。
优选的杂芳基为含有一个或多个选自N、S、O杂原子的5-7元芳族环基或6,6-或6,5-稠合二环基。实例包括吡啶基、嘧啶基、噻唑基、噁唑基、吡唑基、咪唑基、呋喃基、异噁唑基、吡咯基、异噻唑基和薁基、萘基、茚基、喹啉基、异喹啉基、吲哚基、吲嗪基、苯并[b]呋喃基、苯并[b]噻吩基、1H-吲唑基、苯并咪唑基、苯并噻唑基、苯并噁唑基、嘌呤基、4H-喹嗪基、噌啉基、酞嗪基、喹唑啉基、喹喔啉基、1,8-二氮杂萘基、蝶啶基和喹诺酮基。
优选地,R1表示直链C1-6烷基,所述直链C1-6烷基任选被C1-3烷氧基取代,例如,甲基、乙基、正丙基、正丁基、甲氧基甲基或甲氧基乙基。在一个具体的实施方案中,R1为甲基。
在一个具体的实施方案中,Z1为C2-6亚烷基,特别是直链C2-6亚烷基,例如直链C2-4亚烷基。Z1的具体实例是亚正丙基。
在一个具体的实施方案中,X1表示NR5、>N-COR5、NR5CO、NR5SO2或>N-SO2R5。(为了避免引起疑虑,在X1的定义中出现的第一个原子与Z1基团相连。因此,当X1为SO2NR5时,所述硫原子与Z1基团相连,以及所述氮原子与Y1基团相连)。
在另一个实施方案中,X1表示NR5或>N-COR5。
其中R6存在于任意基团X1中,R6合适地选自氢或C1-6烷基例如甲基。
X1的具体实例为基团NR5。
X1基团的另一个具体实例为>N-COR5。
R5基团的具体实例包括氢或C1-6烷基,所述C1-6烷基任选被一个或多个独立选自NR7R8或R9的取代基取代,其中R7、R8和R9如上所定义。
例如,R5表示C1-C6烷基或C1-C4烷基,其任选被一个或多个独立选自NR7R8或R9的取代基取代,其中R7、R8和R9如上所定义。
具体地,R5为C1-C6烷基,特别是C1-C3烷基,例如甲基、乙基或正丙基,所述基团任选被一个或多个独立选自NR7R8的取代基取代,其中R7和R8如上所定义。
在另一个实施方案中,R5为C1-C6亚烷基,其可与C2-C6亚烷基Z1中的碳原子相连,从而形成饱和的4-7元含氮环。具体地,R5与Z1链中的碳原子相连,从而形成例如,其中X1为基团NR5的哌啶环。
在一个具体的实施方案中,Y1表示C1-C6亚烷基,例如CH2基团。
在另一个实施方案中,其中A为杂芳基,其合适地为含有6个原子,其中一个或两个为氮的单环。因此,杂芳基的具体实例包括吡啶基和嘧啶基,合适地为吡啶基。
环A的具体实例为苯基。
当存在时,R2合适地为卤素,例如氟或氯、氰基、羟基、巯基、C1-C3烷基例如甲基、羟基C1-C3烷基例如羟基甲基、卤代C1-C3烷基例如三氟甲基、C1-C3烷氧基例如甲氧基或乙氧基、卤代C1-C3烷氧基例如三氟甲氧基、C1-3烷基硫基例如甲基硫基、C1-3烷基磺酰基例如甲基磺酰基或C1-3烷基亚磺酰基例如甲基亚磺酰基。
然而,优选的是n为0。
在一个具体的实施方案中,R3表示C1-6烷基,其任选被C1-4烷氧基取代。烷基的实例包括甲基、乙基、异丙基、正丙基和正丁基。R3的具体实例为正丁基。烷氧基取代的烷基R3的具体实例为乙氧基甲基和甲氧基乙基。
当存在时,每个Ra合适地独立表示卤素例如氯或氟、氰基、羟基、巯基、C1-C3烷基例如甲基、羟基C1-C3烷基例如羟基甲基、卤代C1-C3烷基例如三氟甲基、C1-C3烷氧基例如甲氧基或乙氧基、卤代C1-C3烷氧基例如三氟甲氧基、C1-3烷基硫基例如甲基硫基、C1-3烷基磺酰基例如甲基磺酰基或C1-3烷基亚磺酰基例如甲基亚磺酰基。
然而合适地,m为0。
R7和R8各自独立地表示氢、含有环成员O、S(O)p或NR10a的3-至8-或5-至6-元饱和杂环,C1-C6或C1-C4或C1-C2烷基或C3-C6或C5-C6环烷基,所述烷基或环烷基任选被一个或多个(例如,一个、两个、三个或四个)独立选自如下的基团取代,所述基团为:卤素(例如,氟、氯、溴或碘)、氰基、S(O)qR11、OR12、CO2R12、OC(O)R12、SO2NR12R13、CONR12R13、NR12R13、NR12SO2R14、NR12COR13或含有环成员O、S(O)p或NR10b的3-至8-或5-至6-元饱和杂环。
或者,R7和R8与它们所连接的氮原子一起形成含有环氮原子和任选一个或多个(例如,一个、两个或三个)独立选自氮、氧、硫和磺酰基的额外杂原子的3-至8-元饱和杂环基团(例如,哌啶基、哌嗪基、吗啉基或吡咯烷基),所述杂环任选被一个或多个(例如,一个、两个、三个或四个)独立选自如下的取代基取代,所述取代基为:卤素(例如,氟、氯、溴或碘)、氰基、S(O)qR15、OR15、CO2R15、COR15、OC(O)R15、SO2NR15R16、CONR15R16、NR15R16、NR15SO2R17、NR15COR16、NR15CO2R16、杂芳基(特别是嘧啶基)、卤代C1-C6或C1-C4或C1-C2烷基(例如,三氟甲基、三氟甲氧基或五氟乙基)、C3-C8或C5-C6环烷基和C1-C6或C1-C4或C1-C2烷基,所述环烷基或烷基任选被一个或多个(例如,一个、两个、三个或四个)独立选自氰基、S(O)qR18、OR18、CO2R18、SO2NR18R19、CONR18R19或NR18R19的基团取代。
在一个实施方案中,R7和R8各自独立地表示氢、含有环成员O或NR10a的5-至6-元饱和杂环或任选被一个或多个(例如,一个、两个、三个或四个)独立选自如下的基团取代的C1-C6或C1-C4或C1-C2烷基,所述基团为:卤素(例如,氟、氯、溴或碘)、氰基、S(O)qR11、OR12、CO2R12、OC(O)R12、SO2NR12R13、CONR12R13、NR12R13、NR12SO2R14、NR12COR13、或含有环成员O、S(O)p或NR10b的3-至8-或5-至6-元饱和杂环。
在另一个实施方案中,R7和R8各自独立地表示氢、含有环成员O或NR10a的5-至6-元饱和杂环或任选被取代一个或两个独立选自如下基团取代的C1-C4烷基,所述基团为卤素(例如,氟、氯、溴或碘)、氰基、S(O)qR11、OR12、CO2R12、OC(O)R12、SO2NR12R13、CONR12R13、NR12R13、NR12SO2R14、NR12COR13或3-至8-或5-至6-元含有环成员O、S(O)p或NR10b的饱和杂环。
在另一个实施方案中,R7和R8各自独立地表示含有环成员O或NR10a的5-至6-元饱和杂环(例如,四氢吡喃基或N-乙酰基哌啶基)或任选被OR12取代的C1-C4烷基。
在可选择的实施方案中,R7和R8与它们所连接的氮原子一起形成3-至8-元,特别是4-至7-或5-至6-元含有环氮原子和任选一个或多个独立选自氮、氧、硫和磺酰基的额外杂原子的饱和杂环,所述杂环任选被一个或多个(例如,一个、两个、三个或四个)独立选自如下的取代基取代,所述取代基为卤素(例如,氟、氯、溴或碘)、氰基、S(O)qR15、OR15、CO2R15、COR15、CONR15R16、NR15CO2R16、杂芳基和C1-C6或C1-C4或C1-C2烷基,所述烷基任选被一个或多个(例如,一个、两个、三个或四个)独立选自氰基、S(O)qR18、OR18、CO2R18、SO2NR18R19、CONR18R19或NR18R19的基团取代。
根据另一个实施方案,R7和R8与它们所连接的氮原子一起形成含有氮原子和任选一个其它选自氮和氧的杂原子的4-至7-元饱和杂环,所述杂环任选被一个或多个独立选自如下的取代基取代,所述取代基为:S(O)qR15、OR15、CO2R15、COR15、CONR15R16、NR15CO2R16、嘧啶基和C1-C2烷基,所述烷基任选被一个或多个独立选自OR18和CO2R18的基团取代。
本发明化合物的实例包括如下化合物和它们中任意一个的药用盐:
2-(4-((3-(4-氨基-2-丁基-1H-咪唑并[4,5-c]喹啉-1-基)丙基氨基)甲基)苯基)乙酸甲酯,
2-(3-((3-(4-氨基-2-丁基-1H-咪唑并[4,5-c]喹啉-1-基)丙基氨基)甲基)苯基)乙酸甲酯,
2-(4-((N-(3-(4-氨基-2-丁基-1H-咪唑并[4,5-c]喹啉-1-基)丙基)-2-(二甲基氨基)乙酰氨基)甲基)苯基)乙酸甲酯,
2-(3-((N-(3-(4-氨基-2-丁基-1H-咪唑并[4,5-c]喹啉-1-基)丙基)-2-(二甲基氨基)乙酰氨基)甲基)苯基)乙酸甲酯,
2-(3-((4-((4-氨基-2-(乙氧基甲基)-1H-咪唑并[4,5-c]喹啉-1-基)甲基)哌啶-1-基)甲基)苯基)乙酸甲酯·二-三氟乙酸盐,
[4-({[3-(4-氨基-2-丁基-1H-咪唑并[4,5-c]喹啉-1-基)丙基][2-(二甲基氨基)乙基]氨基}甲基)苯基]乙酸甲酯,
2-(3-((N-(3-(4-氨基-2-(乙氧基甲基)-1H-咪唑并[4,5-c]喹啉-1-基)丙基)-2-(二甲基氨基)乙酰氨基)甲基)苯基)乙酸甲酯,
2-(3-(((3-(4-氨基-2-丁基-1H-咪唑并[4,5-c]喹啉-1-基)丙基)(1-甲基哌啶-4-基)氨基)甲基)苯基)乙酸甲酯,
2-(4-(((3-(4-氨基-2-丁基-1H-咪唑并[4,5-c]喹啉-1-基)丙基)(1-甲基哌啶-4-基)氨基)甲基)苯基)乙酸甲酯,
2-(4-((N-(3-(4-氨基-2-丁基-1H-咪唑并[4,5-c]喹啉-1-基)丙基)-2-(4-甲基哌嗪-1-基)乙酰氨基)甲基)苯基)乙酸甲酯,
2-(3-(((3-(4-氨基-2-丁基-1H-咪唑并[4,5-c]喹啉-1-基)丙基)(3-(二甲基氨基)丙基)氨基)甲基)苯基)乙酸甲酯,
2-(3-(((3-(4-氨基-2-丁基-1H-咪唑并[4,5-c]喹啉-1-基)丙基)(3-吗啉代丙基)氨基)甲基)苯基)乙酸甲酯,
2-(3-(((3-(4-氨基-2-丁基-1H-咪唑并[4,5-c]喹啉-1-基)丙基)(3-(乙基(甲基)氨基)丙基)氨基)甲基)苯基)乙酸甲酯,
2-(3-(((3-(4-氨基-2-丁基-1H-咪唑并[4,5-c]喹啉-1-基)丙基)(3-(4-甲基哌嗪-1-基)丙基)氨基)甲基)苯基)乙酸甲酯,
2-(4-((N-(3-(4-氨基-2-丁基-1H-咪唑并[4,5-c]喹啉-1-基)丙基)-2-(甲基磺酰基)乙酰氨基)甲基)苯基)乙酸甲酯,
2-(4-((N-(3-(4-氨基-2-丁基-1H-咪唑并[4,5-c]喹啉-1-基)丙基)乙酰氨基)甲基)苯基)乙酸甲酯,
2-(4-((N-(3-(4-氨基-2-丁基-1H-咪唑并[4,5-c]喹啉-1-基)丙基)-2-吗啉代乙酰氨基)甲基)苯基)乙酸甲酯,
2-(4-((N-(3-(4-氨基-2-丁基-1H-咪唑并[4,5-c]喹啉-1-基)丙基)-2-((2-甲氧基乙基)(甲基)氨基)乙酰氨基)甲基)苯基)乙酸甲酯,
2-(4-((2-(4-乙酰基哌嗪-1-基)-N-(3-(4-氨基-2-丁基-1H-咪唑并[4,5-c]喹啉-1-基)丙基)乙酰氨基)甲基)苯基)乙酸甲酯,
(R)-2-(4-((N-(3-(4-氨基-2-丁基-1H-咪唑并[4,5-c]喹啉-1-基)丙基)-2-(3-羟基吡咯烷-1-基)乙酰氨基)甲基)苯基)乙酸甲酯,
2-(4-((N-(3-(4-氨基-2-丁基-1H-咪唑并[4,5-c]喹啉-1-基)丙基)-2-(4-(嘧啶-2-基)哌嗪-1-基)乙酰氨基)甲基)苯基)乙酸甲酯,
4-(2-((3-(4-氨基-2-丁基-1H-咪唑并[4,5-c]喹啉-1-基)丙基)(4-(2-甲氧基-2-氧代乙基)苄基)氨基)-2-氧代乙基)哌嗪-1-甲酸乙酯,
2-(4-((N-(3-(4-氨基-2-丁基-1H-咪唑并[4,5-c]喹啉-1-基)丙基)-2-(4-(乙基磺酰基)哌嗪-1-基)乙酰氨基)甲基)苯基)乙酸甲酯,
2-(4-((N-(3-(4-氨基-2-丁基-1H-咪唑并[4,5-c]喹啉-1-基)丙基)-2-(哌啶-1-基)乙酰氨基)甲基)苯基)乙酸甲酯,
2-(4-((N-(3-(4-氨基-2-丁基-1H-咪唑并[4,5-c]喹啉-1-基)丙基)-2-(4-(叔丁氧基羰基氨基)哌啶-1-基)乙酰氨基)甲基)苯基)乙酸甲酯,
2-(4-((N-(3-(4-氨基-2-丁基-1H-咪唑并[4,5-c]喹啉-1-基)丙基)-2-(4-(叔丁氧基羰基(甲基)氨基)哌啶-1-基)乙酰氨基)甲基)苯基)乙酸甲酯,
2-(1-(2-((3-(4-氨基-2-丁基-1H-咪唑并[4,5-c]喹啉-1-基)丙基)(4-(2-甲氧基-2-氧代乙基)苄基)氨基)-2-氧代乙基)哌啶-4-基)乙酸乙酯,
1-(2-((3-(4-氨基-2-丁基-1H-咪唑并[4,5-c]喹啉-1-基)丙基)(4-(2-甲氧基-2-氧代乙基)苄基)氨基)-2-氧代乙基)哌啶-4-甲酸甲酯,
2-(4-((N-(3-(4-氨基-2-(2-甲氧基乙基)-1H-咪唑并[4,5-c]喹啉-1-基)丙基)-2-(哌啶-1-基)乙酰氨基)甲基)苯基)乙酸甲酯,
2-(4-((N-(3-(4-氨基-2-(2-甲氧基乙基)-1H-咪唑并[4,5-c]喹啉-1-基)丙基)-2-(二甲基氨基)乙酰氨基)甲基)苯基)乙酸甲酯,
2-(3-((N-(3-(4-氨基-2-(2-甲氧基乙基)-1H-咪唑并[4,5-c]喹啉-1-基)丙基)-2-(哌啶-1-基)乙酰氨基)甲基)苯基)乙酸甲酯,
2-(4-((N-(3-(4-氨基-2-(2-甲氧基乙基)-1H-咪唑并[4,5-c]喹啉-1-基)丙基)-2-((2-甲氧基乙基)(甲基)氨基)乙酰氨基)甲基)苯基)乙酸甲酯,
2-(4-((N-(3-(4-氨基-2-(2-甲氧基乙基)-1H-咪唑并[4,5-c]喹啉-1-基)丙基)-3-(哌啶-1-基)丙酰氨基)甲基)苯基)乙酸甲酯,
2-(4-(((3-(4-氨基-2-(2-甲氧基乙基)-1H-咪唑并[4,5-c]喹啉-1-基)丙基)(3-吗啉代丙基)氨基)甲基)苯基)乙酸甲酯,
(S)-2-(4-((N-(3-(4-氨基-2-(2-甲氧基乙基)-1H-咪唑并[4,5-c]喹啉-1-基)丙基)-2-(2-(甲氧基甲基)吡咯烷-1-基)乙酰氨基)甲基)苯基)乙酸甲酯,
(R)-2-(4-((N-(3-(4-氨基-2-(2-甲氧基乙基)-1H-咪唑并[4,5-c]喹啉-1-基)丙基)-2-(2-(甲氧基甲基)吡咯烷-1-基)乙酰氨基)甲基)苯基)乙酸甲酯,
2-(4-((N-(3-(4-氨基-2-(2-甲氧基乙基)-1H-咪唑并[4,5-c]喹啉-1-基)丙基)-2-(吡咯烷-1-基)乙酰氨基)甲基)苯基)乙酸甲酯,
2-(4-((N-(3-(4-氨基-2-(2-甲氧基乙基)-1H-咪唑并[4,5-c]喹啉-1-基)丙基)-2-((2-羟基乙基)(甲基)氨基)乙酰氨基)甲基)苯基)乙酸甲酯,
2-(3-((N-(3-(4-氨基-2-丁基-1H-咪唑并[4,5-c]喹啉-1-基)丙基)-2-((2-甲氧基乙基)(甲基)氨基)乙酰氨基)甲基)苯基)乙酸甲酯,
2-(3-((N-(3-(4-氨基-2-丁基-1H-咪唑并[4,5-c]喹啉-1-基)丙基)-2-(丁基(甲基)氨基)乙酰氨基)甲基)苯基)乙酸甲酯,
3-((N-(3-(4-氨基-2-丁基-1H-咪唑并[4,5-c]喹啉-1-基)丙基)-2-(二丙基氨基)乙酰氨基)甲基)苯基)乙酸甲酯,
2-(3-((N-(3-(4-氨基-2-丁基-1H-咪唑并[4,5-c]喹啉-1-基)丙基)-2-(二(2-羟基乙基)氨基)乙酰氨基)甲基)苯基)乙酸甲酯,
2-(3-((N-(3-(4-氨基-2-丁基-1H-咪唑并[4,5-c]喹啉-1-基)丙基)-2-(甲基(四氢-2H-吡喃-4-基)氨基)乙酰氨基)甲基)苯基)乙酸甲酯,
2-(3-((N-(3-(4-氨基-2-丁基-1H-咪唑并[4,5-c]喹啉-1-基)丙基)-2-(氮杂环丁烷-1-基)乙酰氨基)甲基)苯基)乙酸甲酯,
2-(3-((N-(3-(4-氨基-2-丁基-1H-咪唑并[4,5-c]喹啉-1-基)丙基)-2-(3-羟基氮杂环丁烷-1-基)乙酰氨基)甲基)苯基)乙酸甲酯,
2-(3-((N-(3-(4-氨基-2-丁基-1H-咪唑并[4,5-c]喹啉-1-基)丙基)-2-(吡咯烷-1-基)乙酰氨基)甲基)苯基)乙酸甲酯,
2-(3-((N-(3-(4-氨基-2-丁基-1H-咪唑并[4,5-c]喹啉-1-基)丙基)-2-(3-羟基吡咯烷-1-基)乙酰氨基)甲基)苯基)乙酸甲酯,
(R)-2-(3-((N-(3-(4-氨基-2-丁基-1H-咪唑并[4,5-c]喹啉-1-基)丙基)-2-(3-羟基吡咯烷-1-基)乙酰氨基)甲基)苯基)乙酸甲酯,
2-(3-((N-(3-(4-氨基-2-丁基-1H-咪唑并[4,5-c]喹啉-1-基)丙基)-2-(哌啶-1-基)乙酰氨基)甲基)苯基)乙酸甲酯,
2-(3-((N-(3-(4-氨基-2-丁基-1H-咪唑并[4,5-c]喹啉-1-基)丙基)-2-(4-羟基哌啶-1-基)乙酰氨基)甲基)苯基)乙酸甲酯,
2-(3-((N-(3-(4-氨基-2-丁基-1H-咪唑并[4,5-c]喹啉-1-基)丙基)-2-(4-甲氧基哌啶-1-基)乙酰氨基)甲基)苯基)乙酸甲酯,
2-(3-((N-(3-(4-氨基-2-丁基-1H-咪唑并[4,5-c]喹啉-1-基)丙基)-2-(4-(二甲基氨基甲酰基)哌啶-1-基)乙酰氨基)甲基)苯基)乙酸甲酯,
2-(3-((N-(3-(4-氨基-2-丁基-1H-咪唑并[4,5-c]喹啉-1-基)丙基)-2-吗啉代乙酰氨基)甲基)苯基)乙酸甲酯,
2-(3-((N-(3-(4-氨基-2-丁基-1H-咪唑并[4,5-c]喹啉-1-基)丙基)-2-((2S,6R)-2,6-二甲基吗啉代)乙酰氨基)甲基)苯基)乙酸甲酯,
2-(3-((N-(3-(4-氨基-2-丁基-1H-咪唑并[4,5-c]喹啉-1-基)丙基)-2-(4-甲基哌嗪-1-基)乙酰氨基)甲基)苯基)乙酸甲酯,
2-(3-((N-(3-(4-氨基-2-丁基-1H-咪唑并[4,5-c]喹啉-1-基)丙基)-2-(4-(2-羟基乙基)哌嗪-1-基)乙酰氨基)甲基)苯基)乙酸甲酯,
2-(3-((N-(3-(4-氨基-2-丁基-1H-咪唑并[4,5-c]喹啉-1-基)丙基)-2-(4-(2-甲氧基乙基)哌嗪-1-基)乙酰氨基)甲基)苯基)乙酸甲酯,
2-(3-((2-(4-乙酰基哌嗪-1-基)-N-(3-(4-氨基-2-丁基-1H-咪唑并[4,5-c]喹啉-1-基)丙基)乙酰氨基)甲基)苯基)乙酸甲酯,
2-(3-((N-(3-(4-氨基-2-丁基-1H-咪唑并[4,5-c]喹啉-1-基)丙基)-2-(4-(甲基磺酰基)哌嗪-1-基)乙酰氨基)甲基)苯基)乙酸甲酯,
2-(3-((N-(3-(4-氨基-2-丁基-1H-咪唑并[4,5-c]喹啉-1-基)丙基)-2-(氮杂环庚烷-1-基)乙酰氨基)甲基)苯基)乙酸甲酯,
2-(3-((N-(3-(4-氨基-2-丁基-1H-咪唑并[4,5-c]喹啉-1-基)丙基)-2-(1,4-氧杂氮杂环庚烷-4-基)乙酰氨基)甲基)苯基)乙酸甲酯,
2-(3-((N-(3-(4-氨基-2-丁基-1H-咪唑并[4,5-c]喹啉-1-基)丙基)-2-(4-甲基-1,4-二氮杂环庚烷-1-基)乙酰氨基)甲基)苯基)乙酸甲酯,
2-(3-((2-(4-乙酰基-1,4-二氮杂环庚烷-1-基)-N-(3-(4-氨基-2-丁基-1H-咪唑并[4,5-c]喹啉-1-基)丙基)乙酰氨基)甲基)苯基)乙酸甲酯,
2-(3-((N-(3-(4-氨基-2-丁基-1H-咪唑并[4,5-c]喹啉-1-基)丙基)-2-(4-(乙基氨基甲酰基)-1,4-二氮杂环庚烷-1-基)乙酰氨基)甲基)苯基)乙酸甲酯,
2-(3-((N-(3-(4-氨基-2-丁基-1H-咪唑并[4,5-c]喹啉-1-基)丙基)-2-(4-(甲基磺酰基)-1,4-二氮杂环庚烷-1-基)乙酰氨基)甲基)苯基)乙酸甲酯,
2-(4-((N-(3-(4-氨基-2-丁基-1H-咪唑并[4,5-c]喹啉-1-基)丙基)-2-(4-(2-甲氧基乙基)哌嗪-1-基)乙酰氨基)甲基)苯基)乙酸甲酯,
2-(4-((2-(4-乙酰基-1,4-二氮杂环庚烷-1-基)-N-(3-(4-氨基-2-丁基-1H-咪唑并[4,5-c]喹啉-1-基)丙基)乙酰氨基)甲基)苯基)乙酸甲酯,
2-(4-((N-(3-(4-氨基-2-丁基-1H-咪唑并[4,5-c]喹啉-1-基)丙基)-2-(4-(甲基磺酰基)-1,4-二氮杂环庚烷-1-基)乙酰氨基)甲基)苯基)乙酸甲酯,
2-(4-((2-((1-乙酰基哌啶-4-基)(甲基)氨基)-N-(3-(4-氨基-2-丁基-1H-咪唑并[4,5-c]喹啉-1-基)丙基)乙酰氨基)甲基)苯基)乙酸甲酯,
2-(4-((N-(3-(4-氨基-2-(2-甲氧基乙基)-1H-咪唑并[4,5-c]喹啉-1-基)丙基)-2-(4-甲基哌嗪-1-基)乙酰氨基)甲基)苯基)乙酸甲酯,
2-(4-((N-(3-(4-氨基-2-(2-甲氧基乙基)-1H-咪唑并[4,5-c]喹啉-1-基)丙基)-2-(4-(2-甲氧基乙基)哌嗪-1-基)乙酰氨基)甲基)苯基)乙酸甲酯,
2-(3-((N-(3-(4-氨基-2-(2-甲氧基乙基)-1H-咪唑并[4,5-c]喹啉-1-基)丙基)-2-(4-甲基哌嗪-1-基)乙酰氨基)甲基)苯基)乙酸甲酯,
2-(3-((N-(3-(4-氨基-2-(2-甲氧基乙基)-1H-咪唑并[4,5-c]喹啉-1-基)丙基)-2-(4-(2-甲氧基乙基)哌嗪-1-基)乙酰氨基)甲基)苯基)乙酸甲酯。
本发明还提供制备如上定义的式(I)化合物或其药用盐的方法,所述方法包括:
a)当X1为基团NR5时,使式(II)化合物与式(III)化合物反应,
式(II)化合物为:
其中,Z1、R3、Ra和m如在式(I)中所定义,L1为离去基团,
式(III)化合物为:
其中,Y1、R1、R2、R5、A和n如在式(I)中所定义;或者
(b)当X1为基团NR5以及Y1为C1-C6亚烷基时,在合适的还原剂(例如,三乙酰氧基硼氢化钠)存在下,使式(IV)化合物与式(V)化合物反应,
式(IV)化合物为:
其中,Ra、R3、R5、Z1和m如在式(I)中所定义,
式(V)化合物为:
其中R1、R2、A和n如在式(I)中所定义,以及Y2为键或C1-5亚烷基;
或者
(c)当X1为基团NR5、O或S时,使式(VI)化合物与式(VII)化合物反应,
式(VI)化合物为:
其中,X3为基团NR5、O或S,以及Z1、R3、R5、Ra和m如在式(I)中所定义,
式(VII)化合物为:
其中,Y1、R1、R2、A和n如在式(I)中所定义,以及L2为离去基团;或者
(d)当X1为基团S(O)p,其中p为1或2时,氧化其中X1为S的式(I)化合物;或者
(e)当X1为基团NR5CO、NR5SO2、NR5CONR6或NR6CONR5时,使式(IVA)化合物与式(VIII)化合物反应,
式(IVA)化合物为:
其中,Ra、R3、Z1和m如对式(I)所定义,以及R5a为如对式(I)所定义的基团R5或R6,
式(VIII)化合物为:
其中,L3为离去基团,例如卤素,X2分别为CO、SO2、CONR6或CONR5,以及Y1、R1、R2、A和n如对式(I)所定义;或者
(f)当X1为CONR5或SO2NR5时,使式(IX)化合物与如上定义的式(III)化合物反应,
式(IX)化合物为:
其中X4为活化酸(activated acid)例如酰氯或SO2Cl,Ra、R3、Z1和m如在式(I)中所定义;或者
(h)当X1为>N-COR5或>N-SO2R5时,使式(I)化合物与式(X)或式(XI)化合物分别反应,其中X1为NR5,R5为氢,
L4-COR5
(X)
L4-SO2R5
(XI)
其中L4为离去基团例如卤素(例如氯),以及R5如对式(I)所定义;
以及随后,如果需要或有必要,进行如下的一个或多个步骤:
●将得到的化合物转化为其它式(I)化合物,
●除去任何保护基,
●形成所述化合物的药用盐。
在上述反应(a)和(c)中,合适的离去基团L1和L2为卤素原子例如溴或氯,以及为活化醇例如甲磺酸酯基(mesylate)或甲苯磺酸酯基(tosylate)。所述反应可便利地在有机溶剂(例如乙腈、1-甲基-2-吡咯烷酮或N,N-二甲基甲酰胺)中在例如0至150℃温度范围进行。所述反应可通过存在碱(例如,碳酸钠或碳酸钾)而被合适地进行。
在方法(b)中,所述反应可便利地在有机溶剂(例如1-甲基-2-吡咯烷酮、1,2-二氯乙烷或四氢呋喃)中在例如0至100℃温度范围进行。
式(II)化合物可如在反应方案A中所示的那样制备:
方案A
其中,Ra、m、R3和Z1如对式(I)所定义,以及P为保护基。
通过式(A)化合物的硝化制备式(B)化合物。合适的硝化剂包括硝酸。反应合适地在有机溶剂例如有机酸(例如丙酸)中进行。所述反应可在高温进行,例如从室温至150℃。
式(C)化合物可通过如下方式制备,所述方式为式(B)化合物与亚硫酰氯和DMF的混合物反应,得到芳基氯化物,所述芳基氯化物然后被用氨基烷醇置换。所述氯化合适地在有机溶剂例如二氯甲烷中进行,优选在高温进行。氯化物用氨基烷醇的置换反应合适地在碱(例如三乙胺或Hunigs碱)存在下和在有机溶剂(例如二氯甲烷)中在0至40℃温度范围进行。
通过向羟基末端基团加入合适的保护基制备式(D)化合物。这可使用常规化学如在‘Protective Groups in Organic Synthesis’by TheodoraGreen(publisher:John Wiley & Sons)中所描述的那样进行。针对羟基的保护基P为例如,烷酰基(例如乙酰基),芳酰基(例如苯甲酰基),或芳基甲基(例如苄基),或甲硅烷基例如叔丁基(二甲基)甲硅烷基。
式(D)化合物也可通过向式(B)化合物加入经保护的氨基烷醇制备,使用与上面相同的条件。
然后将式(D)化合物还原形成式(E)化合物。合适的还原剂包括在合适溶剂(例如乙酸)中的铁粉,或在合适溶剂(例如甲醇)中在合适催化剂(例如15%氯化镍)存在下的硼氢化钠,或者氢化。合适的氢化条件包括在高压使用氢气,例如在合适催化剂(例如1%铂/炭催化剂)存在下在2-5巴进行。反应合适地在室温进行。
然后对式(E)化合物进行环化,形成式(F)化合物。合适的环化条件包括在碱例如三乙胺存在下在合适的溶剂例如N-甲基吡咯烷酮中与酰氯反应,或者在偶联剂例如O-(7-氮杂苯并三唑-1-基)-N,N,N’,N’-四甲基六氟磷酸盐(HATU)存在下和在碱(例如三乙胺)存在下在合适溶剂(例如N-甲基吡咯烷)中与酸反应。可选择地,所述式(F)化合物可通过在合适溶剂例如N-甲基吡咯烷酮中在合适催化剂例如10摩尔%甲苯磺酸存在下与原酸酯发生环化反应制备。所述反应合适地在高温实现,例如从30-150℃的温度。
式(F)化合物也可通过与氧化剂例如间氯过氧苯甲酸或过氧化氢反应而被氧化成式(G)化合物。所述反应合适在有机溶剂例如二氯甲烷或乙醇中在低温例如-10℃至室温范围进行。
随后,使所述式(G)化合物与对甲苯磺酰氯和氨水反应,使其转化成式(H)化合物。所述反应合适地在有机溶剂例如二氯甲烷中进行。合适地采用0-40℃温度范围,并且便利地采用在室温进行。
对所得式(H)化合物脱保护得到式(J)化合物。针对上述保护基的脱保护条件必然地随保护基的选择而变化。因此,例如,酰基例如烷酰基或烷氧基羰基或芳酰基可例如,通过用合适的碱(例如碱金属氢氧化物(例如氢氧化锂或氢氧化钠))水解而除去。可选择地,苄基可通过例如经催化剂例如钯/炭氢化而被除去。
然后通过形成合适的离去基团例如卤素(例如氯或溴)或活化醇例如甲磺酸酯基或甲苯磺酸酯基将式(J)产物转化成式(II)化合物。例如,所述氯化物可通过式(J)化合物与亚硫酰氯反应形成。优选地,在溶剂例如二氯甲烷中在20-40℃的温度进行。
式(IV)和式(IVA)化合物可通过与方案B中所示的路线类似的路线制备。
方案B
其中,Ra、m、R3和Z1如关于式(I)中所定义,R5a如关于式(IVA)中所定义,以及P1为氨基保护基。
式(K)或式(L)化合物可通过式(B)化合物与亚硫酰氯和DMF的混合物反应制备,得到芳基氯化物,所述芳基氯化物然后可被用二氨基烷烃或其经保护形式置换。所述氯化合适地在溶剂(例如二氯甲烷)中进行,优选在高温进行。所述氯化物用二氨基烷烃或其经保护形式的置换反应合适地在碱(例如三乙胺或Hunigs碱)存在下在有机溶剂(例如二氯甲烷)中在0至40℃温度范围进行。
当使用二氨基烷烃时,制备了式(K)化合物,所述式(K)化合物随后使用常规方法被保护,形成式(L)化合物。
合适的保护基P1为例如,基团例如烷氧基羰基(例如,甲氧基羰基、乙氧基羰基或叔丁氧基羰基)、芳基甲氧基羰基(例如苄氧基羰基)。针对伯胺的合适的可选择保护剂为例如,邻苯二甲酰基。
使用例如与上述用于式(D)化合物还原的条件类似的条件还原产物式(L)将得到式(M)化合物。该化合物随之可使用与上述用于式(E)化合物环化的那些条件类似的条件被环化成式(N)化合物,使用与上述用于式(F)化合物氧化的那些条件类似的条件氧化成式(Q)化合物,并且使用与上述用于制备式(H)化合物的那些条件类似的条件使所述产物与对甲苯磺酰氯和氨水反应,形成式(S)化合物。
对所得式(S)化合物脱保护,得到式(IV)化合物。针对上述保护基的脱保护条件必要地随保护基的选择而变化。因此,例如,烷氧基羰基可通过例如用合适的碱例如碱金属氢氧化物(例如氢氧化锂或氢氧化钠)水解而被脱除。可选择地,烷氧基羰基例如叔丁氧基羰基可通过例如用合适的酸例如盐酸、硫酸或磷酸或三氟乙酸处理而被脱除,以及芳基甲氧基羰基例如苄氧基羰基可通过例如经由催化剂例如钯/炭氢化而被脱除,或通过用路易斯酸(例如三(三氟乙酸)化硼(boron tris(trifluoroacetate))处理而被脱除。邻苯二甲酰基保护基通过用烷基胺(例如二甲基氨基丙基胺)处理或用肼处理而被脱除。
合适地,在方案B中,R5为氢,其随后可被转化成不同的R5基团,例如,一旦所述式(IV)化合物已经被转化成式(I)化合物。
式(VI)化合物(其中X1为NR5)可通过式(II)化合物与式(XII)化合物反应制备
R5NH2
(XII)
偶联条件与上述用于反应(a)和(c)的那些条件类似。
使用常规方法,式(I)化合物可被转化成其它式(I)化合物。例如,在上述方法(h)中,化合物(其中R5为氢)可与式(X)化合物或式(XI)化合物反应;
L4-COR5 或 L4-SO2R5
(X) (XI)
其中,L4为离去基团例如卤素(例如氯),以及R5关于式(I)中所定义。所述反应合适地在有机溶剂(例如乙腈、二甲基甲酰胺和/或二氯甲烷)中在碱(例如三乙胺)存在下进行。合适地采用0至150℃温度范围。
类似地,式(I)化合物在上述方法(d)中的氧化可在常规条件下进行,例如通过与氧化剂例如间氯过氧苯甲酸或过氧化氢反应进行。所述反应合适地在有机溶剂例如二氯甲烷或乙醇中在例如0-40℃温度范围进行。
上述式(IX)化合物(其中X4为活化酸例如酰氯)合适地通过在方案C中所列的反应制备。
方案C
用于方案C中所示的反应的条件大体上与在方案B类似步骤中使用的那些条件相似。可用碱例如氢氧化锂或氢氧化钠在合适的溶剂例如四氢呋喃或甲醇和水将式化合物Y转化成式Z化合物。可选择地,所述醚可在酸条件(例如HCl水溶液)下被水解,优选在高温被水解。式(I)化合物可由式(Z)化合物通过如下方式制备,所述方式为用试剂例如亚硫酰氯将酸活化成酰卤例如酰氯,然后用式(III)化合物处理。酰氯的形成可便利地间接进行或在有机溶剂例如二氯甲烷中在例如0至80℃温度范围进行。所述活化酸然后用式(III)化合物处理,所述反应可便利地在有机溶剂例如四氢呋喃或二甲基甲酰胺中使用碱例如三乙胺在0至80℃温度范围进行。可选择地,所述酸可用偶联剂例如1,3-二环己基碳二亚胺或苯并三唑-1-基氧基三吡咯烷磷鎓六氟磷酸盐活化。
上述式(IX)化合物(其中X4为SO2Cl)可通过式(II)化合物与亚硫酸钠反应制备,然后用氯化剂例如亚硫酰氯或五氯化磷处理磺酸酯,得到磺酰氯。所述磺酰氯然后可与式(III)化合物反应,得到式(I)化合物。所述反应可便利地在有机溶剂例如四氢呋喃或二氯甲烷中用碱例如三乙胺在0至80℃温度范围进行。
式(I)化合物(其中,X1为NR5,以及R5为氢)可通过与氯乙酰氯反应,然后与式R7R8NH(其中R7和R8如上所定义)的胺反应而被转化为相应的式(I)化合物(其中,R5为-COCH2NR7R8)。第一阶段合适地在有机溶剂例如二氯甲烷或乙腈中进行,使用一当量的氯乙酰氯。合适地采用0℃至50℃温度范围。在第二阶段,所述反应合适地在有机溶剂例如二氯甲烷或乙腈中进行,使用过量的胺R7R8NH。合适地采用0℃至100℃温度范围。
式(I)化合物(其中X1为NR5,以及R5为氢)也可通过与式(XX)化合物L10-R5(其中,L10为离去基团例如卤素(例如氯),以及R5如上定义)反应而被转化成相应的式(I)化合物(其中,R5为被NR7R8取代的C1-C6烷基(例如,丙基))。所述反应合适地在有机溶剂例如二甲基甲醛或乙腈中进行,优选使用一当量的式(XX)化合物,任选在碱例如三乙胺和盐例如碘化钠或碘化钾存在下进行。合适地采用0℃至100℃温度范围。
式(I)化合物(其中,X1为NR5,以及R5为被NR7R8取代的C1-C6烷基(例如,丙基)也可通过式(XIII)化合物与式(XXI)的胺R7R8NH(其中,R7和R8如上所定义)反应制备,
式(XIII)化合物为:
其中L5为离去基团,例如L5为氯或甲磺酸酯基,以及m、Ra、R1、n、R2、R3、A、Z1和Y1如上所定义。所述反应可在有机溶剂例如DMF或二噁烷中在例如40℃-150℃温度范围使用过量的胺R7R8NH进行,可使用碘化钠作为反应中的添加剂。
式(XIII)化合物可以由相应的式(XIV)化合物制备,
式(XIV)化合物为:
可使用常规方法即将所述醇转化成离去基团,例如,通过在合适的溶剂例如DCM中在20-100℃温度与亚硫酰氯反应。
式(XIV)化合物可使用方案A中的路线和上述化学物质形成。
式(III)、(V)、(VII)、(VIII)、A、(XII)、(XX)和(XXI)化合物是已知的化合物,或者可通过常规方法由已知化合物制备。
本领域技术人员应该理解,在本发明的方法中,试剂中的某些官能团例如羟基或氨基可能需要用保护基保护。因此,式(I)的化合物的制备可包括在合适阶段除去一种或多种保护基。
官能团的保护和脱保护在′Protective Groups in Organic Chemistry′,editedby J.W.F.McOmie,Plenum Press(1973)and′Protective Groups in OrganicSynthesis′,3rd edition,T.W.Greene and P.G.M.Wuts,Wiley-Interscience(1999)中描述。
上述式(I)化合物可被转化成其药用盐,优选转化成酸加成盐例如盐酸盐、氢溴酸盐、三氟乙酸盐、硫酸盐、磷酸盐、乙酸盐、富马酸盐、马来酸盐、酒石酸盐、乳酸盐、柠檬酸盐、丙酮酸盐、琥珀酸盐、草酸盐、甲磺酸盐或对甲苯磺酸盐。优选的盐包括二甲磺酸盐、单糖精(monosaccharin)盐、二糖精(disaccharin)盐、二(1-羟基-2-萘甲酸)盐(二-昔萘酸盐)、二苯磺酸盐(二-苯磺酸盐(di-besylate))、扁桃酸盐和富马酸盐。
式(I)化合物可以立体异构体形式存在。应当理解的是,本发明涵盖式(I)化合物的所有几何异构体和光学异构体(包括阻转异构体)和它们的混合物(包括外消旋体)的用途。互变异构体和它们的混合物的用途也形成了本发明的一个方面。特别期望的是对映异构体纯的形式。
所述式(I)化合物和它们的药用盐具有药物活性,特别是作为toll-样受体(特别是TLR7)活性的调节剂,并因此用在治疗如下疾病中:
1.呼吸道:气道阻塞性疾病,包括哮喘,包括支气管哮喘、变应性哮喘、内源性哮喘、外源性哮喘、运动诱发性哮喘、药物诱发性(包括阿司匹林和NSAID诱发的)哮喘和粉尘诱发性哮喘,间歇性哮喘和持续性哮喘,以及各种严重度的哮喘,及其它原因引起的气道高反应性;慢性阻塞性肺病(COPD);支气管炎,包括传染性支气管炎和嗜酸性支气管炎;肺气肿;支气管扩张;囊性纤维化;结节病;农民肺及相关疾病;超敏感性肺炎;肺纤维化,包括隐原性纤维化肺泡炎、特发性间质性肺炎、抗肿瘤治疗和慢性感染(包括结核病和曲霉病及其它真菌感染)并发的纤维化;肺移植的并发症;肺血管的血管炎和血栓形成疾病及肺动脉高压;镇咳活性,包括治疗与气道炎症和分泌情况相关的慢性咳嗽及医源性咳嗽;急性鼻炎和慢性鼻炎,包括药物性鼻炎和血管运动性鼻炎;常年性(perennial)变应性鼻炎和季节性变应性鼻炎,包括神经性鼻炎(花粉症);鼻息肉病;急性病毒感染,包括普通感冒和由呼吸道合胞病毒、流行性感冒、冠状病毒(包括SARS)和腺病毒引起的感染;
2.皮肤:牛皮癣、特应性皮炎、接触性皮炎或其它湿疹性皮肤病及迟发型超敏反应;植物性和光照性皮炎;脂溢性皮炎、疱疹样皮炎、扁平苔癣、萎缩性硬化性苔癣、坏疽性脓皮症、皮肤结节病、盘状红斑狼疮、天疱疮、类天疱疮、大疱性表皮松解、荨麻疹、血管性水肿、血管炎、中毒性红斑、皮肤嗜酸粒细胞增多、斑秃、男性型脱发、斯威特综合征(Sweet’ssyndrome)、韦-克综合征(Weber-Christian syndrome)、多形性红斑;蜂窝组织炎,包括传染性和非传染性蜂窝组织炎;脂膜炎;皮肤淋巴瘤、非黑素瘤皮肤癌和其它发育不良性损伤;药物诱发的疾病,包括固定性药疹;
3.眼:睑炎;结膜炎,包括常年性变应性结膜炎或春季变应性结膜炎;虹膜炎;前色素层炎和后色素层炎;脉络膜炎;自身免疫;影响视网膜的变性或炎性疾病;眼炎,包括交感性眼炎;结节病;感染,包括病毒、真菌和细菌感染;
4.生殖泌尿系统:肾炎,包括间质性肾炎和肾小球性肾炎;肾病综合征;膀胱炎,包括急性和慢性(间质性)膀胱炎和杭纳溃疡(Hunner’s ulcer);急性和慢性尿道炎、前列腺炎、附睾炎、卵巢炎和输卵管炎;女阴阴道炎;佩伦涅病(Peyronie’s disease);勃起机能障碍(男性和女性);
5.同种异体移植物排斥:在例如肾脏、心脏、肝脏、肺脏、骨髓、皮肤或角膜移植后或在输血后出现的急性和慢性同种异体移植物排斥;或慢性移植物抗宿主病;
6.其它自身免疫性和变应性疾病,包括类风湿性关节炎、肠易激病、全身性红斑狼疮、多发性硬化症、桥本甲状腺炎(Hashimoto’s thyroiditis)、格雷夫斯病(Graves’disease)、阿狄森病(Addison’s disease)、糖尿病、特发性血小板减少性紫癜、嗜酸性筋膜炎、高IgE综合征、抗磷脂综合征和Sazary综合征;
7.肿瘤:对一般癌症的治疗,包括前列腺、乳腺、肺、卵巢、胰腺、肠和结肠、胃、皮肤和脑肿瘤及影响骨髓(包括白血病)和淋巴增生系统(例如何杰金(Hodgkin’s)和非何杰金淋巴瘤)的恶性肿瘤;包括对转移性疾病和肿瘤复发及瘤外综合征的预防和治疗;和
8.感染性疾病:病毒性疾病例如生殖器疣、寻常疣(common wart)、足拓疣(plantar wart)、乙型肝炎(hepatitis B)、丙型肝炎(hepatitis C)、单纯性疱疹病毒(herpes simplex virus)、传染性软疣(molluscum contagiosum)、天花(variola)、人免疫缺陷病毒(human immunodeficiency virus)(HIV)、人乳头瘤病毒(human papilloma virus)(HPV)、巨细胞病毒(cytomegalovirus)(CMV)、水痘-带状疱疹病毒(varicella zoster virus)(VZV)、鼻病毒(rhinovirus)、腺病毒(adenovirus)、冠状病毒(coronavirus)、流感(influenza)、副流感(para-influenza);细菌性疾病例如结核病(tuberculosis)和鸟分枝杆菌(mycobacterium avium)、麻风病(leprosy);其它感染性疾病,例如真菌性疾病(fungal disease)、衣原体感染(chlamydia)、念珠菌性腹膜炎(candida)、曲霉感染(aspergillus)、隐球菌性脑膜炎(cryptococcal meningitis)、卡氏肺孢子虫(pneumocystis carnii)、隐孢子虫病(cryptosporidiosis)、组织胞浆菌病(histoplasmosis)、弓形虫病(toxoplasmosis)、锥虫感染(trypanosome infection)和利什曼病(leishmaniasis)。
所述式(I)化合物和它们的药用盐具有前药(antedrug)性质。前药定义为如下活性合成衍生物,所述活性合成衍生物被设计成一旦进入体循环就经历生物转化,成为可容易排泄的较小活性形式,从而使全身性副反应最小化。因此,一旦给药,本发明化合物被快速酶降解,得到具有医学作用(medical effect)被相当大程度减少的降解产物。本文定义的医学作用是指本发明化合物的药理活性,包括特异性干扰素诱导活性和/或抑制IL-4/IL-5产生的活性。
降解产物的医学作用优选比本发明化合物(即,母体化合物)的医学作用低10倍,更优选低100倍。
所述药理活性可使用本领域已知方法测量,优选使用体外评估方法例如购得的ELISA试剂盒或在本说明书实施例7描述的生物测定。
因此,本发明提供前述定义的式(I)化合物或其药用盐,用于治疗。
另一方面,本发明提供本前述定义的式(I)化合物或其药用盐在制备用于治疗的药物中的用途。
在本说明书的上下文中,术语“治疗”也包括“预防”,除非存在相反的具体的说明。术语“治疗的”和“治疗地”也应相应解释。
预防应该与人员的治疗特别相关,这些人员已经遭受先前发作,或者被认为患上所述疾病或病症的危险增加。面临将发展成特定疾病或病症的风险的人员通常包括具有所述疾病或病症家族史的那些人员,或者已由遗传试验或筛选确定为特别易于发展成所述疾病或病症的那些人员。
具体地,本发明化合物可用在治疗哮喘、COPD、变应性鼻炎、变应性结膜炎、特应性皮炎、癌症、乙型肝炎、丙型肝炎、HIV、HPV、细菌感染和皮肤病中。
本文前述定义的所述抗-癌治疗可作为单一疗法施用或可除本发明化合物外包括常规外科手术或放射疗法或化学疗法。所述化学疗法可包括一种或多种如下种类的抗肿瘤剂:
(i)如用于医学肿瘤学的其它抗增殖/抗肿瘤药或其组合,例如烷基化剂(如顺铂、奥沙利铂、卡铂、环磷酰胺、氮芥、美法仓、苯丁酸氮芥、白消安、替莫唑胺或亚硝基脲);抗代谢物(例如吉西他滨和抗叶酸剂,如氟代嘧啶如5-氟尿嘧啶和替加氟、雷替曲塞、甲氨喋呤、阿糖胞苷和羟基脲;抗肿瘤抗生素(例如蒽环类抗生素,如阿霉素、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、更生霉素或光辉霉素);抗有丝分裂剂(例如长春花属生物碱类,如长春新碱、长春碱、长春地辛和长春瑞滨,和紫杉烷类,如紫杉醇和泰索帝和polokinase抑制剂);或拓扑异构酶抑制剂(例如表鬼臼毒素类,如依托泊苷和替尼泊苷、安沙可林、拓扑替康和喜树碱类);
(ii)细胞生长抑制剂如抗雌激素药(例如他莫昔芬、氟维司群、托瑞米芬、雷洛昔芬、屈洛昔芬和iodoxyfene)、抗雄激素药(例如比卡鲁胺、氟他胺、尼鲁米特或醋酸环丙氯地孕酮)、LHRH拮抗剂或LHRH激动剂(例如戈舍瑞林、亮丙瑞林或布舍瑞林)、孕激素类(如醋酸甲地孕酮)、芳香酶抑制剂(例如阿纳托唑、来曲唑、伏氯唑(vorazole)或依西美坦)或5α-还原酶抑制剂如非那雄胺;
(iii)抗入侵剂(例如c-Src激酶家族抑制剂如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;国际专利申请WO01/94341)和N-(2-氯-6-甲基苯基)-2-{6-[4-(2-羟基乙基)哌嗪-1-基]-2-甲基嘧啶-4-基氨基}噻唑-5-甲酰胺(dasatinib,BMS-354825;J.Med.Chem.,2004,47,6658-6661),和金属蛋白酶抑制剂如马立马司他,尿激酶纤维蛋白溶酶原激活剂受体功能的抑制剂或类肝素酶抗体);
(iv)生长因子功能抑制剂,例如所述抑制剂包括:生长因子抗体和生长因子受体抗体(例如抗-erbB2抗体曲妥单抗[HerceptinTM]、抗EGFR抗体panitumumab、抗-erbB1抗体西妥昔单抗[Erbitux,C225])和由Stern et al.Critical reviews in oncology/haematology,2005,Vol.54,pp11-29)披露的任意生长因子或生长因子受体抗体;所述抑制剂还包括酪氨酸激酶抑制剂,例如表皮生长因子家族的抑制剂(例如EGFR家族酪氨酸激酶抑制剂,例如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,AZD1839)、N-(3-乙炔基苯基)-6,7-二(2-甲氧基乙氧基)喹唑啉-4-胺(erlotinib,OSI-774)或6-丙烯酰基氨基-N-(3-氯-4-氟苯基)-7-(3-吗啉代丙氧基)喹唑啉-4-胺(CI 1033))、erbB2酪氨酸激酶抑制剂例如lapatinib、肝细胞生长因子家族的抑制剂、血小板衍生生长因子抑制剂例如伊马替尼(imatinib)、丝氨酸/苏氨酸激酶抑制剂(例如Ras/Raf信号抑制剂例如法尼基转移酶抑制剂例如sorafenib(BAY 43-9006))、经由MEK和/或AKT激酶的细胞信号传导抑制剂、肝细胞生长因子家族抑制剂、c-kit抑制剂、abl激酶抑制剂、IGF受体(胰岛素样生长因子)激酶抑制剂;aurora激酶抑制剂(例如AZD1152、PH739358、VX-680、MLN8054、R763、MP235、MP529、VX-528和AX39459)和细胞周期依赖性激酶抑制剂例如CDK2和/或CDK4抑制剂;
(v)抗血管生成剂,例如那些抑制血管内皮生长因子作用的药物,(例如抗-血管内皮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4-(4-溴-2-氟苯胺基)-6-甲氧基-7-(1-甲基哌啶-4-基甲氧基)喹唑啉(ZD6474;WO 01/32651中的实施例2)、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;WO 00/47212中的实施例240)、vatalanib(PTK787;WO 98/35985)和SU11248(sunitinib;WO01/60814)、例如在国际专利申请WO 97/22596、WO 97/30035、WO 97/32856或WO 98/13354中公开的那些化合物)或者以其它机制起作用的化合物(例如利诺胺、整联蛋白αvβ3功能的抑制剂或血管生长抑素);
(vi)脉管损坏剂如考布他汀A4或国际专利申请WO 99/02166、WO00/40529、WO 00/41669、WO 01/92224、WO 02/04434或WO 02/08213中公开的化合物;
(vii)反义治疗剂,例如定向于上面列出靶点的那些物质如ISIS 2503、抗-ras反义物;
(viii)基因治疗方法,包括例如代替异常基因如异常p53或异常BRCA1或BRCA2的方法、GDEPT(基因定向的酶前药治疗)方法例如那些使用胞嘧啶脱氨酶、胸苷激酶或细菌硝基还原酶的方法和增加患者对化学治疗或放射治疗耐受性的方法例如多元抗药性基因治疗;和
(ix)免疫治疗方法,包括例如在体外和体内增加患者肿瘤细胞免疫原性的方法,如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、减少T-细胞无反应性的方法、使用转染的免疫细胞如转染了细胞因子的树突细胞的方法、使用细胞因子转染的肿瘤细胞系的方法和使用抗独特型抗体的方法。
本发明还提供治疗或减少阻塞性气道疾病或病症(例如,哮喘或COPD)的风险的方法,所述方法包括向有此需要的患者给药治疗有效量的上述定义的式化合物(I)或其药用盐。
对于上述治疗用途,所给予的剂量当然会随所采用的化合物、给药模式、所期望的治疗和所指示的紊乱而变化。例如,如果吸入给药,本发明化合物的日剂量可以是在0.05微克/千克体重(μg/kg)至100微克/千克体重(μg/kg)范围内。可选择地,如果化合物口服给药,则本发明化合物的日剂量可以在0.01微克/千克体重(μg/kg)至100毫克/千克体重(mg/kg)范围内。
式(I)化合物及其药学上可接受的盐可以独自使用,但通常以药物组合物的形式给药,在药物组合物中,式(I)化合物/盐(活性成分)与药学上可接受的助剂、稀释剂或载体相结合。例如,在″Pharmaceuticals-The Science ofDosage Form Designs″,M.E.Aulton,Churchill Livingstone,1988中描述了选择并且制备适当药物制剂的常规方法。
根据给药方式的不同,所述药物组合物优选包含0.05至99w%(重量百分比)的活性成分,更优选0.05至80w%,仍然更优选0.10至70w%,并且甚至更优选0.10至50%w的活性成分,所有重量百分比都以组合物的总重量计。
本发明还提供了药物组合物,该组合物含有如上定义的式(I)化合物或其药用盐,及含有药用助剂、稀释剂或载体。
本发明进一步提供了制备本发明药物组合物的方法,所述方法包括将如上定义的式(I)化合物或其药用盐与药用助剂、稀释剂或载体混合。
药物组合物可以采用如下形式局部给药(例如给药至皮肤或肺和/或气道):例如,乳膏剂、溶液、悬浮剂、七氟烷烃(HFA)气雾剂和干粉制剂,例如,在称为的吸入装置中的制剂;或者全身给药,例如采用如下形式口服给药:片剂、胶囊剂、糖浆剂、粉末剂或颗粒剂;或者以用于注射(包括静脉注射、皮下注射、肌内注射、血管内注射或灌注)的无菌溶液、混悬剂或乳剂的形式非肠道给药;或者以栓剂的形式直肠给药。
本发明化合物(包括药用盐)的干粉制剂和加压HFA气雾剂可以通过口服或鼻吸入来给药。对于吸入而言,希望将化合物精细粉碎(finely divided)。经精细粉碎的化合物优选具有小于10微米(μm)的质量中值直径,并且可借助于分散剂悬浮在推进剂混合物中,所述分散剂例如C8-C20脂肪酸或其盐(例如,油酸)、胆汁盐、磷脂、烷基糖(alkyl saccharide)、全氟化表面活性剂或聚乙氧基化表面活性剂或其它药用分散剂。
本发明化合物也可以通过干粉吸入器来给药。所述吸入器可以是单剂量吸入器或多剂量吸入器,并且可以是呼吸驱动的干粉吸入器。
一种可能性是将精细粉碎的本发明化合物和载体物质混合,所述载体物质为例如,单-、二-或多糖、糖醇或另一种多元醇。合适的载体为糖,例如,乳糖、葡萄糖、棉子糖、松三糖、乳糖醇、麦芽糖醇、海藻糖、蔗糖、甘露醇;以及淀粉。可选择地,可以用另一种物质对精细粉碎的化合物包衣。也可以将粉末混合物分装在硬胶囊中,每个都含有所需剂量的活性化合物。
另一可能性是将精细粉碎的粉末加工成球体,其在吸入步骤期间破碎。可将这种球化粉末填入多剂量吸入器的药物存储器中,例如,填入已知为的吸入器中,其中定量加料器(dosing unit)计量出所需剂量,然后由患者吸入。使用这种系统,活性成分在有或没有载体物质的情况下都能被传递至患者。
就口服而言,本发明化合物可与如下物质混合:助剂或载体,例如,乳糖、蔗糖、山梨糖醇、甘露醇;淀粉,例如,马铃薯淀粉、玉米淀粉或支链淀粉;纤维素衍生物;粘合剂,例如,明胶或聚乙烯吡咯烷酮;和/或润滑剂,例如,硬脂酸镁、硬脂酸钙、聚乙二醇、蜡、石蜡,等等,然后压制成片。如果需要包衣片,可用浓缩的糖液对如上所述制备的片芯进行包衣,所述糖液可以包含,例如,阿拉伯胶、明胶、滑石以及二氧化钛。可选择地,也可以用溶于易挥发有机溶剂中的合适聚合物对片剂进行包衣。
就制备软胶囊剂而言,可以将本发明的化合物与例如植物油或聚乙二醇混合。硬胶囊剂可以含有化合物的颗粒,使用上述用于片剂的赋形剂。也可将本发明化合物的液体或半固体制剂填入硬胶囊剂中。
用于口服的液体制剂可以是糖浆或混悬剂的形式,例如,是包含本发明化合物的溶液,余量是糖和如下物质的混合物:乙醇、水、甘油和丙二醇。任选地,这种液体制剂可以包含着色剂、调味剂、糖精和/或作为增稠剂的羧甲基纤维素或者其它本领域技术人员已知的赋形剂。
本发明化合物也可以与其它用于治疗上述病症的化合物联合给药。
因此,本发明进一步涉及联合治疗法,其中将本发明化合物或含有本发明化合物的药物组合物或药物制剂与另一种或多种治疗剂同时或顺序给药,或者以联合制剂的形式给药,用于治疗一种或多种所列病症。
特别地,就炎性疾病COPD、哮喘和变应性鼻炎的治疗而言,本发明化合物可以与例如下列试剂联用:肿瘤坏死因子α(TNF-α)抑制剂例如抗TNF单克隆抗体(例如Remicade、CDP-870和阿达木单抗(adalimumab))和TNF受体免疫球蛋白分子(例如依那西普(Enbrel));非选择性的环氧合酶COX-1/COX-2抑制剂,不论局部或全身应用(例如吡罗昔康,双氯芬酸,丙酸类例如萘普生、氟比洛芬、非诺洛芬、酮洛芬和布洛芬,芬那酸例如甲芬那酸、消炎痛(Indomethacin)、舒林酸,阿扎丙酮(azapropazone),吡唑酮例如保泰松,水杨酸盐例如阿斯匹林),COX-2抑制剂(例如美洛昔康,塞来考昔,罗非考昔,伐地考昔,鲁马考昔(lumarocoxib),帕来考昔和依托考昔);糖皮质类固醇(无论通过局部、口服、肌内、静脉内或关节内的路径给药);甲氨蝶呤,来氟米特;羟氯喹,d-青霉胺,金诺芬或其它非肠道的或口服的黄金制剂。
本发明更进一步涉及本发明的化合物与下列药物联用:白细胞三烯生物合成抑制剂,5-脂肪氧合酶(5-LO)抑制剂或5-脂肪氧合酶活化蛋白(FLAP)拮抗剂例如:弃留通;ABT-761;芬留顿;替泊沙林;Abbott-79175;Abbott-85761;N-(5-取代的)-噻吩-2-烷基磺酰胺;2,6-二-叔丁基酚腙;甲氧基四氢吡喃例如Zeneca ZD-2138;化合物SB-210661;吡啶基-取代的2-氰基萘化合物例如L-739,010;2-氰基喹啉化合物例如L-746,530;吲哚和喹啉化合物例如MK-591,MK-886和BAY x 1005。
本发明更进一步涉及本发明化合物与选自下列的白细胞三烯(LTB4、LTC4、LTD4和LTE4)的受体拮抗剂的组合:吩噻嗪-3-酮(phenothiazin-3-1s)例如L-651,392;脒基化合物例如CGS-25019c;苯并噁胺(benzoxalamine)例如昂唑司特;苯甲脒(benzenecarboximidamides)例如BIIL 284/260;化合物例如扎鲁司特、阿鲁司特、孟鲁司特、普仑司特、维鲁司特(MK-679)、RG-12525、Ro-245913、伊拉司特(CGP 45715A)和BAY x 7195。
本发明更进一步涉及本发明化合物与下列药物的联用:磷酸二酯酶(PDE)抑制剂例如甲基黄嘌呤(methylxanthanines)包括茶碱和氨茶碱;和选择性的PDE同工酶抑制剂,包括PDE4抑制剂和同工型PDE4D的抑制剂,或PDE5的抑制剂。
本发明更进一步涉及本发明化合物与下列药物的联用:组胺1型受体拮抗剂,例如西替立嗪、氯雷他定、地氯雷他定、非索非那定、阿伐斯丁、特非那定、阿司咪唑、氮卓斯汀、左卡巴斯汀、扑尔敏、普鲁米近、赛克利嗪(cyclizine)或咪唑斯汀;口服、局部或非肠道施用。
本发明更进一步涉及本发明化合物与胃保护组胺2型受体拮抗剂的联用。
本发明进一步涉及本发明化合物与组胺4型受体拮抗剂的联用。
本发明更进一步涉及本发明化合物与下列药物的联用:α-1/α-2肾上腺素受体激动剂,血管收缩剂,拟交感神经药物,例如丙己君(propylhexedrine)、去氧肾上腺素、苯丙醇胺、麻黄碱、假麻黄碱、盐酸萘甲唑啉、盐酸羟甲唑啉、盐酸四氢唑啉、盐酸木甲唑啉、盐酸曲马唑啉或盐酸乙基去甲肾上腺素。
本发明进一步涉及本发明化合物与抗胆碱能药剂的组合,所述抗胆碱能药剂包括毒蕈碱受体(M1、M2和M3)拮抗剂,例如阿托品、东莨菪碱、格隆溴铵、异丙托溴铵、噻托溴铵、氧托溴铵、哌仑西平或替仑西平。
本发明更进一步涉及本发明化合物与下列药物的联用:β-肾上腺素受体激动剂(包括β受体亚型1-4),例如异丙肾上腺素、柳丁氨醇(salbutamol)、福莫特罗、沙美特罗、特布他林(terbutaline)、间羟异丙肾上腺素、甲磺酸比托特罗(bitolterol mesylate)或吡布特罗。
本发明更进一步涉及本发明的化合物与色酮例如色甘酸二钠或奈多罗米钠的联用。
本发明更进一步涉及本发明的化合物与胰岛素样生长因子I型(IGF-1)模拟物的联用。
本发明更进一步涉及本发明的化合物与下列药物的联用:糖皮质激素,例如氟尼缩松、曲安奈德、二丙酸倍氯米松、布地奈德、丙酸氟替卡松、环索奈德或糠酸莫美松。
本发明更进一步涉及本发明化合物与下列抑制剂的联用:基质金属蛋白酶(MMPs)抑制剂,即溶基质蛋白酶(stromelysins)、胶原酶和明胶酶以及蛋白聚糖酶(aggrecanase)的抑制剂;特别是胶原酶-1(MMP-1),胶原酶-2(MMP-8),胶原酶-3(MMP-13),溶基质蛋白酶-1(MMP-3),溶基质蛋白酶-2(MMP-10)和溶基质蛋白酶-3(MMP-11)和MMP-9和MMP-12。
本发明进一步涉及本发明化合物与下列趋化因子受体功能调节剂的联用,例如CCR1、CCR2、CCR2A、CCR2B、CCR3、CCR4、CCR5、CCR6、CCR7、CCR8、CCR9、CCR10和CCR11(C-C家族);CXCR1、CXCR2、CXCR3、CXCR4和CXCR5(C-X-C家族);和CX3CR1(C-X3-C家族)的拮抗剂。
本发明更进一步涉及本发明的化合物与下列细胞因子或细胞因子功能激动剂调节剂的联用:包括α-、β-和γ-干扰素;白介素(IL),包括IL1至15,和白介素拮抗剂或抑制剂,包括作用于细胞因子信号传导途径的药物。
本发明更进一步涉及本发明的化合物与下列药物的联用:免疫球蛋白(Ig)或Ig制剂或调节Ig功能的拮抗剂或抗体,例如抗IgE(例如奥马珠单抗)。
本发明更进一步涉及本发明的化合物与其它系统的或局部施用的抗炎剂例如沙利度胺(thalidomide)或其衍生物、类视黄醇、蒽三酚(dithranol)或卡泊三醇(calcipotriol)的联用。
本发明更进一步涉及本发明的化合物与下列药物的联用:抗菌剂,如青霉素衍生物、四环素、大环内酯、β-内酰胺、氟喹诺酮、甲硝唑和吸入用氨基糖苷类;和抗病毒药,包括阿昔洛韦、泛昔洛韦、伐昔洛韦、更昔洛韦、西多福韦;金刚烷胺,金刚乙胺;利托那韦;扎那米韦(zanamavir)和特敏服(oseltamavir);蛋白酶抑制剂,例如茚地那韦、奈非那韦、利托那韦和沙奎那韦;核苷逆转录酶抑制剂,例如去羟肌苷、拉夫米定、司他夫定(stavudine)、扎西他滨或齐多夫定;或非核苷逆转录酶抑制剂,例如奈韦拉平(nevirapine)或依法韦仑(efavirenz)。
本发明的化合物还可以与治疗癌症的现有治疗剂联用,例如合适的治疗剂包括:
(i)如用于医学肿瘤学的抗增殖/抗肿瘤药或其组合,例如烷基化剂(如顺铂、卡铂、环磷酰胺、氮芥、美法仓、苯丁酸氮芥、白消安或亚硝基脲);抗代谢物(例如抗叶酸剂,如氟代嘧啶如5-氟尿嘧啶或替加氟、雷替曲塞、甲氨喋呤、阿糖胞苷、羟基脲、吉西他滨或紫杉醇);抗肿瘤抗生素(例如蒽环类抗生素,如阿霉素、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、更生霉素或光辉霉素);抗有丝分裂剂(例如长春花属生物碱类,如长春新碱、长春花碱、长春地辛或长春瑞滨,或紫杉烷类,如紫杉醇或多西他赛);或拓扑异构酶抑制剂(例如表鬼臼毒素类,如依托泊苷、替尼泊苷、安沙可林、拓扑替康或喜树碱类);
(ii)细胞生长抑制剂如抗雌激素药(例如他莫昔芬、托瑞米芬、雷洛昔芬、屈洛昔芬或iodoxyfene)、雌激素受体负调节剂(如氟维司群)、抗雄激素药(例如比卡鲁胺、氟他胺、尼鲁米特或醋酸环丙氯地孕酮)、LHRH拮抗剂或LHRH激动剂(例如戈舍瑞林、亮丙瑞林或布舍瑞林)、孕激素类(如醋酸甲地孕酮)、芳香酶抑制剂(例如阿纳托唑、来曲唑、伏氯唑(vorazole)或依西美坦)或5α-还原酶抑制剂如非那雄胺;
(iii)抑制癌细胞入侵的药物(例如金属蛋白酶抑制剂如马立马司他或尿激酶纤维蛋白溶酶原激活剂受体功能的抑制剂);
(iv)生长因子功能抑制剂,例如诸如下述的抑制剂:生长因子抗体(例如抗-erbb2抗体曲妥单抗或抗-erbb1抗体西妥昔单抗[C225])、法尼基转移酶抑制剂、酪氨酸激酶抑制剂或丝氨酸/苏氨酸激酶抑制剂,表皮生长因子家族的抑制剂(例如EGFR家族酪氨酸激酶抑制剂,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,AZD1839)、N-(3-乙炔基苯基)-6,7-二(2-甲氧基乙氧基)喹唑啉-4-胺(erlotinib,OSI-774)或6-丙烯酰基氨基-N-(3-氯-4-氟苯基)-7-(3-吗啉代丙氧基)喹唑啉-4-胺(CI 1033)),血小板衍生的生长因子家族的抑制剂或肝细胞生长因子家族的抑制剂;
(v)抗血管生成剂,例如抑制血管内皮生长因子作用的药物,(例如抗-血管内皮生长因子抗体贝伐单抗,在WO 97/22596、WO 97/30035、WO97/32856或WO 98/13354中公开的那些化合物)或者以其它机制起作用的化合物(例如利诺胺、整联蛋白αvβ3功能的抑制剂或血管生长抑素);
(vi)脉管损坏剂如考布他汀A4或国际专利申请WO 99/02166、WO00/40529、WO 00/41669、WO 01/92224、WO 02/04434或WO 02/08213中公开的化合物;
(vii)用在反义疗法中的治疗剂,例如定向于上面列出靶点的那些物质如ISIS 2503、抗-ras反义物;
(viii)基因治疗方法中使用的药剂,例如代替异常基因如异常p53或异常BRCA1或BRCA2的方法、GDEPT(基因定向的酶前药治疗)方法例如那些使用胞嘧啶脱氨酶、胸苷激酶或细菌硝基还原酶的方法和增加患者对化学治疗或放射治疗耐受性的方法例如多元抗药性基因治疗;或者
(ix)用在以下免疫治疗方法中的药物,例如在体外和体内增加患者肿瘤细胞免疫原性的方法,如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、减少T-细胞无反应性的方法、使用转染的免疫细胞如转染了细胞因子的树突细胞的方法、使用细胞因子转染的肿瘤细胞系的方法和使用抗独特型抗体的方法。
将参照以下说明性实施例进一步解释本发明。
具体实施方式
除非另有说明,有机溶液用硫酸镁干燥。RPHPLC是指反相制备性HPLC,其使用Waters Symmetry C8、Xterra、Xbridge或Phenomenex Gemini柱(适宜地使用乙腈和乙酸铵水溶液、氨、甲酸或三氟乙酸作为缓冲液)。柱色谱法在硅胶上进行。用SCX处理是指将混合物吸收在SCX上,用合适溶剂例如甲醇或乙腈洗脱,然后游离碱形式的产物用氨水/甲醇洗脱。
使用下列缩写:
EtOAc 乙酸乙酯
DCM 二氯甲烷
NMP N-甲基吡咯烷酮
NBS N-溴代琥珀酰亚胺
DMF N,N-二甲基甲酰胺
DMSO 二甲基亚砜
THF 四氢呋喃
MeOH 甲醇
TFA 三氟乙酸
HCl 氯化氢
K2CO3 碳酸钾
NaHCO3 碳酸氢钠
TEA 三乙胺
MeCN 乙腈
HATU O-(7-氮杂苯并三唑-1-基)-N,N,N′,N′-四甲基甲基六氟磷酸盐
EDCI N-(3-二甲基氨基丙基)-N’-乙基碳二亚胺·盐酸盐
HOBt 1-羟基苯并三唑
rt 室温
h 小时
min 分钟
M 摩尔
MS 质谱
PyBop 苯并三唑-1-基氧基三吡咯烷磷鎓六氟磷酸盐
APCI 大气化学电离法(atmospheric chemical ionisation method)
ESI 电喷雾离子化法(electron spray ionisation method)
NMR 核磁共振
设备细节:
XRPD-构造的PANalytical CubiX PRO机器,在2°至40°2的扫描范围内,100-秒暴露/0.02°增量。通过在45kV和40mA操作的铜制长-细聚焦管(long-fine focus tube)产生X-射线。铜X-射线的波长为1.5418将数据收集到零背景支持器(zero background holder)上,其上放置~2mg化合物。所述支持器由单晶硅制成,已经沿非衍射平面对其进行切割,然后在光学平的面漆(optically flat finish)上进行抛光。入射在该表面上的X-射线被Bragg消散(extinction)抵消。
DSC热分析图是使用TA Q1000差示扫描量热计(具有铝盘和经穿孔的盖子(pierced lid))测量的。样品重量在0.3至5mg之间变化。所述方法在氮气流(50ml/min)中进行,研究的温度以10℃/分钟的恒定温度增加速率从25℃增加至300℃。
实施例1
2-(4-((3-(4-氨基-2-丁基-1H-咪唑并[4,5-c]喹啉-1-基)丙基氨基)甲基)苯基)乙酸甲酯
(i)3-硝基喹啉-4-醇
将4-羟基喹啉(22.2g)和丙酸(200mL)合并,并加热至125℃。历时1.5小时滴加硝酸(21.5mL)。将反应混合物在回流温度再搅拌15分钟并冷却至室温。混合物用乙醇洗脱,通过真空过滤收集固体。固体依次用乙醇、水和乙醇洗涤。残余物在乙醇中回流,过滤热混合物并干燥,得到副标题化合物。收率:22g。
1H NMRδ(DMSO-d6)13.00(1H,s),9.19(1H,s),8.26(1H,m),7.81(1H,ddd),7.75-7.71(1H,m),7.53(1H,ddd)
(ii){3-[(3-硝基喹啉-4-基)氨基]丙基}氨基甲酸叔丁基酯
向搅拌的3-硝基喹啉-4-醇(8.15g)于DCM(100mL)中的溶液中加入DMF(3.33mL)和亚硫酰氯(3.47mL),将反应混合物回流2.5小时,此时所有固体都溶解。将溶液冷却至0℃,滴加(3-氨基丙基)-氨基甲酸叔丁酯(8.3g)和Et3N(6.5mL)于DCM(20mL)中的溶液。将反应混合物搅拌过夜,然后倒入饱和碳酸氢钠溶液中,产物用DCM萃取。合并的有机层用盐水、水洗涤,干燥,过滤并蒸发溶剂。残余物用乙醚研磨,得到副标题化合物(13g)。
1H NMRδ(CDCl3)9.66(1H,s),9.36(1H,s),8.32(1H,d),8.00(1H,d),7.77(1H,t),7.49(1H,ddd),4.65(1H,s),4.01(2H,dd),3.33(2H,q),2.02(2H,quintet),1.40(9H,s)
MS:APCI(+ve):347
(iii){3-[(3-氨基喹啉-4-基)氨基]丙基}氨基甲酸叔丁酯
将来自步骤(ii)的产物(12g)溶解在无水THF(250mL)中,加入1%Pt/C催化剂(3g),将反应混合物在室温氢化(H2压力:3巴)72小时。将产物过滤通过玻璃纤维滤纸,并通过中性氧化铝柱纯化(用4%MeOH/DCM洗脱),通过RPHPLC进一步纯化,得到副标题化合物,收率:1.3g。
1H NMRδ(CD3OD)8.34(1H,s),8.09-8.02(1H,m),7.80-7.74(1H,m),7.44-7.38(2H ,m),3.34-3.30(2H,m),3.21-3.10(2H,m),1.78-1.67(2H,m),1.42(9H,s)
(iv)[3-(2-丁基-1H-咪唑并[4,5-c]喹啉-1-基)丙基]氨基甲酸叔丁基酯
将来自步骤(iii)的产物(1.23g)溶解在NMP(25mL)中,滴加戊酰氯(0.46mL)。将反应混合物在室温搅拌1.5小时,加热至50℃,持续24小时,然后加热至80℃,持续2天。蒸发溶剂,将反应混合物倒入DCM中。过滤出固体沉淀物,滤液在硅胶上纯化(用10%MeOH/DCM洗脱),得到副标题化合物(0.9g)。
1H NMRδ(CDCl3)9.29(1H,s),8.28(1H,dd),8.20(1H,d),7.72-7.59(2H,m),4.80-4.69(1H,m),4.60(2H,t),3.03-2.92(2H,m),2.72(1H,s),2.21-2.09(2H,m),1.57-1.50(2H,m),1.48(9H,s),1.02(3H,t)NMP峰下2H
MS:APCI(+ve):383
(v)[3-(2-丁基-5-氧化-1H-咪唑并[4,5-c]喹啉-1-基)丙基]氨基甲酸叔丁酯
将来自步骤(iv)的产物(0.9g)溶解在DCM(25mL)中,冷却至5℃。加入3-氯过氧苯甲酸(0.203g),使反应混合物温热至室温。将反应混合物搅拌2小时,加入更多的3-氯过氧苯甲酸(0.30g),将反应混合物再搅拌2小时。将反应混合物倒入饱和亚硫酸氢钠溶液中,用DCM萃取,干燥,过滤并蒸发,得到副标题化合物(0.9g)。
MS:APCI(+ve):399
(vi)[3-(4-氨基-2-丁基-1H-咪唑并[4,5-c]喹啉-1-基)丙基]氨基甲酸叔丁酯
在0℃,将对甲苯磺酰氯(0.43g)逐份加入到于DCM(25mL)中的来自步骤(v)的产物(0.9g)和氢氧化铵溶液(35%,2.5mL)的剧烈搅拌混合物中。使所述混合物历时2小时温热至室温,然后在水/DCM之间分配,用饱和碳酸氢钠溶液洗涤,干燥,过滤并蒸发溶剂。固体产物用乙醚研磨,得到副标题化合物(0.6g)。
MS:APCI(+ve):398
(vii)1-(3-氨基丙基)-2-丁基-1H-咪唑并[4,5-c]喹啉-4-胺
将来自步骤(vi)的产物(0.6g)溶解在DCM(5mL)中,加入TFA(5mL)。将反应混合物搅拌20分钟,蒸发溶剂,产物通过SCX树脂纯化(用氨/MeOH溶液(3.5%)洗脱),收率:380mg。
1H NMRδ(CDCl3)8.06(1H,d),7.83(1H,d),7.50(1H,t),7.33(1H,t),4.59(2H,t),3.02-2.80(4H,m),2.15-1.97(2H,m),1.96-1.77(2H,m),1.60-1.41(2H ,m),1.01(3H,t).
MS:APCI(+ve):298
(viii)2-(4-((3-(4-氨基-2-丁基-1H-咪唑并[4,5-c]喹啉-1-基)丙基氨基)甲基)苯基)乙酸甲酯
将来自步骤(vii)的产物(55mg)与(4-甲酰基苯基)乙酸甲酯(0.0329g)合并,在THF(15mL)中搅拌16小时。先后加入硼氢化钠(0.015g)和MeOH(3滴),将反应混合物搅拌1小时。所述反应混合物用MeOH稀释,并通过RPHPLC纯化,得到标题化合物。收率:17mg。
1H NMRδ(DMSO-d6)8.12(1H,d),7.60(1H,d),7.40(1H,t),7.30(2H,d),7.23-7.16(3H,m),6.41(2H,s),4.58(2H,t),3.71-3.63(4H,m),3.60(3H,s),2.93(2H,t),2.63-2.57(2H,m),2.02-1.92(2H,m),1.83-1.73(2H,m),1.47-1.37(2H,m),1.00-0.89(3H,m).
MS:APCI(+ve):460
实施例2
2-(3-((3-(4-氨基-2-丁基-1H-咪唑并[4,5-c]喹啉-1-基)丙基氨基)甲基)苯基)乙酸甲酯
通过实施例1的方法使用(3-甲酰基苯基)乙酸甲酯(34mg)制备标题化合物,得到标题化合物,13mg,其为白色固体。
1H NMRδ(DMSO-d6)8.13(1H,d),7.60(1H,d),7.40(1H,t),7.28-7.23(3H,m),7.21-7.16(1H,m),7.15-7.11(1H,m),6.41(2H,s),4.62-4.54(2H,m),3.69(2H,s),3.65(2H,s),3.60(3H,s),2.94(2H,t),2.63-2.58(2H,m),2.02-1.91(2H,m),1.84-1.73(2H,m),1.44(2H,q),0.95(3H,t)
MS:APCI(+ve):460
实施例3
2-(4-((N-(3-(4-氨基-2-丁基-1H-咪唑并[4,5-c]喹啉-1-基)丙基)-2-(二甲基氨基)乙酰氨基)甲基)苯基)乙酸甲酯
将来自实施例1的产物(15mg)溶解在DMF∶DCM(1∶1(5mL))混合物中,加入N,N-二甲基氨基乙酰氯·盐酸盐(8mg)和Et3N(0.01mL)。将反应混合物搅拌72小时。加入更多的N,N-二甲基氨基乙酰氯·盐酸盐(0.050g)和Et3N(0.06mL),将混合物再搅拌16小时。产物通过RPHPLC纯化。
1H NMRδ(CD3OD)8.05-7.96(1H,m),7.73-7.66(1H,m),7.54-7.45(1H,m),7.38-7.29(1H,m),7.17-7.01(4H,m),4.63-4.45(4H,m),3.63(3H,s),3.56(2H,s),3.51-3.33(2H,m),3.01(1H,s),2.94-2.85(2H,m),2.28(3H,s),2.22-2.13(1H,m),2.04(4H,s),1.88-1.78(2H,m),1.52-1.42(2H,m),1.35-1.25(1H,m),1.00(3H,s)
MS:APCI(+ve):545
实施例4
2-(3-((N-(3-(4-氨基-2-丁基-1H-咪唑并[4,5-c]喹啉-1-基)丙基)-2-(二甲基氨基)乙酰氨基)甲基)苯基)乙酸甲酯
通过实施例3的方法使用来自实施例2的产物(27mg)制备标题化合物,得到标题化合物3,其为无色胶状物。
1H NMRδ(CD3OD)8.04-7.95(1H,m),7.73-7.65(1H,m),7.53-7.44(1H,m),7.37-7.30(1H,m),7.20-7.13(1H,m),7.11-6.98(3H,m),4.62(1H,s),4.57-4.44(3H,m),3.63-3.55(2H,m),3.55-3.39(3H,m),3.26(1H,s),3.01(1H,s),2.94-2.83(2H,m),2.28(3H,s),2.22-2.11(1H,m),2.07-1.95(4H,m),1.88-1.77(2H ,m),1.52-1.41(2H,m),1.35-1.24(2H,m),1.02-0.91(3H,m)
MS:APCI(+ve):545
实施例5
2-(3-((4-((4-氨基-2-(乙氧基甲基)-1H-咪唑并[4,5-c]喹啉-1-基)甲基)哌啶-1-基)甲基)苯基)乙酸甲酯二-三氟乙酸盐
(i)2-(乙氧基甲基)-1-(哌啶-4-基甲基)-1H-咪唑并[4,5-c]喹啉-4-胺,二·三氟乙酸盐
通过实施例1步骤(i)-(vii),使用4-(氨基甲基)哌啶-1-甲酸叔丁酯和乙氧基乙酰氯制备副标题化合物。
MS:APCI(+ve):340
(ii)2-(3-((4-((4-氨基-2-(乙氧基甲基)-1H-咪唑并[4,5-c]喹啉-1-基)甲基)哌啶-1-基)甲基)苯基)乙酸甲酯·二-三氟乙酸盐
将来自步骤(i)的产物(0.14g)、[3-(溴甲基)苯基]乙酸甲酯(0.07g)和K2CO3(0.25g)于DMF(5mL)中的混合物在室温搅拌18小时。过滤混合物,然后通过RPHPLC纯化。将产物溶解在甲醇/TFA混合物(4mL 10/1)中,减压蒸发溶剂,残余物用乙醚研磨,收率:25mg。
1H NMRδ(DMSO-d6)14.06(1H,brs);9.69(1H,brs);8.25(1H,d);7.83(1H,d);7.75(1H,t);7.58(1H,t);7.44-7.34(4H,m);4.79(2H,s);4.65(2H,s);4.21(2H,s);3.70(2H,s);3.63-3.55(5H,m);3.33(2H,d);2.90-2.75(2H,m);2.18(1H,brs);1.79-1.62(4H,m);1.18(3H,t)
MS:APCI(+ve):502
实施例6
[4-({[3-(4-氨基-2-丁基-1H-咪唑并[4,5-c]喹啉-1-基)丙基][2-(二甲基氨基)乙基]氨基}甲基)苯基]乙酸甲酯
(i)N-(3-{[叔丁基(二甲基)甲硅烷基]氧基}丙基)-3-硝基喹啉-4-胺向搅拌的3-硝基-喹啉-4-醇(5g)于DCM(70mL)中的溶液中加入DMF(2.3mL),然后加入亚硫酰氯(2.1mL),将反应混合物回流3小时。溶液冷却至0℃,加入3-{[叔丁基(二甲基)甲硅烷基]氧基}丙烷-1-胺(6g),然后滴加Et3N(12mL)。将反应混合物在室温搅拌2小时,然后在DCM和饱和NaHCO3溶液之间分配。有机层用水洗涤,干燥,减压蒸发溶剂。残余物用异己烷研磨,得到副标题化合物(8.7g)。
MS:ESI(+ve):362
(ii)N4-(3-{[叔丁基(二甲基)甲硅烷基]氧基}丙基)喹啉基-3,4-二胺
将来自步骤(i)的产物(8.5g)、铁粉(14g)于乙酸中的混合物在室温搅拌3小时,并在EtOAc/水之间分配。分离有机物,用饱和NaHCO3溶液、盐水洗涤,干燥并减压蒸发,收率:4.85g。
MS:ESI(+ve):332
(iii)戊酸(3-(2-丁基-1H-咪唑并[4,5-c]喹啉-1-基)丙基)酯
在室温,将戊酰氯加入到来自步骤(ii)的产物(4.85g)于NMP中的溶液中。将混合物在室温搅拌15分钟,在100℃加热6小时,冷却,并在EtOAc/饱和NaHCO3溶液之间分配。分离有机物,用水洗涤,干燥并减压蒸发。残余物通过硅胶色谱法纯化(用EtOAc洗脱),收率:2.15g.
MS:ESI(+ve):368
(iv)戊酸(3-(2-丁基-5-氧化-1H-咪唑并[4,5-c]喹啉-1-基)丙基)酯
在5℃,将3-氯过氧苯甲酸(1.6g)加入到来自步骤(iii)的产物(2.15g)于DCM(30mL)中的溶液中。使反应混合物温热至室温,搅拌18小时,并在DCM/饱和亚硫酸氢钠溶液之间分配。分离有机物,用饱和NaHCO3溶液、水洗涤,干燥并减压蒸发。收率:1.77g。
MS:ESI(+ve):384
(v)3-(4-氨基-2-丁基-1H-咪唑并[4,5-c]喹啉-1-基)丙烷-1-醇
在室温,将对甲苯磺酰氯(0.93g)逐份加入到剧烈搅拌的于DCM(50mL)中的来自步骤(iv)的产物(1.77g)和氢氧化铵溶液(35%,5mL)的混合物中。将反应混合物搅拌3小时,然后在水/DCM之间分配。有机物用饱和NaHCO3溶液、水洗涤,干燥并减压蒸发溶剂。残余物溶解在MeOH(40mL)中,先后加入水(20mL)和浓度为6M的NaOH溶液(2mL),将混合物在室温搅拌18小时。过滤出形成的固体,用水洗涤并干燥,收率:965mg。
MS:ESI(+ve):299
(vi)N′-[3-(4-氨基-2-丁基-1H-咪唑并[4,5-c]喹啉-1-基)丙基]-N,N-二甲基乙烷-1,2-二胺
将来自步骤(v)的产物(0.96g)和亚硫酰氯(10mL)于DCM(20mL)中的混合物回流加热6小时,然后减压蒸发。将残余物溶解在乙腈(20mL)中,然后加入N,N-二甲基亚乙基二胺(10mL),混合物回流加热24小时。减压除去溶剂,残余物通过RPHPLC纯化,收率:0.512g。
MS:APCI(+ve):369
(vii)[4-({[3-(4-氨基-2-丁基-1H-咪唑并[4,5-c]喹啉-1-基)丙基][2-(二甲基氨基)乙基]氨基}甲基)苯基]乙酸甲酯
将来自步骤(vi)的产物(0.25g)、(4-甲酰基苯基)乙酸甲酯(0.15g)和三乙酰氧基硼氢化钠(0.2g)于NMP(10mL)中的混合物在室温搅拌18小时,然后在45℃加热3小时。加热另一份(4-甲酰基苯基)乙酸甲酯(0.1g)和三乙酰氧基硼氢化钠(0.2g),然后在45℃搅拌6小时。混合物通过RPHPLC纯化,收率:0.035g。
1H NMRδ(DMSO-d6)8.02(1H,d);7.62(1H,d);7.40(1H,t);7.28(2H,d);7.21(2H,d);7.13(1H,t);6.47(2H,s);4.49-4.45(2H,m);3.66(2H,s);3.60(2H,s);3.59(2H,s);2.89(2H,t);2.61(2H,t);2.35(2H,t);2.07(6H,s);1.96-1.90(2H,m);1.82-1.74(2H,m);1.47-1.38(2H,m);0.94(3H,t)
MS:APCI(+ve):531
实施例7
2-(3-((N-(3-(4-氨基-2-(乙氧基甲基)-1H-咪唑并[4,5-c]喹啉-1-基)丙基)-2-(二甲基氨基)乙酰氨基)甲基)苯基)乙酸甲酯
(i)[3-(2-乙氧基甲基-1H-咪唑并[4,5-c]喹啉-1-基)丙基]氨基甲酸叔丁基酯
将来自实施例1步骤(iii)的产物(790mg)溶解在NMP(5mL)中,然后加入EDCI(1.44g)、HOBt(1g)、甲氧基乙酸(0.71mL)和Et3N(1mL)。将混合物在40℃搅拌15小时,然后在60℃加热5小时。冷却至室温后,将粗制混合物溶解在乙醚中,用盐水洗涤,干燥并减压蒸发,由此得到600mg标题化合物。
MS APCI+ve:385
(ii)[3-(2-乙氧基甲基-5-氧化-1H-咪唑并[4,5-c]喹啉-1-基)丙基]氨基甲酸叔丁酯
通过实施例1步骤(v)的方法,使用来自步骤(i)的产物制备副标题化合物。
MS APCI+ve:401
(iii)[3-(4-氨基-2-乙氧基甲基-1H-咪唑并[4,5-c]喹啉-1-基)丙基]氨基甲酸叔丁酯
通过实施例1步骤(vi)的方法,使用来自步骤(ii)的产物制备副标题化合物。
MS APCI+ve:400
(iv)1-(3-氨基丙基)-2-(乙氧基甲基)-1H-咪唑并[4,5-c]喹啉-4-胺
通过实施例1步骤(vii)的方法,使用来自步骤(iii)的产物制备副标题化合物。
MS APCI+ve:300
(v)2-(3-((3-(4-氨基-2-(乙氧基甲基)-1H-咪唑并[4,5-c]喹啉-1-基)丙基氨基)甲基)苯基)乙酸甲酯
在25℃和氮气气氛中,将2-(3-甲酰基苯基)乙酸甲酯(199mg)加入到于THF(20mL)中的来自步骤(iv)的产物(334mg)中。将所得溶液在室温搅拌6小时。在室温和氮气气氛中,向反应混合物中加入三乙酰氧基硼氢化钠(1183mg),将混合物在室温搅拌15小时。反应混合物用水淬灭,并溶解在MeOH中。产物通过RPHPLC纯化,由此得到25mg所期望的产物,其为白色固体。
MS APCI+ve:462
(vi)2-(3-((N-(3-(4-氨基-2-(乙氧基甲基)-1H-咪唑并[4,5-c]喹啉-1-基)丙基)-2-氯乙酰氨基)甲基)苯基)乙酸甲酯
在室温和氮气气氛中,将氯乙酰氯(0.059mL)加入到于MeCN(2mL)中的来自步骤(v)的产物(25mg)中。将所得溶液在室温搅拌2小时,然后真空浓缩并与甲苯共沸,收率:30mg。
MS APCI+ve:538
(vii)(3-{[[3-(4-氨基-2-乙氧基甲基-1H-咪唑并[4,5-c]喹啉-1-基)丙基](N,N-二甲基氨基乙酰基)氨基]甲基}苯基)乙酸甲酯
在室温和氮气气氛中,将来自步骤(vi)的产物(30mg)溶解在DMF(2mL)中,然后加入二甲基胺(浓度为2M的THF溶液,0.279mL)。将所得溶液在室温搅拌16小时。混合物通过RPHPLC纯化,得到标题化合物,收率:4.5mg。
1H NMRδ(CD3OD)8.05-7.95(1H,m),7.75-7.65(1H,m),7.50-7.44(1H,m),7.39-7.35(1H,m),7.20-7.15(1H,m),7.14-7.07(3H,m),4.87-4.57(8H,m),3.64-3.54(6H,m),3.33-3.05(4H,m),2.31-2.05(7H,m),1.26-1.00(3H,m)
MS APCI+ve:547
实施例8
2-(3-(((3-(4-氨基-2-丁基-1H-咪唑并[4,5-c]喹啉-1-基)丙基)(1-甲基哌啶-4-基)氨基)甲基)苯基)乙酸甲酯
(i)2-丁基-1-(3-(1-甲基哌啶-4-基氨基)丙基)-1H-咪唑并[4,5-c]喹啉-4-胺
在室温,将三乙酰氧基硼氢化钠(1.07g)加入到搅拌的来自实施例1步骤(vii)的产物(502mg)和1-甲基哌啶-4-酮(0.21mL)于NMP(2mL)中的混合物中。将所得溶液在50℃搅拌3小时,然后通过SCX纯化,收率:335mg。
MS:APCI(+ve):395
(ii)2-(3-(((3-(4-氨基-2-丁基-1H-咪唑并[4,5-c]喹啉-1-基)丙基)(1-甲基哌啶-4-基)氨基)甲基)苯基)乙酸甲酯
在室温,将溶解在NMP(10mL)中的2-(3-甲酰基苯基)乙酸甲酯(0.15g)溶液加入到搅拌的来自步骤(i)的产物(0.36g)于NMP(10mL)中的溶液中。向混合物中加入三乙酰氧基硼氢化钠(0.90g),温度增加至50℃,将反应混合物搅拌24小时。将所得溶液溶解在甲醇(0.5mL)中,用乙酸(0.5mL)酸化并通过SCX纯化。粗制产物通过RPHPLC进一步纯化,得到标题产物,收率:22mg。
1H NMRδ(DMSO-d6)7.95(1H,d);7.59(1H,d);7.38(1H,m);7.27-7.04(5H,m);6.41(2H,brs);4.34(2H,m);3.62(3H,m);3.50(2H,s);3.29(3H,s);2.90-2.65(4H,m);2.30-2.40(4H,m);1.85-1.24(9H,m);0.92(3H,t)
MS:APCI(+ve):557
实施例9
2-(4-(((3-(4-氨基-2-丁基-1H-咪唑并[4,5-c]喹啉-1-基)丙基)(1-甲基哌啶-4-基)氨基)甲基)苯基)乙酸甲酯
(i)2-(4-(((3-(4-氨基-2-丁基-1H-咪唑并[4,5-c]喹啉-1-基)丙基)(1-甲基哌啶-4-基)氨基)甲基)苯基)乙酸
在室温,将溶解在NMP(10mL)中的2-(4-甲酰基苯基)乙酸(0.14g)溶液加入到搅拌的来自实施例8步骤(i)的产物(0.34g)于NMP(10mL)中的溶液中。加入三乙酰氧基硼氢化钠(0.90g),将混合物在50℃加热24小时。将所得溶液溶解在甲醇(0.5mL)中,用乙酸(0.5mL)酸化,通过SCX纯化。粗制产物通过RPHPLC进一步纯化,得到小标题产物,收率:0.25g。
MS:APCI(+ve):543
(ii)2-(4-(((3-(4-氨基-2-丁基-1H-咪唑并[4,5-c]喹啉-1-基)丙基)(1-甲基哌啶-4-基)氨基)甲基)苯基)乙酸甲酯
将硫酸(1mL)加入到于MeOH(10mL)中的来自步骤(i)的产物(250mg)中。将混合物在室温搅拌15小时,然后减压蒸发溶剂。残余物通过RPHPLC纯化,得到标题化合物,收率:6.2mg。
1H NMRδ(CD3OD)8.05(1H,d);7.72(1H,d);7.45(1H,m);7.25-7.20(5H,m);3.70-3.62(5H,m);3.35-2.70(8H,m);2.29(3H,s);2.15-1.24(13H,m);0.92(3H,t)
MS:APCI(+ve):557
实施例10
2-(4-((N-(3-(4-氨基-2-丁基-1H-咪唑并[4,5-c]喹啉-1-基)丙基)-2-(4-甲基哌嗪-1-基)乙酰氨基)甲基)苯基)乙酸甲酯
通过实施例7步骤(vi)-(vii)的方法,使用来自实施例1的产物和甲基哌嗪制备标题化合物。
1H NMRδ(DMSO-d6)8.05(1H,m),7.65(1H,m),7.45(1H,m),7.15-7.05(5H,m),4.65-4.40(7H,m),3.71-3.60(5H,m),3.45-2.20(15H,m),2.00-1.25(5H,m),0.95(3H,t)
MS:APCI(+ve):600
实施例11
2-(3-(((3-(4-氨基-2-丁基-1H-咪唑并[4,5-c]喹啉-1-基)丙基)(3-(二甲基氨基)丙基)氨基)甲基)苯基)乙酸甲酯
(i)3-(3-硝基喹啉-4-基氨基)丙烷-1-醇
将亚硫酰氯(6.3mL)加入到3-硝基喹啉-4-醇(15g)和DMF(6.9mL)于DCM(200mL)中的混合物中。将混合物回流加热3小时,然后冷却至0℃。缓慢加入3-氨基-1-丙醇(7.3mL),然后滴加TEA(36mL),将混合物在室温搅拌3小时。过滤沉淀物,先后用DCM和水洗涤。DCM滤液用水洗涤并减压蒸发,然后与过滤的固体混合。合并的固体用乙醚(ether)研磨并过滤,得到黄色固体,19.2g。
MS:APCI(+ve):248
(ii)N-(3-(叔丁基二甲基甲硅烷基氧基)丙基)-3-硝基喹啉-4-胺
将叔丁基二甲基氯硅烷(18g)加入到来自步骤(ii)的产物(19.2g)和咪唑(15g)于DMF(200mL)中的混合物中。将混合物在室温搅拌16小时,然后在乙醚和水之间分配。分离有机物,用水洗涤,减压蒸发。残余物用异己烷研磨并过滤,得到21.8g黄色固体。
MS:APCI(+ve):362
(iii)N4-(3-(叔丁基二甲基甲硅烷基氧基)丙基)喹啉基-3,4-二胺
将铁粉(10g)加入到来自步骤(ii)的产物(20g)于乙酸(200mL)和MeOH(100mL)中的溶液中。将混合物在室温搅拌30分钟,然后减压蒸发。残余物在DCM和水之间分配,分离有机物,用NaHCO3水溶液、水洗涤,干燥并减压蒸发。残余物通过硅胶色谱法纯化(用3-5%MeOH/DCM洗脱),得到棕色油状物,10.1g。
MS:APCI(+ve):332
(iv)2-丁基-1-(3-(叔丁基二甲基甲硅烷基氧基)丙基)-1H-咪唑并[4,5-c]喹啉
在室温和氮气气氛中,将戊酰氯(Pentanoyl chloride)(3.7mL)滴加到搅拌的来自步骤(iii)的产物(10g)和TEA(5mL)于NMP(110mL)中的溶液中。将混合物在室温搅拌2小时,然后加热至100℃,持续6小时。冷却后,将反应混合物在乙醚/水之间分配,分离有机物,用水洗涤,干燥并减压蒸发。残余物通过硅胶色谱法纯化(用50-70%EtOAc/异己烷洗脱),收率:6.58g。
1H NMRδ(CDCl3)9.29(s,1H);8.34-8.26(m,2H);7.69-7.58(m,2H);4.68(t,2H);3.78(t,2H);3.00(t,2H);2.20-2.11(m,2H);2.00-1.90(m,2H);1.59-1.47(m,2H);1.02(H,3H);0.99(s,9H);0.14(s,6H)
(v)2-丁基-1-(3-(叔丁基二甲基甲硅烷基氧基)丙基)-1H-咪唑并[4,5-c]喹啉-4-胺
在0-5℃,将3-氯过氧苯甲酸(4g)逐份加入到来自步骤(iv)的产物(6.5g)于DCM(100mL)中的溶液中。将混合物温热至室温,搅拌3小时,然后在DCM和焦亚硫酸钠水溶液之间分配。分离有机物,用NaHCO3水溶液、水洗涤,干燥并减压蒸发。将残余物溶解在DCM(100mL)中,然后加入0.88氨水(12mL),接着在剧烈搅拌下历时5分钟逐份加入对甲苯磺酰氯(3.24g)。将混合物搅拌3小时,然后在DCM和水之间分配,分离有机物,用NaHCO3水溶液、盐水洗涤,干燥并减压蒸发。收率:6.7g。
MS:APCI(+ve):414
(vi)3-(4-氨基-2-丁基-1H-咪唑并[4,5-c]喹啉-1-基)丙烷-1-醇·二氯化氢
将浓度为4M的HCl/二噁烷(12mL)溶液加入到来自步骤(v)的产物(6.7g)于MeOH(100mL)中的溶液中,在室温搅拌18小时。减压蒸发溶剂,残余物用乙醚研磨,过滤并干燥。收率:5.53g。
MS:APCI(+ve):299
(vii)3-(3-(4-氨基-2-丁基-1H-咪唑并[4,5-c]喹啉-1-基)丙基氨基)丙烷-1-醇
将来自步骤(vi)的产物(5.53g)和亚硫酰氯(15mL)于DCM(100mL)中的混合物回流加热3小时,然后减压蒸发。向残余物中加入DMSO(10mL)、乙腈(80mL)和3-氨基-1-丙醇(25mL),将混合物回流加热4小时。冷却混合物,在水和EtOAc之间分配,水层用EtOAc(4×400mL)萃取,合并有机物,干燥并减压蒸发。残余物用乙醚研磨并过滤,收率:4.21g。
MS:APCI(+ve):356
(viii)2-(3-(((3-(4-氨基-2-丁基-1H-咪唑并[4,5-c]喹啉-1-基)丙基)(3-羟基丙基)氨基)甲基)苯基)乙酸甲酯
在室温和氮气气氛中,将来自步骤(vii)的产物(2g)、2-(3-(溴甲基)苯基)乙酸甲酯(1.4g)和碳酸钾(2.1g)于DMF(20mL)中的混合物搅拌24小时。混合物在DCM/水之间分配,分离有机物,用水洗涤,干燥并减压蒸发。残余物通过硅胶色谱法纯化(用DCM/MeOH/Et3N(1000/50/3)洗脱)。收率:2.43g固体。
MS:APCI(+ve):518
(ix)2-(3-(((3-(4-氨基-2-丁基-1H-咪唑并[4,5-c]喹啉-1-基)丙基)(3-氯丙基)氨基)甲基)苯基)乙酸甲酯
将来自步骤(viii)的产物(2.43g)和亚硫酰氯(10mL)于DCM(30mL)中的混合物在室温搅拌4小时,然后减压蒸发,得到副标题化合物。以粗品形式用在下一步骤中。
MS:APCI(+ve):536/8
(x)2-(3-(((3-(4-氨基-2-丁基-1H-咪唑并[4,5-c]喹啉-1-基)丙基)(3-(二甲基氨基)丙基)氨基)甲基)苯基)乙酸甲酯
在室温,将二甲基胺于THF(2M,6mL)中的溶液加入到来自步骤(ix)的产物(1.17mmol)和碘化钠(250mg)于DMF(5mL)中的混合物中。将混合物在密封容器中在55℃加热24小时,冷却,过滤,滤液通过RPHPLC纯化。蒸干含有所期望化合物的馏分,残余物用乙醚/异己烷研磨,270mg。
1H NMR DMSO-d6:δ8.00(d,1H);7.60(d,1H);7.38(t,1H);7.29-7.21(m,3H);7.15-7.09(m,2H);6.42(s,2H);4.46(t,1H);3.64(s,2H);3.58(s,2H);3.54(s,3H);2.89(t,2H);2.58(t,2H);2.42(t,2H);2.16(t,2H);2.05(s,6H);1.96-1.91(m,2H);1.81-1.73(m,2H);1.63-1.56(m,2H);1.46-1.37(m,2H);0.93(t,3H).
MS:多模式+:545。
实施例12
2-(3-(((3-(4-氨基-2-丁基-1H-咪唑并[4,5-c]喹啉-1-基)丙基)(3-吗啉代丙基)氨基)甲基)苯基)乙酸甲酯
通过实施例11步骤(x)的方法,使用来自实施例11步骤(ix)的产物(627mg)和吗啉(1ml)制备标题化合物,得到产物,其为白色固体:165mg。
1H NMR DMSO-d6:δ8.01(d,1H);7.60(d,1H);7.39(t,1H);7.27-7.12(m,5H);6.46(s,2H);4.47(t,2H);3.64(s,2H);3.57(s,2H);3.55(s,3H);3.47-3.45(t,4H);2.89(t,2H);2.58(t,2H);2.42(t,2H);2.23-2.19(m,6H);1.99-1.91(m,2H);1.81-1.74(m,2H);1.63-1.56(m,2H);1.46-1.37(m,2H);0.93(t,3H).
MS:多模式+:587
实施例13
2-(3-(((3-(4-氨基-2-丁基-1H-咪唑并[4,5-c]喹啉-1-基)丙基)(3-(乙基(甲基)氨基)丙基)氨基)甲基)苯基)乙酸甲酯
通过实施例11步骤(x)的方法,使用实施例11步骤(ix)的产物(627mg)和N-乙基甲基胺(1ml)制备标题化合物,其为白色固体:65mg。
1H NMR DMSO-d6:δ8.01(d,1H);7.60(d,1H);7.39(t,1H);7.29-7.09(m,5H);6.43(s,2H);4.45(t,2H);3.64(s,2H);3.57(s,2H);3.54(s,3H);2.89(t,2H);2.58(t,2H);2.41(t,2H);2.28-2.21(m,4H);2.04(s,3H);1.96-1.92(m,2H);1.81-1.74(m,2H);1.63-1.56(m,2H);1.44-1.39(m,2H);0.93(t,3H);0.89(t,3H).
MS:多模式+:559
实施例14
2-(3-(((3-(4-氨基-2-丁基-1H-咪唑并[4,5-c]喹啉-1-基)丙基)(3-(4-甲基哌嗪-1-基)丙基)氨基)甲基)苯基)乙酸甲酯
通过实施例11步骤(x)的方法,使用来自实施例11步骤(ix)的产物(627mg)和N-甲基哌嗪(1ml)制备标题化合物,其为无色胶状物:120mg。
1H NMR DMSO-d6:δ8.00(d,1H);7.60(d,1H);7.38(t,1H);7.29-7.10(m,5H);6.42(s,2H);4.46(t,2H);3.64(s,2H);3.57(s,2H);3.54(s,3H);2.89(t,2H);2.58(t,2H);2.41(t,2H);2.33-2.13(brm,10H);2.08(s,3H);1.98-1.90(m,2H);1.81-1.73(m,2H);1.63-1.55(m,2H);1.46-1.37(m,2H);0.94(t,3H).
MS:多模式+:600
实施例15
2-(4-((N-(3-(4-氨基-2-丁基-1H-咪唑并[4,5-c]喹啉-1-基)丙基)-2-(甲基磺酰基)乙酰氨基)甲基)苯基)乙酸甲酯
向来自实施例1的产物(221mg)于DCM(10mL)中的溶液中加入2-(甲基磺酰基)乙酸(66.4mg),然后加入TEA(0.201mL)和HATU(201mg)。将反应混合物在室温搅拌16小时,然后蒸发溶剂。粗制产物通过RPHPLC纯化,得到标题化合物(120mg),其为白色固体。
1H NMR DMSO-d6:δ8.07-7.93(m,1H),7.66-7.56(m,1H),7.47-7.37(m,1H),7.29-7.04(m,5H),6.43(s,2H),4.71(s,1H),4.59-4.37(m,5H),3.67-3.55(m,5H),3.15(s,3H),2.93-2.80(m,2H),2.72(s,1H),2.10-1.93(m,2H),1.84-1.68(m,2H),1.49-1.32(m,2H),1.30-1.19(m,1H),0.95(t,3H)
MS:580 ES+
实施例16
2-(4-((N-(3-(4-氨基-2-丁基-1H-咪唑并[4,5-c]喹啉-1-基)丙基)乙酰氨基)甲基)苯基)乙酸甲酯
将来自实施例1的产物(142mg)溶解在DCM(5mL)中,加入TEA(0.065mL)。将反应混合物冷却至0℃。加入乙酰氯(0.029mL),将反应混合物搅拌30分钟。蒸发溶剂,残余物吸收在MeOH中,通过RPHPLC纯化,得到标题化合物(40mg),其为白色固体。
1H NMR DMSO-d6:δ8.02-7.91(m,1H),7.66-7.56(m,1H),7.47-7.36(m,1H ),7.28-7.18(m,2H),7.17-7.07(m,3H),6.43(d,2H),4.58(s,1H),4.49-4.38(m,2H),3.65(s,1H),3.62-3.56(m,3H),3.49-3.40(m,2H),3.17(d,1H),2.92-2.81(m,2H),2.07(d,2H),2.04-1.94(m,2H),1.81-1.71(m,2H),1.47-1.39(m,2H),1.26-1.22(m,2H),0.95(t,3H)
MS:502 ES+
实施例17
2-(4-((N-(3-(4-氨基-2-丁基-1H-咪唑并[4,5-c]喹啉-1-基)丙基)-2-吗啉代乙酰氨基)甲基)苯基)乙酸甲酯
通过实施例7步骤(vi)-(vii)的方法,使用来自实施例1的产物(500mg)和吗啉(0.9ml)制备标题化合物,得到黄色胶状物(102mg)。
1H NMR DMSO-d6:δ8.06-7.93(m,1H),7.64-7.58(m,1H),7.46-7.40(m,1H),7.26-7.20(m,2H),7.16(d,2H),7.11-7.05(m,1H),6.43(d,2H),4.67(s,1H),4.59-4.50(m,1H),4.48-4.38(m,2H),4.11-4.04(m,1H),3.66-3.61(m,2H),3.60(s,3H),3.51-3.37(m,8H),2.90-2.81(m,2H),2.27-2.21(m,1H),2.14-2.05(m,1H),2.03-1.91(m,1H),1.79-1.72(m,2H),1.46-1.38(m,2H),1.29-1.21(m,2H),0.98-0.90(m,3H)
MS:587 ES+
实施例18
2-(4-((N-(3-(4-氨基-2-丁基-1H-咪唑并[4,5-c]喹啉-1-基)丙基)-2-((2-甲氧基乙基)(甲基)氨基)乙酰氨基)甲基)苯基)乙酸甲酯
通过实施例7步骤(vi)-(vii)的方法,使用来自实施例1的产物(500mg)和N-(2-甲氧基乙基)甲基胺(0.97mg)制备标题化合物,得到黄色胶状物(62mg)。
1H NMR DMSO-d6:δ8.03-7.93(m,1H),7.64-7.58(m,1H),7.46-7.39(m,1H),7.29-7.19(m,2H),7.19-7.07(m,3H),6.43(s,2H),4.70(s,1H),4.54-4.37(m,3H),3.67-3.55(m,5H),3.52-3.37(m,2H),3.31-3.17(m,3H),3.16-3.07(m,3H),2.86(td,2H),2.59-2.54(m,1H),2.24(s,2H),2.14-2.02(m,3H),2.00-1.88(m,1H),1.82-1.70(m,2H),1.49-1.38(m,2H),1.29-1.18(m,1H),0.94(t,3H)
MS:589 ES+
实施例19
2-(4-((2-(4-乙酰基哌嗪-1-基)-N-(3-(4-氨基-2-丁基-1H-咪唑并[4,5-c]喹啉-1-基)丙基)乙酰氨基)甲基)苯基)乙酸甲酯
通过实施例7步骤(vi)-(vii)的方法,使用来自实施例1的产物(500mg)和1-乙酰基哌嗪(1.2g)制备标题化合物,得到白色固体(152mg)。
1H NMR DMSO-d6:δ8.06-7.92(m,1H),7.64-7.57(m,1H),7.46-7.39(m,1H),7.28-7.13(m,4H),7.12-7.04(m,1H),6.48-6.40(m,2H),4.69-4.61(m,1H),4.59-4.52(m,1H),4.49-4.38(m,2H),3.66-3.62(m,2H),3.60(s,3H),3.49-3.38(m,2H),3.28-3.23(m,4H),2.91-2.81(m,2H),2.70-2.61(m,2H),2.45-2.33(m,2H),2.23(d,2H),1.98(s,3H),1.77(s,2H),1.43(t,2H),0.94(m,3H)
MS:多模式+:628
实施例20
(R)-2-(4-((N-(3-(4-氨基-2-丁基-1H-咪唑并[4,5-c]喹啉-1-基)丙基)-2-(3-羟基吡咯烷-1-基)乙酰氨基)甲基)苯基)乙酸甲酯
通过实施例7步骤(vi)-(vii)的方法,使用来自实施例1的产物(500mg)和R-(+)-吡咯烷-3-醇(813mg)制备标题化合物,得到白色固体(25mg)。
1H NMR DMSO-d6:δ8.02-7.93(m,1H),7.64-7.59(m,1H),7.46-7.39(m,1H),7.27-7.19(m,2H),7.18-7.14(m,2H),7.12-7.08(m,1H),6.46-6.41(m,2H),4.69-4.64(m,1H),4.55-4.50(m,1H),4.45-4.39(m,2H),3.62(s,3H),3.50-3.35(m,2H),3.25-3.13(m,4H),2.89-2.83(m,2H),2.79-2.77(m,1H),2.70-2.64(m,1H),2.42-2.24(m,2H),2.10-2.01(m,2H),1.99-1.90(m,2H),1.82-1.73(m,2H),1.56-1.35(m,3H),0.98-0.91(m,3H)
MS:多模式+:587
实施例21
2-(4-((N-(3-(4-氨基-2-丁基-1H-咪唑并[4,5-c]喹啉-1-基)丙基)-2-(4-(嘧啶-2-基)哌嗪-1-基)乙酰氨基)甲基)苯基)乙酸甲酯
通过实施例7步骤(vi)-(vii)的方法,使用来自实施例1的产物(1.06mg)和2-(哌嗪-1-基)嘧啶(0.32mg)制备标题化合物,得到40mg,其为白色固体。
1H NMR DMSO-d6:δ8.34(dd,2H),8.05-7.94(m,1H),7.66-7.55(m,1H),7.46-7.34(m,1H),7.30-7.16(m,3H),7.11-7.07(m,1H),6.66-6.57(m,1H),6.50-6.41(m,2H),4.74-4.66(m,1H),4.61-4.52(m,1H),4.50-4.39(m,2H),3.66-3.50(m,3H),3.53-3.30(m,6H),3.27(s,3H),3.13(s,2H),2.86(t,2H),2.39-2.28(m,2H),2.18-2.08(m,1H),2.04-1.94(m,3H),1.82-1.72(m,2H),1.47-1.35(m,2H),1.29-1.18(m,1H),0.99-0.85(m,3H)
MS:多模式+:664
实施例22
4-(2-((3-(4-氨基-2-丁基-1H-咪唑并[4,5-c]喹啉-1-基)丙基)(4-(2-甲氧基-2-氧代乙基)苄基)氨基)-2-氧代乙基)哌嗪-1-甲酸乙酯
通过实施例7步骤(vi)-(vii)的方法,使用来自实施例1的产物(230mg)和哌嗪-1-甲酸乙酯(339mg)制备标题化合物。粗制产物通过RPHPLC纯化,所得残余物用乙酸乙酯∶乙醚的1∶1混合物研磨,得到标题化合物,其为白色固体(74mg)。
1H NMR DMSO-d6:δ8.04-7.94(m,1H),7.64-7.58(m,1H),7.44-7.39(m,1H),7.27-7.21(m,1H),7.18-7.12(m,3H),7.07(d,1H),6.46-6.40(m,2H),4.66(s,1H ),4.54(s,1H),4.47-4.38(m,2H),4.07-3.95(m,3H),3.64-3.58(m,4H),3.47-3.37(m,3H),3.25-3.20(m,3H),3.05-3.02(m,2H),2.88-2.81(m,2H),2.42-2.36(m,2H),2.26-2.20(m,2H),2.14-2.04(m,2H),2.03-1.92(m,2H),1.81-1.71(m,2H),1.48-1.36(m,2H),1.16(dt,3H),0.94(td,3H)
MS:多模式+:658
实施例23
2-(4-((N-(3-(4-氨基-2-丁基-1H-咪唑并[4,5-c]喹啉-1-基)丙基)-2-(4-(乙基磺酰基)哌嗪-1-基)乙酰氨基)甲基)苯基)乙酸甲酯
通过实施例7步骤(vi)-(vii)的方法,使用来自实施例1的产物(230mg)和1-(乙基磺酰基)哌嗪(382mg)制备标题化合物。粗制产物如实施例22中所描述的那样纯化,得到标题化合物,其为白色固体(72mg)。
1H NMR DMSO-d6:δ8.00(dd,1H),7.64-7.55(m,1H),7.47-7.38(m,1H),7.31-7.22(m,1H),7.21-7.12(m,3H),7.13-7.04(m,1H),6.51-6.39(m,2H),4.69-4.60(m,1H),4.61-4.52(m,1H),4.47-4.38(m,2H),3.68-3.56(m,5H),3.48-3.38(m,2H),3.28-3.23(m,2H),3.11-3.00(m,4H),2.99-2.91(m,4H),2.89-2.82(m,2H),2.36-2.30(m,3H),2.15-1.92(m,2H),1.81-1.73(m,2H),1.46-1.38(m,2H),1.20-1.12(m,3H),0.98-0.90(m,3H)
MS:多模式+:678
实施例24
2-(4-((N-(3-(4-氨基-2-丁基-1H-咪唑并[4,5-c]喹啉-1-基)丙基)-2-(哌啶-1-基)乙酰氨基)甲基)苯基)乙酸甲酯
通过实施例7步骤(vi)-(vii)的方法,使用来自实施例1的产物(230mg)和哌啶(183mg)制备标题化合物。粗制产物通过RPHPLC纯化,所得残余物用乙酸乙酯研磨,得到标题化合物,其为白色固体(25mg)。
1H NMR DMSO-d6:δ8.03-7.92(m,1H),7.60(d,1H),7.45-7.40(m,1H),7.26-7.20(m,2H),7.19-7.14(m,2H),7.11-7.03(m,1H),6.45-6.40(m,1H),4.72-4.66(m,1H),4.57-4.51(m,1H),4.48-4.37(m,2H),3.65-3.58(m,5H),3.53-3.35(m,2H),3.14-3.08(m,2H),2.97-2.91(m,2H),2.90-2.78(m,3H),2.38-2.30(m,2H),2.16-1.87(m,2H),1.84-1.72(m,3H),1.49-1.19(m,8H),0.94(td,3H).
MS:多模式+:585
实施例25
2-(4-((N-(3-(4-氨基-2-丁基-1H-咪唑并[4,5-c]喹啉-1-基)丙基)-2-(4-(叔丁氧基羰基氨基)哌啶-1-基)乙酰氨基)甲基)苯基)乙酸甲酯
通过实施例7步骤(vi)-(vii)的方法,使用来自实施例1的产物(230mg)和哌啶-4-基氨基甲酸叔丁酯(430mg)制备标题化合物。粗制产物通过RPHPLC纯化,所得残余物用乙酸乙酯研磨,得到标题化合物,其为白色固体(87mg)。
1H NMR DMSO-d6:δ8.05-7.93(m,1H),7.66-7.54(m,1H),7.48-7.36(m,1H),7.27-7.14(m,3H),7.08-7.03(m,1H),6.75-6.63(m,1H),6.46-6.40(m,2H),4.65-4.60(m,1H),4.58-4.48(m,1H),4.47-4.36(m,2H),3.65-3.58(m,2H),3.48-3.35(m,2H),3.18-3.10(m,2H),2.89-2.81(m,3H),2.80-2.73(m,1H),2.69-2.62(m,2H),2.11-2.01(m,4H),1.97-1.87(m,2H),1.82-1.72(m,2H),1.67-1.56(m,2H),1.48-1.40(m,2H),1.37(t,9H),1.30-1.23(m,3H),0.94(t,3H).
MS:多模式+:700
实施例26
2-(4-((N-(3-(4-氨基-2-丁基-1H-咪唑并[4,5-c]喹啉-1-基)丙基)-2-(4-(叔丁氧基羰基(甲基)氨基)哌啶-1-基)乙酰氨基)甲基)苯基)乙酸甲酯
通过实施例7步骤(vi)-(vii)的方法,使用来自实施例1的产物(230mg)和(哌啶-4-基)氨基(甲基)甲酸酯(440mg)制备标题化合物。粗制产物通过RPHPLC纯化,所得残余物用乙酸乙酯研磨,得到标题化合物,其为白色固体(40mg)。
1H NMR DMSO-d6:δ8.05-7.94(m,1H),7.64-7.58(m,1H),7.45-7.39(m,1H),7.29-7.20(m,1H),7.19-7.14(m,3H),7.10-7.06(m,1H),6.45-6.40(m,2H),4.70-4.66(m,1H),4.58-4.51(m,2H),4.48-4.38(m,2H),3.65(s,3H),3.61(s,3H),3.51-3.38(m,3H),3.18-3.14(m,1H),2.98-2.95(m,1H),2.89-2.81(m,3H),2.68-2.59(m,2H),2.16-1.86(m,6H),1.85-1.71(m,2H),1.53-1.38(m,6H),1.39-1.34(m,9H),0.94(td,3H).
MS:多模式+:714
实施例27
2-(1-(2-((3-(4-氨基-2-丁基-1H-咪唑并[4,5-c]喹啉-1-基)丙基)(4-(2-甲氧基-2-氧代乙基)苄基)氨基)-2-氧代乙基)哌啶-4-基)乙酸乙酯
通过实施例7步骤(vi)-(vii)的方法,使用来自实施例1的产物(230mg)和2-(哌啶-4-基)乙酸乙酯(75mg)制备标题化合物。粗制产物通过RPHPLC纯化,所得残余物用乙酸乙酯研磨,得到标题化合物,其为白色固体(25mg)。
1H NMR DMSO-d6:δ8.03-7.92(m,1H),7.64-7.58(m,1H),7.42(s,1H),7.27-7.20(m,1H),7.18-7.14(m,3H),7.09-7.05(m,1H),6.44-6.40(m,2H),4.69-4.64(m,1H),4.56-4.50(m,1H),4.46-4.38(m,2H),4.03(q,2H),3.65-3.62(m,2H),3.61-3.59(m,3H),3.50-3.38(m,2H),3.14(s,1H),2.97(s,1H),2.88-2.82(m,2H ),2.80-2.75(m,2H),2.16-2.06(m,3H),2.04-1.91(m,3H),1.89-1.72(m,3H),1.60-1.47(m,3H),1.46-1.38(m,2H),1.20-1.12(m,4H),1.12-1.07(m,2H),0.94(td,3H).
MS:多模式+:671
实施例28
1-(2-((3-(4-氨基-2-丁基-1H-咪唑并[4,5-c ]喹啉-1-基)丙基)(4-(2-甲氧基-2-氧代乙基)苄基)氨基)-2-氧代乙基)哌啶-4-甲酸甲酯
通过实施例7步骤(vi)-(vii)的方法,使用来自实施例1的产物(230mg)和哌啶-4-甲酸甲酯(61mg)制备标题化合物。粗制产物通过RPHPLC纯化,所得残余物用乙醚研磨,得到标题化合物,其为白色固体(16mg)。
1H NMR DMSO-d6:δ8.02-7.92(m,1H),7.64-7.58(m,1H),7.45-7.39(m,1H),7.26-7.20(m,2H),7.18-7.14(m,2H),7.07-7.05(m,1H),6.44-6.40(m,2H),4.69-4.66(m,1H),4.56-4.51(m,1H),4.46-4.39(m,2H),3.64-3.62(m,2H),3.60-3.58(m,3H),3.48-3.37(m,2H),3.29-3.28(m,3H),3.17-3.10(m,1H),3.00-2.93(m,1H),2.89-2.82(m,2H),2.80-2.74(m,2H),2.63-2.58(m,2H),2.29-2.18(m,1H),2.14-1.89(m,4H),1.82-1.69(m,4H),1.54-1.37(m,4H),0.94(td,3H).
MS:多模式+:643
实施例29
2-(4-((N-(3-(4-氨基-2-(2-甲氧基乙基)-1H-咪唑并[4,5-c]喹啉-1-基)丙基)-2-(哌啶-1-基)乙酰氨基)甲基)苯基)乙酸甲酯
i)3-(2-(2-甲氧基乙基)-1H-咪唑并[4,5-c]喹啉-1-基)丙基氨基甲酸叔丁酯.
向于NMP(25mL)中的实施例1步骤(iii)的产物(1.9g)中加入3-甲氧基丙酸(0.678mL,7.21mmol),然后在氮气气氛中加入HATU(2.74g)和TEA(0.837mL)。将所得溶液在60℃搅拌15小时。反应混合物用乙醚(300mL)和EtOAc(300mL)稀释,并用水(300mL)、饱和NaHCO3溶液(200mL)和饱和盐水(200mL)洗涤。干燥有机物,过滤并蒸发,得到小标题产物(3.5g)。
MS APCI+ve 385
ii)1-(3-(叔丁氧基羰基氨基)丙基)-2-(2-甲氧基乙基)-1H-咪唑并[4,5-c]喹啉基5-氧化物
通过实施例1步骤(v)的方法,使用来自步骤(i)的产物制备副标题化合物。
MS APCI+ve:401
iii)3-(4-氨基-2-(2-甲氧基乙基)-1H-咪唑并[4,5-c]喹啉-1-基)丙基氨基甲酸叔丁酯
通过实施例1步骤(vi)的方法,使用来自步骤(ii)的产物制备副标题化合物。
MS APCI+ve:400
iv)1-(3-氨基丙基)-2-(2-甲氧基乙基)-1H-咪唑并[4,5-c]喹啉-4-胺
通过实施例1步骤(vii)的方法,使用步骤(iii)的产物制备副标题化合物。
MS APCI+ve:300
2-(4-((3-(4-氨基-2-(2-甲氧基乙基)-1H-咪唑并[4,5-c]喹啉-1-基)丙基氨基)甲基)苯基)乙酸甲酯
向于THF(100mL)中的来自步骤(iv)的产物(1.25g)中加入2-(4-甲酰基苯基)乙酸甲酯(0.818g),然后加入三乙酰氧基硼氢化钠(0.885g)和乙酸(3滴),在室温搅拌16小时。反应混合物用水淬灭,用DCM萃取,用饱和NaHCO3溶液(200mL)洗涤,干燥并除去溶剂。将所得残余物溶解在甲醇中,在SCX上纯化,得到副标题化合物(0.73g)。
MS APCI+ve 462
2-(4-((3-(4-氨基-2-(2-甲氧基乙基)-1H-咪唑并[4,5-c]喹啉-1-基)丙基氨基)甲基)苯基)乙酸甲酯
在0℃,向于MeCN(5mL)中的来自步骤(v)的产物(180mg)中加入2-氯乙酰氯(44.0mg),搅拌7小时。加入哌啶(332mg),在室温搅拌15小时。除去溶剂,粗制产物通过RPHPLC纯化。所得残余物用乙醚研磨,得到标题化合物,其为白色固体(22mg)。
1H NMR DMSO-d6:δ8.03-7.93(m,1H),7.64-7.59(m,1H),7.45-7.40(m,1H),7.28-7.20(m,1H),7.19-7.15(m,3H),7.11-7.07(m,1H),6.47-6.43(m,2H),4.70(s,1H),4.61-4.55(m,1H),4.45(d,2H),3.80(q,2H),3.63(d,2H),3.60(d,3H),3.52-3.46(m,1H),3.44-3.37(m,1H),3.16-3.08(m,3H),2.97(s,1H),2.39-2.31(m,3H),2.23-2.17(m,2H),2.15-2.08(m,1H),2.00-1.92(m,1H),1.46-1.39(m,3H),1.36-1.23(m,7H).
MS:多模式+:587
实施例30
2-(4-((N-(3-(4-氨基-2-(2-甲氧基乙基)-1H-咪唑并[4,5-c]喹啉-1-基)丙基)-2-(二甲基氨基)乙酰氨基)甲基)苯基)乙酸甲酯
通过实施例29步骤(vi)的方法,用实施例29步骤(v)的产物(180mg)和浓度为2M的二甲基胺的THF溶液(0.2ml)制备标题化合物,其为白色固体(15mg)。
1H NMR DMSO-d6:δ8.04-7.94(m,1H),7.65-7.59(m,1H),7.46-7.40(m,1H),7.27-7.20(m,2H),7.19-7.09(m,3H),6.48-6.42(m,2H),4.70-4.67(m,1H),4.58-4.52(m,1H),4.48-4.42(m,2H),3.84-3.77(m,2H),3.65-3.62(m,2H),3.61(s,3H),3.49-3.38(m,2H),3.28(s,3H),3.17-3.09(m,3H),3.01-2.98(m,1H),2.21(s,3H),2.15-2.07(m,2H),2.02(s,3H),1.98-1.94(m,2H).
MS:多模式+:547
实施例31
2-(3-((N-(3-(4-氨基-2-(2-甲氧基乙基)-1H-咪唑并[4,5-c]喹啉-1-基)丙基)-2-(哌啶-1-基)乙酰氨基)甲基)苯基)乙酸甲酯·糖精盐
2-(3-((3-(4-氨基-2-(2-甲氧基乙基)-1H-咪唑并[4,5-c]喹啉-1-基)丙基氨基)甲基)苯基)乙酸甲酯
通过实施例29步骤(v)的方法,使用2-(4-甲酰基苯基)乙酸甲酯制备副标题化合物。得到副标题化合物,其为白色固体。
MS APCI+ve 462
ii)2-(3-((N-(3-(4-氨基-2-(2-甲氧基乙基)-1H-咪唑并[4,5-c]喹啉-1-基)丙基)-2-(哌啶-1-基)乙酰氨基)甲基)苯基)乙酸甲酯·糖精盐
通过实施例29步骤(vi)的方法,使用来自步骤(i)的产物(95mg)和哌啶(18mg)制备标题化合物。粗制产物通过RPHPLC纯化,得到游离碱,其为胶状物(44mg),将所述胶状物溶解在1ml MeOH中。加入糖精(13.9mg)于1ml MeOH中的溶液,蒸干,加入EtOAc(2ml),将悬浮液在室温搅拌2天。过滤收集固体,得到标题化合物,其为白色固体(22mg)。
1H NMR DMSO-d6:δ8.17-8.13(m,1H),7.85-7.83(m,1H),7.70-7.06(m,10H),4.64-4.55(m,6H),4.31-4.10(brm,2H),3.86-3.80(m,2H),3.64(s,2H),3.58(s,3H),3.50-3.46(m,2H),3.32-3.17(m,9H),2.07-1.71(m,6H).
MS:多模式+:587
实施例32
2-(4-((N-(3-(4-氨基-2-(2-甲氧基乙基)-1H-咪唑并[4,5-c]喹啉-1-基)丙基)-2-((2-甲氧基乙基)(甲基)氨基)乙酰氨基)甲基)苯基)乙酸甲酯
通过实施例29步骤(vi)的方法,使用2-甲氧基-N-甲基乙胺(455mg)和实施例29步骤(v)的产物(549mg)制备标题化合物。得到标题化合物,其为白色固体(52mg)。
1H NMR DMSO-d6:δ8.03-7.96(m,1H),7.64-7.61(m,1H),7.44(m,1H),7.28-7.10(m,5H),6.46(brs,2H),4.72-4.67(m,4H),3.80(q,2H),3.63(m,2H),3.51(s,3H),3.42-3.11(m,13H),2.58-2.50(m,2H),2.25-1.98(m,4H),1.11(t,2H).
MS:多模式+:591
实施例33
2-(4-((N-(3-(4-氨基-2-(2-甲氧基乙基)-1H-咪唑并[4,5-c]喹啉-1-基)丙基)-3-(哌啶-1-基)丙酰氨基)甲基)苯基)乙酸甲酯
在室温,向于DMF(5mL)中的来自实施例29步骤(v)的产物(480mg,1.04mmol)中加入3-(哌啶-1-基)丙酸(196mg,1.25mmol)和HATU(475mg,1.25mmol),搅拌2小时。加入1mL甲醇后,粗制产物通过RPHPLC纯化,所得残余物用乙醚∶EtOAc(5∶1)研磨。过滤悬浮液得到标题化合物,其为白色固体(72mg)。
1H NMR DMSO-d6:δ8.03-7.96(m,1H),7.63-7.60(m,1H),7.45-7.40(m,1H),7.28-7.10(m,5H),6.46(brs,2H),4.63-4.47(m,4H),3.80(t,2H),3.65-3.59(m,5H),3.48(m,2H),3.29-3.27(m,7H),3.15(q,2H),2.27-2.00(m,6H),1.39-1.31(m,6H).
MS:多模式+:601
实施例34
2-(4-(((3-(4-氨基-2-(2-甲氧基乙基)-1H-咪唑并[4,5-c]喹啉-1-基)丙基)(3-吗啉代丙基)氨基)甲基)苯基)乙酸甲酯
在室温,将来自实施例29步骤(v)的产物(360mg,0.78mmol)溶解在MeCN(10mL)中,加入4-(3-氯丙基)吗啉·盐酸盐(187mg,0.94mmol)。加入无水K2CO3(323mg,2.34mmol)和碘化钠(117mg,0.78mmol)。将混合物回流15小时。冷却至室温后,粗制产物通过RPHPLC纯化,所得残余物用乙醚∶EtOAc(5∶1)在0℃研磨。过滤悬浮液,得到标题化合物,其为黄色固体(31mg)。
1H NMR DMSO-d6:δ8.03-8.00(m,1H),7.61-7.58(m,1H),7.42-7.37(m,1H),7.29-7.26(m,2H),7.19-7.14(m,2H),7.14-7.09(m,1H),6.45(brs,2H),4.52(m,2H),3.79(t,2H),3.66-3.56(m,5H),3.45(m,4H),3.32-3.27(m,5H),3.16(t,2H),2.58-2.36(m,6H),2.27-2.18(m,4H),1.99-1.59(m,4H).
MS:多模式+:589。
实施例35
(S)-2-(4-((N-(3-(4-氨基-2-(2-甲氧基乙基)-1H-咪唑并[4,5-c]喹啉-1-基)丙基)-2-(2-(甲氧基甲基)吡咯烷-1-基)乙酰氨基)甲基)苯基)乙酸甲酯·二糖精盐
通过实施例29步骤(vi)的方法,使用(S)-2-(甲氧基甲基)吡咯烷(235mg)和来自实施例29步骤(v)的产物(549mg)制备标题化合物,得到游离碱,其为胶状物(97mg)。将该胶状物溶解在MeOH(1ml)中,加入糖精(59mg)于MeOH(1ml)中的溶液,蒸干,加入乙醚(2ml)并在室温搅拌15小时。过滤收集固体,得到标题化合物,其为白色固体22mg。
1H NMR DMSO-d6:δ8.17-8.22(m,1H),7.88-7.85(m,1H),7.74-7.56(m,10H ),7.26-7.13(m,4H),4.64-4.55(m,6H),4.31-4.10(brm,2H),3.86-3.80(m,4H ),3.61-3.14(m,18H),2.32-1.71(m,6H).
MS:多模式+:617
实施例36
(R)-2-(4-((N-(3-(4-氨基-2-(2-甲氧基乙基)-1H-咪唑并[4,5-c]喹啉-1-基)丙基)-2-(2-(甲氧基甲基)吡咯烷-1-基)乙酰氨基)甲基)苯基)乙酸甲酯·二糖精盐
通过实施例29步骤(vi)的方法,使用(S)-2-(甲氧基甲基)吡咯烷(117mg)和来自实施例29步骤(v)的产物(549mg)制备标题化合物,得到游离碱,其为胶状物。如实施例35所述形成二糖精盐,得到标题化合物,其为白色固体68mg。
1H NMR DMSO-d6:δ8.17-8.22(m,1H),7.88-7.85(m,1H),7.74-7.56(m,10H),7.26-7.13(m,4H),4.64-4.55(m,6H),3.86-3.80(m,4H),3.61-3.14(m,18H),2.42-1.71(m,6H).
MS:多模式+:617
实施例37
2-(4-((N-(3-(4-氨基-2-(2-甲氧基乙基)-1H-咪唑并[4,5-c]喹啉-1-基)丙基)-2-(吡咯烷-1-基)乙酰氨基)甲基)苯基)乙酸甲酯·二糖精盐
通过实施例29步骤(vi)的方法,使用吡咯烷(73mg)和实施例29步骤(v)的产物(55mg)制备标题化合物,得到游离碱,其为胶状物。如实施例35所述形成二糖精盐,得到标题化合物,其为白色固体29mg。
1H NMR DMSO-d6:δ8.18-8.22(m,1H),7.88-7.85(m,1H),7.75-7.60(m,10H ),7.23-7.13(m,4H),4.64-4.40(m,6H),3.82(m,4H),3.61-3.14(m,14H),2.44-1.82(m,6H).
MS:多模式+:573
实施例38
2-(4-((N-(3-(4-氨基-2-(2-甲氧基乙基)-1H-咪唑并[4,5-c]喹啉-1-基)丙基)-2-((2-羟基乙基)(甲基)氨基)乙酰氨基)甲基)苯基)乙酸甲酯·二糖精盐
通过实施例29步骤(vi)的方法,使用实施例29步骤(v)的产物(549mg)和2-(甲基氨基)乙醇(81mg)制备标题化合物,得到游离碱,其为胶状物。如实施例35所述形成二糖精盐,得到标题化合物,其为白色固体27mg。
1H NMR DMSO-d6:δ8.17-8.22(m,1H),7.88-7.85(m,1H),7.90-7.56(m,10H),7.26-7.13(m,4H),4.64-4.55(m,6H),3.86-3.80(m,4H),3.61-3.14(m,13H),2.32-1.71(m,6H).
MS:多模式+:573
实施例39
2-(3-((N-(3-(4-氨基-2-丁基-1H-咪唑并[4,5-c]喹啉-1-基)丙基)-2-((2-甲氧基乙基)(甲基)氨基)乙酰氨基)甲基)苯基)乙酸甲酯
(i)2-(3-((N-(3-(4-氨基-2-丁基-1H-咪唑并[4,5-c]喹啉-1-基)丙基)2-氯乙酰氨基)甲基)苯基)乙酸甲酯
在0℃,将氯乙酰氯(0.434mL,5.44mmol)加入到于CHCl3(75mL)中的实施例2的产物(2.50g)中。将所得溶液在0℃搅拌1小时,然后加入0.2NHCl水溶液(100mL),用CHCl3(100mL)萃取。有机层真空干燥并浓缩。
1H NMR(CDCl3)δ8.00(1H,d),7.96(1H,d),7.64(1H,dd),7.55(1H,dd),7.33(1H),7.23(1H,d),7.12(1H,s),7.08(1H,d),4.70(2H,s),4.51(2H,dd),4.16(2H,s),3.70(3H,s),3.66-3.62(2H,m),3.62(2H,s),2.88(2H,dd),2.18-2.10(2H,m),1.93-1.85(2H,m),1.57-1.48(2H,m),1.03(3H,t).
(ii)2-(3-((N-(3-(4-氨基-2-丁基-1H-咪唑并[4,5-c]喹啉-1-基)丙基)-2-((2-甲氧基乙基)(甲基)氨基)乙酰氨基)甲基)苯基)乙酸甲酯
在0℃,将乙腈(75ml)加入到残余物中,然后加入过量的2-甲氧基乙基(甲基)胺。将所得溶液在室温搅拌4小时。蒸发溶剂。向残余物中加入0.2NHCl水溶液(100mL),用CHCl3/MeOH=20/1(100mL)萃取。水层用NH3水溶液中和,然后用EtOAc/己烷=2/1(100ml)萃取。合并的有机层用盐水洗涤,干燥并真空浓缩,得到标题化合物(266mg),其为胶状物。
1H NMR(DMSO-d6)δ8.00(0.5H,d),8.00(0.5H,d),7.66(1H,dd),7.45-7.39(1H,m),7.27-7.20(2H,m),7.16-7.00(3H,m),6.46(2H,brs),4.72(1H,s),4.52-4.38(3H,m),3.64(1H,s),3.60(1H,s),3.57(1.5H,s),3.56(1.5H,s),3.51(1H,t),3.42(1H,t),3.33-3.28(2H,m),3.23(1H,s),3.19(1H,s),3.13(1.5H,s),3.09(1.5H,s),2.90-2.81(2H,m),2.55(1H,t),2.47(1H,t),2.22(1.5H,s),2.12(1.5H,s),2.12-2.05(1H,m),2.01-1.92(1H,m),1.82-1.71(2H,m),1.46-1.38(2H,m),0.94(3H,t).
MS:ESI 589(M+1)
实施例40
2-(3-((N-(3-(4-氨基-2-丁基-1H-咪唑并[4,5-c]喹啉-1-基)丙基)-2-(丁基(甲基)氨基)乙酰氨基)甲基)苯基)乙酸甲酯
通过实施例39的方法,使用来自步骤(i)的产物(312mg)和正丁基-N-甲基胺制备标题化合物,得到标题化合物(276mg)其为胶状物。
1H NMR(DMSO-d6)δ8.00(0.5H,d),7.96(0.5H,d),7.60(1H,dd),7.42(1H,dd),7.27-7.22(2H,m),7.15-7.02(3H,m),6.45(2H,brs),4.71(1H,s),4.50(1H,t),4.47(1H,s),4.42(1H,t),3.64(1H,s),3.60(1H,s),3.58(1.5H,s),3.57(1.5H,s),3.51(1H,t),3.42(1H,t),3.15(1H,s),3.06(1H,s),2.85(2H,t),2.32(1H,t),2.24-2.16(1H,m),2.17(1.5H,s),2.13-2.05(1H,m),2.01(1.5H,s),2.00-1.91(1H,m),1.82-1.71(2H,m),1.47-1.38(2H,m),1.31-1.10(4H,m),0.94(3H,t),0.78(3H,m).
MS:ESI 587(M+1)
实施例41
3-((N-(3-(4-氨基-2-丁基-1H-咪唑并[4,5-c]喹啉-1-基)丙基)-2-(二丙基氨基)乙酰氨基)甲基)苯基)乙酸甲酯
通过实施例39的方法,使用来自步骤(i)的产物(308mg)和二丙基胺制备标题化合物,得到标题化合物(250mg),其为胶状物。
1H NMR(DMSO-d6)δ8.00-7.94(1H,m),7.60(1H,dd),7.45-7.40(1H,m),7.27-7.20(2H,m),7.18-7.02(3H,m),6.46(2H,brs),4.73(1H,s),4.49-4.38(3H,m),3.64(1H,s),3.59(1H,s),3.58(1.5H,s),3.57(1.5H,s),3.55-3.51(1H,m),3.42(1H,t),3.22(1H,s),3.20(1H,s),2.85(2H,t),2.38(2H,t),2.27(2H,t),2.20-2.10(1H,m),2.03-1.92(1H,m),1.82-1.71(2H,m),1.45-1.38(2H,m),1.31-1.22(4H,m),0.94(3H,t),0.73(6H,m)
MS:ESI 601(M+1)
实施例42
2-(3-((N-(3-(4-氨基-2-丁基-1H-咪唑并[4,5-c]喹啉-1-基)丙基)-2-(二(2-羟基乙基)氨基)乙酰氨基)甲基)苯基)乙酸甲酯
通过实施例39的方法,使用来自步骤(i)的产物(240mg)和二乙醇胺制备标题化合物,得到标题化合物(130mg),其为胶状物。
1H NMR(CDCl3)δ7.80(2H,m),7.47-7.51(1H,m),6.93-7.31(5H,m),5.79(2H,brs),4.40-4.53(3H,m),3.68(3H,s),3.53-3.58(7H,m),3.40(1H,m),2.82-2.85(5H,m),2.57-2.59(1H,m),2.08-2.13(4H,m),1.79-1.85(3H,m),1.45-1.50(2H,m),1.25(2H,m),0.98(3H,t).
MS:ESI 605(M+1)
实施例43
2-(3-((N-(3-(4-氨基-2-丁基-1H-咪唑并[4,5-c]喹啉-1-基)丙基)-2-(甲基(四氢-2H-吡喃-4-基)氨基)乙酰氨基)甲基)苯基)乙酸甲酯
通过实施例39的方法,使用来自步骤(i)的产物(260mg)和N-甲基-N-四氢-2H-吡喃-4-基胺制备标题化合物,得到标题化合物(180mg),其为胶状物。
1H NMR(CDCl3)δ7.85(2H,t,),7.52(1H,m),6.83-7.26(5H,m),5.65(2H,brs),4.71(2H,s),4.38-4.57(2H,m),3.96-4.00(2H,m),3.68(3H,s),3.50-3.58(4H,m),3.35(3H,s),2.83-2.87(2H,m),2.60(1H,m),2.07(2H,m),1.80-1.87(6H,m),1.67(2H,m),1.46-1.57(4H,m),1.25(2H,m),0.99(3H,t)
MS:ESI 615(M+1)
实施例44
2-(3-((N-(3-(4-氨基-2-丁基-1H-咪唑并[4,5-c]喹啉-1-基)丙基)-2-(氮杂环丁烷-1-基)乙酰氨基)甲基)苯基)乙酸甲酯
通过实施例39的方法,使用来自步骤(i)的产物(267mg)和氮杂环丁烷制备标题化合物,得到标题化合物(107mg),其为固体.
1H NMR(DMSO-d6)δ8.03(1/2H,d),7.96(1/2H,d,J),7.61-7.56(1H,m),7.43(1H,dd,7.2,7.9),7.31-7.21(2H,m),7.17-7.01(3H,m),6.47(1H,brd),4.63(1H,s),4.52(1H,brt),4.44(1H,s),4.45-4.38(1H,m),3.66(1H,s),3.61(1H,s),3.58(3H,s),3.45-3.35(2H,m),3.24(1H,s),3.17(2H,t),3.08(1H,s),3.02(2H,t),2.89-2.83(2H,m),2.11-2.02(1H,m),1.99-1.91(2H,m),1.86-1.73(3H,m),1.43(2H,q),0.95(3H,t).
MS:ESI 557(M+1)
实施例45
2-(3-((N-(3-(4-氨基-2-丁基-1H-咪唑并[4,5-c]喹啉-1-基)丙基)-2-(3-羟基氮杂环丁烷-1-基)乙酰氨基)甲基)苯基)乙酸甲酯
通过实施例39的方法,使用来自步骤(i)的产物(202mg)和3-氮杂环丁醇制备标题化合物,得到标题化合物(193mg),其为胶状物。
1H NMR(CDCl3)δ7.87-7.83(2H,m),7.54-7.50(1H,m),7.36-7.32(1H,m),7.26-7.23(1H,m),7.17-7.13(1H,m),7.05-7.03(1H,m),7.00-6.97(1H,m),5.61-5.57(2H,m),4.54-4.41(4H,m),3.82-3.78(2H,m),3.68(3H,s),3.57-3.50(4H,m),3.41(2H,s),3.20-3.16(0.5H,m),3.09-3.06(1.5H,m),2.86-2.83(2H,m),2.20-2.15(0.5H,m),2.11-2.04(1.5H,m),1.85-1.74(4H,m),1.51-1.45(2H,m),0.99(3H,t).
MS:ESI 573(M+1)
实施例46
2-(3-((N-(3-(4-氨基-2-丁基-1H-咪唑并[4,5-c]喹啉-1-基)丙基)-2-(吡咯烷-1-基)乙酰氨基)甲基)苯基)乙酸甲酯
通过实施例39的方法,使用来自步骤(i)的产物(300mg)和吡咯烷制备标题化合物,得到标题化合物(289mg),其为胶状物。
1H NMR(DMSO-d6)δ8.01(0.5H,d),7.95(0.5H,d),7.62-7.59(1H,m),7.42(1H,dd),7.29-7.20(2H,m),7.15-7.05(3H,m),6.45(2H,d),4.69(1H,s),4.52(1H,t),4.48(1H,s),4.41(1H,t),3.63(1H,s),3.61(1H,s),3.57(1.5H,s),3.56(1.5H,s),3.51-3.46(1H,m),3.42(1H,t),3.28(1H,s),3.12(1H,s),2.84(2H,t),2.51-2.45(2H,m),2.34-2.28(2H,m),2.12-2.03(1H,m),2.02-1.91(1H,m),1.81-1.72(2H,m),1.66-1.60(2H,m),1.54-1.48(2H,m),0.94(1.5H),0.93(1.5H,t).
MS:ESI 571(M+1)
实施例47
2-(3-((N-(3-(4-氨基-2-丁基-1H-咪唑并[4,5-c]喹啉-1-基)丙基)-2-(3-羟基吡咯烷-1-基)乙酰氨基)甲基)苯基)乙酸甲酯
通过实施例39的方法,使用来自步骤(i)的产物(300mg)和DL-3-吡咯醇制备标题化合物,得到标题化合物(300mg),其为固体。
1H NMR(DMSO-d6)δ7.99(0.5H,d),7.94(0.5H,d),7.60(1H,dd),7.43-7.39(1H,m),7.28-7.20(2H,m),7.14-7.02(3H,m),6.45(2H,brs),4.68-4.66(2H,m),4.65-4.39(3H,m),4.15-4.00(1H,m),3.63(1H,s),3.59(1H,s),3.57(1.5H,s),3.55(1.5H,s),3.52-3.32(2H,m),3.26(1H,s),3.22-3.11(1H,m),2.85-2.74(2.5H,m),2.70-2.62(0.5H,m),2.58-2.49(0.5H,m),2.37-2.24(1.5H,m),2.10-2.00(1H,m),1.98-1.72(4H,m),1.54-1.37(3H,m),0.93(3H,t).
MS:ESI 587(M+1)
实施例48
(R)-2-(3-((N-(3-(4-氨基-2-丁基-1H-咪唑并[4,5-c]喹啉-1-基)丙基)-2-(3-羟基吡咯烷-1-基)乙酰氨基)甲基)苯基)乙酸甲酯
通过实施例39的方法,使用来自步骤(i)的产物(300mg)和(R)-3-吡咯烷醇制备标题化合物,得到标题化合物(169mg),其为固体。
1H NMR(DMSO-d6)δ7.99(0.5H,d),7.94(0.5H,d),7.60(1H,dd),7.43-7.39(1H,m),7.28-7.20(2H,m),7.14-7.02(3H,m),6.45(2H,brs),4.68-4.66(2H,m),4.65-4.39(3H,m),4.15-4.00(1H,m),3.63(1H,s),3.59(1H,s),3.57(1.5H,s),3.55(1.5H,s),3.52-3.32(2H,m),3.26(1H,s),3.22-3.11(1H,m),2.85-2.74(2.5H,m),2.70-2.62(0.5H,m),2.58-2.49(0.5H,m),2.37-2.24(1.5H,m),2.10-2.00(1H,m),1.98-1.72(4H,m),1.54-1.37(3H,m),0.93(3H,t).
MS:ESI 587(M+1)
实施例49
2-(3-((N-(3-(4-氨基-2-丁基-1H-咪唑并[4,5-c]喹啉-1-基)丙基)-2-(哌啶-1-基)乙酰氨基)甲基)苯基)乙酸甲酯
通过实施例39的方法,使用来自步骤(i)的产物(300mg)和哌啶制备标题化合物,得到标题化合物(300mg),其为胶状物。
1H NMR(DMSO-d6)δ8.01(0.5H,d),7.95(0.5H,d),7.63-7.59(1H,m),7.42(1H,dd),7.29-7.20(2H,m),7.15-7.09(2H,m),7.04-7.01(1H,m),6.46(2H,brs),4.69(1H,s),4.53(1H,t),4.48(1H,s),4.40(1H,t),3.63(1H,s),3.60(1H,s),3.58(1.5H,s),3.56(1.5H,s),3.50(1H,t),3.40(1H),3.10(1H,s),2.93(1H,s),2.87-2.81(2H,m),2.38-2.32(2H,m),2.21-2.14(2H,m),2.14-2.06(1H,m),1.99-1.90(1H,m),1.82-1.71(2H,m),1.47-1.31(8H,m),0.94(1.5H,t),0.93(1.5H).
MS:ESI 585(M+1)
实施例50
2-(3-((N-(3-(4-氨基-2-丁基-1H-咪唑并[4,5-c]喹啉-1-基)丙基)-2-(4-羟基哌啶-1-基)乙酰氨基)甲基)苯基)乙酸甲酯
通过实施例39的方法,使用来自步骤(i)的产物(600mg)和4-羟基哌啶制备标题化合物,得到标题化合物(660mg),其为固体。
1H NMR(DMSO-d6)δ8.01(0.5H,d),7.93(0.5H,d),7.60(1H,dd),7.43-7.38(1H,m),7.26-7.19(2H,m),7.13-7.10(2H,m),7.00(1H,brs),6.45(2H,brs),4.68(1H,s),4.54-4.50(2H,m),4.46(1H,s),4.41-4.37(1H,m),3.63(1H,s),3.59(1H,s),3.56(1.5H,s),3.55(1.5H,s),3.52-3.43(1H,m),3.41-3.28(1H,m),3.11(1H,s),2.95(1H,s),2.85-2.80(2H,m),2.68-2.58(1H,m),2.51-2.47(1H,m),2.16-2.12(2H,m),2.00-1.88(2H,m),1.79-1.68(2H,m),1.65-1.53(2H,m),1.48-1.33(2H,m),1.32-1.23(2H,m),0.95-0.90(3H,m).
MS:ESI 601(M+1)
实施例51
2-(3-((N-(3-(4-氨基-2-丁基-1H-咪唑并[4,5-c]喹啉-1-基)丙基)-2-(4-甲氧基哌啶-1-基)乙酰氨基)甲基)苯基)乙酸甲酯
通过实施例39的方法,使用来自步骤(i)的产物(300mg)和4-甲氧基哌啶制备标题化合物,得到标题化合物(230mg),其为胶状物。
1H NMR(DMSO-d6)δ8.00(0.5H,d),7.93(0.5H,d),7.61-7.58(1H,m),7.43-7.37(1H,m),7.26-7.19(2H,m),7.13-7.09(2H,m),7.00(1H,brs),6.45(2H,brd),4.67(1H,s),4.54-4.50(1H,m),4.46(1H,s),4.41-4.37(1H,m),3.62(1H,s),3.59(1H,s),3.57(1.5H,s),3.55(1.5H,s),3.52-3.36(2H,m),3.17(1.5H,s),3.16(1.5H,s),3.13(1H,s),3.12-3.00(1H,m),2.94(1H,s),2.86-2.81(2H,m),2.68-2.63(1H,m),2.53-2.49(1H,m),2.18-2.00(2H,m),1.98-1.88(2H,m),1.80-1.63(4H,m),1.44-1.25(4H,m),0.95-0.90(3H,m).
MS:ESI 615(M+1)
实施例52
2-(3-((N-(3-(4-氨基-2-丁基-1H-咪唑并[4,5-c]喹啉-1-基)丙基)-2-(4-(二甲基氨基甲酰基)哌啶-1-基)乙酰氨基)甲基)苯基)乙酸甲酯
通过实施例39的方法,使用来自步骤(i)的产物(300mg)和N,N-二甲基哌啶-4-甲酰胺制备标题化合物,得到标题化合物(265mg),其为胶状物.
1H NMR(DMSO-d6)δ8.00(0.5H,d),7.93(0.5H,d),7.61-7.58(1H,m),7.43-7.38(1H,m),7.27-7.19(2H,m),7.16-7.09(2H,m),7.00-6.99(1H,m),6.45(2H,brs),4.67(1H,s),4.54-4.50(1H,m),4.46(1H,s),4.41-4.37(1H,m),3.64(1H,s),3.58(1H,s),3.57(1.5H,s),3.55(1.5H,s),3.50-3.47(1H,m),3.41-3.37(1H,m),3.33(1H,s),3.14(1H,s),2.98(1.5H,s),2.95(1.5H,s),2.93(1H,s),2.86-2.74(6H,m),2.68-2.64(1H,m),2.07-1.84(4H,m),1.78-1.70(2H,m),1.55-1.37(6H,m),0.95-0.90(3H,m
MS:ESI 656(M+1)
实施例53
2-(3-((N-(3-(4-氨基-2-丁基-1H-咪唑并[4,5-c]喹啉-1-基)丙基)-2-吗啉代乙酰氨基)甲基)苯基)乙酸甲酯
通过实施例39的方法,使用来自步骤(i)的产物(300mg)和吗啉制备标题化合物,得到标题化合物(294mg),其为固体。
1H NMR(DMSO-d6)δ8.03(0.5H,d),7.95(0.5H,d),7.63-7.59(1H,m),7.42(1H,dd),7.30-7.20(2H,m),7.15-7.08(2H,m),7.04-7.01(1H,m),6.46(2H,d),4.68(1H,s),4.55(1H,t),4.47(1H,s),4.41(1H,t),3.64(1H,s),3.60(1H,s),3.58(1.5H,s),3.57(1.5H,s),3.51-3.39(6H,m),3.17(1H,s),2.98(1H,s),2.88-2.82(2H,m),2.41-2.37(2H,m),2.25-2.20(2H,m),2.15-2.06(1H,m),2.00-1.91(1H,m),1.82-1.72(2H,m),1.47-1.37(2H,m),0.94(1.5H,t),0.93(1.5H,t)
MS:ESI 587(M+1)
实施例54
2-(3-((N-(3-(4-氨基-2-丁基-1H-咪唑并[4,5-c]喹啉-1-基)丙基)-2-((2S,6R)-2,6-二甲基吗啉代)乙酰氨基)甲基)苯基)乙酸甲酯
通过实施例39的方法,使用来自步骤(i)的产物(206mg)和顺式-2,6-二甲基吗啉制备标题化合物,得到标题化合物(232mg),其为固体。
1H NMR(CDCl3)δ7.86-7.84(2H,m),7.55-7.51(1H,m),7.35-7.31(1H,m),7.25-7.21(1H,m),7.14-7.12(1H,m),7.03-6.99(2H,m),5.73(1.5H,brs),5.56(0.5H,brs),4.63(1.5H,s),4.57(0.5H,s),4.42(2H,t),3.68-3.64(5H,m),3.58-3.49(4H,m),3.22(1.5H,s),2.92(0.5H,s),2.86-2.75(4H,m),2.24-2.05(2H,m),1.89-1.81(4H,m),1.51-1.45(2H,m),1.12-1.10(6H,m),0.99(3H,t).
MS:ESI 615(M+1)
实施例55
2-(3-((N-(3-(4-氨基-2-丁基-1H-咪唑并[4,5-c]喹啉-1-基)丙基)-2-(4-甲基哌嗪-1-基)乙酰氨基)甲基)苯基)乙酸甲酯
通过实施例39的方法,使用来自步骤(i)的产物(300mg)和1-甲基哌嗪制备标题化合物,得到标题化合物(320mg),其为胶状物.
1H NMR(CDCl3)δ7.85(1H,m),7.53(1H,m),7.36(1H,m),7.23(2H,m),7.13(1H,m),7.04-7.00(2H,m),5.61(2H,brs),4.66(2H,s),4.44(2H,t,J=7.6Hz),3.67(3H,s),3.56(2H,s),3.51(2H,t),3.25(2H,s),2.84(2H,t),2.67-2.25(6H,m),2.21(3H,s),2.20-2.03(4H,m),1.87-1.79(2H,m),1.52-1.44(2H,m),1.00(3H,t).
MS:ESI 600(M+1)
实施例56
2-(3-((N-(3-(4-氨基-2-丁基-1H-咪唑并[4,5-c]喹啉-1-基)丙基)-2-(4-(2-羟基乙基)哌嗪-1-基)乙酰氨基)甲基)苯基)乙酸甲酯
通过实施例39的方法,使用来自步骤(i)的产物(300mg)和哌嗪-1-乙醇制备标题化合物,得到标题化合物(337mg),其为固体。
1H NMR(CDCl3)δ7.86(1H,m),7.54(1H,m),7.37(1H,m),7.24(2H,m),7.13(1H,m),7.08-6.99(2H,m),5.81(2H,brs),4.66(2H,s),4.45(2H,t),3.67(3H,s),3.58(2H,s),3.52(2H,t),3.48(1H,brs),3.26(2H,s),2.85(2H,t),2.67-2.03(14H,m),1.88-1.81(2H,m),1.52-1.45(2H,m),1.00(3H,t).
MS:ESI 630(M+1)
实施例57
2-(3-((N-(3-(4-氨基-2-丁基-1H-咪唑并[4,5-c]喹啉-1-基)丙基)-2-(4-(2-甲氧基乙基)哌嗪-1-基)乙酰氨基)甲基)苯基)乙酸甲酯
通过实施例39的方法,使用来自步骤(i)的产物(300mg)和1-(2-甲氧基乙基)哌嗪制备标题化合物,得到标题化合物(354mg),其为胶状物。
1H NMR(CDCl3)δ7.87(1H,m),7.54(1H,m),7.38(1H,m),7.24(2H,m),7.14(1H,m),7.06-6.99(2H,m),5.93(2H,brs),4.67(2H,s),4.43(2H,t),3.67(3H,s),3.57(2H,s),3.56-3.46(4H,m),3.32(3H,s),3.25(2H,s),2.84(2H,t),2.59-2.20(10H,m),2.12-2.05(2H,m),1.87-1.80(2H,m),1.52-1.45(2H,m),1.00(3H,t).
MS:ESI 644(M+1)
实施例58
2-(3-((2-(4-乙酰基哌嗪-1-基)-N-(3-(4-氨基-2-丁基-1H-咪唑并[4,5-c]喹啉-1-基)丙基)乙酰氨基)甲基)苯基)乙酸甲酯
通过实施例39的方法,使用来自步骤(i)的产物(300mg)和1-乙酰基哌嗪制备标题化合物,得到标题化合物(333mg),其为固体。
1H NMR(CDCl3)δ7.85(1H,m),7.54(1H,m),7.33(1H,m),7.24(2H,m),7.14(1H,m),7.04-6.97(2H,m),5.72(2H,brs),4.67(2H,s),4.43(2H,t),3.67(3H,s),3.63-3.27(6H,m),3.56(2H,s),3.28(2H,s),2.85(2H,t),2.56-2.07(6H,m),2.06(3H,s),1.86-1.81(2H,m),1.52-1.45(2H,m),1.00(3H,t).
MS:ESI 628(M+1)
实施例59
2-(3-((N-(3-(4-氨基-2-丁基-1H-咪唑并[4,5-c]喹啉-1-基)丙基)-2-(4-(甲基磺酰基)哌嗪-1-基)乙酰氨基)甲基)苯基)乙酸甲酯
通过实施例39的方法,使用来自步骤(i)的产物(297mg)和1-甲磺酰基-哌嗪制备标题化合物,得到标题化合物(286mg),其为固体。
1H NMR(DMSO-d6)δ8.03(0.5H,d),7.96(0.5H,d),7.61(1H,d),7.43(1H,dd),7.30-7.21(2H,m),7.15-7.06(2H,m),7.04-7.02(1H,m),6.51(1H,brs),6.48(1H,brs),4.66(1H,s),4.55(1H,t),4.47(1H,s),4.43(1H,t),3.66(1H,s),3.61(1H ,s),3.58(1.5H,s),3.57(1.5H,s),3.50-3.42(2H,m),3.31(2H,s),3.25(1H,s),3.04(1H,s),2.98-2.90(4H,m),2.89-2.82(2H,m),2.78(1.5H,s),2.77(1.5H,s),2.36-2.30(2H,m),2.12-2.05(1H,m),2.02-1.94(1H,m),1.82-1.73(2H,m),1.46-1.38(2H,m),0.96-0.91(3H,m).
MS:ESI 664(M+1)
实施例60
2-(3-((N-(3-(4-氨基-2-丁基-1H-咪唑并[4,5-c]喹啉-1-基)丙基)-2-(氮杂环庚烷-1-基)乙酰氨基)甲基)苯基)乙酸甲酯
通过实施例39的方法,使用来自步骤(i)的产物(201mg)和高哌啶制备标题化合物,得到标题化合物(221mg),其为胶状物。
1H NMR(CDCl3)δ7.87(0.5H,d),7.84(1.5H,d),7.54-7.50(1H,m),7.32-7.30(1H,m),7.22(1H,d),7.14-7.12(1H,m),7.03-7.01(2H,m),5.59(1.5H,brs),5.50(0.5H,brs),4.73(1.5H,s),4.57(0.5H,s),4.43(2H,t),3.67(3H,s),3.57(2H,s),3.52(2H,t),3.38(1.5H,s),3.23(0.5H,s),2.87-2.78(2H,m),2.71(3H,t),2.57(1H,t),2.25-2.04(2H,m),1.85-1.81(2H,m),1.68-1.53(8H,m),1.51-1.45(2H,m),0.99(3H,t).
MS:ESI 599(M+1)
实施例61
2-(3-((N-(3-(4-氨基-2-丁基-1H-咪唑并[4,5-c]喹啉-1-基)丙基)-2-(1,4-氧杂氮杂环庚烷-4-基)乙酰氨基)甲基)苯基)乙酸甲酯
通过实施例39的方法,使用来自步骤(i)的产物(257mg)和高吗啉制备标题化合物,得到标题化合物(276mg),其为固体。
1H NMR(CDCl3)δ8.02(1/2H,d),7.96(1/2H,d),7.63-7.60(1H,m),7.45-7.40(1H,m),7.30-7.21(2H,m),7.16-7.01(3H,m),6.46(2H,brs),4.68(1H,s),4.57-4.51(1H,m),4.48(1H,s),4.44-4.39(1H,m),3.68-3.29(7H,m),3.58(3/2H,s),3.57(3/2H,s),3.16(1H,s),2.89-2.81(2H,m),2.78-2.65(5H,m),2.17-2.08(1H,m),2.01-1.92(1H,m),1.81-1.61(5H,m),1.48-1.37(2H,m),0.94(3/2H,t),0.94(3/2H,t).
MS:ESI 601(M+1)
实施例62
2-(3-((N-(3-(4-氨基-2-丁基-1H-咪唑并[4,5-c]喹啉-1-基)丙基)-2-(4-甲基-1,4-二氮杂环庚烷-1-基)乙酰氨基)甲基)苯基)乙酸甲酯
通过实施例39的方法,使用来自步骤(i)的产物(200mg)和N-甲基高哌嗪制备标题化合物,得到标题化合物(200mg),其为胶状物。
1H NMR(CDCl3)δ7.86-7.82(2H,m),7.53-7.49(1H,m),7.33-7.31(1H,m),7.25-7.21(1H,m),7.14-7.12(1H,m),7.02-6.99(2H,m),5.46(2H,brs),4.65(1.5H,s),4.56(0.5H,s),4.43(2H,t),3.67(3H,s),3.57-3.49(4H,m),3.41(1.5H,s),3.16(0.5H,s),2.87-2.80(5H,m),2.66-2.56(5H,m),2.35(2.25H,s),2.34(0.75H,s),2.22-2.04(4H,m),1.85-1.81(4H,m),0.99(3H,t).
MS:ESI 614(M+1)
实施例63
2-(3-((2-(4-乙酰基-1,4-二氮杂环庚烷-1-基)-N-(3-(4-氨基-2-丁基-1H-咪唑并[4,5-c]喹啉-1-基)丙基)乙酰氨基)甲基)苯基)乙酸甲酯
通过实施例39的方法,使用来自步骤(i)的产物(270mg)和N-乙酰基高哌嗪制备标题化合物,得到标题化合物(290mg),其为固体。
1H NMR(CDCl3)δ7.82-7.86(2H,m),7.52(1H,m),7.15-7.32(4H,m),6.81-7.00(1H,m),5.59(2H,brs),4.60(2H,d),4.43(2H,t),3.40-3.69(13H,m),2.73-2.86(5H,m),1.81-2.07(12H,m),1.46-1.52(2H,m),1.25(2H,m),0.98-1.01(3H,m).
MS:ESI 642(M+1)
实施例64
2-(3-((N-(3-(4-氨基-2-丁基-1H-咪唑并[4,5-c]喹啉-1-基)丙基)-2-(4-(乙基氨基甲酰基)-1,4-二氮杂环庚烷-1-基)乙酰氨基)甲基)苯基)乙酸甲酯
通过实施例39的方法,使用来自步骤(i)的产物(300mg)和N-乙基-1,4-二氮杂环庚烷-1-甲酰胺制备标题化合物,得到标题化合物(146mg),其为固体。
1H NMR(CDCl3)δ7.83-7.86(2H,m),7.52(1H,t),6.97-7.33(5H,m),5.59(2H,brs),4.55(2H,s),4.40-4.45(2H,m),3.68(3H,d),3.55-3.59(5H,m),3.38(4H,m),3.22-3.25(2H,m),2.73-2.78(3H,m),1.81-2.05(9H,m),1.47-1.49(2H,m),1.26-1.28(2H,m),1.10(3H,t),0.99(3H,t).
MS:ESI 671(M+1)
实施例65
2-(3-((N-(3-(4-氨基-2-丁基-1H-咪唑并[4,5-c]喹啉-1-基)丙基)-2-(4-(甲基磺酰基)-1,4-二氮杂环庚烷-1-基)乙酰氨基)甲基)苯基)乙酸甲酯
通过实施例39的方法,使用来自步骤(i)的产物(301mg)和1-(甲基磺酰基)-1,4-二氮杂环庚烷制备标题化合物,得到标题化合物(239mg),其为固体。
1H NMR(DMSO-d6)δ8.02(0.5H,d),7.98(0.5H,d),7.61(1H,d),7.45-7.40(1H,m),7.29-7.20(2H,m),7.15-7.06(2H,m),7.04-7.01(1H,m),6.48(1H,brs),6.46(1H,brs),4.64(1H,s),4.53(1H,t),4.47(1H,s),4.44(1H,t),3.65(1H,s),3.61(1H,s),3.58(1.5H,s),3.57(1.5H,s),3.43-3.40(3H,m),3.30(1H,s),3.27-3.21(3H,m),3.17(1H,t),3.12-3.08(1H,m),2.88-2.84(2H,m),2.83(1.5H,s),2.82(1.5H,s),2.75-2.66(2H,m),2.60-2.51(1H,m),2.12-2.06(1H,m),2.00-1.94(1H,m),1.78-1.72(2H,m),1.70-1.65(1H,m),1.65-1.57(1H,m),1.46-1.38(2H,m),0.96-0.91(3H,m).
MS:ESI 678(M+1)
实施例66
2-(4-((N-(3-(4-氨基-2-丁基-1H-咪唑并[4,5-c]喹啉-1-基)丙基)-2-(4-(2-甲氧基乙基)哌嗪-1-基)乙酰氨基)甲基)苯基)乙酸甲酯
通过实施例39的方法,使用实施例1步骤(i)的产物制备标题化合物。该产物(204mg)与1-(2-甲氧基乙基)哌嗪反应,得到标题化合物(223mg),其为胶状物。
1H NMR(DMSO-d6)δ8.00(0.5H,d,7.93(0.5H,d),7.61-7.59(1H,m),7.41(1H,t),7.30-7.14(4H,m),7.06(1H,d),6.45(2H,brs),4.66(1H,s),4.53(1H,t),4.44(1H,s),4.40(1H,t),3.63(1H,s),3.62(1H,s),3.59(3H,s),3.48-3.37(2H,m),3.36-3.31(4H,m),3.19(1.5H,s),3.17(1.5H,s),3.13(1H,s),2.97(1H,s),2.87-2.81(2H,m),2.38-2.29(4H,m),2.27-2.19(4H,m),2.15-2.08(1H,m),1.98-1.90(1H,m),1.80-1.70(2H,m),1.46-1.37(2H,m),0.95-0.91(3H,m)
MS:ESI 644(M+1)
实施例67
2-(4-((2-(4-乙酰基-1,4-二氮杂环庚烷-1-基)-N-(3-(4-氨基-2-丁基-1H-咪唑并[4,5-c]喹啉-1-基)丙基)乙酰氨基)甲基)苯基)乙酸甲酯
通过实施例39的方法,使用实施例1步骤(i)的产物制备标题化合物。该产物(290mg)与N-乙酰基高哌嗪反应,得到标题化合物(220mg),其为固体。
1H NMR(CDCl3)δ7.83-7.86(2H,m),7.52(1H,t),7.18-7.33(3H,m),7.02-7.08(2H,m),5.69(2H,brs),4.59(2H,d),3.70(3H,s),3.40-3.64(9H,m),2.73-2.87(5H,m),2.05-2.09(5H,m),1.80-1.87(11H,m),1.46-1.52(2H,m),1.26(2H,m),0.99(3H,t)
MS:ESI 642(M+1)
实施例68
2-(4-((N-(3-(4-氨基-2-丁基-1H-咪唑并[4,5-c]喹啉-1-基)丙基)-2-(4-(甲基磺酰基)-1,4-二氮杂环庚烷-1-基)乙酰氨基)甲基)苯基)乙酸甲酯
通过实施例39的方法,使用实施例1步骤(i)的产物制备标题化合物。该产物(293mg)与1-(甲基磺酰基)-1,4-二氮杂环庚烷反应,得到标题化合物(291mg),其为固体。
1H NMR(DMSO-d6)δ8.02(0.5H,d),7.96(0.5H,d),7.61(1H,d),7.43(1H,dd),7.27-7.21(2H,m),7.17-7.13(2H,m),7.09-7.05(1H,m),6.51(2H,brs),4.63(1H,s),4.54(1H,t),4.44(1H,s),4.42(1H,t),3.64(1H,s),3.62(1H,s),3.60(3H,s),3.43-3.40(3H,m),3.32(1H,s),3.27-3.21(3H,m),3.17(1H,t),3.12-3.08(1H,m),2.90-2.83(2H,m),2.83(3H,s),2.75-2.66(2H,m),2.60-2.51(1H,m),2.12-2.05(1H,m),2.00-1.95(1H,m),1.78-1.72(2H,m),1.70-1.65(1H,m),1.65-1.57(1H,m),1.46-1.38(2H,m),0.94(3H,t).
MS:ESI 678(M+1)
实施例69
2-(4-((2-((1-乙酰基哌啶-4-基)(甲基)氨基)-N-(3-(4-氨基-2-丁基-1H-咪唑并[4,5-c]喹啉-1-基)丙基)乙酰氨基)甲基)苯基)乙酸甲酯
通过实施例39的方法,使用实施例1步骤(i)的产物制备标题化合物。该产物(329mg)与1-乙酰基-N-甲基哌啶-4-胺反应,得到标题化合物(63mg),其为胶状物。
1H NMRδ(DMSO-d6)8.00(0.5H,d),7.94(0.5H,d),7.62-7.58(1H,m),7.43-7.38(1H,m),7.24-7.08(5H,m),6.49(2H,brs),4.66(1H,s),4.53-4.49(1H,m),4.46-4.30(3H,m),3.76-3.70(1H,m),3.63(1H,s),3.62(1H,s),3.58(3H,s),3.48-3.33(2H,m),3.27(1H,s),3.14(1H,s),2.86-2.81(3H,m),2.65-2.30(2H,m),2.18(1.5H ,s),2.17-2.08(1H,m),2.00(1.5H,s),1.99-1.91(4H,m),1.76-1.72(2H,m),1.68-1.54(1H,m),1.52-1.38(3H,m),1.30-1.02(2H,m),0.93(3H,t).
MS:ESI 656(M+1)
实施例70
2-(4-((N-(3-(4-氨基-2-(2-甲氧基乙基)-1H-咪唑并[4,5-c]喹啉-1-基)丙基)-2-(4-甲基哌嗪-1-基)乙酰氨基)甲基)苯基)乙酸甲酯
通过实施例29步骤(vi)的方法,使用N-甲基哌嗪(193mg)和实施例29步骤(v)的产物(207mg)制备标题化合物。得到标题化合物,其为白色固体。51mg。
1H NMR(DMSO-d6)δ8.03-7.91(m,1H),7.63-7.60(m,1H),7.45-7.41(m,1H),7.26-7.07(m,5H),6.45(brs,2H),4.68-4.46(m,4H),3.83-3.78(m,2H),3.64-3.63(m,2H),3.60(s,3H),3.51-3.39(m,2H),3.31-3.27(m,5H),3.15-3.01(m,4H),2.42-1.92(m,11H).
MS:多模式+:602
实施例71
2-(4-((N-(3-(4-氨基-2-(2-甲氧基乙基)-1H-咪唑并[4,5-c]喹啉-1-基)丙基)-2-(4-(2-甲氧基乙基)哌嗪-1-基)乙酰氨基)甲基)苯基)乙酸甲酯
通过实施例29步骤(vi)的方法,使用1-(2-甲氧基乙基)哌嗪(241mg)和实施例29步骤(v)的产物(180mg)制备标题化合物。得到标题化合物,其为无色固体。14mg。
1H NMR(DMSO-d6)δ8.02-7.94(m,1H),7.62(d,1H),7.45-7.41(m,1H),7.29-7.14(m,4H),7.09(d,1H),6.46(s,2H),4.71-4.34(m,4H),3.86-3.75(m,2H),3.65-3.62(m,2H),3.61-3.58(m,3H),3.53-3.38(m,2H),3.38-3.25(m,8H),3.21-3.18(m,3H),3.17-3.09(m,3H),2.43-2.17(m,8H),2.16-1.90(m,2H)
MS:多模式+:646
实施例72
2-(3-((N-(3-(4-氨基-2-(2-甲氧基乙基)-1H-咪唑并[4,5-c]喹啉-1-基)丙基)-2-(4-甲基哌嗪-1-基)乙酰氨基)甲基)苯基)乙酸甲酯
通过实施例29步骤(vi)的方法,使用N-甲基哌嗪(125mg)和实施例31步骤(i)的产物(115mg)制备标题化合物。得到标题化合物,其为胶状物。26mg。
1H NMR(DMSO-d6)δ8.03-7.92(m,1H),7.63-7.61(m,1H),7.45-7.41(m,1H),7.27-7.23(m,1H),7.21-7.12(m,1H),7.03(m,1H),6.45(brs,2H),4.68-4.48(m,4H),3.83-3.77(m,2H),3.64-3.60(m,2H),3.59-3.57(m,3H),3.56-3.39(m,2H),3.31-3.27(m,5H),3.16-3.00(m,4H),2.42-1.94(m,11H).
MS:多模式+:602
实施例73
2-(3-((N-(3-(4-氨基-2-(2-甲氧基乙基)-1H-咪唑并[4,5-c]喹啉-1-基)丙基)-2-(4-(2-甲氧基乙基)哌嗪-1-基)乙酰氨基)甲基)苯基)乙酸甲酯
通过实施例29步骤(vi)的方法,使用1-(2-甲氧基乙基)哌嗪(180mg)和实施例31步骤(i)的产物(115mg)制备标题化合物。得到标题化合物,其为胶状物。34mg
1H NMR(DMSO-d6)δ8.02-7.92(m,1H),7.62-7.60(m,1H),7.45-7.41(m,1H),7.27-7.21(m,1H),7.15-7.11(m,1H),7.03(m,1H),6.45(brs,2H),4.70-4.41(m,4H),3.83-3.77(m,2H),3.64-3.59(m,5H),3.56-3.39(m,2H),3.31-3.98(m,9H),2.41-1.92(m,10H).
MS:多模式+:646
实施例74
2-(4-((N-(3-(4-氨基-2-丁基-1H-咪唑并[4,5-c]喹啉-1-基)丙基)-2-(二甲基氨基)乙酰氨基)甲基)苯基)乙酸甲酯·二甲磺酸盐
将甲磺酸(0.048mL,0.73mmol)加入到来自实施例3的产物(0.2g)于MeCN(10mL)中的溶液中。将悬浮液搅拌3小时,蒸发溶剂。所得固体悬浮在MeCN(2mL)中,搅拌7天。使用离心机过滤混合物,室温干燥并运行XRPD,证实了形成多晶型物A。
实施例75
2-(4-((N-(3-(4-氨基-2-丁基-1H-咪唑并[4,5-c]喹啉-1-基)丙基)-2-(二甲基氨基)乙酰氨基)甲基)苯基)乙酸甲酯·单糖精盐
将于MeOH(1mL)中的糖精(53mg)加入到来自实施例3的产物(160mg)于MeOH(1mL)中的溶液中,在室温搅拌1小时,除去溶剂。将所得残余物溶解在THF(1mL)中,加入MeCN(1mL),搅拌9天。使用离心机过滤出固体,干燥并运行XRPD(参见,图1A)。当在水,MeCN和MeOH中浆化时也形成的相同的多晶型物。
DSC:167℃±2℃.
实施例76
2-(4-((N-(3-(4-氨基-2-丁基-1H-咪唑并[4,5-c]喹啉-1-基)丙基)-2-(二甲基氨基)乙酰氨基)甲基)苯基)乙酸甲酯·二糖精盐
将于MeOH(1mL)中的糖精(106mg)加入到于甲醇(1mL)中的实施例3的产物(160mg)中。将所得残余物溶解在THF(2mL)中,搅拌9天。使用离心机过滤出固体,干燥并运行XRPD(参见图2A)。当在二噁烷、EtOAc∶乙醚(1∶1)、MeCN、EtOAc∶MeCN(1∶1)和THF∶MeCN(1∶1)中搅拌时形成相同的多晶型物。
DSC:200℃±2℃.
实施例77
2-(4-((N-(3-(4-氨基-2-丁基-1H-咪唑并[4,5-c]喹啉-1-基)丙基)-2-(二甲基氨基)乙酰氨基)甲基)苯基)乙酸甲酯,二(1-羟基-萘-2-甲酸)盐
将于MeOH(5mL)中的1-羟基-萘-2-甲酸(138mg)加入到于MeOH(10mL)中的来自实施例3的产物(200mg)中,将溶液在室温搅拌2小时。蒸发溶剂,加入EtOAc(6mL),将混合物在室温搅拌40小时。过滤固体并干燥,运行XRPD(参见图3A)。当在MeOH和EtOH中浆化时也形成了相同的多晶型物(A)。在丙酮、DCM、水和异己烷中浆化时形成了另一种多晶型物(B)(参见图3C)。
DSC(多晶型物A):在120℃±5℃(起始)经历相变。所得相C在153℃±2℃(起始)熔化。
DSC(多晶型物B):熔化起始温度:152℃±2℃
实施例78
2-(4-((N-(3-(4-氨基-2-丁基-1H-咪唑并[4,5-c]喹啉-1-基)丙基)-2-(二甲基氨基)乙酰氨基)甲基)苯基)乙酸甲酯·二苯磺酸盐
将于MeCN(5mL)中的苯磺酸(116mg)加入到于MeCN(10mL)中的来自实施例3的产物(200mg)中。蒸发溶剂,加入EtOAc(12mL),将所得溶液在室温搅拌5天。过滤固体,干燥并运行XRPD(参见图4A)。
实施例79
2-(4-((N-(3-(4-氨基-2-丁基-1H-咪唑并[4,5-c]喹啉-1-基)丙基)-2-(二甲基氨基)乙酰氨基)甲基)苯基)乙酸甲酯·扁桃酸盐
将扁桃酸(56mg)加入到于MeCN(5mL)中的来自实施例3的产物(200mg)中。蒸发溶剂,将所得胶状物在乙醚中浆化4天。过滤固体,干燥并运行XRPD(参见图5A)。
DSC:熔化起始温度:104℃±2℃
实施例80
2-(4-((N-(3-(4-氨基-2-丁基-1H-咪唑并[4,5-c]喹啉-1-基)丙基)-2-(二甲基氨基)乙酰氨基)甲基)苯基)乙酸甲酯·富马酸盐
将溶解在MeOH(10mL)中的富马酸(85mg)加入到于MeOH(10mL)中的实施例3的产物中,搅拌20分钟。除去溶剂,将所得胶状物在EtOAc(5mL)和THF(5mL)的混合物中搅拌10天,然后过滤并运行XRPD(参见图6A)。
DSC:熔化起始温度:175℃±2℃
实施例81
2-(4-((N-(3-(4-氨基-2-丁基-1H-咪唑并[4,5-c]喹啉-1-基)丙基)-2-(二甲基氨基)乙酰氨基)甲基)苯基)乙酸甲酯·二甲磺酸盐
将甲磺酸(0.024mL)加入到于乙腈(10mL)中的来自实施例3的产物(0.2g)中。将混合物搅拌3小时,过滤固体,干燥并运行XRPD,得到多晶型物A(参见图7A)。在室温,在EtOAc中浆化该固体2天,得到多晶型物B(参见图7C)。
DSC(多晶型物A):熔化起始温度:218℃±2℃。
生物测定
人TLR7测定
将人TLR7(由EMBL序列AF240467表示)最常见的变异序列克隆到哺乳动物细胞表达载体pUNO中并转染到已经稳定表达pNiFty2-SEAP报道质粒的HEK293细胞系中;通过用抗生素Zeocin选择来维持所述报道基因的整合。使用抗生素杀稻瘟素选择具有稳定TLR7表达的转染子。在该报道细胞系中,通过NFkB/ELAM-1复合启动子控制分泌的碱性磷酸酶(SEAP)的表达,所述NFkB/ELAM-1复合启动子包含与近端ELAM-1启动子结合的5个NFkB位点。TLR信号传导导致NFkB的易位,以及启动子的活化引起SEAP基因的表达。TLR7-特异性活化通过确定SEAP的水平来评估,所述SEAP是在将细胞在37℃在0.1%(v/v)二甲基亚砜(DMSO)存在下用标准化合物培养过夜产生的。将SEAP经由化合物的浓度依赖性诱导产生表达为产生针对所述化合物的SEAP诱导的最大水平的一半时所述化合物的浓度(pEC50)。
实施例编号 | pEC50 | 实施例编号 | pEC50 |
1 | 6.5 | 2 | 6.4 |
3 | 7.1 | 4 | 7.4 |
5 | 6.5 | 6 | 6.6 |
7 | 6.4 | 8 | 6.5 |
9 | 6.2 | 10 | 6.3 |
11 | 6.6 | 12 | 6.6 |
13 | 6.8 | 14 | 6.6 |
15 | 6.4 | 16 | 6.9 |
17 | 6.8 | 18 | 7.2 |
19 | 6.6 | 20 | 6.6 |
21 | 6.2 | 22 | 6.2 |
23 | 6.6 | 24 | 7.1 |
25 | 6.7 | 26 | 6.5 |
27 | 7.4 | 28 | 6.7 |
29 | 7.0 | 30 | 6.7 |
31 | 6.8 | 32 | 6.8 |
33 | 6.8 | 34 | 6.5 |
实施例编号 | pEC50 | 实施例编号 | pEC50 |
35 | 6.7 | 36 | 6.7 |
37 | 6.4 | 38 | 5.8 |
39 | 6.8 | 40 | 6.9 |
41 | 7.1 | 42 | 5.8 |
43 | 6.9 | 44 | 6.6 |
45 | 5.8 | 46 | 7.2 |
47 | 6.4 | 48 | 6.4 |
49 | 7.1 | 50 | 6.3 |
51 | 6.7 | 52 | 6.2 |
53 | 6.1 | 54 | 6.0 |
55 | 7.1 | 56 | 6.3 |
57 | 7.3 | 58 | 5.9 |
59 | 6.1 | 60 | 7.1 |
61 | 6.4 | 62 | 6.6 |
63 | 6.3 | 64 | 5.9 |
65 | 6.2 | 66 | 6.8 |
67 | 6.3 | 68 | 6.3 |
69 | 6.4 | 70 | 6.4 |
71 | 6.7 | 72 | 6.3 |
73 | 6.3 |
实施例3化合物在大鼠哮喘模型中对抗原诱导的肺部炎症的作用
用与Underwood et al(B ritish Journal of Pharmacology 2002;137:263-275,2002)描述的方式相似的方式,使大鼠敏化和刺激,产生变应性气道炎症。在第0天,用卵清蛋白(OVA)和氢氧化铝使雄性Brown Norway大鼠皮下敏化,并在第14天用雾化OVA溶液刺激。在OVA-刺激前的24小时和OVA-刺激后的24小时,气管内给药实施例3化合物两次,在OVA-刺激后的48小时收集支气管肺泡灌洗液(BALF)。然后测量BALF中的嗜酸性粒细胞和Th2细胞因子(IL-5和IL-13)以评价实施例3化合物的效力。所得结果显示在下表中。
BALF中的嗜酸性粒细胞和Th2细胞因子
组 剂量 嗜酸性粒细胞 IL-5 IL-13
(pg/ml (pg/ml
(n=8) (mg/kg) (cells/BALF)
BALF) BALF)
常规对照 - 7.5±3.5 3.8±3.8 <4.9
OVA-刺激对照 - 476.7±142.8 418.9±151.0 103.2±50.5
实施例3 0.1 67.2±16.3 18.0±8.7 <4.9
实施例3 1 36.2±11.3 11.3±7.5 <4.9
平均值±SE(n=8)
Claims (23)
1.式(I)化合物或其药用盐,
其中,
R1表示直链C1-C6烷基,所述C1-C6烷基任选被一个或多个独立选自卤素、氰基、羟基和C1-C3烷氧基的取代基取代;
Z1表示C2-C6亚烷基或C3-C8亚环烷基;
X1表示NR5或>N-COR5;
Y1表示单键或C1-C6亚烷基;
R3表示C1-6烷基,所述C1-6烷基任选被C1-6烷氧基取代;
R5表示氢、任选在哌啶环的氮上被R10取代的哌啶基、C1-C6烷基或C3-C6环烷基,其中所述C1-C6烷基或C3-C6环烷基任选被一个或多个独立选自NR7R8或R9的取代基取代,
或者,R5为C1-C6亚烷基,所述C1-C6亚烷基与C2-C6亚烷基Z1中的碳原子相连,从而形成哌啶环;
R7和R8各自独立地表示氢、四氢吡喃基、任选在哌啶环的氮上被R10a取代的哌啶基、C1-C6烷基或C3-C6环烷基,其中所述C1-C6烷基或C3-C6环烷基任选被一个或多个独立选自如下的基团取代:卤素、氰基、S(O)qR11、OR12、CO2R12、OC(O)R12、SO2NR12R13、CONR12R13、NR12R13、NR12SO2R14或NR12COR13,
或者,R7和R8与它们所连接的氮原子一起形成选自氮杂环丁烷基、吡咯烷基、哌啶基、哌嗪基或吗啉基,或含有环氮原子和任选一个独立选自氮和氧的额外杂原子的7-元饱和杂环基,所述杂环基任选被一个或多个独立选自如下的取代基取代:卤素、氰基、S(O)qR15、OR15、CO2R15、COR15、OC(O)R15、SO2NR15R16、CONR15R16、NR15R16、NR15SO2R17、NR15COR16、NR15CO2R16、嘧啶基、卤代C1-C6烷基、C3-C8环烷基和C1-C6烷基,其中所述C3-C8环烷基和C1-C6烷基任选被一个或多个独立选自氰基、S(O)qR18、OR18、CO2R18、SO2NR18R19、CONR18R19或NR18R19的基团取代;
R9表示卤素、氰基、CO2R20、S(O)qR20、OR20、SO2NR20R22、CONR20R22、NR20SO2R21、NR20CO2R21或NR20COR22;
R10和R10a独立表示氢、CO2R23、S(O)qR23、COR24、C1-C6烷基、C2-C6烯基、C2-C6炔基或C3-C8环烷基,每个基团任选被一个或多个独立选自卤素、氰基、OR25或NR25R26的取代基取代;
R6、R11、R12、R13、R15、R16、R18、R19、R20、R22、R24、R25和R26各自独立地表示氢、C1-C6烷基或C3-C6环烷基;
R14、R17、R21和R23各自独立地表示C1-C6烷基或C3-C6环烷基;
q各自独立地表示整数0、1或2;以及
A表示苯基。
2.权利要求1的化合物或其药用盐,其中R1为甲基。
3.权利要求1的化合物或其药用盐,其中Z1为亚正丙基。
4.权利要求1的化合物或其药用盐,其中X1为>NCOR5。
5.权利要求1或权利要求4的化合物或其药用盐,其中R5为氢或C1-C6烷基,所述C1-C6烷基任选被一个或多个选自NR7R8或R9的基团取代,其中R7、R8和R9如权利要求1所定义。
6.权利要求1的化合物或其药用盐,其中Y1表示C1-C6亚烷基。
7.权利要求1的化合物或其药用盐,其中R3为正丁基、甲氧基乙基或乙氧基甲基。
8.权利要求1的化合物或其药用盐,其中Z1为C2-6亚烷基基团。
9.权利要求1的化合物或其药用盐,其中Z1为直链C2-4亚烷基基团。
10.权利要求1的化合物或其药用盐,其中R5为任选被一个或多个基团NR7R8取代的C1-C3烷基,其中R7和R8如权利要求1所定义。
11.权利要求1的化合物或其药用盐,其中Y1表示CH2。
12.权利要求1的化合物或其药用盐,其中R7和R8各自独立地表示四氢吡喃基、N-乙酰基哌啶基,或任选被OR12取代的C1-C4烷基,其中R12如权利要求1所定义。
13.权利要求1的化合物或其药用盐,其中:
R1为甲基;
X1为>NCOR5;
R3为正丁基、甲氧基乙基或乙氧基甲基;
Z1为直链C2-4亚烷基基团;
Y1表示CH2;
R5为任选被一个或多个基团NR7R8取代的C1-C3烷基;以及
R7和R8各自独立地表示四氢吡喃基、N-乙酰基哌啶基,或任选被OR12取代的C1-C4烷基,其中R12如权利要求1所定义。
14.权利要求1的化合物,其选自:
2-(4-((3-(4-氨基-2-丁基-1H-咪唑并[4,5-c]喹啉-1-基)丙基氨基)甲基)苯基)乙酸甲酯,
2-(3-((3-(4-氨基-2-丁基-1H-咪唑并[4,5-c]喹啉-1-基)丙基氨基)甲基)苯基)乙酸甲酯,
2-(4-((N-(3-(4-氨基-2-丁基-1H-咪唑并[4,5-c]喹啉-1-基)丙基)-2-(二甲基氨基)乙酰氨基)甲基)苯基)乙酸甲酯,
2-(3-((N-(3-(4-氨基-2-丁基-1H-咪唑并[4,5-c]喹啉-1-基)丙基)-2-(二甲基氨基)乙酰氨基)甲基)苯基)乙酸甲酯,
2-(3-((4-((4-氨基-2-(乙氧基甲基)-1H-咪唑并[4,5-c]喹啉-1-基)甲基)哌啶-1-基)甲基)苯基)乙酸甲酯·二-三氟乙酸盐,
[4-({[3-(4-氨基-2-丁基-1H-咪唑并[4,5-c]喹啉-1-基)丙基][2-(二甲基氨基)乙基]氨基}甲基)苯基]乙酸甲酯,
2-(3-((N-(3-(4-氨基-2-(乙氧基甲基)-1H-咪唑并[4,5-c]喹啉-1-基)丙基)-2-(二甲基氨基)乙酰氨基)甲基)苯基)乙酸甲酯,
2-(3-(((3-(4-氨基-2-丁基-1H-咪唑并[4,5-c]喹啉-1-基)丙基)(1-甲基哌啶-4-基)氨基)甲基)苯基)乙酸甲酯,
2-(4-(((3-(4-氨基-2-丁基-1H-咪唑并[4,5-c]喹啉-1-基)丙基)(1-甲基哌啶-4-基)氨基)甲基)苯基)乙酸甲酯,
2-(4-((N-(3-(4-氨基-2-丁基-1H-咪唑并[4,5-c]喹啉-1-基)丙基)-2-(4-甲基哌嗪-1-基)乙酰氨基)甲基)苯基)乙酸甲酯,
2-(3-(((3-(4-氨基-2-丁基-1H-咪唑并[4,5-c]喹啉-1-基)丙基)(3-(二甲基氨基)丙基)氨基)甲基)苯基)乙酸甲酯,
2-(3-(((3-(4-氨基-2-丁基-1H-咪唑并[4,5-c]喹啉-1-基)丙基)(3-吗啉代丙基)氨基)甲基)苯基)乙酸甲酯,
2-(3-(((3-(4-氨基-2-丁基-1H-咪唑并[4,5-c]喹啉-1-基)丙基)(3-(乙基(甲基)氨基)丙基)氨基)甲基)苯基)乙酸甲酯,
2-(3-(((3-(4-氨基-2-丁基-1H-咪唑并[4,5-c]喹啉-1-基)丙基)(3-(4-甲基哌嗪-1-基)丙基)氨基)甲基)苯基)乙酸甲酯,
2-(4-((N-(3-(4-氨基-2-丁基-1H-咪唑并[4,5-c]喹啉-1-基)丙基)-2-(甲基磺酰基)乙酰氨基)甲基)苯基)乙酸甲酯,
2-(4-((N-(3-(4-氨基-2-丁基-1H-咪唑并[4,5-c]喹啉-1-基)丙基)乙酰氨基)甲基)苯基)乙酸甲酯,
2-(4-((N-(3-(4-氨基-2-丁基-1H-咪唑并[4,5-c]喹啉-1-基)丙基)-2-吗啉代乙酰氨基)甲基)苯基)乙酸甲酯,
2-(4-((N-(3-(4-氨基-2-丁基-1H-咪唑并[4,5-c]喹啉-1-基)丙基)-2-((2-甲氧基乙基)(甲基)氨基)乙酰氨基)甲基)苯基)乙酸甲酯,
2-(4-((2-(4-乙酰基哌嗪-1-基)-N-(3-(4-氨基-2-丁基-1H-咪唑并[4,5-c]喹啉-1-基)丙基)乙酰氨基)甲基)苯基)乙酸甲酯,
(R)-2-(4-((N-(3-(4-氨基-2-丁基-1H-咪唑并[4,5-c]喹啉-1-基)丙基)-2-(3-羟基吡咯烷-1-基)乙酰氨基)甲基)苯基)乙酸甲酯,
2-(4-((N-(3-(4-氨基-2-丁基-1H-咪唑并[4,5-c]喹啉-1-基)丙基)-2-(4-(嘧啶-2-基)哌嗪-1-基)乙酰氨基)甲基)苯基)乙酸甲酯,
4-(2-((3-(4-氨基-2-丁基-1H-咪唑并[4,5-c]喹啉-1-基)丙基)(4-(2-甲氧基-2-氧代乙基)苄基)氨基)-2-氧代乙基)哌嗪-1-甲酸乙酯,
2-(4-((N-(3-(4-氨基-2-丁基-1H-咪唑并[4,5-c]喹啉-1-基)丙基)-2-(4-(乙基磺酰基)哌嗪-1-基)乙酰氨基)甲基)苯基)乙酸甲酯,
2-(4-((N-(3-(4-氨基-2-丁基-1H-咪唑并[4,5-c]喹啉-1-基)丙基)-2-(哌啶-1-基)乙酰氨基)甲基)苯基)乙酸甲酯,
2-(4-((N-(3-(4-氨基-2-丁基-1H-咪唑并[4,5-c]喹啉-1-基)丙基)-2-(4-(叔丁氧基羰基氨基)哌啶-1-基)乙酰氨基)甲基)苯基)乙酸甲酯,
2-(4-((N-(3-(4-氨基-2-丁基-1H-咪唑并[4,5-c]喹啉-1-基)丙基)-2-(4-(叔丁氧基羰基(甲基)氨基)哌啶-1-基)乙酰氨基)甲基)苯基)乙酸甲酯,
2-(1-(2-((3-(4-氨基-2-丁基-1H-咪唑并[4,5-c]喹啉-1-基)丙基)(4-(2-甲氧基-2-氧代乙基)苄基)氨基)-2-氧代乙基)哌啶-4-基)乙酸乙酯,
1-(2-((3-(4-氨基-2-丁基-1H-咪唑并[4,5-c]喹啉-1-基)丙基)(4-(2-甲氧基-2-氧代乙基)苄基)氨基)-2-氧代乙基)哌啶-4-甲酸甲酯,
2-(4-((N-(3-(4-氨基-2-(2-甲氧基乙基)-1H-咪唑并[4,5-c]喹啉-1-基)丙基)-2-(哌啶-1-基)乙酰氨基)甲基)苯基)乙酸甲酯,
2-(4-((N-(3-(4-氨基-2-(2-甲氧基乙基)-1H-咪唑并[4,5-c]喹啉-1-基)丙基)-2-(二甲基氨基)乙酰氨基)甲基)苯基)乙酸甲酯,
2-(3-((N-(3-(4-氨基-2-(2-甲氧基乙基)-1H-咪唑并[4,5-c]喹啉-1-基)丙基)-2-(哌啶-1-基)乙酰氨基)甲基)苯基)乙酸甲酯,
2-(4-((N-(3-(4-氨基-2-(2-甲氧基乙基)-1H-咪唑并[4,5-c]喹啉-1-基)丙基)-2-((2-甲氧基乙基)(甲基)氨基)乙酰氨基)甲基)苯基)乙酸甲酯,
2-(4-((N-(3-(4-氨基-2-(2-甲氧基乙基)-1H-咪唑并[4,5-c]喹啉-1-基)丙基)-3-(哌啶-1-基)丙酰氨基)甲基)苯基)乙酸甲酯,
2-(4-(((3-(4-氨基-2-(2-甲氧基乙基)-1H-咪唑并[4,5-c]喹啉-1-基)丙基)(3-吗啉代丙基)氨基)甲基)苯基)乙酸甲酯,
(S)-2-(4-((N-(3-(4-氨基-2-(2-甲氧基乙基)-1H-咪唑并[4,5-c]喹啉-1-基)丙基)-2-(2-(甲氧基甲基)吡咯烷-1-基)乙酰氨基)甲基)苯基)乙酸甲酯,
(R)-2-(4-((N-(3-(4-氨基-2-(2-甲氧基乙基)-1H-咪唑并[4,5-c]喹啉-1-基)丙基)-2-(2-(甲氧基甲基)吡咯烷-1-基)乙酰氨基)甲基)苯基)乙酸甲酯,
2-(4-((N-(3-(4-氨基-2-(2-甲氧基乙基)-1H-咪唑并[4,5-c]喹啉-1-基)丙基)-2-(吡咯烷-1-基)乙酰氨基)甲基)苯基)乙酸甲酯,
2-(4-((N-(3-(4-氨基-2-(2-甲氧基乙基)-1H-咪唑并[4,5-c]喹啉-1-基)丙基)-2-((2-羟基乙基)(甲基)氨基)乙酰氨基)甲基)苯基)乙酸甲酯,
2-(3-((N-(3-(4-氨基-2-丁基-1H-咪唑并[4,5-c]喹啉-1-基)丙基)-2-((2-甲氧基乙基)(甲基)氨基)乙酰氨基)甲基)苯基)乙酸甲酯,
2-(3-((N-(3-(4-氨基-2-丁基-1H-咪唑并[4,5-c]喹啉-1-基)丙基)-2-(丁基(甲基)氨基)乙酰氨基)甲基)苯基)乙酸甲酯,
3-((N-(3-(4-氨基-2-丁基-1H-咪唑并[4,5-c]喹啉-1-基)丙基)-2-(二丙基氨基)乙酰氨基)甲基)苯基)乙酸甲酯,
2-(3-((N-(3-(4-氨基-2-丁基-1H-咪唑并[4,5-c]喹啉-1-基)丙基)-2-(二(2-羟基乙基)氨基)乙酰氨基)甲基)苯基)乙酸甲酯,
2-(3-((N-(3-(4-氨基-2-丁基-1H-咪唑并[4,5-c]喹啉-1-基)丙基)-2-(甲基(四氢-2H-吡喃-4-基)氨基)乙酰氨基)甲基)苯基)乙酸甲酯,
2-(3-((N-(3-(4-氨基-2-丁基-1H-咪唑并[4,5-c]喹啉-1-基)丙基)-2-(氮杂环丁烷-1-基)乙酰氨基)甲基)苯基)乙酸甲酯,
2-(3-((N-(3-(4-氨基-2-丁基-1H-咪唑并[4,5-c]喹啉-1-基)丙基)-2-(3-羟基氮杂环丁烷-1-基)乙酰氨基)甲基)苯基)乙酸甲酯,
2-(3-((N-(3-(4-氨基-2-丁基-1H-咪唑并[4,5-c]喹啉-1-基)丙基)-2-(吡咯烷-1-基)乙酰氨基)甲基)苯基)乙酸甲酯,
2-(3-((N-(3-(4-氨基-2-丁基-1H-咪唑并[4,5-c]喹啉-1-基)丙基)-2-(3-羟基吡咯烷-1-基)乙酰氨基)甲基)苯基)乙酸甲酯,
(R)-2-(3-((N-(3-(4-氨基-2-丁基-1H-咪唑并[4,5-c]喹啉-1-基)丙基)-2-(3-羟基吡咯烷-1-基)乙酰氨基)甲基)苯基)乙酸甲酯,
2-(3-((N-(3-(4-氨基-2-丁基-1H-咪唑并[4,5-c]喹啉-1-基)丙基)-2-(哌啶-1-基)乙酰氨基)甲基)苯基)乙酸甲酯,
2-(3-((N-(3-(4-氨基-2-丁基-1H-咪唑并[4,5-c]喹啉-1-基)丙基)-2-(4-羟基哌啶-1-基)乙酰氨基)甲基)苯基)乙酸甲酯,
2-(3-((N-(3-(4-氨基-2-丁基-1H-咪唑并[4,5-c]喹啉-1-基)丙基)-2-(4-甲氧基哌啶-1-基)乙酰氨基)甲基)苯基)乙酸甲酯,
2-(3-((N-(3-(4-氨基-2-丁基-1H-咪唑并[4,5-c]喹啉-1-基)丙基)-2-(4-(二甲基氨基甲酰基)哌啶-1-基)乙酰氨基)甲基)苯基)乙酸甲酯,
2-(3-((N-(3-(4-氨基-2-丁基-1H-咪唑并[4,5-c]喹啉-1-基)丙基)-2-吗啉代乙酰氨基)甲基)苯基)乙酸甲酯,
2-(3-((N-(3-(4-氨基-2-丁基-1H-咪唑并[4,5-c]喹啉-1-基)丙基)-2-((2S,6R)-2,6-二甲基吗啉代)乙酰氨基)甲基)苯基)乙酸甲酯,
2-(3-((N-(3-(4-氨基-2-丁基-1H-咪唑并[4,5-c]喹啉-1-基)丙基)-2-(4-甲基哌嗪-1-基)乙酰氨基)甲基)苯基)乙酸甲酯,
2-(3-((N-(3-(4-氨基-2-丁基-1H-咪唑并[4,5-c]喹啉-1-基)丙基)-2-(4-(2-羟基乙基)哌嗪-1-基)乙酰氨基)甲基)苯基)乙酸甲酯,
2-(3-((N-(3-(4-氨基-2-丁基-1H-咪唑并[4,5-c]喹啉-1-基)丙基)-2-(4-(2-甲氧基乙基)哌嗪-1-基)乙酰氨基)甲基)苯基)乙酸甲酯,
2-(3-((2-(4-乙酰基哌嗪-1-基)-N-(3-(4-氨基-2-丁基-1H-咪唑并[4,5-c]喹啉-1-基)丙基)乙酰氨基)甲基)苯基)乙酸甲酯,
2-(3-((N-(3-(4-氨基-2-丁基-1H-咪唑并[4,5-c]喹啉-1-基)丙基)-2-(4-(甲基磺酰基)哌嗪-1-基)乙酰氨基)甲基)苯基)乙酸甲酯,
2-(3-((N-(3-(4-氨基-2-丁基-1H-咪唑并[4,5-c]喹啉-1-基)丙基)-2-(氮杂环庚烷-1-基)乙酰氨基)甲基)苯基)乙酸甲酯,
2-(3-((N-(3-(4-氨基-2-丁基-1H-咪唑并[4,5-c]喹啉-1-基)丙基)-2-(1,4-氧杂氮杂环庚烷-4-基)乙酰氨基)甲基)苯基)乙酸甲酯,
2-(3-((N-(3-(4-氨基-2-丁基-1H-咪唑并[4,5-c]喹啉-1-基)丙基)-2-(4-甲基-1,4-二氮杂环庚烷-1-基)乙酰氨基)甲基)苯基)乙酸甲酯,
2-(3-((2-(4-乙酰基-1,4-二氮杂环庚烷-1-基)-N-(3-(4-氨基-2-丁基-1H-咪唑并[4,5-c]喹啉-1-基)丙基)乙酰氨基)甲基)苯基)乙酸甲酯,
2-(3-((N-(3-(4-氨基-2-丁基-1H-咪唑并[4,5-c]喹啉-1-基)丙基)-2-(4-(乙基氨基甲酰基)-1,4-二氮杂环庚烷-1-基)乙酰氨基)甲基)苯基)乙酸甲酯,
2-(3-((N-(3-(4-氨基-2-丁基-1H-咪唑并[4,5-c]喹啉-1-基)丙基)-2-(4-(甲基磺酰基)-1,4-二氮杂环庚烷-1-基)乙酰氨基)甲基)苯基)乙酸甲酯,
2-(4-((N-(3-(4-氨基-2-丁基-1H-咪唑并[4,5-c]喹啉-1-基)丙基)-2-(4-(2-甲氧基乙基)哌嗪-1-基)乙酰氨基)甲基)苯基)乙酸甲酯,
2-(4-((2-(4-乙酰基-1,4-二氮杂环庚烷-1-基)-N-(3-(4-氨基-2-丁基-1H-咪唑并[4,5-c]喹啉-1-基)丙基)乙酰氨基)甲基)苯基)乙酸甲酯,
2-(4-((N-(3-(4-氨基-2-丁基-1H-咪唑并[4,5-c]喹啉-1-基)丙基)-2-(4-(甲基磺酰基)-1,4-二氮杂环庚烷-1-基)乙酰氨基)甲基)苯基)乙酸甲酯,
2-(4-((2-((1-乙酰基哌啶-4-基)(甲基)氨基)-N-(3-(4-氨基-2-丁基-1H-咪唑并[4,5-c]喹啉-1-基)丙基)乙酰氨基)甲基)苯基)乙酸甲酯,
2-(4-((N-(3-(4-氨基-2-(2-甲氧基乙基)-1H-咪唑并[4,5-c]喹啉-1-基)丙基)-2-(4-甲基哌嗪-1-基)乙酰氨基)甲基)苯基)乙酸甲酯,
2-(4-((N-(3-(4-氨基-2-(2-甲氧基乙基)-1H-咪唑并[4,5-c]喹啉-1-基)丙基)-2-(4-(2-甲氧基乙基)哌嗪-1-基)乙酰氨基)甲基)苯基)乙酸甲酯,
2-(3-((N-(3-(4-氨基-2-(2-甲氧基乙基)-1H-咪唑并[4,5-c]喹啉-1-基)丙基)-2-(4-甲基哌嗪-1-基)乙酰氨基)甲基)苯基)乙酸甲酯,和
2-(3-((N-(3-(4-氨基-2-(2-甲氧基乙基)-1H-咪唑并[4,5-c]喹啉-1-基)丙基)-2-(4-(2-甲氧基乙基)哌嗪-1-基)乙酰氨基)甲基)苯基)乙酸甲酯;或上述任一化合物的药用盐。
15.权利要求1的化合物,其选自:
2-(4-((3-(4-氨基-2-丁基-1H-咪唑并[4,5-c]喹啉-1-基)丙基氨基)甲基)苯基)乙酸甲酯,
2-(3-((3-(4-氨基-2-丁基-1H-咪唑并[4,5-c]喹啉-1-基)丙基氨基)甲基)苯基)乙酸甲酯,
2-(4-((N-(3-(4-氨基-2-丁基-1H-咪唑并[4,5-c]喹啉-1-基)丙基)-2-(二甲基氨基)乙酰氨基)甲基)苯基)乙酸甲酯,
2-(3-((N-(3-(4-氨基-2-丁基-1H-咪唑并[4,5-c]喹啉-1-基)丙基)-2-(二甲基氨基)乙酰氨基)甲基)苯基)乙酸甲酯,
2-(3-((4-((4-氨基-2-(乙氧基甲基)-1H-咪唑并[4,5-c]喹啉-1-基)甲基)哌啶-1-基)甲基)苯基)乙酸甲酯·二-三氟乙酸盐,
[4-({[3-(4-氨基-2-丁基-1H-咪唑并[4,5-c]喹啉-1-基)丙基][2-(二甲基氨基)乙基]氨基}甲基)苯基]乙酸甲酯,
2-(3-((N-(3-(4-氨基-2-(乙氧基甲基)-1H-咪唑并[4,5-c]喹啉-1-基)丙基)-2-(二甲基氨基)乙酰氨基)甲基)苯基)乙酸甲酯,
2-(3-(((3-(4-氨基-2-丁基-1H-咪唑并[4,5-c]喹啉-1-基)丙基)(1-甲基哌啶-4-基)氨基)甲基)苯基)乙酸甲酯,
2-(4-(((3-(4-氨基-2-丁基-1H-咪唑并[4,5-c]喹啉-1-基)丙基)(1-甲基哌啶-4-基)氨基)甲基)苯基)乙酸甲酯,
2-(4-((N-(3-(4-氨基-2-丁基-1H-咪唑并[4,5-c]喹啉-1-基)丙基)-2-(4-甲基哌嗪-1-基)乙酰氨基)甲基)苯基)乙酸甲酯,
2-(3-(((3-(4-氨基-2-丁基-1H-咪唑并[4,5-c]喹啉-1-基)丙基)(3-(二甲基氨基)丙基)氨基)甲基)苯基)乙酸甲酯,
2-(3-(((3-(4-氨基-2-丁基-1H-咪唑并[4,5-c]喹啉-1-基)丙基)(3-吗啉代丙基)氨基)甲基)苯基)乙酸甲酯,
2-(3-(((3-(4-氨基-2-丁基-1H-咪唑并[4,5-c]喹啉-1-基)丙基)(3-(乙基(甲基)氨基)丙基)氨基)甲基)苯基)乙酸甲酯,
2-(3-(((3-(4-氨基-2-丁基-1H-咪唑并[4,5-c]喹啉-1-基)丙基)(3-(4-甲基哌嗪-1-基)丙基)氨基)甲基)苯基)乙酸甲酯,
2-(4-((N-(3-(4-氨基-2-丁基-1H-咪唑并[4,5-c]喹啉-1-基)丙基)-2-(甲基磺酰基)乙酰氨基)甲基)苯基)乙酸甲酯,
2-(4-((N-(3-(4-氨基-2-丁基-1H-咪唑并[4,5-c]喹啉-1-基)丙基)乙酰氨基)甲基)苯基)乙酸甲酯,
2-(4-((N-(3-(4-氨基-2-丁基-1H-咪唑并[4,5-c]喹啉-1-基)丙基)-2-吗啉代乙酰氨基)甲基)苯基)乙酸甲酯,
2-(4-((N-(3-(4-氨基-2-丁基-1H-咪唑并[4,5-c]喹啉-1-基)丙基)-2-((2-甲氧基乙基)(甲基)氨基)乙酰氨基)甲基)苯基)乙酸甲酯,
2-(4-((2-(4-乙酰基哌嗪-1-基)-N-(3-(4-氨基-2-丁基-1H-咪唑并[4,5-c]喹啉-1-基)丙基)乙酰氨基)甲基)苯基)乙酸甲酯,
(R)-2-(4-((N-(3-(4-氨基-2-丁基-1H-咪唑并[4,5-c]喹啉-1-基)丙基)-2-(3-羟基吡咯烷-1-基)乙酰氨基)甲基)苯基)乙酸甲酯,
2-(4-((N-(3-(4-氨基-2-丁基-1H-咪唑并[4,5-c]喹啉-1-基)丙基)-2-(4-(嘧啶-2-基)哌嗪-1-基)乙酰氨基)甲基)苯基)乙酸甲酯,
4-(2-((3-(4-氨基-2-丁基-1H-咪唑并[4,5-c]喹啉-1-基)丙基)(4-(2-甲氧基-2-氧代乙基)苄基)氨基)-2-氧代乙基)哌嗪-1-甲酸乙酯,
2-(4-((N-(3-(4-氨基-2-丁基-1H-咪唑并[4,5-c]喹啉-1-基)丙基)-2-(4-(乙基磺酰基)哌嗪-1-基)乙酰氨基)甲基)苯基)乙酸甲酯,
2-(4-((N-(3-(4-氨基-2-丁基-1H-咪唑并[4,5-c]喹啉-1-基)丙基)-2-(哌啶-1-基)乙酰氨基)甲基)苯基)乙酸甲酯,
2-(4-((N-(3-(4-氨基-2-丁基-1H-咪唑并[4,5-c]喹啉-1-基)丙基)-2-(4-(叔丁氧基羰基氨基)哌啶-1-基)乙酰氨基)甲基)苯基)乙酸甲酯,
2-(4-((N-(3-(4-氨基-2-丁基-1H-咪唑并[4,5-c]喹啉-1-基)丙基)-2-(4-(叔丁氧基羰基(甲基)氨基)哌啶-1-基)乙酰氨基)甲基)苯基)乙酸甲酯,
2-(1-(2-((3-(4-氨基-2-丁基-1H-咪唑并[4,5-c]喹啉-1-基)丙基)(4-(2-甲氧基-2-氧代乙基)苄基)氨基)-2-氧代乙基)哌啶-4-基)乙酸乙酯,
1-(2-((3-(4-氨基-2-丁基-1H-咪唑并[4,5-c]喹啉-1-基)丙基)(4-(2-甲氧基-2-氧代乙基)苄基)氨基)-2-氧代乙基)哌啶-4-甲酸甲酯,
2-(4-((N-(3-(4-氨基-2-(2-甲氧基乙基)-1H-咪唑并[4,5-c]喹啉-1-基)丙基)-2-(哌啶-1-基)乙酰氨基)甲基)苯基)乙酸甲酯,
2-(4-((N-(3-(4-氨基-2-(2-甲氧基乙基)-1H-咪唑并[4,5-c]喹啉-1-基)丙基)-2-(二甲基氨基)乙酰氨基)甲基)苯基)乙酸甲酯,
2-(3-((N-(3-(4-氨基-2-(2-甲氧基乙基)-1H-咪唑并[4,5-c]喹啉-1-基)丙基)-2-(哌啶-1-基)乙酰氨基)甲基)苯基)乙酸甲酯·糖精盐,
2-(4-((N-(3-(4-氨基-2-(2-甲氧基乙基)-1H-咪唑并[4,5-c]喹啉-1-基)丙基)-2-((2-甲氧基乙基)(甲基)氨基)乙酰氨基)甲基)苯基)乙酸甲酯,
2-(4-((N-(3-(4-氨基-2-(2-甲氧基乙基)-1H-咪唑并[4,5-c]喹啉-1-基)丙基)-3-(哌啶-1-基)丙酰氨基)甲基)苯基)乙酸甲酯,
2-(4-(((3-(4-氨基-2-(2-甲氧基乙基)-1H-咪唑并[4,5-c]喹啉-1-基)丙基)(3-吗啉代丙基)氨基)甲基)苯基)乙酸甲酯,
(S)-2-(4-((N-(3-(4-氨基-2-(2-甲氧基乙基)-1H-咪唑并[4,5-c]喹啉-1-基)丙基)-2-(2-(甲氧基甲基)吡咯烷-1-基)乙酰氨基)甲基)苯基)乙酸甲酯·二糖精盐,
(R)-2-(4-((N-(3-(4-氨基-2-(2-甲氧基乙基)-1H-咪唑并[4,5-c]喹啉-1-基)丙基)-2-(2-(甲氧基甲基)吡咯烷-1-基)乙酰氨基)甲基)苯基)乙酸甲酯·二糖精盐,
2-(4-((N-(3-(4-氨基-2-(2-甲氧基乙基)-1H-咪唑并[4,5-c]喹啉-1-基)丙基)-2-(吡咯烷-1-基)乙酰氨基)甲基)苯基)乙酸甲酯·二糖精盐,
2-(4-((N-(3-(4-氨基-2-(2-甲氧基乙基)-1H-咪唑并[4,5-c]喹啉-1-基)丙基)-2-((2-羟基乙基)(甲基)氨基)乙酰氨基)甲基)苯基)乙酸甲酯·二糖精盐,
2-(3-((N-(3-(4-氨基-2-丁基-1H-咪唑并[4,5-c]喹啉-1-基)丙基)-2-((2-甲氧基乙基)(甲基)氨基)乙酰氨基)甲基)苯基)乙酸甲酯,
2-(3-((N-(3-(4-氨基-2-丁基-1H-咪唑并[4,5-c]喹啉-1-基)丙基)-2-(丁基(甲基)氨基)乙酰氨基)甲基)苯基)乙酸甲酯,
3-((N-(3-(4-氨基-2-丁基-1H-咪唑并[4,5-c]喹啉-1-基)丙基)-2-(二丙基氨基)乙酰氨基)甲基)苯基)乙酸甲酯,
2-(3-((N-(3-(4-氨基-2-丁基-1H-咪唑并[4,5-c]喹啉-1-基)丙基)-2-(二(2-羟基乙基)氨基)乙酰氨基)甲基)苯基)乙酸甲酯,
2-(3-((N-(3-(4-氨基-2-丁基-1H-咪唑并[4,5-c]喹啉-1-基)丙基)-2-(甲基(四氢-2H-吡喃-4-基)氨基)乙酰氨基)甲基)苯基)乙酸甲酯,
2-(3-((N-(3-(4-氨基-2-丁基-1H-咪唑并[4,5-c]喹啉-1-基)丙基)-2-(氮杂环丁烷-1-基)乙酰氨基)甲基)苯基)乙酸甲酯,
2-(3-((N-(3-(4-氨基-2-丁基-1H-咪唑并[4,5-c]喹啉-1-基)丙基)-2-(3-羟基氮杂环丁烷-1-基)乙酰氨基)甲基)苯基)乙酸甲酯,
2-(3-((N-(3-(4-氨基-2-丁基-1H-咪唑并[4,5-c]喹啉-1-基)丙基)-2-(吡咯烷-1-基)乙酰氨基)甲基)苯基)乙酸甲酯,
2-(3-((N-(3-(4-氨基-2-丁基-1H-咪唑并[4,5-c]喹啉-1-基)丙基)-2-(3-羟基吡咯烷-1-基)乙酰氨基)甲基)苯基)乙酸甲酯,
(R)-2-(3-((N-(3-(4-氨基-2-丁基-1H-咪唑并[4,5-c]喹啉-1-基)丙基)-2-(3-羟基吡咯烷-1-基)乙酰氨基)甲基)苯基)乙酸甲酯,
2-(3-((N-(3-(4-氨基-2-丁基-1H-咪唑并[4,5-c]喹啉-1-基)丙基)-2-(哌啶-1-基)乙酰氨基)甲基)苯基)乙酸甲酯,
2-(3-((N-(3-(4-氨基-2-丁基-1H-咪唑并[4,5-c]喹啉-1-基)丙基)-2-(4-羟基哌啶-1-基)乙酰氨基)甲基)苯基)乙酸甲酯,
2-(3-((N-(3-(4-氨基-2-丁基-1H-咪唑并[4,5-c]喹啉-1-基)丙基)-2-(4-甲氧基哌啶-1-基)乙酰氨基)甲基)苯基)乙酸甲酯,
2-(3-((N-(3-(4-氨基-2-丁基-1H-咪唑并[4,5-c]喹啉-1-基)丙基)-2-(4-(二甲基氨基甲酰基)哌啶-1-基)乙酰氨基)甲基)苯基)乙酸甲酯,
2-(3-((N-(3-(4-氨基-2-丁基-1H-咪唑并[4,5-c]喹啉-1-基)丙基)-2-吗啉代乙酰氨基)甲基)苯基)乙酸甲酯,
2-(3-((N-(3-(4-氨基-2-丁基-1H-咪唑并[4,5-c]喹啉-1-基)丙基)-2-((2S,6R)-2,6-二甲基吗啉代)乙酰氨基)甲基)苯基)乙酸甲酯,
2-(3-((N-(3-(4-氨基-2-丁基-1H-咪唑并[4,5-c]喹啉-1-基)丙基)-2-(4-甲基哌嗪-1-基)乙酰氨基)甲基)苯基)乙酸甲酯,
2-(3-((N-(3-(4-氨基-2-丁基-1H-咪唑并[4,5-c]喹啉-1-基)丙基)-2-(4-(2-羟基乙基)哌嗪-1-基)乙酰氨基)甲基)苯基)乙酸甲酯,
2-(3-((N-(3-(4-氨基-2-丁基-1H-咪唑并[4,5-c]喹啉-1-基)丙基)-2-(4-(2-甲氧基乙基)哌嗪-1-基)乙酰氨基)甲基)苯基)乙酸甲酯,
2-(3-((2-(4-乙酰基哌嗪-1-基)-N-(3-(4-氨基-2-丁基-1H-咪唑并[4,5-c]喹啉-1-基)丙基)乙酰氨基)甲基)苯基)乙酸甲酯,
2-(3-((N-(3-(4-氨基-2-丁基-1H-咪唑并[4,5-c]喹啉-1-基)丙基)-2-(4-(甲基磺酰基)哌嗪-1-基)乙酰氨基)甲基)苯基)乙酸甲酯,
2-(3-((N-(3-(4-氨基-2-丁基-1H-咪唑并[4,5-c]喹啉-1-基)丙基)-2-(氮杂环庚烷-1-基)乙酰氨基)甲基)苯基)乙酸甲酯,
2-(3-((N-(3-(4-氨基-2-丁基-1H-咪唑并[4,5-c]喹啉-1-基)丙基)-2-(1,4-氧杂氮杂环庚烷-4-基)乙酰氨基)甲基)苯基)乙酸甲酯,
2-(3-((N-(3-(4-氨基-2-丁基-1H-咪唑并[4,5-c]喹啉-1-基)丙基)-2-(4-甲基-1,4-二氮杂环庚烷-1-基)乙酰氨基)甲基)苯基)乙酸甲酯,
2-(3-((2-(4-乙酰基-1,4-二氮杂环庚烷-1-基)-N-(3-(4-氨基-2-丁基-1H-咪唑并[4,5-c]喹啉-1-基)丙基)乙酰氨基)甲基)苯基)乙酸甲酯,
2-(3-((N-(3-(4-氨基-2-丁基-1H-咪唑并[4,5-c]喹啉-1-基)丙基)-2-(4-(乙基氨基甲酰基)-1,4-二氮杂环庚烷-1-基)乙酰氨基)甲基)苯基)乙酸甲酯,
2-(3-((N-(3-(4-氨基-2-丁基-1H-咪唑并[4,5-c]喹啉-1-基)丙基)-2-(4-(甲基磺酰基)-1,4-二氮杂环庚烷-1-基)乙酰氨基)甲基)苯基)乙酸甲酯,
2-(4-((N-(3-(4-氨基-2-丁基-1H-咪唑并[4,5-c]喹啉-1-基)丙基)-2-(4-(2-甲氧基乙基)哌嗪-1-基)乙酰氨基)甲基)苯基)乙酸甲酯,
2-(4-((2-(4-乙酰基-1,4-二氮杂环庚烷-1-基)-N-(3-(4-氨基-2-丁基-1H-咪唑并[4,5-c]喹啉-1-基)丙基)乙酰氨基)甲基)苯基)乙酸甲酯,
2-(4-((N-(3-(4-氨基-2-丁基-1H-咪唑并[4,5-c]喹啉-1-基)丙基)-2-(4-(甲基磺酰基)-1,4-二氮杂环庚烷-1-基)乙酰氨基)甲基)苯基)乙酸甲酯,
2-(4-((2-((1-乙酰基哌啶-4-基)(甲基)氨基)-N-(3-(4-氨基-2-丁基-1H-咪唑并[4,5-c]喹啉-1-基)丙基)乙酰氨基)甲基)苯基)乙酸甲酯,
2-(4-((N-(3-(4-氨基-2-丁基-1H-咪唑并[4,5-c]喹啉-1-基)丙基)-2-(二甲基氨基)乙酰氨基)甲基)苯基)乙酸甲酯·二甲磺酸盐,
2-(4-((N-(3-(4-氨基-2-丁基-1H-咪唑并[4,5-c]喹啉-1-基)丙基)-2-(二甲基氨基)乙酰氨基)甲基)苯基)乙酸甲酯·单糖精盐,
2-(4-((N-(3-(4-氨基-2-丁基-1H-咪唑并[4,5-c]喹啉-1-基)丙基)-2-(二甲基氨基)乙酰氨基)甲基)苯基)乙酸甲酯·二糖精盐,
2-(4-((N-(3-(4-氨基-2-丁基-1H-咪唑并[4,5-c]喹啉-1-基)丙基)-2-(二甲基氨基)乙酰氨基)甲基)苯基)乙酸甲酯·二(1-羟基-2-萘甲酸)盐,
2-(4-((N-(3-(4-氨基-2-丁基-1H-咪唑并[4,5-c]喹啉-1-基)丙基)-2-(二甲基氨基)乙酰氨基)甲基)苯基)乙酸甲酯·二苯磺酸盐,
2-(4-((N-(3-(4-氨基-2-丁基-1H-咪唑并[4,5-c]喹啉-1-基)丙基)-2-(二甲基氨基)乙酰氨基)甲基)苯基)乙酸甲酯·扁桃酸盐,
2-(4-((N-(3-(4-氨基-2-丁基-1H-咪唑并[4,5-c]喹啉-1-基)丙基)-2-(二甲基氨基)乙酰氨基)甲基)苯基)乙酸甲酯·富马酸盐,
2-(4-((N-(3-(4-氨基-2-(2-甲氧基乙基)-1H-咪唑并[4,5-c]喹啉-1-基)丙基)-2-(4-甲基哌嗪-1-基)乙酰氨基)甲基)苯基)乙酸甲酯,
2-(4-((N-(3-(4-氨基-2-(2-甲氧基乙基)-1H-咪唑并[4,5-c]喹啉-1-基)丙基)-2-(4-(2-甲氧基乙基)哌嗪-1-基)乙酰氨基)甲基)苯基)乙酸甲酯,
2-(3-((N-(3-(4-氨基-2-(2-甲氧基乙基)-1H-咪唑并[4,5-c]喹啉-1-基)丙基)-2-(4-甲基哌嗪-1-基)乙酰氨基)甲基)苯基)乙酸甲酯,和
2-(3-((N-(3-(4-氨基-2-(2-甲氧基乙基)-1H-咪唑并[4,5-c]喹啉-1-基)丙基)-2-(4-(2-甲氧基乙基)哌嗪-1-基)乙酰氨基)甲基)苯基)乙酸甲酯。
16.制备如权利要求1中定义的式(I)化合物或其药用盐的方法,所述方法包括:
(a)当X1为基团NR5时,使式(II)化合物与式(III)化合物反应,
式(II)化合物为:
其中,Z1和R3如在式(I)中所定义,Ra为不存在,m表示0,以及L1为离去基团,
式(III)化合物为:
其中,Y1、R1、R5和A如在式(I)中所定义,R2为不存在,n表示0;或者
(b)当X1为基团NR5和Y1为C1-C6亚烷基时,在合适的还原剂存在下,使式(IV)化合物与式(V)化合物反应,
式(IV)化合物为:
其中,R3、R5和Z1如在式(I)中所定义,Ra为不存在,m表示0,
式(V)化合物为:
其中,R1和A如在式(I)中所定义,R2为不存在,n表示0,以及Y2为键或C1-5亚烷基;或者
(c)当X1为基团NR5时,使式(VI)化合物与式(VII)化合物反应,
式(VI)化合物为:
其中,X3为基团NR5,以及Z1、R3和R5如在式(I)中所定义,Ra为不存在,m表示0,
式(VII)化合物为:
其中,Y1、R1和A如在式(I)中所定义,R2为不存在,n表示0,以及L2为离去基团;或者
(d)当X1为>N-COR5时,使式(I)化合物与式(X)化合物反应,其中X1为NR5,其中R5为氢,
L4-COR5
(X)
其中,L4为离去基团,以及R5如对式(I)所定义;
以及随后,任选地进行如下的一个或多个步骤:
●将得到的化合物转化为其它式(I)化合物,
●除去任何保护基,
●形成所述化合物的药用盐。
17.一种药物组合物,其包含权利要求1至15任一项的式(I)化合物或其药用盐和药用助剂。
18.权利要求1至15任一项的式(I)化合物或其药用盐在制备用于治疗变应性或病毒性疾病、癌症、细菌感染或皮肤病的药物中的用途。
19.权利要求1至15任一项的式(I)化合物或其药用盐在制备用于治疗哮喘的药物中的用途。
20.权利要求1至15任一项的式(I)化合物或其药用盐在制备用于治疗COPD的药物中的用途。
21.权利要求1至15任一项的式(I)化合物或其药用盐在制备用于治疗变应性鼻炎的药物中的用途。
22.权利要求1至15任一项的式(I)化合物或其药用盐在制备用于治疗特应性皮炎的药物中的用途。
23.权利要求1至15任一项的式(I)化合物或其药用盐在制备用于治疗阻塞性气道疾病或病症的药物中的用途。
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