CN106279128A - 环氧乙烷衍生物及其制备方法和在医药上的应用 - Google Patents
环氧乙烷衍生物及其制备方法和在医药上的应用 Download PDFInfo
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- CN106279128A CN106279128A CN201510255885.4A CN201510255885A CN106279128A CN 106279128 A CN106279128 A CN 106279128A CN 201510255885 A CN201510255885 A CN 201510255885A CN 106279128 A CN106279128 A CN 106279128A
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- KZITUAIYBZXJFA-UHFFFAOYSA-N tert-butyl 4-bromo-3-hydroxy-2-methylidenebutanoate Chemical compound BrCC(C(C(=O)OC(C)(C)C)=C)O KZITUAIYBZXJFA-UHFFFAOYSA-N 0.000 description 1
- NXGKFQRSMFGZHG-UHFFFAOYSA-N tert-butyl 4-bromo-3-hydroxy-2-methylidenepentanoate Chemical compound BrC(C(C(C(=O)OC(C)(C)C)=C)O)C NXGKFQRSMFGZHG-UHFFFAOYSA-N 0.000 description 1
- MAOAFXHPFSZHAB-UHFFFAOYSA-N tert-butyl 4-bromo-3-hydroxy-3-methyl-2-methylidenebutanoate Chemical compound BrCC(C(C(=O)OC(C)(C)C)=C)(C)O MAOAFXHPFSZHAB-UHFFFAOYSA-N 0.000 description 1
- ILMRJRBKQSSXGY-UHFFFAOYSA-N tert-butyl(dimethyl)silicon Chemical group C[Si](C)C(C)(C)C ILMRJRBKQSSXGY-UHFFFAOYSA-N 0.000 description 1
- 125000005958 tetrahydrothienyl group Chemical group 0.000 description 1
- 125000003698 tetramethyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 125000000383 tetramethylene group Chemical group [H]C([H])([*:1])C([H])([H])C([H])([H])C([H])([H])[*:2] 0.000 description 1
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- 125000000335 thiazolyl group Chemical group 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- 125000002053 thietanyl group Chemical group 0.000 description 1
- 125000004568 thiomorpholinyl group Chemical group 0.000 description 1
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- 210000001519 tissue Anatomy 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- 125000004665 trialkylsilyl group Chemical group 0.000 description 1
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
- 125000000025 triisopropylsilyl group Chemical group C(C)(C)[Si](C(C)C)(C(C)C)* 0.000 description 1
- YFTHZRPMJXBUME-UHFFFAOYSA-N tripropylamine Chemical compound CCCN(CCC)CCC YFTHZRPMJXBUME-UHFFFAOYSA-N 0.000 description 1
- 229910052722 tritium Inorganic materials 0.000 description 1
- 229960004418 trolamine Drugs 0.000 description 1
- 229960000281 trometamol Drugs 0.000 description 1
- SDTYFWAQLSIEBH-UHFFFAOYSA-N undec-3-ene Chemical compound CCCCCCCC=CCC SDTYFWAQLSIEBH-UHFFFAOYSA-N 0.000 description 1
- 125000002948 undecyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000004474 valine Substances 0.000 description 1
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
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Abstract
本发明涉及一种环氧乙烷衍生物及其制备方法和在医药上的应用,具体而言本发明涉及通式(I)所示的化合物或者其立体异构体、水合物、代谢产物、溶剂化物、药学上可接受的盐、共晶或者前药、它们的制备方法、包括其药物组合物以及本发明的化合物药物组合物在医药上的用途,特别作为EGFR靶点抑制剂的用途,
Description
技术领域
本发明涉及一种环氧乙烷衍生物及其制备方法和在医药上的应用,具体是一种具有EGFR靶点抑制作用的新颖环氧乙烷衍生物或其立体异构体、水合物、溶剂化物、代谢产物、药学上可接受的盐、共晶或前药、其药物组合物以及其在医药上的应用。
背景技术
细胞表面受体中的受体酪氨酸激酶超家族通过细胞外生长因子对细胞信号的调节起重要的作用。受体酪氨酸激酶能够催化磷酸基团从ATP转移至底物的酪氨酸基团上。当没有配体激活受体酪氨酸激酶时,这些激酶处于未磷酸化的单体状态,其激酶域呈非活性的结构。当配体与受体酪氨酸激酶的胞外段结合时,受体发生寡聚化,并且自磷酸化,增加激酶的催化活性的同时形成了信号蛋白的结合位点,信号蛋白与其结合,从而激活多条信号通路。这些信号通路相互联系,调控细胞的增殖、生存、分化、功能、迁移和凋亡。当受体酪氨酸激酶失去调控,异常激活时,细胞会发生转化成肿瘤细胞,增殖、生长能力和耐药能力提高,具有较强的成血管能力、侵袭力和转移能力(Yarden和Sliwkowski,2001,Nat Rev Mol Cell Biol,2,127-137)。
ErbB家族属于受体酪氨酸激酶,包含四个成员:表皮生长因子受体(EGFR/HER1/ErbB1)、HER2(neu/ErbB2)、HER3(ErbB3)和HER4(ErbB4)(Olayioye,Neve等,2000,EMBO J,19,3159-3167;Yarden和Sliwkowski,2001,Nat Rev Mol Cell Biol,2,127-137)。他们都含有胞外配体结合域、单跨膜域和胞内酪氨酸激酶和调节域。其功能是催化ATP的磷酸基转移至底物蛋白的酪氨酸基团上。配体依赖的受体寡聚化导致受体调节域的自磷酸化,从而发生胞内信号转导,最终引起细胞增殖。该信号通路与肿瘤的发生和发展密切相关。在多种肿瘤中,超活化的ErbB受体,尤其是EGFR,会导致生长因子信号的失调控。EGFR的激活通常是由于过表达或突变引起的持续活化或配体的自分泌表达。因此抑制EGFR是一个备受关注的抗肿瘤策略。许多靶向EGFR的小分子抑制剂相继被开发,其中一些已经运用于临床治疗。
第一代的EGFR激酶抑制剂如吉非替尼、厄罗替尼在临床上能有效治疗非小细胞肺癌,尤其是那些含有EGFR激酶域发生激活突变的非小细胞肺癌(Mok,Wu等,2009,NEngl J Med,361,947-957;Rosell,Moran等,2009,N Engl J Med,361,958-967)。最常见的EGFR激活突变是L858R和delE746_A750,相对于野生型的EGFR,这些突变能够增加受体对吉非替尼和厄罗替尼的亲和力,而降低受体对ATP的亲和力(Carey,Garton等,2006,Cancer Res,66,8163-8171;Yun,Boggon等,2007,Cancer Cell,11,217-227)。
第二代的EGFR激酶抑制剂普遍具有喹啉结构,是不可逆的EGFR抑制剂。不同于吉非替尼,它们含有亲电子能力,能够与EGFR中保守的半胱氨酸基团(Cys 797)发生迈克尔加成反应。这些化合物的共价性质使它们相较于可逆的抑制剂,具有更强的占据ATP位点的能力,因此,尽管T790M突变能够增加ATP的亲和力,这类抑制剂在临床前模型中还是足以抑制EGFR T790M(Engelman,Zejnullahu等,2007,Cancer Res,67,11924-11932;Li,Ambrogio等,2008,Oncogene,27,4702-4711)。第二代的EGFR激酶抑制剂以阿法替尼(Afatinib),Dacomitinib(PF-00299804)和来那替尼(Neratinib)为代表。三者均为EGFR和HER2的不可逆抑制剂,治疗机理除竞争性地占据EGFR上ATP结合位点外,还能与EGFR结合口袋开口处附近所特有氨基酸残基发生烷基化作用或共价键结合,进而实现对EGFR的不可逆抑制。
随着第一代EGFR激酶抑制剂的持续使用,日益凸显的耐药性成为不可回避的问题。由于获得性耐药的出现,吉非替尼和厄罗替尼的运用最终受到了限制。超过50%的肺癌患者都会出现获得性耐药,其中超过90%都含有EGFR的T790M看门残基突变(Kobayashi,Boggon等,2005,N Engl J Med,352,786-792;Pao,Miller等,2005,PLoS Med,2,e73)。T790M突变并非从空间构象上阻碍药物的结合,而是恢复受体对ATP的亲和力,与野生型相当(Yun,Mengwasser等,2008,Proc Natl Acad Sci U S A,105,2070-2075)。第二代的EGFR激酶抑制剂可通过共价结合克服上述突变带来的问题,大幅升高药物浓度并提供持续的封闭效应,增强对肿瘤细胞的持久抑制。另外,明显的皮肤毒性(如痤疮样皮疹)也是第一代EGFR激酶抑制剂所面临的难题。第二代EGFR激酶抑制剂(如Afatinib)在这方面有了较好的改善。为了满足临床需求,需要继续研发在能够有效克服T790M突变产生耐药的EGFR抑制剂。
目前已有多篇文献报道了蛋白激酶抑制剂及其抗肿瘤的用途。如:
1)CN1481370A中描述了如下通式的具有EGFR抑制活性的化合物:
其中,Ra是苄基,1-苯基乙基或3-氯-4-氟苯基;
Rb是二甲基氨基,N-甲基-N-乙基氨基,二乙基氨基,N-甲基-N-异丙基氨基,N-甲基-N-环丙基氨基,N-甲基-N-(2-甲氧基乙基)-氨基,N-乙基-N-(2-甲氧基乙基)-氨基,双-(2-甲氧基乙基)-氨基,吗啉基,N-甲基-N-(四氢呋喃-3-基)-氨基,N-甲基-N-(四氢呋喃-2-基-甲基)-氨基,N-甲基-N-(四氢呋喃-3-基-甲基)-氨基,N-甲基-N-(四氢吡喃-4-基)-氨基或N-甲-N-(四氢吡喃-4-基-甲基)-氨基;
Rc是环丙基甲氧基,环丁基氧基,环戊基氧基,四氢呋喃-3-基-氧基,四氢呋喃-2-基-甲氧基,四氢呋喃-3-基-甲氧基,四氢吡喃-4-基-氧基或四氢吡喃-4-基-甲氧基;
并排除一些具体的化合物,详见专利原文。
2)CN1972688A中公开了如下通式的化合物:
其中,R1选自F、Br、Cl、或I;
R2选自H、F、Br、Cl、或I;
R3选自
a)任选地被一或多个卤素取代的C1-C3直链或支链烷基;或
b)-(CH2)n-吗啉基、-(CH2)n-哌啶、-(CH2)n-哌嗪、-(CH2)n-哌嗪-N(C1-C3烷基)、-(CH2)n-吡咯烷或-(CH2)n-咪唑;
n为从1至4的整数;
R4为-(CH2)m-Het;
Het为选自吗啉、哌啶、哌嗪、哌嗪-N(C1-C3烷基)、咪唑、吡咯烷、azepane、3,4-二氢-2H-吡啶,或3,6-二氢-2H-吡啶的杂环部分,其中每个杂环部分任选地被选自C1-C3烷基、卤素、OH、NH2、NH(C1-C3烷基)或N(C1-C3烷基)2的1至3个基团取代;
m为从1至3的整数;和
X为O、S或NH。
3)CN101679384A公开了如下通式的用于抑制癌细胞生长的酰胺衍生物化合物:
其中,
A是R4、R5、R6和R7各自独立为氢、卤素、N-C1-6烷基或N-羟基酰氨基或者C-C1-6烷基反酰氨基(-NHCOC1-6)、羟基羰基(-COOH)、C1-6烷氧基羰基(-COOC1-6)、C1-6烷基,或者为被羟基、C1-6二烷基胺或杂环基团取代的C1-6烷基;
R1是被1-5个X取代的芳基或杂环基团,或者是被芳基取代的C1-6烷基;
R2是氢、羟基、C1-6烷氧基,或者是被C1-6烷氧基或杂环基团取代的C1-6烷氧基;
R3是氢、-COOH、C1-6烷氧基羰基,或者是N-未被取代的酰氨基或者N-被Y取代的酰氨基;
na和nb各自为0-6的整数;其中:
X是氢、卤素、羟基、氰基、硝基、(一卤代、二卤代或三卤代)甲基、巯基、C1-6烷硫基、丙烯酰氨基、C1-6烷基、C1-6烯基、C1-6炔基、C1-6烷氧基、芳氧基、C1-6二烷基氨基,或者为被Z取代的C1-6烷基或C1-6烷氧基,条件是当X的数量为两个或更多个时,X基团可以稠合在一起形成环结构;
Y是羟基、C1-6烷基,或者是被Z取代的C1-6烷基,所述C1-6烷基含有1-4个选自N、O、S、SO和SO2的基团;并且
Z是C1-6烷基、芳基或杂环基团,所述芳基基团为C5-12单环或双环芳族基团,所述杂环基团为含有1-4个选自N、O、S、SO和SO2的基团的C5-12单环或双环的芳族或非芳族基团,并且所述芳基和杂环基团是未取代的,或者被选自卤素、羟基、氨基、硝基、氰基、C1-6烷基、C1-6烯基、C1-6炔基、C1-6烷氧基、C1-6单烷基氨基和C1-6二烷基氨基的取代基取代。
发明内容
本发明的主要目的在于提供一种新颖的的具有EGFR抑制剂活性的取代环氧乙烷衍生物或其立体异构体、水合物、代谢产物、溶剂化物、药学上可接受的盐、共晶或前药及其在制备治疗癌症相关药物中的用途。
本发明提供一种通式(I)所示的化合物或其立体异构体、水合物、代谢产物、溶剂化物、药学上可接受的盐、共晶或前药,其中:
R1、R2和R3各自独立的选自H或C1-6烷基,所述的烷基任选进一步被选自0至4个选自F、Cl、Br或I的取代基所取代;
R4选自H或C1-6烷基,所述的烷基任选进一步被选自0至4个选自F、Cl、Br或I的取代基所取代;
X1选自-(CX1aX1b)x-、-C(=O)-或者不存在;
X2选自-C(=O)-、-C(=O)NH-、-NHC(=O)-、-O-、-S-、-CX2a=CX2b-、-(CX2cX2d)x-、-(CX2cX2d)x-≡-、-(CX2cX2d)x-O-、-NH-、-N(C1-4烷基)-或者不存在;
X3和X4各自独立的选自-O-、-S-、-NH-、-CH=、-N(C1-4烷基)-或者不存在;
X1a、X1b、X2c和X2d各自独立的选自H、F、Cl、Br、I或C1-6烷基,所述的烷基任选进一步被选自0至4个选自F、Cl、Br或I的取代基所取代;
X2a和X2b各自独立的选自H、F、Cl、Br、I或C1-6烷基,所述的烷基任选进一步被选自0至4个选自F、Cl、Br或I的取代基所取代;
作为选择,X1a、X1b、X2c、X2d、R4中的任意一个或多个基团与它们相连的原子一起形成C3-6碳环或3至9元的杂环,所述的杂环或碳环任选进一步被0至4个选自R5的取代基所取代,且所述杂环含有1至2个选自N、O或S的杂原子;
R5选自F、Cl、Br、I、NH2、氰基、羧基、C1-6烷基、-C(=O)O-C1-6烷基或-C(=O)NR5aR5b,所述的烷基任选进一步被选自0至4个选自F、Cl、Br或I的取代基所取代;
R5a、R5b各自独立的选自H、羟基或C1-6烷基,所述烷基任选进一步被0至4个选自F、Cl、Br、I、NH2、CF3、氰基、羟基、C1-6烷基、C1-6烷氧基、-NHC1-6烷基、-N(C1-6烷基)-C1-6烷基、-S(=O)C1-6烷基、-S(=O)2C1-6烷基、C6-10碳环基或3至9元的杂环基的取代基所取代,所述的碳环基或杂环基任选进一步被选自0至4个选自F、Cl、Br、I、羟基、NH2、CF3、CHF2、CH2F、硝基、氰基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6烷氧基、-NHC1-6烷基或-N(C1-6烷基)-C1-6烷基的取代基所取代,且所述杂环基含有1至4个选自N、O、S、S(=O)或S(=O)2的杂原子或基团;
作为选择,两个R5与它们相连的原子一起形成3至6元杂环或C3-6碳环,所述杂环或碳环任选进一步被0至4个选自F、Cl、Br、I、羟基、氨基、硝基、氰基、C1-6烷基、C1-6烷氧基、-NHC1-6烷基或-N(C1-6烷基)-C1-6烷基的取代基所取代;
环A、环B各自独立的选自C6-14碳环或5至15元杂环,所述的碳环或杂环任选进一步被0至6个选自R6的取代基所取代,且所述的杂环含有1至4个选自N、O或S的杂原子;
环C选自C6-10碳环、3至15元杂环或者不存在,所述碳环或杂环任选进一步被0至4个选自R6的取代基所取代,且所述的杂环含有1至4个选自N、O或S的杂原子;
R6选自F、Cl、Br、I、NH2、羟基、氰基、硝基、羧基、巯基、丙烯酰胺基、C1-10烷基、C2-10烯基、C2-10炔基、C1-10烷氧基、C1-10烷硫基、(CH2)q-4至9元杂环、-O-(CH2)q-C(=O)C1-10烷基、-O-(CH2)q-O-C(=O)C1-10烷基、-O-(CH2)q-O-C1-10烷基、-C(=O)C1-10烷基、=O、-C(=O)C2-10烯基、-C(=O)C2-10炔基、-S(=O)2-C1-10烷基、-S(=O)2-C3-10碳环、-S(=O)2-NH2、-C(=O)NH-C1-10烷基、-Q-(CH2)q-OH、-Q-(CH2)qR6a、-Q-(CH2)q-NR6bR6c、C3-10碳环或3至15元杂环,所述CH2、NH2、烷基、烯基、炔基、烷氧基、碳环或杂环任选进一步被0至4个选自F、Cl、Br、I、=O、NH2、CF3、-OCF3、羟基、氰基、丙烯酰胺基、硝基、C1-6烷基、C2-6炔基、-C(=O)C1-6烷基、C1-6烷氧基、-NHC1-6烷基、-N(C1-6烷基)-C1-6烷基、C3-10碳环或3至10元杂环的取代基所取代,且所述杂环含有1至4个选自N、O或S的杂原子;
Q选自化学键、-O-、-S-、-NH-、-N(C1-4烷基)-或-NHC(=O)NH-;
R6a选自C1-10烷氧基、C3-10碳环或3至10元杂环,所述的杂环含有1至4个选自N、O或S的杂原子,所述的烷氧基、碳环或杂环任选进一步被0至4个选自F、Cl、Br、I、NH2、CF3、CHF2、CH2F、硝基、巯基、氰基、丙烯酰胺基、=O、C1-6烷基、C1-6烷氧基、-C(=O)NH-C1-6烷基、-NHC1-6烷基、-N(C1-6烷基)-C1-6烷基、-C(=O)C1-6烷基或-OC(=O)C1-6烷基的取代基所取代;
R6b和R6c各自独立的选自H、C1-10烷基、-C(=O)C1-10烷基、-C(=O)C1-10烷氧基或3至6元碳环;
作为选择,R6b、R6c可以与其相连接的氮原子形成一个4至7元的杂环,所述的杂环含有1至2个选自N、O或S的杂原子,所述的杂环任选进一步被0至4个选自F、Cl、Br、I、NH2、氰基、丙烯酰胺基、C1-6烷基、C1-6烷氧基、=O、-C(=O)C1-6烷基、-C(=O)NH-C1-6烷基、-NHC1-6烷基或-N(C1-6烷基)-C1-6烷基的取代基所取代;
q选自0、1、2或3;
x选自1、2、3、4、5或6。
本发明的优选方案,一种通式(I)所示的化合物或其立体异构体、水合物、代谢产物、溶剂化物、药学上可接受的盐、共晶或前药,其中:
环A、环B各自独立的选自C6-14碳环或5至15元杂环,优选C6-10碳环或5至10元杂环,更优选苯环、萘环、吡啶环、喹啉环、异喹啉环、四氢喹啉环、喹唑啉环、四氢异喹啉环、嘧啶环、苯并吲哚环、吡唑[1,5-a]吡啶环、吡唑[1,5-c]嘧啶环、嘌呤环、呋喃环、噻吩环、噻唑环、吡咯环、吲唑环、7H-吡咯[2,3-d]嘧啶环、噻吩[3,2-d]嘧啶环、苯并[d]咪唑环或6,7-二氢-5H-吡咯[2,3-d]嘧啶环;所述的碳环、杂环、萘环、吡啶环、喹啉环、异喹啉环、四氢喹啉环、喹唑啉环、四氢异喹啉环、嘧啶环、苯并吲哚环、吡唑[1,5-a]吡啶环、吡唑[1,5-c]嘧啶环、嘌呤环、呋喃环、噻吩环、噻唑环、吡咯环、吲唑环、7H-吡咯[2,3-d]嘧啶环、噻吩[3,2-d]嘧啶环、苯并[d]咪唑环或6,7-二氢-5H-吡咯[2,3-d]嘧啶环任选进一步被0至6个选自R6的取代基所取代,且所述的杂环含有1至4个选自N、O或S的杂原子;
环C选自C6-10碳环、3至15元杂环或者不存在,优选C6-10碳环、3至10元杂环或者不存在,更优选苯环、萘环、吡啶环、喹啉环、异喹啉环、四氢喹啉环、喹唑啉环、四氢异喹啉环、嘧啶环、苯并吲哚环、吡唑[1,5-a]吡啶环、吡唑[1,5-c]嘧啶环、嘌呤环、呋喃环、噻吩环、噻唑环、吡咯环、吲唑环、7H-吡咯[2,3-d]嘧啶环、噻吩[3,2-d]嘧啶环、苯并[d]咪唑环、6,7-二氢-5H-吡咯[2,3-d]嘧啶环、四氢呋喃环、吗啉环、哌啶环、哌嗪环、吡嗪环、哒嗪环、硫代吗啉环或四氢噻唑环;所述碳环、杂环、苯环、萘环、吡啶环、喹啉环、异喹啉环、四氢喹啉环、喹唑啉环、四氢异喹啉环、嘧啶环、苯并吲哚环、吡唑[1,5-a]吡啶环、吡唑[1,5-c]嘧啶环、嘌呤环、呋喃环、噻吩环、噻唑环、吡咯环、吲唑环、7H-吡咯[2,3-d]嘧啶环、噻吩[3,2-d]嘧啶环、苯并[d]咪唑环、6,7-二氢-5H-吡咯[2,3-d]嘧啶环、四氢呋喃环、吗啉环、哌啶环、哌嗪环、吡嗪环、哒嗪环、硫代吗啉环或四氢噻唑环任选进一步被0至4个选自R6的取代基所取代,且所述的杂环含有1至4个选自N、O或S的杂原子;
R6选自F、Cl、Br、I、NH2、羟基、氰基、硝基、羧基、巯基、丙烯酰胺基、C1-10烷基、C2-10烯基、C2-10炔基、C1-10烷氧基、C1-10烷硫基、(CH2)q-4至9元杂环、-O-(CH2)q-C(=O)C1-10烷基、-O-(CH2)q-O-C(=O)C1-10烷基、-O-(CH2)q-O-C1-10烷基、-C(=O)C1-10烷基、=O、-C(=O)C2-10烯基、-C(=O)C2-10炔基、-S(=O)2-C1-10烷基、-S(=O)2-C3-10环烷基、-S(=O)2-NH2、-C(=O)NH-C1-10烷基、-Q-(CH2)q-OH、-Q-(CH2)qR6a、-Q-(CH2)q-NR6bR6c、C3-10碳环或3至15元杂环,优选F、Cl、Br、I、NH2、羟基、氰基、硝基、巯基、丙烯酰胺基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6烷氧基、C1-6烷硫基、-≡-(CH2)q-杂环、O-(CH2)q-C(=O)C1-6烷基、-O-(CH2)q-O-C(=O)C1-6烷基、-O-(CH2)q-O-C1-6烷基、-C(=O)C1-6烷基、=O、-C(=O)C2-6烯基、-C(=O)C2-6炔基、-S(=O)2-C1-6烷基、-C(=O)NH-C1-6烷基、-Q-(CH2)qR6a、-Q-(CH2)q-NR6bR6c、C3-10碳环或3至15元杂环,所述CH2、NH2、烷基、烯基、炔基、烷氧基、碳环或杂环任选进一步被0至4个选自F、Cl、Br、I、=O、NH2、CF3、-OCF3、羟基、氰基、硝基、丙烯酰胺基、C1-6烷基、C2-6炔基、-C(=O)C1-6烷基、C1-6烷氧基、-NHC1-6烷基、-N(C1-6烷基)-C1-6烷基、C3-10碳环或3至10元杂环的取代基所取代,且所述杂环含有1至4个选自N、O或S的杂原子;
R6a选自C1-10烷氧基、C3-10碳环或3至10元杂环,优选C1-6烷氧基、C3-6碳环或3至6元杂环,所述的杂环含有1至4个选自N、O或S的杂原子,所述的烷氧基、碳环或杂环任选进一步被0至4个选自F、Cl、Br、I、NH2、CF3、CHF2、CH2F、硝基、巯基、氰基、丙烯酰胺基、=O、C1-6烷基、C1-6烷氧基、-C(=O)NH-C1-6烷基、-NHC1-6烷基、-N(C1-6烷基)-C1-6烷基、-C(=O)C1-6烷基或-OC(=O)C1-6烷基的取代基所取代;
R6b和R6c各自独立的选自H、C1-10烷基、-C(=O)C1-10烷基、-C(=O)C1-10烷氧基或3至6元碳环,优选H、C1-6烷基、-C(=O)C1-6烷基、-C(=O)C1-6烷氧基或3至6元碳环;
作为选择,R6b、R6c可以与其相连接的氮原子形成一个4至7元的杂环,所述的杂环含有1至2个选自N、O或S的杂原子,所述的杂环任选进一步被0至4个选自F、Cl、Br、I、NH2、氰基、丙烯酰胺基、C1-6烷基、C1-6烷氧基、=O、-C(=O)C1-6烷基、-C(=O)NH-C1-6烷基、-NHC1-6烷基或-N(C1-6烷基)-C1-6烷基的取代基所取代;
Q选自化学键、-O-、-S-、-NH-、-N(C1-4烷基)-或-NHC(=O)NH-,优选-O-、-S-、-NH-或-N(C1-4烷基)-;
q选自0、1、2或3。
本发明的优选方案,一种通式(I)所示的化合物或其立体异构体、水合物、代谢产物、溶剂化物、药学上可接受的盐、共晶或前药,其中:
R1、R2和R3各自独立的选自H或C1-6烷基,优选H或C1-4烷基,所述的烷基任选进一步被选自0至4个选自F、Cl、Br或I的取代基所取代;
R4选自H或C1-6烷基,优选H或C1-4烷基,所述的烷基任选进一步被选自0至4个选自F、Cl、Br或I的取代基所取代;
X1选自-(CX1aX1b)x-、-C(=O)-或者不存在;
X2选自-C(=O)-、-C(=O)NH-、-NHC(=O)-、-O-、-S-、-CX2a=CX2b-、-(CX2cX2d)x-、-(CX2cX2d)x-≡-、-(CX2cX2d)x-O-、-NH-、-N(C1-4烷基)-或者不存在;
X3选自-O-、-S-、-NH-、-CH=、-N(C1-4烷基)-或者不存在;
X1a、X1b、X2c和X2d各自独立的选自H、F、Cl、Br、I或C1-6烷基,优选H、F、Cl、Br、I或C1-4烷基,更优选H、F、Cl、Br、I、甲基、乙基、丙基或异丙基,所述的烷基任选进一步被选自0至4个选自F、Cl、Br或I的取代基所取代;
X2a和X2b各自独立的选自H、F、Cl、Br、I或C1-6烷基,优选H、F、Cl、Br、I或C1-4烷基,更优选H或C1-4烷基,更优选H、甲基、乙基、丙基或异丙基,所述的烷基任选进一步被选自0至4个选自F、Cl、Br或I的取代基所取代;
作为选择,X1a、X1b、X2c、X2d、R4中的任意一个或多个基团与它们相连的原子一起形成C3-6碳环或3至9元的杂环,所述的杂环或碳环任选进一步被0至4个选自R5的取代基所取代,且所述杂环含有1至2个选自N、O或S的杂原子;
R5选自F、Cl、Br、I、NH2、氰基、羧基、C1-6烷基、-C(=O)O-C1-6烷基或-C(=O)NR5aR5b,所述的烷基任选进一步被选自0至4个选自F、Cl、Br或I的取代基所取代;
R5a、R5b各自独立的选自H、羟基或C1-6烷基,所述烷基任选进一步被0至4个选自F、Cl、Br、I、NH2、CF3、氰基、羟基、C1-6烷基、C1-6烷氧基、-NHC1-6烷基、-N(C1-6烷基)-C1-6烷基、-S(=O)C1-6烷基、-S(=O)2C1-6烷基、C6-10碳环基或3至9元的杂环基的取代基所取代,所述的碳环基或杂环基任选进一步被选自0至4个选自F、Cl、Br、I、羟基、NH2、CF3、CHF2、CH2F、硝基、氰基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6烷氧基、-NHC1-6烷基或-N(C1-6烷基)-C1-6烷基的取代基所取代,且所述杂环基含有1至4个选自N、O、S、S(=O)或S(=O)2的杂原子或基团;
作为选择,两个R5与它们相连的原子一起形成3至6元杂环或C3-6碳环,所述杂环或碳环任选进一步被0至4个选自F、Cl、Br、I、羟基、氨基、硝基、氰基、C1-6烷基、C1-6烷氧基、-NHC1-6烷基或-N(C1-6烷基)-C1-6烷基的取代基所取代;
环A、环B各自独立的选自C6-10碳环或者5至10元杂环,优选苯环、萘环、吡啶环、喹啉环、异喹啉环、四氢喹啉环、喹唑啉环、四氢异喹啉环、嘧啶环、苯并吲哚环、吡唑[1,5-a]吡啶环、吡唑[1,5-c]嘧啶环、嘌呤环、呋喃环、噻吩环、噻唑环、吡咯环、吲唑环、7H-吡咯[2,3-d]嘧啶环、噻吩[3,2-d]嘧啶环、苯并[d]咪唑环或6,7-二氢-5H-吡咯[2,3-d]嘧啶环;所述的碳环、杂环、苯环、萘环、吡啶环、喹啉环、异喹啉环、四氢喹啉环、喹唑啉环、四氢异喹啉环、嘧啶环、苯并吲哚环、吡唑[1,5-a]吡啶环、吡唑[1,5-c]嘧啶环、嘌呤环、呋喃环、噻吩环、噻唑环、吡咯环、吲唑环、7H-吡咯[2,3-d]嘧啶环、噻吩[3,2-d]嘧啶环、苯并[d]咪唑环或6,7-二氢-5H-吡咯[2,3-d]嘧啶环任选进一步被0至6个选自R6的取代基所取代,且所述的杂环含有1至4个选自N、O或S的杂原子;
环C不存在;
X4不存在;
R6选自F、Cl、Br、I、NH2、羟基、氰基、硝基、巯基、丙烯酰胺基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6烷氧基、C1-6烷硫基、(CH2)q-4至9元杂环、-O-(CH2)q-C(=O)C1-6烷基、-O-(CH2)q-O-C(=O)C1-6烷基、-O-(CH2)q-O-C1-6烷基、-C(=O)C1-6烷基、=O、-C(=O)C2-6烯基、-C(=O)C2-6炔基、-S(=O)2-C1-6烷基、-C(=O)NH-C1-6烷基、-Q-(CH2)qR6a、-Q-(CH2)q-NR6bR6c、C3-10碳环或3至15元杂环,所述CH2、烷基、烯基、炔基、烷氧基、碳环或杂环任选进一步被0至4个选自F、Cl、Br、I、=O、NH2、CF3、-OCF3、羟基、氰基、硝基、丙烯酰胺基、C1-4烷基、-C(=O)C1-4烷基、C1-4烷氧基、-NHC1-4烷基、-N(C1-4烷基)-C1-4烷基或3至10元杂环的取代基所取代,且所述杂环含有1至4个选自N、O或S的杂原子;
Q选自化学键、-O-、-S-、-NH-、-N(C1-4烷基)-或-NHC(=O)NH-;
R6a选自C1-6烷氧基、C3-10碳环或3至10元杂环,所述的杂环含有1至4个选自N、O或S的杂原子,所述的烷氧基、碳环或杂环任选进一步被0至4个选自F、Cl、Br、I、NH2、CF3、CHF2、CH2F、硝基、巯基、氰基、丙烯酰胺基、乙酰基、C1-4烷基、C1-4烷氧基、=O、-C(=O)NH-C1-4烷基、-NHC1-4烷基或-N(-C1-4烷基)-C1-4烷基的取代基所取代;
R6b和R6c各自独立的选自H、C1-4烷基、-C(=O)C1-4烷基、-C(=O)C1-4烷氧基或3至6元碳环;
作为选择,R6b、R6c可以与其相连接的氮原子形成一个4至7元的杂环,所述的杂环含有1至2个选自N、O或S的杂原子,所述的杂环任选进一步被0至4个选自F、Cl、Br、I、NH2、氰基、=O、-C(=O)C1-4烷基、C1-4烷基、C1-4烷氧基、-NHC1-4烷基或-N(-C1-4烷基)-C1-4烷基的取代基所取代;
q选自0、1、2或3;
x选自1、2、3、4、5或6。
本发明的一种优选方案,一种通式(I)所示的化合物或其立体异构体、水合物、代谢产物、溶剂化物、药学上可接受的盐、共晶或前药,其中,该化合物选自通式(II)所示的化合物:
R1、R2和R3各自独立的选自H或C1-4烷基,所述的烷基任选进一步被选自0至4个选自F、Cl、Br或I的取代基所取代;
R4选自H或C1-4烷基,所述的烷基任选进一步被选自0至4个选自F、Cl、Br或I的取代基所取代;
X1选自-(CX1aX1b)x-或者不存在;
X2选自-C(=O)-、-C(=O)NH-、-NHC(=O)-、-O-、-S-、-CX2a=CX2b-、-(CX2cX2d)x-≡-、-NH-、-N(C1-4烷基)-或者不存在,优选-O-、-S-、-NH-、-N(C1-4烷基)-或者不存在;
X1a、X1b、X2c和X2d各自独立的选自H、F、Cl、Br、I或C1-4烷基,优选H、F、Cl、Br、I、甲基、乙基或异丙基,所述的烷基、甲基、乙基或异丙基任选进一步被选自0至4个选自F、Cl、Br或I的取代基所取代;
X2a和X2b各自独立的选自H、F、Cl、Br、I或C1-4烷基,优选H、F、Cl、Br、I、甲基、乙基或异丙基;
作为选择,X1a、X1b、X2c、X2d和R4中的任意一个或多个基团与它们相连的原子一起形成C3-6碳环或3至9元的杂环,所述的碳环或者杂环任选进一步被0至4个选自R5的取代基所取代,且所述杂环含有1至2个选自N、O或S的杂原子;
R5选自F、Cl、Br、I、NH2、氰基、羧基、C1-4烷基、-C(=O)O-C1-4烷基或-C(=O)NR5aR5b,所述的烷基任选进一步被选自0至4个选自F、Cl、Br或I的取代基所取代;
R5a、R5b各自独立的选自H、羟基或C1-4烷基,所述烷基任选进一步被0至4个选自F、Cl、Br、I、NH2、CF3、氰基、羟基、C1-4烷基、C1-4烷氧基、-NHC1-4烷基、-N(C1-4烷基)-C1-4烷基、-S(=O)C1-4烷基、-S(=O)2C1-4烷基、C6-10碳环基或3至9元的杂环基的取代基所取代,所述的碳环基或杂环基任选进一步被选自0至4个选自F、Cl、Br、I、羟基、NH2、CF3、CHF2、CH2F、硝基、氰基、C1-4烷基、C2-4烯基、C2-4炔基、C1-4烷氧基、-NHC1-4烷基或-N(C1-4烷基)-C1-4烷基的取代基所取代,且所述杂环基含有1至4个选自N、O、S、S(=O)或S(=O)2的杂原子或基团;
作为选择,两个R5与它们相连的原子一起形成3至6元杂环或C3-6碳环,所述杂环或碳环任选进一步被0至4个选自F、Cl、Br、I、羟基、氨基、硝基、氰基、C1-4烷基、C1-4烷氧基、-NHC1-4烷基或-N(C1-4烷基)-C1-4烷基的取代基所取代;
R7选自H、F、Cl、Br、I、NH2、羟基、氰基、C1-4烷基、C2-4炔基、C1-4烷氧基、(CH2)q-4至9元杂环、-O-(CH2)q-C(=O)C1-4烷基、-O-(CH2)q-O-C(=O)C1-4烷基、-O-(CH2)q-O-C1-4烷基、-Y-(CH2)qR7a或-Y-(CH2)q-NR7bR7c,所述的CH2、烷基、炔基、烷氧基或杂环任选进一步被0至4个选自F、Cl、Br、I、CF3、NH2、羟基、=O、乙酰基、氰基、-OCF3、C1-4烷基、C1-4烷氧基、-NHC1-4烷基、-N(C1-4烷基)-C1-4烷基或3至6元杂环基的取代基所取代,所述的杂环含有1至2个选自N、O或S的杂原子;
Y选自-O-、-S-、-NH-或-N(C1-4烷基)-;
R7a选自C1-4烷氧基、C3-10碳环或3至10元杂环,所述的杂环含有1至4个选自N、O或S的杂原子,所述的烷氧基、碳环或杂环任选进一步被0至4个选自F、Cl、Br、I、NH2、氰基、=O、乙酰基、C1-4烷基、C1-4烷氧基、-NHC1-4烷基或-N(C1-4烷基)-C1-4烷基的取代基所取代;
R7b和R7c各自独立的选自H、C1-4烷基或3至6元碳环;
作为选择,R7b、R7c可以与其相连接的氮原子形成一个4至7元的杂环,所述的杂环含有1至2个选自N、O或S的杂原子,所述的杂环任选进一步被0至4个选自F、Cl、Br、I、NH2、氰基、=O、乙酰基、C1-4烷基、C1-4烷氧基、-NHC1-4烷基或-N(C1-4烷基)-C1-4烷基的取代基所取代;
R8选自H、F、Cl或Br;
Z选自-N-或-C(C≡N);
R9选自H或C1-4烷基;
R10选自C6-10碳环或5至10元杂环,优选苯环、萘环、吲唑环、吡啶环、噻吩环或呋喃环,所述杂环含有1至3个选自N、O或S的杂原子,且所述的碳环、杂环、苯环、萘环、吲唑环、吡啶环、噻吩环或呋喃环任选进一步被0至5个选自R11的取代基所取代;
R11选自F、Cl、Br、I、NH2、氰基、硝基、巯基、丙烯酰胺基、C1-4烷基、C2-4炔基、C1-4烷氧基、C1-4烷硫基、-O-C6-10碳环、-O-5至10元杂环、-OC1-3烷基-C6-10碳环、-OC1-3烷基-5至10元杂环、-NHC1-4烷基或-N(C1-4烷基)-C1-4烷基,所述烷基、炔基、烷氧基、碳环或杂环任选进一步被0至4个选自F、Cl、Br、I、CF3、NH2、C1-4烷基、C1-4烷氧基、氰基或丙烯酰胺基的取代基所取代,且所述的杂环含有1至3个选自N、O或S的杂原子;
q选自0、1、2或3;
x选自1、2、3、4、5或6。
本发明的一种优选方案,一种通式(II)所示的化合物或其立体异构体、水合物、代谢产物、溶剂化物、药学上可接受的盐、共晶或前药,其中,
R1、R2和R3各自独立的选自H、甲基或乙基;
R4选自H、甲基、乙基或丙基;
X1不存在或者选自-CH2CH2CHX1b-,当X1选自-CH2CH2CHX1b-时,X1b、R4与其相连的原子一起形成6元含氮杂环;
X2选自-O-、-NH-、-N(CH3)-或者不存在;
R7选自H、F、Cl、Br、I、CF3、NH2、羟基、氰基、甲基、乙基、乙炔基、甲氧基、乙氧基、-Y-(CH2)qR7a或者-Y-(CH2)q-NR7bR7c;
Y选自-O-、-S-、-NH-或-N(CH3)-;
q选自0、1、2或3;
R7a选自取代的或者未取代的甲氧基、乙氧基、环丙基、四氢呋喃基、四氢吡咯基、哌啶基、哌嗪基、吗啉基、当被取代时,任选进一步被0至4个选自F、Cl、Br、I、NH2、氰基、=O、乙酰基、甲基、乙基、甲氧基、乙氧基、-NHCH3或-N(CH3)2的取代基所取代;
R7b和R7c各自独立的选自H、甲基、乙基或3至6元碳环;
作为选择,R7b、R7c可以与其相连接的氮原子形成四氢吡咯基、哌啶基、哌嗪基或吗啉基,所述的四氢吡咯基、哌啶基、哌嗪基或吗啉基任选进一步被0至4个选自F、Cl、Br、I、NH2、氰基、乙酰基、=O、甲基、乙基、甲氧基、乙氧基、-NHCH3或-N(CH3)2的取代基所取代;
R8选自H、F或Cl,优选H;
Z选自-N-;
R9选自H或甲基,优选H;
R10选自苯基,所述的苯基任选进一步被0至5个选自F、Cl、Br、I、CF3、CHF2、CH2F、NH2、氰基、硝基、甲基、乙基、乙炔基、甲氧基、乙氧基、-O-C6-10碳环、-O-5至10元杂环、-OCH2C6-10碳环或-OCH2-5至10元杂环,所述碳环或杂环任选进一步被0至5个选自F、Cl、Br、I、CF3、CHF2、CH2F、NH2、氰基、甲基、乙基、甲氧基或乙氧基的取代基所取代,所述的杂环含有1至3个选自N、O或S的杂原子。
本发明的一种优选方案,一种通式(II)所示的化合物或其立体异构体、水合物、代谢产物、溶剂化物、药学上可接受的盐、共晶或前药,其中,该化合物选自通式(II)所示的化合物:
R1、R2和R3各自独立的选自H、甲基或乙基;
R4选自H、甲基、乙基或丙基;
X1不存在或者选自-CH2CH2CHX1b-,当X1选自-CH2CH2CHX1b-时,X1b、R4与其相连的原子一起形成6元含氮杂环;
X2选自-O-、-NH-、-N(CH3)-或者不存在;
R7选自H、F、氰基、甲基、乙基、乙炔基、甲氧基、乙氧基、甲氧乙氧基、
R8选自H、F或Cl,优选H;
Z选自-N-;
R9选自H;
R10选自苯基,所述的苯基任选进一步被0至5个选自F、Cl、Br、CF3、CHF2、CH2F、NH2、氰基、甲基、乙基、乙炔基、甲氧基、乙氧基、 的取代基所取代。
本发明优选方案,本发明涉及化合物选自,但不限于:
根据本发明的具体实施方案,本发明的化合物或其立体异构体、水合物、代谢产物、溶剂化物、药学上可接受的盐、共晶或前药,其中所述的盐选自盐酸盐、氢溴酸盐、氢碘酸盐、硫酸盐、磷酸盐、醋酸盐、三氟乙酸盐、硫氰酸盐、马来酸盐、羟基马来酸盐、戊二酸盐、甲磺酸盐、乙磺酸盐、苯磺酸盐、对甲苯磺酸盐、苯甲酸盐、水杨酸盐、苯乙酸盐、肉桂酸盐、乳酸盐、丙二酸盐、特戊酸盐、琥珀酸盐、富马酸盐、苹果酸盐、扁桃酸盐、酒石酸盐、没食子酸盐、葡萄糖酸盐、月桂酸盐、棕榈酸盐、果胶酸盐、苦味酸盐、柠檬酸盐或者它们的组合,优选的,所述的盐选自盐酸盐、氢溴酸盐、硫酸盐、磷酸盐、醋酸盐、马来酸盐、甲磺酸盐、苯磺酸盐、对甲苯磺酸盐、苯甲酸盐、水杨酸盐、肉桂酸盐、乳酸盐、丙二酸盐、琥珀酸盐、富马酸盐、苹果酸盐、酒石酸盐、柠檬酸盐或者它们的组合。
本发明还提供了一种药物组合物,所述的组合物包括:有效剂量的本发明所述的化合物或其立体异构体、水合物、代谢产物、溶剂化物、药学上可接受的盐、共晶或前药,以及药学上可接受的载体、稀释剂、佐剂、媒介物或赋形剂。
根据本发明的具体实施方案,本发明的药物组合物还进一步包括一种或多种其他治疗剂。
根据本发明的具体实施方案,本发明的药物组合物中所述的其他治疗剂包括:顺铂(cisplatin)、卡铂(carboplatin)、奥沙利铂(oxaliplatin)、达卡巴嗪(dacarbazine)、替莫唑胺(temozolomide)、丙卡巴肼(procarbazine)、甲氨蝶呤(methotrexate)、氟尿嘧啶(fluorouracil)、阿糖胞苷(cytarabine)、吉西他滨(gemcitabine)、巯基嘌呤(mercaptopurine)、氟达拉滨(fludarabine)、长春碱(vinblastine)、长春新碱(vincristine)、长春瑞滨(vinorelbine)、紫杉醇(paclitaxel)、多西紫杉醇(docetaxel)、拓扑替康(topotecan)、伊立替康(irinotecan)、依托泊苷(etoposide)、曲贝替定(trabectedin)、更生霉素(dactinomycin)、多柔比星(doxorubicin)、表柔比星(epirubicin)、道诺霉素(daunorubicin)、米托蒽醌(mitoxantrone)、博来霉素(bleomycin)、丝裂霉素C(mitomycin)、伊沙匹隆(ixabepilone)、他莫昔芬(tamoxifen)、氟他胺(flutamide)、西罗莫司(sirolimus)、阿法替尼(afatinib)、alisertib、amuvatinib、阿帕替尼(apatinib)、阿西替尼(axitinib)、硼替佐米(bortezomib)、波舒替尼(bosutinib)、布立尼布(brivanib)、卡博替尼(cabozantinib)、西地尼布(cediranib)、crenolanib、克卓替尼(crizotinib)、达拉非尼(dabrafenib)、达可替尼(dacomitinib)、达鲁舍替(danusertib)、达沙替尼(dasatinib)、多韦替尼(dovitinib)、厄洛替尼(erlotinib)、foretinib、ganetespib、吉非替尼(gefitinib)、依鲁替尼(ibrutinib)、埃克替尼(icotinib)、伊马替尼(imatinib)、iniparib、拉帕替尼(lapatinib)、lenvatinib、linifanib、linsitinib、马赛替尼(masitinib)、momelotinib、莫替沙尼(motesanib)、来那替尼(neratinib)、尼罗替尼(nilotinib)、尼拉帕尼(niraparib)、oprozomib、奥拉帕尼(olaparib)、帕唑帕尼(pazopanib)、pictilisib、帕纳替尼(ponatinib)、奎扎替尼(quizartinib)、瑞格非尼(regorafenib)、氯构色替(rigosertib)、rucaparib、鲁索替尼(ruxolitinib)、塞卡替尼(saracatinib)、saridegib、索拉非尼(sorafenib)、舒尼替尼(sunitinib)、替拉替尼(telatinib)、tivantinib、替肟扎尼(tivozanib)、托法替尼(tofacitinib)、曲美替尼(trametinib)、凡德他尼(vandetanib)、维利帕尼(veliparib)、威罗菲尼(vemurafenib)、维莫德吉(vismodegib)、volasertib、阿仑单抗(alemtuzumab)、贝伐单抗(bevacizumab)、布妥昔单抗(brentuximab vedotin)、卡妥索单抗(catumaxomab)、西妥昔单抗(cetuximab)、地诺单抗(denosumab)、吉妥珠单抗(gemtuzumab)、伊匹单抗(ipilimumab)、尼妥珠单抗(nimotuzumab)、奥法木单抗(ofatumumab)、帕尼单抗(panitumumab)、利妥昔单抗(rituximab)、托西莫单抗(tositumomab)、曲妥珠单抗(trastuzumab)或它们的组合。
本发明还提供了所述的化合物或其立体异构体、水合物、代谢产物、溶剂化物、药学上可接受的盐、共晶或前药或者所述的药物组合物在作为一种EGFR受体酪氨酸激酶抑制剂在制备药物制剂的应用,特别是在用于制备用于治疗和/或预防过度增殖性疾病的药物制剂中的应用。
根据本发明的具体实施方案,本发明的化合物或其立体异构体、水合物、代谢产物、溶剂化物、药学上可接受的盐、共晶或前药或者所述的药物组合物的应用中,所述过度增殖性疾病包括脑瘤、非小细胞肺癌、表皮鳞癌、膀胱癌、胰腺癌、结肠癌、乳腺癌、卵巢癌、子***、子宫内膜癌、结直肠癌、肾癌、食管腺癌、食管鳞状细胞癌、实体瘤、非霍奇金淋巴瘤、肝癌、肺癌,胃癌、皮肤癌、甲状腺癌、头颈癌、***癌、神经胶质瘤和鼻咽癌中的一种或多种;优选非小细胞肺癌、乳腺癌、表皮鳞癌、胃癌和结肠癌中的一种或多种。
本发明通式(II)化合物的合成方法:
其中,R1、R2、R3、R4、X1或X2的定义与通式(II)化合物所述定义一致;R7、R8、R9、R10、Z的定义与通式(II)化合物所述定义一致;
R12选自羟基保护基,“羟基保护基”是指用于羟基保护的基团,该基团适用于保护羟基,使羟基不进行化学反应,但是在分子的其它部分完成所需化学反应之后该基团容易除去。在《有机合成中的保护基》(华东理工大学有机化学教研室译,荣国斌校,华东理工大学出版社,2004;原书为Protective Groups In Organic Synthesis(thirdedition),Theodora W.Green and Peter G.M.Wuts著)中羟基及1,2-二醇和1,3-二醇的保护一章对羟基保护基做了详细介绍,本说明书将《有机合成中的保护基》中第23-199页引用作为本书明书的一部分,本发明所述的羟基保护基优选三烷基硅基或烷基酰基,更优选选自三甲基硅基、二甲基叔丁基硅基、三异丙基硅基、二叔丁基甲基硅基、乙酰基或卤素取代的乙酰基;
R13选自发生亲核反应时离去基团,优选Cl、Br或I;
通式(II-A)化合物为羧酸类化合物,与通式(II-B)化合物在适宜条件下发生酰化反应时生成通式(II-C)化合物;任选地,通式(II-A)化合物与通式(II-B)化合物可在缩合剂如碳二胺类缩合剂(二环己基碳二亚胺(DCC)、二异丙基碳二亚胺(DIC)、1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐(EDCI)或苯并***基磷酸二乙酯(BDP)),或者通式(II-A)化合物与具有活化羧基性质的化合物反应后生成活性羧酸酯或活性酸酐,活性羧酸酯或活性酸酐与通式(II-B)直接反应生成通式(II-C)化合物;
通式(II-C)化合物在适宜条件下脱除羟基保护基生成通式(II-D)化合物,或者通式(II-C)化合物在适宜条件下同时脱除羟基保护基和发生关环反应(一锅法)生成通式(II)化合物;
通式(II-D)化合物在适宜条件下发生关环反应生成通式(II)化合物,反应优选地在碱性试剂条件下进行,所述的碱性试剂选自二异丙基乙基胺、二异丙基胺、三乙胺、氢氧化钠、氢氧化钾、氢氧化锂、碳酸钾、碳酸氢钠、碳酸钠、叔丁醇钠、叔丁醇钾、醋酸钾、醋酸钠、氢化钠或碳酸铯等;
通式(II-B)化合物可通过购买或参考WO2005028470、WO2000078735或WO2005028469等文献制备得到。
发明的详细说明
除非有相反的陈述,在说明书和权利要求书中使用的术语具有下述含义。
本发明所述基团和化合物中所涉及的碳、氢、氧、硫、氮或卤素均包括它们的同位素情况,及本发明所述基团和化合物中所涉及的碳、氢、氧、硫或氮任选进一步被一个或多个它们对应的同位素所替代,其中碳的同位素包括12C、13C和14C,氢的同位素包括氕(H)、氘(D,又叫重氢)、氚(T,又叫超重氢),氧的同位素包括16O、17O和18O,硫的同位素包括32S、33S、34S和36S,氮的同位素包括14N和15N,氟的同位素包括17F和19F,氯的同位素包括35Cl和37Cl,溴的同位素包括79Br和81Br。
“烷基”是指含1至20个碳原子的直链或支链饱和脂肪族烃基,优选为1至8个碳原子的烷基,更优选为1至6个碳原子的烷基,进一步优选为1至4个碳原子的烷基。非限制性实施例包括甲基、乙基、正丙基、异丙基、正丁基、仲丁基、叔丁基、正戊基、2-戊基、3-戊基、2-甲基-2-戊基、3-甲基-2-戊基、4-甲基-2-戊基、3-甲基-3-戊基、2-甲基-3-戊基、2,3-二甲基-2-丁基、3,3-二甲基-2-丁基、正庚基、正辛基及其各种支链异构体;所述的烷基可以任选进一步被0至5个选自F、Cl、Br、I、=O、-CH2F、-CHF2、-CF3、-OCF3、羟基、-SR18、硝基、氰基、异氰基、烯基、炔基、烷基、羟基烷基、烷氧基、丙烯酰胺基、碳环基、杂环基、-(CH2)m-C(=O)-R18、-(CH2)m-C(=O)-O-R18、-(CH2)m-C(=O)-NR18R18a、-(CH2)m-S(=O)n-R18、-O-C(=O)-O-R18或者-NR18R18a的取代基所取代,其中R18和R18a各自独立选自H、羟基、氨基、羧基、C1-8烷基、C1-8烷氧基、C2-8烯基、C2-8炔基、3至10元碳环基、3至10元杂环基、3至10元碳环基氧基或者3至10元杂环基氧基,m选自0、1、2、3、4或者5,n选自0、1或者2。本文中出现的烷基、R18和R18a,其定义如上所述。
“烯基”是指含1至20个碳原子的直链或支链的含有碳-碳双键脂肪族烃基,优选为1至8个碳原子的烯基,更优选为1至6个碳原子的烯基,进一步优选为1至4个碳原子的烯基。非限制性实施例包括乙烯基、烯丙基、1-丙烯基、2-丙烯基、1-丁烯基、2-丁烯基、1-戊烯基、2-戊烯基、3-戊烯基、1-甲基-1-丁烯基、2-甲基-1-丁烯基、2-甲基-3-丁烯基、1-己烯基、2-己烯基、3-己烯基、1-甲基-1-戊烯基、2-甲基-1-戊烯基、1-庚烯基、2-庚烯基、3-庚烯基、4-庚烯基、1-辛烯基、3-辛烯基、1-壬烯基、3-壬烯基、1-癸烯基、4-癸烯基、1,3-丁二烯、1,3-戊二烯、1,4-戊二烯、1,4-己二烯、3-十一烯基、4-十二烯基和4,8,12-十四碳三烯基等。所述的炔基可以任选进一步被0至5个选自F、Cl、Br、I、=O、-CH2F、-CHF2、-CF3、-OCF3、羟基、-SR18、硝基、氰基、异氰基、烯基、炔基、烷基、羟基烷基、烷氧基、丙烯酰胺基、碳环基、杂环基、-(CH2)m-C(=O)-R18、-(CH2)m-C(=O)-O-R18、-(CH2)m-C(=O)-NR18R18a、-(CH2)m-S(=O)n-R18、-O-C(=O)-O-R18或者-NR18R18a的取代基所取代。本文中出现的烯基,其定义如上所述。
“炔基”是指含1至20个碳原子的直链或支链的含有碳-碳三键脂肪族烃基,优选为1至8个碳原子的炔基,更优选为1至6个碳原子的炔基,进一步优选为1至4个碳原子的炔基。非限制性实施例包括乙炔基、炔丙基、1-丙炔基、2-丙炔基、1-丁炔基、2-丁炔基、1-戊炔基、2-戊炔基、3-戊炔基、1-甲基-1-丁炔基、2-甲基-1-丁炔基、1-己炔基、2-己炔基、3-己炔基和1-甲基-1-戊炔基。所述的炔基可以任选进一步被0至5个选自F、Cl、Br、I、=O、-CH2F、-CHF2、-CF3、-OCF3、羟基、-SR18、硝基、氰基、异氰基、烯基、炔基、烷基、羟基烷基、烷氧基、丙烯酰胺基、碳环基、杂环基、-(CH2)m-C(=O)-R18、-(CH2)m-C(=O)-O-R18、-(CH2)m-C(=O)-NR18R18a、-(CH2)m-S(=O)n-R18、-O-C(=O)-O-R18或者-NR18R18a的取代基所取代。本文中出现的烯基,其定义如上所述。
“烷氧基”是指-O-烷基,非限制性实施例包括甲氧基、乙氧基、1-丙氧基、2-丙氧基、1-丁氧基、2-甲基-1-丙氧基、2-丁氧基、2-甲基-2-丙氧基、1-戊氧基、2-戊氧基、3-戊氧基、2-甲基-2-丁氧基、3-甲基-2-丁氧基、3-甲基-1-丁氧基和2-甲基-1-丁氧基。
烷硫基”是指-S-烷基,非限制性实施例包括甲硫基、乙硫基、1-丙硫基、2-丙硫基、1-丁硫基、2-甲基-1-丙硫基、2-丁硫基、2-甲基-2-丙硫基、1-戊硫基、2-戊硫基、3-戊硫基、2-甲基-2-丁硫基、3-甲基-2-丁硫基、3-甲基-1-丁硫基和2-甲基-1-丁硫基。
“碳环基”或“碳环”是指饱和或者不饱和的芳香环或者非芳香环,芳香环或者非芳香环可以是3至10元的单环、4至12元双环或者10至15元三环体系,碳环基可以连接有桥环或者螺环,非限制性实施例包括环丙基、环丁基、环戊基、1-环戊基-1-烯基、1-环戊基-2-烯基、1-环戊基-3-烯基、环己基、1-环己基-2-烯基、1-环己基-3-烯基、环己烯基、环己二烯基、环庚基、环辛基、环壬基、环癸基、环十一烷基、环十二烷基、苯基、萘基、所述的碳环基可以任选进一步被0至8个选自F、Cl、Br、I、=O、-CH2F、-CHF2、-CF3、-OCF3、羟基、-SR18、硝基、氰基、异氰基、烯基、炔基、烷基、羟基烷基、烷氧基、丙烯酰胺基、碳环基、杂环基、-(CH2)m-C(=O)-R18、-(CH2)m-C(=O)-O-R18、-(CH2)m-C(=O)-NR18R18a、-(CH2)m-S(=O)n-R18、-O-C(=O)-O-R18或者-NR18R18a的取代基所取代。本文中出现的碳环基,其定义如上所述。
“杂环”或“杂环基”是指取代的或未取代的饱和或不饱和的芳香环或者非芳香环,芳香环或者非芳香环可以是3至10元的单环、4至12元双环或者10至15元三环体系,且包含1至4个选自N、O或S(=O)n的杂原子或基团,优选4至8元杂环基,杂环基的环中选择性取代的N、S可被氧化成各种氧化态。杂环基可以连接在杂原子或者碳原子上,杂环基可以连接有桥环或者螺环,非限制性实施例包括环氧乙基、环氧丙基、氮杂环丙基、氧杂环丁基、氮杂环丁基、硫杂环丁基、1,3-二氧戊环基、1,4-二氧戊环基、1,3-二氧六环基、氮杂环庚基、氧杂环庚基、硫杂环庚基、氧氮杂卓基、二氮杂卓基、硫氮杂卓基、吡啶基、喹啉基、异喹啉基、苯并吲哚基、吡唑[1,5-a]吡啶基、吡唑[1,5-c]嘧啶基、嘌呤基、噻唑基、吡咯基、吲唑基、7H-吡咯[2,3-d]嘧啶基、噻吩[3,2-d]嘧啶基、苯并[d]咪唑基或6,7-二氢-5H-吡咯[2,3-d]嘧啶基,[1,2,4]***[1,5-a]吡啶基、哌啶基、高哌啶基、呋喃基、噻吩基、吡喃基、N-烷基吡咯基、嘧啶基、吡嗪基、哒嗪基、哌嗪基、高哌嗪基、咪唑基、哌啶基、哌叮基、吗啉基、硫代吗啉基、噻噁烷基、1,3-二噻基、二氢呋喃基、二氢吡喃基、二噻戊环基、四氢呋喃基、四氢噻吩基、四氢吡喃基、四氢噻喃基、四氢吡咯基、四氢咪唑基、四氢噻唑基、四氢吡喃基、苯并咪唑基、苯并吡啶基、吡咯并吡啶基、苯并二氢呋喃基、2-吡咯啉基、3-吡咯啉基、二氢吲哚基、2H-吡喃基、4H-吡喃基、二氧杂环己基、1,3-二氧戊基、吡唑啉基、二噻烷基、二噻茂烷基、二氢噻吩基、吡唑烷基咪唑啉基、咪唑烷基、1,2,3,4-四氢异喹啉基、1,2,3,4-四氢喹啉基、3-氮杂双环[3.1.0]己基、3-氮杂双环[4.1.0]庚基、氮杂双环[2.2.2]己基、3H-吲哚基喹嗪基、N-吡啶基尿素、1,1-二氧硫代吗啉基、氮杂二环[3.2.1]辛烷基、氮杂二环[5.2.0]壬烷基、氧杂三环[5.3.1.1]十二烷基、氮杂金刚烷基和氧杂螺[3.3]庚烷基。所述的杂环基可以任选进一步被0至8个选自F、Cl、Br、I、=O、-CH2F、-CHF2、-CF3、-OCF3、羟基、-SR18、硝基、氰基、异氰基、烯基、炔基、烷基、羟基烷基、烷氧基、丙烯酰胺基、碳环基、杂环基、-(CH2)m-C(=O)-R18、-(CH2)m-C(=O)-O-R18、-(CH2)m-C(=O)-NR18R18a、-(CH2)m-S(=O)n-R18、-O-C(=O)-O-R18或者-NR18R18a的取代基所取代。本文中出现的杂环基,其定义如上所述。
“丙烯酰胺基”是指取代的或者未取代的-NHC(=O)CH=CH2,当被取代时,任选进一步被0至3个选自F、Cl、Br、I、=O、-CH2F、-CHF2、-CF3、-OCF3、羟基、-SR18、硝基、氰基、异氰基、烯基、炔基、烷基、羟基烷基、烷氧基、丙烯酰胺基、碳环基、杂环基、-(CH2)m-C(=O)-R18、-(CH2)m-C(=O)-O-R18、-(CH2)m-C(=O)-NR18R18a、-(CH2)m-S(=O)n-R18、-O-C(=O)-O-R18或者-NR18R18a的取代基所取代。本文中出现的丙烯酰胺基,其定义如上所述。
“=O”是本领域通常习惯用法,是指以双键相连的氧原子,譬如羰基中与碳原子相连的双键氧原子。
“药学上可接受的盐”或者“其药学上可接受的盐”是指本发明化合物保持游离碱的生物有效性和特性,且所述的游离碱通过与无毒的无机酸或者有机酸反应获得的盐。所述的无机酸的非限制性实施例包括氢氟酸、盐酸、氢溴酸、氢碘酸、硫酸盐、磷酸、次氯酸、高氯酸、碘酸、碳酸、亚硝酸、次硝酸、偏硼酸、硼酸、偏硅酸、硅酸、偏亚磷酸、偏磷酸、焦磷酸、氢硫酸、亚硫酸、硫代硫酸和高锰酸;所述的有机酸非限制性实施例包括甲酸、醋酸、三氟乙酸、硫氰酸、马来酸、羟基马来酸、戊二酸、甲磺酸、乙磺酸、苯磺酸、对甲苯磺酸、苯甲酸、水杨酸、苯乙酸、肉桂酸、乳酸、丙二酸、特戊酸、琥珀酸、富马酸、苹果酸、扁桃酸、酒石酸、没食子酸、葡萄糖酸、月桂酸、棕榈酸、果胶酸、苦味酸和柠檬酸。
“载体”是指不会对生物体产生明显刺激且不会消除所给予化合物的生物活性和特性的材料。
“赋形剂”是指加入到药物组合物中以促进化合物给药的惰性物质。非限制性实施例包括碳酸钙、磷酸钙、糖、淀粉、纤维素衍生物(包括微晶纤维素)、明胶、植物油、聚乙二醇类、稀释剂、成粒剂、润滑剂、粘合剂和崩解剂。
“佐剂”是非特异性免疫增强剂,当与抗原一起注射或预先注入机体时,可增强机体对抗原的免疫应答或改变免疫应答类型。
“稀释剂”也叫“填充剂”。把原药加工成粉剂时,或为了使其便于喷施所加入的进行稀释的惰性物质。如:粘土、高岭土、陶土、滑石粉等。
“前药”是指可经体内代谢转化为具有生物活性的本发明化合物,这样的转化受前体药物在血液中水解或在血液组织中经酶转化为母体结构的影响。本发明的前药通过修饰本发明化合物中的功能基团来制备,该修饰可以通过常规的操作或者在体内被除去,而得到母体化合物。
“共晶”是指活性药物成分(active pharmaceutical ingredient,API)和共晶形成物(cocrystal former,CCF)在氢键或其他非共价键的作用下结合而成的晶体,其中API和CCF的纯态在室温下均为固体,并且各组分间存在固定的化学计量比。共晶是一种多组分晶体,既包含两种中性固体之间形成的二元共晶,也包含中性固体与或溶剂化物形成的多元共晶。所述“共晶形成物”的非限定性实例包括丙氨酸、缬氨酸、亮氨酸、异亮氨酸、脯氨酸、苯丙氨酸、色氨酸、蛋氨酸、甘氨酸、丝氨酸、苏氨酸、半胱氨酸、酪氨酸、天冬酰胺、谷氨酰胺、赖氨酸、精氨酸、组氨酸、天冬氨酸、门冬氨酸、谷氨酸、焦谷氨酸、硫酸、磷酸、硝酸、氢溴酸、酸、甲酸、乙酸、丙酸、苯磺酸、苯甲酸、苯乙酸、水杨酸、褐藻酸、氨茴酸、樟脑酸、柠檬酸、乙烯磺酸、蚁酸、富马酸、糠酸、葡萄糖酸、葡萄糖醛酸、谷氨酸、乙醇酸、羟乙磺酸、乳酸、马来酸、苹果酸、扁桃酸、粘液酸、双羟萘酸、泛酸、硬脂酸、琥珀酸、磺胺酸、酒石酸、对甲苯磺酸、丙二酸、2-羟基丙酸、草酸、羟乙酸、葡萄糖醛酸、半乳糖醛酸、枸橼酸、肉桂酸、对甲苯磺酸、甲磺酸、乙磺酸或三氟甲磺酸、氨、异丙基胺、三甲基胺、二乙胺、三乙胺、三丙基胺、二乙醇胺、乙醇胺、二甲基乙醇胺、2-二甲基氨基乙醇、2-二乙基氨基乙醇、二环己基胺、咖啡碱、普鲁卡因、胆碱、甜菜碱、苯明青霉素、乙二胺、葡萄糖胺、甲基葡糖胺、可可碱、三乙醇胺、氨丁三醇、嘌呤、哌嗪、哌啶和N-乙基哌啶。
“立体异构体”是指由分子中原子在空间上排列方式不同所产生的异构体,包括顺反异构体、对映异构体和构象异构体。
“任选”或“任选地”或“选择性的”或“选择性地”是指随后所述的事件或状况可以但未必发生,该描述包括其中发生该事件或状况的情况及其中未发生的情况。例如,“选择性地被烷基取代的杂环基”是指该烷基可以但未必存在,该描述包括其中杂环基被烷基取代的情况,及其中杂环基未被烷基取代的情况。
具体实施方式
以下通过具体实施例并配合附图详细说明本发明的实施过程和产生的有益效果,旨在帮助阅读者更好地理解本发明的实质和特点,不作为对本案可实施范围的限定。
化合物的结构是通过核磁共振(NMR)或(和)质谱(MS)来确定的。NMR位移(δ)以10-6(ppm)的单位给出。
NMR的测定是用(Bruker Avance III 400和Bruker Avance 300)核磁仪,测定溶剂为氘代二甲基亚砜(DMSO-d6),氘代氯仿(CDCl3),氘代甲醇(CD3OD),内标为四甲基硅烷(TMS)。
MS的测定用(Agilent 6120B(ESI)和Agilent 6120B(APCI))。
HPLC的测定使用安捷伦1260DAD高压液相色谱仪(Zorbax SB-C18100×4.6mm)。
薄层层析硅胶板使用烟台黄海HSGF254或青岛GF254硅胶板,薄层色谱法(TLC)使用的硅胶板采用的规格是0.15mm~0.20mm,薄层层析分离纯化产品采用的规格是0.4mm~0.5mm。
柱层析一般使用烟台黄海硅胶200~300目硅胶为载体。
本发明的己知的起始原料可以采用或按照本领域已知的方法来合成,或可购买于泰坦科技、安耐吉化学、上海德默、成都科龙化工、韶远化学科技、百灵威科技等公司。
氮气氛是指反应瓶连接一个约1L容积的氮气气球。氢气氛是指反应瓶连接一个约1L容积的氢气气球。氢化反应通常抽真空,充入氢气,反复操作3次。实施例中无特殊说明,反应在氮气氛下进行。实施例中无特殊说明,溶液是指水溶液。实施例中无特殊说明,反应的温度为室温。实施例中无特殊说明,M为摩尔每升。室温为最适宜的反应温度,20℃为最适宜的反应温度。TBS为叔丁基二甲基硅基。
中间体1:3-乙酰氧基-4-溴-3-甲基-2-甲烯基-丁酸(中间体1)
3-acetoxy-4-bromo-3-methyl-2-methylene-butanoic acid
第一步:溴丙酮(1b)
1-bromopropan-2-one
将1-溴-2,2-二甲氧基丙烷(1a)(20g,109.27mmol)溶于氯仿(100mL)中,加入三氟乙酸(74.75g,655.59mmol),室温反应4小时。反应液加入二氯甲烷(30mL)和水(150mL),萃取分层。有机相用饱和食盐水(100mL×4)洗涤,无水硫酸钠干燥,30℃减压浓缩,得到标题化合物1b,黑色油状(11g,产率73.5%)。
1H NMR(400MHz,CDCl3)δ3.90(s,2H),2.39(s,3H)。
第二步:4-溴-3-羟基-3-甲基-2-甲烯基-丁酸叔丁酯(1c)
tert-butyl 4-bromo-3-hydroxy-3-methyl-2-methylene-butanoate
将六甲基磷酰三胺(21.48g,119.9mmol)溶于四氢呋喃(320mL)中,氮气保护下在0℃加入1.5mol/L二异丁基氢化铝的甲苯溶液(108mmol,72mL),0℃反应0.5小时,加入丙炔酸叔丁酯(10.08g,79.90mmol),继续反应1小时,再加入1b(10.95g,79.90mmol),逐渐升至室温反应5小时。向反应液慢慢加入1M盐酸调节pH至2~3,加入乙酸乙酯(50mL),萃取。水相用乙酸乙酯(50mL×1)萃取,合并有机相。有机相用饱和食盐水(100mL×1)洗涤,无水硫酸钠干燥,过滤,滤液减压浓缩。残留物用硅胶柱色谱分离提纯(乙酸乙酯:石油醚(v/v)=0:1~1:9),得到标题化合物1c,黄色油状(4.2g,产率20%)。
1H NMR(400MHz,CDCl3)δ6.25(d,1H),5.90(d,1H),3.83(d,1H),3.70(s,1H),3.64(d,1H),1.55(s,3H),1.52(s,9H)。
LCMS m/z=286.9[M+Na]。
第三步:3-乙酰氧基-4-溴-3-甲基-2-甲烯基-丁酸叔丁酯(1d)
tert-butyl 3-acetoxy-4-bromo-3-methyl-2-methylene-butanoate
将1c(1.6g,6.0mmol)溶于二氯甲烷(15mL)中,加入乙酸酐(0.92g,9.1mmol),0℃下加入三氟甲磺酸三甲基硅脂(0.034g,0.15mmol)的二氯甲烷(0.2mL)溶液,0℃反应10分钟。反应液加入15mL水(15mL)和二氯甲烷(15mL),萃取分层。有机相用饱和食盐水(15mL×1)洗涤,无水硫酸钠干燥,浓缩。残留物用硅胶柱色谱分离提纯(乙酸乙酯:石油醚(v/v)=0:1~1:19),得到标题化合物1d,黄色液体(1.1g,产率59%)。
1H NMR(400MHz,CDCl3)δ6.21(s,1H),5.76(s,1H),4.10(d,2H),2.08(s,3H),1.82(s,3H),1.50(s,9H)。
LCMS m/z=329.0[M+Na]。
第四步:3-乙酰氧基-4-溴-3-甲基-2-甲烯基-丁酸(中间体1)
3-acetoxy-4-bromo-3-methyl-2-methylene-butanoic acid
将1d(1.7g,5.5mmol)溶于二氯甲烷(8mL)中,加入三氟乙酸(7mL),室温反应2小时。反应液浓缩,残留物用硅胶柱色谱分离提纯(乙酸乙酯:石油醚(v/v)=0:19~1:4),得到标题化合物中间体1,黑色液体(1.1g,产率49%)。
1H NMR(400MHz,CDCl3)δ6.58(s,1H),6.05(s,1H),4.16(d,1H),4.06(d,1H),2.10(d,3H),1.86(s,3H).
中间体2:4-溴-3-[叔丁基(二甲基)硅基]氧基-2-甲烯基-戊酸(中间体2)
4-bromo-3-[tert-butyl(dimethyl)silyl]oxy-2-methylene-pentanoic acid
第一步:2-溴丙醛(2b)
2-bromopropanal
将2-溴-1,1-二甲氧基丙烷(2a)(18g,98.34mmol)溶于氯仿(100mL)中,加入三氟乙酸(67.28g,590.03mmol),室温反应4小时。反应液加入二氯甲烷(30mL)和水(15mL),萃取分层。有机相用饱和食盐水(100mL×4)洗涤,无水硫酸钠干燥,过滤,滤液30℃下减压浓缩得到标题化合物2b,黄色液体(5g,产率37%)。
1H NMR(400MHz,CDCl3)δ9.47(d,1H),4.41–4.30(m,1H),1.76(d,3H)。
第二步:4-溴-3-羟基-2-甲烯基-戊酸叔丁酯(2c)
tert-butyl 4-bromo-3-hydroxy-2-methylene-pentanoate
将六甲基磷酰三胺(10.7g,59.9mmol)溶于四氢呋喃(160mL)中,氮气保护下在0℃加入二异丁基氢化铝(1.5M,36mL),0℃反应0.5小时,加入丙炔酸叔丁酯(5.04g,40mmol),继续反应1小时,然后加入2b(5.47g,40mmol),逐渐升至室温,反应5小时,向反应液中慢慢加入1M盐酸,调节反应液pH至2~3,然后乙酸乙酯(50mL×2)萃取,合并有机相,有机相用饱和食盐水(100mL×1)洗涤,无水硫酸钠干燥,过滤,滤液减压浓缩后,残留物用硅胶柱色谱分离提纯(乙酸乙酯:石油醚(v/v)=0:1~1:9),得到标题化合物2c,黄色油状(2.2g,产率21%)。
1H NMR(400MHz,CDCl3)δ6.31(m,1H),5.90(m,1H),4.58(d,1H),4.44(qd,1H),3.02(d,1H),1.64(d,3H),1.51(s,9H)。
LCMS m/z=287.0[M+Na]。
第三步:4-溴-3-羟基-2-甲烯基-戊酸(2d)
4-bromo-3-hydroxy-2-methylene-pentanoic acid
将2c(0.35g,1.3mmol)溶于二氯甲烷(8mL)中,加入三氟乙酸(1.5mL),室温反应3小时。反应液加入水(20mL),萃取分层。有机相用水(10mL×2)洗涤,合并水相。水相用乙酸乙酯(20mL×2)萃取,合并有机相。有机相用无水硫酸钠干燥,过滤,滤液减压浓缩得到标题化合物2d,黄色液体(0.24g,产率87%)。
1H NMR(400MHz,CDCl3)δ6.62(s,1H),6.19(s,1H),4.71(d,1H),4.50(qd,1H),1.63(d,3H)。
LCMS m/z=231.0[M+Na]。
第四步:4-溴-3-[叔丁基(二甲基)硅基]氧基-2-甲烯基-戊酸(中间体2)
4-bromo-3-[tert-butyl(dimethyl)silyl]oxy-2-methylene-pentanoic acid
将2d(0.210g,1.0mmol)溶于二氯甲烷(8mL)中,加入咪唑(0.684g,10.0mmol),再加入叔丁基二甲基氯硅烷(0.757g,5.02mmol),室温反应4小时。反应液加入氢氧化钠溶液(pH为10~12,20mL),搅拌1分钟。萃取分层,水相用二氯甲烷(10mL×1)萃取,合并有机相。有机相用1M盐酸(10mL×1)洗涤,无水硫酸钠干燥,过滤,滤液减压浓缩。残留物用硅胶柱色谱分离提纯(乙酸乙酯:石油醚(v/v)=0:1~1:9),得到标题化合物中间体2,无色液体(0.325g,产率100%)。
中间体3:4-溴-3-[叔丁基(二甲基)硅基]氧基-2-甲烯基-丁酸(中间体3)
4-bromo-3-[tert-butyl(dimethyl)silyl]oxy-2-methylene-butanoic acid
第一步:2-溴乙醛(3b)
2-bromoacetaldehyde
将溴乙醛二乙缩醛(3a)(100g,0.507mol)溶解在氯仿(300mL)中,慢慢滴加三氟乙酸(150mL,2.019mol),约1小时滴完,室温反应18小时。反应液慢慢加入水(200mL),萃取分层。有机相用饱和食盐水洗涤,每次150mL,直至水相pH至5~6。有机相用无水硫酸钠干燥,过滤,滤液30℃减压浓缩得标题化合物1b粗品(8g),直接用于下一步。
1H NMR(400MHz,CDCl3)δ9.54(t,J=2.6Hz,1H),3.85(d,J=2.6Hz,2H).
第二步:4-溴-3-羟基-2-甲烯基-丁酸叔丁酯(3d)
tert-butyl 4-bromo-3-hydroxy-2-methylene-butanoate
将六甲基磷酰三胺(11.5g,64.2mmol)溶解在干燥四氢呋喃(100mL)中,氮气保护下冷却至0℃,滴加二异丁基氢化铝(1.5M的甲苯溶液)(36mL,54mmol),0℃搅拌30分钟,滴加丙炔酸叔丁酯(3c)(5.4g,43mmol)的干燥四氢呋喃溶液(30mL)中,滴完后搅拌1小时再滴入3b的粗品(8g)溶解在干燥四氢呋喃(30mL)中,加完后,自然升温至室温反应3小时。冷却至0℃,慢慢滴加1M的稀盐酸调节pH至7,萃取分层,水层用乙酸乙酯(30mL×1)萃取,合并有机层,饱和氯化钠(15mL×1)洗涤,无水硫酸钠干燥,减压浓缩后,残留物硅胶柱柱层析纯化(洗脱剂:石油醚:乙酸乙酯(v:v)=1:0~20:1)得标题化合物3d,浅黄色油状物(2.6g,产率24%)。
1H NMR(400MHz,CDCl3)δ6.23(d,1H),5.84(d,1H),4.56(dd,1H),3.63(m,1H),3.44(m,1H),1.44(s,9H)。
LCMS(m/z):274.9[M+23]。
第三步:4-溴-3-羟基-2-甲烯基-丁酸(3e)
4-bromo-3-hydroxy-2-methylene-butanoic acid
将3c(2.6g,10.3mmol)溶解在二氯甲烷(20mL)中,滴加三氟乙酸(5mL),加完后室温反应1小时。加入水(25mL),萃取分层,收集水层,有机层再用水(25mL×1)洗涤,萃取分层,收集水层,合并水层,加入氯化钠(1g),用乙酸乙酯(50mL×2)萃取,合并乙酸乙酯层,用饱和氯化钠溶液(10mL×3)洗涤,无水硫酸钠干燥,减压浓缩至干,得标题化合物3e粗品1.5g,直接用于下一步。
1H NMR(400MHz,CDCl3)δ6.61(s,1H),6.18(s,1H),4.75–4.70(m,1H),3.74(dd,1H),3.55(dd,1H)。
第四步:4-溴-3-[叔丁基(二甲基)硅基]氧基-2-甲烯基-丁酸(中间体3)
4-bromo-3-[tert-butyl(dimethyl)silyl]oxy-2-methylene-butanoic acid
将3e(1.5g,7.7mmol)溶解在二氯甲烷(15mL)中,氮气保护下冷却至0℃,加入咪唑(5.2g,77mmol),再慢慢滴加叔丁基二甲基氯硅烷(5.8g,38.5mmol)的二氯甲烷(5mL)溶液,滴完后,自然升温至室温反应5小时。加入氢氧化钠水溶液(pH为10~12,20mL),搅拌1分钟后萃取分层,水层用乙酸乙酯(30mL×1)萃取,合并有机层,用1M的盐酸水溶液调节pH为5至6,分液,有机层再用饱和氯化钠溶液(10mL×2)洗涤,无水硫酸钠干燥,减压浓缩所得粗品用硅胶柱纯化(洗脱剂为石油醚:乙酸乙酯(v:v)=1:0~20:1~10:1),得标题化合物中间体3,无色油状物(2.3g,产率97%)。
1H NMR(400MHz,CDCl3)δ6.56(s,1H),6.18(s,1H),4.82–4.74(m,1H),3.58(dd,1H),3.40(dd,1H),0.93(s,9H),0.15(s,3H),0.05(s,3H)。
实施例1:1-[4-[4-(3-氯-2,4-二氟-苯胺基)-7-甲氧基-喹唑啉-6-基]氧基-1-哌啶基-2-(环氧乙烷-2-基)丙-2-烯-1-酮(化合物1)
1-[4-[4-(3-chloro-2,4-difluoro-anilino)-7-methoxy-quinazolin-6-yl]oxy-1-piperidyl]-2-(oxiran-2-yl)prop-2-en-1-one
第一步:4-溴-3-[叔丁基(二甲基)甲硅烷基]氧基-1-[4-[4-(3-氯-2,4-二氟-苯胺基)-7-甲氧基喹唑啉-6-基]氧基-1-哌啶基]-2-甲烯基-丁-1-酮(1B)
4-bromo-3-[tert-butyl(dimethyl)silyl]oxy-1-[4-[4-(3-chloro-2,4-difluoro-anilino)-7-methoxy-quinazolin-6-yl]oxy-1-piperidyl]-2-methylene-butan-1-one
将中间体3(0.65g,2.1mmol)溶解在四氢呋喃(7mL)中,加入1-羟基苯并***(0.34g,2.5mmol),再加入1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐(0.48g,2.5mmol),加完后室温搅拌反应1小时,加入1A(0.5g,1.19mmol),继续室温反应2小时。加入水(15mL),用乙酸乙酯(20mL×3)萃取,合并有机层,用饱和氯化钠(15mL×1)洗涤,无水硫酸钠干燥,过滤,滤液减压浓缩,残余物用硅胶柱柱层析纯化(洗脱剂:石油醚:乙酸乙酯(v:v)=4:10~6:10~1:0),得标题化合物1B,白色固体(0.28g,产率33.0%)。
LCMS(m/z):713.0[M+1]。
第二步:4-溴-1-[4-[4-(3-氯-2,4-二氟-苯胺基)-7-甲氧基喹唑啉-6-基]氧基-1-哌啶基]-3-羟基-2-甲烯基-丁-1-酮(1C)
4-bromo-1-[4-[4-(3-chloro-2,4-difluoro-anilino)-7-methoxy-quinazolin-6-yl]oxy-1-piperidyl]-3-hydroxy-2-methylene-butan-1-one
将1B(0.2g,0.28mmol)溶解于二氯甲烷(3mL)中,氮气保护下冰浴冷却至0℃,加入三氟乙酸(1mL),加完后继续搅拌10分钟后,升至室温反应1小时。慢慢滴加饱和碳酸氢钠调节pH至7,加入二氯甲烷(10mL),萃取分层,水层再用二氯甲烷(10mL×1)萃取,合并有机层,饱和氯化钠溶液(5mL×1)洗涤,无水硫酸钠干燥,减压浓缩后,残留物用薄层层析纯化(展开剂为甲醇:二氯甲烷(v:v)=1:20)得标题化合物1C,浅黄色固体(0.045g,产率26.9%)。
1H NMR(400MHz,CDCl3)δ8.64(s,1H),8.23(s,1H),7.32(s,2H),7.08–7.01(m,1H),5.66(s,1H),5.38(s,1H),4.77(s,1H),4.53(t,1H),4.02(s,3H),4.00–3.87(m,2H),3.84–3.70(m,2H),3.65–3.58(m,1H),3.55–3.50(m,1H),2.07-1.95(m,4H)。
LCMS(m/z):597.2[M+1]。
第三步:1-[4-[4-(3-氯-2,4-二氟-苯胺基)-7-甲氧基-喹唑啉-6-基]氧基-1-哌啶基-2-(环氧乙烷-2-基)丙-2-烯-1-酮(化合物1)
1-[4-[4-(3-chloro-2,4-difluoro-anilino)-7-methoxy-quinazolin-6-yl]oxy-1-piperidyl]-2-(oxiran-2-yl)prop-2-en-1-one
将1C(0.045g,0.075mmol)溶解在四氢呋喃(3mL)中,冰浴冷却至0℃,将氢氧化锂(0.003g,0.13mmol)的水溶液(1mL)慢慢滴加到反应液中,滴加完后,继续冰浴下反应1小时。加入水(5mL),用二氯甲烷(10mL×1)萃取,再用甲醇/二氯甲烷(v/v=1/20)的混合溶剂(10mL×1)萃取,合并有机层,用饱和氯化钠溶液(5mL×1)洗涤,无水硫酸钠干燥,减压浓缩后,残留物用硅胶柱层析纯化(洗脱剂:甲醇:二氯甲烷(v:v)=0:1~3:100)得标题化合物化合物1,白色固体(0.030g,产率77.3%)。
1H NMR(400MHz,CDCl3)δ8.62(s,1H),8.19(s,1H),7.37(s,1H),7.31(s,1H),7.08–6.99(m,1H),5.58(s,1H),5.34(s,1H),4.75(s,1H),4.01(s,3H),3.81(s,2H),3.56-3.45(m,3H),3.02–2.96(m,1H),2.88(dd,1H),2.04-1.89(m,4H)。
19F NMR(376MHz,CDCl3)δ-116.36,-121.20。
LCMS(m/z):517.0[M+1]。
实施例2:1-[4-[4-(3-氯-2,4-二氟-苯氨基)-7-甲氧基-喹唑啉-6-基]氧基-1-哌啶基]-2-(3-甲基环氧乙烷基-2-基)丙-2-烯基-1-酮(化合物2)
1-[4-[4-(3-chloro-2,4-difluoro-anilino)-7-methoxy-quinazolin-6-yl]oxy-1-piperidyl]-2-(3-methyloxiran-2-yl)prop-2-en-1-one
第一步:4-溴-3-[叔丁基(二甲基)硅基]氧基-1-[4-[4-(3-氯-2,4-二氟-苯氨基)-7-甲氧基-喹唑啉-6-基]氧基-1-哌啶基]-2--甲烯基-戊烷-1-酮(2B)
4-bromo-3-[tert-butyl(dimethyl)silyl]oxy-1-[4-[4-(3-chloro-2,4-difluoro-anilino)-7-methoxy-quinazolin-6-yl]oxy-1-piperidyl]-2-methylene-pentan-1-one
将中间体2(1.23g,3.8mmol)溶于吡啶(12mL)中,加入1A(0.800g,1.9mmol),加入1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐(1.82g,9.51mmol),室温反应6小时。反应液加入乙酸乙酯(50mL)和水(50mL),萃取分层。水相用乙酸乙酯(30mL×1)萃取,合并有机相,无水硫酸钠干燥,过滤,滤液减压浓缩。残留物用硅胶柱色谱分离提纯(乙酸乙酯:石油醚(v/v)=2:3~4:1),得到标题化合物2B,黄色固体(0.42g,产率30%)。
1H NMR(400MHz,CDCl3)δ8.61(s,1H),8.16(s,1H),7.42(s,1H),7.31(d,1H),7.07–6.97(m,1H),5.71(s,1H),5.34(s,1H),4.78(s,1H),4.74(d,1H),4.27–4.18(m,1H),4.01(m,3H),3.99–3.88(m,2H),3.71–3.55(m,2H),2.09–1.99(m,2H),1.99–1.85(m,2H),1.62(d,3H),0.95(s,9H),0.18(s,3H),0.07(s,3H)。
第二步:1-[4-[4-(3-氯-2,4-二氟-苯氨基)-7-甲氧基-喹唑啉-6-基]氧基-1-哌啶基]-2-(3-甲基环氧乙烷-2-基)丙-2-烯基-1-酮(化合物2)
1-[4-[4-(3-chloro-2,4-difluoro-anilino)-7-methoxy-quinazolin-6-yl]oxy-1-piperidyl]-2-(3-methyloxiran-2-yl)prop-2-en-1-one
将2B(0.400g,0.55mmol)溶于四氢呋喃(10mL)中,加入四丁基氟化铵(0.288g,1.10mmol),室温反应4h。反应液加入乙酸乙酯(20mL),用饱和氯化铵溶液(20mL×2)洗涤,无水硫酸钠干燥,过滤,滤液减压浓缩,残留物用硅胶柱色谱分离提纯(乙酸乙酯:石油醚(v/v)=1:1~1:0)得到标题化合物化合物2,黄色固体(0.19g,产率65%)。
1H NMR(400MHz,CDCl3)δ8.54(s,1H),8.02(s,1H),7.79–7.44(m,1H),7.31(s,1H),6.99(d,1H),5.53(s,1H),5.30(s,1H),4.86(s,1H),4.01(s,3H),3.83(m,2H),3.57(m,2H),3.25(d,1H),3.12(qd,1H),2.10(m,2H),1.92(m,2H),1.36(d,3H)。
LCMS m/z=531.0[M+1]。
实施例3:1-[4-[4-(3-氯-2,4-二氟-苯氨基)-7-甲氧基-喹唑啉-6-基]氧基-1-哌啶基]-2-(2-甲基环氧乙烷-2-基)丙-2-烯基-1-酮(化合物3)
1-[4-[4-(3-chloro-2,4-difluoro-anilino)-7-methoxy-quinazolin-6-yl]oxy-1-piperidyl]-2-(2-methyloxiran-2-yl)prop-2-en-1-one
第一步:[1-(溴甲基)-2-[4-[4-(3-氯-2,4-二氟-苯氨基)-7-甲氧基-喹唑啉-6-基]氧基哌啶-1-羰基]-1-甲基-烯丙基]乙酸酯(3A)
[1-(bromomethyl)-2-[4-[4-(3-chloro-2,4-difluoro-anilino)-7-methoxy-quinazolin-6-yl]oxypiperidine-1-carbonyl]-1-methyl-allyl]acetate
将中间体1(0.400g,1.59mmol)溶于无水二氯甲烷(10mL)中,氮气保护下0℃加入草酰氯(1.62g,12.7mmol),加入两滴无水N,N-二甲基甲酰胺引发反应,室温反应1小时,升温至45℃再反应1小时,浓缩得反应液1。将1A(0.804g,1.91mmol)溶于无水四氢呋喃(15mL)中,0℃加入三乙胺(0.484g,4.78mmol),0℃加入反应液1的四氢呋喃溶液(10mL),逐渐升至室温反应2小时。反应液加入乙酸乙酯(10mL)和水(20mL),萃取分层。有机相用无水硫酸钠干燥,过滤,滤液减压浓缩。残留物用硅胶柱色谱分离提纯(乙酸乙酯:石油醚(v/v)=1:1~1:0),得到标题化合物3A,黄色固体(0.22g,产率21%)。
LCMS m/z=653.0[M+1]。
第二步:1-[4-[4-(3-氯-2,4-二氟-苯氨基)-7-甲氧基-喹唑啉-6-基]氧基-1-哌啶基]-2-(2-甲基环氧乙烷-2-基)丙-2-烯基-1-酮(化合物3)
1-[4-[4-(3-chloro-2,4-difluoro-anilino)-7-methoxy-quinazolin-6-yl]oxy-1-piperidyl]-2-(2-methyloxiran-2-yl)prop-2-en-1-one
将3A(0.220g,0.336mmol)溶于甲醇(5mL)中,加入碳酸钾(0.697g,5.05mmol),室温反应4小时。反应液加入乙酸乙酯(10mL)和水(10mL),萃取分层,有机相用无水硫酸钠干燥,过滤,滤液减压浓缩。残留物用硅胶柱色谱分离提纯(乙酸乙酯:石油醚(v/v)=1:1~1:0;甲醇:二氯甲烷(v/v)=3:97~1:19)得到标题化合物化合物3,白色固体(0.035g,产率20%)。
1H NMR(400MHz,CDCl3)δ8.60(s,1H),8.16(s,1H),7.42(s,1H),7.31(s,1H),7.02(t,1H),5.50(s,1H),5.28(s,1H),4.78(s,1H),4.03(s,3H),3.79(m,2H),3.53(m,2H),3.04(d,1H),2.83(d,1H),2.00(m,2H),1.96–1.85(m,2H),1.54(s,3H)。
LCMS m/z=531.0[M+1]。
实施例4:N-[4-(3-氯-4-氟-苯胺基)-7-[(3S)-四氢呋喃-3-基]氧基-喹唑啉-6-基]-2-(环氧乙烷-2-基)丙-2-烯酰胺(化合物4)
N-[4-(3-chloro-4-fluoro-anilino)-7-[(3S)-tetrahydrofuran-3-yl]oxy-quinazolin-6-yl]-2-(oxiran-2-yl)prop-2-enamide
第一步:4-溴-3-[叔丁基(二甲基)硅基]氧基-N-[4-(3-氯-4-氟-苯胺基)-7-[(3S)-四氢呋喃-3-基]氧基-喹唑啉-6-基]-2-甲烯基-丁酰胺(4B)
4-bromo-3-[tert-butyl(dimethyl)silyl]oxy-N-[4-(3-chloro-4-fluoro-anilino)-7-[(3S)-tetrahydrofuran-3-yl]oxy-quinazolin-6-yl]-2-methylene-butanamide
将中间体3(0.743g,2.4mmol)溶于吡啶(8mL)中,加入N4-(3-氯-4-氟-苯基)-[(3S)-四氢呋喃-3-基]氧基-喹唑啉-4,6–二胺(4A)(0.300g,0.8mmol),加入1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐(0.767g,4.0mmol),室温反应16小时。反应液加入乙酸乙酯(20mL)和水(20mL),萃取分层。水相用乙酸乙酯(20mL×1)萃取,合并有机相,无水硫酸钠干燥,过滤,滤液减压浓缩。残留物用硅胶柱色谱分离提纯(乙酸乙酯:石油醚(v/v)=3:7~4:1),得到标题化合物4B,黄色固体(0.12g,产率23%)。
1H NMR(400MHz,CDCl3)δ9.26(d,1H),9.10(d,1H),8.66(s,1H),7.89(m,2H),7.57–7.49(m,1H),7.45(m,1H),7.18(td,1H),6.28(d,1H),5.84(d,1H),5.21(s,1H),4.93–4.84(m,1H),4.17–4.00(m,3H),3.92(m,1H),3.68(m,1H),3.63–3.53(m,1H),2.48(m,1H),2.26(m,1H),0.91(s,9H),0.23(d,3H),0.13(d,3H)。
第二步:4-溴-N-[4-(3-氯-4-氟-苯胺基)-7-[(3S)-四氢呋喃-3-基]氧基-喹唑啉-6-基]-3-羟基-2-甲烯基-丁酰胺(4C)
4-bromo-N-[4-(3-chloro-4-fluoro-anilino)-7-[(3S)-tetrahydrofuran-3-yl]oxy-quinazolin-6-yl]-3-hydroxy-2-methylene-butanamide
将4B(0.12g,0.18mmol)溶于二氯甲烷(3mL)中,加入三氟乙酸(3mL),室温反应48小时。反应液浓缩,加入二氯甲烷(10mL)和饱和碳酸氢钠溶液(10mL),萃取分层。有机相用饱和食盐水(10mL×1)洗涤,无水硫酸钠干燥,过滤,滤液减压浓缩。残留物用硅胶柱色谱分离提纯(乙酸乙酯:石油醚(v/v)=1:1~1:0;甲醇:二氯甲烷(v/v)=1:19),得到标题化合物4C,黄色油状(0.08g,产率80%)。
1H NMR(400MHz,DMSO)δ10.37(s,1H),10.24(d,1H),9.07(d,1H),8.67(s,1H),8.07(m,1H),7.87–7.66(m,1H),7.47(t,1H),7.29(s,1H),6.67(s,1H),6.23(s,1H),5.85(s,1H),5.34(s,1H),4.77(s,1H),4.04(m,1H),3.93(m,2H),3.84(m,1H),3.70–3.60(m,2H),2.33(dt,1H),2.23–2.07(m,1H)。
19F NMR(376MHz,DMSO)δ-72.13。
LCMS m/z=550.8[M+1]。
第三步:N-[4-(3-氯-4-氟-苯胺基)-7-[(3S)-四氢呋喃-3-基]氧基-喹唑啉-6-基]-2-(环氧乙烷-2-基)丙-2-烯酰胺(化合物4)
N-[4-(3-chloro-4-fluoro-anilino)-7-[(3S)-tetrahydrofuran-3-yl]oxy-quinazolin-6-yl]-2-(oxiran-2-yl)prop-2-enamide
将4C(0.070g,0.13mmol)溶于四氢呋喃(5mL)中,0℃加入氢氧化锂一水合物(0.011g,0.25mmol)的水溶液(1mL),0℃反应30分钟。反应液加入乙酸乙酯(5mL)和水(10mL),萃取分层。有机相用饱和食盐水(10mL×1)洗涤,无水硫酸钠干燥,过滤,滤液减压浓缩。用硅胶柱色谱分离提纯(乙酸乙酯:石油醚(v/v)=1:1~1:0;甲醇:二氯甲烷(v/v)=1:33),得到标题化合物化合物4,白色固体(0.010g,产率14%)。
1H NMR(400MHz,DMSO)δ9.85(s,1H),9.62(s,1H),8.91(s,1H),8.55(s,1H),8.14(dd,1H),7.88–7.74(m,1H),7.71–7.69(m,1H),7.43(t,1H),6.21(s,1H),5.88(s,1H),5.35(s,1H),4.03(m,1H),3.93(m,3H),3.86–3.75(m,1H),3.13(t,1H),2.90(m,1H),2.41–2.24(m,1H),2.14(m,1H)。
19F NMR(376MHz,DMSO)δ-121.61。
LCMS m/z=471.0[M+1]。
实施例5:N-[4-(3-氯-4-氟-苯胺基)-7-[(3S)-四氢呋喃-3-基]氧基-喹唑啉-6-基]-2-(3-甲基环氧乙烷-2-基)丙-2-烯酰胺(化合物5)
N-[4-(3-chloro-4-fluoro-anilino)-7-[(3S)-tetrahydrofuran-3-yl]oxy-quinazolin-6-yl]-2-(3-methyloxiran-2-yl)prop-2-enamide
第一步:4-溴-3-[叔丁基(二甲基)硅基]氧基-N-[4-(3-氯-4-氟-苯胺基)-7-[(3S)-四氢呋喃-3-基]氧基-喹唑啉-6-基]-2-甲烯基-戊酰胺(5A)
4-bromo-3-[tert-butyl(dimethyl)silyl]oxy-N-[4-(3-chloro-4-fluoro-anilino)-7-[(3S)-tetrahydrofuran-3-yl]oxy-quinazolin-6-yl]-2-methylene-pentanamide
将中间体2(1.04g,3.2mmol)溶于吡啶(8mL)中,加入4A(0.400g,1.07mmol),加入1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐(1.02g,5.34mmol),室温反应4小时。反应液浓缩。残留物用硅胶柱色谱分离提纯(乙酸乙酯:石油醚(v/v)=2:3~1:0),得到标题化合物5A,黄色固体(0.55g,产率75.8%)。
1H NMR(400MHz,CDCl3)δ9.12(d,1H),8.96(d,1H),8.64(d,1H),7.83(s,1H),7.76(m,1H),7.42(m,1H),7.25(s,1H),7.12(t,1H),6.22(d,1H),5.83(s,1H),5.21–5.07(m,1H),4.76(dd,1H),4.33(m,1H),4.16–3.99(m,3H),3.97–3.84(m,1H),2.53–2.34(m,1H),2.21(m,1H),1.77(dd,3H),0.92(d,9H),0.22(d,3H),0.11(s,3H)。
19F NMR(376MHz,CDCl3)δ-118.86。
第二步:N-[4-(3-氯-4-氟-苯胺基)-7-[(3S)-四氢呋喃-3-基]氧基-喹唑啉-6-基]-2-(3-甲基环氧乙烷-2-基)丙-2-烯酰胺(化合物5)
N-[4-(3-chloro-4-fluoro-anilino)-7-[(3S)-tetrahydrofuran-3-yl]oxy-quinazolin-6-yl]-2-(3-methyloxiran-2-yl)prop-2-enamide
将5A(0.300g,0.441mmol)溶于四氢呋喃(8mL)中,0℃加入四丁基氟化铵(0.231g,0.882mmol),0℃反应0.5小时。反应液加入乙酸乙酯(20mL),用饱和氯化铵溶液(20mL×2)洗涤,无水硫酸钠干燥,浓缩,残留物用硅胶柱色谱分离提纯(乙酸乙酯:石油醚(v/v)=1:1~1:0),得到标题化合物化合物5,白色固体(0.12g,产率56%)。
1H NMR(400MHz,CDCl3)δ9.92(s,1H),9.05(d,1H),8.63(s,1H),7.99(s,1H),7.95–7.86(m,1H),7.55(m,1H),7.20(s,1H),7.12(t,1H),6.42(d,1H),5.90(s,1H),5.17(d,1H),4.22–4.01(m,3H),3.98(m,1H),3.58(s,1H),3.34–3.22(m,1H),2.47–2.26(m,2H),1.49(dd,3H)。
19F NMR(376MHz,CDCl3)δ-119.23,-119.25。
LCMS m/z=485.0[M+1]。
生物测试例
1、测试癌细胞生长抑制
连续传代肿瘤细胞经胰蛋白酶消化,悬于培养基,计数后种入96孔细胞培养板。非小细胞肺癌细胞NCI-H1975每孔10000个细胞,人上皮细胞癌细胞A431细胞系每孔10000个细胞,在37℃,5%CO2孵箱中,培养过夜。第二天每种细胞取6个孔加入30μl50%三氯乙酸固定;其余各孔分别加入得自实施例的化合物。待测化合物以DMSO配置成溶液,最高浓度10μM,按下述方法5倍稀释10个待测浓度。对于NCI-H1975、A431细胞系,用含0.1%FBS的培养基梯度稀释待测,并使其为终浓度2倍。将种植NCI-H1975、A431细胞的96孔细胞培养板培养基换为新鲜含0.1%FBS的培养基(每孔100μl),再加入100μl含2倍终浓度的待测化合物。各96孔细胞培养板在37℃,5%CO2细胞培养箱孵育72小时。然后每孔加入50μl 50%三氯乙酸,置于4℃冰箱中固定1小时。
将各孔中的三氯乙酸弃去,用300μl双蒸水洗5次。室温下干燥后,每孔加入50μl0.4%SRB(Sulforhodamine-B)染料溶液(1%乙酸/0.4%SRB),反应15min。弃去各孔的染料溶液,用1%乙酸洗6-7次,室温干燥。各孔加入200μl 10mM Tris溶液(pH=10.5),振荡溶解。用酶标仪测定各孔490nm吸光度。以待测化合物浓度为0的孔的读数为对照,使用origin7.5计算和分析实施例化合物的半效抑制浓度(IC50)。
本发明化合物的抗肿瘤细胞增殖活性通过以上的试验进行测定,测得的IC50值见表1。
表1 抗肿瘤细胞增殖活性试验结果
化合物编号 | A431IC50(μM) | H1975IC50(μM) |
化合物1 | 0.019 | 0.126 |
化合物2 | 0.0047 | 0.010 |
化合物3 | 0.112 | 0.808 |
化合物4 | 0.247 | 0.187 |
化合物5 | 0.496 | 0.113 |
结论:本发明化合物具有明显地抑制H1975、A431细胞增殖作用。
Claims (10)
1.一种通式(I)所示的化合物或其立体异构体、水合物、代谢产物、溶剂化物、药学上可接受的盐、共晶或前药,其中:
R1、R2和R3各自独立的选自H或C1-6烷基,所述的烷基任选进一步被选自0至4个选自F、Cl、Br或I的取代基所取代;
R4选自H或C1-6烷基,所述的烷基任选进一步被选自0至4个选自F、Cl、Br或I的取代基所取代;
X1选自-(CX1aX1b)x-、-C(=O)-或者不存在;
X2选自-C(=O)-、-C(=O)NH-、-NHC(=O)-、-O-、-S-、-CX2a=CX2b-、-(CX2cX2d)x-、-(CX2cX2d)x-O-、-NH-、-N(C1-4烷基)-或者不存在;
X3和X4各自独立的选自-O-、-S-、-NH-、-CH=、-N(C1-4烷基)-或者不存在;
X1a、X1b、X2c和X2d各自独立的选自H、F、Cl、Br、I或C1-6烷基,所述的烷基任选进一步被选自0至4个选自F、Cl、Br或I的取代基所取代;
X2a和X2b各自独立的选自H、F、Cl、Br、I或C1-6烷基,所述的烷基任选进一步被选自0至4个选自F、Cl、Br或I的取代基所取代;
作为选择,X1a、X1b、X2c、X2d、R4中的任意一个或多个基团与它们相连的原子一起形成C3-6碳环或3至9元的杂环,所述的杂环或碳环任选进一步被0至4个选自R5的取代基所取代,且所述杂环含有1至2个选自N、O或S的杂原子;
R5选自F、Cl、Br、I、NH2、氰基、羧基、C1-6烷基、-C(=O)O-C1-6烷基或-C(=O)NR5aR5b,所述的烷基任选进一步被选自0至4个选自F、Cl、Br或I的取代基所取代;
R5a、R5b各自独立的选自H、羟基或C1-6烷基,所述烷基任选进一步被0至4个选自F、Cl、Br、I、NH2、CF3、氰基、羟基、C1-6烷基、C1-6烷氧基、-NHC1-6烷基、-N(-C1-6烷基)-C1-6烷基、-S(=O)C1-6烷基、-S(=O)2C1-6烷基、C6-10碳环基或3至9元的杂环基的取代基所取代,所述的碳环基或杂环基任选进一步被选自0至4个选自F、Cl、Br、I、羟基、NH2、CF3、CHF2、CH2F、硝基、氰基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6烷氧基、-NHC1-6烷基或-N(C1-6烷基)-C1-6烷基的取代基所取代,且所述杂环基含有1至4个选自N、O、S、S(=O)或S(=O)2的杂原子或基团;
作为选择,两个R5与它们相连的原子一起形成3至6元杂环或C3-6碳环,所述杂环或碳环任选进一步被0至4个选自F、Cl、Br、I、羟基、氨基、硝基、氰基、C1-6烷基、C1-6烷氧基、-NHC1-6烷基或-N(C1-6烷基)-C1-6烷基的取代基所取代;
环A、环B各自独立的选自C6-14碳环或5至15元杂环,所述的碳环或杂环任选进一步被0至6个选自R6的取代基所取代,且所述的杂环含有1至4个选自N、O或S的杂原子;
环C选自C6-10碳环、3至15元杂环或者不存在,所述碳环或杂环任选进一步被0至4个选自R6的取代基所取代,且所述的杂环含有1至4个选自N、O或S的杂原子;
R6选自F、Cl、Br、I、NH2、羟基、氰基、硝基、羧基、巯基、丙烯酰胺基、C1-10烷基、C2-10烯基、C2-10炔基、C1-10烷氧基、C1-10烷硫基、至9元杂环、-O-(CH2)q-C(=O)C1-10烷基、-O-(CH2)q-O-C(=O)C1-10烷基、-O-(CH2)q-O-C1-10烷基、-C(=O)C1-10烷基、=O、-C(=O)C2-10烯基、-C(=O)C2-10炔基、-S(=O)2-C1-10烷基、-S(=O)2-C3-10碳环、-S(=O)2-NH2、-C(=O)NH-C1-10烷基、-Q-(CH2)q-OH、-Q-(CH2)qR6a、-Q-(CH2)q-NR6bR6c、C3-10碳环或3至15元杂环,所述CH2、NH2、烷基、烯基、炔基、烷氧基、碳环或杂环任选进一步被0至4个选自F、Cl、Br、I、=O、NH2、CF3、-OCF3、羟基、氰基、丙烯酰胺基、硝基、C1-6烷基、C2-6炔基、-C(=O)C1-6烷基、C1-6烷氧基、-NHC1-6烷基、-N(C1-6烷基)-C1-6烷基、C3-10碳环或3至10元杂环的取代基所取代,且所述杂环含有1至4个选自N、O或S的杂原子;
Q选自化学键、-O-、-S-、-NH-、-N(C1-4烷基)-或-NHC(=O)NH-;
R6a选自C1-10烷氧基、C3-10碳环或3至10元杂环,所述的杂环含有1至4个选自N、O或S的杂原子,所述的烷氧基、碳环或杂环任选进一步被0至4个选自F、Cl、Br、I、NH2、CF3、CHF2、CH2F、硝基、巯基、氰基、丙烯酰胺基、=O、C1-6烷基、C1-6烷氧基、-C(=O)NH-C1-6烷基、-NHC1-6烷基、-N(C1-6烷基)-C1-6烷基、-C(=O)C1-6烷基或-OC(=O)C1-6烷基的取代基所取代;
R6b和R6c各自独立的选自H、C1-10烷基、-C(=O)C1-10烷基、-C(=O)C1-10烷氧基或3至6元碳环;
作为选择,R6b、R6c可以与其相连接的氮原子形成一个4至7元的杂环,所述的杂环含有1至2个选自N、O或S的杂原子,所述的杂环任选进一步被0至4个选自F、Cl、Br、I、NH2、氰基、丙烯酰胺基、C1-6烷基、C1-6烷氧基、=O、-C(=O)C1-6烷基、-C(=O)NH-C1-6烷基、-NHC1-6烷基或-N(C1-6烷基)-C1-6烷基的取代基所取代;
q选自0、1、2或3;
x选自1、2、3、4、5或6。
2.根据权利要求1所述的化合物或其立体异构体、水合物、代谢产物、溶剂化物、药学上可接受的盐、共晶或前药,其中:
环A、环B各自独立的选自C6-10碳环或者5至10元杂环,所述的碳环或杂环任选进一步被0至6个选自R6的取代基所取代,且所述的杂环含有1至4个选自N、O或S的杂原子;
环C不存在;
X4不存在;
R6选自F、Cl、Br、I、NH2、羟基、氰基、硝基、巯基、丙烯酰胺基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6烷氧基、C1-6烷硫基、至9元杂环、-O-(CH2)q-C(=O)C1-6烷基、-O-(CH2)q-O-C(=O)C1-6烷基、-O-(CH2)q-O-C1-6烷基、-C(=O)C1-6烷基、=O、-C(=O)C2-6烯基、-C(=O)C2-6炔基、-S(=O)2-C1-6烷基、-C(=O)NH-C1-6烷基、-Q-(CH2)qR6a、-Q-(CH2)q-NR6bR6c、C3-10碳环或3至15元杂环,所述CH2、烷基、烯基、炔基、烷氧基、碳环或杂环任选进一步被0至4个选自F、Cl、Br、I、=O、NH2、CF3、-OCF3、羟基、氰基、硝基、丙烯酰胺基、C1-4烷基、-C(=O)C1-4烷基、C1-4烷氧基、-NHC1-4烷基、-N(-C1-4烷基)-C1-4烷基或3至10元杂环的取代基所取代,且所述杂环含有1至4个选自N、O或S的杂原子;
R6a选自C1-6烷氧基、C3-10碳环或3至10元杂环,所述的杂环含有1至4个选自N、O或S的杂原子,所述的烷氧基、碳环或杂环任选进一步被0至4个选自F、Cl、Br、I、NH2、CF3、CHF2、CH2F、硝基、巯基、氰基、丙烯酰胺基、乙酰基、C1-4烷基、C1-4烷氧基、=O、-C(=O)NH-C1-4烷基、-NHC1-4烷基或-N(C1-4烷基)-C1-4烷基的取代基所取代;
R6b和R6c各自独立的选自H、C1-4烷基、-C(=O)C1-4烷基、-C(=O)C1-4烷氧基或3至6元碳环;
作为选择,R6b、R6c可以与其相连接的氮原子形成一个4至7元的杂环,所述的杂环含有1至2个选自N、O或S的杂原子,所述的杂环任选进一步被0至4个选自F、Cl、Br、I、NH2、氰基、=O、-C(=O)C1-4烷基、C1-4烷基、C1-4烷氧基、-NHC1-4烷基或-N(C1-4烷基)-C1-4烷基的取代基所取代;
Q选自化学键、-O-、-S-、-NH-、-N(C1-4烷基)-或-NHC(=O)NH-;
q选自0、1、2或3。
3.根据权利要求2所述的化合物或其立体异构体、水合物、代谢产物、溶剂化物、药学上可接受的盐、共晶或前药,其中,该化合物选自通式(II)所示的化合物:
R1、R2和R3各自独立的选自H或C1-4烷基,所述的烷基任选进一步被选自0至4个选自F、Cl、Br或I的取代基所取代;
R4选自H或C1-4烷基,所述的烷基任选进一步被选自0至4个选自F、Cl、Br或I的取代基所取代;
X1选自-(CX1aX1b)x-或者不存在;
X2选自-C(=O)-、-C(=O)NH-、-NHC(=O)-、-O-、-S-、-CX2a=CX2b-、-NH-、-N(C1-4烷基)-或者不存在;
X1a、X1b、X2c和X2d各自独立的选自H、F、Cl、Br、I或C1-4烷基,所述的烷基任选进一步被选自0至4个选自F、Cl、Br或I的取代基所取代;
X2a和X2b各自独立的选自H、F、Cl、Br、I或C1-4烷基;
作为选择,X1a、X1b、X2c、X2d和R4中的任意一个或多个基团与它们相连的原子一起形成C3-6碳环或3至9元的杂环,所述的碳环或杂环任选进一步被0至4个选自R5的取代基所取代,且所述杂环含有1至2个选自N、O或S的杂原子;
R5选自F、Cl、Br、I、NH2、氰基、羧基、C1-4烷基、-C(=O)O-C1-4烷基或-C(=O)NR5aR5b,所述的烷基任选进一步被选自0至4个选自F、Cl、Br或I的取代基所取代;
R5a、R5b各自独立的选自H、羟基或C1-4烷基,所述烷基任选进一步被0至4个选自F、Cl、Br、I、NH2、CF3、氰基、羟基、C1-4烷基、C1-4烷氧基、-NHC1-4烷基、-N(-C1-4烷基)-C1-4烷基、-S(=O)C1-4烷基、-S(=O)2C1-4烷基、C6-10碳环基或3至9元的杂环基的取代基所取代,所述的碳环基或杂环基任选进一步被选自0至4个选自F、Cl、Br、I、羟基、NH2、CF3、CHF2、CH2F、硝基、氰基、C1-4烷基、C2-4烯基、C2-4炔基、C1-4烷氧基、-NHC1-4烷基或-N(C1-4烷基)-C1-4烷基的取代基所取代,且所述杂环基含有1至4个选自N、O、S、S(=O)或S(=O)2的杂原子或基团;
作为选择,两个R5与它们相连的原子一起形成3至6元杂环或C3-6碳环,所述杂环或碳环任选进一步被0至4个选自F、Cl、Br、I、羟基、氨基、硝基、氰基、C1-4烷基、C1-4烷氧基、-NHC1-4烷基或-N(-C1-4烷基)-C1-4烷基的取代基所取代;
R7选自H、F、Cl、Br、I、NH2、羟基、氰基、C1-4烷基、C2-4炔基、C1-4烷氧基、至9元杂环、-O-(CH2)q-C(=O)C1-4烷基、-O-(CH2)q-O-C(=O)C1-4烷基、-O-(CH2)q-O-C1-4烷基、-Y-(CH2)qR7a或-Y-(CH2)q-NR7bR7c,所述的CH2、烷基、炔基、烷氧基或杂环任选进一步被0至4个选自F、Cl、Br、I、CF3、NH2、羟基、=O、乙酰基、氰基、-OCF3、C1-4烷基、C1-4烷氧基、-NHC1-4烷基、-N(C1-4烷基)-C1-4烷基或3至6元杂环基的取代基所取代,所述的杂环含有1至2个选自N、O或S的杂原子;
Y选自-O-、-S-、-NH-或-N(C1-4烷基)-;
R7a选自C1-4烷氧基、C3-10碳环或3至10元杂环,所述的杂环含有1至4个选自N、O或S的杂原子,所述的烷氧基、碳环或杂环任选进一步被0至4个选自F、Cl、Br、I、NH2、氰基、=O、乙酰基、C1-4烷基、C1-4烷氧基、-NHC1-4烷基或-N(C1-4烷基)-C1-4烷基的取代基所取代;
R7b和R7c各自独立的选自H、C1-4烷基或3至6元碳环;
作为选择,R7b、R7c可以与其相连接的氮原子形成一个4至7元的杂环,所述的杂环含有1至2个选自N、O或S的杂原子,所述的杂环任选进一步被0至4个选自F、Cl、Br、I、NH2、氰基、=O、乙酰基、C1-4烷基、C1-4烷氧基、-NHC1-4烷基或-N(C1-4烷基)-C1-4烷基的取代基所取代;
R8选自H、F、Cl或Br;
Z选自-N-或
R9选自H或C1-4烷基;
R10选自C6-10碳环或5至10元杂环,所述杂环含有1至3个选自N、O或S的杂原子,且所述的碳环或者杂环任选进一步被0至5个选自R11的取代基所取代;
R11选自F、Cl、Br、I、NH2、氰基、硝基、巯基、丙烯酰胺基、C1-4烷基、C2-4炔基、C1-4烷氧基、C1-4烷硫基、-O-C6-10碳环、-O-5至10元杂环、-OC1-3烷基-C6-10碳环、-OC1-3烷基-5至10元杂环、-NHC1-4烷基或-N(C1-4烷基)-C1-4烷基,所述烷基、炔基、烷氧基、碳环或杂环任选进一步被0至4个选自F、Cl、Br、I、CF3、NH2、C1-4烷基、C1-4烷氧基、氰基或丙烯酰胺基的取代基所取代,且所述的杂环含有1至3个选自N、O或S的杂原子;
q选自0、1、2或3。
4.根据权利要求3所述的化合物或其立体异构体、水合物、代谢产物、溶剂化物、药学上可接受的盐、共晶或前药,其中:
R1、R2和R3各自独立的选自H、甲基或乙基;
R4选自H、甲基、乙基或丙基;
X1不存在或者选自-CH2CH2CHX1b-,当X1选自-CH2CH2CHX1b-时,X1b、R4与其相连的原子一起形成6元含氮杂环;
X2选自-O-、-NH-、-N(CH3)-或者不存在;
R7选自H、F、Cl、Br、I、CF3、NH2、羟基、氰基、甲基、乙基、乙炔基、甲氧基、乙氧基、-Y-(CH2)qR7a或者-Y-(CH2)q-NR7bR7c;
Y选自-O-、-S-、-NH-或-N(CH3)-;
q选自0、1、2或3;
R7a选自取代的或者未取代的甲氧基、乙氧基、环丙基、四氢呋喃基、四氢吡咯基、哌啶基、哌嗪基、吗啉基、当被取代时,任选进一步被0至4个选自F、Cl、Br、I、NH2、氰基、=O、乙酰基、甲基、乙基、甲氧基、乙氧基、-NHCH3或-N(CH3)2的取代基所取代;
R7b和R7c各自独立的选自H、甲基、乙基或3至6元碳环;
作为选择,R7b、R7c可以与其相连接的氮原子形成四氢吡咯基、哌啶基、哌嗪基或吗啉基,所述的四氢吡咯基、哌啶基、哌嗪基或吗啉基任选进一步被0至4个选自F、Cl、Br、I、NH2、氰基、乙酰基、=O、甲基、乙基、甲氧基、乙氧基、-NHCH3或-N(CH3)2的取代基所取代;
R8选自H、F或Cl;
Z选自-N-;
R9选自H或甲基;
R10选自苯基,所述的苯基任选进一步被0至5个选自F、Cl、Br、I、CF3、CHF2、CH2F、NH2、氰基、硝基、甲基、乙基、乙炔基、甲氧基、乙氧基、-O-C6-10碳环、-O-5至10元杂环、-OCH2C6-10碳环或-OCH2-5至10元杂环,所述碳环或杂环任选进一步被0至5个选自F、Cl、Br、I、CF3、CHF2、CH2F、NH2、氰基、甲基、乙基、甲氧基或乙氧基的取代基所取代,所述的杂环含有1至3个选自N、O或S的杂原子。
5.根据权利要求4所述的化合物或其立体异构体、水合物、代谢产物、溶剂化物、药学上可接受的盐、共晶或前药,其中:
R1、R2和R3各自独立的选自H、甲基或乙基;
R4选自H、甲基、乙基或丙基;
X1不存在或者选自-CH2CH2CHX1b-,当X1选自-CH2CH2CHX1b-时,X1b、R4与其相连的原子一起形成6元含氮杂环;
X2选自-O-、-NH-、-N(CH3)-或者不存在;
R7选自H、F、氰基、甲基、乙基、乙炔基、甲氧基、乙氧基、甲氧乙氧基、
R8选自H、F或Cl;
Z选自-N-;
R9选自H;
R10选自苯基,所述的苯基任选进一步被0至5个选自F、Cl、Br、CF3、CHF2、CH2F、NH2、氰基、甲基、乙基、乙炔基、甲氧基、乙氧基、 的取代基所取代。
6.根据权利要求5所述的化合物或其立体异构体、水合物、代谢产物、溶剂化物、药学上可接受的盐、共晶或前药,其中所述化合物选自如下结构:
7.根据权利要求1-6任一所述的化合物或其立体异构体、水合物、代谢产物、溶剂化物、药学上可接受的盐、共晶或前药,其中其药学上可接受的盐中所述的盐选自盐酸盐、氢溴酸盐、氢碘酸盐、硫酸盐、磷酸盐、醋酸盐、三氟乙酸盐、硫氰酸盐、马来酸盐、羟基马来酸盐、戊二酸盐、甲磺酸盐、乙磺酸盐、苯磺酸盐、对甲苯磺酸盐、苯甲酸盐、水杨酸盐、苯乙酸盐、肉桂酸盐、乳酸盐、丙二酸盐、特戊酸盐、琥珀酸盐、富马酸盐、苹果酸盐、扁桃酸盐、酒石酸盐、没食子酸盐、葡萄糖酸盐、月桂酸盐、棕榈酸盐、果胶酸盐、苦味酸盐、柠檬酸盐或者它们的组合。
8.一种药物组合物,所述的组合物包括:有效剂量的根据权利要求1-7中任一项所述的化合物或其立体异构体、水合物、代谢产物、溶剂化物、药学上可接受的盐、共晶或前药,以及药学上可接受的载体、稀释剂、佐剂、媒介物或赋形剂;所述的组合物还可进一步包括一种或多种其他治疗剂;
优选地,所述的其他治疗剂是顺铂(cisplatin)、卡铂(carboplatin)、奥沙利铂(oxaliplatin)、达卡巴嗪(dacarbazine)、替莫唑胺(temozolomide)、丙卡巴肼(procarbazine)、甲氨蝶呤(methotrexate)、氟尿嘧啶(fluorouracil)、阿糖胞苷(cytarabine)、吉西他滨(gemcitabine)、巯基嘌呤(mercaptopurine)、氟达拉滨(fludarabine)、长春碱(vinblastine)、长春新碱(vincristine)、长春瑞滨(vinorelbine)、紫杉醇(paclitaxel)、多西紫杉醇(docetaxel)、拓扑替康(topotecan)、伊立替康(irinotecan)、依托泊苷(etoposide)、曲贝替定(trabectedin)、更生霉素(dactinomycin)、多柔比星(doxorubicin)、表柔比星(epirubicin)、道诺霉素(daunorubicin)、米托蒽醌(mitoxantrone)、博来霉素(bleomycin)、丝裂霉素C(mitomycin),伊沙匹隆(ixabepilone)、他莫昔芬(tamoxifen)、氟他胺(flutamide)、西罗莫司(sirolimus)、阿法替尼(afatinib)、alisertib、amuvatinib、阿帕替尼(apatinib)、阿西替尼(axitinib)、硼替佐米(bortezomib)、波舒替尼(bosutinib)、布立尼布(brivanib)、卡博替尼(cabozantinib)、西地尼布(cediranib)、crenolanib、克卓替尼(crizotinib)、达拉非尼(dabrafenib),达可替尼(dacomitinib)、达鲁舍替(danusertib)、达沙替尼(dasatinib)、多韦替尼(dovitinib)、厄洛替尼(erlotinib)、foretinib、ganetespib、吉非替尼(gefitinib)、依鲁替尼(ibrutinib)、埃克替尼(icotinib)、伊马替尼(imatinib)、iniparib、拉帕替尼(lapatinib)、lenvatinib、linifanib、linsitinib、马赛替尼(masitinib)、momelotinib、莫替沙尼(motesanib)、来那替尼(neratinib)、尼罗替尼(nilotinib)、尼拉帕尼(niraparib)、oprozomib、奥拉帕尼(olaparib)、帕唑帕尼(pazopanib)、pictilisib、帕纳替尼(ponatinib)、奎扎替尼(quizartinib)、瑞格非尼(regorafenib)、氯构色替(rigosertib)、rucaparib、鲁索替尼(ruxolitinib)、塞卡替尼(saracatinib)、saridegib、索拉非尼(sorafenib)、舒尼替尼(sunitinib)、、替拉替尼(telatinib)、tivantinib、替肟扎尼(tivozanib)、托法替尼(tofacitinib)、曲美替尼(trametinib)、凡德他尼(vandetanib)、维利帕尼(veliparib)、威罗菲尼(vemurafenib)、维莫德吉(vismodegib)、volasertib、阿仑单抗(alemtuzumab)、贝伐单抗(bevacizumab)、布妥昔单抗(brentuximab vedotin)、卡妥索单抗(catumaxomab)、西妥昔单抗(cetuximab)、地诺单抗(denosumab),吉妥珠单抗(gemtuzumab)、伊匹单抗(ipilimumab)、尼妥珠单抗(nimotuzumab)、奥法木单抗(ofatumumab)、帕尼单抗(panitumumab)、利妥昔单抗(rituximab)、托西莫单抗(tositumomab)、曲妥珠单抗(trastuzumab)或它们的组合。
9.权利要求1-7中任一项所述的化合物或其立体异构体、水合物、代谢产物、溶剂化物、药学上可接受的盐、共晶或前药或者权利要求8所述的药物组合物在作为EGFR受体酪氨酸激酶抑制剂在制备药物制剂中的应用,特别是在制备用于治疗和/或预防过度增殖性疾病的药物制剂中的应用。
10.根据权利要求9所述的应用,其中所述的过度增殖性疾病包括脑瘤、非小细胞肺癌、表皮鳞癌、膀胱癌、胰腺癌、结肠癌、乳腺癌、卵巢癌、子***、子宫内膜癌、结直肠癌、肾癌、食管腺癌、食管鳞状细胞癌、实体瘤、非霍奇金淋巴瘤、肝癌、肺癌,皮肤癌、甲状腺癌、头颈癌、***癌、神经胶质瘤及鼻咽癌中的一种或多种;优选地,所述过度增殖性疾病包括非小细胞肺癌、乳腺癌、表皮鳞癌、胃癌及结肠癌中的一种或多种。
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