CN105384695B - 嘧啶衍生物及其制备方法和在医药上的应用 - Google Patents
嘧啶衍生物及其制备方法和在医药上的应用 Download PDFInfo
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- CN105384695B CN105384695B CN201510522087.3A CN201510522087A CN105384695B CN 105384695 B CN105384695 B CN 105384695B CN 201510522087 A CN201510522087 A CN 201510522087A CN 105384695 B CN105384695 B CN 105384695B
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- cancer
- trifluoromethyl
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- CZDYPVPMEAXLPK-UHFFFAOYSA-N tetramethylsilane Chemical compound C[Si](C)(C)C CZDYPVPMEAXLPK-UHFFFAOYSA-N 0.000 description 1
- 229960004559 theobromine Drugs 0.000 description 1
- 125000005308 thiazepinyl group Chemical group S1N=C(C=CC=C1)* 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- 125000003777 thiepinyl group Chemical group 0.000 description 1
- 125000002053 thietanyl group Chemical group 0.000 description 1
- 125000003396 thiol group Chemical group [H]S* 0.000 description 1
- 125000004568 thiomorpholinyl group Chemical group 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical class [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
- ITMCEJHCFYSIIV-UHFFFAOYSA-N triflic acid Chemical compound OS(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-N 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
- OUYCCCASQSFEME-UHFFFAOYSA-N tyrosine Natural products OC(=O)C(N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-UHFFFAOYSA-N 0.000 description 1
- 238000001291 vacuum drying Methods 0.000 description 1
- 239000004474 valine Substances 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
- NLVXSWCKKBEXTG-UHFFFAOYSA-N vinylsulfonic acid Chemical compound OS(=O)(=O)C=C NLVXSWCKKBEXTG-UHFFFAOYSA-N 0.000 description 1
- 239000011592 zinc chloride Substances 0.000 description 1
- 235000005074 zinc chloride Nutrition 0.000 description 1
Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
- C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
- C07D239/48—Two nitrogen atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
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Abstract
本发明涉及一种嘧啶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(M)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
本发明涉及一种嘧啶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嘧啶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 RevMol 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,N Engl JMed,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)。但是,临床上,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,NEngl 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)。但是,现有的不可逆抑制剂在细胞系模型上,抑制EGFRT790M突变的能力还是低于抑制仅有EGFR激活突变的能力,并且在临床上可用到的浓度下,这类化合物在体外无法抑制EGFR T790M(Yuza,Glatt等,2007,Cancer Biol Ther,6,661-667;Godin-Heymann,Ulkus等,2008,Mol Cancer Ther,7,874-879)。由于EGFR T790M对ATP的亲和力与野生型的EGFR对ATP的亲和力相似,喹唑啉类的EGFR抑制剂在抑制EGFR T790M的同时,也会抑制野生型的EGFR。在临床上,同时抑制野生型EGFR会导致患者出现皮疹和腹泻,这会限制第二代EGFR抑制剂的使用剂量,以至于药物的血浆浓度用不足以抑制T790M,使这类药物的临床有效性受到较大的限制。例如CI-1033、HKI-272和PF00299804,在临床上针对吉非替尼和厄罗替尼耐药的非小细胞肺癌的治疗非常有限,并且会发生剂量依赖的腹泻和皮疹(Janne,von Pawel等,2007,J Clin Oncol,25,3936-3944;Advani,Coiffier等,2010,J Clin Oncol,28,2085-2093)。
为了能够特异性针对EGFR T790M进行抑制,第三代EGFR突变选择性抑制剂问世。这类不可逆抑制剂比起第二代喹啉类化合物,对EGFR T790M具有更高的选择性,在临床上可能具有更高的活性和更好的耐受。例如共价的嘧啶类EGFR抑制剂WZ4002,在体外实验中,相比喹啉类化合物,对EGFR T790M的选择性高30-100倍,而对野生型EGFR抑制则低100倍。在EGFR T790M衍生的动物肺癌模型中,也展现出较好的药效(Zhou,Ercan等,2009,Nature,462,1070-1074)。另一突变选择性抑制剂co-1686,在体外对EGFR T790M的选择性比对野生型EGFR高10-25倍。能选择性地抑制EGFR的突变,包括耐药突变T790M和激活突变(L858R,del19),而对野生型EGFR无抑制。在体外,口服co-1686能够导致T790M突变的肿瘤衰退,并且不介导肿瘤细胞发生进一步的耐药突变(Walter,Sjin等,2013,Cancer Discov,3,1404-1415)。
CN102083800描述了式I-a或I-b的蛋白激酶抑制剂,其结构式如下:
环A是任选经取代的选自以下的基团:苯基;3元到7元饱和或部分不饱和碳环;8元至10元双环饱和、部分不饱和或芳基环;具有1到4个独立地选自氮、氧或硫的杂原子的5元到6元单环杂芳基环;具有1到3个独立地选自氮、氧或硫的杂原子的4元到7元饱和或部分不饱和杂环;具有1到5个独立地选自氮、氧或硫的杂原子的7元到10元双环饱和或部分不饱和杂环;或具有1到5个独立地选自氮、氧或硫的杂原子的8元到10元双环杂芳基环;
环B是任选经取代的选自以下的基团:苯基;3元到7元饱和或部分不饱和碳环;8元至10元双环饱和、部分不饱和或芳基环;具有1到4个独立地选自氮、氧或硫的杂原子的5元到6元单环杂芳基环;具有1到3个独立地选自氮、氧或硫的杂原子的4元到7元饱和或部分不饱和杂环;具有1到5个独立地选自氮、氧或硫的杂原子的7元到10元双环饱和或部分不饱和杂环;或具有1到5个独立地选自氮、氧或硫的杂原子的8元到10元双环杂芳基环;
R1是弹头基团;
Ry是氢、卤素、-CN、-CF3、C1-4脂肪族基、C1-4卤代脂肪族基、-OR、-C(O)R或-C(O)N(R)2;各R基团独立地位氢,或任选经取代的选自以下的基团:C1-6脂肪族基;苯基;具有1到2个独立地选自氮、氧或硫的杂原子的4元至7元杂环;或具有1到4个独立地选自氮、氧或硫的杂原子的5元到6元单环杂芳基环;
W1和W2各独立地位共价键或二价C1-3亚烷基链,其中W1或W2的一个亚甲基单元任选经-NR2-、-N(R2)C(O)-、-C(O)N(R2)-、-N(R2)SO2-、-SO2N(R2)-、-O-、-OC(O)-、-C(O)O-、-S-、-SO-或-SO2-置换;
R2是氢、任选经取代的C1-6脂肪族基,或-C(O)R,或:R2和环A上的取代基与其间的插入原子一起形成4元到6元饱和、部分不饱和或芳香族稠合环;
R2和Ry与其间的插入原子一起形成4元到6元饱和、部分不饱和或芳香稠合环;
m和p独立地为0到4;且Rx和Rv独立地选自-R、卤素、-OR、-O(CH2)qOR、-CN、-NO2、-SO2R、-SO2N(R)2、-SOR、-C(O)R、-CO2R、-C(O)N(R)2、-NRC(O)R、-NRC(O)R、-NRC(O)NR2、-NRSO2R或-N(R)2,其中q为1到4;或:Rx和R1当同事存在于环B上时,与其间的插入原子一起形成具有0到3个独立地选自氮、氧或硫的杂原子的5元到7元饱和、部分不饱和或芳基环,其中所述经弹头基团和0到3个独立地选自氧代基、卤素、-CN或C1-6脂肪族基的基团取代;或Rv和R1当同时存在于环A上时,与其间的插入原子一起形成具有0到3个独立地选自氮、氧或硫的杂原子的5元到7元饱和、部分不饱和或芳基环,其中所述环经弹头基团和0到3个独立地选自氧代基、卤素、-CN或C1-6脂肪族基的基团取代。不认为此专利中具体描述是本发明的一部分。
CN102482277公开了表皮生长因子受体抑制剂,其结构式如下:
Z1及Z2分别独立为N或CR5;Z3及Z4分别独立为N或C,其中RA及RB在Z3或Z4为N时不存在,其中,Z1、Z2、Z3或Z4的至少一个为N;X为O、S或NR6;Y为不存在、CO、O、S或NR6;每个R6独立为H或烷基;环A为芳香基、杂芳基、碳环或杂环;环B为芳香基、杂芳基、碳环或杂环;RA为H、卤素、OH、NH2、NHR3、卤烷基、CN、N3、NO2;烷基、烯基、芳香基、芳烷基、杂芳基、杂环或碳环,其中每个可任选取代;或RA及RB,连同其中每个所联结的原子形成稠环芳香基、杂芳基、碳环或杂环,其中每个可任选取代;每个R1独立为NH(R3)、N(R3)(R4)、N(R3)CO(R4)、CO2H、C(O)R3、C(O)OR3、C(O)NH2、C(O)NH(R3)、C(O)N(R3)(R4)、SO2R3、SOR3、SR3、烷基、卤烷基、芳香基、芳烷基、烷氧基、杂芳基、杂环或碳环,其中每个可任选取代;每个R2独立为可任选取代的烷基、卤基、 或每个R3及R4独立为H、烷基、烯基、乙烯基、杂环或碳环,其中每个可任选取代;每个R5独立为H、烷基、卤基或卤烷基,其中每个可任选取代;每个R5A独立为卤基或OS(O)pR',其中,p为0、1或2及R’为烷基或芳香基;每个W独立为不存在、CH2、CH2CH2、(CH2)3、(CH2)4、O、S或NR3;环C为具有1、2或3个氮原子的5-6元杂环或杂芳基;m为1、2或3;及n为0、1或2;其中,若X为S,Z2为CR5,及R5为卤基,则环A不为R1对位取代的苯基;或若Y为S,及RA为卤基,则环B不为以R2对位-取代的苯基;其中,若RA及RB连同其中每个所联结的原子形成稠环芳香基、杂芳基、碳环、杂环,则或不存在。不认为此专利中具体描述是本发明的一部分。
WO2012061303描述了杂环化合物,其结构式如下:
其中,W为-O-或-NH;R1为-OR;R独立选自C1-4烷基,C1-4氟代烷基;R2和R3各自独立选自H、-OH或-OR;R4为-CF3、Cl或Br。不认为此专利中具体描述是本发明的一部分。
发明内容
本发明目的是提供一类结构新颖的、效果好、耐受性好、选择性高或毒副作用低的嘧啶衍生物,经过研究表明,本发明化合物作为EGFR靶点抑制剂显示出优异的药效活性、较好的选择性,同时对于BTK、JAK等靶点也有潜在的抑制活性。
本发明提供一种通式(M)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:M1和M2各自独立的选自取代或未取代的迈克尔受体基团,当被取代时,任选进一步被1至3个选自F、Cl、Br、I、C1-4烷基、C1-4烷氧基或-C1-4烷基氨基的取代基所取代,所述的烷基、烷氧基或烷基氨基任选进一步被0至4个选自F、Cl、Br、I、C1-4烷基或C1-4烷氧基的取代基所取代;
环D为6至10元杂环基,且所述的杂环基可以任选进一步被0至4个选自R12的取代基所取代,且所述的杂环基含有1至2个选自N、O或者S的杂原子;
环E、环A各自独立的选自C6-10碳环基或者4至10元杂环基,所述的碳环基或者杂环基可以任选进一步被0至4个选自R12的取代基所取代,且所述的杂环基含有1至2个选自N、O或者S的杂原子;
R12为F、Cl、CF3、C1-4烷氧基、4至10元杂环基或者-Z-(CH2)n-NR13R14,所述的杂环基可以任选进一步被0至3个选自-NH2、-NH(CH3)、-N(CH3)2、C3-8碳环基、C1-4烷基或卤代-C1-4烷基的取代基所取代,且所述的杂环基含有1至3个选自N、O或S的杂原子;
Z为-O-、-NH-或-N(C1-4)-烷基;
n选自0、1、2、3或4;
R13和R14各自独立选自H或C1-4烷基;
作为选择,R13、R14可以与其相连的N原子形成4至10元杂环基,所述的杂环基可以任选进一步被0至3个选自-NH2、C1-4烷基或卤代-C1-4烷基的取代基所取代,且所述的杂环基含有1至3个选自N、O或S的杂原子;
环B、环C各自独立的选自4至7元杂环基或不存在,所述的杂环基可任选进一步被0至4个选自F、-CF3或者Cl的取代基所取代,且所述的杂环基含有1至3个选自N、O或者S的杂原子;
W1和W2各自独立选自NH、O或者S;
W3和W4各自独立选自NH、O、S或者不存在。
本发明优选方案,一种通式(M)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:
M1和M2各自独立的选自取代或未取代的当被取代时,任选进一步被1至3个-CH2N(CH3)2的取代基所取代。
本发明优选方案,一种通式(M)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(A)所示的化合物,其中:
R6和R9各自为H;
R7、R8、R10和R11各自独立选自H或者
本发明优选方案,包括通式(A)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D为6元杂环基,优选嘧啶基,且所述的杂环基可以任选进一步被0至2个选自R12的取代基所取代,且所述的杂环基含有1至2个选自N、O或者S的杂原子;
环E为6元碳环基,优选苯基,所述的碳环基可以进一步被0至3个选自R12的取代基所取代;
R12为F、Cl、CF3、C1-4烷氧基、5至9元杂环基、-Z-(CH2)n-NR13R14,所述的杂环基可以任选进一步被0至3个选自-NH2、-N(CH3)2、-CH3、环丙基或-CH2CH2F的取代基所取代,且所述的杂环基含有1至3个选自N、O或S的杂原子;
Z为-O-、-NH-或-N(CH3)-;
n选自0、1、2或3;
R13和R14各自独立选自H或C1-2烷基;
作为选择,R13、R14可以与其相连的N原子形成4至6元杂环基,所述的杂环基可以任选进一步被0至3个选自-NH2、-N(CH3)2、-CH3或-CH2CH2F的取代基所取代,且所述的杂环基含有1至3个选自N、O或S的杂原子;
R12优选F、Cl、C1-2烷氧基、 或
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和R2各自独立选自H、F、CF3或者Cl;
W1和W2各自独立选自NH、O或者S;
W3和W4各自独立选自NH、O、S或者不存在;
环A为6元碳环基或者4至9元杂环基,所述的碳环基或者杂环基可以进一步被0至2个选自R12的取代基所取代,且所述的杂环基含有1至2个选自N、O或者S的杂原子;
R12为F、Cl、C1-2烷氧基、 或
环B为4至7元杂环基或不存在,所述的杂环基可进一步被0至2个选自F、-CF3或者Cl的取代基所取代,且所述的杂环基含有1至2个选自N、O或者S的杂原子;
环C为4至7元杂环基或不存在,所述的杂环基可进一步被0至2个选自F、-CF3或者Cl的取代基所取代,且所述的杂环基含有1至2个选自N、O或者S的杂原子;
R3、R4和R5各自独立选自H、F、Cl、C1-2烷氧基、 或
R6和R9各自为H;
R7、R8、R10和R11各自独立选自H或者
本发明优选方案,通式(I)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为H、CF3或者Cl,优选CF3或者Cl,更优选CF3;
R2为H;
W1和W2各自独立选自NH或者O,优选NH;
W3和W4各自独立选自NH、O或者不存在;
环A为苯基、或者
环B为或者不存在;
环C为或者不存在;
R3选自H或者甲氧基;
R4为H;
R5选自H、F、或者
R6和R9各自为H;
R7、R8、R10和R11各自独立选自H或者
R12选自或者优选
本发明优选方案,本发明涉及化合物选自,但不限于:
或
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、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。
研究表明,本发明的化合物作为EGFR靶点抑制剂显示出优异的药效活性,同时对于BTK、JAK等靶点也有潜在的抑制活性。
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),dabrafenib(达拉非尼),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,gefitinib(吉非替尼),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(brentuximabvedotin)、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、酯、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/HER2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、酯、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、子宫颈癌、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、前列腺癌、神经胶质瘤和鼻咽癌,优选非小细胞肺癌、乳腺癌、表皮鳞癌、胃癌和结肠癌。
本发明通式(I)化合物合成方法:
其中,R1、R2、R3、R4、R5、R6、R7、R8、R9、R10、环A、环B、环C、W1、W2和W3定义与通式(I)定义一致;
L选自氨基、羟基或者巯基;
G选自硝基、-N-氨基保护基或氨基,氨基保护基可以选自叔丁氧羰基、苄基、对甲苯磺酰基等;
G’选自氨基;
X选自卤素;
通式(I-B)、通式(I-B’)、通式(I-D)化合物是通过购买或参考WO2013014448、WO2012061299、WO2011090760、J.Org.Chem.,2014,79,328-338、WO2003068760等文献方法制得。
通式(I-A)与通式(I-B)化合物在碱条件下反应,得到通式(I-C)化合物,所述的碱选自二异丙基乙基胺、二异丙基胺、三乙胺、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(I-C)与通式(I-D)化合物在碱条件下反应,得到通式(I-E)化合物,所述的碱选自二异丙基乙基胺、二异丙基胺、三乙胺、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;
当G为氨基时,通式(I-E)化合物与丙烯酰卤(例如丙烯酰氯)或丙烯酸在碱存在下反应得到通式(I)化合物,所述的碱选自二异丙基乙基胺、二异丙基胺、三乙胺、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;
当G为硝基时,则通式(I-E)化合物的硝基被还原得到通式(I-E‘)化合物,所述的还原剂选自H2、Pt、Fe、Zn、LiAlH4或NaBH4;通式(I-E’)化合物与丙烯酰卤(例如丙烯酰氯)或丙烯酸在碱存在下反应得到通式(I)化合物,所述的碱选自二异丙基乙基胺、二异丙基胺、三乙胺、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;
当G为-N-氨基保护基时,通式(I-E)化合物先采用本领域常规的脱除氨基保护基的方法脱除保护基转换为通式(I-E’)化合物,比如叔丁基氧羰基保护基保护时,可以在酸性条件下(例如三氟乙酸)脱除氨基保护基;通式(I-E’)化合物与丙烯酰卤(例如丙烯酰氯)或丙烯酸在碱存在下反应得到通式(I)化合物,所述的碱选自二异丙基乙基胺、二异丙基胺、三乙胺、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;
或者,当通式(I-B’)与通式(I-D)相同,R6与R9相同,R7与R10相同,R8与R11相同时:
通式(I-A)化合物在酸性条件下与之反应,得到通式(I-E”)化合物,所述的酸可以选自对甲苯磺酸、三氟乙酸、甲磺酸、苯磺酸等;
当G为氨基时,通式(I-E”)化合物与丙烯酰卤(例如丙烯酰氯)或丙烯酸在碱存在下反应得到通式(I)化合物,所述的碱选自二异丙基乙基胺、二异丙基胺、三乙胺、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;
当G为硝基时,则通式(I-E”)化合物的硝基被还原得到通式(I-E”’)化合物,所述的还原剂选自H2、Pt、Fe、Zn、LiAlH4或NaBH4;通式(I-E”’)化合物与丙烯酰卤(例如丙烯酰氯)或丙烯酸在碱存在下反应得到通式(I)化合物,所述的碱选自二异丙基乙基胺、二异丙基胺、三乙胺、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;
当G为-N-氨基保护基时,通式(I-E”)化合物先采用本领域常规的脱除氨基保护基的方法脱除保护基转换为通式(I-E”’)化合物,比如叔丁基氧羰基保护基保护时,可以在酸性条件下(例如三氟乙酸)脱除氨基保护基;通式(I-E”’)化合物与丙烯酰卤(例如丙烯酰氯)或丙烯酸在碱存在下反应得到通式(I)化合物,所述的碱选自二异丙基乙基胺、二异丙基胺、三乙胺、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;
或者,通式(I-B)或通式(I-D)作为化合物中的其中一个片段可以反应过程中引入取代基;
或者,当通式(I-D)中R5为卤素时:
其中X’选自卤素;
通式(I-C)与通式(I-D’)化合物在碱条件下反应,得到通式(I-E””)化合物,所述的碱选自二异丙基乙基胺、二异丙基胺、三乙胺、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(I-E””)化合物在碱性条件下,与H-R5反应得到通式(I-E),所述碱选自二异丙基乙基胺、二异丙基胺、三乙胺、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。
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、羟基、-SR18、硝基、氰基、异氰基、烯基、炔基、烷基、羟基烷基、烷氧基、碳环基、杂环基、C2-8烯基、C2-8炔基、-(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、4至10元杂环基、3至10元碳环基氧基或者4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。
“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。
“碳环基”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,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、和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、羟基、-SR18、硝基、氰基、异氰基、烯基、炔基、烷基、羟基烷基、烷氧基、碳环基、杂环基、C2-8烯基、C2-8炔基、-(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,m选自0、1、2、3、4或者5,n选自0、1或者2。本文中出现的碳环基,其定义如上所述。
“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,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、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、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、羟基、-SR18、硝基、氰基、异氰基、烯基、炔基、烷基、羟基烷基、烷氧基、碳环基、杂环基、C2-8烯基、C2-8炔基、-(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,m选自0、1、2、3、4或者5,n选自0、1或者2。本文中出现的杂环基,其定义如上所述。
“迈克尔受体基团”是指烯键或炔键与吸电子基团共轭相连形成的基团,所述的吸电子基团的非限制性实施例包括羰基、亚砜、砜或氰基等。
“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、氢溴酸盐、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”是指活性药物成分和共晶形成物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-C18 100×4.6mm)。
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,溶液是指水溶液。
实施例中无特殊说明,反应的温度为室温。
室温温度为20℃~30℃。
本文所用的其他符号具有下列意义:
s:单峰
d:二重峰;
t:三重峰;
q:四重峰;
m:多重峰;
br:宽峰;
J:耦合常数;
Hz:赫兹;
Bn:苄基;
Me:甲基;
Et:乙基;
Ts:对甲苯磺酰基;
TBS:叔丁基二甲基硅基;
Boc:叔丁氧羰基;
Ac:乙酰基。
中间体1:4-(3-氨基苯氧基)哌啶-1-甲酸叔丁酯(中间体1)
tert-butyl 4-(3-aminophenoxy)piperidine-1-carboxylate
第一步:4-羟基哌啶-1-甲酸叔丁酯(1b)
tert-butyl 4-hydroxypiperidine-1-carboxylate
称取N-叔丁氧羰基-4-哌啶酮1a(10g,50mmol)置于250mL圆底烧瓶中,向反应瓶中加入甲醇(100mL),搅拌均匀,0℃下,向反应瓶中分批加入硼氢化钠(3.8g,100mmol),加完后,升至室温反应2小时。向反应瓶中滴加水(50mL)淬灭反应将反应液减压浓缩,残留物用乙酸乙酯萃取(100mL×2),合并后有机相用饱和食盐水洗(50mL×2),无水硫酸钠干燥,过滤,将滤液减压浓缩,硅胶柱层析分离提纯(石油醚/乙酸乙酯(v/v)=4:1)得到黄色油状的4-羟基哌啶-1-甲酸叔丁酯1b(8g,产率80%)。
第二步:4-(3-硝基苯氧基)哌啶-1-甲酸叔丁酯(1c)
tert-butyl 4-(3-nitrophenoxy)piperidine-1-carboxylate
称取4-羟基哌啶-1-甲酸叔丁酯1b(8g,40mmol),置于250mL圆底烧瓶中,向反应瓶中加入四氢呋喃(100mL),搅拌均匀。向反应瓶中依次加入间氨基苯酚(4.36g,40mmol),三苯基磷(15.7g,60mmol)和偶氮二甲酸二异丙酯(12g,60mmol),反应升至70℃下搅拌4小时,减压浓缩,残留物用硅胶柱层析分离提纯(石油醚/乙酸乙酯(v/v)=4:1)得到黄色油状的4-(3-硝基苯氧基)哌啶-1-甲酸叔丁酯1c(10.9g,产率85%)。
1H NMR(400MHz,CDCl3)δ7.81-7.71(m,2H),7.42-7.40(m,1H),7.26-7.20(m,1H),4.58-4.53(m,1H),3.70-3.66(m,2H),3.21-3.16(m,2H),1.83-1.81(m,2H),1.78-1.75(m,2H),1.45(s,9H)。
第三步:4-(3-氨基苯氧基)哌啶-1-甲酸叔丁酯(中间体1)
tert-butyl 4-(3-aminophenoxy)piperidine-1-carboxylate
称取4-(3-硝基苯氧基)哌啶-1-甲酸叔丁酯1c(10.9g,34mmol),置于250mL圆底烧瓶中,向反应瓶中加入甲醇(100mL),搅拌均匀。向反应瓶中加入钯/炭(1.1g,钯含量10%,w/w),室温下搅拌16小时。过滤,减压浓缩,残留物用柱层析分离提纯(石油醚/乙酸乙酯(v/v)=2:1)得到灰色固体状的4-(3-氨基苯氧基)哌啶-1-甲酸叔丁酯(中间体1,8.9g,产率90%)。
1H NMR(400MHz,CDCl3)δ7.06-7.02(m,1H),6.33-6.25(m,4H),5.01-4.94(m,2H),4.42-4.38(m,1H),3.68-3.65(m,2H),3.34-3.30(m,2H),1.88-1.86(m,2H),1.77-1.70(m,2H),1.47(s,9H)。
中间体2:N-(3-氨基苯基)丙烯酰胺(中间体2)
N-(3-aminophenyl)prop-2-enamide
第一步:N-(3-硝基苯基)丙烯酰胺(2b)
N-(3-nitrophenyl)prop-2-enamide
称取间硝基苯胺2a(6.90g,50mmol)置于250mL圆底烧瓶中,向反应瓶中加入二氯甲烷(100mL),搅拌均匀,-78℃下,向反应瓶中加入二异丙基乙基胺(12.92g,100mmol),向反应瓶中缓慢滴加丙烯酰氯(6.80g,75mmol)。滴加完毕后,升至室温反应2小时。减压浓缩,残留物用柱层析分离提纯(石油醚/乙酸乙酯(v/v)=4:1)得到黄色固体状的N-(3-硝基苯基)丙烯酰胺2b(9.6g,产率80%)。
1H NMR(400MHz,DMSO-d6)δ10.66(s,1H),8.71-8.70(m,1H),7.98-7.91(m,2H),7.64-7.60(m,1H),6.45-6.40(m,2H),5.85-5.82(m,1H)。
第二步:N-(3-氨基苯基)丙烯酰胺(中间体2)
N-(3-aminophenyl)prop-2-enamide
称取N-(3-硝基苯基)丙烯酰胺2b(1.92g,10.0mmol)置于100mL圆底烧瓶中,向反应瓶中依次加入乙醇(30mL)、水(10mL)、还原铁粉(1.68g,30.0mmol)和氯化铵(0.37g,7.0mmol),升温回流反应1小时。将反应液冷却至室温,减压浓缩,残留物用硅胶柱层析分离提纯(二氯甲烷/乙酸乙酯(v/v)=1:1)得到灰色固体状的N-(3-氨基苯基)丙烯酰胺(中间体2)(1.14g,产率70%)。
1H NMR(400MHz,CDCl3)δ7.79(s,1H),7.08-7.04(m,2H),6.79-6.77(m,1H),6.40-6.22(m,3H),5.71-5.69(m,1H),3.59(s,2H)。
中间体3:N-[3-[[2-氯-5-(三氟甲基)嘧啶-4-基]氨基]苯基]丙烯酰胺(中间体3)
N-[3-[[2-chloro-5-(trifluoromethyl)pyrimidin-4-yl]amino]phenyl]prop-2-enamide
第一步:N-[3-[[2-氯-5-(三氟甲基)嘧啶-4-基]氨基]苯基]氨基甲酸叔丁酯(3b)
tert-butyl N-[3-[[2-chloro-5-(trifluoromethyl)pyrimidin-4-yl]amino]phenyl]carbamate
称取N-(叔丁氧羰基)-1,3-苯二胺(2.08g,10mmol,BEPHARM)置于100mL圆底烧瓶中,向反应瓶中加入正丁醇(20mL),0℃下向反应瓶中依次滴加2,4-二氯-5-三氟甲基嘧啶3a(2.17g,10mmol,BEPHARM)和N,N-二异丙基乙胺(2.5mL,15mmol),滴加完毕后自然升至室温反应过夜。过滤,滤饼用正丁醇(10mL)洗涤,将得到的滤饼真空干燥得到白色固体,将白色固体置于100mL圆底烧瓶中,0℃下向反应瓶中加入二氯甲烷(20mL),三氟乙酸(10mL)。反应升至室温下搅拌10分钟,减压浓缩,得到N-[3-[[2-氯-5-(三氟甲基)嘧啶-4-基]氨基]苯基]氨基甲酸叔丁酯3b粗产品直接投入下一步。
第二步:N-[3-[[2-氯-5-(三氟甲基)嘧啶-4-基]氨基]苯基]丙烯酰胺(中间体3)
N-[3-[[2-chloro-5-(trifluoromethyl)pyrimidin-4-yl]amino]phenyl]prop-2-enamide
将上述粗产品N-[3-[[2-氯-5-(三氟甲基)嘧啶-4-基]氨基]苯基]氨基甲酸叔丁酯3b置于100mL圆底烧瓶中,向反应瓶中加入二氯甲烷(20mL),-78℃下向反应瓶中加入N,N-二异丙基乙胺(5.0mL,30mmol),缓慢滴加丙烯酰氯(1.6mL,20mmol)的二氯甲烷(10mL)溶液。滴加完毕后,反应升至室温搅拌1小时,减压浓缩,残留物用硅胶柱层析分离(石油醚/乙酸乙酯(v/v)=4:1)得到黄色液体状的N-[3-[[2-氯-5-(三氟甲基)嘧啶-4-基]氨基]苯基]丙烯酰胺(中间体3,1.71g,产率50%)。
1H NMR(400MHz,DMSO-d6)δ10.26(s,1H),9.60(s,1H),8.59(s,1H),7.94(s,1H),7.37(m,1H),7.14(m,1H),6.48(m,1H),6.24(m,1H),5.76(m,1H)。
中间体4:4-(3-氨基苯基)哌啶-1-甲酸叔丁酯(中间体4)
tert-butyl 4-(3-aminophenyl)piperidine-1-carboxylate
第一步:4-(2-对甲苯磺腙)哌啶-1-甲酸叔丁酯(4b)
tert-butyl 4-(2-tosylhydrazono)piperidine-1-carboxylate
称取N-叔丁氧羰基-4-哌啶酮(4a)(9.0g,45mmol),置于500mL圆底烧瓶中,向反应瓶中加入150mL甲醇,搅拌均匀。室温下,向反应瓶中加入对甲苯磺酰肼(8.4g,45mmol),室温下反应18小时。减压除去反应溶剂得到白色固体状的4-(2-对甲苯磺腙)哌啶-1-甲酸叔丁酯(4b)(16.6g)。
第二步:4-(3-硝基苯基)哌啶-1-甲酸叔丁酯(4c)
tert-butyl 4-(3-nitrophenyl)piperidine-1-carboxylate
称取4-(2-对甲苯磺腙)哌啶-1-甲酸叔丁酯(4b)(19.0g,51.7mmol),置于500mL圆底烧瓶中,向反应瓶中加入200mL1,4-二氧六环,搅拌均匀。向反应瓶中依次加入3-硝基苯硼酸(13.0g,77.6mmol),碳酸铯(25.3g,77.6mmol)。反应升温至回流搅拌9小时。将反应体系冷至室温,向反应瓶中加入饱和碳酸氢钠水溶液(100mL)。残余物用乙酸乙酯(150mL)萃取,水相用乙酸乙酯反萃(150mL),合并后的有机相有饱和食盐水(150mL)洗涤,无水硫酸钠干燥,减压浓缩后柱层析[(石油醚/乙酸乙酯(v/v)=15:1)]得到白色固体状的4-(3-硝基苯基)哌啶-1-甲酸叔丁酯(4c)(2.4g,产率15%)。
1H NMR(400MHz,CDCl3)δ8.07-8.04(m,2H),7.52-7.44(m,2H),4.27(br,2H),2.81-2.73(m,3H),1.87-1.83(m,2H),1.69-1.65(m,2H),1.47(s,9H)。
第三步:4-(3-氨基苯基)哌啶-1-甲酸叔丁酯(中间体4)
tert-butyl 4-(3-aminophenyl)piperidine-1-carboxylate
称取4-(3-硝基苯基)哌啶-1-甲酸叔丁酯(4c)(2.4g,7.8mmol),置于100mL圆底烧瓶中,向反应瓶中加入40mL甲醇,搅拌均匀。向反应瓶中加入钯炭(0.4g,10%w/w),室温下搅拌4小时。减压除去甲醇,柱层析分离[(石油醚/乙酸乙酯(v/v)=15:1)]得到白色固体状的4-(3-氨基苯基)哌啶-1-甲酸叔丁酯(中间体4)(2.0g,产率92%)。
1H NMR(400MHz,CDCl3)δ7.12-7.08(m,1H),6.64-6.26(m,3H),4.22(br,4H),2.81-2.74(m,2H),2.57-2.51(m,1H),1.81-1.78(m,2H),1.60-1.54(m,2H),1.47(s,9H)。
中间体5
3-(3-氨基苯氧基)氮杂环丁烷-1-甲酸叔丁酯(中间体5)
tert-butyl 3-(3-aminophenoxy)azetidine-1-carboxylate
第一步:3-(3-硝基苯氧基)氮杂环丁烷-1-甲酸叔丁酯(5b)
tert-butyl 3-(3-nitrophenoxy)azetidine-1-carboxylate
称取N-叔丁氧羰基-3-羟基氮杂环丁烷(5a)(6.93g,40mmol),置于250mL圆底烧瓶中,向反应瓶中加入四氢呋喃(100mL),搅拌均匀。向反应瓶中依次加入间氨基苯酚(4.36g,40mmol),三苯基膦(15.7g,60mmol),偶氮二甲酸二异丙酯(12g,60mmol)。反应升至70℃下搅拌6小时。减压除去四氢呋喃,柱层析分离(石油醚/乙酸乙酯(v/v)=4:1)得到黄色油状的液体3-(3-硝基苯氧基)氮杂环丁烷-1-甲酸叔丁酯(5b)(9.65g,产率82%)。
第二步:3-(3-氨基苯氧基)氮杂环丁烷-1-甲酸叔丁酯(中间体5)
tert-butyl 3-(3-aminophenoxy)azetidine-1-carboxylate
称取3-(3-硝基苯氧基)氮杂环丁烷-1-甲酸叔丁酯(5b)(9.65g,32.8mmol),置于250mL圆底烧瓶中,向反应瓶中加入甲醇(100mL),搅拌均匀。向反应瓶中加入钯炭(0.97g,10%w/w),室温下搅拌16小时。反应完全后,硅藻土过滤,减压除去甲醇,柱层析分离(石油醚/乙酸乙酯(v/v)=2:1)得到棕红色固体状的3-(3-氨基苯氧基)氮杂环丁烷-1-甲酸叔丁酯(中间体5)(7.98g,产率92%)。
LC-MS m/z=209.1[M-tBu+1]。
中间体6
(R)-3-(3-氨基苯氧基)四氢吡咯-1-甲酸叔丁酯(中间体6)
(R)-tert-butyl 3-(3-aminophenoxy)pyrrolidine-1-carboxylate
第一步:(R)-3-(3-硝基苯氧基)四氢吡咯-1-甲酸叔丁酯(6b)
(R)-tert-butyl 3-(3-nitrophenoxy)pyrrolidine-1-carboxylate
称取(R)-3-羟基四氢吡咯-1-甲酸叔丁酯(6a)(7.49g,40mmol),置于250mL圆底烧瓶中,向反应瓶中加入100mL四氢呋喃,搅拌均匀。向反应瓶中依次加入间氨基苯酚(4.36g,40mmol),三苯基膦(15.7g,60mmol),偶氮二甲酸二异丙酯(12g,60mmol)。反应升至70℃下搅拌8小时。减压除去四氢呋喃,柱层析分离(石油醚/乙酸乙酯(v/v)=4:1)得到黄色油状的液体(R)-3-(3-硝基苯氧基)四氢吡咯-1-甲酸叔丁酯(6b)(10.1g,产率:82%)。
LC-MS m/z=253.1[M-tBu+1]。
LC-MS m/z=331.1[M+23]。
第二步:(R)-3-(3-氨基苯氧基)四氢吡咯-1-甲酸叔丁酯(中间体6)
(R)-tert-butyl 3-(3-aminophenoxy)pyrrolidine-1-carboxylate
称取(R)3-(3-硝基苯氧基)四氢吡咯-1-甲酸叔丁酯(6b)(10.1g,32.8mmol),置于250mL圆底烧瓶中,向反应瓶中加入100mL甲醇,搅拌均匀。向反应瓶中加入钯炭(1.0g,10%w/w),室温下搅拌12小时。硅藻土过滤,减压除去甲醇,柱层析分离(石油醚/乙酸乙酯(v/v)=2:1)得到棕黄色固体状的(R)-3-(3-氨基苯氧基)四氢吡咯-1-甲酸叔丁酯(中间体6)(7.58g,产率:83%)。
LC-MS m/z=223.1[M-tBu+1]。
中间体7
(S)-3-(3-氨基苯氧基)四氢吡咯-1-甲酸叔丁酯(中间体7)
(S)-tert-butyl 3-(3-aminophenoxy)piperidine-1-carboxylate
第一步:(S)-3-(3-硝基苯氧基)四氢吡咯-1-甲酸叔丁酯(7b)
(S)-tert-butyl 3-(3-nitrophenoxy)pyrrolidine-1-carboxylate
称取(S)-3-羟基四氢吡啶-1-甲酸叔丁酯(7a)(7.49g,40mmol),置于250mL圆底烧瓶中,向反应瓶中加入100mL四氢呋喃,搅拌均匀。向反应瓶中依次加入间氨基苯酚(4.36g,40mmol),三苯基膦(PPh3)(15.7g,60mmol),偶氮二甲酸二异丙酯(12g,60mmol)。反应升至70℃下搅拌8小时。减压除去四氢呋喃,柱层析分离(石油醚/乙酸乙酯(v/v)=4:1)得到黄色油状的液体(S)-3-(3-硝基苯氧基)四氢吡咯-1-甲酸叔丁酯(7b)(10.7g,产率:87%)。
LC-MS m/z=253.1[M-tBu+1]。
LC-MS m/z=331.1[M+23]。
第二步:(S)-3-(3-氨基苯氧基)四氢吡咯-1-甲酸叔丁酯(中间体7)
(S)-tert-butyl 3-(3-aminophenoxy)pyrrolidine-1-carboxylate
称取(S)-3-(3-硝基苯氧基)四氢吡咯-1-甲酸叔丁酯(7b)(10.7g,34.7mmol),置于250mL圆底烧瓶中,向反应瓶中加入100mL甲醇,搅拌均匀。向反应瓶中加入钯炭(1.1g,10%w/w),室温下搅拌12小时。硅藻土过滤,减压除去甲醇,柱层析分离(石油醚/乙酸乙酯(v/v)=2:1)得到灰色固体状的(S)-3-(3-氨基苯氧基)四氢吡咯-1-甲酸叔丁酯(中间体7)(7.92g,产率:82%)。
LC-MS m/z=223.1[M-tBu+1]。
中间体8
N-[3-[[2,5-二氯嘧啶-4-基]氨基]苯基丙烯酰胺(中间体8)
N-[3-[[2,5-dichloropyrimidin-4-yl]amino]phenyl]prop-2-enamide
称取(3-氨基苯基)氨基甲酸叔丁酯(10.4g,50mmol,BEPHARM),置于250mL圆底烧瓶中,向反应瓶中加入正丁醇(100mL),0℃下,向反应瓶中依次滴加2,4,5-三氯嘧啶(8a)(9.17g,50mmol,BEPHARM),N,N-二异丙基乙胺(12.5mL,75mmol),滴加完毕后自然升至室温反应过夜。反应液出现白色浑浊,过滤,滤饼用正丁醇(20mL)洗涤,将得到的滤饼真空干燥后直接投入下一步。
将上述白色固体置于250mL圆底烧瓶中,0℃下,向反应瓶中加入二氯甲烷(100mL),三氟乙酸(40mL)。反应升至室温下搅拌90分钟。旋蒸除去反应溶剂,粗产品直接投入下一步。
将上述粗产品置于250mL圆底烧瓶中,加入二氯甲烷(100mL)。冷去至-78℃下,加入N,N-二异丙基乙胺(25.0mL,150mmol),通过恒压漏斗滴加丙烯酰氯(8.0mL,100mmol)的二氯甲烷(20mL)溶液。滴加完毕后,反应升至室温搅拌1小时,减压浓缩后柱层析分离(石油醚/乙酸乙酯(v/v)=4:1)得到白色固体的N-[3-[[2,5-二氯嘧啶-4-基]氨基]苯基丙烯酰胺(中间体8)(10.8g,产率70%)。
LC-MS m/z=309.0[M+1]。
实施例1:N-(3-((2-(3-(丙烯酰胺基)苯胺基)-5-(三氟甲基)嘧啶-4-基)氨基)苯基)丙烯胺(化合物1)
N-[3-[[2-[3-(prop-2-enoylamino)anilino]-5-(trifluoromethyl)pyrimidin-4-yl]amino]phen yl]prop-2-enamide
第一步:N2,N4-二(3-氨基苯基)-5-(三氟甲基)嘧啶-2,4-二氨(1B)
N2,N4-bis(3-aminophenyl)-5-(trifluoromethyl)pyrimidine-2,4-diamine
向反应瓶中加入2,4-二氯-5-(三氟甲基)嘧啶3a(5g,23mmol)和N,N-二甲基甲酰胺(60mL),冰浴冷却,加入间苯二胺(12.5g,115mmol),升温至室温反应20分钟,加入对甲苯磺酸(21.9g,115mmol),加热至70℃反应20分钟。冰浴冷却反应液,以饱和碳酸氢钠调节体系pH值至9,加入乙酸乙酯萃取(50mL×3),合并有机相,以水洗涤(30mL×5),有机相无水硫酸钠干燥,过滤,减压浓缩,硅胶柱色谱分离提纯(二氯甲烷/氨甲醇(v/v)=100:1)得到白色固体状的N2,N4-二(3-氨基苯基)-5-(三氟甲基)嘧啶-2,4-二氨1B(4g,产率48%)。
MS m/z(ESI):360.9[M+1];
1H NMR(400MHz,DMSO-d6)δ9.33(s,1H),8.29(d,2H),7.03(t,1H),6.89(s,1H),6.80(t,1H),6.73(d,2H),6.61(d,1H),6.45(d,1H),6.17(d,1H),4.93(s,4H)。
第二步:N-(3-((2-(3-(丙烯酰胺基)苯胺基)-5-(三氟甲基)嘧啶-4-基)氨基)苯基)丙烯胺(化合物1)
N-[3-[[2-[3-(prop-2-enoylamino)anilino]-5-(trifluoromethyl)pyrimidin-4-yl]amino]phen yl]prop-2-enamide
向反应瓶中加入N2,N4-二(3-氨基苯基)-5-(三氟甲基)嘧啶-2,4-二氨1B(1g,2.8mmol)、二异丙基乙基胺(2.15mg,16.7mmol)和二氯甲烷(30mL),冰浴冷却,滴加丙烯酰氯(550mg,6.1mmol)的二氯甲烷溶液(5mL),滴完室温反应1小时。向反应液中饱和碳酸氢钠水溶液(20mL),搅拌分液,水层以二氯甲烷萃取(15mL×6),合并有机相,无水硫酸钠干燥,过滤,将滤液减压浓缩,用乙酸乙酯(10mL×2)打浆得到白色固体状的N-(3-((2-(3-(丙烯酰胺基)苯胺基)-5-(三氟甲基)嘧啶-4-基)氨基)苯基)丙烯胺化合物1(600m g,产率45.8%)。
MS m/z(ESI):469.1[M+1]。
1H NMR(400MHz,DMSO-d6)δ10.23(s,1H),9.99(s,1H),9.68(s,1H),8.70(s,1H),8.34(s,1H),7.79(s,1H),7.64(s,1H),7.54(d,1H),7.44(d,1H),7.30-7.19(m,3H),6.96(t,1H),6.50-6.42(m,2H),6.24(dd,2H),5.73(t,2H)。
实施例2:N-[3-[[5-氯-2-[4-[2-二甲基氨基乙基(甲基)氨基]-3-(丙烯酰胺基)苯胺基]嘧啶-4-基]氨基]苯基]丙烯酰胺(化合物2)
N-[3-[[5-chloro-2-[4-[2-dimethylaminoethyl(methyl)amino]-3-(prop-2-enoylamino)anili no]pyrimidin-4-yl]amino]phenyl]prop-2-enamide
第一步:2,5-二氯-N-(3-硝基苯基)嘧啶-4-胺(2B)
2,5-dichloro-N-(3-nitrophenyl)pyrimidin-4-amine
将2,4,5-三氯嘧啶2A(2.76,15mmol),间硝基苯胺(2.08,15mmol)溶于异丙醇(120ml)中,加入二异丙基乙基胺(3.7ml,22.5mmol),升温至90℃反应过夜。将反应体系冷却至室温,析出固体产品,抽滤后干燥得到浅黄色固体的2,5-二氯-N-(3-硝基苯基)嘧啶-4-胺2B(2.92g,产率68%)。
1H NMR(400MHz,DMSO-d6)δ9.88(s,1H),8.14-8.11(m,1H),8.14-8.11(m,1H),8.03-8.00(m,1H),7.70-7.66(t,1H)。
MS m/z(ESI):285.0[M-1]。
第二步:5-氯-N2-(4-氟-3-硝基苯基)-N4-(3-硝基苯基)嘧啶-2,4-二胺(2C)
5-chloro-N2-(4-fluoro-3-nitrophenyl)-N4-(3-nitrophenyl)pyrimidine-2,4-diamine
将2,5-二氯-N-(3-硝基苯基)嘧啶-4-胺2B(1.42g,5.0mmol)和3-硝基-4-氟苯胺(0.80g,5.1mmol)溶于2-戊醇(30mL)中,加入对甲苯磺酸(1.17g,6.1mmol),升温至120℃反应过夜。将反应体系冷却至室温,析出固体产品,抽滤后干燥得到灰黄色固体的5-氯-N2-(4-氟-3-硝基苯基)-N4-(3-硝基苯基)嘧啶-2,4-二胺2C(1.47g,产率71%)。
1HNMR(400MHz,DMSO-d6)δ9.45(s,1H),8.47-8.44(m,1H),8.32(s,1H),8.16-8.14(m,1H),7.97-9.95(dd,1H),7.89-7.85(m,1H),7.64-7.60(t,1H),7.49-7.43(m,1H)。
MS m/z(ESI):405.0[M+1]。
第三步:5-氯-N2-(4-((2-(二甲基氨基)乙基)(甲基)氨基)-3-硝基苯基)-N4-(3-硝基苯基)嘧啶-2,4-二胺(2D)
5-chloro-N2-(4-((2-(dimethylamino)ethyl)(methyl)amino)-3-nitrophenyl)-N4-(3-nitrophe nyl)pyrimidine-2,4-diamine
微波反应管中加入5-氯-N2-(4-氟-3-硝基苯基)-N4-(3-硝基苯基)嘧啶-2,4-二胺2C(1.78g,4.4mmol),加入N,N-二甲基乙酰胺(15mL)溶解,加入二异丙基乙基胺(1.5mL,8.8mmol),N,N,N’-三甲基乙二胺(0.7mL,5.3mmol),140℃微波反应1小时。将反应体系冷却至室温后减压浓缩,得到橙色液体状的5-氯-N2-(4-((2-(二甲基氨基)乙基)(甲基)氨基)-3-硝基苯基)-N4-(3-硝基苯基)嘧啶-2,4-二胺2D(2.14g)。
第四步:N4-(4-((3-氨基苯基)氨基)-5-氯嘧啶-2-基)-N1-(2-(二甲基氨基)乙基)-N1-甲基苯-1,2,4-三胺(2E)
N4-(4-((3-aminophenyl)amino)-5-chloropyrimidin-2-yl)-N1-(2-(dimethylamino)ethyl)-N1-methylbenzene-1,2,4-triamine
将5-氯-N2-(4-((2-(二甲基氨基)乙基)(甲基)氨基)-3-硝基苯基)-N4-(3-硝基苯基)嘧啶-2,4-二胺2D(2.14g,4.4mmol)、铁粉(1.66g,29.4mmol)、氯化铵(0.19g,3.4mmol)溶于无水乙醇(36mL)和水(12mL)的混合溶剂中,升温至90℃反应过夜。冷却至室温,抽滤,将滤液减压浓缩,残留物用硅胶柱色谱分离提纯(石油醚:乙酸乙酯(v/v)=1:1~乙酸乙酯:甲醇(v/v)=10:1~1:1梯度洗脱)得到红棕色固体状的N4-(4-((3-氨基苯基)氨基)-5-氯嘧啶-2-基)-N1-(2-(二甲基氨基)乙基)-N1-甲基苯-1,2,4-三胺2E(1.34g,产率64%)。
MS m/z(ESI):427.1[M+1]。
第五步:N-[3-[[5-氯-2-[4-[2-二甲基氨基乙基(甲基)氨基]-3-(丙烯酰胺基)苯胺基]嘧啶-4-基]氨基]苯基]丙烯酰胺(化合物2)
N-[3-[[5-chloro-2-[4-[2-dimethylaminoethyl(methyl)amino]-3-(prop-2-enoylamino)anili no]pyrimidin-4-yl]amino]phenyl]prop-2-enamide
将N4-(4-((3-氨基苯基)氨基)-5-氯嘧啶-2-基)-N1-(2-(二甲基氨基)乙基)-N1-甲基苯-1,2,4-三胺2E(0.80g,1.9mmol)溶于四氢呋喃(10mL)和甲醇(3mL)的混合溶剂中,0℃下加入二异丙基乙基胺(1mL,5.9mmol),滴加丙烯酰氯(0.3ml,3.8mmol),室温反应1.5小时。向反应液中加入水(30mL)淬灭反应,水相用乙酸乙酯萃取(30mL×4),合并有机相,无水硫酸钠干燥,过滤,将滤液减压浓缩,残留物用硅胶柱色谱分离提纯(乙酸乙酯~乙酸乙酯:甲醇(v/v)=10:1~1:1)后制备得到白色固体的N-[3-[[5-氯-2-[4-[2-二甲基氨基乙基(甲基)氨基]-3-(丙烯酰胺基)苯胺基]嘧啶-4-基]氨基]苯基]丙烯酰胺化合物2(0.15g,产率16%)。
1H NMR(400MHz,CDCl3)δ10.31(s,1H),8.40-8.39(m,1H),8.17(s,1H),7.54-7.50(m,1H),7.29-7.22(m,1H),7.15-7.09(m,1H),7.05(s,1H),6.46-6.40(m,2H),6.36-6.28(m,2H),5.72-5.69(m,2H),2.85-2.82(m,2H),2.66(s,3H),2.28-2.26(m,2H),2.26(s,6H)。
MS m/z(ESI):535.2[M+1]。
实施例3:N-[3-[[4-[3-[(1-丙烯酰基-4-哌啶基)氧基]苯胺基]-5-(三氟甲基)嘧啶-2-基]氨基]苯基]丙烯酰胺(化合物3)
N-[3-[[4-[3-[(1-prop-2-enoyl-4-piperidyl)oxy]anilino]-5-(trifluoromethyl)pyrimidin-2-yl]amino]phenyl]prop-2-enamide
第一步:N-[3-[[4-氯-5-(三氟甲基)嘧啶-2-基]氨基]苯基]丙烯酰胺(3B)
N-[3-[[4-chloro-5-(trifluoromethyl)pyrimidin-2-yl]amino]phenyl]prop-2-enamide
称取2,4-二氯-5-三氟甲基嘧啶3a(0.43g,2mmol,BEPHARM),置于100mL圆底烧瓶中,向反应瓶中加入叔丁醇(5mL),1,2-二氯乙烷(5mL)。0℃下,向反应瓶中滴加二氯化锌的乙醚溶液(1mol/L,2.4mmol,2.4mL),滴加完毕后继续在0℃下反应1小时。向反应瓶中加入N-(3-氨基苯基)丙烯酰胺(中间体2,0.32g,2mmol),三乙胺(0.3mL,2.2mmol),反应自然升至室温搅拌过夜。向反应瓶中加入水(30mL),用乙酸乙酯(100mL×2)萃取,合并后的有机相用饱和食盐水(30mL×2)洗涤,无水硫酸钠干燥,过滤,减压浓缩后得到黄色固体状的N-[3-[[4-氯-5-(三氟甲基)嘧啶-2-基]氨基]苯基]丙烯酰胺3B粗品(0.68g),直接用于下步反应。
1H NMR(400MHz,CDCl3)δ8.59(s,1H),8.05(s,1H),7.60(s,1H),7.37-7.26(m,4H),6.47-6.43(d,1H),6.28-6.24(m,1H),5.81-5.78(m,1H)。
第二步:4-(3-((2-((3-丙烯酰胺苯基)氨基)-5-三氟甲基)嘧啶-4-基)氨基)苯氧基)嘧啶-1-甲酸叔丁酯(3C)
tert-butyl 4-(3-((2-((3-acrylamidophenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amin o)phenoxy)piperidine-1-carboxylate
称取N-[3-[[4-氯-5-(三氟甲基)嘧啶-2-基]氨基]苯基]丙烯酰胺3B(0.68g,2mmol),置于100mL圆底烧瓶中。向反应瓶中依次加入N,N-二甲基甲酰胺(10mL),N,N-二异丙基乙胺(0.4mL,2.4mmol)和4-(3-氨基苯氧基)哌啶-1-甲酸叔丁酯(中间体1,0.58g,2mmol)。反应升温至90℃下搅拌48小时。减压浓缩,残留物用硅胶柱层析分离提纯(二氯甲烷/乙酸乙酯(v/v)=1:1)得到黄色固体状的4-(3-((2-((3-丙烯酰胺苯基)氨基)-5-三氟甲基)嘧啶-4-基)氨基)苯氧基)嘧啶-1-甲酸叔丁酯3C(0.6g,产率50%)。
1H NMR(400MHz,CDCl3)δ8.33(s,1H),7.78(s,1H),7.57(m,1H),7.49(m,1H),7.30-7.20(m,4H),7.06-7.00(m,2H),6.90(s,1H),6.82-6.80(m,1H),6.45-6.41(m,1H),6.28-6.21(m,1H),5.79-5.76(m,1H),4.37-4.35(m,1H),3.65-3.62(m,2H),3.28-3.21(m,2H),1.88-1.83(m,2H),1.72-1.65(m,2H),1.45(s,9H)。
第三步:N-[3-[[4-[3-[(1-丙烯酰基-4-哌啶基)氧基]苯胺基]-5-(三氟甲基)嘧啶-2-基]氨基]苯基]丙烯酰胺(化合物3)
N-[3-[[4-[3-[(1-prop-2-enoyl-4-piperidyl)oxy]anilino]-5-(trifluoromethyl)pyrimidin-2-yl]amino]phenyl]prop-2-enamide
称取4-(3-((2-((3-丙烯酰胺苯基)氨基)-5-三氟甲基)嘧啶-4-基)氨基)苯氧基)嘧啶-1-甲酸叔丁酯3C(0.6g,1mmol),置于100mL圆底烧瓶中。0℃下,向反应瓶中依次加入二氯甲烷(10mL)和三氟乙酸(10mL)。室温下反应30分钟后,减压浓缩,残留物置于100mL圆底烧瓶中,向反应瓶中依次加入二氯甲烷(5mL)和四氢呋喃(5mL)。-78℃下向反应瓶中加入N,N-二异丙基乙胺(0.66mL,4mmol),缓慢滴加丙烯酰氯(0.16mL,2mmol)的二氯甲烷(5mL)溶液。滴加完毕后,反应升至室温搅拌1小时,减压浓缩后硅胶柱层析分离(二氯甲烷/乙酸乙酯(v/v)=1:1)得到白色固体状的N-[3-[[4-[3-[(1-丙烯酰基-4-哌啶基)氧基]苯胺基]-5-(三氟甲基)嘧啶-2-基]氨基]苯基]丙烯酰胺化合物3(0.46g,产率84%)。
1H NMR(400MHz,CDCl3)δ8.34(s,1H),7.77(s,1H),7.52(s,1H),7.33-7.20(m,5H),7.11(m,1H),6.99(m,1H),6.83(s,1H),6.79(m,1H),6.45-6.21(m,4H),5.79-5.76(m,1H),5.70-5.67(m,1H),4.45(m,1H),3.74-3.44(m,4H),1.88-1.84(m,4H)。
实施例4:N-[3-[[2-[3-[(1-丙烯酰基-4-哌啶基)氧基]苯胺基]-5-(三氟甲基)嘧啶-4-基]氨基]苯基]丙烯酰胺(化合物4)
N-[3-[[2-[3-[(1-prop-2-enoyl-4-piperidyl)oxy]anilino]-5-(trifluoromethyl)pyrimidin-4-yl]amino]phenyl]prop-2-enamide
第一步:4-[3-[[4-[3-(丙烯酰胺基)苯胺基]-5-(三氟甲基)嘧啶-2-基]氨基]苯氧基]哌啶-1-甲酸叔丁酯(4B)
tert-butyl 4-[3-[[4-[3-(prop-2-enoylamino)anilino]-5-(trifluoromethyl)pyrimidin-2-yl]am ino]phenoxy]piperidine-1-carboxylate
称取N-[3-[[2-氯-5-(三氟甲基)嘧啶-4-基]氨基]苯基]丙烯酰胺(中间体3,0.34g,1mmol)置于100mL圆底烧瓶中,向反应瓶中依次加入1,4-二氧六环(10mL)、4-(3-氨基苯氧基)哌啶-1-甲酸叔丁酯(中间体1,0.29g,1mmol)和三氟乙酸的1,4-二氧六环溶液(1M,0.2mL),加热至50℃下搅拌过夜,减压浓缩,残留物用硅胶柱层析分离提纯得到粉红色固体状的4-[3-[[4-[3-(丙烯酰胺基)苯胺基]-5-(三氟甲基)嘧啶-2-基]氨基]苯氧基]哌啶-1-甲酸叔丁酯4B(0.3g,产率50%)。
1H NMR(400MHz,CDCl3)δ11.53(s,1H),8.15(s,1H),7.99(s,1H),7.78(s,1H),7.45-7.30(m,3H),7.18-7.14(m,3H),7.04(m,1H),6.70(d,1H),6.42(m,1H),6.25(m,1H),5.81-5.78(m,1H),4.31-4.28(m,1H),3.62-3.61(m,2H),3.23-3.18(m,2H),1.80(m,2H),1.63-1.61(m,2H),1.48(s,9H)。
第二步:
N-[3-[[2-[3-[(1-丙烯酰基-4-哌啶基)氧基]苯胺基]-5-(三氟甲基)嘧啶-4-基]氨基]苯基]丙烯酰胺(化合物4)
N-[3-[[2-[3-[(1-prop-2-enoyl-4-piperidyl)oxy]anilino]-5-(trifluoromethyl)pyrimidin-4-yl]amino]phenyl]prop-2-enamide
将4-[3-[[4-[3-[(丙烯酰胺基)苯胺]-5-(三氟甲基)嘧啶-2-基]氨基]苯氧基]哌啶-1-甲酸叔丁酯4B(0.6g,1mmol)置于100mL圆底烧瓶中,0℃下向反应瓶中依次加入二氯甲烷(10mL)和三氟乙酸(10mL)。室温下反应30分钟后减压浓缩,将得到的残留物置于100mL圆底烧瓶中,向反应瓶中依次加入二氯甲烷(5mL)和四氢呋喃(5mL),-78℃下向反应瓶中加入N,N-二异丙基乙胺(0.66mL,4mmol),缓慢滴加丙烯酰氯(0.16mL,2mmol)的二氯甲烷(5mL)溶液。滴加完毕后反应升至室温搅拌1小时,减压浓缩,残留物用硅胶柱层析分离提纯(二氯甲烷/乙酸乙酯(v/v)=1:1)得到白色固体状的N-[3-[[2-[3-[(1-丙烯酰基-4-哌啶基)氧基]苯胺基]-5-(三氟甲基)嘧啶-4-基]氨基]苯基]丙烯酰胺(化合物4)(0.4g,产率69%)。
1H NMR(400MHz,CDCl3)δ8.45(br,1H),8.27(s,1H),8.06(s,1H),7.78(s,1H),7.38-7.28(m,3H),7.18-7.16(m,2H),7.04-6.97(m,2H),6.60-6.55(m,2H),6.46(m,1H),6.31-6.22(m,2H),5.79-5.69(m,2H),4.39(m,1H),3.70-3.45(m,4H),1.88-1.71(m,4H)。
实施例5
N-[3-[[2-[4-[2-二甲基氨基乙基(甲基)氨基]-3-(丙烯酰胺基)苯胺基]-5-(三氟甲基嘧啶-4-基]氨基]苯基]丙烯酰胺(化合物5-1)
N-[3-[[2-[4-[2-dimethylaminoethyl(methyl)amino]-3-(prop-2-enoylamino)anilino]-5-(tr ifluoromethyl)pyrimidin-4-yl]amino]phenyl]prop-2-enamide
N-[3-[[4-[4-[2-二甲基氨基乙基(甲基)氨基]-3-(丙烯酰胺基)苯胺基]-5-(三氟甲基)嘧啶-2-基]氨基]苯基]丙烯酰胺(化合物5-2)
N-[3-[[4-[4-[2-dimethylaminoethyl(methyl)amino]-3-(prop-2-enoylamino)anilino]-5-(tr ifluoromethyl)pyrimidin-2-yl]amino]phenyl]prop-2-enamide
第一步:2-氯-N-(3-硝基苯基)-5-(三氟甲基)嘧啶-4-胺(5B-1)
2-chloro-N-(3-nitrophenyl)-5-(trifluoromethyl)pyrimidin-4-amine
4-氯-N-(3-硝基苯基)-5-(三氟甲基)嘧啶-2-胺(5B-2)
4-chloro-N-(3-nitrophenyl)-5-(trifluoromethyl)pyrimidin-2-amine
反应瓶中称取间硝基苯胺(2.22g,16mmol),加入正丁醇(60ml),体系降至0℃,滴加2,4-二氯-5-(三氟甲基)-嘧啶(5A)(3.47g,16mmol),二异丙基乙胺(3.3ml,20mmol),0℃反应7小时后升至50℃反应4小时,室温过夜,80℃反应1小时后停止反应。将反应体系冷却至室温,浓缩,残留物用硅胶柱色谱分离提纯(石油醚:乙酸乙酯(v/v)=10:1~3:1),得到标题化合物4-氯-N-(3-硝基苯基)-5-(三氟甲基)嘧啶-2-胺(5B-2)和2-氯-N-(3-硝基苯基)-5-(三氟甲基)嘧啶-4-胺(5B-1)的混合物,浅黄色固体(4.31g,产率76%)。
第二步:N2-(4-氟-3-硝基苯基)-N4-(3-硝基苯基)-5-(三氟甲基)嘧啶-2,4-二胺(5C-1)
N2-(4-fluoro-3-nitrophenyl)-N4-(3-nitrophenyl)-5-(trifluoromethyl)pyrimidine-2,4-diamine
N4-(4-氟-3-硝基苯基)-N2-(3-硝基苯基)-5-(三氟甲基)嘧啶-2,4-二胺(5C-2)
N4-(4-fluoro-3-nitrophenyl)-N2-(3-nitrophenyl)-5-(trifluoromethyl)pyrimidine-2,4-diamine
取上步所得4-氯-N-(3-硝基苯基)-5-(三氟甲基)嘧啶-2-胺(5B-2)和2-氯-N-(3-硝基苯基)-5-(三氟甲基)嘧啶-4-胺(5B-1)的混合物(2.17g,6.72mmol),和3-硝基-4-氟苯胺(1.05g,6.72mmol)溶于2-戊醇(35mL)中,加入对甲苯磺酸(1.56g,8.2mmol),升温至120℃过夜。将反应体系冷却至室温,浓缩,残留物用硅胶柱色谱分离提纯(石油醚:乙酸乙酯(v/v)=15:1~3:1),得到标题化合物N4-(4-氟-3-硝基苯基)-N2-(3-硝基苯基)-5-(三氟甲基)嘧啶-2,4-二胺(5C-2)和N2-(4-氟-3-硝基苯基)-N4-(3-硝基苯基)-5-(三氟甲基)嘧啶-2,4-二胺(5C-1)的混合物,黄色固体(1.59g,产率58%)。
第三步:N2-(4-((2-(二甲氨基)乙基)(甲基)氨基)-3-硝基苯基)-N4-(3-硝基苯基)-5-(三氟甲基)嘧啶-2,4-二胺(5D-1)
N2-(4-((2-(dimethylamino)ethyl)(methyl)amino)-3-nitrophenyl)-N4-(3-nitrophenyl)-5-(tri fluoromethyl)pyrimidine-2,4-diamine
N4-(4-((2-(二甲氨基)乙基)(甲基)氨基)-3-硝基苯基)-N2-(3-硝基苯基)-5-(三氟甲基)嘧啶-2,4-二胺(5D-2)
N4-(4-((2-(dimethylamino)ethyl)(methyl)amino)-3-nitrophenyl)-N2-(3-nitrophenyl)-5-(tri fluoromethyl)pyrimidine-2,4-diamine
取上步所得N4-(4-氟-3-硝基苯基)-N2-(3-硝基苯基)-5-(三氟甲基)嘧啶-2,4-二胺(5C-2)和N2-(4-氟-3-硝基苯基)-N4-(3-硝基苯基)-5-(三氟甲基)嘧啶-2,4-二胺(5C-1)的混合物(3.2g,7.3mmol)、N,N-二异丙基乙基胺(DIPEA)(1.13g,8.76mmol)和N1,N1,N2-三甲基-1,2-乙二胺(896mg,8.76mmol)溶于N,N-二甲基苯胺(DMA)(10mL)中。微波140℃反应1.5小时。将反应体系浓缩,残留物用硅胶柱色谱分离提纯(二氯甲烷:甲醇(v/v)=1:0~20:1),得到标题化合物N4-(4-((2-(二甲氨基)乙基)(甲基)氨基)-3-硝基苯基)-N2-(3-硝基苯基)-5-(三氟甲基)嘧啶-2,4-二胺(5D-2)和N2-(4-((2-(二甲氨基)乙基)(甲基)氨基)-3-硝基苯基)-N4-(3-硝基苯基)-5-(三氟甲基)嘧啶-2,4-二胺(5D-1)的混合物,红色固体(1.4g,产率36.8%)。
LC-MS m/z=512.2[M+1]。
第四步:N4-(4-((3-氨基苯基)氨基)5-(三氟甲基)嘧啶-2-基)-N1-2-(二甲氨基)乙基)-N1-甲基苯基-1,2,4-三胺(5E-1)
N4-(4-((3-aminophenyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)-N1-(2-(dimethylamin o)ethyl)-N1-methylbenzene-1,2,4-triamine
N4-(2-((3-氨基苯基)氨基)-5-(三氟甲基)嘧啶-4-基)-N1-2-(二甲氨基)乙基)-N1-甲基苯基-1,2,4-三胺(5E-2)
N4-(2-((3-aminophenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-N1-(2-(dimethylamin o)ethyl)-N1-methylbenzene-1,2,4-triamine
取上步所得N4-(4-((2-(二甲氨基)乙基)(甲基)氨基)-3-硝基苯基)-N2-(3-硝基苯基)-5-(三氟甲基)嘧啶-2,4-二胺(5D-2)和N2-(4-((2-(二甲氨基)乙基)(甲基)氨基)-3-硝基苯基)-N4-(3-硝基苯基)-5-(三氟甲基)嘧啶-2,4-二胺(5D-1)的混合物(1.5g,2.88mmol)、还原铁粉(1.29g,23.1mmol)和氯化铵(108mg,2.02mmol)溶于乙醇(30mL)中,再加入水(10mL)。升至90℃反应过夜。将反应体系浓缩,残留物用硅胶柱色谱分离提纯(二氯甲烷:甲醇(v/v)=1:0~10:1),得到标题化合物N4-(2-((3-氨基苯基)氨基)-5-(三氟甲基)嘧啶-4-基)-N1-2-(二甲氨基)乙基)-N1-甲基苯基-1,2,4-三胺(5E-2)和N4-(4-((3-氨基苯基)氨基)-5-(三氟甲基)嘧啶-2-基)-N1-2-(二甲氨基)乙基)-N1-甲基苯基-1,2,4-三胺(5E-1)的混合物,棕色油状(1.2g,产率92.3%)。
LC-MS m/z=461.2[M+1]。第五步:N-[3-[[2-[4-[2-二甲基氨基乙基(甲基)氨基]-3-(丙烯酰胺基)苯胺基]-5-(三氟甲基嘧啶-4-基]氨基]苯基]丙烯酰胺(化合物5-1)
N-[3-[[2-[4-[2-dimethylaminoethyl(methyl)amino]-3-(prop-2-enoylamino)anilino]-5-(trif luoromethyl)pyrimidin-4-yl]amino]phenyl]prop-2-enamide
N-[3-[[4-[4-[2-二甲基氨基乙基(甲基)氨基]-3-(丙烯酰胺基)苯胺基]-5-(三氟甲基)嘧啶-2-基]氨基]苯基]丙烯酰胺(化合物5-2)
N-[3-[[4-[4-[2-dimethylaminoethyl(methyl)amino]-3-(prop-2-enoylamino)anilino]-5-(trif luoromethyl)pyrimidin-2-yl]amino]phenyl]prop-2-enamide
取上步所得N4-(2-((3-氨基苯基)氨基)-5-(三氟甲基)嘧啶-4-基)-N1-2-(二甲氨基)乙基)-N1-甲基苯基-1,2,4-三胺(5E-2)和N4-(4-((3-氨基苯基)氨基)-5-(三氟甲基)嘧啶-2-基)-N1-2-(二甲氨基)乙基)-N1-甲基苯基-1,2,4-三胺(5E-1)的混合物(1.2g,2.6mmol)溶于吡啶(10mL)中,加入1-乙基-3-(3-二甲基氨基丙基)碳酰二亚胺(EDCI)(2.98g,15.6mmol),滴加丙烯酸(0.54mL,7.8mmol),室温反应4小时。旋干吡啶,加入水(100mL)和乙酸乙酯(100mL),分液,有机相用氢氧化钠水溶液(100mL,4mol/L)洗涤,有机相用无水硫酸钠干燥,通过制备得N-[3-[[2-[4-[2-二甲基氨基乙基(甲基)氨基]-3-(丙烯酰胺基)苯胺基]-5-(三氟甲基嘧啶-4-基]氨基]苯基]丙烯酰胺(化合物5-1),白色固体(65mg,4.4%),N-[3-[[4-[4-[2-二甲基氨基乙基(甲基)氨基]-3-(丙烯酰胺基)苯胺基]-5-(三氟甲基)嘧啶-2-基]氨基]苯基]丙烯酰胺(化合物5-2),白色固体(500mg,33.8%)。
LC-MS m/z=569.1[M+1];
LC-MS m/z=567.2[M-1];
化合物5-1:
1H NMR(400MHz,CDCl3)δ10.36(s,1H),8.75(s,1H),8.31(s,1H),7.75(s,1H),7.46(s,3H),7.34–7.27(m,2H),7.18(t,2H),6.83(s,1H),6.49–6.37(m,3H),6.25(dd,1H),5.77–5.70(m,2H),2.90(s,2H),2.71(s,3H),2.33(s,6H),1.67(s,4H)。
实施例6
N-[3-[[2-[3-(1-丙烯酰基-4-哌啶基)苯胺基]-5-(三氟甲基)嘧啶-4-基]氨基]苯基]丙烯酰胺(化合物6)
N-[3-[[2-[3-(1-prop-2-enoyl-4-piperidyl)anilino]-5-(trifluoromethyl)pyrimidin-4-yl]amin o]phenyl]prop-2-enamide
第一步:4-(3-((4-((3-丙烯酰胺基苯基)氨基)-5-(三氟甲基)嘧啶-2-基)氨基)苯基)哌啶-1-甲酸叔丁酯(6B)
tert-butyl 4-(3-((4-((3-acrylamidophenyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)ph enyl)piperidine-1-carboxylate
称取N-[3-[[2-氯-5-(三氟甲基)嘧啶-4-基]氨基]苯基]丙烯酰胺(中间体3)(0.68g,2mmol),置于100mL圆底烧瓶中,向反应瓶中加入1,4-二氧六环(10mL)。向反应瓶中依次加入4-(3-氨基苯氧基)哌啶-1-甲酸叔丁酯(中间体1)(0.55g,2mmol),三氟乙酸的1,4-二氧六环溶液(1mol/L,0.4mL)。反应升至50℃下搅拌过夜。减压除去反应溶剂,柱层析分离(乙酸乙酯)得到粉红色固体状的4-(3-((4-((3-丙烯酰胺基苯基)氨基)-5-(三氟甲基)嘧啶-2-基)氨基)苯基)哌啶-1-甲酸叔丁酯(6B)(0.44g,产率38%)。
1H NMR(400MHz,CDCl3)δ8.30(s,1H),7.99(br,2H),8.05(s,1H),7.61(s,1H),7.38(s,1H),7.30-7.17(m,4H),6.89-6.87(m,2H),6.50-6.25(m,2H),5.79-5.76(m,1H),4.19(br,1H),2.74-2.48(m,3H),1.88-1.69(m,3H),1.53-1.50(m,11H)。
第二步:N-[3-[[2-[3-(1-丙烯酰基-4-哌啶基)苯胺基]-5-(三氟甲基)嘧啶-4-基]氨基]苯基]丙烯酰胺(化合物6)
N-[3-[[2-[3-(1-prop-2-enoyl-4-piperidyl)anilino]-5-(trifluoromethyl)pyrimidin-4-yl]amin o]phenyl]prop-2-enamide
称取4-(3-((4-((3-丙烯酰胺基苯基)氨基)-5-(三氟甲基)嘧啶-2-基)氨基)苯基)哌啶-1-甲酸叔丁酯(6B)(0.44g,0.76mmol),置于100mL圆底烧瓶中。0℃下,向反应瓶中依次加入二氯甲烷(10mL),三氟乙酸(10mL)。室温下反应1小时后,减压除去反应溶剂。将得到的粗产品置于100mL圆底烧瓶中,向反应瓶中依次加入二氯甲烷(5mL),四氢呋喃(5mL)。-78℃下,向反应瓶中加入N,N-二异丙基乙胺(0.39mL,3.0mmol),通过恒压漏斗滴加丙烯酰氯(0.14g,1.5mmol)的5mL二氯甲烷溶液。滴加完毕后,反应升至室温搅拌1小时。减压浓缩后柱层析分离(二氯甲烷/乙酸乙酯(v/v)=1:1)得到白色固体状的N-[3-[[2-[3-(1-丙烯酰基-4-哌啶基)苯胺基]-5-(三氟甲基)嘧啶-4-基]氨基]苯基]丙烯酰胺(化合物6)(0.22g,产率54%)。
1H NMR(400MHz,CDCl3)δ8.75(br,1H),8.29-8.25(m,2H),8.01(s,1H),7.41(s,1H),7.21-7.06(m,5H),6.87-6.85(d,1H),6.62-6.58(m,1H),6.44-6.48(m,1H),6.34-6.30(m,2H),5.76-5.73(m,2H),4.72-4.69(m,1H),4.13-4.06(m,1H),3.12-3.09(m,1H),2.67-2.59(m,2H),1.75-1.10(m,4H)。
LC-MS m/z=537.1[M+1]。
实施例7
N-[3-[[2-[3-(1-丙烯酰基-4-哌啶基)苯胺基]-5-(三氟甲基)嘧啶-4-基]氨基]苯基]丙烯酰胺(化合物7)
N-[3-[[2-[3-(1-prop-2-enoyl-4-piperidyl)anilino]-5-(trifluoromethyl)pyrimidin-4-yl]amin o]phenyl]prop-2-enamide
第一步:4-(3-((2-((3-丙烯酰胺基苯基)氨基)-5-(三氟甲基)嘧啶-4-基)氨基)苯基)哌啶-1-甲酸叔丁酯(7B)
tert-butyl4-(3-((2-((3-acrylamidophenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)phenyl)piperi dine-1-carboxylate
称取N-[3-[[4-氯-5-(三氟甲基)嘧啶-2-基]氨基]苯基]丙烯酰胺(3B)(1.0g,3mmol),置于100mL圆底烧瓶中。向反应瓶中依次加入N,N-二甲基甲酰胺(10mL),N,N-二异丙基乙胺(1.0mL,6mmol),4-(3-氨基苯氧基)哌啶-1-甲酸叔丁酯(中间体1)(0.84g,3mmol)。反应升温至90℃下搅拌48小时。减压浓缩后柱层析分离(石油醚/乙酸乙酯(v/v)=3:1)得到黄色固体状的4-(3-((2-((3-丙烯酰胺基苯基)氨基)-5-(三氟甲基)嘧啶-4-基)氨基)苯基)哌啶-1-甲酸叔丁酯(7B)(0.80g,产率45%)。
LC-MS m/z=583.1[M+1]。
第二步:N-[3-[[2-[3-(1-丙烯酰基-4-哌啶基)苯胺基]-5-(三氟甲基)嘧啶-4-基]氨基]苯基]丙烯酰胺(化合物7)
N-[3-[[2-[3-(1-prop-2-enoyl-4-piperidyl)anilino]-5-(trifluoromethyl)pyrimidin-4-yl]amin o]phenyl]prop-2-enamide
称取4-(3-((2-((3-丙烯酰胺基苯基)氨基)-5-(三氟甲基)嘧啶-4-基)氨基)苯基)哌啶-1-甲酸叔丁酯(7B)(0.77g,1.3mmol),置于100mL圆底烧瓶中。0℃下,向反应瓶中依次加入二氯甲烷(10mL),三氟乙酸(10mL)。室温下反应2小时后,减压除去反应溶剂。将得到的粗产品置于100mL圆底烧瓶中,向反应瓶中依次加入二氯甲烷(5mL),四氢呋喃(5mL)。-78℃下,向反应瓶中加入N,N-二异丙基乙胺(0.88mL,5.3mmol),通过恒压漏斗滴加丙烯酰氯(0.21mL,2.6mmol)的5mL二氯甲烷溶液。滴加完毕后,反应升至室温搅拌2小时。减压浓缩后柱层析分离(乙酸乙酯)得到白色固体状的N-[3-[[2-[3-(1-丙烯酰基-4-哌啶基)苯胺基]-5-(三氟甲基)嘧啶-4-基]氨基]苯基]丙烯酰胺(化合物7)(0.42g,产率59%)。
1H NMR(400MHz,DMSO-d6)δ9.99(s,1H),9.69(s,1H),8.53-8.51(m,1H),8.36-8.35(m,1H),7.72(s,1H),7.48-7.46(m,1H),7.31-7.26(m,4H),7.03-7.01(m,2H),6.86-6.79(m,1H),6.41-6.47(m,1H),6.27-6.24(d,1H),6.13-6.07(d,1H),5.75-5.65(m,2H),4.57-4.55(m,1H),4.16-4.13(m,1H),3.15-3.09(m,1H),2.80-2.60(m,2H),1.82-1.78(m,2H),1.51-1.45(m,2H)。
LC-MS m/z=537.0[M+1]。
实施例8
N-[3-[[5-氯-4-[[3-(丙烯酰胺基)苯基]氨基]嘧啶-2-基]氨基]苯基]丙烯酰胺(化合物8)
N-[3-[[5-chloro-4-[[3-(prop-2-enoylamino)phenyl]amino]pyrimidin-2-yl]amino]phenyl]prop-2-enamide
第一步:N-[3-[[5-氯-4-[[3-(丙烯酰胺基)苯基]氨基]嘧啶-2-基]氨基]苯基]氨基甲酸叔丁酯(8B)
tert-butyl N-[3-[[5-chloro-4-[[3-(prop-2-enoylamino)phenyl]amino]pyrimidin-2-yl]
amino]phenyl]carbamate
称取N-[3-[[2,5-二氯嘧啶-4-基]氨基]苯基丙烯酰胺(中间体8)(0.93g,3mmol),置于100mL圆底烧瓶中,向反应瓶中加入1,4-二氧六环(20mL)。向反应瓶中依次加入(3-氨基苯基)氨基甲酸叔丁酯(0.63g,3mmol,BEPHARM),三氟乙酸的1,4-二氧六环溶液(1mol/L,0.6mL),反应升至50℃搅拌过夜。将反应液减压除去溶剂,柱层析分离得到白色固体状的N-[3-[[5-氯-4-[[3-(丙烯酰胺基)苯基]氨基]嘧啶-2-基]氨基]苯基]氨基甲酸叔丁酯(8B)(0.52g,产率36%)。
LC-MS m/z=481.1[M+1]。
第二步:N-[3-[[5-氯-4-[[3-(丙烯酰胺基)苯基]氨基]嘧啶-2-基]氨基]苯基]丙烯酰胺(化合物8)
N-[3-[[5-chloro-4-[[3-(prop-2-enoylamino)phenyl]amino]pyrimidin-2-yl]amino]phenyl]prop-2-enamide
N-[3-[[5-氯-4-[[3-(丙烯酰胺基)苯基]氨基]嘧啶-2-基]氨基]苯基]氨基甲酸叔丁酯(8B)(0.52g,1.1mmol),置于50mL圆底烧瓶中,0℃下,向反应瓶中依次加入二氯甲烷(10mL),三氟乙酸(5mL),室温下反应30分钟,减压除去溶剂,将得到的粗产品置于50mL圆底烧瓶中,向反应瓶中依次加入二氯甲烷(5mL),四氢呋喃(5mL),冷却至-78℃,加入N,N-二异丙基乙胺(0.74mL,4.3mmol),通过恒压漏斗滴加丙烯酰氯(0.17mL,2.1mmol)的二氯甲烷(5mL)溶液,滴加完毕后,反应升至室温搅拌1小时。减压浓缩后柱层析分离(二氯甲烷/乙酸乙酯(v/v)=1:1)得到白色固体状的N-[3-[[5-氯-4-[[3-(丙烯酰胺基)苯基]氨基]嘧啶-2-基]氨基]苯基]丙烯酰胺(化合物8)(0.2g,产率42.6%)。
LC-MS m/z=435.0[M+1]。
1H NMR(400MHz,DMSO-d6)δ10.11(s,1H),9.98(s,1H),9.29(s,1H),8.88(s,1H),8.15(s,1H),7.88(t,1H),7.72(s,1H),7.56–7.39(m,3H),7.27(dd,2H),7.05(t,1H),6.46(dd,2H),6.25(m,2H),5.75(m,2H)。
实施例9
N-[3-[[4-[4-[2-二甲基氨基乙基(甲基)氨基]-3-(丙烯酰胺基)苯胺基]-5-(三氟甲基)嘧啶-2-基]氨基]苯基]丙烯酰胺甲磺酸盐(化合物9)
N-[3-[[4-[4-[2-dimethylaminoethyl(methyl)amino]-3-(prop-2-enoylamino)anilino]-5-(trif luoromethyl)pyrimidin-2-yl]amino]phenyl]prop-2-enamidemethanesulfonate
将N-[3-[[4-[4-[2-二甲基氨基乙基(甲基)氨基]-3-(丙烯酰胺基)苯胺基]-5-(三氟甲基)嘧啶-2-基]氨基]苯基]丙烯酰胺(化合物5-2)(56.8mg,0.1mmol)溶于乙醇(6mL)中,加入乙酸乙酯(2mL),70℃下滴加甲磺酸(0.048mL,0.075mmol)的乙酸乙酯(2mL)溶液,70℃反应2小时,将反应液旋干得N-[3-[[4-[4-[2-二甲基氨基乙基(甲基)氨基]-3-(丙烯酰胺基)苯胺基]-5-(三氟甲基)嘧啶-2-基]氨基]苯基]丙烯酰胺甲磺酸盐(化合物9),棕色固体(66mg,产率99.4%)。
1H NMR(400MHz,DMSO-d6)δ10.11(s,1H),9.78(s,1H),9.42(s,1H),9.31(s,1H),8.82(s,1H),8.43(s,1H),8.22(s,1H),7.62(s,1H),7.50(d,1H),7.39(t,2H),7.32(d,1H),7.06(t,1H),6.77(dd,1H),6.51(dd,1H),6.39–6.25(m,2H),5.83(ddd,2H),3.40–3.31(m,2H),3.28(d,2H),2.94–2.79(m,6H),2.63(d,3H),2.39(s,3H)。
实施例10
N-(3-((2-(3-(丙烯酰胺基)苯胺基)-5-(三氟甲基)嘧啶-4-基)氨基)苯基)丙烯酰胺盐酸盐(化合物10)
N-[3-[[2-[3-(prop-2-enoylamino)anilino]-5-(trifluoromethyl)pyrimidin-4-yl]amino]phen yl]prop-2-enamide hydrochloric acid
向反应瓶中加入N-(3-((2-(3-(丙烯酰胺基)苯胺基)-5-(三氟甲基)嘧啶-4-基)氨基)苯基)丙烯胺化合物1(50mg,0.11mmol),加入甲醇1mL,冰浴冷却,滴加浓盐酸(16mg)的甲醇溶液0.5mL,滴完冰浴室温反应1小时。过滤,滤饼以甲醇0.5mL洗涤,得白色固体N-(3-((2-(3-(丙烯酰胺基)苯胺基)-5-(三氟甲基)嘧啶-4-基)氨基)苯基)丙烯酰胺盐酸盐(化合物10)(40mg,产率74.2%)。
实施例11
(S)-N-[3-[[2-[3-[(1-丙烯酰基四氢吡咯-3-基)氧基苯基]氨基]-5-(三氟甲基)嘧啶-4-基]氨基]苯基]丙烯酰胺(化合物11)
(S)-N-[3-[[2-[[3-(1-prop-2-enoylpyrrolidin-3-yl)oxyphenyl]amino]-5-(trifluoromethyl)py rimidin-4-yl]amino]phenyl]prop-2-enamide
第一步:(S)-3-[3-[[4-[[3-(丙烯酰胺基)苯基]氨基]-5-(三氟甲基)嘧啶-2-基]氨基]苯氧基]四氢吡咯-1-甲酸叔丁酯(11B)
(S)-tert-butyl 3-[3-[[4-[[3-(prop-2-enoylamino)phenyl]amino]-5-(trifluoromethyl)
pyrimidin-2-yl]amino]phenoxy]pyrrolidine-1-carboxylate
称取N-[3-[[2-氯-5-(三氟甲基)嘧啶-4-基]氨基]苯基]丙烯酰胺(中间体3)(1.02g,3mmol),置于100mL圆底烧瓶中,加入1,4-二氧六环(20mL),再依次加入(S)-3-(3-氨基苯氧基)四氢吡咯-1-甲酸叔丁酯(中间体7)(0.84g,3mmol),三氟乙酸的1,4-二氧六环溶液(1mol/L,0.6mL),反应升至50℃搅拌过夜。将反应液减压除去溶剂,柱层析分离得到米黄色固体状的(S)-3-[3-[[4-[[3-(丙烯酰胺基)苯基]氨基]-5-(三氟甲基)嘧啶-2-基]氨基]苯氧基]四氢吡咯-1-甲酸叔丁酯(11B)(0.56g,产率32%)。
LC-MS m/z=585.1[M+1]。
第二步:(S)-N-[3-[[2-[3-[(1-丙烯酰基四氢吡咯-3-基)氧基苯基]氨基]-5-(三氟甲基)嘧啶-4-基]氨基]苯基]丙烯酰胺(化合物11)
(S)-N-[3-[[2-[[3-(1-prop-2-enoylpyrrolidin-3-yl)oxyphenyl]amino]-5-(trifluoromethyl)py rimidin-4-yl]amino]phenyl]prop-2-enamide
(S)-3-[3-[[4-[[3-(丙烯酰胺基)苯基]氨基]-5-(三氟甲基)嘧啶-2-基]胺基]苯氧基]四氢吡咯-1-甲酸叔丁酯(11B)(0.56g,0.94mmol),置于50mL圆底烧瓶中,冷却至0℃,向反应瓶中依次加入二氯甲烷(10mL)和三氟乙酸(5mL),室温下反应30分钟后,减压除去溶剂,将得到的粗产品置于50mL圆底烧瓶中,向反应瓶中依次加入二氯甲烷(5mL)和四氢呋喃(5mL),冷却至-78℃,加入N,N-二异丙基乙胺(0.62mL,3.8mmol),通过恒压漏斗滴加丙烯酰氯(0.15mL,1.9mmol)的二氯甲烷(5mL)溶液,滴加完毕后,反应升至室温搅拌1小时。减压浓缩后柱层析分离(二氯甲烷/乙酸乙酯(v/v)=1:1)得到白色固体状的(S)-N-[3-[[2-[3-[(1-丙烯酰基四氢吡咯-3-基)氧基苯基]氨基]-5-(三氟甲基)嘧啶-4-基]氨基]苯基]丙烯酰胺(化合物11)(0.32g,产率62%)。
LC-MS m/z=539.0[M+1];
1H NMR(400MHz,CDCl3)δ10.15(s,1H),9.62(s,1H),8.78(s,1H),8.38(s,1H),7.75(s,1H),7.57(d,1H),7.32(t,1H),7.20(m2,1H),6.97(t,1H),6.57-6.27(m,2H),6.27-6.17(m,2H),5.70-5.64(m,2H),4.77(d,1H),3.81-3.31(m,4H),2.11(d,2H)。
实施例12
(R)-N-[3-[[2-[[3-(1-丙烯酰基四氢吡咯-3-基)氧基苯基]氨基]-5-(三氟甲基)嘧啶-4-基]氨基]苯基]丙烯酰胺(化合物12)
(R)-N-[3-[[2-[[3-(1-prop-2-enoylpyrrolidin-3-yl)oxyphenyl]amino]-5-(trifluoromethyl)p yrimidin-4-yl]amino]phenyl]prop-2-enamide
第一步:(R)-3-[3-[[4-[[3-(丙烯酰胺基)苯基]氨基]-5-(三氟甲基)嘧啶-2-基]胺基]苯氧基]四氢吡咯-1-甲酸叔丁酯(12B)
(R)-tert-butyl 3-[3-[[4-[[3-(prop-2-enoylamino)phenyl]amino]-5-(trifluoromethyl)pyrimidin-2-yl]amino]phenoxy]pyrrolidine-1-carboxylate
称取N-[3-[[2-氯-5-(三氟甲基)嘧啶-4-基]氨基]苯基]丙烯酰胺(中间体3)(1.02g,3mmol),置于100mL圆底烧瓶中,加入1,4-二氧六环(20mL),再依次加入(R)-3-(3-氨基苯氧基)四氢吡咯-1-甲酸叔丁酯(中间体6)(0.84g,3mmol),三氟乙酸的1,4-二氧六环溶液(1mol/L,0.6mL),反应升至50℃搅拌过夜,减压除去溶剂,柱层析分离得到米黄色固体状的(R)-3-[3-[[4-[[3-(丙烯酰胺基)苯基]氨基]-5-(三氟甲基)嘧啶-2-基]氨基]苯氧基]四氢吡咯-1-甲酸叔丁酯(12B)(0.95g,产率54%)。
LC-MS m/z=585.1[M+1]。
第二步:(R)-N-[3-[[2-[[3-(1-丙烯酰基四氢吡咯-3-基)氧基苯基]氨基]-5-(三氟甲基)嘧啶-4-基]氨基]苯基]丙烯酰胺(化合物12)
(R)-N-[3-[[2-[[3-(1-prop-2-enoylpyrrolidin-3-yl)oxyphenyl]amino]-5-(trifluoromethyl)p yrimidin-4-yl]amino]phenyl]prop-2-enamide
(R)-3-[3-[[4-[[3-(丙烯酰胺基)苯基]氨基]-5-(三氟甲基)嘧啶-2-基]氨基]苯氧基]四氢吡咯-1-甲酸叔丁酯(12B)(0.95g,1.6mmol),置于50mL圆底烧瓶中。冷却至0℃,依次加入二氯甲烷(10mL)和三氟乙酸(5mL)。室温下反应30分钟后,减压除去溶剂。将得到的粗产品置于50mL圆底烧瓶中,向反应瓶中依次加入二氯甲烷(5mL)和四氢呋喃(5mL),冷却至-78℃,加入N,N-二异丙基乙胺(1.05mL,6.4mmol),通过恒压漏斗滴加丙烯酰氯(0.25mL,3.2mmol)的二氯甲烷(5mL)溶液。滴加完毕后,反应升至室温搅拌1小时。减压浓缩后柱层析分离(二氯甲烷/乙酸乙酯(v/v)=1:1)得到白色固体状的(R)-N-[3-[[2-[[3-(1-(丙烯酰基)四氢吡咯-3-基)氧基苯基]氨基]-5-(三氟甲基)嘧啶-4-基]氨基]苯基]丙烯酰胺(化合物12)(0.62g,产率72%)。
LC-MS m/z=539.0[M+1]。
1H NMR(400MHz,CDCl3)δ10.14(s,1H),9.63(s,1H),8.78(s,1H),8.38(s,1H),7.75(s,1H),7.56(d,1H),7.32(t,1H),7.20(m2,1H),6.97(t,1H),6.40-6.27(m,2H),6.17-6.12(m,2H),5.77-5.67(m,2H),4.78(d,1H),3.79-3.31(m,4H),2.13-2.02(m,2H)。
实施例13
N-[3-[[4-[[3-(1-丙烯酰基氮杂环丁烷-3-基)氧基苯基]氨基]-5-(三氟甲基)嘧啶-2-基]氨基]苯基]丙烯酰胺(化合物13)
N-[3-[[4-[[3-(1-prop-2-enoylazetidin-3-yl)oxyphenyl]amino]-5-(trifluoromethyl)pyrimid in-2-yl]amino]phenyl]prop-2-enamide
第一步:3-[3-[[2-[[3-(丙烯酰胺基)苯基]氨基]-5-(三氟甲基)嘧啶-4-基]氨基]苯氧基]氮杂环丁烷-1-甲酸叔丁酯(13A)
tert-butyl 3-[3-[[2-[[3-(prop-2-enoylamino)phenyl]amino]-5-(trifluoromethyl)pyrimidin-4-yl]amino]phenoxy]azetidine-1-carboxylate
称取N-[3-[[4-氯-5-(三氟甲基)嘧啶-2-基]氨基]苯基]丙烯酰胺(3B)(1.02g,3mmol),置于100mL圆底烧瓶中,依次加入N,N-二甲基甲酰胺(20mL),N,N-二异丙基乙胺(0.6mL,3.6mmol),3-(3-氨基苯氧基)氮杂环丁烷-1-甲酸叔丁酯(中间体5)(0.79g,3mmol)。反应升温至90℃下搅拌48小时。减压浓缩后柱层析分离(二氯甲烷/乙酸乙酯(v/v)=1:1)得到米黄色固体状的3-[3-[[2-[[3-(丙烯酰胺基)苯基]氨基]-5-(三氟甲基)嘧啶-4-基]氨基]苯氧基]氮杂环丁烷-1-甲酸叔丁酯(13A)(0.4g,产率23%)。
LC-MS m/z=571.0[M+1]。
第二步:N-[3-[[4-[[3-(1-丙烯酰基氮杂环丁烷-3-基)氧基苯基]氨基]-5-(三氟甲基)嘧啶-2-基]氨基]苯基]丙烯酰胺(化合物13)
N-[3-[[4-[[3-(1-prop-2-enoylazetidin-3-yl)oxyphenyl]amino]-5-(trifluoromethyl)pyrimid in-2-yl]amino]phenyl]prop-2-enamide
称取3-[3-[[2-[[3-(丙烯酰胺基)苯基]氨基]-5-(三氟甲基)嘧啶-4-基]氨基]苯氧基]氮杂环丁烷-1-甲酸叔丁酯(13A)(0.4g,0.7mmol),置于100mL圆底烧瓶中,冷却至0℃,依次加入二氯甲烷(10mL)和三氟乙酸(5mL)。室温下反应30分钟后,减压除去反应溶剂。将得到的粗产品置于50mL圆底烧瓶中,依次加入二氯甲烷(5mL)和四氢呋喃(5mL),冷却至-78℃下,加入N,N-二异丙基乙胺(0.46mL,4mmol),通过恒压漏斗滴加丙烯酰氯(0.11mL,1.4mmol)的二氯甲烷(5mL)溶液。滴加完毕后,反应升至室温搅拌1小时,减压浓缩后柱层析分离(二氯甲烷/乙酸乙酯(v/v)=1:1)得到白色固体状的N-[3-[[4-[[3-(1-丙烯酰基氮杂环丁烷-3-基)氧基苯基]氨基]-5-(三氟甲基)嘧啶-2-基]氨基]苯基]丙烯酰胺(化合物13)(0.22g,产率60%)。
LC-MS m/z=525.0[M+1];
1H NMR(400MHz,DMSO-d6)δ9.91(s,1H),9.64(s,1H),8.46(s,1H),8.31(s,1H),7.65(s,1H),7.38-7.09(m,4H),6.97(m,2H),6.58(d,1H),6.36(m,1H),6.18(m,2H),6.02(d,1H),5.66(d,1H),5.57(d,1H),4.90(s,1H),4.62-4.43(t,1H),4.27(t,1H),4.03(d,1H),3.77(t,1H)。
实施例14
N-[3-[[2-[[3-(1-(丙烯酰基)氮杂环丁烷-3-基)氧基苯基]氨基]-5-(三氟甲基)嘧啶-4-基]氨基]苯基]丙烯酰胺(化合物14)
N-[3-[[2-[[3-(1-prop-2-enoylazetidin-3-yl)oxyphenyl]amino]-5-(trifluoromethyl)pyrimid in-4-yl]amino]phenyl]prop-2-enamide
第一步:4-[3-[[4-[[3-(丙烯酰胺基)苯基]氨基]-5-(三氟甲基)嘧啶-2-基]氨基]苯氧基]氮杂环丁烷-1-甲酸叔丁酯(14B)
tert-butyl 3-[3-[[4-[[3-(prop-2-enoylamino)phenyl]amino]-5-(trifluoromethyl)pyramid in-2-yl]amino]phenoxy]azetidine-1-carboxylate
称取N-[3-[[2-氯-5-(三氟甲基)嘧啶-4-基]氨基]苯基]丙烯酰胺(中间体3)(1.02g,3mmol),置于100mL圆底烧瓶中,加入1,4-二氧六环(20mL),再依次加入3-(3-氨基苯氧基)氮杂环丁烷-1-甲酸叔丁酯(中间体5)(0.79g,3mmol)和三氟乙酸的1,4-二氧六环溶液(1mol/L,0.6mL),反应升至50℃搅拌过夜。减压除去反应溶剂,柱层析分离得到米黄色固体状的4-[3-[[4-[[3-(丙烯酰胺基)苯基]氨基]-5-(三氟甲基)嘧啶-2-基]氨基]苯氧基]氮杂环丁烷-1-甲酸叔丁酯(14B)(0.69g,产率40%)。
LC-MS m/z=571.2[M+1]。
第二步:N-[3-[[2-[[3-(1-(丙烯酰基)氮杂环丁烷-3-基)氧基苯基]氨基]-5-(三氟甲基)嘧啶-4-基]氨基]苯基]丙烯酰胺(化合物14)
N-[3-[[2-[[3-(1-prop-2-enoylazetidin-3-yl)oxyphenyl]amino]-5-(trifluoromethyl)pyrimid in-4-yl]amino]phenyl]prop-2-enamide
4-[3-[[4-[[3-(丙烯酰胺基)苯基]氨基]-5-(三氟甲基)嘧啶-2-基]氨基]苯氧基]氮杂环丁烷-1-甲酸叔丁酯(14B)(0.69g,1.2mmol),置于50mL圆底烧瓶中。0℃下,向反应瓶中依次加入二氯甲烷(10mL),三氟乙酸(5mL)。室温下反应30分钟后,减压除去反应溶剂。将得到的粗产品置于50mL圆底烧瓶中,向反应瓶中依次加入二氯甲烷(5mL),四氢呋喃(5mL)。-78℃下,向反应瓶中加入N,N-二异丙基乙胺(0.79mL,4.8mmol),通过恒压漏斗滴加丙烯酰氯(0.19mL,2.4mmol)的5mL二氯甲烷溶液。滴加完毕后,反应升至室温搅拌1小时。减压浓缩后柱层析分离(二氯甲烷/乙酸乙酯(v/v)=1:1)得到白色固体状的N-[3-[[2-[[3-(1-(丙烯酰基)氮杂环丁烷-3-基)氧基苯基]氨基]-5-(三氟甲基)嘧啶-4-基]氨基]苯基]丙烯酰胺(化合物14)(0.41g,产率65%)。
LC-MS m/z=525.1[M+1]。
1H NMR(400MHz,CDCl3)δ8.27(s,1H),8.19(s,1H),8.08(s,1H),7.99(s,1H),7.52-7.26(m,3H),7.17-7.14(m,2H),7.06(s,1H),6.91(s,1H),6.43-6.26(m,2H),6.17-6.13(m,3H),5.78-5.69(dd,2H),4.70(s,1H),4.41(t,1H),4.28(t,1H),4.11(d,1H),3.98(d,1H)。
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或阿法替尼。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50μl50%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计算和分析待测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
结论:本发明化合物具有良好的抗肿瘤细胞增殖活性,对非小细胞肺癌细胞H1975活性均<50nM,特别是化合物5-1对非小细胞肺癌细胞H1975的抗肿瘤细胞增殖活性<1nM;相对于非小细胞肺癌细胞H1975、人上皮细胞癌细胞A431细胞系,本发明化合物对非小细胞肺癌细胞H1975有较好的选择性,个别化合物的选择性大于了1000倍。
Claims (10)
1.一种化合物或其药学上可接受的盐,其中所述的化合物选自:
2.根据权利要求1所述的化合物或其药学上可接受的盐,其中其药学上可接受的盐中所述的盐选自盐酸盐、氢溴酸盐、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。
3.根据权利要求2所述的化合物或其药学上可接受的盐,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、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。
4.一种药物组合物,所述的组合物包括:有效剂量的根据权利要求1-3中任一项所述的化合物或其药学上可接受的盐,以及药学上可接受的载体、稀释剂、佐剂、媒介物或赋形剂。
5.根据权利要求4所述的药物组合物,所述的组合物还进一步包括一种或多种其他治疗剂。
6.根据权利要求5所述的药物组合物,其中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),dabrafenib(达拉非尼),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,gefitinib(吉非替尼),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。
7.权利要求1-3中任一项所述的化合物或其药学上可接受的盐或者权利要求4-6任一项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。
8.根据权利要求7所述的应用,其中所述在制备药物制剂中的应用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。
9.根据权利要求8所述的应用,其中所述的过度增殖性疾病为脑瘤、鳞状上皮细胞、膀胱癌、胰腺癌、结肠癌、乳腺癌、卵巢癌、子宫颈癌、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、前列腺癌、神经胶质瘤及鼻咽癌中的一种或多种。
10.根据权利要求8所述的应用,其中,所述过度增殖性疾病为非小细胞肺癌、乳腺癌、表皮鳞癌、胃癌及结肠癌中的一种或多种。
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