CN106928150B - 丙烯酰胺苯胺衍生物及其药学上的应用 - Google Patents
丙烯酰胺苯胺衍生物及其药学上的应用 Download PDFInfo
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- CN106928150B CN106928150B CN201511027848.4A CN201511027848A CN106928150B CN 106928150 B CN106928150 B CN 106928150B CN 201511027848 A CN201511027848 A CN 201511027848A CN 106928150 B CN106928150 B CN 106928150B
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Classifications
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- A61K31/551—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep
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- C07D251/14—Heterocyclic compounds containing 1,3,5-triazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hydrogen or carbon atoms directly attached to at least one ring carbon atom
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- C07D251/18—Heterocyclic compounds containing 1,3,5-triazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hydrogen or carbon atoms directly attached to at least one ring carbon atom to only one ring carbon atom with nitrogen atoms directly attached to the two other ring carbon atoms, e.g. guanamines
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- C07D251/40—Nitrogen atoms
- C07D251/48—Two nitrogen atoms
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- 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
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Abstract
本发明涉及下述通式(I)所示的丙烯酰胺苯胺类化合物或其药学上可接受的盐。该化合物或其药学上可接受的盐主要通过作用于EGFR家族酪蛋白激酶用于临床疾病治疗的用途。
Description
技术领域
本发明涉及表皮生长因子受体(EGFR)酪蛋白激酶家族抑制剂及其药学上的应用。
背景技术
肿瘤包括白血病是导致人类临床死亡的重大疾病之一,特别是恶性肿瘤,如肺癌、胃癌、乳腺癌、胰腺癌、肝癌、肠癌和食管癌等死亡率极高。至今为止仍没有有效的方法与药物完全治愈癌症。临床上急需特异性好、活性高、毒性小、无耐药性产生的优质抗癌药物。
癌症的发生、发展、转移及恶化和许多因素有关,其中正常细胞内信号传导的异常是导致细胞转化与癌化的重要因素之一,特别是跨膜受体介导的多功能信号传导***。酪氨酸蛋白激酶是细胞生长、发育、分化、代谢、老化与凋亡等重要生理功能所必须的酪氨酸磷酸化蛋白质酶,分为膜受体和胞质酪蛋白激酶两种类型。许多酪氨酸蛋白激酶的异常可直接导致临床上不同类型的疾病例如癌症、炎症、免疫***、神经***以及心脑血管类疾病。人们经过几十年的不断努力,许多酪氨酸蛋白激酶例如EGFR、HER2/3/4、VEGFR、PDGFR、Met、IGF-1R、FGFR、CSF-1R、Trk受体、Ephrin受体、TAM受体、Tie-2、FLT-3、RET、ALK、BCR-ABL、JAKs、SRC、FAK、BTK、SYK,BLK等已被鉴定为临床不同疾病的靶蛋白分子。其中一些酪氨酸蛋白激酶抑制剂已成功的应用于临床,并且呈现出良好的治疗效果。
表皮生长因子受体(EGFR)是一类跨膜受体蛋白,为酪蛋白激酶。该激酶家族由EGFR(HER1/ErbB1),HER2/ErbB2,HER3/ErbB3和HER4/ErbB4四个成员组成,此类蛋白激酶介导细胞内重要信号传导途径,控制与调节细胞的诸多生理功能。基础研究与临床基因组大数据显示EGFR、HER2、HER3、HER4基因的异常例如点突变、缺失、扩增、过表达等都可直接导致细胞转化和癌症发生,同时这些基因的异常又和癌细胞的增殖、存活、转移、侵润、肿瘤新血管形成以及药物抗性密切相关。
在临床上,EGFR基因异常变异(过表达、点突变、缺失、***等)常常出现在不同癌症病人中,尤其是肺癌。肺癌是致死率极高的恶性肿瘤之一,其中以腺癌、麟状细胞癌和大细胞肺癌为主的非小细胞肺癌(NSCLC)占整个肺癌的80%左右,而EGFR常常在NSCLC中高频率的发生变异,导致其介导的信号传导途径持续被激活,引起细胞癌化。同样HER2/ErbB2基因的异常(例如突变、扩增、过表达)以一定的比例(>5%)发生在非小细胞肺癌病人中,特别是HER2/ErbB2基因的过表达。除了非小细胞肺癌外,HER2/ErbB2基因的异常频繁发生在许多其它癌症中,有的高达30%以上,例如乳腺癌(20%)、胃癌(22-25%)、食道癌(10-25%)、胰腺癌(2-30%)、膀胱癌(5-15%)、唾管癌(15-37%)、***(1-21%)、恶性胶质瘤(7-15%),其次为非小细胞肺癌(5%)、大肠癌(2-3%)、卵巢癌(6-7%)、头颈癌(3%)、肝癌(2.4%)、黑色素瘤(0-5%)。此外HER2过表达的强弱不仅和肿瘤的恶性程度成正相关,也和许多化疗药物耐药性相关联例如紫杉醇/奥沙利铂耐药性。
EGFR和HER2作为有效的成药靶点已用于抗癌药物的开发。至今为止,已成功开发出多种抗癌新药物,例如作用于EGFR/HER2蛋白分子胞外部分的大分子单抗药西妥昔单抗(Cetuximab),帕尼单抗(Panitumumab)和赫赛汀(Herceptin)以及作用于EGFR/HER2蛋白分子胞内激酶活性部位的小分子药物吉非替尼、厄洛替尼和拉帕替尼等都已在临床上应用多年,呈现良好的治疗效果。然而和诸多其他抗癌药物一样,EGFR类药物也存在获得性抗性的问题。如吉非替尼、厄洛替尼以及拉帕替尼在临床上产生的药物抗性可达50%以上。获得性药物抗性是由多种原因引起,其中靶蛋白分子的结构改变为重要原因之一。临床上使用的第一代EGFR抑制剂化合物核心架构为4-苯胺喹唑啉,以可逆性方式与EGFR蛋白激酶活性区相结合,通过与ATP竞争,起到抑制蛋白激酶活性的作用。基因突变常常导致蛋白分子结构的改变,例如EGFR Exon19缺失和Exon 21的L858R点突变使EGFR蛋白激酶变成激活性突变体,相对的增加了吉非替尼和厄洛替尼药物对EGFR的抑制作用,但Exon20的苏氨酸790(EGFR蛋白激酶活性区守门氨基酸)突变成蛋氨酸(T790M)时,第一代EGFR抑制剂失去与ATP竞争能力,导致药物失效,产生药物抗性,而这种获得性药物抗性使40-55%的临床癌症病人对第一代EGFR抑制剂无治疗效果。尽管在第一代EGFR抑制剂结构基础上,已研发出与EGFR蛋白质中的半胱氨酸797(Cys-797)共价结合的第二代不可逆抑制剂如阿法替尼(Afatinib)和来那替尼(Neratinib),虽然体外可抑制EGFR T790M但仍对野生型EGFR有较强的抑制作用,其临床表现出高副作用与毒性,加上单独使用并没有显示出对表达EGFRT790M的NSCLC病人治疗的明显优势,使其临床应用受到极大限制。同时已发现EGFR第二代抑制剂在临床上应用过程中同样产生不同程度的获得性药物抗性,其部分原因和其它癌基因异常(如Met/HER3扩增,PIK3CA/BRAF突变,NF1缺失,FGFR信号传导激活等)有关。
近来研究发现以苯胺嘧啶为核心骨架的小分子化合物WZ4002能够高活性的作用于EGFR T790M突变株,但对野生型EGFR作用较弱。之后制药公司相继开发的苯胺嘧啶类化合物CO-1686、AZD9291和HM61713,临床实验数据已显示对EGFR T790M表达病人有较高的应答,相对副作用小,是新一代有效的EGFR T790M突变株抑制剂。
尽管抑制EGFR的活性能够有效的抑制非小细胞肺癌的生长。但其它一些基因的异常表达如肝细胞生长因子受体(MET)扩增,间变性淋巴瘤激酶(ALK)扩增与重排,Her2/ErbB2扩增与过表达,同样与非小细胞肺癌的恶性生长和药物抗性密切相关。而在众多的其它恶性肿瘤如胃癌、乳腺癌、食管癌和唾管癌中,MET,HER2/ErbB2和ALK同样是重要的癌症生物标记。
已上市的抗HER2单抗药赫赛汀和唯一小分子化合物拉帕替尼,虽然在临床上已呈现良好的治疗效果,但获得性药物抗性以及血脑屏障等问题使它们的临床应用受到一定程度的限制。多年来我们一直致力于研发特异性好、活性高、毒性低的EGFR酪蛋白激酶家族小分子化合物抑制剂。目标是开发一类即可有效抑制异常高表达EGFR或HER2/ErBB2,同时又能够抑制获得性药物抗性突变株特别是EGFR T790M,HER2 T798I而副作用小的新一代化合物。我们以丙烯酰胺苯胺为核心构架,设计合成一系列新的化合物及其衍生物,通过用高表达EGFR或HER2以及其不同突变株的细胞系,进行体内外肿瘤细胞生长抑制实验,研究与开发新的EGFR和HER2靶向药物。
发明内容
本发明涉及到一系列新的丙烯酰苯胺衍生物及其药学上可接受的盐,能够以不逆的结合方式作用并抑制EGFR突变株(例如EGFR Exon19缺失delE746-A750激活突变体,L858R/T790M和delE746-A750/T790M双突变抗性突变体)和HER2过表达的多种肿瘤细胞系的体内和体外生长,具有应用于多种临床疾病治疗的价值。
EGFR酪蛋白激酶家族是当今临床上成功应用的靶向抗癌治疗的理想靶标。尽管已上市的抗EGFR/HER2蛋白激酶抑制剂能够有效的改进癌症病人的临床治疗效果,但获得性药物抗性或药物引起的严重副作用极大的影响到这些药物的临床治疗效果,满足不了临床需求。我们发明的新化合物无论在体外或体内实验中,均表现出强的抗癌活性。GI50在纳摩尔浓度可有效的抑制表达不同EGFR突变体的癌细胞生长,特别是T790M抗性突变细胞株。对EGFR野生型过表达细胞株的抑制活性较弱,而对正常或无EGFR表达癌细胞相对无抑制作用,这将在临床应用上大大的降低由于野生型EGFR活性被抑制而产生的皮肤和胃肠道副作用的风险例如皮疹、腹泻。
HER2/ErbB2是EGFR家族中另一个酪蛋白激酶,其异常表达和许多恶性肿瘤相关。本发明人意外发现本发明化合物对HER2/ErbB2高表达的不同肿瘤细胞系(如NCI-N87,Calu-3,AU565,SK-RB-30,NCI-H2170,ZR-75-30)的生长有强抑制作用,GI50浓度为纳摩尔,而且对拉帕替尼(唯一临床上应用的HER2/ERB2选择性可逆抑制剂)抗性细胞系HCC1954也呈现出一定的生长抑制作用,这在临床上不但可应用于NSCLC,同样可以用于HER2/ErbB2高表达的胃癌、乳腺癌、食管癌和唾管癌。
本发明包括以下内容。
[1]通式(I)所示的化合物或其药学上可接受的盐、溶剂化物或前药:
其中:
X、Y和R1选择如下a)、b)或c)的任一种方式:
a)R1为-NR5R6时;X和Y彼此相同或不同,并且各自独立地选自N、CR4;
b)R1选自-OR5和-SR5时;X和Y彼此相同或不同,并且各自独立地选自N、CR4;
c)R1为-CR5R6,且R5和R6和与它们所连接的碳原子成环时;X为CR4,Y为N;
R2选自烷氧基、烷硫基或者NR6R6;
R3选自氢、N(Ry)(Rz)、-N(Rv)RuN(Ry)(Rz)、-ORuOR6、-ORuN(Ry)(Rz)、-SR6、-SRuN(Ry)(Rz);
R4选自氢、卤素、烷基、烷氧基、卤代烷基、氰基;
R5和R6选择如下a)、b)或c)的任一种方式:
a)R5为任选取代的芳基、任选取代的杂芳基或者任选取代的杂环基;存在取代基时该取代基选自1-5个R7基团,其中每个R7基团独立地选自氢、卤素、烷基、烯基、炔基、烷氧基、羟基、氨基、卤代烷氧基、环烷基、环烷基烷基、羟基烷基、卤代烷基、芳基、芳基烷基羟基、杂环基、杂环基烷基、杂芳基或杂芳基烷基羟基;其中烷基、烯基、炔基、烷氧基、氨基、卤代烷氧基、环烷基、环烷基烷基、羟基烷基、卤代烷基、芳基、芳基烷基羟基、杂环基、杂芳基或杂芳基烷基羟基任选地用以下的1-5个基团取代:卤素、烷基、烯基、炔基、芳基、羟基、烷氧基、卤代烷氧基、环烷基、酯基、氰基;
R6选自氢、烷基;
b)R5和R6和与它们所连接的氮原子一起形成杂环基、杂芳基或者稠环芳环,且环中含有0-4个独立地选自O、S、N的杂原子;环上有取代基时任选用1-5个取代基取代,所述取代基选自卤素、卤代烷基、烷基、烯基或者氰基;
c)R5和R6和与它们所连接的碳原子一起形成稠环芳环,且芳环中含有0-4个独立地选自O、S、N的杂原子;环上有取代基时任选用1-4个取代基取代,所述取代基选自卤素、卤代烷基、烷基、烯基或者氰基;
每个Ru独立地选自亚烷基、亚烯基或者亚炔基;
Rv选自氢或烷基;
每个Ry和Rz独立地选自以下的a)或b):
a)Ry和Rz各自独立地选自氢、烷基、环烷基、烷氧基烷基、羟基烷基、吡咯烷基、烷基氨基、或者卤代烷基;
b)Ry和Rz和与它们所连接的氮原子一起形成杂环基或者杂芳基,且环中含有0-4个独立地选自O、S、N的杂原子,且环上任选用1-4个取代基取代,所述取代基选自R5或者R7。
[2]上述[1]所述的化合物或其药学上可接受的盐、溶剂化物或前药,其特征在于,所述通式(I)所示化合物为式IIa、IIb或IIc的化合物,
其中R1选择如下a)或b)的方式:
a)通式(I)所示化合物为式IIa、IIb时,R1为-NR5R6
b)通式(I)所示化合物为式IIc时,R1为-NR5R6;或者R1为-CR5R6(且R5和R6和与它们所连接的碳原子成环)
R2为烷氧基;
R3选自氢、N(Ry)(Rz)、-N(Rv)RuN(Ry)(Rz)、-ORuOR6、或-ORuN(Ry)(Rz);
R4、R'4各自独立地选自氢、卤素、烷基、卤代烷基;
R5和R6选择如下a)、b)或c)的任一种方式:
a)R5为任选取代的芳基;存在取代基时该取代基选自1-5个R7基团,其中每个R7基团独立地选自氢、卤素、烷基、烯基、炔基、烷氧基、羟基、氨基、卤代烷氧基、环烷基、环烷基烷基、羟基烷基、卤代烷基、芳基、芳基烷基羟基、杂环基、杂环基烷基、杂芳基或杂芳基烷基羟基;其中芳基、芳基烷基羟基、杂环基、杂环基烷基、杂芳基、杂芳基烷基羟基任选地用以下的0-4个基团取代:卤素、烷基、烯基、炔基、羟基、烷氧基;
R6选自氢、烷基;
b)R5和R6和与它们所连接的氮原子一起形成稠环芳环,且环中含有0-4个独立地选自O、S、N的杂原子;环上有取代基时任选用1-4个取代基取代,所述取代基选自卤素、卤代烷基、烷基、烯基或者氰基;
c)R5和R6和与它们所连接的碳原子一起形成稠环芳环,且芳环中含有0-4个独立地选自O、S、N的杂原子;环上有取代基时任选用1-4个取代基取代,所述取代基选自卤素、卤代烷基、烷基、烯基或者氰基;
每个Ru独立地选自亚烷基;
Rv选自氢或烷基;
每个Ry和Rz独立地选自以下的a)或b):
a)Ry和Rz每一个独立地选自氢、烷基、或者卤代烷基;
b)Ry和Rz和与它们所连接的氮原子一起形成杂环基,且环中含有0-4个独立地选自O、S、N的杂原子,且环上任选用1-4个取代基取代,所述取代基选自卤素、卤代烷基、烷基、烷氧基烷基,烷基羟基、NR6R6、或杂环基。
[3]上述[2]所述的化合物或其药学上可接受的盐、溶剂化物或前药,其特征在于:
R1选择以下的a)或b):
通式(I)所示化合物为式IIa和IIb时,R1选自:
通式(I)所示化合物为式IIc时,R1选自:
R2为烷氧基;
R3选自氢、N(Ry)(Rz)、-N(Rv)RuN(Ry)(Rz)、-ORuOR6、或-ORuN(Ry)(Rz);
R4、R4’、R4”各自独立地选自氢、卤素、或烷基;
R7 a、R7 b、R7 c、R7 d和R7 e彼此相同或不同,并且各自独立地为R7;
R7选自氢、卤素、烷基、烯基、炔基、烷氧基、氰基、羟基、氨基、卤代烷氧基、卤代烷基、芳基、芳基烷基羟基、杂环基、杂环基烷基、杂芳基或杂芳基烷基羟基;其中芳基、芳基烷基羟基、杂环基、杂环基烷基、杂芳基和杂芳基烷基羟基任选地用以下的0-4个基团取代:卤素、烷基、烷氧基;
每个Ru独立地选自亚烷基;
Rv选自氢或烷基;
每个Ry和Rz独立地选自以下的a)或b):
a)Ry和Rz各自独立地选自氢或烷基;
b)Ry和Rz和与它们所连接的氮原子一起形成杂环基,且环中含有0-4个独立地选自O、S、N的杂原子,且环上任选用1-4个取代基取代,所述取代基选自烷基、烷氧基烷基,烷基羟基、NR6R6、或杂环基。
[4]上述[3]所述的化合物或其药学上可接受的盐、溶剂化物或前药,其特征在于:
R1选择a)、b)或c)的任一种方式:
通式(I)所示化合物为式IIa时,R1选自:
b)通式(I)所示化合物为式IIb时,R1为:
c)通式(I)所示化合物为式IIc时,R1选自:
R2选自甲氧基或丙氧基;
R3选自氢、N(Ry)(Rz)、-N(Rv)RuN(Ry)(Rz)、-ORuOR6、或-ORuN(Ry)(Rz);
R4、R4’、R4”各自独立地选自氢、卤素或烷基;
R7 a、R7 b、R7 c、R7 d和R7 e彼此相同或不同,并且各自独立地为R7;
R7选自氢、卤素、烷基、炔基、烷氧基、氰基、卤代烷基、或芳基烷基羟基杂芳基烷基羟基;其中芳基烷基羟基和杂芳基烷基羟基任选地用以下的0-4个基团取代:卤素、烷基;
每个Ru独立地为亚烷基;
Rv选自氢或烷基;
每个Ry和Rz独立地选自以下的a)或b):
a)Ry和Rz各自独立地选自氢或烷基;
b)Ry和Rz和与它们所连接的氮原子一起形成杂环基,且环中含有0-4个独立地选自O、S、N的杂原子,且环上任选用1-4个取代基取代,所述取代基选自烷基、烷氧基烷基,烷基羟基、NR6R6、或杂环基。
[5]上述[1]所述的化合物或其药学上可接受的盐、溶剂化物或前药,其中,所述化合物选自:
N-(5-(4-(3-溴苯基氨基)-嘧啶-2-基氨基)-2-(2-(二甲氨基-乙基)-甲基-氨基)-4-甲氧基-苯基)-丙烯酰胺
N-(5-(4-(3-氯苯基氨基)-嘧啶-2-基氨基)-2-(2-(二甲氨基-乙基)-甲基-氨基)-4-甲氧基-苯基)-丙烯酰胺
N-(5-(4-(3-氟苯基氨基)-嘧啶-2-基氨基)-2-(2-(二甲氨基-乙基)-甲基-氨基)-4-甲氧基-苯基)-丙烯酰胺
N-(5-(4-(3-乙炔基苯基氨基)-嘧啶-2-基氨基)-2-(2-(二甲氨基-乙基)-甲基-氨基)-4-甲氧基-苯基)-丙烯酰胺
N-(5-(4-(3-氯-4-氟苯氨基)嘧啶-2-基氨基)-2-(2-(二甲氨基-乙基)-甲基-氨基)-4-甲氧基-苯基)-丙烯酰胺
N-(5-(4-(3-氯-2-氟苯基氨基)嘧啶-2-基氨基)-2-(2-(二甲氨基-乙基)-甲基-氨基)-4-甲氧基-苯基)-丙烯酰胺
N-(5-(4-(2,4-二氯-5-甲氧基苯基氨基)嘧啶-2-基氨基)-2-(2-(二甲氨基-乙基)-甲基-氨基)-4-甲氧基-苯基)-丙烯酰胺
N-(5-(4-(3-氯-4-(吡啶-2-甲氧基)苯胺基)嘧啶-2-基氨基)-2-((2-(二甲氨基)乙基)(甲基)氨基)-4-甲氧基-苯基)-丙烯酰胺
N-(5-(5-氯-4-(3-氯-4-(吡啶-2-甲氧基)苯胺基)嘧啶-2-基氨基)-2-((2-(二甲氨基)乙基)(甲基)氨基)-4-甲氧基-苯基)-丙烯酰胺
N-(5-(4-(3-氯-4-(吡啶-2-基甲氧基)苯基氨基)嘧啶-2-基氨基)-2-(4-(二甲氨基)哌啶-1-基)-4-甲氧基-苯基)-丙烯酰胺
N-(2-((2-(二甲氨基-乙基)-甲基-氨基)-5-(4-(吲哚啉-1-基)-嘧啶-2-基氨基)-4-甲氧基-苯基)-丙烯酰胺
N-(5-(4-(1H-吲哚-1-基)-嘧啶-2-基氨基)-2-((2-(二甲氨基)-乙基)-甲基-氨基)-4-甲氧基-苯基)-丙烯酰胺
N-(5-(4-(3-甲基-1H-吲哚-1-基)-嘧啶-2-基氨基)-2-(2-(二甲氨基-乙基)-甲基-氨基)-4-甲氧基-苯基)-丙烯酰胺
N-{2-[(2-二甲基氨基-乙基)-甲基-氨基]-4-甲氧基-5-[4-(6-甲氧基-吲哚-1-基)-嘧啶-2-基氨基]-苯基}-丙烯酰胺
N-{2-[(2-二甲基氨基-乙基)-甲基-氨基]-4-甲氧基-5-[4-(6-甲基-吲哚-1-基)-嘧啶-2-基氨基]-苯基}-丙烯酰胺
N-{5-[4-(6-氰基-吲哚-1-基)-嘧啶-2-基氨基]-2-[(2-二甲基氨基-乙基)-甲基-氨基]-4-甲氧基-苯基}-丙烯酰胺
N-(5-(4-(6-氯-1H-吲哚-1-基)-嘧啶-2-基氨基)-2-((2-(二甲氨基)乙基)-甲基-氨基)-4-甲氧基-苯基)-丙烯酰胺
N-(5-(4-(6-溴-1H-吲哚-1-基)-嘧啶-2-基氨基)-2-((2-(二甲氨基)乙基)-甲基-氨基)-4-甲氧基-苯基)-丙烯酰胺
N-(5-(4-(6-氟-1H-吲哚-1-基)-嘧啶-2-基氨基)-2-((2-(二甲氨基)乙基)-甲基-氨基)-4-甲氧基-苯基)-丙烯酰胺
N-(5-(4-(5-甲基-1H-吲哚-1-基)-嘧啶-2-基氨基)-2-((2-二甲氨基-乙基)-甲基-氨基)-4-甲氧基-苯基)-丙烯酰胺
N-(5-(4-(5-甲氧基-1H-吲哚-1-基)-嘧啶-2-基氨基)-2-((2-二甲氨基-乙基)-甲基-氨基)-4-甲氧基-苯基)-丙烯酰胺
2-((2-丙烯酰胺基-5-甲氧基-4-(4-(5-甲氧基-1H-吲哚-1-基)-嘧啶-2-基)-氨基)-苯基)-甲基-N,N-二甲基-N-氧化乙胺
N-(5-(4-(5-氯-1H-吲哚-1-基)-嘧啶-2-基氨基)-2-((2-二甲氨基-乙基)-甲基-氨基)-4-甲氧基-苯基)-丙烯酰胺
N-(5-(4-(5-溴-1H-吲哚-1-基)-嘧啶-2-基氨基)-2-((2-二甲氨基-乙基)-甲基-氨基)-4-甲氧基-苯基)-丙烯酰胺
N-(5-(4-(5-三氟甲基-1H-吲哚-1-基)-嘧啶-2-基氨基)-2-((2-二甲氨基-乙基)-甲基-氨基)-4-甲氧基-苯基)-丙烯酰胺
N-(5-(4-(5-氟-1H-吲哚-1-基)-嘧啶-2-基氨基)-2-((2-(二甲氨基-乙基)-甲基-氨基)-4-甲氧基-苯基)-丙烯酰胺
N-(5-(4-(5-氟-1H-吲哚-1-基)-嘧啶-2-基氨基)-2-(4-(二甲胺甲基)-哌啶-1-基)-4-甲氧基-苯基)-丙烯酰胺
N-(5-(4-(5-氟-1H-吲哚-1-基)-嘧啶-2-基氨基)-2-(4-(4-甲基-哌嗪-1-基)-哌啶-1-基)-4-甲氧基-苯基)-丙烯酰胺
N-(5-(4-(4-甲基-1H-吲哚-1-基)-嘧啶-2-基氨基)-2-(2-(二甲氨基-乙基)-甲基-氨基)-4-甲氧基-苯基)-丙烯酰胺
N-(5-(4-(4-甲氧基-1H-吲哚-1-基)-嘧啶-2-基氨基)-2-(2-(二甲氨基-乙基)-甲基-氨基)-4-甲氧基-苯基)-丙烯酰胺
N-(5-(4-(5,6-二氟-1H-吲哚-1-基)-嘧啶-2-基氨基)-2-(2-(二甲氨基-乙基)-甲基-氨基)-4-甲氧基-苯基)-丙烯酰胺
N-(5-(4-(1H-苯基[d]咪唑-1-基)嘧啶-2-基氨基)-2-((2-(二甲氨基)乙基)(甲基)氨基)-4-甲氧基苯基)丙烯酰胺
N-(5-(4-苯并三氮唑-1-基-嘧啶-2-基氨基)-2-((2-二甲氨基-乙基)-甲基-氨基)-4-甲氧基-苯基)-丙烯酰胺
N-(5-(4-(3-氯-苯基氨基)-[1,3,5]三嗪-2-基氨基)-2-((2-二甲基氨基-乙基)-甲基-氨基)-4-甲氧基-苯基)-丙烯酰胺
N-(5-(4-(3-氯-4-氟-苯基氨基)-[1,3,5]三嗪-2-基氨基)-2-((2-二甲基氨基-乙基)-甲基-氨基)-4-甲氧基-苯基)-丙烯酰胺
N-(5-(4-(3-氯-2-氟-苯基氨基)-[1,3,5]三嗪-2-基氨基)-2-((2-二甲基氨基-乙基)-甲基-氨基)-4-甲氧基-苯基)-丙烯酰胺
N-(5-(4-(3-三氟甲基-苯基氨基)-[1,3,5]三嗪-2-基氨基)-2-((2-二甲基氨基-乙基)-甲基-氨基)-4-甲氧基-苯基)-丙烯酰胺
N-(5-(4-(3-氟-苯基氨基)-[1,3,5]三嗪-2-基氨基)-2-((2-二甲基氨基-乙基)-甲基-氨基)-4-甲氧基-苯基)-丙烯酰胺
N-(5-(4-(3-溴-苯基氨基)-[1,3,5]三嗪-2-基氨基)-2-((2-二甲基氨基-乙基)-甲基-氨基)-4-甲氧基-苯基)-丙烯酰胺
N-[5-[4-(3-溴-苯胺基)-[1,3,5]三嗪-2-氨基]-4-甲氧基-2-(4-(吡咯烷-1-基-哌啶-1-基)-苯基-丙烯酰胺
N-{2-[1,4′]哌啶基-1′-基-5-[4-(3-溴-苯胺基)-[1,3,5]三嗪-2-氨基]-4-甲氧基-苯基}-丙烯酰胺
N-{5-[4-(3-溴-苯胺基)-[1,3,5]三嗪-2-氨基]-2-[4-(2-羟基-乙基)-哌嗪-1-基]-4-甲氧基-苯基}-丙烯酰胺
N-[5-[4-(3-溴-苯基氨基)-[1,3,5]三嗪-2-基氨基]-4-甲氧基-2-(4-甲基-[1,4]二氮杂环庚烷-1-基)-苯基]-丙烯酰胺
N-(5-(6-(3-溴-苯基氨基)-嘧啶-4-基氨基)-2-((2-二甲基氨基-乙基)-甲基-氨基)-4-甲氧基-苯基)-丙烯酰胺
N-(2-((2-二甲基氨基-乙基)-甲基-氨基)-4-甲氧基-5-(6-(3-三氟甲基-苯基氨基)-嘧啶-4-基氨基)-苯基)-丙烯酰胺
N-(5-(6-(3-炔基-苯基氨基)-嘧啶-4-基氨基)-2-((2-二甲基氨基-乙基)-甲基-氨基)-4-甲氧基-苯基)-丙烯酰胺。
[6]EGFR和/或HER2/ErbB2酪蛋白激酶抑制剂,其含有上述[1]~[5]中任一项所述的化合物或其药学上可接受的盐作为有效成分。
[7]上述[1]~[5]中任一项所述的化合物或其药学上可接受的盐在制备EGFR和/或HER2/ErbB2酪蛋白激酶抑制剂中的用途。
[8]上述[1]~[5]中任一项所述的化合物或其药学上可接受的盐在制备预防和/或治疗癌症的药物中的用途。
根据本发明的化合物,对EGFR突变株和HER2/ErbB2高表达肿瘤细胞的生长均具有高活性的抑制作用。
具体实施方式
在本说明书中,除非另有规定,本文使用的所有技术和科学术语具有与本领域技术人员的通常理解相同含义。所有专利、申请、公开的申请和其他出版物均以全部内容并入作为参考。倘若对于本文使用的术语有多个定义,除非另有说明,以本说明书中的为准。
“卤素”包括氟、氯、溴、碘。
“烷基”包括碳数1~18、优选碳数1~10、更优选碳数1~6、还更优选碳数1~4的直链或支链烷基,可例举例如甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、正戊基、异戊基、新戊基、己基、异己基、正庚基、异庚基、正辛基、异辛基、正壬基、正癸基等。本说明书中,“烷基”还包括碳数3~10、优选碳数3~8、更优选碳数4~6的环状烷基,可例举例如环丙基、环丁基、环戊基、环己基、环庚基、环辛基、环壬基、环癸基、十氢萘基、降冰片烷、金刚烷基等。
“烯基”指由碳和氢原子组成的含有至少一个双键的直链或支链的烃链基团,具有2-10个碳原子、优选2-6个碳原子,并通过单键或双键与分子的其余部分连接,例如,乙烯基、丙烯基、丁烯基、戊烯基、戊二烯基、己烯基等。
“烷氧基”指具有式-OR的基团,其中R是如上述定义的烷基。可例举例如甲氧基、乙氧基、丙氧基、异丙氧基、丁氧基、异丁氧基、仲丁氧基、叔丁氧基、环丙氧基、环丁氧基等。
“炔基”指由碳原子和氢原子组成的含有至少一个三键的直链或支链的烃链基团,具有2-10个碳原子、优选2-6个碳原子,并通过单键或三键与分子的其余部分连接,例如,乙炔基、丙炔基、丁炔基、戊炔基、己炔基等。
“烷基酰基”指具有式R(C=O)的基团,其中R是如上述定义的烷基。可例举例如乙酰基、丙酰基、丁酰基、戊酰基、己酰基等。
“芳基”指碳环系的基团,包括单环、二环、三环、四环C6-C18环系,其中至少一个环是芳香环。芳基可以是完全芳香族的基团,例如苯基、萘基、蒽基、菲基等。芳基也可以含有芳香环与非芳香环的组合,例如,茚、芴和苊等。其中,芳基优选苯基、萘基等。
“卤代烷基”指烷基的一个或多个氢原子被卤素取代的烷基,其中烷基可以是如上述定义的烷基。这种基团包括但不仪限于氯甲基、三氟甲基、1-氯-2-氟乙基、2,2-二氟乙基、2-氟丙基、2-氟丙-2-基、2,2,2-三氟乙基、1,1-二氟乙基、1,3-二氟-2-甲基丙基、2,2-二氟环丙基、(三氟甲基)环丙基、4,4-二氟环己基和2,2,2-三氟-1,1-二甲基-乙基等。
“杂环基”,包括环内具有一个以上、优选1-5个的任意选自O、S和N的杂原子的3-15元(例如3-12元、3-9元等)杂环基。杂环基可以是单环、双环、三环或四环环系,其可以包括稠合或桥接环系;杂环基中的氮或硫原子可以任选被氧化;氮原子可以任选被季铵化;杂环基可以是部分或完全饱和的。杂环环系可以在任何杂原子或碳原子处与主结构连接,生成稳定的化合物。具体而言包括吡咯基、咪唑基、吡唑基、吡啶基、哒嗪基、嘧啶基、吡嗪基、***基、三嗪基、四唑基、呋喃基、噻吩基、异唑基、唑基、二唑基、异噻唑基、噻唑基、噻二唑基等五元~六元杂芳基;吡喃基、噻唑烷基、吡咯烷基、吡咯啉基、咪唑烷基、咪唑啉基、吡唑烷基、吡唑啉基、哌啶基、哌嗪基、吗啉基、吗啉代、硫代吗啉基、硫代吗啉代、二氢吡啶基、四氢吡啶基、四氢呋喃基、四氢吡喃基、二氮杂基、四氢二氮杂基等非芳族杂环基;吲哚基、异吲哚基、吲唑基、二氢吲哚基、异二氢吲哚基、喹啉基、异喹啉基、噌啉基、酞嗪基、喹唑啉基、萘啶基、喹喔啉基、嘌呤基、蝶啶基、苯并吡喃基、苯并咪唑基、苯并***基、苯并异唑基、苯并唑基、苯并二唑基、苯并异噻唑基、苯并噻唑基、苯并噻二唑基、苯并呋喃基、异苯并呋喃基、苯并噻吩基、苯并三氮唑基、噻吩并吡啶基、咪唑并噻唑基、苯并咪唑并噻唑基、吡嗪并哒嗪基、喹唑啉基、喹啉基、异喹啉基等二环或三环稠合杂环基等。其中,优选吡咯基、呋喃基、咪唑基、异唑基、唑基、嘧啶基、吡啶基、噻唑基、噻吩基、吗啉基、哌啶基、哌嗪基、吡喃基、吡咯烷基、吲哚基、二氮杂基、苯并噻吩基、苯并三氮唑基、苯并咪唑基等。
“芳烷基”、“芳烷基氧基”、“卤代芳烷基氧基”、“烷基氨基”、“烷基酰基”、“卤代烷基”中的烷基部分也与上述“烷基”定义相同。
“芳氧基”、“芳基氨基”、“芳基硫基”、“芳基氧基”、“芳烷基”、“芳烷基氧基”、“卤代芳烷基氧基”、“卤代芳基”中的芳基部分也与上述“芳基”定义相同。
“杂环基烷氧基”中的杂环部分也与上述“杂环基”定义相同,其中的烷氧基部分也与上述“烷氧基”定义相同。
本说明书中的“任选取代”是指未取代或被一个或多个(例如2、3、4个)取代基取代。其中取代基选自下组:卤素原子、烷基、烯基、炔基、卤代烷基、烷氧基、芳基、卤代芳基、芳氧基、芳烷基、芳烷基氧基、杂环基烷氧基、卤代芳基烷基氧基、烷基氨基、烷基酰基、氰基、或杂环基等。这些取代基还可以进一步被取代。例如,作为取代基的烷基还任选被选自卤素原子、羟基、烷氧基、烷基氨基、吡咯烷基、苯基、吡啶基、或卤代苯基中的一个或多个基团取代。作为取代基的杂环基还任选被选自卤素原子、烷基、烷氧基中的一个或多个基团取代。
R1可以为任选取代的杂环基、任选取代的芳基氨基、任选取代的芳基硫基、或任选取代的芳基氧基等。
R1优选为任选取代的吲哚基、吲哚啉基、噻吩基、吲唑基、吡咯并吡啶基、苯并噻吩基、苯并咪唑基、或苯并三氮唑基等。其中的取代基优选为卤素原子、烷基、环烷基、芳烷基、氰基。R1例如可列举吲哚-1-基、吲哚-3-基、1-甲基-1H-吲哚-3-基、1-乙基-1H-吲哚-3-基、1-丙基-1H-吲哚-3-基、1-异丙基-1H-吲哚-3-基、1-苄基-1H-吲哚-3-基、6-氟-1-甲基-1H-吲哚-3-基、5-氟-1-甲基-1H-吲哚-3-基、5-氟-1-环戊基-1H-吲哚-3-基、苯并咪唑-1-基、或苯并三氮唑-1-基等。
R1优选为任选取代的苯基氨基、或萘基氨基等。其中的取代基优选为卤素原子、烷基、卤代烷基、烷氧基、炔基、芳氧基、杂环基烷氧基、芳烷基氧基、卤代芳基烷基氧基。R1例如可列举苯氧基苯基氨基、甲基苯基氨基、卤代苯基氨基、甲氧基苯基氨基、乙炔基苯基氨基、三氟甲基苯基氨基、氟苄氧基苯基氨基、或吡啶基甲氧基苯基氨基等,优选为卤代苯基氨基。
R1优选为任选取代的苯基硫基、或萘基硫基等。其中的取代基优选为卤素原子、烷基、或烷氧基。R1例如可列举萘基硫基、甲基苯基硫基、或甲氧基苯基硫基等。
R1优选为任选取代的苯基氧基、或萘基氧基等。其中的取代基优选为卤素原子、烷基、或烷氧基。R1例如可列举萘基氧基、甲基苯基氧基、或甲氧基苯基氧基等。
R3可以为任选取代的杂环基、任选取代的烷氧基、任选取代的氨基等。
R3优选为任选取代的哌嗪基、哌啶基、吡咯烷基、二氮杂基、或吡啶基。其中的取代基优选为卤素原子、烷基、氰基、吗啉基、哌啶基、烷基哌嗪基、烷基氨基、烷基哌啶基、羟烷基、烷氧基烷基、羟基烷氧基烷基、吡咯烷基烷基、烷基氨基烷基、烷基酰基、芳烷基、芳基、吡啶基烷基、或卤代芳基烷基等。R3例如可列举甲基哌嗪基、吗啉基哌啶基、甲基哌嗪基哌啶基、二甲氨基哌啶基、叔丁基哌嗪基、二甲氨基吡咯烷基、乙基哌嗪基、环己基甲基哌嗪基、双哌啶基、甲基二氮杂基、甲基哌啶基哌嗪基、羟乙基哌嗪基、甲氧基乙基哌嗪基、羟基乙氧基乙基哌嗪基、二氟吡咯烷基、吡咯烷基哌嗪基、羟丙基哌啶基、吡啶基乙基哌嗪基、苯并二氧甲基哌嗪基、吡咯烷基乙基哌嗪基、氰基乙基哌嗪基、二甲氨基乙基哌嗪基、乙酰基哌嗪基、苄基哌嗪基、苯基哌嗪基、吡啶基甲基哌嗪基、4-甲基2-苯基哌嗪基、双(氟苯基)甲基哌嗪基等。
R3优选为任选取代的乙氧基、丙氧基或丁氧基等。其中的取代基优选为烷基、烷氧基、烷基氨基、吗啉基、吡咯烷基、烯基酰基、或哌嗪基等。R3例如可列举甲氧基乙氧基、甲基哌嗪基乙氧基、吗啉基乙氧基、吡咯烷基乙氧基、丙烯酰基哌嗪基乙氧基、或二甲氨基乙氧基等。
R3中的Ry和Rz各自独立地优选为烷基、卤代烷基、羟基烷基、吡咯烷基、或烷基氨基等,其中的N原子可以被氧化。R3例如可列举二甲氨基、甲基(2-吡咯烷基乙基)氨基、(2-二甲氨基乙基)甲基氨基、[2-(1-氧化吡咯烷-1-基)乙基]甲基氨基、或甲基-N,N-二甲基-N-氧化乙基氨基等。
本发明通式(I)所示的化合物在药学上可接受的盐,可由加酸成盐或加碱成盐。酸可选择无机酸包括但不限于盐酸、硫酸、磷酸、氢溴酸;有机酸可选用但不限于柠檬酸、马来酸、草酸,甲酸、乙酸、丙酸、乙醇酸、苯甲酸、富马酸、三氟乙酸、琥珀酸、酒石酸、乳酸、谷氨酸、天门冬氨酸、水杨酸、丙酮酸、甲磺酸、苯磺酸、对苯磺酸。碱可选择无机碱包括但不限于氢氧化钠、氢氧化钾、氢氧化镁、氢氧化钙;有机碱包括但不限于氢氧化铵、三乙胺、精氨酸或赖氨酸。
本发明通式(I)所示的化合物及药学上可接受的盐可以溶剂化形式或未溶剂化形式存在例如水合式等。
本发明通式(I)所示的化合物,其前药应遵照前药设计原则,在生物体内正常生理状况下,能够通过酶解、水解、酸解或代谢降解,释放出原活性通式(I)所示的化合物。这里包括但不限于化合物上羟基基团的脂化(如形成磷酸脂和碳酸脂),氨基基团和羧基基团的保护。前药设计参照(1)Karaman R,Prodrugs design based on inter-andintramolecular chemical processes.Chem Biol Drug Des.82(6):643-68,2013;(2)Rautio J等,Prodrugs:design and clinical applications.Nat Rev Drug Discov.7(3):255-70 2008;(3)Jampilek J.Prodrugs:pharmaceutical design and currentperspectives.Curr Pharm Des.17(32):3480-1,2011;(4)Bundgaard H.Design ofProgrugs.Elservier,1985。
本发明另一方面将通式(I)所示的化合物或药学上可接受的盐或前药制备成临床上可使用的药物组合物。根据临床适应症,给药途径与方式,其药用制剂包括但不限于口服制剂如片剂、凝胶剂、软/硬胶囊、乳剂、分散性粉剂、颗粒剂、水/油悬乳剂;注射剂包括静脉注射剂、肌肉注射剂、腹腔注射剂、直肠给药栓剂、颅内注射剂,这些剂型可为水溶液也可为油类溶液;局部制剂包括霜剂、软膏剂、凝胶剂、水/油溶液以及包合物制剂;吸入剂型包括细粉、液体气溶胶以及适合于体内植入的各种剂型。
本发明的药物组合物根据需要加入常规药用辅料。这些辅料应符合药物制剂制备工艺规则,与活性成分相兼容。固体口服制剂辅料选用但不限于甘露醇、乳糖、淀粉、硬脂酸镁、纤维素、葡萄糖、蔗糖、环糊精以及促进肠吸收分子载体维生素E-PEG1000。口服制剂可加入适当的着色剂、甜味剂、矫味剂及防腐剂。
本发明通式(I)所示的化合物按0.1-100mg/kg单位剂量给予温血动物。
包含本发明通式(I)所示的化合物或药学上可接受的盐作为有效成分的药物组合物,主要治疗与EGFR和/或HER2相关的临床疾病。其中包括但不限于癌症、糖尿病炎症、免疫***疾病、心血管内疾病、神经类疾病以及呼吸类疾病。
上述临床疾病中,癌症包括但不限于肺癌、胃癌、肝癌、乳腺癌、鼻咽癌、胰腺癌、卵巢癌、***、结肠直肠癌、胶质瘤、黑色素瘤、***癌、肾癌、食道癌、间皮瘤、头颈癌、膀胱癌、唾腺癌、间变性大细胞淋巴瘤、白血病、淋巴瘤、非霍奇金淋巴瘤及多发性骨髓瘤。
本发明药物组合物在上述癌症治疗中,可单独使用,或与临床上常规使用的手术、放射疗法、化学疗法、免疫疗法、融瘤病毒、RNAi、癌症辅助治疗的一种或多种方法联合治疗,其中包括但不限于以下抗肿瘤类药物和治疗方法:
1)烷化剂如顺铂、顺铂、奥沙利铂、苯丁酸氮芥、卡环磷酰胺,氮芥、美法仑、替莫唑胺、白消安、亚硝基脲类。
2)抗肿瘤抗生素类如阿霉素、博来霉素、多柔比星、道诺霉素、表柔比星、伊达比星、丝裂霉素C、放线菌素、光神霉素;抗有丝***药如长春新碱,长春碱,长春地辛,长春瑞滨,紫杉醇、泰索帝、Polo激酶抑制剂。
3)抗代谢和抗叶酸剂如氟嘧啶、雷甲氨蝶呤、阿糖胞苷、替曲塞、羟基脲。
4)拓扑异构酶抑制剂如表鬼臼毒素、喜树碱。
5)细胞生长抑制剂如抗***/抗雄激素类药物如他莫昔芬、氟维司群、托瑞米芬、雷诺昔芬、屈诺昔芬、碘昔芬;如比卡鲁胺、氟他胺、尼鲁米特、醋酸环丙孕酮。
LHRH拮抗剂或LHRH激动剂如戈舍瑞林、亮丙瑞林、和布舍瑞林、孕激素类如醋酸甲地孕酮。
芳香酶抑制剂如阿那曲唑、来曲唑、伏罗唑、伊西美坦、5a-还原酶抑制剂如非那雄胺。
6)抗侵袭剂如c-Src激酶家族抑制剂,金属蛋白酶抑制剂,尿激酶纤溶酶原激活物受体功能的抑制剂或者类肝素酶的抗体。
7)生长功能的抑制剂如生长因子抗体和生长因子受体抗体如抗HER2抗体曲妥珠单抗、抗EGFR抗体帕尼单抗、抗EGFR抗体西妥昔单抗等;这种抑制剂还包括其它酪氨酸激酶抑制剂以及丝氨酸/苏氨酸激酶的抑制剂如Ras/Raf信号传导抑制剂,MEK和/或AKT激酶的细胞信号传导抑制剂、c-kit抑制剂、abl激酶抑制剂、PI3激酶抑制剂、FLT3激酶抑制剂、CSF-1R激酶抑制剂、IGF受体激酶抑制剂,极光激酶抑制剂,细胞周期蛋白依赖性激酶抑制剂如CDK2和/或CDK4,CDK6抑制剂。
8)抗血管生成剂如抑制血管内皮生长因子作用的药剂贝伐珠单抗以及VEGF受体酪氨酸激酶抑制剂。
9)肿瘤免疫治疗法包括任何提高患者肿瘤细胞的免疫原性的体外和体内方法。如细胞因子IL-2、IL-4或者GM-CSF进行转染;降低T细胞无效能的方法如抗PD-1/PD-L单抗;使用转染的免疫细胞如细胞因子转染的树突状细胞的方法;使用细胞因子转染的肿瘤细胞系的方法;降低免疫抑制性细胞如调节性T细胞、髓源性抑制细胞、或表达吲哚胺2,3-脱氧酶的树突状细胞的功能方法;以及肿瘤相关抗原蛋白类或肽类组成的癌症疫苗的方法。
10)嵌合抗原受体T细胞免疫疗(CAR T)。
11)肿瘤基因治疗如CRISPR-Cas 9,RNAi,基因转导。
应予说明,如果任何给定取代基的数量没有规定(例如,卤代烷基),则可以存在一个或多个取代基。例如,“卤代烷基”可以含有一个或多个相同或不同的卤素。
在本文的描述中,如果化学结构和化学名称彼此矛盾时,则是以其化学结构为准。
当在本文使用时,对于任何保护基团和其他化合物的缩写,除非另有说明,以其常用的公认缩写表示,或根据IUPAC-IUB Commission on Biochemical Nomenclature表示(参见,Biochem.1972,77:942-944)。
实施例
以下列举实施例来详细说明本发明,但本发明不受这些实施例的任何限制。
实施例1
N-(5-(4-(3-溴苯基氨基)-嘧啶-2-基氨基)-2-(2-(二甲氨基-乙基)-甲基-氨
基)-4-甲氧基-苯基)-丙烯酰胺(化合物1)的制备
3-溴苯胺(2.7g,15mmol)、2,4-二氯嘧啶(2.7g,18mmol)、碳酸氢钠(2.5g,30mmol)加到30mL异丙醇中,85℃加热反应10小时,减压蒸去异丙醇,再加入水、乙酸乙酯萃取,乙酸乙酯层干燥、浓缩、柱层析得中间体1(3g)。m/z:ESI MH+286.0
中间体1(1.4g,5mmol)、2-甲氧基-4-氟-5-硝基苯胺(0.9g,5mmol)、对甲苯磺酸(1.03g,6mmol)加到15mL2-戊醇中,115℃加热3小时,冷至室温过滤,滤饼用甲基叔丁基醚洗两次,干燥得中间体2(1.6g)。m/z:ESI MH+434.0。
中间体2(43g,1mmol)、N,N,N′-三甲基乙二胺(0.15g,1.5mmol)、无水碳酸钾(0.28g,2mmol)加到2mL DMF中,90℃加热3小时,冷至室温,加入水、乙酸乙酯萃取,乙酸乙酯层浓缩后加入铁粉(0.28g,5mmol)、氯化铵(0.27g,5mmol)、水(5mL)、乙醇(15mL),80℃加热反应5小时,趁热滤除铁泥,滤液浓缩后加水、二氯甲烷萃取,二氯甲烷层干燥、浓缩、柱层析得中间体4(0.24g),m/z:ESI MH+486.1。
中间体4(0.24g,0.5mmol)、N,N-二异丙基乙基胺(0.2g,1.5mmol)加到四氢呋喃中,冰水浴冷却,滴加丙烯酰氯(0.05g,0.55mmol),加完搅拌1小时,升至室温搅拌2小时,加入水、二氯甲烷萃取,二氯甲烷层无水硫酸钠干燥、浓缩、柱层析得目标化合物70mg。
采用与实施例1同样的方式制备表1中的化合物。
表1
实施例2
N-(5-(4-(1H-吲哚-1-基)-嘧啶-2-基氨基)-2-((2-(二甲氨基)-乙基)-甲基-氨
基)-4-甲氧基-苯基)-丙烯酰胺(化合物32)的制备
吲哚(8.7,74mmol)、2,4-二氯嘧啶(16g,107mmol)、HOBT(2g,14.8mmol)、无水碳酸钾(20g,145mmol)加到DMF中,85℃反应15小时,加入水、乙酸乙酯萃取,乙酸乙酯层干燥、浓缩、柱层析得中间体1(8g)。MS m/z:ES+MH+230.1
按照实施例1的方法,可制备目标化合物。
采用与实施例2同样的方式制备表2中的化合物。
表2
实施例3
N-(5-(4-(1H-苯基[d]咪唑-1-基)嘧啶-2-基氨基)-2-((2-(二甲氨基)乙基)(甲
基)氨基)-4-甲氧基苯基)丙烯酰胺(化合物106)的制备
苯并咪唑(2.4g,20mmol)、碳酸钾(5.6g,40mmol)、2,4-二氯嘧啶(4.5g,30mmol)加到5mL DMF中,室温搅拌1小时,反应液倒入水中,乙酸乙酯萃取,乙酸乙酯层干燥、浓缩、柱层析得中间体1(2.1g)。m/z:ESI MH+231.0。
按照实施例1的方法,可制备目标化合物。
采用与实施例3同样的方式制备表3中的化合物。
表3
实施例4
N-(5-(4-(3-氯-苯基氨基)-[1,3,5]三嗪-2-基氨基)-2-((2-二甲基氨基-乙基)-
甲基-氨基)-4-甲氧基-苯基)-丙烯酰胺(化合物108)的制备
3-氯苯胺(2.56g,20mmol)、DIEA(3.08g,24mmol)加到20mL DMF中,冰盐浴冷却,滴加2,4-二氯-1,3,5-三嗪(3.29g,22mmol)的DMF溶液,冰盐浴搅拌2.5小时,反应液倒入水中,乙酸乙酯萃取,乙酸乙酯层干燥、浓缩、柱层析得中间体1(3.65g)。m/z:ESI MH+241.0。
按照实施例1的方法,可制备目标化合物。
采用与实施例4同样的方式制备表4中的化合物。
表4
实施例5
N-(5-(6-(3-溴-苯基氨基)-嘧啶-4-基氨基)-2-((2-二甲基氨基-乙基)-甲基-氨
基)-4-甲氧基-苯基)-丙烯酰胺(化合物133)的制备
3-溴苯胺(2.7g,15mmol)、4,6-二氯嘧啶(2.7g,18mmol)、碳酸氢钠(2.5g,30mmol)加到30mL异丙醇中,85℃加热反应10小时,减压蒸去异丙醇,再加入水、乙酸乙酯萃取,乙酸乙酯层干燥、浓缩、柱层析得中间体1(4g)。m/z:ESI MH+286.0
按照实施例1的方法,可制备目标化合物。
采用与实施例5同样的方式制备表5中的化合物。
表5
实施例6
N-(5-(6-(1H-吲哚-1-基)-嘧啶-4-基氨基)-2-(2-(二甲氨基-乙基)-甲基-氨
基)-4-甲氧基-苯基)-丙烯酰胺(化合物155)的制备
按照实施例2、3的方法用4,6-二氯嘧啶代替2,4-二氯嘧啶,可制备目标化合物。
采用与实施例6同样的方式制备表6中的化合物。
表6
实施例7
N-(4-甲氧基-5-(6-(1-甲基-1H-吲哚-3-基)嘧啶-4-基氨基)-2-(4-甲基哌嗪-1-
基)-苯基)-丙烯酰胺(158)的制备
1-甲基吲哚(2.5mL,23mmol)、4,6-二氯嘧啶(3g,23mmol)、无水三氯化铝(3g,23mmol)加到30mL 1,2-二氯乙烷中,45℃加热反应4小时,冷至室温,加入1M稀盐酸、二氯甲烷萃取,二氯甲烷层干燥、浓缩、柱层析得中间体1(3.5g)。m/z:ESI MH+244.1
中间体1(1.2g,5mmol)、2-甲氧基-4-氟-5-硝基苯胺(0.9g,5mmol)、对甲苯磺酸(1.03g,6mmol)加到15mL 2-戊醇中,115℃加热3小时,冷至室温过滤,滤饼用甲基叔丁基醚洗两次,干燥得中间体2(1.4g)。m/z:ESI MH+394.1。
中间体2(0.4g,1mmol)、N-甲基哌嗪(0.15g,1.5mmol)、无水碳酸钾(0.28g,2mmol)加到2mL DMF中,90℃加热3小时,冷至室温,加入水、乙酸乙酯萃取,乙酸乙酯层浓缩后加入铁粉(0.28g,5mmol)、氯化铵(0.27g,5mmol)、水(5mL)、乙醇(15mL),80℃加热反应5小时,趁热滤除铁泥,滤液浓缩后加水、二氯甲烷萃取,二氯甲烷层干燥、浓缩、柱层析得中间体4(0.23g)。m/z:ESI MH+444.3。
中间体4(0.22g,0.5mmol)、N,N-二异丙基乙基胺(0.2g,1.5mmol)加到四氢呋喃中,冰水浴冷却,滴加丙烯酰氯(0.05g,0.55mmol),加完搅拌1小时,升至室温搅拌2小时,加入水、二氯甲烷萃取,二氯甲烷层无水硫酸钠干燥、浓缩、柱层析得目标化合物70mg。m/z:ESI MH+498.4
实施例8
N-(4-甲氧基-2-(2-甲氧基-乙氧基)-5-(6-(1-甲基-1H-吲哚-3-基)-嘧啶-4-基
氨基)-苯基)-丙烯酰胺(化合物196)的制备
实施例7中的中间体2(0.4g,1mmol)、乙二醇单甲醚(0.15g,2mmol)、氢氧化钠(0.16g,4mmol)加到2mL DMF中,60℃加热5小时,冷至室温,加入水、乙酸乙酯萃取,乙酸乙酯层浓缩后加入铁粉(0.28g,5mmol)、氯化铵(0.27g,5mmol)、水(5mL)、乙醇(15mL),80℃加热反应5小时,趁热滤除铁泥,滤液浓缩后加水、二氯甲烷萃取,二氯甲烷层干燥、浓缩、柱层析得中间体7 0.18g。m/z:ESI MH+420.
中间体7(0.18g,0.43mmol)、N,N-二异丙基乙基胺(0.2g,1.5mmol)加到四氢呋喃中,冰水浴冷却,滴加丙烯酰氯(0.045g,0.5mmol),加完搅拌1小时,升至室温搅拌2小时,加入水、二氯甲烷萃取,二氯甲烷层无水硫酸钠干燥、浓缩、柱层析得目标化合物45mg。
采用与实施例7、8同样的方式制备表7中的化合物。
表7
试验例 化合物活性测定
以下对上述实施例中合成的丙烯酰胺苯胺组合衍生物的代表例,进行表达不同癌基因的肿瘤细胞体外与体内生长抑制活性的测定。测定方法和结果如下。
试验例1
化合物对EGFR野生型和突变型以及HER2/ErbB2表达阳性肿瘤细胞体外生长
50%抑制(GI50)浓度范围的测定
实验材料与方法
1.肿瘤细胞系及细胞培养
肿瘤细胞系是研究肿瘤体外生长抑制的有效细胞模型。我们选择具有代表性的肿瘤细胞系应用于化合物活性测定。所有使用的细胞系分别购于ATCC和中科院细胞库。细胞培养条件与方法按每种细胞系要求进行。每次体外培养不超过3次传代。根据需要,可对细胞系进行单克隆纯化与鉴定。
细胞培养基分别选用RPMI1640(Gibco),MEM(Gibco),McCOY′S5A(Gibco),IMDM(Gibco),加入5-20%胎牛血清(Gibco),1%双抗,2mM谷氨酰胺或者1mM丙酮酸钠。
(1)表达EGFR酪蛋白激酶野生型和突变型的肿瘤细胞系
EGFR野生型细胞系:A431人表皮癌细胞(EGFR野生型/高表达,中科院上海细胞库),NCI-H460人大细胞肺癌细胞(EGFR为野生型,Kras G61H,ATCC),H1299非小细胞肺癌细胞株(EGFR为野生型,ATCC),A375黑色素瘤细胞系(EGFR野生型性,BRAF V600E,中科院上海细胞库),NCI-H292人肺癌(EGFR野生型性,来自人肺粘液表皮样癌/***转移,中科院上海细胞库),用1×RPMI1640,加10%FBS的完全培养基培养以上。用1×Ham'SF12K,加10%FBS,1%双抗,2mM谷氨酰胺的完全培养基培养A549非小细胞肺癌细胞(EGFR野生型,KrasG12S突变型,中科院上海细胞库)。
EGFR突变型细胞系:非小细胞肺癌细胞PC-9(ATCC)和HCC827细胞(中科院上海细胞库)是EGFR Exon19(E746-A750)缺失型突变细胞系,第一代EGFR抑制剂敏感。人非小细胞肺腺癌细胞NCI-H1975,表达EGFRL858R/T790M双突变(ATCC),第一代EGFR抑制剂抗性;PC-9ER由本公司建立的PC-9细胞株厄洛替尼(Erlotinib)获得性抗性细胞系,EGFR为delE746-A750/T790M突变型,第一代EGFR抑制剂抗性。
(2)HER2基因扩增或高表达的细胞系
人胃癌细胞系NCI-N87(ATCC),人乳腺癌细胞株HCC1954((HER2/ERB2选择性可逆抑制剂拉帕替尼Lapatinib耐药性细胞株,GI50>1000nM)和ZR-75-30(ATCC),AU565(ATCC)腺癌细胞系,NCI-H2170人肺鳞状细胞癌(ATCC),分别用1×RPMI1640完全培养基培养(10%FBS)培养;人肺腺癌细胞Calu-3(ATCC)培养基为1×MEM,10%FBS,1%双抗,1%NEAA(Gibco),2mM谷氨酰胺和1mM丙酮酸钠。人乳腺癌细胞SK-BR-3用McCOY′S5A完全培养基(10%FBS)培养。
(3)过表达MET酪蛋白激酶的肿瘤细胞系
MKN-45人胃癌细胞(ATCC)和非小细胞肺癌NCI-H1993(ATCC)分别用1×RPMI1640加10%FBS的完全培养基培养。
(4)表达ALK融合蛋白及突变株的肿瘤细胞系
人非小细胞肺癌细胞株NCI-H2228(ATCC)表达EML4-ALK融合基因,人间变性大细胞淋巴瘤细胞株karpas-299(ATCC)表达NPM-ALK融合基因,用1xRPMI1640(10%FBS)完全培养基培养。神经母细胞瘤细胞SH-SY5Y(中科院上海细胞库)表达ALK F1174L突变蛋白,用MEM完全培养基(1xMEM,10%FBS,1%NEAA,1mM丙酮酸钠)培养。
(5)表达BCR-ABL酪蛋白激酶细胞系
人白血病细胞株K562(ATCC)表达BCR-ABL融合蛋白。用1×RPMI1640加10%FBS的完全培养基培养。
(6)表达FLT3-ITD酪蛋白激酶突变株的细胞系
FLT3属于酪蛋白激酶,其中临床上约20-30%急性髓细胞白血病(AML)病人表达FLT3-ITD突变蛋白。MV4-11表达FLT3-ITD酪蛋白激酶,用1×RPMI1640加10%FBS的完全培养基培养。
(7)表达Jak2 V617F酪蛋白激酶突变株细胞系
Jak2是一种非受体酪蛋白激酶(Janus Kinase 2)。在细胞生长,分化与转化中具有重要的作用。Jak2基因突变往往导致骨髓增生及转化,特别是Jak2 V167F突变常见于临床病人。人红白血病细胞系HEL表达Jak2 V167F,用1×RPMI1640加10%FBS的完全培养基培养。
(8)表达Brutons酪蛋白激酶(BTK)突变株细胞系
RAMOS是BTK酪蛋白激酶表达阳性的人B淋巴细胞白血病细胞系用1×RPMI1640加10%FBS的完全培养基培养。
(9)表达Kit酪蛋白激酶突变株细胞系
Kasumi-1是Kit酪蛋白激酶N822K突变株表达阳性白血病细胞系。Kit酪蛋白激酶异常变异常常出现在一些癌症病人中。Kasumi-1细胞用1×RPMI1640加10%FBS的完全培养基培养。
2.药物处理
贴壁细胞用0.25%胰酶-EDTA(Gibco)消化,悬浮培养细胞直接离心收集(1700rpm,3分钟),弃上清,计数细胞。根据每种细胞生长周期,配制不同的细胞浓度(每毫升5-10×104细胞),接种到96孔板(Coming),每孔100微升,37℃,5%CO2培养过夜。第二天,加入待测化合物到培养细胞中,平行2孔。有机溶剂终浓度不超过千分之一,细胞继续培养72小时,MTT测定。
待测化合物与参比化合物用DMSO(Sigma)溶解,化合物纯度达98%以上。化合物贮存浓度为10mM,-20℃保存,使用前对倍或者10倍系列稀释。
3.MTT检测及GI50计算
MTT检测试剂为Dojindo CCK8试剂盒,酶标测定仪为THERMO MULTISKAN FC仪。
将贴壁细胞培养基吸出,立即加入新配制的含10%CCK8的完全培养基(5%FBS),每孔100ul。悬浮细胞可直接加入CCK8试剂,终浓度为10%,继续培养1-4小时,当溶剂对照孔呈现暗黄色时,测OD450nm光吸收值,按下列公式计算细胞生长率。细胞生长率%=100*(T-T0)/(C-T0),T=药物处理细胞孔光密度值-空白对照孔光密度值;T0=药物处理前细胞孔光密度值-空白对照孔光密度值;C=溶剂对照组细胞孔光密度。通过药物浓度与细胞生长率曲线,计算细胞生长50%抑制的药物浓度即GI50。试验重复进行三次,并对数据进行生物学统计分析。
实验结果
表8总结本发明化合物对不同肿瘤细胞生长抑制GI50浓度范围的结果,GI50值越小,细胞生长抑制活性越强,而化合物对EGFR野生型细胞生长抑制(GI50)浓度越高,即EGFR野生型GI50/EGFR突变型GI50比值越大,化合物选择性越好。
表8
试验例2
化合物对不同肿瘤细胞生长抑制GI50值的测定
选择10个本发明化合物2,18,19,32,106,114,118,140,147,183,采用第三代EGFR抑制剂AZD9291作参比,对表达临床常见癌基因的一些肿瘤细胞进行生长抑制试验。化合物以1000nM为起始浓度,对倍稀释到0.03nM,按照GI50计算方法计算每种化合物的GI50值(表9)。结果显示测试化合物对表达EGFR突变型细胞(H1975,PC-9,HCC827)具有较高的抑制活性,GI50小于20nM,对EGFR野生型高表达细胞A431需要相对高的浓度才呈现明显的抑制作用,而对多数EGFR野生型正常表达细胞株相对无抑制效果。同时发现本发明化合物对HER2基因扩增或高表达的肿瘤细胞系(N87,AU565,SK-RB-3,H2170,ZR-75-30和Calu-3)具有选择性的强抑制作用,活性远强于参比化合物。除化合物114,118,140,147和183对表达FLT3-ITD及BTK基因的MV4-11和Ramos细胞有中等程度的抑制作用外,测试化合物对其它癌基因表达阳性细胞相对无抑制作用。
表9
试验例3
肿瘤细胞体内生长抑制实验
免疫缺陷小鼠的异种移植是测试化合物动物体内抗肿瘤活性的有效模型。一般来讲,人肿瘤细胞异种移植试验的有效性和人体肿瘤临床治疗呈一定的正相关。Bab/c免疫缺陷小鼠是最常用的肿瘤细胞异种移植动物之一。为了测试本发明化合物是否能够同样抑制EGFR突变株细胞和HER2/ErbB2过表达肿瘤细胞的体内生长,首先选用H1975,PC-9和NCI-N87细胞Bab/c裸鼠肿瘤模型进行试验。将生长对数期的H1975,PC-9,NCI-N87肿瘤细胞用胰酶消化,加适量1xRPMI1640培养基(无血清)终止消化,收集细胞于50ml离心管(Coming),1700rm离心3分钟。弃上清,用1xRPMI1640培养基悬浮细胞,计数,配制成5-10x107细胞/毫升,置冰上,皮下接种5-10x106(0.2ml)细胞于6-8周龄(重20克左右)雌性Bab/c裸鼠右侧背部。当肿瘤块生长到大小在100-200mm3体积时,随机分组(每组3-6只),耳扎标记,称重。待测化合物纯度达为99%以上,单杂不高于0.2%,用CM(30%聚乙二醇400,0.5%Tween-80,2.5%丙二醇)将药物配制成乳状混悬液,以0.1ml/每10克的体积每日一次,连续灌胃给药,药量为25mg/kg。每周测量肿瘤3次。当CM对照组肿瘤平均体积达到1500mm3时,或给药到30天时,实验结束。
肿瘤体积按V=1/2 axb2计算,a为长,b为宽。抑瘤率=(对照组平均体积-治疗组平均体积)/对照组平均体积×100%。
测试化合物药量为25mg/kg灌胃给药19天时,三种肿瘤细胞动物模型的肿瘤生长均能够有效的被抑制而动物体重不受影响。
表10本发明化合物对肿瘤细胞体内生长抑制实验(第19天)的结果
Claims (7)
1.一种通式(I)所示的化合物或其药学上可接受的盐:
其中:
R1为如下结构:
其中,
R7 a、R7 b、R7 c、R7 d和R7 e彼此相同或不同,并且各自独立地为R7;
R7选自氢、卤素、C1-6烷基、C2-C6烯基、C2-C6炔基、C1-6烷氧基,其中C1-6烷基、C1-6烷氧基任选被以下的0-4个基团取代:卤素;
X为CR4;
Y为N;
R2选自C1-6烷氧基或C1-6烷硫基;
R3选自-N(Rv)RuN(Ry)(Rz)、-ORuOR6、-ORuN(Ry)(Rz)、-SRuN(Ry)(Rz);
R4和R’4选自氢或C1-6烷基;
R6选自C1-C6烷基;
每个Ru独立地选自C1-6亚烷基;
Rv选自氢或C1-6烷基;
每个Ry和Rz独立地选自以下的a)或b):
a)Ry和Rz各自独立地选自氢、C1-6烷基;
b)Ry和Rz和与它们所连接的氮原子一起形成3至9元杂环基,且环中含有0-4个独立地选自O、S、N的杂原子,且环上任选用1-4个取代基取代,所述取代基选自C1-6烷基。
2.根据权利要求1所述的化合物或其药学上可接受的盐,其特征在于,所述通式(I)所示化合物为通式(IIc)所示的化合物,
R1为如下结构:
其中,
R7 a、R7 b、R7 c、R7 d和R7 e彼此相同或不同,并且各自独立地为R7;
R7选自氢、卤素、C1-6烷基、C2-C6烯基、C2-C6炔基、C1-6烷氧基,其中C1-6烷基、C1-6烷氧基任选被以下的0-4个基团取代:卤素;
R2为C1-6烷氧基;
R3选自-N(Rv)RuN(Ry)(Rz)、-ORuOR6、或-ORuN(Ry)(Rz);
R4、R’4各自独立地选自氢或C1-6烷基;
R6选自C1-C6烷基;
每个Ru独立地选自C1-C6亚烷基;
Rv选自氢或C1-C6烷基;
每个Ry和Rz独立地选自以下的a)或b):
a)Ry和Rz各自独立地选自氢、C1-C6烷基;
b)Ry和Rz和与它们所连接的氮原子一起形成3至9元杂环基,且环中含有0-4个独立地选自O、S、N的杂原子,且环上任选用1-4个取代基取代,所述取代基选自C1-6烷基。
3.权利要求2所述的化合物或其药学上可接受的盐,其特征在于:
R7 a、R7 b、R7 c、R7 d和R7 e彼此相同或不同,并且各自独立地为R7;
R7选自氢、卤素、C1-6烷基、C2-C6炔基、C1-6烷氧基,其中C1-6烷基、C1-6烷氧基任选被以下的0-4个基团取代:卤素;
R2选自甲氧基、丙氧基;
R3、Ru、Rv如权利要求2中所定义;
R4、R’4、Ry、Rz如权利要求2中所定义。
4.一种化合物或其药学上可接受的盐,其中所述化合物选自:
N-(5-(6-(3-溴-苯基氨基)-嘧啶-4-基氨基)-2-((2-二甲基氨基-乙基)-甲基-氨基)-4-甲氧基-苯基)-丙烯酰胺;
N-(2-((2-二甲基氨基-乙基)-甲基-氨基)-4-甲氧基-5-(6-(3-三氟甲基-苯基氨基)-嘧啶-4-基氨基)-苯基)-丙烯酰胺;
N-(5-(6-(3-炔基-苯基氨基)-嘧啶-4-基氨基)-2-((2-二甲基氨基-乙基)-甲基-氨基)-4-甲氧基-苯基)-丙烯酰胺;
N-(5-(6-(2,4-二氯-5-甲氧基-苯基氨基)-嘧啶-4-基氨基)-2-((2-二甲基氨基-乙基)-甲基-氨基)-4-甲氧基-苯基)-丙烯酰胺;
N-(5-(6-(2-氟-3,4-二氯-苯基氨基)-嘧啶-4-基氨基)-2-((2-二甲基氨基-乙基)-甲基-氨基)-4-甲氧基-苯基)-丙烯酰胺;
N-(5-(6-(2-氟-3-氯-苯基氨基)-嘧啶-4-基氨基)-2-((2-二甲基氨基-乙基)-甲基-氨基)-4-甲氧基-苯基)-丙烯酰胺;
N-(5-(6-(3-溴-5-氟-苯基氨基)-嘧啶-4-基氨基)-2-((2-二甲基氨基-乙基)-甲基-氨基)-4-甲氧基-苯基)-丙烯酰胺;
N-(5-(6-(3-氯-4-氟-苯基氨基)-嘧啶-4-基氨基)-2-((2-二甲基氨基-乙基)-甲基-氨基)-4-甲氧基-苯基)-丙烯酰胺;
N-(5-(6-(3-氯-4-氟-苯基氨基)-2-甲基-嘧啶-4-基氨基)-2-((2-二甲基氨基-乙基)-甲基-氨基)-4-甲氧基-苯基)-丙烯酰胺;
N-(5-(6-(3-氯-4-氟-苯基氨基)-嘧啶-4-基氨基)-2-(2-二甲基氨基-乙氧基)-4-甲氧基-苯基)-丙烯酰胺;
N-(5-(6-(3-氯-4-氟-苯基氨基)-嘧啶-4-基氨基)-4-甲氧基-2-(2-吡咯烷-1-基-乙氧基)-苯基)-丙烯酰胺;
N-(5-(6-(3-氯-4-氟-苯基氨基)-嘧啶-4-基氨基)-2-(2-(4-甲基-哌嗪-1基)-乙氧基)-4-甲氧基-苯基)-丙烯酰胺;
N-(5-(6-(3-氯-4-氟-苯基氨基)-嘧啶-4-基氨基)-4-甲氧基-2-(2-吗啉-4-基-乙氧基)-苯基)-丙烯酰胺;
N-(5-(6-(3-氯-4-氟-苯基氨基)-嘧啶-4-基氨基)-2-(2-甲氧基乙氧基)-4-甲氧基-苯基)-丙烯酰胺。
5.一种EGFR和/或HER2/ErbB2蛋白酪氨酸激酶抑制剂,其含有根据权利要求1至4中任一项所述的化合物或其药学上可接受的盐作为有效成分。
6.根据权利要求1至4中任一项所述的化合物或其药学上可接受的盐在制备EGFR和/或HER2/ErbB2蛋白酪氨酸激酶抑制剂中的用途。
7.根据权利要求1至4中任一项所述的化合物或其药学上可接受的盐在制备预防和/或治疗癌症的药物中的用途。
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CN201511027848.4A CN106928150B (zh) | 2015-12-31 | 2015-12-31 | 丙烯酰胺苯胺衍生物及其药学上的应用 |
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EP16881289.9A EP3398939A4 (en) | 2015-12-31 | 2016-12-30 | ACRYLANILIDE DERIVATIVE, PREPARATION METHOD THEREOF, AND PHARMACEUTICAL APPLICATIONS THEREOF |
JP2018553292A JP2019506449A (ja) | 2015-12-31 | 2016-12-30 | アクリルアニリド誘導体、その製造方法及びその薬学的な応用 |
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BR112018013218-7A BR112018013218B1 (pt) | 2015-12-31 | 2016-12-30 | Derivado de acrilanilida, seus usos, e composição farmacêutica |
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EP3399968B8 (en) | 2016-01-07 | 2021-12-01 | Xuanzhu Biopharmaceutical Co., Ltd. | Selective inhibitors of clinically important mutants of the egfr tyrosine kinase |
WO2017205459A1 (en) | 2016-05-26 | 2017-11-30 | Kalyra Pharmaceuticals, Inc. | Egfr inhibitor compounds |
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CN109721589A (zh) * | 2017-10-30 | 2019-05-07 | 如东凌达生物医药科技有限公司 | 一类具有抗肿瘤活性的苯胺咪唑基嘧啶胺类化合物、制备方法和用途 |
TWI798334B (zh) * | 2018-01-31 | 2023-04-11 | 大陸商迪哲(江蘇)醫藥股份有限公司 | Erbb/btk抑制劑 |
CN111617083B (zh) * | 2019-02-28 | 2023-10-27 | 上海医药工业研究院 | 甲氧基取代苯基酰胺类氨基嘧啶衍生物的应用 |
CN111718325A (zh) * | 2019-03-22 | 2020-09-29 | 烟台药物研究所 | 一种2,4,5-取代嘧啶类化合物及其制备方法和应用 |
CN111747950B (zh) * | 2019-03-29 | 2024-01-23 | 深圳福沃药业有限公司 | 用于治疗癌症的嘧啶衍生物 |
WO2021104305A1 (zh) * | 2019-11-26 | 2021-06-03 | 上海翰森生物医药科技有限公司 | 含氮多环类衍生物抑制剂、其制备方法和应用 |
CN111057021B (zh) * | 2019-12-11 | 2023-05-23 | 中国药科大学 | 均三嗪类化合物及其制备方法和用途 |
JP2023508376A (ja) * | 2019-12-23 | 2023-03-02 | 北京賽特明強医薬科技有限公司 | シアノ置換ピリジンおよびシアノ置換ピリミジン系化合物、製造方法およびそれらの使用 |
WO2022033455A1 (zh) * | 2020-08-13 | 2022-02-17 | 上海和誉生物医药科技有限公司 | 具有egfr抑制活性的三嗪衍生物及其制备方法和应用 |
CA3196068A1 (en) * | 2020-12-02 | 2022-06-09 | Abbisko Therapeutics Co., Ltd | 2,3-dihydro-1h-pyrrolo[3,2-b]pyridine derivative, preparation method therefor, and application thereof |
CN117177968A (zh) * | 2021-03-11 | 2023-12-05 | 昂科比克斯有限公司 | 对癌细胞生长表现出抑制作用的新型嘧啶衍生物 |
CN113387935B (zh) * | 2021-07-23 | 2022-06-10 | 苏州雅深智慧科技有限公司 | 抑制三突变表皮生长因子受体酪氨酸激酶的化合物及用途 |
CN115701429B (zh) * | 2021-08-02 | 2024-03-12 | 上海和誉生物医药科技有限公司 | 4-(1h-吲哚-1-基)嘧啶-2-氨基衍生物及其制备方法和应用 |
CN117440945A (zh) * | 2021-08-06 | 2024-01-23 | 上海和誉生物医药科技有限公司 | 嘧啶或吡啶衍生物及其制备方法和在药学上的应用 |
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US10342796B2 (en) | 2019-07-09 |
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