技术领域technical field
本发明涉及新的含杂芳基取代哒嗪酮结构的三唑并吡嗪类化合物及其药学上可接受的盐、水合物、溶剂化物或其前药的制备方法以及含有所述化合物的药物组合物，及其在制备治疗和/或预防癌症的药物中的用途。The present invention relates to a novel triazolopyrazine compound containing a heteroaryl-substituted pyridazinone structure, a preparation method thereof, a pharmaceutically acceptable salt, a hydrate, a solvate or a prodrug thereof, and a medicine containing the compound Composition, and its use in the preparation of medicines for treating and/or preventing cancer.
技术背景technical background
肿瘤是机体在各种致瘤因素作用下，局部组织的细胞在基因水平上失去对其生长的正常调控导致异常增生与分化而形成的新生物。新生物一旦形成，不因病因消除而停止生长，他的生长不受正常机体生理调节，而是破坏正常组织与器官，这一点在恶性肿瘤尤其明显。随着分子生物学等学科的发展以及在细胞水平和分子水平对肿瘤发生机制的深入研究，针对细胞受体、调控因子以及关键基因为靶点的靶向治疗——分子靶向治疗迅速发展起来。分子靶向治疗是在分子生物学的基础上，将与肿瘤相关的特异性分子及其调控信号转导通路作为靶点进行设计药物，使药物进入体内后通过阻断信号传导以达到抑制肿瘤细胞生长或促使肿瘤细胞凋亡的目的。优点是既能发挥抗肿瘤的作用，也可以减轻对正常细胞的毒副作用。Tumor is a new organism formed by the body under the action of various tumorigenic factors, and the cells of local tissues lose their normal regulation of their growth at the gene level, resulting in abnormal proliferation and differentiation. Once a new organism is formed, it does not stop growing due to the elimination of the cause. Its growth is not regulated by normal body physiology, but destroys normal tissues and organs. This is especially obvious in malignant tumors. With the development of molecular biology and other disciplines and the in-depth research on the mechanism of tumorigenesis at the cellular and molecular levels, targeted therapy targeting cell receptors, regulatory factors, and key genes—molecular targeted therapy has developed rapidly . Molecular targeted therapy is based on molecular biology, using specific tumor-related molecules and their regulatory signal transduction pathways as targets to design drugs, so that drugs can inhibit tumor cells by blocking signal transduction after entering the body. The purpose of growth or apoptosis of tumor cells. The advantage is that it can not only play an anti-tumor effect, but also reduce the toxic and side effects on normal cells.
c-Met是原癌基因c-Met编码的蛋白，c-Met作为单链前体蛋白产生。该前体受体被切割以产生位于胞外区糖基化的α链亚基(50kDa)和跨膜β链亚基(145kDa)，两个亚基通过二硫键连接以形成成熟的受体，其结构如Figure 1所示。胞外部分负责结合HGF，包含Sema结构域，富含半胱氨酸的PSI结构域和四个IPT结构域。胞内部分负责信号转导，由近膜结构域、催化区和羧基末端多功能停靠位点组成。其中，近膜结构域在c-Met受体的下调中起关键作用。c-Met is a protein encoded by the proto-oncogene c-Met, which is produced as a single-chain precursor protein. This precursor receptor is cleaved to generate a glycosylated α-chain subunit (50 kDa) located in the extracellular region and a transmembrane β-chain subunit (145 kDa), which are disulfide-bonded to form the mature receptor , whose structure is shown in Figure 1. The extracellular part is responsible for binding HGF and contains a Sema domain, a cysteine-rich PSI domain and four IPT domains. The intracellular portion is responsible for signal transduction and consists of a membrane-proximal domain, a catalytic domain, and a carboxy-terminal multifunctional docking site. Among them, the juxtamembrane domain plays a key role in the downregulation of c-Met receptor.
c-Met激酶广泛存在于上皮组织中，在胚胎发育和创伤愈合中发挥着重要的作用。最近研究表明，c-Met激酶在肺癌、结肠癌、肝癌、直肠癌、胃癌、肾癌、卵巢癌、神经胶质瘤、黑色素瘤、乳腺癌、前列腺癌等肿瘤组织中呈现异常的高表达、突变或活性改变。c-Met激酶能够促进肿瘤细胞的增殖，调节肿瘤细胞的迁移，增强肿瘤细胞的侵袭能力并诱发肿瘤新生血管的生成。目前， c-Met激酶已经成为抗肿瘤药物研究的一个重要靶点。c-Met kinase widely exists in epithelial tissues and plays an important role in embryonic development and wound healing. Recent studies have shown that c-Met kinase is abnormally highly expressed in tumor tissues such as lung cancer, colon cancer, liver cancer, rectal cancer, gastric cancer, kidney cancer, ovarian cancer, glioma, melanoma, breast cancer, and prostate cancer. Mutation or Altered Activity. c-Met kinase can promote the proliferation of tumor cells, regulate the migration of tumor cells, enhance the invasion ability of tumor cells and induce tumor angiogenesis. At present, c-Met kinase has become an important target of antitumor drug research.
目前，已有多种c-Met抑制剂已经上市(如下结构式所示)，根据这些抑制剂的化学结构以及与c-Met蛋白的结合方式不同，主要将其分为ClassⅠ和 ClassⅡ两种类型。如ClassⅠ型抑制剂中的PF-04217903(Cui J J,McTigue M, Nambu M,et al.Discovery of aNovel Class of Exquisitely Selective Mesenchymal-Epithelial Transition Factor(c-MET)Protein Kinase Inhibitors and Identification of the Clinical Candidate2-(4-(1-(Quinolin-6-ylmethyl)-1H-[1,2,3] triazolo[4,5-b]pyrazin-6-yl)-1H-pyrazol-1-yl)ethanol(PF-04217903)for the Treatment ofCancer[J].Journalofmedicinal chemistry,2012,55(18):8091-8109.) 优良的体外抗激酶活性，其对c-Met激酶活性IC50为4.8nM；JNJ-38877605(Eder, J.P.,Woude,G.F.V.,Boerner,S.A.,etal.Novel therapeutic inhibitors of the c-Met signaling pathway in cancer[J].Clinical Cancer Research,2009,15(7): 2207-2214.)的c-Met激酶活性IC50为4nM；AMG-337(Paul E.Hughes,et al. AMG 337,a novel,potent and selective MET kinaseinhibitor,has robust growth inhibitory activity in MET-dependent cancermodels[J].Cancer Res October 1, 201474；728)的c-Met激酶活性IC50小于5nM。ClassⅡ型抑制剂如BMS-777607 是一种强效选择性激酶抑制剂，对MET酶IC50为3.9nM(Schroeder,G.M.,An, Y.,Cai,Z.W.,et al.Discovery of N-(4-(2-amino-3-chloropyridin- 4-yloxy)-3-fluorophenyl)-4-ethoxy-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3 -carboxamide(BMS-777607),a selective and orally efficacious inhibitor oftheMet kinase superfamily[J].Journal ofmedicinal chemistry,2009,52(5):1251-1254.)； Foretinib是第一个进入临床的小分子口服抑制剂，对c-Met激酶的抑制效力达到0.4nM，目前处于临床Ⅱ期(Qian F,et al.Inhibition oftumor cell growth, invasion,and metastasis by EXEL-2880(XL880,GSK1363089),a novel inhibitor of HGF andVEGF receptor tyrosine kinases.Cancer Res,2009,69(20), 8009-8016.)；以及课题组前期研究化合物A表现出较好的体外抗肿瘤活性 (Linxiao Wang1,Xiaobo Liu1,Shan Xu,et al.Discovery of novel pyrrolo-pyridine/pyrimidine derivatives bearingpyridazinone moiety as c-Met kinase inhibitors[J].European Journal ofMedicinal Chemistry,2017, 141:538-551.)，及化合物B(Xiaobo Liu,Jianlan Kou,ZhenXiao,et al.Design, synthesis and biological evaluation of 6,7-disubstituted-4-phenoxyquinoline derivatives bearing pyridazinone moiety as c-Metinhibitors[J].Molecules,2018, 23(7):1543.)表现出优异的体外抗肿瘤活性，对c-Met激酶的抑制效力达到0.6 nM。At present, a variety of c-Met inhibitors have been marketed (as shown in the following structural formula), and these inhibitors are mainly divided into two types: Class I and Class II according to their chemical structures and binding methods with c-Met protein. Such as PF-04217903 (Cui JJ, McTigue M, Nambu M, et al. Discovery of a Novel Class of Exquisitely Selective Mesenchymal-Epithelial Transition Factor (c-MET) Protein Kinase Inhibitors and Identification of the Clinical Candidate2- (4-(1-(Quinolin-6-ylmethyl)-1H-[1,2,3]triazolo[4,5-b]pyrazin-6-yl)-1H-pyrazol-1-yl)ethanol(PF- 04217903) for the Treatment of Cancer[J].Journal of medicinal chemistry,2012,55(18):8091-8109.) Excellent in vitro anti-kinase activity, its IC50 for c-Met kinase activity is 4.8nM; JNJ-38877605(Eder , JP, Woude, GFV, Boerner, SA, etal.Novel therapeutic inhibitors of the c-Met signaling pathway in cancer[J].Clinical Cancer Research,2009,15(7):2207-2214.) c-Met kinase The activity IC50 is 4nM; AMG-337 (Paul E.Hughes, et al. AMG 337, a novel, potent and selective MET kinase inhibitor, has robust growth inhibitory activity in MET-dependent cancer models[J]. Cancer Res October 1, 201474 ; 728) has an IC50 of c-Met kinase activity of less than 5 nM. Class II inhibitors such as BMS-777607 are potent and selective kinase inhibitors with an IC50 of 3.9 nM for METase (Schroeder, GM, An, Y., Cai, ZW, et al. Discovery of N-(4 -(2-amino-3-chloropyridin-4-yloxy)-3-fluorophenyl)-4-ethoxy-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide (BMS-777607) , a selective and orally efficacious inhibitor of the Met kinase superfamily[J].Journal of medicinal chemistry,2009,52(5):1251-1254.); The inhibitory effect reached 0.4nM, and it is currently in clinical phase II (Qian F, et al. Inhibition of tumor cell growth, invasion, and metastasis by EXEL-2880 (XL880, GSK1363089), a novel inhibitor of HGF and VEGF receptor tyrosine kinases. Cancer Res , 2009,69(20), 8009-8016.); and the research group's previous research compound A showed good anti-tumor activity in vitro (Linxiao Wang1 , Xiaobo Liu1 , Shan Xu, et al.Discovery of novel pyrrolo- pyridine/pyrimidine derivatives bearing pyridazinone moiety as c-Met kinase inhibitors[J].European Journal of Medicinal Chemistry,2017,141:538-551.), and Compound B(Xiaobo Liu,Jianlan Kou,ZhenXiao,et al.Design, synthesis and biological evaluation of 6,7-disstituted-4-phenoxyquinoline derivati ves bearing pyridazinone moiety as c-Metinhibitors[J].Molecules,2018, 23(7):1543.) exhibited excellent anti-tumor activity in vitro, and the inhibitory effect on c-Met kinase reached 0.6 nM.
为了研制出新型高效的抗肿瘤药物，本发明在课题组前期研究的基础上，化合物B表现出优异的c-Met激酶，因此对侧链部分的4-氧代哒嗪酮结构进行保留，使其可以形成分子内氢键，从而增强目标化合物的活性；并通过查阅总结参考文献，将ClassⅠ型抑制剂中的活性药效团三唑并吡嗪结构引入到Class Ⅱ抑制剂中，将ClassⅠ型与ClassⅡ型抑制剂中的活性药效团结构进行揉合。设计、合成了一系列结构新颖的含杂芳基取代哒嗪酮结构的三唑并吡嗪类化合物。体外抗肿瘤活性筛选试验表明，该类化合物具有抗肿瘤活性。In order to develop new and efficient anti-tumor drugs, the present invention is based on the previous research of the research group. Compound B shows excellent c-Met kinase, so the 4-oxopyridazinone structure of the side chain is retained, so that It can form intramolecular hydrogen bonds, thereby enhancing the activity of the target compound; and by reviewing and summarizing references, the active pharmacophore triazolopyrazine structure in Class I inhibitors is introduced into Class II inhibitors, and Class I Combined with the active pharmacophore structure in Class II inhibitors. A series of novel triazolopyrazines containing heteroaryl-substituted pyridazinone structures were designed and synthesized. The antitumor activity screening test in vitro shows that the compound has antitumor activity.
发明内容Contents of the invention
本发明涉及通式Ⅰ所示的含杂芳基取代哒嗪酮结构的三唑并吡嗪类化合物及其药学上可接受的盐、水合物、溶剂化物或前药，The present invention relates to a triazolopyrazine compound containing a heteroaryl-substituted pyridazinone structure represented by general formula I and a pharmaceutically acceptable salt, hydrate, solvate or prodrug thereof,
其中in
R1为氢、(C1-C6)烷基、(C1-C6)烷氧基、三氟甲基；R1 is hydrogen, (C1 -C6 ) alkyl, (C1 -C6 ) alkoxy, trifluoromethyl;
R2选自1～4个相同或不同的氢、氟、溴、碘；R2 is selected from1 to 4 identical or different hydrogen, fluorine, bromine, and iodine;
X为O、S、NH；X is O, S, NH;
Y为—Ar1-Ar2；Y is—Ar1 -Ar2 ;
Ar1、Ar2为六元芳杂芳基，杂芳基分别含有1-3个任选自N、O、S的杂原子， Ar1与Ar2相连，且Ar2还任选被1-3个相同或不同的R3取代；Ar1 and Ar2 are six-membered aromatic heteroaryl groups, and the heteroaryl groups contain 1-3 heteroatoms optionally selected from N, O, and S respectively. Ar1 is connected to Ar2 , and Ar2 is also optionally replaced by 1- 3 identical or different R3 substitutions;
R3为1～3个相同或不同的选自氢、卤素、羟基、三氟甲基、三氟甲氧基、氨基、叠氮基、硝基、氰基、巯基、(C1-C4)烷基、(C3-C6)环烷基、(C1-C4)烯基、(C1-C4) 炔基、(C1-C4)烷氧基、(C1-C4)烷硫基、烯丙基、(2-甲基)烯丙基、(C1-C4)烷氧基甲基、(C1-C4)烷基酰基、(C1-C3)亚烷基二氧基的取代基。R3 is 1 to 3 identical or different ones selected from hydrogen, halogen, hydroxyl, trifluoromethyl, trifluoromethoxy, amino, azido, nitro, cyano, mercapto, (C1 -C4 ) alkyl, (C3 -C6 ) cycloalkyl, (C1 -C4 ) alkenyl, (C1 -C4 ) alkynyl, (C1 -C4 ) alkoxy, (C1 - C4 ) alkylthio, allyl, (2-methyl) allyl, (C1 -C4 ) alkoxymethyl, (C1 -C4 ) alkyl acyl, (C1 -C3 ) A substituent of an alkylenedioxy group.
本发明优选还涉及定义如下的通式Ⅰ化合物，或其消旋体或旋光异构体，或其药学上可接受的盐和/或水合物，The present invention preferably also relates to a compound of general formula I as defined below, or its racemate or optical isomer, or a pharmaceutically acceptable salt and/or hydrate thereof,
其中，in,
R1为氢、甲基、三氟甲基；R is hydrogen, methyl, trifluoromethyl;
R2选自1～4个相同或不同的氢、氟；R2 is selected from 1 to 4 identical or different hydrogen and fluorine;
X为O；X is O;
Y为 R3为1～3个相同或不同的选自氢、氟、氯、溴、羟基、三氟甲基、三氟甲氧基、氨基、叠氮基、硝基、氰基、巯基、甲基、乙基、正丙基、环丙基、叔丁基、乙烯基、丙烯基、2-甲基丙烯基、乙炔基、甲氧基、乙氧基、环丙氧基、叔丁氧基、甲硫基、乙硫基、烯丙基、(2-甲基)烯丙基、甲氧基甲基、乙氧基甲基、异丙氧基甲基、甲酰基、乙酰基、丙酰基、环丙酰基、丁酰基、2,3-亚甲基二氧基、2,3-亚乙基二氧基的取代基。Y isR3 is 1 to 3 identical or different ones selected from hydrogen, fluorine, chlorine, bromine, hydroxyl, trifluoromethyl, trifluoromethoxy, amino, azido, nitro, cyano, mercapto, methyl , ethyl, n-propyl, cyclopropyl, tert-butyl, vinyl, propenyl, 2-methylpropenyl, ethynyl, methoxy, ethoxy, cyclopropoxy, tert-butoxy, Methylthio, ethylthio, allyl, (2-methyl)allyl, methoxymethyl, ethoxymethyl, isopropoxymethyl, formyl, acetyl, propionyl, Substituents of cyclopropanoyl, butyryl, 2,3-methylenedioxy, 2,3-ethylenedioxy.
本发明非常特别优选的下列通式Ⅰ衍生物，包括其消旋体或旋光异构体，及其药学上可接受的盐和/或水合物，但这些化合物并不意味着对本发明的任何限制：Very particularly preferred derivatives of the following general formula I of the present invention, including their racemates or optical isomers, and pharmaceutically acceptable salts and/or hydrates thereof, but these compounds do not imply any limitation to the present invention :
(1)N-(4-([1,2,4]三唑并[4,3-a]吡嗪-8-基)氧基)苯基-4-氧代-1-苯基-1,4-二氢哒嗪 -3-甲酰胺(1) N-(4-([1,2,4]triazolo[4,3-a]pyrazin-8-yl)oxy)phenyl-4-oxo-1-phenyl-1 ,4-Dihydropyridazine-3-carboxamide
(2)N-(4-([1,2,4]三唑并[4,3-a]吡嗪-8-基)氧基)苯基-1-(3-氯-4-氟苯基)-4-氧代 -1,4-二氢哒嗪-3-甲酰胺(2) N-(4-([1,2,4]triazolo[4,3-a]pyrazin-8-yl)oxy)phenyl-1-(3-chloro-4-fluorobenzene base)-4-oxo-1,4-dihydropyridazine-3-carboxamide
(3)N-(4-([1,2,4]三唑并[4,3-a]吡嗪-8-基)氧基)苯基-1-(4-氯-3-(三氟甲基)苯基)-4- 氧代-1-,4-二氢哒嗪-3-甲酰胺(3) N-(4-([1,2,4]triazolo[4,3-a]pyrazin-8-yl)oxy)phenyl-1-(4-chloro-3-(tri Fluoromethyl)phenyl)-4-oxo-1-,4-dihydropyridazine-3-carboxamide
(4)N-(4-([1,2,4]三唑并[4,3-a]吡嗪-8-基)氧基)苯基-1-(4-溴-2-氟苯基)-4-氧代 -1,4-二氢哒嗪-3-甲酰胺(4) N-(4-([1,2,4]triazolo[4,3-a]pyrazin-8-yl)oxy)phenyl-1-(4-bromo-2-fluorobenzene base)-4-oxo-1,4-dihydropyridazine-3-carboxamide
(5)N-(4-([1,2,4]三唑并[4,3-a]吡嗪-8-基)氧基)苯基-1-(4-甲氧基苯基)-4-氧代 -1,4-二氢哒嗪-3-甲酰胺(5) N-(4-([1,2,4]triazolo[4,3-a]pyrazin-8-yl)oxy)phenyl-1-(4-methoxyphenyl) -4-oxo-1,4-dihydropyridazine-3-carboxamide
(6)N-(4-([1,2,4]三唑并[4,3-a]吡嗪-8-基)氧基)苯基-1-(4-氟苯基)-4-氧代-1,4-二氢哒嗪-3-甲酰胺(6) N-(4-([1,2,4]triazolo[4,3-a]pyrazin-8-yl)oxy)phenyl-1-(4-fluorophenyl)-4 -Oxo-1,4-dihydropyridazine-3-carboxamide
(7)N-(4-([1,2,4]三唑并[4,3-a]吡嗪-8-基)氧基-3-氟苯基)-4-氧代-1-苯基-1,4-二氢哒嗪-3-甲酰胺(7) N-(4-([1,2,4]triazolo[4,3-a]pyrazin-8-yl)oxy-3-fluorophenyl)-4-oxo-1- Phenyl-1,4-dihydropyridazine-3-carboxamide
(8)N-(4-([1,2,4]三唑并[4,3-a]吡嗪-8-基)氧基-3-氟苯基)-1-(3-氯-4-氟苯基)-4-氧代-1-,4-二氢哒嗪-3-甲酰胺(8) N-(4-([1,2,4]triazolo[4,3-a]pyrazin-8-yl)oxy-3-fluorophenyl)-1-(3-chloro- 4-fluorophenyl)-4-oxo-1-,4-dihydropyridazine-3-carboxamide
(9)N-(4-([1,2,4]三唑并[4,3-a]吡嗪-8-基)氧基-3-氟苯基)-1-(4-氯-3-(三氟甲基)苯基)-4-氧代-1,4-二氢哒嗪-3-甲酰胺(9) N-(4-([1,2,4]triazolo[4,3-a]pyrazin-8-yl)oxy-3-fluorophenyl)-1-(4-chloro- 3-(Trifluoromethyl)phenyl)-4-oxo-1,4-dihydropyridazine-3-carboxamide
(10)N-(4-([1,2,4]三唑并[4,3-a]吡嗪-8-基)氧基-3-氟苯基)-1-(4-溴-2-氟苯基)-4- 氧代-1-,4-二氢哒嗪-3-甲酰胺(10) N-(4-([1,2,4]triazolo[4,3-a]pyrazin-8-yl)oxy-3-fluorophenyl)-1-(4-bromo- 2-fluorophenyl)-4-oxo-1-,4-dihydropyridazine-3-carboxamide
(11)N-(4-([1,2,4]三唑并[4,3-a]吡嗪-8-基)氧基-3-氟苯基)-1-(4-甲氧基苯基)-4- 氧代-1,4-二氢哒嗪-3-甲酰胺(11) N-(4-([1,2,4]triazolo[4,3-a]pyrazin-8-yl)oxy-3-fluorophenyl)-1-(4-methoxy phenyl)-4-oxo-1,4-dihydropyridazine-3-carboxamide
(12)N-(4-([1,2,4]三唑并[4,3-a]吡嗪-8-基)氧基-3-氟苯基)-1-(4-氟苯基)-4-氧代 -1,4-二氢哒嗪-3-甲酰胺(12) N-(4-([1,2,4]triazolo[4,3-a]pyrazin-8-yl)oxy-3-fluorophenyl)-1-(4-fluorobenzene base)-4-oxo-1,4-dihydropyridazine-3-carboxamide
(13)N-(4-((3-甲基-[1,2,4]三唑并[4,3-a]吡嗪-8-基)氧基)苯基)-4-氧代-1-苯基 -1,4-二氢哒嗪-3-甲酰胺(13) N-(4-((3-methyl-[1,2,4]triazolo[4,3-a]pyrazin-8-yl)oxy)phenyl)-4-oxo -1-Phenyl-1,4-dihydropyridazine-3-carboxamide
(14)1-(3-氯-4-氟苯基)-N-(4-((3-甲基-[1,2,4]三唑并[4,3-a]吡嗪-8-基)氧基)苯基)-4-氧代-1,4-二氢哒嗪-3-甲酰胺(14) 1-(3-chloro-4-fluorophenyl)-N-(4-((3-methyl-[1,2,4]triazolo[4,3-a]pyrazine-8 -yl)oxy)phenyl)-4-oxo-1,4-dihydropyridazine-3-carboxamide
(15)1-(4-氯-3-(三氟甲基)苯基)-N-(4-((3-甲基-[1,2,4]三唑并[4,3-a]吡嗪-8-基) 氧基)苯基)-4-氧代-1,4-二氢哒嗪-3-甲酰胺(15) 1-(4-chloro-3-(trifluoromethyl)phenyl)-N-(4-((3-methyl-[1,2,4]triazolo[4,3-a ]pyrazin-8-yl)oxy)phenyl)-4-oxo-1,4-dihydropyridazine-3-carboxamide
(16)1-(4-溴-2-氟苯基)-N-(4-((3-甲基-[1,2,4]三唑并[4,3-a]吡嗪-8-基)氧基)苯基)-4-氧代-1,4-二氢哒嗪-3-甲酰胺(16) 1-(4-bromo-2-fluorophenyl)-N-(4-((3-methyl-[1,2,4]triazolo[4,3-a]pyrazine-8 -yl)oxy)phenyl)-4-oxo-1,4-dihydropyridazine-3-carboxamide
(17)1-(4-甲氧基苯基)-N-(4-((3-甲基-[1,2,4]三唑并[4,3-a]吡嗪-8-基)氧基)苯基)-4-氧代-1-,4-二氢哒嗪-3-甲酰胺(17) 1-(4-methoxyphenyl)-N-(4-((3-methyl-[1,2,4]triazolo[4,3-a]pyrazin-8-yl )oxy)phenyl)-4-oxo-1-,4-dihydropyridazine-3-carboxamide
(18)1-(4-氟苯基)-N-(4-((3-甲基-[1,2,4]三唑并[4,3-a]吡嗪-8-基)氧基)苯基)-4- 氧代-1-,4-二氢哒嗪-3-甲酰胺(18) 1-(4-fluorophenyl)-N-(4-((3-methyl-[1,2,4]triazolo[4,3-a]pyrazin-8-yl)oxy yl)phenyl)-4-oxo-1-,4-dihydropyridazine-3-carboxamide
(19)N-(3-氟-4-((3-甲基-[1,2,4]三唑并[4,3-a]吡嗪-8-基)氧基)苯基)-4-氧代-1- 苯基-1-,4-二氢哒嗪-3-甲酰胺(19) N-(3-fluoro-4-((3-methyl-[1,2,4]triazolo[4,3-a]pyrazin-8-yl)oxy)phenyl)- 4-oxo-1-phenyl-1-,4-dihydropyridazine-3-carboxamide
(20)1-(3-氯-4-氟苯基)-N-(3-氟-4-((3-甲基-[1,2,4]三唑并[4,3-a]吡嗪-8-基)氧基) 苯基)-4-氧代-1,4-二氢哒嗪-3-甲酰胺(20) 1-(3-chloro-4-fluorophenyl)-N-(3-fluoro-4-((3-methyl-[1,2,4]triazolo[4,3-a] Pyrazin-8-yl)oxy)phenyl)-4-oxo-1,4-dihydropyridazine-3-carboxamide
(21)1-(4-氯-3-(三氟甲基)苯基)-N-(3-氟-4-((3-甲基-[1,2,4]三唑并[4,3-a]吡嗪-8-基)氧基)苯基)-4-氧代-1,4-二氢哒嗪-3-甲酰胺(21) 1-(4-chloro-3-(trifluoromethyl)phenyl)-N-(3-fluoro-4-((3-methyl-[1,2,4]triazolo[4 ,3-a]pyrazin-8-yl)oxy)phenyl)-4-oxo-1,4-dihydropyridazine-3-carboxamide
(22)1-(4-溴-2-氟苯基)-N-(3-氟-4-((3-甲基-[1,2,4]三唑并[4,3-a]吡嗪-8-基)氧基) 苯基)-4-氧代-1,4-二氢哒嗪-3-甲酰胺(22) 1-(4-bromo-2-fluorophenyl)-N-(3-fluoro-4-((3-methyl-[1,2,4]triazolo[4,3-a] Pyrazin-8-yl)oxy)phenyl)-4-oxo-1,4-dihydropyridazine-3-carboxamide
(23)N-(3-氟-4-((3-甲基-[1,2,4]三唑并[4,3-a]吡嗪-8-基)氧基)苯基)-1-(4-甲氧基苯基)-4-氧代-1,4-二氢哒嗪-3-甲酰胺(23) N-(3-fluoro-4-((3-methyl-[1,2,4]triazolo[4,3-a]pyrazin-8-yl)oxy)phenyl)- 1-(4-Methoxyphenyl)-4-oxo-1,4-dihydropyridazine-3-carboxamide
(24)N-(3-氟-4-((3-甲基-[1,2,4]三唑并[4,3-a]吡嗪-8-基)氧基)苯基)-1-(4-氟苯基)-4-氧代-1,4-二氢哒嗪-3-甲酰胺(24) N-(3-fluoro-4-((3-methyl-[1,2,4]triazolo[4,3-a]pyrazin-8-yl)oxy)phenyl)- 1-(4-fluorophenyl)-4-oxo-1,4-dihydropyridazine-3-carboxamide
(25)4-氧代-1-苯基-N-(4-((3-(三氟甲基)-[1,2,4]三唑并[4,3-a]吡嗪-8-基)氧基) 苯基)-1,4-二氢哒嗪-3-甲酰胺(25) 4-oxo-1-phenyl-N-(4-((3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyrazine-8 -yl)oxy)phenyl)-1,4-dihydropyridazine-3-carboxamide
(26)1-(3-氯-4-氟苯基)-4-氧代-N-(4-((3-(三氟甲基)-[1,2,4]三唑并[4,3-a]吡嗪 -8-基)氧基)苯基)-1,4-二氢哒嗪-3-甲酰胺(26) 1-(3-chloro-4-fluorophenyl)-4-oxo-N-(4-((3-(trifluoromethyl)-[1,2,4]triazolo[4 ,3-a]pyrazin-8-yl)oxy)phenyl)-1,4-dihydropyridazine-3-carboxamide
(27)N-(3-氟-4-((3-(三氟甲基)-[1,2,4]三唑并[4,3-a]吡嗪-8-基)氧基)苯基)-4-氧代-1-苯基-1,4-二氢哒嗪-3-甲酰胺(27) N-(3-fluoro-4-((3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyrazin-8-yl)oxy) Phenyl)-4-oxo-1-phenyl-1,4-dihydropyridazine-3-carboxamide
(28)1-(3-氯-4-氟苯基)-N-(3-氟-4-((3-(三氟甲基)-[1,2,4]三唑并[4,3-a]吡嗪-8- 基)氧基)苯基)-4-氧代-1,4-二氢哒嗪-3-甲酰胺(28) 1-(3-chloro-4-fluorophenyl)-N-(3-fluoro-4-((3-(trifluoromethyl)-[1,2,4]triazolo[4, 3-a]pyrazin-8-yl)oxy)phenyl)-4-oxo-1,4-dihydropyridazine-3-carboxamide
下面合成路线1-3描述了本发明的通式Ⅰ化合物的制备，所有的原料都是通过这些合成式中描述的方法、通过有机化学领域普通技术人员熟知的方法制备的或者可商购。本发明的全部最终化合物都是通过这些合成式中描述的方法或通过与其类似的方法制备的，这些方法是有机化学领域普通技术人员熟知的。这些合成式中应用的全部可变因数如下文的定义或如权利要求中的定义。The following synthetic schemes 1-3 describe the preparation of the compounds of general formula I of the present invention. All starting materials are prepared by the methods described in these synthetic formulas, by methods well known to those skilled in the art of organic chemistry or are commercially available. All final compounds of the present invention are prepared by the methods described in these synthetic formulas or by methods analogous thereto, which methods are well known to those of ordinary skill in the art of organic chemistry. All variable factors used in these synthetic formulae are as defined below or as defined in the claims.
按照本发明的式Ⅰ化合物，当Y为R3如发明内容部分所定义，均可按在路线1的方法由中间体A和中间体B通过取代反应制得。According to the compound of formula I of the present invention, when Y is R3 , as defined in the Summary of the Invention, can be prepared from intermediate A and intermediate B through substitution reactions according to the method in scheme 1.
路线1Route 1
按照本发明的式Ⅰ化合物，中间体A的制备方法如路线2，其他取代基如权利要求中所定义。According to the compound of formula I of the present invention, the preparation method of intermediate A is as shown in Scheme 2, and other substituents are as defined in the claims.
路线2route 2
按照本发明的式Ⅰ化合物，当Y为中间体B的制备方法如路线3，其他取代基如权利要求中所定义。According to the compound of formula I of the present invention, when Y is The preparation method of intermediate B is as in route 3, and other substituents are as defined in the claims.
路线3Route 3
以上三条路线中所有中间体的取代基R1、R2和R3如权利要求中所定义。The substituents R1 , R2 and R3 of all intermediates in the above three routes are as defined in the claims.
而且，按照本发明所属领域的一些通常方法，本发明的通式Ⅰ的含杂芳基取代哒嗪酮结构的三唑并吡嗪类化合物可以与酸生成它的药学上可接受的盐。酸可以包括无机酸或有机酸，与下列酸形成的盐是特别优选的：盐酸、氢溴酸、硫酸、磷酸、甲磺酸、乙磺酸、甲苯磺酸、苯磺酸、萘二磺酸、乙酸、丙酸、乳酸、三氟乙酸、马来酸、柠檬酸、富马酸、洒石酸、苯磺酸、苯甲酸或对甲苯磺酸等。Moreover, according to some common methods in the field of the present invention, the triazolopyrazine compound containing heteroaryl-substituted pyridazinone structure of the general formula I of the present invention can form its pharmaceutically acceptable salt with an acid. The acids may include inorganic or organic acids, the salts with the following acids being particularly preferred: hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, toluenesulfonic acid, benzenesulfonic acid, naphthalene disulfonic acid , acetic acid, propionic acid, lactic acid, trifluoroacetic acid, maleic acid, citric acid, fumaric acid, tartaric acid, benzenesulfonic acid, benzoic acid or p-toluenesulfonic acid, etc.
此外，本发明还包括本发明化合物的前药。依据本发明，前药是通式Ⅰ化合物的衍生物，它们自身可能具有较弱的活性或甚至没有活性，但是在给药后，在生理条件下(例如通过代谢、溶剂分解或另外的方式)被转化成相应的生物活性形式。Furthermore, the present invention also includes prodrugs of the compounds of the present invention. According to the invention, prodrugs are derivatives of the compounds of general formula I, which themselves may have weak activity or even no activity, but after administration, under physiological conditions (for example by metabolism, solvolysis or otherwise) is converted into the corresponding biologically active form.
除非另外指出，本发明所用的术语“卤代”是指氟代、氯代、溴代或碘代；“烷基”是指直链或支链的烷基；“环烷基”是指取代或未取代的环烷基；“烯基”是指直链或支链的烯基；“炔基”是指直链或支链的炔基；“芳基”是指除去芳烃中的一个氢原子而得的有机基团，如苯基、萘基；5-10元杂芳基包括含有一个或多个选自N、O和S的杂原子，其中每个杂芳基的环状体系可以是单环或多环的，环状体系是芳香性的，一共含有5-10个原子，可以举出例如咪唑基、吡啶基、嘧啶基、吡唑基、(1,2,3)-和(1,2,4)-三唑基、吡嗪基、四唑基、呋喃基、噻吩基、异噁唑基、噁唑基、吡唑基、吡咯基、噻唑基、苯并噻吩基、苯并呋喃基、苯并咪唑基、苯并噻唑基、吲哚基、喹啉基等；5-10元杂环基包括含有一个或多个选自N、O和S的杂原子，其中每个杂芳基的环状体系可以是单环或多环的，但是是非芳香性的，环状体系一共含有5-10个原子，可以任选包括1或2个碳碳双键或碳碳叁键，可以举出例如吡咯烷基、吗啉基、哌嗪基、哌啶基、噻唑啉基等。Unless otherwise indicated, the term "halo" used in the present invention refers to fluoro, chloro, bromo or iodo; "alkyl" refers to straight or branched chain alkyl; "cycloalkyl" refers to substituted or unsubstituted cycloalkyl; "alkenyl" refers to straight-chain or branched alkenyl; "alkynyl" refers to straight-chain or branched alkynyl; "aryl" refers to the removal of one hydrogen in aromatic Atom-derived organic groups, such as phenyl, naphthyl; 5-10 membered heteroaryls include one or more heteroatoms selected from N, O and S, wherein the ring system of each heteroaryl can be It is monocyclic or polycyclic, and the ring system is aromatic, containing 5-10 atoms in total, such as imidazolyl, pyridyl, pyrimidyl, pyrazolyl, (1,2,3)- and (1,2,4)-Triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, oxazolyl, pyrazolyl, pyrrolyl, thiazolyl, benzothienyl, Benzofuryl, benzimidazolyl, benzothiazolyl, indolyl, quinolinyl, etc.; 5-10 membered heterocyclic groups include one or more heteroatoms selected from N, O and S, wherein each The ring system of each heteroaryl group can be monocyclic or polycyclic, but is non-aromatic, and the ring system contains 5-10 atoms in total, and can optionally include 1 or 2 carbon-carbon double bonds or carbon-carbon triple bonds. Bonds include, for example, pyrrolidinyl, morpholinyl, piperazinyl, piperidinyl, thiazolinyl and the like.
本发明可以含有上述通式Ⅰ和Ⅱ的三唑并杂环类化合物，及其药学上可接受的盐、水合物或溶剂化物作为活性成份，与药学上可接受的载体或赋型剂混合制备成组合物，并制备成临床上可接受的剂型，上述药学上可接受的赋型剂是指任何可用于药学领域的稀释剂、辅助剂和/或载体。本发明的衍生物可以与其他活性成份组合使用，只要它们不产生其他不利的作用，例如过敏反应。The present invention can contain triazoloheterocyclic compounds of the above general formulas I and II, and pharmaceutically acceptable salts, hydrates or solvates thereof as active ingredients, mixed with pharmaceutically acceptable carriers or excipients to prepare Composition, and prepared into a clinically acceptable dosage form, the above-mentioned pharmaceutically acceptable excipient refers to any diluent, adjuvant and/or carrier that can be used in the field of pharmacy. The derivatives according to the invention can be used in combination with other active ingredients, as long as they do not produce other adverse effects, such as allergic reactions.
本发明的药用组合物可配制成若干种剂型，其中含有药物领域中一些常用的赋形剂。如上所述的若干种剂型可以采用注射剂、片剂、胶囊剂、气雾剂、栓剂、膜剂、滴丸剂、外用搽剂、软膏剂等剂型药物。The pharmaceutical composition of the present invention can be formulated into several dosage forms, which contain some commonly used excipients in the pharmaceutical field. Several dosage forms as mentioned above can adopt dosage forms such as injection, tablet, capsule, aerosol, suppository, film, dripping pill, external liniment, ointment and so on.
用于本发明药物组合物的载体是药物领域中可得到的常见类型，包括：粘合剂、润滑剂、崩解剂、助溶剂、稀释剂、稳定剂、悬浮剂、无色素、矫味剂、防腐剂、加溶剂和基质等。药物制剂可以经口服或胃肠外方式(例如静脉内、皮下、腹膜内或局部)给药，如果某些药物在胃部条件下不稳定的，可将其配制成肠衣片剂。The carrier used in the pharmaceutical composition of the present invention is a common type available in the pharmaceutical field, including: binder, lubricant, disintegrant, cosolvent, diluent, stabilizer, suspending agent, pigment-free, correctives , preservatives, solubilizers and substrates, etc. Pharmaceutical preparations can be administered orally or parenterally (eg intravenously, subcutaneously, intraperitoneally or topically), and if certain drugs are unstable under gastric conditions, they can be formulated as enteric-coated tablets.
本发明还涉及通式Ⅰ的化合物具有强的抑制c-Met激酶的作用，并且还涉及该类化合物及其药学上可接受的盐、水合物在制备治疗由于c-Met激酶异常高表达所引起疾病的药物中的用途，特别是在制备治疗和/或预防癌症的药物中的用途。The present invention also relates to the compound of the general formula I having a strong inhibitory effect on c-Met kinase, and also relates to the preparation and treatment of such compounds and their pharmaceutically acceptable salts and hydrates caused by abnormally high expression of c-Met kinase. Use in medicines for diseases, especially in the preparation of medicines for treating and/or preventing cancer.
具体实施方式：Detailed ways:
实施例旨在阐述而不是限制本发明的范围。化合物的核磁共振氢谱用BrukerARX-300测定，质谱用Agilent 1100LC/MSD测定；所用试剂均为分析纯或化学纯。The examples are intended to illustrate, not limit, the scope of the invention. The proton nuclear magnetic resonance spectrum of the compound was determined by BrukerARX-300, and the mass spectrum was determined by Agilent 1100LC/MSD; the reagents used were analytically or chemically pure.
按照制备通法1，分别制得实施例1-28化合物(见表一)。According to Preparation General Method 1, the compounds of Examples 1-28 were respectively prepared (see Table 1).
表一：Table I:
实施例1Example 1
N-(4-([1,2,4]三唑并[4,3-a]吡嗪-8-基)氧基)苯基-4-氧代-1-苯基-1,4-二氢哒嗪-3-甲酰胺N-(4-([1,2,4]triazolo[4,3-a]pyrazin-8-yl)oxy)phenyl-4-oxo-1-phenyl-1,4- Dihydropyridazine-3-carboxamide
步骤一2-氯-3-肼基吡嗪(b)Step one 2-chloro-3-hydrazinopyrazine (b)
将2,3-二氯吡嗪(20g，0.134mol)用乙醇溶解，将水合肼(21g，0.42mol) 少量多次加入其中于85℃回流，TLC检测反应直到反应完全。反应液冷却后，加入冰水中搅拌，析出的固体抽滤，滤饼干燥，得土黄色粉末16.8g，收率为 84.1％。2,3-Dichloropyrazine (20 g, 0.134 mol) was dissolved in ethanol, and hydrazine hydrate (21 g, 0.42 mol) was added in small amounts and refluxed at 85° C., and the reaction was detected by TLC until the reaction was complete. After the reaction solution was cooled, it was added to ice water and stirred, the precipitated solid was filtered with suction, and the filter cake was dried to obtain 16.8 g of khaki powder with a yield of 84.1%.
步骤二8-氯-[1,2,4]三唑并[4,3-a]吡嗪(c)Step 2 8-Chloro-[1,2,4]triazolo[4,3-a]pyrazine (c)
将中间体b(5.0g，0.034mol)加至原甲酸三乙酯(50mL)中，80℃下反应，点板监测反应时间。反应液冷直接抽滤，用石油醚洗涤滤饼，滤饼干燥后得黄色粉末4.8g，产率为90.1％。Intermediate b (5.0 g, 0.034 mol) was added to triethyl orthoformate (50 mL), reacted at 80° C., and the reaction time was monitored by spotting a plate. The reaction liquid was cooled and directly sucked and filtered, the filter cake was washed with petroleum ether, and the filter cake was dried to obtain 4.8 g of yellow powder with a yield of 90.1%.
步骤三4–([1,2,4]三唑并[4,3-a]吡嗪-8-基)氧基苯胺(A)Step 3 4-([1,2,4]triazolo[4,3-a]pyrazin-8-yl)oxyaniline (A)
将对氨基苯酚(0.78g，7.2mmol)和叔丁醇钾(1.46g，13.0mmol)加入烧瓶中，用四氢呋喃做溶剂，在氮气保护下，用冰浴搅拌1h；将中间体c(1g， 6.5mmol)及碘化钾(0.12g，0.72mmol)加入烧瓶中，用四氢呋喃做溶剂，升温至80℃搅拌，将上述反应完的对氨基苯酚加入其中，在氮气保护下反应，点板检测反应进程。反应完成后抽滤，将滤液旋蒸，蒸干后加入少量NaOH水溶液超声，有固体析出，抽滤，滤饼干燥，得灰色固体0.45g，收率为30.6％。Add p-aminophenol (0.78g, 7.2mmol) and potassium tert-butoxide (1.46g, 13.0mmol) into the flask, use tetrahydrofuran as solvent, and stir in an ice bath for 1h under nitrogen protection; intermediate c (1g, 6.5mmol) and potassium iodide (0.12g, 0.72mmol) were added to the flask, using tetrahydrofuran as a solvent, the temperature was raised to 80°C and stirred, and the p-aminophenol that had been reacted above was added therein, reacted under the protection of nitrogen, and detected the reaction process by pointing a plate. After the reaction was completed, suction filtered, and the filtrate was rotary evaporated. After evaporation to dryness, a small amount of NaOH aqueous solution was added for sonication. Solids were precipitated. After suction filtration, the filter cake was dried to obtain 0.45 g of gray solid, with a yield of 30.6%.
步骤四(E)-3-氧代-2-(苯基二氮烯基)丁酸乙酯(i)Step 4 (E)-3-oxo-2-(phenyldiazenyl) ethyl butyrate (i)
在冰浴条件下向水(15ml)和盐酸(15ml)的混合液中加入苯胺(5g，0.054 mol)，搅拌15分钟后将NaNO2(3.7g，0.054mol)溶解在水(15ml)中后逐滴加入上面的混合液中搅拌15分钟，如有沉淀没有溶解完，则将其抽滤后取滤液：用另一个圆底烧瓶将乙酰乙酸乙酯(4.0g)溶解在乙醇(100ml)中并加入乙酸钾(53g，0.54mol)搅拌10分钟后，向此烧瓶中逐滴加入制备好的重氮盐溶液，反应在室温下进行，滴加完后点板监测反应进程，在反应过程中有大量沉淀析出，向其中加入大量的水搅拌后抽滤得到黄色固体11.2g，收率 88.5％。Add aniline (5g, 0.054 mol) to the mixed solution of water (15ml) and hydrochloric acid (15ml) under ice-bath condition, after stirring for 15 minutes, dissolve NaNO2 (3.7g, 0.054mol) in water (15ml) Add dropwise to the above mixed solution and stir for 15 minutes. If there is a precipitate that has not been dissolved, it is suction filtered and the filtrate is taken: Dissolve ethyl acetoacetate (4.0g) in ethanol (100ml) with another round bottom flask And after adding potassium acetate (53g, 0.54mol) and stirring for 10 minutes, in this flask, add dropwise the prepared diazonium salt solution, and the reaction is carried out at room temperature. A large amount of precipitates were precipitated, and a large amount of water was added thereto, stirred, and suction filtered to obtain 11.2 g of a yellow solid, with a yield of 88.5%.
步骤五(E)-5-(二甲基氨基)-3-氧代-2-((E)-苯基二氮烯基)戊-4-烯酸乙酯(j)Step 5 (E)-5-(dimethylamino)-3-oxo-2-((E)-phenyldiazenyl)pent-4-enoic acid ethyl ester (j)
将中间体h(6g，0.0256)加入烧瓶中，加入DMF-DMA(80ml)，升温至80℃反应，点板监测反应进程。将反应液冷却后，加入到200ml石油醚里洗去原料及色素，抽滤后得黄色固体7g，收率95.6％。Intermediate h (6g, 0.0256) was added to the flask, DMF-DMA (80ml) was added, the temperature was raised to 80°C for reaction, and the reaction progress was monitored by spotting a plate. After the reaction solution was cooled, it was added to 200 ml of petroleum ether to wash away the raw materials and pigments, and 7 g of a yellow solid was obtained after suction filtration, with a yield of 95.6%.
步骤六4-氧代-1-苯基-1,4-二氢哒嗪-3-羧酸乙酯(k)Step six 4-oxo-1-phenyl-1,4-dihydropyridazine-3-carboxylic acid ethyl ester (k)
将中间体i(5g，0.0173mol)加入到100mL的乙醇中，加入10％的氢氧化钠溶液，升温至80℃回流，点板监测反应进程。反应完后将反应液旋蒸，旋干后加入饱和食盐水有大量固体析出，抽滤，得白色固体，收率85％Intermediate i (5 g, 0.0173 mol) was added to 100 mL of ethanol, 10% sodium hydroxide solution was added, the temperature was raised to 80° C. to reflux, and the reaction progress was monitored by pointing a plate. After the reaction, the reaction solution was rotary evaporated, and after spinning to dryness, a large amount of solid was precipitated by adding saturated brine, and filtered by suction to obtain a white solid with a yield of 85%.
步骤七4-氧代-1-苯基-1,4-二氢哒嗪-3-羧酸(m)Step seven 4-oxo-1-phenyl-1,4-dihydropyridazine-3-carboxylic acid (m)
将乙醇(100mL)和水(10mL)加入到含有中间体j(4g，0.016mol) 的烧瓶中，然后分批加入氢氧化钠(1.3g，0.032mol)，反应在37℃进行室内温度。随着反应的进行，产生大量沉淀物。加入水溶解沉淀物，然后加入活性炭以除去色素和将其从水溶液中除去。抽滤后取滤液，用盐酸调pH3-4得到白色固体，抽滤后滤饼干燥，得3.3g产物，收率93％Ethanol (100 mL) and water (10 mL) were added to a flask containing intermediate j (4 g, 0.016 mol), then sodium hydroxide (1.3 g, 0.032 mol) was added in portions, and the reaction was carried out at 37°C at room temperature. As the reaction proceeded, a large amount of precipitate was produced. Water is added to dissolve the precipitate, then charcoal is added to remove the pigment and remove it from the aqueous solution. After suction filtration, the filtrate was taken, and the pH was adjusted to 3-4 with hydrochloric acid to obtain a white solid. After suction filtration, the filter cake was dried to obtain 3.3 g of the product, and the yield was 93%.
步骤八4-氧代-1-苯基-1,4-二氢哒嗪-3-碳酰氯(B)Step 8 4-oxo-1-phenyl-1,4-dihydropyridazine-3-carbonyl chloride (B)
将中间体k(0.05g，0.23mmol)加入二氯甲烷(10ml)中，加入DMF(0.023 mmol)然后加入适当的草酰氯并通过TLC监测。该溶液无需进一步纯化即可用于下一步。Intermediate k (0.05g, 0.23mmol) was added in dichloromethane (10ml), DMF (0.023mmol) was added followed by the appropriate oxalyl chloride and monitored by TLC. This solution was used in the next step without further purification.
步骤九N-(4-([1,2,4]三唑并[4,3-a]吡嗪-8-基)氧基)苯基-4-氧代-1-苯基-1,4- 二氢哒嗪-3-甲酰胺(I)Step 9 N-(4-([1,2,4]triazolo[4,3-a]pyrazin-8-yl)oxy)phenyl-4-oxo-1-phenyl-1, 4-Dihydropyridazine-3-carboxamide (I)
将中间体A(0.05g，0.22mmol)和N,N-二异丙基乙胺(0.5mL，3mmol) 加至10mL二氯甲烷中，将中间体B(0.23mmol)的二氯甲烷(10mL)溶液在0℃下滴加至上述二氯甲烷溶液中，滴加完毕，缓慢升至室温，反应1-2小时。反应完毕后，加入5mL5％的氢氧化钠水水溶液，搅拌半小时，转移至250 mL分液漏斗中，再加入25mL二氯甲烷，用饱和碳酸钠水溶液洗三次(50 mL*3)，饱和食盐水洗一次，减压蒸去二氯甲烷，得淡黄色固体粉末0.05g，收率46.14％。Intermediate A (0.05g, 0.22mmol) and N,N-diisopropylethylamine (0.5mL, 3mmol) were added to 10mL of dichloromethane, Intermediate B (0.23mmol) in dichloromethane (10mL ) solution was added dropwise to the above dichloromethane solution at 0°C, after the dropwise addition was completed, it was slowly raised to room temperature, and reacted for 1-2 hours. After the reaction is complete, add 5 mL of 5% aqueous sodium hydroxide solution, stir for half an hour, transfer to a 250 mL separatory funnel, add 25 mL of dichloromethane, wash with saturated aqueous sodium carbonate three times (50 mL*3), and wash with saturated salt After washing once with water, dichloromethane was evaporated under reduced pressure to obtain 0.05 g of light yellow solid powder with a yield of 46.14%.
ESI-MS m/z:425.41；1H NMR(400MHz,DMSO-d6)δ11.80(s,1H),9.34(s,1H), 8.89(d,J＝7.7Hz,1H),8.18(d,J＝4.4Hz,1H),7.69(d,J＝8.1Hz,4H),7.49(t,J ＝7.6Hz,2H),7.40(d,J＝7.4Hz,1H),7.24(t,J＝6.0Hz,3H),6.80(d,J＝7.6Hz, 1H).ESI-MS m/z: 425.41;1 H NMR (400MHz, DMSO-d6 ) δ11.80(s, 1H), 9.34(s, 1H), 8.89(d, J=7.7Hz, 1H), 8.18( d,J=4.4Hz,1H),7.69(d,J=8.1Hz,4H),7.49(t,J=7.6Hz,2H),7.40(d,J=7.4Hz,1H),7.24(t, J＝6.0Hz, 3H), 6.80(d, J＝7.6Hz, 1H).
按照实施例1的方法，首先以不同取代的苯胺反应制得不同取代的哒嗪酮酸；之后再与中间体A按照步骤九的方法进行反应，分别制得实施例2～12化合物According to the method of Example 1, first react with different substituted anilines to prepare different substituted pyridazinone acids; then react with intermediate A according to the method of step 9 to prepare the compounds of Examples 2-12 respectively
实施例(2)Example (2)
N-(4-([1,2,4]三唑并[4,3-a]吡嗪-8-基)氧基)苯基-1-(3-氯-4-氟苯基)-4-氧代-1,4-二氢哒嗪-3-甲酰胺N-(4-([1,2,4]triazolo[4,3-a]pyrazin-8-yl)oxy)phenyl-1-(3-chloro-4-fluorophenyl)- 4-oxo-1,4-dihydropyridazine-3-carboxamide
ESI-MS m/z:477.84；1H NMR(400MHz,DMSO-d6)δ11.74(s,1H),9.35(s,1H), 8.91–8.82(m,1H),8.20(d,J＝4.5Hz,1H),8.02(t,J＝4.5Hz,1H),7.72(d,J＝8.7Hz,3H),7.57(s,1H),7.29(d,J＝9.1Hz,3H),6.82(d,J＝7.9Hz,1H).ESI-MS m/z:477.84;1 H NMR (400MHz,DMSO-d6 )δ11.74(s,1H),9.35(s,1H), 8.91–8.82(m,1H),8.20(d,J =4.5Hz,1H),8.02(t,J=4.5Hz,1H),7.72(d,J=8.7Hz,3H),7.57(s,1H),7.29(d,J=9.1Hz,3H), 6.82(d,J=7.9Hz,1H).
实施例(3)Example (3)
N-(4-([1,2,4]三唑并[4,3-a]吡嗪-8-基)氧基)苯基-1-(4-氯-3-(三氟甲基)苯基)-4-氧代-1-,4-二氢哒嗪-3-甲酰胺N-(4-([1,2,4]triazolo[4,3-a]pyrazin-8-yl)oxy)phenyl-1-(4-chloro-3-(trifluoromethyl )phenyl)-4-oxo-1-,4-dihydropyridazine-3-carboxamide
ESI-MS m/z:527.85；1H NMR(400MHz,DMSO-d6)δ11.71(s,1H),9.39(s,1H), 9.03(d,J＝7.9Hz,1H),8.23(d,J＝5.2Hz,2H),8.09(d,J＝8.9Hz,1H),7.92(d,J ＝8.9Hz,1H),7.74(d,J＝8.3Hz,2H),7.30(d,J＝8.6Hz,3H),6.86(d,J＝7.7Hz, 1H).ESI-MS m/z: 527.85;1 H NMR (400MHz, DMSO-d6 ) δ11.71(s, 1H), 9.39(s, 1H), 9.03(d, J=7.9Hz, 1H), 8.23( d,J=5.2Hz,2H),8.09(d,J=8.9Hz,1H),7.92(d,J=8.9Hz,1H),7.74(d,J=8.3Hz,2H),7.30(d, J＝8.6Hz, 3H), 6.86(d, J＝7.7Hz, 1H).
实施例(4)Example (4)
N-(4-([1,2,4]三唑并[4,3-a]吡嗪-8-基)氧基)苯基-1-(4-氯-3-(三氟甲基)苯基)-4-氧代-1-,4-二氢哒嗪-3-甲酰胺N-(4-([1,2,4]triazolo[4,3-a]pyrazin-8-yl)oxy)phenyl-1-(4-chloro-3-(trifluoromethyl )phenyl)-4-oxo-1-,4-dihydropyridazine-3-carboxamide
ESI-MS m/z:522.29；1H NMR(400MHz,DMSO-d6)δ11.60(s,1H),9.38(s,1H), 8.65(s,1H),8.23(d,J＝4.2Hz,1H),7.85(d,J＝10.2Hz,1H),7.71(d,J＝8.8Hz, 3H),7.62(s,1H),7.28(s,3H),6.81(d,J＝8.4Hz,1H).ESI-MS m/z: 522.29;1 H NMR (400MHz, DMSO-d6 ) δ11.60(s, 1H), 9.38(s, 1H), 8.65(s, 1H), 8.23(d, J=4.2 Hz,1H),7.85(d,J=10.2Hz,1H),7.71(d,J=8.8Hz,3H),7.62(s,1H),7.28(s,3H),6.81(d,J=8.4 Hz,1H).
实施例(5)Example (5)
N-(4-([1,2,4]三唑并[4,3-a]吡嗪-8-基)氧基)苯基-1-(4-甲氧基苯基)-4-氧代-1,4-二氢哒嗪-3-甲酰胺N-(4-([1,2,4]triazolo[4,3-a]pyrazin-8-yl)oxy)phenyl-1-(4-methoxyphenyl)-4- Oxo-1,4-dihydropyridazine-3-carboxamide
ESI-MS m/z:455.43；1H NMR(400MHz,DMSO-d6)δ11.97(s,1H),9.39(s,1H), 8.84(s,1H),8.23(s,1H),7.70(d,J＝37.9Hz,3H),7.44(s,1H),7.30(s,2H),7.08 (s,2H),6.84(s,2H),3.77(s,3H).ESI-MS m/z: 455.43;1 H NMR (400MHz, DMSO-d6 ) δ11.97(s,1H), 9.39(s,1H), 8.84(s,1H), 8.23(s,1H), 7.70(d,J=37.9Hz,3H),7.44(s,1H),7.30(s,2H),7.08(s,2H),6.84(s,2H),3.77(s,3H).
实施例(6)Example (6)
N-(4-([1,2,4]三唑并[4,3-a]吡嗪-8-基)氧基)苯基-1-(4-氟苯基)-4-氧代-1,4-二氢哒嗪-3-甲酰胺N-(4-([1,2,4]triazolo[4,3-a]pyrazin-8-yl)oxy)phenyl-1-(4-fluorophenyl)-4-oxo -1,4-dihydropyridazine-3-carboxamide
ESI-MS m/z:443.40；1H NMR(400MHz,DMSO-d6)δ11.81(s,1H),9.37(s,1H), 8.88(s,1H),8.23(s,1H),7.77(d,J＝17.4Hz,4H),7.39(s,2H),7.29(s,3H),6.84 (s,1H).ESI-MS m/z: 443.40;1 H NMR (400MHz, DMSO-d6 ) δ11.81(s,1H), 9.37(s,1H), 8.88(s,1H), 8.23(s,1H), 7.77(d,J=17.4Hz,4H),7.39(s,2H),7.29(s,3H),6.84(s,1H).
实施例(7)Example (7)
N-(4-([1,2,4]三唑并[4,3-a]吡嗪-8-基)氧基-3-氟苯基)-4-氧代-1-苯基-1,4-二氢哒嗪-3-甲酰胺N-(4-([1,2,4]triazolo[4,3-a]pyrazin-8-yl)oxy-3-fluorophenyl)-4-oxo-1-phenyl- 1,4-Dihydropyridazine-3-carboxamide
ESI-MS m/z:443.40；1H NMR(400MHz,DMSO-d6)δ11.97(s,1H),9.42(s,1H), 8.94(d,J＝7.9Hz,1H),8.33–8.25(m,1H),7.89(d,J＝12.5Hz,1H),7.74(d,J＝ 7.8Hz,2H),7.55(t,J＝7.8Hz,2H),7.45(s,3H),7.32(s,1H),6.86(d,J＝7.8Hz, 1H).ESI-MS m/z: 443.40;1 H NMR (400MHz, DMSO-d6 ) δ11.97(s, 1H), 9.42(s, 1H), 8.94(d, J＝7.9Hz, 1H), 8.33– 8.25(m,1H),7.89(d,J=12.5Hz,1H),7.74(d,J=7.8Hz,2H),7.55(t,J=7.8Hz,2H),7.45(s,3H), 7.32(s,1H),6.86(d,J＝7.8Hz, 1H).
实施例(8)Example (8)
N-(4-([1,2,4]三唑并[4,3-a]吡嗪-8-基)氧基-3-氟苯基)-1-(3-氯-4-氟苯基)-4-氧代 -1-,4-二氢哒嗪-3-甲酰胺N-(4-([1,2,4]triazolo[4,3-a]pyrazin-8-yl)oxy-3-fluorophenyl)-1-(3-chloro-4-fluoro Phenyl)-4-oxo-1-,4-dihydropyridazine-3-carboxamide
ESI-MS m/z:495.83；1H NMR(400MHz,DMSO-d6)δ11.86(s,1H),9.42(s,1H), 8.93(d,J＝8.2Hz,1H),8.29(s,1H),8.06(s,1H),7.88(d,J＝12.2Hz,1H),7.78(d, J＝6.4Hz,1H),7.62(t,J＝9.1Hz,1H),7.45(s,2H),7.31(s,1H),6.86(d,J＝7.8 Hz,1H).ESI-MS m/z: 495.83;1 H NMR (400MHz, DMSO-d6 ) δ11.86(s, 1H), 9.42(s, 1H), 8.93(d, J=8.2Hz, 1H), 8.29( s,1H),8.06(s,1H),7.88(d,J=12.2Hz,1H),7.78(d,J=6.4Hz,1H),7.62(t,J=9.1Hz,1H),7.45( s,2H),7.31(s,1H),6.86(d,J=7.8 Hz,1H).
实施例(9)Example (9)
N-(4-([1,2,4]三唑并[4,3-a]吡嗪-8-基)氧基-3-氟苯基)-1-(4-氯-3-(三氟甲基)苯基)-4-氧代-1,4-二氢哒嗪-3-甲酰胺N-(4-([1,2,4]triazolo[4,3-a]pyrazin-8-yl)oxy-3-fluorophenyl)-1-(4-chloro-3-( Trifluoromethyl)phenyl)-4-oxo-1,4-dihydropyridazine-3-carboxamide
ESI-MS m/z:545.84；1H NMR(400MHz,DMSO-d6)δ11.83(s,1H),9.42(s,1H), 9.03(d,J＝7.8Hz,1H),8.29(d,J＝4.7Hz,1H),8.22(s,1H),8.09(d,J＝7.9Hz, 1H),7.93–7.86(m,2H),7.45(s,2H),7.31(d,J＝4.5Hz,1H),6.86(d,J＝7.8Hz, 1H).ESI-MS m/z: 545.84;1 H NMR (400MHz, DMSO-d6 ) δ11.83(s, 1H), 9.42(s, 1H), 9.03(d, J=7.8Hz, 1H), 8.29( d,J=4.7Hz,1H),8.22(s,1H),8.09(d,J=7.9Hz,1H),7.93–7.86(m,2H),7.45(s,2H),7.31(d,J ＝4.5Hz, 1H), 6.86(d, J＝7.8Hz, 1H).
实施例(10)Example (10)
N-(4-([1,2,4]三唑并[4,3-a]吡嗪-8-基)氧基-3-氟苯基)-1-(4-溴-2-氟苯基)-4-氧代 -1-,4-二氢哒嗪-3-甲酰胺N-(4-([1,2,4]triazolo[4,3-a]pyrazin-8-yl)oxy-3-fluorophenyl)-1-(4-bromo-2-fluoro Phenyl)-4-oxo-1-,4-dihydropyridazine-3-carboxamide
ESI-MS m/z:540.28；1HNMR(400MHz,DMSO-d6)δ11.76(s,1H),9.40(d,J＝ 16.9Hz,1H),8.67(s,1H),8.25(d,J＝23.5Hz,1H),7.88(d,J＝11.3Hz,1H),7.65 (d,J＝21.8Hz,1H),7.44(s,1H),7.29(d,J＝11.9Hz,1H),6.99(s,1H),6.84(s, 1H),6.46–6.33(m,1H),5.33(s,1H).ESI-MS m/z: 540.28;1 HNMR (400MHz, DMSO-d6 ) δ11.76(s, 1H), 9.40(d, J＝ 16.9Hz, 1H), 8.67(s, 1H), 8.25(d ,J=23.5Hz,1H),7.88(d,J=11.3Hz,1H),7.65(d,J=21.8Hz,1H),7.44(s,1H),7.29(d,J=11.9Hz,1H ),6.99(s,1H),6.84(s,1H),6.46–6.33(m,1H),5.33(s,1H).
实施例(11)Example (11)
N-(4-([1,2,4]三唑并[4,3-a]吡嗪-8-基)氧基-3-氟苯基)-1-(4-甲氧基苯基)-4-氧代 -1,4-二氢哒嗪-3-甲酰胺N-(4-([1,2,4]triazolo[4,3-a]pyrazin-8-yl)oxy-3-fluorophenyl)-1-(4-methoxyphenyl )-4-oxo-1,4-dihydropyridazine-3-carboxamide
ESI-MS m/z:473.42；1H NMR(400MHz,DMSO-d6)δ12.09(s,1H),9.41(d,J＝12.1Hz,1H),8.86(s,1H),8.28(s,1H),7.88(s,1H),7.65(s,2H),7.45(s,1H),7.31 (s,1H),7.08(s,2H),6.86(s,1H),6.57(s,1H),3.77(s,3H).ESI-MS m/z: 473.42;1 H NMR (400MHz, DMSO-d6 ) δ12.09(s, 1H), 9.41(d, J=12.1Hz, 1H), 8.86(s, 1H), 8.28( s,1H),7.88(s,1H),7.65(s,2H),7.45(s,1H),7.31(s,1H),7.08(s,2H),6.86(s,1H),6.57(s ,1H),3.77(s,3H).
实施例(12)Example (12)
N-(4-([1,2,4]三唑并[4,3-a]吡嗪-8-基)氧基-3-氟苯基)-1-(4-氟苯基)-4-氧代-1,4-二氢哒嗪-3-甲酰胺N-(4-([1,2,4]triazolo[4,3-a]pyrazin-8-yl)oxy-3-fluorophenyl)-1-(4-fluorophenyl)- 4-oxo-1,4-dihydropyridazine-3-carboxamide
ESI-MS m/z:461.39；1H NMR(400MHz,DMSO-d6)δ11.96(s,1H),9.42(s,1H), 8.90(d,J＝8.0Hz,1H),8.29(s,1H),7.88(d,J＝12.5Hz,1H),7.79(s,2H),7.47– 7.37(m,4H),7.31(d,J＝4.7Hz,1H),6.86(d,J＝8.0Hz,1H).ESI-MS m/z: 461.39;1 H NMR (400MHz, DMSO-d6 ) δ11.96(s, 1H), 9.42(s, 1H), 8.90(d, J=8.0Hz, 1H), 8.29( s,1H),7.88(d,J=12.5Hz,1H),7.79(s,2H),7.47– 7.37(m,4H),7.31(d,J=4.7Hz,1H),6.86(d,J =8.0Hz,1H).
实施例(13)Example (13)
N-(4-((3-甲基-[1,2,4]三唑并[4,3-a]吡嗪-8-基)氧基)苯基)-4-氧代-1-苯基-1,4-二氢哒嗪-3-甲酰胺N-(4-((3-Methyl-[1,2,4]triazolo[4,3-a]pyrazin-8-yl)oxy)phenyl)-4-oxo-1- Phenyl-1,4-dihydropyridazine-3-carboxamide
步骤十8-氯-3-甲基-[1,2,4]三唑并[4,3-a]吡嗪(d)Step 10 8-Chloro-3-methyl-[1,2,4]triazolo[4,3-a]pyrazine (d)
将中间体b(5.0g，0.034mol)加至原乙酸三乙酯(50mL)中，80℃下反应，点板监测反应时间。反应液冷直接抽滤，用石油醚洗涤滤饼，滤饼干燥后得黄色粉末4.9g，产率为84.0％。Intermediate b (5.0 g, 0.034 mol) was added to triethyl orthoacetate (50 mL), and reacted at 80° C., and the reaction time was monitored by point plate. The reaction solution was cooled and directly suction-filtered, the filter cake was washed with petroleum ether, and the filter cake was dried to obtain 4.9 g of yellow powder with a yield of 84.0%.
按照实施例1的方法，进行后续反应，分别制得实施例14～24化合物。According to the method of Example 1, subsequent reactions were carried out to obtain the compounds of Examples 14-24 respectively.
ESI-MS m/z:439.44；1H NMR(400MHz,DMSO-d6)δ11.85(s,1H),8.93(d,J＝ 8.0Hz,1H),8.10(s,1H),7.77–7.64(m,4H),7.60–7.40(m,4H),7.28(d,J＝7.0 Hz,2H),6.85(d,J＝8.2Hz,1H),2.66(s,3H).ESI-MS m/z: 439.44;1 H NMR (400MHz, DMSO-d6 ) δ11.85(s, 1H), 8.93(d, J＝ 8.0Hz, 1H), 8.10(s, 1H), 7.77– 7.64(m, 4H), 7.60–7.40(m, 4H), 7.28(d, J=7.0 Hz, 2H), 6.85(d, J=8.2Hz, 1H), 2.66(s, 3H).
实施例(14)Example (14)
1-(3-氯-4-氟苯基)-N-(4-((3-甲基-[1,2,4]三唑并[4,3-a]吡嗪-8-基)氧基)苯基)-4-氧代-1,4-二氢哒嗪-3-甲酰胺1-(3-chloro-4-fluorophenyl)-N-(4-((3-methyl-[1,2,4]triazolo[4,3-a]pyrazin-8-yl) Oxy)phenyl)-4-oxo-1,4-dihydropyridazine-3-carboxamide
ESI-MS m/z:491.87ESI-MS m/z:491.87
实施例(15)Example (15)
1-(4-氯-3-(三氟甲基)苯基)-N-(4-((3-甲基-[1,2,4]三唑并[4,3-a]吡嗪-8-基)氧基)苯基基)-4-氧代-1,4-二氢哒嗪-3-甲酰胺1-(4-chloro-3-(trifluoromethyl)phenyl)-N-(4-((3-methyl-[1,2,4]triazolo[4,3-a]pyrazine -8-yl)oxy)phenyl)-4-oxo-1,4-dihydropyridazine-3-carboxamide
ESI-MS m/z:541.88；1H NMR(400MHz,DMSO-d6)δ11.72(s,1H),8.70(d,J＝8.1Hz,1H),8.22(s,1H),8.11(s,1H),8.03(s,1H),7.93(d,J＝8.4Hz,2H),7.80(d, J＝8.7Hz,1H),7.74(d,J＝8.1Hz,1H),7.28(d,J＝7.2Hz,2H),6.29(d,J＝8.1 Hz,1H),2.66(s,3H).ESI-MS m/z: 541.88;1 H NMR (400MHz, DMSO-d6 ) δ11.72(s, 1H), 8.70(d, J=8.1Hz, 1H), 8.22(s, 1H), 8.11( s,1H),8.03(s,1H),7.93(d,J=8.4Hz,2H),7.80(d,J=8.7Hz,1H),7.74(d,J=8.1Hz,1H),7.28( d,J=7.2Hz,2H),6.29(d,J=8.1Hz,1H),2.66(s,3H).
实施例(16)Example (16)
1-(4-溴-2-氟苯基)-N-(4-((3-甲基-[1,2,4]三唑并[4,3-a]吡嗪-8-基)氧基)苯基)-4-氧代-1,4-二氢哒嗪-3-甲酰胺1-(4-bromo-2-fluorophenyl)-N-(4-((3-methyl-[1,2,4]triazolo[4,3-a]pyrazin-8-yl) Oxy)phenyl)-4-oxo-1,4-dihydropyridazine-3-carboxamide
ESI-MS m/z:536.32ESI-MS m/z:536.32
实施例(17)Example (17)
1-(4-甲氧基苯基)-N-(4-((3-甲基-[1,2,4]三唑并[4,3-a]吡嗪-8-基)氧基)苯基)-4-氧代-1-,4-二氢哒嗪-3-甲酰胺1-(4-methoxyphenyl)-N-(4-((3-methyl-[1,2,4]triazolo[4,3-a]pyrazin-8-yl)oxy )phenyl)-4-oxo-1-,4-dihydropyridazine-3-carboxamide
ESI-MS m/z:469.46；1H NMR(400MHz,DMSO-d6)δ11.85(s,1H),8.89(s,1H), 7.75(s,2H),7.66(s,2H),7.53(s,2H),7.43(s,2H),7.29(s,2H),6.75(s,1H),2.67 (s,3H),1.21(s,3H).ESI-MS m/z: 469.46;1 H NMR (400MHz, DMSO-d6 ) δ11.85(s,1H), 8.89(s,1H), 7.75(s,2H), 7.66(s,2H), 7.53(s,2H),7.43(s,2H),7.29(s,2H),6.75(s,1H),2.67(s,3H),1.21(s,3H).
实施例(18)Example (18)
1-(4-氟苯基)-N-(4-((3-甲基-[1,2,4]三唑并[4,3-a]吡嗪-8-基)氧基)苯基)-4-氧代 -1-,4-二氢哒嗪-3-甲酰胺1-(4-fluorophenyl)-N-(4-((3-methyl-[1,2,4]triazolo[4,3-a]pyrazin-8-yl)oxy)benzene base)-4-oxo-1-,4-dihydropyridazine-3-carboxamide
ESI-MS m/z:457.43；1H NMR(400MHz,DMSO-d6)δ11.85(s,1H),8.90(s,1H), 8.52(s,1H),8.10(s,1H),7.80–7.72(m,3H),7.61(s,1H),7.40(s,1H),7.29(s, 2H),6.85(d,J＝8.3Hz,1H),6.27(s,1H),2.66(s,3H).ESI-MS m/z: 457.43;1 H NMR (400MHz, DMSO-d6 ) δ11.85(s,1H),8.90(s,1H), 8.52(s,1H),8.10(s,1H), 7.80–7.72(m,3H),7.61(s,1H),7.40(s,1H),7.29(s,2H),6.85(d,J＝8.3Hz,1H),6.27(s,1H),2.66 (s,3H).
实施例(19)Example (19)
N-(3-氟-4-((3-甲基-[1,2,4]三唑并[4,3-a]吡嗪-8-基)氧基)苯基)-4-氧代-1-苯基 -1-,4-二氢哒嗪-3-甲酰胺N-(3-fluoro-4-((3-methyl-[1,2,4]triazolo[4,3-a]pyrazin-8-yl)oxy)phenyl)-4-oxo Substituent-1-phenyl-1-,4-dihydropyridazine-3-carboxamide
ESI-MS m/z:457.43；1H NMR(400MHz,DMSO-d6)δ12.01(s,1H),8.95(d,J＝ 7.7Hz,1H),8.16(s,1H),7.88(d,J＝12.6Hz,1H),7.74(d,J＝7.9Hz,2H),7.54(d, J＝8.1Hz,2H),7.44(s,3H),7.31(s,1H),6.86(d,J＝7.7Hz,1H),2.67(s,3H).ESI-MS m/z: 457.43;1 H NMR (400MHz, DMSO-d6 ) δ12.01(s, 1H), 8.95(d, J=7.7Hz, 1H), 8.16(s, 1H), 7.88( d,J=12.6Hz,1H),7.74(d,J=7.9Hz,2H),7.54(d,J=8.1Hz,2H),7.44(s,3H),7.31(s,1H),6.86( d,J=7.7Hz,1H),2.67(s,3H).
实施例(20)Example (20)
1-(3-氯-4-氟苯基)-N-(3-氟-4-((3-甲基-[1,2,4]三唑并[4,3-a]吡嗪-8-基)氧基)苯基)-4-氧代-1,4-二氢哒嗪-3-甲酰胺1-(3-chloro-4-fluorophenyl)-N-(3-fluoro-4-((3-methyl-[1,2,4]triazolo[4,3-a]pyrazine- 8-yl)oxy)phenyl)-4-oxo-1,4-dihydropyridazine-3-carboxamide
ESI-MS m/z:509.86；1H NMR(400MHz,DMSO-d6)δ11.88(s,1H),8.13(s,1H), 8.05(s,1H),7.87(d,J＝12.1Hz,1H),7.78(s,1H),7.60(s,2H),7.45(s,2H),7.30 (s,1H),6.85(s,1H),2.67(s,3H).ESI-MS m/z: 509.86;1 H NMR (400MHz, DMSO-d6 ) δ11.88(s, 1H), 8.13(s, 1H), 8.05(s, 1H), 7.87(d, J=12.1 Hz,1H),7.78(s,1H),7.60(s,2H),7.45(s,2H),7.30(s,1H),6.85(s,1H),2.67(s,3H).
实施例(21)Example (21)
1-(4-氯-3-(三氟甲基)苯基)-N-(3-氟-4-((3-甲基-[1,2,4]三唑并[4,3-a]吡嗪-8-基)氧基)苯基)-4-氧代-1,4-二氢哒嗪-3-甲酰胺1-(4-chloro-3-(trifluoromethyl)phenyl)-N-(3-fluoro-4-((3-methyl-[1,2,4]triazolo[4,3- a] pyrazin-8-yl)oxy)phenyl)-4-oxo-1,4-dihydropyridazine-3-carboxamide
ESI-MS m/z:559.87；1H NMR(400MHz,DMSO-d6)δ11.84(s,1H),9.02(s,1H), 8.21(s,1H),8.10(d,J＝22.5Hz,2H),7.88(d,J＝19.2Hz,2H),7.44(s,2H),7.30 (s,1H),6.88(s,1H),2.67(s,3H).ESI-MS m/z: 559.87;1 H NMR (400MHz, DMSO-d6 ) δ11.84(s, 1H), 9.02(s, 1H), 8.21(s, 1H), 8.10(d, J=22.5 Hz,2H),7.88(d,J=19.2Hz,2H),7.44(s,2H),7.30(s,1H),6.88(s,1H),2.67(s,3H).
实施例(22)Example (22)
1-(4-溴-2-氟苯基)-N-(3-氟-4-((3-甲基-[1,2,4]三唑并[4,3-a]吡嗪-8-基)氧基)苯基)-4-氧代-1,4-二氢哒嗪-3-甲酰胺1-(4-bromo-2-fluorophenyl)-N-(3-fluoro-4-((3-methyl-[1,2,4]triazolo[4,3-a]pyrazine- 8-yl)oxy)phenyl)-4-oxo-1,4-dihydropyridazine-3-carboxamide
ESI-MS m/z:554.31；1H NMR(400MHz,DMSO-d6)δ11.77(s,1H),8.34(d,J＝ 7.8Hz,1H),7.79(d,J＝10.5Hz,1H),7.63(s,1H),7.53(s,3H),7.43(s,1H),7.31 (s,1H),6.35(d,J＝7.8Hz,1H),5.67(s,1H),2.67(s,3H).ESI-MS m/z: 554.31;1 H NMR (400MHz, DMSO-d6 ) δ11.77(s, 1H), 8.34(d, J=7.8Hz, 1H), 7.79(d, J=10.5Hz, 1H),7.63(s,1H),7.53(s,3H),7.43(s,1H),7.31(s,1H),6.35(d,J=7.8Hz,1H),5.67(s,1H), 2.67(s,3H).
实施例(23)Example (23)
N-(3-氟-4-((3-甲基-[1,2,4]三唑并[4,3-a]吡嗪-8-基)氧基)苯基)-1-(4-甲氧基苯基)-4-氧代-1,4-二氢哒嗪-3-甲酰胺N-(3-fluoro-4-((3-methyl-[1,2,4]triazolo[4,3-a]pyrazin-8-yl)oxy)phenyl)-1-( 4-methoxyphenyl)-4-oxo-1,4-dihydropyridazine-3-carboxamide
ESI-MS m/z:487.45ESI-MS m/z:487.45
实施例(24)Example (24)
N-(3-氟-4-((3-甲基-[1,2,4]三唑并[4,3-a]吡嗪-8-基)氧基)苯基)-1-(4-氟苯基)-4-氧代-1,4-二氢哒嗪-3-甲酰胺N-(3-fluoro-4-((3-methyl-[1,2,4]triazolo[4,3-a]pyrazin-8-yl)oxy)phenyl)-1-( 4-fluorophenyl)-4-oxo-1,4-dihydropyridazine-3-carboxamide
ESI-MS m/z:475.42ESI-MS m/z:475.42
实施例(25)Example (25)
4-氧代-1-苯基-N-(4-((3-(三氟甲基)-[1,2,4]三唑并[4,3-a]吡嗪-8-基)氧基)苯基)-1,4-二氢哒嗪-3-甲酰胺4-Oxo-1-phenyl-N-(4-((3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyrazin-8-yl) Oxy)phenyl)-1,4-dihydropyridazine-3-carboxamide
步骤十一中间体(e)Step eleven intermediate (e)
将三氟乙酸酐加入烧瓶中，用乙酸乙酯做溶剂，在冰浴下搅拌，将中间体 b(5g，0.0346mol)中加入乙酸乙酯超声使其混匀后缓慢加入三氟乙酸酐中，在冰浴下搅拌，点板检测反应进程。反应完后直接用NaOH溶液和乙酸乙酯萃取，收集有机相旋蒸得油状物，烘干后得灰色固体10.9g，收率93.3％。Add trifluoroacetic anhydride to the flask, use ethyl acetate as solvent, stir under ice bath, add ethyl acetate to intermediate b (5g, 0.0346mol) and ultrasonically mix it, then slowly add trifluoroacetic anhydride , stirred in an ice bath, and spotted the plate to detect the reaction progress. After the reaction was completed, it was directly extracted with NaOH solution and ethyl acetate, and the organic phase was collected and evaporated to obtain an oily substance. After drying, 10.9 g of a gray solid was obtained, with a yield of 93.3%.
步骤十二3-(三氟甲基)-[1,2,4]三唑并[4,3-a]吡嗪-8-醇(f)Step twelve 3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyrazin-8-ol (f)
将多聚磷酸PPA在70℃下孵育6h，使其能够流动后，将其在80℃下能够搅拌后将中间体e(5g，0.0149mol)逐渐加入其中，点板检测反应进程。将反应完全后的反应液中加入饱和食盐水超声，使PPA全部溶解后搅拌，使产物以沉淀形式析出，抽滤得黄色固体2.8g。收率91.7％。Polyphosphoric acid PPA was incubated at 70°C for 6h to allow it to flow, then stirred at 80°C, intermediate e (5 g, 0.0149 mol) was gradually added therein, and the reaction progress was detected by pointing a plate. Add saturated brine to the reaction solution after the reaction was completed and sonicate to dissolve all the PPA and then stir to precipitate the product in the form of precipitation, which was filtered by suction to obtain 2.8 g of a yellow solid. Yield 91.7%.
步骤十三8-氯-3-(三氟甲基)-[1,2,4]三唑并[4,3-a]吡嗪(g)Step 13 8-Chloro-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyrazine (g)
将中间体f(1g，4.5mmol)加入烧瓶中，向其中加入三氯氧磷(30ml) 在110℃搅拌，点板检测反应进程。将反应完全后的反应液旋干后，加入少量饱和食盐水超声，产物以沉淀形式析出，抽滤得黄色固体0.55g。收率60.0％。Intermediate f (1 g, 4.5 mmol) was added into the flask, phosphorus oxychloride (30 ml) was added thereto and stirred at 110° C., and the progress of the reaction was detected by point plate. After the reaction solution was spin-dried after the completion of the reaction, a small amount of saturated saline was added for sonication, and the product was precipitated in the form of precipitation, and 0.55 g of a yellow solid was obtained by suction filtration. Yield 60.0%.
按照实施例1的方法，进行后续反应，分别制得实施例26～28化合物。According to the method of Example 1, subsequent reactions were carried out to obtain the compounds of Examples 26-28, respectively.
ESI-MS m/z:493.41ESI-MS m/z:493.41
实施例(26)Example (26)
1-(3-氯-4-氟苯基)-4-氧代-N-(4-((3-(三氟甲基)-[1,2,4]三唑并[4,3-a]吡嗪-8-基)氧基)苯基)-1,4-二氢哒嗪-3-甲酰胺1-(3-Chloro-4-fluorophenyl)-4-oxo-N-(4-((3-(trifluoromethyl)-[1,2,4]triazolo[4,3- a] pyrazin-8-yl)oxy)phenyl)-1,4-dihydropyridazine-3-carboxamide
ESI-MS m/z:545.84ESI-MS m/z:545.84
实施例(27)Example (27)
N-(3-氟-4-((3-(三氟甲基)-[1,2,4]三唑并[4,3-a]吡嗪-8-基)氧基)苯基)-4-氧代-1-苯基-1,4-二氢哒嗪-3-甲酰胺N-(3-fluoro-4-((3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyrazin-8-yl)oxy)phenyl) -4-Oxo-1-phenyl-1,4-dihydropyridazine-3-carboxamide
ESI-MS m/z:511.40ESI-MS m/z:511.40
实施例(28)Example (28)
1-(3-氯-4-氟苯基)-N-(3-氟-4-((3-(三氟甲基)-[1,2,4]三唑并[4,3-a]吡嗪-8-基)氧基) 苯基)-4-氧代-1,4-二氢哒嗪-3-甲酰胺1-(3-chloro-4-fluorophenyl)-N-(3-fluoro-4-((3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a ]pyrazin-8-yl)oxy)phenyl)-4-oxo-1,4-dihydropyridazine-3-carboxamide
ESI-MS m/z:563.83ESI-MS m/z:563.83
体外抗肿瘤细胞活性In vitro anti-tumor cell activity
对按照本发明的上式Ⅰ的含杂芳基取代哒嗪酮结构的三唑并吡嗪类化合物进行了体外抑制人前列腺细胞PC-3、人肝癌细胞Hepg-2、人非小细胞肺癌 A549、人胃癌细胞MKN-45和人脑星形胶质母细胞瘤U-87MG活性筛选。The triazolopyrazine compound containing heteroaryl-substituted pyridazinone structure according to the above formula I of the present invention inhibits human prostate cell PC-3, human liver cancer cell Hepg-2, and human non-small cell lung cancer A549 in vitro. , human gastric cancer cell MKN-45 and human brain astroglioblastoma U-87MG activity screening.
(1)细胞复苏并传代2-3次稳定后，用胰蛋白酶溶液(0.25％)使其从培养瓶底部消化下来。将细胞消化液倒入离心管中后，之后加入培养液以终止消化。将离心管在800r/min下离心10min，弃去上清液后加入5mL培养液，吹打混匀细胞，吸取10μL细胞混悬液加入细胞计数板中计数，调整细胞浓度为104个/ 孔。96孔板中除A1孔为空白孔不加细胞外，其余皆加入100μL细胞混悬液。将96孔板放入培养箱中培养24h。(1) After the cells were recovered and passaged for 2-3 times and stabilized, they were digested from the bottom of the culture flask with trypsin solution (0.25%). After the cell digestion solution was poured into the centrifuge tube, the culture medium was added to stop the digestion. Centrifuge the centrifuge tube at 800r/min for 10min, discard the supernatant, add 5mL of culture medium, pipette and mix the cells, draw 10μL of the cell suspension and add it to a cell counting plate for counting, and adjust the cell concentration to 104 cells/well. In the 96-well plate, 100 μL of cell suspension was added to well A1 except well A1 which was a blank well without adding cells. The 96-well plate was placed in an incubator for 24 h.
(2)用50μL二甲基亚砜溶解受试样品，然后加入适量培养液，使样品溶解成2mg/mL药液，然后在24孔板中将样品稀释为20,4,0.8,0.16,0.032μg/mL。(2) Dissolve the test sample with 50 μL dimethyl sulfoxide, then add an appropriate amount of culture medium to dissolve the sample into a 2 mg/mL drug solution, and then dilute the sample to 20, 4, 0.8, 0.16, 0.032 μg/mL.
每个浓度加入3孔，其中周围两行两列细胞长势受环境影响较大，只和为空白细胞孔使用。将96孔板放入培养箱中培养72h。Each concentration was added to 3 wells, and the growth of cells in the surrounding two rows and two columns was greatly affected by the environment, and only used as blank cell wells. The 96-well plate was placed in an incubator for 72 h.
(3)将96孔板中带药培养液弃去，用磷酸缓冲溶液(PbS)将细胞冲洗两遍，在每孔中加入MTT(四氮唑)(0.5mg/mL)100μL放入培养箱中4h后，弃去MTT 溶液，加入二甲基亚砜100μL。在磁力振荡器上振荡使存活细胞与MTT反应产物甲臜充分溶解，放入酶标仪中测定结果。通过bliss法可求出药物IC50值。(3) Discard the drug-carrying culture medium in the 96-well plate, wash the cells twice with phosphate buffer solution (PbS), add 100 μL of MTT (tetrazolium) (0.5 mg/mL) into each well and put it in the incubator After incubation for 4 hours, the MTT solution was discarded, and 100 μL of dimethyl sulfoxide was added. Vibrate on a magnetic oscillator to fully dissolve the formazan, the product of the reaction between the surviving cells and MTT, and put it into a microplate reader to determine the result. The IC50 value of the drug can be calculated by the bliss method.
化合物的抑制人前列腺细胞PC-3、人肝癌细胞Hepg-2、人非小细胞肺癌 A549、人胃癌细胞MKN-45和人脑星形胶质母细胞瘤U-87MG活性结果(见表二)。The compounds inhibit human prostate cell PC-3, human liver cancer cell Hepg-2, human non-small cell lung cancer A549, human gastric cancer cell MKN-45 and human brain astroglioblastoma U-87MG activity results (see Table 2) .
c-Met酶活性试验c-Met Enzyme Activity Assay
用于测量c-Met激酶活性的试验基于酶联免疫吸附试验(ELISA)。具体操作是：The assay used to measure c-Met kinase activity is based on an enzyme-linked immunosorbent assay (ELISA). The specific operation is:
室温下，在0.25mg/mL PGT包被的板上，将实施例化合物、50pM c-Met(His-标记的重组人Met氨基酸974-末端)，通过杆状病毒表达和5μMATP 在试验缓冲液中(25mM MOPS,pH7.4,5mM MgCl2,0.5raM MnCl2,100μM原钒酸钠，0.01％Triton X-100，1mM DTT，最后DMSO浓度1％(v/v))温育20 分钟。通过冲洗除去反应混合物并用0.2μg/mL缀合辣根过氧化物酶(HRP)的磷酸酪氨酸特异性单克隆抗体(PY20)检测磷酸化聚合物底物。加入1M磷酸终止显色后，于450nm处通过分光光度法定量显色的底物(TMb)的颜色。实施例化合物对c-Met激酶的抑制数据(见表二)。表中数据为在目标化合物在1μM 时的抑制率，“NA”表示无活性，“ND”表示未测试。At room temperature, on a 0.25 mg/mL PGT-coated plate, the example compound, 50 pM c-Met (His-tagged recombinant human Met amino acid 974-end), expressed by baculovirus and 5 μM ATP in assay buffer (25 mM MOPS, pH 7.4, 5 mM MgCl2 , 0.5 mM MnCl2 , 100 μM sodium orthovanadate, 0.01% Triton X-100, 1 mM DTT, final DMSO concentration 1% (v/v)) for 20 minutes. The reaction mixture was removed by washing and the phosphorylated polymer substrate was detected with 0.2 μg/mL horseradish peroxidase (HRP)-conjugated phosphotyrosine-specific monoclonal antibody (PY20). The color of the developed substrate (TMb ) was quantified spectrophotometrically at 450 nm after addition of 1 M phosphoric acid to terminate the color development. The inhibitory data of the compounds of the examples on c-Met kinase (see Table 2). The data in the table is the inhibition rate of the target compound at 1 μM, "NA" means no activity, "ND" means not tested.
表二：Table II:
选择活性较好的实施例化合物对VEGFR-2、EGFR、Flt-3激酶进行活性测试，抑制数据见表三。表中抑制率>＝90％，以“+++”表示，90％>抑制率>＝70％，以“++”表示，70％>抑制率>＝50％，以“+”表示，抑制率<＝50％，以“-”表示，“NA”表示无活性，“ND”表示未测试。The compounds of the examples with better activity were selected to test the activity of VEGFR-2, EGFR, and Flt-3 kinases, and the inhibition data are shown in Table 3. In the table, the inhibition rate>=90% is represented by "+++", 90%> inhibition rate>=70% is represented by "++", 70%> inhibition rate>=50% is represented by "+", Inhibition rate<=50%, expressed by "-", "NA" means no activity, "ND" means not tested.
表三Table three
从上述试验结果可以清楚地看出，本发明所要保护的通式Ⅰ的化合物，具有中等至优异的体外抗肿瘤活性，部分活性较好的化合物与阳性对照药 Foretinib活性相当。选择活性较好的化合物实施例6、实施例9、实施例19及实施例21对其进行VEGFR-2、EGFR、Flt-3激酶活性测试，结果表明本发明所要保护的通式Ⅰ的化合物是一类多靶点激酶抑制剂，并且其活性相当或优于对照药Foretinib，对EGFR以及Flt3的活性优于先导化合物Foretinib。From the above test results, it can be clearly seen that the compound of general formula I to be protected by the present invention has moderate to excellent in vitro anti-tumor activity, and some compounds with better activity have the same activity as the positive control drug Foretinib. Select the compounds with better activity in Example 6, Example 9, Example 19 and Example 21 to carry out VEGFR-2, EGFR, Flt-3 kinase activity test, the results show that the compound of the general formula I to be protected by the present invention is A class of multi-target kinase inhibitors, and its activity is equivalent to or better than that of the reference drug Foretinib, and its activity on EGFR and Flt3 is better than that of the lead compound Foretinib.
尽管已经通过特定实施方案描述了本发明，但修改和等价变化对于精通此领域的技术人员而言是显见的，且它们都包含在本发明范围之内。While this invention has been described in terms of specific embodiments, it is apparent that modifications and equivalents will be apparent to those skilled in the art, and these are intended to be encompassed within the scope of this invention.
应用例1：片剂Application Example 1: Tablet
以实施例1化合物10g，按照药剂学一般压片法加辅料20g混匀后，压制成100片，每片重300mg。Take 10 g of the compound of Example 1, add 20 g of excipients and mix uniformly according to the general tableting method of pharmacy, and then compress it into 100 tablets, each weighing 300 mg.
应用例2：胶囊剂Application Example 2: Capsules
以实施例10化合物10g，按照药剂学胶囊剂的要求将辅料20g混匀后，装入空心胶囊，每个胶囊重300mg。With 10 g of the compound of Example 10, mix 20 g of auxiliary materials according to the requirements of pharmaceutical capsules, and then fill them into hollow capsules, each weighing 300 mg.
应用例3：注射剂Application Example 3: Injection
以实施例13化合物10g，按照药剂学常规方法，进行活性炭吸附，经0.65 μm微孔滤膜过滤后，填入氮气罐制成水针制剂，每只装2mL，共灌装100瓶。Take 10 g of the compound of Example 13, according to the conventional method of pharmacy, carry out activated carbon adsorption, filter through a 0.65 μm microporous membrane, fill it into a nitrogen tank to make an aqueous injection preparation, each bottle is filled with 2 mL, and a total of 100 bottles are filled.
应用例4：气雾剂Application Example 4: Aerosol
以实施例20化合物10g，用适量丙二醇溶解后，加入蒸馏水及其他辐料后，制成500mL的澄清溶液即得。Take 10 g of the compound of Example 20, dissolve it with an appropriate amount of propylene glycol, add distilled water and other materials, and make a 500 mL clear solution.
应用例5：栓剂Application Example 5: Suppositories
以实施例19化合物10g，将之研细加入甘油适量，研匀后加入已熔化的甘油明胶，研磨均匀，倾入已涂润滑剂的模型中，制得栓剂50颗。Take 10 g of the compound of Example 19, grind it finely and add an appropriate amount of glycerin, grind it evenly, add melted glycerin gelatin, grind it evenly, pour it into a model coated with lubricant, and make 50 suppositories.
应用例6：膜剂Application Example 6: Membrane
以实施例28化合物10g，将聚乙烯醇、药用甘油、水等搅拌膨胀后加热溶解，80目筛网过滤，再将实施例18化合物加入到滤液中搅拌溶解，涂膜机制膜100片。Take 10 g of the compound of Example 28, stir and expand polyvinyl alcohol, medicinal glycerin, water, etc., heat to dissolve, filter through an 80-mesh screen, then add the compound of Example 18 into the filtrate, stir and dissolve, and apply 100 pieces of membranes.
应用例7：滴丸剂Application Example 7: Dropping Pills
以实施例17化合物10g，与明胶等基质50g加热熔化混匀后，滴入低温液体石蜡中，共制得滴丸1000丸。With 10g of the compound of Example 17, heated, melted and mixed with 50g of substrates such as gelatin, and then dropped into low-temperature liquid paraffin, a total of 1000 dropping pills were prepared.
应用例8：外用搽剂Application Example 8: Liniment for external use
以实施例21化合物10g，按照常规药剂学方法与乳化剂等辅料2.5g混合研磨，再加蒸馏水至200mL制得。Take 10 g of the compound of Example 21, mix and grind it with 2.5 g of auxiliary materials such as emulsifiers according to conventional pharmaceutical methods, and then add distilled water to 200 mL.
应用例9：软膏剂Application Example 9: Ointment
以实施例26化合物10g，研细后与凡士林等油性基质500g研匀制得。Take 10 g of the compound of Example 26, grind it finely, and grind it with 500 g of oily base such as petrolatum to make it homogeneous.
尽管已经通过特定实施方案描述了本发明，但修改和等价变化对于精通此领域的技术人员而言是显见的，且它们都包含在本发明范围之内。While this invention has been described in terms of specific embodiments, it is apparent that modifications and equivalents will be apparent to those skilled in the art, and these are intended to be encompassed within the scope of this invention.
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