CN115724842A - Pyrimidone derivatives and their use in medicine - Google Patents
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Abstract
本发明公开了嘧啶酮衍生物及其在药物中的应用，具体地，本发明涉及一类新颖的嘧啶酮衍生物及包含该类化合物的药物组合物。本发明还涉及制备所述化合物和药物组合物的方法，以及在制备治疗由KRAS G12C介导的疾病和/或病症的药物中的用途，特别是在制备治疗癌症的药物中的用途。The invention discloses pyrimidone derivatives and their application in medicine. Specifically, the invention relates to a novel class of pyrimidone derivatives and a pharmaceutical composition containing the compounds. The present invention also relates to the method for preparing the compound and the pharmaceutical composition, as well as its use in the preparation of medicines for treating diseases and/or conditions mediated by KRAS G12C, especially the use in the preparation of medicines for treating cancer.
Description
发明领域field of invention
本发明属于药物领域，具体涉及一类作为KRAS抑制剂的新化合物、制备它们的方法、包含所述化合物的药物组合物以及所述化合物及其药物组合物在治疗多种疾病中的应用。更具体地说，本发明所述的化合物可以作为KRAS G12C抑制剂。The invention belongs to the field of medicine, and in particular relates to a class of novel compounds as KRAS inhibitors, a method for preparing them, a pharmaceutical composition containing the compound and the application of the compound and the pharmaceutical composition in treating various diseases. More specifically, the compounds described in the present invention are useful as KRAS G12C inhibitors.
背景技术Background technique
KRAS是一种鼠类肉瘤病毒基因，RAS基因家族与人类肿瘤相关的基因有三种——HRAS、KRAS和NRAS，分别定位在11、12和1号染色体上。KRAS因编码21kD的RAS蛋白又名p21基因。在RAS基因中，KRAS对人类癌症影响最大，占所有RAS突变中的86％，它好像分子开关：当正常时能控制调控细胞生长的路径；发生异常时，则导致细胞持续生长，并阻止细胞自我毁灭。它参与细胞内的信号传递，当KRAS基因突变时，该基因永久活化，不能产生正常的RAS蛋白，使细胞内信号传导紊乱，细胞增殖失控而癌变。KRAS is a mouse sarcoma virus gene. There are three genes in the RAS gene family related to human tumors—HRAS, KRAS, and NRAS, which are located on chromosomes 11, 12, and 1, respectively. KRAS is also known as the p21 gene because it encodes a 21kD RAS protein. Among the RAS genes, KRAS has the greatest impact on human cancer, accounting for 86% of all RAS mutations. It is like a molecular switch: when normal, it can control the pathways that regulate cell growth; when abnormal, it causes cells to continue to grow and prevents cells from developing. self-destruct. It participates in intracellular signal transmission. When the KRAS gene is mutated, the gene will be permanently activated, unable to produce normal RAS protein, causing intracellular signal transduction disorder, cell proliferation uncontrolled and cancerous.
G12C突变是KRAS基因突变中比较常见的一个亚型，它是指12号甘氨酸突变为半胱氨酸。KRAS G12C突变在肺癌中最为常见，根据文献(Nat Rev Drug Discov 2014；13:828-851)报道数据可知，KRAS G12C突变占所有肺癌患者的10％左右。几十年来，人们一直致力于靶向RAS的小分子抑制剂研发，然而至今尚未有相关药物上市。科学家一直希望能够研发出直接作用于RAS蛋白的GTP竞争性抑制剂。但是因为GTP与RAS之间具有极强的亲和力(pmol/L级)，而细胞中GTP浓度很高(0.5mM)，以及RAS蛋白结构中缺乏有利于小分子结合的口袋等原因没有成功。G12C mutation is a relatively common subtype of KRAS gene mutation, which refers to the mutation of glycine 12 to cysteine. KRAS G12C mutation is the most common in lung cancer. According to data reported in the literature (Nat Rev Drug Discov 2014; 13:828-851), KRAS G12C mutation accounts for about 10% of all lung cancer patients. For decades, people have been working on the research and development of small molecule inhibitors targeting RAS, but no related drugs have been marketed yet. Scientists have long hoped to develop GTP-competitive inhibitors that act directly on the RAS protein. However, due to the extremely strong affinity (pmol/L level) between GTP and RAS, the high concentration of GTP in cells (0.5mM), and the lack of pockets in the RAS protein structure that are conducive to small molecule binding, it was unsuccessful.
近年来，人们利用KRAS G12C突变体的变构位点进行药物研发取得了一定的进展。2013年，有研究小组报道了KRAS G12C小分子抑制剂的发现(Nature,2013,503,548-551)。他们从KRAS G12C突变体中鉴定出一个位于分子开关II区域下方的新型结合口袋，这些抑制剂结合于该变构口袋，并与附近的Cys12形成共价结合，从而选择性抑制KRAS G12C的活化。另一些研究人员报道了具有细胞活性的KRAS抑制剂(Science,2016,351,604-608)。由于KRAS G12C靶蛋白在病理学上与多种疾病相关，因此目前还需要新型的KRAS G12C抑制剂用于临床治疗。高选择性高活性的KRAS G12C抑制剂可以对KRAS G12C突变导致的癌症等疾病有效治疗，以及具备减少脱靶效应的潜力，因而具有更迫切的临床需求。In recent years, people have made some progress in drug development using the allosteric site of the KRAS G12C mutant. In 2013, a research team reported the discovery of KRAS G12C small molecule inhibitors (Nature, 2013, 503, 548-551). They identified a novel binding pocket located below the molecular switch II region from the KRAS G12C mutant, and these inhibitors bound to this allosteric pocket and formed a covalent bond with nearby Cys12, thereby selectively inhibiting the activation of KRAS G12C. Other researchers reported cell-active KRAS inhibitors (Science, 2016, 351, 604-608). Since KRAS G12C target proteins are pathologically associated with various diseases, novel KRAS G12C inhibitors are still needed for clinical treatment. Highly selective and highly active KRAS G12C inhibitors can effectively treat diseases such as cancers caused by KRAS G12C mutations, and have the potential to reduce off-target effects, so they have more urgent clinical needs.
发明内容Contents of the invention
本发明提供一种化合物，或其药物组合物，其可作为KRAS G12C抑制剂。本发明进一步涉及所述化合物或其药物组合物用于制备药物的用途，该药物通过所述化合物抑制KRAS活性来治疗疾病和/或病症。本发明又进一步描述了所述化合物的合成方法。本发明的化合物显示出优良的生物活性及药代动力学性质。The present invention provides a compound, or a pharmaceutical composition thereof, which can be used as a KRAS G12C inhibitor. The present invention further relates to the use of the compound or its pharmaceutical composition for preparing a medicament for treating diseases and/or conditions by inhibiting KRAS activity with the compound. The present invention further describes the synthesis method of said compound. The compounds of the present invention exhibit excellent biological activity and pharmacokinetic properties.
具体地说：Specifically:
一方面，本发明涉及一种化合物，其为如式(I)所示的化合物，或式(I)所示的化合物的立体异构体、互变异构体、氮氧化物、水合物、溶剂化物、代谢产物、药学上可接受的盐或前药，In one aspect, the present invention relates to a compound, which is a compound represented by formula (I), or a stereoisomer, tautomer, nitrogen oxide, hydrate, or solvates, metabolites, pharmaceutically acceptable salts or prodrugs,
其中：in:
X为-L-X1-，其中，L为键或NH，X1为含氮原子的4-8元单环、含氮原子的5-12元稠环、含氮原子的5-12元螺环或含氮原子的5-12元桥环，其中所述的含氮原子的4-8元单环、含氮原子的5-12元稠环、含氮原子的5-12元螺环和含氮原子的5-12元桥环各自独立任选地被m个Rx取代；X is -LX 1 -, wherein, L is a bond or NH, X 1 is a 4-8 membered monocyclic ring containing a nitrogen atom, a 5-12 membered condensed ring containing a nitrogen atom, a 5-12 membered spiro ring containing a nitrogen atom Or a 5-12-membered bridged ring containing a nitrogen atom, wherein the 4-8-membered monocyclic ring containing a nitrogen atom, the 5-12-membered condensed ring containing a nitrogen atom, the 5-12-membered spiro ring containing a nitrogen atom, and the 5-12-membered spiro ring containing a nitrogen atom The 5-12 member bridged rings of nitrogen atoms are each independently optionally substituted by m R x ;
Y为N或CH；Y is N or CH;
R1为-C(＝O)-CRa＝CRb-Rc、-C(＝O)-C≡C-Rc、-S(＝O)2-CRa＝CRb-Rc或-S(＝O)2-C≡C-Rc；R 1 is -C(=O)-CR a =CR b -R c , -C(=O)-C≡CR c , -S(=O) 2 -CR a =CR b -R c or -S (=O) 2 -C≡CR c ;
Ra和Rb各自独立地为氢、氘、氟、氯、溴、碘、C1-3烷基、C1-3卤代烷基或C1-3烷氧基；其中，所述的C1-3烷基、C1-3卤代烷基和C1-3烷氧基各自独立任选地被1、2、3、4或5个独立地选自氘、氟、氯、溴、碘、羟基、氧代、氨基、硝基、氰基、C1-3烷基、C1-3卤代烷基、C1-3烷氧基、C1-3卤代烷氧基和C1-3羟基烷氧基的基团所取代；R a and R b are each independently hydrogen, deuterium, fluorine, chlorine, bromine, iodine, C 1-3 alkyl, C 1-3 haloalkyl or C 1-3 alkoxy; wherein, the C 1 -3 alkyl, C 1-3 haloalkyl and C 1-3 alkoxy are each independently optionally selected from 1, 2, 3, 4 or 5 independently selected from deuterium, fluorine, chlorine, bromine, iodine, hydroxyl , oxo, amino, nitro, cyano, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy and C 1-3 hydroxyalkoxy replaced by the group;
Rc独立地为氢、氘、C1-6烷基、C2-6烯基、C2-6炔基、C1-6卤代烷基、C1-6烷氧基、C1-6卤代烷氧基、C1-6烷氨基、C3-6环烷基、3-8个原子组成的杂环基或5-6个原子组成的杂芳基；其中，所述的C1-6烷基、C2-6烯基、C2-6炔基、C1-6卤代烷基、C1-6烷氧基、C1-6卤代烷氧基、C1-6烷氨基、C3-6环烷基、3-8个原子组成的杂环基和5-6个原子组成的杂芳基各自独立任选地被1、2、3、4或5个独立地选自氘、氟、氯、溴、碘、羟基、氧代、氨基、硝基、氰基、C1-3烷基、C1-3卤代烷基、C1-3烷氧基、C1-3卤代烷氧基和C1-3羟基烷氧基的基团所取代；R c is independently hydrogen, deuterium, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkane Oxygen, C 1-6 alkylamino, C 3-6 cycloalkyl, heterocyclic group consisting of 3-8 atoms or heteroaryl group consisting of 5-6 atoms; wherein, the C 1-6 alkane C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl , C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 alkylamino, C 3-6 Cycloalkyl, heterocyclic group consisting of 3-8 atoms and heteroaryl group consisting of 5-6 atoms are each independently optionally selected from 1, 2, 3, 4 or 5 independently selected from deuterium, fluorine, chlorine , bromine, iodine, hydroxyl, oxo, amino, nitro, cyano, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy and C 1 -3 hydroxyalkoxy groups are substituted;
R3为C6-12芳基或5-12个原子组成的杂芳基；其中，所述的C6-12芳基和5-12个原子组成的杂芳基各自独立任选地被n个Ry取代；R 3 is a C 6-12 aryl group or a heteroaryl group consisting of 5-12 atoms; wherein, the C 6-12 aryl group and the heteroaryl group consisting of 5-12 atoms are each independently optionally replaced by n R y replaced;
R2a、R2b和R2c各自独立地为氢、氘、氟、氯、溴、碘、羟基、氨基、硝基、氰基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6卤代烷基、C1-6烷氧基、C1-6卤代烷氧基、C1-6烷氨基、C3-8环烷基、3-8个原子组成的杂环基、C6-10芳基或5-12个原子组成的杂芳基；其中，所述的C1-6烷基、C2-6烯基、C2-6炔基、C1-6卤代烷基、C1-6烷氧基、C1-6卤代烷氧基、C1-6烷氨基、C3-8环烷基、3-8个原子组成的杂环基、C6-10芳基和5-12个原子组成的杂芳基各自独立任选地被1、2、3、4或5个独立地选自氘、氟、氯、溴、碘、羟基、氧代、氨基、硝基、氰基、C1-3烷基、C1-3卤代烷基、C1-3烷氧基、C1-3卤代烷氧基和C1-3羟基烷氧基的基团所取代；R 2a , R 2b and R 2c are each independently hydrogen, deuterium, fluorine, chlorine, bromine, iodine, hydroxyl, amino, nitro, cyano, C 1-6 alkyl, C 2-6 alkenyl, C 2 -6 alkynyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 alkylamino, C 3-8 cycloalkyl, 3-8 atoms Heterocyclyl, C 6-10 aryl or heteroaryl consisting of 5-12 atoms; wherein, the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1 -6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 alkylamino, C 3-8 cycloalkyl, heterocyclic group consisting of 3-8 atoms, C 6- 10 aryl groups and heteroaryl groups consisting of 5-12 atoms are each independently optionally selected from 1, 2, 3, 4 or 5 independently selected from deuterium, fluorine, chlorine, bromine, iodine, hydroxyl, oxo, amino , nitro, cyano, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy and C 1-3 hydroxyalkoxy ;
各Rx独立地为氘、氟、氯、溴、碘、羟基、氧代、氨基、硝基、氰基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6卤代烷基、C1-6烷氧基、C1-6卤代烷氧基、C1-6烷氨基、C3-8环烷基或3-8个原子组成的杂环基；其中，所述的C1-6烷基、C2-6烯基、C2-6炔基、C1-6卤代烷基、C1-6烷氧基、C1-6卤代烷氧基、C1-6烷氨基、C3-8环烷基和3-8个原子组成的杂环基各自独立任选地被1、2、3、4或5个独立地选自氘、氟、氯、溴、碘、羟基、氧代、氨基、硝基、氰基、C1-3烷基、C1-3卤代烷基、C1-3烷氧基、C1-3卤代烷氧基和C1-3羟基烷氧基的基团所取代；Each R x is independently deuterium, fluorine, chlorine, bromine, iodine, hydroxyl, oxo, amino, nitro, cyano, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 alkylamino, C 3-8 cycloalkyl or heterocyclic group consisting of 3-8 atoms; where , the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1 -6 alkylamino, C 3-8 cycloalkyl and 3-8 atom heterocyclic groups are independently optionally selected from deuterium, fluorine, chlorine, bromine by 1, 2, 3, 4 or 5 , iodine, hydroxyl, oxo, amino, nitro, cyano, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy and C 1-3 Substituted by hydroxyalkoxy groups;
各Ry独立地为氘、氟、氯、溴、碘、羟基、氨基、硝基、氰基、C1-6烷基、C1-6卤代烷基、C1-6烷氧基、C1-6卤代烷氧基、C1-6羟基烷氧基、C1-6烷氨基、C3-8环烷基、3-8个原子组成的杂环基、C6-10芳基或5-12个原子组成的杂芳基；其中，所述的C1-6烷基、C1-6卤代烷基、C1-6烷氧基、C1-6卤代烷氧基、C1-6羟基烷氧基、C1-6烷氨基、C3-8环烷基、3-8个原子组成的杂环基、C6-10芳基和5-12个原子组成的杂芳基各自独立任选地被1、2、3、4或5个独立地选自氘、氟、氯、溴、碘、羟基、氧代、氨基、硝基、氰基、C1-3烷基、C1-3卤代烷基、C1-3烷氧基、C1-3卤代烷氧基和C1-3羟基烷氧基的基团所取代；Each Ry is independently deuterium, fluorine, chlorine, bromine, iodine, hydroxyl, amino, nitro, cyano, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1 -6 haloalkoxy, C 1-6 hydroxyalkoxy, C 1-6 alkylamino, C 3-8 cycloalkyl, heterocyclic group consisting of 3-8 atoms, C 6-10 aryl or 5- A heteroaryl group consisting of 12 atoms; wherein, the C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalk Oxygen, C 1-6 alkylamino, C 3-8 cycloalkyl, heterocyclic group consisting of 3-8 atoms, C 6-10 aryl and heteroaryl consisting of 5-12 atoms are independently optional 1, 2, 3, 4 or 5 independently selected from deuterium, fluorine, chlorine, bromine, iodine, hydroxyl, oxo, amino, nitro, cyano, C 1-3 alkyl, C 1-3 Haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy and C 1-3 hydroxyalkoxy are substituted;
m为0、1、2、3、4、5、6、7或8；m is 0, 1, 2, 3, 4, 5, 6, 7 or 8;
n为1、2、3、4、5、6或7。n is 1, 2, 3, 4, 5, 6 or 7.
在一些实施方案中，本发明化合物具有式(II)所示结构：In some embodiments, the compound of the present invention has the structure shown in formula (II):
其中，各Y、R1、R2a、R2b、R2c、Rx、Ry和m均具有本发明所描述的含义。Wherein, each of Y, R 1 , R 2a , R 2b , R 2c , R x , R y and m has the meaning described in the present invention.
在一些实施方案中，X为
在一些实施方案中，Ra和Rb各自独立地为氢、氘、氟、氯、溴、碘、甲基、乙基、正丙基、异丙基、三氟甲基、二氟甲基、甲氧基、乙氧基或异丙氧基；其中，所述的甲基、乙基、正丙基、异丙基、二氟甲基、甲氧基、乙氧基和异丙氧基各自独立任选地被1、2、3、4或5个独立地选自氘、氟、氯、溴、碘、羟基、氧代、氨基、硝基、氰基、甲基、乙基、正丙基、异丙基、三氟甲基、二氟甲基、甲氧基、乙氧基、异丙氧基、三氟甲氧基、-OCH2OH和-OCH2CH2OH的基团所取代；In some embodiments, R and R are each independently hydrogen, deuterium, fluorine, chlorine, bromine, iodine, methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, difluoromethyl , methoxy, ethoxy or isopropoxy; wherein, the methyl, ethyl, n-propyl, isopropyl, difluoromethyl, methoxy, ethoxy and isopropoxy Each is independently optionally selected from 1, 2, 3, 4 or 5 independently selected from deuterium, fluorine, chlorine, bromine, iodine, hydroxyl, oxo, amino, nitro, cyano, methyl, ethyl, normal Propyl, isopropyl, trifluoromethyl, difluoromethyl , methoxy, ethoxy, isopropoxy, trifluoromethoxy, -OCH2OH and -OCH2CH2OH radicals replaced by
Rc独立地为氢、氘、甲基、乙基、正丙基、异丙基、烯丙基、丙烯基、炔丙基、丙炔基、-CHF2、-CF3、-CHFCH2F、-CF2CHF2、-CH2CF3、-CH2CF2CHF2、甲氧基、乙氧基、正丙氧基、异丙氧基、-OCHF2、-OCF3、-OCHFCH2F、-OCF2CHF2、-OCH2CF3、-OCH2CF2CHF2、甲氨基、二甲氨基、乙氨基、环丙基、环丁基、环戊基、环己基、氮杂环丁基、氧杂环丁基、吡咯烷基、四氢呋喃基、哌啶基、哌嗪基、吗啉基、吡咯基、吡唑基、咪唑基、三氮唑基、四氮唑基、呋喃基、噻吩基、噻唑基、噁唑基、吡啶基、嘧啶基、吡嗪基或哒嗪基；其中，所述的甲基、乙基、正丙基、异丙基、烯丙基、丙烯基、炔丙基、丙炔基、-CHF2、-CHFCH2F、-CF2CHF2、-CH2CF3、-CH2CF2CHF2、甲氧基、乙氧基、正丙氧基、异丙氧基、-OCHF2、-OCHFCH2F、-OCF2CHF2、-OCH2CF3、-OCH2CF2CHF2、甲氨基、二甲氨基、乙氨基、环丙基、环丁基、环戊基、环己基、氮杂环丁基、氧杂环丁基、吡咯烷基、四氢呋喃基、哌啶基、哌嗪基、吗啉基、吡咯基、吡唑基、咪唑基、三氮唑基、四氮唑基、呋喃基、噻吩基、噻唑基、噁唑基、吡啶基、嘧啶基、吡嗪基和哒嗪基各自独立任选地被1、2、3、4或5个独立地选自氘、氟、氯、溴、碘、羟基、氧代、氨基、硝基、氰基、甲基、乙基、正丙基、异丙基、三氟甲基、二氟甲基、甲氧基、乙氧基、三氟甲氧基、-OCH2OH、-OCH2CH2OH和异丙氧基的基团所取代。R c is independently hydrogen, deuterium, methyl, ethyl, n-propyl, isopropyl, allyl, propenyl, propargyl, propynyl, -CHF 2 , -CF 3 , -CHFCH 2 F , -CF 2 CHF 2 , -CH 2 CF 3 , -CH 2 CF 2 CHF 2 , methoxy, ethoxy, n-propoxy, isopropoxy, -OCHF 2 , -OCF 3 , -OCHFCH 2 F, -OCF 2 CHF 2 , -OCH 2 CF 3 , -OCH 2 CF 2 CHF 2 , methylamino, dimethylamino, ethylamino, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azacyclic Butyl, oxetanyl, pyrrolidinyl, tetrahydrofuryl, piperidinyl, piperazinyl, morpholinyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, furyl , thienyl, thiazolyl, oxazolyl, pyridyl, pyrimidyl, pyrazinyl or pyridazinyl; wherein, the methyl, ethyl, n-propyl, isopropyl, allyl, propenyl , propargyl, propynyl, -CHF 2 , -CHFCH 2 F, -CF 2 CHF 2 , -CH 2 CF 3 , -CH 2 CF 2 CHF 2 , methoxy, ethoxy, n-propoxy , isopropoxy, -OCHF 2 , -OCHFCH 2 F, -OCF 2 CHF 2 , -OCH 2 CF 3 , -OCH 2 CF 2 CHF 2 , methylamino, dimethylamino, ethylamino, cyclopropyl, cyclo Butyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuryl, piperidinyl, piperazinyl, morpholinyl, pyrrolyl, pyrazolyl, imidazolyl , triazolyl, tetrazolyl, furyl, thienyl, thiazolyl, oxazolyl, pyridyl, pyrimidinyl, pyrazinyl and pyridazinyl are each independently optionally replaced by 1, 2, 3, 4 Or 5 independently selected from deuterium, fluorine, chlorine, bromine, iodine, hydroxyl, oxo, amino, nitro, cyano, methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, di Fluoromethyl, methoxy, ethoxy, trifluoromethoxy, -OCH 2 OH, -OCH 2 CH 2 OH and isopropoxy groups.
在一些实施方案中，R3为C6-10芳基或5-10个原子组成的杂芳基，其中，所述的C6-10芳基和5-10个原子组成的杂芳基独立任选地被n个Ry取代；其中n和Ry具有如本发明所述的定义。In some embodiments, R 3 is a C 6-10 aryl group or a heteroaryl group consisting of 5-10 atoms, wherein the C 6-10 aryl group and the heteroaryl group consisting of 5-10 atoms are independently Optionally substituted by n R y ; wherein n and R y have the meanings as described herein.
在一些实施方案中，R3为以下子结构：
在一些实施方案中，R2a、R2b和R2c各自独立地为氢、氘、氟、氯、溴、碘、羟基、氨基、硝基、氰基、C1-4烷基、C2-4烯基、C2-4炔基、C1-4卤代烷基、C1-4烷氧基、C1-4卤代烷氧基、C1-4烷氨基、C3-6环烷基、3-6个原子组成的杂环基、C6-10芳基或5-10个原子组成的杂芳基；其中，所述的C1-4烷基、C2-4烯基、C2-4炔基、C1-4卤代烷基、C1-4烷氧基、C1-4卤代烷氧基、C1-4烷氨基、C3-6环烷基、3-6个原子组成的杂环基、C6-10芳基和5-10个原子组成的杂芳基各自独立任选地被1、2、3、4或5个独立地选自氘、氟、氯、溴、碘、羟基、氧代、氨基、硝基、氰基、C1-3烷基、C1-3卤代烷基、C1-3烷氧基、C1-3卤代烷氧基和C1-3羟基烷氧基的基团所取代。In some embodiments, R 2a , R 2b and R 2c are each independently hydrogen, deuterium, fluorine, chlorine, bromine, iodine, hydroxyl, amino, nitro, cyano, C 1-4 alkyl, C 2- 4 alkenyl, C 2-4 alkynyl, C 1-4 haloalkyl, C 1-4 alkoxy, C 1-4 haloalkoxy, C 1-4 alkylamino, C 3-6 cycloalkyl, 3 -heterocyclic group composed of 6 atoms, C 6-10 aryl group or heteroaryl group composed of 5-10 atoms; wherein, the C 1-4 alkyl, C 2-4 alkenyl, C 2- 4 alkynyl, C 1-4 haloalkyl, C 1-4 alkoxy, C 1-4 haloalkoxy, C 1-4 alkylamino, C 3-6 cycloalkyl, hetero of 3-6 atoms Cyclic group, C 6-10 aryl group and heteroaryl group composed of 5-10 atoms are each independently optionally selected from deuterium, fluorine, chlorine, bromine, iodine, 1, 2, 3, 4 or 5 Hydroxy, oxo, amino, nitro, cyano, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy and C 1-3 hydroxyalkoxy The group of the group is substituted.
在一些实施方案中，R2a、R2b和R2c各自独立地为氢、氘、氟、氯、溴、碘、羟基、氨基、硝基、氰基、甲基、乙基、正丙基、异丙基、烯丙基、丙烯基、炔丙基、丙炔基、-CHF2、-CF3、-CHFCH2F、-CF2CHF2、-CH2CF3、-CH2CF2CHF2、甲氧基、乙氧基、正丙氧基、异丙氧基、-OCHF2、-OCF3、-OCHFCH2F、-OCF2CHF2、-OCH2CF3、-OCH2CF2CHF2、甲氨基、二甲氨基、乙氨基、环丙基、环丁基、环戊基、环己基、氧杂环丁基、氮杂环丁基、吡咯烷基、四氢呋喃基、哌啶基、哌嗪基、吗啉基、苯基、萘基、苯并咪唑基、吡咯基、吡唑基、咪唑基、三氮唑基、四氮唑基、呋喃基、噻吩基、噻唑基、噁唑基、吡啶基、嘧啶基、吡嗪基或哒嗪基；其中，所述的甲基、乙基、正丙基、异丙基、烯丙基、丙烯基、炔丙基、丙炔基、-CHF2、-CHFCH2F、-CF2CHF2、-CH2CF3、-CH2CF2CHF2、甲氧基、乙氧基、正丙基氧基、异丙基氧基、-OCHF2、-OCHFCH2F、-OCF2CHF2、-OCH2CF3、-OCH2CF2CHF2、甲氨基、二甲氨基、乙氨基、环丙基、环丁基、环戊基、环己基、氧杂环丁基、氮杂环丁基、吡咯烷基、四氢呋喃基、哌啶基、哌嗪基、吗啉基、苯基、萘基、苯并咪唑基、吡咯基、吡唑基、咪唑基、三氮唑基、四氮唑基、呋喃基、噻吩基、噻唑基、噁唑基、吡啶基、嘧啶基、吡嗪基和哒嗪基各自独立任选地被1、2、3、4或5个独立地选自氘、氟、氯、溴、碘、羟基、氧代、氨基、硝基、氰基、甲基、乙基、正丙基、异丙基、三氟甲基、二氟甲基、甲氧基、乙氧基、异丙氧基、三氟甲氧基、-OCH2OH和-OCH2CH2OH的基团所取代。In some embodiments, R 2a , R 2b , and R 2c are each independently hydrogen, deuterium, fluorine, chlorine, bromine, iodine, hydroxyl, amino, nitro, cyano, methyl, ethyl, n-propyl, Isopropyl, allyl, propenyl, propargyl, propynyl, -CHF 2 , -CF 3 , -CHFCH 2 F, -CF 2 CHF 2 , -CH 2 CF 3 , -CH 2 CF 2 CHF 2. Methoxy, ethoxy, n-propoxy, isopropoxy, -OCHF 2 , -OCF 3 , -OCHFCH 2 F, -OCF 2 CHF 2 , -OCH 2 CF 3 , -OCH 2 CF 2 CHF 2 , methylamino, dimethylamino, ethylamino, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, azetidinyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl , piperazinyl, morpholinyl, phenyl, naphthyl, benzimidazolyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, furyl, thienyl, thiazolyl, oxa Azolyl, pyridyl, pyrimidyl, pyrazinyl or pyridazinyl; wherein, the methyl, ethyl, n-propyl, isopropyl, allyl, propenyl, propargyl, propynyl , -CHF 2 , -CHFCH 2 F, -CF 2 CHF 2 , -CH 2 CF 3 , -CH 2 CF 2 CHF 2 , methoxy, ethoxy, n-propyloxy, isopropyloxy, -OCHF 2 , -OCHFCH 2 F, -OCF 2 CHF 2 , -OCH 2 CF 3 , -OCH 2 CF 2 CHF 2 , methylamino, dimethylamino, ethylamino, cyclopropyl, cyclobutyl, cyclopentyl , cyclohexyl, oxetyl, azetidinyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, morpholinyl, phenyl, naphthyl, benzimidazolyl, pyrrolyl, pyrrolyl Azolyl, imidazolyl, triazolyl, tetrazolyl, furyl, thienyl, thiazolyl, oxazolyl, pyridyl, pyrimidyl, pyrazinyl and pyridazinyl are each independently optionally replaced by 1, 2, 3, 4 or 5 independently selected from deuterium, fluorine, chlorine, bromine, iodine, hydroxyl, oxo, amino, nitro, cyano, methyl, ethyl, n-propyl, isopropyl, tri fluoromethyl, difluoromethyl, methoxy, ethoxy, isopropoxy, trifluoromethoxy, -OCH 2 OH and -OCH 2 CH 2 OH.
在一些实施方案中，各Rx独立地为氘、氟、氯、溴、碘、羟基、氧代、氨基、硝基、氰基、C1-4烷基、C2-4烯基、C2-4炔基、C1-4卤代烷基、C1-4烷氧基、C1-4卤代烷氧基、C1-4烷氨基、C3-6环烷基或3-6个原子组成的杂环基；其中，所述的C1-4烷基、C2-4烯基、C2-4炔基、C1-4卤代烷基、C1-4烷氧基、C1-4卤代烷氧基、C1-4烷氨基、C3-6环烷基和3-6个原子组成的杂环基各自独立任选地被1、2、3、4或5个独立地选自氘、氟、氯、溴、碘、羟基、氧代、氨基、硝基、氰基、C1-3烷基、C1-3卤代烷基、C1-3烷氧基、C1-3卤代烷氧基和C1-3羟基烷氧基的基团所取代。In some embodiments, each R x is independently deuterium, fluorine, chlorine, bromine, iodine, hydroxyl, oxo, amino, nitro, cyano, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 haloalkyl, C 1-4 alkoxy, C 1-4 haloalkoxy, C 1-4 alkylamino, C 3-6 cycloalkyl or 3-6 atoms The heterocyclic group; wherein, the C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 haloalkyl, C 1-4 alkoxy, C 1-4 Haloalkoxy, C 1-4 alkylamino, C 3-6 cycloalkyl and 3-6 heterocyclyl atoms are independently optionally selected from 1, 2, 3, 4 or 5 independently selected from deuterium , fluorine, chlorine, bromine, iodine, hydroxyl, oxo, amino, nitro, cyano, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy Substituted by groups and C 1-3 hydroxyalkoxy groups.
在一些实施方案中，各Rx独立地为氘、氟、氯、溴、碘、羟基、氧代、氨基、硝基、氰基、甲基、乙基、正丙基、异丙基、烯丙基、丙烯基、炔丙基、丙炔基、-CHF2、-CF3、-CHFCH2F、-CF2CHF2、-CH2CF3、-CH2CF2CHF2、甲氧基、乙氧基、正丙氧基、异丙氧基、-OCHF2、-OCF3、-OCHFCH2F、-OCF2CHF2、-OCH2CF3、-OCH2CF2CHF2、甲氨基、二甲氨基、乙氨基、环丙基、环丁基、环戊基、环己基、氮杂环丁基、氧杂环丁基、吡咯烷基、四氢呋喃基、哌啶基、哌嗪基或吗啉基；其中，所述的甲基、乙基、正丙基、异丙基、烯丙基、丙烯基、炔丙基、丙炔基、-CHF2、-CHFCH2F、-CF2CHF2、-CH2CF3、-CH2CF2CHF2、甲氧基、乙氧基、正丙氧基、异丙氧基、-OCHF2、-OCHFCH2F、-OCF2CHF2、-OCH2CF3、-OCH2CF2CHF2、甲氨基、二甲氨基、乙氨基、环丙基、环丁基、环戊基、环己基、氮杂环丁基、氧杂环丁基、吡咯烷基、四氢呋喃基、哌啶基、哌嗪基和吗啉基各自独立任选地被1、2、3、4或5个独立地选自氘、氟、氯、溴、碘、羟基、氧代、氨基、硝基、氰基、甲基、乙基、正丙基、异丙基、三氟甲基、二氟甲基、甲氧基、乙氧基、异丙氧基、三氟甲氧基、-OCH2OH和-OCH2CH2OH的基团所取代。In some embodiments, each R x is independently deuterium, fluorine, chlorine, bromine, iodine, hydroxyl, oxo, amino, nitro, cyano, methyl, ethyl, n-propyl, isopropyl, alkenyl Propyl, propenyl, propargyl, propynyl, -CHF 2 , -CF 3 , -CHFCH 2 F, -CF 2 CHF 2 , -CH 2 CF 3 , -CH 2 CF 2 CHF 2 , methoxy , ethoxy, n-propoxy, isopropoxy, -OCHF 2 , -OCF 3 , -OCHFCH 2 F, -OCF 2 CHF 2 , -OCH 2 CF 3 , -OCH 2 CF 2 CHF 2 , methylamino , dimethylamino, ethylamino, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl or Morpholinyl; wherein, the methyl, ethyl, n-propyl, isopropyl, allyl, propenyl, propargyl, propynyl, -CHF 2 , -CHFCH 2 F, -CF 2 CHF 2 , -CH 2 CF 3 , -CH 2 CF 2 CHF 2 , methoxy, ethoxy, n-propoxy, isopropoxy, -OCHF 2 , -OCHFCH 2 F, -OCF 2 CHF 2 , -OCH 2 CF 3 , -OCH 2 CF 2 CHF 2 , methylamino, dimethylamino, ethylamino, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl , pyrrolidinyl, tetrahydrofuryl, piperidinyl, piperazinyl and morpholinyl are each independently optionally selected from deuterium, fluorine, chlorine, bromine, iodine, hydroxyl by 1, 2, 3, 4 or 5 , oxo, amino, nitro, cyano, methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, difluoromethyl, methoxy, ethoxy, isopropoxy, tri fluoromethoxy, -OCH 2 OH and -OCH 2 CH 2 OH groups.
在一些实施方案中，各Ry独立地为氘、氟、氯、溴、碘、羟基、氨基、硝基、氰基、C1-4烷基、C1-4卤代烷基、C1-4烷氧基、C1-4卤代烷氧基、C1-4羟基烷氧基、C1-4烷氨基、C3-6环烷基、3-6个原子组成的杂环基、C6-10芳基或5-10个原子组成的杂芳基；其中，所述的C1-4烷基、C1-4卤代烷基、C1-4烷氧基、C1-4卤代烷氧基、C1-4羟基烷氧基、C1-4烷氨基、C3-6环烷基、3-6个原子组成的杂环基、C6-10芳基和5-10个原子组成的杂芳基各自独立任选地被1、2、3、4或5个独立地选自氘、氟、氯、溴、碘、羟基、氧代、氨基、硝基、氰基、C1-3烷基、C1-3卤代烷基、C1-3烷氧基、C1-3卤代烷氧基和C1-3羟基烷氧基的基团所取代。In some embodiments, each Ry is independently deuterium, fluorine, chlorine, bromine, iodine, hydroxyl, amino, nitro, cyano, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 Alkoxy, C 1-4 haloalkoxy, C 1-4 hydroxyalkoxy, C 1-4 alkylamino, C 3-6 cycloalkyl, heterocyclic group consisting of 3-6 atoms, C 6- 10 aryl groups or heteroaryl groups consisting of 5-10 atoms; wherein, the C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy, C 1-4 haloalkoxy, C 1-4 hydroxyalkoxy, C 1-4 alkylamino, C 3-6 cycloalkyl, heterocyclic group consisting of 3-6 atoms, C 6-10 aryl and heterocyclic group consisting of 5-10 atoms Each aryl group is independently optionally selected from 1, 2, 3, 4 or 5 independently selected from deuterium, fluorine, chlorine, bromine, iodine, hydroxyl, oxo, amino, nitro, cyano, C 1-3 alkane Substituted by radical, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy and C 1-3 hydroxyalkoxy groups.
在一些实施方案中，各Ry独立地为氘、氟、氯、溴、碘、羟基、氨基、硝基、氰基、甲基、乙基、正丙基、异丙基、叔丁基、三氟甲基、二氟甲基、甲氧基、乙氧基、异丙氧基、三氟甲氧基、-OCH2OH、-OCH2CH2OH、甲氨基、乙氨基、二甲氨基、二乙氨基、环丙基、环丁基、环戊基、环己基、氮杂环丁基、氧杂环丁基、吡咯烷基、四氢呋喃基、哌啶基、哌嗪基、吗啉基、苯基、吡啶基、嘧啶基、吡咯基、吡唑基、咪唑基、噻吩基、噻唑基、呋喃基或三氮唑基；其中，所述的甲基、乙基、正丙基、异丙基、叔丁基、二氟甲基、甲氧基、乙氧基、异丙氧基、-OCH2OH、-OCH2CH2OH、甲氨基、乙氨基、二甲氨基、二乙氨基、环丙基、环丁基、环戊基、环己基、氮杂环丁基、氧杂环丁基、吡咯烷基、四氢呋喃基、哌啶基、哌嗪基、吗啉基、苯基、吡啶基、嘧啶基、吡咯基、吡唑基、咪唑基、噻吩基、噻唑基、呋喃基和三氮唑基各自独立任选地被1、2、3、4或5个独立地选自氘、氟、氯、溴、碘、羟基、氧代、氨基、硝基、氰基、甲基、乙基、正丙基、异丙基、三氟甲基、二氟甲基、甲氧基、乙氧基、异丙氧基、三氟甲氧基、-OCH2OH和-OCH2CH2OH的基团所取代。In some embodiments, each Ry is independently deuterium, fluorine, chlorine, bromine, iodine, hydroxyl, amino, nitro, cyano, methyl, ethyl, n-propyl, isopropyl, tert-butyl, Trifluoromethyl, difluoromethyl, methoxy, ethoxy, isopropoxy, trifluoromethoxy, -OCH 2 OH, -OCH 2 CH 2 OH, methylamino, ethylamino, dimethylamino , diethylamino, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, morpholinyl , phenyl, pyridyl, pyrimidyl, pyrrolyl, pyrazolyl, imidazolyl, thienyl, thiazolyl, furyl or triazolyl; wherein, the methyl, ethyl, n-propyl, iso Propyl, tert-butyl, difluoromethyl, methoxy, ethoxy, isopropoxy, -OCH 2 OH, -OCH 2 CH 2 OH, methylamino, ethylamino, dimethylamino, diethylamino , cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuryl, piperidinyl, piperazinyl, morpholinyl, phenyl, Pyridyl, pyrimidinyl, pyrrolyl, pyrazolyl, imidazolyl, thienyl, thiazolyl, furyl and triazolyl are each independently optionally selected from 1, 2, 3, 4 or 5 independently selected deuterium , fluorine, chlorine, bromine, iodine, hydroxyl, oxo, amino, nitro, cyano, methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, difluoromethyl, methoxy, ethoxy, isopropoxy, trifluoromethoxy, -OCH 2 OH and -OCH 2 CH 2 OH.
一方面，本发明涉及药物组合物，该药物组合物，包含本发明式(I)所述的化合物，或其立体异构体、互变异构体、氮氧化物、水合物、溶剂化物、代谢产物、药学上可接受的盐或它们的前药。In one aspect, the present invention relates to a pharmaceutical composition, which comprises the compound described in formula (I) of the present invention, or its stereoisomers, tautomers, nitrogen oxides, hydrates, solvates, Metabolites, pharmaceutically acceptable salts or their prodrugs.
其中一些实施方案是，本发明涉及的药物组合物还包含药学上可接受的载体、赋形剂、稀释剂、辅剂、媒介物或它们的组合。In some embodiments, the pharmaceutical composition of the present invention further comprises a pharmaceutically acceptable carrier, excipient, diluent, adjuvant, vehicle or a combination thereof.
一方面，本发明涉及前面所述的化合物或其药物组合物在制备用于预防、治疗或减轻患者由KRAS G12C介导的疾病的药物的用途。In one aspect, the present invention relates to the use of the aforementioned compounds or pharmaceutical compositions thereof in the preparation of medicines for preventing, treating or alleviating diseases mediated by KRAS G12C in patients.
其中一些实施方案是，本发明所述的由KRAS G12C介导的疾病为癌症。In some embodiments, the KRAS G12C-mediated disease of the present invention is cancer.
其中一些实施方案是，本发明所述的癌症为肺癌、淋巴瘤、食道癌、卵巢癌、胰腺癌、直肠癌、脑胶质瘤、子宫颈癌、尿路上皮癌、胃癌、子宫内膜癌、肝癌、胆管癌、乳腺癌、结肠癌、阑尾癌、小肠癌、白血病和黑色素瘤。In some embodiments, the cancer described in the present invention is lung cancer, lymphoma, esophageal cancer, ovarian cancer, pancreatic cancer, rectal cancer, glioma, cervical cancer, urothelial cancer, gastric cancer, endometrial cancer , liver cancer, bile duct cancer, breast cancer, colon cancer, appendix cancer, small bowel cancer, leukemia and melanoma.
另一方面，本发明涉及式(I)所示的化合物的制备、分离和纯化的方法。In another aspect, the present invention relates to methods for the preparation, isolation and purification of compounds represented by formula (I).
前面所述内容只概述了本发明的某些方面，但并不限于这些方面。这些方面及其他的方面的内容将在下面作更加具体完整的描述。The preceding description merely outlines certain aspects of the invention, but is not intended to be limiting. These and other aspects will be described in more detail and more fully below.
本发明的详细说明书Detailed Description of the Invention
定义和一般术语Definitions and General Terms
现在详细描述本发明的某些实施方案，其实例由随附的结构式和化学式说明。本发明意图涵盖所有的替代、修改和等同技术方案，它们均包括在本发明范围内。本领域技术人员应认识到，许多与本文所述类似或等同的方法和材料能够用于实践本发明。本发明绝不限于本文所述的方法和材料。在所结合的文献、专利和类似材料的一篇或多篇与本申请不同或相矛盾的情况下(包括但不限于所定义的术语、术语应用、所描述的技术，等等)，以本申请为准。Certain embodiments of the invention are now described in detail, examples of which are illustrated by the accompanying Structural and Chemical Formulas. The present invention intends to cover all alternatives, modifications and equivalent technical solutions, which are all included in the scope of the present invention. Those skilled in the art will recognize many methods and materials similar or equivalent to those described herein, which could be used in the practice of the present invention. The present invention is in no way limited to the methods and materials described herein. In the event that one or more of the incorporated literature, patents, and similar materials differs from or contradicts this application (including, but not limited to, defined terms, term usage, described techniques, etc.), this Application shall prevail.
应进一步认识到，本发明的某些特征，为清楚可见，在多个独立的实施方案中进行了描述，但也可以在单个实施例中以组合形式提供。反之，本发明的各种特征，为简洁起见，在单个实施方案中进行了描述，但也可以单独或以任意适合的子组合提供。It is further appreciated that certain features of the invention, which, for clarity, have been described in multiple separate embodiments, may also be provided in combination in a single embodiment. Conversely, various features of the invention, which are, for brevity, described in the context of a single embodiment, may also be provided separately or in any suitable subcombination.
除非另外说明，本发明所使用的所有科技术语具有与本发明所属领域技术人员的通常理解相同的含义。本发明涉及的所有专利和公开出版物通过引用方式整体并入本发明。Unless otherwise specified, all technical and scientific terms used in the present invention have the same meaning as commonly understood by those skilled in the art to which the present invention belongs. All patents and publications referred to herein are hereby incorporated by reference in their entirety.
除非另外说明，应当应用本文所使用的下列定义。出于本发明的目的，化学元素与元素周期表CAS版，和《化学和物理手册》，第75版，1994一致。此外，有机化学一般原理可参考"Organic Chemistry",Thomas Sorrell,University Science Books,Sausalito:1999,和"March's Advanced Organic Chemistry”by Michael B.Smith and Jerry March,JohnWiley&Sons,New York:2007中的描述，其全部内容通过引用并入本文。As used herein, the following definitions shall apply unless otherwise stated. For the purposes of the present invention, the chemical elements correspond to the Periodic Table of the Elements, CAS Edition, and Handbook of Chemistry and Physics, 75th Edition, 1994. In addition, the general principles of organic chemistry can refer to the descriptions in "Organic Chemistry", Thomas Sorrell, University Science Books, Sausalito: 1999, and "March's Advanced Organic Chemistry" by Michael B. Smith and Jerry March, John Wiley & Sons, New York: 2007, Its entire content is incorporated herein by reference.
除非另有说明或者上下文中有明显的冲突，本文所使用的冠词“一”、“一个(种)”和“所述”旨在包括“至少一个”或“一个或多个”。因此，本文所使用的这些冠词是指一个或多于一个(即至少一个)宾语的冠词。例如，“一组分”指一个或多个组分，即可能有多于一个的组分被考虑在所述实施方案的实施方式中采用或使用。As used herein, the articles "a", "an" and "the" are intended to include "at least one" or "one or more" unless otherwise stated or clearly contradicted by context. Therefore, as used herein, these articles refer to articles of one or more than one (ie, at least one) object. For example, "a component" refers to one or more components, ie there may be more than one component contemplated to be employed or used in the practice of the described embodiment.
本发明所使用的术语“患者”是指人(包括成人和儿童)或者其他动物。在一些实施方案中，“患者”是指人。The term "patient" as used herein refers to a human (including adults and children) or other animals. In some embodiments, "patient" refers to a human.
术语“包含”为开放式表达，即包括本发明所指明的内容，但并不排除其他方面的内容。The term "comprising" is an open expression, that is, it includes the content specified in the present invention, but does not exclude other content.
“立体异构体”是指具有相同化学构造，但原子或基团在空间上排列方式不同的化合物。立体异构体包括对映异构体、非对映异构体、构象异构体(旋转异构体)、几何异构体(顺/反异构体)、阻转异构体，等等。"Stereoisomers" refer to compounds that have the same chemical structure, but differ in the way the atoms or groups are arranged in space. Stereoisomers include enantiomers, diastereomers, conformational isomers (rotamers), geometric isomers (cis/trans isomers), atropisomers, etc. .
“手性”是指具有与其镜像不能重叠性质的分子；而“非手性”是指与其镜像可以重叠的分子。"Chiral" refers to a molecule that has the property of being nonsuperimposable to its mirror image; and "achiral" refers to a molecule that is superimposable to its mirror image.
“对映异构体”是指一个化合物的两个不能重叠但互成镜像关系的异构体。"Enantiomer" refers to two non-superimposable isomers of a compound that are mirror images of each other.
“非对映异构体”是指有两个或多个手性中心并且其分子不互为镜像的立体异构体。非对映异构体具有不同的物理性质，如熔点、沸点、光谱性质和反应性。非对映异构体混合物可通过高分辨分析操作如电泳和色谱，例如HPLC来分离。"Diastereoisomer" refers to stereoisomers that have two or more chiral centers and whose molecules are not mirror images of each other. Diastereomers have different physical properties such as melting points, boiling points, spectral properties and reactivity. Diastereomeric mixtures can be separated by high resolution analytical procedures such as electrophoresis and chromatography, eg HPLC.
本发明公开化合物的任何不对称原子(例如，碳等)都可以以外消旋或对映体富集的形式存在，例如(R)-、(S)-或(R,S)-构型形式存在。在某些实施方案中，各不对称原子在(R)-或(S)-构型方面具有至少50％对映体过量，至少60％对映体过量，至少70％对映体过量，至少80％对映体过量，至少90％对映体过量，至少95％对映体过量，或至少99％对映体过量。Any asymmetric atom (e.g., carbon, etc.) of the compounds disclosed herein may exist in racemic or enantiomerically enriched form, such as (R)-, (S)- or (R,S)-configuration exist. In certain embodiments, each asymmetric atom has at least 50% enantiomeric excess, at least 60% enantiomeric excess, at least 70% enantiomeric excess, at least 80% enantiomeric excess, at least 90% enantiomeric excess, at least 95% enantiomeric excess, or at least 99% enantiomeric excess.
依据起始物料和方法的选择，本发明化合物可以以可能的异构体中的一个或它们的混合物，例如外消旋体和非对映异构体混合物(这取决于不对称碳原子的数量)的形式存在。光学活性的(R)-或(S)-异构体可使用手性合成子或手性试剂制备，或使用常规技术拆分。如果化合物含有一个双键，取代基可能为E或Z构型；如果化合物中含有二取代的环烷基，环烷基的取代基可能有顺式或反式构型。Depending on the choice of starting materials and methods, the compounds of the present invention can be obtained as one of the possible isomers or as mixtures thereof, such as racemates and diastereomeric mixtures (depending on the number of asymmetric carbon atoms) ) form exists. Optically active (R)- or (S)-isomers can be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques. If the compound contains a double bond, the substituent may be in the E or Z configuration; if the compound contains a disubstituted cycloalkyl group, the substituent of the cycloalkyl group may have the cis or trans configuration.
可以用已知的方法将任何所得终产物或中间体的外消旋体通过本领域技术人员熟悉的方法拆分成光学对映体，如，通过对获得的其非对映异构的盐进行分离。外消旋的产物也可以通过手性色谱来分离，如，使用手性吸附剂的高效液相色谱(HPLC)。特别地，对映异构体可以通过不对称合成制备，例如，可参考Jacques,et al.,Enantiomers,Racematesand Resolutions(Wiley Interscience,New York,1981)；Principles of AsymmetricSynthesis(2nd Ed.Robert E.Gawley,Jeffrey Aubé,Elsevier,Oxford,UK,2012)；Eliel,E.L.Stereochemistry of Carbon Compounds(McGraw-Hill,NY,1962)；Wilen,S.H.Tablesof Resolving Agents and Optical Resolutions p.268(E.L.Eliel,Ed.,Univ.of NotreDame Press,Notre Dame,IN 1972)；Chiral Separation Techniques:A PracticalApproach(Subramanian,G.Ed.,Wiley-VCH Verlag GmbH&Co.KGaA,Weinheim,Germany,2007)。The racemates of any resulting final products or intermediates can be resolved into the optical antipodes by known methods by methods familiar to those skilled in the art, e.g., by subjecting the obtained diastereomeric salts thereof to separate. Racemic products can also be separated by chiral chromatography, eg, high performance liquid chromatography (HPLC) using a chiral adsorbent. In particular, enantiomers may be prepared by asymmetric synthesis, see for example Jacques, et al., Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981); Principles of Asymmetric Synthesis (2 nd Ed. Robert E. Gawley, Jeffrey Aubé, Elsevier, Oxford, UK, 2012); Eliel, ELStereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962); Wilen, SHTables of Resolving Agents and Optical Resolutions p.268 (ELEliel, Ed., Univ.of Notre Dame Press, Notre Dame, IN 1972); Chiral Separation Techniques: A Practical Approach (Subramanian, G. Ed., Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim, Germany, 2007).
术语“互变异构体”或“互变异构形式”是指具有不同能量的可通过低能垒(lowenergy barrier)互相转化的结构异构体。若互变异构是可能的(如在溶液中)，则可以达到互变异构体的化学平衡。例如，质子互变异构体(protontautomer)(也称为质子转移互变异构体(prototropic tautomer))包括通过质子迁移来进行的互相转化，如酮-烯醇异构化和亚胺-烯胺异构化。价键互变异构体(valence tautomer)包括通过一些成键电子的重组来进行的互相转化。酮-烯醇互变异构的具体实例是戊烷-2,4-二酮和4-羟基戊-3-烯-2-酮互变异构体的互变。互变异构的另一个实例是酚-酮互变异构。酚-酮互变异构的一个具体实例是吡啶-4-醇和吡啶-4(1H)-酮互变异构体的互变。除非另外指出，本发明化合物的所有互变异构体形式都在本发明的范围之内。The term "tautomer" or "tautomeric form" refers to structural isomers having different energies that are interconvertible through a low energy barrier. If tautomerism is possible (eg, in solution), then a chemical equilibrium of the tautomers can be achieved. For example, proton tautomers (also known as prototropic tautomers) include interconversions via migration of a proton, such as keto-enol isomerization and imine-enol isomerization Amine isomerization. Valence tautomers include interconversions by recombination of some of the bonding electrons. A specific example of keto-enol tautomerization is the interconversion of pentane-2,4-dione and 4-hydroxypent-3-en-2-one tautomers. Another example of tautomerization is phenol-keto tautomerization. A specific example of phenol-keto tautomerization is the interconversion of pyridin-4-ol and pyridin-4(1H)-one tautomers. Unless otherwise indicated, all tautomeric forms of the compounds of the invention are within the scope of the invention.
术语“任选”或“任选地”是指随后描述的事件或情形可以但不一定出现，并且该描述包括其中所述事件或情形出现的情况以及其它不出现的情况。例如，“任选的键”是指该键可以存在或可以不存在，并且该描述包括单键、双键或三键。The terms "optional" or "optionally" mean that the subsequently described event or circumstance can but do not have to occur, and that the description includes instances where said event or circumstance occurs and other instances where it does not. For example, "an optional bond" means that the bond may or may not be present, and the description includes single, double, or triple bonds.
术语“取代的”表示所给结构中的一个或多个氢原子被具体取代基所取代。像本发明所描述的，本发明的化合物可以任选地被一个或多个取代基所取代，如上面的通式化合物，或者像实施例里面特殊的例子，子类，和本发明所包含的一类化合物。术语“任选地被…….所取代”，可以与术语“未取代或被…..所取代”交换使用，即所述结构是未取代的或者被一个或多个本发明所述的取代基取代；当所述取代基个数大于1时，所述的取代基相互之间可以是相同或不同的。例如，本发明所述的“任选地被1、2、3、4或5个独立选自……的基团所取代”，当所述取代基的个数大于1时，所述取代基可以是相同或者不同的。The term "substituted" means that one or more hydrogen atoms in the given structure have been replaced by a particular substituent. As described in the present invention, the compounds of the present invention can be optionally substituted by one or more substituents, such as the above general formula compounds, or as specific examples in the examples, subclasses, and included in the present invention A class of compounds. The term "optionally substituted with" may be used interchangeably with the term "unsubstituted or substituted", that is, the structure in question is either unsubstituted or substituted with one or more of the compounds described herein substituent; when the number of substituents is greater than 1, the substituents may be the same or different from each other. For example, "optionally substituted by 1, 2, 3, 4 or 5 groups independently selected from ..." described in the present invention, when the number of the substituents is greater than 1, the substituents Can be the same or different.
除非其他方面表明，一个任选的取代基团可以在基团各个可取代的位置进行取代。当所给出的结构式中不止一个位置能被选自具体基团的一个或多个取代基所取代，那么取代基可以相同或不同地在各个位置取代。其中所述的取代基可以是，但并不限于，氘、氧代、卤素、氰基、硝基、羟基、巯基、氨基、烷氨基、芳氨基、氨基烷基、烷基、烯基、炔基、烷基硫基、羟基烷基、羟基烷氧基、卤代烷基、环烷基、杂环基、芳基、杂芳基、烷酰基、芳基酰基、杂芳基酰基、烷氧基、卤代烷氧基、芳氧基、杂芳基氧基、烷基酰氧基、羧基、烷氧基酰基、芳氧基酰基、杂芳氧基酰基、烷基磺酰基、芳基磺酰基、杂芳基磺酰基、烷氧基磺酰基、氨基酰基、烷氨基酰基、氨基磺酰基、烷氨基磺酰基等。Unless otherwise indicated, an optional substituent may be substituted at each substitutable position of the group. When more than one position in a given formula can be substituted by one or more substituents selected from a particular group, then the substituents may be substituted at each position the same or differently. The substituents described therein can be, but are not limited to, deuterium, oxo, halogen, cyano, nitro, hydroxyl, mercapto, amino, alkylamino, arylamino, aminoalkyl, alkyl, alkenyl, alkyne radical, alkylthio, hydroxyalkyl, hydroxyalkoxy, haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, alkanoyl, arylacyl, heteroarylacyl, alkoxyl, Haloalkoxy, aryloxy, heteroaryloxy, alkylacyloxy, carboxyl, alkoxyacyl, aryloxyacyl, heteroaryloxyacyl, alkylsulfonyl, arylsulfonyl, heteroaryl Sulfonyl, alkoxysulfonyl, aminoacyl, alkylaminoacyl, aminosulfonyl, alkylaminosulfonyl, etc.
另外，需要说明的是，除非以其他方式明确指出，在本发明中所采用的描述方式“各…独立地为”与“…各自独立地为”和“…独立地为”可以互换，均应做广义理解，其既可以是指在不同基团中，相同符号之间所表达的具体选项之间互相不影响，也可以表示在相同的基团中，相同符号之间所表达的具体选项之间互相不影响。In addition, it should be noted that, unless otherwise clearly stated, the descriptions used in the present invention "each...independently are" can be interchanged with "...independently" and "...independently". It should be understood in a broad sense. It can mean that in different groups, the specific options expressed between the same symbols do not affect each other, and it can also mean that in the same group, the specific options expressed between the same symbols do not affect each other.
在本说明书的各部分，本发明公开化合物的取代基按照基团种类或范围公开。特别指出，本发明包括这些基团种类和范围的各个成员的每一个独立的次级组合。例如，术语“C1-6烷基”特别指独立公开的甲基、乙基、C3烷基、C4烷基、C5烷基和C6烷基。In each part of this specification, the substituents of the compounds disclosed in the present invention are disclosed according to the type or range of the group. It is specifically intended that the invention includes each individual subcombination of individual members of these radical classes and ranges. For example, the term "C 1-6 alkyl" specifically refers to independently disclosed methyl, ethyl, C 3 alkyl, C 4 alkyl, C 5 alkyl and C 6 alkyl.
在本发明的各部分，描述了连接取代基。当该结构清楚地需要连接基团时，针对该基团所列举的马库什变量应理解为连接基团。例如，如果该结构需要连接基团并且针对该变量的马库什基团定义列举了“烷基”或“芳基”，则应该理解，该“烷基”或“芳基”分别代表连接的亚烷基基团或亚芳基基团。In various sections of the invention linking substituents are described. When the structure clearly requires a linking group, the Markush variables recited for that group are to be understood as linking groups. For example, if the structure requires a linking group and the Markush group definition for that variable recites "alkyl" or "aryl," it is understood that "alkyl" or "aryl" respectively represents the linking group. An alkylene group or an arylene group.
本发明使用的术语“烷基”或“烷基基团”，表示含有1至20个碳原子，饱和的直链或支链一价烃基基团，其中，所述烷基基团可以任选地被一个或多个本发明描述的取代基所取代。除非另外详细说明，烷基基团含有1-20个碳原子。在一些实施方案中，烷基基团含有1-12个碳原子；在另一些实施方案中，烷基基团含有1-6个碳原子；在又一些实施方案中，烷基基团含有1-4个碳原子；还在一些实施方案中，烷基基团含有1-3个碳原子。The term "alkyl" or "alkyl group" used in the present invention means a saturated linear or branched monovalent hydrocarbon group containing 1 to 20 carbon atoms, wherein the alkyl group can be optionally substituted by one or more of the substituents described herein. Unless otherwise specified, an alkyl group contains 1-20 carbon atoms. In some embodiments, the alkyl group contains 1-12 carbon atoms; in other embodiments, the alkyl group contains 1-6 carbon atoms; in still other embodiments, the alkyl group contains 1 - 4 carbon atoms; in still some embodiments, the alkyl group contains 1-3 carbon atoms.
烷基基团的实例包含，但并不限于，甲基(Me、-CH3)，乙基(Et、-CH2CH3)，正丙基(n-Pr、-CH2CH2CH3)，异丙基(i-Pr、-CH(CH3)2)，正丁基(n-Bu、-CH2CH2CH2CH3)，异丁基(i-Bu、-CH2CH(CH3)2)，仲丁基(s-Bu、-CH(CH3)CH2CH3)，叔丁基(t-Bu、-C(CH3)3)，正戊基(-CH2CH2CH2CH2CH3)，2-戊基(-CH(CH3)CH2CH2CH3)，3-戊基(-CH(CH2CH3)2)，2-甲基-2-丁基(-C(CH3)2CH2CH3)，3-甲基-2-丁基(-CH(CH3)CH(CH3)2)，3-甲基-1-丁基(-CH2CH2CH(CH3)2)，2-甲基-1-丁基(-CH2CH(CH3)CH2CH3)，正己基(-CH2CH2CH2CH2CH2CH3)，2-己基(-CH(CH3)CH2CH2CH2CH3)，3-己基(-CH(CH2CH3)(CH2CH2CH3))，2-甲基-2-戊基(-C(CH3)2CH2CH2CH3)，3-甲基-2-戊基(-CH(CH3)CH(CH3)CH2CH3)，4-甲基-2-戊基(-CH(CH3)CH2CH(CH3)2)，3-甲基-3-戊基(-C(CH3)(CH2CH3)2)，2-甲基-3-戊基(-CH(CH2CH3)CH(CH3)2)，2,3-二甲基-2-丁基(-C(CH3)2CH(CH3)2)，3,3-二甲基-2-丁基(-CH(CH3)C(CH3)3)，正庚基，正辛基，等等。Examples of alkyl groups include, but are not limited to, methyl (Me, -CH 3 ), ethyl (Et, -CH 2 CH 3 ), n-propyl (n-Pr, -CH 2 CH 2 CH 3 ), isopropyl (i-Pr, -CH(CH 3 ) 2 ), n-butyl (n-Bu, -CH 2 CH 2 CH 2 CH 3 ), isobutyl (i-Bu, -CH 2 CH (CH 3 ) 2 ), sec-butyl (s-Bu, -CH(CH 3 )CH 2 CH 3 ), tert-butyl (t-Bu, -C(CH 3 ) 3 ), n-pentyl (-CH 2CH 2 CH 2 CH 2 CH 3 ), 2-pentyl (-CH(CH 3 )CH 2 CH 2 CH 3 ), 3-pentyl (-CH(CH 2 CH 3 ) 2 ), 2-methyl -2-butyl (-C(CH 3 ) 2 CH 2 CH 3 ), 3-methyl-2-butyl (-CH(CH 3 )CH(CH 3 ) 2 ), 3-methyl-1- Butyl (-CH 2 CH 2 CH(CH 3 ) 2 ), 2-methyl-1-butyl (-CH 2 CH(CH 3 )CH 2 CH 3 ), n-hexyl (-CH 2 CH 2 CH 2 CH 2 CH 2 CH 3 ), 2-hexyl (-CH(CH 3 )CH 2 CH 2 CH 2 CH 3 ), 3-hexyl (-CH(CH 2 CH 3 )(CH 2 CH 2 CH 3 )), 2-methyl-2-pentyl (-C(CH 3 ) 2 CH 2 CH 2 CH 3 ), 3-methyl-2-pentyl (-CH(CH 3 )CH(CH 3 )CH 2 CH 3 ), 4-methyl-2-pentyl (-CH(CH 3 )CH 2 CH(CH 3 ) 2 ), 3-methyl-3-pentyl (-C(CH 3 )(CH 2 CH 3 ) 2 ), 2-methyl-3-pentyl (-CH(CH 2 CH 3 ) CH(CH 3 ) 2 ), 2,3-dimethyl-2-butyl (-C(CH 3 ) 2 CH (CH 3 ) 2 ), 3,3-dimethyl-2-butyl (-CH(CH 3 )C(CH 3 ) 3 ), n-heptyl, n-octyl, and the like.
术语“烯基”表示含有2-12个碳原子的直链或支链一价烃基，其中至少有一个不饱和位点，即有一个碳-碳sp2双键，其中，所述烯基基团可以任选地被一个或多个本发明所描述的取代基所取代，其包括“cis”和“trans”的定位，或者"E"和"Z"的定位。在一实施方案中，烯基基团包含2-8个碳原子；在另一实施方案中，烯基基团包含2-6个碳原子；在又一实施方案中，烯基基团包含2-4个碳原子。烯基基团的实例包括，但并不限于，乙烯基(-CH＝CH2)、烯丙基(-CH2CH＝CH2)、1-丙烯基(丙烯基，-CH＝CH-CH3)等等。The term "alkenyl" means a linear or branched monovalent hydrocarbon group containing 2-12 carbon atoms, wherein there is at least one unsaturated site, that is, a carbon-carbon sp 2 double bond, wherein the alkenyl group Groups may be optionally substituted with one or more substituents described herein, including the "cis" and "trans" orientations, or the "E" and "Z" orientations. In one embodiment, an alkenyl group contains 2-8 carbon atoms; in another embodiment, an alkenyl group contains 2-6 carbon atoms; in yet another embodiment, an alkenyl group contains 2 - 4 carbon atoms. Examples of alkenyl groups include, but are not limited to, vinyl (-CH=CH 2 ), allyl (-CH 2 CH=CH 2 ), 1-propenyl (propenyl, -CH=CH-CH 3 ) and so on.
术语“炔基”表示含有2-12个碳原子的直链或支链一价烃基，其中至少有一个不饱和位点，即有一个碳-碳sp三键，其中，所述炔基基团可以任选地被一个或多个本发明所描述的取代基所取代。在一些实施方案中，炔基基团包含2-8个碳原子；在另一些实施方案中，炔基基团包含2-6个碳原子；在又一些实施方案中，炔基基团包含2-4个碳原子。炔基基团的实例包括，但并不限于，乙炔基(-C≡CH)、炔丙基(-CH2C≡CH)、1-丙炔基(丙炔基，-C≡C-CH3)等等。The term "alkynyl" means a linear or branched monovalent hydrocarbon group containing 2-12 carbon atoms, wherein there is at least one unsaturated site, that is, a carbon-carbon sp triple bond, wherein the alkynyl group Can be optionally substituted with one or more substituents described herein. In some embodiments, alkynyl groups contain 2-8 carbon atoms; in other embodiments, alkynyl groups contain 2-6 carbon atoms; in yet other embodiments, alkynyl groups contain 2 - 4 carbon atoms. Examples of alkynyl groups include, but are not limited to, ethynyl (-C≡CH), propargyl ( -CH2C≡CH ), 1-propynyl (propynyl, -C≡C-CH 3 ) and so on.
术语“烷氧基”表示烷基基团通过氧原子与分子其余部分相连，其中烷基基团具有如本发明所述的含义。除非另外详细说明，所述烷氧基基团含有1-12个碳原子。在一些实施方案中，烷氧基基团含有1-6个碳原子；在另一些实施方案中，烷氧基基团含有1-4个碳原子；在又一些实施方案中，烷氧基基团含有1-3个碳原子。所述烷氧基基团可以任选地被一个或多个本发明描述的取代基所取代。The term "alkoxy" denotes an alkyl group attached to the rest of the molecule through an oxygen atom, wherein the alkyl group has the meaning described herein. Unless specified otherwise, the alkoxy groups contain 1-12 carbon atoms. In some embodiments, alkoxy groups contain 1-6 carbon atoms; in other embodiments, alkoxy groups contain 1-4 carbon atoms; in still other embodiments, alkoxy groups Groups contain 1-3 carbon atoms. The alkoxy groups may be optionally substituted with one or more substituents described herein.
烷氧基基团的实例包括，但并不限于，甲氧基(MeO、-OCH3)，乙氧基(EtO、-OCH2CH3)，1-丙氧基(n-PrO、n-丙氧基、-OCH2CH2CH3)，2-丙氧基(i-PrO、i-丙氧基、-OCH(CH3)2)，1-丁氧基(n-BuO、n-丁氧基、-OCH2CH2CH2CH3)，2-甲基-l-丙氧基(i-BuO、i-丁氧基、-OCH2CH(CH3)2)，2-丁氧基(s-BuO、s-丁氧基、-OCH(CH3)CH2CH3)，2-甲基-2-丙氧基(t-BuO、t-丁氧基、-OC(CH3)3)，1-戊氧基(n-戊氧基、-OCH2CH2CH2CH2CH3)，2-戊氧基(-OCH(CH3)CH2CH2CH3)，3-戊氧基(-OCH(CH2CH3)2)，2-甲基-2-丁氧基(-OC(CH3)2CH2CH3)，3-甲基-2-丁氧基(-OCH(CH3)CH(CH3)2)，3-甲基-l-丁氧基(-OCH2CH2CH(CH3)2)，2-甲基-l-丁氧基(-OCH2CH(CH3)CH2CH3)，等等。Examples of alkoxy groups include, but are not limited to, methoxy (MeO, -OCH 3 ), ethoxy (EtO, -OCH 2 CH 3 ), 1-propoxy (n-PrO, n- Propoxy, -OCH 2 CH 2 CH 3 ), 2-propoxy (i-PrO, i-propoxy, -OCH(CH 3 ) 2 ), 1-butoxy (n-BuO, n- Butoxy, -OCH 2 CH 2 CH 2 CH 3 ), 2-methyl-l-propoxy (i-BuO, i-butoxy, -OCH 2 CH(CH 3 ) 2 ), 2-butane Oxygen (s-BuO, s-butoxy, -OCH(CH 3 )CH 2 CH 3 ), 2-methyl-2-propoxy (t-BuO, t-butoxy, -OC(CH 3 ) 3 ), 1-pentyloxy (n-pentyloxy, -OCH 2 CH 2 CH 2 CH 2 CH 3 ), 2-pentyloxy (-OCH(CH 3 )CH 2 CH 2 CH 3 ), 3-pentyloxy (-OCH(CH 2 CH 3 ) 2 ), 2-methyl-2-butoxy (-OC(CH 3 ) 2 CH 2 CH 3 ), 3-methyl-2-butoxy (-OCH(CH 3 )CH(CH 3 ) 2 ), 3-methyl-l-butoxy (-OCH 2 CH 2 CH(CH 3 ) 2 ), 2-methyl-l-butoxy ( -OCH2CH ( CH3 ) CH2CH3 ), and so on .
术语“卤代烷基”或“卤代烷氧基”表示烷基或烷氧基基团被一个或多个卤素原子所取代，这样的实例包含，但并不限于，三氟甲基、三氟甲氧基等。The term "haloalkyl" or "haloalkoxy" means an alkyl or alkoxy group substituted with one or more halogen atoms, examples of which include, but are not limited to, trifluoromethyl, trifluoromethoxy wait.
术语“羟基烷氧基”表示烷氧基基团被一个或多个羟基所取代，这样的实例包含，但并不限于，-OCH2OH、-OCH2CH2OH等。The term " hydroxyalkoxy" means that an alkoxy group is substituted with one or more hydroxyl groups, examples of which include, but are not limited to, -OCH2OH , -OCH2CH2OH , and the like.
术语“碳环基”或“碳环”表示含有3-12个碳原子的，单价或多价的非芳香性的饱和或部分不饱和单环、双环或者三环体系。碳双环基包括螺碳双环基、稠合碳双环基和桥碳双环基，合适的碳环基基团包括，但并不限于，环烷基、环烯基和环炔基。碳环基基团的实例进一步包括，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-1-烯基、1-环己基-2-烯基、1-环己基-3-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，等等。The term "carbocyclyl" or "carbocycle" denotes a monovalent or polyvalent non-aromatic saturated or partially unsaturated monocyclic, bicyclic or tricyclic ring system containing 3-12 carbon atoms. Carbobicyclyls include spirocarbobicyclyls, fused carbobicyclyls and bridged carbobicyclyls, and suitable carbocyclyl groups include, but are not limited to, cycloalkyl, cycloalkenyl and cycloalkynyl. Examples of carbocyclyl groups further include, cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopentyl-1-enyl, 1-cyclopentyl-2-enyl, 1-cyclopentyl- 3-alkenyl, cyclohexyl, 1-cyclohexyl-1-enyl, 1-cyclohexyl-2-enyl, 1-cyclohexyl-3-enyl, cyclohexadienyl, cycloheptyl, cyclooctyl Cyclononyl, cyclodecyl, cycloundecyl, cyclododecyl, etc.
术语“环烷基”表示含有3-12个碳原子的，单价或多价的非芳香性的饱和单环、双环或三环体系。在一些实施方案中，环烷基包含3-12个碳原子；在另一些实施方案中，环烷基包含3-8个碳原子；在又一些实施方案中，环烷基包含3-6个碳原子。环烷基基团的实例包括，但并不限于，环丙基、环丁基、环戊基、环己基，等等。所述环烷基基团任选地被一个或多个本发明所描述的取代基所取代。The term "cycloalkyl" denotes a monovalent or polyvalent non-aromatic saturated monocyclic, bicyclic or tricyclic ring system containing 3 to 12 carbon atoms. In some embodiments, cycloalkyl groups contain 3-12 carbon atoms; in other embodiments, cycloalkyl groups contain 3-8 carbon atoms; in still other embodiments, cycloalkyl groups contain 3-6 carbon atom. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like. The cycloalkyl group is optionally substituted with one or more substituents described herein.
术语“杂环”、“杂环基”或“杂环的”在此处可交换使用，是指包含3-14个环原子的，单价或多价的单环、双环或者三环体系，其中环上一个或多个原子独立地被杂原子所替换，所述杂原子具有如本发明所述的含义，环可以是完全饱和的或包含一个或多个不饱和度，但一个芳香性环都不能有。在一些实施方案中，“杂环”，“杂环基”或“杂环的”基团是3-8元环的单环(环原子包含2-6个碳原子和选自N，O，P，S的1-3个杂原子，在此S或P任选地被一个或多个氧原子所取代得到像SO，SO2，PO的基团)，或7-12元的双环(环原子包含4-9个碳原子和选自N，O，P，S的1-3个杂原子，在此S或P任选地被一个或多个氧原子所取代得到像SO，SO2，PO的基团)。在另一些实施方案中，“杂环”，“杂环基”或“杂环的”基团是3-6元环的单环(环原子包含2-4个碳原子和选自N，O，P，S的1-3个杂原子，在此S或P任选地被一个或多个氧原子所取代得到像SO，SO2，PO的基团)。所述杂环基基团任选地被一个或多个本发明所描述的取代基所取代。The terms "heterocycle", "heterocyclyl" or "heterocyclic" are used interchangeably herein to refer to a monovalent or multivalent monocyclic, bicyclic or tricyclic ring system containing 3-14 ring atoms, wherein One or more atoms on the ring are independently replaced by heteroatoms, the heteroatoms have the meaning as described in the present invention, the ring may be fully saturated or contain one or more degrees of unsaturation, but an aromatic ring is not allowed. In some embodiments, a "heterocycle", "heterocyclyl" or "heterocyclic" group is a 3-8 membered ring monocyclic (ring atoms containing 2-6 carbon atoms and selected from N, O, P, 1-3 heteroatoms of S, where S or P is optionally substituted by one or more oxygen atoms to obtain groups like SO, SO 2 , PO), or 7-12 membered bicyclic rings (ring The atoms contain 4-9 carbon atoms and 1-3 heteroatoms selected from N, O, P, S, where S or P is optionally replaced by one or more oxygen atoms to obtain like SO, SO 2 , PO group). In other embodiments, a "heterocycle", "heterocyclyl" or "heterocyclic" group is a 3-6 membered monocyclic ring (the ring atoms contain 2-4 carbon atoms and are selected from N, O , P, 1-3 heteroatoms of S, where S or P is optionally substituted by one or more oxygen atoms to obtain a group like SO, SO 2 , PO). The heterocyclyl group is optionally substituted with one or more substituents described herein.
杂环基可以是碳基或杂原子基；其中，环的-CH2-基团可以任选地被-C(＝O)-替代，环的硫原子可以任选地被氧化成S-氧化物，环的氮原子可以任选地被氧化成N-氧化合物。杂环基的实例包括，但不限于，环氧乙烷基、氮杂环丁基，氧杂环丁基，硫杂环丁基，吡咯烷基，2-吡咯啉基，3-吡咯啉基，吡唑啉基，吡唑烷基，咪唑啉基，咪唑烷基，四氢呋喃基，二氢呋喃基，四氢噻吩基，二氢噻吩基，1,3-二氧环戊基，二硫环戊基，四氢吡喃基，二氢吡喃基，2H-吡喃基，4H-吡喃基，四氢噻喃基，哌啶基，吗啉基，硫代吗啉基，哌嗪基，二噁烷基，二噻烷基，噻噁烷基，高哌嗪基，高哌啶基，氧杂环庚烷基，硫杂环庚烷基，氧氮杂
术语“芳基”表示含有6-14个环原子，或6-12个环原子，或6-10个环原子的单环、双环和三环的碳环体系，其中，至少一个环体系是芳香族的，其中每一个环体系包含3-7个原子组成的环，且有一个或多个附着点与分子的其余部分相连。术语“芳基”可以和术语“芳香环”交换使用。芳基基团的实例可以包括苯基、萘基和蒽基。所述芳基基团任选地被一个或多个本发明所描述的取代基所取代。The term "aryl" denotes monocyclic, bicyclic and tricyclic carbocyclic ring systems containing 6-14 ring atoms, or 6-12 ring atoms, or 6-10 ring atoms, wherein at least one ring system is aromatic family in which each ring system contains rings of 3-7 atoms and has one or more points of attachment to the rest of the molecule. The term "aryl" is used interchangeably with the term "aromatic ring". Examples of aryl groups may include phenyl, naphthyl and anthracenyl. The aryl group is optionally substituted with one or more substituents described herein.
术语“杂芳基”或“杂芳环”表示含有5-14个环原子，或5-10个环原子，或5-6个环原子的，单价或多价的单环、双环或三环体系，其中至少一个环是芳香族的，且至少一个环包含一个或多个杂原子。杂芳基基团通常，但不必须地通过杂芳基基团的芳香性环与母体分子连接。术语“杂芳基”可以与术语“杂芳环”或“杂芳族化合物”交换使用。所述杂芳基基团任选地被一个或多个本发明所描述的取代基所取代。在一些实施方案中，5-10个环原子组成的杂芳基包含1、2、3或4个独立选自O、S和N的杂原子；在另一些实施方案中，5-6个环原子组成的杂芳基为单环体系且包含1、2、3或4个独立选自O、S和N的杂原子。The term "heteroaryl" or "heteroaryl ring" means a monovalent or polyvalent monocyclic, bicyclic or tricyclic ring containing 5-14 ring atoms, or 5-10 ring atoms, or 5-6 ring atoms A system wherein at least one ring is aromatic and at least one ring contains one or more heteroatoms. The heteroaryl group is usually, but not necessarily, attached to the parent molecule through the aromatic ring of the heteroaryl group. The term "heteroaryl" may be used interchangeably with the terms "heteroaryl" or "heteroaromatic". The heteroaryl group is optionally substituted with one or more substituents described herein. In some embodiments, a heteroaryl group consisting of 5-10 ring atoms contains 1, 2, 3, or 4 heteroatoms independently selected from O, S, and N; in other embodiments, 5-6 ring atoms The heteroaryl group of atoms is a monocyclic ring system and contains 1, 2, 3 or 4 heteroatoms independently selected from O, S and N.
杂芳基基团的实例包括，但并不限于，2-呋喃基、3-呋喃基、N-咪唑基、2-咪唑基、4-咪唑基、5-咪唑基、3-异噁唑基、4-异噁唑基、5-异噁唑基、2-噁唑基、4-噁唑基、5-噁唑基、N-吡咯基、2-吡咯基、3-吡咯基、2-吡啶基、3-吡啶基、4-吡啶基、2-嘧啶基、4-嘧啶基、5-嘧啶基、哒嗪基(如3-哒嗪基)、2-噻唑基、4-噻唑基、5-噻唑基、四唑基(如5-四唑基)、三唑基(如2-三唑基和5-三唑基)、2-噻吩基、3-噻吩基、吡唑基(如2-吡唑基)、异噻唑基、1,2,3-噁二唑基、1,2,5-噁二唑基、1,2,4-噁二唑基、1,2,3-三唑基、1,2,3-硫代二唑基、1,3,4-硫代二唑基、1,2,5-硫代二唑基、吡嗪基、1,3,5-三嗪基；也包括以下的双环，但绝不限于这些双环：苯并咪唑基、苯并呋喃基、苯并噻吩基、吲哚基(如2-吲哚基)、嘌呤基、喹啉基(如2-喹啉基，3-喹啉基，4-喹啉基)、异喹啉基(如1-异喹啉基、3-异喹啉基或4-异喹啉基)、氮杂喹啉、咪唑并[1,2-a]吡啶基、吡唑并[1,5-a]吡啶基、吡唑并[1,5-a]嘧啶基、咪唑并[1,2-b]哒嗪基、[1,2,4]三唑并[4,3-b]哒嗪基、[1,2,4]三唑并[1,5-a]嘧啶基、[1,2,4]三唑并[1,5-a]吡啶基，等等。Examples of heteroaryl groups include, but are not limited to, 2-furyl, 3-furyl, N-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl, 3-isoxazolyl , 4-isoxazolyl, 5-isoxazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, N-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 2- Pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, pyridazinyl (such as 3-pyridazinyl), 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, tetrazolyl (such as 5-tetrazolyl), triazolyl (such as 2-triazolyl and 5-triazolyl), 2-thienyl, 3-thienyl, pyrazolyl (such as 2-pyrazolyl), isothiazolyl, 1,2,3-oxadiazolyl, 1,2,5-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,3- Triazolyl, 1,2,3-thiodiazolyl, 1,3,4-thiodiazolyl, 1,2,5-thiodiazolyl, pyrazinyl, 1,3,5- Triazinyl; also includes, but is by no means limited to, the following bicyclic rings: benzimidazolyl, benzofuryl, benzothienyl, indolyl (eg 2-indolyl), purinyl, quinolinyl (such as 2-quinolinyl, 3-quinolinyl, 4-quinolinyl), isoquinolinyl (such as 1-isoquinolinyl, 3-isoquinolinyl or 4-isoquinolinyl), nitrogen Heteroquinoline, imidazo[1,2-a]pyridyl, pyrazolo[1,5-a]pyridyl, pyrazolo[1,5-a]pyrimidinyl, imidazo[1,2-b ]pyridazinyl, [1,2,4]triazolo[4,3-b]pyridazinyl, [1,2,4]triazolo[1,5-a]pyrimidinyl, [1,2 ,4]triazolo[1,5-a]pyridyl, etc.
术语“含氮原子的单环”是指包含1或2个氮原子的4-8个环原子的单环，环可以是完全饱和或包含一个或多个饱和度，但没有芳香性。含氮原子的单环实例包括，但并不限于，氮杂环丁烷、吡咯烷、哌啶、哌嗪等。所述的含氮原子的单环任选地被一个或多个本发明所描述的取代基取代。The term "nitrogen-containing monocyclic ring" refers to a monocyclic ring of 4-8 ring atoms containing 1 or 2 nitrogen atoms, the ring may be fully saturated or contain one or more degrees of saturation, but is not aromatic. Examples of monocyclic rings containing nitrogen atoms include, but are not limited to, azetidine, pyrrolidine, piperidine, piperazine, and the like. The nitrogen-containing monocyclic ring is optionally substituted by one or more substituents described in the present invention.
术语“稠合双环”，“稠环”，“稠合双环基”和“稠环基”在此处可交换使用，都是指包含5-12个环原子的，单价或多价的饱和或部分不饱和的并环体系，所述并环体系是指两个环共用两个邻位环原子形成的非芳香族的双环体系。这样的体系可以包含独立的或共轭的不饱和体系，但其核心结构不包含芳香环或芳杂环(但是芳香族基团可以作为其上的取代基)。术语“含氮原子的稠环”是指包含1或2个氮原子的稠环，含氮原子的稠环的实例包括，但并不限于，八氢吡咯并[3,4-c]吡咯等。所述稠环任选地被一个或多个本发明所描述的取代基所取代。The terms "fused bicyclic", "fused ring", "fused bicyclyl" and "fused cycloyl" are used interchangeably herein to refer to monovalent or multivalent saturated or Partially unsaturated parallel ring system, said parallel ring system refers to a non-aromatic bicyclic ring system formed by two rings sharing two adjacent ring atoms. Such a system may contain independent or conjugated unsaturated systems, but its core structure does not contain aromatic rings or aromatic heterocycles (although aromatic groups may act as substituents thereon). The term "nitrogen atom-containing fused ring" refers to a condensed ring containing 1 or 2 nitrogen atoms. Examples of nitrogen atom-containing fused rings include, but are not limited to, octahydropyrrolo[3,4-c]pyrrole, etc. . The fused ring is optionally substituted with one or more substituents described herein.
术语“螺环基”，“螺环”，“螺双环基”或“螺双环”在此处可交换使用，是指包含5-12个环原子的，单价或多价的饱和或部分不饱和的双环体系，其中一个环起源于另一个环上特定的环碳原子。如式(a)所示，环A和环B在两个饱和的环体系中共享一个碳原子，被称为“螺环”或“螺双环”，而环B和环B’被称为“稠合双环”。螺双环基中的每个环都可以是碳环基或杂环基。术语“含氮原子的螺环”是指包含1或2个氮原子的螺环，含氮原子的螺环的实例包括，但并不限于，2,7-二氮杂螺[3.5]壬烷，2,6-二氮杂螺[3.3]庚烷等。所述螺环任选地被一个或多个本发明所描述的取代基所取代。The terms "spirocyclyl", "spirocycle", "spirobicyclyl" or "spirobicyclo" are used interchangeably herein to refer to monovalent or polyvalent saturated or partially unsaturated A bicyclic ring system in which one ring originates from a specific ring carbon atom on the other ring. As shown in formula (a), ring A and ring B share a carbon atom in two saturated ring systems, which are called "spiro ring" or "spiro bicyclic ring", while ring B and ring B' are called "spiro ring" Fused Bicyclic". Each ring in a spirobicyclyl can be carbocyclyl or heterocyclyl. The term "nitrogen atom-containing spirocycle" refers to a spirocycle containing 1 or 2 nitrogen atoms. Examples of nitrogen atom-containing spirocycles include, but are not limited to, 2,7-diazaspiro[3.5]nonane , 2,6-diazaspiro[3.3]heptane, etc. The spirocycle is optionally substituted with one or more substituents described herein.
术语“桥环”或“桥环基”表示饱和或部分不饱和的桥环体系，其中桥环体系指两个环共用一个烷链或杂烷链形成的环体系，其中所述的烷链或杂烷链至少包括3个链原子，涉及到非芳香族的双环体系，例如式(b)所示，即环A1与环A2共有一个烷链或一个杂烷链，其中所述烷链或杂烷链上的各X3独立任选地为碳原子或杂原子，j为1、2、3或4。这样的体系包含5-12个环原子，可以包含独立的或共轭的不饱和状态，但其核心结构不包含芳香环或芳环(但是芳香族可以作为其上的取代基)。其中每一个环，如A1或A2，包含4-7个原子，术语“含氮原子的桥环”是指包含1或2个氮原子的桥环，含氮原子的桥环这样的实例包括，但并不限于，(1R,5S)-3,8-二氮杂双环[3.2.1]辛烷等。所述桥环任选地被一个或多个本发明所描述的取代基所取代。The term "bridged ring" or "bridged ring group" means a saturated or partially unsaturated bridged ring system, wherein the bridged ring system refers to a ring system formed by two rings sharing an alkane chain or a heteroalkane chain, wherein the alkane chain or The heteroalkane chain includes at least 3 chain atoms, and relates to a non-aromatic bicyclic ring system, such as shown in formula (b), that is, ring A1 and ring A2 share an alkane chain or a heteroalkane chain, wherein the alkane chain or heteroalkane Each X 3 on the alkane chain is independently optionally a carbon atom or a heteroatom, and j is 1, 2, 3 or 4. Such a system contains 5-12 ring atoms and may contain independent or conjugated unsaturation, but its core structure does not contain aromatic rings or aromatic rings (but aromatics can be used as substituents thereon). Wherein each ring, such as A1 or A2, contains 4-7 atoms, the term "nitrogen atom-containing bridged ring" refers to a bridged ring containing 1 or 2 nitrogen atoms, examples of such a nitrogen atom-containing bridged ring include, But not limited to, (1R,5S)-3,8-diazabicyclo[3.2.1]octane and the like. The bridging ring is optionally substituted with one or more substituents described herein.
术语“j’-k’个环原子组成的”或“j’-k’元”在此处可交换使用，表示所述环状基团由j’-k’个成环原子所组成，所述的环原子包括碳原子和/或O、N、S、P等杂原子。所述j’和k’各自独立地为任意非零的自然数，且k’>j’；所述“j’-k’”包括j’、k’和两者之间的任意自然数。例如，“3-8个原子组成的或3-8元”、“3-6个原子组成的或3-6元”、“5-10个原子组成的或5-10元”或“5-6个原子组成的或5-6元”表示所述环状基团由3-8(即，3、4、5、6、7或8)、3-6(即，3、4、5或6)、5-10(即，5、6、7、8、9或10)或5-6(即，5或6)个环原子所组成，所述的环原子包括碳原子和/或O、N、S、P等杂原子。具体来说，例如，“5-10个环原子组成的杂芳基”或“5-10元杂芳基”代表其包括5、6、7、8、9或10个环原子组成的杂芳基，其中5、6、7、8、9或10表示成环原子数目，如吡啶基是由6个环原子组成的杂芳基或6元杂芳基。The terms "j'-k' ring atoms" or "j'-k' members" are used interchangeably herein to indicate that the cyclic group consists of j'-k' ring atoms, so The aforementioned ring atoms include carbon atoms and/or O, N, S, P and other heteroatoms. The j' and k' are each independently any non-zero natural number, and k'>j'; the "j'-k'" includes j', k' and any natural number between them. For example, "3-8 atoms or 3-8 members", "3-6 atoms or 3-6 members", "5-10 atoms or 5-10 members" or "5- 6 atoms or 5-6 members" means that the cyclic group consists of 3-8 (ie, 3, 4, 5, 6, 7 or 8), 3-6 (ie, 3, 4, 5 or 6), 5-10 (i.e., 5, 6, 7, 8, 9 or 10) or 5-6 (i.e., 5 or 6) ring atoms consisting of carbon atoms and/or O , N, S, P and other heteroatoms. Specifically, for example, "heteroaryl consisting of 5-10 ring atoms" or "5-10 membered heteroaryl" means that it includes heteroaryl consisting of 5, 6, 7, 8, 9 or 10 ring atoms group, wherein 5, 6, 7, 8, 9 or 10 represent the number of ring atoms, for example, pyridyl is a heteroaryl group or a 6-membered heteroaryl group composed of 6 ring atoms.
在本发明中所使用的术语“不饱和的”表示基团中含有一个或多个不饱和度。As used herein, the term "unsaturated" means that a group contains one or more degrees of unsaturation.
术语“杂原子”是指O、S、N、P和Si，包括N、S和P任何氧化态的形式；伯、仲、叔胺和季铵盐的形式；或者杂环中氮原子上的氢被取代的形式，例如，N(像3,4-二氢-2H-吡咯基中的N)，NH(像吡咯烷基中的NH)或NR(像N-取代的吡咯烷基中的NR，R为N上的取代基，表示本发明所述的取代基)。The term "heteroatom" refers to O, S, N, P, and Si, including forms in any oxidation state of N, S, and P; forms of primary, secondary, and tertiary amines, and quaternary ammonium salts; or Hydrogen-substituted forms, for example, N (like N in 3,4-dihydro-2H-pyrrolyl), NH (like NH in pyrrolidinyl) or NR (like N-substituted pyrrolidinyl NR, R is a substituent on N, representing the substituent described in the present invention).
术语“卤素”或“卤原子”是指氟(F)、氯(Cl)、溴(Br)或碘(I)。The term "halogen" or "halogen atom" refers to fluorine (F), chlorine (Cl), bromine (Br) or iodine (I).
术语“烷基氨基”或“烷氨基”包括“N-烷基氨基”和“N,N-二烷基氨基”，其中氨基基团分别独立地被一个或两个烷基基团所取代。其中一些实施例是，烷基氨基是一个或两个C1-6烷基连接到氮原子上形成的烷基氨基基团。另外一些实施例是，烷基氨基是被一个或两个C1-3的烷基取代的氨基基团。合适的烷基氨基基团可以是单烷基氨基或二烷基氨基，这样的实例包括，但并不限于，N-甲氨基(甲氨基)，N-乙氨基(乙氨基)，N,N-二甲氨基(二甲氨基)，N,N-二乙氨基(二乙氨基)等等。The term "alkylamino" or "alkylamino" includes "N-alkylamino" and "N,N-dialkylamino", wherein the amino groups are each independently substituted with one or two alkyl groups. In some embodiments, the alkylamino group is an alkylamino group formed by one or two C 1-6 alkyl groups connected to a nitrogen atom. In some other embodiments, the alkylamino group is an amino group substituted by one or two C 1-3 alkyl groups. Suitable alkylamino groups may be mono- or di-alkylamino, examples of which include, but are not limited to, N-methylamino (methylamino), N-ethylamino (ethylamino), N,N -Dimethylamino (dimethylamino), N,N-diethylamino (diethylamino) and the like.
如本发明所描述，取代基(Rx)m由一个键连接到中心的环上形成的环体系代表m个取代基Rx可以在所在的环上任何可取代的位置或任何合理的位置进行取代。例如，式c代表G环可被m个Rx取代，当m大于1时，各Rx可独立地选自相同或不同的取代基团。As described in the present invention, the substituent (R x ) m is connected to the central ring by a bond to form a ring system representing m substituents R x can be carried out at any substitutable position or any reasonable position on the ring. replace. For example, formula c represents that ring G can be substituted by m R x , and when m is greater than 1, each R x can be independently selected from the same or different substituent groups.
如本发明所描述，附着点可以在环上任何可连接的位置与分子其余部分连接。例如，式d代表C环或D环上任何可能被连接的位置均可作为连接的点。As described herein, the point of attachment can be attached to the rest of the molecule at any attachable position on the loop. For example, formula d represents that any possible linking position on ring C or ring D can be used as a linking point.
如本发明所描述，基团X的子结构上有两个连接位点可与分子其余部分相连，两个连接位点的连接方式可以互换。例如，当X为
术语“保护基团”或“PG”是指一个取代基与其他官能团起反应的时候，通常用来阻断或保护特殊的功能性。例如，“氨基的保护基团”是指一个取代基与氨基基团相连来阻断或保护化合物中氨基的功能性，合适的氨基保护基团包括乙酰基，三氟乙酰基，叔丁氧羰基(BOC,Boc)，苄氧羰基(CBZ,Cbz)和9-芴亚甲氧羰基(Fmoc)。相似地，“羟基保护基团”是指羟基的取代基用来阻断或保护羟基的功能性，合适的保护基团包括乙酰基和甲硅烷基。“羧基保护基团”是指羧基的取代基用来阻断或保护羧基的功能性，一般的羧基保护基包括-CH2CH2SO2Ph，氰基乙基，2-(三甲基硅烷基)乙基，2-(三甲基硅烷基)乙氧基甲基，2-(对甲苯磺酰基)乙基，2-(对硝基苯磺酰基)乙基，2-(二苯基膦基)乙基，硝基乙基，等等。对于保护基团一般的描述可参考文献：T W.Greene,Protective Groups in Organic Synthesis,John Wiley&Sons,New York,1991；and P.J.Kocienski,Protecting Groups,Thieme,Stuttgart,2005.The term "protecting group" or "PG" refers to a substituent that reacts with other functional groups, usually to block or protect specific functionality. For example, "amino-protecting group" refers to a substituent attached to the amino group to block or protect the functionality of the amino group in the compound. Suitable amino-protecting groups include acetyl, trifluoroacetyl, tert-butoxycarbonyl (BOC, Boc), benzyloxycarbonyl (CBZ, Cbz) and 9-fluorenylmethyleneoxycarbonyl (Fmoc). Similarly, a "hydroxyl protecting group" refers to a substituent of a hydroxy group used to block or protect the functionality of the hydroxy group, suitable protecting groups include acetyl and silyl groups. "Carboxyl protecting group" refers to the substituent of carboxyl to block or protect the functionality of carboxyl. General carboxyl protecting groups include -CH 2 CH 2 SO 2 Ph, cyanoethyl, 2-(trimethylsilane base) ethyl, 2-(trimethylsilyl)ethoxymethyl, 2-(p-toluenesulfonyl)ethyl, 2-(p-nitrobenzenesulfonyl)ethyl, 2-(diphenyl phosphino)ethyl, nitroethyl, etc. For a general description of protecting groups, refer to: T W. Greene, Protective Groups in Organic Synthesis, John Wiley & Sons, New York, 1991; and PJ Kocienski, Protecting Groups, Thieme, Stuttgart, 2005.
术语“药学上可接受的”是指当给人施用时生理上可耐受的并且一般不产生过敏或相似不适当的反应，例如肠胃不适、眩晕等的分子实体和组合物。The term "pharmaceutically acceptable" refers to molecular entities and compositions that are physiologically tolerable and generally do not produce allergic or similar untoward reactions, such as gastrointestinal upset, dizziness, etc., when administered to a human.
术语“载体”指与所述化合物一同施用的稀释剂、辅剂、赋形剂或基质。这些药物载体可以是无菌液体，例如水和油类，包括石油、动物、植物或合成来源的，例如花生油、大豆油、矿物油、芝麻油等。适宜的药物载体描述于E.W.Martin的“Remington′sPharmaceutical Sciences”中。The term "carrier" refers to a diluent, adjuvant, excipient or base with which the compound is administered. Such pharmaceutical carriers can be sterile liquids, such as water and oils, including those of petroleum, animal, vegetable or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil and the like. Suitable pharmaceutical carriers are described in "Remington's Pharmaceutical Sciences" by E.W. Martin.
本发明所使用的术语“前药”，代表一个化合物在体内转化为式(I)所示的化合物。这样的转化受前体药物在血液中水解或在血液或组织中经酶转化为母体结构的影响。本发明前体药物类化合物可以是酯，在现有的发明中酯可以作为前体药物的有苯酯类，脂肪族(C1-24)酯类，酰氧基甲基酯类，碳酸酯，氨基甲酸酯类和氨基酸酯类。例如，一个化合物包含羟基，即可以将其酰化得到前体药物形式的化合物。其他的前体药物形式包括磷酸酯，如这些磷酸酯类化合物是经母体上的羟基磷酸化得到的。关于前体药物完整的讨论可以参考以下文献：T.Higuchi and V.Stella,Pro-drugs as Novel Delivery Systems,Vol.14ofthe A.C.S.Symposium Series,Edward B.Roche,ed.,Bioreversible Carriers in DrugDesign,American Pharmaceutical Association and Pergamon Press,1987,J.Rautioet al.,Prodrugs:Design and Clinical Applications,Nature Review DrugDiscovery,2008,7,255-270,and S.J.Hecker et al.,Prodrugs of Phosphates andPhosphonates,Journal of Medicinal Chemistry,2008,51,2328-2345。The term "prodrug" used in the present invention means that a compound is transformed into a compound represented by formula (I) in vivo. Such conversion is effected by prodrug hydrolysis in blood or enzymatic conversion in blood or tissue to the parent structure. The prodrug compound of the present invention can be an ester. In the existing invention, the ester can be used as a prodrug with phenyl esters, aliphatic (C 1-24 ) esters, acyloxymethyl esters, and carbonates. , carbamates and amino acid esters. For example, a compound containing a hydroxyl group can be acylated to give the compound in prodrug form. Other prodrug forms include phosphate esters, eg, phosphorylated parent hydroxyl groups. A complete discussion of prodrugs can be found in the following literature: T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems, Vol. 14 of the ACSSymposium Series, Edward B. Roche, ed., Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987, J. Rautio et al., Prodrugs: Design and Clinical Applications, Nature Review Drug Discovery, 2008, 7, 255-270, and SJ Hecker et al., Prodrugs of Phosphates and Phosphonates, Journal of Medicinal Chemistry, 2008, 51, 2328 -2345.
“代谢产物”是指具体的化合物或其盐在体内通过代谢作用所得到的产物。一个化合物的代谢产物可以通过所属领域公知的技术来进行鉴定，其活性可以通过如本发明所描述的那样采用试验的方法进行表征。这样的产物可以是通过给药化合物经过氧化，还原，水解，酰氨化，脱酰氨作用，酯化，脱脂作用，酶裂解等等方法得到。相应地，本发明包括化合物的代谢产物，包括将本发明的化合物与哺乳动物充分接触一段时间所产生的代谢产物。"Metabolite" refers to a product obtained through metabolism of a specific compound or its salt in vivo. Metabolites of a compound can be identified by techniques known in the art, and their activity can be characterized using assays as described herein. Such products can be obtained by oxidation, reduction, hydrolysis, amidation, deamidation, esterification, degreasing, enzymatic cleavage and the like of the administered compound. Accordingly, the invention includes metabolites of the compounds, including metabolites produced by contacting a compound of the invention with a mammal for a substantial period of time.
本发明所使用的“药学上可接受的盐”是指本发明的化合物的有机盐和无机盐。药学上可接受的盐在所属领域是为我们所熟知的，如文献：S.M.Berge et al.,describepharmaceutically acceptable salts in detail in J.Pharmaceutical Sciences,1977,66:1-19.所记载的。药学上可接受的无毒的酸形成的盐包括，但并不限于，无机酸盐，如盐酸盐，氢溴酸盐，磷酸盐，硫酸盐，高氯酸盐，和有机酸盐，如乙酸盐，草酸盐，马来酸盐，酒石酸盐，柠檬酸盐，琥珀酸盐，丙二酸盐等，或通过书籍文献上所记载的其他方法如离子交换法来得到这些盐。可药用碱加成盐包括，但不限于，无机碱盐，例如铵盐和周期表的I族至XII族的金属盐，和有机碱盐，例如与伯胺、仲胺和叔胺形成的盐。The "pharmaceutically acceptable salt" used in the present invention refers to organic and inorganic salts of the compounds of the present invention. Pharmaceutically acceptable salts are well known in the art, as described in the literature: S.M. Berge et al., describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66: 1-19. Pharmaceutically acceptable non-toxic salts of acid formation include, but are not limited to, salts of inorganic acids, such as hydrochlorides, hydrobromides, phosphates, sulfates, perchlorates, and salts of organic acids, such as Acetate, oxalate, maleate, tartrate, citrate, succinate, malonate, etc., or obtain these salts by other methods such as ion exchange methods described in books and literature. Pharmaceutically acceptable base addition salts include, but are not limited to, salts with inorganic bases, such as ammonium salts and salts of metals from Groups I to XII of the Periodic Table, and salts with organic bases, such as those formed with primary, secondary and tertiary amines. Salt.
本发明的“溶剂化物”是指一个或多个溶剂分子与本发明的化合物所形成的缔合物。形成溶剂化物的溶剂包括，但并不限于，水，异丙醇，乙醇，甲醇，二甲亚砜，乙酸乙酯，乙酸和氨基乙醇。术语“水合物”是指溶剂分子是水所形成的缔合物。A "solvate" of the present invention refers to an association of one or more solvent molecules with a compound of the present invention. Solvents that form solvates include, but are not limited to, water, isopropanol, ethanol, methanol, dimethylsulfoxide, ethyl acetate, acetic acid, and aminoethanol. The term "hydrate" refers to an association of solvent molecules with water.
如本发明所使用的术语“治疗”任何疾病或病症，在其中一些实施方案中指改善疾病或病症(即减缓或阻止或减轻疾病或其至少一种临床症状的发展)。在另一些实施方案中，“治疗”指缓和或改善至少一种身体参数，包括可能不为患者所察觉的身体参数。在另一些实施方案中，“治疗”指从身体上(例如稳定可察觉的症状)或生理学上(例如稳定身体的参数)或上述两方面调节疾病或病症。在另一些实施方案中，“治疗”指预防或延迟疾病或病症的发作、发生或恶化。The term "treating" any disease or condition as used herein means, in some embodiments, ameliorating the disease or condition (ie, slowing or arresting or alleviating the development of the disease or at least one clinical symptom thereof). In other embodiments, "treating" refers to alleviating or improving at least one physical parameter, including physical parameters that may not be perceived by the patient. In other embodiments, "treating" refers to modulating a disease or condition either physically (eg, stabilizing a perceived symptom) or physiologically (eg, stabilizing a parameter of the body), or both. In other embodiments, "treating" refers to preventing or delaying the onset, development or worsening of a disease or condition.
术语“治疗有效量”是指当给药于主体来治疗疾病时，化合物的分量足够对这种疾病的治疗起效。“治疗有效量”可以随着化合物，疾病和严重程度，以及有待治疗的主体的条件，年龄，体重，性别等而改变。The term "therapeutically effective amount" means that, when administered to a subject to treat a disease, that amount of the compound is sufficient to effect the treatment of the disease. The "therapeutically effective amount" may vary with the compound, the disease and severity, and the condition, age, weight, sex, etc. of the subject to be treated.
本发明的可药用盐可以用常规化学方法由母体化合物、碱性或酸性部分来合成。一般而言，该类盐可以通过使这些化合物的游离酸形式与化学计量量的适宜碱(如Na、Ca、Mg或K的氢氧化物、碳酸盐、碳酸氢盐等)反应，或者通过使这些化合物的游离碱形式与化学计量量的适宜酸反应来进行制备。该类反应通常在水或有机溶剂或二者的混合物中进行。一般地，在适当的情况中，需要使用非水性介质如乙醚、乙酸乙酯、乙醇、异丙醇或乙腈。在例如“Remington′s Pharmaceutical Sciences”，第20版，Mack Publishing Company，Easton，Pa.，(1985)；和“药用盐手册：性质、选择和应用(Handbook of PharmaceuticalSalts：Properties，Selection，and Use)”，Stahl and Wermuth(Wiley-VCH，Weinheim，Germany，2002)中可找到另外一些适宜盐的列表。The pharmaceutically acceptable salts of this invention can be synthesized from the parent compound, a basic or acidic moiety, by conventional chemical methods. In general, such salts can be prepared by reacting the free acid forms of these compounds with a stoichiometric amount of a suitable base (such as Na, Ca, Mg or K hydroxides, carbonates, bicarbonates, etc.), or by They are prepared by reacting the free base forms of these compounds with stoichiometric amounts of the appropriate acid. Such reactions are usually carried out in water or organic solvents or a mixture of both. Generally, non-aqueous media such as diethyl ether, ethyl acetate, ethanol, isopropanol or acetonitrile will be required where appropriate. In, for example, "Remington's Pharmaceutical Sciences", 20th ed., Mack Publishing Company, Easton, Pa., (1985); and "Handbook of Pharmaceutical Salts: Properties, Selection, and Use )", a further list of suitable salts can be found in Stahl and Wermuth (Wiley-VCH, Weinheim, Germany, 2002).
另外，本发明公开的化合物、包括它们的盐，也可以以它们的水合物形式或包含其溶剂(例如乙醇，DMSO，等等)的形式得到，用于它们的结晶。本发明公开化合物可以与药学上可接受的溶剂(包括水)固有地或通过设计形成溶剂化物；因此，本发明旨在包括溶剂化的和未溶剂化的形式。In addition, the compounds disclosed in the present invention, including their salts, can also be obtained in the form of their hydrates or in the form of solvents (such as ethanol, DMSO, etc.) containing them for their crystallization. The compounds disclosed herein may inherently or by design form solvates with pharmaceutically acceptable solvents, including water; thus, it is intended that the present invention embrace both solvated and unsolvated forms.
本发明给出的任何结构式也意欲表示这些化合物未被同位素富集的形式以及同位素富集的形式。同位素富集的化合物具有本发明给出的通式描绘的结构，除了一个或多个原子被具有所选择原子量或质量数的原子替换。可引入本发明化合物中的示例性同位素包括氢、碳、氮、氧、磷、硫、氟、氯和碘的同位素，如2H，3H，13C，14C，15N，17O，18O，32P，34S，18F，37Cl和125I。同位素富集的本发明化合物可以通过本领域技术人员熟悉的常规技术或本发明中的实施例和制备过程所描述使用合适的同位素标记试剂替代原来使用过的未标记试剂来制备。Any structural formulas given herein are also intended to represent non-isotopically enriched as well as isotopically enriched forms of these compounds. Isotopically enriched compounds have structures depicted by the general formulas given herein, except that one or more atoms are replaced by atoms having a selected atomic mass or mass number. Exemplary isotopes that can be incorporated into the compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine and iodine, such as 2 H, 3 H, 13 C, 14 C, 15 N, 17 O, 18 O, 32 P, 34 S, 18 F, 37 Cl and 125 I. Isotope-enriched compounds of the present invention can be prepared by conventional techniques familiar to those skilled in the art or as described in the examples and preparation processes of the present invention, using suitable isotope-labeled reagents to replace the previously used unlabeled reagents.
除非其他方面表明，本发明的化合物的所有互变异构形式都包含在本发明的范围之内。另外，除非其他方面表明，本发明所描述的化合物的结构式包括一个或多个不同的原子的富集同位素。Unless otherwise indicated, all tautomeric forms of the compounds of the invention are included within the scope of the invention. In addition, unless otherwise indicated, the structural formulas of the compounds described herein include enriched isotopes of one or more different atoms.
本发明所用的术语“癌症”是指或描述患者中通常以失控的细胞生长为特征的生理学病症。“肿瘤”包含一种或多种癌细胞。癌症的实例包括但不限于癌(carcinoma)、淋巴瘤、胚细胞瘤、肉瘤和白血病，或恶性淋巴增殖性疾病(lymphoid malignancies)。此类癌症的更具体的实例包括鳞状细胞癌(如上皮鳞状细胞癌)、肺癌(包括小细胞肺癌、非小细胞肺癌(NSCLC))、食管癌、腹膜癌、胃癌(gastric or stomach cancer)(包括胃肠癌)、胰腺癌、恶性胶质瘤、宫颈癌、卵巢癌、肝癌(liver cancer)、膀胱癌、乳腺癌、结肠癌、直肠癌、阑尾癌、小肠癌、子宫内膜癌或子宫癌、唾液腺癌、肾癌或肾脏癌(kidney or renal cancer)、前列腺癌、外阴癌、甲状腺癌、肛门癌、阴茎癌以及头颈癌。The term "cancer" as used herein refers to or describes a physiological condition in a patient that is often characterized by uncontrolled cell growth. A "tumor" comprises one or more cancer cells. Examples of cancer include, but are not limited to, carcinoma, lymphoma, blastoma, sarcoma, and leukemia, or lymphoid malignancies. More specific examples of such cancers include squamous cell carcinoma (such as epithelial squamous cell carcinoma), lung cancer (including small cell lung cancer, non-small cell lung cancer (NSCLC)), esophageal cancer, peritoneal cancer, gastric cancer (gastric or gastric cancer) ) (including gastrointestinal cancer), pancreatic cancer, malignant glioma, cervical cancer, ovarian cancer, liver cancer, bladder cancer, breast cancer, colon cancer, rectal cancer, appendix cancer, small bowel cancer, endometrial cancer Or uterine cancer, salivary gland cancer, kidney or renal cancer, prostate cancer, vulvar cancer, thyroid cancer, anal cancer, penis cancer, and head and neck cancer.
本发明所用的术语“KRAS G12C抑制剂”是指能与KRAS G12C结合并抑制其活性的物质。The term "KRAS G12C inhibitor" used in the present invention refers to a substance that can bind to KRAS G12C and inhibit its activity.
本发明的化合物详细的描述Detailed description of the compounds of the present invention
本发明提供一种化合物或其药物组合物，其可作为KRAS特别是KRAS G12C的抑制剂。本发明进一步涉及所述化合物或其药物组合物用于制备药物的用途，该药物通过用所述化合物抑制KRAS G12C的活性来治疗疾病和/或病症。本发明又进一步描述了合成所述化合物的方法。本发明的化合物显示出改善的生物活性及药代动力学性质。The present invention provides a compound or a pharmaceutical composition thereof, which can be used as an inhibitor of KRAS, especially KRAS G12C. The present invention further relates to the use of the compound or its pharmaceutical composition for the preparation of a medicament for treating diseases and/or conditions by inhibiting the activity of KRAS G12C with the compound. The present invention further describes methods of synthesizing said compounds. The compounds of the invention exhibit improved biological activity and pharmacokinetic properties.
一方面，本发明涉及一种化合物，其为如式(I)所示的化合物，或式(I)所示的化合物的立体异构体、几何异构体、互变异构体、氮氧化物、水合物、溶剂化物、代谢产物、药学上可接受的盐或前药，In one aspect, the present invention relates to a compound, which is a compound represented by formula (I), or a stereoisomer, geometric isomer, tautomer, nitrogen oxide of the compound represented by formula (I) compounds, hydrates, solvates, metabolites, pharmaceutically acceptable salts or prodrugs,
其中，各X、Y、R1、R2a、R2b、R2c和R3均具有本发明所描述的含义。Wherein, each of X, Y, R 1 , R 2a , R 2b , R 2c and R 3 has the meaning described in the present invention.
在一些实施方案中，本发明化合物具有式(II)所示结构：In some embodiments, the compound of the present invention has the structure shown in formula (II):
其中，各Y、R1、R2a、R2b、R2c、Rx、Ry和m均具有本发明所描述的含义。Wherein, each of Y, R 1 , R 2a , R 2b , R 2c , R x , R y and m has the meaning described in the present invention.
在一些实施方案中，X为-L-X1-，其中，L为键或NH，X1为含氮原子的4-8元单环、含氮原子的5-12元稠环、含氮原子的5-12元螺环或含氮原子的5-12元桥环；其中所述的含氮原子的4-8元单环、含氮原子的5-12元稠环、含氮原子的5-12元螺环和含氮原子的5-12元桥环各自独立任选地被m个Rx取代；其中Rx和m具有本发明所述的含义。其中，本发明所述的含氮原子的4-8元单环、含氮原子的5-12元稠环、含氮原子的5-12元螺环或含氮原子的5-12元桥环是指所述的单环、稠环、螺环和桥环各自独立地含有1或2个氮原子。In some embodiments, X is -LX 1 -, wherein, L is a bond or NH, X 1 is a 4-8 membered monocyclic ring containing a nitrogen atom, a 5-12 membered condensed ring containing a nitrogen atom, a nitrogen atom-containing A 5-12-membered spiro ring or a 5-12-membered bridged ring containing a nitrogen atom; wherein the 4-8-membered monocyclic ring containing a nitrogen atom, the 5-12-membered condensed ring containing a nitrogen atom, and the 5-membered ring containing a nitrogen atom The 12-membered spiro ring and the 5-12-membered bridged ring containing nitrogen atoms are each independently optionally substituted by m R x ; wherein R x and m have the meanings described in the present invention. Among them, the 4-8 membered monocyclic ring containing nitrogen atom, the 5-12 membered condensed ring containing nitrogen atom, the 5-12 membered spiro ring containing nitrogen atom or the 5-12 membered bridged ring containing nitrogen atom described in the present invention It means that the monocyclic ring, condensed ring, spiro ring and bridged ring each independently contain 1 or 2 nitrogen atoms.
在另一些实施方案中，X为
在一些实施方案中，Y为N或CH。In some embodiments, Y is N or CH.
在一些实施方案中，R1为-C(＝O)-CRa＝CRb-Rc、-C(＝O)-C≡C-Rc、-S(＝O)2-CRa＝CRb-Rc或-S(＝O)2-C≡C-Rc；其中Ra、Rb和Rc具有本发明所述的含义。In some embodiments, R 1 is -C(=O)-CR a =CR b -R c , -C(=O)-C≡CR c , -S(=O) 2 -CR a =CR b -R c or -S(=O) 2 -C≡CR c ; wherein R a , R b and R c have the meanings described in the present invention.
在一些实施方案中，各Ra独立地为氢、氘、氟、氯、溴、碘、C1-3烷基、C1-3卤代烷基或C1-3烷氧基；其中，所述的C1-3烷基、C1-3卤代烷基和C1-3烷氧基各自独立任选地被1、2、3、4或5个独立地选自氘、氟、氯、溴、碘、羟基、氧代、氨基、硝基、氰基、C1-3烷基、C1-3卤代烷基、C1-3烷氧基、C1-3卤代烷氧基和C1-3羟基烷氧基的基团所取代。In some embodiments, each R is independently hydrogen, deuterium, fluorine, chlorine, bromine, iodine, C 1-3 alkyl, C 1-3 haloalkyl, or C 1-3 alkoxy; wherein, The C 1-3 alkyl, C 1-3 haloalkyl and C 1-3 alkoxy are each independently optionally selected from 1, 2, 3, 4 or 5 independently selected from deuterium, fluorine, chlorine, bromine, Iodine, hydroxy, oxo, amino, nitro, cyano, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy and C 1-3 hydroxy Alkoxy groups are substituted.
在另一些实施方案中，各Ra独立地为氢、氘、氟、氯、溴、碘、甲基、乙基、正丙基、异丙基、三氟甲基、二氟甲基、甲氧基、乙氧基或异丙氧基；其中，所述的甲基、乙基、正丙基、异丙基、二氟甲基、甲氧基、乙氧基和异丙氧基各自独立任选地被1、2、3、4或5个独立地选自氘、氟、氯、溴、碘、羟基、氧代、氨基、硝基、氰基、甲基、乙基、正丙基、异丙基、三氟甲基、二氟甲基、甲氧基、乙氧基、异丙氧基、三氟甲氧基、-OCH2OH和-OCH2CH2OH的基团所取代。In other embodiments, each R is independently hydrogen, deuterium, fluorine, chlorine, bromine, iodine, methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, difluoromethyl, methyl Oxygen, ethoxy or isopropoxy; wherein, the methyl, ethyl, n-propyl, isopropyl, difluoromethyl, methoxy, ethoxy and isopropoxy are independently Optionally 1, 2, 3, 4 or 5 independently selected from deuterium, fluorine, chlorine, bromine, iodine, hydroxyl, oxo, amino, nitro, cyano, methyl, ethyl, n-propyl , isopropyl, trifluoromethyl, difluoromethyl, methoxy, ethoxy, isopropoxy, trifluoromethoxy, -OCH 2 OH and -OCH 2 CH 2 OH .
在一些实施方案中，各Rb独立地为氢、氘、氟、氯、溴、碘、C1-3烷基、C1-3卤代烷基或C1-3烷氧基；其中，所述的C1-3烷基、C1-3卤代烷基和C1-3烷氧基各自独立任选地被1、2、3、4或5个独立地选自氘、氟、氯、溴、碘、羟基、氧代、氨基、硝基、氰基、C1-3烷基、C1-3卤代烷基、C1-3烷氧基、C1-3卤代烷氧基和C1-3羟基烷氧基的基团所取代。In some embodiments, each R b is independently hydrogen, deuterium, fluorine, chlorine, bromine, iodine, C 1-3 alkyl, C 1-3 haloalkyl, or C 1-3 alkoxy; wherein, the The C 1-3 alkyl, C 1-3 haloalkyl and C 1-3 alkoxy are each independently optionally selected from 1, 2, 3, 4 or 5 independently selected from deuterium, fluorine, chlorine, bromine, Iodine, hydroxy, oxo, amino, nitro, cyano, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy and C 1-3 hydroxy Alkoxy groups are substituted.
在另一些实施方案中，各Rb独立地为氢、氘、氟、氯、溴、碘、甲基、乙基、正丙基、异丙基、三氟甲基、二氟甲基、甲氧基、乙氧基或异丙氧基；其中，所述的甲基、乙基、正丙基、异丙基、二氟甲基、甲氧基、乙氧基和异丙氧基各自独立任选地被1、2、3、4或5个独立地选自氘、氟、氯、溴、碘、羟基、氧代、氨基、硝基、氰基、甲基、乙基、正丙基、异丙基、三氟甲基、二氟甲基、甲氧基、乙氧基、异丙氧基、三氟甲氧基、-OCH2OH和-OCH2CH2OH的基团所取代。In other embodiments, each R is independently hydrogen, deuterium, fluorine, chlorine, bromine, iodine, methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, difluoromethyl, methyl Oxygen, ethoxy or isopropoxy; wherein, the methyl, ethyl, n-propyl, isopropyl, difluoromethyl, methoxy, ethoxy and isopropoxy are independently Optionally 1, 2, 3, 4 or 5 independently selected from deuterium, fluorine, chlorine, bromine, iodine, hydroxyl, oxo, amino, nitro, cyano, methyl, ethyl, n-propyl , isopropyl, trifluoromethyl, difluoromethyl, methoxy, ethoxy, isopropoxy, trifluoromethoxy, -OCH 2 OH and -OCH 2 CH 2 OH .
在一些实施方案中，Rc独立地为氢、氘、C1-6烷基、C2-6烯基、C2-6炔基、C1-6卤代烷基、C1-6烷氧基、C1-6卤代烷氧基、C1-6烷氨基、C3-8环烷基、3-8个原子组成的杂环基或5-6个原子组成的杂芳基；其中，所述的C1-6烷基、C2-6烯基、C2-6炔基、C1-6卤代烷基、C1-6烷氧基、C1-6卤代烷氧基、C1-6烷氨基、C3-8环烷基、3-8个原子组成的杂环基和5-6个原子组成的杂芳基各自独立任选地被1、2、3、4或5个独立地选自氘、氟、氯、溴、碘、羟基、氧代、氨基、硝基、氰基、C1-3烷基、C1-3卤代烷基、C1-3烷氧基、C1-3卤代烷氧基和C1-3羟基烷氧基的基团所取代。In some embodiments, R is independently hydrogen, deuterium, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 alkoxy , C 1-6 haloalkoxy, C 1-6 alkylamino, C 3-8 cycloalkyl, heterocyclic group consisting of 3-8 atoms or heteroaryl group consisting of 5-6 atoms; wherein, the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 alkane Amino, C 3-8 cycloalkyl, heterocyclic group consisting of 3-8 atoms and heteroaryl group consisting of 5-6 atoms are each independently optionally selected by 1, 2, 3, 4 or 5 independently From deuterium, fluorine, chlorine, bromine, iodine, hydroxyl, oxo, amino, nitro, cyano, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 Haloalkoxy and C 1-3 hydroxyalkoxy groups are substituted.
在另一些实施方案中，Rc独立地为氢、氘、甲基、乙基、正丙基、异丙基、烯丙基、丙烯基、炔丙基、丙炔基、-CHF2、-CF3、-CHFCH2F、-CF2CHF2、-CH2CF3、-CH2CF2CHF2、甲氧基、乙氧基、正丙氧基、异丙氧基、-OCHF2、-OCF3、-OCHFCH2F、-OCF2CHF2、-OCH2CF3、-OCH2CF2CHF2、甲氨基、二甲氨基、乙氨基、环丙基、环丁基、环戊基、环己基、氮杂环丁基、氧杂环丁基、吡咯烷基、四氢呋喃基、哌啶基、哌嗪基、吗啉基、吡咯基、吡唑基、咪唑基、三氮唑基、四氮唑基、呋喃基、噻吩基、噻唑基、噁唑基、吡啶基、嘧啶基、吡嗪基或哒嗪基；其中，所述的甲基、乙基、正丙基、异丙基、烯丙基、丙烯基、炔丙基、丙炔基、-CHF2、-CHFCH2F、-CF2CHF2、-CH2CF3、-CH2CF2CHF2、甲氧基、乙氧基、正丙氧基、异丙氧基、-OCHF2、-OCHFCH2F、-OCF2CHF2、-OCH2CF3、-OCH2CF2CHF2、甲氨基、二甲氨基、乙氨基、环丙基、环丁基、环戊基、环己基、氮杂环丁基、氧杂环丁基、吡咯烷基、四氢呋喃基、哌啶基、哌嗪基、吗啉基、吡咯基、吡唑基、咪唑基、三氮唑基、四氮唑基、呋喃基、噻吩基、噻唑基、噁唑基、吡啶基、嘧啶基、吡嗪基和哒嗪基各自独立任选地被1、2、3、4或5个独立地选自氘、氟、氯、溴、碘、羟基、氧代、氨基、硝基、氰基、甲基、乙基、正丙基、异丙基、三氟甲基、二氟甲基、甲氧基、乙氧基、三氟甲氧基、-OCH2OH、-OCH2CH2OH和异丙氧基的基团所取代。In other embodiments, Rc is independently hydrogen, deuterium, methyl, ethyl, n-propyl, isopropyl, allyl, propenyl, propargyl, propynyl, -CHF2 , - CF 3 , -CHFCH 2 F, -CF 2 CHF 2 , -CH 2 CF 3 , -CH 2 CF 2 CHF 2 , methoxy, ethoxy, n-propoxy, isopropoxy, -OCHF 2 , -OCF 3 , -OCHFCH 2 F, -OCF 2 CHF 2 , -OCH 2 CF 3 , -OCH 2 CF 2 CHF 2 , methylamino, dimethylamino, ethylamino, cyclopropyl, cyclobutyl, cyclopentyl , cyclohexyl, azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, morpholinyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, Tetrazolyl, furyl, thienyl, thiazolyl, oxazolyl, pyridyl, pyrimidinyl, pyrazinyl or pyridazinyl; wherein, the methyl, ethyl, n-propyl, isopropyl , allyl, propenyl, propargyl, propynyl, -CHF 2 , -CHFCH 2 F, -CF 2 CHF 2 , -CH 2 CF 3 , -CH 2 CF 2 CHF 2 , methoxy, ethyl Oxygen, n-propoxy, isopropoxy, -OCHF 2 , -OCHFCH 2 F, -OCF 2 CHF 2 , -OCH 2 CF 3 , -OCH 2 CF 2 CHF 2 , methylamino, dimethylamino, ethyl Amino, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, morpholinyl, pyrrolyl , pyrazolyl, imidazolyl, triazolyl, tetrazolyl, furyl, thienyl, thiazolyl, oxazolyl, pyridyl, pyrimidinyl, pyrazinyl and pyridazinyl are each independently optionally replaced by 1, 2, 3, 4 or 5 independently selected from deuterium, fluorine, chlorine, bromine, iodine, hydroxyl, oxo, amino, nitro, cyano, methyl, ethyl, n-propyl, isopropyl , trifluoromethyl, difluoromethyl, methoxy, ethoxy, trifluoromethoxy, -OCH 2 OH, -OCH 2 CH 2 OH and isopropoxy.
在一些实施方案中，R3为C6-12芳基或5-12个原子组成的杂芳基，其中，所述的C6-12芳基和5-12个原子组成的杂芳基各自独立任选地被n个Ry取代；其中，n和Ry具有本发明所述的含义。In some embodiments, R 3 is a C 6-12 aryl group or a heteroaryl group consisting of 5-12 atoms, wherein the C 6-12 aryl group and the heteroaryl group consisting of 5-12 atoms are each independently and optionally substituted by n R y ; wherein, n and R y have the meanings described in the present invention.
在另一些实施方案中，R3为C6-10芳基或5-12个原子组成的杂芳基，其中，所述的C6-10芳基和5-12个原子组成的杂芳基各自独立任选地被n个Ry取代；其中n和Ry具有本发明所述的含义。In other embodiments, R 3 is a C 6-10 aryl group or a heteroaryl group consisting of 5-12 atoms, wherein the C 6-10 aryl group and a heteroaryl group consisting of 5-12 atoms each independently and optionally substituted by n R y ; wherein n and R y have the meanings described in the present invention.
在另一些实施方案中，R3为以下子结构：
在一些实施方案中，R2a为氢、氘、氟、氯、溴、碘、羟基、氨基、硝基、氰基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6卤代烷基、C1-6烷氧基、C1-6卤代烷氧基、C1-6烷氨基、C3-8环烷基、3-8个原子组成的杂环基、C6-10芳基或5-12个原子组成的杂芳基；其中，所述的C1-6烷基、C2-6烯基、C2-6炔基、C1-6卤代烷基、C1-6烷氧基、C1-6卤代烷氧基、C1-6烷氨基、C3-8环烷基、3-8个原子组成的杂环基、C6-10芳基或5-12个原子组成的杂芳基各自独立任选地被1、2、3、4或5个独立地选自氘、氟、氯、溴、碘、羟基、氧代、氨基、硝基、氰基、C1-3烷基、C1-3卤代烷基、C1-3烷氧基、C1-3卤代烷氧基和C1-3羟基烷氧基的基团所取代。In some embodiments, R 2a is hydrogen, deuterium, fluorine, chlorine, bromine, iodine, hydroxyl, amino, nitro, cyano, C alkyl , C alkenyl , C alkyne C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 alkylamino, C 3-8 cycloalkyl, heterocyclic group consisting of 3-8 atoms , C 6-10 aryl or heteroaryl consisting of 5-12 atoms; wherein, the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkane C 1-6 alkoxy group, C 1-6 haloalkoxy group, C 1-6 alkylamino group, C 3-8 cycloalkyl group, heterocyclic group consisting of 3-8 atoms, C 6-10 aryl group Or the heteroaryl group consisting of 5-12 atoms is independently optionally selected from 1, 2, 3, 4 or 5 independently selected from deuterium, fluorine, chlorine, bromine, iodine, hydroxyl, oxo, amino, nitro , cyano, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy and C 1-3 hydroxyalkoxy.
在另一些实施方案中，R2a为氢、氘、氟、氯、溴、碘、羟基、氨基、硝基、氰基、C1-4烷基、C2-4烯基、C2-4炔基、C1-4卤代烷基、C1-4烷氧基、C1-4卤代烷氧基、C1-4烷氨基、C3-6环烷基、3-6个原子组成的杂环基、C6-10芳基或5-10个原子组成的杂芳基；其中，所述的C1-4烷基、C2-4烯基、C2-4炔基、C1-4卤代烷基、C1-4烷氧基、C1-4卤代烷氧基、C1-4烷氨基、C3-6环烷基、3-6个原子组成的杂环基、C6-10芳基和5-10个原子组成的杂芳基各自独立任选地被1、2、3、4或5个独立地选自氘、氟、氯、溴、碘、羟基、氧代、氨基、硝基、氰基、C1-3烷基、C1-3卤代烷基、C1-3烷氧基、C1-3卤代烷氧基和C1-3羟基烷氧基的基团所取代。In other embodiments, R 2a is hydrogen, deuterium, fluorine, chlorine, bromine, iodine, hydroxyl, amino, nitro, cyano, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 Alkynyl, C 1-4 haloalkyl, C 1-4 alkoxy, C 1-4 haloalkoxy, C 1-4 alkylamino , C 3-6 cycloalkyl, heterocyclic ring consisting of 3-6 atoms group, C 6-10 aryl group or heteroaryl group consisting of 5-10 atoms; wherein, the C 1-4 alkyl group, C 2-4 alkenyl group, C 2-4 alkynyl group, C 1-4 Haloalkyl, C 1-4 alkoxy, C 1-4 haloalkoxy, C 1-4 alkylamino, C 3-6 cycloalkyl, heterocyclic group consisting of 3-6 atoms, C 6-10 aromatic The radical and the heteroaryl group consisting of 5-10 atoms are each independently optionally selected from 1, 2, 3, 4 or 5 independently selected from deuterium, fluorine, chlorine, bromine, iodine, hydroxyl, oxo, amino, nitric group, cyano, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy and C 1-3 hydroxyalkoxy.
在另一些实施方案中，R2a为氢、氘、氟、氯、溴、碘、羟基、氨基、硝基、氰基、甲基、乙基、正丙基、异丙基、烯丙基、丙烯基、炔丙基、丙炔基、-CHF2、-CF3、-CHFCH2F、-CF2CHF2、-CH2CF3、-CH2CF2CHF2、甲氧基、乙氧基、正丙氧基、异丙氧基、-OCHF2、-OCF3、-OCHFCH2F、-OCF2CHF2、-OCH2CF3、-OCH2CF2CHF2、甲氨基、二甲氨基、乙氨基、环丙基、环丁基、环戊基、环己基、氧杂环丁基、氮杂环丁基、吡咯烷基、四氢呋喃基、哌啶基、哌嗪基、吗啉基、苯基、萘基、苯并咪唑基、吡咯基、吡唑基、咪唑基、三氮唑基、四氮唑基、呋喃基、噻吩基、噻唑基、噁唑基、吡啶基、嘧啶基、吡嗪基或哒嗪基；其中，所述的甲基、乙基、正丙基、异丙基、烯丙基、丙烯基、炔丙基、丙炔基、-CHF2、-CHFCH2F、-CF2CHF2、-CH2CF3、-CH2CF2CHF2、甲氧基、乙氧基、正丙基氧基、异丙基氧基、-OCHF2、-OCHFCH2F、-OCF2CHF2、-OCH2CF3、-OCH2CF2CHF2、甲氨基、二甲氨基、乙氨基、环丙基、环丁基、环戊基、环己基、氧杂环丁基、氮杂环丁基、吡咯烷基、四氢呋喃基、哌啶基、哌嗪基、吗啉基、苯基、萘基、苯并咪唑基、吡咯基、吡唑基、咪唑基、三氮唑基、四氮唑基、呋喃基、噻吩基、噻唑基、噁唑基、吡啶基、嘧啶基、吡嗪基和哒嗪基各自独立任选地被1、2、3、4或5个独立地选自氘、氟、氯、溴、碘、羟基、氧代、氨基、硝基、氰基、甲基、乙基、正丙基、异丙基、三氟甲基、二氟甲基、甲氧基、乙氧基、异丙氧基、三氟甲氧基、-OCH2OH和-OCH2CH2OH的基团所取代。In other embodiments, R is hydrogen, deuterium, fluorine, chlorine, bromine, iodine, hydroxyl, amino, nitro, cyano, methyl, ethyl, n-propyl, isopropyl, allyl, propenyl, propargyl, propynyl, -CHF 2 , -CF 3 , -CHFCH 2 F, -CF 2 CHF 2 , -CH 2 CF 3 , -CH 2 CF 2 CHF 2 , methoxy, ethoxy , n-propoxy, isopropoxy, -OCHF 2 , -OCF 3 , -OCHFCH 2 F, -OCF 2 CHF 2 , -OCH 2 CF 3 , -OCH 2 CF 2 CHF 2 , methylamino, dimethyl Amino, ethylamino, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, azetidinyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, morpholinyl , phenyl, naphthyl, benzimidazolyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, furyl, thienyl, thiazolyl, oxazolyl, pyridyl, pyrimidinyl , pyrazinyl or pyridazinyl; wherein, the methyl, ethyl, n-propyl, isopropyl, allyl, propenyl, propargyl, propynyl, -CHF 2 , -CHFCH 2 F, -CF 2 CHF 2 , -CH 2 CF 3 , -CH 2 CF 2 CHF 2 , methoxy, ethoxy, n-propyloxy, isopropyloxy, -OCHF 2 , -OCHFCH 2 F , -OCF 2 CHF 2 , -OCH 2 CF 3 , -OCH 2 CF 2 CHF 2 , methylamino, dimethylamino, ethylamino, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetane Base, azetidinyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, morpholinyl, phenyl, naphthyl, benzimidazolyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl Azolyl, tetrazolyl, furyl, thienyl, thiazolyl, oxazolyl, pyridyl, pyrimidinyl, pyrazinyl and pyridazinyl are each independently optionally replaced by 1, 2, 3, 4 or 5 independently selected from deuterium, fluorine, chlorine, bromine, iodine, hydroxyl, oxo, amino, nitro, cyano, methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, difluoromethyl , methoxy, ethoxy, isopropoxy, trifluoromethoxy, -OCH 2 OH and -OCH 2 CH 2 OH.
在一些实施方案中，R2b为氢、氘、氟、氯、溴、碘、羟基、氨基、硝基、氰基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6卤代烷基、C1-6烷氧基、C1-6卤代烷氧基、C1-6烷氨基、C3-8环烷基、3-8个原子组成的杂环基、C6-10芳基或5-12个原子组成的杂芳基；其中，所述的C1-6烷基、C2-6烯基、C2-6炔基、C1-6卤代烷基、C1-6烷氧基、C1-6卤代烷氧基、C1-6烷氨基、C3-8环烷基、3-8个原子组成的杂环基、C6-10芳基和5-12个原子组成的杂芳基各自独立任选地被1、2、3、4或5个独立地选自氘、氟、氯、溴、碘、羟基、氧代、氨基、硝基、氰基、C1-3烷基、C1-3卤代烷基、C1-3烷氧基、C1-3卤代烷氧基和C1-3羟基烷氧基的基团所取代。In some embodiments, R 2b is hydrogen, deuterium, fluorine, chlorine, bromine, iodine, hydroxyl, amino, nitro, cyano, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkyne C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 alkylamino, C 3-8 cycloalkyl, heterocyclic group consisting of 3-8 atoms , C 6-10 aryl or heteroaryl consisting of 5-12 atoms; wherein, the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkane C 1-6 alkoxy group, C 1-6 haloalkoxy group, C 1-6 alkylamino group, C 3-8 cycloalkyl group, heterocyclic group consisting of 3-8 atoms, C 6-10 aryl group and heteroaryl groups consisting of 5-12 atoms are each independently optionally selected from 1, 2, 3, 4 or 5 independently selected from deuterium, fluorine, chlorine, bromine, iodine, hydroxyl, oxo, amino, nitro , cyano, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy and C 1-3 hydroxyalkoxy.
在另一些实施方案中，R2b为氢、氘、氟、氯、溴、碘、羟基、氨基、硝基、氰基、C1-4烷基、C2-4烯基、C2-4炔基、C1-4卤代烷基、C1-4烷氧基、C1-4卤代烷氧基、C1-4烷氨基、C3-6环烷基、3-6个原子组成的杂环基、C6-10芳基或5-10个原子组成的杂芳基；其中，所述的C1-4烷基、C2-4烯基、C2-4炔基、C1-4卤代烷基、C1-4烷氧基、C1-4卤代烷氧基、C1-4烷氨基、C3-6环烷基、3-6个原子组成的杂环基、C6-10芳基和5-10个原子组成的杂芳基各自独立任选地被1、2、3、4或5个独立地选自氘、氟、氯、溴、碘、羟基、氧代、氨基、硝基、氰基、C1-3烷基、C1-3卤代烷基、C1-3烷氧基、C1-3卤代烷氧基和C1-3羟基烷氧基的基团所取代。In other embodiments, R 2b is hydrogen, deuterium, fluorine, chlorine, bromine, iodine, hydroxyl, amino, nitro, cyano, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 Alkynyl, C 1-4 haloalkyl, C 1-4 alkoxy, C 1-4 haloalkoxy, C 1-4 alkylamino , C 3-6 cycloalkyl, heterocyclic ring consisting of 3-6 atoms group, C 6-10 aryl group or heteroaryl group consisting of 5-10 atoms; wherein, the C 1-4 alkyl group, C 2-4 alkenyl group, C 2-4 alkynyl group, C 1-4 Haloalkyl, C 1-4 alkoxy, C 1-4 haloalkoxy, C 1-4 alkylamino, C 3-6 cycloalkyl, heterocyclic group consisting of 3-6 atoms, C 6-10 aromatic The radical and the heteroaryl group consisting of 5-10 atoms are each independently optionally selected from 1, 2, 3, 4 or 5 independently selected from deuterium, fluorine, chlorine, bromine, iodine, hydroxyl, oxo, amino, nitric group, cyano, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy and C 1-3 hydroxyalkoxy.
在另一些实施方案中，R2b为氢、氘、氟、氯、溴、碘、羟基、氨基、硝基、氰基、甲基、乙基、正丙基、异丙基、烯丙基、丙烯基、炔丙基、丙炔基、-CHF2、-CF3、-CHFCH2F、-CF2CHF2、-CH2CF3、-CH2CF2CHF2、甲氧基、乙氧基、正丙氧基、异丙氧基、-OCHF2、-OCF3、-OCHFCH2F、-OCF2CHF2、-OCH2CF3、-OCH2CF2CHF2、甲氨基、二甲氨基、乙氨基、环丙基、环丁基、环戊基、环己基、氧杂环丁基、氮杂环丁基、吡咯烷基、四氢呋喃基、哌啶基、哌嗪基、吗啉基、苯基、萘基、苯并咪唑基、吡咯基、吡唑基、咪唑基、三氮唑基、四氮唑基、呋喃基、噻吩基、噻唑基、噁唑基、吡啶基、嘧啶基、吡嗪基或哒嗪基；其中，所述的甲基、乙基、正丙基、异丙基、烯丙基、丙烯基、炔丙基、丙炔基、-CHF2、-CHFCH2F、-CF2CHF2、-CH2CF3、-CH2CF2CHF2、甲氧基、乙氧基、正丙基氧基、异丙基氧基、-OCHF2、-OCHFCH2F、-OCF2CHF2、-OCH2CF3、-OCH2CF2CHF2、甲氨基、二甲氨基、乙氨基、环丙基、环丁基、环戊基、环己基、氧杂环丁基、氮杂环丁基、吡咯烷基、四氢呋喃基、哌啶基、哌嗪基、吗啉基、苯基、萘基、苯并咪唑基、吡咯基、吡唑基、咪唑基、三氮唑基、四氮唑基、呋喃基、噻吩基、噻唑基、噁唑基、吡啶基、嘧啶基、吡嗪基和哒嗪基各自独立任选地被1、2、3、4或5个独立地选自氘、氟、氯、溴、碘、羟基、氧代、氨基、硝基、氰基、甲基、乙基、正丙基、异丙基、三氟甲基、二氟甲基、甲氧基、乙氧基、异丙氧基、三氟甲氧基、-OCH2OH和-OCH2CH2OH的基团所取代。In other embodiments, R is hydrogen, deuterium, fluorine, chlorine, bromine, iodine, hydroxyl, amino, nitro, cyano, methyl, ethyl, n-propyl, isopropyl, allyl, propenyl, propargyl, propynyl, -CHF 2 , -CF 3 , -CHFCH 2 F, -CF 2 CHF 2 , -CH 2 CF 3 , -CH 2 CF 2 CHF 2 , methoxy, ethoxy , n-propoxy, isopropoxy, -OCHF 2 , -OCF 3 , -OCHFCH 2 F, -OCF 2 CHF 2 , -OCH 2 CF 3 , -OCH 2 CF 2 CHF 2 , methylamino, dimethyl Amino, ethylamino, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, azetidinyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, morpholinyl , phenyl, naphthyl, benzimidazolyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, furyl, thienyl, thiazolyl, oxazolyl, pyridyl, pyrimidinyl , pyrazinyl or pyridazinyl; wherein, the methyl, ethyl, n-propyl, isopropyl, allyl, propenyl, propargyl, propynyl, -CHF 2 , -CHFCH 2 F, -CF 2 CHF 2 , -CH 2 CF 3 , -CH 2 CF 2 CHF 2 , methoxy, ethoxy, n-propyloxy, isopropyloxy, -OCHF 2 , -OCHFCH 2 F , -OCF 2 CHF 2 , -OCH 2 CF 3 , -OCH 2 CF 2 CHF 2 , methylamino, dimethylamino, ethylamino, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetane Base, azetidinyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, morpholinyl, phenyl, naphthyl, benzimidazolyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl Azolyl, tetrazolyl, furyl, thienyl, thiazolyl, oxazolyl, pyridyl, pyrimidinyl, pyrazinyl and pyridazinyl are each independently optionally replaced by 1, 2, 3, 4 or 5 independently selected from deuterium, fluorine, chlorine, bromine, iodine, hydroxyl, oxo, amino, nitro, cyano, methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, difluoromethyl , methoxy, ethoxy, isopropoxy, trifluoromethoxy, -OCH 2 OH and -OCH 2 CH 2 OH.
在一些实施方案中，R2c为氢、氘、氟、氯、溴、碘、羟基、氨基、硝基、氰基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6卤代烷基、C1-6烷氧基、C1-6卤代烷氧基、C1-6烷氨基、C3-8环烷基、3-8个原子组成的杂环基、C6-10芳基或5-12个原子组成的杂芳基；其中，所述的C1-6烷基、C2-6烯基、C2-6炔基、C1-6卤代烷基、C1-6烷氧基、C1-6卤代烷氧基、C1-6烷氨基、C3-8环烷基、3-8个原子组成的杂环基、C6-10芳基和5-12个原子组成的杂芳基各自独立任选地被1、2、3、4或5个独立地选自氘、氟、氯、溴、碘、羟基、氧代、氨基、硝基、氰基、C1-3烷基、C1-3卤代烷基、C1-3烷氧基、C1-3卤代烷氧基和C1-3羟基烷氧基的基团所取代。In some embodiments, R is hydrogen, deuterium, fluorine, chlorine, bromine, iodine, hydroxyl, amino, nitro, cyano, C alkyl , C alkenyl , C alkyne C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 alkylamino, C 3-8 cycloalkyl, heterocyclic group consisting of 3-8 atoms , C 6-10 aryl or heteroaryl consisting of 5-12 atoms; wherein, the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkane C 1-6 alkoxy group, C 1-6 haloalkoxy group, C 1-6 alkylamino group, C 3-8 cycloalkyl group, heterocyclic group consisting of 3-8 atoms, C 6-10 aryl group and heteroaryl groups consisting of 5-12 atoms are each independently optionally selected from 1, 2, 3, 4 or 5 independently selected from deuterium, fluorine, chlorine, bromine, iodine, hydroxyl, oxo, amino, nitro , cyano, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy and C 1-3 hydroxyalkoxy.
在另一些实施方案中，R2c为氢、氘、氟、氯、溴、碘、羟基、氨基、硝基、氰基、C1-4烷基、C2-4烯基、C2-4炔基、C1-4卤代烷基、C1-4烷氧基、C1-4卤代烷氧基、C1-4烷氨基、C3-6环烷基、3-6个原子组成的杂环基、C6-10芳基或5-10个原子组成的杂芳基；其中，所述的C1-4烷基、C2-4烯基、C2-4炔基、C1-4卤代烷基、C1-4烷氧基、C1-4卤代烷氧基、C1-4烷氨基、C3-6环烷基、3-6个原子组成的杂环基、C6-10芳基和5-10个原子组成的杂芳基各自独立任选地被1、2、3、4或5个独立地选自氘、氟、氯、溴、碘、羟基、氧代、氨基、硝基、氰基、C1-3烷基、C1-3卤代烷基、C1-3烷氧基、C1-3卤代烷氧基和C1-3羟基烷氧基的基团所取代。In other embodiments, R 2c is hydrogen, deuterium, fluorine, chlorine, bromine, iodine, hydroxyl, amino, nitro, cyano, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 Alkynyl, C 1-4 haloalkyl, C 1-4 alkoxy, C 1-4 haloalkoxy, C 1-4 alkylamino , C 3-6 cycloalkyl, heterocyclic ring consisting of 3-6 atoms group, C 6-10 aryl group or heteroaryl group consisting of 5-10 atoms; wherein, the C 1-4 alkyl group, C 2-4 alkenyl group, C 2-4 alkynyl group, C 1-4 Haloalkyl, C 1-4 alkoxy, C 1-4 haloalkoxy, C 1-4 alkylamino, C 3-6 cycloalkyl, heterocyclic group consisting of 3-6 atoms, C 6-10 aromatic The radical and the heteroaryl group consisting of 5-10 atoms are each independently optionally selected from 1, 2, 3, 4 or 5 independently selected from deuterium, fluorine, chlorine, bromine, iodine, hydroxyl, oxo, amino, nitric group, cyano, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy and C 1-3 hydroxyalkoxy.
在另一些实施方案中，R2c为氢、氘、氟、氯、溴、碘、羟基、氨基、硝基、氰基、甲基、乙基、正丙基、异丙基、烯丙基、丙烯基、炔丙基、丙炔基、-CHF2、-CF3、-CHFCH2F、-CF2CHF2、-CH2CF3、-CH2CF2CHF2、甲氧基、乙氧基、正丙氧基、异丙氧基、-OCHF2、-OCF3、-OCHFCH2F、-OCF2CHF2、-OCH2CF3、-OCH2CF2CHF2、甲氨基、二甲氨基、乙氨基、环丙基、环丁基、环戊基、环己基、氧杂环丁基、氮杂环丁基、吡咯烷基、四氢呋喃基、哌啶基、哌嗪基、吗啉基、苯基、萘基、苯并咪唑基、吡咯基、吡唑基、咪唑基、三氮唑基、四氮唑基、呋喃基、噻吩基、噻唑基、噁唑基、吡啶基、嘧啶基、吡嗪基或哒嗪基；其中，所述的甲基、乙基、正丙基、异丙基、烯丙基、丙烯基、炔丙基、丙炔基、-CHF2、-CHFCH2F、-CF2CHF2、-CH2CF3、-CH2CF2CHF2、甲氧基、乙氧基、正丙基氧基、异丙基氧基、-OCHF2、-OCHFCH2F、-OCF2CHF2、-OCH2CF3、-OCH2CF2CHF2、甲氨基、二甲氨基、乙氨基、环丙基、环丁基、环戊基、环己基、氧杂环丁基、氮杂环丁基、吡咯烷基、四氢呋喃基、哌啶基、哌嗪基、吗啉基、苯基、萘基、苯并咪唑基、吡咯基、吡唑基、咪唑基、三氮唑基、四氮唑基、呋喃基、噻吩基、噻唑基、噁唑基、吡啶基、嘧啶基、吡嗪基和哒嗪基各自独立任选地被1、2、3、4或5个独立地选自氘、氟、氯、溴、碘、羟基、氧代、氨基、硝基、氰基、甲基、乙基、正丙基、异丙基、三氟甲基、二氟甲基、甲氧基、乙氧基、异丙氧基、三氟甲氧基、-OCH2OH和-OCH2CH2OH的基团所取代。In other embodiments, R is hydrogen, deuterium, fluorine, chlorine, bromine, iodine, hydroxyl, amino, nitro, cyano, methyl, ethyl, n-propyl, isopropyl, allyl, propenyl, propargyl, propynyl, -CHF 2 , -CF 3 , -CHFCH 2 F, -CF 2 CHF 2 , -CH 2 CF 3 , -CH 2 CF 2 CHF 2 , methoxy, ethoxy , n-propoxy, isopropoxy, -OCHF 2 , -OCF 3 , -OCHFCH 2 F, -OCF 2 CHF 2 , -OCH 2 CF 3 , -OCH 2 CF 2 CHF 2 , methylamino, dimethyl Amino, ethylamino, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, azetidinyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, morpholinyl , phenyl, naphthyl, benzimidazolyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, furyl, thienyl, thiazolyl, oxazolyl, pyridyl, pyrimidinyl , pyrazinyl or pyridazinyl; wherein, the methyl, ethyl, n-propyl, isopropyl, allyl, propenyl, propargyl, propynyl, -CHF 2 , -CHFCH 2 F, -CF 2 CHF 2 , -CH 2 CF 3 , -CH 2 CF 2 CHF 2 , methoxy, ethoxy, n-propyloxy, isopropyloxy, -OCHF 2 , -OCHFCH 2 F , -OCF 2 CHF 2 , -OCH 2 CF 3 , -OCH 2 CF 2 CHF 2 , methylamino, dimethylamino, ethylamino, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetane Base, azetidinyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, morpholinyl, phenyl, naphthyl, benzimidazolyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl Azolyl, tetrazolyl, furyl, thienyl, thiazolyl, oxazolyl, pyridyl, pyrimidinyl, pyrazinyl and pyridazinyl are each independently optionally replaced by 1, 2, 3, 4 or 5 independently selected from deuterium, fluorine, chlorine, bromine, iodine, hydroxyl, oxo, amino, nitro, cyano, methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, difluoromethyl , methoxy, ethoxy, isopropoxy, trifluoromethoxy, -OCH 2 OH and -OCH 2 CH 2 OH.
在一些实施方案中，各Rx独立地为氘、氟、氯、溴、碘、羟基、氧代、氨基、硝基、氰基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6卤代烷基、C1-6烷氧基、C1-6卤代烷氧基、C1-6烷氨基、C3-8环烷基或3-8个原子组成的杂环基；其中，所述的C1-6烷基、C2-6烯基、C2-6炔基、C1-6卤代烷基、C1-6烷氧基、C1-6卤代烷氧基、C1-6烷氨基、C3-8环烷基和3-8个原子组成的杂环基各自独立任选地被1、2、3、4或5个独立地选自氘、氟、氯、溴、碘、羟基、氧代、氨基、硝基、氰基、C1-3烷基、C1-3卤代烷基、C1-3烷氧基、C1-3卤代烷氧基和C1-3羟基烷氧基的基团所取代。In some embodiments, each R x is independently deuterium, fluorine, chlorine, bromine, iodine, hydroxyl, oxo, amino, nitro, cyano, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 alkylamino, C 3-8 cycloalkyl or 3-8 atoms The heterocyclic group; wherein, the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 Haloalkoxy, C 1-6 alkylamino, C 3-8 cycloalkyl and heterocyclic group consisting of 3-8 atoms are each independently optionally selected from 1, 2, 3, 4 or 5 independently selected from deuterium , fluorine, chlorine, bromine, iodine, hydroxyl, oxo, amino, nitro, cyano, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy Substituted by groups and C 1-3 hydroxyalkoxy groups.
在另一些实施方案中，各Rx独立地为氘、氟、氯、溴、碘、羟基、氧代、氨基、硝基、氰基、C1-4烷基、C2-4烯基、C2-4炔基、C1-4卤代烷基、C1-4烷氧基、C1-4卤代烷氧基、C1-4烷氨基、C3-6环烷基或3-6个原子组成的杂环基；其中，所述的C1-4烷基、C2-4烯基、C2-4炔基、C1-4卤代烷基、C1-4烷氧基、C1-4卤代烷氧基、C1-4烷氨基、C3-6环烷基和3-6个原子组成的杂环基各自独立任选地被1、2、3、4或5个独立地选自氘、氟、氯、溴、碘、羟基、氧代、氨基、硝基、氰基、C1-3烷基、C1-3卤代烷基、C1-3烷氧基、C1-3卤代烷氧基和C1-3羟基烷氧基的基团所取代。In other embodiments, each R x is independently deuterium, fluorine, chlorine, bromine, iodine, hydroxyl, oxo, amino, nitro, cyano, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 haloalkyl, C 1-4 alkoxy, C 1-4 haloalkoxy, C 1-4 alkylamino, C 3-6 cycloalkyl or 3-6 atoms A heterocyclic group consisting of; wherein, the C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 haloalkyl, C 1-4 alkoxy, C 1- 4 haloalkoxy, C 1-4 alkylamino, C 3-6 cycloalkyl and heterocyclic group consisting of 3-6 atoms are each independently optionally selected from 1, 2, 3, 4 or 5 independently Deuterium, fluorine, chlorine, bromine, iodine, hydroxyl, oxo, amino, nitro, cyano, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkane Oxygen and C 1-3 hydroxyalkoxy groups are substituted.
在另一些实施方案中，各Rx独立地为氘、氟、氯、溴、碘、羟基、氧代、氨基、硝基、氰基、甲基、乙基、正丙基、异丙基、烯丙基、丙烯基、炔丙基、丙炔基、-CHF2、-CF3、-CHFCH2F、-CF2CHF2、-CH2CF3、-CH2CF2CHF2、甲氧基、乙氧基、正丙氧基、异丙氧基、-OCHF2、-OCF3、-OCHFCH2F、-OCF2CHF2、-OCH2CF3、-OCH2CF2CHF2、甲氨基、二甲氨基、乙氨基、环丙基、环丁基、环戊基、环己基、氮杂环丁基、氧杂环丁基、吡咯烷基、四氢呋喃基、哌啶基、哌嗪基或吗啉基；其中，所述的甲基、乙基、正丙基、异丙基、烯丙基、丙烯基、炔丙基、丙炔基、-CHF2、-CHFCH2F、-CF2CHF2、-CH2CF3、-CH2CF2CHF2、甲氧基、乙氧基、正丙氧基、异丙氧基、-OCHF2、-OCHFCH2F、-OCF2CHF2、-OCH2CF3、-OCH2CF2CHF2、甲氨基、二甲氨基、乙氨基、环丙基、环丁基、环戊基、环己基、氮杂环丁基、氧杂环丁基、吡咯烷基、四氢呋喃基、哌啶基、哌嗪基和吗啉基各自独立任选地被1、2、3、4或5个独立地选自氘、氟、氯、溴、碘、羟基、氧代、氨基、硝基、氰基、甲基、乙基、正丙基、异丙基、三氟甲基、二氟甲基、甲氧基、乙氧基、异丙氧基、三氟甲氧基、-OCH2OH和-OCH2CH2OH的基团所取代。In other embodiments, each R x is independently deuterium, fluorine, chlorine, bromine, iodine, hydroxyl, oxo, amino, nitro, cyano, methyl, ethyl, n-propyl, isopropyl, Allyl, propenyl, propargyl, propynyl, -CHF 2 , -CF 3 , -CHFCH 2 F, -CF 2 CHF 2 , -CH 2 CF 3 , -CH 2 CF 2 CHF 2 , methoxy ethoxy, n-propoxy, isopropoxy, -OCHF 2 , -OCF 3 , -OCHFCH 2 F, -OCF 2 CHF 2 , -OCH 2 CF 3 , -OCH 2 CF 2 CHF 2 , Amino, Dimethylamino, Ethylamino, Cyclopropyl, Cyclobutyl, Cyclopentyl, Cyclohexyl, Azetidinyl, Oxetyl, Pyrrolidinyl, Tetrahydrofuranyl, Piperidinyl, Piperazinyl or morpholinyl; wherein, the methyl, ethyl, n-propyl, isopropyl, allyl, propenyl, propargyl, propynyl, -CHF 2 , -CHFCH 2 F, -CF 2 CHF 2 , -CH 2 CF 3 , -CH 2 CF 2 CHF 2 , methoxy, ethoxy, n-propoxy, isopropoxy, -OCHF 2 , -OCHFCH 2 F, -OCF 2 CHF 2 , -OCH 2 CF 3 , -OCH 2 CF 2 CHF 2 , methylamino, dimethylamino, ethylamino, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetidine Base, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl and morpholinyl are each independently optionally selected from 1, 2, 3, 4 or 5 independently selected from deuterium, fluorine, chlorine, bromine, iodine, Hydroxy, Oxo, Amino, Nitro, Cyano, Methyl, Ethyl, n-Propyl, Isopropyl, Trifluoromethyl, Difluoromethyl, Methoxy, Ethoxy, Isopropoxy, Trifluoromethoxy, -OCH 2 OH and -OCH 2 CH 2 OH are substituted.
在一些实施方案中，各Ry独立地为氘、氟、氯、溴、碘、羟基、氨基、硝基、氰基、C1-6烷基、C1-6卤代烷基、C1-6烷氧基、C1-6卤代烷氧基、C1-6羟基烷氧基、C1-6烷氨基、C3-8环烷基、3-8个原子组成的杂环基、C6-10芳基或5-12个原子组成的杂芳基；其中，所述的C1-6烷基、C1-6卤代烷基、C1-6烷氧基、C1-6卤代烷氧基、C1-6羟基烷氧基、C1-6烷氨基、C3-8环烷基、3-8个原子组成的杂环基、C6-10芳基和5-12个原子组成的杂芳基各自独立任选地被1、2、3、4或5个独立地选自氘、氟、氯、溴、碘、羟基、氧代、氨基、硝基、氰基、C1-3烷基、C1-3卤代烷基、C1-3烷氧基、C1-3卤代烷氧基或C1-3羟基烷氧基的基团所取代。In some embodiments, each Ry is independently deuterium, fluorine, chlorine, bromine, iodine, hydroxyl, amino, nitro, cyano, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 Alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkoxy, C 1-6 alkylamino, C 3-8 cycloalkyl, heterocyclic group consisting of 3-8 atoms, C 6- 10 aryl groups or heteroaryl groups consisting of 5-12 atoms; wherein, the C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkoxy, C 1-6 alkylamino, C 3-8 cycloalkyl, heterocyclic group consisting of 3-8 atoms, C 6-10 aryl and heterocyclic group consisting of 5-12 atoms Each aryl group is independently optionally selected from 1, 2, 3, 4 or 5 independently selected from deuterium, fluorine, chlorine, bromine, iodine, hydroxyl, oxo, amino, nitro, cyano, C 1-3 alkane Substituted by radical, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy or C 1-3 hydroxyalkoxy.
在另一些实施方案中，各Ry独立地为氘、氟、氯、溴、碘、羟基、氨基、硝基、氰基、C1-4烷基、C1-4卤代烷基、C1-4烷氧基、C1-4卤代烷氧基、C1-4羟基烷氧基、C1-4烷氨基、C3-6环烷基、3-6个原子组成的杂环基、C6-10芳基或5-10个原子组成的杂芳基；其中，所述的C1-4烷基、C1-4卤代烷基、C1-4烷氧基、C1-4卤代烷氧基、C1-4羟基烷氧基、C1-4烷氨基、C3-6环烷基、3-6个原子组成的杂环基、C6-10芳基和5-10个原子组成的杂芳基各自独立任选地被1、2、3、4或5个独立地选自氘、氟、氯、溴、碘、羟基、氧代、氨基、硝基、氰基、C1-3烷基、C1-3卤代烷基、C1-3烷氧基、C1-3卤代烷氧基和C1-3羟基烷氧基的基团所取代。In other embodiments, each R y is independently deuterium, fluorine, chlorine, bromine, iodine, hydroxyl, amino, nitro, cyano, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 4 alkoxy, C 1-4 haloalkoxy, C 1-4 hydroxyalkoxy, C 1-4 alkylamino, C 3-6 cycloalkyl, heterocyclic group consisting of 3-6 atoms, C 6 -10 aryl or heteroaryl consisting of 5-10 atoms; wherein, the C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy, C 1-4 haloalkoxy , C 1-4 hydroxyalkoxy, C 1-4 alkylamino, C 3-6 cycloalkyl, heterocyclic group consisting of 3-6 atoms, C 6-10 aryl and 5-10 atoms Each heteroaryl group is independently optionally selected from 1, 2, 3, 4 or 5 independently selected from deuterium, fluorine, chlorine, bromine, iodine, hydroxyl, oxo, amino, nitro, cyano, C 1-3 Alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy and C 1-3 hydroxyalkoxy groups are substituted.
在另一些实施方案中，各Ry独立地为氘、氟、氯、溴、碘、羟基、氨基、硝基、氰基、甲基、乙基、正丙基、异丙基、叔丁基、三氟甲基、二氟甲基、甲氧基、乙氧基、异丙氧基、三氟甲氧基、-OCH2OH、-OCH2CH2OH、甲氨基、乙氨基、二甲氨基、二乙氨基、环丙基、环丁基、环戊基、环己基、氮杂环丁基、氧杂环丁基、吡咯烷基、四氢呋喃基、哌啶基、哌嗪基、吗啉基、苯基、吡啶基、嘧啶基、吡咯基、吡唑基、咪唑基、噻吩基、噻唑基、呋喃基或三氮唑基；其中，所述的甲基、乙基、正丙基、异丙基、叔丁基、二氟甲基、甲氧基、乙氧基、异丙氧基、-OCH2OH、-OCH2CH2OH、甲氨基、乙氨基、二甲氨基、二乙氨基、环丙基、环丁基、环戊基、环己基、氮杂环丁基、氧杂环丁基、吡咯烷基、四氢呋喃基、哌啶基、哌嗪基、吗啉基、苯基、吡啶基、嘧啶基、吡咯基、吡唑基、咪唑基、噻吩基、噻唑基、呋喃基或三氮唑基各自独立任选地被1、2、3、4或5个独立地选自氘、氟、氯、溴、碘、羟基、氧代、氨基、硝基、氰基、甲基、乙基、正丙基、异丙基、三氟甲基、二氟甲基、甲氧基、乙氧基、异丙氧基、三氟甲氧基、-OCH2OH和-OCH2CH2OH的基团所取代。In other embodiments, each Ry is independently deuterium, fluorine, chlorine, bromine, iodine, hydroxyl, amino, nitro, cyano, methyl, ethyl, n-propyl, isopropyl, tert-butyl , trifluoromethyl, difluoromethyl, methoxy, ethoxy, isopropoxy, trifluoromethoxy, -OCH 2 OH, -OCH 2 CH 2 OH, methylamino, ethylamino, dimethyl Amino, diethylamino, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, morpholine Base, phenyl, pyridyl, pyrimidinyl, pyrrolyl, pyrazolyl, imidazolyl, thienyl, thiazolyl, furyl or triazolyl; wherein, the methyl, ethyl, n-propyl, Isopropyl, tert-butyl, difluoromethyl, methoxy, ethoxy, isopropoxy, -OCH 2 OH, -OCH 2 CH 2 OH, methylamino, ethylamino, dimethylamino, diethyl Amino, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, morpholinyl, phenyl , pyridyl, pyrimidinyl, pyrrolyl, pyrazolyl, imidazolyl, thienyl, thiazolyl, furyl or triazolyl are each independently optionally selected from 1, 2, 3, 4 or 5 independently Deuterium, fluorine, chlorine, bromine, iodine, hydroxyl, oxo, amino, nitro, cyano, methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, difluoromethyl, methoxy , ethoxy, isopropoxy, trifluoromethoxy, -OCH 2 OH and -OCH 2 CH 2 OH groups.
另一方面，本发明涉及以下其中之一的化合物或以下其中之一的化合物的立体异构体、几何异构体、互变异构体、氮氧化物、溶剂化物、水合物、代谢产物、酯、药学上可接受的盐或它的前药，但绝不限于：In another aspect, the present invention relates to one of the following compounds or stereoisomers, geometric isomers, tautomers, nitrogen oxides, solvates, hydrates, metabolites, Esters, pharmaceutically acceptable salts or prodrugs thereof, but by no means limited to:
另一方面，本发明涉及药物组合物，该药物组合物，包含前面所述的化合物的立体异构体、互变异构体、氮氧化物、水合物、溶剂化物、代谢产物、药学上可接受的盐或前药。In another aspect, the present invention relates to a pharmaceutical composition, which comprises stereoisomers, tautomers, nitrogen oxides, hydrates, solvates, metabolites, pharmaceutically acceptable Accepted salts or prodrugs.
其中一些实施例是，本发明涉及的药物组合物还包含药学上可接受的载体、赋形剂、稀释剂、辅剂、媒介物，或它们的任意组合。In some embodiments, the pharmaceutical composition of the present invention further comprises a pharmaceutically acceptable carrier, excipient, diluent, adjuvant, vehicle, or any combination thereof.
另一方面，本发明涉及前面所述化合物或其药物组合物在制备用于预防、治疗或减轻患者由KRAS G12C介导的疾病的药物中的用途。In another aspect, the present invention relates to the use of the aforementioned compound or its pharmaceutical composition in the preparation of medicines for preventing, treating or alleviating diseases mediated by KRAS G12C in patients.
其中一些实施例是，由KRAS G12C介导的疾病为癌症。In some embodiments, the disease mediated by KRAS G12C is cancer.
其中一些实施方案是，本发明所述的癌症为肺癌、淋巴瘤、食道癌、卵巢癌、胰腺癌、直肠癌、脑胶质瘤、子宫颈癌、尿路上皮癌、胃癌、子宫内膜癌、肝癌、胆管癌、乳腺癌、结肠癌、阑尾癌、小肠癌、白血病和黑色素瘤。In some embodiments, the cancer described in the present invention is lung cancer, lymphoma, esophageal cancer, ovarian cancer, pancreatic cancer, rectal cancer, glioma, cervical cancer, urothelial cancer, gastric cancer, endometrial cancer , liver cancer, bile duct cancer, breast cancer, colon cancer, appendix cancer, small bowel cancer, leukemia and melanoma.
另一方面，本发明涉及式(I)所示的化合物的制备、分离和纯化的方法。In another aspect, the present invention relates to methods for the preparation, isolation and purification of compounds represented by formula (I).
本发明化合物的药物组合物，制剂，给药和用途Pharmaceutical Compositions, Formulations, Administration and Uses of the Compounds of the Invention
本发明的药物组合物的特点包括式(I)所示的化合物、本发明所列出的化合物或实施例的化合物，和药学上可接受的载体。本发明的药物组合物中化合物的量能有效地治疗或减轻患者由KRAS G12C介导的疾病。The characteristics of the pharmaceutical composition of the present invention include the compound represented by formula (I), the compound listed in the present invention or the compound of the examples, and a pharmaceutically acceptable carrier. The amount of the compound in the pharmaceutical composition of the present invention can effectively treat or alleviate the disease mediated by KRAS G12C in a patient.
本发明的化合物存在自由形态，或合适的、作为药学上可接受的衍生物。根据本发明，药学上可接受的衍生物包括，但并不限于，药学上可接受的前药，盐，酯，酯类的盐，或能直接或间接地根据患者的需要给药的其他任何加合物或衍生物，本发明其他方面所描述的化合物，其代谢产物或它的残留物。The compounds of the present invention exist in free form, or suitably, as pharmaceutically acceptable derivatives. According to the present invention, pharmaceutically acceptable derivatives include, but are not limited to, pharmaceutically acceptable prodrugs, salts, esters, salts of esters, or any other compounds that can be administered directly or indirectly according to the needs of patients. Adducts or derivatives, compounds described in other aspects of the invention, metabolites thereof or residues thereof.
像本发明所描述的，本发明药学上可接受的组合物进一步包含药学上可接受的载体，辅剂，或赋形剂，这些像本发明所应用的，包括任何溶剂，稀释剂，或其他液体赋形剂，分散剂或悬浮剂，表面活性剂，等渗剂，增稠剂，乳化剂，防腐剂，固体粘合剂或润滑剂，等等，适合于特有的目标剂型。如以下文献所描述的：In Remington:The Science and Practiceof Pharmacy,21st edition,2005,ed.D.B.Troy,Lippincott Williams&Wilkins,Philadelphia,and Encyclopedia of Pharmaceutical Technology,eds.J.Swarbrickand J.C.Boylan,1988-1999,Marcel Dekker,New York,综合此处文献的内容，表明不同的载体可应用于药学上可接受的组合物的制剂和它们公知的制备方法。除了任何常规的载体媒介与本发明的化合物不相容的范围，例如所产生的任何不良的生物效应或与药学上可接受的组合物的任何其他组分以有害的方式产生的相互作用，它们的用途也是本发明所考虑的范围。As described herein, the pharmaceutically acceptable composition of the present invention further comprises a pharmaceutically acceptable carrier, adjuvant, or vehicle, which, as used in the present invention, includes any solvent, diluent, or other Liquid excipients, dispersing or suspending agents, surfactants, isotonic agents, thickening agents, emulsifying agents, preservatives, solid binders or lubricants, etc., are suitable for the specific target dosage form. As described in: In Remington: The Science and Practice of Pharmacy, 21st edition, 2005, ed. D.B. Troy, Lippincott Williams & Wilkins, Philadelphia, and Encyclopedia of Pharmaceutical Technology, eds. J. Swarbrick and J. C. Boylan, 1988-1999, Marcel Dekker, New York, synthesis of the literature herein, shows that different carriers can be used in the formulation of pharmaceutically acceptable compositions and their known methods of preparation. Except to the extent that any conventional carrier media is incompatible with the compounds of the present invention, such as any adverse biological effects produced or interactions in a deleterious manner with any other components of the pharmaceutically acceptable composition, they The purposes of the present invention are also considered scope.
可作为药学上可接受载体的物质包括，但并不限于，离子交换剂，铝，硬脂酸铝，卵磷脂，血清蛋白，如人血清蛋白，缓冲物质如磷酸盐，甘氨酸，山梨酸，山梨酸钾，饱和植物脂肪酸的部分甘油酯混合物，水，盐或电解质，如硫酸鱼精蛋白，磷酸氢二钠，磷酸氢钾，氯化钠，锌盐，胶体硅，三硅酸镁，聚乙烯吡咯烷酮，聚丙烯酸脂，蜡，聚乙烯-聚氧丙烯-阻断聚合体，羊毛脂，糖，如乳糖，葡萄糖和蔗糖；淀粉如玉米淀粉和土豆淀粉；纤维素和它的衍生物如羧甲基纤维素钠，乙基纤维素和乙酸纤维素；树胶粉；麦芽；明胶；滑石粉；辅料如可可豆脂和栓剂蜡状物；油如花生油，棉子油，红花油，麻油，橄榄油，玉米油和豆油；二醇类化合物，如丙二醇和聚乙二醇；酯类如乙基油酸酯和乙基月桂酸酯；琼脂；缓冲剂如氢氧化镁和氢氧化铝；海藻酸；无热原的水；等渗盐；林格(氏)溶液；乙醇，磷酸缓冲溶液，和其他无毒的合适的润滑剂如月桂硫酸钠和硬脂酸镁，着色剂，释放剂，包衣衣料，甜味剂，调味剂和香料，防腐剂和抗氧化剂。Substances that can be used as pharmaceutically acceptable carriers include, but are not limited to, ion exchangers, aluminum, aluminum stearate, lecithin, serum proteins, such as human serum albumin, buffer substances such as phosphate, glycine, sorbic acid, sorbic acid, Potassium phosphate, partial glyceride mixture of saturated vegetable fatty acids, water, salts or electrolytes such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silicon, magnesium trisilicate, polyethylene Pyrrolidone, polyacrylates, waxes, polyethylene-polyoxypropylene-blocking polymers, lanolin, sugars such as lactose, glucose and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as carboxymethyl sodium cellulose, ethyl cellulose, and cellulose acetate; gum powder; malt; gelatin; talc; excipients such as cocoa butter and suppository waxes; oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, Olive, corn, and soybean oils; glycols, such as propylene glycol and polyethylene glycol; esters, such as ethyl oleate and ethyl laurate; agar; buffers such as magnesium hydroxide and aluminum hydroxide; seaweed acid; pyrogen-free water; isotonic salts; Ringer's solution; ethanol, phosphate buffered solution, and other nontoxic suitable lubricants such as sodium lauryl sulfate and magnesium stearate, colorants, release agents, Coatings, sweeteners, flavors and fragrances, preservatives and antioxidants.
优选地，该化合物与根据施用的形式和常规的药学实践来选择的合适的药物稀释剂，赋形剂，或者载体(在此是指药物制剂)混合施用，施用方式可以是口服片剂，胶囊，酏剂，糖浆等等。Preferably, the compound is administered in admixture with a suitable pharmaceutical diluent, excipient, or carrier (herein referred to as a pharmaceutical preparation) selected according to the form of administration and conventional pharmaceutical practice, and the administration method can be oral tablet, capsule , elixirs, syrups and more.
例如，对于以片剂或者胶囊形式口服施用，活性药物组分可以和一种口服的、非毒性的、药学上可接受的惰性填充剂结合，如乳糖，淀粉，蔗糖，葡萄糖，甲基纤维素，硬脂酸镁，磷酸二钙，硫酸钙，甘露醇，山梨醇等等；对于以液体形式口服施用，口服药物组分可以和任何口服的、非毒性的、药学上可以接受的惰性润湿剂结合，如乙醇，甘油，水等等。而且，当需要或必需时，合适的粘合剂、滑润剂、分解试剂以及着色剂也可以加入到混合物中。合适的粘合剂包括淀粉、明胶、天然糖如葡萄糖或者β-乳糖，玉米甜味剂，天然的和合成的树胶如阿拉伯胶，黄芪胶，或者藻酸钠，羧甲基纤维素，聚乙烯乙二醇，蜡等等。在这些剂型中应用的润滑剂包括油酸钠，硬脂酸钠，硬脂酸镁，苯甲酸钠，乙酸钠，氯化钠等等。分解剂包括，但不限于，淀粉，甲基纤维素，琼脂，膨润土，黄原胶，等等。For example, for oral administration in tablet or capsule form, the active pharmaceutical ingredient can be combined with an oral, nontoxic, pharmaceutically acceptable inert filler such as lactose, starch, sucrose, glucose, methylcellulose, , magnesium stearate, dicalcium phosphate, calcium sulfate, mannitol, sorbitol, etc.; for oral administration in liquid form, oral pharmaceutical ingredients can be wetted with any oral, nontoxic, pharmaceutically acceptable inert Agents, such as ethanol, glycerin, water and so on. Also, when desired or necessary, suitable binders, lubricants, disintegrating agents, and colorants may also be added to the mixture. Suitable binders include starch, gelatin, natural sugars such as glucose or beta-lactose, corn sweeteners, natural and synthetic gums such as acacia, tragacanth, or sodium alginate, carboxymethylcellulose, polyethylene Glycols, waxes and more. Lubricants used in these dosage forms include sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride, and the like. Disintegrants include, but are not limited to, starch, methylcellulose, agar, bentonite, xanthan gum, and the like.
本发明化合物可以以口服剂的形式被施用，如片剂，胶囊(其中的每一个都包括持续释放或者定时释放的配方)，丸剂，粉剂，粒剂，酏剂，酊剂，悬浮剂，糖浆剂，和乳化剂。它们也可以以静脉内(大丸剂或者输液)，腹膜内，皮下或者肌肉内的形式施用，所有使用的剂量形式都是药学领域的普通技术人员所熟知的。它们可以单独施用，但一般将基于所选择的施用方式和标准的药学实践选择一种药学载体一起施用。The compounds of the present invention may be administered in the form of oral dosage forms such as tablets, capsules (each of which includes sustained release or timed release formulations), pills, powders, granules, elixirs, tinctures, suspensions, syrups , and emulsifiers. They can also be administered intravenously (bolus or infusion), intraperitoneally, subcutaneously or intramuscularly, all dosage forms used are well known to those skilled in the art of pharmacy. They can be administered alone, but will generally be administered with a pharmaceutical carrier selected on the basis of the chosen mode of administration and standard pharmaceutical practice.
本发明的化合物可以经过合适的鼻内载体的局部使用以鼻内形式施用，或者通过使用经皮药贴以经皮途径施用。当以经皮传递系统的形式施用时，在整个用药期间施用的剂量是连续的而不是间歇的。The compounds of the invention may be administered in intranasal form via topical use of suitable intranasal vehicles, or by the transdermal route through the use of transdermal patches. When administered in the form of a transdermal delivery system, the dosage administration will be continuous rather than intermittent throughout the dosage period.
本发明化合物也可以以脂质体传递系统的形式施用，如小的单层的囊泡，大的单层的囊泡以及多层囊泡。脂质体可以通过不同的磷脂形成，如胆固醇，硬脂胺，或者磷脂酰胆碱。The compounds of the invention can also be administered in the form of liposomal delivery systems, such as small unilamellar vesicles, large unilamellar vesicles and multilamellar vesicles. Liposomes can be formed from different phospholipids, such as cholesterol, stearylamine, or phosphatidylcholines.
本发明化合物也与可溶性的聚合物偶联，该多聚物作为靶向的药物制剂。这样的多聚物包括聚乙烯吡咯烷酮，吡喃共聚物，聚羟基丙基甲基丙烯酸胺-酚，聚羟基乙基天冬酰胺酚，或者用棕榈酰残基取代的聚乙烯氧化物-聚赖氨酸。而且，本发明化合物可以与一类生物可降解的聚合物偶联，用于完成可控制的药物释放，例如，聚乳酸，聚羟基乙酸，聚乳酸和聚羟基乙酸的共聚物，聚ε己内酯，聚羟基丁酸，聚原酸酯，聚缩醛，聚二氢吡喃，聚氰基丙烯酸酯，和水凝胶的交联的或者两亲性的阻断共聚物。The compounds of the present invention are also conjugated to soluble polymers which serve as targeted drug formulations. Such polymers include polyvinylpyrrolidone, pyran copolymer, polyhydroxypropylmethacrylamine-phenol, polyhydroxyethylaspartamidephenol, or polyethylene oxide-polylysine substituted with palmitoyl residues. acid. Moreover, the compounds of the present invention can be coupled with a class of biodegradable polymers for controlled drug release, for example, polylactic acid, polyglycolic acid, copolymers of polylactic acid and polyglycolic acid, polyεcaprolactone esters, polyhydroxybutyrates, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates, and cross-linked or amphiphilic blocked copolymers of hydrogels.
本发明化合物的给药方案将随已知的各种因素而不同，如特定试剂的药动学特征及其模式和施用途径；接受者的种族，年龄，性别，健康状况，医疗状况和体重；症状的性质和程度；并行的治疗的种类；治疗的频率；施药的途径，病人的肾和肝功能，和希望达到的效果。一个医师或者兽医可以作出决定并开出有效量的药物来预防、抵销或者阻止癌症的发展。The dosing regimen of the compounds of the present invention will vary with known various factors, such as the pharmacokinetic profile of the particular agent and its mode and route of administration; the race, age, sex, health, medical condition and weight of the recipient; Nature and extent of symptoms; type of concurrent therapy; frequency of therapy; route of administration, patient's renal and hepatic function, and desired effect. A physician or veterinarian can make the determination and prescribe an effective amount of drug to prevent, counteract or stop the progression of the cancer.
根据一般的指导原则，为了达到指定的效果，所使用的每一种活性成分的日口服剂量的范围为大约0.001到1000mg/kg体重之间。对于静脉内的施用，在常规速率的输液过程中最优选的剂量范围为大约1到大约10mg/kg体重/分钟。本发明化合物可以以每日一次来施用，或者可以以每日分两次，三次或者四次进行施用。As a general guideline, a daily oral dosage of each active ingredient in the range of about 0.001 to 1000 mg/kg body weight is used to achieve the indicated effect. For intravenous administration, the most preferred dosage range is about 1 to about 10 mg/kg body weight/minute during a conventional rate infusion. The compounds of the present invention may be administered once daily, or may be administered in two, three or four divided times daily.
适于施用的剂型(药物组合物)的每一单位剂量，可以含有大约1mg到大约1000mg的活性成分。在这些药物组合物中，活性成分的重量一般将占组合物的总重量的大约0.5-95％。Dosage forms suitable for administration (pharmaceutical compositions) may contain from about 1 mg to about 1000 mg of active ingredient per unit dose. In these pharmaceutical compositions, the active ingredient will generally comprise from about 0.5% to about 95% by weight of the total composition.
当本发明化合物与其他治疗剂一起施用时，一般地，考虑到联合施用时治疗剂的附加的或者协同的效果，在典型的日剂量和典型的剂型中的每一个组分的量，相对于单独施用时的通常剂量，可以有所下降。When the compound of the present invention is administered together with other therapeutic agents, in general, the amount of each component in a typical daily dosage and a typical dosage form, relative to The usual dosage when administered alone may be reduced.
本发明涉及的化合物或者其药用盐或其水合物能有效用于预防、治疗或减轻患者由KRAS G12C介导的疾病，特别是能有效治疗肺癌、淋巴瘤、食道癌、卵巢癌、胰腺癌、直肠癌、脑胶质瘤、子宫颈癌、尿路上皮癌、胃癌、子宫内膜癌、肝癌、胆管癌、乳腺癌、结肠癌、阑尾癌、小肠癌、白血病和黑色素瘤等。The compounds involved in the present invention or their pharmaceutically acceptable salts or hydrates thereof can be effectively used for preventing, treating or alleviating diseases mediated by KRAS G12C in patients, especially for effectively treating lung cancer, lymphoma, esophageal cancer, ovarian cancer and pancreatic cancer , rectal cancer, glioma, cervical cancer, urothelial cancer, gastric cancer, endometrial cancer, liver cancer, bile duct cancer, breast cancer, colon cancer, appendix cancer, small intestine cancer, leukemia and melanoma, etc.
一般合成过程General Synthesis Process
为描述本发明，以下列出了实施例。但需要理解，本发明不限于这些实施例，只是提供实践本发明的方法。In order to describe the present invention, examples are listed below. However, it should be understood that the present invention is not limited to these examples, but only provides a method of practicing the present invention.
一般地，本发明的化合物可以通过本发明所描述的方法制备得到，除非有进一步的说明，其中取代基的定义如本发明所述。下面的反应方案和实施例用于进一步举例说明本发明的内容。Generally, the compounds of the present invention can be prepared by the methods described in the present invention, and unless otherwise specified, the definitions of the substituents are as described in the present invention. The following reaction schemes and examples serve to further illustrate the present invention.
所属领域的技术人员将认识到：本发明所描述的化学反应可以用来合适地制备本发明的其他化合物，且用于制备本发明的化合物的其它方法都被认为是在本发明的范围之内。例如，根据本发明那些非例证的化合物的合成可以成功地被所属领域的技术人员通过修饰方法完成，如适当的保护干扰基团，通过利用其他已知的试剂除了本发明所描述的，或将反应条件做一些常规的修改。另外，本发明所公开的反应或已知的反应条件也公认地适用于本发明其他化合物的制备。Those skilled in the art will recognize that the chemical reactions described herein can be used to suitably prepare other compounds of the invention and that other methods for preparing compounds of the invention are considered to be within the scope of the invention . For example, the synthesis of those non-exemplified compounds according to the present invention can be successfully accomplished by those skilled in the art through modification methods, such as appropriate protection of interfering groups, by using other known reagents in addition to those described in the present invention, or by incorporating Reaction conditions with some routine modifications. In addition, reactions disclosed herein or known reaction conditions are also recognized to be applicable to the preparation of other compounds of this invention.
下面所描述的实施例，除非其他方面表明所有的温度定为摄氏度。试剂购买于商品供应商如Aldrich Chemical Company,Arco Chemical Company and Alfa ChemicalCompany，使用时都没有经过进一步纯化。除非其他方面表明，一般的试剂从汕头西陇化工厂，广东光华化学试剂厂，广州化学试剂厂，天津好寓宇化学品有限公司，天津市福晨化学试剂厂，武汉鑫华远科技发展有限公司，青岛腾龙化学试剂有限公司，和青岛海洋化工厂购买得到。In the examples described below, unless indicated otherwise, all temperatures are in degrees Celsius. Reagents were purchased from commercial suppliers such as Aldrich Chemical Company, Arco Chemical Company and Alfa Chemical Company and used without further purification. Unless otherwise indicated, general reagents are purchased from Shantou Xilong Chemical Factory, Guangdong Guanghua Chemical Reagent Factory, Guangzhou Chemical Reagent Factory, Tianjin Haoyuyu Chemical Co., Ltd., Tianjin Fuchen Chemical Reagent Factory, Wuhan Xinhuayuan Technology Development Co., Ltd. Company, Qingdao Tenglong Chemical Reagent Co., Ltd., and Qingdao Ocean Chemical Factory purchased it.
无水四氢呋喃，二氧六环，甲苯，乙醚是经过金属钠回流干燥得到。无水二氯甲烷和氯仿是经过氢化钙回流干燥得到。乙酸乙酯，石油醚，正己烷，N,N-二甲基乙酰胺和N,N-二甲基甲酰胺是经无水硫酸钠事先干燥使用。Anhydrous tetrahydrofuran, dioxane, toluene, and ether were obtained by reflux drying over sodium metal. Anhydrous dichloromethane and chloroform were obtained by refluxing and drying over calcium hydride. Ethyl acetate, petroleum ether, n-hexane, N,N-dimethylacetamide and N,N-dimethylformamide were dried over anhydrous sodium sulfate before use.
以下反应一般是在氮气或氩气正压下或在无水溶剂上套一干燥管(除非其他方面表明)，反应瓶都塞上合适的橡皮塞，底物通过注射器打入。玻璃器皿均是经过干燥的。The following reactions were generally carried out under a positive pressure of nitrogen or argon or over anhydrous solvents with a dry tube (unless otherwise indicated), the reaction vials were fitted with suitable rubber stoppers, and the substrate was introduced by syringe. Glassware is dried.
色谱柱是使用硅胶柱。硅胶(300-400目)购于青岛海洋化工厂。The chromatographic column is a silica gel column. Silica gel (300-400 mesh) was purchased from Qingdao Ocean Chemical Factory.
1H NMR谱使用Bruker 400MHz或600MHz核磁共振谱仪记录。1H NMR谱以CDC13、DMSO-d6、CD3OD或丙酮-d6为溶剂(以ppm为单位)，用TMS(0ppm)或氯仿(7.26ppm)作为参照标准。当出现多重峰的时候，将使用下面的缩写：s(singlet，单峰)、d(doublet，双峰)、t(triplet，三重峰)、q(quartet，四重峰)、m(multiplet，多重峰)、br(broadened，宽峰)、brs(broadened singlet，宽的单峰)、dd(doublet of doublets，双二重峰)、ddd(doubletdoublet of doublets，双双二重峰)、dt(doublet of triplets，双三重峰)。偶合常数J，用赫兹(Hz)表示。 1 H NMR spectra were recorded using a Bruker 400 MHz or 600 MHz nuclear magnetic resonance spectrometer. 1 H NMR spectrum uses CDC1 3 , DMSO-d 6 , CD 3 OD or acetone-d 6 as the solvent (in ppm), and TMS (0 ppm) or chloroform (7.26 ppm) as the reference standard. When multiplets appear, the following abbreviations will be used: s (singlet, singlet), d (doublet, doublet), t (triplet, triplet), q (quartet, quartet), m (multiplet, Multiplet), br(broadened, broad peak), brs(broadened singlet, broad singlet), dd(doublet of doublets, double doublet), ddd(doubletdoublet of doublets, double doublet doublet), dt(doublet of triplets, double triplet). Coupling constant J expressed in Hertz (Hz).
低分辨率质谱(MS)数据的测定条件是：Agilent 6120四级杆HPLC-MS(柱子型号：Zorbax SB-C18,2.1×30mm,3.5微米,6min,流速为0.6mL/min。流动相：5％-95％(含0.1％甲酸的CH3CN)在(含0.1％甲酸的H2O)中的比例，采用电喷雾电离(ESI)，在210nm/254nm下，用UV检测。The measurement conditions of low-resolution mass spectrometry (MS) data are: Agilent 6120 quadrupole HPLC-MS (column model: Zorbax SB-C18, 2.1 × 30mm, 3.5 microns, 6min, flow rate is 0.6mL/min. Mobile phase: 5 %-95% (CH 3 CN with 0.1% formic acid) in (H 2 O with 0.1% formic acid) by electrospray ionization (ESI) at 210 nm/254 nm with UV detection.
纯的化合物使用Agilent 1260pre-HPLC或Calesep pump 250pre-HPLC(柱子型号：NOVASEP 50/80mm DAC)，在210nm/254nm下，用UV检测。Pure compounds were detected by UV at 210nm/254nm using Agilent 1260pre-HPLC or Calesep pump 250pre-HPLC (column model: NOVASEP 50/80mm DAC).
下面简写词的使用贯穿本发明：The following abbreviations are used throughout this disclosure:
下列合成方案描述了制备本发明化合物的步骤。除非另外说明，其中各Y、Ra、R2a、R2b、R2c、Rx、R3和m具有本发明所述的定义。The following synthetic schemes describe the steps to prepare the compounds of the invention. Unless otherwise specified, each of Y, R a , R 2a , R 2b , R 2c , R x , R 3 and m has the definition described in the present invention.
合成方案1Synthetic scheme 1
式(15)所示的化合物可以通过合成方案1制备得到：式(1)所示化合物和草酰氯、氨水依次反应得到式(2)所示的化合物；式(2)所示的化合物、式(3)所示化合物和式(4)所示的化合物反应得到式(5)所示的化合物；式(5)所示的化合物在二(三甲基硅基)氨基钾的作用下反应得到式(6)所示的化合物；式(6)所示的化合物在三氯氧磷的作用下反应得到式(7)所示的化合物；式(7)所示的化合物和式(8)所示的化合物在N,N-二异丙基乙胺的作用下反应得到式(9)所示的化合物；式(9)所示的化合物和式(10)所示化合物在[1,1′-[1,1'-双(二苯基膦)二茂铁]二氯化钯二氯甲烷络合物和醋酸钾的作用下反应得到式(11)所示的化合物；式(11)所示的化合物在氰化锌、二(三叔丁基膦)钯和三叔丁基膦(或氰化锌和氯(2-二环己基膦基-2',4',6'-三异丙基-1,1'-联苯基)[2-(2'-氨基-1,1'-联苯)]钯(II))的作用下可以反应得到式(12)所示的化合物；式(12)所示的化合物在三氟乙酸的作用下可以反应得到式(13)所示的化合物；式(13)所示的化合物和式(14)所示化合物在合适的条件下反应得到式(15)所示的化合物。The compound shown in formula (15) can be prepared by Synthesis Scheme 1: the compound shown in formula (1) reacts with oxalyl chloride and ammonia in order to obtain the compound shown in formula ( 2 ); the compound shown in formula ( 2 ), the formula The compound shown in ( 3 ) reacts with the compound shown in formula ( 4 ) to obtain the compound shown in formula ( 5 ); the compound shown in formula ( 5 ) reacts under the action of potassium bis(trimethylsilyl)amide to get The compound shown in formula ( 6 ); the compound shown in formula ( 6 ) reacts under the effect of phosphorus oxychloride to obtain the compound shown in formula ( 7 ); the compound shown in formula ( 7 ) and the compound shown in formula ( 8 ) The compound shown in N,N-diisopropylethylamine is reacted to obtain the compound shown in formula ( 9 ); the compound shown in formula ( 9 ) and the compound shown in formula ( 10 ) are in [1,1′ -[1,1'-bis(diphenylphosphino)ferrocene] palladium dichloride dichloromethane complex and potassium acetate react to obtain the compound shown in formula (11 ) ; The compounds shown are in the presence of zinc cyanide, bis(tri-tert-butylphosphine) palladium and tri-tert-butylphosphine (or zinc cyanide and chloro(2-dicyclohexylphosphino-2',4',6'-triiso Propyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium (II)) can be reacted to obtain the compound shown in formula ( 12 ); The compound shown in formula ( 12 ) can be reacted under the action of trifluoroacetic acid to obtain the compound shown in formula ( 13 ); the compound shown in formula ( 13 ) and the compound shown in formula ( 14 ) can be reacted under suitable conditions to get A compound represented by formula ( 15 ).
以下结合实施例对本发明提供的化合物、药物组合物及其应用进行进一步说明。The compounds, pharmaceutical compositions and applications provided by the present invention will be further described below in conjunction with the examples.
实施例Example
实施例1 4-((2S,5R)-4-丙烯酰基-2,5-二甲基哌嗪-1-基)-1-(4,6-二环丙基嘧啶-5-基)-7-(2-氟苯基)-2-氧代-1,2-二氢吡啶并[2,3-d]嘧啶-6-腈Example 1 4-((2S,5R)-4-acryloyl-2,5-dimethylpiperazin-1-yl)-1-(4,6-dicyclopropylpyrimidin-5-yl)- 7-(2-fluorophenyl)-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidine-6-carbonitrile
第一步4,6-二环丙基嘧啶-5-胺的合成The first step of synthesis of 4,6-dicyclopropylpyrimidin-5-amine
向反应瓶中加入4,6-二氯嘧啶-5-胺(0.34g，2.07mmol)、环丙基硼酸(0.89g，10.35mmol)、磷酸钾(1.32g，6.21mmol)、Pd2(dba)3(0.17g，0.41mmol)和Sphos(0.19g，0.21mmol)，再加入甲苯(18mL)和水(2mL)。反应体系在氮气氛围下，加热至95℃反应1小时。待反应完全后，将反应冷却至室温，加入水(20mL)。混合物用乙酸乙酯(20mL×3)萃取，合并有机相，无水硫酸钠干燥，过滤并减压浓缩。所得残留物经硅胶柱层析(PE/EtOAc(v/v)＝4/1)纯化，得到标题化合物黄色固体(0.36g,收率99.3％)。Add 4,6-dichloropyrimidin-5-amine (0.34g, 2.07mmol), cyclopropylboronic acid (0.89g, 10.35mmol), potassium phosphate (1.32g, 6.21mmol), Pd 2 (dba ) 3 (0.17g, 0.41mmol) and Sphos (0.19g, 0.21mmol), then added toluene (18mL) and water (2mL). The reaction system was heated to 95° C. for 1 hour under nitrogen atmosphere. After the reaction was complete, the reaction was cooled to room temperature, and water (20 mL) was added. The mixture was extracted with ethyl acetate (20 mL×3), and the organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (PE/EtOAc (v/v)=4/1) to obtain the title compound as a yellow solid (0.36 g, yield 99.3%).
MS(ESI,pos.ion)m/z:176.2[M+H]+.MS(ESI,pos.ion)m/z:176.2[M+H] + .
第二步2,5,6-三氯烟酰胺的合成Synthesis of 2,5,6-trichloronicotinamide in the second step
反应瓶中加入2,5,6-三氯烟酸(10.0g,44.2mmol)、二氯甲烷(100mL)和四氢呋喃(100mL)。向体系中缓慢滴入草酰氯(25.5g,0.20mol)，再缓慢滴入DMF(1mL)。体系室温下搅拌反应3小时，然后减压浓缩反应液得到酰氯中间体10.81g(100％)，该中间体直接用于下一步反应。Add 2,5,6-trichloronicotinic acid (10.0 g, 44.2 mmol), dichloromethane (100 mL) and tetrahydrofuran (100 mL) into the reaction flask. Oxalyl chloride (25.5 g, 0.20 mol) was slowly dropped into the system, and then DMF (1 mL) was slowly added dropwise. The system was stirred and reacted at room temperature for 3 hours, and then the reaction solution was concentrated under reduced pressure to obtain 10.81 g (100%) of the acid chloride intermediate, which was directly used in the next reaction.
将上一步得到酰氯中间体(10.81g,44.2mmol)溶于四氢呋喃(50mL)中，0℃下加入浓度为25％的氨水(10mL)，加完后转至室温反应2小时。待反应完全后，减压浓缩反应液，所得残留物中加入乙酸乙酯(50mL)和石油醚(50mL)的混合溶剂，过滤除去不溶物。过滤母液超声后有白色固体析出，抽滤得到标题化合物为白色固体(3.70g,收率37.2％)。The acid chloride intermediate (10.81g, 44.2mmol) obtained in the previous step was dissolved in tetrahydrofuran (50mL), and 25% ammonia water (10mL) was added at 0°C. After the addition was complete, the reaction was carried out at room temperature for 2 hours. After the reaction was complete, the reaction solution was concentrated under reduced pressure, a mixed solvent of ethyl acetate (50 mL) and petroleum ether (50 mL) was added to the obtained residue, and the insoluble matter was removed by filtration. After the filtered mother liquor was sonicated, a white solid precipitated out, and the title compound was obtained by suction filtration as a white solid (3.70 g, yield 37.2%).
第三步2,5,6-三氯-N-((4,6-二环丙基嘧啶-5-基)氨基甲酰基)吡啶甲酰胺的合成The third step is the synthesis of 2,5,6-trichloro-N-((4,6-dicyclopropylpyrimidin-5-yl)carbamoyl)pyridinecarboxamide
反应瓶中加入2,5,6-三氯烟酰胺(0.46g,2.04mmol)和四氢呋喃(20mL)，小心滴入草酰氯(0.39g,3.06mmol)。体系加热至回流反应3小时。减压蒸干反应液，所得残留物中加入四氢呋喃(20mL)，降温至0℃，加入4,6-二环丙基嘧啶-5-胺(0.36g,2.04mmol)。体系转至室温反应2小时，反应液中有白色固体析出，抽滤得到米白色固体，用乙酸乙酯(20mL)洗涤滤饼；将过滤得到的母液减压旋干，所得残留物中加入乙酸乙酯(5mL)，超声后有白色固体析出，再次抽滤得到米白色固体，用乙酸乙酯洗涤固体；合并两次过滤得到的固体后，得到标题化合物为米白色固体(0.42g,收率48.3％)。Add 2,5,6-trichloronicotinamide (0.46g, 2.04mmol) and tetrahydrofuran (20mL) into the reaction flask, and carefully drop oxalyl chloride (0.39g, 3.06mmol). The system was heated to reflux for 3 hours. The reaction solution was evaporated to dryness under reduced pressure, tetrahydrofuran (20 mL) was added to the obtained residue, the temperature was lowered to 0°C, and 4,6-dicyclopropylpyrimidin-5-amine (0.36 g, 2.04 mmol) was added. The system was turned to room temperature and reacted for 2 hours. A white solid precipitated out of the reaction solution. The off-white solid was obtained by suction filtration, and the filter cake was washed with ethyl acetate (20 mL); the mother liquor obtained by filtration was spin-dried under reduced pressure, and acetic acid was added to the obtained residue. Ethyl ester (5mL), a white solid was precipitated after ultrasonication, and the off-white solid was obtained by suction filtration again, and the solid was washed with ethyl acetate; after combining the solids obtained by two filtrations, the title compound was obtained as a off-white solid (0.42g, yield 48.3%).
MS(ESI,pos.ion)m/z:425.9[M+H]+.MS(ESI,pos.ion)m/z:425.9[M+H] + .
第四步6,7-二氯-1-(4,6-二环丙基嘧啶-5-基)吡啶并[2,3-d]嘧啶-2,4(1H,3H)-二酮的合成The fourth step of 6,7-dichloro-1-(4,6-dicyclopropylpyrimidin-5-yl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione synthesis
反应瓶中加入2,5,6-三氯-N-((4,6-二环丙基嘧啶-5-基)氨基甲酰基)吡啶甲酰胺(0.42g,0.98mmol)和四氢呋喃(20mL)。体系降温至-15℃，搅拌下缓缓加入KHMDS(2.5mL,2.5mmol,1.0mol/L)，加完后转为室温反应1小时。待反应完全后，减压蒸干反应液，所得残留物中加入乙酸乙酯(20mL)，依次经饱和氯化铵(15mL)和饱和食盐水(15mL)洗涤，无水硫酸钠干燥，过滤。减压旋干，得到标题化合物为米白色固体(0.38g,收率99.4％)。Add 2,5,6-trichloro-N-((4,6-dicyclopropylpyrimidin-5-yl)carbamoyl)pyridinecarboxamide (0.42g, 0.98mmol) and tetrahydrofuran (20mL) into the reaction flask . The system was cooled down to -15°C, and KHMDS (2.5 mL, 2.5 mmol, 1.0 mol/L) was slowly added under stirring, and then returned to room temperature for 1 hour of reaction after the addition was complete. After the reaction was complete, the reaction solution was evaporated to dryness under reduced pressure, ethyl acetate (20 mL) was added to the obtained residue, washed with saturated ammonium chloride (15 mL) and saturated brine (15 mL) successively, dried over anhydrous sodium sulfate, and filtered. Spin-dried under reduced pressure to obtain the title compound as an off-white solid (0.38 g, yield 99.4%).
MS(ESI,pos.ion)m/z:390.0[M+H]+.MS(ESI,pos.ion)m/z:390.0[M+H] + .
第五步(2R,5S)-4-(6,7-二氯-1-(4,6-二环丙基嘧啶-5-基)-2-氧代-1,2-二氢吡啶[2,3-d]嘧啶-4-基)-2,5-二甲基哌嗪-1-羧酸叔丁酯的合成The fifth step (2R, 5S)-4-(6,7-dichloro-1-(4,6-dicyclopropylpyrimidin-5-yl)-2-oxo-1,2-dihydropyridine[ Synthesis of tert-butyl 2,3-d]pyrimidin-4-yl)-2,5-dimethylpiperazine-1-carboxylate
反应瓶中加入6,7-二氯-1-(4,6-二环丙基嘧啶-5-基)吡啶并[2,3-d]嘧啶-2,4(1H,3H)-二酮(0.38g,0.97mmol)、N,N-二异丙基乙基胺(0.38g,2.91mmol)和乙腈(20mL)，氮气置换反应体系3次，用注射器加入三氯氧磷(0.18mL,1.94mmol)，80℃下搅拌反应5小时。待原料反应完全后，降至室温，减压浓缩得到中间体0.40g(100％)，立即用于下一步反应。Add 6,7-dichloro-1-(4,6-dicyclopropylpyrimidin-5-yl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione to the reaction flask (0.38g, 0.97mmol), N,N-diisopropylethylamine (0.38g, 2.91mmol) and acetonitrile (20mL), the reaction system was replaced with nitrogen three times, and phosphorus oxychloride (0.18mL, 1.94mmol), stirred and reacted at 80°C for 5 hours. After the reaction of the raw materials was complete, the mixture was cooled to room temperature and concentrated under reduced pressure to obtain 0.40 g (100%) of the intermediate, which was immediately used in the next reaction.
将上一步得到的中间体溶于乙腈(20mL)中，加入DIPEA(0.63g,4.90mmol)和(2R,5S)-2,5-二甲基哌嗪-1-羧酸叔丁酯(0.21g,0.98mmol)。反应体系在55℃下搅拌反应2小时。待反应完全后，减压浓缩一半反应液，加入水(50mL)，用乙酸乙酯(15mL×3)萃取。合并有机相，用饱和氯化钠溶液(20mL)洗涤，无水硫酸钠干燥，过滤，减压浓缩，所得残留物经硅胶柱层析(PE/EtOAc(v/v)＝2/1)纯化，得到标题化合物为黄色固体(0.43g,收率75.0％)。The intermediate obtained in the previous step was dissolved in acetonitrile (20 mL), and DIPEA (0.63 g, 4.90 mmol) and (2R,5S)-2,5-dimethylpiperazine-1-carboxylic acid tert-butyl ester (0.21 g, 0.98mmol). The reaction system was stirred and reacted at 55° C. for 2 hours. After the reaction was complete, half of the reaction solution was concentrated under reduced pressure, water (50 mL) was added, and extracted with ethyl acetate (15 mL×3). The organic phases were combined, washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (PE/EtOAc (v/v)=2/1) , the title compound was obtained as a yellow solid (0.43 g, yield 75.0%).
MS(ESI,pos.ion)m/z:586.2[M+H]+.MS(ESI,pos.ion)m/z:586.2[M+H] + .
第六步(2R,5S)-4-(6-氯-1-(4,6-二环丙基嘧啶-5-基)-7-(2-氟苯基)-2-氧代-1,2-二氢吡啶[2,3-d]嘧啶-4-基)-2,5-二甲基哌嗪-1-羧酸叔丁酯的合成The sixth step (2R,5S)-4-(6-chloro-1-(4,6-dicyclopropylpyrimidin-5-yl)-7-(2-fluorophenyl)-2-oxo-1 , Synthesis of tert-butyl 2-dihydropyridin[2,3-d]pyrimidin-4-yl)-2,5-dimethylpiperazine-1-carboxylate
反应瓶中加入(2R,5S)-4-(6,7-二氯-1-(4,6-二环丙基嘧啶-5-基)-2-氧代-1,2-二氢吡啶[2,3-d]嘧啶-4-基)-2,5-二甲基哌嗪-1-羧酸叔丁酯(0.24g,0.40mmol)、2-氟苯硼酸(0.12g,0.82mmol)、Pd(dppf)Cl2的二氯甲烷络合物(0.09g,0.12mmol)、乙酸钾(0.12g,1.26mmol)、1,4-二氧六环(30mL)和水(0.5mL)。氮气置换反应体系3次，加热至95℃下反应6小时。待反应完全后，减压浓缩除掉一半反应液，加入水(50mL)，用乙酸乙酯(15mL×3)萃取。合并有机相，用饱和氯化钠溶液(20mL)洗涤，无水硫酸钠干燥，过滤，减压浓缩，所得残留物经硅胶柱层析(PE/EtOAc(v/v)＝2/1)纯化，得到标题化合物为绿色固体(0.26g,收率100.0％)。Add (2R,5S)-4-(6,7-dichloro-1-(4,6-dicyclopropylpyrimidin-5-yl)-2-oxo-1,2-dihydropyridine to the reaction flask [2,3-d]pyrimidin-4-yl)-2,5-dimethylpiperazine-1-carboxylate tert-butyl ester (0.24g, 0.40mmol), 2-fluorophenylboronic acid (0.12g, 0.82mmol ), Pd(dppf) Cl2 dichloromethane complex (0.09g, 0.12mmol), potassium acetate (0.12g, 1.26mmol), 1,4-dioxane (30mL) and water (0.5mL) . The reaction system was replaced with nitrogen three times, and heated to 95° C. for 6 hours. After the reaction was complete, half of the reaction solution was removed by concentration under reduced pressure, water (50 mL) was added, and extracted with ethyl acetate (15 mL×3). The organic phases were combined, washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (PE/EtOAc (v/v)=2/1) , the title compound was obtained as a green solid (0.26 g, yield 100.0%).
MS(ESI,pos.ion)m/z:646.4[M+H]+.MS(ESI,pos.ion)m/z:646.4[M+H] + .
第七步(2R,5S)-4-(6-氰基-1-(4,6-二环丙基嘧啶-5-基)-7-(2-氟苯基)-2-氧代-1,2-二氢吡啶[2,3-d]嘧啶-4-基)-2,5-二甲基哌嗪-1-羧酸叔丁酯的合成The seventh step (2R,5S)-4-(6-cyano-1-(4,6-dicyclopropylpyrimidin-5-yl)-7-(2-fluorophenyl)-2-oxo- Synthesis of tert-butyl 1,2-dihydropyridin[2,3-d]pyrimidin-4-yl)-2,5-dimethylpiperazine-1-carboxylate
微波管中加入(2R,5S)-4-(6-氯-1-(4,6-二环丙基嘧啶-5-基)-7-(2-氟苯基)-2-氧代-1,2-二氢吡啶[2,3-d]嘧啶-4-基)-2,5-二甲基哌嗪-1-羧酸叔丁酯(0.28g,0.44mmol)、氰化锌(0.52g,4.40mmol)、二(三叔丁基膦)钯(0.67g,1.32mmol)和三叔丁基膦的正己烷溶液(10％,0.5mL)。反应体系微波135℃下反应7小时。过滤，过滤的母液减压浓缩。所得残留物中加入乙酸乙酯(10mL)，超声后有白色固体析出，过滤除去白色固体，将滤液浓缩，所得残留物经硅胶柱层析(PE/EtOAc(v/v)＝2/1)纯化，得到标题化合物为黄色固体(0.20g,收率70.7％)。Add (2R,5S)-4-(6-chloro-1-(4,6-dicyclopropylpyrimidin-5-yl)-7-(2-fluorophenyl)-2-oxo- 1,2-dihydropyridin[2,3-d]pyrimidin-4-yl)-2,5-dimethylpiperazine-1-carboxylic acid tert-butyl ester (0.28g, 0.44mmol), zinc cyanide ( 0.52 g, 4.40 mmol), bis(tri-tert-butylphosphine)palladium (0.67 g, 1.32 mmol) and tri-tert-butylphosphine in n-hexane (10%, 0.5 mL). The reaction system was microwaved at 135°C for 7 hours. After filtration, the filtered mother liquor was concentrated under reduced pressure. Ethyl acetate (10 mL) was added to the resulting residue, and a white solid was precipitated after ultrasonication. The white solid was removed by filtration, and the filtrate was concentrated. The resulting residue was subjected to silica gel column chromatography (PE/EtOAc (v/v)=2/1) Purification afforded the title compound as a yellow solid (0.20 g, yield 70.7%).
MS(ESI,pos.ion)m/z:637.2[M+H]+.MS(ESI,pos.ion)m/z:637.2[M+H] + .
第八步4-((2S,5R)-4-丙烯酰基-2,5-二甲基哌嗪-1-基)-1-(4,6-二环丙基嘧啶-5-基)-7-(2-氟苯基)-2-氧代-1,2-二氢吡啶并[2,3-d]嘧啶-6-腈的合成The eighth step 4-((2S,5R)-4-acryloyl-2,5-dimethylpiperazin-1-yl)-1-(4,6-dicyclopropylpyrimidin-5-yl)- Synthesis of 7-(2-fluorophenyl)-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidine-6-carbonitrile
反应瓶中加入(2R,5S)-4-(6-氰基-1-(4,6-二环丙基嘧啶-5-基)-7-(2-氟苯基)-2-氧代-1,2-二氢吡啶[2,3-d]嘧啶-4-基)-2,5-二甲基哌嗪-1-羧酸叔丁酯(0.20g,0.31mmol)和二氯甲烷(15mL)。室温下滴入三氟乙酸(0.23mL,3.10mmol)，室温下反应3小时，然后减压蒸干。所得残留物中加入二氯甲烷(15mL)和N,N-二异丙基乙基胺(0.08g,0.64mmol)。0℃下向体系中加入丙烯酰氯(0.03g,0.32mmol)，加完后转移至室温反应2小时。待反应完全后，加入水(10mL)，分液。有机相无水硫酸钠干燥，过滤，减压浓缩，所得残留物经硅胶制备板(DCM/MeOH(v/v)＝20/1)纯化，得到标题化合物为黄色固体(0.13g,收率68.9％)。MS(ESI,pos.ion)m/z:591.2[M+H]+.Add (2R,5S)-4-(6-cyano-1-(4,6-dicyclopropylpyrimidin-5-yl)-7-(2-fluorophenyl)-2-oxo -1,2-dihydropyridin[2,3-d]pyrimidin-4-yl)-2,5-dimethylpiperazine-1-carboxylic acid tert-butyl ester (0.20g, 0.31mmol) and dichloromethane (15 mL). Trifluoroacetic acid (0.23 mL, 3.10 mmol) was added dropwise at room temperature, reacted at room temperature for 3 hours, and then evaporated to dryness under reduced pressure. To the resulting residue were added dichloromethane (15 mL) and N,N-diisopropylethylamine (0.08 g, 0.64 mmol). Acryloyl chloride (0.03g, 0.32mmol) was added to the system at 0°C, and after the addition was completed, it was transferred to room temperature for 2 hours. After the reaction was complete, water (10 mL) was added to separate the layers. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified on a silica gel preparative plate (DCM/MeOH (v/v)=20/1) to obtain the title compound as a yellow solid (0.13 g, yield 68.9 %). MS(ESI,pos.ion)m/z:591.2[M+H] + .
1H NMR(400MHz,CDCl3)δ(ppm)8.82(s,1H),8.40(s,1H),7.53(dd,J＝13.7,7.0Hz,1H),7.41(t,J＝7.1Hz,1H),7.23(dd,J＝17.3,9.1Hz,2H),6.61(ddd,J＝35.3,16.6,10.5Hz,1H),6.41(t,J＝14.9Hz,1H),5.83(t,J＝9.0Hz,1H),5.31(s,2H),5.13(d,J＝38.6Hz,1H),4.53–4.31(m,1H),4.15–3.97(m,1H),3.89(d,J＝10.8Hz,1H),3.80–3.40(m,1H),2.92(d,J＝30.1Hz,1H),1.48(dd,J＝12.8,6.7Hz,3H),1.44–1.36(m,3H),1.29(dd,J＝15.3,6.0Hz,8H). 1 H NMR (400MHz, CDCl 3 )δ(ppm) 8.82(s, 1H), 8.40(s, 1H), 7.53(dd, J=13.7, 7.0Hz, 1H), 7.41(t, J=7.1Hz, 1H), 7.23(dd, J=17.3, 9.1Hz, 2H), 6.61(ddd, J=35.3, 16.6, 10.5Hz, 1H), 6.41(t, J=14.9Hz, 1H), 5.83(t, J =9.0Hz,1H),5.31(s,2H),5.13(d,J=38.6Hz,1H),4.53–4.31(m,1H),4.15–3.97(m,1H),3.89(d,J= 10.8Hz, 1H), 3.80–3.40(m, 1H), 2.92(d, J＝30.1Hz, 1H), 1.48(dd, J＝12.8, 6.7Hz, 3H), 1.44–1.36(m, 3H), 1.29(dd,J=15.3,6.0Hz,8H).
实施例2 4-((2S,5R)-4-丙烯酰基-2,5-二甲基哌嗪-1-基)-1-(4,6-二环丙基嘧啶-5-基)-7-(2-氟-5-甲基苯基)-2-氧代-1,2-二氢吡啶并[2,3-d]嘧啶-6-腈Example 2 4-((2S,5R)-4-acryloyl-2,5-dimethylpiperazin-1-yl)-1-(4,6-dicyclopropylpyrimidin-5-yl)- 7-(2-fluoro-5-methylphenyl)-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidine-6-carbonitrile
第一步(2R,5S)-4-(6-氯-1-(4,6-二环丙基嘧啶-5-基)-7-(2-氟-5-甲基苯基)-2-氧代-1,2-二氢吡啶并[2,3-d]嘧啶-4-基)-2,5-二甲基哌嗪-1-羧酸叔丁酯的合成The first step (2R,5S)-4-(6-chloro-1-(4,6-dicyclopropylpyrimidin-5-yl)-7-(2-fluoro-5-methylphenyl)-2 Synthesis of tert-butyl -oxo-1,2-dihydropyrido[2,3-d]pyrimidin-4-yl)-2,5-dimethylpiperazine-1-carboxylate
向反应瓶中加入(2R,5S)-4-(6,7-二氯-1-(4,6-二环丙基嘧啶-5-基)-2-氧代-1,2-二氢吡啶并[2,3-d]嘧啶-4-基)-2,5-二甲基哌嗪-1-羧酸叔丁酯(0.24g,0.40mmol)，2-氟-5-甲基苯硼酸(0.15g,0.97mmol)，[1,1'-双(二苯基膦)二茂铁]二氯化钯二氯甲烷络合物(0.08g,0.10mmol)，乙酸钾(0.12g,1.23mmol)，1,4-二氧六环(30mL)和水(0.5mL)。反应体系在氮气保护下，加热至95℃反应7小时。反应完成后，冷却至室温。反应体系减压浓缩，然后加入水(50mL)，经乙酸乙酯(15mL×3)萃取。合并有机相，经饱和食盐水(20mL)洗涤，无水硫酸钠干燥，过滤，减压浓缩。残余物经硅胶柱层析(PE/EtOAc(v/v)＝2/1)纯化，得到标题化合物为绿色固体(0.26g,收率99.6％)。Add (2R,5S)-4-(6,7-dichloro-1-(4,6-dicyclopropylpyrimidin-5-yl)-2-oxo-1,2-dihydro to the reaction flask Pyrido[2,3-d]pyrimidin-4-yl)-2,5-dimethylpiperazine-1-carboxylic acid tert-butyl ester (0.24g, 0.40mmol), 2-fluoro-5-methylbenzene Boronic acid (0.15g, 0.97mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (0.08g, 0.10mmol), potassium acetate (0.12g, 1.23 mmol), 1,4-dioxane (30 mL) and water (0.5 mL). The reaction system was heated to 95° C. for 7 hours under the protection of nitrogen. After the reaction was complete, it was cooled to room temperature. The reaction system was concentrated under reduced pressure, then water (50 mL) was added, and extracted with ethyl acetate (15 mL×3). The organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE/EtOAc (v/v)=2/1) to obtain the title compound as a green solid (0.26 g, yield 99.6%).
MS(ESI,pos.ion)m/z:660.2[M+H]+.MS(ESI,pos.ion)m/z:660.2[M+H] + .
第二步(2R,5S)-4-(6-氰基-1-(4,6-二环丙基嘧啶-5-基)-7-(2-氟-5-甲基苯基)-2-氧代-1,2-二氢吡啶并[2,3-d]嘧啶-4-基)-2,5-二甲基哌嗪-1-羧酸叔丁酯的合成The second step (2R,5S)-4-(6-cyano-1-(4,6-dicyclopropylpyrimidin-5-yl)-7-(2-fluoro-5-methylphenyl)- Synthesis of tert-butyl 2-oxo-1,2-dihydropyrido[2,3-d]pyrimidin-4-yl)-2,5-dimethylpiperazine-1-carboxylate
向微波管中加入(2R,5S)-4-(6-氯-1-(4,6-二环丙基嘧啶-5-基)-7-(2-氟-5-甲基苯基)-2-氧代-1,2-二氢吡啶并[2,3-d]嘧啶-4-基)-2,5-二甲基哌嗪-1-羧酸叔丁酯(0.26g,0.40mmol)，氰化锌(0.47g,4.00mmol)，二(三叔丁基膦)钯(0.61g,1.20mmol)，DMF(5.0mL)和三叔丁基膦的正己烷溶液(10％,0.5mL)。置于微波反应器中，135℃下反应7小时。反应完成后，降至室温，过滤。滤液减压旋干，再加入乙酸乙酯(10mL)，超声10min后，过滤。滤液减压旋干。残余物经硅胶柱层析(PE/EtOAc(v/v)＝2/1)纯化，得到标题化合物为黄色固体(0.26g,收率98.7％)。Add (2R,5S)-4-(6-chloro-1-(4,6-dicyclopropylpyrimidin-5-yl)-7-(2-fluoro-5-methylphenyl) to the microwave tube -2-Oxo-1,2-dihydropyrido[2,3-d]pyrimidin-4-yl)-2,5-dimethylpiperazine-1-carboxylic acid tert-butyl ester (0.26g, 0.40 mmol), zinc cyanide (0.47g, 4.00mmol), bis(tri-tert-butylphosphine) palladium (0.61g, 1.20mmol), DMF (5.0mL) and n-hexane solution of tri-tert-butylphosphine (10%, 0.5mL). Place in a microwave reactor and react at 135°C for 7 hours. After the reaction was completed, it was lowered to room temperature and filtered. The filtrate was spin-dried under reduced pressure, then added ethyl acetate (10 mL), and filtered after ultrasonication for 10 min. The filtrate was spin-dried under reduced pressure. The residue was purified by silica gel column chromatography (PE/EtOAc (v/v)=2/1) to obtain the title compound as a yellow solid (0.26 g, yield 98.7%).
MS(ESI,pos.ion)m/z:651.3[M+H]+.MS(ESI,pos.ion)m/z:651.3[M+H] + .
第三步4-((2S,5R)-4-丙烯酰基-2,5-二甲基哌嗪-1-基)-1-(4,6-二环丙基嘧啶-5-基)-7-(2-氟-5-甲基苯基)-2-氧代-1,2-二氢吡啶并[2,3-d]嘧啶-6-腈的合成The third step 4-((2S,5R)-4-acryloyl-2,5-dimethylpiperazin-1-yl)-1-(4,6-dicyclopropylpyrimidin-5-yl)- Synthesis of 7-(2-fluoro-5-methylphenyl)-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidine-6-carbonitrile
向反应瓶中加入(2R,5S)-4-(6-氰基-1-(4,6-二环丙基嘧啶-5-基)-7-(2-氟-5-甲基苯基)-2-氧代-1,2-二氢吡啶并[2,3-d]嘧啶-4-基)-2,5-二甲基哌嗪-1-羧酸叔丁酯(0.26g,0.39mmol)和二氯甲烷(15mL)。室温下滴加三氟乙酸(0.29mL,3.90mmol)。体系室温下反应6小时，然后减压蒸干。残余物中加入二氯甲烷(15mL)，DIPEA(0.10mg,0.76mmol)，冷却至0℃，加入丙烯酰氯(0.03g,0.39mmol)。滴加完毕后，体系转移至室温反应1小时。然后反应液经水(20mL)洗涤，无水硫酸钠干燥，过滤，滤液减压旋干。残余物经硅胶柱层析(EtOAc)纯化得到标题化合物为黄色固体(0.13g,收率53.3％)。Add (2R,5S)-4-(6-cyano-1-(4,6-dicyclopropylpyrimidin-5-yl)-7-(2-fluoro-5-methylphenyl) to the reaction flask )-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidin-4-yl)-2,5-dimethylpiperazine-1-carboxylic acid tert-butyl ester (0.26g, 0.39mmol) and dichloromethane (15mL). Trifluoroacetic acid (0.29 mL, 3.90 mmol) was added dropwise at room temperature. The system was reacted at room temperature for 6 hours, and then evaporated to dryness under reduced pressure. Dichloromethane (15 mL), DIPEA (0.10 mg, 0.76 mmol) were added to the residue, cooled to 0°C, and acryloyl chloride (0.03 g, 0.39 mmol) was added. After the dropwise addition, the system was transferred to room temperature to react for 1 hour. Then the reaction solution was washed with water (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was spin-dried under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc) to obtain the title compound as a yellow solid (0.13 g, yield 53.3%).
MS(ESI,pos.ion)m/z:605.4[M+H]+.MS(ESI,pos.ion)m/z:605.4[M+H] + .
1H NMR(400MHz,CDCl3)δ(ppm)8.83(s,1H),8.37(s,1H),7.35-7.29(m,1H),7.23(d,J＝6.5Hz,1H),7.15-7.07(m,1H),6.71-6.52(m,1H),6.42(t,J＝14.8Hz,1H),5.84(t,J＝8.8Hz,1H),5.28-4.90(m,2H),4.54-4.30(m,1H),4.10-3.98(m,1H),3.95-3.84(m,1H),3.75(d,J＝14.0Hz,0.5H),3.48(d,J＝10.7Hz,0.5H),2.34(s,3H),2.06(s,1H),1.90(s,1H),1.51-1.38(m,4H),1.33-1.22(m,6H),1.07-0.96(m,2H),0.95-0.81(m,2H). 1 H NMR (400MHz, CDCl 3 ) δ (ppm) 8.83 (s, 1H), 8.37 (s, 1H), 7.35-7.29 (m, 1H), 7.23 (d, J=6.5Hz, 1H), 7.15- 7.07(m,1H),6.71-6.52(m,1H),6.42(t,J=14.8Hz,1H),5.84(t,J=8.8Hz,1H),5.28-4.90(m,2H),4.54 -4.30(m,1H),4.10-3.98(m,1H),3.95-3.84(m,1H),3.75(d,J＝14.0Hz,0.5H),3.48(d,J＝10.7Hz,0.5H ),2.34(s,3H),2.06(s,1H),1.90(s,1H),1.51-1.38(m,4H),1.33-1.22(m,6H),1.07-0.96(m,2H), 0.95-0.81(m,2H).
实施例3 4-((2S,5R)-4-丙烯酰基-2,5-二甲基哌嗪-1-基)-1-(4,6-二环丙基嘧啶-5-基)-7-(2-氟-3-甲基苯基)-2-氧代-1,2-二氢吡啶并[2,3-d]嘧啶-6-腈Example 3 4-((2S,5R)-4-acryloyl-2,5-dimethylpiperazin-1-yl)-1-(4,6-dicyclopropylpyrimidin-5-yl)- 7-(2-fluoro-3-methylphenyl)-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidine-6-carbonitrile
第一步(2R,5S)-4-(6-氯-1-(4,6-二环丙基嘧啶-5-基)-7-(2-氟-3-甲基苯基)-2-氧代-1,2-二氢吡啶并[2,3-d]嘧啶-4-基)-2,5-二甲基哌嗪-1-羧酸叔丁酯的合成The first step (2R,5S)-4-(6-chloro-1-(4,6-dicyclopropylpyrimidin-5-yl)-7-(2-fluoro-3-methylphenyl)-2 Synthesis of tert-butyl -oxo-1,2-dihydropyrido[2,3-d]pyrimidin-4-yl)-2,5-dimethylpiperazine-1-carboxylate
向反应瓶中加入(2R,5S)-4-(6,7-二氯-1-(4,6-二环丙基嘧啶-5-基)-2-氧代-1,2-二氢吡啶并[2,3-d]嘧啶-4-基)-2,5-二甲基哌嗪-1-羧酸叔丁酯(0.20g,0.35mmol)，2-氟-3-甲基苯硼酸(0.14g,0.89mmol)，[1,1'-双(二苯基膦)二茂铁]二氯化钯二氯甲烷络合物(0.07g,0.08mmol)，乙酸钾(0.10g,1.05mmol)，1,4-二氧六环(30mL)和水(0.5mL)。反应体系在氮气保护下，加热至95℃反应7小时。反应完成后，冷却至室温。反应体系减压浓缩，然后加入水(50mL)，经乙酸乙酯(15mL×3)萃取。合并有机相，经饱和食盐水(20mL)洗涤，无水硫酸钠干燥，过滤，减压浓缩。残余物经硅胶柱层析(PE/EtOAc(v/v)＝2/1)纯化，得到标题化合物为淡黄色固体(0.22g,收率94.4％)。Add (2R,5S)-4-(6,7-dichloro-1-(4,6-dicyclopropylpyrimidin-5-yl)-2-oxo-1,2-dihydro to the reaction flask Pyrido[2,3-d]pyrimidin-4-yl)-2,5-dimethylpiperazine-1-carboxylic acid tert-butyl ester (0.20g, 0.35mmol), 2-fluoro-3-methylbenzene Boronic acid (0.14g, 0.89mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (0.07g, 0.08mmol), potassium acetate (0.10g, 1.05 mmol), 1,4-dioxane (30 mL) and water (0.5 mL). The reaction system was heated to 95° C. for 7 hours under the protection of nitrogen. After the reaction was complete, it was cooled to room temperature. The reaction system was concentrated under reduced pressure, then water (50 mL) was added, and extracted with ethyl acetate (15 mL×3). The organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE/EtOAc (v/v)=2/1) to obtain the title compound as a pale yellow solid (0.22 g, yield 94.4%).
MS(ESI,pos.ion)m/z:660.2[M+H]+.MS(ESI,pos.ion)m/z:660.2[M+H] + .
第二步(2R,5S)-4-(6-氰基-1-(4,6-二环丙基嘧啶-5-基)-7-(2-氟-3-甲基苯基)-2-氧代-1,2-二氢吡啶并[2,3-d]嘧啶-4-基)-2,5-二甲基哌嗪-1-羧酸叔丁酯的合成The second step (2R,5S)-4-(6-cyano-1-(4,6-dicyclopropylpyrimidin-5-yl)-7-(2-fluoro-3-methylphenyl)- Synthesis of tert-butyl 2-oxo-1,2-dihydropyrido[2,3-d]pyrimidin-4-yl)-2,5-dimethylpiperazine-1-carboxylate
向微波管中加入(2R,5S)-4-(6-氯-1-(4,6-二环丙基嘧啶-5-基)-7-(2-氟-3-甲基苯基)-2-氧代-1,2-二氢吡啶并[2,3-d]嘧啶-4-基)-2,5-二甲基哌嗪-1-羧酸叔丁酯(0.22g,0.33mmol)，氰化锌(0.39g,3.32mmol)，二(三叔丁基膦)钯(0.51g,1.00mmol)，DMF(5mL)和三叔丁基膦的正己烷溶液(10％,0.5mL)。置于微波反应器中，135℃下反应7小时。反应完成后，降至室温，过滤。母液减压旋干，再加入乙酸乙酯(10mL)，超声10min后，过滤。母液减压旋干。残余物经硅胶柱层析(PE/EtOAc(v/v)＝2/1)纯化，得到标题化合物为黄色固体(0.21g,收率98.4％)。Add (2R,5S)-4-(6-chloro-1-(4,6-dicyclopropylpyrimidin-5-yl)-7-(2-fluoro-3-methylphenyl) to the microwave tube -2-Oxo-1,2-dihydropyrido[2,3-d]pyrimidin-4-yl)-2,5-dimethylpiperazine-1-carboxylic acid tert-butyl ester (0.22g, 0.33 mmol), zinc cyanide (0.39g, 3.32mmol), bis(tri-tert-butylphosphine) palladium (0.51g, 1.00mmol), DMF (5mL) and n-hexane solution of tri-tert-butylphosphine (10%, 0.5 mL). Place in a microwave reactor and react at 135°C for 7 hours. After the reaction was completed, it was lowered to room temperature and filtered. The mother liquor was spin-dried under reduced pressure, then added ethyl acetate (10 mL), and filtered after ultrasonication for 10 min. The mother liquor was spin-dried under reduced pressure. The residue was purified by silica gel column chromatography (PE/EtOAc (v/v)=2/1) to obtain the title compound as a yellow solid (0.21 g, yield 98.4%).
MS(ESI,pos.ion)m/z:651.3[M+H]+.MS(ESI,pos.ion)m/z:651.3[M+H] + .
第三步4-((2S,5R)-4-丙烯酰基-2,5-二甲基哌嗪-1-基)-1-(4,6-二环丙基嘧啶-5-基)-7-(2-氟-3-甲基苯基)-2-氧代-1,2-二氢吡啶并[2,3-d]嘧啶-6-腈的合成The third step 4-((2S,5R)-4-acryloyl-2,5-dimethylpiperazin-1-yl)-1-(4,6-dicyclopropylpyrimidin-5-yl)- Synthesis of 7-(2-fluoro-3-methylphenyl)-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidine-6-carbonitrile
反应瓶中加入(2R,5S)-4-(6-氰基-1-(4,6-二环丙基嘧啶-5-基)-7-(2-氟-3-甲基苯基)-2-氧代-1,2-二氢吡啶并[2,3-d]嘧啶-4-基)-2,5-二甲基哌嗪-1-羧酸叔丁酯(0.21g,0.32mmol)，二氯甲烷(15mL)。室温下滴入三氟乙酸(0.24mL,3.20mmol)。体系室温下反应6小时，减压蒸干。残余物中加入二氯甲烷(15mL)，DIPEA(0.08g,0.64mmol)，冷却至0℃，加入丙烯酰氯(0.03g,0.39mmol)。滴加完毕后，体系转移至室温反应1小时。然后反应液经水(20mL)洗涤，无水硫酸钠干燥，过滤，减压旋干。残余物经硅胶柱层析(EtOAc)纯化，得到标题化合物为米白色固体(0.17g,收率82.7％)。Add (2R,5S)-4-(6-cyano-1-(4,6-dicyclopropylpyrimidin-5-yl)-7-(2-fluoro-3-methylphenyl) to the reaction flask -2-Oxo-1,2-dihydropyrido[2,3-d]pyrimidin-4-yl)-2,5-dimethylpiperazine-1-carboxylic acid tert-butyl ester (0.21g, 0.32 mmol), dichloromethane (15 mL). Trifluoroacetic acid (0.24 mL, 3.20 mmol) was added dropwise at room temperature. The system reacted at room temperature for 6 hours, and evaporated to dryness under reduced pressure. Dichloromethane (15 mL), DIPEA (0.08 g, 0.64 mmol) were added to the residue, cooled to 0°C, and acryloyl chloride (0.03 g, 0.39 mmol) was added. After the dropwise addition, the system was transferred to room temperature to react for 1 hour. Then the reaction solution was washed with water (20 mL), dried over anhydrous sodium sulfate, filtered, and spin-dried under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc) to obtain the title compound as an off-white solid (0.17 g, yield 82.7%).
MS(ESI,pos.ion)m/z:605.5[M+H]+.MS(ESI,pos.ion)m/z:605.5[M+H] + .
1H NMR(400MHz,CDCl3)δ(ppm)8.81(s,1H),8.38(s,1H),7.36(s,1H),7.25-7.06(m,2H),6.73-6.50(m,1H),6.49-6.34(m,1H),5.83(s,1H),5.38-4.80(m,2H),4.55-4.29(m,1H),4.14-3.82(m,2H),3.75(d,J＝12.7Hz,0.5H),3.49(s,0.5H),2.35(s,3H),2.16-1.94(m,1H),1.51-1.38(m,4H),1.34-1.12(m,7H),1.05-0.92(m,2H),0.91-0.78(m,2H). 1 H NMR (400MHz, CDCl 3 ) δ (ppm) 8.81 (s, 1H), 8.38 (s, 1H), 7.36 (s, 1H), 7.25-7.06 (m, 2H), 6.73-6.50 (m, 1H ),6.49-6.34(m,1H),5.83(s,1H),5.38-4.80(m,2H),4.55-4.29(m,1H),4.14-3.82(m,2H),3.75(d,J ＝12.7Hz,0.5H),3.49(s,0.5H),2.35(s,3H),2.16-1.94(m,1H),1.51-1.38(m,4H),1.34-1.12(m,7H), 1.05-0.92(m,2H),0.91-0.78(m,2H).
实施例4 4-((2S,5R)-4-丙烯酰基-2,5-二甲基哌嗪-1-基)-7-(2-氨基-3-氟苯基)-1-(4,6-二环丙基嘧啶-5-基)-2-氧代-1,2-二氢吡啶并[2,3-d]嘧啶-6-腈Example 4 4-((2S,5R)-4-acryloyl-2,5-dimethylpiperazin-1-yl)-7-(2-amino-3-fluorophenyl)-1-(4 ,6-Dicyclopropylpyrimidin-5-yl)-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidine-6-carbonitrile
第一步(2R,5S)-4-(7-(2-氨基-3-氟苯基)-6-氯-1-(4,6-二环丙基嘧啶-5-基)-2-氧代-1,2-二氢吡啶并[2,3-d]嘧啶-4-基)-2,5-二甲基哌嗪-1-羧酸叔丁酯的合成The first step (2R,5S)-4-(7-(2-amino-3-fluorophenyl)-6-chloro-1-(4,6-dicyclopropylpyrimidin-5-yl)-2- Synthesis of tert-butyl oxo-1,2-dihydropyrido[2,3-d]pyrimidin-4-yl)-2,5-dimethylpiperazine-1-carboxylate
反应瓶中加入(2R,5S)-4-(6,7-二氯-1-(4,6-二环丙基嘧啶-5-基)-2-氧代-1,2-二氢吡啶并[2,3-d]嘧啶-4-基)-2,5-二甲基哌嗪-1-羧酸叔丁酯(0.10g,0.17mmol)，2-氟-6-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)苯胺(0.06g,0.26mmol)，[1,1'-双(二苯基膦)二茂铁]二氯化钯二氯甲烷络合物(0.04g,0.05mmol)，乙酸钾(0.05g,0.55mmol)，1,4-二氧六环(30mL)和水(0.5mL)。反应体系氮气保护下，加热至95℃反应7小时。反应完成后，冷却至室温。反应体系减压浓缩除去一半反应液，然后加入水(50mL)，经乙酸乙酯(15mL×3)萃取。合并有机相，经饱和食盐水(20mL)洗涤，无水硫酸钠干燥，过滤，减压浓缩。残余物经硅胶柱层析(PE/EtOAc(v/v)＝1/1)纯化，得到标题化合物为淡黄色固体(0.22g,收率89.9％)。Add (2R,5S)-4-(6,7-dichloro-1-(4,6-dicyclopropylpyrimidin-5-yl)-2-oxo-1,2-dihydropyridine to the reaction flask And[2,3-d]pyrimidin-4-yl)-2,5-dimethylpiperazine-1-carboxylate tert-butyl ester (0.10g, 0.17mmol), 2-fluoro-6-(4,4 ,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (0.06g, 0.26mmol), [1,1'-bis(diphenylphosphine)bis Ferrocene]palladium dichloride dichloromethane complex (0.04g, 0.05mmol), potassium acetate (0.05g, 0.55mmol), 1,4-dioxane (30mL) and water (0.5mL). Under the protection of nitrogen, the reaction system was heated to 95° C. for 7 hours. After the reaction was complete, it was cooled to room temperature. The reaction system was concentrated under reduced pressure to remove half of the reaction solution, then water (50 mL) was added, and extracted with ethyl acetate (15 mL×3). The organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE/EtOAc (v/v)=1/1) to obtain the title compound as a pale yellow solid (0.22 g, yield 89.9%).
MS(ESI,pos.ion)m/z:661.2[M+H]+.MS(ESI,pos.ion)m/z:661.2[M+H] + .
第二步(2R,5S)-4-(7-(2-氨基-3-氟苯基)-6-氰基-1-(4,6-二环丙基嘧啶-5-基)-2-氧代-1,2-二氢吡啶并[2,3-d]嘧啶-4-基)-2,5-二甲基哌嗪-1-羧酸叔丁酯的合成The second step (2R,5S)-4-(7-(2-amino-3-fluorophenyl)-6-cyano-1-(4,6-dicyclopropylpyrimidin-5-yl)-2 Synthesis of tert-butyl -oxo-1,2-dihydropyrido[2,3-d]pyrimidin-4-yl)-2,5-dimethylpiperazine-1-carboxylate
微波管中加入(2R,5S)-4-(7-(2-氨基-3-氟苯基)-6-氯-1-(4,6-二环丙基嘧啶-5-基)-2-氧代-1,2-二氢吡啶并[2,3-d]嘧啶-4-基)-2,5-二甲基哌嗪-1-羧酸叔丁酯(0.10g,0.15mmol)，氰化锌(0.19g,1.59mmol)，二(三叔丁基膦)钯(0.24g,0.47mmol)，DMF(5mL)，三叔丁基膦的正己烷溶液(10％,0.5mL)。置于微波反应器中，135℃下反应7小时。反应完成后，降至室温，过滤。母液减压旋干，残余物中加入乙酸乙酯(10mL)，超声10min后，过滤。母液减压旋干。残余物经硅胶柱层析(PE/EtOAc(v/v)＝1/2)纯化，得到标题化合物为黄色固体(0.09g,收率96.7％)。Add (2R,5S)-4-(7-(2-amino-3-fluorophenyl)-6-chloro-1-(4,6-dicyclopropylpyrimidin-5-yl)-2 -Oxo-1,2-dihydropyrido[2,3-d]pyrimidin-4-yl)-2,5-dimethylpiperazine-1-carboxylic acid tert-butyl ester (0.10g, 0.15mmol) , zinc cyanide (0.19g, 1.59mmol), bis(tri-tert-butylphosphine) palladium (0.24g, 0.47mmol), DMF (5mL), n-hexane solution of tri-tert-butylphosphine (10%, 0.5mL) . Place in a microwave reactor and react at 135°C for 7 hours. After the reaction was completed, it was lowered to room temperature and filtered. The mother liquor was spin-dried under reduced pressure, and ethyl acetate (10 mL) was added to the residue, and filtered after ultrasonication for 10 min. The mother liquor was spin-dried under reduced pressure. The residue was purified by silica gel column chromatography (PE/EtOAc (v/v)=1/2) to obtain the title compound as a yellow solid (0.09 g, yield 96.7%).
MS(ESI,pos.ion)m/z:652.7[M+H]+.MS(ESI,pos.ion)m/z:652.7[M+H] + .
第三步4-((2S,5R)-4-丙烯酰基-2,5-二甲基哌嗪-1-基)-7-(2-氨基-3-氟苯基)-1-(4,6-二环丙基嘧啶-5-基)-2-氧代-1,2-二氢吡啶并[2,3-d]嘧啶-6-腈的合成The third step 4-((2S,5R)-4-acryloyl-2,5-dimethylpiperazin-1-yl)-7-(2-amino-3-fluorophenyl)-1-(4 , Synthesis of 6-dicyclopropylpyrimidin-5-yl)-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidine-6-carbonitrile
反应瓶中加入(2R,5S)-4-(7-(2-氨基-3-氟苯基)-6-氰基-1-(4,6-二环丙基嘧啶-5-基)-2-氧代-1,2-二氢吡啶并[2,3-d]嘧啶-4-基)-2,5-二甲基哌嗪-1-羧酸叔丁酯(0.09g,0.14mmol)，二氯甲烷(15mL)。室温下滴入三氟乙酸(0.10mL,1.40mmol)。体系室温下反应6小时，然后减压蒸干。残余物中加入二氯甲烷(15mL)，DIPEA(0.04g,0.28mmol)，冷却至0℃，加入丙烯酰氯(0.01g,0.14mmol)。滴加完毕后，体系转移至室温反应1小时。然后反应液经水(20mL)洗涤，无水硫酸钠干燥，过滤，减压旋干。残余物经硅胶柱层析(DCM/MeOH(v/v)＝20/1)纯化，得到标题化合物为黄色固体(0.05g,收率51.3％)。Add (2R,5S)-4-(7-(2-amino-3-fluorophenyl)-6-cyano-1-(4,6-dicyclopropylpyrimidin-5-yl)- 2-oxo-1,2-dihydropyrido[2,3-d]pyrimidin-4-yl)-2,5-dimethylpiperazine-1-carboxylic acid tert-butyl ester (0.09g, 0.14mmol ), dichloromethane (15 mL). Trifluoroacetic acid (0.10 mL, 1.40 mmol) was added dropwise at room temperature. The system was reacted at room temperature for 6 hours, and then evaporated to dryness under reduced pressure. Dichloromethane (15 mL), DIPEA (0.04 g, 0.28 mmol) were added to the residue, cooled to 0°C, and acryloyl chloride (0.01 g, 0.14 mmol) was added. After the dropwise addition, the system was transferred to room temperature to react for 1 hour. Then the reaction solution was washed with water (20 mL), dried over anhydrous sodium sulfate, filtered, and spin-dried under reduced pressure. The residue was purified by silica gel column chromatography (DCM/MeOH (v/v)=20/1) to obtain the title compound as a yellow solid (0.05 g, yield 51.3%).
MS(ESI,pos.ion)m/z:606.2[M+H]+.MS(ESI,pos.ion)m/z:606.2[M+H] + .
1H NMR(400MHz,CDCl3)δ(ppm)9.07-8.87(m,2H),7.87(d,J＝8.0Hz,1H),7.43-7.34(m,1H),7.25-7.13(m,1H),6.74-6.53(m,2H),6.40(t,J＝15.3Hz,1H),5.83(d,J＝11.6Hz,1H),5.38(s,1H),5.10(s,1H),4.53-4.36(m,1H),4.31(d,J＝10.9Hz,0.5H),4.15(d,J＝13.4Hz,0.5H),4.09-3.94(m,1H),3.82-3.63(m,1H),2.11-2.00(m,2H),1.53-1.33(m,6H),1.31-1.25(m,8H). 1 H NMR (400MHz, CDCl 3 ) δ (ppm) 9.07-8.87 (m, 2H), 7.87 (d, J = 8.0Hz, 1H), 7.43-7.34 (m, 1H), 7.25-7.13 (m, 1H ),6.74-6.53(m,2H),6.40(t,J＝15.3Hz,1H),5.83(d,J＝11.6Hz,1H),5.38(s,1H),5.10(s,1H),4.53 -4.36(m,1H),4.31(d,J=10.9Hz,0.5H),4.15(d,J=13.4Hz,0.5H),4.09-3.94(m,1H),3.82-3.63(m,1H ),2.11-2.00(m,2H),1.53-1.33(m,6H),1.31-1.25(m,8H).
实施例5 4-((2S,5R)-4-丙烯酰基-2,5-二甲基哌嗪-1-基)-1-(4,6-二环丙基嘧啶-5-基)-7-(2-氟-5-甲氧基苯基)-2-氧代-1,2-二氢吡啶并[2,3-d]嘧啶-6-腈Example 5 4-((2S,5R)-4-acryloyl-2,5-dimethylpiperazin-1-yl)-1-(4,6-dicyclopropylpyrimidin-5-yl)- 7-(2-fluoro-5-methoxyphenyl)-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidine-6-carbonitrile
第一步(2R,5S)-4-(6-氯-1-(4,6-二环丙基嘧啶-5-基)-7-(2-氟-5-甲氧基苯基)-2-氧代-1,2-二氢吡啶并[2,3-d]嘧啶-4-基)-2,5-二甲基哌嗪-1-羧酸叔丁酯的合成The first step (2R,5S)-4-(6-chloro-1-(4,6-dicyclopropylpyrimidin-5-yl)-7-(2-fluoro-5-methoxyphenyl)- Synthesis of tert-butyl 2-oxo-1,2-dihydropyrido[2,3-d]pyrimidin-4-yl)-2,5-dimethylpiperazine-1-carboxylate
向反应瓶中加入(2R,5S)-4-(6,7-二氯-1-(4,6-二环丙基嘧啶-5-基)-2-氧代-1,2-二氢吡啶并[2,3-d]嘧啶-4-基)-2,5-二甲基哌嗪-1-羧酸叔丁酯(0.37g,0.66mmol)，(2-氟-5-甲氧基苯基)硼酸(0.11g,0.62mmol)，[1,1'-双(二苯基膦)二茂铁]二氯化钯二氯甲烷络合物(0.01g,0.02mmol)，乙酸钾(0.12g,1.24mmol)，1,4-二氧六环(4mL)和水(1mL)。反应体系氮气保护下，加热至回流反应3h。反应完成后，冷却至室温，向其中加入水(30mL)和乙酸乙酯(30mL)，分液。水相经乙酸乙酯(30mL×3)萃取。合并有机相，经饱和食盐水(60mL)洗涤，无水硫酸钠干燥，过滤，减压旋干。残余物经硅胶柱层析(PE/EtOAc(v/v)＝2/1)纯化，得到标题化合物为黄绿色固体(0.18g,收率86.0％)。Add (2R,5S)-4-(6,7-dichloro-1-(4,6-dicyclopropylpyrimidin-5-yl)-2-oxo-1,2-dihydro to the reaction flask Pyrido[2,3-d]pyrimidin-4-yl)-2,5-dimethylpiperazine-1-carboxylic acid tert-butyl ester (0.37g, 0.66mmol), (2-fluoro-5-methoxy phenyl)boronic acid (0.11g, 0.62mmol), [1,1'-bis(diphenylphosphino)ferrocene] dichloropalladium dichloromethane complex (0.01g, 0.02mmol), potassium acetate (0.12g, 1.24mmol), 1,4-dioxane (4mL) and water (1mL). Under the protection of nitrogen, the reaction system was heated to reflux for 3 h. After the reaction was completed, it was cooled to room temperature, water (30 mL) and ethyl acetate (30 mL) were added thereto, and the layers were separated. The aqueous phase was extracted with ethyl acetate (30 mL×3). The organic phases were combined, washed with saturated brine (60 mL), dried over anhydrous sodium sulfate, filtered, and spin-dried under reduced pressure. The residue was purified by silica gel column chromatography (PE/EtOAc (v/v)=2/1) to obtain the title compound as a yellow-green solid (0.18 g, yield 86.0%).
MS(ESI,pos.ion)m/z:676.5[M+H]+.MS(ESI,pos.ion)m/z:676.5[M+H] + .
第二步(2R,5S)-4-(6-氰基-1-(4,6-二环丙基嘧啶-5-基)-7-(2-氟-5-甲氧基苯基)-2-氧代-1,2-二氢吡啶并[2,3-d]嘧啶-4-基)-2,5-二甲基哌嗪-1-羧酸叔丁酯的合成The second step (2R,5S)-4-(6-cyano-1-(4,6-dicyclopropylpyrimidin-5-yl)-7-(2-fluoro-5-methoxyphenyl) Synthesis of tert-butyl 2-oxo-1,2-dihydropyrido[2,3-d]pyrimidin-4-yl)-2,5-dimethylpiperazine-1-carboxylate
向微波管中加入(2R,5S)-4-(6-氯-1-(4,6-二环丙基嘧啶-5-基)-7-(2-氟-5-甲氧基苯基)-2-氧代-1,2-二氢吡啶并[2,3-d]嘧啶-4-基)-2,5-二甲基哌嗪-1-羧酸叔丁酯(0.18g,0.27mmol)，氰化锌(0.16g,1.35mmol)，二(三叔丁基膦)钯(0.07g,0.14mmol)，三叔丁基膦四氟硼酸盐(7.8mg,0.03mmol)和N,N-二甲基甲酰胺(3mL)。反应体系氮气置换后，置于微波反应器中，140℃下反应7小时。反应完成后，降至室温，过滤。母液减压旋干。残余物经硅胶柱层析(PE/EtOAc(v/v)＝2/1)纯化，得到标题化合物为淡黄色固体(0.11g,收率62.0％)。Add (2R,5S)-4-(6-chloro-1-(4,6-dicyclopropylpyrimidin-5-yl)-7-(2-fluoro-5-methoxyphenyl) to the microwave tube )-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidin-4-yl)-2,5-dimethylpiperazine-1-carboxylic acid tert-butyl ester (0.18g, 0.27mmol), zinc cyanide (0.16g, 1.35mmol), bis(tri-tert-butylphosphine) palladium (0.07g, 0.14mmol), tri-tert-butylphosphine tetrafluoroborate (7.8mg, 0.03mmol) and N,N-Dimethylformamide (3 mL). After replacing the reaction system with nitrogen, it was placed in a microwave reactor and reacted at 140° C. for 7 hours. After the reaction was completed, it was lowered to room temperature and filtered. The mother liquor was spin-dried under reduced pressure. The residue was purified by silica gel column chromatography (PE/EtOAc (v/v)=2/1) to obtain the title compound as a pale yellow solid (0.11 g, yield 62.0%).
MS(ESI,pos.ion)m/z:667.6[M+H]+.MS(ESI,pos.ion)m/z:667.6[M+H] + .
第三步4-((2S,5R)-4-丙烯酰基-2,5-二甲基哌嗪-1-基)-1-(4,6-二环丙基嘧啶-5-基)-7-(2-氟-5-甲氧基苯基)-2-氧代-1,2-二氢吡啶并[2,3-d]嘧啶-6-腈The third step 4-((2S,5R)-4-acryloyl-2,5-dimethylpiperazin-1-yl)-1-(4,6-dicyclopropylpyrimidin-5-yl)- 7-(2-fluoro-5-methoxyphenyl)-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidine-6-carbonitrile
向反应瓶中加入(2R,5S)-4-(6-氰基-1-(4,6-二环丙基嘧啶-5-基)-7-(2-氟-5-甲氧基苯基)-2-氧代-1,2-二氢吡啶并[2,3-d]嘧啶-4-基)-2,5-二甲基哌嗪-1-羧酸叔丁酯(0.11g,0.16mmol)，二氯甲烷(2mL)和三氟乙酸(0.5mL)。反应体系室温反应1h，然后减压旋干。残余物中加入二氯甲烷(2mL)，三乙胺(0.05g,0.48mmol)，混合物降温至-10℃，向其中滴入丙烯酰氯(0.03g,0.32mmol)。滴完后混合物转移至室温搅拌1h。向上述混合物中依次加入二氯甲烷(20mL)，水(20mL)，所得混合物分液。水相经二氯甲烷(10mL×3)萃取，合并有机相，经饱和食盐水(30mL)洗涤，无水硫酸钠干燥，过滤，减压旋干。残余物经硅胶柱层析(DCM/MeOH(v/v)＝30/1)纯化，得到标题化合物为黄绿色固体(56.0mg,收率54.7％)。Add (2R,5S)-4-(6-cyano-1-(4,6-dicyclopropylpyrimidin-5-yl)-7-(2-fluoro-5-methoxybenzene Base)-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidin-4-yl)-2,5-dimethylpiperazine-1-carboxylic acid tert-butyl ester (0.11g , 0.16mmol), dichloromethane (2mL) and trifluoroacetic acid (0.5mL). The reaction system was reacted at room temperature for 1 h, and then spin-dried under reduced pressure. Dichloromethane (2 mL) and triethylamine (0.05 g, 0.48 mmol) were added to the residue, the mixture was cooled to -10°C, and acryloyl chloride (0.03 g, 0.32 mmol) was added dropwise thereto. After dropping, the mixture was transferred to room temperature and stirred for 1 h. Dichloromethane (20 mL) and water (20 mL) were successively added to the above mixture, and the resulting mixture was separated. The aqueous phase was extracted with dichloromethane (10 mL×3), and the combined organic phases were washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and spin-dried under reduced pressure. The residue was purified by silica gel column chromatography (DCM/MeOH (v/v)=30/1) to obtain the title compound as a yellow-green solid (56.0 mg, yield 54.7%).
MS(ESI,pos.ion)m/z:621.3[M+H]+.MS(ESI,pos.ion)m/z:621.3[M+H] + .
1H NMR(400MHz,CDCl3)δ(ppm)8.81(s,1H),8.35(s,1H),7.15-7.06(m,1H),7.06-6.98(m,1H),6.86-6.82(m,1H),6.69-6.50(m,1H),6.46-6.34(m,1H),5.86-5.76(m,1H),5.22-4.90(m,2H),4.52-4.30(m,1H),4.08-3.94(m,1H),3.92-3.80(m,1H),3.77-3.68(m,4H),1.51-1.43(m,4H),1.42-1.27(m,4H),1.23-1.14(m,4H),1.03-0.93(m,2H),0.90-0.80(m,2H). 1 H NMR (400MHz, CDCl 3 ) δ (ppm) 8.81 (s, 1H), 8.35 (s, 1H), 7.15-7.06 (m, 1H), 7.06-6.98 (m, 1H), 6.86-6.82 (m ,1H),6.69-6.50(m,1H),6.46-6.34(m,1H),5.86-5.76(m,1H),5.22-4.90(m,2H),4.52-4.30(m,1H),4.08 -3.94(m,1H),3.92-3.80(m,1H),3.77-3.68(m,4H),1.51-1.43(m,4H),1.42-1.27(m,4H),1.23-1.14(m, 4H),1.03-0.93(m,2H),0.90-0.80(m,2H).
实施例6 4-((2S,5R)-4-丙烯酰基-2,5-二甲基哌嗪-1-基)-7-(5-氯-2-氟苯基)-1-(4,6-二环丙基嘧啶-5-基)-2-氧代-1,2-二氢吡啶并[2,3-d]嘧啶-6-腈Example 6 4-((2S,5R)-4-acryloyl-2,5-dimethylpiperazin-1-yl)-7-(5-chloro-2-fluorophenyl)-1-(4 ,6-Dicyclopropylpyrimidin-5-yl)-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidine-6-carbonitrile
第一步(2R,5S)-4-(6-氯-7-(5-氯-2-氟苯基)-1-(4,6-二环丙基嘧啶-5-基)-2-氧代-1,2-二氢吡啶并[2,3-d]嘧啶-4-基)-2,5-二甲基哌嗪-1-羧酸叔丁酯的合成The first step (2R,5S)-4-(6-chloro-7-(5-chloro-2-fluorophenyl)-1-(4,6-dicyclopropylpyrimidin-5-yl)-2- Synthesis of tert-butyl oxo-1,2-dihydropyrido[2,3-d]pyrimidin-4-yl)-2,5-dimethylpiperazine-1-carboxylate
向反应瓶中加入(2R,5S)-4-(6,7-二氯-1-(4,6-二环丙基嘧啶-5-基)-2-氧代-1,2-二氢吡啶并[2,3-d]嘧啶-4-基)-2,5-二甲基哌嗪-1-羧酸叔丁酯(0.22g,0.37mmol)，(5-氯-2-氟苯基)硼酸(0.13g,0.74mmol)，[1,1'-双(二苯基膦)二茂铁]二氯化钯二氯甲烷络合物(0.02g,0.02mmol)，乙酸钾(0.15g,1.48mmol)，1,4-二氧六环(5mL)和水(1mL)。反应体系氮气保护下，加热至回流反应过夜。反应完成后，冷却至室温，向其中加入水(30mL)，乙酸乙酯(30mL)，分液。水相经乙酸乙酯(30mL×3)萃取，合并有机相，饱和食盐水(60mL)洗涤，无水硫酸钠干燥，过滤，减压旋干。残余物经硅胶柱层析(PE/EtOAc(v/v)＝2/1)纯化，得到标题化合物为黄绿色固体(0.23g,收率90.1％)。Add (2R,5S)-4-(6,7-dichloro-1-(4,6-dicyclopropylpyrimidin-5-yl)-2-oxo-1,2-dihydro to the reaction flask Pyrido[2,3-d]pyrimidin-4-yl)-2,5-dimethylpiperazine-1-carboxylic acid tert-butyl ester (0.22g, 0.37mmol), (5-chloro-2-fluorobenzene base) boronic acid (0.13g, 0.74mmol), [1,1'-bis(diphenylphosphino)ferrocene] dichloropalladium dichloromethane complex (0.02g, 0.02mmol), potassium acetate (0.15 g, 1.48 mmol), 1,4-dioxane (5 mL) and water (1 mL). Under the protection of nitrogen, the reaction system was heated to reflux overnight. After the reaction was completed, it was cooled to room temperature, water (30 mL) and ethyl acetate (30 mL) were added thereto, and the layers were separated. The aqueous phase was extracted with ethyl acetate (30 mL×3), the organic phases were combined, washed with saturated brine (60 mL), dried over anhydrous sodium sulfate, filtered, and spin-dried under reduced pressure. The residue was purified by silica gel column chromatography (PE/EtOAc (v/v)=2/1) to obtain the title compound as a yellow-green solid (0.23 g, yield 90.1%).
MS(ESI,pos.ion)m/z:680.2[M+H]+.MS(ESI,pos.ion)m/z:680.2[M+H] + .
第二步(2R,5S)-4-(7-(5-氯-2-氟苯基)-6-氰基-1-(4,6-二环丙基嘧啶-5-基)-2-氧代-1,2-二氢吡啶并[2,3-d]嘧啶-4-基)-2,5-二甲基哌嗪-1-羧酸叔丁酯的合成The second step (2R,5S)-4-(7-(5-chloro-2-fluorophenyl)-6-cyano-1-(4,6-dicyclopropylpyrimidin-5-yl)-2 Synthesis of tert-butyl -oxo-1,2-dihydropyrido[2,3-d]pyrimidin-4-yl)-2,5-dimethylpiperazine-1-carboxylate
向微波管中加入(2R,5S)-4-(6-氯-7-(5-氯-2-氟苯基)-1-(4,6-二环丙基嘧啶-5-基)-2-氧代-1,2-二氢吡啶并[2,3-d]嘧啶-4-基)-2,5-二甲基哌嗪-1-羧酸叔丁酯(0.22g,0.32mmol)，氰化锌(0.19g,1.60mmol)，二(三叔丁基膦)钯(0.08g,0.16mmol)，三叔丁基膦四氟硼酸盐(0.02g,0.06mmol)，N,N-二甲基甲酰胺(3mL)。反应体系氮气置换后，置于微波反应器中，140℃下反应7小时。反应完成后，降至室温，过滤。母液减压旋干。残余物经硅胶柱层析(PE/EtOAc(v/v)＝2/1)纯化，得到标题化合物为淡黄色固体(33mg,收率15.2％)。Add (2R,5S)-4-(6-chloro-7-(5-chloro-2-fluorophenyl)-1-(4,6-dicyclopropylpyrimidin-5-yl)- 2-oxo-1,2-dihydropyrido[2,3-d]pyrimidin-4-yl)-2,5-dimethylpiperazine-1-carboxylic acid tert-butyl ester (0.22g, 0.32mmol ), zinc cyanide (0.19g, 1.60mmol), bis(tri-tert-butylphosphine) palladium (0.08g, 0.16mmol), tri-tert-butylphosphine tetrafluoroborate (0.02g, 0.06mmol), N, N-Dimethylformamide (3 mL). After replacing the reaction system with nitrogen, it was placed in a microwave reactor and reacted at 140° C. for 7 hours. After the reaction was completed, it was lowered to room temperature and filtered. The mother liquor was spin-dried under reduced pressure. The residue was purified by silica gel column chromatography (PE/EtOAc (v/v)=2/1) to obtain the title compound as a pale yellow solid (33 mg, yield 15.2%).
MS(ESI,pos.ion)m/z:671.2[M+H]+.MS(ESI,pos.ion)m/z:671.2[M+H] + .
第三步4-((2S,5R)-4-丙烯酰基-2,5-二甲基哌嗪-1-基)-7-(5-氯-2-氟苯基)-1-(4,6-二环丙基嘧啶-5-基)-2-氧代-1,2-二氢吡啶并[2,3-d]嘧啶-6-腈的合成The third step 4-((2S,5R)-4-acryloyl-2,5-dimethylpiperazin-1-yl)-7-(5-chloro-2-fluorophenyl)-1-(4 , Synthesis of 6-dicyclopropylpyrimidin-5-yl)-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidine-6-carbonitrile
向反应瓶中加入(2R,5S)-4-(7-(5-氯-2-氟苯基)-6-氰基-1-(4,6-二环丙基嘧啶-5-基)-2-氧代-1,2-二氢吡啶并[2,3-d]嘧啶-4-基)-2,5-二甲基哌嗪-1-羧酸叔丁酯(33mg,0.05mmol)，二氯甲烷(2mL)，三氟乙酸(0.5mL)。混合物室温反应0.5h后，减压旋干。残余物中加入二氯甲烷(2.5mL)，三乙胺(0.02g,0.14mmol)，混合物降温至-10℃，向其中滴入丙烯酰氯(0.03g,0.32mmol)，滴完后混合物转移至室温搅拌1h。向上述混合物中依次加入二氯甲烷(20mL)，水(20mL)，分液，水相经二氯甲烷(10mL×3)萃取，合并有机相，饱和食盐水(20mL)洗涤，无水硫酸钠干燥，过滤，减压旋干。残余物经硅胶柱层析(DCM/MeOH(v/v)＝30/1)纯化，得标题化合物为黄绿色固体(15.0mg,收率49％)。Add (2R,5S)-4-(7-(5-chloro-2-fluorophenyl)-6-cyano-1-(4,6-dicyclopropylpyrimidin-5-yl) to the reaction flask -2-Oxo-1,2-dihydropyrido[2,3-d]pyrimidin-4-yl)-2,5-dimethylpiperazine-1-carboxylic acid tert-butyl ester (33mg, 0.05mmol ), dichloromethane (2 mL), trifluoroacetic acid (0.5 mL). After the mixture was reacted at room temperature for 0.5 h, it was spin-dried under reduced pressure. Dichloromethane (2.5mL) and triethylamine (0.02g, 0.14mmol) were added to the residue, the mixture was cooled to -10°C, acryloyl chloride (0.03g, 0.32mmol) was added dropwise thereto, and the mixture was transferred to Stir at room temperature for 1 h. Add dichloromethane (20mL) and water (20mL) to the above mixture successively, separate the layers, extract the aqueous phase with dichloromethane (10mL×3), combine the organic phases, wash with saturated brine (20mL), anhydrous sodium sulfate Dry, filter, and spin dry under reduced pressure. The residue was purified by silica gel column chromatography (DCM/MeOH (v/v)=30/1) to obtain the title compound as a yellow-green solid (15.0 mg, yield 49%).
MS(ESI,pos.ion)m/z:625.2[M+H]+.MS(ESI,pos.ion)m/z:625.2[M+H] + .
1H NMR(400MHz,CDCl3)δ(ppm)8.83(s,1H),8.35(s,1H),7.49-7.44(m,1H),7.43-7.39(m,1H),7.21-7.13(m,1H),6.69-6.51(m,1H),6.47-6.35(m,1H),5.87-5.78(m,1H),5.21-4.89(m,2H),4.69(s,1H),4.53-4.31(m,1H),3.91-3.82(m,1H),3.77-3.70(m,1H),1.52-1.44(m,4H),1.25(s,6H),0.99(s,2H),0.92-0.80(m,4H). 1 H NMR (400MHz, CDCl 3 )δ(ppm)8.83(s,1H),8.35(s,1H),7.49-7.44(m,1H),7.43-7.39(m,1H),7.21-7.13(m ,1H),6.69-6.51(m,1H),6.47-6.35(m,1H),5.87-5.78(m,1H),5.21-4.89(m,2H),4.69(s,1H),4.53-4.31 (m,1H),3.91-3.82(m,1H),3.77-3.70(m,1H),1.52-1.44(m,4H),1.25(s,6H),0.99(s,2H),0.92-0.80 (m,4H).
实施例7 4-((2S,5R)-4-丙烯酰基-2,5-二甲基哌嗪基-1-基)-1-(4,6-二异丙基嘧啶-5-基)-7-(2-氟-5-甲基苯基)-2-氧代-1,2-二氢吡啶并[2,3-d]嘧啶-6-腈Example 7 4-((2S,5R)-4-acryloyl-2,5-dimethylpiperazinyl-1-yl)-1-(4,6-diisopropylpyrimidin-5-yl) -7-(2-fluoro-5-methylphenyl)-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidine-6-carbonitrile
第一步4,6-二(丙-1-烯-2-基)嘧啶-5-胺的合成The first step of synthesis of 4,6-di(prop-1-en-2-yl)pyrimidin-5-amine
向反应瓶中加入4,6-二氯嘧啶-5-胺(2.00g,12.20mmol)，4,4,5,5-四甲基-2-(丙-1-烯-2-基)-1,3,2-二氧杂环戊硼烷(6.15g,36.60mmol)，[1,1'-双(二苯基膦)二茂铁]二氯化钯(0.89g,1.22mmol)，碳酸钠(3.88g,36.60mmol)，1,4-二氧六环(30.0mL)和水(6.0mL)。反应体系氮气保护下，加热至回流反应过夜。反应完成后，冷却至室温，过滤。向母液中加入水(30mL)，经乙酸乙酯(50mL×3)萃取。有机相经饱和食盐水(50mL)洗涤，无水硫酸钠干燥，过滤，减压旋干。残余物经硅胶柱层析(PE/EtOAc(v/v)＝10/1)纯化，得到标题化合物为淡黄绿色油状物(1.50g,收率70.2％)。Add 4,6-dichloropyrimidin-5-amine (2.00g, 12.20mmol), 4,4,5,5-tetramethyl-2-(prop-1-en-2-yl)- 1,3,2-Dioxaborolane (6.15g, 36.60mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (0.89g, 1.22mmol), Sodium carbonate (3.88 g, 36.60 mmol), 1,4-dioxane (30.0 mL) and water (6.0 mL). Under the protection of nitrogen, the reaction system was heated to reflux overnight. After the reaction was completed, it was cooled to room temperature and filtered. Water (30 mL) was added to the mother liquor, extracted with ethyl acetate (50 mL×3). The organic phase was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and spin-dried under reduced pressure. The residue was purified by silica gel column chromatography (PE/EtOAc (v/v)=10/1) to obtain the title compound as a light yellow-green oil (1.50 g, yield 70.2%).
MS(ESI,pos.ion)m/z:176.1[M+H]+.MS(ESI,pos.ion)m/z:176.1[M+H] + .
1H NMR(400MHz,CDCl3)δ(ppm)8.59(s,1H),5.56(s,2H),5.44(s,2H),4.20(s,2H),2.16(s,6H). 1 H NMR (400MHz, CDCl 3 ) δ (ppm) 8.59 (s, 1H), 5.56 (s, 2H), 5.44 (s, 2H), 4.20 (s, 2H), 2.16 (s, 6H).
第二步4,6-二异丙基嘧啶-5-胺的合成The second step of synthesis of 4,6-diisopropylpyrimidin-5-amine
向反应瓶中加入4,6-二(丙-1-烯-2-基)嘧啶-5-胺(1.50g,8.56mmol)，乙酸乙酯(10.0mL)，10％钯碳(1.82g)。反应体系氢气氛围下室温反应过夜。待反应完全后，过滤，母液减压旋干，得到标题化合物为淡黄色固体(1.35g,收率87.98％)。Add 4,6-bis(prop-1-en-2-yl)pyrimidin-5-amine (1.50g, 8.56mmol), ethyl acetate (10.0mL), 10% palladium on carbon (1.82g) to the reaction flask . The reaction system was reacted overnight at room temperature under a hydrogen atmosphere. After the reaction was complete, it was filtered and the mother liquor was spin-dried under reduced pressure to obtain the title compound as a light yellow solid (1.35 g, yield 87.98%).
MS(ESI,pos.ion)m/z:180.3[M+H]+.MS(ESI,pos.ion)m/z:180.3[M+H] + .
第三步2,5,6-三氯-N-((4,6-二异丙基嘧啶-5-基)氨基甲酰基)烟酸酰胺的合成The third step is the synthesis of 2,5,6-trichloro-N-((4,6-diisopropylpyrimidin-5-yl)carbamoyl)nicotinic acid amide
向反应瓶中加入2,5,6-三氯烟酸酰胺(0.60g,2.66mmol)，1,2-二氯乙烷(8.0mL)，草酰氯(0.51g,3.99mmol)。反应体系氮气保护下，加热至80℃反应1h。降温，减压旋干。残余物中加入乙腈(6.0mL)，然后降温至-10℃，向其中滴加4,6-二异丙基嘧啶-5-胺(0.48g,2.66mmol)的乙腈(3.0mL)溶液。滴完后混合物转移至室温搅拌过夜。反应完全后，减压旋干，得到标题化合物为色固体(1.35g,收率100.00％)，直接用于下一步反应。Add 2,5,6-trichloronicotinic acid amide (0.60 g, 2.66 mmol), 1,2-dichloroethane (8.0 mL), oxalyl chloride (0.51 g, 3.99 mmol) into the reaction flask. Under the protection of nitrogen, the reaction system was heated to 80° C. for 1 h. Cool down, spin dry under reduced pressure. Acetonitrile (6.0 mL) was added to the residue, and then cooled to -10°C, a solution of 4,6-diisopropylpyrimidin-5-amine (0.48 g, 2.66 mmol) in acetonitrile (3.0 mL) was added dropwise thereto. After dropping, the mixture was transferred to room temperature and stirred overnight. After the reaction was complete, spin dry under reduced pressure to obtain the title compound as a colored solid (1.35 g, yield 100.00%), which was directly used in the next reaction.
MS(ESI,pos.ion)m/z:430.1[M+H]+.MS(ESI,pos.ion)m/z:430.1[M+H] + .
第四步6,7-二氯-1-(4,6-二异丙基嘧啶-5-基)吡啶并[2,3-d]嘧啶-2,4(1H,3H)-二酮的合成The fourth step of 6,7-dichloro-1-(4,6-diisopropylpyrimidin-5-yl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione synthesis
向反应瓶中加入2,5,6-三氯-N-((4,6-二异丙基嘧啶-5-基)氨基甲酰基)烟酸酰胺(1.14g,2.65mmol)，四氢呋喃(12.0mL)和叔丁醇钠(0.64g,6.63mmol)。反应体系室温反应2h。反应完成后，向体系中加入水(30mL)和乙酸乙酯(40mL)。分液，水相经饱和柠檬酸调节至pH＝7，经乙酸乙酯(40mL×3)萃取。合并有机相，经饱和食盐水(60mL)洗涤，无水硫酸钠干燥，过滤，减压旋干。残余物经硅胶柱层析(PE/EtOAc(v/v)＝3/1)纯化，得到标题化合物淡黄色固体(0.81g,收率77.22％)。Add 2,5,6-trichloro-N-((4,6-diisopropylpyrimidin-5-yl)carbamoyl)nicotinic acid amide (1.14g, 2.65mmol), tetrahydrofuran (12.0 mL) and sodium tert-butoxide (0.64g, 6.63mmol). The reaction system reacted at room temperature for 2h. After the reaction was completed, water (30 mL) and ethyl acetate (40 mL) were added to the system. The layers were separated, and the aqueous phase was adjusted to pH=7 with saturated citric acid, and extracted with ethyl acetate (40 mL×3). The organic phases were combined, washed with saturated brine (60 mL), dried over anhydrous sodium sulfate, filtered, and spin-dried under reduced pressure. The residue was purified by silica gel column chromatography (PE/EtOAc (v/v)=3/1) to obtain the title compound as a pale yellow solid (0.81 g, yield 77.22%).
MS(ESI,pos.ion)m/z:394.3[M+H]+.MS(ESI,pos.ion)m/z:394.3[M+H] + .
第五步6-氯-1-(4,6-二异丙基嘧啶-5-基)-7-(2-氟-5-甲基苯基)吡啶并[2,3-d]嘧啶-2,4(1H,3H)-二酮的合成The fifth step 6-chloro-1-(4,6-diisopropylpyrimidin-5-yl)-7-(2-fluoro-5-methylphenyl)pyrido[2,3-d]pyrimidine- Synthesis of 2,4(1H,3H)-diketones
向反应瓶中加入6,7-二氯-1-(4,6-二异丙基嘧啶-5-基)吡啶并[2,3-d]嘧啶-2,4(1H,3H)-二酮(400.0mg,1.01mmol)，(2-氟-5-甲基苯基)硼酸(0.34g,2.22mmol)，[1,1'-双(二苯基膦)二茂铁]二氯化钯二氯甲烷络合物(0.04g,0.05mmol)，乙酸钾(0.40g,4.04mmol)，1,4-二氧六环(8.0mL)和水(2.0mL)。反应体系氮气保护下，加热至100℃反应3h。将上述体系冷却至室温，过滤，所得白色固体经混合物溶剂(PE/EtOAc(v/v)＝3/1,6mL)洗涤，真空干燥得标题化合物为白色固体(0.29g,收率61.36％)。Add 6,7-dichloro-1-(4,6-diisopropylpyrimidin-5-yl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-di Ketone (400.0mg, 1.01mmol), (2-fluoro-5-methylphenyl)boronic acid (0.34g, 2.22mmol), [1,1'-bis(diphenylphosphino)ferrocene] dichloride Palladium dichloromethane complex (0.04 g, 0.05 mmol), potassium acetate (0.40 g, 4.04 mmol), 1,4-dioxane (8.0 mL) and water (2.0 mL). Under the protection of nitrogen, the reaction system was heated to 100° C. for 3 h. The above system was cooled to room temperature, filtered, and the resulting white solid was washed with a mixture solvent (PE/EtOAc (v/v)=3/1, 6 mL), and dried in vacuo to give the title compound as a white solid (0.29 g, yield 61.36%) .
MS(ESI,pos.ion)m/z:468.4[M+H]+.MS(ESI,pos.ion)m/z:468.4[M+H] + .
第六步(2R,5S)-4-(6-氯-1-(4,6-二异丙基嘧啶-5-基)-7-(2-氟-5-甲基苯基)-2-氧代-1,2-二氢吡啶并[2,3-d]嘧啶-4-基)-2,5-二甲基哌嗪-1-羧酸叔丁酯的合成The sixth step (2R,5S)-4-(6-chloro-1-(4,6-diisopropylpyrimidin-5-yl)-7-(2-fluoro-5-methylphenyl)-2 Synthesis of tert-butyl -oxo-1,2-dihydropyrido[2,3-d]pyrimidin-4-yl)-2,5-dimethylpiperazine-1-carboxylate
向反应瓶中加入6-氯-1-(4,6-二异丙基嘧啶-5-基)-7-(2-氟-5-甲基苯基)吡啶并[2,3-d]嘧啶-2,4(1H,3H)-二酮(0.29g,0.62mmol)，乙腈(5.0mL)，二异丙基乙胺(0.24g,1.86mmol)和三氯氧磷(0.29g,1.86mmol)。反应体系加热至80℃反应3h，然后冷却至室温，减压旋干。残余物中加入乙腈(6.0mL)，二异丙基乙胺(0.17g,1.28mmol)，(2R,5S)-2,5-二甲基哌嗪-1-羧酸叔丁酯(0.14g,0.67mmol)。体系加热至80℃反应4h。反应完全后，冷却至室温，向其中加入水(30mL)，乙酸乙酯(30mL)，分液。水相经乙酸乙酯(30mL×3)萃取，合并有机相，饱和食盐水(60mL)洗涤，无水硫酸钠干燥，过滤，减压旋干。残余物经硅胶柱层析(PE/EtOAc(v/v)＝1/1)纯化，得到标题化合物为淡黄色固体(0.28g,收率65.87％)。Add 6-chloro-1-(4,6-diisopropylpyrimidin-5-yl)-7-(2-fluoro-5-methylphenyl)pyrido[2,3-d] to the reaction flask Pyrimidine-2,4(1H,3H)-dione (0.29g, 0.62mmol), acetonitrile (5.0mL), diisopropylethylamine (0.24g, 1.86mmol) and phosphorus oxychloride (0.29g, 1.86 mmol). The reaction system was heated to 80° C. for 3 h, then cooled to room temperature, and spin-dried under reduced pressure. To the residue were added acetonitrile (6.0 mL), diisopropylethylamine (0.17 g, 1.28 mmol), (2R,5S)-2,5-dimethylpiperazine-1-carboxylic acid tert-butyl ester (0.14 g ,0.67mmol). The system was heated to 80°C for 4 hours. After the reaction was complete, it was cooled to room temperature, and water (30 mL) and ethyl acetate (30 mL) were added thereto for liquid separation. The aqueous phase was extracted with ethyl acetate (30 mL×3), the organic phases were combined, washed with saturated brine (60 mL), dried over anhydrous sodium sulfate, filtered, and spin-dried under reduced pressure. The residue was purified by silica gel column chromatography (PE/EtOAc (v/v)=1/1) to obtain the title compound as a light yellow solid (0.28 g, yield 65.87%).
MS(ESI,pos.ion)m/z:664.1[M+H]+.MS(ESI,pos.ion)m/z:664.1[M+H] + .
第七步(2R,5S)-4-(6-氰基-1-(4,6-二异丙基嘧啶-5-基)-7-(2-氟-5-甲基苯基)-2-氧代-1,2-二氢吡啶并[2,3-d]嘧啶-4-基)-2,5-二甲基哌嗪-1-羧酸叔丁酯的合成The seventh step (2R,5S)-4-(6-cyano-1-(4,6-diisopropylpyrimidin-5-yl)-7-(2-fluoro-5-methylphenyl)- Synthesis of tert-butyl 2-oxo-1,2-dihydropyrido[2,3-d]pyrimidin-4-yl)-2,5-dimethylpiperazine-1-carboxylate
向微波管中加入(2R,5S)-4-(6-氯-1-(4,6-二异丙基嘧啶-5-基)-7-(2-氟-5-甲基苯基)-2-氧代-1,2-二氢吡啶并[2,3-d]嘧啶-4-基)-2,5-二甲基哌嗪-1-羧酸叔丁酯(0.15g,0.23mmol)，氰化锌(0.14g,1.19mmol)，二(三叔丁基膦)钯(0.06g,0.12mmol)，三叔丁基膦四氟硼酸盐(0.01g,0.02mmol)，N,N-二甲基甲酰胺(2.5mL)。反应体系氮气置换后，置于微波反应器中，140℃下反应7小时。反应完成后，降至室温，过滤。母液中加入乙酸乙酯(20mL)和水(20mL)，分液。水相经乙酸乙酯(20mL×3)萃取，合并有机相，经饱和食盐水(40mL)洗涤，无水硫酸钠干燥，过滤，减压旋干。残余物经硅胶柱层析(PE/EtOAc(v/v)＝1/1)纯化，得到标题化合物为淡黄色固体(0.11g,收率71.78％)。Add (2R,5S)-4-(6-chloro-1-(4,6-diisopropylpyrimidin-5-yl)-7-(2-fluoro-5-methylphenyl) to the microwave tube -2-Oxo-1,2-dihydropyrido[2,3-d]pyrimidin-4-yl)-2,5-dimethylpiperazine-1-carboxylic acid tert-butyl ester (0.15g, 0.23 mmol), zinc cyanide (0.14g, 1.19mmol), two (tri-tert-butylphosphine) palladium (0.06g, 0.12mmol), tri-tert-butylphosphine tetrafluoroborate (0.01g, 0.02mmol), N , N-dimethylformamide (2.5 mL). After replacing the reaction system with nitrogen, it was placed in a microwave reactor and reacted at 140° C. for 7 hours. After the reaction was completed, it was lowered to room temperature and filtered. Ethyl acetate (20 mL) and water (20 mL) were added to the mother liquor, and the layers were separated. The aqueous phase was extracted with ethyl acetate (20 mL×3), and the combined organic phases were washed with saturated brine (40 mL), dried over anhydrous sodium sulfate, filtered, and spin-dried under reduced pressure. The residue was purified by silica gel column chromatography (PE/EtOAc (v/v)=1/1) to obtain the title compound as a light yellow solid (0.11 g, yield 71.78%).
MS(ESI,pos.ion)m/z:655.3[M+H]+.MS(ESI,pos.ion)m/z:655.3[M+H] + .
第八步4-((2S,5R)-4-丙烯酰基-2,5-二甲基哌嗪基-1-基)-1-(4,6-二异丙基嘧啶-5-基)-7-(2-氟-5-甲基苯基)-2-氧代-1,2-二氢吡啶并[2,3-d]嘧啶-6-腈的合成The eighth step 4-((2S,5R)-4-acryloyl-2,5-dimethylpiperazinyl-1-yl)-1-(4,6-diisopropylpyrimidin-5-yl) Synthesis of -7-(2-fluoro-5-methylphenyl)-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidine-6-carbonitrile
向反应瓶中加入(2R,5S)-4-(6-氰基-1-(4,6-二异丙基嘧啶-5-基)-7-(2-氟-5-甲基苯基)-2-氧代-1,2-二氢吡啶并[2,3-d]嘧啶-4-基)-2,5-二甲基哌嗪-1-羧酸叔丁酯(0.11g,0.16mmol)，二氯甲烷(2.5mL)和三氟乙酸(0.5mL)。反应体系室温反应0.5h，然后减压旋干。残余物中加入二氯甲烷(2.5mL)，三乙胺(0.05g,0.48mmol)。体系降温至-10℃，向其中滴入丙烯酰氯(0.03g,0.32mmol)。滴完后混合物转移至室温反应30min。待反应结束后，向体系中加入二氯甲烷(15mL)和水(20mL)，分液。水相经二氯甲烷(10mL×3)萃取，合并有机相，经饱和食盐水(30mL)洗涤，无水硫酸钠干燥，过滤，减压旋干。残余物经硅胶柱层析(DCM/MeOH(v/v)＝30/1)纯化，得到标题化合物为淡黄色固体(41.5mg,收率42.61％)。Add (2R,5S)-4-(6-cyano-1-(4,6-diisopropylpyrimidin-5-yl)-7-(2-fluoro-5-methylphenyl) to the reaction flask )-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidin-4-yl)-2,5-dimethylpiperazine-1-carboxylic acid tert-butyl ester (0.11g, 0.16 mmol), dichloromethane (2.5 mL) and trifluoroacetic acid (0.5 mL). The reaction system was reacted at room temperature for 0.5 h, and then spin-dried under reduced pressure. Dichloromethane (2.5 mL), triethylamine (0.05 g, 0.48 mmol) were added to the residue. The system was cooled to -10°C, and acryloyl chloride (0.03g, 0.32mmol) was added dropwise thereto. After dropping, the mixture was transferred to room temperature for 30 min. After the reaction was completed, dichloromethane (15 mL) and water (20 mL) were added to the system, and the layers were separated. The aqueous phase was extracted with dichloromethane (10 mL×3), and the combined organic phases were washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and spin-dried under reduced pressure. The residue was purified by silica gel column chromatography (DCM/MeOH (v/v)=30/1) to obtain the title compound as a pale yellow solid (41.5 mg, yield 42.61%).
MS(ESI,pos.ion)m/z:609.2[M+H]+.MS(ESI,pos.ion)m/z:609.2[M+H] + .
1H NMR(400MHz,CDCl3)δ(ppm)9.15(s,1H),8.37(s,1H),7.26(s,1H),7.07-6.97(m,2H),6.69-6.48(m,1H),6.45-6.33(m,1H),5.84-5.75(m,1H),5.19-4.86(m,2H),4.50-4.28(m,1H),4.03(s,1H),3.92-3.81(m,1H),3.75-3.42(m,1H),2.71-2.55(m,2H),2.27(s,3H),1.51-1.29(m,6H),1.23-1.19(m,6H),1.08-0.97(m,6H). 1 H NMR (400MHz, CDCl 3 ) δ (ppm) 9.15 (s, 1H), 8.37 (s, 1H), 7.26 (s, 1H), 7.07-6.97 (m, 2H), 6.69-6.48 (m, 1H ),6.45-6.33(m,1H),5.84-5.75(m,1H),5.19-4.86(m,2H),4.50-4.28(m,1H),4.03(s,1H),3.92-3.81(m ,1H),3.75-3.42(m,1H),2.71-2.55(m,2H),2.27(s,3H),1.51-1.29(m,6H),1.23-1.19(m,6H),1.08-0.97 (m,6H).
实施例8 4-((2S,5R)-4-丙烯酰基-2,5-二甲基哌嗪-1-基)-7-(5-氰基-2-(二甲基氨基)苯基)-1-(4,6-二环丙基嘧啶-5-基)-2-氧代-1,2-二氢吡啶并[2,3-d]嘧啶-6-腈Example 8 4-((2S,5R)-4-acryloyl-2,5-dimethylpiperazin-1-yl)-7-(5-cyano-2-(dimethylamino)phenyl )-1-(4,6-dicyclopropylpyrimidin-5-yl)-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidine-6-carbonitrile
第一步(2R,5S)-4-(6-氰基-7-(5-氰基-2-(二甲基氨基)苯基)-1-(4,6-二环丙基嘧啶-5-基)-2-氧代-1,2-二氢吡啶并[2,3-d]嘧啶-4-基)-2,5-二甲基哌嗪-1-羧酸叔丁酯的合成The first step (2R,5S)-4-(6-cyano-7-(5-cyano-2-(dimethylamino)phenyl)-1-(4,6-dicyclopropylpyrimidine- 5-yl)-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidin-4-yl)-2,5-dimethylpiperazine-1-carboxylic acid tert-butyl ester synthesis
向反应瓶中加入(2R,5S)-4-(7-(5-氯-2-氟苯基)-6-氰基-1-(4,6-二环丙基嘧啶-5-基)-2-氧代-1,2-二羟基吡啶[2,3-d]嘧啶-4-基)-2,5-二甲基哌嗪-1-甲酸叔丁酯(0.22g,0.32mmol)，氰化锌(0.19g,1.60mmol)，二(三叔丁基膦)钯(0.08g,0.16mmol)，三叔丁基膦四氟硼酸盐(0.02g,0.06mmol)和N,N-二甲基甲酰胺(3mL)。反应体系氮气置换后，置于微波反应器中，140℃下反应7小时。反应完成后，降至室温，过滤。母液减压旋干。残余物经硅胶柱层析(PE/EtOAc(v/v)＝2/1)纯化，得到标题化合物为淡黄色固体(75.0mg,收率33.78％)。Add (2R,5S)-4-(7-(5-chloro-2-fluorophenyl)-6-cyano-1-(4,6-dicyclopropylpyrimidin-5-yl) to the reaction flask -2-Oxo-1,2-dihydroxypyridin[2,3-d]pyrimidin-4-yl)-2,5-dimethylpiperazine-1-carboxylic acid tert-butyl ester (0.22g, 0.32mmol) , zinc cyanide (0.19g, 1.60mmol), bis(tri-tert-butylphosphine) palladium (0.08g, 0.16mmol), tri-tert-butylphosphine tetrafluoroborate (0.02g, 0.06mmol) and N,N - Dimethylformamide (3 mL). After replacing the reaction system with nitrogen, it was placed in a microwave reactor and reacted at 140° C. for 7 hours. After the reaction was completed, it was lowered to room temperature and filtered. The mother liquor was spin-dried under reduced pressure. The residue was purified by silica gel column chromatography (PE/EtOAc (v/v)=2/1) to obtain the title compound as a light yellow solid (75.0 mg, yield 33.78%).
MS(ESI,pos.ion)m/z:687.2[M+H]+.MS(ESI,pos.ion)m/z:687.2[M+H] + .
第二步4-((2S,5R)-4-丙烯酰基-2,5-二甲基哌嗪-1-基)-7-(5-氰基-2-(二甲基氨基)苯基)-1-(4,6-二环丙基嘧啶-5-基)-2-氧代-1,2-二氢吡啶并[2,3-d]嘧啶-6-腈The second step 4-((2S,5R)-4-acryloyl-2,5-dimethylpiperazin-1-yl)-7-(5-cyano-2-(dimethylamino)phenyl )-1-(4,6-dicyclopropylpyrimidin-5-yl)-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidine-6-carbonitrile
向反应瓶中加入(2R,5S)-4-(6-氰基-7-(5-氰基-2-(二甲基氨基)苯基)-6-氰基-1-(4,6-二环丙基嘧啶-5-基)-2-氧代-1,2-二氢吡啶并[2,3-d]嘧啶-4-基)-2,5-二甲基哌嗪-1-羧酸叔丁酯(75.0mg,0.11mmol)，二氯甲烷(2.5mL)和三氟乙酸(0.5mL)。反应体系室温反应0.5h，然后减压旋干。残余物中加入二氯甲烷(2.5mL)，三乙胺(0.03g,0.33mmol)。混合物降温至-10℃，向其中滴入丙烯酰氯(0.02g,0.22mmol)。滴完后混合物转移至室温反应20min。待反应完全后，向体系中加入二氯甲烷(10mL)和水(10mL)，分液。水相经二氯甲烷(10mL×3)萃取，合并有机相，饱和食盐水(20mL)洗涤，无水硫酸钠干燥，过滤，减压旋干。残余物经硅胶柱层析(DCM/MeOH(v/v)＝30/1)纯化，得到标题化合物为黄绿色固体(36.0mg,收率51.08％)。MS(ESI,pos.ion)m/z:641.5[M+H]+.Add (2R,5S)-4-(6-cyano-7-(5-cyano-2-(dimethylamino)phenyl)-6-cyano-1-(4,6 -Dicyclopropylpyrimidin-5-yl)-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidin-4-yl)-2,5-dimethylpiperazine-1 - tert-butyl carboxylate (75.0 mg, 0.11 mmol), dichloromethane (2.5 mL) and trifluoroacetic acid (0.5 mL). The reaction system was reacted at room temperature for 0.5 h, and then spin-dried under reduced pressure. Dichloromethane (2.5 mL), triethylamine (0.03 g, 0.33 mmol) were added to the residue. The mixture was cooled to -10°C, and acryloyl chloride (0.02 g, 0.22 mmol) was added dropwise thereto. After dropping, the mixture was transferred to room temperature for 20 min. After the reaction was complete, dichloromethane (10 mL) and water (10 mL) were added to the system, and the layers were separated. The aqueous phase was extracted with dichloromethane (10 mL×3), and the organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and spin-dried under reduced pressure. The residue was purified by silica gel column chromatography (DCM/MeOH (v/v)=30/1) to obtain the title compound as a yellow-green solid (36.0 mg, yield 51.08%). MS(ESI,pos.ion)m/z:641.5[M+H] + .
1H NMR(400MHz,CDCl3)δ(ppm)8.80(s,1H),8.36(s,1H),7.55-7.47(m,1H),7.43-7.33(m,1H),7.25-7.17(m,1H),6.59(s,1H),6.44-6.37(m,1H),5.85-5.79(m,1H),5.21-4.23(m,3H),3.96-2.99(m,3H),1.77-1.44(m,10H),1.26-1.11(m,7H),0.97(s,2H),0.90-0.77(m,3H). 1 H NMR (400MHz, CDCl 3 ) δ (ppm) 8.80 (s, 1H), 8.36 (s, 1H), 7.55-7.47 (m, 1H), 7.43-7.33 (m, 1H), 7.25-7.17 (m ,1H),6.59(s,1H),6.44-6.37(m,1H),5.85-5.79(m,1H),5.21-4.23(m,3H),3.96-2.99(m,3H),1.77-1.44 (m,10H),1.26-1.11(m,7H),0.97(s,2H),0.90-0.77(m,3H).
实施例9 4-((2S,5R)-4-丙烯酰基-2,5-二甲基哌嗪-1-基)-1-(4,6-二异丙基嘧啶-5-基)-7-(2-氟苯基)-2-氧代-1,2-二氢吡啶并[2,3-d]嘧啶-6-腈Example 9 4-((2S,5R)-4-acryloyl-2,5-dimethylpiperazin-1-yl)-1-(4,6-diisopropylpyrimidin-5-yl)- 7-(2-fluorophenyl)-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidine-6-carbonitrile
第一步6-氯-1-(4,6-二异丙基嘧啶-5-基)-7-(2-氟苯基)-4-羟基吡啶并[2,3-d]嘧啶-2(1H)-酮的合成The first step 6-chloro-1-(4,6-diisopropylpyrimidin-5-yl)-7-(2-fluorophenyl)-4-hydroxypyrido[2,3-d]pyrimidine-2 Synthesis of (1H)-ketone
向反应瓶中加入6,7-二氯-1-(4,6-二异丙基嘧啶-5-基)吡啶并[2,3-d]嘧啶-2,4(1H,3H)-二酮(400.0mg,1.01mmol)，2-氟苯硼酸(0.34g,2.22mmol)，[1,1'-双(二苯基膦)二茂铁]二氯化钯二氯甲烷络合物(0.04g,0.05mmol)，乙酸钾(0.40g,4.04mmol)，1,4-二氧六环(8.0mL)和水(2.0mL)。反应体系氮气保护下，加热至100℃反应3h。将上述体系冷却至室温，向其中加入水(20mL)，经乙酸乙酯(20mL×2)萃取。合并有机相，饱和食盐水(20mL)洗涤，无水硫酸钠干燥，过滤，减压旋干。残余物经硅胶柱层析(PE/EtOAc(v/v)＝3/1)纯化，得到标题化合物为淡黄色固体(0.39g,收率84.61％)。Add 6,7-dichloro-1-(4,6-diisopropylpyrimidin-5-yl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-di Ketone (400.0mg, 1.01mmol), 2-fluorophenylboronic acid (0.34g, 2.22mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex ( 0.04 g, 0.05 mmol), potassium acetate (0.40 g, 4.04 mmol), 1,4-dioxane (8.0 mL) and water (2.0 mL). Under the protection of nitrogen, the reaction system was heated to 100° C. for 3 h. The above system was cooled to room temperature, water (20 mL) was added thereto, and extracted with ethyl acetate (20 mL×2). The organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and spin-dried under reduced pressure. The residue was purified by silica gel column chromatography (PE/EtOAc (v/v)=3/1) to obtain the title compound as a light yellow solid (0.39 g, yield 84.61%).
MS(ESI,pos.ion)m/z:454.3[M+H]+.MS(ESI,pos.ion)m/z:454.3[M+H] + .
第二步(2R,5S)-4-(6-氯-1-(4,6-二异丙基嘧啶-5-基)-7-(2-氟苯基)-2-氧代-1,2-二氢吡啶并[2,3-d]嘧啶-4-基)-2,5-二甲基哌嗪-1-羧酸叔丁酯的合成The second step (2R,5S)-4-(6-chloro-1-(4,6-diisopropylpyrimidin-5-yl)-7-(2-fluorophenyl)-2-oxo-1 , Synthesis of tert-butyl 2-dihydropyrido[2,3-d]pyrimidin-4-yl)-2,5-dimethylpiperazine-1-carboxylate
向反应瓶中加入6-氯-1-(4,6-二异丙基嘧啶-5-基)-7-(2-氟苯基)-4-羟基吡啶并[2,3-d]嘧啶-2(1H)-酮(0.39g,0.62mmol)，乙腈(8.0mL)，二异丙基乙胺(0.33g,2.55mmol)和三氯氧磷(0.39g,2.54mmol)。反应体系加热至回流反应2h，然后冷却至室温，减压旋干。残余物中加入乙腈(8.0mL)，二异丙基乙胺(0.33g,2.55mmol)，(2R,5S)-2,5-二甲基哌嗪-1-羧酸叔丁酯(0.18g,0.85mmol)。反应体系加热至回流反应2h。反应完全后，冷却至室温，向其中加入水(20mL)，乙酸乙酯(20mL)，分液。水相经乙酸乙酯(20mL×3)萃取，合并有机相，饱和食盐水(40mL)洗涤，无水硫酸钠干燥，过滤，减压旋干。残余物经硅胶柱层析(PE/EtOAc(v/v)＝3/1)纯化，得到标题化合物为淡黄色固体(0.33g,收率59.3％)。Add 6-chloro-1-(4,6-diisopropylpyrimidin-5-yl)-7-(2-fluorophenyl)-4-hydroxypyrido[2,3-d]pyrimidine to the reaction flask -2(1H)-one (0.39g, 0.62mmol), acetonitrile (8.0mL), diisopropylethylamine (0.33g, 2.55mmol) and phosphorus oxychloride (0.39g, 2.54mmol). The reaction system was heated to reflux for 2 h, then cooled to room temperature, and spin-dried under reduced pressure. Acetonitrile (8.0 mL), diisopropylethylamine (0.33 g, 2.55 mmol), (2R,5S)-2,5-dimethylpiperazine-1-carboxylic acid tert-butyl ester (0.18 g ,0.85mmol). The reaction system was heated to reflux for 2h. After the reaction was complete, it was cooled to room temperature, and water (20 mL) and ethyl acetate (20 mL) were added thereto to separate the layers. The aqueous phase was extracted with ethyl acetate (20 mL×3), the organic phases were combined, washed with saturated brine (40 mL), dried over anhydrous sodium sulfate, filtered, and spin-dried under reduced pressure. The residue was purified by silica gel column chromatography (PE/EtOAc (v/v)=3/1) to obtain the title compound as a pale yellow solid (0.33 g, yield 59.3%).
MS(ESI,pos.ion)m/z:650.5[M+H]+.MS(ESI,pos.ion)m/z:650.5[M+H] + .
第三步(2R,5S)-4-(6-氰基-1-(4,6-二异丙基嘧啶-5-基)-7-(2-氟苯基)-2-氧代-1,2-二氢吡啶并[2,3-d]嘧啶-4-基)-2,5-二甲基哌嗪-1-羧酸叔丁酯的合成The third step (2R,5S)-4-(6-cyano-1-(4,6-diisopropylpyrimidin-5-yl)-7-(2-fluorophenyl)-2-oxo- Synthesis of tert-butyl 1,2-dihydropyrido[2,3-d]pyrimidin-4-yl)-2,5-dimethylpiperazine-1-carboxylate
向微波管中加入(2R,5S)-4-(6-氯-1-(4,6-二异丙基嘧啶-5-基)-7-(2-氟苯基)-2-氧代-1,2-二氢吡啶并[2,3-d]嘧啶-4-基)-2,5-二甲基哌嗪-1-羧酸叔丁酯(0.33g,0.50mmol)，氰化锌(0.23g,2.00mmol)，二(三叔丁基膦)钯(0.10g,0.20mmol)，三叔丁基膦四氟硼酸盐(0.03g,0.10mmol)，N,N-二甲基甲酰胺(2.5mL)。反应体系氮气置换后，置于微波反应器中，140℃下反应6小时。反应完成后，降至室温，过滤。滤液中加入乙酸乙酯(30mL)，经饱和食盐水(30mL)洗涤，无水硫酸钠干燥，过滤，减压旋干。残余物经硅胶柱层析(PE/EtOAc(v/v)＝4/1)纯化，得到标题化合物为淡黄色油状物(0.14g,收率44.5％)。Add (2R,5S)-4-(6-chloro-1-(4,6-diisopropylpyrimidin-5-yl)-7-(2-fluorophenyl)-2-oxo to the microwave tube -1,2-dihydropyrido[2,3-d]pyrimidin-4-yl)-2,5-dimethylpiperazine-1-carboxylic acid tert-butyl ester (0.33g, 0.50mmol), cyanide Zinc (0.23g, 2.00mmol), bis(tri-tert-butylphosphine) palladium (0.10g, 0.20mmol), tri-tert-butylphosphine tetrafluoroborate (0.03g, 0.10mmol), N,N-dimethyl Dimethyl formamide (2.5 mL). After the reaction system was replaced with nitrogen, it was placed in a microwave reactor and reacted at 140° C. for 6 hours. After the reaction was completed, it was lowered to room temperature and filtered. Ethyl acetate (30 mL) was added to the filtrate, washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and spin-dried under reduced pressure. The residue was purified by silica gel column chromatography (PE/EtOAc (v/v)=4/1) to obtain the title compound as a light yellow oil (0.14 g, yield 44.5%).
MS(ESI,pos.ion)m/z:641.7[M+H]+.MS(ESI,pos.ion)m/z:641.7[M+H] + .
第四步4-((2S,5R)-4-丙烯酰基-2,5-二甲基哌嗪-1-基)-1-(4,6-二异丙基嘧啶-5-基)-7-(2-氟苯基)-2-氧代-1,2-二氢吡啶并[2,3-d]嘧啶-6-腈的合成The fourth step 4-((2S,5R)-4-acryloyl-2,5-dimethylpiperazin-1-yl)-1-(4,6-diisopropylpyrimidin-5-yl)- Synthesis of 7-(2-fluorophenyl)-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidine-6-carbonitrile
向反应瓶中加入(2R,5S)-4-(6-氰基-1-(4,6-二异丙基嘧啶-5-基)-7-(2-氟苯基)-2-氧代-1,2-二氢吡啶并[2,3-d]嘧啶-4-基)-2,5-二甲基哌嗪-1-羧酸叔丁酯(0.14g,0.22mmol)，二氯甲烷(2.5mL)和三氟乙酸(0.5mL)。反应体系室温反应0.5h，然后减压旋干。残余物中加入二氯甲烷(3.0mL)，三乙胺(0.07g,0.66mmol)。体系降温至-10℃，向其中滴入丙烯酰氯(0.04g,0.44mmol)，滴完后混合物转移至室温反应30min。待反应结束后，向体系中加入二氯甲烷(20mL)和水(20mL)，分液。水相经二氯甲烷(20mL×3)萃取，合并有机相，经饱和食盐水(40mL)洗涤，无水硫酸钠干燥，过滤，减压旋干。残余物经硅胶柱层析(DCM/MeOH(v/v)＝30/1)纯化，得到标题化合物为黄绿色固体(56mg,收率43.0％)。Add (2R,5S)-4-(6-cyano-1-(4,6-diisopropylpyrimidin-5-yl)-7-(2-fluorophenyl)-2-oxo Substituent-1,2-dihydropyrido[2,3-d]pyrimidin-4-yl)-2,5-dimethylpiperazine-1-carboxylic acid tert-butyl ester (0.14g, 0.22mmol), di Chloromethane (2.5 mL) and trifluoroacetic acid (0.5 mL). The reaction system was reacted at room temperature for 0.5 h, and then spin-dried under reduced pressure. Dichloromethane (3.0 mL), triethylamine (0.07 g, 0.66 mmol) were added to the residue. The system was cooled to -10°C, and acryloyl chloride (0.04 g, 0.44 mmol) was added dropwise thereto, and the mixture was transferred to room temperature for 30 min after the drop was completed. After the reaction was completed, dichloromethane (20 mL) and water (20 mL) were added to the system, and the layers were separated. The aqueous phase was extracted with dichloromethane (20 mL×3), and the combined organic phases were washed with saturated brine (40 mL), dried over anhydrous sodium sulfate, filtered, and spin-dried under reduced pressure. The residue was purified by silica gel column chromatography (DCM/MeOH (v/v)=30/1) to obtain the title compound as a yellow-green solid (56 mg, yield 43.0%).
MS(ESI,pos.ion)m/z:595.5[M+H]+.MS(ESI,pos.ion)m/z:595.5[M+H] + .
1H NMR(400MHz,CDCl3)δ(ppm)9.17(s,1H),8.37(s,1H),7.53-7.45(m,1H),7.25-7.15(m,3H),6.69-6.49(m,1H),6.47-6.34(m,1H),5.85-5.76(m,1H),5.19-4.89(m,2H),4.54-4.32(m,1H),4.07-3.97(m,1H),3.94-3.82(m,1H),3.79-3.42(m,1H),2.74-2.54(m,2H),1.54-1.40(m,4H),1.35-1.29(m,2H),1.24-1.20(m,6H),1.06-0.98(m,6H). 1 H NMR (400MHz, CDCl 3 ) δ (ppm) 9.17 (s, 1H), 8.37 (s, 1H), 7.53-7.45 (m, 1H), 7.25-7.15 (m, 3H), 6.69-6.49 (m ,1H),6.47-6.34(m,1H),5.85-5.76(m,1H),5.19-4.89(m,2H),4.54-4.32(m,1H),4.07-3.97(m,1H),3.94 -3.82(m,1H),3.79-3.42(m,1H),2.74-2.54(m,2H),1.54-1.40(m,4H),1.35-1.29(m,2H),1.24-1.20(m, 6H),1.06-0.98(m,6H).
实施例10 4-((2S,5R)-4-丙烯酰-2,5-二甲基哌嗪-1-基)-1-(4,6-二环丙基嘧啶-5-基)-7-(2-氟-4-甲基苯基)-2-氧代-1,2-二氢吡啶并[2,3-d]嘧啶-6-腈Example 10 4-((2S,5R)-4-acryloyl-2,5-dimethylpiperazin-1-yl)-1-(4,6-dicyclopropylpyrimidin-5-yl)- 7-(2-fluoro-4-methylphenyl)-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidine-6-carbonitrile
第一步(2R,5S)-4-(6-氯-1-(4,6-二环丙基嘧啶-5-基)-7-(2-氟-4-甲基苯基)-2-氧代-1,2-二氢吡啶并[2,3-d]嘧啶-4-基)-2,5-二甲基哌嗪-1-羧酸叔丁酯的合成The first step (2R,5S)-4-(6-chloro-1-(4,6-dicyclopropylpyrimidin-5-yl)-7-(2-fluoro-4-methylphenyl)-2 Synthesis of tert-butyl -oxo-1,2-dihydropyrido[2,3-d]pyrimidin-4-yl)-2,5-dimethylpiperazine-1-carboxylate
反应瓶中加入(2R,5S)-4-(6,7-二氯-1-(4,6-二环丙基嘧啶-5-基)-2-氧代-1,2-二氢吡啶并[2,3-d]嘧啶-4-基)-2,5-二甲基哌嗪-1-羧酸叔丁酯(0.20g,0.34mmol)，2-氟-4-甲基苯硼酸(0.08g,0.51mmol)，[1,1'-双(二苯基膦)二茂铁]二氯化钯二氯甲烷络合物(0.06g,0.07mmol)，乙酸钾(0.10g,1.02mmol)，1,4-二氧六环(30mL)和水(0.5mL)。反应体系氮气保护下，加热至95℃反应7小时。反应完成后，冷却至室温。反应体系减压浓缩除去一半反应液，然后加入水(50mL)，经乙酸乙酯(15mL×3)萃取。合并有机相，经饱和食盐水(20mL)洗涤，无水硫酸钠干燥，过滤，减压浓缩。残余物经硅胶柱层析法(PE/EtOAc(v/v)＝2/1)纯化，得到标题化合物为淡黄色固体(0.16g,收率72.6％)。Add (2R,5S)-4-(6,7-dichloro-1-(4,6-dicyclopropylpyrimidin-5-yl)-2-oxo-1,2-dihydropyridine to the reaction flask And[2,3-d]pyrimidin-4-yl)-2,5-dimethylpiperazine-1-carboxylate tert-butyl ester (0.20g, 0.34mmol), 2-fluoro-4-methylphenylboronic acid (0.08g, 0.51mmol), [1,1'-bis(diphenylphosphino)ferrocene] dichloropalladium dichloromethane complex (0.06g, 0.07mmol), potassium acetate (0.10g, 1.02 mmol), 1,4-dioxane (30 mL) and water (0.5 mL). Under the protection of nitrogen, the reaction system was heated to 95° C. for 7 hours. After the reaction was complete, it was cooled to room temperature. The reaction system was concentrated under reduced pressure to remove half of the reaction solution, then water (50 mL) was added, and extracted with ethyl acetate (15 mL×3). The organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE/EtOAc (v/v)=2/1) to obtain the title compound as a pale yellow solid (0.16 g, yield 72.6%).
MS(ESI,pos.ion)m/z:660.1[M+H]+.MS(ESI,pos.ion)m/z:660.1[M+H] + .
第二步(2R,5S)-4-(6-氰基-1-(4,6-二环丙基嘧啶-5-基)-7-(2-氟-4-甲基苯基)-2-氧代-1,2-二氢吡啶并[2,3-d]嘧啶-4-基)-2,5-二甲基哌嗪-1-羧酸叔丁酯的合成The second step (2R,5S)-4-(6-cyano-1-(4,6-dicyclopropylpyrimidin-5-yl)-7-(2-fluoro-4-methylphenyl)- Synthesis of tert-butyl 2-oxo-1,2-dihydropyrido[2,3-d]pyrimidin-4-yl)-2,5-dimethylpiperazine-1-carboxylate
微波管中加入(2R,5S)-4-(6-氯-1-(4,6-二环丙基嘧啶-5-基)-7-(2-氟-4-甲基苯基)-2-氧代-1,2-二氢吡啶并[2,3-d]嘧啶-4-基)-2,5-二甲基哌嗪-1-羧酸叔丁酯(0.16g,0.25mmol)，氰化锌(0.29g,2.50mmol)，二(三叔丁基膦)钯(0.38g,0.75mmol)，DMF(5mL)，三叔丁基膦的正己烷溶液(10％,0.5mL)。置于微波反应器中，135℃下反应7小时。反应完成后，降至室温，过滤。母液减压旋干，残余物中加入乙酸乙酯(10mL)，超声10min后，过滤。母液减压旋干。残余物经硅胶柱层析(PE/EtOAc(v/v)＝2/1)纯化，得到标题化合物为黄色固体(0.12g,收率75.0％)。Add (2R,5S)-4-(6-chloro-1-(4,6-dicyclopropylpyrimidin-5-yl)-7-(2-fluoro-4-methylphenyl)- 2-oxo-1,2-dihydropyrido[2,3-d]pyrimidin-4-yl)-2,5-dimethylpiperazine-1-carboxylic acid tert-butyl ester (0.16g, 0.25mmol ), zinc cyanide (0.29g, 2.50mmol), bis(tri-tert-butylphosphine) palladium (0.38g, 0.75mmol), DMF (5mL), n-hexane solution of tri-tert-butylphosphine (10%, 0.5mL ). Place in a microwave reactor and react at 135°C for 7 hours. After the reaction was completed, it was lowered to room temperature and filtered. The mother liquor was spin-dried under reduced pressure, and ethyl acetate (10 mL) was added to the residue, and filtered after ultrasonication for 10 min. The mother liquor was spin-dried under reduced pressure. The residue was purified by silica gel column chromatography (PE/EtOAc (v/v)=2/1) to obtain the title compound as a yellow solid (0.12 g, yield 75.0%).
MS(ESI,pos.ion)m/z:651.3[M+H]+.MS(ESI,pos.ion)m/z:651.3[M+H] + .
第三步4-((2S,5R)-4-丙烯酰-2,5-二甲基哌嗪-1-基)-1-(4,6-二环丙基嘧啶-5-基)-7-(2-氟-4-甲基苯基)-2-氧代-1,2-二氢吡啶并[2,3-d]嘧啶-6-腈的合成The third step 4-((2S,5R)-4-acryloyl-2,5-dimethylpiperazin-1-yl)-1-(4,6-dicyclopropylpyrimidin-5-yl)- Synthesis of 7-(2-fluoro-4-methylphenyl)-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidine-6-carbonitrile
反应瓶中加入(2R,5S)-4-(6-氰基-1-(4,6-二环丙基嘧啶-5-基)-7-(2-氟-4-甲基苯基)-2-氧代-1,2-二氢吡啶并[2,3-d]嘧啶-4-基)-2,5-二甲基哌嗪-1-羧酸叔丁酯(0.12g,0.19mmol)，二氯甲烷(15mL)和三氟乙酸(0.21mL,2.85mmol)。反应体系室温下反应6小时，减压蒸干。残余物中加入二氯甲烷(15mL)，DIPEA(0.05g,0.64mmol)，冷却至0℃，加入丙烯酰氯(0.02g,0.18mmol)。滴加完毕后，体系转移至室温反应1小时。然后反应液经水(20mL)洗涤，无水硫酸钠干燥，过滤，减压旋干。残余物经硅胶柱层析(EtOAc)纯化，得到标题化合物为米白色固体(0.09g,收率75.7％)。Add (2R,5S)-4-(6-cyano-1-(4,6-dicyclopropylpyrimidin-5-yl)-7-(2-fluoro-4-methylphenyl) to the reaction flask -2-Oxo-1,2-dihydropyrido[2,3-d]pyrimidin-4-yl)-2,5-dimethylpiperazine-1-carboxylic acid tert-butyl ester (0.12g, 0.19 mmol), dichloromethane (15 mL) and trifluoroacetic acid (0.21 mL, 2.85 mmol). The reaction system was reacted at room temperature for 6 hours, and evaporated to dryness under reduced pressure. Dichloromethane (15 mL), DIPEA (0.05 g, 0.64 mmol) were added to the residue, cooled to 0°C, and acryloyl chloride (0.02 g, 0.18 mmol) was added. After the dropwise addition, the system was transferred to room temperature to react for 1 hour. Then the reaction solution was washed with water (20 mL), dried over anhydrous sodium sulfate, filtered, and spin-dried under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc) to obtain the title compound as an off-white solid (0.09 g, yield 75.7%).
MS(ESI,pos.ion)m/z:605.5[M+H]+.MS(ESI,pos.ion)m/z:605.5[M+H] + .
1H NMR(400MHz,CDCl3)δ(ppm)8.82(s,1H),8.36(s,1H),7.28(s,1H),7.09-6.99(m,2H),6.71-6.52(m,1H),6.42(t,J＝14.5Hz,1H),5.88-5.78(m,1H),5.27-4.90(m,2H),4.53-4.32(m,1H),4.11-3.98(m,1H),3.89(s,1H),3.75(d,J＝14.2Hz,0.5H),3.48(d,J＝13.3Hz,0.5H),2.42(s,3H),1.83-1.73(m,2H),1.46-1.38(m,3H),1.29-1.25(m,3H),1.20-1.13(m,2H),1.02-0.96(m,2H),0.90-0.84(m,4H). 1 H NMR (400MHz, CDCl 3 ) δ (ppm) 8.82 (s, 1H), 8.36 (s, 1H), 7.28 (s, 1H), 7.09-6.99 (m, 2H), 6.71-6.52 (m, 1H ),6.42(t,J＝14.5Hz,1H),5.88-5.78(m,1H),5.27-4.90(m,2H),4.53-4.32(m,1H),4.11-3.98(m,1H), 3.89(s,1H),3.75(d,J=14.2Hz,0.5H),3.48(d,J=13.3Hz,0.5H),2.42(s,3H),1.83-1.73(m,2H),1.46 -1.38(m,3H),1.29-1.25(m,3H),1.20-1.13(m,2H),1.02-0.96(m,2H),0.90-0.84(m,4H).
实施例11(S)-4-(4-丙烯酰基-2-甲基哌嗪-1-基)-1-(4,6-二环丙基嘧啶-5-基)-7-(2-氟苯基)-2-氧代-1,2-二氢吡啶并[2,3-d]嘧啶-6-腈Example 11 (S)-4-(4-acryloyl-2-methylpiperazin-1-yl)-1-(4,6-dicyclopropylpyrimidin-5-yl)-7-(2- Fluorophenyl)-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidine-6-carbonitrile
第一步(S)-4-(6-氯-1-(4,6-二环丙基嘧啶-5-基)-7-(2-氟苯基)-2-氧代-1,2-二氢吡啶并[2,3-d]嘧啶-4-基)-3-甲基哌嗪-1-羧酸叔丁酯的合成The first step (S)-4-(6-chloro-1-(4,6-dicyclopropylpyrimidin-5-yl)-7-(2-fluorophenyl)-2-oxo-1,2 -Synthesis of tert-butyl dihydropyrido[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate
向反应瓶中加入6-氯-1-(4,6-二环丙基嘧啶-5-基)-7-(2-氟苯基)吡啶并[2,3-d]嘧啶-2,4(1H,3H)-二酮(0.20g,0.44mmol)，乙腈(4.0mL)，三氯氧磷(0.27g,1.76mmol)，二异丙基乙胺(0.23g,1.76mmol)。反应体系氮气保护下，加热至回流反应7h，然后冷却至室温，减压旋干。残余物中加入乙腈(6.0mL)，滴加三乙胺至体系pH＝9。向上述混合物中加入(S)-3-甲基哌嗪-1-羧酸叔丁酯(0.09g,0.44mmol)。体系加热至回流反应2h。加完后混合物升温至回流搅拌2h。反应完全后，冷却至室温，向其中加入水(20mL)，乙酸乙酯(20mL)，分液。水相经乙酸乙酯(20mL×3)萃取，合并有机相，饱和食盐水(40mL)洗涤，无水硫酸钠干燥，过滤，减压旋干。残余物经硅胶柱层析(PE/EtOAc(v/v)＝1/1)纯化，得到标题化合物为淡黄色固体(0.18g,收率66.1％)。Add 6-chloro-1-(4,6-dicyclopropylpyrimidin-5-yl)-7-(2-fluorophenyl)pyrido[2,3-d]pyrimidine-2,4 to the reaction flask (1H,3H)-Diketone (0.20 g, 0.44 mmol), acetonitrile (4.0 mL), phosphorus oxychloride (0.27 g, 1.76 mmol), diisopropylethylamine (0.23 g, 1.76 mmol). Under the protection of nitrogen, the reaction system was heated to reflux for 7 hours, then cooled to room temperature, and spin-dried under reduced pressure. Acetonitrile (6.0 mL) was added to the residue, and triethylamine was added dropwise until the system pH=9. To the above mixture was added (S)-tert-butyl 3-methylpiperazine-1-carboxylate (0.09 g, 0.44 mmol). The system was heated to reflux for 2h. After the addition was complete, the mixture was warmed to reflux and stirred for 2 h. After the reaction was complete, it was cooled to room temperature, and water (20 mL) and ethyl acetate (20 mL) were added thereto to separate the layers. The aqueous phase was extracted with ethyl acetate (20 mL×3), the organic phases were combined, washed with saturated brine (40 mL), dried over anhydrous sodium sulfate, filtered, and spin-dried under reduced pressure. The residue was purified by silica gel column chromatography (PE/EtOAc (v/v)=1/1) to obtain the title compound as a pale yellow solid (0.18 g, yield 66.1%).
MS(ESI,pos.ion)m/z:632.1[M+H]+.MS(ESI,pos.ion)m/z:632.1[M+H] + .
第二步(S)-4-(6-氰基-1-(4,6-二环丙基嘧啶-5-基)-7-(2-氟苯基)-2-氧代-1,2-二氢吡啶并[2,3-d]嘧啶-4-基)-3-甲基哌嗪-1-羧酸叔丁酯的合成The second step (S)-4-(6-cyano-1-(4,6-dicyclopropylpyrimidin-5-yl)-7-(2-fluorophenyl)-2-oxo-1, Synthesis of tert-butyl 2-dihydropyrido[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate
向微波管中加入(S)-4-(6-氯-1-(4,6-二环丙基嘧啶-5-基)-7-(2-氟苯基)-2-氧代-1,2-二氢吡啶并[2,3-d]嘧啶-4-基)-3-甲基哌嗪-1-羧酸叔丁酯(183.7mg,0.29mmol)，氰化锌(0.14g,1.16mmol)，二(三叔丁基膦)钯(59mg,0.12mmol)，三叔丁基膦四氟硼酸盐(8.4mg,0.03mmol)和N,N-二甲基甲酰胺(3.0mL)。反应体系氮气置换后，置于微波反应器中，140℃下反应7小时。反应完成后，降至室温，过滤，滤液减压旋干。残余物经硅胶柱层析(PE/EtOAc(v/v)＝3/1)纯化，得到标题化合物为黄绿色固体(0.11g,收率60.9％)。MS(ESI,pos.ion)m/z:623.2[M+H]+.Add (S)-4-(6-chloro-1-(4,6-dicyclopropylpyrimidin-5-yl)-7-(2-fluorophenyl)-2-oxo-1 to the microwave tube , tert-butyl 2-dihydropyrido[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate (183.7mg, 0.29mmol), zinc cyanide (0.14g, 1.16mmol), bis(tri-tert-butylphosphine) palladium (59mg, 0.12mmol), tri-tert-butylphosphine tetrafluoroborate (8.4mg, 0.03mmol) and N,N-dimethylformamide (3.0mL ). After replacing the reaction system with nitrogen, it was placed in a microwave reactor and reacted at 140° C. for 7 hours. After the reaction was completed, it was lowered to room temperature, filtered, and the filtrate was spin-dried under reduced pressure. The residue was purified by silica gel column chromatography (PE/EtOAc (v/v)=3/1) to obtain the title compound as a yellow-green solid (0.11 g, yield 60.9%). MS(ESI,pos.ion)m/z:623.2[M+H] + .
第三步(S)-4-(4-丙烯酰基-2-甲基哌嗪-1-基)-1-(4,6-二环丙基嘧啶-5-基)-7-(2-氟苯基)-2-氧代-1,2-二氢吡啶并[2,3-d]嘧啶-6-腈The third step (S)-4-(4-acryloyl-2-methylpiperazin-1-yl)-1-(4,6-dicyclopropylpyrimidin-5-yl)-7-(2- Fluorophenyl)-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidine-6-carbonitrile
向反应瓶中加入(S)-4-(6-氰基-1-(4,6-二环丙基嘧啶-5-基)-7-(2-氟苯基)-2-氧代-1,2-二氢吡啶并[2,3-d]嘧啶-4-基)-3-甲基哌嗪-1-羧酸叔丁酯(75mg,0.12mmol)，二氯甲烷(2.0mL)和三氟乙酸(0.5mL)。反应体系室温反应0.5h，然后减压旋干。残余物中加入二氯甲烷(3.0mL)，三乙胺(34mg,0.33mmol)。体系降温至-10℃，向其中滴入丙烯酰氯(20mg,0.22mmol)，滴完后混合物转移至室温反应0.5h。待反应结束后，向体系中加入二氯甲烷(20mL)和水(20mL)，分液。水相经二氯甲烷(20mL×3)萃取，合并有机相，经饱和食盐水(40mL)洗涤，无水硫酸钠干燥，过滤，减压旋干。残余物经硅胶柱层析(DCM/MeOH(v/v)＝30/1)纯化，得到标题化合物为黄绿色固体(45.3mg,收率70.4％)。Add (S)-4-(6-cyano-1-(4,6-dicyclopropylpyrimidin-5-yl)-7-(2-fluorophenyl)-2-oxo- tert-butyl 1,2-dihydropyrido[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate (75mg, 0.12mmol), dichloromethane (2.0mL) and trifluoroacetic acid (0.5 mL). The reaction system was reacted at room temperature for 0.5 h, and then spin-dried under reduced pressure. Dichloromethane (3.0 mL), triethylamine (34 mg, 0.33 mmol) were added to the residue. The system was cooled down to -10°C, and acryloyl chloride (20 mg, 0.22 mmol) was added dropwise thereto, and the mixture was transferred to room temperature for 0.5 h after the drop was completed. After the reaction was completed, dichloromethane (20 mL) and water (20 mL) were added to the system, and the layers were separated. The aqueous phase was extracted with dichloromethane (20 mL×3), and the combined organic phases were washed with saturated brine (40 mL), dried over anhydrous sodium sulfate, filtered, and spin-dried under reduced pressure. The residue was purified by silica gel column chromatography (DCM/MeOH (v/v)=30/1) to obtain the title compound as a yellow-green solid (45.3 mg, yield 70.4%).
MS(ESI,pos.ion)m/z:577.1[M+H]+.MS(ESI,pos.ion)m/z:577.1[M+H] + .
1H NMR(400MHz,CDCl3)δ(ppm)8.81(s,1H),8.35(s,1H),7.55-7.46(m,1H),7.41-7.36(m,1H),7.25-7.17(m,2H),6.59(s,1H),6.44-6.37(m,1H),5.84-5.78(m,1H),4.77(s,1H),4.61-4.25(m,2H),3.94-3.55(m,3H),3.34-3.01(m,1H),1.59-1.42(m,6H),1.20-1.11(m,2H),1.02-0.91(m,2H),0.91-0.76(m,3H).实施例12 4-((2R,6S)-4-丙烯酰基-2,6-二甲基哌嗪-1-基)-1-(4,6-二环丙基嘧啶-5-基)-7-(2-氟苯基)-2-氧代-1,2-二氢吡啶并[2,3-d]嘧啶-6-腈 1 H NMR (400MHz, CDCl 3 )δ(ppm)8.81(s,1H),8.35(s,1H),7.55-7.46(m,1H),7.41-7.36(m,1H),7.25-7.17(m ,2H),6.59(s,1H),6.44-6.37(m,1H),5.84-5.78(m,1H),4.77(s,1H),4.61-4.25(m,2H),3.94-3.55(m ,3H),3.34-3.01(m,1H),1.59-1.42(m,6H),1.20-1.11(m,2H),1.02-0.91(m,2H),0.91-0.76(m,3H).Implementation Example 12 4-((2R,6S)-4-acryloyl-2,6-dimethylpiperazin-1-yl)-1-(4,6-dicyclopropylpyrimidin-5-yl)-7 -(2-fluorophenyl)-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidine-6-carbonitrile
第一步(3S,5R)-4-(6-氯-1-(4,6-二环丙基嘧啶-5-基)-7-(2-氟苯基)-2-氧代-1,2-二氢吡啶并[2,3-d]嘧啶-4-基)-3,5-二甲基哌嗪-1-羧酸叔丁酯的合成The first step (3S,5R)-4-(6-chloro-1-(4,6-dicyclopropylpyrimidin-5-yl)-7-(2-fluorophenyl)-2-oxo-1 , Synthesis of tert-butyl 2-dihydropyrido[2,3-d]pyrimidin-4-yl)-3,5-dimethylpiperazine-1-carboxylate
向反应瓶中加入6-氯-1-(4,6-二环丙基嘧啶-5-基)-7-(2-氟苯基)吡啶并[2,3-d]嘧啶-2,4(1H,3H)-二酮(0.20g,0.44mmol)，乙腈(6.0mL)，三氯氧磷(0.27g,1.76mmol)和二异丙基乙胺(0.23g,1.76mmol)。反应体系氮气保护下，加热至回流反应2h，然后冷却至室温，减压旋干。残余物中加入乙腈(6.0mL)，滴加三乙胺至体系pH＝9。向上述混合物中加入(3S,5R)-3,5-二甲基哌嗪-1-羧酸叔丁酯(0.09g,0.44mmol)。体系加热至回流反应4h。反应完全后，冷却至室温，向其中加入水(20mL)，乙酸乙酯(20mL)，分液。水相经乙酸乙酯(20mL×3)萃取，合并有机相，饱和食盐水(40mL)洗涤，无水硫酸钠干燥，过滤，减压旋干。残余物经硅胶柱层析(PE/EtOAc(v/v)＝1/1)纯化，得到标题化合物为淡黄色固体(116mg,收率40.8％)。MS(ESI,pos.ion)m/z:646.2[M+H]+.Add 6-chloro-1-(4,6-dicyclopropylpyrimidin-5-yl)-7-(2-fluorophenyl)pyrido[2,3-d]pyrimidine-2,4 to the reaction flask (1H,3H)-Diketone (0.20 g, 0.44 mmol), acetonitrile (6.0 mL), phosphorus oxychloride (0.27 g, 1.76 mmol) and diisopropylethylamine (0.23 g, 1.76 mmol). Under the protection of nitrogen, the reaction system was heated to reflux for 2 h, then cooled to room temperature, and spin-dried under reduced pressure. Acetonitrile (6.0 mL) was added to the residue, and triethylamine was added dropwise until the system pH=9. To the above mixture was added tert-butyl (3S,5R)-3,5-dimethylpiperazine-1-carboxylate (0.09 g, 0.44 mmol). The system was heated to reflux for 4h. After the reaction was complete, it was cooled to room temperature, and water (20 mL) and ethyl acetate (20 mL) were added thereto to separate the layers. The aqueous phase was extracted with ethyl acetate (20 mL×3), the organic phases were combined, washed with saturated brine (40 mL), dried over anhydrous sodium sulfate, filtered, and spin-dried under reduced pressure. The residue was purified by silica gel column chromatography (PE/EtOAc (v/v)=1/1) to obtain the title compound as a light yellow solid (116 mg, yield 40.8%). MS(ESI,pos.ion)m/z:646.2[M+H] + .
第二步(3S,5R)-4-(6-氰基-1-(4,6-二环丙基嘧啶-5-基)-7-(2-氟苯基)-2-氧代-1,2-二氢吡啶并[2,3-d]嘧啶-4-基)-3,5-二甲基哌嗪-1-羧酸叔丁酯的合成The second step (3S,5R)-4-(6-cyano-1-(4,6-dicyclopropylpyrimidin-5-yl)-7-(2-fluorophenyl)-2-oxo- Synthesis of tert-butyl 1,2-dihydropyrido[2,3-d]pyrimidin-4-yl)-3,5-dimethylpiperazine-1-carboxylate
向微波管中加入(3S,5R)-4-(6-氯-1-(4,6-二环丙基嘧啶-5-基)-7-(2-氟苯基)-2-氧代-1,2-二氢吡啶并[2,3-d]嘧啶-4-基)-3,5-二甲基哌嗪-1-羧酸叔丁酯(116mg,0.18mmol)，氰化锌(0.08g,0.72mmol)，二(三叔丁基膦)钯(37.0mg,0.07mmol)，三叔丁基膦四氟硼酸盐(5.2mg,0.02mmol)和N,N-二甲基甲酰胺(2.0mL)。反应体系氮气置换后，置于微波反应器中，140℃下反应6小时。反应完成后，降至室温，过滤。滤液减压旋干。残余物经硅胶柱层析(PE/EtOAc(v/v)＝3/1)纯化，得到标题化合物为黄绿色固体(57mg,收率49.7％)。Add (3S,5R)-4-(6-chloro-1-(4,6-dicyclopropylpyrimidin-5-yl)-7-(2-fluorophenyl)-2-oxo to the microwave tube -1,2-dihydropyrido[2,3-d]pyrimidin-4-yl)-3,5-dimethylpiperazine-1-carboxylic acid tert-butyl ester (116mg, 0.18mmol), zinc cyanide (0.08g, 0.72mmol), bis(tri-tert-butylphosphine) palladium (37.0mg, 0.07mmol), tri-tert-butylphosphine tetrafluoroborate (5.2mg, 0.02mmol) and N,N-dimethyl Formamide (2.0 mL). After the reaction system was replaced with nitrogen, it was placed in a microwave reactor and reacted at 140° C. for 6 hours. After the reaction was completed, it was lowered to room temperature and filtered. The filtrate was spin-dried under reduced pressure. The residue was purified by silica gel column chromatography (PE/EtOAc (v/v)=3/1) to obtain the title compound as a yellow-green solid (57 mg, yield 49.7%).
MS(ESI,pos.ion)m/z:637.2[M+H]+.MS(ESI,pos.ion)m/z:637.2[M+H] + .
第三步4-((2R,6S)-4-丙烯酰基-2,6-二甲基哌嗪-1-基)-1-(4,6-二环丙基嘧啶-5-基)-7-(2-氟苯基)-2-氧代-1,2-二氢吡啶并[2,3-d]嘧啶-6-腈的合成The third step 4-((2R,6S)-4-acryloyl-2,6-dimethylpiperazin-1-yl)-1-(4,6-dicyclopropylpyrimidin-5-yl)- Synthesis of 7-(2-fluorophenyl)-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidine-6-carbonitrile
向反应瓶中加入(3S,5R)-4-(6-氰基-1-(4,6-二环丙基嘧啶-5-基)-7-(2-氟苯基)-2-氧代-1,2-二氢吡啶并[2,3-d]嘧啶-4-基)-3,5-二甲基哌嗪-1-羧酸叔丁酯(57mg,0.09mmol)，二氯甲烷(2.5mL)和三氟乙酸(0.5mL)。反应体系室温反应0.5h，然后减压旋干。残余物中加入二氯甲烷(4.0mL)，三乙胺(27mg,0.27mmol)。体系降温至-10℃，向其中滴入丙烯酰氯(16mg,0.18mmol)，滴完后混合物转移至室温反应0.5h。待反应结束后，向体系中加入二氯甲烷(10mL)和水(10mL)，分液。水相经二氯甲烷(10mL×3)萃取，合并有机相，经饱和食盐水(20mL)洗涤，无水硫酸钠干燥，过滤，减压旋干。残余物经硅胶柱层析(DCM/MeOH(v/v)＝30/1)纯化，得到标题化合物为黄绿色固体(19.1mg,收率36.3％)。Add (3S,5R)-4-(6-cyano-1-(4,6-dicyclopropylpyrimidin-5-yl)-7-(2-fluorophenyl)-2-oxo Substituent-1,2-dihydropyrido[2,3-d]pyrimidin-4-yl)-3,5-dimethylpiperazine-1-carboxylic acid tert-butyl ester (57mg, 0.09mmol), dichloro Methane (2.5 mL) and trifluoroacetic acid (0.5 mL). The reaction system was reacted at room temperature for 0.5 h, and then spin-dried under reduced pressure. Dichloromethane (4.0 mL), triethylamine (27 mg, 0.27 mmol) were added to the residue. The system was cooled down to -10°C, and acryloyl chloride (16 mg, 0.18 mmol) was added dropwise thereto, and the mixture was transferred to room temperature for 0.5 h after the drop was completed. After the reaction was completed, dichloromethane (10 mL) and water (10 mL) were added to the system, and the layers were separated. The aqueous phase was extracted with dichloromethane (10 mL×3), and the combined organic phases were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and spin-dried under reduced pressure. The residue was purified by silica gel column chromatography (DCM/MeOH (v/v)=30/1) to obtain the title compound as a yellow-green solid (19.1 mg, yield 36.3%).
MS(ESI,pos.ion)m/z:591.1[M+H]+.MS(ESI,pos.ion)m/z:591.1[M+H] + .
1H NMR(400MHz,CDCl3)δ(ppm)8.79(s,1H),8.44(s,1H),7.55-7.46(m,1H),7.41-7.33(m,1H),7.25-7.15(m,2H),6.70-6.57(m,1H),6.50-6.40(m,1H),5.89-5.79(m,1H),5.39-5.21(m,1H),4.98-4.82(m,1H),4.66-4.48(m,1H),4.01-3.83(m,1H),3.69-3.53(m,1H),3.28-3.06(m,1H),1.74-1.60(m,6H),1.27-1.18(m,4H),1.18-1.10(m,2H),1.02-0.92(m,2H),0.89-0.77(m,2H). 1 H NMR (400MHz, CDCl 3 ) δ (ppm) 8.79 (s, 1H), 8.44 (s, 1H), 7.55-7.46 (m, 1H), 7.41-7.33 (m, 1H), 7.25-7.15 (m ,2H),6.70-6.57(m,1H),6.50-6.40(m,1H),5.89-5.79(m,1H),5.39-5.21(m,1H),4.98-4.82(m,1H),4.66 -4.48(m,1H),4.01-3.83(m,1H),3.69-3.53(m,1H),3.28-3.06(m,1H),1.74-1.60(m,6H),1.27-1.18(m, 4H),1.18-1.10(m,2H),1.02-0.92(m,2H),0.89-0.77(m,2H).
实施例13 4-(4-丙烯酰基哌嗪-1-基)-1-(4,6-二环丙基嘧啶-5-基)-7-(2-氟苯基)-2-氧代-1,2-二氢吡啶并[2,3-d]嘧啶-6-腈Example 13 4-(4-acryloylpiperazin-1-yl)-1-(4,6-dicyclopropylpyrimidin-5-yl)-7-(2-fluorophenyl)-2-oxo -1,2-Dihydropyrido[2,3-d]pyrimidine-6-carbonitrile
第一步4-(6-氯-1-(4,6-二环丙基嘧啶-5-基)-7-(2-氟苯基)-2-氧代-1,2-二氢吡啶并[2,3-d]嘧啶-4-基)哌嗪-1-羧酸叔丁酯的合成The first step 4-(6-chloro-1-(4,6-dicyclopropylpyrimidin-5-yl)-7-(2-fluorophenyl)-2-oxo-1,2-dihydropyridine Synthesis of tert-butyl [2,3-d]pyrimidin-4-yl)piperazine-1-carboxylate
向反应瓶中加入6-氯-1-(4,6-二环丙基嘧啶-5-基)-7-(2-氟苯基)吡啶并[2,3-d]嘧啶-2,4(1H,3H)-二酮(0.25g,0.56mmol)，乙腈(6.0mL)，三氯氧磷(0.34g,2.24mmol)和二异丙基乙胺(0.29g,2.24mmol)。反应体系氮气保护下，加热至回流反应2h，然后冷却至室温，减压旋干。残余物中加入乙腈(6.0mL)，滴加三乙胺至体系pH＝9。向上述混合物中加入哌嗪-1-羧酸叔丁酯(0.13g,0.70mmol)，加完后体系加热至回流搅拌4h。反应完全后，冷却至室温，向其中加入水(20mL)，乙酸乙酯(20mL)，分液。水相经乙酸乙酯(20mL×3)萃取，合并有机相，饱和食盐水(40mL)洗涤，无水硫酸钠干燥，过滤，减压旋干。残余物经硅胶柱层析(PE/EtOAc(v/v)＝3/1)纯化，得到标题化合物为淡黄色固体(173mg,收率50.0％)。Add 6-chloro-1-(4,6-dicyclopropylpyrimidin-5-yl)-7-(2-fluorophenyl)pyrido[2,3-d]pyrimidine-2,4 to the reaction flask (1H,3H)-Diketone (0.25g, 0.56mmol), acetonitrile (6.0mL), phosphorus oxychloride (0.34g, 2.24mmol) and diisopropylethylamine (0.29g, 2.24mmol). Under the protection of nitrogen, the reaction system was heated to reflux for 2 h, then cooled to room temperature, and spin-dried under reduced pressure. Acetonitrile (6.0 mL) was added to the residue, and triethylamine was added dropwise until the system pH=9. To the above mixture was added piperazine-1-carboxylate tert-butyl ester (0.13 g, 0.70 mmol), and after the addition, the system was heated to reflux and stirred for 4 h. After the reaction was complete, it was cooled to room temperature, and water (20 mL) and ethyl acetate (20 mL) were added thereto to separate the layers. The aqueous phase was extracted with ethyl acetate (20 mL×3), the organic phases were combined, washed with saturated brine (40 mL), dried over anhydrous sodium sulfate, filtered, and spin-dried under reduced pressure. The residue was purified by silica gel column chromatography (PE/EtOAc (v/v)=3/1) to obtain the title compound as a pale yellow solid (173 mg, yield 50.0%).
MS(ESI,pos.ion)m/z:618.1[M+H]+.MS(ESI,pos.ion)m/z:618.1[M+H] + .
第二步4-(6-氰基-1-(4,6-二环丙基嘧啶-5-基)-7-(2-氟苯基)-2-氧代-1,2-二氢吡啶并[2,3-d]嘧啶-4-基)哌嗪-1-羧酸叔丁酯的合成The second step 4-(6-cyano-1-(4,6-dicyclopropylpyrimidin-5-yl)-7-(2-fluorophenyl)-2-oxo-1,2-dihydro Synthesis of tert-butyl pyrido[2,3-d]pyrimidin-4-yl)piperazine-1-carboxylate
向微波管中加入4-(6-氯-1-(4,6-二环丙基嘧啶-5-基)-7-(2-氟苯基)-2-氧代-1,2-二氢吡啶并[2,3-d]嘧啶-4-基)哌嗪-1-羧酸叔丁酯(173mg,0.28mmol)，氰化锌(0.13g,1.11mmol)，二(三叔丁基膦)钯(57mg,0.11mmol)，三叔丁基膦四氟硼酸盐(8.1mg,0.03mmol)和N,N-二甲基甲酰胺(3.0mL)。反应体系氮气置换后，置于微波反应器中，140℃下反应6小时。反应完成后，降至室温，过滤，母液减压旋干。残余物经硅胶柱层析(PE/EtOAc(v/v)＝3/1)纯化，得到标题化合物为黄绿色固体(85mg,收率49.9％)。Add 4-(6-chloro-1-(4,6-dicyclopropylpyrimidin-5-yl)-7-(2-fluorophenyl)-2-oxo-1,2-di Hydropyrido[2,3-d]pyrimidin-4-yl)piperazine-1-carboxylate tert-butyl ester (173mg, 0.28mmol), zinc cyanide (0.13g, 1.11mmol), di(tri-tert-butyl Phosphine) palladium (57 mg, 0.11 mmol), tri-tert-butylphosphine tetrafluoroborate (8.1 mg, 0.03 mmol) and N,N-dimethylformamide (3.0 mL). After the reaction system was replaced with nitrogen, it was placed in a microwave reactor and reacted at 140° C. for 6 hours. After the reaction was completed, it was lowered to room temperature, filtered, and the mother liquor was spin-dried under reduced pressure. The residue was purified by silica gel column chromatography (PE/EtOAc (v/v)=3/1) to obtain the title compound as a yellow-green solid (85 mg, yield 49.9%).
MS(ESI,pos.ion)m/z:609.5[M+H]+.MS(ESI,pos.ion)m/z:609.5[M+H] + .
第三步4-(4-丙烯酰基哌嗪-1-基)-1-(4,6-二环丙基嘧啶-5-基)-7-(2-氟苯基)-2-氧代-1,2-二氢吡啶并[2,3-d]嘧啶-6-腈的合成The third step 4-(4-acryloylpiperazin-1-yl)-1-(4,6-dicyclopropylpyrimidin-5-yl)-7-(2-fluorophenyl)-2-oxo Synthesis of -1,2-dihydropyrido[2,3-d]pyrimidine-6-carbonitrile
向反应瓶中加入4-(6-氰基-1-(4,6-二环丙基嘧啶-5-基)-7-(2-氟苯基)-2-氧代-1,2-二氢吡啶并[2,3-d]嘧啶-4-基)哌嗪-1-羧酸叔丁酯(85mg,0.09mmol)，二氯甲烷(2.5mL)和三氟乙酸(0.5mL)。反应体系室温反应0.5h，然后减压旋干。残余物中加入二氯甲烷(4.0mL)，三乙胺(42mg,0.42mmol)。体系降温至-10℃，向其中滴入丙烯酰氯(25mg,0.28mmol)。滴完后混合物转移至室温反应0.5h。待反应结束后，向体系中加入二氯甲烷(20mL)和水(20mL)，分液。水相经二氯甲烷(20mL×3)萃取，合并有机相，经饱和食盐水(40mL)洗涤，无水硫酸钠干燥，过滤，减压旋干。残余物经硅胶柱层析(DCM/MeOH(v/v)＝30/1)纯化，得到标题化合物为黄绿色固体(36mg,收率45.7％)。Add 4-(6-cyano-1-(4,6-dicyclopropylpyrimidin-5-yl)-7-(2-fluorophenyl)-2-oxo-1,2- Dihydropyrido[2,3-d]pyrimidin-4-yl)piperazine-1-carboxylic acid tert-butyl ester (85 mg, 0.09 mmol), dichloromethane (2.5 mL) and trifluoroacetic acid (0.5 mL). The reaction system was reacted at room temperature for 0.5 h, and then spin-dried under reduced pressure. Dichloromethane (4.0 mL), triethylamine (42 mg, 0.42 mmol) were added to the residue. The system was cooled to -10°C, and acryloyl chloride (25mg, 0.28mmol) was added dropwise thereto. After dropping, the mixture was transferred to room temperature for 0.5 h. After the reaction was completed, dichloromethane (20 mL) and water (20 mL) were added to the system, and the layers were separated. The aqueous phase was extracted with dichloromethane (20 mL×3), and the combined organic phases were washed with saturated brine (40 mL), dried over anhydrous sodium sulfate, filtered, and spin-dried under reduced pressure. The residue was purified by silica gel column chromatography (DCM/MeOH (v/v)=30/1) to obtain the title compound as a yellow-green solid (36 mg, yield 45.7%).
MS(ESI,pos.ion)m/z:563.2[M+H]+.MS(ESI,pos.ion)m/z:563.2[M+H] + .
1H NMR(400MHz,CDCl3)δ(ppm)8.82(s,1H),8.46(s,1H),7.57-7.48(m,1H),7.44-7.38(m,1H),7.27-7.19(m,2H),6.68-6.56(m,1H),6.47-6.39(m,1H),5.88-5.81(m,1H),4.19-4.06(m,4H),4.01-3.85(m,4H),1.60-1.52(m,2H),1.26-1.14(m,4H),1.04-0.95(m,2H),0.92-0.80(m,2H). 1 H NMR (400MHz, CDCl 3 )δ(ppm)8.82(s,1H),8.46(s,1H),7.57-7.48(m,1H),7.44-7.38(m,1H),7.27-7.19(m ,2H),6.68-6.56(m,1H),6.47-6.39(m,1H),5.88-5.81(m,1H),4.19-4.06(m,4H),4.01-3.85(m,4H),1.60 -1.52(m,2H),1.26-1.14(m,4H),1.04-0.95(m,2H),0.92-0.80(m,2H).
实施例14 4-((2S,5R)-4-丙烯酰基-2,5-二甲基哌嗪-1-基)-7-(5-氨基-2-(三氟甲基)苯基)-1-(4,6-二环丙基嘧啶-5-基)-2-氧代-1,2-二氢喹唑啉-6-腈Example 14 4-((2S,5R)-4-acryloyl-2,5-dimethylpiperazin-1-yl)-7-(5-amino-2-(trifluoromethyl)phenyl) -1-(4,6-dicyclopropylpyrimidin-5-yl)-2-oxo-1,2-dihydroquinazoline-6-carbonitrile
第一步4-氯-2-氟-5-碘苯甲酰胺的合成The first step of synthesis of 4-chloro-2-fluoro-5-iodobenzamide
向反应瓶中依次加入4-氯-2-氟-5-碘苯甲酸(5.00g,16.64mmol)，二氯甲烷(50.0mL)，N,N-二甲基甲酰胺(0.06g,0.83mmol)和草酰氯(6.33g,49.87mmol)。体系室温反应2h，随后减压旋干溶剂，残余物中加入二氧六环(15mL)稀释。稀释后的溶液滴加到浓氨水(30mL)中。滴完后反应体系室温反应1h。过滤，所得固体经水(50mL)洗涤，真空干燥，得到标题化合物为灰白色固体(4.50g,收率90.30％)。Add 4-chloro-2-fluoro-5-iodobenzoic acid (5.00g, 16.64mmol), dichloromethane (50.0mL), N,N-dimethylformamide (0.06g, 0.83mmol ) and oxalyl chloride (6.33 g, 49.87 mmol). The system was reacted at room temperature for 2 h, and then the solvent was spin-dried under reduced pressure, and dioxane (15 mL) was added to the residue for dilution. The diluted solution was added dropwise to concentrated aqueous ammonia (30 mL). After dropping, the reaction system reacted at room temperature for 1 h. After filtration, the resulting solid was washed with water (50 mL) and dried in vacuo to obtain the title compound as an off-white solid (4.50 g, yield 90.30%).
第二步4-氯-N-((4,6-二环丙基嘧啶-5-基)氨基甲酰基)-2-氟-5-碘苯甲酰胺的合成The second step is the synthesis of 4-chloro-N-((4,6-dicyclopropylpyrimidin-5-yl)carbamoyl)-2-fluoro-5-iodobenzamide
向反应瓶中依次加入4-氯-2-氟-5-碘苯甲酰胺(0.80g,2.67mmol)，1,2-二氯乙烷(10.00mL)，草酰氯(0.51g,4.00mmol)。反应体系氮气置换后，加热至80℃反应1h。反应结束后，将上述体系减压浓缩，加入无水乙腈(10mL)稀释，降温至10℃，向其中滴入无水四氢呋喃(2.0mL)稀释的4,6-二环丙基嘧啶-5-胺(0.47g,2.67mmol)。滴完后体系转移至室温反应1.5h。反应结束后，将上述体系过滤，滤饼经乙腈(5mL)洗涤，干燥，得到标题化合物为白色固体(1.18g,收率88.27％)。Add 4-chloro-2-fluoro-5-iodobenzamide (0.80g, 2.67mmol), 1,2-dichloroethane (10.00mL), oxalyl chloride (0.51g, 4.00mmol) to the reaction flask successively . After replacing the reaction system with nitrogen, it was heated to 80° C. for 1 h. After the reaction, the above system was concentrated under reduced pressure, diluted with anhydrous acetonitrile (10 mL), cooled to 10°C, and 4,6-dicyclopropylpyrimidine-5- Amine (0.47 g, 2.67 mmol). After dropping, the system was transferred to room temperature to react for 1.5h. After the reaction, the above system was filtered, the filter cake was washed with acetonitrile (5 mL), and dried to obtain the title compound as a white solid (1.18 g, yield 88.27%).
MS(ESI,pos.ion)m/z:501.2[M+H]+.MS(ESI,pos.ion)m/z:501.2[M+H] + .
第三步7-氯-1-(4,6-二环丙基嘧啶-5-基)-6-碘喹唑啉-2,4(1H,3H)-二酮的合成The third step is the synthesis of 7-chloro-1-(4,6-dicyclopropylpyrimidin-5-yl)-6-iodoquinazoline-2,4(1H,3H)-dione
向反应瓶中依次加入4-氯-N-((4,6-二环丙基嘧啶-5-基)氨基甲酰基)-2-氟-5-碘苯甲酰胺(1.18g,2.36mmol)，四氢呋喃(20.0mL)。体系降温至-10℃，向其中滴入双(三甲基硅基)氨基钠(5.2mL,5.2mmol,1.0mol/L)，滴完后体系转移至室温反应2h。反应结束后，向上述体系中依次加入水(30mL)，乙酸乙酯(10mL)，经柠檬酸固体调节至pH＝5，分液。水相经乙酸乙酯(20mL×3)萃取。合并有机相，经饱和食盐水(60mL)洗涤，无水硫酸钠干燥，过滤，减压旋干，得到标题化合物为棕黄色固体(1.13g,收率99.61％)。MS(ESI,pos.ion)m/z:481.3[M+H]+.Add 4-chloro-N-((4,6-dicyclopropylpyrimidin-5-yl)carbamoyl)-2-fluoro-5-iodobenzamide (1.18g, 2.36mmol) successively to the reaction flask , tetrahydrofuran (20.0 mL). The system was cooled to -10°C, sodium bis(trimethylsilyl)amide (5.2 mL, 5.2 mmol, 1.0 mol/L) was added dropwise, and the system was transferred to room temperature for 2 hours after the drop was completed. After the reaction, water (30 mL) and ethyl acetate (10 mL) were added to the above system in sequence, and the pH was adjusted to 5 with solid citric acid, and the liquids were separated. The aqueous phase was extracted with ethyl acetate (20 mL×3). The organic phases were combined, washed with saturated brine (60 mL), dried over anhydrous sodium sulfate, filtered, and spin-dried under reduced pressure to obtain the title compound as a tan solid (1.13 g, yield 99.61%). MS(ESI,pos.ion)m/z:481.3[M+H] + .
第四步(2R,5S)-4-(7-氯-1-(4,6-二环丙基嘧啶-5-基)-6-碘-2-氧代-1,2-二氢喹唑啉-4-基)-2,5-二甲基哌嗪-1-羧酸叔丁酯的合成The fourth step (2R,5S)-4-(7-chloro-1-(4,6-dicyclopropylpyrimidin-5-yl)-6-iodo-2-oxo-1,2-dihydroquinone Synthesis of tert-butyl oxazolin-4-yl)-2,5-dimethylpiperazine-1-carboxylate
向反应瓶中依次加入7-氯-1-(4,6-二环丙基嘧啶-5-基)-6-碘喹唑啉-2,4(1H,3H)-二酮(1.13g,2.35mmol)，乙腈(12.0mL)，二异丙基乙胺(1.52g,11.75mmol)和三氯氧磷(1.80g,11.75mmol)。体系体系加热至回流反应2h，然后减压旋干。残余物中加入乙腈(15.0mL)，二异丙基乙胺(0.90g,7.00mmol)，(2R,5S)-2,5-二甲基哌嗪-1-羧酸叔丁酯(0.45g,2.10mmol)。体系氮气氛围下加热至回流反应过夜。反应结束后，冷却至室温，向其中加入水(30mL)和乙酸乙酯(30mL)。分液，经乙酸乙酯(30mL×2)萃取，合并有机相，经饱和食盐水(100mL)洗涤，无水硫酸钠干燥，过滤，减压旋干。残余物经硅胶柱层析(EtOAc/PE(v/v)＝1/2)纯化，得到标题化合物为棕黄色固体(0.54g,收率34.09％)。Add 7-chloro-1-(4,6-dicyclopropylpyrimidin-5-yl)-6-iodoquinazoline-2,4(1H,3H)-dione (1.13g, 2.35mmol), acetonitrile (12.0mL), diisopropylethylamine (1.52g, 11.75mmol) and phosphorus oxychloride (1.80g, 11.75mmol). The system was heated to reflux for 2 hours, and then spin-dried under reduced pressure. Acetonitrile (15.0 mL), diisopropylethylamine (0.90 g, 7.00 mmol), (2R,5S)-2,5-dimethylpiperazine-1-carboxylic acid tert-butyl ester (0.45 g , 2.10mmol). The system was heated to reflux overnight under a nitrogen atmosphere. After the reaction was completed, it was cooled to room temperature, and water (30 mL) and ethyl acetate (30 mL) were added thereto. The layers were separated, extracted with ethyl acetate (30 mL×2), the organic phases were combined, washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and spin-dried under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc/PE (v/v)=1/2) to obtain the title compound as a tan solid (0.54 g, yield 34.09%).
MS(ESI,pos.ion)m/z:677.3[M+H]+.MS(ESI,pos.ion)m/z:677.3[M+H] + .
第五步(2R,5S)-4-(7-氯-6-氰基-1-(4,6-二环丙基嘧啶-5-基)-2-氧代-1,2-二氢喹唑啉-4-基)-2,5-二甲基哌嗪-1-羧酸叔丁酯的合成The fifth step (2R,5S)-4-(7-chloro-6-cyano-1-(4,6-dicyclopropylpyrimidin-5-yl)-2-oxo-1,2-dihydro Synthesis of tert-butyl quinazolin-4-yl)-2,5-dimethylpiperazine-1-carboxylate
向反应瓶中依次加入(2R,5S)-4-(7-氯-1-(4,6-二环丙基嘧啶-5-基)-6-碘-2-氧代-1,2-二氢喹唑啉-4-基)-2,5-二甲基哌嗪-1-羧酸叔丁酯(365.8mg,0.54mmol)，氰化锌(29.0mg,0.25mmol)，双(三叔丁基苯基膦)钯(27.6mg,0.05mmol)，三叔丁基磷四氟硼酸盐(15.7mg,0.05mmol)，N,N-二甲基甲酰胺(8.0mL)。反应体系氮气保护下，加热至60℃反应4h。反应结束后，过滤，所得滤液减压浓缩。残余物中加入乙酸乙酯(20mL)和水(20mL)，分液。水相经乙酸乙酯(20mL×3)萃取，合并有机相，经饱和食盐水(50mL)洗涤，无水硫酸钠干燥，过滤，减压旋干。残余物经硅胶柱层析(EtOAc/PE(v/v)＝1/3)纯化，得到标题化合物为浅棕黄色固体(192.5mg,收率61.88％)。Add (2R,5S)-4-(7-chloro-1-(4,6-dicyclopropylpyrimidin-5-yl)-6-iodo-2-oxo-1,2- Dihydroquinazolin-4-yl)-2,5-dimethylpiperazine-1-carboxylic acid tert-butyl ester (365.8mg, 0.54mmol), zinc cyanide (29.0mg, 0.25mmol), bis(tri tert-butylphenylphosphine) palladium (27.6 mg, 0.05 mmol), tri-tert-butylphosphine tetrafluoroborate (15.7 mg, 0.05 mmol), N,N-dimethylformamide (8.0 mL). Under the protection of nitrogen, the reaction system was heated to 60° C. for 4 h. After the reaction was completed, it was filtered, and the obtained filtrate was concentrated under reduced pressure. Ethyl acetate (20 mL) and water (20 mL) were added to the residue, and the layers were separated. The aqueous phase was extracted with ethyl acetate (20 mL×3), the organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and spin-dried under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc/PE (v/v)=1/3) to obtain the title compound as a light brown solid (192.5 mg, yield 61.88%).
MS(ESI,pos.ion)m/z:576.3[M+H]+.MS(ESI,pos.ion)m/z:576.3[M+H] + .
第六步(2R,5S)-4-(7-(5-氨基-2-(三氟甲基)苯基)-6-氰基-1-(4,6-二环丙基嘧啶-5-基)-2-氧代-1,2-二氢喹唑啉-4-基)-2,5-二甲基哌嗪-1-羧酸叔丁酯的合成The sixth step (2R,5S)-4-(7-(5-amino-2-(trifluoromethyl)phenyl)-6-cyano-1-(4,6-dicyclopropylpyrimidine-5 Synthesis of -yl)-2-oxo-1,2-dihydroquinazolin-4-yl)-2,5-dimethylpiperazine-1-carboxylic acid tert-butyl ester
向反应瓶中依次加入(2R,5S)-4-(7-氯-6-氰基-1-(4,6-二环丙基嘧啶-5-基)-2-氧代-1,2-二氢喹唑啉-4-基)-2,5-二甲基哌嗪-1-羧酸叔丁酯(172.0mg,0.30mmol)，3-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊-2-基)-4-(三氟甲基)苯胺(172.2mg,0.60mmol)，[1,1'-双(二苯基膦)二茂铁]二氯化钯二氯甲烷络合物(12.2mg,0.02mmol)，碳酸钠(95.4mg,0.90mmol)，1,4-二氧六环(4.0mL)和水(1.0mL)。反应体系氮气保护下加热至回流反应过夜。反应结束后，冷却至室温，向其中加入水(30mL)和乙酸乙酯(30mL)，分液。水相经乙酸乙酯(30mL×3)萃取，合并有机相，经饱和食盐水(60mL)洗涤，无水硫酸钠干燥，过滤，减压旋干。残余物经硅胶柱层析(EtOAc/PE(v/v)＝1/1)纯化，得到标题化合物为淡黄色固体(84.5mg,收率40.20％)。MS(ESI,pos.ion)m/z:701.3[M+H]+.Add (2R,5S)-4-(7-chloro-6-cyano-1-(4,6-dicyclopropylpyrimidin-5-yl)-2-oxo-1,2 -Dihydroquinazolin-4-yl)-2,5-dimethylpiperazine-1-carboxylic acid tert-butyl ester (172.0mg, 0.30mmol), 3-(4,4,5,5-tetramethyl 1,3,2-dioxaborol-2-yl)-4-(trifluoromethyl)aniline (172.2mg, 0.60mmol), [1,1'-bis(diphenylphosphine) Ferrocene]palladium dichloride dichloromethane complex (12.2 mg, 0.02 mmol), sodium carbonate (95.4 mg, 0.90 mmol), 1,4-dioxane (4.0 mL) and water (1.0 mL) . The reaction system was heated to reflux overnight under the protection of nitrogen. After the reaction was completed, it was cooled to room temperature, and water (30 mL) and ethyl acetate (30 mL) were added thereto to separate the layers. The aqueous phase was extracted with ethyl acetate (30 mL×3), the organic phases were combined, washed with saturated brine (60 mL), dried over anhydrous sodium sulfate, filtered, and spin-dried under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc/PE (v/v)=1/1) to obtain the title compound as a light yellow solid (84.5 mg, yield 40.20%). MS(ESI,pos.ion)m/z:701.3[M+H] + .
第七步4-((2S,5R)-4-丙烯酰基-2,5-二甲基哌嗪-1-基)-7-(5-氨基-2-(三氟甲基)苯基)-1-(4,6-二环丙基嘧啶-5-基)-2-氧代-1,2-二氢喹唑啉-6-甲腈的合成The seventh step 4-((2S,5R)-4-acryloyl-2,5-dimethylpiperazin-1-yl)-7-(5-amino-2-(trifluoromethyl)phenyl) -Synthesis of 1-(4,6-dicyclopropylpyrimidin-5-yl)-2-oxo-1,2-dihydroquinazoline-6-carbonitrile
向反应瓶中依次加入(2R,5S)-4-(7-(5-氨基-2-(三氟甲基)苯基)-6-氰基-1-(4,6-二环丙基嘧啶-5-基)-2-氧代-1,2-二氢喹唑啉-4-基)-2,5-二甲基哌嗪-1-羧酸叔丁酯(84.5mg,0.12mmol)，二氯甲烷(3.0mL)和三氟乙酸(1.0mL)。反应体系室温反应1h。待原料反应完全后，减压旋干。残余物中加入二氯甲烷(3.0mL)，三乙胺(36.4mg,0.36mmol)，降温至-10℃。向其中滴入丙烯酰氯(10.8mg,0.12mmol)，滴完后体系转移至室温反应0.5h。反应完全后，向其中加入水(10mL)和二氯甲烷(10mL)，分液。水相经二氯甲烷(10mL×3)萃取，合并有机相，经饱和食盐水(30mL)洗涤，无水硫酸钠干燥，过滤，减压旋干。残余物经硅胶柱层析(DCM/MeOH(v/v)＝30/1)纯化，得到标题化合物为淡黄色固体(25.3mg,收率32.20％)。Add (2R,5S)-4-(7-(5-amino-2-(trifluoromethyl)phenyl)-6-cyano-1-(4,6-dicyclopropyl) sequentially to the reaction flask Pyrimidin-5-yl)-2-oxo-1,2-dihydroquinazolin-4-yl)-2,5-dimethylpiperazine-1-carboxylic acid tert-butyl ester (84.5mg, 0.12mmol ), dichloromethane (3.0 mL) and trifluoroacetic acid (1.0 mL). The reaction system was reacted at room temperature for 1 h. After the reaction of the raw materials is complete, spin dry under reduced pressure. Dichloromethane (3.0 mL) and triethylamine (36.4 mg, 0.36 mmol) were added to the residue, and the temperature was lowered to -10°C. Acryloyl chloride (10.8 mg, 0.12 mmol) was added dropwise thereto, and the system was transferred to room temperature to react for 0.5 h after the drop was completed. After the reaction was complete, water (10 mL) and dichloromethane (10 mL) were added thereto, and the layers were separated. The aqueous phase was extracted with dichloromethane (10 mL×3), and the combined organic phases were washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and spin-dried under reduced pressure. The residue was purified by silica gel column chromatography (DCM/MeOH (v/v)=30/1) to obtain the title compound as a pale yellow solid (25.3 mg, yield 32.20%).
MS(ESI,pos.ion)m/z:655.5[M+H]+.MS(ESI,pos.ion)m/z:655.5[M+H] + .
实施例15 4-((2S,5R)-4-丙烯酰基-2,5-二甲基哌嗪-1-基)-7-(5-氨基-2-(三氟甲基)苯基)-1-(4,6-二环丙基嘧啶-5-基)-2-氧代-1,2-二氢吡啶并[2,3-d]嘧啶-6-腈Example 15 4-((2S,5R)-4-acryloyl-2,5-dimethylpiperazin-1-yl)-7-(5-amino-2-(trifluoromethyl)phenyl) -1-(4,6-dicyclopropylpyrimidin-5-yl)-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidine-6-carbonitrile
第一步(2R,5S)-4-(7-(5-氨基-2-(三氟甲基)苯基)-6-氯-1-(4,6-二环丙基嘧啶-5-基)-2-氧代-1,2-二氢吡啶并[2,3-d]嘧啶-4-基)-2,5-二甲基哌嗪-1-羧酸叔丁酯的合成The first step (2R,5S)-4-(7-(5-amino-2-(trifluoromethyl)phenyl)-6-chloro-1-(4,6-dicyclopropylpyrimidine-5- Synthesis of tert-butyl)-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidin-4-yl)-2,5-dimethylpiperazine-1-carboxylate
向反应瓶中依次加入(2R,5S)-4-(6,7-二氯-1-(4,6-二环丙基嘧啶-5-基)-2-氧代-1,2-二氢吡啶并[2,3-d]嘧啶-4-基)-2,5-二甲基哌嗪-1-羧酸叔丁酯(407mg,0.69mmol)，3-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊-2-基)-4-(三氟甲基)苯胺(238mg,0.83mmol)，[1,1'-双(二苯基膦)二茂铁]二氯化钯二氯甲烷络合物(28.2mg,0.03mmol)，碳酸钠(205mg,2.08mmol)，1,4-二氧六环(8.0mL)和水(2.0mL)。反应体系经氮气置换后，在氮气保护下。加热至回流反应过夜。反应完成后，冷却至室温，向其中加入水(20mL)和乙酸乙酯(20mL)，所得混合物分液后水相经乙酸乙酯(20mL×3)萃取。合并有机相，饱和食盐水(40mL)洗涤，无水硫酸钠干燥，过滤，减压旋干。残余物经硅胶柱层析(EtOAc/PE(v/v)＝1/1)纯化，得到标题化合物为黄色固体(310mg,收率63.17％)。Add (2R,5S)-4-(6,7-dichloro-1-(4,6-dicyclopropylpyrimidin-5-yl)-2-oxo-1,2-di Hydropyrido[2,3-d]pyrimidin-4-yl)-2,5-dimethylpiperazine-1-carboxylic acid tert-butyl ester (407mg, 0.69mmol), 3-(4,4,5, 5-Tetramethyl-1,3,2-dioxaborol-2-yl)-4-(trifluoromethyl)aniline (238mg, 0.83mmol), [1,1'-bis(diphenyl phosphino)ferrocene]dichloropalladium dichloromethane complex (28.2mg, 0.03mmol), sodium carbonate (205mg, 2.08mmol), 1,4-dioxane (8.0mL) and water (2.0 mL). After the reaction system was replaced with nitrogen, it was under the protection of nitrogen. Heat to reflux overnight. After the reaction was completed, it was cooled to room temperature, water (20 mL) and ethyl acetate (20 mL) were added thereto, the resulting mixture was separated, and the aqueous phase was extracted with ethyl acetate (20 mL×3). The organic phases were combined, washed with saturated brine (40 mL), dried over anhydrous sodium sulfate, filtered, and spin-dried under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc/PE (v/v)=1/1) to obtain the title compound as a yellow solid (310 mg, yield 63.17%).
MS(ESI,pos.ion)m/z:711.3[M+H]+.MS(ESI,pos.ion)m/z:711.3[M+H] + .
第二步(2R,5S)-4-(7-(5-氨基-2-(三氟甲基)苯基)-6-氰基-1-(4,6-二环丙基嘧啶-5-基)-2-氧代-1,2-二氢吡啶并[2,3-d]嘧啶-4-基)-2,5-二甲基哌嗪-1-羧酸叔丁酯的合成The second step (2R,5S)-4-(7-(5-amino-2-(trifluoromethyl)phenyl)-6-cyano-1-(4,6-dicyclopropylpyrimidine-5 Synthesis of -yl)-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidin-4-yl)-2,5-dimethylpiperazine-1-carboxylic acid tert-butyl ester
向微波管中依次加入(2R,5S)-4-(7-(5-氨基-2-(三氟甲基)苯基)-6-氯-1-(4,6-二环丙基嘧啶-5-基)-2-氧代-1,2-二氢吡啶并[2,3-d]嘧啶-4-基)-2,5-二甲基哌嗪-1-羧酸叔丁酯(0.20g,0.28mmol)，氰化锌(164mg,1.40mmol)，双(三叔丁基磷)钯(43mg,0.08mmol)，三叔丁基磷四氟硼酸盐(8mg,0.03mmol)和N,N-二甲基甲酰胺(1.0mL)。反应体系氮气保护下，置于微波反应器中，在130℃微波反应6h。反应结束后，冷却至室温，过滤。过滤的母液减压旋干，残余物中加入乙酸乙酯(20mL)和水(20mL)稀释，分液，水相经乙酸乙酯(20mL×3)萃取。合并有机相，经饱和食盐水(50mL)洗涤，无水硫酸钠干燥，过滤，过滤，减压旋干。残余物经硅胶柱层析(EtOAc/PE(v/v)＝2/1)纯化，得到标题化合物为白色固体(83.0mg,收率42.24％)。Add (2R,5S)-4-(7-(5-amino-2-(trifluoromethyl)phenyl)-6-chloro-1-(4,6-dicyclopropylpyrimidine) sequentially to the microwave tube -5-yl)-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidin-4-yl)-2,5-dimethylpiperazine-1-carboxylic acid tert-butyl ester (0.20g, 0.28mmol), zinc cyanide (164mg, 1.40mmol), bis(tri-tert-butylphosphine) palladium (43mg, 0.08mmol), tri-tert-butylphosphine tetrafluoroborate (8mg, 0.03mmol) and N,N-dimethylformamide (1.0 mL). Under the protection of nitrogen, the reaction system was placed in a microwave reactor and reacted by microwave at 130° C. for 6 h. After the reaction, cool to room temperature and filter. The filtered mother liquor was spin-dried under reduced pressure, ethyl acetate (20 mL) and water (20 mL) were added to the residue to dilute, the layers were separated, and the aqueous phase was extracted with ethyl acetate (20 mL×3). The organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and spin-dried under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc/PE (v/v)=2/1) to obtain the title compound as a white solid (83.0 mg, yield 42.24%).
MS(ESI,pos.ion)m/z:702.6[M+H]+.MS(ESI,pos.ion)m/z:702.6[M+H] + .
第三步4-((2S,5R)-4-丙烯酰基-2,5-二甲基哌嗪-1-基)-7-(5-氨基-2-(三氟甲基)苯基)-1-(4,6-二环丙基嘧啶-5-基)-2-氧代-1,2-二氢吡啶并[2,3-d]嘧啶-6-腈的合成The third step 4-((2S,5R)-4-acryloyl-2,5-dimethylpiperazin-1-yl)-7-(5-amino-2-(trifluoromethyl)phenyl) Synthesis of -1-(4,6-dicyclopropylpyrimidin-5-yl)-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidine-6-carbonitrile
向反应瓶中依次加入(2R,5S)-4-(7-(5-氨基-2-(三氟甲基)苯基)-6-氰基-1-(4,6-二环丙基嘧啶-5-基)-2-氧代-1,2-二氢吡啶并[2,3-d]嘧啶-4-基)-2,5-二甲基哌嗪-1-羧酸叔丁酯(83mg,0.12mmol)，二氯甲烷(2.0mL)和三氟乙酸(0.5mL)。反应体系室温反应0.5h。原料反应完全后，体系减压旋干。残余物中加入二氯甲烷(4.0mL)和三乙胺(36.4mg,0.36mmol)。体系降温至-20℃，向其中滴加丙烯酰氯(11mg,0.12mmol)的二氯甲烷(1.0mL)。滴加完毕后，转移至室温反应1h。反应结束后，向体系中加入二氯甲烷(20mL)和水(20mL)，分液。有机相无水硫酸钠干燥，过滤，减压旋干。残余物经硅胶柱层析(DCM/MeOH(v/v)＝30/1)纯化，得到标题化合物为淡黄色固体(30mg,收率38.13％)。Add (2R,5S)-4-(7-(5-amino-2-(trifluoromethyl)phenyl)-6-cyano-1-(4,6-dicyclopropyl) sequentially to the reaction flask Pyrimidin-5-yl)-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidin-4-yl)-2,5-dimethylpiperazine-1-carboxylic acid tert-butyl Ester (83 mg, 0.12 mmol), dichloromethane (2.0 mL) and trifluoroacetic acid (0.5 mL). The reaction system reacted at room temperature for 0.5h. After the raw materials reacted completely, the system was spin-dried under reduced pressure. Dichloromethane (4.0 mL) and triethylamine (36.4 mg, 0.36 mmol) were added to the residue. The system was cooled down to -20°C, and acryloyl chloride (11 mg, 0.12 mmol) in dichloromethane (1.0 mL) was added dropwise thereto. After the dropwise addition was completed, it was transferred to room temperature for 1 h. After the reaction, dichloromethane (20 mL) and water (20 mL) were added to the system, and the layers were separated. The organic phase was dried over anhydrous sodium sulfate, filtered, and spin-dried under reduced pressure. The residue was purified by silica gel column chromatography (DCM/MeOH (v/v)=30/1) to obtain the title compound as a light yellow solid (30 mg, yield 38.13%).
MS(ESI,pos.ion)m/z:656.5[M+H]+.MS(ESI,pos.ion)m/z:656.5[M+H] + .
1H NMR(400MHz,CDCl3)δ(ppm)8.82(s,1H),8.14(s,1H),7.88(s,1H),7.34–7.28(m,2H),7.25–7.18(m,2H),6.66–6.48(m,1H),6.43–6.31(m,1H),5.83–5.74(m,1H),5.16–4.77(m,2H),4.47–4.16(m,1H),4.01–3.75(m,2H),3.74–3.37(m,1H),1.62–1.49(m,2H),1.44–1.32(m,4H),1.29–1.16(m,4H),1.00–0.86(m,4H),0.81–0.68(m,2H). 1 H NMR (400MHz, CDCl 3 ) δ (ppm) 8.82 (s, 1H), 8.14 (s, 1H), 7.88 (s, 1H), 7.34–7.28 (m, 2H), 7.25–7.18 (m, 2H ),6.66–6.48(m,1H),6.43–6.31(m,1H),5.83–5.74(m,1H),5.16–4.77(m,2H),4.47–4.16(m,1H),4.01–3.75 (m,2H),3.74–3.37(m,1H),1.62–1.49(m,2H),1.44–1.32(m,4H),1.29–1.16(m,4H),1.00–0.86(m,4H) ,0.81–0.68(m,2H).
生物试验biological test
分析用的LC/MS/MS系统为Waters Xevo G2-XS Qtof飞行时间质谱仪。质谱条件如表A所示：The LC/MS/MS system used for analysis was a Waters Xevo G2-XS Qtof time-of-flight mass spectrometer. Mass spectrometry conditions are shown in Table A:
表ATable A
分析使用Waters Acquity I Class Sepax Bio-C4，2.1×50mm，3μM色谱柱，注入10μL样品。分析条件：流动相为水(含0.1％的甲酸)(A)和乙腈(含0.1％的甲酸)(B)。流速为0.6mL/min。柱温为65℃。流动相梯度如表B所示：For the analysis, a Waters Acquity I Class Sepax Bio-C4, 2.1×50 mm, 3 μM chromatographic column was used to inject 10 μL of the sample. Analysis conditions: the mobile phase is water (containing 0.1% formic acid) (A) and acetonitrile (containing 0.1% formic acid) (B). The flow rate was 0.6 mL/min. The column temperature was 65°C. The mobile phase gradient is shown in Table B:
表BForm B
实施例A人和小鼠肝微粒体中的稳定性Example A Stability in Human and Mouse Liver Microsomes
实验方法：将人或小鼠肝微粒体置于聚丙烯试管中进行双复孔孵育。典型的孵育混合液包括人或小鼠肝微粒体(0.5mg蛋白质/mL)，目标化合物(1μM)和总体积为15μL的NADPH(2.0mM)磷酸钾缓冲液(PBS，100mM，pH值为7.4)，将化合物溶解在DMSO中，并使用PBS将其稀释，使其最终的DMSO溶液的浓度为0.05％。并在37℃下与空气相通的水浴中进行孵育，预孵育3min后向混合液中加入蛋白并开始反应。在不同的时间点(0，NCF(no cofactor,即不含辅酶)，20和60min)，加入同体积冰冷乙腈终止反应。样品于–80℃下保存直到进行LC/MS/MS分析。Experimental method: Human or mouse liver microsomes were placed in polypropylene test tubes for double well incubation. A typical incubation mixture consists of human or mouse liver microsomes (0.5 mg protein/mL), compound of interest (1 μM), and NADPH (2.0 mM) potassium phosphate buffer (PBS, 100 mM, pH 7.4) in a total volume of 15 μL ), the compound was dissolved in DMSO, and diluted with PBS so that the final concentration of the DMSO solution was 0.05%. And incubate at 37° C. in a water bath open to air. After pre-incubation for 3 minutes, add protein to the mixture and start the reaction. At different time points (0, NCF (no cofactor, ie without coenzyme), 20 and 60 min), the same volume of ice-cold acetonitrile was added to terminate the reaction. Samples were stored at -80°C until LC/MS/MS analysis.
化合物在人或小鼠肝微粒体孵育混合物中的浓度是通过LC/MS/MS的方法来测定的。Compound concentrations in human or mouse liver microsome incubation mixtures were determined by LC/MS/MS.
平行孵育试验使用变性的微粒体作为阴性对照，在37℃下孵化，反应在不同的时间点(0，NCF，20和60min)终止。Parallel incubation experiments used denatured microsomes as a negative control, incubated at 37°C, and the reactions were terminated at different time points (0, NCF, 20 and 60 min).
维拉帕米(1μΜ)作为阳性对照，在37℃下孵化，反应在不同的时间点(0，NCF，20和60min)终止。Verapamil (1 μM) was used as a positive control, incubated at 37°C, and the reaction was terminated at different time points (0, NCF, 20 and 60 min).
数据分析data analysis
对于每一个反应，将化合物在人或小鼠肝微粒体孵育中的浓度(以百分比表示)按相对零时间点的百分比作图，以此来推断体内肝固有清除率CLint(参考文献:Naritomi Y,Terashita S,Kimura S,Suzuki A,Kagayama A,Sugiyama Y.Prediction of humanhepatic clearance from in vivo animal experiments and in vitro metabolicstudies with liver microsomes from animals and humans.Drug Metabolism andDisposition 2001,29:1316-1324.)。结果参见表1，表1为本发明实施例提供的化合物在人和小鼠肝微粒中稳定性的实验结果。For each reaction, the in vivo hepatic intrinsic clearance CL int was extrapolated by plotting the compound concentration (expressed as a percentage) in human or mouse liver microsomal incubations as a percentage relative to the zero time point (Reference: Naritomi Y, Terashita S, Kimura S, Suzuki A, Kagayama A, Sugiyama Y. Prediction of human hepatic clearance from in vivo animal experiments and in vitro metabolic studies with liver microsomes from animals and humans. Drug Metabolism and Disposition 2001,29:1316-1324.) . See Table 1 for the results. Table 1 shows the experimental results of the stability of the compounds provided in the examples of the present invention in human and mouse liver microparticles.
表1本发明实施例提供的化合物在肝微粒中稳定性的实验结果Table 1 The experimental results of the stability of the compounds provided by the examples of the present invention in liver microparticles
化合物AMG510具体结构如下：The specific structure of compound AMG510 is as follows:
由实验可知，本发明化合物孵育在人和小鼠的肝微粒体中时，表现出较好的稳定性。It can be known from experiments that the compound of the present invention exhibits better stability when incubated in human and mouse liver microsomes.
实施例B本发明化合物对H358(KRAS G12C)细胞增殖的抑制活性Example B The inhibitory activity of the compounds of the present invention on the proliferation of H358 (KRAS G12C) cells
实验方法：CTG方法检测化合物对细胞增殖的抑制活性。Experimental method: CTG method was used to detect the inhibitory activity of the compound on cell proliferation.
细胞实验条件如表C所示：Cell experiment conditions are shown in Table C:
表CForm C
1)细胞培养1) Cell culture
采用合适的培养基培养细胞，置于37℃、5％二氧化碳培养箱中培养。每日使用倒置显微镜观察细胞1次，隔2-4天换培养液一次。收集细胞离心1,200rpm离心5min，弃上清液，以1:3-1:8比例转移至新的无菌培养皿中培养。The cells were cultured in a suitable medium and placed in a 37°C, 5% carbon dioxide incubator. The cells were observed once a day using an inverted microscope, and the culture medium was changed every 2-4 days. Collect the cells and centrifuge at 1,200rpm for 5min, discard the supernatant, and transfer to a new sterile petri dish at a ratio of 1:3-1:8 for culture.
2)细胞铺板2) Cell plating
收集处于指数生长期的细胞，并用细胞计数仪进行细胞计数。用相应培养基重悬细胞并调整到适当的浓度。每孔加入90μL细胞悬液于96孔细胞培养板中。置于37℃、5％二氧化碳培养箱中过夜培养。Cells in exponential growth phase were collected and counted using a cell counter. Resuspend the cells with the corresponding medium and adjust to an appropriate concentration. Add 90 μL of cell suspension to each well in a 96-well cell culture plate. Place in a 37°C, 5% carbon dioxide incubator for overnight culture.
3)化合物配制及加药处理3) Compound preparation and dosing treatment
a母液配制：用DMSO溶解待测化合物，配置10mM的母液。a Mother solution preparation: Dissolve the compound to be tested in DMSO, and prepare a 10 mM mother solution.
b用时用DMSO将化合物3倍稀释，得到9个浓度梯度的化合物，用完全培养基将上述梯度稀释后的化合物进行20倍稀释，并混合均匀得到10×浓度的药物工作液。b When used, the compound was diluted 3 times with DMSO to obtain 9 concentration gradients of the compound, and the above gradient diluted compound was diluted 20 times with complete medium, and mixed uniformly to obtain a 10× concentration drug working solution.
c加药：取出细胞培养板，将10μL/孔的上述10×浓度的药物工作液加入到细胞培养板的相应孔中，在37℃培养箱中孵育72h。c Dosing: Take out the cell culture plate, add 10 μL/well of the above 10× concentration drug working solution into the corresponding wells of the cell culture plate, and incubate in a 37°C incubator for 72 hours.
4)读板检测4) Plate reading detection
a化合物处理72h后，在倒置显微镜下观察细胞形态，DMSO对照孔中的细胞生长状态正常，未见有污染现象，各孔是否有化合物析出现象。a After compound treatment for 72 hours, the cell morphology was observed under an inverted microscope. The growth state of the cells in the DMSO control wells was normal, and there was no pollution, and whether there was compound precipitation in each well.
b将配制好的CTG溶液放置室温平衡10-20min。b Place the prepared CTG solution at room temperature to balance for 10-20min.
c按照CTG操作说明加入50μL/孔的CTG溶液，置于摇床上避光振荡20min。c According to the CTG operating instructions, add 50 μL/well of CTG solution, place on a shaker and shake for 20 minutes in the dark.
d使用酶标仪测定荧光信号值。d Use a microplate reader to measure the fluorescence signal value.
5)数据分析5) Data analysis
生长抑制率％＝(V阴性组-V实验组)/(V阴性组-V空白组)×100％，其中V阴性组为溶剂对照组的平均值，V实验组为药物处理组的读数，V空白组为无细胞无药物处理组的读数。应用GraphPad Prism5.0软件对数据进行分析并计算IC50值。Growth inhibition rate %=(V negative group -V experimental group )/(V negative group -V blank group )×100%, wherein V negative group is the average value of solvent control group, V experimental group is the reading of drug treatment group, V blank group is the reading of the no-cell no-drug treatment group. GraphPad Prism5.0 software was used to analyze the data and calculate the IC50 value.
实验证明，本发明的化合物对KRAS G12C突变的H358细胞具有较高的抑制活性。具体地，本发明大部分化合物对KRAS G12C突变的NCI-358细胞的抑制活性IC50小于500nM，优选的部分化合物的IC50小于100nM，更优的部分化合物的IC50小于50nM。其中，本发明实施例提供的化合物的抑制试验结果参见表2。Experiments prove that the compound of the present invention has higher inhibitory activity on H358 cells with KRAS G12C mutation. Specifically, the inhibitory activity IC 50 of most of the compounds of the present invention to KRAS G12C mutant NCI-358 cells is less than 500nM, the IC 50 of some preferred compounds is less than 100nM, and the IC 50 of more optimal compounds is less than 50nM. Wherein, the inhibition test results of the compounds provided in the examples of the present invention are shown in Table 2.
表2本发明实施例提供的化合物对H358细胞增殖抑制实验结果Table 2 The compounds provided by the embodiments of the present invention inhibit the proliferation of H358 cells to the experimental results
实施例C本发明化合物与KRAS G12C蛋白的结合情况Embodiment C The binding situation of the compound of the present invention and KRAS G12C protein
实验方法：LC-MS法检测化合物与KRAS G12C蛋白的结合情况。Experimental method: LC-MS method was used to detect the binding of the compound to KRAS G12C protein.
实验步骤：Experimental steps:
1)实验缓冲液准备如表D所示1) Prepare the experimental buffer as shown in Table D
表DForm D
2)将GDP载入KRAS-G12C蛋白2) Load GDP into KRAS-G12C protein
将KRAS G12C蛋白储备液(11.13mg/mL,550μM)用低Mg2+缓冲液5倍稀释至110μM。取1mL 110μM的KRAS G12C蛋白并加入1mL的2×GDP载入缓冲液，轻轻混匀，室温孵育1.5h后，分装成40μL/管，迅速冷冻保存于-80℃冰箱中。The KRAS G12C protein stock solution (11.13 mg/mL, 550 μM) was diluted 5-fold with low Mg 2+ buffer to 110 μM. Take 1mL of 110μM KRAS G12C protein and add 1mL of 2×GDP loading buffer, mix gently, incubate at room temperature for 1.5h, aliquot into 40μL/tube, and quickly freeze and store in a -80°C refrigerator.
3)KRAS G12C结合试验3) KRAS G12C binding assay
用1*孵育缓冲液将GDP载入的KRAS G12C稀释至20μM，按下表E将各试剂混合。Dilute the GDP-loaded KRAS G12C to 20 μM with 1* Incubation Buffer and mix the reagents as shown in Table E below.
表EForm E
注：各试剂用量可根据需要按一定比例变化。Note: The amount of each reagent can be changed in a certain proportion according to the needs.
4)常温下分别孵育5min及1h4) Incubate at room temperature for 5min and 1h respectively
5)加入5μL的5％甲酸终止反应(注：根据孵育溶液体积按10％比例加入5％甲酸溶液)5) Add 5 μL of 5% formic acid to terminate the reaction (note: add 5% formic acid solution at a ratio of 10% according to the volume of the incubation solution)
6)LC-MS检测6) LC-MS detection
孵育液混匀后转移至进样小瓶，进行LC-MS分析检测。分析条件如表F所示：The incubation solution was mixed and transferred to the injection vial for LC-MS analysis and detection. The analysis conditions are as shown in Table F:
表FForm F
7)计算KRAS G12C结合率％7) Calculation of KRAS G12C binding rate %
KRAS G12C结合率％＝复合物峰高/[复合物峰高+未与KRAS G12C结合峰高]×100％KRAS G12C binding rate% = complex peak height / [complex peak height + peak height not bound to KRAS G12C] × 100%
实验结果见表3，表3为本发明实施例提供的化合物的蛋白结合5min和1h实验结果。The experimental results are shown in Table 3. Table 3 shows the experimental results of the protein binding of the compounds provided in the examples of the present invention for 5 minutes and 1 hour.
表3本发明实施例提供的化合物的蛋白结合实验结果Table 3 The protein binding experiment results of the compounds provided by the examples of the present invention
实验结果显示，本发明化合物与KRAS G12C蛋白结合率较高。Experimental results show that the compound of the present invention has a high binding rate to KRAS G12C protein.
实施例D：小鼠在静脉注射和口服定量本发明化合物后的药代动力学评价Example D: Pharmacokinetic Evaluation of Mice After Intravenous Injection and Oral Quantification of Compounds of the Invention
取18-22g雄性ICR小鼠，随机分为两组，一组静脉注射待测化合物，剂量为2.0mg/kg，另一组口服给予待测化合物，剂量为5mg/kg；静脉注射给药后按时间点0.083、0.25、0.5、1、2、4、6、8和24小时尾静脉采血；口服给药后按时间点0.25、0.5、1、2、4、6、8和24小时尾静脉采血。根据样品浓度建立合适范围的标准曲线，使用AB SCIEX API4000型LC-MS/MS，在MRM模式下测定血浆样品中待测化合物的浓度。根据药物浓度-时间曲线，采用WinNonLin6.3软件非房室模型法计算药代动力学参数。实验结果见表4。Take 18-22g male ICR mice, and divide them into two groups at random, one group is injected intravenously with the compound to be tested at a dose of 2.0 mg/kg, and the other group is given the compound to be tested orally at a dose of 5 mg/kg; after intravenous injection Tail vein blood collection at time points 0.083, 0.25, 0.5, 1, 2, 4, 6, 8 and 24 hours; tail vein at time points 0.25, 0.5, 1, 2, 4, 6, 8 and 24 hours after oral administration Blood collection. A standard curve with an appropriate range was established according to the concentration of the sample, and the concentration of the compound to be tested in the plasma sample was determined in MRM mode using AB SCIEX API4000 LC-MS/MS. According to the drug concentration-time curve, the pharmacokinetic parameters were calculated by WinNonLin6.3 software non-compartmental model method. The experimental results are shown in Table 4.
表4化合物在小鼠体内的药代特征的实验结果Table 4 The experimental results of the pharmacokinetic characteristics of the compound in mice
化合物D-1553具体结构如下：The specific structure of compound D-1553 is as follows:
结果显示，将本发明提供的化合物静脉注射给药或口服给药时，表现出良好的药代动力学性质，包括较好的吸收和较好的口服生物利用度。The results show that when the compound provided by the invention is administered intravenously or orally, it exhibits good pharmacokinetic properties, including better absorption and better oral bioavailability.
在本说明书的描述中，参考术语“一个实施例”、“一些实施例”、“示例”、“具体示例”、或“一些示例”等的描述意指结合该实施例或示例描述的具体特征、结构、材料或者特点包含于本发明的至少一个实施例或示例中。在本说明书中，对上述术语的示意性表述不必须针对的是相同的实施例或示例。而且，描述的具体特征、结构、材料或者特点可以在任一个或多个实施例或示例中以合适的方式结合。此外，在不相互矛盾的情况下，本领域的技术人员可以将本说明书中描述的不同实施例或示例以及不同实施例或示例的特征进行结合和组合。In the description of this specification, descriptions referring to the terms "one embodiment", "some embodiments", "example", "specific examples", or "some examples" mean that specific features described in connection with the embodiment or example , structure, material or characteristic is included in at least one embodiment or example of the present invention. In this specification, the schematic representations of the above terms are not necessarily directed to the same embodiment or example. Furthermore, the described specific features, structures, materials or characteristics may be combined in any suitable manner in any one or more embodiments or examples. In addition, those skilled in the art can combine and combine different embodiments or examples and features of different embodiments or examples described in this specification without conflicting with each other.
尽管上面已经示出和描述了本发明的实施例，可以理解的是，上述实施例是示例性的，不能理解为对本发明的限制，本领域的普通技术人员在本发明的范围内可以对上述实施例进行变化、修改、替换和变型。Although the embodiments of the present invention have been shown and described above, it can be understood that the above embodiments are exemplary and should not be construed as limiting the present invention, those skilled in the art can make the above-mentioned The embodiments are subject to changes, modifications, substitutions and variations.
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