技术领域technical field
本发明涉及生物医药领域，具体地，本发明涉及靶向降解FAK蛋白的化合物及其应用。The present invention relates to the field of biomedicine, in particular, the present invention relates to compounds targeted to degrade FAK protein and applications thereof.
背景技术Background technique
FAK蛋白又称PTK2，由PTK2基因编码。FAK激酶在细胞粘附中起重要的作用，包括细胞之间的粘附以及细胞与周围环境的相互作用，并且FAK在细胞在向周围环境的移动中也发挥重要的功能。有证据表明，当FAK激酶的功能受阻，乳腺癌的转移性大大下降。FAK protein, also known as PTK2, is encoded by the PTK2 gene. FAK kinase plays an important role in cell adhesion, including the adhesion between cells and the interaction between cells and the surrounding environment, and FAK also plays an important role in the movement of cells to the surrounding environment. There is evidence that when the function of the FAK kinase is blocked, the metastatic properties of breast cancer are greatly reduced.
FAK的mRNA水平在约37％的卵巢癌细胞和约26％乳腺癌细胞中高表达。由于FAK参与了多种肿瘤的调控，目前针对FAK的抑制剂也相继被开发出来。包括2012年开发的PF-228、PF-271、Y15(1,2,4,5-benzenetetraamine tetrahydrochloride)以及PND-1186。The mRNA level of FAK is highly expressed in about 37% of ovarian cancer cells and about 26% of breast cancer cells. Since FAK is involved in the regulation of various tumors, inhibitors against FAK have also been developed one after another. Including PF-228, PF-271, Y15 (1,2,4,5-benzonetetraamine tetrahydrochloride) and PND-1186 developed in 2012.
2014年，多种FAK抑制剂已经进入临床试验阶段，包括ATP竞争抑制剂VS-6062,Defactinib及PND-1186。Defactinib已经进入临床II期试验用于治疗KRAS突变的非小细胞肺癌。In 2014, a variety of FAK inhibitors have entered clinical trials, including ATP competition inhibitors VS-6062, Defactinib and PND-1186. Defactinib has entered clinical phase II trials for the treatment of KRAS-mutated non-small cell lung cancer.
然而，新的能够有效抑制或降解FAK蛋白的药物还待开发。However, new drugs that can effectively inhibit or degrade FAK protein have yet to be developed.
发明内容Contents of the invention
本发明旨在至少在一定程度上解决现有技术的技术问题之一：The present invention aims to solve one of the technical problems of the prior art at least to a certain extent:
发明人发现，目前的FAK小分子抑制剂大致可分为两大类：ATP依赖型和非ATP依赖型。ATP依赖型FAK小分子抑制剂能干扰FAK催化区域的活性，可能会影响多个下游信号通路，造成较为广泛的副作用，而非ATP依赖型FAK小分子抑制剂如变构FAK抑制剂则可阻滞特定的蛋白质-蛋白质相互作用(如p53与FAK的相互作用)，从而抑制FAK的活性。因此，虽然目前已经开发出许多针对以上两种类型的FAK小分子抑制剂，但由于生物体的复杂性及局限性，真正用于临床的小分子抑制剂非常少。The inventors found that the current small molecule inhibitors of FAK can be roughly divided into two categories: ATP-dependent and ATP-independent. ATP-dependent FAK small-molecule inhibitors can interfere with the activity of the catalytic region of FAK, which may affect multiple downstream signaling pathways and cause a wide range of side effects, while non-ATP-dependent FAK small-molecule inhibitors such as allosteric FAK inhibitors can block Specific protein-protein interaction (such as the interaction between p53 and FAK), thereby inhibiting the activity of FAK. Therefore, although many small-molecule inhibitors targeting the above two types of FAK have been developed, due to the complexity and limitations of organisms, there are very few small-molecule inhibitors that are actually used clinically.
基于以上问题的发现，发明人提出了一种新的化合物，该化合物采用的是双靶点分子结构，结构如图1所示，该类分子一端的结构靶向结合E3连接酶，另一端的结构靶向结合FAK蛋白，两端的结构通过链(linker)相连接，形成一个完整的化合物分子，该化合物通过E3泛素化目标蛋白并引导目标蛋白进入降解通路，对目标蛋白的特异性降解作用强。该化合物可特异性降解FAK，因此在抗肿瘤及生殖系统领域有潜在的应用价值。Based on the discovery of the above problems, the inventors proposed a new compound, which uses a dual-target molecular structure, as shown in Figure 1. The structure at one end of this type of molecule targets E3 ligase, and the structure at the other end The structure is targeted to bind the FAK protein, and the structures at both ends are connected by a linker to form a complete compound molecule. The compound ubiquitinates the target protein through E3 and guides the target protein into the degradation pathway, and specifically degrades the target protein. powerful. The compound can specifically degrade FAK, so it has potential application value in the field of anti-tumor and reproductive system.
为此，在本发明的第一方面，本发明提出了一种化合物，其为式I所示化合物或其立体异构体、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：For this reason, in the first aspect of the present invention, the present invention proposes a compound, which is a compound shown in formula I or its stereoisomers, geometric isomers, tautomers, nitrogen oxides, hydrates , solvates, metabolites, pharmaceutically acceptable salts or prodrugs:
X-Y-ZX-Y-Z
式IFormula I
其中，X表示FAK蛋白(Focal Adhesion Kinase-Related Nonkinase)的配体，Z表示E3连接酶的配体，Y表示连接X和Z的链。Wherein, X represents the ligand of FAK protein (Focal Adhesion Kinase-Related Nonkinase), Z represents the ligand of E3 ligase, and Y represents the chain connecting X and Z.
根据本发明的实施例，上述化合物还可进一步包括如下附加技术特征至少之一：According to an embodiment of the present invention, the above compound may further include at least one of the following additional technical features:
根据本发明的实施例，所述X为式II-1或II-2所示化合物，According to an embodiment of the present invention, the X is a compound represented by formula II-1 or II-2,
Cy1或Cy2分别独立地为苯环，C6-12芳基，5-12个环原子组成的杂芳基，C3-12环烷基或3-12个环原子组成的杂环基；Cy1 or Cy2 are independently a benzene ring, a C6-12 aryl group, a heteroaryl group consisting of 5-12 ring atoms, a C3-12 cycloalkyl group or a heterocyclic group consisting of 3-12 ring atoms ;
L1为-(CRmRw)g-O-(CRmRw)g-，-(CRmRw)g-S-(CRmRw)g-，-(CRmRw)g-N(R1a)-(CRmRw)g-，-(CRmRw)n-，-(CRmRw)g-(CR1a＝CR1a)n-(CRmRw)g-，-(CRmRw)g-(C≡C)n-(CRmRw)g-，-(CRmRw)g-S(＝O)p-(CRmRw)g-，-(CRmRw)g-C(＝O)-(CRmRw)g-，-(CRmRw)g-C(＝O)-O-(CRmRw)g-，-(CRmRw)g-S(＝O)p-N(R1a)-(CRmRw)g-，-(CRmRw)g-C(＝O)-N(R1a)-(CRmRw)g-；L1 is -(CRm Rw )g -O-(CRm Rw )g -, -(CRm Rw )g -S-(CRm Rw )g -, -(CRm Rw )g -N(R1a )-(CRm Rw )g -,-(CRm Rw )n -,-(CRm Rw )g -(CR1a ＝CR1a )n -(CRm Rw )g -, -(CRm Rw )g -(C≡C)n -(CRm Rw )g -, -(CRm Rw )g -S(=O)p -(CRm Rw )g -,-(CRm Rw )g -C(=O)-(CRm Rw )g -,-(CRm Rw )g -C(=O)-O-(CRm Rw )g -, -(CRm Rw )g -S(=O)p -N(R1a )-(CRm Rw )g -, -(CRm Rw )g -C(=O)- N(R1a )-(CRm Rw )g -;
各Cy1或Cy2分别独立地被1、2、3、4、5或6个Rh1所取代；Each Cy1 or Cy2 is independently replaced by 1, 2, 3, 4, 5 or 6Rh1 ;
各L1分别独立地被1、2、3、4、5或6个Rh2所取代；Each L1 is independently replaced by1 , 2, 3, 4, 5 or 6Rh2 ;
各Rh1分别独立地为氢，氘，F，Cl，Br，I，CN，OH，NO2，NH2，COOH，C1-6烷基，C1-6卤代烷基，C1-6烷氧基，C2-6烯基，C2-6炔基，C3-12环烷基，C6-12芳基，3-12个环原子组成的杂环基，5-12个环原子组成的杂芳基，Rg-(CRmRw)g-O-(CRmRw)g-，Rg-(CRmRw)g-S-(CRmRw)g-，Rg-(CRmRw)g-N(R1a)-(CRmRw)g-，Rg-(CRmRw)g-，Rg-(CRmRw)g-(CR1a＝CR1a)n-(CRmRw)g-，Rg-(CRmRw)g-(C≡C)n-(CRmRw)g-，Rg-(CRmRw)g-S(＝O)p-(CRmRw)g-，Rg-(CRmRw)g-C(＝O)-(CRmRw)g-，Rg-(CRmRw)g-C(＝O)-O-(CRmRw)g-，Rg-(CRmRw)g-O-C(＝O)-(CRmRw)g-，Rg-(CRmRw)g-S(＝O)p-N(R1a)-(CRmRw)g-，Rg-(CRmRw)g-N(R1a)-S(＝O)p-(CRmRw)g-，Rg-(CRmRw)g-C(＝O)-N(R1a)-(CRmRw)g-或Rg-(CRmRw)g-N(R1a)-C(＝O)-(CRmRw)g-；Each Rh1 is independently hydrogen, deuterium, F, Cl, Br, I, CN, OH, NO2 , NH2 , COOH, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkane Oxygen, C2-6 alkenyl, C2-6 alkynyl, C3-12 cycloalkyl, C6-12 aryl, heterocyclic group consisting of 3-12 ring atoms, 5-12 ring atoms Heteroaryl consisting of, Rg -(CRm Rw )g -O-(CRm Rw )g -, Rg -(CRm Rw )g -S-(CRm Rw )g -, Rg -(CRm Rw )g -N(R1a )-(CRm Rw )g -, Rg -(CRm Rw )g -, Rg -(CRm Rw )g -( CR1a ＝CR1a )n -(CRm Rw )g -, Rg -(CRm Rw )g -(C≡C)n -(CRm Rw )g -, Rg -(CRm Rw )g -S(=O)p -(CRm Rw )g -, Rg -(CRm Rw )g -C(=O)-(CRm Rw )g -, Rg - (CRm Rw )g -C(=O)-O-(CRm Rw )g -, Rg -(CRm Rw )g -OC(=O)-(CRm Rw )g - , Rg -(CRm Rw )g -S(=O)p -N(R1a )-(CRm Rw )g -, Rg -(CRm Rw )g -N(R1a ) -S(=O)p -(CRm Rw )g -, Rg -(CRm Rw )g -C(=O)-N(R1a )-(CRm Rw )g - or Rg -(CRm Rw )g -N(R1a )-C(=O)-(CRm Rw )g -;
各Rh2分别独立地为氢，氘，F，Cl，Br，I，CN，OH，NO2，NH2，COOH，C1-6烷基，C1-6卤代烷基，C1-6烷氧基，C2-6烯基，C2-6炔基，C3-12环烷基，C6-12芳基，3-12个环原子组成的杂环基，5-12个环原子组成的杂芳基，Rg-(CRmRw)g-O-(CRmRw)g-，Rg-(CRmRw)g-S-(CRmRw)g-，Rg-(CRmRw)g-N(R1a)-(CRmRw)g-，Rg-(CRmRw)g-，Rg-(CRmRw)g-(CR1a＝CR1a)n-(CRmRw)g-，Rg-(CRmRw)g-(C≡C)n-(CRmRw)g-，Rg-(CRmRw)g-S(＝O)p-(CRmRw)g-，Rg-(CRmRw)g-C(＝O)-(CRmRw)g-，Rg-(CRmRw)g-C(＝O)-O-(CRmRw)g-，Rg-(CRmRw)g-O-C(＝O)-(CRmRw)g-，Rg-(CRmRw)g-S(＝O)p-N(R1a)-(CRmRw)g-，Rg-(CRmRw)g-N(R1a)-S(＝O)p-(CRmRw)g-，Rg-(CRmRw)g-C(＝O)-N(R1a)-(CRmRw)g-或Rg-(CRmRw)g-N(R1a)-C(＝O)-(CRmRw)g-；Each Rh2 is independently hydrogen, deuterium, F, Cl, Br, I, CN, OH, NO2 , NH2 , COOH, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkane Oxygen, C2-6 alkenyl, C2-6 alkynyl, C3-12 cycloalkyl, C6-12 aryl, heterocyclic group consisting of 3-12 ring atoms, 5-12 ring atoms Heteroaryl consisting of, Rg -(CRm Rw )g -O-(CRm Rw )g -, Rg -(CRm Rw )g -S-(CRm Rw )g -, Rg -(CRm Rw )g -N(R1a )-(CRm Rw )g -, Rg -(CRm Rw )g -, Rg -(CRm Rw )g -( CR1a ＝CR1a )n -(CRm Rw )g -, Rg -(CRm Rw )g -(C≡C)n -(CRm Rw )g -, Rg -(CRm Rw )g -S(=O)p -(CRm Rw )g -, Rg -(CRm Rw )g -C(=O)-(CRm Rw )g -, Rg - (CRm Rw )g -C(=O)-O-(CRm Rw )g -, Rg -(CRm Rw )g -OC(=O)-(CRm Rw )g - , Rg -(CRm Rw )g -S(=O)p -N(R1a )-(CRm Rw )g -, Rg -(CRm Rw )g -N(R1a ) -S(=O)p -(CRm Rw )g -, Rg -(CRm Rw )g -C(=O)-N(R1a )-(CRm Rw )g - or Rg -(CRm Rw )g -N(R1a )-C(=O)-(CRm Rw )g -;
各Rh1分别独立地被1、2、3、4、5或6个Rh3所取代；EachRh1 is independently replaced by 1, 2, 3, 4, 5 or 6Rh3 ;
各Rh2分别独立地被1、2、3、4、5或6个Rh4所取代；EachRh2 is independently replaced by 1, 2, 3, 4, 5 or 6Rh4 ;
各Rh3分别独立地为氢，氘，F，Cl，Br，I，CN，OH，NO2，NH2，COOH，C1-6烷基，C1-6卤代烷基，C1-6烷氧基，C2-6烯基，C2-6炔基，C3-6环烷基，Rg1-(CRmRw)g-O-(CRmRw)g-，Rg1-(CRmRw)g-S-(CRmRw)g-，Rg1-(CRmRw)g-N(R1a)-(CRmRw)g-，Rg1-(CRmRw)g-，Rg1-(CRmRw)g-(CR1a＝CR1a)n-(CRmRw)g-，Rg1-(CRmRw)g-(C≡C)n-(CRmRw)g-，Rg1-(CRmRw)g-S(＝O)p-(CRmRw)g-，Rg1-(CRmRw)g-C(＝O)-(CRmRw)g-，Rg1-(CRmRw)g-C(＝O)-O-(CRmRw)g-，Rg1-(CRmRw)g-O-C(＝O)-(CRmRw)g-，Rg1-(CRmRw)g-S(＝O)p-N(R1a)-(CRmRw)g-，Rg1-(CRmRw)g-N(R1a)-S(＝O)p-(CRmRw)g-，Rg1-(CRmRw)g-C(＝O)-N(R1a)-(CRmRw)g-或Rg1-(CRmRw)g-N(R1a)-C(＝O)-(CRmRw)g-；Each Rh3 is independently hydrogen, deuterium, F, Cl, Br, I, CN, OH, NO2 , NH2 , COOH, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkane Oxygen, C2-6 alkenyl, C2-6 alkynyl, C3-6 cycloalkyl, Rg1 -(CRm Rw )g -O-(CRm Rw )g -, Rg1 - (CRm Rw )g -S-(CRm Rw )g -, Rg1 -(CRm Rw )g -N(R1a )-(CRm Rw )g -, Rg1 -(CRm Rw )g -, Rg1 -(CRm Rw )g -(CR1a ＝CR1a )n -(CRm Rw )g -, Rg1 -(CRm Rw )g -(C≡ C)n -(CRm Rw )g -, Rg1 -(CRm Rw )g -S(=O)p -(CRm Rw )g -, Rg1 -(CRm Rw )g -C(=O)-(CRm Rw )g -, Rg1 -(CRm Rw )g -C(=O)-O-(CRm Rw )g -, Rg1 -(CRm Rw )g -OC(=O)-(CRm Rw )g -, Rg1 -(CRm Rw )g -S(=O)p -N(R1a )-(CRm Rw )g -, Rg1 -(CRm Rw )g -N(R1a )-S(=O)p -(CRm Rw )g -, Rg1 -(CRm Rw )g -C(= O)-N(R1a )-(CRm Rw )g - or Rg1 -(CRm Rw )g -N(R1a )-C(=O)-(CRm Rw )g -;
各Rh4分别独立地为氢，氘，F，Cl，Br，I，CN，OH，NO2，NH2，COOH，C1-6烷基，C1-6卤代烷基，C1-6烷氧基，C2-6烯基，C2-6炔基，C3-6环烷基，Rg1-(CRmRw)g-O-(CRmRw)g-，Rg1-(CRmRw)g-S-(CRmRw)g-，Rg1-(CRmRw)g-N(R1a)-(CRmRw)g-，Rg1-(CRmRw)g-，Rg1-(CRmRw)g-(CR1a＝CR1a)n-(CRmRw)g-，Rg1-(CRmRw)g-(C≡C)n-(CRmRw)g-，Rg1-(CRmRw)g-S(＝O)p-(CRmRw)g-，Rg1-(CRmRw)g-C(＝O)-(CRmRw)g-，Rg1-(CRmRw)g-C(＝O)-O-(CRmRw)g-，Rg1-(CRmRw)g-O-C(＝O)-(CRmRw)g-，Rg1-(CRmRw)g-S(＝O)p-N(R1a)-(CRmRw)g-，Rg1-(CRmRw)g-N(R1a)-S(＝O)p-(CRmRw)g-，Rg1-(CRmRw)g-C(＝O)-N(R1a)-(CRmRw)g-或Rg1-(CRmRw)g-N(R1a)-C(＝O)-(CRmRw)g-；Each Rh4 is independently hydrogen, deuterium, F, Cl, Br, I, CN, OH, NO2 , NH2 , COOH, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkane Oxygen, C2-6 alkenyl, C2-6 alkynyl, C3-6 cycloalkyl, Rg1 -(CRm Rw )g -O-(CRm Rw )g -, Rg1 - (CRm Rw )g -S-(CRm Rw )g -, Rg1 -(CRm Rw )g -N(R1a )-(CRm Rw )g -, Rg1 -(CRm Rw )g -, Rg1 -(CRm Rw )g -(CR1a ＝CR1a )n -(CRm Rw )g -, Rg1 -(CRm Rw )g -(C≡ C)n -(CRm Rw )g -, Rg1 -(CRm Rw )g -S(=O)p -(CRm Rw )g -, Rg1 -(CRm Rw )g -C(=O)-(CRm Rw )g -, Rg1 -(CRm Rw )g -C(=O)-O-(CRm Rw )g -, Rg1 -(CRm Rw )g -OC(=O)-(CRm Rw )g -, Rg1 -(CRm Rw )g -S(=O)p -N(R1a )-(CRm Rw )g -, Rg1 -(CRm Rw )g -N(R1a )-S(=O)p -(CRm Rw )g -, Rg1 -(CRm Rw )g -C(= O)-N(R1a )-(CRm Rw )g - or Rg1 -(CRm Rw )g -N(R1a )-C(=O)-(CRm Rw )g -;
各Rg分别独立地为H、氘、F、Cl、Br、I、CN、-NO2、OH、氨基、羧基、C1-6烷基、C1-6卤代烷基、C1-6烷氧基、C2-6烯基、C2-6炔基、C3-6环烷基、C6-10芳基、3-12个环原子组成的杂环基或5-10个环原子组成的杂芳基；Each Rg is independently H, deuterium, F, Cl, Br, I, CN, -NO2 , OH, amino, carboxyl, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkane Oxygen, C2-6 alkenyl, C2-6 alkynyl, C3-6 cycloalkyl, C6-10 aryl, heterocyclic group consisting of 3-12 ring atoms or 5-10 ring atoms Consisting of heteroaryl;
各Rg1分别独立地为H、氘、F、Cl、Br、I、CN、-NO2、OH、氨基、羧基、C1-6烷基、C1-6卤代烷基、C1-6烷氧基、C2-6烯基、C2-6炔基、C3-6环烷基、C6-10芳基、3-12个环原子组成的杂环基或5-10个环原子组成的杂芳基；Each Rg1 is independently H, deuterium, F, Cl, Br, I, CN, -NO2 , OH, amino, carboxyl, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkane Oxygen, C2-6 alkenyl, C2-6 alkynyl, C3-6 cycloalkyl, C6-10 aryl, heterocyclic group consisting of 3-12 ring atoms or 5-10 ring atoms Consisting of heteroaryl;
各R1a分别独立地为H，氘，F，Cl，Br，I，CN，-NO2，OH，氨基，羧基，C1-6烷基，C1-6卤代烷基，C1-6烷氧基，C2-6烯基，C2-6炔基，C3-6环烷基，C6-10芳基，3-12个环原子组成的杂环基或5-10个环原子组成的杂芳基；Each R1a is independently H, deuterium, F, Cl, Br, I, CN, -NO2 , OH, amino, carboxyl, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkane Oxygen, C2-6 alkenyl, C2-6 alkynyl, C3-6 cycloalkyl, C6-10 aryl, heterocyclic group consisting of 3-12 ring atoms or 5-10 ring atoms Consisting of heteroaryl;
各Rm或Rw分别独立地为H、氘、F、Cl、Br、I、CN、-NO2、OH、氨基、羧基、C1-6烷基、C1-6卤代烷基、C1-6烷氧基、C2-6烯基、C2-6炔基、C3-6环烷基、C6-10芳基、3-12个环原子组成的杂环基或5-10个环原子组成的杂芳基；Each Rm or Rw is independently H, deuterium, F, Cl, Br, I, CN, -NO2 , OH, amino, carboxyl, C1-6 alkyl, C1-6 haloalkyl, C1 -6 alkoxy, C2-6 alkenyl, C2-6 alkynyl, C3-6 cycloalkyl, C6-10 aryl, heterocyclic group consisting of 3-12 ring atoms or 5-10 A heteroaryl group consisting of ring atoms;
各n分别独立地为1，2，3或4；each n is independently 1, 2, 3 or 4;
各g分别独立地为0，1，2，3或4；each g is independently 0, 1, 2, 3 or 4;
各p分别独立地为1或2。Each p is 1 or 2 independently.
根据本发明的实施例，Cy1或Cy2分别独立地为苯环，C6-10芳基，5-10个环原子组成的杂芳基，C3-6环烷基或3-12个环原子组成的杂环基。According to an embodiment of the present invention, Cy1 or Cy2 are independently a benzene ring, a C6-10 aryl group, a heteroaryl group consisting of 5-10 ring atoms, a C3-6 cycloalkyl group or 3-12 A heterocyclic group composed of ring atoms.
根据本发明的实施例，各Rh1分别独立地为氢，氘，F，Cl，Br，I，CN，OH，NO2，NH2，COOH，C1-4烷基，C1-4卤代烷基，C1-4烷氧基，C2-4烯基，C2-4炔基，C3-6环烷基，C6-10芳基，3-12个环原子组成的杂环基，5-10个环原子组成的杂芳基，Rg-(CRmRw)g-O-(CRmRw)g-，Rg-(CRmRw)g-S-(CRmRw)g-，Rg-(CRmRw)g-N(R1a)-(CRmRw)g-，Rg-(CRmRw)g-，Rg-(CRmRw)g-(CR1a＝CR1a)n-(CRmRw)g-，Rg-(CRmRw)g-(C≡C)n-(CRmRw)g-，Rg-(CRmRw)g-S(＝O)p-(CRmRw)g-，Rg-(CRmRw)g-C(＝O)-(CRmRw)g-，Rg-(CRmRw)g-C(＝O)-O-(CRmRw)g-，Rg-(CRmRw)g-O-C(＝O)-(CRmRw)g-，Rg-(CRmRw)g-S(＝O)p-N(R1a)-(CRmRw)g-，Rg-(CRmRw)g-N(R1a)-S(＝O)p-(CRmRw)g-，Rg-(CRmRw)g-C(＝O)-N(R1a)-(CRmRw)g-或Rg-(CRmRw)g-N(R1a)-C(＝O)-(CRmRw)g-；According to an embodiment of the present invention, each Rh1 is independently hydrogen, deuterium, F, Cl, Br, I, CN, OH, NO2 , NH2 , COOH, C1-4 alkyl, C1-4 haloalkane C1-4 alkoxy, C2-4 alkenyl, C2-4 alkynyl, C3-6 cycloalkyl, C6-10 aryl, heterocyclic group composed of 3-12 ring atoms , heteroaryl group consisting of 5-10 ring atoms, Rg -(CRm Rw )g -O-(CRm Rw )g -, Rg -(CRm Rw )g -S-(CRm Rw )g -, Rg -(CRm Rw )g -N(R1a )-(CRm Rw )g -, Rg -(CRm Rw )g -, Rg -(CRm Rw )g -(CR1a ＝CR1a )n -(CRm Rw )g -, Rg -(CRm Rw )g -(C≡C)n -(CRm Rw )g - , Rg -(CRm Rw )g -S(=O)p -(CRm Rw )g -, Rg -(CRm Rw )g -C(=O)-(CRm Rw )g -, Rg -(CRm Rw )g -C(=O)-O-(CRm Rw )g -, Rg -(CRm Rw )g -OC(=O)-( CRm Rw )g -, Rg -(CRm Rw )g -S(=O)p -N(R1a )-(CRm Rw )g -, Rg -(CRm Rw )g -N(R1a )-S(=O)p -(CRm Rw )g -, Rg -(CRm Rw )g -C(=O)-N(R1a )-(CRm Rw )g - or Rg -(CRm Rw )g -N(R1a )-C(=O)-(CRm Rw )g -;
各Rh2分别独立地为氢，氘，F，Cl，Br，I，CN，OH，NO2，NH2，COOH，C1-4烷基，C1-4卤代烷基，C1-4烷氧基，C2-4烯基，C2-4炔基，C3-6环烷基，C6-10芳基，3-12个环原子组成的杂环基，5-10个环原子组成的杂芳基，Rg-(CRmRw)g-O-(CRmRw)g-，Rg-(CRmRw)g-S-(CRmRw)g-，Rg-(CRmRw)g-N(R1a)-(CRmRw)g-，Rg-(CRmRw)g-，Rg-(CRmRw)g-(CR1a＝CR1a)n-(CRmRw)g-，Rg-(CRmRw)g-(C≡C)n-(CRmRw)g-，Rg-(CRmRw)g-S(＝O)p-(CRmRw)g-，Rg-(CRmRw)g-C(＝O)-(CRmRw)g-，Rg-(CRmRw)g-C(＝O)-O-(CRmRw)g-，Rg-(CRmRw)g-O-C(＝O)-(CRmRw)g-，Rg-(CRmRw)g-S(＝O)p-N(R1a)-(CRmRw)g-，Rg-(CRmRw)g-N(R1a)-S(＝O)p-(CRmRw)g-，Rg-(CRmRw)g-C(＝O)-N(R1a)-(CRmRw)g-或Rg-(CRmRw)g-N(R1a)-C(＝O)-(CRmRw)g-；Each Rh2 is independently hydrogen, deuterium, F, Cl, Br, I, CN, OH, NO2 , NH2 , COOH, C1-4 alkyl, C1-4 haloalkyl, C1-4 alkane Oxygen, C2-4 alkenyl, C2-4 alkynyl, C3-6 cycloalkyl, C6-10 aryl, heterocyclic group consisting of 3-12 ring atoms, 5-10 ring atoms Heteroaryl consisting of, Rg -(CRm Rw )g -O-(CRm Rw )g -, Rg -(CRm Rw )g -S-(CRm Rw )g -, Rg -(CRm Rw )g -N(R1a )-(CRm Rw )g -, Rg -(CRm Rw )g -, Rg -(CRm Rw )g -( CR1a ＝CR1a )n -(CRm Rw )g -, Rg -(CRm Rw )g -(C≡C)n -(CRm Rw )g -, Rg -(CRm Rw )g -S(=O)p -(CRm Rw )g -, Rg -(CRm Rw )g -C(=O)-(CRm Rw )g -, Rg - (CRm Rw )g -C(=O)-O-(CRm Rw )g -, Rg -(CRm Rw )g -OC(=O)-(CRm Rw )g - , Rg -(CRm Rw )g -S(=O)p -N(R1a )-(CRm Rw )g -, Rg -(CRm Rw )g -N(R1a ) -S(=O)p -(CRm Rw )g -, Rg -(CRm Rw )g -C(=O)-N(R1a )-(CRm Rw )g - or Rg -(CRm Rw )g -N(R1a )-C(=O)-(CRm Rw )g -;
各Rh1分别独立地被1、2、3、4、5或6个Rh3所取代；EachRh1 is independently replaced by 1, 2, 3, 4, 5 or 6Rh3 ;
各Rh2分别独立地被1、2、3、4、5或6个Rh4所取代；EachRh2 is independently replaced by 1, 2, 3, 4, 5 or 6Rh4 ;
各Rh3分别独立地为氢，氘，F，Cl，Br，I，CN，OH，NO2，NH2，COOH，C1-4烷基，C1-4卤代烷基，C1-4烷氧基，C2-4烯基，C2-4炔基，C3-6环烷基，Rg1-(CRmRw)g-O-(CRmRw)g-，Rg1-(CRmRw)g-S-(CRmRw)g-，Rg1-(CRmRw)g-N(R1a)-(CRmRw)g-，Rg1-(CRmRw)g-，Rg1-(CRmRw)g-(CR1a＝CR1a)n-(CRmRw)g-，Rg1-(CRmRw)g-(C≡C)n-(CRmRw)g-，Rg1-(CRmRw)g-S(＝O)p-(CRmRw)g-，Rg1-(CRmRw)g-C(＝O)-(CRmRw)g-，Rg1-(CRmRw)g-C(＝O)-O-(CRmRw)g-，Rg1-(CRmRw)g-O-C(＝O)-(CRmRw)g-，Rg1-(CRmRw)g-S(＝O)p-N(R1a)-(CRmRw)g-，Rg1-(CRmRw)g-N(R1a)-S(＝O)p-(CRmRw)g-，Rg1-(CRmRw)g-C(＝O)-N(R1a)-(CRmRw)g-或Rg1-(CRmRw)g-N(R1a)-C(＝O)-(CRmRw)g-；Each Rh3 is independently hydrogen, deuterium, F, Cl, Br, I, CN, OH, NO2 , NH2 , COOH, C1-4 alkyl, C1-4 haloalkyl, C1-4 alkane Oxygen, C2-4 alkenyl, C2-4 alkynyl, C3-6 cycloalkyl, Rg1 -(CRm Rw )g -O-(CRm Rw )g -, Rg1 - (CRm Rw )g -S-(CRm Rw )g -, Rg1 -(CRm Rw )g -N(R1a )-(CRm Rw )g -, Rg1 -(CRm Rw )g -, Rg1 -(CRm Rw )g -(CR1a ＝CR1a )n -(CRm Rw )g -, Rg1 -(CRm Rw )g -(C≡ C)n -(CRm Rw )g -, Rg1 -(CRm Rw )g -S(=O)p -(CRm Rw )g -, Rg1 -(CRm Rw )g -C(=O)-(CRm Rw )g -, Rg1 -(CRm Rw )g -C(=O)-O-(CRm Rw )g -, Rg1 -(CRm Rw )g -OC(=O)-(CRm Rw )g -, Rg1 -(CRm Rw )g -S(=O)p -N(R1a )-(CRm Rw )g -, Rg1 -(CRm Rw )g -N(R1a )-S(=O)p -(CRm Rw )g -, Rg1 -(CRm Rw )g -C(= O)-N(R1a )-(CRm Rw )g - or Rg1 -(CRm Rw )g -N(R1a )-C(=O)-(CRm Rw )g -;
各Rh4分别独立地为氢，氘，F，Cl，Br，I，CN，OH，NO2，NH2，COOH，C1-4烷基，C1-4卤代烷基，C1-4烷氧基，C2-4烯基，C2-4炔基，C3-6环烷基，Rg1-(CRmRw)g-O-(CRmRw)g-，Rg1-(CRmRw)g-S-(CRmRw)g-，Rg1-(CRmRw)g-N(R1a)-(CRmRw)g-，Rg1-(CRmRw)g-，Rg1-(CRmRw)g-(CR1a＝CR1a)n-(CRmRw)g-，Rg1-(CRmRw)g-(C≡C)n-(CRmRw)g-，Rg1-(CRmRw)g-S(＝O)p-(CRmRw)g-，Rg1-(CRmRw)g-C(＝O)-(CRmRw)g-，Rg1-(CRmRw)g-C(＝O)-O-(CRmRw)g-，Rg1-(CRmRw)g-O-C(＝O)-(CRmRw)g-，Rg1-(CRmRw)g-S(＝O)p-N(R1a)-(CRmRw)g-，Rg1-(CRmRw)g-N(R1a)-S(＝O)p-(CRmRw)g-，Rg1-(CRmRw)g-C(＝O)-N(R1a)-(CRmRw)g-或Rg1-(CRmRw)g-N(R1a)-C(＝O)-(CRmRw)g-；Each Rh4 is independently hydrogen, deuterium, F, Cl, Br, I, CN, OH, NO2 , NH2 , COOH, C1-4 alkyl, C1-4 haloalkyl, C1-4 alkane Oxygen, C2-4 alkenyl, C2-4 alkynyl, C3-6 cycloalkyl, Rg1 -(CRm Rw )g -O-(CRm Rw )g -, Rg1 - (CRm Rw )g -S-(CRm Rw )g -, Rg1 -(CRm Rw )g -N(R1a )-(CRm Rw )g -, Rg1 -(CRm Rw )g -, Rg1 -(CRm Rw )g -(CR1a ＝CR1a )n -(CRm Rw )g -, Rg1 -(CRm Rw )g -(C≡ C)n -(CRm Rw )g -, Rg1 -(CRm Rw )g -S(=O)p -(CRm Rw )g -, Rg1 -(CRm Rw)g - C(=O)-(CRm Rw )g -, Rg1 -(CRm Rw )g -C(=O)-O-(CRm Rw )g -, Rg1 -(CRm Rw )g -OC(=O)-(CRm Rw )g -, Rg1 -(CRm Rw )g -S(=O)p -N(R1a )-(CRm Rw )g -, Rg1 -(CRm Rw )g -N(R1a )-S(=O)p -(CRm Rw )g -, Rg1 -(CRm Rw )g -C(=O )-N(R1a )-(CRm Rw )g - or Rg1 -(CRm Rw )g -N(R1a )-C(=O)-(CRm Rw )g -;
各Rg分别独立地为H、氘、F、Cl、Br、I、CN、-NO2、OH、氨基、羧基、C1-4烷基、C1-4卤代烷基、C1-4烷氧基、C2-4烯基、C2-4炔基、C3-6环烷基、C6-10芳基、3-12个环原子组成的杂环基或5-10个环原子组成的杂芳基；Each Rg is independently H, deuterium, F, Cl, Br, I, CN, -NO2 , OH, amino, carboxyl, C1-4 alkyl, C1-4 haloalkyl, C1-4 alkane Oxygen, C2-4 alkenyl, C2-4 alkynyl, C3-6 cycloalkyl, C6-10 aryl, heterocyclic group consisting of 3-12 ring atoms or 5-10 ring atoms Consisting of heteroaryl;
各Rg1分别独立地为H、氘、F、Cl、Br、I、CN、-NO2、OH、氨基、羧基、C1-4烷基、C1-4卤代烷基、C1-4烷氧基、C2-4烯基、C2-4炔基、C3-6环烷基、C6-10芳基、3-12个环原子组成的杂环基或5-10个环原子组成的杂芳基。Each Rg1 is independently H, deuterium, F, Cl, Br, I, CN, -NO2 , OH, amino, carboxyl, C1-4 alkyl, C1-4 haloalkyl, C1-4 alkane Oxygen, C2-4 alkenyl, C2-4 alkynyl, C3-6 cycloalkyl, C6-10 aryl, heterocyclic group consisting of 3-12 ring atoms or 5-10 ring atoms Composition of heteroaryl.
根据本发明的实施例，各R1a分别独立地为H，氘，F，Cl，Br，I，CN，NO2，OH，氨基，羧基，C1-4烷基，C1-4卤代烷基、C1-4烷氧基、C2-4烯基、C2-4炔基、C3-6环烷基、C6-10芳基、3-12个环原子组成的杂环基或5-10个环原子组成的杂芳基；According to an embodiment of the present invention, each R1a is independently H, deuterium, F, Cl, Br, I, CN, NO2 , OH, amino, carboxyl, C1-4 alkyl, C1-4 haloalkyl , C1-4 alkoxy, C2-4 alkenyl, C2-4 alkynyl, C3-6 cycloalkyl, C6-10 aryl, heterocyclic group consisting of 3-12 ring atoms or Heteroaryl consisting of 5-10 ring atoms;
各Rm或Rw分别独立地为H、氘、F、Cl、Br、I、CN、-NO2、OH、氨基、羧基、C1-4烷基、C1-4卤代烷基、C1-4烷氧基、C2-4烯基、C2-4炔基、C3-6环烷基、C6-10芳基、3-12个环原子组成的杂环基或5-10个环原子组成的杂芳基。Each Rm or Rw is independently H, deuterium, F, Cl, Br, I, CN, -NO2 , OH, amino, carboxyl, C1-4 alkyl, C1-4 haloalkyl, C1 -4 alkoxy, C2-4 alkenyl, C2-4 alkynyl, C3-6 cycloalkyl, C6-10 aryl, heterocyclic group consisting of 3-12 ring atoms or 5-10 A heteroaryl group consisting of ring atoms.
根据本发明的实施例，Cy1或Cy2分别独立地为According to an embodiment of the present invention, Cy1 or Cy2 are independently
根据本发明的实施例，各Rh1分别独立地为氢，氘，F，Cl，Br，I，CN，OH，NO2，NH2，COOH，甲基，乙基，正丙基，异丙基，正丁基，异丁基，叔丁基，-CH2F，-CHF2，-CF3，-CH2Cl，-CHCl2，-CCl3，-CH2Br，-CHBr2，-CBr3，-CH2CHF2，-CH2CF3，-CHFCF3，-CF2CHF2，-CF2CF3，-CH2CH2CF3，-CH2CF2CHF2，Rg-(CRmRw)g-O-(CRmRw)g-，Rg-(CRmRw)g-S-(CRmRw)g-，Rg-(CRmRw)g-N(R1a)-(CRmRw)g-或Rg-(CRmRw)g-；According to an embodiment of the present invention, each Rh1 is independently hydrogen, deuterium, F, Cl, Br, I, CN, OH, NO2 , NH2 , COOH, methyl, ethyl, n-propyl, isopropyl Base, n-butyl, isobutyl, tert-butyl, -CH2 F, -CHF2 , -CF3 , -CH2 Cl, -CHCl2 , -CCl3 , -CH2 Br, -CHBr2 , - CBr3 , -CH2 CHF2 , -CH2 CF3 , -CHFCF3 , -CF2 CHF2 , -CF2 CF3 , -CH2 CH2 CF3 , -CH2 CF2 CHF2 , Rg - (CRm Rw )g -O-(CRm Rw )g -, Rg -(CRm Rw )g -S-(CRm Rw )g -, Rg -(CRm Rw )g -N(R1a )-(CRm Rw )g - or Rg -(CRm Rw )g -;
各Rh2分别独立地为氢，氘，F，Cl，Br，I，CN，OH，NO2，NH2，COOH，甲基，乙基，正丙基，异丙基，正丁基，异丁基或叔丁基；Each Rh2 is independently hydrogen, deuterium, F, Cl, Br, I, CN, OH, NO2 , NH2 , COOH, methyl, ethyl, n-propyl, isopropyl, n-butyl, iso Butyl or tert-butyl;
各Rh1分别独立地被1、2、3、4、5或6个Rh3所取代；EachRh1 is independently replaced by 1, 2, 3, 4, 5 or 6Rh3 ;
各Rh2分别独立地被1、2、3、4、5或6个Rh4所取代；EachRh2 is independently replaced by 1, 2, 3, 4, 5 or 6Rh4 ;
各Rh3分别独立地为氢，氘，F，Cl，Br，I，CN，OH，NO2，NH2，COOH，甲基，乙基，正丙基，异丙基，正丁基，异丁基，叔丁基，-Rg1-(CRmRw)g-S(＝O)p-(CRmRw)g-，Rg1-(CRmRw)g-C(＝O)-(CRmRw)g-，Rg1-(CRmRw)g-C(＝O)-O-(CRmRw)g-，Rg1-(CRmRw)g-O-C(＝O)-(CRmRw)g-，Rg1-(CRmRw)g-S(＝O)p-N(R1a)-(CRmRw)g-，Rg1-(CRmRw)g-N(R1a)-S(＝O)p-(CRmRw)g-，Rg1-(CRmRw)g-C(＝O)-N(R1a)-(CRmRw)g-或Rg1-(CRmRw)g-N(R1a)-C(＝O)-(CRmRw)g-；Each Rh3 is independently hydrogen, deuterium, F, Cl, Br, I, CN, OH, NO2 , NH2 , COOH, methyl, ethyl, n-propyl, isopropyl, n-butyl, iso Butyl, tert-butyl, -Rg1 -(CRm Rw )g -S(=O)p -(CRm Rw )g -, Rg1 -(CRm Rw )g -C(=O )-(CRm Rw )g -, Rg1 -(CRm Rw )g -C(=O)-O-(CRm Rw )g -, Rg1 -(CRm Rw )g - OC(=O)-(CRm Rw )g -, Rg1 -(CRm Rw )g -S(=O)p -N(R1a )-(CRm Rw )g -, Rg1 -(CRm Rw )g -N(R1a )-S(=O)p -(CRm Rw )g -, Rg1 -(CRm Rw )g -C(=O)-N( R1a )-(CRm Rw )g - or Rg1 -(CRm Rw )g -N(R1a )-C(=O)-(CRm Rw )g -;
各Rh4分别独立地为氢，氘，F，Cl，Br，I，CN，OH，NO2，NH2，COOH，甲基，乙基，正丙基，异丙基，正丁基，异丁基或叔丁基；Each Rh4 is independently hydrogen, deuterium, F, Cl, Br, I, CN, OH, NO2 , NH2 , COOH, methyl, ethyl, n-propyl, isopropyl, n-butyl, iso Butyl or tert-butyl;
各Rg分别独立地为Each Rg is independently
各Rg1分别独立地为H，氘，甲基，乙基，正丙基、异丙基、正丁基、异丁基或叔丁基。Each Rg1 is independently H, deuterium, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl.
根据本发明的实施例，各R1a分别独立地为H，氘，甲基，乙基，正丙基，异丙基，正丁基，异丁基或叔丁基；According to an embodiment of the present invention, each R1a is independently H, deuterium, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl;
各Rm、Rw或Rg分别独立地为H、氘、甲基，乙基，正丙基，异丙基，正丁基，异丁基或叔丁基。Each Rm , Rw or Rg is independently H, deuterium, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl.
根据本发明的实施例，所述X为式III-1、III-2、III-3、III-4、III-5或III-6所示化合物，According to an embodiment of the present invention, the X is a compound represented by formula III-1, III-2, III-3, III-4, III-5 or III-6,
根据本发明的实施例，所述Z为式IV所示化合物，According to an embodiment of the present invention, the Z is a compound represented by formula IV,
其中，Q为N或CR2；Wherein, Q is N or CR2 ;
M为C(ReRf)，N(R1b)，O或S；M is C(Re Rf ), N(R1b ), O or S;
W，K分别独立地为C(ReRf)，N(R1b)，O或S；W and K are independently C(Re Rf ), N(R1b ), O or S;
R2为氢，氘，F，Cl，Br，I，CN，OH，NO2，NH2，COOH，C1-6烷基，C1-6卤代烷基、C1-6烷氧基、C2-6烯基或C2-6炔基；R2 is hydrogen, deuterium, F, Cl, Br, I, CN, OH, NO2 , NH2 , COOH, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, C2-6 alkenyl or C2-6 alkynyl;
各R2a、R2b分别独立地为氢，氘，F，Cl，Br，I，CN，OH，NO2，NH2，COOH，氧代，C1-6烷基，C1-6卤代烷基，C1-6烷氧基，C2-6烯基，C2-6炔基，C3-12环烷基，C6-12芳基，3-12个环原子组成的杂环基或5-12个环原子组成的杂芳基；Each R2a and R2b are independently hydrogen, deuterium, F, Cl, Br, I, CN, OH, NO2 , NH2 , COOH, oxo, C1-6 alkyl, C1-6 haloalkyl , C1-6 alkoxy, C2-6 alkenyl, C2-6 alkynyl, C3-12 cycloalkyl, C6-12 aryl, heterocyclic group consisting of 3-12 ring atoms or Heteroaryl consisting of 5-12 ring atoms;
各R2c分别独立地为氢，氘，F，Cl，Br，I，CN，OH，NO2，NH2，COOH，C1-6烷基，C1-6卤代烷基，C1-6烷氧基，C2-6烯基，C2-6炔基，C3-12环烷基，C6-12芳基，3-12个环原子组成的杂环基或5-12个环原子组成的杂芳基；Each R2c is independently hydrogen, deuterium, F, Cl, Br, I, CN, OH, NO2 , NH2 , COOH, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkane Oxygen, C2-6 alkenyl, C2-6 alkynyl, C3-12 cycloalkyl, C6-12 aryl, heterocyclic group consisting of 3-12 ring atoms or 5-12 ring atoms Consisting of heteroaryl;
各Re、Rf分别独立地为H、氘、F、Cl、Br、I、CN、-NO2、OH、氨基、羧基、C1-6烷基、C1-6卤代烷基、C1-6烷氧基、C2-6烯基、C2-6炔基、C3-6环烷基、C6-10芳基、3-12个环原子组成的杂环基或5-10个环原子组成的杂芳基；Each Re and Rf are independently H, deuterium, F, Cl, Br, I, CN, -NO2 , OH, amino, carboxyl, C1-6 alkyl, C1-6 haloalkyl, C1 -6 alkoxy, C2-6 alkenyl, C2-6 alkynyl, C3-6 cycloalkyl, C6-10 aryl, heterocyclic group consisting of 3-12 ring atoms or 5-10 A heteroaryl group consisting of ring atoms;
各R1b分别独立地为H，氘，F，Cl，Br，I，CN，-NO2，OH，氨基，羧基，C1-6烷基，C1-6卤代烷基，C1-6烷氧基，C2-6烯基，C2-6炔基，C3-12环烷基，C6-12芳基，3-12个环原子组成的杂环基或5-12个环原子组成的杂芳基；Each R1b is independently H, deuterium, F, Cl, Br, I, CN, -NO2 , OH, amino, carboxyl, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkane Oxygen, C2-6 alkenyl, C2-6 alkynyl, C3-12 cycloalkyl, C6-12 aryl, heterocyclic group consisting of 3-12 ring atoms or 5-12 ring atoms Consisting of heteroaryl;
n1、n2分别独立地为0、1、2或3；n1 and n2 are independently 0, 1, 2 or 3;
n3为0、1、2、3、4或5。n3 is 0, 1, 2,3 , 4 or 5.
根据本发明的实施例，R2为氢，氘，F，Cl，Br，I，CN，OH，NO2，NH2，COOH，C1-4烷基，C1-4卤代烷基，C1-4烷氧基，C2-4烯基或C2-4炔基。According to an embodiment of the present invention, R2 is hydrogen, deuterium, F, Cl, Br, I, CN, OH, NO2 , NH2 , COOH, C1-4 alkyl, C1-4 haloalkyl, C1 -4 alkoxy, C2-4 alkenyl or C2-4 alkynyl.
根据本发明的实施例，各R2a、R2b分别独立地为氢，氘，F，Cl，Br，I，CN，OH，NO2，NH2，COOH，氧代，C1-4烷基，C1-4卤代烷基，C1-4烷氧基，C2-4烯基，C2-4炔基，C3-6环烷基，C6-10芳基，3-12个环原子组成的杂环基或5-10个环原子组成的杂芳基；According to an embodiment of the present invention, each R2a and R2b are independently hydrogen, deuterium, F, Cl, Br, I, CN, OH, NO2 , NH2 , COOH, oxo, C1-4 alkyl , C1-4 haloalkyl, C1-4 alkoxy, C2-4 alkenyl, C2-4 alkynyl, C3-6 cycloalkyl, C6-10 aryl, 3-12 rings A heterocyclic group composed of atoms or a heteroaryl group composed of 5-10 ring atoms;
各R2c分别独立地为氢，氘，F，Cl，Br，I，CN，OH，NO2，NH2，COOH，C1-4烷基，C1-4卤代烷基，C1-4烷氧基，C2-4烯基，C2-4炔基，C3-6环烷基，C6-10芳基，3-12个环原子组成的杂环基或5-10个环原子组成的杂芳基。Each R2c is independently hydrogen, deuterium, F, Cl, Br, I, CN, OH, NO2 , NH2 , COOH, C1-4 alkyl, C1-4 haloalkyl, C1-4 alkane Oxygen, C2-4 alkenyl, C2-4 alkynyl, C3-6 cycloalkyl, C6-10 aryl, heterocyclic group consisting of 3-12 ring atoms or 5-10 ring atoms Composition of heteroaryl.
根据本发明的实施例，各Re、Rf分别独立地为H、氘、F、Cl、Br、I、CN、-NO2、OH、氨基、羧基、C1-4烷基、C1-4卤代烷基、C1-4烷氧基、C2-4烯基、C2-4炔基、C3-6环烷基、C6-10芳基、3-12个环原子组成的杂环基或5-10个环原子组成的杂芳基；According to an embodiment of the present invention, each Re and Rf are independently H, deuterium, F, Cl, Br, I, CN, -NO2 , OH, amino, carboxyl, C1-4 alkyl, C1 -4 haloalkyl, C1-4 alkoxy, C2-4 alkenyl, C2-4 alkynyl, C3-6 cycloalkyl, C6-10 aryl, 3-12 ring atoms Heterocyclic group or heteroaryl group composed of 5-10 ring atoms;
各R1b分别独立地为H，氘，F，Cl，Br，I，CN，-NO2，OH，氨基，羧基，C1-4烷基，C1-4卤代烷基，C1-4烷氧基，C2-4烯基，C2-4炔基，C3-6环烷基，C6-10芳基，3-12个环原子组成的杂环基或5-10个环原子组成的杂芳基。Each R1b is independently H, deuterium, F, Cl, Br, I, CN, -NO2 , OH, amino, carboxyl, C1-4 alkyl, C1-4 haloalkyl, C1-4 alkane Oxygen, C2-4 alkenyl, C2-4 alkynyl, C3-6 cycloalkyl, C6-10 aryl, heterocyclic group consisting of 3-12 ring atoms or 5-10 ring atoms Composition of heteroaryl.
根据本发明的实施例，R2为氢，氘，甲基，乙基，正丙基，异丙基，正丁基，异丁基或叔丁基。According to an embodiment of the present invention, R2 is hydrogen, deuterium, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl.
根据本发明的实施例，各R2a、R2b分别独立地为氢，氘，氧代，甲基，乙基，正丙基，异丙基，正丁基，异丁基或叔丁基；According to an embodiment of the present invention, each R2a and R2b are independently hydrogen, deuterium, oxo, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl;
各R2c分别独立地为氢，氘，甲基，乙基，正丙基，异丙基，正丁基，异丁基或叔丁基。Each R2c is independently hydrogen, deuterium, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl.
根据本发明的实施例，各Re、Rf分别独立地为氢，氘，甲基，乙基，正丙基，异丙基，正丁基，异丁基或叔丁基；According to an embodiment of the present invention, each Re and Rf are independently hydrogen, deuterium, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl;
各R1b分别独立地为H，氘，甲基，乙基，正丙基，异丙基，正丁基，异丁基或叔丁基。Each R1b is independently H, deuterium, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl.
根据本发明的实施例，所述Z为式V-1、V-2、V-3、V-4或V-5所示化合物，According to an embodiment of the present invention, the Z is a compound represented by formula V-1, V-2, V-3, V-4 or V-5,
根据本发明的实施例，所述Y为含有1～30个原子的基团，所述原子包括选自碳原子、硫原子、氧原子、氮原子、硒原子的至少之一。According to an embodiment of the present invention, the Y is a group containing 1 to 30 atoms, and the atoms include at least one selected from carbon atoms, sulfur atoms, oxygen atoms, nitrogen atoms, and selenium atoms.
根据本发明的实施例，所述Y为C1-20烷基、C1-20卤代烷基、C1-20烷氧基、C2-20烯基、C2-20炔基、C3-12环烷基、C6-12芳基、3-12个环原子组成的杂环基或5-12个环原子组成的杂芳基的至少之一构成的基团。According to an embodiment of the present invention, the Y is C1-20 alkyl, C1-20 haloalkyl, C1-20 alkoxy, C2-20 alkenyl, C2-20 alkynyl, C3- A group consisting of at least one of12 cycloalkyl groups, C6-12 aryl groups, heterocyclic groups consisting of 3-12 ring atoms or heteroaryl groups consisting of 5-12 ring atoms.
根据本发明的实施例，所述Y为其中，x1-x23分别独立地为一个键，According to an embodiment of the present invention, the Y is Wherein, x1 -x23 are each independently a key,
R1d为H，氘，F，Cl，Br，I，CN，-NO2，OH，氨基，羧基或C1-4烷基。R1d is H, deuterium, F, Cl, Br, I, CN, -NO2 , OH, amino, carboxy or C1-4 alkyl.
根据本发明的实施例，所述Y为式VI-1或VI-2所示化合物，According to an embodiment of the present invention, the Y is a compound represented by formula VI-1 or VI-2,
各r分别独立地为0～12之间的整数；Each r is independently an integer between 0 and 12;
各k分别独立地为0～12之间的整数；Each k is independently an integer between 0 and 12;
各j分别独立地为0～12之间的整数；Each j is independently an integer between 0 and 12;
各t1或t3分别独立地为键，Each t1 or t3 is independently a bond,
各t2或t4分别独立地为键，Each t2 or t4 is independently a bond,
t5为键或t5 is the key or
R1d为H，氘，甲基，乙基，正丙基，异丙基，正丁基，异丁基或叔丁基。R1d is H, deuterium, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl.
在本发明的第二方面，本发明提出了一种化合物，其为式1～38任一项所示化合物或其立体异构体、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 the second aspect of the present invention, the present invention proposes a compound, which is a compound represented by any one of formulas 1 to 38 or its stereoisomers, geometric isomers, tautomers, nitrogen oxides, Hydrates, solvates, metabolites, pharmaceutically acceptable salts or prodrugs,
在本发明的第三方面，本发明提出了一种药物组合物。根据本发明的实施例，所述药物组合物包括上述任一项所述的化合物。In the third aspect of the present invention, the present invention proposes a pharmaceutical composition. According to an embodiment of the present invention, the pharmaceutical composition includes the compound described in any one of the above.
根据本发明的实施例，上述药物组合物还可进一步包括如下附加技术特征至少之一：According to an embodiment of the present invention, the above pharmaceutical composition may further include at least one of the following additional technical features:
根据本发明的实施例，所述药物组合物进一步包括辅料。According to an embodiment of the present invention, the pharmaceutical composition further includes excipients.
根据本发明的实施例，所述药物组合物进一步包括用于避孕的药物或其他治疗或预防肿瘤或生殖系统有关的疾病的药物。According to an embodiment of the present invention, the pharmaceutical composition further includes drugs for contraception or other drugs for treating or preventing tumors or diseases related to the reproductive system.
根据本发明的实施例，所述肿瘤或生殖系统有关的疾病包括选自乳腺癌、卵巢癌、宫颈癌、肺癌、肝癌、胃癌、结直肠癌、皮肤癌、脑癌、骨肉瘤的至少之一。According to an embodiment of the present invention, the tumor or reproductive system-related diseases include at least one selected from breast cancer, ovarian cancer, cervical cancer, lung cancer, liver cancer, gastric cancer, colorectal cancer, skin cancer, brain cancer, and osteosarcoma. .
根据本发明的实施例，所述其他治疗或预防肿瘤或生殖系统有关的疾病的药物包括选自非替尼、阿法替尼、西妥昔单抗、Gamendazole、testosterone的至少之一。According to an embodiment of the present invention, the other drugs for treating or preventing tumors or diseases related to the reproductive system include at least one selected from fitinib, afatinib, cetuximab, gamendazole, and testosterone.
在本发明的第四方面，本发明提出了上述任一项所述化合物或上述任一项所述的药物组合物在制备药物中的用途，所述药物用于降解FAK蛋白。In the fourth aspect of the present invention, the present invention proposes the use of any one of the above-mentioned compounds or any one of the above-mentioned pharmaceutical compositions in the preparation of medicines for degrading FAK protein.
在本发明的第五方面，本发明提出了上述中任一项所述化合物或上述任一项所述的药物组合物在制备药物中的用途，所述药物用于治疗或预防肿瘤或生殖系统有关的疾病。In the fifth aspect of the present invention, the present invention proposes the use of any of the compounds described above or the pharmaceutical composition described in any of the above in the preparation of medicines for the treatment or prevention of tumors or reproductive system related diseases.
根据本发明的一些实施例，所述肿瘤或生殖系统有关的疾病包括选自乳腺癌、卵巢癌、宫颈癌、肺癌、肝癌、胃癌、结直肠癌、皮肤癌、脑癌、骨肉瘤的至少之一。According to some embodiments of the present invention, the tumor or reproductive system-related diseases include at least one selected from breast cancer, ovarian cancer, cervical cancer, lung cancer, liver cancer, gastric cancer, colorectal cancer, skin cancer, brain cancer, and osteosarcoma. one.
在本发明的第六方面，本发明提出了一种降解FAK蛋白的方法。根据本发明的实施例，所述方法包括：使FAK蛋白与上述任一项所述的化合物或上述任一项所述的药物组合物接触。In the sixth aspect of the present invention, the present invention provides a method for degrading FAK protein. According to an embodiment of the present invention, the method comprises: contacting FAK protein with any one of the above-mentioned compounds or any one of the above-mentioned pharmaceutical compositions.
在本发明的第七方面，本发明提出了一种治疗或预防肿瘤或生殖系统有关的疾病的方法根据本发明的实施例，所述方法包括给予患者上述任一项所述的化合物或上述任一项所述的药物组合物。In the seventh aspect of the present invention, the present invention proposes a method for treating or preventing tumors or diseases related to the reproductive system. According to an embodiment of the present invention, the method includes administering to patients any of the compounds described above or any of the above-mentioned A described pharmaceutical composition.
根据本发明的一些实施例，所述肿瘤或生殖系统有关的疾病包括选自乳腺癌、卵巢癌、宫颈癌、肺癌、肝癌、胃癌、结直肠癌、皮肤癌、脑癌、骨肉瘤的至少之一。According to some embodiments of the present invention, the tumor or reproductive system-related diseases include at least one selected from breast cancer, ovarian cancer, cervical cancer, lung cancer, liver cancer, gastric cancer, colorectal cancer, skin cancer, brain cancer, and osteosarcoma. one.
附图说明Description of drawings
图1为根据本发明实施例的PROTACs(蛋白裂解靶向嵌合体)的基本技术路线示意图；1 is a schematic diagram of the basic technical route of PROTACs (protein cleavage targeting chimera) according to an embodiment of the present invention;
图2为根据本发明实施例的通过click chemistry(点击反应)制备本发明化合物的示意图；Fig. 2 is a schematic diagram of preparing the compound of the present invention by click chemistry (click reaction) according to an embodiment of the present invention;
图3为根据本发明实施例的PF-562271端衍生物的合成路线示意图及PF-562271结构；Fig. 3 is a schematic diagram of the synthesis route of PF-562271-terminal derivatives and the structure of PF-562271 according to an embodiment of the present invention;
图4为根据本发明实施例的式1-式4所示化合物对FAK的降解作用示意图；4 is a schematic diagram of the degradation of FAK by compounds represented by formulas 1 to 4 according to an embodiment of the present invention;
图5为根据本发明实施例的式5-式10所示化合物对FAK的降解作用示意图；5 is a schematic diagram of the degradation of FAK by compounds represented by formulas 5 to 10 according to an embodiment of the present invention;
图6为根据本发明实施例的式2所示化合物对不同肿瘤细胞系中FAK的半数降解率示意图；Fig. 6 is a schematic diagram of the half-degradation rate of FAK in different tumor cell lines by the compound represented by formula 2 according to an embodiment of the present invention;
图7为根据本发明实施例的式2所示化合物对小鼠卵巢及睾丸相关细胞系中FAK的降解作用示意图；Fig. 7 is a schematic diagram of the degradation effect of the compound represented by formula 2 on FAK in mouse ovary and testis-related cell lines according to an embodiment of the present invention;
图8-1为根据本发明实施例的式2所示化合物对小鼠睾丸原代支持细胞中FAK的降解作用曲线示意图；以及Figure 8-1 is a schematic diagram of the degradation curve of FAK in primary Sertoli cells of mouse testis by the compound represented by formula 2 according to an embodiment of the present invention; and
图8-2为根据本发明实施例的式2所示化合物对小鼠睾丸原代支持细胞中FAK的降解作用结果示意图。Fig. 8-2 is a schematic diagram showing the results of degradation of FAK in primary Sertoli cells of mouse testis by the compound represented by formula 2 according to an embodiment of the present invention.
具体实施方式Detailed ways
下面详细描述本发明的实施例，下面描述的实施例是示例性的，旨在用于解释本发明，而不能理解为对本发明的限制。Embodiments of the present invention are described in detail below, and the embodiments described below are exemplary and intended to explain the present invention, but should not be construed as limiting the present invention.
在本文中所使用的术语“给予患者前面所述的化合或其立体异构体、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或前面所述的药物组合物”指将预定量的物质通过某种适合的方式引入病人。本发明的式I、式II、式III、式IV、式V或式VI所述化合物或其立体异构体、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或者药物组合物可以通过任何常见的途径被给药，只要它可以到达预期的组织。给药的各种方式是可以预期的，包括腹膜，静脉，肌肉，皮下，皮层，口服，局部，鼻腔，肺部和直肠，但是本发明不限于这些已举例的给药方式。As used herein, the term "administering to a patient the aforementioned compounds or their stereoisomers, geometric isomers, tautomers, nitrogen oxides, hydrates, solvates, metabolites, pharmaceutically acceptable "Salt or prodrug or the above-mentioned pharmaceutical composition" refers to introducing a predetermined amount of substance into the patient through some suitable means. Compounds described in Formula I, Formula II, Formula III, Formula IV, Formula V or Formula VI of the present invention or their stereoisomers, geometric isomers, tautomers, nitrogen oxides, hydrates, solvates , metabolite, pharmaceutically acceptable salt or prodrug, or pharmaceutical composition can be administered by any common route as long as it can reach the intended tissue. Various modes of administration are contemplated, including peritoneal, intravenous, intramuscular, subcutaneous, dermal, oral, topical, nasal, pulmonary and rectal, but the invention is not limited to these exemplified modes of administration.
本发明的药物组合物的给药频率和剂量可以通过多个相关因素被确定，该因素包括要被治疗的疾病类型，给药途径，病人年龄，性别，体重和疾病的严重程度以及作为活性成分的药物类型。The administration frequency and dosage of the pharmaceutical composition of the present invention can be determined by a number of related factors, including the type of disease to be treated, the route of administration, the patient's age, sex, body weight and severity of the disease and as the active ingredient type of drug.
术语“治疗”用于指获得期望的药理学和/或生理学效果。所述效果就完全或部分预防疾病或其症状而言可以是预防性的，和/或就部分或完全治愈疾病和/或疾病导致的不良作用而言可以是治疗性的。本文使用的“治疗”涵盖哺乳动物、特别是人的疾病的治疗，包括：(a)在容易患病但是尚未确诊得病的个体中预防疾病或病症发生；(b)抑制疾病；或(c)缓解疾病，例如减轻与疾病相关的症状。本文使用的“治疗”涵盖将药物或化合物给予个体以治疗、治愈、缓解、改善、减轻或抑制个体的疾病的任何用药，包括但不限于将含本文所述式I～式VI或式1～18化合物或药物组合物的给予有需要的个体。The term "treatment" is used to refer to obtaining a desired pharmacological and/or physiological effect. The effect may be prophylactic in terms of complete or partial prevention of the disease or its symptoms, and/or therapeutic in terms of partial or complete cure of the disease and/or adverse effects caused by the disease. "Treatment" as used herein encompasses the treatment of disease in mammals, especially humans, including: (a) preventing the disease or condition from occurring in a predisposed but undiagnosed individual; (b) inhibiting the disease; or (c) Palliation of a disease, such as alleviation of symptoms associated with a disease. "Treatment" as used herein encompasses any administration of a drug or compound to an individual to treat, cure, alleviate, ameliorate, lessen, or inhibit a disease in the individual, including but not limited to those comprising formulas I to VI or formulas 1 to 18. Administration of a compound or pharmaceutical composition to an individual in need thereof.
根据本发明的实施例，所述辅料包括制剂领域公知的可药用的赋形剂、润滑剂、填充剂、稀释剂、崩解剂、稳定剂、防腐剂、乳化剂、助溶剂、着色剂、甜味剂，制成片剂、丸剂、胶囊剂、注射剂等不同剂型。According to an embodiment of the present invention, the excipients include pharmaceutically acceptable excipients, lubricants, fillers, diluents, disintegrants, stabilizers, preservatives, emulsifiers, solubilizers, and colorants known in the field of preparations , sweetener, made into different dosage forms such as tablets, pills, capsules, and injections.
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，它们均包括在如权利要求定义的本发明范围内。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 is intended to cover all alternatives, modifications and equivalent technical solutions, which are included within the scope of the present invention as defined by the claims. 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得下列定义。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.
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, conformers (rotamers), geometric isomers (cis/trans) isomers, atropisomers, etc. .
“手性”是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" is a molecule that has the property of being nonsuperimposable to its mirror image; and "achiral" is 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.
本发明所使用的立体化学定义和规则一般遵循S.P.Parker，Ed.，McGraw-HillDictionary of Chemical Terms(1984)McGraw-Hill Book Company，New York；andEliel，E.and Wilen，S.，“Stereochemistry of Organic Compounds”，John Wiley&Sons，Inc.，New York，1994。The stereochemical definitions and rules used in the present invention generally follow S.P. Parker, Ed., McGraw-Hill Dictionary of Chemical Terms (1984) McGraw-Hill Book Company, New York; and Eliel, E. and Wilen, S., "Stereochemistry of Organic Compounds", John Wiley & Sons, Inc., New York, 1994.
许多有机化合物以光学活性形式存在，即它们具有使平面偏振光的平面发生旋转的能力。在描述光学活性化合物时，使用前缀D和L或R和S来表示分子关于其一个或多个手性中心的绝对构型。前缀d和l或(+)和(-)是用于指定化合物所致平面偏振光旋转的符号，其中(-)或l表示化合物是左旋的。前缀为(+)或d的化合物是右旋的。一种具体的立体异构体是对映异构体，这种异构体的混合物称作对映异构体混合物。对映异构体的50:50混合物称为外消旋混合物或外消旋体，当在化学反应或过程中没有立体选择性或立体特异性时，可出现这种情况。Many organic compounds exist in optically active forms, ie they have the ability to rotate the plane of plane polarized light. In describing optically active compounds, the prefixes D and L or R and S are used to denote the absolute configuration of the molecule with respect to its chiral center or centers. The prefixes d and 1 or (+) and (-) are symbols used to designate rotation of plane polarized light by a compound, where (-) or 1 indicates that the compound is levorotatory. Compounds prefixed with (+) or d are dextrorotatory. A specific stereoisomer is an enantiomer and a mixture of such isomers is called an enantiomeric mixture. A 50:50 mixture of enantiomers is called a racemic mixture or racemate and can occur when there is no stereoselectivity or stereospecificity in a chemical reaction or process.
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.
所得的任何立体异构体的混合物可以依据组分物理化学性质上的差异被分离成纯的或基本纯的几何异构体，对映异构体，非对映异构体，例如，通过色谱法和/或分步结晶法。The resulting mixture of any stereoisomers can be separated into pure or substantially pure geometric isomers, enantiomers, diastereoisomers on the basis of differences in the physicochemical properties of the components, for example, by chromatography method and/or fractional crystallization.
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:APracticalApproach(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 (2nd 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: APractical 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.
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。应了解“任选取代的”这个术语与“取代或非取代的”这个术语可以交换使用。一般而言，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。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只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。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. It should be understood that the term "optionally substituted" and the term "substituted or unsubstituted" are used interchangeably. In general, the term "substituted" means that one or more hydrogen atoms in a given structure have been replaced by a particular substituent. 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 can be substituted at each position the same or differently.
如本发明所描述，取代基R’由一个键连接到中心的环上形成的环体系代表取代基R’可以在该环上任何可取代的位置进行取代。例如，式a代表B’环上任何可能被取代的位置均可被R’取代，如式b，式c和式d所示。As described in the present invention, the ring system formed by the substituent R' attached to the central ring by a bond means that the substituent R' can be substituted at any substitutable position on the ring. For example, formula a represents that any position that may be substituted on the B' ring can be substituted by R', as shown in formula b, formula c and formula d.
如本发明所描述，环上的附着点可以在该环上任何可连接的位置与分子其余部分连接。例如，式i代表B’环上任何可能被连接的位置均可作为连接点，如式d、e和f所示。As described in the invention, the attachment point on the ring Attachment to the rest of the molecule can be at any attachable position on the loop. For example, formula i represents that any position on the B' ring that may be connected can be used as a connection point, as shown in formulas d, e and f.
如本发明所描述，同一个环上的两个附着点可以在该环上任何可连接的两个不同的位置与分子其余两部分分别连接，且两端的连接方式可以互换。例如，式j代表D环上任何可能被连接的两个不同的位置均可作为连接点与分子其余两部分分别连接，如式g、h和k所示。As described in the present invention, two attachment points on the same ring Any two different positions that can be connected on the ring can be connected to the other two parts of the molecule respectively, and the connection methods at both ends can be interchanged. For example, formula j represents that any two different positions that may be connected on the D ring can be used as connection points to connect with the other two parts of the molecule respectively, as shown in formulas g, h and k.
如本发明所描述的，若链状结构上有两个连接点可与分子其余部分相连，则两端的连接方式可以互换。像本发明所描述的，例如，“-(CRmRw)g-O-C(＝O)-(CRmRw)g-”或“-(CRmRw)g-S(＝O)p-N(R1a)-(CRmRw)g-”两端的连接方式可以互换。As described in the present invention, if there are two connection points on the chain structure that can be connected to the rest of the molecule, the connection mode of the two ends can be interchanged. As described in the present invention, for example, "-(CRm Rw )g -OC(=O)-(CRm Rw )g -" or "-(CRm Rw )g -S(=O)p -N(R1a )-(CRm Rw )g -" can be interchanged.
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。再例如，0～12之间的整数包括端点0和12，以及0～12之间的任何一个整数，如1、2、3、4、5、6、7、8、9、10或11.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 "C1-6 alkyl" specifically refers to independently disclosed methyl, ethyl, C3 alkyl, C4 alkyl, C5 alkyl and C6 alkyl. For another example, an integer between 0 and 12 includes endpoints 0 and 12, and any integer between 0 and 12, such as 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or 11.
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.
除非另有说明，术语“烷基”，表示1-20个碳原子，或1-10个碳原子，或1-8个碳原子，或1-6个碳原子，或1-4个碳原子，或1-3个碳原子的饱和直链或支链的单价烃基，其中烷基可以独立且任选地被一个或多个本发明所描述的取代基所取代，取代基包括但不限于，氘、氨基、羟基、氰基、F、Cl、Br、I、巯基、硝基、氧代(＝O)等等。烷基的实例包括，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。术语“烷基”和其前缀“烷”在此处使用，都包含直链和支链的饱和碳链。术语“烷撑”在此处使用，表示从直链或支链饱和碳氢化物消去两个氢原子得到的饱和二价烃基，这样的实例包括，但并不限于，亚甲基、次乙基、次异丙基等等。Unless otherwise specified, the term "alkyl" means 1-20 carbon atoms, or 1-10 carbon atoms, or 1-8 carbon atoms, or 1-6 carbon atoms, or 1-4 carbon atoms , or a saturated linear or branched monovalent hydrocarbon group of 1-3 carbon atoms, wherein the alkyl group can be independently and optionally replaced by one or more substituents described in the present invention, the substituents include but not limited to, Deuterium, amino, hydroxyl, cyano, F, Cl, Br, I, mercapto, nitro, oxo (=O), and the like. Examples of alkyl groups include, but are not limited to, methyl (Me, -CH3 ), ethyl (Et, -CH2 CH3 ), n-propyl (n-Pr, -CH2 CH2 CH3 ), Isopropyl (i-Pr, -CH(CH3 )2 ), n-butyl (n-Bu, -CH2 CH2 CH2 CH3 ), isobutyl (i-Bu, -CH2 CH(CH3 )2 ), sec-butyl (s-Bu, -CH(CH3 )CH2 CH3 ), tert-butyl (t-Bu, -C(CH3 )3 ), n-pentyl (-CH2 CH2 CH2 CH2 CH3 ), 2-pentyl (-CH(CH3 )CH2 CH2 CH3 ), 3-pentyl (-CH(CH2 CH3 )2 ), 2-methyl-2 -Butyl (-C(CH3 )2 CH2 CH3 ), 3-methyl-2-butyl (-CH(CH3 )CH(CH3 )2 ), 3-methyl-1-butyl (-CH2 CH2 CH(CH3 )2 ), 2-methyl-1-butyl (-CH2 CH(CH3 )CH2 CH3 ), n-hexyl (-CH2 CH2 CH2 CH2 CH2 CH3 ), 2-hexyl (-CH(CH3 )CH2 CH2 CH2 CH3 ), 3-hexyl (-CH(CH2 CH3 )(CH2 CH2 CH3 )), 2- Methyl-2-pentyl (-C(CH3 )2 CH2 CH2 CH3 ), 3-methyl-2-pentyl (-CH(CH3 )CH(CH3 )CH2 CH3 ), 4-methyl-2-pentyl (-CH(CH3 )CH2 CH(CH3 )2 ), 3-methyl-3-pentyl (-C(CH3 )(CH2 CH3 )2 ) , 2-methyl-3-pentyl (-CH(CH2 CH3 )CH(CH3 )2 ), 2,3-dimethyl-2-butyl (-C(CH3 )2 CH(CH3 )2 ), 3,3-dimethyl-2-butyl (-CH(CH3 )C(CH3 )3 ), n-heptyl, n-octyl and the like. The term "alkyl" and its prefix "alk" are used herein to include straight and branched saturated carbon chains. The term "alkylene" is used herein to denote a saturated divalent hydrocarbon radical obtained by elimination of two hydrogen atoms from a linear or branched saturated hydrocarbon, examples of which include, but are not limited to, methylene, ethylene , Hypoisopropyl and so on.
术语“烯基”表示含有2-15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“tans”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)等等。The term "alkenyl" means a linear or branched monovalent hydrocarbon group containing 2-15 carbon atoms, wherein there is at least one unsaturated site, that is, a carbon-carbon sp2 double bond, wherein the alkenyl group Groups may be optionally substituted with one or more substituents described herein, including the "cis" and "tans" orientation, or the "E" and "Z" orientation. 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, ethenyl (-CH=CH2 ), allyl (-CH2CH=CH2) , and the like.
术语“炔基”表示含有2-15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。在一实施方案中，炔基基团包含2-8个碳原子；在另一实施方案中，炔基基团包含2-6个碳原子；在又一实施方案中，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(-C≡C-CH3)等等。The term "alkynyl" means a linear or branched monovalent hydrocarbon group containing 2-15 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 one embodiment, the alkynyl group contains 2-8 carbon atoms; in another embodiment, the alkynyl group contains 2-6 carbon atoms; in yet another embodiment, the alkynyl group contains 2 - 4 carbon atoms. Examples of alkynyl groups include, but are not limited to, ethynyl (-C≡CH), propargyl (-CH2C≡CH),1 -propynyl (-C≡C-CH3 ), and the like .
术语“环烷基”、“脂环族基”、“环状脂肪族基”、“碳环”、或“碳环基”是指一价或多价，非芳香族，饱和或部分不饱和的环，且不包含杂原子，其中包括3-12个碳原子的单环或7-12个碳原子的二环。具有7-12个原子的双环碳环可以是二环[4,5]、[5,5]、[5,6]或[6,6]体系，同时具有9或10个原子的双环碳环可以是二环[5,6]或[6,6]体系。合适的环状脂肪族基包括，但并不限于，环烷基，环烯基和环炔基。环状脂肪族基的实例包括，但绝不限于，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。并且所述“环状脂肪族基”或“碳环”、“碳环基”、“环烷基”可以是取代或未取代的，其中取代基可以是，但并不限于，氘、羟基、氨基、卤素、氰基、芳基、杂芳基、烷氧基、烷氨基、烷基、烯基、炔基、杂环基、巯基、硝基、芳氧基、羟基取代的烷氧基、羟基取代的烷基-C(＝O)-、烷基-C(＝O)-、烷基-S(＝O)-、烷基-S(＝O)2-、羟基取代的烷基-S(＝O)-、羟基取代的烷基-S(＝O)2-、羧基取代的烷氧基等等。The terms "cycloalkyl", "cycloaliphatic", "cycloaliphatic", "carbocycle", or "carbocyclyl" refer to monovalent or polyvalent, non-aromatic, saturated or partially unsaturated rings without heteroatoms, including monocyclic rings with 3-12 carbon atoms or bicyclic rings with 7-12 carbon atoms. Bicyclic carbocycles with 7-12 atoms can be bicyclic [4,5], [5,5], [5,6] or [6,6] systems, while bicyclic carbocycles with 9 or 10 atoms It can be a bicyclic [5,6] or [6,6] system. Suitable cycloaliphatic groups include, but are not limited to, cycloalkyl, cycloalkenyl and cycloalkynyl. Examples of cycloaliphatic groups include, but are by no means limited to, cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopentyl-1-enyl, 1-cyclopentyl-2-enyl, 1-cyclopentyl-2-enyl, Cyclopentyl-3-enyl, cyclohexyl, 1-cyclohexyl-1-enyl, 1-cyclohexyl-2-enyl, 1-cyclohexyl-3-enyl, cyclohexadienyl, cycloheptyl Cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl, cyclododecyl, etc. And the "cyclic aliphatic group" or "carbocycle", "carbocyclyl", "cycloalkyl" can be substituted or unsubstituted, wherein the substituents can be, but not limited to, deuterium, hydroxyl, Amino, halogen, cyano, aryl, heteroaryl, alkoxy, alkylamino, alkyl, alkenyl, alkynyl, heterocyclyl, mercapto, nitro, aryloxy, hydroxy-substituted alkoxy, Hydroxy-substituted alkyl-C(=O)-, alkyl-C(=O)-, alkyl-S(=O)-, alkyl-S(=O)2 -, hydroxy-substituted alkyl- S(=O)-, hydroxy-substituted alkyl-S(=O)2 -, carboxy-substituted alkoxy, and the like.
术语“杂环”、“杂环基”、“杂脂环族”或“杂环的”在此处可交换使用，都是指单环、双环或三环体系，其中环上一个或多个碳原子独立且任选地被杂原子所取代，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，但绝不是芳香族类，且有一个或多个连接点连接到分子的其他部分。一个或多个环上的氢原子独立且任选地被一个或多个本发明所描述的取代基所取代。其中一些实施方案是，“杂环”、“杂环基”、“杂脂环族”或“杂环的”基团是3-7元环的单环(1-6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例如SO、SO2、PO、PO2的基团，当所述的环为三元环时，其中只有一个杂原子)，或7-10元的双环(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例如SO、SO2、PO、PO2的基团)。The terms "heterocycle", "heterocyclyl", "heteroalicyclic" or "heterocyclic" are used interchangeably herein to refer to monocyclic, bicyclic or tricyclic ring systems in which one or more the carbon atoms are independently and optionally substituted by heteroatoms having the meaning described herein, the rings may be fully saturated or contain one or more unsaturations, but are never aromatic, and There are one or more junctions to other parts of the molecule. One or more ring hydrogen atoms are independently and optionally substituted with one or more substituents described herein. In some of these embodiments, a "heterocycle", "heterocyclyl", "heteroalicyclic" or "heterocyclic" group is a 3-7 membered monocyclic ring (1-6 carbon atoms and selected from 1-3 heteroatoms of N, O, P, S, where S or P is optionally substituted by one or more oxygen atoms to obtain groups such as SO, SO2 , PO, PO2 , when said When the ring is a three-membered ring, wherein there is only one heteroatom), or a 7-10 membered bicyclic ring (4-9 carbon atoms and 1-3 heteroatoms selected from N, O, P, S, where S Or P is optionally substituted by one or more oxygen atoms to give a group such as SO, SO2, PO,PO2) .
杂环基可以是碳基或杂原子基。“杂环基”同样也包括杂环基团与饱和或部分不饱和环或杂环并合所形成的基团。杂环的实例包括，但并不限于，吡咯烷基、四氢呋喃基、二氢呋喃基、四氢噻吩基、四氢吡喃基、二氢吡喃基、四氢噻喃基、哌啶基、吗啉基、硫代吗啉基、噻噁烷基、噻唑烷基、噁唑烷基、哌嗪基、高哌嗪基、氮杂环丁基、氧杂环丁基、硫杂环丁基、高哌啶基、环氧丙基、氮杂环庚基、氧杂环庚基、硫杂环庚基、4-甲氧基-哌啶-1-基、1,2,3,6-四氢吡啶-1-基、氧氮杂基、二氮杂基、硫氮杂基、吡咯啉-1-基、2-吡咯啉基、3-吡咯啉基、二氢吲哚基、2H-吡喃基、4H-吡喃基、二氧杂环己基、1,3-二氧戊基、吡唑啉基、二噻烷基、二噻茂烷基、二氢噻吩基、吡唑烷基、咪唑啉基、咪唑烷基、1,2,3,4-四氢异喹啉基、1,2,6-噻二嗪烷1,1-二氧代-2-基、4-羟基-1,4-氮杂磷烷4-氧化物-1-基、2-羟基-1-(哌嗪-1-基)乙酮-4-基、2-羟基-1-(5,6-二氢-1,2,4-三嗪-1(4H)-基)乙酮-4-基、5,6-二氢-4H-1,2,4-噁二嗪-4-基、2-羟基-1-(5,6-二氢吡啶-1(2H)-基)乙酮-4-基、3-氮杂双环[3.1.0]己基、3-氮杂双环[4.1.0]庚基、氮杂双环[2.2.2]己基、2-甲基-5,6,7,8-四氢-[1.2.4]三唑[1,5-c]嘧啶-6-基、4,5,6,7-四氢异噁唑[4,3-c]吡啶-5-基、3H-吲哚基2-氧-5-氮杂双环[2.2.1]庚烷-5-基、2-氧-5-氮杂双环[2.2.2]辛烷-5-基、喹嗪基和N-吡啶基尿素。杂环基团的实例还包括，1,1-二氧代硫代吗啉基和其中环上两个碳原子被氧原子所取代如嘧啶二酮基。并且所述杂环基可以是取代或未取代的，其中取代基可以是，但并不限于，氘、氧代(＝O)、羟基、氨基、卤素、氰基、杂芳基、烷氧基、烷氨基、烷基、烯基、炔基、杂环基、巯基、硝基、芳氧基、羟基取代的烷氧基、羟基取代的烷基-C(＝O)-、烷基-C(＝O)-、烷基-S(＝O)-、烷基-S(＝O)2-、羟基取代的烷基-S(＝O)-、羟基取代的烷基-S(＝O)2-、羧基取代的烷氧基等等。A heterocyclic group may be a carbon group or a heteroatom group. "Heterocyclyl" also includes the combination of a heterocyclic group and a saturated or partially unsaturated ring or heterocycle. Examples of heterocycles include, but are not limited to, pyrrolidinyl, tetrahydrofuryl, dihydrofuryl, tetrahydrothiophenyl, tetrahydropyranyl, dihydropyranyl, tetrahydrothiopyranyl, piperidinyl, Morpholinyl, Thiomorpholinyl, Thioxanyl, Thiazolidinyl, Oxazolidinyl, Piperazinyl, Homopiperazinyl, Azetidinyl, Oxetanyl, Thietanyl , homopiperidinyl, epoxypropyl, azepanyl, oxepyl, thiepanyl, 4-methoxy-piperidin-1-yl, 1,2,3,6- Tetrahydropyridin-1-yl, oxazepine base, diazepine base, thiazepine Base, pyrrolin-1-yl, 2-pyrrolinyl, 3-pyrrolinyl, indolinyl, 2H-pyranyl, 4H-pyranyl, dioxanexyl, 1,3-di Oxypentyl, pyrazolinyl, dithianyl, dithianolyl, dihydrothienyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, 1,2,3,4-tetrahydroisoquinyl Linyl, 1,2,6-thiadiazinane 1,1-dioxo-2-yl, 4-hydroxy-1,4-azaphosphine 4-oxide-1-yl, 2-hydroxy- 1-(piperazin-1-yl)ethanone-4-yl, 2-hydroxy-1-(5,6-dihydro-1,2,4-triazin-1(4H)-yl)ethanone- 4-yl, 5,6-dihydro-4H-1,2,4-oxadiazin-4-yl, 2-hydroxyl-1-(5,6-dihydropyridin-1(2H)-yl)ethyl Keto-4-yl, 3-azabicyclo[3.1.0]hexyl, 3-azabicyclo[4.1.0]heptyl, azabicyclo[2.2.2]hexyl, 2-methyl-5,6, 7,8-tetrahydro-[1.2.4]triazol[1,5-c]pyrimidin-6-yl, 4,5,6,7-tetrahydroisoxazol[4,3-c]pyridine-5 -yl, 3H-indolyl 2-oxo-5-azabicyclo[2.2.1]heptane-5-yl, 2-oxo-5-azabicyclo[2.2.2]octane-5-yl, Quinazinyl and N-pyridyl urea. Examples of heterocyclic groups also include 1,1-dioxothiomorpholinyl and pyrimidinedione in which two ring carbon atoms are replaced by oxygen atoms. And the heterocyclic group can be substituted or unsubstituted, wherein the substituents can be, but not limited to, deuterium, oxo (=O), hydroxyl, amino, halogen, cyano, heteroaryl, alkoxy , alkylamino, alkyl, alkenyl, alkynyl, heterocyclyl, mercapto, nitro, aryloxy, hydroxy substituted alkoxy, hydroxy substituted alkyl-C(=O)-, alkyl-C (=O)-, alkyl-S(=O)-, alkyl-S(=O)2-, hydroxy-substituted alkyl-S(=O)-, hydroxy-substituted alkyl-S(=O )2-, carboxy-substituted alkoxy and the like.
术语“杂原子”表示一个或多个O、S、N、P和Si原子，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(例如3,4-二氢-2H-吡咯基中的N)、NH(例如吡咯烷基中的NH)或NR(例如N-取代的吡咯烷基中的NR)。The term "heteroatom" means one or more O, S, N, P, and Si atoms, including forms in any oxidation state of N, S, and P; forms of primary, secondary, and tertiary amines, and quaternary ammonium salts; or The form in which the hydrogen on the nitrogen atom is substituted, for example, N (such as N in 3,4-dihydro-2H-pyrrolyl), NH (such as NH in pyrrolidinyl) or NR (such as N-substituted pyrrole NR in the alkyl).
术语“芳基”可以单独使用或作为“芳烷基”、“芳烷氧基”或“芳氧基烷基”的一大部分，表示共含有6-14元环的单环、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元环，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，如芳香环可以包括苯基，萘基和蒽基。并且所述芳基可以是取代或未取代的，其中取代基可以是，但并不限于，氘、羟基、氨基、卤素、氰基、芳基、杂芳基、烷氧基、烷氨基、烷基、烯基、炔基、杂环基、巯基、硝基、芳氧基、羟基取代的烷氧基、羟基取代的烷基-C(＝O)-、烷基-C(＝O)-、烷基-S(＝O)-、烷基-S(＝O)2-、羟基取代的烷基-S(＝O)-、羟基取代的烷基-S(＝O)2-、羧基取代的烷氧基等等。The term "aryl" can be used alone or as a part of "aralkyl", "aralkoxy" or "aryloxyalkyl" and represents monocyclic, bicyclic and tricyclic rings containing 6-14 ring members in total. Ring carbocyclic ring systems wherein at least one ring system is aromatic, wherein each ring system contains 3-7 membered rings and has one or more points of attachment to the rest of the molecule. The term "aryl" may be used interchangeably with the term "aromatic ring", eg aromatic rings may include phenyl, naphthyl and anthracenyl. And the aryl group can be substituted or unsubstituted, wherein the substituents can be, but not limited to, deuterium, hydroxyl, amino, halogen, cyano, aryl, heteroaryl, alkoxy, alkylamino, alkyl radical, alkenyl, alkynyl, heterocyclyl, mercapto, nitro, aryloxy, hydroxy-substituted alkoxy, hydroxy-substituted alkyl-C(=O)-, alkyl-C(=O)- , alkyl-S(=O)-, alkyl-S(=O)2 -, hydroxy-substituted alkyl-S(=O)-, hydroxy-substituted alkyl-S(=O)2- , carboxyl Substituted alkoxy and the like.
术语“杂芳基”可以单独使用或作为“杂芳基烷基”或“杂芳基烷氧基”的一大部分，表示共含有5-14元环的单环、双环和三环体系，其中至少一个环体系是芳香族的，且至少一个环体系包含一个或多个杂原子，其中杂原子具有本发明所述的含义，其中每一个环体系包含3-7元环，且有一个或多个附着点与分子其余部分相连。术语“杂芳基”可以与术语“芳杂环”或“杂芳族化合物”交换使用。并且所述杂芳基可以是取代或未取代的，其中取代基可以是，但并不限于，氘、羟基、氨基、卤素、氰基、芳基、杂芳基、烷氧基、烷氨基、烷基、烯基、炔基、杂环基、巯基、硝基、芳氧基、羟基取代的烷氧基、羟基取代的烷基-C(＝O)-、烷基-C(＝O)-、烷基-S(＝O)-、烷基-S(＝O)2-、羟基取代的烷基-S(＝O)-、羟基取代的烷基-S(＝O)2-、羧基取代的烷氧基等等。The term "heteroaryl" can be used alone or as a part of "heteroarylalkyl" or "heteroarylalkoxy" to represent monocyclic, bicyclic and tricyclic ring systems containing 5-14 ring members in total, Wherein at least one ring system is aromatic, and at least one ring system contains one or more heteroatoms, wherein the heteroatoms have the meaning described in the present invention, wherein each ring system contains 3-7 membered rings, and there is one or Multiple attachment points connect to the rest of the molecule. The term "heteroaryl" may be used interchangeably with the terms "heteroaromatic ring" or "heteroaromatic". And the heteroaryl can be substituted or unsubstituted, wherein the substituents can be, but not limited to, deuterium, hydroxyl, amino, halogen, cyano, aryl, heteroaryl, alkoxy, alkylamino, Alkyl, alkenyl, alkynyl, heterocyclyl, mercapto, nitro, aryloxy, hydroxy-substituted alkoxy, hydroxy-substituted alkyl-C(=O)-, alkyl-C(=O) -, alkyl-S(=O)-, alkyl-S(=O)2 -, hydroxy-substituted alkyl-S(=O)-, hydroxy-substituted alkyl-S(=O)2 -, Carboxy-substituted alkoxy and the like.
另外一些实施方案是，芳杂环包括以下的单环，但并不限于这些单环：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、4-甲基异噁唑-5-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、嘧啶-5-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、1,3,4-噻二唑-2-基、吡嗪基、吡嗪-2-基、1,3,5-三嗪基、苯并[d]噻唑-2-基、咪唑并[1,5-a]吡啶-6-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)和异喹啉基(如1-异喹啉基、3-异喹啉基或4-异喹啉基)。In some other embodiments, aromatic heterocycles include, but are not limited to, the following monocycles: 2-furyl, 3-furyl, N-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5- Imidazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, 4-methylisoxazolyl- 5-yl, N-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, pyrimidin-5-yl, 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, 1,3,4-thiadiazol-2-yl, pyrazinyl, pyrazin-2-yl, 1,3,5-triazinyl, benzo[ d] Thiazol-2-yl, imidazo[1,5-a]pyridin-6-yl; also include, but are by no means limited to, the following bicyclic rings: benzimidazolyl, benzofuranyl, benzothienyl , indolyl (such as 2-indolyl), purinyl, quinolinyl (such as 2-quinolyl, 3-quinolyl, 4-quinolyl) and isoquinolyl (such as 1-isoquinolyl Linyl, 3-isoquinolinyl or 4-isoquinolinyl).
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、式II、式III、式IV、式V或式VI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。例如本发明里的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-drugsas Novel Delivery Systems,Vol.14of the A.C.S.Symposium Series,Edward B.Roche,ed.,Bioreversible Carriers in Drug Design,American Pharmaceutical Associationand Pergamon Press,1987,J.Rautio et al.,Prodrugs:Design and ClinicalApplications,Nature Review Drug Discovery,2008,7,255-270,and S.J.Hecker etal.,Prodrugs of Phosphates and Phosphonates,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, formula II, formula III, formula IV, formula V or formula VI 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 (C1-24 ) esters, acyloxymethyl esters, and carbonates. , carbamates and amino acid esters. For example, a compound of the present invention that contains a hydroxyl group can be acylated to give a prodrug form of the compound. 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-drugsas 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 SJHecker 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，与氨基基团反应形成的无机酸盐有盐酸盐，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，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。其他药学上可接受的盐包括己二酸盐，藻酸盐，抗坏血酸盐，天冬氨酸盐，苯磺酸盐，苯甲酸盐，重硫酸盐，硼酸盐，丁酸盐，樟脑酸盐，樟脑磺酸盐，环戊基丙酸盐，二葡萄糖酸盐，十二烷基硫酸盐，乙磺酸盐，甲酸盐，反丁烯二酸盐，葡庚糖酸盐，甘油磷酸盐，葡萄糖酸盐，半硫酸盐，庚酸盐，己酸盐，氢碘酸盐，2-羟基-乙磺酸盐，乳糖醛酸盐，乳酸盐，月桂酸盐，月桂基硫酸盐，苹果酸盐，丙二酸盐，甲磺酸盐，2-萘磺酸盐，烟酸盐，硝酸盐，油酸盐，棕榈酸盐，扑酸盐，果胶酸盐，过硫酸盐，3-苯基丙酸盐，苦味酸盐，特戊酸盐，丙酸盐，硬脂酸盐，硫氰酸盐，对甲苯磺酸盐，十一酸盐，戊酸盐，等等。通过适当的碱得到的盐包括碱金属，碱土金属，铵和N+(C1-4烷基)4的盐。本发明也拟构思了任何所包含N的基团的化合物所形成的季铵盐。水溶性或油溶性或分散产物可以通过季铵化作用得到。碱金属或碱土金属盐包括钠，锂，钾，钙，镁，等等。药学上可接受的盐进一步包括适当的、无毒的铵，季铵盐和抗平衡离子形成的胺阳离子，如卤化物，氢氧化物，羧化物，硫酸化物，磷酸化物，硝酸化物，C1-8磺酸化物和芳香磺酸化物。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: SM Berge et al., describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66: 1-19. Pharmaceutically acceptable non-toxic acid salts include, but are not limited to, inorganic acid salts formed by reaction with amino groups such as hydrochloride, hydrobromide, phosphate, sulfate, perchlorate, and organic acid salts such as acetate, oxalate, maleate, tartrate, citrate, succinate, malonate, or other methods such as ion exchange methods recorded in books and literature these salts. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, besylate, benzoate, bisulfate, borate, butyrate, camphorate Salt, camphorsulfonate, cyclopentylpropionate, digluconate, lauryl sulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate Salt, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, Malate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, palmitate, pamoate, pectate, persulfate, 3 - Phenylpropionate, picrate, pivalate, propionate, stearate, thiocyanate, p-toluenesulfonate, undecanoate, valerate, etc. Salts obtained with appropriate bases include alkali metal, alkaline earth metal, ammonium and N+ (C1-4 alkyl)4 salts. The present invention also contemplates the quaternary ammonium salts of any compound containing an N group. Water-soluble or oil-soluble or dispersed products can be obtained by quaternization. Alkali metal or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Pharmaceutically acceptable salts further include suitable, non-toxic ammonium, quaternary ammonium salts and amine cations formed as counterions, such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, C1 -8 sulfonates and aromatic sulfonates.
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.
可药用的酸加成盐可与无机酸和有机酸形成，例如乙酸盐、天冬氨酸盐、苯甲酸盐、苯磺酸盐、溴化物/氢溴酸盐、碳酸氢盐/碳酸盐、硫酸氢盐/硫酸盐、樟脑磺酸盐、氯化物/盐酸盐、氯茶碱盐、柠檬酸盐、乙二磺酸盐、富马酸盐、葡庚糖酸盐、葡糖酸盐、葡糖醛酸盐、马尿酸盐、氢碘酸盐/碘化物、羟乙基磺酸盐、乳酸盐、乳糖醛酸盐、月桂基硫酸盐、苹果酸盐、马来酸盐、丙二酸盐、扁桃酸盐、甲磺酸盐、甲基硫酸盐、萘甲酸盐、萘磺酸盐、烟酸盐、硝酸盐、十八酸盐、油酸盐、草酸盐、棕榈酸盐、扑酸盐、磷酸盐/磷酸氢盐/磷酸二氢盐、聚半乳糖酸盐、丙酸盐、硬脂酸盐、琥珀酸盐、磺基水杨酸盐、酒石酸盐、甲苯磺酸盐和三氟乙酸盐。Pharmaceutically acceptable acid addition salts can be formed with inorganic and organic acids such as acetates, aspartates, benzoates, benzenesulfonates, bromides/hydrobromides, bicarbonates/ Carbonate, Bisulfate/Sulfate, Camphorsulfonate, Chloride/HCl, Chlorophylline Salt, Citrate, Ethionate, Fumarate, Glucoheptonate, Glucose Sugarate, Glucuronate, Hippurate, Hydroiodide/Iodide, Isethionate, Lactate, Lactobionate, Lauryl Sulfate, Malate, Malate salt, malonate, mandelate, methanesulfonate, methylsulfate, naphthoate, naphthalenesulfonate, nicotinate, nitrate, octadecanoate, oleate, oxalate Salt, palmitate, pamoate, phosphate/hydrogen phosphate/dihydrogen phosphate, polygalactonate, propionate, stearate, succinate, sulfosalicylate, tartrate , tosylate and trifluoroacetate.
可以由其衍生得到盐的无机酸包括例如盐酸、氢溴酸、硫酸、硝酸、磷酸等。Inorganic acids from which salts can be derived include, for example, hydrochloric, hydrobromic, sulfuric, nitric, phosphoric, and the like.
可以由其衍生得到盐的有机酸包括例如乙酸、丙酸、羟基乙酸、草酸、马来酸、丙二酸、琥珀酸、富马酸、酒石酸、柠檬酸、苯甲酸、扁桃酸、甲磺酸、乙磺酸、对甲苯磺酸、磺基水杨酸等。Organic acids from which salts can be derived include, for example, acetic acid, propionic acid, glycolic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, mandelic acid, methanesulfonic acid , Ethansulfonic acid, p-toluenesulfonic acid, sulfosalicylic acid, etc.
可药用碱加成盐可与无机碱和有机碱形成。Pharmaceutically acceptable base addition salts can be formed with inorganic and organic bases.
可以由其衍生得到盐的无机碱包括，例如铵盐和周期表的I族至XII族的金属。在某些实施方案中，该盐衍生自钠、钾、铵、钙、镁、铁、银、锌和铜；特别适合的盐包括铵、钾、钠、钙和镁盐。Inorganic bases from which salts can be derived include, for example, ammonium salts and metals from Groups I to XII of the Periodic Table. In certain embodiments, the salts are derived from sodium, potassium, ammonium, calcium, magnesium, iron, silver, zinc and copper; particularly suitable salts include ammonium, potassium, sodium, calcium and magnesium salts.
可以由其衍生得到盐的有机碱包括伯胺、仲胺和叔胺，取代的胺包括天然存在的取代的胺、环状胺、碱性离子交换树脂等。某些有机胺包括，例如，异丙胺、苄星青霉素(benzathine)、胆碱盐(cholinate)、二乙醇胺、二乙胺、赖氨酸、葡甲胺(meglumine)、哌嗪和氨丁三醇。Organic bases from which salts can be derived include primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, basic ion exchange resins, and the like. Certain organic amines include, for example, isopropylamine, benzathine, cholinate, diethanolamine, diethylamine, lysine, meglumine, piperazine, and tromethamine .
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、氟和氯的同位素，如2H，3H，11C，13C，14C，15N，17O，18O，18F，31P，32P，35S，36Cl和125I。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 may be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine and chlorine, such as2 H,3 H,11 C,13 C,14 C,15 N,17 O ,18 O,18 F,31 P,32 P,35 S,36 Cl and125 I.
另一方面，本发明所述化合物包括同位素富集的本发明所定义的化合物，例如，其中存在放射性同位素，如3H，14C和18F的那些化合物，或者其中存在非放射性同位素，如2H和13C。该类同位素富集的化合物可用于代谢研究(使用14C)、反应动力学研究(使用例如2H或3H)、检测或成像技术，如正电子发射断层扫描术(PET)或包括药物或底物组织分布测定的单光子发射计算机断层成像术(SPECT)，或可用于患者的放疗中。18F富集的化合物对PET或SPECT研究而言是特别理想的。同位素富集的式I、式II、式III、式IV、式V或式VI所示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。In another aspect, the compounds of the present invention include isotopically enriched compounds as defined in the present invention, for example, those compounds in which radioactive isotopes such as3 H,14 C and18 F are present, or in which non-radioactive isotopes such as2 H and13 C. Such isotopically enriched compounds can be used in metabolic studies (using14 C), reaction kinetics studies (using e.g.2 H or3 H), detection or imaging techniques such as positron emission tomography (PET) or including pharmaceutical or Single-photon emission computed tomography (SPECT) for the determination of substrate tissue distribution may be used in radiation therapy of patients.18 F-enriched compounds are particularly ideal for PET or SPECT studies. Compounds shown in the isotopically enriched formula I, formula II, formula III, formula IV, formula V or formula VI can use suitable isotopes as described in the conventional techniques familiar to those skilled in the art or in the examples and preparation processes of the present invention. Labeled reagents were prepared in place of previously used unlabeled reagents.
此外，较重同位素特别是氘(即，2H或D)的取代可提供某些治疗优点，这些优点是由代谢稳定性更高带来的。例如，体内半衰期增加或剂量需求降低或治疗指数得到改善带来的。可以用同位素富集因子来定义该类较重同位素特别是氘的浓度。如果本发明化合物的取代基被指定为氘，该化合物对各指定的氘原子而言具有至少3500(各指定氘原子处52.5％的氘掺入)、至少4000(60％的氘掺入)、至少4500(67.5％的氘掺入)，至少5000(75％的氘掺入)，至少5500(82.5％的氘掺入)、至少6000(90％的氘掺入)、至少6333.3(95％的氘掺入)、至少6466.7(97％的氘掺入)、至少6600(99％的氘掺入)或至少6633.3(99.5％的氘掺入)的同位素富集因子。本发明可药用的溶剂化物包括其中结晶溶剂可以是同位素取代的例如D2O、丙酮-d6、DMSO-d6的那些溶剂化物。In addition, substitution with heavier isotopes, particularly deuterium (ie,2H or D), may afford certain therapeutic advantages resulting from greater metabolic stability. For example, due to increased in vivo half-life or reduced dosage requirements or improved therapeutic index. An isotopic enrichment factor can be used to define the concentration of such heavier isotopes, especially deuterium. If a substituent of a compound of the invention is designated as deuterium, the compound has, for each designated deuterium atom, at least 3500 (52.5% deuterium incorporation at each designated deuterium atom), at least 4000 (60% deuterium incorporation), At least 4500 (67.5% deuterium incorporation), at least 5000 (75% deuterium incorporation), at least 5500 (82.5% deuterium incorporation), at least 6000 (90% deuterium incorporation), at least 6333.3 (95% deuterium incorporation) Deuterium incorporation), an isotopic enrichment factor of at least 6466.7 (97% deuterium incorporation), at least 6600 (99% deuterium incorporation), or at least 6633.3 (99.5% deuterium incorporation). Pharmaceutically acceptable solvates of the present invention include those wherein the solvent of crystallization may be isotopically substituted egD2O , acetone- d6,DMSO -d6.
另一方面，本发明提供一种药物组合物，所述药物组合物包含本发明化合物，药学上可接受的载体，赋形剂，稀释剂，辅剂，溶媒，或它们的组合。在一些实施方案，药物组合物可以是液体，固体，半固体，凝胶或喷雾剂型。In another aspect, the present invention provides a pharmaceutical composition, which comprises the compound of the present invention, a pharmaceutically acceptable carrier, excipient, diluent, adjuvant, vehicle, or a combination thereof. In some embodiments, the pharmaceutical composition can be in the form of a liquid, solid, semi-solid, gel or spray.
下面将进一步详细描述本发明的实施例，所述实施例是示例性的，旨在用于解释本发明，而不能理解为对本发明的限制。Embodiments of the present invention will be described in further detail below, and the embodiments are exemplary and intended to explain the present invention, but should not be construed as limiting the present invention.
下述实施例中所使用的实验方法如无特殊说明，均为常规方法。The experimental methods used in the following examples are conventional methods unless otherwise specified.
下述实施例中所用的材料、试剂等，如无特殊说明，均可从商业途径得到。The materials and reagents used in the following examples can be obtained from commercial sources unless otherwise specified.
本发明的实施例的小分子化合物可通过Pomalidomide端或Lenalidomide端衍生物和PF-562271端衍生物之间的click chemistry(点击反应)连接而成，如图2所示，其中，Pomalidomid端或Lenalidomide端衍生物的制备方法可参考文献Chemistry&Biology 22,755-763(2015)以及J.Med.Chem.61,462-481(2018).The small molecular compounds of the embodiments of the present invention can be connected by click chemistry (click reaction) between the Pomalidomide end or Lenalidomide end derivatives and the PF-562271 end derivatives, as shown in Figure 2, wherein the Pomalidomide end or Lenalidomide The preparation method of terminal derivatives can refer to literature Chemistry&Biology 22,755-763(2015) and J.Med.Chem.61,462-481(2018).
下述实施例中使用的PF-562271(结构如下所示)端衍生物按照如下方法制备，反应方程式如图3所示：首先将对苯二胺的一端氨基与相应炔酸形成酰胺键；其次将氰基氟代吡啶的氟原子用磺酰胺类似物的氮原子取代，还原氰基后得到苄胺类似物；最后用上述苄胺类似物取代2,4-二氯-5-三氟甲基嘧啶4位氯原子，用上述对苯二胺衍生物的氨基取代2位氯原子即得PF-562271端衍生物。具体制备过程如下：The PF-562271 (structure shown below) terminal derivative used in the following examples is prepared according to the following method, and the reaction equation is as shown in Figure 3: first, one terminal amino group of p-phenylenediamine and the corresponding alkynoic acid form an amide bond; secondly Substituting the fluorine atom of the cyanofluoropyridine with the nitrogen atom of the sulfonamide analog, and reducing the cyano group to obtain the benzylamine analog; finally replacing 2,4-dichloro-5-trifluoromethyl with the above benzylamine analog The chlorine atom at the 4-position of pyrimidine is replaced by the amino group at the 2-position of the p-phenylenediamine derivative to obtain the PF-562271 terminal derivative. Concrete preparation process is as follows:
(1)中间体1a的制备(1) Preparation of Intermediate 1a
在250毫升圆底烧瓶中加入2克对苯二胺、954微升丙炔酸、15毫升氯仿，加入无水DMF直至完全溶解，冷却至零度，加入含有3.18克DCC的20毫升氯仿溶液。零度搅拌1小时，过滤得到澄清滤液，然后用DCM：MeOH＝20：1过硅胶柱得到中间体1a。1H-NMR(400MHz,DMSO-d6,ppm):10.35(s,1H),7.24(d,J＝8.60Hz,2H),6.50(d,J＝8.64Hz,2H),4.97(s,2H),4.25(s,1H).LC-MS:calculated for C9H9N2O[M+H]+:161.06,found 161.28.Add 2 g of p-phenylenediamine, 954 μl of propiolic acid, and 15 ml of chloroform into a 250 ml round-bottom flask, add anhydrous DMF until completely dissolved, cool to zero, and add 3.18 g of DCC in 20 ml of chloroform. Stir at zero for 1 hour, filter to obtain a clear filtrate, and then use DCM:MeOH=20:1 to pass through a silica gel column to obtain intermediate 1a.1 H-NMR (400MHz, DMSO-d6 , ppm): 10.35(s, 1H), 7.24(d, J=8.60Hz, 2H), 6.50(d, J=8.64Hz, 2H), 4.97(s, 2H), 4.25(s,1H).LC-MS: calculated for C9 H9 N2 O[M+H]+ :161.06, found 161.28.
(2)中间体2a的制备(2) Preparation of Intermediate 2a
在100毫升圆底烧瓶中加入2克N-甲基甲磺酰胺、30毫升无水DMF及2.1克叔丁醇钾，室温搅拌20分钟后，加入2.2克2-氟-3-氰基吡啶，回流反应3小时，用水淬灭反应，并用乙酸乙酯萃取，然后用石油醚：乙醇＝2：1过硅胶柱，析出晶体得到2a。1H-NMR(400MHz,CDCl3,ppm):8.65(dd,J＝1.88Hz,J＝4.88Hz,1H),8.06(dd,J＝1.88Hz,J＝7.76Hz,1H),7.41(dd,J＝4.88Hz,J＝7.76Hz,1H),3.38(s,3H),3.18(s,3H).13C-NMR(100MHz,CDCl3,ppm):156.06,152.17,142.74,122.77,115.33,109.50,37.90,37.35.LC-MS:calculatedfor C8H10N3O2S[M+H]+:212.04,found 212.30.Add 2 grams of N-methylmethanesulfonamide, 30 milliliters of anhydrous DMF and 2.1 grams of potassium tert-butoxide into a 100 milliliter round bottom flask, stir at room temperature for 20 minutes, then add 2.2 grams of 2-fluoro-3-cyanopyridine, The reaction was refluxed for 3 hours, quenched with water, extracted with ethyl acetate, and then passed through a silica gel column with petroleum ether:ethanol=2:1, and crystals were precipitated to obtain 2a.1 H-NMR (400MHz, CDCl3 , ppm): 8.65(dd, J=1.88Hz, J=4.88Hz, 1H), 8.06(dd, J=1.88Hz, J=7.76Hz, 1H), 7.41(dd , J＝4.88Hz, J＝7.76Hz, 1H), 3.38(s, 3H), 3.18(s, 3H).13 C-NMR (100MHz, CDCl3 , ppm): 156.06, 152.17, 142.74, 122.77, 115.33 ,109.50,37.90,37.35.LC-MS: calculated for C8 H10 N3 O2 S[M+H]+ :212.04,found 212.30.
(3)中间体3a的制备(3) Preparation of Intermediate 3a
在100毫升圆底烧瓶中加入1克中间体2a溶解于甲醇和无水DMF混合溶剂中，在氩气保护下加入300毫克10％的Pd/C，用氢气置换瓶中氩气，插入氢气球，40度搅拌反应16小时，过滤并旋干溶剂，然后用DCM：甲醇＝20：1过硅胶柱，得到3a。1H-NMR(400MHz,DMSO-d6,ppm):8.40(dd,J＝1.68Hz,J＝4.64Hz,1H),8.06(dd,J＝1.40Hz,J＝7.64Hz,1H),7.45(dd,J＝4.72Hz,J＝7.68Hz,1H),3.85(s,2H),3.13(s,3H),3.12(s,3H),2.89(s,2H).13C-NMR(100MHz,DMSO-d6,ppm):152.24,146.88,138.16,124.03,54.90,40.67,37.31,36.06.LC-MS:calculated for C8H14N3O2S[M+H]+:216.07,found 216.38.Add 1 g of intermediate 2a to a 100 ml round bottom flask and dissolve it in a mixed solvent of methanol and anhydrous DMF, add 300 mg of 10% Pd/C under argon protection, replace the argon in the bottle with hydrogen, and insert a hydrogen balloon , stirred at 40°C for 16 hours, filtered and spin-dried the solvent, and then passed through a silica gel column with DCM:methanol=20:1 to obtain 3a.1 H-NMR (400MHz, DMSO-d6 , ppm): 8.40 (dd, J=1.68Hz, J=4.64Hz, 1H), 8.06 (dd, J=1.40Hz, J=7.64Hz, 1H), 7.45 (dd, J=4.72Hz, J=7.68Hz, 1H), 3.85(s, 2H), 3.13(s, 3H), 3.12(s, 3H), 2.89(s, 2H).13 C-NMR (100MHz ,DMSO-d6 ,ppm):152.24,146.88,138.16,124.03,54.90,40.67,37.31,36.06.LC-MS:calculated for C8 H14 N3 O2 S[M+H]+ :216.07,found 216.38.
(4)中间体4a的制备(4) Preparation of Intermediate 4a
在100毫升圆底烧瓶中加入2.47克中间体3a、2.47克2,4-二氯-5-三氟甲基嘧啶、3.16克碳酸钾、50毫升乙腈，50度搅拌反应2小时，过滤并旋干溶剂，然后用石油醚：乙酸乙酯＝8：1过硅胶柱，旋干溶剂后加入少量DCM超声，过滤得到固体即4a。1H-NMR(400MHz,DMSO-d6,ppm):8.54(t,J＝5.60Hz,1H),8.45(m,2H),7.76(dd,J＝1.48Hz,J＝7.72Hz,1H),7.44(dd,J＝4.68Hz,J＝7.72Hz,1H),4.73(d,J＝5.36Hz,2H),3.26(s,3H),3.11(s,3H).13C-NMR(100MHz,DMSO-d6,ppm):162.58,158.36,155.74,155.69,152.30,147.69,137.24,133.33,124.80,124.15,122.10,105.53,105.21,104.88,37.09,35.77.LC-MS:calculatedfor C13H14ClF3N5O2S[M+H]+:396.04,found 396.41.Add 2.47 grams of intermediate 3a, 2.47 grams of 2,4-dichloro-5-trifluoromethylpyrimidine, 3.16 grams of potassium carbonate, and 50 milliliters of acetonitrile into a 100 milliliter round bottom flask, stir and react at 50 degrees for 2 hours, filter and spin Dry the solvent, then pass through a silica gel column with petroleum ether: ethyl acetate = 8:1, spin dry the solvent, add a small amount of DCM for sonication, and filter to obtain a solid, namely 4a.1 H-NMR (400MHz, DMSO-d6 , ppm): 8.54(t, J=5.60Hz, 1H), 8.45(m, 2H), 7.76(dd, J=1.48Hz, J=7.72Hz, 1H) , 7.44(dd, J=4.68Hz, J=7.72Hz, 1H), 4.73(d, J=5.36Hz, 2H), 3.26(s, 3H), 3.11(s, 3H).13 C-NMR (100MHzH-calcated ClF3 N5 O2 S[M+H]+ :396.04, found 396.41.
(5)中间体5a的制备(5) Preparation of intermediate 5a
在25毫升圆底烧瓶中加入100毫克中间体4a、41毫克中间体1a、2毫升特戊醇、3滴乙酸，90度回流搅拌反应4小时，旋干溶剂，然后用DCM：MeOH＝30：1过硅胶柱，得到中间体5a。1H-NMR(400MHz,CDCl3,ppm):8.41(d,J＝3.44Hz,1H),8.12(s,2H),7.98(d,J＝14.80Hz,1H),7.75(d,J＝7.40Hz,1H),7.49-7.42(m,4H),7.27-7.23(m,1H),6.13(s,1H),4.93(d,J＝4.80Hz,2H),3.27(s,3H),3.07(s,3H),2.92(s,1H).LC-MS:calculated forC22H21F3N7O3S[M+H]+:520.13,found 520.59.Add 100 mg of intermediate 4a, 41 mg of intermediate 1a, 2 ml of pépentyl alcohol, and 3 drops of acetic acid into a 25 ml round-bottomed flask, stir and react at 90°C for 4 hours, spin to dry the solvent, and then use DCM:MeOH=30: 1 through a silica gel column to obtain intermediate 5a.1 H-NMR (400MHz, CDCl3 , ppm): 8.41(d, J=3.44Hz, 1H), 8.12(s, 2H), 7.98(d, J=14.80Hz, 1H), 7.75(d, J= 7.40Hz, 1H), 7.49-7.42(m, 4H), 7.27-7.23(m, 1H), 6.13(s, 1H), 4.93(d, J=4.80Hz, 2H), 3.27(s, 3H), 3.07(s,3H),2.92(s,1H).LC-MS:calculated for C22 H21 F3 N7 O3 S[M+H]+ :520.13,found 520.59.
实施例1式1～38所示化合物的制备The preparation of compound shown in embodiment 1 formula 1～38
在5ml圆底烧瓶中加入17mg Pomalidomide端衍生物、20mg中间体5a、7mg CuSO4、23mg抗坏血酸钠、0.1ml水和0.8ml叔丁醇。70摄氏度搅拌6小时后，水洗、DCM萃取。用二氯甲烷：甲醇＝30：1过硅胶柱得到式1所示化合物，产率为61％。Into a 5ml round bottom flask was added 17mg of Pomalidomide terminal derivative, 20mg of intermediate 5a, 7mg of CuSO4 , 23mg of sodium ascorbate, 0.1ml of water and 0.8ml of tert-butanol. After stirring at 70°C for 6 hours, it was washed with water and extracted with DCM. The compound represented by formula 1 was obtained by passing through a silica gel column with dichloromethane:methanol=30:1, and the yield was 61%.
1H-NMR(400MHz,CDCl3,ppm):8.88(s,1H),8.43(dd,J＝1.80Hz,J＝4.68Hz,1H),8.27(s,1H),8.18(s,1H),7.81(d,J＝7.84Hz,1H),7.59-7.46(m,6H),7.25(m,1H),7.09(d,J＝7.04Hz,2H),6.86(d,J＝8.52Hz,1H),6.46(t,J＝5.28Hz,1H),6.04(s,1H),4.95-4.88(m,3H),4.65(q,J＝4.52Hz,2H),3.97(t,J＝4.68Hz,2H),3.71(t,J＝5.12Hz,2H),3.46(q,J＝5.48Hz,2H),3.28(s,3H),3.07(s,3H),2.76-2.60(m,3H),2.10-2.00(m,1H).LC-MS:calculated for C39H39F3N13O8S[M+H]+:906.26,found 906.88.1 H-NMR (400MHz, CDCl3 , ppm): 8.88(s, 1H), 8.43(dd, J=1.80Hz, J=4.68Hz, 1H), 8.27(s, 1H), 8.18(s, 1H) ,7.81(d,J=7.84Hz,1H),7.59-7.46(m,6H),7.25(m,1H),7.09(d,J=7.04Hz,2H),6.86(d,J=8.52Hz, 1H), 6.46(t, J=5.28Hz, 1H), 6.04(s, 1H), 4.95-4.88(m, 3H), 4.65(q, J=4.52Hz, 2H), 3.97(t, J=4.68 Hz,2H),3.71(t,J=5.12Hz,2H),3.46(q,J=5.48Hz,2H),3.28(s,3H),3.07(s,3H),2.76-2.60(m,3H ),2.10-2.00(m,1H).LC-MS: calculated for C39 H39 F3 N13 O8 S[M+H]+ :906.26,found 906.88.
按照上述制备方法制备式2～38所示化合物。Compounds represented by formulas 2-38 were prepared according to the above preparation methods.
1H-NMR(400MHz,CDCl3,ppm):10.53(s,1H),8.85(s,1H),8.39(d,J＝4.12Hz,2H),8.15(s,2H),7.78(d,J＝7.20Hz,1H),7.51-7.39(m,5H),7.26-7.22(m,1H),7.05(d,J＝7.08Hz,1H),6.87(d,J＝8.56Hz,1H),6.51(t,J＝4.84Hz,1H),6.10(s,1H),4.97-4.92(m,3H),4.57(d,J＝4.36Hz,2H),3.90(t,J＝4.56Hz,2H),3.70(t,J＝4.76Hz,2H),3.62(s,4H),3.45(d,J＝4.80Hz,2H),3.25(s,3H),3.04(s,3H),2.87-2.74(m,3H),2.12-2.03(m,1H).13C-NMR(100MHz,CDCl3,ppm):172.91,169.72,169.45,167.74,160.60,158.92,157.85,154.48,152.77,148.21,146.73,143.29,139.19,136.05,135.51,133.88,132.93,132.52,127.18,126.13,124.37,123.45,120.73,120.38,116.83,111.62,110.30,70.59,70.53,69.27,50.71,48.95,42.30,40.59,37.64,35.51,31.95,31.53,29.72,29.39,22.89,22.72,14.16.LC-MS:calculated for C41H42F3N13O9S[M+H]+:950.29,found 950.77.1 H-NMR (400MHz, CDCl3 , ppm): 10.53(s, 1H), 8.85(s, 1H), 8.39(d, J=4.12Hz, 2H), 8.15(s, 2H), 7.78(d, J＝7.20Hz, 1H), 7.51-7.39(m, 5H), 7.26-7.22(m, 1H), 7.05(d, J＝7.08Hz, 1H), 6.87(d, J＝8.56Hz, 1H), 6.51(t, J=4.84Hz, 1H), 6.10(s, 1H), 4.97-4.92(m, 3H), 4.57(d, J=4.36Hz, 2H), 3.90(t, J=4.56Hz, 2H ),3.70(t,J=4.76Hz,2H),3.62(s,4H),3.45(d,J=4.80Hz,2H),3.25(s,3H),3.04(s,3H),2.87-2.74 (m,3H),2.12-2.03(m,1H).13 C-NMR(100MHz,CDCl3 ,ppm):172.91,169.72,169.45,167.74,160.60,158.92,157.85,154.48,152.77,148.21,146.73, 143.29,139.19,136.05,135.51,133.88,132.93,132.52,127.18,126.13,124.37,123.45,120.73,120.38,116.83,111.62,110.30,70.59,70.53,69.27,50.71,48.95,42.30,40.59,37.64,35.51, 31.95,31.53,29.72,29.39,22.89,22.72,14.16.LC-MS: calculated for C41 H42 F3 N13 O9 S[M+H]+ :950.29,found 950.77.
1H-NMR(400MHz,CDCl3,ppm):10.43(s,1H),8.90(s,1H),8.41(m,2H),8.19(s,2H),7.77(d,J＝7.16Hz,1H),7.56(d,J＝8.80Hz,2H),7.48-7.42(m,3H),7.26-7.22(m,1H),7.08(d,J＝7.04Hz,1H),6.90(d,J＝8.56Hz,1H),6.43(t,J＝5.52Hz,1H),6.10(s,1H),4.97-4.94(m,3H),4.59(t,J＝4.48Hz,2H),3.89(t,J＝4.68Hz,2H),3.72-3.68(m,4H),3.63-3.61(m,6H),3.47(q,J＝5.60Hz,2H),3.27(s,3H),3.06(s,3H),2.89-2.75(m,3H),2.12-2.10(m,1H).LC-MS:calculated for C43H47F3N13O10S[M+H]+:994.32,found 994.85.1 H-NMR (400MHz, CDCl3 , ppm): 10.43(s, 1H), 8.90(s, 1H), 8.41(m, 2H), 8.19(s, 2H), 7.77(d, J=7.16Hz, 1H),7.56(d,J=8.80Hz,2H),7.48-7.42(m,3H),7.26-7.22(m,1H),7.08(d,J=7.04Hz,1H),6.90(d,J =8.56Hz,1H),6.43(t,J=5.52Hz,1H),6.10(s,1H),4.97-4.94(m,3H),4.59(t,J=4.48Hz,2H),3.89(t ,J=4.68Hz,2H),3.72-3.68(m,4H),3.63-3.61(m,6H),3.47(q,J=5.60Hz,2H),3.27(s,3H),3.06(s, 3H),2.89-2.75(m,3H),2.12-2.10(m,1H).LC-MS:calculated for C43 H47 F3 N13 O10 S[M+H]+ :994.32,found 994.85.
1H-NMR(400MHz,CDCl3,ppm):10.25(s,1H),8.92(s,1H),8.40(d,J＝8.80Hz,1H),8.35(s,1H),8.19(s,1H),8.09(s,1H),7.77(d,J＝7.74Hz,1H),7.58(d,J＝8.72Hz,2H),7.48-7.43(m,3H),7.26-7.22(m,1H),7.08(d,J＝7.08Hz,1H),6.90(d,J＝8.52Hz,1H),6.45(t,J＝5.44Hz,1H),6.09(s,1H),4.96-4.93(m,3H),4.59(t,J＝4.56Hz,2H),3.88(t,J＝4.72Hz,2H),3.68-3.59(m,14H),3.44(q,J＝5.20Hz,2H),3.27(s,3H),3.05(s,3H),2.88-2.72(m,3H),2.13-2.03(m,1H).LC-MS:calculated for C45H51F3N13O11S[M+H]+:1038.34,found 1038.84.1 H-NMR (400MHz, CDCl3 , ppm): 10.25(s, 1H), 8.92(s, 1H), 8.40(d, J=8.80Hz, 1H), 8.35(s, 1H), 8.19(s, 1H), 8.09(s, 1H), 7.77(d, J=7.74Hz, 1H), 7.58(d, J=8.72Hz, 2H), 7.48-7.43(m, 3H), 7.26-7.22(m, 1H ), 7.08(d, J=7.08Hz, 1H), 6.90(d, J=8.52Hz, 1H), 6.45(t, J=5.44Hz, 1H), 6.09(s, 1H), 4.96-4.93(m ,3H),4.59(t,J=4.56Hz,2H),3.88(t,J=4.72Hz,2H),3.68-3.59(m,14H),3.44(q,J=5.20Hz,2H),3.27 (s,3H),3.05(s,3H),2.88-2.72(m,3H),2.13-2.03(m,1H).LC-MS: calculated for C45 H51 F3 N13 O11 S[M +H]+ :1038.34, found 1038.84.
1H-NMR(400MHz,CDCl3,ppm):10.19(s,1H),8.91(s,1H),8.40(dd,J＝1.76Hz,J＝4.68Hz,1H),8.36(s,1H),8.19(s,1H),8.00(s,1H),7.77(dd,J＝1.24Hz,J＝7.64Hz,1H),7.67(d,J＝7.08Hz,1H),7.59-7.51(m,4H),7.47(d,J＝8.92Hz,2H),7.25(dd,J＝4.76Hz,J＝7.68Hz,1H),6.10(s,1H),5.01(dd,J＝5.28Hz,J＝12.00Hz,1H),4.93(d,J＝4.96Hz,2H),4.61(t,J＝4.68Hz,2H),3.91(t,J＝4.88Hz,2H),3.62-3.53(m,4H),3.51(t,J＝6.20Hz,2H),3.26(s,3H),3.14(t,J＝7.60Hz,2H),3.05(s,3H),2.89-2.75(m,3H),2.13-2.10(m,1H),1.95-1.92(m,2H).LC-MS:calculated for C42H44F3N12O9S[M+H]+:949.97,found 949.82.1 H-NMR (400MHz, CDCl3 , ppm): 10.19(s, 1H), 8.91(s, 1H), 8.40(dd, J=1.76Hz, J=4.68Hz, 1H), 8.36(s, 1H) ,8.19(s,1H),8.00(s,1H),7.77(dd,J=1.24Hz,J=7.64Hz,1H),7.67(d,J=7.08Hz,1H),7.59-7.51(m, 4H), 7.47(d, J=8.92Hz, 2H), 7.25(dd, J=4.76Hz, J=7.68Hz, 1H), 6.10(s, 1H), 5.01(dd, J=5.28Hz, J= 12.00Hz, 1H), 4.93(d, J=4.96Hz, 2H), 4.61(t, J=4.68Hz, 2H), 3.91(t, J=4.88Hz, 2H), 3.62-3.53(m, 4H) ,3.51(t,J=6.20Hz,2H),3.26(s,3H),3.14(t,J=7.60Hz,2H),3.05(s,3H),2.89-2.75(m,3H),2.13- 2.10(m,1H),1.95-1.92(m,2H).LC-MS:calculated for C42 H44 F3 N12 O9 S[M+H]+ :949.97,found 949.82.
1H-NMR(400MHz,CDCl3,ppm):10.45(s,1H),8.94(s,1H),8.39(d,J＝3.56Hz,1H),8.18(m,3H),7.76(d,J＝7.40Hz,1H),7.58(d,J＝8.72Hz,2H),7.50-7.41(m,3H),7.24(dd,J＝4.80Hz,J＝7.60Hz,1H),7.06(d,J＝7.08Hz,1H),6.86(d,J＝8.56Hz,1H),6.22(t,J＝5.36Hz,1H),6.12(s,1H),4.96-4.92(m,3H),4.40(t,J＝6.96Hz,2H),3.25(s,3H),3.22(m,2H),3.05(s,3H),2.88-2.73(m,3H),2.13-2.11(m,1H),1.92(m,2H),1.64(t,J＝6.60Hz,2H),1.32-1.22(m,8H).LC-MS:calculated for C43H47F3N13O7S[M+H]+:946.98,found946.87.1 H-NMR (400MHz, CDCl3 , ppm): 10.45(s, 1H), 8.94(s, 1H), 8.39(d, J=3.56Hz, 1H), 8.18(m, 3H), 7.76(d, J＝7.40Hz, 1H), 7.58(d, J＝8.72Hz, 2H), 7.50-7.41(m, 3H), 7.24(dd, J＝4.80Hz, J＝7.60Hz, 1H), 7.06(d, J＝7.08Hz, 1H), 6.86(d, J＝8.56Hz, 1H), 6.22(t, J＝5.36Hz, 1H), 6.12(s, 1H), 4.96-4.92(m, 3H), 4.40( t,J＝6.96Hz,2H),3.25(s,3H),3.22(m,2H),3.05(s,3H),2.88-2.73(m,3H),2.13-2.11(m,1H),1.92 (m,2H),1.64(t,J＝6.60Hz,2H),1.32-1.22(m,8H).LC-MS: calculated for C43 H47 F3 N13 O7 S[M+H]+ :946.98,found946.87.
1H-NMR(400MHz,CDCl3,ppm):10.16(s,1H),8.88(s,1H),8.40(d,J＝3.16Hz,1H),8.36(s,1H),8.18(s,1H),8.01(s,1H),7.79-7.63(m,4H),7.55(d,J＝8.24Hz,2H),7.47(d,J＝8.12Hz,2H),7.25-7.22(m,1H),6.09(s,1H),5.05(d,J＝8.12Hz,1H),4.93(m,1H),4.60(m,2H),4.49(m,2H),3.92(m,2H),3.83(m,2H),3.70(m,2H),3.26(s,3H),3.05(s,3H),2.89-2.77(m,3H),2.13-2.05(m,1H).LC-MS:calculated for C42H39F3N12O9S[M+H]+:945.26,found 945.92.1 H-NMR (400MHz, CDCl3 , ppm): 10.16(s, 1H), 8.88(s, 1H), 8.40(d, J=3.16Hz, 1H), 8.36(s, 1H), 8.18(s, 1H), 8.01(s, 1H), 7.79-7.63(m, 4H), 7.55(d, J＝8.24Hz, 2H), 7.47(d, J＝8.12Hz, 2H), 7.25-7.22(m, 1H ),6.09(s,1H),5.05(d,J＝8.12Hz,1H),4.93(m,1H),4.60(m,2H),4.49(m,2H),3.92(m,2H),3.83 (m,2H),3.70(m,2H),3.26(s,3H),3.05(s,3H),2.89-2.77(m,3H),2.13-2.05(m,1H).LC-MS:calculated for C42 H39 F3 N12 O9 S[M+H]+ :945.26, found 945.92.
1H-NMR(400MHz,CDCl3,ppm):10.40(s,1H),8.91(s,1H),8.41(d,J＝3.84Hz,1H),8.15(m,3H),7.82-7.68(m,4H),7.57(d,J＝8.36Hz,2H),7.46(d,J＝8.56Hz,2H),7.26(m,1H),6.11(s,1H),5.11(dd,J＝4.88Hz,J＝10.76Hz,1H),4.92(s,2H),4.43(m,3H),3.70(t,J＝6.12Hz,2H),3.26(s,3H),3.06(s,3H),2.92-2.81(m,3H),2.16(m,1H),2.03-1.97(m,3H),1.72-1.67(m,2H),1.50-1.45(m,2H).LC-MS:calculated for C43H42F3N12O8S[M+H]+:943.28,found 943.83.1 H-NMR (400MHz, CDCl3 , ppm): 10.40(s, 1H), 8.91(s, 1H), 8.41(d, J=3.84Hz, 1H), 8.15(m, 3H), 7.82-7.68( m,4H),7.57(d,J=8.36Hz,2H),7.46(d,J=8.56Hz,2H),7.26(m,1H),6.11(s,1H),5.11(dd,J=4.88 Hz,J=10.76Hz,1H),4.92(s,2H),4.43(m,3H),3.70(t,J=6.12Hz,2H),3.26(s,3H),3.06(s,3H), 2.92-2.81(m,3H),2.16(m,1H),2.03-1.97(m,3H),1.72-1.67(m,2H),1.50-1.45(m,2H).LC-MS: calculated for C43 H42 F3 N12 O8 S[M+H]+ :943.28, found 943.83.
1H-NMR(400MHz,CDCl3,ppm):10.04(s,1H),8.92(s,1H),8.41(s,1H),8.15-7.26(m,12H),6.09(s,1H),5.06-4.93(m,3H),4.40(m,2H),4.12(d,J＝6.56Hz,1H),3.26(s,3H),3.06(s,3H),2.87-2.84(m,3H),2.51(s,2H),2.14-1.25(m,10H).LC-MS:calculatedfor C44H44F3N12O7S[M+H]+:941.31,found 941.84.1 H-NMR (400MHz, CDCl3 , ppm): 10.04(s,1H), 8.92(s,1H), 8.41(s,1H), 8.15-7.26(m,12H), 6.09(s,1H), 5.06-4.93(m,3H),4.40(m,2H),4.12(d,J＝6.56Hz,1H),3.26(s,3H),3.06(s,3H),2.87-2.84(m,3H) ,2.51(s,2H),2.14-1.25(m,10H).LC-MS: calculated for C44 H44 F3 N12 O7 S[M+H]+ :941.31,found 941.84.
1H-NMR(400MHz,CDCl3,ppm):10.62(s,1H),8.92(s,1H),8.38(s,2H),8.21(s,2H),7.83(d,J＝7.32Hz,1H),7.77(d,J＝6.48Hz,1H),7.59-7.55(m,3H),7.49-7.41(m,3H),7.24-7.21(m,1H),6.12(s,1H),5.26(m,1H),4.93(s,2H),4.58-4.32(m,6H),3.86(m,2H),3.77(m,2H),3.64(m,6H),3.26(s,3H),3.05(s,3H),2.85(m,2H),2.37-2.33(m,1H),2.18-2.16(m,1H).LC-MS:calculated for C44H46F3N12O9S[M+H]+:975.31,found 975.85.1 H-NMR (400MHz, CDCl3 , ppm): 10.62(s, 1H), 8.92(s, 1H), 8.38(s, 2H), 8.21(s, 2H), 7.83(d, J=7.32Hz, 1H), 7.77(d, J=6.48Hz, 1H), 7.59-7.55(m, 3H), 7.49-7.41(m, 3H), 7.24-7.21(m, 1H), 6.12(s, 1H), 5.26 (m,1H),4.93(s,2H),4.58-4.32(m,6H),3.86(m,2H),3.77(m,2H),3.64(m,6H),3.26(s,3H), 3.05(s,3H),2.85(m,2H),2.37-2.33(m,1H),2.18-2.16(m,1H).LC-MS: calculated for C44 H46 F3 N12 O9 S[ M+H]+ :975.31, found 975.85.
实施例2本发明化合物对FAK的降解活性Embodiment 2 The degradative activity of compound of the present invention to FAK
本发明化合物对FAK的降解活性较强，下面以式1～10所示小分子化合物为例进行测试。The compound of the present invention has a strong degradation activity to FAK, and the small molecular compound represented by formulas 1-10 is taken as an example to test below.
细胞接种及小分子化合物处理：Cell seeding and small molecule compound treatment:
将细胞融合度达到90％的PA1细胞采用0.25％的胰酶在37℃，消化1分钟，加入含10％FBS的Mycos’5A培养基终止消化并吹打成单细胞悬液，15毫升离心管收集单细胞，800rpm离心3分钟，采用新鲜培养基将细胞重悬，细胞计数板计数细胞个数。按照每孔800k的细胞数将细胞接种于24孔板中。Digest PA1 cells with 90% cell confluency with 0.25% trypsin at 37°C for 1 minute, add Mycos'5A medium containing 10% FBS to stop the digestion and pipette into a single cell suspension, 15 ml centrifuge tube Collect single cells, centrifuge at 800rpm for 3 minutes, resuspend the cells with fresh medium, and count the number of cells on a cell counting plate. Cells were seeded in 24-well plates at a cell number of 800k per well.
12-24小时后，加入待测小分子化合物(1000x)处理，并于37摄氏度，5％CO2培养箱中孵育8小时。8小时化合物处理后，收集细胞，提取蛋白进行蛋白质免疫印迹(Westernblot)分析。After 12-24 hours, add the small molecular compound to be tested (1000x) for treatment, and incubate for 8 hours at 37 degrees Celsius in a 5% CO2 incubator. After 8 hours of compound treatment, cells were harvested and proteins were extracted for Western blot analysis.
细胞总蛋白提取：Total Cell Protein Extraction:
将处理后的细胞，弃去上层培养基，PBS洗两遍，加入细胞裂解液，每孔样品加入100微升RIPA裂解液，冰上孵育20分钟，采用细胞刮，刮下细胞，收集与1.5毫升Eppendorf管中，4摄氏度，2,000rpm离心10分钟。取90微升上清到新的1.5毫升Eppendorf管中。另取2微升上清用于蛋白浓度定量分析。向剩余90微升蛋白提取液中加入30微升的4×LoadingBuffer，95摄氏度加热煮沸10分钟，于-20摄氏度保存或直接用于蛋白质免疫印迹(Westernblot)检测。For the treated cells, discard the upper medium, wash twice with PBS, add cell lysate, add 100 microliters of RIPA lysate to each well sample, incubate on ice for 20 minutes, use a cell scraper, scrape off the cells, collect and 1.5 Centrifuge at 2,000 rpm for 10 minutes at 4°C in a ml Eppendorf tube. Take 90 µl of the supernatant into a new 1.5 ml Eppendorf tube. Another 2 μl supernatant was used for quantitative analysis of protein concentration. Add 30 microliters of 4×LoadingBuffer to the remaining 90 microliters of protein extract, heat and boil at 95 degrees Celsius for 10 minutes, store at -20 degrees Celsius or directly use for Western blot detection.
RIPA缓冲液的成分为：终浓度50mM的Tris-HCl pH 8.0，150mM NaCl，2mM MgCl2，0.1％SDS，1.5％Nonidet-P40，0.5％去氧胆酸钠。另含浓度为5μg/ml的Pepstatin A，10μg/mL的Leupeptin，5μM的MG-132，1mM的PMSF，0.25mM的DTT。The composition of RIPA buffer is: Tris-HCl pH 8.0 with a final concentration of 50 mM, 150 mM NaCl, 2 mM MgCl2 , 0.1% SDS, 1.5% Nonidet-P40, 0.5% sodium deoxycholate. It also contains Pepstatin A at a concentration of 5 μg/ml, Leupeptin at 10 μg/mL, MG-132 at 5 μM, PMSF at 1 mM, and DTT at 0.25 mM.
4×Loading Buffer的成分为：终浓度1％的SDS，6％的β-巯基乙醇，30％的甘油，以及适量的溴酚蓝。The composition of 4×Loading Buffer is: final concentration of 1% SDS, 6% β-mercaptoethanol, 30% glycerol, and an appropriate amount of bromophenol blue.
蛋白质免疫印迹(Westernblot)检测的具体步骤如下：The specific steps of Western blot detection are as follows:
1)配制8％或10％浓度的SDS-PAGE胶。参考《分子克隆实验指南》(科学出版社，第二版)第883页表18.3制备合适浓度的下层分离胶，参考第883页表18.4制备浓度为5％的上层浓缩胶。1) Prepare SDS-PAGE gel with 8% or 10% concentration. Refer to Table 18.3 on page 883 of "Molecular Cloning Experiment Guide" (Science Press, Second Edition) to prepare a lower layer separating gel with a suitable concentration, and refer to Table 18.4 on page 883 to prepare an upper layer of 5% stacking gel.
2)样品制备。根据实验要求制备蛋白样品，取95摄氏度变性10分钟的样品，离心、混匀并上样于SDS-PAGE胶中。根据蛋白定量分析结果，调整适量的上样体积，通常每个孔上样体积为10微升。2) Sample preparation. Prepare protein samples according to the experimental requirements, take the samples denatured at 95 degrees Celsius for 10 minutes, centrifuge, mix and load the samples on SDS-PAGE gel. According to the results of protein quantitative analysis, adjust an appropriate amount of sample volume, usually 10 microliters per well.
3)电泳。接通电源，蛋白样品在浓缩胶中电压为80伏特，待蛋白样品进入分离胶时，我们把电压调整为125伏特继续电泳。待目的条带的蛋白Marker完全分开后，终止电泳。3) Electrophoresis. When the power is turned on, the voltage of the protein sample in the stacking gel is 80 volts. When the protein sample enters the separating gel, we adjust the voltage to 125 volts to continue electrophoresis. After the protein markers of the target band are completely separated, the electrophoresis is terminated.
4)转膜。电泳结束后取下凝胶，按下列顺序安装转膜装置：(负极)、滤纸、凝胶、0.45μmPVDF膜、滤纸、(正极)。切记凝胶和PVDF膜之间绝对不能有气泡。然后夹紧转移装置于转膜槽中，放入冰盒，加入转膜缓冲液，于4摄氏度冷库100V恒压通电1.5小时。4) Transfer film. Remove the gel after electrophoresis, and install the transfer device in the following order: (negative electrode), filter paper, gel, 0.45 μm PVDF membrane, filter paper, (positive electrode). Remember that there must be no air bubbles between the gel and the PVDF membrane. Then clamp the transfer device in the transfer tank, put it in an ice box, add the transfer buffer, and power it on at a constant voltage of 100V for 1.5 hours in a 4°C freezer.
5)封闭。转膜结束后，取出PVDF膜，将PVDF膜浸没在含5％的脱脂奶粉的1x TBST缓冲液中，室温，摇床封闭1小时。5) closed. After the membrane transfer, take out the PVDF membrane, immerse the PVDF membrane in 1x TBST buffer containing 5% skimmed milk powder, and block for 1 hour at room temperature on a shaker.
6)孵育一抗。封闭结束后，用1x TBST缓冲液洗膜3次，每次10分钟，然后加入适度稀释比例的一抗，4摄氏度过夜。回收一抗，将PVDF膜用1x TBST缓冲液荡洗3次，每次10分钟。6) Incubate the primary antibody. After blocking, wash the membrane 3 times with 1x TBST buffer for 10 minutes each time, then add a moderately diluted primary antibody and leave overnight at 4°C. To recover the primary antibody, wash the PVDF membrane with 1x TBST buffer 3 times, 10 minutes each time.
7)孵育二抗。弃去1x TBST缓冲液，加入一定稀释比(通常是1：5000～1：10000)的二抗(鼠抗或者兔抗，由一抗决定)，室温下摇床孵育1小时。弃去二抗，将PVDF膜用1x TBST缓冲液荡洗3次，每次10分钟。7) Incubate the secondary antibody. Discard the 1x TBST buffer, add a certain dilution ratio (usually 1:5000-1:10000) of the secondary antibody (mouse or rabbit antibody, determined by the primary antibody), and incubate on a shaker at room temperature for 1 hour. Discard the secondary antibody, wash the PVDF membrane with 1x TBST buffer 3 times, 10 minutes each time.
8)显色并压片。将ECL显色底物均匀覆盖在PVDF膜上，室温显色2～5分钟。用保鲜膜包裹好膜后，于化学发光仪中曝光、并存储图像。8) Develop color and press into tablets. Evenly cover the ECL chromogenic substrate on the PVDF membrane, and develop color at room temperature for 2 to 5 minutes. After wrapping the film with plastic wrap, expose it in a chemiluminescence instrument and store the image.
本发明小分子化合物对FAK的降解活性如下：The degradation activity of small molecular compound of the present invention to FAK is as follows:
在PA1细胞系中，经式1-式10小分子化合物处理8小时后，蛋白质免疫印迹(Westernblot)结果分析，可以明显观察到式1-式10小分子化合物在不同剂量下对FAK蛋白的降解效果。式1-式4所示化合物在1、10、50nM下对FAK蛋白的降解作用如图4所示，式5-式10所示化合物在1、10nM下对FAK蛋白的降解作用如图5所示(以式2所示小分子化合物为阳性对照)。由上述测试结果可以看出，大部分化合物都能在一定的浓度下降解FAK，其中式2和式5所示小分子化合物降解作用最强(两者在1nM的浓度下可降解50％以上的FAK)。In the PA1 cell line, after being treated with small molecular compounds of formula 1-10 for 8 hours, the results of Western blot (Western blot) analysis showed that the degradation of FAK protein by small molecular compounds of formula 1-10 at different doses could be clearly observed Effect. The degradation effect of the compound shown in Formula 1-Formula 4 on FAK protein at 1, 10, 50nM is shown in Figure 4, and the degradation effect of the compound shown in Formula 5-Formula 10 on FAK protein at 1, 10nM is shown in Figure 5 Shown (with the small molecule compound shown in formula 2 as a positive control). As can be seen from the above test results, most of the compounds can degrade FAK at a certain concentration, and the small molecule compounds shown in formula 2 and formula 5 have the strongest degradation effect (both can degrade more than 50% of the FAK at a concentration of 1nM). FAK).
由此可见，本发明化合物对FAK具有较强的降解活性。It can be seen that the compound of the present invention has strong degradation activity on FAK.
实施例3本发明化合物对不同来源的肿瘤细胞系的半数降解浓度测试Embodiment 3 Compounds of the present invention test the half-degradation concentration of tumor cell lines from different sources
本发明化合物对不同来源的肿瘤细胞系的FAK蛋白均具有较强的降解效果，下面以式2所示小分子化合物为例进行测试。The compound of the present invention has a strong degradation effect on the FAK protein of tumor cell lines from different sources, and the small molecule compound shown in formula 2 is used as an example to test below.
不同肿瘤细胞系：实验选取人源卵巢癌细胞系PA1，SKOV3；人源宫颈癌细胞系HeLa；人源乳腺癌细胞系MDA-MB-436，MDA-MB-453，MDA-MB-231，MCF-7；人源肺癌细胞系A549，H460，PC9，以便考察式2所示小分子化合物对不同来源的肿瘤细胞系的半数降解率活性。Different tumor cell lines: human ovarian cancer cell lines PA1, SKOV3; human cervical cancer cell lines HeLa; human breast cancer cell lines MDA-MB-436, MDA-MB-453, MDA-MB-231, MCF -7; human lung cancer cell lines A549, H460, PC9, in order to investigate the half-degradation rate activity of the small molecule compound shown in formula 2 on tumor cell lines of different origins.
细胞接种及小分子化合物处理：将细胞融合度达到90％的肿瘤细胞系分别采用0.25％的胰酶在37摄氏度，消化1-2分钟，加入含10％FBS的完全培养基终止消化并吹打成单细胞悬液，15毫升离心管收集单细胞，800rpm离心3分钟，采用新鲜培养基将细胞重悬，细胞计数板计数细胞个数。按照每孔800k的细胞数分别将肿瘤细胞接种于24孔板中。Cell inoculation and small molecule compound treatment: The tumor cell lines with a cell confluency of 90% were digested with 0.25% trypsin at 37 degrees Celsius for 1-2 minutes, and the complete medium containing 10% FBS was added to stop the digestion and pipetting To form a single cell suspension, collect the single cells in a 15 ml centrifuge tube, centrifuge at 800 rpm for 3 minutes, resuspend the cells with fresh medium, and count the number of cells on a cell counting plate. Tumor cells were seeded in 24-well plates according to the number of cells per well of 800k.
12-24小时后，加入10个浓度梯度点的(0.3、1、3、10、30、100、300、1000、3000、10000nM)待测小分子化合物(1000x)处理，并于37摄氏度，5％CO2培养箱中孵育8小时。8小时化合物处理后，收集细胞，提取蛋白进行蛋白质免疫印迹(Westernblot)分析。蛋白质免疫印迹(Westernblot)分析实施具体步骤同实施例2。After 12-24 hours, add 10 concentration gradient points (0.3, 1, 3, 10, 30, 100, 300, 1000, 3000, 10000nM) of the small molecule compound to be tested (1000x) for treatment, and heat at 37 degrees Celsius, 5 Incubate for 8 hours in a % CO2 incubator. After 8 hours of compound treatment, cells were harvested and proteins were extracted for Western blot analysis. The specific steps for Western blot analysis are the same as those in Example 2.
本发明式2所示小分子化合物对不同肿瘤细胞系中FAK的半数降解活性如下：The half-degradation activity of the small molecule compound shown in formula 2 of the present invention to FAK in different tumor cell lines is as follows:
式2所示小分子化合物对卵巢癌PA1细胞系及乳腺癌MDA-MB-436，MDA-MB-453，MDA-MB-231细胞系中FAK蛋白的降解作用均具有较强的活性，半数降解浓度小于2nM。对卵巢癌SKOV3细胞系，乳腺癌MCF7及肺癌A549，H460细胞系中FAK蛋白的半数降解浓度(DC50)均小于100nM，结果如图6所示。由此结果可知，式2所示小分子化合物对大部分肿瘤细胞系中的FAK蛋白均具有较强的降解效果。The small molecular compound shown in formula 2 has strong activity on the degradation of FAK protein in ovarian cancer PA1 cell line and breast cancer MDA-MB-436, MDA-MB-453, MDA-MB-231 cell line, half of which are degraded The concentration is less than 2nM. For ovarian cancer SKOV3 cell line, breast cancer MCF7 and lung cancer A549, H460 cell lines, the half-degradation concentration (DC50 ) of FAK protein was less than 100 nM, and the results are shown in FIG. 6 . From the results, it can be seen that the small molecular compound represented by formula 2 has a strong degradation effect on FAK protein in most tumor cell lines.
由此可见，本发明化合物对不同来源的肿瘤细胞系的FAK蛋白均具有较强的降解效果。It can be seen that the compounds of the present invention have strong degradation effects on FAK proteins of tumor cell lines from different sources.
实施例4本发明化合物对小鼠卵巢及小鼠睾丸相关细胞系中FAK的降解作用Example 4 Degradation effect of compounds of the present invention on FAK in mouse ovary and mouse testis-related cell lines
本发明化合物对小鼠生殖相关细胞系中的FAK蛋白具有较强的降解效果，下面以式2所示小分子化合物为例进行测试。The compound of the present invention has a strong degradation effect on the FAK protein in mouse reproductive-related cell lines, and the small molecule compound shown in formula 2 is used as an example to test below.
细胞接种及小分子化合物处理：具体实施步骤同实施例3。Cell inoculation and small molecule compound treatment: the specific implementation steps are the same as in Example 3.
本发明式2所示小分子化合物对小鼠卵巢SRD15及小鼠睾丸TM3细胞系的降解活性如下：The degradation activity of the small molecule compound shown in formula 2 of the present invention to mouse ovary SRD15 and mouse testis TM3 cell line is as follows:
不同梯度浓度下，式2所示小分子化合物在10nM下对小鼠卵巢SRD15细胞系中FAK的降解率大约46％。而在1nM下对小鼠睾丸TM3细胞系中FAK的降解作用达70％以上，结果如图7所示。由此结果可知，式2所示小分子化合物对小鼠生殖相关细胞系中的FAK蛋白具有较强的降解效果。At different gradient concentrations, the degradation rate of the small molecular compound represented by Formula 2 on FAK in the mouse ovary SRD15 cell line is about 46% at 10 nM. However, at 1 nM, the degradation effect on FAK in the mouse testis TM3 cell line is more than 70%, and the results are shown in FIG. 7 . From the results, it can be seen that the small molecular compound represented by formula 2 has a strong degradation effect on the FAK protein in the mouse germ-related cell line.
由此可见，本发明化合物对小鼠生殖相关细胞系中的FAK蛋白具有较强的降解效果。It can be seen that the compound of the present invention has a strong degradation effect on the FAK protein in mouse germ-related cell lines.
实施例5本发明化合物对小鼠睾丸原代支持细胞中FAK的降解作用Example 5 Degradation effect of compounds of the present invention on FAK in primary Sertoli cells of mouse testis
本发明化合物对小鼠睾丸原代支持细胞中的FAK具有较强的降解效果，下面以式2所示小分子化合物为例进行测试。The compound of the present invention has a strong degrading effect on FAK in the primary Sertoli cells of the mouse testis, and the small molecule compound shown in formula 2 is used as an example to test below.
小鼠睾丸原代支持细胞的分离和培养：原代支持细胞由16天小鼠分离得到。断颈处死16天的B6小鼠后，取出睾丸，放入3cm培养皿的PBS中，体视显微镜下去除睾丸组织的白膜，将睾丸组织转移至另一个盛有PBS的3cm培养皿中；体视显微镜下将睾丸组织的曲精小管分散开，然后将睾丸组织转移至含有适量消化液I的15毫升离心管中，室温消化5分钟，并不时轻轻摇晃；室温1500rpm离心5分钟，弃上清；向睾丸组织沉淀加入5倍体积的消化液II，室温消化5分钟，并剧烈摇晃；加入适量的DMEM/F12，终止消化，用70目滤网对消化过的组织进行过滤，除去消化不完全的组织块；过滤后细胞液室温800rpm离心，5分钟；弃上清，用DMEM/F12重悬细胞沉淀，室温1500rpm离心5分钟；沉淀用支持细胞培养基重悬后细胞计数，以0.5X 106细胞/cm2的密度接种于12孔板(铺有基质胶)，在5％CO2，37摄氏度的细胞培养箱培养；24小时后换液，PBS洗去未贴壁的细胞；36小时后用20mM的Tris-HCL PH7.4，清洗3分钟，再用PBS洗涤两次，加入培养基继续培养。Isolation and culture of primary Sertoli cells from mouse testis: Primary Sertoli cells were isolated from 16-day-old mice. After the 16-day-old B6 mice were killed by neck dislocation, the testes were taken out and placed in PBS in a 3cm petri dish, the buffy membrane of the testicular tissue was removed under a stereo microscope, and the testicular tissue was transferred to another 3cm petri dish filled with PBS; Disperse the seminiferous tubules of the testicular tissue under a stereomicroscope, then transfer the testicular tissue to a 15ml centrifuge tube containing an appropriate amount of digestion solution I, digest at room temperature for 5 minutes, and shake gently from time to time; centrifuge at room temperature at 1500rpm for 5 minutes, discard Supernatant; add 5 times the volume of digestion solution II to the testicular tissue pellet, digest at room temperature for 5 minutes, and shake vigorously; add an appropriate amount of DMEM/F12 to terminate the digestion, and filter the digested tissue with a 70-mesh filter to remove the digested tissue. Incomplete tissue pieces; after filtration, the cell solution was centrifuged at 800 rpm at room temperature for 5 minutes; the supernatant was discarded, and the cell pellet was resuspended in DMEM/F12, and centrifuged at 1500 rpm at room temperature for 5 minutes; The density of X 106 cells/cm2 was seeded in 12-well plates (covered with Matrigel), cultured in a cell culture incubator at 5% CO2 at 37 degrees Celsius; after 24 hours, the medium was changed, and unattached cells were washed away with PBS; After 36 hours, wash with 20 mM Tris-HCL pH 7.4 for 3 minutes, then wash twice with PBS, add medium to continue culturing.
上述实验中用到的试剂配方如下：The reagent formulations used in the above experiments are as follows:
消化液I:Ⅳ型胶原酶(2mg/ml,Sigma公司)+DNaseI(75U/ml,Sigma公司),用DMEM/F12(invitrogen公司)配置，经0.22μm的Millipore针头过滤器抽滤。Digestion solution I: type IV collagenase (2mg/ml, Sigma Company) + DNaseI (75U/ml, Sigma Company), prepared with DMEM/F12 (Invitrogen Company), and filtered through a 0.22 μm Millipore syringe filter.
消化液II:IV型胶原酶(2mg/ml,Sigma公司)+IV型透明质酸酶(2mg/ml,Sigma公司)+DNaseI(75U/ml,Sigma公司)，DMEM/F12(invitrogen公司)配置，经0.22μm的Millipore针头过滤器抽滤。Digestive solution II: Type IV collagenase (2mg/ml, Sigma Company)+IV type hyaluronidase (2mg/ml, Sigma Company)+DNaseI (75U/ml, Sigma Company), DMEM/F12 (Invitrogen Company) configuration , filtered through a 0.22 μm Millipore syringe filter.
支持细胞培养基为:DMEM/F12(invitrogen公司)+Bovine insulin(Sigma公司)+Human transferring(R&D公司)+Epidermal growth factor(R&D公司)+1％双抗(invitrogen公司)；Sertoli cell culture medium is: DMEM/F12 (Invitrogen Company)+Bovine insulin (Sigma Company)+Human transferring (R&D Company)+Epidermal growth factor (R&D Company)+1% double antibody (Invitrogen Company);
细胞接种及小分子化合物处理：具体实施步骤同实施例3。Cell inoculation and small molecule compound treatment: the specific implementation steps are the same as in Example 3.
本发明式2所示小分子化合物对小鼠睾丸原代支持细胞中FAK的降解活性如下：The degradation activity of the small molecule compound shown in Formula 2 of the present invention to FAK in the primary Sertoli cells of mouse testis is as follows:
不同梯度浓度下，式2所示小分子化合物对小鼠睾丸原代支持细胞中FAK的半数降解浓度达1.31nM，具有较强的降解效果，结果如图8-1和8-2所示。At different gradient concentrations, the half-degradation concentration of the small molecule compound shown in Formula 2 on primary Sertoli cells in mouse testis reached 1.31nM, which has a strong degradation effect. The results are shown in Figures 8-1 and 8-2.
由此可见，本发明化合物对小鼠睾丸原代支持细胞中的FAK具有较强的降解效果。It can be seen that the compound of the present invention has a strong degradation effect on FAK in primary Sertoli cells of mouse testis.
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 with reference 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, and those skilled in the art can make the above-mentioned The embodiments are subject to changes, modifications, substitutions and variations.
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