ROR1 targeting inhibitor and synthesis method and application thereof

Abstract

The invention provides an ROR1 targeting inhibitor as well as a preparation method and application thereof, and belongs to the technical field of medicinal chemistry. The ROR1 targeting inhibitor provided by the invention is an amide compound and comprises the following structural general formula: # imgabs0 #, and the ROR1 targeting inhibitor provided by the invention has obvious binding activity with ROR1, can inhibit the activity of the ROR1, and has a certain therapeutic effect on ROR1 high expression mediated diseases, especially tumors.

Description

Technical Field

[0001] The present invention relates to the technical field of medicinal chemistry, and particularly relates to an inhibitor targeting ROR1, a synthesis method thereof, and an application thereof. Background Art

[0003] Receptor tyrosine kinase orphan-like receptor 1 (ROR1) is a member of the receptor tyrosine kinase (RTKs) family. Receptor tyrosine kinases are a class of transmembrane proteins that can transmit growth factor signals to maintain various biological responses ranging from cell proliferation to apoptosis and differentiation. ROR1 is considered a pseudokinase because the sequence of its intracellular kinase domain deviates from the typical kinase domain motif, which is why pseudokinases do not have kinase catalytic activity. Due to the lack of phosphotransferase activity, pseudokinases are thought to transmit signals through allosteric regulation of their binding partners. ROR1 is crucial during early embryogenesis and its expression is downregulated after birth. The oncogenic function of ROR1 can be activated through the amplification and overexpression of transcriptional regulatory mechanisms. The high expression of ROR1 is associated with the tumorigenesis and metastasis of various hematological malignancies and solid tumors.

[0004] At present, drugs targeting ROR1 mainly focus on the biopharmaceutical field. By binding to major ligands such as Wnt5a, ROR1 can mediate signal transduction in the non-canonical Wnt signaling pathway, thus playing a key role in various physiological processes including the regulation of cell division, proliferation, and migration. Therefore, blocking the binding of ROR1 to Wnt5a can inhibit signal transduction. Zilovertamab is a human monoclonal antibody that can bind to ROR1 and effectively block the Wnt5A signaling pathway. Currently, an ongoing Phase 1b clinical trial aims to study the efficacy of zilovertamab combined with paclitaxel in the treatment of HER2-negative metastatic or locally advanced unresectable breast cancer. Given the selective expression of ROR1 between cancer cells and normal cells, it is highly suitable as a target for antibody-drug conjugates (ADCs). VLS-101 is an antibody-drug conjugate (ADC) targeting ROR1 that can release the cytotoxic drug monomethyl auristatin E into cells. Currently, a Phase 2 / 3 clinical trial is underway to explore the therapeutic potential of VLS-101 in the treatment of hematological malignancies and solid tumors. Chimeric antigen receptor T cell (CAR-T) therapy targeting ROR1 has also attracted the attention of many researchers. LYL119 is a second-generation chimeric antigen receptor T cell (CAR-T) therapy targeting ROR1 developed through stackable reprogramming technology. This innovative therapy can produce a continuous and strong response to tumors expressing ROR1. KAN0439834 is a small molecule drug designed to target the tyrosine kinase (TK) domain of ROR1. It can dephosphorylate ROR1 in a dose-dependent manner and reduce the survival rate of leukemia cells by inhibiting Wnt5a-induced phosphorylation of ROR1. ARI-1 is a novel ROR1 inhibitor that has a highly specific targeting effect on the extracellular cysteine-rich domain of ROR1. It regulates the PI3K / AKT / mTOR signaling pathway in a strictly ROR1-dependent manner and has a strong inhibitory effect on the proliferation and migration of non-small cell lung cancer (NSCLC) cells. Rigosertib is derived from the native South African anti-cancer herb Coleonema pulchellum and is reported to interact with the intracellular domain of ROR1. This interaction leads to the inhibition of AKT phosphorylation, thereby affecting the survival of triple-negative breast cancer cells. Through computer simulation analysis, a molecule named CID135399549W was found to be able to bind to the intracellular domain of ROR1. The Fan group disclosed a novel ROR1 inhibitor that exhibits excellent anti-proliferative activity against non-small cell lung cancer cells and has good safety. Recently, Luo et al. conducted structure-based virtual screening and subsequent optimization work to identify the novel ROR1 inhibitor compound 19h (KD = 0.1 μM), and compound 19h showed anti-tumor activity in lung and breast cancer cell lines, with IC50 values ranging from 0.36 to 1.37 μM.

[0005] In summary, inhibitors specifically targeting ROR1 have shown good potential in various cancers. Although some ROR1 inhibitors are currently under development, no ROR1 inhibitor has been marketed due to low activity and poor drug-likeness. There is an urgent need to develop new highly active ROR1 inhibitors. SUMMARY OF THE INVENTION

[0006] The object of the present invention is to provide an inhibitor targeting ROR1, its preparation method and application, to solve the above technical problems.

[0007] To achieve the above object of the invention, the present invention provides the following technical solutions:

[0008] The present invention provides an inhibitor targeting ROR1, the inhibitor targeting ROR1 is an amide compound or a pharmaceutically acceptable salt of an amide compound, and the general structural formula of the amide compound includes one of the following structures:

[0009]

[0010] Wherein, R 1 is selected from propargyl, N-Boc pyrazole, 3-amino-5-ethynylpyridine, 5-ethynylindole, 2-amino-4-ethynylpyrimidine, 6-ethynylpurine, 6-ethynylpyridazine, 2-pyridinecarboxamide, 3-pyridinecarboxamide, 4-amino-3-pyridinecarboxamide, 4-amino-3-pyridineacetamide, pyridinecarboxaldehyde hydrazone, isopyridinecarboxaldehyde hydrazone, indolecarboxaldehyde hydrazone, 2-(aminomethyl)pyridine, 3-(aminomethyl)pyridine, 5-(aminomethyl)indole, 4-amino-3-(aminomethyl)pyridine, 5-(aminomethyl)indole, isoquinoline, 4-aminoquinazoline, quinoxaline, benzimidazole, benzothiazole, benzopyrazole, 1-methylbenzopyrazole, 1-methylindazole, 4-aminoquinoline, 4-aminoquinazoline, benzoxazole, isobenzoxazole, 1-methylbenzimidazole, 5-aminobenzoxazole, N-phenylquinazolin-4-amine, N-methylquinazolin-4-amine, N-(2-methoxyphenyl)quinazolin-4-amine, N-(2-fluorophenyl)quinazolin-4-amine, N-(3-methylpyridin-2-yl)quinazolin-4-amine, N-Boc-4-piperazinylquinazoline, N-piperazinylquinazoline, N-(2-methylphenyl)quinazolin-4-amine, N-acetylquinolin-2-amine, N-cyclopropylcarbonylquinolin-2-amine, N-methylquinolin-2-amine, N-phenylquinolin-2-amine, N-(2-methoxyphenyl)quinolin-2-amine, N-(2-fluorophenyl)quinolin-2-amine and N-(2-morpholinophenyl)quinolin-2-amine;

[0011] R 2selected from one of a fluorine atom, a chlorine atom, a hydrogen atom, a trifluoromethyl group and a difluoromethyl group;

[0012] R 3 selected from one of 4-methyl-1H-imidazole, N,N'-diethylpiperazine, N-Boc-piperazine, a hydrogen atom, a chlorine atom, piperazine, N-methyl-N'-acetylpiperazine, N,N-dimethylpiperazine, N-methylethylamine and N-ethylethylamine.

[0013] Furthermore, the ROR1-targeting inhibitor is selected from the following compounds:

[0014] Compound 1: tert-butyl (4-((2-methyl-5-((4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)carbamoyl)phenyl)ethynyl)pyridin-2-yl)carbamate;

[0015] Compound 2: 3-((6-aminopyridin-3-yl)ethynyl)-4-methyl-N-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)benzamide;

[0016] Compound 3: 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)ethynyl)-4-methyl-N-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)benzamide;

[0017] Compound 4: 3-((2-aminopyrimidin-5-yl)ethynyl)-4-methyl-N-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)benzamide;

[0018] Compound 5: 3-(imidazo[1,2-a]pyrazin-3-ylethynyl)-4-methyl-N-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)benzamide;

[0019] Compound 6: 3-(imidazo[1,2-a]pyrimidin-3-ylethynyl)-4-methyl-N-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)benzamide;

[0020] Compound 7: N-(2-methyl-5-((4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)carbamoyl)phenyl)isonicotinamide;

[0021] Compound 8: N-(2-methyl-5-((4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)carbamoyl)phenyl)nicotinamide;

[0022] Compound 9: 6-Amino-N-(2-methyl-5-((4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)carbamoyl)phenyl)nicotinamide;

[0023] Compound 10: 6-Acetamido-N-(2-methyl-5-((4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)carbamoyl)phenyl)nicotinamide;

[0024] Compound 11: (E)-4-Methyl-N-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)-3-((pyridin-3-ylmethylene)amino)benzamide;

[0025] Compound 12: (E)-4-Methyl-N-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)-3-((pyridin-4-ylmethylene)amino)benzamide;

[0026] Compound 13: (E)-3-(((1H-Pyrrolo[2,3-b]pyridin-4-yl)methylene)amino)-4-methyl-N-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)benzamide;

[0027] Compound 14: 3-Methyl-N-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)-3-((pyridin-3-ylmethyl)amino)benzamide;

[0028] Compound 15: 4-Methyl-N-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)-3-((pyridin-4-ylmethyl)amino)benzamide;

[0029] Compound 16: 3-(((1H-Pyrrolo[2,3-b]pyridin-5-yl)methyl)amino)-4-methyl-N-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)benzamide;

[0030] Compound 17: 3-(((6-Aminopyridin-3-yl)methyl)amino)-4-methyl-N-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)benzamide;

[0031] Compound 18: 3-(((1H-Pyrrolo[2,3-b]pyridin-4-yl)methyl)amino)-4-methyl-N-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)benzamide;

[0032] Compound 19: Methyl-N-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)-3-(quinolin-6-yl)benzamide;

[0033] Compound 20: 3-(2-Aminoquinazolin-6-yl)-4-methyl-N-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)benzamide;

[0034] Compound 21: 4-Methyl-N-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)-3-(quinazolin-7-yl)benzamide;

[0035] Compound 22: 3-(1H-Benzimidazol-5-yl)-4-methyl-N-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)benzamide;

[0036] Compound 23: 3-(Benzothiazol-6-yl)-4-methyl-N-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)benzamide;

[0037] Compound 24: 3-(1H-Indazol-5-yl)-4-methyl-N-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)benzamide;

[0038] Compound 25: 4-Methyl-3-(1-methyl-1H-indazol-5-yl)-N-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)benzamide;

[0039] Compound 26: 4-Methyl-3-(2-methyl-2H-indazol-5-yl)-N-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)benzamide;

[0040] Compound 27: 3-(2-Aminoquinolin-6-yl)-4-methyl-N-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)benzamide;

[0041] Compound 28: 3-(2-Aminoquinazolin-7-yl)-4-methyl-N-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)benzamide;

[0042] Compound 29: 3-(Benzoxazol-5-yl)-4-methyl-N-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)benzamide;

[0043] Compound 30: 3-(Benzo[d]oxazol-6-yl)-4-methyl-N-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)benzamide;

[0044] Compound 31: 4-Methyl-3-(1-methyl-1H-benzo[d]imidazol-6-yl)-N-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)benzamide;

[0045] Compound 32: 3-(2-Aminobenzo[d]oxazol-5-yl)-4-methyl-N-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)benzamide;

[0046] Compound 33: 4-Methyl-N-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)-3-(2-(phenylamino)quinazolin-6-yl)benzamide;

[0047] Compound 34: 4-Methyl-3-(2-(methylamino)quinazolin-6-yl)-N-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)benzamide;

[0048] Compound 35: 3-(2-((4-Methoxyphenyl)amino)quinazolin-6-yl)-4-methyl-N-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)benzamide;

[0049] Compound 36: 3-(2-((4-Fluorophenyl)amino)quinazolin-6-yl)-4-methyl-N-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)benzamide;

[0050] Compound 37: 4-Methyl-N-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)-3-(2-((6-methylpyridin-3-yl)amino)quinazolin-6-yl)benzamide;

[0051] Compound 38: tert-Butyl 4-(4-((6-(2-methyl-5-((4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)carbamoyl)phenyl)quinaz;

[0052] Compound 39: 4-Methyl-N-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)-3-(2-((4-(piperazin-1-yl)phenyl)amino)quinazolin-6-yl)benzamide;

[0053] Compound 40: 4-Methyl-N-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)-3-(2-(p-tolylamino)quinazolin-6-yl)benzamide;

[0054] Compound 41: 3-(2-Acetamidoquinolin-6-yl)-4-methyl-N-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)benzamide;

[0055] Compound 42: 3-(2-(Cyclopropanecarboxamido)quinolin-6-yl)-4-methyl-N-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)benzamide;

[0056] Compound 43: 4-Methyl-3-(2-(methylamino)quinolin-6-yl)-N-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)benzamide;

[0057] Compound 44: 4-Methyl-N-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)-3-(2-(phenylamino)quinolin-6-yl)benzamide;

[0058] Compound 45: 3-(2-((4-Methoxyphenyl)amino)quinolin-6-yl)-4-methyl-N-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)benzamide;

[0059] Compound 46: 3-(2-((4-Fluorophenyl)amino)quinolin-6-yl)-4-methyl-N-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)benzamide;

[0060] Compound 47: 3-Methyl-N-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)-3-(2-((4-morpholinophenyl)amino)quinolin-6-yl)benzamide;

[0061] Compound 48: 3-(2-Aminoquinazolin-6-yl)-4-methyl-N-(3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl)benzamide;

[0062] Compound 49: 3-(2-Aminoquinazolin-6-yl)-N-(4-((4-ethylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)-4-methylbenzamide;

[0063] Compound 50: tert-Butyl 4-(4-(3-(2-aminoquinazolin-6-yl)-4-methylbenzamido)-2-(trifluoromethyl)phenyl)piperazine-1-carboxylate;

[0064] Compound 51: 3-(2-Aminoquinazolin-6-yl)-4-methyl-N-(3-(trifluoromethyl)phenyl)benzamide;

[0065] Compound 52: 3-(2-Aminoquinazolin-6-yl)-4-methyl-N-(4-(piperazin-1-yl)-3-(trifluoromethyl)phenyl)benzamide;

[0066] Compound 53: 3-(2-Aminoquinazolin-6-yl)-4-methyl-N-(4-(4-methylpiperazine-1-carbonyl)-3-(trifluoromethyl)phenyl)benzamide;

[0067] Compound 54: 3-(2-Aminoquinazolin-6-yl)-4-methyl-N-(3-((4-methylpiperazin-1-yl)methyl)-5-(trifluoromethyl)phenyl)benzamide;

[0068] Compound 55: 3-(2-Aminoquinazolin-6-yl)-N-(4-chloro-3-(trifluoromethyl)phenyl)-4-methylbenzamide;

[0069] Compound 56: 3-(2-Aminoquinazolin-6-yl)-4-methyl-N-(4-((4-methylpiperazin-1-yl)methyl)phenyl)benzamide;

[0070] Compound 57: 3-(2-Aminoquinazolin-6-yl)-N-(3-fluoro-4-((4-methylpiperazin-1-yl)methyl)phenyl)-4-methylbenzamide;

[0071] Compound 58: 4-(2-Aminoquinazolin-6-yl)-N-(3-chloro-4-((4-methylpiperazin-1-yl)methyl)phenyl)-3-methylbenzamide;

[0072] Compound 59: 3-(2-Aminoquinazolin-6-yl)-N-(3-(difluoromethyl)-4-((4-methylpiperazin-1-yl)methyl)phenyl)-4-methylbenzamide;

[0073] Compound 60: 3-(2-Aminoquinazolin-6-yl)-4-methyl-N-(4-(4-methylpiperazin-1-yl)phenyl)benzamide;

[0074] Compound 61: 3-(2-((4-Fluorophenyl)amino)quinazolin-6-yl)-4-methyl-N-(4-((4-methylpiperazin-1-yl)methyl)phenyl)benzamide;

[0075] Compound 62: 3-(2-((4-Fluorophenyl)amino)quinazolin-6-yl)-4-methyl-N-(3-(trifluoromethyl)phenyl)benzamide;

[0076] Compound 63: N-(3-(Difluoromethyl)-4-((4-methylpiperazin-1-yl)methyl)phenyl)-3-(2-((4-fluorophenyl)amino)quinazolin-6-yl)-4-methylbenzamide;

[0077] Compound 64: 3-(2-Aminoquinazolin-6-yl)-N-(4-((dimethylamino)methyl)-3-(trifluoromethyl)phenyl)-4-methylbenzamide;

[0078] Compound 65: 3-(2-Aminoquinazolin-6-yl)-N-(4-((diethylamino)methyl)-3-(trifluoromethyl)phenyl)-4-methylbenzamide;

[0079] Compound 66: N-(3-(2-Aminoquinazolin-6-yl)-4-methylphenyl)-4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)benzamide;

[0080] Compound 67: N-(3-(2-Aminoquinazolin-6-yl)-4-methylphenyl)-3-fluoro-4-((4-methylpiperazin-1-yl)methyl)benzamide;

[0081] Compound 68: 3-Fluoro-N-(3-(2-((4-fluorophenyl)amino)quinazolin-6-yl)-4-methylphenyl)-4-((4-methylpiperazin-1-yl)methyl)benzamide;

[0082] Compound 69: tert-Butyl 4-(4-((6-(5-(3-fluoro-4-((4-methylpiperazin-1-yl)methyl)benzamido)-2-methylphenyl)quinazolin-2-yl)amino)phenyl)piperazine-1-carboxylate;

[0083] Compound 70: 3-Fluoro-N-(4-methyl-3-(2-((4-(piperazin-1-yl)phenyl)amino)quinazolin-6-yl)phenyl)-4-((4-methylpiperazin-1-yl)methyl)benzamide;

[0084] Compound 71: N-(4-Methyl-3-(2-((4-(piperazin-1-yl)phenyl)amino)quinazolin-6-yl)phenyl)-4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)benzamide;

[0085] Compound 72: N-(3-(2-((4-Fluorophenyl)amino)quinazolin-6-yl)-4-methylphenyl)-4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)benzamide.

[0086] Furthermore, the pharmaceutically acceptable salts of the amide compounds are selected from the acid addition salts formed by the amide compounds and acids, and the acids are selected from: hydrogen chloride, hydrogen bromide, sulfuric acid, carbonic acid, oxalic acid, citric acid, succinic acid, tartaric acid, phosphoric acid, lactic acid, pyruvic acid, acetic acid, maleic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid or ferulic acid.

[0087] The present invention also provides a synthesis method of a ROR1-targeted inhibitor, and the reaction route of the ROR1-targeted inhibitor is as follows:

[0088] Route 1: Synthesis of target compounds 1-6, including the following steps:

[0089]

[0090] 1) React compound 1a and 4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)aniline in the presence of N,N-diisopropylethylamine, 1-(hydroxy-7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate and N,N-dimethylformamide at room temperature for 12 h to obtain 1b;

[0091] 2) React 1b and the alkynyl substituent under the catalysis of bis(triphenylphosphine)palladium dichloride and copper iodide in the presence of triethylamine at 80-100 °C for 12 h to obtain compounds 1-6;

[0092] The alkynyl substituent includes: one of N-(tert-butoxycarbonyl)-4-ethynyl-3-pyridinecarboxamide, 5-ethynyl-2-aminopyridine, 6-ethynylindole, 5-ethynyl-2,4-diaminopyrimidine, 6-ethynyl-1H-pyrazolo[3,4-b]pyridine and 6-ethynyl-1,2-dihydro-2-oxopyrazino[2,3-c]pyridazine;

[0093] Route 2: Synthesis of target compounds 7-10, including the following steps:

[0094]

[0095] 1) React compound 7a and carboxylic acid in the presence of N,N - diisopropylethylamine, 1 - hexafluorophosphate - 7 - azabenzotriazole, and N,N - dimethylformamide at room temperature for 12 h to obtain intermediate compound 7 - 10b;

[0096] 2) Hydrolyze 7 - 10b under the action of lithium hydroxide to obtain 7 - 10c;

[0097] 3) React 7 - 10c and 4 - ((4 - methylpiperazin - 1 - yl)methyl)-3-(trifluoromethyl)aniline in the presence of N,N - diisopropylethylamine, 1 - hexafluorophosphate - 7 - azabenzotriazole, and N,N - dimethylformamide at room temperature for 12 h to obtain compound 7 - 10;

[0098] The carboxylic acid includes one of picolinic acid, nicotinic acid, 4 - amino - 3 - picolinic acid, and 4 - acetamido - 3 - picolinic acid;

[0099] Route 3: Synthesis of target compounds 11 - 18, including the following steps:

[0100]

[0101] 1) React compound 11a and 4 - ((4 - methylpiperazin - 1 - yl)methyl)-3-(trifluoromethyl)aniline in the presence of N,N - diisopropylethylamine, 1 - hexafluorophosphate - 7 - azabenzotriazole, and N,N - dimethylformamide at room temperature for 12 h to obtain compound 11b;

[0102] 2) Reduce compound 11b under a hydrogen atmosphere in the presence of a palladium - carbon catalyst to obtain compound 11c;

[0103] 3) Mix compound 11c with an aldehyde - substituted compound in tetrahydrofuran and react at room temperature for 5 h under acidic conditions to obtain compounds 11 - 13;

[0104] 4) Reduce compounds 11 - 13 under acidic conditions using sodium triacetoxyborohydride to obtain compounds 14 - 18;

[0105] The aldehyde - substituted compound includes one of pyridine - 2 - carbaldehyde, pyridine - 3 - carbaldehyde, indole - 3 - carbaldehyde, 4 - aminopyridine - 3 - carbaldehyde, and 5 - indolecarbaldehyde;

[0106] Route 4: Synthesis of target compounds 19 - 32, including the following steps:

[0107]

[0108] 1) Compound 19a and 4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)aniline were reacted at room temperature for 12 h in the simultaneous presence of N,N-diisopropylethylamine, 1-hexafluorophosphate-7-azabenzotriazole, and N,N-dimethylformamide to obtain compound 19b;

[0109] 2) Compound 19b and the pinacol borate compound were reacted at 70 - 90 °C for 12 h in the presence of cesium carbonate and cesium fluoride under the catalysis of 1,1'-bis(diphenylphosphino)ferrocene dichloropalladium to obtain compounds 19 - 32;

[0110] The pinacol borate compound includes one of 2-quinolineboronic acid pinacol ester, 6-amino-3-pyridazinylboronic acid pinacol ester, isoquinoline-5-boronic acid pinacol ester, 1-indoleboronic acid pinacol ester, benzothiazole-6-boronic acid pinacol ester, 1H-benzo[d]imidazole-5-boronic acid pinacol ester, 1-methyl-1H-pyrrolo[2,3-b]pyridine-5-boronic acid pinacol ester, 6-(1H-1,2,3-triazol-4-yl)pyridine-3-boronic acid pinacol ester, 6-aminoquinoline-3-boronic acid pinacol ester, 2-amino-4H-pyrrolo[2,3-b][1,4]oxazine-6-boronic acid pinacol ester, benzoxazole-5-boronic acid pinacol ester, 7-methyl-1H-indazole-5-boronic acid pinacol ester, and 6-amino-1,3-benzoxazole-5-boronic acid pinacol ester;

[0111] Route 5: Synthesis of target compounds 33 - 40, including the following steps:

[0112]

[0113] 1) Compound 33a and the amino-substituted compound were mixed in N,N-dimethylformamide and N,N-diisopropylethylamine and reacted at 60 - 80 °C to obtain 33 - 40b;

[0114] 2) 33 - 40b and bis(pinacolato)diboron were reacted at 80 - 900 °C under the action of 1,1'-bis(diphenylphosphino)ferrocene dichloropalladium and potassium acetate to obtain 33 - 40c;

[0115] 3) 33 - 40c and compound 19b were reacted at 70 - 90 °C for 12 h in the presence of cesium carbonate and cesium fluoride under the catalysis of 1,1'-bis(diphenylphosphino)ferrocene dichloropalladium to obtain compounds 33 - 40;

[0116] The amino-substituted compound includes one of aniline, 2-methylaniline, 2-methoxyaniline, 3-fluoroaniline, 3-pyridinamine, N1-(4-aminophenyl)-N4,N4-dimethylpiperazine-1-carboxamide, N-(4-aminophenyl)piperazine, and 3-methylaniline;

[0117] Route 6: Synthesis of target compounds 41 - 47, including the following steps:

[0118]

[0119] 1) Mix compound 41a with an acid anhydride compound or an amine compound in N,N-dimethylformamide and N,N-diisopropylethylamine, and react at 60 - 80 °C to obtain 41 - 47b;

[0120] 2) React compound 41 - 47b with bis(pinacolato)diboron under the action of 1,1'-bis(diphenylphosphino)ferrocene dichloropalladium and potassium acetate at 80 - 900 °C to obtain compound 41 - 47c;

[0121] 3) React compound 41 - 47c with compound 19b under the catalytic action of 1,1'-bis(diphenylphosphino)ferrocene dichloropalladium in the presence of cesium carbonate and cesium fluoride at 70 - 90 °C for 12 h to obtain compound 41 - 47;

[0122] The acid anhydride compound includes acetic anhydride or cyclopropanecarboxylic anhydride; the amine compound includes methylamine, aniline, 2-methoxyaniline, 3-fluoroaniline, or 4-(4-aminophenyl)morpholine;

[0123] Route 7: Synthesis of target compounds 48 - 65, including the following steps:

[0124]

[0125] 1) Dissolve compound 48 - 65a and N-bromosuccinimide in N,N-dimethylformamide, and react at 70 °C for 12 hours under the catalysis of azobisisobutyronitrile to obtain 49 - 65b;

[0126] 2) React compound 48 - 65b with different amine compounds in the presence of dichloromethane and N,N-diisopropylethylamine at room temperature for 5 hours to obtain compound 48 - 65c;

[0127] The amine compound includes 2-methylimidazole, N-methylpiperazine, N-ethylpiperazine, piperazine, N-Boc-piperazine, dimethylamine, or diethylamine;

[0128] 3) React compound 48 - 65c in the presence of palladium on carbon and tetrahydrofuran at room temperature for 12 hours to obtain compound 48 - 65d;

[0129] 4) Compounds 48 - 65d and 3 - iodo - 4 - methylbenzoic acid were reacted at room temperature for 12 h in the simultaneous presence of N,N - diisopropylethylamine, 1 - hexafluorophosphate - 7 - azabenzotriazole, and N,N - dimethylformamide to obtain compounds 48 - 65e;

[0130] 5) Compounds 48 - 65e and the boronic acid pinacol ester - substituted compound were reacted at 70 - 90 °C for 12 h in the presence of cesium carbonate and cesium fluoride under the catalysis of 1,1'-bis(diphenylphosphino)ferrocene dichloropalladium to obtain compounds 48 - 65;

[0131] The boronic acid pinacol ester - substituted compound includes 6-(4,4,5,5 - tetramethyl - 1,3,2 - dioxaborolan - 2 - yl)quinazolin - 2 - amine or N-(4 - fluorophenyl)-6-(4,4,5,5 - tetramethyl - 1,3,2 - dioxaborolan - 2 - yl)quinazolin - 2 - amine;

[0132] Route 8: Synthesis of target compounds 66 - 72, including the following steps:

[0133]

[0134] 1) Compounds 66 - 72a and N - bromosuccinimide were dissolved in N,N - dimethylformamide and reacted at 70 °C for 12 h under the catalysis of azobisisobutyronitrile to obtain 66 - 72b;

[0135] 2) Compounds 66 - 72b and N - methylpiperazine were reacted at room temperature for 5 h in the presence of dichloromethane and N,N - diisopropylethylamine to obtain compounds 66 - 72c;

[0136] 3) Compounds 66 - 72c were reacted at room temperature for 2 h in the presence of lithium hydroxide and methanol / water to obtain compounds 66 - 72d;

[0137] 4) Compounds 66 - 72d and 3 - iodo - 4 - methylbenzoic acid were reacted at room temperature for 12 h in the simultaneous presence of N,N - diisopropylethylamine, 1 - hexafluorophosphate - 7 - azabenzotriazole, and N,N - dimethylformamide to obtain compounds 66 - 72e;

[0138] 5) Compounds 66 - 72e and the boronic acid pinacol ester - substituted compound were reacted at 70 - 90 °C for 12 h in the presence of cesium carbonate and cesium fluoride under the catalysis of 1,1'-bis(diphenylphosphino)ferrocene dichloropalladium to obtain compounds 66 - 72;

[0139] The boric acid pinacol ester-substituted compound comprises 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinazolin-2-amine or N-(4-fluorophenyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinazolin-2-amine.

[0140] The present invention also provides a pharmaceutical composition comprising the amide compound or a pharmaceutically acceptable salt thereof described in the present invention and a pharmaceutically acceptable carrier.

[0141] Furthermore, the dosage form of the pharmaceutical composition includes tablets, capsules, powders, syrups, liquids, suspensions, lyophilized powder injections or injections.

[0142] The present invention also provides the use of an inhibitor targeting ROR1 in the preparation of a drug for treating breast cancer.

[0143] The present invention also provides the use of an inhibitor targeting ROR1 in the preparation of a drug for treating or preventing ROR1-mediated diseases.

[0144] The present invention also provides a combined medication, comprising the amide compound, a derivative or stereoisomer of the amide compound, a prodrug, a pharmaceutically acceptable salt, a solvate or a hydrate described in the present invention, or the combined use of the pharmaceutical composition and another drug.

[0145] Furthermore, the combined medication treats or prevents the occurrence and development of related diseases by inhibiting ROR1.

[0146] Advantages of the present invention:

[0147] The novel ROR1 inhibitor designed and synthesized by the present invention can be used for preventing and treating ROR1-mediated related diseases. Description of the Drawings

[0148] Figure 1In vivo anti-tumor activity evaluation of the compounds in the subcutaneous xenograft tumor model. (A) Growth curve depicting the development of MDA-MB-231 xenografts implanted in nude mice over time; (B) Numerical values of tumor growth inhibition rate (TGI) calculated based on tumor volume. TGI = (Average tumor volume of the control group - Average tumor volume of the treatment group) / Average tumor volume of the control group; (C) Photos of dissected MDA-MB-231 tumor tissues, visually showing the appearance and morphology of the tumors; (D) Regular measurement of the body weights of nude mice throughout the experiment; (E) Detection of the morphology of the lungs, heart, kidneys, liver, and spleen of mice in the vehicle control group, ponatinib group, and compound 59 group by hematoxylin-eosin (H&E) staining; compared with the control group, * indicates P < 0.05, ** indicates P < 0.01, *** indicates P < 0.0001, indicating significant differences.

[0149] Figure 2 Compound 59 of the examples can inhibit the proliferation and metastasis of orthotopic breast cancer tumors. (A) Growth curve showing the development of MDA-MB-231 xenografts implanted in the fourth mammary fat pad of nude mice over time; (B) Regular measurement of the body weights of nude mice throughout the experiment; (C) Construction of a xenograft tumor model of MDA-MB-231 cell line expressing luciferase (Luciferase-LUC), and in vivo imaging was performed on the 7th day, 35th day, and 45th day respectively; (D) In vivo imaging pictures obtained by extending the exposure time and magnifying the metastatic sites; (E) Survival curves of mice in different dosing groups; (F) Detection of the morphology of the lungs, heart, kidneys, liver, and spleen of mice in the vehicle control group, ponatinib group, and compound 59 group by hematoxylin-eosin (H&E) staining. Detailed implementation manners

[0150] In the present invention, the inhibitors targeting ROR1 are selected from the following compounds:

[0151] Compound 1: tert-Butyl (4-((2-methyl-5-((4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)carbamoyl)phenyl)ethynyl)pyridin-2-yl)carbamate

[0152]

[0153] Compound 2: 3-((6-aminopyridin-3-yl)ethynyl)-4-methyl-N-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)benzamide

[0154]

[0155] Compound 3: 3-((1H-Pyrrolo[2,3-b]pyridin-5-yl)ethynyl)-4-methyl-N-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)benzamide

[0156]

[0157] Compound 4: 3-((2-Aminopyrimidin-5-yl)ethynyl)-4-methyl-N-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)benzamide

[0158]

[0159] Compound 5: 3-(Imidazo[1,2-a]pyrazin-3-ylethynyl)-4-methyl-N-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)benzamide

[0160]

[0161] Compound 6: 3-(Imidazo[1,2-a]pyrimidin-3-ylethynyl)-4-methyl-N-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)benzamide

[0162]

[0163] Compound 7: N-(2-Methyl-5-((4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)carbamoyl)phenyl)isonicotinamide

[0164]

[0165] Compound 8: N-(2-Methyl-5-((4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)carbamoyl)phenyl)nicotinamide

[0166]

[0167] Compound 9: 6-Amino-N-(2-methyl-5-((4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)carbamoyl)phenyl)nicotinamide

[0168]

[0169] Compound 10: 6-Acetamido-N-(2-methyl-5-((4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)carbamoyl)phenyl)nicotinamide

[0170]

[0171] Compound 11: (E)-4-Methyl-N-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)-3-((pyridin-3-ylmethylene)amino)benzamide

[0172]

[0173] Compound 12: (E)-4-Methyl-N-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)-3-((pyridin-4-ylmethylene)amino)benzamide

[0174]

[0175] Compound 13: (E)-3-(((1H-Pyrrolo[2,3-b]pyridin-4-yl)methylene)amino)-4-methyl-N-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)benzamide

[0176]

[0177] Compound 14: 3-Methyl-N-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)-3-((pyridin-3-ylmethyl)amino)benzamide

[0178]

[0179] Compound 15: 4-Methyl-N-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)-3-((pyridin-4-ylmethyl)amino)benzamide

[0180]

[0181] Compound 16: 3-(((1H-Pyrrolo[2,3-b]pyridin-5-yl)methyl)amino)-4-methyl-N-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)benzamide

[0182]

[0183] Compound 17: 3-(((6-Aminopyridin-3-yl)methyl)amino)-4-methyl-N-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)benzamide

[0184]

[0185] Compound 18: 3-(((1H-Pyrrolo[2,3-b]pyridin-4-yl)methyl)amino)-4-methyl-N-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)benzamide

[0186]

[0187] Compound 19: Methyl-N-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)-3-(quinolin-6-yl)benzamide

[0188]

[0189] Compound 20: 3-(2-Aminoquinazolin-6-yl)-4-methyl-N-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)benzamide

[0190]

[0191] Compound 21: 4-Methyl-N-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)-3-(quinazolin-7-yl)benzamide

[0192]

[0193] Compound 22: 3-(1H-Benzimidazol-5-yl)-4-methyl-N-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)benzamide

[0194]

[0195] Compound 23: 3-(Benzothiazol-6-yl)-4-methyl-N-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)benzamide

[0196]

[0197] Compound 24: 3-(1H-Indazol-5-yl)-4-methyl-N-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)benzamide

[0198]

[0199] Compound 25: 4-Methyl-3-(1-methyl-1H-indazol-5-yl)-N-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)benzamide

[0200]

[0201] Compound 26: 4-Methyl-3-(2-methyl-2H-indazol-5-yl)-N-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)benzamide

[0202]

[0203] Compound 27: 3-(2-Aminoquinolin-6-yl)-4-methyl-N-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)benzamide

[0204]

[0205] Compound 28: 3-(2-Aminoquinazolin-7-yl)-4-methyl-N-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)benzamide

[0206]

[0207] Compound 29: 3-(Benzo[d]oxazol-5-yl)-4-methyl-N-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)benzamide

[0208]

[0209] Compound 30: 3-(Benzo[d]oxazol-6-yl)-4-methyl-N-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)benzamide

[0210]

[0211] Compound 31: 4-Methyl-3-(1-methyl-1H-benzo[d]imidazol-6-yl)-N-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)benzamide

[0212]

[0213] Compound 32: 3-(2-Aminobenzo[d]oxazol-5-yl)-4-methyl-N-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)benzamide

[0214]

[0215] Compound 33: 4-Methyl-N-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)-3-(2-(phenylamino)quinazolin-6-yl)benzamide

[0216]

[0217] Compound 34: 4-Methyl-3-(2-(methylamino)quinazolin-6-yl)-N-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)benzamide

[0218]

[0219] Compound 35: 3-(2-((4-Methoxyphenyl)amino)quinazolin-6-yl)-4-methyl-N-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)benzamide

[0220]

[0221] Compound 36: 3-(2-((4-Fluorophenyl)amino)quinazolin-6-yl)-4-methyl-N-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)benzamide

[0222]

[0223] Compound 37: 4-Methyl-N-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)-3-(2-((6-methylpyridin-3-yl)amino)quinazolin-6-yl)benzamide

[0224]

[0225] Compound 38: tert-Butyl 4-(4-((6-(2-Methyl-5-((4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)carbamoyl)phenyl)quinaz

[0226]

[0227] Compound 39: 4-Methyl-N-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)-3-(2-((4-(piperazin-1-yl)phenyl)amino)quinazolin-6-yl)benzamide

[0228]

[0229] Compound 40: 4-Methyl-N-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)-3-(2-(p-tolylamino)quinazolin-6-yl)benzamide

[0230]

[0231] Compound 41: 3-(2-Acetamidoquinolin-6-yl)-4-methyl-N-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)benzamide

[0232]

[0233] Compound 42: 3-(2-(Cyclopropanecarboxamido)quinolin-6-yl)-4-methyl-N-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)benzamide

[0234]

[0235] Compound 43: 4-Methyl-3-(2-(methylamino)quinolin-6-yl)-N-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)benzamide

[0236]

[0237] Compound 44: 4-Methyl-N-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)-3-(2-(phenylamino)quinolin-6-yl)benzamide

[0238]

[0239] Compound 45: 3-(2-((4-Methoxyphenyl)amino)quinolin-6-yl)-4-methyl-N-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)benzamide

[0240]

[0241] Compound 46: 3-(2-((4-Fluorophenyl)amino)quinolin-6-yl)-4-methyl-N-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)benzamide

[0242]

[0243] Compound 47: 3-Methyl-N-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)-3-(2-((4-morpholinophenyl)amino)quinolin-6-yl)benzamide

[0244]

[0245] Compound 48: 3-(2-Aminoquinazolin-6-yl)-4-methyl-N-(3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl)benzamide

[0246]

[0247] Compound 49: 3-(2-Aminoquinazolin-6-yl)-N-(4-((4-ethylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)-4-methylbenzamide

[0248]

[0249] Compound 50: tert-Butyl 4-(4-(3-(2-aminoquinazolin-6-yl)-4-methylbenzamido)-2-(trifluoromethyl)phenyl)piperazine-1-carboxylate

[0250]

[0251] Compound 51: 3-(2-Aminoquinazolin-6-yl)-4-methyl-N-(3-(trifluoromethyl)phenyl)benzamide

[0252] Compound 52: 3-(2-Aminoquinazolin-6-yl)-4-methyl-N-(4-(piperazin-1-yl)-3-(trifluoromethyl)phenyl)benzamide

[0253]

[0254] Compound 53: 3-(2-Aminoquinazolin-6-yl)-4-methyl-N-(4-(4-methylpiperazine-1-carbonyl)-3-(trifluoromethyl)phenyl)benzamide

[0255]

[0256] Compound 54: 3-(2-Aminoquinazolin-6-yl)-4-methyl-N-(3-((4-methylpiperazin-1-yl)methyl)-5-(trifluoromethyl)phenyl)benzamide

[0257]

[0258] Compound 55: 3-(2-Aminoquinazolin-6-yl)-N-(4-chloro-3-(trifluoromethyl)phenyl)-4-methylbenzamide

[0259]

[0260] Compound 56: 3-(2-Aminoquinazolin-6-yl)-4-methyl-N-(4-((4-methylpiperazin-1-yl)methyl)phenyl)benzamide

[0261]

[0262] Compound 57: 3-(2-Aminoquinazolin-6-yl)-N-(3-fluoro-4-((4-methylpiperazin-1-yl)methyl)phenyl)-4-methylbenzamide

[0263]

[0264] Compound 58: 3-(2-Aminoquinazolin-6-yl)-N-(3-chloro-4-((4-methylpiperazin-1-yl)methyl)phenyl)-4-methylbenzamide

[0265]

[0266] Compound 59: 3-(2-Aminoquinazolin-6-yl)-N-(3-(difluoromethyl)-4-((4-methylpiperazin-1-yl)methyl)phenyl)-4-methylbenzamide

[0267]

[0268] Compound 60: 3-(2-Aminoquinazolin-6-yl)-4-methyl-N-(4-(4-methylpiperazin-1-yl)phenyl)benzamide

[0269]

[0270] Compound 61: 3-(2-((4-Fluorophenyl)amino)quinazolin-6-yl)-4-methyl-N-(4-((4-methylpiperazin-1-yl)methyl)phenyl)benzamide

[0271]

[0272] Compound 62: 3-(2-((4-Fluorophenyl)amino)quinazolin-6-yl)-4-methyl-N-(3-(trifluoromethyl)phenyl)benzamide

[0273]

[0274] Compound 63: N-(3-(Difluoromethyl)-4-((4-methylpiperazin-1-yl)methyl)phenyl)-3-(2-((4-fluorophenyl)amino)quinazolin-6-yl)-4-methylbenzamide

[0275]

[0276] Compound 64: 3-(2-Aminoquinazolin-6-yl)-N-(4-((dimethylamino)methyl)-3-(trifluoromethyl)phenyl)-4-methylbenzamide

[0277]

[0278] Compound 65: 3-(2-Aminoquinazolin-6-yl)-N-(4-((diethylamino)methyl)-3-(trifluoromethyl)phenyl)-4-methylbenzamide

[0279]

[0280] Compound 66: N-(3-(2-Aminoquinazolin-6-yl)-4-methylphenyl)-4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)benzamide

[0281]

[0282] Compound 67: N-(3-(2-Aminoquinazolin-6-yl)-4-methylphenyl)-3-fluoro-4-((4-methylpiperazin-1-yl)methyl)benzamide

[0283]

[0284] Compound 68: 3-Fluoro-N-(3-(2-((4-fluorophenyl)amino)quinazolin-6-yl)-4-methylphenyl)-4-((4-methylpiperazin-1-yl)methyl)benzamide

[0285]

[0286] Compound 69: tert-Butyl 4-(4-((6-(5-(3-fluoro-4-((4-methylpiperazin-1-yl)methyl)benzamido)-2-methylphenyl)quinazolin-2-yl)amino)phenyl)piperazine-1-carboxylate

[0287]

[0288] Compound 70: 3-Fluoro-N-(4-methyl-3-(2-((4-(piperazin-1-yl)phenyl)amino)quinazolin-6-yl)phenyl)-4-((4-methylpiperazin-1-yl)methyl)benzamide

[0289]

[0290] Compound 71: N-(4-methyl-3-(2-((4-(piperazin-1-yl)phenyl)amino)quinazolin-6-yl)phenyl)-4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)benzamide

[0291] Compound 72: N-(3-(2-((4-fluorophenyl)amino)quinazolin-6-yl)-4-methylphenyl)-4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)benzamide

[0292]

[0293] The present invention also provides a method for synthesizing an inhibitor targeting ROR1.

[0294] In the present invention, in Route 1, the molar ratio of Compound 1a to 4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)aniline is 1:1 to 1.5, preferably 1:1.2;

[0295] The molar ratio of Compound 1a, N,N-diisopropylethylamine, and 1-(hydroxy-7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate is 1:1 to 3:1 to 1.5, preferably 1:2:1.3;

[0296] The molar ratio of Compound 1b to the tert-butyl-substituted compound is 1:1 to 1.5, preferably 1:1.3.

[0297] In the present invention, in Route 2, the molar ratio of Compound 7a to the organic acid is 1:1.5, preferably 1:1.2;

[0298] The molar ratio of the compound 7a, N,N-diisopropylethylamine and 1-hexafluorophosphate-7-azabenzotriazole is 1:1 to 3:1 to 1.5, preferably 1:2:1.3;

[0299] The molar ratio of the compound 7-10c and 4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)aniline is 1:1 to 1.5, preferably 1:1.3;

[0300] The molar ratio of the compound 7-10c, N,N-diisopropylethylamine and 1-hexafluorophosphate-7-azabenzotriazole is 1:1 to 3:1 to 1.5, preferably 1:2:1.3.

[0301] In the present invention, in Route 3, the molar ratio of the compound 11a and 4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)aniline is 1:1 to 1.5, preferably 1:1.2;

[0302] The molar ratio of the compound 11a, N,N-diisopropylethylamine and 1-hexafluorophosphate-7-azabenzotriazole is 1:1 to 3:1 to 1.5, preferably 1:2:1.3; the molar ratio of the compound 11c and the aldehyde-substituted compound is 1:1 to 1.5, preferably 1:1.2.

[0303] In the present invention, in Route 4, the molar ratio of the compound 19a and 4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)aniline is 1:1 to 1.5, preferably 1:1.2;

[0304] In the present invention, the molar ratio of the compound 19a, N,N-diisopropylethylamine and 1-hexafluorophosphate-7-azabenzotriazole is 1:1 to 3:1 to 1.5, preferably 1:2:1.3;

[0305] The molar ratio of the compound 19b and the oxygen-containing compound is 1:1 to 1.5, preferably 1:1.3.

[0306] In the present invention, in Route 5, the molar ratio of the compound 33a and the amino-substituted compound is 1:1 to 3, preferably 1:2;

[0307] The molar ratio of the compounds 33-40b and bis(pinacolato)diboron is 1:1 to 3, preferably 1:2;

[0308] The molar ratio of the compounds 33-40c and the compound 19b is 1:1 to 3, preferably 1:1 to 2.

[0309] In the present invention, in Route 6, the molar ratio of Compound 41a to an ether compound or an acid anhydride compound or an amine compound is 1:1 to 3, preferably 1:1 to 2;

[0310] The molar ratio of Compounds 41 to 47b to bis(pinacolato)diboron is 1:1 to 3, preferably 1:2;

[0311] The molar ratio of Compounds 41 to 47c to Compound 19b is 1:1 to 3, preferably 1:1 to 2.

[0312] In the present invention, in Route 7, the molar ratio of Compounds 48 to 65d to 3-iodo-4-methylbenzoic acid is 1:1 to 1.5, preferably 1:1.2;

[0313] The molar ratio of Compounds 48 to 65d, N,N-diisopropylethylamine, and 1-hexafluorophosphate-7-azabenzotriazole is 1:1 to 3:1 to 1.5, preferably 1:2:1.3;

[0314] The molar ratio of Compounds 48 to 65e to an aniline-substituted compound is 1:1 to 3, preferably 1:1 to 2.

[0315] In the present invention, in Route 8, the molar ratio of Compounds 66 to 72a, N,N-diisopropylethylamine, and 1-hexafluorophosphate-7-azabenzotriazole is 1:1 to 3:1 to 1.5, preferably 1:2:1.3;

[0316] The molar ratio of Compounds 66 to 72b to a pinacol borate-substituted compound is 1:1 to 3, preferably 1:1 to 2.

[0317] The present invention also provides a pharmaceutical composition comprising the amide compound or a pharmaceutically acceptable salt thereof described in the present invention and a pharmaceutically acceptable carrier.

[0318] In the present invention, the dosage form of the pharmaceutical composition includes tablets, capsules, powders, syrups, liquids, suspensions, lyophilized powder injections, or injections.

[0319] The present invention also provides the use of an inhibitor targeting ROR1 in the preparation of a drug for treating breast cancer.

[0320] The present invention also provides the use of an inhibitor targeting ROR1 in the preparation of a drug for treating or preventing ROR1-mediated diseases.

[0321] The present invention also provides a combination therapy, comprising the amide compound, a derivative or stereoisomer of the amide compound, a prodrug, a pharmaceutically acceptable salt, a solvate, or a hydrate described in the present invention, or the pharmaceutical composition in combination with another drug.

[0322] In the present invention, the combined drug inhibits ROR1, thereby treating or preventing the occurrence and development of related diseases.

[0323] The technical solutions provided by the present invention are described in detail below in conjunction with the embodiments, but they should not be construed as limiting the protection scope of the present invention.

[0324] Example 1: tert-Butyl (4-((2-methyl-5-((4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)carbamoyl)phenyl)ethynyl)pyridin-2-yl)carbamate (1)

[0325] 1a (262.05 mg, 1 mmol) was reacted with 4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)aniline (327.96 mg, 1.2 mmol) in the presence of N,N-diisopropylethylamine (DIPEA, 258.49 mg, 2 mmol), 1-(hydroxy-7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU, 494.31 mg, 1.3 mmol) and N,N-dimethylformamide (DMF, 5 ml) at room temperature for 12 hours to give 1b, which was then separated by column chromatography. 1b (517.33 mg, 1 mmol) was reacted with tert-butyl(4-ethynylpyridin-2-yl)carbamate (261.91 mg, 1.2 mmol) in the presence of bis(triphenylphosphine)palladium dichloride (Pd(PPh 3 ) 2 Cl 2 , 70.19 mg, 0.1 mmol) and cuprous iodide (CuI, 19.05 mg, 0.1 mmol) were catalyzed by triethylamine (Et 3 N, 101.19 mg, 1 mmol), and reacted at 90°C for 12 hours under nitrogen protection to obtain compound 1 with a yield of 51% as a milky white solid. 1 H NMR (400 MHz, DMSO-d 6 )δ10.54(s,1H),10.01(s,1H),8.32(d,J=5.2Hz,1H),8.23(s,2H),8.10(d,J=8.7Hz,1H),7.97(d,J=9.7Hz,2H),7.71(d,J=8.5Hz,1H),7 .54(d,J=8.1Hz,1H),7.19(d,J=5.1Hz,1H),3.64(s,2H),2.97(s,4H),2.89(s,2H),2.73(s,2H),2.62(s,3H),2.56(s,3H),1.49(s,9H). 1313C NMR(101MHz,DMSO-d 6 )δ165.0,162.8,153.3,153.2,149.0,144.7,138.9,132.6,132.0,131.9,131.7,131.5,130.6,129.5,128.1,127.8,126.1,124.0,123.4,121.7,120.2,117.9,117.8,114.0,92.0,91.3,80.4,57.3,53.8,50.8,46.3,28.5,20.8.HRMS:[M+H] + calcd for C 33 H 37 O 3 N 5 F 3 ,608.2843,found 608.2826。

[0326] Example 2: 3-((6-Aminopyridin-3-yl)ethynyl)-4-methyl-N-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)benzamide (2)

[0327] The synthesis procedure of Compound 2 was similar to that of Compound 1. 1 1H NMR(400MHz,DMSO-d 6 )δ10.59(s,1H),8.25(d,J = 2.2Hz,1H),8.17(d,J = 2.3Hz,1H),8.11(q,J = 3.9,3.1Hz,2H),7.92 - 7.86(m,1H),7.71(d,J = 8.5Hz,1H),7.55(dd,J = 8.6,2.4Hz,1H),7.48(d,J = 8.0Hz,1H),6.50(d,J = 8.4Hz,3H),3.62(s,2H),2.78(s,4H),2.63 - 2.53(m,4H),2.52(s,2H),2.47(s,3H). 13 13C NMR(151MHz,DMSO-d 6)δ166.7,149.0,146.8,143.1,141.2,139.0,133.3,131.6,130.0,128.1,127.9,127.7,127.5,126.7,125.9,125.7,123.9,122.1,118.5,117.7,117.6,117.6,117.6,115.5,113.4,108.9,98.8,57.6,54.4,51.9,44.8,44.5,18.4.HRMS:[M+H] + calcd for C 28 H 29 ON 5 F 3 ,508.2319,found 508.2314。

[0328] Example 3: 3-((1H-Pyrrolo[2,3-b]pyridin-5-yl)ethynyl)-4-methyl-N-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)benzamide (3)

[0329] The synthesis procedure of Compound 3 is similar to that of Compound 1. 1 H NMR(400MHz,DMSO-d 6 )δ11.97(s,1H),10.59(s,1H),8.45(d,J=2.0Hz,1H),8.28-8.17(m,3H),8.12(dd,J=8.5,2.2Hz,1H),7.92(dd,J=8.0,2.0Hz,1H),7.72(d,J=8.6Hz,1H),7.59(t,J=3.0Hz,1H),7.53(d,J=8.1Hz,1H),6.53(dd,J=3.4,1.8Hz,1H),3.64(s,2H),2.88(s,4H),2.59(s,10H). 13 C NMR(151MHz,DMSO-d 6 )δ165.3,148.1,145.6,144.0,138.9,132.6,131.9,131.4,130.8,130.4,130.1,128.4,128.2,128.1,127.9,125.7,124.0,123.9,123.1,122.1,119.7,117.8,117.8,110.8,100.8,93.7,87.9,57.4,53.9,50.9,43.8,20.9.HRMS:[M+H] + calcd forC 30H 29 ON 5 F 3 ,532.2319, found 532.2310。

[0330] Example 4: 3 - ((2 - aminopyrimidin - 5 - yl)ethynyl)-4 - methyl - N-(4 - ((4 - methylpiperazin - 1 - yl)methyl)-3 - (trifluoromethyl)phenyl)benzamide (4)

[0331] The synthesis steps of Compound 4 are similar to those of Compound 1. 1 HNMR(400MHz, DMSO - d 6 )δ10.63(s, 1H), 8.49(s, 2H), 8.26(d, J = 2.2Hz, 1H), 8.13(q, J = 4.2, 3.6Hz, 2H), 7.96 - 7.90(m, 1H), 7.71(d, J = 8.6Hz, 1H), 7.50(d, J = 8.1Hz, 1H), 7.20(s, 2H), 3.67(s, 2H), 2.69(s, 4H), 2.55–2.50(m, 11H). 13 C NMR(151MHz, DMSO - d 6 )δ165.2, 162.5, 160.7, 143.8, 138.9, 132.5, 131.8, 130.7, 130.4, 130.1, 128.3, 128.2, 128.0, 127.9, 127.7, 125.7, 124.0, 123.9, 123.0, 122.1, 117.8, 117.8, 117.7, 106.2, 90.3, 90.2, 57.4, 53.9, 51.1, 45.9, 20.9. HRMS: [M + H] + calcd for C 27 H 28 ON 6 F 3 ,509.2271, found 509.2261。

[0332] Example 5: 3 - (imidazo[1,2 - a]pyrazin - 3 - ylethynyl)-4 - methyl - N-(4 - ((4 - methylpiperazin - 1 - yl)methyl)-3 - (trifluoromethyl)phenyl)benzamide (5)

[0333] The synthesis steps of Compound 5 are similar to those of Compound 1. 1 H NMR(400MHz, DMSO - d 6)δ10.65(s,1H),9.23(s,1H),8.72(d,J=4.6Hz,1H),8.35(d,J=1.9Hz,1H),8.32 - 8.25(m,2H),8.17 - 8.10(m,2H),7.99(dd,J=8.0,2.0Hz,1H),7.72(d,J=8.5Hz,1H),7.58(d,J=8.1Hz,1H),3.65(s,2H),2.97(s,4H),2.62(d,J=10.2Hz,10H). 13 C NMR(151MHz,DMSO - d 6 )δ165.2,144.0,143.7,140.8,140.1,138.9,132.7,131.9,131.8,131.3,131.2,130.5,129.2,128.3,128.1,127.9,127.7,127.5,125.7,124.0,123.9,123.9,122.0,121.9,119.6,117.9,117.8,109.4,98.4,80.3,57.3,53.7,50.6,43.5,21.0.HRMS:[M + H] + calcd forC 29 H 28 ON 6 F 3 ,533.2271,found 533.2261。

[0334] Example 6: 3-(Imidazo[1,2 - a]pyrimidin - 3 - ylethynyl)-4 - methyl - N-(4 - ((4 - methylpiperazin - 1 - yl)methyl)-3-(trifluoromethyl)phenyl)benzamide (6)

[0335] The synthesis procedure of compound 6 is similar to that of compound 1. 1 H NMR(400MHz,DMSO - d 6)δ10.65(s,1H),9.11(dd,J=6.7,2.0Hz,1H),8.71(dd,J=4.2,2.0Hz,1H),8.34(d,J=2.0Hz,1H),8.27 - 8.21(m,2H),8.12(dd,J=8.5,2.2Hz,1H),7.97(dd,J=8.0,2.0Hz,1H),7.72(d,J=8.6Hz,1H),7.56(d,J=8.1Hz,1H),7.31(dd,J=6.7,4.2Hz,1H),3.62(s,2H),2.73(s,4H),2.62(s,7H),2.43(s,3H). 13 C NMR(151MHz,DMSO)δ165.2,152.3,148.8,143.7,140.0,138.8,134.9,132.7,132.1,131.8,131.1,130.5,128.9,128.2,128.0,127.8,127.6,127.5,125.7,124.0,123.9,122.2,122.1,117.8,117.8,110.8,106.9,97.4,80.9,57.5,54.2,51.6,44.5,21.1.HRMS:[M + H] + calcd for C 29 H 28 ON 6 F 3 ,533.2271,found 533.2259。

[0336] Example 7: 14-(2-Methyl-5-((4-((4-Methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)carbamoyl)phenyl)isonicotinamide (7)

[0337] 7a (165.19 mg, 1 mmol) was reacted with isonicotinic acid (147.73 mg, 1.2 mmol) in the presence of DIPEA (258.49 mg, 2 mmol), HATU (494.31 mg, 1.3 mmol) and DMF (5 mL) at room temperature for 12 h to give 7b, which was then separated by column chromatography. 7b (270.29 mg, 1 mmol) was hydrolyzed in a methanol:water (1:1) mixed solvent in the presence of lithium at room temperature for 4 h, and then the pH was adjusted to acidic to give 7c. 7c (256.26 mg, 1 mmol) was reacted with 4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)aniline (327.96 mg, 1.2 mmol) in the presence of DIPEA (258.49 mg, 2 mmol), HATU (494.31 mg, 1.3 mmol) and DMF (5 mL) at room temperature for 12 h, and then subjected to column chromatography to give the final product 7 as a light yellow solid in 52% yield. 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.53 (s, 1H), 10.42 (s, 1H), 8.84 - 8.80 (m, 2H), 8.23 (d, J = 2.1 Hz, 1H), 8.09 (dd, J = 8.5, 2.2 Hz, 1H), 8.02 (d, J = 1.9 Hz, 1H), 7.97 - 7.92 (m, 2H), 7.89 (dd, J = 8.0, 1.9 Hz, 1H), 7.70 (d, J = 8.5 Hz, 1H), 7.48 (d, J = 8.0 Hz, 1H), 3.58 (s, 2H), 2.57 - 2.41 (m, 8H), 2.34 (s, 3H), 2.27 (s, 3H). 13 C NMR (101 MHz, DMSO-d 6 ) δ 165.5, 164.5, 150.9, 141.7, 138.8, 136.4, 132.8, 132.2, 131.7, 131.0, 126.6, 126.2, 124.0, 122.1, 117.8, 57.7, 54.8, 52.5, 45.4, 18.4. HRMS: [M + H] + calcd for C 27 H 29 O 2 N 5 F 3 , 512.2268, found 512.2255.

[0338] Example 8: N-(2-Methyl-5-((4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)carbamoyl)phenyl)nicotinamide (8)

[0339] The synthesis procedure of compound 8 is similar to that of compound 7. 1 H NMR(400MHz,DMSO-d 6 )δ10.50(s,1H),10.29(s,1H),9.18(s,1H),8.80(d,J=4.9Hz,1H),8.36(d,J=8.0Hz,1H),8.23(s,1H),8.10(d,J=8.6Hz,1H),8.03(s,1H),7.86(d,J=8.0Hz,1H),7.71(d,J=8.6Hz,1H),7.61(dd,J=8.0,4.9Hz,1H),7.49(d,J=7.9Hz,1H),3.63(s,2H),2.82(s,4H),2.53(d,J=15.3Hz,7H),2.36(s,3H). 13 CNMR(101MHz,DMSO-d 6 )δ165.6,164.6,152.8,149.2,138.9,138.7,136.6,135.9,132.8,131.8,131.0,130.4,128.1,127.8,127.5,126.5,126.1,126.0,124.1,124.0,123.4,121.7,117.8,117.8,57.4,54.1,51.3,44.2,18.5.HRMS:[M+H] + calcd for C 27 H 29 O 2 N 5 F 3 ,512.2268,found 512.2261。

[0340] Example 9: 6-Amino-N-(2-methyl-5-((4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)carbamoyl)phenyl)nicotinamide (9)

[0341] The synthesis procedure of compound 9 is similar to that of compound 7. 1 H NMR(400MHz,DMSO-d 6)δ10.47(s,1H),9.74(s,1H),8.64(d,J=2.4Hz,1H),8.21(d,J=2.2Hz,1H),8.13 - 8.04(m,1H),8.00 - 7.92(m,2H),7.81(dd,J=8.0,1.9Hz,1H),7.70(d,J=8.6Hz,1H),7.44(d,J=8.0Hz,1H),6.62(s,2H),6.51(d,J=8.7Hz,1H),3.57(s,2H),2.41(s,8H),2.31(s,3H),2.20(s,3H). 13 C NMR(151MHz,DMSO - d 6 )δ165.7,164.8,162.2,149.5,138.8,138.6,137.3,137.0,132.6,132.2,131.7,130.8,128.2,128.0,127.8,127.6,127.5,126.5,125.7,125.4,124.0,123.9,122.1,118.1,117.8,117.7,107.3,57.8,54.8,52.6,45.6,18.6.HRMS:[M + H] + calcd forC 27 H 30 O 2 N 6 F 3 ,527.2377,found 527.2373。

[0342] Example 10: 6 - Acetamido - N-(2 - methyl - 5 - ((4 - ((4 - methylpiperazin - 1 - yl)methyl)-3-(trifluoromethyl)phenyl)carbamoyl)phenyl)nicotinamide (10)

[0343] The synthetic procedure of compound 10 is similar to that of compound 7. 1 HNMR(400MHz,DMSO - d 6)δ 10.85 (s, 1H), 10.53 (s, 1H), 10.19 (s, 1H), 8.96 (d, J = 2.4 Hz, 1H), 8.37 (dd, J = 8.8, 2.4 Hz, 1H), 8.22 (d, J = 8.3 Hz, 2H), 8.11 (d, J = 8.5 Hz, 1H), 8.01 (s, 1H), 7.86 (d, J = 7.9 Hz, 1H), 7.70 (d, J = 8.6 Hz, 1H), 7.47 (d, J = 8.0 Hz, 1H), 3.62 (s, 2H), 2.79 (s, 4H), 2.55 (s, 4H), 2.47 (s, 3H), 2.34 (s, 3H), 2.15 (s, 3H). 13 C NMR (151 MHz, DMSO-d 6 )δ 170.2, 165.6, 164.1, 154.7, 148.4, 138.9, 138.8, 138.4, 136.8, 132.7, 131.8, 131.0, 130.1, 128.2, 128.0, 127.8, 127.6, 127.5, 126.5, 125.9, 125.7, 125.5, 124.0, 123.9, 122.1, 117.9, 117.8, 117.8, 117.7, 112.7, 57.5, 54.1, 51.3, 45.9, 24.5, 18.6. HRMS: [M + H] + calcd for C 29 H 32 O 3 N 6 F 3 , 569.2483, found 569.2468。

[0344] Example 11: (E)-4-Methyl-N-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)-3-((pyridin-3-ylmethylene)amino)benzamide (11)

[0345] Compound 11a (181.15 mg, 1 mmol) was reacted with 4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)aniline (327.96 mg, 1.2 mmol) in the presence of DIPEA (258.49 mg, 2 mmol), HATU (494.31 mg, 1.3 mmol) and DMF (5 mL) at room temperature for 12 h to give 11b, which was then separated by column chromatography. 11b (436.4 mg, 1 mmol) was reduced with palladium-carbon (436.44 mg, 4.1 mmol) under a hydrogen atmosphere to give 11c. 11c (406.45 mg, 1 mmol) and nicotinaldehyde (128.53 mg, 1.2 mmol) were dissolved in tetrahydrofuran (THF, 10 mL), and then reacted at room temperature for 5 h under acidic conditions. Subsequently, column chromatography separation was carried out to obtain the final product 11 as a light yellow solid with a yield of 40%. 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.55 (s, 1H), 9.13 (s, 1H), 8.83 - 8.68 (m, 2H), 8.38 (d, J = 7.9 Hz, 1H), 8.25 (s, 1H), 8.11 (d, J = 8.6 Hz, 1H), 7.86 - 7.66 (m, 3H), 7.59 (dd, J = 7.9, 4.8 Hz, 1H), 7.45 (d, J = 7.9 Hz, 1H), 3.61 (s, 2H), 2.59 (d, J = 62.0 Hz, 9H), 2.39 (d, J = 5.0 Hz, 7H). 13 C NMR (151 MHz, DMSO-d 6 ) δ 164.7, 158.5, 151.5, 149.8, 149.4, 137.9, 135.3, 134.5, 132.4, 130.9, 130.7, 129.7, 129.1, 127.1, 126.9, 126.7, 126.5, 126.5, 124.8, 124.6, 123.5, 122.9, 122.8, 121.0, 116.8, 116.7, 116.7, 116.6, 56.4, 53.1, 50.4, 44.8, 17.0. HRMS: [M + H] + calcd for C 27 H 29 ON 5 F 3 , 496.2319, found 496.2314。

[0346] Example 12: (E)-4-Methyl-N-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)-3-((pyridin-4-ylmethylene)amino)benzamide (12)

[0347] The synthesis procedure of Compound 12 is similar to that of Compound 11. 1 H NMR(400MHz,DMSO-d 6 )δ10.56(s,1H),8.84 - 8.74(m,3H),8.24(d,J=2.2Hz,1H),8.11(dd,J=8.6,2.2Hz,1H),7.96 - 7.90(m,2H),7.85(dd,J=7.8,1.9Hz,1H),7.78(d,J=1.9Hz,1H),7.71(d,J=8.5Hz,1H),7.47(d,J=7.9Hz,1H),3.60(s,2H),3.05(q,J=7.3Hz,1H),2.62(s,4H),2.51 - 2.46(m,4H),2.38(d,J=17.5Hz,7H). 13 C NMR(101MHz,DMSO-d 6 )δ165.7,160.3,151.1,150.0,142.9,138.9,136.6,133.5,131.7,130.9,128.0,127.5,126.3,126.2,124.0,123.4,122.7,117.8,117.7,57.6,54.5,52.0,45.9,18.0.HRMS:[M+H] + calcd for C 27 H 29 ON 5 F 3 ,496.2318,found496.2319。

[0348] Example 13: (E)-3-(((1H-pyrrolo[2,3-b]pyridin-4-yl)methylene)amino)-4-methyl-N-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)benzamide (13)

[0349] The synthesis procedure of Compound 13 is similar to that of Compound 11. 1 HNMR(400MHz,DMSO-d 6)δ11.99(s,1H),10.59(s,1H),9.01(s,1H),8.42(d,J=4.8Hz,1H),8.26(d,J=2.2Hz,1H),8.11(dd,J=8.5,2.3Hz,1H),7.84(d,J=6.6Hz,2H),7.77 - 7.67(m,2H),7.59(d,J=4.9Hz,1H),7.48(d,J=7.9Hz,1H),7.24(dd,J=3.4,1.9Hz,1H),3.59(s,2H),2.51(p,J=1.8Hz,8H),2.47(s,4H),2.30(s,3H). 13 C NMR(151MHz,DMSO - d 6 )δ165.9,161.3,150.7,150.3,143.0,138.9,136.6,134.2,133.6,132.0,131.7,130.8,129.0,128.2,128.0,127.8,127.6,127.5,126.1,125.7,124.0,123.9,122.1,117.9,117.8,117.8,117.7,117.4,117.4,117.3,101.1,57.6,54.4,51.9,45.8,18.3.HRMS:[M + H] + calcd for C 29 H 30 ON 6 F 3 ,535.2428,found 535.2424。

[0350] Example 14: 4 - Methyl - N-(4 - ((4 - methylpiperazin - 1 - yl)methyl)-3-(trifluoromethyl)phenyl)-3 - ((pyridin - 3 - ylmethyl)amino)benzamide (14)

[0351] Under acidic conditions, compound 11 (495.55 mg, 1 mmol) was reduced with sodium triacetoxyborohydride (NaBH(OAc) 3 , 423.88 mg, 2 mmol) at room temperature for 5 hours. Then compound 14 was obtained by column chromatography as a yellow solid in 33% yield. 1 H NMR(400MHz,DMSO - d 6)δ10.26(s,1H),8.61(d,J=2.2Hz,1H),8.43(dd,J=4.8,1.6Hz,1H),8.19(d,J=2.2Hz,1H),8.00(dd,J=8.6,2.2Hz,1H),7.77(dd,J=7.8,2.0Hz,1H),7.66(d,J=8.5Hz,1H),7.35(dd,J=7.8,4.7Hz,1H),7.21 - 7.12(m,2H),7.00(d,J=1.6Hz,1H),5.95(t,J=6.1Hz,1H),4.49(d,J=5.9Hz,2H),3.57(s,2H),2.51(p,J=1.9Hz,8H),2.28(s,3H),2.24(s,3H). 13 C NMR(151MHz,DMSO - d 6 )δ166.7,149.2,148.4,146.5,139.0,135.9,135.3,133.3,131.7,130.1,128.1,127.9,127.8,127.7,127.6,127.5,127.0,125.7,124.0,123.9,123.8,122.1,117.7,117.6,117.6,115.8,109.0,57.6,54.4,51.9,44.8,44.4,18.3.HRMS:[M + H] + calcd for C 27 H 31 ON 5 F 3 ,498.2475,found 498.2471。

[0352] Example 15: 4 - Methyl - N-(4 - ((4 - methylpiperazin - 1 - yl)methyl)-3-(trifluoromethyl)phenyl)-3 - ((pyridin - 4 - ylmethyl)amino)benzamide (15)

[0353] The synthesis procedure of Compound 15 is similar to that of Compound 14. 1 HNMR(400MHz,DMSO - d 6)δ 10.21 (s, 1H), 8.49 (d, J = 4.9 Hz, 2H), 8.16 (s, 1H), 7.96 (d, J = 8.6 Hz, 1H), 7.65 (d, J = 8.7 Hz, 1H), 7.36 (d, J = 5.0 Hz, 2H), 7.17 (d, J = 5.6 Hz, 2H), 6.88 (s, 1H), 6.01 (s, 1H), 4.49 (d, J = 6.0 Hz, 2H), 3.55 (d, J = 5.6 Hz, 2H), 2.51 (s, 8H), 2.27 (s, 3H), 2.19 (s, 3H). 13 C NMR (151 MHz, DMSO-d 6 )δ 166.6, 150.1, 150.0, 146.4, 139.0, 133.3, 131.7, 131.6, 130.1, 128.1, 127.9, 127.7, 127.5, 126.9, 125.7, 123.9, 123.9, 122.6, 122.1, 117.7, 117.7, 117.6, 117.6, 115.8, 108.9, 57.6, 54.4, 51.9, 45.7, 44.9, 18.3. HRMS: [M + H] + calcd for C 27 H 31 ON 5 F 3 , 498.2475, found 498.2465。

[0354] Example 16: 3 - ((((1H - pyrrolo[2,3 - b]pyridin - 5 - yl)methyl)amino) - 4 - methyl - N - (4 - ((4 - methylpiperazin - 1 - yl)methyl) - 3 - (trifluoromethyl)phenyl)benzamide (16)

[0355] The synthetic procedure of Compound 16 is similar to that of Compound 14. 1 H NMR (400 MHz, DMSO - d 6)δ11.57(s,1H),10.29(s,1H),8.29(d,J=2.0Hz,1H),8.20(d,J=2.1Hz,1H),8.02(d,J=8.5Hz,1H),7.94(s,1H),7.66(d,J=8.6Hz,1H),7.42(t,J=2.9Hz,1H),7.16(dd,J=21.7,7.6Hz,3H),6.46–6.31(m,1H),5.83(d,J=5.8Hz,1H),4.55(d,J=5.4Hz,2H),3.57(s,2H),2.62-2.39(m,8H),2.27(d,J=16.8Hz,6H). 13 C NMR(151MHz,DMSO-d 6 )δ172.5,166.8,148.3,146.7,142.9,139.1,133.2,131.6,130.0,128.1,127.9,127.7,127.5,127.1,127.1,127.0,126.9,126.8,125.7,124.0,123.9,122.1,119.9,117.8,117.8,117.7,117.7,115.7,109.2,100.0,57.5,54.2,51.6,49.0,45.8,18.3.HRMS:[M+H] + calcd for C 29 H 32 ON 6 F 3 ,537.2584,found 537.2581。

[0356] Example 17: 3-(((6-Aminopyridin-3-yl)methyl)amino)-4-methyl-N-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)benzamide (17)

[0357] The synthesis procedure of Compound 17 was similar to that of Compound 14. 1 H NMR(400MHz,DMSO-d 6)δ 10.25 (s, 1H), 8.20 (s, 1H), 8.10 - 7.87 (m, 2H), 7.68 (d, J = 8.6 Hz, 1H), 7.40 (d, J = 8.5 Hz, 1H), 7.14 (dd, J = 28.1, 13.3 Hz, 3H), 6.41 (d, J = 8.5 Hz, 1H), 5.77 (s, 2H), 5.58 (s, 1H), 4.23 (s, 2H), 3.56 (s, 2H), 2.52 - 2.23 (m, 8H), 2.19 (d, J = 8.3 Hz, 6H). 13 C NMR (101 MHz, DMSO - d 6 )δ 166.7, 159.3, 147.2, 146.7, 138.9, 137.1, 133.2, 132.0, 131.6, 129.9, 127.9, 127.7, 126.9, 126.2, 123.9, 123.5, 123.0, 117.7, 117.6, 115.5, 109.1, 108.2, 57.9, 55.0, 52.9, 45.9, 44.3, 18.3. HRMS: [M + H] + calcd for C 27 H 32 ON 6 F 3 , 513.2584, found 513.2572。

[0358] Example 18: 3 - ((((1H - pyrrolo[2,3 - b]pyridin - 4 - yl)methyl)amino) - 4 - methyl - N - (4 - ((4 - methylpiperazin - 1 - yl)methyl) - 3 - (trifluoromethyl)phenyl)benzamide (18)

[0359] The synthesis procedure of compound 18 is similar to that of compound 14. 1 H NMR (400 MHz, DMSO - d 6 )δ 11.65 (s, 1H), 10.23 (s, 1H), 8.21 - 8.04 (m, 2H), 7.97 (d, J = 8.5 Hz, 1H), 7.64 (d, J = 8.6 Hz, 1H), 7.44 (t, J = 2.9 Hz, 1H), 7.15 (s, 2H), 7.03 - 6.91 (m, 2H), 6.72 (s, 1H), 6.04 (s, 1H), 4.75 (d, J = 5.9 Hz, 2H), 3.57 (s, 2H), 2.52 (t, J = 24.8 Hz, 9H), 2.31 (d, J = 20.5 Hz, 6H). 13 C NMR (151 MHz, DMSO - d 6)δ166.7,149.0,146.8,143.1,141.2,139.0,133.3,131.6,130.0,128.1,127.9,127.7,127.5,126.7,125.9,125.7,123.9,122.1,118.5,117.7,117.6,117.6,117.6,115.5,113.4,108.9,98.8,57.6,54.4,51.9,44.8,44.5,18.4.HRMS:[M+H] + calcd forC 29 H 32 ON 6 F 3 ,537.2584,found 537.2581。

[0360] Example 19: Methyl - N-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)-3-(quinolin-6-yl)benzamide (19)

[0361] 19a (262.05 mg, 1 mmol) was reacted with 4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)aniline (327.96 mg, 1.2 mmol) in the presence of DIPEA (258.49 mg, 2 mmol), HATU (494.31 mg, 1.3 mmol) and DMF (5 mL) at room temperature for 12 hours to obtain 19b, and then 19b was separated by column chromatography. 19b (517.33 mg, 1 mmol) and 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinoline (331.66 mg, 1.3 mmol) were reacted in the presence of Pd(dppf)Cl 2 (73.17 mg, 0.1 mmol) as a catalyst, in the presence of cesium carbonate (Cs 2 CO 3 , 651.64 mg, 2 mmol) and cesium fluoride (CsF, 75.95 mg, 0.5 mmol) under nitrogen protection at 80 °C for 12 hours to obtain Compound 19 with a yield of 56%, as a light yellow solid. 1 H NMR(400MHz,DMSO-d 6)δ10.51(s,1H),8.97(dd,J=4.2,1.8Hz,1H),8.45(d,J=8.3Hz,1H),8.21(d,J=2.2Hz,1H),8.16 - 8.04(m,3H),8.02(d,J=2.0Hz,1H),8.00 - 7.96(m,1H),7.86(dd,J=8.7,2.1Hz,1H),7.71(d,J=8.6Hz,1H),7.61(dd,J=8.3,4.2Hz,1H),7.56(d,J=8.0Hz,1H),3.63(s,2H),2.86(s,4H),2.63 - 2.47(m,10H),2.38(s,3H). 13 CNMR(151MHz,DMSO - d 6 )δ165.8,151.3,147.3,141.1,140.0,139.1,139.0,137.0,136.7,135.7,134.6,132.5,131.9,131.4,131.2,129.4,129.3,128.5,128.3,128.1,128.0,127.9,127.7,127.6,127.5,125.7,124.0,123.9,122.4,122.0,121.8,117.9,117.8,117.8,117.8,57.2,53.7,50.7,46.2,20.8.HRMS:[M + H] + calcdfor C 30 H 30 ON 4 F 3 ,519.2366,found 519.2364。

[0362] Example 20: 3-(2 - Aminoquinazolin - 6 - yl)-4 - methyl - N-(4 - ((4 - methylpiperazin - 1 - yl)methyl)-3 - (trifluoromethyl)phenyl)benzamide (20)

[0363] The synthesis procedure of Compound 20 is similar to that of Compound 19. 1 H NMR(400MHz,DMSO - d 6)δ10.50(s,1H),9.19(s,1H),8.22(d,J=2.2Hz,1H),8.09(dd,J=8.5,2.2Hz,1H),8.01-7.91(m,2H),7.87(d,J=2.0Hz,1H),7.78(dd,J=8.7,2.1Hz,1H),7.70(d,J=8.6Hz,1H),7.52(dd,J=8.4,3.6Hz,2H),6.93(s,2H),3.60(s,2H),2.60(s,4H),2.49(s,4H),2.36(d,J=6.4Hz,6H). 13 CNMR(151MHz,DMSO-d 6 )δ165.8,163.0,161.5,151.5,140.9,139.9,138.9,135.8,134.3,132.5,132.0,131.7,131.2,129.3,128.3,128.2,128.0,127.8,127.6,127.5,127.4,125.7,124.9,124.0,123.9,122.1,119.7,117.9,117.8,117.8,117.7,57.6,54.4,51.9,44.8,20.8.HRMS:[M+H] + calcd for C 29 H 30 ON 6 F 3 ,535.2428,found 535.2428。

[0364] Example 21: 4-Methyl-N-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)-3-(quinazolin-7-yl)benzamide (21)

[0365] The synthesis procedure of Compound 21 is similar to that of Compound 19. 1 H NMR(400MHz,DMSO-d 6)δ10.49(s,1H),9.71(s,1H),9.37(s,1H),8.29(d,J=8.4Hz,1H),8.19(d,J=2.3Hz,1H),8.06(d,J=6.3Hz,2H),8.04-7.97(m,2H),7.89(dd,J=8.4,1.6Hz,1H),7.70(d,J=8.5Hz,1H),7.57(d,J=7.9Hz,1H),3.58(s,2H),2.48(d,J=25.1Hz,9H),2.38(s,4H),2.28(s,3H). 13 C NMR(151MHz,DMSO-d 6 )δ165.6,161.0,156.0,149.7,147.2,140.3,139.8,138.8,132.6,132.1,131.7,131.4,130.2,129.3,128.3,128.2,128.0,127.9,127.8,127.6,127.5,125.7,124.0,123.9,122.1,121.0,117.9,117.8,117.8,117.7,57.6,54.6,52.1,45.1,20.7.HRMS:[M+H] + calcd for C 29 H 29 ON 5 F 3 ,520.2318,found 520.2315。

[0366] Example 22: 3-(1H-benzo[d]imidazol-5-yl)-4-methyl-N-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)benzamide (22)

[0367] The synthesis procedure of compound 22 was similar to that of compound 19. 1 H NMR(400MHz,DMSO-d 6 )δ12.57(s,1H),10.51(s,1H),8.31-8.17(m,2H),8.10(dd,J=8.5,2.2Hz,1H),7.99-7.84(m,2H),7.76-7.57(m,3H),7.49(d,J=8.0Hz,1H),7.25(dd,J=8.3,1.6Hz,1H),3.62(s,2H),2.80(s,4H),2.53(s,4H),2.48(s,3H),2.34(s,3H). 13CNMR(151MHz, DMSO-d 6 ) δ 165.9, 143.2, 142.6, 140.0, 139.0, 132.3, 131.8, 131.7, 131.0, 130.1, 129.5, 128.2, 128.0, 127.8, 127.6, 127.5, 126.9, 125.7, 124.0, 123.9, 122.1, 117.8, 117.8, 57.4, 54.0, 51.2, 44.1, 20.9. HRMS: [M+H] + calcd for C 28 H 29 ON 5 F 3 , 508.2318, found 508.2312。

[0368] Example 23: 3-(Benzothiazol-6-yl)-4-methyl-N-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)benzamide (23)

[0369] The synthesis procedure of Compound 23 is similar to that of Compound 19. 1 H NMR(400MHz, DMSO-d 6 ) δ 10.56(s, 1H), 9.47(s, 1H), 8.29 - 8.16(m, 3H), 8.11(dd, J = 8.5, 2.2Hz, 1H), 7.97(d, J = 8.0Hz, 2H), 7.70(d, J = 8.6Hz, 1H), 7.62(dd, J = 8.4, 1.8Hz, 1H), 7.52(d, J = 7.8Hz, 1H), 3.61(s, 2H), 2.79(s, 4H), 2.55(s, 4H), 2.47(s, 3H), 2.35(s, 3H). 13 C NMR(151MHz, DMSO-d 6 ) δ 165.8, 157.2, 152.7, 141.2, 140.0, 139.0, 138.3, 134.4, 132.4, 131.8, 131.1, 129.5, 128.2, 128.1, 128.0, 127.8, 127.6, 127.5, 127.5, 125.7, 124.0, 123.9, 123.4, 123.1, 122.1, 117.8, 117.8, 117.8, 57.4, 54.0, 51.2, 44.1, 20.8. HRMS: [M+H] + calcd for C 28 H 28 ON4 F 3 S,525.1930, found 525.1926。

[0370] Example 24: 3-(1H-Indazol-5-yl)-4-methyl-N-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)benzamide (24)

[0371] The synthesis procedure of Compound 24 is similar to that of Compound 19. 1 H NMR(400MHz, DMSO-d 6 ) δ 10.46(s, 1H), 8.21(d, J = 2.2Hz, 1H), 8.14(s, 1H), 8.10 - 8.07(m, 1H), 7.96 - 7.90(m, 2H), 7.79(s, 1H), 7.70(d, J = 8.6Hz, 1H), 7.65(d, J = 8.6Hz, 1H), 7.48(t, J = 8.7Hz, 2H), 7.41(d, J = 8.6Hz, 1H), 3.60(s, 2H), 2.69(s, 4H), 2.51 - 2.47(m, 4H), 2.42(s, 3H), 2.33(s, 3H). 13 C NMR(151MHz, DMSO-d 6 ) δ 165.9, 142.3, 140.0, 139.5, 139.0, 134.2, 133.1, 132.3, 131.8, 131.7, 131.0, 130.1, 129.5, 128.1, 128.0, 127.8, 127.6, 127.5, 127.0, 125.7, 124.0, 123.9, 123.4, 121.1, 117.8, 117.8, 110.4, 57.4, 53.9, 51.0, 43.7, 20.9. HRMS: [M + H] + calcd for C 28 H 29 ON 5 F 3 , 508.2319, found 508.2308。

[0372] Example 25: 4-methyl-3-(1-methyl-1H-indazol-5-yl)-N-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)benzamide (25)

[0373] The synthesis procedure of Compound 25 is similar to that of Compound 19. 1 H NMR(400MHz, DMSO-d 6)δ10.46(s,1H),8.20(d,J=2.2Hz,1H),8.11(d,J=0.9Hz,1H),8.07(dd,J=8.4,2.2Hz,1H),7.95 - 7.90(m,2H),7.79(d,J=1.5Hz,1H),7.74(d,J=8.7Hz,1H),7.70(d,J=8.6Hz,1H),7.53 - 7.44(m,2H),4.11(s,3H),3.59(s,2H),2.52(d,J=1.9Hz,5H),2.45(s,4H),2.32(d,J=12.8Hz,6H). 13 C NMR(101MHz,DMSO - d 6 )δ165.9,142.1,140.0,139.3,138.8,133.2,133.1,132.4,132.1,131.7,131.0,129.5,128.1,127.0,126.6,124.1,124.0,123.8,121.3,117.8,117.7,109.9,57.7,54.7,52.4,45.4,35.9,20.8.HRMS:[M + H] + calcd for C 29 H 31 ON 5 F 3 ,522.2475,found 522.2471。

[0374] Example 26: 4 - Methyl - 3-(2 - methyl - 2H - indazol - 5 - yl)-N-(4 - ((4 - methylpiperazin - 1 - yl)methyl)-3 - (trifluoromethyl)phenyl)benzamide (26)

[0375] The synthesis procedure of Compound 26 is similar to that of Compound 19. 1 H NMR(400MHz,DMSO - d 6 )δ10.46(s,1H),8.40(s,1H),8.21(d,J=2.2Hz,1H),8.08(dd,J=8.5,2.2Hz,1H),7.95 - 7.86(m,2H),7.73 - 7.64(m,3H),7.48(d,J=8.0Hz,1H),7.29(dd,J=8.9,1.7Hz,1H),4.21(s,3H),3.59(s,2H),2.55(s,5H),2.46(s,5H),2.33(d,J=8.1Hz,7H). 13 C NMR(101MHz,DMSO - d 6)δ165.9,147.7,142.4,140.0,138.9,133.6,132.3,132.1,131.7,131.0,129.3,127.8,127.7,127.0,126.2,125.4,124.0,123.5,122.1,120.8,117.9,117.7,117.0,57.7,54.7,52.3,45.3,40.6,20.9.HRMS:[M+H] + calcd for C 29 H 31 ON 5 F 3 ,522.2475,found 522.2468。

[0376] Example 27: 3-(2-Aminoquinolin-6-yl)-4-methyl-N-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)benzamide (27)

[0377] The synthesis procedure of Compound 27 is similar to that of Compound 19. 1 H NMR(400MHz,DMSO-d 6 )δ10.46(s,1H),8.21(d,J = 2.2Hz,1H),8.07(dd,J = 8.5,2.2Hz,1H),7.98 - 7.94(m,2H),7.91(dd,J = 7.9,2.0Hz,1H),7.69(d,J = 8.7Hz,2H),7.54(d,J = 1.3Hz,2H),7.49(d,J = 8.0Hz,1H),6.82(d,J = 8.8Hz,1H),6.51(s,2H),3.56(s,2H),2.38(d,J = 12.2Hz,11H),2.19(s,3H). 13 C NMR(101MHz,DMSO-d 6 )δ165.8,159.0,147.6,141.7,139.9,138.8,137.5,133.7,132.4,131.7,131.1,130.8,129.3,128.1,127.0,126.2,125.3,124.0,123.8,123.0,117.8,117.7,113.4,57.9,55.0,52.9,45.9,20.9.HRMS:[M+H] + calcd for C 30 H 31 ON 5 F 3,534.2475,found 534.2474。

[0378] Example 28: 3-(2-Aminoquinazolin-7-yl)-4-methyl-N-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)benzamide (28)

[0379] The synthesis procedure of Compound 28 is similar to that of Compound 19. 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.50 (s, 1H), 9.18 (s, 1H), 8.21 (d, J = 2.2 Hz, 1H), 8.10 (dd, J = 8.5, 2.2 Hz, 1H), 7.96 (dq, J = 4.2, 2.0 Hz, 2H), 7.90 (d, J = 8.2 Hz, 1H), 7.70 (d, J = 8.6 Hz, 1H), 7.53 (d, J = 8.6 Hz, 1H), 7.42 (d, J = 1.6 Hz, 1H), 7.28 (dd, J = 8.2, 1.6 Hz, 1H), 6.91 (s, 2H), 3.65 (s, 2H), 3.07 (d, J = 31.6 Hz, 4H), 2.67 (s, 7H), 2.35 (s, 3H). 13 C NMR (101 MHz, DMSO-d 6 ) δ 172.5, 165.7, 162.7, 161.7, 152.3, 146.7, 141.2, 139.7, 138.9, 132.5, 132.0, 131.8, 131.3, 128.9, 128.3, 128.0, 127.8, 127.8, 126.1, 124.9, 124.0, 123.9, 123.4, 118.9, 117.8, 117.8, 57.5, 54.4, 51.8, 44.7, 20.7. HRMS: [M+H] + calcd for C 29 H 30 ON 6 F 3 ,535.2428,found 535.2426。

[0380] Example 29: 3-(Benz[d]oxazol-5-yl)-4-methyl-N-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)benzamide (29)

[0381] The synthesis procedure of Compound 29 is similar to that of Compound 19. 1 H NMR (400 MHz, DMSO-d 6)δ10.46(s,1H),8.83(s,1H),8.20(d,J=2.2Hz,1H),8.07(dd,J=8.5,2.2Hz,1H),7.94(d,J=6.2Hz,2H),7.91 - 7.85(m,2H),7.70(d,J=8.5Hz,1H),7.53 - 7.47(m,2H),3.58(s,2H),2.55 - 2.41(m,10H),2.33(s,3H),2.29(s,3H). 13 C NMR(101MHz,DMSO - d 6 )δ165.8,155.4,149.2,141.3,140.4,140.0,138.8,137.8,132.4,132.2,132.0,131.7,131.1,129.5,128.0,127.7,127.4,126.2,124.0,123.4,121.0,117.8,117.7,111.4,57.7,54.7,52.4,45.3,20.8.HRMS:[M + H] + calcd for C 28 H 28 O 2 N 4 F 3 ,509.2159,found 509.2145。

[0382] Example 30: 3-(Benzo[d]oxazol - 6 - yl)-4 - methyl - N-(4 - ((4 - methylpiperazin - 1 - yl)methyl)-3 - (trifluoromethyl)phenyl)benzamide (30)

[0383] The synthesis procedure of compound 30 is similar to that of compound 19. 1 H NMR(400MHz,DMSO - d 6 )δ10.53(s,1H),8.43(d,J=1.8Hz,1H),8.21(dd,J=14.8,2.2Hz,2H),8.06(dd,J=8.5,2.2Hz,1H),7.96–7.87(m,2H),7.70(dd,J=8.6,4.4Hz,2H),7.50(d,J=8.0Hz,1H),7.35(d,J=7.9Hz,1H),3.58(s,2H),2.45(s,9H),2.39(s,2H),2.28(s,4H). 13 C NMR(151MHz,DMSO - d 6)δ166.1,164.4,145.5,142.4,138.7,137.9,134.0,132.2,132.0,131.9,131.8,130.3,129.5,128.3,128.2,128.0,127.8,127.6,127.5,125.7,124.0,123.9,123.9,122.1,117.8,117.8,117.7,101.6,57.6,54.4,51.9,44.8,21.5.HRMS:[M+H] + calcd for C 28 H 28 O 2 N 4 F 3 ,509.2159,found 509.2150。

[0384] Example 31: 4-Methyl-3-(1-methyl-1H-benzo[d]imidazol-6-yl)-N-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)benzamide (31)

[0385] The synthesis procedure of Compound 31 is similar to that of Compound 19. 1 H NMR(400MHz,DMSO-d 6 )δ10.48(s,1H),8.30 - 8.18(m,2H),8.09(dd,J=8.4,2.2Hz,1H),7.96 - 7.87(m,2H),7.72(dd,J=16.7,8.4Hz,2H),7.62(s,1H),7.50(d,J=7.9Hz,1H),7.26(dd,J=8.2,1.6Hz,1H),3.61(s,2H),2.77(s,5H),2.48(s,6H),2.35(s,3H). 13 C NMR(151MHz,DMSO-d 6 )δ164.9,144.7,141.9,141.4,139.0,137.9,134.2,134.1,131.2,130.7,130.6,129.9,128.5,127.1,126.9,126.8,126.6,126.4,125.9,124.6,122.9,122.8,122.3,121.0,118.3,116.8,116.7,116.7,116.6,110.2,56.3,53.0,50.2,43.1,30.2,19.9.HRMS:[M+H] + calcd forC29 H 31 ON 5 F 3 ,522.2475, found 522.2461。

[0386] Example 32: 3-(2-Aminobenzo[d]oxazol-5-yl)-4-methyl-N-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)benzamide (32)

[0387] The synthesis procedure of Compound 32 is similar to that of Compound 19. 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.44 (s, 1H), 8.20 (s, 1H), 8.07 (d, J = 8.6 Hz, 1H), 7.89 (d, J = 8.3 Hz, 2H), 7.69 (d, J = 8.5 Hz, 1H), 7.46 (d, J = 7.4 Hz, 3H), 7.42 (d, J = 8.1 Hz, 1H), 7.23 (s, 1H), 6.99 (d, J = 8.1 Hz, 1H), 3.57 (s, 2H), 2.42 (s, 8H), 2.32 (s, 3H), 2.22 (s, 3H). 13 C NMR (101 MHz, DMSO-d 6 ) δ 165.9, 163.8, 147.8, 144.3, 142.3, 139.8, 138.8, 136.6, 132.3, 131.7, 131.5, 130.9, 129.3, 127.0, 126.2, 124.0, 123.5, 121.5, 117.8, 117.7, 116.4, 108.5, 57.8, 55.0, 52.8, 45.8, 20.8. HRMS: [M + H] + calcd for C 28 H 29 O 2 N 5 F 3 ,524.2268, found 524.2261。

[0388] Example 33: 4-Methyl-N-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)-3-(2-(phenylamino)quinazolin-6-yl)benzamide (33)

[0389] Compound 33a (243.49 mg, 1 mmol) and aniline (186.26 mg, 2 mmol) were dissolved in DMF (5 mL), and reacted at 70 °C for 12 h in the presence of DIEA (387.84 mg, 3 mmol) to obtain 33b. 33b (300.16 mg, 1 mmol) and bis(pinacolato)diboron (507.89 mg, 2 mmol) were reacted at 90 °C for 12 h in the presence of Pd(dppf)Cl2 (73.17 mg, 0.1 mmol) and potassium acetate (AcOK, 196.28 mg, 2 mmol) to obtain 33c. 33c (347.23 mg, 1 mmol) was reacted under the same reaction conditions as those for preparing compound 19 to obtain compound 33 as a light yellow solid in 53% yield. 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.49 (s, 1H), 9.96 (s, 1H), 9.37 (s, 1H), 8.24 - 8.20 (m, 1H), 8.08 (d, J = 8.6 Hz, 1H), 8.01 (dd, J = 14.5, 7.1 Hz, 4H), 7.95 (d, J = 8.1 Hz, 1H), 7.89 (d, J = 8.6 Hz, 1H), 7.77 (d, J = 8.7 Hz, 1H), 7.69 (d, J = 8.6 Hz, 1H), 7.52 (d, J = 8.1 Hz, 1H), 7.35 (t, J = 7.6 Hz, 2H), 7.00 (t, J = 7.3 Hz, 1H), 3.56 (s, 2H), 2.40 (d, J = 17.2 Hz, 11H), 2.23 (s, 3H). 13 C NMR (101 MHz, DMSO-d 6 ) δ 165.7, 162.8, 157.6, 150.4, 141.0, 140.7, 139.9, 138.8, 136.2, 135.9, 132.6, 132.3, 131.7, 131.2, 129.3, 129.0, 128.4, 128.0, 127.7, 127.5, 126.2, 125.9, 124.0, 123.4, 122.1, 120.6, 119.3, 117.8, 117.7, 57.8, 54.9, 52.7, 45.7, 20.8. HRMS: [M + H] + calcd for C 35 H 34 ON 6 F 3 , 611.2741, found 611.2735。

[0390] Example 34: 4-Methyl-3-(2-(methylamino)quinazolin-6-yl)-N-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)benzamide (34)

[0391] The synthesis procedure of compound 34 is similar to that of compound 33. 1 H NMR(400MHz,DMSO--d 6 )δ10.47(s,1H),9.16(s,1H),8.20(d,J=2.2Hz,1H),8.11-8.06(m,1H),8.00-7.91(m,2H),7.86(d,J=2.1Hz,1H),7.77(dd,J=8.6,2.0Hz,1H),7.69(d,J=8.5Hz,1H),7.58(d,J=8.8Hz,1H),7.51(s,1H),7.42(s,1H),3.56(s,2H),2.93(d,J=4.7Hz,3H),2.38(d,J=11.2Hz,11H),2.19(s,3H). 13 CNMR(101MHz,DMSO)δ165.8,162.6,160.8,141.0,139.9,138.8,135.8,134.2,132.5,132.3,131.7,131.2,129.3,128.4,128.2,128.0,127.7,127.3,126.2,125.2,124.0,123.5,119.8,117.8,117.7,57.9,55.0,52.9,45.9,28.5,20.8.HRMS:[M+H] + calcd for C 30 H 32 ON 6 F 3 ,549.2584,found 549.258。

[0392] Example 35: 3-(2-((4-methoxyphenyl)amino)quinazolin-6-yl)-4-methyl-N-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)benzamide (35)

[0393] The synthesis procedure of compound 35 is similar to that of compound 33. 1 H NMR(400MHz,DMSO-d 6)δ10.49(s,1H),9.78(s,1H),9.33(s,1H),8.21(d,J=2.2Hz,1H),8.07(dd,J=8.5,2.2Hz,1H),7.99(d,J=2.0Hz,1H),7.95(dd,J=7.4,2.1Hz,2H),7.90 - 7.85(m,3H),7.71(d,J=8.6Hz,2H),7.52(s,1H),6.95(d,J=9.0Hz,2H),3.76(s,3H),3.57(s,2H),2.39(d,J=4.1Hz,11H),2.20(s,3H). 13 C NMR(101MHz,DMSO - d 6 )δ165.8,155.1,154.5,146.8,141.6,139.9,138.8,137.2,135.1,134.8,132.4,132.3,131.7,131.1,131.0,129.4,129.3,128.2,128.1,128.0,127.7,127.1,126.4,126.2,124.0,123.7,123.5,120.6,117.8,117.7,114.8,114.4,57.8,55.6,55.0,52.8,45.8,20.9.HRMS:[M + H] + calcd for C 36 H 36 O 2 N 6 F 3 ,641.2846,found 641.2833。

[0394] Example 36: 3-(2-((4-Fluorophenyl)amino)quinazolin-6-yl)-4-methyl-N-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)benzamide (36)

[0395] The synthesis procedure of Compound 36 is similar to that of Compound 33. 1 H NMR(400MHz,DMSO - d 6)δ 10.49 (s, 1H), 10.01 (s, 1H), 9.36 (s, 1H), 8.22 (d, J = 2.2 Hz, 1H), 8.06 (ddt, J = 14.0, 6.9, 3.6 Hz, 3H), 8.00 (d, J = 1.9 Hz, 1H), 7.99 - 7.94 (m, 2H), 7.88 (dd, J = 8.6, 2.0 Hz, 1H), 7.74 (d, J = 8.7 Hz, 1H), 7.68 (d, J = 8.6 Hz, 1H), 7.50 (d, J = 8.1 Hz, 1H), 7.18 (t, J = 8.9 Hz, 2H), 3.55 (s, 2H), 2.41 - 2.34 (m, 11H), 2.18 (d, J = 1.6 Hz, 3H). 13 C NMR(101MHz, DMSO - d 6 )δ 165.7, 162.8, 158.9, 157.5, 156.5, 150.4, 140.7, 139.8, 138.8, 137.4, 136.2, 135.9, 132.6, 132.3, 131.6, 131.2, 129.4, 129.3, 128.3, 128.2, 128.0, 127.7, 127.5, 126.2, 125.8, 123.9, 123.4, 120.8, 120.8, 120.7, 117.8, 117.7, 115.6, 115.3, 57.9, 55.0, 52.9, 45.9, 20.7. HRMS: [M + H] + calcd for C 35 H 33 ON 6 F 4 , 629.2647, found 629.2634。

[0396] Example 37: 4 - Methyl - N - (4 - ((4 - methylpiperazin - 1 - yl)methyl)-3-(trifluoromethyl)phenyl)-3-(2 - ((6 - methylpyridin - 3 - yl)amino)quinazolin - 6 - yl)benzamide (37)

[0397] The synthesis procedure of compound 37 is similar to that of compound 33. 1 H NMR(400MHz, DMSO - d 6)δ10.47(s,1H),9.99(s,1H),9.39(s,1H),9.08 - 8.91(m,1H),8.32(dd,J=8.3,2.7Hz,1H),8.21(d,J=2.2Hz,1H),8.11 - 8.05(m,1H),8.03 - 7.95(m,3H),7.92 - 7.87(m,1H),7.77(d,J=8.6Hz,1H),7.69(d,J=8.6Hz,1H),7.53(d,J=8.1Hz,1H),7.23(d,J=8.5Hz,1H),3.58(s,2H),2.54(s,3H),2.45(s,7H),2.38(s,3H),2.30(s,3H). 13 C NMR(101MHz,DMSO - d 6 )δ165.7,163.0,157.6,151.0,150.4,140.7,140.6,139.9,138.8,136.3,136.1,135.2,132.6,132.2,131.7,131.2,129.3,128.4,128.1,127.8,127.5,126.7,126.2,125.9,124.0,123.4,122.9,120.7,117.9,117.8,57.7,54.8,52.4,45.3,23.8,20.7.HRMS:[M + H] + calcdfor C 35 H 35 ON 7 F 3 ,626.2850,found 626.2838。

[0398] Example 38: tert - Butyl 4-(4 - ((6-(2 - methyl - 5 - ((4 - ((4 - methylpiperazin - 1 - yl)methyl)-3-(trifluoromethyl)phenyl)carbamoyl)phenyl)quinazolin - 2 - yl)amino)phenyl)piperazine - 1 - carboxylate(38)

[0399] The synthetic procedure of compound 38 is similar to that of compound 33. 1 H NMR(400MHz,DMSO - d 6)δ10.49(s,1H),9.74(s,1H),9.31(s,1H),8.21(d,J=2.3Hz,1H),8.08(dd,J=8.5,2.2Hz,1H),7.99(d,J=2.0Hz,1H),7.97 - 7.93(m,2H),7.86(dd,J=8.8,1.9Hz,3H),7.69(dd,J=8.6,2.2Hz,2H),7.52(d,J=8.1Hz,1H),6.97(d,J=8.7Hz,2H),3.56(s,2H),3.47(d,J=5.5Hz,4H),3.04(t,J=5.2Hz,4H),2.46 - 2.34(m,11H),2.20(s,3H),1.43(s,9H). 13 C NMR(101MHz,DMSO-d 6 )δ165.7,162.6,157.7,154.3,150.7,146.6,140.8,139.9,138.8,136.1,135.4,133.7,132.6,132.3,131.7,131.2,129.3,128.4,128.2,128.0,127.7,127.4,127.4,126.2,125.7,124.0,123.5,120.5,120.5,117.8,117.7,117.1,79.4,57.9,55.0,52.9,49.8,45.9,28.5,20.8.HRMS:[M + H] + calcd for C 44 H 50 O 3 N 8 F 3 ,795.3953,found 795.3934。

[0400] Example 39: 4-Methyl-N-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)-3-(2-((4-(piperazin-1-yl)phenyl)amino)quinazolin-6-yl)benzamide (39)

[0401] The synthetic procedure of Compound 39 was similar to that of Compound 33. 1 H NMR(400MHz,DMSO-d 6)δ 10.50 (s, 1H), 9.71 (s, 1H), 9.30 (s, 1H), 8.21 (d, J = 2.2 Hz, 1H), 8.07 (dd, J = 8.5, 2.2 Hz, 1H), 7.99 (d, J = 2.0 Hz, 1H), 7.98 - 7.94 (m, 2H), 7.89 - 7.79 (m, 3H), 7.69 (dd, J = 8.7, 5.0 Hz, 2H), 7.52 (d, J = 8.1 Hz, 1H), 7.00 - 6.91 (m, 2H), 3.56 (s, 2H), 3.08 (dd, J = 6.5, 3.6 Hz, 4H), 2.95 (dd, J = 6.2, 3.6 Hz, 4H), 2.36 (d, J = 18.7 Hz, 11H), 2.16 (s, 3H). 13 C NMR (101 MHz, DMSO - d 6 )δ 165.8, 162.6, 157.7, 150.7, 147.1, 140.8, 139.9, 138.7, 136.1, 135.4, 133.3, 132.6, 132.4, 131.7, 131.2, 129.3, 128.4, 128.0, 127.7, 127.4, 126.2, 125.6, 124.0, 123.5, 120.6, 120.4, 117.8, 117.7, 116.5, 57.9, 55.2, 53.1, 49.7, 46.2, 45.4, 20.8. HRMS: [M + H] + calcd for C 39 H 42 ON 8 F 3 , 695.3428, found 695.3414。

[0402] Example 40: 4 - Methyl - N - (4 - ((4 - methylpiperazin - 1 - yl)methyl) - 3 - (trifluoromethyl)phenyl) - 3 - (2 - (p - tolylamino)quinazolin - 6 - yl)benzamide (40)

[0403] The synthesis procedure of Compound 40 is similar to that of Compound 33. 1 H NMR (400 MHz, DMSO - d 6)δ10.48(s,1H),9.82(s,1H),9.33(s,1H),8.20(d,J=2.3Hz,1H),8.05(dd,J=8.5,2.2Hz,1H),8.00 - 7.93(m,3H),7.87(dq,J=8.7,2.8,2.0Hz,3H),7.70(dd,J=16.3,8.6Hz,2H),7.51(d,J=8.1Hz,1H),7.15(d,J=8.1Hz,2H),3.55(s,2H),2.46 - 2.33(m,11H),2.28(s,3H),2.17(s,3H). 13 C NMR(101MHz,DMSOd 6 )δ165.8,162.7,157.6,150.5,140.8,139.9,138.7,138.4,136.2,135.7,132.6,132.4,131.7,131.2,131.0,129.4,129.3,128.3,128.2,127.7,127.4,126.2,125.8,124.0,123.4,120.5,119.4,117.8,117.7,57.9,55.1,53.0,46.0,20.9,20.8.HRMS:[M + H] + calcd for C 36 H 36 ON 6 F 3 ,625.2897,found 625.2880。

[0404] Example 41: 3-(2-Acetamidoquinolin-6-yl)-4-methyl-N-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)benzamide (41)

[0405] 41a (224.06 mg, 1 mmol) and acetic anhydride (153.13 mg, 1.5 mmol) were dissolved in dry DMF (8 mL), and then reacted at 70 °C for 12 h in the presence of DIEA (258.49 mg, 2 mmol) to obtain 41b, which was then separated by column chromatography. 41b (266.10 mg, 1 mmol) was reacted under the same reaction conditions as those for preparing Compound 33 to obtain Compound 41 as a light yellow solid in 33% yield. 1 H NMR(400MHz,DMSO-d 6)δ10.91(s,1H),10.50(s,1H),8.38(q,J=9.1Hz,2H),8.21(d,J=2.2Hz,1H),8.08(dd,J=8.5,2.2Hz,1H),8.01(d,J=2.0Hz,1H),7.96(dd,J=8.0,2.0Hz,2H),7.89(d,J=8.6Hz,1H),7.79(dd,J=8.7,2.0Hz,1H),7.69(d,J=8.6Hz,1H),7.53(d,J=8.1Hz,1H),3.57(s,2H),2.52-2.43(m,8H),2.37(s,3H),2.26(s,3H),2.18(s,3H). 13 C NMR(151MHz,DMSO-d 6 )δ170.4,165.8,152.5,146.0,141.2,140.0,138.9,138.8,137.4,132.5,131.9,131.8,131.8,131.2,129.4,128.2,128.0,127.8,127.6,127.5,127.2,125.9,125.7,124.0,123.9,122.1,117.9,117.8,117.8,117.7,115.1,57.5,54.3,51.6,44.5,24.6,20.8.HRMS:[M+H] + calcdfor C 32 H 33 O 2 N 5 F 3 ,576.2581,found 576.2572。

[0406] Example 42: 3-(2-(Cyclopropanecarboxamido)quinolin-6-yl)-4-methyl-N-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)benzamide (42)

[0407] The synthesis procedure of Compound 42 is similar to that of Compound 41. 1 H NMR(400MHz,DMSO-d 6)δ11.22(s,1H),10.49(s,1H),8.43 - 8.31(m,2H),8.21(d,J=2.2Hz,1H),8.09(dd,J=8.5,2.2Hz,1H),8.01(d,J=1.9Hz,1H),7.96(dd,J=7.6,2.0Hz,2H),7.91(d,J=8.6Hz,1H),7.79(dd,J=8.7,2.0Hz,1H),7.70(d,J=8.6Hz,1H),7.53(d,J=8.1Hz,1H),3.59(s,2H),2.65(s,4H),2.51 - 2.45(m,4H),2.38(d,J=4.2Hz,6H). 13 C NMR(101MHz,DMSO - d 6 )δ176.0,173.7,165.7,152.4,146.0,141.2,140.0,138.9,138.8,137.3,132.5,132.0,131.8,131.8,131.2,129.4,128.2,128.0,127.8,127.5,127.2,126.2,125.9,124.6,124.0,117.8,117.7,115.2,57.6,54.5,51.9,44.8,20.8,14.8,8.4,8.1.HRMS:[M + H] + calcd for C 34 H 35 O 2 N 5 F 3 ,602.2737,found 602.2732。

[0408] Example 43: 4 - Methyl - 3-(2-(methylamino)quinolin - 6 - yl)-N-(4 - ((4 - methylpiperazin - 1 - yl)methyl)-3-(trifluoromethyl)phenyl)benzamide (43)

[0409] 43a (242.50 mg, 1 mmol) and methylamine (124.22 mg, 4 mmol) were dissolved in isopropanol (5 mL), concentrated hydrochloric acid (200 μL) was added, and the reaction was refluxed for 12 hours to obtain 43b. Next, 43b (266.10 mg, 1 mmol) was reacted under the same reaction conditions as for the preparation of compound 33 to obtain compound 43 as a light yellow solid in 40% yield. 1 HNMR(400MHz,DMSO - d 6)δ10.47(s,1H),8.21(d,J=2.2Hz,1H),8.08(dd,J=8.6,2.2Hz,1H),7.95(d,J=2.0Hz,1H),7.93 - 7.88(m,2H),7.72 - 7.67(m,2H),7.61(d,J=8.5Hz,1H),7.53(dd,J=8.6,2.1Hz,1H),7.49(d,J=8.1Hz,1H),7.09(d,J=4.9Hz,1H),6.80(d,J=8.9Hz,1H),3.60(s,2H),2.93(d,J=4.6Hz,3H),2.67(s,4H),2.48(s,4H),2.40(s,3H),2.36(s,3H). 13 C NMR(151MHz,DMSO - d 6 )δ165.9,158.2,147.6,141.8,139.9,139.0,136.7,133.5,132.4,131.8,131.8,131.1,130.7,129.3,128.2,128.0,127.8,127.6,127.5,127.0,125.7,125.7,124.0,123.9,123.0,122.1,117.9,117.8,117.8,117.7,114.0,57.5,54.3,51.7,44.6,28.1,20.9.HRMS:[M + H] + calcd for C 31 H 33 ON 5 F 3 ,548.2631,found 548.2624。

[0410] Example 44: 4 - Methyl - N-(4 - ((4 - methylpiperazin - 1 - yl)methyl)-3-(trifluoromethyl)phenyl)-3-(2-(phenylamino)quinolin - 6 - yl)benzamide (44)

[0411] The synthesis procedure of Compound 44 is similar to that of Compound 41. 1 H NMR(400MHz,DMSO - d 6)δ10.49(s,1H),9.52(s,1H),8.22(d,J=2.3Hz,1H),8.13(d,J=8.9Hz,1H),8.10 - 8.06(m,1H),8.05 - 8.00(m,3H),7.94(dd,J=7.9,1.9Hz,1H),7.82 - 7.76(m,2H),7.72 - 7.65(m,2H),7.52(d,J=8.1Hz,1H),7.36(t,J=7.8Hz,2H),7.14(d,J=8.9Hz,1H),6.98(t,J=7.3Hz,1H),3.57(s,2H),2.40(d,J=3.8Hz,11H),2.20(s,3H). 13 C NMR(101MHz,DMSO - d 6 )δ165.8,154.9,146.6,141.9,141.5,139.9,137.4,135.2,132.5,132.3,131.7,131.1,129.4,129.1,128.2,128.1,128.0,127.7,127.2,126.6,126.2,124.0,123.8,123.5,121.6,118.9,117.8,117.7,115.1,57.9,55.1,53.0,46.0,20.9.HRMS:[M + H] + calcd for C 36 H 35 ON 5 F 3 ,610.2788,found 610.2782。

[0412] Example 45: 3-(2-((4 - Methoxyphenyl)amino)quinolin - 6 - yl)-4 - methyl - N-(4 - ((4 - methylpiperazin - 1 - yl)methyl)-3-(trifluoromethyl)phenyl)benzamide (45)

[0413] The synthesis procedure of Compound 45 is similar to that of Compound 41. 1 H NMR(400MHz,DMSO - d 6)δ10.48(s,1H),9.33(s,1H),8.29 - 8.20(m,1H),8.08(d,J=8.1Hz,2H),8.00(s,1H),7.92(t,J=7.7Hz,3H),7.78 - 7.68(m,3H),7.62(d,J=8.7Hz,1H),7.51(s,1H),7.06(d,J=8.9Hz,1H),6.95(d,J=8.5Hz,2H),3.76(s,3H),3.56(s,2H),2.39(d,J=9.8Hz,11H),2.19(s,3H). 13 C NMR(101MHz,DMSO DMSO - d 6 )δ165.8,155.1,154.5,146.8,141.6,139.9,138.8,137.2,135.1,134.8,132.4,132.3,131.7,131.1,131.0,129.4,129.3,128.2,128.1,128.0,127.7,127.1,126.4,126.2,124.0,123.7,123.5,120.6,117.8,117.7,114.8,114.4,57.8,55.6,55.0,52.8,45.8,20.9.HRMS:[M + H] + calcd for C 37 H 37 O 2 N 5 F 3 ,640.2894,found 640.2884。

[0414] Example 46: 3-(2-((4-Fluorophenyl)amino)quinolin-6-yl)-4-methyl-N-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)benzamide (46)

[0415] The synthetic procedure of Compound 46 is similar to that of Compound 41. 1 H NMR(400MHz,DMSO - d 6)δ 10.48 (s, 1H), 9.55 (s, 1H), 8.22 (dd, J = 4.6, 2.2 Hz, 1H), 8.12 (d, J = 8.9 Hz, 1H), 8.08 - 8.03 (m, 2H), 7.99 (d, J = 2.0 Hz, 1H), 7.97 - 7.87 (m, 2H), 7.82 - 7.73 (m, 2H), 7.71 - 7.63 (m, 2H), 7.50 (d, J = 8.1 Hz, 1H), 7.18 (t, J = 8.9 Hz, 2H), 7.10 (d, J = 8.9 Hz, 1H), 3.56 (s, 2H), 2.44–2.36 (m, 11H), 2.22 (s, 3H). 13 C NMR (101 MHz, DMSO - d 6 )δ 172.5, 165.8, 154.8, 146.5, 141.5, 139.9, 138.8, 138.3, 137.5, 135.2, 132.5, 132.3, 131.7, 131.1, 131.1, 129.4, 129.4, 128.2, 128.1, 128.0, 127.7, 127.2, 126.5, 126.2, 124.0, 123.9, 123.5, 120.4, 120.3, 117.8, 117.7, 115.7, 115.4, 114.9, 57.8, 55.0, 52.8, 45.8, 20.8. HRMS: [M + H] + calcd for C 36 H 34 ON 5 F 4 , 628.2694, found 628.2678。

[0416] Example 47: 3 - Methyl - N-(4 - ((4 - methylpiperazin - 1 - yl)methyl)-3-(trifluoromethyl)phenyl)-3-(2 - ((4 - morpholinophenyl)amino)quinolin - 6 - yl)benzamide (47)

[0417] The synthetic procedure of compound 47 is similar to that of compound 41. 1 H NMR (400 MHz, DMSO - d 6)δ10.51(s,1H),9.33(s,1H),8.23(dd,J=5.1,2.2Hz,1H),8.13 - 8.03(m,2H),7.99(d,J=2.0Hz,1H),7.95 - 7.91(m,1H),7.88 - 7.84(m,2H),7.76(d,J=2.0Hz,1H),7.70(dd,J=8.6,3.1Hz,2H),7.63 - 7.60(m,1H),7.51(d,J=8.2Hz,1H),7.07(d,J=8.9Hz,1H),6.99 - 6.93(m,2H),3.76(dd,J=6.0,3.5Hz,4H),3.60(s,3H),3.10 - 3.04(m,4H),2.65(s,8H),2.39(d,J=5.4Hz,6H). 13 CNMR(101MHz,DMSO - d 6 )δ165.8,146.9,146.5,141.6,139.9,138.8,137.1,134.7,134.4,132.5,132.4,131.7,131.1,131.0,129.3,128.2,128.1,128.0,127.7,127.1,126.3,126.2,124.0,123.6,123.5,120.3,117.8,117.8,117.7,116.3,114.8,66.7,55.1,53.1,49.8,46.1,20.9.HRMS:[M + H] + calcd for C 40 H 42 O 2 N 6 F 3 ,695.3316,found 695.3304。

[0418] Example 48: 3-(2 - Aminoquinazolin - 6 - yl)-4 - methyl - N-(3-(4 - methyl - 1H - imidazol - 1 - yl)-5-(trifluoromethyl)phenyl)benzamide (48)

[0419] 48d (229.33 mg, 1 mmol) was reacted with 3-iodo-4-methylbenzoic acid (314.46 mg, 1.2 mmol) in the presence of DIPEA (258.49 mg, 2 mmol), HATU (494.31 mg, 1.3 mmol) and DMF (5 mL) at room temperature for 12 h to give 48e. 48e (485.25 mg, 1 mmol) and 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinazolin-2-amine (352.47 mg, 1.3 mmol) were reacted under the catalysis of Pd(dppf)Cl2 (73.17 mg, 0.1 mmol) in the presence of cesium carbonate (Cs 2 CO 3 , 651.64 mg, 2 mmol) and cesium fluoride (CsF, 75.95 mg, 0.5 mmol) under nitrogen protection at 80 °C for 12 h to give compound 48 in 41% yield as a pale yellow solid. 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.74 (s, 1H), 9.18 (s, 1H), 8.36 (s, 1H), 8.21 (s, 2H), 8.01 (d, J = 1.9 Hz, 1H), 8.00 - 7.96 (m, 1H), 7.88 (d, J = 2.1 Hz, 1H), 7.79 (dd, J = 8.6, 2.1 Hz, 1H), 7.72 (s, 1H), 7.53 (d, J = 8.4 Hz, 2H), 7.49 (s, 1H), 6.95 (s, 2H), 2.37 (s, 3H), 2.18 (s, 4H). 13 C NMR (151 MHz, DMSO-d 6 ) δ 166.0, 163.0, 161.6, 151.6, 141.8, 141.1, 140.3, 135.8, 134.3, 132.3, 132.1, 131.4, 131.3, 131.2, 129.3, 129.0, 129.0, 128.3, 127.4, 126.8, 125.0, 124.9, 123.2, 121.4, 119.8, 115.4, 114.7, 112.1, 25.4, 20.8. HRMS: [M+H] + calcd for C 27 H 22 ON 6 F 3 , 503.1802, found 503.1797.

[0420] Example 49: 3-(2-Aminoquinazolin-6-yl)-N-(4-((4-ethylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)-4-methylbenzamide (49)

[0421] 49a (205.14 mg, 1 mmol), N-bromosuccinimide (NBS, 73.17 mg, 0.1 mmol) and 2,2'-azobis(2-methylpropionitrile) (AIBN, 73.17 mg, 0.1 mmol) were dissolved in carbon tetrachloride (CCl 4 ), and the reaction was refluxed for 12 h. Then the product was extracted with dichloromethane (DCM), and after evaporation of the solvent, the residue was directly dissolved in acetonitrile. 1-Ethylpiperazine (114.19 mg, 1 mmol) and potassium carbonate (K 2 CO 3 , 276.41 mg, 2 mmol) were added, and the reaction was carried out at room temperature for 2 h. Finally, column chromatography was performed to obtain 49c. Under a hydrogen atmosphere, 49c (317.31 mg, 1 mmol) was reduced to 49d with palladium on carbon (Pd / C, 317.31 mg, 2.98 mmol). 49d (287.33 mg, 1 mmol) and 3-iodo-4-methylbenzoic acid (314.46 mg, 1.2 mmol) were reacted in the presence of DIPEA (258.49 mg, 2 mmol), HATU (494.31 mg, 1.3 mmol) and DMF (5 mL) at room temperature for 12 h to obtain 49e. 49e (485.25 mg, 1 mmol) and 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinazolin-2-amine (352.47 mg, 1.3 mmol) were reacted under the catalysis of Pd(dppf)Cl2 (73.17 mg, 0.1 mmol) in the presence of cesium carbonate (Cs 2 CO 3 , 651.64 mg, 2 mmol) and cesium fluoride (CsF, 75.95 mg, 0.5 mmol) under nitrogen protection at 80 °C for 12 h to obtain compound 49 in a yield of 19%, as a light yellow solid. 1 1H NMR (400 MHz, DMSO-d 6)δ10.48(s,1H),9.18(s,1H),8.21(s,1H),8.08(d,J=8.5Hz,1H),7.99-7.92(m,2H),7.86(s,1H),7.77(d,J=8.7Hz,1H),7.70(d,J=8.6Hz,1H),7.52(t,J=7.6Hz,2H),6.94(s,2H),3.59(s,3H),2.64(d,J=34.2Hz,8H),2.41(s,2H),2.36(s,3H),1.09-1.03(m,3H). 13 C NMR(101MHz,DMSO-d 6 )δ165.8,163.0,161.5,151.5,141.0,139.9,138.9,135.8,134.4,132.5,132.0,131.7,131.2,129.3,128.3,128.0,127.7,127.3,126.2,124.9,124.0,123.2,119.7,117.8,117.7,57.6,52.2,52.1,51.7,20.8,11.4.HRMS:[M+H] + calcd for C 30 H 32 ON 6 F 3 ,549.2584,found 549.2576。

[0422] Example 50: tert-Butyl 4-(4-(3-(2-aminoquinazolin-6-yl)-4-methylbenzamido)-2-(trifluoromethyl)phenyl)piperazine-1-carboxylate (50)

[0423] The synthesis procedure of Compound 50 is similar to that of Compound 49. 1 H NMR(400MHz,DMSO-d 6 )δ10.42(s,1H),9.18(s,1H),8.16(d,J=2.5Hz,1H),8.07(dd,J=8.8,2.5Hz,1H),7.98-7.90(m,2H),7.85(d,J=2.1Hz,1H),7.77(dd,J=8.7,2.1Hz,1H),7.57(d,J=8.8Hz,1H),7.51(t,J=8.2Hz,2H),6.94(s,2H),3.43(t,J=4.4Hz,4H),2.79(t,J=4.8Hz,4H),2.36(s,3H),1.43(s,9H). 1313C NMR (101 MHz, DMSO-d 6 ) δ 165.6, 163.0, 161.5, 154.3, 151.5, 147.6, 141.0, 139.9, 137.1, 135.8, 134.4, 132.5, 131.2, 129.3, 128.3, 127.9, 127.4, 127.3, 126.2, 125.8, 125.2, 124.9, 123.7, 119.7, 118.8, 118.8, 79.4, 74.0, 53.5, 28.5, 20.8. HRMS: [M+H] + calcd for C 32 H 34 O 3 N 6 F 3 , 607.2639, found 607.2628。

[0424] Example 51: 3-(2-Aminoquinazolin-6-yl)-4-methyl-N-(3-(trifluoromethyl)phenyl)benzamide (51)

[0425] The synthesis procedure of Compound 51 was similar to that of Compound 48. 1 1H NMR (400 MHz, DMSO-d 6 ) δ 10.51 (s, 1H), 9.18 (s, 1H), 8.25 (d, J = 2.0 Hz, 1H), 8.09 (d, J = 8.3 Hz, 1H), 8.00 - 7.91 (m, 2H), 7.86 (d, J = 2.0 Hz, 1H), 7.78 (dd, J = 8.7, 2.1 Hz, 1H), 7.60 (t, J = 8.0 Hz, 1H), 7.52 (dd, J = 8.3, 4.1 Hz, 2H), 7.45 (d, J = 7.8 Hz, 1H), 6.94 (s, 2H), 2.37 (s, 3H). 13 13C NMR (101 MHz, DMSO-d 6 ) δ 165.8, 163.0, 161.5, 151.5, 141.0, 139.9, 138.9, 135.8, 134.4, 132.5, 132.0, 131.7, 131.2, 129.3, 128.3, 128.0, 127.7, 127.3, 126.2, 124.9, 124.0, 123.2, 119.7, 117.8, 117.7, 57.6, 52.2, 52.1, 51.7, 20.8, 11.4. HRMS: [M+H] + calcd for C 23 H18 ON 4 F 3 ,423.1427, found 423.1419。

[0426] Example 52: 3-(2-Aminoquinazolin-6-yl)-4-methyl-N-(4-(piperazin-1-yl)-3-(trifluoromethyl)phenyl)benzamide (52)

[0427] The synthesis steps of compound 52 are similar to those of compound 49. 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.57 (s, 1H), 9.36 (s, 1H), 9.17 (s, 2H), 8.19 (s, 1H), 8.11 (d, J = 8.7 Hz, 1H), 7.95 (t, J = 21.2 Hz, 5H), 7.63 - 7.49 (m, 3H), 3.20 (s, 4H), 3.05 (s, 4H), 2.35 (s, 3H). 13 C NMR (151 MHz, DMSO-d 6 ) δ 165.7, 159.7, 146.4, 140.5, 139.9, 137.5, 137.0, 135.6, 132.5, 131.2, 129.3, 128.9, 127.5, 126.9, 126.7, 126.5, 126.3, 126.1, 125.6, 125.4, 125.1, 123.3, 122.2, 121.5, 119.3, 118.9, 118.9, 50.5, 44.0, 20.7. HRMS: [M+H] + calcd for C 27 H 26 ON 6 F 3 ,507.2115, found 507.2106。

[0428] Example 53: 3-(2-Aminoquinazolin-6-yl)-4-methyl-N-(4-(4-methylpiperazine-1-carbonyl)-3-(trifluoromethyl)phenyl)benzamide (53)

[0429] The synthesis steps of compound 53 are similar to those of compound 49. 1 H NMR (400 MHz, DMSO-d 6)δ 10.62 (s, 1H), 9.19 (s, 1H), 8.30 (d, J = 2.0 Hz, 1H), 8.17 (dd, J = 8.3, 2.2 Hz, 1H), 8.01 - 7.91 (m, 2H), 7.87 (d, J = 2.1 Hz, 1H), 7.78 (dd, J = 8.6, 2.1 Hz, 1H), 7.52 (dd, J = 8.4, 3.3 Hz, 2H), 7.44 (d, J = 8.5 Hz, 1H), 6.95 (s, 2H), 3.70 - 3.54 (m, 2H), 3.45 (tt, J = 7.1, 3.5 Hz, 2H), 3.21 - 3.03 (m, 2H), 2.37 (s, 3H), 2.33 - 2.22 (m, 2H), 2.18 (s, 3H). 13 C NMR (101 MHz, DMSO - d 6 )δ 166.5, 166.0, 163.0, 161.5, 151.5, 141.0, 140.5, 140.1, 135.8, 134.3, 132.3, 131.2, 129.9, 129.4, 128.7, 128.3, 127.4, 126.4, 126.0, 125.4, 124.9, 124.0, 122.7, 119.7, 118.0, 117.9, 56.5, 54.6, 54.5, 47.0, 41.5, 20.8. HRMS: [M + H] + calcd for C 29 H 28 O 2 N 6 F 3 , 549.2220, found 549.2213。

[0430] Example 54: 3-(2 - Aminoquinazolin - 6 - yl)-4 - methyl - N-(3 - ((4 - methylpiperazin - 1 - yl)methyl)-5 - (trifluoromethyl)phenyl)benzamide (54)

[0431] The synthesis procedure of Compound 54 is similar to that of Compound 49. 1 H NMR (400 MHz, DMSO - d 6)δ 10.57 (s, 1H), 9.18 (s, 1H), 8.22 (d, J = 2.0 Hz, 1H), 8.06 - 7.91 (m, 3H), 7.88 (d, J = 2.1 Hz, 1H), 7.79 (dd, J = 8.7, 2.1 Hz, 1H), 7.51 (t, J = 7.9 Hz, 2H), 7.34 (s, 1H), 6.94 (s, 2H), 3.53 (s, 2H), 2.38 (d, J = 11.9 Hz, 11H), 2.17 (s, 3H). 13 C NMR(101MHz, DMSO - d 6 )δ 165.9, 163.0, 161.5, 151.5, 141.1, 140.9, 140.5, 139.9, 135.8, 134.4, 132.5, 131.2, 129.8, 129.5, 129.4, 128.3, 127.4, 126.0, 124.9, 124.4, 123.3, 120.4, 120.4, 119.7, 115.6, 115.6, 61.9, 55.0, 52.8, 46.0, 20.8. HRMS: [M + H] + calcd for C 29 H 30 ON 6 F 3 , 535.2428, found 535.242。

[0432] Example 55: 3-(2 - Aminoquinazolin - 6 - yl)-N-(4 - chloro - 3-(trifluoromethyl)phenyl)-4 - methylbenzamide (55)

[0433] The synthetic procedure of compound 55 is similar to that of compound 48. 1 H NMR(400MHz, DMSO - d 6 )δ 10.61 (s, 1H), 9.18 (s, 1H), 8.37 (s, 1H), 8.15 (d, J = 8.9 Hz, 1H), 8.03 - 7.92 (m, 2H), 7.86 (s, 1H), 7.79 (s, 1H), 7.71 (d, J = 8.8 Hz, 1H), 7.52 (d, J = 8.3 Hz, 3H), 6.94 (s, 2H), 2.37 (s, 3H). 13 C NMR(151MHz, DMSO - d 6)δ165.9,163.0,161.5,151.5,141.0,140.2,139.2,135.8,134.3,132.5,132.2,131.2,129.3,128.3,127.4,127.2,127.0,126.8,126.0,125.4,124.9,124.7,124.2,122.4,120.5,119.7,119.5,119.5,119.4,119.4,20.8.HRMS:[M+H] + calcd forC 23 H 17 ON 4 ClF 3 ,457.1038,found 457.1032。

[0434] Example 56: 3-(2-Aminoquinazolin-6-yl)-4-methyl-N-(4-((4-methylpiperazin-1-yl)methyl)phenyl)benzamide (56)

[0435] The synthesis procedure of Compound 56 is similar to that of Compound 49. 1 H NMR(400MHz,DMSO-d 6 )δ10.23(s,1H),9.18(s,1H),7.92(d,J = 10.4Hz,2H),7.88 - 7.84(m,1H),7.80 - 7.76(m,1H),7.73(d,J = 8.1Hz,2H),7.50(dd,J = 12.1,8.3Hz,2H),7.26(d,J = 8.2Hz,2H),6.93(s,2H),3.44(s,2H),2.39(d,J = 28.3Hz,11H),2.25(s,3H). 13 C NMR(101MHz,DMSO-d 6 )δ165.4,163.0,161.5,151.5,140.9,139.5,138.5,135.8,134.5,133.1,131.1,129.6,129.3,128.3,127.2,124.9,120.7,119.8,61.9,54.8,52.3,45.5,20.8.HRMS:[M+H] + calcd forC 28 H 31 ON 6 ,467.2554,found 467.2540。

[0436] Example 57: 3-(2-Aminoquinazolin-6-yl)-N-(3-fluoro-4-((4-methylpiperazin-1-yl)methyl)phenyl)-4-methylbenzamide (57)

[0437] The synthesis procedure of Compound 57 is similar to that of Compound 49. 1 H NMR(400MHz,DMSO-d 6 )δ10.46(s,1H),9.18(s,1H),7.93(d,J=8.2Hz,2H),7.87(d,J=2.1Hz,1H),7.81-7.73(m,2H),7.57(dd,J=8.4,2.0Hz,1H),7.50(t,J=9.0Hz,2H),7.32(t,J=8.5Hz,1H),6.94(s,2H),3.47(s,2H),2.38(d,J=17.7Hz,11H),2.19(s,3H). 13 C NMR(101MHz,DMSO-d 6 )δ165.7,163.0,162.1,161.5,159.7,151.5,140.9,140.4,140.3,139.8,135.8,134.4,132.7,132.0,131.1,129.4,128.3,127.3,124.9,119.7,119.7,119.5,116.2,116.2,107.5,107.2,54.9,54.7,52.4,45.7,20.8.HRMS:[M+H] + calcd for C 28 H 30 ON 6 F,485.2460,found 485.2450。

[0438] Example 58: 4-(2-Aminoquinazolin-6-yl)-N-(3-chloro-4-((4-methylpiperazin-1-yl)methyl)phenyl)-3-methylbenzamide (58)

[0439] The synthesis procedure of Compound 58 is similar to that of Compound 49. 1 HNMR(400MHz,DMSO-d 6)δ10.36(s,1H),9.18(s,1H),7.98(d,J=2.1Hz,1H),7.95 - 7.89(m,2H),7.86(d,J=2.1Hz,1H),7.77(dd,J=8.6,2.1Hz,1H),7.72(dd,J=8.4,2.2Hz,1H),7.51(t,J=8.7Hz,2H),7.42(d,J=8.4Hz,1H),6.93(s,2H),3.54(s,2H),2.59(s,4H),2.50(d,J=1.9Hz,4H),2.35(d,J=6.3Hz,6H). 13 C NMR(101MHz,DMSO - d 6 )δ165.7,163.0,161.5,151.5,140.9,139.8,139.7,135.8,134.4,133.6,132.6,131.5,131.2,130.6,129.3,128.3,127.3,124.9,120.9,119.7,119.2,58.4,54.5,52.0,45.1,20.8.HRMS:[M + H] + calcd for C 28 H 30 ON 6 Cl,501.2164,found501.2159。

[0440] Example 59: 3-(2 - aminoquinazolin - 6 - yl)-N-(3-(difluoromethyl)-4-((4 - methylpiperazin - 1 - yl)methyl)phenyl)-4 - methylbenzamide (59)

[0441] Dissolve 59a - 1 (165.15 mg, 1 mmol) in dry dichloromethane (DCM, 10 mL). Slowly add diethylaminosulfur trifluoride (DAST, 209.54 mg, 1.3 mmol) dropwise at 0 °C. Then allow the reaction to warm to room temperature and react for 7 hours. Monitor the reaction progress by thin - layer chromatography (TLC). After the reaction is completed, add aqueous sodium bicarbonate solution to neutralize, extract with DCM, and perform column chromatography to obtain 59a. The subsequent reaction steps are similar to those of compound 49 to obtain compound 59 as a light brown solid with a yield of 17%. 1 HNMR(400MHz,DMSO - d 6)δ10.41(s,1H),9.19(s,1H),8.10(s,1H),7.99 - 7.90(m,3H),7.89 - 7.84(m,1H),7.78(d,J=8.6Hz,1H),7.51(t,J=9.1Hz,2H),7.37(d,J=7.2Hz,1H),6.95(s,2H),3.56(s,2H),2.39(d,J=27.0Hz,11H),2.29(s,3H). 13 C NMR(151MHz,DMSO - d 6 )δ165.0,162.4,160.9,150.9,140.3,139.2,138.7,135.2,133.8,133.2,133.1,133.0,132.1,131.4,131.3,131.3,130.8,130.6,128.7,127.7,126.7,124.3,121.8,119.2,117.2,117.1,117.1,114.3,112.7,111.2,58.4,54.4,51.9,45.2,20.2.HRMS:[M + H] + calcd for C 29 H 31 ON 6 F 2 ,517.2522,found 517.2511。

[0442] Example 60: 3-(2 - aminoquinazolin - 6 - yl)-4 - methyl - N-(4-(4 - methylpiperazin - 1 - yl)phenyl)benzamide (60)

[0443] The synthesis procedure of Compound 60 is similar to that of Compound 48. 1 H NMR(400MHz,DMSO - d 6 )δ10.13(s,1H),9.18(s,1H),7.92(d,J=7.6Hz,2H),7.87(d,J=2.1Hz,1H),7.78(dd,J=8.7,2.1Hz,1H),7.63(d,J=8.6Hz,2H),7.51(d,J=8.6Hz,1H),7.46(d,J=7.9Hz,1H),6.97 - 6.87(m,4H),3.10(d,J=5.2Hz,4H),2.48(d,J=6.1Hz,4H),2.34(s,3H),2.24(s,3H). 13 C NMR(101MHz,DMSO - d 6) δ 165.0, 163.0, 161.5, 151.5, 147.8, 140.8, 139.1, 135.9, 133.2, 131.6, 131.0, 129.2, 128.3, 127.2, 124.8, 122.0, 119.7, 115.9, 55.0, 48.8, 46.0, 20.8. HRMS: [M+H] + calcd for C 27 H 29 ON 6 , 453.2397, found 453.2387。

[0444] Example 61: 3-(2-((4-Fluorophenyl)amino)quinazolin-6-yl)-4-methyl-N-(4-((4-methylpiperazin-1-yl)methyl)phenyl)benzamide (61)

[0445] The synthesis procedure of Compound 61 is similar to that of Compound 49. 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.27 (s, 1H), 10.01 (s, 1H), 9.38 (s, 1H), 8.06 - 7.99 (m, 3H), 7.96 (d, J = 6.3 Hz, 1H), 7.93 - 7.88 (m, 2H), 7.74 (s, 3H), 7.51 (d, J = 8.0 Hz, 1H), 7.28 (d, J = 8.1 Hz, 3H), 7.20 (t, J = 8.8 Hz, 2H), 3.48 (s, 2H), 2.65 (s, 4H), 2.47 - 2.36 (m, 10H). 13 C NMR (101 MHz, DMSO-d 6 ) δ 165.4, 164.0, 162.9, 158.9, 157.5, 156.5, 150.4, 145.1, 140.6, 139.5, 138.5, 138.3, 137.9, 137.4, 136.3, 136.0, 134.5, 133.1, 131.1, 130.2, 129.6, 129.3, 128.4, 128.2, 125.8, 120.8, 120.8, 120.7, 115.6, 115.4, 61.9, 54.8, 52.4, 45.6, 19.0. HRMS: [M+H] + calcd for C 34 H 34 ON 6 F, 561.2773, found 561.2765。

[0446] Example 62: 3-(2-((4-Fluorophenyl)amino)quinazolin-6-yl)-4-methyl-N-(3-(trifluoromethyl)phenyl)benzamide (62)

[0447] The synthesis procedure of compound 62 is similar to that of compound 48. 1 H NMR(400MHz,DMSO-d 6 )δ10.56(s,1H),10.02(s,1H),9.37(s,1H),8.27(s,1H),8.12 - 7.89(m,7H),7.75(d,J=8.6Hz,1H),7.60(t,J=8.0Hz,1H),7.53(d,J=8.0Hz,1H),7.44(d,J=7.8Hz,1H),7.19(t,J=8.7Hz,2H),2.38(s,3H). 13 C NMR(151MHz,DMSO-d 6 )δ165.9,162.9,158.5,157.5,156.9,150.4,140.7,140.5,140.0,137.4,136.3,135.9,132.6,131.2,130.3,130.1,129.9,129.7,129.4,128.4,127.5,127.3,125.8,125.5,124.3,123.7,121.9,120.8,120.8,120.7,120.3,120.3,116.9,116.9,116.9,116.9,115.6,115.4,20.8.HRMS:[M+H] + calcd forC 29 H 21 ON 4 F 4 ,517.1646,found 517.1638。

[0448] Example 63: N-(3-(Difluoromethyl)-4-((4-methylpiperazin-1-yl)methyl)phenyl)-3-(2-((4-fluorophenyl)amino)quinazolin-6-yl)-4-methylbenzamide (63)

[0449] The synthesis procedure of compound 63 is similar to that of compound 59. 1 H NMR(400MHz,DMSO-d 6)δ 10.42 (s, 1H), 10.01 (s, 1H), 9.37 (s, 1H), 8.14 - 8.08 (m, 1H), 7.96 (dtd, J = 32.2, 10.8, 3.5 Hz, 7H), 7.75 (d, J = 8.7 Hz, 1H), 7.52 (d, J = 8.8 Hz, 2H), 7.40 - 7.35 (m, 2H), 7.19 (t, J = 8.8 Hz, 3H), 3.55 (s, 2H), 2.37 (d, J = 9.6 Hz, 11H), 2.22 (s, 3H). 13 C NMR (101 MHz, DMSO - d 6 )δ 165.6, 162.9, 158.9, 157.5, 156.5, 150.4, 140.7, 139.7, 139.2, 137.4, 136.3, 136.0, 133.9, 133.7, 133.5, 132.8, 131.4, 131.2, 129.3, 128.4, 127.5, 125.8, 122.4, 120.8, 120.8, 120.7, 117.7, 117.7, 115.6, 115.4, 113.3, 59.0, 54.9, 52.4, 45.6, 20.8。

[0450] Example 64: 3-(2 - Aminoquinazolin - 6 - yl)-N-(4 - ((dimethylamino)methyl)-3-(trifluoromethyl)phenyl)-4 - methylbenzamide (64)

[0451] The synthesis procedure of compound 64 is similar to that of compound 49. 1 H NMR (400 MHz, DMSO - d 6 )δ 10.50 (s, 1H), 9.18 (s, 1H), 8.22 (s, 1H), 8.09 (d, J = 8.5 Hz, 1H), 8.01 - 7.90 (m, 2H), 7.87 (d, J = 2.0 Hz, 1H), 7.81 - 7.77 (m, 1H), 7.72 (d, J = 8.8 Hz, 1H), 7.52 (dd, J = 8.4, 2.1 Hz, 2H), 6.94 (s, 2H), 3.51 (s, 2H), 2.37 (s, 3H), 2.19 (d, J = 7.7 Hz, 6H). 13 C NMR (151 MHz, DMSO - d 6)δ165.8, 163.0, 161.5, 151.5, 141.0, 139.9, 135.8, 134.3, 132.5, 131.8, 131.2, 130.1, 129.3, 128.3, 127.3, 125.7, 124.9, 124.0, 119.7, 117.6, 117.6, 59.2, 45.6, 20.8. HRMS: [M+H] + calcd for C 26 H 25 ON 5 F 3 , 480.2006, found 480.1998。

[0452] Example 65: 3-(2-Aminoquinazolin-6-yl)-N-(4-((diethylamino)methyl)-3-(trifluoromethyl)phenyl)-4-methylbenzamide (65)

[0453] The synthesis procedure of Compound 65 is similar to that of Compound 49. 1 H NMR (400 MHz, DMSO-d 6 )δ10.51 (s, 1H), 9.18 (s, 1H), 8.22 (s, 1H), 8.08 (d, J = 8.5 Hz, 1H), 8.02 - 7.92 (m, 2H), 7.87 (d, J = 2.0 Hz, 1H), 7.79 (dd, J = 8.6, 2.1 Hz, 2H), 7.52 (dd, J = 8.4, 4.4 Hz, 2H), 6.94 (s, 2H), 3.64 (s, 2H), 2.37 (s, 4H), 0.99 (s, 6H). 13 C NMR (151 MHz, DMSO-d 6 )δ165.8, 163.0, 161.5, 151.5, 140.9, 139.9, 138.5, 135.8, 134.4, 132.5, 131.4, 131.2, 130.1, 129.3, 128.3, 127.3, 125.8, 124.9, 124.0, 119.8, 117.6, 117.6, 53.4, 47.1, 20.8, 12.2. HRMS: [M+H] + calcd for C 28 H 29 ON 5 F 3 , 508.2319, found 508.2312。

[0454] Example 66: N-(3-(2-Aminoquinazolin-6-yl)-4-methylphenyl)-4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)benzamide (66)

[0455] 66a (262.05 mg, 1 mmol) was reacted with 4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)benzoic acid (343.34 mg, 1.2 mmol) in the presence of DIPEA (258.49 mg, 2 mmol), HATU (494.31 mg, 1.3 mmol) and DMF (5 mL) at room temperature for 12 h to give 66b, which was then separated by column chromatography. 66b (517.33 mg, 1 mmol) and 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinazolin-2-amine (352.47 mg, 1.3 mmol) were reacted under the catalysis of Pd(dppf)Cl2 (73.17 mg, 0.1 mmol) in the presence of cesium carbonate (Cs 2 CO 3 , 651.64 mg, 2 mmol) and cesium fluoride (CsF, 75.95 mg, 0.5 mmol) under nitrogen protection at 80 °C for 12 h to give compound 66 in a yield of 48% as a light yellow solid. 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.49 (s, 1H), 9.18 (s, 1H), 8.31 - 8.21 (m, 2H), 7.92 (d, J = 8.0 Hz, 1H), 7.83 - 7.68 (m, 4H), 7.50 (d, J = 8.6 Hz, 1H), 7.36 - 7.27 (m, 1H), 6.91 (s, 2H), 3.70 (s, 2H), 2.54 (d, J = 15.4 Hz, 4H), 2.49 (d, J = 6.4 Hz, 4H), 2.31 (s, 3H), 2.26 (s, 3H). 13 C NMR (101 MHz, DMSO-d 6 ) δ 164.3, 163.0, 161.5, 151.4, 141.3, 141.0, 137.4, 135.7, 135.1, 134.3, 132.0, 131.2, 131.1, 130.9, 127.9, 127.6, 127.2, 127.0, 126.8, 125.5, 125.5, 124.8, 123.2, 122.2, 119.9, 119.9, 119.7, 57.7, 54.6, 52.4, 45.3, 20.2. HRMS: [M+H] + calcd for C 29 H30 ON 6 F 3 ,535.2428, found 535.2420。

[0456] Example 67: N-(3-(2-Aminoquinazolin-6-yl)-4-methylphenyl)-3-(trifluoromethyl)benzamide (67)

[0457] The synthesis procedure of Compound 67 is similar to that of Compound 66. 1 H NMR(400MHz, DMSO-d 6 ) δ10.31(s, 1H), 9.18(s, 1H), 7.83 - 7.70(m, 6H), 7.55(t, J = 7.7Hz, 1H), 7.50(d, J = 8.6Hz, 1H), 7.31(d, J = 8.2Hz, 1H), 6.91(s, 2H), 3.58(s, 2H), 2.43(s, 8H), 2.25(s, 3H), 2.20(s, 3H). 13 C NMR(151MHz, DMSO-d 6 ) δ163.3, 161.9, 160.6, 160.4, 159.0, 150.3, 139.9, 136.3, 135.2, 135.1, 134.7, 134.0, 130.9, 130.8, 130.0, 129.7, 127.6, 127.5, 126.8, 123.7, 122.9, 122.9, 121.0, 118.8, 118.7, 113.9, 113.7, 53.6, 53.5, 51.2, 44.4, 19.1. HRMS: [M + H] + calcd for C 28 H 30 ON 6 F, 485.2460, found 485.2455。

[0458] Example 68: N-(3-(2-Aminoquinazolin-6-yl)-4-methylphenyl)-4-(4-methylpiperazin-1-yl)-3-(trifluoromethyl)benzamide (68)

[0459] The synthesis procedure of Compound 68 is similar to that of Compound 66. 1 H NMR(400MHz, DMSO-d 6)δ10.31(s,1H),9.99(s,1H),9.37(s,1H),8.03(dd,J=8.8,5.0Hz,2H),7.91(d,J=2.0Hz,1H),7.86 - 7.67(m,6H),7.55(t,J=7.6Hz,1H),7.32(d,J=8.3Hz,1H),7.18(t,J=8.7Hz,2H),3.57(d,J=4.9Hz,2H),2.43(s,8H),2.27(s,3H),2.21(s,3H). 13 C NMR(101MHz,DMSO - d 6 )δ164.4,162.8,162.1,159.6,158.8,157.4,156.5,150.2,140.8,137.5,137.5,137.4,136.7,136.2,136.1,131.9,131.9,131.2,130.8,128.8,128.7,128.0,125.8,124.0,122.1,120.8,120.7,120.7,120.0,115.6,115.4,115.0,114.7,54.8,54.7,52.5,45.7,20.1.HRMS:[M + H] + calcd for C 34 H 33 ON 6 F 2 ,579.2678,found 579.2662。

[0460] Example 69: N-(3-(2 - aminoquinazolin - 6 - yl)-4 - methylphenyl)-4-(4 - methylpiperazine - 1 - carbonyl)-3-(trifluoromethyl)benzamide (69)

[0461] The synthesis procedure of Compound 69 is similar to that of Compound 66. 1 H NMR(400MHz,DMSO - d 6)δ10.31(s,1H),9.73(s,1H),9.30(s,1H),7.89 - 7.83(m,3H),7.82 - 7.72(m,5H),7.67(d,J=8.6Hz,1H),7.55(t,J=7.7Hz,1H),7.32(d,J=8.4Hz,1H),7.00 - 6.90(m,2H),3.57(s,2H),3.47(q,J=4.1,3.1Hz,4H),3.04(t,J=5.2Hz,4H),2.40(s,8H),2.27(s,3H),2.18(s,4H),1.43(s,9H). 13 C NMR(101MHz,DMSO - d 6 )δ164.4,162.6,159.6,157.6,154.3,150.5,146.6,140.9,137.5,136.2,136.2,136.0,133.7,131.9,131.9,131.2,130.8,128.9,128.7,128.0,125.6,124.0,122.1,120.5,119.9,117.1,115.0,114.7,79.4,55.0,54.7,52.6,49.8,45.9,28.5,20.2.HRMS:[M + H] + calcd for C 43 H 50 O 3 N 8 F,745.3984,found 745.3971。

[0462] Example 70: N-(3-(2 - aminoquinazolin - 6 - yl)-4 - methylphenyl)-3 - ((4 - methylpiperazin - 1 - yl)methyl)-5 - (trifluoromethyl)benzamide (70)

[0463] The synthesis procedure of compound 70 is similar to that of compound 66. 1 H NMR(400MHz,DMSO - d 6)δ10.50(s,1H),9.81(s,1H),9.43(s,1H),9.31(s,1H),7.92 - 7.72(m,8H),7.67(d,J=8.6Hz,1H),7.59(t,J=7.6Hz,1H),7.31(d,J=8.4Hz,1H),7.01(d,J=8.5Hz,2H),3.76(s,2H),3.36–3.22(m,8H),3.04(d,J=31.7Hz,4H),2.78(s,4H),2.57(s,3H),2.26(s,3H). 13 C NMR(151MHz,DMSO-d 6 )δ179.9,164.2,162.7,161.7,160.1,157.6,150.4,145.6,140.8,137.4,136.6,136.6,136.3,136.1,134.2,132.1,131.2,130.9,128.0,125.5,124.1,122.1,120.5,120.5,120.0,118.5,117.2,116.5,115.1,114.9,114.5,114.5,56.5,53.9,52.9,49.5,46.9,43.2,20.1.HRMS:[M + H] + calcd for C 38 H 42 ON 8 F,645.3460,found 645.3446。

[0464] Example 71: N-(3-(2-Aminoquinazolin-6-yl)-4-methylphenyl)-4-chloro-3-(trifluoromethyl)benzamide (71)

[0465] The synthetic procedure of compound 71 is similar to that of compound 66. 1 H NMR(400MHz,DMSO-d 6) δ 10.74 (s, 1H), 9.75 (s, 1H), 9.51 (s, 1H), 9.31 (s, 1H), 8.30 (d, J = 8.6 Hz, 2H), 7.93 - 7.86 (m, 4H), 7.82 - 7.75 (m, 3H), 7.67 (d, J = 8.6 Hz, 1H), 7.32 (d, J = 8.5 Hz, 1H), 7.01 (d, J = 8.7 Hz, 2H), 3.76 (s, 2H), 3.32 (d, J = 5.9 Hz, 4H), 3.26 (s, 3H), 3.07 (s, 2H), 2.90 (d, J = 12.2 Hz, 2H), 2.80 (s, 3H), 2.52 - 2.48 (m, 8H), 2.27 (s, 3H). 13 C NMR (151 MHz, DMSO - d 6 ) δ 164.3, 162.7, 157.6, 150.4, 145.6, 140.8, 140.4, 137.4, 136.2, 136.1, 134.5, 134.2, 132.1, 131.2, 131.1, 130.9, 128.2, 128.0, 127.8, 127.6, 127.3, 125.6, 125.5, 125.4, 123.6, 122.3, 121.8, 120.5, 120.4, 120.1, 118.5, 117.1, 116.6, 114.6, 57.0, 53.0, 49.8, 46.8, 43.1, 42.5, 20.1. HRMS: [M + H] + calcd for C 39 H 42 ON 8 F 3 , 695.3428, found 695.3412。

[0466] Example 72: N-(3-(2 - Aminoquinazolin - 6 - yl)-4 - methylphenyl)-4-(difluoromethyl)-3 - ((4 - methylpiperazin - 1 - yl)methyl)benzamide (72)

[0467] First, 72a - 1 (starting material similar to 59a - 1) was converted to 72a according to the method for synthesizing 59a. The subsequent steps were similar to those of compound 66 to obtain compound 72 with a yield of 32%, as a light yellow solid. 1 H NMR (400 MHz, DMSO - d 6)δ10.49(s,1H),9.99(s,1H),9.38(s,1H),8.32 - 8.23(m,2H),8.06 - 8.00(m,2H),7.95 - 7.90(m,2H),7.84(dd,J=8.7,2.1Hz,1H),7.80 - 7.72(m,3H),7.35(d,J=8.3Hz,1H),7.19(t,J=8.9Hz,2H),3.72(s,2H),2.90(s,1H),2.73 - 2.52(m,8H),2.36(s,3H),2.29(s,3H). 13 C NMR(151MHz,DMSO - d 6 )δ164.3,162.9,158.4,157.4,156.9,150.2,141.3,140.8,137.4,137.4,136.6,136.2,134.3,132.1,131.2,131.0,130.1,128.0,127.9,127.7,127.5,127.4,125.8,125.5,125.5,123.7,122.2,120.8,120.7,120.7,120.1,115.6,115.4,57.7,54.5,52.1,45.0,20.1.HRMS:[M + H] + calcd for C 35 H 33 ON 6 F 4 ,629.2647,found 629.2633。

[0468] Example 73: In vitro ROR1 binding activity evaluation and anti - proliferation activity evaluation

[0469] The direct binding of compounds to proteins was detected using surface plasmon resonance (SPR) technology. The detailed experimental procedures are as follows: First, ROR1 (product number #13968-H20B, Sino Biological Inc.) was diluted to 100 ng / μl with sodium acetate buffer at pH 4.0. Subsequently, ROR1 was immobilized on a CM5 chip by amino coupling method. The target response value during this immobilization process was approximately 15,000 response units (Ru). The reference channel was only used to activate the surface of the blocked chip without immobilizing ROR1. The buffer used throughout the experiment was phosphate buffered saline with polysorbate 20 (PBS-P). Next, 5% compound solutions with different concentration gradients and dimethyl sulfoxide (DMSO) calibration solutions (concentration range 4.5% - 5.8%) were prepared. It is necessary to ensure that the DMSO content in the buffer remained at 5%. Then, compounds with different concentrations were passed over the chip surface in sequence. When the compound interacted with ROR1, association and dissociation curves were generated; conversely, if no interaction occurred, no response signal was detected. After each injection, the chip was regenerated by flushing with buffer. Cell viability assay: The cell viability assessment followed the following detailed protocol. First, cells in the logarithmic growth phase were collected from the culture medium. Subsequently, the cells were seeded at a specific density of 5000 cells per well in a 96-well plate. After overnight incubation of the cells, the existing culture medium was removed and fresh culture medium containing the test compound was added. Then, the cells were cultured for an additional 72 hours. At the end of this time period, 5 mg / mL MTT solution was carefully added to each well. Then, the culture plate was incubated in an incubator at 37°C for 4 hours. After the MTT incubation was completed, the culture medium was discarded. Next, 150 μL of dimethyl sulfoxide (DMSO) was added to each well. Then, the absorbance of each well was measured at a wavelength of 490 nm using a microplate reader. For the determination of the half-maximal inhibitory concentration (IC 50 ) value, GraphPad Prism 8 software was used. These values were calculated by plotting the logarithm of the inhibitor against the response, specifically using a three-parameter model.

[0470] Table 1. Binding affinities and in vitro anti-proliferation assay results of Compounds 1 - 6

[0471]

[0472] Table 2. Binding affinities and in vitro anti-proliferation assay results of Compounds 7 - 18

[0473]

[0474]

[0475] Table 3. Binding affinities and in vitro anti-proliferation assay results of Compounds 19 - 32

[0476]

[0477]

[0478]

[0479] Table 4. Binding Affinity and in vitro Anti - proliferation Experiment Results of Compounds 33 - 47

[0480]

[0481]

[0482] Table 5. Binding Affinity and in vitro Anti - proliferation Experiment Results of Compounds 48 - 65

[0483]

[0484]

[0485]

[0486] Table 6. Binding Affinity and in vitro Anti - proliferation Experiment Results of Compounds 66 - 72

[0487]

[0488]

[0489] a : The binding affinity of compounds with receptor tyrosine kinase - like orphan receptor 1 (ROR1) was analyzed by surface plasmon resonance (SPR) technology.

[0490] b : Half - maximal inhibitory concentration (IC 50 ), and the data were expressed as the mean ± standard deviation of three independent experiments.

[0491] Table 7. In vitro Anti - proliferation Experiment and Toxicity Assessment

[0492]

[0493]

[0494] a : Half - maximal inhibitory concentration (IC 50 ), and the data were expressed as the mean ± standard deviation of three independent experiments.

[0495] b: Selectivity index (SI) between human embryonic kidney 293T cells (HEK293T) and breast cancer MDA-MB-231 cells, SI = IC of human embryonic kidney 293T cells 50 / IC of breast cancer MDA-MB-231 cells 50 .

[0496] Example 74: Subcutaneous xenograft tumor experiment

[0497] Female BALB / c nude mice at 5 weeks old, specific pathogen-free (SPF) level, were purchased from Beijing Huafukang Biotechnology Co., Ltd. All experimental operations were carried out in accordance with the guidelines and protocols approved by the Laboratory Animal Ethics Committee of Peking University Health Science Center. MDA-MB-231 cells in the logarithmic growth phase were carefully selected and collected. These cells were resuspended three times with phosphate-buffered saline (PBS) to thoroughly remove any residual serum. Subsequently, PBS was mixed with Matrigel at a ratio of 1:1. Then, MDA-MB-231 cells were added to the mixture and stirred well to ensure the formation of a uniform cell suspension, with a final cell concentration of 5×10 7 cells per milliliter. Next, 0.1 ml of the cell suspension (containing 5×10 6 cells) was carefully injected into the mice. When the average volume of the xenograft tumors reached approximately 100 cubic millimeters, the mice were randomly divided into six groups, with six mice in each group. The grouping was as follows: vehicle control group, ponatinib group (administered dose of 10 mg / kg), compound 59 low-dose group (10 mg / kg), and compound 59 high-dose group (20 mg / kg). The compounds were dissolved in a mixed solution composed of 3% dimethyl sulfoxide (DMSO), 10% Tween 80, and 87% normal saline, and administered by intraperitoneal injection every other day for 30 days. The tumor size and mouse body weight were measured every 2 days. The tumor volume (unit: cubic millimeters) was calculated using the following formula: volume (mm 3 ) = length (mm) × width (mm) 2 ×0.5. After the treatment ended, the mice were humanely sacrificed and dissected, and the tumor tissues were removed and weighed. The tumor growth inhibition rate (TGI) was calculated using the following formula: TGI = (average tumor volume of the vehicle control group - average tumor volume of the treatment group) / average tumor volume of the vehicle control group. After 30 days, the mice were dissected and the important internal organs were removed. Then, hematoxylin-eosin (HE) staining was performed to determine whether compound 59 had toxic effects on the important organs (attached Figure 1 ).

[0498] Example 75: Orthotopic breast cancer xenograft tumor experiment

[0499] Female BALB / c nude mice at 4 - 5 weeks of age were purchased from Beijing Huafukang Biotechnology Co., Ltd. These animals were housed in a designated animal breeding facility. The animal use protocol has been approved by the Laboratory Animal Ethics Committee of Peking University Health Science Center. Subsequently, the nude mice were subcutaneously injected with 3×10 6 MDA-MB-231 cells expressing luciferase. When the average volume of the xenograft tumors reached 100 mm 3 , the mice were randomly divided into three groups and injected with the corresponding compounds every other day. In vivo imaging was performed on the mice on the 7th, 35th, and 45th days after drug administration. Each mouse was injected with 100 μL of D-luciferin (purchased from Shanghai Yisheng Biotechnology Co., Ltd.). Ten minutes later, image acquisition of each mouse was performed using an IVIS Lumina Series III imaging system. Subsequently, the acquired images were analyzed using Living Image 2.11 software. After 45 days, the mice were dissected and important internal organs were removed. Then hematoxylin-eosin (HE) staining was performed to determine whether the tumors had metastasized to the internal organs (Appendix Figure 2 ).

[0500] The above are only the preferred embodiments of the present invention. It should be noted that for those of ordinary skill in the art, without departing from the principle of the present invention, several improvements and refinements can be made, and these improvements and refinements should also be regarded as the protection scope of the present invention.

Claims

1. An inhibitor targeting ROR1, characterized in that The inhibitor targeting ROR1 is an amide compound or a pharmaceutically acceptable salt of an amide compound, and the general structural formula of the amide compound includes one of the following structures: wherein R1 is selected from propargyl, N-tert-butyloxycarbonylpyrazole, 3-amino-5-ethynylpyridine, 5-ethynylindole, 2-amino-4-ethynylpyrimidine, 6-ethynylpurine, 6-ethynylpyridazine, 2-pyridinecarboxamide, 3-pyridinecarboxamide, 4-amino-3-pyridinecarboxamide, 4-amino-3-pyridineacetamide, pyridinecarboxaldehyde hydrazone, isopyridinecarboxaldehyde hydrazone, indolecarboxaldehyde hydrazone, 2-(aminomethyl)pyridine, 3-(aminomethyl)pyridine, 5-(aminomethyl)indole, 4-amino-3-(aminomethyl)pyridine, 5-(aminomethyl)indole, isoquinoline, 4-aminoquinazoline, quinoxaline, benzimidazole, benzothiazole, benzopyrazole, 1-methylbenzopyrazole, 1-methylindazole, 4-aminoquinoline, 4-aminoquinazoline, benzene One of oxazole, isobenzoxazole, 1-methylbenzimidazole, 5-aminobenzoxazole, N-phenylquinazolin-4-amine, N-methylquinazolin-4-amine, N-(2-methoxyphenyl)quinazolin-4-amine, N-(2-fluorophenyl)quinazolin-4-amine, N-(3-methylpyridin-2-yl)quinazolin-4-amine, N-Boc-4-piperazinylquinazoline, N-piperazinylquinazoline, N-(2-methylphenyl)quinazolin-4-amine, N-acetylquinolin-2-amine, N-cyclopropanecarboxylic quinolin-2-amine, N-methylquinolin-2-amine, N-phenylquinolin-2-amine, N-(2-methoxyphenyl)quinolin-2-amine, N-(2-fluorophenyl)quinolin-2-amine and N-(2-morpholinylphenyl)quinolin-2-amine; R2 is selected from one of a fluorine atom, a chlorine atom, a hydrogen atom, a trifluoromethyl group and a difluoromethyl group; R3 is selected from one of 4-methyl-1H-imidazole, N,N'-diethylpiperazine, N-Boc-piperazine, a hydrogen atom, a chlorine atom, piperazine, N-methyl-N'-acetylpiperazine, N,N-dimethylpiperazine, N-methylethylamine and N-ethylethylamine.

2. The ROR1-targeting inhibitor according to claim 1, characterized in that The inhibitor targeting ROR1 is selected from the following compounds: Compound 1: tert-butyl (4-((2-methyl-5-((4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)carbamoyl)phenyl)ethynyl)pyridin-2-yl)carbamate; Compound 2: 3-((6-aminopyridin-3-yl)ethynyl)-4-methyl-N-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)benzamide; Compound 3: 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)ethynyl)-4-methyl-N-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)benzamide; Compound 4: 3-((2-aminopyrimidin-5-yl)ethynyl)-4-methyl-N-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)benzamide; Compound 5: 3-(imidazo[1,2-a]pyrazin-3-ylethynyl)-4-methyl-N-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)benzamide; Compound 6: 3-(imidazo[1,2-a]pyrimidin-3-ylethynyl)-4-methyl-N-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)benzamide; Compound 7: N-(2-methyl-5-((4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)carbamoyl)phenyl)isonicotinamide; Compound 8: N-(2-methyl-5-((4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)carbamoyl)phenyl)nicotinamide; Compound 9: 6-amino-N-(2-methyl-5-((4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)carbamoyl)phenyl)nicotinamide; Compound 10: 6-acetylamino-N-(2-methyl-5-((4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)carbamoyl)phenyl)nicotinamide; Compound 11: (E)-4-methyl-N-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)-3-((pyridin-3-ylmethylene)amino)benzamide; Compound 12: (E)-4-methyl-N-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)-3-((pyridin-4-ylmethylene)amino)benzamide; Compound 13: (E)-3-(((1H-pyrrolo[2,3-b]pyridin-4-yl)methylene)amino)-4-methyl-N-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)benzamide; Compound 14: 3-methyl-N-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)-3-((pyridin-3-ylmethyl)amino)benzamide; Compound 15: 4-methyl-N-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)-3-((pyridin-4-ylmethyl)amino)benzamide; Compound 16: 3-(((1H-pyrrolo[2,3-b]pyridin-5-yl)methyl)amino)-4-methyl-N-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)benzamide; Compound 17: 3-(((6-aminopyridin-3-yl)methyl)amino)-4-methyl-N-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)benzamide; Compound 18: 3-(((1H-pyrrolo[2,3-b]pyridin-4-yl)methyl)amino)-4-methyl-N-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)benzamide; Compound 19: methyl-N-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)-3-(quinolin-6-yl)benzamide; Compound 20: 3-(2-aminoquinazolin-6-yl)-4-methyl-N-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)benzamide; Compound 21: 4-methyl-N-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)-3-(quinazolin-7-yl)benzamide; Compound 22: 3-(1H-benzo[d]imidazol-5-yl)-4-methyl-N-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)benzamide; Compound 23: 3-(Benzo[d]thiazol-6-yl)-4-methyl-N-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)benzamide; Compound 24: 3-(1H-indazol-5-yl)-4-methyl-N-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)benzamide; Compound 25: 4-methyl-3-(1-methyl-1H-indazol-5-yl)-N-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)benzamide; Compound 26: 4-methyl-3-(2-methyl-2H-indazol-5-yl)-N-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)benzamide; Compound 27: 3-(2-aminoquinolin-6-yl)-4-methyl-N-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)benzamide; Compound 28: 3-(2-aminoquinazolin-7-yl)-4-methyl-N-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)benzamide; Compound 29: 3-(Benzo[d]oxazol-5-yl)-4-methyl-N-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)benzamide; Compound 30: 3-(Benzo[d]oxazol-6-yl)-4-methyl-N-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)benzamide; Compound 31: 4-methyl-3-(1-methyl-1H-benzo[d]imidazol-6-yl)-N-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)benzamide; Compound 32: 3-(2-aminobenzo[d]oxazol-5-yl)-4-methyl-N-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)benzamide; Compound 33: 4-methyl-N-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)-3-(2-(phenylamino)quinazolin-6-yl)benzamide; Compound 34: 4-methyl-3-(2-(methylamino)quinazolin-6-yl)-N-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)benzamide; Compound 35: 3-(2-((4-methoxyphenyl)amino)quinazolin-6-yl)-4-methyl-N-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)benzamide; Compound 36: 3-(2-((4-fluorophenyl)amino)quinazolin-6-yl)-4-methyl-N-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)benzamide; Compound 37: 4-methyl-N-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)-3-(2-((6-methylpyridin-3-yl)amino)quinazolin-6-yl)benzamide; Compound 38: tert-butyl 4-(4-((6-(2-methyl-5-((4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)carbamoyl)phenyl)quinazole; Compound 39: 4-methyl-N-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)-3-(2-((4-(piperazin-1-yl)phenyl)amino)quinazolin-6-yl)benzamide; Compound 40: 4-methyl-N-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)-3-(2-(p-tolylamino)quinazolin-6-yl)benzamide; Compound 41: 3-(2-acetylaminoquinolin-6-yl)-4-methyl-N-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)benzamide; Compound 42: 3-(2-(cyclopropanecarboxamido)quinolin-6-yl)-4-methyl-N-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)benzamide; Compound 43: 4-methyl-3-(2-(methylamino)quinolin-6-yl)-N-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)benzamide; Compound 44: 4-methyl-N-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)-3-(2-(phenylamino)quinolin-6-yl)benzamide; Compound 45: 3-(2-((4-methoxyphenyl)amino)quinolin-6-yl)-4-methyl-N-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)benzamide; Compound 46: 3-(2-((4-fluorophenyl)amino)quinolin-6-yl)-4-methyl-N-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)benzamide; Compound 47: 3-methyl-N-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)-3-(2-((4-morpholinophenyl)amino)quinolin-6-yl)benzamide; Compound 48: 3-(2-aminoquinazolin-6-yl)-4-methyl-N-(3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl)benzamide; Compound 49: 3-(2-aminoquinazolin-6-yl)-N-(4-((4-ethylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)-4-methylbenzamide; Compound 50: tert-butyl 4-(4-(3-(2-aminoquinazolin-6-yl)-4-methylbenzamido)-2-(trifluoromethyl)phenyl)piperazine-1-carboxylate; Compound 51: 3-(2-aminoquinazolin-6-yl)-4-methyl-N-(3-(trifluoromethyl)phenyl)benzamide; Compound 52: 3-(2-aminoquinazolin-6-yl)-4-methyl-N-(4-(piperazin-1-yl)-3-(trifluoromethyl)phenyl)benzamide; Compound 53: 3-(2-aminoquinazolin-6-yl)-4-methyl-N-(4-(4-methylpiperazine-1-carbonyl)-3-(trifluoromethyl)phenyl)benzamide; Compound 54: 3-(2-aminoquinazolin-6-yl)-4-methyl-N-(3-((4-methylpiperazin-1-yl)methyl)-5-(trifluoromethyl)phenyl)benzamide; Compound 55: 3-(2-aminoquinazolin-6-yl)-N-(4-chloro-3-(trifluoromethyl)phenyl)-4-methylbenzamide; Compound 56: 3-(2-aminoquinazolin-6-yl)-4-methyl-N-(4-((4-methylpiperazin-1-yl)methyl)phenyl)benzamide; Compound 57: 3-(2-aminoquinazolin-6-yl)-N-(3-fluoro-4-((4-methylpiperazin-1-yl)methyl)phenyl)-4-methylbenzamide; Compound 58: 4-(2-aminoquinazolin-6-yl)-N-(3-chloro-4-((4-methylpiperazin-1-yl)methyl)phenyl)-3-methylbenzamide; Compound 59: 3-(2-aminoquinazolin-6-yl)-N-(3-(difluoromethyl)-4-((4-methylpiperazin-1-yl)methyl)phenyl)-4-methylbenzamide; Compound 60: 3-(2-aminoquinazolin-6-yl)-4-methyl-N-(4-(4-methylpiperazin-1-yl)phenyl)benzamide; Compound 61: 3-(2-((4-fluorophenyl)amino)quinazolin-6-yl)-4-methyl-N-(4-((4-methylpiperazin-1-yl)methyl)phenyl)benzamide; Compound 62: 3-(2-((4-fluorophenyl)amino)quinazolin-6-yl)-4-methyl-N-(3-(trifluoromethyl)phenyl)benzamide; Compound 63: N-(3-(difluoromethyl)-4-((4-methylpiperazin-1-yl)methyl)phenyl)-3-(2-((4-fluorophenyl)amino)quinazolin-6-yl)-4-methylbenzamide; Compound 64: 3-(2-aminoquinazolin-6-yl)-N-(4-((dimethylamino)methyl)-3-(trifluoromethyl)phenyl)-4-methylbenzamide; Compound 65: 3-(2-aminoquinazolin-6-yl)-N-(4-((diethylamino)methyl)-3-(trifluoromethyl)phenyl)-4-methylbenzamide; Compound 66: N-(3-(2-aminoquinazolin-6-yl)-4-methylphenyl)-4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)benzamide; Compound 67: N-(3-(2-aminoquinazolin-6-yl)-4-methylphenyl)-3-fluoro-4-((4-methylpiperazin-1-yl)methyl)benzamide; Compound 68: 3-Fluoro-N-(3-(2-((4-fluorophenyl)amino)quinazolin-6-yl)-4-methylphenyl)-4-((4-methylpiperazin-1-yl)methyl)benzamide; Compound 69: tert-butyl 4-(4-((6-(5-(3-fluoro-4-((4-methylpiperazin-1-yl)methyl)benzamido)-2-methylphenyl)quinazolin-2-yl)amino)phenyl)piperazine-1-carboxylate; Compound 70: 3-fluoro-N-(4-methyl-3-(2-((4-(piperazin-1-yl)phenyl)amino)quinazolin-6-yl)phenyl)-4-((4-methylpiperazin-1-yl)methyl)benzamide; Compound 71: N-(4-methyl-3-(2-((4-(piperazin-1-yl)phenyl)amino)quinazolin-6-yl)phenyl)-4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)benzamide; Compound 72: N-(3-(2-((4-fluorophenyl)amino)quinazolin-6-yl)-4-methylphenyl)-4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)benzamide.

3. The ROR1-targeting inhibitor according to claim 1 or 2, characterized in that: The pharmaceutically acceptable salt of the amide compound is selected from the acid addition salt formed by the amide compound and an acid, and the acid is selected from: hydrogen chloride, hydrogen bromide, sulfuric acid, carbonic acid, oxalic acid, citric acid, succinic acid, tartaric acid, phosphoric acid, lactic acid, pyruvic acid, acetic acid, maleic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid or ferulic acid.

4. The method for synthesizing an inhibitor targeting ROR1 according to any one of claims 1 to 3, characterized in that: The reaction scheme of the inhibitor targeting ROR1 is as follows: Route 1: Synthesis of target compounds 1 to 6, The following steps are involved: 1) Compound 1a and 4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)aniline were reacted in the presence of N,N-diisopropylethylamine, 1-(hydroxy-7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate and N,N-dimethylformamide at room temperature for 12 h to obtain 1b; 2) Compound 1b and an alkynyl substituent are reacted at 80-100° C. for 12 h in the presence of triethylamine under the catalysis of bis(triphenylphosphine)palladium dichloride and cuprous iodide to obtain compounds 1-6; The alkynyl substituent comprises one of: N-(tert-butyloxycarbonyl)-4-ethynyl-3-pyridinecarboxamide, 5-ethynyl-2-aminopyridine, 6-ethynyl indole, 5-ethynyl-2,4-diaminopyrimidine, 6-ethynyl-1H-pyrazolo[3,4-b]pyridine and 6-ethynyl-1,2-dihydro-2-oxopyrazino[2,3-c]pyridazine; Route 2: Synthesis of target compounds 7-10, comprising the following steps: 1) Compound 7a and carboxylic acid are reacted in the presence of N,N-diisopropylethylamine, 1-hexafluorophosphate-7-azabenzotriazole and N,N-dimethylformamide at room temperature for 12 hours to obtain intermediate compound 7-10b; 2) hydrolyzing 7-10b under the action of lithium hydroxide to obtain 7-10c; 3) 7-10c and 4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)aniline were reacted in the presence of N,N-diisopropylethylamine, 1-hexafluorophosphate-7-azabenzotriazole and N,N-dimethylformamide at room temperature for 12 hours to obtain compounds 7-10; The carboxylic acid comprises: one of 2-picolinic acid, 3-picolinic acid, 4-amino-3-picolinic acid and 4-acetylamino-3-picolinic acid; Route 3: Synthesis of target compounds 11-18, comprising the following steps: 1) Compound 11a and 4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)aniline were reacted in the presence of N,N-diisopropylethylamine, 1-hexafluorophosphate-7-azabenzotriazole and N,N-dimethylformamide at room temperature for 12 hours to obtain compound 11b; 2) Reducing compound 11b in a hydrogen atmosphere with a palladium-carbon catalyst to obtain compound 11c; 3) Compound 11c was mixed with an aldehyde-substituted compound in tetrahydrofuran, and reacted at room temperature for 5 h under acidic conditions to obtain compounds 11 to 13; 4) Compounds 11 to 13 were reduced with sodium triacetoxyborohydride under acidic conditions to obtain compounds 14 to 18; The aldehyde substituted compound comprises one of pyridine-2-carboxaldehyde, pyridine-3-carboxaldehyde, indole-3-carboxaldehyde, 4-aminopyridine-3-carboxaldehyde and 5-indolecarboxaldehyde; Route 4: Synthesis of target compounds 19-32, comprising the following steps: 1) Compound 19a and 4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)aniline were reacted in the presence of N,N-diisopropylethylamine, 1-hexafluorophosphate-7-azabenzotriazole and N,N-dimethylformamide at room temperature for 12 hours to obtain compound 19b; 2) Compound 19b and a pinacol borate compound are reacted at 70-90° C. for 12 h in the presence of cesium carbonate and cesium fluoride under the catalysis of 1,1′-bis(diphenylphosphino)ferrocenepalladium dichloride to obtain compounds 19-32; The pinacol borate compounds include 2-quinoline pinacol borate, 6-amino-3-pyridazinyl pinacol borate, isoquinoline-5-pinacol borate, 1-indole pinacol borate, benzothiazole-6-pinacol borate, 1H-benzo[d]imidazole-5-pinacol borate, 1-methyl-1H-pyrrolo[2,3-b]pyridine-5-pinacol borate, 6-(1H-1 ,2,3-triazol-4-yl)pyridine-3-boric acid pinacol ester, 6-aminoquinoline-3-boric acid pinacol ester, 2-amino-4H-pyrrolo[2,3-b][1,4]oxazine-6-boric acid pinacol ester, benzoxazole-5-boric acid pinacol ester, 7-methyl-1H-indazole-5-boric acid pinacol ester and 6-amino-1,3-benzoxazole-5-boric acid pinacol ester; Route 5: Synthesis of target compounds 33-40, comprising the following steps: 1) Compound 33a and an amino-substituted compound are mixed in N,N-dimethylformamide and N,N-diisopropylethylamine, and reacted at 60-80° C. to obtain compounds 33-40b; 2) Compounds 33-40b and bis(pinacol)diboron are reacted at 80-900° C. in the presence of 1,1′-bis(diphenylphosphino)ferrocenepalladium dichloride and potassium acetate to obtain compounds 33-40c; 3) Compounds 33-40c and compound 19b were reacted at 70-90° C. for 12 h in the presence of cesium carbonate and cesium fluoride under the catalysis of 1,1'-bis(diphenylphosphino)ferrocenepalladium dichloride to obtain compounds 33-40; The amino-substituted compound comprises one of aniline, 2-methylaniline, 2-methoxyaniline, 3-fluoroaniline, 3-pyridinamine, N1-(4-aminophenyl)-N4,N4-dimethylpiperazine-1-carboxamide, N-(4-aminophenyl)piperazine and 3-methylaniline; Route 6: Synthesis of target compounds 41-47, comprising the following steps: 1) Compound 41a and an acid anhydride compound or an amine compound are mixed in N,N-dimethylformamide and N,N-diisopropylethylamine, and reacted at 60-80° C. to obtain compounds 41-47b; 2) reacting 41-47b with bis(pinacol)diboron in the presence of 1,1'-bis(diphenylphosphino)ferrocenepalladium dichloride and potassium acetate at 80-900° C. to obtain 41-47c; 3) Compounds 41-47c and compound 19b were reacted at 70-90° C. for 12 h in the presence of cesium carbonate and cesium fluoride under the catalysis of 1,1'-bis(diphenylphosphino)ferrocenepalladium dichloride to obtain compounds 41-47; The acid anhydride compound comprises acetic anhydride or cyclopropanecarboxylic anhydride; the amine compound comprises methylamine, aniline, 2-methoxyaniline, 3-fluoroaniline or 4-(4-aminophenyl)morpholine; Route 7: Synthesis of target compounds 48-65, comprising the following steps: 1) Compounds 48-65a and N-bromosuccinimide were dissolved in N,N-dimethylformamide, and reacted at 70°C for 12 hours under the catalysis of azobisisobutyronitrile to obtain compounds 49-65b; 2) Compounds 48-65b and different amine compounds were reacted in the presence of dichloromethane and N,N-diisopropylethylamine at room temperature for 5 hours to obtain compounds 48-65c; The amine compound comprises 2-methylimidazole, N-methylpiperazine, N-ethylpiperazine, piperazine, N-Boc-piperazine, dimethylamine or diethylamine; 3) Compounds 48-65c were reacted in the presence of palladium carbon and tetrahydrofuran at room temperature for 12 hours to obtain compounds 48-65d; 4) Compounds 48-65d and 3-iodo-4-methylbenzoic acid were reacted in the presence of N,N-diisopropylethylamine, 1-hexafluorophosphate-7-azabenzotriazole and N,N-dimethylformamide at room temperature for 12 hours to obtain compounds 48-65e; 5) Compounds 48-65e and a boronic acid pinacol ester substituted compound are reacted at 70-90° C. for 12 h in the presence of cesium carbonate and cesium fluoride under the catalysis of 1,1'-bis(diphenylphosphino)ferrocenepalladium dichloride to obtain compounds 48-65; The pinacol boronic acid ester substituted compound comprises 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinazolin-2-amine or N-(4-fluorophenyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinazolin-2-amine; Route 8: Synthesis of target compounds 66-72, comprising the following steps: 1) Compounds 66-72a and N-bromosuccinimide were dissolved in N,N-dimethylformamide, and reacted at 70°C for 12 hours in the presence of azobisisobutyronitrile as a catalyst to obtain compounds 66-72b; 2) Compounds 66-72b and N-methylpiperazine were reacted in the presence of dichloromethane and N,N-diisopropylethylamine at room temperature for 5 hours to obtain compounds 66-72c; 3) Compounds 66-72c were reacted in the presence of lithium hydroxide and methanol / water at room temperature for 2 hours to obtain compounds 66-72d; 4) Compounds 66-72d and 3-iodo-4-methylbenzoic acid were reacted in the presence of N,N-diisopropylethylamine, 1-hexafluorophosphate-7-azabenzotriazole and N,N-dimethylformamide at room temperature for 12 hours to obtain compounds 66-72e; 5) Compounds 66-72e and a boronic acid pinacol ester-substituted compound are reacted at 70-90° C. for 12 h in the presence of cesium carbonate and cesium fluoride under the catalysis of 1,1'-bis(diphenylphosphino)ferrocenepalladium dichloride to obtain compounds 66-72; The pinacol boronic acid ester substituted compound comprises 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinazolin-2-amine or N-(4-fluorophenyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinazolin-2-amine.

5. A pharmaceutical composition, characterized in that It comprises the amide compound or a pharmaceutically acceptable salt thereof as described in claim 1 or 2 and a pharmaceutically acceptable carrier.

6. The pharmaceutical composition according to claim 5, characterized in that The dosage form of the pharmaceutical composition includes tablets, capsules, powders, syrups, liquids, suspensions, lyophilized powder injections or injections.

7. Use of the ROR1 targeting inhibitor according to claim 1 or 2 in the preparation of a drug for treating breast cancer.

8. Use of the ROR1-targeting inhibitor according to claim 1 or 2 in the preparation of a medicament for treating or preventing a ROR1-mediated disease.

9. A combination drug, characterized in that: Comprising the amide compound, derivative or stereoisomer, prodrug, pharmaceutically acceptable salt, solvate or hydrate of the amide compound as claimed in claim 1 or 2, or the pharmaceutical composition as claimed in claim 5 for use in combination with another drug.

10. The combined drug according to claim 9, characterized in that: The combined drug treatment inhibits ROR1, thereby treating or preventing the occurrence and development of related diseases.

Images