WO2025223550A1 - Pyridine or pyrazine fused tricyclic compound, and pharmaceutical composition thereof and use thereof - Google Patents

Abstract

Provided in the present invention are a pyridine or pyrazine fused tricyclic compound having a structure as shown in formula (I), or a pharmaceutically acceptable salt thereof, a stereoisomer thereof, a prodrug molecule thereof, or a solvate thereof; and a pharmaceutical composition thereof and the use thereof. The compound provided by the present invention has a good inhibitory effect on an RIOK2 protein, also has a good inhibitory effect on proteins such as AXL, FLT3, m-TOR, PDGFRB and PI3K, and can inhibit the proliferation of various tumor cells with high activity. Moreover, the compound has good pharmacokinetic properties, good cellular and in vivo activities, and high bioavailability. Therefore, the compound is expected to become a small-molecule anti-tumor drug with development prospects.

Description

Pyridine or pyrazine tricyclic compounds and their pharmaceutical compositions and applications

This invention claims priority to Chinese Patent Application No. 2024105153505, filed on April 26, 2024, entitled "Pyridine or pyrazine tricyclic compounds and pharmaceutical compositions and applications thereof", the entire contents of which are incorporated herein by reference.

Technical Field

This invention relates to the field of medicinal chemistry, and more particularly to pyridine or pyrazine tricyclic compounds, their pharmaceutical compositions, and applications.

Background Technology

Malignant tumors (cancer) are a major malignant disease threatening human health. Conventional treatments for cancer include radiotherapy, chemotherapy, surgical resection, and drug therapy. However, these methods often have drawbacks such as significant side effects, unsatisfactory treatment outcomes, and problems with tumor prognosis, recurrence, and metastasis. Therefore, there is an urgent need to develop new treatment technologies to address these issues in cancer treatment. Personalized treatment and targeted therapy have been seen in recent years as the hope for breaking through the current bottlenecks in cancer treatment.

Molecular targeted therapy for tumors is a novel treatment approach developed by regulating key signaling pathways closely related to tumor growth through chemical or biological means. Targeted small molecule drugs are characterized by high specificity, strong selectivity, and relatively mild toxicity; they can be used alone or in combination with existing drugs for cancer treatment. Since the application of small molecule targeted drugs, represented by imatinib mesylate (Novartis), in 2001, tumor targeted therapy has developed rapidly over the past two decades. Currently, dozens of protein kinase small molecule targeted drugs are on the market, becoming an important class of drugs in cancer treatment and ushering in a new era for tumor chemotherapy.

RIOK2 is a pseudokinase highly expressed in various tumors, including gastric cancer, colon cancer, melanoma, glioblastoma, and non-small cell lung cancer, and is directly related to tumor progression. Heterocyclic structures, as "life-saving agents," are core structures in many drug molecules. Developing anti-tumor drugs based on novel heterocyclic structures is an important direction in drug development. In previous work, the inventors of this invention synthesized and constructed a series of distinctive fused-heterocyclic/chiral heterocyclic small molecule libraries, screened for novel lead compounds, and further obtained a highly active and selective RIOK2 (Right Open Reading Frame Kinase 2) inhibitor, the triazoloquinone compound CQ211, through derivatization and optimization. However, this compound has poor solubility in water and organic solvents, and its pharmacokinetic properties and in vivo activity are not ideal, lacking good drug-likeness. Therefore, there is an urgent need to develop new small molecule targeted drugs with better drug-likeness and good in vitro and in vivo activity.

Summary of the Invention

To address the aforementioned problems, this invention provides a pyridine or pyrazine tricyclic compound that exhibits good inhibitory activity against RIOK2 protein, can highly inhibit the proliferation of various tumor cells, and possesses good pharmacokinetic properties.

The present invention includes the following technical solutions.

Pyridine or pyrazine tricyclic compounds having the structure shown in formula (I), or their pharmaceutically acceptable salts, or their stereoisomers, or their prodrug molecules, or their solvates:

In this context, A and B are independently selected from N and C, respectively, and D and E are independently selected from N, NR ₅ , and CR ₆ , respectively. The circular dashed lines in the rings containing A, B, D, and E indicate that each pair of adjacent ring atoms in the ring is connected by a single or double bond to obtain a chemically stable structure.

_X1 , _X2 , and _X3 are independently selected from: N and _CR7 , respectively;

_X4 and _X5 are independently selected from: N and _CR8 , respectively;

R is selected from: one or more _R2- substituted or unsubstituted 5- to 10-membered heteroaryl groups, or one or more _R2- substituted or unsubstituted _C6- to _C10 aryl groups;

_R1 is selected from: H, _C1 - _C18 alkoxy, _C1 - _C18 haloalkoxy, _C3 - _C8 cycloalkyloxy;

_R2 is selected from: H, halogen, _C1 - _C18 alkyl, halogen-substituted C1- _C18 alkyl, _C3 - _C18 cycloalkyl, 3-18 membered heterocyclic alkyl, _C1 - _C18 alkoxy, _C3 - _C8 cycloalkyloxy, _C1 - _C18 alkylamino, ( _{C1 - C18 alkyl)2amino, C3-C8 cycloalkylamino, amino, hydroxyl, cyano, nitro, carboxyl, C1-C18 alkoxycarbonyl, C1-C18 alkyl ester , C1 - C18 alkyl acyl} , _C1 - _C18 alkylamide, _{C1 - C18} alkylsulfonyl, _C1 - _C18 alkylsulfonylamino, _C6 - _C18 aryl, 5-18 membered heteroaryl;

_R3 and _R4 are each independently selected from: H, R9 _- substituted or unsubstituted _C1 - _C18 alkyl, R9-substituted or unsubstituted _C3 - _C8 cycloalkyl, _R9- substituted or unsubstituted 3-18 membered heterocyclic alkyl, _C1 - _C8 alkylacyl, _C2 - _C8 alkenylacyl, _C1 - _C18 alkylsulfonyl, _{R9 -} substituted or unsubstituted 5-18 membered heteroaryl; or _R3 , _R4 and the N atom attached thereto form one or more _R9- substituted or unsubstituted 3-18 membered heterocyclic groups or heterocyclic ketone groups;

Each _R5 is independently selected from: H, _C1 - _C6 alkyl, _C3 - _C8 cycloalkyl, and 3-8 membered heterocyclic alkyl;

Each _R6 is independently selected from: H, hydroxyl, amino, cyano, nitro, halogen, _C1 - _C6 alkoxy, _C1 - _C6 alkyl, _C1 - _C6 alkylamino, ( _C1 - _C6 alkyl) _2amino , _C3 - _C8 cycloalkyl, _C3 - _C8 cycloalkyloxy, _C3 - _C8 cycloalkylamino;

Each _R7 is independently selected from: H, hydroxyl, amino, cyano, nitro, carboxyl, halogen, _C1 - _C6 alkoxy, _C1 - _C6 alkyl, _C1 - _C6 alkylamino, ( _C1 -C6 _alkyl ) _2amino , _C3 - _C8 cycloalkyl, _C3 - _C8 cycloalkyloxy, _C3 - _C8 cycloalkylamino;

Each _R8 is independently selected from: H, hydroxyl, amino, cyano, nitro, carboxyl, halogen, _C1 - _C6 alkoxy, _C1 - _C6 alkyl, halogen-substituted _C1 - _C6 alkyl, _C1 - _C6 alkylamino, ( _C1 - _C6 alkyl) _2amino , _C3 - _C8 cycloalkyl, _C3 - _C8 cycloalkyloxy, _C3 - _C8 cycloalkylamino;

Each _R9 is independently selected from: H, hydroxyl, amino, cyano, nitro, _carboxyl , halogen, _C1 -C6 alkoxy, _R14 substituted or unsubstituted _C1 - _C6 alkyl, _C1 - _C6 alkylamino, ( _C1 - _C6 alkyl) _2amino , R' substituted or unsubstituted _C3 - _C8 cycloalkyl, R' substituted or unsubstituted 3-8 membered heterocyclic group, _C3 - _C8 cycloalkyloxy, _C3 - _C8 cycloalkylamino, _C1 - _C6 alkylacyl, -N( _R11 ) ₂ ;

Each R' is independently selected from: H, hydroxyl, amino, cyano, nitro, carboxyl, _halogen , _C1 -C6 alkoxy, _C1 - _C6 alkyl, halogen-substituted _C1 - _C6 alkyl, _C1 - _C6 alkylamino, ( _C1 - _C6 alkyl) _2amino ;

_R11 is independently selected from: H, _R14 substituted or unsubstituted _C1 - _C6 alkyl, _C3 - _C8 cycloalkyl, _C1 - _C6 alkylacyl;

_R14 is selected from: H, _C1 - _C6 alkoxy, halogen, _C1 - _C6 alkylamino, ( _C1 - _C6 alkyl) _2amino , R' substituted or unsubstituted 3- to 8-membered heterocyclic alkyl.

In some embodiments, A and B are independently selected from N and C, respectively, and D and E are independently selected from N and _CR6 , respectively, and the ring containing A, B, D and E is a heteroaromatic ring.

In some embodiments, the pyridine or pyrazine tricyclic compound has the structure shown in formula (II-1) or formula (II-2):

D and E are independently selected from: N and CR ₆ , respectively.

In some embodiments, the pyridine or pyrazine tricyclic compound has the structure shown in formula (III-1), (III-2), (III-3), (III-4), (III-5), or (III-6):

In some of these embodiments, R is selected from: one or more _R2- substituted or unsubstituted phenyl groups, one or more _R2- substituted or unsubstituted naphthyl groups, one or more _R2- substituted or unsubstituted pyridyl groups, one or more _R2- substituted or unsubstituted pyrimidinyl groups, one or more _R2- substituted or unsubstituted pyrazinyl groups, one or more _R2- substituted or unsubstituted pyridazinyl groups, one or more _R2- substituted or unsubstituted indolyl groups, and one or more _R2- substituted or unsubstituted pyrrolopyridyl groups.

In some embodiments, R is selected from:

Among them, _X6 and _X7 are independently selected from: N and _CR10 , respectively;

Each R ₁₀ is independently selected from: H, hydroxyl, amino, cyano, nitro, _carboxyl , halogen, _C1 - _C6 alkoxy, _C1 - _C6 alkyl, halogen-substituted _C1 - _C6 alkyl, _C1 -C6 alkylamino, _{( C1} - _C6 alkyl) _2amino , _C3 - _C8 cycloalkyl, C3- _C8 cycloalkyloxy, _C3 - _C8 cycloalkylamino.

In some embodiments, _R2 is selected from: H, halogen, _C1 - _C6 alkyl, halogen-substituted _C1 - _C6 alkyl, _C3 - _C8 cycloalkyl, 3-8 membered _heterocyclic alkyl, _C1 - _C6 alkoxy, _C3 - _C8 cycloalkyloxy, C1- _C8 alkylamino, ( _C1 - _C8 alkyl) _2amino , _C3 - _C8 cycloalkylamino, amino, hydroxyl, cyano, nitro, carboxyl, _C1 - _C8 alkoxycarbonyl, _C1 - _C8 alkyl ester, _C1 - _C8 alkyl acyl, _C1 - _C8 alkylamide, _C1 - _C8 alkylsulfonyl, _C1 - _C8 alkylsulfonamide, _C6 - _C10 aryl, 5-10 membered heteroaryl.

In some embodiments, _R2 is selected from: H, halogen, _C1 - _C3 alkyl, halogen-substituted _C1 - _C3 alkyl, _C3 - _C6 cycloalkyl, _4-6 membered _heterocyclic alkyl, _C1 -C3 alkoxy, _C3 - _C6 cycloalkyloxy, _C1 - _C3 alkylamino, (C1- _C3 alkyl) _2amino , _C3 - _C6 cycloalkylamino, amino, hydroxyl, cyano, nitro, carboxyl, _C1 - _C3 alkoxycarbonyl, _C1 - _C3 alkyl ester, _C1 - _C3 alkyl acyl, _C1 - _C3 alkylamide, _C1 - _C3 alkylsulfonyl, _C1 - _C3 alkylsulfonylamino, phenyl, 5-6 membered heteroaryl.

In some of these embodiments, _R2 is selected from: H, fluorine, chlorine, bromine, methyl, ethyl, propyl, methoxy, ethoxy, propoxy, and amino.

In some embodiments, each R ₁₀ is independently selected from: H, hydroxyl, amino, cyano, nitro, carboxyl, halogen, _C1 - _C3 alkoxy, _C1 - _{C3 alkyl, halogen-substituted C1-C3 alkyl , C1} - _C3 alkylamino, ( _C1 - _{C3 alkyl} ) _2amino , C3- _C6 cycloalkyl, _C3 - _C6 cycloalkyloxy, _C3 - _C6 cycloalkylamino.

In some of these embodiments, each R ₁₀ is independently selected from: H, cyano, fluorine, chlorine, bromine, methyl, ethyl, propyl, trifluoromethyl, methoxy, ethoxy, difluoromethyl, monofluoromethyl, and trifluoroethyl.

In some embodiments, R is selected from the following groups:

In some of these embodiments, _R1 is not hydrogen;

R ₂ is selected from: methoxy, ethoxy, propoxy, amino, fluorine, chlorine, bromine;

Each R ₁₀ is independently selected from: H, cyano, fluorine, chlorine, bromine, methyl, ethyl, propyl, trifluoromethyl, methoxy, ethoxy, difluoromethyl, monofluoromethyl, trifluoroethyl;

Preferably, R is selected from the following groups:

In some of these embodiments, _R1 is hydrogen;

R ₂ is selected from: H, fluorine, chlorine, bromine, methyl, ethyl, propyl, methoxy, ethoxy, propoxy, amino;

Each R ₁₀ is independently selected from: H, cyano, fluorine, chlorine, bromine, methyl, ethyl, propyl, trifluoromethyl, methoxy, ethoxy, difluoromethyl, monofluoromethyl, trifluoroethyl;

Preferably, R is selected from the following groups:

In some embodiments, _X7 is selected from N and CH; _X6 is selected from N and _CR10 .

In some of these embodiments, at least one of _X6 and _X7 is N.

In some of these embodiments, _X1 , _X2 , and _X3 are each independently selected from: _CR7 ; and each _R7 is independently selected from: H, fluorine, chlorine, bromine, methyl, ethyl, methoxy, ethoxy, and dimethylamino.

In some of these embodiments, _X4 and _X5 are each independently selected from: _CR8 ; each _R8 is independently selected from: H, fluorine, chlorine, bromine, methyl, ethyl, propyl, methoxy, ethoxy, propoxy, dimethylamino, trifluoromethyl, difluoromethyl.

In some embodiments, _X4 is CH; _X5 is _CR8 , and _R8 is selected from: H, fluorine, chlorine, methyl, methoxy, trifluoromethyl.

In some of these embodiments, _R1 is not hydrogen; _X4 is CH; _X5 is _CR8 , and _R8 is selected from trifluoromethyl or difluoromethyl.

In some of these embodiments, _R1 is hydrogen; _X4 is CH; _X5 is _CR8 ; and _R8 is selected from: H, fluorine, chlorine, bromine, methyl, ethyl, propyl, methoxy, ethoxy, propoxy, dimethylamino, trifluoromethyl, and difluoromethyl.

In some of these embodiments, _R1 is selected from: H, _C1 - _C6 alkoxy, _C1 - _C6 haloalkoxy, _C3 - _C6 cycloalkyloxy.

In some of these embodiments, _R1 is selected from: H, _C1 - _C3 alkoxy, _C1 - _C3 fluoroalkoxy, and _C3 - _C6 cycloalkyloxy.

In some of these embodiments, _R1 is selected from: H, methoxy, ethoxy, cyclopropoxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy, isopropoxy, and n-propoxy.

In some of these embodiments, _R1 is selected from H, methoxy, and ethoxy.

In some embodiments, each _R6 is independently selected from: H, hydroxyl, amino, cyano, nitro, halogen, C1- _C3 alkoxy, _C1 - _C3 alkyl, _C1 - _C3 alkylamino, ( _C1 - _{C3 alkyl} ) _2amino , _C3 - _C6 cycloalkyl, _C3 - _C6 cycloalkyloxy, _C3 - _C6 cycloalkylamino.

In some of these embodiments, each _R6 is independently selected from: H, halogen, methoxy, ethoxy, propoxy, methyl, ethyl, propyl.

In some embodiments, _R3 and _R4 are each independently selected from: H, _R9- substituted or unsubstituted _C1 - _C6 alkyl, _R9- substituted or unsubstituted _C3 - _C8 cycloalkyl, _R9- substituted or unsubstituted 3-8 membered heterocyclic alkyl, _C1 - _C6 alkylacyl, _C2 - _C6 alkenylacyl, _C1 - _C6 alkylsulfonyl, _R9- substituted or unsubstituted 5-8 membered heteroaryl; or _R3 , _R4 and the N atom attached thereto form one or more _R9- substituted or unsubstituted 3-8 membered heterocyclic groups or heterocyclic ketone groups.

In some embodiments, each _R9 is independently selected from: H, hydroxyl, amino, cyano, nitro, carboxyl, halogen, _C1 - _C6 alkoxy, _R14 substituted or unsubstituted _C1 - _C6 alkyl, _C1 - _C3 alkylamino, ( _C1 - _C3 alkyl) _2amino , R' substituted or unsubstituted _C3 - _C8 cycloalkyl, R' substituted or unsubstituted 3-8 membered heterocyclic group, C3- _C8 cycloalkyloxy, _C3 - _C8 cycloalkylamino, _{C1 - C6} alkylacyl, -N( _R11 ) ₂ ;

R' is selected from: H, hydroxyl, amino, cyano, nitro, carboxyl, halogen, _C1 - _C3 alkoxy, _C1 - _C3 alkyl, halogen-substituted _C1 - _C3 alkyl, _C1 - _C3 alkylamino, ( _C1 - _C3 alkyl) _2amino ;

_R11 is independently selected from: H, _R14 substituted or unsubstituted _C1 - _C6 alkyl, _C3 - _C8 cycloalkyl, _C1 - _C6 alkylacyl;

_R14 is selected from: H, _C1 - _C6 alkoxy, halogen, _C1 - _C6 alkylamino, ( _C1 - _C6 alkyl) _2amino , R' substituted or unsubstituted 5- to 6-membered heterocyclic alkyl.

In some embodiments, _R3 and _R4 are each independently selected from: H, _R9- substituted or unsubstituted _C1 - _C3 alkyl, _R9- substituted or unsubstituted _C3 - _C6 cycloalkyl, and _R9- substituted or unsubstituted 4-6 membered heterocyclic alkyl;

Alternatively, _R3 , _R4 , and the N atom bonded to them together form the following structure:

Where each n is independently selected from: 0, 1, 2, or 3;

Each m is independently selected from: 0, 1, 2, or 3;

Z is selected from: -O-, -NR _11- , or -C(R ₁₂ R ₁₃ )-;

_R11 is independently selected from: H, _R14 substituted or unsubstituted _C1 - _C6 alkyl, _C3 - _C8 cycloalkyl, _C1 - _C6 alkylacyl;

_R12 and _R13 are independently selected from: H, _C1 - _C6 alkyl, _C1 - _C6 alkoxy, R'-substituted or unsubstituted _C3 - _C8 cycloalkyl, R'-substituted or unsubstituted 3-8 membered heterocyclic alkyl, -N( _R11 ) ₂ ;

_R14 is selected from: H, _C1 - _C6 alkoxy, _C1 - _C6 alkylamino, ( _C1 - _C6 alkyl) _2amino , R' substituted or unsubstituted 5- to 6-membered heterocyclic alkyl.

In some of these embodiments, _R3 is selected from: hydrogen, methyl, ethyl; _R4 is selected from: dimethylamino-substituted methyl, dimethylamino-substituted ethyl, methylamino-substituted methyl, methylamino-substituted ethyl, 5-membered nitrogen-containing heterocyclic group, 6-membered nitrogen-containing heterocyclic group;

Alternatively, _R3 , _R4 , and the N atom bonded to them together form the following structure:

In some of these embodiments, n is selected from: 0, 1, 2, or 3;

m is selected from: 0, 1, 2, or 3;

Z is selected from: -O-, -NR _11- , or -C(R ₁₂ R ₁₃ )-;

Each _R9 is independently selected from: H, _C1 - _C3 alkoxy, _C1 - _C3 alkyl, halogen-substituted _C1 - _C3 alkyl, dimethylamino, methylamino;

R' is selected from: H, _C1 - _C3 alkoxy, _C1 - _C3 alkyl, halogen-substituted _C1 - _C3 alkyl, dimethylamino, methylamino;

Each _R11 is independently selected from: H, _R14 substituted or unsubstituted _C1 to _C3 alkyl groups;

_R12 and _R13 are each independently selected from: H, _C1 - _C3 alkoxy, _C1 - _C3 alkyl, R'-substituted or unsubstituted 5-6 membered heterocyclic alkyl, -N( _R11 ) ₂ ;

_R14 is selected from: H, _C1 - _C3 alkoxy, amino, dimethylamino, methylamino, R'-substituted or unsubstituted 6-membered heterocyclic alkyl.

In some embodiments, _R3 , _R4, and the N atom attached thereto form the following structure:

In some embodiments, the pyridine or pyrazine tricyclic compound has the structure shown in formula (III-2):

_R3 , _R4 , and the N atom bonded to them together form the following structure:

In some embodiments, the pyridine or pyrazine tricyclic compound has the structure shown in formula (III-3):

_R3 , _R4 , and the N atom bonded to them together form the following structure:

In some embodiments, the pyridine or pyrazine tricyclic compound has the structure shown in formula (IV):

The present invention also provides the application of the pyridine or pyrazine tricyclic compound, or its pharmaceutically acceptable salt, or its stereoisomer, or its prodrug molecule, or its solvate, including the following technical solutions.

The use of the pyridine or pyrazine tricyclic compound, or its pharmaceutically acceptable salt, or its stereoisomer, or its prodrug molecule, or its solvate, as described in this invention, in the preparation of RIOK2 inhibitors.

The use of the pyridine or pyrazine tricyclic compound, or its pharmaceutically acceptable salt, or its stereoisomer, or its prodrug molecule, or its solvate, as described in this invention, in the preparation of medicaments for the prevention and/or treatment of diseases associated with high RIOK2 expression.

The use of the pyridine or pyrazine tricyclic compound, or its pharmaceutically acceptable salt, or its stereoisomer, or its prodrug molecule, or its solvate, as described in this invention, in the preparation of medicaments for the prevention and/or treatment of tumors.

In some embodiments, the tumor is a tumor associated with high RIOK2 expression.

In some embodiments, the tumor is: non-small cell lung cancer, small cell lung cancer, lung adenocarcinoma, lung squamous cell carcinoma, pancreatic cancer, breast cancer, prostate cancer, liver cancer, skin cancer, epithelial cell carcinoma, gastrointestinal stromal tumor, leukemia, histiocytic lymphoma, diffuse large B-cell lymphoma, nasopharyngeal carcinoma, glioma, osteosarcoma, gastric cancer, squamous cell carcinoma of the skin, ovarian cancer, colorectal adenocarcinoma.

The present invention also provides a pharmaceutical composition for treating and/or preventing tumors, comprising the following technical solutions.

A pharmaceutical composition for treating and/or preventing tumors, prepared from an active ingredient and pharmaceutically acceptable excipients, said active ingredient comprising pyridine or pyrazine tricyclic compounds as described in this invention, or pharmaceutically acceptable salts of such compounds, or stereoisomers thereof, or prodrug molecules thereof, or solvates thereof.

The present invention also provides a method for treating and/or preventing tumors, comprising: administering to a subject or patient a safe and effective amount of the pyridine or pyrazine tricyclic compound of the present invention, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a prodrug molecule thereof, or a solvate thereof; or administering to a subject or patient a safe and effective amount of the pharmaceutical composition of the present invention.

In some embodiments, the tumor is: non-small cell lung cancer, small cell lung cancer, lung adenocarcinoma, lung squamous cell carcinoma, pancreatic cancer, breast cancer, prostate cancer, liver cancer, skin cancer, epithelial cell carcinoma, gastrointestinal stromal tumor, leukemia, histiocytic lymphoma, diffuse large B-cell lymphoma, nasopharyngeal carcinoma, glioma, osteosarcoma, gastric cancer, squamous cell carcinoma of the skin, ovarian cancer, colorectal adenocarcinoma.

The pyridine or pyrazine tricyclic compound, or its pharmaceutically acceptable salt, or its stereoisomer, or its prodrug molecule, or its solvate provided by this invention has good solubility, good inhibitory effect on RIOK2 protein, and also good inhibitory effect on AXL, FLT3, m-TOR, PDGFRB, PI3K and other proteins. It can highly inhibit the proliferation of various tumor cells, and has good pharmacokinetic properties, good cellular and in vivo activity, and high bioavailability, and is expected to become a promising small molecule anti-tumor drug.

Attached Figure Description

Figure 1 shows the in vivo efficacy of compound CQ-3196 on HGC-27 xenograft model mice; where A is a line graph of tumor volume, B is a line graph of mouse weight change, C is an anatomical image of the xenograft tumor in mice, and D is a scatter plot of tumor weight; compared with the model control group, the significant difference is indicated by **p<0.01.

Figure 2 shows the effect of compound CQ-3196 on colony formation in HGC-27 and AGS cells; where A and B represent the effect of compound CQ3196 (14 days) on colony formation in HGC-27 cells, and C and D represent the effect of compound CQ3196 (14 days) on colony formation in AGS cells; significance compared with the control group is expressed as p<0.001.

Figure 3 shows the effect of compound CQ3196 on cell adhesion in HGC-27 and AGS cells; where A represents the effect of compound CQ3196 (4h) on the adhesion of HGC-27 cells and B represents the effect of compound CQ3196 (4h) on the adhesion of AGS cells; significance compared with the control group is expressed as p<0.001.

Figure 4 shows the results of apoptosis induced by compound CQ3196 in HGC-27 and AGS cells; where A and B represent the effects of compound CQ3196 (48h) on apoptosis of HGC-27 cells, and C and D represent the effects of compound CQ3196 (48h) on apoptosis of AGS cells; compared with the control group, significance is indicated by **p<0.05.

Detailed Implementation

In the compounds of this invention, when any variable (e.g., ^R8 , ^R9 , etc.) appears more than once in any component, the definition of each occurrence is independent of the definitions of other occurrences. Similarly, combinations of substituents and variables are permitted, provided such combinations stabilize the compound. Lines drawn from a substituent into the ring system indicate that the bond referred to can be attached to any substituted ring atom. If the ring system is polycyclic, it means that such a bond is attached only to any suitable carbon atom of a neighboring ring. It will be understood that those skilled in the art can select the substituents and substitution patterns of the compounds of this invention to provide chemically stable compounds that can be readily synthesized from readily available starting materials using techniques in the art and the methods described below. If a substituent is itself substituted by more than one group, it should be understood that these groups can be on the same carbon atom or different carbon atoms, as long as structural stability is achieved.

As used herein, the term "alkyl" refers to both branched and straight-chain saturated aliphatic hydrocarbon groups having a specific number of carbon atoms. For example, the definition of " _C1 - _C6 " in " _C1 - _C6 alkyl" includes groups having 1, 2, 3, 4, 5, or 6 carbon atoms arranged in a straight or branched chain. Specifically, " _C1 - _C6 alkyl" includes methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, pentyl, and hexyl.

As used herein, the term "cycloalkyl" refers to a monocyclic, bicyclic, or polycyclic cyclic hydrocarbon group whose ring atoms are composed of carbon atoms and are saturated or partially unsaturated. Bicyclic or polycyclic groups include spirocyclic, fused, and bridged rings. For example, "cycloalkyl" includes, but is not limited to, the following groups: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc. wait.

The term "alkoxy" as used in this article refers to a group having an -O-alkyl structure, such as -OCH ₃ , -OCH ₂ CH ₃ , -OCH ₂ CH ₂ CH ₃ , -O-CH ₂ CH(CH ₃ ) ₂ , -OCH ₂ CH ₂ CH ₂ CH ₃ , -O-CH(CH ₃ ) ₂ , etc.

As used herein, the terms "heterocyclic alkyl" or "heterocyclic group" refer to saturated or partially unsaturated monocyclic, bicyclic, or polycyclic cyclic substituents (including spirocyclic, bridged, fused, and fused rings, etc.), wherein one or more ring atoms are selected from N, O, or S(O)m (where m is an integer from 0 to 2), and the remaining ring atoms are carbon. Examples include: morpholinyl, piperidinyl, tetrahydropyrrolyl, pyrrolylalkyl, dihydroimidazolyl, dihydroisoxazolyl, dihydroisothiazolyl, dihydrooxadiazolyl, dihydrooxazolyl, dihydropyrazinyl, dihydropyrazoleyl, dihydropyridinyl, dihydropyrimidinyl, dihydropyrrolyl, dihydrotetrazolyl, dihydrothiadiazolyl, dihydrothiazolyl, dihydrothiophene, dihydrotriazolyl, dihydroazacyclobutane, tetrahydrofuranyl, tetrahydrothiophene, etc. And so on, and their N-oxides. The connection of heterocyclic substituents can be achieved through carbon atoms or through heteroatoms.

As used herein, the term "heterocyclic ketone" refers to a saturated or partially unsaturated monocyclic, bicyclic, or polycyclic cyclic substituent (including spirocyclic, bridged, fused, and fused rings), wherein one or more ring atoms are selected from N, O, or S(O)m (where m is an integer from 0 to 2), and the remaining ring atoms are carbon or C=O, and at least one C=O is present. Examples include: azirrobutanone, azirropentanone, morpholinone, piperidinone, tetrahydropyrrolone, piperazinone, and their N-oxides. The linkage of heterocyclic ketone substituents can be achieved through carbon atoms or through heteroatoms.

As used herein, the term "heteroaryl" refers to an aromatic ring containing one or more heteroatoms selected from O, N, or S. This aromatic ring can be monocyclic, bicyclic, or polycyclic, and includes, but is not limited to: quinolinyl, pyrazolyl, pyrroloyl, thiophenyl, furanyl, pyridyl, pyrimidinyl, pyrazinyl, triazolyl, imidazolyl, oxazolyl, isoxazolyl, pyridazinyl, etc. "Heteroaryl" is also understood to include any N-oxide derivative of a nitrogen-containing heteroaryl group. The linkage of heteroaryl groups can be achieved through carbon atoms or through heteroatoms.

As will be understood by those skilled in the art, the term “halo” or “halogen” as used herein refers to chlorine, fluorine, bromine, and iodine.

This invention includes the free forms of compounds of formulas I-IV, as well as their pharmaceutically acceptable salts and stereoisomers. Some specific exemplary compounds described herein are protonated salts of amine compounds. The term "free form" refers to an amine compound in its non-salt form. Pharmaceutically acceptable salts include not only exemplary salts of the specific compounds described herein, but also typical pharmaceutically acceptable salts of the free forms of all compounds of formulas I-IV. The free forms of specific salts of said compounds can be separated using techniques known in the art. For example, the free form can be regenerated by treating the salt with a suitable dilute aqueous solution of a base, such as dilute aqueous solution of NaOH, potassium carbonate, dilute ammonia, or sodium bicarbonate. The free form may differ somewhat from its respective salt form in certain physical properties, such as solubility in polar solvents, but for the purposes of this invention, such acid salts and base salts are otherwise pharmaceutically equivalent to their respective free forms.

Pharmaceutically acceptable salts of the present invention can be synthesized from compounds of the present invention containing either a basic or acidic moiety using conventional chemical methods. Typically, salts of basic compounds are prepared by ion-exchange chromatography or by reacting a free base with a stoichiometric or excess amount of the desired salt form of an inorganic or organic acid in a suitable solvent or a combination of solvents. Similarly, salts of acidic compounds are formed by reacting with a suitable inorganic or organic base.

Therefore, pharmaceutically acceptable salts of the compounds of the present invention include conventional non-toxic salts of the compounds of the present invention formed by reacting an alkaline compound of the present invention with an inorganic or organic acid. For example, conventional non-toxic salts include salts derived from inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, aminosulfonic acid, phosphoric acid, nitric acid, etc., and also include salts prepared from organic acids such as acetic acid, propionic acid, succinic acid, glycolic acid, stearic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, pyric acid, maleic acid, hydroxymaleic acid, phenylacetic acid, glutamic acid, benzoic acid, salicylic acid, p-aminobenzenesulfonic acid, 2-acetoxybenzoic acid, fumaric acid, toluenesulfonic acid, methanesulfonic acid, ethanedisulfonic acid, oxalic acid, hydroxyethylsulfonic acid, trifluoroacetic acid, etc.

If the compounds of this invention are acidic, then a suitable "pharmaceutically acceptable salt" refers to a salt prepared from a pharmaceutically acceptable non-toxic alkali, including inorganic and organic bases. Salts derived from inorganic bases include aluminum salts, ammonium salts, calcium salts, copper salts, iron salts, ferrous salts, lithium salts, magnesium salts, manganese salts, manganese salts, potassium salts, sodium salts, zinc salts, etc. Ammonium salts, calcium salts, magnesium salts, potassium salts, and sodium salts are particularly preferred. Salts derived from pharmaceutically acceptable organic non-toxic bases, including salts of primary, secondary, and tertiary amines, wherein substituted amines include naturally occurring substituted amines, cyclic amines, and basic ion exchange resins such as arginine, betaine, caffeine, choline, N,N'-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, aminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucosamine, glucosamine, histidine, hydroxycobalamin, isopropylamine, lysine, methylglucosamine, morpholine, piperazine, piperidine, guanidine, polyamine resins, procaine, purine, theobromine, triethylamine, trimethylamine, tripropylamine, aminobutanetriol, etc.

Berg et al., “Pharmaceutical Salts,” J. Pharm. Sci.’ 1977: 66: 1–19, describe in more detail the preparation of the pharmaceutically acceptable salts described above and other typical pharmaceutically acceptable salts.

Since the deprotonated acidic portion of the compound, such as the carboxyl group, can be anionic under physiological conditions, and this charge can then be balanced by the protonated or alkylated basic portion, such as the tetravalent nitrogen atom, which carries a cation, it should be noted that the compounds of the present invention are potential internal salts or zwitterions.

In one embodiment, the present invention provides a method for treating hyperproliferative diseases or symptoms such as tumors in humans or other mammals using compounds having formulas I-IV and their pharmaceutically acceptable salts.

In one embodiment, the compounds of the present invention and their pharmaceutically acceptable salts can be used to treat or control overgrown proliferative diseases such as non-small cell lung cancer, small cell lung cancer, lung adenocarcinoma, lung squamous cell carcinoma, pancreatic cancer, breast cancer, prostate cancer, liver cancer, skin cancer, epithelial cell carcinoma, gastrointestinal stromal tumor, leukemia, histiocytic lymphoma, diffuse large B-cell lymphoma, nasopharyngeal carcinoma, glioma, osteosarcoma, gastric cancer, squamous cell carcinoma of the skin, and ovarian cancer.

The pharmaceutical composition or method for the prevention and/or treatment of tumors provided by this invention comprises (administered to a patient or subject) an active ingredient (i.e., the pyridine or pyrazine tricyclic compound described in this invention, or its pharmaceutically acceptable salt, stereoisomer, prodrug molecule, or solvate), and pharmaceutically acceptable excipients, within a safe and effective range, and wherein the active ingredient is administered to the mammal (such as a human) requiring treatment, wherein the dose administered is a pharmaceutically considered effective dose. Of course, the specific dose should also consider factors such as the route of administration and the patient's health condition, which are all within the scope of a skilled physician's expertise.

The "active ingredient" referred to in this invention refers to the compounds of formulas I-IV described in this invention, or their pharmaceutically acceptable salts or their stereoisomers.

The "active ingredient" and pharmaceutical composition described in this invention can be used to prepare drugs for the prevention and/or treatment of tumors.

"Safe and effective dose" means that the amount of active ingredient is sufficient to significantly improve the condition without causing serious side effects.

"Pharmaceutical acceptable excipients" refer to one or more compatible solid or liquid fillers or gelling substances that are suitable for human use and must have sufficient purity and sufficiently low toxicity.

"Compatibility" here refers to the ability of the components in the composition to interact with and blend with the active ingredients of the present invention without significantly reducing the efficacy of the active ingredients.

Pharmaceutically acceptable examples of excipients include cellulose and its derivatives (such as sodium carboxymethyl cellulose, sodium ethyl cellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (such as stearic acid, magnesium stearate), calcium sulfate, vegetable oils (such as soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (such as propylene glycol, glycerin, mannitol, sorbitol, etc.), and emulsifiers (such as...). Wetting agents (such as sodium dodecyl sulfate), colorants, flavoring agents, stabilizers, antioxidants, preservatives, pyrogen-free water, etc.

In another preferred embodiment, the compounds of formulas I-IV of the present invention can form complexes with macromolecular compounds or polymers through non-bonding interactions. In another preferred embodiment, the compounds of formulas I-IV of the present invention, as small molecules, can also be linked to macromolecular compounds or polymers through chemical bonds. The macromolecular compounds can be biological macromolecules such as polysaccharides, proteins, nucleic acids, polypeptides, etc.

There are no particular limitations on the administration of the active ingredients or pharmaceutical compositions of the present invention. Representative administration methods include (but are not limited to): oral, intratumoral, rectal, parenteral (intravenous, intramuscular or subcutaneous), etc.

Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules.

In these solid dosage forms, the active ingredient is mixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or with the following components:

(a) Fillers or compatibilizers, such as starch, lactose, sucrose, glucose, mannitol and silica;

(b) Adhesives, such as hydroxymethylcellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose and gum arabic;

(c) Moisturizers, such as glycerin;

(d) Disintegrants, such as agar, calcium carbonate, potato starch or tapioca starch, alginate, certain complex silicates, and sodium carbonate;

(e) Slow solvents, such as paraffin;

(f) Absorption accelerators, such as quaternary ammonium compounds;

(g) Wetting agents, such as cetyl alcohol and glyceryl monostearate;

(h) Adsorbents, such as kaolin; and

(i) Lubricants, such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium dodecyl sulfate, or mixtures thereof. In capsules, tablets, and pills, the dosage form may also contain a buffer.

The solid dosage form can also be prepared using coatings and shells, such as casings and other materials known in the art. They may contain opacifying agents, and the release of the active ingredient from this composition can be delayed in a portion of the digestive tract. Examples of suitable encapsulating components are polymers and waxes.

Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, or tinctures. In addition to the active ingredient, liquid dosage forms may contain inert diluents conventionally used in the art, such as water or other solvents, solubilizers and emulsifiers, e.g., ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1,3-butanediol, dimethylformamide, and oils, particularly cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil, and sesame oil, or mixtures thereof. Besides these inert diluents, the composition may also contain adjuvants such as wetting agents, emulsifiers and suspending agents, sweeteners, flavoring agents, and fragrances.

In addition to the active ingredient, the suspension may contain suspending agents, such as ethoxylated isooctadecyl alcohol, polyoxyethylene sorbitol and dehydrated sorbitol esters, microcrystalline cellulose, aluminum methoxide and agar, or mixtures of these substances.

Compositions for parenteral injection may comprise physiologically acceptable sterile aqueous or anhydrous solutions, dispersions, suspensions, or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Suitable aqueous and non-aqueous carriers, diluents, solvents, or excipients include water, ethanol, polyols, and suitable mixtures thereof.

The present invention will be further illustrated below with reference to specific embodiments. It should be understood that these embodiments are for illustrative purposes only and are not intended to limit the scope of the invention. Experimental methods in the following embodiments, unless otherwise specified, are generally performed under conventional conditions or as recommended by the manufacturer. Unless otherwise stated, percentages and parts are by weight.

Unless otherwise defined, all technical and scientific terms used herein have the same meaning as are familiar to those skilled in the art. Furthermore, any methods and materials similar to or equivalent to those described herein may be applied to the methods of this invention. The preferred embodiments and materials described herein are for illustrative purposes only.

All reagents used in the following examples are commercially available.

The abbreviations for the raw materials and reagents used in the following examples are explained below:

DMF: N,N-dimethylformamide;

DCM: Dichloromethane;

THF: Tetrahydrofuran;

PPTS: Pyridine p-toluenesulfonate;

TFA: Trifluoroacetic acid;

CDI: N,N'-carbonyldiimidazole;

DIPEA: N,N-diisopropylethylamine;

HOBT: 1-Hydroxybenzotriazole;

EDCI: 1-Ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride;

DMA: Dimethylacetamide;

NBS: N-bromosuccinimide;

TBAI: Tetrabutylammonium iodide;

EA: Ethyl acetate.

Example 1

4-Methoxy-8-(6-Methoxy-pyridin-3-yl)-1-(4-(piperazin-1-yl)-3-(trifluoromethyl)phenyl)-1H-[1,2,3]triazole[4,5-c]quinoline (Compound 1)

Synthesis of compounds 1-3a: Compound 1-1a (4.39 g, 13.8 mmol) was dissolved in 40 mL of DMF in a 250 mL reaction flask. Then, compound 1-2a (4.52 g, 13.09 mmol) and triethylamine (1.59 g, 15.71 mmol) were added, and the reaction was carried out at room temperature for 4 hours. After the reaction was completed, 100 mL of water was added, and the mixture was extracted with dichloromethane (100 mL × 3). The organic layers were combined, dried over anhydrous sodium sulfate, and rotary evaporated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (dichloromethane:methanol = 100:1) to give 6.17 g of compound 1-3a, with a yield of 75%. ¹ H NMR (400MHz, CDCl ₃ )δ7.90-7.86(m,2H),7.79(d,J＝1.6Hz,1H),7.35(s,1H),7.30(d,J＝8.8Hz,1H),7 .20-7.09(m,1H),3.67-3.51(m,4H),2.97-2.68(m,4H),1.50(s,9H); ESI-MS:m/z 630.1[M+H] ⁺ .

Synthesis of compounds 1-4a: In a 100 mL reaction flask, anhydrous methanol (5.1 mg, 1.58 mmol) was dissolved in 15 mL of dry tetrahydrofuran. NaH (127 mg, 3.18 mmol) was added, and the reaction was carried out for 10 min. Then, compound 1-3a (500 mg, 0.79 mmol) was added, and the reaction was carried out at room temperature for 4 h. After the reaction was completed, 20 mL of saturated _NaHCO3 solution was added, and the mixture was extracted with dichloromethane (100 mL × 3). The organic layers were combined, dried over anhydrous sodium sulfate, and rotary evaporated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (dichloromethane:methanol = 100:1) to give 355 mg of compound 1-4a, with a yield of 72%. ¹ H NMR (400MHz, CDCl ₃ )δ8.01(s,1H),7.74-7.70(m,1H),7.68(d,J＝1.6Hz,1H),7.30(d,J＝2.8Hz,1H),7.26(s,1H), 7.08(dd,J＝8.8,2.4Hz,1H),4.17(s,3H),3.58(m,4H),2.87(m,4H),1.60(s,9H); ESI-MS:m/z 626.1[M+H] ⁺ .

Synthesis of compounds 1-5a: In a 100 ml reaction flask, compounds 1-4a (427 mg, 0.68 mmol) were dissolved in 20 ml of acetic acid, and then iron powder (209 mg, 3.74 mmol) was added. The reaction was carried out at 60 °C for 4 hours. After the reaction was completed, the mixture was filtered through a hot diatomaceous earth filter, and the diatomaceous earth layer was washed with a mixed solvent of DCM/MeOH (50 ml:50 ml). The filtrate was evaporated to dryness, and 100 ml of _DCM was added. The pH was adjusted to alkaline with saturated _Na₂CO₃ solution, and the mixture was extracted with dichloromethane (100 ml × 3). The organic layers were combined, dried over anhydrous sodium sulfate, and evaporated under reduced pressure to obtain product 1-5a, which was used directly in the next step.

Synthesis of compounds 1-6a: Compounds 1-5a (200 mg, 0.33 mmol) were dissolved in 5 mL of acetic acid and reacted at room temperature for 4 h. After the reaction was complete, 30 mL of water was added, the mixture was filtered, and the residue was dried to obtain the product, which was directly used in the next step. ^¹H NMR (400 MHz, _CDCl₃ ) δ 7.99 (d, J = 2.4 Hz, 1H), 7.91–7.83 (m, 2H), 7.76 (dd, J = 8.8, 2.0 Hz, 1H), 7.69 (d, J = 2.0 Hz, 1H), 7.62 (d, J = 8.8 Hz, 1H), 4.32 (s, 3H), 3.75–3.59 (m, 4H), 3.13–2.98 (m, 4H), 1.52 (s, 9H); ESI-MS: m/z 607.1 [M+H] ^⁺ .

Synthesis of compounds 1-7a: Compound 1-6a (149 mg, 0.24 mmol) was dissolved in 5 mL of DCM in a 100 mL reaction flask, followed by the addition of trifluoroacetic acid (2.8 g, 24.6 mmol). The reaction was carried out at room temperature for 4 h. After the reaction was complete, the pH was adjusted to alkaline with saturated _{Na₂CO₃ solution} , and the mixture was extracted with dichloromethane (100 mL × 3). The organic layers were combined, dried over anhydrous sodium sulfate, and rotary evaporated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography with a dichloromethane:methanol mixture of 50:1 (v:v) to give 98 mg of compound 1-7a, in 81% yield. ¹ H NMR (400MHz, DMSO-d ⁶ )δ8.26(d,J＝2.4Hz,1H),8.14(dd,J＝8.8,2.4Hz,1H),7.94-7.81(m,3H),7.46( d,J＝2.0Hz,1H),4.24(s,3H),3.04-2.95(m,4H),2.94-2.84(m,4H); ESI-MS:m/z 507.1[M+H] ⁺ .

Synthesis of Compound 1: Compounds 1-7a (111 mg, 0.19 mmol), 1-8a (51 mg, _0.33 mmol), ( _PPh3 ) _4Pd (5 mg, 0.0044 mmol), and _Cs2CO3 (215 mg, 0.66 mmol) were added to a 25 mL reaction flask under argon protection. Then, 20 mL of a mixed solvent of DMF and _H2O (3:1 v/v) was added, and the mixture was refluxed at 80 °C overnight. After the reaction was complete, the mixture was quenched with water, filtered, and the filter cake was purified by column chromatography (dichloromethane:methanol:triethylamine = 100:10:1) to give 103 mg of a white solid, yield 88%. ¹ H NMR (400MHz, DMSO-d ⁶ )δ8.32(d,J＝2.4Hz,1H),8.25-8.16(m,2H),8.09-7.99(m,2H),7.90(d,J＝8.4Hz,1H),7.75(dd,J＝8.8,2.8Hz ,1H),7.41(d,J＝1.6Hz,1H),6.85(d,J＝8.4Hz,1H),4.26(s,3H),3.88(s,3H),3.11-2.91(m,8H); ESI-MS:m/z 536.2[M+H] ⁺ .

Example 2

4-Methoxy-8-(6-Methoxy-5-(trifluoromethyl)pyridin-3-yl)-1-(4-(piperazin-1-yl)-3-(trifluoromethyl)phenyl)-1H-[1,2,3]triazole[4,5-c]quinoline (Compound 2)

The synthesis method was the same as in Example 1, yielding 150 mg of a white solid, with a yield of 67%.

¹ H NMR (400MHz, CDCl ₃ )δ8.42(s,1H),8.10(d,J＝8.4Hz,1H),8.01(d,J＝2.0Hz,1H),7.92-7.82(m,3H), 7.69-7.59(d,J＝8.2Hz,2H),4.36(s,3H),4.08(s,3H),3.11(m,8H); ESI-MS:m/z 604.2[M+H] ⁺ .

Example 3

4-Methoxy-8-(6-Methoxy-5-methylpyridin-3-yl)-1-(4-(piperazin-1-yl)-3-(trifluoromethyl)phenyl)-1H-[1,2,3]triazole[4,5-c]quinoline (compound 3)

The synthesis method was the same as in Example 1, yielding 123 mg of a white solid, with a yield of 61%.

¹ H NMR (400MHz, CDCl ₃ ) δ8.11-8.04(m 3H),7.98-7.84(m,2H),7.75(d,J＝8.8Hz,1H),7.63(d,J＝1.6Hz,1H),7.43(d,J＝1.6Hz,1H) ,4.37(s,3H),4.00(s,3H),3.38-3.24(m,4H),3.05-2.85ms,4H),2.62(s,3H); ESI-MS:m/z 550.2[M+H] ⁺ .

Example 4

8-(5-fluoro-6-methoxypyridin-3-yl)-4-methoxy-1-(4-(piperazin-1-yl)-3-(trifluoromethyl)phenyl)-1H-[1,2,3]triazole[4,5-c]quinoline (compound 4)

The synthesis method was the same as in Example 1, yielding 117 mg of a white solid, with a yield of 71%.

¹ H NMR (400MHz, CDCl ₃ )δ8.08(d,J＝8.8Hz,1H),8.02-7.98(m,2H),7.94-7.89(m,1H),7.88-7.84(m,1H),7.82(d,J＝1.6Hz,1 H),7.62(d,J＝8.8Hz,1H),7.35-7.30(m,1H),4.37(s,3H),3.85(s,3H),3.18-3.02(m,8H); ESI-MS:m/z 554.2[M+H] ⁺ .

Example 5

8-(5,6-dimethoxypyridin-3-yl)-4-methoxy-1-(4-(piperazin-1-yl)-3-(trifluoromethyl)phenyl)-1H-[1,2,3]triazole[4,5-c]quinoline (compound 5)

The synthesis method was the same as in Example 1, yielding 145 mg of a white solid, with a yield of 67%.

¹ H NMR (400MHz, CDCl ₃ )δ8.12-805(m,2H),7.98-7.92(m,1H),7.89-7.84(m,1H),7.78-7.72(m,2H),7.63(d,J＝1.6Hz,1 H),7.12(d,J＝2.0Hz,1H),4.38(s,3H),4.05(s,3H),3.92(s,3H),3.45-3.25(m,8H); ESI-MS:m/z 566.2[M+H] ⁺ .

Example 6

8-(6-Fluoropyridin-3-yl)-4-methoxy-1-(4-(piperazin-1-yl)-3-(trifluoromethyl)phenyl)-1H-[1,2,3]triazole[4,5-c]quinoline (compound 6)

The synthesis method was the same as in Example 1, yielding 132 mg of a white solid, with a yield of 68%.

¹ H NMR (400MHz, DMSO-d ⁶ )δ8.34-8.27(m,2H),8.24-8.17(m,1H),8.13-8.03(m,3H),7.90-7.85(d,J＝8.8Hz,1H) ,7.55(d,J＝2.0Hz,1H),7.30-7.25(m,1H),4.26(s,3H),3.05-2.90(m,8H); ESI-MS:m/z 524.2[M+H] ⁺ .

Example 7

5-(4-methoxy-1-(4-(piperazin-1-yl)-3-(trifluoromethyl)phenyl)-1H-[1,2,3]triazol[4,5-c]quinoline-8-yl)pyrimidine-2-amino (compound 7)

The synthesis method was the same as in Example 1, yielding 150 mg of a white solid, with a yield of 67%.

¹ H NMR (400MHz, DMSO-d ⁶ )δ8.34(s,2H),8.31(d,J＝2.0Hz,1H),8.21-8.13(m,1H),8.05-7.98(m,2H),7.86(d, J＝8.8Hz,1H),7.44(s,1H),6.91(s,2H),4.25(s,3H),3.02-2.85(m,8H); ESI-MS:m/z 519.2[M+H] ⁺ .

Example 8

5-(4-methoxy-1-(4-(piperazin-1-yl)-3-(trifluoromethyl)phenyl)-1H-[1,2,3]triazol[4,5-c]quinoline-8-yl)-3-(trifluoromethyl)pyridine-2-amino (compound 8)

The synthesis method was the same as in Example 1, yielding 138 mg of a white solid, with a yield of 67%.

¹ H NMR (400MHz, DMSO-d ⁶ )δ8.36(s,1H),8.28(d,J＝2.0Hz,1H),8.20-8.14(m,1H),8.09-7.97(m,2H),7.81(d,J＝8.4Hz,1 H),7.65(s,1H),7.46(d,J＝1.6Hz,1H),6.67(s,2H),4.25(s,3H),3.02-2.82(m,8H); ESI-MS:m/z 589.2[M+H] ⁺ .

Example 9

1-(3-fluoro-4-(piperazin-1-yl)phenyl)-4-methoxy-8-(6-methoxypyridin-3-yl)-1H-[1,2,3]triazole[4,5-c]quinoline (compound 9)

The synthesis method was the same as in Example 1, yielding 141 mg of a white solid, with a yield of 69%.

¹ H NMR (400MHz, CDCl ₃ )δ8.27(d,J＝2.0Hz,1H),8.08(d,J＝8.4Hz,1H),7.88-7.82(m,1H),7.74(d,J＝1.6Hz,1H),7.68-7.64(m,1H),7.48 -7.38(m,2H),7.25-7.16(m,1H),6.81(d,J＝8.4Hz,1H),4.37(s,3H),3.99(s,3H),3.29-3.12(m,8H); ESI-MS:m/z 486.2[M+H] ⁺ .

Example 10

1-(3-chloro-4-(piperazin-1-yl)phenyl)-4-methoxy-8-(6-methoxypyridin-3-yl)-1H-[1,2,3]triazole[4,5-c]quinoline (compound 10)

The synthesis method was the same as in Example 1, yielding 136 mg of a white solid, with a yield of 67%.

¹ H NMR (400MHz, CDCl ₃ )δ8.28(d,J＝2.0Hz,1H),8.11(d,J＝8.4Hz,1H),7.89-7.81(m,1H),7.72(d,J＝1.6Hz,1H),7.69-7.65(m,1H),7.49 -7.39(m,2H),7.23-7.17(m,1H),6.84(d,J＝8.4Hz,1H),4.38(s,3H),3.97(s,3H),3.30-3.12(m,8H); ESI-MS:m/z 502.2[M+H] ⁺ .

Example 11

4-Methoxy-8-(6-methoxypyridin-3-yl)-1-(3-methyl-4-(piperazin-1-yl)phenyl)-1H-[1,2,3]triazole[4,5-c]quinoline (Compound 11)

The synthesis method was the same as in Example 1, yielding 138 mg of a white solid, with a yield of 67%.

¹ H NMR (400MHz, DMSO-d ⁶ )δ8.23(s,1H),8.05-7.96(m,2H),7.78-7.62(m,3H),7.47(s,1H),7.43-7.37(d,J＝8.4Hz,1H) ,6.88(d,J＝8.8Hz,1H),4.25(s,3H),3.88(s,3H),3.16-3.03(m,8H),2.41(s,3H); ESI-MS:m/z 482.2[M+H] ⁺ .

Example 12

4-Methoxy-1-(3-Methoxy-4-(piperazin-1-yl)phenyl)-8-(6-methoxypyridin-3-yl)-1H-[1,2,3]triazole[4,5-c]quinoline (compound 12)

The synthesis method was the same as in Example 1, yielding 138 mg of a white solid, with a yield of 67%.

¹ H NMR (400MHz, DMSO-d ⁶ )δ8.23(s,1H),8.05-7.95(m,2H),7.75(d,J＝8.8Hz,1H),7.50-7.45(m,2H),7.38(d,J＝8.0Hz,1H),7.27(d,J＝8.0Hz,1H),6 .89(d,J＝8.8Hz,1H),4.25(s,3H),3.89(s,3H),3.82(s,3H),3.22-3.16(m,4H),3.12-3.06(m,4H); ESI-MS:m/z498.2[M+H] ⁺ .

Example 13

4-Methoxy-8-(6-methoxypyridin-3-yl)-1-(4-(piperazin-1-yl)phenyl)-1H-[1,2,3]triazole[4,5-c]quinoline (compound 13)

The synthesis method was the same as in Example 1, yielding 131 mg of a white solid, with a yield of 73%.

^1H NMR(400MHz,DMSO)δ8.30(s,1H),8.10-8.00(m,2H),7.80-7.70(m,3H),7.58(s,1H),7.40-7.30(m,2H ), 6.90 (d, J = 8.0Hz, 1H), 4.25 (s, 3H), 3.90 (s, 3H), 3.50-3.44 (m, 4H), 3.18-3.12 (m, 4H); ESI-MS: m/z 468.2[M+H] ⁺ .

Example 14

4-Ethoxy-8-(6-methoxypyridin-3-yl)-1-(4-(piperazin-1-yl)-3-(trifluoromethyl)phenyl)-1H-[1,2,3]triazole[4,5-c]quinoline (compound 14)

The synthesis method was the same as in Example 1, yielding 132 mg of a white solid, with a yield of 67%.

¹ H NMR (400MHz, DMSO-d ⁶ )δ8.35(d,J＝2.4Hz,1H),8.23(dd,J＝9.2,2.4Hz,2H),8.06(dd,J＝8.8,2.0Hz,1H),8.00(d,J＝8.8Hz,1H),7.93(d,J＝8.8Hz,1H),7.75(dd,J＝8. 8,2.4Hz,1H),7.43(d,J＝1.6Hz,1H),6.87(d,J＝8.4Hz,1H),4.75(q,J＝7.2Hz,2H),3.88(s,3H),3.14(m,8H),1.53(t,J＝6.8Hz,3H); ESI-MS: m/z 550.2[M+H] ⁺ .

Example 15

4-Cyclopropoxy-8-(6-methoxypyridin-3-yl)-1-(4-(piperazin-1-yl)-3-(trifluoromethyl)phenyl)-1H-[1,2,3]triazolo[4,5-c]quinoline (Compound 15)

The synthesis method was the same as in Example 1, yielding 137 mg of a white solid, with a yield of 63%.

¹ H NMR (400MHz, DMSO-d ⁶ )δ8.31(d,J＝2.4Hz,1H),8.23(d,J＝2.4Hz,1H),8.18(dd,J＝8.4,2.0Hz,1H),8.12-8.00(m,2H),7.89(d,J＝8.4Hz,1H),7.76(dd,J＝8. 8, 2.4Hz, 1H), 7.41 (s, 1H), 6.85 (d, J = 8.8Hz, 1H), 4.84-4.75 (m, 1H), 3.88 (s, 3H), 3.11-2.87 (m, 8H), 1.03-0.89 (m, 4H); ESI-MS: m/z 562.2[M+H] ⁺ .

Example 16

4-Isopropoxy-8-(6-methoxypyridin-3-yl)-1-(4-(piperazin-1-yl)-3-(trifluoromethyl)phenyl)-1H-[1,2,3]triazole[4,5-c]quinoline (compound 16)

The synthesis method was the same as in Example 1, yielding 127 mg of a white solid, with a yield of 67%.

¹ H NMR (400MHz, CDCl ₃ )δ8.25(d,J＝2.4Hz,1H),8.05-8.02(m,2H),7.89(dd,J＝8.4,2.4Hz,1H),7.85(dd,J＝8.8,2.0Hz,1H),7.66(d,J＝8.4Hz,1H),7 .62-7.60(m,2H),6.77(d,J＝8.8Hz,1H),5.93-5.87(m,1H),3.98(s,3H),3.13-3.12(m,8H),1.61(d,J＝6.4Hz,6H); ESI-MS:m/z 564.2[M+H] ⁺ .

Example 17

4-(cyclopentoxy)-8-(6-methoxypyridin-3-yl)-1-(4-(piperazin-1-yl)-3-(trifluoromethyl)phenyl)-1H-[1,2,3]triazole[4,5-c]quinoline (compound 17)

The synthesis method was the same as in Example 1, yielding 131 mg of a white solid, with a yield of 67%.

^1H NMR (400MHz, CDCl3 ₎ )δ8.25(d,J＝2.4Hz,1H),8.05(d,J＝8.4Hz,1H),8.02(d,J＝2.4Hz,1H),7.89(d d,J＝8.8,2.8Hz,1H),7.85(dd,J＝8.8,2.0Hz,1H),7.66(d,J＝8.4Hz,1H),7.64- 7.58(m,2H),6.77(d,J＝8.4Hz,1H),6.01-5.92(m,1H),3.98(s,3H),3.14-3.1 2(m,8H),2.27-2.05(m,4H),1.98-1.97(m,2H),1.76-1.72(m,2H); ESI-MS:m/z 590.2[M+H] ⁺ .

Example 18

4-Cyclobutoxy-8-(6-methoxypyridin-3-yl)-1-(4-(piperazin-1-yl)-3-(trifluoromethyl)phenyl)-1H-[1,2,3]triazolo[4,5-c]quinoline (compound 18)

The synthesis method was the same as in Example 1, yielding 150 mg of a white solid, with a yield of 67%.

¹ H NMR (400MHz, DMSO-d ⁶ )δ8.30(d,J＝2.4Hz,1H),8.24-8.15(m,2H),8.01(dd,J＝8.8,2.0Hz,1H),7.95(d,J ＝8.8Hz,1H),7.89(d,J＝8.4Hz,1H),7.74(dd,J＝8.4,2.4Hz,1H),7.37(d,J＝2.0Hz,1 H),6.85(d,J＝8.8Hz,1H),5.61-5.52(m,1H),3.87(s,3H),3.12-2.87(m,8H),2.63 -2.54(m,2H),2.35-2.20(m,2H),1.95-1.85(m,1H),1.85-1.71(m,1H); ESI-MS:m/z 576.2[M+H] ⁺ .

Example 19

(S)-4-methoxy-8-(6-methoxypyridin-3-yl)-1-(4-(3-methylpiperazin-1-yl)-3-(trifluoromethyl)phenyl)-1H-[1,2,3]triazole[4,5-c]quinoline (compound 19)

The synthesis method was the same as in Example 1, yielding 131 mg of a white solid, with a yield of 67%.

¹ H NMR (400MHz, DMSO-d ⁶ )δ8.29(s,1H),8.21-8.14(m,2H),8.05-7.96(m,2H),7.87(d,J＝8.4Hz,1H),7.72(d,J＝8.4Hz,1H),7.37(s,1H),6.81(d,J＝ 8.8Hz,1H),4.24(s,3H),3.87(s,3H),3.11-2.83(m,6H),2.61-2.52(m,1H),1.04(d,J＝6.0Hz,3H); ESI-MS:m/z550.2[M+H] ⁺ .

Example 20

4-Methoxy-8-(6-methoxypyridin-3-yl)-1-(4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)-3-(trifluoromethyl)phenyl)-1H-[1,2,3]triazole[4,5-c]quinoline (Compound 20)

The synthesis method was the same as in Example 1, yielding 142 mg of a white solid, with a yield of 76%.

¹ H NMR (400MHz, CDCl ₃ )δ8.25(s,1H),8.08(d,J＝8.4Hz,1H),8.00(s,1H),7.89-7.82(M,2H),7.66-7.58(m,3H),6.77(d,J＝8.8Hz,1H),4.36(s,3H),3.9 8(s,3H),3.42-3.30(m,2H),2.97-2.85(m,2H),2.79-2.40(m,9H),2.35(s,3H),2.06-1.96(m,2H),1.90-1.82(m,2H); ESI-MS:m/z 633.3[M+H] ⁺ .

Example 21

1-(4-((1R,5S)-3,6-diazabicyclo[3.1.1]heptane-3-yl)-3-(trifluoromethyl)phenyl)-4-methoxy-8-(6-methoxypyridin-3-yl)-1H-[1,2,3]triazole[4,5-c]quinoline (compound 21)

The synthesis method was the same as in Example 1, yielding 132 mg of a white solid, with a yield of 67%.

¹ H NMR (400MHz, DMSO-d ⁶ )δ8.33(s,1H),8.29-8.14(m,3H),8.10-7.95(m,2H),7.74(d,J＝8.0Hz,1H),7.45(s,1H),6.84(d,J＝8.0Hz,1H),4.25(s,3H ),3.86(s,3H),3.80-3.72(m,2H),3.66-3.56(m,2H),3.50-3.41(m,2H),2.60-2.52(m,1H),2.04-1.96(m,1H); ESI-MS:m/z 548.2[M+H] ⁺ .

Example 22

1-(4-((1R,4R)-2,5-diazabicyclo[2.2.1]heptane-2-yl)-3-(trifluoromethyl)phenyl)-4-methoxy-8-(6-methoxypyridin-3-yl)-1H-[1,2,3]triazole[4,5-c]quinoline (compound 22)

The synthesis method was the same as in Example 1, yielding 121 mg of a white solid, with a yield of 67%.

^1H NMR (400MHz, DMSO-d6 ⁾ )δ8.30(s,1H),8.12(s,1H),8.07-7.98(m,2H),7.96-7.88(m,1H),7.84-7. 78(m,1H),7.63(s,1H),7.34(d,J＝9.2Hz,1H),6.93(d,J＝8.2Hz,1H),4.56(s ,1H),4.25(s,3H),3.89(s,3H),3.83-3.77(m,1H),3.73(s,1H),3.23-3.13( m,2H),3.06-2.99(m,1H),1.95-1.87(m,1H),1.81-1.73(m,1H); ESI-MS:m/z 548.2[M+H] ⁺ .

Example 23

4-(1-(4-(4-methoxy-8-(6-methoxypyridin-3-yl)-1H-[1,2,3]triazol[4,5-c]quinoline-1-yl)-2-(trifluoromethyl)phenyl)piperidin-4-yl)morpholine (compound 23)

The synthesis method was the same as in Example 1, yielding 118 mg of a white solid, with a yield of 61%.

¹ H NMR (400MHz, CDCl ₃ )δ8.27(s,1H),8.09(d,J＝8.8Hz,1H),8.02(s,1H),7.90-7.84(m,2H),7.67-7.59(m,3H),6.78(d,J＝8.4Hz,1H),4.37(s,3H),3.99(s,3H ),3.80(m,4H),3.42-3.34(m,2H),2.97-3.86(m,2H),2.66(m,4H),2.45-2.35(m,1H),2.08-1.97(m,2H),1.90-1.76(m,2H); ESI-MS: m/z 620.3[M+H] ⁺ .

Example 24

1-(4-((3S,5S)-3,5-dimethylpiperazin-1-yl)-3-(trifluoromethyl)phenyl)-4-methoxy-8-(6-methoxypyridin-3-yl)-1H-[1,2,3]triazole[4,5-c]quinoline (compound 24)

The synthesis method was the same as in Example 1, yielding 109 mg of a white solid, with a yield of 67%.

¹ H NMR (400MHz, CDCl ₃ )δ8.25(s,1H),8.12-8.06(m,2H),7.98-7.93(m,1H),7.90-7.86(m,1H),7.75(d,J＝8.4Hz,1H),7.65-7.60(m,2H),6.79(d,J＝8. 4Hz,1H),4.38(s,3H),3.98(s,3H),3.80-3.60(m,2H),3.40-3.25(m,2H),3.05-2.90(m,2H),1.48(d,J＝6.4Hz,6H); ESI-MS:m/z 564.2[M+H] ⁺ .

Example 25

1-(4-((3S,5R)-3,5-dimethylpiperazin-1-yl)-3-(trifluoromethyl)phenyl)-4-methoxy-8-(6-methoxypyridin-3-yl)-1H-[1,2,3]triazole[4,5-c]quinoline (compound 25)

The synthesis method was the same as in Example 1, yielding 127 mg of a white solid, with a yield of 61%.

¹ H NMR (400MHz, CDCl ₃ )δ8.27(s,1H),8.09(d,J＝8.8Hz,1H),8.03(s,1H),7.90-7.84(m,2H),7.67-7.59(m,3H),6.78(d,J＝8.4H z,1H),4.37(s,3H),3.98(s,3H),3.25-3.10(m,4H),2.60-2.50(m,2H),1.17(d,J＝6.4Hz,6H); ESI-MS:m/z 564.2[M+H] ⁺ .

Example 26

1-(4-(4,7-diazaspiro[2.5]octane-7-yl)-3-(trifluoromethyl)phenyl)-4-methoxy-8-(6-methoxypyridin-3-yl)-1H-[1,2,3]triazole[4,5-c]quinoline (compound 26)

The synthesis method was the same as in Example 1, yielding 119 mg of a white solid, with a yield of 61%.

¹ H NMR (400MHz, DMSO-d ⁶ )δ8.33-8.27(m,1H),8.23-8.13(m,2H),8.08-7.97(m,2H),7.89(d,J＝8.4Hz,1H),7.73(d,J＝8.8Hz,1H),7.40-7.34(m,1H),6.81(d,J＝8.8Hz ,1H),4.25(s,3H),3.88(s,3H),3.02(d,J＝3.2Hz,2H),2.97(d,J＝3.2Hz,2H),2.88(s,2H),0.65-0.53(m,2H),0.53-0.46(m,2H); ESI-MS: m/z 562.2[M+H] ⁺ .

Example 27

1-(4-(2,6-diazaspiro[3.3]heptane-2-yl)-3-(trifluoromethyl)phenyl)-4-methoxy-8-(6-methoxypyridin-3-yl)-1H-[1,2,3]triazole[4,5-c]quinoline (compound 27)

The synthesis method was the same as in Example 1, yielding 131 mg of a white solid, with a yield of 63%.

¹ H NMR (400MHz, DMSO-d ⁶ )δ8.30(d,J＝2.4Hz,1H),8.12(d,J＝2.4Hz,1H),8.03(d,J＝0.8Hz,2H),7.93(dd,J＝8.8,2.4Hz,1H),7.79(dd,J＝8.8, 2.4Hz,1H),7.69-7.64(m,1H),6.94-6.585(m,2H),4.34(s,4H),4.25(s,3H),4.04(s,4H),3.90(s,3H); ESI-MS:m/z 548.2[M+H] ⁺ .

Example 28

^N1- (4-(4-methoxy-8-(6-methoxypyridin-3-yl)-1H-[1,2,3]triazolo[4,5-c]quinoline-1-yl)-2-(trifluoromethyl)phenyl) ^-N1 , ^N2 -dimethylethane-1,2-diamine (compound 28)

The synthesis method was the same as in Example 1, yielding 121 mg of a white solid, with a yield of 63%.

¹ H NMR (400MHz, DMSO-d ⁶ )δ8.28(d,J＝2.8Hz,1H),8.25(d,J＝2.4Hz,1H),8.16(dd,J＝8.4,2.4Hz,1H) ,8.06-7.99(m,2H),7.92(d,J＝8.4Hz,1H),7.73(dd,J＝8.4,2.8Hz,1H),7.4 8(d,J＝1.2Hz,1H),6.85(d,J＝8.4Hz,1H),4.25(s,3H),3.87(s,3H),3.22(t ,J＝6.8Hz,2H),2.85(s,3H),2.64(t,J＝6.8Hz,2H),2.23(s,3H); ESI-MS:m/z 538.2[M+H] ⁺ .

Example 29

1-(4-(3,8-diazabicyclo[3.2.1]octane-8-yl)-3-(trifluoromethyl)phenyl)-4-methoxy-8-(6-methoxypyridin-3-yl)-1H-[1,2,3]triazole[4,5-c]quinoline (compound 29)

The synthesis method was the same as in Example 1, yielding 127 mg of a white solid, with a yield of 67%.

¹ H NMR (400MHz, DMSO-d ⁶ )δ8.22(d,J＝2.4Hz,1H),8.20(d,J＝2.4Hz,1H),8.07-7.96(m,3H),7.80(d d,J＝8.8,2.4Hz,1H),7.53(d,J＝8.8Hz,1H),7.49(d,J＝1.6Hz,1H),6.85(d ,J＝8.8Hz,1H),4.24(s,3H),4.02-3.93(m,2H),3.88(s,3H),3.03(d,J＝12 .0Hz, 2H), 2.73 (dd, J＝12.0Hz, 1.6Hz, 2H), 2.03-1.89 (m, 4H); ESI-MS: m/z 562.2[M+H] ⁺ .

Example 30

1-(4-(4-methoxy-8-(6-methoxypyridin-3-yl)-1H-[1,2,3]triazolo[4,5-c]quinoline-1-yl)-2-(trifluoromethyl)phenyl)-N,N-dimethylpiperidin-4-amine (Compound 30)

The synthesis method was the same as in Example 1, yielding 131 mg of a white solid, with a yield of 63%.

¹ H NMR (400MHz, DMSO-d ⁶ )δ8.31(d,J＝2.0Hz,1H),8.25-8.15(m,2H),8.09-7.97(m,2H),7.90(d, J＝8.4Hz,1H),7.74(dd,J＝8.8,2.0Hz,1H),7.45-7.36(m,1H),6.85(d,J＝ 8.8Hz,1H),4.26(s,3H),3.88(s,3H),3.30-3.22(m,3H),2.95(t,J＝11. 2Hz,2H),2.38(s,6H),2.03-1.95(m,2H),1.71-1.60(m,2H); ESI-MS:m/z 578.2[M+H] ⁺ .

Example 31

(R)-4-methoxy-8-(6-methoxypyridin-3-yl)-1-(4-(3-methylpiperazin-1-yl)-3-(trifluoromethyl)phenyl)-1H-[1,2,3]triazole[4,5-c]quinoline (compound 31)

The synthesis method was the same as in Example 1, yielding 132 mg of a white solid, with a yield of 65%.

¹ H NMR (400MHz, DMSO-d ⁶ )δ8.30(d,J＝2.4Hz,1H),8.22(d,J＝2.4Hz,1H),8.18(dd,J＝8.8,2.4Hz,1H ),8.08-7.98(m,2H),7.88(d,J＝8.8Hz,1H),7.74(dd,J＝8.8,2.8Hz,1H),7 .40(d,J＝1.2Hz,1H),6.83(d,J＝8.8Hz,1H),4.26(s,3H),3.88(s,3H),3.0 9-2.87(m,6H),2.58(t,J＝10.0Hz,1H),1.05(d,J＝6.4Hz,3H); ESI-MS:m/z 550.2[M+H] ⁺ .

Example 32

1-(4-(3,6-diazabicyclo[3.1.1]heptane-6-yl)-3-(trifluoromethyl)phenyl)-4-methoxy-8-(6-methoxypyridin-3-yl)-1H-[1,2,3]triazole[4,5-c]quinoline (compound 32)

The synthesis method was the same as in Example 1, yielding 129 mg of a white solid, with a yield of 63%.

¹ H NMR (400MHz, DMSO-d ⁶ )δ8.35(d,J＝1.6Hz,1H),8.09-8.00(m,3H),7.95(dd,J＝8.8,1.6Hz,1H),7.76(dd,J＝8.8, 2.4Hz,1H),7.72-7.65(m,1H),7.29(d,J＝8.8Hz,1H),6.91(d,J＝8.8Hz,1H),5.68(d,J＝8. 0Hz,1H),4.80(d,J＝3.2Hz,1H),4.25(s,3H),4.10-(m,1H),3.90(s,3H),3.79-3.63(m,1H ),3.00-2.86(m,2H),2.85-2.76(m,1H),2.18-2.05(m,1H),1.70-1.56(s,1H); ESI-MS:m/z 548.2[M+H] ⁺ .

Example 33

1-(4-(3,3-dimethylpiperazin-1-yl)-3-(trifluoromethyl)phenyl)-4-methoxy-8-(6-methoxypyridin-3-yl)-1H-[1,2,3]triazole[4,5-c]quinoline (compound 33)

The synthesis method was the same as in Example 1, yielding 139 mg of a white solid, with a yield of 63%.

¹ H NMR (400MHz, DMSO-d ⁶ )δ8.32(d,J＝2.4Hz,1H),8.20(dd,J＝8.4,2.4Hz,2H),8.05-7.96(m,2H),7.92(d,J＝8.8Hz,1H),7.71(dd,J＝8.4,2.4Hz,1H),7.36(d, J＝1.6Hz,1H),6.81(d,J＝8.4Hz,1H),4.24(s,3H),3.87(s,3H),3.17(s,1H),3.03-2.97(m,4H),2.82(s,1H),1.23(s,6H); ESI-MS:m/z 564.2[M+H] ⁺ .

Example 34

(S)-1-(4-(3-isopropylpiperazin-1-yl)-3-(trifluoromethyl)phenyl)-4-methoxy-8-(6-methoxypyridin-3-yl)-1H-[1,2,3]triazole[4,5-c]quinoline (compound 34)

The synthesis method was the same as in Example 1, yielding 135 mg of a white solid, with a yield of 65%.

^1H NMR (400MHz, DMSO-d6 ⁾ )δ8.27(s,1H),8.18-8.15(m,2H),7.97(s,2H),7.87(d,J＝8.0Hz,1H),7.69( d,J＝8.0Hz,1H),7.38(s,1H),6.78(d,J＝8.4Hz,1H),4.22(s,3H),3.86(s,3H ),3.13(d,J＝9.8Hz,1H),3.03(m,2H),2.89(m,2H),2.64-2.53(m,2H),1.91( s,1H),1.61(s,1H),0.96(d,J＝2.8Hz,3H),0.90(d,J＝2.8Hz,3H); ESI-MS:m/z 578.2[M+H] ⁺ .

Example 35

1-(4-(4-methoxy-8-(6-methoxypyridin-3-yl)-1H-[1,2,3]triazol[4,5-c]quinoline-1-yl)-2-(trifluoromethyl)phenyl)-N-methylpiperidin-4-amino (Compound 35)

The synthesis method was the same as in Example 1, yielding 136 mg of a white solid, with a yield of 66%.

¹ H NMR (400MHz, DMSO-d ⁶ )δ8.28(d,J＝2.0Hz,1H),8.21-8.10(m,2H),8.04-7.95(m,2H),7.89(d,J ＝8.8Hz,1H),7.72(dd,J＝8.8,2.4Hz,1H),7.37(s,1H),6.82(d,J＝8.8Hz, 1H),4.24(s,3H),3.88(s,3H),3.22(d,J＝11.6Hz,3H),2.93(t,J＝10.4Hz ,2H),2.34(s,3H),1.97(d,J＝12.8Hz,2H),1.60-1.39(m,2H); ESI-MS:m/z 564.2[M+H] ⁺ .

Example 36

N-(4-(4-methoxy-8-(6-methoxypyridin-3-yl)-1H-[1,2,3]triazol[4,5-c]quinoline-1-yl)-2-(trifluoromethyl)phenyl)-N-methylpiperidin-4-amino (Compound 36)

The synthesis method was the same as in Example 1, yielding 131 mg of a white solid, with a yield of 61%.

^1H NMR (400MHz, DMSO-d6 ⁾ )δ8.30(s,1H),8.23(s,1H),8.21(d,J＝8.4Hz,1H),8.03(s,2H),7.98(d,J＝8 .8Hz,1H),7.77(d,J＝8.4Hz,1H),7.52(s,1H),6.83(d,J＝8.8Hz,1H),4.25(s ,3H),3.88(s,3H),3.18-3.26(m,2H),3.06(d,J＝12.4Hz,2H),2.73(s,3H),2 .59(t,J＝11.6Hz,2H),1.80(d,J＝11.2Hz,2H),1.57-1.41(m,2H); ESI-MS:m/z 564.2[M+H] ⁺ .

Example 37

(S)-1-(4-(3-ethylpiperazin-1-yl)-3-(trifluoromethyl)phenyl)-4-methoxy-8-(6-methoxypyridin-3-yl)-1H-[1,2,3]triazole[4,5-c]quinoline (compound 37)

The synthesis method was the same as in Example 1, yielding 135 mg of a white solid, with a yield of 67%.

¹ H NMR (400MHz, CDCl ₃ )δ8.27(d,J＝2.4Hz,1H),8.09(d,J＝8.4Hz,1H),8.03(d,J＝2.4Hz,1H),7.92-7.83(m,2H),7.68-7.59(m,3H),6.78(d,J＝8.8Hz,1H),4.37 (s,3H),3.98(s,3H),3.30-3.10(m,4H),3.06-2.87(m,2H),2.62(t,J＝10.4Hz,1H),1.59-1.43(m,2H),1.02(t,J＝7.2Hz,3H); ESI-MS:m/z 564.2[M+H] ⁺ .

Example 38

1-(4-(3,8-diazabicyclo[3.2.1]octane-3-yl)-3-(trifluoromethyl)phenyl)-4-methoxy-8-(6-methoxypyridin-3-yl)-1H-[1,2,3]triazole[4,5-c]quinoline (compound 38)

The synthesis method was the same as in Example 1, yielding 133 mg of a white solid, with a yield of 63%.

^1H NMR (400MHz, DMSO) δ8.38-8.31(m,1H),8.25(d,J＝8.0Hz,1H),8.22-8.15(m, 1H),8.11-7.94(m,3H),7.72(d,J＝8.8Hz,1H),7.40-7.34(m,1H),6.85(d,J＝8 .8Hz,1H),4.25(s,3H),3.88(s,3H),3.80-3.71(m,2H),3.27(d,J＝10.8Hz,2 H),2.92(d,J＝10.8Hz,2H),2.09-1.99(m,2H),1.88-1.76(m,2H); ESI-MS:m/z 562.2[M+H] ⁺ .

Example 39

1-(4-(1,4-diazaheptan-1-yl)-3-(trifluoromethyl)phenyl)-4-methoxy-8-(6-methoxypyridin-3-yl)-1H-[1,2,3]triazole[4,5-c]quinoline (compound 39)

The synthesis method was the same as in Example 1, yielding 134 mg of a white solid, with a yield of 63%.

¹ H NMR (400MHz, DMSO-d ⁶ )δ8.27(d,J＝1.6Hz,1H),8.21(d,J＝1.6Hz,1H),8.15(dd,J＝8.4,1.6Hz,1H),8.08-7.96(m,2H),7.90(d,J＝8.8Hz,1H),7.75(dd,J＝8.8,1.6Hz, 1H),7.46-7.39(m,1H),6.83(d,J＝8.4Hz,1H),4.25(s,3H),3.87(s,3H ),3.36-3.33(m,4H),3.13-2.96(m,4H),2.00-1.87(m,2H); ESI-MS:m/z 550.2[M+H] ⁺ .

Example 40

4-Methoxy-8-(6-methoxypyridin-3-yl)-1-(4-(piperazin-1-yl)-3-(trifluoromethyl)phenyl)-1H-imidazo[4,5-c]quinoline (compound 40)

Synthesis of compound 40-2a: In a 100 mL reaction flask, compound 1-5a (377 mg, 0.63 mmol) and PPTS (1.6 mg, 0.0063 mmol) were dissolved in 5 mL of compound 40-1a, and the reaction was carried out overnight at 105 °C. After the reaction was complete, the mixture was cooled to room temperature, 20 mL of n-hexane was added, and the mixture was filtered. The residue was evaporated to dryness to give 285 mg of the product, with a yield of 75%. ¹ H NMR (400MHz, CDCl ₃ )δ7.98(s,1H),7.85(d,J＝8.8Hz,1H),7.83(d,J＝2.4Hz,1H),7.70(dd,J＝8.8,2.8Hz,1H),7.64 -7.55(m,2H),7.30(d,J＝2.0Hz,1H),4.28(s,3H),3.74-3.56(m,4H),3.04(m,4H),1.51(s,9H).

Synthesis of compound 40-3a: Compound 40-2a (100 mg, 0.16 mmol) was dissolved in 5 mL of DCM in a 100 mL reaction flask, followed by the addition of trifluoroacetic acid (1.9 g, 16.5 mmol ₎ . The reaction was carried out at room temperature for 4 h. After the reaction was complete, the pH was adjusted to alkaline with saturated _Na₂CO₃ solution, and the mixture was extracted with dichloromethane (100 mL × 3). The organic layers were combined, dried over anhydrous sodium sulfate, and rotary evaporated under reduced pressure to obtain the product, which was directly used in the next reaction.

Synthesis of compound 40: Compound 40-3a (89 mg, 0.17 mmol), compound 40-4a (40 mg, _0.255 mmol), ( _PPh3 ) _4Pd (4 mg, 0.034 mmol), and _Cs2CO3 (166 mg, 0.51 mmol) were added to a 25 mL reaction flask under argon protection. Then, 20 mL of a mixed solvent of DMF and _H2O (volume ratio 3:1) was added, and the mixture was refluxed at 80 °C overnight. After the reaction was complete, the mixture was quenched with water, filtered, and the filter cake was purified by column chromatography (dichloromethane:methanol:triethylamine = 100:10:1) to give 80 mg of a white solid, yield 88%. ¹ H NMR (400MHz, DMSO-d ⁶ )δ8.54(s,1H),8.18(d,J＝2.4Hz,1H),8.12(d,J＝2.4Hz,1H),8.08(dd,J＝8.4,2.4Hz,1H),7.96(d,J＝8.8Hz,1H),7.96-7.80(m,2H), 7.71(dd,J＝8.8,2.4Hz,1H),7.15(d,J＝1.6Hz,1H),6.81(d,J＝8.4Hz,1H),4.18(s,3H),3.86(s,3H),3.08-2.90(m,8H); ESI-MS:m/z 535.2[M+H] ⁺ .

Example 41

1-(4-(3,6-diazabicyclo[3.1.1]heptane-6-yl)-3-(trifluoromethyl)phenyl)-4-methoxy-8-(6-methoxypyridin-3-yl)-1H-imidazol[4,5-c]quinoline (compound 41)

The synthesis method was the same as in Example 40, yielding 135 mg of a white solid, with a yield of 73%.

¹ H NMR (400MHz, DMSO-d ⁶ )δ8.43(s,1H),8.31(d,J＝28.8Hz,1H),7.96(d,J＝8.4Hz,1H),7.93-7.76(m,3H),7.75-7.63 (m,1H),7.48(d,J＝32.0Hz,1H),7.23(d,J＝8.8Hz,1H),6.88(dd,J＝34.2,8.4Hz,1H),5.55(d, J＝8.0Hz,1H),4.82-4.65(m,1H),4.18(s,3H),4.08-3.93(m,1H),3.89(s,3H),3.78-3.63(m, 1H),2.99-2.82(m,2H),2.82-2.72(m,1H),2.15-2.03(m,1H),1.68-1.54(m,1H); ESI-MS:m/z 547.2[M+H] ⁺ .

Example 42

1-(4-(4-methoxy-8-(6-methoxypyridin-3-yl)-1H-imidazol[4,5-c]quinoline-1-yl)-2-(trifluoromethyl)phenyl)-N-methylpiperidin-4-amino (Compound 42)

The synthesis method was the same as in Example 40, yielding 137 mg of a white solid, with a yield of 73%.

¹ H NMR (400MHz, CDCl ₃ )δ8.19(d,J＝2.4Hz,1H),8.05(d,J＝8.8Hz,1H),8.02(s,1H),7.88(d,J＝2.4Hz,1H),7. 78-7.69(m,2H),7.61(d,J＝8.4Hz,1H),7.56(dd,J＝8.4,2.4Hz,1H),7.29(s,1H),6.73( d,J＝8.8Hz,1H),4.33(s,3H),3.97(s,3H),3.31(s,2H),2.93(t,J＝10.0Hz,2H),2.62( t,J＝10.0Hz,1H),2.53(s,3H),2.10-2.07(m,2H),1.64(m,2H); ESI-MS:m/z563.2[M+H] ⁺ .

Example 43

1-(4-(1,4-diazaheptan-1-yl)-3-(trifluoromethyl)phenyl)-4-methoxy-8-(6-methoxypyridin-3-yl)-1H-imidazol[4,5-c]quinoline (compound 43)

The synthesis method was the same as in Example 40, yielding 133 mg of a white solid, with a yield of 73%.

¹ H NMR (400MHz, DMSO-d ⁶ )δ8.59-8.49(m,1H),8.21-8.11(m,2H),8.07(d,J＝8.4Hz,1H),7.96(d,J＝8.0Hz,1H),7.93-7.84(m,2H),7.72(d,J＝8.0Hz,1H),7.21 -7.15(m,1H),6.81(d,J＝8.8Hz,1H),4.18(s,3H),3.87(s,3H),3.32-3.28(m,4H),3.14-2.97(m,4H),2.01-1.89(m,2H); ESI-MS:m/z 549.2[M+H] ⁺ .

Example 44

1-(4-(3,6-diazabicyclo[3.1.1]heptane-3-yl)-3-(trifluoromethyl)phenyl)-4-methoxy-8-(6-methoxypyridin-3-yl)-1H-imidazol[4,5-c]quinoline (compound 44)

The synthesis method was the same as in Example 40, yielding 131 mg of a white solid, with a yield of 75%.

¹ H NMR (400MHz, CDCl ₃ )δ8.18(d,J＝2.0Hz,1H),8.09-8.01(m,2H),7.94(d,J＝2.4Hz,1H),7.88(d,J＝8.8Hz,1H),7.84-7.72(m,2H),7.59(dd,J＝8. 4,2.8Hz,1H),7.31(d,J＝2.0Hz,1H),6.74(d,J＝8.8Hz,1H),4.34(s,3H),3.99-3.88(m,5H),3.70-3.50(m,4H),2.85-2.75(m 1H),2.20-2.15(m,1H); ESI-MS:m/z 547.2[M+H] ⁺ .

Example 45

4-Methoxy-8-(6-methoxypyridin-3-yl)-2-methyl-1-(4-(piperazin-1-yl)-3-(trifluoromethyl)phenyl)-1H-imidazo[4,5-c]quinoline (compound 45)

Synthesis of compound 45-2a: In a 100 mL reaction flask, compound 1-5a (92 mg, 0.63 mmol) and PPTS (0.4 mg, 0.0063 mmol) were dissolved in 5 mL of compound 45-1a, and the reaction was carried out overnight at 105 °C. After the reaction was complete, the mixture was cooled to room temperature, 20 mL of n-hexane was added, and the mixture was filtered. The residue was evaporated to dryness to give 280 mg of the product, with a yield of 72%.

Synthesis of compound 45-3a: Compound 45-2a (85 mg, 0.13 mmol) was dissolved in 5 ml of DCM in a 100 ml reaction flask, and then trifluoroacetic acid (1.5 g, 13.4 mmol ₎ was added. The reaction was carried out at room temperature for 4 h. After the reaction was completed, the pH was adjusted to alkaline with saturated _Na₂CO₃ solution, and the mixture was extracted with dichloromethane (100 ml × 3). The organic layers were combined, dried over anhydrous sodium sulfate, and rotary evaporated under reduced pressure to obtain the product, which was directly used in the next reaction.

Synthesis of compound 45: Compound 45-3a (70 mg, 0.13 mmol), compound 45-4a (31 mg, _0.20 mmol), ( _PPh3 ) _4Pd (3 mg, 0.003 mmol), and _Cs2CO3 (127 mg, 0.39 mmol) were added to a 25 mL reaction flask under argon protection. Then, 20 mL of a mixed solvent of DMF and _H2O (volume ratio 3:1) was added, and the mixture was refluxed at 80 °C overnight. After the reaction was complete, the mixture was quenched with water, filtered, and the filter cake was purified by column chromatography (dichloromethane:methanol:triethylamine = 100:10:1) to give 70 mg of a white solid, yield 63%. ¹ H NMR (400MHz, DMSO-d ⁶ )δ8.16(d,J＝2.0Hz,1H),8.09-8.00(m,2H),7.92(d,J＝8.8Hz,1H),7.88(d,J＝8.8Hz,1H),7.83(dd,J＝8.8,2.0Hz,1H),7.69(dd,J＝8 .8,2.4Hz,1H),6.86(d,J＝1.6Hz,1H),6.80(d,J＝8.8Hz,1H),4.16(s,3H),3.86(s,3H),3.11-2.88(m,8H),2.44(s,3H); ESI-MS:m/z 549.2[M+H] ⁺ .

Example 46

8-(6-methoxypyridin-3-yl)-1-(4-(piperazin-1-yl)-3-(trifluoromethyl)phenyl)-1-hydro-[1,2,3]triazole[4,5-c]quinoline (compound 46)

Synthesis of compound 46-2a: Compound 46-1a (5 g, 18.59 mmol) was dissolved in 20 mL of POCl3 in _a 100 mL reaction flask and refluxed at 150 °C for 4 hours. After the reaction was completed, the mixture was cooled to room temperature and then quenched with ice water. The pH of the reaction solution was adjusted to alkaline with sodium bicarbonate solution, 100 mL of water was added, and the mixture was extracted with ethyl acetate (100 mL × 3). The organic layers were combined, dried over anhydrous sodium sulfate, and rotary evaporated under reduced pressure to obtain the crude product, which was directly used in the next step.

Synthesis of compound 46-4a: In a 100 mL reaction flask, compounds 46-2a (3.9 g, 13.56 mmol) and 46-3a (3.9 g, 13.56 mmol) were dissolved in 60 mL of acetic acid and reacted overnight at room temperature. After the reaction was complete, 100 mL of water was added, and the mixture was extracted with dichloromethane (100 mL × 3). The organic layers were combined, dried over anhydrous sodium sulfate, and rotary evaporated under reduced pressure to obtain the crude product, which was directly used in the next step. ¹ H NMR (400MHz, CDCl ₃ )δ10.51(s,1H),9.48(s,1H),7.93(d,J＝8.8Hz,1H),7.79(d,J＝8.8Hz,1H),7.60(s,1H),7.47(s,1H),7. 35(d,J＝8.4Hz,1H),7.28(s,1H),3.78(m,2H),3.63(m,2H),2.94-2.93(m,4H),2.15(s,3H); ESI-MS:m/z 538.1[M+H] ⁺ .

Synthesis of compound 46-5a: In a 100 mL reaction flask, compound 46-4a (5.39 g, 10 mmol), iron powder (2.79 g, 50 mmol), and ammonium chloride (4.28 g, 80 mmol) were dissolved in 200 mL of a mixed solvent of EtOH and _H₂O (4:1), and the mixture was refluxed at 80 °C overnight. After the reaction was complete, the mixture was filtered through diatomaceous earth, water was added, and the pH was adjusted to alkaline with sodium carbonate. The mixture was extracted with dichloromethane (100 mL × 3), and the organic layers were combined. The residue was dried over anhydrous sodium sulfate and evaporated under reduced pressure to obtain the crude product. Recrystallization gave 4 g of a pale yellow solid, with a yield of 78%. ¹ H NMR (400MHz, CDCl ₃ )δ8.61(s,1H),7.88(t,J＝5.6Hz,2H),7.54(dd,J＝8.8,2.0Hz,1H),7.16(d,J＝8.8Hz,1H),6.97(d,J＝2.8Hz,1H),6.66(dd,J＝ 8.8,2.8Hz,1H),5.85(s,1H),4.08(s,2H),3.77-3.65(m,2H),3.60-3.52(m,2H),2.84-2.78(m,4H),2.12(s,3H); ESI-MS:m/z 508.1[M+H] ⁺ .

Synthesis of compound 46-6a: 46-5a was dissolved in 3M HCl at 0℃. After 10 minutes, _1.2M NaNO₂ was added, and the reaction was carried out at 45℃ for 1 hour. After the reaction was complete, the pH was adjusted to alkaline with 1M NaOH solution, and then filtered. The resulting solid was used directly in the next step. ¹ H NMR (400MHz, DMSO-d ⁶ )δ9.74(s,1H),8.34(d,J＝2.4Hz,1H),8.28-8.18(m,2H),8.04(dd,J＝8.8,2.4Hz,1H),7.94(d, J＝8.8Hz,1H),7.69(d,J＝2.0Hz,1H),3.64(m,4H),3.13-2.96(m,4H),2.08(s,3H); ESI-MS:m/z 519.1[M+H] ⁺ .

Synthesis of compound 46-7a: Compound 46-6a (100 mg, 0.19 mmol) was dissolved in a mixed solvent of 2 mL hydrochloric acid and 2 mL ethanol, and refluxed at 120 °C for 4 h. After the reaction was complete, the ethanol was evaporated to dryness, and the pH was adjusted to neutral with 1 M NaOH solution. The mixture was then filtered, dried in an oven, and used directly in the next reaction. ^¹H NMR (400 MHz, DMSO- ^d⁶ ) δ 9.74 (s, 1H), 8.37 (d, J = 1.2 Hz, 1H), 8.29–8.16 (m, 2H), 8.05 (dd, J = 8.8, 1.6 Hz, 1H), 7.93 (d, J = 8.4 Hz, 1H), 7.71 (s, 1H), 3.25 (m, 8H).

Synthesis of Compound 46: Under argon protection, compounds 46-7a (87 mg, 0.18 mmol), 46-8a (42 mg, 0.27 mmol), ( _Ph₃P ) _₄Pd (4.2 mg, 0.004 mmol), and _Cs₂CO₃ (179 mg, 0.55 mmol) were dissolved in a mixed solvent of 8 mL _DMF and 2 mL water. The mixture was stirred at 80 °C for 3 h. After the reaction was completed, the mixture was cooled to room temperature, 100 mL of water was added, and the mixture was extracted with dichloromethane (100 mL × 3). The organic layers were combined, dried over anhydrous sodium sulfate, and evaporated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (dichloromethane:methanol = 5:1) to give 70 mg of a yellow solid, with a yield of 77%. ¹ H NMR (400MHz, DMSO-d ⁶ )δ9.68(s,1H),8.37-8.35(m,2H),8.31(d,J＝2.4Hz,1H),8.23-8.20(m,2H),7.90(d,J＝8.8Hz,1H),7.83(d, J＝8.8,2.8Hz,1H)7.61(d,J＝2.0Hz,1H),6.89(d,J＝8.8Hz,1H),3.89(s,3H),3.02-2.94(m,8H); ESI-MS:m/z 506.2[M+H] ⁺ .

Example 47

8-(6-methoxyphenyl)-1-(4-(piperazin-1-yl)-3-(trifluoromethyl)phenyl)-1-hydro-[1,2,3]triazole[4,5-c]quinoline (compound 47)

The synthesis method was the same as in Example 46, yielding 143g of a white solid with a yield of 78%.

¹ H NMR (400MHz, DMSO-d ⁶ )δ9.64(s,1H),8.38(d,J＝2.4Hz,1H),8.31(d,J＝8.4Hz,1H),8.19(dd,J＝8.4,2.0Hz,1H),8.16(dd,J＝8.8,2.0Hz,1H),7.91(d, J＝8.8Hz,1H),7.64(d,J＝2.0Hz,1H),7.45(d,J＝8.8Hz,2H),6.98(d,J＝8.8Hz,2H),3.80(s,3H),3.10-2.86(m,8H); ESI-MS:m/z 505.2[M+H] ⁺ .

Example 48

8-(4-methoxy-3-methylphenyl)-1-(4-(piperazin-1-yl)-3-(trifluoromethyl)phenyl)-1-hydro-[1,2,3]triazole[4,5-c]quinoline (compound 48)

The synthesis method was the same as in Example 46, yielding 143 mg of a white solid, with a yield of 78%.

¹ H NMR (400MHz, CDCl ₃ )δ9.61(s,1H),8.37(d,J＝8.8Hz,1H),8.09(s,1H),8.04(d,J＝8.4Hz,1H),7.93(d,J＝8.4Hz,1H),7.87(s,1H),7.67(d,J＝8.0Hz ,1H),7.34(d,J＝8.4Hz,1H),7.27(s,1H),6.89(d,J＝8.4Hz,1H),3.90(s,3H),3.12(m,8H),2.27(s,3H); ESI-MS:m/z519.2[M+H] ⁺ .

Example 49

8-(2-Methoxypyrimidin-5-yl)-1-(4-(piperazin-1-yl)-3-(trifluoromethyl)phenyl)-1-hydro-[1,2,3]triazole[4,5-c]quinoline (compound 49)

The synthesis method was the same as in Example 46, yielding 141 mg of a white solid, with a yield of 78%.

¹ H NMR (400MHz, DMSO-d ⁶ )δ9.72(s,1H),8.77(s,2H),8.40(d,J＝8.4Hz,1H),8.37(s,1H),8.27(d,J＝8.4Hz,1H),8. 24(s,1H),7.91(d,J＝8.4Hz,1H),7.72(s,1H),3.97(s,3H),3.10-3.08(m,8H); ESI-MS:m/z 507.2[M+H] ⁺ .

Example 50

1-(4-(piperazin-1-yl)-3-(trifluoromethyl)phenyl)-8-(pyridin-3-yl)-1-hydro-[1,2,3]triazole[4,5-c]quinoline (compound 50)

The synthesis method was the same as in Example 46, yielding 141 mg of a white solid, with a yield of 71%.

¹ H NMR (400MHz, DMSO-d ⁶ )δ9.71(s,1H),8.73(s,1H),8.61(d,J＝4.8Hz,1H),8.40(d,J＝9.6Hz,2H),8.31-8.21(m,2H),7.94(d ,J＝7.6Hz,1H),7.90(d,J＝8.4Hz,1H),7.77(s,1H),7.51-7.46(m,1H),3.04-3.01(m,8H); ESI-MS:m/z 476.2[M+H] ⁺ .

Example 51

8-(5-methoxypyridin-3-yl)-1-(4-(piperazin-1-yl)-3-(trifluoromethyl)phenyl)-1-hydro-[1,2,3]triazole[4,5-c]quinoline (compound 51)

The synthesis method was the same as in Example 46, yielding 127 mg of a white solid, with a yield of 71%.

¹ H NMR (400MHz, DMSO-d ⁶ )δ9.71(s,1H),8.39(d,J＝8.4Hz,1H),8.33(d,J＝6.8Hz,3H),8.29(s,1H),8.25(d,J＝8.4Hz,1H ),7.88(d,J＝8.4Hz,1H),7.78(s,1H),7.48(s,1H),3.89(s,3H),3.04-3.01(m,8H); ESI-MS:m/z 506.2[M+H] ⁺ .

Example 52

8-(5-fluoro-6-methoxypyridin-3-yl)-1-(4-(piperazin-1-yl)-3-(trifluoromethyl)phenyl)-1-hydro-[1,2,3]triazole[4,5-c]quinoline (compound 52)

The synthesis method was the same as in Example 46, yielding 121 mg of a white solid, with a yield of 73%.

¹ H NMR (400MHz, DMSO-d ⁶ )δ9.71(s,1H),8.35(d,J＝8.4Hz,1H),8.30(s,1H),8.21(d,J＝2.4Hz,2H),8.14(d,J＝8.4Hz,1H),7. 98(s,1H),7.85(d,J＝8.8Hz,1H),7.79(d,J＝8.8Hz,1H),3.74(s,3H),2.98-2.96(m,8H); ESI-MS:m/z 524.2[M+H] ⁺ .

Example 53

1-(4-(piperazin-1-yl)-3-(trifluoromethyl)phenyl)-8-(5-(trifluoromethyl)pyridin-3-yl-1-hydro-[1,2,3]triazole[4,5-c]quinoline (compound 53)

The synthesis method was the same as in Example 46, yielding 121 mg of a white solid, with a yield of 73%.

¹ H NMR (400MHz, DMSO-d ⁶ )δ9.75(s,1H),9.08(s,1H),9.03(s,1H),8.43(d,J＝8.4Hz,1H),8.39(d,J＝8.8Hz,1H),8.35(s ,1H),8.25(d,J＝8.4Hz,2H),7.89(s,1H),7.84(d,J＝8.8Hz,1H),2.97-2.92(m,8H); ESI-MS:m/z 544.2[M+H] ⁺ .

Example 54

8-(6-methylpyridin-3-yl)-1-(4-(piperazin-1-yl)-3-(trifluoromethyl)phenyl)-1-hydro-[1,2,3]triazole[4,5-c]quinoline (compound 54)

The synthesis method was the same as in Example 46, yielding 121 mg of a white solid, with a yield of 71%.

¹ H NMR (400MHz, DMSO-d ⁶ )δ9.69(s,1H),8.60(s,1H),8.37(s,2H),8.24(d,J＝8.8Hz,2H),7.89(d,J＝8.4Hz,1H),7.79(d ,J＝8.0Hz,1H),7.73(s,1H),7.33(d,J＝8.0Hz,1H),3.02-2.98(m,8H),2.51(s,3H); ESI-MS:m/z 490.2[M+H] ⁺ .

Example 55

4-Methoxy-1-(3-Methoxy-4-(piperazin-1-yl)phenyl)-8-(6-methoxypyridin-3-yl)-1H-[1,2,3]triazolo[4,5-c]quinoline (compound 55)

The synthesis method was the same as in Example 46, yielding 131 mg of a white solid, with a yield of 73%.

¹ H NMR (400MHz, DMSO-d ⁶ )δ9.65(s,1H),8.34-8.28(m,2H),8.18(dd,J＝8.8,2.0Hz,1H),7.82(dd,J＝8.8,2.4Hz,1H),7.65(d,J＝2.0Hz,1H),7.49(d,J＝2.0Hz,1H),7.41( dd,J＝8.4,2.0Hz,1H),7.26(d,J＝8.4Hz,1H),6.91(d,J＝8.8Hz,1H),3.90(s,3H),3.82(s,3H),3.17-3.10(m,4H),3.05-2.97(m,4H); ESI-MS: m/z 468.2[M+H] ⁺ .

Example 56

1-(3-chloro-4-(piperazin-1-yl)phenyl)-4-methoxy-8-(6-methoxypyridin-3-yl)-1H-[1,2,3]triazolo[4,5-c]quinoline (compound 56)

The synthesis method was the same as in Example 46, yielding 121 mg of a white solid, with a yield of 77%.

¹ H NMR (400MHz, DMSO-d ⁶ )δ9.65(s,1H),8.37-8.28(m,2H),8.18(dd,J＝8.8,2.0Hz,1H),8.11(d,J＝2.0Hz,1H),7.93-7.82(m,2H),7.68(d,J＝1. 6Hz,1H),7.52(d,J＝8.4Hz,1H),6.92(d,J＝8.8Hz,1H),3.90(s,3H),3.15-3.04(m,4H),3.02-2.91(m,4H); ESI-MS:m/z 472.2[M+H] ⁺ .

Example 57

1-(3-fluoro-4-(piperazin-1-yl)phenyl)-4-methoxy-8-(6-methoxypyridin-3-yl)-1H-[1,2,3]triazolo[4,5-c]quinoline (compound 57)

The synthesis method was the same as in Example 46, yielding 121 mg of a white solid, with a yield of 69%.

¹ H NMR (400MHz, CDCl ₃ )δ9.65(s,1H),8.38-8.30(m,2H),8.18(dd,J＝8.8,2.0Hz,1H),7.87(dd,J＝6.4,2.4Hz,1H),7.84(d,J＝2.4Hz,1H),7.74- 7.64(m,2H),7.40(t,J＝8.8Hz,1H),6.93(d,J＝8.8Hz,1H),3.90(s,3H),3.16-3.12(m,4H),3.00-2.92(m,4H); ESI-MS:m/z 456.2[M+H] ⁺ .

Example 58

4-Methoxy-8-(6-methoxypyridin-3-yl)-1-(4-(piperazin-1-yl)phenyl)-1H-[1,2,3]triazolo[4,5-c]quinoline (compound 58)

The synthesis method was the same as in Example 46, yielding 121 mg of a white solid, with a yield of 73%.

¹ H NMR (400MHz, DMSO-d ⁶ )δ9.63(s,1H),8.40-8.28(m,2H),8.17(d,J＝8.4Hz,1H),7.84(d,J＝8.0Hz,1H),7.77-7.72(m,1H),7.72-7.62( m,2H),7.37-7.21(m,2H),6.92(d,J＝8.4Hz,1H),3.90(s,3H),3.34-3.27(m,4H),3.00-2.85(m,4H); ESI-MS:m/z 438.2[M+H] ⁺ .

Example 59

5-(1-(4-(piperazin-1-yl)-3-(trifluoromethyl)phenyl)-1H-[1,2,3]triazole[4,5-c]quinoline-8-yl)-3-(trifluoromethyl)pyridine-2-amino (compound 59)

The synthesis method was the same as in Example 46, yielding 127 mg of a white solid, with a yield of 71%.

¹ H NMR (400MHz, DMSO-d ⁶ )δ9.65(s,1H),8.44(s,1H),8.38-8.27(m,2H),8.23(t,J＝6.8Hz,2H),7.85(d,J＝ 8.4Hz,1H),7.76(s,1H),7.65(s,1H),6.79(s,2H),3.03-3.00(m,8H); ESI-MS:m/z 559.2[M+H] ⁺ .

Example 60

5-(1-(4-(piperazin-1-yl)-3-(trifluoromethyl)phenyl)-1H-[1,2,3]triazole[4,5-c]quinoline-8-yl)pyrimidine-2-amino (compound 60)

The synthesis method was the same as in Example 46, yielding 127 mg of a white solid, with a yield of 71%.

¹ H NMR (400MHz, DMSO-d ⁶ )δ9.64(s,1H),8.41(s,2H),8.35(d,J＝2.4Hz,1H),8.31(d,J＝8.4Hz,1H),8.19-8.16(m,2H),7.88(d ,J＝8.8Hz,1H),7.63(d,J＝1.6Hz,1H),6.99(s,2H),3.00-2.99(m,4H),2.96-2.89(m,4H); ESI-MS:m/z 492.2[M+H] ⁺ .

Example 61

5-(1-(4-(piperazin-1-yl)-3-(trifluoromethyl)phenyl)-1H-[1,2,3]triazole[4,5-c]quinoline-8-yl)pyridine-2-amino (compound 61)

The synthesis method was the same as in Example 46, yielding 117 mg of a white solid, with a yield of 63%.

¹ H NMR (400MHz, DMSO-d ⁶ )δ9.61(s,1H),8.35(d,J＝2.0Hz,1H),8.27(d,J＝8.8Hz,1H),8.20(dd,J＝8.4,2.0Hz,1H),8.17-8.09(m,2H),7.89(d,J＝8.8Hz,1H),7. 58(d,J＝1.6Hz,1H),7.47(dd,J＝8.4,2.4Hz,1H),6.47(d,J＝8.8Hz,1H),6.28(s,2H),2.99-2.98(m,4H),2.93-2.92(m,4H); ESI-MS:m/z 491.2[M+H] ⁺ .

Example 62

2-Methoxy-5-(1-(4-(piperazin-1-yl)-3-(trifluoromethyl)phenyl)-1H-[1,2,3]triazol[4,5-c]quinoline-8-yl)benzonitrile (Compound 62)

The synthesis method was the same as in Example 46, yielding 119 mg of a white solid, with a yield of 65%.

¹ H NMR (400MHz, DMSO-d ⁶ )δ9.69(s,1H),8.40-8.32(m,2H),8.27-8.19(m,2H),7.95-7.84(m,2H),7.74(d,J＝2.0Hz,1 H),7.70(d,J＝1.6Hz,1H),7.33(d,J＝8.8Hz,1H),3.97(s,3H),3.10-2.94(m,8H); ESI-MS:m/z 530.2[M+H] ⁺ .

Example 63

1-(4-(piperazin-1-yl)-3-(trifluoromethyl)phenyl)-8-(1H-pyrrolo[2,3-b]pyridin-5-yl)-1H-[1,2,3]triazolo[4,5-c]quinoline (compound 63)

The synthesis method was the same as in Example 46, yielding 131 mg of a white solid, with a yield of 71%.

¹ H NMR (400MHz, DMSO-d ⁶ )δ11.85(s,1H),9.68(s,1H),8.44(d,J＝2.0Hz,1H),8.41(d,J＝2.0Hz,1H),8.37(d,J＝8.8Hz,1H),8.33-8.19(m,2H),8.03(d,J＝2.0 Hz,1H),7.93(d,J＝8.4Hz,1H),7.73(d,J＝1.6Hz,1H),7.60-7.53(m,1H),6.44(dd,J＝3.2,1.6Hz,1H),3.16-2.92(m,8H); ESI-MS:m/z 515.2[M+H] ⁺ .

Example 64

5-(1-(3-fluoro-4-(piperazin-1-yl)phenyl)-1H-[1,2,3]triazol[4,5-c]quinoline-8-yl)-3-(trifluorotoluene)pyridine-2-amino (compound 64)

The synthesis method was the same as in Example 46, yielding 132 mg of a white solid, with a yield of 71%.

¹ H NMR (400MHz, DMSO-d ⁶ )δ9.64(s,1H),8.50(d,J＝2.0Hz,1H),8.31(d,J＝8.8Hz,1H),8.23(dd,J＝8.8,2.0Hz,1H),7.89(dd,J＝13.2,2.4Hz,1H),7.80(d,J＝1. 6Hz,1H),7.76(d,J＝1.6Hz,1H),7.73-7.67(m,1H),7.39-7.35(m,1H),6.81(s,2H),3.19-3.12(m,4H),3.00-2.99(m,4H); ESI-MS:m/z 509.2[M+H] ⁺ .

Example 65

5-(1-(3-methoxy-4-(piperazin-1-yl)phenyl)-1H-[1,2,3]triazol[4,5-c]quinoline-8-yl)-3-(trifluorotoluene)pyridine-2-amino (compound 65)

The synthesis method was the same as in Example 46, yielding 119 mg of a white solid, with a yield of 71%.

¹ H NMR (400MHz, CDCl ₃ )δ9.60(s,1H),8.43-8.32(m,2H),7.94(dd,J＝8.8,2.0Hz,1H),7.87(d,J＝2.0Hz,1H),7.79(d,J＝1.6Hz,1H),7.29- 7.26(m,1H),7.18(d,J＝8.4Hz,1H),7.14(d,J＝2.4Hz,1H),5.14(s,2H),3.90(s,3H),3.20-3.14(m,8H); ESI-MS:m/z 521.2[M+H] ⁺ .

Example 66

5-(1-(3-chloro-4-(piperazin-1-yl)phenyl)-1H-[1,2,3]triazol[4,5-c]quinoline-8-yl)-3-(trifluorotoluene)pyridine-2-amino (compound 66)

The synthesis method was the same as in Example 46, yielding 123 mg of a white solid, with a yield of 69%.

¹ H NMR (400MHz, DMSO-d ⁶ )δ9.64(s,1H),8.48(d,J＝2.4Hz,1H),8.32(d,J＝8.8Hz,1H),8.23(dd,J＝8.8,2.0Hz,1H),8.12(d,J＝2.4Hz,1H),7.89(dd,J＝8.4,2.4Hz, 1H),7.80(d,J＝2.0Hz,1H),7.75(d,J＝2.0Hz,1H),7.48(d,J＝8.8Hz,1H),6.80(s,2H),3.10-3.09(m,4H),2.99-2.97(m,4H); ESI-MS: m/z 525.2[M+H] ⁺ .

Example 67

5-(1-(3-methyl-4-(piperazin-1-yl)phenyl)-1H-[1,2,3]triazol[4,5-c]quinoline-8-yl)-3-(trifluorotoluene)pyridine-2-amino (compound 67)

The synthesis method was the same as in Example 46, yielding 131 mg of a white solid, with a yield of 73%.

¹ H NMR (400MHz, DMSO-d ⁶ )δ9.64(s,1H),8.45(s,1H),8.31(d,J＝8.8Hz,1H),8.19(dd,J＝8.8,2.0Hz,1H),7.77-7.76(m,2H),7.7 6-7.69(m,2H),7.40(d,J＝8.4Hz,1H),6.78(s,2H),3.23(m,4H),3.13(m,4H),2.42(s,3H); ESI-MS:m/z 505.2[M+H] ⁺ .

Example 68

5-(1-(4-(piperazin-1-yl)phenyl)-1H-[1,2,3]triazol[4,5-c]quinoline-8-yl)-3-(trifluoromethyl)pyridine-2-amino (compound 68)

The synthesis method was the same as in Example 46, yielding 121 mg of a white solid, with a yield of 71%.

¹ H NMR (400MHz, DMSO-d ⁶ )δ9.62(s,1H),8.51(d,J＝1.9Hz,1H),8.30(d,J＝8.7Hz,1H),8.22(dd,J＝8.7,2.0Hz,1H),7.81-7.76(m,2H), 7.69(d,J＝8.9Hz,2H),7.24(d,J＝8.9Hz,2H),6.79(s,2H),3.29-3.24(m,5H),2.98-2.89(m,4H); ESI-MS:m/z 491.2[M+H] ⁺ .

Example 69

5-(7-fluoro-1-(4-(piperazin-1-yl)-3-(trifluoromethyl)phenyl)-1H-[1,2,3]triazolo[4,5-c]quinolin-8-yl)-3-(trifluoromethyl)pyridine-2-amino (compound 69)

The synthesis method was the same as in Example 46, yielding 127 mg of a white solid, with a yield of 71%.

¹ H NMR (400MHz, DMSO-d ⁶ )δ9.72(s,1H),8.37-8.28(m,2H),8.26-8.15(m,2H),7.82(d,J＝8.8Hz,1H),7 .74(s,1H),7.58(d,J＝8.4Hz,1H),6.89(s,2H),3.09-2.89(m,8H); ESI-MS:m/z 577.2[M+H] ⁺ .

Example 70

4-Methoxy-8-(6-methoxypyridin-3-yl)-1-(4-(piperazin-1-yl)-3-(trifluoromethyl)phenyl)-1H-pyrazolo[4,3-c]quinoline (Compound 70)

Synthesis of compound 70-3a: In a 100 mL reaction flask, compound 70-1a (1.97 g, 8 mmol), CDI (1.43 g, 8.8 mmol), compound 70-2a (2.04 g, 14 mmol), and magnesium chloride (761 mg, 8 mmol) were dissolved in ultradry THF and reacted at 70 °C for 1 h. After the reaction was complete, the mixture was extracted with ethyl acetate and water. The organic phase was dried over anhydrous sodium sulfate and then evaporated to dryness to give 1.8 g of the product, with a yield of 72%. ^¹H NMR (400 MHz, _CDCl₃ ) δ 8.05 (d, J = 8.8 Hz, 1H), 7.76 (d, J = 7.2 Hz, 1H), 7.65 (s, 1H), 4.17 (q, J = 7.2 Hz, 2H), 3.86 (s, 2H), 1.25 (t, J = 7.2 Hz, 3H).

Synthesis of compound 70-5a: Compound 70-3a (1.82 g, 5.75 mmol) and compound 70-4a (3.42 g, 28.75 mmol) were dissolved in 20 mL of toluene in a 100 mL reaction flask and refluxed overnight. After the reaction was complete, the product was directly filtered and evaporated to dryness to give 1.53 g of product, yield 72%. ^¹H NMR (400 MHz, _CDCl₃ ) δ 8.02 (s, 1H), 7.93 (d, J = 8.4 Hz, 1H), 7.59 (dd, J = 8.8, 1.2 Hz, 1H), 7.48 (s, 1H), 3.88 (q, J = 7.2 Hz, 2H), 3.40 (s, 3H), 3.12 (s, 3H), 0.89 (t, J = 7.2 Hz, 3H).

Synthesis of compound 70-7a: Compound 70-5a (1.53 g, 4 mmol) and compound 70-6a (988 mg, 4 mmol) were dissolved in 20 mL of ethanol in a 100 mL reaction flask and reacted at 90 °C for 4 h. After the reaction was complete, the solvent was evaporated and purified by column chromatography (dichloromethane:methanol = 100:5) to give 1.63 g of a yellow solid, yield 81%.

Synthesis of compound 70-8a: In a 100 mL reaction flask, compound 70-7a (1.62 g, 3.12 mmol), iron powder (872 mg, 15.62 mmol), and ammonium chloride (1.34 g, 24.96 mmol) were dissolved in 25 mL of a mixed solvent of EtOH and _H₂O (volume ratio 4:1). The mixture was refluxed at 80 °C overnight. After the reaction was complete, the mixture was filtered through diatomaceous earth, water was added, and the pH was adjusted to alkaline with sodium carbonate. The mixture was extracted with dichloromethane (100 mL × 3), and the organic layers were combined. The residue was dried over anhydrous sodium sulfate and evaporated under reduced pressure to obtain the crude product. Recrystallization gave 1.41 g of a pale yellow solid, yield 93%.

Synthesis of compound 70-9a: In a 100 ml reaction flask, compound 70-8a (1.41 g, 2.9 mmol) was dissolved in a mixed solution of 30 ml ethanol and 30 ml hydrochloric acid (10%). The reaction was carried out at room temperature for 4 h. After the reaction was completed, the product was filtered and dried to obtain 1.24 g of product, with a yield of 97%.

Synthesis of compound 70-10a: Compound 70-9a (1.24 g, 2.8 mmol) was dissolved in a mixed solution of 7.7 mL _POCl3 and 1.5 mL DIPEA in a 100 mL reaction flask and reacted at 100 °C for 16 h. After the reaction was completed, the mixture was cooled to room temperature and then quenched with ice water. The pH of the reaction solution was adjusted to alkaline with sodium bicarbonate solution, 100 mL of water was added, and the mixture was extracted with ethyl acetate (100 mL × 3). The organic layers were combined, dried over anhydrous sodium sulfate, and rotary evaporated under reduced pressure to obtain the crude product, which was directly added to the next step.

Synthesis of compound 70-11a: In a 100 mL reaction flask, anhydrous methanol (186 mg, 5.8 mmol) was dissolved in 20 mL of dry tetrahydrofuran. NaH (473 mg, 11.8 mmol) was added and the reaction was carried out for 10 min. Then, compound 70-10a (1.36 g, 2.9 mmol) was added, and the reaction was carried out at room temperature for 4 h. After the reaction was completed, 20 mL of saturated _NaHCO3 was added, and the mixture was extracted with dichloromethane (100 mL × 3). The organic layers were combined, dried over anhydrous sodium sulfate, and rotary evaporated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (dichloromethane:methanol = 100:1) to give 934 mg of compound 70-11a, with a yield of 71%. ¹ H NMR (400MHz, CD ₂ Cl ₂ ) δ8.35 (s, 1H), 8.05 (s, 1H), 7.86 (t, J = 6.4 Hz, 3H), 7.72 (d, J = 13.2 Hz, 2H), 4.24 (s, 3H).

Synthesis of compound 70-13a: Under argon protection, compounds 70-11a (934 mg, 2.05 mmol), 70-12a (470 mg, 3.08 mmol), ( _Ph₃P ) _₄Pd (47 mg, 0.041 mmol), and _Cs₂CO₃ (2 g, 6.15 mmol) were dissolved in a mixed solvent of 8 mL _DMF and 2 mL water. The mixture was stirred at 80 °C for 3 h. After the reaction was completed, the mixture was cooled to room temperature, 100 mL of water was added, and the mixture was extracted with dichloromethane (100 mL × 3). The organic layers were combined, dried over anhydrous sodium sulfate, and evaporated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (dichloromethane:methanol = 5:1) to give 848 mg of a yellow solid, with a yield of 77%. ¹ H NMR (400MHz, CDCl ₃ )δ8.34(s,1H),8.25(s,1H),8.12-8.00(m,2H),7.84-7.77(m,3H),7.64(s, 1H),7.56(d,J＝8.8Hz,1H),6.79(d,J＝8.8Hz,1H),4.25(s,3H),3.98(s,3H).

Synthesis of compound 70: Compound 70-13a (150 mg, 0.31 mmol), piperazine (107 mg, 1.24 mmol), potassium tert-butoxide (70 mg, 0.62 mmol), and _Pd₂ (dba) _₃ were added to a 25 mL reaction flask, followed by 10 mL of dioxane. The mixture was refluxed at 120 °C overnight. After the reaction was completed, the mixture was quenched with water, filtered, and the filter cake was purified by column chromatography (dichloromethane:methanol:triethylamine = 100:10:1 (V/V)) to give compound 70, 97 mg of white solid, yield 59%. ¹ H NMR (400MHz, CDCl ₃ )δ8.17(s,1H),7.85(q,J＝8.8Hz,2H),7.69(s,1H),7.62(d,J＝8.4Hz,1H),7.48-7.39(m,2H),7.33(d, J＝9.2Hz,2H),6.75(d,J＝8.3Hz,1H),4.13(s,3H),3.93(s,3H),3.23(m,4H),3.13(m,4H); ESI-MS:m/z 535.2[M+H] ⁺ .

Example 71

1-(4-(4-methoxy-8-(6-methoxypyridin-3-yl)-1H-pyrazolo[4,3-c]quinoline-1-yl)-2-(trifluoromethyl)phenyl)-N,N-dimethylpiperidin-4-amino (Compound 71)

The synthesis method was the same as in Example 70, yielding 117 mg of a white solid, with a yield of 69%.

¹ H NMR (400MHz, CDCl ₃ )δ8.13(s,1H),7.83(dd,J＝18.3,8.7Hz,2H),7.57(s,1H),7.51(d,J＝8.6H z,1H),7.45(s,1H),7.37(d,J＝8.8Hz,1H),7.30(s,1H),6.73(d,J＝8.7Hz,1 H),4.14(s,3H),3.95(s,3H),3.19(d,J＝11.4Hz,2H),2.77(t,J＝11.4Hz,2H ), 2.35 (s, 7H), 1.90 (d, J = 12.1Hz, 2H), 1.74 (d, J = 10.6Hz, 2H); ESI-MS: m/z 577.3[M+H] ⁺ .

Example 72

^N1- (4-(4-methoxy-8-(6-methoxypyridin-3-yl)-1H-pyrazolo[4,3-c]quinoline-1-yl)-2-(trifluoromethyl)phenyl) ^-N1 , ^N2 -dimethylethane-1,2-diamino (compound 72)

The synthesis method was the same as in Example 70. The product was a white solid, 108 mg, with a yield of 67%.

¹ H NMR (400MHz, CDCl ₃ )δ8.23(s,1H),7.85(s,3H),7.80(d,J＝8.8Hz,1H),7.64(s,1H),7.52-7.44(m,3H),6.80(d,J＝8.8Hz,1H),4 .11(s,3H),3.95(s,3H),3.40(t,J＝5.0Hz,2H),3.07(t,J＝5.0Hz,2H),2.74(s,3H),2.67(s,3H); ESI-MS:m/z 537.2[M+H] ⁺ .

Example 73

(S)-4-methoxy-8-(6-methoxypyridin-3-yl)-1-(4-(3-methylpiperazin-1-yl)-3-(trifluoromethyl)phenyl)-1H-pyrazolo[4,3-c]quinoline (compound 73)

The synthesis method was the same as in Example 70. The product was a white solid, 113 mg, with a yield of 63%.

^1H NMR (400MHz, DMSO) δ10.04(s,1H),8.63(d,J＝6.3Hz,2H),8.14(dd,J＝28.0,8.0Hz,2H),7.79(d,J＝8.3Hz,1H),7.59(d,J＝ 13.2Hz, 3H), 6.96 (d, J = 8.4Hz, 1H), 4.01 (s, 3H), 3.90 (s, 3H), 3.04 (d, J = 11.2Hz, 7H), 2.88 (d, J = 11.2Hz, 3H); ESI-MS: m/z 549.2[M+H] ⁺ .

Example 74

4-Methoxy-8-(6-methoxypyridin-3-yl)-1-(4-(piperazin-1-yl)-3-(trifluoromethyl)phenyl)-imidazo[1,2-a]quinoxaline (compound 74)

Synthesis of compound 74-3a: Compound 74-1a (1.9 g, 10 mmol) was dissolved in 30 mL of DMF in a 100 mL reaction flask. Then, compound 74-2a (1.12 g, 10 mmol), HOBT (2.03 g, 15 mmol), and EDCI (2.88 g, 15 mmol) were added to the reaction system, and the reaction was carried out at room temperature for 21 h. After the reaction was completed, the mixture was extracted with ethyl acetate (100 mL × 3), the organic layers were combined, dried over anhydrous sodium sulfate, and rotary evaporated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (petroleum ether: ethyl acetate = 10:1) to obtain 960 mg of compound 74-3a, with a yield of 34%.

Synthesis of compound 74-4a: Compound 74-3a (1.96 g, 6.9 mmol) was dissolved in 30 mL of DMA in a 100 mL reaction flask, and NaH (359 mg, 8.97 mmol) was added. The mixture was refluxed at 170 °C for 4 h. After the reaction was complete, the mixture was cooled to room temperature, water was added, and the solution was directly filtered to obtain 1.64 g of compound 74-4a, with a yield of 91%.

Synthesis of compound 74-5a: Compound 74-4a (1.64 g, 6.2 mmol) was dissolved in _POCl3 (17.4 mL, 186.4 mmol) in a 100 mL reaction flask. DIPEA (1.8 mL, 18.6 mmol) was added at 15 °C, and the reaction was carried out at 100 °C for 16 h. After the reaction was complete, the solution was slowly poured into ice water to quench the reaction. The pH was then adjusted to greater than 7 with sodium bicarbonate solution. The product was directly obtained by filtration, yielding 1.75 g of compound 74-5a in 99% yield.

Synthesis of compound 74-6a: In a 100 mL reaction flask, ultradry methanol (397 mg, 12.4 mmol) was dissolved in 20 mL of ultradry tetrahydrofuran, followed by the addition of NaH (992 mg, 24.8 mmol). After reacting for 10 min, compound 74-5a (1.75 g, 6.2 mmol) was added, and the reaction was carried out at room temperature for 4 h. After the reaction was complete, the sample was directly evaporated to dryness with silica gel and purified by column chromatography (dichloromethane:methanol = 100:1) to give 1.31 g of compound 74-6a, with a yield of 76%. ^¹H NMR (400 MHz, _CDCl₃ ) δ 7.99 (s, 1H), 7.94 (d, J = 1.6 Hz, 1H), 7.72 (d, J = 8.8 Hz, 2H), 7.60 (dd, J = 8.8, 1.6 Hz, 1H), 4.24 (s, 3H).

Synthesis of compound 74-7a: Under argon protection, compound 74-6a (1.26 g, 4.5 mmol), p-methoxypyridinephenylboronic acid (1 g, 6.8 mmol), ( _Ph₃P ) _₄Pd (104 mg, 0.09 mmol), and _Cs₂CO₃ ( _4.4 g, 13.5 mmol) were dissolved in a mixed solvent of 27 mL DMF and 9 mL water. The mixture was stirred at 80 °C for 3 h. After the reaction was completed, the mixture was cooled to room temperature, 100 mL of water was added, and the mixture was extracted with dichloromethane (100 mL × 3). The organic layers were combined, dried over anhydrous sodium sulfate, and evaporated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (dichloromethane:methanol = 5:1) to give 1.3 g of a yellow solid, with a yield of 97%. ¹ H NMR (400MHz, DMSO-d ⁶ )δ9.31(s,1H),8.59(s,1H),8.11(d,J＝8.4Hz,1H),7.94-7.85(m,2H),7.81(s,1H),6.98(d,J＝8.4Hz,1H),4.14(s,3H),3.93(s,3H).

Synthesis of compound 74-8a: In a 100 mL reaction flask, compound 74-7a (1.3 g, 4.5 mmol) was dissolved in 40 mL of DMF. Then, NBS (1.2 g, 6.75 mmol) was dissolved in 10 mL of DMF and slowly added dropwise to the reaction flask. The reaction was carried out at room temperature for 3 h, and then slowly increased to 80 °C and reacted overnight. After the reaction was completed, the mixture was cooled to room temperature, 100 mL of water was added, and the mixture was extracted with dichloromethane (100 mL × 3). The organic layers were combined, dried over anhydrous sodium sulfate, and evaporated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (dichloromethane:methanol = 20:1) to give 1.47 g of a yellow solid, with a yield of 85%.

Synthesis of compound 74-10a: In a 100 mL reaction flask, compounds 74-8a (150 mg, 0.39 mmol), 74-9a (218 mg, 0.58 mmol), ( _Ph₃P ) _₄Pd (9 mg, 0.008 mmol), and _Cs₂CO₃ (381 mg, 1.17 mmol) were dissolved in 9 mL of DMF and 3 mL of water and a mixed solvent. The mixture was stirred at 80 °C for 3 h. After the reaction was complete, the _mixture was cooled to room temperature, and 100 mL of water was added. The mixture was extracted with dichloromethane (100 mL × 3). The organic layers were combined, dried over anhydrous sodium sulfate, and evaporated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (dichloromethane:methanol = 5:1) to give 182 mg of a yellow solid, with a yield of 74%. ¹ H NMR (400MHz, DMSO-d ⁶ )δ8.02(s,1H),7.97(d,J＝8.4Hz,1H),7.92(s,1H),7.86(d,J＝7.6Hz,2H),7.82-7.74(m,2H),7.73-7.68(m ,1H),7.26(s,1H),6.82(d,J＝8.4Hz,1H),4.18(s,3H),3.86(s,3H),3.53(m,4H),3.00(m,4H),1.45(s,9H).

Synthesis of compound 74: Compound 74-10a (182 mg, 0.28 mmol) was dissolved in 10 mL of dichloromethane in a 100 mL reaction flask, followed by the addition of trifluoroacetic acid (2.2 mL, 28 mmol) and the reaction was carried out at room temperature for 4 h. After the reaction was complete, the solvent was evaporated and the mixture was purified by column chromatography (dichloromethane:methanol = 20:1) to give 114 mg of compound 74, with a yield of 75%. ¹ H NMR (400MHz, DMSO-d ⁶ )δ7.99(s,1H),7.95(d,J＝8.4Hz,1H),7.93(s,1H),7.82(d,J＝8.4Hz,1H),7.77(dd,J＝11.2,7.2Hz,3H),7.63(dd ,J＝8.8,2.0Hz,1H),7.24(s,1H),6.76(d,J＝8.4Hz,1H),4.16(s,3H),3.84(s,3H),3.00-2.96(m,8H); ESI-MS:m/z 535.2[M+H] ⁺ .

Example 75

4-(4-(4-methoxy-8-(6-methoxypyridin-3-yl)-1H-[1,2,3]triazol[4,5-c]quinolin-1-yl)-2-(trifluoromethyl)phenyl)piperazin-2-one (Compound 75)

The synthesis method was the same as in Example 1, yielding 125 mg of a white solid, with a yield of 71%.

¹ H NMR (400MHz, CDCl ₃ )δ8.22(d,J＝2.0Hz,1H),8.08(d,J＝8.4Hz,2H),7.98-7.82(m,2H),7.70-7.59(m,3H),6.79(d,J＝8.8Hz ,1H),6.14(s,1H),4.35(s,3H),3.97(s,3H),3.84(s,2H),3.57(m,2H),3.45-3.28(m,2H); ESI-MS:m/z 550.2[M+H] ⁺ .

Example 76

(R)-4-methoxy-8-(6-methoxypyridin-3-yl)-1-(4-(2-methylpiperazin-1-yl)-3-(trifluoromethyl)phenyl)-1H-[1,2,3]triazole[4,5-c]quinoline (compound 76)

The synthesis method was the same as in Example 1, yielding 123 mg of a white solid, with a yield of 70%.

¹ H NMR (400MHz, CDCl ₃ )δ8.25(d,J＝2.4Hz,1H),8.12-8.05(m,2H),7.91(dd,J＝17.6,8.8Hz,2H),7.80(d,J＝8.4Hz,1H),7.65-7.55(m,2H),6.74(d,J＝8. 4Hz,1H),4.38(s,3H),3.97(s,3H),3.25(m,2H),3.15(m,4H),2.90(m,1H),2.83-2.75(m,1H),0.92(d,J＝6.0Hz,3H); ESI-MS:m/z 550.2[M+H] ⁺ .

Example 77

(S)-4-methoxy-8-(6-methoxypyridin-3-yl)-1-(4-(3-methylpiperazin-1-yl)-3-(trifluoromethyl)phenyl)-1H-imidazol[4,5-c]quinoline (compound 77)

The synthesis method was the same as in Example 40, yielding 133 mg of a white solid, with a yield of 73%.

¹ H NMR (400MHz, CDCl ₃ )δ8.18(s,1H),8.03(d,J＝8.8Hz,1H),8.00(s,1H),7.88(d,J＝2.4Hz,1H),7 .78-7.68(m,2H),7.61(d,J＝8.4Hz,1H),7.53(dd,J＝8.8,2.4Hz,1H),7.26(s ,1H),6.71(d,J＝8.8Hz,1H),4.31(s,3H),3.94(s,3H),3.27-3.06(m,5H),3 .02-2.89(m,1H),2.63(t,J＝10.4Hz,1H),1.17(d,J＝6.4Hz,3H); ESI-MS:m/z 549.2[M+H] ⁺ .

Example 78

^N1- (4-(4-methoxy-8-(6-methoxypyridin-3-yl)-1H-imidazol[4,5-c]quinoline-1-yl)-2-(trifluoromethyl)phenyl) ^-N1 , ^N2 -dimethylethane-1,2-diamino (Compound 78)

The synthesis method was the same as in Example 40, yielding 117 mg of a white solid, with a yield of 71%.

¹ H NMR (400MHz, CDCl ₃ )δ8.19(d,J＝2.0Hz,1H),8.06(d,J＝8.8Hz,1H),8.03(s,1H),7.91(d,J＝2. 0Hz,1H),7.80-7.71(m,2H),7.67(d,J＝8.8Hz,1H),7.59(dd,J＝8.8,2.4Hz, 1H),7.33(s,1H),6.76(d,J＝8.8Hz,1H),4.33(s,3H),3.96(s,3H),3.29(d, J＝6.0Hz,2H),2.88(s,3H),2.82(t,J＝6.0Hz,2H),2.47(s,3H); ESI-MS:m/z 537.2[M+H] ⁺ .

Example 79

1-(4-(4-methoxy-8-(6-methoxypyridin-3-yl)-1H-pyrazol[4,3-c]quinoline-1-yl)-2-(trifluoromethyl)phenyl)-N-methylpiperidin-4-amino (Compound 79)

The synthesis method is as described in Example 70.

¹ H NMR (400MHz, CDCl ₃ )δ8.13(s,1H),7.83(dd,J＝18.4,8.8Hz,2H),7.57(s,1H),7.51(d,J＝8.6H z,1H),7.45(s,1H),7.37(d,J＝8.8Hz,1H),7.30(s,1H),6.73(d,J＝8.7Hz,1 H),4.14(s,3H),3.95(s,3H),3.19(d,J＝11.4Hz,2H),2.77(t,J＝11.4Hz,2H ), 2.35 (s, 4H), 1.90 (d, J = 12.1Hz, 2H), 1.74 (d, J = 10.6Hz, 2H); ESI-MS: m/z 563.2

Example 80

(S)-1-(4-(3-ethylpiperazin-1-yl)-3-(trifluoromethyl)phenyl)-4-methoxy-8-(6-methoxypyridin-3-yl)-1H-pyrazole[4,3-c]quinoline (compound 80)

The synthesis method is as described in Example 70.

¹ H NMR (400MHz, CDCl ₃ )δ8.15(s,1H),7.89(d,J＝8.4Hz,1H),7.84(d,J＝8.8Hz,1H),7.67-7.57(m,2H), 7.50-7.40(m,2H),7.34(d,J＝8.8Hz,1H),7.09-7.04(m,1H),6.76(d,J＝8.4Hz,1 H),4.15(s,3H),3.94(s,3H),3.39-3.31(m,1H),3.30-3.16(m,4H),3.16-3.09( m,1H),3.00-2.93(m,1H),1.02(t,J＝7.2Hz,3H),0.92-0.80(m,2H); ESI-MS:m/z 563.2[M+H] ⁺ .

Example 81

(S)-1-(4-(3-ethylpiperazin-1-yl)-3-(trifluoromethyl)phenyl)-4-methoxy-8-(6-methoxypyridin-3-yl)-1H-imidazo[4,5-c]quinoline (compound 81)

The synthesis method was the same as in Example 40, yielding 117 mg of a white solid, with a yield of 65%.

¹ H NMR (400MHz, DMSO-d ⁶ )δ8.54(s,1H),8.18(s,2H),8.08(d,J＝7.8Hz,1H),7.97(d,J＝8.8Hz,1H),7 .87(t,J＝8.4Hz,2H),7.71(d,J＝8.4Hz,1H),7.19(s,1H),6.81(s,1H),4.19( s,3H),3.87(s,3H),3.07(d,J＝10.8Hz,3H),2.95(s,2H),2.79(s,1H),2.00 (d, J＝8.0Hz, 1H), 1.44 (d, J＝6.8Hz, 2H), 0.92 (t, J＝7.5Hz, 3H).; ESI-MS: m/z 563.2[M+H] ⁺ .

Example 82

4-Methoxy-8-(6-Methoxy-pyridin-3-yl)-1-(4-(piperazin-1-yl)-3-(trifluoromethyl)phenyl)-[1,2,4]triazolo[4,3-a]quinoxaline (compound 82)

Synthesis of compound 82-3a: Compound 82-1a (1 g, 3.52 mmol) was added to a 100 mL round-bottom flask, followed by 15 mL of _CH3COOH , and then compound 82-2a (1.48 g, 3.52 mmol). The reaction flask was then transferred to an oil bath at 120 °C and refluxed with water for 4 h. After the reaction was complete, the solvent was removed by concentration under reduced pressure. The pH was adjusted to neutral by adding _NaHCO3 aqueous solution. The mixture was extracted three times with ₄₀ mL of EA and washed with saturated brine. The organic phase was dried over _Na2SO4 and then concentrated under reduced pressure under vacuum to remove the solvent. The crude product was purified by silica gel column chromatography (DCM:MeOH = 15:1) to obtain 1.6 g of compound 82-3a, with a yield of 75%.

Synthesis of compound 82-4a: Compound 82-3a (0.6 g, 0.96 mmol) was added to a 50 mL round-bottom flask, followed by 10 mL of trifluoroacetic acid and 0.5 mL of trifluoromethanesulfonic acid. The reaction flask was then transferred to an oil bath at 90 °C and reacted for 16 h. After the reaction was complete, the solvent was removed by vacuum concentration, and the pH was adjusted to neutral by adding saturated _{Na₂CO₃ solution} . The mixture was then filtered through a Buchner funnel, and the filter cake was dried in a vacuum drying oven at 65 °C before being directly added to the next step.

Synthesis of compound 82-5a: In a 100 ml reaction flask, compound 82-4a (255 mg, 0.52 mmol), potassium carbonate (108 mg, 0.78 mmol), and TBAI (38 mg, 0.1 mmol) were dissolved in 15 ml of _CH3CN . Then, benzyl bromide (106 mg, 0.62 mmol) was added to the reaction system, and the reaction was carried out at room temperature for 21 h. After the reaction was complete, the sample was extracted with ethyl acetate (100 ml × 3), the organic layers were combined, dried over anhydrous sodium sulfate, and rotary evaporated under reduced pressure to obtain the crude product. Column chromatography yielded 170 mg of compound 82-5a, with a yield of 56%. ^¹H NMR (400 MHz, _CDCl₃ ) δ 7.97 (s, 1H), 7.88 (s, 1H), 7.68 (s, 1H), 7.51 (d, J = 9.6 Hz, 2H), 7.37 (s, 4H), 7.27 (s, 1H), 7.22 (s, 1H), 3.62 (s, 2H), 3.14 (m, 4H), 2.68 (m, 4H).

Synthesis of compound 82-6a: In a 100 mL reaction flask, compound 82-5a (170 mg, 0.29 mmol), _POCl3 (1.34 g, 9 mmol), and DIPEA (113 mg, 0.88 mmol) were added to the reaction system and reacted at 100 °C for 16 h. After the reaction was complete, the mixture was extracted with ethyl acetate (100 mL × 3), the organic layers were combined, dried over anhydrous sodium sulfate, and rotary evaporated under reduced pressure to obtain the crude product. Column chromatography yielded 162 mg of compound 82-3a, with a yield of 93%.

Synthesis of compound 82-7a: In a 100 ml reaction flask, methanol (16 mg, 0.48 mmol) was dissolved in ultra-dry THF, and then NaH (39 mg, 0.97 mmol) was added. The reaction was allowed to proceed for 10 minutes, and then 82-6a (145 mg, 0.24 mmol) was added. The reaction was allowed to proceed for 5 hours at room temperature. After the reaction was complete, the sample was extracted with ethyl acetate (100 ml × 3), the organic layers were combined, dried over anhydrous sodium sulfate, and rotary evaporated under reduced pressure to obtain the crude product. Column chromatography yielded 68 mg of compound 82-4a, with a yield of 47%. ^¹H NMR (400 MHz, _CDCl₃ ) δ 8.02 (d, J = 2.0 Hz, 1H), 7.91–7.83 (m, 1H), 7.76 (d, J = 8.8 Hz, 1H), 7.63 (dd, J = 8.8, 2.0 Hz, 1H), 7.61–7.58 (m, 1H), 7.50–7.29 (m, 6H), 4.32 (s, 3H), 3.70 (s, 2H), 3.34–3.05 (m, 4H), 2.91–2.57 (m, 4H).

Synthesis of compound 82-9a: In a 100 mL reaction flask, compounds 82-7a (68 mg, 0.11 mmol), 82-8a (26 mg, 0.17 mmol), ( _Ph₃P ) _₄Pd (2.5 mg, 0.002 mmol), and _Cs₂CO₃ (108 mg, 0.33 mmol ₎ were dissolved in a mixed solvent of 9 mL DMF and 3 mL water. The mixture was stirred at 80 °C for 3 h. After the reaction was completed, the mixture was cooled to room temperature, 100 mL of water was added, and the mixture was extracted with dichloromethane (100 mL × 3). The organic layers were combined, dried over anhydrous sodium sulfate, and evaporated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (dichloromethane:methanol = 5:1) to give 61 mg of a yellow solid, with a yield of 90%.

Synthesis of compound 82: In a 100 mL reaction flask, compound 82-6a (76 mg, 0.11 mmol) was dissolved in 10 mL of methanol, and then Pd-C (47 mg) was added. The mixture was stirred at 75 °C for 5 h. After the reaction was completed, the mixture was cooled to room temperature, 100 mL of water was added, and the mixture was extracted with dichloromethane (100 mL × 3). The organic layers were combined, dried over anhydrous sodium sulfate, and evaporated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography to give 30 mg of a yellow solid, with a yield of 52%. ¹ H NMR (400MHz, DMSO-d ⁶ )δ8.24-8.18(m,1H),8.18-8.08(m,2H),8.07-8.00(m,1H),7.93-7.84(m,2H),7.69(d,J＝7.8Hz,1H) ,7.30-7.18(m,1H),6.84(d,J＝8.3Hz,1H),4.24(s,3H),3.86(s,3H),3.21-3.12(m,8H); ESI-MS:m/z 536.2[M+H] ⁺ .

Example 83

4-Methoxy-8-(6-Methoxy-pyridin-3-yl)-1-(4-(piperazin-1-yl)-3-(trifluoromethyl)phenyl)-imidazo[1,5-a]quinoxaline (Compound 83)

Synthesis of compound 83-2a: In a 500 mL reaction flask, compound 83-1a (24 g, 100 mmol), N-benzylpiperazine (21.13 g, 120 mmol), and _K₂CO₃ (20.73 g, 150 mmol) were added to 100 mL of DMSO and heated at 120 °C for 24 _h . After the reaction was completed, the mixture was quenched with water, extracted with ethyl acetate (200 mL × 3), washed successively with water and saturated sodium chloride, and the organic layers were combined, dried over anhydrous sodium sulfate, and rotary evaporated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (ethyl acetate: petroleum ether = 1:10) to give 13 g of white solid, yield 32%.

Synthesis of compound 83-3a: Compound 83-2a (5.84 g, 14.67 mmol) was added to a 250 mL reaction flask under Ar protection at -78 °C, followed by 70 mL of a mixed solvent of toluene and THF (volume ratio 1:1), and the reaction was allowed to proceed for 1 h. Then, 3.7 mL of triethyl borate was slowly added dropwise to the mixture, and the reaction was continued for another 3 h. The temperature was then slowly raised to 0 °C, and 20 mL of saturated ammonium chloride was added. The mixture was stirred at room temperature for 30 min. After the reaction was complete, the sample was extracted with ethyl acetate (100 mL × 3), washed with saturated sodium chloride, and the organic layers were combined. The sample was dried over anhydrous sodium sulfate and evaporated under reduced pressure to obtain the crude product, which was used directly in the next reaction.

Synthesis of compound 83-5a: Compound 83-3a (5.6 g, 15 mmol), compound 83-4a (1.47 g, 10 mmol), ( _PPh3 ) _2Cl2Pd (700 mg, 1 mmol), and _Cs2CO3 (6.5 g, 20 mmol) were added to a 250 _mL reaction flask under Ar _protection . Then, 100 mL of a mixed solvent of 1,4-dioxane and _H2O (volume ratio 4:1) was added, and the mixture was refluxed at 100 °C overnight. After the reaction was complete, the solvent was removed under reduced pressure, water was added, and the mixture was extracted with ethyl acetate (100 mL × 3). The ethyl acetate was removed under reduced pressure, and the mixture was washed with 30 mL of ethyl acetate/petroleum ether (1:2) to obtain the crude compound 83-5a, which was directly used in the next reaction.

Synthesis of compound 83-7a: In a 250 mL reaction flask, compound 83-5a (4 g, 10 mmol), compound 83-6a (2.6 g, 12 mmol), _{and Cs₂CO₃} (4.88 g, 15 mmol) were added to 80 mL of acetonitrile and refluxed overnight. After the reaction was completed, the solvent was removed under reduced pressure, water was added, and the mixture was extracted with ethyl acetate (100 mL × 3). The extract was washed with saturated sodium chloride, the organic layers were combined, dried over anhydrous sodium sulfate, and rotary evaporated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (ethyl acetate: petroleum ether = 1:1.5) to give 4.7 g of a pale yellow solid, yield 79%.

Synthesis of compound 83-8a: In a 100 mL reaction flask, compound 83-7a (407 mg, 0.69 mmol) was dissolved in 37.5 mL of a mixed solvent of EtOH and _H₂O (volume ratio 3:1). Then, _NH₄Cl (295 mg, 5.52 mmol) and iron powder (193 mg, 3.45 mmol) were added, and the reaction was carried out at 80 °C for 3 h. After the reaction was completed, the mixture was filtered through diatomaceous earth and extracted with ethyl acetate (100 mL × 3). The organic layers were combined, dried over anhydrous sodium sulfate, and rotary evaporated under reduced pressure to obtain the crude product. Column chromatography yielded 354 mg of compound 83-2a, with a yield of 92.4%.

Synthesis of compound 83-9a: In a 100 ml reaction flask, compound 82-8a (354 mg, 0.64 mmol) was dissolved in 25 ml toluene, and then triphosgene (77.2 mg, 0.26 mmol) was added. The mixture was refluxed at 120 °C for 16 h. After the reaction was complete, the sample was extracted with ethyl acetate (100 ml × 3), the organic layers were combined, dried over anhydrous sodium sulfate, and rotary evaporated under reduced pressure to obtain the crude product. Column chromatography yielded 261 mg of compound 83-9a, with a yield of 70.4%. ^¹H NMR (400 MHz, _CDCl₃ ) δ 10.78 (s, 1H), 8.18 (s, 1H), 7.94 (s, 1H), 7.79 (d, J = 8.0 Hz, 1H), 7.52 (d, J = 8.0 Hz, 1H), 7.42–7.29 (m, 6H), 7.29 (d, J = 7.2 Hz, 1H), 7.23 (s, 1H), 3.63 (s, 2H), 3.12 (m, 4H), 2.69 (m, 4H).

Synthesis of compound 83-10a: In a 100 mL reaction flask, compound 83-9a (261 mg, 0.45 mmol), _POCl3 (2.07 g, 13.5 mmol), and DIPEA (174 mg, 1.35 mmol) were added to the reaction system and reacted at 100 °C for 16 h. After the reaction was complete, the mixture was extracted with ethyl acetate (100 mL × 3), the organic layers were combined, dried over anhydrous sodium sulfate, and rotary evaporated under reduced pressure to obtain the crude product. Column chromatography yielded 242 mg of compound 83-10a, with a yield of 90%.

Synthesis of compound 83-11a: In a 100 mL reaction flask, methanol (130 mg, 4 mmol) was dissolved in 20 mL of ultradry THF, followed by the addition of NaH (320 mg, 8 mmol). The reaction was allowed to proceed for 10 minutes, then compound 83-10a (1.2 g, 2 mmol) was added, and the reaction was allowed to continue at room temperature for 5 h. After the reaction was complete, the mixture was extracted with ethyl acetate (100 mL × 3), and the organic layers were combined, dried over anhydrous sodium sulfate, and rotary evaporated under reduced pressure to obtain the crude product. Column chromatography yielded 900 mg of compound 83-11a, with a yield of 75.6%.

Synthesis of compound 83-13a: In a 100 mL reaction flask, compound 83-11a (304 mg, 0.51 mmol), compound 84-12a (118 mg, 0.77 mmol), ( _Ph₃P ) _₄Pd (11.56 mg, 0.01 mmol), and _Cs₂CO₃ (498.5 mg, 1.53 mmol ₎ were dissolved in a mixed solvent of 9 mL DMF and 3 mL water. The mixture was stirred at 80 °C for 3 h. After the reaction was completed, the mixture was cooled to room temperature, 100 mL of water was added, and the mixture was extracted with dichloromethane (100 mL × 3). The organic layers were combined, dried over anhydrous sodium sulfate, and evaporated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (dichloromethane:methanol = 5:1) to give 279 mg of a yellow solid, yield 87.7%.

Synthesis of compound 83: Compound 83-13a (279 mg, 0.47 mmol) was dissolved in 20 mL of methanol in a 100 mL reaction flask, followed by the addition of Pd-C (20 mg). The mixture was stirred at 75 °C for 5 h. After the reaction was complete, the mixture was cooled to room temperature, and 100 mL of water was added. The mixture was extracted with dichloromethane (100 mL × 3). The organic layers were combined, dried over anhydrous sodium sulfate, and evaporated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography to give 160 mg of a yellow solid, with a yield of 63.7%. ¹ H NMR (400MHz, DMSO-d ⁶ )δ8.06(s,1H),8.05-8.01(m,1H),7.98(d,J＝2.4Hz,1H),7.93(s,1H),7.79(d,J＝8.8Hz,1H),7.78-7.72(m,2H),7.67( dd,J＝8.8,2.4Hz,1H),7.29(d,J＝1.5Hz,1H),6.79(d,J＝8.8Hz,1H),4.15(s,3H),3.85(s,3H),3.04(m,8H); ESI-MS:m/z 535.2[M+H] ⁺ .

Example 84

1-(4-(4-methoxy-8-(6-methoxypyridin-3-yl)-1H-imidazol[4,5-c]quinoline-1-yl)-2-(trifluoromethyl)phenyl)-N-dimethylpiperidin-4-amino (Compound 84)

The synthesis method was the same as in Example 40, yielding 137 mg of a white solid, with a yield of 71%.

¹ H NMR (400MHz, CDCl ₃ )δ8.19(d,J＝2.4Hz,1H),8.05(d,J＝8.8Hz,1H),8.02(s,1H),7.88(d,J＝2.4Hz,1H),7. 78-7.69(m,2H),7.61(d,J＝8.4Hz,1H),7.56(dd,J＝8.4,2.4Hz,1H),7.29(s,1H),6.73( d,J＝8.8Hz,1H),4.33(s,3H),3.97(s,3H),3.31(s,2H),2.93(t,J＝10.0Hz,2H),2.62( t,J＝10.0Hz,1H),2.53(s,6H),2.10-2.07(m,2H),1.64(m,2H); ESI-MS:m/z577.2[M+H] ⁺ .

Example 85

In vitro antitumor activity of the compounds: The cell lines used in this experiment—MKN-1 (human gastric cancer cells), U87MG (human glioblastoma cells), MOLT-4 (human acute lymphoblastic leukemia cells), OCILY-3 (human diffuse large B-cell lymphoma cells), HT-29 (human colorectal adenocarcinoma cells), and HGC-27 (human gastric cancer cells)—were obtained from ATCC, Shanghai Cell Bank, Shanghai Cell Bank, Shanghai Cell Bank, Shanghai Cell Bank, and the Cell Bank of Type Culture Collection of the Chinese Academy of Sciences, respectively. 3000-10000 cells/well were seeded into 96-well plates and incubated overnight. Different concentrations of the compounds (0-30 μM) were then added for 72 hours of continuous treatment. CCK8 reagent was then added, and incubation continued for 1-3 hours. The absorbance at 450 nm and 650 nm was then measured using a microplate reader. The half-maximal inhibitory concentration ( _IC50 ) was calculated using GrapPadprism 5.0 software.

The results showed that the pyridine or pyrazine tricyclic compounds of the present invention significantly inhibited the proliferation of MKN-1, U87MG, MOLT-4, OCILY-3, HT-29, and HGC27 tumor cells, and most of the compounds exhibited better activity than compound CQ-211. Specific data are shown in Table 1.

Table 1. In vitro antitumor cell activity of the compounds ( _IC50 /μM)

Example 86

Affinity Kd test of pyridine or pyrazine tricyclic compounds to RIOK2 kinase

KINOMEscan ^™ technology is the industry's most comprehensive high-throughput screening system for detecting the activity of compounds against a large number of human kinases (Fabian et al. (2005) Nat. Biotechnol. 23, 329; Karaman et al. (2008) Nat. Biotechnol. 26, 127). KINOMEscan ^™ is a detection method based on competitive binding, quantitatively detecting the binding ability of a compound to an enzyme by the competitive binding of the compound to the kinase's active site with an immobilized ligand. The assay mainly consists of three components: a kinase linked to a DNA tag, an immobilized ligand, and the compound being tested. The competitive ability of the compound to the immobilized ligand is determined by quantitative PCR of the DNA tag linked to the kinase.

Kinase activity assay: Kinase-tagged T7 phages were amplified in parallel in BL21-derived *E. coli* in 24-well plates. When *E. coli* reached the logarithmic growth phase, the cells were infected with frozen T7 phages (multiple of infection = 0.4) and incubated with shaking at 32°C until bacterial lysis (90–150 min). The lysate was centrifuged (6000 x g) and filtered (0.2 μm) to remove debris. The collected supernatant was used to infect HEK293 cells and amplified therein, thereby producing DNA-tagged kinases for qPCR detection. Biotin-linked small ligands were reacted with streptavidin-coated magnetic beads at room temperature for 30 min to provide affinity resin for the experiment. The liganded magnetic beads were blocked with excess biotin and washed with blocking buffer (SeaBlock (Pierce), 1% BSA, 0.05% Tween 20, 1 mM DTT) to remove unbound ligands and reduce nonspecific phage binding. The binding reaction involved mixing the kinase, magnetic beads containing the binding ligand, and 1x binding buffer (20% SeaBlock, 0.17×PBS, 0.05% Tween 20, 6mM DTT) with the test compound. The test compound was prepared as a 100X stock solution using 100% DMSO and diluted directly into the reaction system. All reactions were performed in 384-well polypropylene plates with a final reaction volume of 0.02 ml. The plates were incubated at room temperature with shaking for 1 hour. The magnetic beads were then washed with washing buffer (1×PBS, 0.05% Tween 20). The beads were resuspended in elution buffer (1×PBS, 0.05% Tween 20, 0.5 μM non-biotinylated affinity ligand) and incubated with shaking at room temperature for 30 minutes. The kinase concentration was determined by detecting the amount of DNA tag on the kinase using qPCR.

The constant (Kds) is obtained using the Hill equation and calculated from the standard dose-response curve:

The Hill slope value is -1.

Table 2 lists the representative compound numbers and their corresponding Kd results. The results showed that the pyridine or pyrazine tricyclic compounds of this invention exhibited strong binding affinity to RIOK2 kinase.

Table 2. Binding ability of compounds to RIOK2 kinase

Using the KINOMEscan ^™ platform (Eurofins DiscoverX, San Diego, CAUSA), selectivity analysis was performed on compounds 1, 46, and 59 using 468 kinases. The results showed that compound 1 exhibited good selectivity for RIOK2 kinase at a concentration of 1000 nM, with only RIOK2 kinase showing a survival rate of less than 20%. For compound 46, kinases with a survival rate of less than 10% at a concentration of 1000 nM included m-TOR, PIK3C2G, PIK3CA(H1047L), PIK3CA(I800L), PIK3CB, PIK3CD, PIK3CG, PIP5K2C, RIOK2, and VPS34. Compound 46 showed high affinity for these kinases, with a Kd of 12 nM for binding to RIOK2. Compound 59 exhibits a survival rate of less than 1% for the following kinases at a concentration of 1000 nM: m-TOR, PIK3C2B, PIK3C2G, PIK3CA(H1047L), PIK3CA(I800L), PIK3CD, PIK3CG, and VPS34. Compound 59 demonstrates a high affinity for these kinases.

Example 87

Eighteen male SPF-grade SD rats were randomly divided into 6 groups (n=3 per group) according to body weight. Compound 1 was administered via intravenous injection and gavage at doses of 5 mg/kg and 10 mg/kg, respectively; Compound 30 (CQ-3196) was administered via intravenous injection and gavage at doses of 5 mg/kg and 10 mg/kg, respectively; Compound 46 was administered via intravenous injection and gavage at doses of 5 mg/kg and 10 mg/kg, respectively; and Compound CQ-211 was administered via intravenous injection and gavage at doses of 5 mg/kg and 10 mg/kg, respectively.

Blood samples were collected from the orbital venous plexus at 5 min, 15 min, 30 min, 1 h, 2 h, 4 h, 6 h, 8 h, and 24 h after administration in both intravenous and oral groups. The blood samples were temporarily stored in an ice box and plasma was separated by centrifugation at 4500 rpm for 10 min at 4°C. Plasma drug concentrations were determined by LC-MS. Blood drug concentration data were processed using Phoenix WinNonlin 8.1, and key pharmacokinetic parameters were calculated using a non-compartmental model.

The results are shown in Table 3. The bioavailability of compound 1 was 50.8%, that of compound 30 (CQ-3196) was 45%, that of compound 46 was 66%, while that of CQ-211 was only 3%. Compared with CQ-211, the bioavailability of compounds 1, 30, and 46 was significantly improved.

Table 3. Pharmacokinetic data of compounds 1, 30 (CQ-3196), 46 and CQ-211 in SD rats.

Example 88

In this embodiment, an HGC-27 xenograft mouse model was constructed to test the therapeutic effect of compound 30 (CQ-3196) in SCID-CB17 rats.

Animal experiments were approved by the Institutional Animal Care and Use Committee. Male BALB/c-Nude mice (6 weeks old) were purchased from Guangdong Yaokang Laboratory Animal Technology Co., Ltd. HGC-27 (2 × ^10⁷ cells/200 μL) was subcutaneously injected into the right axilla of mice. When the average tumor volume reached approximately 200 ^mm³ , mice were randomly divided into three groups (n = 6): a model control group (Vihecle group), a low-dose group (CQ3196, 25 mg/kg), and a high-dose group (CQ3196, 50 mg/kg). Compound CQ3196 was diluted with 5% CMC-Na aqueous solution. Mice were administered the CQ3196 compound solution by gavage every two days, while the model control group was administered an equal volume of 5% CMC-Na aqueous solution by gavage for 12 days. Mice were observed for their condition, and tumor volume and mouse weight were monitored daily. Tumor volume (V) was calculated using the formula: V = L × ^W² /2 (L is tumor length; W is tumor width). Animals were sacrificed 6 hours after the last administration, tumors were collected by dissection, and the tumor tissue was preserved at -80°C for Western blot analysis.

The results showed that gavage administration of 50 mg/kg significantly inhibited tumor growth, with a tumor growth inhibition index (TGI) of 62.3%, indicating that compound 30 (CQ-3196) had good tumor-suppressive activity in rats. Furthermore, no significant weight loss was observed throughout the experiment, suggesting good tolerability of the drug (Figure 1).

Example 89

This embodiment tests the effect of compound 30 (CQ-3196) on colony formation in HGC-27 and AGS cells.

HGC-27 and AGS cells were seeded at a density of 1000 cells/well in 6-well plates and incubated overnight in a constant temperature incubator to allow for complete cell adhesion. The drug-treated group was treated with compound CQ3196 dissolved in DMSO, while the negative control group was treated with the same volume of DMSO. Each concentration was used in triplicate. The culture medium was changed and the drug was re-administered every two days. After 14 days of culture, the old culture medium was discarded. The 6-well plates were washed twice with PBS, and 1 mL of 0.5% crystal violet staining solution was added to each well. Staining was performed at room temperature for 1 hour. Residual crystal violet staining solution was washed away, and cell colonies larger than 50 were counted using ImageJ software.

The results showed that compound 30 (CQ-3196) could completely inhibit colony formation in HGC-27 and AGS cells at 300 nM and 1000 nM (Figure 2).

Example 90

This embodiment tested the effect of compound 30 (CQ-3196) on cell adhesion ability.

HGC-27 and AGS cells were seeded into 12-well plates (5 × ^10⁴ cells/cell). Different concentrations of compound CQ3196 dissolved in DMSO were added to the drug-treated groups, while an equal volume of DMSO was added to the negative control group. Cells were incubated for 4 hours, with three replicates for each concentration. Cells were then washed twice with PBS to remove cells that had lost their adhesion ability. 1 mL of 4% paraformaldehyde was added, and the cells were fixed at room temperature for 30 min. After fixation, 1 mL of 0.1% violet staining solution was added, and the cells were stained at room temperature for 20 min. Residual violet staining solution was then washed away with water, and the cells were air-dried and photographed under an inverted microscope (10x). Cell counts were calculated using ImageJ software.

The results showed that compound 30 (CQ-3196) significantly reduced cell adhesion in HGC-27 and AGS cells at 300 nM and 1000 nM (Figure 3).

Example 91

This embodiment tested the effect of compound 30 (CQ-3196) on cell apoptosis.

HGC-27 and AGS cells were digested and collected, and seeded at a density of 3 × ^{10⁵ cells} /well in 6-well plates. The cells were incubated at 37°C with 5% _CO₂ for 24 h. The next day, different concentrations of compound CQ3196 dissolved in DMSO were added to the culture medium, and the negative control group was added with the same volume of DMSO. The plates were incubated for another 48 h. After incubation, suspended and adherent cells were collected from the 6-well plates, centrifuged at 1000 rpm for 5 min, the supernatant was discarded, and the cells were resuspended in PBS. 200 μL of cell suspension from each group was transferred to single-labeled tubes containing 7-AAD and AV. 1X Binging Buffer was prepared, and 100 μL of 1X Binging Buffer was added to each group to resuspend the cells. 2.5 μL of Annexin-V and 2.5 μL of 7-AAD were added to each group, and the reaction was carried out at room temperature in the dark for 15 min. After 15 minutes, add 400 μL of 1X Binging Buffer, transfer to ice, protect from light, and then perform the test.

The results showed that compound 30 (CQ3196) induced apoptosis in HGC-27 and AGS cells in a dose-dependent manner (Figure 4).

The technical features of the above embodiments can be combined in any way. For the sake of brevity, not all possible combinations of the technical features in the following embodiments are described. However, as long as there is no contradiction in the combination of these technical features, they should be considered to be within the scope of this specification.

The embodiments described above are merely illustrative of several implementations of the present invention, and while the descriptions are specific and detailed, they should not be construed as limiting the scope of the present invention. It should be noted that those skilled in the art can make various modifications and improvements without departing from the concept of the present invention, and these modifications and improvements all fall within the scope of protection of the present invention. Therefore, the scope of protection of this patent should be determined by the appended claims.

Claims (40)

Pyridine or pyrazine tricyclic compounds having the structure shown in formula (I), or their pharmaceutically acceptable salts, or their stereoisomers, or their prodrug molecules, or their solvates:
In this context, A and B are independently selected from N and C, respectively, and D and E are independently selected from N, NR ₅ , and CR ₆ , respectively. The circular dashed lines in the rings containing A, B, D, and E indicate that each pair of adjacent ring atoms in the ring is connected by a single or double bond to obtain a chemically stable structure. _X1 , _X2 , and _X3 are independently selected from: N and _CR7 , respectively; _X4 and _X5 are independently selected from: N and _CR8 , respectively; R is selected from: one or more _R2- substituted or unsubstituted 5- to 10-membered heteroaryl groups, or one or more _R2- substituted or unsubstituted _C6- to _C10 aryl groups; _R1 is selected from: H, _C1 - _C18 alkoxy, _C1 - _C18 haloalkoxy, _C3 - _C8 cycloalkyloxy; _R2 is selected from: H, halogen, _C1 - _C18 alkyl, halogen-substituted C1- _C18 alkyl, _C3 - _C18 cycloalkyl, 3-18 membered heterocyclic alkyl, _C1 - _C18 alkoxy, _C3 - _C8 cycloalkyloxy, _C1 - _C18 alkylamino, ( _{C1 - C18 alkyl)2amino, C3-C8 cycloalkylamino, amino, hydroxyl, cyano, nitro, carboxyl, C1-C18 alkoxycarbonyl, C1-C18 alkyl ester , C1 - C18 alkyl acyl} , _C1 - _C18 alkylamide, _{C1 - C18} alkylsulfonyl, _C1 - _C18 alkylsulfonylamino, _C6 - _C18 aryl, 5-18 membered heteroaryl; _R3 and _R4 are each independently selected from: H, R9 _- substituted or unsubstituted _C1 - _C18 alkyl, R9-substituted or unsubstituted _C3 - _C8 cycloalkyl, _R9- substituted or unsubstituted 3-18 membered heterocyclic alkyl, _C1 - _C8 alkylacyl, _C2 - _C8 alkenylacyl, _C1 - _C18 alkylsulfonyl, _{R9 -} substituted or unsubstituted 5-18 membered heteroaryl; or _R3 , _R4 and the N atom attached thereto form one or more _R9- substituted or unsubstituted 3-18 membered heterocyclic groups or heterocyclic ketone groups; Each _R5 is independently selected from: H, _C1 - _C6 alkyl, _C3 - _C8 cycloalkyl, and 3-8 membered heterocyclic alkyl; Each _R6 is independently selected from: H, hydroxyl, amino, cyano, nitro, halogen, _C1 - _C6 alkoxy, _C1 - _C6 alkyl, _C1 - _C6 alkylamino, ( _C1 - _C6 alkyl) _2amino , _C3 - _C8 cycloalkyl, _C3 - _C8 cycloalkyloxy, _C3 - _C8 cycloalkylamino; Each _R7 is independently selected from: H, hydroxyl, amino, cyano, nitro, carboxyl, halogen, _C1 - _C6 alkoxy, _C1 - _C6 alkyl, _C1 - _C6 alkylamino, ( _C1 -C6 _alkyl ) _2amino , _C3 - _C8 cycloalkyl, _C3 - _C8 cycloalkyloxy, _C3 - _C8 cycloalkylamino; Each _R8 is independently selected from: H, hydroxyl, amino, cyano, nitro, carboxyl, halogen, _C1 - _C6 alkoxy, _C1 - _C6 alkyl, halogen-substituted _C1 - _C6 alkyl, _C1 - _C6 alkylamino, ( _C1 - _C6 alkyl) _2amino , _C3 - _C8 cycloalkyl, _C3 - _C8 cycloalkyloxy, _C3 - _C8 cycloalkylamino; Each _R9 is independently selected from: H, hydroxyl, amino, cyano, nitro, carboxyl, halogen, _C1 - _C6 alkoxy, _R14 substituted or unsubstituted _C1 - _C6 alkyl, _C1 - _C6 alkylamino, ( _C1 - _C6 alkyl) _2amino , R' substituted or unsubstituted _C3 - _C8 cycloalkyl, R' substituted or unsubstituted 3-8 membered heterocyclic group, _C3 - _C8 cycloalkyloxy, _C3 - _C8 cycloalkylamino, _C1 - _C6 alkylacyl, -N( _R11 ) ₂ ; Each R' is independently selected from: H, hydroxyl, amino, cyano, nitro, carboxyl, _halogen , _C1 -C6 alkoxy, _C1 - _C6 alkyl, halogen-substituted _C1 - _C6 alkyl, _C1 - _C6 alkylamino, ( _C1 - _C6 alkyl) _2amino ; _R11 is independently selected from: H, _R14 substituted or unsubstituted _C1 - _C6 alkyl, _C3 - _C8 cycloalkyl, _C1 - _C6 alkylacyl; _R14 is selected from: H, _C1 - _C6 alkoxy, halogen, _C1 - _C6 alkylamino, ( _C1 - _C6 alkyl) _2amino , R' substituted or unsubstituted 3- to 8-membered heterocyclic alkyl. The pyridine or pyrazine tricyclic compound, or its pharmaceutically acceptable salt, or its stereoisomer, or its prodrug molecule, or its solvate according to claim 1, is characterized in that A and B are independently selected from N and C, respectively, D and E are independently selected from N and _CR6 , respectively, and the rings containing A, B, D, and E are heteroaromatic rings. According to claim 1, the pyridine or pyrazinotricyclic compound, or its pharmaceutically acceptable salt, or its stereoisomer, or its prodrug molecule, or its solvate, is characterized in that the pyridine or pyrazinotricyclic compound has the structure shown in formula (II-1) or formula (II-2):
D and E are independently selected from: N and CR ₆ , respectively. According to claim 3, the pyridine or pyrazinotricyclic compound, or its pharmaceutically acceptable salt, or its stereoisomer, or its prodrug molecule, or its solvate, is characterized in that the pyridine or pyrazinotricyclic compound has the structure shown in formula (III-1), (III-2), (III-3), (III-4), (III-5), or (III-6):
The pyridine or pyrazinotricyclic compound according to any one of claims 1-4, or its pharmaceutically acceptable salt, or its stereoisomer, or its prodrug molecule, or its solvate, is characterized in that R is selected from: one or more _R2- substituted or unsubstituted phenyl groups, one or more _R2- substituted or unsubstituted naphthyl groups, one or more _R2- substituted or unsubstituted pyridyl groups, one or more _R2- substituted or unsubstituted pyrimidinyl groups, one or more _{R2 -} substituted or unsubstituted pyridazinyl groups, one or more _R2 -substituted or unsubstituted indoleyl groups, and one or more _R2- substituted or unsubstituted pyrrolopyridinyl groups. According to claim 5, the pyridine or pyrazine tricyclic compound, or its pharmaceutically acceptable salt, or its stereoisomer, or its prodrug molecule, or its solvate, is characterized in that R is selected from:
Among them, _X6 and _X7 are independently selected from: N and _CR10 , respectively; Each R ₁₀ is independently selected from: H, hydroxyl, amino, cyano, nitro, _carboxyl , halogen, _C1 - _C6 alkoxy, _C1 - _C6 alkyl, halogen-substituted _C1 - _C6 alkyl, _C1 -C6 alkylamino, _{( C1} - _C6 alkyl) _2amino , _C3 - _C8 cycloalkyl, C3- _C8 cycloalkyloxy, _C3 - _C8 cycloalkylamino. According to claim 6, the pyridine or pyrazinotricyclic compound, or its pharmaceutically acceptable salt, or its stereoisomer, or its prodrug molecule, or its solvate, is characterized in that _R2 is selected from: H, halogen, _C1 - _C6 alkyl, halogen-substituted _C1 - _C6 alkyl, _C3 -C8 cycloalkyl, _3-8 membered _heterocyclic alkyl, _C1 - _C6 alkoxy, _C3 - _C8 cycloalkyloxy, _C1 - _C8 alkylamino, ( _C1 - _C8 alkyl)2amino, _C3 - _C8 cycloalkylamino, amino, hydroxyl, cyano, nitro, carboxyl, _C1 - _C8 alkoxycarbonyl, _{C1 - C8} alkyl ester, _C1 - _C8 alkylacyl, _C1 - _C8 alkylamide, _C1 - _{C8 alkylsulfonyl, C1-C8 alkylsulfonamide} , _C6 ~C ₁₀ aryl, 5-10 heteroaryl. According to claim 7, the pyridine or pyrazine tricyclic compound, or its pharmaceutically acceptable salt, or its stereoisomer, or its prodrug molecule, or its solvate, is characterized in that _R2 is selected from: H, halogen, _C1 - _C3 alkyl, halogen-substituted _C1 - _C3 alkyl, _C3 - _C6 cycloalkyl, _4-6 membered heterocyclic alkyl, _C1 -C3 alkoxy, _C3 - _C6 cycloalkyloxy, _C1 - _C3 alkylamino, ( _C1 - _C3 alkyl) _2amino , _C3 - _C6 cycloalkylamino, amino, hydroxyl, cyano, nitro, carboxyl, _C1 - _C3 alkoxycarbonyl, _C1 - _C3 alkyl ester, _C1 - _C3 alkyl acyl, _C1 - _C3 alkylamide, _C1 - _C3 alkylsulfonyl, _C1 -C3... _3- alkylsulfonamide, phenyl, 5-6 heteroaryl. The pyridine or pyrazine tricyclic compound, or its pharmaceutically acceptable salt, or its stereoisomer, or its prodrug molecule, or its solvate according to claim 8, is characterized in that _R2 is selected from: H, fluorine, chlorine, bromine, methyl, ethyl, propyl, methoxy, ethoxy, propoxy, amino. The pyridine or pyrazine tricyclic compound according to claim 6, or its pharmaceutically acceptable salt, or its stereoisomer, or its prodrug molecule, or its solvate, is characterized in that each _R10 is independently selected from: H, hydroxyl, amino, cyano, nitro, carboxyl, halogen, _C1 - _C3 alkoxy, _C1 - _C3 alkyl, halogen-substituted _C1 - _C3 alkyl, _C1 - _C3 alkylamino, ( _C1 - _C3 alkyl) _2amino , _C3 - _C6 cycloalkyl, _C3 - _C6 cycloalkyloxy, _C3 - _C6 cycloalkylamino. The pyridine or pyrazine tricyclic compound, or its pharmaceutically acceptable salt, or its stereoisomer, or its prodrug molecule, or its solvate according to claim 10, is characterized in that each R ₁₀ is independently selected from: H, cyano, fluorine, chlorine, bromine, methyl, ethyl, propyl, trifluoromethyl, methoxy, ethoxy, difluoromethyl, monofluoromethyl, trifluoroethyl. According to claim 6, the pyridine or pyrazine tricyclic compound, or its pharmaceutically acceptable salt, or its stereoisomer, or its prodrug molecule, or its solvate, is characterized in that R is selected from the following groups:
According to claim 6, the pyridine or pyrazine tricyclic compound, or its pharmaceutically acceptable salt, or its stereoisomer, or its prodrug molecule, or its solvate, is characterized in that _R1 is not hydrogen; R ₂ is selected from: methoxy, ethoxy, propoxy, amino, fluorine, chlorine, bromine; Each R ₁₀ is independently selected from: H, cyano, fluorine, chlorine, bromine, methyl, ethyl, propyl, trifluoromethyl, methoxy, ethoxy, difluoromethyl, monofluoromethyl, trifluoroethyl; Preferably, R is selected from the following groups:
According to claim 6, the pyridine or pyrazine tricyclic compound, or its pharmaceutically acceptable salt, or its stereoisomer, or its prodrug molecule, or its solvate, is characterized in that _R1 is hydrogen; R ₂ is selected from: H, fluorine, chlorine, bromine, methyl, ethyl, propyl, methoxy, ethoxy, propoxy, amino; Each R ₁₀ is independently selected from: H, cyano, fluorine, chlorine, bromine, methyl, ethyl, propyl, trifluoromethyl, methoxy, ethoxy, difluoromethyl, monofluoromethyl, trifluoroethyl; Preferably, R is selected from the following groups:
The pyridine or pyrazine tricyclic compound, or its pharmaceutically acceptable salt, or its stereoisomer, or its prodrug molecule, or its solvate according to claim 6, is characterized in that _X7 is selected from: N, CH; _X6 is selected from: N, _CR10 . The pyridine or pyrazine tricyclic compound, or its pharmaceutically acceptable salt, or its stereoisomer, or its prodrug molecule, or its solvate according to claim 6, is characterized in that at least one of _X6 and _X7 is N. The pyridine or pyrazine tricyclic compound, or its pharmaceutically acceptable salt, or its stereoisomer, or its prodrug molecule, or its solvate according to any one of claims 1-4, is characterized in that _X1 , _X2 , and _X3 are each independently selected from: _CR7 ; and each _R7 is independently selected from: H, fluorine, chlorine, bromine, methyl, ethyl, methoxy, ethoxy, and dimethylamino. The pyridine or pyrazine tricyclic compound, or its pharmaceutically acceptable salt, or its stereoisomer, or its prodrug molecule, or its solvate according to any one of claims 1-4, is characterized in that _X4 and _X5 are each independently selected from: _CR8 ; each _R8 is independently selected from: H, fluorine, chlorine, bromine, methyl, ethyl, propyl, methoxy, ethoxy, propoxy, dimethylamino, trifluoromethyl, difluoromethyl. The pyridine or pyrazine tricyclic compound, or its pharmaceutically acceptable salt, or its stereoisomer, or its prodrug molecule, or its solvate according to claim 18, is characterized in that _X4 is CH; _X5 is _CR8 , and _R8 is selected from: H, fluorine, chlorine, methyl, methoxy, trifluoromethyl. The pyridine or pyrazine tricyclic compound, or its pharmaceutically acceptable salt, or its stereoisomer, or its prodrug molecule, or its solvate according to any one of claims 1-4, is characterized in that _R1 is not hydrogen; _X4 is CH; _X5 is _CR8 , and _R8 is selected from: trifluoromethyl, difluoromethyl. The pyridine or pyrazine tricyclic compound, or its pharmaceutically acceptable salt, or its stereoisomer, or its prodrug molecule, or its solvate according to any one of claims 1-4, is characterized in that _R1 is hydrogen; _X4 is CH; _X5 is _CR8 ; and _R8 is selected from: H, fluorine, chlorine, bromine, methyl, ethyl, propyl, methoxy, ethoxy, propoxy, dimethylamino, trifluoromethyl, difluoromethyl. The pyridine or pyrazine tricyclic compound, or its pharmaceutically acceptable salt, or its stereoisomer, or its prodrug molecule, or its solvate, according to any one of claims 1-4, is characterized in that _R1 is selected from: _H , _C1 -C6 alkoxy, _C1 - _C6 haloalkoxy, _C3 - _C6 cycloalkyloxy; Preferably, _R1 is selected from: H, _C1 - _C3 alkoxy, _C1 - _C3 fluoroalkoxy, _C3 - _C6 cycloalkyloxy; Preferably, _R1 is selected from: H, methoxy, ethoxy, cyclopropoxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy, isopropoxy, and n-propoxy; Preferably, _R1 is selected from: H, methoxy, ethoxy. The pyridine or pyrazine tricyclic compound, or its pharmaceutically acceptable salt, or its stereoisomer, or its prodrug molecule, or its solvate according to any one of claims 1-3, is characterized in that each _R6 is independently selected from: H, hydroxyl, amino, cyano, nitro, halogen, _C1 - _C3 alkoxy, _C1 - _C3 alkyl, _C1 - _C3 alkylamino, ( _C1 - _C3 alkyl) _2amino , _C3 - _C6 cycloalkyl, _C3 - _C6 cycloalkyloxy, _C3 - _C6 cycloalkylamino; Preferably, each _R6 is independently selected from: H, halogen, methoxy, ethoxy, propoxy, methyl, ethyl, propyl. The pyridine or pyrazine tricyclic compound, or its pharmaceutically acceptable salt, or its stereoisomer, or its prodrug molecule, or its solvate according to any one of claims 1-4, is characterized in that _R3 and _R4 are each independently selected from: H, _R9- substituted or unsubstituted _C1 - _C6 alkyl, _R9- substituted or unsubstituted _C3 - _C8 cycloalkyl, _R9- substituted or unsubstituted 3-8 membered heterocyclic alkyl, _C1 - _C6 alkylacyl, _C2 - _C6 alkenylacyl, _C1 - _C6 alkylsulfonyl, _R9- substituted or unsubstituted 5-8 membered heteroaryl; or _R3 , _R4, and the N atom attached thereto form one or more _R9- substituted or unsubstituted 3-8 membered heterocyclic groups or heterocyclic ketone groups. Preferably, each _R9 is independently selected from: H, hydroxyl, amino, cyano, nitro, carboxyl, halogen, _C1 - _C6 alkoxy, _R14 substituted or unsubstituted _C1 - _C6 alkyl, _C1 - _C3 alkylamino, ( _C1 - _C3 alkyl) _2amino , R' substituted or unsubstituted C3- _C8 cycloalkyl, R' substituted or unsubstituted 3-8 membered heterocyclic group, _{C3 - C8} cycloalkyloxy, _C3 - _C8 cycloalkylamino, _C1 - _C6 alkylacyl, -N( _R11 ) ₂ ; R' is selected from: H, hydroxyl, amino, cyano, nitro, carboxyl, halogen, _C1 - _C3 alkoxy, _C1 - _C3 alkyl, halogen-substituted _C1 - _C3 alkyl, _C1 - _C3 alkylamino, ( _C1 - _C3 alkyl) _2amino ; _R11 is independently selected from: H, _R14 substituted or unsubstituted _C1 - _C6 alkyl, _C3 - _C8 cycloalkyl, _C1 - _C6 alkylacyl; _R14 is selected from: H, _C1 - _C6 alkoxy, halogen, _C1 - _C6 alkylamino, ( _C1 - _C6 alkyl) _2amino , R' substituted or unsubstituted 5- to 6-membered heterocyclic alkyl. The pyridine or pyrazine tricyclic compound or its pharmaceutically acceptable salt or its stereoisomer or its prodrug molecule or its solvate according to claim 24, characterized in that _R3 and _R4 are each independently selected from: H, _R9- substituted or unsubstituted _C1 - _C3 alkyl, R9 _- substituted or unsubstituted _C3 - _C6 cycloalkyl, _R9- substituted or unsubstituted 4-6 membered heterocyclic alkyl; Alternatively, _R3 , _R4 , and the N atom bonded to them together form the following structure:
Where each n is independently selected from: 0, 1, 2, or 3; Each m is independently selected from: 0, 1, 2, or 3; Z is selected from: -O-, -NR _11- , or -C(R ₁₂ R ₁₃ )-; _R11 is independently selected from: H, _R14 substituted or unsubstituted _C1 - _C6 alkyl, _C3 - _C8 cycloalkyl, _C1 - _C6 alkylacyl; _R12 and _R13 are independently selected from: H, _C1 - _C6 alkyl, _C1 - _C6 alkoxy, R'-substituted or unsubstituted _C3 - _C8 cycloalkyl, R'-substituted or unsubstituted 3-8 membered heterocyclic alkyl, -N( _R11 ) ₂ ; _R14 is selected from: H, _C1 - _C6 alkoxy, _C1 - _C6 alkylamino, ( _C1 - _C6 alkyl) _2amino , R' substituted or unsubstituted 5- to 6-membered heterocyclic alkyl. According to claim 25, the pyridine or pyrazine tricyclic compound, or its pharmaceutically acceptable salt, or its stereoisomer, or its prodrug molecule, or its solvate, is characterized in that _R3 is selected from: hydrogen, methyl, ethyl; _R4 is selected from: dimethylamino-substituted methyl, dimethylamino-substituted ethyl, methylamino-substituted methyl, methylamino-substituted ethyl, 5-membered nitrogen-containing heterocyclic group, 6-membered nitrogen-containing heterocyclic group; Alternatively, _R3 , _R4 , and the N atom bonded to them together form the following structure:
The pyridine or pyrazine tricyclic compound, or its pharmaceutically acceptable salt, or its stereoisomer, or its prodrug molecule, or its solvate, according to claim 26, is characterized in that... n is selected from: 0, 1, 2, or 3; m is selected from: 0, 1, 2, or 3; Z is selected from: -O-, -NR _11- , or -C(R ₁₂ R ₁₃ )-; Each _R9 is independently selected from: H, _C1 - _C3 alkoxy, _C1 - _C3 alkyl, halogen-substituted _C1 - _C3 alkyl, dimethylamino, methylamino; R' is selected from: H, _C1 - _C3 alkoxy, _C1 - _C3 alkyl, halogen-substituted _C1 - _C3 alkyl, dimethylamino, methylamino; Each _R11 is independently selected from: H, _R14 substituted or unsubstituted _C1 to _C3 alkyl groups; _R12 and _R13 are each independently selected from: H, _C1 - _C3 alkoxy, _C1 - _C3 alkyl, R'-substituted or unsubstituted 5-6 membered heterocyclic alkyl, -N( _R11 ) ₂ ; _R14 is selected from: H, _C1 - _C3 alkoxy, amino, dimethylamino, methylamino, R'-substituted or unsubstituted 6-membered heterocyclic alkyl. The pyridine or pyrazine tricyclic compound, or its pharmaceutically acceptable salt, or its stereoisomer, or its prodrug molecule, or its solvate according to any one of claims 1-4, is characterized in that _R3 , _R4, and the N atom attached thereto form the following structure:

The pyridine or pyrazinotricyclic compound, or its pharmaceutically acceptable salt, or its stereoisomer, or its prodrug molecule, or its solvate, according to any one of claims 1-4, is characterized in that the pyridine or pyrazinotricyclic compound has the structure shown in formula (III-2):
_R3 , _R4 , and the N atom bonded to them together form the following structure:
The pyridine or pyrazinotricyclic compound, or its pharmaceutically acceptable salt, or its stereoisomer, or its prodrug molecule, or its solvate, according to any one of claims 1-4, is characterized in that the pyridine or pyrazinotricyclic compound has the structure shown in formula (III-3) below:
_R3 , _R4 , and the N atom bonded to them together form the following structure:
According to claim 1, the pyridine or pyrazinotricyclic compound, or its pharmaceutically acceptable salt, or its stereoisomer, or its prodrug molecule, or its solvate, is characterized in that the pyridine or pyrazinotricyclic compound has the structure shown in formula (IV):
According to claim 1, the pyridine or pyrazinotricyclic compound, or its pharmaceutically acceptable salt, or its stereoisomer, or its prodrug molecule, or its solvate, is characterized in that the pyridine or pyrazinotricyclic compound is selected from the following compounds:






The use of the pyridine or pyrazine tricyclic compound, or its pharmaceutically acceptable salt, or its stereoisomer, or its prodrug molecule, or its solvate, as described in any one of claims 1-32, in the preparation of RIOK2 inhibitors. The use of the pyridine or pyrazine tricyclic compound of any one of claims 1-32, or its pharmaceutically acceptable salt, or its stereoisomer, or its prodrug molecule, or its solvate in the preparation of a medicament for the prevention and/or treatment of diseases associated with high RIOK2 expression. The use of the pyridine or pyrazine tricyclic compound, or its pharmaceutically acceptable salt, or its stereoisomer, or its prodrug molecule, or its solvate, as described in any one of claims 1-32, in the preparation of a medicament for the prevention and/or treatment of tumors. The application according to claim 35 is characterized in that the tumor is a tumor associated with high RIOK2 expression. According to the application of claim 35, the tumor is characterized in that it is: non-small cell lung cancer, small cell lung cancer, lung adenocarcinoma, lung squamous cell carcinoma, pancreatic cancer, breast cancer, prostate cancer, liver cancer, skin cancer, epithelial cell carcinoma, gastrointestinal stromal tumor, leukemia, histiocytic lymphoma, diffuse large B-cell lymphoma, nasopharyngeal carcinoma, glioma, osteosarcoma, gastric cancer, squamous cell carcinoma of the skin, ovarian cancer, or colorectal adenocarcinoma. A pharmaceutical composition for treating and/or preventing tumors, characterized in that it is prepared from an active ingredient and pharmaceutically acceptable excipients, said active ingredient comprising a pyridine or pyrazine tricyclic compound as described in any one of claims 1-32, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a prodrug molecule thereof, or a solvate thereof. A method for treating and/or preventing tumors, characterized in that it comprises: administering to a subject or patient a safe and effective amount of a pyridine or pyrazine tricyclic compound of any one of claims 1-32, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a prodrug molecule thereof, or a solvate thereof; or administering to a subject or patient a safe and effective amount of a pharmaceutical composition of claim 38. The method for treating and/or preventing tumors according to claim 39, wherein the tumor is: non-small cell lung cancer, small cell lung cancer, lung adenocarcinoma, lung squamous cell carcinoma, pancreatic cancer, breast cancer, prostate cancer, liver cancer, skin cancer, epithelial cell carcinoma, gastrointestinal stromal tumor, leukemia, histiocytic lymphoma, diffuse large B-cell lymphoma, nasopharyngeal carcinoma, glioma, osteosarcoma, gastric cancer, squamous cell carcinoma of the skin, ovarian cancer, or colorectal adenocarcinoma.