WO2023155826A1 - Multi-substituted tricyclic fused heterocyclic compound, pharmaceutical composition thereof and use thereof - Google Patents

Abstract

The present invention provides a tricyclic fused heterocyclic compound having a structure represented by formula (I) or a pharmaceutically acceptable salt thereof or a stereoisomer thereof, a pharmaceutical composition thereof and use thereof. The compound and the pharmaceutically acceptable salt thereof to which the present invention relates can effectively inhibit the growth of various tumor cells, and can be used to prepare anti-tumor drugs.

Description

A class of multi-substituted tricyclic and heterocyclic compounds and their pharmaceutical compositions and applications technical field

The invention relates to the technical field of chemistry and medicine, in particular to a class of multi-substituted tricyclic and heterocyclic compounds, pharmaceutical compositions and applications thereof.

Background technique

Malignant tumor (cancer) is a kind of major malignant disease that threatens human health. Conventional cancer treatment methods include radiotherapy, chemotherapy, surgical resection, and drug therapy. However, these methods often have disadvantages such as large side effects, poor therapeutic effect, recurrence and metastasis of tumor prognosis. Therefore, there is an urgent need to develop new therapeutic techniques to address these issues in cancer treatment. Personalized therapy and targeted therapy are seen as the hope of breaking through the current bottleneck of cancer treatment in recent years.

Tumor molecular targeted therapy is a new treatment method developed based on the regulation of key signaling pathways closely related to tumor growth through chemical or biological means. Targeted small molecule drugs have the characteristics of high specificity, strong selectivity, and mild side effects; they can be used alone or in combination with existing drugs for the treatment of cancer. Since the application of small-molecule targeted drugs represented by imatinib mesylate (Novartis) in 2001, targeted tumor therapy has developed rapidly in the past two decades, and dozens of protein kinases have been developed. The launch of small molecule targeted drugs has become an important class of drugs in cancer treatment, creating a new era for tumor chemotherapy.

RIOK2 is a pseudokinase that is highly expressed in various tumors such as gastric cancer, colon cancer, melanoma, glioblastoma, and non-small cell lung cancer, and is directly related to the degree of tumor progression. In the previous work, the inventors of the present invention synthesized and constructed a series of characteristic heterocyclic/chiral heterocyclic small molecule libraries, screened and obtained hit compounds with novel structures, and further obtained the current CQ211 is the most active and selective RIOK2 inhibitor reported, but its in vivo activity is still not ideal. Therefore, there is an urgent need for the development of small molecule targeted drugs with better cellular activity.

Contents of the invention

In view of the above problems, the present invention provides a class of multi-substituted tricyclic heterocyclic compounds, the core part of which is mainly a quinoxalinone five-membered heterocyclic structure or analogues with substituents attached to the amide nitrogen. This type of novel multi-substituted heterocyclic compound has good solubility, has good inhibitory effect on RIOK2 protein, and can inhibit the proliferation of various tumor cells with high activity.

The present invention includes following technical solutions:

A tricyclic and heterocyclic compound having a structure represented by formula (I) or a pharmaceutically acceptable salt thereof or a stereoisomer thereof:

Wherein, A, B, D and E are independently selected from: N, NR ₁₀ , C, CR ₁₁ or C=O, and the circular dotted line in the ring where A, B, D and E are located indicates that every two Adjacent ring atoms are connected by single or double bonds to obtain a chemically stable structure;

X is selected from: NR ₂ ;

X ₁ and X ₂ are independently selected from: N, or CR ₉ ';

X ₃ , X ₄ , and X ₅ are each independently selected from: N, or CR ₅ ;

X ₆ , X ₇ , X ₈ , and X ₉ are each independently selected from: N, or CR ₆ ;

n is selected from: 1, 2, 3, 4, 5;

R ₁ and R ₂ are independently selected from: H, C ₁ -C ₁₈ alkyl, C ₃ -C ₈ cycloalkyl, 3-8 membered heterocycloalkyl, C ₁ -C ₈ acyl, sulfonyl, C ₆ -C ₁₈ aryl, C ₁ -C ₈ alkyl substituted by C ₆ -C ₁₈ aryl, 5-18 membered heteroaryl, and R ₁ and R ₂ are not H at the same time; or R ₁ , R ₂ Together with the X connected to it, a 4-8 member _R12 substituted or unsubstituted heterocyclic group is formed;

Each of R ₃ and R ₄ is independently selected from: H, halogen, hydroxyl, C ₁ -C ₈ alkyl, C ₃ -C ₈ cycloalkyl; or R ₃ , R ₄ and the carbon atom connected to it together form 3 -8-membered cycloalkyl; or R ₃ , R ₄ and the carbon atom connected to it together form C=O; or R ₃ , R ₂ and the carbon atom connected to it and X together form a 4-8-membered R ₁ substituted or not Substituted heterocyclyl;

Each R ₅ is independently selected from: H, hydroxyl, amino, cyano, nitro, halogen, trifluoromethyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ alkyl, C ₁ -C ₆ Alkylamino, C ₃ ~C ₆ cycloalkyl;

Each R ₆ is independently selected from: H, hydroxyl, amino, cyano, nitro, halogen, trifluoromethyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ alkyl, C ₁ -C ₆ Alkylamino, C ₃ ~C ₆ cycloalkyl;

R ₇ and R ₈ are independently selected from: H, C ₁ -C ₈ alkyl, C ₁ -C ₈ alkyl substituted by R ₁₃ , C ₃ -C ₈ cycloalkyl, 3-18 membered heterocycloalkyl , C ₁ -C ₈ acyl, alkenyl acyl, sulfonyl, 5-18 membered heteroaryl; or R ₇ , R ₈ and the N atom connected to it together form a R ₁₆ substituted or unsubstituted 3-10 membered heterocyclic ring group, or R ₇ , R ₈ and the N atom connected to it together form R ₁₆ substituted or unsubstituted 5-10 membered heteroaryl;

R ₉ is selected from: H, halogen, C ₁ -C ₁₈ alkyl, halogen-substituted C ₁ -C ₁₈ alkyl, C ₃ -C ₁₈ cycloalkyl, 3-18 membered heterocycloalkyl, C ₁ -C ₁₈ alkoxy, halogen-substituted C ₁ -C ₁₈ alkoxy, C ₁ -C ₁₈ alkylamino, amino, hydroxyl, cyano, nitro, ester, amido, sulfonyl, sulfonylamino, C ₆ -C ₁₈ aryl, C ₁ -C ₁₈ alkyl substituted by C ₆ -C ₁₈ aryl, 5-18 membered hetero Aryl;

Each R ₉ ' is independently selected from: H, halogen, C ₁ -C ₁₈ alkyl, halogen-substituted C ₁ -C ₁₈ alkyl, C ₃ -C ₁₈ cycloalkyl, 3-18 membered heterocycloalkyl , C ₁ ~C ₁₈ alkoxy, halogen substituted C ₁ ~C ₁₈ alkoxy, C ₁ ~C ₁₈ alkylamino, amino, hydroxyl, cyano, nitro, ester, amido, sulfonyl, Sulfonylamino, C ₆ -C ₁₈ aryl, C ₁ -C ₁₈ aryl substituted C ₁ -C ₁₈ alkyl, 5-18 membered heteroaryl; or R ₉ and one R ₉ ' together form 3-10 A membered heterocyclic group; or R ₉ and a R ₉ 'together form a 5-10 membered heteroaryl group;

R ₁₀ is selected from: H, C ₁ -C ₁₈ alkyl;

R ₁₁ is selected from: H, halogen, C ₁ -C ₁₈ alkyl, C ₃ -C ₁₈ cycloalkyl, 3-18 membered heterocycloalkyl, C ₁ -C ₁₈ alkoxy, C ₁ -C ₁₈ alkane Amino, amino, hydroxyl, cyano, nitro, ester, amido, sulfonyl, sulfonylamino, C ₆ -C ₁₈ aryl, C ₁ -C ₁₈ alkyl substituted by C ₆ -C ₁₈ aryl , 5-18 membered heteroaryl;

R ₁₂ is selected from: H, C ₁ -C ₁₈ alkyl, C ₁ -C ₁₈ alkyl substituted by hydroxy, C ₁ -C ₁₈ alkyl substituted by C ₁ -C 18 alkoxy, C ₁ -C ₁₈ alkyl substituted by halogen C ₁₈ alkyl, C ₃ -C ₁₈ cycloalkyl, 3-18 membered heterocycloalkyl, C ₁ -C ₁₈ alkoxy, C ₁ -C ₁₈ alkylamino, C ₁ -C ₈ acyl, halogen, Amino, hydroxyl, cyano, nitro, ester, amido, sulfonyl, sulfonylamino, C ₆ ~C ₁₈ aryl, C ₁ ~C 18 alkyl substituted by C ₆ ~ _{C 18 aryl} , 5~ 18-membered heteroaryl; or R ₁₂ forms a carbonyl with a connected carbon atom;

R ₁₃ is selected from: hydroxyl, C ₁ -C ₈ alkoxy,

R ₁₄ and R ₁₅ are independently selected from: H, C ₁ -C ₈ alkyl, or R ₁₄ , R ₁₅ and the N atom connected to them together form R ₁₆ substituted or unsubstituted 3-10 membered heterocyclic group;

R ₁₆ is selected from: H, C ₁ -C ₁₈ alkyl, C ₁ -C ₁₈ alkyl substituted by hydroxy, C ₁ -C ₁₈ alkyl substituted by C ₁ -C ₁₈ alkoxy, C ₃ -C ₁₈ ring Alkyl group, 3-18 membered heterocycloalkyl group, C ₁ -C ₁₈ alkoxy group, C ₁ -C ₁₈ alkylamino group, C ₁ -C ₈ acyl group, amino group, hydroxyl group, cyano group, nitro group, ester group, Amino group, sulfonyl group, sulfonylamino group, C ₆ ~C ₁₈ aryl group, C ₁ ~C ₁₈ alkyl group substituted by C ₆ ~C ₁₈ aryl group, 5~18 membered heteroaryl group; or R ₁₆ and the connected carbon Atoms form a carbonyl group.

In some of these embodiments, the tricyclic and heterocyclic compound has the structure shown in the following formula (II):

Wherein, n ₁ is selected from: 0, 1, 2, 3;

n ₂ is selected from: 0, 1, 2, 3, 4;

D and E are independently selected from: N, CR ₁₁ .

In some of these embodiments, the tricyclic heterocyclic compound has the structure shown in the following formula (III):

Wherein, n ₁ is selected from: 0, 1, 2, 3;

n ₂ is selected from: 0, 1, 2, 3, 4;

D and E are independently selected from: N, CR ₁₁ .

In some of these embodiments, the tricyclic heterocyclic compound has the structure shown in the following formula (IV):

Wherein, n ₁ is selected from: 0, 1, 2, 3;

n ₂ is selected from: 0, 1, 2, 3, 4;

B is selected from: N, CR ₁₁ .

In some of these embodiments, one of X ₁ and X ₂ is N or CH, and the other is CR ₉ ′.

In some of these embodiments, R ₁ and R ₂ are independently selected from: H, C ₁ -C ₆ alkyl, C ₃ -C ₆ cycloalkyl, 5-8 membered heterocycloalkyl, C ₁ -C ₃ acyl, sulfonyl, C ₆ -C ₁₀ aryl, C ₁ -C ₃ alkyl substituted by C ₆ -C ₁₀ aryl, 5-8 membered heteroaryl; or R ₁ , R ₂ and X connected to it Together form a 4-8 member R ₁₂ substituted or unsubstituted heterocyclic group;

R ₁₂ is selected from: H, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkyl substituted by hydroxy, C ₁ -C ₆ alkyl substituted by C ₁ -C ₆ alkoxy, halogen C ₁ to C ₆ alkyl, C ₃ to C ₆ cycloalkyl, 3 to 8 membered heterocycloalkyl, C ₁ to C ₆ alkoxy, C ₁ to C ₆ alkylamino, C ₁ to C ₃ acyl, halogen, amino, hydroxyl, cyano, nitro, ester, amido, sulfonyl, sulfonylamino, C ₆ ~C ₁₀ aryl, C ₆ ~C ₁₀ aryl substituted C ₁ ~C ₆ alkyl, 5-10 membered heteroaryl; or R ₁₂ forms a carbonyl with the connected carbon atom.

In some of these embodiments, R ₁ , R ₂ and the X connected thereto together form the following structure:

Wherein, n ₃ is selected from: 0, 1, 2, 3, 4;

R ₁ is selected from: H, C ₁ -C ₆ alkyl;

R ₂ is selected from: C ₁ -C ₆ alkyl;

R ₁₂ is selected from: H, C ₁ -C ₆ alkyl;

R' ₁₂ is selected from: C ₁ -C ₆ alkyl substituted by methoxy, C ₁ -C ₆ alkyl substituted by halogen, halogen, C ₁ -C ₆ alkoxy.

In some of these embodiments, R ₁ , R ₂ and the X connected thereto together form the following structure:

Wherein, n ₃ is selected from: 0, 1, 2, 3;

R _is selected from: H, methyl, ethyl;

_R is selected from: methyl, ethyl;

_R'12 is selected from: methoxy substituted methyl, halogen substituted methyl, halogen, methoxy, ethoxy.

In some of these embodiments, _{both R3} and _R4 are H, and n is selected from: 2, 3, 4.

In some of these embodiments, each _R is independently selected from: H, hydroxyl, amino, cyano, nitro, halogen, trifluoromethyl, methoxy, ethoxy, n-propoxy, isopropyl Oxy, methyl, ethyl, n-propyl, isopropyl, cyclopentyl, cyclohexyl.

In some of these embodiments, each _R is independently selected from: H, hydroxyl, amino, cyano, nitro, halogen, trifluoromethyl, methoxy, ethoxy, n-propoxy, isopropyl Oxy, methyl, ethyl, n-propyl, isopropyl, cyclopentyl, cyclohexyl.

In some of these embodiments, R ₇ and R ₈ are independently selected from: C ₁ -C ₃ alkyl; or R ₇ , R ₈ and the N atom connected to them together form R ₁₆ substituted or unsubstituted 5-8 membered heterocyclyl;

R ₁₆ is selected from: H, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkyl substituted by hydroxy, C ₁ -C ₆ alkyl substituted by C ₁ -C ₆ alkoxy, C ₃ -C ₈ ring Alkyl, 3-8 membered heterocycloalkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ alkylamino, C ₁ -C ₃ acyl, C ₆ -C ₁₀ aryl, C ₆ -C ₁₀ Aryl-substituted C ₁ -C ₆ alkyl, 5-10 membered heteroaryl; or R ₁₆ forms a carbonyl group with a connected carbon atom.

In some of these embodiments, R ⁷ and R ⁸ form the following structure together with the N atom connected to them: R ₁₆ is selected from: H, C ₁ -C ₃ alkyl, C ₁ -C ₃ acyl.

In some of these embodiments, R ₉ is selected from: H, halogen, C ₁ -C ₆ alkyl, halogen-substituted C ₁ -C ₆ alkyl, C ₃ -C ₆ cycloalkyl, 3-8 membered heterocycle Alkyl, C ₁ ~C ₆ alkoxy, halogen substituted C ₁ ~C ₆ alkoxy, C ₁ ~C ₆ alkylamino, amino, hydroxyl, cyano, nitro, ester, amido, sulfo Acyl, sulfonylamino, C ₆ -C ₁₀ aryl, C ₁ -C ₆ alkyl substituted by C ₆ -C ₁₀ aryl, 5-10 membered heteroaryl;

Each R ₉ ' is independently selected from: H, halogen, C ₁ -C ₆ alkyl, halogen-substituted C ₁ -C ₆ alkyl, C ₃ -C ₆ cycloalkyl, 3-8 membered heterocycloalkyl , C ₁ ~C ₆ alkoxy, halogen substituted C ₁ ~C ₆ alkoxy, C ₁ ~C ₆ alkylamino, amino, hydroxyl, cyano, nitro, ester, amido, sulfonyl, Sulfonylamino, C ₆ -C ₁₀ aryl, C ₆ -C ₁₀ aryl substituted C ₁ -C ₆ alkyl, 5-10 membered heteroaryl;

Or R ₉ and one R ₉ ' together form a 5-8 membered heterocyclic group;

Or _R9 and one _R9 ' together form a 5-8 membered heteroaryl.

In some of these embodiments, _R is selected from: methoxy, trifluoromethoxy, difluoromethoxy, dimethylamino, halogen, amino;

Each R ₉ ' is independently selected from: H, halogen, methyl, methoxy, trifluoromethyl, cyano;

Or R ₉ and one R ₉ ' together form a 5-6 membered oxygen-containing heterocyclic group;

Or R ₉ and one R ₉ ′ together form a 5-6 membered nitrogen-containing heteroaryl group.

In some of these embodiments, one of X ₁ and X ₂ is N or CH, and the other is CH; R ₉ is selected from: C ₁ -C ₃ alkoxy, halogen, amino.

In some of these embodiments, one of _X1 and _X2 is CH, and the other is _CR9 ';

R ₉ is selected from: C ₁ -C ₃ alkoxy, halogen, amino;

R ₉ 'is selected from: halogen, C ₁ -C ₃ alkoxy, trifluoromethyl;

Or R ₉ and R ₉ ′ together form a 5-6 membered oxygen-containing heterocyclic group.

In some of these embodiments, one of X ₁ and X ₂ is N, and the other is CR ₉ ';

R ₉ is selected from: C ₁ -C ₃ alkoxy, halogen, amino;

R ₉ 'is selected from: halogen, C ₁ -C ₃ alkoxy, trifluoromethyl, C ₁ -C ₃ alkyl;

Or R ₉ and one R ₉ ′ together form a 5-6 membered nitrogen-containing heteroaryl group.

In some of these embodiments, R ₁₀ is selected from: H, C ₁ -C ₆ alkyl; R ₁₁ is selected from: H, halogen, and C ₁ -C ₆ alkyl.

The present invention also provides the application of the above-mentioned tricyclic heterocyclic compound or its pharmaceutically acceptable salt or its stereoisomer, including the following technical scheme:

Use of the above-mentioned tricyclic and heterocyclic compounds or pharmaceutically acceptable salts or stereoisomers thereof in the preparation of drugs for preventing or treating tumors.

In some of these 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 Glioma, leukemia, histiocytic lymphoma, diffuse large B-cell lymphoma, nasopharyngeal carcinoma, glioma, osteosarcoma, gastric cancer, skin squamous cell carcinoma, ovarian cancer.

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

A pharmaceutical composition for preventing or treating tumors, prepared from active ingredients and pharmaceutically acceptable adjuvants, the active ingredients including the above-mentioned tricyclic and heterocyclic compounds or their pharmaceutically acceptable salts or their stereoisomeric compounds Construct.

The multi-substituted tricyclic and heterocyclic compound of the present invention or its pharmaceutically acceptable salt or its stereoisomer has better solubility, has better inhibitory effect on RIOK2 protein, and can effectively inhibit the growth of various tumor cells growth, can be used to prepare antitumor drugs, and can be used to treat transitional proliferative diseases such as tumors of humans and other mammals.

Detailed ways

In compounds described herein, when any variable (eg, _R3 , _R4, etc.) occurs more than once in any component, its definition at each occurrence is independent of each other occurrence. Also, combinations of substituents and variables are permissible only if such combinations render the compounds stable. A line drawn from a substituent into a ring system indicates that the indicated bond may be attached to any substitutable ring atom. If the ring system is polycyclic it means that such bonds are only to any suitable carbon atoms of adjacent rings. It is understood that one of ordinary skill in the art can select substituents and substitution patterns on the compounds of the present invention to provide compounds that are chemically stable and can be readily synthesized from readily available starting materials by skill in the art and by methods set forth below. If a substituent is itself substituted with more than one group, it is understood that these groups may be on the same carbon atom or on different carbon atoms, so long as the structure is stabilized.

The term "alkyl" as used herein is meant to include both branched and straight chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms. For example, the definition of "C ₁ -C ₆ " in "C ₁ -C ₆ alkyl" includes groups having 1, 2, 3, 4, 5 or 6 carbon atoms arranged in a linear or branched chain. For example, "C ₁ -C ₆ alkyl" specifically includes methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, pentyl, hexyl.

The term "cycloalkyl" refers to a monocyclic saturated aliphatic hydrocarbon group having the specified number of carbon atoms. For example "cycloalkyl" includes cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl and the like.

The term "alkoxy" refers to a group with 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 and the like.

The term "heterocycloalkyl" or "heterocyclyl" is a saturated or partially unsaturated monocyclic or polycyclic ring substituent in which 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, for example: morpholinyl, piperidinyl, tetrahydropyrrolyl, pyrrolidinyl, dihydroimidazolyl, dihydroisoxazolyl, dihydroisoxazolyl, Hydroisothiazolyl, Dihydrooxadiazolyl, Dihydrooxazolyl, Dihydropyrazinyl, Dihydropyrazolyl, Dihydropyridyl, Dihydropyrimidinyl, Dihydropyrrolyl, Dihydrotetrazolyl , dihydrothiadiazolyl, dihydrothiazolyl, dihydrothienyl, dihydrotriazolyl, dihydroazetidinyl, tetrahydrofuranyl, tetrahydrothienyl, etc., and their N-oxides, hetero Linkage of ring substituents can be via carbon atoms or via heteroatoms.

The term "heteroaryl" refers to an aromatic ring containing one or more heteroatoms selected from O, N or S. The heteroaryl groups within the scope of the present invention include but are not limited to: quinolinyl, pyrazolyl, pyrrolyl , Thienyl, furyl, pyridyl, pyrimidinyl, pyrazinyl, Triazolyl, imidazolyl, oxazolyl, isoxazolyl, pyridazinyl; "heteroaryl" is also understood to include the N-oxide derivative of any nitrogen-containing heteroaryl.

As used herein, "halo" or "halo" means chlorine, fluorine, bromine and iodine, as understood by those skilled in the art.

Unless otherwise defined, alkyl, cycloalkyl, aryl, heteroaryl, and heterocycloalkyl substituents can be unsubstituted or substituted. For example, C ₁ -C ₆ alkyl may be substituted with one, two or three substituents selected from OH, halogen, alkoxy, dialkylamino or heterocyclic groups such as morpholinyl, piperidinyl and the like.

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

The pharmaceutically acceptable salts of the present invention can be synthesized from compounds of the present invention that contain a basic or acidic moiety by conventional chemical methods. Generally, the salts of basic compounds are prepared by ion exchange chromatography or by reacting the free base with a stoichiometric amount or excess of the desired salt form of an inorganic or organic acid in a suitable solvent or combination of solvents. Similarly, salts of acidic compounds are formed by reaction with an appropriate inorganic or organic base.

Accordingly, 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 a basic compound of the present invention with an inorganic or organic acid. For example, conventional nontoxic salts include those derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric, and the like, as well as organic acids such as acetic, propionic, succinic, glycolic, hard Fatty acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, pamoic acid, maleic acid, hydroxymaleic acid, phenylacetic acid, glutamic acid, benzoic acid, salicylic acid, sulfanilic acid, 2-acetyl Salts prepared from oxy-benzoic acid, fumaric acid, toluenesulfonic acid, methanesulfonic acid, ethanedisulfonic acid, oxalic acid, isethionic acid, trifluoroacetic acid, etc.

If the compound of the present invention is acidic, appropriate "pharmaceutically acceptable salts" refer to salts prepared from pharmaceutically acceptable non-toxic bases including inorganic bases and organic bases. Salts derived from inorganic bases include aluminum salts, ammonium salts, Salt, calcium salt, copper salt, iron salt, ferrous salt, lithium salt, magnesium salt, manganese salt, manganous salt, potassium salt, sodium salt, zinc salt, etc. Particular preference is given to ammonium, calcium, magnesium, potassium and sodium salts. Salts derived from pharmaceutically acceptable organic non-toxic bases including salts of primary, secondary and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins such as amino acid, betaine, caffeine, choline, N,N'-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, aminoethanol, ethanolamine, ethyl Diamine, N-Ethylmorpholine, N-Ethylpiperidine, Glucosamine, Glucosamine, Histidine, Hydroxocobalamin, Isopropylamine, Lysine, Methylglucamine, Morpholine, Piperazine ,Piperidine, quack, polyamine resin, procaine, purine, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine, 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, as well as other typical pharmaceutically acceptable salts.

Since deprotonated acidic moieties such as carboxyl groups can be anionic in compounds under physiological conditions, and such The charge can then be balanced by a protonated or alkylated basic moiety such as a quaternary nitrogen atom bearing a cation inside, so it should be noted that the compounds of the invention are potential internal salts or zwitterions.

In one embodiment, the present application provides a method for treating transitional proliferative diseases or symptoms such as tumors in humans or other mammals by using the compounds of formulas I-IV and pharmaceutically acceptable salts thereof.

In one embodiment, the compound of the present application and its pharmaceutically acceptable salt can be used for treating or controlling 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, skin squamous cell carcinoma, ovarian cancer, etc. proliferative disease.

The present invention also provides a pharmaceutical composition, which contains active ingredients within a safe and effective dose range, and pharmaceutically acceptable carriers or auxiliary materials.

The "active ingredient" in the present invention refers to the compound of formula I-IV or its pharmaceutically acceptable salt or its stereoisomer in the present invention.

The "active ingredient" and pharmaceutical composition described in the present invention can be used to prepare drugs for preventing and/or treating tumors.

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

"Pharmaceutically acceptable carrier or excipient" refers to: one or more compatible solid or liquid fillers or gel substances, which are suitable for human use, and must have sufficient purity and low enough toxicity.

"Compatibility" here means that each component in the composition can be blended with the active ingredient of the present invention and with each other without significantly reducing the efficacy of the active ingredient.

Some examples of pharmaceutically acceptable carriers or auxiliary materials include cellulose and its derivatives (such as sodium carboxymethyl cellulose, sodium ethyl cellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (such as hard fatty acid, magnesium stearate), calcium sulfate, vegetable oil (such as soybean oil, sesame oil, peanut oil, olive oil, etc.), polyalcohol (such as propylene glycol, glycerin, mannitol, sorbitol, etc.), emulsifier (such as Tween ), wetting agent (such as sodium lauryl sulfate), coloring agent, flavoring agent, stabilizer, antioxidant, preservative, pyrogen-free water, etc.

In another preferred example, the compounds of formulas I-IV of the present invention can form complexes with macromolecular compounds or macromolecules through non-bonding interactions. In another preferred example, the compounds of formulas I-IV of the present invention, as small molecules, can also be connected with macromolecular compounds or macromolecules through chemical bonds. The macromolecular compound may be a biomacromolecule such as polysaccharide, protein, nucleic acid, polypeptide, etc.

The administration method of the active ingredient or pharmaceutical composition of the present invention is not particularly limited, and representative administration methods include (but not limited to): oral, intratumoral, rectal, parenteral (intravenous, intramuscular or subcutaneous) and the like.

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

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

(a) fillers or extenders such as starch, lactose, sucrose, glucose, mannitol and silicic acid;

(b) binders such as hydroxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose and acacia;

(c) humectants, for example, glycerin;

(d) disintegrants, for example, agar, calcium carbonate, potato or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate;

(e) slow solvents, such as paraffin;

(f) absorption accelerators, for example, quaternary ammonium compounds;

(g) humectants such as cetyl alcohol and glyceryl monostearate;

(h) sorbents, for example, kaolin; and

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

The solid dosage form can also be prepared with coatings and shell materials, such as enteric coatings and other materials known in the art. They may contain opacifying agents and the release of the active ingredient from such compositions may be in a certain part of the alimentary canal in a delayed manner. Examples of usable embedding components are polymeric substances and waxy substances.

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, for example, ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1 , 3-butanediol, dimethylformamide and oils, especially cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil and sesame oil or mixtures of these substances, etc. Besides such inert diluents, the compositions can also contain adjuvants, such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.

Suspensions, in addition to the active ingredient, may contain suspending agents, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar, mixtures of these substances, and the like.

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 vehicles include water, ethanol, polyols, and suitable mixtures thereof.

Below in conjunction with specific embodiment, further illustrate the present invention. It should be understood that these examples are only used to illustrate the present invention and are not intended to limit the scope of the present invention. The experimental method that does not indicate specific conditions in the following examples, usually according to conventional conditions such as Sambrook et al., molecular cloning: the conditions described in the laboratory manual (NewYork: Cold Spring Harbor Laboratory Press, 1989), or according to the manufacturer's instructions suggested conditions. Percentages and parts are by weight unless otherwise indicated.

Unless otherwise defined, all professional and scientific terms used herein have the same meanings as are familiar to those skilled in the art. In addition, any methods and materials similar or equivalent to those described can be applied to the method of the present invention. The preferred implementation methods and materials described herein are for demonstration purposes only.

All reagents used in the following examples are commercially available.

The corresponding Chinese name of the English abbreviation of reagent used in the embodiment is as follows:

Example 1

8-(6-methoxypyridin-3-yl)-1-(4-(piperazin-1-yl)-3-(trifluoromethyl)phenyl)-5-(2-(pyrrolidine- 1-yl)ethyl)-1,5-dihydro-4H-[1,2,3]triazol[4,5-c]quinolin-4-one (CQ314)

Synthesis of compound 1-2a: In a 250ml reaction flask, compound 1-1a (2.25g, 10mmol), anhydrous piperazine (1.29g, 15mmol) and K ₂ CO ₃ (2.76g, 20mmol) were added in 20ml DMSO , under argon protection, stirred at 80°C for 4h. After the reaction was completed, cool to room temperature, add 100ml of water, extract with ethyl acetate (100ml×3), combine the organic layers, dry over anhydrous sodium sulfate, and rotary evaporate under reduced pressure to obtain the crude product, which was purified by column chromatography (dichloromethane: methanol =10:1), 2.36 g of yellow solid was obtained, yield 86%.

The synthesis of compound 1-3a: in 100ml reaction flask, compound 1-2a (2.75g, 10mmol) was dissolved in 10ml THF, then added triethylamine (1.67ml, 12mmol), after 10min, then added acetic anhydride ( 1.13ml, 12mmol), stirred at room temperature for 2h. Extracted with dichloromethane (100ml×3), washed with water and saturated sodium chloride solution, combined organic layers, dried over anhydrous sodium sulfate, and rotary evaporated under reduced pressure to obtain a crude product, which was directly used in the next reaction.

Synthesis of compound 1-4a: In a 250ml reaction flask, dissolve compound 1-3a (3.17g, 10mml), iron powder (2.78g, 50mmol), ammonium chloride (4.28g, 80mmol) in 50ml EtOH/H ₂ O (4:1 by volume), reflux at 80°C overnight. After the reaction was completed, suction filter with diatomaceous earth, add water, adjust the pH to alkaline with sodium carbonate, extract with dichloromethane (100ml×3), combine the organic layers, dry over anhydrous sodium sulfate, and rotary evaporate under reduced pressure to obtain the crude product, which was weighed Crystallization gave 2.32 g of a light yellow solid, with a yield of 81%. ¹ HNMR (400MHz, DMSO-d ⁶ ) δ7.08(d, J=8.4Hz, 1H), 6.89(d, J=2.8Hz, 1H), 6.77(dd, J=8.4Hz, 2.8Hz, 1H) ,3.88-3.97(m,2H),3.68(brs,2H),3.39-3.52(m,2H),2.74-2.79(m,4H),2.10(s,3H); ESI-MS: m/z 288.1 [M+H] ⁺ .

Synthesis of compound 1-5a: in a 250ml reaction flask, at 0°C, dissolve compound 1-4a (2.00g, 7mmol) in 15ml of HCl, then add 10ml of water and stir until dissolved; then, at 0°C, mix 5ml NaNO ₂ (0.68g, 9.8mmol) aqueous solution was added dropwise to the solution, and the reaction was continued for 1h at 0°C; finally, 5ml NaN ₃ (0.64g, 9.8mmol) aqueous solution was added dropwise to the mixed solution at 0°C, The stirring reaction was continued for 0.5h. The reaction was completed, neutralized with _K2CO3 aqueous solution, extracted with ethyl acetate (100ml×3), combined the organic layers, dried over anhydrous sodium sulfate, and rotary evaporated under reduced pressure at 45°C to obtain the crude product, _which was purified by column chromatography (dichloromethane : Methanol=50:1 (V/V)), 1.82 g of a light brown solid was obtained, and the yield was 83%.

Synthesis of Compound 1-7a: Compound 1-6a (4.70g, 10mmol), Compound 1-5a (3.44g, 11mmol), CuI (0.19g, 1mmol) and K ₂ CO ₃ (2.76g, 20mmol) were added to 25ml In the reaction flask, protected by argon, and heated at 110° C., 20 ml of DMSO was added to the reaction liquid, and the reaction was stirred for 4 h. The reaction was completed, cooled to room temperature, quenched by adding 2ml of ammonia water, extracted with dichloromethane (50ml×3), washed with saturated sodium chloride solution and water, combined the organic layers, dried over anhydrous sodium sulfate, and rotary evaporated under reduced pressure to obtain the crude product, which was washed by Purified by column chromatography (ethyl acetate) to obtain 3.41 g of a white solid with a yield of 52%. ¹ H NMR (400MHz, DMSO-d ⁶ ) δ7.93(d, J=2.4Hz, 1H), 7.84(dd, J=8.4Hz, 2.4Hz, 1H), 7.61(d, J=8.4Hz, 1H ), 7.55(dd, J=9.2Hz, J=2.4Hz, 1H), 7.43(d, J=2.0Hz, 1H), 7.34(d, J=9.2Hz, 1H), 7.17(d, J=8.8 Hz,2H),6.82(d,J＝8.8Hz,2H),3.79-3.94(m,2H),3.75(s,3H),3.67-3.70(m,2H),3.06-3.11(m,4H) ,2.17(s,3H); ESI-MS: m/z 655.1[M+H] ⁺ .

Synthesis of compound 1-8a: In a 25ml reaction flask, compound 1-7a (3.36g, 5mmol) was dissolved in TFA (200mmol) and TfOH (25mmol), and stirred overnight at room temperature. After the reaction was completed, it was quenched by adding water, adjusted to alkaline with saturated sodium bicarbonate, filtered with suction, and the filter cake was dried in an oven to obtain a crude product, which was directly used in the next reaction.

Synthesis of Compound 1-10a: Compound 1-8a (0.53g, 1mmol), Compound 1-9a (0.23g, 1.5mmol),

(PPh ₃ ) ₄ Pd (23mg, 0.02mmol) and Cs ₂ CO ₃ (0.65g, 2mmol) were added to a 25ml reaction flask, protected by argon, and then 20ml DMF/H ₂ O (volume ratio 3:1), 80 °C reflux reaction overnight. After the reaction was completed, it was quenched by adding water, filtered with suction, and the filter cake was purified by column chromatography (dichloromethane:methanol:triethylamine=100:10:1) to obtain 0.35 g of a white solid with a yield of 62%. ¹ H NMR (400MHz, DMSO-d ⁶ )δ12.04(s,1H),8.31(s,1H),8.19(d,J=8.4Hz,1H),8.10(s,1H),7.95(d, J=8.8Hz, 1H), 7.92(d, J=9.2Hz, 1H), 7.65(d, J=8.0Hz, 1H), 7.59(d, J=8.4Hz, 1H), 7.09(s, 1H) ,6.85(d,J＝8.4Hz,1H),3.86(s,3H),3.65(m,4H),3.07(m,4H),3.07-3.00(m,4H),2.08(s,3H); ESI-MS: m/z 564.2[M+H] ⁺ .

Synthesis of Compound 1-12a: Compound 1-10a (0.56g, 1mmol), Cs ₂ CO ₃ (0.98g, 3mmol), TBAI (37mg, 0.1mmol) were added to a 50ml reaction flask, then 20ml DMSO was added, at room temperature After stirring for 10 min, (2-bromoethoxy)-tert-butyldimethylsilane (0.29 g, 1.2 mmol) was added and reacted overnight at 70°C. After the reaction was completed, water was added to quench the suction filtration, and the filter cake was dried in an oven to obtain a crude product, which was directly used in the next reaction.

Synthesis of compound 1-13a: Add compound 1-12a (0.72g, 1mmol) into a 50ml reaction flask, then add 20ml THF, then add TBAF (0.29g 1.1mmol), and continue to stir at room temperature for 1h. After the reaction was completed, extracted with dichloromethane (100ml×3), washed with saturated sodium chloride solution and water, combined the organic layers, dried over anhydrous sodium sulfate, and rotary evaporated under reduced pressure to obtain intermediate 1-13a, which was directly used in the next reaction.

Synthesis of Compound 1-14a: Compound 1-13a (0.6g, 1mmol) was dissolved in 20ml of chloroform, stirred in an ice bath for 10min, then phosphorus tribromide (0.75g, 3mmol) was slowly added dropwise, and reacted overnight at room temperature. After the reaction was completed, extracted with dichloromethane (100ml×3), washed with saturated sodium chloride solution, combined the organic layers, dried over anhydrous sodium sulfate, and rotary evaporated under reduced pressure to obtain the crude product 1-14a, which was directly used in the next reaction.

Synthesis of compound 1-15a: Dissolve 1-14a (0.67g, 1mmol), K ₂ CO ₃ (0.56g, 4mmol), KI (66mg, 0.4mmol) in 30ml DMF, then add tetrahydropyrrole (94mg, 2 mmol), react overnight at room temperature. The reaction was completed, extracted with dichloromethane (100ml×3), washed with saturated sodium chloride solution, combined the organic layers, dried over anhydrous sodium sulfate, and rotary evaporated under reduced pressure to obtain the crude product, which was purified by column chromatography (dichloromethane:methanol=15 : 1), obtain white solid 0.46g, yield 70%. ¹ H NMR (400MHz,DMSO-d ⁶ )δ8.33(s,1H),8.20(d,J＝8.4Hz,1H),8.10(s,1H),8.03(d,J＝8.8Hz,1H) ,7.97(d,J=8.4Hz,1H),7.80(d,J=8.8Hz,1H),7.68(d,J=8.4Hz,1H),7.20(s,1H),6.85(d,J= 8.4Hz, 1H), 4.54(t, J=6.8Hz, 2H), 3.87(s, 3H), 3.65(s, 4H), 3.08(s, 2H), 3.02(s, 2H), 2.73(t, J＝6.8Hz, 2H), 2.59(s, 4H), 2.09(s, 3H), 1.71(s, 4H); ESI-MS: m/z 661.3[M+H] ⁺ .

Synthesis of compound CQ314: Compound 1-15a was dissolved in 6N HCl, refluxed at 70° C. for 5 h, cooled to room temperature after the reaction, and then adjusted to neutral with NaOH. Extracted with dichloromethane (100ml×3), washed with saturated sodium chloride solution, combined organic layers, dried over anhydrous sodium sulfate, and rotary evaporated under reduced pressure to obtain the crude product, which was purified by column chromatography (dichloromethane:methanol=15:1) , to obtain a white solid 0.36g, yield 60%. ¹ HNMR (400MHz, DMSO-d ⁶ ) δ8.30(d, J=2.4Hz, 1H), 8.17(dd, J=8.8, 2.0Hz, 1H), 8.09(d, J=2.0Hz, 1H), 8.02(dd, J=8.8,2.0Hz,1H),7.90(d,J=8.8Hz,1H),7.79(d,J=9.2Hz,1H),7.67(dd,J=8.4,2.4Hz,1H ),7.20(d,J=2.0Hz,1H),6.83(d,J=8.4Hz,1H),4.53(t,J=6.8Hz,2H),3.86(s,3H),3.04(m,4H ), 3.01(m, 4H), 2.73(t, J=6.8Hz, 2H), 2.60(m, 4H), 1.71(m, 4H); ESI-MS: m/z 619.3[M+H] ⁺ .

Example 2

5-(2-(Dimethylamino)ethyl)-8-(6-methoxypyridin-3-yl)-1-(4-(piperazin-1-yl)-3-(trifluoromethyl )phenyl)-1,5-dihydro-4H-[1,2,3]triazol[4,5-c]quinolin-4-one (CQ265)

Synthesis of compound 2-1a: 1-14a (0.67g, 1mmol), K ₂ CO ₃ (0.56g, 4mmol), KI (66mg, 0.4mmol) Dissolve in 30ml DMF, then add dimethylamine (90.2mg, 2mmol) and react overnight at room temperature. After the reaction was completed, extracted with dichloromethane (100ml×3), washed with saturated sodium chloride solution, combined the organic layers, 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 CQ265: the synthesis method was the same as that of compound CQ314 to obtain 0.3 g of white solid with a yield of 75%.

¹ HNMR (400MHz, DMSO-d ⁶ )δ8.29(d, J=2.4Hz, 1H), 8.16(dd, J=8.8, 2.4Hz, 1H), 8.10(d, J=2.4Hz, 1H), 8.03(dd, J=8.8,2.4Hz,1H),7.89(d,J=8.8Hz,1H),7.81(d,J=8.8Hz,1H),7.69(dd,J=8.8,2.4Hz,1H ),7.20(d,J=2.4Hz,1H),6.83(d,J=8.8Hz,1H),4.53(t,J=6.8Hz,2H),3.86(s,3H),3.02(m,4H ), 2.96-2.95(m, 4H), 2.57(t, J=6.8Hz, 2H), 2.28(s, 6H); ESI-MS: m/z 593.2[M+H] ⁺ .

Example 3

5-(3-hydroxypropyl)-8-(6-methoxypyridin-3-yl)-1-(4-(piperazin-1-yl)-3-(trifluoromethyl)phenyl) -1,5-Dihydro-4H-[1,2,3]triazol[4,5-c]quinolin-4-one (CQ266)

Synthesis of compound 3-2a: the synthesis method is the same as that of compound 1-12a.

Synthesis of compound 3-3a: the synthesis method is the same as that of compound 1-13a.

Synthesis of compound CQ266: the synthesis method was the same as the synthesis of compound CQ314 to obtain 0.3 g of white solid with a yield of 75%.

¹ H NMR (400MHz, DMSO-d ⁶ ) δ8.28(d, J=2.4Hz, 1H), 8.16(dd, J=8.4, 2.0Hz, 1H), 8.07(d, J=2.4Hz, 1H) ,7.99(dd,J=9.2,2.0Hz,1H),7.89(d,J=8.4Hz,1H),7.83(d,J=9.2Hz,1H),7.65(dd,J=8.8,2.4Hz, 1H), 7.17(d, J=2.0Hz, 1H), 6.80(d, J=8.4Hz, 1H), 4.49–4.35(m, 2H), 3.85(s, 3H), 3.58(t, J=6.0 Hz, 2H), 3.02(m, 4H), 2.96-2.95(m, 4H), 1.87-1.80(m, 2H); ESI-MS: m/z 580.1[M+H]+.

Example 4

5-(4-hydroxybutyl)-8-(6-methoxypyridin-3-yl)-1-(4-(piperazin-1-yl)-3-(trifluoromethyl)phenyl) -1,5-Dihydro-4H-[1,2,3]triazol[4,5-c]quinolin-4-one (CQ267)

Referring to Example 3 for the synthesis method, 0.3 g of white solid was obtained with a yield of 76%.

¹ H NMR (400MHz, DMSO-d ⁶ ) δ8.34(d, J=2.4Hz, 1H), 8.23(dd, J=8.4, 2.4Hz, 1H), 8.10(d, J=2.4Hz, 1H) ,8.00(dd,J=9.2,2.0Hz,1H),7.96(d,J=8.8Hz,1H),7.82(d,J=9.2Hz,1H),7.65(dd,J=8.8,2.4Hz, 1H), 7.20(d, J=2.0Hz, 1H), 6.84(d, J=8.4Hz, 1H), 4.40–4.36(m, 2H), 3.86(s, 3H), 3.48-3.45(m, 2H ),1.73-1.68(m,2H),1.60-1.55(m,2H).

Example 5

8-(6-methoxypyridin-3-yl)-5-(2-(methylamino)ethyl)-1-(4-(piperazin-1-yl)-3-(trifluoromethyl )phenyl)-1,5-dihydro-4H-[1,2,3]triazol[4,5-c]quinolin-4-one (CQ268)

Synthesis of compound 5-2a: Dissolve 1-14a (0.67g, 1mmol), K ₂ CO ₃ (0.56g, 4mmol), KI (66mg, 0.4mmol) in 30ml DMF, then add methylamine (63mg, 2mmol ), react overnight at room temperature. After the reaction was completed, extracted with dichloromethane (100ml×3), washed with saturated sodium chloride solution, combined the organic layers, 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 CQ268: the synthesis method was the same as that of compound CQ314 to obtain 0.5 g of a white solid with a yield of 72%.

¹ H NMR (400MHz, DMSO-d ⁶ )δ8.27(s, 1H), 8.16(dd, J=8.4, 2.4Hz, 1H), 8.12(d, J=2.4Hz, 1H), 8.02(dd, J=8.8,2.0Hz,1H),7.97-7.88(m,2H),7.69(dd,J=8.8,2.4Hz,1H),7.22(d,J=2.0Hz,1H),6.84(d,J =8.4Hz, 1H), 4.62(t, J=6.4Hz, 2H), 3.86(s, 3H), 3.21-2.97(m, 10H), 2.49(s, 3H); ESI-MS: m/z 579.1 [M+H] ⁺ .

Example 6

8-(6-methoxypyridin-3-yl)-5-(2-morpholinoethyl)-1-(4-(piperazin-1-yl)-3-(trifluoromethyl)phenyl )-1,5-dihydro-4H-[1,2,3]triazol[4,5-c]quinolin-4-one (CQ301)

Synthesis of compound 6-2a: Dissolve 1-14a (0.67g, 1mmol), K ₂ CO ₃ (0.56g, 4mmol), KI (66mg, 0.4mmol) in 30ml DMF, then add morpholine (174mg, 2mmol ), react overnight at room temperature. After the reaction was completed, extracted with dichloromethane (100ml×3), washed with saturated sodium chloride solution, combined the organic layers, 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 CQ301: the synthesis method is the same as that of compound CQ314, white solid 0.45 g, yield 72%.

¹ HNMR (400MHz, DMSO-d ⁶ )δ8.23(d, J＝2.1Hz, 1H), 8.17–8.13(m, 2H), 8.00–7.93(m, 2H), 7.83(d, J＝8.8Hz ,1H),7.69(dd,J=8.4,2.4Hz,1H),7.37(d,J=2.0Hz,1H),6.77(d,J=8.4Hz,1H),4.57(t,J=7.2Hz ,2H),3.89(s,3H),3.61–3.59(m,4H),3.11-3.10(m,4H),3.05-3.04(m,4H),2.70(t,J＝7.2Hz,2H), 2.56(m,4H); ESI-MS: m/z 635.3[M+H] ⁺ .

Example 7

5-(3-(Dimethylamino)propyl)-8-(6-methoxypyridin-3-yl)-1-(4-(piperazin-1-yl)-3-(trifluoromethyl )phenyl)-1,5-dihydro-4H-[1,2,3]triazol[4,5-c]quinolin-4-one (CQ302)

Referring to Example 2 for the synthesis method, 0.3 g of white solid was obtained with a yield of 71%.

¹ H NMR (400MHz, CDCl ₃ )δ8.13(s,1H),7.94(s,1H),7.82(d,J=8.0Hz,1H),7.78(d,J=9.2Hz,1H),7.72 (d,J=8.8Hz,1H),7.62(d,J=8.4Hz,1H),7.48(d,J=8.4Hz,1H),7.43(s,1H),6.72(d,J=8.4Hz ,1H),4.52(t,J=7.2Hz,2H),3.94(s,3H),3.09(m,8H),2.47(t,J=6.4Hz,2H),2.29(s,6H),2.01 –1.95(m,2H); ESI-MS: m/z 607.3[M+H] ⁺ .

Example 8

8-(6-methoxypyridin-3-yl)-1-(4-(piperazin-1-yl)-3-(trifluoromethyl)phenyl)-5-(2-(piperidine- 1-yl)ethyl)-1,5-dihydro-4H-[1,2,3]triazol[4,5-c]quinolin-4-one (CQ303)

Synthesis of compound 8-2a: Dissolve 1-14a (0.67g, 1mmol), K ₂ CO ₃ (0.56g, 4mmol), KI (66mg, 0.4mmol) in 30ml DMF, then add hexahydropyridine (170mg, 2 mmol), react overnight at room temperature. After the reaction was completed, extracted with dichloromethane (100ml×3), washed with saturated sodium chloride solution, combined the organic layers, 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 CQ303: the synthesis method was the same as that of compound CQ314 to obtain 0.4 g of a white solid with a yield of 69%.

¹ H NMR (400MHz,DMSO-d ⁶ )δ8.31(s,1H),8.19(d,J＝8.8Hz,1H),8.10(s,1H),8.02(d,J＝8.8Hz,1H) ,7.92(d,J=8.4Hz,1H),7.78(d,J=9.2Hz,1H),7.67(d,J=8.8Hz,1H),7.20(s,1H),6.83(d,J= 8.4Hz, 1H), 4.48(t, J=6.8Hz, 2H), 3.86(s, 3H), 3.08(m, 8H), 2.56(t, J=6.8Hz, 2H), 2.50(m, 4H) ,1.51(m,4H),1.39(m,2H);ESI-MS:m/z 633.3[M+H] ⁺ .

Example 9

8-(6-methoxypyridin-3-yl)-1-(4-(piperazin-1-yl)-3-(trifluoromethyl)phenyl)-5-(2-(piperazine- 1-yl)ethyl)-1,5-dihydro-4H-[1,2,3]triazol[4,5-c]quinolin-4-one (CQ304)

Synthesis of compound 9-2a: Dissolve 1-14a (0.67g, 1mmol), K ₂ CO ₃ (0.56g, 4mmol), KI (66mg, 0.4mmol) in 30ml DMF, and then add 1-tert-butoxycarbonyl Piperazine (372mg, 2mmol), react overnight at room temperature. After the reaction was completed, extract with dichloromethane (100ml×3), wash with saturated sodium chloride solution, combine the organic layers, dry over anhydrous sodium sulfate, and depressurize The crude product obtained by rotary evaporation was directly used in the next step.

Synthesis of compound CQ304: the synthesis method was the same as that of compound CQ314 to obtain 0.4 g of a white solid with a yield of 67%.

¹ H NMR (400MHz, CDCl ₃ ) 8.12(s, 1H), 7.93(s, 1H), 7.83(d, J=7.6Hz, 1H), 7.79(d, J=8.4Hz, 1H), 7.64(m ,2H),7.48(d,J=7.6Hz,1H),7.42(s,1H),6.71(d,J=8.0Hz,1H),4.59(t,J=7.2Hz,2H),3.93(s ,3H),3.08-3.10(m,8H),2.93(d,J=4.0Hz,4H),2.73(t,J=7.2Hz,2H),2.62(m,4H),2.41(m,4H) ;ESI-MS: m/z 634.3[M+H] ⁺ .

Example 10

5-(2-(azepan-1-yl)ethyl)-8-8-(6-methoxypyridin-3-yl)-1-(4-(piperazin-1-yl)- 3-(Trifluoromethyl)phenyl)-1,5-dihydro-4H-[1,2,3]triazol[4,5-c]quinolin-4-one (CQ315)

Synthesis of compound 10-2a: Dissolve 1-14a (0.67g, 1mmol), K ₂ CO ₃ (0.56g, 4mmol), KI (66mg, 0.4mmol) in 30ml DMF, then add cycloheximide (198mg , 2 mmol), react overnight at room temperature. After the reaction was completed, extracted with dichloromethane (100ml×3), washed with saturated sodium chloride solution, combined the organic layers, 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 CQ315: the synthesis method was the same as that of compound CQ314 to obtain 0.5 g of a white solid with a yield of 78%.

¹ H NMR (400MHz, DMSO-d ⁶ ) δ8.27(d, J=2.4Hz, 1H), 8.14(dd, J=8.4, 2.4Hz, 1H), 8.09(d, J=2.4Hz, 1H) ,8.01(dd,J=8.8,2.0Hz,1H),7.88(d,J=8.8Hz,1H),7.81(d,J=9.2Hz,1H),7.68(dd,J=8.4,2.4Hz, 1H), 7.19(d, J=2.0Hz, 1H), 6.82(d, J=8.8Hz, 1H), 4.47(t, J=7.2Hz, 2H), 3.86(s, 3H), 2.99(s, 4H), 2.91(d, J=4.0Hz, 4H), 2.78(m, 2H), 2.76-2.74(m, 4H), 1.60(m, 4H), 1.54(m, 4H); ESI-MS: m /z 647.3[M+H] ⁺ .

Example 11

8-(6-methoxypyridin-3-yl)-5-(2-(4-methylpiperazin-1-yl)ethyl)-1-(4-(piperazin-1-yl)- 3-(Trifluoromethyl)phenyl)-1,5-dihydro-4H-[1,2,3]triazol[4,5-c]quinolin-4-one (CQ316)

Synthesis of compound 11-2a: Dissolve 1-14a (0.67g, 1mmol), K ₂ CO ₃ (0.56g, 4mmol), KI (66mg, 0.4mmol) in 30ml DMF, then add N-methylpiperazine (200mg, 2mmol), react overnight at room temperature. After the reaction was completed, extracted with dichloromethane (100ml×3), washed with saturated sodium chloride solution, combined the organic layers, 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 CQ316: the synthesis method was the same as that of compound CQ314 to obtain 0.5 g of a white solid with a yield of 78%.

¹ H NMR (400MHz, DMSO-d ⁶ )δ8.27(d, J=2.4Hz, 1H), 8.15(dd, J=8.8, 2.4Hz 1H), 8.09(d, J=2.0Hz, 1H), 8.02(dd, J=9.2,2.0Hz,1H),7.88(d,J=8.4Hz,1H),7.81(d,J=9.2Hz,1H),7.69(dd,J=8.4,2.4Hz,1H ), 7.19(d, J=2.0Hz, 1H), 6.82(d, J=8.8Hz, 1H), 4.53(t, J=6.8Hz, 2H), 3.86(s, 3H), 2.99(m, 4H ),2.91(m,4H),2.61(t,J=6.8Hz,2H),2.59(m,4H),2.33(m,4H),2.16(s,3H); ESI-MS: m/z 648.3 [M+H] ⁺ .

Example 12

5-(2-(Diethylamino)ethyl)-8-(6-methoxypyridin-3-yl)-1-(4-(piperazin-1-yl)-3-(trifluoromethyl Base)phenyl)-1,5-dihydro-4H-[1,2,3]triazol[4,5-c]quinolin-4-one (CQ317)

Synthesis of compound 12-2a: Dissolve 1-14a (0.67g, 1mmol), K ₂ CO ₃ (0.56g, 4mmol), KI (66mg, 0.4mmol) in 30ml DMF, then add diethylamine (146mg, 2 mmol), react overnight at room temperature. After the reaction was completed, extracted with dichloromethane (100ml×3), washed with saturated sodium chloride solution, combined the organic layers, 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 CQ317: the synthesis method was the same as that of compound CQ314 to obtain 0.46 g of a white solid with a yield of 75%.

¹ H NMR (400MHz, DMSO-d ⁶ )δ8.27(s, 1H), 8.14(d, J=8.4Hz, 1H), 8.08(s, 1H), 8.02(d, J＝8.4Hz, 1H), 7.88(d, J＝8.8Hz, 1H), 7.77(d, J＝9.2Hz, 1H), 7.68(d, J＝8.4Hz, 1H), 7.19(s, 1H) ,6.81(d,J=8.4Hz,1H),4.44(t,J=6.8Hz,2H),3.85(s,3H),2.99(m,4H),2.90(m,4H),2.67(t, J＝6.8Hz, 2H), 2.59(q, 4H), 0.97(t, J＝7.2Hz, 6H); ESI-MS: m/z 621.3[M+H] ⁺ .

Example 13

5-(2-(Diisopropylamino)ethyl)-8-(6-methoxypyridin-3-yl)-1-(4-(piperazin-1-yl)-3-(trifluoro Methyl)phenyl)-1,5-dihydro-4H-[1,2,3]triazol[4,5-c]quinolin-4-one (CQ318)

Synthesis of compound 13-2a: Dissolve 1-14a (0.67g, 1mmol), K ₂ CO ₃ (0.56g, 4mmol), KI (66mg, 0.4mmol) in 30ml DMF, then add diisopropylamine (202mg, 2 mmol), react overnight at room temperature. After the reaction was completed, extracted with dichloromethane (100ml×3), washed with saturated sodium chloride solution, combined the organic layers, 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 CQ318: the synthesis method was the same as that of compound CQ314 to obtain 0.47 g of white solid with a yield of 73%.

¹ H NMR (400MHz, DMSO-d ⁶ ) δ8.28(d, J=2.4Hz, 1H), 8.16(dd, J=8.4, 2.4Hz, 1H), 8.11(d, J=2.4Hz, 1H) ,8.07(dd,J=8.8,2.0Hz,1H),7.90(d,J=8.4Hz,1H),7.78(d,J=9.2Hz,1H),7.70(dd,J=8.8,2.8Hz, 1H), 7.22(d, J=2.4Hz, 1H), 6.83(d, J=8.4Hz, 1H), 4.38(t, J=6.8Hz, 2H), 3.86(s, 3H), 3.11–3.08( m,2H),3.06-3.05(m,4H),3.01-3.00(m,4H),2.70(t,J=6.8Hz,2H),0.99(d,J=6.4Hz,12H); ESI-MS :m/z 649.3[M+H] ⁺ .

Example 14

1-(2-(8-(6-methoxypyridin-3-yl)-4-oxo-1-(4-(piperazin-1-yl)-3-(trifluoromethyl)phenyl )-1,4-dihydro-5H-[1,2,3]triazol[4,5-c]quinolin-5-yl]ethyl)pyrrolidine-2,5-dione (CQ319)

Synthesis of compound 14-2a: Dissolve 1-14a (0.67g, 1mmol), K ₂ CO ₃ (0.56g, 4mmol), KI (66mg, 0.4mmol) in 30ml DMF, then add succinimide ( 200mg, 2mmol), react overnight at room temperature. After the reaction was completed, extracted with dichloromethane (100ml×3), washed with saturated sodium chloride solution, combined the organic layers, 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 CQ319: the synthesis method was the same as that of compound CQ314 to obtain 0.38 g of a white solid with a yield of 59%.

¹ H NMR (400MHz, DMSO-d ⁶ )δ8.26(d, J=2.0Hz, 1H), 8.16(s, 1H), 8.13(s, 1H), 8.07(dd, J=8.8Hz, 1.6Hz ,1H),7.92(d,J=8.8Hz,2H),7.87(d,J=8.8Hz,1H),7.73(dd,J=8.4,2.4Hz,1H),7.23(s,1H),6.83 (d, J=8.8Hz, 1H), 4.57(t, J=5.6Hz, 2H), 3.86(s, 3H), 3.78(t, J=5.6Hz, 2H), 3.00(m, 4H), 2.92 (m,4H), 2.60(m,4H); ESI-MS: m/z 647.2[M+H] ⁺ .

Example 15

8-(6-methoxypyridin-3-yl)-1-(4-morpholino-3-(trifluoromethyl)phenyl)-5-(2-(pyrrolidin-1-yl)ethane base)-1,5-dihydro-4H-[1,2,3]triazol[4,5-c]quinolin-4-one (CQ320)

Referring to Example 1 for the synthesis method, 0.2 g of white solid was obtained with a yield of 70%.

¹ H NMR (400MHz,DMSO-d ⁶ )δ8.31(s,1H),8.20(d,J＝8.4Hz,1H),8.09(s,1H),8.03(d,J＝8.4Hz,1H) ,7.98(d,J=8.8Hz,1H),7.80(d,J=8.8Hz,1H),7.68(d,J=8.4Hz,1H),7.20(s,1H),6.84(d,J= 8.8Hz, 1H), 4.55(t, J=6.8Hz, 2H), 3.85(s, 3H), 3.81(m, 4H), 3.08(m, 4H), 2.75(t, J=6.8Hz, 2H) ,2.61(m,4H),1.72(m,4H);ESI-MS:m/z 620.3[M+H] ⁺ .

Example 16

5-(2-(Dimethylamino)ethyl)-8-(6-methoxypyridin-3-yl)-1-(4-morpholino-3-(trifluoromethyl)phenyl) -1,5-Dihydro-4H-[1,2,3]triazol[4,5-c]quinolin-4-one (CQ321)

Referring to Example 2 for the synthesis method, 0.2 g of white solid was obtained with a yield of 63%.

¹ H NMR (400MHz,DMSO-d ⁶ )δ8.32(s,1H),8.20(d,J＝8.8Hz,1H),8.10(s,1H),8.03(d,J＝9.2Hz,1H) ,7.98(d,J=8.4Hz,1H),7.81(d,J=8.8Hz,1H),7.69(d,J=8.4Hz,1H),7.21(s,1H),6.84(d,J= 8.8Hz, 1H), 4.54(t, J=6.8Hz, 2H), 3.85(s, 3H), 3.81(m, 4H), 3.08(m, 4H), 2.58(t, J=6.8Hz, 2H) ,2.29(s,6H); ESI-MS: m/z 594.2[M+H] ⁺ .

Example 17

1-(4-(4-acetylpiperazin-1-yl)-3-(trifluoromethyl)phenyl)-8-(6-methoxypyridin-3-yl)-5-(2-( Pyrrolidin-1-yl)ethyl)-1,5-dihydro-4H-[1,2,3]triazol[4,5-c]quinolin-4-one (CQ322)

Referring to Example 1 for the synthesis method, 0.5 g of white solid was obtained with a yield of 77%.

¹ H NMR (400MHz,DMSO-d ⁶ )δ8.33(s,1H),8.20(d,J＝8.4Hz,1H),8.10(s,1H),8.03(d,J＝8.8Hz,1H) ,7.97(d,J=8.4Hz,1H),7.80(d,J=8.8Hz,1H),7.68(d,J=8.4Hz,1H),7.20(s,1H),6.85(d,J= 8.4Hz, 1H), 4.54(t, J=6.8Hz, 2H), 3.87(s, 3H), 3.65(m, 4H), 3.08-3.02(m, 4H), 2.73(t, J=6.8Hz, 2H), 2.59(m,4H), 2.09(s,3H), 1.71(m,4H); ESI-MS: m/z 661.3[M+H] ⁺ .

Example 18

8-(6-methoxypyridin-3-yl)-1-(4-(piperazin-1-yl)-3-(trifluoromethyl)phenyl)-5-(3-(pyrrole-1 -yl)propyl)-1,5-dihydro-4H-[1,2,3]triazol[4,5-c]quinolin-4-one (CQ323)

Referring to Example 1 for the synthesis method, 0.5 g of white solid was obtained with a yield of 77%.

¹ H NMR (400MHz, CDCl ₃ ) δ8.13 (d, J = 2.4Hz, 1H), 7.94 (d, J = 2.4Hz, 1H), 7.82 (dd, J = 8.8, 2.4Hz 1H), 7.75 ( d,J=1.6Hz,1H),7.48(s,1H),7.62(d,J=8.8Hz,1H),7.48(dd,J=8.4, 2.4Hz 1H), 7.42(d, J=1.6Hz, 1H), 6.72(d, J=8.4Hz, 1H), 4.55(t, J=7.2Hz, 2H), 3.94(s, 2H), 3.09- 3.08(m,8H),2.69(t,J=7.2Hz,2H),2.60(m,4H),2.09-2.05(m,2H),1.83-1.81(m,4H); ESI-MS:m/ z 633.3[M+H] ⁺ .

Example 19

8-(4-methoxyphenyl)-1-(4-(piperazin-1-yl)-3-(trifluoromethyl)phenyl)-5-(2-(pyrrol-1-yl) Ethyl)-1,5-dihydro-4H-[1,2,3]triazol[4,5-c]quinolin-4-one (CQ324)

Synthesis of compound 19-3a: In a 250ml reaction vial, compound 19-1a (5.34g, 10mmol), N-chloroethylpyrrolidine hydrochloride (2.55g, 15mmol), TBAI (369mg, 1mmol) and Cs ₂ CO ₃ (8.14g, 25mmol) was added into 100ml DMSO, and stirred at 80°C for 4h. After the reaction was completed, cool to room temperature, add 100ml of water, extract with dichloromethane (100ml×3), combine the organic layers, dry over anhydrous sodium sulfate, and rotary evaporate under reduced pressure to obtain the crude product, which was purified by column chromatography (dichloromethane:methanol =10:1), 5 g of yellow solid was obtained, and the yield was 79%.

Synthesis of Compound 19-4a: Compound 19-3a (632 mg, 1 mmol), 10 ml of hydrochloric acid, and 10 ml of ethanol were reacted under reflux at 120° C. for 4 h in a 50 ml reaction flask. After the reaction, cool to room temperature, spin dry, then adjust the pH to alkaline with sodium hydroxide solution, filter with suction, and dry to obtain 500 mg of yellow solid with a yield of 85%, which is directly used for the next step.

Synthesis of compound CQ-324: under argon atmosphere, compound 19-4a (295 mg, 5 mmol), 19-5a p-methoxyphenylboronic acid (1.14 g, 7.5 mmol), (PPh ₃ ) ₄ Pd (115 mg, 0.1mmol) and Cs ₂ CO ₃ (4.8g, 15mmol) were placed in a 25ml reaction flask, 30ml DMF and 10ml water were added, and the reaction was stirred at 80°C for 3h. After the reaction was completed, cool to room temperature, add 100ml of water, extract with dichloromethane (100ml×3), combine the organic layers, dry over anhydrous sodium sulfate, and rotary evaporate under reduced pressure to obtain the crude product, which was passed through the column layer Purification by analysis (dichloromethane:methanol=5:1) gave 308 mg of a yellow solid with a yield of 64%. ¹ H NMR (400MHz, DMSO-d ⁶ )δ8.31(s, 1H), 8.16(d, J=8.4Hz, 1H), 7.98(d, J=8.8Hz, 1H), 7.88(d, J= 8.4Hz, 1H), 7.76(d, J=8.8Hz, 1H), 7.28(s, 1H), 7.26(m, 2H), 6.91(d, J=8.0Hz, 2H), 4.53(t, J= 7.2Hz, 2H), 3.77(s, 3H), 2.99(m, 4H), 2.97(m, 4H), 2.73(t, J=7.2Hz, 2H), 2.60(m, 4H), 1.71(m, 4H); ESI-MS: m/z618.3[M+H] ⁺ .

Example 20

8-(3-fluoro-4-methoxyphenyl)-1-(4-(piperazin-1-yl)-3-(trifluoromethyl)phenyl)-5-(2-(pyrrole- 1-yl)ethyl)-1,5-dihydro-4H-[1,2,3]triazol[4,5-c]quinolin-4-one (CQ325)

Referring to Example 19 for the synthesis method, 0.3 g of white solid was obtained with a yield of 77%.

¹ H NMR (400MHz, DMSO-d ⁶ ) δ8.31(s, 1H), 8.16(d, J=8.4Hz, 1H), 8.02(d, J=8.8Hz, 1H), 7.88(d, J= 8.4Hz, 1H), 7.77(d, J=8.8Hz, 1H), 7.24(s, 1H), 7.18(m, 1H), 7.12(s, 1H), 7.06(d, J=12.4Hz, 1H) ,4.53(t,J=6.4Hz,2H),3.86(s,3H),3.00(m,4H),2.97(m,4H),2.73(t,J=6.4Hz,2H),2.59(m, 4H), 1.71(m,4H); ESI-MS: m/z 636.3[M+H] ⁺ .

Example 21

8-(4-methoxy-3-methylphenyl)-1-(4-(piperazin-1-yl)-3-(trifluoromethyl)phenyl)-5-(2-(pyrrole -1-yl)ethyl)-1,5-dihydro-4H-[1,2,3]triazol[4,5-c]quinolin-4-one (CQ326)

Referring to Example 19 for the synthesis method, 0.2 g of white solid was obtained with a yield of 67%.

¹ H NMR (400MHz, DMSO-d ⁶ )δ8.32(s, 1H), 8.17(d, J=8.8Hz, 1H), 7.97(d, J=9.2Hz, 1H), 7.88(d, J= 8.8Hz, 1H), 7.76(d, J=9.2Hz, 1H), 7.27(s, 1H), 7.19(d, J=8.8Hz, 1H), 7.07(s, 1H), 6.91(d, J= 8.4Hz, 1H), 4.52(d, J=6.4Hz, 2H), 3.80(s, 3H), 3.03-3.02(m, 4H), 3.00-2.98(m,4H),2.74(t,J＝6.4Hz,2H),2.82-2.60(m,4H),2.13(s,3H),1.73-1.70(m,4H);ESI-MS: m/z 632.7[M+H] ⁺ .

Example 22

8-(Benzo[d][1,3]dioxolan-5-yl)-1-(4-(piperazin-1-yl)-3-(trifluoromethyl)phenyl)-5 -(2-(Pyrrol-1-yl)ethyl)-1,5-dihydro-4H-[1,2,3]triazol[4,5-c]quinolin-4-one (CQ327)

Referring to Example 19 for the synthesis method, 0.4 g of white solid was obtained with a yield of 79%.

¹ H NMR (400MHz, DMSO-d ⁶ )δ8.31(s, 1H), 8.16(d, J=8.8Hz, 1H), 7.97(d, J=8.8Hz, 1H), 7.89(d, J= 8.4Hz, 1H), 7.75(d, J=9.2Hz, 1H), 7.19(s, 1H), 6.91(d, J=8.0Hz, 1H), 6.85(d, J=8.0Hz, 1H), 6.80 (s,1H),6.05(s,2H),4.53(t,J=6.4Hz,2H),3.03(m,4H),3.01(m,4H),2.73(t,J=6.4Hz,2H) ,2.60(m,4H),1.71(m,4H);ESI-MS:m/z 632.3[M+H] ⁺ .

Example 23

8-(3,4-Methoxyphenyl)-1-(4-(piperazin-1-yl)-3-(trifluoromethyl)phenyl)-5-(2-(pyrrole-1- Base) ethyl) -1,5-dihydro-4H-[1,2,3]triazol[4,5-c]quinolin-4-one (CQ328)

Referring to Example 19 for the synthesis method, 0.3 g of white solid was obtained with a yield of 71%.

¹ H NMR (400MHz, DMSO-d ⁶ )δ8.28(s, 1H), 8.17(d, J=8.0Hz, 1H), 8.02(d, J=8.8Hz, 1H), 7.83(d, J= 8.4Hz, 1H), 7.77(d, J=8.8Hz, 1H), 7.31(s, 1H), 6.94(s, 1H), 6.90(d, J=8.4Hz, 1H), 6.83(d, J= 8.0Hz, 1H), 4.54(t, J=7.6Hz, 2H), 3.76(s, 3H), 3.75(s, 3H), 2.99(m, 4H), 2.95(m, 4H), 2.73(t, J＝7.6Hz, 2H), 2.60(m, 4H), 1.71(m, 4H); ESI-MS: m/z 648.3[M+H] ⁺ .

Example 24

8-(3-Chloro-4-methoxyphenyl)-1-(4-(piperazin-1-yl)-3-(trifluoromethyl)phenyl)-5-(2-(pyrrole- 1-yl)ethyl)-1,5-di Hydrogen-4H-[1,2,3]triazol[4,5-c]quinolin-4-one (CQ329)

Referring to Example 19 for the synthesis method, 0.4 g of white solid was obtained with a yield of 77%.

¹ H NMR (400MHz, DMSO-d ⁶ )δ8.29(s, 1H), 8.17(d, J=8.4Hz, 1H), 8.01(d, J=8.8Hz, 1H), 7.86(d, J= 8.4Hz, 1H), 7.78(d, J=8.8Hz, 1H), 7.36(d, J=8.8Hz, 1H), 7.28(s, 2H), 7.14(d, J=8.4Hz, 1H), 4.53 (d,J=7.2Hz,2H),3.87(s,3H),3.04–3.01(m,4H),2.96–2.93(m,4H),2.73(t,J=7.2Hz,2H),2.60( m,4H), 1.71(m,4H); ESI-MS: m/z 652.2[M+H] ⁺ .

Example 25

8-(4-methoxy-3-(trifluoromethyl)phenyl)-1-(4-(piperazin-1-yl)-3-(trifluoromethyl)phenyl)-5-( 2-(Pyrrol-1-yl)ethyl)-1,5-dihydro-4H-[1,2,3]triazol[4,5-c]quinolin-4-one (CQ330)

Referring to Example 19 for the synthesis method, 0.5 g of white solid was obtained with a yield of 77%.

¹ H NMR (400MHz, DMSO-d ⁶ )δ8.29(s, 1H), 8.19(d, J=8.4Hz, 1H), 8.05(d, J=8.8Hz, 1H), 7.84–7.81(m, 2H), 7.71(d, J=8.8Hz, 1H), 7.44(s, 1H), 7.35(s, 1H), 7.30(d, J=8.8Hz, 1H), 4.55(t, J=7.2Hz, 1H), 3.92(s, 3H), 3.04(m, 8H), 2.75(t, J=7.2Hz, 2H), 2.61(m, 4H), 1.72(m, 4H); ESI-MS: m/z 686.3[M+H] ⁺ .

Example 26

1-(4-(piperazin-1-yl)-3-(trifluoromethyl)phenyl)-5-(2-(pyrrol-1-yl)ethyl)-8-(4-(trifluoro Methoxy)phenyl)-1,5-dihydro-4H-[1,2,3]triazol[4,5-c]quinolin-4-one (CQ331)

Referring to Example 19 for the synthesis method, 0.4 g of white solid was obtained with a yield of 70%.

¹ H NMR (400MHz, DMSO-d ⁶ )δ8.31(s, 1H), 8.17(d, J=8.4Hz, 1H), 8.04(d, J=8.8Hz, 1H), 7.88(d, J= 8.4Hz, 1H), 7.82(d, J=8.4Hz, 1H), 7.45(d, J=8.0Hz, 2H), 7.36(d, J=8.0Hz, 2H), 7.28(s, 1H), 4.54 (d,J=7.6Hz,2H),2.99–2.98(m,4H),2.96–2.94(m,4H),2.74(t,J=6.8Hz,2H),2.60(m,4H),1.71( m,4H); ESI-MS: m/z 672.3[M+H] ⁺ .

Example 27

2-methoxy-5-(4-oxo-1-(4-(piperazin-1-yl)-3-(trifluoromethyl)phenyl)-5-(2-(pyrrol-1-yl) )ethyl)-4,5-dihydro-1H-[1,2,3]triazol[4,5-c]quinolin-8-yl)benzonitrile (CQ332)

Referring to Example 19 for the synthesis method, 0.1 g of white solid was obtained with a yield of 57%.

¹ H NMR (400MHz, DMSO-d ⁶ )δ8.33(d, J=2.4Hz, 1H), 8.21(dd, J=8.4, 2.4Hz, 1H), 8.06(dd, J=8.8, 2.0Hz, 1H), 7.91(d, J=8.4Hz, 1H), 7.83(d, J=9.2Hz, 1H), 7.74(dd, J=9.2, 2.4Hz, 1H), 7.55(d, J=2.4Hz, 1H), 7.31(d, J=2.0Hz, 1H), 7.28(d, J=8.8Hz, 1H), 4.57(t, J=6.4Hz, 2H), 3.95(s, 3H), 3.19(m, 4H), 3.16(m, 4H), 2.79(t, J=6.4Hz, 2H), 2.66(m, 4H), 1.73(m, 4H); ESI-MS: m/z 643.3[M+H] ⁺ .

Example 28

8-(6-(dimethylamino)pyridin-3-yl)-1-(4-(piperazin-1-yl)-3-(trifluoromethyl)phenyl)-5-(2-( Pyrrol-1-yl)ethyl)-1,5-dihydro-4H-[1,2,3]triazol[4,5-c]quinolin-4-one (CQ333)

Referring to Example 19 for the synthesis method, 0.2 g of white solid was obtained with a yield of 72%.

¹ H NMR (400MHz, DMSO-d ⁶ ) δ8.31(d, J=2.0Hz, 1H), 8.18(dd, J=8.8, 2.4Hz, 1H), 8.01(d, J=2.4Hz, 1H) ,7.96(dd,J=9.2,2.0Hz,1H),7.92(dd,J=9.2Hz,1H),7.75(d,J=8.8Hz,1H),7.49(dd,J=8.8,2.4Hz, 1H), 7.11(d, J=2.0Hz, 1H), 6.60(d, J=9.2Hz, 1H), 4.54(t, J=6.8Hz, 2H), 3.12(m, 4H), 3.03(m, 10H), 2.74(t, J=7.2Hz, 2H), 2.62(m, 4H), 1.72(m, 4H); ESI-MS: m/z 632.3[M+H] ⁺ .

Example 29

8-(6-fluoropyridin-3-yl)-1-(4-(piperazin-1-yl)-3-(trifluoromethyl)phenyl)-5-(2-(pyrrol-1-yl) )ethyl)-1,5-dihydro-4H-[1,2,3]triazol[4,5-c]quinolin-4-one (CQ334)

Referring to Example 19 for the synthesis method, 0.1 g of white solid was obtained with a yield of 77%.

¹ H NMR (400MHz, DMSO-d ⁶ ) δ8.30 (d, J=2.4Hz, 1H), 8.19–8.16 (m, 2H), 8.09 (dd, J=9.2, 2.4Hz, 1H), 7.80– 7.95(m,1H),7.89–7.85(m,2H),7.34(d,J=2.0Hz,1H),7.25(dd,J=8.4,2.8Hz,1H),4.56(t,J=6.8Hz ,2H),3.03(m,4H),3.01(m,4H),2.74(t,J＝6.8Hz,2H),2.60(m,4H),1.71(m,4H); ESI-MS: m/ z 607.3[M+H] ⁺ .

Example 30

8-(5-fluoro-6-methoxypyridin-3-yl)-1-(4-(piperazin-1-yl)-3-(trifluoromethyl)phenyl)-5-(2- (Pyrrol-1-yl)ethyl)-1,5-dihydro-4H-[1,2,3]triazol[4,5-c]quinolin-4-one (CQ335)

Referring to Example 19 for the synthesis method, 0.2 g of white solid was obtained with a yield of 47%.

¹ H NMR (400MHz,DMSO-d ⁶ )δ8.26(s,1H),8.15(s,2H),7.98(d,J=6.4Hz,1H),7.86–7.82(m,2H),7.62– 7.60(m,2H),4.58(s,2H),3.70(s,3H),3.06(m,7H),2.78(s,2H),2.64(m,4H),1.72(m,4H);ESI -MS: m/z 637.3[M+H] ⁺ .

Example 31

8-(6-Amino-5-(trifluoromethyl)pyridin-3-yl)-1-(4-(piperazin-1-yl)-3-(trifluoromethyl)phenyl)-5- (2-(Pyrrol-1-yl)ethyl)-1,5-dihydro-4H-[1,2,3]triazol[4,5-c]quinolin-4-one (CQ336)

Referring to Example 19 for the synthesis method, 0.5 g of white solid was obtained with a yield of 77%.

¹ H NMR (400MHz, DMSO-d ⁶ )δ8.26(d, J=10.4Hz, 2H), 8.17(d, J=8.4Hz, 1H), 8.03(d, J=8.8Hz, 1H), 7.82 (d,J=8.8Hz,1H),7.78(d,J=8.8Hz,1H),7.60(s,1H),7.26(s,1H),6.69(s,2H),4.55(t,J= 7.2Hz, 2H), 3.03–3.02(m, 8H), 2.74(t, J=6.4Hz, 2H), 2.61(m, 4H), 1.71(m, 4H); ESI-MS: m/z 672.3[ M+H] ⁺ .

Example 32

8-(5,6-dimethoxypyridin-3-yl)-1-(4-(piperazin-1-yl)-3-(trifluoromethyl)phenyl)-5-(2-( Pyrrol-1-yl)ethyl)-1,5-dihydro-4H-[1,2,3]triazol[4,5-c]quinolin-4-one (CQ337)

Referring to Example 19 for the synthesis method, 0.2 g of white solid was obtained with a yield of 68%.

¹ H NMR (400MHz, DMSO-d ⁶ )δ8.27(s, 1H), 8.18(d, J=8.0Hz, 1H), 8.07(d, J=8.4Hz, 1H), 7.86(d, J= 8.4Hz, 1H), 7.80(d, J=9.2Hz, 1H), 7.55(s, 1H), 7.30(s, 1H), 7.26(s, 1H), 4.55(t, J=7.2Hz, 2H) ,3.86(s,3H),3.80(s,3H),3.03(m,4H),2.97(m,4H),2.74(t,J=6.8Hz,2H),2.60(m,4H),1.71( m,4H); ESI-MS: m/z 649.3[M+H] ⁺ .

Example 33

8-(6-methyl-5-methoxypyridin-3-yl)-1-(4-(piperazin-1-yl)-3-(trifluoromethyl)phenyl)-5-(2 -(pyrrol-1-yl)ethyl)-1,5-dihydro-4H-[1,2,3]triazol[4,5-c]quinolin-4-one (CQ338)

Referring to Example 19 for the synthesis method, 0.2 g of white solid was obtained with a yield of 70%.

¹ H NMR (400MHz,DMSO-d ⁶ )δ8.30(s,1H),8.17(d,J＝8.0Hz,1H),8.01(d,J＝8.4Hz,1H),7.95(s,1H) ,7.89(d,J=8.4Hz,1H),7.79(d,J=8.8Hz,1H),7.47(s,1H),7.20(s,1H),4.53(t,J=7.2Hz,2H) ,3.88(s,3H),3.03(m,4H),2.96(m,4H),2.73(t,J=7.2Hz,2H),2.60(m,4H),2.14(s,3H),1.71( m,4H); ESI-MS: m/z 633.3[M+H] ⁺ .

Example 34

8-(6-Methyl-5-(trifluoromethyl)pyridin-3-yl)-1-(4-(piperazin-1-yl)-3-(trifluoromethyl)phenyl)-5 -(2-(Pyrrol-1-yl)ethyl)-1,5-dihydro-4H-[1,2,3]triazol[4,5-c]quinolin-4-one (CQ339)

Referring to Example 19 for the synthesis method, 0.2 g of white solid was obtained with a yield of 77%.

¹ H NMR (400MHz,DMSO-d ⁶ )δ8.45(s,1H),8.27(s,1H),8.18(d,J=8.4Hz,1H),8.13(d,J=8.8Hz,1H) ,7.96(s,1H),7.85–7.82(m,2H),7.31(s,1H),4.56(t,J＝6.0Hz,2H),4.01(s,3H),3.01(m,4H), 2.97(m, 4H), 2.74(t, J=6.8Hz, 2H), 2.60(m, 4H), 1.71(m, 4H); ESI-MS: m/z687.3[M+H] ⁺ .

Example 35

8-(5-Chloro-6-methoxypyridin-3-yl)-1-(4-(piperazin-1-yl)-3-(trifluoromethyl)phenyl)-5-(2- (Pyrrol-1-yl)ethyl)-1,5-dihydro-4H-[1,2,3]triazol[4,5-c]quinolin-4-one (CQ340)

Referring to Example 19 for the synthesis method, 0.2 g of white solid was obtained with a yield of 67%.

¹ H NMR (400MHz,DMSO-d ⁶ )δ8.28(s,1H),8.17(d,J＝8.4Hz,1H),8.10(s,1H),8.07(d,J＝8.8Hz,1H) ,7.88(d,J=8.4Hz,1H),7.80(m,2H),7.22(s,1H),4.54(t,J=6.0Hz,2H),3.95(s,3H),3.04(m, 4H), 2.96(m, 4H), 2.73(t, J=6.4Hz, 2H), 2.59(m, 4H), 1.71(m, 4H); ESI-MS: m/z 653.2[M+H] ⁺ .

Example 36

1-(4-(piperazin-1-yl)-3-(trifluoromethyl)phenyl)-5-(2-(pyrrol-1-yl)-8-(6-(trifluoromethoxy )pyridin-3-yl)-1,5-dihydro-4H-[1,2,3]triazol[4,5-c]quinolin-4-one (CQ341)

Referring to Example 19 for the synthesis method, 0.2 g of white solid was obtained with a yield of 67%.

¹ H NMR (400MHz,DMSO-d ⁶ )δ8.29(s,1H),8.22(s,1H),8.17(d,J=8.4Hz,1H),8.10(d,J=8.8Hz,1H) ,8.04(d,J=8.4Hz,1H),7.90(d,J=8.4Hz,1H),7.86(d,J=9.2Hz,1H),7.34(d,J=8.4Hz,1H),7.28 (s,1H),4.56(t,J=7.2Hz,2H),3.01(m,4H),2.97(m,4H),2.74(t,J=7.2Hz,2H),2.60(m,4H) ,1.71(m,4H); ESI-MS: m/z 673.2[M+H] ⁺ .

Example 37

8-(6-(Difluoromethoxy)pyridin-3-yl)-1-(4-(piperazin-1-yl)-3-(trifluoromethyl)phenyl)-5-(2- (Pyrrol-1-yl)ethyl)-1,5-dihydro-4H-[1,2,3]triazol[4,5-c]quinolin-4-one (CQ342)

Referring to Example 19 for the synthesis method, 0.51 g of a white solid was obtained with a yield of 77%.

¹ H NMR (400MHz,DMSO-d ⁶ )δ8.29(s,1H),8.19–8.17(m,2H),8.08(d,J＝8.8Hz,1H),7.89–7.83(m,3H), 7.68-7.49(s,1H),7.27(s,1H),7.14(d,J=8.4Hz,1H),4.55(d,J=7.2Hz,2H),3.03(m,4H),3.00(m ,4H),2.74(t,J=6.8Hz,2H),2.60(m,4H),1.71(m,4H); ESI-MS:m/z655.3[M+H] ⁺ .

Example 38

1-(4-(piperazin-1-yl)-3-(trifluoromethyl)phenyl)-5-(2-(pyrrol-1-yl)-8-(1H-pyrrole[2,3- b]pyridin-5-yl)-1,5-dihydro-4H-[1,2,3]triazol[4,5-c]quinolin-4-one (CQ343)

Referring to Example 19 for the synthesis method, 0.2 g of white solid was obtained with a yield of 57%.

¹ H NMR (400MHz, DMSO-d ⁶ ) δ11.80(s, 1H), 8.35(s, 1H), 8.25(s, 1H), 8.16(d, J=8.4Hz, 1H), 8.09(d, J＝8.8Hz, 1H), 7.88(d, J＝8.4Hz, 1H), 7.82(s, 2H), 7.53(s, 1H), 7.32(s, 1H), 6.38(s, 1H), 4.55( t, J=7.2Hz, 2H), 2.97(m, 4H), 2.94(m, 4H), 2.75(t, J=6.4Hz, 2H), 2.61(m, 4H), 1.72(m, 4H); ESI-MS: m/z 628.3[M+H] ⁺ .

Example 39

(S)-5-(2-(3-(methoxymethyl)pyrrol-1-yl)ethyl)-8-(6-methoxypyridin-3-yl)-1-(4-( Piperazin-1-yl)-3-(trifluoromethyl)phenyl)-1,5-dihydro-4H-[1,2,3]triazol[4,5-c]quinoline-4 - Ketone (CQ344)

Synthesis of compound 39-1a: In a 100ml reaction vial, compound CQ-211 (521mg, 1mmol) was dissolved in 50ml DMSO, then (Boc) ₂ O (327mg, 1.5mmol) was added, and the reaction was stirred overnight at room temperature. After the reaction is over, add 100ml water, extracted with dichloromethane (100ml×3), combined the organic layers, 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 39-3a: In a 100ml reaction bottle, compound 39-1a (310mg, 0.5mmol), (R)-1-(2-chloroethyl)-3-(methoxymethyl)-N - Pyrrolidine hydrochloride (107mg, 0.5mmol), TBAI (18mg, 0.05mmol) and Cs ₂ CO ₃ (325g, 1mmol) were added to 30ml DMSO, stirred at 80°C for 4h. After the reaction was completed, cool to room temperature, add 100ml of water, extract with dichloromethane (100ml×3), combine the organic layers, dry over anhydrous sodium sulfate, and rotary evaporate under reduced pressure to obtain the crude product, which was purified by column chromatography (dichloromethane:methanol =10:1), 300mg of yellow solid was obtained, yield 78%.

Synthesis of compound CQ344: Compound 39-3a (300 mg, 0.42 mmol) was dissolved in 10 ml TFA and 10 ml dichloromethane in a 100 ml reaction vial, and stirred at room temperature overnight. After the reaction was completed, spin to dry, adjust the pH to alkaline with sodium bicarbonate solution, add 100ml of water, extract with dichloromethane (100ml×3), combine the organic layers, dry over anhydrous sodium sulfate, and rotary evaporate under reduced pressure to obtain the crude product, which was obtained by Purified by column chromatography (dichloromethane:methanol=10:1) to obtain 264 mg of white solid with a yield of 90%. ¹ HNMR (400MHz, DMSO-d ⁶ )δ8.28(d, J=2.4Hz, 1H), 8.16(dd, J=8.4, 2.0Hz, 1H), 8.09(d, J=2.4Hz, 1H), 8.02(dd, J=9.2,2.0Hz,1H),7.88(d,J=8.4Hz,1H),7.79(d,J=9.2Hz,1H),7.68(dd,J=8.8,2.8Hz,1H ), 7.19(d, J=2.4Hz, 1H), 6.82(d, J=8.4Hz, 1H), 4.52(t, J=7.2Hz, 2H), 3.86(s, 3H), 3.24(s, 3H ),3.22(s,2H),3.02–3.01(m,4H),2.95–2.94(m,4H),2.74(s,3H),2.72–2.70(m,2H),2.63–2.60(m,2H) 2.39–2.36(m,2H),1.87-1.82(m,2H),1.40-1.34(m,1H); ESI-MS: m/z663.3[M+H] ⁺ .

Example 40

(S)-5-(2-(3-(fluoromethyl)pyrrol-1-yl)ethyl)-8-(6-methoxypyridin-3-yl)-1-(4-(piperazine -1-yl)-3-(trifluoromethyl)phenyl)-1,5-dihydro-4H-[1,2,3]triazol[4,5-c]quinolin-4-one (CQ345)

Referring to Example 39 for the synthesis method, 0.4 g of white solid was obtained with a yield of 77%.

¹ H NMR (400MHz, DMSO-d ⁶ ) δ8.28(d, J=2.4Hz, 1H), 8.16(dd, J=8.4, 2.0Hz, 1H), 8.09(d, J=2.4Hz, 1H) ,8.02(dd,J=8.4,2.0Hz,1H),7.88(d,J=8.4Hz,1H),7.80(d,J=8.8Hz,1H),7.68(dd,J=8.4,2.4Hz, 1H), 7.19(d, J=2.4Hz, 1H), 6.82(d, J=8.8Hz, 1H), 4.53(m, 2H), 4.37(d, J=6.4Hz, 1H), 4.25(d, J＝6.4Hz,1H),3.86(s,3H),3.00–2.92(m,8H),2.73–2.71(m,3H),2.64–2.61(m,2H),2.48(m,2H),1.90 –1.83(m,1H),1.45-1.38(m,1H);ESI-MS:m/z 651.3[M +H] ⁺ .

Example 41

(S)-5-(2-(3-fluoropyrrol-1-yl)ethyl)-8-(6-methoxypyridin-3-yl)-1-(4-(piperazin-1-yl )-3-(trifluoromethyl)phenyl)-1,5-dihydro-4H-[1,2,3]triazol[4,5-c]quinolin-4-one (CQ346)

Referring to Example 39 for the synthesis method, 0.1 g of white solid was obtained with a yield of 57%.

¹ H NMR (400MHz, DMSO-d ⁶ ) δ8.28(d, J=2.4Hz, 1H), 8.15(dd, J=8.8, 2.4Hz, 1H), 8.09(d, J=2.4Hz, 1H) ,8.02(dd,J=8.8,2.0Hz,1H),7.88(d,J=8.4Hz,1H),7.82(d,J=8.8Hz,1H),7.68(dd,J=8.4,2.4Hz, 1H), 7.20(d, J=2.0Hz, 1H), 6.82(d, J=8.4Hz, 1H), 5.34–5.12(m, 1H), 4.55(t, J=6.8Hz, 2H), 3.86( s,3H),3.03-2.90(m,10H),2.82-2.67(m,3H),2.47-2.45(m,1H),2.20-2.01(m,1H),1.97-1.82(m,1H); ESI-MS: m/z 637.3[M+H] ⁺ .

Example 42

(R)-8-(6-methoxypyridin-3-yl)-5-(2-(3-methoxypyrrol-1-yl)ethyl)-1-(4-(piperazine-1 -yl)-3-(trifluoromethyl)phenyl)-1,5-dihydro-4H-[1,2,3]triazol[4,5-c]quinolin-4-one (CQ347 )

Referring to Example 39 for the synthesis method, 0.2 g of white solid was obtained with a yield of 67%.

¹ H NMR (400MHz,DMSO-d ⁶ )δ8.29(s,1H),8.16(d,J＝8.4Hz,1H),8.10(s,1H),8.02(d,J＝8.4Hz,1H) ,7.89(d,J=8.4Hz,1H),7.80(d,J=9.2Hz,1H),7.68(d,J=8.8Hz,1H),7.20(s,1H),6.83(d,J= 8.4Hz, 1H), 4.53(t, J=7.6Hz, 1H), 3.89(m, 1H), 3.86(s, 3H), 3.19(s, 3H), 3.02(m, 4H), 2.96(m, 4H ),2.84-2.79(m,1H),2.73-2.71(m,3H),2.64-2.62(m,1H),2.56-2.54(m,1H),2.01-1.96(m,1H),1.67(m ,1H); ESI-MS: m/z 649.3[M+H] ⁺ .

Example 43

8-(6-methoxypyridin-3-yl)-5-(2-oxo-2-(pyrrol-1-yl)ethyl)-1-(4-(piperazin-1-yl)-3 -(trifluoromethyl)phenyl)-1,5-dihydro-4H-[1,2,3]triazol[4,5-c]quinolin-4-one (CQ348)

Referring to Example 39 for the synthesis method, 0.3 g of white solid was obtained with a yield of 77%.

¹ H NMR (400MHz, DMSO-d ⁶ ) δ8.32(d, J=2.4Hz, 1H), 8.18(dd, J=8.4, 2.0Hz, 1H), 8.10(d, J=2.4Hz, 1H) ,7.95(dd,J=9.2,2.4Hz,1H),7.88(d,J=8.8Hz,1H),7.68(dd,J=8.8,2.4Hz,1H),7.58(d,J=8.8Hz, 1H), 7.19(d, J=2.0Hz, 1H), 6.82(d, J=8.8Hz, 1H), 5.25(s, 2H), 3.86(s, 3H), 3.73(t, J=7.2Hz, 2H),2.99(m,4H),2.91-2.90(m,4H),2.05-1.98(m,2H),1.89-1.82(m,2H); ESI-MS: m/z 633.3[M+H] ⁺ .

Example 44

5-(2-(6,6-Dimethyl-3-azabicyclo[3.1.0]hexane-3-yl)ethyl-8-(6-methoxypyridin-3-yl)-1 -(4-(piperazin-1-yl)-3-(trifluoromethyl)phenyl)-1,5-dihydro-4H-[1,2,3]triazole[4,5-c ]quinolin-4-one (CQ349)

Referring to Example 39 for the synthesis method, 0.2 g of white solid was obtained with a yield of 77%.

¹ H NMR (400MHz, CDCl ₃ ) δ8.13 (d, J=2.4Hz, 1H), 7.98 (d, J=2.4Hz, 1H), 7.87 (dd, J=8.4, 2.4Hz, 1H), 7.82 (dd, J=8.8,2.0Hz,1H),7.74(d,J=9.2Hz,1H),7.70(d,J=8.4Hz,1H),7.51(dd,J=8.4,2.4Hz,1H) ,7.44(d,J=2.4Hz,1H),6.76(d,J=8.8Hz,1H),4.61(t,J=7.6Hz,1H,2H),3.96(s,3H),3.24–3.22( m,4H),3.20–3.19(m,4H),3.14–3.10(m,2H),3.01–2.96(m,4H),1.41(s,2H),1.17(s,3H),1.04(s,3H ); ESI-MS: m/z 659.3[M+H] ⁺ .

Example 45

5-(2-(3-Azabicyclo[3.1.0]hexane-3-yl)ethyl-8-(6-methoxypyridin-3-yl)-1-(4-(piperazine- 1-yl)-3-(trifluoromethane Base)phenyl)-1,5-dihydro-4H-[1,2,3]triazol[4,5-c]quinolin-4-one (CQ350)

Referring to Example 39 for the synthesis method, 0.5 g of white solid was obtained with a yield of 77%.

¹ H NMR (400MHz, CDCl ₃ ) δ8.14 (d, J=2.4Hz, 1H), 7.97 (d, J=2.3Hz, 1H), 7.86 (dd, J=8.4, 2.3Hz, 1H), 7.81 (dd, J=8.9,2.0Hz,1H),7.71(d,J=9.1Hz,1H),7.68(d,J=8.6Hz,1H),7.51(dd,J=8.6,2.5Hz,1H) ,7.44(d,J=2.0Hz,1H),6.75(d,J=8.6Hz,1H),4.65–4.52(m,2H),3.96(s,3H),3.23(d,J=8.6Hz, 2H), 3.17(d, J=6.3Hz, 8H), 2.96–2.87(m, 2H), 2.60(d, J=8.1Hz, 2H), 1.44(d, J=3.8Hz, 2H), 0.75– 0.68(m, 1H), 0.43(td, J=7.8, 4.7Hz, 1H); ESI-MS: m/z 631.3[M+H] ⁺ .

Example 46

5-(2-(2-Oxo-6-azaspiro[3.3]heptane-6-yl)ethyl)-8-(6-methoxypyridin-3-yl)-1-(4- (Piperazin-1-yl)-3-(trifluoromethyl)phenyl)-1,5-dihydro-4H-[1,2,3]triazol[4,5-c]quinoline- 4-keto (CQ351)

Referring to Example 39 for the synthesis method, 0.5 g of white solid was obtained with a yield of 77%.

¹ H NMR (400MHz, DMSO-d ⁶ ) δ8.29(d, J=2.8Hz, 1H), 8.16(dd, J=8.4, 2.4Hz, 1H), 8.09(d, J=2.4Hz, 1H) ,8.01(dd,J=9.2,2.4Hz,1H),7.88(d,J=8.8Hz,1H),7.80(d,J=9.2Hz,1H),7.68(dd,J=8.8,2.4Hz, 1H), 7.19(d, J=2.4Hz, 1H), 6.82(d, J=8.4Hz, 1H), 4.37(t, J=7.2Hz, 2H), 3.86(s, 3H), 3.46(m, 4H), 3.00(s, 8H), 2.94–2.92(m, 4H), 2.73(t, J=6.8Hz, 2H); ESI-MS: m/z 647.3[M+H] ⁺ .

Example 47

(R)-8-(6-methoxypyridin-3-yl)-5-((1-methylpyrrol-2-yl)methyl)-1-(4-(piperazin-1-yl) -3-(Trifluoromethyl)phenyl)-1,5-dihydro-4H-[1,2,3]triazol[4,5-c]quinolin-4-one (CQ352)

Referring to Example 39 for the synthesis method, 0.5 g of white solid was obtained with a yield of 77%.

¹ H NMR (400MHz, CDCl ₃ ) δ8.13(s, 1H), 7.95(s, 1H), 7.82(d, J=8.0Hz, 1H), 7.80–7.76(m, 2H), 7.62(d, J＝8.8Hz, 1H), 7.48(d, J＝8.4Hz, 1H), 7.42(s, 1H), 6.72(d, J＝8.4Hz, 1H), 4.77-4.72(m, 1H), 4.35- 4.30(m,1H),3.94(s,3H),3.15(m,1H),3.09(m,8H),2.91-2.89(m,1H),2.47(s,3H),2.32-2.27(m, 1H), 1.89(m,3H), 1.74(m,1H); ESI-MS: m/z 619.3[M+H] ⁺ .

Example 48

5-(2-(azetidin-1-yl)ethyl)-8-(6-methoxypyridin-3-yl)-1-(4-(piperazin-1-yl)-3 -(trifluoromethyl)phenyl)-1,5-dihydro-4H-[1,2,3]triazol[4,5-c]quinolin-4-one (CQ353)

Referring to Example 39 for the synthesis method, 0.5 g of white solid was obtained with a yield of 77%.

¹ H NMR (400MHz, CDCl ₃ ) δ8.14 (d, J=2.4Hz, 1H), 7.96 (d, J=2.4Hz, 1H), 7.84 (dd, J=8.4, 2.4Hz, 1H), 7.81 (dd, J=8.8,2.0Hz,1H),7.71(d,J=8.8Hz,1H),7.67(d,J=8.4Hz,1H),7.50(dd,J=8.4,2.4Hz,1H) ,7.44(d,J=2.0Hz,1H),6.75(d,J=8.8Hz,1H),4.50(t,J=7.6Hz,2H),3.97(m,3H),3.83-3.76(m, 2H), 3.68-3.64(m, 2H), 3.14-3.13(m, 8H), 2.91(t, J=7.6Hz, 2H), 2.19(t, J=7.2Hz, 2H); ESI-MS: m /z 605.3[M+H] ⁺ .

Example 49

5-(2-(Aziridine-1-yl)ethyl)-8-(6-methoxypyridin-3-yl)-1-(4-(piperazin-1-yl)-3- (Trifluoromethyl)phenyl)-1,5-dihydro-4H-[1,2,3]triazol[4,5-c]quinolin-4-one (CQ354)

Referring to Example 39 for the synthesis method, 0.5 g of white solid was obtained with a yield of 77%.

¹ H NMR (400MHz, CDCl ₃ ) δ8.15(d, J=2.4Hz, 1H), 7.98(d, J=2.4Hz, 1H), 7.86(m, 2H), 7.84(d, J=2.4Hz ,1H),7.65(d,J=8.4Hz,1H),7.50(dd,J=8.4,2.4Hz,1H),7.45(s,1H),6.75(d,J=8.8Hz,1H),4.73 (t, J=6.4Hz, 2H), 4.40(t, J=7.6Hz, 2H), 3.96(s, 3H), 3.88(t, J=8.0Hz, 2H), 3.74(t, J=6.4Hz ,2H), 3.11-3.10(m,8H); ESI-MS: m/z 591.2[M+H] ⁺ .

Example 50

7-fluoro-8-(6-methoxy-5-methylpyridin-3-yl)-1-(4-(piperazin-1-yl)-3-(trifluoromethyl)phenyl-5 -(2-(Pyrrol-1-yl)ethyl)-1,5-dihydro-4H-[1,2,3]triazol[4,5-c]quinolin-4-one (CQ355)

Synthesis of compound 50-2a: In a 100ml reaction flask, compound 50-1a (5g, 18.59mmol) was dissolved in 20ml POCl ₃ and refluxed at 150°C for 4 hours. After the reaction was completed, it was cooled to room temperature and then quenched with ice water. Adjust the pH to alkaline with sodium bicarbonate solution, add 100ml of water, extract with ethyl acetate (100ml×3), combine the organic layers, dry over anhydrous sodium sulfate, and rotary evaporate under reduced pressure to obtain the crude product, which is directly injected into the next step.

Synthesis of compound 50-4a: In a 100ml reaction flask, compound 50-2a (2.88g, 10mmol) and compound 50-3a (3.45g, 12mmol) were dissolved in 30ml of acetic acid, and stirred at room temperature for 4 hours. After the reaction was completed, 100ml of water was added, extracted with dichloromethane (100ml×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 injected into the next step.

Synthesis of compound 50-5a: In a 100ml reaction flask, dissolve compound 50-4a (2.69g, 5mmol), iron powder (1.4g, 25mmol), ammonium chloride (2.14g, 40mmol) in 50ml EtOH/H ₂ In O(4:1), reflux overnight at 80°C. After the reaction was completed, suction filter with diatomaceous earth, add water, adjust the pH to alkaline with sodium carbonate, extract with dichloromethane (100ml×3), combine the organic layers, dry over anhydrous sodium sulfate, and rotary evaporate under reduced pressure to obtain the crude product, which was weighed Crystallized to obtain 2 g of light yellow solid, yield 80%.

Synthesis of compound 50-6a: Dissolve 50-5a in 3M HCl at 0°C, add 1.2M NaNO ₂ after 10 minutes, react at 45°C for 1 hour. After the reaction was completed, the pH was adjusted to alkaline with 1M NaOH, and then suction filtered, and the obtained solid was directly used in the next step.

Synthesis of compound 50-7a: Compound 50-6a (564mg, 1mmol) was dissolved in 30ml of dichloromethane, cooled to 0°C, m-CPBA (285mg, 1.1mmol) was added, and reacted overnight at room temperature. After the reaction was completed, it was neutralized with 1M NaOH, extracted with dichloromethane (100ml×3), the organic layers were combined, dried over anhydrous sodium sulfate, and rotary evaporated under reduced pressure to obtain a crude product, which was purified by column chromatography (dichloromethane:methanol=50 : 1), 160mg of yellow solid was obtained, yield 29%. ¹ HNMR (400MHz, CDCl ₃ ) δ9.27(s, 1H), 8.79(d, J=8.8Hz, 1H), 8.01(s, 1H), 7.97(d, J=6.0Hz, 1H), 7.89( d,J=8.4Hz,1H),7.66(d,J=8.8Hz,1H),3.88(m,2H),3.73(m,2H),3.14-3.13(m,4H),2.20(s,3H ).

Synthesis of Compound 50-8a: Dissolve 160mg of Compound 50-7a in 10ml of acetic anhydride, and react under reflux at 140°C for 4 hours. After the reaction is complete, spin dry the acetic anhydride, beat with (PE:EA=5:5ml) for 30 minutes, Then it was suction filtered, and the resulting solid was directly cast into the next reaction.

Synthesis of compound 50-10a: In a 50ml reaction bottle, compound 50-8a (142mg, 0.26mmol), 50-9aN-chloroethylpyrrolidine hydrochloride (53mg, 0.31mmol), TBAI (10mg, 0.026mmol ) and Cs ₂ CO ₃ (338mg, 1.04mmol) were added to 10ml DMSO, and stirred at 60°C for 4h. After the reaction was completed, cool to room temperature, add 100ml of water, extract with dichloromethane (100ml×3), combine the organic layers, dry over anhydrous sodium sulfate, and rotary evaporate under reduced pressure to obtain the crude product, which was purified by column chromatography (dichloromethane:methanol =10:1), 96mg of yellow solid was obtained, yield 57%.

Synthesis of Compound 50-11a: Compound 50-10a (90 mg, 0.15 mmol), 10 ml of hydrochloric acid, and 10 ml of ethanol were reacted under reflux at 120° C. for 4 h in a 50 ml reaction flask. After the reaction, cool to room temperature, spin dry, then adjust the pH to alkaline with sodium hydroxide solution, filter with suction, and dry to obtain 84 mg of yellow solid with a yield of 93%, which is directly used for the next step.

Synthesis of compound CQ-355: under argon atmosphere, compound 50-11a (84mg, 0.14mmol), compound 50-12a (35mg, 0.21mmol), (PPh ₃ ) ₄ Pd (16mg, 0.014mmol) and Cs ₂ CO ₃ (137mg, 0.42mmol) was placed in a 25ml reaction flask, 30ml DMF and 10ml water were added, and the reaction was stirred at 80°C for 3h. After the reaction was completed, cool to room temperature, add 100ml of water, extract with dichloromethane (100ml×3), combine the organic layers, dry over anhydrous sodium sulfate, and rotary evaporate under reduced pressure to obtain the crude product, which was purified by column chromatography (dichloromethane:methanol =5:1), 70mg of yellow solid was obtained, the yield was 77%. ¹ H NMR (400MHz, DMSO-d ⁶ ) δ8.27(d, J=2.4Hz, 1H), 8.15(dd, J=8.4, 2.4Hz, 1H), 7.87-7.85(m, 2H), 7.75( d,J=13.6Hz,1H),7.44(s,1H),7.11(d,J=8.4Hz,1H),4.53(t,J=6.8Hz,2H),3.89(s,3H),3.00- 2.99(m, 8H), 2.75(t, J=6.8Hz, 2H), 2.60(m, 4H), 2.14(s, 3H), 1.70(m, 4H); ESI-MS: m/z 651.3[M +H] ⁺ .

Example 51

7-fluoro-8-(6-methoxypyridin-3-yl)-1-(4-(piperazin-1-yl)-3-(trifluoromethyl)phenyl-5-(2-( Pyrrol-1-yl)ethyl)-1,5-dihydro-4H-[1,2,3]triazol[4,5-c]quinolin-4-one (CQ356)

Referring to Example 50 for the synthesis method, 0.5 g of white solid was obtained with a yield of 72%.

¹ H NMR (400MHz, DMSO-d ⁶ )δ8.27(d, J=2.0Hz, 1H), 8.15(dd, J=8.8, 2.0Hz, 1H), 8.02(s, 1H), 7.86(d, J＝8.8Hz, 1H), 7.76(d, J＝13.6Hz, 1H), 7.67(d, J＝8.8Hz, 1H), 7.10(d, J＝8.4Hz, 1H), 6.87(d, J＝ 8.4Hz, 1H), 4.54(t, J=6.8Hz, 2H), 3.87(s, 3H), 2.99(m, 8H), 2.75(t, J=6.8Hz, 2H), 2.60(m, 4H) ,1.70(m,4H); ESI-MS: m/z 637.3[M+H] ⁺ .

Example 52

8-(6-Amino-5-(trifluoromethyl)pyridin-3-yl)-7-fluoro-1-(4-(piperazin-1-yl)-3-(trifluoromethyl)phenyl -5-(2-(pyrrol-1-yl)ethyl)-1,5-dihydro-4H-[1,2,3]triazol[4,5-c]quinolin-4-one ( CQ357)

Referring to Example 50 for the synthesis method, 0.6 g of white solid was obtained with a yield of 72%.

¹ H NMR (400MHz, DMSO-d ⁶ )δ8.26(d, J=2.0Hz, 1H), 8.17-8.14(m, 2H), 7.81(d, J=8.8Hz, 1H), 7.76(d, J＝13.6Hz, 1H), 7.60(s, 1H), 7.16(d, J＝8.4Hz, 1H), 6.80(s, 2H), 4.54(t, J＝6.8Hz, 2H), 2.76(t, J＝6.8Hz, 2H), 2.61(m, 4H), 1.71(m, 4H); ESI-MS: m/z 690.3[M+H] ⁺ .

Example 53

(S)-7-fluoro-5-(2-(3-(fluoromethyl)pyrrol-1-yl)ethyl)-8-(6-methoxy-5-methylpyridin-3-yl) -1-(4-(piperazin-1-yl)-3-(trifluoromethyl)phenyl-1,5-dihydro-4H-[1,2,3]triazol[4,5- c] Quinolin-4-one (CQ358)

Referring to Example 50 for the synthesis method, 0.5 g of white solid was obtained with a yield of 75%.

¹ H NMR (400MHz, CDCl ₃ ) δ7.94(d, J=2.4Hz, 1H), 7.90(s, 1H), 7.85(dd, J=8.4, 2.4Hz, 1H), 7.71(d, J= 8.4Hz, 1H), 7.43(d, J=12.8Hz, 1H), 7.35(s, 1H), 7.31(d, J=8.0Hz, 1H), 4.55(t, J=7.2Hz, 2H), 4.41 (d,J=6.4Hz,1H),4.29(d,J=6.8Hz,1H),3.96(s,3H),3.93–3.88(m,1H),3.26(m,8H),2.93–2.85( m,2H),2.84–2.76(m,2H),2.68–2.58(m,2H),2.19(s,3H),2.08–1.94(m,2H); ESI-MS: m/z 682.3[M+ H] ⁺ .

Example 54

8-(6-methoxypyridin-3-yl)-3-methyl-1-(4-(piperazin-1-yl)-3-(trifluoromethyl)phenyl)-5-(2 -(pyrrol-1-yl)ethyl)-3,5-dihydro-1H-imidazo[4,5-c]quinoline-2,4-dione (CQ359)

Synthesis of compound 54-2a: In a 100ml reaction flask, compound 54-1a (5g, 18.59mmol) was dissolved in 20ml POCl ₃ and refluxed at 150°C for 4 hours. After the reaction was completed, it was cooled to room temperature and then quenched with ice water. Adjust the pH to alkaline with sodium bicarbonate solution, add 100ml of water, extract with ethyl acetate (100ml×3), combine the organic layers, dry over anhydrous sodium sulfate, and rotary evaporate under reduced pressure to obtain the crude product, which is directly injected into the next step.

Synthesis of compound 54-4a: In a 100ml reaction flask, compound 54-2a (2.88g, 10mmol) and compound 54-3a (3.45g, 12mmol) were dissolved in 30ml of acetic acid, and stirred at room temperature for 4 hours. After the reaction was completed, 100ml of water was added, extracted with dichloromethane (100ml×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 injected into the next step.

Synthesis of compound 54-5a: In a 100ml reaction flask, dissolve compound 54-4a (2.69g, 5mmol), iron powder (1.4g, 25mmol), ammonium chloride (2.14g, 40mmol) in 50ml EtOH/H ₂ In O(4:1), reflux overnight at 80°C. After the reaction was completed, suction filter with diatomaceous earth, add water, adjust the pH to alkaline with sodium carbonate, extract with dichloromethane (100ml×3), combine the organic layers, dry over anhydrous sodium sulfate, and rotary evaporate under reduced pressure to obtain the crude product, which was weighed Crystallized to obtain 2 g of light yellow solid, yield 80%.

Synthesis of Compound 54-6a: Compound 54-5a (2.6g, 5.1mmol) and CDI (1.66g, 10.2mmol) were dissolved in THF, heated to 60°C, and reacted overnight. After the reaction was complete, it was filtered with suction, and the solid was washed with THF, and directly sent to the next step.

Synthesis of compound 54-7a: Dissolve compound 54-6a (1.73g, 3.3mmol) and NaH (0.4g, 9.9mmol) in 20ml DMF, react for 20min, add iodomethane (1.02g, 7.2 mmol), stirred at room temperature for 5h. After the reaction was complete, water was added to quench, filtered with suction, and the solid was dried in vacuo to obtain a white solid. ¹ H NMR (400MHz,DMSO-d ⁶ )δ9.06(s,1H),8.08-8.02(m,1H),8.00-7.93(m,2H),7.87-7.85(m,1H),7.68-7.66 (m,1H),6.98-6.96(m,1H),3.68-3.60(m,4H),3.60(s,3H),3.05-3.00(m,2H),2.99-2.92(m,2H),2.07 (s,3H).

Synthesis of Compound 54-9a: Compound 54-7a (0.55g, 1mmol) and m-CPBA (0.27g, 1.1mmol) were dissolved in 10ml of dichloromethane and stirred overnight at room temperature. After the reaction was complete, the pH was adjusted to alkaline with NaOH, washed with dichloromethane (50 mL x 3), and the organic phase was washed with brine, concentrated, and dried to obtain the crude compound 54-8a, which was directly used in the next step. Compound 54-8a (0.06g, 0.1mmol) was dissolved in 5ml of acetic anhydride, refluxed at 140°C for 1h, after the reaction was complete, spin-dried, the solid was washed with EA/PE (1:1, 10mL), suction filtered, and spin-dried for use react in the next step. ¹ H NMR (400MHz, DMSO-d ⁶ )δ12.12(s, 1H), 8.01(d, J=2.4Hz, 1H), 7.93(dd, J=8.4, 2.4Hz, 1H), 7.82(d, J＝8.4Hz, 1H), 7.52(dd, J＝8.8, 2.0Hz, 1H), 7.36(d, J＝8.8Hz, 1H), 6.53(d, J＝2.0Hz, 1H), 3.66(s, 3H),3.19-3.08(m,8H).

Synthesis of compound 54-11a: In a 50ml reaction bottle, compound 54-9a (564mg, 1mmol), 54-10a N-chloroethylpyrrolidine hydrochloride (255mg, 1.5mmol), TBAI (36.9mg, 0 .mmol) and Cs ₂ CO ₃ (814mg, 2.5mmol) were added to 10ml DMSO, and stirred at 60°C for 4h. After the reaction was completed, cool to room temperature, add 100ml of water, extract with dichloromethane (100ml×3), combine the organic layers, dry over anhydrous sodium sulfate, and rotary evaporate under reduced pressure to obtain the crude product, which was purified by column chromatography (dichloromethane:methanol =10:1), 500mg of yellow solid was obtained, yield 79%.

Synthesis of Compound 54-12a: Compound 54-11a (500 mg, 1 mmol), 10 ml of hydrochloric acid, and 10 ml of ethanol were reacted under reflux at 120° C. for 4 h in a 50 ml reaction flask. After the reaction, cool to room temperature, spin dry, then adjust the pH to alkaline with sodium hydroxide solution, filter with suction, and dry to obtain 400 mg of yellow solid with a yield of 85%, which is directly used in the next step.

Synthesis of compound CQ-359: under argon atmosphere, compound 54-12a (295 mg, 5 mmol), 54-3a p-methoxyphenylboronic acid (1.14 g, 7.5 mmol), (PPh ₃ ) ₄ Pd (115 mg, 0.1mmol) and Cs ₂ CO ₃ (4.8g, 15mmol) were placed in a 25ml reaction flask, 30ml DMF and 10ml water were added, and the reaction was stirred at 80°C for 3h. After the reaction was completed, cool to room temperature, add 100ml of water, extract with dichloromethane (100ml×3), combine the organic layers, dry over anhydrous sodium sulfate, and rotary evaporate under reduced pressure to obtain the crude product, which was purified by column chromatography (dichloromethane:methanol =5:1), 308mg of yellow solid was obtained, the yield was 64%.

¹ H NMR (400MHz, CDCl ₃ ) δ7.97(d, J=2.4Hz, 1H), 7.77(d, J=2.4Hz, 1H), 7.74–7.59(m, 4H), 7.38(dd, J= 8.8,2.8Hz,1H),6.93(d,J=2.0Hz,1H),6.66(d,J=8.4Hz,1H),4.65(t,J=7.2Hz,2H),3.91(s,3H) ,3.87(s,3H),3.14–3.12(m,4H),3.10–3.07(m,4H),2.93(t,J＝8.0Hz,2H),2.86–2.83(m,4H),1.92–1.91 (m,4H); ESI-MS: m/z 648.3[M+H] ⁺ .

Example 55

8-(6-methoxy-5-methylpyridin-3-yl)-3-methyl-1-(4-(piperazin-1-yl)-3-(trifluoromethyl)phenyl) -5-(2-(Pyrrol-1-yl)ethyl)-3,5-dihydro-1H-imidazo[4,5-c]quinoline-2,4-dione (CQ360)

Referring to Example 54 for the synthesis method, 0.5 g of white solid was obtained with a yield of 77%.

¹ H NMR (400MHz, DMSO-d ⁶ )δ8.02(d, J=2.4Hz, 1H), 7.91(dd, J=8.4, 2.4Hz, 1H), 7.80(s, 1H), 7.78(s, 1H), 7.73(d, J=2.0Hz, 1H), 7.67(d, J=9.2Hz, 1H), 7.42(d, J=2.0Hz, 1H), 6.80(d, J=2.0Hz, 1H) ,4.50(t,J＝7.2Hz,2H),3.85(s,3H),3.68(s,3H),2.96–2.93(m,4H),2.92–2.87(m,4H),2.67(t,J =7.6Hz, 2H), 2.59–2.56(m,4H), 2.12(s,3H), 1.72–1.69(m,4H); ESI-MS: m/z 662.3[M+H] ⁺ .

Example 56

8-(6-Amino-5-(trifluoromethyl)pyridin-3-yl)-3-methyl-1-(4-(piperazin-1-yl)-3-(trifluoromethyl)benzene Base)-5-(2-(pyrrol-1-yl)ethyl)-3,5-dihydro-1H-imidazo[4,5-c]quinoline-2,4-dione (CQ361)

Referring to Example 54 for the synthesis method, 0.5 g of white solid was obtained with a yield of 77%.

¹ H NMR (400MHz, DMSO-d ⁶ ) δ8.05 (d, J=2.4Hz, 1H), 7.96 (dd, J=8.4, 2.4Hz, 1H), 7.93 (s, 1H), 7.83–7.78( m,2H),7.71(d,J=8.8Hz,1H),7.61(d,J=2.0Hz,1H),6.79(d,J=2.0Hz,1H),6.64(s,2H),4.51( t, J＝7.6Hz, 2H), 3.68(s, 3H), 3.16–3.14(m, 8H), 2.76(t, J＝7.2Hz, 2H), 2.66(m, 4H), 1.73(m, 4H) ); ESI-MS: m/z 701.3[M+H] ⁺

Example 57

8-(6-methoxypyridin-3-yl)-1-(4-(piperazin-1-yl)-3-(trifluoromethyl)phenyl)-5-(2-(pyrrole-1 -yl)ethyl)imidazo[1,2-a]quinoxalin-4(5H)-one (CQ362)

Synthesis of compound 57-3a: Dissolve compound 57-1a (3.95g, 35.27mmol) in 100ml DMF, then add compound 57-2a (6.7g, 35.27mmol), HOBT (7.15g, 52.91mmol), EDCI (10.14g, 52.91mmol), reacted at room temperature for 21h. After the reaction was completed, ethyl acetate was extracted (100ml×3), the organic layers were combined, dried over anhydrous sodium sulfate, and purified by column chromatography (DCM) to obtain 2.8g with a yield of 28%. ¹ H NMR (400MHz, CDCl ₃ ) δ11.06(s, 1H), 9.28(s, 1H), 8.28(t, J=8.8Hz, 1H), 7.34(m, 2H), 7.24(s, 2H) .

Synthesis of compound 57-4a: Dissolve compound 57-3a (2.7g, 9.5mmol) in 40ml DMA, then add NaH (494mg, 12.4mmol), and reflux overnight at 170°C. After the reaction is complete, add 100ml of water to precipitate a solid, spin dry and directly put into the next reaction.

Synthesis of compound 57-6a: compound 57-4a (1.71g, 6.48mmol), compound 57-5a (1.46g, 9.72mmol), cesium carbonate (6.3g, 19mmol), (PPh ₃ ) ₂ Cl ₂ Pd (455mg , 0.65mmol) was dissolved in dioxane: water = 30ml:10ml mixed solvent, and reacted overnight at 100°C. After the reaction was completed, add 100ml water, and suction filtered to obtain the product compound 57-6a, which was directly used in the next reaction .

Synthesis of compound 57-7a: Dissolve compound 57-6a (1.44g, 4.93mmol) in 60ml of DMF, slowly add NBS (1.32g, 7.39mmol), react at room temperature for 3h, then raise the temperature to 80°C and react overnight . After the reaction was completed, it was directly sucked and filtered to obtain 600 mg of the product with a yield of 33%. ¹ HNMR (400MHz, DMSO-d ⁶ ) δ12.09(s, 1H), 9.15(d, J=1.6Hz, 1H), 8.53(d, J=2.4Hz, 1H), 8.05(dd, J=8.8 , 2.8Hz, 1H), 7.79(dd, J=8.4, 1.6Hz, 1H), 7.70(s, 1H), 7.50(d, J=8.8Hz, 1H), 6.96(d, J=8.8Hz, 1H ).

Synthesis of compound 57-9a: In a 100ml reaction vial, compound 57-7a (571mg, 1.54mmol), compound 57-8a (866mg, 2.31mmol), (PPh ₃ ) ₂ Cl ₂ Pd (108mg, 0.15mmol) , cesium carbonate (1.5g, 4.62mmol) was dissolved in dioxane: water = 30ml:10ml mixed solvent, reacted overnight at 100°C, after the reaction was completed, add 100ml of water, and suction filtered to obtain the product. ¹ H NMR (400MHz, CDCl ₃ ) δ12.22(s, 1H), 7.93–7.87(m, 2H), 7.77(d, J=8.4Hz, 1H), 7.71(d, J=8.4Hz, 1H) ,7.64(s,1H),7.55(d,J=8.4Hz,1H),7.52(dd,J=8.4,1.6Hz,1H),7.45(dd,J=8.8,2.4Hz,1H),7.24( d,J=1.6Hz,1H),6.68(d,J=8.8Hz,1H),3.92(s,3H),3.64(m,4H),3.04(m,4H),1.51(s,9H).

Synthesis of compound 57-11a: In a 50ml reaction bottle, compound 57-9a (256mg, 0.38mmol), N-chloroethylpyrrolidine hydrochloride (78mg, 0.46mmol), TBAI (14mg, 0.038mmol) and Cs ₂ CO ₃ (495mg, 1.52mmol) was added into 10ml DMSO, and stirred at 60°C for 4h. After the reaction was completed, cool to room temperature, add 100ml of water, extract with dichloromethane (100ml×3), combine the organic layers, dry over anhydrous sodium sulfate, and rotary evaporate under reduced pressure to obtain the crude product, which was purified by column chromatography (dichloromethane:methanol =10:1), 152mg of yellow solid was obtained, yield 56%.

Synthesis of compound CQ-362: In a 50ml reaction bottle, dissolve compound 57-11a in 3ml TFA and 10ml DCM, stir at room temperature for 4h, after the reaction is completed, spin dry, adjust the pH to alkaline with sodium bicarbonate solution, Then suction filtered, spin-dried, extracted with dichloromethane (100ml×3), combined organic layers, dried over anhydrous sodium sulfate, and rotary evaporated under reduced pressure to obtain the crude product, which was purified by column chromatography (dichloromethane:methanol=10:1 ), to obtain yellow solid 100mg, yield 81%. ¹ H NMR (400MHz, DMSO-d ⁶ )δ8.00(s, 1H), 7.98(d, J=8.0Hz, 1H), 7.85(d, J=4.0Hz, 1H), 7.81(d, J= 8.0Hz, 1H), 7.79–7.75(m, 1H), 7.72(d, J=8.0Hz, 1H), 7.67(s, 1H), 7.64(dd, J=8.8, 2.8Hz, 1H), 7.26( d,J=1.6Hz,1H),6.80(d,J=9.2Hz,1H),4.48(t,J=7.2Hz,2H),3.84(s,3H),3.14-3.12(m,8H), 2.80(t, J=6.8Hz, 2H), 2.64(m, 4H), 1.73(m, 4H); ESI-MS: m/z 617.3[M+H] ⁺ .

Example 58

8-(6-methoxypyridin-3-yl)-1-(4-(piperazin-1-yl)-3-(trifluoromethyl)phenyl)-5-(2-(pyrrole-1 -yl)ethyl)-1,5-dihydro-4H-pyrazolo[4,3-c]quinolin-4-one (CQ363)

Synthesis of compound 58-2a: In a 100ml reaction flask, add compound 58-1a (5g, 20.32mmol) and CDI (3.62g, 22.36mmol) into 40ml THF, stir at room temperature for 1h; then mix well with EtO ₂ CCH ₂ CO ₂ K (5.19g, 30.48mmol) and magnesium chloride (1.93g, 20.32mmol) were added to the above mixture, and the mixture was refluxed overnight. After the reaction was completed, cool to room temperature, wash with 10% potassium bisulfate and saturated sodium chloride solution, extract with ethyl acetate (100ml×3), combine the organic layers, dry over anhydrous sodium sulfate, and rotary evaporate under reduced pressure to obtain the crude compound. used directly in the next reaction.

Synthesis of compound 58-4a: In a 100ml reaction flask, compound 58-2a (1.6g, 5.06mmol) and compound 58-3a (3.36ml, 25.31mmol) were added to 20ml toluene, and refluxed for 4h. After the reaction was completed, it was cooled to room temperature, and the solvent was removed to obtain the crude compound 58-4a, which was directly used in the next reaction.

Synthesis of compound 58-6a: In a 100ml reaction flask, compound 58-4a (1.88g, 5.06mmol) and compound 58-5a (1.25g, 5.06mmol) were added to 20ml of absolute ethanol, and refluxed overnight. After the reaction was completed, it was cooled until a solid precipitated out, and the crude compound 58-6a was obtained by suction filtration, which was directly used in the next reaction.

Synthesis of compound 58-7a: In a 100ml reaction flask, compound 58-6a (1g, 1.93mmol), iron powder (0.54g, 9.65mmol), ammonium chloride (0.83g, 15.44mmol) were dissolved in 20ml EtOH/ In H ₂ O (4:1), reflux overnight at 80°C. After the reaction was completed, suction filter with diatomaceous earth, add water, adjust the pH to alkaline with sodium carbonate, extract with dichloromethane (100ml×3), combine the organic layers, dry over anhydrous sodium sulfate, and rotary evaporate under reduced pressure to obtain the crude product, which was weighed Compound 58-7a was obtained by crystallization, 0.7 g of light yellow solid, yield 74%. ¹ H NMR (400MHz, DMSO-d ⁶ )δ8.26(s, 1H), 7.86(d, J=2.4Hz, 1H), 7.80(d, J=8.8Hz, 1H), 7.65(dd, J= 8.4Hz, 2.4Hz, 1H), 7.25(dd, J=8.8Hz, 2.4Hz, 1H), 7.18(d, J=2.4Hz, 1H), 6.60(d, J=8.8Hz, 1H), 5.24( s, 2H), 4.12(q, J=7.2Hz, 2H), 1.13(t, J=7.2Hz, 3H); ESI-MS: m/z 488.0[M+H] ⁺ .

Synthesis of compound 58-8a: In a 50ml reaction flask, compound 58-7a (0.5g, 1.01mmol) was dissolved in 10ml EtOH, and 10d of concentrated hydrochloric acid was added dropwise at 70°C to react overnight. After the reaction was completed, it was cooled to room temperature, and the crude compound 58-8a was obtained by suction filtration, which was directly used in the next reaction.

Synthesis of Compound 58-9a: Compound 58-8a (0.44g, 1mmol), (6-methoxypyridin-3-yl)boronic acid (0.23g, 1.5mmol), (PPh ₃ )Cl ₂ Pd (70mg, 0.1mmol) and Cs ₂ CO ₃ (0.65g, 2mmol) were added to a 25ml reaction flask, protected by Ar, then 12ml DMF/H ₂ O (3:1) was added, and the reaction was refluxed at 80°C overnight. After the reaction was completed, water was added to quench, and the crude compound 58-9a was obtained by suction filtration, which was directly used in the next reaction.

Synthesis of compound 58-11a: Add compound 58-9a (0.47g, 1mmol), BOC piperazine (0.74g, 4mmol) and Cs ₂ CO ₃ (0.65g, 2mmol) into a 25ml reaction flask, then add 10ml DMF, 140 °C reflux reaction overnight. After the reaction was completed, it was quenched with water, filtered with suction, and the filter cake was purified by column chromatography (dichloromethane: methanol: triethylamine = 100:10:1 (V/V)) to obtain compound 58-11a, 0.2 g of white solid , yield 38%.

Synthesis of compound 58-12a: In a 50ml reaction bottle, compound 58-11a (235mg, 0.38mmol), N-chloroethylpyrrolidine hydrochloride (78mg, 0.46mmol), TBAI (14mg, 0.038mmol) and Cs ₂ CO ₃ (495mg, 1.52mmol) was added into 10ml DMSO, and stirred at 60°C for 4h. After the reaction was completed, cool to room temperature, add 100ml of water, extract with dichloromethane (100ml×3), combine the organic layers, dry over anhydrous sodium sulfate, and rotary evaporate under reduced pressure to obtain the crude product, which was purified by column chromatography (dichloromethane:methanol =10:1), 152mg of yellow solid was obtained, yield 56%.

Synthesis of compound CQ-363: In a 50ml reaction vial, dissolve compound 58-12a (120mg, 0.17mmol) in 20ml DCM, then add 5ml TFA, react for 4h. After the reaction was completed, the solvent was spin-dried, and the pH was adjusted to alkaline with sodium bicarbonate solution, then suction filtered, extracted with dichloromethane (100ml×3), the organic layers were combined, dried over anhydrous sodium sulfate, and rotary evaporated under reduced pressure to obtain the crude product , and purified by column chromatography (dichloromethane:methanol=10:1) to obtain 80 mg of yellow solid with a yield of 78%. ¹ H NMR (400MHz, CDCl ₃ ) δ8.42(s, 1H), 8.05(d, J=2.4Hz, 1H), 7.89(d, J=2.0Hz, 1H), 7.79–7.75(m, 3H) ,7.63(d,J=8.4Hz,1H),7.45(dd,J=8.8,2.8Hz,1H),7.31(s,1H),6.70(d,J=8.4Hz,1H),4.69(t, J＝7.6Hz, 2H), 3.92(s, 3H), 3.15–3.12(m, 8H), 3.04(t, J＝7.6Hz, 2H), 2.98(m, 4H), 1.99(m, 4H); ESI-MS: m/z 617.3[M+H] ⁺ .

Example 59

8-(6-methoxypyridin-3-yl)-1-(4-(piperazin-1-yl)-3-(trifluoromethyl)phenyl)-5-(2-(pyrrole-1 -yl)ethyl)-1,5-dihydro-4H-imidazo[4,5-c]quinolin-4-one (CQ364)

Synthesis of Compound 59-2a: Add Compound 59-1a (5 g, 18.59 mmol) into a 100 ml reaction flask, then add 20 ml of phosphorus oxychloride, and react under reflux at 110° C. for 4 h. After the reaction was completed, cool to 0°C, quench with ice water, adjust the pH to alkaline with saturated sodium bicarbonate, then extract with ethyl acetate (100ml×3), combine the organic layers, dry over anhydrous sodium sulfate, and rotary evaporate under reduced pressure The crude compound 59-2a was obtained, which was directly used in the next reaction.

Synthesis of compound 59-4a: In a 100ml reaction flask, compound 59-3a (3.45g, 12mmol) was dissolved in 30ml of glacial acetic acid, then compound 59-2a (2.88g, 10mmol) was slowly added, and stirred at room temperature for 3h. After the reaction was completed, quenched with water, extracted with dichloromethane (100ml×3), washed with saturated sodium chloride, combined organic layers, dried over anhydrous sodium sulfate, and rotary evaporated under reduced pressure to obtain a crude product, which was purified by column chromatography (dichloromethane) , to obtain compound 59-4a, yellow solid 4.04g, yield 75%. ¹ H NMR (400MHz, DMSO-d ⁶ )δ10.49(s, 1H), 9.47(s, 1H), 7.91(d, J=8.8Hz, 1H), 7.78(dd, J=8.8Hz, 2.0Hz ,1H),7.60(d,J=2.0Hz,1H),7.47(d,J=2.4Hz,1H),7.34(d,J=8.6Hz,1H),7.28(d,J=2.8Hz,1H ),3.80-3.75(m,2H),3.64-3.58(m,2H),2.97-2.89(m,4H),2.14(s,3H); ESI-MS: m/z 538.1[M+H] ⁺ .

Synthesis of compound 59-5a: in a 250ml reaction flask, compound 59-4a (2.50g, 4.64mml), iron powder (1.29g, 23.19mmol), ammonium chloride (1.98g, 37.12mmol) were dissolved in 50ml EtOH /H ₂ O (4:1), reflux overnight at 80°C. After the reaction was completed, suction filter with diatomaceous earth, add water, adjust the pH to alkaline with sodium carbonate, extract with dichloromethane (100ml×3), combine the organic layers, dry over anhydrous sodium sulfate, and rotary evaporate under reduced pressure to obtain the crude product, which was weighed Compound 59-5a was obtained by crystallization, 2.15 g of light yellow solid, yield 91%. ¹ H NMR (400MHz, DMSO-d ⁶ ) δ8.60(s, 1H), 7.90(d, J=2.4Hz, 1H), 7.85(d, J=8.8Hz, 1H), 7.51(dd, J= 9.0Hz, 2.2Hz, 1H), 7.13(d, J=8.6Hz, 1H), 6.98(d, J=2.8Hz, 1H), 6.64(dd, J=8.6Hz, 2.8Hz, 1H), 6.27( s,1H),4.16(s,2H),3.91-3.57(m,2H),3.48-3.54(m,2H),2.82(t,J＝4.8Hz,2H),2.76(t,J＝4.8Hz ,2H), 2.11(s,3H); ESI-MS: m/z 508.1[M+H] ⁺ .

Synthesis of compound 59-6a: In a 50ml reaction flask, compound 59-5a (0.6g, 1.18mmol) was added into 12ml of triethyl orthoformate, and reacted under reflux at 150°C for 3h. After the reaction was completed, the crude product was obtained by rotary evaporation under reduced pressure, which was purified by column chromatography (dichloromethane:methanol=10:1) to obtain compound 59-6a, 0.5 g of white solid, with a yield of 82%. ¹ H NMR (400MHz,DMSO-d ⁶ )δ9.39(s,1H),8.28-8.03(m,2H),7.87(s,1H),7.69-7.76(m,2H),7.59-7.61(m ,1H),7.46-7.47(m,1H),3.870-3.80(m,4H),3.01-3.19(m,4H),2.17(s,3H); ESI-MS: m/z 518.1[M+H ] ⁺ .

Synthesis of compound 59-7a: In a 25ml reaction bottle, add compound 59-6a (0.52g, 1.0mmol) to 0.22ml 30% Hydrogen peroxide and 3ml of glacial acetic acid were stirred overnight at 80°C. Cool to room temperature, concentrate by rotary evaporation under reduced pressure, neutralize with saturated sodium bicarbonate, filter with suction, and dry the filter cake to obtain the intermediate. The intermediate obtained above was then added to 2.5 ml of acetic anhydride, refluxed for 1 h, and rotary evaporated under reduced pressure to obtain a crude product, which was purified by column chromatography (dichloromethane:methanol=10:1) to obtain compound 59-7a as a white solid 0.32g, yield 60%. ¹ H NMR (400MHz, DMSO-d ⁶ ) δ11.83(s, 1H), 8.37(s, 1H), 8.14(d, J=2.4Hz, 1H), 8.08-8.01(m, 1H), 7.88( d,J=8.4Hz,1H),7.55(dd,J=8.8Hz,2.0Hz,1H),7.39(d,J=8.8Hz,1H),6.81(d,J=1.6Hz,1H),3.56 -3.72(m,4H),3.05-2.90(m,4H),2.07(s,3H); ESI-MS: m/z534.1[M+H] ⁺ .

Synthesis of compound 59-8a: In a 50ml reaction vial, compound 59-7a (533mg, 1mmol), N-chloroethylpyrrolidine hydrochloride (255mg, 1.5mmol), TBAI (36.9mg, 0.01mmol) and Cs ₂ CO ₃ (814mg, 2.5mmol) was added into 10ml DMSO, and stirred at 60°C for 4h. After the reaction was completed, cool to room temperature, add 100ml of water, extract with dichloromethane (100ml×3), combine the organic layers, dry over anhydrous sodium sulfate, and rotary evaporate under reduced pressure to obtain the crude product, which was purified by column chromatography (dichloromethane:methanol =10:1), 500mg of yellow solid was obtained, yield 79%.

Synthesis of Compound 59-9a: Compound 59-8a (630 mg, 1 mmol), 10 ml of hydrochloric acid, and 10 ml of ethanol were reacted under reflux at 120° C. for 4 h in a 50 ml reaction flask. After the reaction, cool to room temperature, spin dry, then adjust the pH to alkaline with sodium hydroxide solution, filter with suction, dry the solid and put it directly into the next step to obtain 400 mg of yellow solid with a yield of 69%.

Synthesis of compound CQ-364: under argon atmosphere, compound 59-9a (294mg, 0.5mmol), 2-methoxy-5 boronate pyridine (114mg, 0.75mmol), (PPh ₃ ) ₄ Pd (11.5 mg, 0.01mmol) and Cs ₂ CO ₃ (480mg, 1.5mmol) were placed in a 25ml reaction flask, 30ml DMF and 10ml water were added, and the reaction was stirred at 80°C for 3h. After the reaction was completed, cool to room temperature, add 100ml of water, extract with dichloromethane (100ml×3), combine the organic layers, dry over anhydrous sodium sulfate, and rotary evaporate under reduced pressure to obtain the crude product, which was purified by column chromatography (dichloromethane:methanol =5:1), 200mg of yellow solid was obtained, the yield was 65%. ¹ H NMR (400MHz, DMSO-d ⁶ )δ8.39(s, 1H), 8.15(s, 1H), 8.05(d, J=8.4Hz, 1H), 7.99(s, 1H), 7.85(d, J=8.0Hz, 2H), 7.71(d, J=8.8Hz, 1H), 7.66(d, J=8.8Hz, 1H), 7.00(s, 1H), 6.79(d, J=8.8Hz, 1H) ,4.53(t,J=6.8Hz,2H),3.84(s,3H),2.99–2.90(m,8H),2.69(t,J=6.4Hz,2H),2.59(m,4H),1.71( m,4H); ESI-MS: m/z 618.3[M+H] ⁺ .

Example 60

8-(6-methoxypyridin-3-yl)-1-(4-(piperazin-1-yl)-3-(trifluoromethyl)phenyl)-5-(2-(pyrrole-1 -yl)ethyl)-1,5-dihydro-4H-imidazo[1,5-a]quinoxalin-4(5H)-one (CQ365)

Synthesis of compound 60-2a: in a 500ml reaction flask, compound 60-1a (24g, 100mmol), N-Boc piperazine (22.35g, 120mmol) and K ₂ CO ₃ (20.73g, 150mmol), add 100ml DMSO , heating at 120°C for 24h. After the reaction was completed, it was quenched with water, extracted with ethyl acetate (200ml×3), washed with water and saturated sodium chloride successively, the organic layers were combined, dried over anhydrous sodium sulfate, and rotary evaporated under reduced pressure to obtain the crude product, which was purified by column chromatography (acetic acid Ethyl ester:petroleum ether=1:10), 13g of white solid was obtained, yield 31%.

Synthesis of compound 60-3a: Add compound 60-2a (6g, 14.67mmol) into a 250ml reaction flask at -78°C under the protection of Ar, then add 70ml of toluene/THF (1:1), and react for 1h. Then 3.7ml of triethyl borate was slowly dropped into the above mixture, and the reaction was continued for 3h. Then the temperature was slowly raised to 0°C, 20ml of saturated ammonium chloride was added, and stirred at room temperature for 30min. After the reaction was completed, it was extracted with ethyl acetate (100ml×3), washed with saturated sodium chloride, and the organic layers were combined, dried over anhydrous sodium sulfate, and rotary evaporated under reduced pressure to obtain a crude product, which was directly used in the next reaction.

Synthesis of compound 60-5a: compound 60-3a (5.6g, 15mmol), compound 60-4a (1.47g, 10mmol), (PPh ₃ ) ₂ Cl ₂ Pd (700mg, 1mmol) and Cs ₂ CO ₃ (6.5 g, 20 mmol) was added into a 250 ml reaction flask, protected by Ar, and then 100 ml of 1,4-dioxane/H ₂ O (4:1) was added, and the reaction was refluxed at 100° C. overnight. After the reaction was completed, the solvent was removed under reduced pressure, water was added, and Ethyl acetate extraction (100ml×3), ethyl acetate was removed under reduced pressure, and then washed with 30ml ethyl acetate/petroleum ether (1:2) to obtain crude compound 60-5a, which was directly used in the next reaction.

Synthesis of compound 60-7a: In a 250ml reaction flask, compound 60-5a (4g, 10mmol), compound 60-6a (2.6g, 12mmol) and Cs ₂ CO ₃ (4.88g, 15mmol) were added to 80ml of acetonitrile , reflux overnight. After the reaction was completed, the solvent was removed under reduced pressure, water was added, extracted with ethyl acetate (100ml×3), washed with saturated sodium chloride, the organic layers were combined, dried over anhydrous sodium sulfate, and rotary evaporated under reduced pressure to obtain a crude product, which was purified by column chromatography (acetic acid Ethyl ester:petroleum ether=1:1.5) to obtain 4.7g of a light yellow solid with a yield of 79%.

Synthesis of compound 60-8a: In a 250ml reaction flask, dissolve compound 60-7a (6g, 10mml), iron powder (2.79g, 50mmol), ammonium chloride (4.28g, 80mmol) in 80ml EtOH/H ₂ O (4:1), reflux overnight at 80°C. After the reaction was completed, suction filter with diatomaceous earth, add water, adjust the pH to alkaline with sodium carbonate, extract with dichloromethane (100ml×3), combine the organic layers, dry over anhydrous sodium sulfate, and rotary evaporate under reduced pressure to obtain the crude product, which was weighed Crystallization gave 4.64 g of a light yellow solid, with a yield of 82%.

Synthesis of compound 60-9a: In a 25ml reaction flask, compound 60-8a (0.56g, 1mmol) and CDI (0.24g, 1.5mmol) were added to 10ml 1,2-dichlorobenzene, and refluxed for 3h. After the reaction was completed, it was applied to the column by wet method and purified by column chromatography (ethyl acetate:petroleum ether=3:1) to obtain 0.29g of white solid with a yield of 50%.

Synthesis of Compound 60-11a: Compound 60-9a (0.59g, 1mmol), Compound 60-10a (0.23g, 1.5mmol), (PPh ₃ ) ₂ Cl ₂ Pd (70mg, 0.1mmol) and Cs ₂ CO ₃ (0.65g, 2mmol) was added to a 25ml reaction flask, protected by Ar, then 20ml of 1,4-dioxane/H ₂ O (4:1) was added, and the reaction was refluxed at 100°C overnight. After the reaction was completed, the solvent was removed under reduced pressure, water was added, extracted with ethyl acetate (100ml×3), the organic layers were combined, dried over anhydrous sodium sulfate, and rotary evaporated under reduced pressure to obtain a crude product, which was directly used in the next reaction.

Synthesis of compound 60-12a: In a 50ml reaction bottle, compound 60-11a (620mg, 1mmol), N-chloroethylpyrrolidine hydrochloride (255mg, 1.5mmol), TBAI (36.9mg, 0.01mmol) and Cs ₂ CO ₃ (814mg, 2.5mmol) was added into 10ml DMSO, and stirred at 60°C for 4h. After the reaction was completed, cool to room temperature, add 100ml of water, extract with dichloromethane (100ml×3), combine the organic layers, dry over anhydrous sodium sulfate, and rotary evaporate under reduced pressure to obtain the crude product, which was purified by column chromatography (dichloromethane:methanol =10:1), 480mg of yellow solid was obtained, the yield was 67%.

Synthesis of compound CQ-365: In a 25ml reaction flask, compound 60-12a (0.72g, 1mmol) was dissolved in 10ml of dichloromethane, then 3ml of trifluoroacetic acid was added, and stirred at room temperature for 1h. After the reaction was completed, the solvent was removed under reduced pressure, the pH was adjusted to alkaline with saturated sodium bicarbonate, suction filtered, and the filter cake was purified by column chromatography (dichloromethane: methanol = 5:1) to obtain 0.4 g of a white solid with a yield of 65%. . ¹ H NMR (400MHz, CDCl ₃ ) δ8.14(s, 1H), 7.98(d, J=1.6Hz, 1H), 7.96(d, J=2.4Hz, 1H), 7.86(d, J=8.0Hz ,1H),7.59–7.52(m,3H),7.42(d,J=1.6Hz,1H),7.39(dd,J=8.8,2.8Hz,1H),6.67(d,J=8.8Hz,1H) ,4.52(t,J=7.6Hz,2H),3.91(s,3H),3.15–3.13(m,8H),2.95(t,J=7.6Hz,2H),2.83(m,4H),1.91( m,4H); ESI-MS: m/z 618.3[M+H] ⁺ .

Example 61

In vitro anti-tumor activity of compounds: The cell lines MKN-1 (human gastric cancer cells), U87MG (human malignant glioblastoma cells), and OCILY3 (diffuse large B-cell lymphoma) cell lines used in this experiment were from ATCC, Shanghai Cell Bank, Cell Bank of Type Culture Collection Committee, Chinese Academy of Sciences. 3000-10000 cells/well of the above-mentioned cells were seeded into a 96-well plate, and after overnight, different concentrations of compounds (0-30 μM) were added for continuous treatment for 72 hours. Then add CCK8 reagent, continue to incubate for 1-3 hours, and then measure its absorbance at 450nm and 650nm with a super microplate reader. Using GraphPadprism 5.0 The software calculates its half inhibitory concentration (IC50).

As a result, it was found that the tricyclic heterocyclic compound of the present invention can significantly inhibit the proliferation of MKN-1, U87MG and OCILY3 tumor cells. See Table 1 for specific data.

Anti-tumor cell activity of compounds in Table 1 in vitro (IC ₅₀ /μM)

The technical features of the above-mentioned embodiments can be combined arbitrarily. To make the description concise, all possible combinations of the technical features in the following embodiments are not described. However, as long as there is no contradiction in the combination of these technical features, should be considered as within the scope of this specification.

The above-mentioned embodiments only express several implementation modes of the present invention, and the description thereof is relatively specific and detailed, but should not be construed as limiting the patent scope of the present invention. It should be noted that, for those skilled in the art, several modifications and improvements can be made without departing from the concept of the present invention, and these all belong to the protection scope of the present invention. Therefore, the protection scope of the patent for the present invention should be based on the appended claims.

Claims (23)

1. A tricyclic and heterocyclic compound having a structure represented by formula (I) or a pharmaceutically acceptable salt thereof or a stereoisomer thereof:
   

   Wherein, A, B, D and E are independently selected from: N, NR ₁₀ , C, CR ₁₁ or C=O, and the circular dotted line in the ring where A, B, D and E are located indicates that every two Adjacent ring atoms are connected by single or double bonds to obtain a chemically stable structure;

   X is selected from: NR ₂ ;

   X ₁ and X ₂ are independently selected from: N, or CR ₉ ';

   X ₃ , X ₄ , and X ₅ are each independently selected from: N, or CR ₅ ;

   X ₆ , X ₇ , X ₈ , and X ₉ are each independently selected from: N, or CR ₆ ;

   n is selected from: 1, 2, 3, 4, 5;

   R ₁ and R ₂ are independently selected from: H, C ₁ -C ₁₈ alkyl, C ₃ -C ₈ cycloalkyl, 3-8 membered heterocycloalkyl, C ₁ -C ₈ acyl, sulfonyl, C ₆ -C ₁₈ aryl, C ₁ -C ₈ alkyl substituted by C ₆ -C ₁₈ aryl, 5-18 membered heteroaryl, and R ₁ and R ₂ are not H at the same time; or R ₁ , R ₂ Together with the X connected to it, a 4-8 member _R12 substituted or unsubstituted heterocyclic group is formed;

   Each of R ₃ and R ₄ is independently selected from: H, halogen, hydroxyl, C ₁ -C ₈ alkyl, C ₃ -C ₈ cycloalkyl; or R ₃ , R ₄ and the carbon atom connected to it together form 3 -8-membered cycloalkyl; or R ₃ , R ₄ and the carbon atom connected to it together form C=O; or R ₃ , R ₂ and the carbon atom connected to it and X together form a 4-8-membered R ₁ substituted or not Substituted heterocyclyl;

   Each R ₅ is independently selected from: H, hydroxyl, amino, cyano, nitro, halogen, trifluoromethyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ alkyl, C ₁ -C ₆ Alkylamino, C ₃ ~C ₆ cycloalkyl;

   Each R ₆ is independently selected from: H, hydroxyl, amino, cyano, nitro, halogen, trifluoromethyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ alkyl, C ₁ -C ₆ Alkylamino, C ₃ ~C ₆ cycloalkyl;

   R ₇ and R ₈ are independently selected from: H, C ₁ -C ₈ alkyl, C ₁ -C ₈ alkyl substituted by R ₁₃ , C ₃ -C ₈ cycloalkyl, 3-18 membered heterocycloalkyl , C ₁ -C ₈ acyl, alkenyl acyl, sulfonyl, 5-18 membered heteroaryl; or R ₇ , R ₈ and the N atom connected to it together form a R ₁₆ substituted or unsubstituted 3-10 membered heterocyclic ring group, or R ₇ , R ₈ and the N atom connected to it together form R ₁₆ substituted or unsubstituted 5-10 membered heteroaryl;

   R ₉ is selected from: H, halogen, C ₁ -C ₁₈ alkyl, halogen-substituted C ₁ -C ₁₈ alkyl, C ₃ -C ₁₈ cycloalkyl, 3-18 membered heterocycloalkyl, C ₁ -C ₁₈ alkoxy, halogen-substituted C ₁ -C ₁₈ alkoxy, C ₁ -C ₁₈ alkylamino, amino, hydroxyl, cyano, nitro, Ester group, amido group, sulfonyl group, sulfonylamino group, C ₆ ~C ₁₈ aryl group, C ₁ ~C ₁₈ alkyl group substituted by C ₆ ~C ₁₈ aryl group, 5~18 membered heteroaryl group;

   Each R ₉ ' is independently selected from: H, halogen, C ₁ -C ₁₈ alkyl, halogen-substituted C ₁ -C ₁₈ alkyl, C ₃ -C ₁₈ cycloalkyl, 3-18 membered heterocycloalkyl , C ₁ ~C ₁₈ alkoxy, halogen substituted C ₁ ~C ₁₈ alkoxy, C ₁ ~C ₁₈ alkylamino, amino, hydroxyl, cyano, nitro, ester, amido, sulfonyl, Sulfonylamino, C ₆ -C ₁₈ aryl, C ₁ -C ₁₈ aryl substituted C ₁ -C ₁₈ alkyl, 5-18 membered heteroaryl; or R ₉ and one R ₉ ' together form 3-10 A membered heterocyclic group; or R ₉ and a R ₉ 'together form a 5-10 membered heteroaryl group;

   R ₁₀ is selected from: H, C ₁ -C ₁₈ alkyl;

   R ₁₁ is selected from: H, halogen, C ₁ -C ₁₈ alkyl, C ₃ -C ₁₈ cycloalkyl, 3-18 membered heterocycloalkyl, C ₁ -C ₁₈ alkoxy, C ₁ -C ₁₈ alkane Amino, amino, hydroxyl, cyano, nitro, ester, amido, sulfonyl, sulfonylamino, C ₆ -C ₁₈ aryl, C ₁ -C ₁₈ alkyl substituted by C ₆ -C ₁₈ aryl , 5-18 membered heteroaryl;

   R ₁₂ is selected from: H, C ₁ -C ₁₈ alkyl, C ₁ -C ₁₈ alkyl substituted by hydroxy, C ₁ -C ₁₈ alkyl substituted by C ₁ -C 18 alkoxy, C ₁ -C ₁₈ alkyl substituted by halogen C ₁₈ alkyl, C ₃ -C ₁₈ cycloalkyl, 3-18 membered heterocycloalkyl, C ₁ -C ₁₈ alkoxy, C ₁ -C ₁₈ alkylamino, C ₁ -C ₈ acyl, halogen, Amino, hydroxyl, cyano, nitro, ester, amido, sulfonyl, sulfonylamino, C ₆ ~C ₁₈ aryl, C ₁ ~C 18 alkyl substituted by C ₆ ~ _{C 18 aryl} , 5~ 18-membered heteroaryl; or R ₁₂ forms a carbonyl with a connected carbon atom;

   R ₁₃ is selected from: hydroxyl, C ₁ -C ₈ alkoxy,

   R ₁₄ and R ₁₅ are independently selected from: H, C ₁ -C ₈ alkyl, or R ₁₄ , R ₁₅ and the N atom connected to them together form R ₁₆ substituted or unsubstituted 3-10 membered heterocyclic group;

   R ₁₆ is selected from: H, C ₁ -C ₁₈ alkyl, C ₁ -C ₁₈ alkyl substituted by hydroxy, C ₁ -C ₁₈ alkyl substituted by C ₁ -C ₁₈ alkoxy, C ₃ -C ₁₈ ring Alkyl group, 3-18 membered heterocycloalkyl group, C ₁ -C ₁₈ alkoxy group, C ₁ -C ₁₈ alkylamino group, C ₁ -C ₈ acyl group, amino group, hydroxyl group, cyano group, nitro group, ester group, Amino group, sulfonyl group, sulfonylamino group, C ₆ ~C ₁₈ aryl group, C ₁ ~C ₁₈ alkyl group substituted by C ₆ ~C ₁₈ aryl group, 5~18 membered heteroaryl group; or R ₁₆ and the connected carbon Atoms form a carbonyl group.
2. The tricyclic heterocyclic compound or its pharmaceutically acceptable salt or its stereoisomer according to claim 1, characterized in that it has the structure shown in the following formula (II):
   

   Wherein, n ₁ is selected from: 0, 1, 2, 3;

   n ₂ is selected from: 0, 1, 2, 3, 4;

   D and E are independently selected from: N, CR ₁₁ .
3. The tricyclic heterocyclic compound or its pharmaceutically acceptable salt or its stereoisomer according to claim 1, characterized in that it has the structure shown in the following formula (III):
   

   Wherein, n ₁ is selected from: 0, 1, 2, 3;

   n ₂ is selected from: 0, 1, 2, 3, 4;

   D and E are independently selected from: N, CR ₁₁ .
4. The tricyclic heterocyclic compound or its pharmaceutically acceptable salt or its stereoisomer according to claim 1, characterized in that it has the structure shown in the following formula (IV):
   

   Wherein, n ₁ is selected from: 0, 1, 2, 3;

   n ₂ is selected from: 0, 1, 2, 3, 4;

   B is selected from: N, CR ₁₁ .
5. The tricyclic and heterocyclic compound according to any one of claims 1-5 or its pharmaceutically acceptable salt or its immediate isomer, characterized in that one of _X1 and _X2 is N or CH, and the other is _CR9 '.
6. The tricyclic heterocyclic compound or its pharmaceutically acceptable salt or its stereoisomer according to any one of claims 1-5, characterized in that _R and _R are independently selected from: H, C ₁ to C ₆ alkyl, C ₃ to C ₆ cycloalkyl, 5 to 8 membered heterocycloalkyl, C ₁ to C ₃ acyl, sulfonyl, C ₆ to C ₁₀ aryl, C ₆ to C ₁₀ aryl C ₁ -C ₃ alkyl, 5-8 membered heteroaryl; or R ₁ , R ₂ and the X connected to them together form a 4-8 membered R ₁₂ substituted or unsubstituted heterocyclic group;

   R ₁₂ is selected from: H, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkyl substituted by hydroxy, C ₁ -C ₆ alkyl substituted by C ₁ -C 6 alkoxy, C ₁ -C ₆ alkyl substituted by halogen C ₆ alkyl, C ₃ -C ₆ cycloalkyl, 3-8 membered heterocycloalkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ alkylamino, C ₁ -C ₃ acyl, halogen, Amino, hydroxyl, cyano, nitro, ester, amido, sulfonyl, sulfonylamino, C ₆ ～C ₁₀ aryl, C ₁ ～C ₆ alkyl substituted by C ₆ ～C ₁₀ aryl, 5～ 10-membered heteroaryl; or R ₁₂ and the attached carbon atom form a carbonyl.
7. The tricyclic heterocyclic compound or its pharmaceutically acceptable salt or its stereoisomer according to claim 6, characterized in that R ₁ , R ₂ and the X connected thereto together form the following structure:
   

   Wherein, n ₃ is selected from: 0, 1, 2, 3, 4;

   R ₁ is selected from: H, C ₁ -C ₆ alkyl;

   R ₂ is selected from: C ₁ -C ₆ alkyl;

   R ₁₂ is selected from: H, C ₁ -C ₆ alkyl;

   R' ₁₂ is selected from: C ₁ -C ₆ alkyl substituted by methoxy, C ₁ -C ₆ alkyl substituted by halogen, halogen, C ₁ -C ₆ alkoxy.
8. The tricyclic heterocyclic compound or its pharmaceutically acceptable salt or its stereoisomer according to claim 7, characterized in that R ₁ , R ₂ and the X connected thereto together form the following structure:
   

   Wherein, n ₃ is selected from: 0, 1, 2, 3;

   R _is selected from: H, methyl, ethyl;

   _R is selected from: methyl, ethyl;

   _R'12 is selected from: methoxy substituted methyl, halogen substituted methyl, halogen, methoxy, ethoxy.
9. The tricyclic and heterocyclic compound or its pharmaceutically acceptable salt or its stereoisomer according to any one of claims 1-5, characterized in that _R3 and _R4 are both H, and n is selected from: 2, 3, 4.
10. The tricyclic and heterocyclic compound according to any one of claims 1-5 or its pharmaceutically acceptable salt or its Stereoisomers, characterized in that each _R is independently selected from: H, hydroxyl, amino, cyano, nitro, halogen, trifluoromethyl, methoxy, ethoxy, n-propoxy, Isopropoxy, methyl, ethyl, n-propyl, isopropyl, cyclopentyl, cyclohexyl.
11. The tricyclic and heterocyclic compound according to any one of claims 1-5, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein each _R is independently selected from: H, hydroxyl, Amino, cyano, nitro, halogen, trifluoromethyl, methoxy, ethoxy, n-propoxy, isopropoxy, methyl, ethyl, n-propyl, isopropyl, cyclopentyl , Cyclohexyl.
12. The tricyclic and heterocyclic compound or its pharmaceutically acceptable salt or its stereoisomer according to any one of claims 1-5, characterized in that R ₇ and R ₈ are independently selected from: C ₁ ~C ₃ alkyl; or R ₇ , R ₈ and the N atom connected to them together form R ₁₆ substituted or unsubstituted 5-8 membered heterocyclic group;

    R ₁₆ is selected from: H, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkyl substituted by hydroxy, C ₁ -C ₆ alkyl substituted by C ₁ -C ₆ alkoxy, C ₃ -C ₈ ring Alkyl, 3-8 membered heterocycloalkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ alkylamino, C ₁ -C ₃ acyl, C ₆ -C ₁₀ aryl, C ₆ -C ₁₀ Aryl-substituted C ₁ -C ₆ alkyl, 5-10 membered heteroaryl; or R ₁₆ forms a carbonyl group with a connected carbon atom.
13. The tricyclic heterocyclic compound or its pharmaceutically acceptable salt or its stereoisomer according to claim 12, characterized in that R ⁷ and R ⁸ form the following structure together with the N atom connected to them: R ₁₆ is selected from: H, C ₁ -C ₃ alkyl, C ₁ -C ₃ acyl.
14. The tricyclic heterocyclic compound or its pharmaceutically acceptable salt or its stereoisomer according to any one of claims 1-5, characterized in that R ₉ is selected from: H, halogen, C ₁ -C _6- alkyl, C ₁ -C ₆ alkyl substituted by halogen, C ₃ -C ₆ cycloalkyl, 3-8 membered heterocycloalkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ substituted by halogen Alkoxy, C ₁ ~C ₆ alkylamino, amino, hydroxyl, cyano, nitro, ester, amido, sulfonyl, sulfonylamino, C ₆ ~C ₁₀ aryl, C ₆ ~C ₁₀ aryl C ₁ -C ₆ alkyl, 5-10 membered heteroaryl;

    Each R ₉ ' is independently selected from: H, halogen, C ₁ -C ₆ alkyl, halogen-substituted C ₁ -C ₆ alkyl, C ₃ -C ₆ cycloalkyl, 3-8 membered heterocycloalkyl , C ₁ ~C ₆ alkoxy, halogen substituted C ₁ ~C ₆ alkoxy, C ₁ ~C ₆ alkylamino, amino, hydroxyl, cyano, nitro, ester, amido, sulfonyl, Sulfonylamino, C ₆ -C ₁₀ aryl, C ₆ -C ₁₀ aryl substituted C ₁ -C ₆ alkyl, 5-10 membered heteroaryl;

    Or R ₉ and one R ₉ ' together form a 5-8 membered heterocyclic group;

    Or _R9 and one _R9 ' together form a 5-8 membered heteroaryl.
15. The tricyclic heterocyclic compound or its pharmaceutically acceptable salt or its stereoisomer according to claim 14, characterized in that, _R is selected from: methoxy, trifluoromethoxy, difluoromethane Oxygen, dimethylamino, halogen, amino;

    Each R ₉ ' is independently selected from: H, halogen, methyl, methoxy, trifluoromethyl, cyano;

    Or R ₉ and one R ₉ ' together form a 5-6 membered oxygen-containing heterocyclic group;

    Or R ₉ and one R ₉ ′ together form a 5-6 membered nitrogen-containing heteroaryl group.
16. The tricyclic and heterocyclic compound according to any one of claims 1-5 or its pharmaceutically acceptable salt or its Stereoisomers, characterized in that one of X ₁ and X ₂ is N or CH, and the other is CH; R ₉ is selected from: C ₁ -C ₃ alkoxy, halogen, amino.
17. The tricyclic and heterocyclic compound or its pharmaceutically acceptable salt or its stereoisomer according to any one of claims 1-5, characterized in that one of _X1 and _X2 is CH, and the other for CR ₉ ';

    R ₉ is selected from: C ₁ -C ₃ alkoxy, halogen, amino;

    R ₉ 'is selected from: halogen, C ₁ -C ₃ alkoxy, trifluoromethyl;

    Or R ₉ and R ₉ ′ together form a 5-6 membered oxygen-containing heterocyclic group.
18. The tricyclic and heterocyclic compound or its pharmaceutically acceptable salt or its stereoisomer according to any one of claims 1-5, characterized in that one of X _{and X} is N, and the other for CR ₉ ';

    R ₉ is selected from: C ₁ -C ₃ alkoxy, halogen, amino;

    R ₉ 'is selected from: halogen, C ₁ -C ₃ alkoxy, trifluoromethyl, C ₁ -C ₃ alkyl;

    Or R ₉ and one R ₉ ′ together form a 5-6 membered nitrogen-containing heteroaryl group.
19. The tricyclic heterocyclic compound or its pharmaceutically acceptable salt or its stereoisomer according to any one of claims 1-5, characterized in that R ₁₀ is selected from: H, C ₁ -C ₆ alkane group; R ₁₁ is selected from: H, halogen, C ₁ -C ₆ alkyl.
20. The tricyclic and heterocyclic compound or its pharmaceutically acceptable salt or its stereoisomer according to claim 1, characterized in that, the tricyclic and heterocyclic compound is selected from the following compounds:
    
    
    
    
    
    
    
    
21. Use of the tricyclic heterocyclic compound or its pharmaceutically acceptable salt or its stereoisomer according to any one of claims 1-20 in the preparation of drugs for preventing or treating tumors.
22. The application according to claim 21, 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 cancer, Cell carcinoma, gastrointestinal stromal tumor, leukemia, histiocytic lymphoma, diffuse large B-cell lymphoma, nasopharyngeal carcinoma, glioma, osteosarcoma, gastric cancer, skin squamous cell carcinoma, ovarian cancer.
23. A pharmaceutical composition for preventing or treating tumors, characterized in that it is prepared from active ingredients and pharmaceutically acceptable excipients, and the active ingredients include the tricyclic and heterocyclic rings described in any one of claims 1-20. A compound or a pharmaceutically acceptable salt thereof or a stereoisomer thereof.