Polysubstituted tricyclic heterocyclic compound and medicinal composition and application thereof

Abstract

The invention provides a tricyclic heterocyclic compound with a structure as shown in a formula I, or pharmaceutically acceptable salt or stereoisomer thereof, and a pharmaceutical composition and application thereof. The compound and the pharmaceutically acceptable salt thereof can effectively inhibit the growth of various tumor cells, and can be used for preparing antitumor drugs. # imgabs0 #

Description

A class of polysubstituted tricyclic and heterocyclic compounds and their pharmaceutical compositions and applications Technical Field

[0001] The present invention relates to the technical field of chemical medicine, and in particular to a class of polysubstituted tricyclic and heterocyclic compounds and pharmaceutical compositions and applications thereof. Background Art

[0002] Malignant tumors (cancer) are a major threat to human health. Conventional cancer treatments include radiotherapy, chemotherapy, surgical resection, and drug therapy. However, these methods often suffer from significant side effects, poor therapeutic efficacy, and a high risk of tumor recurrence and metastasis. Therefore, the development of new therapeutic technologies is urgently needed to address these challenges in cancer treatment. In recent years, personalized and targeted therapies have been seen as promising approaches to breaking through the current bottlenecks in cancer treatment.

[0003] Molecular targeted tumor therapy is a new treatment approach developed by regulating key signaling pathways closely related to tumor growth through chemical or biological means. Targeted small molecule drugs offer high specificity, strong selectivity, and minimal toxic side effects; they can be used alone or in combination with existing drugs to treat cancer. Since the introduction of small molecule targeted drugs, such as imatinib mesylate (Novartis), in 2001, targeted tumor therapy has developed rapidly over the past two decades. Currently, dozens of small molecule targeted protein kinase drugs are on the market, becoming an important class of drugs in cancer treatment and ushering in a new era for tumor chemotherapy.

[0004] RIOK2 is a pseudokinase that is highly expressed in a variety of tumors, including gastric cancer, colon cancer, melanoma, glioblastoma, and non-small cell lung cancer, and is directly correlated with tumor progression. In previous work, the inventors synthesized and constructed a series of distinctive heterocyclic / chiral heterocyclic small molecule libraries, screening for novel lead compounds. Further derivatization and optimization yielded CQ211, the most active and selective RIOK2 inhibitor reported to date. However, its in vivo activity remains suboptimal. Therefore, there is an urgent need for the development of small molecule targeted drugs with improved cellular activity.

[0005] Summary of the Invention

[0006] To address these issues, the present invention provides a class of polysubstituted tricyclic heterocyclic compounds. The core of these compounds consists primarily of a quinoxalinone-five-membered heterocyclic structure or analogue with substituents attached to the amide nitrogen. These novel polysubstituted heterocyclic compounds exhibit good solubility and potent inhibitory effects on the RIOK2 protein, demonstrating high potency in inhibiting the proliferation of various tumor cells.

[0007] The present invention includes the following technical solutions:

[0008] A tricyclic heterocyclic compound having a structure represented by formula (I) or a pharmaceutically acceptable salt or a stereoisomer thereof:

[0009] Wherein, A, B, D and E are independently selected from: N, NR 10 , C, CR 11 Or C=O, and the circular dashed line in the ring where A, B, D and E are located indicates that every two adjacent ring atoms in the ring are connected by a single bond or a double bond to obtain a chemically stable structure;

[0010] X is selected from: NR2;

[0011] X1 and X2 are independently selected from: N, or CR9';

[0012] X3, X4, and X5 are independently selected from: N, or CR5;

[0013] X6, X7, X8, and X9 are independently selected from: N, or CR6;

[0014] n is selected from: 1, 2, 3, 4, 5;

[0015] R1 and R2 are independently selected from: H, C1-C 18 Alkyl, C3~C8 cycloalkyl, 3~8 membered heterocycloalkyl, C1~C8 acyl, sulfonyl, C6~C 18 Aryl, C6~C 18 Aryl-substituted C1-C8 alkyl, 5-18 membered heteroaryl, and R1 and R2 are not H at the same time; or R1, R2 and the X connected thereto together form a 4-8 membered R 12 a substituted or unsubstituted heterocyclic group;

[0016] Each R3 and R4 are independently selected from the group consisting of: H, halogen, hydroxy, C1-C8 alkyl, C3-C8 cycloalkyl; or R3, R4 and the carbon atom to which they are attached together form a 3-8 membered cycloalkyl; or R3, R4 and the carbon atom to which they are attached together form C=O; or R3, R2 and the carbon atom to which they are attached and X together form a 4-8 membered R1-substituted or unsubstituted heterocyclic group;

[0017] Each R5 is independently selected from the group consisting of: H, hydroxyl, amino, cyano, nitro, halogen, trifluoromethyl, C1-C6 alkoxy, C1-C6 alkyl, C1-C6 alkylamino, and C3-C6 cycloalkyl;

[0018] Each R6 is independently selected from the group consisting of: H, hydroxyl, amino, cyano, nitro, halogen, trifluoromethyl, C1-C6 alkoxy, C1-C6 alkyl, C1-C6 alkylamino, and C3-C6 cycloalkyl;

[0019] R7 and R8 are independently selected from: H, C1-C8 alkyl, R 13 Substituted C1-C8 alkyl, C3-C8 cycloalkyl, 3-18 membered heterocycloalkyl, C1-C8 acyl, alkenyl acyl, sulfonyl, 5-18 membered heteroaryl; or R7, R8 and the nitrogen atom to which they are attached together form R 16 a substituted or unsubstituted 3-10 membered heterocyclic group, or R7, R8 and the nitrogen atom to which they are attached together form R 16 a substituted or unsubstituted 5- to 10-membered heteroaryl group;

[0020] R9 is selected from: H, halogen, C1-C 18 Alkyl, halogen substituted C1~C 18 Alkyl, C3~C 18 Cycloalkyl, 3-18 membered heterocycloalkyl, C1-C 18 Alkoxy, halogen substituted C1~C 18 Alkoxy, C1~C 18 Alkylamino, amino, hydroxyl, cyano, nitro, ester, amide, sulfonyl, sulfonylamino, C6~C 18 Aryl, C6~C 18 Aryl-substituted C1~C 18 Alkyl, 5- to 18-membered heteroaryl;

[0021] Each R9' is independently selected from: H, halogen, C1-C 18 Alkyl, halogen substituted C1~C 18 Alkyl, C3~C 18 Cycloalkyl, 3-18 membered heterocycloalkyl, C1-C 18 Alkoxy, halogen substituted C1~C 18 Alkoxy, C1~C 18 Alkylamino, amino, hydroxyl, cyano, nitro, ester, amide, sulfonyl, sulfonylamino, C6~C 18 Aryl, C6~C 18 Aryl-substituted C1~C 18 Alkyl, 5-18 membered heteroaryl; or R9 and an R9' together form a 3-10 membered heterocyclic group; or R9 and an R9' together form a 5-10 membered heteroaryl;

[0022] R 10 Selected from: H, C1~C 18 alkyl;

[0023] R11 Selected from: H, halogen, C1~C 18 Alkyl, C3~C 18 Cycloalkyl, 3-18 membered heterocycloalkyl, C1-C 18 Alkoxy, C1~C 18 Alkylamino, amino, hydroxyl, cyano, nitro, ester, amide, sulfonyl, sulfonylamino, C6~C 18 Aryl, C6~C 18 Aryl-substituted C1~C 18 Alkyl, 5- to 18-membered heteroaryl;

[0024] R 12 Selected from: H, C1~C 18 Alkyl, hydroxy substituted C1~C 18 Alkyl, C1~C 18 Alkoxy-substituted C1~C 18 Alkyl, halogen substituted C1~C 18 Alkyl, C3~C 18 Cycloalkyl, 3-18 membered heterocycloalkyl, C1-C 18 Alkoxy, C1~C 18 Alkylamino, C1-C8 acyl, halogen, amino, hydroxyl, cyano, nitro, ester, amide, sulfonyl, sulfonylamino, C6-C 18 Aryl, C6~C 18 Aryl-substituted C1~C 18 Alkyl, 5-18 membered heteroaryl; or R 12 It forms a carbonyl group with the attached carbon atom;

[0025] R 13 Selected from: hydroxyl, C1-C8 alkoxy,

[0026] R 14 and R 15 are independently selected from: H, C1-C8 alkyl, or R 14 、R 15 Together with the N atom to which it is attached, it forms R 16 a substituted or unsubstituted 3-10 membered heterocyclic group;

[0027] R 16 Selected from: H, C1~C 18 Alkyl, hydroxy substituted C1~C 18 Alkyl, C1~C 18 Alkoxy-substituted C1~C 18 Alkyl, C3~C 18 Cycloalkyl, 3-18 membered heterocycloalkyl, C1-C 18 Alkoxy, C1~C 18Alkylamino, C1-C8 acyl, amino, hydroxyl, cyano, nitro, ester, amide, sulfonyl, sulfonylamino, C6-C 18 Aryl, C6~C 18 Aryl-substituted C1~C 18 Alkyl, 5-18 membered heteroaryl; or R 16 It forms a carbonyl group with the attached carbon atom.

[0028] In some embodiments, the tricyclic heterocyclic compound has a structure shown in the following formula (II):

[0029] Wherein, n1 is selected from: 0, 1, 2, 3;

[0030] n2 is selected from: 0, 1, 2, 3, 4;

[0031] D and E are independently selected from: N, CR 11 .

[0032] In some embodiments, the tricyclic heterocyclic compound has a structure shown in the following formula (III):

[0033] Wherein, n1 is selected from: 0, 1, 2, 3;

[0034] n2 is selected from: 0, 1, 2, 3, 4;

[0035] D and E are independently selected from: N, CR 11 .

[0036] In some embodiments, the tricyclic heterocyclic compound has a structure shown in the following formula (IV):

[0037] Wherein, n1 is selected from: 0, 1, 2, 3;

[0038] n2 is selected from: 0, 1, 2, 3, 4;

[0039] B is selected from: N, CR 11 .

[0040] In some embodiments, one of X1 and X2 is N or CH, and the other is CR9'.

[0041] In some embodiments, R1 and R2 are independently selected from: H, C1-C6 alkyl, C3-C6 cycloalkyl, 5-8 membered heterocycloalkyl, C1-C3 acyl, sulfonyl, C6-C 10 Aryl, C6~C 10Aryl-substituted C1-C3 alkyl, 5-8 membered heteroaryl; or R1, R2 and the X connected thereto together form a 4-8 membered R 12 a substituted or unsubstituted heterocyclic group;

[0042] R 12 Selected from: H, C1-C6 alkyl, C1-C6 alkyl substituted with hydroxyl, C1-C6 alkyl substituted with C1-C6 alkoxy, C1-C6 alkyl substituted with halogen, C3-C6 cycloalkyl, 3-8 membered heterocycloalkyl, C1-C6 alkoxy, C1-C6 alkylamino, C1-C3 acyl, halogen, amino, hydroxyl, cyano, nitro, ester, amide, sulfonyl, sulfonylamino, C6-C 10 Aryl, C6~C 10 Aryl-substituted C1-C6 alkyl, 5-10 membered heteroaryl; or R 12 It forms a carbonyl group with the attached carbon atom.

[0043] In some embodiments, R1, R2 and the X to which they are attached together form the following structure:

[0044] Wherein, n3 is selected from: 0, 1, 2, 3, 4;

[0045] R1 is selected from: H, C1-C6 alkyl;

[0046] R2 is selected from: C1-C6 alkyl;

[0047] R 12 Selected from: H, C1-C6 alkyl;

[0048] R' 12 Selected from: C1-C6 alkyl substituted by methoxy, C1-C6 alkyl substituted by halogen, halogen, C1-C6 alkoxy.

[0049] In some embodiments, R1, R2 and the X to which they are attached together form the following structure:

[0050] Wherein, n3 is selected from: 0, 1, 2, 3;

[0051] R1 is selected from: H, methyl, ethyl;

[0052] R2 is selected from: methyl, ethyl;

[0053] R' 12 Selected from: methoxy-substituted methyl, halogen-substituted methyl, halogen, methoxy, ethoxy.

[0054] In some embodiments, R3 and R4 are both H, and n is selected from the group consisting of 2, 3, and 4.

[0055] In some embodiments, each R5 is independently selected from: H, hydroxyl, amino, cyano, nitro, halogen, trifluoromethyl, methoxy, ethoxy, n-propoxy, isopropoxy, methyl, ethyl, n-propyl, isopropyl, cyclopentyl, cyclohexyl.

[0056] In some embodiments, each R6 is independently selected from: H, hydroxyl, amino, cyano, nitro, halogen, trifluoromethyl, methoxy, ethoxy, n-propoxy, isopropoxy, methyl, ethyl, n-propyl, isopropyl, cyclopentyl, and cyclohexyl.

[0057] In some embodiments, R7 and R8 are independently selected from: C1-C3 alkyl; or R7, R8 and the nitrogen atom to which they are attached together form R 16 a substituted or unsubstituted 5- to 8-membered heterocyclic group;

[0058] R 16 Selected from: H, C1-C6 alkyl, C1-C6 alkyl substituted with hydroxyl, C1-C6 alkyl substituted with C1-C6 alkoxy, C3-C8 cycloalkyl, 3-8 membered heterocycloalkyl, C1-C6 alkoxy, C1-C6 alkylamino, C1-C3 acyl, C6-C 10 Aryl, C6~C 10 Aryl-substituted C1-C6 alkyl, 5-10 membered heteroaryl; or R 16 It forms a carbonyl group with the attached carbon atom.

[0059] In some embodiments, R 7 、R 8 Together with the N atoms connected to it, it forms the following structure: R 16 Selected from: H, C1-C3 alkyl, C1-C3 acyl.

[0060] In some embodiments, R9 is selected from the group consisting of: H, halogen, C1-C6 alkyl, halogen-substituted C1-C6 alkyl, C3-C6 cycloalkyl, 3-8 membered heterocycloalkyl, C1-C6 alkoxy, halogen-substituted C1-C6 alkoxy, C1-C6 alkylamino, amino, hydroxyl, cyano, nitro, ester, amide, sulfonyl, sulfonylamino, C6-C 10 Aryl, C6~C 10 Aryl-substituted C1-C6 alkyl, 5-10 membered heteroaryl;

[0061] Each R9' is independently selected from the group consisting of: H, halogen, C1-C6 alkyl, halogen-substituted C1-C6 alkyl, C3-C6 cycloalkyl, 3-8 membered heterocycloalkyl, C1-C6 alkoxy, halogen-substituted C1-C6 alkoxy, C1-C6 alkylamino, amino, hydroxyl, cyano, nitro, ester, amide, sulfonyl, sulfonylamino, C6-C10 Aryl, C6~C 10 Aryl-substituted C1-C6 alkyl, 5-10 membered heteroaryl;

[0062] or R9 and one R9' together form a 5-8 membered heterocyclic group;

[0063] Alternatively, R9 and one R9' together form a 5-8 membered heteroaryl group.

[0064] In some embodiments, R9 is selected from the group consisting of: methoxy, trifluoromethoxy, difluoromethoxy, dimethylamino, halogen, and amino;

[0065] Each R9' is independently selected from: H, halogen, methyl, methoxy, trifluoromethyl, cyano;

[0066] or R9 and one R9' together form a 5-6 membered oxygen-containing heterocyclic group;

[0067] Alternatively, R9 and one R9' together form a 5-6 membered nitrogen-containing heteroaryl group.

[0068] In some embodiments, one of X1 and X2 is N or CH, and the other is CH; R9 is selected from the group consisting of C1-C3 alkoxy, halogen, and amino.

[0069] In some embodiments, one of X1 and X2 is CH, and the other is CR9';

[0070] R9 is selected from: C1-C3 alkoxy, halogen, amino;

[0071] R9' is selected from: halogen, C1-C3 alkoxy, trifluoromethyl;

[0072] Alternatively, R9 and R9' together form a 5-6 membered oxygen-containing heterocyclic group.

[0073] In some embodiments, one of X1 and X2 is N, and the other is CR9';

[0074] R9 is selected from: C1-C3 alkoxy, halogen, amino;

[0075] R9' is selected from: halogen, C1-C3 alkoxy, trifluoromethyl, C1-C3 alkyl;

[0076] Alternatively, R9 and one R9' together form a 5-6 membered nitrogen-containing heteroaryl group.

[0077] In some embodiments, R 10 Selected from: H, C1-C6 alkyl; R 11 Selected from: H, halogen, C1-C6 alkyl.

[0078] The present invention also provides the use of the above-mentioned tricyclic heterocyclic compound or its pharmaceutically acceptable salt or its stereoisomer, including the following technical solutions:

[0079] Use of the above-mentioned tricyclic heterocyclic compound or its pharmaceutically acceptable salt or its stereoisomer in the preparation of drugs for preventing or treating tumors.

[0080] In some embodiments, the tumor is: non-small cell lung cancer, small cell lung cancer, lung adenocarcinoma, lung squamous cell carcinoma, pancreatic cancer, breast cancer, prostate cancer, liver cancer, skin cancer, epithelial cell carcinoma, gastrointestinal stromal tumor, leukemia, histiocytic lymphoma, diffuse large B-cell lymphoma, nasopharyngeal carcinoma, glioma, osteosarcoma, gastric cancer, skin squamous cell carcinoma, ovarian cancer.

[0081] The present invention also provides a pharmaceutical composition for preventing or treating tumors, which includes the following technical solutions.

[0082] A pharmaceutical composition for preventing or treating tumors is prepared from active ingredients and pharmaceutically acceptable excipients. The active ingredients include the above-mentioned tricyclic heterocyclic compound or a pharmaceutically acceptable salt or a stereoisomer thereof.

[0083] The polysubstituted tricyclic heterocyclic compounds of the present invention, or pharmaceutically acceptable salts thereof, or stereoisomers thereof have good solubility, have a good inhibitory effect on RIOK2 protein, can effectively inhibit the growth of various tumor cells, can be used to prepare anti-tumor drugs, and can be used to treat transitional proliferative diseases such as tumors in humans and other mammals. DETAILED DESCRIPTION

[0084] In the compounds described herein, when any variable (e.g., R3, R4, etc.) occurs more than once in any component, its definition at each occurrence is independent of its definition at every other occurrence. Likewise, combinations of substituents and variables are permitted so long as such combinations result in a stable compound. A line drawn from a substituent into the ring system indicates that the indicated bond may be attached to any substitutable ring atom. If the ring system is polycyclic, this means that such bonds are attached only to any suitable carbon atom of an adjacent ring. It will be understood that one of ordinary skill in the art can select substituents and substitution patterns in the compounds of the present invention to provide chemically stable compounds that can be readily synthesized from readily available raw materials using techniques in the art and the methods set forth below. If a substituent is itself substituted with more than one group, it will be understood that these groups may be on the same carbon atom or on different carbon atoms so long as the structure is stable.

[0085] As used herein, the term "alkyl" is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups having a specified number of carbon atoms. For example, the definition of "C1-C6 alkyl" includes groups having 1, 2, 3, 4, 5, or 6 carbon atoms in a straight or branched chain. For example, "C1-C6 alkyl" specifically includes methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, pentyl, and hexyl.

[0086] The term "cycloalkyl" refers to a monocyclic saturated aliphatic hydrocarbon group having a specific number of carbon atoms. For example, "cycloalkyl" includes cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.

[0087] The term "alkoxy" refers to a group having an -O-alkyl structure, such as -OCH3, -OCH2CH3, -OCH2CH2CH3, -O-CH2CH(CH3)2, -OCH2CH2CH2CH3, -O-CH(CH3)2, etc.

[0088] The term "heterocycloalkyl" or "heterocyclyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic substituent in which one or more ring atoms are selected from N, O or S(O)m (wherein m is an integer from 0 to 2) and the remaining ring atoms are carbon atoms, for example: morpholinyl, piperidinyl, tetrahydropyrrolyl, pyrrolidinyl, dihydroimidazolyl, dihydroisoxazolyl, dihydroisothiazolyl, dihydrooxadiazolyl, dihydrooxazolyl, dihydropyrazinyl, dihydropyrazolyl, dihydropyridinyl, dihydropyrimidinyl, dihydropyrrolyl, dihydrotetrazolyl, dihydrothiadiazolyl, dihydrothiazolyl, dihydrothiophenyl, dihydrotriazolyl, dihydroazetidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, etc., and N-oxides thereof. The attachment of the heterocyclic substituent may be achieved through a carbon atom or through a heteroatom.

[0089] The term "heteroaryl" refers to an aromatic ring containing one or more heteroatoms selected from O, N or S. Heteroaryl within the scope of the present invention includes, but is not limited to, quinolyl, pyrazolyl, pyrrolyl, thienyl, furyl, pyridyl, pyrimidinyl, pyrazinyl, triazolyl, imidazolyl, oxazolyl, isoxazolyl, and pyridazinyl; "heteroaryl" is also understood to include any N-oxide derivative of heteroaryl containing nitrogen.

[0090] As will be understood by those skilled in the art, "halo" or "halo" as used herein refers to chlorine, fluorine, bromine and iodine.

[0091] Unless otherwise defined, alkyl, cycloalkyl, aryl, heteroaryl and heterocycloalkyl substituents may be unsubstituted or substituted. For example, C1-C6 alkyl may be substituted by one, two or three substituents selected from OH, halogen, alkoxy, dialkylamino or heterocyclic radicals such as morpholinyl, piperidinyl etc.

[0092] The present invention encompasses the free forms of the compounds of Formulas I-IV, as well as their pharmaceutically acceptable salts and stereoisomers. Certain specific exemplary compounds described herein are protonated salts of amine compounds. The term "free form" refers to the amine compounds in their non-salt form. Pharmaceutically acceptable salts encompassed include not only the exemplary salts of the specific compounds described herein, but also all typical pharmaceutically acceptable salts of the free forms of the compounds of Formulas I-IV. The free forms of specific salts of the compounds described can be isolated using techniques known in the art. For example, the free forms can be regenerated by treating the salts with a suitable dilute aqueous base solution, 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 for the purposes of the present invention, such acid and base salts are otherwise pharmaceutically equivalent to their respective free forms.

[0093] Pharmaceutically acceptable salts of the present invention can be synthesized from compounds of the present invention containing a basic or acidic moiety by conventional chemical methods. Typically, salts of basic compounds are prepared by ion exchange chromatography or by reacting a free base with a stoichiometric amount or an excess of an inorganic or organic acid in the desired salt form in a suitable solvent or combination of solvents. Similarly, salts of acidic compounds are formed by reaction with a suitable inorganic or organic base.

[0094] Therefore, pharmaceutically acceptable salts of the compounds of this invention include conventional non-toxic salts of the compounds of this invention formed by reacting an alkaline compound of this invention with an inorganic or organic acid. For example, conventional non-toxic salts include salts derived from inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid, phosphoric acid, nitric acid, and the like, and also include salts prepared from organic acids such as acetic acid, propionic acid, succinic acid, glycolic acid, stearic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, pamoic acid, maleic acid, hydroxymaleic acid, phenylacetic acid, glutamic acid, benzoic acid, salicylic acid, p-aminobenzenesulfonic acid, 2-acetoxy-benzoic acid, fumaric acid, toluenesulfonic acid, methanesulfonic acid, ethanedisulfonic acid, oxalic acid, isethionic acid, trifluoroacetic acid, and the like.

[0095] If the compound of the present invention is acidic, suitable "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, calcium salts, copper salts, ferric salts, ferrous salts, lithium salts, magnesium salts, manganic salts, manganous salts, potassium salts, sodium salts, zinc salts, and the like. Ammonium salts, calcium salts, magnesium salts, potassium salts, and sodium salts are particularly preferred. Salts derived from pharmaceutically acceptable organic non-toxic bases, including salts of primary, secondary and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins such as arginine, betaine, caffeine, choline, N,N'-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, aminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucosamine, glucosamine, histidine, hydroxocobalamin, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, guaiac, polyamine resins, procaine, purine, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine and the like.

[0096] Berg et al., "Pharmaceutical Salts," J. Pharm. Sci. '1977: 66: 1-19, describes in more detail the preparation of the pharmaceutically acceptable salts described above and other typical pharmaceutically acceptable salts.

[0097] Since deprotonated acidic moieties, such as carboxyl groups, in compounds may be anionic under physiological conditions, and this charge may then be balanced by internal cationic protonated or alkylated basic moieties, such as tetravalent nitrogen atoms, it should be noted that the compounds of the present invention are potential inner salts or zwitterions.

[0098] In one embodiment, the present application provides a method for treating hyperproliferative diseases or symptoms such as tumors in humans or other mammals using compounds having Formula I-IV and pharmaceutically acceptable salts thereof.

[0099] In one embodiment, the compounds of the present application and pharmaceutically acceptable salts thereof can be used to treat or control transitional proliferative diseases such as non-small cell lung cancer, small cell lung cancer, lung adenocarcinoma, lung squamous cell carcinoma, pancreatic cancer, breast cancer, prostate cancer, liver cancer, skin cancer, epithelial cell carcinoma, gastrointestinal stromal tumor, leukemia, histiocytic lymphoma, diffuse large B-cell lymphoma, nasopharyngeal carcinoma, glioma, osteosarcoma, gastric cancer, skin squamous cell carcinoma, ovarian cancer, etc.

[0100] The present invention also provides a pharmaceutical composition comprising an active ingredient within a safe and effective amount, and a pharmaceutically acceptable carrier or excipient.

[0101] The "active ingredient" of the present invention refers to the compound of formula I-IV of the present invention or a pharmaceutically acceptable salt or stereoisomer thereof.

[0102] The "active ingredient" and pharmaceutical composition of the present invention can be used to prepare drugs for preventing and / or treating tumors.

[0103] "Safe and effective amount" means the amount of active ingredient is sufficient to significantly improve the condition without causing serious side effects.

[0104] "Pharmaceutically acceptable carrier or excipient" refers to one or more compatible solid or liquid fillers or gel substances that are suitable for human use and must be sufficiently pure and have sufficiently low toxicity.

[0105] "Compatibility" herein means that the components of the composition can be mixed with the active ingredient of the present invention and with each other without significantly reducing the efficacy of the active ingredient.

[0106] Examples of pharmaceutically acceptable carriers or excipients include cellulose and its derivatives (such as sodium carboxymethyl cellulose, sodium ethyl cellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (such as stearic acid, magnesium stearate), calcium sulfate, vegetable oils (such as soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (such as propylene glycol, glycerol, mannitol, sorbitol, etc.), emulsifiers (such as Tween ), wetting agents (such as sodium lauryl sulfate), colorants, flavorings, stabilizers, antioxidants, preservatives, pyrogen-free water, etc.

[0107] In another preferred embodiment, the compounds of Formulas I-IV of the present invention can form complexes with macromolecular compounds or polymers through non-bonding interactions. In another preferred embodiment, the compounds of Formulas I-IV of the present invention, as small molecules, can also be linked to macromolecular compounds or polymers through chemical bonds. The macromolecular compounds can be biological macromolecules such as polysaccharides, proteins, nucleic acids, polypeptides, and the like.

[0108] There is no particular limitation on the administration of the active ingredient or pharmaceutical composition of the present invention. Representative administration methods include (but are not limited to): oral, intratumoral, rectal, parenteral (intravenous, intramuscular or subcutaneous) and the like.

[0109] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules.

[0110] In these solid dosage forms, the active ingredient is mixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or with:

[0111] (a) fillers or extenders, for example, starch, lactose, sucrose, glucose, mannitol and silicic acid;

[0112] (b) binders, for example, hydroxymethylcellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose and gum arabic;

[0113] (c) humectants, for example, glycerin;

[0114] (d) disintegrants, for example, agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate;

[0115] (e) buffering solvents, such as paraffin;

[0116] (f) absorption accelerators, for example, quaternary ammonium compounds;

[0117] (g) wetting agents, such as cetyl alcohol and glyceryl monostearate;

[0118] (h) adsorbents, for example, kaolin; and

[0119] (i) Lubricants, for example, 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 a buffering agent.

[0120] The solid dosage forms can also be prepared using coatings and shells, such as enteric coatings and other materials known in the art. They can contain opacifying agents, and the release of the active ingredient in such compositions can be delayed in a certain portion of the digestive tract. Examples of embedding components that can be used are polymeric substances and waxes.

[0121] Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, or tinctures. In addition to the active ingredient, the liquid dosage form may contain inert diluents commonly used in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropyl alcohol, ethyl carbonate, ethyl acetate, propylene glycol, 1,3-butylene glycol, dimethylformamide, and oils, particularly cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil, and sesame oil, or mixtures thereof. In addition to these inert diluents, the composition may also contain adjuvants, such as wetting agents, emulsifiers and suspending agents, sweeteners, flavoring agents, and fragrances.

[0122] In addition to the active ingredients, suspensions may contain suspending agents such as, for example, ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar, or mixtures of these substances.

[0123] Compositions for parenteral injection may comprise physiologically acceptable sterile aqueous or anhydrous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Suitable aqueous and non-aqueous carriers, diluents, solvents or excipients include water, ethanol, polyols and suitable mixtures thereof.

[0124] The present invention will be further described below in conjunction with specific examples. It should be understood that these examples are intended to illustrate the present invention only and are not intended to limit the scope of the present invention. The experimental methods in the following examples, for which specific conditions are not specified, are generally based on conventional conditions such as those described in Sambrook et al., Molecular Cloning: A Laboratory Manual (New York: Cold Spring Harbor Laboratory Press, 1989), or according to the conditions recommended by the manufacturer. Unless otherwise stated, percentages and parts are calculated by weight.

[0125] Unless otherwise defined, all technical and scientific terms used herein have the same meanings as those familiar to those skilled in the art. Furthermore, any methods and materials similar or equivalent to those described herein can be applied to the methods of the present invention. The preferred embodiments and materials described herein are for illustrative purposes only.

[0126] The reagents used in the following examples are all commercially available.

[0127] The Chinese names corresponding to the English abbreviations of the reagents used in the examples are as follows:

[0128] Example 1

[0129] 8-(6-Methoxypyridin-3-yl)-1-(4-(piperazin-1-yl)-3-(trifluoromethyl)phenyl)-5-(2-(pyrrolidin-1-yl)ethyl)-1,5-dihydro-4H-[1,2,3]triazolo[4,5-c]quinolin-4-one (CQ314)

[0130] Synthesis of Compound 1-2a: In a 250 ml reaction flask, compound 1-1a (2.25 g, 10 mmol), anhydrous piperazine (1.29 g, 15 mmol), and K2CO3 (2.76 g, 20 mmol) were added to 20 ml of DMSO under argon atmosphere and stirred at 80°C for 4 h. After the reaction was completed, the mixture was cooled to room temperature, 100 ml of water was added, and extraction was performed with ethyl acetate (100 ml x 3). The organic layers were combined, dried over anhydrous sodium sulfate, and evaporated under reduced pressure to obtain a crude product. The product was purified by column chromatography (dichloromethane:methanol = 10:1) to obtain 2.36 g of a yellow solid, with a yield of 86%.

[0131] Synthesis of Compound 1-3a: In a 100 ml reaction flask, compound 1-2a (2.75 g, 10 mmol) was dissolved in 10 ml of THF. Triethylamine (1.67 ml, 12 mmol) was added. After 10 min, acetic anhydride (1.13 ml, 12 mmol) was added and the mixture was stirred at room temperature for 2 h. Extraction was performed with dichloromethane (100 ml x 3), followed by washing with water and saturated sodium chloride solution. The organic layers were combined, dried over anhydrous sodium sulfate, and evaporated under reduced pressure to obtain the crude product, which was used directly in the next reaction.

[0132] Synthesis of Compound 1-4a: In a 250 ml reaction flask, compound 1-3a (3.17 g, 10 mmol), iron powder (2.78 g, 50 mmol), and ammonium chloride (4.28 g, 80 mmol) were dissolved in 50 ml of EtOH / H₂O (4:1 volume ratio) and refluxed at 80°C overnight. After the reaction, the mixture was filtered through celite, water was added, and the pH was adjusted to alkaline with sodium carbonate. The mixture was extracted with dichloromethane (100 ml x 3). The organic layers were combined, dried over anhydrous sodium sulfate, and evaporated under reduced pressure to obtain a crude product. Recrystallization gave 2.32 g of a light yellow solid (81% yield). 1 HNMR (400 MHz, 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),3.88-3.9 7(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] + .

[0133] Synthesis of Compound 1-5a: In a 250 ml reaction flask, compound 1-4a (2.00 g, 7 mmol) was dissolved in 15 ml of HCl at 0°C, and 10 ml of water was added and stirred until dissolved. Subsequently, 5 ml of an aqueous solution of NaNO2 (0.68 g, 9.8 mmol) was added dropwise to the mixture at 0°C, and the reaction was continued at 0°C for 1 hour. Finally, 5 ml of an aqueous solution of NaN3 (0.64 g, 9.8 mmol) was added dropwise to the mixture at 0°C, and the reaction was continued with stirring for 0.5 hour. After completion of the reaction, the mixture was neutralized with aqueous K2CO3 and extracted with ethyl acetate (100 ml x 3). The organic layers were combined, dried over anhydrous sodium sulfate, and evaporated under reduced pressure at 45°C to obtain the crude product, which was purified by column chromatography (dichloromethane:methanol = 50:1 (v / v)) to afford 1.82 g of a light brown solid (83% yield).

[0134] Synthesis of compound 1-7a: Compound 1-6a (4.70 g, 10 mmol), compound 1-5a (3.44 g, 11 mmol), CuI (0.19 g, 1 mmol), and K2CO3 (2.76 g, 20 mmol) were added to a 25 ml reaction flask under argon protection. 20 ml of DMSO was added to the reaction solution while heating at 110°C and stirring for 4 h. After the reaction was completed, the mixture was cooled to room temperature and quenched with 2 ml of aqueous ammonia. The mixture was extracted with dichloromethane (50 ml x 3), washed with saturated sodium chloride solution and water, and the organic layers were combined, dried over anhydrous sodium sulfate, and evaporated under reduced pressure to obtain a crude product. The crude product was purified by column chromatography (ethyl acetate) to obtain 3.41 g of a white solid (52% yield). 1 H NMR (400 MHz, 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=9.2 Hz,1H),7.17(d,J=8.8Hz,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] + .

[0135] Synthesis of Compound 1-8a: In a 25 ml reaction flask, compound 1-7a (3.36 g, 5 mmol) was dissolved in TFA (200 mmol) and TfOH (25 mmol) and stirred overnight at room temperature. After the reaction was complete, the mixture was quenched with water, the pH was adjusted to alkaline with saturated sodium bicarbonate, and the mixture was filtered. The filter cake was oven-dried to obtain the crude product, which was used directly in the next reaction.

[0136] Synthesis of compound 1-10a: Compound 1-8a (0.53 g, 1 mmol), compound 1-9a (0.23 g, 1.5 mmol),

[0137] (PPh3)4Pd (23 mg, 0.02 mmol) and Cs2CO3 (0.65 g, 2 mmol) were added to a 25 ml reaction flask under argon. 20 ml of DMF / H2O (3:1 volume ratio) was added and the mixture was refluxed at 80°C overnight. After completion of the reaction, the mixture was quenched with water and filtered. The filter cake was purified by column chromatography (dichloromethane:methanol:triethylamine = 100:10:1) to afford 0.35 g of a white solid in a 62% yield. 1H NMR (400 MHz, 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),7.5 9(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] + .

[0138] Synthesis of Compound 1-12a: Compound 1-10a (0.56 g, 1 mmol), Cs2CO3 (0.98 g, 3 mmol), and TBAI (37 mg, 0.1 mmol) were added to a 50 ml reaction flask. DMSO (20 ml) was then added and stirred at room temperature for 10 min. (2-Bromoethoxy)-tert-butyldimethylsilane (0.29 g, 1.2 mmol) was then added and the mixture was allowed to react at 70°C overnight. After the reaction was complete, the mixture was quenched with water and filtered. The filter cake was oven-dried to obtain the crude product, which was used directly in the next reaction.

[0139] Synthesis of Compound 1-13a: Compound 1-12a (0.72 g, 1 mmol) was added to a 50 mL reaction flask, followed by 20 mL of THF and TBAF (0.29 g, 1.1 mmol). Stirring was continued at room temperature for 1 hour. After the reaction, the mixture was extracted with dichloromethane (100 mL x 3), washed with saturated sodium chloride solution and water, and the organic layers were combined, dried over anhydrous sodium sulfate, and evaporated under reduced pressure to obtain Intermediate 1-13a, which was used directly in the next reaction.

[0140] Synthesis of Compound 1-14a: Dissolve Compound 1-13a (0.6 g, 1 mmol) in 20 ml of chloroform and stir on ice for 10 min. Then slowly add phosphorus tribromide (0.75 g, 3 mmol) dropwise and allow to react overnight at room temperature. After the reaction, extract with dichloromethane (100 ml x 3), wash with saturated sodium chloride solution, combine the organic layers, dry over anhydrous sodium sulfate, and evaporate under reduced pressure to obtain crude product 1-14a, which was used directly in the next reaction.

[0141] Synthesis of compound 1-15a: Dissolve 1-14a (0.67 g, 1 mmol), K2CO3 (0.56 g, 4 mmol), and KI (66 mg, 0.4 mmol) in 30 mL of DMF. Then, add tetrahydropyrrole (94 mg, 2 mmol) and react at room temperature overnight. After completion of the reaction, extract with dichloromethane (100 mL x 3), wash with saturated sodium chloride solution, combine the organic layers, dry over anhydrous sodium sulfate, and evaporate under reduced pressure to obtain the crude product. Purify by column chromatography (dichloromethane:methanol = 15:1) to obtain 0.46 g of a white solid, with a yield of 70%. 1 H NMR (400 MHz, 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] + .

[0142] Synthesis of Compound CQ314: Compound 1-15a was dissolved in 6N HCl and refluxed at 70°C for 5 h. After completion of the reaction, the mixture was cooled to room temperature and the pH was adjusted to neutral with NaOH. Extraction was performed with dichloromethane (100 ml x 3), followed by washing with saturated sodium chloride solution. The combined organic layers were dried over anhydrous sodium sulfate, and rotary evaporation under reduced pressure afforded the crude product. Purification by column chromatography (dichloromethane:methanol = 15:1) afforded 0.36 g of a white solid, a 60% yield. 1 HNMR (400 MHz, 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] + .

[0143] Example 2

[0144] 5-(2-(Dimethylamino)ethyl)-8-(6-methoxypyridin-3-yl)-1-(4-(piperazin-1-yl)-3-(trifluoromethyl)phenyl)-1,5-dihydro-4H-[1,2,3]triazolo[4,5-c]quinolin-4-one (CQ265)

[0145] Synthesis of compound 2-1a: Dissolve 1-14a (0.67 g, 1 mmol), K2CO3 (0.56 g, 4 mmol), and KI (66 mg, 0.4 mmol) in 30 mL of DMF. Add dimethylamine (90.2 mg, 2 mmol) and allow to react overnight at room temperature. After completion of the reaction, extract with dichloromethane (100 mL x 3), wash with saturated sodium chloride solution, combine the organic layers, dry over anhydrous sodium sulfate, and evaporate under reduced pressure to obtain the crude product, which was used directly in the next step.

[0146] Synthesis of compound CQ265: The synthesis method was the same as that of compound CQ314, and 0.3 g of white solid was obtained with a yield of 75%.

[0147] 1 HNMR (400 MHz, 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] + .

[0148] Example 3

[0149] 5-(3-Hydroxypropyl)-8-(6-methoxypyridin-3-yl)-1-(4-(piperazin-1-yl)-3-(trifluoromethyl)phenyl)-1,5-dihydro-4H-[1,2,3]triazolo[4,5-c]quinolin-4-one (CQ266)

[0150] Synthesis of compound 3-2a: The synthesis method is the same as that of compound 1-12a.

[0151] Synthesis of compound 3-3a: The synthesis method is the same as that of compound 1-13a.

[0152] Synthesis of compound CQ266: The synthesis method was the same as that of compound CQ314, and 0.3 g of white solid was obtained with a yield of 75%.

[0153] 1 H NMR (400 MHz, 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=8.8,2.4 Hz,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=6.0Hz,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]+.

[0154] Example 4

[0155] 5-(4-Hydroxybutyl)-8-(6-methoxypyridin-3-yl)-1-(4-(piperazin-1-yl)-3-(trifluoromethyl)phenyl)-1,5-dihydro-4H-[1,2,3]triazolo[4,5-c]quinolin-4-one (CQ267)

[0156] The synthesis method was similar to that of Example 3, and 0.3 g of a white solid was obtained with a yield of 76%.

[0157] 1 H NMR (400 MHz, 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).

[0158] Example 5

[0159] 8-(6-Methoxypyridin-3-yl)-5-(2-(methylamino)ethyl)-1-(4-(piperazin-1-yl)-3-(trifluoromethyl)phenyl)-1,5-dihydro-4H-[1,2,3]triazolo[4,5-c]quinolin-4-one (CQ268)

[0160] Synthesis of compound 5-2a: Dissolve 1-14a (0.67 g, 1 mmol), K2CO3 (0.56 g, 4 mmol), and KI (66 mg, 0.4 mmol) in 30 ml of DMF. Then add methylamine (63 mg, 2 mmol) and react at room temperature overnight. After the reaction, extract with dichloromethane (100 ml x 3), wash with saturated sodium chloride solution, and combine the organic layers, dry over anhydrous sodium sulfate, and evaporate under reduced pressure to obtain the crude product, which was used directly in the next step.

[0161] Synthesis of compound CQ268: The synthesis method was the same as that of compound CQ314, and 0.5 g of white solid was obtained with a yield of 72%.

[0162] 1 H NMR (400 MHz, 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=8.8,2.4 Hz,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] + .

[0163] Example 6

[0164] 8-(6-Methoxypyridin-3-yl)-5-(2-morpholinoethyl)-1-(4-(piperazin-1-yl)-3-(trifluoromethyl)phenyl)-1,5-dihydro-4H-[1,2,3]triazolo[4,5-c]quinolin-4-one (CQ301)

[0165] Synthesis of compound 6-2a: Dissolve 1-14a (0.67 g, 1 mmol), K2CO3 (0.56 g, 4 mmol), and KI (66 mg, 0.4 mmol) in 30 ml of DMF. Add morpholine (174 mg, 2 mmol) and allow to react overnight at room temperature. After completion of the reaction, extract with dichloromethane (100 ml x 3), wash with saturated sodium chloride solution, combine the organic layers, dry over anhydrous sodium sulfate, and evaporate under reduced pressure to obtain the crude product, which was used directly in the next step.

[0166] Synthesis of compound CQ301: The synthesis method was the same as that of compound CQ314, yielding 0.45 g of white solid with a yield of 72%.

[0167] 1 HNMR (400 MHz, 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] + .

[0168] Example 7

[0169] 5-(3-(Dimethylamino)propyl)-8-(6-methoxypyridin-3-yl)-1-(4-(piperazin-1-yl)-3-(trifluoromethyl)phenyl)-1,5-dihydro-4H-[1,2,3]triazolo[4,5-c]quinolin-4-one (CQ302)

[0170] The synthesis method was similar to that of Example 2, and 0.3 g of a white solid was obtained with a yield of 71%.

[0171] 1H NMR (400MHz, CDCl3) 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] + .

[0172] Example 8

[0173] 8-(6-Methoxypyridin-3-yl)-1-(4-(piperazin-1-yl)-3-(trifluoromethyl)phenyl)-5-(2-(piperidin-1-yl)ethyl)-1,5-dihydro-4H-[1,2,3]triazolo[4,5-c]quinolin-4-one (CQ303)

[0174] Synthesis of compound 8-2a: Dissolve 1-14a (0.67 g, 1 mmol), K2CO3 (0.56 g, 4 mmol), and KI (66 mg, 0.4 mmol) in 30 ml of DMF. Then add hexahydropyridine (170 mg, 2 mmol) and react at room temperature overnight. After the reaction, extract with dichloromethane (100 ml x 3), wash with saturated sodium chloride solution, and combine the organic layers, dry over anhydrous sodium sulfate, and evaporate under reduced pressure to obtain the crude product, which was used directly in the next step.

[0175] Synthesis of compound CQ303: The synthesis method was the same as that of compound CQ314, and 0.4 g of white solid was obtained with a yield of 69%.

[0176] 1 H NMR (400 MHz, 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] + .

[0177] Example 9

[0178] 8-(6-Methoxypyridin-3-yl)-1-(4-(piperazin-1-yl)-3-(trifluoromethyl)phenyl)-5-(2-(piperazin-1-yl)ethyl)-1,5-dihydro-4H-[1,2,3]triazolo[4,5-c]quinolin-4-one (CQ304)

[0179] Synthesis of compound 9-2a: Dissolve 1-14a (0.67 g, 1 mmol), K2CO3 (0.56 g, 4 mmol), and KI (66 mg, 0.4 mmol) in 30 ml of DMF. Add 1-tert-butyloxycarbonylpiperazine (372 mg, 2 mmol) and allow to react overnight at room temperature. After completion of the reaction, extract with dichloromethane (100 ml x 3), wash with saturated sodium chloride solution, combine the organic layers, dry over anhydrous sodium sulfate, and evaporate under reduced pressure to obtain the crude product, which was used directly in the next step.

[0180] Synthesis of compound CQ304: The synthesis method was the same as that of compound CQ314, and 0.4 g of white solid was obtained with a yield of 67%.

[0181] 1H NMR(400MHz, CDCl3)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] + .

[0182] Example 10

[0183] 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]triazolo[4,5-c]quinolin-4-one (CQ315)

[0184] Synthesis of compound 10-2a: Dissolve 1-14a (0.67 g, 1 mmol), K2CO3 (0.56 g, 4 mmol), and KI (66 mg, 0.4 mmol) in 30 ml of DMF. Add cycloheximide (198 mg, 2 mmol) and allow to react overnight at room temperature. After completion of the reaction, extract with dichloromethane (100 ml x 3), wash with saturated sodium chloride solution, and combine the organic layers, dry over anhydrous sodium sulfate, and evaporate under reduced pressure to obtain the crude product, which was used directly in the next step.

[0185] Synthesis of compound CQ315: The synthesis method was the same as that of compound CQ314, and 0.5 g of white solid was obtained with a yield of 78%.

[0186] 1 H NMR (400 MHz, 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),7.1 9(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] + .

[0187] Example 11

[0188] 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]triazolo[4,5-c]quinolin-4-one (CQ316)

[0189] Synthesis of compound 11-2a: Dissolve 1-14a (0.67 g, 1 mmol), K2CO3 (0.56 g, 4 mmol), and KI (66 mg, 0.4 mmol) in 30 ml of DMF. Add N-methylpiperazine (200 mg, 2 mmol) and allow to react overnight at room temperature. After completion of the reaction, extract with dichloromethane (100 ml x 3), wash with saturated sodium chloride solution, combine the organic layers, dry over anhydrous sodium sulfate, and evaporate under reduced pressure to obtain the crude product, which was used directly in the next step.

[0190] Synthesis of compound CQ316: The synthesis method was the same as that of compound CQ314, and 0.5 g of white solid was obtained with a yield of 78%.

[0191] 1 H NMR (400 MHz, 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] + .

[0192] Example 12

[0193] 5-(2-(Diethylamino)ethyl)-8-(6-methoxypyridin-3-yl)-1-(4-(piperazin-1-yl)-3-(trifluoromethyl)phenyl)-1,5-dihydro-4H-[1,2,3]triazolo[4,5-c]quinolin-4-one (CQ317)

[0194] Synthesis of compound 12-2a: Dissolve 1-14a (0.67 g, 1 mmol), K2CO3 (0.56 g, 4 mmol), and KI (66 mg, 0.4 mmol) in 30 ml of DMF. Add diethylamine (146 mg, 2 mmol) and allow to react overnight at room temperature. After completion of the reaction, extract with dichloromethane (100 ml x 3), wash with saturated sodium chloride solution, combine the organic layers, dry over anhydrous sodium sulfate, and evaporate under reduced pressure to obtain the crude product, which was used directly in the next step.

[0195] Synthesis of compound CQ317: The synthesis method was the same as that of compound CQ314, and 0.46 g of white solid was obtained with a yield of 75%.

[0196] 1 H NMR (400 MHz, 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] + .

[0197] Example 13

[0198] 5-(2-(Diisopropylamino)ethyl)-8-(6-methoxypyridin-3-yl)-1-(4-(piperazin-1-yl)-3-(trifluoromethyl)phenyl)-1,5-dihydro-4H-[1,2,3]triazolo[4,5-c]quinolin-4-one (CQ318)

[0199] Synthesis of compound 13-2a: Dissolve 1-14a (0.67 g, 1 mmol), K2CO3 (0.56 g, 4 mmol), and KI (66 mg, 0.4 mmol) in 30 ml of DMF. Add diisopropylamine (202 mg, 2 mmol) and allow to react overnight at room temperature. After completion of the reaction, extract with dichloromethane (100 ml x 3), wash with saturated sodium chloride solution, combine the organic layers, dry over anhydrous sodium sulfate, and evaporate under reduced pressure to obtain the crude product, which was used directly in the next step.

[0200] Synthesis of compound CQ318: The synthesis method was the same as that of compound CQ314, and 0.47 g of white solid was obtained with a yield of 73%.

[0201] 1 H NMR (400 MHz, 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] + .

[0202] Example 14

[0203] 1-(2-(8-(6-methoxypyridin-3-yl)-4-oxo-1-(4-(piperazin-1-yl)-3-(trifluoromethyl)phenyl)-1,4-dihydro-5H-[1,2,3]triazolo[4,5-c]quinolin-5-yl]ethyl)pyrrolidine-2,5-dione (CQ319)

[0204] Synthesis of Compound 14-2a: Dissolve 1-14a (0.67 g, 1 mmol), K2CO3 (0.56 g, 4 mmol), and KI (66 mg, 0.4 mmol) in 30 ml of DMF. Then add succinimide (200 mg, 2 mmol) and react at room temperature overnight. After the reaction, extract with dichloromethane (100 ml x 3), wash with saturated sodium chloride solution, and combine the organic layers, dry over anhydrous sodium sulfate, and evaporate under reduced pressure to obtain the crude product, which was used directly in the next step.

[0205] Synthesis of compound CQ319: The synthesis method was the same as that of compound CQ314, and 0.38 g of white solid was obtained with a yield of 59%.

[0206] 1 H NMR (400 MHz, DMSO-d 6)δ8.26(d,J=2.0Hz,1H),8.16(s,1H),8.13(s,1H),8.07(dd,J=8.8Hz,1.6H z,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] + .

[0207] Example 15

[0208] 8-(6-Methoxypyridin-3-yl)-1-(4-morpholino-3-(trifluoromethyl)phenyl)-5-(2-(pyrrolidin-1-yl)ethyl)-1,5-dihydro-4H-[1,2,3]triazolo[4,5-c]quinolin-4-one (CQ320)

[0209] The synthesis method was similar to that of Example 1, and 0.2 g of a white solid was obtained with a yield of 70%.

[0210] 1 H NMR (400 MHz, 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] + .

[0211] Example 16

[0212] 5-(2-(Dimethylamino)ethyl)-8-(6-methoxypyridin-3-yl)-1-(4-morpholino-3-(trifluoromethyl)phenyl)-1,5-dihydro-4H-[1,2,3]triazolo[4,5-c]quinolin-4-one (CQ321)

[0213] The synthesis method was similar to that of Example 2, and 0.2 g of a white solid was obtained with a yield of 63%.

[0214] 1 H NMR (400 MHz, 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] + .

[0215] Example 17

[0216] 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]triazolo[4,5-c]quinolin-4-one (CQ322)

[0217] The synthesis method was similar to that of Example 1, and 0.5 g of a white solid was obtained with a yield of 77%.

[0218] 1 H NMR (400 MHz, 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] + .

[0219] Example 18

[0220] 8-(6-Methoxypyridin-3-yl)-1-(4-(piperazin-1-yl)-3-(trifluoromethyl)phenyl)-5-(3-(pyrrol-1-yl)propyl)-1,5-dihydro-4H-[1,2,3]triazolo[4,5-c]quinolin-4-one (CQ323)

[0221] The synthesis method was similar to that of Example 1, and 0.5 g of a white solid was obtained with a yield of 77%.

[0222] 1 H NMR (400MHz, CDCl3) 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),3.09-3.0 8(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] + .

[0223] Example 19

[0224] 8-(4-Methoxyphenyl)-1-(4-(piperazin-1-yl)-3-(trifluoromethyl)phenyl)-5-(2-(pyrrol-1-yl)ethyl)-1,5-dihydro-4H-[1,2,3]triazolo[4,5-c]quinolin-4-one (CQ324)

[0225] Synthesis of compound 19-3a: In a 250 ml reaction flask, compound 19-1a (5.34 g, 10 mmol), N-chloroethylpyrrolidine hydrochloride (2.55 g, 15 mmol), TBAI (369 mg, 1 mmol), and Cs2CO3 (8.14 g, 25 mmol) were added to 100 ml of DMSO and stirred at 80°C for 4 h. After the reaction was completed, the mixture was cooled to room temperature, 100 ml of water was added, and the mixture was extracted with dichloromethane (100 ml x 3). The organic layers were combined, dried over anhydrous sodium sulfate, and evaporated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (dichloromethane:methanol = 10:1) to obtain 5 g of a yellow solid, with a yield of 79%.

[0226] Synthesis of Compound 19-4a: In a 50 ml reaction flask, compound 19-3a (632 mg, 1 mmol), 10 ml of hydrochloric acid, and 10 ml of ethanol were refluxed at 120°C for 4 h. After the reaction, the mixture was cooled to room temperature, dried by rotary evaporation, and the pH was adjusted to alkaline with sodium hydroxide solution. The mixture was filtered and dried to obtain 500 mg of a yellow solid (85% yield), which was used directly in the next step.

[0227] 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), (PPh3)4Pd (115 mg, 0.1 mmol), and Cs2CO3 (4.8 g, 15 mmol) were placed in a 25 ml reaction flask. 30 ml of DMF and 10 ml of water were added, and the mixture was stirred at 80°C for 3 h. After the reaction was completed, the mixture was cooled to room temperature, 100 ml of water was added, and the mixture was extracted with dichloromethane (100 ml x 3). The organic layers were combined, dried over anhydrous sodium sulfate, and evaporated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (dichloromethane:methanol = 5:1) to obtain 308 mg of a yellow solid, with a yield of 64%. 1 H NMR (400 MHz, 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] + .

[0228] Example 20

[0229] 8-(3-Fluoro-4-methoxyphenyl)-1-(4-(piperazin-1-yl)-3-(trifluoromethyl)phenyl)-5-(2-(pyrrol-1-yl)ethyl)-1,5-dihydro-4H-[1,2,3]triazolo[4,5-c]quinolin-4-one (CQ325)

[0230] The synthesis method was similar to that of Example 19, and 0.3 g of a white solid was obtained with a yield of 77%.

[0231] 1 H NMR (400 MHz, 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] + .

[0232] Example 21

[0233] 8-(4-Methoxy-3-methylphenyl)-1-(4-(piperazin-1-yl)-3-(trifluoromethyl)phenyl)-5-(2-(pyrrol-1-yl)ethyl)-1,5-dihydro-4H-[1,2,3]triazolo[4,5-c]quinolin-4-one (CQ326)

[0234] The synthesis method was similar to that of Example 19, and 0.2 g of a white solid was obtained with a yield of 67%.

[0235] 1 H NMR (400 MHz, 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,1 H),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] + .

[0236] Example 22

[0237] 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]triazolo[4,5-c]quinolin-4-one (CQ327)

[0238] The synthesis method was similar to that of Example 19, and 0.4 g of a white solid was obtained with a yield of 79%.

[0239] 1 H NMR (400 MHz, 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=8.4 Hz,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] + .

[0240] Example 23

[0241] 8-(3,4-Methoxyphenyl)-1-(4-(piperazin-1-yl)-3-(trifluoromethyl)phenyl)-5-(2-(pyrrol-1-yl)ethyl)-1,5-dihydro-4H-[1,2,3]triazolo[4,5-c]quinolin-4-one (CQ328)

[0242] The synthesis method was similar to that of Example 19, and 0.3 g of a white solid was obtained with a yield of 71%.

[0243] 1 H NMR (400 MHz, 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] + .

[0244] Example 24

[0245] 8-(3-chloro-4-methoxyphenyl)-1-(4-(piperazin-1-yl)-3-(trifluoromethyl)phenyl)-5-(2-(pyrrol-1-yl)ethyl)-1,5-dihydro-4H-[1,2,3]triazolo[4,5-c]quinolin-4-one (CQ329)

[0246] The synthesis method was similar to that of Example 19, and 0.4 g of a white solid was obtained with a yield of 77%.

[0247] 1 H NMR (400 MHz, 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] + .

[0248] Example 25

[0249] 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]triazolo[4,5-c]quinolin-4-one (CQ330)

[0250] The synthesis method was similar to that of Example 19, and 0.5 g of a white solid was obtained with a yield of 77%.

[0251] 1 H NMR (400 MHz, 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] + .

[0252] Example 26

[0253] 1-(4-(piperazin-1-yl)-3-(trifluoromethyl)phenyl)-5-(2-(pyrrol-1-yl)ethyl)-8-(4-(trifluoromethoxy)phenyl)-1,5-dihydro-4H-[1,2,3]triazolo[4,5-c]quinolin-4-one (CQ331)

[0254] The synthesis method was similar to that of Example 19, and 0.4 g of a white solid was obtained with a yield of 70%.

[0255] 1 H NMR (400 MHz, 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=8.0 Hz,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] + .

[0256] Example 27

[0257] 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]triazolo[4,5-c]quinolin-8-yl)benzonitrile (CQ332)

[0258] The synthesis method was similar to that of Example 19, and 0.1 g of a white solid was obtained with a yield of 57%.

[0259] 1 H NMR (400 MHz, 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),7.9 1(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] + .

[0260] Example 28

[0261] 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]triazolo[4,5-c]quinolin-4-one (CQ333)

[0262] The synthesis method was similar to that of Example 19, and 0.2 g of a white solid was obtained with a yield of 72%.

[0263] 1 H NMR (400 MHz, 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(d d,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),3.1 2(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] + .

[0264] Example 29

[0265] 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]triazolo[4,5-c]quinolin-4-one (CQ334)

[0266] The synthesis method was similar to that of Example 19, and 0.1 g of a white solid was obtained with a yield of 77%.

[0267] 1 H NMR (400 MHz, 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] + .

[0268] Example 30

[0269] 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]triazolo[4,5-c]quinolin-4-one (CQ335)

[0270] The synthesis method was similar to that of Example 19, and 0.2 g of a white solid was obtained with a yield of 47%.

[0271] 1 H NMR (400 MHz, 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] + .

[0272] Example 31

[0273] 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]triazolo[4,5-c]quinolin-4-one (CQ336)

[0274] The synthesis method was similar to that of Example 19, and 0.5 g of a white solid was obtained with a yield of 77%.

[0275] 1H NMR (400 MHz, 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] + .

[0276] Example 32

[0277] 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]triazolo[4,5-c]quinolin-4-one (CQ337)

[0278] The synthesis method was similar to that of Example 19, and 0.2 g of a white solid was obtained with a yield of 68%.

[0279] 1 H NMR (400 MHz, 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] + .

[0280] Example 33

[0281] 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]triazolo[4,5-c]quinolin-4-one (CQ338)

[0282] The synthesis method was similar to that of Example 19, and 0.2 g of a white solid was obtained with a yield of 70%.

[0283] 1 H NMR (400 MHz, 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] + .

[0284] Example 34

[0285] 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]triazolo[4,5-c]quinolin-4-one (CQ339)

[0286] The synthesis method was similar to that of Example 19, and 0.2 g of a white solid was obtained with a yield of 77%.

[0287] 1 H NMR (400 MHz, 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] + .

[0288] Example 35

[0289] 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]triazolo[4,5-c]quinolin-4-one (CQ340)

[0290] The synthesis method was similar to that of Example 19, and 0.2 g of a white solid was obtained with a yield of 67%.

[0291] 1 H NMR (400 MHz, 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] + .

[0292] Example 36

[0293] 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]triazolo[4,5-c]quinolin-4-one (CQ341)

[0294] The synthesis method was similar to that of Example 19, and 0.2 g of a white solid was obtained with a yield of 67%.

[0295] 1 H NMR (400 MHz, 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] + .

[0296] Example 37

[0297] 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]triazolo[4,5-c]quinolin-4-one (CQ342)

[0298] The synthesis method was similar to that of Example 19, and 0.51 g of a white solid was obtained with a yield of 77%.

[0299] 1 H NMR (400 MHz, 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] + .

[0300] Example 38

[0301] 1-(4-(Piperazin-1-yl)-3-(trifluoromethyl)phenyl)-5-(2-(pyrrol-1-yl)-8-(1H-pyrrolo[2,3-b]pyridin-5-yl)-1,5-dihydro-4H-[1,2,3]triazolo[4,5-c]quinolin-4-one (CQ343)

[0302] The synthesis method was similar to that of Example 19, and 0.2 g of a white solid was obtained with a yield of 57%.

[0303] 1 H NMR (400 MHz, 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] + .

[0304] Example 39

[0305] (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]triazolo[4,5-c]quinolin-4-one (CQ344)

[0306] Synthesis of Compound 39-1a: In a 100-ml reaction flask, compound CQ-211 (521 mg, 1 mmol) was dissolved in 50 ml of DMSO. (Boc)2O (327 mg, 1.5 mmol) was then added and stirred at room temperature overnight. After the reaction, 100 ml of water was added and the mixture was extracted with dichloromethane (3 x 100 ml). The organic layers were combined, dried over anhydrous sodium sulfate, and evaporated under reduced pressure to obtain the crude product, which was directly used in the next step.

[0307] Synthesis of compound 39-3a: In a 100 ml reaction flask, compound 39-1a (310 mg, 0.5 mmol), (R)-1-(2-chloroethyl)-3-(methoxymethyl)-N-pyrrolidine hydrochloride (107 mg, 0.5 mmol), TBAI (18 mg, 0.05 mmol), and Cs2CO3 (325 g, 1 mmol) were added to 30 ml of DMSO and stirred at 80°C for 4 h. After the reaction was completed, the mixture was cooled to room temperature, 100 ml of water was added, and the mixture was extracted with dichloromethane (100 ml x 3). The organic layers were combined, dried over anhydrous sodium sulfate, and evaporated under reduced pressure to obtain the crude product. The product was purified by column chromatography (dichloromethane:methanol = 10:1) to obtain 300 mg of a yellow solid, with a yield of 78%.

[0308] Synthesis of Compound CQ344: In a 100-ml reaction flask, compound 39-3a (300 mg, 0.42 mmol) was dissolved in 10 ml of TFA and 10 ml of dichloromethane and stirred at room temperature overnight. After the reaction, the mixture was dried by rotary evaporation, the pH adjusted to alkaline with sodium bicarbonate solution, 100 ml of water was added, and the mixture was extracted with dichloromethane (100 ml x 3). The organic layers were combined, dried over anhydrous sodium sulfate, and evaporated under reduced pressure to obtain the crude product. The product was purified by column chromatography (dichloromethane:methanol = 10:1) to afford 264 mg of a white solid, a 90% yield. 1 HNMR (400 MHz, 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),2.7 2–2.70(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] + .

[0309] Example 40

[0310] (S)-5-(2-(3-(fluoromethyl)pyrrol-1-yl)ethyl)-8-(6-methoxypyridin-3-yl)-1-(4-(piperazin-1-yl)-3-(trifluoromethyl)phenyl)-1,5-dihydro-4H-[1,2,3]triazolo[4,5-c]quinolin-4-one (CQ345)

[0311] The synthesis method was similar to that of Example 39, and 0.4 g of a white solid was obtained with a yield of 77%.

[0312] 1 H NMR (400 MHz, 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,8 H),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] + .

[0313] Example 41

[0314] (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]triazolo[4,5-c]quinolin-4-one (CQ346)

[0315] The synthesis method was similar to that of Example 39, and 0.1 g of a white solid was obtained with a yield of 57%.

[0316] 1 H NMR (400 MHz, 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=8.8,2.0 Hz,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=2.0 Hz,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] + .

[0317] Example 42

[0318] (R)-8-(6-methoxypyridin-3-yl)-5-(2-(3-methoxypyrrol-1-yl)ethyl)-1-(4-(piperazin-1-yl)-3-(trifluoromethyl)phenyl)-1,5-dihydro-4H-[1,2,3]triazolo[4,5-c]quinolin-4-one (CQ347)

[0319] The synthesis method was similar to that of Example 39, and 0.2 g of a white solid was obtained with a yield of 67%.

[0320] 1 H NMR (400 MHz, 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=7.6 Hz,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] +.

[0321] Example 43

[0322] 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]triazolo[4,5-c]quinolin-4-one (CQ348)

[0323] The synthesis method was similar to that of Example 39, and 0.3 g of a white solid was obtained with a yield of 77%.

[0324] 1 H NMR (400 MHz, 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=7.2H z,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] + .

[0325] Example 44

[0326] 5-(2-(6,6-dimethyl-3-azabicyclo[3.1.0]hexan-3-yl)ethyl-8-(6-methoxypyridin-3-yl)-1-(4-(piperazin-1-yl)-3-(trifluoromethyl)phenyl)-1,5-dihydro-4H-[1,2,3]triazolo[4,5-c]quinolin-4-one (CQ349)

[0327] The synthesis method was similar to that of Example 39, and 0.2 g of a white solid was obtained with a yield of 77%.

[0328] 1H NMR (400MHz, CDCl3) 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] + .

[0329] Example 45

[0330] 5-(2-(3-azabicyclo[3.1.0]hexan-3-yl)ethyl-8-(6-methoxypyridin-3-yl)-1-(4-(piperazin-1-yl)-3-(trifluoromethyl)phenyl)-1,5-dihydro-4H-[1,2,3]triazolo[4,5-c]quinolin-4-one (CQ350)

[0331] The synthesis method was similar to that of Example 39, and 0.5 g of a white solid was obtained with a yield of 77%.

[0332] 1H NMR (400MHz, CDCl3) 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] + .

[0333] Example 46

[0334] 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]triazolo[4,5-c]quinolin-4-one (CQ351)

[0335] The synthesis method was similar to that of Example 39, and 0.5 g of a white solid was obtained with a yield of 77%.

[0336] 1 H NMR (400 MHz, 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] + .

[0337] Example 47

[0338] (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]triazolo[4,5-c]quinolin-4-one (CQ352)

[0339] The synthesis method was similar to that of Example 39, and 0.5 g of a white solid was obtained with a yield of 77%.

[0340] 1 H NMR (400MHz, CDCl3) 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] + .

[0341] Example 48

[0342] 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]triazolo[4,5-c]quinolin-4-one (CQ353)

[0343] The synthesis method was similar to that of Example 39, and 0.5 g of a white solid was obtained with a yield of 77%.

[0344] 1 H NMR (400MHz, CDCl3) 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,2 H),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] + .

[0345] Example 49

[0346] 5-(2-(aziridin-1-yl)ethyl)-8-(6-methoxypyridin-3-yl)-1-(4-(piperazin-1-yl)-3-(trifluoromethyl)phenyl)-1,5-dihydro-4H-[1,2,3]triazolo[4,5-c]quinolin-4-one (CQ354)

[0347] The synthesis method was similar to that of Example 39, and 0.5 g of a white solid was obtained with a yield of 77%.

[0348] 1H NMR (400MHz, CDCl3) 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] + .

[0349] Example 50

[0350] 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]triazolo[4,5-c]quinolin-4-one (CQ355)

[0351] Synthesis of Compound 50-2a: In a 100 ml reaction flask, compound 50-1a (5 g, 18.59 mmol) was dissolved in 20 ml of POCl₃ and refluxed at 150°C for 4 hours. After the reaction, the mixture was cooled to room temperature and quenched with ice water. The pH was adjusted to alkaline with sodium bicarbonate solution, 100 ml of water was added, and the mixture was extracted with ethyl acetate (100 ml x 3). The organic layers were combined, dried over anhydrous sodium sulfate, and evaporated under reduced pressure to obtain the crude product, which was directly used in the next step.

[0352] Synthesis of Compound 50-4a: In a 100 ml reaction flask, compound 50-2a (2.88 g, 10 mmol) and compound 50-3a (3.45 g, 12 mmol) were dissolved in 30 ml of acetic acid and stirred at room temperature for 4 hours. After the reaction, 100 ml of water was added and the mixture was extracted with dichloromethane (100 ml x 3). The organic layers were combined, dried over anhydrous sodium sulfate, and evaporated under reduced pressure to obtain the crude product, which was directly used in the next step.

[0353] Synthesis of compound 50-5a: In a 100 ml reaction flask, compound 50-4a (2.69 g, 5 mmol), iron powder (1.4 g, 25 mmol), and ammonium chloride (2.14 g, 40 mmol) were dissolved in 50 ml of EtOH / H₂O (4:1) and refluxed at 80°C overnight. After the reaction, the mixture was filtered through celite, water was added, and the pH was adjusted to alkaline with sodium carbonate. The mixture was extracted with dichloromethane (100 ml x 3). The organic layers were combined, dried over anhydrous sodium sulfate, and evaporated under reduced pressure to obtain the crude product, which was recrystallized to give 2 g of a light yellow solid in 80% yield.

[0354] Synthesis of compound 50-6a: Dissolve 50-5a in 3M HCl at 0°C. After 10 minutes, add 1.2M NaNO2 and react at 45°C for 1 hour. After completion of the reaction, adjust the pH to alkaline with 1M NaOH, filter, and use the resulting solid directly in the next step.

[0355] Synthesis of Compound 50-7a: Compound 50-6a (564 mg, 1 mmol) was dissolved in 30 ml of dichloromethane, cooled to 0°C, and m-CPBA (285 mg, 1.1 mmol) was added. The mixture was allowed to react overnight at room temperature. After completion, the mixture was neutralized with 1 M NaOH and extracted with dichloromethane (100 ml x 3). The organic layers were combined, dried over anhydrous sodium sulfate, and rotary evaporated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (dichloromethane:methanol = 50:1) to afford 160 mg of a yellow solid, in a 29% yield. 1 HNMR(400MHz, CDCl3) 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).

[0356] Synthesis of compound 50-8a: 160 mg of compound 50-7a was dissolved in 10 ml of acetic anhydride and refluxed at 140°C for 4 hours. After the reaction, the acetic anhydride was dried and slurried with (PE:EA=5:5ml) for 30 minutes, then filtered and the obtained solid was directly used for the next reaction.

[0357] Synthesis of compound 50-10a: In a 50 ml reaction flask, compound 50-8a (142 mg, 0.26 mmol), 50-9a N-chloroethylpyrrolidine hydrochloride (53 mg, 0.31 mmol), TBAI (10 mg, 0.026 mmol), and Cs2CO3 (338 mg, 1.04 mmol) were added to 10 ml of DMSO and stirred at 60°C for 4 h. After the reaction was completed, the mixture was cooled to room temperature, 100 ml of water was added, and the mixture was extracted with dichloromethane (100 ml x 3). The organic layers were combined, dried over anhydrous sodium sulfate, and evaporated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (dichloromethane:methanol = 10:1) to obtain 96 mg of a yellow solid, with a yield of 57%.

[0358] Synthesis of Compound 50-11a: In a 50 ml reaction flask, compound 50-10a (90 mg, 0.15 mmol), 10 ml of hydrochloric acid, and 10 ml of ethanol were refluxed at 120°C for 4 h. After the reaction, the mixture was cooled to room temperature, dried by rotary evaporation, and the pH was adjusted to alkaline with sodium hydroxide solution. The mixture was filtered and dried to obtain 84 mg of a yellow solid (93% yield), which was used directly in the next step.

[0359] Synthesis of Compound CQ-355: Under argon atmosphere, compound 50-11a (84 mg, 0.14 mmol), compound 50-12a (35 mg, 0.21 mmol), (PPh3)4Pd (16 mg, 0.014 mmol), and Cs2CO3 (137 mg, 0.42 mmol) were placed in a 25 ml reaction flask. 30 ml of DMF and 10 ml of water were added, and the mixture was stirred at 80°C for 3 h. After the reaction was completed, the mixture was cooled to room temperature, 100 ml of water was added, and the mixture was extracted with dichloromethane (100 ml x 3). The organic layers were combined, dried over anhydrous sodium sulfate, and evaporated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (dichloromethane:methanol = 5:1) to obtain 70 mg of a yellow solid, with a yield of 77%. 1 H NMR (400 MHz, 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] + .

[0360] Example 51

[0361] 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]triazolo[4,5-c]quinolin-4-one (CQ356)

[0362] The synthesis method was similar to that of Example 50, and 0.5 g of a white solid was obtained with a yield of 72%.

[0363] 1 H NMR (400 MHz, 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] + .

[0364] Example 52

[0365] 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]triazolo[4,5-c]quinolin-4-one (CQ357)

[0366] The synthesis method was similar to that of Example 50, and 0.6 g of a white solid was obtained with a yield of 72%.

[0367] 1 H NMR (400 MHz, 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] + .

[0368] Example 53

[0369] (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]triazolo[4,5-c]quinolin-4-one (CQ358)

[0370] The synthesis method was similar to that of Example 50, and 0.5 g of a white solid was obtained with a yield of 75%.

[0371] 1 H NMR (400MHz, CDCl3) 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] + .

[0372] Example 54

[0373] 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)

[0374] Synthesis of Compound 54-2a: In a 100 ml reaction flask, compound 54-1a (5 g, 18.59 mmol) was dissolved in 20 ml of POCl₃ and refluxed at 150°C for 4 hours. After the reaction, the mixture was cooled to room temperature and quenched with ice water. The pH was adjusted to alkaline with sodium bicarbonate solution, 100 ml of water was added, and the mixture was extracted with ethyl acetate (100 ml x 3). The organic layers were combined, dried over anhydrous sodium sulfate, and evaporated under reduced pressure to obtain the crude product, which was directly used in the next step.

[0375] Synthesis of Compound 54-4a: In a 100-ml reaction flask, compound 54-2a (2.88 g, 10 mmol) and compound 54-3a (3.45 g, 12 mmol) were dissolved in 30 ml of acetic acid and stirred at room temperature for 4 hours. After the reaction, 100 ml of water was added and the mixture was extracted with dichloromethane (100 ml x 3). The organic layers were combined, dried over anhydrous sodium sulfate, and evaporated under reduced pressure to obtain the crude product, which was directly used in the next step.

[0376] Synthesis of compound 54-5a: In a 100 ml reaction flask, compound 54-4a (2.69 g, 5 mmol), iron powder (1.4 g, 25 mmol), and ammonium chloride (2.14 g, 40 mmol) were dissolved in 50 ml of EtOH / H₂O (4:1) and refluxed at 80°C overnight. After the reaction, the mixture was filtered through celite, water was added, and the pH was adjusted to alkaline with sodium carbonate. The mixture was extracted with dichloromethane (100 ml x 3). The organic layers were combined, dried over anhydrous sodium sulfate, and evaporated under reduced pressure to obtain the crude product, which was recrystallized to give 2 g of a light yellow solid in 80% yield.

[0377] Synthesis of Compound 54-6a: Compound 54-5a (2.6 g, 5.1 mmol) and CDI (1.66 g, 10.2 mmol) were dissolved in THF, heated to 60°C, and reacted overnight. After the reaction was complete, the solid was filtered, washed with THF, and directly used in the next step.

[0378] Synthesis of Compound 54-7a: Compound 54-6a (1.73 g, 3.3 mmol) and NaH (0.4 g, 9.9 mmol) were dissolved in 20 ml of DMF and allowed to react for 20 min. Iodomethane (1.02 g, 7.2 mmol) was then added at 0°C and stirred at room temperature for 5 h. After the reaction was complete, water was added to quench the reaction, the mixture was filtered, and the solid was dried under vacuum to obtain a white solid. 1 H NMR (400 MHz, 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).

[0379] Synthesis of Compound 54-9a: Compound 54-7a (0.55 g, 1 mmol) and m-CPBA (0.27 g, 1.1 mmol) were dissolved in 10 mL of dichloromethane and stirred overnight at room temperature. After the reaction was complete, the pH was adjusted to alkaline with NaOH and the organic phase was washed with dichloromethane (50 mL x 3). The organic phase was washed with brine, concentrated, and dried to obtain crude compound 54-8a, which was used directly in the next step. Compound 54-8a (0.06 g, 0.1 mmol) was dissolved in 5 mL of acetic anhydride and refluxed at 140°C for 1 h. After the reaction was complete, the solid was dried by evaporation. The solid was washed with EA / PE (1:1, 10 mL), filtered, and dried by evaporation for use in the next step. 1 H NMR (400 MHz, 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(d d,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).

[0380] Synthesis of compound 54-11a: In a 50 ml reaction flask, compound 54-9a (564 mg, 1 mmol), 54-10a N-chloroethylpyrrolidine hydrochloride (255 mg, 1.5 mmol), TBAI (36.9 mg, 0.mmol), and Cs2CO3 (814 mg, 2.5 mmol) were added to 10 ml of DMSO and stirred at 60°C for 4 h. After the reaction was completed, the mixture was cooled to room temperature, 100 ml of water was added, and the mixture was extracted with dichloromethane (100 ml x 3). The organic layers were combined, dried over anhydrous sodium sulfate, and evaporated under reduced pressure to obtain the crude product. The product was purified by column chromatography (dichloromethane:methanol = 10:1) to obtain 500 mg of a yellow solid, with a yield of 79%.

[0381] Synthesis of Compound 54-12a: In a 50 ml reaction flask, compound 54-11a (500 mg, 1 mmol), 10 ml of hydrochloric acid, and 10 ml of ethanol were refluxed at 120°C for 4 h. After the reaction, the mixture was cooled to room temperature, dried by rotary evaporation, and the pH was adjusted to alkaline with sodium hydroxide solution. The mixture was filtered and dried to obtain 400 mg of a yellow solid (85% yield), which was used directly in the next step.

[0382] 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), (PPh3)4Pd (115 mg, 0.1 mmol), and Cs2CO3 (4.8 g, 15 mmol) were placed in a 25 ml reaction flask. 30 ml of DMF and 10 ml of water were added, and the mixture was stirred at 80°C for 3 h. After the reaction was completed, the mixture was cooled to room temperature, 100 ml of water was added, and the mixture was extracted with dichloromethane (100 ml x 3). The organic layers were combined, dried over anhydrous sodium sulfate, and evaporated under reduced pressure to obtain the crude product. The product was purified by column chromatography (dichloromethane:methanol = 5:1) to obtain 308 mg of a yellow solid, with a yield of 64%.

[0383] 1 H NMR (400MHz, CDCl3) 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] + .

[0384] Example 55

[0385] 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)

[0386] The synthesis method was similar to that of Example 54, and 0.5 g of a white solid was obtained with a yield of 77%.

[0387] 1 H NMR (400 MHz, 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] + .

[0388] Example 56

[0389] 8-(6-amino-5-(trifluoromethyl)pyridin-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 (CQ361)

[0390] The synthesis method was similar to that of Example 54, and 0.5 g of a white solid was obtained with a yield of 77%.

[0391] 1 H NMR (400 MHz, 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] +

[0392] Example 57

[0393] 8-(6-methoxypyridin-3-yl)-1-(4-(piperazin-1-yl)-3-(trifluoromethyl)phenyl)-5-(2-(pyrrol-1-yl)ethyl)imidazo[1,2-a]quinoxalin-4(5H)-one (CQ362)

[0394] Synthesis of Compound 57-3a: Compound 57-1a (3.95 g, 35.27 mmol) was dissolved in 100 ml of DMF, followed by the addition of Compound 57-2a (6.7 g, 35.27 mmol), HOBT (7.15 g, 52.91 mmol), and EDCI (10.14 g, 52.91 mmol). The mixture was allowed to react at room temperature for 21 h. After completion of the reaction, the mixture was extracted with ethyl acetate (100 ml x 3). The combined organic layers were dried over anhydrous sodium sulfate, and purified by column chromatography (DCM) to yield 2.8 g (28% yield). 1 H NMR (400MHz, CDCl3) δ11.06 (s, 1H), 9.28 (s, 1H), 8.28 (t, J = 8.8Hz, 1H), 7.34 (m, 2H), 7.24 (s, 2H).

[0395] Synthesis of Compound 57-4a: Dissolve compound 57-3a (2.7 g, 9.5 mmol) in 40 mL of DMA, then add NaH (494 mg, 12.4 mmol) and reflux overnight at 170°C. After the reaction is complete, add 100 mL of water to precipitate the solid, spin-dry it, and use it directly in the next reaction.

[0396] Synthesis of compound 57-6a: Compound 57-4a (1.71 g, 6.48 mmol), compound 57-5a (1.46 g, 9.72 mmol), cesium carbonate (6.3 g, 19 mmol), and (PPh3)2Cl2Pd (455 mg, 0.65 mmol) were dissolved in a mixed solvent of dioxane: water = 30 ml:10 ml, and the mixture was reacted at 100°C overnight. After the reaction was completed, 100 ml of water was added and the product, compound 57-6a, was filtered and used directly in the next reaction.

[0397] Synthesis of Compound 57-7a: Compound 57-6a (1.44 g, 4.93 mmol) was dissolved in 60 ml of DMF. NBS (1.32 g, 7.39 mmol) was slowly added. The reaction was allowed to proceed at room temperature for 3 h, then heated to 80°C and allowed to react overnight. After completion of the reaction, the product was directly filtered to obtain 600 mg of the product, with a yield of 33%. 1 HNMR (400 MHz, 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).

[0398] Synthesis of compound 57-9a: In a 100 ml reaction flask, compound 57-7a (571 mg, 1.54 mmol), compound 57-8a (866 mg, 2.31 mmol), (PPh3)2Cl2Pd (108 mg, 0.15 mmol), and cesium carbonate (1.5 g, 4.62 mmol) were dissolved in a mixed solvent of dioxane: water = 30 ml:10 ml, and the mixture was reacted at 100°C overnight. After the reaction was completed, 100 ml of water was added and the product was filtered off. 1 H NMR (400MHz, CDCl3) 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).

[0399] Synthesis of compound 57-11a: In a 50 ml reaction flask, compound 57-9a (256 mg, 0.38 mmol), N-chloroethylpyrrolidine hydrochloride (78 mg, 0.46 mmol), TBAI (14 mg, 0.038 mmol), and Cs2CO3 (495 mg, 1.52 mmol) were added to 10 ml of DMSO and stirred at 60°C for 4 h. After the reaction was completed, the mixture was cooled to room temperature, 100 ml of water was added, and the mixture was extracted with dichloromethane (100 ml x 3). The organic layers were combined, dried over anhydrous sodium sulfate, and evaporated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (dichloromethane:methanol = 10:1) to obtain 152 mg of a yellow solid, with a yield of 56%.

[0400] Synthesis of compound CQ-362: In a 50 ml reaction flask, compound 57-11a was dissolved in 3 ml of TFA and 10 ml of DCM and stirred at room temperature for 4 h. After completion of the reaction, the mixture was spin-dried and the pH was adjusted to alkaline with sodium bicarbonate solution. The mixture was then filtered and spin-dried. The mixture was extracted with dichloromethane (100 ml x 3). The organic layers were combined, dried over anhydrous sodium sulfate, and evaporated under reduced pressure to obtain a crude product. The crude product was purified by column chromatography (dichloromethane:methanol = 10:1) to obtain 100 mg of a yellow solid, with a yield of 81%. 1 H NMR (400 MHz, 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,1 H),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] + .

[0401] Example 58

[0402] 8-(6-Methoxypyridin-3-yl)-1-(4-(piperazin-1-yl)-3-(trifluoromethyl)phenyl)-5-(2-(pyrrol-1-yl)ethyl)-1,5-dihydro-4H-pyrazolo[4,3-c]quinolin-4-one (CQ363)

[0403] Synthesis of Compound 58-2a: In a 100 ml reaction flask, compound 58-1a (5 g, 20.32 mmol) and CDI (3.62 g, 22.36 mmol) were added to 40 ml of THF and stirred at room temperature for 1 h. EtO₂CCH₂CO₂K (5.19 g, 30.48 mmol) and magnesium chloride (1.93 g, 20.32 mmol) were then added to the mixture and refluxed overnight. After the reaction, the mixture was cooled to room temperature and washed with 10% potassium bisulfate and saturated sodium chloride solutions, respectively. The mixture was extracted with ethyl acetate (100 ml x 3). The organic layers were combined, dried over anhydrous sodium sulfate, and evaporated under reduced pressure to obtain the crude compound, which was used directly in the next step.

[0404] Synthesis of Compound 58-4a: In a 100 mL reaction flask, Compound 58-2a (1.6 g, 5.06 mmol) and Compound 58-3a (3.36 mL, 25.31 mmol) were added to 20 mL of toluene and refluxed for 4 h. After the reaction was complete, the mixture was cooled to room temperature and the solvent removed to afford crude Compound 58-4a, which was used directly in the next reaction.

[0405] Synthesis of Compound 58-6a: In a 100 mL reaction flask, Compound 58-4a (1.88 g, 5.06 mmol) and Compound 58-5a (1.25 g, 5.06 mmol) were added to 20 mL of anhydrous ethanol and refluxed overnight. After the reaction was complete, the mixture was cooled until a solid precipitated. The crude product of Compound 58-6a was filtered and used directly in the next reaction.

[0406] Synthesis of compound 58-7a: In a 100 ml reaction flask, compound 58-6a (1 g, 1.93 mmol), iron powder (0.54 g, 9.65 mmol), and ammonium chloride (0.83 g, 15.44 mmol) were dissolved in 20 ml of EtOH / H₂O (4:1) and refluxed at 80°C overnight. After the reaction, the mixture was filtered through celite, water was added, and the pH was adjusted to alkaline with sodium carbonate. The mixture was extracted with dichloromethane (100 ml x 3). The organic layers were combined, dried over anhydrous sodium sulfate, and evaporated under reduced pressure to obtain the crude product. The product was recrystallized to obtain compound 58-7a as a light yellow solid (0.7 g, 74% yield). 1 H NMR (400 MHz, 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,1 H),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] + .

[0407] Synthesis of Compound 58-8a: In a 50 ml reaction flask, compound 58-7a (0.5 g, 1.01 mmol) was dissolved in 10 ml of EtOH. 10 d of concentrated hydrochloric acid was added dropwise at 70°C and allowed to react overnight. After the reaction was complete, the mixture was cooled to room temperature and filtered to obtain the crude product, compound 58-8a, which was used directly in the next reaction.

[0408] Synthesis of compound 58-9a: Compound 58-8a (0.44 g, 1 mmol), (6-methoxypyridin-3-yl)boronic acid (0.23 g, 1.5 mmol), (PPh3)Cl2Pd (70 mg, 0.1 mmol), and Cs2CO3 (0.65 g, 2 mmol) were added to a 25 ml reaction flask. Ar was then added, and 12 ml of DMF / H2O (3:1) was added. The reaction was refluxed at 80°C overnight. After completion of the reaction, the reaction was quenched with water and filtered to obtain the crude product, compound 58-9a, which was used directly in the next step.

[0409] Synthesis of compound 58-11a: Compound 58-9a (0.47 g, 1 mmol), BOC piperazine (0.74 g, 4 mmol), and Cs2CO3 (0.65 g, 2 mmol) were added to a 25 ml reaction flask. 10 ml of DMF was then added and the mixture was refluxed at 140°C overnight. After completion of the reaction, the mixture was quenched with water and filtered. The filter cake was purified by column chromatography (dichloromethane:methanol:triethylamine = 100:10:1 (v / v)) to afford compound 58-11a as a white solid (0.2 g, 38% yield).

[0410] Synthesis of compound 58-12a: In a 50 ml reaction flask, compound 58-11a (235 mg, 0.38 mmol), N-chloroethylpyrrolidine hydrochloride (78 mg, 0.46 mmol), TBAI (14 mg, 0.038 mmol), and Cs2CO3 (495 mg, 1.52 mmol) were added to 10 ml of DMSO and stirred at 60°C for 4 h. After the reaction was completed, the mixture was cooled to room temperature, 100 ml of water was added, and the mixture was extracted with dichloromethane (100 ml x 3). The organic layers were combined, dried over anhydrous sodium sulfate, and evaporated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (dichloromethane:methanol = 10:1) to afford 152 mg of a yellow solid, in a yield of 56%.

[0411] Synthesis of Compound CQ-363: In a 50 mL reaction flask, compound 58-12a (120 mg, 0.17 mmol) was dissolved in 20 mL of DCM, followed by the addition of 5 mL of TFA and the reaction mixture for 4 h. After completion of the reaction, the solvent was evaporated, the pH was adjusted to alkaline with sodium bicarbonate solution, and the mixture was filtered and extracted with dichloromethane (100 mL x 3). The organic layers were combined, dried over anhydrous sodium sulfate, and evaporated under reduced pressure to obtain the crude product. Purification by column chromatography (dichloromethane:methanol = 10:1) afforded 80 mg of a yellow solid, a yield of 78%. 1H NMR (400MHz, CDCl3) 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),3.1 5–3.12(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] + .

[0412] Example 59

[0413] 8-(6-Methoxypyridin-3-yl)-1-(4-(piperazin-1-yl)-3-(trifluoromethyl)phenyl)-5-(2-(pyrrol-1-yl)ethyl)-1,5-dihydro-4H-imidazo[4,5-c]quinolin-4-one (CQ364)

[0414] Synthesis of Compound 59-2a: Compound 59-1a (5 g, 18.59 mmol) was added to a 100 ml reaction flask, followed by the addition of 20 ml of phosphorus oxychloride. The mixture was refluxed at 110°C for 4 h. After completion of the reaction, the mixture was cooled to 0°C, quenched with ice water, and the pH was adjusted to alkaline with saturated sodium bicarbonate. The mixture was then extracted with ethyl acetate (100 ml x 3). The organic layers were combined, dried over anhydrous sodium sulfate, and evaporated under reduced pressure to obtain crude compound 59-2a, which was used directly in the next step.

[0415] Synthesis of Compound 59-4a: In a 100 ml reaction flask, compound 59-3a (3.45 g, 12 mmol) was dissolved in 30 ml of glacial acetic acid, followed by the slow addition of compound 59-2a (2.88 g, 10 mmol). The mixture was stirred at room temperature for 3 h. After completion of the reaction, the mixture was quenched with water and extracted with dichloromethane (100 ml x 3). The mixture was washed with saturated sodium chloride. The organic layers were combined, dried over anhydrous sodium sulfate, and evaporated under reduced pressure to obtain a crude product. The product was purified by column chromatography (dichloromethane) to afford 4.04 g of compound 59-4a as a yellow solid in a 75% yield. 1 H NMR (400 MHz, 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] + .

[0416] Synthesis of compound 59-5a: In a 250 ml reaction flask, compound 59-4a (2.50 g, 4.64 mmol), iron powder (1.29 g, 23.19 mmol), and ammonium chloride (1.98 g, 37.12 mmol) were dissolved in 50 ml of EtOH / H₂O (4:1) and refluxed at 80°C overnight. After the reaction, the mixture was filtered through celite, water was added, and the pH was adjusted to alkaline with sodium carbonate. The mixture was extracted with dichloromethane (100 ml x 3). The organic layers were combined, dried over anhydrous sodium sulfate, and evaporated under reduced pressure to obtain the crude product. The product was recrystallized to obtain 2.15 g of compound 59-5a as a light yellow solid in a 91% yield. 1 H NMR (400 MHz, 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] + .

[0417] Synthesis of compound 59-6a: In a 50 ml reaction flask, compound 59-5a (0.6 g, 1.18 mmol) was added to 12 ml of triethyl orthoformate and refluxed at 150°C for 3 h. After completion of the reaction, the crude product was evaporated under reduced pressure and purified by column chromatography (dichloromethane:methanol = 10:1) to afford compound 59-6a as a white solid (0.5 g, 82% yield). 1 H NMR (400 MHz, DMSO-d6 )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] + .

[0418] Synthesis of Compound 59-7a: In a 25 ml reaction flask, compound 59-6a (0.52 g, 1.0 mmol) was added to 0.22 ml of 30% hydrogen peroxide and 3 ml of glacial acetic acid and stirred at 80°C overnight. The mixture was cooled to room temperature, concentrated by rotary evaporation under reduced pressure, neutralized with saturated sodium bicarbonate, filtered, and dried to obtain the intermediate. The intermediate was then added to 2.5 ml of acetic anhydride and refluxed for 1 hour. The crude product was then evaporated under reduced pressure and purified by column chromatography (dichloromethane:methanol = 10:1) to afford compound 59-7a as a white solid (0.32 g, 60% yield). 1 H NMR (400 MHz, 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] + .

[0419] Synthesis of compound 59-8a: In a 50 ml reaction flask, compound 59-7a (533 mg, 1 mmol), N-chloroethylpyrrolidine hydrochloride (255 mg, 1.5 mmol), TBAI (36.9 mg, 0.01 mmol), and Cs2CO3 (814 mg, 2.5 mmol) were added to 10 ml of DMSO and stirred at 60°C for 4 h. After the reaction was completed, the mixture was cooled to room temperature, 100 ml of water was added, and the mixture was extracted with dichloromethane (100 ml x 3). The organic layers were combined, dried over anhydrous sodium sulfate, and evaporated under reduced pressure to obtain the crude product. The product was purified by column chromatography (dichloromethane:methanol = 10:1) to obtain 500 mg of a yellow solid, with a yield of 79%.

[0420] Synthesis of compound 59-9a: In a 50 ml reaction flask, compound 59-8a (630 mg, 1 mmol), 10 ml of hydrochloric acid, and 10 ml of ethanol were refluxed at 120°C for 4 h. After the reaction, the mixture was cooled to room temperature, dried, and the pH was adjusted to alkaline with sodium hydroxide solution. The solid was filtered, dried, and used directly in the next step to obtain 400 mg of a yellow solid in a 69% yield.

[0421] Synthesis of Compound CQ-364: Under argon atmosphere, compound 59-9a (294 mg, 0.5 mmol), 2-methoxy-5-boronic acid pyridine (114 mg, 0.75 mmol), (PPh3)4Pd (11.5 mg, 0.01 mmol), and Cs2CO3 (480 mg, 1.5 mmol) were placed in a 25 ml reaction flask. 30 ml of DMF and 10 ml of water were added, and the mixture was stirred at 80°C for 3 h. After the reaction was completed, the mixture was cooled to room temperature, 100 ml of water was added, and the mixture was extracted with dichloromethane (100 ml x 3). The organic layers were combined, dried over anhydrous sodium sulfate, and evaporated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (dichloromethane:methanol = 5:1) to obtain 200 mg of a yellow solid, in a 65% yield. 1 H NMR (400 MHz, 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,1 H),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] + .

[0422] Example 60

[0423] 8-(6-Methoxypyridin-3-yl)-1-(4-(piperazin-1-yl)-3-(trifluoromethyl)phenyl)-5-(2-(pyrrol-1-yl)ethyl)-1,5-dihydro-4H-imidazo[1,5-a]quinoxalin-4(5H)-one (CQ365)

[0424] Synthesis of compound 60-2a: In a 500 ml reaction flask, compound 60-1a (24 g, 100 mmol), N-Boc piperazine (22.35 g, 120 mmol), and K2CO3 (20.73 g, 150 mmol) were added to 100 ml of DMSO and heated at 120°C for 24 h. After completion of the reaction, the mixture was quenched with water and extracted with ethyl acetate (200 ml x 3). The mixture was washed sequentially with water and saturated sodium chloride. The organic layers were combined, dried over anhydrous sodium sulfate, and evaporated under reduced pressure to obtain the crude product. The product was purified by column chromatography (ethyl acetate:petroleum ether = 1:10) to afford 13 g of a white solid in a 31% yield.

[0425] Synthesis of Compound 60-3a: At -78°C under Ar protection, compound 60-2a (6 g, 14.67 mmol) was added to a 250 mL reaction flask. 70 mL of toluene / THF (1:1) was then added and the reaction was allowed to proceed for 1 hour. 3.7 mL of triethyl borate was then slowly added dropwise to the mixture, and the reaction was continued for 3 hours. The temperature was then slowly raised to 0°C, 20 mL of saturated ammonium chloride was added, and the mixture was stirred at room temperature for 30 minutes. After the reaction, the mixture was extracted with ethyl acetate (100 mL x 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 the crude product, which was used directly in the next step.

[0426] Synthesis of compound 60-5a: Compound 60-3a (5.6 g, 15 mmol), compound 60-4a (1.47 g, 10 mmol), (PPh3)2Cl2Pd (700 mg, 1 mmol), and Cs2CO3 (6.5 g, 20 mmol) were added to a 250 ml reaction flask. Ar was then added, and 100 ml of 1,4-dioxane / H2O (4:1) was added. The reaction was refluxed at 100°C overnight. After the reaction was completed, the solvent was removed under reduced pressure, water was added, and extraction with ethyl acetate (100 ml x 3) was performed. The ethyl acetate was removed under reduced pressure, and the mixture was washed with 30 ml of ethyl acetate / petroleum ether (1:2) to obtain crude compound 60-5a, which was used directly in the next reaction.

[0427] Synthesis of compound 60-7a: In a 250 ml reaction flask, compound 60-5a (4 g, 10 mmol), compound 60-6a (2.6 g, 12 mmol), and Cs2CO3 (4.88 g, 15 mmol) were added to 80 ml of acetonitrile and refluxed overnight. After the reaction, the solvent was removed under reduced pressure, water was added, and the mixture was extracted with ethyl acetate (100 ml x 3). The mixture was washed with saturated sodium chloride, and the organic layers were combined, dried over anhydrous sodium sulfate, and rotary evaporated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (ethyl acetate:petroleum ether = 1:1.5) to obtain 4.7 g of a light yellow solid, with a yield of 79%.

[0428] Synthesis of compound 60-8a: In a 250 ml reaction flask, compound 60-7a (6 g, 10 mmol), iron powder (2.79 g, 50 mmol), and ammonium chloride (4.28 g, 80 mmol) were dissolved in 80 ml of EtOH / H₂O (4:1) and refluxed at 80°C overnight. After the reaction, the mixture was filtered through celite, water was added, and the pH was adjusted to alkaline with sodium carbonate. The mixture was extracted with dichloromethane (100 ml x 3). The organic layers were combined, dried over anhydrous sodium sulfate, and evaporated under reduced pressure to obtain the crude product, which was recrystallized to give 4.64 g of a light yellow solid (82% yield).

[0429] Synthesis of compound 60-9a: In a 25 ml reaction flask, compound 60-8a (0.56 g, 1 mmol) and CDI (0.24 g, 1.5 mmol) were added to 10 ml of 1,2-dichlorobenzene and refluxed for 3 h. After completion of the reaction, the product was wet loaded onto a column and purified by column chromatography (ethyl acetate:petroleum ether = 3:1) to afford 0.29 g of a white solid in a 50% yield.

[0430] Synthesis of compound 60-11a: Compound 60-9a (0.59 g, 1 mmol), compound 60-10a (0.23 g, 1.5 mmol), (PPh3)2Cl2Pd (70 mg, 0.1 mmol), and Cs2CO3 (0.65 g, 2 mmol) were added to a 25 ml reaction flask, protected with Ar, and then 20 ml of 1,4-dioxane / H2O (4:1) was added. The reaction was refluxed at 100°C overnight. After the reaction was completed, the solvent was removed under reduced pressure, water was added, and the mixture was extracted with ethyl acetate (100 ml x 3). The organic layers were combined, dried over anhydrous sodium sulfate, and rotary evaporated under reduced pressure to obtain the crude product, which was used directly in the next reaction.

[0431] Synthesis of compound 60-12a: In a 50 ml reaction flask, compound 60-11a (620 mg, 1 mmol), N-chloroethylpyrrolidine hydrochloride (255 mg, 1.5 mmol), TBAI (36.9 mg, 0.01 mmol), and Cs2CO3 (814 mg, 2.5 mmol) were added to 10 ml of DMSO and stirred at 60°C for 4 h. After the reaction was completed, the mixture was cooled to room temperature, 100 ml of water was added, and the mixture was extracted with dichloromethane (100 ml x 3). The organic layers were combined, dried over anhydrous sodium sulfate, and evaporated under reduced pressure to obtain the crude product. The product was purified by column chromatography (dichloromethane:methanol = 10:1) to obtain 480 mg of a yellow solid, with a yield of 67%.

[0432] Synthesis of Compound CQ-365: In a 25-ml reaction flask, compound 60-12a (0.72 g, 1 mmol) was dissolved in 10 ml of dichloromethane. 3 ml of trifluoroacetic acid was added and the mixture was stirred at room temperature for 1 hour. After completion of the reaction, the solvent was removed under reduced pressure, the pH was adjusted to alkaline with saturated sodium bicarbonate, and the mixture was filtered. The filter cake was purified by column chromatography (dichloromethane:methanol = 5:1) to afford 0.4 g of a white solid in a 65% yield. 1 H NMR (400MHz, CDCl3) 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] + .

[0433] Example 61

[0434] In vitro antitumor activity of the compounds: The MKN-1 (human gastric cancer cell) cell line, U87MG (human glioblastoma) cell line, and OCILY3 (diffuse large B-cell lymphoma) cell line used in this experiment were obtained from ATCC, Shanghai Cell Bank, and the Cell Bank of the Committee for Typical Culture Collection of the Chinese Academy of Sciences, respectively. 3,000-10,000 cells / well of these cells were seeded into 96-well plates. After overnight incubation, various concentrations of the compounds (0-30 μM) were added and treated for 72 hours. CCK8 reagent was then added, and incubation continued for 1-3 hours. The absorbance at 450 nm and 650 nm was then measured using a super microplate reader. The half-maximal inhibitory concentration (IC50) was calculated using GraphPad Prism 5.0 software.

[0435] The results showed that the tricyclic heterocyclic compound of the present invention can significantly inhibit the proliferation of MKN-1, U87MG and OCILY3 tumor cells. Specific data are shown in Table 1.

[0436] Table 1 In vitro anti-tumor cell activity of compounds (IC 50 / μM)

[0437] The technical features of the above-described embodiments can be combined arbitrarily. To make the description concise, not all possible combinations of the technical features in the following embodiments are described. However, as long as there is no contradiction in the combination of these technical features, they should be considered to be within the scope of this specification.

[0438] The above-described embodiments merely illustrate several implementations of the present invention, and while their descriptions are relatively specific and detailed, they should not be construed as limiting the scope of the present invention. It should be noted that a person skilled in the art would be able to make numerous variations and improvements without departing from the spirit of the present invention, all of which fall within the scope of protection of the present invention. Therefore, the scope of protection of the present invention shall be determined by the appended claims.

Claims

1. A tricyclic heterocyclic compound having the structure represented by formula (I) or a pharmaceutically acceptable salt or stereoisomer thereof: in, A, B, D and E are independently selected from: N, NR 10 , C, CR 11 Or C=O, and the circular dashed line in the ring where A, B, D and E are located indicates that every two adjacent ring atoms in the ring are connected by a single bond or a double bond to obtain a chemically stable structure; X is selected from: NR2; X1 and X2 are independently selected from: N, or CR9'; X3, X4, and X5 are independently selected from: N, or CR5; X6, X7, X8, and X9 are independently selected from: N, or CR6; n is selected from: 1, 2, 3, 4, 5; R1 and R2 are independently selected from: H, C1-C 18 Alkyl, C3~C8 cycloalkyl, 3~8 membered heterocycloalkyl, C1~C8 acyl, sulfonyl, C6~C 18 Aryl, C6~C 18 Aryl-substituted C1-C8 alkyl, 5-18 membered heteroaryl, and R1 and R2 are not H at the same time; or R1, R2 and the X connected thereto together form a 4-8 membered R 12 a substituted or unsubstituted heterocyclic group; Each R3 and R4 are independently selected from the group consisting of: H, halogen, hydroxy, C1-C8 alkyl, C3-C8 cycloalkyl; or R3, R4 and the carbon atom to which they are attached together form a 3-8 membered cycloalkyl; or R3, R4 and the carbon atom to which they are attached together form C=O; or R3, R2 and the carbon atom to which they are attached and X together form a 4-8 membered R1-substituted or unsubstituted heterocyclic group; Each R5 is independently selected from the group consisting of: H, hydroxyl, amino, cyano, nitro, halogen, trifluoromethyl, C1-C6 alkoxy, C1-C6 alkyl, C1-C6 alkylamino, and C3-C6 cycloalkyl; Each R6 is independently selected from the group consisting of: H, hydroxyl, amino, cyano, nitro, halogen, trifluoromethyl, C1-C6 alkoxy, C1-C6 alkyl, C1-C6 alkylamino, and C3-C6 cycloalkyl; R7 and R8 are independently selected from: H, C1-C8 alkyl, R 13 Substituted C1-C8 alkyl, C3-C8 cycloalkyl, 3-18 membered heterocycloalkyl, C1-C8 acyl, alkenyl acyl, sulfonyl, 5-18 membered heteroaryl; or R7, R8 and the nitrogen atom to which they are attached together form R 16 a substituted or unsubstituted 3-10 membered heterocyclic group, or R7, R8 and the nitrogen atom to which they are attached together form R 16 a substituted or unsubstituted 5- to 10-membered heteroaryl group; R9 is selected from: H, halogen, C1-C 18 Alkyl, halogen substituted C1~C 18 Alkyl, C3~C 18 Cycloalkyl, 3-18 membered heterocycloalkyl, C1-C 18 Alkoxy, halogen substituted C1~C 18 Alkoxy, C1~C 18 Alkylamino, amino, hydroxyl, cyano, nitro, Ester group, amide group, sulfonyl group, sulfonylamino group, C6~C 18 Aryl, C6~C 18 Aryl-substituted C1~C 18 Alkyl, 5- to 18-membered heteroaryl; Each R9' is independently selected from: H, halogen, C1-C 18 Alkyl, halogen substituted C1~C 18 Alkyl, C3~C 18 Cycloalkyl, 3-18 membered heterocycloalkyl, C1-C 18 Alkoxy, halogen substituted C1~C 18 Alkoxy, C1~C 18 Alkylamino, amino, hydroxyl, cyano, nitro, ester, amide, sulfonyl, sulfonylamino, C6~C 18 Aryl, C6~C 18 Aryl-substituted C1~C 18 Alkyl, 5-18 membered heteroaryl; or R9 and an R9' together form a 3-10 membered heterocyclic group; or R9 and an R9' together form a 5-10 membered heteroaryl; R 10 Selected from: H, C1~C 18 alkyl; R 11 Selected from: H, halogen, C1~C 18 Alkyl, C3~C 18 Cycloalkyl, 3-18 membered heterocycloalkyl, C1-C 18 Alkoxy, C1~C 18 Alkylamino, amino, hydroxyl, cyano, nitro, ester, amide, sulfonyl, sulfonylamino, C6~C 18 Aryl, C6~C 18 Aryl-substituted C1~C 18 Alkyl, 5- to 18-membered heteroaryl; R 12 Selected from: H, C1~C 18 Alkyl, hydroxy substituted C1~C 18 Alkyl, C1~C 18 Alkoxy-substituted C1~C 18 Alkyl, halogen substituted C1~C 18 Alkyl, C3~C 18 Cycloalkyl, 3-18 membered heterocycloalkyl, C1-C 18 Alkoxy, C1~C 18 Alkylamino, C1-C8 acyl, halogen, amino, hydroxyl, cyano, nitro, ester, amide, sulfonyl, sulfonylamino, C6-C 18 Aryl, C6~C 18 Aryl-substituted C1~C 18 Alkyl, 5-18 membered heteroaryl; or R 12 It forms a carbonyl group with the attached carbon atom; R 13 Selected from: hydroxyl, C1-C8 alkoxy, R 14 and R 15 are independently selected from: H, C1-C8 alkyl, or R 14 、R 15 Together with the N atom to which it is attached, it forms R 16 a substituted or unsubstituted 3-10 membered heterocyclic group; R 16 Selected from: H, C1~C 18 Alkyl, hydroxy substituted C1~C 18 Alkyl, C1~C 18 Alkoxy-substituted C1~C 18 Alkyl, C3~C 18 Cycloalkyl, 3-18 membered heterocycloalkyl, C1-C 18 Alkoxy, C1~C 18 Alkylamino, C1-C8 acyl, amino, hydroxyl, cyano, nitro, ester, amide, sulfonyl, sulfonylamino, C6-C 18 Aryl, C6~C 18 Aryl-substituted C1~C 18 Alkyl, 5-18 membered heteroaryl; or R 16 It forms a carbonyl group with the attached carbon atom.

2. The tricyclic heterocyclic compound or a pharmaceutically acceptable salt or a stereoisomer thereof according to claim 1, characterized in that: It has the structure shown in the following formula (II): Wherein, n1 is selected from: 0, 1, 2, 3; n2 is selected from: 0, 1, 2, 3, 4; D and E are independently selected from: N, CR 11 .

3. The tricyclic heterocyclic compound or a pharmaceutically acceptable salt or a stereoisomer thereof according to claim 1, characterized in that: It has the structure shown in the following formula (III): Wherein, n1 is selected from: 0, 1, 2, 3; n2 is selected from: 0, 1, 2, 3, 4; D and E are independently selected from: N, CR 11 .

4. The tricyclic heterocyclic compound or a pharmaceutically acceptable salt or a stereoisomer thereof according to claim 1, wherein: It has the structure shown in the following formula (IV): Wherein, n1 is selected from: 0, 1, 2, 3; n2 is selected from: 0, 1, 2, 3, 4; B is selected from: N, CR 11 .

5. The tricyclic heterocyclic compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, characterized in that: One of X1 and X2 is N or CH, and the other is CR9'.

6. The tricyclic heterocyclic compound or a pharmaceutically acceptable salt or a stereoisomer thereof according to any one of claims 1 to 5, characterized in that: R1 and R2 are independently selected from the group consisting of: H, C1-C6 alkyl, C3-C6 cycloalkyl, 5-8 membered heterocycloalkyl, C1-C3 acyl, sulfonyl, C6-C 10 Aryl, C6~C 10 Aryl-substituted C1-C3 alkyl, 5-8 membered heteroaryl; or R1, R2 and the X connected thereto together form a 4-8 membered R 12 a substituted or unsubstituted heterocyclic group; R 12 Selected from: H, C1-C6 alkyl, C1-C6 alkyl substituted with hydroxyl, C1-C6 alkyl substituted with C1-C6 alkoxy, C1-C6 alkyl substituted with halogen, C3-C6 cycloalkyl, 3-8 membered heterocycloalkyl, C1-C6 alkoxy, C1-C6 alkylamino, C1-C3 acyl, halogen, amino, hydroxyl, cyano, nitro, ester, amide, sulfonyl, sulfonylamino, C6-C 10 Aryl, C6~C 10 Aryl-substituted C1-C6 alkyl, 5-10 membered heteroaryl; or R 12 It forms a carbonyl group with the attached carbon atom.

7. The tricyclic heterocyclic compound or a pharmaceutically acceptable salt or a stereoisomer thereof according to claim 6, characterized in that: R1, R2 and the X connected thereto together form the following structure: Wherein, n3 is selected from: 0, 1, 2, 3, 4; R1 is selected from: H, C1-C6 alkyl; R2 is selected from: C1-C6 alkyl; R 12 Selected from: H, C1-C6 alkyl; R' 12 Selected from: C1-C6 alkyl substituted by methoxy, C1-C6 alkyl substituted by halogen, halogen, C1-C6 alkoxy.

8. The tricyclic heterocyclic compound or a pharmaceutically acceptable salt or a stereoisomer thereof according to claim 7, wherein: R1, R2 and the X connected thereto together form the following structure: Wherein, n3 is selected from: 0, 1, 2, 3; R1 is selected from: H, methyl, ethyl; R2 is selected from: methyl, ethyl; R' 12 Selected from: methoxy-substituted methyl, halogen-substituted methyl, halogen, methoxy, ethoxy.

9. The tricyclic heterocyclic compound or a pharmaceutically acceptable salt or a stereoisomer thereof according to any one of claims 1 to 5, characterized in that: R3 and R4 are both H, and n is selected from: 2, 3, 4.

10. The tricyclic heterocyclic compound or a pharmaceutically acceptable salt or a stereoisomer thereof according to any one of claims 1 to 5, characterized in that: Each R5 is independently selected from the group consisting of: H, hydroxy, amino, cyano, nitro, halogen, trifluoromethyl, methoxy, ethoxy, n-propoxy, isopropoxy, methyl, ethyl, n-propyl, isopropyl, cyclopentyl, and cyclohexyl.

11. The tricyclic heterocyclic compound or a pharmaceutically acceptable salt or a stereoisomer thereof according to any one of claims 1 to 5, characterized in that: Each R6 is independently selected from the group consisting of: H, hydroxy, amino, cyano, nitro, halogen, trifluoromethyl, methoxy, ethoxy, n-propoxy, isopropoxy, methyl, ethyl, n-propyl, isopropyl, cyclopentyl, and cyclohexyl.

12. The tricyclic heterocyclic compound or a pharmaceutically acceptable salt or a stereoisomer thereof according to any one of claims 1 to 5, characterized in that: R7 and R8 are independently selected from: C1-C3 alkyl; or R7, R8 and the nitrogen atom to which they are connected together form R 16 a substituted or unsubstituted 5- to 8-membered heterocyclic group; R 16 Selected from: H, C1-C6 alkyl, C1-C6 alkyl substituted with hydroxyl, C1-C6 alkyl substituted with C1-C6 alkoxy, C3-C8 cycloalkyl, 3-8 membered heterocycloalkyl, C1-C6 alkoxy, C1-C6 alkylamino, C1-C3 acyl, C6-C 10 Aryl, C6~C 10 Aryl-substituted C1-C6 alkyl, 5-10 membered heteroaryl; or R 16 It forms a carbonyl group with the attached carbon atom.

13. The tricyclic heterocyclic compound or a pharmaceutically acceptable salt or a stereoisomer thereof according to claim 12, wherein: R 7 、R 8 Together with the N atoms connected to it, it forms the following structure: R 16 Selected from: H, C1-C3 alkyl, C1-C3 acyl.

14. The tricyclic heterocyclic compound or a pharmaceutically acceptable salt or a stereoisomer thereof according to any one of claims 1 to 5, characterized in that: R9 is selected from the group consisting of: H, halogen, C1-C6 alkyl, halogen-substituted C1-C6 alkyl, C3-C6 cycloalkyl, 3-8 membered heterocycloalkyl, C1-C6 alkoxy, halogen-substituted C1-C6 alkoxy, C1-C6 alkylamino, amino, hydroxyl, cyano, nitro, ester, amide, sulfonyl, sulfonylamino, C6-C 10 Aryl, C6~C 10 Aryl-substituted C1-C6 alkyl, 5-10 membered heteroaryl; Each R9' is independently selected from the group consisting of: H, halogen, C1-C6 alkyl, halogen-substituted C1-C6 alkyl, C3-C6 cycloalkyl, 3-8 membered heterocycloalkyl, C1-C6 alkoxy, halogen-substituted C1-C6 alkoxy, C1-C6 alkylamino, amino, hydroxyl, cyano, nitro, ester, amide, sulfonyl, sulfonylamino, C6-C 10 Aryl, C6~C 10 Aryl-substituted C1-C6 alkyl, 5-10 membered heteroaryl; or R9 and one R9' together form a 5-8 membered heterocyclic group; Alternatively, R9 and one R9' together form a 5-8 membered heteroaryl group.

15. The tricyclic heterocyclic compound or a pharmaceutically acceptable salt or a stereoisomer thereof according to claim 14, characterized in that: R9 is selected from the group consisting of methoxy, trifluoromethoxy, difluoromethoxy, dimethylamino, halogen, and amino; Each R9' is independently selected from: H, halogen, methyl, methoxy, trifluoromethyl, cyano; or R9 and one R9' together form a 5-6 membered oxygen-containing heterocyclic group; Alternatively, R9 and one R9' together form a 5-6 membered nitrogen-containing heteroaryl group.

16. The tricyclic heterocyclic compound or a pharmaceutically acceptable salt or a stereoisomer thereof according to any one of claims 1 to 5, characterized in that: One of X1 and X2 is N or CH, and the other is CH; R9 is selected from the group consisting of C1-C3 alkoxy, halogen, and amino.

17. The tricyclic heterocyclic compound or a pharmaceutically acceptable salt or a stereoisomer thereof according to any one of claims 1 to 5, characterized in that: One of X1 and X2 is CH, and the other is CR9'; R9 is selected from: C1-C3 alkoxy, halogen, amino; R9' is selected from: halogen, C1-C3 alkoxy, trifluoromethyl; Alternatively, R9 and R9' together form a 5-6 membered oxygen-containing heterocyclic group.

18. The tricyclic heterocyclic compound or a pharmaceutically acceptable salt or a stereoisomer thereof according to any one of claims 1 to 5, characterized in that: One of X1 and X2 is N, and the other is CR9'; R9 is selected from: C1-C3 alkoxy, halogen, amino; R9' is selected from: halogen, C1-C3 alkoxy, trifluoromethyl, C1-C3 alkyl; Alternatively, R9 and one R9' together form a 5-6 membered nitrogen-containing heteroaryl group.

19. The tricyclic heterocyclic compound or a pharmaceutically acceptable salt or a stereoisomer thereof according to any one of claims 1 to 5, characterized in that: R 10 Selected from: H, C1-C6 alkyl; R 11 Selected from: H, halogen, C1-C6 alkyl.

20. The tricyclic heterocyclic compound or a pharmaceutically acceptable salt or a stereoisomer thereof according to claim 1, wherein: The tricyclic heterocyclic compound is selected from the following compounds:

21. Use of the tricyclic heterocyclic compound according to any one of claims 1 to 20, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof in the preparation of a medicament for preventing or treating tumors.

22. The use according to claim 21, characterized in that The tumors are: 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, and ovarian cancer.

23. A pharmaceutical composition for preventing or treating tumors, characterized in that: The invention is prepared from active ingredients and pharmaceutically acceptable excipients, wherein the active ingredients include the tricyclic heterocyclic compound according to any one of claims 1 to 20 or a pharmaceutically acceptable salt or a stereoisomer thereof.

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