Cyclic compounds and their applications

Abstract

The present invention provides a cyclic compound of the structure shown in formula (I) or a pharmaceutically acceptable salt thereof or a stereoisomer thereof or a prodrug molecule thereof, and its application. The compound and its pharmaceutically acceptable salt thereof can be used as a protein kinase inhibitor, have strong inhibitory activity on TRKs kinase, and have strong inhibitory activity on wild-type and drug-resistant cell proliferation of Ba / F3-TRKs stable strains, can inhibit the proliferation, migration and invasion of various tumor cells, and can especially overcome the drug resistance of existing clinical drugs, can be used to prepare drugs for preventing or treating diseases (such as tumors) mediated by TRK tyrosine kinases, and for treating transitional proliferative diseases such as tumors in humans and other mammals, such as non-small cell lung cancer, breast cancer, colon cancer, prostate cancer, thyroid cancer, malignant melanoma, neuroblastoma and breast-like secretory carcinoma.

Description

Technical Field

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

[0002] Cancer has become one of the major diseases threatening human health. In recent years, the incidence and mortality of cancer have shown a continuous upward trend. Traditional treatments for malignant tumors (surgery, radiotherapy and chemotherapy) have certain limitations and toxic side effects. Improving the survival rate and quality of life of cancer patients has become the primary issue to be addressed in cancer treatment. In the past 20 years, targeted anti-tumor drugs have played an increasingly important role in the clinical treatment of tumors, but the problem of drug resistance has also become increasingly serious.

[0003] Tropomyosin receptor kinase (TRK) contains three highly homologous subtypes, TrkA, TrkB and TrkC, which are encoded by NTRK1, NTRK2 and NTRK3 genes, respectively. The extracellular domain of Trk kinase exerts its effects by binding to different neurotrophins (NT). When the ligand binds to the corresponding Trk protein, Trk kinase dimerizes and phosphorylates in turn, activating downstream signaling pathways (mainly PI3K / AKT pathway, Ras / Raf / MAPK pathway and PLCγ / PKC pathway), regulating a series of biological functions such as cell proliferation, differentiation, survival and migration. Studies have found that TRK mainly promotes the proliferation and survival of tumor cells by genetic fusion with its partner protein. TRKs gene fusion has been found in many tumors such as thyroid cancer, lung cancer, breast cancer, glioma, etc., and the fusion forms include LMNA-NTRK1, BCR-NTRK2, ETV6-NTRK3 and many others. The launch of two “cancer-agnostic” TRK kinase inhibitors, larotrectinib and entrectinib, has proven that TRK kinase has become an effective “pan-cancer” target.

[0004] Larotrectinib is a selective TRKA / B / C inhibitor developed by LOXO Oncology. Entrectinib is a multi-target kinase inhibitor with inhibitory activity on kinases such as ALK, ROS1, and TRKs. Larotrectinib and entrectinib were launched in 2018 and 2019, respectively, for the treatment of TRK fusion-positive tumors. They are first-generation TRK inhibitors, but clinical drug resistance problems soon arose with clinical use. Clinical studies have successively discovered mutations such as G595R, G667C, F589L, G667S of NTRK1 and G623R, G696A of NTRK3, which have greatly reduced the clinical therapeutic effect of the drug. TRK second-generation inhibitors such as LOXO-195 and TPX-0005 are currently in clinical research. They mainly target TRK solvent frontier mutations such as G595R of NTRK1 and G623R of NTRK3, but are ineffective against xDFG mutation sites. Currently, there are no inhibitors targeting these mutations on the market. Summary of the invention

[0005] Based on this, the present invention provides a novel cyclic compound or a pharmaceutically acceptable salt thereof or a stereoisomer thereof, which can be used as a protein kinase inhibitor, can effectively inhibit the activity of TRK protein kinase and can inhibit the proliferation, migration and invasion of various tumor cells, and can especially overcome the drug resistance of existing clinical drugs.

[0006] The specific technical solutions include the following:

[0007] A cyclic compound having a structure represented by formula (I) or a pharmaceutically acceptable salt thereof or a stereoisomer thereof or a prodrug molecule thereof:

[0008]

[0009] Wherein, B is selected from: C1-C4 alkylene, or -CH=CH-;

[0010] A is selected from: or And R is connected to Y;

[0011] E, Z, M, Q are independently selected from: CR5 or N;

[0012] T is selected from: N, CR7 or NR6; V is selected from: N, C or CR7; U and W are independently selected from: CR7 or N;

[0013] R5, R6, and R7 are independently selected from: H, halogen, C1-C6 alkyl, substituted or unsubstituted C3-C7 cycloalkyl;

[0014] R is selected from: substituted or unsubstituted phenyl, -C(=O)-, -C(=O)NR8R9 or -NR8R9; wherein R8 is selected from: H, C1~C 20 Alkyl, -(CH2) m NR 10 R 11 、-(CH2) n CR 10 R 11 R 12 ; R9 is selected from: C1~C 20 Alkylene, or R8, R9 together with the nitrogen atom to which they are attached form a substituted or unsubstituted heterocyclic group;

[0015] R 10 , R 11 , R 12 are independently selected from: H, C1-C 20 Alkyl, or R 10 , R 11 Together with the nitrogen atom or carbon atom to which they are attached, they form a substituted or unsubstituted monocyclic, condensed, spirocyclic or bridged ring containing 0 to 3 heteroatoms;

[0016] m and n are independently selected from: integers of 0-10;

[0017] X and Y are independently selected from: -O-, -N(R 13 )-, -S-, -S(=O)-, -S(O)2-, -C(=O)-, -NR 13 (C=O)-; R 13 Selected from: H, C1-C6 alkyl;

[0018] L is selected from: substituted or unsubstituted C2~C 12 Alkylene, substituted or unsubstituted C2~C 12 Unsaturated chain hydrocarbon group;

[0019] X1 and X2 are independently selected from: -N(R 13 ), or none;

[0020] R1 is selected from: H, halogen, C1~C 20 Alkyl, C1~C 20 Alkoxy or halogen substituted C1~C 20 alkyl;

[0021] G is selected from: R' substituted or unsubstituted C6~C 10 Aryl, R' substituted or unsubstituted 5-10 membered heteroaryl;

[0022] Each R' is independently selected from: H, halogen, substituted or unsubstituted C1-C20 Alkyl, substituted or unsubstituted C1~C 20 Alkoxy, nitro, substituted or unsubstituted C3~C 12 Cycloalkyl, substituted or unsubstituted C6~C 10 aryl, substituted or unsubstituted 3-12 membered heterocyclyl, substituted or unsubstituted 5-10 membered heteroaryl.

[0023] In some embodiments, G is selected from: R'-substituted or unsubstituted phenyl, R'-substituted or unsubstituted 5-6 membered heteroaryl containing 1-3 N ring atoms.

[0024] In some embodiments, the cyclic compound has a structure shown in the following formula (II) or formula (III):

[0025]

[0026] Wherein, R2 is selected from: H, halogen, C1~C 20 Alkyl, C1~C 20 Alkoxy, halogen substituted C1~C 20 Alkyl, C3~C 12 Cycloalkyl;

[0027] R3 is selected from: H, halogen, substituted or unsubstituted C1-C 20 Alkyl, substituted or unsubstituted 5-6 membered heterocyclyl containing 1-3 N ring atoms;

[0028] R4 is selected from: H, halogen, nitro, substituted or unsubstituted C1-C 20 Alkyl, substituted or unsubstituted C1~C 20 Alkoxy, substituted or unsubstituted C3~C 12 Cycloalkyl, substituted or unsubstituted 3-12 membered heterocyclyl, substituted or unsubstituted 5-10 membered heteroaryl;

[0029] R'4 is selected from: H, substituted or unsubstituted C1-C 20 Alkyl, substituted or unsubstituted C3~C 12 Cycloalkyl, substituted or unsubstituted C6~C 10 aryl, substituted or unsubstituted 3-12 membered heterocyclyl, substituted or unsubstituted 5-10 membered heteroaryl.

[0030] In some embodiments, R4 is selected from: H, halogen, C1-C4 alkyl, nitro, halogen-substituted C1-C4 alkyl, C1-C4 alkoxy, halogen-substituted C1-C4 alkoxy, -(CH2) p NR 15 R 16 , by one or more R 17A substituted or unsubstituted 5-6 membered heterocyclic group, 1-3 R 17 Substituted or unsubstituted 5-6 membered heteroaryl; p is selected from: 1, 2 or 3;

[0031] R 15 , R 16 Together with the nitrogen atom to which they are attached, they form R 17 a substituted or unsubstituted 5-12 membered heterocyclic group;

[0032] Each R 17 Each is independently selected from: H, C1-C6 alkyl, C3-C8 cycloalkyl, 5-8 membered heterocyclic group, dimethylamino, and methanesulfonyl.

[0033] In some embodiments, R4 is selected from: H, halogen, nitro, methyl, ethyl, propyl, methoxy, ethoxy, propoxy, trifluoromethyl, trifluoroethyl,

[0034] Each R 17 Each is independently selected from: H, methyl, ethyl, propyl, dimethylamino, cyclohexyl, and methanesulfonyl.

[0035] In some embodiments, R2 is selected from: H, halogen, C1-C6 alkyl, C1-C6 alkoxy, halogen-substituted C1-C6 alkyl, C3-C8 cycloalkyl.

[0036] In some embodiments, R2 is selected from: H, fluorine, methyl, ethyl, propyl, isopropyl, tert-butyl, difluoromethyl, difluoroethyl, trifluoromethyl, trifluoroethyl, cyclopropyl.

[0037] In some embodiments, R3 is selected from: H, halogen, C1-C6 alkyl, halogen-substituted C1-C6 alkyl, -(CH2) p NR 15 R 16 ; p is selected from: 1, 2 or 3;

[0038] R 15 , R 16 Together with the nitrogen atom to which they are attached, they form R 17 a substituted or unsubstituted 5-8 membered heterocyclic group;

[0039] Among them, R 17 Selected from: H, C1-C6 alkyl.

[0040] In some embodiments, R3 is selected from: H, halogen, difluoromethyl, difluoroethyl, trifluoromethyl, trifluoroethyl, Where R 17 Selected from: H, methyl, ethyl, propyl.

[0041] In some embodiments, R'4 is selected from: H, C1-C6 alkyl, C3-C8 cycloalkyl, R 17 Substituted or unsubstituted phenyl; wherein R 17 Selected from: H, C1-C6 alkyl.

[0042] In some embodiments, A is selected from:

[0043]

[0044] In some embodiments, A is selected from:

[0045]

[0046] In some embodiments, R is selected from: -C(=O)-, -C(=O)NR8R9 or -NR8R9; wherein R8 is selected from: H, C1-C6 alkyl, -(CH2) m NR 10 R 11 ; R9 is selected from: C1-C6 alkylene, or R8, R9 and the nitrogen atom to which they are connected together form one or more R 14 a substituted or unsubstituted 3-8 membered heterocyclic group;

[0047] R 10 , R 11 Each independently selected from: H, C1-C6 alkyl;

[0048] m is selected from: an integer from 1 to 5;

[0049] R 14 Selected from: H, C1~C6 alkyl.

[0050] In some embodiments, R is selected from: -C(=O)-, -C(=O)NR8R9 or -NR8R9; wherein R8 is selected from: H, C1-C3 alkyl; R9 is selected from: C1-C3 alkylene, or R8, R9 and the nitrogen atom to which they are attached form one or more R 14 Substituted or unsubstituted morpholinyl, pyrrolidinyl, piperidinyl or piperazinyl; R 14 Selected from: H, C1~C3 alkyl.

[0051] In some embodiments, R is selected from: -C(=O)-, x is selected from: 0, 1, 2, 3; y is selected from: an integer between 0-8; R8 is selected from: H, C1~C6 alkyl.

[0052] In some embodiments, A is selected from:

[0053]

[0054] In some embodiments, X and Y are independently selected from: -O-, -N(R 13 )-、-NR 13 (C=O)-; R 13 Selected from: H, C1~C3 alkyl.

[0055] In some embodiments, X is -O-; Y is selected from: -N(R 13 )-、-NR 13 (C=O)-; R 13 Selected from: H, methyl.

[0056] In some embodiments, L is selected from: C2-C8 alkylene, C2-C8 unsaturated chain hydrocarbon group.

[0057] In some embodiments, L is selected from: q is selected from: 1, 2, 3, 4, 5, 6, 7.

[0058] In some embodiments, A and Y together form the following structure:

[0059] L is selected from: q is 3; X is -O-; R4 is selected from: R 17 Selected from: H, methyl, ethyl, propyl.

[0060] In some embodiments, R is -C(=O)-; Y is -NH-; L is selected from: q is 6 or 7.

[0061] In some embodiments, R1 is selected from: H, halogen, C1-C3 alkyl.

[0062] In some of these embodiments, X1 is NH or none, and X2 is NH.

[0063] In some embodiments, B is selected from: -CH2CH2-, or -CH=CH-.

[0064] The present invention also provides the use of the above-mentioned cyclic compound or its pharmaceutically acceptable salt or its stereoisomer or its prodrug molecule.

[0065] The specific technical solutions are as follows:

[0066] Use of the above-mentioned cyclic compound or its pharmaceutically acceptable salt or its stereoisomer or its prodrug molecule in the preparation of TRK inhibitors.

[0067] Use of the above-mentioned cyclic compound or its pharmaceutically acceptable salt or its stereoisomer or its prodrug molecule in the preparation of drugs for preventing and / or treating diseases mediated by TRK kinase.

[0068] In some embodiments, the disease mediated by TRK kinase is a tumor.

[0069] In some embodiments, the tumor is non-small cell lung cancer, breast cancer, colon cancer, prostate cancer, thyroid cancer, malignant melanoma, neuroblastoma and mammary secretory carcinoma.

[0070] The present invention also provides a pharmaceutical composition for preventing and / or treating tumors.

[0071] The specific technical solutions are as follows:

[0072] A pharmaceutical composition for preventing and / or treating tumors is prepared from active ingredients and pharmaceutically acceptable excipients. The active ingredients include the above-mentioned cyclic compound or its pharmaceutically acceptable salt or its stereoisomer or its prodrug molecule.

[0073] The cyclic compound provided by the present invention can be used as a protein kinase inhibitor, has strong inhibitory activity against TRKs kinase, and has strong inhibitory activity against wild-type and drug-resistant cell proliferation of Ba / F3-TRKs stable strains, can inhibit the proliferation, migration and invasion of various tumor cells, and can especially overcome the anti-drug resistance of existing clinical drugs. The cyclic compound provided by the present invention can be used to prepare drugs for preventing or treating diseases (such as tumors) mediated by TRK tyrosine kinases, and can be used to treat transitional proliferative diseases such as tumors in humans and other mammals, such as non-small cell lung cancer, breast cancer, colon cancer, prostate cancer, thyroid cancer, malignant melanoma, neuroblastoma and breast-like secretory carcinoma. DETAILED DESCRIPTION

[0074] The experimental methods in the following examples of the present invention, where no specific conditions are specified, are usually carried out under conventional conditions or under conditions recommended by the manufacturers. The various commonly used chemical reagents used in the examples are all commercially available products.

[0075] Unless otherwise defined, all technical and scientific terms used in the present invention have the same meaning as those commonly understood by those skilled in the art of the present invention. The terms used in the specification of the present invention are only for the purpose of describing specific embodiments and are not intended to limit the present invention.

[0076] The terms "including" and "having" and any variations thereof of the present invention are intended to cover non-exclusive inclusions. For example, a process, method, device, product or equipment comprising a series of steps is not limited to the listed steps or modules, but may optionally include steps not listed, or may optionally include other steps inherent to these processes, methods, products or equipment.

[0077] In the present invention, the term "multiple" refers to two or more than two. "And / or" describes the association relationship of associated objects, indicating that three relationships may exist. For example, A and / or B can represent the following three situations: A exists alone, A and B exist at the same time, and B exists alone. The character " / " generally indicates that the associated objects are in an "or" relationship.

[0078] In the compounds described in the present invention, when any variable (such as R 14 , R 17 If a (, etc.) compound 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 stable compounds. 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 is to be understood that one of ordinary skill in the art can select substituents and substitution patterns for the compounds of the invention to provide compounds that are chemically stable and that can be readily synthesized from readily available raw materials by techniques in the art and the methods set forth below. If a substituent is itself substituted with more than one group, it is to be understood that these groups may be on the same carbon atom or on different carbon atoms so long as the structure is stable.

[0079] As used herein, the term "alkyl" is intended to include branched and straight chain saturated aliphatic hydrocarbon groups having a specific number of carbon atoms. For example, the definition of "C1-C6" in "C1-C6 alkyl" includes groups having 1, 2, 3, 4, 5 or 6 carbon atoms in a straight or branched arrangement. For example, "C1-C6 alkyl" specifically includes methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, pentyl, and hexyl.

[0080] The term "alkylene" refers to an "alkyl" radical which is based on an alkyl radical minus one hydrogen, for example, -CH2-, -CH2CH2-, -CH2CH2CH2-, -CH2CH2CH2CH2-, and the like.

[0081] The term "cycloalkyl" refers to a monocyclic saturated aliphatic hydrocarbon group having a specific number of carbon atoms. For example, "C3-C7 cycloalkyl" includes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, etc.

[0082] The term "unsaturated chain hydrocarbon group" refers to branched and straight-chain unsaturated aliphatic hydrocarbon groups having a specific number of carbon atoms, that is, non-cyclic chain hydrocarbon groups, and the carbon chain contains one or more carbon-carbon double bonds, or carbon-carbon triple bonds, such as: -CH=CH-, -CH2CH=CH-, -CH2CH=CHCH2-, -CH=CHCH2CH2-, -(CH2)2(CH=CH)(CH2)2CH2-, -CH2CH=CHCH2CH=CHCH2-, etc.

[0083] 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, and the like.

[0084] The term "heterocycloalkyl" or "heterocyclic group" is a saturated or partially unsaturated monocyclic, fused, spiro or bridged cyclic substituent, wherein one or more of the ring atoms are selected from N, O or S(O)m (wherein m is an integer from 0 to 2) heteroatoms, and the remaining ring atoms are carbon, for example: morpholinyl, piperidinyl, tetrahydropyrrolyl, oxetanyl, piperazinyl, pyrrolidinyl, dihydroimidazolyl, dihydroisoxazolyl, dihydroisothiazolyl, dihydrooxadiazolyl, dihydrooxazolyl, dihydropyrazinyl, dihydropyrazolyl, dihydropyridinyl, dihydropyrimidinyl, dihydropyrrolyl, dihydrotetrazolyl, dihydrothiadiazolyl, dihydrothiazolyl, dihydrothiophenyl, dihydrotriazolyl, dihydroazetidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, and the like, and N-oxides thereof. The connection of the heterocyclic substituent may be achieved through a carbon atom or through a heteroatom.

[0085] The term "heteroaryl" as used herein 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, furanyl, pyridyl, pyrimidyl, pyrazinyl, triazolyl, imidazolyl, oxazolyl, isoxazolyl, pyridazinyl, benzofuranyl, benzothienyl, benzoxazole, indolyl, etc.; "heteroaryl" is also understood to include any N-oxide derivatives of heteroaryl containing nitrogen. The connection of the heteroaryl can be achieved through a carbon atom or through a heteroatom.

[0086] As used herein, the term "substituted" refers to the replacement of hydrogen radicals in a particular structure with the radical of a specified substituent.

[0087] As will be appreciated by those skilled in the art, "halo" or "halo" as used herein refers to chlorine, fluorine, bromine and iodine.

[0088] Unless otherwise defined, alkyl, cycloalkyl, aryl, heteroaryl and heterocycloalkyl substituents may be unsubstituted or substituted. For example, C1-C6 alkyl may be substituted with one, two or three substituents selected from OH, halogen, alkoxy, dialkylamino or heterocyclic radicals such as morpholinyl, piperidinyl, etc.

[0089] The present invention includes free forms of compounds of formula (I)-(III), as well as pharmaceutically acceptable salts and stereoisomers thereof. The term "free form" refers to an amine compound in a non-salt form. The pharmaceutically acceptable salts included include not only the exemplary salts of the specific compounds described herein, but also typical pharmaceutically acceptable salts of the free forms of all compounds of formula (I)-(III). The free forms of specific salts of the compounds can be isolated using techniques known in the art. For example, the free forms can be regenerated by treating the salt with a suitable dilute aqueous base solution, such as a dilute aqueous solution of NaOH, a dilute aqueous solution of potassium carbonate, a dilute aqueous ammonia, and a dilute aqueous solution of 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 invention, such acid salts and base salts are equivalent to their respective free forms in other pharmaceutical aspects.

[0090] 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 excess of an inorganic or organic acid in the desired salt form in an appropriate solvent or combination of solvents. Similarly, salts of acidic compounds are formed by reacting with an appropriate inorganic or organic base.

[0091] Therefore, the pharmaceutically acceptable salts of the compounds of this invention include conventional non-toxic salts of the compounds of this invention formed by reacting alkaline compounds of this invention with inorganic or organic acids. 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, etc., and also include salts prepared from organic acids such as acetic acid, propionic acid, succinic acid, glycolic acid, stearic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, 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, etc.

[0092] If the compound of the present invention is acidic, then 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, iron salts, ferrous salts, lithium salts, magnesium salts, manganic salts, manganous salts, potassium salts, sodium salts, zinc salts, etc. Ammonium salts, calcium salts, magnesium salts, potassium salts and sodium salts are particularly preferred. Salts derived from pharmaceutically acceptable organic non-toxic bases, including salts of primary, secondary and tertiary amines, 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.

[0093] Berg et al., "Pharmaceutical Salts," J. Pharm. Sci. '1977: 66: 1-19, describes in more detail the preparation of the above-mentioned pharmaceutically acceptable salts and other typical pharmaceutically acceptable salts.

[0094] Since deprotonated acidic moieties such as carboxyl groups in the compounds may be anionic under physiological conditions, and this charge may then be balanced by the internal protonated or alkylated basic moieties such as quaternary nitrogen atoms carrying cations, it should be noted that the compounds of the present invention are potential inner salts or zwitterions.

[0095] In some embodiments, the present invention provides a method for treating hyperproliferative diseases or symptoms such as tumors in humans or other mammals using compounds having structures represented by formula (I)-(III) and pharmaceutically acceptable salts thereof.

[0096] In some embodiments, the compounds of the present invention and pharmaceutically acceptable salts thereof can be used to treat or control transitional proliferative diseases such as non-small cell lung cancer, breast cancer, colon cancer, prostate cancer, thyroid cancer, malignant melanoma, neuroblastoma and mammary secretory carcinoma.

[0097] Drug metabolites and prodrugs

[0098] The metabolites of the compounds involved in the present invention and their pharmaceutically acceptable salts, as well as prodrugs that can be converted into the structures of the compounds involved in the present invention and their pharmaceutically acceptable salts in vivo, are also included in the claims of the present invention.

[0099] The present invention is further described in the following examples, but the examples are not intended to limit the scope of protection of the present invention.

[0100] Example 1: (1 3 S)-N-(3-chloro-5-(trifluoromethyl)phenyl)-5 6 -methyl-7-oxo-6,14-diazo-2(6,3)-imidazo[1,2-b]pyridazine-1(1,3)-piperidin-5(1,3)-benzocyclotetradec-3-yne-5 5 - Preparation of formamide (named WZQ-6C)

[0101]

[0102] Step 1: Preparation of 3-iodo-2-methyl-5-nitrobenzoic acid (Compound 2)

[0103]

[0104] Compound 1 (4.0 g, 20.49 mmol) was dissolved in 50 mL of concentrated sulfuric acid in a 200 mL round-bottom flask and heated to 60°C. NIS (4.96 g, 28.69 mmol) was added to the mixture in three portions within 30 minutes. After reacting for 2-3 hours, the reaction solution was slowly added to ice water to precipitate a yellow-white precipitate. The precipitate was filtered off with suction, and the filter cake was rinsed with ice water and cyclohexane 2-3 times. 4.0 g of a white solid was obtained by column chromatography (yield: 60.79%).

[0105] 1 H NMR(400MHz, DMSO-d6)δ8.71(d,J=2.5Hz,1H),8.45(d,J=2.5Hz,1H),2.69(s,3H).LC-MS(ESI)m / z 306.0[MH] -

[0106] Step 2: Preparation of N-(3-chloro-5-(trifluoromethyl)phenyl)-3-iodo-2-methyl-5-nitrobenzamide (Compound 4)

[0107]

[0108] Compound 2 (6.0 g, 19.69 mmol) was dissolved in 40 mL of DMF solvent, HATU (7.4 g, 19.69 mmol) and DIPEA (5.9 mL, 35.8 mmol) were added and reacted for 0.5 hour, and compound 3 (3.5 g, 17.90 mmol) was added and stirred at room temperature overnight, and then extracted with ethyl acetate and water 2-3 times. The organic layer was dried after adding anhydrous Na2SO4 and then spin-dried. 2.3 g of white solid was obtained by column chromatography (yield: 26.52%).

[0109] 1 H NMR (400MHz, DMSO-d6) δ11.08(s,1H),8.73(d,J=2.4Hz,1H),8.43(d,J=2.4Hz,1H),8.08(d ,J=2.0Hz,1H),8.05(d,J=2.0Hz,1H),7.64(s,1H),2.55(s,3H).LC-MS(ESI)m / z482.3[MH] - .

[0110] Step 3: Preparation of N-(3-chloro-5-(trifluoromethyl)phenyl)-2-methyl-5-nitro-3-((trimethylsilyl)ethynyl)benzamide (Compound 5)

[0111]

[0112] In a 100mL two-necked bottle, compound 4 (3.2g, 6.60mmol), cuprous iodide (125.7mg, 0.66mmol), bis(triphenylphosphine)palladium dichloride (231.7mg, 0.33mmol), 30mL of anhydrous DMF solvent, N,N-diisopropylethylamine (3.3mL, 19.81mmol) were added, argon was replaced, the reaction system was sealed, and trimethylsilyl acetylene (2.8mL, 19.81mmol) was injected with a syringe, and stirred at 60°C for 6 hours. The reaction solution was filtered with diatomaceous earth, the solvent was spin-dried to obtain a black mixture, which was directly used for the next step reaction.

[0113] Step 4: Preparation of N-(3-chloro-5-(trifluoromethyl)phenyl)-3-ethynyl-2-methyl-5-nitrobenzamide (Compound 6)

[0114]

[0115] The crude product of the previous step was dissolved in methanol, and about 4 mL of 1 mol / L tetrabutylammonium fluoride-tetrahydrofuran solution was added, and stirred at room temperature for 2 hours. The reaction system was spin-dried and column chromatography was performed to obtain 1.1 g of a white solid (total yield of two steps: 43.53%).

[0116] 1 H NMR (400MHz, DMSO-d6) δ11.08(s,1H),8.43(d,J=2.5Hz,1H),8.38(d,J=2.5Hz,1H),8.09(d, J=2.0Hz,1H),8.07(d,J=2.0Hz,1H),7.64(s,1H),4.83(s,1H),2.58(s,3H).LC-MS(ESI)m / z 381.0[MH] - .

[0117] Step 5: Preparation of tert-butyl (S)-(1-(3-iodoimidazo[1,2-b]pyridazin-6-yl)piperidin-3-yl)carbamate (Compound 9)

[0118]

[0119] Compound 7 (1.0 g, 3.58 mmol) was dissolved in 20 mL of dimethyl sulfoxide (DMSO), and compound 8 (3.58 g, 17.89 mmol) and potassium fluoride (2.49 g, 42.94 mmol) were added, and the mixture was heated and stirred at 120° C. for 3 hours. The reaction solution was extracted 3 times with ethyl acetate and water, and the organic layer was dried by adding anhydrous Na2SO4 and then spin-dried, and 1.1 g of yellow solid was obtained by column chromatography (yield: 69.3%).

[0120] 1 H NMR (400MHz, DMSO-d6) δ7.79(d,J=9.9Hz,1H),7.58(s,1H),7.12(d,J=9.9Hz,1H),6.96(d,J=7.4Hz,1H),4.03–3.90(m,2H),3.43 (s,1H),3.08(t,J=11.3Hz,1H),2.97(dd,J=12.9,9.1Hz,1H),1.88–1.78(m,2H),1.59–1.45(m,2H),1.39(s,9H).LC-MS(ESI)m / z 444.1[M+H] + .

[0121] Step 6: Preparation of tert-butyl-(S)-(1-(3-((3-((3-chloro-5-(trifluoromethyl)phenyl)carbamoyl)-2-methyl-5-nitrophenyl)ethynyl)imidazo[1,2-b]pyridazin-6-yl)piperidin-3-yl)carbamate (Compound 10)

[0122]

[0123] Compound 6 (500 mg, 1.31 mmol) and compound 9 (579.13 mg, 1.31 mmol) were dissolved in 15 mL of anhydrous N, N-dimethylformamide (DMF), and then cuprous iodide (24.8 mg, 0.13 mmol), bis(triphenylphosphine)palladium dichloride (45.8 mg, 0.065 mmol), and DIPEA (0.65 mL, 3.93 mmol) were added, and the argon gas was replaced and the reaction system was sealed. The mixture was heated and stirred at 80°C and reacted overnight. After filtering with diatomaceous earth, the filtrate was dried and column chromatography was performed to obtain 550 mg of a yellow solid (yield: 60.31%).

[0124] 1 H NMR (400MHz, DMSO-d6) δ11.14(s,1H),8.44(d,J=2.5Hz,1H),8.42(d,J=2.6Hz,1H),8.12(s,2H) ,7.97(s,1H),7.94(d,J=9.9Hz,1H),7.65(s,1H),7.30(d,J=10.0Hz,1H),6.97(d,J=7.7Hz,1H) ,4.15(d,J=11.4Hz,1H),4.00(d,J=13.0Hz,1H),3.45-3.38(m,1H),3.02(t,J=11.8Hz,1H),2.8 8–2.80(m,1H),2.73(s,3H),1.90–1.75(m,2H),1.59-1.42(m,2H),1.26(s,9H).LC-MS(ESI)m / z 697.9[M+H] + .

[0125] Step 7: Preparation of tert-butyl-(S)-(1-(3-((5-amino-3-((3-chloro-5-(trifluoromethyl)phenyl)carbamoyl)-2-methylphenyl)ethynyl)imidazo[1,2-b]pyridazin-6-yl)piperidin-3-yl)carbamate (Compound 11)

[0126]

[0127] Compound 10 (1.0 g, 1.43 mmol) was dissolved in 20 mL of a 5:1 mixed solvent of ethanol: water, and solid NH4Cl (383 mg, 7.16 mmol) and iron powder (399 mg, 7.16 mmol) were added. The mixture was heated to 70°C for 4 hours and filtered through diatomaceous earth. The filtrate was dried and subjected to column chromatography to obtain 600 mg of a yellow-white solid (yield: 62.69%).

[0128] 1H NMR (400MHz, DMSO-d6) δ10.85(s,1H),8.16(s,1H),8.14(s,1H),7.89(d,J=10.0Hz,1H),7.86(s,1H),7.56( s,1H),7.24(d,J=10.0Hz,1H),6.95(d,J=7.7Hz,1H),6.88(d,J=2.4Hz,1H),6.73(d,J=2.4Hz,1H),5.36(s,2 H),4.13(d,J=12.7Hz,1H),3.98(d,J=12.9Hz,1H),3.44-3.38(m,1H),2.97(t,J=11.9Hz,1H),2.86–2.76(m, 1H),2.44(s,3H),1.89–1.73(m,2H),1.54(q,J=11.8Hz,1H),1.49–1.39(m,1H),1.26(s,9H).LC-MS(ESI)m / z 668.3[M+H] + .

[0129] Step 8: Preparation of tert-butyl-(S)-(1-(3-((5-(7-bromoheptylamino)-3-((3-chloro-5-(trifluoromethyl)phenyl)carbamoyl)-2-methylphenyl)ethynyl)imidazo[1,2-b]pyridazin-6-yl)piperidin-3-yl)carbamate (Compound 12)

[0130]

[0131] 7-Bromoheptanoic acid (184.29 mg, 0.881 mmol) was dissolved in DMF (10 mL), and HATU (335 mg, 0.881 mmol) and DIPEA (0.23 mL, 1.36 mmol) were added and stirred for 0.5 hour. Compound 11 (453 mg, 0.678 mmol) was then added and reacted at room temperature for 4-5 hours. The reaction solution was extracted with ethyl acetate and water 2-3 times. The organic layer was dried by adding anhydrous Na2SO4 and then spin-dried. 219 mg of yellow-white solid was obtained by column chromatography (yield: 37.59%).

[0132] 1H NMR (400MHz, DMSO-d6) δ10.98(s,1H),10.14(s,1H),8.13(s,2H),8.03(s,1H),7.94(s,1H),7.92(d,J=9.8Hz, 1H),7.66(s,1H),7.60(s,1H),7.27(d,J=10.0Hz,1H),6.97(d,J=7.6Hz,1H),4.15(d,J=10.7Hz,1H),4.00(d,J =12.9Hz,1H),3.53(t,J=6.6Hz,2H),2.99(t,J=12.0Hz,1H),2.85–2.77(m,1H),2.55(s,3H),2.34(t,J=7.3Hz ,2H),1.84-1.77(m,4H),1.64-1.55(m,3H),1.45-1.38(m,3H),1.37-1.29(m,3H),1.25(s,9H).LC-MS(ESI)m / z 858.3[M+H] + .

[0133] Step 9: (1 3 S)-N-(3-chloro-5-(trifluoromethyl)phenyl)-5 6 -methyl-7-oxo-6,14-diazo-2(6,3)-imidazo[1,2-b]pyridazine-1(1,3)-piperidin-5(1,3)-benzocyclotetradec-3-yne-5 5 - Preparation of formamide (compound WZQ-6C)

[0134]

[0135] Compound 12 (200 mg, 0.23 mmol) was dissolved in 10 mL of dichloromethane, and 4 mL of trifluoroacetic acid was added and stirred at room temperature for 3-4 hours, and the solvent was dried by spin drying, and the organic layer was extracted 3 times with ethyl acetate and saturated NaHCO3 solution, and anhydrous Na2SO4 was added to the organic layer, and then dried by spin drying to obtain a crude yellow-white solid. The crude product was directly dissolved in 10 mL of DMF, and K2CO3 (42 mg, 0.3 mmol) was added and heated to 80°C for 5 hours. After the solvent was drained by oil pump, 41 mg of white solid was obtained by column chromatography (total yield: 25.97%).

[0136] 1H NMR(600MHz,DMSO-d6)δ10.96(s,1H),10.17(s,1H),8.13(s,1H),8.11(s,1H),7.92(t,J=5.0Hz,3H),7 .61(s,1H),7.53(d,J=2.2Hz,1H),7.33(d,J=10.1Hz,1H),4.62(d,J=8.5Hz,1H),4.03(d,J=12.4Hz,1H ),2.88(t,J=11.2Hz,1H),2.79–2.55(m,4H),2.49(s,3H),2.37–2.30(m,2H),2.03–1.97(m,1H),1.81- 1.79(m,1H),1.72-1.69(m,2H),1.61–1.52(m,1H),1.47-1.43(m,2H),1.38-1.33(m,5H).HRMS(ESI)for C 35 H 35 ClF3N7O2[M+H] + :calcd,678.2566,found.678.2552.

[0137] Example 2: (1 3 S)-N-(3-chloro-5-(trifluoromethyl)phenyl)-5-methyl-7-oxo-6,13-diazo-2(6,3)-imidazo[1,2-b]pyridazine-1(1,3)-piperidin-5(1,3)-benzocyclotridecane-3-yne-5 5 - Preparation of formamide (named WZQ-5C)

[0138]

[0139] The synthesis method is as in Example 1.

[0140] 1H NMR (400MHz, DMSO-d6) δ10.95(s,1H),10.11(s,1H),8.12(d,J=2.3Hz,1H),8.11(s,1H),8.00(d,J=2.2Hz,1H),7.90(d,J= 10.1Hz,2H),7.61(s,1H),7.39(d,J=2.2Hz,1H),7.33(d,J=10.1Hz,1H),4.58(d,J=12.6Hz,1H),4.06(d,J=12.6Hz,1H),2 .82(t,J=12.0Hz,1H),2.76–2.66(m,1H),2.61(q,J=8.2,5.9Hz,2H),2.50(s,3H),2.32(d,J=7.0Hz,2H),2.10(d,J=12.2H z,1H),1.86–1.67(m,2H),1.65–1.52(m,2H),1.42(dd,J=23.2,6.4Hz,4H),1.24(s,2H),1.20-1.05(m,1H).HRMS(ESI)for C 34 H 33 ClF3N7O2[M+H] + :calcd,664.2409,found.664.2398.

[0141] Example 3: (1 3 S)-N-(3-chloro-5-(trifluoromethyl)phenyl)-5 6 -methyl-7-oxo-6,15-diazo-2(6,3)-imidazo[1,2-b]pyridazine-1(1,3)-piperidin-5(1,3)-benzocyclopentane-3-yne-5 5 - Preparation of formamide (named WZQ-7C)

[0142]

[0143] The synthesis method is as in Example 1.

[0144] 1H NMR (400MHz, DMSO-d6) δ10.95(s,1H),10.12(s,1H),8.12(dd,J=6.0,4.1Hz,2H),7.92(d,J=2.3Hz,1H),7 .91–7.87(m,2H),7.71(d,J=2.2Hz,1H),7.61(s,1H),7.29(d,J=10.1Hz,1H),4.62(d,J=10.6Hz,1H),4.0 2(d,J=13.1Hz,1H),3.01–2.90(m,1H),2.69–2.54(m,4H),2.48(s,3H),2.38-2.26(m,2H),1.98(d,J=12. 0Hz,1H),1.76(d,J=13.2Hz,1H),1.69(s,2H),1.49(q,J=12.7Hz,2H),1.37–1.27(m,8H).HRMS(ESI)forC 36 H 37 ClF3N7O2[M+H] + :calcd,692.2722,found,692.2710.

[0145] Embodiment 4: (1 3 S)-N-(3-chloro-5-(trifluoromethyl)phenyl)-5 6 -methyl-11-oxo-6-oxo-12-aza-2(6,3)-imidazo[1,2-b]pyridazine-1(1,3)-piperidin-5(1,3)-benzocyclododecane-3-yne-5 5 - Preparation of formamide (named WZQ2-144)

[0146]

[0147] Step 1: Preparation of methyl 3-iodo-2-methyl-5-nitrobenzoate (Compound 2)

[0148]

[0149] Compound 1 (1.0 g, 3.26 mmol) was first dissolved in DMF, and K2CO3 (900 mg, 6.51 mmol) and iodomethane (0.24 mL, 3.91 mmol) were added and reacted at room temperature for 4 hours. After extraction with ethyl acetate and water three times, the organic layer was dried and column chromatography was performed to obtain 860 mg of yellow-white solid (yield: 82.24%).

[0150] 1H NMR (400 MHz, DMSO-d6) δ8.74 (d, J = 2.4 Hz, 1H), 8.47 (d, J = 2.4 Hz, 1H), 3.90 (s, 3H), 2.66 (s, 3H). LC-MS (ESI) m / z 319.9 [MH] - .

[0151] Step 2: Preparation of methyl 3-iodo-2-methyl-5-nitrobenzoate (Compound 3)

[0152]

[0153] Compound 2 (750 mg, 2.34 mmol) was dissolved in 15 mL of a mixed solvent of ethanol: water in a ratio of 4:1. Iron powder (652.2 mg, 11.68 mmol) and NH4Cl (624.7 mg, 11.68 mmol) were added and reacted at 70°C for 2 hours. After filtration with diatomaceous earth, 620 mg of off-white solid was obtained by column chromatography (yield: 91.18%).

[0154] 1 H NMR (400 MHz, DMSO-d6) δ7.29 (d, J = 2.4 Hz, 1H), 6.94 (d, J = 2.4 Hz, 1H), 5.34 (s, 2H), 3.79 (s, 3H), 2.35 (s, 3H). LC-MS (ESI) m / z 292.0 [M+H] + .

[0155] Step 3: Preparation of 5-hydroxy-3-iodo-2-methylbenzoic acid methyl ester (Compound 4)

[0156]

[0157] Compound 3 (4.2 g, 14.43 mmol) was added to 50 mL of H2SO4 (2.0%) solution, heated to 80°C to dissolve it completely, and then the reaction solution was moved to 0°C. NaNO2 (1.49 g, 21.64 mmol) was dissolved in 10 mL of water and slowly added dropwise to the reaction solution, and reacted for 2 hours under ice bath. The reaction solution was then added dropwise to 20 mL of boiling H2SO4 (2.0%) solution, reacted at 80°C for 1 hour, extracted with ethyl acetate 2-3 times, the organic layer was spin-dried, and 2.7 g of yellow solid was obtained by column chromatography (yield: 64.07%).

[0158] 1H NMR (400 MHz, DMSO-d6) δ9.92 (s, 1H), 7.46 (d, J = 2.6 Hz, 1H), 7.12 (d, J = 2.7 Hz, 1H), 3.81 (s, 3H), 2.42 (s, 3H). LC-MS (ESI) m / z 293.0 [M+H] + .

[0159] Step 4: Preparation of methyl 5-((5-(tert-butoxy)-5-oxopentyl)oxy)-3-iodo-2-methylbenzoate (Compound 5)

[0160]

[0161] Compound 4 (1.02 g, 3.49 mmol) was dissolved in 15 mL of DMF, and K2CO3 (965 mg, 6.98 mmol) and tert-butyl 5-bromovalerate (993.7 mg, 4.19 mmol) were added, and the mixture was stirred at room temperature overnight. After the DMF was dried with an oil pump, 1.06 g of a yellow oil was obtained by column chromatography (yield: 67.71%).

[0162] 1 H NMR (400MHz, CDCl3) δ7.55(d,J=2.8Hz,1H),7.30(d,J=2.8Hz,1H),3.96(t,J=5.8Hz,2H),3.9 1(s,3H),2.59(s,3H),2.30(t,J=6.8Hz,2H),1.82-1.75(m,4H),1.47(s,9H).LC-MS(ESI)m / z 449.1[M+H] + .

[0163] Step 5: Preparation of methyl 5-((5-(tert-butoxy)-5-oxo)oxy)-2-methyl-3-((trimethylsilyl)ethynyl)benzoate (Compound 6)

[0164]

[0165] In a 50mL two-necked bottle, compound 5 (1.06g, 2.36mmol), cuprous iodide (45.03mg, 0.236mmol), bis(triphenylphosphine)palladium dichloride (118.2mg, 0.118mmol), 20mL of anhydrous acetonitrile solvent, N,N-diisopropylethylamine (1.17mL, 7.09mmol) were added, argon was replaced, the reaction system was sealed, and trimethylsilyl acetylene (1.0mL, 7.09mmol) was injected with a syringe, and stirred at 60°C for 4 hours. The reaction solution was filtered with diatomaceous earth, the solvent was spin-dried to obtain a black mixture, which was directly used for the next step reaction.

[0166] Step 6: Preparation of methyl 5-((5-(tert-butoxy)-5-oxopentyl)oxy)-3-ethynyl-2-methylbenzoate (Compound 7)

[0167]

[0168] The crude product of the previous step was dissolved in methanol, and about 3 mL of 1 mol / L tetrabutylammonium fluoride-tetrahydrofuran solution was added, and stirred at room temperature for 2 hours. The reaction system was spin-dried and column chromatography was performed to obtain 687.6 mg of a yellow oily liquid (total yield of two steps: 84%).

[0169] 1 H NMR (400MHz, CDCl3) δ7.38(d,J=2.8Hz,1H),7.16(d,J=2.8Hz,1H),3.97(t,J=5.8Hz,2H),3.89(s,3 H),3.31(s,1H),2.62(s,3H),2.30(t,J=6.9Hz,2H),1.82-1.74(m,4H),1.46(s,9H).LC-MS(ESI)m / z 347.3[M+H] + .

[0170] Step 7: Preparation of methyl (S)-5-((5-(tert-butoxy)-5-oxopentyl)oxy)-3-((6-(3-((tert-butoxycarbonyl)amino)piperidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)ethynyl)-2-methylbenzoate (Compound 9)

[0171]

[0172] Compound 7 (430 mg, 1.24 mmol) and compound 8 (660.28 mg, 1.49 mmol) were dissolved in 15 mL of anhydrous N, N-dimethylformamide (DMF), and then cuprous iodide (23.64 mg, 0.12 mmol), bis(triphenylphosphine)palladium dichloride (43.56 mg, 0.062 mmol), DIPEA (0.61 mL, 3.72 mmol) were added, argon was replaced, and the reaction system was sealed. Stirred and heated at 80°C for overnight reaction. After filtering with diatomaceous earth, the filtrate was dried and column chromatography was performed to obtain 300 mg of a yellow oil (yield: 36.52%).

[0173] 1H NMR (400MHz, DMSO-d6) δ7.90(d,J=9.9Hz,1H),7.86(s,1H),7.30(d,J=2.8Hz,1H),7.27(d,J=2.8Hz,1H),7.24 (d,J=10.0Hz,1H),6.96(d,J=7.4Hz,1H),4.10(d,J=8.9Hz,1H),4.03(t,J=6.2Hz,2H),3.97(d,J=13.2Hz,1H), 3.85(s,3H),3.44-3.41(m,1H),3.07(t,J=11.3Hz,1H),2.91(dd,J=12.9,9.4Hz,1H),2.66(s,3H),2.27(t,J= 7.1Hz,2H),1.89–1.75(m,2H),1.75–1.61(m,4H),1.59–1.44(m,2H),1.40(s,9H),1.34(s,9H).LC-MS(ESI)m / z 661.8[M+H] + .

[0174] Step 8: Methyl (1 3 S)-5 6 -methyl-11-oxo-6-oxo-12-aza-2(6,3)-imidazo[1,2-b]pyridazine-1(1,3)-piperidin-5(1,3)-benzocyclododecane-3-yne-5 5 - Preparation of carboxylic acid ester (Compound 10)

[0175]

[0176] Compound 9 (100 mg, 0.15 mmol) was dissolved in 10 mL of 1,4-dioxane solvent, and 2 mL of hydrochloric acid-1,4-dioxane solution was added. The mixture was stirred at room temperature for 2 hours. The solvent was dried by spin drying to obtain a yellow-brown solid. The crude product was dissolved in 15 mL of dichloromethane solvent, and 2 mL of DMF was added followed by DIPEA (0.12 mL, 0.75 mmol) and FDPP (69.67 mg, 0.18 mmol). The mixture was stirred at room temperature overnight, extracted with DCM and water 3 times, the organic layer was dried by spin drying, and 54 mg of a yellow-white solid was obtained by column chromatography (yield: 73.30%).

[0177] 1H NMR (400MHz, CDCl3) δ7.77(s,1H),7.68(d,J=9.9Hz,1H),7.35(d,J=2.8Hz,1H),7.24(d,J=2.6Hz,1H ),6.84(d,J=9.9Hz,1H),5.37(d,J=7.9Hz,1H),4.77(dd,J=12.7,4.4Hz,1H),4.09(s,1H),3.97(t,J =7.6Hz,2H),3.86(s,3H),2.87-2.80(m,1H),2.65(s,3H),2.55(dd,J=12.5,10.7Hz,1H),2.45-2.39 (m,1H),2.13-2.06(m,2H),2.04-1.95(m,1H),1.93-1.75(m,4H),1.75–1.61(m,2H).LC-MS(ESI)m / z 488.3[M+H] + .

[0178] Step 9: (1 3 S)-N-(3-chloro-5-(trifluoromethyl)phenyl)-5 6 -methyl-11-oxo-6-oxo-12-aza-2(6,3)-imidazo[1,2-b]pyridazine-1(1,3)-piperidin-5(1,3)-benzocyclododecane-3-yne-5 5 - Preparation of formamide (compound WZQ 2-144)

[0179]

[0180] Under argon protection, compound 10 (20 mg, 0.041 mmol) and compound 11 (9.6 mg, 0.049 mmol) were dissolved in 8 mL of anhydrous THF and stirred in an ice bath for 5 minutes. Then, lithium bis(trimethylsilyl)amide (25 μL, 0.12 mmol) was added to the mixture with a syringe. After reacting for 3 hours, the mixture was extracted with NH4Cl solution and ethyl acetate 1-2 times. 13 mg of white solid was obtained by column chromatography (yield: 48.67%).

[0181] 1H NMR (400MHz, DMSO-d6) δ10.88(s,1H),8.12(s,2H),7.93(d,J=3.5Hz,1H),7.90(d,J=2.2Hz,2H),7.60(s, 1H),7.33(d,J=10.1Hz,1H),7.14(d,J=2.7Hz,1H),7.10(d,J=2.7Hz,1H),4.74–4.64(m,1H),4.14–4.04( m,3H),3.76(dd,J=11.8,7.1Hz,1H),2.88–2.81(m,1H),2.46(s,3H),2.20(d,J=5.8Hz,2H),2.00(q,J=7. 4Hz,1H),1.90(d,J=11.8Hz,1H),1.83-1.77(m,4H),1.66–1.54(m,2H),1.49–1.40(m,1H).HRMS(ESI)forC 33 H 30 ClF3N6O3[M+H] + :calcd,651.2093,found.651.2064.

[0182] Example 5: (1 3 S)-N-(3-chloro-5-(trifluoromethyl)phenyl)-5 6 -methyl-7,12-dioxy-6,13-diaza-2(6,3)-imidazo[1,2-b]pyridazine-1(1,3)-piperidin-5(1,3)-benzocyclotridecane-3-yne-5 5 - Preparation of formamide (named WZQ 2-148)

[0183]

[0184] The synthesis method is as in Example 1.

[0185] 1H NMR (400MHz, MeOD) δ8.09(d,J=2.1Hz,1H),8.03(s,1H),7.86(d,J=2.3Hz,1H),7.80–7.75(m,2H),7.57(d,J =2.2Hz,1H),7.48(d,J=1.9Hz,1H),7.28(d,J=10.0Hz,1H),4.75(dd,J=12.7,4.6Hz,1H),4.08(d,J=12.7Hz ,1H),3.97-3.89(m,2H),2.93–2.86(m,1H),2.61(s,3H),2.52–2.45(m,2H),2.43-2.36(m,1H),2.28–2.20( m,1H),2.16(d,J=12.6Hz,1H),1.92(t,J=12.4Hz,2H),1.86–1.70(m,5H),1.51-1.41(m,2H).HRMS(ESI)forC 34 H 31 ClF3N7O3[M+H] + :calcd,678.2202,found.678.2182.

[0186] Example 6: (1 3 S)-N-(3-chloro-5-(trifluoromethyl)phenyl)-5 6 -methyl-11-oxo-6-oxo-12-aza-2(6,3)-imidazo[1,2-b]pyridazine-1(1,3)-pyrrolidine-5(1,3)-benzocyclododecane-3-yne-5 5 - Preparation of formamide (named WZQ 2-152)

[0187]

[0188] The synthesis method is as in Example 4.

[0189] 1H NMR (400MHz, DMSO-d6) δ10.88(s,1H),8.33(d,J=6.8Hz,1H),8.12(s,2H),7.92(d,J=9.8Hz,1H),7.82(s,1H),7 .59(s,1H),7.11(d,J=2.8Hz,1H),7.09(d,J=2.7Hz,1H),6.97(d,J=9.8Hz,1H),4.37–4.29(m,1H),4.15(dd,J=1 1.0,7.7Hz,1H),4.05-3.92(m,2H),3.72(t,J=9.1Hz,1H),3.52-3.45(m,1H),3.05(dd,J=11.1,8.7Hz,1H),2.46 (s,3H),2.31–2.22(m,2H),2.20–2.13(m,1H),2.13–2.04(m,1H),1.91-1.78(m,3H),1.65(s,1H).HRMS(ESI)for C 32 H 28 ClF3N6O3[M+H] + :calcd,637.1936,found.637.1943.

[0190] Example 7: Preparation of N-(3-chloro-5-(trifluoromethyl)phenyl)-4,6,14-dimethyl-10-oxo-5-oxo-11,14-diazo-1(3,6)-imidazo[1,2-b]pyridazine-4(1,3)-benzocyclotetradecane-2-yne-45-carboxamide (named WZQ 2-154)

[0191]

[0192] The synthesis method is as in Example 4.

[0193] 1H NMR (400MHz, CDCl3) δ9.15(s,1H),8.13(s,1H),7.93(s,1H),7.66(s,1H),7.57(d,J=9.8 Hz,1H),7.40(d,J=1.9Hz,1H),7.09(d,J=2.7Hz,1H),6.86(d,J=2.7Hz,1H),6.64(d,J=9 .9Hz,1H),6.15(t,J=5.6Hz,1H),3.98(t,J=6.1Hz,2H),3.73–3.66(m,2H),3.52-3.46(m ,2H),3.08(s,3H),2.52(s,3H),2.20(t,J=7.0Hz,2H),1.81-1.78(m,4H).HRMS(ESI)for C 31 H 28 ClF3N6O3[M+H] + :calcd,625.1936,found.625.1917.

[0194] Example 8:4 6 ,14-dimethyl-N-(3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl)-10-oxo-5-oxo-11,14-diazo-1(3,6)-imidazo[1,2-b]pyridazine-4(1,3)-benzocyclotetradecane-2-yne-4 5 - Preparation of formamide (named WZQ 3-1)

[0195]

[0196] The synthesis method is as in Example 4.

[0197] 1H NMR(400MHz, DMSO-d6)δ10.86(s,1H),8.19(d,J=1.5Hz,1H),8.18(s,1H),8.11(s,1H),7.97(s,1H), 7.93(d,J=10.0Hz,1H),7.89(s,1H),7.74(s,1H),7.47(t,J=1.3Hz,1H),7.29(d,J=2.7Hz,1H),7.13 (d,J=10.0Hz,1H),7.10(d,J=2.7Hz,1H),4.14(t,J=7.4Hz,2H),3.76–3.69(m,2H),3.43-3.37(m,2H ),3.14(s,3H),2.49(s,3H),2.22-2.20(m,2H),2.19–2.18(m,3H),1.83–1.70(m,4H).HRMS(ESI)for C 35 H 33 F3N8O3[M+H] + :calcd,671.2700,found.671.2692.

[0198] Embodiment 9: (1 3 S)-N-(3-chloro-5-(trifluoromethyl)phenyl)-5 6 -methyl-12-oxo-6-oxo-13-aza-2(6,3)-imidazo[1,2-b]pyridazine-1(1,3)-piperidin-5(1,3)-benzocyclotridecane-3-yne-5 5 - Preparation of formamide (named WZQ 3-3)

[0199]

[0200] The synthesis method is as in Example 4.

[0201] 1H NMR (400MHz, DMSO-d6) δ10.89(s,1H),8.12(d,J=2.3Hz,2H),7.91(dd,J=9.0,6.1Hz,3H),7.60(d,J=1.8Hz,1H),7.3 4(d,J=10.1Hz,1H),7.18(d,J=2.7Hz,1H),7.09(d,J=2.6Hz,1H),4.59(dd,J=12.6,4.5Hz,1H),4.17(t,J=5.7Hz,2H) ,4.10(d,J=12.9Hz,1H),3.81–3.70(m,1H),2.88–2.79(m,1H),2.46(s,3H),2.29-2.21(m,1H),2.07-2.0(m,1H),1. 92(d,J=12.0Hz,1H),1.83(d,J=13.3Hz,1H),1.77-1.69(m,3H),1.63–1.51(m,2H),1.51–1.32(m,4H).HRMS(ESI)for C 34 H 32 ClF3N6O3[M+H] + :calcd,665.2249,found.665.2253.

[0202] Example 10: 4 6 ,14-dimethyl-N-(3-((4-methylpiperazin-1-yl)methyl)-5-(trifluoromethyl)phenyl)-10-oxo-5-oxo-11,14-diazo-1(3,6)-imidazo[1,2-b]pyridazine-4(1,3)-benzocyclotetradecane-2-yne-4 5 - Preparation of formamide (named WZQ 3-9)

[0203]

[0204] The synthesis method is as in Example 4.

[0205] 1H NMR(400MHz,MeOD)δ8.08(s,1H),7.89(s,1H),7.77–7.70(m,2H),7.46(s, 1H),7.25(d,J=2.7Hz,1H),7.05(d,J=8.2Hz,1H),7.03(s,1H),4.13(t,J= 7.0Hz,2H),3.88–3.80(m,2H),3.63(s,2H),3.60–3.52(m,2H),3.18(s,3H) ),2.56(d,J=16.1Hz,11H),2.34(s,5H),1.91-1.85(m,4H).HRMS(ESI)for C 37 H 41 F3N8O3[M+H] + :calcd,703.3326,found.703.3330.

[0206] Example 11:4 6 ,13-dimethyl-N-(3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl)-9-oxo-5-oxo-10,13-diazo-1(3,6)-imidazo[1,2-b]pyridazine-4(1,3)-phenylcyclotridecan-2-yne-4 5 - Preparation of formamide (named WZQ3-19)

[0207]

[0208] The synthesis method is as in Example 4.

[0209] 1 H NMR (400MHz, DMSO-d6) δ10.86(s,1H),8.19(s,1H),8.18(s,1H),8.11(s,1H),8.07(t,J=5.3Hz,1H ),7.93(d,J=9.9Hz,1H),7.87(s,1H),7.74(s,1H),7.47(s,1H),7.45(d,J=2.7Hz,1H),7.12(d,J= 10.0Hz,1H),7.09(d,J=2.7Hz,1H),4.19(t,J=7.5Hz,2H),3.80–3.72(m,2H),3.42–3.37(m,2H),3 .14(s,3H),2.49(s,3H),2.23-2.20(m,2H),2.18(s,3H),1.95(q,J=9.2,8.4Hz,2H).HRMS(ESI)for C 34 H 31 F3N8O3[M+H]+ :calcd,657.2544,found.657.2528.

[0210] Example 12: 4 6 ,13-dimethyl-N-(3-((4-methylpiperazin-1-yl)methyl)-5-(trifluoromethyl)phenyl)-9-oxo-5-oxo-10,13-diazo-1(3,6)-imidazo[1,2-b]pyridazine-4(1,3)-benzocyclotridecane-2-yne-4 5 - Preparation of formamide (named WZQ 3-22)

[0211]

[0212] The synthesis method is as in Example 4.

[0213] 1 HNMR(400MHz,MeOD)δ8.02(s,1H),7.97(s,1H),7.75(d,J=10.0Hz,1H),7.71(s,1H),7.47 (s,1H),7.35(d,J=2.8Hz,1H),7.08(d,J=10.0Hz,1H),7.04(d,J=2.7Hz,1H),4.19(t,J=7 .1Hz,2H),3.91–3.83(m,2H),3.69(s,2H),3.60–3.52(m,2H),3.19(s,3H),2.97(s,4H),2 .69(s,4H),2.64(s,3H),2.54(s,3H),2.38–2.33(m,2H),2.12-2.07(m,2H).HRMS(ESI)for C 36 H 39 F3N8O3[M+H] + :calcd,689.3170,found.689.3143.

[0214] Example 13: 4 6 ,11-dimethyl-N-(3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl)-10-oxo-5-oxo-11,14-diazo-1(3,6)-imidazo[1,2-b]pyridazine-4(1,3)-benzocyclotetradecane-2-yne-4 5 - Preparation of formamide (named WZQ 3-48)

[0215]

[0216] The synthesis method is as in Example 4.

[0217] 1 H NMR(400MHz,DMSO-d6)δ10.86(s,1H),8.21–8.16(m,2H),8.11(s,1H),7.79(d,J=10.3Hz, 2H),7.75(s,1H),7.47(s,1H),7.23(d,J=2.7Hz,1H),7.13(s,1H),7.09(d,J=2.6Hz,1H), 6.76(d,J=9.8Hz,1H),4.01(t,J=7.6Hz,2H),3.62-3.57(m,1H),3.52-3.48(m,3H),3.08( s,3H),2.48(s,3H),2.44(t,J=5.1Hz,2H),2.19(s,3H),1.86-1.73(m,4H).HRMS(ESI)for C 35 H 33 F3N8O3[M+H] + :calcd,671.2700,found.671.2698.

[0218] Example 14: 4 6 -methyl-N-(3-(4-methyl-1H-imidazol-1-yl)-5-trifluoromethylphenyl)-10-oxo-5-oxa-11,14-diaza-1(3,6)-imidazo[1,2-b]pyridazine-4(1,3)-benzocyclotetradecane-2-yne-4 5 - Preparation of formamide (named WZQ 3-99)

[0219]

[0220] The synthesis method is as in Example 4.

[0221] 1 H NMR(400MHz,DMSO-d6)δ10.87(s,1H),8.20(s,1H),8.18(s,1H),8.10(s,1H),8.08(t, J=5.2Hz,1H),7.79(m,2H),7.74(s,1H),7.47(s,1H),7.26(t,J=5.3Hz,1H),7.19(d,J= 2.7Hz,1H),7.09(d,J=2.6Hz,1H),6.74(d,J=9.7Hz,1H),4.06(t,J=7.5Hz,2H),3.47– 3.37(m,4H),2.48(s,3H),2.20(m,2H),2.18(s,3H),1.86–1.71(m,4H).HRMS(ESI)forC 34 H31 F3N8O3[M+H] + :calcd,657.2544,found.657.2561.

[0222] Example 15:4 6 -methyl-N-(3-(4-methyl-1H-imidazol-1-yl)-5-trifluoromethylphenyl)-11-oxo-5-oxa-10,14-diaza-1(3,6)-imidazo[1,2-b]pyridazine-4(1,3)-benzocyclotetradecane-2-yne-4 5 - Preparation of formamide (named WZQ 3-115)

[0223]

[0224] The synthesis method is as in Example 4.

[0225] 1 H NMR (400MHz, DMSO-d6) δ10.87(s,1H),8.20(s,1H),8.18(s,1H),8.11(s,1H),8.05(t,J=5.7Hz,1H),7 .81(s,1H),7.78(d,J=9.7Hz,1H),7.74(s,1H),7.47(s,1H),7.34(t,J=5.7Hz,1H),7.18(d,J=2.7Hz,1 H),7.09(d,J=2.6Hz,1H),6.73(d,J=9.7Hz,1H),4.19–4.09(m,2H),3.59-3.53(m,2H),3.18-3.14(m, 2H),2.63–2.57(m,2H),2.49(s,3H),2.18(s,3H),1.85-1.77(m,2H),1.65-1.56(m,2H).HRMS(ESI)for C 34 H 31 F3N8O3[M+H] + :calcd,657.2544,found,657.2552.

[0226] Example 16: 4 6 , 10-dimethyl-N-(3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl)-11-oxo-5-oxa-10,14-diaza-1(3,6)-imidazo[1,2-b]pyridazine-4(1,3)-benzocyclotetradecano-2-ynyl-4 5 - Preparation of formamide (named WZQ 3-151)

[0227]

[0228] The synthesis method is as in Example 4.

[0229] 1 H NMR(400MHz,DMSO-d6)δ10.86(s,1H),8.20(s,1H),8.17(s,1H),8.10(s,1H),7.80(s,1H),7 .77(d,J=9.5Hz,1H),7.74(s,1H),7.47(s,1H),7.35(t,J=5.8Hz,1H),7.08(s,1H),7.05(s, 1H),6.74(d,J=9.7Hz,1H),4.12(t,J=7.5Hz,2H),3.54(q,J=7.3Hz,2H),3.44–3.39(m,2H), 2.93(s,3H),2.82-2.75(m,2H),2.47(s,3H),2.18(s,3H),1.78-1.64(m,4H).HRMS(ESI)for C 35 H 33 F3N8O3[M+H] + :calcd,671.2700,found,671.2738.

[0230] Example 17: 4 6 -methyl-N-(3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl)-13-oxo-5-oxo-12-aza-1(3,6)-imidazo[1,2-b]pyridazine-4(1,3)-benzocyclotridecane-2-yne-4 5 - Preparation of formamide (named WZQ3-87)

[0231]

[0232] Step 1: Preparation of methyl 5-((6-((tert-butyloxycarbonyl)amino)hexyl)oxy)-3-iodo-2-methylbenzoate (Compound 2)

[0233]

[0234] Compound 1 (3.0 g, 10.27 mmol), tert-butyl (6-hydroxyhexyl) carbamate (2.68 g, 12.33 mmol) and PPh3 (4.04 g, 15.40 mmol) were added to a 100 mL two-necked flask. After evacuation under argon protection, 30 mL of anhydrous THF was added. The reaction flask was placed in an ice bath and DIAD (2.7 mL, 15.4 mmol) was added within 20 minutes. After 0.5 hour, the mixture was moved to room temperature and reacted for 6 hours. The solvent was spin-dried and column chromatography was performed to obtain 4.0 g of a yellow oil (yield: 79.25%).

[0235] 1 H NMR (400MHz, CDCl3) δ7.54(d,J=2.8Hz,1H),7.29(d,J=2.6Hz,1H),4.61(s,1H),3.92(t,J=8.3Hz,2H),3.90(s,3H),3. 13(q,J=6.8Hz,2H),2.58(s,3H),1.79-1.72(m,2H),1.56-1.48(m,4H),1.46(s,9H),1.41-1.35(m,2H).LC-MS(ESI)m / z 490.1[MH] - .

[0236] Step 2: Preparation of methyl 5-((6-((tert-butoxycarbonyl)amino)hexyl)oxy)-2-methyl-3-((trimethylsilyl)ethynyl)benzoate (Compound 3)

[0237]

[0238] Compound 3 was obtained by referring to the synthetic method of step 5 in Example 4, and the crude product was directly used in the next step.

[0239] Step 3: Preparation of methyl 5-((6-((tert-butoxycarbonyl)amino)hexyl)oxy)-3-ethynyl-2-methylbenzoate (Compound 4)

[0240]

[0241] Compound 4 was obtained by referring to the synthetic method of step 6 in Example 4.

[0242] 1H NMR (400MHz, CDCl3) δ7.32(d,J=2.9Hz,1H),7.10(d,J=2.9Hz,1H),4.71(s,1H),3.88(t,J=6.4Hz,2H),3.84(s,3H),3 .29(s,1H),3.07(q,J=6.7Hz,2H),2.57(s,3H),1.74-1.68(m,2H),1.49-1.43(m,4H),1.40(s,9H),1.36–1.30(m,2H). LC-MS(ESI)m / z388.3[MH] - .

[0243] Step 4: Preparation of tert-butyl (6-(3-ethynyl-4-methyl-5-((3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl)carbamoyl)phenoxy)hexyl)carbamate (Compound 5)

[0244]

[0245] Compound 5 was obtained by referring to the synthetic method of step 9 in Example 4.

[0246] 1 H NMR (400MHz, CDCl3) δ8.73(s,1H),8.24(s,1H),7.78(s,2H),7.35(s,1H),7.09(t,J=3.3Hz,2H),7.02(d,J=2.7Hz,1H),4.54(s,1H),3.96(t,J =6.3Hz,2H),3.32(s,1H),3.08(q,J=6.7Hz,2H),2.51(s,3H),2.28(s,3H),1.78-1.71(m,2H),1.51-1.42(m,4H),1.39(s,11H).LC-MS(ESI)m / z 597.3[MH] - .

[0247] Step 5: Preparation of methyl 3-iodoimidazole [1,2-b] pyridazine-6-carboxylate (Compound 7)

[0248]

[0249] Compound 6 (970 mg, 5.47 mmol) was dissolved in 20 mL of DMF, and NIS (2.46 g, 10.95 mmol) was added. After heating to 90°C for 2 hours, the mixture was extracted with ethyl acetate and water 2-3 times. The organic layer was dried by spin drying and column chromatography was used to obtain 500 mg of a yellow solid (yield: 30.13%).

[0250] 1 H NMR (400MHz, DMSO-d6) δ8.27(d,J=9.5Hz,1H),8.10(s,1H),7.76(d,J=9.5Hz,1H),3.99(s,3H).LC-MS(ESI)m / z 304.0[M+H] + .

[0251] Step 6: Preparation of methyl 3-((5-((tert-butyloxycarbonyl)amino)hexyl)oxy)-2-methyl-3-((3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl)carbamoyl)phenyl)ethynyl)imidazole[1,2-b]pyridazine-6-carboxylate (Compound 8)

[0252]

[0253] Compound 8 was obtained by referring to the synthetic method of step 7 in Example 4.

[0254] 1 H NMR(400MHz, DMSO-d6)δ10.90(s,1H),8.40(d,J=9.7Hz,2H),8.22(s,1H),8.19(s,1H),8.11(s ,1H),7.86(d,J=9.5Hz,1H),7.76(s,1H),7.50(s,1H),7.29(d,J=2.6Hz,1H),7.21(d,J=2.7Hz, 1H),6.78(t,J=5.0Hz,1H),4.07(t,J=6.6Hz,2H),3.96(s,3H),2.91(q,J=6.6Hz,2H),2.60(s,3 H),2.19(s,3H),1.76-1.70(m,2H),1.45-1.29(m,6H),1.36(s,9H).LC-MS(ESI)m / z774.7[M+H] + .

[0255] Step 7: Preparation of 3-((5-((6-((tert-butyloxycarbonyl)amino)hexyl)oxy)-2-methyl-3-((3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl)carbamoyl)phenyl)ethynyl)imidazole[1,2-b]pyridazine-6-carboxylic acid (Compound 9)

[0256]

[0257] Compound 8 (150 mg, 0.19 mmol) was dissolved in 12 mL of a mixed solvent of THF / H2O=5:1, and LiOH (23.2 mg, 0.97 mmol) was added and stirred at room temperature overnight. After THF was dried, the pH was adjusted to acidic with 2N HCl solution, and a yellow solid was precipitated. The crude product (108 mg, yield: about 73.33%) was obtained by filtration and used directly in the next step.

[0258] Step 8:4 6 -methyl-N-(3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl)-13-oxo-5-oxo-12-aza-1(3,6)-imidazo[1,2-b]pyridazine-4(1,3)-benzocyclotridecane-2-yne-4 5 - Preparation of formamide (compound WZQ 3-87)

[0259]

[0260] Compound 9 (108 mg, 0.14 mmol) was dissolved in 10 mL of DCM, and 2 mL of TFA was added to react at room temperature for 2 hours. The crude product was obtained by spin drying the solvent, and dissolved in 30 mL of a DMF / DCM mixed solvent. DIPEA (0.12 mL, 0.71 mmol) and FDPP (81.99 mg, 0.21 mmol) were added to react overnight, and then extracted twice with DCM and H2O. 28 mg of a yellow solid was obtained by column chromatography (total yield of two steps: 30.7%).

[0261] 1 H NMR (400MHz, DMSO-d6) δ10.90(s,1H),8.91(t,J=5.6Hz,1H),8.36(t,J=4.7Hz,2H),8.20(s, 1H),8.17(d,J=2.2Hz,1H),8.12(s,1H),7.77(d,J=9.4Hz,1H),7.75(s,1H),7.53(d,J=2.8Hz ,1H),7.47(s,1H),7.14(d,J=2.7Hz,1H),4.29(t,J=8.1Hz,2H),3.45-3.41(m,2H),2.54(s, 3H),2.19(s,3H),1.79-1.72(m,2H),1.66-1.58(m,4H),1.48(q,J=7.2Hz,2H).HRMS(ESI)for C 34 H 30 F3N7O3[M+H] + :calcd,642.2435,found,642.2462.

[0262] Example 18: 4 6 -methyl-N-(3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl)-12-oxo-5-oxo-11-aza-1(3,6)-imidazo[1,2-b]pyridazine-4(1,3)-benzocyclododec-2-yne-4 5 - Preparation of formamide (named WZQ3-95)

[0263]

[0264] The synthesis method is similar to that of Example 17.

[0265] 1 H NMR (400MHz, DMSO-d6) δ10.88(s,1H),8.66(t,J=5.6Hz,1H),8.38(d,J=9.4Hz,1H),8. 32(s,1H),8.20(s,2H),8.11(s,1H),7.77(d,J=9.4Hz,2H),7.48(s,1H),7.37(d,J=2.7 Hz,1H),7.17(d,J=2.6Hz,1H),4.21(t,J=7.2Hz,2H),3.39(q,J=5.7Hz,2H),2.52(s,3H ),2.19(s,3H),1.84–1.77(m,2H),1.71-1.66(m,2H),1.61–1.53(m,2H).HRMS(ESI)for C 33 H 28 F3N7O3[M+H] + :calcd,628.2278,found.628.2292.

[0266] Example 19: 4 6 -methyl-N-(3-(4-methyl-1H-imidazol-1-yl)-5-trifluoromethylphenyl)-14-oxo-5-oxa-13-aza-1(3,6)-imidazo[1,2-b]pyridazine-4(1,3)-benzocyclotetradecane-2-ynyl-4 5 - Preparation of formamide (named WZQ 3-109)

[0267]

[0268] The synthesis method is similar to that of Example 17.

[0269] 1H NMR(400MHz,DMSO-d6)δ10.89(s,1H),8.88(t,J=5.6Hz,1H),8.37-8.35(m,2H),8.20(s,1H), 8.19(s,1H),8.12(s,1H),7.80(d,J=9.4Hz,1H),7.75(s,1H),7.57(d,J=2.7Hz,1H),7.48(s,1 H),7.16(d,J=2.6Hz,1H),4.24(t,J=7.5Hz,2H),3.40(q,J=6.0Hz,2H),2.54(s,3H),2.19(s,3 H),1.80-1.73(m,2H),1.66-1.60(m,2H),1.52-1.48(m,2H),1.48-1.43(m,4H).HRMS(ESI)for C 35 H 32 F3N7O3[M+H] + :calcd,656.2591,found,656.2602.

[0270] Example 20:4 6 -methyl-N-(3-(4-methyl-1H-imidazol-1-yl)-5-trifluoromethylphenyl)-15-oxo-5-oxa-14-aza-1(3,6)-imidazo[1,2-b]pyridazine-4(1,3)-benzocyclopentadecane-2-ynyl-4 5 - Preparation of formamide (named WZQ 3-143)

[0271]

[0272] The synthesis method is similar to that of Example 17.

[0273] 1 H NMR(400MHz,DMSO-d6)δ10.91(s,1H),8.86(s,1H),8.39(s,1H),8.35(s,2H) ,8.22(s,1H),8.12(s,1H),7.81-7.78(m,2H),7.61(s,1H),7.56(s,1H),7.2 0(s,1H),4.16(t,J=6.8Hz,2H),3.40(q,J=6.6Hz,2H),2.54(s,3H),2.21(s, 3H),1.83-1.77(m,2H),1.66-1.60(m,2H),1.49-1.42(m,8H).HRMS(ESI)for C36H34F3N7O3[M+H] +:calcd,670.2748,found,670.2780.

[0274] Example 21:4 6 -methyl-N-(3-(4-methyl-1H-imidazol-1-yl)-5-trifluoromethylphenyl)-11,14-dioxo-5-oxa-10,13-diaza-1(3,6)-imidazo[1,2-b]pyridazine-4(1,3)-benzocyclotetradecane-2-yne-4 5 - Preparation of formamide (named WZQ 3-152)

[0275]

[0276] The synthesis method is similar to that of Example 17.

[0277] 1 H NMR (400MHz, DMSO-d6) δ10.90(s,1H),8.97(d,J=5.5Hz,1H),8.40(d,J=9.4Hz,1H),8.38(s ,1H),8.26(t,J=6.0Hz,1H),8.20(s,2H),8.12(s,1H),7.86(d,J=9.4Hz,1H),7.75(s,1H), 7.59(s,1H),7.48(s,1H),7.16(s,1H),4.23(t,J=7.6Hz,2H),4.02(d,J=5.2Hz,2H),3.23- 3.19(m,2H),2.54(s,3H),2.18(s,3H),1.87-1.80(m,2H),1.67-1.62(m,2H).HRMS(ESI)for C 34 H 29 F3N8O4[M+H] + :calcd,671.2337,found,671.2353.

[0278] Example 22: 4 6 -methyl-N-(4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)-14-oxo-5-oxa-13-aza-1(3,6)-imidazo[1,2-b]pyridazine-4(1,3)-benzocyclotetradecane-2-yne-4 5 - Preparation of formamide (named WZQ 4-5)

[0279]

[0280] The synthesis method is similar to that of Example 17.

[0281] 1 H NMR (400MHz, DMSO-d6) δ10.71(s,1H),8.87(t,J=5.5Hz,1H),8.36(d,J=8.3Hz,1H),8.35(s, 1H),8.21(s,1H),7.97(d,J=8.6Hz,1H),7.80(d,J=9.4Hz,1H),7.71(d,J=8.5Hz,1H),7.54(s ,1H),7.10(s,1H),4.23(t,J=7.6Hz,2H),3.63(s,2H),3.44-3.40(m,2H),2.86(s,4H),2.54 (s,4H),2.48(s,3H),1.79-1.73(m,2H),1.66-1.60(m,2H),1.54-1.42(m,6H).HRMS(ESI)for C 37 H 40 F3N7O3[M+H] + :calcd,688.3217,found,688.3250.

[0282] Example 23: N-(3-chloro-5-trifluoromethyl)-4-(4-(2-(trifluoromethyl)-3-yl)-1-nitropropene ... 6 -methyl-14-oxo-5-oxa-13-aza-1(3,6)-imidazo[1,2-b]pyridazine-4(1,3)-benzocyclotetradecane-2-yne-4 5 - Preparation of formamide (named WZQ 4-12)

[0283]

[0284] The synthesis method is similar to that of Example 17.

[0285] 1 H NMR (400MHz, DMSO-d6) δ10.89(s,1H),8.87(t,J=5.5Hz,1H),8.36-8.34(m,2H),8.13(s,2H),7.80(d,J=9.4Hz,1H),7.59(s,1H),7.55(s,1H), 7.15(s,1H),4.23(t,J=7.5Hz,2H),3.39(q,J=6.1Hz,2H),2.51(s,3H),1.83-1.72(m,2H),1.65-1.60(m,2H),1.51-1.45(m,6H).HRMS(ESI)for C 31 H 27 ClF3N5O3[M+H] +:calcd,610.1827,found,610.1847.

[0286] Example 24: 4 6 -methyl-N-(3-(4-methylpiperazin-1-yl)methyl)-5-(trifluoromethyl)phenyl)-14-oxo-5-oxa-13-aza-1(3,6)-imidazo[1,2-b]pyridazine-4(1,3)-benzocyclohexane-2-yne-4 5 - Preparation of formamide (named WZQ 4-13)

[0287]

[0288] The synthesis method is similar to that of Example 17.

[0289] 1 H NMR (400MHz, DMSO-d6) δ10.74 (s, 1H), 8.87 (t, J = 5.5Hz, 1H), 8.38-8.34 (m, 2H), 8.14 ( s,1H),7.95(s,1H),7.80(d,J=9.5Hz,1H),7.54(d,J=2.7Hz,1H),7.39(s,1H),7.12(d ,J=2.6Hz,1H),4.23(t,J=7.4Hz,2H),3.59(s,2H),3.40(q,J=5.5Hz,2H),2.67(s,8H) ,2.39(s,3H),1.80-1.73(m,2H),1.67-1.60(m,2H),1.54-1.42(m,6H).HRMS(ESI)for C 37 H 40 F3N7O3[M+H] + :calcd,688.3217,found,688.3220.

[0290] Example 25:4 6 -methyl-N-(3-(4-morpholinopiperidin-1-yl)-5-(trifluoromethyl)phenyl)-14-oxo-5-oxa-13-aza-1(3,6)-imidazo[1,2-b]pyridazine-4(1,3)-benzocyclotetradecane-2-yne-4-yl)- 5 - Preparation of formamide (named WZQ4-21)

[0291]

[0292] The synthesis method is similar to that of Example 17.

[0293] 1H NMR (400MHz, DMSO-d6) δ10.54(s,1H),8.88(t,J=6.0Hz,1H),8.38-8.35(m,2H),7.80(d,J=9.4Hz,1H),7.62(s,1H) ,7.60(s,1H),7.55(s,1H),7.09(s,1H),7.03(s,1H),4.23(t,J=7.6Hz,2H),4.04-3.92(m,4H),3.66(t,J=12.4Hz,2 H),3.50(d,J=12.5Hz,2H),3.39(q,J=6.8Hz,2H),3.19-3.05(m,2H),2.85(t,J=12.8Hz,2H),2.49(s,3H),2.46(t,J =10.5Hz,1H),2.16(d,J=10.2Hz,2H),1.79-1.74(m,2H),1.68-1.63(m,4H),1.51-1.45(m,6H).HRMS(ESI)for[M+H] + :calcd,744.3480,found,744.3484.

[0294] Example 26: N-(3-tert-butyl)-1-(4-chlorophenyl)-1H-pyrazol-5-yl)-4 6 -methyl-14-oxo-5-oxa-13-aza-1(7,2)-pyrrolo[1,2-b]pyridine-4(1,3)-benzocyclotetraene-2-yne-4 5 - Preparation of formamide (named WZQ 4-24)

[0295]

[0296] The synthesis method is similar to that of Example 17.

[0297] 1 H NMR (400MHz, DMSO-d6) δ10.42(s,1H),8.85(t,J=5.6Hz,1H),8.36(t,J=4.7Hz,2H) ,7.79(d,J=9.4Hz,1H),7.58(q,J=2.5Hz,4H),7.52(d,J=2.7Hz,1H),7.01(d,J=2.6 Hz,1H),6.47(s,1H),4.21(t,J=7.5Hz,2H),3.39(q,J=6.0Hz,2H),2.38(s,3H),1. 79-1.71(m,2H),1.65-1.58(m,2H),1.50-1.44(m,6H),1.32(s,9H).HRMS(ESI)forC37 H 38 ClN7O3[M+H] + :calcd,664.2797,found,664.2808.

[0298] Example 27:4 6 -methyl-N-(3-(4-methyl-1,4-diazepin-1-yl)methyl)-5-(trifluoromethyl)phenyl)-14-oxo-5-oxa-13-aza-1(3,6)-imidazo[1,2-b]pyridazine-4(1,3)-benzocyclotetradecane-2-ynyl-4 5 - Preparation of formamide (named WZQ 4-28)

[0299]

[0300] The synthesis method is similar to that of Example 17.

[0301] 1 H NMR (400MHz, DMSO-d6) δ10.72(s,1H),8.87(t,J=5.6Hz,1H),8.37-8.35(m,2H),8.15(s,1 H),7.93(s,1H),7.80(d,J=9.4Hz,1H),7.54(d,J=2.7Hz,1H),7.39(s,1H),7.12(d,J=2.7 Hz,1H),4.23(t,J=7.4Hz,2H),3.69(s,2H),3.42-3.39(m,2H),2.68-2.62(m,4H),2.59-2 .55(m,4H),2.25(s,3H),1.78-1.70(m,4H),1.63(s,2H),1.52-1.45(m,6H).HRMS(ESI)for C 38 H 42 F3N7O3[M+Na] + :calcd,724.3193,found,724.3211.

[0302] Example 28: 4 6 -methyl-N-(3-morpholinomethyl)-5-trifluoromethylphenyl)-14-oxo-5-oxa-13-aza-1(3,6)-imidazo[1,2-b]pyridazine-4(1,3)-benzocyclotetradecane-2-yne-4 5 - Preparation of formamide (named WZQ 4-45)

[0303]

[0304] The synthesis method is similar to that of Example 17.

[0305] 1 H NMR(400MHz,DMSO-d6)δ10.72(s,1H),8.86(s,1H),8.35(s,2H),8.16(s,1H),7. 94(s,1H),7.79(d,J=9.4Hz,1H),7.53(s,1H),7.39(s,1H),7.13(s,1H),4.23(t, J=8.3Hz,2H),3.59(s,4H),3.55(s,2H),3.39(q,J=6.6Hz,2H),2.52(s,3H),2.3 9(s,4H),1.80-1.74(m,2H),1.65-1.60(m,2H),1.50-1.45(m,6H).HRMS(ESI)for C36H37F3N6O4[M+H] + :calcd,675.2901,found,675.2927.

[0306] Example 29: N-(3-isopropyl-5-(4-methylpiperazin-1-yl)methyl)phenyl)-4-(4-methylpiperazin-1-yl)methyl)phenyl 6 -methyl-14-oxo-5-oxa-13-aza-1(3,6)-imidazo[1,2-b]pyridazine-4(1,3)-benzocyclotetradecane-2-ynyl-4 5 - Preparation of formamide (named WZQ 4-48)

[0307]

[0308] The synthesis method is similar to that of Example 17.

[0309] 1 H NMR (400MHz, DMSO-d6) δ10.34(s,1H),8.86(t,J=5.6Hz,1H),8.36(d,J=9.1Hz,1H),8.35(s,1H) ,7.80(d,J=9.4Hz,1H),7.60(s,1H),7.52(s,1H),7.51(s,1H),7.05(d,J=2.6Hz,1H),6.93(s,1 H),4.22(t,J=7.4Hz,2H),3.49(s,2H),3.41(t,J=6.2Hz,2H),2.89-2.83(m,1H),2.49(s,8H),1 .80-1.73(m,2H),1.66-1.60(m,2H),1.55-1.39(m,6H),1.22(s,3H),1.20(s,3H).HRMS(ESI)for C39 H 47 N7O3[M+Na] + :calcd,684.3633,found,684.3662.

[0310] Example 30: N-(3-cyclopropyl-5-(4-methylpiperazin-1-yl)methyl)phenyl)-4-(4-methylpiperazin-1-yl)methyl)phenyl 6 -methyl-14-oxo-5-oxa-13-aza-1(3,6)-imidazo[1,2-b]pyridazine-4(1,3)-benzocyclotetradecane-2-yne-4 5 - Preparation of formamide (named WZQ4-69)

[0311]

[0312] The synthesis method is similar to that of Example 17.

[0313] 1 H NMR (400MHz, DMSO-d6) δ10.29(s,1H),8.86(t,J=5.6Hz,1H),8.36(d,J=9.4Hz,1H),8.35(s,1H),7.80(d,J= 9.4Hz,1H),7.52(s,1H),7.51(s,1H),7.34(d,J=1.8Hz,1H),7.05(d,J=2.6Hz,1H),6.78(s,1H),4.22(t,J= 7.4Hz,2H),3.42(s,2H),3.40(q,J=6.1Hz,2H),2.50(s,3H),2.48(s,4H),2.32(s,4H),1.93-1.86(m,1H),1 .80-1.73(m,2H),1.66-1.60(m,2H),1.53-1.43(m,6H),0.98-0.93(m,2H),0.65-0.60(m,2H).HRMS(ESI)for C 39 H 45 N7O3[M+H] + :calcd,660.3657,found,660.3654.

[0314] Example 31: N-(3-tert-butyl)-5-(4-methylpiperazin-1-yl)methylphenyl)-4-(4-methylpiperazin-1-yl)methylphenyl 6 -methyl-14-oxo-5-oxa-13-aza-1(3,6)-imidazo[1,2-b]pyridazine-4(1,3)-benzocyclotetradecane-2-yne-4 5 - Preparation of formamide (named WZQ4-85)

[0315]

[0316] The synthesis method is similar to that of Example 17.

[0317] 1 H NMR (400MHz, DMSO-d6) δ10.31(s,1H),8.86(t,J=5.6Hz,1H),8.36(d,J=9.4Hz,1H),8.35(s, 1H),7.79(d,J=9.4Hz,1H),7.65(s,1H),7.61(s,1H),7.51(d,J=2.7Hz,1H),7.07-7.05(m,2H ),4.22(t,J=7.5Hz,2H),3.44(s,2H),3.40(q,J=7.1Hz,2H),2.50(s,3H),2.38(s,8H),2.18 (s,3H),1.79-1.73(m,2H),1.66-1.60(m,2H),1.52-1.45(m,6H),1.28(s,9H).HRMS(ESI)for C 40 H 49 N7O3[M+Na] + :calcd,698.3789,found,698.3820.

[0318] Example 32: Preparation of N-(3-cyclopropyl-5-(4-methylpiperazin-1-yl)methyl)phenyl)-14-oxo-5-oxa-13-aza-1(3,6)-imidazo[1,2-b]pyridazine-4(1,3)-benzocyclotetradecane-2-ynyl-4-carboxamide (named WZQ 4-107)

[0319]

[0320] The synthesis method is similar to that of Example 17.

[0321] 1H NMR (400MHz, DMSO-d6) δ10.10(s,1H),8.94(t,J=5.5Hz,1H),8.37(d,J=9.7Hz,1H),8.36(s,1H),7.82(d,J=9.4 Hz,1H),7.70(d,J=7.9Hz,1H),7.59(s,1H),7.53(s,1H),7.30(s,1H),7.29(d,J=8.6Hz,1H),6.78(s,1H),4.36 (t,J=7.8Hz,2H),3.48(s,3H),3.42(q,J=6.7Hz,2H),2.82(s,4H),2.52(s,4H),2.35(s,3H),1.94-1.88(m,1H) ,1.87-1.81(m,2H),1.65-1.61(m,2H),1.55-1.41(m,6H),0.99–0.93(m,2H),0.67–0.61(m,2H).HRMS(ESI)for C 38 H 43 N7O3[M+H] + :calcd,646.3500,found,646.3508.

[0322] Example 33: N-(3-isopropyl-5-(4-methylpiperazin-1-yl)methyl)phenyl)-4-(4-(3-isopropyl) ... 6 -methyl-14-oxo-5-oxa-13-aza-1(3,6)-imidazo[1,2-b]pyridazine-4(1,3)-benzocyclotetradecane-4 5 - Preparation of formamide (named WZQ 4-81)

[0323]

[0324] Steps: Dissolve compound 1 (30 mg, 0.045 mmol) in 10 mL of methanol, add 10 mg of palladium-carbon, react overnight under hydrogen conditions, then remove the palladium-carbon by filtration with diatomaceous earth, and obtain 5 mg of yellow-white solid by column chromatography (yield: 16.57%).

[0325] 1H NMR (400MHz, CDCl3) δ8.08(d,J=9.4Hz,1H),7.89(d,J=9.4Hz,1H),7.83(s,1H),7.54(s,1H),7.50(s,1 H),7.47(t,J=5.3Hz,1H),7.41(s,1H),7.01(s,2H),6.92(d,J=2.6Hz,1H),4.07(t,J=6.1Hz,2H),3.57 (q,J=6.4Hz,2H),3.54(s,2H),3.37-3.30(m,2H),3.09-3.03(m,2H),2.98-2.91(m,1H),2.51(s,8H),2 .42(s,3H),2.32(s,3H),1.81-1.76(m,6H),1.56-1.49(m,4H),1.30(s,3H),1.29(s,3H).HRMS(ESI)for C 39 H 51 N7O3[M+Na] + :calcd,688.3946,found,688.3947.

[0326] Example 34: (E)-N-(3-isopropyl-5-(4-methylpiperazin-1-yl)methyl)phenyl)-4-(4-(2 ... 6 -methyl-14-oxo-5-oxa-13-aza-1(3,6)-imidazo[1,2-b]pyridine-4(1,3)-benzocyclotetradecane-2-ene-4 5 - Preparation of formamide (named WZQ4-92)

[0327]

[0328] Step 1: Preparation of tert-butyl (7-(3-iodo-5-(3-isopropyl-5-(4-methylpiperazin-1-yl)methyl)phenyl)carbamoyl)-4-methylphenoxy)heptyl)carbamate (Compound 2)

[0329]

[0330] Compound 2 was obtained by referring to the synthetic method of step 9 in Example 4.

[0331] 1H NMR (400MHz, CDCl3) δ7.73 (s, 1H), 7.47 (d, J = 2.5Hz, 1H), 7.45 (s, 1H), 7.39 (s, 1 H),6.98(s,2H),4.58(s,1H),3.93(t,J=6.4Hz,2H),3.50(s,2H),3.10(q,J=6.7 Hz,2H),2.95-1.88(m,1H),2.54-2.43(m,11H),2.30(s,3H),1.79-1.72(m,2H), 1.52-1.43(m,13H),1.39-1.33(m,4H),1.27(s,3H),1.25(s,3H).LC-MS(ESI)m / z 721.2[M+H] + .

[0332] Step 2: Preparation of methyl 3-vinylimidazolo[1,2-b]pyridazine-6-carboxylate (Compound 4)

[0333]

[0334] Compound 3 (100 mg, 0.33 mmol) and tributyl vinyl tin (418 mg, 1.32 mmol) were dissolved in 10 mL of toluene, and then tetrakistriphenylphosphine palladium (38.11 mg, 0.03 mmol) was added, and the reaction system was reacted at 90° C. overnight under argon protection. The reaction system was spin-dried, and 54 mg of a yellow solid was obtained by column chromatography (yield: 80.54%).

[0335] 1 H NMR (400MHz, CDCl3) δ8.06(d,J=9.4Hz,1H),8.03(s,1H),7.77(d,J=9.5Hz,1H),7.13(dd,J=17.9,1 1.7Hz,1H),6.34(dd,J=17.9,1.2Hz,1H),5.56(dd,J=11.7,1.3Hz,1H),4.07(s,3H).LC-MS(ESI)m / z 204.1[M+H] + .

[0336] Step 3: Preparation of (E)-3-(5-(7-tert-butoxycarbonylamino)heptyl)oxy)-3-(3-isopropyl-5-(4-methylpiperazin-1-yl)methyl)phenyl)carbamoyl)-2-methylphenylimidazo[1,2-b]pyridazine-6-carboxylic acid methyl ester (Compound 5)

[0337]

[0338] Compound 2 (200 mg, 0.28 mmol) and compound 4 (56.4 mg, 0.28 mmol) were dissolved in 15 mL of ultra-dry DMF, and then palladium acetate (4.9 mg, 0.02 mmol), tri(o-methylphenyl)phosphine (13.5 mg, 0.04 mmol) and N,N-diisopropylethylamine (0.18 mL, 1.11 mmol) were added. After reacting at 90 ° C for 12 hours, the mixture was extracted with ethyl acetate and water for 2-3 times, the organic layers were combined, and 107 mg of yellow-brown oil was obtained by column chromatography (yield: 48.44%).

[0339] 1 H NMR (400MHz, CDCl3) δ8.25(d,J=16.4Hz,1H),8.09(s,1H),8.08(d,J=9.0Hz,1H),7.83(s,1H),7.80(d,J=9.4Hz,1 H),7.51(s,1H),7.49(s,1H),7.32(d,J=16.3Hz,1H),7.28(s,1H),6.99(s,1H),6.96(d,J=2.7Hz,1H),4.56(s,1H) ,4.07(s,3H),4.03(t,J=6.4Hz,2H),3.57(s,2H),3.13(q,J=6.0Hz,2H),2.98-2.93(m,1H),2.64(s,8H),2.53(s, 3H),2.40(s,3H),1.86-1.79(m,2H),1.54-1.47(m,4H),1.44(s,9H),1.41-1.36(m,4H),1.30(s,3H),1.28(s,3H).

[0340] Step 4: Preparation of (E)-3-(5-(7-tert-butyloxycarbonylamino)heptyl)oxy)-3-(3-isopropyl-5-(4-methylpiperazin-1-yl)methyl)phenyl)carbamoyl)-2-methylphenyl)imidazo[1,2-b]pyridazine-6-carboxylic acid (Compound 6)

[0341]

[0342] Compound 6 was obtained by referring to the synthetic method of step 7 in Example 17, and the crude product was directly used in the next step.

[0343] Step 5: (E)-N-(3-isopropyl-5-(4-methylpiperazin-1-yl)methyl)phenyl)-4-(4-(2-(2-methylpiperazin-1-yl)methyl)phenyl)- ...methylpiperazin-1-yl)methyl)phenyl)-4-(2-methylpiperazin-1-yl)methyl)phenyl)-4- 6 -methyl-14-oxo-5-oxa-13-aza-1(3,6)-imidazo[1,2-b]pyridine-4(1,3)-benzocyclotetradecane-2-ene-4 5- Preparation of formamide (compound WZQ4-92)

[0344]

[0345] Compound WZQ 4-92 was obtained by referring to the synthetic method of Step 8 in Example 17.

[0346] 1 H NMR (400MHz, DMSO-d6) δ10.26(s,1H),8.97(t,J=5.4Hz,1H),8.56(s,1H),8.28(d,J=9.4Hz,1H),7.87(d,J= 16.6Hz,1H),7.73(d,J=16.5Hz,1H),7.67(d,J=9.4Hz,1H),7.56(s,1H),7.54(s,2H),6.90(s,1H),6.89(s, 1H),4.24(t,J=7.6Hz,2H),3.43(s,2H),3.40(q,J=6.6Hz,2H),2.89-2.82(m,1H),2.43-2.39(m,11H),2.24 (s,3H),1.87-1.80(m,2H),1.66-1.60(m,2H),1.55-1.43(m,6H),1.21(s,3H),1.19(s,3H).HRMS(ESI)forC 39 H 49 N7O3[M+H] + :calcd,664.3970,found,664.3983.

[0347] Example 35: 1-(4-chloro-3-trifluoromethylphenyl)-3-(-4 6 -methyl-14-oxo-5-oxa-13-aza-1(3,6)-imidazo[1,2-b]pyridazine-4(1,3)-benzocyclotetradecane-2-ynyl-4 5 -yl) urea (named WZQ4-52).

[0348]

[0349] The synthesis method is similar to that of Example 17.

[0350] 1H NMR (400MHz, DMSO-d6) δ9.56 (s, 1H), 8.81 (t, J = 5.6Hz, 1H), 8.35 (d, J = 9.4Hz, 1 H),8.33(s,1H),8.19(s,1H),8.10(s,1H),7.77(d,J=9.4Hz,1H),7.64(s,2H),7 .52(d,J=2.4Hz,1H),7.15(d,J=2.4Hz,1H),4.15(t,J=7.3Hz,2H),3.39(q,J=5. 3Hz,2H),2.42(s,3H),1.77-1.71(m,2H),1.65-1.58(m,2H),1.48-1.44(m,6H).

[0351] Example 36 IC of Compounds against TRKs Kinases 50 test

[0352] Kinase activity detection: application of Z′-LYTE TM The technology (using fluorescence detection, enzyme coupling format, based on the difference in sensitivity of phosphorylated and non-phosphorylated peptides to proteolytic cleavage) uses the principle of fluorescence resonance energy transfer (FRET) and uses Z′-LYTE TM FRET peptide substrates and secondary reactions were used to detect the inhibitory activity of compounds against TRKs (TRKA, TRKC, TRKA-G667C, TRKA-G595R) kinases (Life Technologies Corporation, PV3144, PV3616, PV3617).

[0353] Enzymatic reaction: Add 5 μL of enzyme-substrate system [50 mM 4-hydroxyethylpiperazineethanesulfonic acid (HEPES) pH 7.5, 0.01% BRIJ-35, 10 mM magnesium chloride (MgCl2), 1 mM ethylene glycol bis(2-aminoethyl ether) tetraacetic acid (EGTA), 2 μM Tyr 01 peptide substrate] to a 384-well plate, and transfer 5 nL of the test compound (concentration gradient) using the echo520 ultra-micro liquid pipetting system. After shaking at room temperature for 10-20 minutes, transfer 200 nL, 12.5 nL, and 25 nL ATP (final concentrations of 400 uM, 25 uM, and 50 uM, respectively) using the echo520 ultra-micro liquid pipetting system, shake and mix, then centrifuge and react at 30°C in the dark for 1.5 hours.

[0354] Detection reaction: Add 2.5 μL of development solution (1:128 dilution) to each well and incubate at 37°C in the dark for 1 hour, then add 5 μL of stop solution (Stop Reagent).

[0355] Plate reading: The fluorescence signal was detected by a multi-label microplate reader (Perkin Elmer EnVision Multimode Plate Reader) (excitation wavelength was 400 nm, emission wavelength was 460 nm, 535 nm).

[0356] Calculation: The inhibition rate of each well is calculated through the fully active wells and the control signal wells. The data analysis method is as follows:

[0357] Phosphorylation ratio = 1–{(emission ratio × F100%–C100%) / [C 0%–C 100% + emission ratio × (F100%–F0%)]} × 100;

[0358] Inhibition rate = 100 × (1 - compound phosphorylation ratio / negative control phosphorylation ratio).

[0359] IC 50 The values ​​were calculated using medical graphics software (GraphPad Prism 5.0).

[0360] The results of the kinase activity test are shown in Table 1.

[0361] Table 1 Kinase activity test results of compounds (IC 50 :nM)

[0362]

[0363]

[0364] IC 50 :*<10nM; 10≦**<100nM; 100≦***<1000nM; ****≧1μM.

[0365] It can be seen from the data in Table 1 that the novel cyclic compound of the present invention has a strong inhibitory activity on TRKs kinase.

[0366] Example 37: Study on cell proliferation inhibition activity based on Ba / F3-TRKs stable strain

[0367] The BaF3 cells (mouse pre-B cells) used in this experiment were purchased from the Japanese Cell Bank. The BaF3-CD74-NTRK1, BaF3-ETV6-NTRK3, CD74-NTRK1-G667C, and CD74-NTRK1-G595R monoclonal stable strains were all constructed by our laboratory and were completely correct through positive drug activity, protein expression, and gene sequencing experiments.

[0368] The brief steps for stable strain construction are as follows: construct a pCDNA3.1(+) plasmid vector carrying genes such as CD74-NTRK1, ETV6-NTRK3, CD74-NTRK1-G667C, and CD74-NTRK1-G595R; use Cell Line Kit V kit is used to electroporate the plasmid into Ba / F3 cells; after 48 hours of electroporation, Geneticin (G418) with a final concentration of 1000μg / ml is added for screening for two weeks and interleukin 3 (IL3) is removed for continued screening to obtain polyclonal stable strains; then single clones are selected by limiting dilution method; and then positive drugs, protein immunoblotting (Western Blot, WB), and gene sequencing are used to identify the stable strains; the completely correctly identified single clones can be used for the study of the cell proliferation inhibition activity of the inhibitor.

[0369] Study on cell proliferation inhibition activity: 8000-12000 cells in the logarithmic growth phase were inoculated into 96-well plates. Different concentrations of inhibitors (0-10 μM) were added the next day and cultured for 72 hours. Then 10 μL Cell Counting Kit-8 cell counting reagent (CCK-8 reagent) was added to each well and incubated for 1-3 hours. The absorbance at 450nm and 650nm was then measured using a super microplate reader. The half inhibitory concentration (IC) was calculated using medical graphics software (GraphPad Prism 8.0.0). 50 ). The test results are shown in Table 2.

[0370] Table 2 Test results of the inhibitory activity of compounds on cell proliferation (IC 50 :nM)

[0371]

[0372]

[0373] IC 50 :*<10nM; 10≦**<100nM; 100≦***<1000nM; ****≧1μM.

[0374] It can be seen from the data in Table 2 that the novel cyclic compound of the present invention has a strong inhibitory activity on the cell proliferation of the Ba / F3-TRKs stable strain.

[0375] Example 38: Study on the inhibitory activity of drug-resistant cell proliferation based on Ba / F3-TRKs stable strain

[0376] The BaF3 cells (mouse pre-B cells) used in this experiment were purchased from the Japanese Cell Bank, BaF3-CD74-NTRK1-G667S, BaF3-CD74-NTRK1-G667A, BaF3-CD74-NTRK1-F589L, BaF3-CD74-NTRK1-V573M, BaF3-ETV6-NTRK3-G696C, BaF3-ETV6-NTRK3-G The 696A, BaF3-ETV6-NTRK3-G696S, BaF3-ETV6-NTRK3-G623R, BaF3-ETV6-NTRK3-G623E, BaF3-ETV6-NTRK3-F617L, and BaF3-ETV6-NTRK3-V601M monoclonal stable strains were constructed by our laboratory and were identified as completely correct through positive drug activity, protein expression, and gene sequencing experiments.

[0377] The brief steps for stable strain construction are as follows: construct a pCDNA3.1(+) plasmid vector carrying genes such as BaF3-CD74-NTRK1-G667S, BaF3-CD74-NTRK1-G667A, BaF3-CD74-NTRK1-F589L, BaF3-CD74-NTRK1-V573M, BaF3-ETV6-NTRK3-G696C, BaF3-ETV6-NTRK3-G696A, BaF3-ETV6-NTRK3-G696S, BaF3-ETV6-NTRK3-G623R, BaF3-ETV6-NTRK3-G623E, BaF3-ETV6-NTRK3-F617L, BaF3-ETV6-NTRK3-V601M; Cell Line Kit V kit is used to electroporate the plasmid into Ba / F3 cells; after 48 hours of electroporation, Geneticin (G418) with a final concentration of 1000μg / ml is added for screening for two weeks and interleukin 3 (IL3) is removed for continued screening to obtain polyclonal stable strains; then single clones are selected by limiting dilution method; and then positive drugs, protein immunoblotting (Western Blot, WB), and gene sequencing are used to identify the stable strains; the completely correctly identified single clones can be used for the study of the cell proliferation inhibition activity of the inhibitor.

[0378] Study on cell proliferation inhibition activity: 8000-12000 cells in the logarithmic growth phase were inoculated into 96-well plates. Different concentrations of inhibitors (0-10 μM) were added the next day and cultured for 72 hours. Then 10 μL Cell Counting Kit-8 (CCK-8) was added to each well and incubated for 1-3 hours. The absorbance at 450 nm and 650 nm was measured using a super microplate reader. The half inhibitory concentration (IC) was calculated using medical graphics software (GraphPad Prism 8.0.0). 50 ).

[0379] The test results are shown in Table 3.

[0380] Table 3 The results of the inhibitory activity test of compound WZQ4-69 on the proliferation of drug-resistant cells (IC 50 :nM)

[0381] Compound Number WZQ4-69 LOXO-195 TPX-0005 BaF3-CD74-NTRK1-G667S ** ** * BaF3-CD74-NTRK1-G667A * * * BaF3-CD74-NTRK1-F589L * ** * BaF3-CD74-NTRK1-V573M * ** ** BaF3-ETV6-NTRK3-G696C * ** ** BaF3-ETV6-NTRK3-G696A * * * BaF3-ETV6-NTRK3-G696S * ** * BaF3-ETV6-NTRK3-G623E * * * BaF3-ETV6-NTRK3-G623R * * * BaF3-ETV6-NTRK3-F617L * ** * BaF3-ETV6-NTRK3-V601M ** ** **

[0382] IC 50 :*<10nM; 10≦**<100nM; 100≦***<1000nM; ****≧1μM.

[0383] It can be seen from the data in Table 3 that the novel cyclic compound WZQ4-69 of the present invention has a strong inhibitory activity on the proliferation of various drug-resistant cells of Ba / F3-TRKs stable strains, and the inhibitory effect is significantly better than that of the second-generation TRK inhibitor LOXO-195.

[0384] The technical features of the above-described embodiments may be arbitrarily combined. 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.

[0385] The above-mentioned embodiments only express several implementation methods of the present invention, and the description thereof is relatively specific and detailed, but it cannot be understood as limiting the scope of the patent of the present invention. It should be pointed out that, for ordinary technicians in this field, several variations and improvements can be made without departing from the concept of the present invention, which all belong to the protection scope of the present invention. Therefore, the protection scope of the patent of the present invention shall be subject to the attached claims.

Claims

1. A cyclic compound having a structure represented by formula (II) or a pharmaceutically acceptable salt thereof or a stereoisomer thereof: in, B is selected from: A is selected from: And R is connected to Y; Each R5 is independently selected from: H, halogen, C1-C6 alkyl, C3-C7 cycloalkyl; R is selected from: -C(=O)- or -NR8R9; Wherein, R8 is selected from: H, C1-C6 alkyl, -(CH2) m NR 10 R 11 ; R9 is selected from: C1-C6 alkylene, or R8, R9 and the nitrogen atom to which they are connected together form one or more R 14 Substituted or unsubstituted 3-8 1-membered heterocyclic group; R 10 , R 11 Each independently selected from: H, C1-C6 alkyl; m is selected from: an integer from 1 to 5; R 14 Selected from: H, C1-C6 alkyl; X and Y are independently selected from: -O-, -N(R 13 )-, -S-, -S(=O)-, -S(O)2-, -C(=O)-, -NR 13 (C=O)-; R 13 Selected from: H, C1-C6 alkyl; L is selected from: C2~C 12 Alkylene; X1 is none, X2 is -NH-; R1 is selected from: H, halogen, C1~C 20 Alkyl, C1~C 20 Alkoxy or halogen substituted C1~C 20 alkyl; R2 is selected from: H, halogen, C1~C 20 Alkyl, C1~C 20 Alkoxy or halogen substituted C1~C 20 alkyl; R3 is selected from: H, halogen, C1~C 20 Alkyl, halogen-substituted C1-C4 alkyl, 5-6 membered heterocyclic group containing 1-3 N ring atoms; R4 is selected from the group consisting of: H, halogen, C1-C4 alkyl, nitro, halogen-substituted C1-C4 alkyl, C1-C4 alkoxy, halogen-substituted C1-C4 alkoxy, -(CH2) p NR 15 R 16 , by one or more R 17 A substituted or unsubstituted 5-6 membered heterocyclic group, 1-3 R 17 Substituted or unsubstituted 5-6 membered heteroaryl; p is selected from: 1, 2 or 3; R 15 , R 16 Together with the nitrogen atom to which they are attached, they form R 17 a substituted or unsubstituted 5-12 membered heterocyclic group; Each R 17 Each is independently selected from: H, C1-C6 alkyl, C3-C8 cycloalkyl, and 5-8 membered heterocyclic group.

2. A cyclic compound having a structure represented by formula (II) or a pharmaceutically acceptable salt thereof or a stereoisomer thereof: in, B is selected from: C1-C4 alkylene, or -CH=CH-; A is selected from: And R is connected to Y; Each R5 is independently selected from: H, halogen, C1-C6 alkyl, C3-C7 cycloalkyl; R is selected from: -C(=O)-, -C(=O)NR8R9 or -NR8R9; Wherein, R8 is selected from: H, C1-C6 alkyl, -(CH2) m NR 10 R 11 ; R9 is selected from: C1-C6 alkylene, or R8, R9 and the nitrogen atom to which they are connected together form one or more R 14 a substituted or unsubstituted 3-8 membered heterocyclic group; R 10 , R 11 Each independently selected from: H, C1-C6 alkyl; m is selected from: an integer from 1 to 5; R 14 Selected from: H, C1-C6 alkyl; X and Y are independently selected from: -O-, -N(R 13 )-, -S-, -S(=O)-, -S(O)2-, -C(=O)-, -NR 13 (C=O)-; R 13 Selected from: H, C1-C6 alkyl; L is selected from: C2~C 12 Alkylene; X1 and X2 are independently selected from: -N(R 13 ), or None, and X1 and X2 are not both None; R1 is selected from: H, halogen, C1~C 20 Alkyl, C1~C 20 Alkoxy or halogen substituted C1~C 20 alkyl; R2 is selected from: H, halogen, C1~C 20 Alkyl, C1~C 20 Alkoxy, halogen substituted C1~C 20 Alkyl, C3~C 12 Cycloalkyl; R3 is selected from: H, halogen, C1-C6 alkyl, halogen-substituted C1-C6 alkyl, -(CH2) p NR 15 R 16 ; p is selected from: 1, 2 or 3; R in R3 15 , R 16 Together with the nitrogen atom to which they are attached, they form a C1-C6 alkyl-substituted or unsubstituted 5-8 membered heterocyclic group; R4 is selected from the group consisting of: H, halogen, C1-C4 alkyl, nitro, halogen-substituted C1-C4 alkyl, C1-C4 alkoxy, halogen-substituted C1-C4 alkoxy, -(CH2) p NR 15 R 16 , by one or more R 17 A substituted or unsubstituted 5-6 membered heterocyclic group, 1-3 R 17 Substituted or unsubstituted 5-6 membered heteroaryl; p is selected from: 1, 2 or 3; R in R4 15 , R 16 Together with the nitrogen atom to which they are attached, they form R 17 a substituted or unsubstituted 5-12 membered heterocyclic group; Each R 17 Each is independently selected from: H, C1-C6 alkyl, C3-C8 cycloalkyl, and 5-8 membered heterocyclic group.

3. A cyclic compound having a structure represented by formula (III) or a pharmaceutically acceptable salt thereof or a stereoisomer thereof: in, B is selected from: C1-C4 alkylene, or -CH=CH-; A is selected from: And R is connected to Y; Each R5 is independently selected from: H, halogen, C1-C6 alkyl, C3-C7 cycloalkyl; R is selected from: -C(=O)-, -C(=O)NR8R9 or -NR8R9; Wherein, R8 is selected from: H, C1-C6 alkyl, -(CH2) m NR 10 R 11 ; R9 is selected from: C1-C6 alkylene, or R8, R9 and the nitrogen atom to which they are connected together form one or more R 14 a substituted or unsubstituted 3-8 membered heterocyclic group; R 10 , R 11 Each independently selected from: H, C1-C6 alkyl; m is selected from: an integer from 1 to 5; R 14 Selected from: H, C1-C6 alkyl; X and Y are independently selected from: -O-, -N(R 13 )-, -S-, -S(=O)-, -S(O)2-, -C(=O)-, -NR 13 (C=O)-; R 13 Selected from: H, C1-C6 alkyl; L is selected from: C2~C 12 Alkylene; X1 and X2 are independently selected from: -N(R 13 ), or None, and X1 and X2 are not both None; R1 is selected from: H, halogen, C1~C 20 Alkyl, C1~C 20 Alkoxy or halogen substituted C1~C 20 alkyl; R2 is selected from: H, halogen, C1~C 20 Alkyl, C1~C 20 Alkoxy, halogen substituted C1~C 20 Alkyl, C3~C 12 Cycloalkyl; R'4 is selected from: H, C1-C6 alkyl, C3-C8 cycloalkyl, R 17 Substituted or unsubstituted phenyl; wherein R 17 Selected from: H, C1-C6 alkyl.

4. The cyclic compound or the pharmaceutically acceptable salt or the stereoisomer thereof according to claim 1 or 2, characterized in that: R4 is selected from: H, halogen, nitro, methyl, ethyl, propyl, methoxy, ethoxy, propoxy, trifluoromethyl, trifluoroethyl, Each R 17 Each is independently selected from: H, methyl, ethyl, propyl, and cyclohexyl.

5. The cyclic compound or the pharmaceutically acceptable salt or the stereoisomer thereof according to claim 2 or 3, characterized in that: R2 is selected from the group consisting of: H, halogen, C1-C6 alkyl, C1-C6 alkoxy, halogen-substituted C1-C6 alkyl, and C3-C8 cycloalkyl.

6. The cyclic compound or the pharmaceutically acceptable salt or the stereoisomer thereof according to claim 5, characterized in that: R2 is selected from the group consisting of: H, fluorine, methyl, ethyl, propyl, isopropyl, tert-butyl, difluoromethyl, difluoroethyl, trifluoromethyl, trifluoroethyl, cyclopropyl.

7. The cyclic compound or a pharmaceutically acceptable salt thereof or a stereoisomer thereof according to claim 1, characterized in that: R2 is selected from the group consisting of: H, fluorine, methyl, ethyl, propyl, isopropyl, tert-butyl, difluoromethyl, difluoroethyl, trifluoromethyl, trifluoroethyl.

8. The cyclic compound or a pharmaceutically acceptable salt thereof or a stereoisomer thereof according to claim 2, characterized in that: R3 is selected from: H, halogen, difluoromethyl, difluoroethyl, trifluoromethyl, trifluoroethyl, Where R 17 Selected from: H, methyl, ethyl, propyl.

9. The cyclic compound or a pharmaceutically acceptable salt thereof or a stereoisomer thereof according to claim 1, characterized in that: R3 is selected from: H, halogen, difluoromethyl, difluoroethyl, trifluoromethyl, trifluoroethyl.

10. The cyclic compound or a pharmaceutically acceptable salt thereof or a stereoisomer thereof according to any one of claims 1 to 3, characterized in that: A is selected from:

11. The cyclic compound or a pharmaceutically acceptable salt thereof or a stereoisomer thereof according to any one of claims 2 to 3, characterized in that: R is selected from: -C(=O)-, -C(=O)NR8R9 or -NR8R9; Wherein, R8 is selected from: H, C1-C3 alkyl; R9 is selected from: C1-C3 alkylene, or R8, R9 and the nitrogen atom to which they are connected together form one or more R 14 Substituted or unsubstituted morpholinyl, pyrrolidinyl, piperidinyl or piperazinyl; R 14 Selected from: H, C1~C3 alkyl.

12. The cyclic compound or a pharmaceutically acceptable salt thereof or a stereoisomer thereof according to claim 1, characterized in that: R is selected from: -C(=O)- or -NR8R9; Wherein, R8 is selected from: H, C1-C3 alkyl; R9 is selected from: C1-C3 alkylene, or R8, R9 and the nitrogen atom to which they are connected together form one or more R 14 Substituted or unsubstituted morpholinyl, pyrrolidinyl, piperidinyl or piperazinyl; R 14 Selected from: H, C1~C3 alkyl.

13. The cyclic compound or a pharmaceutically acceptable salt thereof or a stereoisomer thereof according to any one of claims 2 to 3, characterized in that: R is selected from: -C(=O)-, -C(=O)NR8R9-, NR8R9, x is selected from: 0, 1, 2, 3; R8 is selected from: H, C1-C6 alkyl; R9 is selected from: C1-C6 alkylene.

14. The cyclic compound or a pharmaceutically acceptable salt thereof or a stereoisomer thereof according to claim 1, characterized in that: R is selected from: -C(=O)-, -NR8R9, x is selected from: 0, 1, 2, 3; R8 is selected from: H, C1-C6 alkyl; R9 is selected from: C1-C6 alkylene.

15. The cyclic compound or a pharmaceutically acceptable salt thereof or a stereoisomer thereof according to any one of claims 2 to 3, characterized in that: A is selected from:

16. The cyclic compound or a pharmaceutically acceptable salt thereof or a stereoisomer thereof according to claim 1, characterized in that: A is selected from:

17. The cyclic compound or a pharmaceutically acceptable salt thereof or a stereoisomer thereof according to any one of claims 1 to 3, characterized in that: X and Y are independently selected from: -O-, -N(R 13 )-、-NR 13 (C=O)-; R 13 Selected from: H, C1~C3 alkyl.

18. The cyclic compound or the pharmaceutically acceptable salt or the stereoisomer thereof according to claim 15, characterized in that: X is -O-; Y is selected from: -N(R 13 )-、-NR 13 (C=O)-; R 13 Selected from: H, methyl.

19. The cyclic compound or a pharmaceutically acceptable salt thereof or a stereoisomer thereof according to any one of claims 1 to 3, characterized in that: L is selected from: C2-C8 alkylene.

20. The cyclic compound or a pharmaceutically acceptable salt thereof or a stereoisomer thereof according to any one of claims 2 to 3, characterized in that: L is selected from: q is selected from: 1, 2, 3, 4, 5, 6, 7.

21. The cyclic compound or a pharmaceutically acceptable salt thereof or a stereoisomer thereof according to claim 1, characterized in that: L is selected from: q is selected from: 1, 2, 3, 4, 5, 6.

22. The cyclic compound or a pharmaceutically acceptable salt thereof or a stereoisomer thereof according to any one of claims 2 to 3, characterized in that: A and Y together form the following structure: L is selected from: q is 3; X is -O-; R4 is selected from: R 17 Selected from: H, methyl, ethyl, propyl.

23. The cyclic compound or a pharmaceutically acceptable salt thereof or a stereoisomer thereof according to any one of claims 2 to 3, characterized in that: R is -C(=O)-; Y is -NH-; L is selected from: q is 6 or 7.

24. The cyclic compound or a pharmaceutically acceptable salt thereof or a stereoisomer thereof according to claim 1, characterized in that: R is -C(=O)-; Y is -NH-; L is selected from: q is 6.

25. The cyclic compound or a pharmaceutically acceptable salt thereof or a stereoisomer thereof according to any one of claims 1 to 3, characterized in that: R1 is selected from: H, halogen, C1-C3 alkyl.

26. The cyclic compound or a pharmaceutically acceptable salt thereof or a stereoisomer thereof according to any one of claims 2 to 3, characterized in that: X1 is NH or not, and X2 is NH.

27. The cyclic compound or a pharmaceutically acceptable salt thereof or a stereoisomer thereof according to claim 2, characterized in that: B is selected from: -CH2CH2- or -CH=CH-.

28. The cyclic compound or a pharmaceutically acceptable salt thereof or a stereoisomer thereof according to claim 3, characterized in that: B is selected from: -CH2CH2- or -CH=CH-.

29. A cyclic compound or a pharmaceutically acceptable salt thereof or a stereoisomer thereof, characterized in that: The cyclic compound is selected from the following compounds:

30. Use of the cyclic compound according to any one of claims 1 to 29, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof in the preparation of a TRK inhibitor.

31. Use of the cyclic compound according to any one of claims 1 to 29 or a pharmaceutically acceptable salt thereof or a stereoisomer thereof in the preparation of a medicament for preventing and / or treating a disease mediated by TRK kinase.

32. The use according to claim 31, characterized in that The disease mediated by TRK kinase is a tumor.

33. The use according to claim 32, characterized in that The tumors are: non-small cell lung cancer, breast cancer, colon cancer, prostate cancer, thyroid cancer, malignant melanoma, neuroblastoma and mammary secretory carcinoma.

34. A pharmaceutical composition for preventing and / or treating tumors, characterized in that: The invention is prepared from active ingredients and pharmaceutically acceptable excipients, wherein the active ingredients include the cyclic compound according to any one of claims 1 to 29 or a pharmaceutically acceptable salt thereof or a stereoisomer thereof.

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